WO2019032941A1 - Lincosamide antibiotics and uses thereof - Google Patents

Lincosamide antibiotics and uses thereof 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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PCT/US2018/046178
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French (fr)
Inventor
Andrew G. Myers
Matthew James MITCHELTREE
Ioana MOGA
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President And Fellows Of Harvard College
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Publication of WO2019032941A1 publication Critical patent/WO2019032941A1/en

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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

Provided are lincosamide compounds for the treatment of infectious diseases. The lincosamides described herein are modified at the amino acid (southern) region. The lincosamides may have further modification at the C-1 and C-7 positions of the aminooctose (northern) region, thus distinguishing them from lincomycin and clindamycin. Also provided are methods for preparing the lincosamide compounds, pharmaceutical compositions comprising the lincosamide compounds, and methods of treating infectious diseases using the disclosed lincosamide compounds.

Description

LINCOS AMIDE ANTIBIOTICS AND USES THEREOF
RELATED APPLICATIONS
[0001] This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Applications, U.S.S.N. 62/543,808, filed August 10, 2017; U.S.S.N. 62/557,893, filed September 13, 2017; U.S.S.N. 62/558,143, filed September 13, 2017; U.S.S.N. 62/568,657, filed October 5, 2017; U.S.S.N. 62/585,271, filed November 13, 2017; and U.S.S.N.
62/650,965, filed March 30, 2018. The entire content of each is incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] Emerging resistance to existing antibiotics is rapidly developing as a crisis of global proportions, especially for infections originating from drug-resistant Gram-negative bacteria. Pathogenic bacteria can transmit genes coding for antibiotic resistance both vertically (to their progeny) and horizontally (to neighboring bacteria of different lineages), and as a result antibiotic resistance can evolve quickly, particularly in nosocomial (hospital) settings. See, e.g., Wright, Chem. Commun. (2011) 47:4055-4061. More than 99,000 people die annually in the U.S. from healthcare-associated infections, more than all casualties from car accidents, HIV, and breast cancer combined, creating an estimated burden of up to $45 billion in U.S. healthcare costs. See, e.g., Klevens et ah, Public Health Rep (2007) 122: 160-166. The current crisis is exacerbated by decreased research in the development of new antibiotics by most major pharmaceutical companies. See, e.g., Projan, Curr. Opin. Microbiol. (2003) 6:427-430. The current rate of introduction of new antibiotics does not adequately address growing resistance, and with the ease of international travel and increasing population densities, the need for innovation in the field has never been higher.
[0003] 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.
[0004] The first lincosamide to be discovered was lincomycin, but the use of lincomycin as an antibiotic has been largely superseded by clindamycin, which exhibits improved antibacterial activity. Clindamycin also exhibits some activity against parasitic protozoa and has been used to treat toxoplasmosis and malaria. 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.
Figure imgf000003_0001
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.
[0006] In addition, 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. For example, clindamycin, currently the only lincosamide in clinical use, carries a black-box warning for its tendency to promote C. difficile-associated diarrhea (CDAD).
[0007] Accordingly, the discovery and development of new antibiotics effective against drug-resistant bacteria, particularly lincosamides, represents a currently unmet medical need. SUMMARY OF THE INVENTION
[0008] 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. Moreover, 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.
[0009] In one aspect, the present disclosure provides compounds of Formula (I):
Figure imgf000004_0001
(I),
and pharmaceutically acceptable salts thereof, wherein:
P is independently hydrogen or a protecting group;
A is substituted or unsubstituted carbocyclyl, substituted or unsubstituted
heterocyclyl,
Figure imgf000004_0002
, , or ;
R1 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,–ORA,–N(RA)2, or–SRA;
R2 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 aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaliphatic,–ORA,–N3,–N(RA)2,–SRA,–CN,– SCN,–C(=NRA)RA,–C(=NRA)ORA,–C(=NRA)N(RA)2,–C(=O)RA,–C(=O)ORA,–
C(=O)N(RA)2,–NO2,–NRAC(=O)RA,–NRAC(=O)ORA,–NRAC(=O)N(RA)2,– NRAC(=NRA)N(RA)2,–OC(=O)RA,–OC(=O)ORA,–OC(=O)N(RA)2,–NRAS(O)2RA, - OS(O)2RA, or -S(O)2RA;
R3 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;
R4 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;
R5 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or
unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroaliphatic;
R6a, R6b, and R6c 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;
R7 is hydrogen or unsubstituted alkyl; or A and R7 are joined to form a substituted or unsubstituted heterocyclic ring;
R8 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaliphatic,– C(=NRA)RA,–C(=NRA)ORA,–C(=NRA)N(RA)2,–C(=O)RA,–C(=O)ORA,–C(=O)N(RA)2, - S(O)2RA, or a nitrogen protecting group;
each occurrence of R9 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,–ORA,–N(RA)2,–SRA,–CN,–SCN,–C(=NRA)RA,–C(=NRA)ORA,– C(=NRA)N(RA)2,–C(=O)RA,–C(=O)ORA,–C(=O)N(RA)2,–NO2,–NRAC(=O)RA,–
NRAC(=O)ORA,–NRAC(=O)N(RA)2,–NRAC(=NRA)N(RA)2,–OC(=O)RA,–OC(=O)ORA,– OC(=O)N(RA)2,–NRAS(O)2RA, -OS(O)2RA, or -S(O)2RA; or two R9 groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring;
p is 0-4;
each occurrence of RA 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
unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted hetaralkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two RA groups are joined to form a substituted or unsubstituted heterocyclic ring, or a substituted or unsubstituted heteroaryl ring; and
represents a single or double bond;
provided that when R1 is–SRA wherein RA is C1-6 substituted or unsubstituted alkyl,
A is not unsubstituted carbocyclyl,
Figure imgf000006_0001
.
[0010] In certain embodiments, 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):
Figure imgf000006_0002
Figure imgf000007_0001
Figure imgf000008_0001
and pharmaceutically acceptable salts thereof.
[0011] In another aspect, the present disclosure provides compounds of Formula (II):
Figure imgf000009_0001
(II),
or a pharmaceutically acceptable salt thereof, wherein:
P is independently hydrogen or a protecting group;
A is substituted or unsubstituted carbocyclyl, substituted or unsubstituted
heterocyclyl,
Figure imgf000009_0002
R1 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,–ORA,–N(RA)2, or–SRA;
R2 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 aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaliphatic,–ORA,–N3,–N(RA)2,–SRA,–CN,– SCN,–C(=NRA)RA,–C(=NRA)ORA,–C(=NRA)N(RA)2,–C(=O)RA,–C(=O)ORA,–
C(=O)N(RA)2,–NO2,–NRAC(=O)RA,–NRAC(=O)ORA,–NRAC(=O)N(RA)2,–
NRAC(=NRA)N(RA)2,–OC(=O)RA,–OC(=O)ORA,–OC(=O)N(RA)2,–NRAS(O)2RA,– OS(O)2RA, or -S(O)2RA;
R3 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; R4 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;
R5 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or
unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroaliphatic;
R6a, R6b, and R6c 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;
R7 is hydrogen or unsubstituted alkyl; or A and R7 are joined to form a substituted or unsubstituted heterocyclic ring;
R8 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaliphatic,– C(=NRA)RA,–C(=NRA)ORA,–C(=NRA)N(RA)2,–C(=O)RA,–C(=O)ORA,–C(=O)N(RA)2, - S(O)2RA, or a nitrogen protecting group;
each occurrence of R9 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,–ORA,–N(RA)2,–SRA,–CN,–SCN,–C(=NRA)RA,–C(=NRA)ORA,– C(=NRA)N(RA)2,–C(=O)RA,–C(=O)ORA,–C(=O)N(RA)2,–NO2,–NRAC(=O)RA,–
NRAC(=O)ORA,–NRAC(=O)N(RA)2,–NRAC(=NRA)N(RA)2,–OC(=O)RA,–OC(=O)ORA,– OC(=O)N(RA)2,–NRAS(O)2RA, -OS(O)2RA, or -S(O)2RA;
each occurrence of RA 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
unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted hetaralkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two RA groups are joined to form a substituted or unsubstituted heterocyclic ring, or a substituted or unsubstituted heteroaryl ring;
E is substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted carbocyclylene, or substituted or unsubstituted heterocyclylene;
Rb and Rc 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
heteroaliphatic,–C(=O)RA, -S(O)2RA, or a nitrogen protecting group; or Rb and Rc are joined to form a substituted or unsubstituted heterocyclic ring; and
represents a single or double bond.
[0012] In certain embodiments, 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):
Figure imgf000011_0001
Figure imgf000012_0001
Figure imgf000013_0001
Figure imgf000014_0001
and pharmaceutically acceptable salts thereof.
[0013] 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.
[0014] Methods of preparing the compounds are also provided herein. In certain embodiments, the disclosed compounds are prepared by an amide coupling of the aminooctose (northern) and amino-acid (southern) portions.
[0015] The details of certain embodiments of the invention are set forth in the Detailed Description of Certain Embodiments, as described below. Other features, objects, and advantages of the invention will be apparent from the Definitions, Examples, and Claims. DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS
[0016] The compounds disclosed herein include lincosamide analogues. The disclosed compounds have increased structural diversity over known lincosamides, such as lincomycin and clindamycin. In particular, 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).
[0017] In one aspect, provided are compounds of Formula (I):
Figure imgf000015_0001
and pharmaceutically acceptable salts thereof, wherein:
P is independently hydrogen or a protecting group;
A is substituted or unsubstituted carbocyclyl, substituted or unsubstituted
heterocyclyl,
Figure imgf000015_0002
;
R1 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,–ORA,–N(RA)2, or–SRA; R2 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 aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaliphatic,–ORA,–N3,–N(RA)2,–SRA,–CN,– SCN,–C(=NRA)RA,–C(=NRA)ORA,–C(=NRA)N(RA)2,–C(=O)RA,–C(=O)ORA,–
C(=O)N(RA)2,–NO2,–NRAC(=O)RA,–NRAC(=O)ORA,–NRAC(=O)N(RA)2,–
NRAC(=NRA)N(RA)2,–OC(=O)RA,–OC(=O)ORA,–OC(=O)N(RA)2,–NRAS(O)2RA, - OS(O)2RA, or -S(O)2RA;
R3 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;
R4 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;
R5 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or
unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroaliphatic;
R6a, R6b, and R6c 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;
R7 is hydrogen or unsubstituted alkyl; or A and R7 are joined to form a substituted or unsubstituted heterocyclic ring;
R8 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaliphatic,– C(=NRA)RA,–C(=NRA)ORA,–C(=NRA)N(RA)2,–C(=O)RA,–C(=O)ORA,–C(=O)N(RA)2, - S(O)2RA, or a nitrogen protecting group;
each occurrence of R9 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,–ORA,–N(RA)2,–SRA,–CN,–SCN,–C(=NRA)RA,–C(=NRA)ORA,– C(=NRA)N(RA)2,–C(=O)RA,–C(=O)ORA,–C(=O)N(RA)2,–NO2,–NRAC(=O)RA,–
NRAC(=O)ORA,–NRAC(=O)N(RA)2,–NRAC(=NRA)N(RA)2,–OC(=O)RA,–OC(=O)ORA,– OC(=O)N(RA)2,–NRAS(O)2RA, -OS(O)2RA, or -S(O)2RA; or two R9 groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring;
p is 0-4;
each occurrence of RA 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
unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted hetaralkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two RA groups are joined to form a substituted or unsubstituted heterocyclic ring, or a substituted or unsubstituted heteroaryl ring; and
represents a single or double bond;
provided that when R1 is–SRA wherein RA is C1-6 substituted or unsubstituted alkyl,
Figure imgf000017_0001
[0018] In certain embodiments of the compound of Formula (I), when R1 is–SRA wherein
RA is C1-6 substituted or unsubstituted alkyl, A is not unsubstituted carbocyclyl,
Figure imgf000017_0002
,
Figure imgf000017_0003
wherein RA 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. [0019] In certain embodiments of the compound of Formula (I), when R1 is–SRA, A is not
, or
Figure imgf000018_0001
[0020] In certain embodiments of the compound of Formula (I), when R1 is–SRA wherein RA is C1-6 substituted or unsubstituted alkyl, A is not unsubstituted C3-6 cycloalkyl,
Figure imgf000018_0002
wherein RA 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; and
provided that when A is
Figure imgf000018_0003
, R1 is not substituted or unsubstituted alkyl, or– ORA wherein RA is substituted or unsubstituted alkyl.
[0021] In certain embodiments of the compound of Formula (I), when R1 is–SRA, A is not
,
Figure imgf000018_0004
provided that when A is
Figure imgf000018_0005
, R1 is not–ORA, or substituted or unsubstituted alkyl.
[0022] In certain embodiments of the compound of Formula (I), each P is hydrogen.
[0023] In another aspect, provided are compounds of Formula (II): R8
Figure imgf000019_0001
(II),
and pharmaceutically acceptable salts thereof, wherein:
P is independently hydrogen or a protecting group;
A is substituted or unsubstituted carbocyclyl, substituted or unsubstituted
heterocyclyl,
Figure imgf000019_0002
;
R1 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,–ORA,–N(RA)2, or–SRA;
R2 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 aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaliphatic,–ORA,–N3,–N(RA)2,–SRA,–CN,– SCN,–C(=NRA)RA,–C(=NRA)ORA,–C(=NRA)N(RA)2,–C(=O)RA,–C(=O)ORA,–
C(=O)N(RA)2,–NO2,–NRAC(=O)RA,–NRAC(=O)ORA,–NRAC(=O)N(RA)2,–
NRAC(=NRA)N(RA)2,–OC(=O)RA,–OC(=O)ORA,–OC(=O)N(RA)2,–NRAS(O)2RA, - OS(O)2RA, or -S(O)2RA;
R3 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;
R4 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;
R5 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or
unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroaliphatic;
R6a, R6b, and R6c 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;
R7 is hydrogen or unsubstituted alkyl; or A and R7 are joined to form a substituted or unsubstituted heterocyclic ring;
R8 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaliphatic,– C(=NRA)RA,–C(=NRA)ORA,–C(=NRA)N(RA)2,–C(=O)RA,–C(=O)ORA,–C(=O)N(RA)2, - S(O)2RA, or a nitrogen protecting group;
each occurrence of R9 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,–ORA,–N(RA)2,–SRA,–CN,–SCN,–C(=NRA)RA,–C(=NRA)ORA,– C(=NRA)N(RA)2,–C(=O)RA,–C(=O)ORA,–C(=O)N(RA)2,–NO2,–NRAC(=O)RA,–
NRAC(=O)ORA,–NRAC(=O)N(RA)2,–NRAC(=NRA)N(RA)2,–OC(=O)RA,–OC(=O)ORA,– OC(=O)N(RA)2,–NRAS(O)2RA, -OS(O)2RA, or -S(O)2RA;
each occurrence of RA 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
unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted hetaralkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two RA groups are joined to form a substituted or unsubstituted heterocyclic ring, or a substituted or unsubstituted heteroaryl ring;
E is substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, or substituted or unsubstituted alkynylene;
Rb and Rc 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
heteroaliphatic,–C(=O)RA, -S(O)2RA, or a nitrogen protecting group; or Rb and Rc are joined to form a substituted or unsubstituted heterocyclic ring; and
represents a single or double bond.
[0024] In certain embodiments of the compound of Formula (II), each P is hydrogen.
[0025] Unless otherwise stated, any formulae described herein are also meant to include salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, and isotopically labeled derivatives thereof. In certain embodiments, the provided compound is a salt of any of the formulae described herein. In certain embodiments, the provided compound is a pharmaceutically acceptable salt of any of the formulae described herein. In certain embodiments, the provided compound is a solvate of any of the formulae described herein. In certain embodiments, the provided compound is a hydrate of any of the formulae described herein. In certain embodiments, the provided compound is a polymorph of any of the formulae described herein. In certain embodiments, 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 19F with 18F, or the replacement of a 12C by a 13C or 14C 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
[0026] As generally defined herein, A is substituted or unsubstituted carbocyclyl,
substituted or unsubstituted heterocyclyl,
Figure imgf000022_0001
;
R2 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 aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaliphatic,–ORA,–N3,–N(RA)2,–SRA,–CN,– SCN,–C(=NRA)RA,–C(=NRA)ORA,–C(=NRA)N(RA)2,–C(=O)RA,–C(=O)ORA,–
C(=O)N(RA)2,–NO2,–NRAC(=O)RA,–NRAC(=O)ORA,–NRAC(=O)N(RA)2,–
NRAC(=NRA)N(RA)2,–OC(=O)RA,–OC(=O)ORA,–OC(=O)N(RA)2,–NRAS(O)2RA, - OS(O)2RA, or -S(O)2RA;
R3 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;
R4 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;
R5 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or
unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroaliphatic; and
R6a, R6b, and R6c 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. [0027] In certain embodiments, A is
Figure imgf000023_0001
.
[0028] In certain embodiments, A is
Figure imgf000023_0002
.
[0029] In certain embodiments, R2 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 heteroaryl, substituted or unsubstituted heteroalkyl,–ORA,–N3,–N(RA)2,–SRA,–NRAC(=O)RA, or– OC(=O)N(RA)2.
[0030] In certain embodiments, R2 is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heteroaryl,–ORA,–N3,–N(RA)2,–SRA, –NRAC(=O)RA, or–OC(=O)N(RA)2. In certain embodiments, R2 is substituted or
unsubstituted heteroaryl. In certain embodiments, R2 is substituted or unsubstituted 5- membered heteroaryl. In certain embodiments, R2 is substituted or unsubstituted pyrrolyl, imidazolyl, pyrazolyl, or triazolyl.
[0031] In certain embodiments, R2 is halogen, substituted or unsubstituted alkyl,–ORA,– N3,–N(RA)2, or–SRA. In certain embodiments, R2 is halogen or–SRA. In certain
embodiments, R2 is -Cl or–SCH3. In certain embodiments, R2 is -Cl. In certain embodiments, R2 is–SCH3.
[0032] In certain embodiments, R3 is hydrogen, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkenyl. In certain embodiments, R3 is hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R3 is hydrogen. In certain embodiments, R3 is substituted or unsubstituted C1-6 alkyl. In certain embodiments, R3 is unsubstituted C1-6 alkyl. In certain embodiments, R3 is unsubstituted C1-3 alkyl. In certain embodiments, R3 is unsubstituted C1-2 alkyl. In certain embodiments, R3 is ethyl. In certain embodiments, R3 is methyl.
[0033] In certain embodiments, R4 is hydrogen, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkenyl. In certain embodiments, R4 is hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R4 is hydrogen. In certain embodiments, R4 is substituted or unsubstituted C1-6 alkyl. In certain embodiments, R4 is unsubstituted C1-6 alkyl. In certain embodiments, R4 is unsubstituted C1-3 alkyl. In certain embodiments, R4 is unsubstituted C1-2 alkyl. In certain embodiments, R4 is ethyl. In certain embodiments, R4 is methyl.
[0034] In certain embodiments, R2 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 heteroaryl, substituted or unsubstituted heteroalkyl,–ORA,–N3,–N(RA)2,–SRA,–NRAC(=O)RA, or– OC(=O)N(RA)2; R3 is hydrogen, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkenyl; and R4 is hydrogen, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkenyl.
[0035] In certain embodiments, R2 is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heteroaryl,–ORA,–N3,–N(RA)2,–SRA, –NRAC(=O)RA, or–OC(=O)N(RA)2; R3 is hydrogen, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkenyl; and R4 is hydrogen, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkenyl.
[0036] In certain embodiments, R2 is halogen, substituted or unsubstituted alkyl,–ORA,– N3,–N(RA)2, or–SRA; R3 is hydrogen, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkenyl; and R4 is hydrogen, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkenyl.
[0037] In certain embodiments, R2 is halogen, substituted or unsubstituted alkyl,–ORA,– N3,–N(RA)2, or–SRA; R3 is hydrogen or substituted or unsubstituted alkyl; and R4 is hydrogen or substituted or unsubstituted alkyl.
[0038] In certain embodiments, R2 is halogen,–ORA, or–SRA; R3 is hydrogen or substituted or unsubstituted alkyl; and R4 is hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R2 is is halogen or–SRA; R3 is substituted or unsubstituted alkyl; and R4 is hydrogen. In certain embodiments, R2 is is -Cl or–SCH3; R3 is substituted or unsubstituted alkyl; and R4 is hydrogen.
[0039] In certain embodiments, R2 is halogen; R3 is halogen; and R4 is hydrogen or halogen. In certain embodiments, R2 is halogen; R3 is halogen; and R4 is halogen. In certain embodiments, R2 is -F; R3 is -F; and R4 is -F. In certain embodiments, R2 is -F; R3 is -F; and R4 is hydrogen. In certain embodiments, R2 is -F; R3 is hydrogen; and R4 is hydrogen.
[0040] In certain embodiments, A is -CF3, -CHF2, or -CH2F. In certain embodiments, A is - CF3. In certain embodiments, A is -CHF2. In certain embodiments, A is -CH2F. [0041] In certain embodiments, where R4 is methyl and R3 is hydrogen, R2 is not methyl, chlorine, or hydroxyl.
[0042] In certain embodiments, A is
Figure imgf000025_0001
, wherein R4 is hydrogen, halogen, C1-4
alkyl, or C1-4 haloalkyl. In certain embodiments, A is
Figure imgf000025_0002
, wherein R4 is hydrogen, fluorine, chlorine, or C1-4 alkyl.
[0043] In certain embodiments, A is
Figure imgf000025_0003
, wherein R2 is halogen,–ORA, or–SRA.
In certain embodiments, A is
Figure imgf000025_0004
, wherein R2 is halogen,–ORA, or–SRA; and RA is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, or hydrogen.
[0044] In certain embodiments, A is , , or
[0045] In certain embodiments, A is
Figure imgf000025_0005
; and RA is substituted or unsubstituted aryl, or substituted or unsubstituted alkyl.
[0046] In certain embodiments, A is ; and RA
Figure imgf000025_0006
is substituted or unsubstituted aryl.
[0047] In certain embodiments, A is
Figure imgf000025_0007
; and RA is substituted aryl. [0048] In certain embodiments, A is and RA is
Figure imgf000026_0001
substituted phenyl.
[0049] In certain embodiments, A is of the formula:
Figure imgf000026_0002
Figure imgf000026_0003
; ,
[0050] In certain embodiments, A is of the formula:
Figure imgf000026_0004
[0051] In certain embodiments, A is of the formula:
Figure imgf000026_0005
[0052] In certain embodiments, A is of the formula:
Figure imgf000026_0006
[0053] In certain embodiments, A is
Figure imgf000026_0007
[0054] In certain embodiments, A is or . [0055] In certain embodiments, A is
Figure imgf000027_0001
. In certain embodiments, A is
Figure imgf000027_0002
rtain embodiments, A is . In certain embodiments, A is
Figure imgf000027_0003
In certain embodiments, A is In certain embodiments, A is
Figure imgf000027_0004
. ce ta e bod e ts, s and RA is substituted or unsubstituted aryl, or substituted or unsubstituted alkyl.
[0058] I certain embodiments, A is of the formula:
Figure imgf000027_0005
[0059] I certain embodiments, A is of the formula:
Figure imgf000027_0006
[0060] In certain embodiments, A is of the formula:
Figure imgf000028_0001
.
[0061] In certain embodiments, A is of the formula:
Figure imgf000028_0002
.
[0062] In certain embodiments, A is of the formula:
Figure imgf000028_0003
.
[0063] In certain embodiments, A is .
[0064] In certain embodiments, A is
Figure imgf000028_0004
.
Figure imgf000028_0005
[0066] In certain embodiments, A is of the formula:
Figure imgf000029_0001
[0067] In certain embodiments, A is of the formula:
,
Figure imgf000029_0002
,
Figure imgf000030_0001
[0068] In certain embodiments, A is of the formula:
Figure imgf000030_0002
[0069] In certain embodiments, A is of the formula:
Figure imgf000031_0001
[0070] In certain embodiments, A is of the formula:
Figure imgf000031_0002
.
[0071] In certain embodiments, A is of the formula:
,
Figure imgf000031_0003
[0072] In certain embodiments, A is
Figure imgf000032_0001
.
[0073] In certain embodiments, R5 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In certain embodiments, R5 is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In certain embodiments, R5 is substituted or unsubstituted aryl. In certain embodiments, R5 is substituted or unsubstituted phenyl. In certain embodiments, R5 is substituted or unsubstituted heteroaryl. In certain embodiments, R5 is substituted or unsubstituted pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyrrolyl, oxazolyl, isoxazolyl, thienyl, furanyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazolinyl. In certain embodiments, R5 is hydrogen.
[0074] In certain embodiments, A is
Figure imgf000032_0002
.
[0075] In certain embodiments, A is
Figure imgf000032_0003
.
[0076] In certain embodiments, R6a, R6b, and R6c 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, R6a, R6b, and R6c are each hydrogen.
[0077] In certain embodiments, A is
Figure imgf000032_0004
.
[0078] In certain embodiments, 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 C3-6 cycloalkyl or C3-6 cycloalkenyl. In certain embodiments, A is substituted or unsubstituted C3-6 cycloalkyl. In certain embodiments, A is substituted or unsubstituted C3-6 cycloalkenyl. In certain embodiments, 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.
[0079] In certain embodiments, A is of the formula:
Figure imgf000033_0001
. Group R1
[0080] As generally defined herein, R1 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,–ORA,–N(RA)2, or– SRA.
[0081] In certain embodiments, R1 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,–ORA,–N(RA)2, or–SRA.
[0082] In certain embodiments, R1 is substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heteroaralkyl, or–SRA.
[0083] In certain embodiments, R1 is substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, or–SRA.
[0084] In certain embodiments, R1 is
Figure imgf000033_0002
; wherein R1a and R1b 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,–ORA,– N3,–N(RA)2,–SRA,–CN,–SCN,–C(=NRA)RA,–C(=NRA)ORA,–C(=NRA)N(RA)2,–
C(=O)RA,–C(=O)ORA,–C(=O)N(RA)2,–NO2,–NRAC(=O)RA,–NRAC(=O)ORA,–
NRAC(=O)N(RA)2,–NRAC(=NRA)N(RA)2,–OC(=O)RA,–OC(=O)ORA,–OC(=O)N(RA)2,– NRAS(O)2RA, -OS(O)2RA, or -S(O)2RA, or R1a and R1b are joined to form a substituted or unsubstituted heterocyclic ring, or a substituted or unsubstituted carbocyclic ring.
[0085] In certain embodiments, R1a and R1b 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,–ORA, -OS(O)2RA,–N3,–N(RA)2, or R1a and R1b are joined to form a substituted or unsubstituted carbocyclic ring.
[0086] In certain embodiments, R1a and R1b are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, or–N(RA)2; or R1a and R1b are joined to form a substituted or unsubstituted carbocyclic ring.
[0087] In certain embodiments, R1a and R1b are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, or–N(RA)2; or R1a and R1b are joined to form a substituted or unsubstituted carbocyclic ring.
[0088] In certain embodiments, R1a and R1b together with the carbon to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl.
[0089] In certain embodiments, R1a and R1b together with the carbon to which they are attached, form an optionally substituted cycloalkyl. In certain embodiments, R1a and R1b together with the carbon to which they are attached, form an optionally substituted C3-6 cycloalkyl. In certain embodiments, R1a and R1b together with the carbon to which they are attached, form an optionally substituted C3-5 cycloalkyl. In certain embodiments, R1a and R1b together with the carbon to which they are attached, form an optionally substituted C3-4 cycloalkyl. In certain embodiments, R1a and R1b together with the carbon to which they are attached, form an optionally substituted cyclopentyl. In certain embodiments, R1a and R1b together with the carbon to which they are attached, form an optionally substituted cyclobutyl. In certain embodiments, R1a and R1b together with the carbon to which they are attached, form an optionally substituted cyclopropyl. In certain embodiments, R1a and R1b together with the carbon to which they are attached, form an unsubstituted cyclopropyl. [0090] In certain embodiments, R1a and R1b together with the carbon to which they are attached, form an optionally substituted heterocyclyl. In certain embodiments, R1a and R1b together with the carbon to which they are attached, form an optionally substituted 3-7 membered heterocyclyl. In certain embodiments, R1a and R1b together with the carbon to which they are attached, form an optionally substituted 4-7 membered heterocyclyl. In certain embodiments, R1a and R1b together with the carbon to which they are attached, form an optionally substituted 4-6 membered heterocyclyl. In certain embodiments, R1a and R1b 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, R1a and R1b together with the carbon to which they are attached, form an optionally substituted azetidine, pyrrolidine, or piperidine. In certain embodiments, R1a and R1b together with the carbon to which they are attached, form a substituted azetidine, pyrrolidine, or piperidine.
[0091] In certain embodiments, R1 is
–
Figure imgf000035_0001
[0092] In certain embodiments, R1 is
–
Figure imgf000035_0002
[0093] In certain embodiments, R1 is
–SRA,
Figure imgf000035_0003
and RA is substituted or unsubstituted aryl or substituted or unsubstituted alkyl.
[0094] In certain embodiments, R1 is of the formula:
–SR
Figure imgf000035_0004
; and RA is substituted or unsubstituted aryl or substituted or unsubstituted alkyl. [0095] In certain embodiments, R1 is–SRA. In certain embodiments, R1 is–SRA; and RA is a substituted or unsubstituted alkyl. In certain embodiments, R1 is–SRA; and RA is an unsubstituted alkyl. In certain embodiments, R1 is–SRA; and RA is an unsubstituted C1-4 alkyl. In certain embodiments, R1 is–SCH3. Group R7
[0096] As generally defined herein, R7 is hydrogen or unsubstituted alkyl; or A and R7 are joined to form a substituted or unsubstituted heterocyclic ring.
[0097] In certain embodiments, R7 is hydrogen or unsubstituted alkyl. In certain embodiments, R7 is unsubstituted alkyl. In certain embodiments, R7 is unsubstituted C1-6 alkyl. In certain embodiments, R7 is unsubstituted C1-4 alkyl. In certain embodiments, R7 is unsubstituted C1-3 alkyl. In certain embodiments, R7 is unsubstituted C1-2 alkyl. In certain embodiments, R7 is ethyl. In certain embodiments, R7 is methyl. In certain embodiments, R7 is hydrogen.
[0098] In certain embodiments, A and R7 are joined to form a substituted or unsubstituted heterocyclic ring. In certain embodiments, A and R7 are joined to form a substituted or unsubstituted pyrrolidine, piperidine, piperazine, azepine, or azepane. In certain
embodiments, A and R7 are joined to form a substituted or unsubstituted pyrrolidine.
[0099] In certain embodiments, A and R7 are joined to form
Figure imgf000036_0001
. Group R8
[00100] As generally defined herein, R8 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaliphatic,–C(=NRA)RA,–C(=NRA)ORA,–C(=NRA)N(RA)2,–C(=O)RA,– C(=O)ORA,–C(=O)N(RA)2, -S(O)2RA, or a nitrogen protecting group.
[00101] In certain embodiments, R8 is hydrogen, substituted or unsubstituted alkyl, or– C(=O)RA. In certain embodiments, R8 is hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R8 is hydrogen or unsubstituted alkyl. In certain embodiments, R8 is hydrogen or unsubstituted C1-6 alkyl. In certain embodiments, R8 is hydrogen or unsubstituted C1-4 alkyl. In certain embodiments, R8 is hydrogen or unsubstituted C1-3 alkyl. In certain embodiments, R8 is hydrogen or unsubstituted C1-2 alkyl. In certain embodiments, R8 is hydrogen or ethyl. In certain embodiments, R8 is hydrogen or methyl. In certain
embodiments, R8 is hydrogen.
[00102] In certain embodiments, R8 is unsubstituted C1-6 alkyl. In certain embodiments, R8 is unsubstituted C1-4 alkyl. In certain embodiments, R8 is unsubstituted C1-3 alkyl. In certain embodiments, R8 is unsubstituted C1-2 alkyl. In certain embodiments, R8 is ethyl. In certain embodiments, R8 is methyl. Group R9
[00103] As generally defined herein, each occurrence of R9 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,–ORA,–N(RA)2,–SRA,–CN,–SCN,–
C(=NRA)RA,–C(=NRA)ORA,–C(=NRA)N(RA)2,–C(=O)RA,–C(=O)ORA,–C(=O)N(RA)2,– NO2,–NRAC(=O)RA,–NRAC(=O)ORA,–NRAC(=O)N(RA)2,–NRAC(=NRA)N(RA)2,– OC(=O)RA,–OC(=O)ORA,–OC(=O)N(RA)2,–NRAS(O)2RA, -OS(O)2RA, or -S(O)2RA; or two R9 groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring.
[00104] In certain embodiments, R9 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,–ORA, or–N(RA)2; or two R9 groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring.
[00105] In certain embodiments, R9 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,–C(=O)ORA,–C(=O)N(RA)2,– C(=NRA)N(RA)2,–ORA, or–N(RA)2; or two R9 groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring. [00106] In certain embodiments, R9 is halogen, substituted or unsubstituted alkenyl, substituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl; or two R9 groups are joined to form a substituted or unsubstituted carbocyclyl ring.
[00107] In certain embodiments, R9 is halogen, unsubstituted ethenyl, substituted or unsubstituted phenethynyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted phenethyl; or two R9 groups are joined to form a unsubstituted cycloalkyl ring.
[00108] In certain embodiments, R9 is substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl. In certain embodiments, R9 is substituted or unsubstituted aryl or substituted or unsubstituted aralkyl. In certain
embodiments, R9 is substituted or unsubstituted phenyl or substituted or unsubstituted phenethyl.
[00109] In certain embodiments, R9 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.
[00110] In certain embodiments, R9 is substituted or unsubstituted alkyl. In certain embodiments, R9 is substituted or unsubstituted C1-6 alkyl. In certain embodiments, R9 is substituted or unsubstituted C1-4 alkyl. In certain embodiments, R9 is substituted or unsubstituted C1-3 alkyl. In certain embodiments, R9 is substituted or unsubstituted C1-2 alkyl. In certain embodiments, R9 is substituted or unsubstituted n-butyl. In certain embodiments, R9 is substituted or unsubstituted n-propyl. In certain embodiments, R9 is substituted or unsubstituted ethyl. In certain embodiments, R9 is substituted or unsubstituted methyl.
[00111] In certain embodiments, R9 is substituted alkyl. In certain embodiments, R9 is substituted C1-6 alkyl. In certain embodiments, R9 is substituted C1-4 alkyl. In certain embodiments, R9 is substituted C1-3 alkyl. In certain embodiments, R9 is substituted C1-2 alkyl. In certain embodiments, R9 is substituted n-butyl. In certain embodiments, R9 is substituted n-propyl. In certain embodiments, R9 is substituted ethyl. In certain embodiments, R9 is substituted methyl.
[00112] In certain embodiments, R9 is haloalkyl. In certain embodiments, R9 is C1-6 haloalkyl. In certain embodiments, R9 is C1-4 haloalkyl. In certain embodiments, R9 is C1-3 haloalkyl. In certain embodiments, R9 is C1-2 haloalkyl. In certain embodiments, R9 is halobutyl. In certain embodiments, R9 is halopropyl. In certain embodiments, R9 is haloethyl. In certain embodiments, R9 is halomethyl. [00113] In certain embodiments, R9 is fluoroalkyl. In certain embodiments, R9 is C1-6 fluoroalkyl. In certain embodiments, R9 is C1-4 fluoroalkyl. In certain embodiments, R9 is C1-3 fluoroalkyl. In certain embodiments, R9 is C1-2 fluoroalkyl. In certain embodiments, R9 is fluorobutyl. In certain embodiments, R9 is 1-fluorobutyl. In certain embodiments, R9 is fluoropropyl. In certain embodiments, R9 is fluoroethyl. In certain embodiments, R9 is fluoromethyl.
[00114] In certain embodiments, 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
[00115] As generally defined herein, E is substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted carbocyclylene, or substituted or unsubstituted heterocyclylene. In certain embodiments, E is substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, or substituted or unsubstituted carbocyclylene. In certain embodiments, E is substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, or substituted or unsubstituted cycloalkylene. In certain embodiments, E is substituted or unsubstituted alkylene, or substituted or unsubstituted alkenylene.
[00116] In certain embodiments, E is substituted or unsubstituted alkenylene. In certain embodiments, E is substituted or unsubstituted C2-6 alkenylene. In certain embodiments, E is substituted or unsubstituted C2-4 alkenylene. In certain embodiments, E is substituted or unsubstituted C2-3 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. In certain embodiments, the carbon-carbon double bond of any of the foregoing substituted or unsubstituted alkenylenes is a trans isomer. [00117] In certain embodiments, E is substituted or unsubstituted alkylene. In certain embodiments, E is substituted or unsubstituted C1-6 alkylene. In certain embodiments, E is substituted or unsubstituted C1-4 alkylene. In certain embodiments, E is substituted or unsubstituted C1-3 alkylene. In certain embodiments, E is substituted or unsubstituted C1-2 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.
[00118]
,
[00119]
[00120]
.
[00121]
[00122]
Figure imgf000040_0001
[00123] In certain embodi .
[00124] In certain embodi
Figure imgf000041_0001
.
[00125] In certain embodiments, E is
Figure imgf000041_0002
.
[00126] In certain embodiments, E is
Figure imgf000041_0003
.
[00127] In certain embodiments, E is
Figure imgf000041_0004
Groups Rb and Rc
[00128] As generally defined herein, Rb and Rc 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 heteroaliphatic,–C(=O)RA, -S(O)2RA, or a nitrogen protecting group; or Rb and Rc are joined to form a substituted or unsubstituted heterocyclic ring.
[00129] In certain embodiments, Rb and Rc are each independently, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, or -S(O)2RA; or Rb and Rc are joined to form a substituted or unsubstituted heterocyclic ring.
[00130] In certain embodiments, Rb and Rc are each independently, hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkylalkyl; or Rb and Rc are joined to form a substituted or unsubstituted heterocyclic ring.
[00131] In certain embodiments, Rb and Rc are each independently, hydrogen, haloalkyl, or cycloalkylhaloalkyl; or Rb and Rc are joined to form a halo-substituted heterocyclic ring. In certain embodiments, Rb and Rc are each independently, hydrogen, haloalkyl, or cycloalkylhaloalkyl. In certain embodiments, Rb and Rc are each independently, hydrogen, C1-6 haloalkyl, or C3-6 cycloalkylhaloalkyl. In certain embodiments, Rb and Rc are each independently, hydrogen, C1-4 haloalkyl, or C3-6 cycloalkylhaloalkyl. In certain embodiments, Rb and Rc are joined to form a halo-substituted heterocyclic ring. In certain embodiments, Rb and Rc are joined to form a halo-substituted piperidine or pyrrolidine ring.
[00132] In certain embodiments, at least one of Rb and Rc is haloalkyl or
cycloalkylhaloalkyl; or Rb and Rc are joined to form a halo-substituted heterocyclic ring. In certain embodiments, at least one of Rb and Rc is haloalkyl or cycloalkylhaloalkyl. In certain embodiments, at least one of Rb and Rc is C1-6 haloalkyl or C3-6 cycloalkylhaloalkyl. In certain embodiments, at least one of Rb and Rc is C1-4 haloalkyl or C3-6 cycloalkylhaloalkyl. 00133 In certain embodiments Rb and Rc are each inde endentl
Figure imgf000042_0001
nts, Rb and Rc are joined to form
Figure imgf000042_0002
,
Figure imgf000042_0003
, embodiments, Rb and Rc are joined to form
Figure imgf000043_0001
.
1 In r in m imn Rb n Rc r h in n nl
,
Figure imgf000043_0002
, . ,
Figure imgf000043_0003
.
1 In r in m imn Rb n Rc r h in n nl
Figure imgf000043_0004
-H, , F F , , , , or . In certain embodiments, Rb and Rc are joined to form
Figure imgf000043_0005
.
1 In r in m imn l n f Rb n Rc i
Figure imgf000043_0006
, F F , , , , or .
[0013 In r in m imn
Figure imgf000043_0007
Figure imgf000044_0001
,
Figure imgf000045_0001
Figure imgf000046_0001
. Embodiments of Formula (I)
[00140] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-a):
Figure imgf000046_0002
or a pharmaceutically acceptable salt thereof, wherein A, R1, R7, R8, R9, and p are as defined herein.
[00141] In certain embodiments of the compound of Formula (I-a), R7 is hydrogen; R8 is hydrogen or methyl; and R9 is substituted or unsubstituted C1-6 alkyl. In certain embodiments of the compound of Formula (I-a), R7 is hydrogen; R8 is hydrogen or methyl; and R9 is substituted C1-6 alkyl. In certain embodiments of the compound of Formula (I-a), R7 is hydrogen; R8 is hydrogen; and R9 is substituted C1-6 alkyl. In certain embodiments of the compound of Formula (I-a), R7 is hydrogen; R8 is methyl; and R9 is substituted C1-6 alkyl.
[00142] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-b):
Figure imgf000046_0003
or a pharmaceutically acceptable salt thereof, wherein A, R1, R7, R8, R9, and p are as defined herein.
[00143] In certain embodiments of the compound of Formula (I-b), R7 is hydrogen; R8 is hydrogen or methyl; and R9 is substituted or unsubstituted C1-6 alkyl. In certain embodiments of the compound of Formula (I-b), R7 is hydrogen; R8 is hydrogen or methyl; and R9 is substituted C1-6 alkyl. In certain embodiments of the compound of Formula (I-b), R7 is hydrogen; R8 is hydrogen; and R9 is substituted C1-6 alkyl. In certain embodiments of the compound of Formula (I-b), R7 is hydrogen; R8 is methyl; and R9 is substituted C1-6 alkyl.
[00144] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-c):
Figure imgf000047_0001
or a pharmaceutically acceptable salt thereof, wherein A, R1, R7, R8, R9, and p are as defined herein.
[00145] In certain embodiments of the compound of Formula (I-c), R7 is hydrogen; R8 is hydrogen or methyl; and R9 is substituted or unsubstituted C1-6 alkyl. In certain embodiments of the compound of Formula (I-c), R7 is hydrogen; R8 is hydrogen or methyl; and R9 is substituted C1-6 alkyl. In certain embodiments of the compound of Formula (I-c), R7 is hydrogen; R8 is hydrogen; and R9 is substituted C1-6 alkyl. In certain embodiments of the compound of Formula (I-c), R7 is hydrogen; R8 is methyl; and R9 is substituted C1-6 alkyl.
[00146] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-d):
Figure imgf000048_0001
or a pharmaceutically acceptable salt thereof, wherein A, R1, R7, R8, and R9 are as defined herein.
[00147] In certain embodiments of the compound of Formula (I-d), R7 is hydrogen; R8 is hydrogen or methyl; and R9 is substituted or unsubstituted C1-6 alkyl. In certain embodiments of the compound of Formula (I-d), R7 is hydrogen; R8 is hydrogen or methyl; and R9 is substituted C1-6 alkyl. In certain embodiments of the compound of Formula (I-d), R7 is hydrogen; R8 is hydrogen; and R9 is substituted C1-6 alkyl. In certain embodiments of the compound of Formula (I-d), R7 is hydrogen; R8 is methyl; and R9 is substituted C1-6 alkyl.
[00148] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-e):
Figure imgf000048_0002
or a pharmaceutically acceptable salt thereof, wherein A, R1, R7, R8, and R9 are as defined herein.
[00149] In certain embodiments of the compound of Formula (I-e), R7 is hydrogen; R8 is hydrogen or methyl; and R9 is substituted or unsubstituted C1-6 alkyl. In certain embodiments of the compound of Formula (I-e), R7 is hydrogen; R8 is hydrogen or methyl; and R9 is substituted C1-6 alkyl. In certain embodiments of the compound of Formula (I-e), R7 is hydrogen; R8 is hydrogen; and R9 is substituted C1-6 alkyl. In certain embodiments of the compound of Formula (I-e), R7 is hydrogen; R8 is methyl; and R9 is substituted C1-6 alkyl.
[00150] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-f):
Figure imgf000049_0001
or a pharmaceutically acceptable salt thereof, wherein A, R1, R7, R8, and R9 are as defined herein.
[00151] In certain embodiments of the compound of Formula (I-f), R7 is hydrogen; R8 is hydrogen or methyl; and R9 is substituted or unsubstituted C1-6 alkyl. In certain embodiments of the compound of Formula (I-f), R7 is hydrogen; R8 is hydrogen or methyl; and R9 is substituted C1-6 alkyl. In certain embodiments of the compound of Formula (I-f), R7 is hydrogen; R8 is hydrogen; and R9 is substituted C1-6 alkyl. In certain embodiments of the compound of Formula (I-f), R7 is hydrogen; R8 is methyl; and R9 is substituted C1-6 alkyl.
[00152] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-g):
Figure imgf000049_0002
or a pharmaceutically acceptable salt thereof, wherein A, R1, R7, R8, and R9 are as defined herein.
[00153] In certain embodiments of the compound of Formula (I-g), R7 is hydrogen; R8 is hydrogen or methyl; and R9 is substituted or unsubstituted C1-6 alkyl. In certain embodiments of the compound of Formula (I-g), R7 is hydrogen; R8 is hydrogen or methyl; and R9 is substituted C1-6 alkyl. In certain embodiments of the compound of Formula (I-g), R7 is hydrogen; R8 is hydrogen; and R9 is substituted C1-6 alkyl. In certain embodiments of the compound of Formula (I-g), R7 is hydrogen; R8 is methyl; and R9 is substituted C1-6 alkyl.
[00154] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-h):
Figure imgf000050_0001
or a pharmaceutically acceptable salt thereof, wherein A, R1, R7, R8, and R9 are as defined herein.
[00155] In certain embodiments of the compound of Formula (I-h), R7 is hydrogen.
[00156] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-i):
Figure imgf000050_0002
or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R8, and R9 are as defined herein.
[00157] In certain embodiments of the compound of Formula (I-i), R8 is hydrogen or methyl; and R9 is substituted or unsubstituted C1-6 alkyl. In certain embodiments of the compound of Formula (I-i), R8 is hydrogen or methyl; and R9 is substituted C1-6 alkyl. In certain embodiments of the compound of Formula (I-i), R8 is hydrogen; and R9 is substituted C1-6 alkyl. In certain embodiments of the compound of Formula (I-i), R8 is methyl; and R9 is substituted C1-6 alkyl.
[00158] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-j):
Figure imgf000051_0001
or a pharmaceutically acceptable salt thereof, wherein R1, R2, R4, R8, and R9 are as defined herein.
[00159] In certain embodiments of the compound of Formula (I-j), R8 is hydrogen or methyl; and R9 is substituted or unsubstituted C1-6 alkyl. In certain embodiments of the compound of Formula (I-j), R8 is hydrogen or methyl; and R9 is substituted C1-6 alkyl. In certain embodiments of the compound of Formula (I-j), R8 is hydrogen; and R9 is substituted C1-6 alkyl. In certain embodiments of the compound of Formula (I-j), R8 is methyl; and R9 is substituted C1-6 alkyl.
[00160] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-k):
Figure imgf000051_0002
or a pharmaceutically acceptable salt thereof, wherein R1, RA, R4, R8, and R9 are as defined herein.
[00161] In certain embodiments of the compound of Formula (I-k), R8 is hydrogen or methyl; and R9 is substituted or unsubstituted C1-6 alkyl. In certain embodiments of the compound of Formula (I-k), R8 is hydrogen or methyl; and R9 is substituted C1-6 alkyl. In certain embodiments of the compound of Formula (I-k), R8 is hydrogen; and R9 is substituted C1-6 alkyl. In certain embodiments of the compound of Formula (I-k), R8 is methyl; and R9 is substituted C1-6 alkyl.
[00162] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-l):
Figure imgf000052_0001
or a pharmaceutically acceptable salt thereof, wherein R1, R4, R8, and R9 are as defined herein.
[00163] In certain embodiments of the compound of Formula (I-l), R8 is hydrogen or methyl; and R9 is substituted or unsubstituted C1-6 alkyl. In certain embodiments of the compound of Formula (I-l), R8 is hydrogen or methyl; and R9 is substituted C1-6 alkyl. In certain embodiments of the compound of Formula (I-l), R8 is hydrogen; and R9 is substituted C1-6 alkyl. In certain embodiments of the compound of Formula (I-l), R8 is methyl; and R9 is substituted C1-6 alkyl.
[00164] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-m):
Figure imgf000052_0002
or a pharmaceutically acceptable salt thereof, wherein R2, R3, R4, R8, and R9 are as defined herein; and R1a and R1b 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,–ORA,–N3,–N(RA)2,–SRA,–CN,–SCN,–C(=NRA)RA,–C(=NRA)ORA,– C(=NRA)N(RA)2,–C(=O)RA,–C(=O)ORA,–C(=O)N(RA)2,–NO2,–NRAC(=O)RA,–
NRAC(=O)ORA,–NRAC(=O)N(RA)2,–NRAC(=NRA)N(RA)2,–OC(=O)RA,–OC(=O)ORA,– OC(=O)N(RA)2,–NRAS(O)2RA, -OS(O)2RA, or -S(O)2RA; or R1a and R1b are joined to form a substituted or unsubstituted heterocyclic ring, or a substituted or unsubstituted carbocyclic ring.
[00165] In certain embodiments of the compound of Formula (I-m), R1a and R1b 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,–ORA, - OS(O)2RA,–N3, or–N(RA)2, or R1a and R1b are joined to form a substituted or unsubstituted carbocyclic ring.
[00166] In certain embodiments of the compound of Formula (I-m), R1a and R1b are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, or–N(RA)2; or R1a and R1b are joined to form a substituted or unsubstituted carbocyclic ring.
[00167] In certain embodiments of the compound of Formula (I-m), R8 is hydrogen or methyl; and R9 is substituted or unsubstituted C1-6 alkyl. In certain embodiments of the compound of Formula (I-m), R8 is hydrogen or methyl; and R9 is substituted C1-6 alkyl. In certain embodiments of the compound of Formula (I-m), R8 is hydrogen; and R9 is substituted C1-6 alkyl. In certain embodiments of the compound of Formula (I-m), R8 is methyl; and R9 is substituted C1-6 alkyl.
[00168] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-n):
Figure imgf000054_0001
or a pharmaceutically acceptable salt thereof, wherein R1a, R1b, RA, R4, R8, and R9 are as defined herein.
[00169] In certain embodiments of the compound of Formula (I-n), R1a and R1b 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,–ORA, - OS(O)2RA,–N3,–N(RA)2; or R1a and R1b are joined to form a substituted or unsubstituted carbocyclic ring.
[00170] In certain embodiments of the compound of Formula (I-n), R1a and R1b are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, or–N(RA)2; or R1a and R1b are joined to form a substituted or unsubstituted carbocyclic ring.
[00171] In certain embodiments of the compound of Formula (I-n), R8 is hydrogen or methyl; and R9 is substituted or unsubstituted C1-6 alkyl. In certain embodiments of the compound of Formula (I-n), R8 is hydrogen or methyl; and R9 is substituted C1-6 alkyl. In certain embodiments of the compound of Formula (I-n), R8 is hydrogen; and R9 is substituted C1-6 alkyl. In certain embodiments of the compound of Formula (I-n), R8 is methyl; and R9 is substituted C1-6 alkyl. [00172] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-o):
Figure imgf000055_0001
or a pharmaceutically acceptable salt thereof, wherein R1a, R1b, R4, R8, and R9 are as defined herein.
[00173] In certain embodiments of the compound of Formula (I-o), R1a and R1b 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,–ORA, - OS(O)2RA,–N3, or–N(RA)2; or R1a and R1b are joined to form a substituted or unsubstituted carbocyclic ring.
[00174] In certain embodiments of the compound of Formula (I-o), R1a and R1b are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, or–N(RA)2; or R1a and R1b are joined to form a substituted or unsubstituted carbocyclic ring.
[00175] In certain embodiments of the compound of Formula (I-o), R8 is hydrogen or methyl; and R9 is substituted or unsubstituted C1-6 alkyl. In certain embodiments of the compound of Formula (I-o), R8 is hydrogen or methyl; and R9 is substituted C1-6 alkyl. In certain embodiments of the compound of Formula (I-o), R8 is hydrogen; and R9 is substituted C1-6 alkyl. In certain embodiments of the compound of Formula (I-o), R8 is methyl; and R9 is substituted C1-6 alkyl. Embodiments of Formula (II)
[00176] In certain embodiments, the compound of Formula (II) is a compound of Formula (II-a):
R1
Figure imgf000056_0001
(II-a),
or a pharmaceutically acceptable salt thereof, wherein A, R1, E, Rb, Rc, R7, and R8 are as defined herein.
[00177] In certain embodiments of the compound of Formula (II-a), 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.
[00178] In certain embodiments of the compound of Formula (II-a), R1 is–SRA; R7 is hydrogen; and R8 is hydrogen or methyl. In certain embodiments of the compound of Formula (II-a), R1 is–SCH3; R7 is hydrogen; and R8 is hydrogen or methyl. In certain embodiments of the compound of Formula (II-a), R1 is–SCH3; R7 is hydrogen; and R8 is hydrogen. In certain embodiments of the compound of Formula (II-a), R1 is–SCH3; R7 is hydrogen; and R8 is methyl.
[00179] In certain embodiments, the compound of Formula (II) is a compound of Formula (II-b):
Figure imgf000056_0002
or a pharmaceutically acceptable salt thereof, wherein A, R1, E, Rb, Rc, R7, and R8 are as defined herein. [00180] In certain embodiments of the 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.
[00181] In certain embodiments of the compound of Formula (II-b), R1 is–SRA; R7 is hydrogen; and R8 is hydrogen or methyl. In certain embodiments of the compound of Formula (II-b), R1 is–SCH3; R7 is hydrogen; and R8 is hydrogen or methyl. In certain embodiments of the compound of Formula (II-b), R1 is–SCH3; R7 is hydrogen; and R8 is hydrogen. In certain embodiments of the compound of Formula (II-b), R1 is–SCH3; R7 is hydrogen; and R8 is methyl.
[00182] In certain embodiments, the compound of Formula (II) is a compound of Formula (II-c):
Figure imgf000057_0001
or a pharmaceutically acceptable salt thereof, wherein A, R1, Rb, Rc, R7, R8, and R9 are as defined herein; Rd and Re are each independently hydrogen, halogen, or substituted or unsubstituted alkyl; or optionally one instance of Rd and Re together form an oxo group; and q is 1-6.
[00183] In certain embodiments of the compound of Formula (II-c), Rd and Re are each hydrogen; or optionally one instance of Rd and Re together form an oxo group. In certain embodiments of the compound of Formula (II-c), Rd and Re are each hydrogen; or optionally one instance of Rd and Re together form an oxo group; and q is 2-4. In certain embodiments of the compound of Formula (II-c), Rd and Re are each hydrogen; or optionally one instance of Rd and Re together form an oxo group; and q is 3. In certain embodiments of the compound of Formula (II-c), Rd and Re are each hydrogen. In certain embodiments of the compound of Formula (II-c), Rd and Re are each hydrogen; and q is 2-4. In certain embodiments of the compound of Formula (II-c), Rd and Re are each hydrogen; and q is 3. In certain
embodiments of the compound of Formula (II-c), Rd and Re are each independently hydrogen or substituted or unsubstituted alkyl. In certain embodiments of the compound of Formula (II-c), Rd and Re are each independently hydrogen or substituted or unsubstituted alkyl; and q is 2-4. In certain embodiments of the compound of Formula (II-c), Rd and Re are each independently hydrogen or substituted or unsubstituted alkyl; and q is 3.
[00184] In certain embodiments of the compound of Formula (II-c), R1 is–SRA; R7 is hydrogen; and R8 is hydrogen or methyl. In certain embodiments of the compound of Formula (II-c), R1 is–SCH3; R7 is hydrogen; and R8 is hydrogen or methyl. In certain embodiments of the compound of Formula (II-c), R1 is–SCH3; R7 is hydrogen; and R8 is hydrogen. In certain embodiments of the compound of Formula (II-c), R1 is–SCH3; R7 is hydrogen; and R8 is methyl.
[00185] In certain embodiments, the compound of Formula (II) is a compound of Formula (II-d):
Figure imgf000058_0001
(II-d),
or a pharmaceutically acceptable salt thereof, wherein A, R1, Rb, Rc, Rd, Re, R7, R8, and q are as defined herein.
[00186] In certain embodiments of the compound of Formula (II-d), Rd and Re are each hydrogen; or optionally one instance of Rd and Re together form an oxo group. In certain embodiments of the compound of Formula (II-d), Rd and Re are each hydrogen; or optionally one instance of Rd and Re together form an oxo group; and q is 2-4. In certain embodiments of the compound of Formula (II-d), Rd and Re are each hydrogen; or optionally one instance of Rd and Re together form an oxo group; and q is 3. In certain embodiments of the compound of Formula (II-d), Rd and Re are each hydrogen. In certain embodiments of the compound of Formula (II-d), Rd and Re are each hydrogen; and q is 2-4. In certain embodiments of the compound of Formula (II-d), Rd and Re are each hydrogen; and q is 3. In certain
embodiments of the compound of Formula (II-d), Rd and Re are each independently hydrogen or substituted or unsubstituted alkyl. In certain embodiments of the compound of Formula (II-d), Rd and Re are each independently hydrogen or substituted or unsubstituted alkyl; and q is 2-4. In certain embodiments of the compound of Formula (II-d), Rd and Re are each independently hydrogen or substituted or unsubstituted alkyl; and q is 3.
[00187] In certain embodiments of the compound of Formula (II-d), R1 is–SRA; R7 is hydrogen; and R8 is hydrogen or methyl. In certain embodiments of the compound of Formula (II-d), R1 is–SCH3; R7 is hydrogen; and R8 is hydrogen or methyl. In certain embodiments of the compound of Formula (II-d), R1 is–SCH3; R7 is hydrogen; and R8 is hydrogen. In certain embodiments of the compound of Formula (II-d), R1 is–SCH3; R7 is hydrogen; and R8 is methyl.
[00188] In certain embodiments, the compound of Formula (II) is a compound of Formula (II-e):
Figure imgf000059_0001
(II-e),
or a pharmaceutically acceptable salt thereof, wherein A, R1, Rb, Rc, Rd, Re, R7, R8, and q are as defined herein.
[00189] In certain embodiments of the compound of Formula (II-e), Rd and Re are each hydrogen; or optionally one instance of Rd and Re together form an oxo group. In certain embodiments of the compound of Formula (II-e), Rd and Re are each hydrogen; or optionally one instance of Rd and Re together form an oxo group; and q is 2-4. In certain embodiments of the compound of Formula (II-e), Rd and Re are each hydrogen; or optionally one instance of Rd and Re together form an oxo group; and q is 3. In certain embodiments of the compound of Formula (II-e), Rd and Re are each hydrogen. In certain embodiments of the compound of Formula (II-e), Rd and Re are each hydrogen; and q is 2-4. In certain embodiments of the compound of Formula (II-e), Rd and Re are each hydrogen; and q is 3. In certain
embodiments of the compound of Formula (II-e), Rd and Re are each independently hydrogen or substituted or unsubstituted alkyl. In certain embodiments of the compound of Formula (II-e), Rd and Re are each independently hydrogen or substituted or unsubstituted alkyl; and q is 2-4. In certain embodiments of the compound of Formula (II-e), Rd and Re are each independently hydrogen or substituted or unsubstituted alkyl; and q is 3.
[00190] In certain embodiments of the compound of Formula (II-e), R1 is–SRA; R7 is hydrogen; and R8 is hydrogen or methyl. In certain embodiments of the compound of Formula (II-e), R1 is–SCH3; R7 is hydrogen; and R8 is hydrogen or methyl. In certain embodiments of the compound of Formula (II-e), R1 is–SCH3; R7 is hydrogen; and R8 is hydrogen. In certain embodiments of the compound of Formula (II-e), R1 is–SCH3; R7 is hydrogen; and R8 is methyl.
[00191] In certain embodiments, the compound of Formula (II) is a compound of Formula (II-f):
Figure imgf000060_0001
or a pharmaceutically acceptable salt thereof, wherein A, R1, Rb, Rc, R7, R8, and q are as defined herein.
[00192] In certain embodiments of the compound of Formula (II-f), R1 is–SRA; R7 is hydrogen; R8 is hydrogen or methyl; and q is 2-4. In certain embodiments of the compound of Formula (II-f), R1 is–SRA; R7 is hydrogen; R8 is hydrogen or methyl; and q is 3. In certain embodiments of the compound of Formula (II-f), R1 is–SCH3; R7 is hydrogen; R8 is hydrogen or methyl; and q is 2-4. In certain embodiments of the compound of Formula (II-f), R1 is–SCH3; R7 is hydrogen; R8 is hydrogen or methyl; and q is 3. In certain embodiments of the compound of Formula (II-f), R1 is–SCH3; R7 is hydrogen; R8 is hydrogen; and q is 2-4. In certain embodiments of the compound of Formula (II-f), R1 is–SCH3; R7 is hydrogen; R8 is hydrogen; and q is 3. In certain embodiments of the compound of Formula (II-f), R1 is– SCH3; R7 is hydrogen; R8 is methyl; and q is 2-4. In certain embodiments of the compound of Formula (II-f), R1 is–SCH3; R7 is hydrogen; R8 is methyl; and q is 3. [00193] In certain embodiments, the compound of Formula (II) is a compound of Formula (II-g):
Figure imgf000061_0001
or a pharmaceutically acceptable salt thereof, wherein A, R1, Rb, Rc, R7, and R8 are as defined herein.
[00194] In certain embodiments of the compound of Formula (II-g), R1 is–SRA; R7 is hydrogen; and R8 is hydrogen or methyl. In certain embodiments of the compound of Formula (II-g), R1 is–SCH3; R7 is hydrogen; and R8 is hydrogen or methyl. In certain embodiments of the compound of Formula (II-g), R1 is–SCH3; R7 is hydrogen; and R8 is hydrogen. In certain embodiments of the compound of Formula (II-g), R1 is–SCH3; R7 is hydrogen; and R8 is methyl.
[00195] In certain embodiments, the compound of Formula (II) is a compound of Formula (II-h):
Figure imgf000061_0002
(II-h),
or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, Rb, Rc, and R8 are as defined herein.
[00196] In certain embodiments of the compound of Formula (II-h), R1 is–SRA; and R8 is hydrogen or methyl. In certain embodiments of the compound of Formula (II-h), R1 is– SCH3; and R8 is hydrogen. In certain embodiments of the compound of Formula (II-h), R1 is –SCH3; and R8 is methyl.
[00197] In certain embodiments, the compound of Formula (II) is a compound of Formula (II-i):
Figure imgf000062_0001
or a pharmaceutically acceptable salt thereof, wherein R1, R2, R4, Rb, Rc, and R8 are as defined herein.
[00198] In certain embodiments of the compound of Formula (II-i), R1 is–SRA; and R8 is hydrogen or methyl. In certain embodiments of the compound of Formula (II-i), R1 is–SCH3; and R8 is hydrogen. In certain embodiments of the compound of Formula (II-i), R1 is–SCH3; and R8 is methyl.
[00199] In certain embodiments, the compound of Formula (II) is a compound of Formula (II-j):
Figure imgf000062_0002
or a pharmaceutically acceptable salt thereof, wherein R1, RA, R4, Rb, Rc, and R8 are as defined herein.
[00200] In certain embodiments of the compound of Formula (II-j), R1 is–SRA; and R8 is hydrogen or methyl. In certain embodiments of the compound of Formula (II-j), R1 is– SCH3; and R8 is hydrogen. In certain embodiments of the compound of Formula (II-j), R1 is –SCH3; and R8 is methyl.
[00201] In certain embodiments, the compound of Formula (II) is a compound of Formula (II-k):
Figure imgf000063_0001
or a pharmaceutically acceptable salt thereof, wherein R1, R4, Rb, Rc, and R8 are as defined herein.
[00202] In certain embodiments of the compound of Formula (II-k), R1 is–SRA; and R8 is hydrogen or methyl. In certain embodiments of the compound of Formula (II-k), R1 is– SCH3; and R8 is hydrogen. In certain embodiments of the compound of Formula (II-k), R1 is –SCH3; and R8 is methyl.
[00203] In certain embodiments, the compound of Formula (II) is a compound of Formula (II-l):
Figure imgf000063_0002
or a pharmaceutically acceptable salt thereof, wherein R2, R3, R4, Rb, Rc, and R8 are as defined herein; and R1a and R1b 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,–ORA,–N3,–N(RA)2,–SRA,–CN,–SCN,–C(=NRA)RA,–C(=NRA)ORA,– C(=NRA)N(RA)2,–C(=O)RA,–C(=O)ORA,–C(=O)N(RA)2,–NO2,–NRAC(=O)RA,–
NRAC(=O)ORA,–NRAC(=O)N(RA)2,–NRAC(=NRA)N(RA)2,–OC(=O)RA,–OC(=O)ORA,– OC(=O)N(RA)2,–NRAS(O)2RA, -OS(O)2RA, or -S(O)2RA, or R1a and R1b are joined to form a substituted or unsubstituted heterocyclic ring, or a substituted or unsubstituted carbocyclic ring.
[00204] In certain embodiments of the compound of Formula (II-l), R1a and R1b 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,–ORA, - OS(O)2RA,–N3,–N(RA)2, or R1a and R1b are joined to form a substituted or unsubstituted carbocyclic ring.
[00205] In certain embodiments of the compound of Formula (II-l), R1a and R1b are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, or–N(RA)2; or R1a and R1b are joined to form a substituted or unsubstituted carbocyclic ring.
[00206] In certain embodiments of the compound of Formula (II-l), R1a and R1b are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, or–N(RA)2; or R1a and R1b are joined to form a substituted or unsubstituted carbocyclic ring; and R8 is hydrogen or methyl.
[00207] In certain embodiments of the compound of Formula (II-l), R1a and R1b are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, or–N(RA)2; or R1a and R1b are joined to form a substituted or unsubstituted carbocyclic ring; and R8 is hydrogen. In certain embodiments of the compound of Formula (II-l), R1a and R1b are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, or–N(RA)2; or R1a and R1b are joined to form a substituted or unsubstituted carbocyclic ring; and R8 is methyl. [00208] In certain embodiments, the compound of Formula (II) is a compound of Formula (II-m):
Figure imgf000065_0001
or a pharmaceutically acceptable salt thereof, wherein R1a, R1b, RA, R4, Rb, Rc, and R8 are as defined herein.
[00209] In certain embodiments of the compound of Formula (II-m), R1a and R1b 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,–ORA, - OS(O)2RA,–N3, or–N(RA)2, or R1a and R1b are joined to form a substituted or unsubstituted carbocyclic ring.
[00210] In certain embodiments of the compound of Formula (II-m), R1a and R1b are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, or–N(RA)2; or R1a and R1b are joined to form a substituted or unsubstituted carbocyclic ring.
[00211] In certain embodiments of the compound of Formula (II-m), R1a and R1b are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, or–N(RA)2; or R1a and R1b are joined to form a substituted or unsubstituted carbocyclic ring; and R8 is hydrogen or methyl.
[00212] In certain embodiments of the compound of Formula (II-m), R1a and R1b are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, or–N(RA)2; or R1a and R1b are joined to form a substituted or unsubstituted carbocyclic ring; and R8 is hydrogen. In certain embodiments of the compound of Formula (II-m), R1a and R1b are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, or–N(RA)2; or R1a and R1b are joined to form a substituted or unsubstituted carbocyclic ring; and R8 is methyl.
[00213] In certain embodiments, the compound of Formula (II) is a compound of Formula (II-n):
Figure imgf000066_0001
or a pharmaceutically acceptable salt thereof, wherein R1a, R1b, R4, Rb, Rc, and R8 are as defined herein.
[00214] In certain embodiments of the compound of Formula (II-n), R1a and R1b 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,–ORA, - OS(O)2RA,–N3, or–N(RA)2, or R1a and R1b are joined to form a substituted or unsubstituted carbocyclic ring.
[00215] In certain embodiments of the compound of Formula (II-n), R1a and R1b are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, or–N(RA)2; or R1a and R1b are joined to form a substituted or unsubstituted carbocyclic ring.
[00216] In certain embodiments of the compound of Formula (II-n), R1a and R1b are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, or–N(RA)2; or R1a and R1b are joined to form a substituted or unsubstituted carbocyclic ring; and R8 is hydrogen or methyl.
[00217] In certain embodiments of the compound of Formula (II-n), R1a and R1b are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, or–N(RA)2; or R1a and R1b are joined to form a substituted or unsubstituted carbocyclic ring; and R8 is hydrogen. In certain embodiments of the compound of Formula (II-n), R1a and R1b are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, or–N(RA)2; or R1a and R1b are joined to form a substituted or unsubstituted carbocyclic ring; and R8 is methyl.
[00218] In certain embodiments, the compound of Formula (II) is a compound of Formula (II-o):
Figure imgf000067_0001
or a pharmaceutically acceptable salt thereof, wherein RA, R4, Rb, Rc, and R8 are as defined herein.
[00219] In certain embodiments of the compound of Formula (II-o), R8 is hydrogen or methyl. In certain embodiments of the compound of Formula (II-o), R8 is hydrogen. In certain embodiments of the compound of Formula (II-o), R8 is methyl.
[00220] In certain embodiments of the compound of Formula (II-o), RA is methyl; and R8 is hydrogen or methyl. In certain embodiments of the compound of Formula (II-o), RA is methyl; and R8 is hydrogen. In certain embodiments of the compound of Formula (II-o), RA is methyl; and R8 is methyl.
[00221] In certain embodiments, the compound of Formula (II) is a compound of Formula (II-p):
Figure imgf000068_0001
or a pharmaceutically acceptable salt thereof, wherein RA, Rb, Rc, and R8 are as defined herein.
[00222] In certain embodiments of the compound of Formula (II-p), R8 is hydrogen or methyl. In certain embodiments of the compound of Formula (II-p), R8 is hydrogen. In certain embodiments of the compound of Formula (II-p), R8 is methyl.
[00223] In certain embodiments of the compound of Formula (II-p), RA is methyl; and R8 is hydrogen or methyl. In certain embodiments of the compound of Formula (II-p), RA is methyl; and R8 is hydrogen. In certain embodiments of the compound of Formula (II-p), RA is methyl; and R8 is methyl.
[00224] In certain embodiments, the compound of Formula (II) is a compound of Formula (II-q):
Figure imgf000068_0002
or a pharmaceutically acceptable salt thereof, wherein Rb, Rc, and R8 are as defined herein. [00225] In certain embodiments of the compound of Formula (II-q), R8 is hydrogen or methyl. In certain embodiments of the compound of Formula (II-q), R8 is hydrogen. In certain embodiments of the compound of Formula (II-q), R8 is methyl. Exemplary compounds
[00226] Exemplary compounds of Formula (I) include, but are not limited to the compounds listed in Table 1, and pharmaceutically acceptable salts thereof.
Table 1. Exemplary compounds of Formula (I)
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
[00227] Exemplary compounds of Formula (II) include, but are not limited to, the compounds listed in Table 2, and pharmaceutically acceptable salts thereof.
Table 2. Exemplary compounds of Formula (II)
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Additional compounds
[00228] Also disclosed are the compounds in Table 3, and pharmaceutically acceptable salts thereof. Table 3. Additional Compounds
Figure imgf000079_0002
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Preparation of compounds of Formulae (I) and (II)
[00229] Exemplary methods that may be used in the preparation of a compound of the present disclosure are described below, and are not to be construed as limiting. The compounds herein may be prepared by other methods of synthesis known in the art, and the procedures described herein may be modified or combined with other known methods. [00230] In certain embodiments, compounds of the present disclosure are prepared by coupling a compound of Formula (A) and a compound of Formula (B) as depicted in Scheme 1 below. Scheme 1.
Figure imgf000093_0001
(I) wherein A, P, R1, R7, R8, R9, and p are as defined herein for a compound of Formula (I), unless otherwise stated.
[00231] In certain embodiments, 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). In certain embodiments, the amide coupling reagent (e.g., HATU, EDC, HOBt) is reacted with the compound of Formula (B). In certain embodiments, the amide coupling reagent (e.g., HATU, EDC, HOBt) is reacted with the compound of Formula (B) prior to amide coupling with the compound of Formula (A). In certain embodiments, the amide coupling reagent is HATU.
[00232] In certain embodiments, 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. In certain
embodiments, 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.
[00233] In certain embodiments, an additional reagent may be added to the amide bond forming reaction. In certain embodiments, the additional reagent may facilitate amide coupling by protecting the free hydroxyls of the compound of Formula (A). In certain embodiments, the additional reagent is a silylating reagent. In certain embodiments, 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. In certain embodiments, the additional reagent is added to the compound of Formula (A) before the amide coupling. In certain embodiments, the additional reagent is N,O-bis(trimethylsilyl)trifluoroacetamide. In certain embodiments, 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.
[00234] 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.
[00235] In certain embodiments, 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.
Scheme 2.
Figure imgf000094_0001
wherein A, P, R1, R7, R8, Rb, Rc, and E are as defined herein for a compound of Formula (II), unless otherwise stated.
[00236] In certain embodiments, 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.
Figure imgf000095_0001
wherein A, P, R1, R7, and R8 are as defined herein for a compound of Formula (II), and each P1 is independently hydrogen or a protecting group, or two instances of P1 are joined to form a heterocyclic ring.
[00237] In certain embodiments, 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). In certain embodiments, the amide coupling reagent (e.g., HATU, EDC, HOBt) is reacted with the compound of Formula (C) or (D). In certain embodiments, the amide coupling reagent (e.g., HATU, EDC, HOBt) is reacted with the compound of Formula (C) or (D) prior to amide coupling with the compound of Formula (A). In certain embodiments, the amide coupling reagent is HATU.
[00238] In certain embodiments, 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. In certain
embodiments, 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.
[00239] In certain embodiments, an additional reagent may be added to the amide bond forming reaction. In certain embodiments, the additional reagent may facilitate amide coupling by protecting the free hydroxyls of the compound of Formula (A). In certain embodiments, the additional reagent is a silylating reagent. In certain embodiments, 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. In certain embodiments, the additional reagent is added to the compound of Formula (A) before the amide coupling. In certain embodiments, the additional reagent is N,O-bis(trimethylsilyl)trifluoroacetamide. In certain embodiments, 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.
[00240] In certain embodiments, 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.
Scheme 4.
Figure imgf000096_0001
[00241] In certain embodiments, the deprotection is achieved under acidic conditions, e.g., HCl.
[00242] In certain embodiments, 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.
Figure imgf000096_0002
[00243] In certain embodiments, the compound of Formula (II-g-1) is the compound of Formula (II-g).
[00244] In another aspect, the present disclosure provides methods of preparing compounds of Formula (G):
Figure imgf000097_0001
or a salt thereof, the method comprising cross metathesis of an olefin: and
Figure imgf000097_0004
a compound of Formula (H):
Figure imgf000097_0002
or salt thereof, wherein R8 is as defined herein; P2 is hydrogen or a protecting group; and R20 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, substituted or unsubstituted heteroaliphatic,–C(=NRA)RA,–C(=NRA)ORA,–C(=NRA)N(RA)2, –C(=O)RA,–C(=O)ORA, or–C(=O)N(RA)2.
[00245] In certain embodiments, 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):
Figure imgf000097_0003
or a salt thereof.
[00246] In certain embodiments, the compound of Formula (G) is the compound of Formula (G-1):
Figure imgf000098_0001
or a salt thereof.
[00247] In certain embodiments, the compound of Formula (H) is the compound of Formula (H-1):
Figure imgf000098_0002
or a salt thereof.
[00248] In certain embodiments, 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.
Figure imgf000098_0003
[00249] In certain embodiments, 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. In certain embodiments, the transition metal catalyst is a tungsten (W), molybdenum (Mo), or ruthenium (Ru) catalyst. In certain embodiments, the catalyst is a ruthenium catalyst. [00250] For examples of olefin metathesis reagents, catalysts, and reaction conditions useful in the present methods, see, e.g., Schrodi, Y.; Pederson, R. L. Aldrichimica Acta 2007, 40, 45; Adv. Synth. Catal.2007, 349, 1–268; Grubbs, R. H. Tetrahedron 2004, 60, 7117; Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH: Weinheim, 2003; Vols.1–3; Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res.2001, 34, 18 ; Fürstner, A. Angew. Chem., Int. Ed.2000, 39, 3012; Schuster, M.; Blechert, S. Angew. Chem., Int. Ed.1997, 36, 2036; Ritter, T. et al. Organometallics 2006, 25, 5740; Chatterjee, A. K. et al. J. Am. Chem. Soc.2000, 122, 3783; Chatterjee, A. K.; Grubbs, R. H. Org. Lett.1999, 1, 1751; Murelli, R. P.; Snapper, M. L. Org. Lett.2007, 9, 1749; Stewart, I. C. et al. Org. Lett.2007, 9, 1589; Ung, T. et al. Organometallics 2004, 23, 5399; Benitez, D.; Goddard, W. A., III. J. Am. Chem. Soc.2005, 127, 12218; Love, J. A. et al. Angew. Chem., Int. Ed.2002, 41, 4035; Sanford, M. S. et al. Organometallics 2001, 20, 5314; Choi, T.-L.; Grubbs, R. H. Angew. Chem.2003, 115, 1785; Ritter, T. et al. Organometallics 2006, 25, 5740; and references cited therein; each of which is incorporated herein by reference.
[00251] In certain embodiments, the metathesis catalyst is a Grubbs catalyst. In certain embodiments, the Grubbs catalyst is of the formula:
Figure imgf000099_0001
Benzylidenebis– (tricyclohexylphosphine)–dichlororuthenium (X = Cl); Benzylidenebis– (tricyclohexylphosphine)–dibromoruthenium (X = Br); Benzylidenebis–
(tricyclohexylphosphine)–diiodoruthenium (X = I);
Figure imgf000099_0002
X = Cl; Br; I
R = cyclohexyl (Cy); phenyl (Ph); benzyl (Bn)
1,3–(Bis(mesityl)–2–imidazolidinylidene)dichloro–(phenylmethylene) (tricyclohexyl– phosphine)ruthenium (X = Cl; R = cyclohexyl); 1,3–(Bis(mesityl)–2– imidazolidinylidene)dibromo–(phenylmethylene) (tricyclohexyl–phosphine)ruthenium (X = Br; R = cyclohexyl); 1,3–(Bis(mesityl)–2–imidazolidinylidene)diiodo–(phenylmethylene) (tricyclohexyl–phosphine)ruthenium (X = I; R = cyclohexyl); 1,3–(Bis(mesityl)–2– imidazolidinylidene)dichloro–(phenylmethylene) (triphenylphosphine)ruthenium (X = Cl; R = phenyl); 1,3–(Bis(mesityl)–2–imidazolidinylidene)dichloro–(phenylmethylene)
(tribenz l hos hine ruthenium X = Cl R = benz l
Figure imgf000100_0001
[00252] In certain embodiments, the metathesis catalyst is a Grubbs-Hoveyda catalyst. In certain embodiments, the Grubbs-Hoveyda catalyst is of the formula:
Figure imgf000100_0002
. Pharmaceutical Compositions and Administration
[00253] The present disclosure provides pharmaceutical compositions comprising a compound as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
[00254] Pharmaceutically acceptable excipients include any and all solvents, diluents, or other liquid vehicles, dispersions, suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. General considerations in formulation and/or manufacture of pharmaceutical compositions agents can be found, for example, in
Remington’s Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980), and Remington: The Science and Practice of Pharmacy, 21st Edition (Lippincott Williams & Wilkins, 2005).
[00255] Pharmaceutical 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.
[00256] Pharmaceutical compositions can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses. As used herein, 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.
[00257] 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. By way of example, the composition may comprise between 0.1% and 100% (w/w) compound.
[00258] Pharmaceutically acceptable excipients used in the manufacture of provided pharmaceutical compositions include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition. [00259] Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the compounds, 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. Besides inert diluents, the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. In certain embodiments for parenteral administration, the conjugates of the invention are mixed with solubilizing agents, and mixtures thereof.
[00260] 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. Among the acceptable vehicles and solvents that can be employed are water, Ringer’s solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.
[00261] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, 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 glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may comprise buffering agents.
[00262] 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. Generally, the compound is admixed under sterile conditions with a pharmaceutically acceptable carrier and/or any needed preservatives and/or buffers as can be required. [00263] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical
compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation.
[00264] 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.
[00265] 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. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the agent, the therapeutic regimen, and/or the condition of the subject. Oral administration is the preferred mode of administration. However, in certain embodiments, 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.
[00266] An effective amount may be included in a single dose (e.g., single oral dose) or multiple doses (e.g., multiple oral doses). In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, any two doses of the multiple doses include different or substantially the same amounts of a compound described herein. In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, 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. In certain embodiments, a dose (e.g., a single dose, or any dose of multiple doses) described herein includes
independently between 0.1 µg and 1 µg, between 0.001 mg and 0.01 mg, between 0.01 mg and 0.1 mg, between 0.1 mg and 1 mg, between 1 mg and 3 mg, between 3 mg and 10 mg, between 10 mg and 30 mg, between 30 mg and 100 mg, between 100 mg and 300 mg, between 300 mg and 1,000 mg, or between 1 g and 10 g, inclusive, of a compound described herein.
[00267] It will be also appreciated that 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. In general, each agent will be administered at a dose and/or on a time schedule determined for that agent. In will further be appreciated that 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. In general, it is expected that 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.
[00268] 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,
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.
[00269] In certain embodiments, the additional therapeutically active agent is an antibiotic. Exemplary antibiotics include, but are not limited to, penicillins (e.g., penicillin, amoxicillin), cephalosporins (e.g., cephalexin), compounds (e.g., erythromycin, clarithormycin,
azithromycin, troleandomycin), fluoroquinolones (e.g., ciprofloxacin, levofloxacin, ofloxacin), sulfonamides (e.g., co-trimoxazole, trimethoprim), 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)),
aminoglycosides (e.g., gentamicin, tobramycin, paromomycin), aminocyclitol (e.g., spectinomycin), chloramphenicol, sparsomycin, and quinupristin/dalfoprisin (Syndercid™).
[00270] Also encompassed by the invention are 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). In certain embodiments, provided kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of an inventive pharmaceutical composition or compound. In certain embodiments, the inventive
pharmaceutical composition or compound provided in the container and the second container are combined to form one unit dosage form. Methods of Treatment and Uses
[00271] 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.
[00272] Thus, as generally described herein, provided is 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.
[00273] In certain embodiments, the effective amount is a therapeutically effective amount. For example, in certain embodiments, the method slows the progress of an infectious disease in the subject. In certain embodiments, the method improves the condition of the subject suffering from an infectious disease. In certain embodiments, the subject has a suspected or confirmed infectious disease.
[00274] In certain embodiments, the effective amount is a prophylactically effective amount. For example, in certain embodiments, 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. In certain embodiments, 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).
[00275] In one aspect, provided is a method of killing a microorganism (e.g., fungus, bacterium, virus, parasite) 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.
[00276] In another aspect, provided is a method of inhibiting the growth of a
microorganism (e.g., fungus, bacterium, virus, parasite) 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.
[00277] In another aspect, provided is 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.
[00278] In another aspect, provided is 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. In another aspect, provided is 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) with an effective amount of a compound of the present disclosure. In certain embodiments, 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.
[00279] As used herein,“infectious disease” and“microbial infection” are used
interchangeably, and refer to an infection with a pathogen, such as a fungus, bacteria, virus, or a parasite. In certain embodiments, the infectious disease is caused by a fungus, bacteria, or a parasite. In certain embodiments, the infectious disease is caused by a pathogen resistant to other treatments. In certain embodiments, 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.
[00280] In certain embodiments, the infectious disease is a bacterial infection. For example, in certain embodiments, provided is a method of treating a bacterial 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.
[00281] In certain embodiments, the compound has a mean inhibitory concentration (MIC), with respect to a particular bacteria, of less than 50 µg/mL, less than 25 µg/mL, less than 20 µg/mL, less than 10 µg/mL, less than 5 µg/mL, or less than 1 µg/mL.
[00282] In certain embodiments, the bacteria is susceptible (e.g., responds to) or resistant to known commercial compounds, such as azithromycin, lincomycin, clindamycin,
telithromycin, erythromycin, spiramycin, and the like. In certain embodiments, the bacteria is resistant to a known compound. For example, in certain embodiments, the bacteria is lincomycin or clindamycin resistant.
[00283] In certain embodiments, the bacterial infection is resistant to other antibiotics (e.g., non-compound) therapy. For example, in certain embodiments, the pathogen is vancomycin resistant (VR). In certain embodiments, the pathogen is methicillin-resistant (MR), e.g., in certain embodiments, the bacterial infection is an methicillin-resistant S. aureus infection (a MRSA infection). In certain embodiments, the pathogen is quinolone resistant (QR). In certain embodiments, the pathogen is fluoroquinolone resistant (FR).
[00284] 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
Planctomycetes/Verrucomicrobia/Chlamydiae (PVC), phylum Proteobacteria, phylum Spirochaetes, or phylum Synergistetes); or other bacteria (e.g., of the phylum Acidobacteria, phylum Chlroflexi, phylum Chrystiogenetes, phylum Cyanobacteria, phylum
Deferrubacteres, phylum Dictyoglomi, phylum Thermodesulfobacteria, or phylum
Thermotogae).
[00285] In certain embodiments, the bacterial infection is an infection with a Gram positive bacterium. [00286] In certain embodiments, the Gram positive bacterium is a bacterium of the phylum Firmicutes.
[00287] In certain embodiments, 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.
faecium, E. gallinarum, E. solitarius, E. casseliflavus, and E. raffinosus.
[00288] In certain embodiments, 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.
haemolyticus, S. hominis, S. hyicus, S. intermedius, S. kloosii, S. leei, S. lenus, S. lugdunesis, S. lutrae, S. lyticans, S. massiliensis, S. microti, S. muscae, S. nepalensis, S. pasteuri, S.
penttenkoferi, S. piscifermentans, S. psuedointermedius, S. psudolugdensis, S. pulvereri, S. rostri, S. saccharolyticus, S. saprophyticus, S. schleiferi, S. sciuri, S. simiae, S. simulans, S. stepanovicii, S. succinus, S. vitulinus, S. warneri, and S. xylosus. In certain embodiments, the Staphylococcus infection is an S. aureus infection.
[00289] In certain embodiments, 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.
[00290] In certain embodiments, the S. aureus has a methylase (e.g., erm) genotype. In certain embodiments, 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.
[00291] In certain embodiments, the bacteria is a member of the phylum Firmicutes and the genus Bacillus, i.e., the bacterial infection is a Bacillus infection. Exemplary 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. In certain embodiments, the Bacillus infection is a B. subtilis infection. In certain embodiments, the B. subtilis has an efflux (e.g., mef, msr) genotype. In certain embodiments, the B. subtilis has a methylase (e.g., erm) genotype.
[00292] In certain embodiments, 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. salivarius, S. thermophilus, S. sanguinis, S. sobrinus, S. suis, S. uberis, S. vestibularis, S. viridans, and S. zooepidemicus. In certain embodiments, the Strepococcus infection is an S. pyogenes infection. In certain embodiments, the Strepococcus infection is an S. pneumoniae infection. In certain embodiments, the S. pneumoniae has an efflux (e.g., mef, msr) genotype. In certain embodiments, the S. pneumoniae has a methylase (e.g., erm) genotype.
[00293] In certain embodiments, the bacteria is a member of the phylum Firmicutes and the genus Clostridium, i.e., the bacterial infection is a Clostridium infection. Exemplary
Clostridia bacteria include, but are not limited to, C. botulinum, C. difficile, C. perfringens, C. tetani, and C. sordellii.
[00294] In certain embodiments, the compounds of the disclosure are a safer alternative to clindamycin, due to reduced incidence of pseudomembranous colitis. In certain
embodiments, the compounds of the disclosure have increased activity against Clostridium difficile (C. difficile) in comparison to clindamycin. In certain embodiments, the compounds have a mean inhibitory concentration (MIC), with respect to C. difficile, of less than 50 µg/mL, less than 25 µg/mL, less than 20 µg/mL, less than 10 µg/mL, less than 5 µg/mL, or less than 1 µg/mL.
[00295] In certain embodiments, the bacterial infection is an infection with a Gram negative bacteria.
[00296] In certain embodiments, 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.
blattae, E. coli, E. fergusonii, E. hermannii, and E. vulneris. In certain embodiments, the Escherichia infection is an E. coli infection.
[00297] In certain embodiments, 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. In certain embodiments, the Haemophilus infection is an H. influenzae infection.
[00298] In certain embodiments, 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. In certain embodiments, the Acinetobacter infection is an A. baumanii infection.
[00299] In certain embodiments, 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. In certain
embodiments, the Klebsiella infection is a K. pneumoniae infection.
[00300] In certain embodiments, 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. In certain embodiments, the Pseudomonas infection is a P. aeruginosa infection.
[00301] In certain embodiments, 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.
distasonis, B. ovatus, B. thetaiotaomicron, and B. vulgatus. In certain embodiments, the Bacteroides infection is a B. fragilis infection.
[00302] In certain embodiments, the bacteria is an atypical bacteria, i.e., are neither Gram positive nor Gram negative.
[00303] In certain embodiments, the infectious disease is an infection with a parasitic infection. Thus, in certain embodiments, provided is 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.
[00304] In certain embodiments, the compound has an IC50 (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.
[00305] 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. flaciparum), Crytosporidium spp., Isospora spp., Balantidium spp., Pneumocystis spp., Babesia, Loa Loa, Ascaris lumbricoides, Dirofilaria immitis, and Toxoplasma ssp. (e.g. T. gondii).
[00306] As generally described herein, 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. Such a method can be conducted in vivo (i.e., by administration to a subject) or in vitro (e.g., upon contact with the pathogen, tissue, or cell culture). Treating, as used herein, encompasses therapeutic treatment and prophylactic treatment.
[00307] In certain embodiments, the effective amount is a therapeutically effective amount. For example, in certain embodiments, the method slows the progress of an inflammatory condition in the subject. In certain embodiments, the method improves the condition of the subject suffering from an inflammatory condition. In certain embodiments, the subject has a suspected or confirmed inflammatory condition.
[00308] In certain embodiments, the effective amount is a prophylatically effective amount. For example, in certain embodiments, 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. In certain embodiments, the subject is at risk to an inflammatory condition.
[00309] 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.
[00310] In certain embodiments, the inflammatory condition is an acute inflammatory condition (e.g., for example, inflammation resulting from an infection). In certain embodiments, the inflammatory condition is a chronic inflammatory condition. In certain embodiments, the inflammatory condition is inflammation associated with cancer.
[00311] As generally described herein, 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. Such 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.
[00312] In certain embodiments, the effective amount is a therapeutically effective amount. For example, in certain embodiments, the method slows the progress of a central nervous system disorder in the subject. In certain embodiments, the method improves the condition of the subject suffering from a central nervous system disorder. In certain embodiments, the subject has a suspected or confirmed central nervous system disorder.
[00313] In certain embodiments, the effective amount is a prophylatically effective amount. For example, in certain embodiments, 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. In certain embodiments, the subject is at risk of developing a central nervous system disorder.
[00314] In certain embodiments, compounds of the present disclosure may treat a central nervous system disorder by modulating the serotonin 5-HT2C receptor. In certain
embodiments, the compounds of the present disclosure are allosteric modulators of the serotonin 5-HT2C receptor, e.g., see Zhou et al. ACS Chemical Neuroscience 2012, 3, 538– 545, and Dinh et al. Molecular Pharmacology 2003, 64, 78–84.
[00315] In certain embodiments, the central nervous system disorder is addiction, anxiety, depression, obesity, eating disorders, Parkinson’s disease, or schizophrenia. DEFINITIONS
Chemical terms
[00316] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March March’s Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987.
[00317] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and/or diastereomers. For example, 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. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S.H. Tables of Resolving Agents and Optical
Resolutions p.268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The invention additionally encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.
[00318] In a formula, is a single bond where the stereochemistry of the moieties immediately attached thereto is not specified, is absent or a single bond, and or is a single or double bond.
[00319] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of 19F with 18F, or the replacement of 12C with 13C or 14C are within the scope of the disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.
[00320] When a range of values is listed, it is intended to encompass each value and sub- range within the range. For example“C1-6 alkyl” is intended to encompass, C1, C2, C3, C4, C5, C6, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl.
[00321] 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 (“C1-10 alkyl”). In certain embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9 alkyl”). In certain embodiments, an alkyl group has 1 to 8 carbon atoms (“C1-8 alkyl”). In certain embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7 alkyl”). In certain embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-6 alkyl”). In certain embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5 alkyl”). In certain embodiments, an alkyl group has 1 to 4 carbon atoms (“C1-4 alkyl”). In certain embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3 alkyl”). In certain embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2 alkyl”). In certain embodiments, an alkyl group has 1 carbon atom (“C1 alkyl”). In certain embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6 alkyl”). Examples of C1-6 alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, iso-butyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tertiary amyl), and hexyl (C6) (e.g., n-hexyl). Additional examples of alkyl groups include n-heptyl (C7), n- octyl (C8), 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). In certain embodiments, the alkyl group is an unsubstituted C1-10 alkyl (such as unsubstituted C1-6 alkyl, e.g.,−CH3 (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)). In certain embodiments, the alkyl group is a substituted C1-10 alkyl (such as substituted C1-6 alkyl, e.g.,−CF3, Bn).
[00323] The term“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. In certain embodiments, the haloalkyl moiety has 1 to 8 carbon atoms (“C1-8 haloalkyl”). In certain embodiments, the haloalkyl moiety has 1 to 6 carbon atoms (“C1-6 haloalkyl”). In certain embodiments, the haloalkyl moiety has 1 to 4 carbon atoms (“C1-4 haloalkyl”). In certain embodiments, the haloalkyl moiety has 1 to 3 carbon atoms (“C1-3 haloalkyl”). In certain embodiments, the haloalkyl moiety has 1 to 2 carbon atoms (“C1-2 haloalkyl”).
Examples of haloalkyl groups include−CF3,−CF2CF3,−CF2CF2CF3,−CCl3,−CFCl2, −CF2Cl, and the like.
[00324] The term“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. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 10 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-10 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1 or more heteroatoms within the parent chain
(“heteroC1-9 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-8 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 (“heteroC1-7 alkyl”). In certain
embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-6 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 (“heteroC1-5 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 (“heteroC1-4 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“heteroC1-3 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroC1-2 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroC1 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 (“heteroC2-6 alkyl”). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an
“unsubstituted heteroalkyl”) or substituted (a“substituted heteroalkyl”) with one or more substituents. In certain embodiments, the heteroalkyl group is an unsubstituted heteroC1-10 alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC1-10 alkyl.
[00325] The term“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). In certain embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2-9 alkenyl”). In certain embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-8 alkenyl”). In certain embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2-7 alkenyl”). In certain embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-6 alkenyl”). In certain embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-5 alkenyl”). In certain embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2-4 alkenyl”). In certain embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-3 alkenyl”). In certain embodiments, an alkenyl group has 2 carbon atoms (“C2 alkenyl”). The one or more carbon- carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C2-4 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1- butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an“unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents. In certain embodiments, the alkenyl group is an unsubstituted C2-10 alkenyl. In certain embodiments, the alkenyl group is a substituted C2-10 alkenyl. In an alkenyl group, a C=C double bond for which the stereochemistry is not specified (e.g.,−CH=CHCH3 or may be an (E)- or (Z)-
Figure imgf000116_0001
double bond.
[00326] The term“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. In certain embodiments, 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 (“heteroC2-10 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-9 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 (“heteroC2-8 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
(“heteroC2-7 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain
(“heteroC2-6 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-5 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 (“heteroC2-4 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 (“heteroC2-3 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-6 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 heteroC2-10 alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC2-10 alkenyl.
[00327] The term“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) (“C2-10 alkynyl”). In certain embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2-9 alkynyl”). In certain embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2-8 alkynyl”). In certain embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2-7 alkynyl”). In certain embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2-6 alkynyl”). In certain embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2-5 alkynyl”). In certain embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2-4 alkynyl”). In certain embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-3 alkynyl”). In certain embodiments, an alkynyl group has 2 carbon atoms (“C2 alkynyl”). The one or more carbon- carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C2-4 alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2- propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an“unsubstituted alkynyl”) or substituted (a“substituted alkynyl”) with one or more substituents. In certain embodiments, the alkynyl group is an unsubstituted C2-10 alkynyl. In certain embodiments, the alkynyl group is a substituted C2-10 alkynyl.
[00328] The term“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. In certain embodiments, 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 (“heteroC2-10 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-9 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 (“heteroC2-8 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 (“heteroC2- 7 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-6 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 (“heteroC2-5 alkynyl”). In certain
embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and 1or 2 heteroatoms within the parent chain (“heteroC2-4 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 (“heteroC2-3 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 (“heteroC2-6 alkynyl”). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an“unsubstituted heteroalkynyl”) or substituted (a “substituted heteroalkynyl”) with one or more substituents. In certain embodiments, the heteroalkynyl group is an unsubstituted heteroC2-10 alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC2-10 alkynyl.
[00329] The term“carbocyclyl” or“carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C3-14 carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. In certain embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C3-10 carbocyclyl”). In certain embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8 carbocyclyl”). In certain embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C3-7 carbocyclyl”). In certain
embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In certain embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C4-6 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C5-6
carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10 carbocyclyl”). Exemplary C3-6 carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3-8 carbocyclyl groups include, without limitation, the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C3-10 carbocyclyl groups include, without limitation, the aforementioned C3-8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. As the foregoing examples illustrate, in certain embodiments, 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. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an“unsubstituted
carbocyclyl”) or substituted (a“substituted carbocyclyl”) with one or more substituents. In certain embodiments, the carbocyclyl group is an unsubstituted C3-14 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3-14 carbocyclyl.
[00330] In certain embodiments,“carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms (“C3-14 cycloalkyl”). In certain embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms (“C3-10 cycloalkyl”). In certain embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8 cycloalkyl”). In certain embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6 cycloalkyl”). In certain embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms (“C4-6 cycloalkyl”). In certain embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C5-6 cycloalkyl”). In certain embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10 cycloalkyl”). Examples of C5-6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-6 cycloalkyl groups include the aforementioned C5-6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8 cycloalkyl groups include the aforementioned C3-6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an“unsubstituted cycloalkyl”) or substituted (a“substituted cycloalkyl”) with one or more substituents. In certain embodiments, the cycloalkyl group is an unsubstituted C3-14 cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C3-14 cycloalkyl.
[00331] “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.
[00332] The term“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”). In heterocyclyl groups that contain one or more nitrogen atoms, 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. Unless otherwise specified, each instance of heterocyclyl is independently unsubstituted (an“unsubstituted heterocyclyl”) or substituted (a“substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-14 membered heterocyclyl.
[00333] In certain embodiments, 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”). In certain embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is
independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In certain embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is
independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In certain embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
[00334] 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,
dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. 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, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepinyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H- thieno[2,3-c]pyranyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3- b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2- c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like.
[00335] “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.
[00336] The term“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 (“C6-14 aryl”). In certain embodiments, an aryl group has 6 ring carbon atoms (“C6 aryl”; e.g., phenyl). In certain embodiments, an aryl group has 10 ring carbon atoms (“C10 aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In certain embodiments, an aryl group has 14 ring carbon atoms (“C14 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
independently unsubstituted (an“unsubstituted aryl”) or substituted (a“substituted aryl”) with one or more substituents. In certain embodiments, the aryl group is an unsubstituted C6- 14 aryl. In certain embodiments, the aryl group is a substituted C6-14 aryl.
[00337] “Aralkyl” is a subset of“alkyl” and refers to an alkyl group substituted by an aryl group, wherein the point of attachment is on the alkyl moiety.
[00338] The term“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”). In heteroaryl groups that contain one or more nitrogen atoms, 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).
[00339] In certain embodiments, 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”). In certain embodiments, 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”). In certain embodiments, 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”). In certain embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, 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
“unsubstituted heteroaryl”) or substituted (a“substituted heteroaryl”) with one or more substituents. In certain embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.
[00340] 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,
benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include, without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl and phenazinyl. [00341] “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.
[00342] Affixing the suffix“-ene” to a group indicates the group is a divalent moiety, e.g., 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, and heteroarylene is the divalent moiety of heteroaryl.
[00343] A group is optionally substituted unless expressly provided otherwise. The term “optionally substituted” refers to being substituted or unsubstituted. In certain embodiments, 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” heteroalkynyl,“substituted” or“unsubstituted” carbocyclyl, “substituted” or“unsubstituted” heterocyclyl,“substituted” or“unsubstituted” aryl or “substituted” or“unsubstituted” heteroaryl group). In general, 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. Unless otherwise indicated, 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. The term“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. For purposes of this invention, 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. [00344] Exemplary carbon atom substituents include, but are not limited to, halogen,−CN, −NO2,−N3,−SO2H,−SO3H,−OH,−ORaa,−ON(Rbb)2,−N(Rbb)2,−N(Rbb) +
3 X−,−N(ORcc)Rbb, −SH,−SRaa,−SSRcc,−C(=O)Raa,−CO2H,−CHO,−C(ORcc)2,−CO2Raa,−OC(=O)Raa, −OCO2Raa,−C(=O)N(Rbb)2,−OC(=O)N(Rbb)2,−NRbbC(=O)Raa,−NRbbCO2Raa,
−NRbbC(=O)N(Rbb)2,−C(=NRbb)Raa,−C(=NRbb)ORaa,−OC(=NRbb)Raa,−OC(=NRbb)ORaa, −C(=NRbb)N(Rbb)2,−OC(=NRbb)N(Rbb)2,−NRbbC(=NRbb)N(Rbb)2,−C(=O)NRbbSO2Raa, −NRbbSO2Raa,−SO2N(Rbb)2,−SO2Raa,−SO2ORaa,−OSO2Raa,−S(=O)Raa,−OS(=O)Raa, −Si(Raa)3,−OSi(Raa)3−C(=S)N(Rbb)2,−C(=O)SRaa,−C(=S)SRaa,−SC(=S)SRaa,
−SC(=O)SRaa,−OC(=O)SRaa,−SC(=O)ORaa,−SC(=O)Raa,−P(=O)2Raa,−OP(=O)2Raa, −P(=O)(Raa)2,−OP(=O)(Raa)2,−OP(=O)(ORcc)2,−P(=O)2N(Rbb)2,−OP(=O)2N(Rbb)2, −P(=O)(NRbb)2,−OP(=O)(NRbb)2,−NRbbP(=O)(ORcc)2,−NRbbP(=O)(NRbb)2,−P(Rcc)2, −P(Rcc)3,−OP(Rcc)2,−OP(Rcc)3,−B(Raa)2,−B(ORcc)2,−BRaa(ORcc), C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroC1-10 alkyl, heteroC2-10 alkenyl, heteroC2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 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 Rdd groups;
or two geminal hydrogens on a carbon atom are replaced with the group =O, =S, =NN(Rbb)2, =NNRbbC(=O)Raa, =NNRbbC(=O)ORaa, =NNRbbS(=O)2Raa, =NRbb, or =NORcc; each instance of Raa is, independently, selected from C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroC1-10 alkyl, heteroC2-10alkenyl, heteroC2-10alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Raa 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 Rdd groups;
each instance of Rbb is, independently, selected from hydrogen,−OH,−ORaa, −N(Rcc)2,−CN,−C(=O)Raa,−C(=O)N(Rcc)2,−CO2Raa,−SO2Raa,−C(=NRcc)ORaa, −C(=NRcc)N(Rcc)2,−SO2N(Rcc)2,−SO2Rcc,−SO2ORcc,−SORaa,−C(=S)N(Rcc)2,−C(=O)SRcc, −C(=S)SRcc,−P(=O)2Raa,−P(=O)(Raa)2,−P(=O)2N(Rcc)2,−P(=O)(NRcc)2, C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroC1-10alkyl, heteroC2-10alkenyl, heteroC2- 10alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Rbb 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 Rdd groups;
each instance of Rcc is, independently, selected from hydrogen, C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroC1-10 alkyl, heteroC2-10 alkenyl, heteroC2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Rcc 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 Rdd groups;
each instance of Rdd is, independently, selected from halogen,−CN,−NO2,−N3, −SO2H,−SO3H,−OH,−ORee,−ON(Rff)2,−N(Rff)2,−N(Rff) +
3 X−,−N(ORee)Rff,−SH,−SRee, −SSRee,−C(=O)Ree,−CO2H,−CO2Ree,−OC(=O)Ree,−OCO2Ree,−C(=O)N(Rff)2, −OC(=O)N(Rff)2,−NRffC(=O)Ree,−NRffCO2Ree,−NRffC(=O)N(Rff)2,−C(=NRff)ORee, −OC(=NRff)Ree,−OC(=NRff)ORee,−C(=NRff)N(Rff)2,−OC(=NRff)N(Rff)2,
−NRffC(=NRff)N(Rff)2,−NRffSO2Ree,−SO2N(Rff)2,−SO2Ree,−SO2ORee,−OSO2Ree, −S(=O)Ree,−Si(Ree)3,−OSi(Ree)3,−C(=S)N(Rff)2,−C(=O)SRee,−C(=S)SRee,−SC(=S)SRee, −P(=O)2Ree,−P(=O)(Ree)2,−OP(=O)(Ree)2,−OP(=O)(ORee)2, C1-6 alkyl, C1-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, heteroC1-6alkyl, heteroC2-6alkenyl, heteroC2-6alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, C6-10 aryl, 5-10 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 Rgg groups, or two geminal Rdd substituents can be joined to form =O or =S;
each instance of Ree is, independently, selected from C1-6 alkyl, C1-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, heteroC1-6 alkyl, heteroC2-6alkenyl, heteroC2-6 alkynyl, C3-10 carbocyclyl, C6-10 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 Rgg groups;
each instance of Rff is, independently, selected from hydrogen, C1-6 alkyl, C1-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, heteroC1-6alkyl, heteroC2-6alkenyl, heteroC2-6alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, C6-10 aryl and 5-10 membered heteroaryl, or two Rff 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 Rgg groups; and
each instance of Rgg is, independently, halogen,−CN,−NO2,−N3,−SO2H,−SO3H,
Figure imgf000127_0001
−NH(OH),−SH,−SC1-6 alkyl,−SS(C1-6 alkyl),−C(=O)(C1-6 alkyl),−CO2H,−CO2(C1-6 alkyl),−OC(=O)(C1-6 alkyl),−OCO2(C1-6 alkyl),−C(=O)NH2,−C(=O)N(C1-6 alkyl)2, −OC(=O)NH(C1-6 alkyl),−NHC(=O)( C1-6 alkyl),−N(C1-6 alkyl)C(=O)( C1-6 alkyl), −NHCO2(C1-6 alkyl),−NHC(=O)N(C1-6 alkyl)2,−NHC(=O)NH(C1-6 alkyl),−NHC(=O)NH2, −C(=NH)O(C1-6 alkyl),−OC(=NH)(C1-6 alkyl),−OC(=NH)OC1-6 alkyl,−C(=NH)N(C1-6 alkyl)2,−C(=NH)NH(C1-6 alkyl),−C(=NH)NH2,−OC(=NH)N(C1-6 alkyl)2,−OC(NH)NH(C1- 6 alkyl),−OC(NH)NH2,−NHC(NH)N(C1-6 alkyl)2,−NHC(=NH)NH2,−NHSO2(C1-6 alkyl), −SO2N(C1-6 alkyl)2,−SO2NH(C1-6 alkyl),−SO2NH2,−SO2C1-6 alkyl,−SO2OC1-6 alkyl, −OSO2C1-6 alkyl,−SOC1-6 alkyl,−Si(C1-6 alkyl)3,−OSi(C1-6 alkyl)3−C(=S)N(C1-6 alkyl)2, C(=S)NH(C1-6 alkyl), C(=S)NH2,−C(=O)S(C1-6 alkyl),−C(=S)SC1-6 alkyl,−SC(=S)SC1-6 alkyl,−P(=O)2(C1-6 alkyl),−P(=O)(C1-6 alkyl)2,−OP(=O)(C1-6 alkyl)2,−OP(=O)(OC1-6 alkyl)2, C1-6 alkyl, C1-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, heteroC1-6alkyl, heteroC2- 6alkenyl, heteroC2-6alkynyl, C3-10 carbocyclyl, C6-10 aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal Rgg substituents can be joined to form =O or =S;
wherein X− is a counterion.
[00345] The term“halo” or“halogen” refers to fluorine (fluoro,−F), chlorine (chloro,−Cl), bromine (bromo,−Br), or iodine (iodo,−I).
[00346] The term“hydroxyl” or“hydroxy” refers to the group−OH. The term“substituted hydroxyl” or“substituted hydroxyl,” by extension, refers to a hydroxyl group wherein the oxygen atom directly attached to the parent molecule is substituted with a group other than hydrogen, and includes groups selected from−ORaa,−ON(Rbb)2,−OC(=O)SRaa,
−OC(=O)Raa,−OCO2Raa,−OC(=O)N(Rbb)2,−OC(=NRbb)Raa,−OC(=NRbb)ORaa,
−OC(=NRbb)N(Rbb)2,−OS(=O)Raa,−OSO2Raa,−OSi(Raa)3,−OP(Rcc)2,−OP(Rcc)3, −OP(=O)2Raa,−OP(=O)(Raa)2,−OP(=O)(ORcc)2,−OP(=O)2N(Rbb)2, and−OP(=O)(NRbb)2, wherein Raa, Rbb, and Rcc are as defined herein.
[00347] The term“amino” refers to the group−NH2. The term“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
disubstituted amino group. [00348] The term“monosubstituted amino” refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with one hydrogen and one group other than hydrogen, and includes groups selected from−NH(Rbb),−NHC(=O)Raa, −NHCO2Raa,−NHC(=O)N(Rbb)2,−NHC(=NRbb)N(Rbb)2,−NHSO2Raa,−NHP(=O)(ORcc)2, and−NHP(=O)(NRbb)2, wherein Raa, Rbb and Rcc are as defined herein, and wherein Rbb of the group−NH(Rbb) is not hydrogen.
[00349] The term“disubstituted amino” refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with two groups other than hydrogen, and includes groups selected from−N(Rbb)2,−NRbb C(=O)Raa,−NRbbCO2Raa, −NRbbC(=O)N(Rbb)2,−NRbbC(=NRbb)N(Rbb)2,−NRbbSO2Raa,−NRbbP(=O)(ORcc)2, and −NRbbP(=O)(NRbb)2, wherein Raa, Rbb, and Rcc are as defined herein, with the proviso that the nitrogen atom directly attached to the parent molecule is not substituted with hydrogen.
[00350] The term“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(Rbb)3 and
Figure imgf000128_0001
wherein Rbb and X− are as defined herein.
[00351] The term“sulfonyl” refers to a group selected from−SO2N(Rbb)2,−SO2Raa, and −SO2ORaa, wherein Raa and Rbb are as defined herein.
[00352] The term“sulfinyl” refers to the group−S(=O)Raa, wherein Raa is as defined herein.
[00353] The term“acyl” refers to a group having the general formula−C(=O)RX1, −C(=O)ORX1,−C(=O)−O−C(=O)RX1,−C(=O)SRX1,−C(=O)N(RX1)2,−C(=S)RX1, −C(=S)N(RX1)2, and−C(=S)S(RX1),−C(=NRX1)RX1,−C(=NRX1)ORX1,−C(=NRX1)SRX1, and −C(=NRX1)N(RX1)2, wherein RX1 is hydrogen; halogen; substituted or unsubstituted hydroxyl; substituted or unsubstituted thiol; substituted or unsubstituted amino; substituted or unsubstituted acyl, cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched
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 RX1 groups taken together form a 5- to 6-membered heterocyclic ring. Exemplary acyl groups include aldehydes (−CHO), carboxylic acids (−CO2H), 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, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, and the like, each of which may or may not be further substituted).
[00354] The term“silyl” refers to the group−Si(Raa)3, wherein Raa is as defined herein.
[00355] The term“oxo” refers to the group =O, and the term“thiooxo” refers to the group =S.
[00356] Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen,−OH,−ORaa,−N(Rcc)2,−CN, −C(=O)Raa,−C(=O)N(Rcc)2,−CO2Raa,−SO2Raa,−C(=NRbb)Raa,−C(=NRcc)ORaa,
−C(=NRcc)N(Rcc)2,−SO2N(Rcc)2,−SO2Rcc,−SO2ORcc,−SORaa,−C(=S)N(Rcc)2,−C(=O)SRcc, −C(=S)SRcc,−P(=O)2Raa,−P(=O)(Raa)2,−P(=O)2N(Rcc)2,−P(=O)(NRcc)2, C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroC1-10alkyl, heteroC2-10alkenyl, heteroC2- 10alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Rcc groups attached to an N atom 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 Rdd groups, and wherein Raa, Rbb, Rcc and Rdd are as defined above.
[00357] In certain embodiments, the substituent present on the nitrogen atom is an nitrogen protecting group (also referred to herein as an“amino protecting group”). Nitrogen protecting groups include, but are not limited to,−OH,−ORaa,−N(Rcc)2,−C(=O)Raa,−C(=O)N(Rcc)2, −CO2Raa,−SO2Raa,−C(=NRcc)Raa,−C(=NRcc)ORaa,−C(=NRcc)N(Rcc)2,−SO2N(Rcc)2, −SO2Rcc,−SO2ORcc,−SORaa,−C(=S)N(Rcc)2,−C(=O)SRcc,−C(=S)SRcc, C1-10 alkyl (e.g., aralkyl, heteroaralkyl), C2-10 alkenyl, C2-10 alkynyl, heteroC1-10 alkyl, heteroC2-10 alkenyl, heteroC2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups, and wherein Raa, Rbb, Rcc and Rdd are as defined herein. 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, 3rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
[00358] For example, nitrogen protecting groups such as amide groups (e.g.,−C(=O)Raa) include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3- pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide, p-phenylbenzamide, o- nitophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N’- dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o- nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o- phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o- nitrocinnamide, N-acetylmethionine derivative, o-nitrobenzamide and o- (benzoyloxymethyl)benzamide.
[00359] Nitrogen protecting groups such as carbamate groups (e.g.,−C(=O)ORaa) 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- methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2- dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate
(TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-1- methylethyl carbamate (t-Bumeoc), 2-(2’- and 4’-pyridyl)ethyl carbamate (Pyoc), 2-(N,N- dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitobenzyl carbamate, p-bromobenzyl carbamate, p- chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3- dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4- dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2- triphenylphosphonioisopropyl carbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, m- chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5- benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4- dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p- decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl carbamate, o-(N,N- dimethylcarboxamido)benzyl carbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p’-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 1- methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate, 1-methyl-1-(3,5- dimethoxyphenyl)ethyl carbamate, 1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1- methyl-1-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4- (trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.
[00360] Nitrogen protecting groups such as sulfonamide groups (e.g.,−S(=O)2Raa) 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 (Ms), β- trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4’,8’- dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide,
trifluoromethylsulfonamide, and phenacylsulfonamide.
[00361] Other 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-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4- nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4- methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N- [(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7- dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-picolylamino N’- oxide, N-1,1-dimethylthiomethyleneamine, N-benzylideneamine, N-p- methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2- pyridyl)mesityl]methyleneamine, N-(N’,N’-dimethylaminomethylene)amine, N,N’- isopropylidenediamine, N-p-nitrobenzylideneamine, N-salicylideneamine, N-5- chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N- cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivative, N-diphenylborinic acid derivative, N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide,
diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt),
diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4- dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4- methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys).
[00362] In certain embodiments, the substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as an“hydroxyl protecting group”). Oxygen protecting groups include, but are not limited to,−Raa,−N(Rbb)2,−C(=O)SRaa,−C(=O)Raa, −CO2Raa,−C(=O)N(Rbb)2,−C(=NRbb)Raa,−C(=NRbb)ORaa,−C(=NRbb)N(Rbb)2,−S(=O)Raa, −SO2Raa,−Si(Raa)3,−P(Rcc)2,−P(Rcc)3,−P(=O)2Raa,−P(=O)(Raa)2,−P(=O)(ORcc)2, −P(=O)2N(Rbb)2, and−P(=O)(NRbb)2, wherein Raa, Rbb, and Rcc are as defined herein. 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, 3rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
[00363] Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl,
(phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p- methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2- methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2- (trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3- bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4- methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4- methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4- methoxypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1- (2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1- benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t- butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p- methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6- dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N- oxido, diphenylmethyl, p,p’-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α- naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p- methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4’- bromophenacyloxyphenyl)diphenylmethyl, 4,4′,4″-tris(4,5- dichlorophthalimidophenyl)methyl, 4,4′,4″-tris(levulinoyloxyphenyl)methyl, 4,4′,4″- tris(benzoyloxyphenyl)methyl, 3-(imidazol-1-yl)bis(4′,4″-dimethoxyphenyl)methyl, 1,1- bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10- oxo)anthryl, 1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxido, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS),
diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t- butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl,
diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), 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 (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec), 2-(triphenylphosphonio) ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, t-butyl carbonate (BOC or Boc), p- nitrophenyl carbonate, benzyl carbonate, p-methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzyl thiocarbonate, 4- ethoxy-1-napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4- nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2- (methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2- (methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4- (1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate, o- (methoxyacyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N’,N’- tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).
[00364] In certain embodiments, the substituent present on an sulfur atom is a sulfur protecting group (also referred to as a“thiol protecting group”). Sulfur protecting groups include, but are not limited to,−Raa,−N(Rbb)2,−C(=O)SRaa,−C(=O)Raa,−CO2Raa, −C(=O)N(Rbb)2,−C(=NRbb)Raa,−C(=NRbb)ORaa,−C(=NRbb)N(Rbb)2,−S(=O)Raa,−SO2Raa, −Si(Raa)3,−P(Rcc)2,−P(Rcc)3,−P(=O)2Raa,−P(=O)(Raa)2,−P(=O)(ORcc)2,−P(=O)2N(Rbb)2, and−P(=O)(NRbb)2, wherein Raa, Rbb, and Rcc are as defined herein. 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, 3rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
[00365] As used herein, a“leaving group” (LG) is an art-understood term referring to a molecular fragment that departs with a pair of electrons in heterolytic bond cleavage, wherein the molecular fragment is an anion or neutral molecule. As used herein, 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). Exemplary leaving groups include, but are not limited to, halo (e.g., chloro, bromo, iodo),−ORaa (when the O atom is attached to a carbonyl group, wherein Raa is as defined herein),−O(C=O)RLG, or−O(SO)2RLG (e.g., tosyl, mesyl, besyl), wherein RLG is optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl. In certain embodiments, the leaving group is a halogen. In certain embodiments, the leaving group is I.
[00366] As used herein, use of the 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.
[00367] A“non-hydrogen group” refers to any group that is defined for a particular variable that is not hydrogen. [00368] 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). The term“sugar” refers to monosaccharides, disaccharides, or polysaccharides. Monosaccharides are the simplest carbohydrates in that they cannot be hydrolyzed to smaller carbohydrates. Most monosaccharides can be represented by the general formula CyH2yOy (e.g., C6H12O6 (a hexose such as glucose)), wherein 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. For example, deoxyribose is of the formula C5H10O4 and is a monosaccharide. Monosaccharides usually consist of five or six carbon atoms and are referred to as pentoses and hexoses, receptively. If 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. Examples of aldotetrose sugars include erythrose and threose; and ketotetrose sugars include erythrulose. Aldopentose sugars include ribose, arabinose, xylose, and lyxose; and ketopentose sugars include ribulose, arabulose, xylulose, and lyxulose. Examples of 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. Each carbon atom of a monosaccharide bearing a hydroxyl group (−OH), with the exception of the first and last carbons, is asymmetric, making the carbon atom a stereocenter with two possible configurations (R or S). Because of this asymmetry, a number of isomers may exist for any given monosaccharide formula. The aldohexose D-glucose, for example, has the formula C6H12O6, of which all but two of its six carbons atoms are stereogenic, making D-glucose one of the 16 (i.e., 24) 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. During the conversion from the straight-chain form to the cyclic form, the carbon atom containing the carbonyl oxygen, called the anomeric carbon, 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. In an α anomer, the−OH substituent on the anomeric carbon rests on the opposite side (trans) of the ring from the −CH2OH side branch. The alternative form, in which the−CH2OH substituent and the anomeric hydroxyl are on the same side (cis) of the plane of the ring, is called a β anomer. A carbohydrate including two or more joined monosaccharide units is called a disaccharide or polysaccharide (e.g., a trisaccharide), respectively. The two or more monosaccharide units bound together by a covalent bond known as a glycosidic linkage formed via a dehydration reaction, resulting in the loss of a hydrogen atom from one monosaccharide and a hydroxyl group from another. 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. The term carbohydrate also includes other natural or synthetic stereoisomers of the carbohydrates described herein.
[00369] These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and claims. The invention is not intended to be limited in any manner by the above exemplary listing of substituents. Other definitions
[00370] As used herein, the term“salt” refers to any and all salts, and encompasses pharmaceutically acceptable salts.
[00371] The term“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. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate,
ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, 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 alkali metal, alkaline earth metal, ammonium, and N+(C1-4 alkyl)−
4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
[00372] The term“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. Conventional 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
pharmaceutically acceptable solvates and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances, 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.
[00373] The term“hydrate” refers to a compound that is associated with water. Typically, 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 H2O, 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 H2O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R⋅2 H2O) and hexahydrates (R⋅6 H2O)).
[00374] The term“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.
[00375] It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed“isomers”. Isomers that differ in the arrangement of their atoms in space are termed“stereoisomers”.
[00376] Stereoisomers that are not mirror images of one another are termed
“diastereomers” and those that are non-superimposable mirror images of each other are termed“enantiomers”. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. 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”.
[00377] The term“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.
[00378] The term“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. C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, aryl, C7-12 substituted aryl, and C7-C12 arylalkyl esters of the compounds described herein may be preferred.
[00379] The terms“composition” and“formulation” are used interchangeably.
[00380] 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. In certain embodiments, 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)). In certain embodiments, 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.
[00381] The term“administer,”“administering,” or“administration” refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a composition thereof, in or on a subject.
[00382] As used herein, and unless otherwise specified, 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”). [00383] In general, the“effective amount” of a compound refers to an amount sufficient to elicit the desired biological response. As will be appreciated by those of ordinary skill in this art, 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.
[00384] As used herein, and unless otherwise specified, 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.
[00385] As used herein, and unless otherwise specified, 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.
[00386] 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, pernicious anemia, inflammatory dermatoses, usual interstitial pneumonitis (UIP), asbestosis, silicosis, bronchiectasis, berylliosis, talcosis, pneumoconiosis, sarcoidosis, desquamative interstitial pneumonia, lymphoid interstitial pneumonia, giant cell interstitial pneumonia, cellular interstitial pneumonia, extrinsic allergic alveolitis, Wegener’s granulomatosis and related forms of angiitis (temporal arteritis and polyarteritis nodosa), inflammatory dermatoses, hepatitis, delayed-type hypersensitivity reactions (e.g., poison ivy dermatitis), pneumonia, respiratory tract inflammation, Adult Respiratory Distress Syndrome (ARDS), encephalitis, immediate hypersensitivity reactions, asthma, hayfever, allergies, acute anaphylaxis, rheumatic fever, glomerulonephritis, pyelonephritis, cellulitis, cystitis, chronic cholecystitis, ischemia (ischemic injury), reperfusion injury, allograft rejection, host-versus-graft rejection, appendicitis, arteritis, blepharitis, bronchiolitis, bronchitis, cervicitis, cholangitis,
chorioamnionitis, conjunctivitis, dacryoadenitis, dermatomyositis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, gingivitis, ileitis, iritis, 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, uveitis, vaginitis, vasculitis, vulvitis, vulvovaginitis, angitis, chronic bronchitis, osteomyelitis, optic neuritis, temporal arteritis, transverse myelitis, necrotizing fasciitis, and necrotizing enterocolitis. An ocular inflammatory disease includes, but is not limited to, post-surgical inflammation. EXAMPLES
[00387] In order that the invention described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope. Synthesis of Lincosamide Analogues [00388] General Experimental Procedures: All reactions were performed in oven- or flame-dried round-bottomed or modified Schlenk flasks fitted with rubber septa under a positive pressure of argon (dried by passage through a column of Drierite calcium sulfate desiccant), unless otherwise noted. Air- and moisture-sensitive liquids and solutions were transferred via syringe or stainless steel cannula. When necessary (so noted), solutions were deoxygenated by three cycles of freezing (liquid nitrogen), evacuation, and thawing under static vacuum. Organic solutions were concentrated by rotary evaporation (house vacuum, ~60 Torr) at 23–30 °C. Flash-column chromatography was performed as described by Still et al., (Still, W. C.; Kahn, M.; Mitra, A., J. Org. Chem.1978, 43 (14), 2923–2925), employing silica gel (60-Å pore size, 230–400 mesh, Agela Technologies, Chicago, IL; or RediSep silica cartridges, Teledyne Isco, Lincoln, NE). Analytical thin-layer chromatography (TLC) was performed using glass plates pre-coated with silica gel (0.25 mm, 60-Å pore size, 230–400 mesh, Merck KGA) impregnated with a fluorescent indicator (254 nm). In special cases (so noted), analytical TLC was performed with aminopropyl-modified silica gel (NH2 silica gel, 60-Å 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 (I2), basic aqueous potassium permanganate solution (KMnO4), 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). In some cases, reaction monitoring was carried out by analytical liquid chromatography–mass spectrometry (LCMS), or by flow-injection analysis–high- resolution mass spectrometry (FIA-HRMS).
[00389] Materials: Commercial reagents and solvents were used as received, unless mentioned otherwise. Dichloromethane, diethyl ether, tetrahydrofuran, 1,4-dioxane, N,N- dimethylformamide, toluene, and benzene were purified by passage through Al2O3 under argon, according to the method of Pangborn et al. (Pangborn, A. B.; Giardello, M. A.;
Grubbs, R. H.; Rosen, R. K.; Timmers, F. J. Organometallics 1996, 15 (5), 1518–1520) Ethynyltriisopropylsilane, triethylphosphonoacetate, 1,8-diazabicyclo[5.4.0]undec-7-ene, (–)- diethyl-D-tartrate, tert-butyldiphenylchlorosilane, imidazole, trimethyl phosphite, sodium triacetoxyborohydride, trifluoroacetic acid, 1-[2- (trimethylsilyl)ethoxycarbonyloxy]pyrrolidin-2,5-dione (Teoc-OSu), Oxone monopersulfate compound, and HATU were purchased from Oakwood Products, Inc. (Estill, SC, USA). Tungsten hexacarbonyl (99%, <0.3% molybdenum) was purchased from Strem Chemicals, Inc. (Newburyport, MA, USA). N-Boc-β-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. (Monmouth Jct., NJ, USA).4- Pyridin-3-ylaniline was purchased from Maybridge Chemical Company (Altrincham, UK).4- Ethynylpyrimidin-2-amine was prepared according to literature procedures (Tibiletti, F.; Simonetti, M.; Nicholas, K. M.; Palmisano, G.; Parravicini, M.; Imbesi, F.; Tollari, S.;
Penoni, A. Tetrahedron 2010, 66 (6), 1280–1288.). All other chemicals and reagents were purchased from Sigma-Aldrich Corporation (Natick, MA, USA).
[00390] Instrumentation: Proton nuclear magnetic resonance (1H NMR) spectra and carbon nuclear magnetic resonance (13C NMR) spectra were recorded on Varian Mercury 400 (400 MHz/100 MHz), Varian Inova 500 (500 MHz/125 MHz), or Varian Inova 600 (600 MHz/150 MHz) NMR spectrometers at 23 °C. Proton chemical shifts are expressed in parts per million (ppm, δ scale) and are referenced to residual protium in the NMR solvent (CHCl3, δ 7.26; CHD3OD, δ 3.31; C6H5D, δ 7.16). Carbon chemical shifts are expressed as parts per million (ppm, δ scale) and are referenced to the carbon resonance of the NMR solvent (CDCl3, δ 77.2; CD3OD, δ 49.0; C6D6, δ 128.1). Data are reported as follows: Chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, qn = quintet, dd = doublet of doublets, td = triplet of doublets, ABq = AB quartet, m = multiplet, br = broad, app = apparent), integration, and coupling constant (J) in Hertz (Hz). Infrared transmittance (IR) spectra were obtained using a Bruker ALPHA FTIR spectrophotometer referenced to a polystyrene standard. Data are represented as follows: Frequency of absorption (cm–1), and intensity (s = strong, m = medium, br = broad). Melting points were determined using a Thomas Scientific capillary melting point apparatus. High-resolution mass spectrometry (including FIA-HRMS reaction monitoring) was performed at the Harvard University Mass Spectrometry Facility using a Bruker micrOTOF-QII mass spectrometer. X-ray
crystallographic analysis was performed at the Harvard University X-Ray Crystallographic Laboratory by Dr. Shao-Liang Zheng. Ultra high-performance liquid chromatography–mass spectrometry (LCMS) was performed using an Agilent Technologies 1260-series analytical HPLC system in tandem with an Agilent Technologies 6120 Quadrupole mass spectrometer; a Zorbax Eclipse Plus reverse-phase C18 column (2.1 × 50 mm, 1.8 µm pore size, 600 bar rating; Agilent Technologies, Santa Clara, CA) was employed as stationary phase. LCMS samples were eluted at a flow rate of 650 µL/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).
Figure imgf000144_0001
[00391] To a solution of ethynyltriisopropylsilane (1, 20.0 g, 110 mmol, 1 equiv) in diethyl ether (100 mL) was added n-butyllithium solution (2.12 M in hexane, 51.7 mL, 110 mmol, 1.00 equiv) slowly by cannula at 0 °C over approximately 15 min. The resulting solution was stirred at 0 °C for an additional 40 min. 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). The resulting biphasic mixture was stirred at 0 °C for 1 h, and then the layers were separated. The aqueous phase was extracted with diethyl ether (3 × 150 mL), and the combined organic extracts were washed with saturated aqueous sodium chloride solution (150 mL). The washed organic solution was dried over sodium sulfate, the dried solution was filtered, and the filtrate was concentrated to give 3- (triisopropylsilyl)propiolaldehyde (2) as a colorless oil that was used in the next step without further purification. The 1H NMR data matched literature values.
[00392] An oven-dried 2-L round-bottomed flask was charged with lithium chloride (5.60 g, 132 mmol, 1.20 equiv), and the apparatus was flame-dried. Once cooled, the flask was charged with a magnetic stir bar and acetonitrile (1.3 L), and the resulting suspension was stirred at 23 °C for 10 min (lithium chloride does not fully dissolve).3- (Triisopropylsilyl)propriolaldehyde (2, theoretically 110 mmol, 1 equiv) and triethyl phosphonoacetate (22.5 mL, 112 mmol, 1.02 equiv) were then added sequentially.1,8- Diazabicyclo[5.4.0]undec-7-ene (DBU, 16.6 mL, 110 mmol, 1.00 equiv) was added dropwise over 5 min, causing the mixture to warm to approximately 40 °C with concomitant transformation of the originally colorless reaction solution to an opaque, off-white suspension. Progress was monitored by TLC (20% dichloromethane–hexanes, UV+PAA); after 10 min, the reaction was judged to be complete. The mixture was concentrated by rotary evaporation to a volume of approximately 300 mL, and the concentrated mixture was transferred to a separatory funnel containing saturated aqueous ammonium chloride solution (400 mL) and diethyl ether (300 mL). The mixture was shaken, and the layers were separated. The aqueous phase was extracted with diethyl ether (3 × 300 mL); the combined organic layers were then washed sequentially with water (250 mL) and saturated aqueous sodium chloride solution (250 mL). The washed organic solution was dried over sodium sulfate, the dried solution was filtered, and the filtrate was concentrated to give ethyl (E)-5- (triisopropylsilyl)pent-2-en-4-ynoate as a colorless oil that was used in the next step without further purification. The 1H NMR data matched literature values.
[00393] To a rapidly stirred solution of crude ethyl (E)-5-(triisopropylsilyl)pent-2-en-4- ynoate (theoretically 110 mmol, 1 equiv) in diethyl ether (220 mL) was added diisobutyl aluminum hydride (1.0 M solution in hexane, 243 mL, 2.2 equiv) by cannula at–78 °C. The mixture was stirred at–78 °C for 1 h, then at 0 °C for 1.5 h. The 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. 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. The mixture was stirred at 23 °C overnight under an atmosphere of nitrogen gas, during which time the emulsion separated into a biphasic mixture. The layers were separated at the end of this period, and the aqueous phase was extracted with diethyl ether (3 × 200 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 light yellow oil. This residue was purified by flash-column
chromatography (500 g silica gel, eluting with 5% ethyl acetate–hexanes initially, grading to 10% ethyl acetate–hexanes) to afford allylic alcohol 3 as a colorless oil (19.7 g, 75%, 3 steps). The 1H NMR data matched literature values.
Figure imgf000145_0001
[00394] 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-Å 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. (–)-Diethyl-D-tartrate (7.21 mL, 41.9 mmol, 0.500 equiv) was added. Titanium(IV) isopropoxide (9.83 mL, 33.6 mmol, 0.400 equiv) was then added dropwise over 2 min, causing the internal temperature to rise to–26 °C briefly. The resulting mixture was stirred at–30 °C for 20 min, after which time a solution of allylic alcohol 3 (20.0 g, 84.0 mmol, 1 equiv) in dichloromethane (295 mL) was added slowly by cannula over 10 min. The mixture was incubated at–30 °C for 30 min. tert-Butylhydroperoxide solution (TBHP, ~5.5 M solution in decane, 30.5 mL, 170 mmol, 2.0 equiv) was finally added at a rate of 2.0 mL/min with 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. A solution comprising iron(II) sulfate heptahydrate (27 g, 97 mmol, 1.2 equiv), DL-tartaric acid (62 g, 0.41 mol, 4.9 equiv), and water (517 mL) was added to the reaction mixture, and the resulting biphasic mixture was stirred at 0 °C for 10 min at a moderate stir rate (350 rpm) The mixture was then transferred to a separatory funnel where the layers were separated. The aqueous phase was extracted with diethyl ether (3 × 300 mL), and the combined organic layers were washed with saturated aqueous sodium chloride solution (2 × 200 mL). The washed organic solution was dried over sodium sulfate, the dried solution was filtered, and the filtrate was concentrated to give a slightly cloudy colorless oil. This residue was purified by flash-column chromatography (800 g silica gel, eluting with 5% ethyl acetate–hexanes initially, grading to 15% ethyl acetate–hexanes) to give epoxyalcohol 4 as a colorless, viscous oil (14.9 g, 70%). The 1H NMR data matched reported values.
[00395] The enantiomeric excess was determined by conversion to the corresponding Mosher esters. In this procedure, a solution of epoxyalcohol 4 (10 mg, 39 µmol, 1 equiv) in 4:1 dichloromethane–pyridine (200 µL) was treated with (R)-3,3,3-trifluoro-2-methoxy-2- phenylpropanoyl chloride (8.8 µL, 47 µmol, 1.2 equiv) at 23 °C. The mixture was stirred at 23 °C for 30 min, at which point TLC analysis (50% ethyl acetate–hexanes, UV+KMnO4) indicated complete consumption of starting material. The reaction mixture was concentrated, and the crude residue was subjected to 1H NMR analysis (600 MHz, CDCl3). Integration of the major methylene resonance at δ 4.60 (dd, J = 12.3, 3.2 Hz, 1H) relative to its minor diastereomeric counterpart at δ 4.66 (dd, J = 12.5, 3.0 Hz, 1H, derived from undesired (2S,3S)-product enantiomer) demonstrated an enantiomeric ratio of 94:6 (88% ee). Use of the enantiomeric (S)-Mosher acyl chloride reagent gave the same result.
Figure imgf000147_0001
[00396] A solution of epoxyalcohol 4 (14.9 g, 58.6 mmol, 1 equiv) in dichloromethane (468 mL) and anhydrous dimethyl sulfoxide (117 mL) was treated with triethylamine (65.3 mL, 468 mmol, 8.00 equiv). Sulfur trioxide–pyridine complex (37.3 g, 234 mmol, 4.00 equiv) was then added in three portions over 15 min at 23 °C. The resulting salmon-pink solution was stirred at 23 °C, and after 2 h, TLC analysis (30% ethyl acetate–hexanes, PAA) indicated complete consumption of starting material. 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. This residue was purified by flash-column chromatography (600 g silica gel, eluting with 5% ethyl acetate–hexanes initially, grading to 10% ethyl acetate–hexanes) to afford 5 as a colorless oil (12.0 g, 81%).1H NMR (500 MHz, CDCl3): δ 9.02 (d, J = 6.1 Hz, 1H), 3.69 (d, J = 1.8 Hz, 1H), 3.54 (dd, J = 6.1, 1.8 Hz, 1H), 1.07 (s, 21H).
Figure imgf000147_0002
[00397] Acetyl chloride (123 mL, 1.73 mol, 12.8 equiv) was added dropwise over 15 min to a solution of (R)-1-nitropropan-2-yl acetate (6, 20.0 g, 136 mmol, 1 equiv) in methanol (1.23 L) at 0 °C. Following the addition of acetyl chloride, the mixture was allowed to warm to 23 °C; progress was monitored by TLC (40% ethyl acetate–hexanes, KMnO4). After 2 h, complete consumption of starting material was noted, and the mixture was concentrated by rotary evaporation to obtain (R)-1-nitropropan-2-ol as a faint yellow oil. Residual methanol present in the crude product was removed azeotropic removal of benzene. The crude product thus obtained was used in the next step without further purification.
[00398] To a solution of (R)-1-nitropropan-2-ol (theoretically 136 mmol) in 1:2
dichloromethane–hexane (412 mL) was added benzyl 2,2,2-trichloroacetimidate (30.5 mL, 163 mmol, 1.20 equiv). Trifluoromethanesulfonic acid (1.21 mL, 13.6 mmol, 0.100 equiv) was then added dropwise over 30 min at 23 °C, causing a white precipitate to appear. After 5 h, TLC analysis (20% ethyl acetate–hexanes, UV+KMnO4) indicated that all starting material had been consumed. 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 1H 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 Rt = 14.7 min, minor enantiomer Rt = 11.7 min.
Figure imgf000148_0001
[00399] To a mixture of (R,R)-diaminocyclohexane ligand 8 (1.75 g, 47.5 mmol, 0.0100 equiv), and anhydrous copper(II) acetate (863 mg, 4.75 mmol, 0.0100 equiv) was added 1,4- dioxane (47.5 mL mL). The resulting dark forest-green solution was stirred at 23 °C for 30 min before N,N-diisopropylethylamine (830 µL, 4.75 mmol, 0.0100 equiv) was added. The catalyst mixture was then stirred an additional 10 min at 23 °C before cooling to 5–10 °C in an ice-water bath. 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 µL) were diluted with ethyl acetate (2 mL), and the diluted samples were washed with saturated aqueous ammonium chloride solution (1 mL). The washed samples were then dried by passage through a short plug of sodium sulfate (1 × 2 cm), and the dried filtrate was concentrated. The green-brown residue thus obtained was analyzed by 1H NMR (CDCl3), where consumption of aldehyde 5 was gauged relative to the triisopropylsilyl signal (δ 1.15– 1.00, 21H). After 48 h at 4 °C, conversion of aldehyde 5 had reached≥95%, and
triethylamine (13.3 mL, 95.0 mmol, 2.00 equiv) was added to induce cyclization. The mixture was warmed to 23 °C and stirred for 20 h, whereupon aliquot NMR analysis (as above) showed the absence of epoxide methine resonances (ca. δ 3.45, 3.30), with
concomitant formation of isoxazoline N-oxide products as a 98:2 diastereomeric mixture. The product mixture was poured into a separatory funnel containing 175 mL saturated aqueous ammonium chloride solution, and the resulting mixture was extracted with ethyl acetate (3 × 150 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (50 mL), and the washed organic phase was dried over sodium sulfate. The dried product solution was filtered, and the filtrate was concentrated to afford crude product as a dark brown oil. This residue was purified by flash-column chromatography (2.0 kg silica; eluting 10% ethyl acetate–hexanes initially, grading to 30% ethyl acetate–hexanes) to afford the isoxazoline N-oxide 9 as an amber-brown, viscous oil (16.4 g, 77%).1H NMR (600 MHz, CDCl3): δ 7.37–7.29 (m, 5H), 5.14 (app t, J = 6.9 Hz, 1H), 4.77 (app t, J = 5.4 Hz, 1H), 4.66 (d, J = 12.1 Hz, 1H), 4.63 (q, J = 6.7 Hz, 1H), 4.43 (d, J = 12.2 Hz, 1H), 3.92 (dd, J = 6.7, 5.6 Hz, 1H), 3.60 (d, J = 7.2 Hz, 1H), 3.35 (d, J = 5.8 Hz, 1H), 1.49 (d, J = 6.7 Hz, 3H), 1.09 (br s, 21H). HRMS (ESI+, m/z): [M+H]+ calcd for C24H37NO5Si, 448.2514; found 448.2529.
Figure imgf000149_0001
[00400] A solution of tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 88 mL, 88 mmol, 2.5 equiv) was added via cannula over 5 min to a solution of alkynyl silane 9 (15.8 g, 35.3 mmol, 1 equiv) in tetrahydrofuran (118 mL) at 0 °C. The mixture was then warmed to 23 °C, and after 90 min of stirring at this temperature, TLC analysis (50% ethyl acetate– hexanes, UV+KMnO4) indicated full conversion of starting material. 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. This residue was purified by flash-column chromatography (500 g silica; eluting 35% ethyl acetate–hexanes initially, grading to 50% ethyl acetate–hexanes) to afford alkyne 10 as a sand-colored, powdery solid (9.38 g, 91%).1H NMR (600 MHz, CDCl3): δ 7.37–7.29 (m, 5H), 5.22 (d, J = 6.7 Hz, 1H), 4.77 (dd, J = 6.3, 2.3 Hz, 1H), 4.61 (q, J = 6.7 Hz, 1H), 4.60 (d, J = 12.2 Hz, 1H), 4.45 (d, J = 12.1 Hz, 1H), 4.06 (app t, J = 6.5 Hz, 1H), 4.03 (br s, 1H), 2.59 (d, J = 2.2 Hz, 1H), 1.48 (d, J = 6.7 Hz, 3H). HRMS (ESI+, m/z): [M+Na]+ calcd for C15H17NO5, 314.0999; found 314.1009.
Figure imgf000150_0001
[00401] A mixture of diol 10 (9.38 g, 32.2 mmol, 1 equiv) and imidazole (6.58 g, 97.0 mmol, 3.00 equiv) was dissolved in dichloromethane (161 mL), and the resulting solution was cooled to 0 °C. tert-Butyl(chloro)diphenylsilane (12.4 mL, 48.3 mmol, 1.50 equiv) was then added in one portion, and the solution was warmed to 23 °C. Within 2–5 min of addition of the silyl chloride, a precipitate formed, imparting a cloudy appearance to the reaction mixture. Progress was monitored by TLC (60% ethyl acetate–hexanes, UV+KMnO4), and after 45 min, full consumption of starting material was observed. The reaction mixture was quenched with the addition of 150 mL saturated aqueous sodium bicarbonate solution, and the mixture was stirred rapidly at 23 °C for 10 min. The biphasic mixture was then extracted with dichloromethane (3 × 50 mL), and the combined organic extracts were washed with brine (50 mL). The organic solution was then dried over sodium sulfate, and the dried solution was filtered. 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%).1H NMR (500 MHz, CDCl3): δ 7.75–7.68 (m, 4H), 7.49–7.44 (m, 2H), 7.43–7.28 (m, 9H), 5.17 (app t, J = 7.6 Hz, 1H), 4.72 (dd, J = 4.6, 2.2 Hz, 1H), 4.66 (q, J = 6.8 Hz, 1H), 4.64 (d, J = 12.2 Hz, 1H), 4.46 (d, J = 12.1 Hz, 1H), 4.02 (dd, J = 6.9, 4.7 Hz, 1H), 3.59 (d, J = 8.3 Hz, 1H), 2.45 (d, J = 2.3 Hz, 1H), 1.50 (d, J = 6.8 Hz, 3H), 1.09 (s, 9H). HRMS (ESI+, m/z): [M+Na]+ calcd for C31H35NO5Si, 552.2177; found 552.2177.
Figure imgf000151_0001
[00402] A 500-mL round-bottomed flask was charged with isoxazoline N-oxide 11 (15.7 g, 29.6 mmol), and this substrate was dried by azeotropic removal of benzene. Once dried, the starting material was dissolved in trimethyl phosphite (119 mL; CAUTION: Trimethyl phosphite is a highly malodorous, volatile substance– all operations up to and including the aqueous acid quench should be carried out in a well-ventilated fume hood), and the flask was sealed. 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
hydrochloric acid solution (2 × 75 mL). The combined aqueous washes were extracted with fresh portions of diethyl ether (2 × 75 mL). The combined organic phases were then washed sequentially with half-saturated aqueous sodium chloride solution (50 mL), and saturated aqueous sodium chloride solution (50 mL). The organic layer was then dried over sodium sulfate, the dried solution was filtered, and the filtrate was concentrated to afford crude product as a light yellow oil. The crude material was purified by flash-column
chromatography (700 g silica; eluting with 5% ethyl acetate–hexanes initially, grading to 25% ethyl acetate–hexanes) to provide the isoxazoline 12 as a light peach-colored, highly viscous oil (11.5 g, 75%).1H NMR (600 MHz, CDCl3): δ 7.79–7.76 (m, 4H), 7.50–7.46 (m, 2H), 7.44–7.41 (m, 4H), 7.37–7.34 (m, 4H), 7.32–7.29 (m, 1H), 5.28 (app t, J = 8.3 Hz, 1H), 4.88 (dd, J = 4.0, 2.3 Hz, 1H), 4.58 (q, J = 6.8 Hz, 1H), 4.56 (d, J = 12.3 Hz, 1H), 4.53 (d, J = 12.0 Hz, 1H), 4.23 (d, J = 8.2, 4.0 Hz, 1H), 4.15 (d, J = 8.6 Hz, 1H), 2.48 (d, J = 2.3 Hz, 1H), 1.59 (d, J = 6.8 Hz, 3H), 1.10 (s, 9H). HRMS (ESI+, m/z): [M+H]+ calcd for C31H35NO4Si, 514.2408; found 514.2424.
Figure imgf000152_0001
[00403] A mixture of isoxazoline 12 (11.4 g, 22.1 mmol, 1 equiv) and sodium
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. Progress was monitored by TLC (30% ethyl acetate–hexanes, UV+PAA), and after 2.5 h, starting material was fully consumed. The mixture was cooled to 0 °C, and was then transferred via cannula to a stirred, ice-cold mixture of dichloromethane (300 mL) and 2N aqueous sodium hydroxide solution (1.10 L, 2.21 mol). The resulting biphasic mixture was stirred rapidly for 10 min. Additional sodium hydroxide solution was added as necessary, until the aqueous phase attained pH > 8. The mixture was then transferred to a separatory funnel, and the layers were separated. The aqueous layer was extracted with dichloromethane (3 × 300 mL), and the combined organic extracts were washed with brine (300 mL). The washed organic layer was dried over sodium sulfate, the dried solution was filtered, and the filtrate was concentrated to afford crude isoxazolidine 13 as a colorless oil. This material was used in the next step without further purification.
[00404] For characterization purposes, a small quantity (ca.25 mg) of crude residue was purified by HPLC (eluting with 0.1% trifluoroacetic acid–25% acetonitrile–water, grading to 0.1% trifluoroacetic acid–95% acetonitrile–water over 45 min, with a flow rate of 15 mL/min; monitored by UV absorbance at 254 nm; product Rt = 33.5 min). The trifluoroacetic acid salt thus obtained (13• CF3CO2H) exhibited the following spectral properties: 1H NMR (600 MHz, CDCl3) δ 7.76–7.69 (m, 4H), 7.48–7.43 (m, 2H), 7.42–7.28 (m, 9H), 4.91 (dd, J = 5.1, 2.8 Hz, 1H), 4.74 (dd, J = 4.9, 2.2 Hz, 1H), 4.66 (d, J = 11.5 Hz, 1H), 4.40 (d, J = 11.6 Hz, 1H), 3.98 (app t, J = 5.0 Hz, 1H), 3.81 (m, 1H), 3.51 (app t, J = 3.3 Hz, 1H), 2.40 (d, J = 2.2 Hz, 1H), 1.39 (d, J = 6.2 Hz, 3H), 1.09 (s, 9H). HRMS (ESI+, m/z): [M+Na]+ calcd for C31H37NO4Si, 538.2384; found 538.2385.
Figure imgf000153_0001
[00405] A 200-mL round-bottomed flask was charged with isoxazolidine 13 (crude product from the preceding directed reduction step, theoretically 22.1 mmol). The starting material was dissolved in 1,4-dioxane (55 mL) and to the resulting solution, triethylamine (15.4 mL, 110 mmol, 5.00 equiv) and N-[2-(trimethylsilyl)ethoxycarbonyloxy]succinimide (Teoc-OSu, 8.59 g, 33.1 mmol, 1.50 equiv) were added sequentially. The reaction mixture was heated to 40 °C, and consumption of starting material was monitored by LCMS. After 16 h, the 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). 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. This material 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).1H NMR (600 MHz, CDCl3): δ 7.78–7.74 (m, 4H), 7.48–7.44 (m, 2H), 7.42– 7.36 (m, 4H), 7.35–7.27 (m, 5H), 4.90 (app t, J = 3.8 Hz, 1H), 4.79 (dd, J = 6.2, 2.2 Hz, 1H), 4.67 (d, J = 11.8 Hz, 1H), 4.48 (d, J = 11.8 Hz, 1H), 4.25–4.12 (m, 4H), 3.65 (app p, J = 6.3 Hz, 1H), 3.31 (d, J = 3.9 Hz, 1H), 2.36 (d, J = 2.2 Hz, 1H), 1.33 (d, J = 6.2 Hz, 3H), 1.10 (s, 9H), 1.05–0.94 (m, 2H), 0.04 (s, 9H). HRMS (ESI+, m/z): [M+H]+ calcd for C37H49NO6Si2, 660.3171; found 660.3161.
Figure imgf000154_0001
[00406] In a 200-mL round-bottomed flask, alkynol 14 (4.17 g, 6.32 mmol, 1 equiv) was dried by azeotropic removal of benzene under vacuum. 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
photochemistry safety cabinet. A positive pressure of dry argon was maintained via tubing connected to an argon-filled balloon placed outside of the lightbox. The reaction mixture was refluxed with constant UV irradiation from an adjacent 200-Watt mercury-vapor bulb filtered through a water-cooled Pyrex glass jacket (CAUTION: Exposure to high-intensity UV light can cause irreversible vision loss– never open the safety cabinet when the UV lamp is on.). Progress was monitored by TLC (20% ethyl acetate–hexanes, UV+KMnO4). After 3 d, full consumption of the alkynol substrate was achieved, and the crude product mixture was concentrated under a stream of dry nitrogen. 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%).1H NMR (500 MHz, CDCl3): 7.77–7.74 (m, 2H), 7.70–7.67 (m, 2H), 7.44–7.38 (m, 2H), 7.37–7.31 (m, 4H), 7.27– 7.23 (m, 3H), 7.22–7.19 (m, 2H), 6.10 (dd, J = 6.4, 2.3 Hz, 1H), 4.67 (app dt, J = 6.5, 1.9 Hz, 1H), 4.62 (d, J = 2.9 Hz, 1H), 4.56–4.51 (m, 2H), 4.36 (d, J = 11.7 Hz, 1H), 4.36–4.31 (m, 1H), 4.24 (td, J = 10.4, 6.9 Hz, 1H), 4.20 (app dt, J = 4.6, 2.3 Hz, 1H), 4.10 (d, J = 5.1 Hz, 1H), 3.72 (app p, J = 6.2 Hz, 1H), 1.27 (d, J = 6.4 Hz, 3H), 1.08 (s, 9H), 0.07 (s, 9H). HRMS (ESI+, m/z): [M+H]+ calcd for C37H49NO6Si2, 660.3171; found 660.3164.
Figure imgf000155_0001
[00407] A solution of glycal 15 (1.45 g, 2.20 µmol, 1 equiv) in dichloromethane (22.0 mL) was cooled to 0 °C, whereupon dimethyldioxirane solution (0.0997 M, 26.4 mL, 2.64 µmol, 1.20 equiv) was added dropwise over 1 min. The reaction mixture was stirred at 0 °C for 15 min, at which point TLC analysis (20% ethyl acetate–hexanes, UV+PAA) indicated full consumption of starting material. The mixture was then concentrated under a stream of dry argon, and the residue was dried by azeotropic removal of benzene to afford glycal epoxide 16 as a colorless oil that was suitable for use without further purification (quantitative yield, ≥95% purity by NMR).1H NMR (500 MHz, C6D6) δ 7.89–7.83 (m, 2H), 7.77–7.71 (m, 2H), 7.21–7.09 (m, 7H), 7.08–7.00 (m, 4H), 4.66 (dd, J = 2.6, 1.0 Hz, 1H), 4.42 (d, J = 5.1 Hz, 1H), 4.34–4.21 (m, 4H), 4.21 (d, J = 11.8 Hz, 1H), 4.12–4.08 (m, 1H), 4.05 (d, J = 11.8 Hz, 1H), 3.56 (app p, J = 6.2 Hz, 1H), 2.97–2.92 (m, 1H), 1.19 (d, J = 0.7 Hz, 9H), 0.95 (d, J = 6.4 Hz, 3H), 0.91 (ddd, J = 9.4, 6.7, 3.9 Hz, 2H),–0.11 (d, J = 0.7 Hz, 9H). HRMS (ESI+, m/z): [M+H]+ calcd for C37H49NO7Si2, 676.3120; found 676.3118.
Figure imgf000155_0002
[00408] An oven-dried 100-mL round-bottom flask was charged with a stir bar and divinylzinc solution (0.15 M solution in tetrahydrofuran–dioxane, 21.7 mL, 3.3 mmol, 2.3 equiv; prepared according to the method of Brubaker and Myers;17 titrated according to the method of Krasovskiy and Knochel18). This solution was chilled to 0 °C, and trifluoroacetic acid (250 µL, 3.3 mmol, 2.3 equiv) was then added dropwise. The resulting solution was stirred for 30 min at 0 °C prior to use.
[00409] In a separate 100-mL round-bottom flask, 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. The resulting solution was stirred at 0 °C for 4 h, at which point TLC analysis (NH2 silica gel, 20% ethyl acteate–hexanes + 2% methanol, UV+CAM) indicated full consumption of epoxide starting material. The reaction was quenched with the addition of 35 mL of saturated aqueous ammonium chloride solution, and the resulting biphasic mixture was stirred for 10 min. The layers were then separated, and the aqueous phase was extracted with dichloromethane (3 × 20 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution, and the washed organic product solution was dried over sodium sulfate. The dried solution was filtered, and the filtrate was concentrated to afford crude product as a faint yellow oil. The product was purified by flash-column chromatography (40 g silica, eluting with 5% ethyl acetate–hexanes initially, grading to 20% ethyl acetate–hexanes) to afford 17 as a colorless oil (846 mg, 1.20 mmol, 85%).1H NMR (600 MHz, C6D6) δ 7.96–7.94 (m, 2H), 7.83–7.79 (m, 2H), 7.22–7.19 (m, 2H), 7.18–7.16 (m, 1H), 7.15–7.11 (m, 4H), 7.07–7.00 (m, 4H).5.74 (ddd, J = 17.6, 11.0, 4.1 Hz, 1H), 5.20 (app dt, J = 17.6, 2.1 Hz, 1H), 4.95 (app dt, J = 11.1, 2.1 Hz, 1H), 4.57 (app dt, J = 9.7, 5.0 Hz, 1H), 4.53 (d, J = 2.4 Hz, 1H), 4.50 (app ddt, J = 6.1, 4.3, 2.2 Hz, 1H), 4.40 (d, J = 5.4 Hz, 1H), 4.33 (app td, J = 10.3, 6.5 Hz, 1H), 4.30–4.25 (m, 2H), 4.23 (app t, J = 3.0 Hz, 1H), 4.09 (d, J = 11.8 Hz, 1H), 4.01 (dd, J = 9.7, 3.6 Hz, 1H), 3.60 (app qn, J = 6.2 Hz, 1H), 1.71 (d, J = 4.2 Hz, 1H), 1.18 (s, 9H), 1.07 (d, J = 6.3 Hz, 3H), 0.97–0.91 (m, 2H),– 0.09 (s, 9H). HRMS (ESI+, m/z): [M+H]+ calcd for C39H53NO7Si2, 704.3433; found
704.3418.
Figure imgf000156_0001
[00410] In a 10-mL round-bottomed flask, isoxazolidine 17 (150 mg, 213 µmol, 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). While cleavage of the 2-(trimethylsilyl)ethyl carbamoyl protecting group is rapid, the tert-butyldiphenylsilyl ether group is less labile– after 2 h of stirring at 0 °C, LCMS analysis showed that global desilylation was complete, and the reaction mixture was treated with saturated aqueous sodium bicarbonate solution (2 mL) and saturated aqueous sodium chloride solution (5 mL). This mixture was extracted with dichloromethane (3 × 10 mL), and the combined extracts were dried directly over sodium sulfate. The dried solution was then filtered, the filtrate was concentrated, and the crude residue was purified by flash- column chromatography (12 g silica gel, eluting with dichloromethane initially, grading to 10% methanol–dichloromethane) to furnish isoxazolidine diol 18 as a viscous, colorless oil (66.4 mg, 97%).
[00411] In its free-base form, this product displayed substantial 1H- and 13C-NMR peak broadening, likely owing to a nitrogen inversion process occurring on the NMR timescale. Thus, for NMR characterization purposes, the product was converted to its hydrochloride-salt form by treating an ice-cold solution of free base (61 mg, 190 µmol, 1 equiv) in methanol (5.0 mL) with hydrogen chloride solution (4.0 M in 1,4-dioxane, 190 µL, 760 µmol, 4.0 equiv). The mixture was then concentrated in vacuo to provide the hydrochloride salt 18• HCl as a white solid.1H NMR (hydrochloride salt, 500 MHz, CD3OD) δ 7.39–7.33 (m, 4H), 7.30–7.27 (m, 1H), 6.09 (ddd, J = 17.4, 10.8, 5.2 Hz, 1H), 5.43 (app dt, J = 17.4, 1.9 Hz, 1H), 5.40 (app dt, J = 10.1, 1.8 Hz, 1H), 5.01 (dd, J = 3.4, 2.1 Hz, 1H), 4.71–4.70 (m, 1H), 4.67 (d, J = 11.1 Hz, 1H), 4.57–4.55 (m, 1H), 4.53 (d, J = 11.1 Hz, 1H), 4.14 (app t, J = 2.5 Hz, 1H), 4.09 (qd, J = 6.2, 3.0 Hz, 1H), 3.96–3.95 (m, 2H), 1.40 (d, J = 6.3 Hz, 3H). HRMS (ESI+, m/z): [M+H]+ calcd for C17H23NO5, 322.1649; found 322.1658.
Figure imgf000157_0001
[00412] In a 10-mL round-bottomed flask, isoxazolidine 18 (67.6 mg, 0.189 mmol, 1 equiv) was dissolved methanol (1.00 mL), and the solution was treated with hydrogen chloride solution (4.0 M in 1,4-dioxane, 190 µL, 4.0 equiv). The mixture was then
concentrated to dryness to provide the hydrochloride salt of the starting material; this salt was dissolved in methanol (1.89 mL), and the solution was treated with palladium on carbon (10% w/w, 20 mg). The headspace of the flask was replaced with hydrogen gas, and the black suspension was stirred at 23 °C for 8 h, whereupon LCMS analysis revealed that olefin saturation, isoxazolidine hydrogenation, and debenzylation were all complete. The mixture was filtered through a pad of Celite to remove the catalyst, and the filter cake was washed with fresh methanol (3 × 1 mL). The filtrate was concentrated to afford 19• HCl as a white foaming solid (54.3 mg, 106%).1H NMR (600 MHz, CD3OD) δ 4.20 (app t, J = 2.9 Hz, 1H), 4.13 (app p, J = 6.2 Hz, 1H), 3.94–3.91 (m, 2H), 3.87 (td, J = 7.0, 4.6 Hz, 1H), 3.77 (dd, J = 8.2, 3.1 Hz, 1H), 3.63 (app t, J = 6.4 Hz, 1H), 1.64 (app p, J = 7.3 Hz, 2H), 1.29 (d, J = 6.4 Hz, 3H), 0.96 (t, J = 7.3 Hz, 3H). HRMS (ESI+, m/z): [M+H]+ calcd for C10H21NO5,
236.1492; found 236.1488.
Figure imgf000158_0001
[00413] In a 4-mL glass vial fitted with a magnetic stir bar, aminotetraol 19• HCl (54 mg, 0.20 mmol, 1 equiv) was dissolved in N,N-dimethylformamide (990 µL), and triethylamine (120 0.84 mmol, 4.2 equiv) was added. The mixture was chilled to 0 °C before N,O- bis(trimethylsilyl)trifluoroacetamide (110 µL, 0.40 mmol, 2.0 equiv) was added; the mixture was then warmed to 23 °C and was stirred for 1 h to ensure complete O-silylation. 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 washed organic solution was then dried over sodium sulfate, filtered, and concentrated. The residue was re-dissolved in 50% v/v acetic acid–methanol, and the resulting solution was stirred at 40 °C overnight in order to remove pendant trimethylsilyl groups from the coupled product. The mixture was then concentrated, and the crude residue was purified by flash-column chromatography (12 g silica gel, eluting with dichloromethane initially, grading to 10% methanol–dichloromethane) to provide the product as a white solid (76 mg, 72%).1H NMR (1:1 ratio of rotamers, asterisk [*] denotes rotamer peaks that could be resolved; 600 MHz, CD3OD) δ 8.07 (d, J = 8.9 Hz, 1H), 7.90 (d, J = 9.3 Hz, 1H),* 5.49 (d, J = 6.2 Hz, 1H), 5.46 (d, J = 6.2 Hz, 1H),* 4.49–4.42 (m, 2H), 4.36 (q, J = 6.1 Hz, 1H), 4.07– 4.01 (m, 1H), 4.01–3.95 (m, 2H), 3.94–3.92 (m, 1H), 3.87–3.80 (m, 3H), 3.71 (d, J = 7.5 Hz, 1H),* 3.67 (ddd, J = 15.3, 11.7, 3.9 Hz, 1H), 3.59–3.56 (m, 1H), 2.77–2.69 (m, 1H), 2.50– 2.38 (m, 2H), 2.34–2.32 (m, 1H), 2.01–1.97 (m, 2H), 1.67–1.59 (m, 4H), 1.53–1.49 (m, 2H), 1.48 (s, 9H), 1.45 (s, 9H),* 1.21 (d, J = 6.3 Hz, 3H), 1.18 (d, J = 6.3 Hz, 3H),* 0.96 (t, J = 7.5 Hz, 3H), 0.95 (t, J = 7.5 Hz, 3H). HRMS (ESI+, m/z): [M+H]+ calcd for C26H45FN2O8, 533.3233; found 533.3256.
Figure imgf000159_0001
[00414] A 4-mL glass vial was charged with hydrogen chloride solution (4.0 M in 1,4- dioxane, 750 µL), and this solution was chilled to 0 °C in an ice-water bath. Azepine 21 (20 mg, 38 µmol, 1 equiv) was then added, the cooling bath was removed, and the resulting solution was stirred at 23 °C for 35 min, whereupon LCMS analysis showed that Boc removal was complete. The mixture was diluted with toluene (1 mL), and the mixture was concentrated in vacuo. Residual dioxane was removed by re-concentration from 50% v/v methanol–toluene. 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. This residue was purified by preparative HPLC on a Waters SunFire Prep C18 column (5 µm, 250 × 19 mm; eluting with 0.1% formic acid–2% acetonitrile–water initially, grading to 0.1% formic acid–50% acetonitrile–water over 40 min, with a flow rate of 15 mL/min; monitored by UV absorbance at 210 nm) to provide the product (FSA-212009• HCO2H, 12 mg, 65%) as a white solid.1H NMR (600 MHz, CD3OD) δ 8.43 (s, 1H), 4.42 (dt, J = 47.5, 6.0 Hz, 2H), 4.23 (dd, J = 8.5, 5.7 Hz, 4.09–4.05 (m, 2H), 3.96 (dd, J = 10.0, 6.2 Hz, 1H), 3.90 (d, J = 3.1 Hz, 1H), 3.83 (ddd, J = 11.3, 6.2, 3.3 Hz, 1H), 3.64 (d, J = 8.4 Hz, 1H), 3.57 (dd, J = 10.1, 3.1 Hz, 1H), 3.42 (ddd, J = 13.7, 6.0, 2.1 Hz, 1H), 3.11 (app t, J = 12.4 Hz, 1H), 2.21–2.11 (m, 2H), 2.00 (app dt, J = 15.3, 3.9 Hz, 1H), 1.90 (app ddt, J = 15.4, 8.1, 4.0 Hz, 1H), 1.71– 1.54 (m, 6H), 1.54–1.46 (m, 3H), 1.36–1.32 (m, 2H), 1.17 (d, J = 6.3 Hz, 3H), 0.96 (t, J = 7.4 Hz, 3H). HRMS (ESI+, m/z): [M+H]+ calcd for C32H39FN2O6, 435.2865; found 435.2884.
Figure imgf000160_0001
[00415] In a 1-mL glass vial, an ice-cold solution of tetraol 21 (15 mg, 28 µmol, 1 equiv) in pyridine (100 µL) was treated with hexamethyldisilazane (15 µL, 71 µmol, 2.5 equiv) and chlorotrimethylsilane (21 µL, 0.16 mmol, 5.7 equiv). A white suspension of pyridinium hydrochloride formed upon addition of chlorotrimethylsilane. The mixture was then warmed to 23 °C, and was stirred at that temperature for 2 h before it was concentrated to dryness. 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 dried residue was re-dissolved in methanol (500 µL), and 80% v/v acetic acid–water (75 µL) was added at 23 °C. This mixture was stirred for 30 min, at which point TLC analysis showed that no tetrasilylated intermediate (Rf = 0.65, 20% ethyl acetate– hexanes, CAM) remained. The mixture was basified with the addition of saturated aqueous sodium bicarbonate solution (200 µL), and the mixture was then concentrated to dryness. The residue was partitioned between water (10 mL) and 50% v/v ethyl acetate–hexanes (10 mL). The layers were shaken vigorously before they were separated. The organic layer was washed with a fresh portion of water (10 mL), and was then dried over sodium sulfate. The dried product solution was concentrated to provide 2,3,4-tris-O-trimethylsilylated intermediate (18 mg, 23 µmol).
[00416] This intermediate was transferred to a 1-mL glass vial, where it was dried by azeotropic removal of benzene before it was dissolved in chloroform (100 µL). This solution was chilled to 0 °C, and was then treated with triethylamine (7.9 µL, 57 µmol, 2.5 equiv) and methanesulfonyl chloride (3.5 µL, 45 µmol, 2.0 equiv). After 5 min of stirring at 0 °C, TLC analysis showed that no alcohol starting material remained (alcohol Rf = 0.24,
methanesulfonate ester Rf = 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 µmol).
[00417] Finally, in a 0.2–0.5 mL glass microwave vial, this material was dried by azeotropic removal of benzene. To the dried residue were added (4- mercaptophenyl)(morpholino)methanone (22, 10 mg, 46 µmol, 2.0 equiv), potassium carbonate (9.5 mg, 69 µmol, 3.0 equiv) and N,N-dimethylformamide (57 µL). The vial was sealed, and the mixture was heated to 80 °C for 1 h. The thick gel that formed was then cooled to 23 °C before it was diluted with dichloromethane. Trifluoroacetic acid (200 µL) 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 µm, 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).1H NMR (60:40 mixture of rotamers, asterisk [*] denotes minor rotamer peaks that could be resolved; 500 MHz, CD3OD) δ 7.70 (d, J = 9.6 Hz, 1H), 7.62 (d, J = 9.3 Hz, 1H),* 7.46 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 5.50 (br app s, 1H), 4.59 (dd, J = 11.0, 3.4 Hz, 1H),* 4.51 (dd, J = 11.9, 4.1 Hz, 1H), 4.46–4.42 (m, 2H), 4.37–4.35 (m, 1H), 4.05–3.93 (m, 2H), 3.91–3.78 (m, 5H), 3.76–3.60 (m, 6H), 3.59–3.40 (m, 3H), 2.82–2.74 (m, 1H), 2.49–2.39 (m, 2H), 2.35–2.32 (m, 1H), 2.01 (app t, J = 7.4 Hz, 2H), 1.69–1.56 (m, 4H), 1.55–1.51 (m, 2H), 1.49 (s, 9H), 1.47 (s, 9H),* 1.34 (d, J = 6.7 Hz, 3H), 0.80 (t, J = 7.4 Hz, 3H). HRMS (ESI+, m/z): [M+H]+ calcd for C37H56FN3O9S, 638.3270; found 638.3258.
Figure imgf000162_0001
[00418] In a 4-mL glass vial fitted with a stir bar, azepine 23 (8.8 mg, 12 µmol) was dissolved in 33% v/v trifluoroacetic acid–dichloromethane (300 µL). After 1.5 h, LCMS analysis showed that Boc removal was complete, and the mixture was diluted with toluene (500 µL). The diluted mixture was concentrated to dryness. The residue was re-dissolved in methanol (500 µL), and the solution was treated with palladium hydroxide on carbon (20% w/w, 8.0 mg). 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 µm, 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• HCO2H, 3.0 mg, 37%) as a white solid.1H NMR (600 MHz, CD3OD) δ 8.46 (br, 1H), 7.44 (dd, J = 8.4, 1.3 Hz, 2H), 7.38 (dd, J = 8.3, 1.3 Hz, 2H), 4.57 (d, J = 9.4 Hz, 1H), 4.41 (dtd, J = 47.6, 6.1, 1.3 Hz, 2H), 4.05–3.99 (m, 2H), 3.96 (dd, J = 10.1, 6.0 Hz, 1H), 3.87 (d, J = 9.8 Hz, 1H), 3.85–3.80 (m, 2H), 3.78–3.60 (m, 6H), 3.57 (dd, J = 10.2, 3.1 Hz, 1!H), 3.55–3.39 (m, 3H), 3.12 (app t, J = 12.6 Hz, 1H), 2.25–2.14 (m, 2H), 2.05–1.98 (m, 1H), 1.93 (app td, J = 11.0, 6.8 Hz, 1H), 1.71–1.61 (m, 4H), 1.59–1.53 (2H), 1.47–1.40 (m, 3H), 1.35 (d, J = 6.7 Hz, 3H), 1.35–1.32 (m, 2H), 0.97 (t, J = 7.3 Hz, 3H). HRMS (ESI+, m/z): [M+H]+ calcd for C32H50FN3O7S, 640.3426; found 640.3435.
Figure imgf000163_0001
[00419] In a 10-mL glass microwave vial, an ice-cold solution of isoxazolidine 18 (66 mg, 0.21 mmol, 1 equiv) in methanol (2.1 mL) was treated with hydrogen chloride solution (4.0 M in 1,4-dioxane, 210 µL, 0.82 mmol, 4.0 equiv). This mixture was immediately
concentrated to dryness to provide the hydrochloride salt of the starting material, which was re-dissolved in methanol (2.1 mL). This solution was then treated with palladium on carbon (10% w/w, 22 mg), the headspace of the reaction flask was replaced with hydrogen gas, and the black suspension was stirred under hydrogen gas (1 atm) at 23 °C for 5 h, at which point LCMS analysis indicated that olefin saturation, isoxazolidine hydrogenolysis, and
debenzylation were all complete. Consequently, triethylamine (140 µL, 1.0 mmol, 5.0 equiv) was added to basify the reaction mixture, and methyl trifluoroacetate (100 µL, 1.0 mmol, 5.0 equiv) was added to protect the primary amine that had been generated in the hydrogenolytic operation. After 10 min of stirring at 23 °C, LCMS analysis indicated that trifluoroacetylation was complete, and the mixture was filtered through a pad of Celite to remove the
heterogeneous catalyst. The filter cake was rinsed with methanol (3 × 1 mL), and the filtrate was concentrated in vacuo to give a white solid containing crude product contaminated with triethylamine hydrochloride. The latter was removed as follows: The crude product mixture was partitioned between ethyl acetate (15 mL) and saturated aqueous sodium chloride solution (15 mL). The layers were shaken, then separated; and the organic layer was washed with a fresh portion of saturated aqueous sodium chloride solution. These combined aqueous washes were then themselves extracted with fresh ethyl acetate (2 × 10 mL), and the combined organic extracts (35 mL in total) were dried over sodium sulfate. The dried product solution was filtered, and the filtrate was concentrated to give pure trifluoroacetamide as a white solid (43 mg, 63%).1H NMR (500 MHz, CD3OD) δ 4.20 (app t, J = 7.0 Hz, 1H), 4.10 (qd, J = 7.1, 1.7 Hz, 1H), 4.01–3.96 (m, 2H), 3.88–3.82 (m, 2H), 1.70–1.60 (m, 2H), 1.17 (dd, J = 6.4, 1.7 Hz, 3H), 0.96 (t, J = 6.8 Hz, 3H). MS (ESI–, m/z): [M–H]– calcd for
C12H20F3NO6, 330.1; found 330.1.
Figure imgf000164_0001
[00420] In a 2–5 mL glass microwave vial, an ice-cold heterogeneous mixture of tetraol 24 (44 mg, 0.13 mmol, 1 equiv) and 1,2-dichloroethane (2.2 mL) was treated with 1- (chloromethylene)pipiridin-1-ium chloride (130 mg, 0.80 mmol, 6.0 equiv). The vial was sealed, and the mixture was stirred at 0 °C for 15 min, during which time the originally light- yellow suspension clarified to form a light-yellow solution. The mixture was then heated to 60 °C for 21 h, at which point LCMS analysis showed that deoxychlorination was complete, as evidenced by the disappearance of (oligo)formylated starting material congeners (ESI–, [M–H]– m/z = 358, 386, 414). The mixture was chilled to 0 °C, and excess Vilsmeier reagent was quenched with the addition of aqueous sodium hydroxide solution (0.50 M, 1.60 mL, 0.80 mmol, 6.0 equiv). The resulting aqueous layer was still acidic, so additional sodium hydroxide solution (0.50 M) was added to achieve (and maintain) pH ~10. 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. The crude residue thus obtained was purified by flash-column chromatography (4 g silica gel, eluting with dichloromethane initially, grading to 7% methanol–dichloromethane) to provide the product as a white solid (30 mg, 65%).1H NMR (500 MHz, CD3OD) δ 4.63 (qd, J = 6.9, 1.7 Hz, 1H), 4.50 (dd, J = 9.8, 1.6 Hz, 1H), 3.97 (dd, J = 10.1, 6.3 Hz, 1H), 3.87–3.83 (m, 2H), 3.77 (dd, J = 3.3, 1.3 Hz, 1H), 3.56 (dd, J = 10.2, 3.3 Hz, 1H), 1.73–1.62 (m, 2H), 1.44 (d, J = 6.9 Hz, 3H), 1.02 (t, J = 7.4 Hz, 3H). HRMS (ESI+, m/z): [M+H]+ calcd for C12H19ClF3NO5, 350.0977; found 350.0981.
Figure imgf000165_0001
[00421] In a 4-mL glass vial, trifluoroacetamide 25 (30 mg, 86 µmol, 1 equiv) was dissolved in methanol (50 µL). To this solution was then added ice-cold aqueous sodium hydroxide solution (1.0 M, 450 µL). Vigorous stirring was maintained, and the mixture was held at 4 °C for 18 h, at which point LCMS analysis indicated that no starting material remained. The micture was diluted with 400 µL of ice-cold water, and the white suspension was filtered. This filter cake was washed with 300 µL 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 µL) 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. The filtrate was concentrated to provide additional product (11 mg, estimated 80% pure by 1H NMR, ~40%). 1H NMR (500 MHz, CD3OD) δ 4.62 (q, J = 6.7 Hz, 1H), 4.08 (app t, J = 2.6 Hz, 1H), 3.91 (dd, J = 9.4, 5.7 Hz, 1H), 3.78 (app q, J = 6.8 Hz, 1H), 3.63 (dd, J = 9.4, 3.4 Hz, 1H), 3.48 (dd, J = 9.3, 1.9 Hz, 1H), 3.10 (d, J = 9.2 Hz, 1H), 1.63 (app p, J = 7.4 Hz, 2H), 1.56 (d, J = 6.9 Hz, 3H), 0.99 (t, J = 7.4 Hz, 3H). HRMS (ESI+, m/z): [M+H]+ calcd for C10H20ClNO4, 254.1154; found 254.1154.
Figure imgf000165_0002
[00422] A solution of aminotriol 26 (12.9 mg, 51.0 µmol, 1 equiv) in N,N- dimethylformamide (254 µL) was treated sequentially with triethylamine (22.7 µL, 163 µmol, 3.20 equiv) and N,O-bis(trimethylsilyl)trifluoroacetamide (20.5 µL, 76.0 µmol, 1.50 equiv) at 23 °C. The mixture was stirred for 1 h to ensure complete O-silylation before a solution of azepine acid 20 (17.6 mg, 56.0 µmol, 1.10 equiv) in N,N-dimethylformamide (200 µL) was added. The reaction mixture was then treated with HATU (25.1 mg, 66.0 µmol, 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 µL). 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 mixture was filtered through a pad of Celite to remove the heterogeneous catalyst, and the filter cake was rinsed with methanol (3 × 1 mL). The filtrate was concentrated to give a brown film, which was subjected to preparative HPLC-MS on a Waters SunFire Prep C18 column (5 µm, 250 × 19 mm; eluting with 0.1% formic acid–5% acetonitrile–water initially, grading to 0.1% formic acid–40% acetonitrile–water over 40 min, with a flow rate of 15 mL/min; monitored by UV absorbance at 210 nm and ESI+ selected ion monitoring [m/z = 453]) to provide the product (FSA-213008• HCO2H, 3.0 mg, 50%, 2 steps) as a white solid.1H NMR (600 MHz,
CD3OD) δ 8.42 (s, 1H), 4.64 (q, J = 6.8 Hz, 1H), 4.42 (dt, J = 47.5, 6.0 Hz, 2H), 4.41 (d, J = 9.7 Hz, 1H), 4.10 (app t, J = 5.6 Hz, 1H), 3.96 (dd, J = 10.1, 6.3 Hz, 1H), 3.85 (ddd, J = 10.1, 6.2, 3.2 Hz, 1H), 3.80 (app s, 1H), 3.68 (d, J = 9.7 Hz, 1H), 3.57 (dd, J = 10.3, 3.0 Hz, 1H), 3.44 (dd, J = 13.3, 4.5 Hz, 1H), 3.13 (app t, J = 12.5 Hz, 1H), 2.25–2.14 (m, 2H), 2.02 (br d, J = 14.9 Hz, 1H), 1.94 (ddd, J = 14.8, 8.2, 4.0 Hz, 1H), 1.72–1.61 (m, 5H), 1.61–1.53 (m, 1H), 1.47–1.42 (m, 3H), 1.44 (d, J = 6.7 Hz, 3H), 1.37–1.33 (m, 2H), 1.02 (t, J = 7.3 Hz, 3H). HRMS (ESI+, m/z): [M+H]+ calcd for C21H38ClFN2O5, 453.2526; found 453.2526.
Figure imgf000167_0001
[00423] A solution of 17 (654 mg, 0.929 mmol, 1 equiv) in 50% v/v dichloromethane– methanol (18.6 mL) was chilled to–78 °C. A mixture of ozone and dioxygen from an ozone generator was bubbled gently through the reaction solution, until an azure color appeared and persisted for 15 seconds, signaling saturation of the solution with ozone gas with concomitant disappearance of starting material. Ozone bubbling was then discontinued, and nitrogen gas was bubbled through the solution for 5 minutes in order to flush the solution of residual ozone. 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). The combined organic extracts were washed with saturated aqueous sodium chloride solution, the washed solution was dried over sodium sulfate, and the dried solution was concentrated to afford 27 as a brilliant white solid (644 mg, 98%). This material was suitable for use without further purification.1H NMR (500 MHz, CDCl3) δ 7.78–7.75 (m, 2H), 7.69–7.66 (m, 2H), 7.46–7.41 (m, 2H), 7.40–7.35 (m, 4H), 7.25–7.22 (m, 3H), 7.17–7.13 (m, 2H), 4.51 (d, J = 11.6 Hz, 1H), 4.39 (d, J = 3.1 Hz, 1H), 4.35–4.26 (m, 4H), 4.03 (t, J = 3.3 Hz, 1H), 4.00 (app q, J = 5.9 Hz, 1H), 3.95 (d, J = 5.2 Hz, 1H), 3.92 (dd, J = 8.8, 3.3 Hz, 1H), 3.67 (dd, J = 11.9, 4.7 Hz, 1H), 3.61 (app tt, J = 11.8, 6.7 Hz, 2H), 2.06 (s, 1H), 1.89 (s, 1H), 1.24 (d, J = 6.4 Hz, 3H), 1.09 (s, 9H), 1.07 (m, 2H), 0.08 (s, 9H). HRMS (ESI+, m/z): [M+H]+ calcd for
C38H53NO8Si2, 708.3382; found 708.3366.
Figure imgf000167_0002
[00424] A flame-dried 25-mL round-bottomed flask was charged with diol 27 (1.05 g, 1.48 mmol, 1 equiv), and this starting material was dried by azeotropic removal of benzene.
Anhydrous pyridine (5.0 mL) was then added, and the resulting solution was chilled to 0 °C. Solid p-toluenesulfonyl chloride (481 mg, 2.52 mmol, 1.70 equiv) was added to the ice-cold solution, causing a golden yellow color to evolve.4-Dimethylaminopyridine (DMAP, 9.1 mg, 74 µmol, 0.050 equiv) was then added, and the resulting solution was stirred at 0 °C for 5 minutes; the cooling bath was then removed and the mixture was allowed to warm to 23 °C with constant stirring. The golden color dissipated within 30 minutes, leaving a colorless solution. Progress was monitored by TLC (60% ethyl acetate–hexanes, UV+CAM), and after 48 h, the reaction was judged to be complete. The mixture was concentrated in vacuo, and the residue was purified by flash-column chromatography (80 g silica, eluting with 10% ethyl acetate–hexanes initially, grading to 30% ethyl acetate–hexanes) to afford sulfonate ester 28 as a white foaming solid (1.15 g, 90%).1H NMR (500 MHz, CDCl3) δ 7.75–7.72 (m, 2H), 7.68–7.64 (m, 4H), 7.46–7.41 (m, 2H), 7.39–7.34 (m, 4H), 7.26–7.22 (m, 3H), 7.19–7.16 (m, 2H), 4.51 (d, J = 11.7 Hz, 1H), 4.44 (d, J = 2.8 Hz, 1H), 4.30 (d, J = 11.8 Hz, 1H), 4.28–4.24 (m, 3H), 4.10–4.00 (m, 3H), 3.96 (t, J = 3.2 Hz, 1H), 3.93 (d, J = 5.4 Hz, 1H), 3.83 (dd, J = 9.2, 3.4 Hz, 1H), 3.57 (app p, J = 6.2 Hz, 1H), 2.41 (s, 3H), 1.86 (d, J = 3.7 Hz, 1H), 1.22 (d, J = 6.3 Hz, 3H), 1.07 (s, 9H), 1.07–1.03 (m, 2H), 0.07 (s, 9H). HRMS (ESI+, m/z): [M+Na]+ calcd for C45H59NO10SSi2, 884.3290; found 884.3262.
Figure imgf000168_0001
[00425] In a 100-mL round-bottomed flask, a solution of carbamate 28 (1.15 g, 1.34 mmol, 1 equiv) in tetrahydrofuran (13.4 mL) was chilled to 0 °C was treated with
tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran, 4.0 mL, 4.0 mmol, 3.0 equiv). Following the addition of TBAF, the ice-water cooling bath was removed, and the reaction solution was allowed to warm to 23 °C. Progress was monitored by LCMS; cleavage of the (trimethylsilyl)ethyl carbamate was observed within 15 minutes, while cleavage of the tert-butyldiphenylsilyl ether was comparatively slower. After 2 hours, the reaction was judged to be complete, and 20 mL of saturated aqueous sodium bicarbonate solution was added. The resulting mixture was extracted with dichloromethane (4 × 15 mL), and the combined organic layers were dried over sodium sulfate. The dried product solution was filtered, and the filtrate was concentrated to afford a colorless oil. This material was purified by flash-column chromatography (40 g silica, eluting with 1% methanol–dichloromethane initially, grading to 10% methanol–dichloromethane) to afford 29 as a white foaming solid (508 mg, 79%).1H NMR (600 MHz, CDCl3) δ 7.76 (d, J = 8.3 Hz, 2H), 7.34–7.30 (m, 2H), 7.29–7.25 (m, 5H), 4.70 (dd, J = 4.1, 2.1 Hz, 1H), 4.61 (d, J = 11.6 Hz, 1H), 4.32 (d, J = 11.7 Hz, 1H), 4.26–4.21 (m, 2H), 4.18 (app dt, J = 6.9, 5.0 Hz, 1H), 3.97 (dd, J = 8.4, 5.3 Hz, 1H), 3.88 (app t, J = 4.0 Hz, 1H), 3.79 (dd, J = 8.4, 3.8 Hz, 1H), 3.57 (br s, 1H), 3.23 (dd, J = 3.9, 2.1 Hz, 1H), 2.39 (s, 3H), 1.27 (d, J = 6.3 Hz, 3H). HRMS (ESI+, m/z): [M+H]+ calcd for C23H29NO8S, 480.1687; found 480.1711.
Figure imgf000169_0001
[00426] In a 25-mL round-bottomed flask, a solution of isoxazolidine 29 (368 mg, 767 µmol, 1 equiv) in methanol (8.00 mL) was cooled to 0 °C, and was treated with hydrogen chloride solution (4.0 M in 1,4-dioxane, 770 µL, 3.1 mmol, 4.0 equiv). This solution was immediately concentrated to dryness, and the white residue obtained was re-dissolved in fresh methanol (7.67 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. After 5 h, LCMS analysis indicated that isoxazolidine ring and benzyl ether hydrogenolsis were complete, and the headspace of the flask was flushed with nitrogen gas. The reaction mixture was filtered through a Celite pad, and the filter cake was rinsed with methanol (2 × 3 mL). The filtrate was concentrated to give the product as a dull white crystalline solid (327 mg, 100%). This material was suitable for use in subsequent transformations without further purification. Crystals suitable for X-ray analysis were prepared as follows: In a 1-mL glass sample vial, 30• HCl (3 mg) was deposited, and this material was dissolved in approximately 200 of 190-proof ethanol. The vial containing the ethanolic solution was then placed inside a 20-mL scintillation vial containing
approximately 3 mL of acetonitrile. The large vial was capped, and the assembly was allowed to stand undisturbed at 23 °C. After 2 days, needle-shaped crystals of sufficient size for X-ray analysis had formed.1H NMR (600 MHz, CD3OD) δ 7.80 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 4.35 (dd, J = 11.7, 9.6 Hz, 1H), 4.24–4.21 (m, 2H), 4.18 (app s, 1H), 4.09 (app p, J = 6.3 Hz, 1H), 3.99 (dd, J = 7.1, 2.8 Hz, 1H), 3.95 (dd, J = 8.3, 5.0 Hz, 1H), 3.66 (dd, J = 8.3, 3.0 Hz, 1H), 3.56 (app t, J = 6.4 Hz, 1H), 2.46 (s, 3H), 1.26 (d, J = 6.4 Hz, 3H). HRMS (ESI+, m/z): [M+Na]+ calcd for C16H25NO8S, 414.1193; found 414.1203.
Figure imgf000170_0001
[00427] In a 2–5 mL glass microwave vial, an ice-cold solution of aminotetraol 30• HCl (249 mg, 0.582 mmol, 1 equiv) in N,N-dimethylformamide (2.91 mL) was treated
sequentially with triethylamine (341µL, 2.44 mmol, 4.20 equiv) and N,O- bis(trimethylsilyl)trifluoroacetamide (312 µL, 1.15 mmol, 2.00 equiv). The mixture was warmed to 23 °C and was stirred at this temperature for 1 h to ensure complete O-silylation before a solution of azepine acid 20 (202 mg, 0.640 mmol, 1.10 equiv) in N,N- dimethylformamide (1.50 mL) was added by cannula. The mixture was then treated with HATU (288 mg, 0.756 mmol, 1.30 equiv), causing the cloudy mixture to attain a golden yellow color. After stirring at 23 °C for 3 h, 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. This crude product was purified by flash-column chromatography (48 g silica gel, eluting with dichloromethane initially, grading to 10% methanol–dichloromethane) to furnish the product as a white foaming solid (369 mg, 92%).1H NMR (1:1 mixture of rotamers, asterisk [*] denotes rotameric peaks that could be resolved; 500 MHz, CDCl3) δ 7.81 (d, J = 8.1 Hz, 2H), 7.45 (d, J = 8.1 Hz, 2H), 5.48 (br s, 1H), 4.50–4.32 (m, 4H), 4.26 (dd, J = 11.3, 2.7 Hz, 1H), 4.18 (ddd, J = 9.4, 6.6, 2.7 Hz, 1H), 4.10–3.95 (m, 3H) 3.94–3.70 (m, 3H), 3.65 (app t, J = 12.9 Hz, 1H), 3.47 (dd, J = 10.1, 3.3 Hz, 1H), 2.72 (app q, J = 14.4 Hz, 1H), 2.46 (s, 3H), 2.46–2.40 (br, 2H), 2.32 (br, 1H), 2.28 (br, 1H),* 1.99 (br, 2H), 1.65–1.59 (m, 2H), 1.53–1.48 (m, 2H), 1.47 (s, 9H), 1.44 (s, 9H),* 1.20 (d, J = 6.3 Hz, 3H), 1.15 (d, J = 6.3 Hz, 3H).* HRMS (ESI+, m/z): [M+H]+ calcd for C32H49FN2O11S, 689.3114; found 689.3135.
Figure imgf000171_0001
[00428] A 0.5–2 mL conical glass microwave vial was charged with a magnetic stir bar, p- toluenesulfonate ester 31 (150 mg, 0.218 mmol, 1 equiv), sodium azide (142 mg, 2.18 mmol, 10.0 equiv), and N,N-dimethylformamide (1.09 mL). The vial was sealed, and the mixture was heated to 80 °C in a pre-heated oil bath. After 2 d of stirring at elevated temperature, LCMS analysis of the reaction mixture showed that no starting material remained. The mixture was cooled to room temperature, and was then partitioned between ethyl acetate (15 mL) and saturated aqueous sodium chloride solution (15 mL). The layers were shaken, then separated. The aqueous phase was extracted with additional ethyl acetate (2 × 10 mL), and the combined organic extracts were dried over sodium sulfate. The dried product solution was then filtered, and the filtrate was concentrated to give a crude residue that was subjected to flash-column chromatography (12 g silica gel, eluting with dichloromethane initially, grading to 10% methanol–dichloromethane) to furnish the product as a white powder (116 mg, 96%). 1H NMR (60:40 mixture of rotamers, asterisk [*] denotes minor rotameric peaks that could be resolved; 500 MHz, CD3OD) δ 5.48 (br s, 1H), 4.50–4.43 (m, 2H), 4.38–4.35 (m, 1H), 4.18– 4.99 (m, 4H), 3.98–3.93 (, 1H), 3.89–3.80 (m, 2H), 3.73–3.64 (m, 2H), 3.56 (d, J = 9.9 Hz, 1H), 3.46 (dd, J = 13.5, 3.1 Hz, 1H), 3.41 (dd, J = 13.8, 3.0 Hz, 1H),* 2.73 (app q, J = 10.8 Hz, 1H), 2.50–2.28 (m, 2H), 2.34 (br, 1H), 2.30 (br, 1H),* 2.00 (br, 2H), 1.68–1.57 (m, 2H), 1.53–1.49(m, 2H), 1.48 (s, 9H), 1.45 (s, 9H),* 1.22 (d, J = 6.4 Hz, 3H),* 1.20 (d, J = 6.5 Hz, 3H). MS (ESI+, m/z): [M+H–N2]+ calcd for C25H42FN5O8, 532.3; found 532.3.
Figure imgf000172_0001
[00429] In a 1-mL glass fitted with a magnetic stir bar, azide 32 (11.6 mg, 20.8 µmol, 1 equiv) was dissolved in 2:2:1 tert-butanol–methanol–water (138
Figure imgf000172_0002
To this solution were then added 3-dimethylamino-1-propyne (4.48 µL, 41.0 µmol, 2.00 equiv), aqueous sodium ascorbate solution (0.100 M, 41.5 µL, 4.15 µmol, 0.200 equiv), and aqueous cupric sulfate solution (0.100 M, 10.4 µL, 1.04 µmol, 0.0500 equiv). This mixture was stirred at 23 °C for 1 h, by which time LCMS analysis showed that no starting material remained. The reaction mixture was diluted with 50% v/v saturated aqueous sodium bicarbonate solution–saturated aqueous sodium chloride solution, and this diluted mixture was extracted with
dichloromethane (3 × 3 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated.
[00430] This residue was transferred to a 4-mL glass vial, where it was re-dissolved in 33% v/v trifluoroacetic acid–dichloromethane (600 µL). After 1 h of stirring at 23 °C, LCMS analysis showed that Boc removal was complete; the mixture was diluted with toluene (1 mL), and the diluted mixture was concentrated to dryness. This residue was then dissolved in methanol (300 µL), the solution was treated with palladium on carbon (10% w/w, 7.00 mg), and the headspace above the reaction mixture was replaced with hydrogen gas. 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 filtrate was concentrated to give a colorless oil, which was purified by preparative HPLC on a Waters SunFire Prep C18 column (5 µm, 250 × 19 mm; eluting with 0.1% formic acid–2% acetonitrile–water initially, grading to 0.1% formic acid–20% acetonitrile–water over 30 min, with a flow rate of 15 mL/min; monitored by UV absorbance at 210 nm) to provide the product (FSA-212022• HCO2H, 11.8 mg, 89%, 2 steps) as a brilliant white solid.1H NMR (600 MHz, CD3OD) δ 8.37 (br, 1H), 8.26 (s, 1H), 4.90 (app t, J = 12.7 Hz, 1H), 4.75 (d, J = 14.4 Hz, 1H), 4.50–4.47 (m, 1H), 4.43–4.39 (m, 2H), 4.41 (dt, J = 47.5, 6.0 Hz, 2H), 4.14–4.08 (m, 3H), 4.05–4.02 (m, 2H), 3.78 (app p, J = 6.1 Hz, 1H), 3.71 (d, J = 9.6 Hz, 1H), 3.43 (d, J = 9.3 Hz, 1H), 3.13 (app t, J = 12.4 Hz, 1H), 2.86 (s, 6H), 2.21–2.10 (m, 2H), 2.00 (d, J = 15.2 Hz, 1H), 1.93–1.88 (m, 1H), 1.71–1.62 (m, 3H), 1.57 (app q, J = 11.3 Hz, 1H), 1.46–1.37 (m, 3H), 1.35–1.31 (m, 2H), 1.08 (d, J = 6.2 Hz, 3H). HRMS (ESI+, m/z): [M+H]+ calcd for C25H45FN6O6, 545.3457; found 545.3468.
Figure imgf000173_0001
[00431] In a 1-mL glass fitted with a magnetic stir bar, azide 32 (11.6 mg, 20.8 µmol, 1 equiv) was dissolved in 2:2:1 tert-butanol–methanol–water (138
Figure imgf000173_0002
To this solution were then added 2-ethynylpyridine (4.16 µL, 41.5 µmol, 2.00 equiv), aqueous sodium ascorbate solution (0.100 M, 41.5 µL, 4.15 µmol, 0.200 equiv), and aqueous cupric sulfate solution (0.100 M, 10.4 µL, 1.04 µmol, 0.0500 equiv). This mixture was stirred at 23 °C for 1.5 h, by which time LCMS analysis showed that no starting material remained. The reaction mixture was diluted with 50% v/v saturated aqueous sodium bicarbonate solution–saturated aqueous sodium chloride solution, and this diluted mixture was extracted with dichloromethane (3 × 3 mL). The combined organic extracts were dried over sodium sulfate, filtered, and
concentrated to give a colorless oil.
[00432] This residue was transferred to a 4-mL glass vial, where it was re-dissolved in 33% v/v trifluoroacetic acid–dichloromethane (600 µL). After 10 min of stirring at 23 °C, LCMS analysis showed that Boc removal was complete; the mixture was diluted with toluene (1 mL), and the diluted mixture was concentrated to dryness. This residue was purified by preparative HPLC on a Waters SunFire Prep C18 column (5 µm, 250 × 19 mm; eluting with 0.1% formic acid–2% acetonitrile–water initially, grading to 0.1% formic acid–20% acetonitrile–water over 30 min, with a flow rate of 15 mL/min; monitored by UV absorbance at 210 nm) to provide the product (FSA-212019• HCO2H, 4.5 mg, 34%, 2 steps) as a brilliant white solid.1H NMR (600 MHz, CD3OD) δ 8.59 (d, J = 4.9 Hz, 1H), 8.47 (s, 1H), 8.28 (br, 2H), 8.06 (d, J = 7.9 Hz, 1H), 7.92 (td, J = 7.8, 1.7 Hz, 1H), 7.38 (dd, J = 7.0, 5.4 Hz, 1H), 5.67 (app t, J = 1H), 4.92 (dd, J = 14.9, 11.3 Hz, 1H), 4.78 (dd, J = 14.9, 3.0 Hz, 1H), 4.54 (ddd, J = 11.3, 6.3, 2.9 Hz, 1H), 4.43 (dt, J = 47.5, 6.0 Hz, 2H), 4.16 (dd, J = 9.8, 6.3, 1H), 4.09–4.05 (m, 3H), 4.00 (dd, J = 9.1, 3.1 Hz, 1H), 3.83 (app p, J = 6.3 Hz, 1H), 3.72 (dd, J = 9.8, 3.1 Hz, 1H), 3.44 (ddd, J = 13.4, 7.5, 1.9 Hz, 1H), 3.16 (dd, J = 12.4, 9.6 Hz, 1H), 2.69–2.62 (m, 2H), 2.57 (dd, J = 17.3, 10.0 Hz, 1H), 2.46 (dd, J = 17.0, 7.1 Hz, 1H), 2.12 (app t, J = 7.5 Hz, 2H), 1.72–1.64 (m, 2H), 1.56–1.51 (m, 2H), 1.09 (d, J = 6.4 Hz, 3H). HRMS (ESI+, m/z): [M+H]+ calcd for C27H39FN6O6, 563.3; found 563.3.
Figure imgf000174_0001
[00433] In a 1-mL glass fitted with a magnetic stir bar, azide 32 (11.6 mg, 20.8 µmol, 1 equiv) was dissolved in 2:2:1 tert-butanol–methanol–water (138
Figure imgf000174_0002
To this solution were then added 3-ethynylaniline (4.76 µL, 41.5 µmol, 2.00 equiv), aqueous sodium ascorbate solution (0.100 M, 41.5 µL, 4.15 µmol, 0.200 equiv), and aqueous cupric sulfate solution (0.100 M, 10.4 µL, 1.04 µmol, 0.0500 equiv). This mixture was stirred at 23 °C for 1.5 h, by which time LCMS analysis showed that no starting material remained. The reaction mixture was diluted with 50% v/v saturated aqueous sodium bicarbonate solution–saturated aqueous sodium chloride solution, and this diluted mixture was extracted with dichloromethane (3 × 3 mL). The combined organic extracts were dried over sodium sulfate, filtered, and
concentrated to give a colorless oil.
[00434] This residue was transferred to a 4-mL glass vial, where it was re-dissolved in 33% v/v trifluoroacetic acid–dichloromethane (600 µL). After 10 min of stirring at 23 °C, LCMS analysis showed that Boc removal was complete; the mixture was diluted with toluene (1 mL), and the diluted mixture was concentrated to dryness. This residue was then dissolved in methanol (300 µL), the solution was treated with palladium on carbon (10% w/w, 7.00 mg), and the headspace above the reaction mixture was replaced with hydrogen gas. 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 µm, 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• HCO2H, 7.3 mg, 61%, 2 steps) as a brilliant white solid.1H NMR (600 MHz, CD3OD) δ 8.28 (s, 1H), 8.19 (br, 2H), 7.19–7.13 (m, 3H), 6.72 (dd, J = 7.7, 2.1 Hz, 1H), 4.89–4.87 (m, 2H), 4.73 (dd, J = 14.9, 2.9 Hz, 1H), 4.52–4.49 (m, 1H), 4.41 (dt, J = 47.5, 6.0 Hz, 2H), 4.17–4.11 (m, 3H), 4.05–4.04 (m, 2H), 3.83 (app p, J = 6.2 Hz, 1H), 3.72 (dd, J = 9.9, 3.2 Hz, 1H), 3.42 (dd, J = 13.4, 5.6 Hz, 1H), 3.14 (app t, J = 12.7 Hz, 1H), 2.19–2.08 (m, 2H), 2.00 (d, J = 14.8 Hz, 1H), 1.91 (app ddt, J = 16.1, 8.4, 4.2 Hz, 1H), 1.71–1.62 (m, 3H), 1.57 (app q, J = 11.5 Hz, 1H),, 1.45–1.38 (m, 3H), 1.35–1.31 (m, 2H), 1.09 (d, J = 6.2 Hz, 3H). HRMS (ESI+, m/z): [M+2H]2+ calcd for C28H43FN6O6, 290.1687; found 290.1693.
Figure imgf000175_0001
[00435] In a 1-mL glass fitted with a magnetic stir bar, azide 32 (14.3 mg, 25.6 µmol, 1 equiv) was dissolved in 2:2:1 tert-butanol–methanol–water (170
Figure imgf000175_0002
To this solution were then added (4-ethynylphenyl)(morpholino)methanone (33, 11.0 mg, 51.1 µmol, 2.00 equiv), aqueous sodium ascorbate solution (0.100 M, 51.1 µL, 5.11 µmol, 0.200 equiv), and aqueous cupric sulfate solution (0.100 M, 12.8 µL, 1.28 µmol, 0.0500 equiv). This mixture was stirred at 23 °C for 16 h, by which time LCMS analysis showed that no starting material remained. The reaction mixture was diluted with 50% v/v saturated aqueous sodium bicarbonate solution–saturated aqueous sodium chloride solution, and this diluted mixture was extracted with dichloromethane (3 × 3 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated to give a colorless oil.
[00436] This residue was transferred to a 4-mL glass vial, where it was re-dissolved in 33% v/v trifluoroacetic acid–dichloromethane (600 µL). After 10 min of stirring at 23 °C, LCMS analysis showed that Boc removal was complete; the mixture was diluted with toluene (1 mL), and the diluted mixture was concentrated to dryness. This residue was then dissolved in methanol (300 µL), the solution was treated with palladium on carbon (10% w/w, 10.0 mg), and the headspace above the reaction mixture was replaced with hydrogen gas. 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). The filtrate was concentrated to give a colorless oil, which was purified by preparative HPLC on a Waters SunFire Prep C18 column (5 µm, 250 × 19 mm; eluting with 0.1% formic acid–2% acetonitrile–water initially, grading to 0.1% formic acid–40% 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-212015• HCO2H, 9.6 mg, 56%, 2 steps) as a brilliant white solid.1H NMR (600 MHz, CD3OD) δ 8.49 (s, 1H), 8.29 (br, 1H), 7.95 (d, J = 8.2 Hz, 2H), 7.53 (d, J = 8.2 Hz, 2H), 4.90 (dd, J = 14.9, 11.4 Hz, 1H), 4.77 (dd, J = 15.0, 2.9 Hz, 1H), 4.51 (ddd, J = 11.4, 6.4, 2.9 Hz, 1H), 4.41 (dt, J = 47.5, 6.0 Hz, 2H), 4.18–4.11 (m, 3H), 4.06–4.05 (m, 2H), 3.85–3.47 (m, 10H), 3.41 (ddd, J = 13.9, 5.8, 2.4 Hz, 1H), 3.14 (app t, J = 12.4 Hz, 1H), 2.18 (app ddt, J = 16.5, 8.4, 4.1 Hz, 1H), 2.11 (app dtd, J = 15.6, 7.6, 3.7 Hz, 1H), 2.00 (app dt, J = 15.7, 4.1 Hz, 1H), 1.91 (app ddt, J = 14.9, 8.0, 4.1 Hz, 1H), 1.71– 1.62 (m, 3H), 1.56 (app dtd, J = 15.3, 11.1, 2.3 Hz, 1H), 1.46–1.38 (m, 3H), 1.36–1.32 (m, 2H), 1.09 (d, J = 6.4 Hz, 3H). HRMS (ESI+, m/z): [M+H]+ calcd for C33H49FN6O8, 677.3669; found 677.3683.
Figure imgf000176_0001
[00437] In a 4-mL glass vial, at 23 °C, trifluoroacetic acid (100 µL) was added to a suspension of azide 32 (50 mg, 89 µmol, 1 equiv) in dichloromethane (200 µL). After stirring for 30 min, LCMS analysis showed that Boc removal was complete, and the mixture was diluted with toluene (1 mL). The diluted mixture was concentrated to dryness, and the residue was re-dissolved in methanol (500 µL). This solution was treated with palladium on carbon (10% w/w, 25 mg), the headspace of the vial was replaced with hydrogen gas, and the black suspension was stirred under hydrogen gas (1 atm) at 23 °C. After 1 h, LCMS analysis showed that azepine hydrogenation was complete, and the mixture was filtered through a Celite pad to remove heterogeneous catalyst. The filter cake was rinsed with methanol (3 × 1 mL), and the filtrate was concentrated to give the product as a colorless oil (61 mg, 103%).
[00438] 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 µm, 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• HCO2H) as a brilliant white solid.1H NMR (hydroformate salt, 600 MHz, CD3OD) δ 8.51 (br, 2H), 4.42 (dt, J = 47.6, 6.0 Hz, 2H), 4.26–4.24 (m, 1H), 4.10 (dd, J = 7.7, 4.4 Hz, 1H), 4.07 (dd, J = 9.4, 6.5 Hz, 1H), 4.01 (br, 1H), 3.96–3.92 (m, 2H), 3.86 (d, J = 8.2 Hz, 1H), 3.57 (d, J = 8.6 Hz, 1H), 3.39– 3.33 (m, 2H), 3.24 (dd, J = 13.4, 4.0 Hz, 1H), 3.08 (app t, J = 12.3 Hz, 1H), 2.17–2.09 (m, 2H), 1.99 (d, J = 15.0 Hz, 1H), 1.90–1.86 (m, 1H), 1.71–1.61 (m, 3H), 1.55 (app q, J = 11.5 Hz, 1H), 1.46–1.38 (m, 3H), 1.36–1.32 (m, 2H), 1.30 (d, J = 6.5 Hz, 3H). HRMS (ESI+, m/z): [M+H]+ calcd for C20H38FN3O6, 436.2817; found 436.2830.
Figure imgf000177_0001
[00439] A 12 × 75 mm glass test tube was charged with a magnetic stir bar, diamine FSA- 212023• 2 CF3CO2H (15 mg, 23 µmol), and water (377 µL). A solution of 2,5- dioxopyrrolidin-1-yl 4-hydroxybenzoate (34, 5.9 mg, 25 µmol, 1.1 equiv) in acetonitrile (1.9 mL) was added next. Finally, the pH of the mixture was adjusted to pH 8–9 with the addition of aqueous sodium bicarbonate solution (1.1 M, 40 µL, 44 µmol, 1.9 equiv). After 21 h of stirring at 23 °C, LCMS analysis showed that no starting material remained. The mixture was concentrated to dryness, and the residue was subjected to preparative HPLC on a Waters SunFire Prep C18 column (5 µm, 250 × 19 mm; eluting with 0.1% formic acid–5% acetonitrile–water initially, grading to 0.1% formic acid–30% acetonitrile–water over 30 min, with a flow rate of 15 mL/min; monitored by UV absorbance at 254 nm) to provide the product as a brilliant white solid (4.7 mg, 35%).1H NMR (600 MHz, CD3OD) δ 8.46 (br, 1H), 7.73 (d, J = 8.7 Hz, 2H), 6.83 (d, J = 8.8 Hz, 2H), 4.41 (dt, J = 47.5, 6.0 Hz, 2H), 4.22 (ddd, J = 11.3, 6.4, 3.5 Hz, 1H), 4.17 (dd, J = 8.3, 5.0 Hz, 1H), 4.06 (d, J = 10.0, 6.4 Hz, 1H), 4.01 (dd, J = 6.0, 4.8 Hz, 1H), 3.95 (qd, J = 6.5, 1.5 Hz), 3.92–3.88 (m, 3H), 3.66 (dd, J = 10.0, 3.2 Hz, 1H), 3.59 (dd, J = 14.6, 3.6 Hz, 1H), 3.40 (ddd, J = 13.8, 5.6, 1.9 Hz, 1H), 3.08 (app t, J = 12.3 Hz, 1H), 2.19–2.08 (m, 2H), 2.00–1.97 (m, 1H), 1.88 (app ddt, J = 15.5, 8.4, 4.1 Hz, 1H), 1.71–1.52 (m, 4H), 1.45–1.38 (m, 3H), 1.37–1.31 (m, 2H), 1.10 (d, J = 6.5 Hz, 3H). HRMS (ESI+, m/z): [M+H]+ calcd for C27H42FN3O8, 556.3038; found 556.3036.
Figure imgf000178_0001
[00440] In a 16 × 100 mm glass test tube, diamine FSA-212023• 2 CF3CO2H (12 mg, 18 µmol, 1 equiv) was dissolved in water (300 µL). A solution of 2,5-dioxopyrrolidin-1-yl 2- hydroxybenzoate (35, 4.7 mg, 20 µmol, 1.1 equiv)25 in acetonitrile (1.5 mL) was added, and the mixture was basified with the addition of saturated aqueous sodium bicarbonate solution (~20 until pH 8–9 was achieved. After 1 h, LCMS showed the reaction had stalled due to acidification of the reaction mixture; additional sodium bicarbonate solution was added to re-establish pH 8–9. After 20 h of additional stirring, LCMS showed that no starting material remained. The mixture was concentrated to dryness, and the residue was purified by preparative HPLC on a Waters SunFire Prep C18 column (5 µm, 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 15 mL/min; monitored by UV absorbance at 254 nm) to provide the product as a eggshell-white powder (8.0 mg, 74%).1H NMR (500 MHz, CD3OD) δ 8.44 (br, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.38 (t, J = 7.7 Hz, 1H), 6.91 (d, J = 8.8 Hz, 1H), 4.41 (dt, J = 47.6, 6.0 Hz, 2H), 4.26–4.20 (m, 2H), 4.08 (dd, J = 10.0, 6.4 Hz, 1H), 4.05–4.00 (m, 2H), 3.94 (d, J = 3.1 Hz, 1H), 3.91–3.84 (m, 2H), 3.69 (dd, J = 11.0, 3.5 Hz, 1H), 3.67 (dd, J = 6.3, 3.3 Hz, 1H), 3.40 (dd, J = 13.6, 4.7 Hz, 1H), 3.09 (app t, J = 12.4 Hz, 1H), 2.20–2.08 (m, 2H), 2.00–1.97 (m, 1H), 1.88 (ddd, J = 15.2, 8.1, 3.9 Hz, 1H), 1.71– 1.52 (m, 4H), 1.46–1.37 (m, 3H), 1.35–1.30 (m, 2H), 1.10 (d, J = 6.4 Hz, 3H). HRMS (ESI+, m/z): [M+H]+ calcd for C27H42FN3O8, 556.3029; found 556.3054.
Figure imgf000179_0001
[00441] In a 16 × 100 mm glass test tube, diamine FSA-212023• 2 CF3CO2H (12 mg, 18 µmol, 1 equiv) was dissolved in water (300 µL). A solution of 2,5-dioxopyrrolidin-1-yl 3- methyl-1H-pyrazole-5-carboxylate (36, 4.4 mg, 20 µmol, 1.1 equiv) in acetonitrile (1.5 mL) was added, and the mixture was basified with the addition of saturated aqueous sodium bicarbonate solution (~20 µL), until pH 8–9 was achieved. After 13 h of stirring at 23 °C, LCMS analysis indicated that no starting material remained. The mixture was concentrated to dryness, and the residue was subjected to preparative HPLC on a Waters SunFire Prep C18 column (5 µm, 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 15 mL/min; monitored by UV absorbance at 254 nm) to provide the product as a white solid (3.7 mg, 35%).1H NMR (500 MHz, CD3OD) δ 8.44 (br, 1H), 6.50 (s, 1H), 4.42 (dt, J = 47.6, 6.0 Hz, 2H), 4.23–4.17 (m, 1H), 4.12 (app t, J = 6.4 Hz, 1H), 4.08 (dd, J = 9.7, 6.7 Hz, 1H), 4.04–4.02 (m, 2H), 3.94–3.87 (m, 3H), 3.66 (d, J = 9.9 Hz, 1H), 3.55 (d, J = 14.6 Hz, 1H), 3.44 (dd, J = 14.0, 5.5 Hz, 1H), 3.14 (app t, J = 12.5 Hz, 1H), 2.32 (s, 3H), 2.16–2.07 (m, 2H), 2.02 (dd, J = 13.1, 5.0 Hz, 1H), 1.91–1.83 (m, 1H), 1.72–1.67 (m, 1H), 1.67–1.54 (m, 3H), 1.48–1.39 (m, 3H), 1.37–1.32 (m, 2H), 1.11 (d, J = 6.4 Hz, 3H). FTIR (neat, cm–1): 3267 (br), 2931 (m), 1639 (s), 1582 (s), 1420 (m), 1346 (w), 1078 (m). HRMS (ESI+, m/z): [M+Na]+ calcd for C25H42FN5O7, 566.2960; found 566.2975.
Figure imgf000180_0001
[00442] In a 2–5 mL glass microwave vial, an ice-cold solution of tetraol 32 (64.5 mg, 115 µmol, 1 equiv) in pyridine (192 µL) was treated sequentially with hexamethyldisilazane (139 662 µmol, 5.74 equiv) and chlorotrimethylsilane (37.3 µL, 292 µmol, 2.53 equiv). The resulting milky white suspension was warmed to 23 °C, and after 2 h of stirring at this temperature, the mixture was concentrated to dryness. The dried residue was partitioned between water (10 mL) and 20% v/v ethyl acetate hexanes (20 mL), the layers were shaken vigorously until both were clear, and then the layers were separated. The organic phase was washed with a fresh portion of water (10 mL), dried over sodium sulfate, filtered, and concentrated to provide 2,3,4,7-tetrakis-O-trimethylsilylated intermediate (Rf = 0.52, 20% ethyl acetate–hexanes, CAM). This material was then re-dissolved in methanol (500 µL), and 80% v/v acetic acid–water (75
Figure imgf000180_0002
was added. After stirring for 10 min at 23 °C, TLC analysis showed that no tetrasilylated intermediate remained; the mixture was neutralized with the addition of saturated aqueous sodium bicarbonate solution (150
Figure imgf000180_0003
The basified mixture was partitioned between water (10 mL) and 20% v/v ethyl acetate–hexanes (20 mL), and the layers were shaken vigorously before they were separated. The organic phase was then washed with a fresh portion of water (10 mL), dried over sodium sulfate, filtered, and concentrated to afford 2,3,4-tris-O-trimethylsilylated intermediate as a white foaming solid (85.7 mg, 96%).
[00443] A portion of this intermediate (56.1 mg, 72.3 µmol, 1 equiv) was transferred to a clean 2–5 mL glass microwave vial, where it was dissolved with chloroform (241 µL). This solution was chilled to 0 °C, and was treated sequentially with triethylamine (25.2 µL, 181 µmol, 2.50 equiv) and methanesulfonyl chloride (11.3 µL, 145 µmol, 2.00 equiv). After 3 min of stirring at 0 °C, TLC analysis (40% ethyl acetate–hexanes) showed complete consumption of 7-hydroxy intermediate. The reaction mixture was diluted with
dichloromethane (5 mL), and the diluted solution was washed with saturated aqueous sodium bicarbonate solution (2 × 2 mL). The washed product solution was then dried over sodium sulfate, filtered, and concentrated to give 7-O-methanesulfonyl ester intermediate as a colorless oil (67.6 mg, 109%).
[00444] Finally, in a 0.2–0.5 mL glass vial fitted with a magnetic stir bar and PTFE-lined screw cap, this 7-O-methanesulfonyl ester intermediate, (4- mercaptophenyl)(morpholino)methanone (22, 35.0 mg, 157 µmol, 2.00 equiv) and potassium carbonate (32.5 mg, 235 µmol, 3.00 equiv) were dissolved in N,N-dimethylformamide (196 µL). The vial was sealed, and the contents were heated with stirring to 80 °C for 90 min, at which point TLC analysis (40% ethyl acetate–hexanes, UV+PAA) showed that no sulfonate ester electrophile remained. The mixture was cooled to 23 °C and was diluted with ethyl acetate (5 mL); this diluted solution was washed with water (2 × 1 mL), and the washed solution was concentrated. The residue was re-dissolved in 50% v/v acetic acid–methanol, and the resulting solution was stirred at 40 °C overnight in order to effect global desilylation. The desilylated product mixture was concentrated to dryness, and was purified by flash- column chromatography (12 g silica gel, eluting with dichloromethane initially, grading to 10% methanol–dichloromethane) to provide arenesulfide 33 as a brilliant white solid (46.5 mg, 81% overall).1H NMR (600 MHz, CDCl3) δ 7.51 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.2 Hz, 2H), 6.73 (d, J = 9.1 Hz, 1H), 5.43 (app t, J = 6.7 Hz, 1H), 4.53 (dd, J = 11.3, 4.2 Hz, 1H), 4.43 (dt, J = 47.3, 6.0 Hz, 2H), 4.26–2.33 (m, 1H), 4.17 (app td, J = 9.6, 2.2 Hz, 1H), 4.11–4.07 (1H), 4.04 (dd, J = 9.7, 6.5 Hz, 1H), 3.85–3.56 (m, 12H), 3.52 (dd, J = 9.6, 3.7 Hz, 1H), 3.48–3.39 (m, 1H). MS (ESI+, m/z): [M+H–Boc]+ calcd for C36H53FN6O9S, 665.4; found 665.4.
Figure imgf000182_0001
[00445] In a 1-mL glass vial fitted with a magnetic stir bar and a PTFE-lined screw cap, azide 33 (12.9 mg, 16.9 µmol, 1 equiv) was dissolved in 2:2:1 v/v/v tert-butanol–methanol– water (112 µL). To this solution were then added 1-ethynyl-3-fluorobenzene (3.93 µL, 3.38 µmol, 2.00 equiv), aqueous sodium ascorbate solution (0.100 M, 33.7 µL, 3.37 µmol, 0.200 equiv), and aqueous cupric sulfate solution (0.100 M, 8.43 µL, 0.843 mmol, 0.0500 equiv) at 23 °C. Upon addition of copper catalyst, the mixture attained a fluorescent lemon-yellow color. The reaction was shielded from light using aluminum foil, and after stirring for 24 h, LCMS analysis showed that no starting material remained. Saturated aqueous sodium bicarbonate solution (1 mL) and saturated aqueous sodium chloride solution (1 mL) were added, and the diluted mixture was extracted with dichloromethane (3 × 2 mL). The combined extracts were dried over sodium sulfate, filtered, and concentrated to give a light yellow-green foaming solid.
[00446] This residue was then transferred to a 4-mL glass vial, where it was dissolved in 33% v/v trifluoroacetic acid–dichloromethane (300 µL). After stirring at 23 °C for 30 min, LCMS analysis showed that Boc removal was complete, and the mixture was concentrated to dryness. The residue was then dissolved in methanol (300 µL), palladium on carbon (10% w/w, 20.0 mg) was added, and the vial was transferred to a Parr stainless-steel high-pressure reaction flask, where 150 psi of hydrogen gas pressure was applied. After stirring for 4 d, the pressure reactor was carefully depressurized, and the reaction mixture was filtered through a pad of Celite to remove the heterogeneous catalyst. The filter cake was rinsed with methanol (3 × 1 mL), the filtrate was concentrated, and the residue thus obtained was subjected to preparative HPLC on a Waters SunFire Prep C18 column (5 µm, 250 × 19 mm; eluting with 0.1% formic acid–5% acetonitrile–water initially, grading to 0.1% formic acid–50% acetonitrile–water over 30 min, with a flow rate of 15 mL/min; monitored by UV absorbance at 280 nm) to provide FSA-212066• HCO2H as a white solid (4.9 mg, 35%, 2 steps).1H NMR (600 MHz, CD3OD) δ 8.41 (br, 1H), 7.52 (d, J = 7.8 Hz, 1H), 7.47 (d, J = 10.0 Hz, 1H), 7.40 (td, J = 8.0, 5.8 Hz, 1H), 7.25 (d, J = 7.9 Hz, 2H), 7.17 (d, J = 7.9 Hz, 2H), 7.06 (td, J = 8.5, 2.6 Hz, 1H), 4.80 (dd, J = 14.9, 10.7 Hz, 1H), 4.74–4.69 (m, 2H), 4.53 (dd, J = 9.5, 3.0 Hz, 1H), 4.41 (dt, J = 47.6, 5.8 Hz, 2H), 4.12 (dd, J = 8.9, 5.5 Hz, 1H), 4.09–4.04 (m, 2H), 4.01–3.97 (br, 1H), 3.78–3.59 (br, 6H), 3.56 (dd, J = 6.9, 3.1 Hz, 1H), 3.42 (dd, J = 14.1, 5.5 Hz, 1H), 3.11 (app t, J = 12.6 Hz, 1H), 2.22–2.11 (m, 2H), 2.05–1.98 (m, 1H), 1.92– 1.87 (m, 1H), 1.70–1.62 (m, 3H), 1.60–1.52 (m, 1H), 1.47–1.37 (m, 3H), 1.36–1.31 (m, 2H), 1.11 (d, J = 6.8 Hz, 3H). HRMS (ESI+, m/z): [M+H]+ calcd for C39H52F2N6O7S, 787.3659; found 787.3648.
Figure imgf000183_0001
[00447] In a 1-mL glass vial fitted with a magnetic stir bar and a PTFE-lined screw cap, azide 33 (12.5 mg, 16.3 µmol, 1 equiv) was dissolved in 2:2:1 v/v/v tert-butanol–methanol– water (109 To this solution were then added 3-ethynylaniline (3.68 µL, 3.27 µmol, 2.00 equiv), aqueous sodium ascorbate solution (0.100 M, 32.7 µL, 3.27 µmol, 0.200 equiv), and aqueous cupric sulfate solution (0.100 M, 8.17 µL, 0.817 mmol, 0.0500 equiv) at 23 °C. Upon addition of copper catalyst, the mixture attained a golden yellow color. The reaction was shielded from light using aluminum foil, and after stirring for 2 h, LCMS analysis showed that no starting material remained. Saturated aqueous sodium bicarbonate solution (1 mL) and saturated aqueous sodium chloride solution (1 mL) were added, and the diluted mixture was extracted with dichloromethane (3 × 2 mL). The combined extracts were dried over sodium sulfate, filtered, and concentrated to give a light brown foaming solid.
[00448] This residue was then transferred to a 4-mL glass vial, where it was dissolved in 33% v/v trifluoroacetic acid–dichloromethane (300 µL). After stirring at 23 °C for 30 min, LCMS analysis showed that Boc removal was complete, and the mixture was concentrated to dryness. The residue was then dissolved in methanol (300 µL), palladium on carbon (10% w/w, 15.0 mg) was added, and the vial was transferred to a Parr stainless-steel high-pressure reaction flask, where 150 psi of hydrogen gas pressure was applied. After stirring for 2 d, the pressure reactor was carefully depressurized, and the reaction mixture was filtered through a pad of Celite to remove the heterogeneous catalyst. The filter cake was rinsed with methanol (3 × 1 mL), the filtrate was concentrated, and the residue thus obtained was subjected to preparative HPLC on a Waters SunFire Prep C18 column (5 µm, 250 × 19 mm; eluting with 0.1% formic acid–5% acetonitrile–water initially, grading to 0.1% formic acid–50% acetonitrile–water over 40 min, with a flow rate of 15 mL/min; monitored by UV absorbance at 280 nm) to provide FSA-212062b• HCO2H as a white solid (3.3 mg, 23%, 2 steps).
1H NMR (600 MHz, CD3OD) δ 8.43 (s, 1H), 7.65 (d, J = 8.6 Hz, 1H), 7.47 (t, J = 7.9 Hz, 1H), 7.45–7.44 (m, 1H), 7.22 (d, J = 7.9 Hz, 1H), 7.11 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 8.2 Hz, 2H), 4.84–4.81 (m, 1H), 4.74 (dd, J = 14.4, 2.3 Hz, 1H), 4.61 (dd, J =9.7, 2.7 Hz, 1H), 4.40 (dt, J = 47.6, 6.0 Hz, 2H), 4.17 (dd, J = 9.3, 5.7 Hz, 1H), 4.11 (dd, J = 6.8, 4.1 Hz, 1H), 3.96–3.95 (m, 1H), 3.80–3.68 (m, 4H), 3.64–3.59 (m, 1H), 3.59–3.53 (m, 1H), 3.44 (ddd, J = 14.0, 5.9, 2.6 Hz, 1H), 3.38–3.33 (m, 1H), 3.14 (app t, J = 12.3 Hz, 1H), 2.26–2.13 (m, 2H), 2.03–1.99 (m, 1H), 1.92 (app td, J = 10.4, 9.4, 4.6 Hz, 1H), 1.70–1.61 (m, 3H), 1.59–1.53 (m, 1H), 1.46–1.36 (m, 3H), 1.34–1.29 (m, 2H), 1.08 (d, J = 6.8 Hz, 3H). HRMS (ESI+, m/z): [M+H]+ calcd for C39H52FN7O7S, 784.3862; found 784.3855.
Figure imgf000184_0001
[00449] A 50-mL round-bottomed flask was charged with isoxazolidine 29 (508 mg, 1.06 mmol, 1 equiv). Methanol (10.6 mL) was added, the resulting solution was chilled to 0 °C, and the stirred solution was treated with hydrogen chloride (1.06 mL, 4 M solution in dioxane, 4.24 mmol, 4.00 equiv). The mixture was then concentrated in vacuo to remove methanol, dioxane, and excess hydrogen chloride; and the dried residue (29• HCl) was re- dissolved in methanol (10.6 mL). To this solution was added 10% w/w palladium on carbon (113 mg). The reaction flask was fitted with a 3-way stopcock to which a hydrogen-filled balloon had been affixed. The headspace in the flask was replaced with hydrogen gas by three evacuation–backfilling cycles, and the black reaction mixture was stirred at 23 °C. After 105 min, LCMS analysis indicated that isoxazolidine hydrogenolysis and O-debenzylation were complete. At this point, triethylamine (738 µL, 5.30 mmol, 5.00 equiv) and methyl trifluoroacetate (533 µL, 5.30 mmol, 5.00 equiv) were added sequentially. After an additional 25 min, LCMS analysis demonstrated complete conversion of the primary amine intermediate to the corresponding trifluoroacetamide. The reaction mixture was filtered through a pad of Celite to remove catalyst, and the filtrate was concentrated to give product alongside triethylamine hydrochloride. In order to remove the latter, the crude residue was suspended in ethyl acetate (30 mL), and the organic solution was washed with saturated aqueous sodium chloride solution (3 × 10 mL). The combined aqueous washes were extracted with ethyl acetate (2 × 10 mL), and these extracts were washed with a fresh portion of saturated aqueous sodium chloride solution (10 mL). The combined organic layers were dried over sodium sulfate, the dried solution was filtered, and the filtrate was concentrated to give the product as a white solid (529 mg, 102%). This material was sufficiently pure (≥90%, based on 1H NMR analysis) for use without further purification. An analytically pure sample (~25 mg) was prepared by flash-column chromatography (4.5 g silica gel, eluting with 3% methanol– dichloromethane initially, grading to 10% methanol–dichloromethane).1H NMR (600 MHz, CD3OD) δ 7.81 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.1 Hz, 2H), 4.41 (dd, J = 11.4, 9.6 Hz, 1H), 4.28 (dd, J = 11.4, 2.8 Hz, 1H), 4.21 (q, J = 7.1 Hz, 1H), 4.18 (ddd, J = 9.5, 7.0, 2.9 Hz, 1H), 3.98–3.95 (m, 2H), 3.87 (dd, J = 7.2, 1.4 Hz, 1H), 3.48 (dd, J = 10.1, 3.2 Hz, 1H), 2.46 (s, 3H), 1.15 (d, J = 6.4 Hz, 3H). HRMS (ESI+, m/z): [M+H]+ calcd for C18H24F3NO9S,
488.1197; found 488.1192.
Figure imgf000185_0001
[00450] An oven-dried 20-mL microwave vial was charged with a stir bar and 37 (400 mg, 821 µmol, 1 equiv), and this material was dried by azeotropic removal of benzene. Sodium azide (533 mg, 8.21 mmol, 10.0 equiv) and anhydrous N,N-dimethylformamide (4.10 mL) were then added, and the vial was sealed. The mixture was heated to 80 °C with rapid stirring. After 3 days, LCMS analysis indicated complete consumption of starting material; at this time the mixture was cooled, and the cooled reaction mixture was diluted with water (5 mL) and saturated aqueous sodium chloride solution (35 mL). This mixture was extracted with ethyl acetate (4 × 20 mL). The combined organic extracts were dried over sodium sulfate, the dried product solution was filtered, and the filtrate was concentrated to give a light brown oil. In order to remove residual N,N-dimethylformamide, the crude residue was concentrated repeatedly from 10% methanol–toluene, affording 38 as a dull brown solid (281 mg, 96%). This material could be used in subsequent steps without further purification; an analytically pure sample (~20 mg) was prepared by flash-column chromatography (10 g silica gel, eluting with 5% methanol–dichloromethane initially, grading to 10% methanol– dichloromethane), affording a brilliant white crystalline solid. Melting point: 140–143 °C.1H NMR (600 MHz, CD3OD) δ 4.26 (app t, J = 6.9 Hz, 1H), 4.18 (ddd, J = 10.1, 6.5, 3.1 Hz, 1H), 4.05–3.97 (m, 4H), 3.71 (dd, J = 13.8, 10.5 Hz, 1H), 3.56 (dd, J = 9.9, 3.3 Hz, 1H), 3.45 (dd, J = 13.8, 3.1 Hz 1H), 1.19 (d, J = 6.4 Hz, 3H). HRMS (ESI+, m/z): [M+H]+ calcd for C11H17F3N4O6, 359.1173; found 359.1180.
Figure imgf000186_0001
[00451] A flame-dried 20-mL microwave vial was charged with azidotetraol 38 (250 mg, 698 µmol, 1 equiv), and this starting material was dried by azeotropic removal of benzene. The dried residue was suspended in 1,2-dichloroethane (11.6 mL), and the resulting suspension was cooled to 0 °C. Chloromethylenepipiridinium chloride (704 mg, 4.19 mmol, 6.00 equiv) was added in one portion, and the mixture was stirred rapidly at 0 °C. After 15 min, the originally light yellow suspension had clarified, forming a yellow homogeneous solution. The reaction mixture was then heated to 60 °C, and over the course of 2 h the solution attained an intense sunset orange color. After 20 h, LCMS analysis indicated that deoxychlorination was complete (evidenced by the disappearance of starting material and its mono- and di-formylated congeners; ESI– m/z = 357, 385, and 413, respectively). The reaction mixture was cooled to 23 °C, and the cooled solution was transferred by cannula to a rapidly stirred, ice-cold sodium hydroxide solution (8.38 mL, 0.5 M, 4.19 mmol, 6.00 equiv). In order to saponify the formyl etsers formed upon workup, the biphasic mixture was treated with additional 0.5 M sodium hydroxide solution until the aqueous phase achieved pH = 11; the mixture was then warmed to 23 °C with constant vigorous stirring, and additional sodium hydroxide solution was added periodically to maintain pH = 11. After 24 h, deformylation was complete by LCMS analysis. The mixture was transferred to a separatory funnel, and the layers were separated. The aqueous phase was then treated with solid sodium chloride until saturation was achieved, and the resulting aqueous solution was extracted with dichloromethane (5 × 7 mL). The combined organic layers were dried over sodium sulfate, the dried solution was filtered, and the filtrate was concentrated to give a brown oil. This residue was purified by flash-column chromatography (12 g silica, eluting with
dichloromethane initially, grading to 8% methanol–dichloromethane) to give the product as a brilliant white solid (170 mg, 65%).1H NMR (600 MHz, CD3OD) δ 4.64 (qd, J = 6.8, 1.9 Hz, 1H), 4.51 (dd, J = 9.6, 1.8 Hz, 1H), 4.15 (ddd, J = 9.6, 6.5, 3.1 Hz, 1H), 4.01 (dd, J = 9.9, 6.6 Hz, 1H), 3.97 (dd, J = 9.5, 1.4 Hz, 1H), 3.82 (dd, J = 3.3, 1.3 Hz, 1H), 3.66 (dd, J = 13.8, 9.4 Hz, 1H), 3.60 (dd, J = 13.8, 3.2 Hz, 1H), 3.53 (dd, J = 9.9, 3.2 Hz, 1H), 1.44 (d, J = 6.8 Hz, 3H). HRMS (ESI–, m/z): [M–H]– calcd for C11H16ClF3N4O5, 375.0689; found 375.0692.
Figure imgf000187_0001
[00452] In a 10-mL round-bottomed flask, trifluoroacetamide 39 (170 mg, 451 µmol, 1 equiv) was dissolved in a minimal quantity of methanol (500
Figure imgf000187_0002
This solution was chilled to 0 °C before it was treated with ice-cold aqueous sodium hydroxide solution (1.00 M, 2.26 mL, 2.26 mmol, 5.0 equiv). The mixture was stirred at 4 °C for 18 h, at which point LCMS analysis showed that no starting material remained. The mixture was acidified with the addition of aqueous hydrogen chloride solution (1.0 M), until the pH < 2 was attained. The acidified mixture was then concentrated to dryness to give a light yellow residue comprising deacylated product, sodium chloride, and sodium trifluoroacetate. This mixture was suspended in ethanol (190 proof, 5 mL), and the suspension was filtered. The solids were rinsed with fresh ethanol (190 proof, 2 × 2 mL), and the combined filtrates were
concentrated. This residue was then re-dissolved in methanol (10 mL), the solution was cooled to 0 °C, and the mixture was treated with Amberlyst A26 resin (hydroxide form, 2.0 g). After stirring for 1 h at 0 °C, the ion-exchange beads were removed by filtration, and the filtrate was concentrated to provide aminotriol intermediate (132 mg, 104%). [00453] A portion of this crude aminotriol (100 mg, 360 µmol, 1 equiv) transferred to a 2–5 mL glass microwave vial containing a magnetic stir bar, where it was dissolved in N,N- dimethylformamide (1.78 mL). This solution was chilled to 0 °C, triethylamine (169 µL, 1.21 mmol, 3.40 equiv) and N,O-bis(trimethylsilyl)trifluoroacetamide (143 µL, 534 µmol, 1.50 equiv) were added, and the mixture was warmed immediately back to 23 °C. After 1 h of stirring at this temperature, the mixture was transferred via cannula to a separate 4-mL glass vial (fitted with a magnetic stir bar and silicone septum screw cap) containing azepine acid 20 (135 mg, 427 µmol, 1.20 equiv). The mixture was then treated with HATU (176 mg, 463 µmol, 1.30 equiv), causing the dull brown solution to turn the color of chartreuse. After 5 h, the mixture was diluted with ethyl acetate (40 mL), and the diluted solution was washed sequentially with 10% w/v aqueous citric acid solution (2 × 10 mL), saturated aqueous sodium bicarbonate solution (2 × 10 mL), and saturated aqueous sodium chloride solution (10 mL). The product solution was then dried over sodium sulfate, filtered, and concentrated; the residue obtained was re-dissolved in 50% v/v acetic acid–methanol (8 mL), and the resulting solution was stirred at 40 °C overnight in order to effect global desilylation. The mixture was then diluted with toluene (10 mL) and the diluted solution was concentrated. The dried residue was purified by flash-column chromatography (24 g silica gel, eluting with dichloromethane initially, grading to 10% methanol–dichloromethane) to provide the product as white solid (98.2 mg, 50%, 2 steps).1H NMR (600 MHz, CD3OD) δ 5.53–5.48 (m, 1H), 4.70–4.63 (m, 1H), 4.53 (dd, J = 12.0, 4.1 Hz, 1H), 4.41 (dt, J = 47.5, 5.9 Hz, 2H), 4.30 (d, J = 9.5 Hz, 1H), 4.14 (ddd, J = 9.6, 6.7, 3.2 Hz, 1H), 4.03–3.98 (m, 1H), 3.90–3.85 (m, 1H), 3.83 (dd, J = 4.8, 3.8 Hz, 1H), 3.80–3.73 (m, 2H), 3.67–3.57 (m, 2H), 3.54 (dd, J = 10.0, 3.2 Hz, 1H), 2.83–2.74 (m, 1H), 2.51–2.38 (m, 2H), 2.34–2.30 (d, J = 17.8 Hz, 1H), 2.01 (app t, J = 7.6 Hz, 2H), 1.69–1.58 (m, 2H), 1.54–1.44 (m, 14H). HRMS (ESI+, m/z): [M+H]+ calcd for C25H41ClFN5O7, 578.2751; found 578.2738.
Figure imgf000188_0001
[00454] To a 1-dram vial containing azidotriol 40 (40.0 mg, 69.0 µmol, 1 equiv) was added methanol (690 µL) and 10% palladium on carbon (4.0 mg). The vial was fitted with a rubber septum and the headspace above the reaction mixture was flushed with hydrogen gas. The black heterogeneous reaction mixture was stirred at 23 °C under an atmosphere of hydrogen gas supplied by a balloon. After 26 h, complete consumption of starting material was noted by LCMS analysis, and the reaction mixture was filtered through a pad of Celite (1 × 1 cm) to remove catalyst. The filter pad was rinsed with methanol (3 × 2 mL), and the filtrate was concentrated to give a colorless oil. The residue was purified by preparative HPLC on a Waters SunFire Prep C18 column (5 µm, 250 × 19 mm; eluting with 0.1% formic acid–5% acetonitrile–water initially, grading to 0.1% formic acid–25% acetonitrile–water over 10 min, then grading to 0.1% formic acid–55% acetonitrile–water over the next 30 min, with a flow rate of 15 mL/min; monitored by UV absorbance at 210 nm) to provide the product as a brilliant white solid (25.4 mg, 61%).1H NMR (65:35 mixture of rotamers, asterisk [*] denotes minor rotamer peaks that could be resolved, 500 MHz, CD3OD) δ 8.49 (br, 1H), 4.73 (q, J = 6.5 Hz, 1H), 4.51 (dd, J = 12.6, 5.8 Hz, 1H),* 4.47–4.35 (m, 4H).4.22 (app dq, J = 6.1, 4.2 Hz, 1H), 4.08 (dd, J = 9.4, 6.4 Hz, 1H),* 4.05 (dd, J = 9.5, 6.3 Hz, 1H), 3.97–3.86 (m, 2H), 3.68 (d, J = 9.5 Hz, 1H), 3.66 (d, J = 9.7 Hz, 1H),* 3.54 (dd, J = 9.5, 3.2 Hz, 1H), 3.36 (app dt, J = 13.5, 4.1 Hz, 1H), 3.21 (ddd, J = 13.3, 9.0, 3.1 Hz, 1H), 3.11 (dd, J = 15.1, 11.7 Hz, 1H), 3.05 (dd, J = 14.7, 12.0 Hz, 1H),* 2.37–2.25 (m, 1H), 1.99–1.95 (m, 1H), 1.88–1.60 (m, 4H), 1.48 (s, 9H), 1.46–1.37 (m, 3H), 1.31–1.26 (m, 2H), 1.21–1.07 (m, 2H). HRMS (ESI+, m/z): [M+H]+ calcd for C25H45ClFN3O7, 554.3003; found 554.3005.
Figure imgf000189_0001
[00455] A 1-mL vial was charged sequentially with aminotriol 41 (5.0 mg, 8.3 µmol, 1 equiv), N,N-dimethylformamide (83 µL), triethylamine (3.5 µL, 25 µmol, 3.0 equiv), and 2- (methylthio)acetic acid (1.1 µL, 10 µmol, 1.2 equiv). N-(3-Dimethylaminopropyl-N’- ethylcarbodiimide hydrochloride (EDC, 1.8 mg, 9.2 µmol, 1.1 equiv) was then added. The resulting solution was stirred at 23 °C for 1 h, at which time additional triethylamine (6.0 µL, 43 µmol, 5.2 equiv) and 2-(methylthio)acetic acid (1.1 µL, 10 µmol, 1.2 equiv) were added. After 19 h, LCMS analysis showed no starting material remained. Methanol (200 µL) and toluene (200 µL) were added, and the resulting solution was concentrated to dryness. The residue was then re-dissolved in 33% trifluoroacetic acid–dichloromethane (200 µL), and after 30 min of stirring at 23 °C, LCMS analysis indicated that Boc removal was complete. Toluene (300 µL) was added, and the resulting solution was concentrated to dryness. The crude residue was purified by preparative HPLC on a Waters SunFire Prep C18 column (5 µm 250 × 19 mm, eluting with 0.1% formic acid–5% acetonitrile–water, grading to 0.1% formic acid–50% acetonitrile–water over 30 min, with a flow rate of 15 mL/min; monitored by UV absorbance at 210 nm) to afford FSA-213039c• HCO2H (2.4 mg, 55%) and FSA- 213039d• HCO2H (2.6 mg, 53%) as white solids.
[00456] FSA-213039c: 1H NMR (600 MHz, CD3OD) δ 8.08 (s, 1H), 4.71 (qd, J = 6.8, 1.8 Hz, 1H), 4.44 (dd, J = 9.6, 1.8 Hz, 1H), 4.43 (dd, J = 47.6, 6.0 Hz, 2H), 4.16 (ddd, J = 10.7, 6.5, 4.2 Hz, 1H), 4.05–4.00 (m, 2H), 3.81 (dd, J = 3.4, 1.2 Hz, 1H), 3.66 (d, J = 9.6 Hz, 1H), 3.63–3.53 (m, 3H), 3.37 (ddd, J = 14.0, 6.3, 3.4 Hz, 1H), 2.33 (ddt, J = 15.4, 6.8, 2.6 Hz, 1H), 2.10–2.03 (m, 2H), 1.93 (dtd, J = 15.4, 11.6, 2.0 Hz, 1H), 1.73–1.52 (m, 4H), 1.50–1.45 (m, 2H), 1.44 (d, J = 6.9 Hz, 3H), 1.42–1.35 (m, 3H). One methylene proton corresponding to the ζ position of the azepane is obfuscated by CHD2OD signal. HRMS (ESI+, m/z): [M+H]+ calcd for C21H37ClFN3O6, 482.2428; found 482.2438.
[00457] FSA-213039d: 1H NMR (600 MHz, CD3OD) δ 4.70 (q, J = 6.3 Hz, 1H), 4.47–4.43 (m, 1H), 4.42 (dd, J = 47.4, 5.9 Hz, 2H), 4.17 (ddd, J = 10.5, 6.4, 4.0 Hz, 1H), 4.06–3.99 (m, 2H), 3.82 (d, J = 3.3 Hz, 1H), 3.70 (d, J = 9.6 Hz, 1H), 3.65–3.53 (m, 3H), 3.37 (ddd, J = 13.9, 6.3, 3.2 Hz, 1H), 3.20 (app q, J = 15.1 Hz, 2H), 2.37–2.30 (m, 1H), 2.15 (s, 3H), 2.09– 2.02 (m, 2H), 1.93 (app q, J = 12.6 Hz, 1H), 1.74–1.53 (m, 4H), 1.50–1.45 (m, 2H), 1.44 (d, J = 6.9 Hz, 3H), 1.43–1.34 (m, 3H). One methylene proton corresponding to the ζ position of the azepane is obfuscated by CHD2OD signal. HRMS (ESI+, m/z): [M+H]+ calcd for
C23H41ClFN3O6S, 542.2461; found 542.2451.
Figure imgf000191_0001
[00458] A solution of aminotriol 41 (5.0 mg, 8.3 µmol, 1 equiv) and N,N- diisopropylethylamine (7.3 µL, 42 µmol, 5.0 equiv) in dichloromethane (83 µL) was chilled to–50 °C. Benzoyl chloride (1.1 µL, 9.2 µmol, 1.1 equiv) was then added, causing a light white suspension to form. After 15 min, excess benzoyl chloride was quenched with the addition of methanol (50 µL), the cooling bath was removed, and the mixture was
concentrated to dryness. The residue was then re-dissolved in 33% v/v trifluoroacetic acid– dichloromethane (600 µL), and the resulting solution was stirred at 23 °C for 2 h. After this time, toluene (1 mL) was added, and the diluted mixture was concentrated in vacuo. The residue was purified by preparative HPLC on a Waters SunFire Prep C18 column (5 µm, 250 × 19 mm; eluting with 0.1% formic acid–5% acetonitrile–water initially, grading to 0.1% formic acid–25% acetonitrile–water over 10 min, then grading to 0.1% formic acid–55% acetonitrile–water over the next 25 min, with a flow rate of 15 mL/min; monitored by UV absorbance at 254 nm) to provide the product as a white solid (0.9 mg, 18%).1H NMR (600 MHz, CD3OD) δ 8.29 (br, 1H), 7.83 (d, J = 7.2 Hz, 2H), 7.54 (t, J = 7.4 Hz, 1H), 7.46 (t, J = 7.6 Hz, 2H), 4.66 (q, J= 6.8 Hz, 1H), 4.49–4.48 (m, 1H), 4.42 (dt, J = 47.4, 6.0 Hz, 2H), 4.33 (ddd, J = 10.5, 6.4, 4.1 Hz, 1H), 4.07 (dd, J = 9.9, 6.3 Hz, 1H), 3.99 (dd, J = 11.5, 3.0 Hz, 1H), 3.84–3.71 (m, 4H), 3.68 (dd, J = 9.9, 3.3 Hz, 1H), 2.34–2.30 (m, 1H), 2.09–2.02 (m, 2H), 1.91 (app q, J = 12.3 Hz, 1H), 1.72–1.65 (m, 2H), 1.63–1.58 (m, 1H), 1.57–1.51 (m, 1H), 1.49–1.42 (m, 2H), 1.39 (d, J = 7.0 Hz, 3H), 1.39–1.35 (m, 3H). Two proton signals were not observed: Both are believed to be obfuscated by the CHD2OD signal. HRMS (ESI+, m/z): [M+H]+ calcd for C27H41ClFN3O6, 558.2741; found 558.2754.
Figure imgf000192_0001
[00459] To a 1-mL vial, aminotriol 41 (5.0 mg, 9.02 µmol, 1 equiv), methanol (180 µL), ammonium acetate (2.1 mg, 27 µmol, 3.0 equiv), glyoxal (40% w/w aqueous solution, 3.9 µL, 27 µmol, 3.0 equiv), and formalin (37% w/w, 2.0 µL, 27 µmol, 3.0 equiv) were added sequentially. The mixture was stirred at 23 °C. After 3 h, additional glyoxal (3.9 µL, 3.0 equiv) and formalin (2.0 µL, 3.0 equiv) were added. After an additional 14 h, no starting material remained by LCMS, and the mixture was diluted with benzene (300 µL). The mixture was concentrated, and the dried residue was re-dissolved in 33% trifluoroacetic acid– dichloromethane (200 µL). After 30 min of stirring at 23 °C, LCMS analysis indicated that Boc removal was complete. Toluene (500 µL) was added, and the mixture was concentrated. The dried residue was purified by preparative HPLC on a Waters SunFire Prep C18 column (5 µm, 250 × 19 mm; eluting with 0.1% formic acid–5% acetonitrile–water initially, grading to 1% formic acid–50% acetonitrile–water over 40 min, with a flow rate of 15 mL/min; monitored by UV absorbance at 210 nm) to afford FSA-213040• HCO2H as a white solid (2.9 mg, 54%).1H NMR (600 MHz, CD3OD) δ 8.78 (s, 1H), 8.10 (br, 1H), 7.65 (s, 1H), 7.51 (s, 1H), 4.66–4.52 (m, 3H), 4.47–4.44 (m, 1H), 4.43 (dd, J = 47.2, 6.0 Hz, 2H), 4.25 (app q, J = 6.6 Hz, 1H), 4.14 (dd, J = 9.7, 6.3 Hz, 1H), 4.10–4.05 (m, 1H), 3.92–3.89 (m, 1H), 3.84 (d, J = 9.6 Hz, 1H), 3.67 (dd, J = 9.9, 3.0 Hz, 1H), 3.38 (ddd, J = 14.3, 6.2, 3.3 Hz, 1H), 2.33 (dd, J = 14.8, 6.3 Hz, 1H), 2.09–2.02 (m, 2H), 1.92 (app q, J = 12.2 Hz, 1H), 1.74–1.53 (m, 4H), 1.50–1.38 (m, 5H), 1.37 (d, J = 7.0 Hz, 3H). One methylene proton corresponding to the ζ position of the azepane is obfuscated by CHD +
2OD signal. HRMS (ESI+, m/z): [M+H] calcd for C23H38ClFN4O5, 505.2588; found 505.2590.
Figure imgf000193_0001
[00460] A solution of isoamyl nitrite (501 µL, 3.73 mmol) in tetrahydrofuran (2.50 mL) was cooled to 0 °C and was treated with chlorotrimethylsilane (475 µL, 3.73 mmol). The resulting 1.08 M solution was stirred at 0 °C for 1.5 h prior to use. In a 1-mL vial, aminotriol 41 (5.0 mg, 9.0 µmol, 1 equiv) was dried by azeotropic removal of benzene. The dried starting material was then dissolved in tetrahydrofuran, and the resulting solution was cooled to 0 °C with stirring. Nitrosyl chloride solution (1.08 M, 100 µL, 108 µmol, 12.0 equiv) was then added, and the resulting solution was stirred at 0 °C. After 2.5 h, LCMS analysis indicated no starting material remained; the reaction mixture was concentrated under a stream of nitrogen. The dried residue was re-dissolved in 33% trifluoroacetic acid–dichloromethane, and the resulting solution was stirred at 23 °C for 30 min, at which point LCMS analysis indicated that Boc removal was complete. Toluene (1 mL) was added, and the resulting mixture was concentrated to dryness. The residue was purified by preparative HPLC on a Waters SunFire Prep C18 column (5 µm, 250 × 19 mm; eluting with 1% formic acid–5% acetonitrile–water initially, grading to 0.1% formic acid–50% acetonitrile–water over 40 min, with a flow rate of 15 mL/min; monitored by UV absorbance at 210 nm) to afford FSA- 213038• HCO2H as a white solid (2.2 mg, 52%).1H NMR (600 MHz, CD3OD) δ 4.69 (q, J = 7.0 Hz, 1H), 4.43 (dt, J = 47.5, 6.0 Hz, 2H), 4.40 (m, 1H), 4.17 (app dt, J = 8.9, 5.8 Hz, 1H), 4.03 (dd, J = 10.0, 6.5 Hz, 1H), 4.00 (dd, J = 10.1, 2.6 Hz, 1H), 3.85 (m, 2.0 H), 3.81 (d, J = 3.2 Hz, 1H), 3.76 (d, J = 9.7 Hz, 1H), 3.54 (d, J = 10.0, 3.2 Hz, 1H), 3.36 (ddd, J = 14.0, 6.2, 3.1 Hz, 1H), 2.32 (m, 1H), 2.04 (m, 2H), 1.93 (m, 1H), 1.73–1.52 (m, 4H), 1.49–1.45 (m, 2H), 1.44 (d, J = 6.9 Hz, 3H), 1.42–1.36 (m, 3H). One methylene proton corresponding to the ζ position of the azepane is obfuscated by CHD2OD signal. HRMS (ESI+, m/z): [M+H]+ calcd for C20H35Cl2FN2O5, 473.1980; found 473.1983.
Figure imgf000194_0001
[00461] In a 2–5 mL glass microwave vial fitted with a magnetic stir bar, a solution of diethylzinc (43.9 µL, 0.426 mmol, 3.00 equiv) in 1,2-dichloroethane (800 µL) was chilled to 0 °C. Chloroiodomethane (61.9 µL, 0.852 mmol, 6.00 equiv) was then added dropwise to this solution, and the mixture was aged at 0 °C for 5 min before a solution of olefin 17 (100 mg, 0.142 mmol, 1 equiv) in 1,2-dichloroethane (100 µL) was added by cannula. The reaction mixture was stirred at 0 °C for 3 h, whereupon TLC analysis (30% ethyl acetate–hexanes, UV+CAM) showed complete consumption of starting material. Excess Simmons–Smith reagent was quenched with the addition of saturated aqueous ammonium chloride solution (2 mL), and the resuling biphasic mixture was extracted with dichloromethane (3 × 10 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (10 mL), dried over sodium sulfate, filtered, and concentrated. The residue thus obtained was purified by flash-column chromatography (12 g silica gel, eluting with 20% ethyl acetate– hexanes initially, grading to 50% ethyl acetate–hexanes) to furnish the product as a colorless oil (90.9 mg, 89%).1H NMR (600 MHz, CDCl3) δ 7.83–7.81 (m, 2H), 7.72–7.71 (m, 2H), 7.44–7.40 (m, 2H), 7.38–7.34 (m, 4H), 7.22–7.21 (m, 3H), 7.16–7.14 (m, 2H), 4.51 (d, J = 11.5 Hz, 1H), 4.41 (d, J = 2.0 Hz, 1H), 4.31 (d, J = 11.7 Hz, 1H), 4.30–4.26 (m, 2H), 4.20 (app dtd, J = 7.6, 5.0, 2.5 Hz, 1H), 4.02–4.00 (m, 2H), 3.95 (d, J = 5.3 Hz, 1H), 3.62 (app p, J = 6.2 Hz, 1H), 3.03 (dd, J = 9.6, 5.4 Hz, 1H), 1.75 (d, J = 4.8 Hz, 1H), 1.25 (d, J = 6.3 Hz, 3H), 1.11 (s, 9H), 1.09–1.06 (m, 2H), 0.61–0.52 (m, 2H), 0.40 (tt, J = 9.7, 3.9 Hz, 1H), 0.25 (ddt, J = 16.1, 9.2, 4.6 Hz, 2H), 0.08 (s, 9H). HRMS (ESI+, m/z): [M+H]+ calcd for
C40H55NO7Si2, 718.3590; found 718.3569.
Figure imgf000194_0002
[00462] To an ice-cold solution of 17 (88 mg, 0.12 mmol, 1 equiv) in tetrahydrofuran (1.2 mL) was added tetra-n-butylammonium fluoride solution (1.0 M in tetrahydrofuran, 370 µL, 370 µmol, 3.0 equiv). The mixture was warmed to 23 °C, and desilylation was monitored by LCMS. While cleavage of the (trimethylsilyl)ethyl carbamate group was rapid (~30 min), the tert-butyldiphenylsilyl ether linkage underwent more sluggish deprotection. After 4.5 h, the reaction was complete, and the mixture was diluted with saturated aqueous sodium bicarbonate solution. The mixture was then extracted with dichloromethane (4 × 10 mL), the combined extracts were dried over sodium sulfate, the dried solution was filtered, and the filtrate was concentrated. This crude residue was purified by flash-column chromatography (4 g silica gel, eluting with dichloromethane initially, grading to 10% methanol–
dichloromethane) to furnish the product in its free-base form. This material was then converted to its hydrochloride salt by dissolving it in methanol (3 mL), treating the resulting solution with hydrogen chloride solution (4.0 M in 1,4-dioxane, 120 µL, 0.49 mmol, 4.0 equiv), and concentrating the acidified solution to dryness. This gave the product (43• HCl) as a light sand-colored solid.1H NMR (hydrochloride salt, 600 MHz, CDCl3) δ 7.40 (d, J = 7.0 Hz, 2H), 7.35 (t, J = 7.5 Hz, 2H), 7.28 (t, J = 7.3 Hz, 1H), 5.05 (app t, J = 3.7 Hz, 1H), 4.74 (app t, J = 4.1 Hz, 1H), 4.68 (d, J = 11.1 Hz, 1H), 4.55 (d, J = 11.2 Hz, 1H), 4.17 (dd, J = 7.7, 4.1 Hz, 1H), 4.11–4.07 (m, 2H), 3.88 (dd, J = 7.7, 3.7 Hz, 1H), 3.14 (dd, J = 9.8, 3.7 Hz, 1H), 1.41 (d, J = 6.0 Hz, 1H), 1.15 (app tp, J = 8.6, 4.6 Hz, 1H), 0.65 (app tt, J = 8.3, 4.3 Hz, 1H), 0.58 (app tt, J = 9.1, 4.1 Hz, 1H), 0.36–0.28 (m, 2H). HRMS (ESI+, m/z): [M+H]+ calcd for C18H25NO5, 336.1805; found 336.1820.
Figure imgf000195_0001
[00463] A 2–5 mL glass microwave vial was charged with a magnetic stir bar,
isoxazolidine salt 43• HCl (38 mg, 0.10 mmol, 1 equiv), methanol (1.0 mL) and palladium on carbon (10% w/w, 11 mg). The headspace above the reaction mixture was flushed with hydrogen gas, and the mixture was stirred at 23 °C under a baloonful of hydrogen gas. After 21 h, LCMS analysis indicated that isoxazolidine hydrogenolysis and O-debenzylation were 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 afford analytically pure product as a white solid (32 mg, 111%).1H NMR (600 MHz, CD3OD) δ 4.18 (app t, J = 2.3 Hz, 1H), 4.12 (app p, J = 6.3 Hz, 1H), 4.06 (dd, J = 7.4, 2.4 Hz, 1H), 3.96 (dd, J = 8.7, 5.0 Hz, 1H), 3.89 (dd, J = 8.7, 3.2 Hz, 1H), 3.55 (app t, J = 6.4 Hz, 1H), 3.11 (dd, J = 9.9, 5.0 Hz, 1H), 1.29 (d, J = 6.4 Hz, 3H), 1.15 (app ddq, J = 12.9, 9.3, 4.8 Hz, 1H), 0.71 (tdd, J = 8.5, 5.9, 4.4 Hz, 1H), 0.53 (app tt, J = 9.1, 5.3 Hz, 1H), 0.35 (dq, J = 9.7, 4.8 Hz, 1H), 0.29 (dq, J = 9.6, 4.9 Hz, 1H). HRMS (ESI+, m/z): [M+H]+ calcd for C11H21NO5, 248.1492; found 248.1498.
Figure imgf000196_0001
[00464] In a 4-mL glass vial fitted with a magnetic stir bar and silicone septum screw cap, an ice-cold solution of aminotetraol hydrochloride salt 44• HCl (32 mg, 0.11 mmol) and triethylamine (66 µL, 0.47 mmol, 4.2 equiv) in N,N-dimethylformamide (564 µL) was treated with N,O-bis(trimethylsilyl)trifluoroacetamide (61 µL, 0.23 mmol, 2.0 equiv). The mixture was warmed to 23 °C and was stirred at that temperature for 1 h to ensure complete O- silylation before it was transferred via cannula to a separate 4-mL glass vial (fitted with a magnetic stir bar and silicone septum screw cap) containing azepine acid 20 (39 mg, 0.12 mmol, 1.1 equiv). The resulting mixture was then treated with HATU (56 mg, 0.15 mmol, 1.3 equiv), and the yellow solution was stirred at 23 °C. After 3 h, this solution was diluted with ethyl acetate (20 mL), and the 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 product solution was then dried over sodium sulfate, filtered, and concentrated to give a residue that was re-dissolved in 50% v/v acetic acid–methanol (4 mL). This solution was stirred at 40 °C overnight to effect global desilylation, the desilylated mixture was diluted with toluene (4 mL), and the diluted mixture was concentrated to dryness in vacuo. The residue thus obtained was purified by flash-column chromatography (12 g silica gel, eluting with dichloromethane initially, grading to 10% methanol–dichloromethane) to provide the product as a white solid (44 mg, 71%).1H NMR (60:40 mixture of rotamers, asterisk [*] denotes minor rotamer signals that could be resolved, 600 MHz, CD3OD) δ 7.97 (d, J = 8.9 Hz, 1H),* 7.83 (d, J = 9.3 Hz, 1H), 5.50–5.46 (m, 1H), 4.48 (dd, J = 12.3, 4.5 Hz, 1H), 4.40 (app dq, J = 47.5, 6.3 Hz, 2H), 4.12–4.07 (m, 1H), 4.07–4.02 (m, 1H), 4.01–4.91 (m, 3H), 3.88 (d, J = 8.1 Hz, 1H), 3.86–3.80 (m, 1H), 3.78–3.74 (m, 1H), 3.71–3.64 (m, 1H), 3.07 (dd, J = 9.8, 6.8 Hz, 1H), 2.74 (app q, J = 15.5 Hz, 1H), 2.49–2.37 (m, 2H), 2.32 (br s, 1H), 2.29 (br s, 1H),* 1.99 (app q, J = 7.2 Hz, 1H), 1.67–1.57 (m, 2H), 1.52–1.48 (m, 2H), 1.48 (s, 9H), 1.45 (s, 9H),* 1.22 (d, J = 6.3 Hz, 3H), 1.19 (d, J = 6.4 Hz, 3H),* 1.15–1.09 (m, 1H), 0.74 (tdd, J = 8.5, 6.0, 4.4 Hz, 1H), 0.50 (tq, J = 9.2, 4.9 Hz, 1H), 0.37 (dq, J = 9.8, 4.9 Hz, 1H), 0.27 (dq, J = 10.0, 5.1 Hz, 1H).
Figure imgf000197_0001
[00465] In a 4-mL glass vial fitted with a magnetic stir bar and PTFE-lined screw cap, azepine 45 (10 mg, 18 µmol, 1 equiv) was dissolved in hydrogen chloride solution (4.0 M in 1,4-dioxane, 370 µL). After 15 min of stirring at 23 °C, a white precipitate had formed, and LCMS analysis showed that Boc removal was complete. Toluene (1 mL) was added, and the mixture was concentrated to dryness. The residue was then re-dissolved in methanol (500 µL), and palladium on carbon (10% w/w, 5.0 mg) was added. The headspace above the mixture was replaced with hydrogen gas, and the mixture was stirred under a balloonful of hydrogen gas at 23 °C. After 1 h, LCMS analysis indicated that azepine hydrogenation was complete, and the mixture was filtered through a Celite pad to remove the heterogeneous catalyst. The filter cake was rinsed with methanol (3 × 1 mL), and the filtrate was concentrated. This residue was purified by preparative HPLC on a Waters SunFire Prep C18 column (5 µm, 250 × 19 mm; eluting with 0.1% formic acid–2% acetonitrile–water initially, grading to 0.1% formic acid–40% acetonitrile–water over 40 min, with a flow rate of 15 mL/min; monitored by UV absorbance at 210 nm) to provide FSA-212011• HCO2H as a white solid (6.2 mg, 69%).1H NMR (600 MHz, CD3OD) δ 8.39 (s, 1H), 4.42 (dt, J = 47.6, 6.0 Hz, 2H), 4.28 (dd, J = 9.1, 5.1 Hz, 1H), 4.12 (app p, J = 6.3 Hz, 1H), 4.08 (br, 1H), 3.97 (dd, J = 9.9, 6.1 Hz, 1H), 3.90 (br, 1H), 3.80–3.74 (m, 2H), 3.43 (dd, J = 12.1, 4.3 Hz, 1H), 3.12 (app t, J = 12.5 Hz, 1H), 3.06 (dd, J = 10.1, 6.1 Hz, 1H), 2.22–2.13 (m, 2H), 2.00 (d, J = 14.5 Hz, 1H), 1.93–1.88 (m, 1H), 1.72–1.55 (m, 4H), 1.55–1.47 (m, 3H), 1.36–1.32 (m, 2H), 1.20 (d, J = 6.4 Hz, 3H), 1.17–1.10 (m, 1H), 0.75 (tt, J = 8.4, 4.9 Hz, 1H), 0.51 (tt, J = 8.7, 4.8 Hz, 1H), 0.38 (dq, J = 9.8, 4.8 Hz, 1H), 0.25 (dq, J = 9.6, 4.7 Hz, 1H). HRMS (ESI+, m/z): [M+H]+ calcd for C22H39FN2O6, 447.2865; found 447.2871.
Figure imgf000198_0001
[00466] In a 1-mL glass vial fitted with a magnetic stir bar, an ice-cold solution of tetraol 45 (20.3 mg, 37.3 µmol, 1 equiv) in pyridine (62.1 µL) was treated sequentially with hexamethyldisilazane (44.8 µL, 214 µmol, 5.74 equiv) and chlorotrimethylsilane (12.1 µL, 94.3 µmol, 2.53 equiv). The cooling bath was then removed, and the milky white suspension was stirred at 23 °C for 2 h before it was concentrated to dryness. The dried residue was partitioned between water (10 mL) and 50% v/v ethyl acetate–hexanes (10 mL); the biphasic mixture was shaken vigorously until the layers were clear, and then the layers were separated. The organic layer was washed with a fresh portion of water (5 mL). The washed organic solution was dried over sodium sulfate, filtered, and concentrated to give 2,3,4,7-tetrakis-O- trimethylsilylated intermediate as a colorless oil. This material was dissolved in methanol (500 µL), and 80% v/v acetic acid–water (75 µL) was added. Desilylation was monitored by TLC, and after 1.5 h, complete disappearance of starting material (Rf = 0.50, 20% ethyl acetate–hexanes, CAM) was observed. The mixture was neutralized with the addition of saturated aqueous sodium bicarbonate solution (200 µL), and the basified mixture was concentrated to dryness. The dried residue was partitioned between water (10 mL) and 50% diethyl ether–hexanes (10 mL), the biphasic mixture was agitated, and the layers were separated. The organic product solution was then washed with a fresh portion of water (5 mL), dried over sodium sulfate, filtered, and concentrated to give 2,3,4,-tris-O- trimethylsilylated intermediate as a colorless oil.
[00467] This material was transferred to a clean 1-mL glass vial containing a magnetic stir bar, where it was dissolved in chloroform (123 µL). The solution was chilled to 0 °C before triethylamine (12.8 µL, 92.0 µmol, 2.50 equiv) and methanesulfonyl chloride (5.73 µL, 73.6 µmol, 2.00 equiv) were added sequentially by micropipette. After 5 min of stirring at 0 °C, TLC analysis (40% ethyl acetate–hexanes, CAM) indicated that no 2,3,4,-tris-O- trimethylsilylated intermediate remained. The reaction mixture was diluted with
dichloromethane (5 mL), and the mixture was washed with saturated aqueous sodium bicarbonate solution (2 × 2 mL). The washed product solution was then dried over sodium sulfate, filtered, and concentrated to give 2,3,4-tris-O-trimethylsilyl-7-O-methanesulfonyl intermediate as a foaming, off-white solid.
[00468] Finally, in a 1-mL glass vial, methanesulfonate ester intermediate (25.6 mg, 30.5 µmol, 1 equiv), (4-mercaptophenyl)(morpholino)methanone (22, 13.6 mg, 61.0 µmol, 2.00 equiv),21 and potassium carbonate (12.7 mg, 91.5 µmol, 3.00 equiv) were suspended in N,N- dimethylformamide (76.0 µL). This mixture was heated to 80 °C for 1.5 h, whereupon TLC analysis (40% ethyl acetate–hexanes, UV+PAA) showed that no sulfonate ester intermediate remained. The reaction mixture was diluted with ethyl acetate (5 mL), the diluted solution was washed with water (2 × 1 mL), and the washed solution was concentrated. The residue was re-dissolved in 50% v/v acetic acid–methanol (2 mL), and the resulting solution was stirred at 40 °C over night in order to effect global desilylation. The desilylated product mixture was concentrated to dryness, and the dried residue was subjected to flash-column chromatography (4 g silica gel, eluting with dichloromethane initially, grading to 10% methanol–dichloromethane) to furnish the product as a colorless oil (18.2 mg, 69% overall). Rf = 0.26 (10% methanol–dichloromethane, UV+PAA).1H NMR (500 MHz, CDCl3) δ 7.44 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.3 Hz, 2H), 6.68 (d, J = 9.2 Hz, 1H), 5.44 (app t , J = 6.8 Hz, 1H), 4.55 (dd, J = 11.5, 3.5 Hz, 1H), 4.43 (dt, J = 47.3, 6.0 Hz, 2H), 4.19 (app td, J = 9.6, 2.2 Hz, 1H), 4.14–4.07 (m, 1H), 4.01 (dd, J = 9.6, 6.0 Hz, 1H), 3.88–3.77 (m, 3H), 3.76–3.76 (m, 7H), 3.20 (dd, J = 9.6, 6.2 Hz, 1H), 2.81–2.77 (br, 1H), 2.76–2.49 (br, 1H), 2.48–2.35 (br, 1H), 2.34–2.26 (m, 1H), 2.02–1.95 (m, 2H), 1.70–1.59 (m, 2H), 1.54–1.41 (m, 11H), 1.29– 1.23 (m, 3H), 1.03–0.96 (br, 1H), 0.74–0.67 (br, 1H), 0.42–0.28 (br, 2H), 0.26–0.15 (br, 1H). MS (ESI+, m/z): [M+H]+ calcd for C38H56FN3O9S, 750.4; found 750.4.
Figure imgf000200_0001
[00469] In a 4-mL glass vial fitted with a magnetic stir bar and silicone septum screw-cap, azepine 46 (18.2 mg, 24.3 µmol, 1 equiv) was dissolved in 33% v/v trifluoroacetic acid– dichloromethane (450 µL), and the resulting solution was stirred at 23 °C. After 15 min, LCMS analysis indicated that Boc removal was complete; toluene (1 mL) was added, and the mixture was concentrated to dryness. The residue was then re-dissolved in methanol (500 µL), palladium on carbon (10% w/w, 20 mg) was added, the headspace above the reaction mixture was replaced with hydrogen gas, and the mixture was stirred at 23 °C under a balloonful of hydrogen gas. After 2 d, LCMS showed that azepine hydrogenation was ~75% complete, and the mixture was filtered through a Celite pad to remove the heterogeneous catalyst. The filter cake was rinsed with methanol (3 × 1 mL), and the filtrate was
concentrated to give a colorless oil. This residue was purified by preparative HPLC on a Waters SunFire Prep C18 column (5 µm, 250 × 19 mm; eluting with 0.1% formic acid–10% acetonitrile–water initially, grading to 0.1% formic acid–50% acetonitrile–water over 30 min, with a flow rate of 15 mL/min; monitored by UV absorbance at 254 nm) to provide FSA- 212052a• HCO2H (3.3 mg, 20%) and FSA-212052b• HCO2H (6.9 mg, 41%) as white solids.
[00470] FSA-212052a: 1H NMR (600 MHz, CD3OD) δ 8.26 (s, 1H), 7.48 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H), 5.73 (app t, J = 6.4 Hz, 1H), 4.53 (dd, J = 9.9, 2.3 Hz, 1H), 4.42 (dt, J = 47.5, 5.9 Hz, 2H), 4.11 (dd, J = 9.9, 1.2 Hz, 1H), 4.01 (qd, J = 7.5, 2.8 Hz, 1H), 3.98–3.95 (m, 2H), 3.86 (d, J = 3.6 Hz, 1H), 3.80–3.69 (br, 4H), 3.76 (dd, J = 10.0, 3.4 Hz, 1H), 3.67–3.59 (br, 2H), 3.48 (ddd, J = 13.5, 7.4, 2.2 Hz, 2H), 2.78–2.69 (m, 2H), 2.62–2.57 (m, 2H), 2.48–2.44 (m, 2H), 2.13 (app t, J = 7.7 Hz, 1H), 1.72–1.64 (m, 2H), 1.59–1.53 (m, 2H), 1.37 (d, J = 7.0 Hz, 3H), 1.10–1.04 (m, 1H), 0.62 (tdd, J = 8.5, 6.2, 4.6 Hz, 1H), 0.28 (qd, J = 10.0, 4.8 Hz, 1H), 0.13–0.08 (m, 1H), 0.04 (ddt, J = 9.2, 6.3, 4.7 Hz, 1H). MS (ESI+, m/z): [M+H]+ calcd for C33H48FN3O7S, 650.3; found 650.4.
[00471] FSA-212052b: 1H NMR (600 MHz, CD3OD) δ 8.38 (br, 1H), 7.47 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 8.3 Hz, 2H), 4.54 (dd, J = 9.8, 2.3 Hz, 1H), 4.42 (dt, J = 47.5, 6.0 Hz, 2H), 4.12–4.08 (m, 2H), 4.00 (qd, J = 6.8, 2.2 Hz, 1H), 3.97 (dd, J = 10.1, 6.1 Hz, 1H), 3.88 (d, J = 3.3 Hz, 1H), 3.77 (dd, J = 10.2, 3.3 Hz, 1H), 3.76–3.69 (br, 4H), 3.68–3.60 (br, 2H), 3.57– 3.48 (br, 2H), 3.45 (dd, J = 13.5, 4.3 Hz, 1H), 3.14 (app t, J = 12.6 Hz, 3.06 (dd, J = 10.1, 6.1 Hz, 1H), 2.27–2.16 (m, 2H), 2.06–2.00 (m, 1H), 1.96–1.91 (m, 1H), 1.72–1.55 (m, 4H), 1.48–1.41 (m, 3H), 1.38 (d, J = 6.9 Hz, 3H), 1.37–1.33 (m, 2H), 1.07 (tdd, J = 12.9, 6.6, 4.0 Hz, 1H), 0.64–0.59 (m, 1H), 0.28 (dq, J = 9.5, 4.8 Hz, 1H), 0.10 (tt, J = 8.5, 5.1 Hz, 1H), 0.04 (ddd, J = 11.0, 9.3, 5.1 Hz, 1H). HRMS (ESI+, m/z): [M+H]+ calcd for C33H50FN3O7S, 652.3426; found 652.3443.
Figure imgf000201_0001
[00472] Thionyl chloride (14.26 mL, 195 mmol, 1.5 equiv.) was added dropwise via syringe to an ice-cooled suspension of L-allylglycine (47; 15 g, 130 mmol, 1 equiv.) in methanol (261 mL). The resulting colorless solution was warmed to 23 °C and stirred for 16 h. The solvent was removed in vacuo to provide L-allylglycine methyl ester• HCl (48; 21.36 g, 99%) as a colorless oil. The crude product was used directly in the next step without purification.1H NMR (500 MHz, CDCl3), δ: 8.78 (br s, 3H), 5.83-5.89 (m, 1H), 5.32 (d, J = 17.6 Hz, 1H), 5.26 (d, J = 10.3 Hz, 1H), 4.24 (m, 1H), 3.80 (s, 3H), 2.85 (m, 2H). HRMS (ESI): Calcd for (C6H11NO2 + H)+: 129.79. Found: 129.0793.
Figure imgf000201_0002
[00473] Triethylamine (44.9 mL, 322 mmol, 2.5 equiv.) was added to a solution of L- allylglycine methyl ester• HCl (48; 21.36 g, 129 mmol, 1 equiv.) in dichloromethane (322 mL). The resulting white suspension was cooled to 0 °C and 4-nitrobenzenesulfonyl chloride (30 g, 135 mmol, 1.05 equiv.) was added in three portions. The bright orange solution was warmed to 23 °C and stirred for 16 h. Water was added and the mixture was stirred for 10 min. The two layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with water 1x and brine 1x, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (30% ethyl acetate-hexanes) to provide methyl (S)-2-((4- nitrophenyl)sulfonamido)pent-4-enoate (49; 29.6 g, 73%) as a white solid.1H NMR (500 MHz, CDCl3), δ: 8.34 (d, J = 8.8 Hz, 2H), 8.03 (d, J = 8.8 Hz, 2H), 5.6 (m, 1H), 5.13 (m, 2H), 4.13 (m, 1H), 3.58 (s, 3H), 2.51 (m, 2H). HRMS (ESI): Calcd for (C12H14N2O6S + H)+: 314.0573. Found: 314.0577.
Figure imgf000202_0001
[00474] To a stirred solution of sulfonamide methyl (S)-2-((4- nitrophenyl)sulfonamido)pent-4-enoate (49; 10 g, 31.8 mmol, 1 equiv.) in tetrahydrofuran (159 mL) at 0 °C, 3-butyn-1-ol (3.37 mL, 44.5 mmol, 1.4 equiv.) and triphenylphosphine (16.69 g, 63.6 mmol, 2 equiv.), respectively, were added. Subsequently, DIAD (12.37 mL, 63.6 mmol, 2 equiv.) was added slowly over 1 h. The reaction mixture was allowed to warm to 23 °C and was stirred at this temperature for 16 h. Volatiles were removed in vacuo and the residue was dissolved in 10% ethyl acetate-hexanes. The solids were filtered and the filtrate was concentrated and purified by flash column chromatography (15% ethyl acetate- hexanes) to afford methyl (S)-2-((N-(but-3-yn-1-yl)-4-nitrophenyl)sulfonamido)pent-4- enoate (50; 8.16 g, 70%) as a yellow oil.1H NMR (500 MHz, CDCl3), δ: 8.35 (d, J = 8.8 Hz, 2H), 8.01 (d, J = 8.8 Hz, 2H), 5.73 (m, 1H), 5.18 (m, 2H), 4.63 (dd, J = 9.5, 6.1 Hz, 1H), 3.53 (s, 3H), 3.45 (ddd, J = 15.6, 10.2, 5.4 Hz, 1H), 3.33 (ddd, J = 15.5, 10.4, 5.4 Hz, 1H), 2.72 (m, 2H), 2.52 (m, 2H), 2.01 (t, J = 2.4 Hz, 1H). HRMS (ESI): Calcd for (C16H18N2O6S + H)+: 366.0886. Found: 366.0887.
Figure imgf000202_0002
[00475] Grubbs I (1.341 g, 1.602 mmol, 0.1 equiv.) was added to a solution of methyl (S)- 2-((N-(but-3-yn-1-yl)-4-nitrophenyl)sulfonamido)pent-4-enoate (50; 5.87g, 16.02 mmol, 1 equiv.) in dichloromethane (320 mL). The resulting solution was stirred at 45 °C for 16 h. The solvent was concentrated in vacuo and the residue was purified by flash column chromatography (20% ethyl acetate-hexanes) to afford methyl (S)-1-((4- nitrophenyl)sulfonyl)-5-vinyl-2,3,6,7-tetrahydro-1H-azepine-2-carboxylate (51; 4.81 g, 82%) as a dark greenish-brown liquid.1H NMR (500 MHz, CDCl3), δ: 8.32 (d, J = 8.8 Hz, 2H), 8.01 (d, J = 8.8 Hz, 2H), 6.23 (dd, J = 17.6, 10.7 Hz, 1H), 5.71 (t, J = 6.6 Hz, 1H), 5.04 (d, J = 17.6 Hz, 1H), 4.97 (d, J = 10.7 Hz, 1H), 4.87 (dd, J = 7.8, 3.9 Hz, 1H), 3.87 (dt, J = 14.6, 4.6 Hz, 1H), 3.62 (s, 3H), 3.45 (ddd, J = 14.8, 8.2, 5.4 Hz, 1H), 2.88 (dt, J = 15.9, 7.7 Hz, 1H), 2.67 (dt, J = 15.7, 5.1 Hz, 1H), 2.55 (t, J = 4.6 Hz, 2H). HRMS (ESI): Calcd for (C16H18N2O6S + H)+: 366.0886. Found: 366.0905.
Figure imgf000203_0001
[00476] Methyl (S)-1-((4-nitrophenyl)sulfonyl)-5-vinyl-2,3,6,7-tetrahydro-1H-azepine-2- carboxylate (51; 5.60 g, 15.28 mmol, 1 equiv.) was dissolved in dimethylformamide (153 mL) and the solution was cooled to 0 °C. Thiophenol (4.72 mL, 45.9 mmol, 3 equiv.) was added dropwise and then potassium carbonate (4.22 g, 30.6 mmol, 2 equiv.) was added in 3 portions over 15 min. The ice bath was removed and the reaction mixture was allowed to warm to 23 °C and stirred for 4 h. The reaction was then cooled to 0 °C again and di-tert- butyl dicarbonate (12.42 mL, 53.5 mmol, 3.5 equiv.) was added. The ice bath was removed and the solution was allowed to warm to 23 °C and stirred for 3 h. The reaction mixture was diluted with ethyl acetate, washed with water 4x, a saturated aqueous solution of sodium bicarbonate 1x and brine 1x. The organic layer was dried over sodium sulfate, concentrated in vacuo and purified by flash column chromatography (10 - 20% ethyl acetate-hexanes) to afford 1-(tert-butyl) 2-methyl (S)-5-vinyl-2,3,6,7-tetrahydro-1H-azepine-1,2-dicarboxylate (52; 2.88 g, 67%) as a yellow oil.1H NMR (500 MHz, CDCl3), δ: 6.29 (m, 1H), 5.71 (m, 1H), 5.07 (dd, J = 17.6, 6.5 Hz, 1H), 4.97 (dd, J = 10.6, 4.7 Hz, 1H), 4.71 and 4.51 (dd, J = 11.4, 4.4 Hz, 1H), 3.99 and 3.9 (dt, J = 15.2, 4.6 Hz, 1H), 3.79 and 3.63 (ddd, J = 15.1, 11.6, 3.2 Hz, 1H), 3.70 (s, 3H), 2.79 (m, 1H), 2.58 (ddd, J = 16, 7.8, 3.8 Hz, 2H), 2.46 (m, 1H), 1.46 and 1.40 (s, 9H). HRMS (ESI): Calcd for (C15H23NO4 + H)+: 281.1627. Found:
281.1636.
Figure imgf000204_0001
[00477] Lithium hydroxide (1M in water) (2.13 mL, 2.12 mmol, 1.2 equiv.) was added to a solution of 1-(tert-butyl) 2-methyl (S)-5-vinyl-2,3,6,7-tetrahydro-1H-azepine-1,2- dicarboxylate (52; 0.5 g, 1.777 mmol, 1 equiv.) in a 1:1 mixture of tetrahydrofuran-methanol (8.89 mL-8.89 mL). The reaction mixture was stirred at 23 °C for 16 h. The reaction mixture was concentrated and the residue was partitioned between water and ethyl acetate. The aqueous phase was washed with ethyl acetate 1x, then it was acidified to pH=2 with a 1 M solution in water of hydrogen chloride, extracted with ethyl acetate 3x, dried over sodium sulfate and concentrated in vacuo to afford (S)-1-(tert-butoxycarbonyl)-5-vinyl-2,3,6,7- tetrahydro-1H-azepine-2-carboxylic acid (53; 0.45 g, 95%) as an off-white solid.1H NMR (500 MHz, CDCl3), δ: 6.29 (m, 1H), 5.72 (m, 1H), 5.08 (dd, J = 17.3, 7.3 Hz, 1H), 4.97 (d, J = 10.6 Hz, 1H), 4.69 and 4.53 (dd, J = 11.4, 4.4 Hz, 1H), 3.97 and 3.86 (dt, J = 14.8, 4.6 Hz, 1H), 3.79 and 3.62 (ddd, J = 14.9, 11.6, 3.2 Hz, 1H), 2.85 (m, 1H), 2.62 (m, 2H), 2.42 (m, 1H), 1.47 and 1.41 (s, 9H).13C NMR (500 MHz, CDCl3), δ: 178.50, 176.83, 156.29, 154.92, 140.48, 140.23, 140.18, 139.59, 126.09, 125.43, 112.44, 111.89, 80.93, 80.75, 59.90, 58.79, 40.47, 39.57, 30.15, 29.76, 28.39, 28.23, 27.36, 27.19. FTIR (neat), cm-1: 3308, 2361, 2342, 1674, 1410, 1161. HRMS (ESI): Calcd for (C14H21NO4 + H)+: 267.1471. Found: 267.1473.
Figure imgf000204_0002
[00478] (S)-1-(tert-butoxycarbonyl)-5-vinyl-2,3,6,7-tetrahydro-1H-azepine-2-carboxylic acid (53; 71.9 mg, 0.269 mmol, 1.0 equiv.) and N-cyclopentylacrylamide (74.9 mg, 0.538 mmol, 2 equiv.) were dissolved in dichloromethane (5.4 mL) in an oven-dried flask. Argon was purged 3x. Grubbs II catalyst (22.83 mg, 0.027 mmol, 0.1 equiv.) was then added and the reaction mixture was heated to reflux for 5h. The mixture was concentrated in vacuo and was purified by flash column chromatography (0-100% ethyl acetate-hexanes) to obtain (S,E)-1- (tert-butoxycarbonyl)-5-(3-(cyclopentylamino)-3-oxoprop-1-en-1-yl)-2,3,6,7-tetrahydro-1H- azepine-2-carboxylic acid (54; 63.6 mg, 63%) as an off-white solid.
[00479] 1H NMR (500 MHz, CD3OD), δ 7.11 (dd, J = 15.6, 6.7 Hz, 1H), 6.11 (dt, J = 13.4, 7.1 Hz, 1H), 5.99– 5.85 (m, 1H), 4.63– 4.52 (ddd, J = 10.2, 4.3, 1.4 Hz, 1H), 4.18 (td, J = 7.5, 3.7 Hz, 1H), 3.95– 3.81 (m, 2H), 2.97– 2.84 (m, 1H), 2.81– 2.73 (m, 1H), 2.67– 2.44 (m, 2H), 2.00– 1.88 (m, 2H), 1.80– 1.68 (m, 2H), 1.67– 1.54 (m, 2H), 1.45 (d, J = 19.9, 9H). HRMS (ESI): Calcd for (C20H30N2O5 + H)+: 378.2155. Found: 378.2136.
Figure imgf000205_0001
[00480] HATU (70.3 mg, 0.185 mmol, 1.1 equiv.) was added to a solution of (S,E)-1-(tert- butoxycarbonyl)-5-(3-(cyclopentylamino)-3-oxoprop-1-en-1-yl)-2,3,6,7-tetrahydro-1H- azepine-2-carboxylic acid (54; 63.6 mg, 0.168 mmol, 1.0 equiv.) in dimethylformamide (0.84 mL) and the mixture was stirred for 10 min at 23 °C. (2R,3R,4S,5R,6R)-2-((1S,2S)-1-amino- 2-chloropropyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol (68.5 mg, 0.252 mmol, 1.5 equiv.) was added and the mixture was stirred for 20 min at 23 °C. N-ethyl-N- isopropylpropan-2-amine (0.074 mL, 0.42 mmol, 2.5 equiv.) was added dropwise and the reaction mixture was allowed to stir at 23 °C for 2h. It was then concentrated in vacuo and purified by flash column chromatography (3% MeOH-DCM + 0.5% NH4OH) to obtain tert- butyl (S)-2-(((1S,2S)-2-chloro-1-((2R,3R,4S,5R,6R)-3,4,5-trihydroxy-6- (methylthio)tetrahydro-2H-pyran-2-yl)propyl)carbamoyl)-5-((E)-3-(cyclopentylamino)-3- oxoprop-1-en-1-yl)-2,3,6,7-tetrahydro-1H-azepine-1-carboxylate (55; 71.8 mg, 68%) as a white solid.1H NMR (500 MHz, CD3OD), δ 7.13 (d, J = 15.6 Hz, 1H), 6.16 (s, 1H), 5.96 (d, J = 15.5 Hz, 1H), 5.30 (d, J = 5.5 Hz, 1H), 4.67– 4.56 (m, 2H), 4.41 (d, J = 9.9 Hz, 1H), 4.24 – 4.17 (m, 2H), 4.12– 4.05 (m, 1H), 3.98– 3.89 (m, 2H), 3.89– 3.80 (m, 1H), 3.56 (dd, J = 10.2, 3.4 Hz, 1H), 3.02– 2.95 (m, 1H), 2.71 (ddd, J = 16.2, 8.2, 4.4 Hz, 1H), 2.65 (d, J = 15.1 Hz, 1H), 2.49 (d, J = 17.6 Hz, 1H), 2.15 (d, J = 4.8 Hz, 3H), 2.01– 1.91 (m, 2H), 1.81– 1.70 (m, 2H), 1.69– 1.57 (m, 2H), 1.54– 1.42 (m, 13H).
Figure imgf000206_0001
[00481] tert-Butyl (S)-2-(((1S,2S)-2-chloro-1-((2R,3R,4S,5R,6R)-3,4,5-trihydroxy-6- (methylthio)tetrahydro-2H-pyran-2-yl)propyl)carbamoyl)-5-((E)-3-(cyclopentylamino)-3- oxoprop-1-en-1-yl)-2,3,6,7-tetrahydro-1H-azepine-1-carboxylate (55; 71.8 mg, 0.114 mmol, 1 equiv.) was dissolved in dichloromethane (1.1 mL). After the flask was evacuated and back-filled with argon 3x, trifluoroacetic acid (0.14 mL, 1.817 mmol, 16 equiv.) was added and the reaction was stirred at 23 °C for 30 min. The reaction mixture was concentrated in vacuo and the residue was purified by preparative HPLC (10-40% acetonitrile-water + 0.1% formic acid over 30 min) to afford (S)-N-((1S,2S)-2-chloro-1-((2R,3R,4S,5R,6R)-3,4,5- trihydroxy-6-(methylthio)tetrahydro-2H-pyran-2-yl)propyl)-5-((E)-3-(cyclopentylamino)-3- oxoprop-1-en-1-yl)-2,3,6,7-tetrahydro-1H-azepine-2-carboxamide (56; 28.3 mg, 47%) as a white solid.1H NMR (500 MHz, CD3OD), δ 7.16 (d, J = 15.6 Hz, 1H), 6.30 (dd, J = 7.5, 5.3 Hz, 1H), 6.06 (d, J = 15.5 Hz, 1H), 5.33 (d, J = 5.6 Hz, 1H), 4.64– 4.48 (m, 2H), 4.31 (d, J = 10.0 Hz, 1H), 4.21– 4.15 (m, 2H), 4.10 (dd, J = 10.2, 5.6 Hz, 1H), 3.87 (d, J = 3.2 Hz, 1H), 3.60 (dd, J = 10.7, 3.0 Hz, 2H), 3.11– 2.86 (m, 2H), 2.86– 2.70 (m, 2H), 2.16 (s, 3H), 2.04– 1.89 (m, 2H), 1.77– 1.70 (m, 2H), 1.68– 1.54 (m, 2H), 1.53– 1.46 (m, 2H), 1.44 (d, J = 6.8 Hz, 3H). HRMS (ESI): Calcd for (C24H38ClN3O6S + H)+: 531.217. Found: 531.2162.
Figure imgf000207_0001
[00482] (S)-N-((1S,2S)-2-chloro-1-((2R,3R,4S,5R,6R)-3,4,5-trihydroxy-6- (methylthio)tetrahydro-2H-pyran-2-yl)propyl)-5-((E)-3-(cyclopentylamino)-3-oxoprop-1-en- 1-yl)-2,3,6,7-tetrahydro-1H-azepine-2-carboxamide (56; 28.3 mg, 0.053 mmol, 1 equiv.) was dissolved in methanol (2 mL). After the flask was evacuated and back-filled with argon, a spatula tip of palladium hydroxide on carbon was added and hydrogen was bubbled in the suspension for 15 min. The reaction was stirred under hydrogen at 23 °C for 5 h. The flask was purged with argon and then the reaction mixture was filtered through Celite. The filtrate was concentrated in vacuo and purified by preparative HPLC (10-30% acetonitrile-water + 0.1% formic acid over 30 min) to afford (2S,5R)-N-((1S,2S)-2-chloro-1-((2R,3R,4S,5R,6R)- 3,4,5-trihydroxy-6-(methylthio)tetrahydro-2H-pyran-2-yl)propyl)-5-(3-(cyclopentylamino)-3- oxopropyl)azepane-2-carboxamide (FSA-410034; 13.9 mg, 49%) as a white solid.1H NMR (500 MHz, CD3OD), δ 5.32 (d, J = 5.6 Hz, 1H), 4.59 (q, J = 6.7, 1H), 4.54 (dd, J = 10.0, 1.6 Hz, 1H), 4.31 (d, J = 9.9 Hz, 1H), 4.10 (td, J = 7.6, 6.5, 2.9 Hz, 3H), 3.85 (d, J = 3.3 Hz, 1H), 3.60 (dd, J = 10.2, 3.2 Hz, 1H), 3.46 (dd, J = 14.2, 5.1 Hz, 1H), 3.14 (t, J = 12.5 Hz, 1H), 2.21 (t, J = 7.6 Hz, 4H), 2.16 (s, 4H), 2.08– 2.00 (m, 1H), 2.00– 1.87 (m, 4H), 1.76– 1.70 (m, 2H), 1.67– 1.56 (m, 7H), 1.50– 1.40 (m, 7H). HRMS (ESI): Calcd for (C24H42ClN3O6S + H)+: 535.2483. Found: 535.2487.
Figure imgf000207_0002
[00483] tert-Butyl (S)-5-((E)-2-(1,3-dioxolan-2-yl)vinyl)-2-(((1S,2S)-2-chloro-1- ((2R,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(methylthio)tetrahydro-2H-pyran-2- yl)propyl)carbamoyl)-2,3,6,7-tetrahydro-1H-azepine-1-carboxylate (57; 117.2 mg, 0.198 mmol, 1 equiv; prepared in a manner analogous to the method used for preparing 54) was dissolved in dichloromethane (2 mL) and a 1 M solution in water of hydrogen chloride (1.98 ml, 1.98 mmol, 10 equiv.) was added. The reaction mixture was stirred at 23 °C for 45 min. The reaction was quenched with a saturated aqueous solution of sodium bicarbonate, the aqueous layer was extracted with dichloromethane 3x, the combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo to afford tert-butyl (S)-2-(((1S,2S)-2-chloro-1-((2R,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(methylthio)tetrahydro- 2H-pyran-2-yl)propyl)carbamoyl)-5-((E)-3-oxoprop-1-en-1-yl)-2,3,6,7-tetrahydro-1H- azepine-1-carboxylate (58; 107 mg, 99%) as an off-white solid.1H NMR (600 MHz, CD3OD) δ 9.52 (d, J = 7.7 Hz, 1H), 7.27 (d, J = 15.6 Hz, 1H), 6.43– 6.33 (m, 1H), 6.09 (dd, J = 15.7, 7.7 Hz, 1H), 5.28 (d, J = 5.6 Hz, 1H), 4.66– 4.53 (m, 2H), 4.41 (d, J = 9.7 Hz, 1H), 4.22 (d, J = 9.8 Hz, 1H), 4.07 (dt, J = 10.0, 6.3 Hz, 1H), 3.97 (dt, J = 15.3, 4.6 Hz, 1H), 3.92– 3.77 (m, 2H), 3.55 (dd, J = 10.2, 3.4 Hz, 1H), 3.09– 3.00 (m, 1H), 2.75 (ddd, J = 16.1, 8.4, 4.4 Hz, 1H), 2.72– 2.60 (m, 1H), 2.53 (d, J = 18.2 Hz, 1H), 2.19– 2.10 (s, 3H), 1.47 (d, J = 4.9 Hz, 9H), 1.23 (d, J = 6.3 Hz, 2H).
Figure imgf000208_0001
[00484] 2-Cyclobutyl-2,2-difluoroethan-1-amine (24.62 mg, 0.182 mmol, 2 equiv.) was added to a solution of tert-butyl (S)-2-(((1S,2S)-2-chloro-1-((2R,3R,4S,5R,6R)-3,4,5- trihydroxy-6-(methylthio)tetrahydro-2H-pyran-2-yl)propyl)carbamoyl)-5-((E)-3-oxoprop-1- en-1-yl)-2,3,6,7-tetrahydro-1H-azepine-1-carboxylate (58; 50 mg, 0.091 mmol, 1 equiv.) in dichloromethane (0.9 mL). The reaction mixture was stirred at 23 °C for 30 min. Sodium triacetoxyhydroborate (38.6 mg, 0.182 mmol, 2 equiv.) was added and the reaction mixture was stirred at 23 °C for 16h. Trifluoroacetic acid (112 µl, 1.457 mmol, 16 equiv.) was added and the mixture was stirred for 30 min. Volatiles were removed in vacuo and the residue was purified by preparative HPLC (0-30% acetonitrile-water + 0.1% formic acid over 30 min) to provide (S)-N-((1S,2S)-2-chloro-1-((2R,3R,4S,5R,6R)-3,4,5-trihydroxy-6- (methylthio)tetrahydro-2H-pyran-2-yl)propyl)-5-((E)-3-((2-cyclobutyl-2,2- difluoroethyl)amino)prop-1-en-1-yl)-2,3,6,7-tetrahydro-1H-azepine-2-carboxamide (59; 25.7 mg, 50%) as a white solid.1H NMR (500 MHz, CD3OD), δ 6.52 (d, J = 15.4 Hz, 1H), 6.11 (t, J = 6.3 Hz, 1H), 5.76 (dt, J = 15.1, 7.1 Hz, 1H), 5.32 (d, J = 5.5 Hz, 1H), 4.61– 4.55 (m, 1H), 4.53 (dd, J = 10.0, 1.6 Hz, 1H), 4.32 (dd, J = 10.1, 3.3 Hz, 1H), 4.21– 4.14 (m, 1H), 4.10 (dt, J = 10.1, 4.6 Hz, 1H), 3.87 (d, J = 3.4 Hz, 1H), 3.80 (d, J = 7.1 Hz, 2H), 3.62– 3.58 (m, 2H), 3.45 (t, J = 15.2 Hz, 2H), 3.29 (d, J = 12.6 Hz, 1H), 3.01– 2.86 (m, 4H), 2.84– 2.63 (m, 2H), 2.23– 2.14 (m, 6H), 2.14– 1.97 (m, 4H), 1.93– 1.85 (m, 1H), 1.44 (d, J = 6.6 Hz, 3H).
HRMS (ESI): Calcd for (C25H40ClF2N3O5S + H)+: 567.2345. Found: 567.2381.
Figure imgf000209_0001
[00485] (S)-N-((1S,2S)-2-chloro-1-((2R,3R,4S,5R,6R)-3,4,5-trihydroxy-6- (methylthio)tetrahydro-2H-pyran-2-yl)propyl)-5-((E)-3-((2-cyclobutyl-2,2- difluoroethyl)amino)prop-1-en-1-yl)-2,3,6,7-tetrahydro-1H-azepine-2-carboxamide (59; 25.7 mg, 0.045 mmol, 1 equiv.) was dissolved in methanol (2 mL). After the flask was evacuated and back-filled with argon, a spatula tip of palladium hydroxide on carbon was added and hydrogen was bubbled in the suspension for 15 min. The reaction was stirred under hydrogen at 23 °C for 3 h. The flask was purged with argon and then the reaction mixture was filtered through Celite. The filtrate was concentrated in vacuo and purified by preparative HPLC (0- 30% acetonitrile-water + 0.1% formic acid over 30 min) to afford (2S,5S)-N-((1S,2S)-2- chloro-1-((2R,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(methylthio)tetrahydro-2H-pyran-2- yl)propyl)-5-(3-((2-cyclobutyl-2,2-difluoroethyl)amino)propyl)azepane-2-carboxamide (FSA-413006; 9.7 mg, 38%) as a white solid.1H NMR (600 MHz, CD3OD), δ 5.30 (d, J = 5.7 Hz, 1H), 4.57 (q, J = 6.9 Hz, 1H), 4.52 (d, J = 9.9 Hz, 1H), 4.30 (d, J = 10.0 Hz, 1H), 4.15– 4.04 (m, 2H), 3.84 (d, J = 3.3 Hz, 1H), 3.58 (dd, J = 10.2, 3.2 Hz, 1H), 3.44 (dd, J = 13.8, 5.6 Hz, 1H), 3.13 (t, J = 12.6 Hz, 1H), 2.99– 2.81 (m, 3H), 2.28– 2.11 (m, 6H), 2.11– 1.99 (m, 4H), 1.97– 1.90 (m, 1H), 1.89– 1.82 (m, 1H), 1.75– 1.63 (m, 3H), 1.58 (q, J = 12.0 Hz, 1H), 1.44 (d, J = 6.8 Hz, 3H), 1.34 (m, 2H). HRMS (ESI): Calcd for (C25H44ClF2N3O5S + H)+: 571.2658. Found: 571.2697.
Figure imgf000210_0001
[00486] Diethoxymethylsilane (0.48 mL, 3.00 mmol, 1.1 equiv.) was added to a solution of methyl (S)-2-((N-(but-3-yn-1-yl)-4-nitrophenyl)sulfonamido)pent-4-enoate (50; 1 g, 2.73 mmol, 1 equiv.) in dichloromethane (55 mL). The resulting solution was cooled to 0 °C and tris(acetonitrile)cyclopentadienylruthenium(II) hexafluorophosphate (0.06 g, 0.136 mmol, 0.05 equiv.) was added. The ice bath was removed and the reaction mixture was allowed to stir at 23 °C for 30 minutes. The solvent was then concentrated in vacuo and the residue was purified by flash column chromatography (30% ethyl acetate-hexanes) to afford methyl (S)- 2-((N-(3-(diethoxy(methyl)silyl)but-3-en-1-yl)-4-nitrophenyl)sulfonamido)pent-4-enoate (60; 0.88 g, 65%) as a light yellow liquid.1H NMR (500 MHz, CDCl3), δ 8.35 (d, J = 8.7 Hz, 2H), 8.04 (d, J = 8.8 Hz, 2H), 5.86– 5.71 (m, 2H), 5.61 (d, J = 2.8 Hz, 1H), 5.26– 5.10 (m, 2H), 4.65 (dd, J = 9.5, 5.8 Hz, 1H), 3.77 (q, J = 7.0 Hz, 4H), 3.53 (s, 3H), 3.35– 3.20 (m, 2H), 2.79 (dtt, J = 15.1, 6.2, 1.5 Hz, 1H), 2.65– 2.53 (m, 2H), 2.42 (td, J = 12.3, 5.2 Hz, 1H), 1.22 (t, J = 7.0 Hz, 6H), 0.22 (s, 3H).
Figure imgf000210_0002
[00487] Grubbs II (0.254 g, 0.30 mmol, 0.2 equiv.) was added to a solution of (S)-2-((N-(3- (diethoxy(methyl)silyl)but-3-en-1-yl)-4-nitrophenyl)sulfonamido)pent-4-enoate (60; 0.75 g, 1.50 mmol, 1.0 equiv.) in toluene (30 mL). High vacuum was applied to the flask for 2 minutes, and then it was charged with argon. This procedure was repeated 3 times. The resulting solution was stirred at 35 °C for 2 h. The solvent was concentrated in vacuo and the residue was purified by flash column chromatography (30% ethyl acetate-hexanes) to afford methyl (S)-5-(diethoxy(methyl)silyl)-1-((4-nitrophenyl)sulfonyl)-2,3,6,7-tetrahydro-1H- azepine-2-carboxylate (61; 0.62 g, 88%) as a light brown liquid.1H NMR (500 MHz, CDCl3), δ 8.35 (d, J = 8.8 Hz, 2H), 8.03 (d, J = 8.8 Hz, 2H), 6.31 (ddd, J = 7.1, 4.9, 1.7 Hz, 1H), 4.97 (dd, J = 6.6, 3.5 Hz, 1H), 3.88– 3.79 (m, 1H), 3.70 (q, J = 7.0 Hz, 4H), 3.61 (s, 3H), 3.23 (ddd, J = 14.3, 9.0, 3.5 Hz, 1H), 2.97 (dt, J = 15.6, 7.0 Hz, 1H), 2.69 (dt, J = 15.5, 4.1 Hz, 1H), 2.55– 2.44 (m, 2H), 1.19 (t, J = 7.0 Hz, 6H), 0.13 (s, 3H).
Figure imgf000211_0001
[00488] Methyl (S)-5-(diethoxy(methyl)silyl)-1-((4-nitrophenyl)sulfonyl)-2,3,6,7- tetrahydro-1H-azepine-2-carboxylate (61; 0.61 g, 1.28 mmol, 1 equiv.) was dissolved in dimethylformamide (13 mL) and the solution was cooled to 0 °C. Thiophenol (0.40 mL, 3.85 mmol, 3 equiv.) was added dropwise and then potassium carbonate (0.35 g, 2.57 mmol, 2 equiv.) was added in 3 portions over 15 min. The ice bath was removed and the reaction mixture was allowed to warm to 23 °C and stirred for 4h. The reaction was then cooled to 0 °C again and di-tert-butyl dicarbonate (1.04 mL, 4.50 mmol, 3.5 equiv.) was added. The ice bath was removed and the solution was allowed to warm to 23 °C and stirred for 3h. The reaction mixture was diluted with ethyl acetate, washed with water 4x, a saturated aqueous solution of sodium bicarbonate 1x and brine 1x. The organic layer was dried over sodium sulfate, concentrated in vacuo and purified by flash column chromatography (10 - 30% ethyl acetate-hexanes) to afford 1-(tert-butyl) 2-methyl (S)-5-(diethoxy(methyl)silyl)-2,3,6,7- tetrahydro-1H-azepine-1,2-dicarboxylate (62; 0.35 g, 71%) as a yellow oil.1H NMR (500 MHz, CDCl3), δ 6.20 (dt, J = 20.1, 6.2 Hz, 1H), 4.80 and 4.57 (dd, J = 10.1, 4.3 Hz, 1H), 3.84 (tdd, J = 15.1, 7.3, 3.0 Hz, 1H), 3.73 (q, J = 7.0 Hz, 4H), 3.70 (s, 3H), 3.52 (ddd, J = 14.5, 10.4, 3.4 Hz, 1H), 2.86– 2.74 (m, 1H), 2.61 (ddt, J = 15.7, 10.9, 6.0 Hz, 1H), 2.55– 2.33 (m, 2H), 1.47 and 1.41 (s, 9H), 1.22– 1.15 (m, 6H), 0.15 (s, 3H).
Figure imgf000211_0002
[00489] 1-(tert-Butyl) 2-methyl (S)-5-(diethoxy(methyl)silyl)-2,3,6,7-tetrahydro-1H- azepine-1,2-dicarboxylate (62; 30 mg, 0.077 mmol, 1 equiv.) was dissolved in a 1:1 mixture of tetrahydrofuran/methanol (0.78 mL : 0.78 mL). Potassium bicarbonate (46.5 mg, 0.464 mmol, 6 equiv.), potassium fluoride (13.49 mg, 0.232 mmol, 3 equiv.) and H2O2 (79 µl, 0.774 mmol, 10 equiv.) were sequentially added and the reaction mixture was stirred at 23 °C for 2h. An aqueous saturated solution of sodium bicarbonate was then added. The aqueous phase was extracted with dichloromethane 4x, the combined organic layers were dried over sodium sulfate and concentrated in vacuo to afford 1-(tert-butyl) 2-methyl (S)-5-oxoazepane-1,2- dicarboxylate (63; 21 mg, 99%) as a colorless oil.1H NMR (500 MHz, CDCl3), δ 5.03 and 4.74 (dd, J = 9.1, 5.6 Hz, 1H), 4.07 and 3.93 (dt, J = 15.3, 4.6 Hz, 1H), 3.73 (s, 3H), 3.27 (dt, J = 15.4, 4.5 Hz, 1H), 2.69– 2.60 (m, 2H), 2.54– 2.40 (m, 2H), 2.17– 2.12 (m, 2H), 1.46 and 1.43 (s, 9H).
Figure imgf000212_0001
[00490] 1-(tert-Butyl) 2-methyl (S)-5-oxoazepane-1,2-dicarboxylate (63; 21 mg, 0.077 mmol, 1 equiv.) was dissolved in THF (0.78 mL) and the solution was cooled to -78 °C. A 1M solution of NaHMDS in THF (93 µl, 0.093 mmol, 1.2 equiv.) was added dropwise down the side of the flask and the reaction mixture was stirred at -78 °C for 30 min.2-(N,N- Bis(trifluoromethylsulfonyl)amino)-5-chloropyridine (36.5 mg, 0.093 mmol, 1.2 equiv.) was added in one portion and the reaction was stirred at -78 °C for 1h. The reaction was quenched with a saturated aqueous solution of ammonium chloride, warmed to 23 °C, diluted with ethyl acetate and water. The aqueous phase was extracted with ethyl acetate 3x, the combined organic layers were washed with brine, dried over sodium sulfate, concentrated in vacuo and purified by flash column chromatography (0 - 50% ethyl acetate-hexanes) to afford an inseparable mixture of 1-(tert-butyl) 2-methyl (S)-5-(((trifluoromethyl)sulfonyl)oxy)-2,3,6,7- tetrahydro-1H-azepine-1,2-dicarboxylate and 1-(tert-butyl) 2-methyl (S)-5- (((trifluoromethyl)sulfonyl)oxy)-2,3,4,7-tetrahydro-1H-azepine-1,2-dicarboxylate (64/65; 6.24 mg, 20%) as a white solid.1H NMR (500 MHz, CDCl3), δ 5.84– 5.74 (m, 1H), 4.84 and 4.64 (dd, J = 9.5, 4.1 Hz, 1H), 3.86 and 3.68 (m, 2H), 3.75 (s, 3H), 2.83– 2.73 (m, 2H), 2.70 – 2.57 (m, 2H), 1.48 and 1.42 (s, 9H).
Figure imgf000213_0001
[00491] A mixture of 1-(tert-butyl) 2-methyl (S)-5-(((trifluoromethyl)sulfonyl)oxy)-2,3,6,7- tetrahydro-1H-azepine-1,2-dicarboxylate and 1-(tert-butyl) 2-methyl (S)-5- (((trifluoromethyl)sulfonyl)oxy)-2,3,4,7-tetrahydro-1H-azepine-1,2-dicarboxylate (64/65; 38 mg, 0.094 mmol, 1 equiv.), potassium carbonate (39.1 mg, 0.283 mmol, 3 equiv.), 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (7.69 mg, 9.42 µmol, 0.1 equiv.) and benzyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6- dihydropyridine-1(2H)-carboxylate (38.8 mg, 0.113 mmol, 1.2 equiv.) were dissolved in DMF (0.63 mL). The reaction mixture was heated to 80 °C and stirred at this temperature for 2 h. It was then cooled down to 23 °C, diluted with ethyl acetate and a saturated aqueous solution of sodium bicarbonate. The aqueous layer was extracted with ethyl acetate 3x, the combined organic layers were dried over sodium sulfate, concentrated in vacuo and purified by flash column chromatography (0 - 100% ethyl acetate-hexanes) to afford a mixture of 1- (tert-butyl) 2-methyl (S)-5-(1-((benzyloxy)carbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-2,3,6,7- tetrahydro-1H-azepine-1,2-dicarboxylate and 1-(tert-butyl) 2-methyl (S)-5-(1- ((benzyloxy)carbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-2,3,4,7-tetrahydro-1H-azepine-1,2- dicarboxylate (66/67; 26.6 mg, 60%) as a light yellow liquid.1H NMR (500 MHz, CDCl3), δ 7.45– 7.31 (m, 5H), 5.69 (d, J = 33.8 Hz, 2H), 5.17 (s, 2H), 4.72 and 4.52 (dd, J = 10.8, 4.3 Hz, 1H), 4.14– 4.03 (m, 2H), 4.03– 3.88 (m, 1H), 3.88– 3.77 (m, 1H), 3.72 (s, 3H), 3.70– 3.61 (m, 2H), 3.61– 3.51 (m, 1H), 2.96– 2.70 (m, 1H), 2.66– 2.45 (m, 2H), 2.27 (s, 2H), 1.48 and 1.42 (s, 9H).
[00492] The following compounds were prepared in an analogous manner to the example compounds prepared above using appropriate intermediates and starting materials:
Figure imgf000214_0001
[00493] FSA-47068: 1H NMR (600 MHz, CD3OD), δ 5.30 (d, J = 5.7 Hz, 1H), 4.60– 4.54 (m, 1H), 4.53 (d, J = 9.9, 1H), 4.30 (d, J = 10.0 Hz, 1H), 4.12– 4.06 (m, 2H), 3.83 (d, J = 3.2 Hz, 1H), 3.58 (dd, J = 10.2, 3.1 Hz, 1H), 3.47– 3.41 (m, 1H), 3.12 (t, J = 12.5 Hz, 1H), 2.26 – 2.14 (m, 5H), 2.05– 1.98 (m, 2H), 1.96– 1.90 (m, 1H), 1.67– 1.61 (m, 1H), 1.61– 1.52 (m, 1H), 1.47– 1.36 (m, 4H), 1.37– 1.23 (m, 8H), 0.90 (t, J = 7.1 Hz, 3H). HRMS (ESI): Calcd for (C21H39ClN2O5S + H)+: 466.2268. Found: 466.229.
Figure imgf000214_0002
[00494] FSA-47077: 1H NMR (600 MHz, CD3OD), δ 5.30 (d, J = 5.8 Hz, 1H), 4.64– 4.50 (m, 2H), 4.31 (d, J = 9.9 Hz, 1H), 4.09 (dd, J = 10.2, 5.6 Hz, 1H), 3.90 (t, J = 4.7 Hz, 1H), 3.78 (d, J = 3.2 Hz, 1H), 3.58 (dd, J = 10.2, 3.1 Hz, 1H), 3.45– 3.38 (m, 1H), 2.82 (s, 3H), 2.22 (q, J = 4.7, 4.2 Hz, 1H), 2.14 (s, 3H), 2.06– 2.00 (m, 1H), 1.88– 1.83 (m, 1H), 1.64– 1.52 (m, 2H), 1.45 (d, J = 6.8 Hz, 3H), 1.41– 1.21 (m, 9H), 0.90 (t, J = 7.1 Hz, 3H). HRMS (ESI): Calcd for (C22H41ClN2O5S + H)+: 480.2425. Found: 480.2446.
Figure imgf000214_0003
[00495] FSA-46033: 1H NMR (600 MHz, CD3OD), δ 6.06 (dd, J = 15.8, 4.5 Hz, 1H), 5.86 – 5.80 (m, 1H), 5.77– 5.68 (m, 1H), 5.30 (d, J = 5.3 Hz, 1H), 4.60– 4.54 (m, 1H), 4.52 (d, J = 10.0 Hz, 1H), 4.30 (d, J = 9.9 Hz, 1H), 4.13– 3.97 (m, 2H), 3.86– 3.78 (m, 1H), 3.61– 3.55 (m, 1H), 3.55– 3.43 (m, 1H), 3.26– 3.15 (m, 1H), 2.93– 2.84 (m, 1H), 2.84– 2.72 (m, 2H), 2.72– 2.62 (m, 1H), 2.14 (d, J = 3.6 Hz, 3H), 1.43 (d, J = 6.7 Hz, 3H), 1.38 (q, J = 7.7 Hz, 2H), 1.33 (q, J = 7.6 Hz, 2H), 0.91 (t, J = 7.2 Hz, 3H). HRMS (ESI): Calcd for
(C22H37ClN2O5S + H)+: 476.2112. Found: 476.2132.
Figure imgf000215_0001
[00496] FSA-46036: 1H NMR (600 MHz, CD3OD) δ 5.30 (d, J = 5.6 Hz, 1H), 4.57 (q, J = 6.8 Hz, 1H), 4.53 (d, J = 10.0 Hz, 1H), 4.30 (d, J = 10.0 Hz, 1H), 4.08 (dd, J = 9.9, 5.5 Hz, 2H), 3.82 (s, 1H), 3.58 (dd, J = 10.2, 3.2 Hz, 1H), 3.49– 3.40 (m, 1H), 3.11 (t, J = 12.6 Hz, 1H), 2.22 (ddt, J = 16.4, 12.1, 6.7 Hz, 1H), 2.19– 2.15 (m, 1H), 2.14 (s, 3H), 2.00 (d, J = 15.6 Hz, 1H), 1.92 (ddd, J = 13.2, 8.5, 3.8 Hz, 1H), 1.63 (s, 1H), 1.56 (q, J = 12.2, 11.7 Hz, 1H), 1.44 (d, J = 6.8 Hz, 3H), 1.43– 1.38 (m, 1H), 1.36– 1.27 (m, 9H), 0.90 (t, J = 6.9 Hz, 2H). HRMS (ESI): Calcd for (C22H41ClN2O5S + H)+: 480.2425. Found: 480.2431.
Figure imgf000215_0002
[00497] FSA-47091: (500 MHz, CD3OD) δ 5.30 (d, J = 5.2 Hz, 1H), 4.67– 4.58 (m, 1H), 4.46 (d, J = 10.0 Hz, 1H), 4.23 (d, J = 10.0 Hz, 1H), 4.13– 4.06 (m, 1H), 3.77 (s, 1H), 3.60– 3.54 (m, 1H), 3.52 (s, 1H), 3.20– 2.99 (m, 2H), 2.64 (s, 3H), 2.16– 2.02 (m, 4H), 2.01– 1.93 (m, 1H), 1.83– 1.74 (m, 1H), 1.52– 1.42 (m, 4H), 1.29 (s, 9H), 0.89 (t, J = 6.9 Hz, 3H). HRMS (ESI): Calcd for (C23H43ClN2O5S + H)+: 494.2581. Found: 494.2595.
Figure imgf000216_0001
[00498] FSA-47060: 1H NMR (600 MHz, CD3OD) δ 5.31 (d, J = 5.5 Hz, 1H), 4.61– 4.48 (m, 2H), 4.30 (d, J = 9.9 Hz, 1H), 4.12– 4.05 (m, 1H), 3.84 (s, 1H), 3.58 (d, J = 10.1 Hz, 1H), 3.45 (d, J = 15.0 Hz, 1H), 3.19– 3.08 (m, 1H), 2.24– 2.12 (m, 5H), 2.06– 1.97 (m, 1H), 1.97– 1.89 (m, 1H), 1.66– 1.53 (m, 2H), 1.46– 1.37 (m, 4H), 1.31 (s, 9H), 0.89 (t, J = 6.9 Hz, 2H). HRMS (ESI): Calcd for (C23H43ClN2O5S + H)+: 494.2581. Found: 494.2614.
Figure imgf000216_0002
[00499] FSA-47072: 1H NMR (600 MHz, CD3OD) δ 5.30 (d, J = 5.7 Hz, 1H), 4.61 (q, J = 7.1 Hz, 1H), 4.52 (d, J = 9.8 Hz, 1H), 4.29 (d, J = 9.9 Hz, 1H), 4.09 (dd, J = 10.2, 5.6 Hz, 1H), 3.77 (d, J = 3.4 Hz, 2H), 3.58 (dd, J = 10.2, 3.2 Hz, 1H), 3.42 (dd, J = 14.4, 9.5 Hz, 1H), 3.29– 3.19 (m, 1H), 2.76 (s, 2H), 2.24– 2.08 (m, 5H), 2.05– 1.97 (m, 1H), 1.87– 1.75 (m, 1H), 1.58– 1.51 (m, 2H), 1.46 (d, J = 6.7 Hz, 3H), 1.34– 1.23 (m, 11H), 0.89 (t, J = 7.0 Hz, 2H). HRMS (ESI): Calcd for (C24H45ClN2O5S + H)+: 508.2738. Found: 508.2748.
Figure imgf000216_0003
[00500] FSA-47090: 1H NMR (500 MHz, CD3OD) δ 5.32 (d, J = 5.3 Hz, 1H), 4.63– 4.49 (m, 2H), 4.32 (d, J = 10.0 Hz, 1H), 4.14– 4.08 (m, 2H), 3.84 (s, 1H), 3.59 (dd, J = 10.3, 3.2 Hz, 1H), 3.49– 3.41 (m, 1H), 3.13 (t, J = 12.7 Hz, 1H), 2.26– 2.12 (m, 5H), 2.07– 2.00 (m, 1H), 1.99– 1.91 (m, 1H), 1.70– 1.52 (m, 2H), 1.49– 1.42 (m, 4H), 1.32 (s, 14H), 0.91 (t, J = 6.9 Hz, 3H). HRMS (ESI): Calcd for (C24H45ClN2O5S + H)+: 508.2738. Found: 508.2756.
Figure imgf000217_0001
[00501] FSA-48010: 1H NMR (600 MHz, CD3OD) δ 5.30 (d, J = 5.6 Hz, 1H), 4.60– 4.49 (m, 2H), 4.30 (d, J = 9.9 Hz, 1H), 4.08 (dd, J = 10.2, 5.8 Hz, 2H), 3.82 (s, 1H), 3.57 (d, J = 10.3 Hz, 1H), 3.46– 3.42 (m, 1H), 3.12 (t, J = 12.6 Hz, 1H), 2.14 (s, 4H), 2.08– 1.96 (m, 2H), 1.96– 1.88 (m, 1H), 1.67– 1.58 (m, 2H), 1.48– 1.38 (m, 4H), 1.30 (s, 14H), 0.89 (t, J = 6.9 Hz, 2H). HRMS (ESI): Calcd for (C25H47ClN2O5S + H)+: 522.2894. Found: 522.2912.
Figure imgf000217_0002
[00502] FSA-48016: 1H NMR (600 MHz, CD3OD) δ 5.30 (d, J = 5.6 Hz, 1H), 4.61 (q, J = 6.8 Hz, 1H), 4.51 (d, J = 10.1 Hz, 1H), 4.28 (d, J = 9.5 Hz, 1H), 4.09 (dd, J = 10.1, 5.6 Hz, 1H), 3.77 (dd, J = 3.3, 1.3 Hz, 1H), 3.71 (s, 1H), 3.58 (dd, J = 10.1, 3.2 Hz, 1H), 3.25– 3.17 (m, 1H), 2.74 (s, 3H), 2.21– 2.12 (m, 4H), 2.05– 1.98 (m, 1H), 1.86– 1.79 (m, 1H), 1.55– 1.50 (d, J = 11.4 Hz, 2H), 1.47 (d, J = 6.8 Hz, 3H), 1.29 (s, 12H), 0.89 (t, J = 7.1 Hz, 3H). HRMS (ESI): Calcd for (C26H49ClN2O5S + H)+: 536.3051. Found: 536.3056.
Figure imgf000218_0001
[00503] FSA-48014: 1H NMR (600 MHz, CD3OD) δ 5.30 (d, J = 5.6 Hz, 1H), 4.57 (q, J = 6.8 Hz, 1H), 4.53 (d, J = 10.0 Hz, 1H), 4.30 (d, J = 9.9 Hz, 1H), 4.08 (dd, J = 10.1, 5.5 Hz, 2H), 3.82 (s, 1H), 3.57 (d, J = 7.2 Hz, 1H), 3.43 (d, J = 8.2 Hz, 1H), 3.11 (t, J = 12.7 Hz, 1H), 2.27– 2.10 (m, 5H), 2.00 (d, J = 16.1 Hz, 1H), 1.96– 1.89 (m, 1H), 1.64 (s, 1H), 1.56 (q, J = 12.0 Hz, 1H), 1.48– 1.37 (m, 5H), 1.29 (s, 16H), 0.89 (t, J = 6.9 Hz, 2H). HRMS (ESI): Calcd for (C26H49ClN2O5S + H)+: 536.3051. Found: 536.3067.
Figure imgf000218_0002
[00504] FSA-48027: 1H NMR (600 MHz, CD3OD) δ 5.22 (d, J = 5.6 Hz, 1H), 4.60– 4.53 (m, 1H), 4.48 (s, 1H), 4.33 (d, J = 9.8 Hz, 1H), 4.12 (d, J = 9.8 Hz, 1H), 4.01 (dd, J = 10.2, 5.6 Hz, 1H), 3.68 (d, J = 3.3 Hz, 1H), 3.50 (dd, J = 10.1, 3.4 Hz, 1H), 2.99– 2.83 (m, 2H), 2.47 (s, 3H), 2.10– 2.03 (m, 4H), 1.99– 1.92 (m, 1H), 1.89– 1.84 (m, 1H), 1.69– 1.62 (m, 1H), 1.41 (d, J = 6.8 Hz, 3H), 1.37– 1.28 (m, 3H), 1.20 (s, 16H), 0.81 (t, J = 6.9 Hz, 3H). HRMS (ESI): Calcd for (C27H51ClN2O5S + H)+: 550.3207. Found: 550.3219.
Figure imgf000219_0001
[00505] FSA-47095: 1H NMR (600 MHz, CD3OD) δ 6.06 (d, J = 15.7 Hz, 1H), 5.81 (t, J = 6.5 Hz, 1H), 5.72 (dt, J = 15.7, 7.0 Hz, 1H), 5.30 (d, J = 5.7 Hz, 1H), 4.56 (q, J = 6.8 Hz, 1H), 4.51 (d, J = 10.0 Hz, 1H), 4.30 (d, J = 10.0 Hz, 1H), 4.08 (dd, J = 10.2, 5.6 Hz, 1H), 4.04 (d, J = 9.4 Hz, 1H), 3.83 (s, 1H), 3.57 (dd, J = 10.2, 3.2 Hz, 1H), 3.50 (dd, J = 13.5, 7.7 Hz, 1H), 3.24– 3.17 (m, 1H), 2.88 (ddd, J = 15.6, 9.3, 5.7 Hz, 1H), 2.82– 2.72 (m, 2H), 2.66 (dd, J = 17.3, 9.7 Hz, 1H), 2.14 (s, 2H), 2.11 (q, J = 7.0 Hz, 2H), 1.45– 1.36 (m, 5H), 1.36– 1.22 (m, 7H), 0.89 (t, J = 7.0 Hz, 3H). HRMS (ESI): Calcd for (C25H43ClN2O5S + H)+: 518.2581. Found: 518.2602.
Figure imgf000219_0002
[00506] FSA-48013: 1H NMR (600 MHz, CD3OD) δ 6.06 (d, J = 15.6 Hz, 1H), 5.81 (t, J = 6.4 Hz, 1H), 5.72 (dt, J = 15.6, 7.0 Hz, 1H), 5.31 (d, J = 5.6 Hz, 1H), 4.55 (q, J = 6.8 Hz, 1H), 4.51 (d, J = 10.0 Hz, 1H), 4.30 (d, J = 10.0 Hz, 1H), 4.12– 4.04 (m, 2H), 3.84 (s, 1H), 3.58 (dd, J = 10.2, 3.2 Hz, 1H), 3.51 (dd, J = 13.8, 7.3 Hz, 1H), 3.22 (t, J = 11.8 Hz, 1H), 2.89 (ddd, J = 15.9, 9.4, 5.6 Hz, 1H), 2.84– 2.73 (m, 2H), 2.67 (dd, J = 17.3, 9.7 Hz, 1H), 2.14 (s, 3H), 2.11 (q, J = 7.1 Hz, 2H), 1.46– 1.36 (m, 5H), 1.30 (s, 9H), 0.89 (t, J = 7.0 Hz, 2H). HRMS (ESI): Calcd for (C26H45ClN2O5S + H)+: 532.2738. Found: 532.2763.
Figure imgf000220_0001
[00507] FSA-45062: 1H NMR (600 MHz, CD3OD) δ 5.29 (d, J = 5.7 Hz, 1H), 4.60 (q, J = 6.8 Hz, 1H), 4.38 (d, J = 10.0 Hz, 1H), 4.20 (d, J = 10.0 Hz, 1H), 4.08 (dd, J = 10.2, 5.6 Hz, 1H), 3.77 (d, J = 3.5 Hz, 1H), 3.60 (t, J = 5.9 Hz, 1H), 3.56 (dd, J = 10.2, 3.4 Hz, 1H), 3.06 (ddd, J = 14.1, 5.3, 2.8 Hz, 1H), 2.72 (ddd, J = 14.2, 11.1, 1.9 Hz, 1H), 2.14 (s, 3H), 2.05– 1.95 (m, 2H), 1.91– 1.84 (m, 1H), 1.72 (td, J = 10.2, 3.8 Hz, 1H), 1.44 (d, J = 6.8 Hz, 3H), 1.39– 1.20 (m, 6H), 0.90 (t, J = 7.4 Hz, 3H). HRMS (ESI): Calcd for (C18H33ClN2O5S + H)+: 424.1799. Found: 424.1803.
Figure imgf000220_0002
[00508] FSA-48053: 1H NMR (600 MHz, CD3OD) δ 6.06 (d, J = 15.7 Hz, 1H), 5.82 (t, J = 6.5 Hz, 1H), 5.71 (dt, J = 15.6, 7.0 Hz, 1H), 5.30 (d, J = 5.6 Hz, 1H), 4.56 (q, J = 6.8 Hz, 1H), 4.51 (d, J = 10.0 Hz, 1H), 4.30 (d, J = 10.0 Hz, 1H), 4.13– 4.01 (m, 2H), 3.83 (d, J = 3.3 Hz, 1H), 3.57 (dd, J = 10.2, 3.2 Hz, 1H), 3.50 (dd, J = 13.7, 7.1 Hz, 1H), 3.21 (t, J = 11.7 Hz, 1H), 2.88 (ddd, J = 15.4, 9.2, 5.6 Hz, 1H), 2.84– 2.71 (m, 2H), 2.66 (dd, J = 17.3, 9.7 Hz, 1H), 2.20– 2.07 (m, 5H), 1.55 (dp, J = 13.3, 6.7 Hz, 1H), 1.42 (d, J = 6.8 Hz, 3H), 1.28 (q, J = 7.2 Hz, 2H), 0.89 (d, J = 6.6 Hz, 6H). HRMS (ESI): Calcd for (C23H39ClN2O5S + H)+: 490.2269. Found: 490.2273.
Figure imgf000221_0001
[00509] FSA-48063: 1H NMR (600 MHz, CD3OD) δ 5.19 (d, J = 5.6 Hz, 1H), 4.45 (q, J = 6.6 Hz, 1H), 4.41 (d, J = 9.7 Hz, 1H), 4.18 (d, J = 10.0 Hz, 1H), 4.00– 3.94 (m, 2H), 3.71 (s, 1H), 3.46 (dd, J = 10.5, 2.9 Hz, 1H), 3.32 (d, J = 12.6 Hz, 1H), 3.00 (t, J = 12.5 Hz, 1H), 2.16 – 2.04 (m, 2H), 2.03 (s, 3H), 1.91– 1.86 (m, 1H), 1.86– 1.77 (m, 1H), 1.52 (s, 1H), 1.49– 1.37 (m, 3H), 1.32 (d, J = 6.8 Hz, 4H), 1.31– 1.26 (m, 1H), 1.19 (s, 6H), 1.09– 1.05 (m, 2H), 0.76 (d, J = 6.6 Hz, 5H). HRMS (ESI): Calcd for (C23H43ClN2O5S + H)+: 494.2581. Found: 494.2593.
Figure imgf000221_0002
[00510] FSA-47039: 1H NMR (500 MHz, CD3OD) δ 6.08 (d, J = 15.7 Hz, 1H), 5.84 (t, J = 6.3 Hz, 1H), 5.74 (dt, J = 15.1, 7.1 Hz, 1H), 5.32 (d, J = 5.5 Hz, 1H), 4.58 (q, J = 6.6 Hz, 1H), 4.53 (d, J = 10.0 Hz, 1H), 4.32 (d, J = 9.9 Hz, 1H), 4.13– 4.04 (m, 2H), 3.84 (s, 1H), 3.59 (d, J = 10.0 Hz, 1H), 3.57– 3.48 (m, 1H), 3.24 (t, J = 11.7 Hz, 1H), 2.91 (dt, J = 14.9, 6.6 Hz, 1H), 2.87– 2.73 (m, 2H), 2.68 (dd, J = 17.3, 9.1 Hz, 1H), 2.16 (s, 3H), 2.14 (t, J = 7.0 Hz, 2H), 1.90 (hept, J = 7.7 Hz, 1H), 1.80– 1.71 (m, 2H), 1.70– 1.58 (m, 2H), 1.61– 1.49 (m, 2H), 1.44 (d, J = 6.8 Hz, 3H), 1.24– 1.12 (m, 2H). HRMS (ESI): Calcd for
(C24H39ClN2O5S + H)+: 502.2268. Found: 502.2277.
Figure imgf000222_0001
[00511] FSA-47041: 1H NMR (500 MHz, CD3OD) δ 5.32 (d, J = 5.7 Hz, 1H), 4.59 (q, J = 6.6 Hz, 1H), 4.55 (d, J = 10.1 Hz, 1H), 4.32 (d, J = 9.9 Hz, 1H), 4.12– 4.07 (m, 2H), 3.84 (s, 1H), 3.60 (dd, J = 10.2, 3.0 Hz, 1H), 3.13 (t, J = 12.6 Hz, 1H), 2.16 (s, 3H), 1.99– 1.87 (m, 1H), 1.78 (s, 3H), 1.69– 1.50 (m, 5H), 1.46 (d, J = 6.7 Hz, 3H), 1.41– 1.28 (m, 6H), 1.15– 1.03 (m, 2H). HRMS (ESI): Calcd for (C24H44ClN2O5S + H)+: 506.2581. Found: 506.2598.
Figure imgf000222_0002
[00512] FSA-47078: 1H NMR (600 MHz, CD3OD) δ 5.30 (d, J = 5.7 Hz, 1H), 4.57 (q, J = 6.7 Hz, 1H), 4.52 (d, J = 10.0 Hz, 1H), 4.29 (d, J = 10.0 Hz, 1H), 4.12– 4.03 (m, 2H), 3.81 (s, 1H), 3.57 (dd, J = 10.2, 3.2 Hz, 1H), 3.46– 3.39 (m, 1H), 3.09 (t, J = 12.6 Hz, 1H), 2.20 (tdd, J = 20.3, 8.3, 3.8 Hz, 2H), 2.14 (s, 3H), 2.03– 1.97 (m, 1H), 1.92 (ddd, J = 12.4, 8.6, 4.1 Hz, 1H), 1.76– 1.68 (m, 4H), 1.68– 1.60 (m, 2H), 1.59– 1.52 (m, 2H), 1.52 (s, 1H), 1.47 (d, J = 6.9 Hz, 1H), 1.44 (d, J = 6.8 Hz, 3H), 1.42– 1.37 (m, 1H), 1.37– 1.31 (m, 2H), 1.31– 1.13 (m, 9H), 0.94– 0.82 (m, 2H). HRMS (ESI): Calcd for (C +
25H45ClN2O5S + H) : 520.2738. Found: 520.273.
Figure imgf000222_0003
[00513] FSA-49036: 1H NMR (600 MHz, CD3OD) δ 5.30 (d, J = 5.6 Hz, 1H), 4.62 (q, J = 6.7, 6.0 Hz, 1H), 4.50 (d, J = 9.9 Hz, 1H), 4.27 (d, J = 10.0 Hz, 1H), 4.09 (dd, J = 10.2, 5.6 Hz, 1H), 3.76 (s, 1H), 3.68 (s, 1H), 3.59 (dd, J = 10.2, 3.4 Hz, 1H), 3.26– 3.15 (m, 2H), 2.72 (s, 2H), 2.22– 2.16 (m, 2H), 2.15 (s, 3H), 2.00 (d, J = 15.0 Hz, 1H), 1.92 (s, 3H), 1.84– 1.78 (m, 1H), 1.74 (d, J = 11.9 Hz, 3H), 1.66 (d, J = 12.2 Hz, 3H), 1.59– 1.36 (m, 12H), 1.32 (q, J = 11.0 Hz, 2H), 1.21 (dt, J = 11.1, 6.2 Hz, 2H), 1.11– 1.01 (m, 2H). HRMS (ESI): Calcd for (C29H49ClN2O5S + H)+: 572.3051. Found: 572.305.
Figure imgf000223_0001
[00514] FSA-49005: 1H NMR (600 MHz, CD3OD) δ 7.82– 7.71 (m, 3H), 7.60 (s, 1H), 7.40 (dddd, J = 18.5, 8.2, 6.9, 1.6 Hz, 2H), 7.33 (dd, J = 8.3, 2.0 Hz, 1H), 6.06 (dd, J = 15.6, 3.3 Hz, 1H), 5.82– 5.71 (m, 2H), 5.30 (d, J = 5.6 Hz, 1H), 4.58– 4.43 (m, 2H), 4.29 (d, J = 10.0 Hz, 1H), 4.11– 4.01 (m, 2H), 3.83 (s, 1H), 3.58 (dd, J = 10.2, 3.3 Hz, 1H), 3.48 (dd, J = 14.0, 7.3 Hz, 1H), 3.18 (t, J = 11.7 Hz, 1H), 2.87 (t, J = 7.6 Hz, 2H), 2.84– 2.81 (m, 1H), 2.81– 2.59 (m, 4H), 2.52 (q, J = 7.4 Hz, 2H), 2.13 (s, 3H), 1.36 (d, J = 6.8 Hz, 3H). HRMS (ESI): Calcd for (C30H39ClN2O5S + H)+: 574.2268. Found: 574.2284.
Figure imgf000223_0002
[00515] FSA-49006: 1H NMR (600 MHz, CD3OD) δ 7.77 (dd, J = 16.7, 8.1 Hz, 3H), 7.60 (s, 1H), 7.40 (dt, J = 19.9, 7.1 Hz, 2H), 7.33 (d, J = 8.4 Hz, 1H), 5.30 (d, J = 5.6 Hz, 1H), 4.55 (q, J = 6.8 Hz, 1H), 4.51 (d, J = 9.8 Hz, 1H), 4.29 (d, J = 10.0 Hz, 1H), 4.11– 4.04 (m, 2H), 3.82 (s, 1H), 3.56 (d, J = 3.2 Hz, 1H), 3.40 (dd, J = 14.1, 5.5 Hz, 1H), 3.08 (t, J = 12.5 Hz, 1H), 2.78 (t, J = 7.6 Hz, 2H), 2.23– 2.15 (m, 1H), 2.14 (s, 3H), 1.98– 1.92 (m, 1H), 1.88 (dt, J = 19.3, 5.9 Hz, 1H), 1.72 (p, J = 7.4 Hz, 2H), 1.61 (s, 1H), 1.53 (q, J = 12.0 Hz, 1H), 1.41 (d, J = 7.0 Hz, 3H), 1.40– 1.30 (m, 5H). HRMS (ESI): Calcd for (C30H43ClN2O5S + H)+: 578.2581. Found: 578.2593.
Figure imgf000224_0001
[00516] FSA-48099: 1H NMR (600 MHz, CD3OD) δ 7.22 (dd, J = 8.2, 5.2 Hz, 1H), 6.98 (dd, J = 9.2, 2.5 Hz, 1H), 6.89 (td, J = 8.8, 2.6 Hz, 1H), 6.21 (dd, J = 15.0, 2.4 Hz, 1H), 5.91 (t, J = 6.5 Hz, 1H), 5.81 (dq, J = 14.2, 6.9 Hz, 1H), 5.37 (d, J = 5.7 Hz, 1H), 4.65 (q, J = 6.5, 5.5 Hz, 1H), 4.57 (d, J = 9.9 Hz, 1H), 4.35 (d, J = 10.0 Hz, 1H), 4.15 (dd, J = 10.2, 5.6 Hz, 1H), 4.08 (d, J = 9.0 Hz, 1H), 3.88 (s, 1H), 3.64 (dd, J = 10.2, 3.2 Hz, 1H), 3.55 (dd, J = 13.7, 7.3 Hz, 1H), 3.28 (p, J = 8.2, 7.3 Hz, 2H), 2.98– 2.76 (m, 5H), 2.73 (d, J = 9.3 Hz, 1H), 2.67 – 2.61 (m, 1H), 2.39 (dt, J = 14.2, 7.2 Hz, 1H), 2.36– 2.29 (m, 1H), 2.22 (s, 3H), 1.84 (ddtd, J = 12.7, 8.7, 7.2, 1.8 Hz, 1H), 1.50 (d, J = 6.8 Hz, 3H). HRMS (ESI): Calcd for
(C28H38ClFN2O5S + H)+: 568.2174. Found: 568.2199.
Figure imgf000224_0002
[00517] FSA-49001: 1H NMR (600 MHz, CD3OD) δ 7.13 (dd, J = 8.2, 5.2 Hz, 1H), 6.87 (dd, J = 9.3, 2.6 Hz, 1H), 6.80 (td, J = 8.8, 2.5 Hz, 1H), 5.30 (d, J = 5.6 Hz, 1H), 4.57 (q, J = 6.5, 6.0 Hz, 1H), 4.53 (d, J = 9.9 Hz, 1H), 4.30 (d, J = 10.0 Hz, 1H), 4.14– 4.05 (m, 2H), 3.83 (s, 1H), 3.58 (dd, J = 10.2, 3.2 Hz, 1H), 3.45 (dd, J = 14.0, 5.5 Hz, 1H), 3.17– 3.05 (m, 2H), 2.86 (ddd, J = 13.9, 8.5, 4.7 Hz, 1H), 2.76 (dt, J = 15.7, 8.3 Hz, 1H), 2.31 (dtd, J = 12.6, 8.0, 4.6 Hz, 1H), 2.21 (dddt, J = 22.4, 11.5, 8.4, 4.1 Hz, 2H), 2.14 (s, 3H), 2.02 (d, J = 15.2 Hz, 1H), 1.94 (td, J = 9.2, 4.3 Hz, 1H), 1.81 (tt, J = 11.3, 5.8 Hz, 1H), 1.70 (dp, J = 11.9, 8.6, 8.2 Hz, 2H), 1.58 (q, J = 12.6 Hz, 1H), 1.49– 1.31 (m, 10H). HRMS (ESI): Calcd for (C28H42ClFN2O5S + H)+: 572.2487. Found: 572.2503.
Figure imgf000225_0001
[00518] FSA-46027: 1H NMR (600 MHz, CD3OD) δ 7.33 (d, J = 15.9 Hz, 1H), 6.39 (s, 1H), 5.99 (d, J = 15.8 Hz, 1H), 5.30 (d, J = 5.4 Hz, 1H), 4.57 (q, J = 6.9 Hz, 1H), 4.53 (d, J = 9.9 Hz, 1H), 4.31 (d, J = 10.1 Hz, 1H), 4.14– 4.05 (m, 2H), 3.83 (s, 1H), 3.74 (s, 3H), 3.61– 3.51 (m, 2H), 3.27 (t, J = 12.1 Hz, 1H), 3.04– 2.96 (m, 1H), 2.92 (dd, J = 17.9, 7.5 Hz, 1H), 2.82 (dd, J = 17.5, 7.1 Hz, 1H), 2.74 (dd, J = 17.8, 9.3 Hz, 1H), 2.15 (s, 3H), 1.43 (d, J = 7.0 Hz, 3H). HRMS (ESI): Calcd for (C20H31ClN2O7S + H)+: 478.154 Found: 478.1548.
Figure imgf000225_0002
[00519] FSA-46029: 1H NMR (600 MHz, CD3OD) δ 5.30 (d, J = 5.7 Hz, 1H), 4.61 (q, J = 6.7 Hz, 1H), 4.56 (d, J = 10.1 Hz, 1H), 4.41 (d, J = 10.0 Hz, 1H), 4.10 (dd, J = 10.2, 5.6 Hz, 1H), 4.01 (d, J = 7.1 Hz, 1H), 3.93 (s, 1H), 3.85 (t, J = 7.3 Hz, 1H), 3.62 (dd, J = 10.2, 3.2 Hz, 1H), 3.51 (td, J = 12.3, 11.7, 5.2 Hz, 1H), 3.33 (dd, J = 13.9, 5.2 Hz, 1H), 2.63 (dd, J = 16.5, 7.9 Hz, 1H), 2.55 (dd, J = 16.5, 6.7 Hz, 1H), 2.38– 2.32 (m, 1H), 2.18 (dd, J = 15.1, 5.8 Hz, 2H), 2.15 (s, 4H), 1.97 (ddd, J = 13.8, 8.8, 5.2 Hz, 1H), 1.87– 1.79 (m, 1H), 1.73– 1.65 (m, 1H), 1.45 (d, J = 6.8 Hz, 3H). HRMS (ESI): Calcd for (C20H35ClN2O7S + H)+: 482.1853. Found: 482.1864.
Figure imgf000226_0001
[00520] FSA-45070: 1H NMR (600 MHz, CD3OD) δ 7.30 (d, J = 15.8 Hz, 1H), 6.38 (t, J = 6.6 Hz, 1H), 5.94 (d, J = 15.8 Hz, 1H), 5.30 (d, J = 5.6 Hz, 1H), 4.58 (q, J = 6.8 Hz, 2H), 4.54 (d, J = 10.1 Hz, 1H), 4.31 (d, J = 9.9 Hz, 1H), 4.11– 4.05 (m, 2H), 3.80 (s, 1H), 3.57 (dd, J = 10.2, 3.3 Hz, 2H), 3.26 (ddt, J = 13.9, 9.7, 2.2 Hz, 1H), 3.00 (ddd, J = 15.4, 9.7, 5.4 Hz, 1H), 2.93 (ddd, J = 17.5, 7.5, 2.3 Hz, 1H), 2.82 (dd, J = 17.4, 7.2 Hz, 1H), 2.79– 2.71 (m, 1H), 2.15 (s, 3H), 1.43 (d, J = 6.9 Hz, 3H). HRMS (ESI): Calcd for (C19H29ClN2O7S + H)+: 464.1384. Found: 464.1385.
Figure imgf000226_0002
[00521] FSA-45076: 1H NMR (600 MHz, CD3OD) δ 5.30 (d, J = 5.7 Hz, 1H), 4.58 (q, J = 6.8 Hz, 1H), 4.53 (d, J = 9.9 Hz, 1H), 4.30 (d, J = 10.1 Hz, 1H), 4.08 (dd, J = 10.2, 5.7 Hz, 2H), 3.81 (s, 1H), 3.58 (dd, J = 10.1, 2.9 Hz, 1H), 3.45 (d, J = 14.3 Hz, 1H), 3.12 (t, J = 13.9 Hz, 1H), 2.43– 2.36 (m, 1H), 2.33 (t, J = 7.5 Hz, 2H), 2.28– 2.21 (m, 1H), 2.20– 2.16 (m, 1H), 2.15 (s, 3H), 2.03 (d, J = 15.1 Hz, 1H), 1.97 (d, J = 14.9 Hz, 1H), 1.69 (s, 1H), 1.60 (q, J = 7.3 Hz, 2H), 1.44 (d, J = 6.7 Hz, 3H). HRMS (ESI): Calcd for (C19H33ClN2O7S + H)+: 468.1697. Found: 468.1682.
Figure imgf000227_0001
[00522] FSA-45090: 1H NMR (500 MHz, CD3OD) δ 7.18 (d, J = 15.7 Hz, 1H), 6.30 (t, J = 6.4 Hz, 1H), 6.05 (d, J = 15.7 Hz, 1H), 5.29 (d, J = 5.5 Hz, 1H), 4.58 (q, J = 6.8 Hz, 1H), 4.49 (d, J = 10.3 Hz, 1H), 4.26 (d, J = 10.0 Hz, 1H), 4.08 (dd, J = 10.2, 5.6 Hz, 1H), 3.99 (s, 1H), 3.78 (s, 1H), 3.56 (dd, J = 10.2, 3.0 Hz, 1H), 3.53– 3.42 (m, 1H), 3.48 (s, 1H), 3.23 (t, J = 12.3 Hz, 1H), 2.91 (s, 1H), 2.79-2.63 (m, 2H), 2.14 (d, J = 0.9 Hz, 2H), 1.43 (dd, J = 6.9, 1.2 Hz, 2H). HRMS (ESI): Calcd for (C19H30ClN3O6S + H)+: 463.1544. Found: 463.1539.
Figure imgf000227_0002
[00523] FSA-46001: 1H NMR (500 MHz, CD3OD) δ 5.32 (d, J = 5.7 Hz, 1H), 4.60 (d, J = 7.3 Hz, 1H), 4.53 (ddd, J = 9.7, 7.8, 1.6 Hz, 1H), 4.31 (dd, J = 10.1, 1.3 Hz, 1H), 4.10 (dd, J = 10.2, 5.8 Hz, 2H), 3.81 (s, 1H), 3.59 (dd, J = 10.2, 3.3 Hz, 1H), 3.20– 3.08 (m, 1H), 2.56 (q, J = 7.0 Hz, 2H), 2.25– 2.12 (m, 7H), 2.09– 1.98 (m, 2H), 1.99– 1.91 (m, 1H), 1.68– 1.52 (m, 4H), 1.46 (d, J = 6.7 Hz, 3H), 1.44– 1.25 (m, 3H). HRMS (ESI): Calcd for
(C20H35ClN2O6S + H)+: 466.1904. Found: 466.1909.
Figure imgf000228_0001
[00524] FSA-410001: 1H NMR (600 MHz, CD3OD) δ 5.30 (d, J = 5.7 Hz, 1H), 4.57 (q, J = 6.9 Hz, 1H), 4.53 (d, J = 10.0 Hz, 1H), 4.30 (d, J = 9.8 Hz, 1H), 4.11– 4.02 (m, 2H), 3.81 (d, J = 3.3 Hz, 1H), 3.58 (dd, J = 17.7, 3.3 Hz, 1H), 3.47– 3.40 (m, 1H), 3.12 (t, J = 7.1 Hz, 2H), 2.74 (d, J = 8.2 Hz, 1H), 2.21 (t, J = 7.5 Hz, 3H), 2.14 (s, 3H), 2.03 (d, J = 14.9 Hz, 1H), 1.99 – 1.92 (m, 1H), 1.69– 1.62 (m, 1H), 1.62– 1.56 (m, 3H), 1.56– 1.49 (m, 2H), 1.44 (d, J = 6.7 Hz, 4H), 0.91 (t, J = 7.4 Hz, 3H). HRMS (ESI): Calcd for (C22H40ClN3O6S + H)+:
509.2326. Found: 509.2332.
Figure imgf000228_0002
[00525] FSA-410037: 1H NMR (600 MHz, CD3OD) δ 5.30 (d, J = 5.6 Hz, 1H), 4.57 (q, J = 6.8 Hz, 1H), 4.52 (d, J = 10.0 Hz, 1H), 4.29 (d, J = 10.0 Hz, 1H), 4.12– 4.03 (m, 2H), 3.82 (d, J = 3.2 Hz, 1H), 3.57 (dd, J = 10.1, 3.2 Hz, 1H), 3.43 (dd, J = 13.7, 5.3 Hz, 1H), 3.15 (t, J = 7.0 Hz, 2H), 3.11 (t, J = 12.7 Hz, 1H), 2.21 (t, J = 7.6 Hz, 3H), 2.18– 2.10 (m, 5H), 2.02 (d, J = 14.0 Hz, 1H), 1.97– 1.90 (m, 1H), 1.67– 1.53 (m, 5H), 1.50– 1.39 (m, 6H), 1.35 (h, J = 7.3 Hz, 2H), 0.93 (t, J = 7.4 Hz, 3H). HRMS (ESI): Calcd for (C +
23H42ClN3O6S + H) :
523.2483. Found: 523.2462.
Figure imgf000229_0001
[00526] FSA-410061: 1H NMR (600 MHz, CD3OD) δ 5.35 (d, J = 5.7 Hz, 1H), 4.63 (q, J = 6.9 Hz, 1H), 4.57 (d, J = 10.0 Hz, 1H), 4.34 (d, J = 10.0 Hz, 1H), 4.17– 4.07 (m, 2H), 3.86 (d, J = 3.2 Hz, 1H), 3.63 (dd, J = 10.2, 3.2 Hz, 1H), 3.43 (tt, J = 14.6, 6.1 Hz, 6H), 3.16 (t, J = 12.6 Hz, 1H), 2.44 (t, J = 7.7 Hz, 2H), 2.31– 2.16 (m, 5H), 2.08 (d, J = 15.8 Hz, 1H), 2.03– 1.97 (m, 1H), 1.74 (s, 1H), 1.64 (q, J = 7.5, 6.9 Hz, 4H), 1.49 (d, J = 7.0 Hz, 4H), 1.24 (t, J = 7.1 Hz, 3H), 1.15 (t, J = 7.1 Hz, 3H). HRMS (ESI): Calcd for (C23H42ClN3O6S + H)+:
523.2483. Found: 523.2505.
Figure imgf000229_0002
[00527] FSA-410049: 1H NMR (600 MHz, CD3OD) δ 5.30 (d, J = 5.6 Hz, 1H), 4.60– 4.54 (m, 1H), 4.53 (d, J = 10.0 Hz, 1H), 4.30 (d, J = 10.0 Hz, 1H), 4.12– 4.05 (m, 2H), 3.83 (s, 1H), 3.58 (dd, J = 10.2, 3.2 Hz, 1H), 3.44 (d, J = 11.8 Hz, 1H), 3.41– 3.34 (m, 1H), 3.12 (t, J = 12.5 Hz, 1H), 2.26– 2.16 (m, 2H), 2.14 (s, 3H), 2.03 (d, J = 13.7 Hz, 2H), 1.93 (s, 1H), 1.68– 1.50 (m, 5H), 1.44 (d, J = 6.8 Hz, 3H), 1.31 (s, 9H). HRMS (ESI): Calcd for
(C23H42ClN3O6S + H)+: 523.2483. Found: 523.2469.
Figure imgf000230_0001
[00528] FSA-410060: 1H NMR (500 MHz, CD3OD) δ 5.32 (d, J = 5.6 Hz, 1H), 4.59 (q, J = 6.7, 6.3 Hz, 1H), 4.55 (dd, J = 10.0, 1.6 Hz, 1H), 4.31 (d, J = 9.9 Hz, 1H), 4.14– 4.04 (m, 2H), 3.83 (d, J = 3.4 Hz, 1H), 3.59 (dd, J = 10.2, 3.4 Hz, 1H), 3.51 (t, J = 6.8 Hz, 2H), 3.48– 3.45 (m, 1H), 3.42 (t, J = 6.9 Hz, 3H), 3.14 (t, J = 12.6 Hz, 1H), 2.38 (t, J = 7.6 Hz, 2H), 2.27 – 2.13 (m, 5H), 2.09– 1.94 (m, 5H), 1.90 (p, J = 7.1 Hz, 2H), 1.71 (s, 1H), 1.62 (q, J = 7.2 Hz, 3H), 1.46 (d, J = 6.8 Hz, 4H). HRMS (ESI): Calcd for (C23H40ClN3O6S + H)+: 521.2326. Found: 521.2365.
Figure imgf000230_0002
[00529] FSA-410052: 1H NMR (600 MHz, CD3OD) δ 5.30 (d, J = 5.6 Hz, 1H), 4.59– 4.51 (m, 2H), 4.30 (d, J = 10.0 Hz, 1H), 4.11 (t, J = 5.6 Hz, 1H), 4.08 (dd, J = 10.2, 5.7 Hz, 1H), 3.85 (s, 1H), 3.58 (dd, J = 10.2, 3.3 Hz, 1H), 3.45 (dd, J = 13.7, 5.7 Hz, 1H), 3.29 (s, 1H), 3.12 (t, J = 12.5 Hz, 1H), 3.00 (t, J = 6.1 Hz, 2H), 2.22 (t, J = 7.6 Hz, 4H), 2.14 (s, 3H), 2.09 – 2.00 (m, 2H), 1.99– 1.89 (m, 1H), 1.76– 1.70 (m, 4H), 1.69– 1.54 (m, 6H), 1.44 (d, J = 6.7 Hz, 5H), 1.31– 1.15 (m, 4H), 0.92 (q, J = 12.2 Hz, 2H). HRMS (ESI): Calcd for
(C26H46ClN3O6S + H)+: 563.2796. Found: 563.2778.
Figure imgf000231_0001
[00530] FSA-410095: 1H NMR (500 MHz, CD3OD) δ 7.37– 7.25 (m, 2H), 7.06 (t, J = 8.8 Hz, 2H), 5.32 (d, J = 5.6 Hz, 1H), 4.59 (q, J = 6.8 Hz, 2H), 4.54 (d, J = 9.9 Hz, 1H), 4.34 (s, 2H), 4.31 (d, J = 10.0 Hz, 1H), 4.10 (dd, J = 10.2, 5.5 Hz, 2H), 3.84 (s, 1H), 3.60 (dd, J = 10.2, 3.3 Hz, 1H), 3.44 (dd, J = 13.9, 5.6 Hz, 1H), 3.11 (t, J = 12.5 Hz, 1H), 2.28 (t, J = 7.3 Hz, 2H), 2.20 (s, 2H), 2.16 (s, 3H), 2.07– 1.99 (m, 1H), 1.99– 1.90 (m, 1H), 1.62 (dd, J = 12.5, 5.6 Hz, 4H), 1.46 (d, J = 6.7 Hz, 3H). HRMS (ESI): Calcd for (C26H39ClFN3O6S + H)+: 575.2232. Found: 575.225.
Figure imgf000231_0002
[00531] FSA-410033: 1H NMR (500 MHz, CD3OD) δ 7.55 (d, J = 11.3 Hz, 1H), 7.30 (q, J = 7.6 Hz, 1H), 7.24 (d, J = 8.2 Hz, 1H), 6.82 (t, J = 8.4 Hz, 1H), 5.32 (d, J = 5.6 Hz, 1H), 4.63– 4.50 (m, 2H), 4.31 (d, J = 10.0 Hz, 1H), 4.18– 4.05 (m, 2H), 3.90– 3.82 (m, 1H), 3.60 (dd, J = 10.2, 3.1 Hz, 1H), 3.49 (dd, J = 14.4, 5.5 Hz, 1H), 3.32 (s, 2H), 3.16 (t, J = 12.6 Hz, 1H), 2.44 (t, J = 7.0 Hz, 2H), 2.31– 2.19 (m, 2H), 2.16 (s, 3H), 2.09 (d, J = 12.9 Hz, 1H), 2.04– 1.97 (m, 1H), 1.79– 1.60 (m, 4H), 1.46 (d, J = 6.6 Hz, 3H). HRMS (ESI): Calcd for (C25H37ClFN3O6S + H)+: 561.2076. Found: 561.207.
Figure imgf000232_0001
[00532] FSA-45086: 1H NMR (600 MHz, CD3OD) δ 6.43 (d, J = 15.8 Hz, 1H), 6.04 (t, J = 6.4 Hz, 1H), 5.71 (dt, J = 15.8, 6.8 Hz, 1H), 5.30 (d, J = 5.6 Hz, 1H), 4.59 (q, J = 6.8 Hz, 1H), 4.46 (d, J = 10.0 Hz, 1H), 4.24 (d, J = 10.0 Hz, 1H), 4.08 (dd, J = 10.2, 5.6 Hz, 1H), 4.02 (dd, J = 7.8, 3.5 Hz, 1H), 3.75 (s, 1H), 3.61 (d, J = 6.1 Hz, 2H), 3.54 (dd, J = 10.2, 3.3 Hz, 1H), 3.45 (ddd, J = 13.8, 7.2, 2.4 Hz, 1H), 3.30– 3.21 (m, 1H), 2.94– 2.82 (m, 2H), 2.73 (dd, J = 17.4, 6.9 Hz, 1H), 2.64 (dd, J = 17.4, 9.9 Hz, 1H), 2.14 (s, 3H), 1.43 (d, J = 6.8 Hz, 3H). HRMS (ESI): Calcd for (C19H32ClN3O5S + H)+: 449.1751. Found: 449.1757.
Figure imgf000232_0002
[00533] FSA-45098: 1H NMR (600 MHz, CD3OD) δ 5.30 (d, J = 5.6 Hz, 1H), 4.60– 4.54 (m, 1H), 4.53 (d, J = 8.6 Hz, 1H), 4.30 (d, J = 10.0 Hz, 1H), 4.15– 4.11 (m, 1H), 4.08 (dd, J = 10.2, 5.6 Hz, 1H), 3.84 (s, 1H), 3.58 (d, J = 10.3 Hz, 1H), 3.51– 3.37 (m, 1H), 3.15 (t, J = 12.6 Hz, 1H), 2.91 (t, J = 7.6 Hz, 2H), 2.23– 2.15 (m, 2H), 2.14 (s, 3H), 2.07– 2.00 (m, 2H), 1.94 (d, J = 13.5 Hz, 1H), 1.67 (p, J = 7.7 Hz, 2H), 1.59 (d, J = 15.4 Hz, 1H), 1.44 (d, J = 6.8 Hz, 3H), 1.38 (p, J = 7.9, 6.9 Hz, 2H).HRMS (ESI): Calcd for (C19H36ClN3O5S + H)+:
453.2064. Found: 453.2042.
Figure imgf000232_0003
[00534] FSA-411081: 1H NMR (600 MHz, CD3OD) δ 5.30 (d, J = 5.6 Hz, 1H), 4.57 (q, J = 6.4 Hz, 1H), 4.52 (d, J = 9.8 Hz, 1H), 4.30 (d, J = 9.9 Hz, 1H), 4.13– 4.05 (m, 2H), 3.83 (s, 1H), 3.58 (dd, J = 10.2, 3.4 Hz, 1H), 3.43 (dd, J = 13.0, 4.9 Hz, 1H), 3.13 (t, J = 12.7 Hz, 1H), 2.96 (t, J = 7.5 Hz, 2H), 2.68 (s, 3H), 2.25– 2.17 (m, 2H), 2.14 (s, 3H), 2.03 (d, J = 14.9 Hz, 2H), 1.98– 1.89 (m, 1H), 1.74– 1.65 (m, 3H), 1.64– 1.53 (m, 2H), 1.44 (d, J = 6.6 Hz, 3H), 1.42– 1.32 (m, J = 8.8, 8.4 Hz, 3H). HRMS (ESI): Calcd for (C20H38ClN3O5S + H)+: 467.2221. Found: 467.2248.
Figure imgf000233_0001
[00535] FSA-411056: 1H NMR (600 MHz, CD3OD) δ 5.30 (d, J = 5.6 Hz, 1H), 4.57 (q, J = 6.7 Hz, 1H), 4.52 (d, J = 9.8 Hz, 1H), 4.30 (d, J = 10.0 Hz, 1H), 4.16– 4.05 (m, 2H), 3.84 (s, 1H), 3.58 (dd, J = 10.2, 3.2 Hz, 1H), 3.43 (dd, J = 13.6, 5.5 Hz, 1H), 3.14 (t, J = 12.6 Hz, 1H), 3.08 (t, J = 7.9 Hz, 2H), 2.71 (p, J = 5.6 Hz, 1H), 2.26– 2.17 (m, 2H), 2.14 (s, 3H), 2.02 (d, J = 15.3 Hz, 1H), 1.98– 1.90 (m, 1H), 1.77– 1.65 (m, 3H), 1.63– 1.58 (m, 2H), 1.44 (d, J = 6.7 Hz, 4H), 1.38 (p, J = 8.4, 7.3 Hz, 3H), 0.87 (d, J = 5.9 Hz, 4H). HRMS (ESI): Calcd for (C22H40ClN3O5S + H)+: 493.2377. Found: 493.2389.
Figure imgf000233_0002
[00536] FSA-411019: 1H NMR (600 MHz, CD3OD) δ 5.30 (d, J = 5.6 Hz, 1H), 4.57 (q, J = 6.8 Hz, 1H), 4.52 (d, J = 10.1 Hz, 1H), 4.30 (d, J = 9.9 Hz, 1H), 4.15– 4.03 (m, 2H), 3.84 (d, J = 3.4 Hz, 1H), 3.58 (dd, J = 10.2, 3.2 Hz, 1H), 3.47– 3.40 (m, 1H), 3.14 (t, J = 12.7 Hz, 1H), 2.89 (t, J = 7.7 Hz, 2H), 2.68 (s, 1H), 2.27– 2.15 (m, 3H), 2.14 (s, 3H), 2.08 (s, 5H), 2.02 (d, J = 15.5 Hz, 1H), 1.95– 1.89 (m, 1H), 1.66 (p, J = 7.7 Hz, 3H), 1.58 (q, J = 12.0 Hz, 1H), 1.44 (d, J = 6.8 Hz, 3H), 1.37 (q, J = 7.4 Hz, 2H). HRMS (ESI): Calcd for (C24H42ClN3O5S + H)+: 519.2534. Found: 519.2527.
Figure imgf000234_0001
[00537] FSA-411030: 1H NMR (600 MHz, CD3OD) δ 5.30 (d, J = 5.7 Hz, 1H), 4.61– 4.56 (m, 1H), 4.53 (d, J = 9.6 Hz, 1H), 4.30 (d, J = 9.9 Hz, 1H), 4.14– 4.02 (m, 2H), 3.82 (s, 1H), 3.58 (dd, J = 10.3, 3.3 Hz, 1H), 3.48– 3.42 (m, 1H), 3.30– 3.22 (m, 2H), 3.14 (t, J = 12.7 Hz, 1H), 2.69 (t, J = 6.9 Hz, 2H), 2.27– 2.21 (m, 1H), 2.20– 2.14 (m, 4H), 2.08– 2.00 (m, 1H), 2.00– 1.91 (m, 1H), 1.72– 1.50 (m, 5H), 1.44 (d, J = 6.8 Hz, 3H), 1.34 (p, J = 8.4, 7.1 Hz, 2H). HRMS (ESI): Calcd for (C21H37ClF3N3O5S + H)+: 535.2095. Found: 535.2105.
Figure imgf000234_0002
[00538] FSA-411055: 1H NMR (600 MHz, CD3OD) δ 5.30 (d, J = 5.7 Hz, 1H), 4.58 (q, J = 6.0, 5.5 Hz, 1H), 4.52 (d, J = 10.2 Hz, 1H), 4.29 (d, J = 9.9 Hz, 1H), 4.08 (dd, J = 10.1, 5.6 Hz, 1H), 4.06– 4.01 (m, 1H), 3.57 (d, J = 10.3 Hz, 1H), 3.05 (q, J = 9.8 Hz, 2H), 2.53 (t, J = 7.3 Hz, 2H), 2.40 (s, 2H), 2.25– 2.20 (m, 1H), 2.15 (s, 4H), 2.06– 2.00 (m, 2H), 1.96– 1.88 (m, 2H), 1.64 (s, 1H), 1.59– 1.48 (m, 3H), 1.44 (d, J = 6.8 Hz, 3H), 1.32 (q, J = 7.0 Hz, 2H). HRMS (ESI): Calcd for (C22H39ClF3N3O5S + H)+: 549.2251. Found: 549.2261.
Figure imgf000235_0001
[00539] FSA-414012: 1H NMR (600 MHz, CD3OD) δ 5.32 (d, J = 5.5 Hz, 1H), 4.63– 4.51 (m, 3H), 4.32 (d, J = 10.0 Hz, 1H), 4.15 (s, 1H), 4.13– 4.06 (m, 1H), 3.88 (s, 1H), 3.60 (d, J = 10.4 Hz, 1H), 3.54– 3.42 (m, 1H), 3.31– 3.19 (m, 2H), 2.72 (q, J = 5.8 Hz, 1H), 2.29– 2.19 (m, 9H), 2.16 (s, 3H), 2.09– 1.99 (m, 1H), 1.99– 1.91 (m, 2H), 1.64 (s, 2H), 1.55– 1.40 (m, 7H), 1.39– 1.30 (m, 3H), 1.08 (d, J = 6.4 Hz, 3H).
Figure imgf000235_0002
[00540] FSA-410097: 1H NMR (500 MHz, CD3OD) δ 7.59– 7.48 (m, 2H), 7.21 (t, J = 8.5 Hz, 2H), 5.32 (d, J = 5.6 Hz, 1H), 4.64– 4.56 (m, 1H), 4.53 (d, J = 10.2 Hz, 1H), 4.31 (d, J = 9.9 Hz, 1H), 4.20 (s, 2H), 4.10 (dd, J = 10.1, 5.6 Hz, 2H), 3.86 (s, 1H), 3.60 (d, J = 9.9 Hz, 1H), 3.47– 3.38 (m, 1H), 3.19– 3.09 (m, 1H), 3.02 (t, J = 7.9 Hz, 2H), 2.27– 2.17 (m, 2H), 2.16 (s, 3H), 2.06– 2.00 (m, 1H), 1.98– 1.91 (m, 1H), 1.75 (s, 2H), 1.67 (s, 1H), 1.63– 1.55 (m, 1H), 1.45 (d, J = 6.8 Hz, 3H), 1.41– 1.35 (m, 2H). HRMS (ESI): Calcd for
(C26H41ClFN3O5S + H)+: 561.2439. Found: 561.2439.
Figure imgf000235_0003
[00541] FSA-411057: 1H NMR (600 MHz, CD3OD) δ 5.30 (d, J = 5.7 Hz, 1H), 4.58 (q, J = 6.7 Hz, 1H), 4.52 (d, J = 10.0 Hz, 1H), 4.29 (d, J = 9.9 Hz, 1H), 4.11– 4.04 (m, 2H), 3.82 (d, J = 3.3 Hz, 1H), 3.57 (dd, J = 10.2, 3.3 Hz, 1H), 3.45– 3.38 (m, 1H), 3.12 (t, J = 12.6 Hz, 2H), 3.05– 3.00 (m, 2H), 2.25– 2.16 (m, 2H), 2.14 (s, 3H), 2.06– 1.99 (m, 1H), 1.94 (ddt, J = 15.3, 8.1, 3.8 Hz, 1H), 1.85 (s, 3H), 1.75 (h, J = 6.2 Hz, 3H), 1.71– 1.63 (m, 2H), 1.57 (q, J = 11.7 Hz, 2H), 1.48– 1.38 (m, 4H), 1.34 (q, J = 7.3 Hz, 2H). HRMS (ESI): Calcd for (C24H44ClN3O5S + H)+: 521.269. Found: 521.2699.
Figure imgf000236_0001
[00542] FSA-411058: 1H NMR (600 MHz, CD3OD) δ 5.30 (d, J = 5.7 Hz, 1H), 4.58 (q, J = 6.9 Hz, 1H), 4.52 (d, J = 10.0 Hz, 1H), 4.30 (d, J = 10.0 Hz, 1H), 4.08 (dd, J = 10.2, 5.5 Hz, 1H), 3.82 (s, 4H), 3.58 (dd, J = 10.1, 3.2 Hz, 1H), 3.46– 3.39 (m, 1H), 3.13 (t, J = 12.6 Hz, 1H), 2.94 (s, 3H), 2.79 (t, J = 7.9 Hz, 2H), 2.27– 2.15 (m, 2H), 2.14 (s, 2H), 2.03 (d, J = 14.3 Hz, 1H), 1.94 (t, J = 10.4 Hz, 1H), 1.68 (q, J = 9.1, 8.1 Hz, 2H), 1.57 (dd, J = 24.7, 12.0 Hz, 1H), 1.44 (d, J = 6.9 Hz, 3H), 1.34 (q, J = 7.5 Hz, 2H). HRMS (ESI): Calcd for
(C23H42ClN3O6S + H)+: 523.2483. Found: 523.2494.
Figure imgf000236_0002
[00543] FSA-410082: 1H NMR (600 MHz, CD3OD) δ 5.30 (d, J = 5.7 Hz, 1H), 4.58 (q, J = 6.9 Hz, 1H), 4.53 (d, J = 9.9 Hz, 1H), 4.29 (d, J = 10.0 Hz, 1H), 4.12– 4.02 (m, 2H), 3.80 (s, 1H), 3.58 (dd, J = 10.2, 3.4 Hz, 1H), 3.41 (dd, J = 13.8, 5.8 Hz, 1H), 3.09 (t, J = 12.7 Hz, 1H), 2.82 (t, J = 6.8 Hz, 2H), 2.42 (s, 3H), 2.25– 2.16 (m, 2H), 2.15 (s, 3H), 1.95 (d, J = 15.1 Hz, 1H), 1.92– 1.82 (m, 1H), 1.64– 1.46 (m, 4H), 1.44 (d, J = 6.7 Hz, 3H), 1.37 (qd, J = 12.3, 10.1, 5.5 Hz, 1H), 1.28 (q, J = 7.5 Hz, 2H). HRMS (ESI): Calcd for (C26H42ClN3O7S2 + H)+: 607.2153. Found: 607.2191.
Figure imgf000237_0001
[00544] FSA-410090: 1H NMR (600 MHz, CD3OD) δ 7.33– 7.29 (m, 1H), 7.29– 7.22 (m, 2H), 5.30 (d, J = 5.7 Hz, 1H), 4.57 (q, J = 6.8 Hz, 1H), 4.52 (d, J = 10.0 Hz, 1H), 4.35 (s, 2H), 4.29 (d, J = 9.9 Hz, 1H), 4.11– 4.02 (m, 2H), 3.82 (s, 1H), 3.58 (dd, J = 10.2, 3.3 Hz, 1H), 3.45– 3.37 (m, 1H), 3.08 (t, J = 12.4 Hz, 1H), 2.27 (t, J = 7.3 Hz, 2H), 2.21– 2.15 (m, 2H), 2.14 (s, 3H), 2.04– 1.97 (m, 1H), 1.97– 1.89 (m, 1H), 1.66– 1.52 (m, 4H), 1.44 (d, J = 6.8 Hz, 3H). HRMS (ESI): Calcd for (C26H40ClN3O6S + H)+: 557.2326. Found: 557.2334.
Figure imgf000237_0002
[00545] FSA-411090: 1H NMR (600 MHz, CD3OD) δ 5.30 (d, J = 5.7 Hz, 1H), 4.58 (q, J = 7.3, 6.3 Hz, 1H), 4.52 (d, J = 10.0 Hz, 1H), 4.30 (d, J = 10.0 Hz, 1H), 4.08 (dd, J = 10.2, 5.5 Hz, 2H), 3.81 (s, 1H), 3.57 (dd, J = 10.1, 3.3 Hz, 1H), 3.52 (d, J = 12.3 Hz, 2H), 3.42 (d, J = 12.5 Hz, 2H), 3.12 (t, J = 12.8 Hz, 1H), 2.92 (t, J = 8.2 Hz, 2H), 2.78 (t, J = 12.4 Hz, 3H), 2.56– 2.45 (m, 2H), 2.50 (s, 1H), 2.24– 2.16 (m, 2H), 2.14 (s, 3H), 2.09 (d, J = 13.7 Hz, 2H), 2.02 (d, J = 15.0 Hz, 2H), 1.97– 1.91 (m, 1H), 1.82 (q, J = 12.6 Hz, 3H), 1.75– 1.64 (m, 4H), 1.63– 1.53 (m, 2H), 1.44 (d, J = 6.8 Hz, 4H), 1.33 (q, J = 7.3 Hz, 2H). HRMS (ESI): Calcd for (C25H43ClF3N3O5S + H)+: 589.2564. Found: 589.2573.
Figure imgf000238_0001
[00546] FSA-411089: 1H NMR (500 MHz, CD3OD) δ 5.32 (d, J = 5.6 Hz, 1H), 4.59 (q, J = 6.8 Hz, 1H), 4.54 (d, J = 9.8 Hz, 1H), 4.31 (d, J = 9.9 Hz, 1H), 4.17– 4.07 (m, 2H), 3.86 (s, 1H), 3.60 (d, J = 10.3 Hz, 1H), 3.49– 3.40 (m, 1H), 3.28– 3.19 (m, 1H), 3.19– 3.11 (m, 1H), 3.03 (t, J = 7.7 Hz, 2H), 2.25– 2.17 (m, 5H), 2.16 (s, 3H), 2.07– 2.01 (m, 1H), 1.99– 1.86 (m, 4H), 1.71 (t, J = 11.9 Hz, 5H), 1.66– 1.57 (m, 2H), 1.45 (d, J = 6.8 Hz, 3H), 1.43– 1.35 (m, 2H). HRMS (ESI): Calcd for (C25H44ClF2N3O5S + H)+: 571.2658. Found: 571.2668.
Figure imgf000238_0002
[00547] FSA-411085: 1H NMR (600 MHz, CD3OD) δ 5.30 (d, J = 5.7 Hz, 1H), 4.57 (q, J = 6.1 Hz, 1H), 4.53 (d, J = 10.0 Hz, 1H), 4.30 (d, J = 10.0 Hz, 1H), 4.11 (t, J = 5.5 Hz, 1H), 4.08 (dd, J = 10.2, 5.6 Hz, 1H), 3.83 (s, 1H), 3.58 (dd, J = 10.2, 3.3 Hz, 1H), 3.43 (dd, J = 13.7, 5.5 Hz, 1H), 3.27 (t, J = 6.7 Hz, 1H), 3.14 (t, J = 12.7 Hz, 1H), 3.00 (t, J = 8.1 Hz, 2H), 2.38 (s, 1H), 2.27– 2.17 (m, 2H), 2.14 (s, 3H), 2.06– 2.00 (m, 1H), 1.97– 1.84 (m, 7H), 1.84 – 1.77 (m, 2H), 1.76– 1.66 (m, 3H), 1.59 (q, J = 11.8 Hz, 1H), 1.44 (d, J = 6.8 Hz, 4H), 1.37 (q, J = 7.4 Hz, 2H). HRMS (ESI): Calcd for (C26H45ClF3N3O5S + H)+: 603.2721. Found: 603.2729.
Figure imgf000239_0001
[00548] FSA-410041: 1H NMR (600 MHz, CD3OD) δ 5.30 (d, J = 5.6 Hz, 1H), 4.57 (q, J = 6.7 Hz, 1H), 4.53 (d, J = 10.0 Hz, 1H), 4.30 (d, J = 9.9 Hz, 1H), 4.14– 4.04 (m, 2H), 3.83 (s, 1H), 3.58 (dd, J = 10.2, 3.3 Hz, 1H), 3.45 (dd, J = 14.1, 5.4 Hz, 1H), 3.11 (t, J = 7.9 Hz, 3H), 2.95 (s, 3H), 2.27– 2.17 (m, 2H), 2.14 (s, 3H), 2.04 (d, J = 15.2 Hz, 1H), 1.98– 1.92 (m, 1H), 1.88– 1.80 (m, 2H), 1.70 (s, 1H), 1.60 (q, J = 11.5, 11.0 Hz, 1H), 1.48– 1.42 (m, 6H). HRMS (ESI): Calcd for (C20H37ClN2O7S2 + H)+: 516.1731. Found: 516.1737.
Figure imgf000239_0002
[00549] FSA-48036: 1H NMR (600 MHz, CD3OD) δ 7.86 (d, J = 7.7 Hz, 1H), 7.72 (t, J = 7.4 Hz, 1H), 7.62 (t, J = 7.6 Hz, 1H), 6.14 (d, J = 15.7 Hz, 1H), 5.90 (t, J = 6.4 Hz, 1H), 5.60 (dt, J = 15.4, 7.5 Hz, 1H), 5.31 (d, J = 5.6 Hz, 1H), 4.55 (q, J = 6.9 Hz, 1H), 4.50 (d, J = 10.0 Hz, 1H), 4.29 (d, J = 10.1 Hz, 1H), 4.08 (dd, J = 10.3, 5.2 Hz, 2H), 4.01 (d, J = 7.5 Hz, 1H), 3.84 (s, 1H), 3.65– 3.55 (m, 1H), 3.52 (t, J = 10.7 Hz, 1H), 3.22 (t, J = 11.5 Hz, 1H), 2.97– 2.86 (m, 1H), 2.80 (dd, J = 17.8, 7.2 Hz, 1H), 2.75– 2.61 (m, 1H), 2.14 (s, 3H), 1.40 (d, J = 6.8 Hz, 3H). HRMS (ESI): Calcd for + H)+
Figure imgf000239_0003
: 574.1574. Found: 574.1596.
Figure imgf000240_0001
[00550] FSA-48039: 1H NMR (500 MHz, CD3OD) δ 7.94 (dt, J = 7.2, 2.0 Hz, 1H), 7.81– 7.70 (m, 1H), 7.67 (t, J = 7.7 Hz, 1H), 5.32 (d, J = 5.6 Hz, 1H), 4.63– 4.56 (m, 1H), 4.54 (d, J = 10.0 Hz, 0H), 4.31 (dd, J = 10.0, 3.3 Hz, 1H), 4.13– 4.06 (m, 2H), 3.84 (s, 1H), 3.60 (d, J = 10.1 Hz, 1H), 3.50– 3.36 (m, 1H), 3.26– 3.19 (m, 2H), 3.14– 3.06 (m, 1H), 2.25– 2.18 (m, 1H), 2.16 (s, 3H), 2.08– 1.85 (m, 2H), 1.76– 1.68 (m, 1H), 1.66– 1.60 (m, 1H), 1.60– 1.50 (m, 1H), 1.45(d, J = 6.8 Hz, 3H), 1.43– 1.36 (m, 3H), 1.36– 1.23 (m, 1H), 0.94 (t, J = 7.2 Hz, 1H). HRMS (ESI): Calcd for (C25H39ClN2O7S2 + H)+: 578.1887. Found: 578.1905.
Figure imgf000240_0002
[00551] FSA-411004: 1H NMR (600 MHz, CD3OD) δ 7.89 (ddt, J = 9.1, 4.9, 2.7 Hz, 2H), 7.30 (t, J = 8.5 Hz, 1H), 5.30 (d, J = 5.7 Hz, 1H), 4.60– 4.55 (m, 1H), 4.51 (d, J = 9.7 Hz, 1H), 4.29 (d, J = 10.0 Hz, 1H), 4.11– 4.05 (m, 1H), 4.00 (d, J = 11.3 Hz, 1H), 3.82 (s, 1H), 3.58 (dd, J = 10.2, 3.4 Hz, 1H), 3.38– 3.32 (m, 1H), 3.28– 3.24 (m, 1H), 3.21 (s, 1H), 3.10 (t, J = 12.7 Hz, 1H), 2.85 (t, J = 6.8 Hz, 2H), 2.33– 2.27 (m, 1H), 2.20 (s, 1H), 2.14 (s, 2H), 1.98 (d, J = 13.2 Hz, 2H), 1.94– 1.85 (m, 1H), 1.58– 1.46 (m, 4H), 1.43 (d, J = 6.8 Hz, 3H), 1.41– 1.25 (m, 4H). HRMS (ESI): Calcd for (C25H39ClFN3O7S2 + H)+: 611.1902. Found: 611.1907.
Figure imgf000241_0001
[00552] FSA-411015: 1H NMR (500 MHz, CD3OD) δ 7.78 (d, J = 8.9 Hz, 2H), 7.08 (d, J = 8.9 Hz, 2H), 5.32 (d, J = 5.7 Hz, 1H), 4.59 (q, J = 6.7 Hz, 1H), 4.54 (d, J = 9.8 Hz, 1H), 4.31 (d, J = 9.9 Hz, 1H), 4.14– 4.06 (m, 2H), 3.59 (dd, J = 10.2, 3.3 Hz, 1H), 3.46– 3.39 (m, 1H), 3.11 (t, J = 12.4 Hz, 1H), 2.83 (t, J = 6.7 Hz, 2H), 2.16 (s, 5H), 1.97 (d, J = 15.1 Hz, 1H), 1.93– 1.86 (m, 1H), 1.66– 1.56 (m, 1H), 1.56– 1.36 (m, 7H), 1.29 (q, J = 7.0 Hz, 2H). HRMS (ESI): Calcd for (C26H42ClN3O8S2 + H)+: 623.2102. Found: 623.2108.
Figure imgf000241_0002
[00553] FSA-411082: 1H NMR (600 MHz, CD3OD) δ 5.30 (d, J = 5.7 Hz, 1H), 4.57 (q, J = 6.9 Hz, 1H), 4.52 (d, J = 10.0 Hz, 1H), 4.29 (d, J = 10.0 Hz, 1H), 4.13– 4.05 (m, 2H), 3.83 (s, 1H), 3.58 (dd, J = 10.3, 3.2 Hz, 1H), 3.42 (dd, J = 13.9, 5.7 Hz, 1H), 3.13 (t, J = 12.8 Hz, 1H), 3.06 (t, J = 8.1 Hz, 2H), 2.84 (s, 5H), 2.27– 2.16 (m, 2H), 2.14 (s, 3H), 2.03 (d, J = 14.8 Hz, 1H), 1.99– 1.90 (m, 1H), 1.79– 1.64 (m, 3H), 1.58 (q, J = 12.0 Hz, 1H), 1.44 (d, J = 6.7 Hz, 4H), 1.34 (q, J = 7.4 Hz, 2H). HRMS (ESI): Calcd for (C21H40ClN3O5S + H)+: 481.2377. Found: 481.2385.
Figure imgf000242_0001
[00554] FSA-46057: 1H NMR (600 MHz, CD3OD) δ 7.26 (dd, J = 8.6, 6.8 Hz, 1H), 7.20– 7.11 (m, 2H), 6.13 (d, J = 15.6 Hz, 1H), 5.92– 5.78 (m, 2H), 5.30 (d, J = 5.6 Hz, 1H), 4.57 (q, J = 6.7 Hz, 1H), 4.49 (d, J = 10.2 Hz, 1H), 4.28 (d, J = 10.4 Hz, 1H), 4.07 (dd, J = 10.2, 5.6 Hz, 1H), 3.99 (s, 1H), 3.79 (s, 1H), 3.57 (dd, J = 10.2, 3.2 Hz, 1H), 3.43 (d, J = 6.9 Hz, 3H), 3.18 (t, J = 11.3 Hz, 1H), 2.91– 2.77 (m, 2H), 2.73 (dd, J = 17.5, 6.8 Hz, 1H), 2.67– 2.60 (m, 1H), 2.14 (s, 2H), 1.42 (d, J = 7.0 Hz, 3H). HRMS (ESI): Calcd for (C25H35ClN2O5S + H)+: 510.1955. Found: 510.1974.
Figure imgf000242_0002
[00555] FSA-46069b: 1H NMR (600 MHz, CD3OD) δ 7.25 (t, J = 7.5 Hz, 2H), 7.19 (d, J = 7.0 Hz, 2H), 7.17– 7.14 (m, 1H), 5.45 (t, J = 7.6 Hz, 1H), 5.30 (d, J = 5.5 Hz, 1H), 4.59– 4.53 (m, 1H), 4.48 (d, J = 10.1 Hz, 1H), 4.28 (d, J = 10.0 Hz, 1H), 4.08 (dd, J = 10.2, 5.6 Hz, 1H), 3.81 (s, 1H), 3.74 (dd, J = 34.6, 10.9 Hz, 1H), 3.58 (dt, J = 10.3, 3.6 Hz, 1H), 3.29– 3.22 (m, 1H), 2.88– 2.78 (m, 1H), 2.74– 2.64 (m, 2H), 2.54– 2.40 (m, 4H), 2.36 (dq, J = 14.8, 7.4 Hz, 2H), 2.31– 2.25 (m, 1H), 2.14 (s, 3H), 1.87– 1.77 (m, 1H), 1.43 (d, J = 6.8 Hz, 3H). HRMS (ESI): Calcd for (C25H37ClN2O5S + H)+: 512.2112. Found: 512.2114.
Figure imgf000243_0001
[00556] FSA-46069: 1H NMR (600 MHz, CD3OD) δ 7.28– 7.21 (m, 2H), 7.15 (dd, J = 19.0, 7.6 Hz, 2H), 5.30 (d, J = 5.5 Hz, 1H), 4.57 (q, J = 7.1, 6.6 Hz, 1H), 4.52 (d, J = 9.6 Hz, 1H), 4.29 (d, J = 10.0 Hz, 1H), 4.08 (dd, J = 10.3, 5.7 Hz, 1H), 3.81 (s, 1H), 3.57 (dd, J = 10.2, 3.0 Hz, 1H), 3.45– 3.37 (m, 1H), 3.09 (t, J = 12.8 Hz, 1H), 2.60 (t, J = 7.5 Hz, 2H), 2.25– 2.18 (m, 1H), 2.14 (s, 3H), 2.00 (t, J = 15.1 Hz, 1H), 1.94– 1.88 (m, 1H), 1.66 (h, J = 8.4 Hz, 3H), 1.54 (q, J = 12.3, 11.7 Hz, 1H), 1.43 (d, J = 6.8 Hz, 3H), 1.42– 1.28 (m, 3H). HRMS (ESI): Calcd for (C25H39ClN2O5S + H)+: 514.2268. Found: 514.2288.
Figure imgf000243_0002
[00557] FSA-46044: 1H NMR (600 MHz, CD3OD) δ 7.23 (t, J = 7.5 Hz, 1H), 7.20– 7.16 (m, 2H), 7.13 (t, J = 7.4 Hz, 1H), 6.06 (d, J = 15.7 Hz, 1H), 5.68 (t, J = 6.6 Hz, 1H), 5.60 (dt, J = 14.7, 6.9 Hz, 1H), 5.28 (d, J = 5.7 Hz, 1H), 4.63 (q, J = 6.7 Hz, 1H), 4.28 (d, J = 9.9 Hz, 1H), 4.09 (d, J = 10.0 Hz, 1H), 4.06 (dd, J = 10.2, 5.6 Hz, 1H), 3.71 (d, J = 3.4 Hz, 1H), 3.63 (dd, J = 7.7, 3.0 Hz, 1H), 3.54 (dd, J = 10.2, 3.5 Hz, 1H), 3.13 (ddd, J = 13.8, 6.2, 3.4 Hz, 1H), 3.07 (ddd, J = 13.6, 10.3, 2.2 Hz, 1H), 2.77– 2.66 (m, 3H), 2.62 (dt, J = 15.7, 7.2 Hz, 1H), 2.49 (dd, J = 17.0, 5.9 Hz, 1H), 2.40 (tt, J = 15.8, 8.2 Hz, 3H), 2.13 (s, 3H), 1.46 (d, J = 6.9 Hz, 3H). HRMS (ESI): Calcd for (C26H37ClN2O5S + H)+: 524.2112. Found: 524.2127.
Figure imgf000244_0001
[00558] FSA-46049b: 1H NMR (600 MHz, CD3OD) δ 7.24 (t, J = 7.6 Hz, 2H), 7.18– 7.06 (m, 2H), 5.66– 5.58 (m, 1H), 5.30 (d, J = 5.6 Hz, 1H), 4.55 (q, J = 6.7 Hz, 1H), 4.50 (d, J = 9.8 Hz, 1H), 4.29 (d, J = 10.0 Hz, 1H), 4.08 (dd, J = 10.2, 5.6 Hz, 1H), 3.95 (s, 1H), 3.81 (s, 1H), 3.57 (dd, J = 10.3, 3.2 Hz, 1H), 3.43 (s, 1H), 3.13– 3.05 (m, 1H), 2.75– 2.64 (m, 2H), 2.62 (t, J = 7.6 Hz, 2H), 2.54 (dd, J = 17.6, 9.5 Hz, 1H), 2.40 (dd, J = 16.6, 7.0 Hz, 1H), 2.34 – 2.26 (m, 1H), 2.14 (s, 3H), 2.12– 2.04 (m, 2H), 1.65– 1.58 (m, 2H), 1.49– 1.42 (m, 2H), 1.41 (d, J = 6.8 Hz, 3H). HRMS (ESI): Calcd for (C 26 H 39 ClN 2 O 5 S + H)+: 526.2268. Found: 526.2284.
Figure imgf000244_0002
[00559] FSA-46049: 1H NMR (600 MHz, CD3OD) δ 7.23 (t, J = 7.5 Hz, 2H), 7.20– 7.09 (m, 2H), 5.30 (d, J = 5.6 Hz, 1H), 4.60– 4.53 (m, 1H), 4.51 (d, J = 10.1 Hz, 1H), 4.31– 4.26 (m, 1H), 4.08 (dd, J = 10.2, 5.6 Hz, 1H), 3.86– 3.79 (m, 1H), 3.60– 3.54 (m, 1H), 3.11– 3.00 (m, 1H), 2.61 (t, J = 7.6 Hz, 2H), 2.22– 2.16 (m, 1H), 2.14 (s, 3H), 2.01– 1.93 (m, 1H), 1.92– 1.85 (m, 1H), 1.61 (p, J = 7.5 Hz, 2H), 1.58– 1.46 (m, 2H), 1.43 (d, J = 6.8 Hz, 3H), 1.42– 1.28 (m, 5H). HRMS (ESI): Calcd for (C26H41ClN2O5S + H)+: 528.2425. Found:
528.2439.
Figure imgf000245_0001
[00560] FSA-48069: 1H NMR (600 MHz, CD3OD) δ 7.28 (t, J = 7.6 Hz, 1H), 7.24– 7.17 (m, 2H), 6.10 (d, J = 15.7 Hz, 1H), 5.86 (t, J = 6.5 Hz, 1H), 5.77 (dt, J = 15.6, 7.0 Hz, 1H), 5.35 (d, J = 5.6 Hz, 1H), 4.59 (q, J = 6.8 Hz, 1H), 4.56 (d, J = 10.1 Hz, 1H), 4.34 (d, J = 10.0 Hz, 1H), 4.16– 4.08 (m, 2H), 3.88 (s, 1H), 3.62 (dd, J = 10.2, 3.3 Hz, 1H), 3.55 (ddd, J = 13.5, 7.7, 2.1 Hz, 1H), 3.30– 3.22 (m, 1H), 2.93 (ddd, J = 15.7, 9.5, 5.6 Hz, 1H), 2.89– 2.76 (m, 2H), 2.75– 2.69 (m, 1H), 2.65 (t, J = 7.6 Hz, 2H), 2.21– 2.16 (m, 5H), 1.76 (p, J = 7.5 Hz, 2H), 1.46 (d, J = 6.7 Hz, 3H). HRMS (ESI): Calcd for (C27H39ClN2O5S + H)+: 538.2268. Found: 538.2283.
Figure imgf000245_0002
[00561] FSA-48072: 1H NMR (600 MHz, CD3OD) δ 7.32 (t, J = 7.6 Hz, 2H), 7.23 (dd, J = 16.3, 7.6 Hz, 2H), 5.39 (d, J = 5.7 Hz, 1H), 4.66 (q, J = 6.9, 5.8 Hz, 1H), 4.62 (d, J = 10.1 Hz, 1H), 4.39 (d, J = 10.0 Hz, 1H), 4.21– 4.13 (m, 2H), 3.91 (s, 1H), 3.67 (dd, J = 10.2, 3.3 Hz, 1H), 3.51 (dd, J = 14.4, 5.0 Hz, 1H), 3.19 (t, J = 12.5 Hz, 1H), 2.69 (t, J = 7.7 Hz, 2H), 2.34– 2.24 (m, 2H), 2.23 (s, 4H), 2.08 (d, J = 15.1 Hz, 1H), 2.04– 1.95 (m, 1H), 1.71 (p, J = 7.5 Hz, 3H), 1.68– 1.56 (m, 2H), 1.53 (d, J = 6.7 Hz, 3H), 1.51– 1.33 (m, 8H). HRMS (ESI): Calcd for (C27H43ClN2O5S + H)+: 542.2581. Found: 542.2601.
Figure imgf000246_0001
[00562] FSA-48052: 1H NMR (600 MHz, CD3OD) δ 7.23 (t, J = 7.6 Hz, 2H), 7.18– 7.10 (m, 2H), 6.05 (d, J = 15.7 Hz, 1H), 5.80 (t, J = 6.4 Hz, 1H), 5.70 (dt, J = 15.6, 7.0 Hz, 1H), 5.30 (d, J = 5.6 Hz, 1H), 4.54 (q, J = 6.8 Hz, 1H), 4.51 (d, J = 10.0 Hz, 1H), 4.30 (d, J = 10.0 Hz, 1H), 4.11– 4.01 (m, 2H), 3.83 (s, 1H), 3.58 (dd, J = 10.2, 3.1 Hz, 1H), 3.50 (dd, J = 13.6, 7.4 Hz, 1H), 3.21 (t, J = 11.6 Hz, 1H), 2.88 (ddd, J = 15.4, 9.1, 5.6 Hz, 1H), 2.82– 2.71 (m, 2H), 2.65 (dd, J = 17.4, 9.7 Hz, 1H), 2.60 (t, J = 7.7 Hz, 2H), 2.17– 2.12 (m, 4H), 1.61 (tt, J = 9.0, 6.9 Hz, 2H), 1.47– 1.37 (m, 5H). HRMS (ESI): Calcd for (C28H41ClN2O5S + H)+: 552.2425. Found: 552.2448.
Figure imgf000246_0002
[00563] FSA-48058: 1H NMR (600 MHz, CD3OD) δ 7.23 (t, J = 7.5 Hz, 2H), 7.13 (dd, J = 15.5, 7.5 Hz, 2H), 5.30 (d, J = 5.6 Hz, 1H), 4.57 (q, J = 6.7 Hz, 1H), 4.53 (d, J = 9.7 Hz, 1H), 4.30 (d, J = 10.0 Hz, 1H), 4.08 (dd, J = 10.2, 5.5 Hz, 2H), 3.82 (s, 1H), 3.58 (dd, J = 10.1, 3.1 Hz, 1H), 3.42 (d, J = 12.6 Hz, 1H), 3.10 (t, J = 12.6 Hz, 1H), 2.59 (t, J = 7.7 Hz, 2H), 2.25– 2.16 (m, 2H), 2.14 (s, 3H), 2.03– 1.96 (m, 2H), 1.94– 1.86 (m, 1H), 1.66– 1.50 (m, 5H), 1.44 (d, J = 6.9 Hz, 3H), 1.42– 1.24 (m, 10H). HRMS (ESI): Calcd for (C28H45ClN2O5S + H)+: 556.2738. Found: 556.2746.
Figure imgf000247_0001
[00564] FSA-48020: 1H NMR (600 MHz, CD3OD) δ 7.07 (d, J = 8.7 Hz, 2H), 6.80 (d, J = 8.6 Hz, 2H), 6.05 (d, J = 15.7 Hz, 1H), 5.81– 5.77 (m, 1H), 5.72 (dt, J = 14.9, 6.7 Hz, 1H), 5.31 (d, J = 5.6 Hz, 1H), 4.55 (q, J = 6.8 Hz, 1H), 4.51 (d, J = 9.8 Hz, 1H), 4.30 (d, J = 10.0 Hz, 1H), 4.13– 4.00 (m, 2H), 3.88– 3.80 (m, 1H), 3.74 (s, 2H), 3.58 (dd, J = 10.2, 3.2 Hz, 1H), 3.50 (dd, J = 12.9, 8.0 Hz, 1H), 3.20 (t, J = 11.6 Hz, 1H), 2.87 (ddd, J = 15.9, 9.3, 5.3 Hz, 1H), 2.83– 2.69 (m, 2H), 2.63 (t, J = 8.2 Hz, 3H), 2.38 (q, J = 7.4 Hz, 2H), 2.14 (s, 3H), 1.41 (d, J = 6.8 Hz, 3H). HRMS (ESI): Calcd for (C27H39ClN2O6S + H)+: 554.2217. Found: 554.2225.
Figure imgf000247_0002
[00565] FSA-48023: 1H NMR (600 MHz, CD3OD) δ 7.15 (d, J = 11.6 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H), 5.39 (d, J = 9.9 Hz, 1H), 4.69– 4.57 (m, 2H), 4.43– 4.34 (m, 1H), 4.23– 4.15 (m, 2H), 3.92 (s, 1H), 3.84 (t, J = 3.8 Hz, 2H), 3.72– 3.63 (m, 1H), 3.58– 3.47 (m, 1H), 3.24 – 3.14 (m, 1H), 2.69– 2.58 (m, 2H), 2.34– 2.26 (m, 1H), 2.26– 2.20 (m, 3H), 2.07 (d, J = 14.7 Hz, 1H), 2.04– 1.94 (m, 1H), 1.75– 1.59 (m, 4H), 1.57– 1.47 (m, 4H), 1.49– 1.32 (m, 5H). HRMS (ESI): Calcd for (C27H43ClN2O6S + H)+: 558.253. Found: 558.2541.
Figure imgf000248_0001
[00566] FSA-48021: 1H NMR (600 MHz, CD3OD) δ 7.62 (d, J = 8.2 Hz, 2H), 7.37 (d, J = 8.2 Hz, 2H), 6.05 (d, J = 15.7 Hz, 1H), 5.80 (t, J = 6.4 Hz, 1H), 5.72 (dt, J = 15.7, 6.9 Hz, 1H), 5.31 (d, J = 5.6 Hz, 1H), 4.55 (q, J = 6.8 Hz, 1H), 4.50 (d, J = 10.0 Hz, 1H), 4.30 (d, J = 10.0 Hz, 1H), 4.13– 4.02 (m, 2H), 3.84 (s, 1H), 3.58 (dd, J = 10.2, 3.2 Hz, 1H), 3.51 (dd, J = 13.7, 7.2 Hz, 1H), 3.20 (t, J = 11.6 Hz, 1H), 2.88 (ddd, J = 15.6, 9.6, 5.7 Hz, 1H), 2.80 (t, J = 7.5 Hz, 2H), 2.78– 2.69 (m, 1H), 2.65 (dd, J = 17.2, 9.5 Hz, 1H), 2.45 (q, J = 7.3 Hz, 2H), 2.14 (s, 3H), 1.40 (d, J = 6.8 Hz, 3H). HRMS (ESI): Calcd for (C27H36ClN3O5S + H)+:
549.2064. Found: 549.2091.
Figure imgf000248_0002
[00567] FSA-48024: 1H NMR (600 MHz, CD3OD) δ 7.45 (d, J = 7.8 Hz, 2H), 7.20 (d, J = 7.8 Hz, 2H), 5.13 (d, J = 5.6 Hz, 1H), 4.40 (q, J = 6.3 Hz, 1H), 4.35 (d, J = 9.6 Hz, 1H), 4.12 (d, J = 10.0 Hz, 1H), 3.94– 3.87 (m, 2H), 3.63 (s, 1H), 3.40 (dd, J = 10.2, 3.2 Hz, 1H), 3.24 (d, J = 12.2 Hz, 1H), 2.92 (t, J = 12.6 Hz, 1H), 2.53 (t, J = 7.7 Hz, 2H), 2.09– 1.99 (m, 1H), 1.97 (s, 3H), 1.86– 1.77 (m, 2H), 1.73 (d, J = 13.5 Hz, 1H), 1.46 (q, J = 8.9, 8.1 Hz, 2H), 1.43– 1.32 (m, 2H), 1.26 (d, J = 6.8 Hz, 3H), 1.18 (d, J = 12.4 Hz, 5H). HRMS (ESI): Calcd for (C27H40ClN3O5S + H)+: 553.2377. Found: 553.2398.
Figure imgf000249_0001
[00568] FSA-48066: 1H NMR (500 MHz, CD3OD) δ 7.57 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 7.9 Hz, 2H), 6.09 (d, J = 15.7 Hz, 1H), 5.83 (t, J = 6.4 Hz, 1H), 5.75 (dt, J = 15.7, 6.9 Hz, 1H), 5.32 (d, J = 5.6 Hz, 1H), 4.57 (q, J = 6.8 Hz, 2H), 4.52 (d, J = 10.0 Hz, 1H), 4.31 (d, J = 10.0 Hz, 1H), 4.14– 4.03 (m, 2H), 3.85 (s, 1H), 3.60 (dd, J = 10.2, 3.1 Hz, 1H), 3.56– 3.48 (m, 1H), 3.27– 3.18 (m, 1H), 2.90 (ddd, J = 15.3, 9.0, 5.4 Hz, 1H), 2.82 (t, J = 7.5 Hz, 3H), 2.79– 2.71 (m, 1H), 2.67 (dd, J = 17.3, 9.2 Hz, 1H), 2.48 (q, J = 7.4 Hz, 2H), 2.16 (s, 3H), 1.42 (d, J = 6.8 Hz, 3H). HRMS (ESI): Calcd for (C27H36ClF3N2O5S + H)+: 592.1986. Found: 592.2015.
Figure imgf000249_0002
[00569] FSA-48070: 1H NMR (600 MHz, CD3OD) δ 7.16– 7.08 (m, 1H), 7.09– 7.04 (m, 1H), 6.95 (ddt, J = 8.3, 3.8, 1.7 Hz, 1H), 5.30 (d, J = 5.6 Hz, 1H), 4.56 (q, J = 6.8 Hz, 1H), 4.51 (d, J = 1.6 Hz, 1H), 4.29 (d, J = 10.0 Hz, 1H), 4.15– 4.05 (m, 2H), 3.84 (s, 1H), 3.58 (dd, J = 10.2, 3.2 Hz, 1H), 3.48– 3.40 (m, 1H), 3.11 (t, J = 12.5 Hz, 1H), 2.60 (t, J = 7.6 Hz, 2H), 2.19 (ddd, J = 14.6, 11.3, 5.5 Hz, 1H), 2.14 (s, 3H), 1.99 (d, J = 14.3 Hz, 1H), 1.90 (ddd, J = 14.6, 7.7, 3.8 Hz, 1H), 1.67– 1.49 (m, 4H), 1.43 (d, J = 6.9 Hz, 3H), 1.41– 1.26 (m, 5H). HRMS (ESI): Calcd for (C27H40ClF3N2O5S + H)+: 596.2299. Found: 596.2303.
Figure imgf000250_0001
FSA-47004
[00570] FSA-47004: 1H NMR (600 MHz, CD3OD) δ 7.55 (d, J = 7.9 Hz, 2H), 7.37 (d, J = 8.1 Hz, 2H), 5.30 (d, J = 5.6 Hz, 1H), 4.57 (q, J = 6.7 Hz, 1H), 4.50 (d, J = 9.5 Hz, 1H), 4.28 (d, J = 9.9 Hz, 1H), 4.08 (dd, J = 10.1, 5.6 Hz, 1H), 4.02 (s, 1H), 3.81 (s, 1H), 3.57 (dd, J = 10.4, 3.1 Hz, 1H), 3.37 (d, J = 15.6 Hz, 1H), 3.06 (t, J = 12.8 Hz, 1H), 2.70 (t, J = 7.6 Hz, 2H), 2.18 (d, J = 8.9 Hz, 1H), 2.14 (s, 4H), 2.03– 1.96 (m, 2H), 1.93– 1.87 (m, 1H), 1.73– 1.59 (m, 3H), 1.58– 1.46 (m, 2H), 1.43 (d, J = 6.8 Hz, 3H), 1.39– 1.26 (m, 4H). HRMS (ESI): Calcd for (C26H38ClF3N2O5S + H)+: 582.2142. Found: 582.2149.
Figure imgf000250_0002
[00571] FSA-46082: 1H NMR (600 MHz, CD3OD) δ 7.26– 7.14 (m, 2H), 7.10– 7.03 (m, 1H), 7.02– 6.97 (m, 1H), 6.05 (d, J = 15.7 Hz, 1H), 5.80 (t, J = 6.5 Hz, 1H), 5.74 (dt, J = 14.9, 7.0 Hz, 1H), 5.30 (d, J = 5.6 Hz, 1H), 4.55 (q, J = 6.6 Hz, 1H), 4.51 (d, J = 10.0 Hz, 1H), 4.30 (d, J = 10.0 Hz, 1H), 4.11– 4.03 (m, 2H), 3.83 (s, 1H), 3.58 (dd, J = 10.2, 3.1 Hz, 1H), 3.51 (dd, J = 13.6, 7.4 Hz, 1H), 3.25– 3.16 (m, 1H), 2.88 (ddd, J = 15.6, 9.4, 5.6 Hz, 1H), 2.82– 2.77 (m, 1H), 2.74 (t, J = 7.6 Hz, 3H), 2.65 (dd, J = 17.5, 9.5 Hz, 1H), 2.41 (q, J = 7.4 Hz, 2H), 2.14 (s, 3H), 1.41 (d, J = 6.8 Hz, 3H). HRMS (ESI): Calcd for
(C26H36ClFN2O5S + H)+: 542.2017. Found: 542.2031.
Figure imgf000251_0001
[00572] FSA-46085: 1H NMR (600 MHz, CD3OD) δ 7.23– 7.18 (m, 1H), 7.18– 7.14 (m, 1H), 7.06 (td, J = 7.6, 2.6 Hz, 1H), 6.99 (t, J = 9.3 Hz, 1H), 5.30 (d, J = 5.6 Hz, 1H), 4.63– 4.55 (m, 1H), 4.52 (d, J = 9.9 Hz, 1H), 4.29 (d, J = 9.8 Hz, 1H), 4.12– 4.03 (m, 1H), 3.78 (d, J = 18.1 Hz, 1H), 3.61– 3.54 (m, 1H), 3.46– 3.39 (m, 1H), 3.10 (t, J = 12.8 Hz, 1H), 2.75 (d, J = 16.8 Hz, 1H), 2.65 (t, J = 7.4 Hz, 2H), 2.25– 2.16 (m, 1H), 2.14 (s, 3H), 2.01 (d, J = 19.0 Hz, 1H), 1.90 (d, J = 13.6 Hz, 1H), 1.67– 1.48 (m, 4H), 1.43 (d, J = 6.9 Hz, 3H), 1.40– 1.32 (m, 4H). HRMS (ESI): Calcd for (C26H40ClFN2O5S + H)+: 546.233. Found: 546.2344.
Figure imgf000251_0002
[00573] FSA-46084: 1H NMR (600 MHz, CD3OD) δ 7.25 (td, J = 7.9, 6.0 Hz, 1H), 6.99 (d, J = 7.6 Hz, 1H), 6.95– 6.84 (m, 2H), 6.07 (d, J = 15.7 Hz, 1H), 5.81 (t, J = 6.4 Hz, 1H), 5.73 (dt, J = 15.6, 6.9 Hz, 1H), 5.30 (d, J = 5.6 Hz, 1H), 4.55 (q, J = 6.8 Hz, 1H), 4.51 (d, J = 10.0 Hz, 1H), 4.29 (d, J = 10.0 Hz, 1H), 4.11– 4.01 (m, 2H), 3.83 (s, 1H), 3.58 (dd, J = 10.2, 3.1 Hz, 1H), 3.54– 3.46 (m, 1H), 3.25– 3.15 (m, 1H), 2.87 (ddd, J = 15.5, 9.2, 5.5 Hz, 1H), 2.84 – 2.75 (m, 1H), 2.75– 2.69 (m, 3H), 2.65 (dd, J = 17.4, 9.4 Hz, 1H), 2.43 (q, J = 7.6 Hz, 2H), 2.14 (s, 3H), 1.41 (d, J = 6.8 Hz, 3H). HRMS (ESI): Calcd for (C26H36ClFN2O5S + H)+:
542.2017. Found: 542.2038.
Figure imgf000252_0001
[00574] FSA-46090: 1H NMR (600 MHz, CD3OD) δ 7.24 (td, J = 7.9, 6.1 Hz, 1H), 6.98 (d, J = 7.6 Hz, 1H), 6.94– 6.82 (m, 2H), 5.30 (d, J = 5.6 Hz, 1H), 4.57 (q, J = 6.1, 5.4 Hz, 1H), 4.53 (d, J = 10.1 Hz, 1H), 4.29 (d, J = 9.9 Hz, 1H), 4.12– 4.05 (m, 2H), 3.82 (s, 1H), 3.58 (dd, J = 10.1, 2.8 Hz, 1H), 3.46– 3.39 (m, 1H), 3.11 (t, J = 12.5 Hz, 1H), 2.63 (t, J = 7.6 Hz, 2H), 2.25– 2.14 (m, 2H), 2.14 (s, 3H), 2.03– 1.95 (m, 1H), 1.94– 1.86 (m, 1H), 1.62 (p, J = 7.6 Hz, 2H), 1.55 (q, J = 11.6, 10.8 Hz, 1H), 1.43 (d, J = 6.8 Hz, 3H), 1.42– 1.28 (m, 5H). HRMS (ESI): Calcd for (C26H40ClFN2O5S + H)+: 546.233. Found: 546.2332.
Figure imgf000252_0002
[00575] FSA-46071: 1H NMR (600 MHz, CD3OD) δ 7.22– 7.11 (m, 2H), 7.02– 6.92 (m, 2H), 6.05 (d, J = 15.7 Hz, 1H), 5.80 (t, J = 6.4 Hz, 1H), 5.72 (dt, J = 15.6, 6.9 Hz, 1H), 5.30 (d, J = 5.6 Hz, 1H), 4.56 (q, J = 6.8 Hz, 1H), 4.51 (d, J = 10.0 Hz, 1H), 4.30 (d, J = 9.9 Hz, 1H), 4.08 (dd, J = 10.2, 5.6 Hz, 1H), 4.04 (d, J = 9.3 Hz, 1H), 3.82 (d, J = 3.2 Hz, 1H), 3.57 (dd, J = 10.2, 3.1 Hz, 1H), 3.50 (dd, J = 13.3, 7.3 Hz, 1H), 3.25– 3.16 (m, 1H), 2.87 (ddd, J = 15.5, 9.4, 5.5 Hz, 1H), 2.83– 2.73 (m, 2H), 2.71– 2.67 (m, 2H), 2.64 (dd, J = 17.3, 9.5 Hz, 1H), 2.41 (q, J = 6.9 Hz, 2H), 2.14 (s, 3H), 1.41 (d, J = 6.7 Hz, 3H). HRMS (ESI): Calcd for (C26H36ClFN2O5S + H)+: 542.2017. Found: 542.2037.
Figure imgf000253_0001
[00576] FSA-46073: 1H NMR (600 MHz, CD3OD) δ 7.20– 7.13 (m, 2H), 6.96 (t, J = 8.7 Hz, 1H), 5.30 (d, J = 5.6 Hz, 1H), 4.57 (q, J = 6.8 Hz, 1H), 4.53 (d, J = 9.9 Hz, 1H), 4.30 (d, J = 9.9 Hz, 1H), 4.12– 4.05 (m, 2H), 3.83 (s, 1H), 3.58 (dd, J = 10.3, 3.1 Hz, 1H), 3.43 (dd, J = 14.5, 5.2 Hz, 1H), 3.11 (t, J = 12.5 Hz, 1H), 2.60 (t, J = 7.6 Hz, 2H), 2.24– 2.15 (m, 2H), 2.14 (s, 3H), 2.02– 1.95 (m, 1H), 1.94– 1.86 (m, 1H), 1.65– 1.50 (m, 4H), 1.43 (d, J = 6.8 Hz, 3H), 1.41– 1.28 (m, 5H). HRMS (ESI): Calcd for (C26H40ClFN2O5S + H)+: 546.233. Found: 546.2355.
Figure imgf000253_0002
[00577] FSA-49057: 1H NMR (600 MHz, CD3OD) δ 7.22 (tt, J = 8.4, 6.4 Hz, 1H), 6.93– 6.86 (m, 2H), 6.02 (d, J = 15.6 Hz, 1H), 5.78 (t, J = 6.5 Hz, 1H), 5.72 (dt, J = 15.0, 7.1 Hz, 1H), 5.30 (d, J = 5.6 Hz, 1H), 4.57 (q, J = 6.8, 1H), 4.48 (d, J = 10.0 Hz, 1H), 4.27 (d, J = 10.0 Hz, 1H), 4.08 (dd, J = 10.2, 5.6 Hz, 1H), 4.01– 3.92 (m, 1H), 3.80 (s, 1H), 3.57 (dd, J = 10.2, 3.3 Hz, 1H), 3.51– 3.39 (m, 1H), 3.16 (dd, J = 13.3, 9.9 Hz, 1H), 2.84 (dd, J = 16.5, 6.3 Hz, 1H), 2.81– 2.73 (m, 3H), 2.69 (dd, J = 17.2, 7.0 Hz, 1H), 2.61 (dd, J = 17.1, 9.8 Hz, 1H), 2.39 (q, J = 7.3 Hz, 2H), 2.14 (s, 3H), 1.42 (d, J = 6.9 Hz, 3H). HRMS (ESI): Calcd for (C26H35ClF2N2O5S + H)+: 560.1923. Found: 560.1923.
Figure imgf000254_0001
[00578] FSA-49060: 1H NMR (600 MHz, CD3OD) δ 7.20 (tt, J = 8.4, 6.5 Hz, 1H), 6.89 (t, J = 7.7 Hz, 1H), 5.30 (d, J = 5.6 Hz, 1H), 4.56 (q, J = 6.7 Hz, 1H), 4.52 (d, J = 10.0 Hz, 1H), 4.29 (d, J = 10.0 Hz, 1H), 4.12– 4.05 (m, 2H), 3.83 (d, J = 3.4 Hz, 1H), 3.58 (dd, J = 10.2, 3.3 Hz, 1H), 3.47– 3.40 (m, 1H), 3.11 (t, J = 12.5 Hz, 1H), 2.68 (t, J = 7.5 Hz, 2H), 2.25– 2.15 (m, 2H), 2.14 (s, 3H), 2.02– 1.95 (m, 1H), 1.94– 1.86 (m, 1H), 1.67– 1.51 (m, 5H), 1.44 (d, J = 6.9 Hz, 3H), 1.41– 1.29 (m, 6H). HRMS (ESI): Calcd for (C26H39ClF2N2O5S + H)+: 564.2236. Found: 564.2282.
Figure imgf000254_0002
[00579] FSA-49050: 1H NMR (600 MHz, CD3OD) δ 7.02 (td, J = 9.2, 4.5 Hz, 1H), 6.98 (ddd, J = 9.0, 5.8, 3.2 Hz, 1H), 6.94– 6.87 (m, 1H), 6.05 (d, J = 15.7 Hz, 1H), 5.81 (t, J = 6.5 Hz, 1H), 5.73 (dt, J = 14.9, 7.0 Hz, 1H), 5.30 (d, J = 5.6 Hz, 1H), 4.55 (q, J = 6.6 Hz, 1H), 4.50 (d, J = 10.0 Hz, 1H), 4.29 (d, J = 10.0 Hz, 1H), 4.11– 4.02 (m, 2H), 3.83 (s, 1H), 3.58 (dd, J = 10.2, 3.3 Hz, 1H), 3.55– 3.46 (m, 1H), 3.24– 3.16 (m, 1H), 2.87 (ddd, J = 15.7, 9.6, 5.6 Hz, 1H), 2.82– 2.75 (m, 1H), 2.73 (t, J = 7.5 Hz, 2H), 2.65 (dd, J = 17.3, 9.6 Hz, 1H), 2.42 (q, J = 7.3 Hz, 2H), 2.14 (s, 3H), 1.41 (d, J = 6.8 Hz, 3H). HRMS (ESI): Calcd for (C26H35ClF2N2O5S + H)+: 560.1923. Found: 560.1934.
Figure imgf000255_0001
[00580] FSA-49053: 1H NMR (600 MHz, CD3OD) δ 7.02 (td, J = 9.2, 4.6 Hz, 1H), 6.98 (ddd, J = 9.0, 5.9, 3.1 Hz, 1H), 6.93– 6.88 (m, 1H), 5.30 (d, J = 5.6 Hz, 1H), 4.56 (q, J = 6.4 Hz, 1H), 4.52 (d, J = 9.9 Hz, 1H), 4.29 (d, J = 10.0 Hz, 1H), 4.12– 4.05 (m, 2H), 3.83 (s, 1H), 3.58 (dd, J = 10.3, 3.1 Hz, 1H), 3.46– 3.40 (m, 1H), 3.11 (t, J = 12.6 Hz, 1H), 2.64 (t, J = 7.6 Hz, 2H), 2.24– 2.16 (m, 1H), 2.14 (s, 3H), 2.03– 1.95 (m, 1H), 1.96– 1.86 (m, 1H), 1.67– 1.51 (m, 4H), 1.43 (d, J = 6.6 Hz, 4H), 1.41– 1.30 (m, 5H). HRMS (ESI): Calcd for (C26H39ClF2N2O5S + H)+: 564.2236. Found: 564.2254.
Figure imgf000255_0002
[00581] FSA-48079: 1H NMR (500 MHz, CD3OD) δ 7.25 (t, J = 7.7 Hz, 1H), 7.22– 7.16 (m, 2H), 7.12 (dt, J = 7.6, 1.4 Hz, 1H), 6.08 (d, J = 15.7 Hz, 1H), 5.82 (t, J = 6.5 Hz, 1H), 5.74 (dt, J = 15.7, 6.9 Hz, 1H), 5.32 (d, J = 5.6 Hz, 1H), 4.57 (q, J = 6.7 Hz, 1H), 4.52 (d, J = 10.1 Hz, 1H), 4.31 (d, J = 9.9 Hz, 1H), 4.10 (dd, J = 10.2, 5.6 Hz, 1H), 4.06 (d, J = 8.7 Hz, 1H), 3.84 (s, 1H), 3.60 (dd, J = 10.2, 3.2 Hz, 1H), 3.52 (dd, J = 13.6, 7.2 Hz, 1H), 3.21 (t, J = 11.5 Hz, 1H), 2.89 (ddd, J = 15.4, 9.1, 5.6 Hz, 1H), 2.83– 2.74 (m, 2H), 2.72 (t, J = 7.5 Hz, 3H), 2.66 (dd, J = 17.2, 9.3 Hz, 1H), 2.44 (q, J = 7.3 Hz, 2H), 2.16 (s, 3H), 1.43 (d, J = 6.8 Hz, 3H). HRMS (ESI): Calcd for (C26H36Cl2N2O5S + H)+: 558.1722. Found: 558.1731.
Figure imgf000256_0001
[00582] FSA-46053: 1H NMR (600 MHz, CD3OD) δ 7.98 (d, J = 5.9 Hz, 1H), 6.88 (dd, J = 6.0, 2.0 Hz, 1H), 6.62 (d, J = 2.1 Hz, 1H), 6.45 (d, J = 15.8 Hz, 1H), 6.02 (t, J = 6.4 Hz, 1H), 5.91 (dt, J = 15.9, 5.9 Hz, 1H), 5.30 (d, J = 5.5 Hz, 1H), 4.76 (d, J = 5.9 Hz, 2H), 4.55 (q, J = 6.8 Hz, 1H), 4.51 (d, J = 10.0 Hz, 1H), 4.30 (d, J = 10.0 Hz, 1H), 4.14– 4.04 (m, 2H), 3.84 (s, 1H), 3.61– 3.57 (m, 1H), 3.56– 3.50 (m, 1H), 3.29– 3.24 (m, 1H), 2.93 (ddd, J = 15.3, 9.0, 5.3 Hz, 1H), 2.88– 2.77 (m, 2H), 2.72 (dd, J = 17.4, 9.4 Hz, 1H), 2.14 (s, 2H), 1.41 (d, J = 6.8 Hz, 2H). HRMS (ESI): Calcd for (C24H33ClFN3O6S + H)+: 545.1763. Found: 545.178.
Figure imgf000256_0002
[00583] FSA-48060: 1H NMR (600 MHz, CD3OD) δ 7.16– 7.04 (m, 2H), 6.96 (ddt, J = 8.2, 3.8, 1.6 Hz, 1H), 6.05 (d, J = 15.6 Hz, 1H), 5.81 (t, J = 6.4 Hz, 1H), 5.71 (dt, J = 15.7, 6.9 Hz, 1H), 5.31 (d, J = 5.6 Hz, 1H), 4.54 (q, J = 6.9, 6.2 Hz, 2H), 4.51 (d, J = 10.0 Hz, 1H), 4.30 (d, J = 10.0 Hz, 1H), 4.11– 4.03 (m, 2H), 3.85 (s, 1H), 3.58 (dd, J = 10.2, 3.1 Hz, 1H), 3.51 (dd, J = 13.7, 7.4 Hz, 1H), 3.21 (t, J = 11.6 Hz, 1H), 2.92– 2.83 (m, 1H), 2.79 (d, J = 7.6 Hz, 1H), 2.75 (t, J = 7.4 Hz, 1H), 2.74– 2.61 (m, 4H), 2.41 (q, J = 7.3 Hz, 2H), 2.14 (s, 3H), 1.41 (d, J = 6.8 Hz, 3H). HRMS (ESI): Calcd for (C26H35ClF2N2O5S + H)+: 560.1923. Found: 560.1941.
Figure imgf000257_0001
[00584] FSA-48067: 1H NMR (600 MHz, CD3OD) δ 7.16– 7.08 (m, 1H), 7.09– 7.04 (m, 1H), 6.95 (ddt, J = 8.3, 3.8, 1.7 Hz, 1H), 5.30 (d, J = 5.6 Hz, 1H), 4.56 (qd, J = 6.7, 2.0 Hz, 1H), 4.52 (dd, J = 9.9, 1.6 Hz, 1H), 4.29 (d, J = 10.0 Hz, 1H), 4.13– 4.05 (m, 2H), 3.84 (s, 1H), 3.58 (dd, J = 10.2, 3.2 Hz, 1H), 3.47– 3.40 (m, 1H), 3.11 (t, J = 12.5 Hz, 1H), 2.60 (t, J = 7.6 Hz, 2H), 2.25– 2.15 (m, 2H), 2.14 (s, 3H), 1.99 (d, J = 14.3 Hz, 1H), 1.90 (ddd, J = 14.6, 7.7, 3.8 Hz, 1H), 1.67– 1.50 (m, 4H), 1.43 (d, J = 6.9 Hz, 3H), 1.41– 1.27 (m, 5H). HRMS (ESI): Calcd for (C26H39ClF2N2O5S + H)+: 564.2236. Found: 564.2264.
Figure imgf000257_0002
[00585] FSA-48056: 1H NMR (600 MHz, CD3OD) δ 6.84– 6.76 (m, 2H), 6.72 (tt, J = 9.2, 2.4 Hz, 1H), 6.07 (d, J = 15.6 Hz, 1H), 5.82 (t, J = 6.5 Hz, 1H), 5.71 (dt, J = 15.9, 6.9 Hz, 1H), 5.31 (d, J = 5.6 Hz, 1H), 4.55 (q, J = 6.7 Hz, 1H), 4.50 (d, J = 10.0 Hz, 1H), 4.30 (d, J = 10.0 Hz, 1H), 4.11– 4.03 (m, 2H), 3.84 (s, 1H), 3.58 (dd, J = 10.2, 3.2 Hz, 1H), 3.51 (dd, J = 13.6, 7.5 Hz, 1H), 3.20 (t, J = 11.7 Hz, 1H), 2.88 (ddd, J = 15.8, 9.3, 5.4 Hz, 1H), 2.82– 2.69 (m, 4H), 2.65 (dd, J = 17.2, 9.5 Hz, 1H), 2.43 (q, J = 7.4 Hz, 2H), 2.14 (s, 3H), 1.41 (d, J = 6.8 Hz, 3H). HRMS (ESI): Calcd for (C26H35ClF2N2O5S + H)+: 560.1923. Found: 560.1939.
Figure imgf000258_0001
[00586] FSA-48065: 1H NMR (600 MHz, CD3OD) δ 6.79 (dtd, J = 8.5, 6.3, 2.4 Hz, 2H), 6.71 (tt, J = 9.3, 2.4 Hz, 1H), 5.30 (d, J = 5.6 Hz, 1H), 4.56 (q, J = 6.8 Hz, 1H), 4.52 (d, J = 10.0 Hz, 1H), 4.29 (d, J = 10.0 Hz, 1H), 4.13– 4.05 (m, 2H), 3.83 (s, 1H), 3.58 (dd, J = 10.2, 3.2 Hz, 1H), 3.47– 3.40 (m, 1H), 3.11 (t, J = 12.5 Hz, 1H), 2.63 (t, J = 7.6 Hz, 2H), 2.20 (tdd, J = 16.1, 7.2, 3.6 Hz, 2H), 2.14 (s, 3H), 2.00 (dd, J = 16.1, 11.6 Hz, 1H), 1.94– 1.87 (m, 1H), 1.65– 1.51 (m, 4H), 1.43 (d, J = 6.8 Hz, 3H), 1.41– 1.29 (m, 5H). HRMS (ESI): Calcd for (C26H39ClF2N2O5S + H)+: 564.2236. Found: 564.2259.
Figure imgf000258_0002
[00587] FSA-48086: 1H NMR (600 MHz, CD3OD) δ 7.28 (q, J = 7.9 Hz, 1H), 6.90 (t, J = 8.8 Hz, 2H), 6.08 (d, J = 15.7 Hz, 1H), 5.85 (t, J = 6.5 Hz, 1H), 5.77 (dt, J = 15.0, 7.0 Hz, 1H), 5.36 (d, J = 5.7 Hz, 1H), 4.59 (q, J = 6.8 Hz, 1H), 4.56 (d, J = 10.1 Hz, 1H), 4.35 (d, J = 10.0 Hz, 1H), 4.16– 4.08 (m, 2H), 3.90 (s, 1H), 3.64 (dd, J = 10.3, 3.2 Hz, 1H), 3.57 (dd, J = 13.7, 7.5 Hz, 1H), 3.29– 3.22 (m, 1H), 2.93 (ddd, J = 15.9, 9.5, 5.5 Hz, 1H), 2.85– 2.67 (m, 6H), 2.44 (q, J = 7.4 Hz, 2H), 2.19 (s, 3H), 1.45 (d, J = 6.9 Hz, 4H). HRMS (ESI): Calcd for (C26H35ClF2N2O5S + H)+: 560.1923. Found: 560.1948.
Figure imgf000259_0001
[00588] FSA-48087: 1H NMR (600 MHz, CD3OD) δ 7.23 (td, J = 8.4, 6.4 Hz, 1H), 6.88– 6.81 (m, 1H), 5.30 (d, J = 5.7 Hz, 1H), 4.57 (q, J = 6.7 Hz, 1H), 4.52 (d, J = 10.0 Hz, 1H), 4.29 (d, J = 10.0 Hz, 1H), 4.12– 4.05 (m, 2H), 3.83 (s, 1H), 3.58 (dd, J = 10.2, 3.2 Hz, 1H), 3.43 (dd, J = 13.7, 5.3 Hz, 1H), 3.11 (t, J = 12.5 Hz, 1H), 2.62 (t, J = 7.6 Hz, 2H), 2.25– 2.16 (m, 2H), 2.14 (s, 3H), 1.99 (d, J = 15.3 Hz, 1H), 1.93– 1.86 (m, 1H), 1.67– 1.52 (m, 4H), 1.43 (d, J = 6.8 Hz, 3H), 1.41– 1.28 (m, 5H). HRMS (ESI): Calcd for (C26H39ClF2N2O5S + H)+: 564.2236. Found: 564.2237.
Figure imgf000259_0002
[00589] FSA-48043: 1H NMR (600 MHz, CD3OD) δ 7.65 (dd, J = 15.1, 7.7 Hz, 4H), 7.58 (d, J = 8.0 Hz, 2H), 7.47 (t, J = 7.7 Hz, 2H), 7.37 (t, J = 7.5 Hz, 1H), 6.95 (d, J = 16.2 Hz, 1H), 6.71 (d, J = 16.2 Hz, 1H), 6.16 (d, J = 6.4 Hz, 1H), 5.36 (d, J = 5.7 Hz, 1H), 4.63 (q, J = 6.4 Hz, 1H), 4.58 (d, J = 10.0 Hz, 1H), 4.36 (d, J = 9.8 Hz, 1H), 4.19– 4.09 (m, 2H), 3.90 (d, J = 3.3 Hz, 1H), 3.68– 3.60 (m, 2H), 3.35– 3.29 (m, 1H), 3.07– 2.82 (m, 5H), 2.20 (s, 3H), 1.50 (d, J = 6.9 Hz, 3H). HRMS (ESI): Calcd for (C +
30H37ClN2O5S + H) : 572.2112. Found: 572.2127.
Figure imgf000260_0001
[00590] FSA-48046: 1H NMR (600 MHz, CD3OD) δ 7.57 (d, J = 7.7 Hz, 2H), 7.52 (d, J = 7.8 Hz, 2H), 7.41 (t, J = 7.6 Hz, 2H), 7.27 (d, J = 8.1 Hz, 3H), 5.30 (d, J = 5.7 Hz, 1H), 4.56 (q, J = 6.4 Hz, 1H), 4.53 (d, J = 9.9 Hz, 1H), 4.30 (dd, J = 10.1, 3.4 Hz, 1H), 4.12– 4.02 (m, 2H), 3.82 (s, 1H), 3.58 (dd, J = 8.6, 4.7 Hz, 1H), 3.49– 3.43 (m, 1H), 3.38 (s, 1H), 3.11 (t, J = 12.5 Hz, 1H), 2.70 (q, J = 7.3 Hz, 2H), 2.23 (d, J = 28.8 Hz, 2H), 2.14 (s, 3H), 2.10 (s, 1H), 2.04– 1.97 (m, 1H), 1.92 (q, J = 12.5 Hz, 1H), 1.72– 1.59 (m, 5H), 1.54– 1.46 (m, 2H), 1.45 (d, J = 6.9 Hz, 3H). HRMS (ESI): Calcd for (C30H41ClN2O5S + H)+: 576.2425. Found:
576.2438.
Figure imgf000260_0002
[00591] FSA-48098: 1H NMR (600 MHz, CD3OD) δ 7.43– 7.30 (m, 4H), 6.81 (d, J = 16.3 Hz, 1H), 6.59 (d, J = 16.3 Hz, 1H), 6.07 (t, J = 6.6 Hz, 1H), 5.31 (d, J = 5.5 Hz, 1H), 4.59– 4.52 (m, 1H), 4.52 (d, J = 10.0 Hz, 1H), 4.31 (dd, J = 10.0, 4.7 Hz, 1H), 4.10 (d, J = 5.7 Hz, 2H), 3.86 (s, 1H), 3.59 (dd, J = 10.4, 3.3 Hz, 2H), 3.27 (t, J = 11.8 Hz, 1H), 2.94 (td, J = 16.4, 15.5, 8.6 Hz, 2H), 2.83 (ddd, J = 34.4, 17.0, 8.6 Hz, 2H), 2.14 (d, J = 4.6 Hz, 3H), 1.44 (d, J = 6.7 Hz, 3H), 1.30 (s, 8H). HRMS (ESI): Calcd for (C28H41ClN2O5S + H)+: 552.2425.
Found: 552.2456.
Figure imgf000261_0001
[00592] FSA-49002: 1H NMR (600 MHz, CD3OD) δ 7.43 (d, J = 7.8 Hz, 2H), 7.24 (d, J = 7.5 Hz, 2H), 5.44 (d, J = 5.5 Hz, 1H), 4.76– 4.70 (m, 1H), 4.67 (d, J = 10.1 Hz, 1H), 4.44 (d, J = 10.0 Hz, 1H), 4.22 (dd, J = 10.2, 5.7 Hz, 2H), 3.97 (s, 1H), 3.72 (d, J = 10.1 Hz, 1H), 3.64– 3.56 (m, 1H), 3.29– 3.22 (m, 1H), 2.75 (t, J = 7.8 Hz, 2H), 2.31– 2.30 (m, 2H), 2.28 (s, 3H), 2.23– 2.17 (m, 1H), 2.15– 2.08 (m, 1H), 1.83– 1.71 (m, 4H), 1.58 (d, J = 6.8 Hz, 3H), 1.42 (s, 9H). HRMS (ESI): Calcd for (C28H45ClN2O5S + H)+: 556.2738. Found:
556.2754.
Figure imgf000261_0002
[00593] FSA-49023: 1H NMR (600 MHz, CD3OD) δ 7.26 (t, J = 7.5 Hz, 2H), 7.20 (d, J = 5.9 Hz, 1H), 7.17 (t, J = 7.3 Hz, 1H), 6.11 (d, J = 15.8 Hz, 1H), 5.93– 5.84 (m, 2H), 5.32 (d, J = 5.6 Hz, 1H), 4.56 (q, J = 6.7 Hz, 1H), 4.52 (d, J = 10.1 Hz, 1H), 4.31 (d, J = 9.9 Hz, 1H), 4.09 (dd, J = 10.3, 5.5 Hz, 2H), 3.86 (s, 1H), 3.59 (d, J = 10.3 Hz, 1H), 3.53 (dd, J = 13.8, 7.3 Hz, 1H), 3.23 (t, J = 11.7 Hz, 1H), 2.95– 2.86 (m, 1H), 2.85– 2.73 (m, 2H), 2.69 (dd, J = 17.8, 9.6 Hz, 1H), 2.14 (s, 3H), 2.07 (s, 6H), 1.43 (d, J = 6.7 Hz, 3H). HRMS (ESI): Calcd for (C +
29H39ClN2O5S + H) : 562.2268. Found: 562.2276.
Figure imgf000262_0001
[00594] FSA-49025a: 1H NMR (600 MHz, CD3OD) δ 7.28– 7.20 (m, 2H), 7.19– 7.10 (m, 2H), 5.30 (d, J = 5.7 Hz, 1H), 4.61– 4.54 (m, 1H), 4.53 (d, J = 10.0 Hz, 1H), 4.29 (d, J = 10.0 Hz, 1H), 4.08 (dd, J = 10.2, 5.6 Hz, 1H), 4.08– 4.03 (m, 1H), 3.81 (s, 1H), 3.58 (dd, J = 10.4, 3.2 Hz, 1H), 3.42 (d, J = 11.6 Hz, 1H), 3.10 (t, J = 12.6 Hz, 1H), 2.22 (d, J = 8.6 Hz, 1H), 2.17 (s, 1H), 2.15 (s, 3H), 2.02 (d, J = 16.1 Hz, 2H), 1.98– 1.91 (m, 1H), 1.88 (s, 6H), 1.66 (s, 1H), 1.60– 1.54 (m, 3H), 1.45 (d, J = 6.8 Hz, 3H), 1.38– 1.30 (m, 2H). HRMS (ESI): Calcd for (C29H43ClN2O5S + H)+: 566.2581. Found: 566.2591.
Figure imgf000262_0002
[00595] FSA-49025b: 1H NMR (600 MHz, CD3OD) δ 7.24 (t, J = 7.5 Hz, 2H), 7.17 (d, J = 7.6 Hz, 2H), 7.12 (t, J = 7.5 Hz, 1H), 5.30 (d, J = 5.5 Hz, 1H), 4.60– 4.54 (m, 1H), 4.53 (d, J = 10.3 Hz, 1H), 4.30 (d, J = 9.9 Hz, 1H), 4.08 (s, 2H), 3.83 (s, 1H), 3.58 (d, J = 9.8 Hz, 1H), 3.51 (t, J = 8.9 Hz, 1H), 3.43 (s, 1H), 3.11 (s, 1H), 2.23 (d, J = 27.2 Hz, 1H), 2.17– 2.09 (m, 5H), 2.02 (s, 2H), 1.88 (t, J = 10.1 Hz, 3H), 1.58 (s, 2H), 1.46– 1.37 (m, 5H), 1.25 (s, 3H). HRMS (ESI): Calcd for (C +
29H45ClN2O5S + H) : 568.2738. Found: 568.2757.
Figure imgf000263_0001
[00596] FSA-413005: 1H NMR (600 MHz, CD3OD) δ 5.30 (d, J = 5.6 Hz, 1H), 4.62– 4.49 (m, 3H), 4.30 (d, J = 10.0 Hz, 1H), 4.08 (dd, J = 10.3, 5.7 Hz, 2H), 3.83 (s, 1H), 3.58 (dd, J = 10.2, 3.2 Hz, 1H), 3.48– 3.40 (m, 1H), 3.25 (t, J = 16.4 Hz, 2H), 3.12 (t, J = 12.8 Hz, 1H), 2.67 (t, J = 7.2 Hz, 2H), 2.28– 2.11 (m, 5H), 2.06– 1.98 (m, 2H), 1.98– 1.89 (m, 1H), 1.71– 1.50 (m, 5H), 1.44 (d, J = 6.7 Hz, 3H), 1.40– 1.29 (m, 2H). HRMS (ESI): Calcd for
(C22H37ClF5N3O5S + H)+: 585.2063. Found: 585.2095.
Figure imgf000263_0002
[00597] FSA-413007: 1H NMR (600 MHz, CD3OD) δ 5.30 (d, J = 5.7 Hz, 1H), 4.57 (q, J = 6.9 Hz, 1H), 4.53 (d, J = 10.0 Hz, 1H), 4.30 (d, J = 10.0 Hz, 1H), 4.13 (t, J = 5.5 Hz, 1H), 4.08 (dd, J = 10.3, 5.7 Hz, 1H), 3.84 (s, 1H), 3.58 (dd, J = 10.1, 3.2 Hz, 1H), 3.45 (t, J = 14.5 Hz, 3H), 3.14 (t, J = 12.6 Hz, 1H), 2.98 (t, J = 7.9 Hz, 2H), 2.30– 2.11 (m, 5H), 2.06– 1.99 (m, 1H), 1.99– 1.91 (m, 1H), 1.79– 1.65 (m, 6H), 1.59 (q, J = 12.1 Hz, 2H), 1.44 (d, J = 6.9 Hz, 3H), 1.35 (q, J = 7.4 Hz, 2H). HRMS (ESI): Calcd for (C22H40ClF2N3O5S + H)+:
531.2345. Found: 531.2368.
Figure imgf000263_0003
[00598] FSA-413008: 1H NMR (600 MHz, CD3OD) δ 5.30 (d, J = 5.6 Hz, 1H), 4.57 (q, J = 6.9 Hz, 2H), 4.52 (d, J = 10.0 Hz, 2H), 4.29 (d, J = 9.9 Hz, 1H), 4.15– 4.06 (m, 2H), 3.84 (s, 1H), 3.62– 3.53 (m, 3H), 3.43 (dd, J = 14.3, 5.4 Hz, 2H), 3.13 (t, J = 12.7 Hz, 1H), 3.01 (t, J = 8.2 Hz, 2H), 2.27– 2.12 (m, 5H), 2.07– 2.00 (1, 2H), 1.99– 1.91 (m, 1H), 1.77– 1.63 (m, 2H), 1.58 (q, J = 12.3 Hz, 2H), 1.44 (d, J = 6.6 Hz, 3H), 1.38– 1.33 (m, 3H), 1.10 (s, 9H). HRMS (ESI): Calcd for (C25H46ClF2N3O5S + H)+: 573.2815. Found: 573.2762.
Figure imgf000264_0001
[00599] FSA-413010: 1H NMR (600 MHz, CD3OD) δ 5.30 (d, J = 5.6 Hz, 1H), 4.62– 4.48 (m, 2H), 4.29 (d, J = 10.0 Hz, 1H), 4.15– 4.06 (m, 2H), 3.84 (s, 1H), 3.58 (dd, J = 10.2, 3.2 Hz, 1H), 3.52– 3.40 (m, 3H), 3.13 (t, J = 12.7 Hz, 1H), 2.94 (t, J = 7.9 Hz, 2H), 2.24– 2.10 (m, 5H), 2.09– 1.99 (m, 1H), 1.99– 1.92 (m, 1H), 1.74– 1.65 (m, 2H), 1.63– 1.53 (m, 1H), 1.44 (d, J = 6.8 Hz, 4H), 1.38– 1.32 (m, 2H), 0.69 (d, J = 6.6 Hz, 4H). HRMS (ESI): Calcd for (C24H42ClF2N3O5S + H)+: 557.2502. Found: 557.253.
Figure imgf000264_0002
[00600] FSA-413025: 1H NMR (600 MHz, CD3OD) δ 5.30 (d, J = 5.6 Hz, 1H), 4.61– 4.48 (m, 2H), 4.30 (d, J = 10.0 Hz, 1H), 4.21– 4.11 (m, 2H), 4.08 (dd, J = 10.2, 5.7 Hz, 2H), 3.84 (s, 1H), 3.62– 3.52 (m, 2H), 3.45 (dd, J = 13.5, 5.6 Hz, 1H), 3.23 (q, J = 9.6 Hz, 1H), 3.19– 3.08 (m, 2H), 2.98 (s, 4H), 2.83 (t, J = 6.3 Hz, 1H), 2.28– 2.11 (m, 5H), 2.07– 1.90 (m, 4H), 1.87– 1.80 (m, 1H), 1.77– 1.64 (m, 3H), 1.64– 1.65 (m, 2H), 1.47– 1.31 (m, 7H). HRMS (ESI): Calcd for (C24H44ClF3N4O5S + H)+: 592.2673. Found: 592.2724.
Figure imgf000265_0001
[00601] FSA-410025: 1H NMR (600 MHz, CD3OD) δ 5.30 (d, J = 5.6 Hz, 1H), 4.62– 4.54 (m, 1H), 4.53 (d, J = 10.0 Hz, 1H), 4.30 (d, J = 10.0 Hz, 1H), 4.13– 4.02 (m, 2H), 3.81 (s, 1H), 3.58 (d, J = 10.2 Hz, 1H), 3.43 (d, J = 14.6 Hz, 1H), 3.29– 3.23 (m, 1H), 3.11 (t, J = 13.0 Hz, 1H), 3.06 (s, 3H), 2.92 (s, 3H), 2.41 (t, J = 7.6 Hz, 2H), 2.28– 2.20 (m, 1H), 2.19– 2.16 (m, 1H), 2.14 (s, 3H), 2.04 (d, J = 14.7 Hz, 1H), 2.00– 1.92 (m, 1H), 1.73– 1.65 (m, 1H), 1.65– 1.53 (m, 3H), 1.44 (d, J = 7.0 Hz, 3H).
Figure imgf000265_0002
[00602] FSA-410014: 1H NMR (600 MHz, CD3OD) δ 5.31 (d, J = 5.6 Hz, 1H), 4.60– 4.49 (m, 2H), 4.30 (d, J = 9.9 Hz, 1H), 4.13 (s, 1H), 4.08 (dd, J = 10.3, 5.6 Hz, 1H), 3.86 (s, 1H), 3.58 (d, J = 10.3 Hz, 1H), 3.45 (dd, J = 14.2, 5.8 Hz, 1H), 3.13 (t, J = 12.1 Hz, 1H), 2.22– 2.16 (m, 2H), 2.14 (s, 3H), 2.08– 1.97 (m, 2H), 1.97– 1.86 (m, 1H), 1.65– 1.53 (m, 2H), 1.44 (d, J = 6.7 Hz, 3H), 1.40– 1.24 (m, 6H), 1.21– 1.09 (m, 2H), 0.87 (m, 6H).
Figure imgf000265_0003
[00603] FSA-410016: 1H NMR (500 MHz, CD3OD) δ 5.32 (d, J = 5.7 Hz, 1H), 4.59 (q, J = 7.7, 6.8 Hz, 2H), 4.55 (d, J = 10.0 Hz, 1H), 4.31 (d, J = 9.9 Hz, 1H), 4.15– 4.07 (m, 2H), 3.84 (s, 1H), 3.59 (dd, J = 10.2, 3.3 Hz, 1H), 3.45 (dd, J = 14.3, 6.0 Hz, 1H), 3.13 (t, J = 12.1 Hz, 1H), 2.29– 2.19 (m, 2H), 2.16 (s, 3H), 2.02 (d, J = 13.3 Hz, 1H), 1.99– 1.89 (m, 1H), 1.67 (d, J = 11.8 Hz, 2H), 1.60 (d, J = 10.4 Hz, 2H), 1.57– 1.50 (m, 3H), 1.46 (d, J = 6.7 Hz, 3H), 1.42 (s, 7H), 1.37– 1.30 (m, 3H), 1.30– 1.19 (m, 5H), 1.21– 1.00 (m, 6H).
Figure imgf000266_0001
[00604] FSA-410021: 1H NMR (600 MHz, CD3OD) δ 7.09 (d, J = 8.1 Hz, 2H), 6.82 (d, J = 8.0 Hz, 2H), 5.30 (d, J = 5.5 Hz, 1H), 4.57 (m, 1H), 4.52 (d, J = 9.6 Hz, 1H), 4.29 (d, J = 10.0 Hz, 1H), 4.11– 4.04 (m, 2H), 3.81 (s, 1H), 3.75 (s, 3H), 3.58 (d, J = 9.8 Hz, 1H), 3.47– 3.41 (m, 1H), 3.08 (t, J = 12.1 Hz, 1H), 2.62– 2.56 (m, 2H), 2.24– 2.17 (m, 1H), 2.14 (s, 3H), 2.11– 2.03 (m, 2H), 2.03– 1.95 (m, 1H), 1.60 (s, 5H), 1.44 (d, J = 6.7 Hz, 3H).
Figure imgf000266_0002
[00605] FSA-413028: 1H NMR (500 MHz, CD3OD) δ 5.32 (d, J = 5.7 Hz, 1H), 4.59 (q, J = 6.9 Hz, 1H), 4.55 (d, J = 9.9 Hz, 1H), 4.32 (d, J = 10.0 Hz, 1H), 4.17– 4.07 (m, 2H), 3.86 (s, 1H), 3.60 (dd, J = 10.2, 3.2 Hz, 1H), 3.53 (t, J = 15.4 Hz, 2H), 3.49– 3.43 (m, 1H), 3.16 (t, J = 12.7 Hz, 1H), 3.00 (t, J = 7.9 Hz, 2H), 2.27– 2.19 (m, 2H), 2.16 (s, 3H), 2.10– 2.02 (m, 1H), 2.01– 1.87 (m, 8H), 1.79– 1.68 (m, 8H), 1.70– 1.56 (m, 2H), 1.46 (d, J = 6.8 Hz, 5H), 1.39 (q, J = 8.2, 7.4 Hz, 3H), 0.87 (p, J = 6.5 Hz, 1H), 0.60 (d, J = 7.7 Hz, 2H), 0.24 (d, J = 5.0 Hz, 2H).
Figure imgf000267_0001
[00606] FSA-45064: 1H NMR (600 MHz, CD3OD) δ 7.26 (d, J = 16.1 Hz, 1H), 6.43 (t, J = 6.5 Hz, 1H), 6.20 (d, J = 16.1 Hz, 1H), 5.29 (d, J = 5.6 Hz, 1H), 4.63– 4.54 (m, 1H), 4.46 (d, J = 10.1 Hz, 1H), 4.24 (d, J = 9.9 Hz, 1H), 4.07 (dd, J = 10.1, 5.7 Hz, 1H), 3.95 (s, 1H), 3.76 (s, 1H), 3.54 (d, J = 9.9 Hz, 1H), 3.45– 3.36 (m, 1H), 3.21– 3.13 (m, 1H), 2.91 (s, 2H), 2.78 – 2.69 (m, 1H), 2.69– 2.61 (m, 1H), 2.30 (s, 3H), 2.14 (s, 3H), 1.44 (d, J = 6.9 Hz, 3H).
Figure imgf000267_0002
[00607] FSA-45030: 1H NMR (600 MHz, CD3OD) δ 6.36 (dd, J = 17.4, 10.8 Hz, 1H), 5.84 (t, J = 6.5 Hz, 1H), 5.27 (d, J = 5.6 Hz, 1H), 5.11 (d, J = 17.5 Hz, 1H), 4.96 (d, J = 10.8 Hz, 1H), 4.62 (q, J = 6.8 Hz, 1H), 4.31 (d, J = 10.0 Hz, 1H), 4.11 (d, J = 9.9 Hz, 1H), 4.06 (dd, J = 10.2, 5.6 Hz, 1H), 3.71 (d, J = 3.4 Hz, 1H), 3.63 (dd, J = 8.1, 3.0 Hz, 1H), 3.53 (dd, J = 10.2, 3.4 Hz, 1H), 3.18 (ddd, J = 13.9, 6.6, 2.9 Hz, 1H), 3.04 (ddd, J = 13.9, 10.2, 2.3 Hz, 1H), 2.73 (dd, J = 16.3, 6.9 Hz, 1H), 2.70– 2.61 (m, 1H), 2.56 (dd, J = 16.7, 6.5 Hz, 1H), 2.41 (dd, J = 17.0, 10.0 Hz, 1H), 2.13 (s, 3H), 1.46 (d, J = 6.8 Hz, 3H).
Figure imgf000267_0003
[00608] FSA-45031a: 1H NMR (600 MHz, CD3OD) δ 5.67 (t, J = 5.7 Hz, 1H), 5.30 (d, J = 5.7 Hz, 1H), 4.58 (q, J = 6.9 Hz, 1H), 4.52 (d, J = 9.3 Hz, 1H), 4.30 (d, J = 10.1 Hz, 1H), 4.08 (dd, J = 10.2, 5.6 Hz, 1H), 4.02– 3.97 (m, 1H), 3.80 (s, 1H), 3.58 (dd, J = 10.2, 3.3 Hz, 1H), 3.47 (ddd, J = 13.5, 7.4, 2.3 Hz, 1H), 3.15 (t, J = 11.8 Hz, 1H), 2.81– 2.67 (m, 2H), 2.59 (dd, J = 17.3, 10.1 Hz, 1H), 2.44 (dd, J = 17.2, 7.4 Hz, 1H), 2.15 (s, 3H), 2.10 (q, J = 7.4 Hz, 2H), 1.44 (d, J = 6.8 Hz, 3H), 1.03 (t, J = 7.4 Hz, 3H).
Figure imgf000268_0001
[00609] FSA-45031b: 1H NMR (600 MHz, CD3OD) δ 5.54 (q, J = 6.6 Hz, 1H), 5.30 (d, J = 5.6 Hz, 1H), 4.57 (d, J = 6.9 Hz, 1H), 4.51 (d, J = 9.9 Hz, 1H), 4.29 (d, J = 10.5 Hz, 1H), 4.08 (dd, J = 10.2, 5.6 Hz, 1H), 3.93 (d, J = 11.6 Hz, 1H), 3.81 (s, 1H), 3.58 (dd, J = 10.2, 3.3 Hz, 1H), 3.53– 3.45 (m, 1H), 3.22– 3.10 (m, 1H), 2.67– 2.46 (m, 4H), 2.38– 2.30 (m, 1H), 2.15 (s, 3H), 1.96– 1.86 (m, 1H), 1.63 (d, J = 6.9 Hz, 3H), 1.43 (d, J = 6.8 Hz, 3H).
Figure imgf000268_0002
[00610] FSA-47042: 1H NMR (600 MHz, CD3OD) δ 6.02 (d, J = 15.6 Hz, 1H), 5.76 (t, J = 6.5 Hz, 1H), 5.65 (dt, J = 15.2, 7.4 Hz, 1H), 5.29 (d, J = 5.6 Hz, 0H), 4.65– 4.56 (m, 1H), 4.41 (d, J = 10.0 Hz, 1H), 4.20 (d, J = 10.0 Hz, 1H), 4.07 (dd, J = 10.2, 5.6 Hz, 0H), 3.84– 3.79 (m, 1H), 3.76 (d, J = 3.3 Hz, 1H), 3.55 (dd, J = 10.2, 3.4 Hz, 0H), 3.24– 3.15 (m, 2H), 3.16– 3.08 (m, 1H), 2.78– 2.72 (m, 2H), 2.69– 2.60 (m, 2H), 2.58– 2.48 (m, 1H), 2.14 (s, 3H), 2.00 (t, J = 7.2 Hz, 2H), 1.71 (d, J = 11.8 Hz, 3H), 1.65 (d, J = 12.5 Hz, 1H), 1.52 (s, 2H), 1.44 (d, J = 6.8 Hz, 3H), 1.28– 1.22 (m, 2H), 0.99– 0.85 (m, 3H).
Figure imgf000269_0001
[00611] FSA-47056: 1H NMR (600 MHz, CD3OD) δ 6.08 (d, J = 15.7 Hz, 1H), 5.84 (t, J = 6.3 Hz, 1H), 5.74 (dt, J = 14.8, 6.9 Hz, 1H), 5.33 (d, J = 5.6 Hz, 1H), 4.64– 4.55 (m, 1H), 4.53 (d, J = 10.0 Hz, 1H), 4.32 (d, J = 9.9 Hz, 1H), 4.10 (dd, J = 10.1, 5.6 Hz, 2H), 3.86 (s, 1H), 3.60 (d, J = 10.1 Hz, 1H), 3.58– 3.50 (m, 1H), 3.28– 3.19 (m, 1H), 2.96– 2.85 (m, 1H), 2.85– 2.75 (m, 2H), 2.69 (dd, J = 17.5, 8.9 Hz, 1H), 2.16 (s, 3H), 2.14– 2.08 (m, 2H), 1.44 (d, J = 6.7 Hz, 3H), 1.44– 1.37 (m, 4H), 1.37– 1.25 (m, 4H), 0.92 (t, J = 6.9 Hz, 3H).
Figure imgf000269_0002
[00612] FSA-47063: 1H NMR (600 MHz, CD3OD) δ 6.06 (d, J = 15.7 Hz, 1H), 5.82 (t, J = 6.5 Hz, 1H), 5.72 (dt, J = 15.6, 7.0 Hz, 1H), 5.31 (d, J = 5.6 Hz, 1H), 4.55 (q, J = 6.8, 6.2 Hz, 1H), 4.51 (d, J = 10.1 Hz, 1H), 4.30 (d, J = 10.0 Hz, 1H), 4.08 (dd, J = 10.3, 5.9 Hz, 2H), 3.84 (s, 1H), 3.61– 3.55 (m, 1H), 3.52 (dd, J = 13.4, 7.4 Hz, 1H), 3.22 (t, J = 11.4 Hz, 1H), 2.90 (dd, J = 17.1, 6.2 Hz, 1H), 2.83– 2.73 (m, 2H), 2.67 (dd, J = 17.5, 9.5 Hz, 1H), 2.14 (s, 3H), 2.09 (q, J = 7.1 Hz, 2H), 2.03 (s, 3H), 1.47– 1.40 (m, 5H), 0.91 (t, J = 7.4 Hz, 3H).
Figure imgf000269_0003
[00613] FSA-217098: (isolated as the trifluoroacetate salt) 1H NMR (500 MHz, CD3OD) δ 5.26 (d, J = 5.7 Hz, 1H), 4.42 (dt, J = 47.6, 6.0 Hz, 2H), 4.28 (dd, J = 8.8, 5.8 Hz, 1H), 4.09– 4.06 (m, 3H), 3.88 (d, J = 3.4 Hz, 1H), 3.54 (dd, J = 10.2, 3.3 Hz, 1H), 3.44 (ddd, J = 13.9, 6.0, 2.2 Hz, 1H), 3.13 (app t, J = 12.3 Hz, 1H), 2.34–2.26 (m, 1H), 2.23–2.12 (m, 2H), 2.10 (s, 3H), 2.04–2.00 (m, 1H), 1.95–1.89 (m, 1H), 1.79–1.54 (m, 10H), 1.47–1.29 (m, 6H), 1.29–1.21 (m, 1H). HRMS (ESI+, m/z): [M+H]+ calcd for C23H41FN2O5S, 477.2793; found 477.2791.
Figure imgf000270_0001
[00614] FSA-217099: (isolated as the bis-trifluoroacetate salt) 1H NMR (500 MHz, CD3OD) δ 5.25 (d, J = 5.6 Hz, 1H), 4.28 (dd, J = 8.8, 5.7 Hz, 1H), 4.11–4.05 (m, 3H), 4.01 (q, J = 9.0 Hz, 2H), 3.88 (dd, J = 3.5, 1.1 Hz, 1H), 3.54 (dd, J = 10.2, 3.3 Hz, 1H), 3.45 (ddd, J = 13.8, 5.9, 2.1 Hz, 1H), 3.19–3.11 (m, 3H), 2.34–2.27 (m, 1H), 2.23–2.12 (m, 2H), 2.10 (s, 3H), 2.06–2.01 (m, 1H), 1.95–1.89 (m, 1H), 1.79–1.53 (m, 10H), 1.43–1.32 (m, 4H), 1.28– 1.20 (m, 1H). HRMS (ESI+, m/z): [M+H]+ calcd for C24H42F3N3O5S, 542.2870; found 542.2867.
Figure imgf000270_0002
[00615] FSA-218002: (isolated as the tris-trifluoroacetate salt) 1H NMR (600 MHz, CD3OD) δ 5.26 (d, J = 5.8 Hz, 1H), 4.39 (dd, J = 10.2, 3.3 Hz, 1H), 4.13 (dd, J = 10.1, 1.2 Hz, 1H), 4.08 (dd, J = 10.3, 5.7 Hz, 1H), 4.04–3.99 (m, 3H), 3.80 (dd, J = 3.4, 1.1 Hz, 1H), 3.66 (br d, J = 12.5 Hz, 1H), 3.57 (br d, J = 12.1 Hz, 1H), 3.50 (dd, J = 10.3, 3.3 Hz, 1H), 3.45 (ddd, J = 14.0, 5.8, 2.4 Hz, 1H), 3.16–3.11 (m, 3H), 3.03–2.93 (m, 4H), 2.27–2.17 (m, 2H), 2.15–2.09 (m, 1H), 2.13 (s, 3H), 2.05–1.95 (m, 2H), 1.94–1.86 (m, 2H), 1.78–1.58 (m, 8H), 1.44 (app dtd, J = 12.9, 8.9, 3.8 Hz, 1H), 1.40–1.36 (m, 2H), 0.99 (t, J = 7.4 Hz, 1H). HRMS (ESI+, m/z): [M+2H]2+ calcd for C27H49F3N4O5S, 299.1682; found 299.1688.
Figure imgf000271_0001
[00616] FSA-218008: (isolated as the tris-trifluoroacetate salt) 1H NMR (600 MHz, CD3OD) δ 5.24 (d, J = 5.6 Hz, 1H), 4.26 (t, J = 5.6 Hz, 1H), 4.18 (dd, J = 6.1, 1.4 Hz, 1H), 4.08–4.06 (m, 2H), 4.01 (q, J = 9.0 Hz, 1H), 3.88 (dd, J = 3.3, 1.3 Hz, 1H), 3.59–3.56 (m, 3H), 3.44 (ddd, J = 13.9, 5.8, 2.1 Hz, 1H), 3.15–3.11 (m, 3H), 3.02 (t, J = 8.3 Hz, 2H), 2.93 (td, J = 13.0, 2.9 Hz, 2H), 2.24–2.14 (m, 2H), 2.13 (s, 3H), 2.03–1.94 (m, 4H), 1.86 (td, J = 9.4, 4.4 Hz, 1H), 1.79–1.59 (m, 9H), 1.43 (dtd, J = 12.9, 8.9, 3.5 Hz, 1H), 1.39–1.35 (m, 2H), 1.01 (t, J = 7.4 Hz, 3H).19F NMR (376 MHz, CD3OD) δ–70.15 (t, J = 9.0 Hz, 3F),–77.19 (s, 9F). HRMS (ESI+, m/z): [M+H]+ calcd for C27H49F3N4O5S, 599.3449; found 599.3436.
Figure imgf000271_0002
[00617] FSA-413055: 1H NMR (600 MHz, CD3OD) δ 5.30 (d, J = 5.7 Hz, 1H), 4.57 (q, J = 6.8 Hz, 1H), 4.52 (d, J = 9.9 Hz, 1H), 4.30 (d, J = 10.0 Hz, 1H), 4.11– 4.04 (m, 3H), 3.82 (s, 1H), 3.58 (dd, J = 10.2, 3.3 Hz, 1H), 3.53 (d, J = 12.3 Hz, 2H), 3.44– 3.37 (m, 2H), 2.96 (t, J = 12.2 Hz, 2H), 2.84 (s, 3H), 2.39 (dd, J = 16.4, 6.5 Hz, 1H), 2.14 (s, 3H), 2.05– 1.98 (m, 2H), 1.99– 1.89 (m, 4H), 1.73– 1.64 (m, 1H), 1.64– 1.49 (m, 5H), 1.44 (d, J = 6.8 Hz, 3H).
Figure imgf000272_0001
[00618] FSA-413075C: 1H NMR (500 MHz, CD3OD) δ 5.32 (d, J = 5.6 Hz, 1H), 4.62– 4.55 (m, 2H), 4.54 (d, J = 10.2 Hz, 1H), 4.33 (d, J = 10.0 Hz, 1H), 4.14– 4.06 (m, 4H), 3.93 (s, 1H), 3.62 (d, J = 10.3 Hz, 1H), 3.45 (s, 1H), 2.53– 2.40 (m, 3H), 2.36 (s, 2H), 2.16 (s, 3H), 2.10– 1.99 (m, 4H), 1.94 (dd, J = 16.3, 10.8 Hz, 1H), 1.90– 1.82 (m, 1H), 1.82– 1.64 (m, 1H), 1.64– 1.50 (m, 3H), 1.46 (d, J = 6.8 Hz, 3H).
Figure imgf000272_0002
[00619] FSA-413075A: 1H NMR (500 MHz, CD3OD) δ 5.32 (d, J = 5.6 Hz, 1H), 4.58 (q, J = 6.9 Hz, 1H), 4.53 (d, J = 10.0 Hz, 1H), 4.32 (d, J = 10.0 Hz, 1H), 4.10 (dd, J = 10.2, 5.6 Hz, 1H), 4.04 (d, J = 11.5 Hz, 1H), 3.84 (s, 1H), 3.60 (dd, J = 10.2, 3.2 Hz, 1H), 3.44– 3.34 (m, 2H), 3.28 (q, J = 9.8 Hz, 2H), 2.91 (s, 1H), 2.38 (dd, J = 15.8, 6.4 Hz, 1H), 2.16 (s, 3H), 2.04 (dd, J = 14.4, 7.5 Hz, 2H), 1.91 (q, J = 12.0 Hz, 1H), 1.77– 1.68 (m, 2H), 1.69– 1.61 (m, 1H), 1.61– 1.48 (m, 6H), 1.48– 1.39 (m, 5H), 1.37 (s, 2H).
Figure imgf000273_0001
[00620] FSA-413075B: 1H NMR (500 MHz, CD3OD) δ 5.32 (d, J = 5.6 Hz, 1H), 4.58 (q, J = 6.6 Hz, 1H), 4.53 (d, J = 10.1 Hz, 1H), 4.32 (d, J = 10.0 Hz, 1H), 4.10 (dd, J = 10.2, 5.6 Hz, 1H), 4.03 (d, J = 11.5 Hz, 1H), 3.84 (s, 1H), 3.60 (dd, J = 10.2, 3.2 Hz, 1H), 3.40 (q, J = 9.6 Hz, 4H), 2.62 (s, 1H), 2.37 (dd, J = 15.7, 6.4 Hz, 1H), 2.16 (s, 3H), 2.06 (s, 1H), 2.04– 1.95 (m, 5H), 1.96– 1.83 (m, 2H), 1.78 (s, 1H), 1.72– 1.62 (m, 1H), 1.53 (t, J = 8.9 Hz, 2H), 1.45 (d, J = 6.8 Hz, 3H), 1.37– 1.26 (m, 2H), 1.19 (q, J = 10.9, 9.5 Hz, 4H).
Figure imgf000273_0002
[00621] FSA-413089: 1H NMR (600 MHz, CD3OD) δ 7.36 (d, J = 7.8 Hz, 2H), 7.32 (t, J = 7.5 Hz, 2H), 7.26 (t, J = 7.2 Hz, 1H), 6.17 (t, J = 6.4 Hz, 1H), 5.30 (d, J = 5.6 Hz, 1H), 4.57 (q, J = 6.9 Hz, 1H), 4.53 (d, J = 10.0 Hz, 1H), 4.31 (d, J = 10.0 Hz, 1H), 4.08 (dd, J = 10.1, 5.8 Hz, 2H), 3.85 (s, 1H), 3.64– 3.54 (m, 5H), 3.07– 2.84 (m, 4H), 2.14 (s, 3H), 1.42 (d, J = 6.7 Hz, 3H).
Figure imgf000273_0003
[00622] FSA-413090: 1H NMR (600 MHz, CD3OD) δ 7.32– 7.27 (m, 2H), 7.24 (d, J = 7.6 Hz, 1H), 7.22– 7.17 (m, 2H), 5.31 (d, J = 5.7 Hz, 1H), 4.62– 4.57 (m, 1H), 4.54 (dd, J = 20.0, 10.4 Hz, 1H), 4.31 (dd, J = 10.4, 3.8 Hz, 1H), 4.24– 4.18 (m, 2H), 4.10 (dd, J = 10.0, 6.1 Hz, 1H), 3.84 (s, 1H), 3.59 (dd, J = 10.3, 3.3 Hz, 1H), 3.47 (t, J = 13.8 Hz, 1H), 3.40– 3.35 (m, 1H), 3.28– 3.19 (m, 1H), 2.92– 2.79 (m, 1H), 2.39 (d, J = 15.6 Hz, 1H), 2.34– 2.27 (m, 1H), 2.15 (s, 4H), 2.09– 2.00 (m, 2H), 1.90 (dt, J = 36.9, 12.4 Hz, 1H), 1.45 (d, J = 6.4 Hz, 2H). Biological Assays
[00623] Minimum inhibitory concentrations (MICs) for compounds described herein have been determined for strains of several Gram positive and Gram negative strains. Data for exemplary compounds described herein is shown in Tables 4-29.
Table 4. MIC (µg/mL) of compounds against Gram positive and Gram negative strains
Figure imgf000275_0001
Table 5. MIC (µg/mL) of compounds against Gram positive and Gram negative strains
Figure imgf000275_0002
Figure imgf000276_0001
Figure imgf000277_0001
Figure imgf000278_0001
Figure imgf000279_0001
Figure imgf000280_0001
Figure imgf000281_0001
Figure imgf000282_0001
Figure imgf000283_0003
Table 20. MIC (µg/mL) of compounds against Gram positive and Gram negative strains
Figure imgf000283_0001
Table 21. MIC (µg/mL) of compounds against Gram positive and Gram negative strains
Figure imgf000283_0002
Figure imgf000284_0003
Table 22. MIC (µg/mL) of compounds against Gram positive and Gram negative strains
Figure imgf000284_0001
Table 23. MIC (µg/mL) of compounds against Gram positive and Gram negative strains
Figure imgf000284_0002
Figure imgf000285_0003
Table 24. MIC (µg/mL) of compounds against Gram positive and Gram negative strains
Figure imgf000285_0001
Table 25. MIC (µg/mL) of compounds against Gram positive and Gram negative strains
Figure imgf000285_0002
Table 26. MIC (µg/mL) of compounds against Gram positive and Gram negative strains
Figure imgf000286_0001
Table 27. MIC (µg/mL) of compounds against Gram positive and Gram negative strains
Figure imgf000286_0002
Figure imgf000287_0003
Table 28. MIC (µg/mL) of compounds against Gram positive and Gram negative strains
Table 29. MIC (µg/mL) of compounds against Gram positive and Gram negative strains
Figure imgf000287_0002
[00624] The hemolytic activity of several exemplary compounds was also determined.
[00625] Materials and Methods: Human blood (with potassium/EDTA)-commercial source; Phosphate buffer saline– pH = 7.4; 0.9% Saline– 9 g/ L; 20 % TritonX-100 (positive Control): 20 mL of Triton X 100 + 80 mL of water– sonicate/mix vigorously; 96 well plates (U bottom and Flat bottom) plates; Centrifuge.
[00626] Procedure: Prepare sterile 0.9% NaCl by adding 9 g of NaCl in 1 L of water. Prepare 20 % Triton X– 100 by adding 20 mL of Triton X-100 in 80 mL of water– sonicate or mix vigorously. Human blood (with anti-coagulants– EDTA/ Citrate salts) was purchased from commercial source (Lampire Biological Laboratory).25 mL of blood was transferred into a 50 mL screw cap vial and centrifuged at 500 x g for 5 minutes. Plasma was removed carefully and an equal volume of 0.9% NaCl was added to the vials and mixed well by inverting the vial slowly.The vials were centrifuged again at 500 x g for 5 minutes and supernatant aspirated, which was replaced by equal volume of 0.9 % NaCl.
[00627] This procedure was repeated 2 more times and then the supernatant was aspirated and an equal volume of Phosphate Buffer Saline was replaced. The vial was mixed gently to allow suspension of all the red blood cells homogenously and the centrifugation step was performed once again. The aspirated supernatant was replaced by equal volume of PBS and the vials were mixed well.1 mL of this sample was diluted in 49 mL of PBS (pH = 7.4)– 1:50 dilution and the vial was inverted several times to allow proper mixing.
[00628] 20 mM stock solutions of compounds to be tested were prepared in DMSO. Stock solution was diluted 1:2 times in DMSO to achieve varying concentrations of 20000 µM, 10000 µM, 5000 µM, 2500 µM, 1250 µM, 625 µM, 312.5 µM, 156.25 µM and 78.125 µM in DMSO with each test compound.2 uL of solution from each dilution (each compound) was transferred into 96 well plate in triplicates.198 uL of RBC-containing solution was transferred into each well (1:100 dilution). The final concentrations in wells were 200 µM, 100 µM, 50 µM, 25 µM, 12.5 µM, 6.25 µM, 3.125 µM, 1.5625 µM and 0.7812 µM. Positive control (20 % Triton X-100) and DMSO control were also included in each plate in similar volumes (2 µL).
[00629] Incubation: These 96 well plates were incubated at 370 C for 1 hour and the plates were removed and centrifuged at 500 x g for 5 minutes.100 - 125 uL of supernatant was collected carefully from all the test and controls and transferred into 96 well flat bottom plates with proper labeling. Absorbance was measured at 450 nm using plate reader.
[00630] Calculation of Hemolysis: % Hemolysis = (abs of sample)– (abs of– ve control)/(abs of +ve control)– (abs of -ve control) x 100.
[00631] The hemolytic activity (% hemolysis) of several exemplary compounds at a series of compound concentrations are shown in Tables 30-32. Table 30. Hemolytic activity of exemplary compounds
Figure imgf000289_0001
Table 31. Hemolytic activity of exemplary compounds
Figure imgf000289_0002
Table 32. Hemolytic activity of exemplary compounds
Figure imgf000289_0003
Figure imgf000290_0001
QUIVALENTS AND COPE
[00632] In the claims articles such as“a,”“an,” and“the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include“or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.
[00633] Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular elements and/or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms“comprising” and“containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.
[00634] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the invention can be excluded from any claim, for any reason, whether or not related to the existence of prior art.
[00635] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims.

Claims

CLAIMS What is claimed is: 1. A compound of Formula (I):
Figure imgf000292_0001
(I),
or a pharmaceutically acceptable salt thereof, wherein:
P is independently hydrogen or a protecting group;
A is substituted or unsubstituted carbocyclyl, substituted or unsubstituted
heterocyclyl,
Figure imgf000292_0002
;
R1 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,–ORA,–N(RA)2, or–SRA;
R2 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 aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaliphatic,–ORA,–N3,–N(RA)2,–SRA,–CN,– SCN,–C(=NRA)RA,–C(=NRA)ORA,–C(=NRA)N(RA)2,–C(=O)RA,–C(=O)ORA,–
C(=O)N(RA)2,–NO2,–NRAC(=O)RA,–NRAC(=O)ORA,–NRAC(=O)N(RA)2,–
NRAC(=NRA)N(RA)2,–OC(=O)RA,–OC(=O)ORA,–OC(=O)N(RA)2,–NRAS(O)2RA, - OS(O)2RA, or -S(O)2RA; R3 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;
R4 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;
R5 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or
unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroaliphatic;
R6a, R6b, and R6c 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;
R7 is hydrogen or unsubstituted alkyl; or A and R7 are joined to form a substituted or unsubstituted heterocyclic ring;
R8 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaliphatic,– C(=NRA)RA,–C(=NRA)ORA,–C(=NRA)N(RA)2,–C(=O)RA,–C(=O)ORA,–C(=O)N(RA)2, - S(O)2RA, or a nitrogen protecting group;
each occurrence of R9 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,–ORA,–N(RA)2,–SRA,–CN,–SCN,–C(=NRA)RA,–C(=NRA)ORA,– C(=NRA)N(RA)2,–C(=O)RA,–C(=O)ORA,–C(=O)N(RA)2,–NO2,–NRAC(=O)RA,–
NRAC(=O)ORA,–NRAC(=O)N(RA)2,–NRAC(=NRA)N(RA)2,–OC(=O)RA,–OC(=O)ORA,– OC(=O)N(RA)2,–NRAS(O)2RA, -OS(O)2RA, or -S(O)2RA;
p is 0-4; each occurrence of RA 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
unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted hetaralkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two RA groups are joined to form a substituted or unsubstituted heterocyclic ring, or a substituted or unsubstituted heteroaryl ring; and
Figure imgf000294_0004
represents a single or double bond;
provided that when R1 is–SRA wherein RA is C1-6 substituted or unsubstituted alkyl,
A is not unsubstituted carbocyclyl,
Figure imgf000294_0001
2. A compound of Formula (II):
Figure imgf000294_0002
(II),
or a pharmaceutically acceptable salt thereof, wherein:
P is independently hydrogen or a protecting group;
A is substituted or unsubstituted carbocyclyl, substituted or unsubstituted
Figure imgf000294_0003
R1 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,–ORA,–N(RA)2, or–SRA;
R2 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 aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaliphatic,–ORA,–N3,–N(RA)2,–SRA,–CN,– SCN,–C(=NRA)RA,–C(=NRA)ORA,–C(=NRA)N(RA)2,–C(=O)RA,–C(=O)ORA,–
C(=O)N(RA)2,–NO2,–NRAC(=O)RA,–NRAC(=O)ORA,–NRAC(=O)N(RA)2,–
NRAC(=NRA)N(RA)2,–OC(=O)RA,–OC(=O)ORA,–OC(=O)N(RA)2,–NRAS(O)2RA, - OS(O)2RA, or -S(O)2RA;
R3 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;
R4 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;
R5 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or
unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroaliphatic;
R6a, R6b, and R6c 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;
R7 is hydrogen or unsubstituted alkyl; or A and R7 are joined to form a substituted or unsubstituted heterocyclic ring;
R8 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaliphatic,– C(=NRA)RA,–C(=NRA)ORA,–C(=NRA)N(RA)2,–C(=O)RA,–C(=O)ORA,–C(=O)N(RA)2, - S(O)2RA, or a nitrogen protecting group;
each occurrence of R9 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,–ORA,–N(RA)2,–SRA,–CN,–SCN,–C(=NRA)RA,–C(=NRA)ORA,– C(=NRA)N(RA)2,–C(=O)RA,–C(=O)ORA,–C(=O)N(RA)2,–NO2,–NRAC(=O)RA,– NRAC(=O)ORA,–NRAC(=O)N(RA)2,–NRAC(=NRA)N(RA)2,–OC(=O)RA,–OC(=O)ORA,– OC(=O)N(RA)2,–NRAS(O)2RA, -OS(O)2RA, or -S(O)2RA; or two R9 groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring;
each occurrence of RA 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
unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted hetaralkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two RA groups are joined to form a substituted or unsubstituted heterocyclic ring, or a substituted or unsubstituted heteroaryl ring;
E is substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted carbocyclylene, or substituted or unsubstituted heterocyclylene;
Rb and Rc 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 heteroaliphatic,–C(=O)RA, -S(O)2RA, or a nitrogen protecting group; or Rb and Rc are joined to form a substituted or unsubstituted heterocyclic ring; and
represents a single or double bond.
3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein:
Figure imgf000297_0001
.
4. The compound of any of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein:
Figure imgf000297_0002
.
5. The compound claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein:
A is substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl.
6. The compound claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein:
A is substituted or unsubstituted carbocyclyl.
7. The compound of any of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein:
A is
Figure imgf000297_0003
.
8. The compound of any of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein:
R1 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,–ORA,–N(RA)2, or–SRA.
9. The compound of any of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein:
R1 is substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heteroaralkyl, or–SRA.
10. The compound of any of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein:
R1 is substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, or– SRA.
11. The compound of any of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein:
R1 is–SRA,
Figure imgf000298_0001
.
12. The compound of any of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein:
R1 is–SRA.
13. The compound of any of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein:
R1 is–SCH3.
14. The compound of any of claims 1-4 or 8-13, or a pharmaceutically acceptable salt thereof, wherein:
R2 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 heteroaryl, substituted or
unsubstituted heteroalkyl,–ORA,–N3,–N(RA)2,–SRA,–NRAC(=O)RA, or–OC(=O)N(RA)2.
15. The compound of any of claims 1-4 or 8-14, or a pharmaceutically acceptable salt thereof, wherein: R2 is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heteroaryl,–ORA,–N3,–N(RA)2,–SRA,–NRAC(=O)RA, or– OC(=O)N(RA)2.
16. The compound of any of claims 1-4 or 8-15, or a pharmaceutically acceptable salt thereof, wherein:
R2 is halogen, substituted or unsubstituted alkyl,–ORA,–N(RA)2, or–SRA.
17. The compound of any of claims 1-4 or 8-16, a pharmaceutically acceptable salt thereof, wherein:
R2 is halogen or–SRA.
18. The compound of any of claims 1-4 or 8-17, or a pharmaceutically acceptable salt thereof, wherein:
R3 is hydrogen, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkenyl.
19. The compound of any of claims 1-4 or 8-18, or a pharmaceutically acceptable salt thereof, wherein:
R3 is hydrogen or substituted or unsubstituted alkyl.
20. The compound of any of claims 1-4 or 8-19, or a pharmaceutically acceptable salt thereof, wherein:
R3 is hydrogen.
21. The compound of any of claims 1-4 or 8-20, or a pharmaceutically acceptable salt thereof, wherein:
R4 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl.
22. The compound of any of claims 1-4 or 8-21, or a pharmaceutically acceptable salt thereof, wherein:
R4 is hydrogen or substituted or unsubstituted alkyl.
23. The compound of any of claims 1-4 or 8-13, or a pharmaceutically acceptable salt thereof, wherein:
R5 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or
unsubstituted aryl, or substituted or unsubstituted heteroaryl.
24. The compound of any of claims 1-4, 8-13, or 23, or a pharmaceutically acceptable salt thereof, wherein:
R5 is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
25. The compound of any of claims 1-4 or 8-13, or a pharmaceutically acceptable salt thereof, wherein:
R6a, R6b, and R6c are each independently hydrogen, halogen, substituted or
unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted acyl.
26. The compound of any of claims 1-4, 8-13, or 25, or a pharmaceutically acceptable salt thereof, wherein:
R6a, R6b, and R6c are each hydrogen.
27. The compound of any of claims 1, 2, or 8-13, or a pharmaceutically acceptable salt thereof, wherein:
A and R7 are joined to form a substituted or unsubstituted heterocyclic ring.
28. The compound of any of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein:
R7 is hydrogen.
29. The compound of any of claims 1-28, or a pharmaceutically acceptable salt thereof, wherein:
R8 is hydrogen, substituted or unsubstituted alkyl, or–C(=O)RA.
30. The compound of any of claims 1-29, or a pharmaceutically acceptable salt thereof, wherein:
R8 is hydrogen or substituted or unsubstituted alkyl.
31. The compound of any of claims 1-30, or a pharmaceutically acceptable salt thereof, wherein:
R8 is hydrogen or methyl.
32. The compound of any of claims 1-31, or a pharmaceutically acceptable salt thereof, wherein:
R8 is hydrogen.
33. The compound of any of claims 1-31, or a pharmaceutically acceptable salt thereof, wherein:
R8 is methyl.
34. The compound of any of claims 1-33, or a pharmaceutically acceptable salt thereof, wherein:
R9 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.
35. The compound of any of claims 1 or 3-34, or a pharmaceutically acceptable salt thereof, wherein:
R9 is substituted or unsubstituted alkyl.
36. The compound of any of claims 1 or 3-35, or a pharmaceutically acceptable salt thereof, wherein:
p is 1.
37. The compound of any of claims 1-36, or a pharmaceutically acceptable salt thereof, wherein:
each occurrence of RA is, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted hetaralkyl, or two RA groups are joined to form a substituted or unsubstituted heteroaryl ring.
38. The compound of claim 1, wherein the compound is of Formula (I-a):
Figure imgf000302_0001
(I-a),
or a pharmaceutically acceptable salt thereof.
39. The compound of claim 1 or 38, wherein the compound is of Formula (I-b):
Figure imgf000302_0002
(I-b),
or a pharmaceutically acceptable salt thereof.
40. The compound of any of claims 1, 38, or 39, wherein the compound is of Formula (I- c):
Figure imgf000303_0001
(I-c),
or a pharmaceutically acceptable salt thereof.
41. The compound of any of claims 1, 38, or 39, wherein the compound is of Formula (I- d):
Figure imgf000303_0002
(I-d),
or a pharmaceutically acceptable salt thereof.
42. The compound of any of claims 1 or 38-41, wherein the compound is of Formula (I- f):
Figure imgf000304_0001
(I-f),
or a pharmaceutically acceptable salt thereof.
43. The compound of any of claims 1 or 38-42, wherein the compound is of Formula (I- g):
Figure imgf000304_0002
(I-g),
or a pharmaceutically acceptable salt thereof.
44. The compound of any of claims 1 or 38-43, wherein the compound is of Formula (I- h):
Figure imgf000305_0001
(I-h),
or a pharmaceutically acceptable salt thereof.
45. The compound of any of claims 1 or 38-42, wherein the compound is of Formula (I-i):
Figure imgf000305_0002
(I-i),
or a pharmaceutically acceptable salt thereof.
46. The compound of any of claims 1, 38-42, or 45, wherein the compound is of Formula (I-j):
R1 R2
Figure imgf000306_0001
(I-j),
or a pharmaceutically acceptable salt thereof.
47. The compound of any of claims 1, 38-42, 45, or 46, wherein the compound is of Formula (I-k):
Figure imgf000306_0002
(I-k),
or a pharmaceutically acceptable salt thereof.
48. The compound of any of claims 1, 38-42, 45, or 46, wherein the compound is of Formula (I-l):
Figure imgf000307_0001
(I-l),
or a pharmaceutically acceptable salt thereof.
49. The compound of any of claims 1, 38-42, or 45, wherein the compound is of Formula (I-m):
Figure imgf000307_0002
(I-m),
or a pharmaceutically acceptable salt thereof, wherein:
R1a and R1b 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,–ORA,–N3,–N(RA)2,–SRA,–CN,–SCN,–C(=NRA)RA,–C(=NRA)ORA,– C(=NRA)N(RA)2,–C(=O)RA,–C(=O)ORA,–C(=O)N(RA)2,–NO2,–NRAC(=O)RA,–
NRAC(=O)ORA,–NRAC(=O)N(RA)2,–NRAC(=NRA)N(RA)2,–OC(=O)RA,–OC(=O)ORA,– OC(=O)N(RA)2,–NRAS(O)2RA, -OS(O)2RA, or -S(O)2RA; or R1a and R1b are joined to form a substituted or unsubstituted heterocyclic ring, or a substituted or unsubstituted carbocyclic ring.
50. The compound of claim 49, wherein the compound is of Formula (I-n):
Figure imgf000308_0001
(I-n),
or a pharmaceutically acceptable salt thereof.
51. The compound of claim 49, wherein the compound is of Formula (I-o):
Figure imgf000308_0002
(I-o),
or a pharmaceutically acceptable salt thereof.
52. The compound of claim 2, wherein the compound is of Formula (II-a):
R1
Figure imgf000309_0001
(II-a),
or a pharmaceutically acceptable salt thereof.
53. The compound of claim 2 or 52, wherein the compound is of Formula (II-b):
Figure imgf000309_0002
(II-b),
or a pharmaceutically acceptable salt thereof.
54. The compound of any of claims 2, 52, or 53, wherein the compound is of Formula (II- c):
Figure imgf000310_0001
(II-c),
or a pharmaceutically acceptable salt thereof, wherein:
Rd and Re are each independently, hydrogen, halogen, or substituted or unsubstituted alkyl; or optionally one instance of Rd and Re together form an oxo group; and
q is 1-6.
55. The compound of claim 54, wherein the compound is of Formula (II-d):
Figure imgf000310_0002
(II-d),
or a pharmaceutically acceptable salt thereof.
56. The compound of claim 54 or 55, wherein the compound is of Formula (II-e):
Figure imgf000311_0001
(II-e),
or a pharmaceutically acceptable salt thereof.
57. The compound of any of claims 54-56, or a pharmaceutically acceptable salt thereof, wherein:
Rd and Re are each hydrogen; or optionally one instance of Rd and Re together form an oxo group.
58. The compound of any of claims 54-57, or a pharmaceutically acceptable salt thereof, wherein:
Rd and Re are each hydrogen.
59. The compound of any of claims 52-56, wherein the compound is of Formula (II-f):
Figure imgf000311_0002
(II-f),
or a pharmaceutically acceptable salt thereof.
60. The compound of any of claims 54-59, or a pharmaceutically acceptable salt thereof, wherein:
q is 3.
61. The compound of any of claims 2, 52-56, or 59, wherein the compound is of Formula (II-g):
Figure imgf000312_0001
(II-g),
or a pharmaceutically acceptable salt thereof.
62. The compound of any of claims 2, 52-56, 59, or 61, wherein the compound is of Formula (II-h):
Figure imgf000312_0002
(II-h),
or a pharmaceutically acceptable salt thereof.
63. The compound of any of claims 2, 52-56, 59, 61, or 62, wherein the compound is of Formula (II-i):
Figure imgf000313_0001
(II-i),
or a pharmaceutically acceptable salt thereof.
64. The compound of any of claims 2, 52-56, 59, or 61-63, wherein the compound is of Formula (II-j):
Figure imgf000313_0002
(II-j),
or a pharmaceutically acceptable salt thereof.
65. The compound of any of claims 2, 52-56, 59, or 61-63, wherein the compound is of Formula (II-k):
Figure imgf000314_0001
(II-k),
or a pharmaceutically acceptable salt thereof.
66. The compound of any of claims 2, 52-56, 59, 61, or 62, wherein the compound is of Formula (II-l):
Figure imgf000314_0002
(II-l),
or a pharmaceutically acceptable salt thereof, wherein:
R1a and R1b 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,–ORA,–N3,–N(RA)2,–SRA,–CN,–SCN,–C(=NRA)RA,–C(=NRA)ORA,– C(=NRA)N(RA)2,–C(=O)RA,–C(=O)ORA,–C(=O)N(RA) A
2,–NO2,–NR C(=O)RA,– NRAC(=O)ORA,–NRAC(=O)N(RA)2,–NRAC(=NRA)N(RA)2,–OC(=O)RA,–OC(=O)ORA,– OC(=O)N(RA)2,–NRAS(O)2RA, -OS(O)2RA, or -S(O)2RA, or R1a and R1b are joined to form a substituted or unsubstituted heterocyclic ring, or a substituted or unsubstituted carbocyclic ring.
67. The compound of claim 67, wherein the compound is of Formula (II-m):
Figure imgf000315_0001
(II-m),
or a pharmaceutically acceptable salt thereof.
68. The compound of claim 66, wherein the compound is of Formula (II-n):
Figure imgf000315_0002
(II-n),
or a pharmaceutically acceptable salt thereof.
69. The compound of any of claims 49-51 or 66-68, or a pharmaceutically acceptable salt thereof, wherein:
R1a and R1b 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,–ORA, -OS(O)2RA,–N3,–N(RA)2, or R1a and R1b are joined to form a substituted or unsubstituted carbocyclic ring.
70. The compound of any of claims 49-51 or 66-69, or a pharmaceutically acceptable salt thereof, wherein:
R1a and R1b are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, or–N(RA)2; or R1a and R1b are joined to form a substituted or unsubstituted carbocyclic ring.
71. The compound of any of claims 2, 52-56, 59, 61-63, or 65, wherein the compound is of Formula (II-o):
Figure imgf000316_0001
(II-o),
or a pharmaceutically acceptable salt thereof.
72. The compound of any of claims 2, 52-56, 59, 61-63, 65, or 71, wherein the compound is of Formula (II-p):
Figure imgf000317_0001
(II-p),
or a pharmaceutically acceptable salt thereof.
73. The compound of any of claims 2, 52-56, 59, 61-63, 65, 71, or 72, wherein the compound is of Formula (II-q):
Figure imgf000317_0002
(II-q),
or a pharmaceutically acceptable salt thereof.
74. The compound of any of claims 2 or 52-73, or a pharmaceutically acceptable salt thereof, wherein:
Rb and Rc are each independently, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, or -S(O)2RA; or Rb and Rc are joined to form a substituted or unsubstituted heterocyclic ring.
75. The compound of any of claims 2 or 52-74, or a pharmaceutically acceptable salt thereof, wherein:
Rb and Rc are each independently, hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkylalkyl; or Rb and Rc are joined to form a substituted or unsubstituted heterocyclic ring.
76. The compound of any of claims 2 or 52-75, or a pharmaceutically acceptable salt thereof, wherein:
Rb and Rc are each independently, hydrogen, haloalkyl, or cycloalkylhaloalkyl; or Rb and Rc are joined to form a halo-substituted heterocyclic ring.
77. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is:
Figure imgf000318_0001
Figure imgf000319_0001
Figure imgf000320_0001
Figure imgf000321_0001
78. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein the compound is:
Figure imgf000322_0001
Figure imgf000323_0001
Figure imgf000324_0001
Figure imgf000325_0001
Figure imgf000326_0001
Figure imgf000327_0001
Figure imgf000328_0001
79. A pharmaceutical composition comprising a compound of any of claims 1-78, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
80. A kit comprising a compound of any of claims 1-78, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 79, and instructions for administering the compound or pharmaceutical composition to a subject in need thereof.
81. A method of treating an infectious disease comprising administering an effective amount of a compound of any of claims 1-78, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 79, to a subject in need thereof.
82. The method of claim 81, wherein the infectious disease is a bacterial infection.
83. The method of claim 82, wherein the bacterial infection is an infection with a Gram positive bacteria.
84. The method of claim 82, wherein the bacterial infection is an infection with a Gram negative bacteria.
85. The method of claim 82, wherein the bacterial infection is a Staphylococcus infection, a Streptococcus infection, an Enterococcus infection, an Acetinobacter infection, a
Clostridium infection, a Bacterioides infection, an Escherichia infection, a Pseudomonas infection, a Klebsiella infection, or a Haemophilus infection.
86. The method of claim 81, wherein the bacterial infection is a C. difficile infection or a B. fragilis infection.
87. The method of claim 81, wherein the infectious disease is a parasitic infection.
88. A method of killing a microorganism comprising contacting the microorganism with an effective amount of a compound of any of claims 1-78, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 79, to a subject in need thereof.
89. A method of inhibiting the growth of a microorganism comprising contacting the microorganism with an effective amount of a compound of any of claims 1-78, or
pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 79, to a subject in need thereof.
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Citations (3)

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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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