WO2020251953A1 - Streptogramin compositions and the use thereof - Google Patents

Streptogramin compositions and the use thereof Download PDF

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Publication number
WO2020251953A1
WO2020251953A1 PCT/US2020/036845 US2020036845W WO2020251953A1 WO 2020251953 A1 WO2020251953 A1 WO 2020251953A1 US 2020036845 W US2020036845 W US 2020036845W WO 2020251953 A1 WO2020251953 A1 WO 2020251953A1
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substituted
unsubstituted
membered
alkyl
nhc
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PCT/US2020/036845
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French (fr)
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Ian B. SEIPLE
Qi Li
James S. Fraser
Jenna PELLEGRINO
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The Regents Of The University Of California
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Publication of WO2020251953A1 publication Critical patent/WO2020251953A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06—Antimalarials
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
    • C07D513/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
    • C07F7/0814—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring said ring is substituted at a C ring atom by Si

Definitions

  • Streptogramin antibiotics are used clinically to treat bacterial infections, but their poor physicochemical properties and narrow spectra of activity have limited their clinical utility. New methods to chemically modify streptogramin compounds would enable structural optimization to overcome these limitations as well as to combat growing resistance to the class. Disclosed herein, inter alia, are solutions to these and other problems within the art. BRIEF SUMMARY
  • Y is–O- or–NH-.
  • L 1 is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.
  • R 2 is hydrogen or unsubstituted C 1 -C 8 alkyl.
  • R 4A is substituted or unsubstituted C 2 -C 10 alkyl.
  • R 3 and R 5 are independently hydrogen, oxo, halogen, -CCI 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCI 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO3H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHC
  • R 6 is hydrogen, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or an amino acid side chain
  • R 6 and R 7 may optionally be joined to form an unsubstituted heterocycloalkyl or unsubstituted heteroaryl.
  • R 8 is independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO3H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H,
  • Ring A is cycloalkylene, heterocycloalkylene, arylene, or heteroarylene.
  • z8 is an integer from 0 to 10.
  • R 9 is hydrogen, oxo, halogen, -CCI 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO3H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 ,
  • R 10 is hydrogen, oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO3H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2
  • R 11 is hydrogen, oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO3H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCI 2
  • R 12 hydrogen, oxo, halogen, -CCI 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCI 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO3H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCI 2 ,
  • R 4 is hydrogen, oxo, halogen, -CCI 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO3H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)
  • a method of treating an infectious disease including administering to a subject in need thereof an effective amount of a compound described herein.
  • FIGS.1A-1F Natural and semisynthetic streptogramins and their molecular mechanisms of action and resistance.
  • FIG.1A Selected natural and semisynthetic streptogramin analogs. Group A streptogramins (left) are 23-membered macrolactones; group B streptogramins (right) are 19-membered cyclic depsipeptides. Modifications installed by semisynthesis are highlighted.
  • FIG.1B 2.5- ⁇ cryoEM structure of VM2 bound to the 50S subunit of the E. coli ribosome. Coulomb potential density is contoured at 1s.
  • FIG.1C Surface rendering of the peptidyltransferase center of the ribosome with VM2 bound.
  • FIG.1D Graphical representation of interactions between VM2 and residues in the ribosomal binding site.
  • FIG.1E Surface rendering of the binding site in the resistance protein virginiamycin acetyltransferase A (VatA) with VM1 bound.
  • FIG.1F Graphical representation of the binding interactions between VM1 and VatA, highlighting the extensive hydrophobic interactions at C3-C6 (acetylation occurs at the C14 alcohol).
  • FIGS.2A-2D Modular synthesis enables access to >60 fully synthetic group A streptogramins.
  • FIG.2A Convergent route to VM2 from seven variable building blocks, slightly modified from reference (13). This route serves as the template for the synthesis of analogs herein, with modifications when necessary to accommodate unusual building blocks.
  • FIG.2B Seventeen analogs of accessed by building block variation. The fragments displayed in the dashed boxes represent the structural variability within each analogue compared to the parent scaffold (VM2, center). Overall yields for the synthesis of each analog are displayed for the left half sequence (top number) and for the right half sequence (bottom number).
  • FIG.2C Access to 34 analogs (17 in each diastereomeric series) with variability on the C3 sidechain by means of carbamate formation followed by desilylation.
  • FIG.2D Synthesis of tertiary-amine containing analogues by oxidation and reductive amination.
  • FIGS.3A-3C Antibiotic activity and VatA acetylation rates of selected group A streptogramins.
  • FIG.3A MIC values for 10 fully synthetic group A streptogramins against two strains of S. aureus.“WT” denotes ATCC 29213,“VatA” denotes VatA-expressing strain from reference (3).
  • FIGS.2A-2D Structural differences compared to VM2 are highlighted by building block according to the color scheme in FIGS.2A-2D.
  • FIG.3B MIC values against an expanded panel of pathogens for the analogs in panel (FIG.3A) and for combinations with the synergistic group B streptogramin VS1. In vitro translation data for each analog or combination at 10 ⁇ M is shown in the bar chart to the right of the table.
  • FIG.3C In vitro acetylation rates of selected analogs by virginiamycin acetyltransferase A (VatA).
  • FIGS.4A-4F High resolution CryoEM reveals occupancy of a novel antibiotic binding pocket.
  • FIG.4A PTC model refined from CryoEM map of the apo-ribosome with key residues for antibiotics modeled.
  • FIG.4B 2.5- ⁇ CryoEM potential density map (contoured in dark blue at 1.5s and light gray at 1.0s) for ribosomes bound to 46 reveal that the side chain extends towards A2602.
  • FIG.4C 2.5- ⁇ CryoEM potential density map for ribosomes bound to 47 reveal an extension towards the VS1 binding site.
  • FIG.4D 2.7- ⁇ CryoEM potential density map for ribosomes bound to 46 and VS1 show tight packing of both compounds around A2062.
  • FIG.4E The side chain of 46 extends into the P-site and mimics the terminal A of the P-site tRNA, which base pairs with Gm2251.
  • FIG.4F An overlay of known PTC-site antibiotics shows how the side chain of 46 and the extension of 47 occupy areas distinct to previously characterized antibiotics. The compatibility of 47 with VS1 (FIG.3B) suggests that the area between these two compounds is a site for future optimization.
  • FIG.5. Chemical structures of compounds. DETAILED DESCRIPTION
  • substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH 2 O- is equivalent to -OCH 2 -.
  • the term“alkyl,” by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched carbon chain (or carbon), or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include mono-, di- and multivalent radicals.
  • the alkyl may include a designated number of carbons (e.g., C1-C10 means one to ten carbons).
  • Alkyl is an uncyclized chain.
  • saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n- butyl, t-butyl, isobutyl, sec-butyl, methyl, homologs and isomers of, for example, n-pentyl, n- hexyl, n-heptyl, n-octyl, and the like.
  • An unsaturated alkyl group is one having one or more double bonds or triple bonds.
  • Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4- pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers.
  • An alkoxy is an alkyl attached to the remainder of the molecule via an oxygen linker (-O-).
  • An alkyl moiety may be an alkenyl moiety.
  • An alkyl moiety may be an alkynyl moiety.
  • An alkyl moiety may be fully saturated.
  • alkenyl may include more than one double bond and/or one or more triple bonds in addition to the one or more double bonds.
  • An alkynyl may include more than one triple bond and/or one or more double bonds in addition to the one or more triple bonds.
  • alkyl refers to an aliphatic hydrocarbyl.
  • an alkyl moiety is not an alkenyl moiety. In embodiments, an alkyl moiety is not an alkynyl moiety.
  • alkylene by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, as exemplified, but not limited by, -CH 2 CH 2 CH 2 CH 2 -.
  • an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred herein.
  • A“lower alkyl” or“lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.
  • alkenylene by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene.
  • heteroalkyl by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or combinations thereof, including at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and S), and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized.
  • the heteroatom(s) e.g., N, S, Si, or P
  • Heteroalkyl is an uncyclized chain. Examples include, but are not limited to: -CH 2 -CH 2 -O-CH 3 , -CH 2 -CH 2 -NH-CH 3 ,
  • a heteroalkyl moiety may include one heteroatom (e.g., O, N, S, Si, or P).
  • a heteroalkyl moiety may include two optionally different heteroatoms (e.g., O, N, S, Si, or P).
  • a heteroalkyl moiety may include three optionally different heteroatoms (e.g., O, N, S, Si, or P).
  • a heteroalkyl moiety may include four optionally different heteroatoms (e.g., O, N, S, Si, or P).
  • a heteroalkyl moiety may include five optionally different heteroatoms (e.g., O, N, S, Si, or P).
  • a heteroalkyl moiety may include up to 8 optionally different heteroatoms (e.g., O, N, S, Si, or P).
  • the term “heteroalkenyl,” by itself or in combination with another term, means, unless otherwise stated, a heteroalkyl including at least one double bond.
  • a heteroalkenyl may optionally include more than one double bond and/or one or more triple bonds in additional to the one or more double bonds.
  • the term“heteroalkynyl,” by itself or in combination with another term, means, unless otherwise stated, a heteroalkyl including at least one triple bond.
  • heteroalkynyl may optionally include more than one triple bond and/or one or more double bonds in additional to the one or more triple bonds.
  • heteroalkylene by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH 2 -CH 2 -S-CH 2 -CH 2 - and -CH 2 -S-CH 2 -CH 2 -NH-CH 2 -.
  • heteroalkylene groups heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula - C(O)2R'- represents both -C(O)2R'- and -R'C(O)2-.
  • heteroalkyl groups include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C(O)R', -C(O)NR', -NR'R'', -OR', -SR', and/or -SO 2 R'.
  • heteroalkyl is recited, followed by recitations of specific heteroalkyl groups, such as - NR'R'' or the like, it will be understood that the terms heteroalkyl and -NR'R'' are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity.
  • heteroalkyl should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R'' or the like.
  • cycloalkyl examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
  • heterocycloalkyl examples include, but are not limited to, 1- (1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3- morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl,
  • cycloalkyl means a monocyclic, bicyclic, or a multicyclic cycloalkyl ring system.
  • monocyclic ring systems are cyclic hydrocarbon groups containing from 3 to 8 carbon atoms, where such groups can be saturated or unsaturated, but not aromatic.
  • cycloalkyl groups are fully saturated. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.
  • Bicyclic cycloalkyl ring systems are bridged monocyclic rings or fused bicyclic rings.
  • bridged monocyclic rings contain a monocyclic cycloalkyl ring where two non adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms (i.e., a bridging group of the form (CH 2 ) w , where w is 1, 2, or 3).
  • bicyclic ring systems include, but are not limited to,
  • fused bicyclic cycloalkyl ring systems contain a monocyclic cycloalkyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl.
  • the bridged or fused bicyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkyl ring.
  • cycloalkyl groups are optionally substituted with one or two groups which are independently oxo or thia.
  • the fused bicyclic cycloalkyl is a 5 or 6 membered monocyclic cycloalkyl ring fused to either a phenyl ring, a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a 5 or 6 membered monocyclic heteroaryl, wherein the fused bicyclic cycloalkyl is optionally substituted by one or two groups which are independently oxo or thia.
  • multicyclic cycloalkyl ring systems are a monocyclic cycloalkyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two other ring systems independently selected from the group consisting of a phenyl, a bicyclic aryl, a monocyclic or bicyclic heteroaryl, a monocyclic or bicyclic cycloalkyl, a monocyclic or bicyclic cycloalkenyl, and a monocyclic or bicyclic heterocyclyl.
  • multicyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the base ring.
  • multicyclic cycloalkyl ring systems are a monocyclic cycloalkyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two other ring systems independently selected from the group consisting of a phenyl, a monocyclic heteroaryl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, and a monocyclic heterocyclyl.
  • Examples of multicyclic cycloalkyl groups include, but are not limited to tetradecahydrophenanthrenyl, perhydrophenothiazin-1-
  • a cycloalkyl is a cycloalkenyl.
  • the term“cycloalkenyl” is used in accordance with its plain ordinary meaning.
  • a cycloalkenyl is a monocyclic, bicyclic, or a multicyclic cycloalkenyl ring system. In embodiments, monocyclic
  • cycloalkenyl ring systems are cyclic hydrocarbon groups containing from 3 to 8 carbon atoms, where such groups are unsaturated (i.e., containing at least one annular carbon carbon double bond), but not aromatic.
  • monocyclic cycloalkenyl ring systems include cyclopentenyl and cyclohexenyl.
  • bicyclic cycloalkenyl rings are bridged monocyclic rings or a fused bicyclic rings.
  • bridged monocyclic rings contain a monocyclic cycloalkenyl ring where two non adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms (i.e., a bridging group of the form (CH 2 ) w , where w is 1, 2, or 3).
  • alkylene bridge of between one and three additional carbon atoms
  • bicyclic cycloalkenyls include, but are not limited to, norbornenyl and bicyclo[2.2.2]oct 2 enyl.
  • fused bicyclic cycloalkenyl ring systems contain a monocyclic cycloalkenyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl.
  • the bridged or fused bicyclic cycloalkenyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkenyl ring.
  • cycloalkenyl groups are optionally substituted with one or two groups which are independently oxo or thia.
  • multicyclic cycloalkenyl rings contain a monocyclic cycloalkenyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two ring systems independently selected from the group consisting of a phenyl, a bicyclic aryl, a monocyclic or bicyclic heteroaryl, a monocyclic or bicyclic cycloalkyl, a monocyclic or bicyclic cycloalkenyl, and a monocyclic or bicyclic heterocyclyl.
  • multicyclic cycloalkenyl is attached to the parent molecular moiety through any carbon atom contained within the base ring.
  • multicyclic cycloalkenyl rings contain a monocyclic cycloalkenyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two ring systems independently selected from the group consisting of a phenyl, a monocyclic heteroaryl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, and a monocyclic heterocyclyl.
  • a heterocycloalkyl is a heterocyclyl.
  • the term“heterocyclyl” as used herein, means a monocyclic, bicyclic, or multicyclic heterocycle.
  • the heterocyclyl monocyclic heterocycle is a 3, 4, 5, 6 or 7 membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S where the ring is saturated or unsaturated, but not aromatic.
  • the 3 or 4 membered ring contains 1 heteroatom selected from the group consisting of O, N, and S.
  • the 5 membered ring can contain zero or one double bond and one, two or three heteroatoms selected from the group consisting of O, N, and S.
  • the 6 or 7 membered ring contains zero, one or two double bonds and one, two or three heteroatoms selected from the group consisting of O, N, and S.
  • the heterocyclyl monocyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heterocyclyl monocyclic heterocycle.
  • heterocyclyl monocyclic heterocycles include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl
  • the heterocyclyl bicyclic heterocycle is a monocyclic heterocycle fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocycle, or a monocyclic heteroaryl.
  • the heterocyclyl bicyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the monocyclic heterocycle portion of the bicyclic ring system.
  • bicyclic heterocyclyls include, but are not limited to, 2,3- dihydrobenzofuran-2-yl, 2,3-dihydrobenzofuran-3-yl, indolin-1-yl, indolin-2-yl, indolin-3-yl, 2,3-dihydrobenzothien-2-yl, decahydroquinolinyl, decahydroisoquinolinyl, octahydro-1H- indolyl, and octahydrobenzofuranyl.
  • heterocyclyl groups are optionally substituted with one or two groups which are independently oxo or thia.
  • the bicyclic heterocyclyl is a 5 or 6 membered monocyclic heterocyclyl ring fused to a phenyl ring, a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a 5 or 6 membered monocyclic heteroaryl, wherein the bicyclic heterocyclyl is optionally substituted by one or two groups which are independently oxo or thia.
  • Multicyclic heterocyclyl ring systems are a monocyclic heterocyclyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two other ring systems independently selected from the group consisting of a phenyl, a bicyclic aryl, a monocyclic or bicyclic heteroaryl, a monocyclic or bicyclic cycloalkyl, a monocyclic or bicyclic cycloalkenyl, and a monocyclic or bicyclic heterocyclyl.
  • multicyclic heterocyclyl is attached to the parent molecular moiety through any carbon atom or nitrogen atom contained within the base ring.
  • multicyclic heterocyclyl ring systems are a monocyclic heterocyclyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two other ring systems independently selected from the group consisting of a phenyl, a monocyclic heteroaryl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, and a monocyclic heterocyclyl.
  • multicyclic heterocyclyl groups include, but are not limited to 10H-phenothiazin-10-yl, 9,10-dihydroacridin-9-yl, 9,10-dihydroacridin-10-yl, 10H-phenoxazin-10-yl, 10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl, 1,2,3,4- tetrahydropyrido[4,3-g]isoquinolin-2-yl, 12H-benzo[b]phenoxazin-12-yl, and dodecahydro- 1H-carbazol-9-yl.
  • halo or“halogen”, by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as“haloalkyl” are meant to include monohaloalkyl and polyhaloalkyl.
  • halo(C 1 -C 4 )alkyl includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
  • acyl means, unless otherwise stated, -C(O)R where R is a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • aryl means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent, which can be a single ring or multiple rings (preferably from 1 to 3 rings) that are fused together (i.e., a fused ring aryl) or linked covalently.
  • a fused ring aryl refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring.
  • a fused ring aryl refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring and wherein the multiple rings are attached to the parent molecular moiety through any carbon atom contained within an aryl ring of the multiple rings.
  • heteroaryl refers to aryl groups (or rings) that contain at least one heteroatom such as N, O, or S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized.
  • heteroaryl includes fused ring heteroaryl groups (i.e., multiple rings fused together wherein at least one of the fused rings is a heteroaromatic ring).
  • a fused ring heteroaryl group is multiple rings fused together wherein at least one of the fused rings is a heteroaromatic ring and wherein the multiple rings are attached to the parent molecular moiety through any atom contained within a heteroaromatic ring of the multiple rings.
  • a 5,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 5 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring.
  • a 6,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring.
  • a 6,5-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 5 members, and wherein at least one ring is a heteroaryl ring.
  • a heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom.
  • Non-limiting examples of aryl and heteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, benzoxazoyl benzimidazolyl, benzofuran, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl, isoquinolyl, quinoxalinyl, quinolyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2- pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imid
  • Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below.
  • An“arylene” and a“heteroarylene,” alone or as part of another substituent, mean a divalent radical derived from an aryl and heteroaryl, respectively.
  • a heteroaryl group substituent may be -O- bonded to a ring heteroatom nitrogen.
  • Spirocyclic rings are two or more rings wherein adjacent rings are attached through a single atom.
  • the individual rings within spirocyclic rings may be identical or different.
  • Individual rings in spirocyclic rings may be substituted or unsubstituted and may have different substituents from other individual rings within a set of spirocyclic rings.
  • Possible substituents for individual rings within spirocyclic rings are the possible substituents for the same ring when not part of spirocyclic rings (e.g., substituents for cycloalkyl or
  • Spirocylic rings may be substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heterocycloalkylene and individual rings within a spirocyclic ring group may be any of the immediately previous list, including having all rings of one type (e.g., all rings being substituted heterocycloalkylene wherein each ring may be the same or different substituted heterocycloalkylene).
  • heterocyclic spirocyclic rings means a spirocyclic rings wherein at least one ring is a heterocyclic ring and wherein each ring may be a different ring.
  • substituted spirocyclic rings means that at least one ring is substituted and each substituent may optionally be different.
  • oxo means an oxygen that is double bonded to a carbon atom.
  • alkylarylene as an arylene moiety covalently bonded to an alkylene moiety (also referred to herein as an alkylene linker).
  • alkylarylene group has the formula: .
  • An alkylarylene moiety may be substituted (e.g., with a substituent group) on the alkylene moiety or the arylene linker (e.g., at carbons 2, 3, 4, or 6) with halogen, oxo, -N 3 , -CF 3 , -CCI 3 , -CBr 3 , -CI 3 , -CN, -CHO, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 2 CH3 -SO 3 H, -OSO 3 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , substituted or
  • alkylarylene is unsubstituted.
  • heterocycloalkyl includes both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.
  • R, R', R'', R'', and R''' each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups.
  • aryl e.g., aryl substituted with 1-3 halogens
  • substituted or unsubstituted heteroaryl substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups.
  • each of the R groups is independently selected as are each R', R'', R''', and R''' group when more than one of these groups is present.
  • R' and R'' are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7- membered ring.
  • -NR'R'' includes, but is not limited to, 1-pyrrolidinyl and 4- morpholinyl.
  • alkyl is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF 3 and -CH 2 CF 3 ) and acyl (e.g., -C(O)CH 3 , -C(O)CF 3 , -C(O)CH 2 OCH 3 , and the like).
  • haloalkyl e.g., -CF 3 and -CH 2 CF 3
  • acyl e.g., -C(O)CH 3 , -C(O)CF 3 , -C(O)CH 2 OCH 3 , and the like.
  • R', R'', R'', and R'''' are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
  • each of the R groups is independently selected as are each R', R'', R''', and R'''' groups when more than one of these groups is present.
  • Substituents for rings may be depicted as substituents on the ring rather than on a specific atom of a ring (commonly referred to as a floating substituent).
  • the substituent may be attached to any of the ring atoms (obeying the rules of chemical valency) and in the case of fused rings or spirocyclic rings, a substituent depicted as associated with one member of the fused rings or spirocyclic rings (a floating substituent on a single ring), may be a substituent on any of the fused rings or spirocyclic rings (a floating substituent on multiple rings).
  • the multiple substituents may be on the same atom, same ring, different atoms, different fused rings, different spirocyclic rings, and each substituent may optionally be different.
  • a point of attachment of a ring to the remainder of a molecule is not limited to a single atom (a floating substituent)
  • the attachment point may be any atom of the ring and in the case of a fused ring or spirocyclic ring, any atom of any of the fused rings or spirocyclic rings while obeying the rules of chemical valency.
  • a ring, fused rings, or spirocyclic rings contain one or more ring heteroatoms and the ring, fused rings, or spirocyclic rings are shown with one more floating substituents (including, but not limited to, points of attachment to the remainder of the molecule), the floating substituents may be bonded to the heteroatoms.
  • the ring heteroatoms are shown bound to one or more hydrogens (e.g., a ring nitrogen with two bonds to ring atoms and a third bond to a hydrogen) in the structure or formula with the floating substituent, when the heteroatom is bonded to the floating substituent, the substituent will be understood to replace the hydrogen, while obeying the rules of chemical valency.
  • Two or more substituents may optionally be joined to form aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups.
  • Such so-called ring-forming substituents are typically, though not necessarily, found attached to a cyclic base structure.
  • the ring-forming substituents are attached to adjacent members of the base structure.
  • two ring-forming substituents attached to adjacent members of a cyclic base structure create a fused ring structure.
  • the ring-forming substituents are attached to a single member of the base structure.
  • two ring- forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure.
  • the ring-forming substituents are attached to non-adjacent members of the base structure.
  • Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form a ring of the formula -T-C(O)-(CRR') q -U-, wherein T and U are
  • q is an integer of from 0 to 3.
  • two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH 2 ) r -B-, wherein A and B are independently -CRR'-, -O-, -NR-, -S-, -S(O) -, -S(O) 2 -, -S(O) 2 NR'-, or a single bond, and r is an integer of from 1 to 4.
  • One of the single bonds of the new ring so formed may optionally be replaced with a double bond.
  • two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CRR')s-X'- (C''R''R'')d-, where s and d are independently integers of from 0 to 3, and X' is -O-, -NR'-, -S-, -S(O)-, -S(O) 2 -, or -S(O) 2 NR'-.
  • R, R', R'', and R''' are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
  • heteroatom or“ring heteroatom” are meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).
  • A“substituent group,” as used herein, means a group selected from the following moieties:
  • alkyl e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl
  • heteroalkyl e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered
  • heteroalkyl cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl), heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl), heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), substituted with at least one substituent selected from: (i) oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I,
  • heterocycloalkyl 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • unsubstituted aryl e.g., C 6 -C 10 aryl, C10 aryl, or phenyl
  • unsubstituted heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl
  • alkyl e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl
  • heteroalkyl e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • cycloalkyl e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl
  • heterocycloalkyl e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • aryl e.g., C6- C 10 aryl, C 10 aryl, or phenyl
  • heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5
  • A“size-limited substituent” or“ size-limited substituent group,” as used herein, means a group selected from all of the substituents described above for a“substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C 1 -C 20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 3 -C 8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C 6 -C 10 aryl, and each substituted or unsubstituted heteroary
  • A“lower substituent” or“ lower substituent group,” as used herein, means a group selected from all of the substituents described above for a“substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C 1 -C 8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 3 - C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C 6 -C 10 aryl, and each substituted or unsubstituted heteroaryl is a group selected
  • each substituted group described in the compounds herein is substituted with at least one substituent group. More specifically, in some embodiments, each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted
  • heterocycloalkyl substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene described in the compounds herein are substituted with at least one substituent group. In other embodiments, at least one or all of these groups are substituted with at least one size-limited substituent group. In other embodiments, at least one or all of these groups are substituted with at least one lower substituent group.
  • each substituted or unsubstituted alkyl may be a substituted or unsubstituted C1-C20 alkyl
  • each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl
  • each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 3 -C 8 cycloalkyl
  • each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered
  • each substituted or unsubstituted aryl is a substituted or unsubstituted C6- C 10 aryl
  • each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl.
  • each substituted or unsubstituted alkylene is a substituted or unsubstituted C 1 -C 20 alkylene
  • each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 20 membered
  • each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C 3 -C 8 cycloalkylene
  • each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 8 membered heterocycloalkylene
  • each substituted or unsubstituted arylene is a substituted or unsubstituted C 6 -C 10 arylene
  • each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 10 membered heteroarylene.
  • each substituted or unsubstituted alkyl is a substituted or unsubstituted C 1 -C 8 alkyl
  • each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl
  • each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 3 -C 7 cycloalkyl
  • each substituted or unsubstituted or unsubstituted alkyl is a substituted or unsubstituted C 1 -C 8 alkyl
  • each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl
  • each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 3 -C 7 cycloalkyl
  • heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl
  • each substituted or unsubstituted aryl is a substituted or unsubstituted C 6 -C 10 aryl
  • each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl.
  • each substituted or unsubstituted alkylene is a substituted or unsubstituted C 1 -C 8 alkylene
  • each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 8 membered heteroalkylene
  • each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C7 cycloalkylene
  • each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 7 membered heterocycloalkylene
  • each substituted or unsubstituted arylene is a substituted or unsubstituted C 6 -C 10 arylene
  • each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 9 membered heteroarylene.
  • the compound is a chemical species set forth in the Examples section, figures, or tables below
  • a substituted or unsubstituted moiety e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and/or substituted or unsubstituted heteroarylene) is unsubstituted (e.g., is an unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted
  • a substituted or unsubstituted moiety e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and/or substituted or unsubstituted heteroarylene) is substituted (e.g., is a substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alky
  • a substituted moiety e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene
  • is substituted with at least one substituent group wherein if the substituted moiety is substituted with a plurality of substituent groups, each substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of substituent groups, each substituent group is different.
  • a substituted moiety e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene
  • is substituted with at least one size-limited substituent group wherein if the substituted moiety is substituted with a plurality of size-limited substituent groups, each size-limited substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of size-limited substituent groups, each size-limited substituent group is different.
  • a substituted moiety e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene
  • is substituted with at least one lower substituent group wherein if the substituted moiety is substituted with a plurality of lower substituent groups, each lower substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of lower substituent groups, each lower substituent group is different.
  • a substituted moiety e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene
  • the substituted moiety is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group
  • Certain compounds of the present disclosure possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)- or, as (D)- or (L)- for amino acids, and individual isomers are encompassed within the scope of the present disclosure.
  • the compounds of the present disclosure do not include those that are known in art to be too unstable to synthesize and/or isolate.
  • the present disclosure is meant to include compounds in racemic and optically pure forms.
  • Optically active (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.
  • the term“isomers” refers to compounds having the same number and kind of atoms, and hence the same molecular weight, but differing in respect to the structural arrangement or configuration of the atoms.
  • tautomer refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another. [0051] It will be apparent to one skilled in the art that certain compounds of this disclosure may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the disclosure.
  • structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure.
  • structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13 C- or 14 C-enriched carbon are within the scope of this disclosure.
  • the compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.
  • bioconjugate reactive moiety or“bioconjugate reactive group” refers to a chemical moiety which participates in a reaction to form bioconjugate linker (e.g., covalent linker) or the resulting association between atoms or molecules of bioconjugate reactive moieties.
  • the association can be direct or indirect.
  • a conjugate between a first bioconjugate reactive group (e.g.,–NH 2 ,–COOH,–N-hydroxysuccinimide, or–maleimide) and a second bioconjugate reactive group (e.g., sulfhydryl, sulfur-containing amino acid, amine, amine sidechain containing amino acid, or carboxylate) can be direct, e.g., by covalent bond or linker (e.g., a first linker of second linker), or indirect, e.g., by non- covalent bond (e.g., electrostatic interactions (e.g., ionic bond, hydrogen bond, halogen bond), van der Waals interactions (e.g., dipole-dipole, dipole-induced dipole, London dispersion), ring stacking (pi effects), hydrophobic interactions and the like).
  • a first bioconjugate reactive group e.g.,–NH 2 ,–COOH,–N-hydroxysuccinimide, or–male
  • bioconjugates or bioconjugate linkers are formed using bioconjugate chemistry (i.e., the association of two bioconjugate reactive groups) including, but are not limited to nucleophilic substitutions (e.g., reactions of amines and alcohols with acyl halides, active esters), electrophilic substitutions (e.g., enamine reactions) and additions to carbon-carbon and carbon-heteroatom multiple bonds (e.g., Michael reaction, Diels-Alder addition).
  • nucleophilic substitutions e.g., reactions of amines and alcohols with acyl halides, active esters
  • electrophilic substitutions e.g., enamine reactions
  • additions to carbon-carbon and carbon-heteroatom multiple bonds e.g., Michael reaction, Diels-Alder addition.
  • the first bioconjugate reactive group e.g., maleimide moiety
  • the second bioconjugate reactive group e.g., a sulfhydryl
  • the first bioconjugate reactive group e.g., haloacetyl moiety
  • the second bioconjugate reactive group e.g., a sulfhydryl
  • the first bioconjugate reactive group (e.g., pyridyl moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl).
  • the first bioconjugate reactive group (e.g.,–N-hydroxysuccinimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., an amine).
  • the first bioconjugate reactive group e.g., maleimide moiety
  • the first bioconjugate reactive group (e.g.,–sulfo–N-hydroxysuccinimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., an amine).
  • bioconjugate reactive moieties used for bioconjugate chemistries herein include, for example:
  • haloalkyl groups wherein the halide can be later displaced with a nucleophilic group such as, for example, an amine, a carboxylate anion, thiol anion, carbanion, or an alkoxide ion, thereby resulting in the covalent attachment of a new group at the site of the halogen atom;
  • a nucleophilic group such as, for example, an amine, a carboxylate anion, thiol anion, carbanion, or an alkoxide ion
  • dienophile groups which are capable of participating in Diels-Alder reactions such as, for example, maleimido or maleimide groups;
  • aldehyde or ketone groups such that subsequent derivatization is possible via formation of carbonyl derivatives such as, for example, imines, hydrazones, semicarbazones or oximes, or via such mechanisms as Grignard addition or alkyllithium addition;
  • amine or sulfhydryl groups (e.g., present in cysteine), which can be, for example, acylated, alkylated or oxidized;
  • alkenes which can undergo, for example, cycloadditions, acylation, Michael addition, etc;
  • biotin conjugate can react with avidin or strepavidin to form a avidin-biotin complex or streptavidin-biotin complex.
  • bioconjugate reactive groups can be chosen such that they do not participate in, or interfere with, the chemical stability of the conjugate described herein.
  • a reactive functional group can be protected from participating in the crosslinking reaction by the presence of a protecting group.
  • the bioconjugate comprises a molecular entity derived from the reaction of an unsaturated bond, such as a maleimide, and a sulfhydryl group.
  • Analog or“analogue” is used in accordance with its plain ordinary meaning within Chemistry and Biology and refers to a chemical compound that is structurally similar to another compound (i.e., a so-called“reference” compound) but differs in composition, e.g., in the replacement of one atom by an atom of a different element, or in the presence of a particular functional group, or the replacement of one functional group by another functional group, or the absolute stereochemistry of one or more chiral centers of the reference compound. Accordingly, an analog is a compound that is similar or comparable in function and appearance but not in structure or origin to a reference compound.
  • A“derivative” is a compound derived from a chemical compound via a chemical reaction. A derivative of a compound described herein may refer to the compound described herein with the addition or removal of a substituent.
  • the terms“a” or“an,” as used in herein means one or more.
  • the phrase “substituted with a[n],” as used herein, means the specified group may be substituted with one or more of any or all of the named substituents.
  • a group such as an alkyl or heteroaryl group, is“substituted with an unsubstituted C1-C20 alkyl, or unsubstituted 2 to 20 membered heteroalkyl,” the group may contain one or more unsubstituted C 1 -C 20 alkyls, and/or one or more unsubstituted 2 to 20 membered heteroalkyls.
  • R-substituted where a moiety is substituted with an R substituent, the group may be referred to as“R-substituted.” Where a moiety is R-substituted, the moiety is substituted with at least one R substituent and each R substituent is optionally different. Where a particular R group is present in the description of a chemical genus (such as Formula (I)), a Roman alphabetic symbol may be used to distinguish each appearance of that particular R group. For example, where multiple R 13 substituents are present, each R 13 substituent may be distinguished as R 13A , R 13B , R 13C , R 13D , etc., wherein each of R 13A , R 13B , R 13C , R 13D , etc.
  • A“detectable agent” or“detectable moiety” is an atom, molecule, substance, or composition detectable by appropriate means such as spectroscopic, photochemical, biochemical, immunochemical, chemical, magnetic resonance imaging, or other physical means.
  • useful detectable agents include 18 F, 32 P, 33 P, 45 Ti, 47 Sc, 52 Fe, 59 Fe, 62 Cu, 64 Cu, 67 Cu, 67 Ga, 68 Ga, 77 As, 86 Y, 90 Y, 89 Sr, 89 Zr, 94 Tc, 94 Tc, 99m Tc, 99 Mo, 105 Pd, 105 Rh, 111 Ag, 111 In, 123 I, 124 I, 125 I, 131 I, 142 Pr, 143 Pr, 149 Pm, 153 Sm, 154-1581 Gd, 161 Tb, 166 Dy, 166 Ho, 169 Er, 175 Lu, 177 Lu, 186 Re, 188 Re, 189 Re, 194 Ir, 198 Au, 199 Au, 211 At, 211 Pb, 212 Bi, 212 Pb, 213 Bi, 223 Ra, 225 Ac, Cr, V, Mn, Fe, Co, Ni, Cu, La, Ce, Pr, Nd, Pm,
  • Gadolinium chelate (“Gd-chelate”) molecules, Gadolinium, radioisotopes, radionuclides (e.g., carbon-11, nitrogen-13, oxygen-15, fluorine-18, rubidium-82), fluorodeoxyglucose (e.g., fluorine-18 labeled), any gamma ray emitting radionuclides, positron-emitting radionuclide, radiolabeled glucose, radiolabeled water, radiolabeled ammonia, biocolloids, microbubbles (e.g., including microbubble shells including albumin, galactose, lipid, and/or polymers; microbubble gas core including air, heavy gas(es), perfluorcarbon, nitrogen,
  • radionuclides e.g., carbon-11, nitrogen-13, oxygen-15, fluorine-18, rubidium-82
  • fluorodeoxyglucose e.g., fluorine-18 labeled
  • iodinated contrast agents e.g., iohexol, iodixanol, ioversol, iopamidol, ioxilan, iopromide, diatrizoate, metrizoate, ioxaglate
  • barium sulfate thorium dioxide, gold, gold nanoparticles, gold nanoparticle aggregates, fluorophores, two-photon fluorophores, or haptens and proteins or other entities which can be made detectable, e.g., by incorporating a radiolabel into a peptide or antibody specifically reactive with a target peptide.
  • a detectable moiety is a monovalent detectable agent or a detectable agent capable of forming a bond with another composition.
  • Radioactive substances e.g., radioisotopes
  • Radioactive substances include, but are not limited to, 18 F, 32 P, 33 P, 45 Ti, 47 Sc, 52 Fe, 59 Fe, 62 Cu, 64 Cu, 67 Cu, 67 Ga, 68 Ga, 77 As, 86 Y, 90 Y, 89 Sr, 89 Zr, 94 Tc, 94 Tc, 99m Tc, 99 Mo, 105 Pd, 105 Rh, 111 Ag, 111 In, 123 I, 124 I, 125 I, 131 I, 142 Pr, 143 Pr, 149 Pm, 153 Sm, 154-1581 Gd, 161 Tb, 166 Dy, 166 Ho, 169 Er, 175 Lu, 177 Lu, 186 Re, 188 Re, 189 Re, 194 Ir, 198 Au, 199 Au, 211 At, 211 Pb, 212 Bi, 212
  • Paramagnetic ions that may be used as additional imaging agents in accordance with the embodiments of the disclosure include, but are not limited to, ions of transition and lanthanide metals (e.g., metals having atomic numbers of 21-29, 42, 43, 44, or 57-71). These metals include ions of Cr, V, Mn, Fe, Co, Ni, Cu, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb and Lu.
  • transition and lanthanide metals e.g., metals having atomic numbers of 21-29, 42, 43, 44, or 57-71.
  • These metals include ions of Cr, V, Mn, Fe, Co, Ni, Cu, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb and Lu.
  • nucleic acid or protein when applied to a nucleic acid or protein, denotes that the nucleic acid or protein is essentially free of other cellular components with which it is associated in the natural state. It can be, for example, in a homogeneous state and may be in either a dry or aqueous solution. Purity and homogeneity are typically determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis or high performance liquid chromatography. A protein that is the predominant species present in a preparation is substantially purified.
  • variable e.g., moiety or linker
  • a compound or of a compound genus e.g., a genus described herein
  • the unfilled valence(s) of the variable will be dictated by the context in which the variable is used.
  • variable of a compound as described herein when a variable of a compound as described herein is connected (e.g., bonded) to the remainder of the compound through a single bond, that variable is understood to represent a monovalent form (i.e., capable of forming a single bond due to an unfilled valence) of a standalone compound (e.g., if the variable is named“methane” in an embodiment but the variable is known to be attached by a single bond to the remainder of the compound, a person of ordinary skill in the art would understand that the variable is actually a monovalent form of methane, i.e., methyl or–CH3).
  • variable is the divalent form of a standalone compound (e.g., if the variable is assigned to“PEG” or “polyethylene glycol” in an embodiment but the variable is connected by two separate bonds to the remainder of the compound, a person of ordinary skill in the art would understand that the variable is a divalent (i.e., capable of forming two bonds through two unfilled valences) form of PEG instead of the standalone compound PEG).
  • salt refers to acid or base salts of the compounds used in the methods of the present invention.
  • acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid and the like) salts, quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts.
  • salts are meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic,
  • salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al.,“Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19).
  • Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
  • the compounds of the present disclosure may exist as salts, such as with pharmaceutically acceptable acids.
  • the present disclosure includes such salts.
  • Non-limiting examples of such salts include hydrochlorides, hydrobromides, phosphates, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, propionates, tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid, and quaternary ammonium salts (e.g., methyl iodide, ethyl iodide, and the like). These salts may be prepared by methods known to those skilled in the art.
  • the neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents.
  • the present disclosure provides compounds, which are in a prodrug form.
  • Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present disclosure.
  • Prodrugs of the compounds described herein may be converted in vivo after administration.
  • prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment, such as, for example, when contacted with a suitable enzyme or chemical reagent.
  • Certain compounds of the present disclosure can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present disclosure. Certain compounds of the present disclosure may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure.
  • “Pharmaceutically acceptable excipient” and“pharmaceutically acceptable carrier” refer to a substance that aids the administration of an active agent to and absorption by a subject and can be included in the compositions of the present invention without causing a significant adverse toxicological effect on the patient.
  • “pharmaceutically acceptable excipient” and“pharmaceutically acceptable carrier” refer to a substance that aids the administration of an active agent to and absorption by a subject and can be included in the compositions of the present invention without causing a significant adverse toxicological effect on the patient.
  • pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer’s solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like.
  • Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention.
  • auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention.
  • auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention.
  • auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents
  • the term“preparation” is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it.
  • a carrier which is thus in association with it.
  • cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
  • the term“about” means a range of values including the specified value, which a person of ordinary skill in the art would consider reasonably similar to the specified value. In embodiments, about means within a standard deviation using
  • about means a range extending to +/- 10% of the specified value. In embodiments, about includes the specified value.
  • electrophilic refers to a chemical group that is capable of accepting electron density.
  • An“electrophilic substituent,”“electrophilic chemical moiety,” or“electrophic moiety” refers to an electron-poor chemical group, substitutent, or moiety (monovalent chemical group), which may react with an electron-donating group, such as a nucleophile, by accepting an electron pair or electron density to form a bond.
  • the electrophilic substituent of the compound is capable of reacting with a cysteine residue.
  • the electrophilic substituent is capable of forming a covalent bond with a cysteine residue (e.g., LC3, p62, NBR1, NDP52, or Optineurin cysteine residue) and may be referred to as a“covalent cysteine modifier moiety” or“covalent cysteine modifier substituent.”
  • the covalent bond formed between the electrophilic substituent and the sulfhydryl group of the cysteine may be a reversible or irreversible bond.
  • the electrophilic substituent of the compound is capable of reacting with a lysine residue.
  • the electrophilic substituent of the compound is capable of reacting with a serine residue.
  • the electrophilic substituent of the compound is capable of reacting with a methionine residue.
  • Nucleophilic refers to a chemical group that is capable of donating electron density.
  • the term“leaving group” is used in accordance with its ordinary meaning in chemistry and refers to a moiety (e.g., atom, functional group, molecule) that separates from the molecule following a chemical reaction (e.g., bond formation, reductive elimination, condensation, cross-coupling reaction) involving an atom or chemical moiety to which the leaving group is attached, also referred to herein as the“leaving group reactive moiety”, and a complementary reactive moiety (i.e., a chemical moiety that reacts with the leaving group reactive moiety) to form a new bond between the remnants of the leaving groups reactive moiety and the complementary reactive moiety.
  • a chemical reaction e.g., bond formation, reductive elimination, condensation, cross-coupling reaction
  • a complementary reactive moiety i.e., a chemical moiety that reacts with the leaving group reactive moiety
  • Non limiting examples of leaving groups include hydrogen, hydroxide, organotin moieties (e.g., organotin heteroalkyl), halogen (e.g., Br), perfluoroalkylsulfonates (e.g., triflate), tosylates, mesylates, water, alcohols, nitrate, phosphate, thioether, amines, ammonia, fluoride, carboxylate, phenoxides, boronic acid, boronate esters, substituted or unsubstituted piperazinyl, and alkoxides.
  • organotin moieties e.g., organotin heteroalkyl
  • halogen e.g., Br
  • perfluoroalkylsulfonates e.g., triflate
  • tosylates mesylates, water, alcohols, nitrate, phosphate, thioether, amines, ammonia,
  • two molecules with leaving groups are allowed to contact, and upon a reaction and/or bond formation (e.g., acyloin condensation, aldol condensation, Claisen condensation, Stille reaction) the leaving groups separates from the respective molecule.
  • a leaving group is a bioconjugate reactive moiety.
  • at least two leaving groups e.g., R 1 and R 13
  • the leaving groups are allowed to contact such that the leaving groups are sufficiently proximal to react, interact or physically touch.
  • the leaving groups is designed to facilitate the reaction.
  • the leaving group is a substituent group.
  • protecting group is used in accordance with its ordinary meaning in organic chemistry and refers to a moiety covalently bound to a heteroatom, heterocycloalkyl, or heteroaryl to prevent reactivity of the heteroatom, heterocycloalkyl, or heteroaryl during one or more chemical reactions performed prior to removal of the protecting group.
  • a protecting group is bound to a heteroatom (e.g., O) during a part of a multipart synthesis wherein it is not desired to have the heteroatom react (e.g., a chemical reduction) with the reagent. Following protection the protecting group may be removed (e.g., by modulating the pH).
  • the protecting group is an alcohol protecting group.
  • alcohol protecting groups include acetyl, benzoyl, benzyl, methoxymethyl ether (MOM), tetrahydropyranyl (THP), and silyl ether (e.g., trimethylsilyl (TMS)).
  • the protecting group is an amine protecting group.
  • Non-limiting examples of amine protecting groups include carbobenzyloxy (Cbz), tert-butyloxycarbonyl (BOC), 9-fluorenylmethyloxycarbonyl (FMOC), acetyl, benzoyl, benzyl, carbamate, p- methoxybenzyl ether (PMB), and tosyl (Ts).
  • the protecting group is -PO 3 H or -SO3H.
  • the protecting group is a substituent group.
  • polypeptide “peptide,” and“protein” are used interchangeably herein to refer to a polymer of amino acid residues, wherein the polymer may optionally be conjugated to a moiety that does not consist of amino acids.
  • the terms apply to amino acid polymers in which one or more amino acid residue is an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymer.
  • a polypeptide, or a cell is“recombinant” when it is artificial or engineered, or derived from or contains an artificial or engineered protein or nucleic acid (e.g., non-natural or not wild-type).
  • an artificial or engineered protein or nucleic acid e.g., non-natural or not wild-type.
  • a polynucleotide that is inserted into a vector or any other heterologous location e.g., in a genome of a recombinant organism, such that it is not associated with nucleotide sequences that normally flank the polynucleotide as it is found in nature is a recombinant polynucleotide.
  • a protein expressed in vitro or in vivo from a recombinant polynucleotide is an example of a recombinant polypeptide.
  • a polynucleotide sequence that does not appear in nature for example a variant of a naturally occurring gene, is recombinant.
  • compositions described herein are administered at the same time, just prior to, or just after the administration of one or more additional therapies.
  • the compounds of the invention can be administered alone or can be coadministered to the patient. Coadministration is meant to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound).
  • the preparations can also be combined, when desired, with other active substances (e.g., to reduce metabolic degradation).
  • the compositions of the present invention can be delivered transdermally, by a topical route, or formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.
  • A“cell” as used herein, refers to a cell carrying out metabolic or other function sufficient to preserve or replicate its genomic DNA.
  • a cell can be identified by well-known methods in the art including, for example, presence of an intact membrane, staining by a particular dye, ability to produce progeny or, in the case of a gamete, ability to combine with a second gamete to produce a viable offspring.
  • Cells may include prokaryotic and eukaroytic cells.
  • Prokaryotic cells include but are not limited to bacteria.
  • Eukaryotic cells include but are not limited to yeast cells and cells derived from plants and animals, for example mammalian, insect (e.g., spodoptera) and human cells. Cells may be useful when they are naturally nonadherent or have been treated not to adhere to surfaces, for example by trypsinization.
  • the terms“treating” or“treatment” refers to any indicia of success in the treatment or amelioration of an injury, disease, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient’s physical or mental well-being.
  • the treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neuropsychiatric exams, and/or a psychiatric evaluation. For example, the certain methods presented herein successfully treat cancer by decreasing the incidence of cancer and or causing remission of cancer.
  • treating cancer includes slowing the rate of growth or spread of cancer cells, reducing metastasis, or reducing the growth of metastatic tumors.
  • the term“treating” and conjugations thereof, include prevention of an injury, pathology, condition, or disease.
  • treating is preventing.
  • treating does not include preventing.
  • the treating or treatment is no prophylactic treatment.
  • An“effective amount” is an amount sufficient for a compound to accomplish a stated purpose relative to the absence of the compound (e.g., achieve the effect for which it is administered, treat a disease, reduce enzyme activity, increase enzyme activity, reduce signaling pathway, reduce one or more symptoms of a disease or condition (e.g., reduce signaling pathway stimulated by an autophagy adapter protein, reduce the signaling pathway activity of an autophagy protein).
  • An example of an“effective amount” is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease, which could also be referred to as a“therapeutically effective amount” when referred to in this context.
  • A“reduction” of a symptom or symptoms means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s).
  • A“prophylactically effective amount” of a drug is an amount of a drug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of an injury, disease, pathology or condition, or reducing the likelihood of the onset (or reoccurrence) of an injury, disease, pathology, or condition, or their symptoms.
  • the full prophylactic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses.
  • a prophylactically effective amount may be administered in one or more administrations.
  • An“activity decreasing amount,” as used herein, refers to an amount of antagonist required to decrease the activity of an enzyme relative to the absence of the antagonist.
  • A“function disrupting amount,” as used herein, refers to the amount of antagonist required to disrupt the function of an enzyme or protein relative to the absence of the antagonist.
  • Control or“control experiment” is used in accordance with its plain ordinary meaning and refers to an experiment in which the subjects or reagents of the experiment are treated as in a parallel experiment except for omission of a procedure, reagent, or variable of the experiment.
  • the control is used as a standard of comparison in evaluating experimental effects.
  • a control is the measurement of the activity (e.g., signaling pathway) of a protein in the absence of a compound as described herein (including embodiments, examples, figures, or Tables).
  • Contacting is used in accordance with its plain ordinary meaning and refers to the process of allowing at least two distinct species (e.g., chemical compounds including biomolecules, or cells) to become sufficiently proximal to react, interact or physically touch. It should be appreciated; however, the resulting reaction product can be produced directly from a reaction between the added reagents or from an intermediate from one or more of the added reagents which can be produced in the reaction mixture.
  • species e.g., chemical compounds including biomolecules, or cells
  • the term“contacting” may include allowing two species to react, interact, or physically touch, wherein the two species may be a compound as described herein and a cellular component (e.g., protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, virus, lipid droplet, vesicle, small molecule, protein complex, protein aggregate, or macromolecule).
  • a cellular component e.g., protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, virus, lipid droplet, vesicle, small molecule, protein complex, protein aggregate, or macromolecule.
  • contacting includes allowing a compound described herein to interact with a cellular component (e.g., protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, virus, lipid droplet, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule) that is involved in a signaling pathway.
  • a cellular component e.g., protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, virus, lipid droplet, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule
  • the term“inhibition,”“inhibit,”“inhibiting” and the like in reference to a cellular component-inhibitor interaction means negatively affecting (e.g., decreasing) the activity or function of the cellular component (e.g., decreasing the signaling pathway stimulated by a cellular component (e.g., protein, ion, lipid, virus, lipid droplet, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or
  • a cellular component e.g., protein, ion, lipid, virus, lipid droplet, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or
  • inhibition refers to reduction of a disease or symptoms of disease. In some embodiments, inhibition refers to a reduction in the activity of a signal transduction pathway or signaling pathway (e.g., reduction of a pathway involving the cellular component).
  • inhibition includes, at least in part, partially or totally blocking stimulation, decreasing, preventing, or delaying activation, or inactivating, desensitizing, or down-regulating the signaling pathway or enzymatic activity or the amount of a cellular component.
  • modulator refers to a composition that increases or decreases the level of a target molecule or the function of a target molecule or the physical state of the target of the molecule (e.g., a target may be a cellular component (e.g., protein, ion, lipid, virus, lipid droplet, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular
  • a target may be a cellular component (e.g., protein, ion, lipid, virus, lipid droplet, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular
  • modulate is used in accordance with its plain ordinary meaning and refers to the act of changing or varying one or more properties.“Modulation” refers to the process of changing or varying one or more properties. For example, as applied to the effects of a modulator on a target protein, to modulate means to change by increasing or decreasing a property or function of the target molecule or the amount of the target molecule.
  • “Patient” or“subject in need thereof” refers to a living organism suffering from or prone to a disease or condition that can be treated by administration of a pharmaceutical composition as provided herein.
  • Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammalian animals.
  • a patient is human.
  • Disease or“condition” refer to a state of being or health status of a patient or subject capable of being treated with the compounds or methods provided herein.
  • the disease is a disease related to (e.g., caused by) a cellular component (e.g., protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule).
  • a cellular component e.g., protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule.
  • the term“associated” or“associated with” in the context of a substance or substance activity or function associated with a disease means that the disease (e.g., infectious disease) is caused by (in whole or in part), or a symptom of the disease is caused by (in whole or in part) the substance or substance activity or function.
  • the infectious disease is a bacteria associated disease (e.g., actinomycosis, anthrax, abscesses in tissues (e.g., mouth in gastrointestinal tract, pelvic cavity, or lungs), whooping cough, lyme disease, brucellosis, enteritis, Guillain-Barre syndrome, pneumonia, conjunctivitis, trachoma, botulism, pseudomembranous colitis, food poisoning, tetanus, diphtheria, ehrlichiosis, bacterial endocarditis, urinary tract infection, diarrhea, meningitis (e.g., bacterial meningitis), sepsis, fever, tularemia, bronchitis, peptic ulcer, gastritis, Legionnaire’s disease, Pontiac fever, leptospirosis, listeriosis, leprosy, gonorrhea, opthalmia, nocardiosis, typhoid fever, salmonellosis,
  • aberrant refers to different from normal. When used to describe enzymatic activity or protein function, aberrant refers to activity or function that is greater or less than a normal control or the average of normal non-diseased control samples. Aberrant activity may refer to an amount of activity that results in a disease, wherein returning the aberrant activity to a normal or non-disease-associated amount (e.g., by administering a compound or using a method as described herein), results in reduction of the disease or one or more disease symptoms.
  • A“therapeutic agent” as used herein refers to an agent (e.g., compound or composition described herein) that when administered to a subject will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of an injury, disease, pathology or condition, or reducing the likelihood of the onset (or reoccurrence) of an injury, disease, pathology, or condition, or their symptoms or the intended therapeutic effect, e.g., treatment or amelioration of an injury, disease, pathology or condition, or their symptoms including any objective or subjective parameter of treatment such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; or improving a patient’s physical or mental well-being.
  • an agent e.g., compound or composition described herein
  • immune response refers, in the usual and customary sense, to a response by an organism that protects against disease.
  • the response can be mounted by the innate immune system or by the adaptive immune system, as well known in the art.
  • modulating immune response refers to a change in the immune response of a subject as a consequence of administration of an agent, e.g., a compound as disclosed herein, including embodiments thereof. Accordingly, an immune response can be activated or deactivated as a consequence of administration of an agent, e.g., a compound as disclosed herein, including embodiments thereof.
  • infectious disease refers to a disease or condition that can be caused by organisms such as a bacterium, virus, fungi, parasite, or any other pathogenic microbial agents.
  • infectious disease is caused by a pathogenic bacteria.
  • Pathogenic bacteria are bacteria that cause diseases (e.g., in humans).
  • infectious disease is a bacteria-associated disease (e.g., tuberculosis, which is caused by Mycobacterium tuberculosis).
  • Non-limiting bacteria associated diseases include pneumonia, which may be caused by bacteria such as Streptococcus and Pseudomonas; or foodborne illnesses, which can be caused by bacteria such as Shigella, Campylobacter, and Salmonella.
  • Bacteria-associated diseases also include tetanus, typhoid fever, diphtheria, syphilis, and leprosy.
  • the disease is bacterial vaginosis (i.e., bacteria that change the vaginal microbiota caused by an overgrowth of bacteria that crowd out the Lactobacilli species that maintain healthy vaginal microbial populations) (e.g., yeast infection, or Trichomonas vaginalis); bacterial meningitis (i.e., a bacterial inflammation of the meninges); bacterial pneumonia (i.e., a bacterial infection of the lungs); urinary tract infection; bacterial gastroenteritis; or bacterial skin infections (e.g., impetigo, or cellulitis).
  • bacteria vaginosis i.e., bacteria that change the vaginal microbiota caused by an overgrowth of bacteria that crowd out the Lactobacilli species that maintain healthy vaginal microbial populations
  • yeast infection e.g., yeast infection, or Trichomonas vaginalis
  • bacterial meningitis i.e., a bacterial inflammation of the meninges
  • the infectious disease is a Campylobacter jejuni, Enterococcus faecalis, Haemophilus influenzae, Helicobacter pylori, Klebsiella pneumoniae, Legionella pneumophila, Neisseria gonorrhoeae, Neisseria meningitides, Staphylococcus aureus, Streptococcus pneumonia, or Vibrio cholera infection.
  • the infectious disease is caused by a parasite.
  • group A streptococcal infection is an infection with group A
  • GAS streptococcus
  • Group A streptococcus refer to species of Gram-positive bacteria, non- motile and non-sporing cocci, which express the Lancefield group A antigen.
  • Non-limiting examples of GAS include Streptococcus pyogenes, Streptococcus dysgalactiae, and
  • Streptococcus anginosus GAS typically colonize the throat, genital mucosa, rectum, and skin. Such bacteria can cause a variety of diseases such as streptococcal pharyngitis, rheumatic fever, rheumatic heart disease, and scarlet fever.
  • gram-positive bacteria is used in accordance with its plain ordinary meaning and refers to bacteria that give a positive result in the gram stain test. For example, gram-positive bacteria take up the stain used in the test, and then appear to be purple- coloured when seen through a microscope due to the peptidoglycan layer in the bacterial cell wall. In contrast, gram-negative bacteria cannot retain the violet stain.
  • the term“gram-negative bacteria” is used in accordance with its plain ordinary meaning and refers to bacteria that are enclosed in a protective capsule.
  • the protective capsule may help to prevent white blood cells from ingesting the bacteria.
  • gram-positive bacterial infection is used in accordance with its plain ordinary meaning and refers to an infection caused by gram-positive bacteria.
  • examples of gram-positive bacterial infections include, but are not limited to, anthrax, diphtheria, enterococcal infections, erysipelothricosis, listeriosis, pneumococcal infections,
  • staphylococcal aureus infections staphylococcal aureus infections, steptrococcal infections, and toxic shock syndrome.
  • gram-negative bacterial infection is used in accordance with its plain ordinary meaning and refers to an infection caused by gram-negative bacteria.
  • examples of gram-negative bacterial infections include, but are not limited to, brucellosis, Campylobacter infections, cat-scratch disease, cholera, Escherichia coli infections, Klebsiella infections, Legionnaires’ disease, pertussis, plague, Pseudomonas infections, salmonella, shigellosis, tularemia, typhoid fever, pneumonia, peritonitis, urinary tract infections, bloodstream inections, wound or surgical site infections, and meningitis.
  • bacteriostatic agent is used in accordance with its ordinary meaning and refers to a compound (e.g., a compound described herein) that inhibits bacteria reproduction. In embodiments, the bacteriostatic agent does not kill the bacterial cell. In embodiments, when a compound (e.g., a compound described herein) is administered to treat an infectious disease and it does not kill the bacteria cells but inhibits (e.g., reduces reproduction, ceases reproduction) bacteria cell reproduction, it may be considered a bacteriostatic agent.
  • Y is–O- or–NH-.
  • L 1 is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.
  • R 2 is hydrogen or unsubstituted C 1 -C 8 alkyl.
  • R 4A is substituted or unsubstituted C2-C10 alkyl.
  • R 3 and R 5 are independently hydrogen, oxo, halogen, -CCI 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO3H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3
  • R 6 is hydrogen, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or an amino
  • R 7 is hydrogen, -CH 2 COOH, -CONH 2 , -OH, -SH, -NO 2 , -NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 6 and R 7 may optionally be joined to form an unsubstituted heterocycloalkyl or unsubstituted heteroaryl.
  • R 8 is independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO3H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCI
  • Ring A is cycloalkylene, heterocycloalkylene, arylene, or heteroarylene.
  • z8 is an integer from 0 to 10.
  • R 9 is hydrogen, oxo, halogen, -CCI 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCI 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO3H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCI
  • R 10 is hydrogen, oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OC
  • R 11 is hydrogen, oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO3H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCHCl 2
  • R 12 hydrogen, oxo, halogen, -CCI 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCI 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO3H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl
  • the compound has the formula:
  • Y is -O- or -NH-;
  • L 1 is a bond, substituted or
  • R 2 is hydrogen or unsubstituted C 1 -C 3 alkyl
  • R 4A is substituted or unsubstituted C 2 -C 10 alkyl
  • R 3 and R 5 are independently hydrogen, oxo, halogen, -CCI3, -CBn, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI 2 , -CH 2 CI, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO2, -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -0NH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHSO 2 H, -NHC(0)H,
  • the compound has the formula:
  • Y, L 1 , R 2 , R 3 , R 4A , R 5 , R 6 , R 7 , Ring A, R 8 , z8, R 9 , R 10 , R 11 , and R 12 are as described herein, including in embodiments.
  • R 4A is a substituted C 2 -C 10 alkyl. In embodiments, R 4A is an unsubstituted C2-C10 alkyl. In embodiments, R 4A is a substituted or unsubstituted C3-C10 alkenyl. In embodiments, R 4A is a substituted C 3 -C 10 alkenyl. In embodiments, R 4A is an unsubstituted C3-C10 alkenyl. In embodiments, R 4A is a substituted or unsubstituted C 3 -C 6 alkenyl. In embodiments, R 4A is a substituted C 3 -C 6 alkenyl.
  • R 4A is an unsubstituted C 3 -C 6 alkenyl. In embodiments, R 4A is an unsubstituted C3 alkenyl. In embodiments, R 4A is an unsubstituted C 4 alkenyl. In embodiments, R 4A is an unsubstituted C 5 alkenyl. In embodiments, R 4A is an unsubstituted C 6 alkenyl. In embodiments, R 4A is .
  • a substituted R 4A (e.g., substituted alkyl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 4A is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • R 4A when R 4A is substituted, it is substituted with at least one substituent group.
  • R 4A when R 4A is substituted, it is substituted with at least one size-limited substituent group.
  • R 4A when R 4A is substituted, it is substituted with at least one lower substituent group.
  • Y is–O-. In embodiments, Y is–NH-.
  • L 1 is a bond, substituted or unsubstituted alkylene (e.g., C 1 -C 8 alkylene, C 1 -C 6 alkylene, or C 1 -C 4 alkylene), or substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene).
  • alkylene e.g., C 1 -C 8 alkylene, C 1 -C 6 alkylene, or C 1 -C 4 alkylene
  • heteroalkylene e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene
  • a substituted L 1 (e.g., substituted alkylene and/or substituted heteroalkylene) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted L 1 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • when L 1 is substituted it is substituted with at least one substituent group.
  • when L 1 is substituted it is substituted with at least one size-limited substituent group.
  • when L 1 is substituted it is substituted with at least one lower substituent group.
  • L 1 is a bond. In embodiments, L 1 is a substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. In embodiments, L 1 is a substituted or unsubstituted alkylene. In embodiments, L 1 is a substituted or unsubstituted alkenylene. In embodiments, L 1 is a substituted or unsubstituted heteroalkylene.
  • L 1 is a substituted or unsubstituted alkylene (e.g., C 1 -C 8 alkylene, C 1 -C 6 alkylene, or C 1 -C 4 alkylene). In embodiments, L 1 is a substituted alkylene (e.g., C 1 -C 8 alkylene, C 1 -C 6 alkylene, or C 1 -C 4 alkylene). In embodiments, L 1 is an unsubstituted alkylene (e.g., C 1 -C 8 alkylene, C 1 -C 6 alkylene, or C 1 -C 4 alkylene). In embodiments, L 1 is an unsubstituted C 1 -C 8 alkylene.
  • L 1 is an unsubstituted C 2 -C 6 alkylene. In embodiments, L 1 is an unsubstituted C2-C4 alkylene. In embodiments, L 1 is an unsubstituted C 2 -C 3 alkylene.
  • L 1 is a substituted or unsubstituted alkenylene (e.g., C 1 -C 8 alkenylene, C 1 -C 6 alkenylene, or C 1 -C 4 alkenylene). In embodiments, L 1 is a substituted alkenylene (e.g., C 1 -C 8 alkenylene, C 1 -C 6 alkenylene, or C 1 -C 4 alkenylene). In embodiments, L 1 is an unsubstituted alkenylene (e.g., C 1 -C 8 alkenylene, C 1 -C 6 alkenylene, or C 1 -C 4 alkenylene).
  • L 1 is an unsubstituted C 1 -C 8 alkenylene. In embodiments, L 1 is an unsubstituted C2-C6 alkenylene. In embodiments, L 1 is an unsubstituted C2-C4 alkenylene. In embodiments, L 1 is an unsubstituted C 2 -C 3 alkenylene.
  • L 1 is a substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered
  • L 1 is a substituted heteroalkylene (e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene). In embodiments, L 1 is an unsubstituted heteroalkylene (e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene).
  • L 1 is a substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. In embodiments, L 1 is a substituted or unsubstituted alkenylene. In embodiments, L 1 is a substituted or unsubstituted C1-C3 alkenylene. In embodiments, L 1 has the formula: , wherein n1 is an integer from 0 to 10. In embodiments, n1 is 0. In embodiments, n1 is 1. In embodiments, n1 is 2. In embodiments, n1 is 3. In embodiments, L 1 is . In embodiments, L 1 is .
  • L 1 is a bond, R 61 -substituted or unsubstituted alkylene (e.g., C 1 -C 8 alkylene, C 1 -C 6 alkylene, or C 1 -C 4 alkylene), or R 61 -substituted or unsubstituted
  • heteroalkylene e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene.
  • L 1 is R 61 -substituted or unsubstituted alkylene (e.g., C 1 -C 8 alkylene, C 1 -C 6 alkylene, or C 1 -C 4 alkylene). In embodiments, L 1 is R 61 -substituted alkylene (e.g., C 1 -C 8 alkylene, C 1 -C 6 alkylene, or C 1 -C 4 alkylene). In embodiments, L 1 is an unsubstituted alkylene (e.g., C 1 -C 8 alkylene, C 1 -C 6 alkylene, or C 1 -C 4 alkylene).
  • L 1 is R 61 -substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered
  • L 1 is R 61 -substituted heteroalkylene (e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene). In embodiments, L 1 is an unsubstituted heteroalkylene (e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene).
  • R 2 is hydrogen or unsubstituted methyl. In embodiments, R 2 is hydrogen. In embodiments, R 2 is an unsubstituted C1-C3 alkyl. In embodiments, R 2 is an unsubstituted methyl. In embodiments, R 2 is an unsubstituted C 2 alkyl. In embodiments, R 2 is an unsubstituted C3 alkyl. In embodiments, R 2 is an unsubstituted C4 alkyl. In embodiments, R 2 is an unsubstituted C 5 alkyl. In embodiments, R 2 is an unsubstituted C 6 alkyl. In embodiments, R 2 is an unsubstituted C7 alkyl. In embodiments, R 2 is an unsubstituted C 8 alkyl.
  • R 2 is hydrogen or unsubstituted C 1 -C 3 alkyl. In embodiments, R 2 is an unsubstituted methyl. In embodiments, R 2 is an unsubstituted ethyl. In embodiments, R 2 is an unsubstituted propyl. In embodiments, R 2 is an unsubstituted n-propyl. In embodiments, R 2 is an unsubstituted isopropyl.
  • R 3 is hydrogen, oxo, halogen, -CCI 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCI 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO3H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2
  • a substituted R 3 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 3 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • R 3 when R 3 is substituted, it is substituted with at least one substituent group.
  • R 3 when R 3 is substituted, it is substituted with at least one size-limited substituent group.
  • R 3 when R 3 is substituted, it is substituted with at least one lower substituent group.
  • R 3 is hydrogen, oxo, halogen, -CCI 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCI 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO3H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 ,
  • R 3 is -CCI 3 . In embodiments, R 3 is -CBr 3 . In embodiments, R 3 is -CF 3 . In embodiments, R 3 is -CI 3 . In embodiments, R 3 is -CHCl 2 . In embodiments, R 3 is -CHBr 2 . In embodiments, R 3 is -CHF 2 . In embodiments, R 3 is -CHI 2 . In embodiments, R 3 is -CH 2 Cl. In embodiments, R 3 is -CH 2 Br. In embodiments, R 3 is -CH 2 F. In embodiments, R 3 is -CH 2 I. In embodiments, R 3 is -CN. In embodiments, R 3 is -OH.
  • R 3 is -NH 2 . In embodiments, R 3 is -COOH. In embodiments, R 3 is -CONH 2 . In embodiments, R 3 is -NO 2 . In embodiments, R 3 is -SH. In embodiments, R 3 is -SO3H. In embodiments, R 3 is -SO 4 H. In embodiments, R 3 is -SO 2 NH 2 . In embodiments, R 3 is -NHNH 2 . In embodiments, R 3 is -ONH 2 . In embodiments, R 3 is -NHC(O)NHNH 2 . In embodiments, R 3 is -NHC(O)NH 2 . In embodiments, R 3 is -NHSO 2 H.
  • R 3 is -NHC(O)H. In embodiments, R 3 is -NHC(O)OH. In embodiments, R 3 is -NHOH. In embodiments, R 3 is -OCCl 3 . In embodiments, R 3 is -OCF 3 . In embodiments, R 3 is -OCBr 3 . In embodiments, R 3 is -OCI 3 . In embodiments, R 3 is -OCHCl 2 . In embodiments, R 3 is -OCHBr 2 . In embodiments, R 3 is -OCHI 2 . In embodiments, R 3 is -OCHF 2 . In embodiments, R 3 is -OCH 2 Cl. In
  • R 3 is -OCH 2 Br. In embodiments, R 3 is -OCH 2 I. In embodiments, R 3 is -OCH 2 F. In embodiments, R 3 is -N 3 . In embodiments, R 3 is hydrogen or substituted or unsubstituted alkyl. In embodiments, R 3 is -OPO 3 H. In embodiments, R 3 is -OSO 3 H.
  • R 3 is a substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 3 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl.
  • R 3 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) alkyl.
  • R 3 is an unsubstituted alkyl.
  • R 3 is a substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C1-C2).
  • R 3 is a substituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C1-C2). In embodiments, R 3 is an unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ).
  • R 3 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl.
  • R 3 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroalkyl.
  • R 3 is an unsubstituted heteroalkyl.
  • R 3 is a substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 3 is a substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R 3 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 3 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl.
  • R 3 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) cycloalkyl.
  • R 3 is an unsubstituted cycloalkyl.
  • R 3 is a substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 , or C 5 -C 6 ).
  • R 3 is a substituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C 5 -C 6 ). In embodiments, R 3 is an unsubstituted cycloalkyl (e.g., C3- C 8 , C 3 -C 6 , C 4 -C 6 , or C 5 -C 6 ).
  • R 3 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl.
  • R 3 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heterocycloalkyl.
  • R 3 is an unsubstituted heterocycloalkyl.
  • R 3 is a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R 3 is a substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R 3 an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R 3 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted aryl.
  • R 3 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) aryl.
  • R 3 is an unsubstituted aryl.
  • R 3 is a substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl).
  • R 3 is substituted aryl (e.g., C 6 -C 10 or phenyl).
  • R 3 is an unsubstituted aryl (e.g., C 6 -C 10 or phenyl).
  • R 3 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl.
  • R 3 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroaryl.
  • R 3 is an unsubstituted heteroaryl.
  • R 3 is a substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 3 is a substituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R 3 is an unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 3 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 3 is hydrogen, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 3 is hydrogen or R 38 -substituted or unsubstituted alkyl (e.g., C 1 - C8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), R 38 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 38 - substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl), R 38 -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
  • R 3 is R 38 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 - C6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 3 is R 38 -substituted alkyl (e.g., C 1 -C 8 alkyl, C1- C 6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 3 is an unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 - C6 alkyl, or C 1 -C 4 alkyl).
  • R 3 is R 38 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 3 is R 38 -substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 3 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 3 is R 38 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl).
  • R 3 is R 38 -substituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl).
  • R 3 is an unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl).
  • R 3 is R 38 -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 3 is R 38 -substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 3 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 3 is R 38 -substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl). In embodiments, R 3 is R 38 -substituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl). In embodiments, R 3 is an unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl).
  • R 3 is R 38 -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R 3 is R 38 -substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R 3 is an
  • unsubstituted heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R 5 is hydrogen, oxo, halogen, -CCI 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCI 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO3H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2
  • a substituted R 5 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 5 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • R 5 when R 5 is substituted, it is substituted with at least one substituent group.
  • R 5 when R 5 is substituted, it is substituted with at least one size-limited substituent group.
  • R 5 when R 5 is substituted, it is substituted with at least one lower substituent group.
  • R 5 is hydrogen, oxo, halogen, -CCI 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCI 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO3H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI 3 , -OCF 3 , -OCBr 3 , -OCI 3 ,
  • R 5 is hydrogen, oxo, halogen, -CCI 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCI 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO3H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 ,
  • R 5 is -CCI 3 . In embodiments, R 5 is -CBr 3 . In embodiments, R 5 is -CF 3 . In embodiments, R 5 is -CI 3 . In embodiments, R 5 is -CHCl 2 . In embodiments, R 5 is -CHBr 2 . In embodiments, R 5 is -CHF 2 . In embodiments, R 5 is -CHI 2 . In embodiments, R 5 is -CH 2 Cl. In embodiments, R 5 is -CH 2 Br. In embodiments, R 5 is -CH 2 F. In embodiments, R 5 is -CH 2 I. In embodiments, R 5 is -CN. In embodiments, R 5 is -OH.
  • R 5 is -NH 2 . In embodiments, R 5 is -COOH. In embodiments, R 5 is -CONH 2 . In embodiments, R 5 is -NO 2 . In embodiments, R 5 is -SH. In embodiments, R 5 is -SO3H. In embodiments, R 5 is -SO 4 H. In embodiments, R 5 is -SO 2 NH 2 . In embodiments, R 5 is -NHNH 2 . In embodiments, R 5 is -ONH 2 . In embodiments, R 5 is -NHC(O)NHNH 2 . In embodiments, R 5 is -NHC(O)NH 2 . In embodiments, R 5 is -NHSO 2 H.
  • R 5 is -NHC(O)H. In embodiments, R 5 is -NHC(O)OH. In embodiments, R 5 is -NHOH. In embodiments, R 5 is -OCCl 3 . In embodiments, R 5 is -OCF 3 . In embodiments, R 5 is -OCBr 3 . In embodiments, R 5 is -OCI 3 . In embodiments, R 5 is -OCHCl 2 . In embodiments, R 5 is -OCHBr 2 . In embodiments, R 5 is -OCHI 2 . In embodiments, R 5 is -OCHF 2 . In embodiments, R 5 is -OCH 2 Cl. In
  • R 5 is -OCH 2 Br. In embodiments, R 5 is -OCH 2 I. In embodiments, R 5 is -OCH 2 F. In embodiments, R 5 is -N 3 . In embodiments, R 5 is -OPO3H. In embodiments, R 5 is -OSO 3 H.
  • R 5 is a substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 5 is R 33 -substituted or unsubstituted alkyl, R 33 -substituted or unsubstituted heteroalkyl, R 33 -substituted or unsubstituted cycloalkyl, R 33 -substituted or unsubstituted heterocycloalkyl, R 33 -substituted or unsubstituted aryl, or R 33 -substituted or unsubstituted heteroaryl.
  • R 5 is R 33 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C1- C 6 alkyl, or C 1 -C 4 alkyl), R 33 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 33 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl), R 33 - substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocyclo
  • R 5 is R 33 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C1- C 6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 5 is R 33 -substituted alkyl (e.g., C 1 -C 8 alkyl, C 1 - C6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 5 is an unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C1- C 6 alkyl, or C 1 -C 4 alkyl).
  • R 5 is R 33 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 5 is R 33 -substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 5 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 5 is R 33 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl).
  • R 5 is R 33 -substituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl).
  • R 5 is an unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl).
  • R 5 is R 33 -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 5 is R 33 -substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 5 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 5 is R 33 -substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl). In embodiments, R 5 is R 33 -substituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl). In embodiments, R 5 is an unsubstituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl).
  • R 5 is R 33 -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R 5 is R 33 -substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R 5 is an
  • unsubstituted heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R 5 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 5 is hydrogen, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 5 is a substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 5 is an unsubstituted C 1 -C 6 alkyl.
  • R 5 is an unsubstituted C3 alkyl.
  • R 5 is an unsubstituted isopropyl.
  • R 5 is:
  • R 5 is hydrogen, oxo, halogen, -CCI 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCI 2 , -CHBr 2 , -CHF2, -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO3H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OC
  • R 5 is a substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 5 is a substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted C 6 -C 10 aryl, or substituted or unsubstituted 5 to 10 membered heteroaryl.
  • R 5 is a substituted or unsubstituted C 1 -C 8 alkyl.
  • R 5 is a substituted or unsubstituted C1-C3 alkyl.
  • R 33 is independently oxo, halogen, -CCI 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCI 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO3H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl
  • a substituted R 33 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 33 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • R 33 when R 33 is substituted, it is substituted with at least one substituent group.
  • R 33 when R 33 is substituted, it is substituted with at least one size-limited substituent group.
  • R 33 when R 33 is substituted, it is substituted with at least one lower substituent group.
  • R 33 is oxo, halogen, -CCI 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCI 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -
  • R 33 is a substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 33 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl.
  • R 33 is substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) alkyl.
  • R 33 is an unsubstituted alkyl.
  • R 33 is a substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C1-C2).
  • R 33 is a substituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C1-C2). In embodiments, R 33 is an unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ).
  • R 33 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl.
  • R 33 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroalkyl.
  • R 33 is an unsubstituted heteroalkyl.
  • R 33 is a substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 33 is substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R 33 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 33 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl.
  • R 33 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) cycloalkyl.
  • R 33 is an unsubstituted cycloalkyl.
  • R 33 is a substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 , or C 5 -C 6 ).
  • R 33 is a substituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 , or C 5 -C 6 ). In embodiments, R 33 is an unsubstituted cycloalkyl (e.g., C 3 - C8, C 3 -C 6 , C4-C6, or C 5 -C 6 ).
  • R 33 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl.
  • R 33 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heterocycloalkyl.
  • R 33 is an unsubstituted heterocycloalkyl.
  • R 33 is a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R 33 is a substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R 33 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R 33 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted aryl.
  • R 33 is substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) aryl.
  • R 33 is an unsubstituted aryl.
  • R 33 is a substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl).
  • R 33 is a substituted aryl (e.g., C 6 -C 10 or phenyl).
  • R 33 is an unsubstituted aryl (e.g., C 6 -C 10 or phenyl).
  • R 33 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl.
  • R 33 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroaryl.
  • R 33 is an unsubstituted heteroaryl.
  • R 33 is a substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 33 is a substituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R 33 is an unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 33 is oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO3H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -
  • R 33 is independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCI 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -
  • R 33 is R 36 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C1- C 6 alkyl, or C 1 -C 4 alkyl), R 36 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 36 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl), R 36 - substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocyclo
  • R 33 is R 36 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 - C6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 33 is R 36 -substituted alkyl (e.g., C 1 -C 8 alkyl, C1- C 6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 33 is an unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl).
  • R 33 is R 36 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 33 is R 36 -substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 33 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 33 is R 36 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl). In embodiments, R 33 is R 36 -substituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl).
  • R 33 is an unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl).
  • R 33 is R 36 -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 33 is R 36 -substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 33 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 33 is R 36 -substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl). In embodiments, R 33 is R 36 -substituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl). In embodiments, R 33 is an unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl).
  • R 33 is R 36 -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R 33 is R 36 -substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R 33 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 36 is independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCHCl 2
  • R 36 is R 37 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 - C6 alkyl, or C 1 -C 4 alkyl), R 37 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 37 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl), R 37 - substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycl
  • R 36 is R 37 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 - C6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 36 is R 37 -substituted alkyl (e.g., C 1 -C 8 alkyl, C1- C 6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 36 is an unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl).
  • R 36 is R 37 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 36 is R 37 -substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 36 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 36 is R 37 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl).
  • R 36 is R 37 -substituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl).
  • R 36 is an unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl).
  • R 36 is R 37 -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 36 is R 37 -substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 36 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 36 is R 37 -substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl). In embodiments, R 36 is R 37 -substituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl). In embodiments, R 36 is an unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl).
  • R 36 is R 37 -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 36 is R 37 -substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 36 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 5 is an unsubstituted C4 alkyl. In embodiments, R 5 is an unsubstituted C 3 alkyl. In embodiments, R 5 is isopropyl. In embodiments, R 5 is tert-butyl.
  • R 5 is wherein R 33 is as described herein. In embodiments, R 5 is . In embodiments, R 5 is . In embodiments, R 5 is In embodiments, R 5 is In
  • R 5 is In embodiments, R 5 is In embodiments, R 5 is
  • R 5 is , wherein n33 is an integer from 0 to 20. In embodiments, n33 is an integer from 0 to 4. [0200] In embodiments, R 5 is . In embodiments, R 5 is . In embodiments, R 5 is In embodiments, R 5 is a
  • R 5 is . In embodiments, R 5 is . In embodiments, R 5 is . In embodiments, R 5 is . In embodiments, R 5 is . In embodiments, R 5 is
  • R 5 is . In embodiments, R 5 . In embodiments, R 5 is . In embodiments, R 5 is In embodiments, R 5 is In embodiments, R 5 is In embodiments, R 5 is . In embodiments, R 5 is . In embodiments, R 5 is . In embodiments, R 5 i . In embodiments, R 5 is . In embodiments, R 5 is In embodiments, R 5 is . In embodiments, R 5 is .
  • R 5 is . In embodiments, R 5 is H . In embodiments, R 5 is . In embodiments, R 5 is
  • R 5 is In embodiments, R 5 is . In embodiments, R 5 is . In embodiments, R 5 is . In embodiments, R 5 is In embodiments, R 5 is . In embodiments, R 5 is . In embodiments, R 5 is In embodiments, R 5 is . In embodiments, R 5 is In embodiments, R 5 is . In embodiments, R 5 is In embodiments, R 5 is In embodiments, R 5 is . In embodiments, R 5 is In embodiments, R 5 is In embodiments, R 5 is In embodiments, R 5 is In embodiments, R 5 is In embodiments, R 5 is In embodiments, R 5 is In embodiments, R 5 is .
  • R 5 is . In embodiments, R 5 is In embodiments, R 5 is .
  • R 5 is:
  • R 5 is In embodiments, R 5 is . In embodiments, R 5 is . In embodiments, R 5 is In embodiments, R 5 is . In embodiments, R 5 is . In embodiments, R 5 is
  • R 5 is . In embodiments, R 5 is . In embodiments, R 5 is . In embodiments, R 5 is . In embodiments, R 5 is . In embodiments, R 5 is . In embodiments, R 5 is . In embodiments, R 5 is . In embodiments, R 5 is . In embodiments, R 5 is . In embodiments, R 5 is . In embodiments, R 5 is . In embodiments, R 5 is . In embodiments, R 5 is . In embodiments, R 5 is . In embodiments, R 5 is . In embodiments, R 5 is . In embodiments, R 5 is . In embodiments, R 5 is . In embodiments, R 5 is . In embodiments, R 5 is . In embodiments, R 5 is . In embodiments, R 5 is . In embodiments, R 5 is . In embodiments, R 5 is . In embodiments, R 5 is . In embodiments, R 5 is . In embodiments, R 5 is . In embodiments, R 5
  • R 5 is . In embodiments, R 5 is . In embodiments, R 5 is . In embodiments, R 5 is . In embodiments, R 5 is . In embodiments, R 5 is . In embodiments,
  • R 5 is . In embodiments, R 5 is .
  • R 5 is . In embodiments, R 5 is .
  • R 5 is . In embodiments, R 5 is In
  • R 5 is In embodiments, R 5 is In
  • R 5 is . In embodiments, R 5 is In
  • R 5 is In embodiments, R 5 is n
  • R 5 is . In embodiments, R 5 is In embodiments,
  • R 5 is In embodiments, R 5 is
  • R 6 is hydrogen, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO3H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered,
  • R 6 is hydrogen, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO3H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to
  • a substituted R 6 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 6 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • R 6 when R 6 is substituted, it is substituted with at least one substituent group.
  • R 6 when R 6 is substituted, it is substituted with at least one size-limited substituent group.
  • R 6 when R 6 is substituted, it is substituted with at least one lower substituent group.
  • R 6 is hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCHCl 2 , -
  • R 6 is -CCI 3 . In embodiments, R 6 is -CBr 3 . In embodiments, R 6 is -CF 3 . In embodiments, R 6 is -CI 3 . In embodiments, R 6 is -CHCl 2 . In embodiments, R 6 is -CHBr 2 . In embodiments, R 6 is -CHF 2 . In embodiments, R 6 is -CHI 2 . In embodiments, R 6 is -CH 2 Cl. In embodiments, R 6 is -CH 2 Br. In embodiments, R 6 is -CH 2 F. In embodiments, R 6 is -CH 2 I. In embodiments, R 6 is -CN. In embodiments, R 6 is -OH.
  • R 6 is -NH 2 . In embodiments, R 6 is -COOH. In embodiments, R 6 is -CONH 2 . In embodiments, R 6 is -NO 2 . In embodiments, R 6 is -SH. In embodiments, R 6 is -SO3H. In embodiments, R 6 is -SO 4 H. In embodiments, R 6 is -SO 2 NH 2 . In embodiments, R 6 is -NHNH 2 . In embodiments, R 6 is -ONH 2 . In embodiments, R 6 is -NHC(O)NHNH 2 . In embodiments, R 6 is -NHC(O)NH 2 . In embodiments, R 6 is -NHSO 2 H.
  • R 6 is -NHC(O)H. In embodiments, R 6 is -NHC(O)OH. In embodiments, R 6 is -NHOH. In embodiments, R 6 is -OCCl 3 . In embodiments, R 6 is -OCF 3 . In embodiments, R 6 is -OCBr 3 . In embodiments, R 6 is -OCI 3 . In embodiments, R 6 is -OCHCl 2 . In embodiments, R 6 is -OCHBr 2 . In embodiments, R 6 is -OCHI 2 . In embodiments, R 6 is -OCHF 2 . In embodiments, R 6 is -OCH 2 Cl. In embodiments, R 6 is -OCH 2 Br.
  • R 6 is -OCH 2 I. In embodiments, R 6 is -OCH 2 F. In embodiments, R 6 is -N 3 . In embodiments, R 6 is -CH3. In embodiments, R 6 is substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.
  • R 6 is hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCI
  • R 6 is hydrogen, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or an amino acid side chain.
  • R 6 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl.
  • R 6 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) alkyl.
  • R 6 is unsubstituted alkyl.
  • R 6 is a substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ).
  • R 6 is a substituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ). In embodiments, R 6 is an unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ). In embodiments, R 6 is an unsubstituted C1-C2 alkyl. In embodiments, R 6 is an unsubstituted C1- C 4 alkyl. In embodiments, R 6 is an unsubstituted C 1 -C 6 alkyl.
  • R 6 is an unsubstituted C 1 -C 8 alkyl. In embodiments, R 6 is a substituted C1-C2 alkyl. In embodiments, R 6 is a substituted C 1 -C 4 alkyl. In embodiments, R 6 is a substituted C 1 -C 6 alkyl. In embodiments, R 6 is a substituted C 1 -C 8 alkyl. In embodiments, R 6 is a substituted C4 alkyl. In embodiments, R 6 is an alkyl substituted with–NH 2 , phenyl, indolyl, or imidazolyl. In
  • R 6 is or .
  • R 6 is a substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.
  • R 6 is a side chain of an amino acid (e.g., a side chain of a non-natural amino acid or a side chain natural NH
  • R 6 is hydrogen, , N , , , , , , , , , , , , , , , , , , , or NH
  • R 6 is N , , ,
  • R 6 is:
  • R 6 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl.
  • R 6 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroalkyl.
  • R 6 is an unsubstituted heteroalkyl.
  • R 6 is a substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 6 is a substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R 6 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 6 is an unsubstituted C 1 -C 3 alkyl. In embodiments, R 6 is an unsubstituted methyl.
  • R 6 is R 39 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C1- C 6 alkyl, or C 1 -C 4 alkyl), R 39 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 39 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl), R 39 - substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocyclo
  • R 6 is R 39 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C1- C 6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 6 is R 39 -substituted alkyl (e.g., C 1 -C 8 alkyl, C 1 - C6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 6 is an unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C1- C 6 alkyl, or C 1 -C 4 alkyl).
  • R 6 is R 39 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 6 is R 39 -substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 6 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 6 is R 39 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl).
  • R 6 is R 39 -substituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl).
  • R 6 is an unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl).
  • R 6 is R 39 -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 6 is R 39 -substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 6 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 6 is R 39 -substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl). In embodiments, R 6 is R 39 -substituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl). In embodiments, R 6 is an unsubstituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl).
  • R 6 is R 39 -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R 6 is R 39 -substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R 6 is an
  • unsubstituted heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R 39 is independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO3H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCI
  • R 39 is R 40 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 - C6 alkyl, or C 1 -C 4 alkyl), R 40 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 40 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl), R 40 - substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycl
  • R 39 is R 40 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 - C6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 39 is R 40 -substituted alkyl (e.g., C 1 -C 8 alkyl, C1- C 6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 39 is an unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl).
  • R 39 is R 40 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 39 is R 40 -substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 39 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 39 is R 40 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl).
  • R 39 is R 40 -substituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl).
  • R 39 is an unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl).
  • R 39 is R 40 -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 39 is R 40 -substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 39 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 39 is R 40 -substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl).
  • R 39 is R 40 -substituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl).
  • R 39 is an unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl).
  • R 39 is R 40 -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 39 is R 40 -substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 39 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 40 is independently oxo, halogen, -CCI 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCI 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO3H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl
  • R 40 is R 41 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C1- C 6 alkyl, or C 1 -C 4 alkyl), R 41 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 41 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl), R 41 - substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocyclo
  • R 40 is R 41 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 - C6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 40 is R 41 -substituted alkyl (e.g., C 1 -C 8 alkyl, C1- C 6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 40 is an unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl).
  • R 40 is R 41 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 40 is R 41 -substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 40 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 40 is R 41 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl). In embodiments, R 40 is R 41 -substituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl).
  • R 40 is an unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl).
  • R 40 is R 41 -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 40 is R 41 -substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 40 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 40 is R 41 -substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl). In embodiments, R 40 is R 41 -substituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl). In embodiments, R 40 is an unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl).
  • R 40 is R 41 -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R 40 is R 41 -substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R 40 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 6 and R 7 are joined to form a substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • a substituted or unsubstituted heterocycloalkylene e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered
  • substituted or unsubstituted heteroarylene e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered.
  • a substituted moiety formed when R 6 and R 7 are joined is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted moiety formed when R 6 and R 7 are joined is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • when the moiety formed when R 6 and R 7 are joined is substituted it is substituted with at least one substituent group.
  • R 6 and R 7 are joined to form a substituted or unsubstituted heterocycloalkylene or heteroarylene. In embodiments, R 6 and R 7 are joined to form a substituted or unsubstituted 3 to 6 membered heterocycloalkylene, or substituted or unsubstituted 5 to 6 membered heteroarylene. In embodiments, R 6 and R 7 are joined to form a substituted or unsubstituted 3 to 6 membered heterocycloalkylene. In embodiments, R 6 and R 7 are joined to form a substituted or unsubstituted pyrrolidinylene, or substituted or unsubstituted 2,3-dihydropyrrolylene.
  • R 6 and R 7 are joined to form a substituted pyrrolidinylene or substituted 2,3-dihydropyrrolylene. In embodiments, R 6 and R 7 are joined to form a substituted pyrrolidinylene. In embodiments, R 6 and R 7 are joined to form a substituted 2,3-dihydropyrrolylene. In embodiments, R 6 and R 7 are joined to form an unsubstituted pyrrolidinylene. In embodiments, R 6 and R 7 are joined to form an
  • R 6 and R 7 may optionally be joined to form an unsubstituted heterocycloalkylene or unsubstituted heteroarylene.
  • R 6 and R 7 are joined to form a substituted or unsubstituted heterocycloalkylene, or substituted or unsubstituted heteroarylene, which may be referred to herein as Ring B, shown below:
  • R 30 is independently halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 ,
  • R 30 is independently halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 ,
  • a substituted R 30 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 30 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • R 30 when R 30 is substituted, it is substituted with at least one substituent group.
  • R 30 when R 30 is substituted, it is substituted with at least one size-limited substituent group.
  • R 30 when R 30 is substituted, it is substituted with at least one lower substituent group.
  • R 30 is halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO3H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCI 2
  • R 30 is halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCI 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCI 2 , -OCHB
  • R 30 is R 58 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C1- C 6 alkyl, or C 1 -C 4 alkyl), R 58 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 58 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl), R 58 - substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membere
  • R 30 is independently R 58 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), R 58 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 58 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl), R 58 -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or
  • R 30 is R 58 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C1- C 6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 30 is R 58 -substituted alkyl (e.g., C 1 -C 8 alkyl, C 1 - C6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 30 is an unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl).
  • R 30 is R 58 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 30 is R 58 -substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 30 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 30 is R 58 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl).
  • R 30 is R 58 -substituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl).
  • R 30 is an unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl).
  • R 30 is R 58 -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 30 is R 58 -substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 30 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 30 is R 58 -substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl). In embodiments, R 30 is R 58 -substituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl). In embodiments, R 30 is an unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl).
  • R 30 is R 58 -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 30 is R 58 -substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 30 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • z30 is 0. In embodiments, z30 is 1. In embodiments, z30 is 2. In embodiments, z30 is 3. In embodiments, z30 is 4. In embodiments, z30 is 5. In embodiments,
  • z30 is 6.
  • R 31 is hydrogen, halogen, -CCI 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCI 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 ,
  • a substituted R 31 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 31 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • R 31 when R 31 is substituted, it is substituted with at least one substituent group.
  • R 31 when R 31 is substituted, it is substituted with at least one size-limited substituent group.
  • R 31 when R 31 is substituted, it is substituted with at least one lower substituent group.
  • R 31 is R 59 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 - C6 alkyl, or C 1 -C 4 alkyl), R 59 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 59 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl), R 59 - substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 member
  • R 31 is R 59 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 - C6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 31 is R 59 -substituted alkyl (e.g., C 1 -C 8 alkyl, C1- C 6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 31 is an unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl).
  • R 31 is R 59 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 31 is R 59 -substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 31 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 31 is R 59 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl).
  • R 31 is R 59 -substituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl).
  • R 31 is an unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl).
  • R 31 is R 59 -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 31 is R 59 -substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 31 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 31 is R 59 -substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl). In embodiments, R 31 is R 59 -substituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl). In embodiments, R 31 is an unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl).
  • R 31 is R 59 -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 31 is R 59 -substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 31 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 6 and R 7 are joined to form an unsubstituted 3 to 6 membered heterocycloalkylene, or an unsubstituted 5 to 6 membered heteroarylene. In embodiments, R 6 and R 7 are joined to form an unsubstituted 3 to 6 membered heterocycloalkylene.
  • R 6 and R 7 are joined to form a 4 to 8 membered
  • R 6 and R 7 are joined to form a 4 membered heterocycloalkylene. In embodiments, R 6 and R 7 are joined to form a 5 membered heterocycloalkylene. In embodiments, R 6 and R 7 are joined to form a 6 membered heterocycloalkylene. In embodiments, R 6 and R 7 are joined to form a 7 membered heterocycloalkylene. In embodiments, R 6 and R 7 are joined to form an 8 membered heterocycloalkylene. In embodiments, R 6 and R 7 are joined to form a 4 to 6 membered heterocycloalkylene. In embodiments, R 6 and R 7 are joined to form azetidinylene.
  • R 6 and R 7 are joined to form a substituted or unsubstituted heterocycloalkylene. In embodiments, R 6 and R 7 are joined to form a substituted
  • R 6 and R 7 are joined to form an unsubstituted heterocycloalkylene. In embodiments, R 6 and R 7 are joined to form a substituted or unsubstituted 3 to 10 membered heterocycloalkylene. In embodiments, R 6 and R 7 are joined to form a substituted 3 to 10 membered heterocycloalkylene. In embodiments, R 6 and R 7 are joined to form an unsubstituted 3 to 10 membered heterocycloalkylene. In embodiments, R 6 and R 7 are joined to form an R 30 -substituted or unsubstituted 5 to 10 membered
  • R 6 and R 7 are joined to form an R 30 -substituted 5 to 10 membered heterocycloalkylene. In embodiments, R 6 and R 7 are joined to form an unsubstituted 5 to 10 membered heterocycloalkylene.
  • R 6 and R 7 are joined to form a substituted or unsubstituted 3 membered heterocycloalkylene. In embodiments, R 6 and R 7 are joined to form a substituted or unsubstituted 4 membered heterocycloalkylene. In embodiments, R 6 and R 7 are joined to form a substituted or unsubstituted 5 membered heterocycloalkylene. In embodiments, R 6 and R 7 are joined to form a substituted or unsubstituted 6 membered heterocycloalkylene. In embodiments, R 6 and R 7 are joined to form a substituted 3 membered heterocycloalkylene.
  • R 6 and R 7 are joined to form a substituted 4 membered heterocycloalkylene. In embodiments, R 6 and R 7 are joined to form a substituted 5 membered heterocycloalkylene. In embodiments, R 6 and R 7 are joined to form a substituted 6 membered heterocycloalkylene. In embodiments, R 6 and R 7 are joined to form an unsubstituted 3 membered
  • heterocycloalkylene In embodiments, R 6 and R 7 are joined to form an unsubstituted 4 membered heterocycloalkylene. In embodiments, R 6 and R 7 are joined to form an unsubstituted 5 membered heterocycloalkylene. In embodiments, R 6 and R 7 are joined to form an unsubstituted 6 membered heterocycloalkylene.
  • R 6 and R 7 are joined to form a substituted or unsubstituted aziridinylene, azirinylene, azetidinylene, dihydroazetylene, diazetidinylene, azetylene, pyrrolidinylene, pyrrolinylene, pyrrolylene, pyrazolidinylene, imidazolidinylene, pyrazolinylene, pyrazolylene, thiazolidinylene, thiazolylene, isothiazolylene, piperidinylene, piperazinylene, morpholinylene, oxazinylene, thiomorpholinylene, thiazinylene,
  • R 6 and R 7 are joined to form a substituted aziridinylene, azirinylene, azetidinylene, dihydroazetylene, diazetidinylene, azetylene, pyrrolidinylene, pyrrolinylene, pyrrolylene, pyrazolidinylene, imidazolidinylene, pyrazolinylene, pyrazolylene, thiazolidinylene, thiazolylene, isothiazolylene, piperidinylene, piperazinylene, morpholinylene, oxazinylene, thiomorpholinylene, thiazinylene, decahydroquinolinylene, dihydroazepinylene, azepanylene, or azocanylene.
  • R 6 and R 7 are joined to form a substituted aziridinylene, azirinylene, azetidinylene, dihydroazetylene, diazet
  • pyrazolinylene pyrazolylene, thiazolidinylene, thiazolylene, isothiazolylene, piperidinylene, piperazinylene, morpholinylene, oxazinylene, thiomorpholinylene, thiazinylene,
  • R 6 and R 7 are joined to form an unsubstituted pyrrolidinylene or 2,3-dihydropyrrolylene.
  • R 7 is hydrogen, -CH 2 COOH, -CONH 2 , -OH, -SH, -NO 2 , -NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or 2 to 3 membered), substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 , or C 5 -C 6 ), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3
  • a substituted R 7 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 7 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R 7 is substituted, it is substituted with at least one substituent group.
  • R 7 when R 7 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 7 is substituted, it is substituted with at least one lower substituent group.
  • R 7 is hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -COOH, -CH 2 COOH, -CONH 2 , -OH, -SH, -NO 2 , -NH 2 , -NHNH 2 , -ONH 2 , or -NHC(O)NHNH 2 .
  • R 7 is a substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 7 is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. In embodiments, R 7 is hydrogen.
  • R 7 is hydrogen, -CH 2 COOH, -CONH 2 , -OH, -SH, -NO 2 , -NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 7 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl.
  • R 7 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) alkyl.
  • R 7 is an unsubstituted alkyl.
  • R 7 is a substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C1-C2).
  • R 7 is a substituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C1-C2). In embodiments, R 7 is an unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ).
  • R 7 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl.
  • R 7 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroalkyl.
  • R 7 is an unsubstituted heteroalkyl.
  • R 7 is a substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 7 is a substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R 7 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 7 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl.
  • R 7 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) cycloalkyl.
  • R 7 is an unsubstituted cycloalkyl.
  • R 7 is a substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 , or C 5 -C 6 ).
  • R 7 is a substituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C 5 -C 6 ). In embodiments, R 7 is an unsubstituted cycloalkyl (e.g., C3- C 8 , C 3 -C 6 , C 4 -C 6 , or C 5 -C 6 ).
  • R 7 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl.
  • R 7 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heterocycloalkyl.
  • R 7 is an unsubstituted heterocycloalkyl.
  • R 7 is a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R 7 is a substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R 7 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R 7 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted aryl.
  • R 7 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) aryl.
  • R 7 is an unsubstituted aryl.
  • R 7 is a substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl).
  • R 7 is a substituted aryl (e.g., C 6 -C 10 or phenyl).
  • R 7 is an unsubstituted aryl (e.g., C 6 -C 10 or phenyl).
  • R 7 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl.
  • R 7 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroaryl.
  • R 7 is an unsubstituted heteroaryl.
  • R 7 is a substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 7 is a substituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R 7 is an unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0277] In embodiments, R 7 is hydrogen or substituted or unsubstituted C 1 -C 6 alkyl. In embodiments, R 7 is hydrogen.
  • R 7 is R 42 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C1- C 7 alkyl, or C 1 -C 4 alkyl), R 42 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 7 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 42 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 7 cycloalkyl, or C 5 -C 7 cycloalkyl), R 42 - substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 7 membered heterocycloalkyl, or 5 to 7 membered heterocyclo
  • R 7 is R 42 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C1- C 7 alkyl, or C 1 -C 4 alkyl). In embodiments, R 7 is R 42 -substituted alkyl (e.g., C 1 -C 8 alkyl, C 1 - C7 alkyl, or C 1 -C 4 alkyl). In embodiments, R 7 is an unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C1- C 7 alkyl, or C 1 -C 4 alkyl).
  • R 7 is R 42 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 7 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 7 is R 42 -substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 7 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 7 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 7 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 7 is R 42 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 7 cycloalkyl, or C 5 -C 7 cycloalkyl).
  • R 7 is R 42 -substituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C3-C7 cycloalkyl, or C5-C7 cycloalkyl).
  • R 7 is an unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 7 cycloalkyl, or C 5 -C 7 cycloalkyl).
  • R 7 is R 42 -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 7 membered heterocycloalkyl, or 5 to 7 membered heterocycloalkyl).
  • R 7 is R 42 -substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 7 membered heterocycloalkyl, or 5 to 7 membered heterocycloalkyl).
  • R 7 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 7 membered heterocycloalkyl, or 5 to 7 membered heterocycloalkyl).
  • R 7 is R 42 -substituted or unsubstituted aryl (e.g., C7-C10 aryl, C10 aryl, or phenyl). In embodiments, R 7 is R 42 -substituted aryl (e.g., C 7 -C 10 aryl, C 10 aryl, or phenyl). In embodiments, R 7 is an unsubstituted aryl (e.g., C7-C10 aryl, C10 aryl, or phenyl).
  • R 7 is R 42 -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 7 membered heteroaryl). In embodiments, R 7 is R 42 -substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 7 membered heteroaryl). In embodiments, R 7 is an
  • unsubstituted heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 7 membered heteroaryl.
  • R 8 is independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCI 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -
  • a substituted R 8 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 8 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • R 8 when R 8 is substituted, it is substituted with at least one substituent group.
  • R 8 when R 8 is substituted, it is substituted with at least one size-limited substituent group.
  • R 8 when R 8 is substituted, it is substituted with at least one lower substituent group.
  • R 8 is oxo, halogen, -CCI 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCI 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO3H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -
  • R 8 is oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 ,
  • R 8 is -CCI 3 . In embodiments, R 8 is -CBr 3 . In embodiments, R 8 is -CF 3 . In embodiments, R 8 is -CI 3 . In embodiments, R 8 is -CHCl 2 . In embodiments, R 8 is -CHBr 2 . In embodiments, R 8 is -CHF 2 . In embodiments, R 8 is -CHI 2 . In embodiments, R 8 is -CH 2 Cl. In embodiments, R 8 is -CH 2 Br. In embodiments, R 8 is -CH 2 F. In embodiments, R 8 is -CH 2 I. In embodiments, R 8 is -CN. In embodiments, R 8 is -OH.
  • R 8 is -NH 2 . In embodiments, R 8 is -COOH. In embodiments, R 8 is -CONH 2 . In embodiments, R 8 is -NO 2 . In embodiments, R 8 is -SH. In embodiments, R 8 is -SO3H. In embodiments, R 8 is -SO 4 H. In embodiments, R 8 is -SO 2 NH 2 . In embodiments, R 8 is -NHNH 2 . In embodiments, R 8 is -ONH 2 . In embodiments, R 8 is -NHC(O)NHNH 2 . In embodiments, R 8 is -NHC(O)NH 2 . In embodiments, R 8 is -NHSO 2 H.
  • R 8 is -NHC(O)H. In embodiments, R 8 is -NHC(O)OH. In embodiments, R 8 is -NHOH. In embodiments, R 8 is -OCCl 3 . In embodiments, R 8 is -OCF 3 . In embodiments, R 8 is -OCBr 3 . In embodiments, R 8 is -OCI 3 . In embodiments, R 8 is -OCHCl 2 . In embodiments, R 8 is -OCHBr 2 . In embodiments, R 8 is -OCHI 2 . In embodiments, R 8 is -OCHF 2 . In embodiments, R 8 is -OCH 2 Cl. In
  • R 8 is -OCH 2 Br. In embodiments, R 8 is -OCH 2 I. In embodiments, R 8 is -OCH 2 F. In embodiments, R 8 is -N 3 . [0289] In embodiments, R 8 is a substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 8 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl.
  • R 8 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) alkyl.
  • R 8 is an unsubstituted alkyl.
  • R 8 is a substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C1-C2).
  • R 8 is a substituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C1-C2). In embodiments, R 8 is an unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ).
  • R 8 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl.
  • R 8 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroalkyl.
  • R 8 is an unsubstituted heteroalkyl.
  • R 8 is a substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 8 is a substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R 8 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 8 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl.
  • R 8 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) cycloalkyl.
  • R 8 is an unsubstituted cycloalkyl.
  • R 8 is a substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 , or C 5 -C 6 ).
  • R 8 is a substituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C 5 -C 6 ). In embodiments, R 8 is an unsubstituted cycloalkyl (e.g., C3- C 8 , C 3 -C 6 , C 4 -C 6 , or C 5 -C 6 ).
  • R 8 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl.
  • R 8 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heterocycloalkyl.
  • R 8 is an unsubstituted heterocycloalkyl.
  • R 8 is a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R 8 is a substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R 8 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R 8 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted aryl.
  • R 8 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) aryl.
  • R 8 is an unsubstituted aryl.
  • R 8 is a substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl).
  • R 8 is a substituted aryl (e.g., C 6 -C 10 or phenyl).
  • R 8 is an unsubstituted aryl (e.g., C 6 -C 10 or phenyl).
  • R 8 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl.
  • R 8 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroaryl.
  • R 8 is an unsubstituted heteroaryl.
  • R 8 is a substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 8 is a substituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R 8 is an unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 8 is R 43 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C1- C 6 alkyl, or C 1 -C 4 alkyl), R 43 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 43 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl), R 43 - substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocyclo
  • R 8 is R 43 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 - C6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 8 is R 43 -substituted alkyl (e.g., C 1 -C 8 alkyl, C1- C 6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 8 is an unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 - C6 alkyl, or C 1 -C 4 alkyl).
  • R 8 is R 43 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 8 is R 43 -substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 8 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 8 is R 43 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl). In embodiments, R 8 is R 43 -substituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl).
  • R 8 is an unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl).
  • R 8 is R 43 -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 8 is R 43 -substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 8 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 8 is R 43 -substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl). In embodiments, R 8 is R 43 -substituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl). In embodiments, R 8 is an unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl).
  • R 8 is R 43 -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R 8 is R 43 -substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R 8 is an
  • R 43 is independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)H, --NHC(O)H, --NHC(O)H, --NHC(O)H, --NHC(O)H, -
  • R 43 is R 44 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 - C6 alkyl, or C 1 -C 4 alkyl), R 44 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 44 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl), R 44 - substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycl
  • R 43 is R 44 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 - C6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 43 is R 44 -substituted alkyl (e.g., C 1 -C 8 alkyl, C1- C 6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 43 is an unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl).
  • R 43 is R 44 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 43 is R 44 -substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 43 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 43 is R 44 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl). In embodiments, R 43 is R 44 -substituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl).
  • R 43 is an unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl).
  • R 43 is R 44 -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 43 is R 44 -substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 43 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 43 is R 44 -substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl). In embodiments, R 43 is R 44 -substituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl). In embodiments, R 43 is an unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl).
  • R 43 is R 44 -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R 43 is R 44 -substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R 43 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 44 is independently oxo, halogen, -CCI 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCI 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO3H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl
  • R 44 is R 45 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C1- C 6 alkyl, or C 1 -C 4 alkyl), R 45 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 45 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl), R 45 - substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocyclo
  • R 44 is R 45 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C1- C 6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 44 is R 45 -substituted alkyl (e.g., C 1 -C 8 alkyl, C 1 - C6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 44 is an unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl).
  • R 44 is R 45 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 44 is R 45 -substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 44 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 44 is R 45 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl). In embodiments, R 44 is R 45 -substituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl).
  • R 44 is an unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl).
  • R 44 is R 45 -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 44 is R 45 -substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 44 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 44 is R 45 -substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl). In embodiments, R 44 is R 45 -substituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl). In embodiments, R 44 is an unsubstituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl).
  • R 44 is R 45 -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R 44 is R 45 -substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R 44 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 8.3 , R 8.4 , and R 8.5 are each independently hydrogen or R 8 at a fixed position on the attached ring.
  • R 8.3 , R 8.4 , and R 8.5 may independently be any substituent of R 8 described herein, including in any aspect, embodiment, example, figure, or claim.
  • R 8.4 is hydrogen, halogen, -CCI 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCI 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -COOH, -CH 2 COOH, -CONH 2 , -OH, -SH, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.
  • R 8.3 and R 8.5 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO3H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , ,
  • R 8.3 , R 8.4 , and R 8.5 are each hydrogen or R 8 at a fixed position on the attached ring.
  • R 8.3 , R 8.4 , and R 8.5 may be any substituent of R 8 described herein, including in any aspect, embodiment, example, figure, or claim.
  • R 8.4 is hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -COOH, -CH 2 COOH, -CONH 2 , -OH, -SH, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.
  • R 8.3 and R 8.5 are independently hydrogen, halogen, -CCI 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCI 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OC
  • a substituted R 8.3 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 8.3 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • R 8.3 when R 8.3 is substituted, it is substituted with at least one substituent group.
  • R 8.3 when R 8.3 is substituted, it is substituted with at least one size-limited substituent group.
  • R 8.3 when R 8.3 is substituted, it is substituted with at least one lower substituent group.
  • a substituted R 8.4 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 8.4 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • R 8.4 when R 8.4 is substituted, it is substituted with at least one substituent group.
  • R 8.4 when R 8.4 is substituted, it is substituted with at least one size-limited substituent group.
  • R 8.4 when R 8.4 is substituted, it is substituted with at least one lower substituent group.
  • a substituted R 8.5 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 8.5 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • R 8.5 when R 8.5 is substituted, it is substituted with at least one substituent group.
  • R 8.5 when R 8.5 is substituted, it is substituted with at least one size-limited substituent group.
  • R 8.5 when R 8.5 is substituted, it is substituted with at least one lower substituent group.
  • R 8.3 , R 8.4 , and R 8.5 are each independently R 43 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), R 43 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 43 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl), R 43 -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membere
  • R 8.3 , R 8.4 , and R 8.5 are each independently R 43 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 8.3 , R 8.4 , and R 8.5 are each independently R 43 -substituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl).
  • R 8.3 , R 8.4 , and R 8.5 are each independently an unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl).
  • R 8.3 , R 8.4 , and R 8.5 are each independently R 43 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 8.3 , R 8.4 , and R 8.5 are each independently R 43 -substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 8.3 , R 8.4 , and R 8.5 are each independently an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 8.3 , R 8.4 , and R 8.5 are each independently R 43 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl).
  • R 8.3 , R 8.4 , and R 8.5 are each independently R 43 -substituted cycloalkyl (e.g., C3- C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl).
  • R 8.3 , R 8.4 , and R 8.5 are each independently an unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl).
  • R 8.3 , R 8.4 , and R 8.5 are each independently R 43 -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 8.3 , R 8.4 , and R 8.5 are each independently R 43 -substituted heterocycloalkyl (e.g., 3 to 8 membered
  • R 8.3 , R 8.4 , and R 8.5 are each independently an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 8.3 , R 8.4 , and R 8.5 are each independently R 43 -substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl). In embodiments, R 8.3 , R 8.4 , and R 8.5 are each independently R 43 -substituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl). In embodiments, R 8.3 , R 8.4 , and R 8.5 are each independently an unsubstituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl).
  • R 8.3 , R 8.4 , and R 8.5 are each independently R 43 -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 8.3 , R 8.4 , and R 8.5 are each independently R 43 - substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 8.3 , R 8.4 , and R 8.5 are each independently an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • z8 is an integer from 0 to 5. In embodiments, z8 is an integer from 0 to 3. In embodiments, z8 is an integer from 0 to 2. In embodiments, z8 is an integer from 1 to 2. In embodiments, z8 is 0. In embodiments, z8 is 1. In embodiments, z8 is 2. In embodiments, z8 is 3. In embodiments, z8 is 4. In embodiments, z8 is 5. In embodiments, z8 is 6. In embodiments, z8 is 7. In embodiments, z8 is 8. In embodiments, z8 is 9. In embodiments, z8 is 10.
  • R 9 is hydrogen, oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO3H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI 3 , -OCF 3 , -OCBr 3 , -OCI 3 ,
  • a substituted R 9 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 9 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • R 9 when R 9 is substituted, it is substituted with at least one substituent group.
  • R 9 when R 9 is substituted, it is substituted with at least one size-limited substituent group.
  • R 9 when R 9 is substituted, it is substituted with at least one lower substituent group.
  • R 9 is hydrogen, oxo, halogen, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO3H, or -N 3 .
  • R 9 is an unsubstituted alkyl, or unsubstituted heteroalkyl.
  • R 9 is an unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 - C2).
  • R 9 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 9 is hydrogen.
  • R 9 is oxo.
  • R 9 is halogen.
  • R 9 is–CN.
  • R 9 is–OH.
  • R 9 is -NH 2 .
  • R 9 is– COOH.
  • R 9 is -CONH 2 .
  • R 9 is -NO 2 .
  • R 9 is–SH.
  • R 9 is -SO 3 H.
  • R 9 is -N 3 .
  • R 9 is oxo or halogen.
  • R 9 is oxo or halogen.
  • R 9 is oxo or–F.
  • R 9 is–F.
  • R 9 is halogen, oxo, -NH 2 , unsubstituted alkyl, or unsubstituted heteroalkyl. In embodiments, R 9 is–F, oxo, or -NH 2 , or unsubstituted heteroalkyl. In embodiments, R 9 is -NH 3 (e.g., a salt of NH 2 ).
  • R 9 is hydrogen. In embodiments, R 9 is oxo. In embodiments, R 9 is halogen. In embodiments, R 9 is–F. In embodiments, R 9 is–Cl. In embodiments, R 9 is– Br. In embodiments, R 9 is–I. In embodiments, R 9 is -CCl 3 . In embodiments, R 9 is -CBr 3 . In embodiments, R 9 is -CF 3 . In embodiments, R 9 is -CI 3 . In embodiments, R 9 is -CHCI 2 . In embodiments, R 9 is -CHBr 2 . In embodiments, R 9 is -CHF 2 . In embodiments, R 9 is -CHI 2 .
  • R 9 is -CH 2 Cl. In embodiments, R 9 is -CH 2 Br. In embodiments, R 9 is -CH 2 F. In embodiments, R 9 is -CH 2 I. In embodiments, R 9 is -CN. In embodiments, R 9 is -OH. In embodiments, R 9 is -NH 2 . In embodiments, R 9 is -COOH. In embodiments, R 9 is -CONH 2 . In embodiments, R 9 is -NO 2 . In embodiments, R 9 is -SH. In embodiments, R 9 is -SO3H. In embodiments, R 9 is -SO 4 H. In embodiments, R 9 is -SO 2 NH 2 .
  • R 9 is -NHNH 2 . In embodiments, R 9 is -ONH 2 . In embodiments, R 9 is -NHC(O)NHNH 2 . In embodiments, R 9 is -NHC(O)NH 2 . In embodiments, R 9 is -NHSO 2 H. In embodiments, R 9 is -NHC(O)H. In embodiments, R 9 is -NHC(O)OH. In embodiments, R 9 is -NHOH. In embodiments, R 9 is -OCCI 3 . In embodiments, R 9 is -OCF 3 . In embodiments, R 9 is -OCBr 3 . In embodiments, R 9 is -OCI 3 .
  • R 9 is -OCHCl 2 . In embodiments, R 9 is -OCHBr 2 . In embodiments, R 9 is -OCHI 2 . In embodiments, R 9 is -OCHF 2 . In embodiments, R 9 is -OCH 2 Cl. In embodiments, R 9 is -OCH 2 Br. In embodiments, R 9 is -OCH 2 I. In embodiments, R 9 is -OCH 2 F. In embodiments, R 9 is -N 3 .
  • R 9 is hydrogen, oxo, halogen, -CCI 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCI 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO3H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 ,
  • R 9 is R 46 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C1- C 6 alkyl, or C 1 -C 4 alkyl), R 46 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 46 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl), R 46 - substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocyclo
  • R 9 is R 46 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 - C6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 9 is R 46 -substituted alkyl (e.g., C 1 -C 8 alkyl, C1- C 6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 9 is an unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 - C6 alkyl, or C 1 -C 4 alkyl).
  • R 9 is R 46 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 9 is R 46 -substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 9 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 9 is R 46 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl). In embodiments, R 9 is R 46 -substituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl).
  • R 9 is an unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl).
  • R 9 is R 46 -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 9 is R 46 -substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 9 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 9 is R 46 -substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl). In embodiments, R 9 is R 46 -substituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl). In embodiments, R 9 is an unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl).
  • R 9 is R 46 -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R 9 is R 46 -substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R 9 is an
  • unsubstituted heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R 10 and R 12 are independently hydrogen, substituted or unsubstituted C1-C3 alkyl, or substituted or unsubstituted 2 to 3 membered heteroalkyl.
  • R 10 is hydrogen, oxo, halogen, -CCI 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCI 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO3H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 ,
  • a substituted R 10 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 10 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • R 10 when R 10 is substituted, it is substituted with at least one substituent group.
  • R 10 when R 10 is substituted, it is substituted with at least one size-limited substituent group.
  • R 10 when R 10 is substituted, it is substituted with at least one lower substituent group.
  • R 10 is hydrogen, substituted or unsubstituted C1-C3 alkyl, or substituted or unsubstituted 2 to 3 membered heteroalkyl.
  • R 10 is hydrogen or unsubstituted methyl. In embodiments, R 10 is hydrogen. In embodiments, R 10 is an unsubstituted C1-C3 alkyl. In embodiments, R 10 is an unsubstituted C 2 alkyl. In embodiments, R 10 is an unsubstituted C 3 alkyl. In embodiments, R 10 is unsubstituted methyl. In embodiments, R 10 and R 12 are independently hydrogen, substituted or unsubstituted C 1 -C 3 alkyl, or substituted or unsubstituted 2 to 3 membered heteroalkyl.
  • R 10 is a substituted or unsubstituted C1-C3 alkyl, or substituted or unsubstituted 2 to 3 membered heteroalkyl.
  • R 10 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl.
  • R 10 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) alkyl.
  • R 10 is unsubstituted alkyl.
  • R 10 is a substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C1-C2). In embodiments, R 10 is a substituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ). In embodiments, R 10 is an unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C1-C2).
  • R 10 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl.
  • R 10 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroalkyl.
  • R 10 is an unsubstituted heteroalkyl.
  • R 10 is substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 10 is a substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R 10 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 10 is hydrogen, oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO3H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI 3 , -OCF 3 , -OCBr 3 , -OCI 3 ,
  • R 10 is R 47 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C1- C 6 alkyl, or C 1 -C 4 alkyl), R 47 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 47 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl), R 47 - substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocyclo
  • R 10 is R 47 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C1- C 6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 10 is R 47 -substituted alkyl (e.g., C 1 -C 8 alkyl, C 1 - C6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 10 is an unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl).
  • R 10 is R 47 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 10 is R 47 -substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 10 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 10 is R 47 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl). In embodiments, R 10 is R 47 -substituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl).
  • R 10 is an unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl).
  • R 10 is R 47 -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 10 is R 47 -substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 10 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 10 is R 47 -substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl). In embodiments, R 10 is R 47 -substituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl). In embodiments, R 10 is an unsubstituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl).
  • R 10 is R 47 -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R 10 is R 47 -substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R 10 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 11 is hydrogen, oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI 3 , -OCF 3 , -OCBr 3 , -OCI 3 ,
  • a substituted R 11 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 11 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • R 11 when R 11 is substituted, it is substituted with at least one substituent group.
  • R 11 when R 11 is substituted, it is substituted with at least one size-limited substituent group.
  • R 11 when R 11 is substituted, it is substituted with at least one lower substituent group.
  • R 11 is hydrogen, oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3
  • R 11 is hydrogen. In embodiments, R 11 is oxo. In embodiments, R 11 is halogen. In embodiments, R 11 is -CCl 3 . In embodiments, R 11 is -CBr 3 . In embodiments, R 11 is -CF 3 . In embodiments, R 11 is -CI 3 . In embodiments, R 11 is -CHCI 2 . In embodiments, R 11 is -CHBr 2 . In embodiments, R 11 is -CHF 2 . In embodiments, R 11 is -CHI 2 . In embodiments, R 11 is -CH 2 Cl. In embodiments, R 11 is -CH 2 Br. In embodiments, R 11 is -CH 2 F.
  • R 11 is -CH 2 I. In embodiments, R 11 is -CN. In embodiments, R 11 is -OH. In embodiments, R 11 is -NH 2 . In embodiments, R 11 is -COOH. In embodiments, R 11 is -CONH 2 . In embodiments, R 11 is -NO 2 . In embodiments, R 11 is–SH. In embodiments, R 11 is -SO 3 H. In embodiments, R 11 is -SO 4 H. In embodiments, R 11 is -SO 2 NH 2 . In embodiments, R 11 is -NHNH 2 . In embodiments, R 11 is -ONH 2 . In embodiments, R 11 is -NHC(O)NHNH 2 .
  • R 11 is -NHC(O)NH 2 . In embodiments, R 11 is -NHSO 2 H. In embodiments, R 11 is -NHC(O)H. In embodiments, R 11 is -NHC(O)OH. In embodiments, R 11 is -NHOH. In embodiments, R 11 is -OCCl 3 . In embodiments, R 11 is -OCF 3 . In embodiments, R 11 is -OCBr 3 . In embodiments, R 11 is -OCI 3 . In embodiments, R 11 is -OCHCI 2 . In embodiments, R 11 is -NHC(O)NH 2 . In embodiments, R 11 is -NHSO 2 H. In embodiments, R 11 is -NHC(O)H. In embodiments, R 11 is -NHC(O)OH. In embodiments, R 11 is -NHOH. In embodiments, R 11 is -OCCl 3 . In embodiments, R 11 is -OCF 3 . In embodiments,
  • R 11 is -OCHBr 2 . In embodiments, R 11 is -OCHI 2 . In embodiments, R 11 is -OCHF 2 . In embodiments, R 11 is -OCH 2 Cl. In embodiments, R 11 is -OCH 2 Br. In embodiments, R 11 is -OCH 2 I. In embodiments, R 11 is -OCH 2 F. In embodiments, R 11 is -N 3 . In embodiments, R 11 is -OH, -NH 2 , or–SH.
  • R 11 is a substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 11 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl.
  • R 11 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) alkyl.
  • R 11 is an unsubstituted alkyl.
  • R 11 is a substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ).
  • R 11 is a substituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ). In embodiments, R 11 is an unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C1-C2).
  • R 11 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl.
  • R 11 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroalkyl.
  • R 11 is an unsubstituted heteroalkyl.
  • R 11 is a substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 11 is a substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R 11 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 11 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl.
  • R 11 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) cycloalkyl.
  • R 11 is an unsubstituted cycloalkyl.
  • R 11 is a substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C 5 -C 6 ).
  • R 11 is a substituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 , or C 5 -C 6 ). In embodiments, R 11 is an unsubstituted cycloalkyl (e.g., C 3 - C8, C 3 -C 6 , C4-C6, or C 5 -C 6 ).
  • R 11 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl.
  • R 11 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heterocycloalkyl.
  • R 11 is an unsubstituted heterocycloalkyl.
  • R 11 is a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R 11 is a substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R 11 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R 11 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted aryl.
  • R 11 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) aryl.
  • R 11 is an unsubstituted aryl.
  • R 11 is a substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl).
  • R 11 is a substituted aryl (e.g., C 6 -C 10 or phenyl).
  • R 11 is an unsubstituted aryl (e.g., C 6 -C 10 or phenyl).
  • R 11 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl.
  • R 11 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroaryl.
  • R 11 is an unsubstituted heteroaryl.
  • R 11 is a substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 11 is a substituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R 11 is an unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 11 is oxo, halogen,–OH, or -NH 2 . In embodiments, R 11 is–F.
  • R 11 hydrogen, oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO3H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI 3 , -OCF 3 , -OCBr 3 , -OCI 3 ,
  • R 11 is R 48 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 - C6 alkyl, or C 1 -C 4 alkyl), R 48 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 48 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl), R 48 - substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycl
  • R 11 is R 48 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 - C6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 11 is R 48 -substituted alkyl (e.g., C 1 -C 8 alkyl, C1- C 6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 11 is an unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl).
  • R 11 is R 48 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 11 is R 48 -substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 11 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 11 is R 48 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl). In embodiments, R 11 is R 48 -substituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl).
  • R 11 is an unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl).
  • R 11 is R 48 -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 11 is R 48 -substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 11 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 11 is R 48 -substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl).
  • R 11 is R 48 -substituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl).
  • R 11 is an unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl).
  • R 11 is R 48 -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R 11 is R 48 -substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R 11 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 12 is hydrogen, oxo, halogen, -CCI 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCI 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO3H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 ,
  • a substituted R 12 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 12 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R 12 is substituted, it is substituted with at least one substituent group.
  • R 12 when R 12 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 12 is substituted, it is substituted with at least one lower substituent group. [0380] In embodiments, R 12 is hydrogen, substituted or unsubstituted C 1 -C 3 alkyl, or substituted or unsubstituted 2 to 3 membered heteroalkyl.
  • R 12 is hydrogen or unsubstituted methyl. In embodiments, R 12 is hydrogen. In embodiments, R 12 is an unsubstituted C 1 -C 3 alkyl. In embodiments, R 12 is an unsubstituted C2 alkyl. In embodiments, R 12 is an unsubstituted C3 alkyl. In embodiments, R 12 is an unsubstituted methyl. In embodiments, R 12 is hydrogen or an unsubstituted C 1 -C 3 alkyl.
  • R 12 is a substituted or unsubstituted C1-C3 alkyl, or substituted or unsubstituted 2 to 3 membered heteroalkyl.
  • R 12 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl.
  • R 12 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) alkyl.
  • R 12 is an unsubstituted alkyl.
  • R 12 is a substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C1-C2). In embodiments, R 12 is a substituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ). In embodiments, R 12 is an unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C1-C2).
  • R 12 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl.
  • R 12 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroalkyl.
  • R 12 is an unsubstituted heteroalkyl.
  • R 12 is a substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 12 is a substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R 12 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 12 hydrogen, oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO3H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI 3 , -OCF 3 , -OCBr 3 , -OCI 3 ,
  • R 12 is R 49 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 - C6 alkyl, or C 1 -C 4 alkyl), R 49 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 49 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl), R 49 - substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycl
  • R 12 is R 49 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 - C6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 12 is R 49 -substituted alkyl (e.g., C 1 -C 8 alkyl, C1- C 6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 12 is an unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl).
  • R 12 is R 49 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 12 is R 49 -substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 12 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 12 is R 49 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl). In embodiments, R 12 is R 49 -substituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl).
  • R 12 is an unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl).
  • R 12 is R 49 -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 12 is R 49 -substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 12 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 12 is R 49 -substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl). In embodiments, R 12 is R 49 -substituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl). In embodiments, R 12 is an unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl).
  • R 12 is R 49 -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R 12 is R 49 -substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R 12 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • Ring A is a substituted (e.g., R 8 -substituted) or unsubstituted C 3 -C 6 cycloalkylene, substituted (e.g., R 8 -substituted) or unsubstituted 3 to 6 membered
  • Ring A is a substituted (e.g., R 8 -substituted) or unsubstituted 5 to 6 membered heteroarylene. In embodiments, Ring A is a substituted (e.g., R 8 -substituted) or unsubstituted oxazolylene.
  • Ring A is a substituted (e.g., R 8 -substituted) or unsubstituted cycloalkylene. In embodiments, Ring A is a substituted (e.g., R 8 -substituted) or unsubstituted heterocycloalkylene. In embodiments, Ring A is a substituted (e.g., R 8 -substituted) or unsubstituted arylene. In embodiments, Ring A is a substituted (e.g., R 8 -substituted) or unsubstituted heteroarylene.
  • Ring A is a substituted (e.g., R 8 -substituted) or unsubstituted (C 3 -C 10 ) cycloalkylene, substituted (e.g., R 8 -substituted) or unsubstituted 3 to 10 membered heterocycloalkylene, substituted (e.g., R 8 -substituted) or unsubstituted (C 6 -C 10 ) arylene, or substituted (e.g., R 8 -substituted) or unsubstituted 5 to 10 membered heteroarylene.
  • Ring A is a substituted (e.g., R 8 -substituted) or unsubstituted (C3-C10) cycloalkylene. In embodiments, Ring A is substituted (e.g., R 8 -substituted) or unsubstituted 3 to 10 membered heterocycloalkylene. In embodiments, Ring A is a substituted (e.g., R 8 - substituted) or unsubstituted (C 6 -C 10 ) arylene. In embodiments, Ring A is a substituted (e.g., R 8 -substituted) or unsubstituted 5 to 10 membered heteroarylene.
  • Ring A is a substituted (e.g., R 8 -substituted) or unsubstituted (C 3 -C 6 ) cycloalkylene. In embodiments, Ring A is a substituted (e.g., R 8 -substituted) or unsubstituted 3 to 6 membered
  • Ring A is a substituted (e.g., R 8 -substituted) or unsubstituted phenylene. In embodiments, Ring A is a substituted (e.g., R 8 -substituted) or unsubstituted naphthylene. In embodiments, Ring A is a substituted (e.g., R 8 -substituted) or unsubstituted 5 to 9 membered heteroarylene. In embodiments, Ring A is a substituted (e.g., R 8 -substituted) or unsubstituted 5 to 6 membered heteroarylene.
  • Ring A is an unsubstituted 5 to 6 membered heteroarylene. In embodiments, Ring A is a substituted (e.g., R 8 -substituted) or unsubstituted 5 membered heteroarylene. In embodiments, Ring A is a substituted (e.g., R 8 -substituted) 5 membered heteroarylene. In embodiments, Ring A is an unsubstituted 5 membered heteroarylene.
  • Ring A is R 8 -substituted or unsubstituted (C 3 -C 10 ) cycloalkylene, R 8 -substituted or unsubstituted 5 to 10 membered heterocycloalkylene, R 8 -substituted or unsubstituted (C 6 -C 10 ) arylene, or R 8 -substituted or unsubstituted 5 to 10 membered heteroarylene.
  • Ring A is R 8 -substituted or unsubstituted (C3-C10) cycloalkylene or R 8 -substituted or unsubstituted 5 to 10 membered heterocycloalkylene. In embodiments, Ring A is R 8 -substituted or unsubstituted (C3-C10) cycloalkylene. In embodiments, Ring A is R 8 -substituted or unsubstituted 3 to 10 membered
  • Ring A is R 8 -substituted or unsubstituted (C 6 -C 10 ) arylene. In embodiments, Ring A is R 8 -substituted or unsubstituted 5 to 10 membered heteroarylene. In embodiments, Ring A is R 8 -substituted or unsubstituted (C 3 -C 6 ) cycloalkylene. In embodiments, Ring A is R 8 -substituted or unsubstituted 3 to 6 membered heterocycloalkylene. In embodiments, Ring A is R 8 -substituted or unsubstituted phenylene.
  • Ring A is R 8 -substituted or unsubstituted naphthylene. In embodiments, Ring A is R 8 -substituted or unsubstituted 5 to 9 membered heteroarylene. In embodiments, Ring A is R 8 -substituted or unsubstituted 5 to 6 membered heteroarylene.
  • Ring A is R 8 -substituted or unsubstituted thienylene. In embodiments, Ring A is R 8 -substituted or unsubstituted phenylene. In embodiments, Ring A is R 8 -substituted or unsubstituted benzothienylene. In embodiments, Ring A is R 8 -substituted or unsubstituted naphthylene. In embodiments, Ring A is R 8 -substituted or unsubstituted benzofuranylene. In embodiments, Ring A is R 8 -substituted or unsubstituted furanylene.
  • Ring A is R 8 -substituted or unsubstituted pyrrolylene. In embodiments, Ring A is R 8 -substituted or unsubstituted oxazolylene. In embodiments, Ring A is R 8 -substituted or unsubstituted oxadiazolylene. In embodiments, Ring A is R 8 -substituted or unsubstituted triazolylene. In embodiments, Ring A is R 8 -substituted or unsubstituted thiazolylene.
  • Ring A is a substituted (e.g., R 8 -substituted) cycloalkylene. In embodiments, Ring A is a substituted (e.g., R 8 -substituted) heterocycloalkylene. In embodiments, Ring A is a substituted (e.g., R 8 -substituted) arylene. In embodiments, Ring A is a substituted (e.g., R 8 -substituted) heteroarylene.
  • Ring A is a substituted (e.g., R 8 -substituted) (C3-C10) cycloalkylene, substituted (e.g., R 8 -substituted) 3 to 10 membered heterocycloalkylene, substituted (e.g., R 8 -substituted) (C 6 -C 10 ) arylene, or substituted (e.g., R 8 -substituted) 5 to 10 membered heteroarylene.
  • Ring A is a substituted (e.g., R 8 -substituted) (C 3 -C 10 ) cycloalkylene.
  • Ring A is a substituted (e.g., R 8 -substituted) 3 to 10 membered heterocycloalkylene. In embodiments, Ring A is a substituted (e.g., R 8 -substituted) (C 6 -C 10 ) arylene. In embodiments, Ring A is a substituted (e.g., R 8 -substituted) 5 to 10 membered heteroarylene. In embodiments, Ring A is a substituted (e.g., R 8 -substituted) (C 3 -C 6 ) cycloalkylene.
  • Ring A is a substituted (e.g., R 8 -substituted) 3 to 6 membered heterocycloalkylene. In embodiments, Ring A is a substituted (e.g., R 8 -substituted) phenylene. In embodiments, Ring A is a substituted (e.g., R 8 -substituted) naphthylene. In embodiments, Ring A is a substituted (e.g., R 8 -substituted) 5 to 9 membered heteroarylene. In embodiments, Ring A is a substituted (e.g., R 8 -substituted) 5 to 6 membered heteroarylene.
  • Ring A is R 8 - substituted (C 3 -C 10 ) cycloalkylene, R 8 -substituted 5 to 10 membered heterocycloalkylene, R 8 - substituted (C 6 -C 10 ) arylene, or R 8 -substituted 5 to 10 membered heteroarylene.
  • Ring A is R 8 -substituted (C 3 -C 10 ) cycloalkylene or R 8 -substituted 5 to 10 membered heterocycloalkylene.
  • Ring A is R 8 -substituted (C3-C10) cycloalkylene.
  • Ring A is R 8 -substituted 3 to 10 membered
  • Ring A is R 8 -substituted (C 6 -C 10 ) arylene. In embodiments, Ring A is R 8 -substituted 5 to 10 membered heteroarylene. In embodiments, Ring A is R 8 -substituted (C 3 -C 6 ) cycloalkylene. In embodiments, Ring A is R 8 -substituted 3 to 6 membered heterocycloalkylene. In embodiments, Ring A is R 8 -substituted phenylene. In embodiments, Ring A is R 8 -substituted naphthylene. In embodiments, Ring A is R 8 - substituted 5 to 9 membered heteroarylene.
  • Ring A is R 8 -substituted 5 to 6 membered heteroarylene. In embodiments, Ring A is R 8 -substituted thienylene. In embodiments, Ring A is R 8 -substituted phenylene. In embodiments, Ring A is R 8 -substituted benzothienylene. In embodiments, Ring A is R 8 -substituted naphthylene. In embodiments, Ring A is R 8 -substituted benzofuranylene. In embodiments, Ring A is R 8 -substituted furanylene. In embodiments, Ring A is R 8 -substituted pyrrolylene.
  • Ring A is R 8 -substituted oxazolylene. In embodiments, Ring A is R 8 -substituted oxadiazolylene. In embodiments, Ring A is R 8 -substituted triazolylene. In embodiments, Ring A is R 8 - substituted thiazolylene.
  • Ring A is an unsubstituted cycloalkylene. In embodiments, Ring A is an unsubstituted heterocycloalkylene. In embodiments, Ring A is an unsubstituted arylene. In embodiments, Ring A is an unsubstituted heteroarylene. In embodiments, Ring A is an unsubstituted (C3-C10) cycloalkylene, unsubstituted 3 to 10 membered
  • Ring A is an unsubstituted (C3-C10) cycloalkylene. In embodiments, Ring A is an unsubstituted 3 to 10 membered heterocycloalkylene. In embodiments, Ring A is an unsubstituted (C 6 -C 10 ) arylene. In embodiments, Ring A is an unsubstituted 5 to 10 membered heteroarylene. In embodiments, Ring A is an unsubstituted (C 3 -C 6 ) cycloalkylene. In embodiments, Ring A is an unsubstituted 3 to 6 membered heterocycloalkylene. In embodiments, Ring A is an unsubstituted phenylene. In
  • Ring A is an unsubstituted naphthylene. In embodiments, Ring A is an unsubstituted 5 to 9 membered heteroarylene. In embodiments, Ring A is an unsubstituted 5 to 6 membered heteroarylene. In embodiments, Ring A is an unsubstituted (C3-C10) cycloalkylene, unsubstituted 5 to 10 membered heterocycloalkylene, unsubstituted (C 6 -C 10 ) arylene, or unsubstituted 5 to 10 membered heteroarylene.
  • Ring A is an unsubstituted (C 3 -C 10 ) cycloalkylene or unsubstituted 5 to 10 membered heterocycloalkylene. In embodiments, Ring A is an unsubstituted (C3-C10) cycloalkylene. In embodiments, Ring A is an unsubstituted 3 to 10 membered heterocycloalkylene. In embodiments, Ring A is an unsubstituted (C 6 -C 10 ) arylene. In embodiments, Ring A is an unsubstituted 5 to 10 membered heteroarylene. In embodiments, Ring A is unsubstituted (C 3 -C 6 ) cycloalkylene.
  • Ring A is an unsubstituted 3 to 6 membered heterocycloalkylene. In embodiments, Ring A is an unsubstituted phenylene. In embodiments, Ring A is an unsubstituted naphthylene. In embodiments, Ring A is an unsubstituted 5 to 9 membered heteroarylene. In embodiments, Ring A is an unsubstituted 5 to 6 membered heteroarylene. In embodiments, Ring A is an unsubstituted thienylene. In embodiments, Ring A is an unsubstituted phenylene. In embodiments, Ring A is an unsubstituted benzothienylene.
  • Ring A is an unsubstituted naphthylene. In embodiments, Ring A is an unsubstituted benzofuranylene. In embodiments, Ring A is an unsubstituted furanylene. In embodiments, Ring A is an unsubstituted pyrrolylene. In embodiments, Ring A is an unsubstituted oxazolylene. In embodiments, Ring A is an unsubstituted phenylene. In embodiments, Ring A is an unsubstituted oxadiazolylene. In embodiments, Ring A is an unsubstituted triazolylene. In embodiments, Ring A is an unsubstituted thiazolylene.
  • Ring A is C 3 -C 6 cycloalkylene, 3 to 6 membered
  • Ring A is C 3 -C 6 cycloalkylene. In embodiments, Ring A is 3 to 6 membered heterocycloalkylene.
  • Ring A is C 6 -C 10 arylene or 5 to 10 membered heteroarylene. In embodiments, Ring A is C 6 -C 10 arylene or 5 to 10 membered heteroarylene. In embodiments, Ring A is C 6 -C 10 arylene. In embodiments, Ring A is phenylene. In embodiments, Ring A is naphthylene. In embodiments, Ring A is 5 to 10 membered heteroarylene. In embodiments, Ring A is 5 to 6 membered heteroarylene. In embodiments, Ring A is thienylene. In embodiments, Ring A is furanylene. In embodiments, Ring A is pyrrolylene. In
  • Ring A is imidazolylene. In embodiments, Ring A is pyrazolylene. In embodiments, Ring A is oxazolylene. In embodiments, Ring A is isoxazolylene. In embodiments, Ring A is thaizolylene. In embodiments, Ring A is pyridinylene. In embodiments, Ring A is pyridylene. In embodiments, Ring A is pyrazinylene. In embodiments, Ring A is pyrimidinylene. In embodiments, Ring A is pyridazinylene. In embodiments, Ring A is 1,2,3-triazinylene. In embodiments, Ring A is 1,2,4-triazinylene. In embodiments, Ring A is 1,3,5-triazinylene.
  • Ring A is a substituted (e.g., R 8 -substituted) C 6 -C 10 arylene or substituted (e.g., R 8 -substituted) 5 to 10 membered heteroarylene. In embodiments, Ring A is a substituted (e.g., R 8 -substituted) C 6 -C 10 arylene or substituted (e.g., R 8 -substituted) 5 to 10 membered heteroarylene. In embodiments, Ring A is a substituted (e.g., R 8 -substituted) C6- C 10 arylene.
  • Ring A is substituted (e.g., R 8 -substituted) phenylene. In embodiments, Ring A is a substituted (e.g., R 8 -substituted) naphthylene. In embodiments, Ring A is a substituted (e.g., R 8 -substituted) 5 to 10 membered heteroarylene. In embodiments, Ring A is a substituted (e.g., R 8 -substituted) 5 to 6 membered heteroarylene. In embodiments, Ring A is a substituted (e.g., R 8 -substituted) thienylene.
  • Ring A is a substituted (e.g., R 8 -substituted) furanylene. In embodiments, Ring A is a substituted (e.g., R 8 -substituted) pyrrolylene. In embodiments, Ring A is a substituted (e.g., R 8 -substituted) imidazolylene. In embodiments, Ring A is a substituted (e.g., R 8 -substituted) pyrazolylene. In embodiments, Ring A is a substituted (e.g., R 8 -substituted) oxazolylene.
  • Ring A is a substituted (e.g., R 8 -substituted) isoxazolylene. In embodiments, Ring A is a substituted (e.g., R 8 -substituted) thaizolylene. In embodiments, Ring A is a substituted (e.g., R 8 -substituted) pyridinylene. In embodiments, Ring A is a substituted (e.g., R 8 -substituted) pyridylene. In embodiments, Ring A is a substituted (e.g., R 8 -substituted) pyrazinylene.
  • Ring A is a substituted (e.g., R 8 -substituted) pyrimidinylene. In embodiments, Ring A is a substituted (e.g., R 8 -substituted) pyridazinylene.
  • Ring A is a substituted (e.g., R 8 -substituted) 1,2,3-triazinylene. In embodiments, Ring A is a substituted (e.g., R 8 -substituted) 1,2,4-triazinylene. In embodiments, Ring A is a substituted (e.g., R 8 -substituted) 1,3,5-triazinylene.
  • Ring A is an unsubstituted C 6 -C 10 arylene or unsubstituted 5 to 10 membered heteroarylene. In embodiments, Ring A is an unsubstituted C 6 -C 10 arylene or unsubstituted 5 to 10 membered heteroarylene. In embodiments, Ring A is an unsubstituted C 6 -C 10 arylene. In embodiments, Ring A is an unsubstituted phenylene. In embodiments, Ring A is an unsubstituted naphthylene. In embodiments, Ring A is an unsubstituted 5 to 10 membered heteroarylene.
  • Ring A is an unsubstituted 5 to 6 membered heteroarylene. In embodiments, Ring A is an unsubstituted thienylene. In embodiments, Ring A is an unsubstituted furanylene. In embodiments, Ring A is an unsubstituted pyrrolylene. In embodiments, Ring A is an unsubstituted imidazolylene. In embodiments, Ring A is an unsubstituted pyrazolylene. In embodiments, Ring A is an unsubstituted oxazolylene. In embodiments, Ring A is an unsubstituted isoxazolylene. In embodiments, Ring A is an unsubstituted thaizolylene.
  • Ring A is an unsubstituted pyridinylene. In embodiments, Ring A is an unsubstituted pyridylene. In embodiments, Ring A is an unsubstituted pyrazinylene. In embodiments, Ring A is an unsubstituted
  • Ring A is an unsubstituted pyridazinylene.
  • Ring A is an unsubstituted 1,2,3-triazinylene. In embodiments, Ring A is an unsubstituted 1,2,4-triazinylene. In embodiments, Ring A is an unsubstituted 1,3,5- triazinylene. [0402] In embodiments, Ring A is a 4 to 8 membered heterocycloalkylene.
  • Ring A is a 4 membered heterocycloalkylene. In embodiments, Ring A is a 5 membered heterocycloalkylene. In embodiments, Ring A is a 6 membered
  • Ring A is a 7 membered heterocycloalkylene. In embodiments, Ring A is an 8 membered heterocycloalkylene. In embodiments, Ring A is a 4 to 6 membered heterocycloalkylene. In embodiments, Ring A is azetidinylene.
  • Ring A is a substituted (e.g., R 8 -substituted) or unsubstituted heterocycloalkylene. In embodiments, Ring A is a substituted (e.g., R 8 -substituted) heterocycloalkylene. In embodiments, Ring A is an unsubstituted heterocycloalkylene. In embodiments, Ring A is a substituted (e.g., R 8 -substituted) or unsubstituted 3 to 10 membered heterocycloalkylene. In embodiments, Ring A is a substituted (e.g., R 8 - substituted) 3 to 10 membered heterocycloalkylene.
  • Ring A is an unsubstituted 3 to 10 membered heterocycloalkylene. In embodiments, Ring A is a R 6 - substituted or unsubstituted 5 to 10 membered heterocycloalkylene. In embodiments, Ring A is R 6 -substituted 5 to 10 membered heterocycloalkylene. In embodiments, Ring A is an unsubstituted 5 to 10 membered heterocycloalkylene.
  • Ring A is a substituted (e.g., R 8 -substituted) or unsubstituted 3 membered heterocycloalkylene. In embodiments, Ring A is a substituted (e.g., R 8 - substituted) or unsubstituted 4 membered heterocycloalkylene. In embodiments, Ring A is a substituted (e.g., R 8 -substituted) or unsubstituted 5 membered heterocycloalkylene. In embodiments, Ring A is a substituted (e.g., R 8 -substituted) or unsubstituted 6 membered heterocycloalkylene.
  • Ring A is a substituted (e.g., R 8 -substituted) 3 membered heterocycloalkylene. In embodiments, Ring A is a substituted (e.g., R 8 - substituted) 4 membered heterocycloalkylene. In embodiments, Ring A is a substituted (e.g., R 8 -substituted) 5 membered heterocycloalkylene. In embodiments, Ring A is a substituted (e.g., R 8 -substituted) 6 membered heterocycloalkylene. In embodiments, Ring A is an unsubstituted 3 membered heterocycloalkylene.
  • Ring A is an unsubstituted 4 membered heterocycloalkylene. In embodiments, Ring A is an unsubstituted 5 membered heterocycloalkylene. In embodiments, Ring A is an unsubstituted 6 membered
  • Ring A is a substituted (e.g., R 8 -substituted) (i.e., R 8 -substituted) or unsubstituted aziridinylene, azirinylene, azetidinylene, dihydroazetylene, diazetidinylene, azetylene, pyrrolidinylene, pyrrolinylene, pyrrolylene, pyrazolidinylene, imidazolidinylene, pyrazolinylene, pyrazolylene, thiazolidinylene, thiazolylene, isothiazolylene, piperidinylene, piperazinylene, morpholinylene, oxazinylene, thiomorpholinylene, thiazinylene,
  • Ring A is a substituted (e.g., R 8 -substituted) (i.e., R 8 -substituted) aziridinylene, azirinylene, azetidinylene, dihydroazetylene, diazetidinylene, azetylene, pyrrolidinylene, pyrrolinylene, pyrrolylene, pyrazolidinylene, imidazolidinylene, pyrazolinylene, pyrazolylene,
  • thiazolidinylene thiazolylene, isothiazolylene, piperidinylene, piperazinylene,
  • Ring A is an
  • aziridinylene unsubstituted aziridinylene, azirinylene, azetidinylene, dihydroazetylene, diazetidinylene, azetylene, pyrrolidinylene, pyrrolinylene, pyrrolylene, pyrazolidinylene, imidazolidinylene, pyrazolinylene, pyrazolylene, thiazolidinylene, thiazolylene, isothiazolylene, piperidinylene, piperazinylene, morpholinylene, oxazinylene, thiomorpholinylene, thiazinylene,
  • decahydroquinolinylene dihydroazepinylene, azepanylene, or azocanylene.
  • Ring A is imidazolylene, pyrrolylene, pyrazolylene, triazolylene, tetrazolylene, furanylene, oxazolylene, isoxazolylene, oxadiazolylene, oxatriazolylene, thienylene, thiazolylene, isothiazolylene, pyridinylene, pyrazinylene, pyrimidinylene, pyridazinylene, or triazinylene.
  • Ring A is oxazolylene, thiazolylene, isoxazolylene, or
  • Ring A is , , , , , or . In embodiments, Ring A is . In embodiments, Ring A is . In embodiments, Ring A is . In embodiments, Ring A is . In embodiments, Ring A is . [0409] Ring A may be substituted with one R 8 . Ring A may be substituted with two optionally different R 8 substituents. Ring A may be substituted with three optionally different R 8 substituents. Ring A may be substituted with four optionally different R 8 substituents. Ring A may be substituted with five optionally different R 8 substituents. Ring A may be substituted with six optionally different R 8 substituents.
  • Ring A may be substituted with seven optionally different R 8 substituents. Ring A may be substituted with eight optionally different R 8 substituents. Ring A may be substituted with nine optionally different R 8 substituents. Ring A may be substituted with ten optionally different R 8 substituents.
  • R 37 , R 38 , R 41 , R 42 , R 45 , R 46 , R 47 , R 48 , R 49 , R 58 , R 59 , R 60 , R 61 , and R 63 are
  • R 37 , R 38 , R 41 , R 42 , R 45 , R 46 , R 47 , R 48 , R 49 , R 58 , R 59 , R 60 , R 61 , and R 62 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCI 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO3H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO
  • R 37 , R 38 , R 41 , R 42 , R 45 , R 46 , R 47 , R 48 , R 49 , R 58 , R 59 , R 60 , R 61 , and R 63 are independently halogen.
  • R 37 , R 38 , R 41 , R 42 , R 45 , R 46 , R 47 , R 48 , R 49 , R 58 , R 59 , R 60 , R 61 , and R 63 are independently unsubstituted methyl.
  • R 37 , R 38 , R 41 , R 42 , R 45 , R 46 , R 47 , R 48 , R 49 , R 58 , R 59 , R 60 , R 61 , and R 62 are independently halogen.
  • R 37 , R 38 , R 41 , R 42 , R 45 , R 46 , R 47 , R 48 , R 49 , R 58 , R 59 , R 60 , R 61 , and R 62 are independently unsubstituted methyl.
  • R 37 , R 38 , R 41 , R 42 , R 45 , R 46 , R 47 , R 48 , R 49 , R 58 , R 59 , R 60 , R 61 , and R 63 are independently unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3
  • R 37 , R 38 , R 41 , R 42 , R 45 , R 46 , R 47 , R 48 , R 49 , R 58 , R 59 , R 60 , R 61 , and R 62 are independently unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3
  • R 37 , R 38 , R 41 , R 42 , R 45 , R 46 , R 47 , R 48 , R 49 , R 58 , R 59 , R 60 , R 61 , and R 63 are independently unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl).
  • R 37 , R 38 , R 41 , R 42 , R 45 , R 46 , R 47 , R 48 , R 49 , R 58 , R 59 , R 60 , R 61 , and R 63 are independently unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 37 , R 38 , R 41 , R 42 , R 45 , R 46 , R 47 , R 48 , R 49 , R 58 , R 59 , R 60 , R 61 , and R 63 are independently unsubstituted cycloalkyl (e.g., C 3 - C8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl).
  • R 37 , R 38 , R 41 , R 42 , R 45 , R 46 , R 47 , R 48 , R 49 , R 58 , R 59 , R 60 , R 61 , and R 63 are independently unsubstituted
  • R 37 , R 38 , R 41 , R 42 , R 45 , R 46 , R 47 , R 48 , R 49 , R 58 , R 59 , R 60 , R 61 , and R 63 are independently unsubstituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl).
  • R 37 , R 38 , R 41 , R 42 , R 45 , R 46 , R 47 , R 48 , R 49 , R 58 , R 59 , R 60 , R 61 , and R 63 are independently unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 37 , R 38 , R 41 , R 42 , R 45 , R 46 , R 47 , R 48 , R 49 , R 58 , R 59 , R 60 , R 61 , and R 62 are independently unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl).
  • R 37 , R 38 , R 41 , R 42 , R 45 , R 46 , R 47 , R 48 , R 49 , R 58 , R 59 , R 60 , R 61 , and R 62 are independently unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 37 , R 38 , R 41 , R 42 , R 45 , R 46 , R 47 , R 48 , R 49 , R 58 , R 59 , R 60 , R 61 , and R 62 are independently unsubstituted cycloalkyl (e.g., C3- C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl).
  • R 37 , R 38 , R 41 , R 42 , R 45 , R 46 , R 47 , R 48 , R 49 , R 58 , R 59 , R 60 , R 61 , and R 62 are independently unsubstituted
  • R 37 , R 38 , R 41 , R 42 , R 45 , R 46 , R 47 , R 48 , R 49 , R 58 , R 59 , R 60 , R 61 , and R 62 are independently unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl).
  • R 37 , R 38 , R 41 , R 42 , R 45 , R 46 , R 47 , R 48 , R 49 , R 58 , R 59 , R 60 , R 61 , and R 62 are independently unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • the compound has the formula:
  • the compound has the formula: .
  • the compound has the formula: .
  • the compound has the formula:
  • the compound has the formula: .
  • the compound has the formula: .
  • the compound has the formula:
  • the compound has the formula:
  • R 4 is hydrogen, oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCI 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3
  • the compound has the formula:
  • R 2 is hydrogen or unsubstituted C 1 -C 3 alkyl; R 10 , R 11 , and R 12 are as described herein; R 4 is hydrogen, oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 , -NHSO
  • R 7 is hydrogen, -CH 2 COOH, -CONH 2 , -OH, -SH, -NO 2 , -NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted substituted or unsubstituted
  • Ring A is cycloalkylene, heterocycloalkylene, arylene, or hetero
  • heterocycloalkyl substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • the compound has the formula:
  • Y, L 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , Ring A, R 8 , z8, R 10 , R 11 , and R 12 are as described herein, including in embodiments.
  • the compound has the formula: R 4 is as described herein, including in
  • L 2 is substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.
  • R 33A is hydrogen or any substituent of R 33 described herein, including in any aspect, embodiment, example, figure, or claim.
  • the compound has the formula:
  • R 4 is as described herein, including in embodiments.
  • L 2 is substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.
  • R 33A is hydrogen oxo, halogen, -CCI 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCI 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO3H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCI 2 ,
  • R 4 is hydrogen, oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3
  • a substituted R 4 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 4 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • R 4 when R 4 is substituted, it is substituted with at least one substituent group.
  • R 4 when R 4 is substituted, it is substituted with at least one size-limited substituent group.
  • R 4 when R 4 is substituted, it is substituted with at least one lower substituent group.
  • R 4 is hydrogen, oxo, halogen, -CCI 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCI 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO3H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 ,
  • R 4 is -CCI 3 . In embodiments, R 4 is -CBr 3 . In embodiments, R 4 is -CF 3 . In embodiments, R 4 is -CI 3 . In embodiments, R 4 is -CHCl 2 . In embodiments, R 4 is -CHBr 2 . In embodiments, R 4 is -CHF 2 . In embodiments, R 4 is -CHI 2 . In embodiments, R 4 is -CH 2 Cl. In embodiments, R 4 is -CH 2 Br. In embodiments, R 4 is -CH 2 F. In embodiments, R 4 is -CH 2 I. In embodiments, R 4 is -CN. In embodiments, R 4 is -OH.
  • R 4 is -NH 2 . In embodiments, R 4 is -COOH. In embodiments, R 4 is -CONH 2 . In embodiments, R 4 is -NO 2 . In embodiments, R 4 is -SH. In embodiments, R 4 is -SO3H. In embodiments, R 4 is -SO 4 H. In embodiments, R 4 is -SO 2 NH 2 . In embodiments, R 4 is -NHNH 2 . In embodiments, R 4 is -ONH 2 . In embodiments, R 4 is -NHC(O)NHNH 2 . In embodiments, R 4 is -NHC(O)NH 2 . In embodiments, R 4 is -NHSO 2 H.
  • R 4 is -NHC(O)H. In embodiments, R 4 is -NHC(O)OH. In embodiments, R 4 is -NHOH. In embodiments, R 4 is -OCCl 3 . In embodiments, R 4 is -OCF 3 . In embodiments, R 4 is -OCBr 3 . In embodiments, R 4 is -OCI 3 . In embodiments, R 4 is -OCHCl 2 . In embodiments, R 4 is -OCHBr 2 . In embodiments, R 4 is -OCHI 2 . In embodiments, R 4 is -OCHF 2 . In embodiments, R 4 is -OCH 2 Cl. In embodiments, R 4 is -OCH 2 Br.
  • R 4 is -OCH 2 I. In embodiments, R 4 is -OCH 2 F. In embodiments, R 4 is -N 3 . In embodiments, R 4 is hydrogen or substituted or unsubstituted alkyl. In embodiments, R 4 is hydrogen or a substituted or unsubstituted C 1 -C 6 alkyl. In embodiments, R 4 is -OPO3H. In embodiments, R 4 is -OSO3H.
  • R 4 is a substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 4 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl.
  • R 4 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) alkyl.
  • R 4 is unsubstituted alkyl.
  • R 4 is a substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ).
  • R 4 is a substituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ). In embodiments, R 4 is an unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C1-C2).
  • R 4 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl.
  • R 4 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroalkyl.
  • R 4 is an unsubstituted heteroalkyl.
  • R 4 is a substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 4 is a substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R 4 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). [0433] In embodiments, R 4 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl.
  • R 4 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) cycloalkyl.
  • R 4 is an unsubstituted cycloalkyl.
  • R 4 is a substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C 5 -C 6 ).
  • R 4 is a substituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 , or C 5 -C 6 ).
  • R 4 is an unsubstituted cycloalkyl (e.g., C 3 - C8, C 3 -C 6 , C4-C6, or C 5 -C 6 ).
  • R 4 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl.
  • R 4 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heterocycloalkyl.
  • R 4 is an unsubstituted heterocycloalkyl.
  • R 4 is a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R 4 is a substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R 4 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R 4 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted aryl.
  • R 4 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) aryl.
  • R 4 is an unsubstituted aryl.
  • R 4 is a substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl).
  • R 4 is a substituted aryl (e.g., C 6 -C 10 or phenyl).
  • R 4 is an unsubstituted aryl (e.g., C 6 -C 10 or phenyl).
  • R 4 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl.
  • R 4 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroaryl.
  • R 4 is an unsubstituted heteroaryl.
  • R 4 is a substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 4 is a substituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R 4 is an unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 4 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 4 is hydrogen, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 4 is hydrogen or R 34 -substituted or unsubstituted alkyl (e.g., C 1 - C8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), R 34 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 34 - substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl), R 34 -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
  • R 4 is R 34 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 - C6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 4 is R 34 -substituted alkyl (e.g., C 1 -C 8 alkyl, C1- C 6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 4 is an unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 - C6 alkyl, or C 1 -C 4 alkyl).
  • R 4 is R 34 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 4 is R 34 -substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 4 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 4 is R 34 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl). In embodiments, R 4 is R 34 -substituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl).
  • R 4 is an unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl).
  • R 4 is R 34 -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 4 is R 34 -substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 4 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 4 is R 34 -substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl). In embodiments, R 4 is R 34 -substituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl). In embodiments, R 4 is an unsubstituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl).
  • R 4 is R 34 -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R 4 is R 34 -substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R 4 is an
  • unsubstituted heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R 34 is independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO3H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCI
  • R 62 is independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OC
  • R 4 is a substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 4 is a substituted or unsubstituted C 1 -C 6 alkyl.
  • R 4 is an unsubstituted C 1 -C 3 alkyl.
  • R 4 is an unsubstituted methyl.
  • R 34 is halogen, R 62 -substituted or unsubstituted alkyl, R 62 -substituted or
  • R 62 unsubstituted heteroalkyl, R 62 -substituted or unsubstituted cycloalkyl, R 62 -substituted or unsubstituted heterocycloalkyl, R 62 -substituted or unsubstituted aryl, or R 62 -substituted or unsubstituted heteroaryl.
  • R 34 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted aryl, or substituted (e.g., substituted with a substituent group, a
  • R 34 is an unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.
  • R 34 is R 62 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C1- C 6 alkyl, or C 1 -C 4 alkyl), R 62 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 62 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl), R 62 - substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membere
  • R 34 is R 62 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C1- C 6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 34 is R 62 -substituted alkyl (e.g., C 1 -C 8 alkyl, C 1 - C6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 34 is an unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl).
  • R 34 is R 62 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 34 is R 62 -substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 34 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 34 is R 62 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl). In embodiments, R 34 is R 62 -substituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl).
  • R 34 is an unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl).
  • R 34 is R 62 -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 34 is R 62 -substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 34 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 34 is R 62 -substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl). In embodiments, R 34 is R 62 -substituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl). In embodiments, R 34 is an unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl).
  • R 34 is R 62 -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R 34 is R 62 -substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R 34 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • L 2 is substituted or unsubstituted alkylene (e.g., C 1 -C 8 , C 1 -C 6 , C1- C 4 , or C 1 -C 2 ), substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or 2 to 3 membered), substituted or unsubstituted cycloalkylene (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 , or C 5 -C 6 ), substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted arylene (e.g., C 6 -C 10 or phenylene), or substituted or unsubstituted ary
  • a substituted L 2 e.g., substituted alkylene, substituted
  • heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted L 2 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • L 2 when L 2 is substituted, it is substituted with at least one substituent group.
  • when L 2 is substituted it is substituted with at least one size-limited substituent group.
  • L 2 when L 2 is substituted, it is substituted with at least one lower substituent group.
  • L 2 is substituted or unsubstituted C 1 -C 8 alkylene, substituted or unsubstituted 2 to 8 membered heteroalkylene, substituted or unsubstituted C 3 -C 8 cycloalkylene, substituted or unsubstituted 3 to 8 membered heterocycloalkylene, substituted or unsubstituted C 6 -C 10 arylene, or substituted or unsubstituted 5 to 10 membered heteroarylene.
  • L 2 is substituted or unsubstituted C 1 -C 8 alkylene, or substituted or unsubstituted 2 to 8 membered heteroalkylene.
  • L 2 is R 35 -substituted or unsubstituted C 1 -C 8 alkylene, R 35 - substituted or unsubstituted 2 to 8 membered heteroalkylene, R 35 -substituted or unsubstituted C 3 -C 8 cycloalkylene, R 35 -substituted or unsubstituted 3 to 8 membered heterocycloalkylene, R 35 -substituted or unsubstituted C 6 -C 10 arylene, or R 35 -substituted or unsubstituted 5 to 10 membered heteroarylene.
  • L 2 is R 35 -substituted or unsubstituted C 1 -C 8 alkylene, or R 35 -substituted or unsubstituted 2 to 8 membered heteroalkylene.
  • R 35 is independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO3H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCI
  • R 35 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted aryl, or substituted (e.g., substituted with a substituent group, a
  • R 35 is an unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.
  • R 35 is R 60 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C1- C 6 alkyl, or C 1 -C 4 alkyl), R 60 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 60 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl), R 60 - substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocyclo
  • R 35 is R 60 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C1- C 6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 35 is R 60 -substituted alkyl (e.g., C 1 -C 8 alkyl, C 1 - C6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 35 is an unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl).
  • R 35 is R 60 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 35 is R 60 -substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 35 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 35 is R 60 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl). In embodiments, R 35 is R 60 -substituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl).
  • R 35 is an unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl).
  • R 35 is R 60 -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 35 is R 60 -substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 35 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 35 is R 60 -substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl). In embodiments, R 35 is R 60 -substituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl). In embodiments, R 35 is an unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl).
  • R 35 is R 60 -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R 35 is R 60 -substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R 35 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 33A is hydrogen oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI 3 , -OCF 3 , -OCBr 3 , -OCI 3 ,
  • a substituted R 33A (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 33A is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • R 33A when R 33A is substituted, it is substituted with at least one substituent group.
  • R 33A when R 33A is substituted, it is substituted with at least one size-limited substituent group.
  • R 33A when R 33A is substituted, it is substituted with at least one lower substituent group.
  • the compound has the formula:
  • the compound has the formula:
  • the compound has the formula:
  • the compound has the formula:
  • the compound has the formula:
  • the compound has the formula:
  • the compound has the formula:
  • the compound has the formula:
  • the compound has the formula:
  • the compound has the formula:
  • the compound has the formula:
  • the compound has the formula:
  • the compound does not have the formula:
  • the compound does not have the formula:
  • the compound has the formula:
  • the compound has the formula:
  • the compound has the formula:
  • the compound has the formula:
  • the compound has the formula:
  • the compound has the formula: . In embodiments, the compound has the formula:
  • the compound has the formula: In embodiments, the compound
  • the compound has the formula:
  • the compound has the
  • the compound has the formula: In embodiments, the compound has the formula:
  • the compound has
  • the compound has the formula: . In embodiments, the compound has the formula:
  • the compound has the formula: In embodiments, the
  • the compound has the formula: In embodiments, the compound has the formula:
  • the compound has
  • the compound has the formula: In embodiments, the compound has the formula: . In embodiments, the compound has the formula:
  • the compound has the formula: In embodiments, the compound has the formula:
  • the compound has the formula: . In embodiments, the
  • the compound has the formula: S . In embodiments, the compound has the formula:
  • the compound has
  • N compound has the formula: HN .
  • the compound has the formula: .
  • the compound has the formula:
  • the compound has the formula: . In embodiments, the compound has the formula:
  • the compound has the formula: . In embodiments, the
  • the compound has the formula: . In embodiments, the compound has the formula:
  • Y, L 1 , R 2 , R 3 , R 5 , R 6 , R 7 , Ring A, R 8 , z8, R 10 , R 11 , and R 12 are as described herein.
  • the compound has the formula: .
  • Y, L 1 , R 2 , R 3 , R 5 , R 6 , R 7 , Ring A, R 8 , z8, R 10 , R 11 , and R 12 are as described herein, including in embodiments.
  • the compound has the formula:
  • the compound has the formula:
  • the compound is useful as a comparator compound.
  • the comparator compound can be used to assess the activity of a test compound as set forth in an assay described herein (e.g., in the Examples section, figures, or tables).
  • the compound is a compound described herein (e.g., in the Compounds section, Examples Section, Methods Section, or in a claim, table, or figure).
  • a pharmaceutical composition including a compound described herein and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition includes an effective amount of the compound.
  • the pharmaceutical composition includes a therapeutically effective amount of the compound.
  • the pharmaceutical composition includes a second agent.
  • the pharmaceutical composition includes a second agent in a therapeutically effective amount.
  • the second agent is a Group A streptogramin.
  • the second agent is a Group B streptogramin.
  • the second agent is an agent for treating an infectious disease (e.g., bacterial infection).
  • the second agent is an agent for treating a group A streptococcus infection (e.g.,
  • the second agent is an agent for treating a gram-positive or a gram-negative bacterial infection. In embodiments, the second agent is an agent for treating a gram-positive bacterial infection. In embodiments, the second agent is an agent for treating a Staphylococcus aureus infection. In embodiments, the second agent is an agent for treating a gram-negative bacterial infection. In embodiments, the second agent is an agent for treating an infection associated with S. aureus, E. facium, E. faecalis, K.
  • the second agent is VM1.
  • the second agent is a derivative of VM1.
  • the second agent is an agent that binds a ribosome (e.g., bacterial ribosome) at the same binding site as VM1.
  • the second agent is an agent that competes with VM1 for binding to the ribosome (e.g., bacterial ribosome).
  • the second agent is VM2.
  • the second agent is a derivative of VM2.
  • the second agent is an agent that binds a ribosome (e.g., bacterial ribosome) at the same binding site as VM2. In embodiments, the second agent is an agent that competes with VM2 for binding to the ribosome (e.g., bacterial ribosome). In embodiments, the second agent is VS1. In embodiments, the second agent is bound to a ribosome (e.g., a bacterial ribosome). In embodiments, the second agent is a derivative of VS1. In embodiments, the second agent is an agent that binds a ribosome (e.g., bacterial ribosome) at the same binding site as VS1. In embodiments, the second agent is an agent that competes with VS1 for binding to the ribosome (e.g., bacterial ribosome).
  • the second agent is an agent that competes with VS1 for binding to the ribosome (e.g., bacterial ribosome).
  • a method of treating an infectious disease including administering to a subject in need thereof an effective amount of a compound described herein.
  • the method includes administering to a subject in need thereof a therapeutically effective amount of a compound described herein.
  • the infectious disease is a bacterial infection.
  • the infectious disease is a group A streptococcus infection (e.g., Streptococcus pyogenes infection).
  • the infectious disease is a gram-positive or a gram-negative bacterial infection.
  • the infectious disease is a gram-positive bacterial infection.
  • the infectious disease is a Staphylococcus aureus infection.
  • the infectious disease is a gram-negative bacterial infection.
  • the infectious disease is an infection associated with S. aureus, E. facium, E. faecalis, K. pneumonoiaea, H. influenzaea, or P.
  • the infectious disease is a S. aureus, E. facium, E. faecalis, K. pneumonoiaea, H. influenzaea, or P. aeruginosa infection.
  • the treatment includes inhibiting bacterial growth. In embodiments, the treatment reduces bacterial reproduction, relative to a control. In embodiments, the treatment does not kill the bacterial cell.
  • the infectious disease is a bacteria-associated disease (e.g., actinomycosis, anthrax, abscesses in tissues (e.g., mouth in gastrointestinal tract, pelvic cavity, or lungs), whooping cough, lyme disease, brucellosis, enteritis, Guillain-Barre syndrome, pneumonia, conjunctivitis, trachoma, botulism, pseudomembranous colitis, food poisoning, tetanus, diphtheria, ehrlichiosis, bacterial endocarditis, urinary tract infection, diarrhea, meningitis (e.g., bacterial meningitis), sepsis, fever, tularemia, bronchitis, peptic ulcer, gastritis, Legionnaire’s disease, Pontiac fever, leptospirosis, listeriosis, leprosy, gonorrhea, opthalmia, nocardiosis, typhoid fever,
  • the bacteria-associated disease is actinomycosis, anthrax, abscesses in tissues (e.g., mouth in gastrointestinal tract, pelvic cavity, or lungs), whooping cough, lyme disease, brucellosis, enteritis, Guillain-Barre syndrome, pneumonia, conjunctivitis, trachoma, botulism, pseudomembranous colitis, food poisoning, tetanus, diphtheria, ehrlichiosis, bacterial endocarditis, urinary tract infection, diarrhea, meningitis (e.g., bacterial meningitis), sepsis, fever, tularemia, bronchitis, peptic ulcer, gastritis, Legionnaire’s disease, Pontiac fever, leptospirosis, listeriosis, leprosy, gonorrhea, opthalmia, nocardiosis, typhoid fever, salmonellosis, shigellosis
  • the bacteria-associated disease is actinomycosis. In embodiments, the bacteria associated disease is anthrax. In embodiments, the bacteria-associated disease is abscesses in tissues (e.g., mouth in gastrointestinal tract, pelvic cavity, or lungs). In embodiments, the bacteria-associated disease is whooping cough. In embodiments, the bacteria-associated disease is lyme disease. In embodiments, the bacteria-associated disease is brucellosis. In embodiments, the bacteria-associated disease is enteritis. In embodiments, the bacteria-associated disease is Guillain-Barre syndrome. In embodiments, the bacteria- associated disease is pneumonia. In embodiments, the bacteria-associated disease is conjunctivitis. In embodiments, the bacteria-associated disease is trachoma. In
  • the bacteria-associated disease is botulism. In embodiments, the bacteria- associated disease is pseudomembranous colitis. In embodiments, the bacteria-associated disease is food poisoning. In embodiments, the bacteria-associated disease is tetanus. In embodiments, the bacteria-associated disease is diphtheria. In embodiments, the bacteria-associated disease is ehrlichiosis. In embodiments, the bacteria-associated disease is bacterial endocarditis. In embodiments, the bacteria-associated disease is urinary tract infection. In embodiments, the bacteria-associated disease is diarrhea. In embodiments, the bacteria- associated disease is meningitis (e.g., bacterial meningitis). In embodiments, the bacteria- associated disease is sepsis. In embodiments, the bacteria-associated disease is fever.
  • the bacteria-associated disease is botulism. In embodiments, the bacteria- associated disease is pseudomembranous colitis. In embodiments, the bacteria-associated disease is food poisoning. In embodiments, the bacteria-associated disease is tetanus. In embodiments,
  • the bacteria-associated disease is tularemia. In embodiments, the bacteria- associated disease is bronchitis. In embodiments, the bacteria-associated disease is peptic ulcer. In embodiments, the bacteria-associated disease is gastritis. In embodiments, the bacteria-associated disease is Legionnaire’s disease. In embodiments, the bacteria-associated disease is Pontiac fever. In embodiments, the bacteria-associated disease is leptospirosis. In embodiments, the bacteria-associated disease is listeriosis. In embodiments, the bacteria-associated disease is leprosy. In embodiments, the bacteria-associated disease is gonorrhea. In embodiments, the bacteria-associated disease is opthalmia. In embodiments, the bacteria- associated disease is nocardiosis.
  • the bacteria-associated disease is typhoid fever. In embodiments, the bacteria-associated disease is salmonellosis. In embodiments, the bacteria-associated disease is shigellosis. In embodiments, the bacteria-associated disease is impetigo. In embodiments, the bacteria-associated disease is cystitis. In embodiments, the bacteria-associated disease is Scarlet fever. In embodiments, the bacteria-associated disease is syphilis. In embodiments, the bacteria-associated disease is cholera. In embodiments, the bacteria-associated disease is plague. [0508] In embodiments, the bacterial infection is a Staphylococcus infection, an antigenital infections.
  • Enterococcus infection an Acinetobacter infection, a Bacillus infection, a Streptococcus infection, an Escherichia infection, a Pseudomonas infection, a Klebsiella infection, or a Haemophilus infection.
  • the bacterial infection is a Staphylococcus infection, a Streptococcus infection, or an Enterococcus infection.
  • the bacterial infection is an A. baumannii infection, an E. coli infection, a K. pneumonia infection, a P. aeruginosa infection, an H. influenzae infection, an E. faecalis infection, an E. faecium infection, an S. aureus infection, or an S. pneumoniae infection.
  • the bacterial infection is an A. baumannii infection, an E. coli infection, a K. pneumonia infection, a P. aeruginosa infection, or an H. influenzae infection.
  • the bacterial infection is an E. faecalis infection, an E. faecium infection, an S. aureus infection, or an S. pneumoniae infection.
  • the bacterial infection is an A. baumannii infection. In embodiments, the bacterial infection is an E. coli infection. In embodiments, the bacterial infection is a K. pneumonia infection. In embodiments, the bacterial infection is a P. aeruginosa infection. In embodiments, the bacterial infection is an H. influenzae infection. In embodiments, the bacterial infection is an E. faecalis infection. In embodiments, the bacterial infection is an E. faecium infection. In embodiments, the bacterial infection is an S. aureus infection. In embodiments, the bacterial infection is an S. pneumoniae infection.
  • the method includes the compound (e.g., a compound described herein) binding to the peptidyl transferase domain of the 50s ribosomal subunit.
  • the method includes the compound (e.g., a compound described herein) and a second agent simultaneously bound to a ribosome (e.g., bacterial ribosome).
  • a ribosome e.g., bacterial ribosome
  • the second agent is a Group A streptogramin. In embodiments, the second agent is a Group B streptogramin. In embodiments, the second agent is an agent for treating an infectious disease (e.g., bacterial infection). In embodiments, the second agent is an agent for treating a group A streptococcus infection (e.g., Streptococcus pyogenes infection). In embodiments, the second agent is an agent for treating a gram-positive or a gram-negative bacterial infection. In embodiments, the second agent is an agent for treating a gram-positive bacterial infection. In embodiments, the second agent is an agent for treating a
  • the second agent is an agent for treating a gram-negative bacterial infection.
  • the second agent is an agent for treating an infection associated with S. aureus, E. facium, E. faecalis, K. pneumonoiaea, H. influenzaea, or P. aeruginosa.
  • the second agent is VM1.
  • the second agent is a derivative of VM1.
  • the second agent is an agent that binds a ribosome (e.g., bacterial ribosome) at the same binding site as VM1.
  • a ribosome e.g., bacterial ribosome
  • the second agent is an agent that competes with VM1 for binding to the ribosome (e.g., bacterial ribosome).
  • the second agent is VM2.
  • the second agent is a derivative of VM2.
  • the second agent is an agent that binds a ribosome (e.g., bacterial ribosome) at the same binding site as VM2.
  • the second agent is an agent that competes with VM2 for binding to the ribosome (e.g., bacterial ribosome).
  • the second agent is VS1.
  • the second agent is bound to a ribosome (e.g., a bacterial ribosome).
  • the second agent is a derivative of VS1.
  • the second agent is an agent that binds a ribosome (e.g., bacterial ribosome) at the same binding site as VS1.
  • the second agent is an agent that competes with VS1 for binding to the ribosome (e.g., bacterial ribosome).
  • the infectious disease is a parasitic infection.
  • the infectious disease is malaria.
  • the parasitic infection is a Plasmodium falciparum parasitic infection.
  • the parasitic infection is a Trypanosoma cruzi parasitic infection.
  • Embodiment P A compound, or salt thereof, having the formula:
  • Y is–O- or–NH-
  • L 1 is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted
  • R 2 is hydrogen or unsubstituted C1-C3 alkyl
  • R 4A is substituted or unsubstituted C2-C10 alkyl
  • R 3 and R 5 are independently hydrogen, oxo, halogen, -CCI 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCI 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO3H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHC
  • R 6 is hydrogen, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO3H, -SO 4 H,
  • R 7 is hydrogen, -CH 2 COOH, -CONH 2 , -OH, -SH, -NO 2 , -NH 2 , -NHNH 2 , -ONH 2 ,
  • R 6 and R 7 may optionally be joined to form an unsubstituted heterocycloalkyl or
  • R 8 is oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO3H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 ,
  • Ring A is cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;
  • z8 is an integer from 0 to 10;
  • R 9 is hydrogen, oxo, halogen, -CCI 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCI 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCI 2 ,
  • R 10 and R 12 are independently hydrogen, substituted or unsubstituted C1-C3 alkyl, or substituted or unsubstituted 2 to 3 membered heteroalkyl;
  • R 11 is hydrogen, oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO3H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCI 2
  • Embodiment P2 The compound of embodiment P1, wherein R 4A is unsubstituted C 2 -C 10 alkyl.
  • Embodiment P3 The compound of one of embodiments P1 to P2, wherein R 4A is unsubstituted C3-C10 alkenyl.
  • Embodiment P4 The compound of any one of embodiments P1 to P3, wherein [0517] Embodiment P5.
  • L 1 is a substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.
  • Embodiment P6 The compound of any one of embodiments P1 to P5, wherein L 1 is a substituted or unsubstituted alkenylene.
  • Embodiment P7 The compound of any one of embodiments P1 to P6, wherein L 1 is a substituted or unsubstituted C1-C3 alkenylene.
  • Embodiment P8 The compound of any one of embodiments P1 to P7, wherein R 2 is hydrogen.
  • Embodiment P9 The compound of any one of embodiments P1 to P8, wherein R 3 is hydrogen or substituted or unsubstituted alkyl.
  • Embodiment P10 The compound of any one of embodiments P1 to P9, wherein R 3 is hydrogen.
  • Embodiment P11 The compound of any one of embodiments P1 to P10, wherein R 5 is hydrogen, oxo, halogen, -CCI 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCI 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI 3 , -OCF 3 ,
  • Embodiment P12 The compound of any one of embodiments P1 to P11, wherein R 5 is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • Embodiment P13 The compound of any one of embodiments P1 to P12, wherein R 5 is substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted C 6 -C 10 aryl, or substituted or unsubstituted 5 to 10 membered heteroaryl.
  • Embodiment P14 The compound of any one of embodiments P1 to P13, wherein R 5 is substituted or unsubstituted C 1 -C 8 alkyl.
  • Embodiment P15 The compound of any one of embodiments P1 to P14, wherein R 5 is substituted or unsubstituted C 1 -C 3 alkyl.

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Abstract

Disclosed herein, inter alia, are streptogramin compounds, compositions, and methods of use thereof. A method of treating an infectious disease, the method including administering to a subject in need thereof an effective amount of a compound described herein.

Description

STREPTOGRAMIN COMPOSITIONS AND THE USE THEREOF CROSS-REFERENCES TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional Application No.62/859,614, filed June 10, 2019, which is incorporated herein by reference in its entirety and for all purposes. STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT
[0002] This invention was made with government support under grant nos. GM123159 and GM128656 awarded by The National Institutes of Health. The government has certain rights in the invention. BACKGROUND
[0003] Streptogramin antibiotics are used clinically to treat bacterial infections, but their poor physicochemical properties and narrow spectra of activity have limited their clinical utility. New methods to chemically modify streptogramin compounds would enable structural optimization to overcome these limitations as well as to combat growing resistance to the class. Disclosed herein, inter alia, are solutions to these and other problems within the art. BRIEF SUMMARY
[0004] In an aspect is provided a compound, or salt thereof, having the formula:
Figure imgf000003_0001
. Y is–O- or–NH-. L1 is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. R2 is hydrogen or unsubstituted C1-C8 alkyl. R4A is substituted or unsubstituted C2-C10 alkyl. R3 and R5 are independently hydrogen, oxo, halogen, -CCI3, -CBr3, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, -OPO3H, -OSO3H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R6 is hydrogen, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or an amino acid side chain. R7 is hydrogen, -CH2COOH, -CONH2, -OH, -SH, -NO2, -NH2, -NHNH2, -ONH2,
-NHC(O)NHNH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R6 and R7 may optionally be joined to form an unsubstituted heterocycloalkyl or unsubstituted heteroaryl. R8 is independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H,
-NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. Ring A is cycloalkylene, heterocycloalkylene, arylene, or heteroarylene. z8 is an integer from 0 to 10. R9 is hydrogen, oxo, halogen, -CCI3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,
-NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R10 is hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R11 is hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R12 hydrogen, oxo, halogen, -CCI3, -CBr3, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0005] In an aspect is provided a compound, or salt thereof, having the formula:
Y, L1, R2, R3, R5, R6, R7, Ring A, R8, z8, R10, R11,
Figure imgf000005_0001
and R12 are as described herein. R4 is hydrogen, oxo, halogen, -CCI3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, -OPO3H, -OSO3H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0006] In an aspect is provided a method of treating an infectious disease, the method including administering to a subject in need thereof an effective amount of a compound described herein. BRIEF DESCRIPTION OF THE DRAWINGS
[0007] FIGS.1A-1F. Natural and semisynthetic streptogramins and their molecular mechanisms of action and resistance. FIG.1A: Selected natural and semisynthetic streptogramin analogs. Group A streptogramins (left) are 23-membered macrolactones; group B streptogramins (right) are 19-membered cyclic depsipeptides. Modifications installed by semisynthesis are highlighted. FIG.1B: 2.5-Å cryoEM structure of VM2 bound to the 50S subunit of the E. coli ribosome. Coulomb potential density is contoured at 1s. FIG.1C: Surface rendering of the peptidyltransferase center of the ribosome with VM2 bound. Surface coloring is according to heavy atom type. FIG.1D: Graphical representation of interactions between VM2 and residues in the ribosomal binding site. FIG.1E: Surface rendering of the binding site in the resistance protein virginiamycin acetyltransferase A (VatA) with VM1 bound. FIG.1F: Graphical representation of the binding interactions between VM1 and VatA, highlighting the extensive hydrophobic interactions at C3-C6 (acetylation occurs at the C14 alcohol).
[0008] FIGS.2A-2D. Modular synthesis enables access to >60 fully synthetic group A streptogramins. FIG.2A: Convergent route to VM2 from seven variable building blocks, slightly modified from reference (13). This route serves as the template for the synthesis of analogs herein, with modifications when necessary to accommodate unusual building blocks. FIG.2B: Seventeen analogs of accessed by building block variation. The fragments displayed in the dashed boxes represent the structural variability within each analogue compared to the parent scaffold (VM2, center). Overall yields for the synthesis of each analog are displayed for the left half sequence (top number) and for the right half sequence (bottom number). FIG.2C: Access to 34 analogs (17 in each diastereomeric series) with variability on the C3 sidechain by means of carbamate formation followed by desilylation. FIG.2D: Synthesis of tertiary-amine containing analogues by oxidation and reductive amination. [0009] FIGS.3A-3C. Antibiotic activity and VatA acetylation rates of selected group A streptogramins. FIG.3A: MIC values for 10 fully synthetic group A streptogramins against two strains of S. aureus.“WT” denotes ATCC 29213,“VatA” denotes VatA-expressing strain from reference (3). Structural differences compared to VM2 are highlighted by building block according to the color scheme in FIGS.2A-2D. FIG.3B: MIC values against an expanded panel of pathogens for the analogs in panel (FIG.3A) and for combinations with the synergistic group B streptogramin VS1. In vitro translation data for each analog or combination at 10 µM is shown in the bar chart to the right of the table. FIG.3C: In vitro acetylation rates of selected analogs by virginiamycin acetyltransferase A (VatA).
[0010] FIGS.4A-4F. High resolution CryoEM reveals occupancy of a novel antibiotic binding pocket. FIG.4A: PTC model refined from CryoEM map of the apo-ribosome with key residues for antibiotics modeled. FIG.4B: 2.5-Å CryoEM potential density map (contoured in dark blue at 1.5s and light gray at 1.0s) for ribosomes bound to 46 reveal that the side chain extends towards A2602. FIG.4C: 2.5-Å CryoEM potential density map for ribosomes bound to 47 reveal an extension towards the VS1 binding site. FIG.4D: 2.7-Å CryoEM potential density map for ribosomes bound to 46 and VS1 show tight packing of both compounds around A2062. FIG.4E: The side chain of 46 extends into the P-site and mimics the terminal A of the P-site tRNA, which base pairs with Gm2251. FIG.4F: An overlay of known PTC-site antibiotics shows how the side chain of 46 and the extension of 47 occupy areas distinct to previously characterized antibiotics. The compatibility of 47 with VS1 (FIG.3B) suggests that the area between these two compounds is a site for future optimization.
[0011] FIG.5. Chemical structures of compounds. DETAILED DESCRIPTION
I. Definitions
[0012] The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.
[0013] Where substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH2O- is equivalent to -OCH2-. [0014] The term“alkyl,” by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched carbon chain (or carbon), or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include mono-, di- and multivalent radicals. The alkyl may include a designated number of carbons (e.g., C1-C10 means one to ten carbons). Alkyl is an uncyclized chain. Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n- butyl, t-butyl, isobutyl, sec-butyl, methyl, homologs and isomers of, for example, n-pentyl, n- hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4- pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers. An alkoxy is an alkyl attached to the remainder of the molecule via an oxygen linker (-O-). An alkyl moiety may be an alkenyl moiety. An alkyl moiety may be an alkynyl moiety. An alkyl moiety may be fully saturated. An alkenyl may include more than one double bond and/or one or more triple bonds in addition to the one or more double bonds. An alkynyl may include more than one triple bond and/or one or more double bonds in addition to the one or more triple bonds. In embodiments, alkyl refers to an aliphatic hydrocarbyl. In
embodiments, an alkyl moiety is not an alkenyl moiety. In embodiments, an alkyl moiety is not an alkynyl moiety.
[0015] The term“alkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, as exemplified, but not limited by, -CH2CH2CH2CH2-. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred herein. A“lower alkyl” or“lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms. The term“alkenylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene.
[0016] The term“heteroalkyl,” by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or combinations thereof, including at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and S), and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) (e.g., N, S, Si, or P) may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Heteroalkyl is an uncyclized chain. Examples include, but are not limited to: -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3,
-CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -S-CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3,
-O-CH2-CH3, and -CN. Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. A heteroalkyl moiety may include one heteroatom (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include two optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include three optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include four optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include five optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include up to 8 optionally different heteroatoms (e.g., O, N, S, Si, or P). The term “heteroalkenyl,” by itself or in combination with another term, means, unless otherwise stated, a heteroalkyl including at least one double bond. A heteroalkenyl may optionally include more than one double bond and/or one or more triple bonds in additional to the one or more double bonds. The term“heteroalkynyl,” by itself or in combination with another term, means, unless otherwise stated, a heteroalkyl including at least one triple bond. A heteroalkynyl may optionally include more than one triple bond and/or one or more double bonds in additional to the one or more triple bonds. [0017] Similarly, the term“heteroalkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. For
heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula - C(O)2R'- represents both -C(O)2R'- and -R'C(O)2-. As described above, heteroalkyl groups, as used herein, include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C(O)R', -C(O)NR', -NR'R'', -OR', -SR', and/or -SO2R'. Where “heteroalkyl” is recited, followed by recitations of specific heteroalkyl groups, such as - NR'R'' or the like, it will be understood that the terms heteroalkyl and -NR'R'' are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term“heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R'' or the like. [0018] The terms“cycloalkyl” and“heterocycloalkyl”, by themselves or in combination with other terms, mean, unless otherwise stated, cyclic versions of“alkyl” and“heteroalkyl”, respectively. Cycloalkyl and heterocycloalkyl are not aromatic. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 1- (1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3- morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl,
tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. A“cycloalkylene” and a “heterocycloalkylene”, alone or as part of another substituent, means a divalent radical derived from a cycloalkyl and heterocycloalkyl, respectively.
[0019] In embodiments, the term“cycloalkyl” means a monocyclic, bicyclic, or a multicyclic cycloalkyl ring system. In embodiments, monocyclic ring systems are cyclic hydrocarbon groups containing from 3 to 8 carbon atoms, where such groups can be saturated or unsaturated, but not aromatic. In embodiments, cycloalkyl groups are fully saturated. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Bicyclic cycloalkyl ring systems are bridged monocyclic rings or fused bicyclic rings. In embodiments, bridged monocyclic rings contain a monocyclic cycloalkyl ring where two non adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms (i.e., a bridging group of the form (CH2)w, where w is 1, 2, or 3).
Representative examples of bicyclic ring systems include, but are not limited to,
bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane. In embodiments, fused bicyclic cycloalkyl ring systems contain a monocyclic cycloalkyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. In embodiments, the bridged or fused bicyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkyl ring. In embodiments, cycloalkyl groups are optionally substituted with one or two groups which are independently oxo or thia. In embodiments, the fused bicyclic cycloalkyl is a 5 or 6 membered monocyclic cycloalkyl ring fused to either a phenyl ring, a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a 5 or 6 membered monocyclic heteroaryl, wherein the fused bicyclic cycloalkyl is optionally substituted by one or two groups which are independently oxo or thia. In embodiments, multicyclic cycloalkyl ring systems are a monocyclic cycloalkyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two other ring systems independently selected from the group consisting of a phenyl, a bicyclic aryl, a monocyclic or bicyclic heteroaryl, a monocyclic or bicyclic cycloalkyl, a monocyclic or bicyclic cycloalkenyl, and a monocyclic or bicyclic heterocyclyl. In embodiments, the multicyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the base ring. In embodiments, multicyclic cycloalkyl ring systems are a monocyclic cycloalkyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two other ring systems independently selected from the group consisting of a phenyl, a monocyclic heteroaryl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, and a monocyclic heterocyclyl. Examples of multicyclic cycloalkyl groups include, but are not limited to tetradecahydrophenanthrenyl, perhydrophenothiazin-1-yl, and
perhydrophenoxazin-1-yl.
[0020] In embodiments, a cycloalkyl is a cycloalkenyl. The term“cycloalkenyl” is used in accordance with its plain ordinary meaning. In embodiments, a cycloalkenyl is a monocyclic, bicyclic, or a multicyclic cycloalkenyl ring system. In embodiments, monocyclic
cycloalkenyl ring systems are cyclic hydrocarbon groups containing from 3 to 8 carbon atoms, where such groups are unsaturated (i.e., containing at least one annular carbon carbon double bond), but not aromatic. Examples of monocyclic cycloalkenyl ring systems include cyclopentenyl and cyclohexenyl. In embodiments, bicyclic cycloalkenyl rings are bridged monocyclic rings or a fused bicyclic rings. In embodiments, bridged monocyclic rings contain a monocyclic cycloalkenyl ring where two non adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms (i.e., a bridging group of the form (CH2)w, where w is 1, 2, or 3). Representative examples of bicyclic cycloalkenyls include, but are not limited to, norbornenyl and bicyclo[2.2.2]oct 2 enyl. In embodiments, fused bicyclic cycloalkenyl ring systems contain a monocyclic cycloalkenyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. In embodiments, the bridged or fused bicyclic cycloalkenyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkenyl ring. In embodiments, cycloalkenyl groups are optionally substituted with one or two groups which are independently oxo or thia. In embodiments, multicyclic cycloalkenyl rings contain a monocyclic cycloalkenyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two ring systems independently selected from the group consisting of a phenyl, a bicyclic aryl, a monocyclic or bicyclic heteroaryl, a monocyclic or bicyclic cycloalkyl, a monocyclic or bicyclic cycloalkenyl, and a monocyclic or bicyclic heterocyclyl. In embodiments, the multicyclic cycloalkenyl is attached to the parent molecular moiety through any carbon atom contained within the base ring. In embodiments, multicyclic cycloalkenyl rings contain a monocyclic cycloalkenyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two ring systems independently selected from the group consisting of a phenyl, a monocyclic heteroaryl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, and a monocyclic heterocyclyl.
[0021] In embodiments, a heterocycloalkyl is a heterocyclyl. The term“heterocyclyl” as used herein, means a monocyclic, bicyclic, or multicyclic heterocycle. The heterocyclyl monocyclic heterocycle is a 3, 4, 5, 6 or 7 membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S where the ring is saturated or unsaturated, but not aromatic. The 3 or 4 membered ring contains 1 heteroatom selected from the group consisting of O, N, and S. The 5 membered ring can contain zero or one double bond and one, two or three heteroatoms selected from the group consisting of O, N, and S. The 6 or 7 membered ring contains zero, one or two double bonds and one, two or three heteroatoms selected from the group consisting of O, N, and S. The heterocyclyl monocyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heterocyclyl monocyclic heterocycle.
Representative examples of heterocyclyl monocyclic heterocycles include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and trithianyl. The heterocyclyl bicyclic heterocycle is a monocyclic heterocycle fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocycle, or a monocyclic heteroaryl. The heterocyclyl bicyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the monocyclic heterocycle portion of the bicyclic ring system.
Representative examples of bicyclic heterocyclyls include, but are not limited to, 2,3- dihydrobenzofuran-2-yl, 2,3-dihydrobenzofuran-3-yl, indolin-1-yl, indolin-2-yl, indolin-3-yl, 2,3-dihydrobenzothien-2-yl, decahydroquinolinyl, decahydroisoquinolinyl, octahydro-1H- indolyl, and octahydrobenzofuranyl. In embodiments, heterocyclyl groups are optionally substituted with one or two groups which are independently oxo or thia. In certain embodiments, the bicyclic heterocyclyl is a 5 or 6 membered monocyclic heterocyclyl ring fused to a phenyl ring, a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a 5 or 6 membered monocyclic heteroaryl, wherein the bicyclic heterocyclyl is optionally substituted by one or two groups which are independently oxo or thia. Multicyclic heterocyclyl ring systems are a monocyclic heterocyclyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two other ring systems independently selected from the group consisting of a phenyl, a bicyclic aryl, a monocyclic or bicyclic heteroaryl, a monocyclic or bicyclic cycloalkyl, a monocyclic or bicyclic cycloalkenyl, and a monocyclic or bicyclic heterocyclyl. The multicyclic heterocyclyl is attached to the parent molecular moiety through any carbon atom or nitrogen atom contained within the base ring. In embodiments, multicyclic heterocyclyl ring systems are a monocyclic heterocyclyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two other ring systems independently selected from the group consisting of a phenyl, a monocyclic heteroaryl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, and a monocyclic heterocyclyl. Examples of multicyclic heterocyclyl groups include, but are not limited to 10H-phenothiazin-10-yl, 9,10-dihydroacridin-9-yl, 9,10-dihydroacridin-10-yl, 10H-phenoxazin-10-yl, 10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl, 1,2,3,4- tetrahydropyrido[4,3-g]isoquinolin-2-yl, 12H-benzo[b]phenoxazin-12-yl, and dodecahydro- 1H-carbazol-9-yl.
[0022] The terms“halo” or“halogen”, by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as“haloalkyl” are meant to include monohaloalkyl and polyhaloalkyl. For example, the term“halo(C1-C4)alkyl” includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
[0023] The term“acyl” means, unless otherwise stated, -C(O)R where R is a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0024] The term“aryl” means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent, which can be a single ring or multiple rings (preferably from 1 to 3 rings) that are fused together (i.e., a fused ring aryl) or linked covalently. A fused ring aryl refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring. In embodiments, a fused ring aryl refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring and wherein the multiple rings are attached to the parent molecular moiety through any carbon atom contained within an aryl ring of the multiple rings. The term“heteroaryl” refers to aryl groups (or rings) that contain at least one heteroatom such as N, O, or S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. Thus, the term“heteroaryl” includes fused ring heteroaryl groups (i.e., multiple rings fused together wherein at least one of the fused rings is a heteroaromatic ring). In embodiments, a fused ring heteroaryl group is multiple rings fused together wherein at least one of the fused rings is a heteroaromatic ring and wherein the multiple rings are attached to the parent molecular moiety through any atom contained within a heteroaromatic ring of the multiple rings. A 5,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 5 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. Likewise, a 6,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. And a 6,5-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 5 members, and wherein at least one ring is a heteroaryl ring. A heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, benzoxazoyl benzimidazolyl, benzofuran, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl, isoquinolyl, quinoxalinyl, quinolyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2- pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4- oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2- thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. An“arylene” and a“heteroarylene,” alone or as part of another substituent, mean a divalent radical derived from an aryl and heteroaryl, respectively. A heteroaryl group substituent may be -O- bonded to a ring heteroatom nitrogen.
[0025] Spirocyclic rings are two or more rings wherein adjacent rings are attached through a single atom. The individual rings within spirocyclic rings may be identical or different. Individual rings in spirocyclic rings may be substituted or unsubstituted and may have different substituents from other individual rings within a set of spirocyclic rings. Possible substituents for individual rings within spirocyclic rings are the possible substituents for the same ring when not part of spirocyclic rings (e.g., substituents for cycloalkyl or
heterocycloalkyl rings). Spirocylic rings may be substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heterocycloalkylene and individual rings within a spirocyclic ring group may be any of the immediately previous list, including having all rings of one type (e.g., all rings being substituted heterocycloalkylene wherein each ring may be the same or different substituted heterocycloalkylene). When referring to a spirocyclic ring system, heterocyclic spirocyclic rings means a spirocyclic rings wherein at least one ring is a heterocyclic ring and wherein each ring may be a different ring. When referring to a spirocyclic ring system, substituted spirocyclic rings means that at least one ring is substituted and each substituent may optionally be different. [0026] The symbol“ ” denotes the point of attachment of a chemical moiety to the remainder of a molecule or chemical formula.
[0027] The term“oxo,” as used herein, means an oxygen that is double bonded to a carbon atom.
[0028] The term“alkylarylene” as an arylene moiety covalently bonded to an alkylene moiety (also referred to herein as an alkylene linker). In embodiments, the alkylarylene group has the formula:
Figure imgf000016_0001
.
[0029] An alkylarylene moiety may be substituted (e.g., with a substituent group) on the alkylene moiety or the arylene linker (e.g., at carbons 2, 3, 4, or 6) with halogen, oxo, -N3, -CF3, -CCI3, -CBr3, -CI3, -CN, -CHO, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO2CH3 -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, substituted or
unsubstituted C1-C5 alkyl or substituted or unsubstituted 2 to 5 membered heteroalkyl). In embodiments, the alkylarylene is unsubstituted.
[0030] Each of the above terms (e.g.,“alkyl,”“heteroalkyl,”“cycloalkyl,”
“heterocycloalkyl,”“aryl,” and“heteroaryl”) includes both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.
[0031] Substituents for the alkyl and heteroalkyl radicals (including those groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be one or more of a variety of groups selected from, but not limited to, -OR', =O, =NR', =N-OR', -NR'R'', -SR', halogen, -SiR'R''R''', -OC(O)R', -C(O)R', -CO2R', -CONR'R'', -OC(O)NR'R'', -NR''C(O)R',
-NR'-C(O)NR''R''', -NR''C(O)2R', -NR-C(NR'R''R''')=NR'''', -NR-C(NR'R'')=NR''', -S(O)R', -S(O)2R', -S(O)2NR'R'', -NRSO2R', -NR'NR''R''', -ONR'R'', -NR'C(O)NR''NR'''R'''', -CN, -NO2, -NR'SO2R'', -NR'C(O)R'', -NR'C(O)-OR'', -NR'OR'', in a number ranging from zero to (2m'+1), where m' is the total number of carbon atoms in such radical. R, R', R'', R''', and R'''' each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups. When a compound described herein includes more than one R group, for example, each of the R groups is independently selected as are each R', R'', R''', and R'''' group when more than one of these groups is present. When R' and R'' are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7- membered ring. For example, -NR'R'' includes, but is not limited to, 1-pyrrolidinyl and 4- morpholinyl. From the above discussion of substituents, one of skill in the art will understand that the term“alkyl” is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF3 and -CH2CF3) and acyl (e.g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, and the like).
[0032] Similar to the substituents described for the alkyl radical, substituents for the aryl and heteroaryl groups are varied and are selected from, for example: -OR', -NR'R'', -SR', halogen, -SiR'R''R''', -OC(O)R', -C(O)R', -CO2R', -CONR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'-C(O)NR''R''', -NR''C(O)2R', -NR-C(NR'R''R''')=NR'''', -NR-C(NR'R'')=NR''', -S(O)R', -S(O)2R', -S(O)2NR'R'', -NRSO2R', -NR'NR''R''', -ONR'R'', -NR'C(O)NR''NR'''R'''', -CN, -NO2, -R', -N3, -CH(Ph)2, fluoro(C1-C4)alkoxy, and fluoro(C1-C4)alkyl, -NR'SO2R'',
-NR'C(O)R'', -NR'C(O)-OR'', -NR'OR'', in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R', R'', R''', and R'''' are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. When a compound described herein includes more than one R group, for example, each of the R groups is independently selected as are each R', R'', R''', and R'''' groups when more than one of these groups is present.
[0033] Substituents for rings (e.g., cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene) may be depicted as substituents on the ring rather than on a specific atom of a ring (commonly referred to as a floating substituent). In such a case, the substituent may be attached to any of the ring atoms (obeying the rules of chemical valency) and in the case of fused rings or spirocyclic rings, a substituent depicted as associated with one member of the fused rings or spirocyclic rings (a floating substituent on a single ring), may be a substituent on any of the fused rings or spirocyclic rings (a floating substituent on multiple rings). When a substituent is attached to a ring, but not a specific atom (a floating substituent), and a subscript for the substituent is an integer greater than one, the multiple substituents may be on the same atom, same ring, different atoms, different fused rings, different spirocyclic rings, and each substituent may optionally be different. Where a point of attachment of a ring to the remainder of a molecule is not limited to a single atom (a floating substituent), the attachment point may be any atom of the ring and in the case of a fused ring or spirocyclic ring, any atom of any of the fused rings or spirocyclic rings while obeying the rules of chemical valency. Where a ring, fused rings, or spirocyclic rings contain one or more ring heteroatoms and the ring, fused rings, or spirocyclic rings are shown with one more floating substituents (including, but not limited to, points of attachment to the remainder of the molecule), the floating substituents may be bonded to the heteroatoms. Where the ring heteroatoms are shown bound to one or more hydrogens (e.g., a ring nitrogen with two bonds to ring atoms and a third bond to a hydrogen) in the structure or formula with the floating substituent, when the heteroatom is bonded to the floating substituent, the substituent will be understood to replace the hydrogen, while obeying the rules of chemical valency.
[0034] Two or more substituents may optionally be joined to form aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups. Such so-called ring-forming substituents are typically, though not necessarily, found attached to a cyclic base structure. In one embodiment, the ring-forming substituents are attached to adjacent members of the base structure. For example, two ring-forming substituents attached to adjacent members of a cyclic base structure create a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single member of the base structure. For example, two ring- forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure. In yet another embodiment, the ring-forming substituents are attached to non-adjacent members of the base structure.
[0035] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form a ring of the formula -T-C(O)-(CRR')q-U-, wherein T and U are
independently -NR-, -O-, -CRR'-, or a single bond, and q is an integer of from 0 to 3.
Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH2)r-B-, wherein A and B are independently -CRR'-, -O-, -NR-, -S-, -S(O) -, -S(O)2-, -S(O)2NR'-, or a single bond, and r is an integer of from 1 to 4. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CRR')s-X'- (C''R''R''')d-, where s and d are independently integers of from 0 to 3, and X' is -O-, -NR'-, -S-, -S(O)-, -S(O)2-, or -S(O)2NR'-. The substituents R, R', R'', and R''' are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
[0036] As used herein, the terms“heteroatom” or“ring heteroatom” are meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).
[0037] A“substituent group,” as used herein, means a group selected from the following moieties:
(A) oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBr3, -OCI3,-OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -N3, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6- C10 aryl, C10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and
(B) alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered
heteroalkyl), cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), substituted with at least one substituent selected from: (i) oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3,-OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -N3, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6- C10 aryl, C10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and (ii) alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (e.g., C6- C10 aryl, C10 aryl, or phenyl), heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), substituted with at least one substituent selected from:
(a) oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCI2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -N3, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered
heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and
(b) alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (e.g., C6- C10 aryl, C10 aryl, or phenyl), heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), substituted with at least one substituent selected from: oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCI2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBr3, -OCI3,-OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -N3, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0038] A“size-limited substituent” or“ size-limited substituent group,” as used herein, means a group selected from all of the substituents described above for a“substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C10 aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl. [0039] A“lower substituent” or“ lower substituent group,” as used herein, means a group selected from all of the substituents described above for a“substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3- C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C10 aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl.
[0040] In some embodiments, each substituted group described in the compounds herein is substituted with at least one substituent group. More specifically, in some embodiments, each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted
heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene described in the compounds herein are substituted with at least one substituent group. In other embodiments, at least one or all of these groups are substituted with at least one size-limited substituent group. In other embodiments, at least one or all of these groups are substituted with at least one lower substituent group.
[0041] In other embodiments of the compounds herein, each substituted or unsubstituted alkyl may be a substituted or unsubstituted C1-C20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered
heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6- C10 aryl, and/or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl. In some embodiments of the compounds herein, each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C20 alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 20 membered
heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C8 cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 8 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C10 arylene, and/or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 10 membered heteroarylene.
[0042] In some embodiments, each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl, each substituted or unsubstituted
heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C10 aryl, and/or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl. In some embodiments, each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C8 alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 8 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C7 cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 7 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C10 arylene, and/or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 9 membered heteroarylene. In some embodiments, the compound is a chemical species set forth in the Examples section, figures, or tables below.
[0043] In embodiments, a substituted or unsubstituted moiety (e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and/or substituted or unsubstituted heteroarylene) is unsubstituted (e.g., is an unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted alkylene, unsubstituted heteroalkylene, unsubstituted cycloalkylene, unsubstituted heterocycloalkylene, unsubstituted arylene, and/or unsubstituted heteroarylene, respectively). In embodiments, a substituted or unsubstituted moiety (e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and/or substituted or unsubstituted heteroarylene) is substituted (e.g., is a substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene, respectively).
[0044] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene) is substituted with at least one substituent group, wherein if the substituted moiety is substituted with a plurality of substituent groups, each substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of substituent groups, each substituent group is different.
[0045] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene) is substituted with at least one size-limited substituent group, wherein if the substituted moiety is substituted with a plurality of size-limited substituent groups, each size-limited substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of size-limited substituent groups, each size-limited substituent group is different.
[0046] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene) is substituted with at least one lower substituent group, wherein if the substituted moiety is substituted with a plurality of lower substituent groups, each lower substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of lower substituent groups, each lower substituent group is different. [0047] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted moiety is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group is different.
[0048] Certain compounds of the present disclosure possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)- or, as (D)- or (L)- for amino acids, and individual isomers are encompassed within the scope of the present disclosure. The compounds of the present disclosure do not include those that are known in art to be too unstable to synthesize and/or isolate. The present disclosure is meant to include compounds in racemic and optically pure forms. Optically active (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.
[0049] As used herein, the term“isomers” refers to compounds having the same number and kind of atoms, and hence the same molecular weight, but differing in respect to the structural arrangement or configuration of the atoms.
[0050] The term“tautomer,” as used herein, refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another. [0051] It will be apparent to one skilled in the art that certain compounds of this disclosure may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the disclosure.
[0052] Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure.
[0053] Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13C- or 14C-enriched carbon are within the scope of this disclosure.
[0054] The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine-125 (125I), or carbon-14 (14C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.
[0055] It should be noted that throughout the application that alternatives are written in Markush groups, for example, each amino acid position that contains more than one possible amino acid. It is specifically contemplated that each member of the Markush group should be considered separately, thereby comprising another embodiment, and the Markush group is not to be read as a single unit.
[0056] The term“bioconjugate reactive moiety” or“bioconjugate reactive group” refers to a chemical moiety which participates in a reaction to form bioconjugate linker (e.g., covalent linker) or the resulting association between atoms or molecules of bioconjugate reactive moieties. The association can be direct or indirect. For example, a conjugate between a first bioconjugate reactive group (e.g.,–NH2,–COOH,–N-hydroxysuccinimide, or–maleimide) and a second bioconjugate reactive group (e.g., sulfhydryl, sulfur-containing amino acid, amine, amine sidechain containing amino acid, or carboxylate) provided herein can be direct, e.g., by covalent bond or linker (e.g., a first linker of second linker), or indirect, e.g., by non- covalent bond (e.g., electrostatic interactions (e.g., ionic bond, hydrogen bond, halogen bond), van der Waals interactions (e.g., dipole-dipole, dipole-induced dipole, London dispersion), ring stacking (pi effects), hydrophobic interactions and the like). In
embodiments, bioconjugates or bioconjugate linkers are formed using bioconjugate chemistry (i.e., the association of two bioconjugate reactive groups) including, but are not limited to nucleophilic substitutions (e.g., reactions of amines and alcohols with acyl halides, active esters), electrophilic substitutions (e.g., enamine reactions) and additions to carbon-carbon and carbon-heteroatom multiple bonds (e.g., Michael reaction, Diels-Alder addition). These and other useful reactions are discussed in, for example, March, ADVANCED ORGANIC CHEMISTRY, 3rd Ed., John Wiley & Sons, New York, 1985; Hermanson,
BIOCONJUGATE TECHNIQUES, Academic Press, San Diego, 1996; and Feeney et al., MODIFICATION OF PROTEINS; Advances in Chemistry Series, Vol.198, American Chemical Society, Washington, D.C., 1982. In embodiments, the first bioconjugate reactive group (e.g., maleimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g., haloacetyl moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g., pyridyl moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g.,–N-hydroxysuccinimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., an amine). In embodiments, the first bioconjugate reactive group (e.g., maleimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g.,–sulfo–N-hydroxysuccinimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., an amine).
[0057] Useful bioconjugate reactive moieties used for bioconjugate chemistries herein include, for example:
(a) carboxyl groups and various derivatives thereof including, but not limited to, N- hydroxysuccinimide esters, N-hydroxybenztriazole esters, acid halides, acyl imidazoles, thioesters, p-nitrophenyl esters, alkyl, alkenyl, alkynyl and aromatic esters;
(b) hydroxyl groups which can be converted to esters, ethers, aldehydes, etc.;
(c) haloalkyl groups wherein the halide can be later displaced with a nucleophilic group such as, for example, an amine, a carboxylate anion, thiol anion, carbanion, or an alkoxide ion, thereby resulting in the covalent attachment of a new group at the site of the halogen atom;
(d) dienophile groups which are capable of participating in Diels-Alder reactions such as, for example, maleimido or maleimide groups;
(e) aldehyde or ketone groups such that subsequent derivatization is possible via formation of carbonyl derivatives such as, for example, imines, hydrazones, semicarbazones or oximes, or via such mechanisms as Grignard addition or alkyllithium addition;
(f) sulfonyl halide groups for subsequent reaction with amines, for example, to form sulfonamides;
(g) thiol groups, which can be converted to disulfides, reacted with acyl halides, or bonded to metals such as gold, or react with maleimides;
(h) amine or sulfhydryl groups (e.g., present in cysteine), which can be, for example, acylated, alkylated or oxidized;
(i) alkenes, which can undergo, for example, cycloadditions, acylation, Michael addition, etc;
(j) epoxides, which can react with, for example, amines and hydroxyl compounds; (k) phosphoramidites and other standard functional groups useful in nucleic acid synthesis;
(l) metal silicon oxide bonding;
(m) metal bonding to reactive phosphorus groups (e.g., phosphines) to form, for example, phosphate diester bonds;
(n) azides coupled to alkynes using copper catalyzed cycloaddition click chemistry; and
(o) biotin conjugate can react with avidin or strepavidin to form a avidin-biotin complex or streptavidin-biotin complex.
[0058] The bioconjugate reactive groups can be chosen such that they do not participate in, or interfere with, the chemical stability of the conjugate described herein. Alternatively, a reactive functional group can be protected from participating in the crosslinking reaction by the presence of a protecting group. In embodiments, the bioconjugate comprises a molecular entity derived from the reaction of an unsaturated bond, such as a maleimide, and a sulfhydryl group.
[0059] “Analog” or“analogue” is used in accordance with its plain ordinary meaning within Chemistry and Biology and refers to a chemical compound that is structurally similar to another compound (i.e., a so-called“reference” compound) but differs in composition, e.g., in the replacement of one atom by an atom of a different element, or in the presence of a particular functional group, or the replacement of one functional group by another functional group, or the absolute stereochemistry of one or more chiral centers of the reference compound. Accordingly, an analog is a compound that is similar or comparable in function and appearance but not in structure or origin to a reference compound. A“derivative” is a compound derived from a chemical compound via a chemical reaction. A derivative of a compound described herein may refer to the compound described herein with the addition or removal of a substituent.
[0060] The terms“a” or“an,” as used in herein means one or more. In addition, the phrase “substituted with a[n],” as used herein, means the specified group may be substituted with one or more of any or all of the named substituents. For example, where a group, such as an alkyl or heteroaryl group, is“substituted with an unsubstituted C1-C20 alkyl, or unsubstituted 2 to 20 membered heteroalkyl,” the group may contain one or more unsubstituted C1-C20 alkyls, and/or one or more unsubstituted 2 to 20 membered heteroalkyls.
[0061] Moreover, where a moiety is substituted with an R substituent, the group may be referred to as“R-substituted.” Where a moiety is R-substituted, the moiety is substituted with at least one R substituent and each R substituent is optionally different. Where a particular R group is present in the description of a chemical genus (such as Formula (I)), a Roman alphabetic symbol may be used to distinguish each appearance of that particular R group. For example, where multiple R13 substituents are present, each R13 substituent may be distinguished as R13A, R13B, R13C, R13D, etc., wherein each of R13A, R13B, R13C, R13D, etc. is defined within the scope of the definition of R13 and optionally differently. When a substituent or linker (e.g., an R group or an L linker) appears multiple times, each appearance of that substituent or linker can be different, i.e., each occurrence of the substituent or the linker may be independently a member of the Markush group for that variable, wherein each occurrence may be optionally different. [0062] A“detectable agent” or“detectable moiety” is an atom, molecule, substance, or composition detectable by appropriate means such as spectroscopic, photochemical, biochemical, immunochemical, chemical, magnetic resonance imaging, or other physical means. For example, useful detectable agents include 18F, 32P, 33P, 45Ti, 47Sc, 52Fe, 59Fe, 62Cu, 64Cu, 67Cu, 67Ga, 68Ga, 77As, 86Y, 90Y, 89Sr, 89Zr, 94Tc, 94Tc, 99mTc, 99Mo, 105Pd, 105Rh, 111Ag, 111In, 123I, 124I, 125I, 131I, 142Pr, 143Pr, 149Pm, 153Sm, 154-1581Gd, 161Tb, 166Dy, 166Ho, 169Er, 175Lu, 177Lu, 186Re, 188Re, 189Re, 194Ir, 198Au, 199Au, 211At, 211Pb, 212Bi, 212Pb, 213Bi, 223Ra, 225Ac, Cr, V, Mn, Fe, Co, Ni, Cu, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, 32P, fluorophore (e.g., fluorescent dyes), electron-dense reagents, enzymes (e.g., as commonly used in an ELISA), biotin, digoxigenin, paramagnetic molecules, paramagnetic nanoparticles, ultrasmall superparamagnetic iron oxide ("USPIO") nanoparticles, USPIO nanoparticle aggregates, superparamagnetic iron oxide ("SPIO") nanoparticles, SPIO nanoparticle aggregates, monochrystalline iron oxide nanoparticles, monochrystalline iron oxide, nanoparticle contrast agents, liposomes or other delivery vehicles containing
Gadolinium chelate ("Gd-chelate") molecules, Gadolinium, radioisotopes, radionuclides (e.g., carbon-11, nitrogen-13, oxygen-15, fluorine-18, rubidium-82), fluorodeoxyglucose (e.g., fluorine-18 labeled), any gamma ray emitting radionuclides, positron-emitting radionuclide, radiolabeled glucose, radiolabeled water, radiolabeled ammonia, biocolloids, microbubbles (e.g., including microbubble shells including albumin, galactose, lipid, and/or polymers; microbubble gas core including air, heavy gas(es), perfluorcarbon, nitrogen,
octafluoropropane, perflexane lipid microsphere, perflutren, etc.), iodinated contrast agents (e.g., iohexol, iodixanol, ioversol, iopamidol, ioxilan, iopromide, diatrizoate, metrizoate, ioxaglate), barium sulfate, thorium dioxide, gold, gold nanoparticles, gold nanoparticle aggregates, fluorophores, two-photon fluorophores, or haptens and proteins or other entities which can be made detectable, e.g., by incorporating a radiolabel into a peptide or antibody specifically reactive with a target peptide. A detectable moiety is a monovalent detectable agent or a detectable agent capable of forming a bond with another composition.
[0063] Radioactive substances (e.g., radioisotopes) that may be used as imaging and/or labeling agents in accordance with the embodiments of the disclosure include, but are not limited to, 18F, 32P, 33P, 45Ti, 47Sc, 52Fe, 59Fe, 62Cu, 64Cu, 67Cu, 67Ga, 68Ga, 77As, 86Y, 90Y, 89Sr, 89Zr, 94Tc, 94Tc, 99mTc, 99Mo, 105Pd, 105Rh, 111Ag, 111In, 123I, 124I, 125I, 131I, 142Pr, 143Pr, 149Pm, 153Sm, 154-1581Gd, 161Tb, 166Dy, 166Ho, 169Er, 175Lu, 177Lu, 186Re, 188Re, 189Re, 194Ir, 198Au, 199Au, 211At, 211Pb, 212Bi, 212Pb, 213Bi, 223Ra, and 225Ac. Paramagnetic ions that may be used as additional imaging agents in accordance with the embodiments of the disclosure include, but are not limited to, ions of transition and lanthanide metals (e.g., metals having atomic numbers of 21-29, 42, 43, 44, or 57-71). These metals include ions of Cr, V, Mn, Fe, Co, Ni, Cu, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb and Lu.
[0064] Descriptions of compounds of the present disclosure are limited by principles of chemical bonding known to those skilled in the art. Accordingly, where a group may be substituted by one or more of a number of substituents, such substitutions are selected so as to comply with principles of chemical bonding and to give compounds which are not inherently unstable and/or would be known to one of ordinary skill in the art as likely to be unstable under ambient conditions, such as aqueous, neutral, and several known physiological conditions. For example, a heterocycloalkyl or heteroaryl is attached to the remainder of the molecule via a ring heteroatom in compliance with principles of chemical bonding known to those skilled in the art thereby avoiding inherently unstable compounds.
[0065] The term“isolated”, when applied to a nucleic acid or protein, denotes that the nucleic acid or protein is essentially free of other cellular components with which it is associated in the natural state. It can be, for example, in a homogeneous state and may be in either a dry or aqueous solution. Purity and homogeneity are typically determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis or high performance liquid chromatography. A protein that is the predominant species present in a preparation is substantially purified.
[0066] A person of ordinary skill in the art will understand when a variable (e.g., moiety or linker) of a compound or of a compound genus (e.g., a genus described herein) is described by a name or formula of a standalone compound with all valencies filled, the unfilled valence(s) of the variable will be dictated by the context in which the variable is used. For example, when a variable of a compound as described herein is connected (e.g., bonded) to the remainder of the compound through a single bond, that variable is understood to represent a monovalent form (i.e., capable of forming a single bond due to an unfilled valence) of a standalone compound (e.g., if the variable is named“methane” in an embodiment but the variable is known to be attached by a single bond to the remainder of the compound, a person of ordinary skill in the art would understand that the variable is actually a monovalent form of methane, i.e., methyl or–CH3). Likewise, for a linker variable (e.g., L1, L2, or L3 as described herein), a person of ordinary skill in the art will understand that the variable is the divalent form of a standalone compound (e.g., if the variable is assigned to“PEG” or “polyethylene glycol” in an embodiment but the variable is connected by two separate bonds to the remainder of the compound, a person of ordinary skill in the art would understand that the variable is a divalent (i.e., capable of forming two bonds through two unfilled valences) form of PEG instead of the standalone compound PEG).
[0067] As used herein, the term“salt” refers to acid or base salts of the compounds used in the methods of the present invention. Illustrative examples of acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid and the like) salts, quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts.
[0068] The term“pharmaceutically acceptable salts” is meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic,
monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p- tolylsulfonic, citric, tartaric, oxalic, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al.,“Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. [0069] Thus, the compounds of the present disclosure may exist as salts, such as with pharmaceutically acceptable acids. The present disclosure includes such salts. Non-limiting examples of such salts include hydrochlorides, hydrobromides, phosphates, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, propionates, tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid, and quaternary ammonium salts (e.g., methyl iodide, ethyl iodide, and the like). These salts may be prepared by methods known to those skilled in the art.
[0070] The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents.
[0071] In addition to salt forms, the present disclosure provides compounds, which are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present disclosure. Prodrugs of the compounds described herein may be converted in vivo after administration. Additionally, prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment, such as, for example, when contacted with a suitable enzyme or chemical reagent.
[0072] Certain compounds of the present disclosure can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present disclosure. Certain compounds of the present disclosure may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure.
[0073] “Pharmaceutically acceptable excipient” and“pharmaceutically acceptable carrier” refer to a substance that aids the administration of an active agent to and absorption by a subject and can be included in the compositions of the present invention without causing a significant adverse toxicological effect on the patient. Non-limiting examples of
pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer’s solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention. One of skill in the art will recognize that other pharmaceutical excipients are useful in the present invention.
[0074] The term“preparation” is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
[0075] As used herein, the term“about” means a range of values including the specified value, which a person of ordinary skill in the art would consider reasonably similar to the specified value. In embodiments, about means within a standard deviation using
measurements generally acceptable in the art. In embodiments, about means a range extending to +/- 10% of the specified value. In embodiments, about includes the specified value.
[0076] The term“electrophilic” as used herein refers to a chemical group that is capable of accepting electron density. An“electrophilic substituent,”“electrophilic chemical moiety,” or“electrophic moiety” refers to an electron-poor chemical group, substitutent, or moiety (monovalent chemical group), which may react with an electron-donating group, such as a nucleophile, by accepting an electron pair or electron density to form a bond. In some embodiments, the electrophilic substituent of the compound is capable of reacting with a cysteine residue. In some embodiments, the electrophilic substituent is capable of forming a covalent bond with a cysteine residue (e.g., LC3, p62, NBR1, NDP52, or Optineurin cysteine residue) and may be referred to as a“covalent cysteine modifier moiety” or“covalent cysteine modifier substituent.” The covalent bond formed between the electrophilic substituent and the sulfhydryl group of the cysteine may be a reversible or irreversible bond. In some embodiments, the electrophilic substituent of the compound is capable of reacting with a lysine residue. In some embodiments, the electrophilic substituent of the compound is capable of reacting with a serine residue. In some embodiments, the electrophilic substituent of the compound is capable of reacting with a methionine residue.
[0077] “Nucleophilic” as used herein refers to a chemical group that is capable of donating electron density.
[0078] The term“leaving group” is used in accordance with its ordinary meaning in chemistry and refers to a moiety (e.g., atom, functional group, molecule) that separates from the molecule following a chemical reaction (e.g., bond formation, reductive elimination, condensation, cross-coupling reaction) involving an atom or chemical moiety to which the leaving group is attached, also referred to herein as the“leaving group reactive moiety”, and a complementary reactive moiety (i.e., a chemical moiety that reacts with the leaving group reactive moiety) to form a new bond between the remnants of the leaving groups reactive moiety and the complementary reactive moiety. Thus, the leaving group reactive moiety and the complementary reactive moiety form a complementary reactive group pair. Non limiting examples of leaving groups include hydrogen, hydroxide, organotin moieties (e.g., organotin heteroalkyl), halogen (e.g., Br), perfluoroalkylsulfonates (e.g., triflate), tosylates, mesylates, water, alcohols, nitrate, phosphate, thioether, amines, ammonia, fluoride, carboxylate, phenoxides, boronic acid, boronate esters, substituted or unsubstituted piperazinyl, and alkoxides. In embodiments, two molecules with leaving groups are allowed to contact, and upon a reaction and/or bond formation (e.g., acyloin condensation, aldol condensation, Claisen condensation, Stille reaction) the leaving groups separates from the respective molecule. In embodiments, a leaving group is a bioconjugate reactive moiety. In embodiments, at least two leaving groups (e.g., R1 and R13) are allowed to contact such that the leaving groups are sufficiently proximal to react, interact or physically touch. In embodiments, the leaving groups is designed to facilitate the reaction. In embodiments, the leaving group is a substituent group.
[0079] The term“protecting group” is used in accordance with its ordinary meaning in organic chemistry and refers to a moiety covalently bound to a heteroatom, heterocycloalkyl, or heteroaryl to prevent reactivity of the heteroatom, heterocycloalkyl, or heteroaryl during one or more chemical reactions performed prior to removal of the protecting group.
Typically a protecting group is bound to a heteroatom (e.g., O) during a part of a multipart synthesis wherein it is not desired to have the heteroatom react (e.g., a chemical reduction) with the reagent. Following protection the protecting group may be removed (e.g., by modulating the pH). In embodiments the protecting group is an alcohol protecting group. Non-limiting examples of alcohol protecting groups include acetyl, benzoyl, benzyl, methoxymethyl ether (MOM), tetrahydropyranyl (THP), and silyl ether (e.g., trimethylsilyl (TMS)). In embodiments the protecting group is an amine protecting group. Non-limiting examples of amine protecting groups include carbobenzyloxy (Cbz), tert-butyloxycarbonyl (BOC), 9-fluorenylmethyloxycarbonyl (FMOC), acetyl, benzoyl, benzyl, carbamate, p- methoxybenzyl ether (PMB), and tosyl (Ts). In embodiments, the protecting group is -PO3H or -SO3H. In embodiments, the protecting group is a substituent group.
[0080] The terms“polypeptide,”“peptide,” and“protein” are used interchangeably herein to refer to a polymer of amino acid residues, wherein the polymer may optionally be conjugated to a moiety that does not consist of amino acids. The terms apply to amino acid polymers in which one or more amino acid residue is an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymer.
[0081] A polypeptide, or a cell is“recombinant” when it is artificial or engineered, or derived from or contains an artificial or engineered protein or nucleic acid (e.g., non-natural or not wild-type). For example, a polynucleotide that is inserted into a vector or any other heterologous location, e.g., in a genome of a recombinant organism, such that it is not associated with nucleotide sequences that normally flank the polynucleotide as it is found in nature is a recombinant polynucleotide. A protein expressed in vitro or in vivo from a recombinant polynucleotide is an example of a recombinant polypeptide. Likewise, a polynucleotide sequence that does not appear in nature, for example a variant of a naturally occurring gene, is recombinant.
[0082] “Co-administer” is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies. The compounds of the invention can be administered alone or can be coadministered to the patient. Coadministration is meant to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound). Thus, the preparations can also be combined, when desired, with other active substances (e.g., to reduce metabolic degradation). The compositions of the present invention can be delivered transdermally, by a topical route, or formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols. [0083] A“cell” as used herein, refers to a cell carrying out metabolic or other function sufficient to preserve or replicate its genomic DNA. A cell can be identified by well-known methods in the art including, for example, presence of an intact membrane, staining by a particular dye, ability to produce progeny or, in the case of a gamete, ability to combine with a second gamete to produce a viable offspring. Cells may include prokaryotic and eukaroytic cells. Prokaryotic cells include but are not limited to bacteria. Eukaryotic cells include but are not limited to yeast cells and cells derived from plants and animals, for example mammalian, insect (e.g., spodoptera) and human cells. Cells may be useful when they are naturally nonadherent or have been treated not to adhere to surfaces, for example by trypsinization.
[0084] The terms“treating” or“treatment” refers to any indicia of success in the treatment or amelioration of an injury, disease, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient’s physical or mental well-being. The treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neuropsychiatric exams, and/or a psychiatric evaluation. For example, the certain methods presented herein successfully treat cancer by decreasing the incidence of cancer and or causing remission of cancer. In some embodiments of the compositions or methods described herein, treating cancer includes slowing the rate of growth or spread of cancer cells, reducing metastasis, or reducing the growth of metastatic tumors. The term“treating” and conjugations thereof, include prevention of an injury, pathology, condition, or disease. In embodiments, treating is preventing. In embodiments, treating does not include preventing. In embodiments, the treating or treatment is no prophylactic treatment.
[0085] An“effective amount” is an amount sufficient for a compound to accomplish a stated purpose relative to the absence of the compound (e.g., achieve the effect for which it is administered, treat a disease, reduce enzyme activity, increase enzyme activity, reduce signaling pathway, reduce one or more symptoms of a disease or condition (e.g., reduce signaling pathway stimulated by an autophagy adapter protein, reduce the signaling pathway activity of an autophagy protein). An example of an“effective amount” is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease, which could also be referred to as a“therapeutically effective amount” when referred to in this context. A“reduction” of a symptom or symptoms (and grammatical equivalents of this phrase) means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s). A“prophylactically effective amount” of a drug is an amount of a drug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of an injury, disease, pathology or condition, or reducing the likelihood of the onset (or reoccurrence) of an injury, disease, pathology, or condition, or their symptoms. The full prophylactic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations. An“activity decreasing amount,” as used herein, refers to an amount of antagonist required to decrease the activity of an enzyme relative to the absence of the antagonist. A“function disrupting amount,” as used herein, refers to the amount of antagonist required to disrupt the function of an enzyme or protein relative to the absence of the antagonist. The exact amounts will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols.1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).
[0086] “Control” or“control experiment” is used in accordance with its plain ordinary meaning and refers to an experiment in which the subjects or reagents of the experiment are treated as in a parallel experiment except for omission of a procedure, reagent, or variable of the experiment. In some instances, the control is used as a standard of comparison in evaluating experimental effects. In some embodiments, a control is the measurement of the activity (e.g., signaling pathway) of a protein in the absence of a compound as described herein (including embodiments, examples, figures, or Tables).
[0087] “Contacting” is used in accordance with its plain ordinary meaning and refers to the process of allowing at least two distinct species (e.g., chemical compounds including biomolecules, or cells) to become sufficiently proximal to react, interact or physically touch. It should be appreciated; however, the resulting reaction product can be produced directly from a reaction between the added reagents or from an intermediate from one or more of the added reagents which can be produced in the reaction mixture. [0088] The term“contacting” may include allowing two species to react, interact, or physically touch, wherein the two species may be a compound as described herein and a cellular component (e.g., protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, virus, lipid droplet, vesicle, small molecule, protein complex, protein aggregate, or macromolecule). In some embodiments contacting includes allowing a compound described herein to interact with a cellular component (e.g., protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, virus, lipid droplet, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule) that is involved in a signaling pathway.
[0089] As defined herein, the term“inhibition,”“inhibit,”“inhibiting” and the like in reference to a cellular component-inhibitor interaction means negatively affecting (e.g., decreasing) the activity or function of the cellular component (e.g., decreasing the signaling pathway stimulated by a cellular component (e.g., protein, ion, lipid, virus, lipid droplet, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or
macromolecule)), relative to the activity or function of the cellular component in the absence of the inhibitor. In some embodiments inhibition refers to reduction of a disease or symptoms of disease. In some embodiments, inhibition refers to a reduction in the activity of a signal transduction pathway or signaling pathway (e.g., reduction of a pathway involving the cellular component). Thus, inhibition includes, at least in part, partially or totally blocking stimulation, decreasing, preventing, or delaying activation, or inactivating, desensitizing, or down-regulating the signaling pathway or enzymatic activity or the amount of a cellular component.
[0090] The term“modulator” refers to a composition that increases or decreases the level of a target molecule or the function of a target molecule or the physical state of the target of the molecule (e.g., a target may be a cellular component (e.g., protein, ion, lipid, virus, lipid droplet, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular
compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule)) relative to the absence of the composition.
[0091] The term“modulate” is used in accordance with its plain ordinary meaning and refers to the act of changing or varying one or more properties.“Modulation” refers to the process of changing or varying one or more properties. For example, as applied to the effects of a modulator on a target protein, to modulate means to change by increasing or decreasing a property or function of the target molecule or the amount of the target molecule.
[0092] “Patient” or“subject in need thereof” refers to a living organism suffering from or prone to a disease or condition that can be treated by administration of a pharmaceutical composition as provided herein. Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammalian animals. In some embodiments, a patient is human.
[0093] “Disease” or“condition” refer to a state of being or health status of a patient or subject capable of being treated with the compounds or methods provided herein. In some embodiments, the disease is a disease related to (e.g., caused by) a cellular component (e.g., protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule).
[0094] The term“associated” or“associated with” in the context of a substance or substance activity or function associated with a disease (e.g., a disease associated with bacterial infection activity) means that the disease (e.g., infectious disease) is caused by (in whole or in part), or a symptom of the disease is caused by (in whole or in part) the substance or substance activity or function. In embodiments, the infectious disease is a bacteria associated disease (e.g., actinomycosis, anthrax, abscesses in tissues (e.g., mouth in gastrointestinal tract, pelvic cavity, or lungs), whooping cough, lyme disease, brucellosis, enteritis, Guillain-Barre syndrome, pneumonia, conjunctivitis, trachoma, botulism, pseudomembranous colitis, food poisoning, tetanus, diphtheria, ehrlichiosis, bacterial endocarditis, urinary tract infection, diarrhea, meningitis (e.g., bacterial meningitis), sepsis, fever, tularemia, bronchitis, peptic ulcer, gastritis, Legionnaire’s disease, Pontiac fever, leptospirosis, listeriosis, leprosy, gonorrhea, opthalmia, nocardiosis, typhoid fever, salmonellosis, shigellosis, impetigo, cystitis, Scarlet fever, syphilis, cholera, or plague.
[0095] The term“aberrant” as used herein refers to different from normal. When used to describe enzymatic activity or protein function, aberrant refers to activity or function that is greater or less than a normal control or the average of normal non-diseased control samples. Aberrant activity may refer to an amount of activity that results in a disease, wherein returning the aberrant activity to a normal or non-disease-associated amount (e.g., by administering a compound or using a method as described herein), results in reduction of the disease or one or more disease symptoms.
[0096] A“therapeutic agent” as used herein refers to an agent (e.g., compound or composition described herein) that when administered to a subject will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of an injury, disease, pathology or condition, or reducing the likelihood of the onset (or reoccurrence) of an injury, disease, pathology, or condition, or their symptoms or the intended therapeutic effect, e.g., treatment or amelioration of an injury, disease, pathology or condition, or their symptoms including any objective or subjective parameter of treatment such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; or improving a patient’s physical or mental well-being.
[0097] The terms“immune response” and the like refer, in the usual and customary sense, to a response by an organism that protects against disease. The response can be mounted by the innate immune system or by the adaptive immune system, as well known in the art.
[0098] The terms“modulating immune response” and the like refer to a change in the immune response of a subject as a consequence of administration of an agent, e.g., a compound as disclosed herein, including embodiments thereof. Accordingly, an immune response can be activated or deactivated as a consequence of administration of an agent, e.g., a compound as disclosed herein, including embodiments thereof.
[0099] The term“infection” or“infectious disease” refers to a disease or condition that can be caused by organisms such as a bacterium, virus, fungi, parasite, or any other pathogenic microbial agents. In embodiments, the infectious disease is caused by a pathogenic bacteria. Pathogenic bacteria are bacteria that cause diseases (e.g., in humans). In embodiments, the infectious disease is a bacteria-associated disease (e.g., tuberculosis, which is caused by Mycobacterium tuberculosis). Non-limiting bacteria associated diseases include pneumonia, which may be caused by bacteria such as Streptococcus and Pseudomonas; or foodborne illnesses, which can be caused by bacteria such as Shigella, Campylobacter, and Salmonella. Bacteria-associated diseases also include tetanus, typhoid fever, diphtheria, syphilis, and leprosy. In embodiments, the disease is bacterial vaginosis (i.e., bacteria that change the vaginal microbiota caused by an overgrowth of bacteria that crowd out the Lactobacilli species that maintain healthy vaginal microbial populations) (e.g., yeast infection, or Trichomonas vaginalis); bacterial meningitis (i.e., a bacterial inflammation of the meninges); bacterial pneumonia (i.e., a bacterial infection of the lungs); urinary tract infection; bacterial gastroenteritis; or bacterial skin infections (e.g., impetigo, or cellulitis). In embodiments, the infectious disease is a Campylobacter jejuni, Enterococcus faecalis, Haemophilus influenzae, Helicobacter pylori, Klebsiella pneumoniae, Legionella pneumophila, Neisseria gonorrhoeae, Neisseria meningitides, Staphylococcus aureus, Streptococcus pneumonia, or Vibrio cholera infection. In embodiments, the infectious disease is caused by a parasite.
[0100] The term“group A streptococcal infection” is an infection with group A
streptococcus (GAS). Group A streptococcus refer to species of Gram-positive bacteria, non- motile and non-sporing cocci, which express the Lancefield group A antigen. Non-limiting examples of GAS include Streptococcus pyogenes, Streptococcus dysgalactiae, and
Streptococcus anginosus. GAS typically colonize the throat, genital mucosa, rectum, and skin. Such bacteria can cause a variety of diseases such as streptococcal pharyngitis, rheumatic fever, rheumatic heart disease, and scarlet fever.
[0101] The term“gram-positive bacteria” is used in accordance with its plain ordinary meaning and refers to bacteria that give a positive result in the gram stain test. For example, gram-positive bacteria take up the stain used in the test, and then appear to be purple- coloured when seen through a microscope due to the peptidoglycan layer in the bacterial cell wall. In contrast, gram-negative bacteria cannot retain the violet stain.
[0102] The term“gram-negative bacteria” is used in accordance with its plain ordinary meaning and refers to bacteria that are enclosed in a protective capsule. The protective capsule may help to prevent white blood cells from ingesting the bacteria.
[0103] The term“gram-positive bacterial infection” is used in accordance with its plain ordinary meaning and refers to an infection caused by gram-positive bacteria. Examples of gram-positive bacterial infections include, but are not limited to, anthrax, diphtheria, enterococcal infections, erysipelothricosis, listeriosis, pneumococcal infections,
staphylococcal aureus infections, steptrococcal infections, and toxic shock syndrome.
[0104] The term“gram-negative bacterial infection” is used in accordance with its plain ordinary meaning and refers to an infection caused by gram-negative bacteria. Examples of gram-negative bacterial infections include, but are not limited to, brucellosis, Campylobacter infections, cat-scratch disease, cholera, Escherichia coli infections, Klebsiella infections, Legionnaires’ disease, pertussis, plague, Pseudomonas infections, salmonella, shigellosis, tularemia, typhoid fever, pneumonia, peritonitis, urinary tract infections, bloodstream inections, wound or surgical site infections, and meningitis.
[0105] The term“bacteriostatic agent” is used in accordance with its ordinary meaning and refers to a compound (e.g., a compound described herein) that inhibits bacteria reproduction. In embodiments, the bacteriostatic agent does not kill the bacterial cell. In embodiments, when a compound (e.g., a compound described herein) is administered to treat an infectious disease and it does not kill the bacteria cells but inhibits (e.g., reduces reproduction, ceases reproduction) bacteria cell reproduction, it may be considered a bacteriostatic agent.
II. Compounds
[0106] In an aspect is provided a compound, or salt thereof, having the formula:
Figure imgf000043_0001
.
[0107] Y is–O- or–NH-.
[0108] L1 is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.
[0109] R2 is hydrogen or unsubstituted C1-C8 alkyl.
[0110] R4A is substituted or unsubstituted C2-C10 alkyl.
[0111] R3 and R5 are independently hydrogen, oxo, halogen, -CCI3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, -OPO3H, -OSO3H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0112] R6 is hydrogen, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or an amino acid side chain.
[0113] R7 is hydrogen, -CH2COOH, -CONH2, -OH, -SH, -NO2, -NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0114] R6 and R7 may optionally be joined to form an unsubstituted heterocycloalkyl or unsubstituted heteroaryl.
[0115] R8 is independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0116] Ring A is cycloalkylene, heterocycloalkylene, arylene, or heteroarylene.
[0117] z8 is an integer from 0 to 10.
[0118] R9 is hydrogen, oxo, halogen, -CCI3, -CBr3, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0119] R10 is hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0120] R11 is hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0121] R12 hydrogen, oxo, halogen, -CCI3, -CBr3, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0122] In embodiments, the compound has the formula:
Y is -O- or -NH-; L1 is a bond, substituted or
Figure imgf000046_0001
unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; R2 is hydrogen or unsubstituted C1-C3 alkyl; R4A is substituted or unsubstituted C2-C10 alkyl; R3 and R5 are independently hydrogen, oxo, halogen, -CCI3, -CBn, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, -CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -0NH2, -NHC(0)NHNH2, -NHC(0)NH2, -NHSO2H, -NHC(0)H, -NHC(0)0H, -NHOH, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, -N3, -OPO3H, -OSO3H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R6 is hydrogen, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, -NHC(0)NH2, -NHSO2H, -NHC(0)H, -NHC(0)0H, -NHOH, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or an amino acid side chain; R7 is hydrogen, -CH2COOH, -CONH2, -OH, -SH, -NO2, -NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R6 and R7 may optionally be joined to form an unsubstituted heterocycloalkyl or unsubstituted heteroaryl; R8 is oxo, halogen, -CCI3, -CBr3, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, -CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -S04H, -SO2NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, -NHC(0)NH2, -NHSO2H, -NHC(0)H, -NHC(0)0H, -NHOH, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Ring A is cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; z8 is an integer from 0 to 10; R9 is hydrogen, oxo, halogen, -CCI3, -CBr3, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R10 and R12 are independently hydrogen, substituted or unsubstituted C1-C3 alkyl, or substituted or unsubstituted 2 to 3 membered heteroalkyl; R11 is hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0123] In embodiments, the compound has the formula:
Figure imgf000047_0001
Y, L1, R2, R3, R4A, R5, R6, R7, Ring A, R8, z8, R9, R10, R11, and R12 are as described herein, including in embodiments.
[0124] In embodiments, R4A is a substituted C2-C10 alkyl. In embodiments, R4A is an unsubstituted C2-C10 alkyl. In embodiments, R4A is a substituted or unsubstituted C3-C10 alkenyl. In embodiments, R4A is a substituted C3-C10 alkenyl. In embodiments, R4A is an unsubstituted C3-C10 alkenyl. In embodiments, R4A is a substituted or unsubstituted C3-C6 alkenyl. In embodiments, R4A is a substituted C3-C6 alkenyl. In embodiments, R4A is an unsubstituted C3-C6 alkenyl. In embodiments, R4A is an unsubstituted C3 alkenyl. In embodiments, R4A is an unsubstituted C4 alkenyl. In embodiments, R4A is an unsubstituted C5 alkenyl. In embodiments, R4A is an unsubstituted C6 alkenyl. In embodiments, R4A is
Figure imgf000048_0001
.
[0125] In embodiments, a substituted R4A (e.g., substituted alkyl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R4A is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size- limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R4A is substituted, it is substituted with at least one substituent group. In embodiments, when R4A is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R4A is substituted, it is substituted with at least one lower substituent group.
[0126] In embodiments, Y is–O-. In embodiments, Y is–NH-.
[0127] In embodiments, L1 is a bond, substituted or unsubstituted alkylene (e.g., C1-C8 alkylene, C1-C6 alkylene, or C1-C4 alkylene), or substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene).
[0128] In embodiments, a substituted L1 (e.g., substituted alkylene and/or substituted heteroalkylene) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted L1 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when L1 is substituted, it is substituted with at least one substituent group. In embodiments, when L1 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when L1 is substituted, it is substituted with at least one lower substituent group.
[0129] In embodiments, L1 is a bond. In embodiments, L1 is a substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. In embodiments, L1 is a substituted or unsubstituted alkylene. In embodiments, L1 is a substituted or unsubstituted alkenylene. In embodiments, L1 is a substituted or unsubstituted heteroalkylene.
[0130] In embodiments, L1 is a substituted or unsubstituted alkylene (e.g., C1-C8 alkylene, C1-C6 alkylene, or C1-C4 alkylene). In embodiments, L1 is a substituted alkylene (e.g., C1-C8 alkylene, C1-C6 alkylene, or C1-C4 alkylene). In embodiments, L1 is an unsubstituted alkylene (e.g., C1-C8 alkylene, C1-C6 alkylene, or C1-C4 alkylene). In embodiments, L1 is an unsubstituted C1-C8 alkylene. In embodiments, L1 is an unsubstituted C2-C6 alkylene. In embodiments, L1 is an unsubstituted C2-C4 alkylene. In embodiments, L1 is an unsubstituted C2-C3 alkylene.
[0131] In embodiments, L1 is a substituted or unsubstituted alkenylene (e.g., C1-C8 alkenylene, C1-C6 alkenylene, or C1-C4 alkenylene). In embodiments, L1 is a substituted alkenylene (e.g., C1-C8 alkenylene, C1-C6 alkenylene, or C1-C4 alkenylene). In embodiments, L1 is an unsubstituted alkenylene (e.g., C1-C8 alkenylene, C1-C6 alkenylene, or C1-C4 alkenylene). In embodiments, L1 is an unsubstituted C1-C8 alkenylene. In embodiments, L1 is an unsubstituted C2-C6 alkenylene. In embodiments, L1 is an unsubstituted C2-C4 alkenylene. In embodiments, L1 is an unsubstituted C2-C3 alkenylene.
[0132] In embodiments, L1 is a substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered
heteroalkylene). In embodiments, L1 is a substituted heteroalkylene (e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene). In embodiments, L1 is an unsubstituted heteroalkylene (e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene).
[0133] In embodiments, L1 is a substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. In embodiments, L1 is a substituted or unsubstituted alkenylene. In embodiments, L1 is a substituted or unsubstituted C1-C3 alkenylene. In embodiments, L1 has the formula:
Figure imgf000049_0001
, wherein n1 is an integer from 0 to 10. In embodiments, n1 is 0. In embodiments, n1 is 1. In embodiments, n1 is 2. In embodiments, n1 is 3. In embodiments, L1 is
Figure imgf000049_0003
. In embodiments, L1 is
Figure imgf000049_0002
.
[0134] In embodiments, L1 is a bond, R61-substituted or unsubstituted alkylene (e.g., C1-C8 alkylene, C1-C6 alkylene, or C1-C4 alkylene), or R61-substituted or unsubstituted
heteroalkylene (e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene).
[0135] In embodiments, L1 is R61-substituted or unsubstituted alkylene (e.g., C1-C8 alkylene, C1-C6 alkylene, or C1-C4 alkylene). In embodiments, L1 is R61-substituted alkylene (e.g., C1-C8 alkylene, C1-C6 alkylene, or C1-C4 alkylene). In embodiments, L1 is an unsubstituted alkylene (e.g., C1-C8 alkylene, C1-C6 alkylene, or C1-C4 alkylene).
[0136] In embodiments, L1 is R61-substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered
heteroalkylene). In embodiments, L1 is R61-substituted heteroalkylene (e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene). In embodiments, L1 is an unsubstituted heteroalkylene (e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene).
[0137] In embodiments, R2 is hydrogen or unsubstituted methyl. In embodiments, R2 is hydrogen. In embodiments, R2 is an unsubstituted C1-C3 alkyl. In embodiments, R2 is an unsubstituted methyl. In embodiments, R2 is an unsubstituted C2 alkyl. In embodiments, R2 is an unsubstituted C3 alkyl. In embodiments, R2 is an unsubstituted C4 alkyl. In embodiments, R2 is an unsubstituted C5 alkyl. In embodiments, R2 is an unsubstituted C6 alkyl. In embodiments, R2 is an unsubstituted C7 alkyl. In embodiments, R2 is an unsubstituted C8 alkyl.
[0138] In embodiments, R2 is hydrogen or unsubstituted C1-C3 alkyl. In embodiments, R2 is an unsubstituted methyl. In embodiments, R2 is an unsubstituted ethyl. In embodiments, R2 is an unsubstituted propyl. In embodiments, R2 is an unsubstituted n-propyl. In embodiments, R2 is an unsubstituted isopropyl.
[0139] In embodiments, R3 is hydrogen, oxo, halogen, -CCI3, -CBr3, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, -OPO3H, -OSO3H, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or 2 to 3 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6- C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0140] In embodiments, a substituted R3 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R3 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R3 is substituted, it is substituted with at least one substituent group. In embodiments, when R3 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R3 is substituted, it is substituted with at least one lower substituent group.
[0141] In embodiments, R3 is hydrogen, oxo, halogen, -CCI3, -CBr3, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, or -N3. In embodiments, R3 is hydrogen. In embodiments, R3 is oxo. In embodiments, R3 is halogen. In
embodiments, R3 is -CCI3. In embodiments, R3 is -CBr3. In embodiments, R3 is -CF3. In embodiments, R3 is -CI3. In embodiments, R3 is -CHCl2. In embodiments, R3 is -CHBr2. In embodiments, R3 is -CHF2. In embodiments, R3 is -CHI2. In embodiments, R3 is -CH2Cl. In embodiments, R3 is -CH2Br. In embodiments, R3 is -CH2F. In embodiments, R3 is -CH2I. In embodiments, R3 is -CN. In embodiments, R3 is -OH. In embodiments, R3 is -NH2. In embodiments, R3 is -COOH. In embodiments, R3 is -CONH2. In embodiments, R3 is -NO2. In embodiments, R3 is -SH. In embodiments, R3 is -SO3H. In embodiments, R3 is -SO4H. In embodiments, R3 is -SO2NH2. In embodiments, R3 is -NHNH2. In embodiments, R3 is -ONH2. In embodiments, R3 is -NHC(O)NHNH2. In embodiments, R3 is -NHC(O)NH2. In embodiments, R3 is -NHSO2H. In embodiments, R3 is -NHC(O)H. In embodiments, R3 is -NHC(O)OH. In embodiments, R3 is -NHOH. In embodiments, R3 is -OCCl3. In embodiments, R3 is -OCF3. In embodiments, R3 is -OCBr3. In embodiments, R3 is -OCI3. In embodiments, R3 is -OCHCl2. In embodiments, R3 is -OCHBr2. In embodiments, R3 is -OCHI2. In embodiments, R3 is -OCHF2. In embodiments, R3 is -OCH2Cl. In
embodiments, R3 is -OCH2Br. In embodiments, R3 is -OCH2I. In embodiments, R3 is -OCH2F. In embodiments, R3 is -N3. In embodiments, R3 is hydrogen or substituted or unsubstituted alkyl. In embodiments, R3 is -OPO3H. In embodiments, R3 is -OSO3H. [0142] In embodiments, R3 is a substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0143] In embodiments, R3 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl. In embodiments, R3 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) alkyl. In embodiments, R3 is an unsubstituted alkyl. In embodiments, R3 is a substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R3 is a substituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R3 is an unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2).
[0144] In embodiments, R3 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl. In embodiments, R3 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroalkyl. In embodiments, R3 is an unsubstituted heteroalkyl. In embodiments, R3 is a substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R3 is a substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R3 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
[0145] In embodiments, R3 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl. In embodiments, R3 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) cycloalkyl. In embodiments, R3 is an unsubstituted cycloalkyl. In embodiments, R3 is a substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, R3 is a substituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, R3 is an unsubstituted cycloalkyl (e.g., C3- C8, C3-C6, C4-C6, or C5-C6).
[0146] In embodiments, R3 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl. In embodiments, R3 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heterocycloalkyl. In embodiments, R3 is an unsubstituted heterocycloalkyl. In embodiments, R3 is a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R3 is a substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R3 an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
[0147] In embodiments, R3 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted aryl. In embodiments, R3 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) aryl. In embodiments, R3 is an unsubstituted aryl. In embodiments, R3 is a substituted or unsubstituted aryl (e.g., C6-C10 or phenyl). In embodiments, R3 is substituted aryl (e.g., C6-C10 or phenyl). In embodiments, R3 is an unsubstituted aryl (e.g., C6-C10 or phenyl).
[0148] In embodiments, R3 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl. In embodiments, R3 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroaryl. In embodiments, R3 is an unsubstituted heteroaryl. In embodiments, R3 is a substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R3 is a substituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R3 is an unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
[0149] In embodiments, R3 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, R3 is hydrogen, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0150] In embodiments, R3 is hydrogen or R38-substituted or unsubstituted alkyl (e.g., C1- C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R38-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R38- substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R38-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R38-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R38-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0151] In embodiments, R3 is R38-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1- C6 alkyl, or C1-C4 alkyl). In embodiments, R3 is R38-substituted alkyl (e.g., C1-C8 alkyl, C1- C6 alkyl, or C1-C4 alkyl). In embodiments, R3 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1- C6 alkyl, or C1-C4 alkyl).
[0152] In embodiments, R3 is R38-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R3 is R38-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R3 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
[0153] In embodiments, R3 is R38-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R3 is R38-substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R3 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
[0154] In embodiments, R3 is R38-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R3 is R38-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R3 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
[0155] In embodiments, R3 is R38-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R3 is R38-substituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R3 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). [0156] In embodiments, R3 is R38-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R3 is R38-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R3 is an
unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0157] In embodiments, R5 is hydrogen, oxo, halogen, -CCI3, -CBr3, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, -OPO3H, -OSO3H, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or 2 to 3 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6- C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
[0158] In embodiments, a substituted R5 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R5 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R5 is substituted, it is substituted with at least one substituent group. In embodiments, when R5 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R5 is substituted, it is substituted with at least one lower substituent group.
[0159] In embodiments, R5 is hydrogen, oxo, halogen, -CCI3, -CBr3, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0160] In embodiments, R5 is hydrogen, oxo, halogen, -CCI3, -CBr3, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, or -N3. In embodiments, R5 is hydrogen. In embodiments, R5 is oxo. In embodiments, R5 is halogen. In
embodiments, R5 is -CCI3. In embodiments, R5 is -CBr3. In embodiments, R5 is -CF3. In embodiments, R5 is -CI3. In embodiments, R5 is -CHCl2. In embodiments, R5 is -CHBr2. In embodiments, R5 is -CHF2. In embodiments, R5 is -CHI2. In embodiments, R5 is -CH2Cl. In embodiments, R5 is -CH2Br. In embodiments, R5 is -CH2F. In embodiments, R5 is -CH2I. In embodiments, R5 is -CN. In embodiments, R5 is -OH. In embodiments, R5 is -NH2. In embodiments, R5 is -COOH. In embodiments, R5 is -CONH2. In embodiments, R5 is -NO2. In embodiments, R5 is -SH. In embodiments, R5 is -SO3H. In embodiments, R5 is -SO4H. In embodiments, R5 is -SO2NH2. In embodiments, R5 is -NHNH2. In embodiments, R5 is -ONH2. In embodiments, R5 is -NHC(O)NHNH2. In embodiments, R5 is -NHC(O)NH2. In embodiments, R5 is -NHSO2H. In embodiments, R5 is -NHC(O)H. In embodiments, R5 is -NHC(O)OH. In embodiments, R5 is -NHOH. In embodiments, R5 is -OCCl3. In embodiments, R5 is -OCF3. In embodiments, R5 is -OCBr3. In embodiments, R5 is -OCI3. In embodiments, R5 is -OCHCl2. In embodiments, R5 is -OCHBr2. In embodiments, R5 is -OCHI2. In embodiments, R5 is -OCHF2. In embodiments, R5 is -OCH2Cl. In
embodiments, R5 is -OCH2Br. In embodiments, R5 is -OCH2I. In embodiments, R5 is -OCH2F. In embodiments, R5 is -N3. In embodiments, R5 is -OPO3H. In embodiments, R5 is -OSO3H.
[0161] In embodiments, R5 is a substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, R5 is R33-substituted or unsubstituted alkyl, R33-substituted or unsubstituted heteroalkyl, R33-substituted or unsubstituted cycloalkyl, R33-substituted or unsubstituted heterocycloalkyl, R33-substituted or unsubstituted aryl, or R33-substituted or unsubstituted heteroaryl.
[0162] In embodiments, R5 is R33-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1- C6 alkyl, or C1-C4 alkyl), R33-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R33-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R33- substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R33-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R33-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0163] In embodiments, R5 is R33-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1- C6 alkyl, or C1-C4 alkyl). In embodiments, R5 is R33-substituted alkyl (e.g., C1-C8 alkyl, C1- C6 alkyl, or C1-C4 alkyl). In embodiments, R5 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1- C6 alkyl, or C1-C4 alkyl).
[0164] In embodiments, R5 is R33-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R5 is R33-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R5 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
[0165] In embodiments, R5 is R33-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R5 is R33-substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R5 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
[0166] In embodiments, R5 is R33-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R5 is R33-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R5 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
[0167] In embodiments, R5 is R33-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R5 is R33-substituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R5 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).
[0168] In embodiments, R5 is R33-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R5 is R33-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R5 is an
unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0169] In embodiments, R5 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, R5 is hydrogen, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0170] In embodiments, R5 is a substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, R5 is an unsubstituted C1-C6 alkyl. In embodiments, R5 is an unsubstituted C3 alkyl. In embodiments, R5 is an unsubstituted isopropyl.
[0171] In embodiments, R5 is:
Figure imgf000058_0001
[0172] In embodiments, R5 is hydrogen, oxo, halogen, -CCI3, -CBr3, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. In embodiments, R5 is a substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, R5 is a substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, or substituted or unsubstituted 5 to 10 membered heteroaryl. In embodiments, R5 is a substituted or unsubstituted C1-C8 alkyl. In embodiments, R5 is a substituted or unsubstituted C1-C3 alkyl.
[0173] R33 is independently oxo, halogen, -CCI3, -CBr3, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or 2 to 3 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
[0174] In embodiments, a substituted R33 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R33 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R33 is substituted, it is substituted with at least one substituent group. In embodiments, when R33 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R33 is substituted, it is substituted with at least one lower substituent group.
[0175] In embodiments, R33 is oxo, halogen, -CCI3, -CBr3, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, R33 is a substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0176] In embodiments, R33 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl. In embodiments, R33 is substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) alkyl. In embodiments, R33 is an unsubstituted alkyl. In embodiments, R33 is a substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R33 is a substituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R33 is an unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2).
[0177] In embodiments, R33 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl. In embodiments, R33 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroalkyl. In embodiments, R33 is an unsubstituted heteroalkyl. In embodiments, R33 is a substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R33 is substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R33 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
[0178] In embodiments, R33 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl. In embodiments, R33 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) cycloalkyl. In embodiments, R33 is an unsubstituted cycloalkyl. In embodiments, R33 is a substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, R33 is a substituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, R33 is an unsubstituted cycloalkyl (e.g., C3- C8, C3-C6, C4-C6, or C5-C6).
[0179] In embodiments, R33 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl. In embodiments, R33 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heterocycloalkyl. In embodiments, R33 is an unsubstituted heterocycloalkyl. In embodiments, R33 is a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R33 is a substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R33 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
[0180] In embodiments, R33 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted aryl. In embodiments, R33 is substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) aryl. In embodiments, R33 is an unsubstituted aryl. In embodiments, R33 is a substituted or unsubstituted aryl (e.g., C6-C10 or phenyl). In embodiments, R33 is a substituted aryl (e.g., C6-C10 or phenyl). In embodiments, R33 is an unsubstituted aryl (e.g., C6-C10 or phenyl).
[0181] In embodiments, R33 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl. In embodiments, R33 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroaryl. In embodiments, R33 is an unsubstituted heteroaryl. In embodiments, R33 is a substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R33 is a substituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R33 is an unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
[0182] In embodiments, R33 is oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, R36-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R36-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R36-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R36-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R36-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R36-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0183] In embodiments, R33 is independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, R36-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R36- substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R36-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R36-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R36-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R36-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0184] In embodiments, R33 is R36-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1- C6 alkyl, or C1-C4 alkyl), R36-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R36-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R36- substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R36-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R36-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0185] In embodiments, R33 is R36-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1- C6 alkyl, or C1-C4 alkyl). In embodiments, R33 is R36-substituted alkyl (e.g., C1-C8 alkyl, C1- C6 alkyl, or C1-C4 alkyl). In embodiments, R33 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).
[0186] In embodiments, R33 is R36-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R33 is R36-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R33 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
[0187] In embodiments, R33 is R36-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R33 is R36-substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R33 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
[0188] In embodiments, R33 is R36-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R33 is R36-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R33 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
[0189] In embodiments, R33 is R36-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R33 is R36-substituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R33 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).
[0190] In embodiments, R33 is R36-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R33 is R36-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R33 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0191] R36 is independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, R37-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R37-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R37-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R37-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R37-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R37-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0192] In embodiments, R36 is R37-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1- C6 alkyl, or C1-C4 alkyl), R37-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R37-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R37- substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R37-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R37-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0193] In embodiments, R36 is R37-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1- C6 alkyl, or C1-C4 alkyl). In embodiments, R36 is R37-substituted alkyl (e.g., C1-C8 alkyl, C1- C6 alkyl, or C1-C4 alkyl). In embodiments, R36 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).
[0194] In embodiments, R36 is R37-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R36 is R37-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R36 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). [0195] In embodiments, R36 is R37-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R36 is R37-substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R36 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
[0196] In embodiments, R36 is R37-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R36 is R37-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R36 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
[0197] In embodiments, R36 is R37-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R36 is R37-substituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R36 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).
[0198] In embodiments, R36 is R37-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R36 is R37-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R36 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0199] In embodiments, R5 is an unsubstituted C4 alkyl. In embodiments, R5 is an unsubstituted C3 alkyl. In embodiments, R5 is isopropyl. In embodiments, R5 is tert-butyl.
In embodiments, R5 is
Figure imgf000065_0006
wherein R33 is as described herein. In embodiments, R5 is
Figure imgf000065_0001
. In embodiments, R5 is
Figure imgf000065_0005
. In embodiments, R5 is
Figure imgf000065_0004
In
embodiments, R5 is In embodiments, R5 is In embodiments, R5 is
Figure imgf000065_0002
Figure imgf000065_0003
Figure imgf000066_0001
. In embodiments, R5 is
Figure imgf000066_0002
, wherein n33 is an integer from 0 to 20. In embodiments, n33 is an integer from 0 to 4. [0200] In embodiments, R5 is
Figure imgf000066_0003
. In embodiments, R5 is
Figure imgf000066_0004
. In embodiments, R5 is In embodiments, R5 is
Figure imgf000066_0006
Figure imgf000066_0005
. In
embodiments, R5 is
Figure imgf000066_0014
. In embodiments, R5 is
Figure imgf000066_0007
. In embodiments, R5 is
Figure imgf000066_0013
. In embodiments, R5 is
Figure imgf000066_0011
In embodiments, R5 is
Figure imgf000066_0012
. In embodiments, R5 . In embodiments, R5 is
Figure imgf000066_0010
. In embodiments, R5 is In embodiments, R5 is In embodiments, R5 is In embodiments, R5 is . In embodiments, R5 is . In embodiments, R5 i . In embodiments, R5 is
Figure imgf000066_0008
Figure imgf000066_0009
Figure imgf000067_0018
. In embodiments, R5 is
Figure imgf000067_0017
In embodiments, R5 is
Figure imgf000067_0016
. In
F embodiments, R5 is . In embodiments, R5 is
Figure imgf000067_0015
H . In embodiments, R5 is
Figure imgf000067_0014
. In embodiments, R5 is
Figure imgf000067_0013
In embodiments, R5 is
Figure imgf000067_0012
In embodiments, R5 is
Figure imgf000067_0001
. In embodiments, R5 is
Figure imgf000067_0011
. In embodiments, R5 is
Figure imgf000067_0002
. In embodiments, R5 is
Figure imgf000067_0010
In embodiments, R5 is
Figure imgf000067_0003
. In embodiments, R5 is
Figure imgf000067_0009
. In embodiments, R5 is
Figure imgf000067_0004
In embodiments, R5 is
Figure imgf000067_0008
In embodiments, R5 is . In embodiments, R5 is
Figure imgf000067_0007
In embodiments, R5 is
Figure imgf000067_0005
In embodiments, R5 is In embodiments, R5 is
Figure imgf000067_0006
In embodiments, R5 is In embodiments, R5 is
Figure imgf000068_0006
Figure imgf000068_0007
Figure imgf000068_0005
. In embodiments, R5 is
Figure imgf000068_0003
. In embodiments, R5 is In
Figure imgf000068_0004
embodiments, R5 is
Figure imgf000068_0002
.
[0201] In embodiments, R5 is:
Figure imgf000068_0001
Figure imgf000069_0001
[0202] In embodiments, R5 is
Figure imgf000069_0007
In embodiments, R5 is
Figure imgf000069_0008
. In embodiments, R5 is
Figure imgf000069_0006
. In embodiments, R5 is In
Figure imgf000069_0003
embodiments, R5 is
Figure imgf000069_0004
. In embodiments, R5 is
In embodiments, R5 is . In embodiments,
Figure imgf000069_0005
Figure imgf000069_0002
R5 is . In embodiments, R5 is . In embodiments, R5 is . In embodiments, R5 is . In embodiments, R5 is . In embodiments, R5 is . In embodiments, R5 is . In embodiments, R5 is . In embodiments, R5 is . In embodiments, R5 is . In embodiments, R5 is . In embodiments, R5 is . In embodiments, R5 is . In embodiments, R5 is . In embodiments, R5 is . In embodiments, R5 is . In embodiments, R5 is
. In embodiments, R5 is . In embodiments, R5 is . In embodiments, R5 is . In
Figure imgf000071_0001
embodiments, R5 is . In embodiments, R5 is .
In embodiments, R5 is . In embodiments, R5 is .
In embodiments, R5 is . In embodiments, R5 is In
embodiments, R5 is In embodiments, R5 is In
embodiments, R5 is . In embodiments, R5 is In
embodiments, R5 is In embodiments, R5 is n
Figure imgf000071_0004
embodiments, R5 is . In embodiments, R5 is In embodiments,
Figure imgf000071_0003
Figure imgf000071_0002
. In embodiments, R5 is In embodiments, R5 is
Figure imgf000071_0006
Figure imgf000071_0005
.
[0203] In embodiments, R6 is hydrogen, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or 2 to 3 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered), or an amino acid side chain.
[0204] In embodiments, R6 is hydrogen, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or 2 to 3 membered), or an amino acid side chain.
[0205] In embodiments, a substituted R6 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R6 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R6 is substituted, it is substituted with at least one substituent group. In embodiments, when R6 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R6 is substituted, it is substituted with at least one lower substituent group.
[0206] In embodiments, R6 is hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, or -N3. In embodiments, R6 is hydrogen. In embodiments, R6 is oxo. In embodiments, R6 is halogen. In
embodiments, R6 is -CCI3. In embodiments, R6 is -CBr3. In embodiments, R6 is -CF3. In embodiments, R6 is -CI3. In embodiments, R6 is -CHCl2. In embodiments, R6 is -CHBr2. In embodiments, R6 is -CHF2. In embodiments, R6 is -CHI2. In embodiments, R6 is -CH2Cl. In embodiments, R6 is -CH2Br. In embodiments, R6 is -CH2F. In embodiments, R6 is -CH2I. In embodiments, R6 is -CN. In embodiments, R6 is -OH. In embodiments, R6 is -NH2. In embodiments, R6 is -COOH. In embodiments, R6 is -CONH2. In embodiments, R6 is -NO2. In embodiments, R6 is -SH. In embodiments, R6 is -SO3H. In embodiments, R6 is -SO4H. In embodiments, R6 is -SO2NH2. In embodiments, R6 is -NHNH2. In embodiments, R6 is -ONH2. In embodiments, R6 is -NHC(O)NHNH2. In embodiments, R6 is -NHC(O)NH2. In embodiments, R6 is -NHSO2H. In embodiments, R6 is -NHC(O)H. In embodiments, R6 is -NHC(O)OH. In embodiments, R6 is -NHOH. In embodiments, R6 is -OCCl3. In embodiments, R6 is -OCF3. In embodiments, R6 is -OCBr3. In embodiments, R6 is -OCI3. In embodiments, R6 is -OCHCl2. In embodiments, R6 is -OCHBr2. In embodiments, R6 is -OCHI2. In embodiments, R6 is -OCHF2. In embodiments, R6 is -OCH2Cl. In embodiments, R6 is -OCH2Br. In embodiments, R6 is -OCH2I. In embodiments, R6 is -OCH2F. In embodiments, R6 is -N3. In embodiments, R6 is -CH3. In embodiments, R6 is substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.
[0207] In embodiments, R6 is hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0208] In embodiments, R6 is hydrogen, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or an amino acid side chain.
[0209] In embodiments, R6 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl. In embodiments, R6 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) alkyl. In embodiments, R6 is unsubstituted alkyl. In embodiments, R6 is a substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R6 is a substituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R6 is an unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R6 is an unsubstituted C1-C2 alkyl. In embodiments, R6 is an unsubstituted C1- C4 alkyl. In embodiments, R6 is an unsubstituted C1-C6 alkyl. In embodiments, R6 is an unsubstituted C1-C8 alkyl. In embodiments, R6 is a substituted C1-C2 alkyl. In embodiments, R6 is a substituted C1-C4 alkyl. In embodiments, R6 is a substituted C1-C6 alkyl. In embodiments, R6 is a substituted C1-C8 alkyl. In embodiments, R6 is a substituted C4 alkyl. In embodiments, R6 is an alkyl substituted with–NH2, phenyl, indolyl, or imidazolyl. In
embodiments, R6 is or . In embodiments, R6 is a substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. In embodiments, R6 is a side chain of an amino acid (e.g., a side chain of a non-natural amino acid or a side chain natural NH
amino acid). In embodiments, R6 is hydrogen, , N , , , , , , , , , , , , , , , , or NH
. In embodiments, R6 is N , , ,
, or .
[0210] In embodiments, R6 is:
, , , , or .
[0211] In embodiments, R6 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl. In embodiments, R6 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroalkyl. In embodiments, R6 is an unsubstituted heteroalkyl. In embodiments, R6 is a substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R6 is a substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R6 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
[0212] In embodiments, R6 is an unsubstituted C1-C3 alkyl. In embodiments, R6 is an unsubstituted methyl.
[0213] In embodiments, R6 is R39-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1- C6 alkyl, or C1-C4 alkyl), R39-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R39-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R39- substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R39-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R39-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0214] In embodiments, R6 is R39-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1- C6 alkyl, or C1-C4 alkyl). In embodiments, R6 is R39-substituted alkyl (e.g., C1-C8 alkyl, C1- C6 alkyl, or C1-C4 alkyl). In embodiments, R6 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1- C6 alkyl, or C1-C4 alkyl).
[0215] In embodiments, R6 is R39-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R6 is R39-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R6 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
[0216] In embodiments, R6 is R39-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R6 is R39-substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R6 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
[0217] In embodiments, R6 is R39-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R6 is R39-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R6 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
[0218] In embodiments, R6 is R39-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R6 is R39-substituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R6 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).
[0219] In embodiments, R6 is R39-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R6 is R39-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R6 is an
unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0220] R39 is independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, R40-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R40-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R40-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R40-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R40-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R40-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0221] In embodiments, R39 is R40-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1- C6 alkyl, or C1-C4 alkyl), R40-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R40-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R40- substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R40-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R40-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0222] In embodiments, R39 is R40-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1- C6 alkyl, or C1-C4 alkyl). In embodiments, R39 is R40-substituted alkyl (e.g., C1-C8 alkyl, C1- C6 alkyl, or C1-C4 alkyl). In embodiments, R39 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).
[0223] In embodiments, R39 is R40-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R39 is R40-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R39 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
[0224] In embodiments, R39 is R40-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R39 is R40-substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R39 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
[0225] In embodiments, R39 is R40-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R39 is R40-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R39 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). [0226] In embodiments, R39 is R40-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R39 is R40-substituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R39 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).
[0227] In embodiments, R39 is R40-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R39 is R40-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R39 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0228] R40 is independently oxo, halogen, -CCI3, -CBr3, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, R41-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R41-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R41-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R41-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R41-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R41-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0229] In embodiments, R40 is R41-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1- C6 alkyl, or C1-C4 alkyl), R41-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R41-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R41- substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R41-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R41-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0230] In embodiments, R40 is R41-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1- C6 alkyl, or C1-C4 alkyl). In embodiments, R40 is R41-substituted alkyl (e.g., C1-C8 alkyl, C1- C6 alkyl, or C1-C4 alkyl). In embodiments, R40 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).
[0231] In embodiments, R40 is R41-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R40 is R41-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R40 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
[0232] In embodiments, R40 is R41-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R40 is R41-substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R40 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
[0233] In embodiments, R40 is R41-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R40 is R41-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R40 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
[0234] In embodiments, R40 is R41-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R40 is R41-substituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R40 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).
[0235] In embodiments, R40 is R41-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R40 is R41-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R40 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0236] In embodiments, R6 and R7 are joined to form a substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
[0237] In embodiments, a substituted moiety formed when R6 and R7 are joined (e.g., substituted heterocycloalkylene and/or substituted heteroarylene) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted moiety formed when R6 and R7 are joined is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when the moiety formed when R6 and R7 are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the moiety formed when R6 and R7 are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the moiety formed when R6 and R7 are joined is substituted, it is substituted with at least one lower substituent group.
[0238] In embodiments, R6 and R7 are joined to form a substituted or unsubstituted heterocycloalkylene or heteroarylene. In embodiments, R6 and R7 are joined to form a substituted or unsubstituted 3 to 6 membered heterocycloalkylene, or substituted or unsubstituted 5 to 6 membered heteroarylene. In embodiments, R6 and R7 are joined to form a substituted or unsubstituted 3 to 6 membered heterocycloalkylene. In embodiments, R6 and R7 are joined to form a substituted or unsubstituted pyrrolidinylene, or substituted or unsubstituted 2,3-dihydropyrrolylene. In embodiments, R6 and R7 are joined to form a substituted pyrrolidinylene or substituted 2,3-dihydropyrrolylene. In embodiments, R6 and R7 are joined to form a substituted pyrrolidinylene. In embodiments, R6 and R7 are joined to form a substituted 2,3-dihydropyrrolylene. In embodiments, R6 and R7 are joined to form an unsubstituted pyrrolidinylene. In embodiments, R6 and R7 are joined to form an
unsubstituted 2,3-dihydropyrrolylene.
[0239] In embodiments, R6 and R7 may optionally be joined to form an unsubstituted heterocycloalkylene or unsubstituted heteroarylene. [0240] In embodiments, R6 and R7 are joined to form a substituted or unsubstituted heterocycloalkylene, or substituted or unsubstituted heteroarylene, which may be referred to herein as Ring B, shown below:
Figure imgf000081_0001
, wherein the“ ” moiety attached to Ring B is a bond to the carbonyl moiety on the remainder of the compound, and z30 is an integer from 0 to 6.
[0241] R30 is independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R30 is independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,
-NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0242] In embodiments, a substituted R30 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R30 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R30 is substituted, it is substituted with at least one substituent group. In embodiments, when R30 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R30 is substituted, it is substituted with at least one lower substituent group.
[0243] In embodiments, R30 is halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R30 is halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0244] In embodiments, R30 is R58-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1- C6 alkyl, or C1-C4 alkyl), R58-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R58-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R58- substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R58-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R58-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0245] In embodiments, R30 is independently R58-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R58-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R58-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R58-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R58-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R58-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0246] In embodiments, R30 is R58-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1- C6 alkyl, or C1-C4 alkyl). In embodiments, R30 is R58-substituted alkyl (e.g., C1-C8 alkyl, C1- C6 alkyl, or C1-C4 alkyl). In embodiments, R30 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).
[0247] In embodiments, R30 is R58-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R30 is R58-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R30 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). [0248] In embodiments, R30 is R58-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R30 is R58-substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R30 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
[0249] In embodiments, R30 is R58-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R30 is R58-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R30 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
[0250] In embodiments, R30 is R58-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R30 is R58-substituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R30 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).
[0251] In embodiments, R30 is R58-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R30 is R58-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R30 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0252] In embodiments, z30 is 0. In embodiments, z30 is 1. In embodiments, z30 is 2. In embodiments, z30 is 3. In embodiments, z30 is 4. In embodiments, z30 is 5. In
embodiments, z30 is 6.
[0253] R31 is hydrogen, halogen, -CCI3, -CBr3, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0254] In embodiments, a substituted R31 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R31 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R31 is substituted, it is substituted with at least one substituent group. In embodiments, when R31 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R31 is substituted, it is substituted with at least one lower substituent group.
[0255] In embodiments, R31 is R59-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1- C6 alkyl, or C1-C4 alkyl), R59-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R59-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R59- substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R59-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R59-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0256] In embodiments, R31 is R59-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1- C6 alkyl, or C1-C4 alkyl). In embodiments, R31 is R59-substituted alkyl (e.g., C1-C8 alkyl, C1- C6 alkyl, or C1-C4 alkyl). In embodiments, R31 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).
[0257] In embodiments, R31 is R59-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R31 is R59-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R31 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
[0258] In embodiments, R31 is R59-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R31 is R59-substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R31 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
[0259] In embodiments, R31 is R59-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R31 is R59-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R31 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
[0260] In embodiments, R31 is R59-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R31 is R59-substituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R31 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).
[0261] In embodiments, R31 is R59-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R31 is R59-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R31 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0262] In embodiments, R6 and R7 are joined to form an unsubstituted 3 to 6 membered heterocycloalkylene, or an unsubstituted 5 to 6 membered heteroarylene. In embodiments, R6 and R7 are joined to form an unsubstituted 3 to 6 membered heterocycloalkylene.
[0263] In embodiments, R6 and R7 are joined to form a 4 to 8 membered
heterocycloalkylene. In embodiments, R6 and R7 are joined to form a 4 membered heterocycloalkylene. In embodiments, R6 and R7 are joined to form a 5 membered heterocycloalkylene. In embodiments, R6 and R7 are joined to form a 6 membered heterocycloalkylene. In embodiments, R6 and R7 are joined to form a 7 membered heterocycloalkylene. In embodiments, R6 and R7 are joined to form an 8 membered heterocycloalkylene. In embodiments, R6 and R7 are joined to form a 4 to 6 membered heterocycloalkylene. In embodiments, R6 and R7 are joined to form azetidinylene.
[0264] In embodiments, R6 and R7 are joined to form a substituted or unsubstituted heterocycloalkylene. In embodiments, R6 and R7 are joined to form a substituted
heterocycloalkylene. In embodiments, R6 and R7 are joined to form an unsubstituted heterocycloalkylene. In embodiments, R6 and R7 are joined to form a substituted or unsubstituted 3 to 10 membered heterocycloalkylene. In embodiments, R6 and R7 are joined to form a substituted 3 to 10 membered heterocycloalkylene. In embodiments, R6 and R7 are joined to form an unsubstituted 3 to 10 membered heterocycloalkylene. In embodiments, R6 and R7 are joined to form an R30-substituted or unsubstituted 5 to 10 membered
heterocycloalkylene. In embodiments, R6 and R7 are joined to form an R30-substituted 5 to 10 membered heterocycloalkylene. In embodiments, R6 and R7 are joined to form an unsubstituted 5 to 10 membered heterocycloalkylene.
[0265] In embodiments, R6 and R7 are joined to form a substituted or unsubstituted 3 membered heterocycloalkylene. In embodiments, R6 and R7 are joined to form a substituted or unsubstituted 4 membered heterocycloalkylene. In embodiments, R6 and R7 are joined to form a substituted or unsubstituted 5 membered heterocycloalkylene. In embodiments, R6 and R7 are joined to form a substituted or unsubstituted 6 membered heterocycloalkylene. In embodiments, R6 and R7 are joined to form a substituted 3 membered heterocycloalkylene. In embodiments, R6 and R7 are joined to form a substituted 4 membered heterocycloalkylene. In embodiments, R6 and R7 are joined to form a substituted 5 membered heterocycloalkylene. In embodiments, R6 and R7 are joined to form a substituted 6 membered heterocycloalkylene. In embodiments, R6 and R7 are joined to form an unsubstituted 3 membered
heterocycloalkylene. In embodiments, R6 and R7 are joined to form an unsubstituted 4 membered heterocycloalkylene. In embodiments, R6 and R7 are joined to form an unsubstituted 5 membered heterocycloalkylene. In embodiments, R6 and R7 are joined to form an unsubstituted 6 membered heterocycloalkylene.
[0266] In embodiments, R6 and R7 are joined to form a substituted or unsubstituted aziridinylene, azirinylene, azetidinylene, dihydroazetylene, diazetidinylene, azetylene, pyrrolidinylene, pyrrolinylene, pyrrolylene, pyrazolidinylene, imidazolidinylene, pyrazolinylene, pyrazolylene, thiazolidinylene, thiazolylene, isothiazolylene, piperidinylene, piperazinylene, morpholinylene, oxazinylene, thiomorpholinylene, thiazinylene,
decahydroquinolinylene, dihydroazepinylene, azepanylene, or azocanylene. In embodiments, R6 and R7 are joined to form a substituted aziridinylene, azirinylene, azetidinylene, dihydroazetylene, diazetidinylene, azetylene, pyrrolidinylene, pyrrolinylene, pyrrolylene, pyrazolidinylene, imidazolidinylene, pyrazolinylene, pyrazolylene, thiazolidinylene, thiazolylene, isothiazolylene, piperidinylene, piperazinylene, morpholinylene, oxazinylene, thiomorpholinylene, thiazinylene, decahydroquinolinylene, dihydroazepinylene, azepanylene, or azocanylene. In embodiments, R6 and R7 are joined to form an unsubstituted
aziridinylene, azirinylene, azetidinylene, dihydroazetylene, diazetidinylene, azetylene, pyrrolidinylene, pyrrolinylene, pyrrolylene, pyrazolidinylene, imidazolidinylene,
pyrazolinylene, pyrazolylene, thiazolidinylene, thiazolylene, isothiazolylene, piperidinylene, piperazinylene, morpholinylene, oxazinylene, thiomorpholinylene, thiazinylene,
decahydroquinolinylene, dihydroazepinylene, azepanylene, or azocanylene. In embodiments, R6 and R7 are joined to form an unsubstituted pyrrolidinylene or 2,3-dihydropyrrolylene.
[0267] In embodiments, R7 is hydrogen, -CH2COOH, -CONH2, -OH, -SH, -NO2, -NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or 2 to 3 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
[0268] In embodiments, a substituted R7 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R7 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R7 is substituted, it is substituted with at least one substituent group. In embodiments, when R7 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R7 is substituted, it is substituted with at least one lower substituent group. [0269] In embodiments, R7 is hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -COOH, -CH2COOH, -CONH2, -OH, -SH, -NO2, -NH2, -NHNH2, -ONH2, or -NHC(O)NHNH2. In embodiments, R7 is a substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, R7 is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. In embodiments, R7 is hydrogen.
[0270] In embodiments, R7 is hydrogen, -CH2COOH, -CONH2, -OH, -SH, -NO2, -NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0271] In embodiments, R7 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl. In embodiments, R7 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) alkyl. In embodiments, R7 is an unsubstituted alkyl. In embodiments, R7 is a substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R7 is a substituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R7 is an unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2).
[0272] In embodiments, R7 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl. In embodiments, R7 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroalkyl. In embodiments, R7 is an unsubstituted heteroalkyl. In embodiments, R7 is a substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R7 is a substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R7 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
[0273] In embodiments, R7 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl. In embodiments, R7 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) cycloalkyl. In embodiments, R7 is an unsubstituted cycloalkyl. In embodiments, R7 is a substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, R7 is a substituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, R7 is an unsubstituted cycloalkyl (e.g., C3- C8, C3-C6, C4-C6, or C5-C6).
[0274] In embodiments, R7 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl. In embodiments, R7 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heterocycloalkyl. In embodiments, R7 is an unsubstituted heterocycloalkyl. In embodiments, R7 is a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R7 is a substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R7 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
[0275] In embodiments, R7 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted aryl. In embodiments, R7 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) aryl. In embodiments, R7 is an unsubstituted aryl. In embodiments, R7 is a substituted or unsubstituted aryl (e.g., C6-C10 or phenyl). In embodiments, R7 is a substituted aryl (e.g., C6-C10 or phenyl). In embodiments, R7 is an unsubstituted aryl (e.g., C6-C10 or phenyl).
[0276] In embodiments, R7 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl. In embodiments, R7 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroaryl. In embodiments, R7 is an unsubstituted heteroaryl. In embodiments, R7 is a substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R7 is a substituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R7 is an unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0277] In embodiments, R7 is hydrogen or substituted or unsubstituted C1-C6 alkyl. In embodiments, R7 is hydrogen.
[0278] In embodiments, R7 is R42-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1- C7 alkyl, or C1-C4 alkyl), R42-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 7 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R42-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C7 cycloalkyl, or C5-C7 cycloalkyl), R42- substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 7 membered heterocycloalkyl, or 5 to 7 membered heterocycloalkyl), R42-substituted or unsubstituted aryl (e.g., C7-C10 aryl, C10 aryl, or phenyl), or R42-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 7 membered heteroaryl).
[0279] In embodiments, R7 is R42-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1- C7 alkyl, or C1-C4 alkyl). In embodiments, R7 is R42-substituted alkyl (e.g., C1-C8 alkyl, C1- C7 alkyl, or C1-C4 alkyl). In embodiments, R7 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1- C7 alkyl, or C1-C4 alkyl).
[0280] In embodiments, R7 is R42-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 7 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R7 is R42-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 7 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R7 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 7 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
[0281] In embodiments, R7 is R42-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C7 cycloalkyl, or C5-C7 cycloalkyl). In embodiments, R7 is R42-substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C7 cycloalkyl, or C5-C7 cycloalkyl). In embodiments, R7 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C7 cycloalkyl, or C5-C7 cycloalkyl).
[0282] In embodiments, R7 is R42-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 7 membered heterocycloalkyl, or 5 to 7 membered heterocycloalkyl). In embodiments, R7 is R42-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 7 membered heterocycloalkyl, or 5 to 7 membered heterocycloalkyl). In embodiments, R7 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 7 membered heterocycloalkyl, or 5 to 7 membered heterocycloalkyl).
[0283] In embodiments, R7 is R42-substituted or unsubstituted aryl (e.g., C7-C10 aryl, C10 aryl, or phenyl). In embodiments, R7 is R42-substituted aryl (e.g., C7-C10 aryl, C10 aryl, or phenyl). In embodiments, R7 is an unsubstituted aryl (e.g., C7-C10 aryl, C10 aryl, or phenyl).
[0284] In embodiments, R7 is R42-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 7 membered heteroaryl). In embodiments, R7 is R42-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 7 membered heteroaryl). In embodiments, R7 is an
unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 7 membered heteroaryl).
[0285] In embodiments, R8 is independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or 2 to 3 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6- C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
[0286] In embodiments, a substituted R8 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R8 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R8 is substituted, it is substituted with at least one substituent group. In embodiments, when R8 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R8 is substituted, it is substituted with at least one lower substituent group.
[0287] In embodiments, R8 is oxo, halogen, -CCI3, -CBr3, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0288] In embodiments, R8 is oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, or -N3. In embodiments, R8 is hydrogen. In embodiments, R8 is oxo. In embodiments, R8 is halogen. In
embodiments, R8 is -CCI3. In embodiments, R8 is -CBr3. In embodiments, R8 is -CF3. In embodiments, R8 is -CI3. In embodiments, R8 is -CHCl2. In embodiments, R8 is -CHBr2. In embodiments, R8 is -CHF2. In embodiments, R8 is -CHI2. In embodiments, R8 is -CH2Cl. In embodiments, R8 is -CH2Br. In embodiments, R8 is -CH2F. In embodiments, R8 is -CH2I. In embodiments, R8 is -CN. In embodiments, R8 is -OH. In embodiments, R8 is -NH2. In embodiments, R8 is -COOH. In embodiments, R8 is -CONH2. In embodiments, R8 is -NO2. In embodiments, R8 is -SH. In embodiments, R8 is -SO3H. In embodiments, R8 is -SO4H. In embodiments, R8 is -SO2NH2. In embodiments, R8 is -NHNH2. In embodiments, R8 is -ONH2. In embodiments, R8 is -NHC(O)NHNH2. In embodiments, R8 is -NHC(O)NH2. In embodiments, R8 is -NHSO2H. In embodiments, R8 is -NHC(O)H. In embodiments, R8 is -NHC(O)OH. In embodiments, R8 is -NHOH. In embodiments, R8 is -OCCl3. In embodiments, R8 is -OCF3. In embodiments, R8 is -OCBr3. In embodiments, R8 is -OCI3. In embodiments, R8 is -OCHCl2. In embodiments, R8 is -OCHBr2. In embodiments, R8 is -OCHI2. In embodiments, R8 is -OCHF2. In embodiments, R8 is -OCH2Cl. In
embodiments, R8 is -OCH2Br. In embodiments, R8 is -OCH2I. In embodiments, R8 is -OCH2F. In embodiments, R8 is -N3. [0289] In embodiments, R8 is a substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0290] In embodiments, R8 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl. In embodiments, R8 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) alkyl. In embodiments, R8 is an unsubstituted alkyl. In embodiments, R8 is a substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R8 is a substituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R8 is an unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2).
[0291] In embodiments, R8 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl. In embodiments, R8 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroalkyl. In embodiments, R8 is an unsubstituted heteroalkyl. In embodiments, R8 is a substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R8 is a substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R8 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
[0292] In embodiments, R8 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl. In embodiments, R8 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) cycloalkyl. In embodiments, R8 is an unsubstituted cycloalkyl. In embodiments, R8 is a substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, R8 is a substituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, R8 is an unsubstituted cycloalkyl (e.g., C3- C8, C3-C6, C4-C6, or C5-C6).
[0293] In embodiments, R8 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl. In embodiments, R8 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heterocycloalkyl. In embodiments, R8 is an unsubstituted heterocycloalkyl. In embodiments, R8 is a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R8 is a substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R8 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
[0294] In embodiments, R8 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted aryl. In embodiments, R8 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) aryl. In embodiments, R8 is an unsubstituted aryl. In embodiments, R8 is a substituted or unsubstituted aryl (e.g., C6-C10 or phenyl). In embodiments, R8 is a substituted aryl (e.g., C6-C10 or phenyl). In embodiments, R8 is an unsubstituted aryl (e.g., C6-C10 or phenyl).
[0295] In embodiments, R8 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl. In embodiments, R8 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroaryl. In embodiments, R8 is an unsubstituted heteroaryl. In embodiments, R8 is a substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R8 is a substituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R8 is an unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
[0296] In embodiments, R8 is R43-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1- C6 alkyl, or C1-C4 alkyl), R43-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R43-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R43- substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R43-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R43-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0297] In embodiments, R8 is R43-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1- C6 alkyl, or C1-C4 alkyl). In embodiments, R8 is R43-substituted alkyl (e.g., C1-C8 alkyl, C1- C6 alkyl, or C1-C4 alkyl). In embodiments, R8 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1- C6 alkyl, or C1-C4 alkyl).
[0298] In embodiments, R8 is R43-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R8 is R43-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R8 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
[0299] In embodiments, R8 is R43-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R8 is R43-substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R8 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
[0300] In embodiments, R8 is R43-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R8 is R43-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R8 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
[0301] In embodiments, R8 is R43-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R8 is R43-substituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R8 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).
[0302] In embodiments, R8 is R43-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R8 is R43-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R8 is an
unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0303] R43 is independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, R44-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R44-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R44-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R44-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R44-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R44-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0304] In embodiments, R43 is R44-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1- C6 alkyl, or C1-C4 alkyl), R44-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R44-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R44- substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R44-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R44-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0305] In embodiments, R43 is R44-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1- C6 alkyl, or C1-C4 alkyl). In embodiments, R43 is R44-substituted alkyl (e.g., C1-C8 alkyl, C1- C6 alkyl, or C1-C4 alkyl). In embodiments, R43 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).
[0306] In embodiments, R43 is R44-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R43 is R44-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R43 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). [0307] In embodiments, R43 is R44-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R43 is R44-substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R43 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
[0308] In embodiments, R43 is R44-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R43 is R44-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R43 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
[0309] In embodiments, R43 is R44-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R43 is R44-substituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R43 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).
[0310] In embodiments, R43 is R44-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R43 is R44-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R43 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0311] R44 is independently oxo, halogen, -CCI3, -CBr3, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, R45-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R45-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R45-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R45-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R45-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R45-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0312] In embodiments, R44 is R45-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1- C6 alkyl, or C1-C4 alkyl), R45-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R45-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R45- substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R45-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R45-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0313] In embodiments, R44 is R45-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1- C6 alkyl, or C1-C4 alkyl). In embodiments, R44 is R45-substituted alkyl (e.g., C1-C8 alkyl, C1- C6 alkyl, or C1-C4 alkyl). In embodiments, R44 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).
[0314] In embodiments, R44 is R45-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R44 is R45-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R44 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
[0315] In embodiments, R44 is R45-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R44 is R45-substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R44 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
[0316] In embodiments, R44 is R45-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R44 is R45-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R44 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
[0317] In embodiments, R44 is R45-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R44 is R45-substituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R44 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).
[0318] In embodiments, R44 is R45-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R44 is R45-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R44 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0319] R8.3, R8.4, and R8.5 are each independently hydrogen or R8 at a fixed position on the attached ring. R8.3, R8.4, and R8.5 may independently be any substituent of R8 described herein, including in any aspect, embodiment, example, figure, or claim. In embodiments, R8.4 is hydrogen, halogen, -CCI3, -CBr3, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -COOH, -CH2COOH, -CONH2, -OH, -SH, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. In embodiments, R8.3 and R8.5 are independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2,
-NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.
[0320] In embodiments, R8.3, R8.4, and R8.5 are each hydrogen or R8 at a fixed position on the attached ring. R8.3, R8.4, and R8.5 may be any substituent of R8 described herein, including in any aspect, embodiment, example, figure, or claim. In embodiments, R8.4 is hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -COOH, -CH2COOH, -CONH2, -OH, -SH, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. In embodiments, R8.3 and R8.5 are independently hydrogen, halogen, -CCI3, -CBr3, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.
[0321] In embodiments, a substituted R8.3 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R8.3 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R8.3 is substituted, it is substituted with at least one substituent group. In embodiments, when R8.3 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R8.3 is substituted, it is substituted with at least one lower substituent group.
[0322] In embodiments, a substituted R8.4 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R8.4 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R8.4 is substituted, it is substituted with at least one substituent group. In embodiments, when R8.4 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R8.4 is substituted, it is substituted with at least one lower substituent group.
[0323] In embodiments, a substituted R8.5 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R8.5 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R8.5 is substituted, it is substituted with at least one substituent group. In embodiments, when R8.5 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R8.5 is substituted, it is substituted with at least one lower substituent group.
[0324] In embodiments, R8.3, R8.4, and R8.5 are each independently R43-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R43-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R43-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R43-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R43-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R43-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0325] In embodiments, R8.3, R8.4, and R8.5 are each independently R43-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R8.3, R8.4, and R8.5 are each independently R43-substituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R8.3, R8.4, and R8.5 are each independently an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).
[0326] In embodiments, R8.3, R8.4, and R8.5 are each independently R43-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R8.3, R8.4, and R8.5 are each independently R43-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R8.3, R8.4, and R8.5 are each independently an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
[0327] In embodiments, R8.3, R8.4, and R8.5 are each independently R43-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R8.3, R8.4, and R8.5 are each independently R43-substituted cycloalkyl (e.g., C3- C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R8.3, R8.4, and R8.5 are each independently an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
[0328] In embodiments, R8.3, R8.4, and R8.5 are each independently R43-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R8.3, R8.4, and R8.5 are each independently R43-substituted heterocycloalkyl (e.g., 3 to 8 membered
heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R8.3, R8.4, and R8.5 are each independently an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
[0329] In embodiments, R8.3, R8.4, and R8.5 are each independently R43-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R8.3, R8.4, and R8.5 are each independently R43-substituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R8.3, R8.4, and R8.5 are each independently an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).
[0330] In embodiments, R8.3, R8.4, and R8.5 are each independently R43-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R8.3, R8.4, and R8.5 are each independently R43- substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R8.3, R8.4, and R8.5 are each independently an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0331] In embodiments, z8 is an integer from 0 to 5. In embodiments, z8 is an integer from 0 to 3. In embodiments, z8 is an integer from 0 to 2. In embodiments, z8 is an integer from 1 to 2. In embodiments, z8 is 0. In embodiments, z8 is 1. In embodiments, z8 is 2. In embodiments, z8 is 3. In embodiments, z8 is 4. In embodiments, z8 is 5. In embodiments, z8 is 6. In embodiments, z8 is 7. In embodiments, z8 is 8. In embodiments, z8 is 9. In embodiments, z8 is 10.
[0332] In embodiments, R9 is hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or 2 to 3 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
[0333] In embodiments, a substituted R9 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R9 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R9 is substituted, it is substituted with at least one substituent group. In embodiments, when R9 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R9 is substituted, it is substituted with at least one lower substituent group.
[0334] In embodiments, R9 is hydrogen, oxo, halogen, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, or -N3. In embodiments, R9 is an unsubstituted alkyl, or unsubstituted heteroalkyl. In embodiments, R9 is an unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1- C2). In embodiments, R9 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R9 is hydrogen. In embodiments, R9 is oxo. In embodiments, R9 is halogen. In embodiments, R9 is–CN. In embodiments, R9 is–OH. In embodiments, R9 is -NH2. In embodiments, R9 is– COOH. In embodiments, R9 is -CONH2. In embodiments, R9 is -NO2. In embodiments, R9 is–SH. In embodiments, R9 is -SO3H. In embodiments, R9 is -N3. In embodiments, R9 is oxo or halogen. In embodiments, R9 is oxo or–F. In embodiments, R9 is–F. In
embodiments, R9 is halogen, oxo, -NH2, unsubstituted alkyl, or unsubstituted heteroalkyl. In embodiments, R9 is–F, oxo, or -NH2, or unsubstituted heteroalkyl. In embodiments, R9 is -NH3 (e.g., a salt of NH2).
[0335] In embodiments, R9 is hydrogen. In embodiments, R9 is oxo. In embodiments, R9 is halogen. In embodiments, R9 is–F. In embodiments, R9 is–Cl. In embodiments, R9 is– Br. In embodiments, R9 is–I. In embodiments, R9 is -CCl3. In embodiments, R9 is -CBr3. In embodiments, R9 is -CF3. In embodiments, R9 is -CI3. In embodiments, R9 is -CHCI2. In embodiments, R9 is -CHBr2. In embodiments, R9 is -CHF2. In embodiments, R9 is -CHI2. In embodiments, R9 is -CH2Cl. In embodiments, R9 is -CH2Br. In embodiments, R9 is -CH2F. In embodiments, R9 is -CH2I. In embodiments, R9 is -CN. In embodiments, R9 is -OH. In embodiments, R9 is -NH2. In embodiments, R9 is -COOH. In embodiments, R9 is -CONH2. In embodiments, R9 is -NO2. In embodiments, R9 is -SH. In embodiments, R9 is -SO3H. In embodiments, R9 is -SO4H. In embodiments, R9 is -SO2NH2. In embodiments, R9 is -NHNH2. In embodiments, R9 is -ONH2. In embodiments, R9 is -NHC(O)NHNH2. In embodiments, R9 is -NHC(O)NH2. In embodiments, R9 is -NHSO2H. In embodiments, R9 is -NHC(O)H. In embodiments, R9 is -NHC(O)OH. In embodiments, R9 is -NHOH. In embodiments, R9 is -OCCI3. In embodiments, R9 is -OCF3. In embodiments, R9 is -OCBr3. In embodiments, R9 is -OCI3. In embodiments, R9 is -OCHCl2. In embodiments, R9 is -OCHBr2. In embodiments, R9 is -OCHI2. In embodiments, R9 is -OCHF2. In embodiments, R9 is -OCH2Cl. In embodiments, R9 is -OCH2Br. In embodiments, R9 is -OCH2I. In embodiments, R9 is -OCH2F. In embodiments, R9 is -N3.
[0336] In embodiments, R9 is hydrogen, oxo, halogen, -CCI3, -CBr3, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, R46-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R46-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R46-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R46-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R46-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R46-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0337] In embodiments, R9 is R46-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1- C6 alkyl, or C1-C4 alkyl), R46-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R46-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R46- substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R46-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R46-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0338] In embodiments, R9 is R46-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1- C6 alkyl, or C1-C4 alkyl). In embodiments, R9 is R46-substituted alkyl (e.g., C1-C8 alkyl, C1- C6 alkyl, or C1-C4 alkyl). In embodiments, R9 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1- C6 alkyl, or C1-C4 alkyl).
[0339] In embodiments, R9 is R46-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R9 is R46-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R9 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
[0340] In embodiments, R9 is R46-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R9 is R46-substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R9 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
[0341] In embodiments, R9 is R46-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R9 is R46-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R9 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
[0342] In embodiments, R9 is R46-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R9 is R46-substituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R9 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).
[0343] In embodiments, R9 is R46-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R9 is R46-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R9 is an
unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0344] In embodiments, R10 and R12 are independently hydrogen, substituted or unsubstituted C1-C3 alkyl, or substituted or unsubstituted 2 to 3 membered heteroalkyl.
[0345] In embodiments, R10 is hydrogen, oxo, halogen, -CCI3, -CBr3, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or 2 to 3 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
[0346] In embodiments, a substituted R10 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R10 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R10 is substituted, it is substituted with at least one substituent group. In embodiments, when R10 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R10 is substituted, it is substituted with at least one lower substituent group.
[0347] In embodiments, R10 is hydrogen, substituted or unsubstituted C1-C3 alkyl, or substituted or unsubstituted 2 to 3 membered heteroalkyl.
[0348] In embodiments, R10 is hydrogen or unsubstituted methyl. In embodiments, R10 is hydrogen. In embodiments, R10 is an unsubstituted C1-C3 alkyl. In embodiments, R10 is an unsubstituted C2 alkyl. In embodiments, R10 is an unsubstituted C3 alkyl. In embodiments, R10 is unsubstituted methyl. In embodiments, R10 and R12 are independently hydrogen, substituted or unsubstituted C1-C3 alkyl, or substituted or unsubstituted 2 to 3 membered heteroalkyl.
[0349] In embodiments, R10 is a substituted or unsubstituted C1-C3 alkyl, or substituted or unsubstituted 2 to 3 membered heteroalkyl. In embodiments, R10 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl. In embodiments, R10 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) alkyl. In embodiments, R10 is unsubstituted alkyl. In embodiments, R10 is a substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R10 is a substituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R10 is an unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2).
[0350] In embodiments, R10 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl. In embodiments, R10 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroalkyl. In embodiments, R10 is an unsubstituted heteroalkyl. In embodiments, R10 is substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R10 is a substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R10 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
[0351] In embodiments, R10 is hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, R47-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R47-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R47-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R47-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R47-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R47-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0352] In embodiments, R10 is R47-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1- C6 alkyl, or C1-C4 alkyl), R47-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R47-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R47- substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R47-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R47-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0353] In embodiments, R10 is R47-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1- C6 alkyl, or C1-C4 alkyl). In embodiments, R10 is R47-substituted alkyl (e.g., C1-C8 alkyl, C1- C6 alkyl, or C1-C4 alkyl). In embodiments, R10 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).
[0354] In embodiments, R10 is R47-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R10 is R47-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R10 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
[0355] In embodiments, R10 is R47-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R10 is R47-substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R10 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
[0356] In embodiments, R10 is R47-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R10 is R47-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R10 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
[0357] In embodiments, R10 is R47-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R10 is R47-substituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R10 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).
[0358] In embodiments, R10 is R47-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R10 is R47-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R10 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0359] In embodiments, R11 is hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or 2 to 3 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
[0360] In embodiments, a substituted R11 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R11 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R11 is substituted, it is substituted with at least one substituent group. In embodiments, when R11 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R11 is substituted, it is substituted with at least one lower substituent group.
[0361] In embodiments, R11 is hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, or -N3. In embodiments, R11 is hydrogen. In embodiments, R11 is oxo. In embodiments, R11 is halogen. In embodiments, R11 is -CCl3. In embodiments, R11 is -CBr3. In embodiments, R11 is -CF3. In embodiments, R11 is -CI3. In embodiments, R11 is -CHCI2. In embodiments, R11 is -CHBr2. In embodiments, R11 is -CHF2. In embodiments, R11 is -CHI2. In embodiments, R11 is -CH2Cl. In embodiments, R11 is -CH2Br. In embodiments, R11 is -CH2F. In embodiments, R11 is -CH2I. In embodiments, R11 is -CN. In embodiments, R11 is -OH. In embodiments, R11 is -NH2. In embodiments, R11 is -COOH. In embodiments, R11 is -CONH2. In embodiments, R11 is -NO2. In embodiments, R11 is–SH. In embodiments, R11 is -SO3H. In embodiments, R11 is -SO4H. In embodiments, R11 is -SO2NH2. In embodiments, R11 is -NHNH2. In embodiments, R11 is -ONH2. In embodiments, R11 is -NHC(O)NHNH2. In embodiments, R11 is -NHC(O)NH2. In embodiments, R11 is -NHSO2H. In embodiments, R11 is -NHC(O)H. In embodiments, R11 is -NHC(O)OH. In embodiments, R11 is -NHOH. In embodiments, R11 is -OCCl3. In embodiments, R11 is -OCF3. In embodiments, R11 is -OCBr3. In embodiments, R11 is -OCI3. In embodiments, R11 is -OCHCI2. In
embodiments, R11 is -OCHBr2. In embodiments, R11 is -OCHI2. In embodiments, R11 is -OCHF2. In embodiments, R11 is -OCH2Cl. In embodiments, R11 is -OCH2Br. In embodiments, R11 is -OCH2I. In embodiments, R11 is -OCH2F. In embodiments, R11 is -N3. In embodiments, R11 is -OH, -NH2, or–SH.
[0362] In embodiments, R11 is a substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0363] In embodiments, R11 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl. In embodiments, R11 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) alkyl. In embodiments, R11 is an unsubstituted alkyl. In embodiments, R11 is a substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R11 is a substituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R11 is an unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2).
[0364] In embodiments, R11 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl. In embodiments, R11 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroalkyl. In embodiments, R11 is an unsubstituted heteroalkyl. In embodiments, R11 is a substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R11 is a substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R11 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
[0365] In embodiments, R11 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl. In embodiments, R11 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) cycloalkyl. In embodiments, R11 is an unsubstituted cycloalkyl. In embodiments, R11 is a substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, R11 is a substituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, R11 is an unsubstituted cycloalkyl (e.g., C3- C8, C3-C6, C4-C6, or C5-C6).
[0366] In embodiments, R11 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl. In embodiments, R11 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heterocycloalkyl. In embodiments, R11 is an unsubstituted heterocycloalkyl. In embodiments, R11 is a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R11 is a substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R11 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). [0367] In embodiments, R11 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted aryl. In embodiments, R11 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) aryl. In embodiments, R11 is an unsubstituted aryl. In embodiments, R11 is a substituted or unsubstituted aryl (e.g., C6-C10 or phenyl). In embodiments, R11 is a substituted aryl (e.g., C6-C10 or phenyl). In embodiments, R11 is an unsubstituted aryl (e.g., C6-C10 or phenyl).
[0368] In embodiments, R11 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl. In embodiments, R11 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroaryl. In embodiments, R11 is an unsubstituted heteroaryl. In embodiments, R11 is a substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R11 is a substituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R11 is an unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
[0369] In embodiments, R11 is oxo, halogen,–OH, or -NH2. In embodiments, R11 is–F.
[0370] In embodiments, R11 hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, R48-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R48-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R48-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R48-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R48-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R48-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0371] In embodiments, R11 is R48-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1- C6 alkyl, or C1-C4 alkyl), R48-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R48-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R48- substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R48-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R48-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0372] In embodiments, R11 is R48-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1- C6 alkyl, or C1-C4 alkyl). In embodiments, R11 is R48-substituted alkyl (e.g., C1-C8 alkyl, C1- C6 alkyl, or C1-C4 alkyl). In embodiments, R11 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).
[0373] In embodiments, R11 is R48-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R11 is R48-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R11 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
[0374] In embodiments, R11 is R48-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R11 is R48-substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R11 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
[0375] In embodiments, R11 is R48-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R11 is R48-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R11 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). [0376] In embodiments, R11 is R48-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R11 is R48-substituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R11 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).
[0377] In embodiments, R11 is R48-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R11 is R48-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R11 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0378] In embodiments, R12 is hydrogen, oxo, halogen, -CCI3, -CBr3, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or 2 to 3 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
[0379] In embodiments, a substituted R12 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R12 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R12 is substituted, it is substituted with at least one substituent group. In embodiments, when R12 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R12 is substituted, it is substituted with at least one lower substituent group. [0380] In embodiments, R12 is hydrogen, substituted or unsubstituted C1-C3 alkyl, or substituted or unsubstituted 2 to 3 membered heteroalkyl.
[0381] In embodiments, R12 is hydrogen or unsubstituted methyl. In embodiments, R12 is hydrogen. In embodiments, R12 is an unsubstituted C1-C3 alkyl. In embodiments, R12 is an unsubstituted C2 alkyl. In embodiments, R12 is an unsubstituted C3 alkyl. In embodiments, R12 is an unsubstituted methyl. In embodiments, R12 is hydrogen or an unsubstituted C1-C3 alkyl.
[0382] In embodiments, R12 is a substituted or unsubstituted C1-C3 alkyl, or substituted or unsubstituted 2 to 3 membered heteroalkyl. In embodiments, R12 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl. In embodiments, R12 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) alkyl. In embodiments, R12 is an unsubstituted alkyl. In embodiments, R12 is a substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R12 is a substituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R12 is an unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2).
[0383] In embodiments, R12 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl. In embodiments, R12 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroalkyl. In embodiments, R12 is an unsubstituted heteroalkyl. In embodiments, R12 is a substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R12 is a substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R12 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
[0384] In embodiments, R12 hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, R49-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R49-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R49-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R49-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R49-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R49-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0385] In embodiments, R12 is R49-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1- C6 alkyl, or C1-C4 alkyl), R49-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R49-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R49- substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R49-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R49-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0386] In embodiments, R12 is R49-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1- C6 alkyl, or C1-C4 alkyl). In embodiments, R12 is R49-substituted alkyl (e.g., C1-C8 alkyl, C1- C6 alkyl, or C1-C4 alkyl). In embodiments, R12 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).
[0387] In embodiments, R12 is R49-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R12 is R49-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R12 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
[0388] In embodiments, R12 is R49-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R12 is R49-substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R12 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). [0389] In embodiments, R12 is R49-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R12 is R49-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R12 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
[0390] In embodiments, R12 is R49-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R12 is R49-substituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R12 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).
[0391] In embodiments, R12 is R49-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R12 is R49-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R12 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0392] In embodiments, Ring A is a substituted (e.g., R8-substituted) or unsubstituted C3-C6 cycloalkylene, substituted (e.g., R8-substituted) or unsubstituted 3 to 6 membered
heterocycloalkylene, substituted (e.g., R8-substituted) or unsubstituted phenylene, or substituted (e.g., R8-substituted) or unsubstituted 5 to 6 membered heteroarylene. In embodiments, Ring A is a substituted (e.g., R8-substituted) or unsubstituted 5 to 6 membered heteroarylene. In embodiments, Ring A is a substituted (e.g., R8-substituted) or unsubstituted oxazolylene.
[0393] In embodiments, Ring A is a substituted (e.g., R8-substituted) or unsubstituted cycloalkylene. In embodiments, Ring A is a substituted (e.g., R8-substituted) or unsubstituted heterocycloalkylene. In embodiments, Ring A is a substituted (e.g., R8-substituted) or unsubstituted arylene. In embodiments, Ring A is a substituted (e.g., R8-substituted) or unsubstituted heteroarylene. In embodiments, Ring A is a substituted (e.g., R8-substituted) or unsubstituted (C3-C10) cycloalkylene, substituted (e.g., R8-substituted) or unsubstituted 3 to 10 membered heterocycloalkylene, substituted (e.g., R8-substituted) or unsubstituted (C6-C10) arylene, or substituted (e.g., R8-substituted) or unsubstituted 5 to 10 membered heteroarylene. In embodiments, Ring A is a substituted (e.g., R8-substituted) or unsubstituted (C3-C10) cycloalkylene. In embodiments, Ring A is substituted (e.g., R8-substituted) or unsubstituted 3 to 10 membered heterocycloalkylene. In embodiments, Ring A is a substituted (e.g., R8- substituted) or unsubstituted (C6-C10) arylene. In embodiments, Ring A is a substituted (e.g., R8-substituted) or unsubstituted 5 to 10 membered heteroarylene. In embodiments, Ring A is a substituted (e.g., R8-substituted) or unsubstituted (C3-C6) cycloalkylene. In embodiments, Ring A is a substituted (e.g., R8-substituted) or unsubstituted 3 to 6 membered
heterocycloalkylene. In embodiments, Ring A is a substituted (e.g., R8-substituted) or unsubstituted phenylene. In embodiments, Ring A is a substituted (e.g., R8-substituted) or unsubstituted naphthylene. In embodiments, Ring A is a substituted (e.g., R8-substituted) or unsubstituted 5 to 9 membered heteroarylene. In embodiments, Ring A is a substituted (e.g., R8-substituted) or unsubstituted 5 to 6 membered heteroarylene. In embodiments, Ring A is an unsubstituted 5 to 6 membered heteroarylene. In embodiments, Ring A is a substituted (e.g., R8-substituted) or unsubstituted 5 membered heteroarylene. In embodiments, Ring A is a substituted (e.g., R8-substituted) 5 membered heteroarylene. In embodiments, Ring A is an unsubstituted 5 membered heteroarylene.
[0394] In embodiments, Ring A is R8-substituted or unsubstituted (C3-C10) cycloalkylene, R8-substituted or unsubstituted 5 to 10 membered heterocycloalkylene, R8-substituted or unsubstituted (C6-C10) arylene, or R8-substituted or unsubstituted 5 to 10 membered heteroarylene. In embodiments, Ring A is R8-substituted or unsubstituted (C3-C10) cycloalkylene or R8-substituted or unsubstituted 5 to 10 membered heterocycloalkylene. In embodiments, Ring A is R8-substituted or unsubstituted (C3-C10) cycloalkylene. In embodiments, Ring A is R8-substituted or unsubstituted 3 to 10 membered
heterocycloalkylene. In embodiments, Ring A is R8-substituted or unsubstituted (C6-C10) arylene. In embodiments, Ring A is R8-substituted or unsubstituted 5 to 10 membered heteroarylene. In embodiments, Ring A is R8-substituted or unsubstituted (C3-C6) cycloalkylene. In embodiments, Ring A is R8-substituted or unsubstituted 3 to 6 membered heterocycloalkylene. In embodiments, Ring A is R8-substituted or unsubstituted phenylene. In embodiments, Ring A is R8-substituted or unsubstituted naphthylene. In embodiments, Ring A is R8-substituted or unsubstituted 5 to 9 membered heteroarylene. In embodiments, Ring A is R8-substituted or unsubstituted 5 to 6 membered heteroarylene.
[0395] In embodiments, Ring A is R8-substituted or unsubstituted thienylene. In embodiments, Ring A is R8-substituted or unsubstituted phenylene. In embodiments, Ring A is R8-substituted or unsubstituted benzothienylene. In embodiments, Ring A is R8-substituted or unsubstituted naphthylene. In embodiments, Ring A is R8-substituted or unsubstituted benzofuranylene. In embodiments, Ring A is R8-substituted or unsubstituted furanylene. In embodiments, Ring A is R8-substituted or unsubstituted pyrrolylene. In embodiments, Ring A is R8-substituted or unsubstituted oxazolylene. In embodiments, Ring A is R8-substituted or unsubstituted oxadiazolylene. In embodiments, Ring A is R8-substituted or unsubstituted triazolylene. In embodiments, Ring A is R8-substituted or unsubstituted thiazolylene.
[0396] In embodiments, Ring A is a substituted (e.g., R8-substituted) cycloalkylene. In embodiments, Ring A is a substituted (e.g., R8-substituted) heterocycloalkylene. In embodiments, Ring A is a substituted (e.g., R8-substituted) arylene. In embodiments, Ring A is a substituted (e.g., R8-substituted) heteroarylene. In embodiments, Ring A is a substituted (e.g., R8-substituted) (C3-C10) cycloalkylene, substituted (e.g., R8-substituted) 3 to 10 membered heterocycloalkylene, substituted (e.g., R8-substituted) (C6-C10) arylene, or substituted (e.g., R8-substituted) 5 to 10 membered heteroarylene. In embodiments, Ring A is a substituted (e.g., R8-substituted) (C3-C10) cycloalkylene. In embodiments, Ring A is a substituted (e.g., R8-substituted) 3 to 10 membered heterocycloalkylene. In embodiments, Ring A is a substituted (e.g., R8-substituted) (C6-C10) arylene. In embodiments, Ring A is a substituted (e.g., R8-substituted) 5 to 10 membered heteroarylene. In embodiments, Ring A is a substituted (e.g., R8-substituted) (C3-C6) cycloalkylene. In embodiments, Ring A is a substituted (e.g., R8-substituted) 3 to 6 membered heterocycloalkylene. In embodiments, Ring A is a substituted (e.g., R8-substituted) phenylene. In embodiments, Ring A is a substituted (e.g., R8-substituted) naphthylene. In embodiments, Ring A is a substituted (e.g., R8-substituted) 5 to 9 membered heteroarylene. In embodiments, Ring A is a substituted (e.g., R8-substituted) 5 to 6 membered heteroarylene. In embodiments, Ring A is R8- substituted (C3-C10) cycloalkylene, R8-substituted 5 to 10 membered heterocycloalkylene, R8- substituted (C6-C10) arylene, or R8-substituted 5 to 10 membered heteroarylene. In embodiments, Ring A is R8-substituted (C3-C10) cycloalkylene or R8-substituted 5 to 10 membered heterocycloalkylene. In embodiments, Ring A is R8-substituted (C3-C10) cycloalkylene. In embodiments, Ring A is R8-substituted 3 to 10 membered
heterocycloalkylene. In embodiments, Ring A is R8-substituted (C6-C10) arylene. In embodiments, Ring A is R8-substituted 5 to 10 membered heteroarylene. In embodiments, Ring A is R8-substituted (C3-C6) cycloalkylene. In embodiments, Ring A is R8-substituted 3 to 6 membered heterocycloalkylene. In embodiments, Ring A is R8-substituted phenylene. In embodiments, Ring A is R8-substituted naphthylene. In embodiments, Ring A is R8- substituted 5 to 9 membered heteroarylene. In embodiments, Ring A is R8-substituted 5 to 6 membered heteroarylene. In embodiments, Ring A is R8-substituted thienylene. In embodiments, Ring A is R8-substituted phenylene. In embodiments, Ring A is R8-substituted benzothienylene. In embodiments, Ring A is R8-substituted naphthylene. In embodiments, Ring A is R8-substituted benzofuranylene. In embodiments, Ring A is R8-substituted furanylene. In embodiments, Ring A is R8-substituted pyrrolylene. In embodiments, Ring A is R8-substituted oxazolylene. In embodiments, Ring A is R8-substituted oxadiazolylene. In embodiments, Ring A is R8-substituted triazolylene. In embodiments, Ring A is R8- substituted thiazolylene.
[0397] In embodiments, Ring A is an unsubstituted cycloalkylene. In embodiments, Ring A is an unsubstituted heterocycloalkylene. In embodiments, Ring A is an unsubstituted arylene. In embodiments, Ring A is an unsubstituted heteroarylene. In embodiments, Ring A is an unsubstituted (C3-C10) cycloalkylene, unsubstituted 3 to 10 membered
heterocycloalkylene, unsubstituted (C6-C10) arylene, or unsubstituted 5 to 10 membered heteroarylene. In embodiments, Ring A is an unsubstituted (C3-C10) cycloalkylene. In embodiments, Ring A is an unsubstituted 3 to 10 membered heterocycloalkylene. In embodiments, Ring A is an unsubstituted (C6-C10) arylene. In embodiments, Ring A is an unsubstituted 5 to 10 membered heteroarylene. In embodiments, Ring A is an unsubstituted (C3-C6) cycloalkylene. In embodiments, Ring A is an unsubstituted 3 to 6 membered heterocycloalkylene. In embodiments, Ring A is an unsubstituted phenylene. In
embodiments, Ring A is an unsubstituted naphthylene. In embodiments, Ring A is an unsubstituted 5 to 9 membered heteroarylene. In embodiments, Ring A is an unsubstituted 5 to 6 membered heteroarylene. In embodiments, Ring A is an unsubstituted (C3-C10) cycloalkylene, unsubstituted 5 to 10 membered heterocycloalkylene, unsubstituted (C6-C10) arylene, or unsubstituted 5 to 10 membered heteroarylene. In embodiments, Ring A is an unsubstituted (C3-C10) cycloalkylene or unsubstituted 5 to 10 membered heterocycloalkylene. In embodiments, Ring A is an unsubstituted (C3-C10) cycloalkylene. In embodiments, Ring A is an unsubstituted 3 to 10 membered heterocycloalkylene. In embodiments, Ring A is an unsubstituted (C6-C10) arylene. In embodiments, Ring A is an unsubstituted 5 to 10 membered heteroarylene. In embodiments, Ring A is unsubstituted (C3-C6) cycloalkylene. In embodiments, Ring A is an unsubstituted 3 to 6 membered heterocycloalkylene. In embodiments, Ring A is an unsubstituted phenylene. In embodiments, Ring A is an unsubstituted naphthylene. In embodiments, Ring A is an unsubstituted 5 to 9 membered heteroarylene. In embodiments, Ring A is an unsubstituted 5 to 6 membered heteroarylene. In embodiments, Ring A is an unsubstituted thienylene. In embodiments, Ring A is an unsubstituted phenylene. In embodiments, Ring A is an unsubstituted benzothienylene. In embodiments, Ring A is an unsubstituted naphthylene. In embodiments, Ring A is an unsubstituted benzofuranylene. In embodiments, Ring A is an unsubstituted furanylene. In embodiments, Ring A is an unsubstituted pyrrolylene. In embodiments, Ring A is an unsubstituted oxazolylene. In embodiments, Ring A is an unsubstituted phenylene. In embodiments, Ring A is an unsubstituted oxadiazolylene. In embodiments, Ring A is an unsubstituted triazolylene. In embodiments, Ring A is an unsubstituted thiazolylene.
[0398] In embodiments, Ring A is C3-C6 cycloalkylene, 3 to 6 membered
heterocycloalkylene, phenylene, or a 5 to 6 membered heteroarylene. In embodiments, Ring A is C3-C6 cycloalkylene. In embodiments, Ring A is 3 to 6 membered heterocycloalkylene.
[0399] In embodiments, Ring A is C6-C10 arylene or 5 to 10 membered heteroarylene. In embodiments, Ring A is C6-C10 arylene or 5 to 10 membered heteroarylene. In embodiments, Ring A is C6-C10 arylene. In embodiments, Ring A is phenylene. In embodiments, Ring A is naphthylene. In embodiments, Ring A is 5 to 10 membered heteroarylene. In embodiments, Ring A is 5 to 6 membered heteroarylene. In embodiments, Ring A is thienylene. In embodiments, Ring A is furanylene. In embodiments, Ring A is pyrrolylene. In
embodiments, Ring A is imidazolylene. In embodiments, Ring A is pyrazolylene. In embodiments, Ring A is oxazolylene. In embodiments, Ring A is isoxazolylene. In embodiments, Ring A is thaizolylene. In embodiments, Ring A is pyridinylene. In embodiments, Ring A is pyridylene. In embodiments, Ring A is pyrazinylene. In embodiments, Ring A is pyrimidinylene. In embodiments, Ring A is pyridazinylene. In embodiments, Ring A is 1,2,3-triazinylene. In embodiments, Ring A is 1,2,4-triazinylene. In embodiments, Ring A is 1,3,5-triazinylene.
[0400] In embodiments, Ring A is a substituted (e.g., R8-substituted) C6-C10 arylene or substituted (e.g., R8-substituted) 5 to 10 membered heteroarylene. In embodiments, Ring A is a substituted (e.g., R8-substituted) C6-C10 arylene or substituted (e.g., R8-substituted) 5 to 10 membered heteroarylene. In embodiments, Ring A is a substituted (e.g., R8-substituted) C6- C10 arylene. In embodiments, Ring A is substituted (e.g., R8-substituted) phenylene. In embodiments, Ring A is a substituted (e.g., R8-substituted) naphthylene. In embodiments, Ring A is a substituted (e.g., R8-substituted) 5 to 10 membered heteroarylene. In embodiments, Ring A is a substituted (e.g., R8-substituted) 5 to 6 membered heteroarylene. In embodiments, Ring A is a substituted (e.g., R8-substituted) thienylene. In embodiments, Ring A is a substituted (e.g., R8-substituted) furanylene. In embodiments, Ring A is a substituted (e.g., R8-substituted) pyrrolylene. In embodiments, Ring A is a substituted (e.g., R8-substituted) imidazolylene. In embodiments, Ring A is a substituted (e.g., R8-substituted) pyrazolylene. In embodiments, Ring A is a substituted (e.g., R8-substituted) oxazolylene. In embodiments, Ring A is a substituted (e.g., R8-substituted) isoxazolylene. In embodiments, Ring A is a substituted (e.g., R8-substituted) thaizolylene. In embodiments, Ring A is a substituted (e.g., R8-substituted) pyridinylene. In embodiments, Ring A is a substituted (e.g., R8-substituted) pyridylene. In embodiments, Ring A is a substituted (e.g., R8-substituted) pyrazinylene. In embodiments, Ring A is a substituted (e.g., R8-substituted) pyrimidinylene. In embodiments, Ring A is a substituted (e.g., R8-substituted) pyridazinylene. In
embodiments, Ring A is a substituted (e.g., R8-substituted) 1,2,3-triazinylene. In embodiments, Ring A is a substituted (e.g., R8-substituted) 1,2,4-triazinylene. In embodiments, Ring A is a substituted (e.g., R8-substituted) 1,3,5-triazinylene.
[0401] In embodiments, Ring A is an unsubstituted C6-C10 arylene or unsubstituted 5 to 10 membered heteroarylene. In embodiments, Ring A is an unsubstituted C6-C10 arylene or unsubstituted 5 to 10 membered heteroarylene. In embodiments, Ring A is an unsubstituted C6-C10 arylene. In embodiments, Ring A is an unsubstituted phenylene. In embodiments, Ring A is an unsubstituted naphthylene. In embodiments, Ring A is an unsubstituted 5 to 10 membered heteroarylene. In embodiments, Ring A is an unsubstituted 5 to 6 membered heteroarylene. In embodiments, Ring A is an unsubstituted thienylene. In embodiments, Ring A is an unsubstituted furanylene. In embodiments, Ring A is an unsubstituted pyrrolylene. In embodiments, Ring A is an unsubstituted imidazolylene. In embodiments, Ring A is an unsubstituted pyrazolylene. In embodiments, Ring A is an unsubstituted oxazolylene. In embodiments, Ring A is an unsubstituted isoxazolylene. In embodiments, Ring A is an unsubstituted thaizolylene. In embodiments, Ring A is an unsubstituted pyridinylene. In embodiments, Ring A is an unsubstituted pyridylene. In embodiments, Ring A is an unsubstituted pyrazinylene. In embodiments, Ring A is an unsubstituted
pyrimidinylene. In embodiments, Ring A is an unsubstituted pyridazinylene. In
embodiments, Ring A is an unsubstituted 1,2,3-triazinylene. In embodiments, Ring A is an unsubstituted 1,2,4-triazinylene. In embodiments, Ring A is an unsubstituted 1,3,5- triazinylene. [0402] In embodiments, Ring A is a 4 to 8 membered heterocycloalkylene. In
embodiments, Ring A is a 4 membered heterocycloalkylene. In embodiments, Ring A is a 5 membered heterocycloalkylene. In embodiments, Ring A is a 6 membered
heterocycloalkylene. In embodiments, Ring A is a 7 membered heterocycloalkylene. In embodiments, Ring A is an 8 membered heterocycloalkylene. In embodiments, Ring A is a 4 to 6 membered heterocycloalkylene. In embodiments, Ring A is azetidinylene.
[0403] In embodiments, Ring A is a substituted (e.g., R8-substituted) or unsubstituted heterocycloalkylene. In embodiments, Ring A is a substituted (e.g., R8-substituted) heterocycloalkylene. In embodiments, Ring A is an unsubstituted heterocycloalkylene. In embodiments, Ring A is a substituted (e.g., R8-substituted) or unsubstituted 3 to 10 membered heterocycloalkylene. In embodiments, Ring A is a substituted (e.g., R8- substituted) 3 to 10 membered heterocycloalkylene. In embodiments, Ring A is an unsubstituted 3 to 10 membered heterocycloalkylene. In embodiments, Ring A is a R6- substituted or unsubstituted 5 to 10 membered heterocycloalkylene. In embodiments, Ring A is R6-substituted 5 to 10 membered heterocycloalkylene. In embodiments, Ring A is an unsubstituted 5 to 10 membered heterocycloalkylene.
[0404] In embodiments, Ring A is a substituted (e.g., R8-substituted) or unsubstituted 3 membered heterocycloalkylene. In embodiments, Ring A is a substituted (e.g., R8- substituted) or unsubstituted 4 membered heterocycloalkylene. In embodiments, Ring A is a substituted (e.g., R8-substituted) or unsubstituted 5 membered heterocycloalkylene. In embodiments, Ring A is a substituted (e.g., R8-substituted) or unsubstituted 6 membered heterocycloalkylene. In embodiments, Ring A is a substituted (e.g., R8-substituted) 3 membered heterocycloalkylene. In embodiments, Ring A is a substituted (e.g., R8- substituted) 4 membered heterocycloalkylene. In embodiments, Ring A is a substituted (e.g., R8-substituted) 5 membered heterocycloalkylene. In embodiments, Ring A is a substituted (e.g., R8-substituted) 6 membered heterocycloalkylene. In embodiments, Ring A is an unsubstituted 3 membered heterocycloalkylene. In embodiments, Ring A is an unsubstituted 4 membered heterocycloalkylene. In embodiments, Ring A is an unsubstituted 5 membered heterocycloalkylene. In embodiments, Ring A is an unsubstituted 6 membered
heterocycloalkylene.
[0405] In embodiments, Ring A is a substituted (e.g., R8-substituted) (i.e., R8-substituted) or unsubstituted aziridinylene, azirinylene, azetidinylene, dihydroazetylene, diazetidinylene, azetylene, pyrrolidinylene, pyrrolinylene, pyrrolylene, pyrazolidinylene, imidazolidinylene, pyrazolinylene, pyrazolylene, thiazolidinylene, thiazolylene, isothiazolylene, piperidinylene, piperazinylene, morpholinylene, oxazinylene, thiomorpholinylene, thiazinylene,
decahydroquinolinylene, dihydroazepinylene, azepanylene, or azocanylene. In embodiments, Ring A is a substituted (e.g., R8-substituted) (i.e., R8-substituted) aziridinylene, azirinylene, azetidinylene, dihydroazetylene, diazetidinylene, azetylene, pyrrolidinylene, pyrrolinylene, pyrrolylene, pyrazolidinylene, imidazolidinylene, pyrazolinylene, pyrazolylene,
thiazolidinylene, thiazolylene, isothiazolylene, piperidinylene, piperazinylene,
morpholinylene, oxazinylene, thiomorpholinylene, thiazinylene, decahydroquinolinylene, dihydroazepinylene, azepanylene, or azocanylene. In embodiments, Ring A is an
unsubstituted aziridinylene, azirinylene, azetidinylene, dihydroazetylene, diazetidinylene, azetylene, pyrrolidinylene, pyrrolinylene, pyrrolylene, pyrazolidinylene, imidazolidinylene, pyrazolinylene, pyrazolylene, thiazolidinylene, thiazolylene, isothiazolylene, piperidinylene, piperazinylene, morpholinylene, oxazinylene, thiomorpholinylene, thiazinylene,
decahydroquinolinylene, dihydroazepinylene, azepanylene, or azocanylene.
[0406] In embodiments, Ring A is imidazolylene, pyrrolylene, pyrazolylene, triazolylene, tetrazolylene, furanylene, oxazolylene, isoxazolylene, oxadiazolylene, oxatriazolylene, thienylene, thiazolylene, isothiazolylene, pyridinylene, pyrazinylene, pyrimidinylene, pyridazinylene, or triazinylene.
[0407] In embodiments, Ring A is oxazolylene, thiazolylene, isoxazolylene, or
oxadiazolylene.
[0408] In embodiments, Ring A is , , , , , or . In embodiments, Ring A is . In embodiments, Ring A is . In embodiments, Ring A is . In embodiments, Ring A is . In embodiments, Ring A is . In embodiments, Ring A is . [0409] Ring A may be substituted with one R8. Ring A may be substituted with two optionally different R8 substituents. Ring A may be substituted with three optionally different R8 substituents. Ring A may be substituted with four optionally different R8 substituents. Ring A may be substituted with five optionally different R8 substituents. Ring A may be substituted with six optionally different R8 substituents. Ring A may be substituted with seven optionally different R8 substituents. Ring A may be substituted with eight optionally different R8 substituents. Ring A may be substituted with nine optionally different R8 substituents. Ring A may be substituted with ten optionally different R8 substituents.
[0410] R37, R38, R41, R42, R45, R46, R47, R48, R49, R58, R59, R60, R61, and R63 are
independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCI2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0411] In embodiments, R37, R38, R41, R42, R45, R46, R47, R48, R49, R58, R59, R60, R61, and R62 are independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCI2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCI2, -OCHBr2, -OCHF2, -OCHI2, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0412] In embodiments, R37, R38, R41, R42, R45, R46, R47, R48, R49, R58, R59, R60, R61, and R63 are independently halogen. In embodiments, R37, R38, R41, R42, R45, R46, R47, R48, R49, R58, R59, R60, R61, and R63 are independently unsubstituted methyl.
[0413] In embodiments, R37, R38, R41, R42, R45, R46, R47, R48, R49, R58, R59, R60, R61, and R62 are independently halogen. In embodiments, R37, R38, R41, R42, R45, R46, R47, R48, R49, R58, R59, R60, R61, and R62 are independently unsubstituted methyl.
[0414] In embodiments, R37, R38, R41, R42, R45, R46, R47, R48, R49, R58, R59, R60, R61, and R63 are independently unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0415] In embodiments, R37, R38, R41, R42, R45, R46, R47, R48, R49, R58, R59, R60, R61, and R62 are independently unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0416] In embodiments, R37, R38, R41, R42, R45, R46, R47, R48, R49, R58, R59, R60, R61, and R63 are independently unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R37, R38, R41, R42, R45, R46, R47, R48, R49, R58, R59, R60, R61, and R63 are independently unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R37, R38, R41, R42, R45, R46, R47, R48, R49, R58, R59, R60, R61, and R63 are independently unsubstituted cycloalkyl (e.g., C3- C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R37, R38, R41, R42, R45, R46, R47, R48, R49, R58, R59, R60, R61, and R63 are independently unsubstituted
heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R37, R38, R41, R42, R45, R46, R47, R48, R49, R58, R59, R60, R61, and R63 are independently unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R37, R38, R41, R42, R45, R46, R47, R48, R49, R58, R59, R60, R61, and R63 are independently unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0417] In embodiments, R37, R38, R41, R42, R45, R46, R47, R48, R49, R58, R59, R60, R61, and R62 are independently unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R37, R38, R41, R42, R45, R46, R47, R48, R49, R58, R59, R60, R61, and R62 are independently unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R37, R38, R41, R42, R45, R46, R47, R48, R49, R58, R59, R60, R61, and R62 are independently unsubstituted cycloalkyl (e.g., C3- C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R37, R38, R41, R42, R45, R46, R47, R48, R49, R58, R59, R60, R61, and R62 are independently unsubstituted
heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R37, R38, R41, R42, R45, R46, R47, R48, R49, R58, R59, R60, R61, and R62 are independently unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R37, R38, R41, R42, R45, R46, R47, R48, R49, R58, R59, R60, R61, and R62 are independently unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0418] In embodiments, the compound has the formula:
Figure imgf000129_0001
embodiments,
the compound has the formula:
Figure imgf000129_0004
. In embodiments, the
compound has the formula:
Figure imgf000129_0005
.
[0419] In embodiments, the compound has the formula:
Figure imgf000129_0002
embodiments, the compound has the formula:
Figure imgf000129_0006
. In
embodiments, the compound has the formula:
Figure imgf000129_0003
.
[0420] In embodiments, the compound has the formula:
Figure imgf000130_0001
.
[0421] In embodiments, the compound has the formula:
Figure imgf000130_0002
.
[0422] In an aspect is provided a compound, or salt thereof, having the formula:
Y, L1, R2, R3, R5, R6, R7, Ring A, R8, z8, R10, R11,
Figure imgf000130_0003
and R12 are as described herein. R4 is hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, -OPO3H, -OSO3H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0423] In embodiments, the compound has the formula:
;Y is–O- or–NH-; L1 is a bond, substituted or
Figure imgf000131_0001
unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; R2 is hydrogen or unsubstituted C1-C3 alkyl; R10, R11, and R12 are as described herein; R4 is hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, -OPO3H, -OSO3H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R3 and R5 are independently hydrogen, oxo, halogen, -CCI3, -CBr3, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, -OPO3H, -OSO3H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R6 is hydrogen, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,
-NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or an amino acid side chain; R7 is hydrogen, -CH2COOH, -CONH2, -OH, -SH, -NO2, -NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R6 and R7 may optionally be joined to form an unsubstituted heterocycloalkyl or unsubstituted heteroaryl; R8 is oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,
-NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Ring A is cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; z8 is an integer from 0 to 10; R10 and R12 are independently hydrogen, substituted or unsubstituted C1-C3 alkyl, or substituted or unsubstituted 2 to 3 membered heteroalkyl; R11 is hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0424] In embodiments, the compound has the formula:
Figure imgf000132_0001
Y, L1, R2, R3, R4, R5, R6, R7, Ring A, R8, z8, R10, R11, and R12 are as described herein, including in embodiments.
[0425] In embodiments, the compound has the formula: R4 is as described herein, including in
Figure imgf000133_0001
embodiments. L2 is substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. R33A is hydrogen or any substituent of R33 described herein, including in any aspect, embodiment, example, figure, or claim.
[0426] In embodiments, the compound has the formula:
Figure imgf000133_0002
R4 is as described herein, including in embodiments. L2 is substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. R33A is hydrogen oxo, halogen, -CCI3, -CBr3, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0427] In embodiments, R4 is hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, -OPO3H, -OSO3H, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or 2 to 3 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6- C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
[0428] In embodiments, a substituted R4 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R4 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R4 is substituted, it is substituted with at least one substituent group. In embodiments, when R4 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R4 is substituted, it is substituted with at least one lower substituent group.
[0429] In embodiments, R4 is hydrogen, oxo, halogen, -CCI3, -CBr3, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, or -N3. In embodiments, R4 is hydrogen. In embodiments, R4 is oxo. In embodiments, R4 is halogen. In
embodiments, R4 is -CCI3. In embodiments, R4 is -CBr3. In embodiments, R4 is -CF3. In embodiments, R4 is -CI3. In embodiments, R4 is -CHCl2. In embodiments, R4 is -CHBr2. In embodiments, R4 is -CHF2. In embodiments, R4 is -CHI2. In embodiments, R4 is -CH2Cl. In embodiments, R4 is -CH2Br. In embodiments, R4 is -CH2F. In embodiments, R4 is -CH2I. In embodiments, R4 is -CN. In embodiments, R4 is -OH. In embodiments, R4 is -NH2. In embodiments, R4 is -COOH. In embodiments, R4 is -CONH2. In embodiments, R4 is -NO2. In embodiments, R4 is -SH. In embodiments, R4 is -SO3H. In embodiments, R4 is -SO4H. In embodiments, R4 is -SO2NH2. In embodiments, R4 is -NHNH2. In embodiments, R4 is -ONH2. In embodiments, R4 is -NHC(O)NHNH2. In embodiments, R4 is -NHC(O)NH2. In embodiments, R4 is -NHSO2H. In embodiments, R4 is -NHC(O)H. In embodiments, R4 is -NHC(O)OH. In embodiments, R4 is -NHOH. In embodiments, R4 is -OCCl3. In embodiments, R4 is -OCF3. In embodiments, R4 is -OCBr3. In embodiments, R4 is -OCI3. In embodiments, R4 is -OCHCl2. In embodiments, R4 is -OCHBr2. In embodiments, R4 is -OCHI2. In embodiments, R4 is -OCHF2. In embodiments, R4 is -OCH2Cl. In embodiments, R4 is -OCH2Br. In embodiments, R4 is -OCH2I. In embodiments, R4 is -OCH2F. In embodiments, R4 is -N3. In embodiments, R4 is hydrogen or substituted or unsubstituted alkyl. In embodiments, R4 is hydrogen or a substituted or unsubstituted C1-C6 alkyl. In embodiments, R4 is -OPO3H. In embodiments, R4 is -OSO3H.
[0430] In embodiments, R4 is a substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0431] In embodiments, R4 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl. In embodiments, R4 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) alkyl. In embodiments, R4 is unsubstituted alkyl. In embodiments, R4 is a substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R4 is a substituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R4 is an unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2).
[0432] In embodiments, R4 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl. In embodiments, R4 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroalkyl. In embodiments, R4 is an unsubstituted heteroalkyl. In embodiments, R4 is a substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R4 is a substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R4 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). [0433] In embodiments, R4 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl. In embodiments, R4 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) cycloalkyl. In embodiments, R4 is an unsubstituted cycloalkyl. In embodiments, R4 is a substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, R4 is a substituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, R4 is an unsubstituted cycloalkyl (e.g., C3- C8, C3-C6, C4-C6, or C5-C6).
[0434] In embodiments, R4 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl. In embodiments, R4 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heterocycloalkyl. In embodiments, R4 is an unsubstituted heterocycloalkyl. In embodiments, R4 is a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R4 is a substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R4 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
[0435] In embodiments, R4 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted aryl. In embodiments, R4 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) aryl. In embodiments, R4 is an unsubstituted aryl. In embodiments, R4 is a substituted or unsubstituted aryl (e.g., C6-C10 or phenyl). In embodiments, R4 is a substituted aryl (e.g., C6-C10 or phenyl). In embodiments, R4 is an unsubstituted aryl (e.g., C6-C10 or phenyl).
[0436] In embodiments, R4 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl. In embodiments, R4 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroaryl. In embodiments, R4 is an unsubstituted heteroaryl. In embodiments, R4 is a substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R4 is a substituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R4 is an unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
[0437] In embodiments, R4 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, R4 is hydrogen, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0438] In embodiments, R4 is hydrogen or R34-substituted or unsubstituted alkyl (e.g., C1- C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R34-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R34- substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R34-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R34-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R34-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0439] In embodiments, R4 is R34-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1- C6 alkyl, or C1-C4 alkyl). In embodiments, R4 is R34-substituted alkyl (e.g., C1-C8 alkyl, C1- C6 alkyl, or C1-C4 alkyl). In embodiments, R4 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1- C6 alkyl, or C1-C4 alkyl).
[0440] In embodiments, R4 is R34-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R4 is R34-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R4 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
[0441] In embodiments, R4 is R34-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R4 is R34-substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R4 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
[0442] In embodiments, R4 is R34-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R4 is R34-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R4 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
[0443] In embodiments, R4 is R34-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R4 is R34-substituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R4 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).
[0444] In embodiments, R4 is R34-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R4 is R34-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R4 is an
unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0445] R34 is independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, R62-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R62-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R62-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R62-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R62-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R62-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0446] R62 is independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, R63-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R63-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R63-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R63-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R63-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R63-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0447] In embodiments, R4 is a substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, R4 is a substituted or unsubstituted C1-C6 alkyl. In embodiments, R4 is an unsubstituted C1-C3 alkyl. In embodiments, R4 is an unsubstituted methyl. In embodiments,
Figure imgf000139_0001
wherein R34 is halogen, R62-substituted or unsubstituted alkyl, R62-substituted or
unsubstituted heteroalkyl, R62-substituted or unsubstituted cycloalkyl, R62-substituted or unsubstituted heterocycloalkyl, R62-substituted or unsubstituted aryl, or R62-substituted or unsubstituted heteroaryl.
[0448] In embodiments, R34 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted aryl, or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl.
[0449] In embodiments, R34 is an unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.
[0450] In embodiments, R34 is R62-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1- C6 alkyl, or C1-C4 alkyl), R62-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R62-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R62- substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R62-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R62-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0451] In embodiments, R34 is R62-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1- C6 alkyl, or C1-C4 alkyl). In embodiments, R34 is R62-substituted alkyl (e.g., C1-C8 alkyl, C1- C6 alkyl, or C1-C4 alkyl). In embodiments, R34 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).
[0452] In embodiments, R34 is R62-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R34 is R62-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R34 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
[0453] In embodiments, R34 is R62-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R34 is R62-substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R34 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
[0454] In embodiments, R34 is R62-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R34 is R62-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R34 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
[0455] In embodiments, R34 is R62-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R34 is R62-substituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R34 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).
[0456] In embodiments, R34 is R62-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R34 is R62-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R34 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0457] In embodiments, L2 is substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, C1- C4, or C1-C2), substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or 2 to 3 membered), substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted arylene (e.g., C6-C10 or phenylene), or substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
[0458] In embodiments, a substituted L2 (e.g., substituted alkylene, substituted
heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted L2 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when L2 is substituted, it is substituted with at least one substituent group. In embodiments, when L2 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when L2 is substituted, it is substituted with at least one lower substituent group. [0459] In embodiments, L2 is substituted or unsubstituted C1-C8 alkylene, substituted or unsubstituted 2 to 8 membered heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, substituted or unsubstituted 3 to 8 membered heterocycloalkylene, substituted or unsubstituted C6-C10 arylene, or substituted or unsubstituted 5 to 10 membered heteroarylene. In embodiments, L2 is substituted or unsubstituted C1-C8 alkylene, or substituted or unsubstituted 2 to 8 membered heteroalkylene.
[0460] In embodiments, L2 is R35-substituted or unsubstituted C1-C8 alkylene, R35- substituted or unsubstituted 2 to 8 membered heteroalkylene, R35-substituted or unsubstituted C3-C8 cycloalkylene, R35-substituted or unsubstituted 3 to 8 membered heterocycloalkylene, R35-substituted or unsubstituted C6-C10 arylene, or R35-substituted or unsubstituted 5 to 10 membered heteroarylene. In embodiments, L2 is R35-substituted or unsubstituted C1-C8 alkylene, or R35-substituted or unsubstituted 2 to 8 membered heteroalkylene.
[0461] R35 is independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, R60-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R60-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R60-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R60-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R60-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R60-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0462] In embodiments, R35 is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted aryl, or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl.
[0463] In embodiments, R35 is an unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.
[0464] In embodiments, R35 is R60-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1- C6 alkyl, or C1-C4 alkyl), R60-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R60-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R60- substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R60-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R60-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0465] In embodiments, R35 is R60-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1- C6 alkyl, or C1-C4 alkyl). In embodiments, R35 is R60-substituted alkyl (e.g., C1-C8 alkyl, C1- C6 alkyl, or C1-C4 alkyl). In embodiments, R35 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).
[0466] In embodiments, R35 is R60-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R35 is R60-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R35 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
[0467] In embodiments, R35 is R60-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R35 is R60-substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R35 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). [0468] In embodiments, R35 is R60-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R35 is R60-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R35 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
[0469] In embodiments, R35 is R60-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R35 is R60-substituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R35 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).
[0470] In embodiments, R35 is R60-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R35 is R60-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R35 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
Figure imgf000144_0001
[0472] In embodiments, R33A is hydrogen oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or 2 to 3 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
[0473] In embodiments, a substituted R33A (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R33A is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R33A is substituted, it is substituted with at least one substituent group. In embodiments, when R33A is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R33A is substituted, it is substituted with at least one lower substituent group.
[0474] In embodiments, -L2-R33 is
Figure imgf000145_0001
Figure imgf000146_0001
[0475] In embodiments, the compound has the formula:
Figure imgf000147_0001
[0476] In embodiments, the compound has the formula:
Figure imgf000148_0001
Figure imgf000149_0001
[0477] In embodiments, the compound has the formula:
Figure imgf000149_0002
Figure imgf000150_0001
,
,
Figure imgf000151_0001
Figure imgf000152_0001
,
Figure imgf000153_0001
Figure imgf000154_0001
[0478] In embodiments, the compound has the formula:
Figure imgf000154_0002
,
Figure imgf000155_0001
,
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0001
,
Figure imgf000159_0001
,
Figure imgf000160_0001
,
Figure imgf000161_0001
[0479] In embodiments, the compound has the formula:
Figure imgf000162_0001
Figure imgf000163_0001
[0480] In embodiments, the compound has the formula:
Figure imgf000163_0002
Figure imgf000164_0001
[0481] In embodiments, the compound has the formula:
Figure imgf000164_0002
.
[0482] In embodiments, the compound has the formula:
Figure imgf000165_0001
[0483] In embodiments, the compound has the formula:
Figure imgf000165_0002
[0484] In embodiments, the compound has the formula:
Figure imgf000165_0003
[0485] In embodiments, the compound has the formula:
Figure imgf000165_0004
[0486] In embodiments, the compound has the formula:
Figure imgf000166_0004
[0487] In embodiments, the compound does not have the formula:
Figure imgf000166_0003
[0488] In embodiments, the compound does not have the formula:
Figure imgf000166_0002
[0489] In embodiments, the compound has the formula:
Figure imgf000166_0001
[0490] In embodiments, the compound has the formula:
Figure imgf000167_0001
[0491] In embodiments, the compound has the formula:
Figure imgf000167_0002
Figure imgf000168_0001
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
Figure imgf000172_0001
Figure imgf000173_0001
,
Figure imgf000174_0001
.
[0492] In embodiments, the compound has the formula:
Figure imgf000174_0002
Figure imgf000175_0001
Figure imgf000176_0001
Figure imgf000177_0001
Figure imgf000178_0001
,
Figure imgf000179_0001
,
Figure imgf000180_0001
,
Figure imgf000181_0002
[0493] In embodiments, the compound has the formula:
In embodiments, the compound has the formula: . In embodiments, the compound has the formula:
. In embodiments, the compound has the
Figure imgf000181_0001
formula:
Figure imgf000182_0005
In embodiments, the compound
has the formula:
Figure imgf000182_0004
In embodiments, the
compound has the formula: In
Figure imgf000182_0003
embodiments, the compound has the formula:
Figure imgf000182_0002
. In embodiments, the compound has the
H
formula: In embodiments, the
Figure imgf000182_0001
compound has the formula:
Figure imgf000183_0005
In embodiments, the compound has the formula:
Figure imgf000183_0004
In embodiments, the compound has
the formula:
Figure imgf000183_0003
In embodiments, the
compound has the formula:
Figure imgf000183_0002
. In embodiments, the compound has the formula:
In embodiments, the compound has the
Figure imgf000183_0001
formula:
Figure imgf000184_0005
In embodiments, the
compound has the formula:
Figure imgf000184_0004
In embodiments, the compound has the formula:
Figure imgf000184_0003
In embodiments, the compound has
the formula:
Figure imgf000184_0002
In embodiments, the
compound has the formula:
Figure imgf000184_0001
In embodiments, the compound has the formula:
Figure imgf000185_0005
. In embodiments, the compound has the
formula:
Figure imgf000185_0004
. In embodiments, the compound
H
has the formula:
Figure imgf000185_0003
. In embodiments,
the compound has the formula:
Figure imgf000185_0002
In embodiments, the compound has the formula:
In embodiments, the compound has
Figure imgf000185_0001
the formula: . In embodiments, the
O H N O OH N H N Me F
N N O O
Me H N
O N
Me O
compound has the formula: S . In embodiments, the compound has the formula:
O H N O OH N H N Me F
N N O O
Me H N
O N HN Me O
Me N . In embodiments, the compound has
the formula: . In embodiments, the
O H N O OH N H N Me F
N N O O
Me H N
O N
Me O
N compound has the formula: HN . In embodiments, the compound has the formula: . In embodiments, the compound has the
formula: . In embodiments, the compound
has the formula: . In embodiments, the
compound has the formula: . In embodiments, the compound has the formula:
. In embodiments, the compound has the formula: . In embodiments, the
compound has the formula: . In embodiments, the compound has the formula:
.
[0494] In an aspect is provided a compound, or salt thereof, having the formula:
. Y, L1, R2, R3, R5, R6, R7, Ring A, R8, z8, R10, R11, and R12 are as described herein.
[0495] In embodiments, the compound has the formula: . Y, L1, R2, R3, R5, R6, R7, Ring A, R8, z8, R10, R11, and R12 are as described herein, including in embodiments.
[0496] In embodiments, the compound has the formula:
.
[0497] In embodiments, the compound has the formula:
.
[0498] In embodiments, the compound is useful as a comparator compound. In embodiments, the comparator compound can be used to assess the activity of a test compound as set forth in an assay described herein (e.g., in the Examples section, figures, or tables).
[0499] In embodiments, the compound is a compound described herein (e.g., in the Compounds section, Examples Section, Methods Section, or in a claim, table, or figure).
III. Pharmaceutical compositions
[0500] In an aspect is provided a pharmaceutical composition including a compound described herein and a pharmaceutically acceptable excipient. [0501] In embodiments, the pharmaceutical composition includes an effective amount of the compound. In embodiments, the pharmaceutical composition includes a therapeutically effective amount of the compound.
[0502] In embodiments, the pharmaceutical composition includes a second agent. In embodiments, the pharmaceutical composition includes a second agent in a therapeutically effective amount. In embodiments, the second agent is a Group A streptogramin. In embodiments, the second agent is a Group B streptogramin. In embodiments, the second agent is an agent for treating an infectious disease (e.g., bacterial infection). In embodiments, the second agent is an agent for treating a group A streptococcus infection (e.g.,
Streptococcus pyogenes infection). In embodiments, the second agent is an agent for treating a gram-positive or a gram-negative bacterial infection. In embodiments, the second agent is an agent for treating a gram-positive bacterial infection. In embodiments, the second agent is an agent for treating a Staphylococcus aureus infection. In embodiments, the second agent is an agent for treating a gram-negative bacterial infection. In embodiments, the second agent is an agent for treating an infection associated with S. aureus, E. facium, E. faecalis, K.
pneumonoiaea, H. influenzaea, or P. aeruginosa. In embodiments, the second agent is VM1. In embodiments, the second agent is a derivative of VM1. In embodiments, the second agent is an agent that binds a ribosome (e.g., bacterial ribosome) at the same binding site as VM1. In embodiments, the second agent is an agent that competes with VM1 for binding to the ribosome (e.g., bacterial ribosome). In embodiments, the second agent is VM2. In embodiments, the second agent is a derivative of VM2. In embodiments, the second agent is an agent that binds a ribosome (e.g., bacterial ribosome) at the same binding site as VM2. In embodiments, the second agent is an agent that competes with VM2 for binding to the ribosome (e.g., bacterial ribosome). In embodiments, the second agent is VS1. In embodiments, the second agent is bound to a ribosome (e.g., a bacterial ribosome). In embodiments, the second agent is a derivative of VS1. In embodiments, the second agent is an agent that binds a ribosome (e.g., bacterial ribosome) at the same binding site as VS1. In embodiments, the second agent is an agent that competes with VS1 for binding to the ribosome (e.g., bacterial ribosome).
IV. Methods
[0503] In an aspect is provided a method of treating an infectious disease, the method including administering to a subject in need thereof an effective amount of a compound described herein. In embodiments, the method includes administering to a subject in need thereof a therapeutically effective amount of a compound described herein.
[0504] In embodiments, the infectious disease is a bacterial infection. In embodiments, the infectious disease is a group A streptococcus infection (e.g., Streptococcus pyogenes infection). In embodiments, the infectious disease is a gram-positive or a gram-negative bacterial infection. In embodiments, the infectious disease is a gram-positive bacterial infection. In embodiments, the infectious disease is a Staphylococcus aureus infection. In embodiments, the infectious disease is a gram-negative bacterial infection. In embodiments, the infectious disease is an infection associated with S. aureus, E. facium, E. faecalis, K. pneumonoiaea, H. influenzaea, or P. aeruginosa. In embodiments, the infectious disease is a S. aureus, E. facium, E. faecalis, K. pneumonoiaea, H. influenzaea, or P. aeruginosa infection. In embodiments, the treatment includes inhibiting bacterial growth. In embodiments, the treatment reduces bacterial reproduction, relative to a control. In embodiments, the treatment does not kill the bacterial cell.
[0505] In embodiments, the infectious disease is a bacteria-associated disease (e.g., actinomycosis, anthrax, abscesses in tissues (e.g., mouth in gastrointestinal tract, pelvic cavity, or lungs), whooping cough, lyme disease, brucellosis, enteritis, Guillain-Barre syndrome, pneumonia, conjunctivitis, trachoma, botulism, pseudomembranous colitis, food poisoning, tetanus, diphtheria, ehrlichiosis, bacterial endocarditis, urinary tract infection, diarrhea, meningitis (e.g., bacterial meningitis), sepsis, fever, tularemia, bronchitis, peptic ulcer, gastritis, Legionnaire’s disease, Pontiac fever, leptospirosis, listeriosis, leprosy, gonorrhea, opthalmia, nocardiosis, typhoid fever, salmonellosis, shigellosis, impetigo, cystitis, Scarlet fever, syphilis, cholera, or plague.
[0506] In embodiments, the bacteria-associated disease is actinomycosis, anthrax, abscesses in tissues (e.g., mouth in gastrointestinal tract, pelvic cavity, or lungs), whooping cough, lyme disease, brucellosis, enteritis, Guillain-Barre syndrome, pneumonia, conjunctivitis, trachoma, botulism, pseudomembranous colitis, food poisoning, tetanus, diphtheria, ehrlichiosis, bacterial endocarditis, urinary tract infection, diarrhea, meningitis (e.g., bacterial meningitis), sepsis, fever, tularemia, bronchitis, peptic ulcer, gastritis, Legionnaire’s disease, Pontiac fever, leptospirosis, listeriosis, leprosy, gonorrhea, opthalmia, nocardiosis, typhoid fever, salmonellosis, shigellosis, impetigo, cystitis, Scarlet fever, syphilis, cholera, or plague. [0507] In embodiments, the bacteria-associated disease is actinomycosis. In embodiments, the bacteria associated disease is anthrax. In embodiments, the bacteria-associated disease is abscesses in tissues (e.g., mouth in gastrointestinal tract, pelvic cavity, or lungs). In embodiments, the bacteria-associated disease is whooping cough. In embodiments, the bacteria-associated disease is lyme disease. In embodiments, the bacteria-associated disease is brucellosis. In embodiments, the bacteria-associated disease is enteritis. In embodiments, the bacteria-associated disease is Guillain-Barre syndrome. In embodiments, the bacteria- associated disease is pneumonia. In embodiments, the bacteria-associated disease is conjunctivitis. In embodiments, the bacteria-associated disease is trachoma. In
embodiments, the bacteria-associated disease is botulism. In embodiments, the bacteria- associated disease is pseudomembranous colitis. In embodiments, the bacteria-associated disease is food poisoning. In embodiments, the bacteria-associated disease is tetanus. In embodiments, the bacteria-associated disease is diphtheria. In embodiments, the bacteria- associated disease is ehrlichiosis. In embodiments, the bacteria-associated disease is bacterial endocarditis. In embodiments, the bacteria-associated disease is urinary tract infection. In embodiments, the bacteria-associated disease is diarrhea. In embodiments, the bacteria- associated disease is meningitis (e.g., bacterial meningitis). In embodiments, the bacteria- associated disease is sepsis. In embodiments, the bacteria-associated disease is fever. In embodiments, the bacteria-associated disease is tularemia. In embodiments, the bacteria- associated disease is bronchitis. In embodiments, the bacteria-associated disease is peptic ulcer. In embodiments, the bacteria-associated disease is gastritis. In embodiments, the bacteria-associated disease is Legionnaire’s disease. In embodiments, the bacteria-associated disease is Pontiac fever. In embodiments, the bacteria-associated disease is leptospirosis. In embodiments, the bacteria-associated disease is listeriosis. In embodiments, the bacteria- associated disease is leprosy. In embodiments, the bacteria-associated disease is gonorrhea. In embodiments, the bacteria-associated disease is opthalmia. In embodiments, the bacteria- associated disease is nocardiosis. In embodiments, the bacteria-associated disease is typhoid fever. In embodiments, the bacteria-associated disease is salmonellosis. In embodiments, the bacteria-associated disease is shigellosis. In embodiments, the bacteria-associated disease is impetigo. In embodiments, the bacteria-associated disease is cystitis. In embodiments, the bacteria-associated disease is Scarlet fever. In embodiments, the bacteria-associated disease is syphilis. In embodiments, the bacteria-associated disease is cholera. In embodiments, the bacteria-associated disease is plague. [0508] In embodiments, the bacterial infection is a Staphylococcus infection, an
Enterococcus infection, an Acinetobacter infection, a Bacillus infection, a Streptococcus infection, an Escherichia infection, a Pseudomonas infection, a Klebsiella infection, or a Haemophilus infection. In embodiments, the bacterial infection is a Staphylococcus infection, a Streptococcus infection, or an Enterococcus infection.
[0509] In embodiments, the bacterial infection is an A. baumannii infection, an E. coli infection, a K. pneumonia infection, a P. aeruginosa infection, an H. influenzae infection, an E. faecalis infection, an E. faecium infection, an S. aureus infection, or an S. pneumoniae infection. In embodiments, the bacterial infection is an A. baumannii infection, an E. coli infection, a K. pneumonia infection, a P. aeruginosa infection, or an H. influenzae infection. In embodiments, the bacterial infection is an E. faecalis infection, an E. faecium infection, an S. aureus infection, or an S. pneumoniae infection. In embodiments, the bacterial infection is an A. baumannii infection. In embodiments, the bacterial infection is an E. coli infection. In embodiments, the bacterial infection is a K. pneumonia infection. In embodiments, the bacterial infection is a P. aeruginosa infection. In embodiments, the bacterial infection is an H. influenzae infection. In embodiments, the bacterial infection is an E. faecalis infection. In embodiments, the bacterial infection is an E. faecium infection. In embodiments, the bacterial infection is an S. aureus infection. In embodiments, the bacterial infection is an S. pneumoniae infection.
[0510] In embodiments, the method includes the compound (e.g., a compound described herein) binding to the peptidyl transferase domain of the 50s ribosomal subunit. In embodiments, the method includes the compound (e.g., a compound described herein) and a second agent simultaneously bound to a ribosome (e.g., bacterial ribosome). In
embodiments, the second agent is a Group A streptogramin. In embodiments, the second agent is a Group B streptogramin. In embodiments, the second agent is an agent for treating an infectious disease (e.g., bacterial infection). In embodiments, the second agent is an agent for treating a group A streptococcus infection (e.g., Streptococcus pyogenes infection). In embodiments, the second agent is an agent for treating a gram-positive or a gram-negative bacterial infection. In embodiments, the second agent is an agent for treating a gram-positive bacterial infection. In embodiments, the second agent is an agent for treating a
Staphylococcus aureus infection. In embodiments, the second agent is an agent for treating a gram-negative bacterial infection. In embodiments, the second agent is an agent for treating an infection associated with S. aureus, E. facium, E. faecalis, K. pneumonoiaea, H. influenzaea, or P. aeruginosa. In embodiments, the second agent is VM1. In embodiments, the second agent is a derivative of VM1. In embodiments, the second agent is an agent that binds a ribosome (e.g., bacterial ribosome) at the same binding site as VM1. In
embodiments, the second agent is an agent that competes with VM1 for binding to the ribosome (e.g., bacterial ribosome). In embodiments, the second agent is VM2. In embodiments, the second agent is a derivative of VM2. In embodiments, the second agent is an agent that binds a ribosome (e.g., bacterial ribosome) at the same binding site as VM2. In embodiments, the second agent is an agent that competes with VM2 for binding to the ribosome (e.g., bacterial ribosome). In embodiments, the second agent is VS1. In embodiments, the second agent is bound to a ribosome (e.g., a bacterial ribosome). In embodiments, the second agent is a derivative of VS1. In embodiments, the second agent is an agent that binds a ribosome (e.g., bacterial ribosome) at the same binding site as VS1. In embodiments, the second agent is an agent that competes with VS1 for binding to the ribosome (e.g., bacterial ribosome).
[0511] In embodiments, the infectious disease is a parasitic infection. In embodiments, the infectious disease is malaria. In embodiments, the parasitic infection is a Plasmodium falciparum parasitic infection. In embodiments, the parasitic infection is a Trypanosoma cruzi parasitic infection.
[0512] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.
V. Embodiments
[0513] Embodiment P1. A compound, or salt thereof, having the formula:
Figure imgf000194_0001
wherein
Y is–O- or–NH-;
L1 is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted
heteroalkylene;
R2 is hydrogen or unsubstituted C1-C3 alkyl;
R4A is substituted or unsubstituted C2-C10 alkyl;
R3 and R5 are independently hydrogen, oxo, halogen, -CCI3, -CBr3, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, -OPO3H, -OSO3H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R6 is hydrogen, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H,
-SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or an amino acid side chain; R7 is hydrogen, -CH2COOH, -CONH2, -OH, -SH, -NO2, -NH2, -NHNH2, -ONH2,
-NHC(O)NHNH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R6 and R7 may optionally be joined to form an unsubstituted heterocycloalkyl or
unsubstituted heteroaryl;
R8 is oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
Ring A is cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;
z8 is an integer from 0 to 10;
R9 is hydrogen, oxo, halogen, -CCI3, -CBr3, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R10 and R12 are independently hydrogen, substituted or unsubstituted C1-C3 alkyl, or substituted or unsubstituted 2 to 3 membered heteroalkyl; and
R11 is hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0514] Embodiment P2. The compound of embodiment P1, wherein R4A is unsubstituted C2-C10 alkyl.
[0515] Embodiment P3. The compound of one of embodiments P1 to P2, wherein R4A is unsubstituted C3-C10 alkenyl.
[0516] Embodiment P4. The compound of any one of embodiments P1 to P3, wherein
Figure imgf000196_0001
[0517] Embodiment P5. The compound of any one of embodiments P1 to P4, wherein L1 is a substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.
[0518] Embodiment P6. The compound of any one of embodiments P1 to P5, wherein L1 is a substituted or unsubstituted alkenylene.
[0519] Embodiment P7. The compound of any one of embodiments P1 to P6, wherein L1 is a substituted or unsubstituted C1-C3 alkenylene.
[0520] Embodiment P8. The compound of any one of embodiments P1 to P7, wherein R2 is hydrogen.
[0521] Embodiment P9. The compound of any one of embodiments P1 to P8, wherein R3 is hydrogen or substituted or unsubstituted alkyl.
[0522] Embodiment P10. The compound of any one of embodiments P1 to P9, wherein R3 is hydrogen.
[0523] Embodiment P11. The compound of any one of embodiments P1 to P10, wherein R5 is hydrogen, oxo, halogen, -CCI3, -CBr3, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0524] Embodiment P12. The compound of any one of embodiments P1 to P11, wherein R5 is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0525] Embodiment P13. The compound of any one of embodiments P1 to P12, wherein R5 is substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, or substituted or unsubstituted 5 to 10 membered heteroaryl. [0526] Embodiment P14. The compound of any one of embodiments P1 to P13, wherein R5 is substituted or unsubstituted C1-C8 alkyl.
[0527] Embodiment P15. The compound of any one of embodiments P1 to P14, wherein R5 is substituted or unsubstituted C1-C3 alkyl.
[0528] Embodiment P16. The compound of any one of embodiments P1 to P15, wherein R5 is:
Figure imgf000198_0001
Figure imgf000199_0001
, , , , o .
[0529] Embodiment P17. The compound of one of embodiments P1 to P16, wherein Y is -O-.
[0530] Embodiment P18. The compound of one of embodiments P1 to P17, wherein R6 is substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.
[0531] Embodiment P19. The compound of one of embodiments P1 to P17, wherein R6 is hydrogen,
Figure imgf000199_0004
Figure imgf000199_0002
[0532] Embodiment P20. The compound of one of embodiments P1 to P17, wherein R6 is
Figure imgf000199_0003
[0533] Embodiment P21. The compound of one of embodiments P1 to P17, wherein R6 and R7 are joined to form an unsubstituted heterocycloalkyl or unsubstituted heteroaryl. [0534] Embodiment P22. The compound of one of embodiments P1 to P21, wherein R6 and R7 are joined to form an unsubstituted 3 to 6 membered heterocycloalkyl, or an unsubstituted 5 to 6 membered heteroaryl.
[0535] Embodiment P23. The compound of one of embodiments P1 to P17, wherein R6 and R7 are joined to form an unsubstituted 3 to 6 membered heterocycloalkyl.
[0536] Embodiment P24. The compound of one of embodiments P1 to P17, wherein R6 and R7 are joined to form an unsubstituted pyrrolidinyl or 2,3-dihydropyrrolyl.
[0537] Embodiment P25. The compound of one of embodiments P1 to P17, wherein R7 is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.
[0538] Embodiment P26. The compound of one of embodiments P1 to P17, wherein R7 is hydrogen.
[0539] Embodiment P27. The compound of one of embodiments P1 to P26, wherein Ring A is C3-C6 cycloalkylene, 3 to 6 membered heterocycloalkylene, phenylene, or a 5 to 6 membered heteroarylene.
[0540] Embodiment P28. The compound of one of embodiments P1 to P27, wherein Ring A is 5 to 6 membered heteroarylene.
[0541] Embodiment P29. The compound of one of embodiments P1 to P28, wherein Ring A is imidazolylene, pyrrolylene, pyrazolylene, triazolylene, tetrazolylene, furanylene, oxazolylene, isoxazolylene, oxadiazolylene, oxatriazolylene, thienylene, thiazolylene, isothiazolylene, pyridinylene, pyrazinylene, pyrimidinylene, pyridazinylene, or triazinylene.
[0542] Embodiment P30. The compound of one of embodiments P1 to P29, wherein Ring A is oxazolylene, thiazolylene, isoxazolylene, or oxadiazolylene.
[0543] Embodiment P31. The compound of one of embodiments P1 to P30, wherein z8 is 0.
[0544] Embodiment P32. The compound of one of embodiments P1 to P31, wherein R9 is halogen, oxo, -NH2, unsubstituted alkyl, or unsubstituted heteroalkyl.
[0545] Embodiment P33. The compound of one of embodiments P1 to P32, wherein R9 is –F, oxo, -NH2, or unsubstituted heteroalkyl. [0546] Embodiment P34. The compound of one of embodiments P1 to P33, wherein R10 is hydrogen.
[0547] Embodiment P35. The compound of one of embodiments P1 to P34, wherein R11 is -OH, -NH2, or -SH.
[0548] Embodiment P36. The compound of one of embodiments P1 to P35, wherein R11 is–OH.
[0549] Embodiment P37. The compound of one of embodiments P1 to P36, wherein R12 is hydrogen or an unsubstituted C1-C3 alkyl.
[0550] Embodiment P38. The compound of one of embodiments P1 to P37, wherein the compound has the formula:
Figure imgf000201_0001
[0551] Embodiment P39. A compound, or salt thereof, having the formula:
Figure imgf000201_0002
wherein
Y is–O- or–NH-;
L1 is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene;
R2 is hydrogen or unsubstituted C1-C3 alkyl; R3, R4, and R5 are independently hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, -OPO3H, -OSO3H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R6 is hydrogen, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H,
-SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or an amino acid side chain; R7 is hydrogen, -CH2COOH, -CONH2, -OH, -SH, -NO2, -NH2, -NHNH2, -ONH2,
-NHC(O)NHNH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R6 and R7 may optionally be joined to form an unsubstituted heterocycloalkyl or
unsubstituted heteroaryl;
R8 is oxo, halogen, -CCI3, -CBr3, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
Ring A is cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;
z8 is an integer from 0 to 10;
R10 and R12 are independently hydrogen, substituted or unsubstituted C1-C3 alkyl, or substituted or unsubstituted 2 to 3 membered heteroalkyl; and R11 is hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
wherein the compound does not have the formula:
Figure imgf000203_0001
[0552] Embodiment P40. The compound of embodiment P39, having the formula:
Figure imgf000203_0002
wherein
L2 is substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; and R33 is hydrogen, oxo, halogen, -CCI3, -CBr3, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0553] Embodiment P41. The compound of one of embodiments P39 to P40, wherein R4 is substituted or unsubstituted alkyl.
[0554] Embodiment P42. The compound of one of embodiments P40 to P41, wherein -L2- is substituted or unsubstituted C1-C8 alkylene, substituted or unsubstituted 2 to 8 membered heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, substituted or unsubstituted 3 to 8 membered heterocycloalkylene, substituted or unsubstituted C6-C10 arylene, or substituted or unsubstituted 5 to 10 membered heteroarylene.
[0555] Embodiment P43. The compound of any one of embodiments P40 to P42, wherein -L2- is substituted or unsubstituted C1-C8 alkylene, or substituted or unsubstituted 2 to 8 membered heteroalkylene.
[0556] Embodiment P44. The compound of any one of embodiments P40 to P43, wherein -L2- is
Figure imgf000204_0001
[0557] Embodiment P45. The compound of any one of embodiments P40 to P44, wherein -L2-R33 is
Figure imgf000204_0002
Figure imgf000205_0001
[0558] Embodiment P46. The compound of any one of embodiments P39 to P45, having the formula:
Figure imgf000206_0001
.
[0559] Embodiment P47. A pharmaceutical composition comprising a compound of embodiments P1 to P46, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
[0560] Embodiment P48. A method of treating an infectious disease, said method comprising administering to a subject in need thereof an effective amount of a compound of embodiments P1 to P46.
[0561] Embodiment P49. The method of embodiment P48, wherein said infectious disease is a bacterial infection.
[0562] Embodiment P50. The method of one of embodiments P48 to P49, wherein the infectious disease is a gram-positive bacterial infection.
[0563] Embodiment P51. The method of one of embodiments P48 to P49, wherein the infectious disease is a gram-negative bacterial infection.
[0564] Embodiment P52. The method of one of embodiments P48 to P49, wherein the bacterial infection is a Staphylococcus infection, an Enterococcus infection, an Acinetobacter infection, a Bacillus infection, a Streptococcus infection, an Escherichia infection, a Pseudomonas infection, a Klebsiella infection, or a Haemophilus infection.
[0565] Embodiment P53. The method of one of embodiments P48 to P49, wherein the bacterial infection is a Staphylococcus infection, a Streptococcus infection, or an
Enterococcus infection.
[0566] Embodiment P54. The method of embodiment P48, wherein the infectious disease is a parasitic infection. [0567] Embodiment P55. The method of embodiment P54, wherein the parasitic infection is a Plasmodium falciparum parasitic infection.
[0568] Embodiment P56. The method of embodiment P54, wherein the parasitic infection is a Trypanosoma cruzi parasitic infection.
VI. Additional embodiments
[0569] Embodiment 1. A compound, or salt thereof, having the formula:
Figure imgf000207_0001
wherein
Y is–O- or–NH-;
L1 is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene;
R2 is hydrogen or unsubstituted C1-C3 alkyl;
R4A is substituted or unsubstituted C2-C10 alkyl;
R3 and R5 are independently hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, -OPO3H, -OSO3H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R6 is hydrogen, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H,
-SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or an amino acid side chain; R7 is hydrogen, -CH2COOH, -CONH2, -OH, -SH, -NO2, -NH2, -NHNH2, -ONH2,
-NHC(O)NHNH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R6 and R7 may optionally be joined to form an unsubstituted heterocycloalkyl or
unsubstituted heteroaryl;
R8 is oxo, halogen, -CCI3, -CBr3, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
Ring A is cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;
z8 is an integer from 0 to 10;
R9 is hydrogen, oxo, halogen, -CCI3, -CBr3, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R10 and R12 are independently hydrogen, substituted or unsubstituted C1-C3 alkyl, or substituted or unsubstituted 2 to 3 membered heteroalkyl; and
R11 is hydrogen, oxo, halogen, -CCI3, -CBr3, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0570] Embodiment 2. The compound of embodiment 1, wherein R4A is unsubstituted C2-C10 alkyl.
[0571] Embodiment 3. The compound of any one of embodiments 1 to 2, wherein R4A is unsubstituted C3-C10 alkenyl.
[0572] Embodiment 4. The compound of any one of embodiments 1 to 3, wherein R4A
Figure imgf000209_0001
[0573] Embodiment 5. The compound of any one of embodiments 1 to 4, wherein L1 is a substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.
[0574] Embodiment 6. The compound of any one of embodiments 1 to 5, wherein L1 is a substituted or unsubstituted alkenylene.
[0575] Embodiment 7. The compound of any one of embodiments 1 to 6, wherein L1 is a substituted or unsubstituted C1-C3 alkenylene.
[0576] Embodiment 8. The compound of any one of embodiments 1 to 7, wherein R2 is hydrogen.
[0577] Embodiment 9. The compound of any one of embodiments 1 to 8, wherein R3 is hydrogen or substituted or unsubstituted alkyl.
[0578] Embodiment 10. The compound of any one of embodiments 1 to 9, wherein R3 is hydrogen.
[0579] Embodiment 11. The compound of any one of embodiments 1 to 10, wherein R5 is hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0580] Embodiment 12. The compound of any one of embodiments 1 to 11, wherein R5 is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0581] Embodiment 13. The compound of any one of embodiments 1 to 12, wherein R5 is substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, or substituted or unsubstituted 5 to 10 membered heteroaryl.
[0582] Embodiment 14. The compound of any one of embodiments 1 to 13, wherein R5 is substituted or unsubstituted C1-C8 alkyl.
[0583] Embodiment 15. The compound of any one of embodiments 1 to 14, wherein R5 is substituted or unsubstituted C1-C3 alkyl.
[0584] Embodiment 16. The compound of any one of embodiments 1 to 15, wherein R5 is:
Figure imgf000210_0001
Figure imgf000211_0001
[0585] Embodiment 17. The compound of any one of embodiments 1 to 16, wherein Y is -O-.
[0586] Embodiment 18. The compound of any one of embodiments 1 to 17, wherein R6 is substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. [0587] Embodiment 19. The compound of any one of embodiments 1 to 17, wherein R6
Figure imgf000212_0002
[0588] Embodiment 20. The compound of any one of embodiments 1 to 17, wherein R6
Figure imgf000212_0001
[0589] Embodiment 21. The compound of any one of embodiments 1 to 17, wherein R6 and R7 are joined to form an unsubstituted heterocycloalkyl or unsubstituted heteroaryl.
[0590] Embodiment 22. The compound of any one of embodiments 1 to 21, wherein R6 and R7 are joined to form an unsubstituted 3 to 6 membered heterocycloalkyl, or an unsubstituted 5 to 6 membered heteroaryl.
[0591] Embodiment 23. The compound of any one of embodiments 1 to 17, wherein R6 and R7 are joined to form an unsubstituted 3 to 6 membered heterocycloalkyl.
[0592] Embodiment 24. The compound of any one of embodiments 1 to 17, wherein R6 and R7 are joined to form an unsubstituted pyrrolidinyl or 2,3-dihydropyrrolyl.
[0593] Embodiment 25. The compound of any one of embodiments 1 to 17, wherein R7 is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.
[0594] Embodiment 26. The compound of any one of embodiments 1 to 17, wherein R7 is hydrogen.
[0595] Embodiment 27. The compound of any one of embodiments 1 to 26, wherein Ring A is C3-C6 cycloalkylene, 3 to 6 membered heterocycloalkylene, phenylene, or a 5 to 6 membered heteroarylene. [0596] Embodiment 28. The compound of any one of embodiments 1 to 27, wherein Ring A is 5 to 6 membered heteroarylene.
[0597] Embodiment 29. The compound of any one of embodiments 1 to 28, wherein Ring A is imidazolylene, pyrrolylene, pyrazolylene, triazolylene, tetrazolylene, furanylene, oxazolylene, isoxazolylene, oxadiazolylene, oxatriazolylene, thienylene, thiazolylene, isothiazolylene, pyridinylene, pyrazinylene, pyrimidinylene, pyridazinylene, or triazinylene.
[0598] Embodiment 30. The compound of any one of embodiments 1 to 29, wherein Ring A is oxazolylene, thiazolylene, isoxazolylene, or oxadiazolylene.
[0599] Embodiment 31. The compound of any one of embodiments 1 to 30, wherein z8 is 0.
[0600] Embodiment 32. The compound of any one of embodiments 1 to 31, wherein R9 is halogen, oxo, -NH2, unsubstituted alkyl, or unsubstituted heteroalkyl.
[0601] Embodiment 33. The compound of any one of embodiments 1 to 32, wherein R9 is–F, oxo, -NH2, or unsubstituted heteroalkyl.
[0602] Embodiment 34. The compound of any one of embodiments 1 to 33, wherein R10 is hydrogen.
[0603] Embodiment 35. The compound of any one of embodiments 1 to 34, wherein R11 is -OH, -NH2, or -SH.
[0604] Embodiment 36. The compound of any one of embodiments 1 to 35, wherein R11 is–OH.
[0605] Embodiment 37. The compound of any one of embodiments 1 to 36, wherein R12 is hydrogen or an unsubstituted C1-C3 alkyl.
[0606] Embodiment 38. The compound of embodiment 1, wherein the compound has the formula:
Figure imgf000213_0001
[0607] Embodiment 39. The compound of embodiment 1, wherein the compound has the formula:
Figure imgf000214_0002
.
[0608] Embodiment 40. A compound, or salt thereof, having the formula:
Figure imgf000214_0001
wherein
Y is–O- or–NH-;
L1 is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene;
R2 is hydrogen or unsubstituted C1-C3 alkyl;
R3, R4, and R5 are independently hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, -OPO3H, -OSO3H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R6 is hydrogen, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H,
-SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or an amino acid side chain; R7 is hydrogen, -CH2COOH, -CONH2, -OH, -SH, -NO2, -NH2, -NHNH2, -ONH2,
-NHC(O)NHNH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R6 and R7 may optionally be joined to form an unsubstituted heterocycloalkyl or
unsubstituted heteroaryl;
R8 is oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
Ring A is cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;
z8 is an integer from 0 to 10;
R10 and R12 are independently hydrogen, substituted or unsubstituted C1-C3 alkyl, or substituted or unsubstituted 2 to 3 membered heteroalkyl; and
R11 is hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein the compound does not have the formula:
Figure imgf000216_0001
[0609] Embodiment 41. The compound of embodiment 40, having the formula:
Figure imgf000216_0002
wherein
L2 is substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; and R33 is hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0610] Embodiment 42. The compound of any one of embodiments 40 to 41, wherein R4 is substituted or unsubstituted alkyl.
[0611] Embodiment 43. The compound of any one of embodiments 41 to 42, wherein -L2- is substituted or unsubstituted C1-C8 alkylene, substituted or unsubstituted 2 to 8 membered heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, substituted or unsubstituted 3 to 8 membered heterocycloalkylene, substituted or unsubstituted C6-C10 arylene, or substituted or unsubstituted 5 to 10 membered heteroarylene.
[0612] Embodiment 44. The compound of any one of embodiments 41 to 43, wherein -L2- is substituted or unsubstituted C1-C8 alkylene, or substituted or unsubstituted 2 to 8 membered heteroalkylene.
[0613] Embodiment 45. The compound of any one of embodiments 41 to 44, wherein -L2- is
Figure imgf000217_0001
[0614] Embodiment 46. The compound of any one of embodiments 41 to 45, wherein -L2-R33 is
Figure imgf000217_0002
Figure imgf000218_0001
[0615] Embodiment 47. The compound of any one of embodiments 40 to 46, having the formula:
Figure imgf000218_0002
. [0616] Embodiment 48. A pharmaceutical composition comprising a compound of any one of embodiments 1 to 47, or pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable excipient.
[0617] Embodiment 49. A method of treating an infectious disease, said method comprising administering to a subject in need thereof an effective amount of a compound of any one of embodiments 1 to 47.
[0618] Embodiment 50. The method of embodiment 49, wherein said infectious disease is a bacterial infection.
[0619] Embodiment 51. The method of any one of embodiments 49 to 50, wherein the infectious disease is a gram-positive bacterial infection.
[0620] Embodiment 52. The method of any one of embodiments 49 to 50, wherein the infectious disease is a gram-negative bacterial infection.
[0621] Embodiment 53. The method of any one of embodiments 49 to 50, wherein the bacterial infection is a Staphylococcus infection, an Enterococcus infection, an Acinetobacter infection, a Bacillus infection, a Streptococcus infection, an Escherichia infection, a Pseudomonas infection, a Klebsiella infection, or a Haemophilus infection.
[0622] Embodiment 54. The method of any one of embodiments 49 to 50, wherein the bacterial infection is a Staphylococcus infection, a Streptococcus infection, or an
Enterococcus infection.
[0623] Embodiment 55. The method of embodiment 49, wherein the infectious disease is a parasitic infection.
[0624] Embodiment 56. The method of embodiment 55, wherein the parasitic infection is a Plasmodium falciparum parasitic infection.
[0625] Embodiment 57. The method of embodiment 55, wherein the parasitic infection is a Trypanosoma cruzi parasitic infection. EXAMPLES
Example 1: Synthesis and mechanisms of action of group A streptogramin antibiotics that overcome resistance
[0626] Natural products serve as chemical blueprints for the majority of classes of antibiotics in our clinical arsenal (1). The evolutionary process by which these molecules arise is inherently accompanied by the co-evolution of resistance mechanisms that shorten the clinical lifetime of any given class (2). Virginiamycin acetyltransferases (Vats) are resistance proteins that provide protection against streptogramins, which are potent Gram-positive antibiotics that inhibit the bacterial ribosome (3). Due to the challenge of selectively modifying the chemically complex, 23-membered macrocyclic scaffold of group A streptogramins, analogues that overcome Vat resistance have not been previously accessible. Here we present a platform for the design, synthesis, and biomolecular characterization of group A streptogramin antibiotics with unprecedented structural variability. Using cryo- electron microscopy and new energy function refinement techniques, we characterize the binding of nine analogues to the bacterial ribosome at high resolution (2.4-2.8 Å), revealing new binding interactions that extend into the peptidyl tRNA binding site and towards synergistic binders in the nascent peptide exit tunnel. Two of these analogues have excellent activity against a streptogramin-resistant strain of S. aureus expressing VatA and exhibit decreased acetylation rates in vitro. When combined with the group B streptogramin virginiamycin S1, these analogues gain activity against bacteria expressing two other streptogramin resistance mechanisms mediated by ABC-F proteins (4) and by Cfr methyltransferase (5). Our results demonstrate that the combination of rational structural design and modular chemical synthesis can revitalize classes of antibiotics that are limited by naturally arising resistance mechanisms, restocking our arsenal of antibiotics to fight multidrug-resistant infections.
[0627] Lack of new antibiotics and limitations of semisynthesis. Natural product antibiotics are secondary metabolites that have arisen through millions of years of evolutionary optimization, resulting in excellent antimicrobial activity. This process selects for properties that are favorable for the producing organisms in their native environment; however, these selected properties are not necessarily transferable to therapeutics due to attributes such as solubility and bioavailability (1). Furthermore, the evolution of natural product antibiotics is inherently coupled with the evolution of resistance mechanisms, both to protect the producing organism and to provide defenses for competing organisms (2). These resistance mechanisms can be passed to progeny and to other species by horizontal gene transfer. As a result, many potent antimicrobial natural products are poorly suited for clinical use. A primary means by which researchers have overcome poor therapeutic attributes or resistance is semisynthesis: the chemical modification of natural products that are obtained through fermentation (1). Semisynthesis has been effective to improve the pharmacological properties of myriad natural product classes, such as b-lactams (e.g., amoxicillin), macrolides (e.g., azithromycin), and lincosamides (e.g., clindamycin). In overcoming natural resistance mechanisms, however, semisynthesis has been met with limited success. Often researchers are forced to implement other therapeutic modalities, such as combination therapy with inhibitors of resistance proteins, as in b-lactams/b-lactamase inhibitors (6). Recently, advances in chemistry have enabled several classes of antibiotics to be accessed by fully synthetic routes, greatly expanding structural variability compared to semisynthesis and providing a renewed avenue to overcome resistance (1).
[0628] Streptogramin background and semi-synthetic limitations in particular. For many antibiotic classes, methods to overcome resistance mechanisms have yet to be discovered. A salient example is the streptogramin class, which comprises two structurally disparate components (A and B) that are produced by Streptomyces spp. (FIGS.1A to 1F) (7). Streptogramins exhibit potent activity against several species of Gram-positive bacteria but suffer from poor water solubility and susceptibility to several resistance mechanisms that limit their spectrum of activity (8). Rohne-Polenc developed the water-soluble streptogramin combination quinupristin/dalfopristin (1/2, trade name: Synercid) by semisynthesis from the natural products pristinamycin IA (3) and virginiamycin M1 (VM1) (9).
Quinupristin/dalfopristin was approved in the United States in 1999 and served as a valuable weapon against bacteremia caused by vancomycin-resistant E. faecium (VRE). However, its use quickly dwindled due to several drawbacks, including common side effects (e.g., venous irritation, arthralgias, myalgias) (10) and extensive clinical resistance (11). In the two decades since the approval of quinupristin/dalfopristin, the only other streptogramin combination to enter the clinic was NXL-103, an orally administered combination of semisynthetic streptogramins flopristin (4) and linopristin (5) (12). NXL-103 failed to overcome any of the streptogramin resistance mechanisms and was not available in an IV formulation; further clinical development has not been reported since a successful phase-II trial in 2010.
Quinupristin/dalfopristin and NXL-103 are accessed by semisynthetic modifications at only three positions on the two components (see highlights in FIG.1A): C16 and C26 in group A compounds, and the pipecolic acid residue in group B compounds. These positions were likely selected in part due to their chemical accessibility. We recently reported a modular, fully synthetic route to group A streptogramins that enables modification at sites that are not practical to modify with semisynthesis (13). Herein we report the application of this route to the synthesis of analogues designed to overcome streptogramin resistance.
[0629] Group A and group B streptogramins work in concert to inhibit protein synthesis by binding to adjacent sites in the catalytic center of the bacterial ribosome (14). The group A component effectively serves as an anchor: its binding to the peptidyltransferase centre (PTC) is associated with an increase in affinity of the group B component to the adjacent nascent peptide exit tunnel (NPET) (15). Together, the two components act synergistically, achieving bactericidal activity in many organisms (16). Like many antibiotics that target the PTC, resistance to streptogramins can be mediated by ABC-F family proteins that dislodge antibiotics (17) or by Cfr methyltransferases that directly interfere with binding by modifying A2503 (18). An additional and specific resistance mechanism for group A streptogramins is deactivation by acetyltransferases of the Vat family (3). These proteins function by transferring an acetyl group to the C14 alcohol, disrupting a hydrogen bond to the phosphodiester backbone at residue U2504 in the PTC and greatly reducing binding affinity to the ribosome.
[0630] CryoEM enables rapid structural characterization of streptogramins created by total synthesis. We chose as a parent scaffold for our study the natural product virginiamycin M2 (VM2) due to its ease of access by our synthetic route (vide infra) and to its ability to be converted to more active analogues (e.g., flopristin, 4) by C16 fluorination. Co-crystallographic data for group A streptogramins bound to bacterial (15,19,20) and archeal (21,22) ribosomes have revealed general binding determinants, but no structural data for VM2 bound to bacterial ribosomes existed at the outset of this study. To guide the design of analogues that maintain ribosomal activity while overcoming binding to Vat proteins, we obtained a 2.5-Å resolution cryoEM structure of fully synthetic VM2 bound to the large subunit of the E. coli ribosome (FIG.1B). Consistent with the characterized binding of other group A streptogramins, we observed high quality density corresponding to a single binding site for VM2 in the PTC, spanning the A- and P-tRNA binding sites. To enable structure- based design of analogues, it is important that careful attention is paid to the chemical restraints of the group A streptogramins macrocycles during model refinement. For model refinement, we used a version of phenix.real_space_refine that exploits the OPLS3e forcefield to generate low energy conformations that are consistent with the electron density. Both the quality of the density, enabled by the advantageous properties of the ribosome as a cryoEM sample, and the model, enabled by the forcefield-guided refinement, are sufficient to guide hypothesis-driven alterations of the molecule.
[0631] The positioning of the C14 alcohol in VM2 is consistent with a hydrogen bond to the phosphodiester backbone at U2504, an interaction that would be disrupted by acetylation (FIGS.1B, 1C, and 1D). The C3 isopropyl group participates in hydrophobic interactions with the face of U2585, but it otherwise appears to lack binding interactions, suggesting that modifications off of this position would be tolerated. Similarly, the C4 methyl group does not appear to make binding interactions and is angled towards the group B streptogramin binding site in the exit tunnel. Previous mutagenesis and crystallography revealed how contacts between binding site residues (Val61, Ile62, Met107, and Pro108) in the resistance enzyme VatA and the C3 isopropyl group, the C4 methyl group, and the C6 proton are required for drug deactivation by acetylation (3) (FIGS.1E and 1F). Structural modifications to these positions might overcome Vat resistance, but only one semisynthetic streptogramin with modifications at one of these locations has been reported, resulting from hydrogenation of the C5-C6 double bond (3,23). Broader semisynthetic modifications of these positions are impractical due to the lack of proximal functional groups for chemoselective activation. These results suggest that modifications to the C3 and C4 groups on VM2 might disrupt binding to VatA while maintaining ribosomal activity.
[0632] Modular synthesis enables access to a diverse library of group A streptogramin analogues. To directly test the hypothesis that structural modifications at these positions could overcome resistance to Vat enzymes, we developed a pipeline for the synthesis of group A streptogramins that enables access to unprecedented structural diversity and performed detailed antimicrobial analysis, high resolution cryoEM to visualize the structural determinants of binding, and in vitro analysis of translation and resistance activities. Our route to group A streptogramins (e.g., VM2 in FIG.2A) comprises the convergent assembly of seven simple chemical building blocks, each of which is diversifiable, enabling a high level of flexibility in the generation of analogues by building block exchange (13). Before outlining the details of our synthesis, our general design strategy merits brief discussion: We synthesize two halves of similar complexity; the halves are joined by amide bond coupling, and macrocyclization is accomplished by means of a Stille cross-coupling reaction. Removal of the silyl groups is the only step required after macrocyclization to complete the synthesis. Overall, the route is seven linear steps (11 total steps) from the starting building blocks, facilitating rapid generation of analogues. Importantly, the synthesis of the left and right halves is highly scalable. By pooling decagram quantities of each half, we are able to rapidly synthesize analogues with modifications on the complimentary half without repeating the entire synthesis. This benefit of convergency enables new building blocks to be incorporated in seven steps, provided sufficient quantities of the complementary half are available.
[0633] FIG.2A depicts the application of our strategy to the natural product virginiamycin M2 (2), which serves as the parent scaffold for the present study. Details of the development of this route can be found in the original report (13); here we will focus the discussion on modifications and improvements. The synthesis of the left half (13) proceeds in 74% overall yield from building blocks 7 and 8. Our previous synthesis delivered the right half (19) in three steps and 42% overall yield from 14 and 15, but we found that purification of 19 was challenging on >1-g scale due to the presence of several contaminants including unreacted thiazole 18, cleaved thiazolidinethione auxiliary, and a byproduct resulting from nucleophilic ring opening of the thazolidinethione present in 17. We avoided this complication by first converting 17 to a Weinreb amide (24) followed by treatment with the dianion of 18 to deliver right half 19. Although this operational change adds a step, it results in higher overall yield (90% over 2 steps compared to 71% over one step) and simplifies purification of 19. The two halves are coupled by means of HATU in the presence of Hünig’s base in 91% yield, and the resulting macrocycle precursor 20 is cyclized in the presence of Pd2(dba)3 and JackiePhos (10) (65% yield on 1-g scale; 59% yield on <100-mg scale (8)). Removal of the silyl groups with buffered tetrabutylammonium fluoride delivers virginiamycin M2 (2) in 90% yield. The yields of these three final steps improved with the larger scales used in this study (all reactions conducted on >1 mmol scale). The modified synthesis of 2 proceeds with an overall yield of 40% through the left half sequence and 28% yield through the right half sequence, and is seven linear steps in each case.
[0634] We first sought to systematically modify structural features of group A
streptogramins by exchanging building blocks. To inform structure–activity relationships, we varied positions on the scaffold that had not previously been explored with semisynthetic approaches, such as the C3 and C4 positions. We prioritized building blocks that were readily available, would be compatible with the chemistry for assembly, and would avoid steric clashes in the binding site. As shown in FIG.2B, we were readily able to prepare 18 streptogramins by building block variation, including the natural products virginiamycin M2 (VM2, parent scaffold), virginiamycin M1 (VM1), and madumycin I (33). The overall yields for each analogue from the starting building blocks are displayed in blue for the left half sequence (top) and right half sequence (bottom). The template synthesis of 2 (FIG.2A) was used directly or with trivial modifications (e.g., addition of a deprotection step for a Boc or PMB group) in most cases to deliver analogues in good yield (10-40% overall). For certain analogues, overall efficiency was impacted by functional group incompatibilities with the chemistry for assembly. For example, the Stille reaction en route to analogue 21, which contains a monosubstituted alkene, proceeded in low yield (20%). In rare cases, a
substantially modified route was required to complete the synthesis, exemplified by the oxadiazole-containing analogue 28, which was assembled with a 6-step route to the right half to accommodate the instability of the oxadiazole in strongly basic conditions (see
Experimental Procedures in Example 3). FIG.2B demonstrates that our platform enables access to unprecedented diversity in streptogramin functionality.
[0635] While incorporation of building blocks represents an effective approach to access novel structural modifications, it is burdened by the requisite multistep synthesis for each new analogue. In order to greatly expand library diversity, we incorporated building blocks with functional groups that serve as handles for late-stage diversification at positions that are not sterically encumbered in the binding site. By means of example, replacement of isobutyraldehyde (7) with para-methoxybenzyl-protected (R)- or (S)-3-hydroxy-2- methylpropanal in the left half sequence enabled access to C3-isopropyl-modified analogues 38 and 39 (FIG.2C, >1 g of each prepared). Each of these alcohol-appended streptogramins was allowed to react with 17 commercially available arylisocyanates in the presence of catalytic DMAP, followed by subsequent desilylation with buffered fluoride. Thus, from two building block substitutions we were able to access 34 novel streptogramin analogues with arylcarbamate side chains at the C3 position (40a-q and 41a-q). The alcohols in 38 and 39 also served as effective precursors for the installation of secondary amines by
oxidation/reductive amination (42-44, FIG.2D) and for incorporation of fluorine by treatment with diethylaminosulfur trifluoride (see Experimental Procedures in Example 3). Additionally, we were able to install a fluorine at C16 by a 4-step sequence (see Experimental Procedures in Example 3), providing the clinical candidate flopristin (4) and several fluorinated analogues (vide infra).
[0636] Most modifications are deleterious, but targeted modifications towards SB site and P site show promise against VatA resistant strains. Our platform has provided 62 streptogramin analogues as well as four natural products and the clinical candidate flopristin (4). We evaluated the activity of each analogue against a strain of S. aureus expressing the VatA resistance protein (3), using wild-type S. aureus (ATCC 29213) as a comparator. A diverse sampling of analogues and their accompanying activities are depicted in FIG.3A. Several structural modifications proved deleterious to activity in both strains. For example, installation of a methyl group at C9 (23) or a primary or tertiary amine (32 and 42, respectively) resulted in complete loss of activity in wild type S. aureus (virginiamycin M2 activity: 16 µg/mL in WT, >64 in VatA). Removal of the C12 methyl group (24) also resulted in loss of activity, which may provide justification of the four additional biosynthetic steps required for its installation by means of a SAM methyltransferase (25). Some structural modifications resulted in no statistically significant change in activity, such as the replacement of the oxazole heterocycle with a thiazole (45). Modifications to the C3 and C4 side chains, however, granted increased activity against WT and VatA-expressing S. aureus. The isoquinoloyl carbamate-containing analogue 40q had a 4-fold decrease in MIC against WT S. aureus (16 ® 4 µg/mL) and a >4-fold decrease in MIC against the VatA strain (>64 ® 16 µg/mL). The C3 allyl-containing analogue 21 displayed identical improvements in activity. Further decreases in MIC values were achieved by installing a fluorine at C16, which had previously been shown to increase activity of the semisynthetic streptogramin flopristin (4). Thiazole-containing fluorinated analogue 45 displayed identical activity to flopristin (0.5 µg/mL in WT, 8 µg/mL in VatA). Notably, C3-modified fluorinated analogue 46 showed a 2-fold improvement of activity in the WT strain (4 ® 2 µg/mL) and a 16-fold improvement in the VatA strain (16 ® 1 µg/mL). It is interesting to note that the activity of this analogue in the streptogramin-resistant strain is actually better than its activity in the WT strain. Finally, C4-modified fluorinated analogue 47 exhibited a 32-fold decrease in MIC against both the WT strain (4 ® 0.125 µg/mL) and the VatA strain (16 ® 0.5 µg/mL). Taken together, these results support the hypothesis that modifications to C3 and C4 of the group A streptogramin scaffold can overcome resistance caused by Vat proteins.
[0637] Modified compounds maintain relatively broad spectrum activity and start to overcome other resistance mechanisms. To further explore the functional effects of streptogramin modifications, we tested each of our analogues against a panel of 20 bacterial pathogens (see Experimental Procedures in Example 3) and measured cell-free inhibitory activities for selected analogues using an in vitro translation (IVT) assay at 10 µM. FIG.3B depicts MIC data for 12 fully synthetic streptogramins against 10 strains of bacteria, including three strains with well-characterized mechanisms of resistance to the class (VatA and Cfr in S. aureus, ABC-F in E. faecalis). Despite significantly improved activity in WT and VatA S. aureus, non-fluorinated analogues 26, 40q, and 21 displayed approximately equal activity to virginiamycin M2 (VM2) in E. faecium and S. pneumoniae. Analogues 23, 24, 32, and 42 had little to no cellular activity in all strains, but interestingly, 42 inhibited translation as effectively VM2. The poor cellular activity likely results from decreased entry or increased efflux, highlighting the challenge of designing antibiotics with both high on- target activity and high cellular accumulation (26). C16-fluorinated analogues 45, 46, and 47 displayed increased potency compared to their non-fluorinated counterparts against most strains, which was accompanied by greater inhibition of translation in vitro. Notably, the C4- allyl, C16-fluoro analogue 47 was more potent than flopristin (4) in many strains and showed moderate activity (32 µg/mL) against E. faecalis, which intrinsically expresses ABC-F proteins (4,17) that have recently been shown to dislodge antibiotics from the catalytic center of the ribosome. Furthermore, although Gram-negative pathogens are usually highly resistant to streptogramins, 47 had moderate against the E. coli (16 µg/mL).
[0638] We were interested in the ability of our streptogramin analogues to synergize with group B streptogramins, which has been shown to greatly improve activity against many Gram-positive pathogens and, in some cases, grant bactericidal activity. It is conceivable that modifications that improve the activity of the group A component would be deleterious for synergy with the B component. Conversely, it is possible that modifications that do not increase the activity of a single component could greatly bolster synergy. We measured the activity of virginiamycin S1 (VS1) against the panel of pathogens in the presence and absence of its natural partner, VM1. Unsurprisingly, the combination of VM1 and VS1 (7:3 weight by weight, the ratio found in nature) was significantly more potent than 8 alone against strains that do not harbor resistance mechanisms to either component. We were delighted to find that the combination of C3-modified 46 or C4 modified 47 with VS1 resulted in improved activity in many strains, and in many cases growth was completely inhibited even at the lowest concentration tested (0.06 µg/mL). In E. faecalis, an organism that is inherently resistant to group A streptogramins, significant reductions in MIC were observed for the 46/VS1 combination (>64, 2 µg/mL ® 0.5 µg/mL) and the 47/VS1 combination (32, 8 µg/mL ® 0.25 µg/mL). These results showcase the utility of synergistic streptogramin combinations and demonstrate that modifications to the group A streptogramin scaffold can facilitate improved activity of the combination. [0639] C3 and C4 modifications lead to decreased acetylation rate by VatA. We were interested in whether the greatly improved activity in VatA-expressing S. aureus of some of our analogues was due to a decreased acetylation rate by the VatA protein or to improved protein synthesis inhibition. We measured the rate of C14 acetylation using purified VatA (FIG.3C) for VM2, flopristin (4), and three analogues (40q, 46, 47). We found that the trend in acetylation rate tracked well with the activity in the VatA expressings train of S. aureus: analogs with lower MIC values showed decreased consumption of Ac-CoA in vitro, indicating slower deactivation by acetylation. It is likely that both decreased acetylation rate and increased ribosomal inhibition contribute to the dramatically improved activity in VatA expressing S. aureus.
[0640] Binding structures of modified compounds. In order to gain insight into the structural basis for antimicrobial activity, we characterized the binding of several of our analogues to the E. coli ribosome using cryoEM. The PTC is highly conserved across pathogenic species of bacteria, and the E. coli ribosome has been shown to be a good model for group A streptogramin binding in both Gram-negative organisms and Gram-positive organisms such as S. aureus (5). Compared to VM2, analogues 46 and 47 have extensions off of C3 and C4 on the macrocycle, respectively. The 2.5-Å structure of 46 bound to the PTC revealed that its macrocyclic core occupies the same position as VM2, and the arylcarbamate extension reaches into peptidyl tRNA binding site (P-site, FIG.4B). The The isoquinoline group overlaps with the terminal adenine in the conserved CCA tail of P-site bound tRNA (FIG.4F, P-tRNA modeled from PDB #1KC8). To the best of our knowledge, no other ribosomal inhibitors occupy this binding pocket, although the non-selective inhibitor blasticidin has been shown to mimic the cytosines in the CCA tail (21). Our 2.6-Å structure of analogue 47 bound to the ribosome clearly reveals the position of the C4 allyl extension, which points towards the streptogramin B binding site in the NPET. A 2.7-Å structure of 46 and the group B streptogramin VS1 bound simultaneously to the ribosome (FIG.4D) shows the hallmark sandwiching of A2062 by the group A and group B components.
[0641] As depicted in FIG.4E, the bacterial PTC is an opulent binding site for antibiotics, including oxazolidinones (e.g., linezolid), lincomycins (e.g., clindamycin), phenicols (e.g., chloramphenicol), pleuromutilins (e.g., lefamulin), and many others (e.g., lankacidin). The adjacent binding site in the exit tunnel is where macrolides (e.g., erythromycin), group B streptogramins (e.g., VS1), and lankamycin. It is striking that the arylcarbamate side chain in 46 and the allyl side chain in 47 reach into a sites that are not occupied by any of the other ligands. Thus, these modifications can serve as templates for the development of other PTC- binding antibiotics. Additionally, we believe that further optimization will result in greater improvements in binding affinity and potentially overcome resistance caused by binding site modifications, such as methylation of A2503 by Cfr methyltransferases. An analogy can be drawn to ketolides, such as telithromycin and solithromycin, which possess biaryl side chains that enhance activity against ribosomes modified by erythromycin methyltransferases at residue A2058 in the exit tunnel (erm resistance).
[0642] By marrying convergent chemical synthesis, microbiological analysis, and high- resolution cryo-electron microscopy, we have developed a pipeline for the synthesis and optimization of group A streptogramin antibiotics. Our approach enabled the preparation of >60 novel analogues by means of building block variation and late-stage diversification, providing valuable structure–activity relationships for the class. Modifications at two previously unexplored positions on the scaffold resulted in the first members of the streptogramin class to overcome resistance caused by virginiamycin acetyltransferase enzymes. The molecular mechanism by which these analogues interact with the ribosome can serve as a template for modifications on other antibiotics that bind to the peptidyltransferase centre. By design, our dynamic approach is adaptable to combat existing and emerging resistance mechanisms, and we believe it will greatly extend the clinical longevity of the streptogramin class.
Example 2: Additional data
[0643] Several modified group A streptogramins exhibited good to excellent activity against several Gram-positive pathogens and, e.g., the Gram-negative pathogen H. influenzae. Compounds 46 and 47 displayed excellent activity against Gram-postive pathogens against which they were tested, and compound 47 also displayed activity against E. faecalis (32 µg/mL) and E. coli, two species that are inherently resistant to group A streptogramins.
[0644] The combination of 46 or 47 with the group B streptogramin virginiamycin S1 (VS1) displayed greatly improved activity compared to either component against many Gram-positive pathogens. These two combinations (46+VS1 and 47+VS1) had excellent activity (<4 µg/mL) against every Gram-positive pathogen tested. In many cases they were active even at the lowest concentration tested (0.06 µg/mL).
[0645] Both Synercid and NXL-103 have been shown to be effective against infections caused by multidrug-resistant Gram-positive bacteria. We can make a direct comparison to the group A streptogramin component of NXL-103 (flopristin). Compound 47 is more active than flopristin in every strain examined in this study (in some cases up to 16-fold more active). It is likely that this increase in cellular efficacy will translate to increased potency as a human therapeutic, as was shown for flopristin vs dalfopristin, two well-studied group A streptogramins that have been tested in humans.
[0646] Table 1. Gram-negative activity.
Figure imgf000230_0001
Figure imgf000231_0001
Figure imgf000232_0001
1 American Type Culture Collection; 2 Micromyx Isolate Number; a Pinpoint growth at or beyond the MIC; VSE: Vancomycin-susceptible Enterococcus; VRE: vancomycin-resistant Enterococcus.
[0647] Table 2. Additional Gram-negative activity.
Figure imgf000232_0002
Figure imgf000233_0001
Figure imgf000234_0001
beyond the MIC; VSE: Vancomycin-susceptible Enterococcus; VRE: vancomycin-resistant Enterococcus.
[0648] Table 3. Gram-positive activity.
Figure imgf000234_0002
Figure imgf000235_0001
Figure imgf000236_0001
1 American Type Culture Collection; 2 Micromyx Isolate Number; a Pinpoint growth at or beyond the MIC; VSE: Vancomycin-susceptible Enterococcus; VRE: vancomycin-resistant Enterococcus.
[0649] Table 4. Additional Gram-positive activity.
Figure imgf000236_0002
Figure imgf000237_0001
Figure imgf000238_0001
Figure imgf000239_0001
1 American Type Culture Collection; 2 Micromyx Isolate Number; a Pinpoint growth at or beyond the MIC; VSE: Vancomycin-susceptible Enterococcus; VRE: vancomycin-resistant Enterococcus.
[0650] Table 5. Solubility data.
Figure imgf000239_0002
Figure imgf000240_0001
Figure imgf000241_0001
1 TrP = lowest concentration at which a trace of drug precipitation was visible; 2 DCP = lowest concentration at which distinct compound precipitation was visible.
Example 3: Experimental procedures and characterization for compounds
[0651] General Methods. All reactions were performed in flame- or oven-dried glassware fitted with rubber septa under a positive pressure of nitrogen or argon, unless otherwise noted. All reaction mixtures were stirred throughout the course of each procedure using Teflon-coated magnetic stir bars. Air- and moisture-sensitive liquids were transferred via syringe or stainless steel cannula. Solutions were concentrated by rotary evaporation below 35 °C. 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, SILICYCLE INC) impregnated with a fluorescent indicator (254 nm). TLC plates were visualized by exposure to ultraviolet light (UV), and then were stained by submersion in a basic aqueous solution of potassium permanganate or with an acidic ethanolic solution of anisaldehyde, followed by brief heating.
[0652] DCM, DMF, THF, ethyl ether, and acetonitrile to be used in anhydrous reaction mixtures were dried by passage through activated alumina columns immediately prior to use. Hexanes used were ³85% n-hexane. Other commercial solvents and reagents were used as received, unless otherwise noted.
[0653] Proton nuclear magnetic resonance (1H NMR) spectra and carbon nuclear magnetic resonance (13C NMR) spectra were recorded on 300 or 400 MHz Bruker Avance III HD 2- channel instrument NMR spectrometers at 23 °C or 50 °C. Proton chemical shifts are expressed in parts per million (ppm, d scale) and are referenced to residual protium in the NMR solvent (CHCI3: d 7.26, CHDCI2: d 5.32 and CHD2OD: d 3.31 ). Carbon chemical shifts are expressed in parts per million (ppm, d scale) and are referenced to the carbon resonance of the NMR solvent (CDCI3: d 77.0, CD2CI2: d 53.84 and CD3OD: d 49.00). Data are represented as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, dt = doublet of triplets, sxt = sextet, m = multiplet, br = broad, app = apparent), integration, and coupling constant (J) in hertz (Hz). Optical rotations were measured using a JASCO P-2000 polarimeter. High-resolution mass spectra were obtained at the QB3/Chemistry Mass Spectrometry Facility at University of California, Berkeley using a Thermo LTQ-FT mass spectrometer. Melting points were recorded on a Electrothermal IA6304 Melting Point Apparatus.
[0654] Scheme I Convergent route to VM2 from seven simple building block (FIG.2A). [0655] Mukaiyama Aldol product 9
Figure imgf000242_0001
[0656] An oven-dried 250-mL round-bottom flask was charged with phenylboronic acid (1.22 g, 10.0 mmol, 0.5 equiv) and (S)-diphenyl(pyrrolidin-2-yl)methanol (2.53 g, 10.0 mmol, 0.5 equiv). The vessel was equipped with a reflux condenser, evacuated and flushed with nitrogen (the process of nitrogen exchange was repeated a total of 3 times). Toluene (50 mL) was added, and the resulting clear solution was brought to reflux by means of a 145 °C oil bath. After 12 h, the reaction mixture was allowed to cool to 23 ºC and was concentrated. The resulting white solid was dried at £1 Torr for 1 h. The vessel was flushed with nitrogen and DCM (80 mL) was added. The resulting colorless solution was cooled to -78 °C and TfOH (0.80 mL, 8.99 mmol, 0.45 equiv) was added dropwise over 5 min by means of glass syringe (CAUTION: TfOH rapidly corrodes most plastic syringes!). Some of the TfOH freezes upon contact with the solution. After 1 h the solids had dissolved, and a mixture of isobutyraldehyde (6, 1.82 mL, 20.0 mmol, 1 equiv), silyl dienolether 7 (5.70 g, 25.0 mmol, 1.25 equiv), and 2-propanol (1.68 mL, 22.0 mmol, 1.1 equiv) in DCM (20 mL) was added dropwise over 2 h by syringe pump. The mixture was stirred at -78 °C for another 1.5 h and saturated aqueous NaHCO3 solution (50 mL) was added in one portion. The vessel was removed from the cooling bath and the system was allowed to warm to 23 °C while it was rapidly stirred. The biphasic mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with DCM (2 × 30 mL). The organic layers were combined and the resulting solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The crude residue was purified by flash chromatography (silica gel, eluent: EtOAc:hexanes = 1:10 to 1:6) to afford Mukaiyama Aldol product 9 (3.48 g, 94%) as a colorless oil.
[0657] TLC (EtOAc:hexanes = 1:6): Rf = 0.25 (UV, KMnO4). [0658] [a]23 D = + 23.5 (c = 1.0, CHCl3). [0659] 1H NMR (400 MHz, CDCI3) d 6.92 (dd, J = 15.7, 8.1 Hz, 1H), 5.86 (dd, J = 15.7, 1.2 Hz, 1H), 3.72 (s, 3H), 3.26 (t, J = 5.8 Hz, 1H), 2.59– 2.39 (m, 1H), 1.78-1.64 (m, 1H), 1.59 (br s, 1H), 1.09 (d, J = 6.7 Hz, 3H), 0.92 (d, J = 6.8 Hz, 3H), 0.90 (d, J = 6.8 Hz, 3H.
[0660] 13C NMR (100 MHz, CDCI3) d 167.1, 152.2, 120.4, 80.0, 51.4, 39.9, 30.9, 19.6, 16.5, 13.9.
[0661] HRMS-EI m/z calcd for C10H19O3 + [M + H]+ 187.1329, found 187.1331.
[0662] Determination of enantiomeric excess: To a solution of 9 (20 mg, 0.11 mmol, 1 equiv) in DCM (2 mL) at 23 °C was added successively Et3N (0.12 mL, 0.86 mmol, 8.0 equiv), DMAP (18 mg, 0.15 mmol, 1.4 equiv) and (S) or (R)-Mosher acid chloride (80 mL, 0.43 mmol, 4.0 equiv). After 2 h, the mixture was diluted with EtOAc (15 mL). The mixture was transferred to a separatory funnel and washed successively with 1 M aqueous KHSO4 solution (3 x 5 mL), 1 M aqueous NaOH solution (5 mL) and saturated aqueous NaHCO3 solution (3 x 5 mL). The organic phase was dried over MgSO4, the dried solution was filtered, and the filtrate concentrated. The crude residue was analyzed by 1H-NMR.
[0663] For (S)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl chloride: The enantiomeric excess was calculated from integration of the double dublet at 5.82 ppm (major), 5.84 ppm (minor). The ee was 87%.
[0664] For (R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl chloride: The enantiomeric excess was calculated from integration of the double dublet at 5.84 ppm (major), 5.82 ppm (minor). The ee was 87%.
[0665] Reference: Simsek, S.; Kalesse, M. Tetrahedron Lett.2009, 50, 3485-3488
[0666] Amide SI-1
Figure imgf000244_0001
[0667] An oven-dried 500-mL round-bottom flask was charged with propargylamine (10, 4.40 mL, 68.7 mmol, 4.0 equiv) and dry DCM (115 mL). The resulting colorless solution was cooled to 0 °C by means of ice-water bath. A solution of AlMe3 in heptane (1 M, 68.7 mL, 68.7 mmol, 4.0 equiv) was added dropwise over 30 min (CAUTION: Gas evolution!). The mixture was allowed to warm to 23 °C. After stirring for 30 min, a solution of 9 (3.20 g, 17.2 mmol, 1 equiv) in DCM (20 mL) was added over 10 min (CAUTION: Gas evolution!). The vessel was equipped with a reflux condenser and the solution was brought to reflux by means of a 50 °C oil bath. After 3 h, the mixture was cooled to 0 °C by means of ice-water bath and MeOH (10 mL) was added (CAUTION: Gas evolution!). Once gas evolution ceased, saturated aqueous potassium sodium tartrate solution (100 mL) was added. After stirring for 1 h, the biphasic mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with DCM (2 × 30 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL) and the washed solution was dried
(Na2SO4). The dried solution was filtered and the filtrate was concentrated. The crude residue was purified by flash chromatography (silica gel, eluent: EtOAc:hexanes = 1:1) to afford amide SI-1 (3.22 g, 90%) as a white solid.
[0668] m. p.88– 90 °C (Hexanes)
[0669] TLC (EtOAc:hexanes = 1:1): Rf = 0.15 (UV).
[0670] [a]24D = + 29.7 (c = 1.0, DCM).
[0671] 1H NMR (400 MHz, CDCI3) d 6.84 (dd, J = 15.4, 7.9 Hz, 1H), 5.82 (dd, J = 15.4, 1.2 Hz, 1H), 5.78 (s, 1H), 4.12 (dd, J = 5.3, 2.6 Hz, 2H), 3.30 - 3.22 (m, 1H), 2.56 - 2.43 (m, 1H), 2.24 (t, J = 2.6 Hz, 1H), 1.80 - 1.65 (m, 1H), 1.59 (d, J = 5.1 Hz, 1H), 1.08 (d, J = 6.7 Hz, 3H), 0.92 (d, J = 6.7 Hz, 6H).
[0672] 13C NMR (100 MHz, CDCl3) d 165.4, 148.4, 122.6, 79.4, 79.2, 71.7, 39.6, 30.8, 29.2, 19.7, 16.7, 13.9. [0673] HRMS-ESI m/z calcd for C12H20NO2 + [M + H]+ 210.1489, found 210.1487.
[0674] Vinyl stannane 11
Figure imgf000245_0001
[0675] An oven-dried 500-mL round-bottom flask charged with CuCN (2.65 g, 29.6 mmol, 2.0 equiv) was evacuated and flushed with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. Dry THF (200 mL) was added, resulting a white suspension and the vessel was cooled to -78 °C in a dry ice-acetone bath. To this suspension was added a solution of n-BuLi in hexanes (2.5 M, 24.9 mL, 62.2 mmol, 4.2 equiv) dropwise over 10 min and the resulting light yellow solution was stirred for 30 min. Bu3SnH (16.8 mL, 62.2 mmol, 4.2 equiv) was added dropwise over 5 min. After stirring for 30 min, a solution of SI-1 (3.10 g, 14.8 mmol, 1 equiv) in THF (15 mL) was added dropwise over 15 min. After 1 h, saturated aqueous NH4Cl solution (100 mL) was added in one portion. The vessel was removed from the cooling bath and the system was allowed to warm to 23 °C while the mixture was rapidly stirred. The biphasic mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with water (2 × 100 mL) and brine (100 mL). The washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The crude residue was purified by flash chromatography (silica gel, eluent: EtOAc:hexanes = 0:1 to 1:3) to afford vinyl stannane 11 (7.4 g, 100%, ³20:1 E:Z) as a colorless oil.
[0676] TLC (EtOAc:hexanes = 1:3): Rf = 0.25 (UV).
[0677] [a]24D = + 10.6 (c = 1.0, CHCI3).
[0678] Note regarding NMR spectra: Satellite peaks caused by geminal coupling between the vinyl proton and 117Sn/119Sn isotopes appear in the spectra. Only the major peaks and 1H- 1H coupling constants are reported below. On page S36– S37, we provide inset spectra highlighting the peaks in question in two solvents as well as a reference that supports the minor peaks arising due to geminal 1H/Sn coupling. Additionally, we provide variable temperature 1H-NMR data that supports the hypothesis that these are not amide rotamers (the ratio does not change even at 140 ºC in DMSO-d6). These peaks are present only for the intermediates in the synthesis that contain vinyl tin functionality.
[0679] 1H NMR (400 MHz, CDCI3) d 6.82 (dd, J = 15.4, 7.9 Hz, 1H), 6.12 (dt, J = 19.0, 1.5 Hz, 1H), 5.97 (dt, J = 19.0, 5.1 Hz, 1H), 5.83 (dd, J = 15.4, 1.2 Hz, 1H), 5.58 (br s, 1H), 4.04– 3.94 (m, 2H), 3.26 (q, J = 5.6 Hz, 1H), 2.56– 2.42 (m, 1H), 1.80– 1.67 (m, 1H), 1.53 – 1.40 (m, 6H), 1.29 (m, 6H), 1.09 (d, J = 6.6 Hz, 3H), 0.94– 0.83 (m, 21H).
[0680] 13C NMR (100 MHz, CDCl3) d 165.5, 147.4, 143.4, 130.4, 123.3, 79.2, 44.9, 39.6, 30.8, 29.0, 27.2, 19.7, 16.7, 14.0, 13.7, 9.4.
[0681] HRMS-ESI m/z calcd for C24H47NNaO2Sn+ [M + Na]+ 524.2521, found 524.2515.
[0682] Reference: a. Entwistle, D. A.; Jordan, S. I.; Montgomery, J.; Pattenden, G.
Synthesis 1998, 603-612; b. Cochran,J. C.; Bayef,S.C.;Bolbo,J. T.;Brown,M. S.; Colen, L. B.; Gaspirini, F. J.; Goldsmith, D. W.; Jamin, M. D.; Nealy, K. A.; Res- nick, C.
T.;Schwartz,G.J.; Short, W. M.; Skarda, K. R.; Spring, J. P.; Strause, W. L. Organometallics 1982, 1, 586-590.
[0683] Left half 13
Figure imgf000246_0001
[0684] An oven-dried 100-mL round-bottom flask was charged with 12 (2.00 g, 5.94 mmol, 1.35 equiv), DMAP (0.11 g, 0.88 mmol, 0.2 equiv) and 11 (2.20 g, 4.40 mmol, 1 equiv). Dry DCM (44 mL) was added, resulting in a colorless solution. DCC (1.36 g, 6.60 mmol, 1.5 equiv) was added in one portion at 23 °C, resulting in a white suspension. After 5 h, the alcohol 11 was entirely consumed by TLC analysis (eluent: EtOAc:hexanes = 1:2). Diethylamine (22 mL) was added. After stirring for additional 3 h, the mixture was filtered through a pad of celite and the filter cake was washed with DCM (2 × 20 mL). The filtrate was concentrated and the crude residue was purified by flash chromatography (silica gel, eluent: NH4OH:MeOH:DCM = 0.2:1:100 to 0.2:1:50) to afford left half 13 (2.32 g, 88%) as light yellow oil.
[0685] TLC (MeOH:DCM = 1:20): Rf = 0.20 (UV).
[0686] [a]24 D = + 13.9 (c = 0.1, CHCl3).
[0687] 1H NMR (400 MHz, CDCl3) d 6.70 (dd, J = 15.4, 7.8 Hz, 1H), 6.11 (dt, J = 19.0, 1.5 Hz, 1H), 5.96 (dt, J = 19.0, 5.1 Hz, 1H), 5.82 (dd, J = 15.4, 1.2 Hz, 1H), 5.59 (t, J = 5.9 Hz, 1H), 4.81 (dd, J = 6.9, 5.4 Hz, 1H), 4.03– 3.89 (m, 2H), 3.76 (dd, J = 8.5, 5.6 Hz, 1H), 3.07 (ddd, J = 10.2, 7.4, 6.1 Hz, 1H), 2.89 (ddd, J = 10.2, 7.1, 6.2 Hz, 1H), 2.65 (dtd, J = 8.0, 6.8, 1.2 Hz, 1H), 2.13 (dtd, J = 12.3, 8.1, 6.6 Hz, 1H), 2.07 (s, 1H), 1.94– 1.79 (m, 2H), 1.80 – 1.65 (m, 2H), 1.56– 1.39 (m, 6H), 1.35– 1.21 (m, 6H), 1.04 (d, J = 6.8 Hz, 3H), 0.95– 0.80 (m, 21H).
[0688] 13C NMR (100 MHz, CDCl3) d 175.3, 165.2, 145.2, 143.4, 130.4, 123.8, 80.3, 59.9, 46.9, 44.9, 38.2, 30.5, 29.8, 29.0, 27.2, 25.4, 19.6, 16.8, 14.7, 13.7, 9.4.
[0689] HRMS-ESI m/z calcd for C29H55N2O3Sn+ [M + H]+ 599.3229, found 599.3219.
[0690] b-hydroxyl amide 16
Figure imgf000247_0001
[0691] An oven-dried 250-mL round-bottom flask charged with 15 (7.96 g, 39.1 mmol, 1.1 equiv) was evacuated and flushed with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. Dry DCM (80 mL) was added, resulting in a yellow solution and the vessel was cooled to -78 °C in a dry ice-acetone bath. A solution of TiCl4 in DCM (1 M, 42.7 mL, 42.7 mmol, 1.2 equiv) dropwise, resulting in a deep yellow solution. After 5 min, iPr2EtN (7.46 mL, 42.7 mmol, 1.2 equiv) was added by syringe pump over 30 min, and the resulting deep red solution was stirred for 2 h at -78 °C. A solution of aldehyde 14 (5.30 g, 35.6 mmol, 1 equiv) in DCM (10 mL) was added via syringe pump over 30 min. After stirring for 30 min, water (100 mL) was added. The vessel was removed from the cooling bath and the system was allowed to warm to 23 °C while the mixture was rapidly stirred. The biphasic mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with DCM (2 × 30 mL). The combined organic layers were washed with water (2 × 100 mL) and brine (100 mL) and the washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The crude residue was purified by flash chromatography (silica gel, eluent: EtOAc: hexanes = 1:10 to 1:2.5) to afford b-hydroxyl amide 16 (8.3 g, 64%) as a yellow oil.
[0692] TLC (EtOAc:hexanes = 1:5): Rf = 0.25 (UV and KMnO4).
[0693] [a]24 D = - 320 (c = 1.0, CHCl3).
[0694] 1H NMR (400 MHz, CDCl3) d 5.95 (dq, J = 8.9, 1.3 Hz, 1H), 5.14 (ddd, J = 7.7, 6.3, 1.1 Hz, 1H), 4.80 (tdd, J = 8.4, 4.4, 3.3 Hz, 1H), 3.59 (dd, J = 17.6, 3.3 Hz, 1H), 3.53 (dd, J = 11.5, 8.0 Hz, 1H), 3.32 (dd, J = 17.7, 8.4 Hz, 1H), 3.03 (dd, J = 11.5, 1.1 Hz, 1H), 2.98 (d, J = 4.6 Hz, 1H), 2.45 - 2.25 (m, 1H), 2.32 (d, J = 1.4 Hz, 3H), 1.05 (d, J = 6.8 Hz, 3H), 0.97 (d, J = 6.9 Hz, 3H).
[0695] 13C NMR (100 MHz, CDCl3) d 202.9, 171.8, 132.4, 124.2, 71.3, 65.7, 44.8, 30.7, 30.6, 24.1, 19.0, 17.7.
[0696] HRMS-ESI m/z calcd for C12H17BrNO2S2+ [M - H]– 349.9890, found 349.9886.
[0697] Reference: Romo, D.; Choi, N. S.; Li, S.; Buchler, I.; Shi, Z.; Liu, J. O. J. Am. Chem. Soc.2004, 34, 10582-10588.
[0698] TBS ether SI-2
Figure imgf000248_0001
[0699] An oven-dried 250-mL round-bottom flask charged with b-hydroxyl amide 16 (4.71 g, 13.4 mmol, 1 equiv) was evacuated and flushed with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. DCM (134 mL) was added followed by 2,6-lutidine (3.1 mL, 26.8 mmol, 2.0 equiv), resulting a yellow solution. The vessel was cooled to 0 °C by means of ice-water bath. TBSOTf (3.69 mL, 16.0 mmol, 1.2 equiv) was added dropwise over 10 min. After stirring for 30 min, the mixture was transferred to a separatory funnel and washed with water (2 × 100 mL) and brine (100 mL). The washed solution was dried (Na2SO4). The dried solution was filtrated and the filtrate was
concentrated. The resulting crude residue was purified by flash chromatography (silica gel, eluent: EtOAc:hexanes = 1:20) to afford TBS ether SI-2 (5.76 g, 92%) as a light yellow oil.
[0700] TLC (EtOAc:hexanes = 1:50): Rf = 0.20 (UV).
[0701] [a]24
D = - 479 (c = 1.0, CHCl3).
[0702] 1H NMR (400 MHz, CDCl3) d5.87 (dq, J = 8.9, 1.3 Hz, 1H), 5.03 (ddd, J = 7.6, 6.2, 1.1 Hz, 1H), 4.96– 4.86 (m, 1H), 3.63 (dd, J = 16.5, 8.3 Hz, 1H), 3.47 (dd, J = 11.5, 7.9 Hz, 1H), 3.18 (dd, J = 16.5, 4.3 Hz, 1H), 3.03 (dd, J = 11.4, 1.1 Hz, 1H), 2.36 (dq, J = 13.5, 6.8 Hz, 1H), 2.31 (d, J = 1.3 Hz, 3H), 1.06 (d, J = 6.8 Hz, 3H), 0.97 (d, J = 7.0 Hz, 3H), 0.84 (s, 9H), 0.05 (s, 3H), 0.05 (s, 3H).
[0703] 13C NMR (100 MHz, CDCl3) d 202.8, 170.7, 134.5, 121.7, 71.7, 67.2, 45.6, 30.9, 30.8, 25.7, 24.1, 19.1, 18.0, 17.8, -4.5, -5.0.
[0704] HRMS-EI m/z calcd for C18H32BrNO2S2Si+ [M]+ 465.0827, found 465.0819.
[0705] Weinreb amide 17
Figure imgf000249_0001
[0706] An oven-dried 500-mL round-bottom flask charged with HN(OMe)Me•HCl (2.26 g, 23.1 mmol, 2.0 equiv) was evacuated and flushed with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. DCM (115 mL) was added, resulting in a white suspension and the vessel and its contents were cooled to 0 °C in a dry ice-water bath. TEA (4.01 mL, 28.9 mmol, 2.5 equiv) was added. After 30 min, a solution of SI-2 (5.40 g, 11.6 mmol, 1 equiv) and DMAP (0.141 g, 1.16 mmol, 0.1 equiv) in DCM (15 mL) was added. Then the reaction mixture was warmed to 23 °C and stirred overnight. The reaction mixture was quenched with water (150 mL). The resulting biphasic mixture was transferred to a separatory funnel and the layers were separated. The organic layers were washed with water (100 mL) and brine (100 mL) and the washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The resulting crude residue was purified by flash chromatography (silica gel, eluent: EtOAc:hexanes = 1:15) to afford Weinreb amide 17 (4.06 g, 96%) as a colorless oil.
[0707] TLC (EtOAc:hexanes = 1:5): Rf = 0.20 (UV).
[0708] 1H NMR (400 MHz, CDCI3) d 5.86 (dq, J = 9.0, 1.3 Hz, 1H), 4.84 (ddd, J = 9.0, 7.9, 5.3 Hz, 1H), 3.69 (s, 3H), 3.17 (s, 3H), 2.83 (dd, J = 14.8, 8.0 Hz, 1H), 2.41 (dd, J = 14.7, 5.3 Hz, 1H), 2.30 (d, J = 1.3 Hz, 3H), 0.85 (s, 9H), 0.05 (s, 3H), 0.05 (s, 3H).
[0709] 13C NMR (100 MHz, CDCI3) d 171.0, 135.0, 121.4, 67.5, 61.4, 40.0, 32.0, 25.7, 24.1, 18.0, -4.6, -5.1.
[0710] Right half 19
Figure imgf000250_0001
[0711] An oven-dried 250-mL round-bottom flask charged with acid 18 (1.76 g, 8.19 mmol, 2.0 equiv) was evacuated and flushed with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. THF (82 mL) was added, resulting in a light yellow solution and the vessel and its contents were cooled to -78 °C in a dry ice-acetone bath. A solution of n-BuLi in hexanes (2.5 M, 6.55 mL, 16.4 mmol, 4.0 equiv) was added dropwise over 15 min, resulting in a deep red solution. After 30 min, a solution of Weinreb amide 17 (1.50 g, 4.09 mmol, 1 equiv) in THF (10 mL) was added over 30 min by syringe pump. After an additional 30 min, water (50 mL) was added, followed by 1 M aqueous KHSO4 solution (20 mL). The system was allowed to warm to 23 °C while the mixture was rapidly stirred. The biphasic mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with water (2 × 100 mL) and brine (100 mL) and the washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The resulting crude residue was purified by flash chromatography (silica gel, eluent: MeOH:DCM = 1:70) to afford right half 19 (2.00 g, 94%) as a yellow solid.
[0712] m. p.143– 146 °C (DCM)
[0713] TLC (MeOH:DCM = 1:20): Rf = 0.30 (UV).
[0714] [a]24D = - 24.5 (c = 1.0, CHCI3).
[0715] 1H NMR (400 MHz, CDCI3) d 5.81 (dq, J = 9.0, 1.3 Hz, 1H), 4.79 (ddd, J = 9.1, 8.2, 4.6 Hz, 1H), 4.13 (d, J = 17.1 Hz, 1H), 4.05 (d, J = 17.1 Hz, 1H), 2.86 (dd, J = 15.6, 8.1 Hz, 1H), 2.55 (dd, J = 15.6, 4.6 Hz, 1H), 2.27 (d, J = 1.3 Hz, 3H), 0.84 (s, 9H), 0.37 (s, 9H), 0.04 (s, 6H).
[0716] 13C NMR (100 MHz, CDCl3) d 200.5, 165.4, 165.3, 161.1, 140.7, 134.2, 121.8, 66.9, 49.7, 43.7, 25.7, 24.0, 18.9, 18.0, -2.1, -4.6, -5.1.
[0717] HRMS-ESI m/z calcd for C20H35BrNO5Si2 [M + H]+ 504.1232, found 504.1227.
[0718] Reference: Wood, R. D.; Ganem, B. Tetrahedron Lett.1983, 24, 4391-4392.
[0719] Stille Coupling precursor 20
Figure imgf000251_0001
[0720] An oven-dried 50-mL round-bottom flask was charged with iPr2EtN (0.39 mL, 2.24 mmol, 2.0 equiv), amine 13 (0.67 g, 1.12 mmol, 1 equiv) and acid 19 (0.62 g, 1.23 mmol, 1.1 equiv). DCM (12 mL) was added, resulting in a colorless solution. HATU (0.53 g, 1.40 mmol, 1.25 equiv) was added in one portion at 23 °C. After 5 h, the mixture was diluted with DCM (30 mL). The resulting solution was transferred to a separatory funnel and was washed with water (2 × 25 mL) and brine (25 mL). The washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The resulting crude residue was purified by flash chromatography (silica gel, eluent: EtOAc:hexanes = 1:6 to 1:4) to afford Stille Coupling precursor 20 (1.10 g, 91%) as a light yellow oil. [0721] TLC (EtOAc:hexanes = 1:4): Rf = 0.30 (UV).
[0722] [a]24 D = - 10.7 (c = 1.0, CHCl3).
[0723] 1H NMR (400 MHz, CDCl3, mixtures of rotamers) d 6.76– 6.53 (m, 1H), 6.11 (dd, J = 18.9, 1.6 Hz, 1H), 6.03– 5.90 (m, 1H), 5.89– 5.71 (m, 2H), 5.70– 5.54 (m, 1H), 4.86– 4.55 (m, 3H), 4.14– 3.82 (m, 5H), 3.81– 3.61 (m, 1H), 2.90– 2.75 (m, 1H), 2.68– 2.45 (m, 2H), 2.35– 2.22 (m, 4H), 2.09– 1.75 (m, 4H), 1.52– 1.42 (m, J = 8.3, 6.0 Hz, 6H), 1.35– 1.22 (dq, J = 13.3, 6.6, 6.0 Hz, 6H), 1.08– 0.99 (m, 3H), 0.99– 0.78 (m, 30H), 0.37– 0.26 (m, 9H), 0.11– 0.01 (m, 6H).
[0724] 13C NMR (100 MHz, CDCI3, mixtures of rotamers) d 201.1, 200.7, 172.34165.4, 165.1, 163.2, 162.5, 161.5, 159.1, 145.4, 145.2, 145.1, 143.4, 143.3, 134.2, 130.4, 130.2, 123.9, 123.8, 121.8, 80.8, 80.4, 67.0, 66.9, 60.5, 59.9, 49.6, 48.8, 47.1, 44.91, 44.86, 44.2, 44.0, 38.4, 38.1, 31.6, 29.9, 29.8, 29.7, 29.1, 29.0, 28.9, 27.5, 27.2, 27.0, 25.69, 25.67, 25.6, 25.2, 24.00, 23.99, 21.5, 19.7, 19.5, 18.0, 17.0, 16.8, 14.9, 14.6, 13.7, 11.14, 11.06, 9.4, 7.8, 7.7, -1.77, -1.79, -4.57, -5.13, -5.15.
[0725] HRMS-ESI m/z calcd for C49H87BrN3O7Si2Sn+ [M + H]+ 1084.4282, found 1084.4275.
[0726] Stille Coupling Product SI-3
Figure imgf000252_0001
[0727] An oven-dried 500-mL round-bottom flask was charged with JackiePhos (0.16 g, 0.20 mmol, 0.2 equiv), Stille Coupling precursor 20 (1.10 g, 1.02 mmol, 1 equiv) and Pd2(dba)3 (93 mg, 0.10 mmol, 0.1 equiv). The vessel was evacuated and filled with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. Toluene (200 mL) was added, resulting in a red suspension. A stream of argon was passed through the solution for 30 min. The vessel and its contents were then heated in a 50 ºC oil bath. After 3 h, SI-3 was entirely consumed and the mixture was allowed to cool to 23 ºC. The mixture was concentrated and the resulting crude residue was purified by flash chromatography (silica gel, eluent: EtOAc:hexanes = 1:2.5 to 1:2) to afford Stille Coupling product SI-3 (0.46 g, 64%) as a white solid.
[0728] m. p.105– 110 °C (Hexanes)
[0729] TLC (EtOAc:hexanes = 1:2): Rf = 0.20 (UV).
[0730] [a]24 D = - 57.1 (c = 1.0, CHCl3).
[0731] 1H NMR (400 MHz, CDCI3) d 6.49 (dd, J = 16.3, 4.2 Hz, 1H), 6.19– 6.10 (m, 1H), 6.07 (dd, J = 9.2, 3.2 Hz, 1H), 5.77 (dd, J = 16.4, 2.0 Hz, 1H), 5.57 (ddd, J = 15.5, 9.4, 4.2 Hz, 1H), 5.42 (d, J = 8.9 Hz, 1H), 5.00 (ddd, J = 8.9, 7.0, 5.9 Hz, 1H), 4.85– 4.72 (m, 2H), 4.57– 4.43 (m, 1H), 3.89 (d, J = 17.2 Hz, 1H), 3.78– 3.69 (m, 3H), 3.39 (ddd, J = 14.8, 9.5, 3.3 Hz, 1H), 2.92 (dd, J = 15.9, 7.0 Hz, 1H), 2.79– 2.68 (m, 2H), 2.18– 2.04 (m, 1H), 1.90 (dddd, J = 24.9, 15.9, 11.3, 6.8 Hz, 3H), 1.77– 1.68 (m, 1H), 1.66 (d, J = 1.2 Hz, 3H), 1.08 (d, J = 6.9 Hz, 3H), 0.99 (d, J = 6.5 Hz, 3H), 0.94 (d, J = 6.8 Hz, 3H), 0.85 (s, 9H), 0.30 (s, 9H), 0.05 (s, 3H), 0.02 (s, 3H).
[0732] 13C NMR (100 MHz, CDCI3) d 201.0, 172.1, 166.4, 161.8, 161.3, 159.6, 145.1, 144.8, 136.7, 134.7, 132.4, 124.9, 123.7, 81.1, 65.4, 58.7, 50.6, 48.4, 43.7, 41.3, 36.7, 29.3, 28.2, 25.7, 24.8, 19.9, 18.6, 18.1, 12.67, 9.9, -1.8, -4.5, -5.0.
[0733] HRMS-ESI m/z calcd for C37H60N3O7Si2+ [M + H]+ 714.3964, found 714.3968.
[0734] Virginiamycin M2
Figure imgf000253_0001
[0735] An oven-dried 100-mL round-bottom flask charged with Stille Coupling product SI- 3 (0.46 g, 0.64 mmol, 1 equiv) was evacuated and filled with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. THF (1.6 mL) was added, resulting in a light yellow solution. In a separate flask, imidazole•HCl (0.67 g, 6.44 mmol, 10.0 equiv) was added to a solution of tetrabutylammonium fluoride in THF (1 M, 6.44 mL, 6.44 mmol, 10.0 equiv). The resulting colorless solution was added dropwise to the solution of SI-3. After 12 h, the mixture was concentrated and the residue was dissolved in DCM (50 mL). The resulting solution was transferred to a separatory funnel and was washed with water (3 × 50 mL) and brine (50 mL). The washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The resulting crude residue was purified by flashed chromatography (silica gel, eluent: MeOH:DCM = 1:40) to afford virginiamycin M2 (2, 0.31 g, 90%) as a light yellow solid.
[0736] m. p.120– 125 °C (DCM)
[0737] TLC (MeOH:DCM = 1:20): Rf = 0.30 (UV).
[0738] [a]25 D = - 67.4 (c = 0.3, DCM).
[0739] 1H NMR (400 MHz, CDCl3) d 8.08 (s, 1H), 6.47 (dd, J = 16.4, 5.0 Hz, 1H), 6.39 (dd, J = 9.0, 3.7 Hz, 1H), 6.11 (m, J = 15.6 Hz, 1H), 5.78 (dd, J = 16.4, 1.9 Hz, 1H), 5.69 (ddd, J = 15.6, 9.2, 4.6 Hz, 1H), 5.41 (d, J = 8.8 Hz, 1H), 4.90 (dt, J = 8.9, 5.6 Hz, 1H), 4.73 (dd, J = 10.1, 2.0 Hz, 1H), 4.70 (dd, J = 8.9, 3.2 Hz, 1H), 4.45 (ddd, J = 13.9, 8.9, 4.6 Hz, 1H), 4.00– 3.92 (m, 1H), 3.82 (s, 2H), 3.79– 3.70 (m, 1H), 3.39 (ddd, J = 14.0, 9.2, 3.6 Hz, 1H), 3.05 (dd, J = 17.0, 6.0 Hz, 1H), 2.89 (dd, J = 17.0, 5.2 Hz, 1H), 2.74 (ddt, J = 6.9, 4.9, 2.0 Hz, 1H), 2.60 (br s, 1H), 2.24– 2.08 (m, 1H), 2.01– 1.88 (m, 3H), 1.88– 1.75 (m, 1H), 1.71 (d, J = 1.2 Hz, 3H), 1.03 (d, J = 6.9 Hz, 3H), 0.98 (d, J = 6.5 Hz, 3H), 0.95 (d, J = 6.8 Hz, 3H).
[0740] 13C NMR (100 MHz, CDCl3) d 202.1, 171.6, 166.5, 160.2, 156.9, 144.5, 143.9, 136.92, 136.86, 134.3, 132.7, 125.2, 124.0, 81.4, 65.0, 59.6, 48.9, 48.4, 43.3, 40.9, 36.6, 29.4, 28.3, 25.0, 19.7, 18.7, 12.6, 10.4.
[0741] HRMS-ESI m/z calcd for C28H38N3O7 + [M + H]+ 528.2704, found 528.2703.
[0742] Reference: Austad, B. A.; Calkins, T. L.; Chase, C. E.; Fang, F. G.; Horstmann, T. E.; Hu, Y.; Lewis, B. M.; Niu, X.; Noland, T. A.; Orr, J. D.; Schnaderbeck, M. J.; Zhang, H.; Asakawa, N.; Asai, N.; Chiba, H.; Hasebe, T.; Hoshino, Y.; Ishizuka, H.; Kajima, T.
Kayano, A.; Komatsu, Y.; Kubota, M.; Kuroda, H.; Miyazawa, M. Tagami K.; Watanabe, T. Synlett, 2013, 24, 333-337.
[0743] Scheme II Synthesis of analogue 21
Figure imgf000255_0001
[0744] Mukaiyama Aldol Product SI-5
Figure imgf000256_0001
[0745] An oven-dried 100-mL round-bottom flask was charged with phenylboronic acid (0.41 g, 3.36 mmol, 0.50 equiv) and (S)-diphenyl(pyrrolidin-2-yl)methanol (0.85 g, 3.36 mmol, 0.50 equiv). The vessel was equipped with a reflux condenser, evacuated and flushed with nitrogen (this process was repeated a total of 3 times). Toluene (25 mL) was added, and the resulting solution was brought to reflux by means of a 145 °C oil bath. After 12 h, the reaction mixture was allowed to cool to 23 °C and was concentrated in vacuum. The resulting white solid was dried under high vacuum for 1 h. The vessel was flushed with nitrogen and DCM (26 mL) was added. The resulting colorless solution was cooled to -78 °C and TfOH (0.27 mL, 3.03 mmol, 0.45 equiv) was added dropwise over 5 min by glass syringe
(CAUTION: plastic syringes should be avoided as they are not compatible with TfOH). NOTE: Some of TfOH freezes upon contact with the solution. After 1.5 h the solids had completely dissolved, and a mixture of isobutyraldehyde (6, 0.62 mL, 6.72 mmol, 1 equiv), silyl trienolether SI-4 (2.14 g, 8.40 mmol, 1.25 equiv) and 2-propanol (0.57 mL, 7.39 mmol, 1.1 equiv) in DCM (7 mL) was added dropwise into the solution over 2 h by syringe pump. The mixture was stirred at -78 °C for another 2.5 h and saturated aqueous NaHCO3 solution (17 mL) was added in one portion. The vessel was removed from the cooling bath and the system was allowed to warm to 23 °C. The biphasic mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with DCM (2 x 15 mL). The organic layers were combined and the resulting solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The crude residue was purified by flash chromatography (silica gel, eluent: EtOAc:hexanes = 1:10 to 1:6) to afford
Mukaiyama aldol product SI-5 (0.85 g, 60%) as colorless oil.
[0746] TLC (EtOAc: hexanes = 1:6): Rf = 0.2 (UV, KMnO4)
[0747] 1H NMR (300 MHz, CDCI3) d 6.78 (dd, J = 15.7, 9.6 Hz, 1H), 5.84 (dd, J = 15.7, 0.8 Hz, 1H), 5.80– 5.61 (m, 1H), 5.09– 4.99 (m, 2H), 3.73 (s, 3H), 3.41-3.33 (m, 1H), 2.58– 2.31 (m, 2H), 2.25– 2.12 (m, 1H), 1.79– 1.66 (m, 1H), 1.47 (d, J = 5.7 Hz, 1H), 0.95 (d, J = 6.9 Hz, 3H), 0.86 (d, J = 6.8 Hz, 3H).
[0748] 13C NMR (100 MHz, CDCI3) d 166.79, 149.46, 136.90, 122.11, 116.87, 77.95, 51.53, 46.49, 34.49, 30.84, 20.07, 15.13.
[0749] Amide SI-6
Figure imgf000257_0001
[0750] An oven-dried 250-mL round-bottom flask was charged with propargylamine (10, 1.00 mL, 16.0 mmol, 4.0 equiv) and DCM (27 mL). The resulting colorless solution was cooled to 0 °C by means of ice-water bath. A solution of AlMe3 in heptane (1.00 M, 16.0 mL, 16.0 mmol, 4.0 equiv) was added dropwise over 30 min (Caution: Gas evolution!). The mixture was allowed to 22 °C. After 30 min, a solution of Mukaiyama aldol product SI-5 (0.85 g, 4.00 mmol, 1 equiv) in DCM (4.8 mL) was added over 10 min (Caution: Gas evolution!). The vessel was equipped with a reflux condenser and the solution was brought to reflux by means of a 50 °C oil bath. After 3 h, the mixture was cooled to 0 °C by means of ice-water bath and MeOH (3.0 mL) was added (Caution: Gas evolution!). Once gas evolution ceased, saturated aqueous potassium sodium tartrate solution (30 mL) was added. After 1 h, the biphasic mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with DCM (2 x 10 mL). The combined organic layers were washed with water (30 mL) and brine (30 mL) and the organic extracts were dried (Na2SO4). The dried solution was filtered and the filtrated was concentrated. The crude residue was purified by flash chromatography (silica gel, eluent: EtOAc:hexanes = 1:1) to afford amide SI-6 (0.71 g, 76%) as white solids.
[0751] TLC (EtOAc: hexanes = 1:1): Rf = 0.40 (UV)
[0752] 1H NMR (300 MHz, CDCl3) d 6.70 (ddd, J = 15.3, 9.6, 1.6 Hz, 1H), 5.81 (d, J = 1.5 Hz, 1H), 5.79– 5.65 (m, 1H), 5.62 (br s, 1H), 5.10– 4.98 (m, 2H), 4.13 (m, 2H), 3.40– 3.34 (m, 1H), 2.49 (d, J = 6.0 Hz, 1H), 2.39 (q, J = 9.5 Hz, 1H), 2.26 (q, J = 2.3 Hz, 1H), 2.18 (dt, J = 15.2, 8.3 Hz, 1H), 1.73 (m, 1H), 1.57 (s, 1H), 0.95 (dd, J = 6.9, 1.5 Hz, 3H), 0.86 (dd, J = 6.8, 1.6 Hz, 3H).
[0753] 13C NMR (75 MHz, CDCI3) d 165.42, 146.22, 136.47, 124.24, 117.08, 79.73, 78.38, 72.10, 46.66, 34.76, 31.03, 29.60, 20.38, 15.62.
[0754] HRMS-ESI m/z calcd for C14H21NNaO2 + [M + Na]+ 258.1465, found 258.1458.
[0755] Vinyl stannane SI-7
Figure imgf000258_0001
[0756] An oven-dried 250-mL round-bottom flask charged with CuCN (0.54 g, 6.07 mmol, 2.0 equiv) was evacuated and flushed with nitrogen (this process was repeated a total of 3 times) and was sealed with rubber septum. THF (40.0 mL) was added, resulting a white suspension and the vessel was cooled to -78 °C by dry ice-acetone bath. To this suspension, a solution of n-BuLi in hexanes (2.50 M, 5.1 mL, 12.7 mmol, 4.2 equiv) was added dropwise over 10 min and the resulting solution was stirred for 30 min. Bu3SnH (3.43 mL, 12.7 mmol, 4.2 equiv) was added dropwise over 5 min. After 30 minutes, a solution of amide SI-6 (071 g, 3.03 mmol, 1 equiv) in THF (3.2 mL) was added dropwise over 15 min. After 1 h, saturated aqueous ammonium chloride solution (25 mL) was added in one portion. The vessel was removed from the cooling bath and the system was allowed to warm 23 °C while the mixture was rapidly stirring. The biphasic mixture was transferred to a separatory funnel and the layers were separated. The aqueous layers were extracted with aqueous ammonium hydroxide solution (2 x 25 mL) and ethyl acetate (2 x 25 mL). The organic extracts were washed with water (2 x 25 mL) and brine (25 mL). The washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The crude residue was purified by flash chromatography (silica gel, eluent: EtOAc:hexanes = 0:1 to 1:3) to afford vinyl stannane SI-7 (1.38 g, 87%) as a colorless oil.
[0757] TLC (EtOAc:hexanes = 1:3): Rf = 0.20 (UV) [0758] 1H NMR (400 MHz, CDCl3) d 6.67 (dd, J = 15.3, 9.6 Hz, 1H), 6.12 (dt, J = 18.9, 1.5 Hz, 1H), 5.98 (dt, J = 19.0, 5.1 Hz, 1H), 5.83– 5.69 (m, 2H), 5.52 (t, J = 5.9 Hz, 1H), 5.10– 4.96 (m, 2H), 4.04– 3.95 (m, 2H), 3.41– 3.34 (m, 1H), 2.55– 2.47 (m, 1H), 2.44– 2.32 (m, 1H), 2.24– 2.12 (m, 1H), 1.80– 1.70 (m, 1H), 1.59– 1.36 (m, 6H), 1.34– 1.26 (m, 6H), 0.99– 0.77 (m, 21H).
[0759] 13C NMR (100 MHz, CDCl3) d 165.16, 144.84, 143.38, 136.29, 130.52, 124.72, 116.64, 78.08, 46.35, 44.97, 34.60, 30.67, 29.06, 27.27, 20.09, 15.22, 13.70, 9.47.
[0760] HRMS-ESI m/z calcd for C26H50NO2Sn+ [M + H]+ 528.2858 found 528.2866.
[0761] Amine SI-8
Figure imgf000259_0001
[0762] An oven-dried 100-mL round-bottom flask was charged with 12 (1.16 g, 3.42 mmol, 1.35 equiv), DMAP (62.0 mg, 0.51 mmol, 0.2 equiv) and vinyl stannane SI-7 (1.34 g, 2.54 mmol, 1 equiv). DCM (25 mL) was added, resulting in a colorless solution. DCC (0.79 g, 3.81 mmol, 1.50 equiv) was added in one portion at 23 °C, resulting in a white suspension. After 5 h, 52 was entirely consumed by TLC analysis (eluent: EtOAc:hexanes = 1:2). Diethyl amine (13.0 mL) was added. After stirring for additional 3 h, the mixture was filtered through a pad of celite and the filter cake was washedwith DCM (2 x 20 mL). The filtrate was concentrated and the crude residue was purified by flash chromatography (silica gel, eluent: NH4OH:MeOH:DCM = 0.2:1:100 to 0.2:1:50) to afford amine SI-8 (1.28 g, 81%) as light yellow oil.
[0763] TLC (MeOH:DCM = 1:20) : Rf = 0.20 (UV)
[0764] 1H NMR (400 MHz, CDCI3) d 6.58 (dd, J = 15.3, 9.5 Hz, 1H), 6.11 (dt, J = 19.0, 1.5 Hz, 1H), 5.96 (dt, J = 19.0, 5.1 Hz, 1H), 5.81 (d, J = 15.3 Hz, 1H), 5.72– 5.60 (m, 1H), 5.57 (br, 1H), 5.03– 4.95 (m, 2H), 4.89 (dd, J = 8.1, 4.2 Hz, 1H), 4.01– 3.95 (m, 2H), 3.80 (dd, J = 8.4, 5.7 Hz, 1H), 3.09 (dt, J = 10.2, 6.8 Hz, 1H), 2.92 (dt, J = 10.2, 6.6 Hz, 1H), 2.55 (m, 1H), 2.38 (s, 1H), 2.28– 2.02 (m, 3H), 1.94– 1.72 (m, 4H), 1.54– 1.40 (m, 6H), 1.33– 1.24 (m, 6H), 0.91– 0.83 (m, 21H).
[0765] 13C NMR (100 MHz, CDCl3) d 175.07, 164.81, 143.32, 142.94, 135.33, 130.54, 125.51, 117.09, 79.24, 59.94, 46.93, 44.98, 44.53, 34.44, 30.48, 29.95, 29.05, 27.27, 25.48, 19.85, 15.94, 13.70, 9.46.
[0766] HRMS-ESI m/z calcd for C31H57N2O3Sn+ [M + H]+ 625.3386 found 625.3390.
[0767] Stille Coupling precursor SI-9
Figure imgf000260_0001
[0768] An oven-dried 50-mL round-bottom flask was charged with iPr2EtN (0.18 mL, 1.06 mmol, 2.0 equiv), amine SI-8 (0.33 g, 0.53 mmol, 1 equiv) and acid 19 (0.29 g, 0.58 mmol, 1.1 equiv). DCM (6 mL) was added, resulting in colorless solution. HATU (0.25 g, 0.66 mmol, 1.25 equiv) was added in one portion at 23 °C. After 5 h, the mixture was diluted with DCM (22 mL) and the resulting solution was transferred to a separatory funnel and then washed with water (2 x 28 mL) and brine (18 mL). The washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The resulting crude residue was purified by flash chromatography (silica gel, eluent: EtOAc:hexanes = 1:6 to 1:4) to afford Stille Coupling precursor SI-9 (0.34 g, 58%) as a light yellow foam.
[0769] TLC (EtOAc:hexanes = 1:4) : Rf = 0.25 (UV)
[0770] 1H NMR (400 MHz, CDCl3, mixtures of rotamers) d 6.56 (ddd, J = 20.2, 15.3, 9.5 Hz, 1H), 6.20– 6.07 (m, 1H), 6.05– 5.90 (m, 1H), 5.87– 5.79 (m, 1H), 5.77– 5.59 (m, 2H), 5.00– 4.87 (m, 3H), 4.87– 4.76 (m, 1H), 4.14– 3.90 (m, 4H), 3.89– 3.69 (m, 2H), 2.85 (dt, J = 16.3, 8.3 Hz, 1H), 2.55 (pd, J = 9.2, 4.5 Hz, 1H), 2.34– 2.24 (m, 4H), 2.17– 1.79 (m, 2H), 1.56– 1.42 (m, 6H), 1.38– 1.26 (m, 9H), 0.96– 0.82 (m, 30H), 0.38– 0.30 (m, 9H), 0.08– 0.03 (m, 6H).
[0771] 13C NMR (100 MHz, CDCI3, mixtures of rotamers) d 201.10, 200.66, 172.39, 172.24, 165.07, 164.77, 163.32, 162.51, 161.52, 159.23, 159.10, 145.25, 145.09, 143.44, 143.34, 143.09, 142.84, 135.55, 135.36, 134.26, 130.44, 130.24, 125.58, 121.80, 117.00, 116.94, 79.54, 79.44, 67.06, 66.89, 60.70, 59.92, 49.68, 49.64, 48.82, 47.12, 44.96, 44.91, 44.72, 44.32, 44.24, 44.01, 34.31, 33.95, 31.74, 30.07, 29.89, 29.05, 27.85, 27.27, 26.85, 25.72, 25.66, 25.29, 24.02, 23.93, 21.64, 19.96, 19.64, 17.99, 17.55, 16.35, 16.21, 13.70, 13.61, 9.45, -1.73, -1.75, -4.54, -5.10, -5.12.
[0772] HRMS-ESI m/z calcd for C51H89BrN3O7Si2Sn+ [M + H]+ 1110.4439 found
1110.4449.
[0773] Stille Coupling product SI-10
Figure imgf000261_0001
[0774] An oven-dried 100-mL round-bottom flask was charged with JackiePhos (23.0 mg, 29.0 mmol, 0.2 equiv), Stille Coupling precursor SI-9 (0.16 g, 0.15 mmol, 1 equiv) and Pd2(dba)3 (13.4 mg, 14.6 mmol, 0.1 equiv). The vessel was evacuated and filled with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. Toluene (30 mL) was added, resulting in a red suspension. A stream of argon was passed through the solution for 30 min. The vessel and its contents were then heated in 80 ºC oil bath. After 16 h, 54 was entirely consumed and the mixture was allowed to cool to 23 ºC. The mixture was concentrated and the resulting crude residue was purified by flash chromatography (silica gel, eluent: EtOAc:hexanes = 1:2.5 to 1:2) to afford Stille Coupling product SI-10 (28.6 mg, 26%) as a white foam.
[0775] TLC (EtOAc:hexanes = 1:2) : Rf = 0.30 (UV) [0776] 1H NMR (400 MHz, CDCl3) d 6.50 (dd, J = 16.2, 5.1 Hz, 1H), 6.14 (d, J = 15.6 Hz, 1H), 6.10– 6.00 (m, 1H), 5.93– 5.76 (m, 2H), 5.62 (ddd, J = 15.6, 9.1, 4.3 Hz, 1H), 5.42 (d, J = 8.8 Hz, 1H), 5.19– 4.98 (m, 3H), 4.87 (ddd, J = 15.3, 9.3, 2.7 Hz, 2H), 4.50 (ddd, J = 14.1, 8.8, 4.4 Hz, 1H), 3.97– 3.86 (m, 1H), 3.86– 3.72 (m, 2H), 3.67 (dd, J = 4.1, 2.1 Hz, 1H), 3.42 (ddd, J = 14.9, 9.1, 3.1 Hz, 1H), 3.00– 2.89 (m, 1H), 2.78 (dd, J = 15.9, 6.0 Hz, 1H), 2.44 (d, J = 14.5 Hz, 1H), 2.30– 2.11 (m, 2H), 2.08– 1.83 (m, 2H), 1.84– 1.71 (m, 1H), 1.02– 0.85 (m, 18H), 0.33 (s, 9H), 0.06 (d, J = 12.7 Hz, 6H).
[0777] 13C NMR (100 MHz, CDCl3) d 201.08, 171.88, 166.02, 161.88, 161.30, 160.90, 159.68, 145.08, 142.87, 136.58, 135.82, 134.66, 132.50, 124.76, 117.07, 81.51, 65.45, 58.88, 50.49, 48.48, 43.77, 41.67, 41.21, 30.39, 29.44, 28.28, 25.78, 24.90, 19.91, 18.74, 12.76, - 1.82, -4.47, -4.94.
[0778] HRMS-ESI m/z calcd for C39H62N3O7Si2+ [M + H]+ 740.4121 found 740.4116.
[0779] Analogue 21
Figure imgf000262_0001
[0780] An oven-dried 50 mL round-bottom flask charged with Stille Coupling product SI-4 (30 mg, 41 mmol, 1 equiv) was evacuated and filled with nitrogen (repeated this process 3 times) and was sealed with a rubber septum. THF (0.8 mL) was added, resulting a light yellow solution. In a separate flask, imidazole•HCl (43 mg, 0.41 mmol, 10.0 equiv) was added to a solution of tetrabutylammonium fluoride in THF (1 M, 0.41 mL, 0.41 mmol, 10.0 equiv). The resulting colorless solution was added dropwise to the solution of SI-10. After 12 h, the mixture was concentrated and the residue was dissolved in DCM (30 mL). The resulting solution was transferred to a separatory funnel and was washed with water (3 x 15 mL) and brine (15 mL). The washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The resulting crude residue was purified by flashed chromatography (silica gel, eluent: MeOH:DCM = 1:40) to afford analogue 21 (7.3 mg, 33%) as a white solid. [0781] TLC (MeOH:DCM = 1:20) : Rf = 0.15 (UV)
[0782] 1H NMR (400 MHz, CDCl3) d 7.98 (s, 1H), 6.69 (dd, J = 10.1 Hz, 1H), 6.38 (dd, J = 16.3, 6.7 Hz, 1H), 6.06 (d, J = 15.7 Hz, 1H), 5.86 (dd, J = 16.2, 1.4 Hz, 1H), 5.71 (ddt, J = 14.3, 9.8, 5.9 Hz, 2H), 5.25 (d, J = 8.8 Hz, 1H), 5.04– 4.96 (m, 2H), 4.90 (td, J = 7.2, 5.0 Hz, 1H), 4.80 (dd, J = 9.8, 2.2 Hz, 1H), 4.69 (dd, J = 8.8, 3.3 Hz, 1H), 4.46 (ddd, J = 14.2, 8.8, 4.9 Hz, 1H), 3.93– 3.86 (m, 1H), 3.82 (d, J = 15.4 Hz, 1H), 3.78– 3.70 (m, 1H), 3.65 (dd, J = 4.0, 1.9 Hz, 1H), 3.44– 3.34 (m, 1H), 3.04 (dd, J = 16.3, 6.8 Hz, 1H), 2.91– 2.81 (m, 1H), 2.69– 2.61 (m, 1H), 2.44– 2.31 (m, 2H), 2.28– 2.17 (m, 1H), 2.16– 2.06 (m, 1H), 2.06– 1.85 (m, 3H), 0.95 (d, J = 6.6 Hz, 6H).
[0783] 13C NMR (100 MHz, CDCI3) d 201.89, 171.44, 166.31, 160.51, 156.61, 143.95, 141.77, 137.03, 136.86, 135.77, 134.75, 132.21, 126.07, 125.44, 116.91, 81.83, 65.45, 60.05, 48.52, 43.94, 41.97, 41.27, 40.67, 30.99, 29.61, 28.54, 25.15, 19.69, 18.97, 12.80.
[0784] HRMS-ESI m/z calcd for C30H39N3NaO7+ [M + H]+ 576.2680, found 576.2678.
[0785] Scheme III Synthesis of analogue 22
Figure imgf000264_0001
[0787] An oven-dried 200-mL round-bottom flask was charged with (R)-but-3-yn-2-amine (SI-11, 1.04 g, 15.0 mmol, 4.0 equiv) and dry DCM (25 mL). The resulting colorless solution was cooled to 0 °C by means of ice-water bath. A solution of AlMe3 in heptane (2 M, 7.5 mL, 15.0 mmol, 4.0 equiv) was added dropwise over 30 min (CAUTION: Gas evolution!). The mixture was allowed to warm to 23 °C. After stirring for 30 min, a solution of 9 (3.20 g, 17.2 mmol, 1 equiv) in DCM (20 mL) was added over 10 min (CAUTION: Gas evolution!). The vessel was equipped with a reflux condenser and the solution was brought to reflux by means of a 50 °C oil bath. After 3 h, the mixture was cooled to 0 °C by means of ice-water bath and MeOH (10 mL) was added (CAUTION: Gas evolution!). Once gas evolution ceased, saturated aqueous potassium sodium tartrate solution (50 mL) was added. After stirring for 1 h, the biphasic mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with DCM (2 × 30 mL). The combined organic layers were washed with water (60 mL) and brine (60 mL) and the washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The crude residue was purified by flash chromatography (silica gel, eluent: EtOAc:hexanes = 1:1) to afford amide SI-12 (0.72 g, 86%) as a white solid.
[0788] TLC (EtOAc:hexanes = 1:1) : Rf = 0.25 (UV)
[0789] 1H NMR (400 MHz, CDCI3) d 6.79 (dd, J = 15.4, 7.8 Hz, 1H), 6.30 (d, J = 8.0 Hz, 1H), 5.81 (dd, J = 15.5, 1.2 Hz, 1H), 4.91– 4.76 (m, 1H), 3.22 (t, J = 5.8 Hz, 1H), 2.46 (dddd, J = 8.0, 6.9, 5.6, 1.3 Hz, 1H), 2.24 (d, J = 2.4 Hz, 2H), 1.69 (dq, J = 13.2, 6.6 Hz, 1H), 1.40 (d, J = 6.9 Hz, 3H), 1.04 (d, J = 6.8 Hz, 3H), 0.89 (d, J = 6.6 Hz, 3H), 0.87 (d, J = 6.9 Hz, 3H).
[0790] 13C NMR (100 MHz, CDCI3) d 164.9, 148.2, 122.8, 84.1, 79.0, 70.3, 39.5, 36.7, 30.8, 22.1, 19.6, 17.0, 13.6.
[0791] HRMS-ESI m/z calcd for C13H22NO2 + [M + H]+ 224.1645, found 224.1648.
[0792] Vinyl stannane SI-13
Figure imgf000266_0001
[0793] An oven-dried 200-mL round-bottom flask charged with CuCN (0.56 g, 6.27 mmol, 2.0 equiv) was evacuated and flushed with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. Dry THF (63 mL) was added, resulting a white suspension and the vessel was cooled to -78 °C in a dry ice-acetone bath. To this suspension was added a solution of n-BuLi in hexanes (2.5 M, 5.27 mL, 13.2 mmol, 4.2 equiv) dropwise over 10 min and the resulting light yellow solution was stirred for 30 min. Bu3SnH (3.55 mL, 13.2 mmol, 4.2 equiv) was added dropwise over 5 min. After stirring for 30 min, a solution of SI-12 (0.70 g, 3.13 mmol, 1 equiv) in THF (5 mL) was added dropwise over 15 min. After stirring for 1 h, saturated aqueous NH4Cl solution (50 mL) was added in one portion. The vessel was removed from the cooling bath and the system was allowed to warm to 23 °C while the mixture was rapidly stirred. The biphasic mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with water (2 × 100 mL) and brine (100 mL). The washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The crude residue was purified by flash chromatography (silica gel, eluent: EtOAc:hexanes = 0:1 to 1:3) to afford vinyl stannane SI-13 (1.61 g, 100%, ³20:1 E:Z) as a colorless oil.
[0794] TLC (EtOAc:hexanes = 1:3): Rf = 0.25 (UV).
[0795] 1H NMR (400 MHz, CDCl3) d 6.79 (dd, J = 15.3, 7.8 Hz, 1H), 6.06 (dd, J = 19.1, 1.5 Hz, 1H), 5.95 (dd, J = 19.2, 4.1 Hz, 1H), 5.81 (dd, J = 15.3, 1.2 Hz, 1H), 5.48 (d, J = 8.6 Hz, 1H), 4.70– 4.57 (m, 1H), 3.25 (q, J = 5.6 Hz, 1H), 2.48 (dddd, J = 8.0, 7.0, 5.9, 1.2 Hz, 1H), 1.80 (d, J = 5.1 Hz, 1H), 1.78– 1.68 (m, 1H), 1.55– 1.41 (m, 6H), 1.34– 1.25 (m, 6H), 1.24 (d, J = 6.8 Hz, 3H), 1.07 (d, J = 6.7 Hz, 3H), 0.97– 0.77 (m, 21H).
[0796] 13C NMR (100 MHz, CDCl3) d 164.9, 148.6, 147.3, 127.1, 123.5, 79.1, 48.8, 39.6, 30.7, 29.0, 27.2, 20.4, 19.7, 16.8, 13.9, 13.6, 9.4. [0797] HRMS-ESI m/z calcd for C25H50NO2Sn+ [M + H]+ 516.2858, found 516.2863.
[0798] Amine SI-14
Figure imgf000267_0001
[0799] An oven-dried 100-mL round-bottom flask was charged with 12 (0.89 g, 2.62 mmol, 1.35 equiv), DMAP (48 mg, 0.39 mmol, 0.2 equiv) and SI-13 (1.00 g, 1.94 mmol, 1 equiv). Dry DCM (20 mL) was added, resulting in a colorless solution. DCC (0.60 g, 2.92 mmol, 1.5 equiv) was added in one portion at 23 °C, resulting in a white suspension. After 5 h, the alcohol 56 was entirely consumed by TLC analysis (eluent: EtOAc:hexanes = 1:2). Diethyl amine (11 mL) was added. After stirring for additional 3 h, the mixture was filtered through a pad of celite and the filter cake was washed with DCM (2 × 10 mL). The filtrate was concentrated and the crude residue was purified by flash chromatography (silica gel, eluent: NH4OH:MeOH:DCM = 0.2:1:100 to 0.2:1:50) to afford amine SI-14 (1.10 g, 93%) as light yellow oil.
[0800] TLC (MeOH:DCM= 1:20): Rf = 0.20 (UV).
[0801] 1H NMR (400 MHz, CDCI3) d 6.68 (dd, J = 15.4, 7.7 Hz, 1H), 6.06 (dd, J = 19.2, 1.5 Hz, 1H), 5.94 (dd, J = 19.1, 4.1 Hz, 1H), 5.81 (dd, J = 15.4, 1.2 Hz, 1H), 5.48 (d, J = 8.6 Hz, 1H), 4.82 (dd, J = 6.7, 5.6 Hz, 1H), 4.68– 4.56 (m, 1H), 4.02 (br s, 1H), 3.89 (dd, J = 8.5, 5.6 Hz, 1H), 3.14 (ddd, J = 10.4, 7.5, 6.1 Hz, 1H), 3.05– 2.95 (m, 1H), 2.70– 2.60 (m, 1H), 2.25– 2.15 (m, 1H), 1.97– 1.87 (m, 2H), 1.85– 1.71 (m, 2H), 1.53– 1.40 (m, 6H), 1.34 – 1.24 (m, 6H), 1.23 (d, J = 6.8 Hz, 3H), 1.03 (d, J = 6.8 Hz, 3H), 0.92– 0.79 (m, 21H).
[0802] 13C NMR (100 MHz, CDCl3) d 174.1, 164.5, 148.5, 144.9, 127.1, 124.2, 80.9, 59.7, 48.8, 46.7, 38.0, 30.2, 29.7, 29.0, 27.2, 25.1, 20.4, 19.5, 16.9, 14.6, 13.7, 9.4.
[0803] HRMS-ESI m/z calcd for C30H57N2O3Sn+ [M + H]+ 613.3386, found 613.3380.
[0804] Stille Coupling precursor SI-15
Figure imgf000268_0001
[0805] An oven-dried 100-mL round-bottom flask was charged with iPr2EtN (0.63 mL, 3.60 mmol, 2.0 equiv), amine SI-14 (1.10 g, 1.80 mmol, 1 equiv) and acid 19 (1.00 g, 1.98 mmol, 1.1 equiv). DCM (18 mL) was added, resulting in a colorless solution. HATU (0.86 g, 2.25 mmol, 1.25 equiv) was added in one portion at 23 °C. After 5 h, the mixture was diluted with DCM (30 mL). The resulting solution was transferred to a separatory funnel and was washed with water (2 × 25 mL) and brine (25 mL). The washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The resulting crude residue was purified by flash chromatography (silica gel, eluent: EtOAc:hexanes = 1:6 to 1:4) to afford Stille Coupling precursor SI-15 (1.58 g, 80%) as a light yellow oil.
[0806] TLC (EtOAc:hexanes = 1:4): Rf = 0.30 (UV).
[0807] 1H NMR (400 MHz, CDCI3, mixtures of rotamers) d 6.70– 6.56 (m, 1H), 6.09– 5.99 (m, 1H), 5.97– 5.87 (m, 1H), 5.86– 5.68 (m, 2H), 5.61– 5.46 (m, 1H), 4.84– 4.68 (m, 2H), 4.67– 4.51 (m, 2H), 4.13– 3.90 (m, 1H), 3.92– 3.80 (m, 2H), 3.80– 3.58 (m, 1H), 2.90 – 2.70 (m, 1H), 2.68– 2.41 (m, 2H), 2.31– 2.10 (m, 4H), 1.95– 1.72 (m, 4H), 1.54– 1.35 (m, 6H), 1.35– 1.15 (m, 9H), 0.97– 0.72 (m, 33H), 0.38– 0.21 (m, 9H), 0.06– -0.03 (m, 6H).
[0808] 13C NMR (100 MHz, CDCl3, mixtures of rotamers) d 201.0, 200.6, 172.30, 172.29, 164.71, 164.69, 164.4, 163.1, 162.4, 161.5, 161.4, 159.0, 148.57, 148.53, 145.24, 145.12, 145.10, 144.8, 134.2, 126.97, 126.86, 124.16, 124.11, 121.73, 121.71, 80.8, 80.4, 67.0, 66.8, 60.4, 59.8, 49.58, 49.55, 48.74, 48.70, 48.66, 47.0, 44.2, 44.0, 38.3, 37.9, 29.85, 29.73, 28.96, 28.85, 27.2, 25.64, 25.59, 23.95, 23.93, 20.38, 20.35, 19.58, 19.38, 17.9, 17.0, 16.9, 14.7, 14.4, 13.6, 9.4, -1.81, -1.82, -4.62, -4.70, -5.18, -5.20.
[0809] HRMS-ESI m/z calcd for C50H89BrN3O7Si2Sn+ [M + H]+ 1098.4439, found 1098.4455. [0810] Stille Coupling Product SI-16
Figure imgf000269_0001
[0811] An oven-dried 500-mL round-bottom flask was charged with JackiePhos (0.22 g, 0.27 mmol, 0.2 equiv), Stille Coupling precursor SI-15 (1.50 g, 1.02 mmol, 1 equiv) and Pd2(dba)3 (0.13 g, 0.14 mmol, 0.1 equiv). The vessel was evacuated and filled with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. Toluene (270 mL) was added, resulting in a red suspension. A stream of argon was passed through the solution for 30 min. The vessel and its contents were then heated in a 50 ºC oil bath. After 3 h, SI-15 was entirely consumed and the mixture was allowed to cool to 23 ºC. The mixture was concentrated and the resulting crude residue was purified by flash chromatography (silica gel, eluent: EtOAc:hexanes = 1:2.5 to 1:2) to afford Stille Coupling product SI-16 (0.71 g, 71%) as a white solid.
[0812] TLC (EtOAc:hexanes = 1:2): Rf = 0.20 (UV).
[0813] 1H NMR (400 MHz, CDCI3) d 6.82 (dd, J = 15.5, 4.3 Hz, 1H), 6.22 (d, J = 15.4 Hz, 1H), 5.67– 5.55 (m, 2H), 5.45 (d, J = 8.6 Hz, 1H), 5.32 (dd, J = 15.4, 8.6 Hz, 1H), 5.05 (td, J = 8.4, 3.2 Hz, 1H), 4.85– 4.70 (m, 2H), 4.62– 4.50 (m, 1H), 3.82 (d, J = 17.3 Hz, 1H), 3.78 – 3.71 (m, 1H), 3.68 (d, J = 17.3 Hz, 1H), 3.56 (ddd, J = 11.4, 8.8, 3.1 Hz, 1H), 2.97 (dd, J = 18.4, 3.2 Hz, 1H), 2.75– 2.63 (m, 1H), 2.64 (dd, J = 18.4, 8.2 Hz, 1H), 2.02– 1.81 (m, 5H), 1.66 (d, J = 1.2 Hz, 3H), 1.23 (d, J = 6.7 Hz, 3H), 1.04 (d, J = 6.7 Hz, 3H), 0.95 (d, J = 6.5 Hz, 3H), 0.93 (d, J = 6.8 Hz, 3H), 0.82 (s, 9H), 0.29 (s, 9H), 0.04 (s, 3H), 0.01 (s, 3H).
[0814] 13C NMR (100 MHz, CDCI3) d 201.0, 169.8, 164.1, 161.54, 161.48, 159.8, 147.5, 145.1, 136.2, 135.3, 130.9, 129.3, 122.6, 80.4, 64.5, 58.9, 50.5, 48.2, 47.4, 43.1, 36.9, 29.3, 28.5, 25.7, 24.4, 21.1, 19.7, 18.5, 18.0, 12.5, 9.2, -1.9, -4.6, -5.0.
[0815] HRMS-ESI m/z calcd for C38H62N3O7Si2+ [M + H]+ 728.4121, found 728.4127. [0816] Analogue 22
Figure imgf000270_0001
[0817] An oven-dried 100-mL round-bottom flask charged with Stille Coupling product SI- 16 (0.70 g, 0.96 mmol, 1 equiv) was evacuated and filled with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. THF (9.6 mL) was added, resulting in a light yellow solution. In a separate flask, imidazole•HCl (1.01 g, 9.60 mmol, 10.0 equiv) was added to a solution of tetrabutylammonium fluoride in THF (1 M, 9.60 mL, 9.60 mmol, 10.0 equiv). The resulting colorless solution was added dropwise to the solution of 59. After 12 h, the mixture was concentrated and the residue was dissolved in DCM (100 mL). The resulting solution was transferred to a separatory funnel and was washed with water (3 × 100 mL) and brine (100 mL). The washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The resulting crude residue was purified by flashed chromatography (silica gel, eluent: MeOH:DCM = 1:40) to
afford analogue 22 (0.36 g, 69%) as a light yellow solid.
[0818] TLC (MeOH:DCM = 1:20): Rf = 0.30 (UV).
[0819] 1H NMR (400 MHz, CDCI3) d 8.13 (s, 1H), 6.87 (dd, J = 15.5, 4.2 Hz, 1H), 6.29 (d, J = 15.4 Hz, 1H), 5.66– 5.53 (m, 3H), 5.40 (dd, J = 15.4, 8.9 Hz, 1H), 4.99 (td, J = 8.3, 3.5 Hz, 1H), 4.82 (dd, J = 10.3, 1.9 Hz, 1H), 4.77 (dd, J = 8.3, 2.5 Hz, 1H), 4.62– 4.52 (m, 1H), 3.84 (d, J = 17.4 Hz, 1H), 3.80– 3.70 (m, 2H), 3.77 (d, J = 17.4 Hz, 1H), 3.29 (dd, J = 18.4, 3.4 Hz, 1H), 2.79– 2.67 (m, 2H), 2.08– 1.99 (m, 1H), 1.99– 1.86 (m, 3H), 1.72 (d, J = 1.2 Hz, 3H), 1.60– 1.45 (m, 1H), 1.26 (d, J = 6.8 Hz, 3H), 1.05 (d, J = 6.7 Hz, 3H), 0.95 (d, J = 6.5 Hz, 3H), 0.94 (d, J = 6.8 Hz, 3H).
[0820] 13C NMR (100 MHz, CDCI3) d 203.4, 169.6, 164.1, 159.9, 157.4, 147.9, 143.8, 137.2, 135.5, 133.7, 133.3, 130.0, 122.3, 80.6, 64.4, 59.1, 49.1, 48.4, 47.7, 42.6, 36.9, 29.3, 28.3, 24.6, 21.0, 19.7, 18.5, 12.6, 9.2. [0821] HRMS-ESI m/z calcd for C29H39N3NaO7 + [M + Na]+ 564.2680, found 564.2678.
[0822] Scheme IV Synthesis of Analogue 23
Figure imgf000271_0001
[0823] Amide SI-18
Figure imgf000272_0001
[0824] An oven-dried 100-mL round-bottom flask was charged with (S)-but-3-yn-2-amine (SI-17, 1.04 g, 15.0 mmol, 4.0 equiv) and dry DCM (25 mL). The resulting colorless solution was cooled to 0 °C by means of ice-water bath. A solution of AlMe3 in heptane (2 M, 7.5 mL, 15.0 mmol, 4.0 equiv) was added dropwise over 30 min (CAUTION: Gas evolution!). The mixture was allowed to warm to 23 °C. After stirring for 30 min, a solution of 9 (3.20 g, 17.2 mmol, 1 equiv) in DCM (10 mL) was added over 10 min (CAUTION: Gas evolution!). The vessel was equipped with a reflux condenser and the solution was brought to reflux by means of a 50 °C oil bath. After 3 h, the mixture was cooled to 0 °C by means of ice-water bath and MeOH (10 mL) was added (CAUTION: Gas evolution!). Once gas evolution ceased, saturated aqueous potassium sodium tartrate solution (50 mL) was added. After stirring for 1 h, the biphasic mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with DCM (2 × 30 mL). The combined organic layers were washed with water (60 mL) and brine (60 mL) and the washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The crude residue was purified by flash chromatography (silica gel, eluent: EtOAc:hexanes = 1:1) to afford amide SI-18 (0.71 g, 85%) as a white solid.
[0825] TLC (EtOAc:hexanes = 1:1): Rf = 0.25 (UV)
[0826] 1H NMR (400 MHz, CDCl3) d 6.81 (dd, J = 15.4, 7.8 Hz, 1H), 6.06 (d, J = 8.1 Hz, 1H), 5.80 (dd, J = 15.4, 0.8 Hz, 1H), 4.94– 4.80 (m, 1H), 3.23 (t, J = 5.8 Hz, 1H), 2.52– 2.42 (m, 1H), 2.26 (d, J = 2.3 Hz, 1H), 1.97 (s, 1H), 1.71 (dq, J = 13.2, 6.6 Hz, 1H), 1.42 (d, J = 6.9 Hz, 3H), 1.06 (d, J = 6.8 Hz, 3H), 0.90 (d, J = 6.6 Hz, 3H), 0.89 (d, J = 6.8 Hz, 3H).
[0827] 13C NMR (100 MHz, CDCI3) d 164.8, 148.3, 122.8, 84.1, 79.1, 70.4, 39.5, 36.8, 30.8, 22.2, 19.7, 16.9, 13.7.
[0828] HRMS-ESI m/z calcd for C13H22NO2 + [M + H]+ 224.1645, found 224.1648.
[0829] Vinyl stannane SI-19
Figure imgf000273_0001
[0830] An oven-dried 200-mL round-bottom flask charged with CuCN (0.56 g, 6.27 mmol, 2.0 equiv) was evacuated and flushed with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. Dry THF (63 mL) was added, resulting a white suspension and the vessel was cooled to -78 °C in a dry ice-acetone bath. To this suspension was added 2.5 M n-BuLi in hexanes (5.27 mL, 13.2 mmol, 4.2 equiv) dropwise over 10 min and the resulting light yellow solution was stirred for 30 min. Bu3SnH (3.55 mL, 13.2 mmol, 4.2 equiv) was added dropwise over 5 min. After stirring for 30 min, a solution of SI-18 (0.70 g, 3.13 mmol, 1 equiv) in THF (5 mL) was added dropwise over 15 min. After stirring for 1 h, saturated aqueous NH4Cl solution (50 mL) was added in one portion. The vessel was removed from the cooling bath and the system was allowed to warm to 23 °C while the mixture was rapidly stirred. The biphasic mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with water (2 × 100 mL) and brine (100 mL). The washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The crude residue was purified by flash chromatography (silica gel, eluent: EtOAc:hexanes = 0:1 to 1:3) to afford vinyl stannane SI-19 (1.61 g, 100%, ³20:1 E:Z) as a colorless oil.
[0831] TLC (EtOAc:hexanes = 1:3): Rf = 0.25 (UV).
[0832] 1H NMR (400 MHz, CDCI3) d 6.81 (dd, J = 15.3, 7.8 Hz, 1H), 6.07 (dd, J = 19.1, 1.5 Hz, 1H), 5.96 (dd, J = 19.1, 4.1 Hz, 1H), 5.81 (dd, J = 15.3, 1.2 Hz, 1H), 5.43 (d, J = 8.6 Hz, 1H), 4.70– 4.55 (m, 1H), 3.26 (q, J = 5.6 Hz, 1H), 2.49 (dddd, J = 8.0, 7.0, 5.8, 1.3 Hz, 1H), 1.74 (dq, J = 13.3, 6.6 Hz, 1H), 1.64 (d, J = 5.1 Hz, 1H), 1.52– 1.42 (m, 6H), 1.34– 1.26 (m, 6H), 1.24 (d, J = 6.8 Hz, 3H), 1.08 (d, J = 6.6 Hz, 3H), 0.92 (d, J = 2.0 Hz, 3H), 0.91 (d, J = 2.1 Hz, 3H), 0.88 (t, J = 7.4 Hz, 15H). [0833] 13C NMR (100 MHz, CDCl3) d 164.8, 148.6, 147.2, 127.1, 123.5, 79.2, 48.8, 39.5, 30.8, 29.0, 27.2, 20.4, 19.7, 16.8, 13.8, 13.7, 9.4.
[0834] HRMS-ESI m/z calcd for C25H50NO2Sn+ [M + H]+ 516.2858, found 516.2863.
[0835] Amine SI-20
Figure imgf000274_0001
[0836] An oven-dried 100-mL round-bottom flask was charged with 12 (0.73 g, 2.15 mmol, 1.35 equiv), DMAP (39 mg, 0.32 mmol, 0.2 equiv) and SI-19 (0.82 g, 1.59 mmol, 1 equiv). Dry DCM (16 mL) was added, resulting in a colorless solution. DCC (0.49 g, 2.39 mmol, 1.5 equiv) was added in one portion at 23 °C, resulting in a white suspension. After 5 h, the alcohol 61 was entirely consumed by TLC analysis (eluent: EtOAc:hexanes = 1:2). Diethyl amine (8 mL) was added. After stirring for additional 3 h, the mixture was filtered through a pad of celite and the filter cake was washed with DCM (2 × 20 mL). The filtrate was concentrated and the crude residue was purified by flash chromatography (silica gel, eluent: NH4OH:MeOH:DCM = 0.2:1:100 to 0.2:1:50) to afford amine SI-20 (0.85 g, 87%) as light yellow oil.
[0837] TLC (MeOH:DCM= 1:20): Rf = 0.20 (UV).
[0838] 1H NMR (400 MHz, CDCI3) d 6.69 (dd, J = 15.4, 7.6 Hz, 1H), 6.06 (dd, J = 19.2, 1.5 Hz, 1H), 5.95 (dd, J = 19.2, 4.2 Hz, 1H), 5.81 (dd, J = 15.5, 1.2 Hz, 1H), 5.53 (d, J = 8.6 Hz, 1H), 4.82 (t, J = 6.1 Hz, 1H), 4.67– 4.56 (m, 1H), 4.52 (br s, 1H), 3.93 (dd, J = 8.5, 5.6 Hz, 1H), 3.16 (ddd, J = 10.6, 7.5, 6.1 Hz, 1H), 3.03 (dt, J = 10.5, 6.8 Hz, 1H), 2.66 (q, J = 6.4 Hz, 1H), 2.31– 2.07 (m, 1H), 2.01– 1.69 (m, 4H), 1.54– 1.37 (m, 6H), 1.35– 1.20 (m, 6H), 1.23 (d, J = 6.7 Hz, 4H), 1.03 (d, J = 6.8 Hz, 3H), 0.95– 0.75 (m, 22H).
[0839] 13C NMR (100 MHz, CDCl3) d 173.6, 164.5, 148.5, 144.9, 127.2, 124.1, 81.1, 59.7, 48.8, 46.6, 38.0, 30.1, 29.7, 29.0, 27.2, 24.9, 20.4, 19.5, 16.9, 14.5, 13.6, 9.4. [0840] HRMS-ESI m/z calcd for C30H57N2O3Sn+ [M + H]+ 613.3386, found 613.3380.
[0841] Stille Coupling precursor SI-21
Figure imgf000275_0001
[0842] An oven-dried 100-mL round-bottom flask was charged with iPr2EtN (0.34 mL, 1.96 mmol, 2.0 equiv), amine SI-20 (0.60 g, 0.98 mmol, 1 equiv) and acid 19 (0.55 g, 1.08 mmol, 1.1 equiv). DCM (10 mL) was added, resulting in a colorless solution. HATU (0.47 g, 1.23 mmol, 1.25 equiv) was added in one portion at 23 °C. After 5 h, the mixture was diluted with DCM (30 mL). The resulting solution was transferred to a separatory funnel and was washed with water (2 × 50 mL) and brine (50 mL). The washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The resulting crude residue was purified by flash chromatography (silica gel, eluent: EtOAc:hexanes = 1:6 to 1:4) to afford Stille Coupling precursor SI-21 (0.80 g, 74%) as a light yellow oil.
[0843] TLC (EtOAc:hexanes = 1:4): Rf = 0.30 (UV).
[0844] 1H NMR (400 MHz, CDCI3, mixtures of rotamers) d 6.75– 6.57 (m, 1H), 6.13– 6.04 (m, 1H), 6.01– 5.93 (m, 1H), 5.84– 5.70 (m, 2H), 5.51– 5.38 (m, 1H), 4.86– 4.69 (m, 2H), 4.63 (ddd, J = 11.6, 8.3, 3.2 Hz, 2H), 4.17– 3.93 (m, 1H), 3.93– 3.82 (m, 2H), 3.82– 3.61 (m, 1H), 2.90– 2.75 (m, 1H), 2.68– 2.43 (m, 2H), 2.33– 2.19 (m, 3H), 2.24– 2.14 (m, 1H), 2.15– 1.75 (m, 4H), 1.70– 1.57 (m, 1H), 1.54– 1.40 (m, 6H), 1.38– 1.18 (m, 9H), 1.07 – 0.66 (m, 33H), 0.41– 0.21 (m, 9H), 0.10– -0.05 (m, 6H).
[0845] 13C NMR (100 MHz, CDCl3, mixtures of rotamers) d 201.1, 200.6, 172.33, 172.31, 164.65, 164.63, 164.41, 163.2, 162.5, 161.52, 161.42, 159.07, 159.03, 148.59, 148.52, 145.37, 145.30, 145.2, 145.0, 134.2, 127.19, 127.11, 124.09, 124.03, 121.79, 121.78, 80.8, 80.3, 67.0, 66.9, 60.5, 59.8, 49.64, 49.62, 48.85, 48.80, 48.74, 47.1, 44.2, 44.0, 38.5, 38.1, 30.0, 29.8, 29.0, 28.9, 27.2, 25.7, 25.6, 20.41, 20.38, 19.7, 19.5, 18.0, 17.5, 16.82, 16.78, 15.1, 14.7, 13.7, 13.6, 9.4, -1.76, -1.77, -4.6, -5.13, -5.14. [0846] HRMS-ESI m/z calcd for C50H89BrN3O7Si2Sn+ [M + H]+ 1098.4439, found 1098.4455.
[0847] Stille Coupling product SI-22
Figure imgf000276_0001
[0848] An oven-dried 250-mL round-bottom flask was charged with JackiePhos (0.12 g, 0.15 mmol, 0.2 equiv), Stille Coupling precursor SI-21 (0.80 g, 0.73 mmol, 1 equiv) and Pd2(dba)3 (67 mg, 0.073 mmol, 0.1 equiv). The vessel was evacuated and filled with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. Toluene (146 mL) was added, resulting in a red suspension. A stream of argon was passed through the solution for 30 min. The vessel and its contents were then heated in a 50 ºC oil bath. After 3 h, 63 was entirely consumed and the mixture was allowed to cool to 23 ºC. The mixture was concentrated and the resulting crude residue was purified by flash chromatography (silica gel, eluent: EtOAc:hexanes = 1:2.5 to 1:2) to afford Stille Coupling product SI-22 (0.35 g, 61%) as a white solid.
[0849] TLC (EtOAc:hexanes = 1:2): Rf = 0.20 (UV).
[0850] 1H NMR (400 MHz, CDCl3) d 6.46 (dd, J = 16.3, 4.3 Hz, 1H), 6.07 (dd, J = 16.1, 1.6 Hz, 1H), 5.83– 5.73 (m, 2H), 5.68 (dd, J = 16.0, 4.4 Hz, 1H), 5.41 (d, J = 8.7 Hz, 1H), 5.00 (dt, J = 8.7, 6.4 Hz, 1H), 4.82– 4.69 (m, 3H), 3.86 (d, J = 17.0 Hz, 1H), 3.79– 3.73 (m, 2H), 3.70 (d, J = 17.0 Hz, 1H), 2.89 (dd, J = 16.2, 6.6 Hz, 1H), 2.78 (dd, J = 16.2, 6.2 Hz, 1H), 2.76– 2.66 (m, 1H), 2.14– 2.02 (m, 1H), 2.00– 1.80 (m, 3H), 1.78– 1.69 (m, 1H), 1.67 (s, 3H), 1.28 (d, J = 6.8 Hz, 3H), 1.08 (d, J = 6.9 Hz, 3H), 0.97 (d, J = 6.5 Hz, 3H), 0.92 (d, J = 6.7 Hz, 3H), 0.84 (s, 9H), 0.29 (s, 9H), 0.04 (s, 3H), 0.00 (s, 3H).
[0851] 13C NMR (100 MHz, CDCl3) d 201.1, 172.0, 165.6, 161.6, 161.4, 159.7, 145.1, 144.6, 134.5, 132.5, 132.4, 129.6, 123.9, 80.9, 65.4, 58.9, 50.2, 48.4, 44.3, 43.5, 36.5, 29.3, 28.2, 25.7, 24.8, 19.8, 18.8, 18.6, 18.04, 12.8, 10.2, -1.9, -4.5, -5.0. [0852] HRMS-ESI m/z calcd for C38H62N3O7Si2 + [M + H]+ 728.4121, found 728.4127.
[0853] Analogue 23
Figure imgf000277_0001
[0854] An oven-dried 100-mL round-bottom flask charged with Stille Coupling product SI- 22 (0.30 g, 0.41 mmol, 1 equiv) was evacuated and filled with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. THF (4.1 mL) was added, resulting in a light yellow solution. In a separate flask, imidazole•HCl (0.43 g, 4.1 mmol, 10.0 equiv) was added to a solution of tetrabutylammonium fluoride in THF (1 M, 4.1 mL, 4.1 mmol, 10.0 equiv). The resulting colorless solution was added dropwise to the solution of 64. After 12 h, the mixture was concentrated and the residue was dissolved in DCM (100 mL). The resulting solution was transferred to a separatory funnel and was washed with water (3 × 100 mL) and brine (100 mL). The washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The resulting crude residue was purified by flashed chromatography (silica gel, eluent: MeOH:DCM = 1:40) to afford analogue 23 (0.18 g, 81%) as a light yellow solid.
[0855] TLC (MeOH:DCM = 1:20): Rf = 0.30 (UV).
[0856] 1H NMR (400 MHz, CDCI3) d 8.05 (s, 1H), 6.46 (dd, J = 16.3, 5.1 Hz, 1H), 6.20 (d, J = 9.0 Hz, 1H), 6.06 (dd, J = 16.1, 1.5 Hz, 1H), 5.85– 5.75 (m, 2H), 5.32 (d, J = 8.6 Hz, 1H), 4.89 (dt, J = 8.7, 5.8 Hz, 1H), 4.81– 4.66 (m, 3H), 3.97 (dt, J = 10.9, 7.2 Hz, 1H), 3.84 (d, J = 15.6 Hz, 1H), 3.84 -3.74 (m, 1H), 3.78 (d, J = 15.5 Hz, 1H), 3.00 (dd, J = 16.6, 6.4 Hz, 1H), 2.87 (dd, J = 16.6, 5.3 Hz, 1H), 2.77– 2.67 (m, 1H), 2.21– 2.11 (m, 1H), 2.02– 1.78 (m, 4H), 1.71 (s, 3H), 1.27 (d, J = 6.8 Hz, 3H), 1.04 (d, J = 6.9 Hz, 3H), 0.96 (d, J = 6.5 Hz, 3H), 0.93 (d, J = 6.7 Hz, 3H). [0857] 13C NMR (100 MHz, CDCl3) d 202.1, 171.7, 165.9, 160.2, 156.9, 144.1, 143.9, 137.0, 135.0, 132.4, 131.8, 130.5, 124.4, 81.3, 65.2, 59.7, 48.48, 48.46, 44.3, 43.5, 36.5, 29.5, 28.4, 25.0, 19.7, 19.2, 18.8, 12.9, 10.9.
[0858] HRMS-ESI m/z calcd for C29H39N3NaO7 + [M + Na]+ 564.2680, found 564.2678. [0859] Scheme V Synthesis of Analogue 24
Figure imgf000278_0001
[0860] b-hydroxyl amide SI-24
Figure imgf000279_0001
[0861] A 250-mL round-bottom flask charged with 15 (1.94 g, 9.54 mmol, 1.1 equiv) was evacuated and flushed with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. Dry DCM (50 mL) was added, resulting in a yellow solution and the vessel was cooled to -78 °C in a dry ice-acetone bath. A solution of TiCl4 in DCM (1 M, 10.4 mL, 10.4 mmol, 1.2 equiv) dropwise, resulting in a deep yellow solution. After 5 min, iPr2EtN (1.80 mL, 10.4 mmol, 1.2 equiv) was added by syringe pump over 30 min, and the resulting deep red solution was stirred for 2 h at -78 °C. A solution of aldehyde SI-23 (1.17 g, 8.67 mmol, 1 equiv) in DCM (10 mL) was added via syringe pump over 30 min. After stirring for 30 min, water (100 mL) was added. The vessel was removed from the cooling bath and the system was allowed to warm to 23 °C while the mixture was rapidly stirred. The biphasic mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with DCM (2 × 30 mL). The combined organic layers were washed with water (2 × 100 mL) and brine (100 mL) and the washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The crude residue was purified by flash chromatography (silica gel, eluent: EtOAc:hexanes = 1:5 to 1:2) to afford b-hydroxyl amide SI-24 (1.46 g, 50%) as a yellow oil.
[0862] TLC (EtOAc:hexanes = 1:4): Rf = 0.25 (UV, KMnO4).
[0863] 1H NMR (400 MHz, CDCl3) d 6.44 (dd, J = 13.5, 1.4 Hz, 1H), 6.28 (dd, J = 13.6, 5.6 Hz, 1H), 5.15 (ddd, J = 7.7, 6.2, 1.1 Hz, 1H), 4.72– 4.62 (m, 1H), 3.69 (dd, J = 17.7, 3.1 Hz, 1H), 3.54 (dd, J = 11.5, 7.9 Hz, 1H), 3.29 (dd, J = 17.7, 8.6 Hz, 1H), 3.06 (br s, 1H), 3.04 (dd, J = 11.4, 1.1 Hz, 1H), 2.45– 2.25 (m, 1H), 1.06 (d, J = 6.8 Hz, 3H), 0.98 (d, J = 6.9 Hz, 3H).
[0864] 13C NMR (100 MHz, CDCl3) d 203.0, 171.8, 137.7, 108.1, 71.3, 68.5, 44.6, 30.8, 30.7, 19.1, 17.8.
[0865] HRMS-ESI m/z calcd for C11H15BrNOS2+ [M - OH]+ 319.9773, found 319.9777. [0866] TBS ether SI-25
Figure imgf000280_0001
[0867] A 250-mL round-bottom flask charged with b-hydroxyl amide SI-24 (1.45 g, 4.29 mmol, 1 equiv) was evacuated and flushed with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. DCM (43 mL) was added followed by 2,6- lutidine (1.0 mL, 8.57 mmol, 2.0 equiv), resulting a yellow solution. The vessel was cooled to 0 °C by means of ice-water bath. TBSOTf (1.48 mL, 6.43 mmol, 1.2 equiv) was added dropwise over 10 min. After stirring for 30 min, the mixture was transferred to a separatory funnel and washed with water (2 × 100 mL) and brine (100 mL). The washed solution was dried (Na2SO4). The dried solution was filtrated and the filtrate was concentrated. The resulting crude residue was purified by flash chromatography (silica gel, eluent:
EtOAc:hexanes = 1:20) to afford TBS ether SI-25 (1.79 g, 92%) as a light yellow oil.
[0868] TLC (EtOAc:hexanes = 1:50): Rf = 0.20 (UV, KMnO4).
[0869] 1H NMR (400 MHz, CDCl3) d 6.38– 6.23 (m, 2H), 5.04 (ddd, J = 7.7, 6.3, 1.1 Hz, 1H), 4.73 (ddd, J = 7.7, 5.9, 4.6 Hz, 1H), 3.61 (dd, J = 16.8, 7.8 Hz, 1H), 3.48 (dd, J = 11.5, 7.8 Hz, 1H), 3.26 (dd, J = 16.8, 4.6 Hz, 1H), 3.03 (dd, J = 11.5, 1.1 Hz, 1H), 2.42– 2.28 (m, 1H), 1.06 (d, J = 6.8 Hz, 3H), 0.97 (d, J = 6.9 Hz, 3H), 0.86 (s, 9H), 0.05 (s, 6H).
[0870] 13C NMR (100 MHz, CDCl3) d 202.8, 170.5, 139.5, 107.1, 71.6, 70.0, 45.8, 30.8, 30.7, 25.7, 19.1, 18.0, 17.8, -4.5, -5.0.
[0871] HRMS-ESI m/z calcd for C17H30BrNNaO2S2Si+ [M + Na]+ 474.0563, found 474.0569.
[0872] Acid SI-26
Figure imgf000281_0001
[0873] A 100-mL round-bottom flask charged with 18 (0.34 g, 1.68 mmol, 2.0 equiv) was evacuated and flushed with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. THF (17 mL) was added, resulting in a light yellow solution and the vessel and its contents were cooled to -78 °C in a dry ice-acetone bath. A solution of n- BuLi in hexanes (2.5 M, 1.34 mL, 3.36 mmol, 4.0 equiv) was added dropwise over 15 min, resulting in a deep red solution. After 30 min, a solution of SI-25 (0.38 g, 0.84 mmol, 1 equiv) in THF (5.0 mL) was added over 30 min by syringe pump. After an additional 30 min, water (100 mL) was added, followed by 1 M aqueous KHSO4 solution (5 mL). The system was allowed to warm to 23 °C while the mixture was rapidly stirred. The biphasic mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with EtOAc (2 × 40 mL). The combined organic layers were washed with water (2 × 70 mL) and brine (70 mL) and the washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The resulting crude residue was purified by flash chromatography (silica gel, eluent: AcOH:EtOAc:hexanes = 0.5:50:50) to afford carboxylic acid SI-26 (0.33 g, 80%) as a yellow solid.
[0874] TLC (MeOH:DCM = 1:20): Rf = 0.20 (UV, KMnO4).
[0875] 1H NMR (400 MHz, CDCI3) d 9.38 (s, 1H), 6.31 (dd, J = 13.5, 1.0 Hz, 1H), 6.19 (dd, J = 13.6, 6.3 Hz, 1H), 4.64 (dddd, J = 7.5, 6.1, 4.9, 1.1 Hz, 1H), 4.15 (d, J = 17.0 Hz, 1H), 4.06 (d, J = 17.0 Hz, 1H), 2.84 (dd, J = 15.9, 7.6 Hz, 1H), 2.64 (dd, J = 15.9, 4.9 Hz, 1H), 0.86 (s, 9H), 0.37 (s, 9H), 0.04 (s, 6H).
[0876] 13C NMR (100 MHz, CDCl3) d 200.4, 165.3, 165.2, 161.0, 140.8, 139.1, 107.3, 69.5, 49.9, 43.5, 25.7, 18.0, -2.2, -4.6, -5.1.
[0877] HRMS-ESI m/z calcd for C19H32BrNNaO5Si2+ [M + Na]+ 512.0895, found
512.0920 [0878] Stille Couplingo precursor SI-27
Figure imgf000282_0001
[0879] An oven-dried 50-mL round-bottom flask was charged with iPr2EtN (0.11 mL, 0.64 mmol, 2.0 equiv), amine 13 (0.19 g, 0.32 mmol, 1 equiv) and acid SI-26 (0.17 g, 0.33 mmol, 1.1 equiv). DCM (6.5 mL) was added, resulting in a colorless solution. HATU (0.15 g, 0.40 mmol, 1.25 equiv) was added in one portion at 23 °C. After 5 h, the mixture was diluted with DCM (30 mL). The resulting solution was transferred to a separatory funnel and was washed with water (2 × 25 mL) and brine (25 mL). The washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The resulting crude residue was purified by flash chromatography (silica gel, eluent: EtOAc:hexanes = 1:3) to afford Stille Coupling precursor SI-27 (0.26 g, 76%) as a light yellow oil.
[0880] TLC (EtOAc:hexanes = 1:2): Rf = 0.30 (UV, KMnO4).
[0881] 1H NMR (400 MHz, CDCl3, mixtures of rotamers) d 6.76– 6.56 (m, 1H), 6.35– 6.25 (m, 1H), 6.25– 6.16 (m, 1H), 6.11 (dq, J = 19.0, 1.5 Hz, 1H), 5.96 (dt, J = 19.1, 5.1 Hz, 1H), 5.87– 5.72 (m, 1H), 5.72– 5.55 (m, 1H), 4.80 (t, J = 6.2 Hz, 0.6H), 4.73 (t, J = 6.2 Hz, 0.4H), 4.66– 4.46 (m, 2H), 4.15– 3.64 (m, 6H), 2.88– 2.74 (m, 1H), 2.71– 2.40 (m, 2H), 2.33– 2.15 (m, 1H), 2.10– 1.82 (m, 4H), 1.57– 1.37 (m, 6H), 1.35– 1.32 (m, 6H), 1.07– 0.92 (m, 6H), 0.92– 0.77 (m, 27H), 0.37– 0.27 (m, 9H), 0.07– 0.01 (m, 6H).
[0882] 13C NMR (100 MHz, CDCI3, mixtures of rotamers) d 201.0, 200.5, 172.34, 172.32, 165.4, 165.1, 163.2, 162.5, 161.5, 161.4, 159.01, 158.97, 145.37, 145.26, 145.22, 145.13, 143.4, 143.3, 139.23, 139.20, 130.4, 130.2, 123.9, 123.8, 107.3, 80.8, 80.4, 69.6, 69.5, 60.5, 59.9, 49.8, 48.8, 47.1, 44.9, 44.9, 44.1, 43.8, 38.4, 38.1, 31.6, 29.9, 29.8, 29.1, 29.0, 28.9, 27.2, 25.73, 25.68, 25.2, 21.5, 19.7, 19.5, 18.0, 17.0, 16.9, 14.9, 14.6, 13.7, 9.4, -1.74, -1.77, - 1.79, -4.6, -5.10, -5.13. [0883] HRMS-ESI m/z calcd for C48H85BrN3O7Si2Sn+ [M + H]+ 1070.4126, found 1070.4136.
[0884] Stille Coupling product SI-28
Figure imgf000283_0001
[0885] An oven-dried 100-mL round-bottom flask was charged with JackiePhos (15 mg, 19 µmol, 0.2 equiv), Stille Coupling precursor SI-27 (100 mg, 94 µmol, 1 equiv) and Pd2(dba)3 (9 mg, 9 µmol, 0.1 equiv). The vessel was evacuated and filled with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. Toluene (19 mL) was added, resulting in a red suspension. A stream of argon was passed through the solution for 30 min. The vessel and its contents were then heated in a 50 ºC oil bath. After 3 h, SI-27 was entirely consumed and the mixture was allowed to cool to 23 °C. The mixture was concentrated and the resulting crude residue was purified by flash cheomatography (silica gel, eluent: EtOAc:hexanes = 1:3 to 1:1.5) to afford Stille Coupling product SI-28 (35 mg, 53%) as a white solid.
[0886] TLC (EtOAc:hexanes = 1:2.5): Rf = 0.30 (UV, p-anisaldehyde).
[0887] 1H NMR (400 MHz, CDCl3) d 6.45 (dd, J = 16.3, 4.6 Hz, 1H), 6.19– 6.03 (m, 2H), 5.99 (dd, J = 7.5, 3.6 Hz, 1H), 5.78 (dd, J = 16.3, 1.9 Hz, 1H), 5.72– 5.56 (m, 2H), 4.84– 4.70 (m, 3H), 4.26 (dt, J = 14.3, 6.5 Hz, 1H), 3.90 (d, J = 16.4 Hz, 1H), 3.85– 3.80 (m, 2H), 3.73 (d, J = 16.4 Hz, 1H), 3.56 (ddd, J = 15.2, 7.5, 3.5 Hz, 1H), 2.86 (dd, J = 16.3, 7.0 Hz, 1H), 2.78– 2.68 (m, 1H), 2.70 (dd, J = 16.3, 5.7 Hz, 1H), 2.20– 2.06 (m, 1H), 2.03– 1.77 (m, 4H), 1.08 (d, J = 6.8 Hz, 3H), 1.00 (d, J = 6.4 Hz, 3H), 0.95 (d, J = 6.8 Hz, 3H), 0.87 (s, 9H), 0.30 (s, 9H), 0.07 (s, 3H), 0.04 (s, 3H).
[0888] 13C NMR (100 MHz, CDCl3) d 201.0, 172.4, 166.7, 161.7, 161.6, 159.6, 145.2, 144.7, 135.5, 131.9, 129.0, 128.9, 123.8, 81.3, 69.0, 59.1, 50.8, 48.5, 43.341.1, 36.7, 29.4, 28.29, 25.8, 25.1, 19.8, 18.6, 18.1, 9.9, -1.8, -4.5, -5.0. [0889] HRMS-ESI m/z calcd for C36H58N3O7Si2 + [M + H]+ 700.3808, found 700.3816.
[0890] Analogue 24
Figure imgf000284_0001
[0891] An oven-dried 100-mL round-bottom flask charged with SI-28 (35 mg, 50 µmol, 1 equiv) was evacuated and filled with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. THF (1.0 mL) was added, resulting in a light yellow solution. In a separate flask, imidazole•HCl (52 mg, 0.50 mmol, 10.0 equiv) was added to a solution of tetrabutylammonium fluoride in THF (1 M, 0.50 mL, 0.50 mmol, 10.0 equiv). The resulting colorless solution was added dropwise to the solution of SI-28. After 12 h, the mixture was concentrated and the residue was dissolved in DCM (25 mL). The resulting solution was transferred to a separatory funnel and was washed with water (5 × 40 mL) and brine (40 mL). The washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The resulting crude residue was purified by flashed
chromatography (silica gel, eluent: MeOH:DCM = 1:40) to afford analogue 24 (22 mg, 86%) as a light yellow solid.
[0892] TLC (EtOAc:hexanes = 1:2.5): Rf = 0.30 (UV, p-anisaldehyde).
[0893] 1H NMR (400 MHz, CDCI3) d 8.14 (s, 1H), 6.48 (dd, J = 16.4, 4.8 Hz, 1H), 6.27– 6.15 (m, 1H), 6.15– 6.04 (m, 2H), 5.78 (dd, J = 16.4, 2.1 Hz, 1H), 5.73– 5.58 (m, 2H), 4.71 (ddd, J = 12.7, 9.3, 2.8 Hz, 2H), 4.60 (q, J = 6.3 Hz, 1H), 4.33 (ddd, J = 14.4, 8.1, 5.0 Hz, 1H), 4.10– 3.96 (m, 1H), 3.95– 3.85 (m, 1H), 3.84 (s, 2H), 3.48 (ddd, J = 15.0, 7.9, 3.5 Hz, 1H), 3.01 (dd, J = 16.8, 5.4 Hz, 1H), 2.91 (dd, J = 16.9, 5.7 Hz, 1H), 2.80– 2.71 (m, 1H), 2.68 (br s, 1H), 2.23– 2.10 (m, 1H), 2.01– 1.79 (m, 4H), 1.05 (d, J = 6.7 Hz, 3H), 0.99 (d, J = 6.3 Hz, 3H), 0.95 (d, J = 6.6 Hz, 3H).
[0894] 13C NMR (100 MHz, CDCI3) d 202.4, 171.7, 166.7, 160.1, 157.0, 144.6, 144.1, 137.2, 133.9, 131.6, 130.4, 130.1, 124.1, 81.6, 69.0, 59.6, 48.9, 48.6, 43.1, 40.9, 36.7, 29.4, 28.4, 25.1, 19.7, 18.7, 10.2 [0895] HRMS-ESI m/z calcd for C27H34N3O6 + [M– H2O]+ 496.2442, found 496.2454.
[0896] Scheme VI Synthesis of ananlogue 25
Figure imgf000285_0001
[0897] b-hydroxyl Amide SI-30
Figure imgf000286_0001
[0898] A 250-mL round-bottom flask charged with SI-29 (0.38 g, 1.61 mmol, 1.2 equiv) was evacuated and flushed with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. Dry DCM (8 mL) was added, resulting in a colorless solution and the vessel was cooled to 0 °C in a dry ice-water bath. A solution of n-Bu2BOTf in DCM (1 M, 1.88 mL, 1.88 mmol, 1.2 equiv) dropwise, resulting in a yellow solution. After 5 min, Et3N (0.28 mL, 2.01 mmol, 1.5 equiv) was added by syringe pump over 15 min, and the resulting colorless solution was stirred for 1 h at 0 °C. Then the flask was cooled to -78 °C and a solution of aldehyde 14 (0.20 g, 1.34 mmol, 1 equiv) in DCM (2 mL) was added via syringe pump over 30 min. After 3 h, the reaction mixture was cautiously quenched with pH = 7 buffer (10 mL), MeOH (20 mL) and 30% H2O2 (10 mL) maintaining the internal temperature between 0-5 °C. The resulting cloudy mixture was stirred for 1 h and was transferred to a separatory funnel, and the layers were separated. The aqueous layer was extracted with DCM (2 × 30 mL). The combined organic layers were washed with water (2 × 100 mL) and brine (100 mL) and the washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The crude residue was purified by flash chromatography (silica gel, eluent: EtOAc:hexanes = 1:5 to 1:2) to afford b-hydroxyl amide SI-30 (0.48 g, 94%, dr > 20:1) as a yellow oil.
[0899] TLC (EtOAc:hexanes = 1:4): Rf = 0.25 (UV, KMnO4).
[0900] 1H NMR (400 MHz, CDCl3) d 7.30– 7.17 (m, 3H), 7.15– 7.08 (m, 2H), 5.90 (dq, J = 8.9, 1.3 Hz, 1H), 4.61 (ddt, J = 9.4, 7.6, 3.2 Hz, 1H), 4.51 (dd, J = 8.9, 5.1 Hz, 1H), 4.17 (dd, J = 9.1, 7.6 Hz, 1H), 4.11 (dd, J = 9.1, 2.9 Hz, 1H), 3.84 (qd, J = 7.0, 5.0 Hz, 1H), 3.16 (dd, J = 13.4, 3.4 Hz, 1H), 2.72 (dd, J = 13.4, 9.4 Hz, 1H), 2.58 (br s, 1H), 2.24 (d, J = 1.4 Hz, 3H), 1.23 (d, J = 7.0 Hz, 3H).
[0901] 13C NMR (100 MHz, CDCl3) d 175.4, 153.1, 134.9, 131.4, 129.3, 128.9, 127.4, 124.6, 69.9, 66.2, 55.1, 42.8, 37.7, 24.2, 12.1.
[0902] Weinreb amide SI-31
Figure imgf000287_0001
[0903] A 250-mL round-bottom flask charged with HN(OMe)Me•HCl (0.84 g, 8.58 mmol, 4.0 equiv) was evacuated and flushed with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. Dry THF (43 mL) was added, resulting in a white suspension and the vessel was cooled to 0 °C in a dry ice-water bath. A solution of AlMe3 in heptane (2.0 M, 4.18 mL, 8.37 mmol, 3.9 equiv) was added dropwise. The reaction mixture was maintained at 0 °C for 30 min and then at room temperature for 90 min. The reaction mixture was cooled to -10 °C, and a solution of b-hydroxyl amide SI-30 (0.82 g, 2.15 mmol, 1 equiv) in THF (10 mL) was added by cannula. The temperature was increased to 0 °C, and the reaction mixture was stirred for 90 min. The reaction mixture was carefully quenched with 1.0 M HCl (30 mL) and diluted with DCM (50 mL) at 0 °C. After 1 h, the resulting mixture was transferred to a separatory funnel, and the layers were separated. The aqueous layer was extracted with DCM (2 × 30 mL). The combined organic layers were washed with water (2 × 100 mL) and brine (100 mL) and the washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The crude residue was used for next step without further purification.
[0904] The above crude residue was dissolved with DCM (22 mL) and was cooled to 0 °C in a ice-water bath. Then 2,6-lutidine (1.00 mL, 8.58 mmol, 4.0 equiv) was added, followed by TBSOTf (0.99 mL, 4.29 mmol, 2.0 equiv). After 15 min, the reaction mixture was diluted with DCM (50 mL). The solution was washed with cold KHSO4 (0.5 M; 20 mL), water (2 × 70 mL) and brine (70 mL) and the washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The crude residue was purified by flash chromatography (silica gel, eluent: EtOAc:hexanes = 1:40) to afford Weinreb amide SI-31 (0.71 g, 87%) as a yellow oil.
[0905] TLC (EtOAc:hexanes = 1:10): Rf = 0.25 (UV, KMnO4). [0906] 1H NMR (400 MHz, CDCl3) d 5.78 (dt, J = 9.3, 1.4 Hz, 1H), 4.34 (t, J = 9.1 Hz, 1H), 3.66 (s, 3H), 3.13 (s, 3H), 3.01 (br s, 1H), 2.23 (d, J = 1.3 Hz, 3H), 1.18 (d, J = 6.8 Hz, 3H), 0.87 (s, 9H), 0.05 (s, 3H), 0.03 (s, 3H).
[0907] 13C NMR (100 MHz, CDCl3) d 175.0, 134.3, 122.0, 72.1, 61.6, 42.1, 32.0, 25.7, 24.2, 18.1, 14.3, -4.4, -5.0.
[0908] Acid SI-32
Figure imgf000288_0001
[0909] A 100-mL round-bottom flask charged with 18 (0.52 g, 2.63 mmol, 2.0 equiv) was evacuated and flushed with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. THF (26 mL) was added, resulting in a light yellow solution and the vessel and its contents were cooled to -78 °C in a dry ice-acetone bath. A solution of n- BuLi in hexanes (2.5 M, 2.10 mL, 5.26 mmol, 4.0 equiv) was added dropwise over 15 min, resulting in a deep red solution. After 30 min, a solution of SI-31 (0.50 g, 1.31 mmol, 1 equiv) in THF (5.0 mL) was added over 30 min by syringe pump. After an additional 30 min, water (100 mL) was added, followed by 1 M aqueous KHSO4 solution (7 mL). The system was allowed to warm to 23 °C while the mixture was rapidly stirred. The biphasic mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with EtOAc (2 × 40 mL). The combined organic layers were washed with water (2 × 70 mL) and brine (70 mL) and the washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The resulting crude residue was purified by flash chromatography (silica gel, eluent: MeOH:DCM = 1:75) to afford carboxylic acid SI-32 (0.54 g, 79%) as a yellow solid.
[0910] TLC (MeOH:DCM = 1:20): Rf = 0.20 (UV, KMnO4).
[0911] 1H NMR (400 MHz, CDCl3) d 5.79 (dd, J = 9.4, 1.4 Hz, 1H), 4.44 (dd, J = 9.4, 6.8 Hz, 1H), 4.19 (d, J = 17.1 Hz, 1H), 4.14 (d, J = 17.1 Hz, 1H), 2.88 (p, J = 6.9 Hz, 1H), 2.23 (d, J = 1.4 Hz, 3H), 1.15 (d, J = 6.9 Hz, 3H), 0.88 (s, 10H), 0.38 (s, 9H), 0.06 (s, 3H), 0.04 (s, 3H).
[0912] 13C NMR (100 MHz, CDCI3) d 204.8, 165.3, 165.0, 161.3, 140.7, 133.0, 122.5, 71.5, 52.2, 43.0, 25.7, 24.1, 18.1, 12.5, -2.1, -4.4, -5.1.
[0913] HRMS-ESI m/z calcd for C21H37BrNO5Si2 + [M + H]+ 518.1388, found 518.1392.
[0914] Stille Coupling precursor SI-33
Figure imgf000289_0001
[0915] An oven-dried 50-mL round-bottom flask was charged with iPr2EtN (0.32 mL, 1.84 mmol, 2.0 equiv), amine 13 (0.55 g, 0.92 mmol, 1 equiv) and acid SI-32 (0.53 g, 1.01 mmol, 1.1 equiv). DCM (9.2 mL) was added, resulting in a colorless solution. HATU (0.44 g, 1.15 mmol, 1.25 equiv) was added in one portion at 23 °C. After 5 h, the mixture was diluted with DCM (50 mL). The resulting solution was transferred to a separatory funnel and was washed with water (2 × 50 mL) and brine (50 mL). The washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The resulting crude residue was purified by flash chromatography (silica gel, eluent: EtOAc:hexanes = 1:3) to afford Stille Coupling precursor SI-33 (0.72 g, 71%) as a light yellow oil.
[0916] TLC (EtOAc:hexanes = 1:2): Rf = 0.30 (UV, KMnO4).
[0917] 1H NMR (400 MHz, CDCl3, mixtures of rotamers) d 6.75– 6.55 (m, 1H), 6.16– 6.05 (m, 1H), 5.95 (dt, J = 19.1, 5.1 Hz, 1H), 5.87– 5.73 (m, 2H), 5.73– 5.58 (m, 1H), 4.84– 4.59 (m, 2H), 4.54– 4.34 (m, 1H), 4.13– 3.83 (m, 5H), 3.83– 3.61 (m, 1H), 2.84 (dp, J = 27.1, 6.9 Hz, 1H), 2.71– 2.44 (m, 1H), 2.43– 2.11 (m, 4H), 2.13– 1.82 (m, 3H), 1.60– 1.35 (m, 6H), 1.35– 1.23 (m, 6H), 1.23– 0.98 (m, 6H), 0.99– 0.75 (m, 30H), 0.39– 0.23 (m, 9H), 0.09– -0.04 (m, 6H). [0918] 13C NMR (100 MHz, CDCl3, mixtures of rotamers) d 205.3, 205.0, 172.37, 172.33, 165.43, 165.39, 165.1, 163.1, 162.4, 161.6, 161.5, 159.31, 159.29, 145.35, 145.30, 145.25, 145.15, 143.44, 143.42, 143.32, 132.92, 132.91, 130.4, 130.1, 123.9, 123.9, 122.56, 122.50, 80.7, 80.4, 71.61, 71.57, 60.4, 59.93, 59.89, 51.94, 51.89, 48.8, 47.0, 46.2, 44.89, 44.86, 43.52, 43.49, 38.4, 38.09, 38.05, 31.6, 29.93, 29.81, 29.0, 27.2, 25.70, 25.68, 24.05, 19.7, 19.5, 18.10, 18.04, 16.95, 16.92, 15.0, 14.6, 13.7, 12.6, 9.4, -1.76, -1.78, -4.4, -4.5, -5.11, - 5.16.
[0919] HRMS-ESI m/z calcd for C50H89BrN3O7Si2Sn+ [M + H]+ 1098.4439, found 1098.4455.
[0920] Stille Coupling product SI-34
Figure imgf000290_0001
[0921] An oven-dried 250-mL round-bottom flask was charged with JackiePhos (97 mg, 0.12 mmol, 0.2 equiv), Stille Coupling precursorSI-33 (0.67 g, 0.61 mmol, 1 equiv) and Pd2(dba)3 (56 mg, 61 mmol, 0.1 equiv). The vessel was evacuated and filled with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. Toluene (122 mL) was added, resulting in a red suspension. A stream of argon was passed through the solution for 30 min. The vessel and its contents were then heated in a 50 ºC oil bath. After 12 h, SI-33 was entirely consumed and the mixture was allowed to cool to 23 °C. The mixture was concentrated and the resulting crude residue was purified by flash chromatography (silica gel, eluent: EtOAc:hexanes = 1:3 to 1:1.5) to afford Stille Coupling product SI-34 (0.21 g, 46%) as a white solid.
[0922] TLC (EtOAc:hexanes = 1:2.5): Rf = 0.30 (UV, p-anisaldehyde).
[0923] 1H NMR (400 MHz, CDCl3) d 6.54 (dd, J = 9.5, 2.9 Hz, 1H), 6.49 (dd, J = 16.4, 3.8 Hz, 1H), 6.16 (d, J = 16.0 Hz, 1H), 5.78 (dd, J = 16.4, 2.1 Hz, 1H), 5.52 (ddd, J = 15.5, 10.0, 3.8 Hz, 1H), 5.35 (d, J = 8.9 Hz, 1H), 4.90 (dd, J = 8.9, 4.1 Hz, 1H), 4.82 (dd, J = 10.2, 1.8 Hz, 1H), 4.69– 4.56 (m, 1H), 4.41 (t, J = 9.2 Hz, 1H), 3.95 (d, J = 18.0 Hz, 1H), 3.87– 3.77 (m, 1H), 3.82 (d, J = 18.0 Hz, 1H), 3.48 (dt, J = 11.2, 7.0 Hz, 1H), 3.34 (ddd, J = 14.7, 10.0, 2.8 Hz, 1H), 2.83 (dd, J = 9.1, 6.8 Hz, 1H), 2.80– 2.70 (m, 1H), 2.14 (dq, J = 12.9, 8.3 Hz, 1H), 1.99– 1.86 (m, 2H), 1.86– 1.77 (m, 1H), 1.77– 1.66 (m, 1H), 1.57 (d, J = 1.2 Hz, 3H), 1.22 (d, J = 6.7 Hz, 3H), 1.08 (d, J = 6.9 Hz, 3H), 0.96 (d, J = 6.5 Hz, 3H), 0.93 (d, J = 6.7 Hz, 3H), 0.86 (s, 9H), 0.29 (s, 9H), 0.03 (s, 3H), -0.04 (s, 3H).
[0924] 13C NMR (100 MHz, CDCI3) d 206.0, 172.1, 166.6, 162.4, 160.0, 159.4, 145.0, 144.6, 136.2, 133.9, 133.1, 126.0, 123.4, 80.9, 70.7, 58.0, 52.8, 48.5, 43.9, 41.6, 36.7, 29.3, 28.2, 25.8, 25.7, 24.7, 19.9, 18.6, 18.1, 14.2, 12.7, 10.3, -1.8, -4.3, -5.0.
[0925] HRMS-ESI m/z calcd for C38H62N3O7Si2+ [M + H]+ 728.4121, found 728.4127.
[0926] Analogue 25
Figure imgf000291_0001
[0927] An oven-dried 100-mL round-bottom flask charged with Stille Coupling product SI- 34 (0.19 g, 0.26 mmol, 1 equiv) was evacuated and filled with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. THF (5.2 mL) was added, resulting in a light yellow solution. In a separate flask, imidazole•HCl (0.55 g, 5.22 mmol, 20.0 equiv) was added to a solution of tetrabutylammonium fluoride in THF (1 M, 5.2 mL, 5.22 mmol, 20.0 equiv). The resulting colorless solution was added dropwise to the solution of SI-34. After 24 h, the mixture was concentrated and the residue was dissolved in DCM (50 mL). The resulting solution was transferred to a separatory funnel and was washed with water (5 × 40 mL) and brine (40 mL). The washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The resulting crude residue was purified by flashed chromatography (silica gel, eluent: MeOH:DCM = 1:40) to afford analogue 25 (80 mg, 57%) as a light yellow solid.
[0928] TLC (MeOH:DCM = 1:20): Rf = 0.25 (UV, p-anisaldehyde). [0929] 1H NMR (400 MHz, CDCl3) d 7.94 (s, 1H), 6.85 (d, J = 8.6 Hz, 1H), 6.47 (dd, J = 16.4, 5.4 Hz, 1H), 6.09 (d, J = 15.7 Hz, 1H), 5.82 (dd, J = 16.4, 1.7 Hz, 1H), 5.69 (ddd, J = 15.6, 8.5, 4.7 Hz, 1H), 5.16 (d, J = 9.2 Hz, 1H), 4.74 (ddd, J = 11.3, 9.5, 2.9 Hz, 2H), 4.56 (t, J = 8.7 Hz, 1H), 4.48 (td, J = 9.0, 8.4, 4.0 Hz, 1H), 3.99 (d, J = 15.7 Hz, 1H), 3.92 (dt, J = 11.0, 7.0 Hz, 1H), 3.83– 3.73 (m, 1H), 3.75 (d, J = 15.7 Hz, 1H), 3.41 (ddd, J = 15.1, 8.6, 3.3 Hz, 1H), 2.97– 2.80 (m, 1H), 2.73 (dtd, J = 8.9, 7.0, 5.1 Hz, 1H), 2.30– 2.06 (m, 2H), 2.04– 1.81 (m, 4H), 1.70 (d, J = 1.2 Hz, 3H), 1.24 (d, J = 6.9 Hz, 3H), 1.01 (d, J = 6.9 Hz, 3H), 0.94 (d, J = 6.7 Hz, 6H).
[0930] 13C NMR (100 MHz, CDCI3) d 205.0, 171.6, 166.9, 160.8, 156.7, 144.1, 143.4, 136.8, 136.8, 136.2, 131.1, 125.9, 124.4, 81.4, 69.2, 59.7, 51.7, 48.5, 42.8, 40.8, 36.6, 29.5, 28.4, 25.0, 19.6, 18.9, 13.4, 12.8, 11.1.
[0931] HRMS-ESI m/z calcd for C29H39N3NaO7+ [M + Na]+ 564.2680, found 564.2678.
[0932] Scheme VII Synthesis of analogue 26 and its derived analogues
Figure imgf000293_0001
Figure imgf000294_0001
[0933] Acid SI-36
Figure imgf000294_0002
[0934] A 100-mL round-bottom flask charged with SI-35 (0.46 g, 2.15 mmol, 2.0 equiv) was evacuated and flushed with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. THF (20 mL) was added, resulting in a light yellow solution and the vessel and its contents were cooled to -78 °C in a dry ice-acetone bath. A solution of n-BuLi in hexanes (1.6 M, 2.70 mL, 4.30 mmol, 4.0 equiv) was added dropwise over 15 min, resulting in a deep red solution. After 30 min, a solution of 16 (0.50 g, 1.10 mmol, 1 equiv) in THF (5 mL) was added over 30 min by syringe pump. After an additional 30 min, water (30 mL) was added, followed by 1 M aqueous KHSO4 solution (6 mL). The system was allowed to warm to 23 °C while the mixture was rapidly stirred. The biphasic mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with EtOAc (2 × 30 mL). The combined organic layers were washed with water (2 × 50 mL) and brine (50 mL) and the washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The resulting crude residue was purified by flash chromatography (silica gel, eluent: AcOH:EtOAc:hexanes = 0.5:50:50) to afford carboxylic acid SI-36 (0.41 g, 73%) as a yellow solid.
[0935] TLC (MeOH:DCM = 1:25): Rf = 0.30 (UV, KMnO4).
[0936] 1H NMR (400 MHz, CDCI3) d 9.56 (br s, 1H), 5.82 (dd, J = 9.1, 1.4 Hz, 1H), 4.82 (ddd, J = 9.1, 8.0, 4.8 Hz, 1H), 4.36 (d, J = 18.2 Hz, 1H), 4.27 (d, J = 18.2 Hz, 1H), 2.89 (dd, J = 15.6, 8.0 Hz, 1H), 2.60 (dd, J = 15.6, 4.8 Hz, 1H), 2.28 (d, J = 1.3 Hz, 3H), 0.83 (s, 9H), 0.40 (s, 9H), 0.04 (s, 3H), 0.03 (s, 3H).
[0937] 13C NMR (100 MHz, CDCl3) d 202.2, 165.0, 164.3, 149.6, 146.8, 134.2, 121.8, 66.9, 50.1, 47.4, 25.7, 24.0, 18.0, -0.5, -4.5, -5.1.
[0938] HRMS-ESI m/z calcd for C20H33BrNO4SSi2– [M– H]– 518.0858, found 518.0868.
[0939] Stille Coupling precursor SI-37
Figure imgf000295_0001
[0940] An oven-dried 50-mL round-bottom flask was charged with iPr2EtN (0.51 mL, 2.85 mmol, 2.0 equiv), amine 13 (0.85 g, 1.42 mmol, 1 equiv) and acid SI-36 (0.82 g, 1.56 mmol, 1.1 equiv). DCM (14 mL) was added, resulting in a colorless solution. HATU (0.68 g, 1.78 mmol, 1.25 equiv) was added in one portion at 23 °C. After 5 h, the mixture was diluted with DCM (50 mL). The resulting solution was transferred to a separatory funnel and was washed with water (2 × 50 mL) and brine (50 mL). The washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The resulting crude residue was purified by flash chromatography (silica gel, eluent: EtOAc:hexanes = 1:5) to afford Stille Coupling precursor SI-37 (1.42 g, 91%) as a light yellow oil.
[0941] TLC (EtOAc:hexanes = 1:5): Rf = 0.20 (UV, KMnO4).
[0942] 1H NMR (400 MHz, CDCI3, mixtures of rotamers) d 6.74– 6.55 (m, 1H), 6.10 (dt, J = 19.0, 1.5 Hz, 1H), 5.95 (dtd, J = 19.0, 5.0, 2.1 Hz, 1H), 5.89– 5.77 (m, 2H), 5.77– 5.59 (m, 1H), 4.87– 4.75 (m, 2H), 4.75– 4.58 (m, 1H), 4.21– 3.62 (m, 6H), 2.87 (ddd, J = 15.5, 8.0, 2.3 Hz, 1H), 2.73– 2.40 (m, 2H), 2.41– 2.14 (m, 5H), 2.12– 1.87 (m, 3H), 1.60– 1.35 (m, 6H), 1.35– 1.22 (m, 6H), 1.09– 0.92 (m, 6H), 0.92– 0.70 (m, 27H), 0.40– 0.28 (m, 9H), 0.08– -0.02 (m, 6H).
[0943] 13C NMR (100 MHz, CDCl3, mixtures of rotamers) d 202.4, 202.2, 172.5, 172.1, 172.0, 165.42, 165.37, 165.0, 163.1, 163.0, 162.9, 162.8, 161.7, 155.0, 154.3, 145.4, 145.2, 145.0, 143.4, 143.3, 142.7, 141.0, 135.2, 134.3, 134.3, 130.3, 130.2, 130.1, 124.0, 123.9, 121.7, 80.7, 80.4, 67.9, 66.94, 66.86, 61.3, 59.8, 49.9, 49.8, 49.2, 48.03, 47.7, 47.4, 44.8, 38.4, 38.1, 31.7, 29.9, 29.8, 29.7, 29.0, 27.2, 25.7, 25.1, 24.00, 23.98, 23.89, 21.9, 19.7, 19.4, 18.0, 17.0, 16.8, 15.1, 14.5, 13.7, 9.4, 0.2, 0.1, -4.6, -5.1.
[0944] HRMS-ESI m/z calcd for C49H87BrN3O6SSi2Sn+ [M + H]+ 1100.4054, found 1100.4078.
[0945] Stille Coupling Product SI-38
Figure imgf000296_0001
[0946] An oven-dried 500-mL round-bottom flask was charged with JackiePhos (0.21 g, 0.26 mmol, 0.2 equiv), Stille Coupling precursor SI-37 (1.42 g, 1.29 mmol, 1 equiv) and Pd2(dba)3 (0.12 g, 1.13 mmol, 0.1 equiv). The vessel was evacuated and filled with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. Toluene (258 mL) was added, resulting in a red suspension. A stream of argon was passed through the solution for 30 min. The vessel and its contents were then heated in a 50 ºC oil bath. After 3 h, SI-37 was entirely consumed and the mixture was allowed to cool to 23 °C. The mixture was concentrated and the resulting crude residue was purified by flash chromatography (silica gel, eluent: EtOAc:hexanes = 1:3 to 1:1.5) to afford Stille Couping product SI-38 (0.58 g, 62%) as a white solid.
[0947] TLC (EtOAc:hexanes = 1:2.5): Rf = 0.30 (UV, p-anisaldehyde).
[0948] 1H NMR (400 MHz, CDCl3) d 6.49 (dd, J = 16.3, 4.1 Hz, 1H), 6.13 (d, J = 15.6 Hz, 1H), 6.00 (dd, J = 8.8, 2.9 Hz, 1H), 5.77 (dd, J = 16.3, 2.0 Hz, 1H), 5.55 (ddd, J = 15.5, 9.5, 4.3 Hz, 1H), 5.39 (d, J = 9.0 Hz, 1H), 4.97 (ddd, J = 9.0, 7.8, 5.3 Hz, 1H), 4.77 (ddd, J = 8.7, 6.6, 2.9 Hz, 2H), 4.48 (ddd, J = 13.4, 8.9, 4.1 Hz, 1H), 4.10 (d, J = 17.2 Hz, 1H), 3.90 (d, J = 17.2 Hz, 1H), 3.68– 3.50 (m, 2H), 3.39 (ddd, J = 14.7, 9.5, 3.3 Hz, 1H), 2.89 (dd, J = 16.1, 7.8 Hz, 1H), 2.75 (dd, J = 16.0, 5.3 Hz, 1H), 2.79– 2.69 (m, 1H), 2.19– 2.05 (m, 2H), 1.99– 1.89 (m, 1H), 1.89– 1.68 (m, 2H), 1.64 (d, J = 1.2 Hz, 3H), 1.08 (d, J = 6.9 Hz, 3H), 1.00 (d, J = 6.4 Hz, 3H), 0.94 (d, J = 6.8 Hz, 3H), 0.84 (s, 9H), 0.31 (s, 9H), 0.03 (s, 3H), 0.00 (s, 3H).
[0949] 13C NMR (100 MHz, CDCl3) d 202.2, 172.2, 166.4, 163.3, 163.2, 155.4, 144.8, 140.1, 137.0, 134.7, 132.5, 124.7, 123.7, 80.9, 65.3, 58.8, 50.8, 48.8, 47.4, 41.3, 36.6, 29.3, 28.6, 25.7, 25.0, 19.9, 18.6, 18.0, 12.7, 9.7, -0.0, -4.5, -5.0.
[0950] HRMS-ESI m/z calcd for C37H60N3O6SSi2 + [M + H]+ 730.3736, found 730.3758.
[0951] Analogue 26
Figure imgf000297_0001
[0952] An oven-dried 100-mL round-bottom flask charged with SI-38 (0.30 g, 0.41 mmol, 1 equiv) was evacuated and filled with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. THF (4.1 mL) was added, resulting in a light yellow solution. In a separate flask, imidazole•HCl (0.43 g, 4.11 mmol, 10.0 equiv) was added to a solution of tetrabutylammonium fluoride in THF (1 M, 4.11 mL, 4.11 mmol, 10.0 equiv). The resulting colorless solution was added dropwise to the solution of SI-8. After 12 h, the mixture was concentrated and the residue was dissolved in DCM (50 mL). The resulting solution was transferred to a separatory funnel and was washed with water (3 × 50 mL) and brine (50 mL). The washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The resulting crude residue was purified by flashed
chromatography (silica gel, eluent: MeOH:DCM = 1:40) to afford analogue 26 (0.19 g, 84%) as a light yellow solid.
[0953] TLC (MeOH:DCM = 1:20): Rf = 0.30 (UV, p-anisaldehyde).
[0954] 1H NMR (400 MHz, CDCI3) d 7.91 (s, 1H), 6.53 (dd, J = 16.3, 4.7 Hz, 1H), 6.40 (dd, J = 8.4, 4.1 Hz, 1H), 6.12 (d, J = 15.6 Hz, 1H), 5.76 (dd, J = 16.2, 1.9 Hz, 1H), 5.61 (ddd, J = 15.6, 8.9, 4.4 Hz, 1H), 5.40 (d, J = 8.9 Hz, 1H), 4.91 (dt, J = 8.7, 6.1 Hz, 1H), 4.82 – 4.64 (m, 2H), 4.32 (ddd, J = 13.7, 8.5, 4.6 Hz, 1H), 3.98 (d, J = 2.3 Hz, 2H), 3.85 (dt, J = 10.9, 7.3 Hz, 1H), 3.71 (ddd, J = 11.1, 7.8, 4.9 Hz, 1H), 3.45 (ddd, J = 14.8, 9.0, 4.0 Hz, 1H), 3.05 (dd, J = 16.8, 6.6 Hz, 2H), 2.82 (dd, J = 16.8, 5.7 Hz, 1H), 2.73 (ddq, J = 6.9, 4.4, 2.3 Hz, 1H), 2.14 (dtd, J = 13.2, 9.4, 7.4 Hz, 1H), 1.99– 1.71 (m, 4H), 1.68 (d, J = 1.2 Hz, 3H), 1.05 (d, J = 6.8 Hz, 3H), 0.98 (d, J = 6.5 Hz, 3H), 0.94 (d, J = 6.7 Hz, 3H).
[0955] 13C NMR (100 MHz, CDCl3) d 203.5, 171.7, 166.4, 161.4, 160.6, 150.6, 144.9, 136.5, 134.4, 132.7, 126.1, 125.2, 123.9, 81.2, 64.7, 59.6, 49.4, 49.1, 47.5, 40.9, 36.57, 29.4, 28.5, 25.1, 19.7, 18.6, 12.7, 10.2.
[0956] HRMS-ESI m/z calcd for C28H38N3O6S+ [M + H]+ 544.2476, found 544.2480.
[0957] Analogue SI-39
Figure imgf000298_0001
[0958] An oven-dried 50-mL round-bottom flask charged with MgSO4 (60 mg, 0.50 mmol, 10.0 equiv), NH4OAc (19 mg, 0.25 mmol, 5.0 equiv) and NaBH3CN (7.5 mg, 0.12 mmol, 2.4 equiv) was evacuated and filled with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. MeOH (5 mL) was added and the resulting suspension. After stirring for 30 min, a solution of compound 26 (27 mg, 50 µmol, 1 equiv) in MeOH (1 mL) was added at 23 °C. After 20 h, the reaction mixture is filtered on Celite and the Celite washed with MeOH (10 mL). The filtrate is concentrated under reduced pressure to give a oil. The residue was purified by prepared HPLC to afford analogue S-39 TFA salt (10 mg, 31%) as a white solid.
[0959] 1H NMR (400 MHz, MeOD) d 8.12 (s, 1H), 6.83 (dd, J = 15.7, 4.4 Hz, 1H), 6.31 (dd, J = 15.5, 1.0 Hz, 1H), 5.88 (dd, J = 15.7, 2.0 Hz, 1H), 5.77– 5.66 (m, 1H), 5.50 (d, J = 8.6 Hz, 1H), 4.90– 4.80 (m, 1H), 4.82– 4.71 (m, 2H), 4.11 (dd, J = 14.3, 9.1 Hz, 1H), 3.92– 3.82(m, 2H), 3.77 (dt, J = 11.2, 7.6 Hz, 1H), 3.61– 3.48 (m, 2H), 3.37 (dd, J = 15.6, 6.9 Hz, 1H), 2.89– 2.77 (m, 1H), 2.45 (ddd, J = 14.7, 5.1, 3.1 Hz, 1H), 2.22– 2.07 (m, 1H), 2.03– 1.90 (m, 3H), 1.83 (d, J = 1.2 Hz, 3H), 1.81– 1.72 (m, 2H), 1.63– 1.50 (m, 1H), 1.14 (d, J = 6.8 Hz, 3H), 1.00 (d, J = 6.9 Hz, 3H), 0.97 (d, J = 6.5 Hz, 3H).
[0960] 13C NMR (100 MHz, MeOD) d 172.1, 167.5, 164.0, 163.0, 151.9, 148.34138.7, 136.3, 134.9, 128.0, 126.3, 124.2, 82.4, 67.0, 61.1, 50.98, 50.95, 41.3, 39.8, 38.0, 35.5, 30.7, 29.8, 26.4, 20.2, 18.8, 13.2, 9.6.
[0961] HRMS-ESI m/z calcd for C28H39N4O4S+ [M– OH]+ 527.2687, found 527.2708.
[0962] Analogue SI-40
Figure imgf000299_0001
[0963] An oven-dried 50-mL round-bottom flask charged with analogue 26 (27 mg, 50 µmol, 1 equiv) was evacuated and filled with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. THF (1 mL) and MeOH (4 mL) were added, resulting in a colorless solution that was cooled to -78 °C in a dry ice-acetone bath. A solution of Et2BOMe in THF (1.0 M, 60 µL, 60 µmol, 1.2 equiv) was added dropwise over 5 min at - 78 °C. After stirring for 30 min, NaBH4 (2.8 mg, 74 µmol, 1.5 equiv) was added in one portion at -78 °C. After stirring for additional 3 h, acetic acid (1 mL) and EtOAc (25 mL) were added and the system was allowed to warm to 23 °C while the mixture was rapidly stirred. The solution was transferred to a separatory funnel and was washed with saturated aqueous NaHCO3 solution (20 mL), water (3 × 40 mL) and brine (40 mL). The washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was
concentrated. The resulting crude residue was purified by flashed chromatography (silica gel, eluent: MeOH:DCM = 1:40 to 1:20) to afford analogue SI-40 (21 mg, 77%) as a white solid.
[0964] TLC (MeOH:DCM = 1:20): Rf = 0.30 (UV, KMnO4).
[0965] 1H NMR (400 MHz, CDCl3) d 8.06 (s, 1H), 6.52 (dd, J = 16.3, 4.3 Hz, 1H), 6.19 (d, J = 15.5 Hz, 1H), 5.93 (dd, J = 8.7, 3.9 Hz, 1H), 5.80 (dd, J = 16.3, 2.0 Hz, 1H), 5.65 (ddd, J = 15.5, 9.4, 4.1 Hz, 1H), 5.38 (d, J = 9.2 Hz, 1H), 4.95– 4.71 (m, 3H), 4.46 (ddd, J = 13.5, 8.6, 4.1 Hz, 1H), 4.33 (td, J = 8.1, 4.0 Hz, 1H), 4.07 (ddd, J = 12.5, 8.0, 4.5 Hz, 1H), 3.86 (dt, J = 11.1, 7.2 Hz, 1H), 3.44 (ddd, J = 14.2, 9.4, 3.8 Hz, 1H), 3.17 (dd, J = 16.3, 7.5 Hz, 1H), 3.04 (dd, J = 16.3, 3.7 Hz, 1H), 2.97 (br s, 1H), 2.83– 2.68 (m, 1H), 2.20– 2.05 (m, 2H), 2.05– 1.83 (m, 3H), 1.78 (s, 3H), 1.76– 1.60 (m, 2H), 1.10 (d, J = 6.9 Hz, 3H), 1.01 (d, J = 6.5 Hz, 3H), 0.95 (d, J = 6.7 Hz, 3H).
[0966] 13C NMR (100 MHz, CDCI3) d 171.8, 166.4, 166.3, 161.0, 149.7, 145.0, 136.6, 134.8, 134.0, 126.6, 125.2, 123.7, 81.0, 68.4, 66.9, 59.7, 49.3, 42.6, 41.4, 40.8, 36.6, 29.4, 28.4, 25.3, 19.9, 18.6, 13.0,10.0.
[0967] HRMS-ESI m/z calcd for C28H39N3NaO6S+ [M + Na]+ 568.2452, found 568.2473.
[0968] Analogue SI-41
Figure imgf000300_0001
[0969] An oven-dried 50-mL round-bottom flask charged with Me4N•BH(OAc)3 (0.12 g, 0.46 mmol, 5.0 equiv) was evacuated and flushed with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. Acetonitrile (5 mL) and acetic acid (5 mL) was added, and the resulting colorless solution was cooled to -10 °C by means of ice- acetone bath. A solution of 26 (50 mg, 0.093 mmol, 1 equiv) in acetonitrile (2.5 mL) was added dropwise (the syringe was rinsed with another 1 mL acetonitrile). The mixture was allowed to warm to 23 °C slowly. After stirring for 5 h, aqueous saturated NaHCO3 solution was added (CAUTION: Gas evolution!). EtOAc (50 mL) was added and the biphasic mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL) and the washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The crude residue was purified by flash chromatography (silica gel, eluent: MeOH: DCM = 1:30) to afford analogue SI-41 (45 mg, 90%) as a white solid.
[0970] TLC (MeOH:DCM = 1:20): Rf = 0.20 (UV, p-anisaldehyde).
[0971] 1H NMR (400 MHz, CDCI3) d 7.96 (s, 1H), 6.51 (dd, J = 16.2, 4.5 Hz, 1H), 6.20 (dd, J = 15.6, 1.1 Hz, 1H), 6.14 (dd, J = 8.6, 4.0 Hz, 1H), 5.76 (dd, J = 16.2, 2.0 Hz, 1H), 5.72– 5.66 (m, 1H), 5.66– 5.59 (m, 1H), 4.86 (dt, J = 9.6, 4.9 Hz, 1H), 4.77– 4.66 (m, 2H), 4.42– 4.28 (m, 2H), 4.04 (br s, 1H), 3.92– 3.72 (m, 2H), 3.44 (ddd, J = 14.0, 9.4, 4.1 Hz, 1H), 3.23– 3.02 (m, 3H), 2.74 (dqd, J = 7.4, 4.8, 2.6 Hz, 1H), 2.12 (dq, J = 13.2, 8.1, 7.3 Hz, 1H), 2.05– 1.86 (m, 4H), 1.85– 1.78 (m, 2H), 1.77 (d, J = 1.2 Hz, 3H), 1.07 (d, J = 6.8 Hz, 3H), 1.01 (d, J = 6.5 Hz, 3H), 0.94 (d, J = 6.8 Hz, 3H).
[0972] 13C NMR (100 MHz, CDCI3) d 172.0, 166.5, 166.1, 161.3, 150.3, 145.1, 137.3, 133.9, 133.4, 125.8, 125.0, 123.7, 81.3, 68.6, 66.7, 59.6, 49.2, 41.9, 41.1, 40.47, 36.7, 29.4, 28.5, 25.5, 19.8, 18.6, 12.8, 9.7.
[0973] HRMS-ESI m/z calcd for C28H39N3NaO6S+ [M + Na]+ 568.2452, found 568.2473.
[0974] Mono-TBS ether SI-42
Figure imgf000301_0001
[0975] To a solution of anti-diol SI-41 (45 mg, 82 mmol, 1 equiv) and DMAP (1 mg, 8 µmol, 0.1 equiv) in DCM (8 mL) was added iPr2NEt (0.22 mL, 1.20 mmol, 15.0 equiv) and TBS-Cl (0.19 g, 1.2 mmol, 15.0 equiv) at 23 °C. After stirring for 24 h. The reaction was concentrated under vacuum and the resulting residue was purified by flash chromatography (silica gel, eluent: acetone:hexanes = 1:4) to afford mono-TBS ether SI-42 (43 mg, 79 %) as a white solid.
[0976] TLC (acetone:hexanes = 1:2): Rf = 0.30 (UV, p-anisaldehyde).
[0977] 1H NMR (400 MHz, CDCI3) d 7.98 (s, 1H), 6.44 (dd, J = 16.4, 4.5 Hz, 1H), 6.18 (d, J = 15.6 Hz, 1H), 6.05 (dd, J = 9.3, 3.5 Hz, 1H), 5.76 (dd, J = 16.4, 2.0 Hz, 1H), 5.73– 5.62 (m, 2H), 4.93 (ddd, J = 9.4, 4.9, 2.8 Hz, 1H), 4.73– 4.64 (m, 2H), 4.55– 4.42 (m, 2H), 4.37 (br s, 1H), 3.84 (dt, J = 11.1, 6.6 Hz, 1H), 3.72 (dt, J = 11.5, 6.8 Hz, 1H), 3.32 (ddd, J = 13.9, 10.2, 3.5 Hz, 1H), 3.23 (dd, J = 16.0, 3.1 Hz, 1H), 3.06 (dd, J = 16.1, 8.8 Hz, 1H), 2.75 (ddt, J = 6.7, 4.3, 2.0 Hz, 1H), 2.13 (dtd, J = 16.4, 5.7, 4.7, 2.1 Hz, 1H), 1.96 (tt, J = 11.0, 4.7 Hz, 2H), 1.85– 1.75 (m, 4H), 1.72 (d, J = 1.2 Hz, 3H), 1.06 (d, J = 5.8 Hz, 3H), 1.04 (d, J = 5.4 Hz, 3H), 0.95 (d, J = 6.7 Hz, 3H), 0.89 (s, 9H), 0.08 (s, 3H), 0.03 (s, 3H).
[0978] 13C NMR (100 MHz, CDCl3) d 172.4, 167.1, 166.3, 161.3, 150.5, 144.4, 137.2, 133.6, 132.0, 125.7, 125.2, 123.9, 81.5, 69.2, 68.1, 59.8, 49.0, 43.3, 41.4, 40.7, 36.8, 29.4, 28.4, 25.8, 25.71, 19.9, 18.6, 17.92, 12.7, 9.37, -4.4, -5.3.
[0979] HRMS-ESI m/z calcd for C34H54N3O6SSi+ [M + H]+ 660.3497, found 660.3521.
[0980] Fluorine SI-43
Figure imgf000302_0001
[0981] An oven-dried 50-mL round-bottom flask charged with mono-TBS ether SI-42 (42 mg, 64 µmol, 1 equiv) was evacuated and flushed with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. DCM (5 mL) was added, and the resulting colorless solution was cooled to 0 °C by means of ice-water bath. DAST (21 mL, 0.16 mmol, 2.50 equiv) was added dropwise at 0 °C under nitrogen. The reaction was warmed to 23 °C and stirred for 3 h. The reaction mixture was quenched with aqueous saturated NaHCO3 solution, diluted with DCM (20 mL) and transferred to a separate funnel. The organic solution was washed with water and brine. The washed solution was dried with Na2SO4 and the dried solution was concentrated under vacuum. The residue was purified by flash chromatography (silica gel, eluent: acetone:hexanes = 1:5) to afford fluorine SI-43 (40 mg, 95%) as a white solid.
[0982] TLC (acetone:hexanes = 1:2.5): Rf = 0.30 (UV, p-anisaldehyde).
[0983] 1H NMR (400 MHz, CDCI3) d 7.92 (s, 1H), 6.49 (dd, J = 16.4, 4.1 Hz, 1H), 6.21 (dd, J = 15.5, 1.4 Hz, 1H), 5.91 (dd, J = 9.4, 3.2 Hz, 1H), 5.80 (dd, J = 16.4, 2.0 Hz, 1H), 5.61 (ddd, J = 15.5, 9.6, 4.0 Hz, 1H), 5.34 (d, J = 9.2 Hz, 1H), 5.20 (dtt, J = 49.7, 11.6, 3.0 Hz, 1H), 4.85– 4.70 (m, 3H), 4.59 (ddd, J = 13.4, 8.4, 3.3 Hz, 1H), 4.06 (dt, J = 11.7, 6.9 Hz, 1H), 3.76 (dt, J = 11.7, 6.4 Hz, 1H), 3.45– 3.24 (m, 2H), 3.04 (ddd, J = 30.6, 16.5, 3.5 Hz, 1H), 2.75 (ddt, J = 7.2, 5.0, 2.4 Hz, 1H), 2.15 (dtd, J = 13.6, 6.7, 3.8 Hz, 2H), 2.03– 1.77 (m, 5H), 1.73 (s, 3H), 1.09 (d, J = 6.9 Hz, 3H), 1.01 (d, J = 6.4 Hz, 3H), 0.94 (d, J = 6.7 Hz, 3H), 0.87 (s, 9H), 0.05 (s, 3H), 0.02 (s, 3H).
[0984] 13C NMR (100 MHz, CDCl3) d 172.2, 166.5, 164.1 (d, 3JCF = 3.5 Hz), 161.5, 150.1, 144.6, 137.0, 134.9, 133.4, 124.9, 124.7, 123.9, 89.9 (d, 1JCF = 169.5 Hz), 80.8, 66.4, 59.1, 49.3, 43.6 (d, 2JCF = 20.0 Hz), 41.5, 38.7 (d, 2JCF = 22.8 Hz), 36.6, 29.3, 28.5, 25.78, 25.75, 25.4, 19.9, 18.5, 18.1, 12.62, 12.60, 9.8, -4.4, -4.9.
[0985] HRMS-ESI m/z calcd for C34H53FN3O5SSi+ [M + H]+ 662.3454, found 662.3482.
[0986] Analogue 45
Figure imgf000303_0001
[0987] An oven-dried 100-mL round-bottom flask charged with SI-43 (20 mg, 30 µmol, 1 equiv) was evacuated and filled with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. THF (3 mL) was added, resulting in a light yellow solution. In a separate flask, imidazole•HCl (32 mg, 0.30 mmol, 10.0 equiv,) was added to a solution of tetrabutylammonium fluoride in THF (1 M, 0.30 mL, 0.30 mmol, 10.0 equiv). The resulting colorless solution was added dropwise to the above solution. After 12 h, the mixture was concentrated and the residue was dissolved in DCM (50 mL). The resulting solution was transferred to a separatory funnel and was washed with water (5 × 50 mL) and brine (50 mL). The washed solution was dried Na2SO4). The dried solution was filtered and the filtrate was concentrated. The resulting crude residue was purified by flashed chromatography (silica gel, eluent: MeOH:DCM = 1:100 to 1:50) to afford analogue 45 (16 mg, 97%) as a light yellow solid.
[0988] TLC (MeOH:DCM = 1:30): Rf = 0.20 (UV, p-anisaldehyde).
[0989] 1H NMR (400 MHz, CDCI3) d 7.95 (s, 1H), 6.51 (dd, J = 16.4, 4.2 Hz, 1H), 6.23 (d, J = 15.7 Hz, 1H), 5.96 (dd, J = 8.9, 3.5 Hz, 1H), 5.81 (dd, J = 16.3, 2.0 Hz, 1H), 5.68 (ddd, J = 15.9, 9.3, 4.1 Hz, 1H), 5.39 (d, J = 9.2 Hz, 1H), 5.34– 5.10 (m, 2JHF = 47.9, 1H), 4.88– 4.71 (m, 3H), 4.55 (ddd, J = 14.2, 9.0, 4.0 Hz, 1H), 4.06 (dt, J = 11.6, 6.4 Hz, 1H), 3.78 (dt, J = 11.6, 6.3 Hz, 1H), 3.52– 3.31 (m, 2H), 3.10 (ddd, J = 27.6, 16.4, 4.1 Hz, 1H), 2.82– 2.68 (m, 1H), 2.29– 2.09 (m, 2H), 2.00– 1.80 (m, 5H), 1.78 (s, 3H), 1.10 (d, J = 6.7 Hz, 3H), 1.02 (d, J = 6.3 Hz, 3H), 0.95 (d, J = 6.5 Hz, 3H).
[0990] 13C NMR (100 MHz, CDCI3) d 172.2, 166.5, 163.9 (d, 3JCF = 4.3 Hz), 161.5, 150.1, 144.8, 136.2, 135.8, 133.4, 125.48, 125.2, 123.8, 90.0 (d, 1JCF = 169.9 Hz), 80.9, 65.6, 59.2, 49.3, 42.1 (d, 2JCF = 20.6 Hz), 41.3, 38.5 (d, 2JCF = 22.8 Hz), 36.6, 29.4, 28.5, 25.4, 19.9, 18.5, 12.8, 9.8.
[0991] HRMS-ESI m/z calcd for C28H39FN3O5S+ [M + H]+ 548.2589, found 548.2593.
[0992] Scheme VIII Synthesis of Analogue 27
Figure imgf000305_0001
[0993] Acid SI-45
Figure imgf000305_0002
[0994] An oven-dried 100-mL round-bottom flask charged with acid SI-44 (0.21 g, 1.06 mmol, 2.0 equiv) was evacuated and flushed with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. THF (12 ml) was added, resulting in a light- yellow solution and the vessel and its contents were cooled to -78 o C in a dry ice-acetone bath. A solution of n-BuLi in hexanes (2.5 M, 0.85 mL, 2.13 mmol, 4.0 equiv) was added dropwise over 15 min, resulting in a deep red solution. After 30 min, a solution of 17 (0.20 g, 0.53 mmol, 1 equiv) in THF (2 mL) was added over 30 min by syringe pump. After an additional 30 min, water (40 mL) was added, followed by 1 M aqueous KHSO4 solution (2.5 mL). The system was allowed to warm to 23 °C while the mixture was rapidly stirred. The biphasic mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with EtOAc (2 × 30 mL). The combined organic layers were washed with water (2 × 150 mL) and brine (50 mL) and the washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The crude product is purified by flash chromatography (silica gel, eluent: DCM:MeOH=150:1 to 100:1) afford acid SI-45 (0.26 g, 98% yield).
[0995] TLC (DCM: MeOH = 5:1): Rf = 0.45 (UV).
[0996] 1H NMR (400 MHz, CDCI3) d 6.84 (s, 1H), 5.83 (dd, J = 9.1, 1.2 Hz, 1H), 4.83 (ddd, J = 9.0, 7.9, 4.9 Hz, 1H), 4.00 (d, J = 7.6 Hz, 2H), 2.90– 2.80 (m, 1H), 2.56 (dd, J = 16.0, 4.9 Hz, 1H), 2.30 (d, J = 1.1 Hz, 3H), 0.86 (d, J = 8.6 Hz, 9H), 0.31 (s, 9H), 0.07 (t, J = 3.5 Hz, 6H).
[0997] 13C NMR (100 MHz, CDCl3) d 200.74, 171.26, 163.64, 159.60, 134.19, 121.99, 112.12, 66.58, 49.97, 42.85, 25.73, 24.04, 18.02, -0.36, -4.55, -5.05.
[0998] HRMS-ESI m/z calcd for C20H33BrNO5Si2- [M - H]- 502.1086 found 502.1091.
[0999] Stille Coupling Precursor SI-46
Figure imgf000306_0001
[1000] A 25-mL round-bottom flask was charged with 13 (0.31 g, 0.52 mmol 2.6 equiv), iPr2EtN (0.18 mL, 1.03 mmol, 5.2 equiv) and acid SI-45 (0.10 g, 0.20 mmol, 1 equiv). DCM (5 mL) was added, resulting in a clear, colorless solution and HATU (0.24 g, 0.64 mmol, 3.2 equiv) was added to this solution in one portion at 23 °C. After stirring for 5 h, the mixture was diluted with DCM (30 mL). The solution was transferred to a separatory funnel and was washed with water (2 × 30 mL) and brine (30 mL). The washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The resulting crude residue was purified by flash chromatography (silica gel, eluent: EtOAc:hexanes = 1:6 to 1:4) to afford Stille Coupling precursor SI-46 (0.18 g, 84 %) as a light yellow foam. [1001] TLC (EtOAc:hexanes = 1:4): Rf = 0.3 (UV)
[1002] 1H NMR (400 MHz, CDCl3, mixtures of rotamers) d 6.70 (dt, J = 16.6, 8.4 Hz, 1H), 6.25– 6.04 (m, 1H), 5.98 (dt, J = 19.0, 5.0 Hz, 1H), 5.82 (ddd, J = 10.6, 9.2, 6.6 Hz, 2H), 5.68 (dt, J = 41.8, 5.6 Hz, 1H), 5.19 (dd, J = 8.5, 2.5 Hz, 1H), 4.90– 4.70 (m, 2H), 4.64 (dd, J = 8.6, 3.2 Hz, 1H), 4.09– 3.78 (m, 6H), 3.78– 3.67 (m, 1H), 2.80 (ddd, J = 15.8, 11.5, 7.8 Hz, 1H), 2.72– 2.58 (m, 1H), 2.51 (ddd, J = 15.8, 11.8, 4.9 Hz, 1H), 2.38– 2.25 (m, 4H), 2.25– 2.02 (m, 2H), 1.97 (ddd, J = 22.8, 12.9, 6.3 Hz, 2H), 1.80– 1.73 (m, 1H), 1.61– 1.40 (m, 7H), 1.31 (dq, J = 14.3, 7.1 Hz, 7H), 1.10– 0.75 (m, 35H), 0.28 (dd, J = 18.5, 6.7 Hz, 9H), 0.14– 0.02 (m, 6H).
[1003] 13C NMR (100 MHz, CDCI3, mixtures of rotamers) d 200.89, 171.72, 169.31, 169.24, 165.41, 165.15, 162.64, 162.47, 160.53, 145.25, 143.49, 143.37, 134.25, 130.41, 130.19, 124.06, 123.92, 121.90, 112.04, 111.36, 81.09, 80.82, 66.74, 66.59, 60.83, 59.53, 49.87, 49.74, 49.11, 47.25, 44.90, 42.78, 38.23, 38.10, 31.55, 29.93, 29.74, 29.39, 29.15, 29.05, 28.95, 27.27, 26.99, 25.73, 24.82, 24.03, 22.11, 19.51, 19.38, 18.01, 17.01, 16.63, 14.77, 14.61, 13.70, 11.09, 9.45, 7.73, -0.18, -0.29, -4.55, -5.06, -5.08.
[1004] HRMS-ESI m/z calcd for C49H87BrN3O7Si2Sn+ [M + H]+ 1084.4282 found
1084.4292.
[1005] Stille Coupling product SI-47
Figure imgf000307_0001
[1006] An oven-dried 100-mL round-bottom flask was charged with JackiePhos (13.2 mg, 16.6 µmol， 0.2 equiv), Pd2(dba)3 (7.6 mg, 8.3 µmol, 0.1 equiv) and Stille Coupling precursor SI-46 (90.0 mg, 83.0 µmol, 1 equiv). The vessel was evacuated and filled with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. Toluene (17 ml) was added, resulting in a red suspension. A stream of argon was passed through the solution for 30 min. The mixture was heated at 50o C by means of oil bath. After 15 h, TLC analysis (eluent: EtOAc:hexanes = 1:2) and the mixture was allowed to cool to 23 ºC. The mixture was concentrated and resulting crude residue was purified by flash chromatography (silica gel, eluent: EtOAc:hexanes =1:3 to 1:1.5) to afford SI-47 (19.2 mg, 32 %) as a light yellow solid.
[1007] TLC (EtOAc:hexanes = 1:2): Rf = 0.15 (UV)
[1008] 1H NMR (400 MHz, CDCI3) d 6.81 (d, J = 7.1 Hz, 1H), 6.67 (dd, J = 15.6, 8.2 Hz, 1H), 6.28 (d, J = 15.5 Hz, 1H), 5.92 (dd, J = 15.7, 0.9 Hz, 1H), 5.77– 5.65 (m, 1H), 5.52 (d, J = 9.3 Hz, 1H), 4.97– 4.83 (m, 2H), 4.61 (dd, J = 8.3, 5.5 Hz, 1H), 4.48– 4.38 (m, 1H), 4.05 (d, J = 17.4 Hz, 1H), 3.75– 3.61 (m, 2H), 3.60– 3.49 (m, 1H), 3.39 (dd, J = 13.3, 8.9 Hz, 1H), 2.98– 2.89 (m, 1H), 2.80 (dd, J = 11.9, 5.8 Hz, 1H), 2.63– 2.53 (m, 1H), 2.36 (dd, J = 15.0, 7.3 Hz, 1H), 2.14 (ddd, J = 16.1, 9.5, 4.6 Hz, 2H), 2.03– 1.91 (m, 2H), 1.73 (s, 1H), 1.56 (d, J = 15.1 Hz, 3H), 1.29– 1.24 (m, 1H), 1.15 (d, J = 7.3 Hz, 3H), 1.02– 0.82 (m, 21H), 0.33– 0.15 (m, 12H), 0.12– -0.04 (m, 9H).
[1009] 13C NMR (100 MHz, CDCl3) d 200.86, 170.43, 169.75, 166.02, 161.91, 161.55, 142.51, 138.14, 134.65, 132.37, 125.87, 125.19, 110.43, 82.30, 66.79, 60.39, 51.18, 49.00, 43.60, 41.90, 40.60, 29.53, 28.89, 25.74, 25.07, 20.85, 19.60, 18.10, 16.46, 13.20, -0.70, - 0.90, -4.49, -4.92.
[1010] HRMS-ESI m/z calcd for C37H59N3NaO7Si2+ [M + Na]+ 736.3784, found 736.3791.
[1011] Analogue 27
Figure imgf000308_0001
[1012] An oven-dried 25-mL round-bottom flask charged with SI-47 (60.0 mg, 84.0 µmol, 1 equiv) was evacuated and filled with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. THF (2.5 ml) was added, resulting in a light yellow solution. In a separate flask, imidazole•HCl (0.13 g, 1.30 mmol, 15.0 equiv) was added to a solution of tetrabutylammonium fluoride in THF (1 M, 1.30 mL, 1.30 mmol, 15.0 equiv). The resulting colorless solution was added dropwise to the solution of SI-47. After 7 d, the mixture was concentrated and the residue was dissolved in DCM (50 mL). The resulting solution was transferred to a separatory funnel and was washed with water (50 × 5 mL) and brine (50 mL). The washed solution was dried in Na2SO4 anhydrous. The dried solution was filtered and the filtrate was concentrated. The crude product is purified by prepared TLC plate (eluent: MeOH:DCM = 1:25) to afford analogue 27 (25 mg, 56 %). [1013] TLC (MeOH:DCM = 1:20): Rf = 0.40 (UV)。 [1014] 1H NMR (400 MHz, CDCI3) d 7.34 (dd, J = 8.8, 3.6 Hz, 1H), 6.18 (dd, J = 16.4, 8.1 Hz, 1H), 6.13 (d, J = 15.2 Hz, 1H), 5.90– 5.72 (m, 2H), 5.19 (d, J = 8.9 Hz, 1H), 4.97 (td, J = 8.7, 4.6 Hz, 1H), 4.75 (dd, J = 9.9, 2.4 Hz, 1H), 4.69 (dd, J = 8.8, 3.0 Hz, 1H), 4.48 (ddd, J = 13.9, 8.8, 5.0 Hz, 1H), 4.15– 3.95 (m, 2H), 3.92 (d, J = 16.0 Hz, 1H), 3.69 (d, J = 16.0 Hz, 1H), 3.33 (ddd, J = 13.4, 9.1, 3.6 Hz, 1H), 2.91 (dd, J = 15.3, 4.6 Hz, 1H), 2.81 (dd, J = 15.2, 8.6 Hz, 1H), 2.61– 2.51 (m, 1H), 2.48 (br s, 1H), 2.40– 2.20 (m, 1H), 2.17– 2.02 (m, 3H), 1.94– 1.83 (m, 1H), 1.78 (s, 3H), 0.92 (d, J = 6.8 Hz, 3H), 0.86 (d, J = 6.7 Hz, 3H), 0.86 (d, J = 6.7 Hz, 3H).
[1015] 13C NMR (100 MHz, CDCl3) d 201.6, 171.0, 166.8, 166.0, 159.3, 158.9, 142.8, 136.7, 136.1, 131.7, 127.1, 125.8, 104.1, 82.2, 65.1, 61.1, 49.5, 49.3, 41.9, 40.6, 36.9, 29.7, 29.1, 25.1, 19.4, 18.8, 13.3, 12.4.
[1016] HRMS-ESI m/z calcd for C28H37N3NaO7 + [M + Na]+ 550.2524, found 550.2515.
[1017] Scheme IX synthesis of analogue 28
Figure imgf000310_0001
[1019] An oven-dried 250-mL round-bottom flask charged with TBS ether SI-2 (3.00 g, 6.43mmol, 1 equiv) was evacuated and filled with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. DCM (65 ml) was added, resulting in a light yellow solution. After cooling to -78 °C, a solution of DIBAL-H in hexanes (1.0 M, 12.86 mL, 12.86 mmol, 2.0 equiv) dropwise over 10 min under nitrogen. After 1 h, the reaction was quenched with aqueous saturated solution of potassium sodium tartrate (50 mL) carefully. After stirring at 23 °C for 1h, the biphasic mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with DCM (2 × 30 mL). The combined organic layers were washed with water (2 × 100 mL) and brine (100 mL) and the washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The crude product is purified by flash chromatography (silica gel, eluent: EtOAc:hexanes = 1:15) to afford aldehyde SI-48 (1.87 g, 95%) as a colorless oil.
[1020] TLC (EtOAc:hexanes = 1:5): Rf = 0.4 (KMnO4).
[1021] 1H NMR (400 MHz, CDCI3) d 9.76 (t, J = 2.1 Hz, 1H), 5.88 (dq, J = 9.0, 1.3 Hz, 1H), 4.82 (ddd, J = 9.0, 7.7, 4.8 Hz, 1H), 2.69 (ddd, J = 16.1, 7.7, 2.3 Hz, 1H), 2.57– 2.47 (m, 1H), 2.30 (d, J = 1.3 Hz, 3H), 0.86 (s, 9H), 0.06 (s, 6H).
[1022] 13C NMR (100 MHz, CDCI3) d 200.4, 134.3, 121.6, 65.9, 51.2, 25.6, 24.0, 18.0, - 4.4, -5.1.
[1023] Keto ester SI-50
Figure imgf000311_0001
[1024] An oven-dried 250-mL round-bottom flask charged with activated zinc (2.80 g, 42.0 mmol, 20.0 equiv) was evacuated and filled with nitrogen (this process was repeated a total of 3 times) at 100 °C and was sealed with a rubber septum. THF (42 mL) was added, resulting in a grey suspension.1,2-dibromoethane (0.36 mL, 4.20 mmol, 2.0 equiv) is added and the mixture heated to reflux for 30 min. After cooling to 23 °C, TMSCl (0.27 mL, 2.10 mmol, 1 equiv) was added and stirred for another 15 min. After the reaction mixture was cooled to 0 °C, BF3•Et2O (0.52 mL, 4.20 mmol, 2.0 equiv) was added, followed by a solution of SI-48 (0.65 g, 2.10 mmol, 1 equiv) in THF (8 mL). Then a solution of iodide compound SI-49 in THF (8 mL) was added dropwise in 10 minutes. The mixture was sonicated for 5 min. The color of the upper liquid changes to deep green in seconds. After 1.5 h in 0 °C, TLC plate (EtOAc:hexanes = 1:2, Rf = 0.85) shows the aldehyde is totally consumed. The reaction mixture was quenched with saturated NH4Cl solution (30 mL) and the resulting biphasic solution was transferred to a separated funnel. The aqueous phase was extracted with EtOAc (2 × 50 ml). The combined organic phase was washed with water (100 mL) and brine (100 ml). The washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The crude product is purified by flash chromatography (silica gel, eluent: EtOAc:hexanes = 1:7 to 1:9) to afford Reformatsky product SI-54(1:1 mixture, 0.81 g, 83%) as a colorless oil.
[1025] An oven-dried 1000-mL round-bottom flask charged with Reformatsky product SI- 54 (0.81 g, 1.75 mmol, 1 equiv) was evacuated and filled with nitrogen (this process was repeated a total of 3 times) at 23 °C and was sealed with a rubber septum. DCM (480 mL) was added, resulting in a colorless solution. To this mixture was added a solution of Dess–Martin periodinane (3.71 g, 8.74 mmol, 5.0 equiv) in CH2Cl2 (120 mL). After stirring for 1 h, the reaction mixture was quenched with saturated aqueous Na2S2O3 solution (50 mL) and saturated aqueous NaHCO3 solution (50 mL). Then organic layer was washed with water (200 mL) and brine (200 ml). The washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The crude product is purified by flash chromatography (silica gel, eluent: eluent: EtOAc:hexanes = 1:7 to 1:9) afford keto ester SI- 50 (0.52 g, 65%) as a colorless oil.
[1026] TLC (EtOAc:hexanes = 1:3): Rf = 0.7 (UV).
[1027] 1H NMR (400 MHz, MeOD) d 5.87 (dd, J = 9.1, 1.3 Hz, 1H), 4.93– 4.88 (m, 1H), 4.48 (q, J = 7.1 Hz, 2H), 3.33 (dt, J = 3.2, 1.6 Hz, 1H), 2.97 (dd, J = 15.9, 7.9 Hz, 1H), 2.77 (dd, J = 15.9, 4.7 Hz, 1H), 2.32 (d, J = 1.3 Hz, 3H), 1.43 (t, J = 7.1 Hz, 3H), 0.88 (d, J = 11.9 Hz, 9H), 0.11– 0.04 (m, 6H).
[1028] 13C NMR (100 MHz, MeOD) d 199.76, 175.44, 161.90, 157.51, 134.20, 121.65, 67.72, 66.66, 62.51, 49.39, 24.85, 22.95, 17.49, 12.92, -5.75, -6.23.
[1029] Acid SI-51
Figure imgf000312_0001
[1030] An oven-dried 100-mL round-bottom flask equipped condenser was charged with ethyl ester SI-50 (0.13 g, 0.27 mmol, 1 equiv). The vessel was evacuated and filled with nitrogen (this process was repeated a total of 3 times) at 23 °C and sealed with a rubber septum. DCE (5.4 mL) was added, resulting in a colorless solution. To this mixture was added Me3SnOH (0.25 g, 1.36 mmol, 5.0 equiv). The reaction mixture was heated at 80 °C for 1 h. After cooling to 23 °C, the solvent was removed via rotavap and the resulting residue was dissolved with EtOAc (50 mL). Then the solution was washed with 0.1 N KHSO4 (30 mL), water (2 × 50 mL) and brine (50 mL). The washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The crude product is purified by flash chromatography (silica gel, eluent: EtOAC:hexanes =1:2.5) to afford acid SI-51 (27.0 mg, 23%) as a colorless oil which showed a mixture of keto-enol tautomers (2:1) in NMR spectra.
[1031] TLC (EtOAc:hexanes = 1:1): Rf = 0.3 (UV).
[1032] Keto-form.1H NMR (300 MHz, CDCl3) d 5.81 (d, J = 8.9 Hz, 1H), 4.84– 4.72 (m, 1H), 3.53 (s, 2H), 2.83 (dd, J = 15.7, 8.0 Hz, 1H), 2.56 (dd, J = 15.5, 4.7 Hz, 1H), 2.30 (s, 3H), 0.84 (s, 9H), 0.04 (s, 6H).
[1033] Enol-form.1H NMR (300 MHz, CDCl3) d 12.77 (s, 1H), 5.82 (d, J = 8.9 Hz, 1H), 4.98 (s, 1H), 4.71– 4.61 (m, 1H), 2.27 (s, 3H), 0.84 (s, 9H), 0.04 (s, 6H).
[1034] Stille Coupling precursor SI-52
Figure imgf000313_0001
[1035] A 25-mL round-bottom flask was charged with amine 13 (32.6 mg, 54.6 µmol, 1 equiv), acid SI-51 (26.0 mg, 60.0 µmol, 1.1 equiv) and iPr2EtN (19.7 µL, 0.11 mmol, 2.0 equiv). DCM (5 mL) was added, resulting in a colorless solution. HATU (25.9 mg, 68.2 µmol, 1.25 equiv) was added to this solution in one portion at 23 °C. After stirring for 5 h, the mixture was diluted with DCM (20 mL). The solution was transferred to a separatory funnel and was washed with water (2 × 20 mL) and brine (20 mL). The washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The resulting crude residue was purified by flash chromatography (silica gel, eluent: EtOAc:hexanes = 1:6 to 1:4) to Stille Coupling precursor SI-52 (27 mg, 57 %) as a light yellow foam.
[1036] TLC (EtOAc:hexanes = 1:3): Rf = 0.3 (UV).
[1037] 1H NMR (300 MHz, CDCl3, mixtures of rotamers) d 6.67 (dd, J = 15.5, 8.0 Hz, 1H), 6.16– 6.07 (m, 1H), 5.96 (dt, J = 19.0, 5.0 Hz, 1H), 5.90– 5.57 (m, 3H), 4.88– 4.73 (m, 2H), 4.53 (ddd, J = 10.1, 8.3, 3.2 Hz, 1H), 4.08– 3.87 (m, 2H), 3.62– 3.54 (m, 1H), 3.47 (dq, J = 13.0, 3.9, 3.3 Hz, 2H), 2.87 (dd, J = 16.2, 7.8 Hz, 1H), 2.70– 2.50 (m, 2H), 2.34– 2.15 (m, 4H), 2.12– 1.83 (m, 4H), 1.58– 1.42 (m, 6H), 1.37– 1.17 (m, 9H), 1.10– 1.00 (m, 3H), 1.00– 0.77 (m, 27H), 0.10– 0.00 (m, 6H).
[1038] Stille Coupling product SI-53
Figure imgf000314_0001
[1039] An oven-dried 10-mL round-bottom flask was charged with Jackiephos (4.1 mg, 5.1 µmol, 0.2 equiv), Pd2(dba)3 (2.4 mg, 2.6 µmol, 0.1 equiv) and stille Coupling precursor SI-52 (26 mg, 26 µmol, 1 equiv) . The vessel was evacuated and filled with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. Toluene (5.2 mL) was added, resulting in a red suspension. A stream of argon was passed through the solution for 30 min. The mixture was heated at 50 °C by means of oil bath. After 15 h, TLC analysis (eluent: EtOAc:hexanes = 1:1) and the mixture was allowed to cool to 23 ºC. The mixture was concentrated and resulting crude residue was purified by flash chromatography (silica gel, eluent: EtOAc:hexanes = 1:2 to to 1:1) to afford Stille Coupling product SI-53 (9.3 mg, 56%).
[1040] TLC (EtOAc:hexanes = 1:1): Rf = 0.15 (UV).
[1041] 1H NMR (300 MHz, CDCI3) d 6.56 (dd, J = 16.2, 5.6 Hz, 1H), 6.13 (d, J = 16.2 Hz, 1H), 5.97– 5.78 (m, 2H), 5.78– 5.58 (m, 2H), 4.99 (td, J = 10.2, 3.4 Hz, 1H), 4.83 (dd, J = 10.4, 2.3 Hz, 1H), 4.60 -4.40 (m, 2H), 3.55 (d, J = 18.9 Hz, 1H), 3.44– 3.18 (m, 4H), 3.12– 2.95 (m, 1H), 2.84– 2.68 (m, 1H), 2.58 (dd, J = 17.5, 3.4 Hz, 1H), 2.20– 1.70 (m, 5H), 1.82 (s, 3H), 1.08 (d, J = 6.7 Hz, 3H), 1.03 (d, J = 6.5 Hz, 3H), 0.98 (d, J = 6.7 Hz, 3H), 0.85 (s, 9H), 0.05 (s, 3H), 0.01 (s, 3H).
[1042] Analogue 28
Figure imgf000315_0001
[1043] An oven-dried 25-mL round-bottom flask charged with Stille Coupling product SI- 53 (9.3 mg, 14.5 µmol, 1 equiv) was evacuated and filled with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. THF (2 ml) was added, resulting in a light yellow solution. In a separate flask, imidazole•HCl (30 mg, 0.29 mmol, 20.0 equiv) was added to a solution of tetrabutylammonium fluoride in THF (1 M, 0.29 mL, 0.29 mmol, 20.0 equiv). The resulting colorless solution was added to the solution of SI-53 dropwise. After 72 h, the mixture was concentrated and the residue was dissolved in DCM (50 mL). The resulting solution was transferred to a separatory funnel and was washed with water (50 × 5 mL) and brine (50 mL). The washed solution was dried in Na2SO4 anhydrous. The dried solution was filtered and the filtrate was concentrated. The crude product is purified by prepared TLC plate (eluent: MeOH:DCM = 1:25) to afford analogue 28 (2.8 mg, 37%).
[1044] TLC (MeOH:DCM = 1:20): Rf = 0.40 (UV).
[1045] 1H NMR (300 MHz, CDCI3) d 6.57 (dd, J = 16.3, 5.6 Hz, 1H), 6.12 (dt, J = 15.7, 2.0 Hz, 1H), 5.98– 5.82 (m, 3H), 5.71 (dt, J = 16.2, 3.3 Hz, 1H), 4.98 (dd, J = 10.2, 6.9 Hz, 1H), 4.81 (dd, J = 10.4, 2.2 Hz, 1H), 4.61– 4.44 (m, 2H), 3.56 (d, J = 18.8 Hz, 1H), 3.43 (d, J = 12.6 Hz, 1H), 3.35 (d, J = 12.7 Hz, 1H), 3.28 (ddd, J = 10.7, 7.1, 4.1 Hz, 1H), 3.09 (td, J = 9.9, 8.7, 4.9 Hz, 1H), 3.01– 2.89 (m, 2H), 2.82– 2.67 (m, 1H), 2.73 (dd, J = 17.0, 3.4 Hz, 1H), 2.20– 2.03 (m, 1H), 2.03– 1.90 (m, 2H), 1.87 (d, J = 1.2 Hz, 3H), 1.84– 1.72 (m, 2H), 1.09 (d, J = 6.8 Hz, 3H), 1.02 (d, J = 6.5 Hz, 3H), 0.98 (d, J = 6.8 Hz, 3H). [1046] Scheme X General route to amino acid analogues 29-32
Figure imgf000316_0001
[1047] Scheme X-1 General Procedure A for preparation of primary amine SI-56a-d
Figure imgf000316_0002
[1048] An oven-dried 50-mL round-bottom flask was charged with vinyl stannane 11 (0.20 g, 0.40 mmol, 1 equiv), D-Fmoc-amino acid SI-55a-d (0.60 mmol, 1.5 equiv), and DMAP (10 mg, 80 mmol, 0.2 equiv). DCM (4 mL) was added, resulting in a colorless solution. DCC (0.13 g, 0.64 mmol, 1.6 equiv) was added in one portion by briefly removing the septum, resulting in a white suspension. After 5 h, the alcohol 11 was entirely consumed as indicated by TLC analysis (eluent: EtOAc:hexanes = 1:3) and diethyl amine (2 mL) was added. After an additional 3 h, the mixture was filtered through a pad of celite and the filter cake was washed with DCM (2 × 20 mL). The filtrate was concentrated and the crude residue was purified by flash chromatography (silica gel, eluent: NH4OH:MeOH:DCM = 0.2:1:100 to 0.2:1:50) to afford amine SI-56a-d as a light yellow oil.
[1049] Amine SI-56a
Figure imgf000317_0001
[1050] Prepared according to general procedure A from alcohol 11 (0.20 g, 0.40 mmol, 1 equiv), Fmoc-D-Trp(Boc)-OH (SI-55a, 0.32 g, 0.60 mmol, 1.5 equiv), DMAP (10 mg, 80 mmol, 0.2 equiv) and DCC (0.13 g, 0.64 mmol, 1.6 equiv). Amine SI-56a (0.28 g, 89%) was obtained as a light yellow oil.
[1051] TLC (MeOH:DCM = 1:20): Rf = 0.30 (UV).
[1052] 1H NMR (400 MHz, CDCl3) d 8.14 (d, J = 8.2 Hz, 1H), 7.60– 7.53 (m, 1H), 7.49 (s, 1H), 7.32 (ddd, J = 8.4, 7.2, 1.3 Hz, 1H), 7.29– 7.21 (m, 2H), 6.72 (dd, J = 15.4, 8.2 Hz, 1H), 6.12 (dt, J = 19.0, 1.5 Hz, 1H), 5.96 (dt, J = 19.0, 5.1 Hz, 1H), 5.79 (dd, J = 15.4, 1.1 Hz, 1H), 5.54 (t, J = 5.9 Hz, 1H), 4.86 (dd, J = 7.4, 4.7 Hz, 1H), 4.03– 3.95 (m, 2H), 3.87 (dd, J = 8.9, 4.8 Hz, 1H), 3.26 (dd, J = 14.5, 4.7 Hz, 1H), 2.86 (dd, J = 14.4, 8.9 Hz, 1H), 2.68– 2.58 (m, 1H), 1.99– 1.85 (m, 1H), 1.66 (s, 9H), 1.53– 1.43 (m, 6H), 1.35– 1.23 (m, 6H), 0.99 (d, J = 6.8 Hz, 3H), 0.95– 0.75 (m, 21H).
[1053] 13C NMR (100 MHz, CDCl3) d 174.7, 165.1, 149.6, 145.1, 143.3, 135.6, 130.6, 130.3, 124.5, 124.1, 124.0, 122.5, 118.9, 116.3, 115.4, 83.6, 80.7, 54.6, 44.9, 38.4, 30.9, 29.9, 29.0, 28.2, 27.2, 19.8, 16.5, 15.4, 13.7, 9.4.
[1054] HRMS-ESI m/z calcd for C40H66N3O5Sn+ [M + H]+ 788.4019, found 788.4017.
[1055] Amine SI-56b
Figure imgf000318_0001
[1056] Prepared according to general procedure A from alcohol 11 (0.20 g, 0.40 mmol, 1 equiv), Fmoc-D-Tyr(tBu)-OH (SI-55b, 0.28 g, 0.60 mmol, 1.5 equiv), DMAP (0.010 g, 0.080 mmol, 0.2 equiv) and DCC (0.13 g, 0.64 mmol, 1.6 equiv). Amine SI-56b (0.23 g, 79%) was obtained as a light yellow oil.
[1057] TLC (MeOH:DCM = 1:20): Rf = 0.30 (UV).
[1058] 1H NMR (400 MHz, CDCI3) d 7.12 (d, J = 8.4 Hz, 2H), 6.92 (d, J = 8.4 Hz, 2H), 6.69 (dd, J = 15.4, 8.2 Hz, 1H), 6.12 (d, J = 19.0 Hz, 1H), 5.96 (dt, J = 19.0, 5.1 Hz, 1H), 5.77 (dd, J = 15.3, 1.1 Hz, 1H), 5.62 (t, J = 5.3 Hz, 1H), 4.81 (dd, J = 7.2, 4.9 Hz, 1H), 3.98 (t, J = 4.8 Hz, 2H), 3.72 (dd, J = 8.2, 5.5 Hz, 1H), 3.10 (dd, J = 13.7, 5.5 Hz, 1H), 2.74 (dd, J = 13.7, 8.4 Hz, 1H), 2.66– 2.49 (m, 1H), 1.96– 1.82 (m, 1H), 1.56– 1.41 (m, 6H), 1.32 (s, 9H), 1.36– 1.22 (m, 6H), 0.96 (d, J = 6.7 Hz, 3H), 0.93– 0.78 (m, 21H).
[1059] 13C NMR (100 MHz, CDCl3) d 174.8, 165.2, 154.1, 145.0, 143.4, 132.2, 130.4, 129.7, 124.3, 123.9, 80.6, 78.4, 56.1, 44.9, 40.5, 38.4, 29.8, 29.0, 28.8, 27.2, 19.8, 16.5, 15.4, 13.7, 9.4.
[1060] HRMS-ESI m/z calcd for C37H64N2NaO4Sn+ [M + Na]+ 743.3780, found 743.3776.
[1061] Amine SI-56c
Figure imgf000319_0001
[1062] Prepared according to general procedure A from alcohol 11 (0.20 g, 0.40 mmol, 1 equiv), Fmoc-D-Phe-OH (SI-55c, 0.23 g, 0.60 mmol, 1.5 equiv), DMAP (0.010 g, 0.080 mmol, 0.2 equiv) and DCC (0.13 g, 0.64 mmol, 1.6 equiv). Amine SI-56c (0.21 g, 81%) was obtained as a light yellow oil.
[1063] TLC (MeOH:DCM = 1:20): Rf = 0.30 (UV).
[1064] 1H NMR (400 MHz, CDCI3) d 7.34– 7.27 (m, 2H), 7.25– 7.19 (m, 3H), 6.70 (dd, J = 15.4, 8.0 Hz, 1H), 6.12 (dt, J = 19.0, 1.5 Hz, 1H), 5.97 (dt, J = 19.0, 5.1 Hz, 1H), 5.81 (dd, J = 15.4, 1.2 Hz, 1H), 5.56 (t, J = 5.9 Hz, 1H), 4.83 (dd, J = 7.2, 4.9 Hz, 1H), 4.02– 3.95 (m, 2H), 3.75 (dd, J = 8.9, 5.0 Hz, 1H), 3.16 (dd, J = 13.6, 5.0 Hz, 1H), 2.76 (dd, J = 13.6, 8.9 Hz, 1H), 2.68– 2.56 (m, 1H), 1.98– 1.82 (m, 1H), 1.57 (br s, 2H), 1.55– 1.41 (m, 6H), 1.36 – 1.22 (m, 7.3 Hz, 6H), 0.98 (d, J = 6.8 Hz, 3H), 0.95– 0.77 (m, 21H).
[1065] 13C NMR (100 MHz, CDCl3) d 174.7, 165.2, 145.1, 143.3, 137.5, 130.5, 129.3, 128.6, 126.8, 123.9, 80.6, 56.1, 44.9, 41.2, 38.3, 29.9, 29.0, 27.2, 19.7, 16.6, 15.2, 13.7, 9.4.
[1066] HRMS-ESI m/z calcd for C33H57N2O3Sn+ [M + H]+ 649.3386, found 649.3378.
[1067] Amine SI-56d
Figure imgf000319_0002
[1068] Prepared according to general procedure A from alcohol 11 (0.20 g, 0.40 mmol, 1 equiv), Fmoc-D-Lys(Boc)-OH (SI-55d, 0.28 g, 0.60 mmol, 1.5 equiv), DMAP (0.010 g, 0.080 mmol, 0.2 equiv) and DCC (0.13 g, 0.64 mmol, 1.6 equiv). Amine SI-56d (0.27 g, 93%) was obtained as a light yellow oil.
[1069] TLC (MeOH:DCM = 1:20): Rf = 0.30 (UV).
[1070] 1H NMR (400 MHz, CDCI3) d 6.73 (dd, J = 15.2, 7.5 Hz, 1H), 6.09 (d, J = 19.0 Hz, 1H), 6.02– 5.88 (m, 2H), 5.84 (d, J = 15.4 Hz, 1H), 4.79 (q, J = 6.2 Hz, 2H), 3.97 (t, J = 5.4 Hz, 2H), 3.47 (s, 1H), 3.09 (q, J = 7.3, 6.7 Hz, 2H), 2.71– 2.55 (m, 1H), 1.97– 1.84 (m, 1H), 1.67– 1.34 (m, 21H), 1.35– 1.22 (m, 6H), 1.03 (d, J = 6.7 Hz, 3H), 0.97– 0.77 (m, 21H).
[1071] 13C NMR (100 MHz, CDCl3) d 175.7, 165.2, 156.1, 145.4, 143.5, 130.1, 123.8, 80.5, 79.0, 54.4, 44.9, 40.3, 38.0, 34.6, 29.8, 29.1, 29.0, 28.4, 27.2, 22.9, 19.6, 17.2, 14.3, 13.6, 9.4.
[1072] HRMS-ESI m/z calcd for C35H68N3O5Sn+ [M + H]+ 730.4175, found 730.4164. [1073] Scheme X-2 General Procedure B for preparation of Stille Coupling precursors SI- 57a-d
Figure imgf000320_0001
[1074] A 250-mL round-bottom flask was charged with amine Si-56a-d (1 equiv), iPr2EtN (2.0 equiv) and acid 19 (1.1 equiv). DCM (about 0.1 M) was added, resulting in a clear, colorless solution and HATU (1.25 equiv) was added to this solution in one portion at 23 °C. After stirring for 5 h, the mixture was diluted with DCM (50 mL). The solution was transferred to a separatory funnel and was washed with water (2 × 50 mL) and brine (50 mL). The washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The resulting crude residue was purified by flash chromatography (silica gel, eluent: EtOAc:hexanes = 1:6 to 1:4) to afford Stille Coupling precursor SI-57a-d as a light yellow foam. [1075] Stille Coupling Precursor SI-57a
Figure imgf000321_0001
[1076] Prepared according to general procedure B from amine SI-56a (0.28 g, 0.36 mmol, 1 equiv), acid 19 (0.20 g, 0.39 mmol, 1.1 equiv), iPr2EtN (0.12 mL, 0.71 mmol, 2.0 equiv) and HATU (0.17 g, 0.45 mmol, 1.25 equiv). Stille Coupling precursor SI-57a (0.35 g, 77%) was obtained as a light yellow oil.
[1077] TLC (EtOAc:hexanes = 1:3): Rf = 0.2 (UV).
[1078] 1H NMR (400 MHz, CDCI3) d 8.10 (d, J = 8.2 Hz, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.47 (s, 1H), 7.41 (d, J = 8.7 Hz, 1H), 7.29 (t, J = 7.7 Hz, 1H), 7.20 (t, J = 7.4 Hz, 1H), 6.66 (dd, J = 15.3, 8.1 Hz, 1H), 6.11 (dt, J = 19.0, 1.4 Hz, 1H), 5.96 (dt, J = 19.1, 5.0 Hz, 1H), 5.85– 5.78 (m, 1H), 5.78– 5.65 (m, 2H), 5.11 (dt, J = 8.9, 6.4 Hz, 1H), 4.86– 4.71 (m, 2H), 3.97 (t, J = 5.3 Hz, 2H), 3.88 (s, 2H), 3.32 (dd, J = 15.0, 6.1 Hz, 1H), 3.24 (dd, J = 14.8, 6.7 Hz, 1H), 2.80 (dd, J = 15.3, 8.2 Hz, 1H), 2.55– 2.43 (m, 2H), 2.27 (d, J = 1.3 Hz, 3H), 1.89– 1.76 (m, 1H), 1.64 (s, 9H), 1.56– 1.40 (m, 6H), 1.35– 1.20 (m, 6H), 0.99– 0.82 (m, 27H), 0.81 (d, J = 6.7 Hz, 3H), 0.77 (d, J = 6.7 Hz, 3H), 0.34 (s, 9H), 0.04 (s, 3H), 0.03 (s, 3H).
[1079] 13C NMR (100 MHz, CDCl3) d 200.7, 171.3, 165.3, 161.2, 161.1, 159.6, 149.5, 144.7, 143.5, 135.4, 134.2, 130.4, 130.3, 130.2, 124.5, 124.2, 124.1, 122.6, 121.8, 119.1, 115.2, 115.1, 83.5, 81.6, 67.0, 52.1, 49.6, 44.9, 44.1, 38.1, 29.7, 29.0, 28.2, 27.9, 27.3, 25.7, 24.0, 19.5, 18.0, 16.6, 14.9, 13.7, 9.4, -2.00, -4.6, -5.1.
[1080] HRMS-ESI m/z calcd for C48H72BrN4O9Si2+ [M– SnBu3 + H]+ 983.4016, found 983.4026.
[1081] Stille Coupling Precursor SI-57b
Figure imgf000322_0001
[1082] Prepared according to general procedure B from amine SI-56b (0.23 g, 0.32 mmol, 1 equiv), acid 19 (0.18 g, 0.35 mmol, 1.1 equiv), iPr2EtN (0.11 mL, 0.64 mmol, 2.0 equiv) and HATU (0.15 g, 0.40 mmol, 1.25 equiv). Stille Coupling precursor SI-57b (0.28 g, 73%) was obtained as a light yellow oil.
[1083] TLC (EtOAc:hexanes = 1:3): Rf = 0.2 (UV).
[1084] 1H NMR (400 MHz, CDCI3) d 7.30 (d, J = 8.9 Hz, 1H), 7.13 (d, J = 8.5 Hz, 2H), 6.89 (d, J = 8.4 Hz, 2H), 6.66 (dd, J = 15.4, 8.2 Hz, 1H), 6.12 (d, J = 19.0 Hz, 1H), 5.97 (dt, J = 19.0, 5.0 Hz, 1H), 5.90– 5.70 (m, 3H), 5.05– 4.95 (m, 1H), 4.83– 4.72 (m, 2H), 3.98 (t, J = 4.7 Hz, 2H), 3.91 (s, 2H), 3.17 (dd, J = 14.3, 6.5 Hz, 1H), 3.08 (dd, J = 14.0, 6.9 Hz, 1H), 2.83 (dd, J = 15.2, 8.2 Hz, 1H), 2.58– 2.48 (m, 2H), 2.28 (d, J = 1.3 Hz, 3H), 1.90 -1.75 (m, 1H), 1.56– 1.41 (m, 6H), 1.30 (s, 9H), 1.30– 1.22 (m, 6H), 0.92– 0.83 (m, 27H), 0.80 (d, J = 6.8 Hz, 3H), 0.78 (d, J = 6.7 Hz, 3H), 0.33 (s, 9H), 0.05 (s, 3H), 0.05 (s, 3H).
[1085] 13C NMR (100 MHz, CDCI3) d 200.8, 171.3, 165.3, 161.1, 160.9, 159.6, 154.2, 144.8, 143.5, 143.5, 134.2, 131.0, 130.2, 129.8, 124.3, 124.2, 121.8, 81.4, 78.4, 67.1, 52.9, 49.7, 44.9, 44.1, 38.1, 37.5, 29.8, 29.0, 28.8, 27.2, 25.7, 24.0, 19.6, 18.0, 16.6, 15.1, 13.7, 9.4, -2.0, -4.6, -5.1.
[1086] HRMS-ESI m/z calcd for C57H97BrN3O8Si2Sn+ [M + H]+ 1206.5014, found 1206.5034.
[1087] Stille Coupling Precursor SI-57c
Figure imgf000323_0001
[1088] Prepared according to general procedure B from amine SI-56c (0.18 g, 0.28 mmol, 1 equiv), acid 19 (0.16 g, 0.31 mmol, 1.1 equiv), iPr2EtN (0.10 mL, 0.56 mmol, 2.0 equiv) and HATU (0.13 g, 0.35 mmol, 1.25 equiv). Stille Coupling precursor SI-57c (0.285, 80%) was obtained as a light yellow oil.
[1089] TLC (EtOAc:hexanes = 1:3): Rf = 0.2 (UV).
[1090] 1H NMR (400 MHz, CDCI3) d 7.37– 7.16 (m, 6H), 6.67 (dd, J = 15.4, 8.0 Hz, 1H), 6.13 (dt, J = 19.0, 1.5 Hz, 1H), 5.97 (dt, J = 18.9, 5.0 Hz, 1H), 5.86– 5.74 (m, 3H), 5.08– 4.98 (m, 1H), 4.82– 4.74 (m, 2H), 3.99 (t, J = 5.2 Hz, 2H), 3.91 (s, 2H), 3.24 (dd, J = 14.1, 6.1 Hz, 1H), 3.11 (dd, J = 14.0, 7.4 Hz, 1H), 2.83 (dd, J = 15.2, 8.2 Hz, 1H), 2.62– 2.48 (m, 2H), 2.28 (d, J = 1.3 Hz, 3H), 1.91– 1.79 (m, 1H), 1.60– 1.36 (m, 6H), 1.36– 1.24 (m, 6H), 1.07– 0.73 (m, 33H), 0.33 (s, 9H), 0.053 (s, 6H), 0.050 (s, 6H).
[1091] 13C NMR (100 MHz, CDCI3) d 200.8, 171.2, 165.3, 161.1, 160.9, 159.6, 144.8, 143.5, 143.4, 136.0, 134.2, 130.2, 129.3, 128.5, 126.9, 124.2, 121.8, 81.4, 67.1, 52.8, 49.6, 44.9, 44.1, 38.1, 37.9, 29.8, 29.0, 27.2, 25.7, 24.0, 19.5, 18.0, 16.6, 14.8, 13.7, 9.4, -2.0, -4.6, -5.2.
[1092] HRMS-ESI m/z calcd for C53H89BrN3O7Si2Sn+ [M + H]+ 1134.4439, found 1134.4455. Stille Coupling Precursor SI-57d
Figure imgf000324_0001
[1093] Prepared according to general procedure B from amine SI-56d (0.27 g, 0.37 mmol, 1 equiv), acid 19 (0.21 g, 0.41 mmol, 1.1 equiv), iPr2EtN (0.13 mL, 0.74 mmol, 2.0 equiv) and HATU (0.18 g, 0.46 mmol, 1.25 equiv). Stille Coupling precursor SI-57d (0.39, 87%) was obtained as a light yellow oil.
[1094] TLC (EtOAc:hexanes = 1:3): Rf = 0.2 (UV).
[1095] 1H NMR (400 MHz, CDCl3) d 7.35 (d, J = 8.6 Hz, 1H), 6.75 (dd, J = 15.3, 7.4 Hz, 1H), 6.10 (dt, J = 18.9, 1.5 Hz, 1H), 6.05 (s, 1H), 5.96 (dt, J = 19.1, 5.1 Hz, 1H), 5.91– 5.76 (m, 2H), 4.91– 4.62 (m, 4H), 3.98 (t, J = 5.1 Hz, 2H), 3.93 (s, 2H), 3.18– 3.02 (m, 2H), 2.84 (dd, J = 15.3, 8.2 Hz, 1H), 2.71– 2.60 (m, 1H), 2.53 (dd, J = 15.3, 4.6 Hz, 1H), 2.28 (d, J = 1.3 Hz, 3H), 2.01– 1.84 (m, 2H), 1.84– 1.66 (m, 1H), 1.60– 1.36 (m, 19H), 1.34– 1.21 (m, 6H), 1.03 (d, J = 6.8 Hz, 3H), 0.99– 0.70 (m, 30H), 0.34 (s, 9H), 0.05 (s, 6H).
[1096] 13C NMR (100 MHz, CDCI3) d 200.8, 171.8, 165.2, 161.1, 161.0, 159.6, 156.1, 145.3, 143.6, 143.5, 134.2, 130.2, 124.0, 121.8, 81.3, 79.1, 67.0, 51.8, 49.7, 44.9, 44.1, 40.3, 37.8, 32.4, 29.8, 29.6, 29.0, 28.4, 27.2, 25.7, 24.0, 22.7, 19.5, 18.0, 17.3, 14.0, 13.7, 9.4, -2.0, -4.6, -5.1.
[1097] HRMS-ESI m/z calcd for C55H100BrN4O9Si2Sn+ [M + H]+ 1215.5229, found 1215.5249.
[1098] Scheme X-3 General Procedure C for preparation of Stille Coupling products SI- 58a-d
Figure imgf000325_0002
[1099] An oven-dried round-bottom flask was charged with Jackiephos (0.2 equiv), Pd2(dba)3 (0.1 equiv) and Stille Coupling precursor SI-57a-d (1 equiv). The vessel was evacuated and filled with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. Toluene (about 0.005 M) was added, resulting in a red suspension. A stream of argon was passed through the solution for 30 min. The mixture was heated at 50 °C by means of oil bath. After 3 - 12 h, SI-11 was entirely consumed by TLC analysis (eluent: EtOAc:hexanes = 1:2) and the mixture was allowed to cool to 23 ºC. The mixture was concentrated and resulting crude residue was purified by flash chromatography (silica gel, eluent: EtOAc:hexanes = 1:3 to 1:1.5) to afford Stille Coupling product SI-58a-d as a light yellow solid.
[1100] Stille Coupling product SI-58a
Figure imgf000325_0001
[1101] Prepared according to general procedure C from Jackiephos (44 mg, 55 mmol, 0.2 equiv), Pd2(dba)3 (25 mg, 28 mmol, 0.1 equiv) and Stille Couping precursor SI-57a (0.35 g, 0.28 mmol, 1 equiv). Stille Coupling product SI-58a (0.18, 71%) was obtained as a light yellow foam.
[1102] TLC (EtOAc:hexanes = 1:2): Rf = 0.2 (UV).
[1103] 1H NMR (400 MHz, CDCl3) d 8.09 (d, J = 8.2 Hz, 1H), 7.55– 7.37 (m, 3H), 7.27 (t, J = 7.4 Hz, 1H), 7.17 (d, J = 7.4 Hz, 1H), 6.45 (dd, J = 16.2, 5.5 Hz, 1H), 6.19 (d, J = 15.7 Hz, 1H), 5.87 (dd, J = 7.9, 4.0 Hz, 1H), 5.79 (dd, J = 16.2, 1.7 Hz, 1H), 5.60 (ddd, J = 15.7, 7.9, 3.7 Hz, 1H), 5.45 (d, J = 8.9 Hz, 1H), 5.13 (td, J = 8.7, 4.7 Hz, 1H), 4.93 (td, J = 8.7, 5.3 Hz, 1H), 4.76 (dd, J = 10.1, 1.9 Hz, 1H), 4.44– 4.30 (m, 1H), 3.88 (d, J = 17.4 Hz, 1H), 3.71 (d, J = 17.4 Hz, 1H), 3.64 (ddd, J = 11.6, 7.8, 3.9 Hz, 1H), 3.32 (dd, J = 15.2, 4.8 Hz, 1H), 2.93 (dt, J = 14.4, 8.8 Hz, 2H), 2.82 (dd, J = 14.4, 5.3 Hz, 1H), 2.78– 2.68 (m, 1H), 2.04– 1.92 (m, 1H), 1.63 (s, 9H), 1.63 (s, 3H), 1.03 (d, J = 6.8 Hz, 3H), 0.96 (d, J = 7.0 Hz, 2H), 0.94 (d, J = 6.7 Hz, 4H), 0.85 (s, 9H), 0.27 (s, 9H), 0.04 (s, 3H), 0.01 (s, 3H).
[1104] 13C NMR (100 MHz, CDCl3) d 201.1, 172.6, 166.7, 161.0, 160.5, 159.9, 149.5, 144.2, 143.4, 135.2, 133.6, 133.4, 130.3, 125.1, 124.5, 124.4, 123.7, 122.6, 118.9, 115.4, 115.2, 83.6, 83.3, 66.3, 51.4, 50.2, 43.9, 41.1, 37.0, 29.5, 29.0, 28.2, 25.8, 19.9, 18.7, 18.1, 13.0, 10.1, -2.1, -4.5, -5.0.
[1105] HRMS-ESI m/z calcd for C48H71N4O9Si2+ [M + H]+ 903.4754, found 903.4737.
[1106] Stille Coupling product SI-58b
Figure imgf000326_0001
[1107] Prepared according to general procedure C from Jackiephos (37 mg, 47 mmol, 0.2 equiv), Pd2(dba)3 (22 mg, 24 mmol, 0.1 equiv) and Stille Coupling precursor SI-57b (0.28 g, 0.24 mmol, 1 equiv). Stille Coupling product SI-58b (0.11, 54%) was obtained as a light yellow foam.
[1108] TLC (EtOAc:hexanes = 1:2): Rf = 0.2 (UV).
[1109] 1H NMR (400 MHz, CDCI3) d 7.33 (d, J = 8.9 Hz, 1H), 7.05 (d, J = 8.4 Hz, 2H), 6.84 (d, J = 8.4 Hz, 2H), 6.40 (dd, J = 16.2, 5.2 Hz, 1H), 6.20 (d, J = 15.8 Hz, 1H), 5.83 (dd, J = 8.1, 3.9 Hz, 1H), 5.78 (dd, J = 16.2, 1.8 Hz, 1H), 5.64 (ddd, J = 15.7, 8.2, 3.8 Hz, 1H), 5.45 (d, J = 8.9 Hz, 1H), 5.04 (td, J = 8.3, 5.1 Hz, 1H), 4.95 (td, J = 8.6, 5.6 Hz, 1H), 4.75 (dd, J = 10.2, 1.8 Hz, 1H), 4.47– 4.33 (m, 1H), 3.90 (d, J = 17.4 Hz, 1H), 3.73 (d, J = 17.4 Hz, 1H), 3.64 (ddd, J = 15.7, 8.2, 3.8 Hz, 1H), 3.23 (dd, J = 14.4, 5.2 Hz, 1H), 2.94– 2.67 (m, 4H), 2.03– 1.90 (m, 1H), 1.73 (d, J = 1.2 Hz, 3H), 1.28 (s, 9H), 1.04 (d, J = 6.8 Hz, 3H), 0.95 (d, J = 6.8 Hz, 3H), 0.92 (d, J = 6.5 Hz, 3H), 0.86 (s, 9H), 0.29 (s, 9H), 0.05 (s, 3H), 0.02 (s, 3H).
[1110] 13C NMR (100 MHz, CDCI3) d 201.3, 172.5, 166.6, 160.7, 160.4, 159.8, 154.2, 144.2, 143.4, 135.4, 133.6, 133.5, 130.7, 129.6, 125.3, 124.4, 124.1, 83.1, 78.3, 66.3, 52.1, 50.2, 44.0, 41.1, 38.0, 36.9, 29.5, 28.8, 25.8, 19.9, 18.7, 18.1, 13.0, 10.2, -2.1, -4.4, -5.0.
[1111] HRMS-ESI m/z calcd for C45H70N3O8Si2+ [M + H]+ 836.4696, found 836.4712.
[1112] Stille Coupling product SI-58c
Figure imgf000327_0001
[1113] Prepared according to general procedure C from Jackiephos (28 mg, 35 mmol, 0.2 equiv), Pd2(dba)3 (16 mg, 18 mmol, 0.1 equiv) and Stille Coupling precursor SI-57c (0.20 g, 0.18 mmol, 1 equiv). Stille Coupling product SI-58c (0.077, 57%) was obtained as a light yellow foam.
[1114] TLC (EtOAc:hexanes = 1:2): Rf = 0.2 (UV).
[1115] 1H NMR (400 MHz, CDCl3) d 7.30 (d, J = 8.9 Hz, 1H), 7.25– 7.15 (m, 3H), 7.12 (dd, J = 7.8, 1.7 Hz, 2H), 6.42 (dd, J = 16.3, 5.0 Hz, 1H), 6.18 (d, J = 15.6 Hz, 1H), 5.86– 5.74 (m, 2H), 5.52 (ddd, J = 15.2, 8.2, 3.5 Hz, 1H), 5.43 (d, J = 8.9 Hz, 1H), 5.06 (ddd, J = 9.0, 7.5, 5.2 Hz, 1H), 4.93 (td, J = 8.8, 5.3 Hz, 1H), 4.75 (dd, J = 10.2, 1.8 Hz, 1H), 4.52– 4.35 (m, 1H), 3.89 (d, J = 17.5 Hz, 1H), 3.73 (d, J = 17.6 Hz, 1H), 3.56 (ddd, J = 15.8, 8.4, 3.4 Hz, 1H), 3.29 (dd, J = 14.2, 5.3 Hz, 1H), 2.94– 2.68 (m, 4H), 2.06– 1.94 (m, 6.6 Hz, 1H), 1.67 (s, 3H), 1.08 (d, J = 6.9 Hz, 3H), 0.95 (d, J = 6.8 Hz, 3H), 0.93 (d, J = 6.4 Hz, 3H), 0.85 (s, 9H), 0.29 (s, 9H), 0.04 (s, 3H), 0.02 (s, 3H).
[1116] 13C NMR (100 MHz, CDCI3) d 201.4, 172.5, 166.7, 160.7, 160.5, 159.8, 144.1, 143.3, 135.7, 135.4, 133.6, 133.4, 129.3, 128.4, 126.9, 125.4, 124.5, 83.5, 66.4, 52.1, 50.2, 44.1, 41.1, 38.5, 36.8, 29.5, 25.7, 19.9, 18.7, 18.1, 13.1, 10.1, -2.1, -4.5, -5.0. [1117] HRMS-ESI m/z calcd for C41H61N3NaO7Si2 + [M + Na]+ 786.3940, found 786.3914.
[1118] Stille product SI-58d
Figure imgf000328_0001
[1119] Prepared according to general procedure C from Jackiephos (0.052 g, 0.065 mmol, 0.2 equiv), Pd2(dba)3 (0.030 g, 0.033 mmol, 0.1 equiv) and Stille precursor SI-57d (0.39 g, 0.33 mmol, 1 equiv). Stille coupling product SI-58d (0.17, 62%) was obtained as a light yellow foam.
[1120] TLC (EtOAc:hexanes = 1:2): Rf = 0.2 (UV).
[1121] 1H NMR (400 MHz, CDCI3) d 7.37 (d, J = 9.0 Hz, 1H), 6.65 (dd, J = 15.8, 4.5 Hz, 1H), 6.47 (s, 1H), 6.22 (d, J = 15.6 Hz, 1H), 5.86 (dd, J = 16.0, 1.9 Hz, 1H), 5.64– 5.51 (m, 1H), 5.47 (d, J = 9.0 Hz, 1H), 5.07– 4.90 (m, 2H), 4.82 (d, J = 10.2 Hz, 1H), 4.80– 4.70 (m, 1H), 4.25– 4.11 (m, 1H), 3.91 (d, J = 17.2 Hz, 1H), 3.86– 3.78 (m, 1H), 3.74 (d, J = 17.1 Hz, 1H), 3.10 (dt, J = 13.2, 6.6 Hz, 1H), 3.05– 2.91 (m, 2H), 2.85 (dd, J = 15.0, 5.6 Hz, 1H), 2.80– 2.67 (m, 1H), 2.25– 2.05 (m, 1H), 2.02– 1.84 (m, 2H), 1.68 (s, 3H), 1.65– 1.47 (m, 3H), 1.42 (s, 9H), 1.09 (d, J = 6.8 Hz, 3H), 0.95 (d, J = 6.8 Hz, 3H), 0.89 (d, J = 6.3 Hz, 3H), 0.85 (s, 9H), 0.34 (s, 9H), 0.03 (s, 3H), 0.01 (s, 3H).
[1122] 13C NMR (100 MHz, CDCI3) d 201.3, 172.2, 166.1, 160.9, 160.2, 159.9, 156.2, 145.4, 143.6, 135.4, 133.9, 133.0, 125.2, 124.0, 82.2, 79.1, 66.1, 50.9, 50.3, 43.9, 40.9, 40.3, 36.6, 32.6, 29.8, 29.5, 28.4, 25.8, 22.2, 19.8, 18.7, 18.1, 13.0, 10.0, -2.0, -4.5, -5.0.
[1123] HRMS-ESI m/z calcd for C43H72N4NaO9Si2+ [M + Na]+ 867.4730, found 867.4721.
[1124] Analogue 29
Figure imgf000329_0001
[1125] An oven-dried 25-mL sealed tube was charged with Stille Coupling product SI-58a (40 mg, 45 mmol, 1 equiv). The vessel was evacuated and filled with nitrogen (this process was repeated a total of 3 times) and o-chlorobenzene (4.5 mL) was added, resulting in a colorless solution. Then the sealed tube was sealed with a TFP cap quickly. The mixture was heated at 180 °C by means of oil bath for 2 h, SI-58a was entirely consumed by TLC analysis (eluent: EtOAc:hexanes = 1:2) and the mixture was allowed to cool to 23 ºC. The mixture was purified by flash chromatography (silica gel, eluent: EtOAc:hexanes = 1:2) to afford compound SI-59 (26 mg, 73%) as a white solid.
[1126] TLC (EtOAc:hexanes = 1:2): Rf = 0.1 (UV).
[1127] 1H NMR (400 MHz, CDCI3) d 8.20 (s, 1H), 7.53 (d, J = 8.5 Hz, 1H), 7.47 (d, J = 7.9 Hz, 1H), 7.25 (d, J = 7.9 Hz, 1H), 7.10 (t, J = 7.5 Hz, 1H), 7.03– 6.93 (m, 2H), 6.42 (dd, J = 16.1, 5.2 Hz, 1H), 6.11 (d, J = 15.7 Hz, 1H), 5.77 (dd, J = 8.0, 4.1 Hz, 1H), 5.68 (dd, J = 16.2, 1.8 Hz, 1H), 5.58 (ddd, J = 15.8, 7.2, 3.8 Hz, 1H), 5.35 (d, J = 9.0 Hz, 1H), 5.13 (dt, J = 8.5, 5.3 Hz, 1H), 4.88 (ddd, J = 8.8, 7.5, 6.2 Hz, 1H), 4.81 (dd, J = 10.1, 1.8 Hz, 1H), 4.40 (dd, J = 14.8, 7.9 Hz, 1H), 3.84 (d, J = 17.2 Hz, 1H), 3.69 (d, J = 17.2 Hz, 1H), 3.66– 3.58 (m, 1H), 3.50 (dd, J = 15.3, 4.8 Hz, 1H), 3.19 (dd, J = 15.3, 5.8 Hz, 1H), 2.86 (dd, J = 14.4, 6.3 Hz, 1H), 2.78– 2.66 (m, 1H), 2.56 (dd, J = 14.4, 7.6 Hz, 1H), 2.07– 1.89 (m, 1H), 1.61 (s, 3H), 1.00 (d, J = 6.9 Hz, 3H), 0.95 (d, J = 6.9 Hz, 3H), 0.93 (d, J = 6.7 Hz, 3H), 0.83 (s, 9H), 0.33 (s, 9H), 0.02 (s, 3H), -0.01 (s, 3H). [1128] 13C NMR (100 MHz, CDCl3) d 201.5, 172.4, 166.7, 161.0, 160.2, 159.7, 145.3, 143.6, 135.9, 134.9, 134.0, 132.8, 127.7, 125.0, 124.3, 123.0, 122.0, 119.3, 118.7, 111.0, 109.7, 83.4, 66.3, 52.3, 49.6, 44.1, 40.9, 36.6, 29.7, 27.8, 25.7, 19.9, 18.8, 18.1, 13.0, 10.4, -2.0, -4.5, -5.0.
[1129] HRMS-ESI m/z calcd for C43H63N4O7Si2+ [M + H]+ 803.4230, found 803.4214.
[1130] An oven-dried 50-mL round-bottom flask charged with SI-59 (13 mg, 16 mmol, 1 equiv) was evacuated and filled with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. THF (1.6 mL) was added, resulting in a light yellow solution. In a separate flask, imidazole•HCl (17 mg, 0.16 mmol, 10.0 equiv) was added to a solution of tetrabutylammonium fluoride in THF (1 M, 0.16 mL, 0.16 mmol, 10.0 equiv). The resulting colorless solution was added dropwise to the solution of SI-59. After 12 h, the mixture was concentrated and the residue was dissolved in DCM (50 mL). The resulting solution was transferred to a separatory funnel and was washed with water (3 × 50 mL) and brine (50 mL). The washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The resulting crude residue was purified by prepared TLC plate (silica gel, eluent: MeOH:DCM = 1:20) to afford analogue 29 (8 mg, 81%) as a white solid.
[1131] TLC (MeOH:DCM = 1:20): Rf = 0.1 (UV).
[1132] 1H NMR (400 MHz, CD2CI2) d 8.35 (s, 1H), 8.05 (s, 1H), 7.52 (d, J = 7.9 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.26 (d, J = 8.1 Hz, 1H), 7.10 (t, J = 7.3 Hz, 1H), 7.05 (d, J = 2.2 Hz, 1H), 6.99 (t, J = 7.2 Hz, 1H), 6.58 (dd, J = 16.0, 5.6 Hz, 1H), 6.01 (d, J = 15.9 Hz, 1H), 5.98– 5.93 (m, 1H), 5.84 (dd, J = 16.0, 1.8 Hz, 1H), 5.70 (ddd, J = 15.8, 6.2, 3.6 Hz, 1H), 5.17 (d, J = 8.5 Hz, 1H), 5.02 (ddd, J = 8.5, 6.5, 4.7 Hz, 1H), 4.86 (dd, J = 10.1, 1.9 Hz, 1H), 4.82– 4.72 (m, 1H), 4.40– 4.27 (m, 1H), 3.80 (d, J = 16.9 Hz, 1H), 3.72 (d, J = 16.9 Hz, 1H), 3.76– 3.69 (m, 1H), 3.49 (dd, J = 15.1, 4.7 Hz, 1H), 3.20 (dd, J = 15.2, 6.5 Hz, 1H), 2.80– 2.71 (m, 1H), 2.76 (dd, J = 16.0, 6.8 Hz, 1H), 2.62 (dd, J = 16.1, 6.1 Hz, 1H), 2.36 (br s, 1H), 2.09– 1.95 (m, 1H), 1.70 (s, 3H), 1.12 (d, J = 6.9 Hz, 3H), 0.98 (d, J = 6.8 Hz, 3H), 0.94 (d, J = 6.5 Hz, 3H).
[1133] 13C NMR (100 MHz, CD2Cl2) d 202.4, 172.1, 166.6, 163.2, 160.1, 158.3, 146.2, 141.6, 136.5, 135.4, 134.3, 132.7, 128.0, 126.2, 124.8, 124.0, 122.2, 119.6, 118.9, 111.6, 109.9, 83.8, 65.3, 53.0, 48.8, 43.8, 40.8, 37.0, 30.2, 27.9, 19.9, 18.9, 13.1, 11.0.
[1134] HRMS-ESI m/z calcd for C34H40N4NaO7 + [M + Na]+ 639.2789, found 639.2790. Analogue 30
Figure imgf000331_0001
[1135] An oven-dried 25-mL round-bottom flask charged with Stille Coupling product SI- 58b (10 mg, 12 µmol, 1 equiv) was evacuated and filled with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. DCM (1 mL) was added, resulting in a colorless solution. After cooling to 0 °C, 2,6-lutidine (33 µL, 287 µmol, 24.0 equiv) was added, followed by TMSOTf (43 µL, 239 µmol, 20.0 equiv). The mixture was warmed to 23 °C and stirred for 36 h. The mixture was diluted with DCM (30 mL) and the resulting solution was transferred to a separatory funnel which was washed with water (3 × 50 mL) and brine (50 mL). The washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The resulting crude residue SI-60 was used for next steps without further purification.
[1136] An oven-dried 50-mL round-bottom flask charged with SI-60 was evacuated and filled with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. THF (1.6 mL) was added, resulting in a light yellow solution. In a separate flask, imidazole•HCl (13 mg, 0.12 mmol, 10.0 equiv) was added to a solution of
tetrabutylammonium fluoride in THF (1 M, 0.12 mL, 0.12 mmol, 10.0 equiv). The resulting colorless solution was added dropwise to the solution of SI-60. After 12 h, the mixture was concentrated and the residue was dissolved in DCM (30 mL). The resulting solution was transferred to a separatory funnel and was washed with water (3 × 50 mL) and brine (50 mL). The washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The resulting crude residue was purified by prepared TLC plate (silica gel, eluent: MeOH:DCM = 1:20) to afford 30 (2.8 mg, 39% over 2 steps.) as a white solid.
[1137] TLC (MeOH:DCM = 1:20): Rf = 0.1 (UV).
[1138] 1H NMR (400 MHz, CD2Cl2)) d 8.07 (s, 1H), 7.22 (d, J = 8.5 Hz, 1H), 6.94 (d, J = 8.4 Hz, 2H), 6.68 (d, J = 8.5 Hz, 2H), 6.55 (dd, J = 16.2, 5.0 Hz, 1H), 6.11 (d, J = 15.5 Hz, 1H), 6.10 (br s, 1H), 5.84 (m, 1H), 5.54 (ddd, J = 15.7, 8.0, 3.6 Hz, 1H), 5.40 (d, J = 8.9 Hz, 1H), 4.95– 4.84 (m, 2H), 4.78 (dd, J = 10.1, 1.9 Hz, 1H), 4.35– 4.20 (m, 1H), 3.89 (d, J = 17.3 Hz, 1H), 3.80 (d, J = 17.2 Hz, 1H), 3.61 (ddd, J = 16.0, 8.2, 4.2 Hz, 1H), 3.24 (dd, J = 14.3, 4.9 Hz, 1H), 2.97– 2.77 (m, 4H), 2.10– 1.90 (m, 1H), 1.67 (s, 3H), 1.13 (d, J = 6.9 Hz, 3H), 0.97 (d, J = 6.7 Hz, 3H), 0.93 (d, J = 6.4 Hz, 3H).
[1139] 13C NMR (100 MHz, CD2Cl2) d 202.1, 172.4, 167.3, 160.3, 158.4, 156.01145.6, 142.1, 136.2, 135.7, 135.6, 132.6, 130.8, 127.3, 126.3, 124.6, 115.9, 84.0, 65.7, 49.4, 44.1, 41.4, 37.3, 37.2, 30.0, 29.0, 20.0, 18.9, 13.2, 10.5.
[1140] HRMS-ESI m/z calcd for C32H39N3NaO8 + [M + Na]+ 616.2969, found 616.2969.
[1141] Analogue 31
Figure imgf000332_0001
[1142] An oven-dried 50-mL round-bottom flask charged with SI-58c (40 mg, 52 mmol, 1 equiv) was evacuated and filled with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. THF (5.2 mL) was added, resulting in a light yellow solution. In a separate flask, imidazole•HCl (55 mg, 0.52 mmol, 10.0 equiv) was added to a solution of tetrabutylammonium fluoride in THF (1 M, 0.52 mL, 0.52 mmol, 10.0 equiv). The resulting colorless solution was added dropwise to the solution of SI-58c. After 12 h, the mixture was concentrated and the residue was dissolved in DCM (50 mL). The resulting solution was transferred to a separatory funnel and was washed with water (3 × 50 mL) and brine (50 mL). The washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The resulting crude residue was purified by flashed
chromatography (silica gel, eluent: MeOH:DCM = 1:100 to 1:50) to afford analogue 31 (20 mg, 66%) as a light yellow solid.
[1143] TLC (MeOH:DCM = 1:20): Rf = 0.2 (UV).
[1144] 1H NMR (400 MHz, CDCl3) d 8.04 (s, 1H), 7.26– 7.11 (m, 5H), 6.50 (dd, J = 16.2, 5.6 Hz, 1H), 6.11 (d, J = 15.7 Hz, 1H), 6.01 (dd, J = 7.8, 4.4 Hz, 1H), 5.84 (dd, J = 16.1, 1.7 Hz, 1H), 5.69– 5.59 (m, 1H), 5.43 (d, J = 8.8 Hz, 1H), 5.01– 4.86 (m, 2H), 4.78 (dd, J = 10.2, 1.9 Hz, 1H), 4.42– 4.23 (m, 1H), 3.86 (d, J = 16.8 Hz, 1H), 3.77 (d, J = 16.8 Hz, 1H), 3.69 (ddd, J = 16.5, 7.5, 4.4 Hz, 1H), 3.32 (dd, J = 14.3, 5.1 Hz, 1H), 3.05– 2.85 (m, 3H), 2.83– 2.72 (m, 1H), 2.55 (br s, 1H), 2.08– 1.92 (m, 1H), 1.73 (d, J = 1.2 Hz, 3H), 1.09 (d, J = 6.9 Hz, 3H), 0.97 (d, J = 6.8 Hz, 3H), 0.94 (d, J = 6.5 Hz, 3H).
[1145] 13C NMR (100 MHz, CDCl3) d 201.6, 171.8, 166.5, 159.9, 157.6, 144.5, 141.7, 135.8, 135.8, 135.2, 134.9, 132.0, 129.1, 128.6, 127.0, 125.7, 124.5, 83.5, 65.3, 52.7, 48.7, 43.6, 40.7, 37.9, 36.9, 29.5, 19.8, 18.7, 13.0, 10.4.
[1146] HRMS-ESI m/z calcd for C32H39N3NaO7 + [M + Na]+ 600.2680, found 600.2654.
[1147] Analogue 32
Figure imgf000333_0001
[1148] An oven-dried 25-mL round-bottom flask charged with SI-58d (16 mg, 19 µmol, 1 equiv) was evacuated and filled with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. Dry DCM (2 mL) was added, resulting in a colorless solution. After cooling to 0 °C, 2,6-lutidine (11 µL, 96 µmol, 4.0 equiv) was added, followed by TBSOTf (18 µL, 96 µmol, 5.0 equiv). The mixture was warmed to 23 °C and stirred for 12 h. The mixture was diluted with DCM (30 mL) and the resulting solution was transferred to a separatory funnel which was washed with water (3 × 50 mL) and brine (50 mL). The washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was
concentrated. The resulting crude residue was purified by flash chromatography (silica gel, eluent: EtOAc:hexanes = 1:2) to afford Stille product TBS carbamate SI-61 (16 mg, 94%) as a white solid.
[1149] TLC (EtOAc:hexanes = 1:2): Rf = 0.25 (UV).
[1150]
Figure imgf000334_0001
7.39 (d, J = 8.9 Hz, 1H), 6.66 (dd, J = 16.1, 4.4 Hz, 1H), 6.52– 6.40 (m, 1H), 6.22 (d, J = 15.8 Hz, 1H), 5.86 (d, J = 16.0 Hz, 1H), 5.70– 5.50 (m, 1H), 5.47 (d, J = 9.0 Hz, 1H), 5.37– 5.27 (m, 1H), 4.94 (q, J = 7.9 Hz, 1H), 4.89– 4.68 (m, 2H), 4.27– 4.10 (m, 1H), 3.92 (d, J = 17.2 Hz, 1H), 3.86– 3.70 (m, 1H), 3.75 (d, J = 17.0 Hz, 1H), 3.24– 3.08 (m, 1H), 3.07– 2.90 (m, 2H), 2.86 (dd, J = 15.1, 5.4 Hz, 1H), 2.76 (s, 1H), 2.05– 1.80 (m, 2H), 1.78– 1.58 (m, 1H), 1.68 (s, 3H), 1.59– 1.44 (m, 3H), 1.09 (d, J = 6.8 Hz, 3H), 0.96 (d, J = 6.9 Hz, 3H), 0.92– 0.87 (m, 3H), 0.91 (s, 9H), 0.85 (s, 9H), 0.34 (s, 9H), 0.25 (s, 6H), 0.04 (s, 3H), 0.02 (s, 3H).
[1151] An oven-dried 50-mL round-bottom flask charged with TBS carbamate SI-61 (42 mg, 46 µmol, 1 equiv) was evacuated and filled with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. THF (2.3 mL) was added, resulting in a light yellow solution. In a separate flask, imidazole•HCl (49 mg, 460 µmol, 10.0 equiv) was added to a solution of tetrabutylammonium fluoride in THF (1 M, 0.46 mL, 460 µmol, 10.0 equiv). The resulting colorless solution was added dropwise to the solution of SI-61. After 12 h, the mixture was concentrated and the residue was dissolved deionized water (5 mL) which was purified with prepared HPLC to afford analogue 32 TFA salt (15 mg, 48%) as a white solid.
[1152] TLC (MeOH): Rf = 0.3 (UV). [1153] 1H NMR (400 MHz, MeOD) d 8.34 (s, 1H), 6.64 (dd, J = 15.9, 6.1 Hz, 1H), 6.14 (d, J = 15.7 Hz, 1H), 5.98 (dd, J = 15.9, 1.6 Hz, 1H), 5.73 (ddd, J = 15.8, 6.5, 3.7 Hz, 1H), 5.42 (d, J = 9.1 Hz, 1H), 5.25– 4.75 (m, 2H), 4.74– 4.65 (m, 1H), 4.20 (d, J = 17.1 Hz, 1H), 4.07 (d, J = 17.2 Hz, 1H), 3.87 (d, J = 17.3 Hz, 1H), 3.73– 3.60 (m, 1H), 3.01 (dd, J = 16.3, 8.2 Hz, 1H), 2.97– 2.88 (m, 3H), 2.88– 2.79 (m, 1H), 2.13– 1.95 (m, 3H), 1.80 (s, 3H), 1.70 (q, J = 7.8 Hz, 2H), 1.43 (q, J = 7.9 Hz, 2H), 1.15 (d, J = 6.9 Hz, 3H), 1.00 (d, J = 6.8 Hz, 3H), 0.91 (d, J = 6.5 Hz, 3H).
[1154] 13C NMR (100 MHz, MeOD) d 203.1, 172.5, 168.4, 162.5, 160.5, 147.8, 143.3, 136.9, 136.0, 135.5, 133.8, 126.4, 125.0, 84.4, 65.2, 52.6, 50.3, 41.4, 40.5, 40.4, 37.8, 32.5, 30.7, 28.1, 23.4, 20.0, 18.9, 13.3, 11.5.
[1155] HRMS-ESI m/z calcd for C29H43N4O7 + [M + H]+ 559.3126, found 559.3096.
[1156] Scheme XI Synthesis of Analogues 35
Figure imgf000336_0001
Figure imgf000337_0001
[1159] An oven-dried 100-mL round-bottom flask charged with Weinreb amide SI-63 (0.35 g, 1.10 mmol, 1 equiv) was evacuated and flushed with nitrogen (the process of nitrogen exchange was repeated a total of 3 times). The vessel was sealed with septa. Dry DCM (11 mL) was added, and the resulting clear solution was allowed to cool to -78 ºC. A solution of DIBAL-H in toluene (1.2 M, 2.70 mL, 3.20 mmol, 3.0 equiv) was added dropwise to this solution. After 1 h, the started material was consumed (detected by TLC). The reaction mixture was quenched with MeOH (1 mL) and saturated Rochelle salt, and the mixture was warmed to 23 °C and stirred for another 1.5 h. The biphasic mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with DCM (2 × 30 mL). The organic layers were combined and the resulting solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The crude aldehyde was used for next step without further purification immediately.
[1160] A separate oven-dried 50-mL round-bottom flask charged with 60% NaH (0.13 g, 3.20 mmol, 3.0 equiv) was evacuated and flushed with nitrogen (the process of nitrogen exchange was repeated a total of 3 times). THF (11 mL) was added, and the resulting suspension was allowed to cool to 0 ºC. A solution of SI-64 (0.52 mL, 3.20 mmol, 3.0 equiv) in THF (2 mL) was added to above suspension dropwise. After 1 h, the mixture was cooled down to– 78 °C and a solution of the above aldehyde in THF (2 mL) was added. The resulting mixture was warmed to 0 °C slowly. After 2 h, the mixture was quenched with saturated aqueous NH4Cl solution. The biphasic mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with ether (2 × 30 mL). The organic layers were combined and the resulting solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The resulting residue was purified by flash chromatography (silica gel, eluent: EtOAc:hexanes = 1:5) to afford methyl ester SI-65 (0.26 g, 75% over 2 steps) as a colorless oil.
[1161] TLC (EtOAc:hexanes = 1:4): Rf = 0.20 (UV, KMnO4).
[1162] 1H NMR (400 MHz, CDCl3) d 7.23 (d, J = 8.6 Hz, 2H), 7.00 (dd, J = 15.8, 7.7 Hz, 1H), 6.88 (d, J = 8.6 Hz, 2H), 5.82 (dd, J = 15.8, 1.3 Hz, 1H), 4.43 (s, 2H), 3.81 (s, 3H), 3.72 (s, 3H), 3.63 (dd, J = 10.2, 3.8 Hz, 1H), 3.53 (d, J = 4.3 Hz, 1H), 3.47 (dt, J = 7.0, 4.5 Hz, 1H), 3.42 (dd, J = 9.2, 6.8 Hz, 1H), 2.50– 2.34 (m, 1H), 1.95– 1.85 (m, 1H), 1.09 (d, J = 6.7 Hz, 3H), 0.93 (d, J = 7.0 Hz, 3H).
[1163] 13C NMR (100 MHz, CDCl3) d 167.1, 159.4, 152.6, 129.5, 129.4, 120.4, 113.9, 78.9, 74.6, 73.3, 55.3, 51.4, 40.1, 35.7, 14.3, 13.0.
[1164] HRMS-ESI m/z calcd for C36H52NaO10+ [2M + Na]+ 667.3453, found 667.3456. [1165] Amide SI-66
Figure imgf000339_0001
[1166] A 200-mL round-bottom flask was charged with propargylamine (10, 2.30 mL, 36.0 mmol, 4.0 equiv) and dry DCM (60 mL) under N2. The resulting colorless solution was cooled to 0 °C by means of ice-water bath. A solution of AlMe3 in heptane (1 M, 36.0 mL, 36.0 mmol, 4.0 equiv) was added dropwise over 30 min (CAUTION: Gas evolution!). The mixture was allowed to warm to 23 °C. After stirring for 30 min, a solution of SI-65 (2.90 g, 9.0 mmol, 1 equiv) in DCM (9 mL) was added over 10 min (CAUTION: Gas evolution!). The vessel was equipped with a reflux condenser and the solution was brought to reflux by means of a 50 °C oil bath. After 3 h, the mixture was cooled to 0 °C by means of ice-water bath and MeOH (10 mL) was added (CAUTION: Gas evolution!). Once gas evolution ceased, saturated aqueous potassium sodium tartrate solution (100 mL) was added.
After stirring for 1 h, the biphasic mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with DCM (2 × 50 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL) and the washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The crude residue was purified by flash chromatography (silica gel, eluent: EtOAc:hexanes = 1:1) to afford amide SI-66 (2.86 g, 92%) as a white, waxy solid.
[1167] TLC (EtOAc:hexanes = 1:1): Rf = 0.30 (UV, KMnO4).
[1168] 1H NMR (400 MHz, CDCl3) d 7.23 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 6.84 (dd, J = 15.5, 1.3 Hz, 1H), 5.86 (s, 1H), 5.76 (dd, J = 15.5, 1.3 Hz, 1H), 4.42 (s, 2H), 4.09 (dd, J = 5.3, 2.6 Hz, 2H), 3.80 (s, 3H), 3.61 (dd, J = 9.2, 3.9 Hz, 1H), 3.54– 3.39 (m, 3H), 2.49– 2.36 (m, 1H), 2.22 (t, J = 2.6 Hz, 1H), 1.89 (m, 2H), 1.07 (d, J = 6.7 Hz, 3H), 0.92 (d, J = 7.0 Hz, 3H).
[1169] 13C NMR (100 MHz, CDCl3) d 165.6, 159.3, 148.4, 129.6, 129.39, 129.36, 122.5, 113.8, 99.9, 79.6, 78.6, 77.3, 77.0, 76.7, 74.4, 73.2, 71.5, 55.3, 39.7, 35.6, 29.1, 14.4, 12.9. [1170] HRMS-ESI m/z calcd for C20H28NO4 + [M + H]+ 346.2013, found 346.2012.
[1171] Vinyl stannane SI-67
Figure imgf000340_0001
[1172] An oven-dried 500-mL round-bottom flask charged with CuCN (1.56 g, 17.4 mmol, 2.0 equiv) was evacuated and flushed with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. Dry THF (120 mL) was added, resulting a white suspension and the vessel was cooled to -78 °C in a dry ice-acetone bath. To this suspension was added a solution of n-BuLi in hexanes (2.5 M, 14.6 mL, 36.5 mmol, 4.2 equiv) dropwise over 10 min and the resulting light yellow solution was stirred for 30 min. Bu3SnH (9.83 mL, 36.5 mmol, 4.2 equiv) was added dropwise over 5 min. After stirring for 30 min, a solution of SI-66 (3.00 g, 8.68 mmol, 1 equiv) in THF (17 m) was added dropwise over 15 min. After stirring for 1 h, saturated aqueous NH4Cl solution (100 mL) was added in one portion. The vessel was removed from the cooling bath and the system was allowed to warm to 23 °C while the mixture was rapidly stirred. The biphasic mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with water (2 × 100 mL) and brine (100 mL). The washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The crude residue was purified by flash chromatography (silica gel, eluent: EtOAc:hexanes = 0:1 to 1:3) to afford vinyl stannane SI-67 (5.38 g, 97%) as a colorless oil.
[1173] TLC (EtOAc:hexanes = 1:2.5): Rf = 0.30 (UV, KMnO4).
[1174] 1H NMR (400 MHz, CDCl3) d 7.23 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 6.83 (dd, J = 15.5, 7.5 Hz, 1H), 6.11 (dt, J = 19.0, 1.4 Hz, 1H), 5.97 (dt, J = 19.0, 5.1 Hz, 1H), 5.79 (dd, J = 15.5, 1.3 Hz, 1H), 5.54 (br t, J = 5.9 Hz, 1H), 4.43 (s, 2H), 4.00– 3.93 (m, 2H), 3.80 (s, 3H), 3.62 (dd, J = 9.2, 3.9 Hz, 1H), 3.50– 3.40 (m, 3H), 2.49– 2.37 (m, 1H), 1.95– 1.85 (m, 1H), 1.54– 1.41 (m, 6H), 1.37– 1.24 (m, 6H), 1.08 (d, J = 6.7 Hz, 3H), 0.93 (d, J = 7.0 Hz, 3H), 0.91– 0.77 (m, 15H). [1175] 13C NMR (100 MHz, CDCl3) d 165.6, 159.3, 147.5, 143.5, 130.3, 129.6, 129.4, 123.2, 113.8, 78.7, 74.4, 73.2, 55.3, 44.9, 39.7, 35.6, 29.0, 27.3, 14.4, 13.7, 13.1, 9.4.
[1176] HRMS-ESI m/z calcd for C32H56NO4Sn+ [M + H]+ 638.3226, found 638.3219.
Figure imgf000341_0001
[1178] An oven-dried 250-mL round-bottom flask was charged with 12 (1.34 g, 3.96 mmol, 1.5 equiv), alcohol Si-67 (1.68 g, 2.64 mmol, 1 equiv) and DMAP (0.065 g, 0.53 mmol, 0.2 equiv). DCM (26 mL) was added, resulting in a colorless solution. DCC (0.87 g, 4.22 mmol, 1.6 equiv) was added in one portion by briefly removing the septum, resulting in a white suspension. After 5 h, the alcohol SI-67 was entirely consumed as indicated by TLC analysis (eluent: EtOAc:hexanes = 1:3) and diethyl amine (13 mL) was added. After an additional 3 h, the mixture was filtered through a pad of celite and the filter cake was washed with DCM (2 × 30 mL). The filtrate was concentrated and the crude residue was purified by flash chromatography (silica gel, eluent: NH4OH:MeOH:DCM = 0.2:1:100 to 0.2:1:50) to afford amine SI-68 (1.80 g, 93%) as a light yellow oil.
[1179] TLC (MeOH: DCM = 1:20): Rf = 0.20 (UV, KMnO4).
[1180] 1H NMR (400 MHz, CDCl3) d 7.24 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 6.67 (dd, J = 15.5, 7.4 Hz, 1H), 6.11 (dt, J = 19.0, 1.5 Hz, 1H), 5.95 (dt, J = 19.0, 5.1 Hz, 1H), 5.74 (dd, J = 15.5, 1.3 Hz, 1H), 5.54 (br t, J = 5.9 Hz, 1H), 4.97 (t, J = 6.2 Hz, 1H), 4.37 (s, 2H), 4.03– 3.90 (m, 2H), 3.79 (s, 3H), 3.70 (dd, J = 8.5, 5.6 Hz, 1H), 3.45 (dd, J = 9.2, 5.0 Hz, 1H), 3.21 (dd, J = 9.2, 6.4 Hz, 1H), 3.03 (ddd, J = 10.2, 7.5, 6.2 Hz, 1H), 2.87 (ddd, J = 10.2, 7.0, 6.2 Hz, 1H), 2.80– 2.67 (m, 1H), 2.19– 2.05 (m, 2H), 1.90– 1.64 (m, 3H), 1.57 – 1.36 (m, 6H), 1.36– 1.22 (m, 6H), 1.03 (d, J = 6.9 Hz, 3H), 0.95 (d, J = 6.9 Hz, 3H), 0.91– 0.77 (m, 15H). [1181] 13C NMR (100 MHz, CDCl3) d 175.0, 165.3, 159.1, 145.1, 143.4, 130.4, 130.3, 129.3, 124.2, 113.7, 77.7, 72.8, 71.3, 59.9, 55.2, 46.9, 44.9, 37.8, 35.4, 30.4, 29.0, 27.2, 25.4, 14.8, 13.9, 13.7, 9.4.
[1182] HRMS-ESI m/z calcd for C37H63N2O5Sn+ [M + H]+ 735.3753, found 735.3740.
[1183] Stille precursor SI-69
Figure imgf000342_0001
[1184] A 250-mL round-bottom flask was charged with amine SI-68 (1.80 g, 2.45 mmol, 1 equiv), iPr2EtN (0.86 mL, 4.91mmol, 2.0 equiv) and acid 19 (1.36 g, 2.70 mmol, 1.1 equiv). DCM (45 mL) was added, resulting in a clear, colorless solution and HATU (1.17 g, 3.07 mmol, 1.25 equiv) was added to this solution in one portion at 23 °C. After stirring for 5 h, the mixture was diluted with DCM (100 mL). The solution was transferred to a separatory funnel and was washed with water (2 × 100 mL) and brine (100 mL). The washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The resulting crude residue was purified by flash chromatography (silica gel, eluent:
EtOAc:hexanes = 1:6 to 1:4) to afford Stille Coupling precursor SI-69 (2.72 g, 91%) as a light yellow foam.
[1185] TLC (EtOAc:Hexanes = 1:3): Rf = 0.20 (UV, p-Anisaldehyde).
[1186] 1H NMR (400 MHz, CDCl3, mixtures of rotamers) d 7.26– 7.16 (m, 2H), 6.85 (dt, J = 8.9, 2.0 Hz, 2H), 6.70– 6.52 (m, 1H), 6.18– 6.00 (m, 1H), 6.03– 5.90 (m, 1H), 5.84– 5.70 (m, 2H), 5.68– 5.50 (m, 2H), 4.97– 4.83 (m, 1H), 4.82– 4.65 (m, 1H), 4.59 (td, J = 8.6, 3.5 Hz, 1H), 4.40 (s, 1H), 4.31 (s, 1H), 4.15– 3.85 (m, 5H), 3.85– 3.59 (m, 5H), 3.31– 3.10 (m, 1H), 2.89– 2.32 (m, 3H), 2.32– 2.25 (m, 3H), 2.24– 1.70 (m, 2H), 1.60– 1.37 (m, 6H), 1.29 (h, J = 6.7, 6.1 Hz, 6H), 1.01 (ddd, J = 6.9, 5.5, 2.3 Hz, 4H), 0.97– 0.71 (m, 26H), 0.42 – 0.23 (m, 9H), 0.10– 0.01 (m, 6H). [1187] 13C NMR (100 MHz, CDCl3, mixtures of rotamers) d 201.0, 200.7, 172.3, 172.0, 171.8, 165.4, 165.0, 164.6, 163.8, 163.3, 162.3, 161.5, 161.4, 159.20, 159.08, 159.05, 158.96, 145.2, 145.1, 145.03, 143.5, 143.3, 142.8, 135.0, 134.2, 134.2, 130.9, 130.8, 130.4, 130.3, 130.0, 129.3, 129.3, 129.2, 124.4, 124.3, 121.8, 121.7, 121.0, 113.7, 113.7, 113.6, 78.4, 77.7, 72.7, 72.6, 71.5, 70.9, 67.8, 67.0, 66.1, 60.5, 59.8, 55.2, 55.2, 49.6, 49.5, 48.8, 48.7047.1, 44.9, 44.8, 44.18, 43.9, 38.1, 37.8, 35.7, 35.6, 31.6, 29.0, 27.2, 25.7, 25.6, 25.2, 24.0, 21.5, 17.9, 14.9, 14.8, 14.76, 14.0, 13.6, 9.4, -1.75, -1.78, -4.6, -5.15, -5.17.
[1188] HRMS-ESI m/z calcd for C57H95BrN3O9Si2Sn+ [M + H]+ 1220.4807, found 1220.4827.
[1189] Stille coupling product SI-70
Figure imgf000343_0001
[1190] An oven-dried 1000-mL round-bottom flask was charged with Jackiephos (0.36 g, 0.45 mmol, 0.2 equiv), Pd2(dba)3 (0.20 g, 0.22 mmol, 0.1 equiv) and Stille Coupling precursor SI-69 (2.72 g, 2.23 mmol, 1 equiv). The vessel was evacuated and filled with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. Toluene (446 mL) was added, resulting in a red suspension. A stream of argon was passed through the solution for 30 min. The mixture was heated at 50 °C by means of oil bath overnight. The mixture was allowed to cool to 23 °C. The mixture was concentrated and resulting crude residue was purified by flash chromatography (silica gel, eluent:
EtOAc:hexanes = 1:3 to 1:1.5) to afford SI-70 (1.0 g, 56%) as a light yellow foam.
[1191] TLC (EtOAc:Hexanes = 1:3): Rf = 0.20 (UV, p-Anisaldehyde).
[1192] 1H NMR (400 MHz, CDCI3) d 7.27 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H), 6.49 (dd, J = 16.4, 4.1 Hz, 1H), 6.14 (dd, J = 15.5, 1.3 Hz, 1H), 6.09 (dd, J = 9.0, 3.4 Hz, 1H), 5.77 (dd, J = 16.4, 2.1 Hz, 1H), 5.57 (ddd, J = 15.5, 9.5, 4.2 Hz, 1H), 5.43 (d, J = 8.8 Hz, 1H), 5.11 (dd, J = 10.5, 1.8 Hz, 1H), 5.02 (ddd, J = 9.0, 6.9, 5.8 Hz, 1H), 4.78 (dd, J = 8.8, 3.3 Hz, 1H), 4.56– 4.36 (m, 3H), 3.89 (d, J = 17.1 Hz, 1H), 3.83– 3.68 (m, 7H), 3.51 (dd, J = 9.1, 3.1 Hz, 1H), 3.39 (ddd, J = 14.9, 9.7, 3.5 Hz, 1H), 3.31 (dd, J = 9.1, 5.6 Hz, 1H), 2.94 (dd, J = 16.1, 7.0 Hz, 1H), 2.76 (dd, J = 16.1, 5.8 Hz, 1H), 2.75– 2.65 (m, 1H), 2.16– 2.10 (m, 2H), 1.91– 1.80 (m, 2H), 1.76– 1.69 (m, 1H), 1.68 (d, J = 1.2 Hz, 3H), 1.08 (d, J = 6.9 Hz, 3H), 1.02 (d, J = 6.9 Hz, 3H), 0.85 (s, 9H), 0.30 (s, 9H), 0.05 (s, 3H), 0.02 (s, 3H).
[1193] 13C NMR (100 MHz, CDCl3) d 200.9, 171.9, 166.5, 161.5, 161.5, 159.5, 158.9, 145.1, 144.5, 136.7, 134.8, 132.4, 130.9, 129.4, 124.9123.8, 113.6, 76.2, 73.0, 71.6, 65.3, 58.8, 55.2, 50.8, 48.5, 43.5, 41.3, 36.4, 35.4, 28.3, 25.7, 24.9, 18.0, 13.9, 12.7, 9.6, -1.8, -4.5, -5.0.
[1194] HRMS-ESI m/z calcd for C45H67N3NaO9Si2+ [M + Na]+ 872.4308, found 872.4348.
[1195] Primary Alcohol 38
Figure imgf000344_0001
[1196] A oven-dried 200-mL round-bottom charged with compound SI-70 (0.57 g, 0.67 mmol, 1 equiv) was evacuated and refilled with N2 (this process was repeated 3 times). DCM (67 mL) was added, resulting a yellow solution. The reaction mixture was cooled down to 0 °C and a solution of BCl3•DMS in DCM (2 M, 0.54 mL, 1.07 mmol, 1.6 equiv) was added dropwise. After stirring for another 20 min, saturated NaHCO3 (20 mL) was added. The two phases mixture was stirred for 1 h at 0 °C and transferred to a separatory funnel. The organic layer was washed with water (2 × 100 mL) and brine (100 mL). The washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The resulting crude residue was purified by flash chromatography (silica gel, eluent:
acetone:hexanes = 1:3.5 to 1:2.5) to afford Primary alcohol 38 (0.33 g, 67%) as a light yellow solid.
[1197] TLC (Acetone:Hexanes = 1:2.5): Rf = 0.20 (UV, p-anisaldehyde). [1198] 1H NMR (400 MHz, CDCl3) d 6.48 (dd, J = 16.4, 4.4 Hz, 1H), 6.16 (d, J = 15.7 Hz, 1H), 6.05 (dd, J = 9.0, 2.8 Hz, 1H), 5.75 (dd, J = 16.3, 2.0 Hz, 1H), 5.58 (ddd, J = 15.6, 9.0, 4.4 Hz, 1H), 5.43 (d, J = 8.8 Hz, 1H), 5.09– 4.94 (m, 2H), 4.58 (dd, J = 8.4, 5.2 Hz, 1H), 4.50 (ddd, J = 14.1, 8.7, 4.2 Hz, 1H), 3.91– 3.78 (m, 4H), 3.69 (d, J = 16.9 Hz, 1H), 3.52 (dd, J = 11.6, 3.2 Hz, 1H), 3.40 (ddd, J = 15.3, 9.0, 2.8 Hz, 1H), 2.93 (dd, J = 16.8, 6.2 Hz, 1H), 2.79 (dd, J = 16.9, 5.8 Hz, 1H), 2.79– 2.69 (m, 1H), 2.21– 2.07 (m, 1H), 2.05– 1.95 (m, 1H), 1.90– 1.80 (m, 2H), 1.81– 1.71 (m, 1H), 1.71 (d, J = 1.2 Hz, 3H), 1.07 (d, J = 6.9 Hz, 3H), 1.03 (d, J = 7.0 Hz, 3H), 0.84 (s, 9H), 0.30 (s, 9H), 0.04 (s, 3H), 0.00 (s, 3H).
[1199] 13C NMR (100 MHz, CDCI3) d 200.7, 172.8, 166.9, 162.3, 161.8, 159.8, 144.6, 144.5, 136.8, 135.1, 132.0, 124.2, 123.6, 77.5, 65.0, 64.6, 59.5, 50.8, 49.1, 43.1, 41.1, 36.4, 36.2, 28.1, 25.7, 25.5, 18.0, 14.0, 12.7, 9.4, -1.9, -4.5, -5.0.
[1200] HRMS-ESI m/z calcd for C37H59N3NaO8Si2+ [M + Na]+ 752.3733, found 752.3731.
[1201] Analogue 35
Figure imgf000345_0001
[1202] An oven-dried 25-mL round-bottom flask charged with compound 38 (36 mg, 49 mmol, 1 equiv) was evacuated and filled with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. THF (2.0 mL) was added, resulting in a light yellow solution. In a separate flask, Im•HCl (0.010 g, 0.10 mmol, 2.0 equiv) was added to a solution of tetrabutylammonium fluoride in THF (1 M, 0.15 mL, 0.15 mmol, 3.0 equiv). The resulting colorless solution was added dropwise to the above solution of 38 at 0 °C. After 1 h, the mixture was concentrated and the residue was purified by prepared TLC plate (eluent: MeOH:DCM = 1:25) to afford analogue 35 (0.016 g, 61%) as a light yellow solid.
[1203] TLC (acetone:Hexanes = 1:2.5): Rf = 0.20 (UV, p-anisaldehyde).
[1204] 1H NMR (400 MHz, CDCl3) d 8.09 (s, 1H), 6.48 (dd, J = 16.4, 5.0 Hz, 1H), 6.40– 6.30 (m, 1H), 6.12 (d, J = 15.6 Hz, 1H), 5.78 (dd, J = 16.4, 1.8 Hz, 1H), 5.69 (ddd, J = 14.7, 9.1, 4.8 Hz, 1H), 5.42 (d, J = 8.7 Hz, 1H), 5.03 (dd, J = 10.7, 1.8 Hz, 1H), 4.90 (dt, J = 9.1, 5.7 Hz, 1H), 4.60 (dd, J = 8.6, 4.3 Hz, 1H), 4.48 (ddd, J = 14.1, 8.9, 4.7 Hz, 1H), 4.02 (dt, J = 11.2, 6.8 Hz, 1H), 3.84– 3.73 (m, 4H), 3.53 (dd, J = 11.4, 2.9 Hz, 1H), 3.37 (ddd, J = 14.8, 9.0, 3.1 Hz, 1H), 3.01 (dd, J = 17.3, 5.6 Hz, 1H), 2.89 (dd, J = 17.2, 5.4 Hz, 1H), 2.77– 2.66 (m, 1H), 2.27– 2.15 (m, 1H), 1.99– 1.78 (m, 4H), 1.72 (d, J = 1.2 Hz, 3H), 1.05 (d, J = 6.9 Hz, 6H).
[1205] 13C NMR (100 MHz, CDCI3) d 202.4, 172.6, 166.9, 160.4, 157.1, 145.6, 144.3, 137.0, 136.8, 134.2, 132.7, 125.1, 124.1, 77.6, 65.1, 64.2, 60.0, 48.9, 48.7, 43.1, 40.8, 36.5, 36.2, 28.2, 25.5, 14.0, 12.7, 9.9.
[1206] HRMS-ESI m/z calcd for C28H38N3O8+ [M + H]+ 544.2653, found 544.2651.
[1207] Fluoride SI-71
Figure imgf000346_0001
[1208] An oven-dried 25-mL round-bottom flask charged with of alcohol 38 (25 mg, 34 mmol, 1 equiv) was evacuated and filled with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. DCM (3.4 mL) was added, resulting in a light yellow solution. To this solution was added DAST (12 mL, 89 mmol, 2.6 equiv) dropwise at 0 °C under N2. The reaction was warmed to 23 °C and stirred for 3 h. The reaction mixture was quenched with aqueous saturated NaHCO3 solution, diluted with 20 mL DCM and transferred to a separate funnel. The organic solution was washed with water and brine. The washed solution was dried with Na2SO4 and the dried solution was concentrated under vacuum. The residue was purified by flash chromatography (silica gel, eluent: acetone: hexanes = 1:5) to afford fluorinated product SI-71 (13 mg, 52%) as a white solid.
[1209] TLC (acetoneH:hexanes = 1:2.5): Rf = 0.30 (UV, p-anisaldehyde).
[1210] 1H NMR (400 MHz, CDCl3) d 6.48 (dd, J = 16.4, 4.1 Hz, 1H), 6.14 (d, J = 15.7 Hz, 1H), 6.09 (dd, J = 8.8, 2.6 Hz, 1H), 5.79 (dd, J = 16.3, 2.0 Hz, 1H), 5.57 (ddd, J = 15.5, 9.3, 4.3 Hz, 1H), 5.42 (d, J = 8.9 Hz, 1H), 5.07 (dd, J = 10.5, 1.8 Hz, 1H), 5.01 (dt, J = 8.9, 6.4 Hz, 1H), 4.75 (dd, J = 8.9, 3.5 Hz, 1H), 4.57– 4.41 (m, 2H), 4.38 (ddd, J = 47.5, 9.2, 5.2 Hz 1H), 3.88 (d, J = 17.1 Hz, 1H), 3.81– 3.70 (m, 2H), 3.73 (d, J = 17.1 Hz, 1H), 3.39 (ddd, J = 14.9, 9.4, 3.2 Hz, 1H), 2.91 (dd, J = 16.1, 6.8 Hz, 1H), 2.80– 2.69 (m, 1H), 2.91 (dd, J = 16.0, 5.9 Hz, 1H), 2.20– 2.05 (m, 2H), 1.90– 1.80 (m, 3H), 1.67 (d, J = 1.2 Hz, 3H), 1.11 (d, J = 6.9 Hz, 3H), 1.08 (d, J = 6.9 Hz, 3H), 0.85 (s, 9H), 0.31 (s, 9H), 0.05 (s, 3H), 0.02 (s, 3H).
[1211] 13C NMR (100 MHz, CDCl3) d 201.0, 172.1, 166.3, 161.8, 161.7, 159.7, 144.9, 144.0, 136.7, 134.9, 132.3, 124.7, 124.1, 85.05 (d, JCF = 169.7 Hz), 75.1 (d, JCF = 5.2 Hz), 65.3, 58.8, 50.6, 48.5, 43.6, 41.3, 36.3, 35.8 (d, JCF = 19.2 Hz), 28.2, 25.7, 25.0, 18.1, 12.9 (d, JCF = 4.7 Hz), 12.7, 9.7, -1.9, -4.50, -4.96.
[1212] HRMS-ESI m/z calcd for C37H59FN3O7Si2+ [M + H]+ 732.3870, found 732.3905.
[1213] Analogue SI-72
Figure imgf000347_0001
[1214] An oven-dried 25-mL round-bottom flask charged with fluoride SI-71 (13 mg, 18 mmol, 1 equiv) was evacuated and filled with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. THF (1.6 mL) was added, resulting in a light yellow solution. In a separate flask, Im•HCl (19 mg, 0.18 mmoL, 10.0 equiv) was added to a solution of tetrabutylammonium fluoride in THF (1 M, 0.18 mL, 0.18 mmol, 10.0 equiv). The resulting colorless solution was added dropwise to the above solution of 100. After 12 h, the mixture was concentrated and the residue was dissolved in DCM (30 mL). The resulting solution was transferred to a separatory funnel and was washed with water (3 × 30 mL) and brine (30 mL). The washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The resulting crude residue was purified by prepared TLC plate (eluent: MeOH:DCM = 1:25) to afford analogue SI-72 (6.1 mg, 63%) as a light yellow solid.
[1215] TLC (acetone:hexanes = 1:2): Rf = 0.20 (UV, p-anisaldehyde). [1216] 1H NMR (400 MHz, CDCl3) d 8.11 (s, 1H), 6.49 (dd, J = 16.4, 5.0 Hz, 1H), 6.48– 6.40 (m, 1H), 6.13 (d, J = 15.7 Hz, 1H), 5.83 (d, J = 16.4 Hz, 1H), 5.72 (ddd, J = 14.8, 9.1, 4.6 Hz, 1H), 5.42 (d, J = 8.8 Hz, 1H), 5.03 (d, J = 10.4 Hz, 1H), 4.93 (dt, J = 9.6, 5.6 Hz, 1H), 4.69 (dd, J = 8.9, 3.2 Hz, 1H), 4.55– 4.30 (m, 3H), 4.01 (dt, J = 11.5, 7.2 Hz, 1H), 3.84 (s, 2H), 3..81– 3.71 (m, 1H), 3.41 (ddd, J = 13.8, 9.2, 3.7 Hz, 1H), 3.07 (dd, J = 17.0, 5.9 Hz, 1H), 3.03– 2.95 (m, 1H), 2.90 (dd, J = 17.0, 5.1 Hz, 1H), 2.75 (br t, J = 6.6 Hz, 1H), 2.25– 2.11 (m, 2H), 2.00– 1.84 (m, 3H), 1.74 (s, 3H), 1.09 (d, J = 6.9 Hz, 6H).
[1217] 13C NMR (100 MHz, CDCl3) d 202.3, 171.6, 166.5, 160.2, 156.8, 144.0, 143.6, 137.0, 134.4, 132.6, 125.3, 125.3, 124.6, 85.3 (d, JCF = 170.4 Hz), 76.1 (d, JCF = 4.8 Hz), 65.2, 59.6, 52.1, 48.8, 48.5, 43.3, 40.9, 36.4, 35.8 (d, JCF = 19.1 Hz), 29.7, 28.3, 25.13, 25.11, 20.2, 13.5, 13.0 (d, JCF = 5.2 Hz), 12.7, 10.1.
[1218] HRMS-ESI m/z calcd for C28H37FN3O7+ [M + H]+ 546.2610, found 546.2630.
[1219] Scheme XIII synthesis of analogues 36 and 107
Figure imgf000349_0001
Figure imgf000350_0001
[1221] An oven-dried 250-mL round-bottom flask was charged with phenylboronic acid (1.22 g, 9.99 mmol, 0.5 equiv) and (S)-diphenyl(pyrrolidin-2-yl)methanol (2.53 g, 9.99 mmol, 0.5 equiv). The vessel was equipped with a Dean-Stark apparatus and a reflux condenser, evacuated and flushed with nitrogen (the process of nitrogen exchange was repeated a total of 3 times). Toluene (50 mL) was added, and the resulting clear solution was brought to reflux by means of a 145 °C oil bath. After 12 h, the reaction mixture was allowed to cool to 23 ºC and was concentrated. The resulting white solid was dried at £1 Torr for 1 h. The vessel was flushed with nitrogen and DCM (80 mL) was added. The resulting colorless solution was cooled to -78 °C and TfOH (0.79 mL, 8.99 mmol, 0.45 equiv) was added dropwise over 5 min by means of glass syringe (CAUTION: TfOH rapidly corrodes most plastic syringes!). Some of the TfOH freezes upon contact with the solution. After 1 h the solids had dissolved, and a solution of aldehyde SI-73 (4.16 g, 20.0 mmol, 1 equiv)，TBS ether 8 (5.70 g, 25.0 mmol 1.25 equiv) and isopropanol (1.91 mL, 25.0 mmol, 1.25 equiv) in DCM (20 mL) was added dropwise over 2 h by syringe pump. The mixture was stirred at -78 °C for another 1.5 h and saturated aqueous NaHCO3 solution (50 mL) was added in one portion. The vessel was removed from the cooling bath and the system was allowed to warm to 23 °C while it was rapidly stirred. The biphasic mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with DCM (2 × 30 mL). The organic layers were combined and the resulting solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The crude residue was purified by flash chromatography (silica gel, eluent: EtOAc:hexanes = 1:6 to 1:4) to afford
Vinylogous Aldol product SI-74 (4.52 g, 70%) as a colorless oil.
[1222] TLC (EtOAc:hexanes = 1:4): Rf = 0.20 (UV, KMnO4).
[1223] 1H NMR (400 MHz, CDCl3) d 7.23 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 6.79 (dd, J = 15.7, 9.3 Hz, 1H), 5.85 (dd, J = 15.7, 0.7 Hz, 1H), 4.45 (d, J = 11.6 Hz, 1H), 4.41 (d, J = 11.6 Hz, 1H), 3.80 (s, 3H), 3.72 (s, 3H), 3.63 (dt, J = 9.0, 2.3 Hz, 1H), 3.52 (dd, J = 9.0, 3.9 Hz, 1H), 3.46 (dd, J = 9.0, 4.9 Hz, 1H), 2.85 (d, J = 2.9 Hz, 1H), 2.51– 2.38 (m, 1H), 1.78 (dddd, J = 7.9, 7.0, 6.1, 2.6 Hz, 1H), 1.14 (d, J = 6.6 Hz, 3H), 0.94 (d, J = 7.0 Hz, 3H).
[1224] 13C NMR (100 MHz, CDCI3) d 167.0, 159.2, 151.1, 129.9, 129.2, 120.8, 113.8, 76.9, 75.2, 73.2, 55.3, 51.5, 40.8, 35.8, 16.7, 9.7.
[1225] HRMS-ESI m/z calcd for C36H52NaO10 + [2M + Na]+ 667.3453, found 667.3456.
[1226] Amide SI-75
Figure imgf000351_0001
[1227] A oven-dried 250-mL round-bottom flask was charged with propargylamine (10, 3.10 mL, 48.0 mmol, 4.0 equiv) and dry DCM (80 mL) under N2. The resulting colorless solution was cooled to 0 °C by means of ice-water bath. A solution of AlMe3 in heptane (1 M, 48.0 mL, 48.0 mmol, 4.0 equiv) was added dropwise over 30 min (CAUTION: Gas evolution!). The mixture was allowed to warm to 23 °C. After stirring for 30 min, a solution of SI-74 (3.50 g, 12.0 mmol, 1 equiv) in DCM (20 mL) was added over 10 min (CAUTION: Gas evolution!). The vessel was equipped with a reflux condenser and the solution was brought to reflux by means of a 50 °C oil bath. After 3 h, the mixture was cooled to 0 °C by means of ice-water bath and MeOH (10 mL) was added (CAUTION: Gas evolution!). Once gas evolution ceased, saturated aqueous potassium sodium tartrate solution (100 mL) was added. After stirring for 1 h, the biphasic mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with DCM (2 × 50 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL) and the washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The crude residue was purified by flash chromatography (silica gel, eluent: EtOAc:hexanes = 1:1) to afford amide SI-75 (3.22 g, 90%) as a white, waxy solid.
[1228] TLC (EtOAc:hexanes = 1:1): Rf = 0.30 (UV, KMnO4).
[1229] 1H NMR (400 MHz, CDCI3) d 7.21 (d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 6.70 (dd, J = 15.3, 9.2 Hz, 1H), 5.92 (br t, J = 5.2 Hz, 1H), 5.79 (dd, J = 15.3, 0.9 Hz, 1H), 4.43 (d, J = 11.5 Hz, 1H), 4.39 (d, J = 11.5 Hz, 1H), 4.09 (dd, J = 5.3, 2.6 Hz, 2H), 3.79 (s, 3H), 3.61 (dt, J = 9.0, 2.2 Hz, 1H), 3.51 (dd, J = 9.0, 3.9 Hz, 1H), 3.45 (dd, J = 9.0, 4.8 Hz, 1H), 2.95 (d, J = 2.8 Hz, 1H), 2.47– 2.34 (m, 1H), 2.23 (t, J = 2.6 Hz, 1H), 1.84– 1.71 (m, 1H), 1.12 (d, J = 6.6 Hz, 3H), 0.92 (d, J = 7.0 Hz, 3H).
[1230] 13C NMR (100 MHz, CDCl3) d 165.3, 159.2, 147.4, 129.9, 129.2, 122.6, 113.8, 79.4, 76.94, 76.7, 75.2, 73.1, 71.6, 55.2, 40.5, 35.7, 29.1, 16.8, 9.8.
[1231] HRMS-ESI m/z calcd for C20H28NO4 + [M + H]+ 346.2013, found 346.2012.
[1232] Vinyl Stannane SI-76
Figure imgf000352_0001
[1233] An oven-dried 500-mL round-bottom flask charged with CuCN (1.92 g, 21.4 mmol, 2.0 equiv) was evacuated and flushed with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. Dry THF (140 mL) was added, resulting a white suspension and the vessel was cooled to -78 °C in a dry ice-acetone bath. To this suspension was added s solution of n-BuLi in hexanes (2.5 M, 18 mL, 45.0 mmol, 4.2 equiv) dropwise over 10 min and the resulting light yellow solution was stirred for 30 min. Bu3SnH (12.1 mL, 45.0 mmol, 4.2 equiv) was added dropwise over 5 min. After stirring for 30 min, a solution of amide SI-75 (3.70 g, 10.7 mmol, 1 equiv) in THF (10 mL) was added dropwise over 15 min. After stirring for 1 h, saturated aqueous NH4Cl solution (100 mL) was added in one portion. The vessel was removed from the cooling bath and the system was allowed to warm to 23 °C while the mixture was rapidly stirred. The biphasic mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with water (2 × 100 mL) and brine (100 mL). The washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The crude residue was purified by flash chromatography (silica gel, eluent: EtOAc:hexanes = 0:1 to 1:3) to afford vinyl stannane SI-76 (6.80 g, 100%, ³20:1 E:Z) as a colorless oil.
[1234] TLC (EtOAc:hexanes = 1:2.5): Rf = 0.30 (UV, KMnO4).
[1235] 1H NMR (400 MHz, CDCI3) d 7.22 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 6.69 (dd, J = 15.2, 9.2 Hz, 1H), 6.12 (dt, J = 19.0, 1.5 Hz, 1H), 5.97 (dt, J = 19.0, 5.1 Hz, 1H), 5.81 (dd, J = 15.3, 0.8 Hz, 1H), 5.50 (br t, J = 5.9 Hz, 1H), 4.45 (d, J = 11.6 Hz, 1H), 4.40 (d, J = 11.6 Hz, 1H), 4.04– 3.92 (m, 2H), 3.80 (s, 3H), 3.63 (dt, J = 9.0, 2.4 Hz, 1H), 3.53 (dd, J = 9.0, 3.8 Hz, 1H), 3.46 (dd, J = 9.0, 4.6 Hz, 1H), 2.91 (d, J = 2.6 Hz, 1H), 2.50– 2.35 (m, 1H), 1.88– 1.76 (m, 1H), 1.54– 1.41 (m, 6H), 1.30 (h, J = 7.3 Hz, 6H), 1.14 (d, J = 6.6 Hz, 3H), 0.95 (d, J = 7.1 Hz, 3H), 0.88 (t, J = 7.3 Hz, 15H).
[1236] 13C NMR (100 MHz, CDCI3) d 165.3, 159.2, 146.5, 143.4, 130.5, 130.0, 129.2, 123.4, 113.8, 77.2, 75.4, 73.2, 55.3, 44.9, 40.6, 35.66, 29.0, 27.2, 16.9, 13.7, 9.8, 9.4.
[1237] HRMS-ESI m/z calcd for C32H56NO4Sn+ [M + H]+ 638.3226, found 638.3219.
[1238] Amine SI-77
Figure imgf000353_0001
[1239] An oven-dried 500-mL round-bottom flask was charged with 12 (5.40 g, 16.0 mmol, 1.5 equiv), SI-76 (6.80 g, 10.7 mmol, 1 equiv) and DMAP (0.26 g, 2.14 mmol, 0.2 equiv). DCM (160 mL) was added, resulting in a colorless solution. DCC (3.53 g, 17.1 mmol, 1.6 equiv) was added in one portion by briefly removing the septum, resulting in a white suspension. After 5 h, the alcohol SI-76was entirely consumed as indicated by TLC analysis (eluent: EtOAc:hexanes = 1:3) and diethyl amine (80 mL) was added. After an additional 3 h, the mixture was filtered through a pad of celite and the filter cake was washed with DCM (2 × 30 mL). The filtrate was concentrated and the crude residue was purified by flash chromatography (silica gel, eluent: NH4OH:MeOH:DCM = 0.2:1:100 to 0.2:1:50) to afford amine SI-77 (6.96 g, 89%) as a light yellow oil.
[1240] TLC (MeOH: DCM = 1:20): Rf = 0.20 (UV, KMnO4).
[1241] 1H NMR (400 MHz, CDCI3) d 7.23 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 6.68 (dd, J = 15.4, 8.2 Hz, 1H), 6.11 (dt, J = 19.0, 1.5 Hz, 1H), 5.95 (dt, J = 18.9, 5.1 Hz, 1H), 5.81 (dd, J = 15.5, 1.1 Hz, 1H), 5.55 (br s, 1H), 5.11 (dd, J = 8.1, 3.6 Hz, 1H), 4.38 (d, J = 11.5 Hz, 1H), 4.34 (d, J = 11.5 Hz, 1H), 4.00– 3.90 (m, 2H), 3.79 (s, 3H), 3.72 (dd, J = 8.5, 5.6 Hz, 1H), 3.34– 3.17 (m, 2H), 3.12– 2.99 (m, 1H), 2.88 (ddd, J = 10.2, 7.1, 6.2 Hz, 1H), 2.73– 2.59 (m, 1H), 2.18– 1.95 (m, 4H), 1.93– 1.75 (m, 1H), 1.75– 1.61 (m, 1H), 1.57 – 1.38 (m, 6H), 1.38– 1.24 (m, 6H), 1.03 (d, J = 6.7 Hz, 3H), 0.96– 0.81 (m, 18H).
[1242] 13C NMR (100 MHz, CDCI3) d 175.0, 165.1, 159.1, 144.7, 143.4, 130.4, 130.3, 129.3, 124.1, 113.7, 76.5, 72.9, 72.5, 59.9, 55.2, 46.9, 44.9, 38.5, 35.5, 30.4, 29.0, 27.2, 25.4, 15.8, 13.7, 11.2, 9.4.
[1243] HRMS-ESI m/z calcd for C37H63N2O5Sn+ [M + H]+ 735.3753, found 735.3740.
[1244] Stille Coupling Precursor SI-78
Figure imgf000354_0001
[1245] A 250-mL round-bottom flask was charged with amine SI-77 (6.76 g, 9.21 mmol, 1 equiv), iPr2EtN (3.22 mL, 18.4 mmol, 2.0 equiv) and acid 19 (5.11 g, 10.1 mmol, 1.1 equiv). DCM (92 mL) was added, resulting in a clear, colorless solution and HATU (4.38 g, 11.5 mmol, 1.25 equiv) was added to this solution in one portion at 23 °C. After stirring for 5 h, the mixture was diluted with DCM (100 mL). The solution was transferred to a separatory funnel and was washed with water (2 × 100 mL) and brine (100 mL). The washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The resulting crude residue was purified by flash chromatography (silica gel, eluent:
EtOAc:hexanes = 1:6 to 1:4) to afford Stille Coupling precursor SI-78 (10.0 g, 89%) as a light yellow foam.
[1246] TLC (EtOAc:Hexanes = 1:3): Rf = 0.20 (UV, p-Anisaldehyde).
[1247] 1H NMR (400 MHz, CDCl3, mixtures of rotamers) d 7.26– 7.15 (m, 2H), 6.91– 6.78 (m, 2H), 6.63 (m, 1H), 6.10 (m, 1H), 6.01– 5.91 (m, 1H), 5.85– 5.68 (m, 2H), 5.68– 5.53 (m, 1H), 5.05 (m, 1H), 4.82– 4.71 (m, 1H), 4.64 (m, 1H), 4.45– 4.22 (m, 2H), 4.11– 3.64 (m, 9H), 3.33 (m, 1H), 3.17 (d, J = 6.6 Hz, 1H), 2.81 (m, 1H), 2.69– 2.42 (m, 2H), 2.26 (m, 3H), 2.22– 1.84 (m, 5H), 1.47 (m, 6H), 1.29 (m, 6H), 1.08– 0.73 (m, 30H), 0.39– 0.25 (m, 9H), 0.08– -0.00 (m, 6H).
[1248] 13C NMR (100 MHz, CDCI3, mixtures of rotamers) d 201.1, 200.6, 172.1, 171.9, 165.3, 165.1, 163.4, 162.3, 161.5, 161.4, 159.2, 159.1, 159.04, 159.00, 145.2, 145.1, 144.8, 144.6, 143.43, 143.35, 134.2, 130.7, 130.31, 130.3, 130.2, 129.3, 129.2, 124.19, 124.15, 121.8, 113.70, 113.65, 72.8, 72.7, 72.6, 72.3, 67.0, 66.8, 60.6, 59.8, 55.2, 49.6, 48.8, 47.1, 44.9, 44.2, 43.9, 38.7, 38.5, 35.8, 35.4, 31.6, 29.0, 27.2, 25.7, 25.7, 25.6, 25.2, 24.0, 21.5, 18.0, 15.7, 13.7, 11.4, 11.3, 9.4, -1.73, -1.77, -4.6, -5.14, -5.16.
[1249] HRMS-ESI m/z calcd for C57H95BrN3O9Si2Sn+ [M + H]+ 1220.4807, found 1220.4827.
[1250] Stille Coupling Product SI-79
Figure imgf000355_0001
[1251] An oven-dried round-bottom flask was charged with Jackiephos (0.54 g, 0.67 mmol, 0.2 equiv), Pd2(dba)3 (0.31 g, 0.34 mmol, 0.1 equiv) and Stille Coupling precursor SI-78 (4.10 g, 3.36 mmol, 1 equiv). The vessel was evacuated and filled with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. Toluene (672 mL) was added, resulting in a red suspension. A stream of argon was passed through the solution for 30 min. The mixture was heated at 50 °C by means of oil bath. After 12 h, SI-78 was entirely consumed by TLC analysis (eluent: EtOAc:hexanes = 1:2) and the mixture was allowed to cool to 23 °C. The mixture was concentrated and resulting crude residue was purified by flash chromatography (silica gel, eluent: EtOAc:hexanes = 1:3 to 1:1.5) to afford Stille Coupling product SI-79 (1.68 g, 59%) as a light yellow foam.
[1252] TLC (EtOAc:Hexanes = 1:3): Rf = 0.20 (UV, p-Anisaldehyde).
[1253] 1H NMR (400 MHz, CDCl3) d 7.21 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 6.47 (dd, J = 16.3, 4.1 Hz, 1H), 6.20– 6.10 (m, 2H), 5.75 (dd, J = 16.3, 2.1 Hz, 1H), 5.56 (ddd, J = 15.5, 9.5, 4.2 Hz, 1H), 5.41 (d, J = 8.9 Hz, 1H), 5.08 (dd, J = 9.6, 1.8 Hz, 1H), 5.00 (ddd, J = 8.9, 7.1, 5.8 Hz, 1H), 4.80 (dd, J = 8.6, 3.3 Hz, 1H), 4.51 (ddd, J = 13.9, 9.0, 4.1 Hz, 1H), 4.43 (d, J = 11.7 Hz, 1H), 4.38 (d, J = 11.7 Hz, 1H), 3.89 (d, J = 17.2 Hz, 1H), 3.80 (s, 3H), 3.74 (d, J = 17.2 Hz, 1H), 3.74– 3.68 (m, 2H), 3.37 (qt, J = 9.4, 4.1 Hz, 3H), 2.91 (dd, J = 15.7, 7.2 Hz, 1H), 2.73 (dd, J = 15.7, 7.2 Hz, 1H), 2.80– 2.69 (m, 1H), 2.17– 2.03 (m, 2H), 1.91– 1.78 (m, 2H), 1.78– 1.67 (m, 1H), 1.65 (d, J = 1.2 Hz, 3H), 1.08 (d, J = 6.9 Hz, 3H), 1.04 (s, 3H), 0.85 (s, 9H), 0.30 (s, 9H), 0.05 (s, 3H), 0.02 (s, 3H).
[1254] 13C NMR (100 MHz, CDCI3) d 201.1, 172.0, 166.5, 161.8, 161.3, 159.6, 159.2, 145.0, 144.8, 136.6, 134.6, 132.5, 130.2, 129.1, 125.0, 123.5, 113.8, 78.1, 72.9, 71.9, 65.4, 58.7, 55.3, 50.6, 48.4, 43.8, 41.3, 37.2, 35.1, 28.3, 25.7, 24.8, 18.1, 14.9, 12.7, 10.6, -1.8, - 4.5, -5.0.
[1255] HRMS-ESI m/z calcd for C45H67N3NaO9Si2 + [M + Na]+ 872.4308, found 872.4348.
[1256] Analogue SI-80
Figure imgf000357_0001
[1257] An oven-dried 25-mL round-bottom flask charged with compound SI-79 (30 mg, 38 mmol, 1 equiv) was evacuated and filled with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. THF (4 mL) was added, resulting in a light yellow solution. In a separate flask, Im•HCl (40 mg, 0.38 mmol, 10.0 equiv) was added to a tetrabutylammonium fluoride solution in THF (1 M, 0.38 mL, 0.38 mmol, 10.0 equiv). The resulting colorless solution was added dropwise to the solution of SI-79. After 12 h, the mixture was concentrated and the residue was dissolved in DCM (30 mL). The resulting solution was transferred to a separatory funnel and was washed with water (5 × 30 mL) and brine (30 mL). The washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The resulting crude residue was purified by prepared TLC plate (eluent: MeOH:DCM = 1:25) to afford analogue SI-80 (21 mg, 82%) as a light yellow solid.
[1258] TLC (MeOH:DCM = 1:25): Rf = 0.20 (UV, p-anisaldehyde).
[1259] 1H NMR (400 MHz, CDCI3) d 8.06 (s, 1H), 7.21 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 6.48 (dd, J = 16.3, 5.0 Hz, 1H), 6.41 (dd, J = 8.9, 3.6 Hz, 1H), 6.09 (d, J = 15.6 Hz, 1H), 5.76 (dd, J = 16.4, 1.8 Hz, 1H),, 5.72– 5.63 (m, 1H), 5.36 (d, J = 8.7 Hz, 1H), 5.01 (dd, J = 9.1, 2.0 Hz, 1H), 4.90 (dt, J = 8.9, 5.8 Hz, 1H), 4.69 (dd, J = 9.0, 3.0 Hz, 1H), 4.52– 4.32 (m, 3H), 3.97 (dt, J = 11.2, 7.6 Hz, 1H), 3.86– 3.68 (m, 7H), 3.44– 3.30 (m, 3H), 3.04 (dd, J = 16.8, 6.2 Hz, 1H), 2.87 (dd, J = 16.8, 5.1 Hz, 1H), 2.76 (ddd, J = 9.1, 4.6, 2.0 Hz, 1H), 2.22– 2.04 (m, 2H), 1.91 (m, 2H), 1.81 (m, 1H), 1.71 (d, J = 1.2 Hz, 3H), 1.03 (d, J = 6.8 Hz, 3H), 1.01 (d, J = 6.7 Hz, 3H).
[1260] 13C NMR (100 MHz, CDCl3) d 202.2, 171.6, 166.7, 160.3, 159.2, 156.8, 144.4, 143.9, 137.0, 136.7, 134.4, 132.4, 130.1, 129.1, 125.4, 124.1, 113.8, 78.5, 72.9, 71.9, 65.2, 59.6, 55.3, 48.7, 48.41, 43.4, 40.9, 37.2, 34.9, 28.4, 25.0, 14.7, 12.7, 11.1.
[1261] HRMS-EI m/z calcd for C36H46N3O9 + [M + 1] 664.3229, found 664.3251.
[1262] Primary Alcohol 39
Figure imgf000358_0001
[1263] A oven-fried round-bottom charged with compound SI-79 (0.83 g, 0.98 mmol, 1 equiv) was evacuated and refilled with N2 (this process was repeated 3 times). DCM (98 mL) was added, resulting a yellow solution. The reaction mixture was cooled down to 0 °C and a solution of BCI3•DMS in DCM (2 M, 0.78 mL, 1.56 mmol, 1.6 equiv) was added dropwise. After stirring for another 20 min, saturated NaHCO3 (20 mL) was added. The two phases mixture was stirred for 1 h at 0 °C and transferred to a separatory funnel. The organic layer was washed with water (2 × 100 mL) and brine (100 mL). The washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The resulting crude residue was purified by flash chromatography (silica gel, eluent: acetone:hexanes = 1:3.5 to 1:2.5) to afford 39 (0.40 g, 56%) as a light yellow solid.
[1264] TLC (acetone:hexanes = 1:2.5): Rf = 0.20 (UV, p-anisaldehyde).
[1265] 1H NMR (400 MHz, CDCI3) d 6.51 (dd, J = 16.3, 4.3 Hz, 1H), 6.19 (dd, J = 8.9, 3.2 Hz, 1H), 6.14 (d, J = 15.7 Hz, 1H), 5.77 (dd, J = 16.3, 2.0 Hz, 1H), 5.56 (ddd, J = 15.5, 9.3, 4.2 Hz, 1H), 5.41 (d, J = 8.9 Hz, 1H), 5.16 (dd, J = 8.6, 1.9 Hz, 1H), 4.99 (ddd, J = 8.9, 7.2, 5.8 Hz, 1H), 4.79 (dd, J = 8.6, 3.5 Hz, 1H), 4.49 (ddd, J = 13.6, 8.8, 4.2 Hz, 1H), 3.89 (d, J = 17.2 Hz, 1H), 3.74 (d, J = 17.2 Hz, 1H), 3.82– 3.67 (m, 3H), 3.59 (d, J = 5.0 Hz, 2H), 3.39 (ddd, J = 14.8, 9.4, 3.2 Hz, 1H), 2.91 (dd, J = 15.7, 7.2 Hz, 1H), 2.83 (ddq, J = 6.6, 4.3, 2.3 Hz, 1H), 2.74 (dd, J = 15.7, 5.8 Hz, 1H), 2.20– 2.06 (m, 2H), 2.06– 1.96 (m, 1H), 1.94– 1.80 (m, 2H), 1.65 (d, J = 1.2 Hz, 3H), 1.13 (d, J = 6.9 Hz, 3H), 1.03 (d, J = 6.7 Hz, 3H), 0.85 (s, 9H), 0.30 (s, 9H), 0.05 (s, 3H), 0.01 (s, 3H).
[1266] 13C NMR (100 MHz, CDCl3) d 201.1, 172.1, 166.4, 161.9, 161.3, 159.7, 144.94, 144.85, 136.6, 134.6, 132.5, 124.9, 123.6, 77.0, 65.4, 64.6, 58.8, 50.6, 48.5, 43.7, 41.3, 37.4, 37.0, 28.3, 25.7, 24.9, 18.1, 13.9, 12.7, 11.0, -1.8, -4.51, -4.97.
[1267] HRMS-ESI m/z calcd for C37H59N3NaO8Si2+ [M + Na]+ 752.3733, found 752.3731.
[1268] Analogue 36
Figure imgf000359_0001
[1269] An oven-dried 25-mL round-bottom flask charged with compound 39 (36 mg, 49 mmol, 1 equiv) was evacuated and filled with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. THF (2.0 mL) was added, resulting in a light yellow solution. In a separate flask, Im•HCl (10 mg, 0.10 mmol, 2.0 equiv) was added to a solution of tetrabutylammonium fluoride in THF (1 M, 0.15 mL, 0.15 mmol, 3.0 equiv). The resulting colorless solution was added dropwise to the above solution of 39 at 0 °C. After 1 h, the mixture was concentrated and the residue was purified by prepared TLC plate (eluent: MeOH:DCM = 1:25) to afford analogue 36 (18 mg, 67%) as a light yellow solid.
[1270] TLC (acetone:hexanes = 1:2.5): Rf = 0.20 (UV, p-anisaldehyde).
[1271] 1H NMR (400 MHz, CDCI3) d 8.06 (s, 1H), 6.82– 6.63 (m, 1H), 6.52 (dd, J = 16.3, 5.1 Hz, 1H), 6.08 (d, J = 15.7 Hz, 1H), 5.80 (dd, J = 16.3, 1.8 Hz, 1H), 5.75– 5.62 (m, 1H), 5.34 (d, J = 8.6 Hz, 1H), 5.09 (d, J = 9.1 Hz, 1H), 4.90 (dt, J = 8.8, 5.8 Hz, 1H), 4.70 (dd, J = 8.8, 3.3 Hz, 1H), 4.48– 4.32 (m, 1H), 4.01– 3.88 (m, 1H), 3.88– 3.72 (m, 3H), 3.64– 3.50 (m, 2H), 3.41 (ddd, J = 15.0, 8.4, 3.7 Hz, 1H), 3.30 (br s, 2H), 3.00 (dd, J = 16.5, 6.2 Hz, 1H), 2.94– 2.78 (m, 2H), 2.24– 2.11 (m, 1H), 2.05– 1.74 (m, 4H), 1.70 (s, 3H), 1.07 (d, J = 6.8 Hz, 3H), 0.99 (d, J = 7.1 Hz, 3H).
[1272] 13C NMR (100 MHz, CDCI3) d 202.2, 171.7, 166.6, 160.4, 157.0, 144.6, 143.9, 136.9, 136.3, 134.4, 132.6, 125.3, 124.1, 77.8, 65.1, 64.4, 59.0, 48.7, 48.6, 43.4, 40.8, 37.3, 36.8, 28.5, 25.0, 13.8, 12.7, 11.4.
[1273] HRMS-ESI m/z calcd for C28H38N3O8+ [M + H]+ 544.2653, found 544.2651.
[1274] Scheme XIV Synthesis of Analogue 42
Figure imgf000360_0001
Figure imgf000360_0002
[1275] To a solution of alcohol 39 (30 mg, 41 mmol, 1 equiv) in EtOAc (2 mL) was added IBX (35 mg, 0.12 mmol, 3.0 equiv) and the resulting suspension was heated at 80 °C for 3 h. The reaction was cooled to room temperature and filtered through a pad of celite. The filter cake was washed with ethyl acetate (3 × 2 mL) and the combined filtrates were concentrated to yield a crude aldehyde which was used without further purification.
[1276] An oven-dried 25-mL round-bottom flask charged with NaBH(OAc)3 (17 mg, 82 mmol, 2.0 equiv) was evacuated and filled with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. DCE (2 mL) and morpholine (7 mL, 82 mmol, 2.0 equiv) was added, resulting in a light yellow solution. To this solution was added a solution of the above aldehyde in DCE (2 mL) at 23 °C. The resulting yellow solution was stirred for 3 h. The reaction mixture was quenched by adding aqueous saturated NaHCO3 (10 mL) and extracted with EtOAc (3 ×15 mL). The combined organic layers was washed with water (2 × 20 mL) and brine (20 mL). The washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The resulting residue was purified by flash chromatography (silica gel, eluent: acetone:hexanes = 1:3) to afford SI-81 (16 mg, 49%, 2 steps).
[1277] TLC (acetone:hexanes = 1:4): Rf = 0.30 (UV, p-anisaldehyde).
[1278] 1H NMR (400 MHz, CDCl3) d 6.50 (dd, J = 16.3, 4.1 Hz, 1H), 6.20– 6.05 (m, 2H), 5.77 (dd, J = 16.3, 2.0 Hz, 1H), 5.56 (ddd, J = 14.8, 9.5, 4.1 Hz, 1H), 5.41 (d, J = 8.9 Hz, 1H), 5.05– 4.95 (m, 2H), 4.80 (dd, J = 8.7, 3.3 Hz, 1H), 4.49 (ddd, J = 14.1, 9.0, 4.1 Hz, 1H), 3.88 (d, J = 17.2 Hz, 1H), 3.81– 3.56 (m, 7H), 3.40 (ddd, J = 13.5, 9.7, 3.1 Hz, 1H), 2.91 (dd, J = 15.8, 5.8 Hz, 1H), 2.95– 2.80 (m, 1H), 2.73 (dd, J = 15.7, 5.8 Hz, 1H), 2.52– 2.29 (m, 6H), 2.29– 1.75 (m, 5H), 1.65 (s, 3H), 1.11 (d, J = 6.9 Hz, 3H), 0.98 (d, J = 6.5 Hz, 3H), 0.85 (s, 9H), 0.30 (s, 9H), 0.05 (s, 3H), 0.02 (s, 3H).
[1279] 13C NMR (100 MHz, CDCI3) d 201.0, 171.9, 166.4, 161.8, 161.3, 159.6, 145.0, 144.8, 136.7, 134.7, 132.5, 124.9, 123.6, 79.1, 67.0, 65.4, 62.6, 58.7, 54.1, 50.6, 48.4, 43.7, 41.3, 37.6, 31.7, 28.3, 25.7, 24.8, 18.1, 15.8, 12.7, 10.9, -1.9, -4.5, -5.0.
[1280] HRMS-ESI m/z calcd for C41H67N4O8Si2+ [M + H]+ 799.4492, found 799.4499.
[1281] An oven-dried 25-mL round-bottom flask charged with SI-81 (16 mg, 20 mmol, 1 equiv) was evacuated and filled with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. THF (2.0 mL) was added, resulting in a light yellow solution. In a separate flask, Im•HCl (21 mg, 0.20 mmol, 10.0 equiv) was added to a solution of tetrabutylammonium fluoride in THF (1 M, 0.20 mL, 0.20 mmol, 10.0 equiv). The resulting colorless solution was added dropwise to the above solution of SI-81. After 12 h, the mixture was concentrated and the residue was dissolved in DCM (30 mL). The resulting solution was transferred to a separatory funnel and was washed with water (5 × 30 mL) and brine (30 mL). The washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The resulting crude residue was purified by prepared TLC plate (eluent: MeOH:DCM = 1:25) to afford analogue 42 (6.4 mg, 52%) as a light yellow solid.
[1282] TLC (MeOH:DCM = 1:25): Rf = 0.30 (UV, p-anisaldehyde).
[1283] 1H NMR (400 MHz, CDCI3) d 8.04 (s, 1H), 6.51 (dd, J = 16.3, 5.1 Hz, 1H), 6.45 (dd, J = 8.9, 3.7 Hz, 1H), 6.09 (d, J = 15.6 Hz, 1H), 5.79 (dd, J = 16.3, 1.8 Hz, 1H), 5.69 (ddd, J = 15.6, 8.8, 4.6 Hz, 1H), 5.34 (d, J = 8.8 Hz, 1H), 5.00– 4.84 (m, 2H), 4.70 (dd, J = 8.9, 3.1 Hz, 1H), 4.45 (ddd, J = 14.0, 8.7, 4.6 Hz, 1H), 3.98 (dt, J = 11.3, 7.5 Hz, 1H), 3.84 (d, J = 15.5 Hz, 1H), 3.79 (d, J = 15.7 Hz, 1H), 3.77– 3.60 (m, 5H), 3.40 (ddd, J = 14.9, 8.9, 3.6 Hz, 1H), 3.05 (dd, J = 16.7, 6.4 Hz, 1H), 3.01– 2.90 (m, 1H), 2.87 (dd, J = 16.8, 5.0 Hz, 1H), 2.52– 2.29 (m, 4H), 2.29– 1.75 (m, 7H), 1.71 (d, J = 1.2 Hz, 3H), 1.06 (d, J = 6.8 Hz, 3H), 0.96 (d, J = 6.5 Hz, 3H).
[1284] 13C NMR (100 MHz, CDCl3) d 202.1, 171.6, 166.6, 160.3, 156.7, 144.3, 143.9, 137.0, 136.7, 134.5, 132.4, 125.4, 124.2, 79.6, 66.9, 65.3, 62.7, 59.7, 54.1, 48.7, 48.43, 43.5, 40.9, 37.5, 31.5, 28.5, 25.0, 15.7, 12.7, 11.4.
[1285] HRMS-ESI m/z calcd for C32H44N4NaO8 + [M + Na]+ 635.3051, found 635.3054. [1286] Scheme XV Synthesis of analogue 43
Figure imgf000362_0001
[1287] To a solution of alcohol 39 (30 mg, 41 mmol, 1 equiv) in EtOAc (2 mL) was added IBX (35 mg, 0.12 mmol, 3.0 equiv) and the resulting suspension was heated at 80 °C for 3 h. The reaction was cooled to room temperature and filtered through a pad of celite. The filter cake was washed with ethyl acetate (3 × 2 mL) and the combined filtrates were concentrated to yield a crude aldehyde which was used without further purification.
[1288] An oven-dried 25-mL round-bottom flask charged with NaBH(OAc)3 (17 mg, 82 mmol, 2.0 equiv) was evacuated and filled with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. DCE (2 mL) and N-methylpiperazine (9 mL, 82 mmol, 2.0 equiv) was added, resulting in a light yellow solution. To this solution was added a solution of aldehyde in DCE (2 mL) at 23 °C. The resulting yellow solution was stirred for 3 h. The reaction mixture was quenched by adding aqueous saturated NaHCO3 (10 mL) and extracted with EtOAc (3 ×15 mL). The combined organic layers were washed with water (2 × 20 mL) and brine (20 mL). The washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The resulting residue was purified by flash chromatography (silica gel, eluent: acetone:hexanes = 1:1) to afford SI-82 (14 mg, 41%, 2 steps) as a white solid.
[1289] An oven-dried 25-mL round-bottom flask charged with SI-82 (14 mg, 17 mmol, 1 equiv) was evacuated and filled with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. THF (1.7 mL) was added, resulting in a light yellow solution. In a separate flask, Im•HCl (17 mg, 0.17 mmol, 10.0 equiv) was added to a solution of tetrabutylammonium fluoride in THF (1 M, 0.17 mL, 0.17 mmol, 10.0 equiv). The reaction mixture was concentrated by rotovap and the resulting crude residue was purified by prepared HPLC (eluent: H2O:acetonitrile = 95:5 to 5:95 over 15 min ) to afford analogue 43 (5 mg, 31%) as a white solid.
[1290] (300 MHz, MeOD) d 8.29 (s, 1H), 6.76 (dd, J = 15.9, 4.7 Hz, 1H), 6.22 (d, J = 15.9 Hz, 1H), 5.89 (d, J = 15.7 Hz, 1H), 5.68 (dd, J = 14.8, 7.5 Hz, 1H), 5.43 (d, J = 9.3 Hz, 1H), 5.15– 5.05 (m, 1H), 5.05– 4.95 (m, 1H), 4.85- 4.75 (m, 2H), 4.05– 3.80 (m, 5H), 3.78– 3.65 (m, 1H), 3.60– 3.40 (m, 1H), 3.24– 2.68 (m, 14H), 2.50– 2.25 (m, 4H), 2.25– 2.00 (m, 4H), 1.95– 1.85 (m, 1H), 1.78 (d, J = 1.7 Hz, 3H), 1.19 (d, J = 6.7 Hz, 3H), 1.12 (d, J = 6.3 Hz, 3H).
[1291] HRMS-ESI m/z calcd for C35H52N5O7 + [M + H]+ 654.3861, found 654.3867.
[1292] Scheme XVI Synthesis of Analogue 44
Figure imgf000363_0001
[1293] To a solution of alcohol 39 (30 mg, 41 mmol, 1 equiv) in EtOAc (2 mL) was added IBX (35 mg, 0.12 mmol, 3.0 equiv) and the resulting suspension was heated at 80 °C for 3 h. The reaction was cooled to room temperature and filtered through a pad of celite. The filter cake was washed with ethyl acetate (3 × 2 mL) and the combined filtrates were concentrated to yield a crude aldehyde which was used without further purification.
[1294] An oven-dried 25-mL round-bottom flask charged with sodium NaBH(OAc)3 (17 mg, 82 mmol, 2.0 equiv) was evacuated and filled with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. DCE (2 mL), iPr2EtN (29 mL, 0.16 mmol, 4.0 equiv) and 4-(dimethylammonio)piperidinium dichloride (33 mg, 0.16 mmol, 4.0 equiv) were added, resulting in a light yellow solution. After stirring for 30 min, to this solution was added a solution of the above aldehyde in DCE (2 mL) at 23 °C. The resulting yellow solution was stirred for 3 h. The reaction mixture was quenched by adding aqueous saturated NaHCO3 (10 mL) and extracted with EtOAc (3 ×15 mL). The combined organic layers were washed with water (2 × 20 mL) and brine (20 mL). The washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The resulting residue was purified by flash chromatography (silica gel, eluent: acetone:hexanes = 1:1) to afford SI-83 (15 mg, 45%, 2 steps) as a white solid.
[1295] An oven-dried 25-mL round-bottom flask charged with SI-21 (15 mg, 18 mmol, 1 equiv) was evacuated and filled with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. THF (2.0 mL) was added, resulting in a light yellow solution. In a separate flask, Im•HCl (19 mg, 0.18 mmol, 10.0 equiv) was added to a solution of tetrabutylammonium fluoride in THF (1 M, 0.18 mL, 0.18 mmol, 10.0 equiv). The reaction mixture was concentrated by rotovap and the resulting crude residue was purified by prepared HPLC (eluent: H2O:acetonitrile = 95:5 to 5:95 over 15 min) to afford analogue 44 (5 mg, 32%) as a light yellow solid.
[1296] TLC (MeOH:DCM = 1:25): Rf = 0.30 (UV, p-anisaldehyde).
[1297] 1H NMR (300 MHz, MeOD) d 8.28 (s, 1H), 6.79 (dd, J = 15.8, 4.7 Hz, 1H), 6.21 (d, J = 15.9 Hz, 1H), 5.86 (d, J = 16.2 Hz, 1H), 5.67 (d, J = 14.3 Hz, 1H), 5.41 (d, J = 9.1 Hz, 1H), 5.20– 5.10 (m, 1H), 5.00 (d, J = 8.3 Hz, 1H), 4.85– 4.75 m, 1H), 4.75 (d, J = 9.9 Hz, 1H), 4.00 (d, J = 16.8 Hz, 1H), 3.95– 3.80 (m, 3H), 3.27– 2.68 (m, 14H), 2.50– 2.35 (m, 1H), 2.35– 2.25 (m, 2H), 2.15– 2.00 (s, 2H), 1.78 (s, 3H), 1.16 (d, J = 6.7 Hz, 3H), 0.98 (d, J = 6.6 Hz, 3H).
[1298] HRMS-ESI m/z calcd for C
Figure imgf000364_0001
[M + H]+ 626.3548, found 626.3552. [1299] Scheme XVI Analogue 37
Figure imgf000365_0002
[1300] Mukaiyama Aldol Product SI-85
Figure imgf000365_0001
[1301] An oven-dried 100-mL round-bottom flask was charged with phenylboronic acid (0.30 g, 2.50 mmol, 0.5 equiv) and (S)-diphenyl(pyrrolidin-2-yl)methanol (0.63 g, 2.50 mmol, 0.5 equiv). The vessel was equipped with a Dean-Stark apparatus and a reflux condenser, evacuated and flushed with nitrogen (the process of nitrogen exchange was repeated a total of 3 times). Toluene (25 mL) was added, and the resulting clear solution was brought to reflux by means of a 145 °C oil bath. After 12 h, the reaction mixture was allowed to cool to 23 ºC and was concentrated. The resulting white solid was dried at £1 Torr for 1 h. The vessel was flushed with nitrogen and DCM (25 mL) was added. The resulting colorless solution was cooled to -78 °C and TfOH (0.20 mL, 2.25 mmol, 0.45 equiv) was added dropwise over 5 min by means of glass syringe (CAUTION: TfOH rapidly corrodes most plastic syringes!). Some of the TfOH freezes upon contact with the solution. After 1 h the solids had dissolved, and a solution of aldehyde SI-84 (0.43 g, 5.00 mmol, 1 equiv), TBS dienol ether 8 (1.43 g, 6.24 mmol 1.25 equiv) and isopropanol (0.48 mL, 6.24 mmol, 1.25 equiv) in DCM (10 mL) was added dropwise over 2 h by syringe pump. The mixture was stirred at -78 °C for another 1.5 h and saturated aqueous NaHCO3 solution (50 mL) was added in one portion. The vessel was removed from the cooling bath and the system was allowed to warm to 23 °C while it was rapidly stirred. The biphasic mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with DCM (2 × 30 mL). The organic layers were combined and the resulting solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The crude residue was purified by flash chromatography (silica gel, eluent: EtOAc:hexanes = 1:6 to 1:4) to afford Mukaiyama Aldol product SI-85 (0.37 g, 37%) as a colorless oil.
[1302] Amide SI-86
Figure imgf000366_0001
[1303] A 100-mL round-bottom flask was charged with propargylamine (10, 0.47 mL, 7.40 mmol, 4.0 equiv) and dry DCM (15 mL) under N2. The resulting colorless solution was cooled to 0 °C by means of ice-water bath. A solution of AlMe3 in heptane (1 M, 7.40 mL, 7.40 mmol, 4.0 equiv) was added dropwise over 30 min (CAUTION: Gas evolution!). The mixture was allowed to warm to 23 °C. After stirring for 30 min, a solution of SI-85 (0.37 g, 1.85 mmol, 1 equiv) in DCM (5 mL) was added over 10 min (CAUTION: Gas evolution!). The vessel was equipped with a reflux condenser and the solution was brought to reflux by means of a 50 °C oil bath. After 3 h, the mixture was cooled to 0 °C by means of ice-water bath and MeOH (3 mL) was added (CAUTION: Gas evolution!). Once gas evolution ceased, saturated aqueous potassium sodium tartrate solution (50 mL) was added. After stirring for 1 h, the biphasic mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with DCM (2 × 50 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL) and the washed solution was dried
(Na2SO4). The dried solution was filtered and the filtrate was concentrated. The crude residue was purified by flash chromatography (silica gel, eluent: EtOAc:hexanes = 1:1) to afford amide SI-86 (0.30 g, 73%) as a white, waxy solid.
[1304] TLC (EtOAc:hexanes = 1:1): Rf = 0.30 (UV, KMnO4).
[1305] 1H NMR (300 MHz, CDCl3) d 6.91 (dd, J = 15.4, 8.1 Hz, 1H), 5.75 (dd, J = 15.4, 1.1 Hz, 1H), 5.61 (s, 1H), 4.13 (dd, J = 5.4, 2.5 Hz, 2H), 3.29 (d, J = 4.2 Hz, 1H), 2.71– 2.53 (m, 1H), 2.25 (t, J = 2.5 Hz, 1H), 1.11 (d, J = 6.8 Hz, 3H), 0.95 (s, 9H).
[1306] Vinyl Stannane SI-87
Figure imgf000367_0001
[1307] An oven-dried 100-mL round-bottom flask charged with CuCN (0.30 g, 1.35 mmol, 2.0 equiv) was evacuated and flushed with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. Dry THF (14 mL) was added, resulting a white suspension and the vessel was cooled to -78 °C in a dry ice-acetone bath. To this suspension was added a solution of n-BuLi in hexanes (2.5 M, 2.30 mL, 5.66 mmol, 4.2 equiv) dropwise over 10 min and the resulting light yellow solution was stirred for 30 min. Bu3SnH (1.53 mL, 5.66 mmol, 4.2 equiv) was added dropwise over 5 min. After stirring for 30 min, a solution of amide SI-86 (0.30 g, 1.35 mmol, 1 equiv) in THF (5 mL) was added dropwise over 15 min. After stirring for 1 h, saturated aqueous NH4Cl solution (100 mL) was added in one portion. The vessel was removed from the cooling bath and the system was allowed to warm to 23 °C while the mixture was rapidly stirred. The biphasic mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with water (2 × 100 mL) and brine (100 mL). The washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The crude residue was purified by flash chromatography (silica gel, eluent: EtOAc:hexanes = 0:1 to 1:3) to afford vinyl stannane SI-87 (0.50 g, 73%, ³20:1 E:Z) as a colorless oil.
[1308] TLC (EtOAc:hexanes = 1:2.5): Rf = 0.30 (UV, KMnO4).
[1309] 1H NMR (300 MHz, CDCI3) d 6.89 (dd, J = 15.7, 8.0 Hz, 1H), 6.12 (d, J = 19.1 Hz, 1H), 5.97 (dt, J = 18.6, 5.5 Hz, 1H),), 5.84– 5.70 (m, 1H), 5.54– 5.40 (m, 1H), 4.04– 3.94 (m, 2H), 3.36– 3.26 (m, 1H), 2.67– 2.54 (m, 1H), 1.54– 1.40 (m, 6H), 1.38– 1.20 (m, 6H), 1.11 (d, J = 6.7 Hz, 3H), 0.95 (s, 9H), 1.00– 0.80 (m, 15H).
[1310] Amine SI-88
Figure imgf000368_0001
[1311] An oven-dried 100-mL round-bottom flask was charged with 12 (0.11 g, 0.32 mmol, 1.5 equiv), DMAP (5.2 mg, 0.042 mmol, 0.2 equiv) and SI-87 (0.11 g, 0.21 mmol, 1 equiv). Dry DCM (3 mL) was added, resulting in a colorless solution. DCC (0.071 g, 0.34 mmol, 1.6 equiv) was added in one portion at 23 °C, resulting in a white suspension. After 5 h, the alcohol 110 was entirely consumed by TLC analysis (eluent: EtOAc:hexanes = 1:2). Diethyl amine (1.5 mL) was added. After stirring for additional 3 h, the mixture was filtered through a pad of celite and the filter cake was washed with DCM (2 × 5 mL). The filtrate was concentrated and the crude residue was purified by flash chromatography (silica gel, eluent: NH4OH:MeOH:DCM = 0.2:1:100 to 0.2:1:50) to afford amine SI-88 (85 mg, 65%) as light yellow oil.
[1312] TLC (MeOH:DCM= 1:20): Rf = 0.20 (UV).
[1313] 1H NMR (300 MHz, CDCI3) d 6.77 (dd, J = 15.4, 8.3 Hz, 1H), 6.10 (dt, J = 18.9, 1.4 Hz, 1H), 5.95 (dt, J = 19.0, 4.9 Hz, 1H), 5.78 (dd, J = 15.4, 1.0 Hz, 1H), 5.62 (t, J = 5.8 Hz, 1H), 4.75 (d, J = 5.7 Hz, 1H), 3.97 (t, J = 5.3 Hz, 2H), 3.77 (dd, J = 8.4, 5.7 Hz, 1H), 3.07 (dt, J = 10.2, 6.8 Hz, 1H), 2.89 (dt, J = 10.3, 6.6 Hz, 1H), 2.78– 2.62 (m, 1H), 2.22 (br s, 1H), 2.19– 2.05 (m, 1H), 1.97– 1.79 (m, 1H), 1.80– 1.66 (m, 2H), 1.57– 1.39 (m, 6H), 1.38– 1.19 (m, 6H), 1.02 (d, J = 6.9 Hz, 3H), 0.92 (s, 9H), 0.92– 0.82 (m, 15H).
[1314] 13C NMR (75 MHz, CDCl3) d 175.0, 165.4, 147.3, 143.4, 130.3, 122.7, 82.0, 59.9, 46.9, 44.9, 37.5, 35.7, 30.4, 29.0, 27.2, 26.6, 25.5, 16.5, 13.7, 9.4.
[1315] Stille Coupling Precursor SI-89
Figure imgf000369_0001
[1316] A 50-mL round-bottom flask was charged with amine SI-88 (80 mg, 0.13 mmol, 1 equiv), iPr2EtN (46 µL, 0.26 mmol, 2.0 equiv) and acid 19 (73 mg, 0.14 mmol, 1.1 equiv). DCM (1.3 mL) was added, resulting in a clear, colorless solution and HATU (62 mg, 0.16 mmol, 1.25 equiv) was added to this solution in one portion at 23 °C. After stirring for 5 h, the mixture was diluted with DCM (10 mL). The solution was transferred to a separatory funnel and was washed with water (2 × 10 mL) and brine (10 mL). The washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The resulting crude residue was purified by flash chromatography (silica gel, eluent:
EtOAc:hexanes = 1:6 to 1:4) to afford Stille Coupling precursor SI-89(0.12 g, 84%) as a light yellow foam.
[1317] TLC (EtOAc:Hexanes = 1:3): Rf = 0.20 (UV, p-Anisaldehyde). [1318] 1H NMR (300 MHz, CDCl3, mixtures of rotamers) d 6.80– 6.58 (m, 1H), 6.09 (d, J = 19.0 Hz, 1H), 5.93 (dt, J = 19.0, 5.0 Hz, 1H), 5.86– 5.60 (m, 3H), 4.85– 4.58 (m, 3H), 4.15– 3.63 (m, 6H), 2.91– 2.71 (m, 1H), 2.75– 2.57 (m, 1H), 2.56– 2.43 (m, 1H), 2.31– 2.20 (m, 1H), 2.26 (s, 3H), 2.09– 1.85 (m, 3H), 1.55– 1.35 (m, 6H), 1.35– 1.15 (m, 9H), 1.05– 0.73 (m, 33H), 0.36– 0.23 (m, 9H), 0.09– -0.05 (m, 6H).
[1319] 13C NMR (75 MHz, CDCl3, mixtures of rotamers) d 201.1, 200.8, 172.15, 172.06, 165.7, 165.3, 163.2, 162.5, 161.4, 159.11, 159.05, 147.3, 147.2, 145.2, 145.0, 143.45, 143.35, 134.2, 130.2, 123.0, 122.9, 122.6, 121.7, 82.3, 81.8, 67.0, 66.8, 60.4, 59.8, 49.6, 49.5, 48.7, 47.0, 44.8, 44.2, 43.9, 37.5, 37.4, 36.6, 35.73, 35.68, 29.0, 27.2, 26.77, 26.70, 25.6, 23.95, 23.93, 17.9, 16.2, 16.0, 13.6, 9.4, -1.3, -4.6, -5.18, -5.21.
[1320] Stille Coupling Product SI-90
Figure imgf000370_0001
[1321] An oven-dried 25-mL round-bottom flask charged with Jackiephos Pd G3 (16 mg, 14 µmol, 0.3 equiv) was evacuated and filled with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. Toluene (8 mL) was added and a stream of argon was passed through the solution by means of a 20-G needle for 10 min. A solution of KOtBu in THF (1.6 M, 8.5 µL, 14 µmol, 0.3 equiv) was added, and the resulting orange mixture was heated to 80 ºC for 5 minutes, during which time the mixture turned deep brown- red. In a scintillation vial, a stream of argon was passed through a solution of Stille Precursor SI-89 (50 mg, 46 µmol, 1 equiv) in Toluene (2 mL) for 5 minutes. The resulting degassed solution was added dropwise over 1 min to the solution of catalyst, which was already stirring at 80 ºC. The mixture was stirred under a positive pressure of nitrogen for 40 h, after which time the starting material was completely consumed by TLC analysis (eluent: 1:2
EtOAc:hexanes, stain: anisaldehyde).The mixture was allowed to cool to 23 ºC and was concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, eluent: EtOAc:hexanes = 1:2) to afford SI-90 (8.0 mg, 24 %) as a light yellow oil.
[1322] TLC (EtOAc:Hexanes = 1:3): Rf = 0.20 (UV, p-Anisaldehyde).
[1323] 1H NMR (300 MHz, CDCI3) d 6.45 (dd, J = 16.3, 4.4 Hz, 1H), 6.14 (d, J = 15.7 Hz, 1H), 6.08 (s, 1H), 5.75 (dd, J = 16.3, 2.0 Hz, 1H), 5.56 (ddd, J = 15.0, 9.6, 4.2 Hz, 1H), 5.41 (d, J = 8.8 Hz, 1H), 5.08– 4.95 (m, 1H), 4.88 (d, J = 1.5 Hz, 1H), 4.84 (dd, J = 8.8, 3.1 Hz, 1H), 4.50 (ddd, J = 13.8, 9.0, 4.2 Hz, 1H), 3.89 (d, J = 17.2 Hz, 1H), 3.82– 3.69 (m, 3H), 3.38 (ddd, J = 13.9, 9.6, 3.0 Hz, 1H), 2.89 (dd, J = 16.1, 6.7 Hz, 1H), 2.88– 2.78 (m, 1H), 2.73 (dd, J = 16.0, 6.0 Hz, 1H), 2.20– 2.10 (m, 1H), 2.17 (s, 3H), 1.95– 1.85 (m, 3H), 1.15 (d, J = 6.8 Hz, 3H), 1.03 (s, 9H), 0.85 (s, 9H), 0.30 (s, 9H), 0.05 (s, 3H), 0.02 (s, 3H).
[1324] Analogue 37
Figure imgf000371_0001
[1325] An oven-dried 10-mL round-bottom flask charged with compound SI-90 (8 mg, 11 µmol, 1 equiv) was evacuated and filled with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. THF (0.5 mL) was added, resulting in a light yellow solution. In a separate flask, Im•HCl (23 mg, 0.22 mmol, 20.0 equiv) was added to a tetrabutylammonium fluoride solution in THF (1 M, 0.22 mL, 0.22 mmol, 20.0 equiv). The resulting colorless solution was added dropwise to the solution of SI-90. After 12 h, the mixture was concentrated and the residue was dissolved in DCM (30 mL). The resulting solution was transferred to a separatory funnel and was washed with water (5 × 30 mL) and brine (30 mL). The washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The resulting crude residue was purified by prepared TLC plate (eluent: MeOH:DCM = 1:25) to afford analogue 37 (5.5 mg, 92%) as a light yellow solid.
[1326] TLC (MeOH:DCM = 1:25): Rf = 0.20 (UV, p-anisaldehyde). [1327] 1H NMR (300 MHz, CDCl3) d 8.13 (s, 1H), 6.44 (dd, J = 16.3, 5.2 Hz, 1H), 6.19 (d, J = 7.0 Hz, 1H), 6.11 (d, J = 15.5 Hz, 1H), 5.85– 5.71 (m, 1H), 5.71– 5.60 (m, 1H), 5.44 (d, J = 8.7 Hz, 1H), 4.91 (dt, J = 9.1, 5.4 Hz, 1H), 4.81 (d, J = 1.5 Hz, 1H), 4.72 (dd, J = 8.6, 3.1 Hz, 1H), 4.45 (ddd, J = 13.9, 9.0, 4.6 Hz, 1H), 3.98 (dt, J = 11.3, 7.1 Hz, 1H), 3.82 (s, 3H), 3.48 (s, 1H), 3.37 (ddd, J = 13.8, 9.2, 3.4 Hz, 1H), 3.00 (dd, J = 17.4, 5.3 Hz, 1H), 2.92– 2.75 (m, 2H), 2.63 (s, 1H), 2.28– 2.12 (m, 1H), 1.91 (dtt, J = 12.2, 7.6, 4.3 Hz, 3H), 1.72 (d, J = 1.3 Hz, 3H), 1.11 (d, J = 6.8 Hz, 3H), 1.03 (s, 9H). [1328] Scheme XVII General Procedure D for preparation of carbamate analogues 40a-q and 41a-q
Figure imgf000372_0001
[1329] (1) A oven-fried round-bottom charged with primary alcohol 38 or 39 (1 equiv) and DMAP (0.1 equiv) was evacuated and refilled with N2 (this process was repeated 3 times). Toluene or DCM (0.01 M) and aryl isocyanate or a solution of heteroaryl isocyanate in toluene (0.1 M 2.0– 10.0 equiv) was added, resulting a yellow solution. The reaction mixture was stirred at 23 °C or 80 °C overnight. The solvent was removed by rotovap. The resulting crude residue was purified by flash chromatography (silica gel, eluent: acetone:hexanes = 1:5) to afford cabamate SI-91 or SI-92 as a white solid.
[1330] (2) An oven-dried 50-mL round-bottom flask charged with carbamate SI-92 or SI- 92 (1 equiv) was evacuated and filled with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. THF (0.01 M) was added, resulting in a light yellow solution. In a separate flask, imidazole•HCl (15.0 equiv) was added to a solution of 1 M tetrabutylammonium fluoride in THF (15.0 equiv). The resulting colorless solution was added dropwise to the solution of SI-91 or SI-92. After 12 h, the mixture was concentrated and the residue was dissolved in DCM (50 mL). The resulting solution was transferred to a separatory funnel and was washed with water (5 × 50 mL) and brine (50 mL). The washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The resulting crude residue was purified by prepared TLC plate (eluent: MeOH:DCM = 1:20) to afford carbamate analogues 40 or 41 as a white solid.
[1331] Analogue 40a
Figure imgf000373_0001
[1332] Prepared according to general procedure D from primary alcohol 38 (20 mg, 27 mmol, 1 equiv), DMAP (0.3 mg, 3 mmol, 0.1 equiv) and phenyl isocyanate (9 mL, 82 mmol, 3.0 equiv). DCM was employed as solvent and the reaction was run at 23 °C. Analogue 40a (10 mg, 54% over 2 steps) was obtained as a white solid.
[1333] TLC (MeOH;DCM = 1:20): Rf = 0.30 (UV, p-anisaldehyde).
[1334] 1H NMR (400 MHz, CDCI3) d 9.04 (br s, 1H), 8.20 (s, 1H), 7.49 (d, J = 8.0 Hz, 2H), 7.32– 7.20 (m, 2H), 7.00 (t, J = 7.4 Hz, 1H), 6.54 (dd, J = 16.2, 4.2 Hz, 1H), 6.18 (d, J = 15.6 Hz, 1H), 6.00 (dd, J = 8.4, 4.3 Hz, 1H), 5.80 (dd, J = 16.2, 2.0 Hz, 1H), 5.69 (ddd, J = 15.6, 9.3, 4.4 Hz, 1H), 5.57 (d, J = 8.7 Hz, 1H), 5.17 (dd, J = 9.7, 1.9 Hz, 1H), 4.96 (dt, J = 9.0, 5.6 Hz, 1H), 4.77 (dd, J = 8.7, 2.7 Hz, 1H), 4.58 (dd, J = 11.6, 3.7 Hz, 1H), 4.37 (ddd, J = 13.6, 8.3, 4.4 Hz, 1H), 4.00– 3.80 (m, 2H), 3.84 (s, 2H), 3.75 (dd, J = 11.6, 9.5 Hz, 1H), 3.48 (ddd, J = 14.0, 9.3, 4.2 Hz, 1H), 3.13 (dd, J = 17.7, 4.9 Hz, 1H), 2.92 (dd, J = 17.7, 6.1 Hz, 1H), 2.78 (br s, 1H), 2.76– 2.66 (m, 1H), 2.40– 2.25 (m, 1H), 2.17– 2.03 (m, 1H), 2.00 – 1.80 (m, 2H), 1.74 (d, J = 1.1 Hz, 3H), 1.11 (d, J = 6.9 Hz, 3H), 0.97 (d, J = 7.0 Hz, 3H). [1335] 13C NMR (100 MHz, CDCl3) d 202.6, 170.8, 165.9, 160.2, 157.3, 153.7, 144.5, 139.1, 137.1, 136.7, 134.1, 132.9, 128.8, 125.1, 124.2, 122.7, 118.4, 79.2, 68.4, 64.9, 59.9, 49.2, 48.7, 42.6, 41.1, 37.1, 33.8, 28.5, 24.7, 13.5, 12.7, 10.2.
[1336] HRMS-ESI m/z calcd for C
Figure imgf000374_0001
[M + H]+ 663.3025, found 663.3021.
[1337] Analog 40b
Figure imgf000374_0002
[1338] Prepared according to general procedure D from primary alcohol 38 (20 mg, 27 mmol, 1 equiv), DMAP (0.3 mg, 3 mmol, 0.1 equiv) and 4-fluorodephenyl isocyanate (10 mL, 82 mmol, 3.0 equiv). DCM was employed as solvent and the reaction was run at 23 °C. Analog 40b (6.8 mg, 36% over 2 steps) was obtained as a white solid.
[1339] TLC (MeOH;DCM = 1:20): Rf = 0.30 (UV, p-anisaldehyde).
[1340] 1H NMR (400 MHz, CDCI3) d 8.91 (br s, 1H), 8.18 (s, 1H), 7.36 (d, J = 8.5 Hz, 2H), 7.05 (d, J = 8.2 Hz, 2H), 6.53 (dd, J = 16.2, 4.2 Hz, 1H), 6.17 (d, J = 15.6 Hz, 1H), 6.04 (d, J = 7.8 Hz, 1H), 5.79 (dd, J = 16.2, 2.0 Hz, 1H), 5.67 (ddd, J = 14.9, 9.3, 4.4 Hz, 1H), 5.55 (d, J = 8.7 Hz, 1H), 5.15 (dd, J = 9.7, 1.9 Hz, 1H), 4.95 (dt, J = 9.0, 5.6 Hz, 1H), 4.75 (dd, J = 8.7, 2.7 Hz, 1H), 4.54 (dd, J = 11.5, 3.8 Hz, 1H), 4.36 (ddd, J = 13.5, 8.2, 4.5 Hz, 1H), 4.01– 3.84 (m, 2H), 3.83 (s, 2H), 3.74 (dd, J = 11.5, 9.3 Hz, 1H), 3.48 (ddd, J = 14.2, 9.3, 4.2 Hz, 1H), 3.12 (dd, J = 17.6, 5.0 Hz, 1H), 2.91 (dd, J = 17.6, 6.1 Hz, 1H), 2.83 (br s, 1H), 2.77– 2.67 (m, 1H), 2.40– 2.31 (m, 1H), 2.27 (s, 3H), 2.15– 2.00 (m, 1H), 1.99– 1.80 (m, 3H), 1.73 (d, J = 1.2 Hz, 3H), 1.10 (d, J = 6.8 Hz, 3H), 0.95 (d, J = 7.0 Hz, 3H).
[1341] 13C NMR (100 MHz, CDCI3) d 202.6, 170.8, 165.9, 160.2, 157.3, 153.8, 144.5, 144.5, 137.5, 136.7, 136.5, 134.10132.9, 132.1, 129.3, 125.1, 124.2, 118.4, 79.1, 68.7, 64.9, 59.8, 49.3, 48.6, 42.6741.1, 37.0, 33.8, 28.5, 24.7, 20.7, 13.3, 12.7, 10.2.
[1342] HRMS-ESI m/z calcd for C [M + H]+ 677.3181, found 677.3190. [1343] Analog 40c
Figure imgf000375_0001
[1344] Prepared according to general procedure D from primary alcohol 38 (20 mg, 27 mmol, 1 equiv), DMAP (0.3 mg, 3 mmol, 0.1 equiv) and 4-methoxyphenyl isocyanate (11 mL, 82 mmol, 3.0 equiv). DCM was employed as solvent and the reaction was run at 23 °C.
Analogue 40c (3.2 mg, 17% over 2 steps) was obtained as a white solid.
[1345] TLC (MeOH;DCM = 1:20): Rf = 0.30 (UV, p-anisaldehyde).
[1346] 1H NMR (400 MHz, CDCl3) d 8.88 (s, 1H), 8.17 (s, 1H), 7.39 (d, J = 9.0 Hz, 2H), 6.80 (d, J = 9.0 Hz, 2H), 6.54 (dd, J = 16.2, 4.2 Hz, 1H), 6.17 (d, J = 15.6 Hz, 1H), 6.12– 5.98 (m, 1H), 5.79 (dd, J = 16.2, 2.0 Hz, 1H), 5.67 (ddd, J = 15.5, 9.3, 4.4 Hz, 1H), 5.55 (d, J = 8.7 Hz, 1H), 5.15 (dd, J = 9.6, 1.9 Hz, 1H), 4.95 (dt, J = 8.6, 5.6 Hz, 1H), 4.76 (dd, J = 8.8, 2.7 Hz, 1H), 4.54 (dd, J = 11.6, 3.7 Hz, 1H), 4.35 (ddd, J = 13.6, 8.3, 4.5 Hz, 1H), 3.98– 3.84 (m, 2H), 3.82 (s, 2H), 3.76 (s, 3H), 3.80– 3.68 (m, 1H), 3.49 (ddd, J = 14.2, 9.4, 4.2 Hz, 1H), 3.12 (dd, J = 17.6, 5.0 Hz, 1H), 2.91 (dd, J = 17.6, 6.1 Hz, 1H), 2.86 (br s, 1H), 2.72 (ddt, J = 6.7, 4.3, 2.2 Hz, 1H), 2.40– 2.24 (m, 1H), 2.16– 2.02 (m, 1H), 2.00– 1.81 (m, 3H), 1.73 (s, 3H), 1.10 (d, J = 6.9 Hz, 3H), 0.95 (d, J = 7.0 Hz, 3H).
[1347] 13C NMR (100 MHz, CDCl3) d 202.6, 170.8, 165.9, 160.2, 157.4, 155.3, 154.0, 144.5, 144.4, 137.0, 136.7, 134.1, 132.9, 132.3, 125.1, 124.2, 112.0, 114.0, 79.1, 68.7, 64.9, 59.8, 55.5, 49.2, 48.6, 42.7, 41.1, 37.0, 33.8, 28.5, 24.7, 13.3, 12.7, 10.2.
[1348] Analogue 40d
Figure imgf000376_0001
[1349] Prepared according to general procedure D from primary alcohol 38 (20 mg, 27 mmol, 1 equiv), DMAP (0.3 mg, 3 mmol, 0.1 equiv) and 4-trifluoromethoxyphenyl isocyanate (12 mL, 82 mmol, 3.0 equiv). DCM was employed as solvent and the reaction was run at 23 °C. Analogue 40d (11 mg, 52% over 2 steps) was obtained as a white solid.
[1350] TLC (MeOH;DCM = 1:20): Rf = 0.30 (UV, p-anisaldehyde).
[1351] 1H NMR (400 MHz, CDCl3) d 9.25 (br s, 1H), 8.19 (s, 1H), 7.52 (d, J = 9.1 Hz, 2H), 7.10 (d, J = 8.6 Hz, 2H), 6.54 (dd, J = 16.2, 4.2 Hz, 1H), 6.18 (d, J = 15.6 Hz, 1H), 5.96 (dd, J = 8.2, 4.3 Hz, 1H), 5.80 (dd, J = 16.2, 2.0 Hz, 1H), 5.68 (ddd, J = 15.6, 9.3, 4.4 Hz, 1H), 5.57 (d, J = 8.6 Hz, 1H), 5.17 (dd, J = 9.6, 1.9 Hz, 1H), 4.96 (q, J = 7.0, 6.5 Hz, 1H), 4.74 (dd, J = 8.8, 2.6 Hz, 1H), 4.61 (dd, J = 11.5, 3.5 Hz, 1H), 4.36 (ddd, J = 13.7, 8.3, 4.5 Hz, 1H), 4.02– 3.85 (m, 2H), 3.84 (s, 2H), 3.72 (dd, J = 11.6, 9.8 Hz, 1H), 3.50 (ddd, J = 14.2, 9.2, 4.3 Hz, 1H), 3.13 (dd, J = 17.7, 4.9 Hz, 1H), 2.91 (dd, J = 17.7, 6.2 Hz, 1H), 2.82– 2.62 (m, 2H), 2.40– 2.25 (m, 1H), 2.16– 2.04 (m, 1H), 2.02– 1.81 (m, 3H), 1.74 (d, J = 1.2 Hz, 3H), 1.11 (d, J = 6.8 Hz, 3H), 0.96 (d, J = 7.0 Hz, 3H).
[1352] 13C NMR (100 MHz, CDCl3) d 202.6, 170.6, 165.8, 160.3, 157.5, 153.7, 151.2, 144.5, 144.5, 137.9, 137.0, 136.7, 134.1, 132.9, 125.1, 124.2, 121.6, 119.3, 79.3, 69.1, 64.9, 59.9, 49.2, 48.7, 42.6, 41.1, 37.1, 33.8, 28.5, 24.7, 13.2, 12.7, 10.2.
[1353] HRMS-ESI m/z calcd for C36H42F3N4O10 + [M + H]+ 747.2848, found 747.2838.
[1354] Analogue 40e
Figure imgf000377_0001
[1355] Prepared according to general procedure D from primary alcohol 38 (20 mg, 27 mmol, 1 equiv), DMAP (0.3 mg, 3 mmol, 0.1 equiv) and 4-trifluoromethylphenyl isocyanate (12 mL, 82 mmol, 3.0 equiv). DCM was employed as solvent and the reaction was run at 23 °C. Analogue 40e (12 mg, 59% over 2 steps) was obtained as a white solid.
[1356] TLC (MeOH;DCM = 1:20): Rf = 0.30 (UV, p-anisaldehyde).
[1357] 1H NMR (400 MHz, CDCl3) d 9.40 (s, 1H), 8.20 (s, 1H), 7.62 (d, J = 8.5 Hz, 2H), 7.49 (d, J = 8.6 Hz, 2H), 6.54 (dd, J = 16.2, 4.2 Hz, 1H), 6.18 (d, J = 15.6 Hz, 1H), 5.98 (dd, J = 8.3, 4.4 Hz, 1H), 5.80 (dd, J = 16.2, 2.0 Hz, 1H), 5.68 (ddd, J = 15.6, 9.3, 4.4 Hz, 1H), 5.57 (d, J = 8.6 Hz, 1H), 5.18 (dd, J = 9.6, 2.0 Hz, 1H), 4.96 (dt, J = 9.3, 5.6 Hz, 1H), 4.73 (dd, J = 8.7, 2.6 Hz, 1H), 4.62 (dd, J = 11.6, 3.6 Hz, 1H), 4.35 (ddd, J = 13.7, 8.2, 4.5 Hz, 1H), 3.98– 3.86 (m, 2H), 3.84 (s, 2H), 3.73 (dd, J = 11.6, 9.8 Hz, 1H), 3.50 (ddd, J = 14.2, 9.3, 4.3 Hz, 1H), 3.13 (dd, J = 17.7, 4.9 Hz, 1H), 2.92 (dd, J = 17.7, 6.1 Hz, 1H), 2.80 (br s, 1H), 2.80– 2.65 (m, 1H), 2.40– 2.25 (m, 1H), 2.18– 2.05 (m, 1H), 2.00– 1.80 (m, 3H), 1.74 (d, J = 1.2 Hz, 3H), 1.11 (d, J = 6.9 Hz, 3H), 0.97 (d, J = 7.0 Hz, 3H).
[1358] 13C NMR (100 MHz, CDCl3) d 202.6, 170.6, 165.7, 160.3, 157.5, 153.5, 144.6, 144.4, 142.3, 137.0, 136.7, 134.1, 133.0, 126.0 (q, 3J = 4.2 Hz), 125.1, 124.2, 117.9, 79.3, 69.2, 64.9, 59.9, 49.2, 48.7, 42.6, 41.1, 37.1, 33.7, 28.5, 24.7, 13.2, 12.7, 10.2.
[1359] HRMS-ESI m/z calcd for C36H41F3N4NaO+ [M + Na]+ 753.2718, found 753.2717.
[1360] Analogue 40f
Figure imgf000378_0001
[1361] Prepared according to general procedure D from primary alcohol 38 (20 mg, 27 mmol, 1 equiv), DMAP (0.3 mg, 3 mmol, 0.1 equiv) and 4-fluorodephenyl isocyanate (9 mL, 82 mmol, 3.0 equiv). DCM was employed as solvent and the reaction was run at 23 °C.
Analogue 40f (7.3 mg, 39% over 2 steps) was obtained as a white solid.
[1362] TLC (MeOH;DCM = 1:20): Rf = 0.30 (UV, p-anisaldehyde).
[1363] 1H NMR (400 MHz, CDCI3) d 9.07 (br s, 1H), 8.19 (s, 1H), 7.50– 7.41 (m, 2H), 6.94 (t, J = 8.7 Hz, 2H), 6.53 (dd, J = 16.2, 4.2 Hz, 1H), 6.17 (d, J = 15.6 Hz, 1H), 5.99– 5.91 (m, 1H), 5.80 (dd, J = 16.2, 2.0 Hz, 1H), 5.69 (ddd, J = 15.7, 9.3, 4.5 Hz, 1H), 5.56 (d, J = 8.8 Hz, 1H), 5.16 (dd, J = 9.6, 1.9 Hz, 1H), 5.03– 4.90 (m, 1H), 4.75 (dd, J = 8.7, 2.6 Hz, 1H), 4.58 (dd, J = 11.6, 3.7 Hz, 1H), 4.36 (td, J = 8.6, 8.2, 4.0 Hz, 1H), 3.98– 3.85 (m, 2H), 3.84 (s, 2H), 3.76– 3.68 (m, 1H), 3.48 (ddd, J = 14.1, 9.3, 4.2 Hz, 1H), 3.12 (dd, J = 17.7, 4.9 Hz, 1H), 2.91 (dd, J = 17.7, 6.1 Hz, 1H), 2.80 -2.60 (m, 2H), 2.40– 2.25 (m, 1H), 2.20– 2.03 (m, 2H), 2.00 -1.80 (m, 2H), 1.74 (d, J = 1.2 Hz, 3H), 1.11 (d, J = 6.8 Hz, 3H), 0.96 (d, J = 7.1 Hz, 3H).
[1364] 13C NMR (100 MHz, CDCl3) d 202.5, 170.7, 165.8, 160.3, 157.5, 153.8, 144.6, 144.4, 137.0, 136.7, 135.1, 134.1, 133.0, 125.1, 124.2, 119.9 (d, 3JCF = 7.7 H), 115.3 (d, 2JCF = 22.3 H), 79.2, 68.9, 64.8, 59.8, 49.2, 48.7, 42.6, 41.1, 37.0, 33.8, 28.5, 24.7, 13.2, 12.7, 10.3.
[1365] HRMS-ESI m/z calcd for C35H42FN4O9+ [M + H]+ 681.2930, found 681.2935.
[1366] Analogue 40g
Figure imgf000379_0001
[1367] Prepared according to general procedure D from primary alcohol 38 (25 mg, 34 mmol, 1 equiv), DMAP (0.4 mg, 3 mmol, 0.1 equiv) and a solution of 3-isocyanatopyridine in toluene (0.1 M, 1.0 mL, 0.10 mmol, 3.0 equiv). Toluene was employed as solvent and the reaction was run at 80 °C. Analogue 40g (12 mg, 53% over 2 steps) was obtained as a white solid.
[1368] TLC (MeOH;DCM = 1:20): Rf = 0.30 (UV, p-anisaldehyde).
[1369] 1H NMR (400 MHz, CDCI3) d 9.38 (br s, 1H), 8.54 (d, J = 2.6 Hz, 1H), 8.22 (dd, J = 4.7, 1.5 Hz, 1H), 8.20 (s, 1H), 8.11 (ddd, J = 8.4, 2.6, 1.5 Hz, 1H), 7.21 (dd, J = 8.4, 4.7 Hz, 1H), 6.54 (dd, J = 16.2, 4.1 Hz, 1H), 6.18 (d, J = 15.6 Hz, 1H), 6.06 (dd, J = 8.3, 4.4 Hz, 1H), 5.80 (dd, J = 16.2, 2.0 Hz, 1H), 5.67 (ddd, J = 15.6, 9.2, 4.4 Hz, 1H), 5.57 (d, J = 8.7 Hz, 1H), 5.17 (dd, J = 9.5, 1.9 Hz, 1H), 4.95 (dt, J = 8.7, 5.6 Hz, 1H), 4.74 (dd, J = 8.7, 2.7 Hz, 1H), 4.61 (dd, J = 11.6, 3.7 Hz, 1H), 4.34 (ddd, J = 13.6, 8.2, 4.4 Hz, 1H), 3.90 (dd, J = 8.5, 5.6 Hz, 2H), 3.83 (d, J = 1.5 Hz, 2H), 3.74 (dd, J = 11.6, 9.7 Hz, 1H), 3.50 (td, J = 9.6, 4.6 Hz, 1H), 3.12 (dd, J = 17.5, 5.1 Hz, 1H), 2.93 (dd, J = 17.5, 6.0 Hz, 1H), 2.80– 2.65 (m, 1H), 2.40– 2.25 (m, 1H), 2.20– 2.00 (m, 1H), 2.00– 1.80 m, 3H), 1.73 (d, J = 1.2 Hz, 3H), 1.11 (d, J = 6.9 Hz, 3H), 0.97 (d, J = 7.0 Hz, 3H).
[1370] 13C NMR (100 MHz, CDCl3) d 202.5, 170.6, 165.8, 160.4, 157.5, 153.8, 144.5, 144.5, 143.6, 140.3, 136.9, 136.6, 136.1, 134.0, 133.1125.3, 125.0, 124.2, 123.5, 79.2, 69.2, 64.8, 59.8, 49.2, 48.8, 42.6, 41.1, 37.0, 33.7, 28.5, 24.7, 13.3, 12.7, 10.2.
[1371] HRMS-ESI m/z calcd for C34H42N5O9 + [M + H]+ 664.2977, found 664.2988.
[1372] Analogue 40h
Figure imgf000380_0001
[1373] Prepared according to general procedure D from primary alcohol 38 (21 mg, 29 mmol, 1 equiv), DMAP (0.4 mg, 3 mmol, 0.1 equiv) and a solution of 2-isocyanatopyridine in toluene (0.1 M, 0.86 mL, 0.086 mmol, 3.0 equiv). Toluene was employed as solvent and the reaction was run at 80 °C. Analogue 40h (10 mg, 57% over 2 steps) was obtained as a white solid.
[1374] TLC (MeOH;DCM = 1:20): Rf = 0.30 (UV, p-anisaldehyde).
[1375] 1H NMR (400 MHz, CDCl3) d 8.93 (s, 1H), 8.34 (s, 1H), 8.23 (dd, J = 5.1, 1.8 Hz, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.64 (td, J = 8.0, 2.0 Hz, 1H), 6.94 (dd, J = 7.3, 5.0 Hz, 1H), 6.49 (dd, J = 16.3, 4.6 Hz, 1H), 6.18 (dd, J = 8.7, 3.7 Hz, 1H), 6.13 (d, J = 15.6 Hz, 1H), 5.79 (dd, J = 16.3, 1.9 Hz, 1H), 5.67 (ddd, J = 15.0, 9.3, 4.4 Hz, 1H), 5.49 (d, J = 8.7 Hz, 1H), 5.07 (dd, J = 10.0, 1.8 Hz, 1H), 4.91 (dt, J = 9.3, 5.5 Hz, 1H), 4.74 (dd, J = 8.8, 3.1 Hz, 1H), 4.42 (ddd, J = 13.9, 8.7, 4.5 Hz, 1H), 4.27 (dd, J = 11.2, 4.6 Hz, 1H), 4.15 (dd, J = 11.2, 5.7 Hz, 1H), 3.97 (dt, J = 11.4, 7.3 Hz, 1H), 3.85– 3.75 (m, 1H), 3.83 (d, J = 16.1 Hz, 1H), 3.78 (d, J = 16.2 Hz, 1H), 3.40 (ddd, J = 13.8, 9.3, 3.7 Hz, 1H), 3.05 (dd, J = 17.6, 5.2 Hz, 1H), 2.91 (dd, J = 17.5, 5.8 Hz, 1H), 2.73 (ddd, J = 9.1, 4.6, 2.2 Hz, 1H), 2.37– 2.21 (m, 1H), 2.21 – 2.04 (m, 1H), 1.90 (qq, J = 7.4, 3.2 Hz, 2H), 1.84– 1.70 (m, 1H), 1.72 (s, 3H), 1.08 (d, J = 6.8 Hz, 3H), 1.04 (d, J = 7.0 Hz, 3H).
[1376] 13C NMR (100 MHz, CDCI3) d 202.8, 171.5, 166.4, 160.2, 157.0, 153.7, 152.1, 147.8, 145.1, 144.1, 138.0, 137.0, 136.3, 134.0, 132.9, 125.1, 124.2, 118.5, 112.6, 77.8, 67.8, 65.0, 59.8, 48.9, 48.5, 42.8, 41.0, 36.7, 34.1, 28.2, 25.0, 14.1, 12.7, 10.0.
[1377] HRMS-ESI m/z calcd for C34H42N5O9+ [M + H]+ 664.2977, found 664.2988.
[1378] Analogue 40i
Figure imgf000381_0001
[1379] Prepared according to general procedure D from primary alcohol 38 (21 mg, 29 mmol, 1 equiv), DMAP (0.4 mg, 3 mmol, 0.1 equiv) and a solution of 2-isocyanatopyrazine in toluene (0.1 M 0.86 mL, 0.086 mmol, 3.0 equiv). Toluene was employed as solvent and the reaction was run at 80 °C. Analogue 40i (10 mg, 43% over 2 steps) was obtained as a white solid.
[1380] TLC (MeOH;DCM = 1:20): Rf = 0.30 (UV, p-anisaldehyde).
[1381] 1H NMR (400 MHz, CDCI3) d 9.41 (br s, 1H), 9.28 (d, J = 1.5 Hz, 1H), 8.36 (s, 1H), 8.23 (d, J = 2.7 Hz, 1H), 8.19 (dd, J = 2.6, 1.5 Hz, 1H), 6.50 (dd, J = 16.3, 4.5 Hz, 1H), 6.14 (d, J = 15.6 Hz, 1H), 6.05 (dd, J = 9.0, 3.8 Hz, 1H), 5.80 (dd, J = 16.3, 2.0 Hz, 1H), 5.68 (ddd, J = 15.6, 9.2, 4.5 Hz, 1H), 5.53 (d, J = 8.6 Hz, 1H), 5.11 (dd, J = 9.9, 1.9 Hz, 1H), 4.93 (q, J = 6.2 Hz, 1H), 4.74 (dd, J = 8.9, 3.0 Hz, 1H), 4.50– 4.35 (m, 2H), 4.09 (dd, J = 11.3, 6.9 Hz, 1H), 3.98 (dd, J = 11.5, 7.3 Hz, 1H), 3.90– 3.75 (m, 3H), 3.42 (ddd, J = 14.0, 9.3, 3.8 Hz, 1H), 3.07 (dd, J = 17.6, 5.0 Hz, 1H), 2.92 (dd, J = 17.7, 5.8 Hz, 1H), 2.86 (br s, 1H), 2.78 – 2.68 (m, 1H), 2.40– 2.25 (m 1H), 2.20– 2.07 (m, 1H), 1.97– 1.85 (m, 2H), 1.84– 1.74 (m, 1H), 1.73 (s, 3H), 1.10 (d, J = 6.8 Hz, 3H), 1.04 (d, J = 7.0 Hz, 3H).
[1382] 13C NMR (100 MHz, CDCI3) d 202.7, 171.3, 166.2, 160.3, 157.2, 153.4, 149.0, 145.1, 144.1, 141.9, 138.8, 137.0, 136.7, 136.2, 134.0, 132.9, 125.1, 124.2, 78.2, 68.6, 65.0, 59.8, 49.048.6, 42.7, 41.1, 36.8, 33.9, 28.3, 25.0, 14.0, 12.7, 10.0.
[1383] HRMS-ESI m/z calcd for C33H41N6O9+ [M + Na]+ 687.2749, found 687.2744.
[1384] Analogue 40j
Figure imgf000382_0001
[1385] Prepared according to general procedure D from primary alcohol 38 (25 mg, 34 mmol, 1 equiv), DMAP (0.4 mg, 3 mmol, 0.1 equiv) and a solution of 4-isocyanato-2- methyloxazole in toluene (0.1 M, 1.0 mL, 0.10 mmol, 3.0 equiv). Toluene was employed as solvent and the reaction was run at 80 °C. Analogue 40j (12 mg, 52% over 2 steps) was obtained as a white solid.
[1386] TLC (MeOH;DCM = 1:20): Rf = 0.30 (UV, p-anisaldehyde).
[1387] 1H NMR (400 MHz, CDCI3) d 9.15 (br s, 1H), 8.53 (s, 1H), 7.67 (s, 1H), 6.49 (dd, J = 16.3, 4.3 Hz, 1H), 6.15 (d, J = 15.6 Hz, 1H), 6.04 (d, J = 9.4 Hz, 1H), 5.79 (dd, J = 16.3, 2.0 Hz, 1H), 5.68 (ddd, J = 14.9, 9.2, 4.4 Hz, 1H), 5.54 (d, J = 8.7 Hz, 1H), 5.10 (d, J = 9.4 Hz, 1H), 4.93 (q, J = 6.4 Hz, 1H), 4.76 (dd, J = 9.1, 2.8 Hz, 1H), 4.49– 4.29 (m, 2H), 4.06– 3.70 (m, 5H), 3.42 (ddd, J = 14.1, 9.3, 3.8 Hz, 1H), 3.09 (dd, J = 17.7, 4.9 Hz, 1H), 2.91 (dd, J = 17.8, 6.0 Hz, 1H), 2.87 (br s, 1H), 2.77– 2.66 (m, 1H), 2.37 (s, 3H), 2.34– 2.24 (m, 1H), 2.20– 2.06 (m, 1H), 1.95– 1.85 (m, 3H), 1.73 (s, 3H), 1.10 (d, J = 6.8 Hz, 3H), 0.99 (d, J = 7.0 Hz, 3H).
[1388] 13C NMR (100 MHz, CDCl3) d 202.8, 171.2, 166.1, 160.3, 159.2, 157.12153.5, 145.53144.3, 137.5, 137.0, 136.7, 134.0, 133.0, 125.1, 124.2, 123.9, 78.5, 69.0, 64.9, 59.8, 49.0, 48.5, 42.7, 41.1, 36.9, 33.9, 28.3, 24.9, 14.0, 13.7, 12.7, 10.2.
[1389] HRMS-ESI m/z calcd for C33H42N5O10 + [M + H]+ 668.2926, found 668.2932.
[1390] Analogue 40k
Figure imgf000383_0001
[1391] Prepared according to general procedure D from primary alcohol 38 (25 mg, 34 mmol, 1 equiv), DMAP (0.4 mg, 3 mmol, 0.1 equiv) and a solution of 4-isocyanato-2- methylthiazole in toluene (0.1 M 1.0 mL, 0.10 mmol, 3.0 equiv). Toluene was employed as solvent and the reaction was run at 80 °C. Analogue 40k (11 mg, 47% over 2 steps) was obtained as a white solid.
[1392] TLC (MeOH;DCM = 1:20): Rf = 0.30 (UV, p-anisaldehyde).
[1393] 1H NMR (400 MHz, CDCI3) d 9.32 (br s, 1H), 8.55 (s, 1H), 7.07 (s, 1H), 6.48 (dd, J = 16.3, 4.4 Hz, 1H), 6.14 (d, J = 15.6 Hz, 1H), 6.07 (d, J = 8.3 Hz, 1H), 5.79 (dd, J = 16.3, 2.0 Hz, 1H), 5.68 (ddd, J = 15.5, 9.3, 4.4 Hz, 1H), 5.52 (d, J = 8.7 Hz, 1H), 5.07 (dd, J = 9.8, 1.8 Hz, 1H), 4.92 (dt, J = 9.1, 5.4 Hz, 1H), 4.74 (dd, J = 8.7, 3.1 Hz, 1H), 4.44 (ddd, J = 13.8, 8.8, 4.5 Hz, 1H), 4.32 (dd, J = 11.2, 4.5 Hz, 1H), 4.08 (dd, J = 11.3, 6.8 Hz, 1H), 4.05– 3.93 (m, 1H), 3.91– 3.74 (m, 3H), 3.39 (ddd, J = 13.9, 9.4, 3.7 Hz, 1H), 3.06 (dd, J = 17.7, 5.0 Hz, 1H), 2.92 (dd, J = 17.7, 5.8 Hz, 1H), 2.79 (s, 1H), 2.76– 2.6 (m, 1H), 2.61 (s, 3H), 2.37– 2.23 (m, 1H), 2.22– 2.08 (m, 1H), 1.98– 1.80 (m, 2H), 1.84– 1.76 (m, 1H), 1.73 (s, 3H), 1.10 (d, J = 6.8 Hz, 3H), 1.03 (d, J = 7.0 Hz, 3H).
[1394] 13C NMR (100 MHz, CDCI3) d 202.9, 171.4, 166.4, 163.5, 160.2, 157.0, 153.9, 147.3, 145.6, 144.2, 137.0, 136.8, 134.0, 132.9, 125.1, 124.2, 98.0, 78.0168.3, 65.0, 59.8, 48.9, 48.4542.7, 41.1, 36.9, 34.0, 28.2, 25.0, 19.0, 14.1, 12.7, 10.0.
[1395] HRMS-ESI m/z calcd for C
Figure imgf000383_0002
[M + H]+ 684.2698, found 684.2726.
[1396] Analogue 40l
Figure imgf000384_0001
[1397] Prepared according to general procedure D from primary alcohol 38 (25 mg, 34 mmol, 1 equiv), DMAP (0.4 mg, 3 mmol, 0.1 equiv) and a solution of 4-isocyanato-2- methyloxazole in toluene (0.1 M, 1.0 mL, 0.10 mmol, 3.0 equiv). Toluene was employed as solvent and the reaction was run at 80 °C. Analogue 40l (12 mg, 52% over 2 steps) was obtained as a white solid.
[1398] TLC (MeOH;DCM = 1:20): Rf = 0.30 (UV, p-anisaldehyde).
[1399] 1H NMR (400 MHz, CDCl3) d 9.01 (br s, 1H), 8.43 (s, 1H), 7.19 (d, J = 2.3 Hz, 1H), 6.50 (dd, J = 16.3, 4.4 Hz, 1H), 6.42 (s, 1H), 6.14 (d, J = 15.4 Hz, 2H), 5.79 (dd, J = 16.3, 1.9 Hz, 1H), 5.67 (ddd, J = 15.6, 9.3, 4.5 Hz, 1H), 5.51 (d, J = 8.6 Hz, 1H), 5.09 (dd, J = 9.7, 1.8 Hz, 1H), 4.93 (dd, J = 8.8, 5.2 Hz, 1H), 4.77 (dd, J = 8.9, 2.8 Hz, 1H), 4.46– 4.26 (m, 2H), 4.05– 3.87 (m, 2H), 3.88– 3.77 (m, 3H), 3.75 (s, 3H), 3.42 (ddd, J = 14.0, 9.2, 3.9 Hz, 1H), 3.07 (dd, J = 17.6, 5.1 Hz, 1H), 2.92 (br s, 1H), 2.91 (dd, J = 17.5, 5.9 Hz, 1H), 2.76 – 2.66 (m, 1H), 2.40– 2.20 (m, 1H), 2.20– 2.01 (m, 1H), 2.00– 1.80 (m, 3H), 1.72 (s, 3H), 1.09 (d, J = 6.8 Hz, 3H), 0.99 (d, J = 7.0 Hz, 3H).
[1400] 13C NMR (100 MHz, CDCI3) d 202.8, 171.3, 166.2, 160.2, 157.0, 153.9, 147.6, 145.3144.3, 137.0, 136.7, 134.0, 133.0, 130.6, 125.1, 124.2, 96.1, 78.3, 68.4, 65.0, 59.8, 49.0, 48.5, 42.8, 41.0, 38.7, 36.9, 33.9, 28.3, 24.9, 13.8, 12.7, 10.2.
[1401] HRMS-ESI m/z calcd for C33H42N6NaO9+ [M + Na]+ 689.2905, found 689.2935.
[1402] Analogue 40m
Figure imgf000385_0001
[1403] Prepared according to general procedure D from primary alcohol 38 (25 mg, 34 mmol, 1 equiv), DMAP (0.4 mg, 3 mmol, 0.1 equiv) and a solution of 3-isocyanato-5- methylisoxazole in toluene (0.1 M, 1.0 mL, 0.10 mmol, 3.0 equiv). Toluene was employed as solvent and the reaction was run at 80 °C. Analogue 40m (2.6 mg, 13% over 2 steps) was obtained as a white solid.
[1404] TLC (MeOH;DCM = 1:20): Rf = 0.30 (UV, p-anisaldehyde).
[1405] 1H NMR (400 MHz, CDCl3) d 9.79 (s, 1H), 8.46 (s, 1H), 6.54– 6.44 (m, 2H), 6.16 (d, J = 15.6 Hz, 1H), 6.03 (dd, J = 8.6, 4.0 Hz, 1H), 5.79 (dd, J = 16.3, 2.0 Hz, 1H), 5.67 (ddd, J = 15.6, 9.3, 4.4 Hz, 1H), 5.56 (d, J = 8.6 Hz, 1H), 5.11 (dd, J = 9.6, 1.8 Hz, 1H), 4.93 (dt, J = 8.7, 5.4 Hz, 1H), 4.72 (dd, J = 9.0, 3.0 Hz, 1H), 4.44 (dd, J = 11.3, 3.9 Hz, 1H), 4.39 (td, J = 8.7, 4.1 Hz, 1H), 4.02– 3.89 (m, 2H), 3.90– 3.80 (m, 1H), 3.84 (d, J = 16.6 Hz, 1H), 3.78 (d, J = 16.6 Hz, 1H), 3.43 (ddd, J = 14.1, 9.4, 3.9 Hz, 1H), 3.10 (dd, J = 17.8, 4.9 Hz, 1H), 2.93 (dd, J = 17.8, 5.9 Hz, 2H), 2.90 (br s,1H), 2.77– 2.66 (m, 1H), 2.36 (d, J = 0.9 Hz, 3H), 2.35– 2.25 (m, 1H), 2.20– 2.05 (m, 1H), 1.97– 1.80 (m, 3H), 1.73 (d, J = 1.2 Hz, 3H), 1.10 (d, J = 6.8 Hz, 3H), 0.99 (d, J = 7.0 Hz, 3H).
[1406] 13C NMR (100 MHz, CDCl3) d 202.9, 171.2, 169.3, 166.1, 160.3, 158.9, 157.2, 153.5, 145.6, 144.2, 136.8, 136.8, 133.9, 133.1, 125.0, 124.2, 95.7, 78.6, 69.2, 64.9, 59.8, 49.1, 48.6, 42.6, 41.1, 37.0, 33.7, 28.3, 24.9, 13.6, 12.7, 12.6, 10.0.
[1407] HRMS-ESI m/z calcd for C33H40N5O9 + [M– H2O]+ 650.2821, found 650.2822.
[1408] Analogue 40n
Figure imgf000386_0001
[1409] Prepared according to general procedure D from primary alcohol 38 (25 mg, 34 mmol, 1 equiv), DMAP (0.4 mg, 3 mmol, 0.1 equiv) and a solution of 3-isocyanato-6- bromopyridine in toluene (0.1 M, 1.0 mL, 0.10 mmol, 3.0 equiv). Toluene was employed as solvent and the reaction was run at 80 °C. Analogue 40n (11 mg, 43% over 2 steps) was obtained as a white solid.
[1410] TLC (MeOH;DCM = 1:20): Rf = 0.30 (UV, p-anisaldehyde).
[1411] 1H NMR (400 MHz, CDCl3) d 9.50 (br s, 1H), 8.37 (d, J = 2.8 Hz, 1H), 8.19 (s, 1H), 8.02 (dd, J = 8.7, 2.9 Hz, 1H), 7.36 (d, J = 8.7 Hz, 1H), 6.54 (dd, J = 16.2, 4.1 Hz, 1H), 6.18 (d, J = 15.6 Hz, 1H), 5.93 (dd, J = 8.2, 4.4 Hz, 1H), 5.80 (dd, J = 16.2, 2.0 Hz, 1H), 5.68 (ddd, J = 15.6, 9.2, 4.4 Hz, 1H), 5.57 (d, J = 8.7 Hz, 1H), 5.17 (dd, J = 9.5, 1.9 Hz, 1H), 4.95 (dt, J = 8.7, 5.5 Hz, 1H), 4.71 (dd, J = 8.8, 2.6 Hz, 1H), 4.63 (dd, J = 11.6, 3.7 Hz, 1H), 4.35 (ddd, J = 13.5, 8.1, 4.6 Hz, 1H), 3.95– 3.85 (m, 2H), 3.84 (d, J = 2.6 Hz, 2H), 3.71 (dd, J = 11.6, 10.0 Hz, 1H), 3.51 (ddd, J = 14.2, 9.2, 4.4 Hz, 1H), 3.13 (dd, J = 17.7, 5.0 Hz, 1H), 2.93 (dd, J = 17.7, 6.0 Hz, 1H), 2.83– 2.68 (m, 2H), 2.40– 2.22 (m, 1H), 2.16– 2.04 (m, 1H), 1.98– 1.83 (m, 2H), 1.74 (d, J = 1.3 Hz, 3H), 1.72– 1.62 (m, 1H), 1.12 (d, J = 6.9 Hz, 3H), 0.97 (d, J = 7.0 Hz, 3H).
[1412] 13C NMR (100 MHz, CDCI3) d 202.6, 170.5, 165.8, 160.4, 157.5, 153.6, 144.6, 144.5, 140.4, 136.9, 136.6, 135.8, 134.1, 134.0, 133.0, 128.1, 127.7, 125.1, 124.2, 79.3, 69.4, 64.9, 59.9, 49.2, 48.8, 42.6, 41.1, 37.1, 33.7, 28.5, 24.7, 13.3, 12.8, 10.2.
[1413] HRMS-ESI m/z calcd for C34H39BrN5O8+ [M– H2O]+ 724.1977, found 724.1988.
[1414] Analogue 40o
Figure imgf000387_0001
[1415] Prepared according to general procedure D from primary alcohol 38 (25 mg, 34 mmol, 1 equiv), DMAP (0.4 mg, 3 mmol, 0.1 equiv) and a solution of 4-isocyanato-2- bromopyridine in toluene (0.1 M, 1.0 mL, 0.10 mmol, 3.0 equiv). Toluene was employed as solvent and the reaction was run at 80 °C. Analogue 40o (17 mg, 67% over 2 steps) was obtained as a white solid.
[1416] TLC (MeOH;DCM = 1:20): Rf = 0.30 (UV, p-anisaldehyde).
[1417] 1H NMR (400 MHz, CDCl3) d 9.65 (br s, 1H), 8.22 (s, 1H), 8.12 (d, J = 5.6 Hz, 1H), 7.73 (d, J = 1.9 Hz, 1H), 7.43 (dd, J = 5.7, 1.9 Hz, 1H), 6.54 (dd, J = 16.2, 4.1 Hz, 1H), 6.18 (d, J = 15.6 Hz, 1H), 6.01 (dd, J = 8.1, 4.5 Hz, 1H), 5.80 (dd, J = 16.2, 2.0 Hz, 1H), 5.67 (ddd, J = 15.6, 9.1, 4.4 Hz, 1H), 5.58 (d, J = 8.7 Hz, 1H), 5.17 (dd, J = 9.4, 1.9 Hz, 1H), 4.96 (dt, J = 8.8, 5.6 Hz, 1H), 4.70 (dd, J = 8.8, 2.6 Hz, 1H), 4.61 (dd, J = 11.6, 3.6 Hz, 1H), 4.33 (ddd, J = 13.6, 8.0, 4.4 Hz, 1H), 3.91 (dd, J = 8.6, 5.5 Hz, 2H), 3.84 (s, 2H), 3.73 (dd, J = 11.6, 9.9 Hz, 1H), 3.52 (ddd, J = 14.2, 9.2, 4.4 Hz, 1H), 3.14 (dd, J = 17.6, 5.0 Hz, 1H), 3.00 – 2.80, (m, 1H), 2.93 (dd, J = 17.6, 6.1 Hz, 1H), 2.78– 2.66 (m, 1H), 2.40– 2.20 (m, 1H), 2.20– 2.00 (m, 1H), 1.99– 1.81 (m, 3H), 1.74 (d, J = 1.1 Hz, 3H), 1.12 (d, J = 6.8 Hz, 3H), 0.97 (d, J = 7.0 Hz, 3H).
[1418] 13C NMR (100 MHz, CDCI3) d 202.4, 170.4, 165.6, 160.3, 157.7, 153.0, 150.2, 148.2, 144.6, 144.4, 142.5, 136.9, 136.6, 134.13133.0, 125.01124.2, 116.2, 112.0, 79.2, 69.5, 64.8, 59.8, 49.3, 48.8, 42.6, 41.1, 37.0, 33.7, 28.4, 24.6, 13.3, 12.7, 10.3.
[1419] HRMS-ESI m/z calcd for C34H39BrN5O8+ [M– H2O]+ 724.1977, found 724.1988.
[1420] Analogue 40p
Figure imgf000388_0001
[1421] Prepared according to general procedure D from primary alcohol 38 (25 mg, 34 mmol, 1 equiv), DMAP (0.4 mg, 3 mmol, 0.1 equiv) and a solution of 2-isocyanatoquinoline in toluene (0.1 M, 3.0 mL, 0.34 mmol, 10.0 equiv). Toluene was employed as solvent and the reaction was run at 80 °C. Analogue 40p (12 mg, 49% over 2 steps) was obtained as a white solid.
[1422] TLC (MeOH;DCM = 1:20): Rf = 0.30 (UV, p-anisaldehyde).
[1423] 1H NMR (400 MHz, CDCl3) d 9.08 (br s, 1H), 8.20 (d, J = 9.0 Hz, 1H), 8.11 (d, J = 9.0 Hz, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.74 (dd, J = 8.1, 1.3 Hz, 1H), 7.63 (ddd, J = 8.5, 6.8, 1.5 Hz, 1H), 7.40 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 6.48 (dd, J = 16.3, 4.6 Hz, 1H), 6.24– 6.16 (m, 1H), 6.13 (d, J = 15.7 Hz, 1H), 5.79 (dd, J = 16.3, 1.9 Hz, 1H), 5.67 (ddd, J = 15.6, 9.3, 4.5 Hz, 1H), 5.50 (d, J = 8.7 Hz, 1H), 5.06 (dd, J = 10.1, 1.8 Hz, 1H), 4.91 (dt, J = 9.3, 5.4 Hz, 1H), 4.74 (dd, J = 8.7, 3.2 Hz, 1H), 4.45 (ddd, J = 13.9, 8.8, 4.5 Hz, 1H), 4.27 (d, J = 4.8 Hz, 2H), 4.01 (dt, J = 11.3, 7.3 Hz, 1H), 3.92– 3.73 (m, 3H), 3.38 (ddd, J = 14.6, 9.4, 3.6 Hz, 1H), 3.04 (dd, J = 17.6, 5.1 Hz, 1H), 2.94 (dd, J = 17.6, 5.6 Hz, 1H), 2.89 (s, 1H), 2.79– 2.63 (m, 1H), 2.38– 2.23 (m, 1H), 2.20– 2.10 (m, 1H), 2.01– 1.82 (m, 3H), 1.72 (d, J = 1.2 Hz, 3H), 1.13– 1.07 (m, 3H), 1.06 (s, 3H).
[1424] 13C NMR (100 MHz, CDCI3) d 202.8, 171.6, 166.6, 160.2, 157.0, 154.0, 151.5, 146.8, 145.5, 144.0, 138.2, 137.0, 136.9, 133.9, 132.9, 129.7, 127.5, 127.14125.7, 125.1, 124.6, 124.2, 113.3, 77.6, 67.6, 65.1, 59.8, 48.9, 48.5, 42.8, 41.1, 36.7, 34.1, 28.2, 25.2, 14.4, 12.7, 9.9.
[1425] HRMS-ESI m/z calcd for C38H43N5NaO9+ [M + Na]+ 736.2953, found 736.2957.
[1426] Analogue 40q
Figure imgf000389_0001
[1427] Prepared according to general procedure D from primary alcohol 38 (25 mg, 34 mmol, 1 equiv), DMAP (0.4 mg, 3 mmol, 0.1 equiv) and a solution of 3- isocyanatoisoquinoline in toluene (0.1 M, 3.0 mL, 0.34 mmol, 10.0 equiv).. Toluene was employed as solvent and the reaction was run at 80 °C. Analogue 40q (16 mg, 65% over 2 steps) was obtained as a white solid.
[1428] TLC (MeOH;DCM = 1:20): Rf = 0.30 (UV, p-anisaldehyde).
[1429] 1H NMR (400 MHz, CDCl3) d 8.98 (s, 1H), 8.95 (s, 1H), 8.39 (s, 1H), 8.28 (s, 1H), 7.89– 7.83 (m, 1H), 7.76 (d, J = 8.3 Hz, 1H), 7.60 (ddd, J = 8.2, 6.8, 1.2 Hz, 1H), 7.42 (ddd, J = 8.1, 6.8, 1.1 Hz, 1H), 6.50 (dd, J = 16.3, 4.6 Hz, 1H), 6.15 (broad t, J = 4.7 Hz, 1H), 6.12 (d, J = 8.2 Hz, 1H), 5.80 (dd, J = 16.3, 1.9 Hz, 1H), 5.68 (ddd, J = 15.5, 9.3, 4.5 Hz, 1H), 5.50 (d, J = 8.7 Hz, 1H), 5.10 (dd, J = 10.0, 1.8 Hz, 1H), 4.92 (dt, J = 8.6, 5.4 Hz, 1H), 4.78 (dd, J = 8.8, 3.1 Hz, 1H), 4.44 (ddd, J = 14.0, 8.9, 4.5 Hz, 1H), 4.32 (dd, J = 11.2, 4.7 Hz, 1H), 4.22 (dd, J = 11.2, 5.6 Hz, 1H), 3.99 (dt, J = 11.4, 7.4 Hz, 1H), 3.89– 3.73 (m, 3H), 3.39 (ddd, J = 14.1, 9.3, 3.6 Hz, 1H), 3.06 (dd, J = 17.6, 5.1 Hz, 1H), 2.92 (dd, J = 17.6, 5.7 Hz, 1H), 2.74 (ddt, J = 6.9, 4.5, 2.1 Hz, 1H), 2.41– 2.26 (m, 1H), 2.23– 2.10 (m, 1H), 2.01– 1.75 (m, 4H), 1.72 (d, J = 1.2 Hz, 3H), 1.10 (d, J = 6.8 Hz, 3H), 1.07 (d, J = 7.0 Hz, 3H).
[1430] 13C NMR (100 MHz, CDCl3) d 202.8, 171.6, 166.4, 160.2, 157.0, 153.8, 151.0, 147.2, 145.19, 144.1, 138.0, 137.1, 136.8, 134.0, 132.9, 130.5, 127.4, 126.5, 125.90, 125.2, 125.1, 124.2, 106.2, 77.9, 67.8, 65.1, 59.8, 48.9, 48.5, 42.8, 41.1, 36.7, 34.2, 28.3, 25.1, 14.2, 12.7, 10.03.
[1431] HRMS-ESI m/z calcd for C38H43N5NaO9+ [M + Na]+ 736.2953, found 736.2957.
[1432] Analog 41a
Figure imgf000390_0001
[1433] Prepared according to general procedure D from primary alcohol 39 (40 mg, 55 mmol, 1 equiv), DMAP (0.7 mg, 6 mmol, 0.1 equiv) and phenyl isocyanate (18 mL, 0.16 mmol, 3.0 equiv). DCM was employed as solvent and the reaction was run at 23 °C.
Analogue 41a (18 mg, 50% over 2 steps) was obtained as a white solid.
[1434] TLC (MeOH;DCM = 1:20): Rf = 0.30 (UV, p-anisaldehyde).
[1435] 1H NMR (400 MHz, CDCl3) d 8.06 (s, 1H), 7.54 (br s, 1H), 7.45 (d, J = 8.0 Hz, 2H), 7.36– 7.26 (m, 2H), 7.05 (tt, J = 7.4, 1.2 Hz, 1H), 6.50 (dd, J = 16.3, 4.9 Hz, 1H), 6.24 (dd, J = 8.2, 2.9 Hz, 1H), 6.11 (d, J = 15.7 Hz, 1H), 5.79 (dd, J = 16.3, 1.8 Hz, 1H), 5.69 (ddd, J = 15.6, 9.0, 4.5 Hz, 1H), 5.42 (d, J = 8.6 Hz, 1H), 5.17 (d, J = 4.3 Hz, 1H), 4.91 (d, J = 7.6 Hz, 1H), 4.74 (dd, J = 9.0, 3.1 Hz, 1H), 4.44 (ddd, J = 13.9, 8.7, 4.6 Hz, 1H), 4.24 (dd, J = 11.0, 3.7 Hz, 1H), 4.08 (dd, J = 10.9, 4.3 Hz, 1H), 3.99 (dt, J = 11.2, 7.4 Hz, 1H), 3.82 (s, 2H), 3.81– 3.73 (m, 1H), 3.40 (ddd, J = 14.5, 9.1, 3.8 Hz, 1H), 3.04 (dd, J = 17.2, 5.7 Hz, 1H), 2.89 (dd, J = 17.2, 5.4 Hz, 1H), 2.81– 2.71 (m, 1H), 2.58 (br s, 1H), 2.20 (td, J = 8.9, 3.7 Hz, 2H), 1.94 (ddt, J = 11.9, 7.3, 3.7 Hz, 2H), 1.88– 1.76 (m, 1H), 1.72 (d, J = 1.2 Hz, 3H), 1.14 (d, J = 6.8 Hz, 6H).
[1436] 13C NMR (100 MHz, CDCI3) d 202.4, 171.3, 166.4, 160.2, 157.0, 153.7, 144.1, 143.8, 138.2, 137.0, 136.5, 134.3, 132.6, 128.9, 125.3, 124.3, 123.3, 118.9, 76.8, 67.8, 65.1, 59.7, 48.8, 48.5, 43.1, 41.0, 36.5, 35.0, 28.4, 25.0, 13.8, 12.7, 11.0.
[1437] HRMS-ESI m/z calcd for C35H42N4NaO9+ [M + Na]+ 685.2844, found 685.2850.
[1438] Analog 41b
Figure imgf000391_0001
[1439] Prepared according to general procedure D from primary alcohol 39 (50 mg, 68 mmol, 1 equiv), DMAP (0.9 mg, 7 mmol, 0.1 equiv) and 4-methylphenyl isocyanate (17 mL, 0.14 mmol, 2.0 equiv). DCM was employed as solvent and the reaction was run at 23 °C. Analogue 41b (22 mg, 47% over 2 steps) was obtained as a white solid.
[1440] TLC (MeOH:DCM = 1:20): Rf = 0.30 (UV, p-anisaldehyde).
[1441] 1H NMR (400 MHz, CDCl3) d 8.05 (s, 1H), 7.48 (br s, 1H), 7.31 (d, J = 8.0 Hz, 2H), 7.08 (d, J = 8.1 Hz, 2H), 6.50 (dd, J = 16.3, 5.0 Hz, 1H), 6.33 (br s, 1H), 6.10 (d, J = 15.6 Hz, 1H), 5.79 (dd, J = 16.3, 1.8 Hz, 1H), 5.68 (ddd, J = 15.6, 8.9, 4.5 Hz, 1H), 5.41 (d, J = 8.7 Hz, 1H), 5.14 (d, J = 6.5 Hz, 1H), 4.91 (dt, J = 8.8, 5.7 Hz, 1H), 4.73 (dd, J = 9.0, 3.1 Hz, 1H), 4.42 (ddd, J = 14.1, 8.6, 4.7 Hz, 1H), 4.21 (dd, J = 11.0, 3.8 Hz, 1H), 4.07 (dd, J = 11.0, 4.3 Hz, 1H), 3.97 (dt, J = 11.4, 7.5 Hz, 1H), 3.87– 3.72 (m, 1H), 3.81 (s, 2H), 3.46– 3.36 (m, 1H), 3.03 (dd, J = 17.0, 5.8 Hz, 1H), 2.89 (dd, J = 17.0, 5.5 Hz, 1H), 2.76 (td, J = 6.2, 5.3, 2.7 Hz, 1H), 2.29 (s, 3H), 2.24– 2.10 (m, 2H), 1.99– 1.89 (m, 2H), 1.85– 1.75 (m, 1H), 1.71 (d, J = 1.2 Hz, 3H), 1.12 (d, J = 7.0 Hz, 3H), 1.11 (d, J = 6.9 Hz, 3H).
[1442] 13C NMR (100 MHz, CDCl3) d 202.38, 171.3, 166.4, 160.2, 157.0, 153.8, 144.0, 143.9, 137.0, 136.5, 135.5, 134.3, 132.9, 132.6, 129.4, 125.3, 124.3, 119.0, 76.7, 67.6, 65.1, 59.7, 48.8, 48.53, 43.1, 41.0, 38.6, 34.9, 28.4, 25.0, 20.7, 13.8, 12.7, 11.0.
[1443] HRMS-ESI m/z calcd for C
Figure imgf000391_0002
[M + H]+ 677.3181, found 677.3190.
[1444] Analog 41c
Figure imgf000392_0001
[1445] Prepared according to general procedure D from primary alcohol 39 (50 mg, 68 mmol, 1 equiv), DMAP (0.9 mg, 7 mmol, 0.1 equiv) and 4-methoxyphenyl isocyanate (28 mL, 0.21 mmol, 3.0 equiv). DCM was employed as solvent and the reaction was run at 23 °C. Analogue 41c (25 mg, 53% over 2 steps) was obtained as a white solid.
[1446] TLC (MeOH;DCM = 1:20): Rf = 0.30 (UV, p-anisaldehyde).
[1447] 1H NMR (400 MHz, CDCl3) d 8.04 (br s, 1H), 7.43 (s, 1H), 7.34 (d, J = 8.0 Hz, 2H), 6.83 (d, J = 9.0 Hz, 2H), 6.50 (d, J = 16.4 Hz, 1H), 6.28 (s, 1H), 6.10 (d, J = 15.6 Hz, 1H), 5.79 (d, J = 16.3 Hz, 1H), 5.69 (ddd, J = 15.5, 8.9, 4.5 Hz, 1H), 5.41 (d, J = 8.7 Hz, 1H), 5.16 (s, 1H), 4.91 (dt, J = 8.6, 5.6 Hz, 1H), 4.80– 4.67 (m, 1H), 4.43 (ddd, J = 14.0, 8.7, 4.6 Hz, 1H), 4.21 (dd, J = 11.0, 3.7 Hz, 1H), 4.07 (dd, J = 11.0, 4.3 Hz, 1H), 3.98 (dt, J = 11.3, 7.5 Hz, 1H), 3.81 (s, 2H), 3.78 (s, 3H), 3.41 (ddd, J = 14.6, 8.9, 3.7 Hz, 1H), 3.03 (dd, J = 17.1, 5.8 Hz, 1H), 2.89 (dd, J = 17.1, 5.4 Hz, 1H), 2.76 (s, 1H), 2.64 (s, 1H), 2.25– 2.10 (m, 2H), 2.00– 1.83 (m, 2H), 1.87– 1.79 (m, 1H), 1.72 (d, J = 1.2 Hz, 3H), 1.12 (d, J = 6.8 Hz, 6H).
[1448] 13C NMR (100 MHz, CDCI3) d 202.40, 171.34, 166.46, 160.22, 157.02, 144.08, 143.86, 137.05, 136.56, 134.35, 132.56, 131.19, 125.34, 124.33, 120.87, 114.13, 76.86, 67.73, 65.14, 59.67, 55.49, 48.80, 48.53, 43.13, 41.00, 38.76, 34.97, 28.42, 25.03, 13.82, 12.73, 10.99.
[1449] HRMS-ESI m/z calcd for C36H45N4O10 + [M + H]+ 693.3130, found 693.3138.
[1450] Analog 41d
Figure imgf000393_0001
[1451] Prepared according to general procedure D from primary alcohol 39 (50 mg, 68 mmol, 1 equiv), DMAP (0.9 mg, 7 mmol, 0.1 equiv) and 4-trifluoromethoxyphenyl isocyanate (31 mL, 0.21 mmol, 3.0 equiv). DCM was employed as solvent and the reaction was run at 23 °C. Analogue 41d (15 mg, 30% over 2 steps) was obtained as a white solid.
[1452] TLC (MeOH;DCM = 1:20): Rf = 0.30 (UV, p-anisaldehyde).
[1453] 1H NMR (400 MHz, CDCl3) d 8.05 (s, 1H), 7.92 (br s, 1H), 7.51 (d, J = 8.7 Hz, 2H), 7.13 (d, J = 8.6 Hz, 2H), 6.50 (dd, J = 16.3, 4.8 Hz, 1H), 6.16 (s, 1H), 6.12 (d, J = 15.6 Hz, 1H), 5.79 (dd, J = 16.3, 1.8 Hz, 1H), 5.75– 5.63 (m, 1H), 5.45 (d, J = 8.7 Hz, 1H), 5.22 (d, J = 4.8 Hz, 1H), 4.91 (q, J = 7.6, 6.6 Hz, 1H), 4.75 (dd, J = 9.0, 3.0 Hz, 1H), 4.43 (ddd, J = 14.0, 8.7, 4.6 Hz, 1H), 4.30 (dd, J = 10.9, 3.3 Hz, 1H), 4.07 (dd, J = 10.9, 3.9 Hz, 1H), 3.98 (dt, J = 11.4, 7.5 Hz, 2H), 3.83 (s, 2H), 3.83– 3.74 (m, 1H), 3.41 (ddd, J = 13.7, 9.0, 3.7 Hz, 1H), 3.04 (dd, J = 17.3, 5.6 Hz, 1H), 2.90 (dd, J = 17.2, 5.5 Hz, 1H), 2.79– 2.69 (m, 1H), 2.56 (br s, 1H), 2.30– 2.13 (m, 2H), 2.00– 1.88 (m, 2H), 1.87– 1.75 (m, 1H), 1.73 (d, J = 1.2 Hz, 3H), 1.16 (d, J = 2.8 Hz, 3H), 1.14 (d, J = 2.9 Hz, 3H).
[1454] 13C NMR (100 MHz, CDCI3) d 202.39, 171.20, 166.41, 160.24, 157.18, 153.76, 144.56, 144.01, 143.84, 137.16, 137.09, 136.59, 134.31, 132.64, 125.29, 124.30, 121.65, 119.93, 76.58, 68.59, 65.10, 59.67, 48.87, 48.59, 43.02, 41.08, 39.49, 35.27, 28.43, 25.01, 13.51, 12.73, 11.01.
[1455] HRMS-ESI m/z calcd for C36H40F3N4O9 + [M– H2O]+ 729.2742, found 729.2754.
[1456] Analog 41e
Figure imgf000394_0001
[1457] Prepared according to general procedure D from primary alcohol 39 (40 mg, 55 mmol, 1 equiv), DMAP (0.7 mg, 6 mmol, 0.1 equiv) and 4-trifluoromethylphenyl isocyanate (18 mL, 0.16 mmol, 3.0 equiv). DCM was employed as solvent and the reaction was run at 23 °C. Analogue 41e (19 mg, 47% over 2 steps) was obtained as a white solid.
[1458] TLC (MeOH;DCM = 1:20): Rf = 0.30 (UV, p-anisaldehyde).
[1459] 1H NMR (400 MHz, CDCl3) d 8.18 (br s, 1H), 8.06 (s, 1H), 7.62 (d, J = 8.5 Hz, 2H), 7.52 (d, J = 8.7 Hz, 2H), 6.50 (dd, J = 16.3, 4.9 Hz, 1H), 6.18– 6.10 (m, 1H), 6.12 (d, J = 15.4 Hz, 1H), 5.80 (dd, J = 16.3, 1.8 Hz, 1H), 5.69 (ddd, J = 15.5, 9.1, 4.4 Hz, 1H), 5.46 (d, J = 8.7 Hz, 1H), 5.25 (dd, J = 4.7, 2.2 Hz, 1H), 4.92 (d, J = 7.7 Hz, 1H), 4.75 (dd, J = 9.0, 3.1 Hz, 1H), 4.42 (ddd, J = 13.7, 8.5, 4.4 Hz, 1H), 4.33 (dd, J = 10.9, 3.2 Hz, 1H), 4.08 (dd, J = 11.0, 3.7 Hz, 1H), 4.04– 3.91 (m, 1H), 3.83 (s, 2H), 3.82– 3.76 (m, 1H), 3.42 (ddd, J = 15.0, 9.1, 3.8 Hz, 1H), 3.04 (dd, J = 17.3, 5.6 Hz, 1H), 2.91 (dd, J = 17.3, 5.5 Hz, 1H), 2.79– 2.69 (m, 1H), 2.60 (br s, 1H), 2.24– 2.14 (m, 2H), 2.00– 1.90 (m, 2H), 1.85– 1.76 (m, 1H), 1.73 (d, J = 1.2 Hz, 3H), 1.17 (d, J = 4.2 Hz, 3H), 1.15 (d, J = 4.2 Hz, 3H).
[1460] 13C NMR (100 MHz, CDCl3) d 202.4, 171.2, 166.4, 160.3, 157.3, 153.6, 144.0, 141.7, 137.1, 136.6, 134.3, 132.69, 126.1 (q, 3J CF= 3.6 Hz), 125.3, 124.3, 118.4, 76.5, 68.8, 65.0, 59.7, 48.9, 48.6, 43.0, 41.1, 35.3, 31.6, 25.0, 22.6, 14.1, 12.72, 11.0.
[1461] HRMS-ESI m/z calcd for C36H41F3N4NaO9 + [M + Na]+ 753,2718, found 753.2717.
[1462] Analogue 41f
Figure imgf000395_0001
[1463] Prepared according to general procedure D from primary alcohol 39 (50 mg, 68 mmol, 1 equiv), DMAP (0.9 mg, 7 mmol, 0.1 equiv) and 4-fluorodephenyl isocyanate (16 mL, 0.14 mmol, 2.0 equiv). DCM was employed as solvent and the reaction was run at 23 °C. Analogue 41f (18 mg, 39% over 2 steps) was obtained as a white solid.
[1464] TLC (MeOH;DCM = 1:20): Rf = 0.30 (UV, p-anisaldehyde).
[1465] 1H NMR (400 MHz, CDCl3) d 8.04 (s, 1H), 7.73 (br s, 1H), 7.42 (br s, 2H), 6.98 (t, J = 8.7 Hz, 2H), 6.50 (dd, J = 16.3, 4.9 Hz, 1H), 6.19 (d, J = 8.6 Hz, 1H), 6.11 (d, J = 15.6 Hz, 1H), 5.79 (dd, J = 16.3, 1.8 Hz, 1H), 5.69 (ddd, J = 15.5, 9.0, 4.5 Hz, 1H), 5.43 (d, J = 8.7 Hz, 1H), 5.19 (d, J = 3.0 Hz, 1H), 4.95– 4.85 (m, 1H), 4.74 (dd, J = 8.9, 3.0 Hz, 1H), 4.43 (ddd, J = 14.1, 8.9, 4.7 Hz, 1H), 4.25 (dd, J = 10.9, 3.4 Hz, 1H), 4.07 (dd, J = 10.9, 4.0 Hz, 1H), 3.98 (dt, J = 11.4, 7.5 Hz, 1H), 3.82 (s, 2H), 3.80– 3.72 (m, 1H), 3.41 (ddd, J = 15.0, 9.1, 3.8 Hz, 1H), 3.04 (dd, J = 17.2, 5.6 Hz, 1H), 2.90 (dd, J = 17.2, 5.5 Hz, 1H), 2.79– 2.72 (m, 1H), 2.60 (br s, 1H), 2.26– 2.12 (m, 2H), 1.94 (dp, J = 11.2, 3.8 Hz, 2H), 1.87– 1.77 (m, 1H), 1.73 (d, J = 1.2 Hz, 3H), 1.14 (d, J = 6.6 Hz, 6H).
[1466] 13C NMR (100 MHz, CDCl3) d 202.4, 171.3, 166.4, 160.2, 157.1, 153.9, 144.1, 143.8, 137.1, 136.6, 134.3, 132.6, 125.3, 124.3, 120.7 (d, 3JCF = 7.7 Hz), 115.5 (d, 2JCF = 22.6 Hz), 76.7, 68.3, 65.1, 59.7, 48.8, 48.6, 43.0, 41.06, 39.3, 35.2, 28.42, 25.0, 13.6, 12.7, 11.0.
[1467] HRMS-ESI m/z calcd for C
Figure imgf000395_0002
[M + H]+ 681.2930, found 681.2935.
[1468] Analogue 41g
Figure imgf000396_0001
[1469] Prepared according to general procedure D from primary alcohol 39 (25 mg, 34 mmol, 1 equiv), DMAP (0.4 mg, 3 mmol, 0.1 equiv) and a solution of 3-isocyanatopyridine in toluene (0.1 M, 1.0 mL, 0.10 mmol, 3.0 equiv). Toluene was employed as solvent and the reaction was run at 80 °C. Analogue 41g (10 mg, 44% over 2 steps) was obtained as a white solid.
[1470] TLC (MeOH;DCM = 1:20): Rf = 0.30 (UV, p-anisaldehyde).
[1471] 1H NMR (400 MHz, CDCl3) d 8.52 (d, J = 2.6 Hz, 1H), 8.37 (br s, 1H), 8.24 (dd, J = 4.7, 1.5 Hz, 1H), 8.09 (br s, 1H), 8.08 (s, 1H), 7.23 (dd, J = 8.4, 4.8 Hz, 1H), 6.49 (dd, J = 16.3, 4.8 Hz, 1H), 6.15 (d, J = 9.5 Hz, 1H), 6.11 (d, J = 15.8 Hz, 1H), 5.80 (dd, J = 16.3, 1.8 Hz, 1H), 5.68 (ddd, J = 15.7, 8.7, 4.3 Hz, 1H), 5.46 (d, J = 8.7 Hz, 1H), 5.25 (dd, J = 4.2, 2.2 Hz, 1H), 4.91 (dt, J = 8.7, 5.7 Hz, 1H), 4.76 (dd, J = 9.0, 3.2 Hz, 1H), 4.41 (ddd, J = 13.7, 8.1, 4.0 Hz, 1H), 4.26 (dd, J = 10.9, 2.9 Hz, 1H), 4.15 (dd, J = 10.9, 3.7 Hz, 1H), 3.98 (dt, J = 11.5, 7.4 Hz, 1H), 3.88 (td, J = 7.5, 7.0, 3.8 Hz, 1H), 3.82 (s, 2H), 3.44 (ddd, J = 15.2, 8.7, 3.8 Hz, 1H), 3.07– 2.91 (m, 2H), 2.76– 2.66 (m, 1H), 2.28– 2.08 (m, 2H), 2.00– 1.90 (m, 2H), 1.89– 1.75 (m, 1H), 1.72 (d, J = 1.2 Hz, 3H), 1.18 (d, J = 7.9 Hz, 3H), 1.16 (d, J = 7.4 Hz, 3H).
[1472] 13C NMR (100 MHz, CDCI3) d 202.4, 171.1, 166.4, 160.4, 157.4, 154.1, 144.2, 144.0, 143.8, 140.8, 137.0, 136.1, 135.6, 134.2, 132.8, 126.3, 125.2, 124.4, 123.6, 76.2, 69.3, 65.1, 59.7, 48.8, 48.7, 43.1, 41.0, 40.1, 35.5, 28.5, 25.0, 13.5, 12.7, 11.0.
[1473] HRMS-ESI m/z calcd for C34H42N5O9+ [M + H]+ 664.2977, found 664.2988.
[1474] Analogue 41h
Figure imgf000397_0001
[1475] Prepared according to general procedure D from primary alcohol 39 (35 mg, 40 mmol, 1 equiv), DMAP (0.5 mg, 4 mmol, 0.1 equiv) and a solution of 2-isocyanatopyridine in toluene (0.1 M, 4.0 mL, 0.40 mmol, 10.0 equiv). Toluene was employed as solvent and the reaction was run at 80 °C. Analogue 41h (11 mg, 31% over 2 steps) was obtained as a white solid.
[1476] TLC (MeOH;DCM = 1:20): Rf = 0.30 (UV, p-anisaldehyde).
[1477] 1H NMR (400 MHz, CDCl3) d 8.52 (s, 1H), 8.32 (s, 1H), 8.29– 8.21 (m, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.68 (ddd, J = 8.7, 7.4, 1.9 Hz, 1H), 6.99 (ddd, J = 7.3, 4.9, 1.0 Hz, 1H), 6.55– 6.44 (m, 1H), 6.37 (dd, J = 8.9, 3.6 Hz, 1H), 6.11 (d, J = 15.6 Hz, 1H), 5.79 (dd, J = 16.3, 1.8 Hz, 1H), 5.69 (ddd, J = 15.6, 8.9, 4.6 Hz, 1H), 5.41 (d, J = 8.7 Hz, 1H), 5.11 (dd, J = 7.3, 2.2 Hz, 1H), 4.92 (dt, J = 8.7, 5.6 Hz, 1H), 4.71 (dd, J = 8.7, 3.3 Hz, 1H), 4.45 (ddd, J = 14.1, 8.9, 4.6 Hz, 1H), 4.21 (dd, J = 11.1, 4.1 Hz, 1H), 4.12 (dd, J = 11.1, 4.7 Hz, 1H), 4.05 – 3.97 (m, 1H), 3.84– 3.74 (m, 1H), 3.81 (s, 2H), 3.39 (ddd, J = 14.9, 8.9, 3.6 Hz, 1H), 3.05 (dd, J = 17.2, 5.7 Hz, 1H), 2.89 (dd, J = 17.3, 5.3 Hz, 1H), 2.82– 2.70 (m, 1H), 2.27– 2.11 (m, 2H), 1.98– 1.78 (m, 3H), 1.72 (d, J = 1.2 Hz, 3H), 1.12 (d, J = 6.8 Hz, 6H).
[1478] 13C NMR (100 MHz, CDCI3) d 202.5, 171.6, 166.5, 160.3, 157.0, 153.4, 151.6, 147.6, 144.7, 143.7, 138.4, 136.9, 136.6, 134.2, 132.7, 125.3, 124.4, 119.0, 112.6, 76.9, 67.7, 65.1, 59.7, 48.7, 48.5, 43.2, 40.9, 38.2, 34.7, 28.3, 25.1, 14.03, 12.7, 10.9.
[1479] HRMS-ESI m/z calcd for C34H42N5O9+ [M + H]+ 664.2977, found 681.2988.
[1480] Analogue 41i
Figure imgf000398_0001
[1481] Prepared according to general procedure D from primary alcohol 39 (21 mg, 29 mmol, 1 equiv), DMAP (0.4 mg, 3 mmol, 0.1 equiv) and a solution of 2-isocyanatopyrazine in toluene (0.1 M, 0.86 mL, 0.086 mmol, 3.0 equiv). Toluene was employed as solvent and the reaction was run at 80 °C. Analogue 41i (7.3 mg, 43% over 2 steps) was obtained as a white solid.
[1482] TLC (MeOH;DCM = 1:20): Rf = 0.30 (UV, p-anisaldehyde).
[1483] 1H NMR (400 MHz, CDCl3) d 9.31 (br s, 1H), 8.84 (s, 1H), 8.38 (d, J = 3.5 Hz, 1H), 8.28 (d, J = 2.6 Hz, 1H), 8.22 (t, J = 2.0 Hz, 1H), 6.49 (dd, J = 16.3, 4.9 Hz, 1H), 6.29 (d, J = 8.7 Hz, 1H), 6.10 (d, J = 15.7 Hz, 1H), 5.79 (dd, J = 16.2, 1.8 Hz, 1H), 5.68 (ddd, J = 15.6, 8.8, 4.5 Hz, 1H), 5.43 (d, J = 8.7 Hz, 1H), 5.17 (dd, J = 6.1, 2.1 Hz, 1H), 4.91 (dt, J = 8.7, 5.5 Hz, 1H), 4.71 (dd, J = 8.6, 3.3 Hz, 1H), 4.43 (dd, J = 11.7, 6.4 Hz, 1H), 4.27 (dd, J = 11.0, 3.6 Hz, 1H), 4.15 (dd, J = 11.0, 4.2 Hz, 1H), 4.07– 3.96 (m, 1H), 3.89– 3.83 (m, 1H), 3.81 (s, 2H), 3.39 (ddd, J = 14.9, 8.9, 3.6 Hz, 1H), 3.03 (dd, J = 17.1, 5.5 Hz, 1H), 2.91 (dd, J = 17.1, 5.5 Hz, 1H), 2.80– 2.70 (m, 1H), 2.27– 2.14 (m, 2H), 1.90 (ddd, J = 18.9, 10.3, 4.4 Hz, 3H), 1.72 (s, 3H), 1.15 (d, J = 6.5 Hz, 3H), 1.13 (s, 3H).
[1484] 13C NMR (100 MHz, CDCl3) d 202.5, 171.6, 166.5, 160.3, 157.1, 153.2, 148.5, 145.0, 143.6, 141.7, 139.3, 136.9, 136.51136.1, 134.2, 132.8, 125.2, 124.4, 76.4, 68.9, 65.1, 59.7, 48.8, 48.6, 43.1, 40.9, 39.0, 34.9, 28.3, 25.2, 13.7, 12.7, 10.8.
[1485] HRMS-ESI m/z calcd for C33H41N6O9 + [M + H]+ 665.2930, found 665.2963.
[1486] Analogue 41j
Figure imgf000399_0001
[1487] Prepared according to general procedure D from primary alcohol 39 (25 mg, 34 mmol, 1 equiv), DMAP (0.4 mg, 3 mmol, 0.1 equiv) and a solution of 4-isocyanato-2- methyloxazole in toluene (0.1 M, 1.0 mL, 0.10 mmol, 3.0 equiv). Toluene was employed as solvent and the reaction was run at 80 °C. Analogue 41j (11 mg, 33% over 2 steps) was obtained as a white solid.
[1488] TLC (MeOH;DCM = 1:20): Rf = 0.30 (UV, p-anisaldehyde).
[1489] 1H NMR (400 MHz, CDCl3) d 8.89 (s, 1H), 8.65 (s, 1H), 7.67 (s, 1H), 6.46 (dd, J = 16.4, 4.8 Hz, 1H), 6.21– 6.07 (m, 2H), 5.78 (dd, J = 16.4, 1.9 Hz, 1H), 5.68 (ddd, J = 15.6, 9.2, 4.5 Hz, 1H), 5.47 (d, J = 8.6 Hz, 1H), 5.24– 5.13 (m, 1H), 4.91 (dt, J = 8.9, 5.3 Hz, 1H), 4.71 (dd, J = 8.7, 3.2 Hz, 1H), 4.47 (ddd, J = 13.9, 9.0, 4.6 Hz, 1H), 4.18 (dd, J = 10.7, 2.9 Hz, 1H), 4.15– 3.99 (m, 2H), 3.90– 3.75 (m, 3H), 3.35 (ddd, J = 13.8, 9.1, 3.5 Hz, 1H), 3.04 (dd, J = 17.7, 5.0 Hz, 1H), 2.91 (dd, J = 17.6, 5.7 Hz, 1H), 2.2.80– 2.60 (m, 2H), 2.40 (s, 3H), 2.27– 2.14 (m, 2H), 1.98– 1.78 (m, 3H), 1.73 (d, J = 1.2 Hz, 3H), 1.16 (d, J = 7.0 Hz, 3H), 1.14 (d, J = 6.9 Hz, 3H).
[1490] 13C NMR (100 MHz, CDCI3) d 202.8, 171.5, 166.5, 160.2, 159.3, 157.0, 153.5, 146.1, 143.7, 137.2, 136.9, 136.7, 134.0, 132.9, 125.1, 124.3, 123.9, 76.2, 69.4, 65.0, 59.7, 48.8, 48.5, 42.9, 41.0, 40.035.2, 28.3, 25.2, 13.9, 13.6, 12.7, 10.6.
[1491] HRMS-ESI m/z calcd for C33H41N5NaO10+ [M + Na]+ 690.2746, found 690.2773.
[1492] Analogue 41k
Figure imgf000400_0001
[1493] Prepared according to general procedure D from primary alcohol 39 (38 mg, 52 mmol, 1 equiv), DMAP (0.6 mg, 5 mmol, 0.1 equiv) and a solution of 4-isocyanato-2- methylthiazole in toluene (0.1 M, 1.60 mL, 0.16 mmol, 3.0 equiv). Toluene was employed as solvent and the reaction was run at 80 °C. Analogue 41k (17 mg, 52% over 2 steps) was obtained as a white solid.
[1494] TLC (MeOH;DCM = 1:20): Rf = 0.30 (UV, p-anisaldehyde).
[1495] 1H NMR (400 MHz, CDCl3) d 8.81 (s, 1H), 8.66 (s, 1H), 7.08 (s, 1H), 6.47 (dd, J = 16.3, 4.9 Hz, 1H), 6.37– 6.18 (m, 1H), 6.10 (d, J = 15.7 Hz, 1H), 5.78 (dd, J = 16.4, 1.8 Hz, 1H), 5.68 (ddd, J = 15.5, 9.0, 4.5 Hz, 1H), 5.44 (d, J = 8.7 Hz, 1H), 5.14 (dd, J = 5.8, 2.1 Hz, 1H), 4.91 (dt, J = 9.6, 5.6 Hz, 1H), 4.70 (dd, J = 8.8, 3.2 Hz, 1H), 4.45 (ddd, J = 14.2, 9.0, 4.7 Hz, 1H), 4.19 (dd, J = 10.9, 3.5 Hz, 1H), 4.10 (dd, J = 10.9, 4.2 Hz, 1H), 4.01 (dt, J = 11.1, 7.1 Hz, 1H), 3.87– 3.71 (m, 1H), 3.81 (s, 2H), 3.36 (ddd, J = 14.8, 9.1, 3.5 Hz, 1H), 3.04 (dd, J = 17.4, 5.3 Hz, 1H), 2.91 (dd, J = 17.4, 5.3 Hz, 1H), 2.85 (br s, 1H), 2.76- 2.67 (m, 1H), 2.63 (s, 3H), 2.26– 2.10 (m, 2H), 2.01– 1.82 (m, 3H), 1.72 (s, 3H), 1.14 (d, J = 3.7 Hz, 3H), 1.12 (d, J = 3.7 Hz, 3H).
[1496] 13C NMR (100 MHz, CDCl3) d 202.7, 171.5, 166.6, 163.7, 160.2, 157.0, 153.7, 146.8, 145.6, 143.7, 136.9, 136.7, 134.1, 132.8, 125.2, 124.3, 98.2, 76.5, 68.6765.1, 59.7, 48.8, 48.5, 43.0, 41.0, 39.4, 35.0, 28.3, 25.2, 18.9, 13.8, 12.7, 10.7.
[1497] HRMS-ESI m/z calcd for C
Figure imgf000400_0002
[M + H]+ 684.2698, found 684.2726.
[1498] Analogue 41l
Figure imgf000401_0001
[1499] Prepared according to general procedure D from primary alcohol 39 (25 mg, 34 mmol, 1 equiv), DMAP (0.4 mg, 3 mmol, 0.1 equiv) and a solution of 4-isocyanato-2- methyloxazole in toluene (0.1 M, 1.0 mL, 0.10 mmol, 3.0 equiv). Toluene was employed as solvent and the reaction was run at 80 °C. Analogue 41l (0.011 g, 48% over 2 steps) was obtained as a white solid.
[1500] TLC (MeOH;DCM = 1:20): Rf = 0.30 (UV, p-anisaldehyde).
[1501] 1H NMR (400 MHz, CDCl3) d 8.57 (s, 1H), 8.44 (s, 1H), 7.21 (d, J = 2.3 Hz, 1H), 6.47 (dd, J = 16.4, 5.0 Hz, 1H), 6.44 (br s, 1H), 6.31 (brs, 1H), 6.10 (d, J = 15.6 Hz, 1H), 5.77 (dd, J = 16.3, 1.8 Hz, 1H), 5.69 (ddd, J = 15.6, 9.0, 4.5 Hz, 1H), 5.42 (d, J = 8.6 Hz, 1H), 5.18– 5.01 (m, 1H), 4.91 (q, J = 6.4 Hz, 1H), 4.71 (dd, J = 8.7, 3.2 Hz, 1H), 4.45 (ddd, J = 14.1, 8.8, 4.6 Hz, 1H), 4.13 (qd, J = 11.0, 4.0 Hz, 2H), 4.00 (dt, J = 11.3, 7.1 Hz, 1H), 3.85 - 3.75 (m, 1H), 3.81 (s, 2H), 3.78 (s, 3H), 3.37 (ddd, J = 14.3, 9.1, 3.5 Hz, 1H), 3.03 (dd, J = 17.3, 5.4 Hz, 1H), 2.90 (dd, J = 17.3, 5.6 Hz, 1H), 2.83 (br s, 1H), 2.72 (br t, J = 6.5 Hz, 1H), 2.25– 2.10 (m, 2H), 1.99– 1.82 (m, 3H), 1.72 (d, J = 1.2 Hz, 3H), 1.12 (d, J = 6.6 Hz, 3H).
[1502] 13C NMR (100 MHz, CDCI3) d 202.7, 171.5, 166.5, 160.2, 157.0, 153.8, 147.3, 145.4, 143.8, 136.9, 136.6, 134.1, 132.7, 130.8, 125.3, 124.3, 96.1, 76.7, 68.2, 65.1, 59.7, 48.7, 48.5, 43.1, 41.0, 39.1, 38.7, 35.0, 28.3, 25.1, 13.9, 12.7, 10.8.
[1503] HRMS-ESI m/z calcd for C33H43N6O9+ [M + H]+ 667.3086, found 667.3093.
[1504] Analogue 41m
Figure imgf000402_0001
[1505] Prepared according to general procedure D from primary alcohol 39 (25 mg, 34 mmol, 1 equiv), DMAP (0.4 mg, 3 mmol, 0.1 equiv) and a solution of 3-isocyanato-5- methylisoxazole in toluene (0.1 M, 1.0 mL, 0.10 mmol, 3.0 equiv). Toluene was employed as solvent and the reaction was run at 80 °C. Analogue 41m (11 mg, 48% over 2 steps) was obtained as a white solid.
[1506] TLC (MeOH;DCM = 1:20): Rf = 0.30 (UV, p-anisaldehyde).
[1507] 1H NMR (400 MHz, CDCl3) d 9.35 (s, 1H), 8.85 (s, 1H), 6.52 (s, 1H), 6.45 (dd, J = 16.3, 4.7 Hz, 1H), 6.11 (d, J = 15.7 Hz, 2H), 5.78 (dd, J = 16.4, 1.8 Hz, 1H), 5.68 (ddd, J = 14.9, 9.3, 4.5 Hz, 1H), 5.49 (d, J = 8.7 Hz, 1H), 5.23 (s, 1H), 4.95– 4.85 (m, 1H), 4.70 (dd, J = 8.7, 3.3 Hz, 1H), 4.52– 4.42 (m, 1H), 4.21 (dd, J = 10.8, 2.6 Hz, 1H), 4.10 (dd, J = 10.8, 3.6 Hz, 1H), 4.10– 4.00 (m, 1H), 3.88– 3.75 (m, 3H), 3.34 (ddd, J = 13.8, 9.3, 3.4 Hz, 1H), 3.05 (dd, J = 17.2, 4.9 Hz, 1H), 2.91 (dd, J = 17.8, 5.7 Hz, 1H), 2.78 (br s, 1H), 2.72– 2.63 (m, 1H), 2.37 (d, J = 0.9 Hz, 2H), 2.23– 2.12 (m, 2H), 1.98– 1.89 (m, 1H), 1.91– 1.79 (m, 2H), 1.73 (d, J = 1.1 Hz, 3H), 1.18 (s, 3H), 1.15 (d, J = 6.9 Hz, 3H).
[1508] 13C NMR (100 MHz, CDCI3) d 203.0, 171.5, 169.4, 166.6, 160.3, 158.79, 157.0, 153.7, 146.6, 143.5, 136.8, 136.7, 133.9, 133.0, 125.1, 124.3, 95.6, 75.9, 70.3, 65.0, 59.8, 48.8, 48.6, 42.7, 41.1, 40.8, 35.41, 28.2, 25.3, 13.4, 12.7, 12.6, 10.5.
[1509] HRMS-ESI m/z calcd for C33H40N5O9+ [M– H2O]+ 650.2821, found 650.2822.
[1510] Analogue 41n
Figure imgf000403_0001
[1511] Prepared according to general procedure D from primary alcohol 39 (25 mg, 34 mmol, 1 equiv), DMAP (0.4 mg, 3 mmol, 0.1 equiv) and a solution of 3-isocyanato-6- brolmopyridine in toluene (0.1 M, 1.0 mL, 0.10 mmol, 3.0 equiv). Toluene was employed as solvent and the reaction was run at 80 °C. Analogue 41n (11 mg, 40% over 2 steps) was obtained as a white solid.
[1512] TLC (MeOH;DCM = 1:20): Rf = 0.30 (UV, p-anisaldehyde).
[1513] 1H NMR (400 MHz, CDCl3) d 8.66 (br s, 1H), 8.41 (d, J = 2.8 Hz, 1H), 8.15– 7.95 (m, 1H), 8.07 (s, 1H), 7.23 (d, J = 8.7 Hz, 1H), 6.51 (dd, J = 16.2, 4.8 Hz, 1H), 6.19 (br s, 1H), 6.11 (d, J = 15.6 Hz, 1H), 5.79 (dd, J = 16.3, 1.8 Hz, 1H), 5.67 (ddd, J = 15.6, 8.9, 4.4 Hz, 1H), 5.46 (d, J = 8.7 Hz, 1H), 5.27 (dd, J = 3.9, 2.2 Hz, 1H), 4.91 (dt, J = 9.1, 5.7 Hz, 1H), 4.76 (dd, J = 8.9, 3.1 Hz, 1H), 4.37 (ddd, J = 14.0, 8.1, 4.3 Hz, 1H), 4.30 (dd, J = 11.0, 2.7 Hz, 1H), 4.09 (dd, J = 10.9, 3.4 Hz, 1H), 3.93 (dt, J = 11.7, 7.6 Hz, 1H), 3.89– 3.78 (m, 1H), 3.82 (s, 2H), 3.46 (ddd, J = 15.0, 9.0, 4.0 Hz, 1H), 3.02 (dd, J = 17.1, 5.6 Hz, 1H), 2.97 – 2.83 (m, 2H), 2.75– 2.58 (m, 1H), 2.30– 2.10 (m, 1H), 2.00– 1.86 (m, 2H), 1.84– 1.74 (m, 2H), 1.72 (d, J = 1.2 Hz, 3H), 1.16 (dd, J = 6.9, 3.5 Hz, 6H).
[1514] 13C NMR (100 MHz, CDCI3) d 202.4, 170.9, 166.3, 160.4, 157.4, 153.9, 144.0, 144.0, 140.2, 136.9, 136.4, 134.9, 134.3, 132.8, 128.9, 127.7, 125.2, 124.2, 124.0, 76.2, 69.6, 65.0, 59.6, 48.9, 48.7, 42.9, 41.1, 40.2, 35.5, 28.4, 24.9, 13.3, 12.7, 11.0.
[1515] HRMS-ESI m/z calcd for C34H40BrN5NaO9+ [M + Na]+ 764.1902, found 764.1928
[1516] Analogue 41o
Figure imgf000404_0001
[1517] Prepared according to general procedure D from primary alcohol 39 (25 mg, 34 mmol, 1 equiv), DMAP (0.4 mg, 3 mmol, 0.1 equiv) and a solution of 4-isocyanato-2- bromopyridine in toluene (0.1 M, 1.0 mL, 0.10 mmol, 3.0 equiv). Toluene was employed as solvent and the reaction was run at 80 °C. Analogue 41o (13 mg, 53% over 2 steps) was obtained as a white solid.
[1518] TLC (MeOH;DCM = 1:20): Rf = 0.30 (UV, p-anisaldehyde).
[1519] 1H NMR (400 MHz, CDCl3) d 8.91 (s, 1H), 8.20– 8.10 (m, 2H), 7.71 (d, J = 1.9 Hz, 1H), 7.63– 7.52 (m, 1H), 6.50 (dd, J = 16.2, 4.7 Hz, 1H), 6.13 (d, J = 15.8 Hz, 2H), 6.09 (d, J = 3.8 Hz, 1H), 5.78 (dd, J = 16.2, 1.9 Hz, 1H), 5.73– 5.65 (m, 1H), 5.50 (d, J = 8.7 Hz, 1H), 5.30 (t, J = 2.7 Hz, 1H), 4.92 (dt, J = 8.7, 5.5 Hz, 1H), 4.75 (dd, J = 8.9, 3.1 Hz, 1H), 4.47– 4.36 (m, 1H), 4.34 (dd, J = 10.8, 2.6 Hz, 1H), 4.09 (dd, J = 10.9, 3.1 Hz, 1H), 3.99– 3.85 (m, 2H), 3.84 (s, 2H), 3.45 (ddd, J = 14.2, 9.1, 4.0 Hz, 1H), 3.04 (dd, J = 17.3, 5.6 Hz, 1H), 2.93 (dd, J = 17.2, 5.5 Hz, 1H), 2.75– 2.65 (m, 1H), 2.27– 2.08 (m, 2H), 1.99– 1.89 (m, 2H), 1.87– 1.76 (m, 1H), 1.73 (d, J = 1.2 Hz, 6H), 1.17 (d, J = 6.9 Hz, 6H).
[1520] 13C NMR (100 MHz, CDCI3) d 202.4, 170.8, 166.3, 160.4, 157.5, 153.2, 150.3, 148.1, 144.0, 143.9142.4, 137.0, 136.5, 134.3, 132.8, 125.2, 124.2, 116.4, 112.1, 76.0, 70.3, 65.0, 59.6, 49.0, 48.8, 42.8, 41.2, 40.7, 35.5, 28.5, 24.9413.1, 12.7, 11.0.
[1521] HRMS-ESI m/z calcd for C34H40BrN5NaO9+ [M + Na]+ 764.1902, found 764.1928.
[1522] Analogue 41p
Figure imgf000405_0001
[1523] Prepared according to general procedure D from primary alcohol 39 (25 mg, 34 mmol, 1 equiv), DMAP (0.4 mg, 3 mmol, 0.1 equiv) and a solution of 2-isocyanatoquinoline in toluene (0.1 M, 1.0 mL, 0.10 mmol, 3.0 equiv). Toluene was employed as solvent and the reaction was run at 80 °C. Analogue 41p (10 mg, 46% over 2 steps) was obtained as a white solid.
[1524] TLC (MeOH;DCM = 1:20): Rf = 0.30 (UV, p-anisaldehyde).
[1525] 1H NMR (400 MHz, CDCl3) d 8.61 (br s, 1H), 8.43 (s, 1H), 8.18 (q, J = 9.0 Hz, 2H), 7.84– 7.72 (m, 2H), 7.65 (ddd, J = 8.5, 6.9, 1.5 Hz, 1H), 7.44 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 6.49 (dd, J = 16.3, 4.9 Hz, 1H), 6.35 (d, J = 6.0 Hz, 1H), 6.12 (d, J = 15.7 Hz, 1H), 5.81 (dd, J = 16.3, 1.8 Hz, 1H), 5.70 (ddd, J = 15.6, 8.9, 4.5 Hz, 1H), 5.43 (d, J = 8.7 Hz, 1H), 5.13 (dd, J = 7.1, 2.1 Hz, 1H), 4.93 (dt, J = 8.7, 5.5 Hz, 1H), 4.72 (dd, J = 8.6, 3.3 Hz, 1H), 4.47 (ddd, J = 14.3, 9.1, 4.7 Hz, 1H), 4.25 (dd, J = 11.0, 4.1 Hz, 1H), 4.15 (dd, J = 11.0, 4.6 Hz, 1H), 4.00 (dt, J = 11.3, 7.2 Hz, 1H), 3.87– 3.75 (m, 1H), 3.82 (s, 2H), 3.38 (ddd, J = 14.8, 9.0, 3.6 Hz, 1H), 3.06 (dd, J = 17.3, 5.5 Hz, 1H), 2.90 (dd, J = 17.2, 5.5 Hz, 1H), 2.80– 2.70 (m, 1H), 2.30– 2.11 (m, 2H), 2.02– 1.78 (m, 3H), 1.73 (d, J = 1.2 Hz, 3H), 1.14 (d, J = 3.2 Hz, 3H), 1.13 (d, J = 3.2 Hz, 3H).
[1526] 13C NMR (100 MHz, CDCI3) d 202.6, 171.6, 166.5, 160.2, 157.0, 153.6, 151.0, 146.5, 144.9, 143.7, 138.7, 137.0, 136.6, 134.2, 132.7, 130.1, 127.6, 126.9, 125.9, 125.3, 125.0124.45113.1, 76.7, 68.0, 65.1, 59.7, 48.7, 48.5, 43.1, 41.0, 38.4, 34.8, 28.3, 25.2, 14.0, 12.8, 10.8.
[1527] HRMS-ESI m/z calcd for C38H43N5NaO9+ [M + Na]+ 736.2953, found 736.2957.
[1528] Analogue 41q
Figure imgf000406_0001
[1529] Prepared according to general procedure D from primary alcohol 39 (35 mg, 34 mmol, 1 equiv), DMAP (0.6 mg, 5 mmol, 0.1 equiv) and a solution of 2- isocyanatoisoquinoline in toluene (0.1 M, 3.40 mL, 0.34 mmol, 10.0 equiv). Toluene was employed as solvent and the reaction was run at 80 °C. Analogue 41q (11 mg, 31% over 2 steps) was obtained as a white solid.
[1530] TLC (MeOH;DCM = 1:20): Rf = 0.30 (UV, p-anisaldehyde).
[1531] 1H NMR (400 MHz, CDCI3) d 8.97 (s, 1H), 8.46 (s, 1H), 8.32 (s, 1H), 8.25 (s, 1H), 7.88 (d, J = 8.2 Hz, 1H), 7.79 (d, J = 8.3 Hz, 1H), 7.62 (ddd, J = 8.2, 6.8, 1.2 Hz, 1H), 7.45 (ddd, J = 8.1, 6.8, 1.1 Hz, 1H), 6.50 (dd, J = 16.3, 4.9 Hz, 1H), 6.36 (dd, J = 8.8, 3.7 Hz, 1H), 6.10 (d, J = 15.6 Hz, 1H), 5.80 (dd, J = 16.3, 1.8 Hz, 1H), 5.69 (ddd, J = 15.6, 8.9, 4.5 Hz, 1H), 5.41 (d, J = 8.7 Hz, 1H), 5.14 (dd, J = 7.4, 2.2 Hz, 1H), 4.92 (dt, J = 8.8, 5.5 Hz, 1H), 4.72 (dd, J = 8.7, 3.3 Hz, 1H), 4.26 (dd, J = 11.0, 4.1 Hz, 1H), 4.17 (dd, J = 11.0, 4.8 Hz, 1H), 3.99 (dt, J = 11.3, 7.1 Hz, 1H), 3.81 (s, 3H), 3.37 (ddd, J = 14.9, 8.9, 3.6 Hz, 1H), 3.05 (dd, J = 17.1, 5.7 Hz, 1H), 2.89 (dd, J = 17.1, 5.5 Hz, 1H), 2.80 (ddt, J = 7.3, 4.9, 2.2 Hz, 1H), 2.37– 2.08 (m, 2H), 2.00– 1.74 (m, 4H), 1.72 (d, J = 1.2 Hz, 3H), 1.19– 1.14 (m, 3H), 1.13 (s, 3H).
[1532] 13C NMR (100 MHz, CDCI3) d 202.5, 171.6, 166.5, 160.3, 157.0, 153.4, 151.0, 146.5, 144.67, 143.7, 138.0, 137.0, 136.6, 134.2, 132.7, 130.8, 127.5, 126.6, 126.1, 125.5, 125.3, 124.5, 106.3, 77.0, 67.6, 65.1, 59.7, 48.7, 48.5, 43.2, 40.9, 38.2, 34.7, 28.4, 25.1, 14.1, 12.7, 10.9.
[1533] HRMS-ESI m/z calcd for C38H43N5NaO9+ [M + Na]+ 736.2953, found 736.2957.
[1534] Scheme XVIII Synthesis of Analogue 46
Figure imgf000407_0001
[1535] Syn-diol SI-93and anti-diol SI-94
Figure imgf000408_0001
[1536] An oven-dried 50-mL round-bottom flask charged with Me4N•BH(OAc)3 (87 mg, 0.33 mmol, 5.0 equiv) was evacuated and flushed with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. Acetonitrile (6.6 mL) and acetic acid (1.3 mL) was added, and the resulting colorless solution was cooled to -10 °C by means of ice-acetone bath. A solution of analogue 40q (47 mg, 66 mmol, 1 equiv) in acetonitrile (1.2 mL) was added dropwise (the syringe was rinsed with another 0.6 mL acetonitrile). The mixture was allowed to warm to 23 °C slowly. After stirring for 5 h, aqueous saturated NaHCO3 solution was added (CAUTION: Gas evolution!). EtOAc (50 mL) was added and the biphasic mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL) and the washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The crude residue was purified by flash chromatography (silica gel, eluent: MeOH: DCM = 1:30) to afford SI-93 (7 mg, 15%) and SI-94 (33 mg, 70 %) as white solid.
[1537] SI-93. TLC (MeOH:DCM = 1:20): Rf = 0.30 (UV, p-anisaldehyde).
[1538] 1H NMR (400 MHz, CDCI3) d 9.18 (s, 1H), 8.94 (s, 1H), 8.32 (s, 1H), 8.28 (s, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.76 (d, J = 8.3 Hz, 1H), 7.60 (ddd, J = 8.2, 6.8, 1.3 Hz, 1H), 7.42 (ddd, J = 8.1, 6.8, 1.1 Hz, 1H), 6.53 (dd, J = 16.2, 4.2 Hz, 1H), 6.18 (d, J = 15.7 Hz, 1H), 5.98 (dd, J = 8.9, 3.8 Hz, 1H), 5.82 (dd, J = 16.2, 2.0 Hz, 1H), 5.65 (ddd, J = 15.6, 9.3, 4.2 Hz, 1H), 5.45 (d, J = 9.0 Hz, 1H), 5.17 (dd, J = 10.0, 1.9 Hz, 1H), 4.95– 4.80 (m, 2H), 4.46 (ddd, J = 14.0, 8.1, 4.3 Hz, 1H), 4.38 (dd, J = 11.3, 4.2 Hz, 1H), 4.32– 4.24 (m, 1H), 4.14 (dd, J = 11.3, 6.5 Hz, 2H), 4.05 (ddd, J = 12.2, 8.2, 4.1 Hz, 2H), 3.91 (dt, J = 11.6, 7.5 Hz, 1H), 3.43 (ddd, J = 14.7, 9.3, 3.7 Hz, 1H), 3.00 (dd, J = 16.6, 6.1 Hz, 1H), 2.81 (dd, J = 16.6, 5.7 Hz, 1H), 2.77– 2.65 (m, 1H), 2.40– 2.25 (m, 2H), 2.20– 2.04 (m, 2H), 1.97– 1.80 (m 4H), 1.79 (s, 3H), 1.13 (d, J = 6.9 Hz, 3H), 1.04 (d, J = 7.0 Hz, 3H).
[1539] 13C NMR (100 MHz, CDCI3) d 171.4, 165.9, 161.8, 160.5, 153.9, 151.0, 147.3, 144.8, 144.6, 138.0, 136.7, 136.3, 134.4, 134.3, 130.5, 127.4, 126.5, 125.9, 125.2, 125.0, 124.1, 106.3, 77.9, 68.3, 68.1, 67.6, 59.7, 48.7, 42.9, 41.2, 36.6, 35.6, 34.2, 28.2, 24.9, 13.89, 13.1, 10.6.
[1540] HRMS-ESI m/z calcd for C38H44N5O8 + [M– H2O]+ 698.3184, found 698.3190.
[1541] SI-94. TLC (MeOH:DCM = 1:20): Rf = 0.30 (UV, p-anisaldehyde).
[1542] 1H NMR (400 MHz, CDCl3) d 9.16 (s, 1H), 8.93 (s, 1H), 8.28 (s, 1H), 8.26 (s, 1H), 7.84 (d, J = 8.2 Hz, 1H), 7.75 (d, J = 8.3 Hz, 1H), 7.59 (ddd, J = 8.2, 6.8, 1.2 Hz, 1H), 7.41 (ddd, J = 8.1, 6.8, 1.1 Hz, 1H), 6.46 (dd, J = 16.4, 4.1 Hz, 1H), 6.21– 6.09 (m, 2H), 5.82– 5.76 (m, 1H), 5.75 (t, J = 2.2 Hz, 1H), 5.67 (ddd, J = 15.0, 9.8, 4.5 Hz, 1H), 5.09 (dd, J = 10.2, 1.8 Hz, 1H), 4.97 (dt, J = 8.6, 4.0 Hz, 1H), 4.77 (dd, J = 8.7, 3.5 Hz, 1H), 4.43 (td, J = 14.1, 11.7, 5.9 Hz, 2H), 4.34 (dd, J = 11.2, 4.5 Hz, 1H), 4.18 (dd, J = 11.2, 5.9 Hz, 1H), 3.88 – 3.73 (m, 2H), 3.35 (ddd, J = 14.0, 9.8, 3.8 Hz, 1H), 3.04 (dd, J = 16.4, 3.0 Hz, 1H), 2.88 (dd, J = 16.5, 9.8 Hz, 1H), 2.95– 2.80 (m, 2H), 2.77- 2.67 (m, 1H), 2.31 (ddd, J = 10.7, 6.8, 4.5 Hz, 1H), 2.20 (ddd, J = 14.4, 3.8, 2.0 Hz, 1H), 2.14– 2.04 (m, 2H), 1.93 (ddd, J = 14.0, 9.3, 4.4 Hz, 1H), 1.88– 1.76 (m, 2H), 1.72 (s, 3H), 1.09 (d, J = 6.8 Hz, 3H), 1.03 (d, J = 7.0 Hz, 3H).
[1543] 13C NMR (100 MHz, CDCl3) d 171.9, 166.5, 161.1, 160.5, 153.9, 151.0, 147.12, 144.3, 144.2, 138.0, 137.2, 136.4, 133.7, 133.3, 130.6, 127.3, 126.5, 125.9, 125.2, 124.9, 124.1, 106.3, 77.8, 67.9, 67.5, 66.8, 59.5, 48.3, 41.6, 41.3, 36.7, 35.2, 34.1, 28.1, 25.4, 13.9, 12.5, 9.7.
[1544] HRMS-ESI m/z calcd for C38H44N5O8+ [M– H2O]+ 698.3184, found 698.3190.
[1545] Mono-TBS ether SI-95
Figure imgf000410_0001
[1546] To a solution of anit-diol SI-94 (45 mg, 82 mmol, 1 equiv) and DMAP (1 mg, 8 mmol, 0.10 equiv) in DCM (8 mL) was added iPr2NEt (0.22 mL, 1.20 mmol, 15.0
equiv) and TBS-Cl (0.19 g, 1.2 mmol, 15.0 equiv) at 23 °C. After stirring for 24 h. The reaction was concentrated under vacuum and the resulting residue was purified by flash chromatography (silica gel, eluent: acetone:hexanes = 1:4) to afford mono-TBS ether SI- 95(43 mg, 79%) as a white solid.
[1547] TLC (MeOH:DCM = 1:20): Rf = 0.30 (UV, p-anisaldehyde).
[1548] 1H NMR (400 MHz, CDCl3) d 9.13 (s, 1H), 8.93 (s, 1H), 8.37 (s, 1H), 8.27 (s, 1H), 7.84 (d, J = 8.2 Hz, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.59 (ddd, J = 8.2, 6.8, 1.2 Hz, 1H), 7.41 (ddd, J = 8.0, 6.7, 1.1 Hz, 1H), 6.44 (dd, J = 16.4, 4.1 Hz, 1H), 6.17 (s, 1H), 6.07– 5.93 (m, 1H), 5.82– 5.72 (m, 2H), 5.67 (ddd, J = 15.1, 10.3, 4.2 Hz, 1H), 5.07 (dd, J = 10.1, 1.8 Hz, 1H), 4.99 (ddd, J = 9.6, 4.9, 2.2 Hz, 1H), 4.76 (dd, J = 8.7, 3.7 Hz, 1H), 4.60– 4.44 (m, 2H), 4.46– 4.29 (m, 2H), 4.20 (dd, J = 11.3, 6.0 Hz, 1H), 3.92– 3.72 (m, 2H), 3.29 (ddd, J = 13.9, 10.4, 3.4 Hz, 1H), 3.03 (d, J = 2.4 Hz, 1H), 2.86– 2.67 (m, 2H), 2.35 (d, J = 13.4 Hz, 2H), 2.14– 2.06 (m, 1H), 2.00– 1.85 (m, 2H), 1.90– 1.73 (m, 2H), 1.70 (s, 3H), 1.09 (d, J = 6.8 Hz, 3H), 1.06 (d, J = 7.0 Hz, 3H), 0.90 (s, 9H), 0.09 (s, 3H), 0.04 (s, 3H).
[1549] 13C NMR (100 MHz, CDCl3) d 172.1, 166.9, 161.1, 160.5, 153.9, 151.0, 147.3, 144.5, 143.7, 138.0, 137.2, 136.5, 134.1, 131.62, 130.4, 127.3, 126.5, 125.9, 125.1, 125.0, 124.2, 106.1, 77.9, 69.8, 67.9, 66.7, 59.6, 48.1, 42.9, 41.6, 36.9, 35.0, 34.0, 28.1, 25.7, 25.6, 17.9, 14.1, 12.4, 9.4, -4.5, -5.3.
[1550] Analogue 46
Figure imgf000411_0001
[1551] An oven-dried 50-mL round-bottom flask charged with mono-TBS ether SI-95 (42 mg, 64 mmol, 1 equiv) was evacuated and flushed with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. DCM (5 mL) was added, and the resulting colorless solution was cooled to 0 °C by means of ice-water bath. A solution of DAST in DCM (2 M, 0.13 mL, 0.27mmol, 10.0 equiv) dropwise at 0 °C under N2. The reaction was warmed to 23 °C and stirred for 3 h. The reaction mixture was quenched with aqueous saturated NaHCO3 solution, diluted with 20 mL DCM and transferred to a separate funnel. The organic solution was washed with water and brine. The washed solution was dried with Na2SO4 and the dried solution was concentrated under vacuum. The residue SI-96 (22 mg) was used without further purification.
[1552] An oven-dried 100-mL round-bottom flask charged with crude SI-96 (22 mg, 26 mmol, 1 equiv) was evacuated and filled with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. THF (3 mL) was added, resulting in a light yellow solution. In a separate flask, Im•HCl (28 mg, 0.26 mmol, 10.0 equiv) was added to a solution of tetrabutylammonium fluoride in THF (1 M, 0.26 mL, 0.26 mmol, 10.0 equiv). The resulting colorless solution was added dropwise to the solution. After 12 h, the mixture was concentrated and the residue was dissolved in DCM (50 mL). The resulting solution was transferred to a separatory funnel and was washed with water (5 × 50 mL) and brine (50 mL). The washed solution was dried Na2SO4). The dried solution was filtered and the filtrate was concentrated. The resulting crude residue was purified by prepared TLC plate (silica gel, eluent: MeOH:DCM = 1:20) to afford analogue 46 (6.5 mg, 34%) as a white solid.
[1553] TLC (MeOH:DCM = 1:20): Rf = 0.30 (UV, p-anisaldehyde).
[1554] 1H NMR (400 MHz, CDCl3) d 9.16 (s, 1H), 8.94 (s, 1H), 8.35– 8.21 (m, 2H), 7.85 (dd, J = 8.2, 1.1 Hz, 1H), 7.76 (d, J = 8.3 Hz, 1H), 7.59 (ddd, J = 8.3, 6.9, 1.2 Hz, 1H), 7.41 (ddd, J = 8.1, 6.9, 1.1 Hz, 1H), 6.52 (dd, J = 16.3, 4.3 Hz, 1H), 6.19 (d, J = 15.7 Hz, 1H), 6.06– 5.96 (m, 1H), 5.84 (dd, J = 16.3, 2.0 Hz, 1H), 5.69 (ddd, J = 15.3, 8.5, 4.1 Hz, 1H), 5.40 (d, J = 9.0 Hz, 1H), 5.16 (dd, J = 10.1, 1.9 Hz, 1H), 5.11 (dm, 2JHF = 41.8 Hz, 1H), 4.88 (dd, J = 8.7, 3.4 Hz, 1H), 4.79 (td, J = 9.0, 4.4 Hz, 1H), 4.61– 4.46 (m, 1H), 4.39 (ddd, J = 11.3, 4.4, 1.8 Hz, 1H), 4.19– 4.05 (m, 2H), 3.87 (dt, J = 11.4, 6.9 Hz, 1H), 3.45 (ddd, J = 15.5, 8.6, 3.1 Hz, 1H), 3.19 (ddd, J = 18.9, 16.6, 5.8 Hz, 1H), 3.03– 2.87 (m, 1H), 2.82– 2.66 (m, 1H), 2.46– 2.26 (m, 2H), 2.27– 2.07 (m, 3H), 1.95– 1.80 (m, 2H), 1.81 (d, J = 1.3 Hz, 3H), 1.13 (d, J = 6.9 Hz, 3H), 1.03 (d, J = 6.9 Hz, 3H).
[1555] 13C NMR (100 MHz, CDCl3) d 171.6, 166.1, 160.5, 159.8 (d, 3JCF = 8.2 Hz), 153.8, 151.0, 147.2, 144.4, 144.3, 138.0, 136.6, 135.9, 135.6, 133.5, 130.5, 127.4, 126.5, 125.9, 125.2, 125.2, 124.1, 106.3, 89.3 (d, 1JCF = 169.9 Hz), 77.9, 68.2, 65.7, 59.4, 48.7, 42.3 (d, 2JCF = 20.1 Hz), 41.0, 36.6, 34.1, 33.6 (d, 2JCF = 25.2 Hz), 28.2, 24.9, 13.8, 12.9, 10.3.
[1556] HRMS-ESI m/z calcd for C38H44FN5NaO8+ [M + Na]+ 740.3066, found 740.3058.
[1557] Analogue SI-99
Figure imgf000413_0001
[1559] An oven-dried 50-mL round-bottom flask charged with Me4N•BH(OAc)3 (0.13 g, 0.50 mmol, 5.0 equiv) was evacuated and flushed with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. Acetonitrile (5 mL) and acetic acid (5 mL) was added, and the resulting colorless solution was cooled to -10 °C by means of ice- acetone bath. A solution of 23 (54 mg, 0.10 mmol, 1 equiv) in acetonitrile (2.5 mL) was added dropwise (the syringe was rinsed with another 1 mL acetonitrile). The mixture was allowed to warm to 23 °C slowly. After stirring for 5 h, aqueous saturated NaHCO3 solution was added (CAUTION: Gas evolution!). EtOAc (50 mL) was added and the biphasic mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL) and the washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The crude residue was purified by flash chromatography (silica gel, eluent: MeOH: DCM = 1:30) to afford anti-diol SI-97 (45 mg, 83%) as a white solid.
[1560] TLC (MeOH:DCM = 1:20): Rf = 0.20 (UV, p-anisaldehyde).
[1561] 1H NMR (400 MHz, CDCI3) d 8.11 (s, 1H), 6.42 (dd, J = 16.4, 4.3 Hz, 1H), 6.14 (d, J = 16.1 Hz, 1H), 5.82 (dd, J = 16.1, 4.8 Hz, 1H), 5.79– 5.71 (m, 3H), 4.98 (dt, J = 8.6, 4.0 Hz, 1H), 4.82– 4.73 (m, 1H), 4.73– 4.66 (m, 2H), 4.46 (tt, J = 9.6, 2.6 Hz, 1H), 3.81 (ddd, J = 13.7, 7.2, 4.7 Hz, 2H), 3.05 (dd, J = 16.5, 3.1 Hz, 1H), 2.89 (dd, J = 16.4, 9.8 Hz, 1H), 2.80 – 2.68 (m, 1H), 2.25– 2.19 (m, 1H), 2.09 (dtd, J = 11.3, 6.4, 5.8, 2.9 Hz, 1H), 2.00– 1.76 (m, 5H), 1.74 (d, J = 1.2 Hz, 3H), 1.31 (d, J = 6.9 Hz, 3H), 1.06 (d, J = 6.9 Hz, 3H), 0.99 (d, J = 6.5 Hz, 3H), 0.93 (d, J = 6.7 Hz, 3H).
[1562] 13C NMR (100 MHz, CDCI3) d 172.1, 166.2, 161.2, 160.3, 144.5, 143.3, 136.6, 133.7, 133.1, 132.5, 129.8, 123.8, 81.4, 67.6, 66.8, 59.3, 48.3, 44.0, 41.5, 36.6, 35.1, 29.3, 28.2, 25.3, 19.8, 18.6, 17.9, 12.8, 9.7.
[1563] Mono-TBS ether SI-98
Figure imgf000414_0001
[1564] To a solution of anti-diol SI-97 (40 mg, 74 mmol, 1 equiv) and DMAP (0.9 mg, 7.4 µmol, 0.1 equiv) in DCM (7.4 mL) was added iPr2NEt (0.19 mL, 1.10 mmol, 15.0 equiv) and TBS-Cl (0.17 g, 1.10 mmol, 15.0 equiv) at 23 °C. After stirring for 24 h. The reaction was concentrated under vacuum and the resulting residue was purified by flash chromatography (silica gel, eluent: ethyl acetate:hexanes = 1:3 to 1:1) to afford mono-TBS ether SI-98 (43 mg, 89 %) as a white solid.
[1565] TLC (ethyl acetate:hexanes = 1:1): Rf = 0.10 (UV, p-anisaldehyde).
[1566] 1H NMR (400 MHz, CDCI3) d 8.11 (s, 1H), 6.39 (dd, J = 16.4, 4.3 Hz, 1H), 6.15 (d, J = 16.2 Hz, 1H), 5.81 (dd, J = 16.1, 4.6 Hz, 1H), 5.79– 5.63 (m, 3H), 5.02– 4.94 (m, 1H), 4.86– 4.72 (m, 1H), 4.72– 4.64 (m, 2H), 4.51 (s, 1H), 4.45 (t, J = 10.0 Hz, 1H), 3.85– 3.71 (m, 2H), 3.05 (dd, J = 16.8, 2.5 Hz, 1H), 2.80 (dd, J = 16.8, 10.3 Hz, 1H), 2.76– 2.67 (m, 1H), 2.31 (d, J = 14.3 Hz, 1H), 2.16– 2.02 (m, 1H), 1.99– 1.72 (m, 5H), 1.70 (d, J = 1.2 Hz, 3H), 1.34 (d, J = 6.9 Hz, 3H), 1.05 (d, J = 6.9 Hz, 3H), 1.00 (d, J = 6.5 Hz, 3H), 0.93 (d, J = 6.7 Hz, 3H), 0.89 (s, 9H), 0.08 (s, 3H), 0.04 (s, 3H).
[1567] 13C NMR (100 MHz, CDCI3) d 172.2, 166.4, 161.1, 160.3, 144.2, 143.3, 136.6, 133.6, 132.4, 131.9, 129.5, 123.8, 81.4, 69.9, 66.6, 59.2, 48.1, 43.8, 42.4, 36.7, 35.1, 29.3, 28.1, 25.7, 25.5, 19.9, 18.6, 17.9, 17.2, 12.5, 9.4, -4.5, -5.3.
[1568] Analogue SI-99
Figure imgf000415_0001
[1569] An oven-dried 50-mL round-bottom flask charged with mono-TBS ether SI-98 (42 mg, 64 µmol, 1 equiv) was evacuated and flushed with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. DCM (5 mL) was added, and the resulting colorless solution was cooled to 0 °C by means of ice-water bath. DAST (21 mL, 0.16 mmol, 2.50 equiv) was added dropwise at 0 °C under nitrogen. The reaction was warmed to 23 °C and stirred for 3 h. The reaction mixture was quenched with aqueous saturated NaHCO3 solution, diluted with DCM (20 mL) and transferred to a separate funnel. The organic solution was washed with water and brine. The washed solution was dried with Na2SO4 and the dried solution was concentrated under vacuum. The residue was purified by flash chromatography (silica gel, eluent: acetone:hexanes = 1:5) to afford fluorine SI-100 (40 mg, 95%) as a white solid. [1570] TLC (acetone:hexanes = 1:2.5): Rf = 0.30 (UV, p-anisaldehyde).
[1571] 1H NMR (400 MHz, CDCl3) d 8.09 (s, 1H), 6.50 (dd, J = 16.3, 4.3 Hz, 1H), 6.14 (d, J = 16.1 Hz, 1H), 5.93– 5.68 (m, 3H), 5.34 (d, J = 9.0 Hz, 1H), 5.06 (dm, 1JHF = 48.8 Hz, 1H), 4.91– 4.78 (m, 3H), 4.73 (td, J = 9.6, 3.8 Hz, 1H), 4.10 (ddd, J = 12.3, 8.1, 4.9 Hz, 1H), 3.83 (dt, J = 11.2, 6.9 Hz, 1H), 3.16 (td, J = 16.8, 6.5 Hz, 1H), 2.91 (ddd, J = 21.5, 16.4, 5.6 Hz, 1H), 2.81– 2.66 (m, 1H), 2.20– 2.03 (m, 2H), 1.92 (ddq, J = 12.0, 7.7, 4.9, 3.4 Hz, 4H), 1.78 (s, 4H), 1.71– 1.51 (m, 1H), 1.31 (d, J = 6.8 Hz, 3H), 1.10 (d, J = 6.9 Hz, 3H), 0.98 (d, J = 6.5 Hz, 3H), 0.94 (d, J = 6.7 Hz, 3H), 0.88 (s, 9H), 0.06 (s, 3H), 0.02 (s, 3H).
[1572] 13C NMR (100 MHz, CDCl3) d 171.6, 165.6, 160.0 (d, 3JCF = 7.8 Hz), 144.7, 143.2, 136.8, 134.3, 133.7, 132.6, 129.6, 124.0, 89.1 (d, 1JCF = 169.0 Hz), 66.5, 59.0, 48.6, 44.6, 43.5 (d, 2JCF = 20.5 Hz), 36.4, 33.8 (d, 2JCF = 25.3 Hz), 29.4, 28.2, 25.8, 24.8, 19.8, 19.2, 18.6, 18.1, 13.1, 10.7, -4.4, -4.9.
[1573] An oven-dried 100-mL round-bottom flask charged with SI-100 (20 mg, 30 µmol, 1 equiv) was evacuated and filled with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. THF (3 mL) was added, resulting in a light yellow solution. In a separate flask, imidazole•HCl (32 mg, 0.30 mmol, 10.0 equiv,) was added to a solution of tetrabutylammonium fluoride in THF (1 M, 0.30 mL, 0.30 mmol, 10.0 equiv). The resulting colorless solution was added dropwise to the above solution. After 12 h, the mixture was concentrated and the residue was dissolved in DCM (50 mL). The resulting solution was transferred to a separatory funnel and was washed with water (5 × 50 mL) and brine (50 mL). The washed solution was dried Na2SO4). The dried solution was filtered and the filtrate was concentrated. The resulting crude residue was purified by prepared TLC plate (eluent:
MeOH:DCM = 1:25) to afford analogue SI-99 (16 mg, 97%) as a light yellow solid.
[1574] TLC (MeOH:DCM = 1:30): Rf = 0.20 (UV, p-anisaldehyde).
[1575] 1H NMR (400 MHz, CDCI3) d 8.10 (s, 1H), 6.51 (dd, J = 16.3, 4.5 Hz, 1H), 6.15 (d, J = 16.1 Hz, 1H), 5.92– 5.72 (m, 3H), 5.38 (d, J = 8.9 Hz, 1H), 5.06 (dm, 2JHF = 48.0 Hz, 1H), 4.89– 4.69 (m, 4H), 4.08 (ddd, J = 12.5, 8.4, 4.7 Hz, 1H), 3.81 (dt, J = 11.4, 7.1 Hz, 1H), 3.21 (td, J = 16.7, 5.4 Hz, 1H), 2.99 (td, J = 15.9, 7.0 Hz, 1H), 2.81– 2.67 (m, 1H), 2.25 – 2.05 (m, 2H), 2.05– 1.75 (m, 4H), 1.83 (s, 3H), 1.75– 1.53 (m, 1H), 1.29 (d, J = 6.8 Hz, 3H), 1.10 (d, J = 6.9 Hz, 3H), 0.98 (d, J = 6.5 Hz, 3H), 0.94 (d, J = 6.8 Hz, 3H). [1576] 13C NMR (100 MHz, CDCl3) d 171.7, 165.6, 160.4, 159.7 (d, 3JCF = 10.7 Hz), 144.7, 143.2, 136.8, 136.4, 132.7, 132.0, 130.8, 124.1, 89.1 (d, 1JCF = 169.8 Hz), 81.0, 65.7, 59.1, 48.6, 44.6, 42.3 (d, 2JCF = 20.3 Hz), 36.4, 33.7 (d, 2JCF = 25.7 Hz), 29.4, 28.3, 24.8, 19.9, 19.8, 18.6, 13.2, 10.7.
[1577] HRMS-ESI m/z calcd for C29H41FN3O6+ [M + H]+ 546.2974, found 546.2964.
[1578] Synthesis of analogue 47
Figure imgf000418_0001
[1579] b-hydroxyl amide SI-102
Figure imgf000419_0001
[1580] An oven-dried 500-mL round-bottom flask charged with SI-101 (4.37 g, 21.5 mmol, 1.2 equiv) was evacuated and flushed with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. Dry DCM (110 mL) was added, resulting in a yellow solution and the vessel was cooled to -78 °C in a dry ice-acetone bath. A solution of TiCl4 in DCM (1 M, 23.3 mL, 23.3 mmol, 1.3 equiv) dropwise, resulting in a deep yellow solution. After 5 min, iPr2EtN (4.06 mL, 23.3 mmol, 1.3 equiv) was added by syringe pump over 30 min, and the resulting deep red solution was stirred for 2 h at -78 °C. A solution of aldehyde SI-48 (5.50 g, 17.9 mmol, 1 equiv) in DCM (18 mL) was added via syringe pump over 30 min. After stirring for 30 min, water (150 mL) was added. The vessel was removed from the cooling bath and the system was allowed to warm to 23 °C while the mixture was rapidly stirred. The biphasic mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with DCM (2 × 50 mL). The combined organic layers were washed with water (2 × 100 mL) and brine (100 mL) and the washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was
concentrated. The crude residue was purified by flash chromatography (silica gel, eluent: EtOAc: hexanes = 1:10 to 1:2.5) to afford b-hydroxyl amide SI-102 (9.0 g, 98%) as a yellow oil.
[1581] TLC (EtOAc:hexanes = 1:3): Rf = 0.25 (UV).
[1582] 1H NMR (400 MHz, CDCl3) d 5.92 (dq, J = 8.8, 1.3 Hz, 1H), 5.21– 5.10 (m, 1H), 4.67– 4.57 (m, 1H), 4.38 (dddd, J = 10.7, 5.4, 4.2, 2.8 Hz, 1H), 3.56– 3.47 (m, 2H), 3.23 (dd, J = 17.7, 9.1 Hz, 1H), 3.03 (dd, J = 11.5, 1.1 Hz, 1H), 2.37 (dq, J = 13.5, 6.8 Hz, 1H), 2.26 (d, J = 1.3 Hz, 3H), 1.70– 1.56 (m, 2H), 1.06 (d, J = 6.8 Hz, 3H), 0.98 (d, J = 6.9 Hz, 3H), 0.88 (s, 9H), 0.09 (s, 3H), 0.06 (s, 3H).
[1583] 13C NMR (100 MHz, CDCl3) d 202.9, 172.6, 135.6, 120.2, 71.4, 67.6, 64.5, 45.9, 43.5, 30.9, 30.6, 25.8, 23.9, 19.1, 18.07, 17.8, -4.5, -5.1. [1584] TES ether SI-103
Figure imgf000420_0001
[1585] An oven-dried 250-mL round-bottom flask charged with b-hydroxyl amide SI-102 (7.00 g, 13.7 mmol, 1 equiv) was evacuated and flushed with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. DCM (140 mL) was added followed by iPr2EtN (7.20 mL, 41.1 mmol, 3.0 equiv), resulting a colorless solution. The vessel was cooled to 0 °C by means of ice-water bath. TESCl (3.50 mL, 20.6 mmol, 1.5 equiv) was added dropwise over 10 min. The reaction mixture was warmed to 23 °C. After stirring for 3 h, the mixture was transferred to a separatory funnel and washed with water (2 × 100 mL) and brine (100 mL). The washed solution was dried (Na2SO4). The dried solution was filtrated and the filtrate was concentrated. The resulting crude residue was purified by flash chromatography (silica gel, eluent: EtOAc:hexanes = 1:50) to afford TES ether SI-103 (8.45 g, 98%) as a light yellow oil.
[1586] TLC (EtOAc:hexanes = 1:10): Rf = 0.20 (UV).
[1587] 1H NMR (400 MHz, CDCI3) d 5.83 (d, J = 9.2 Hz, 1H), 5.07 (t, J = 7.0 Hz, 1H), 4.52– 4.32 (m, 2H), 3.59 (dd, J = 17.2, 7.3 Hz, 1H), 3.46 (dd, J = 11.4, 7.8 Hz, 1H), 3.29 (dd, J = 17.2, 4.6 Hz, 1H), 3.02 (d, J = 11.5 Hz, 1H), 2.37 (dq, J = 13.5, 6.8 Hz, 1H), 2.25 (s, 3H), 1.81 (ddd, J = 13.7, 7.9, 5.8 Hz, 1H), 1.62 (dt, J = 13.9, 5.4 Hz, 1H), 1.06 (d, J = 6.8 Hz, 3H), 0.94 (t, J = 8.1 Hz, 9H), 0.87 (s, 9H), 0.60 (q, J = 7.8 Hz, 6H), 0.05 (s, 3H), 0.05 (s, 3H).
[1588] 13C NMR (100 MHz, CDCI3) d 202.6, 171.3, 136.1, 120.7, 71.5, 67.5, 66.2, 46.5, 46.2, 30.8, 30.8, 25.9, 23.86, 19.1, 18.1, 17.9, 7.0, 5.2, -4.0, -4.7.
[1589] Amide SI-104
Figure imgf000421_0001
[1590] An oven-dried 500-mL round-bottom flask charged with H-Ser-OMe·HCl (3.36 g, 21.6 mmol, 1.5 equiv) was evacuated and flushed with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. THF (110 mL) was added, resulting in a white suspension, followed by iPr2EtN (5.01 mL, 28.8 mmol, 2.0 equiv) After 30 min, a solution of SI-103 (9.00 g, 14.4 mmol, 1 equiv) in THF (15 mL) was added.5 min later, Im (2.94 g, 43.2 mmol, 3.0 equiv) was added and the reaction mixture was stirred overnight. The reaction mixture was concentrated via rotovap and the residue was dissolved with DCM (150 mL). The resulting mixture was transferred to a separatory funnel and was washed with water (100 mL) and brine (100 mL). The washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The resulting crude residue was purified by flash chromatography (silica gel, eluent: EtOAc:hexanes = 1:10 to 1:1) to afford amide SI- 104 (7.75 g, 92%) as a colorless oil.
[1591] TLC (EtOAc:hexanes = 1:5): Rf = 0.20 (UV).
[1592] 1H NMR (400 MHz, CDCI3) d 7.11 (d, J = 7.4 Hz, 1H), 5.79 (dt, J = 9.0, 1.4 Hz, 1H), 4.62 (dt, J = 7.5, 3.8 Hz, 1H), 4.36 (ddd, J = 9.4, 7.5, 5.4 Hz, 1H), 4.17– 4.07 (m, 1H), 3.96– 3.82 (m, 2H), 3.74 (s, 3H), 3.01 (br s, 1H), 2.51 (dd, J = 14.7, 4.8 Hz, 1H), 2.32 (dd, J = 14.7, 5.0 Hz, 1H), 2.24 (s, 3H), 1.79 (ddd, J = 13.7, 7.5, 6.0 Hz, 1H), 1.64 (dt, J = 13.9, 5.7 Hz, 1H), 0.93 (t, J = 7.9 Hz, 9H), 0.84 (s, 9H), 0.61 (q, J = 8.1 Hz, 6H), 0.02 (s, 3H), 0.01 (s, 3H).
[1593] 13C NMR (100 MHz, CDCI3) d 170.9, 170.7, 135.6, 121.1, 67.3, 66.3, 63.3, 54.7, 52.5, 45.2, 44.3, 25.7, 23.8, 18.0, 6.7, 4.8, -4.0, -4.7.
[1594] Oxazoline 105
Figure imgf000422_0001
[1595] An oven-dried 250-mL round-bottom flask charged with amide SI-104 (7.60 g, 13.0 mmol, 1 equiv) was evacuated and flushed with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. DCM (130 mL) was added, and the resulting colorless solution was cooled to -78 °C by means of dry ice-acetone bath. DAST (2.15 mL, 16.3mmol, 1.25 equiv) was added dropwise at -78 °C under nitrogen. After stirring for 3 h, the reaction mixture was quenched with aqueous saturated NaHCO3 solution (50 mL) and transferred to a separate funnel. The organic layer was washed with water and brine. The washed solution was dried with Na2SO4 and the dried solution was concentrated under vacuum. The residue was purified by flash chromatography (silica gel, eluent:
acetone:hexanes = 1:8) to afford oxazoline SI-105 (5.78 g, 79%) as a white solid.
[1596] TLC (EtOAc:hexanes = 1:5): Rf = 0.20 (UV).
[1597] 1H NMR (400 MHz, CDCl3) d 5.82 (dq, J = 9.3, 1.4 Hz, 1H), 4.71 (dd, J = 10.6, 8.0 Hz, 1H), 4.48– 4.34 (m, 3H), 4.18 (tdd, J = 7.0, 5.9, 4.1 Hz, 1H), 3.78 (s, 3H), 2.52 (ddd, J = 8.1, 6.5, 1.0 Hz, 1H), 2.25 (d, J = 1.4 Hz, 3H), 1.76 (ddd, J = 14.0, 8.5, 4.0 Hz, 1H), 1.60– 1.53 (m, 1H), 0.95 (t, J = 7.9 Hz, 9H), 0.86 (s, 9H), 0.59 (q, J = 8.0 Hz, 6H), 0.03 (s, 3H), 0.03 (s, 3H).
[1598] 13C NMR (100 MHz, CDCl3) d 171.5, 167.9, 136.0, 120.8, 69.2, 68.1, 67.1, 66.5, 52.6, 46.1, 37.2, 25.8, 23.8, 18.0, 6.8, 5.1, -3.8, -4.7.
[1599] Oxazole SI-106
Figure imgf000422_0002
[1600] An oven-dried 250-mL round-bottom flask charged with oxazoline SI-105 (5.78 g, 10.2 mmol, 1 equiv) was evacuated and flushed with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. DCM (130 mL) and BrCCl3 (5.04 mL, 51.2 mmol, 5.0 equiv) were added, and the resulting colorless solution was cooled to 0 °C by means of ice-water bath. DBU (7.71 mL, 51.2 mmol, 5.0 equiv) was added dropwise at 0 °C under nitrogen. After stirring for 24 h at 0 °C, the reaction mixture was quenched with aqueous saturated NH4Cl solution and transferred to a separate funnel. The organic solution was washed with water and brine. The washed solution was dried with Na2SO4 and the dried solution was concentrated under vacuum. The residue was purified by flash chromatography (silica gel, eluent: acetone:hexanes = 1:10) to afford oxazole SI-106 (5.57 g, 97%) as a colorless oil.
[1601] TLC (EtOAc:hexanes = 1:5): Rf = 0.20 (UV).
[1602] 1H NMR (400 MHz, Chloroform-d) d 8.16 (s, 1H), 5.81 (dt, J = 9.3, 1.5 Hz, 1H), 4.44 (td, J = 8.9, 4.0 Hz, 1H), 4.29 (qd, J = 6.5, 4.1 Hz, 1H), 3.91 (d, J = 0.7 Hz, 3H), 2.99 (d, J = 6.3 Hz, 2H), 2.26 (d, J = 1.3 Hz, 3H), 1.78– 1.66 (m, 1H), 1.63– 1.53 (m, 1H), 0.93 (t, J = 8.0 Hz, 9H), 0.85 (s, 9H), 0.57 (q, J = 8.0 Hz, 6H), 0.04 (s, 3H), 0.02 (s, 3H).
[1603] 13C NMR (100 MHz, CDCI3) d 163.1, 161.7, 143.9, 135.9, 133.3, 120.9, 67.3, 67.1, 52.1, 46.0, 37.2, 25.8, 23.8, 18.0, 6.8, 5.0, -3.7, -4.7.
[1604] Acid SI-107
Figure imgf000423_0001
[1605] To a solution of oxazole SI-106 (5.57 g, 9.90 mmol, 1 equiv) in MeOH (100 mL) was added PPTS (0.25 g, 0.99 mmol, 0.1 equiv) at 23 °C. After stirring for 1 h, a solution of LiOH in water (1 M, 29.7 mL, 29.7 mmol, 3.0 equiv) was added and the mixture was stirred overnight. The reaction mixture was concentrated under rotovap. To this residue was added water (200 mL) and EtOAc (200 mL) and 1.0 N HCl aqueous solution (40 mL) was added to adjust the pH = 3. The resulting biphasic mixture was transferred to a separatory funnel and the layers were separated. The organic layer was washed with water (100 mL) and brine (100 mL) and the washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The crude residue (3.80 g, 88%) was used for next step without further purification.
[1606] Stille precursor SI-108
Figure imgf000424_0001
[1607] A 50-mL round-bottom flask was charged with acid SI-107 (0.40 g, 0.92 mmol 1 equiv), iPr2EtN (0.32 mL, 1.84 mmol, 2.0 equiv) and amine SI-8 (0.57 g, 0.92 mmol, 1 equiv). DCM (10 mL) was added, resulting in a clear, colorless solution and HATU (0.44 g, 1.15 mmol, 1.25 equiv) was added to this solution in one portion at 23 °C. After stirring for 5 h, the mixture was diluted with DCM (30 mL). The solution was transferred to a separatory funnel and was washed with water (2 × 30 mL) and brine (30 mL). The washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The resulting crude residue was purified by flash chromatography (silica gel, eluent: EtOAc:hexanes = 1:6 to 1:4) to afford Stille Coupling precursor SI-108 (0.70 g, 73%) as a light yellow foam.
[1608] TLC (EtOAc:hexanes = 1:4): Rf = 0.3 (UV)
[1609] 1H NMR (400 MHz, CDCl3) d 8.14 (s, 1H), 6.49 (dt, J = 15.3, 9.6 Hz, 1H), 6.18– 6.05 (m, 1H), 6.07– 5.95 (m, 1H), 5.91 (dq, J = 8.7, 1.3 Hz, 1H), 5.84– 5.41 (m, 3H), 4.97– 4.82 (m, 3H), 4.66 (dp, J = 8.4, 4.3 Hz, 2H), 4.43– 4.19 (m, 1H), 4.09 (tt, J = 6.8, 3.1 Hz, 1H), 3.96 (dtt, J = 7.1, 5.5, 2.7 Hz, 2H), 3.83– 3.61 (m, 2H), 2.97– 2.79 (m, 2H), 2.52 (tdd, J = 9.8, 6.7, 3.7 Hz, 1H), 2.33– 2.19 (m, 4H), 2.15– 1.84 (m, 6H), 1.66 (dq, J = 8.5, 4.6, 3.7 Hz, 2H), 1.53– 1.38 (m, 6H), 1.33– 1.15 (m, 6H), 0.99– 0.77 (m, 30H), 0.15– -0.04 (m, 6H).
[1610] 13C NMR (100 MHz, CDCl3) d 172.7, 171.7, 165.3, 164.7, 162.12, 162.11, 160.3, 160.1, 143.58, 143.55, 143.50, 143.3, 142.7, 142.4, 136.73, 136.67, 135.54, 135.29, 135.25, 130.4, 130.2, 125.9, 125.6, 120.4, 120.3, 116.9, 116.8, 80.0, 79.9, 67.7, 65.6, 65.2, 60.9, 60.3, 48.8, 47.3, 50.0, 44.9, 44.7, 43.95, 43.90, 43.5, 36.1, 35.8, 33.98, 33.93, 33.7, 30.0, 29.0, 28.8, 27.2, 25.8, 25.7, 23.87, 23.84, 19.9, 19.6, 18.0, 16.8, 16.6, 13.7, 9.42, 9.40, -4.46, -4.50, -5.0 -5.2.
[1611] Stille product SI-109
Figure imgf000425_0001
[1612] An oven-dried 500-mL round-bottom flask was charged with JackiePhos (92 mg, 0.12 mmol, 0.2 equiv), Pd2(dba)3 (53 mg, 53 µmol, 0.1 equiv) and Stille Coupling precursor SI-108 (0.60 g, 0.58 mmol, 1 equiv). The vessel was evacuated and filled with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. Toluene (115 ml) was added, resulting in a red suspension. A stream of argon was passed through the solution for 30 min. The mixture was heated at 50o C by means of oil bath. After 60 h, TLC analysis (eluent: EtOAc:hexanes = 1:1) and the mixture was allowed to cool to 23 ºC. The mixture was concentrated and resulting crude residue was purified by flash chromatography (silica gel, eluent: EtOAc:hexanes =1:3 to 1:1) to afford Stille product SI-109 (76 mg, 20 %) as a light yellow solid.
[1613] TLC (EtOAc:hexanes = 1:1): Rf = 0.15 (UV)
[1614] 1H NMR (400 MHz, CDCl3) d 8.10 (s, 1H), 6.28 (dd, J = 16.3, 5.3 Hz, 1H), 6.18 (d, J = 15.5 Hz, 1H), 5.96 (d, J = 8.6 Hz, 1H), 5.84 (d, J = 16.3 Hz, 1H), 5.81– 5.63 (m, 3H), 5.14– 5.01 (m, 2H), 4.96 (ddt, J = 9.2, 4.5, 2.0 Hz, 1H), 4.72 (tt, J = 7.4, 2.2 Hz, 2H), 4.57– 4.36 (m, 3H), 3.79 (t, J = 6.0 Hz, 2H), 3.29 (ddd, J = 13.9, 10.3, 3.3 Hz, 1H), 3.04 (d, J = 16.8 Hz, 1H), 2.79 (dd, J = 16.7, 10.4 Hz, 1H), 2.69– 2.58 (m, 1H), 2.45– 2.33 (m, 1H), 2.29 (d, J = 13.8 Hz, 1H), 2.21– 2.08 (m, 2H), 2.08– 1.73 (m, 4H), 1.70 (s, 3H), 0.99 (d, J = 6.3 Hz, 3H), 0.94 (d, J = 6.6 Hz, 3H), 0.88 (s, 9H), 0.08 (s, 3H), 0.03 (s, 3H). [1615] 13C NMR (100 MHz, CDCl3) d 172.0, 166.8, 161.1, 160.3, 143.2, 142.0, 137.4, 136.6, 135.7, 134.0, 131.6, 125.2, 124.8, 116.9, 81.9, 69.8, 66.6, 59.2, 48.1, 42.8, 41.9, 41.6, 35.1, 29.6, 29.3, 28.1, 25.7, 25.6, 19.9, 18.6, 17.9, 12.4, -4.5, -5.3.
[1616] Fluorinated product SI-110
Figure imgf000426_0001
[1617] An oven-dried 50-mL round-bottom flask charged with Stille product SI-109 (70 mg, 0.10 mmol, 1 equiv) was evacuated and flushed with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. DCM (5 mL) was added, and the resulting colorless solution was cooled to -78 °C by means of dry ice-acetone bath. DAST (34 mL, 0.26 mmol, 2.50 equiv) was added dropwise at -78 °C under nitrogen. After stirring for 3 h, the reaction mixture was quenched with aqueous saturated NaHCO3 solution, diluted with DCM (30 mL) and transferred to a separate funnel. The organic solution was washed with water (50 mL) and brine (50 mL). The washed solution was dried with Na2SO4 and the dried solution was concentrated under vacuum. The residue was purified by flash chromatography (silica gel, eluent: ethyl acetate:hexanes = 1:2) to afford Fluorinated product SI-110 (56 mg, 80%) as a white solid.
[1618] TLC (ethyl acetate:hexanes = 1:1): Rf = 0.30 (UV, p-anisaldehyde).
[1619] 1H NMR (400 MHz, CDCl3) d 8.07 (s, 1H), 6.50 (dd, J = 16.3, 5.2 Hz, 1H), 6.17 (d, J = 15.5 Hz, 1H), 6.02 (d, J = 8.5 Hz, 1H), 5.89 (d, J = 16.2 Hz, 1H), 5.80– 5.70 (m, 1H), 5.72– 5.58 (m, 1H), 5.36– 5.19 (m, 1H), 5.18– 5.02 (m, 2H), 5.02– 4.76 (m, 2H), 4.72 (td, J = 10.1, 3.8 Hz, 1H), 4.63– 4.41 (m, 1H), 4.15– 4.00 (m, 1H), 3.94– 3.78 (m, 1H), 3.65 (s, 2H), 3.54– 3.34 (m, 1H), 3.15 (td, J = 16.9, 7.0 Hz, 1H), 3.02– 2.82 (m, 1H), 2.73– 2.59 (m, 1H), 2.50– 2.35 (m, 1H), 2.28– 2.11 (m, 3H), 2.09– 1.93 (m, 3H), 1.77 (s, 3H), 1.71– 1.53 (m, 1H), 0.97 (d, J = 7.1 Hz, 3H), 0.95 (d, J = 7.4 Hz, 3H), 0.87 (s, 9H), 0.05 (s, 3H), 0.01 (s, 3H). [1620] 13C NMR (100 MHz, CDCl3) d 171.4, 166.0, 160.6, 160.1 (d, 3JCF = 7.2 Hz), 143.2, 142.8, 136.7, 136.5, 135.8, 134.7, 133.4, 125.0, 124.5, 117.1, 89.1 (d, 1JCF = 169.5 Hz), 81.4, 66.5, 59.0, 48.6, 43.6 (d, 2JCF = 20.5 Hz), 41.5, 41.2, 33.9 (d, 2JCF = 205.2 Hz), 30.6, 29.4, 28.2, 25.8, 24.9, 19.8, 18.7, 18.1, 12.9, -4.4, -4.9.
[1621] Analogue 47
Figure imgf000427_0001
[1622] An oven-dried 50-mL round-bottom flask charged with SI-110 (35 mg, 52 µmol, 1 equiv) was evacuated and filled with nitrogen (this process was repeated a total of 3 times) and was sealed with a rubber septum. THF (5.2 mL) was added, resulting in a light yellow solution. In a separate flask, imidazole•HCl (82 mg, 0.78 mmol, 15.0 equiv,) was added to a solution of tetrabutylammonium fluoride in THF (1 M, 0.78 mL, 0.78 mmol, 15.0 equiv). The resulting colorless solution was added dropwise to the above solution. After 12 h, the mixture was concentrated and the residue was dissolved in DCM (50 mL). The resulting solution was transferred to a separatory funnel and was washed with water (5 × 50 mL) and brine (50 mL). The washed solution was dried (Na2SO4). The dried solution was filtered and the filtrate was concentrated. The resulting crude residue was purified by prepared TLC plate (eluent:
MeOH:DCM = 1:25) to afford analogue 47 (22 mg, 76 %) as a white solid.
[1623] TLC (MeOH:DCM = 1:25): Rf = 0.10 (UV, p-anisaldehyde).
[1624] 1H NMR (400 MHz, CDCI3) d 8.07 (s, 1H), 6.50 (dd, J = 16.2, 5.4 Hz, 1H), 6.16 (d, J = 15.7 Hz, 1H), 6.10 (d, J = 6.0 Hz, 1H), 5.88 (dd, J = 16.2, 1.7 Hz, 1H), 5.85– 5.65 (m, 2H), 5.32 (d, J = 9.0 Hz, 1H), 5.16– 4.93 (m, 3H), 4.91– 4.71 (m, 3H), 4.50 (ddd, J = 14.5, 8.7, 4.3 Hz, 1H), 4.04 (ddd, J = 11.9, 8.0, 4.8 Hz, 1H), 3.84 (dt, J = 11.4, 7.2 Hz, 1H), 3.46 (ddd, J = 15.9, 8.1, 3.2 Hz, 1H), 3.19 (td, J = 16.9, 5.8 Hz, 1H), 2.96 (td, J = 17.1, 6.4 Hz, 1H), 2.72– 2.60 (m, 1H), 2.47– 2.35 (m, 1H), 2.25– 2.10 (m, 3H), 2.10– 1.87 (m, 5H), 1.80 (s, 3H), 1.73– 1.52 (m, 1H), 0.96 (d, J = 6.5 Hz, 3H), 0.94 (d, J = 6.8 Hz, 3H). [1625] 13C NMR (100 MHz, CDCl3) d 171.4, 165.9, 160.5, 159.8 (d, 3JCF = 9.4 Hz), 143.3, 143.0, 136.7, 135.8, 135.73, 135.69, 133.1, 125.4, 125.0, 117.1, 89.1 (d, 1JCF = 169.9 Hz), 81.6, 65.7 (d, 3JCF = 2.4 Hz), 59.1, 48.6, 42.3 (d, 2JCF = 20.5 Hz), 41.5, 40.8, 33.7 (d, 2JCF = 25.5 Hz), 30.6, 29.4, 28.2, 24.9, 19.8, 18.7, 13.0.
[1626] HRMS-ESI m/z calcd for C30H40FN3NaO6+ [M + Na]+ 580.2793, found 580.2794.
Example 4: Additional compounds and data
[1627] Table 6. In vitro activity against Gram-negative bacteria.
Figure imgf000428_0001
Figure imgf000429_0002
1 American Type Culture Collection; 3
Figure imgf000429_0001
CLSI QC ranges shown in parentheses where applicable; 4 Combination of Flopristin and virginiamycin S1.
[1628] Table 7. Additional in vitro activity against Gram-negative bacteria.
Figure imgf000429_0003
Figure imgf000430_0001
1 Combination of Flopristin and virginiamycin S1.
[1629] Table 8. In vitro activity against Gram-positive bacteria.
Figure imgf000431_0001
Figure imgf000432_0001
1 American Type Culture Collection; 2 Micromyx collection number; 3 CLSI QC ranges shown in parentheses where applicable; 4 Trailing pinpoint of growth beyond the MIC; 5 Unable to determine MIC due to compound precipitation; 6 Combination of Flopristin and virginiamycin S1.
[1630] Table 9. Additional in vitro activity against Gram-positive bacteria.
Figure imgf000432_0002
Figure imgf000433_0001
Figure imgf000434_0001
1 Trailing pinpoint of growth beyond the MIC; 2 Combination of Flopristin and virginiamycin S1.
Example 5: Additional experimental procedures and characterization data
[1631] Synthetic scheme for preparation of C-4 modified analogs
Figure imgf000435_0001
[1633] An oven-dried 250-mL round-bottom flask which was charged with oxazolidinone 1 (5.95 g, 16.8 mmol, 1 equiv) was evacuated and flushed with nitrogen (this process was repeated a total of 3 times). Then the vessel was sealed with a rubber septum. Dry DCM (84 mL) was added, resulting in a yellow solution, and the vessel was cooled to -78 °C by means of a dry ice-acetone bath. TEA (3.1 mL, 21.9 mmol, 1.3 equiv) was added, followed by a 1 M solution of Bu2BOTf (20.2 mL, 20.2 mmol, 1.2 equiv) in DCM, resulting in a colorless solution. After 30 min, the reaction mixture was stirred at 0 °C for 90 min. Then the vessel was re-cooled to -78 °C, and isobutyraldehyde (2, 3.64 g, 50.5 mmol, 3.0 equiv) was added via syringe pump over 30 min. After 2 h, the vessel was warmed to 0 °C, the reaction mixture was then cautiously quenched dropwise with pH = 7 phosphate buffer and MeOH (1:3, 15.6 mL), followed by 30% H2O2 maintaining the internal temperature between 0-5 °C. After 1 h, the resulting biphasic mixture was transferred to a separatory funnel, and the layers were separated. The aqueous layer was extracted with DCM (2 × 30 mL). The combined organic layers were washed with water (2 × 100 mL) and brine (100 mL), and the washed solution was dried (Na2SO4). The dried solution was filtered, and the filtrate was concentrated. The resulting crude residue was purified by flash chromatography (silica gel, eluent: EtOAc: hexanes = 1:10 to 1:2.5) to afford alcohol B (6.84 g, 96%) as a colorless oil.
[1634] TLC (EtOAc:hexanes = 1:5): Rf = 0.20 (UV).
[1635] 1H NMR (400 MHz, Chloroform-d) d 7.40– 7.23 (m, 8H), 7.16– 7.09 (m, 2H), 4.58 (ddt, J = 10.6, 7.7, 2.9 Hz, 1H), 4.52 (d, J = 11.6 Hz, 1H), 4.48 (d, J = 11.6 Hz, 1H), 4.33 (ddd, J = 9.7, 4.1, 3.0 Hz, 1H), 4.12 (t, J = 8.2 Hz, 1H), 4.03 (dd, J = 9.1, 2.6 Hz, 1H), 3.72– 3.59 (m, 2H), 3.56 (dt, J = 7.6, 3.9 Hz, 1H), 3.18 (dd, J = 13.4, 3.2 Hz, 1H), 2.85 (d, J = 3.9 Hz, 1H), 2.29 (dddd, J = 14.7, 9.8, 8.0, 5.1 Hz, 1H), 2.12 (dd, J = 13.4, 10.5 Hz, 1H), 2.02 (dtd, J = 14.5, 4.9, 2.9 Hz, 1H), 1.83– 1.71 (m, J = 6.8 Hz, 1H), 1.03 (d, J = 6.6 Hz, 3H), 0.99 (d, J = 6.8 Hz, 3H).
[1636] 13C NMR (100 MHz, CDCI3) d 176.5, 153.0, 138.1, 135.6, 129.2, 128.7, 128.3, 128.1, 127.6, 127.0, 76.9, 73.2, 68.9, 65.8, 55.7, 43.4, 37.0, 31.3, 26.8, 19.2, 18.4.
[1637] Preparation of Weinreb amide 4
Figure imgf000437_0001
[1638] To a solution of alcohol 3 (6.60 g, 15.5 mmol, 1 equiv) in THF-H2O (120 mL-40 mL) was added H2O2 (7.9 mL, 77.6 mmol, 1 equiv) at 0 °C, followed by H2O2 (7.9 mL, 77.6 mmol, 5.0 equiv). After 3 h, THF was concentrated under vacuum, and water (100 mL) and EtOAc (100 mL) were added, followed by and 2 M HCl to acidify to pH = 2. The resulting biphasic solution was transferred to a separate funnel, and the layers were separated. The aqueous layer was washed with EtOAc (100 mL). The resulting suspension was abstracted with EtOAc (2 × 50 mL) twice, and the combined organic layer was washed with water (100 mL) and brine (100 mL). The washed solution was dried (Na2SO4), and the dried solution was concentrated under vacuum. The resulting crude acid was used for next step without further purification.
[1639] An oven-dried 250-mL round-bottom flask was charged with crude acid (3.58 g, 13.4 mmol, 1 equiv), DIPEA (7.0 mL, 40.3 mmol, 3.0 equiv), Weinreb amine (2.62 g, 26.9 mmol, 2.0 equiv) and DCM (134 mL). To the resulting colorless solution was added HATU (6.39 g, 16.8 mmol, 1.25 equiv) n in one portion at 23 °C. After 3 h, the mixture was transferred to a separatory funnel and washed with water (2 × 50 mL) and brine (50 mL). The washed solution was dried (Na2SO4), the dried solution was filtered. The filtrate was concentrated, and the resulting crude residue was purified by flash chromatography (silica gel, eluent: EtOAc:hexanes = 1:6 to 1:4) to Weinreb amide 4 (3.54 g, 85.1%) as a colorless oil.
[1640] TLC (EtOAc:hexanes = 1:5): Rf = 0.50 (UV).
[1641] 1H NMR (400 MHz, Chloroform-d) d 7.41– 7.24 (m, 5H), 4.50 (d, J = 11.9 Hz, 1H), 4.46 (d, J = 11.9 Hz, 1H), 3.64 (s, 3H), 3.59 (dt, J = 9.6, 5.5 Hz, 1H), 3.52 (br s, 1H), 3.50– 3.41 (m, 2H), 3.41– 3.33 (m, 1H), 3.15 (s, 3H), 2.19– 2.05 (m, 1H), 2.01– 1.88 (m, 1H), 1.85– 1.66 (m, 1H), 1.03 (d, J = 6.6 Hz, 3H), 0.92 (d, J = 6.7 Hz, 3H).
[1642] 13C NMR (100 MHz, CDCI3) d 177.1, 138.2, 128.1, 127.4, 127.3, 77.1, 72.7, 68.4, 61.3, 39.3, 31.9, 30.7, 25.8, 19.0, 18.8. [1643] Preparation of compound 5
Figure imgf000438_0001
[1644] A 100-mL round-bottom flask containing Weinreb amide 4 (3.00 g, 9.70 mmol, 1 equiv) was evacuated and flushed with nitrogen (the process of nitrogen exchange was repeated a total of 3 times). Dry DCM (97 mL) was added, and the resulting clear solution was cooled to -78 ºC by means of a dry ice/acetone bath. A solution of DIBAL-H in DCM (1.0 M, 29.1 mL, 29.1 mmol, 3.0 equiv) was added dropwise to this solution. After 1 h, 4 was consumed as indicated by TLC analysis, and MeOH (10 mL) was carefully added
(CAUTION: Gas evolution!), followed by saturated aqueous potassium sodium tartrate solution (50 ml). The mixture was allowed to warm to 23 ºC. After 1.5 h, the biphasic mixture was transferred to a separatory funnel, and the layers were separated. The aqueous layer was extracted with DCM (2 × 30 mL). The combined organic layers were washed with water (2 × 50 mL) and brine (50 mL), and the washed solution was dried (Na2SO4). The dried solution was filtered, and the filtrate was concentrated. The crude aldehyde was used for next step immediately without further purification.
[1645] A separate oven-dried 1000-mL round-bottom flask containing 60% NaH (1.55 g, 38.8 mmol, 3.0 equiv) was evacuated and flushed with nitrogen (the process of nitrogen exchange was repeated a total of 3 times). THF (750 mL) was added, and the resulting suspension was cooled to 0 ºC by means of an ice/water bath. A solution of crude in THF (20 mL) was added dropwise at 0 ºC. After 1 h, a solution of the above aldehyde in THF (2 mL) was added. After 2 h, the saturated aqueous ammonium chloride solution (25 mL) was carefully added, and the resulting biphasic mixture was transferred to a separatory funnel. The layers were separated, and the aqueous layer was extracted with ether (2 × 30 mL). The combined organic layers were washed with water (2 × 50 mL) and brine (50 mL), and the washed solution was dried (Na2SO4). The dried solution was filtered, and the filtrate was concentrated. The resulting residue was purified by flash chromatography (silica gel, eluent: EtOAc:hexanes = 1:5) to afford methyl ester 5 (2.10 g, 71% yield over 2 steps) as a colorless oil. [1646] TLC (EtOAc:hexanes = 1:5): Rf = 0.50 (UV).
[1647] 1H NMR (400 MHz, Chloroform-d) d 7.40– 7.27 (m, 5H), 6.83 (dd, J = 15.7, 9.9 Hz, 1H), 5.84 (d, J = 15.7 Hz, 1H), 4.53 (d, J = 11.9 Hz, 1H), 4.48 (d, J = 11.9 Hz, 1H), 3.75 (s, 3H), 3.55 (dt, J = 9.4, 5.4 Hz, 1H), 3.43 (td, J = 9.0, 4.8 Hz, 1H), 3.34 (ddd, J = 7.7, 5.8, 4.2 Hz, 1H), 2.60– 2.49 (m, 1H), 2.30 (d, J = 5.9 Hz, 1H), 2.09 (dddd, J = 14.1, 8.9, 5.4, 3.8 Hz, 1H), 1.77– 1.65 (m, 2H), 0.97 (d, J = 6.8 Hz, 3H), 0.88 (d, J = 6.7 Hz, 3H).
[1648] 13C NMR (100 MHz, CDCl3) d 166.8, 149.8, 138.0, 128.4, 127.7, 127.6, 121.8, 77.9, 73.0, 67.7, 51.5, 43.9, 30.9, 30.1, 20.1, 15.3.
[1649] Preparation of alkyne 16
Figure imgf000439_0001
[1650] A 500-mL round-bottom flask was charged with propargylamine (1.80 mL, 27.4 mmol, 4.0 equiv) and dry DCM (115 mL) under nitrogen. The resulting colorless solution was cooled to 0 ºC by means of an ice/water bath. A solution of AlMe3 in heptane (2 M, 9.8 mL, 19.6 mmol, 4.0 equiv) was added dropwise over 30 min (CAUTION: Gas evolution!). The mixture was allowed to warm to 23 ºC. After 30 min, a solution of 5 (2.10 g, 6.85 mmol, 1 equiv) in DCM (20 mL) was added over 10 min (CAUTION: Gas evolution!). The vessel was equipped with a reflux condenser, and the solution was brought to reflux by means of a 50 ºC oil bath. After 3 h, the mixture was cooled to 0 °C by means of an ice/water bath, and MeOH (10 mL) was added dropwise (CAUTION: Gas evolution!). Once gas evolution ceased, saturated aqueous potassium sodium tartrate solution (100 mL) was added. After 1 h, the biphasic mixture was transferred to a separatory funnel, and the layers were separated. The aqueous layer was extracted with DCM (2 × 30 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL), and the washed solution was dried (Na2SO4). The dried solution was filtered, and the filtrate was concentrated. The resulting crude residue was purified by flash chromatography (silica gel, eluent: EtOAc:hexanes = 1:1) to afford amide 16 (2.05 g, 91% yield) as a white solid.
[1651] TLC (EtOAc:hexanes = 1:1): Rf = 0.20 (UV). [1652] 1H NMR (400 MHz, Chloroform-d) d 7.39– 7.26 (m, 5H), 6.66 (dd, J = 15.4, 9.8 Hz, 1H), 5.91 (t, J = 5.3 Hz, 1H), 5.64 (d, J = 15.4 Hz, 1H), 4.51 (d, J = 12.0 Hz, 1H), 4.40 (d, J = 12.0 Hz, 1H), 4.06 (dd, J = 5.3, 2.6 Hz, 2H), 3.50 (dt, J = 9.5, 5.3 Hz, 1H), 3.38 (td, J = 9.0, 4.7 Hz, 1H), 3.27 (q, J = 5.5 Hz, 1H), 2.54 (d, J = 5.9 Hz, 1H), 2.48 (tdd, J = 9.7, 7.2, 3.6 Hz, 1H), 2.25 (t, J = 2.5 Hz, 1H), 2.05 (dddd, J = 14.2, 8.9, 5.4, 3.6 Hz, 1H), 1.77– 1.55 (m, 2H), 0.91 (d, J = 6.8 Hz, 3H), 0.84 (d, J = 6.7 Hz, 1H).
[1653] 13C NMR (100 MHz, CDCI3) d 165.2, 145.9, 138.2, 128.4, 127.9, 127.6, 123.8, 79.4, 78.0, 72.8, 71.6, 67.5, 43.4, 30.8, 29.7, 29.1, 20.0, 15.6.
[1654] Preparation of vinyl tin 6
Figure imgf000440_0001
[1655] A 500-mL round-bottom flask containing cyanocopper (1.09 g, 12.1 mmol, 2.0 equiv) was evacuated and flushed with nitrogen (this process was repeated a total of 3 times). THF (120 mL) was added, resulting in a white suspension, and the vessel and its contents were cooled to -78 ºC by means of a dry ice/acetone bath. A solution of n-BuLi in hexanes butyllithium (2.5 M, 10.2 mL, 25.5 mmol, 4.2 equiv) was added dropwise over 10 min, and the resulting light-yellow solution was stirred for 30 min. tributylstannane (6.87mL, 25.5 mmol, 4.2 equiv) was added dropwise over 5 min. After 30 min, a solution of alkyne 16 (2.00 g, 6.07 mmol, 1 equiv) in THF (15 mL) was added dropwise over 15 min. After 1 h, saturated aqueous ammonium chloride solution (100 mL) was added in one portion. The vessel was removed from the cooling bath, and the system was allowed to warm to 23 ºC while the mixture was rapidly stirred. The biphasic mixture was transferred to a separatory funnel, and the layers were separated. The aqueous layer was extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with water (2 × 100 mL) and brine (100 mL). The washed solution was dried (Na2SO4). The dried solution was filtered, and the filtrate was concentrated. The resulting crude residue was purified by flash chromatography (silica gel, eluent: EtOAc:hexanes = 0:1 to 1:3) to afford vinyl tin 6 (3.49 g, 93% yield) as a colorless oil. [1656] TLC (EtOAc:hexanes = 1:3): Rf = 0.20 (UV).
[1657] 1H NMR (400 MHz, Chloroform-d) d 7.37– 7.26 (m, 5H), 6.65 (dd, J = 15.3, 9.7 Hz, 1H), 6.12 (dt, J = 19.0, 1.5 Hz, 1H), 5.97 (dt, J = 19.0, 5.1 Hz, 1H), 5.65 (d, J = 15.3 Hz, 1H), 5.43 (t, J = 5.8 Hz, 1H), 4.53 (d, J = 12.0 Hz, 1H), 4.42 (d, J = 12.0 Hz, 1H), 3.97 (td, J = 5.4, 1.5 Hz, 2H), 3.53 (dt, J = 9.4, 5.3 Hz, 1H), 3.40 (td, J = 9.1, 4.6 Hz, 1H), 3.31 (ddd, J = 7.6, 5.6, 4.1 Hz, 1H), 2.55– 2.43 (m, 1H), 2.28 (d, J = 5.8 Hz, 1H), 2.06 (ddt, J = 14.2, 8.8, 3.0 Hz, 1H), 1.77– 1.57 (m, 2H), 1.58– 1.39 (m, 6H), 1.37– 1.23 (m, 6H), 1.00– 0.75 (m, 21H).
[1658] 13C NMR (100 MHz, CDCl3) d 165.2, 145.0, 143.3, 138.3, 130.5, 128.4, 127.9, 127.6, 124.6, 78.0, 72.9, 67.5, 44.9, 43.5, 30.8, 30.0, 29.0, 27.2, 20.1, 15.3, 13.7, 9.4.
[1659] Preparation of proline ester 7
Figure imgf000441_0001
[1660] A 100-mL round-bottom flask was charged with Fmoc-D-Pro-OH (2.40 g, 7.12 mmol, 1.30 equiv), DMAP (0.13 g, 1.10 mmol, 0.2 equiv) and alcohol 6 (3.40 g, 5.48 mmol, 1 equiv). DCM (55 mL) was added, resulting in a colorless solution. DCC (1.70 g, 8.22 mmol, 1.50 equiv) was added in one portion. resulting in a white suspension. After 5 h, alcohol 6 was entirely consumed as indicated by TLC analysis (eluent: EtOAc:hexanes = 1:2), and diethylamine (28 mL) was added. After, 3 h, the mixture was filtered through a pad of celite, and the filter cake was washed with DCM (2 × 20 mL). The combined filtrates were concentrated, and the resulting crude residue was purified by flash chromatography (silica gel, eluent: NH4OH:MeOH:DCM = 0.2:1:100 to 0.2:1:50) to afford left half 13 (3.64 g, 93% yield) as light-yellow oil.
[1661] TLC (MeOH:DCM = 1:5): Rf = 0.20 (UV).
[1662] 1H NMR (400 MHz, Chloroform-d) d 7.38– 7.26 (m, 5H), 6.49 (dd, J = 15.2, 9.8 Hz, 1H), 6.12 (d, J = 19.0 Hz, 1H), 5.96 (dt, J = 19.0, 5.1 Hz, 1H), 5.62 (d, J = 15.2 Hz, 1H), 5.43 (t, J = 5.8 Hz, 1H), 4.85 (dd, J = 7.7, 4.5 Hz, 1H), 4.51 (d, J = 12.0 Hz, 1H), 4.35 (d, J = 12.0 Hz, 1H), 3.95 (t, J = 5.2 Hz, 2H), 3.79 (dd, J = 8.5, 5.8 Hz, 1H), 3.44 (ddd, J = 9.7, 6.0, 3.9 Hz, 1H), 3.33 (td, J = 9.5, 4.8 Hz, 1H), 3.09 (dt, J = 10.2, 6.8 Hz, 1H), 2.92 (dt, J = 10.3, 6.7 Hz, 1H), 2.70 (tdd, J = 10.6, 7.7, 2.9 Hz, 1H), 2.54 (s, 1H), 2.21– 2.08 (m, 1H), 1.97– 1.69 (m, 6H), 1.60– 1.38 (m, 6H), 1.37– 1.22 (m, 6H), 0.99– 0.78 (m, 21H).
[1663] 13C NMR (100 MHz, CDCl3) d 175.0, 164.7, 143.3, 142.8, 138.5, 130.5, 128.3, 127.9, 127.5, 125.7, 79.7, 72.7, 66.9, 59.9, 46.9, 44.9, 41.0, 30.4, 30.0, 29.4, 29.0, 27.2, 25.4, 19.7, 16.1, 13.7, 9.4.
[1664] Preparation of Stille precursor 17
Figure imgf000442_0001
[1665] A 500-mL round-bottom flask was charged with acid 8 (6.50 g, 15.0 mmol 1 equiv), iPr2EtN (5.23 mL, 30.0 mmol, 2.0 equiv) and amine 8 (10.7 g, 15.0 mmol, 1.0 equiv). DCM (150 mL) was added, resulting in a clear, colorless solution, and HATU (7.11 g, 18.7 mmol, 1.25 equiv) was added in one portion. After 5 h, the mixture was diluted with DCM (30 mL), and the solution was transferred to a separatory funnel and was washed with water (2 × 150 mL) and brine (150 mL). The washed solution was dried (Na2SO4), and the dried solution was filtered. The filtrate was concentrated, and the resulting crude residue was purified by flash chromatography (silica gel, eluent: EtOAc:hexanes = 1:6 to 1:3) to afford Stille coupling precursor 17 (14.5 g, 86% yield) as a light-yellow foam.
[1666] TLC (EtOAc:hexanes = 1:2): Rf = 0.3 (UV)
[1667] 1H NMR (400 MHz, Chloroform-d) d 8.13 (s, 0.5H), 8.12 (s, 0.5H), 7.38– 7.23 (m, 5H), 6.51– 6.33 (m, 1H), 6.13 (d, J = 19.0 Hz, 1H), 6.03– 5.86 (m, 2H), 5.81 (t, J = 5.7 Hz, 0.5H), 5.66 (d, J = 15.5 Hz, 0.5H), 5.60– 5.45 (m, 1H), 4.89– 4.73 (m, 1H), 4.72– 4.58 (m, 1H), 4.50– 4.17 (m, 3H), 4.08 (t, J = 6.6 Hz, 1H), 4.02– 3.89 (m, 2H), 3.83– 3.68 (m, 1H), 3.71– 3.58 (m, 1H), 3.41 (ddd, J = 10.0, 6.2, 4.0 Hz, 1H), 3.35– 3.23 (m, 1H), 2.91– 2.84 (m, 1H), 2.79 (dd, J = 6.0, 3.2 Hz, 1H), 2.66 (ddt, J = 9.9, 6.6, 3.1 Hz, 1H), 2.35– 2.21 (m, 5H), 2.18– 1.82 (m, 5H), 1.71– 1.55 (m, 3H), 1.56– 1.37 (m, 6H), 1.30 (dqd, J = 14.1, 7.2, 2.7 Hz, 6H), 1.00– 0.77 (m, 30H), 0.15– -0.01 (m, 6H).
[1668] 13C NMR (100 MHz, CDCI3) d 172.71, 171.85, 165.20, 164.70, 162.19, 162.08, 160.37, 160.14, 143.53, 143.50, 143.28, 143.24, 142.76, 142.46, 138.51, 138.43, 136.64, 135.68, 135.28, 130.55, 130.30, 128.32, 128.31, 127.87, 127.84, 127.78, 127.52, 125.99, 125.71, 120.41, 120.19, 80.49, 80.22, 72.73, 67.66, 67.53, 67.20, 67.18, 65.50, 65.09, 60.97, 60.21, 48.78, 47.24, 44.99, 44.91, 44.05, 43.49, 41.25, 40.77, 36.19, 35.80, 31.67, 30.08, 30.05, 29.03, 27.25, 25.82, 25.79, 25.73, 21.68, 19.81, 19.53, 18.06, 16.87, 16.83, 13.67, 9.43, 9.41, -4.46, -4.49, -4.92, -5.15.
[1669] Preparation of Stille product 9
Figure imgf000443_0001
[1670] A 3000-mL round-bottom flask containing BrettPhos (1.37 g, 2.56 mmol, 0.2 equiv), Pd2(dba)3 (1.17 g, 1.28 mmol, 0.1 equiv) and Stille coupling precursor 17 (14.5 g, 12.79 mmol, 1 equiv) was evacuated and flushed with nitrogen (this process was repeated a total of 3 times). Toluene (2500 mL) was added, resulting in a red suspension. A stream of argon was passed through the solution by a stainless-steel needle for 30 min. The mixture was heated by means of a 50 °C oil bath. After 12 h, 17 was entirely consumed as indicated by TLC analysis (eluent: EtOAc:hexanes = 1:1), and the mixture was allowed to cool to 23 ºC. The mixture was concentrated, and the resulting crude residue was purified by flash chromatography (silica gel, eluent: EtOAc:hexanes =1:3 to 1:1) to afford Stille coupling product 9 (5.56 g, 57% yield) as a light-yellow solid.
[1671] TLC (EtOAc:hexanes = 1:1): Rf = 0.1 (UV)
[1672] 1H NMR (400 MHz, Chloroform-d) d 8.11 (s, 1H), 7.38– 7.25 (m, 5H), 6.24– 6.14 (m, 2H), 5.95 (dd, J = 9.4, 3.1 Hz, 1H), 5.82 (dd, J = 16.3, 1.5 Hz, 1H), 5.76 (d, J = 9.1 Hz, 1H), 5.66 (ddd, J = 15.1, 10.3, 4.3 Hz, 1H), 4.98 (ddd, J = 9.2, 4.8, 2.2 Hz, 1H), 4.75– 4.64 (m, 2H), 4.57– 4.39 (m, 5H), 3.80 (t, J = 6.5 Hz, 2H), 3.58 (ddd, J = 9.2, 6.7, 4.2 Hz, 1H), 3.44 (td, J = 9.0, 5.7 Hz, 1H), 3.30 (ddd, J = 13.7, 10.4, 3.0 Hz, 1H), 3.05 (dd, J = 16.7, 2.4 Hz, 1H), 2.85– 2.72 (m, 2H), 2.32 (d, J = 14.0 Hz, 1H), 2.12 (tdd, J = 12.9, 8.8, 5.4 Hz, 1H), 2.05– 1.76 (m, 6H), 1.71 (s, 3H), 1.62 (ddt, J = 15.0, 10.4, 5.1 Hz, 1H), 0.99 (d, J = 6.4 Hz, 3H), 0.95 (d, J = 6.8 Hz, 3H), 0.90 (s, 9H), 0.09 (s, 3H), 0.04 (s, 3H).
[1673] 13C NMR (100 MHz, CDCI3) d 172.2, 167.1, 161.2, 160.3, 143.2, 141.9, 138.3, 137.5, 136.6, 134.2, 131.6, 128.3, 127.5, 127.5, 125.151, 124.7, 82.4, 73.1, 69.8, 67.8, 66.7, 59.2, 48.1, 42.8, 41.7, 39.4, 35.0, 29.3, 28.2, 25.7, 25.6, 25.5, 19.9, 18.4, 17.9, 12.4, -4.5, - 5.3.
[1674] Preparation of fluorinated compound 18
Figure imgf000444_0001
[1675] A 1000-mL round-bottom flask containing Stille product 9 (5.50 g, 7.20 mmol, 1 equiv) was evacuated and flushed with nitrogen (this process was repeated a total of 3 times). DCM (360 mL) was added, and the resulting colorless solution was cooled to -78 ºC by means of a dry ice/acetone bath. DAST (2.38 mL, 18.00 mmol, 2.50 equiv) was added dropwise, and the vessel and its contents were warmed to 0 ºC by means of an ice/water bath. After 3 h, saturated aqueous NaHCO3 solution (200 mL) was added. After stirring for 30 min, the biphasic mixture was transferred to a separatory funnel, the layers were separated. The organic layer was washed with water (250 mL) and brine (250 mL), and the washed solution was dried (Na2SO4). The dried solution was concentrated, and the residue was purified by flash chromatography (silica gel, eluent: EtOAc:hexanes = 1:2) to afford fluorinated product 18 (4.18 g, 76% yield) as a white solid.
[1676] TLC (EtOAc:hexanes = 1:1): Rf = 0.30 (UV, p-anisaldehyde).
[1677] 1H NMR (400 MHz, Chloroform-d) d 8.06 (s, 1H), 7.37– 7.27 (m, 5H), 6.42 (dd, J = 16.2, 6.0 Hz, 1H), 6.17 (d, J = 15.6 Hz, 1H), 6.01 (dd, J = 8.8, 3.2 Hz, 1H), 5.86 (dd, J = 16.2, 1.5 Hz, 1H), 5.66 (ddd, J = 15.6, 8.5, 4.3 Hz, 1H), 5.30 (d, J = 8.9 Hz, 1H), 5.04 (dm, J = 48.7 Hz, 1H), 4.89– 4.76 (m, 2H), 4.76– 4.68 (m, 1H), 4.59– 4.44 (m, 3H), 4.07 (ddd, J = 11.2, 8.1, 5.0 Hz, 1H), 3.85 (dt, J = 11.3, 7.0 Hz, 1H), 3.59 (ddd, J = 9.3, 6.7, 4.2 Hz, 1H), 3.54– 3.41 (m, 2H), 3.15 (td, J = 16.8, 6.4 Hz, 1H), 2.91 (ddd, J = 20.7, 16.4, 5.6 Hz, 1H), 2.83– 2.70 (m, 1H), 2.23– 2.06 (m, 2H), 2.07– 1.88 (m, 5H), 1.78 (s, 3H), 1.70– 1.50 (m, 2H), 0.96 (d, J = 6.1 Hz, 3H), 0.94 (d, J = 6.2 Hz, 3H), 0.87 (s, 9H), 0.05 (s, 3H), 0.02 (s, 3H).
[1678] 13C NMR (100 MHz, CDCl3) d 171.5, 166.2, 160.5, 160.03, 159.95, 143.1, 142.7, 138.3, 136.7, 136.5, 134.7, 133.4, 128.4, 127.54, 127.49, 125.1, 124.5, 89.1 (d, J = 169.5 Hz), 81.9, 73.1, 67.8, 66.5, 59.1, 48.5, 43.6 (d, J = 20.5 Hz), 41.2, 38.9, 33.9 (d, J = 25.2 Hz),, 29.4, 28.3, 26.4, 25.8, 24.9, 19.8, 18.5, 18.1, 12.9, -4.4, -5.0.
[1679] Preparation of primary alcohol 10
Figure imgf000445_0001
[1680] A 200-mL round-bottom charged with compound 18 (1.60 g, 2.09 mmol, 1 equiv) was evacuated and reflushed with nitrogen (this process was repeated 3 times). DCM (108 mL) and DMS (36 mL) were added, followed by a solution of BCI3•DMS in DCM (2 M, 5.22 mL, 10.4 mmol, 5.0 equiv). After stirring for 5 hours at 23 °C, the reaction mixture was quenched with methanol (10 mL) and saturated aqueous NaHCO3 solution (50 mL). The resulting biphasic mixture was stirred for 1 h at 23 °C, and was transferred to a separatory funnel. The organic layer was washed with water (2 × 100 mL) and brine (100 mL). The washed solution was dried (Na2SO4). The dried solution was filtered, and the filtrate was concentrated. The resulting crude residue was purified by flash chromatography (silica gel, eluent: acetone:hexanes = 1:3.5 to 1:2.5) to afford primary alcohol 10 (0.92 g, 65% yield) as a light-yellow solid.
[1681] TLC (acetone:hexanes = 1:2.5): Rf = 0.20 (UV, p-anisaldehyde).
[1682] 1H NMR (400 MHz, Chloroform-d) d 8.06 (s, 1H), 6.43 (dd, J = 16.2, 6.1 Hz, 1H), 6.21– 6.12 (m, 2H), 5.88 (dd, J = 16.1, 1.5 Hz, 1H), 5.65 (ddd, J = 15.7, 8.5, 4.3 Hz, 1H), 5.29 (d, J = 9.0 Hz, 1H), 5.03 (dm, J = 48.7 Hz, 1H), 4.89– 4.77 (m, 2H), 4.77– 4.66 (m, 1H), 4.49 (ddd, J = 15.0, 6.8, 2.8 Hz, 1H), 4.06 (ddd, J = 11.3, 8.2, 5.0 Hz, 1H), 3.83 (dt, J = 11.3, 7.1 Hz, 1H), 3.79– 3.69 (m, 1H), 3.66– 3.53 (m, 1H), 3.45 (ddd, J = 15.4, 8.5, 3.2 Hz, 1H), 3.14 (td, J = 16.7, 6.4 Hz, 1H), 2.91 (ddd, J = 21.6, 16.4, 5.6 Hz, 1H), 2.85– 2.74 (m, 1H), 2.29 (br s, 1H), 2.23– 2.08 (m, 2H), 1.94 (dddd, J = 19.2, 11.6, 9.7, 6.1 Hz, 5H), 1.77 (s, 3H), 1.71– 1.52 (m, 2H), 0.95 (d, J = 6.5 Hz, 3H), 0.94 (d, J = 6.8 Hz, 3H), 0.86 (s, 9H), 0.04 (s, 3H), 0.00 (s, 3H).
[1683] 13C NMR (100 MHz, CDCI3) d 171.5, 166.3, 160.6, 160.1, 160.0, 143.1, 142.7, 136.6, 136.4, 134.6, 133.4, 125.1, 124.4, 89.0 (d, J = 169.5 Hz), 81.9, 66.5, 59.9, 59.1, 48.5, 43.5 (d, J = 20.6 Hz), 41.2, 38.5, 33.8 (d, J = 25.1 Hz), 29.4, 28.9, 28.3, 25.7, 24.9, 19.7, 18.5, 18.1, 12.9, -4.5, -5.0.
[1684] Preparation of aldehyde 19
Figure imgf000446_0001
[1685] To a stirred solution of alcohol 10 (1.95 g, 2.88 mmol, 1 equiv) in DCM (100 mL) was added DMSO (2.05 mL, 28.8 mmol, 10.0 equiv) and and TEA ( 2,40 mL, 17.3 mmol, 6.0 equiv), followed by SO3•py (1.38, 8.65 mmol, 3 equiv) at room temperature. The resulting mixture was stirred for 1 h before it was quenched with H2O (50 mL) and extracted with EtOAc (3× 50 mL). The combined organic layers were dried (Na2SO4), the dried solution was filtered, and the filtrate was concentrated. The resulting crude residue was purified by flash chromatography (silica gel, eluent: acetone:hexanes = 1:3.5 to 1:2.5) to afford primary alcohol 19 (1.74 g, 90% yield) as a light-yellow solid.
[1686] TLC (acetone:hexanes = 1:2.5): Rf = 0.30 (UV, p-anisaldehyde).
[1687] 1H NMR (400 MHz, Chloroform-d) d 9.80 (d, J = 1.5 Hz, 1H), 8.06 (s, 1H), 6.48 (dd, J = 16.2, 4.9 Hz, 1H), 6.16 (d, J = 15.6 Hz, 1H), 6.11 (dd, J = 9.1, 3.2 Hz, 1H), 5.82 (dd, J = 16.2, 1.8 Hz, 1H), 5.63 (ddd, J = 15.6, 8.7, 4.3 Hz, 1H), 5.20 (d, J = 48.4 Hz, 1H), 4.91 (dd, J = 10.3, 2.0 Hz, 1H), 4.81 (dd, J = 8.6, 3.6 Hz, 1H), 4.72 (td, J = 9.7, 3.9 Hz, 1H), 4.50 (ddd, J = 13.7, 8.6, 4.2 Hz, 1H), 4.05 (ddd, J = 11.2, 7.6, 5.3 Hz, 1H), 3.83 (dt, J = 11.3, 6.9 Hz, 1H), 3.51– 3.36 (m, 1H), 3.28 (ddq, J = 9.0, 4.5, 2.2 Hz, 1H), 3.13 (td, J = 16.9, 6.7 Hz, 1H), 2.89 (ddd, J = 21.9, 16.6, 5.2 Hz, 1H), 2.74– 2.58 (m, 2H), 2.27– 2.06 (m, 3H), 1.87 (dddd, J = 23.4, 13.0, 10.1, 6.0 Hz, 4H), 1.76 (s, 3H), 1.61 (dddd, J = 40.3, 14.3, 10.3, 2.0 Hz, 1H), 0.96 (d, J = 6.4 Hz, 3H), 0.94 (d, J = 6.7 Hz, 3H), 0.86 (s, 9H), 0.04 (s, 3H), 0.00 (s, 3H).
[1688] 13C NMR (100 MHz, CDCl3) d 199.8, 171.3, 165.4, 160.6, 160.2, 160.1, 143.1, 141.7, 136.5, 136.5, 134.6, 133.4, 125.1, 124.4, 89.1 (d, J = 169.0 Hz), 80.5, 66.5, 58.9, 48.6, 43.5 (d, J = 20.1 Hz), 41.1, 40.8, 36.3, 33.8 (d, J = 25.1 Hz), 29.7, 28.2, 25.7, 24.9, 19.6, 18.5, 18.1, 12.87, -4.5, -5.0.
[1689] Preparation of key intermediate acid 11
Figure imgf000447_0001
[1690] The aldehyde 19 (1.74 g, 2.58 mmol, 1 equiv) and isoamylene (1.81 g, 25.8 mmol, 10.0 equiv) were dissolved with t-BuOH (46 mL). To the resulting solution was added an aqueous solution (23 ml) of NaH2PO4 (1.55g, 12.9 mmol, 5.0 equiv) and NaClO2 (1.17 g, 10.3 mmol, 4.0 equiv) at 0 °C. After 2 h, the reaction mixture was acidified to pH = 3 with 1 M HCl and extracted with EtOAc (3× 50 mL). The combined organic layers were dried (Na2SO4), the dried solution was filtered, and the filtrate was concentrated. The resulting crude acid (1.70 g, 95% yield) was used without further purification.
[1691] TLC (MeOH:DCM = 1:25): Rf = 0.30 (UV, p-anisaldehyde).
[1692] 1H NMR (400 MHz, Chloroform-d) d 8.09 (s, 1H), 6.55 (dd, J = 16.4, 4.8 Hz, 1H), 6.30 (dd, J = 8.9, 3.2 Hz, 1H), 6.17 (d, J = 15.6 Hz, 1H), 6.00 (dd, J = 16.3, 1.7 Hz, 1H), 5.62 (ddd, J = 15.7, 9.0, 4.3 Hz, 1H), 5.31 (d, J = 8.9 Hz, 1H), 5.09 (dm, J = 47.6 Hz, 1H), 4.83 (ddd, J = 17.8, 9.4, 2.7 Hz, 2H), 4.72 (td, J = 9.6, 3.7 Hz, 1H), 4.54 (ddd, J = 14.9, 6.7, 2.8 Hz, 1H), 4.06 (ddd, J = 12.2, 7.7, 5.3 Hz, 1H), 3.84 (dt, J = 11.6, 7.0 Hz, 1H), 3.42 (ddd, J = 15.2, 9.0, 3.2 Hz, 1H), 3.25– 3.18 (m, 1H), 3.13 (dd, J = 17.2, 6.5 Hz, 1H), 2.90 (ddd, J = 21.7, 16.6, 5.2 Hz, 1H), 2.65 (dd, J = 16.5, 2.7 Hz, 1H), 2.42 (dd, J = 16.3, 11.3 Hz, 1H), 2.17 (ddd, J = 12.8, 9.3, 5.7 Hz, 2H), 1.98– 1.84 (m, 4H), 1.77 (s, 3H), 1.61 (dddd, J = 40.3, 14.3, 10.3, 2.0 Hz, 1H), 0.98 (d, J = 6.4 Hz, 3H), 0.98 (d, J = 6.6 Hz, 3H), 0.87 (s, 9H), 0.05 (s, 3H), 0.02 (s, 3H).
[1693] Preparation of click chemistry precursor 12
Figure imgf000448_0001
[1694] A 50-mL round-bottom flask was charged with iPr2EtN (0.12 mL, 0.70 mmol, 2.0 equiv), 2-azidoethan-1-amine (45.3 mg, 0.53 mmol, 1.5 equiv), and acid 11 (0.24 g, 0.35 mmol, 1 equiv). DCM (12 mL) was added, resulting in a colorless solution. HATU (0.17 g, 0.44 mmol, 1.25 equiv) was added in one portion. After 5 h, the mixture was diluted with DCM (30 mL). The resulting solution was transferred to a separatory funnel and was washed with water (2 × 25 mL) and brine (25 mL). The washed solution was dried (Na2SO4). The dried solution was filtered, and the filtrate was concentrated. The resulting crude residue was purified by flash chromatography (silica gel, eluent: acetone:hexanes = 1:6 to 1:2) to afford click chemistry precursor 12 (0.22 g, 84% yield) as a white solid.
[1695] TLC (acetone:hexanes = 1:2): Rf = 0.30 (UV, p-anisaldehyde).
[1696] 1H NMR (400 MHz, Chloroform-d) d 8.08 (s, 1H), 6.49 (dd, J = 16.2, 5.4 Hz, 1H), 6.24– 6.13 (m, 2H), 6.07 (dd, J = 9.1, 3.2 Hz, 1H), 5.87 (dd, J = 16.2, 1.7 Hz, 1H), 5.66 (ddd, J = 15.6, 8.6, 4.4 Hz, 1H), 5.30 (d, J = 9.0 Hz, 1H), 5.02 (dm, J = 48.6 Hz, 1H), 4.91 (dd, J = 10.2, 2.0 Hz, 1H), 4.83 (dd, J = 9.0, 3.2 Hz, 1H), 4.73 (td, J = 9.6, 3.9 Hz, 1H), 4.52 (ddd, J = 14.2, 8.9, 4.3 Hz, 1H), 4.08 (ddd, J = 12.2, 8.1, 4.7 Hz, 1H), 3.82 (dt, J = 11.3, 7.2 Hz, 1H), 3.54– 3.31 (m, 6H), 3.32– 3.23 (m, 1H), 3.24– 3.14 (m, 1H), 2.93 (ddd, J = 20.5, 16.4, 5.6 Hz, 1H), 2.54 (dd, J = 14.9, 3.5 Hz, 1H), 2.17 (dddd, J = 15.7, 13.3, 8.1, 4.7 Hz, 3H), 2.01– 1.91 (m, 2H), 1.91– 1.83 (m, 1H), 1.77 (s, 3H), 1.71– 1.52 (m, 1H), 0.99 (d, J = 6.7 Hz, 3H), 0.96 (d, J = 6.5 Hz, 3H), 0.87 (s, 9H), 0.05 (s, 3H), 0.01 (s, 3H).
[1697] 13C NMR (100 MHz, CDCI3) d 171.3, 170.9, 165.7, 160.5, 160.4, 160.3, 142.8, 142.1, 136.5, 136.4, 134.6, 133.5, 124.8, 124.6, 89.1 (d, J = 169.4 Hz), 80.9, 66.4, 59.1, 50.7, 48.6, 43.6 (d, J = 20.4 Hz), 41.1, 39.1, 38.9, 33.9 (d, J = 25.1 Hz), 33.6, 29.6, 28.4, 25.8, 24.9, 19.7, 18.6, 18.1, 12.9, -4.4, -4.9.
[1698] General procedure A for preparation of C-4 analogs 13
Figure imgf000449_0001
12 13 [1699] To a suspension of azide compound 12 (1 equiv) and alkyne (3.00 equiv) in t- BuOH-H2O (3 mL-1 mL) were added an aqueous solution of sodium ascorbate (0.05 M, 0.20 equiv) and an aqueous solution of copper(II) sulfate (0.05 M, 0.05 equiv) at 23 °C. After stirring at 23 °C for 12 h, the solvent was removed under vacuum. The residue was purified by column chromatography over silica gel (5®10% methanol in dichloromethane) to afford the product as an off white solid. Then the white solid was dissolved with 0.1% TFA in MeCN-H2O (95/5 v/v), and the solution was stirred for 12 hours at RT. The reaction mixture was concentrated, and the resulting crude residue was purified by preparative HPLC (eluent: 0.1% TFA in H2O: 0.1% TFA in acetonitrile = 95:5 to 5:95 over 15 min) to afford C-4 modified analog 13 TFA salt as a white solid.
[1700] Analog 13a (SA0113142)
Figure imgf000449_0002
[1701] Prepared according to general procedure A. Analogue 13a (8 mg, 55% yield over 2 steps) was obtained as a white solid.
[1702] 1H NMR (400 MHz, Methanol-d4) d 8.26 (s, 1H), 8.05 (s, 1H), 6.56 (dd, J = 16.0, 5.0 Hz, 1H), 6.27 (d, J = 15.7 Hz, 1H), 5.93 (dd, J = 16.0, 1.7 Hz, 1H), 5.77 (ddd, J = 15.6, 8.0, 4.1 Hz, 1H), 5.40 (d, J = 9.1 Hz, 1H), 5.07 (dm, J = 47.7Hz, 1H), 4.96 (dd, J = 10.3, 2.2 Hz, 1H), 4.81 (dd, J = 8.7, 3.2 Hz, 1H), 4.72 (td, J = 9.1, 4.9 Hz, 1H), 4.55 (t, J = 5.7 Hz, 2H), 4.25 (s, 2H), 4.21– 4.05 (m, 2H), 3.84– 3.66 (m, 3H), 3.62 (dt, J = 14.3, 5.7 Hz, 1H), 3.28– 3.02 (m, 3H), 2.55 (dd, J = 15.2, 3.5 Hz, 1H), 2.39 (dd, J = 15.1, 11.1 Hz, 1H), 2.25– 1.98 (m, 4H), 1.98– 1.87 (m, 2H), 1.84 (s, 3H), 1.78– 1.69 (m, 1H), 1.00 (d, J = 6.7 Hz, 3H), 0.94 (d, J = 6.4 Hz, 3H).
[1703] 13C NMR (100 MHz, MeOD) d 174.4, 171.6, 167.4, 162.5, 162.1, 145.1, 144.9, 141.1, 137.8, 136.9, 136.7, 134.7, 126.1, 125.9, 125.6, 90.4 (d, J = 169.5 Hz), 82.4, 66.0, 60.4, 50.8, 50.1, 43.1 (d, J = 19.9 Hz), 41.7, 40.6, 39.9, 35.5, 34.1 (d, J = 25.2 Hz), 33.5, 30.7, 29.2, 25.9, 20.1, 18.7, 13.2.
[1704] Analog 13b (SA0113143)
Figure imgf000450_0001
[1705] Prepared according to general procedure A. Analogue 13b (6.5 mg, 33% yield over 2 steps) was obtained as a white solid.
[1706] 1H NMR (400 MHz, Chloroform-d) d 8.57 (s, 1H), 8.23 (s, 1H), 8.17– 8.05 (m, 2H), 7.81 (t, J = 7.7 Hz, 1H), 6.61 (s, 1H), 6.52 (dd, J = 16.2, 5.5 Hz, 1H), 6.50 (s,1H), 6.15 (d, J = 15.6 Hz, 1H), 5.90 (d, J = 16.0 Hz, 1H), 5.68 (ddd, J = 15.7, 8.1, 4.1 Hz, 1H), 5.34 (d, J = 8.9 Hz, 1H), 5.05 (dm, J = 48.7 Hz, 1H), 4.86 (d, J = 9.9 Hz, 1H), 4.77 (td, J = 9.0, 4.0 Hz, 2H), 4.55 (t, J = 5.6 Hz, 2H), 4.31 (s, 1H), 4.04 (ddd, J = 12.9, 8.0, 4.8 Hz, 1H), 3.91– 3.70 (m, 3H), 3.60– 3.45 (m, 1H), 3.20 (td, J = 16.9, 16.4, 5.4 Hz, 2H), 2.99 (td, J = 16.3, 6.8 Hz, 1H), 2.52 (dd, J = 15.2, 3.4 Hz, 1H), 2.35– 2.21 (m, 2H), 2.21– 2.06 (m, 3H), 1.96– 1.84 (m, 4H), 1.79 (s, 3H), 1.69– 1.50 (m, 1H), 1.02– 0.95 (d, J = 6.6 Hz, 3H), 0.93 (d, J = 6.4 Hz, 3H).
[1707] 13C NMR (100 MHz, CDCI3) d 171.3, 171.0, 165.7, 160.4, 159.9, 159.8, 149.2, 143.2, 142.7, 137.3, 136.7, 136.0, 135.2, 133.0, 125.5, 124.7, 123.23, 123.19, 123.14, 120.4, 89.2 (d, J = 170.1 Hz), 80.9, 65.6, 59.0, 49.9, 48.5, 42.2 (d, J = 20.5 Hz), 40.7, 39.5, 38.9, 33.6 (d, J = 25.5 Hz), 33.2, 29.5, 28.3, 24.8, 19.7, 18.5, 13.0.
[1708] Analog 13c (SA0113144)
Figure imgf000451_0001
[1709] Prepared according to general procedure A. Analogue 13c (11.5 mg, 58% yield over 2 steps) was obtained as a white solid.
[1710] 1H NMR (400 MHz, Chloroform-d) d 8.98 (s, 1H), 8.49 (d, J = 4.7 Hz, 1H), 8.28 (s, 1H), 8.17 (dd, J = 8.0, 1.9 Hz, 1H), 8.07 (s, 1H), 7.32 (dd, J = 8.0, 4.8 Hz, 1H), 7.03 (t, J = 6.0 Hz, 1H), 6.58– 6.42 (m, 2H), 6.17 (d, J = 15.7 Hz, 1H), 5.90 (dd, J = 16.1, 1.6 Hz, 1H), 5.72 (ddd, J = 15.7, 7.7, 4.1 Hz, 1H), 5.35 (d, J = 9.0 Hz, 1H), 5.05 (dm, J = 47.4 Hz, 1H), 4.87 (dd, J = 10.1, 2.1 Hz, 1H), 4.78 (dt, J = 9.2, 4.6 Hz, 1H), 4.75– 4.65 (m, 1H), 4.52 (q, J = 4.5 Hz, 2H), 4.39 (dd, J = 16.9, 7.8 Hz, 1H), 3.98 (ddq, J = 20.6, 10.8, 4.8 Hz, 2H), 3.73 (ddt, J = 14.3, 11.1, 4.8 Hz, 2H), 3.50 (ddd, J = 16.4, 8.0, 3.5 Hz, 1H), 3.28– 3.11 (m, 2H), 2.97 (td, J = 16.7, 6.6 Hz, 1H), 2.53 (dd, J = 15.0, 3.5 Hz, 1H), 2.29– 2.10 (m, 3H), 1.98– 1.90 (m, 2H), 1.80 (s, 3H), 1.76– 1.51 (m, 4H), 0.95 (d, J = 6.7 Hz, 3H), 0.92 (d, J = 6.4 Hz, 3H).
[1711] 13C NMR (100 MHz, CDCI3) d 171.5, 171.1, 165.7, 160.4, 160.040, 159.9, 148.9, 146.8, 144.5, 143.1, 142.4, 136.6, 135.9, 135.3, 133.2, 133.0, 126.7, 125.3, 124.8, 123.8, 122.1, 89.1 (d, J = 169.8 Hz), 80.8, 65.5, 59.0, 50.1, 48.6, 42.3 (d, J = 20.2 Hz), 40.7, 39.5, 38.9, 33.6 (d, J = 25.3 Hz), 33.3, 29.5, 28.252, 24.705, 19.6, 18.5, 13.0.
[1712] Analog 13d (SA0113146)
Figure imgf000451_0002
[1713] Prepared according to general procedure A. Analogue 13d (11.5 mg, 58% yield over 2 steps) was obtained as a white solid. [1714] 1H NMR (400 MHz, Chloroform-d) d 8.60 (d, J = 6.2 Hz, 2H), 8.36 (s, 1H), 8.07 (s, 1H), 7.80 (d, J = 6.1 Hz, 2H), 6.64 (t, J = 6.0 Hz, 1H), 6.46 (dd, J = 16.1, 5.4 Hz, 1H), 6.34 (dd, J = 8.6, 3.4 Hz, 1H), 6.16 (d, J = 15.7 Hz, 1H), 5.88 (dd, J = 16.1, 1.6 Hz, 1H), 5.69 (ddd, J = 15.8, 7.8, 4.2 Hz, 1H), 5.34 (d, J = 8.9 Hz, 1H), 5.16– 4.93 (m, 1H), 4.88 (dd, J = 10.1, 2.2 Hz, 1H), 4.79 (dt, J = 9.2, 4.6 Hz, 1H), 4.73 (dd, J = 9.0, 3.4 Hz, 1H), 4.59– 4.40 (m, 3H), 4.00 (ddq, J = 19.6, 11.0, 4.9 Hz, 2H), 3.74 (dq, J = 12.3, 6.1, 4.8 Hz, 2H), 3.48 (ddd, J = 16.0, 7.8, 3.3 Hz, 1H), 3.29– 3.13 (m, 2H), 2.99 (td, J = 16.7, 6.5 Hz, 1H), 2.52 (dd, J = 14.9, 3.5 Hz, 1H), 2.25– 2.15 (m, 2H), 2.11– 1.93 (m, 4H), 1.80 (s, 3H), 1.72– 1.52 (m, 3H), 0.96 (d, J = 6.7 Hz, 3H), 0.93 (d, J = 6.4 Hz, 3H).
[1715] 13C NMR (100 MHz, CDCl3) d 171.4, 171.2, 165.8, 160.4, 160.1, 160.0, 150.2, 145.1, 143.1, 142.2, 138.1, 136.5, 135.8, 135.5, 133.3, 125.1, 124.9, 123.4, 120.0, 89.1 (d, J = 169.8 Hz), 80.8, 65.5, 59.0, 50.1, 48.6, 42.2 (d, J = 21.2 Hz), 40.7, 39.5, 38.9, 33.6 (d, J = 26.1 Hz), 33.3, 29.5, 28.3, 24.8, 19.6, 18.5, 13.0.
[1716] Analog 13f (SA0113147)
Figure imgf000452_0001
[1717] Prepared according to general procedure A. Analogue 13f (13 mg, 66% yield over 2 steps) was obtained as a white solid.
[1718] 1H NMR (400 MHz, Chloroform-d) d 8.75 (d, J = 4.8 Hz, 2H), 8.27 (s, 1H), 8.09 (s, 1H), 7.22 (t, J = 4.6 Hz, 1H), 6.69– 6.50 (m, 2H), 6.15 (d, J = 15.6 Hz, 1H), 5.93 (d, J = 15.9 Hz, 1H), 5.66 (ddd, J = 15.7, 7.8, 4.2 Hz, 1H), 5.34 (d, J = 8.9 Hz, 1H), 5.04 (dm, J = 47.4 Hz, 1H), 4.85 (dd, J = 10.0, 2.0 Hz, 1H), 4.74 (dd, J = 8.7, 3.6 Hz, 2H), 4.55 (t, J = 5.8 Hz, 3H), 4.22 (dd, J = 14.0, 8.6 Hz, 1H), 4.00 (ddd, J = 12.2, 8.1, 4.6 Hz, 1H), 3.90– 3.65 (m, 4H), 3.65– 3.55 (m, 1H), 3.29 (d, J = 11.4 Hz, 1H), 3.19 (td, J = 17.0, 5.3 Hz, 1H), 2.98 (td, J = 16.6, 6.6 Hz, 1H), 2.54 (td, J = 21.5, 18.3, 8.8 Hz, 1H), 2.41– 2.29 (m, 1H), 2.21– 1.95 (m, 5H), 1.87 (ddd, J = 12.9, 6.7, 3.4 Hz, 2H), 1.77 (s, 3H), 0.94 (d, J = 7.0 Hz, 3H), 0.91 (d, J = 8.3 Hz, 3H).
[1719] Analog 13g (SA0113149)
Figure imgf000453_0001
[1720] Prepared according to general procedure A. Analogue 13g (15 mg, 65% yield over 2 steps) was obtained as a white solid.
[1721] 1H NMR (400 MHz, Methanol-d4) d 8.54 (s, 1H), 8.39 (s, 1H), 8.25 (s, 1H), 8.10 (t, J = 2.0 Hz, 1H), 7.97 (s, 1H), 6.61 (dt, J = 16.1, 4.1 Hz, 1H), 6.26 (d, J = 15.7 Hz, 1H), 5.90 (d, J = 15.8 Hz, 1H), 5.74 (ddd, J = 15.8, 8.4, 4.0 Hz, 1H), 5.39 (d, J = 9.1 Hz, 1H), 5.06 (dm, J = 51.3 Hz, 1H), 4.94– 4.74 (m, 3H), 4.71 (td, J = 8.9, 5.1 Hz, 1H), 4.61 (t, J = 5.7 Hz, 2H), 4.05 (m, 1H), 3.84– 3.67 (m, 4H), 3.27– 3.02 (m, 3H), 2.56 (dd, J = 15.3, 3.5 Hz, 1H), 2.40 (dd, J = 15.4, 10.6 Hz, 1H), 2.20– 1.95 (m, 4H), 1.95– 1.85 (m, 2H), 1.82 (s, 3H), 1.69 (ddd, J = 13.4, 9.1, 4.3 Hz, 1H), 0.98 (d, J = 6.7 Hz, 3H), 0.92 (d, J = 6.4 Hz, 3H).
[1722] Analog 13h (SA0113150)
Figure imgf000453_0002
[1723] Prepared according to general procedure A. Analogue 13h (5.2 mg, 15% yield over 2 steps) was obtained as a white solid.
[1724] 1H NMR (400 MHz, Methanol-d4) d 8.40– 8.35 (m, 2H), 8.31 (s, 1H), 8.26 (s, 1H), 7.12 (d, J = 9.3 Hz, 1H), 6.61 (dd, J = 15.9, 5.0 Hz, 1H), 6.26 (d, J = 15.7 Hz, 1H), 5.90 (dd, J = 16.0, 1.7 Hz, 1H), 5.75 (ddd, J = 15.7, 8.1, 4.1 Hz, 1H), 5.40 (d, J = 9.1 Hz, 1H), 5.07 (dm, J = 47.6 Hz, 1H), 4.97– 4.77 (m, 3H), 4.71 (td, J = 8.9, 5.1 Hz, 1H), 4.58 (td, J = 5.7, 2.0 Hz, 2H), 4.14– 4.02 (m, 1H), 3.86– 3.60 (m, 5H), 3.16 (dddd, J = 50.5, 19.5, 16.5, 5.7 Hz, 2H), 2.56 (dd, J = 15.2, 3.5 Hz, 1H), 2.39 (dd, J = 15.2, 10.7 Hz, 1H), 2.19– 1.98 (m, 3H), 1.94– 1.86 (m, 2H), 1.83 (s, 3H), 1.76– 1.68 (m, 1H), 0.98 (d, J = 6.7 Hz, 3H), 0.92 (d, J = 6.5 Hz, 3H).
[1725] Analog 13i (SA0113152)
Figure imgf000454_0001
[1726] Prepared according to general procedure A. Analogue 13i (7 mg, 30% yield over 2 steps) was obtained as a white solid.
[1727] 1H NMR (400 MHz, Methanol-d4) d 8.54 (s, 1H), 8.31 (d, J = 5.2 Hz, 1H), 8.25 (s, 1H), 7.25 (d, J = 5.2 Hz, 1H), 6.64 (dd, J = 16.0, 4.9 Hz, 1H), 6.26 (d, J = 15.7 Hz, 1H), 5.92 (dd, J = 16.0, 1.8 Hz, 1H), 5.75 (ddd, J = 15.7, 8.3, 4.1 Hz, 1H), 5.40 (d, J = 9.1 Hz, 1H), 5.09 (dm, J = 48.2 Hz, 1H), 4.93 (dd, J = 10.3, 2.2 Hz, 1H), 4.80 (dd, J = 8.6, 3.2 Hz, 1H), 4.72 (dt, J = 9.0, 4.4 Hz, 1H), 4.66– 4.51 (m, 4H), 4.16– 3.98 (m, 2H), 3.84– 3.63 (m, 4H), 3.28– 3.02 (m, 3H), 2.57 (dd, J = 15.3, 3.6 Hz, 1H), 2.40 (dd, J = 15.3, 10.6 Hz, 1H), 2.22– 1.97 (m, 4H), 1.96– 1.84 (m, 2H), 1.83 (s, 3H), 1.78– 1.67 (m, 1H), 0.96 (d, J = 6.7 Hz, 3H), 0.92 (d, J = 6.4 Hz, 3H).
[1728] 13C NMR (100 MHz, MeOD) d 174.3, 171.5, 167.3, 164.9, 162.5, 162.1, 162.1, 159.8, 159.5, 147.5, 145.4, 144.9, 137.8, 137.0, 136.7, 134.6, 126.3, 126.2, 125.4, 107.2, 90.5 (d, J = 168.8 Hz), 82.6, 60.4, 50.9, 50.1, 43.0 (d, J = 20.1 Hz), 41.7, 40.6, 39.9, 34.0 (d, J = 24.7 Hz), 33.3, 30.7, 29.2, 25.9, 20.1, 18.8, 13.2.
[1729] Analog 13j (SA0113153)
Figure imgf000454_0002
[1730] Prepared according to general procedure A. Analogue 13j (7 mg, 30% yield over 2 steps) was obtained as a white solid.
[1731] 1H NMR (400 MHz, Methanol-d4) d 8.27 (s, 1H), 8.25 (s, 1H), 7.20 (t, J = 1.8 Hz, 1H), 7.19– 7.11 (m, 2H), 6.71 (dt, J = 7.2, 2.2 Hz, 1H), 6.65 (dd, J = 15.9, 4.9 Hz, 1H), 6.26 (d, J = 15.6 Hz, 1H), 5.92 (dd, J = 16.0, 1.8 Hz, 1H), 5.76 (dq, J = 11.6, 4.1 Hz, 1H), 5.40 (d, J = 9.0 Hz, 1H), 5.07 (dm, J = 47.9 Hz, 1H), 4.94 (dd, J = 10.3, 2.1 Hz, 1H), 4.78 (dd, J = 8.6, 3.2 Hz, 1H), 4.71 (td, J = 8.9, 5.2 Hz, 1H), 4.64– 4.50 (m, 3H), 4.06 (tt, J = 10.1, 4.4 Hz, 2H), 3.74 (ddt, J = 14.9, 12.9, 7.8 Hz, 4H), 3.27– 3.14 (m, 2H), 3.09 (ddd, J = 20.2, 16.5, 5.2 Hz, 1H), 2.57 (dd, J = 15.3, 3.7 Hz, 1H), 2.40 (dd, J = 15.3, 10.8 Hz, 1H), 2.19– 1.95 (m, 3H), 1.96– 1.85 (m, 2H), 1.83 (s, 3H), 1.77– 1.55 (m, 1H), 0.97 (d, J = 6.7 Hz, 3H), 0.92 (d, J = 6.5 Hz, 3H).
[1732] 13C NMR (100 MHz, MeOD) d 174.3, 171.5, 167.3, 162.5, 162.13, 162.06, 149.49, 149.40, 145.3, 144.9, 137.8, 137.0, 136.7, 134.6, 132.3, 130.7, 126.3, 125.4, 122.7, 116.5, 116.5, 113.4, 90.5 (d, J = 169.3 Hz), 82.6, 66.0, 60.4, 50.8, 50.1, 43.0 (d, J = 20.2 Hz), 41.7, 40.7, 39.9, 34.0 (d, J = 24.5 Hz), 33.3, 30.6, 29.2, 25.9, 20.1, 18.7, 13.2.
[1733] Analog 13k (SA0113154)
Figure imgf000455_0001
[1734] Prepared according to general procedure A. Analogue 13k (7 mg, 34% yield over 2 steps) was obtained as a white solid.
[1735] 1H NMR (400 MHz, Methanol-d4) d 8.68 (s, 1H), 8.26 (s, 1H), 7.88 (dd, J = 6.8, 0.7 Hz, 1H), 7.49 (dd, J = 1.6, 0.7 Hz, 1H), 7.35 (td, J = 7.2, 1.7 Hz, 1H), 6.61 (dd, J = 15.9, 5.0 Hz, 1H), 6.26 (d, J = 15.7 Hz, 1H), 5.91 (dd, J = 15.9, 1.8 Hz, 1H), 5.75 (ddd, J = 15.8, 8.1, 4.1 Hz, 1H), 5.40 (d, J = 9.1 Hz, 1H), 5.07 (dm, J = 48.0 Hz, 1H), 4.94 (dd, J = 10.3, 2.2 Hz, 1H), 4.80 (dd, J = 8.7, 3.3 Hz, 1H), 4.75– 4.69 (m, 1H), 4.62 (ddd, J = 6.5, 4.8, 1.8 Hz, 3H), 4.08 (dt, J = 12.9, 4.2 Hz, 2H), 3.82– 3.66 (m, 4H), 3.24– 2.99 (m, 3H), 2.56 (dd, J = 15.2, 3.6 Hz, 1H), 2.39 (dd, J = 15.2, 10.7 Hz, 1H), 2.21– 2.00 (m, 3H), 1.94– 1.88 (m, 2H), 1.83 (s, 3H), 1.74– 1.66 (m, 1H), 0.98 (d, J = 6.7 Hz, 3H), 0.92 (d, J = 6.4 Hz, 3H).
[1736] Analog 13l (SA0113156)
Figure imgf000456_0001
[1737] Prepared according to general procedure A. Analogue 13l (8 mg, 40% yield over 2 steps) was obtained as a white solid.
[1738] 1H NMR (400 MHz, Methanol-d4) d 8.28 (s, 1H), 8.25 (s, 1H), 7.73 (d, J = 2.4 Hz, 1H), 6.76 (d, J = 2.2 Hz, 1H), 6.65 (dd, J = 15.9, 5.0 Hz, 1H), 6.27 (d, J = 15.7 Hz, 1H), 5.94 (dd, J = 15.9, 1.8 Hz, 1H), 5.78 (ddd, J = 15.6, 8.1, 4.1 Hz, 1H), 5.49 (s, 1H), 5.41 (d, J = 9.1 Hz, 1H), 5.19– 5.10 (m, 1H), 4.80 (dd, J = 8.6, 3.2 Hz, 1H), 4.72 (dt, J = 8.9, 4.4 Hz, 1H), 4.59 (q, J = 5.8 Hz, 3H), 4.14– 4.03 (m, 2H), 3.80– 3.64 (m, 4H), 3.26– 3.03 (m, 3H), 2.58 (dd, J = 15.2, 3.6 Hz, 1H), 2.40 (dd, J = 15.2, 10.8 Hz, 1H), 2.17– 1.99 (m, 4H), 1.98– 1.89 (m, 2H), 1.84 (s, 3H), 1.77– 1.65 (m, 1H), 0.98 (d, J = 6.8 Hz, 3H), 0.92 (d, J = 6.5 Hz, 3H).
[1739] Analog 13m (SA0113157)
Figure imgf000456_0002
[1740] Prepared according to general procedure A. Analogue 13m (10 mg, 50% yield over 2 steps) was obtained as a white solid.
[1741] 1H NMR (400 MHz, Methanol-d4) d 8.32 (s, 1H), 8.25 (s, 1H), 7.80 (dd, J = 2.9, 1.3 Hz, 1H), 7.52 (qd, J = 5.0, 2.1 Hz, 2H), 6.64 (dd, J = 15.9, 4.9 Hz, 1H), 6.27 (d, J = 15.6 Hz, 1H), 5.96 (d, J = 1.8 Hz, 1H), 5.78 (ddd, J = 15.6, 8.3, 4.1 Hz, 1H), 5.41 (d, J = 9.1 Hz, 1H), 5.19– 4.99 (m, 1H), 4.96 (dd, J = 10.3, 2.2 Hz, 1H), 4.79 (dd, J = 8.6, 3.3 Hz, 1H), 4.72 (td, J = 9.0, 5.1 Hz, 1H), 4.63– 4.46 (m, 3H), 4.08 (dd, J = 11.7, 4.3 Hz, 2H), 3.83– 3.58 (m, 4H), 3.28– 3.15 (m, 2H), 3.09 (ddd, J = 20.5, 16.5, 5.3 Hz, 1H), 2.57 (dd, J = 15.2, 3.7 Hz, 1H), 2.39 (dd, J = 15.2, 10.9 Hz, 1H), 2.18– 1.95 (m, 3H), 1.93– 1.78 (m, 1H), 1.85 (s, 3H), 1.67 (dddd, J = 38.0, 12.1, 9.3, 5.0 Hz, 1H), 0.98 (d, J = 6.7 Hz, 3H), 0.92 (d, J = 6.5 Hz, 3H).
[1742] Analog 13n (SA0113165)
Figure imgf000457_0001
[1743] Prepared according to general procedure A. Analogue 13n (7 mg, 35% yield over 2 steps) was obtained as a white solid.
[1744] 1H NMR (400 MHz, Methanol-d4) d 8.34 (s, 1H), 8.26 (s, 1H), 7.74 (s, 1H), 6.61 (dd, J = 15.9, 5.1 Hz, 1H), 6.26 (d, J = 15.7 Hz, 1H), 5.95 (dd, J = 15.9, 1.7 Hz, 1H), 5.77 (ddd, J = 15.7, 7.9, 4.1 Hz, 1H), 5.40 (d, J = 9.0 Hz, 1H), 5.09 (dm, J = 47.8 Hz, 1H), 4.93 (dd, J = 10.3, 2.2 Hz, 1H), 4.80 (dd, J = 8.7, 3.3 Hz, 1H), 4.72 (td, J = 9.0, 5.1 Hz, 1H), 4.64 – 4.52 (m, 3H), 4.16– 4.04 (m, 2H), 3.84– 3.64 (m, 4H), 3.27– 3.06 (m, 3H), 2.69 (s, 3H), 2.56 (dd, J = 15.2, 3.5 Hz, 1H), 2.40 (dd, J = 15.2, 10.9 Hz, 1H), 2.22– 2.02 (m, 3H), 1.96– 1.87 (m, 2H), 1.84 (s, 3H), 1.76– 1.68 (m, 1H), 0.99 (d, J = 6.7 Hz, 3H), 0.92 (d, J = 6.4 Hz, 3H).
[1745] 13C NMR (100 MHz, MeOD) d 174.4, 171.6, 167.3, 162.5, 162.1, 162.0, 146.5, 145.3, 144.9, 137.8, 136.9, 136.8, 136.7, 134.7, 126.2, 125.8, 125.8, 124.0, 116.0, 90.4 (d, J = 169.2 Hz), 82.6, 66.0, 60.4, 51.0, 50.0, 43.0 (d, J = 20.7 Hz), 41.7, 40.6, 40.0, 34.0 (d, J = 24.5 Hz), 33.4, 30.7, 29.2, 25.9, 20.1, 18.7, 13.2, 11.4.
[1746] Analog 13o (SA0113166)
Figure imgf000457_0002
[1747] Prepared according to general procedure A. Analogue 13o (7 mg, 44% yield over 2 steps) was obtained as a white solid.
[1748] 1H NMR (400 MHz, Methanol-d4) d 9.25 (s, 1H), 8.64 (s, 1H), 8.62 (s, 1H), 8.55 (d, J = 2.6 Hz, 1H), 8.25 (s, 1H), 6.63 (dd, J = 15.9, 4.9 Hz, 1H), 6.26 (d, J = 15.7 Hz, 1H), 5.91 (dd, J = 16.0, 1.8 Hz, 1H), 5.77 (ddd, J = 15.6, 8.3, 4.1 Hz, 1H), 5.40 (d, J = 9.1 Hz, 1H), 5.07 (dm, J = 47.8 Hz, 1H), 4.94 (dd, J = 10.3, 2.2 Hz, 1H), 4.79 (dd, J = 8.6, 3.2 Hz, 1H), 4.71 (td, J = 9.0, 5.2 Hz, 1H), 4.62 (qd, J = 8.5, 6.9, 3.9 Hz, 3H), 4.07 (ddt, J = 12.7, 8.2, 4.3 Hz, 2H), 3.82– 3.65 (m, 4H), 3.28– 3.16 (m, 2H), 3.09 (ddd, J = 20.3, 16.5, 5.3 Hz, 1H), 2.57 (dd, J = 15.2, 3.6 Hz, 1H), 2.40 (dd, J = 15.2, 10.7 Hz, 1H), 2.07 (ddddd, J = 31.3, 13.0, 10.4, 7.0, 3.5 Hz, 3H), 1.96– 1.86 (m, 2H), 1.83 (s, 3H), 1.77– 1.66 (m, 1H), 0.97 (d, J = 6.7 Hz, 3H), 0.92 (d, J = 6.5 Hz, 3H).
[1749] 13C NMR (100 MHz, MeOD) d 174.3, 171.5, 167.3, 162.5, 162.13, 162.07, 147.4, 146.5, 145.9, 145.3, 144.9, 144.69, 142.6, 137.8, 137.0, 136.7, 134.6, 126.3, 125.8, 125.5, 90.5 (d, J = 169.2 Hz), 82.6, 66.1, 66.0, 60.4, 51.0, 50.1, 43.0 (d, J = 20.0 Hz), 41.7, 40.6, 39.9, 34.0 (d, J = 24.5 Hz), 33.4, 30.7, 29.2, 25.8, 20.1, 18.7, 13.2.
[1750] Analog 13p (SA0113167)
Figure imgf000458_0001
[1751] Prepared according to general procedure A. Analogue 13p (7 mg, 35% yield over 2 steps) was obtained as a white solid.
[1752] 1H NMR (400 MHz, Methanol-d4) d 8.87 (s, 2H), 8.42 (s, 1H), 8.25 (s, 1H), 6.60 (dd, J = 16.0, 5.0 Hz, 1H), 6.26 (d, J = 15.6 Hz, 1H), 5.92 (dd, J = 16.0, 1.8 Hz, 1H), 5.77 (ddd, J = 15.6, 8.0, 4.0 Hz, 1H), 5.41 (s, 1H), 5.07 (dm, J = 47.7 Hz, 1H), 4.95 (dd, J = 10.3, 2.3 Hz, 1H), 4.79 (dd, J = 8.7, 3.2 Hz, 1H), 4.72 (td, J = 9.0, 5.0 Hz, 1H), 4.64– 4.47 (m, 3H), 4.17– 4.04 (m, 2H), 3.85– 3.60 (m, 4H), 3.27– 3.16 (m, 2H), 3.15– 3.04 (m, 1H), 2.56 (dd, J = 15.2, 3.5 Hz, 1H), 2.38 (dd, J = 15.1, 11.0 Hz, 1H), 2.18– 1.97 (m, 3H), 1.90 (dt, J = 9.0, 6.0 Hz, 2H), 1.84 (s, 3H), 1.78– 1.64 (m, 1H), 0.99 (d, J = 6.7 Hz, 3H), 0.93 (d, J = 6.5 Hz, 3H).
[1753] 13C NMR (100 MHz, MeOD) d 174.4, 171.6, 167.2, 162.5, 162.12, 162.05, 155.8, 145.1, 144.0, 142.3, 137.8, 136.8, 136.8, 134.6, 126.3, 125.6, 122.9, 116.1, 90.4 (d, J = 169.4 Hz), 82.6, 66.0, 60.4, 51.0, 50.1, 43.0 (d, J = 20.6 Hz), 41.7, 40.6, 39.9, 34.0 (d, J = 24.7 Hz), 33.5, 30.7, 29.2, 25.8, 20.1, 18.7, 13.2.
[1754] Analog 13q (SA0113169)
Figure imgf000459_0001
[1755] Prepared according to general procedure A. Analogue 13q (10 mg, 49% yield over 2 steps) was obtained as a white solid.
[1756] 1H NMR (400 MHz, Methanol-d4) d 8.71 (s, 1H), 8.33 (d, J = 6.4 Hz, 1H), 8.26 (s, 1H), 7.61– 7.46 (m, 1H), 6.61 (dd, J = 16.0, 4.9 Hz, 1H), 6.26 (d, J = 15.7 Hz, 1H), 5.89 (d, J = 15.9 Hz, 1H), 5.75 (dq, J = 11.6, 4.1 Hz, 1H), 5.40 (d, J = 9.1 Hz, 1H), 5.09 (dm, J = 47.8 Hz, 1H), 4.93 (dd, J = 11.4, 2.2 Hz, 1H), 4.80 (dd, J = 8.7, 3.2 Hz, 1H), 4.71 (td, J = 8.9, 5.2 Hz, 1H), 4.64 (t, J = 5.8 Hz, 3H), 4.15– 3.99 (m, 2H), 3.83– 3.63 (m, 4H), 3.24– 3.02 (m, 3H), 2.56 (dd, J = 15.3, 3.5 Hz, 1H), 2.40 (dd, J = 15.3, 10.6 Hz, 1H), 2.22– 1.96 (m, 3H), 1.90 (pd, J = 9.2, 3.2 Hz, 2H), 1.83 (s, 3H), 1.76– 1.66 (m, 1H), 0.97 (d, J = 6.7 Hz, 3H), 0.92 (d, J = 6.5 Hz, 3H).
[1757] Analog 13r (SA0113170)
Figure imgf000459_0002
[1758] Prepared according to general procedure A. Analogue 13r (10 mg, 69% yield over 2 steps) was obtained as a white solid.
[1759] 1H NMR (400 MHz, Methanol-d4) d 8.50 (s, 1H), 8.36 (s, 1H), 8.25 (s, 1H), 7.91 (s, 1H), 6.64 (dd, J = 16.0, 5.0 Hz, 1H), 6.26 (d, J = 15.7 Hz, 1H), 5.91 (dd, J = 15.9, 1.8 Hz, 1H), 5.83– 5.70 (m, 1H), 5.40 (d, J = 9.1 Hz, 1H), 5.18– 5.00 (m, 2H), 4.79 (dd, J = 8.7, 3.2 Hz, 1H), 4.71 (td, J = 8.9, 5.0 Hz, 1H), 4.66– 4.58 (m, 3H), 4.06 (td, J = 15.1, 10.1 Hz, 2H), 3.75 (tt, J = 12.3, 5.3 Hz, 4H), 3.26– 3.04 (m, 3H), 2.56 (dd, J = 15.3, 3.6 Hz, 1H), 2.40 (dd, J = 15.2, 10.6 Hz, 1H), 2.18– 1.99 (m, 3H), 1.94– 1.85 (m, 2H), 1.83 (s, 3H), 1.70 (dt, J = 11.2, 6.5 Hz, 1H), 0.96 (d, J = 6.7 Hz, 3H), 0.91 (d, J = 6.6 Hz, 3H).
[1760] Analog 13s (SA0113171)
Figure imgf000460_0001
[1761] Prepared according to general procedure A. Analogue 13s (10 mg, 50% yield over 2 steps) was obtained as a white solid.
[1762] Analog 13t (SA0113173)
Figure imgf000460_0002
[1763] Prepared according to general procedure A. Analogue 13t (9 mg, 54% yield over 2 steps) was obtained as a white solid.
[1764] Analog 13u (SA0113174)
Figure imgf000461_0001
[1765] Prepared according to general procedure A. Analogue 13u (10 mg, 60% yield over 2 steps) was obtained as a white solid.
[1766] 1H NMR (400 MHz, Methanol-d4) d 8.86– 8.78 (m, 2H), 8.52 (s, 1H), 8.24 (s, 1H), 7.65 (d, J = 3.5 Hz, 1H), 6.79 (d, J = 3.5 Hz, 1H), 6.68– 6.59 (m, 1H), 6.24 (d, J = 15.7 Hz, 1H), 5.92 (dd, J = 15.9, 1.8 Hz, 1H), 5.73 (ddd, J = 15.5, 8.2, 4.0 Hz, 1H), 5.37 (d, J = 9.1 Hz, 1H), 5.17– 4.92 (m, 1H), 4.77 (dd, J = 8.6, 3.3 Hz, 1H), 4.70 (td, J = 8.9, 5.1 Hz, 1H), 4.61 (tt, J = 5.5, 2.6 Hz, 3H), 4.04 (dq, J = 15.0, 5.7 Hz, 2H), 3.86– 3.56 (m, 4H), 3.27– 2.99 (m, 3H), 2.57 (dd, J = 15.3, 3.6 Hz, 1H), 2.41 (dd, J = 15.1, 10.8 Hz, 1H), 2.17– 1.93 (m, 3H), 1.94– 1.84 (m, 2H), 1.81 (s, 3H), 1.72– 1.52 (m, 1H), 0.97 (d, J = 6.7 Hz, 3H), 0.91 (d, J = 6.5 Hz, 3H).
[1767] Analog 13v (SA0113177)
Figure imgf000461_0002
[1768] Prepared according to general procedure A. Analogue 13v (8 mg, 51% yield over 2 steps) was obtained as a white solid.
[1769] Analog 13w (SA0113178)
Figure imgf000462_0001
[1770] Prepared according to general procedure A. Analogue 13w (8 mg, 51% yield over 2 steps) was obtained as a white solid.
[1771] 1H NMR (400 MHz, Methanol-d4) d 8.68 (s, 1H), 8.41 (dd, J = 7.5, 1.6 Hz, 1H), 8.25 (s, 1H), 7.92 (dd, J = 6.3, 1.6 Hz, 1H), 7.04 (dd, J = 7.5, 6.3 Hz, 1H), 6.59 (dd, J = 16.0, 4.9 Hz, 1H), 6.26 (d, J = 15.7 Hz, 1H), 5.90 (dd, J = 15.9, 1.7 Hz, 1H), 5.75 (ddd, J = 15.6, 8.2, 4.1 Hz, 1H), 5.40 (d, J = 9.1 Hz, 1H), 5.09 (dm, J = 47.8 Hz, 1H), 4.93 (dd, J = 10.6, 2.1 Hz, 1H), 4.79 (dd, J = 8.7, 3.3 Hz, 1H), 4.71 (td, J = 8.9, 5.1 Hz, 1H), 4.63 (td, J = 5.5, 1.6 Hz, 2H), 4.09 (dq, J = 11.7, 3.9 Hz, 2H), 3.90– 3.61 (m, 4H), 3.29– 3.02 (m, 3H), 2.56 (dd, J = 15.2, 3.5 Hz, 1H), 2.39 (dd, J = 15.2, 10.8 Hz, 1H), 2.25– 1.96 (m, 3H), 1.95– 1.84 (m, 2H), 1.83 (s, 3H), 1.70 (ddd, J = 14.4, 8.4, 2.9 Hz, 1H), 0.97 (d, J = 6.7 Hz, 3H), 0.92 (d, J = 6.4 Hz, 3H).
[1772] Analog 13x (SA0113179)
Figure imgf000462_0002
[1773] Prepared according to general procedure A. Analogue 13x (5 mg, 30% yield over 2 steps) was obtained as a white solid.
[1774] 1H NMR (400 MHz, Methanol-d4) d 8.32 (s, 1H), 8.26 (s, 1H), 8.10 (s, 1H), 6.64 (dd, J = 15.9, 4.9 Hz, 1H), 6.26 (d, J = 15.7 Hz, 1H), 5.90 (dd, J = 16.0, 1.8 Hz, 1H), 5.75 (ddd, J = 15.5, 8.3, 4.1 Hz, 1H), 5.41 (d, J = 9.0 Hz, 1H), 5.16– 4.90 (m, 2H), 4.80 (dd, J = 8.7, 3.1 Hz, 1H), 4.71 (td, J = 8.8, 5.1 Hz, 1H), 4.55 (tdd, J = 13.7, 7.5, 5.3 Hz, 3H), 4.16– 3.99 (m, 2H), 3.83– 3.55 (m, 4H), 3.28– 3.00 (m, 3H), 2.57 (dd, J = 15.4, 3.6 Hz, 1H), 2.39 (dd, J = 15.3, 10.6 Hz, 1H), 2.20– 2.00 (m, 3H), 2.00– 1.85 (m, 2H), 1.83 (s, 3H), 1.77– 1.62 (m, 1H), 0.98 (d, J = 6.6 Hz, 3H), 0.92 (d, J = 6.5 Hz, 3H).
[1775] 13C NMR (100 MHz, MeOD) d 174.3, 171.5, 167.3, 164.1, 162.5, 162.13, 162.06, 152.8, 145.5, 144.9, 140.8, 139.2, 137.8, 137.0, 136.7, 134.6, 126.3, 125.3, 124.2, 106.0, 91.5 (d, J = 169.8 Hz), 82.6, 66.1, 60.4, 50.6, 50.1, 43.0 (d, J = 19.9 Hz), 41.7, 40.6, 39.9, 34.0 (d, J = 23.8 Hz), 33.3, 30.6, 29.2, 25.9, 20.1, 18.8, 13.1.
[1776] Analog 13y (SA0113180)
Figure imgf000463_0001
[1777] Prepared according to general procedure A. Analogue 13x (8 mg, 48% yield over 2 steps) was obtained as a white solid.
[1778] 1H NMR (400 MHz, Methanol-d4) d 8.94 (dd, J = 4.5, 1.5 Hz, 1H), 8.85 (s, 1H), 8.55 (s, 1H), 8.39 (dd, J = 9.4, 1.6 Hz, 1H), 8.24 (s, 1H), 7.72 (dd, J = 9.3, 4.5 Hz, 1H), 6.57 (dd, J = 15.9, 4.9 Hz, 1H), 6.24 (d, J = 15.6 Hz, 1H), 5.85 (dd, J = 15.9, 1.7 Hz, 1H), 5.71 (ddd, J = 15.6, 8.3, 4.1 Hz, 1H), 5.39 (d, J = 9.0 Hz, 1H), 5.06 (dm, J = 47.5 Hz, 1H), 4.96– 4.86 (m, 1H), 4.77 (dd, J = 8.7, 3.2 Hz, 1H), 4.70 (q, J = 7.2, 5.9 Hz, 3H), 4.05 (ddd, J = 12.3, 8.2, 4.5 Hz, 1H), 3.95 (dd, J = 15.3, 3.5 Hz, 1H), 3.87– 3.72 (m, 3H), 3.67 (dd, J = 15.3, 8.3 Hz, 1H), 3.27– 3.14 (m, 2H), 3.08 (ddd, J = 21.4, 16.5, 5.2 Hz, 1H), 2.56 (dd, J = 15.3, 3.6 Hz, 1H), 2.39 (dd, J = 15.3, 10.6 Hz, 1H), 2.20– 1.94 (m, 3H), 1.94– 1.84 (m, 2H), 1.81 (s, 3H), 1.74– 1.52 (m, 1H), 0.95 (d, J = 6.7 Hz, 3H), 0.90 (d, J = 6.4 Hz, 3H).
[1779] Analog 13z (SA0113181)
Figure imgf000463_0002
[1780] Prepared according to general procedure A. Analogue 13z (10 mg, 60% yield over 2 steps) was obtained as a white solid.
[1781] 1H NMR (400 MHz, Methanol-d4) d 9.51 (d, J = 7.0 Hz, 1H), 8.62 (d, J = 1.5 Hz, 1H), 8.42 (s, 1H), 8.25 (s, 1H), 8.13– 7.98 (m, 2H), 7.62 (td, J = 6.8, 1.7 Hz, 1H), 6.55 (dt, J = 16.1, 4.7 Hz, 1H), 6.23 (d, J = 15.6 Hz, 1H), 5.86 (dd, J = 16.0, 1.9 Hz, 1H), 5.71 (ddd, J = 15.6, 8.1, 4.0 Hz, 1H), 5.38 (d, J = 9.1 Hz, 1H), 5.15– 4.98 (m, 1H), 4.96– 4.90 (m, 1H), 4.78 (dd, J = 8.7, 3.2 Hz, 1H), 4.75– 4.65 (m, 3H), 4.03 (dddd, J = 27.0, 10.8, 6.5, 3.9 Hz, 2H), 3.88 (dt, J = 14.4, 5.6 Hz, 1H), 3.83– 3.59 (m, 3H), 3.28– 3.00 (m, 3H), 2.55 (dd, J = 15.4, 3.4 Hz, 1H), 2.40 (dd, J = 15.4, 10.8 Hz, 1H), 2.21– 1.96 (m, 3H), 1.95– 1.87 (m, 2H), 1.82 (s, 3H), 1.75– 1.58 (m, 1H), 0.97 (d, J = 6.7 Hz, 3H), 0.91 (d, J = 6.4 Hz, 3H).
[1782] Analog 13aa (SA0113183)
Figure imgf000464_0001
[1783] Prepared according to general procedure A. Analogue 13aa (8 mg, 48%yield over 2 steps) was obtained as a white solid.
[1784] 1H NMR (400 MHz, Methanol-d4) d 9.27 (d, J = 5.6 Hz, 2H), 8.53 (s, 1H), 8.34 (s, 1H), 8.25 (s, 1H), 8.10 (s, 1H), 6.62 (dd, J = 15.9, 4.9 Hz, 1H), 6.24 (d, J = 15.7 Hz, 1H), 5.90 (dd, J = 15.9, 1.8 Hz, 1H), 5.73 (ddd, J = 15.6, 8.3, 4.0 Hz, 1H), 5.39 (d, J = 9.0 Hz, 1H), 5.18– 4.96 (m, 1H), 4.95– 4.89 (m, 1H), 4.79 (dd, J = 8.7, 3.2 Hz, 1H), 4.71 (tt, J = 9.0, 4.1 Hz, 1H), 4.63 (td, J = 10.3, 8.7, 5.2 Hz, 2H), 4.12– 3.94 (m, 2H), 3.84– 3.63 (m, 4H), 3.27– 3.01 (m, 3H), 2.57 (dd, J = 15.2, 3.6 Hz, 1H), 2.41 (dd, J = 15.3, 10.5 Hz, 1H), 2.22– 1.99 (m, 3H), 1.94– 1.84 (m, 2H), 1.82 (s, 3H), 1.77– 1.67 (m, 1H), 0.97 (d, J = 6.6 Hz, 3H), 0.91 (d, J = 6.4 Hz, 3H).
[1785] 13C NMR (100 MHz, MeOD) d 174.3, 171.5, 167.3, 162.5, 162.13, 162.06, 145.9, 145.4, 144.9, 141.4, 137.8, 137.0, 136.7, 134.7, 131.2, 131.1, 126.2, 125.4, 125.2, 117.7, 91.5 (d, J = 169.1 Hz), 82.5, 66.0, 60.4, 50.9, 50.0, 43.0 (d, J = 20.1 Hz), 41.7, 40.5, 39.9, 34.0 (d, J = 24.4 Hz), 33.4, 30.7, 29.2, 25.9, 20.1, 18.8, 13.1. [1786] Analog 13ab (SA0113184)
Figure imgf000465_0001
[1787] Prepared according to general procedure A. Analogue 13ab (10 mg, 50% yield over 2 steps) was obtained as a white solid.
[1788] 1H NMR (400 MHz, Methanol-d4) d 8.70 (s, 1H), 8.59 (d, J = 0.9 Hz, 1H), 8.26 (s, 1H), 7.15 (d, J = 0.9 Hz, 1H), 6.57 (dd, J = 15.9, 5.0 Hz, 1H), 6.25 (d, J = 15.7 Hz, 1H), 5.91 (dd, J = 15.9, 1.8 Hz, 1H), 5.75 (ddd, J = 15.7, 8.0, 4.1 Hz, 1H), 5.40 (d, J = 9.1 Hz, 1H), 5.17– 4.98 (m, 1H), 4.94 (dd, J = 10.3, 2.2 Hz, 1H), 4.80 (dd, J = 8.4, 5.0 Hz, 1H), 4.71 (td, J = 9.0, 5.0 Hz, 2H), 4.65 (t, J = 5.7 Hz, 2H), 4.10 (td, J = 12.4, 11.3, 4.6 Hz, 2H), 3.88– 3.62 (m, 4H), 3.27– 3.03 (m, 4H), 2.55 (dd, J = 15.2, 3.5 Hz, 1H), 2.37 (dd, J = 15.1, 10.8 Hz, 1H), 2.22– 1.96 (m, 3H), 1.96– 1.86 (m, 2H), 1.83 (s, 3H), 1.77– 1.66 (m, 1H), 0.98 (d, J = 6.7 Hz, 3H), 0.93 (d, J = 6.5 Hz, 3H).
[1789] Analog 13ac (SA0113185)
Figure imgf000465_0002
[1790] Prepared according to general procedure A. Analogue 13ac (14 mg, 54% yield over 2 steps) was obtained as a white solid.
[1791] 1H NMR (400 MHz, Methanol-d4) d 8.60– 8.52 (m, 1H), 8.26 (s, 1H), 6.62– 6.53 (m, 2H), 6.24 (d, J = 15.7 Hz, 1H), 5.95 (dd, J = 15.9, 1.7 Hz, 1H), 5.76 (ddd, J = 15.6, 7.7, 4.0 Hz, 1H), 5.38 (d, J = 9.0 Hz, 1H), 5.15– 4.97 (m, 1H), 4.94– 4.89 (m, 1H), 4.80 (dd, J = 8.6, 3.4 Hz, 1H), 4.71 (td, J = 9.0, 5.0 Hz, 2H), 4.67– 4.59 (m, 2H), 4.18– 4.01 (m, 2H), 3.86– 3.60 (m, 4H), 3.25– 3.03 (m, 3H), 2.55 (dd, J = 15.2, 3.5 Hz, 1H), 2.40 (d, J = 11.1 Hz, 1H), 2.23– 1.96 (m, 3H), 1.90 (d, J = 13.1 Hz, 2H), 1.83 (s, 3H), 1.77– 1.63 (m, 1H), 0.98 (d, J = 6.6 Hz, 3H), 0.92 (d, J = 6.4 Hz, 3H).
[1792] Analog 13ad (SA0113186)
Figure imgf000466_0001
[1793] Prepared according to general procedure A. Analogue 13ad (10 mg, 48% yield over 2 steps) was obtained as a white solid.
[1794] 1H NMR (400 MHz, Methanol-d4) d 8.64 (s, 1H), 8.30 (t, J = 4.5 Hz, 2H), 8.24 (s, 1H), 8.20 (d, J = 8.9 Hz, 1H), 6.63 (dd, J = 15.9, 5.0 Hz, 1H), 6.24 (d, J = 15.6 Hz, 1H), 5.91 (dd, J = 15.9, 1.7 Hz, 1H), 5.73 (ddd, J = 15.5, 8.2, 4.1 Hz, 1H), 5.39 (d, J = 9.0 Hz, 1H), 5.16– 4.96 (m, 1H), 4.94– 4.89 (m, 1H), 4.78 (dd, J = 8.6, 3.2 Hz, 1H), 4.71 (dt, J = 8.7, 4.3 Hz, 1H), 4.65 (q, J = 5.5 Hz, 3H), 4.11– 3.96 (m, 2H), 3.82– 3.64 (m, 4H), 3.28– 3.00 (m, 4H), 2.58 (dd, J = 15.3, 3.6 Hz, 1H), 2.41 (dd, J = 15.3, 10.7 Hz, 1H), 2.18– 1.95 (m, 3H), 1.90 (d, J = 6.6 Hz, 2H), 1.82 (s, 3H), 1.76– 1.54 (m, 1H), 0.94 (d, J = 6.7 Hz, 3H), 0.90 (d, J = 6.4 Hz, 3H).
[1795] Preparation of click chemistry precursor 14
Figure imgf000466_0002
[1796] A 50-mL round-bottom flask was charged with iPr2EtN (0.18 mL, 1.04 mmol, 2.0 equiv), 2-azidopropan-1-amine (78.4 mg, 0.78 mmol, 1.5 equiv), and acid 11 (0.36 g, 0.52 mmol, 1 equiv). DCM (12 mL) was added, resulting in a colorless solution. HATU (0.25 g, 0.65 mmol, 1.25 equiv) was added in one portion. After 5 h, the mixture was diluted with DCM (30 mL). The resulting solution was transferred to a separatory funnel and was washed with water (2 × 25 mL) and brine (25 mL). The washed solution was dried (Na2SO4). The dried solution was filtered, and the filtrate was concentrated. The resulting crude residue was purified by flash chromatography (silica gel, eluent: acetone:hexanes = 1:6 to 1:2) to afford click chemistry precursor 14 (0.34 g, 85% yield) as a white solid.
[1797] TLC (acetone:hexanes = 1:2): Rf = 0.30 (UV, p-anisaldehyde).
[1798] 1H NMR (400 MHz, Chloroform-d) d 8.08 (s, 1H), 6.48 (dd, J = 16.2, 5.4 Hz, 1H), 6.32 (t, J = 5.9 Hz, 1H), 6.24– 6.10 (m, 2H), 5.86 (dd, J = 16.2, 1.7 Hz, 1H), 5.65 (ddd, J = 15.6, 8.6, 4.3 Hz, 1H), 5.29 (d, J = 9.0 Hz, 1H), 5.04 (dm, J = 48.1 Hz, 1H), 4.89 (dd, J = 10.2, 2.0 Hz, 1H), 4.81 (dd, J = 8.9, 3.3 Hz, 1H), 4.71 (td, J = 9.9, 3.8 Hz, 1H), 4.51 (ddd, J = 13.8, 8.6, 4.1 Hz, 1H), 4.07 (ddd, J = 11.2, 8.1, 4.6 Hz, 1H), 3.80 (dt, J = 11.2, 7.2 Hz, 1H), 3.46– 3.22 (m, 7H), 3.14 (td, J = 16.7, 6.5 Hz, 1H), 2.92 (ddd, J = 21.9, 16.5, 5.6 Hz, 1H), 2.50 (dd, J = 14.7, 3.4 Hz, 1H), 2.23– 2.10 (m, 5H), 1.99– 1.77 (m, 3H), 1.75 (s, 3H), 1.57 (dddd, J = 40.5, 14.2, 10.2, 1.8 Hz, 1H), 0.98 (d, J = 6.7 Hz, 3H), 0.93 (d, J = 6.4 Hz, 3H), 0.85 (s, 9H), 0.03 (s, 3H), -0.00 (s, 3H).
[1799] 13C NMR (100 MHz, CDCI3) d 171.2, 170.8, 165.7, 160.4, 160.3, 160.3, 142.8, 142.3, 136.4, 136.3, 134.5, 133.5, 124.7, 124.5, 89.1 (d, J = 169.6 Hz), 81.0, 66.4, 59.0, 49.3, 48.5, 43.5 (d, J = 20.3 Hz), 41.0, 39.0, 37.2, 33.8 (d, J = 25.2 Hz), 33.6, 29.5, 28.7, 28.3, 25.7, 24.8, 19.6, 18.5, 18.1, 12.8, -4.5, -5.0.
[1800] General procedure for preparation of C-4 analogs 15
Figure imgf000467_0001
[1801] To a suspension of chemistry precursor 14 (1 equiv) and alkyne (, 3.00 equiv) in DCM-H2O (3 mL-1 mL) were added an aqueous solution of sodium ascorbate (0.05 M, 0.20 equiv) and an aqueous solution of copper(II) sulfate (0.05 M, 0.05 equiv) at 23 °C. After stirring at 23 °C for 12 h, the solvent was removed under vacuum. The residue was purified by column chromatography over silica gel (5®10% methanol in dichloromethane) to afford the product as an off white solid. Then the white solid was dissolved with 0.1% TFA in MeCN-H2O (95/5 v/v), and the solution was stirred for 12 hours at RT. The reaction mixture was concentrated, and the resulting crude residue was purified by preparative HPLC (eluent: 0.1% TFA in H2O: 0.1% TFA in acetonitrile = 95:5 to 5:95 over 15 min) to afford C-4 modified analogue 15 TFA salt as a white solid.
[1802] Analog 15a (SA0113193)
Figure imgf000468_0001
[1803] Prepared according to general procedure A. Analogue 15a (11.5 mg, 47% yield over 2 steps) was obtained as a white solid.
[1804] 1H NMR (400 MHz, Methanol-d4) d 9.30 (s, 1H), 8.95 (d, J = 8.1 Hz, 1H), 8.78 (d, J = 5.6 Hz, 1H), 8.69 (s, 1H), 8.26 (s, 1H), 8.10 (ddd, J = 8.3, 5.5, 2.6 Hz, 1H), 6.74– 6.64 (m, 1H), 6.25 (d, J = 15.6 Hz, 1H), 6.00 (dd, J = 15.9, 1.7 Hz, 1H), 5.75 (ddd, J = 15.6, 8.2, 4.1 Hz, 1H), 5.40 (d, J = 9.0 Hz, 1H), 5.23– 5.00 (m, 1H), 5.00– 4.94 (m, 1H), 4.83 (dd, J = 8.7, 3.4 Hz, 1H), 4.71 (td, J = 9.0, 5.1 Hz, 1H), 4.54 (t, J = 7.0 Hz, 2H), 4.09 (qd, J = 12.3, 10.4, 6.3 Hz, 2H), 3.78 (dt, J = 11.5, 7.6 Hz, 1H), 3.74– 3.60 (m, 1H), 3.28– 3.02 (m, 5H), 2.60 (dd, J = 15.0, 3.7 Hz, 1H), 2.49 (dd, J = 14.2, 10.9 Hz, 1H), 2.20 (pt, J = 6.6, 4.0 Hz, 3H), 2.10 (td, J = 9.4, 8.3, 3.9 Hz, 2H), 1.98– 1.88 (m, 2H), 1.82 (s, 3H), 1.78– 1.70 (m, 1H), 1.02 (d, J = 6.7 Hz, 3H), 0.95 (d, J = 6.4 Hz, 3H).
[1805] Analog 15b (SA0113194)
Figure imgf000468_0002
[1806] Prepared according to general procedure A. Analogue 15b (11 mg, 45% yield over 2 steps) was obtained as a white solid.
[1807] 1H NMR (400 MHz, Methanol-d4) d 8.93 (s, 1H), 8.84 (d, J = 6.9 Hz, 2H), 8.48 (d, J = 6.9 Hz, 2H), 8.26 (s, 1H), 6.68 (dd, J = 15.9, 5.2 Hz, 1H), 6.25 (d, J = 15.6 Hz, 1H), 6.00 (dd, J = 16.0, 1.8 Hz, 1H), 5.75 (ddd, J = 15.7, 8.1, 4.1 Hz, 1H), 5.40 (d, J = 9.2 Hz, 1H), 5.13– 5.00 (m, 1H), 4.98 (dd, J = 10.2, 2.3 Hz, 1H), 4.83 (dd, J = 8.9, 2.7 Hz, 1H), 4.71 (td, J = 9.0, 5.0 Hz, 1H), 4.56 (t, J = 7.0 Hz, 2H), 4.10 (ddt, J = 12.0, 8.4, 4.1 Hz, 2H), 3.84– 3.76 (m, 1H), 3.66 (dd, J = 15.5, 8.1 Hz, 1H), 3.29– 3.01 (m, 5H), 2.59 (dd, J = 15.0, 3.7 Hz, 1H), 2.47 (dd, J = 14.9, 11.0 Hz, 1H), 2.24– 2.16 (m, 3H), 2.13– 2.06 (m, 2H), 1.99– 1.88 (m, 2H), 1.82 (s, 3H), 1.78– 1.67 (m, 1H), 1.02 (d, J = 6.7 Hz, 3H), 0.95 (d, J = 6.5 Hz, 3H).
[1808] 13C NMR (100 MHz, MeOD) d 174.2, 171.7, 167.3, 162.5, 162.13, 162.06, 149.1, 145.2, 144.8, 143.6, 143.4, 137.8, 136.8, 136.7, 134.6, 127.8, 126.2, 125.7, 123.4, 90.4 (d, J = 169.4 Hz), 82.5, 66.0, 60.6, 50.1, 49.3, 43.0 (d, J = 19.8 Hz), 41.6, 40.2, 37.3, 34.0 (d, J = 24.4 Hz), 33.7, 31.0, 30.7, 29.2, 25.9, 20.1, 18.7, 13.2.
[1809] Analog 15c (SA0113195)
Figure imgf000469_0001
[1810] Prepared according to general procedure A. Analogue 15c (12 mg, 48% yield over 2 steps) was obtained as a white solid.
[1811] 1H NMR (400 MHz, Methanol-d4) d 8.45 (s, 1H), 8.26 (s, 1H), 7.90 (dd, J = 4.1, 2.2 Hz, 2H), 7.61 (t, J = 8.1 Hz, 1H), 7.38 (dd, J = 8.0, 2.2 Hz, 1H), 6.68 (dd, J = 15.9, 5.1 Hz, 1H), 6.24 (d, J = 15.7 Hz, 1H), 6.00 (dd, J = 16.0, 1.7 Hz, 1H), 5.77 (dd, J = 8.1, 4.2 Hz, 1H), 5.39 (d, J = 9.0 Hz, 1H), 5.23– 5.06 (m, 2H), 4.82 (dd, J = 8.7, 3.5 Hz, 1H), 4.71 (td, J = 8.9, 5.1 Hz, 1H), 4.50 (t, J = 6.9 Hz, 2H), 4.17– 3.97 (m, 2H), 3.78 (dt, J = 11.5, 7.6 Hz, 1H), 3.68 (dd, J = 15.3, 7.9 Hz, 1H), 3.28– 3.01 (m, 5H), 2.58 (dd, J = 14.9, 3.8 Hz, 1H), 2.46 (dd, J = 14.8, 11.0 Hz, 1H), 2.27– 2.14 (m, 3H), 2.14– 2.02(m, 2H), 1.99– 1.85 (m, 2H), 1.82 (s, 3H), 1.79– 1.67 (m, 1H), 1.01 (d, J = 6.7 Hz, 3H), 0.94 (d, J = 6.5 Hz, 3H).
[1812] Analog 15d (SA0113197)
Figure imgf000470_0001
[1813] Prepared according to general procedure A. Analogue 15d (10 mg, 41% yield over 2 steps) was obtained as a white solid.
[1814] 1H NMR (400 MHz, Methanol-d4) d 9.02 (s, 2H), 8.55 (s, 1H), 8.26 (s, 1H), 6.68 (dd, J = 16.0, 5.1 Hz, 1H), 6.25 (d, J = 15.7 Hz, 1H), 6.07– 5.94 (m, 1H), 5.76 (ddd, J = 15.6, 7.9, 3.7 Hz, 1H), 5.40 (d, J = 9.0 Hz, 1H), 5.19– 4.94 (m, 2H), 4.83 (dd, J = 8.6, 3.1 Hz, 1H), 4.71 (td, J = 9.0, 5.0 Hz, 1H), 4.61 (s, 2H), 4.11 (ddd, J = 11.9, 8.1, 4.4 Hz, 2H), 3.78 (dt, J = 11.5, 7.6 Hz, 1H), 3.66 (dd, J = 15.3, 8.0 Hz, 1H), 3.28– 3.00 (m, 5H), 2.59 (dd, J = 15.0, 3.5 Hz, 1H), 2.46 (dd, J = 14.8, 10.9 Hz, 1H), 2.35– 2.15 (m, 3H), 2.15– 2.04 (m, 2H), 2.01– 1.89 (m, 2H), 1.82 (s, 3H), 1.73 (dd, J = 11.9, 8.6 Hz, 1H), 1.01 (d, J = 6.6 Hz, 3H), 0.94 (d, J = 6.4 Hz, 3H).
[1815] Preparation of C3-C4 hybrid analog (SA0113336)
Figure imgf000471_0001
[1816] All the intermediates were prepared by aforementioned procedures.
Figure imgf000471_0002
[1817] 1H NMR (400 MHz, Chloroform-d) d 9.24 (s, 1H), 8.95 (s, 1H), 8.26 (s, 1H), 8.24 (s, 1H), 7.88– 7.84 (m, 1H), 7.75 (d, J = 8.2 Hz, 1H), 7.59 (ddd, J = 8.2, 6.8, 1.2 Hz, 1H), 7.41 (ddd, J = 8.1, 6.8, 1.1 Hz, 1H), 6.56 (dd, J = 16.1, 5.0 Hz, 1H), 6.17 (d, J = 15.7 Hz, 1H), 6.05 (dd, J = 8.8, 3.2 Hz, 1H), 5.93 (dd, J = 16.1, 1.8 Hz, 1H), 5.85– 5.61 (m, 2H), 5.37 (d, J = 9.0 Hz, 1H), 5.25 (dd, J = 10.0, 2.2 Hz, 1H), 5.17– 4.97 (m, 3H), 4.91 (dd, J = 8.8, 3.3 Hz, 1H), 4.78 (td, J = 9.2, 4.3 Hz, 1H), 4.59– 4.45 (m, 1H), 4.41 (dd, J = 11.4, 4.0 Hz, 1H), 4.13 (ddd, J = 11.6, 8.3, 4.8 Hz, 1H), 4.03 (dd, J = 11.4, 7.3 Hz, 1H), 3.84 (dt, J = 11.5, 7.2 Hz, 1H), 3.45 (ddd, J = 16.0, 8.0, 3.1 Hz, 1H), 3.19 (ddd, J = 17.9, 16.4, 5.7 Hz, 1H), 2.95 (td, J = 16.9, 6.4 Hz, 1H), 2.65 (ddt, J = 10.5, 5.1, 2.5 Hz, 1H), 2.48– 2.34 (m, 2H), 2.30– 2.06 (m, 6H), 1.98– 1.88 (m, 1H), 1.80 (s, 3H), 1.73– 1.51 (m, 1H), 1.02 (d, J = 7.0 Hz, 3H).
[1818] 13C NMR (100 MHz, CDCI3) d 171.3, 165.5, 160.6, 159.74, 159.65, 153.8, 151.1, 147.2, 144.16, 142.8, 138.0, 136.6, 135.8, 135.5, 135.3, 133.2, 130.5, 127.4, 126.5, 125.9, 125.3, 125.2, 125.1, 117.4, 106.3, 89.2 (d, J = 169.9 Hz), 78.8, 68.4, 65.6, 59.4, 48.7, 42.32 (d, J = 20.2 Hz), 41.4, 40.7, 34.2, 33.6 (d, J = 25.3 Hz), 30.6, 28.2, 24.8, 13.7, 12.9. REFERENCES
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Oxazolidinones, Pleuromutilins, and Streptogramin A antibiotics. Antimicrob. Agents Chemother.50, 2500–2505 (2006). 6. Drawz, S. M. & Bonomo, R. A. Three decades of beta-lactamase inhibitors. Clin. Microbiol. Rev.23, 160–201 (2010). 7. Vazquez, D. The Streptogramin Family of Antibiotics. in Mechanism of Action (eds. Gottlieb, D. & Shaw, P. D.) 387–403 (Springer Berlin Heidelberg, 1967). 8. Johnston, N. J., Mukhtar, T. A. & Wright, G. D. Streptogramin antibiotics: mode of action and resistance. Curr. Drug Targets 3, 335–344 (2002). 9. Delgado, G., Jr, Neuhauser, M. M., Bearden, D. T. & Danziger, L. H. Quinupristin-dalfopristin: an overview. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy 20, 1469–1485 (2000). 10. Allington, D. R. & Rivey, M. P. Quinupristin/dalfopristin: a therapeutic review. Clin. Ther.23, 24–44 (2001). 11.
Hershberger, E., Donabedian, S., Konstantinou, K. & Zervos, M. J. Quinupristin-dalfopristin resistance in gram-positive bacteria: mechanism of resistance and epidemiology. Clin. Infect. Dis.38, 92–98 (2004). 12. Politano, A. D. & Sawyer, R. G. NXL-103, a combination of flopristin and linopristin, for the potential treatment of bacterial infections including community-acquired pneumonia and MRSA. Curr. Opin. Investig. Drugs 11, 225–236 (2010). 13. Li, Q. & Seiple, I. B. Modular, Scalable Synthesis of Group A Streptogramin Antibiotics. J. Am. Chem. Soc.139, 13304–13307 (2017). 14. Wilson, D. N. The A-Z of bacterial translation inhibitors. Crit. Rev. Biochem. Mol. Biol.44, 393–433 (2009). 15.
Noeske, J. et al. Synergy of streptogramin antibiotics occurs independently of their effects on translation. Antimicrob. Agents Chemother.58, 5269–5279 (2014). 16. Vidaillac, C., Parra- Ruiz, J., Winterfield, P. & Rybak, M. J. In vitro pharmacokinetic/pharmacodynamic activity of NXL103 versus clindamycin and linezolid against clinical Staphylococcus aureus and Streptococcus pyogenes isolates. Int. J. Antimicrob. Agents 38, 301–306 (2011). 17. Sharkey, L. K. R. & O’Neill, A. J. Antibiotic Resistance ABC-F Proteins: Bringing Target Protection into the Limelight. ACS Infect Dis 4, 239–246 (2018). 18. Leclercq, R. & Courvalin, P. Bacterial resistance to macrolide, lincosamide, and streptogramin antibiotics by target modification. Antimicrob. Agents Chemother.35, 1267–1272 (1991). 19. Harms, J. M., Schlünzen, F., Fucini, P., Bartels, H. & Yonath, A. Alterations at the peptidyl transferase centre of the ribosome induced by the synergistic action of the streptogramins dalfopristin and quinupristin. BMC Biol.2, 4 (2004). 20. Osterman, I. A. et al. Madumycin II inhibits peptide bond formation by forcing the peptidyl transferase center into an inactive state.
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Claims

WHAT IS CLAIMED IS: 1. A compound, or salt thereof, having the formula:
Figure imgf000475_0001
wherein
Y is–O- or–NH-;
L1 is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene;
R2 is hydrogen or unsubstituted C1-C3 alkyl;
R4A is substituted or unsubstituted C2-C10 alkyl;
R3 and R5 are independently hydrogen, oxo, halogen, -CCI3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, -OPO3H, -OSO3H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R6 is hydrogen, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or an amino acid side chain;
R7 is hydrogen, -CH2COOH, -CONH2, -OH, -SH, -NO2, -NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R6 and R7 may optionally be joined to form an unsubstituted heterocycloalkyl or unsubstituted heteroaryl; R8 is oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
Ring A is cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; z8 is an integer from 0 to 10;
R9 is hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R10 and R12 are independently hydrogen, substituted or unsubstituted C1-C3 alkyl, or substituted or unsubstituted 2 to 3 membered heteroalkyl; and
R11 is hydrogen, oxo, halogen, -CCI3, -CBr3, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
2. The compound of claim 1, wherein R4A is unsubstituted C2-C10 alkyl.
3. The compound of claim 1, wherein R4A is unsubstituted C3-C10 alkenyl.
4. The compound of claim 1, wherein R4A is
Figure imgf000477_0001
.
5. The compound of claim 1, wherein L1 is a substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.
6. The compound of claim 1, wherein L1 is a substituted or unsubstituted alkenylene.
7. The compound of claim 1, wherein L1 is a substituted or unsubstituted C1-C3 alkenylene.
8. The compound of claim 1, wherein R2 is hydrogen.
9. The compound of claim 1, wherein R3 is hydrogen or substituted or unsubstituted alkyl.
10. The compound of claim 1, wherein R3 is hydrogen.
11. The compound of claim 1, wherein R5 is hydrogen, oxo, halogen, -CCI3, -CBr3, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
12. The compound of claim 1, wherein R5 is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
13. The compound of claim 1, wherein R5 is substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, or substituted or unsubstituted 5 to 10 membered heteroaryl.
14. The compound of claim 1, wherein R5 is substituted or unsubstituted C1-C8 alkyl.
15. The compound of claim 1, wherein R5 is substituted or unsubstituted C1-C3 alkyl.
16. The compound of claim 1, wherein R5 is:
Figure imgf000478_0001
Figure imgf000479_0001
17. The compound of claim 1, wherein Y is -O-.
18. The compound of claim 1, wherein R6 is substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.
19. The compound of claim 1, wherein R6 is hydrogen,
Figure imgf000479_0002
20. The compound of claim 1, wherein R6 is
Figure imgf000479_0003
, ,
Figure imgf000479_0004
21. The compound of claim 1, wherein R6 and R7 are joined to form an unsubstituted heterocycloalkyl or unsubstituted heteroaryl.
22. The compound of claim 1, wherein R6 and R7 are joined to form an unsubstituted 3 to 6 membered heterocycloalkyl, or an unsubstituted 5 to 6 membered heteroaryl.
23. The compound of claim 1, wherein R6 and R7 are joined to form an unsubstituted 3 to 6 membered heterocycloalkyl.
24. The compound of claim 1, wherein R6 and R7 are joined to form an unsubstituted pyrrolidinyl or 2,3-dihydropyrrolyl.
25. The compound of claim 1, wherein R7 is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.
26. The compound of claim 1, wherein R7 is hydrogen.
27. The compound of claim 1, wherein Ring A is C3-C6 cycloalkylene, 3 to 6 membered heterocycloalkylene, phenylene, or a 5 to 6 membered heteroarylene.
28. The compound of claim 1, wherein Ring A is 5 to 6 membered heteroarylene.
29. The compound of claim 1, wherein Ring A is imidazolylene, pyrrolylene, pyrazolylene, triazolylene, tetrazolylene, furanylene, oxazolylene, isoxazolylene, oxadiazolylene, oxatriazolylene, thienylene, thiazolylene, isothiazolylene, pyridinylene, pyrazinylene, pyrimidinylene, pyridazinylene, or triazinylene.
30. The compound of claim 1, wherein Ring A is oxazolylene, thiazolylene, isoxazolylene, or oxadiazolylene.
31. The compound of claim 1, wherein z8 is 0.
32. The compound of claim 1, wherein R9 is halogen, oxo, -NH2, unsubstituted alkyl, or unsubstituted heteroalkyl.
33. The compound of claim 1, wherein R9 is–F, oxo, -NH2, or unsubstituted heteroalkyl.
34. The compound of claim 1, wherein R10 is hydrogen.
35. The compound of claim 1, wherein R11 is -OH, -NH2, or -SH.
36. The compound of claim 1, wherein R11 is–OH.
37. The compound of claim 1, wherein R12 is hydrogen or an unsubstituted C1-C3 alkyl.
38. The compound of claim 1, wherein the compound has the formula:
Figure imgf000481_0001
39. The compound of claim 1, wherein the compound has the formula:
Figure imgf000481_0002
.
40. A compound, or salt thereof, having the formula:
Figure imgf000482_0001
wherein
Y is–O- or–NH-;
L1 is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene;
R2 is hydrogen or unsubstituted C1-C3 alkyl;
R3, R4, and R5 are independently hydrogen, oxo, halogen, -CCI3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,
-NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, -OPO3H, -OSO3H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R6 is hydrogen, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or an amino acid side chain;
R7 is hydrogen, -CH2COOH, -CONH2, -OH, -SH, -NO2, -NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R6 and R7 may optionally be joined to form an unsubstituted heterocycloalkyl or unsubstituted heteroaryl;
R8 is oxo, halogen, -CCI3, -CBr3, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
Ring A is cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; z8 is an integer from 0 to 10;
R10 and R12 are independently hydrogen, substituted or unsubstituted C1-C3 alkyl, or substituted or unsubstituted 2 to 3 membered heteroalkyl; and
R11 is hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
wherein the compound does not have the formula:
Figure imgf000483_0001
41. The compound of claim 40, having the formula:
Figure imgf000483_0002
wherein
L2 is substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; and
R33 is hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
42. The compound of claim 40, wherein R4 is substituted or unsubstituted alkyl.
43. The compound of claim 41, wherein -L2- is substituted or unsubstituted C1-C8 alkylene, substituted or unsubstituted 2 to 8 membered heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, substituted or unsubstituted 3 to 8 membered
heterocycloalkylene, substituted or unsubstituted C6-C10 arylene, or substituted or unsubstituted 5 to 10 membered heteroarylene.
44. The compound of claim 41, wherein -L2- is substituted or unsubstituted C1-C8 alkylene, or substituted or unsubstituted 2 to 8 membered heteroalkylene.
45. The compound of claim 41, wherein -L2- is
Figure imgf000484_0001
46. The compound of claim 41, wherein -L2-R33 is
Figure imgf000485_0001
Figure imgf000486_0003
47. The compound of claim 40, having the formula:
Figure imgf000486_0001
Figure imgf000486_0002
48. A pharmaceutical composition comprising a compound of one of claims 1 to 47, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
49. A method of treating an infectious disease, said method comprising administering to a subject in need thereof an effective amount of a compound of one of claims 1 to 47.
50. The method of claim 49, wherein said infectious disease is a bacterial infection.
51. The method of claim 49, wherein the infectious disease is a gram- positive bacterial infection.
52. The method of claim 49, wherein the infectious disease is a gram- negative bacterial infection.
53. The method of claim 49, wherein the bacterial infection is a Staphylococcus infection, an Enterococcus infection, an Acinetobacter infection, a Bacillus infection, a Streptococcus infection, an Escherichia infection, a Pseudomonas infection, a Klebsiella infection, or a Haemophilus infection.
54. The method of claim 49, wherein the bacterial infection is a Staphylococcus infection, a Streptococcus infection, or an Enterococcus infection.
55. The method of claim 49, wherein the infectious disease is a parasitic infection.
56. The method of claim 55, wherein the parasitic infection is a Plasmodium falciparum parasitic infection.
57. The method of claim 55, wherein the parasitic infection is a Trypanosoma cruzi parasitic infection.
PCT/US2020/036845 2019-06-10 2020-06-09 Streptogramin compositions and the use thereof WO2020251953A1 (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020143041A1 (en) * 2000-01-22 2002-10-03 Pascal Desmazeau Streptogramin derivatives, their preparation and compositions which contain them
US20030162962A1 (en) * 2001-12-26 2003-08-28 Eric Bacque Streptogramin derivatives, their preparation and compositions containing them
WO2019028084A1 (en) * 2017-08-01 2019-02-07 The Regents Of The University Of California Methods of making streptogramin compositions and the use thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020143041A1 (en) * 2000-01-22 2002-10-03 Pascal Desmazeau Streptogramin derivatives, their preparation and compositions which contain them
US20030162962A1 (en) * 2001-12-26 2003-08-28 Eric Bacque Streptogramin derivatives, their preparation and compositions containing them
WO2019028084A1 (en) * 2017-08-01 2019-02-07 The Regents Of The University Of California Methods of making streptogramin compositions and the use thereof

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