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WO2016037072A2 - Analogues d'enopeptine s et leurs procédés d'utilisation - Google Patents

Analogues d'enopeptine s et leurs procédés d'utilisation Download PDF

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WO2016037072A2
WO2016037072A2 PCT/US2015/048568 US2015048568W WO2016037072A2 WO 2016037072 A2 WO2016037072 A2 WO 2016037072A2 US 2015048568 W US2015048568 W US 2015048568W WO 2016037072 A2 WO2016037072 A2 WO 2016037072A2
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optionally substituted
alkyl
alkenyl
alkynyl
hydrogen
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WO2016037072A3 (fr
WO2016037072A8 (fr
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Jason K SELLO
Daniel William CARNEY
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Brown University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/48—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a saturated carbon skeleton containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/49—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a carbon atom of an acyclic unsaturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/50—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to an acyclic carbon atom of an unsaturated carbon skeleton containing rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • Infectious diseases are the third leading cause of death in developed countries and the second leading cause of death worldwide (see, e.g., World Health Organization (WHO) Geneva, World Health Report (2002); Nathan, Nature (2004) 431:899).
  • the efficacy of many antibacterial drugs has been compromised by the emergence of drug resistant, pathogenic bacteria (see, e.g., National Nosocomial Infections Surveillance (NNIS) System, Am. J. Infect. Control (2004) 32:470).
  • NIS National Nosocomial Infections Surveillance
  • the Infectious Disease Society of America has recently outlined the deadly implications of a growing number of drug-resistant pathogens (see, e.g., Boucher et al., J. Clin. Infect. Dis. (2009) 48: 1). Methicillin-resistant
  • Staphylococcus aureus MRSA
  • vancomycin-resistant Enterococci VRE
  • penicillin- resistant Streptococcus epidermis are especially worrisome in clinical settings.
  • MRSA vancomycin-resistant Enterococci
  • VRE vancomycin-resistant Enterococci
  • Streptococcus epidermis penicillin- resistant Streptococcus epidermis
  • A54556 A and B were isolated from Streptomyces hawaiienesis by a research group at Eli Lilly (U.S. Patent 4,492,650).
  • the enopeptins attracted attention because of their potent activity against drug-resistant bacterial pathogens, including MRSA and VRE (see, e.g., Brotz-Oesterhelt et al., Nat. Med. (2005) 11: 1082).
  • the apparent lack of cross-resistance for all antibacterial agents on the market or those in clinical development has been ascribed to a peculiar mechanism of action.
  • the enopeptin antibiotics inhibit cell division and cause cell death by binding and deregulating the activity of the casein lytic protease (ClpP) (see, e.g., Brotz-Oesterhelt, supra). Under normal conditions, this fourteen-subunit protease selectively degrades proteins through a physical and functional association with accessory ATPases that recognize and unfold its substrates (see, e.g., Maurizi et al., Biochemistry (1999) 37:7778; Singh et al, Proc. Natl. Acad. Set, USA. (2000) 97:8898; Baker et al, Trends Biochem. Sci. (2006) 31:647; Hsiung et al., FEBS Lett.
  • ClpP casein lytic protease
  • ADEP cyclic acyldepsipeptide
  • Exemplary fragments of cyclic ADEP scaffold include compounds of Formula (I) or (II):
  • R 1 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • each instance of R 2A and R 3A is independently optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl,
  • R 3A groups are joined to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring;
  • R 4 is hydrogen, -OH, -SH, -NH 2 , substituted hydroxyl, substituted thiol, substituted amino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • R 5 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR 5A or -NHR 5A , wherein each instance of R 5A is independently optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • each instance of R 6 is independently halogen, -OH, -SH, -NH 2 , -CN, -N0 2 , -N 3 , - S0 2 H, -SO3H, substituted hydroxyl, substituted thiol, substituted amino, sulfonyl, sulfinyl, carbonyl, silyl, boronyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • n is 0 or an integer of between 1 and 5, inclusive;
  • Y is O, S, or NR Y wherein R Y is hydrogen, optionally substituted alkyl, or a nitrogen protecting group;
  • X is O, S, or NR xb ,
  • R is hydrogen, optionally substituted alkyl, or a nitrogen protecting group
  • R Xa is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • R Xa and R xb are joined to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring.
  • the compound of Formula (II) is not:
  • a pharmaceutical composition comprising an effective amount of a compound of Formula (I) or (II), or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a method of treating a microbial infection in a subject comprising administering an effective amount of a compound of Formula (I) or (II), or pharmaceutically acceptable salt thereof, to the subject.
  • the microbial infection is a bacterial infection.
  • the bacterial infection is an M. tuberculosis infection.
  • the method further comprises administering the compound in combination with an antibiotic.
  • a method of treating microbial virulence comprising contacting an effective amount of a compound of Formula (I) or (II), or pharmaceutically acceptable salt thereof, to a microorganism.
  • the compound blocks virulence factor production.
  • the microbial virulence is bacterial virulence
  • the microorganism is a bacterium.
  • a method of potentiating the activity of an antibacterial agent against a bacterium comprising contacting the anti-bacterial agent in combination with a compound of Formula (I) or (II), or pharmaceutically acceptable salt thereof, with a bacterium.
  • the ratio of the compound or a pharmaceutically acceptable salt thereof to the anti-bacterial agent (molar excess) is between about 1: 1 and about 100: 1, inclusive.
  • the compound is of Formula (II) or a pharmaceutically acceptable salt thereof.
  • the anti-bacterial agent is an enopeptin.
  • Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and/or diastereomers.
  • the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
  • Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses.
  • HPLC high pressure liquid chromatography
  • the invention additionally encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.
  • alkyl refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 30 carbon atoms (“Ci_ 30 alkyl”). In some embodiments, an alkyl group has 1 to 20 carbon atoms (“Ci_ 2 o alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“Ci_io alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“Ci_9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“Ci_8 alkyl”).
  • an alkyl group has 1 to 7 carbon atoms (“Ci_ 7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“Ci_6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“Ci_5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“Ci_ 3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“Ci_ 2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“Ci alkyl”).
  • an alkyl group has 2 to 6 carbon atoms ("C 2 _6 alkyl").
  • Ci_6 alkyl groups include methyl (CO, ethyl (C 2 ), n-propyl (C 3 ), isopropyl (C 3 ), n-butyl (C 4 ), tert-butyl (C 4 ), sec-butyl (C 4 ), iso-butyl (C 4 ), n-pentyl (C 5 ), 3- pentanyl (C 5 ), amyl (C 5 ), neopentyl (C 5 ), 3-methyl-2-butanyl (C 5 ), tertiary amyl (C 5 ), and n- hexyl (Ce).
  • Additional examples of alkyl groups include n-heptyl (C 7 ), n-octyl (C 8 ) and the like. Unless otherwise specified, each instance of an alkyl group is independently
  • the alkyl group is an unsubstituted Ci_i 0 alkyl (e.g., -CH 3 ). In certain embodiments, the alkyl group is a substituted Cno alkyl.
  • Haloalkyl is a substituted alkyl group as defined herein wherein at least one of the hydrogen atoms is independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo.
  • Perhaloalkyl is a substituted alkyl group as defined herein wherein all of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo.
  • the alkyl moiety has 1 to 8 carbon atoms ("Ci_ 8 perhaloalkyl”).
  • the alkyl moiety has 1 to 6 carbon atoms (“Ci_6 perhaloalkyl”).
  • the alkyl moiety has 1 to 4 carbon atoms ("C ⁇ perhaloalkyl").
  • the alkyl moiety has 1 to 3 carbon atoms ("Ci_ 3 perhaloalkyl”). In some embodiments, the alkyl moiety has 1 to 2 carbon atoms ("Ci_ 2 perhaloalkyl”). In some embodiments, all of the hydrogen atoms are replaced with fluoro. In some embodiments, all of the hydrogen atoms are replaced with chloro. Examples of perhaloalkyl groups include - CF 3 , -CF 2 CF 3 , -CF 2 CF 2 CF 3 , -CC1 3 , -CFC1 2 , -CF 2 C1, and the like.
  • heteroalkyl refers to an alkyl group as defined herein which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
  • a heteroalkyl group refers to a saturated group having from 1 to 10 carbon atoms and 1 or more
  • heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroCi_9 alkyl”).
  • a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi_ 8 alkyl”).
  • a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi_ 7 alkyl").
  • a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroCi_6 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms within the parent chain ("heteroCi_5 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and lor 2 heteroatoms within the parent chain alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain
  • heteroCi_3 alkyl a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroCi_ 2 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroCi alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC 2 -6 alkyl").
  • each instance of a heteroalkyl group is independently unsubstituted (an "unsubstituted heteroalkyl") or substituted (a "substituted heteroalkyl") with one or more substituents.
  • the heteroalkyl group is an unsubstituted heteroCi_io alkyl.
  • the heteroalkyl group is a substituted heteroCi_io alkyl.
  • alkenyl refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 30 carbon atoms and one or more carbon-carbon double bonds (“C 2 -3o alkenyl”). In some embodiments, an alkenyl group has 2 to 20 carbon atoms (“C2-20 alkenyl”). In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C2-10 alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2-9 alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C 2 _8 alkenyl”).
  • an alkenyl group has 2 to 7 carbon atoms ("C 2 _ 7 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C 2 -6 alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C 2 _5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C 2 ⁇ alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C 2 _ 3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms ("C 2 alkenyl”).
  • the one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1- butenyl).
  • Examples of C 2 ⁇ alkenyl groups include ethenyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1-butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ), and the like.
  • Examples of C 2 -6 alkenyl groups include the aforementioned C 2 ⁇ alkenyl groups as well as pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 ), and the like.
  • alkenyl examples include heptenyl (C 7 ), octenyl (C 8 ), octatrienyl (C 8 ), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an "unsubstituted alkenyl") or substituted (a "substituted alkenyl") with one or more substituents. In certain embodiments, the alkenyl group is an unsubstituted C 2 _ 10 alkenyl. In certain embodiments, the alkenyl group is a substituted C 2 -io alkenyl.
  • heteroalkenyl refers to an alkenyl group as defined herein which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
  • a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 2 -io alkenyl").
  • a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain ("heteroC 2 -9 alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain ("heteroC 2 -8 alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 2 -7 alkenyl").
  • a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain ("heteroC 2 -6 alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2
  • heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and lor 2 heteroatoms within the parent chain ("heteroC 2 ⁇ alkenyl”).
  • a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain ("heteroC 2 -3 alkenyl”).
  • a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 2 -6 alkenyl”). Unless otherwise specified, each instance of a heteroalkenyl group is
  • the heteroalkenyl group is an unsubstituted heteroC 2 -io alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC 2 -io alkenyl.
  • alkynyl refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 30 carbon atoms and one or more carbon-carbon triple bonds (“C2-30 alkynyl”). In certain embodiments, the alkynyl group optionally and
  • an alkynyl group has 2 to 20 carbon atoms ("C2-20 alkynyl”). In some embodiments, an alkynyl group has 2 to 10 carbon atoms ("C 2 -io alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C 2 _9 alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C 2 _8 alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C 2 _ 7 alkynyl").
  • an alkynyl group has 2 to 6 carbon atoms ("C 2 -6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C 2 _5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms ("C 2 ⁇ alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C 2 _3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms ("C 2 alkynyl”).
  • the one or more carbon- carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl).
  • Examples of C 2 ⁇ alkynyl groups include, without limitation, ethynyl (C 2 ), 1-propynyl (C 3 ), 2-propynyl (C 3 ), 1-butynyl (C 4 ), 2-butynyl (C 4 ), and the like.
  • Examples of C 2 _6 alkenyl groups include the aforementioned C 2 ⁇ alkynyl groups as well as pentynyl (C 5 ), hexynyl (C 6 ), and the like.
  • alkynyl examples include heptynyl (C 7 ), octynyl (C 8 ), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an "unsubstituted alkynyl") or substituted (a "substituted alkynyl") with one or more substituents. In certain embodiments, the alkynyl group is an unsubstituted C 2 _io alkynyl. In certain embodiments, the alkynyl group is a substituted C 2 _io alkynyl.
  • heteroalkynyl refers to an alkynyl group as defined herein which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
  • a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2 _i 0 alkynyl").
  • a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain ("heteroC 2 _9 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2 _ 8 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2 _7 alkynyl").
  • a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain ("heteroC 2 _6 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 2 _5 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and lor 2 heteroatoms within the parent chain (“heteroC 2 ⁇ alkynyl").
  • a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain ("heteroC 2 _ 3 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 2 _6 alkynyl”). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an "unsubstituted heteroalkynyl") or substituted (a "substituted heteroalkynyl") with one or more substituents.
  • the heteroalkynyl group is an unsubstituted heteroC 2 _io alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC 2 _io alkynyl.
  • Carbocyclyl or “carbocyclic” refers to a radical of a non- aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms ("C 3 _i 4
  • carbocyclyl and zero heteroatoms in the non-aromatic ring system.
  • a carbocyclyl group has 3 to 10 ring carbon atoms ("C 3 _io carbocyclyl").
  • a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3 _8 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms ("C 3 _ 7 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3 _6 carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms ("C 4 _6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms ("C 5 -6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("Cs-io
  • C 3 _6 carbocyclyl groups include, without limitation, cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), and the like.
  • Exemplary C 3 8 carbocyclyl groups include, without limitation, the aforementioned C 3 _6 carbocyclyl groups as well as cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (Cg), cyclooctenyl (Cg), bicyclo[2.2.1]heptanyl (C 7 ), bicyclo[2.2.2]octanyl (Cg), and the like.
  • Exemplary C 3 _io carbocyclyl groups include, without limitation, the
  • C 3 _ 8 carbocyclyl groups as well as cyclononyl (C 9 ), cyclononenyl (C 9 ), cyclodecyl (C10), cyclodecenyl (C10), octahydro-lH-indenyl (C9), decahydronaphthalenyl (Cio), spiro[4.5]decanyl (C10), and the like.
  • the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or can contain one or more carbon-carbon double or triple bonds.
  • Carbocyclyl also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system.
  • each instance of a carbocyclyl group is independently unsubstituted (an "unsubstituted carbocyclyl") or substituted (a "substituted carbocyclyl”) with one or more substituents.
  • the carbocyclyl group is an unsubstituted C 3 _i 4 carbocyclyl.
  • the carbocyclyl group is a substituted C 3 _i 4 carbocyclyl.
  • carbocyclyl is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms ("C 3 _i 4 cycloalkyl"). In some embodiments,
  • Carbocyclyl is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms ("C 3 _io cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C 3 _8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3 _6 cycloalkyl”). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms ("C 4 _6 cycloalkyl").
  • a cycloalkyl group has 5 to 6 ring carbon atoms ("C 5 _6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C5-10 cycloalkyl”). Examples of C5-6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C 3 _6 cycloalkyl groups include the aforementioned C5-6 cycloalkyl groups as well as cyclopropyl (C 3 ) and cyclobutyl (C 4 ).
  • C 3 _ 8 cycloalkyl groups include the aforementioned C 3 _6 cycloalkyl groups as well as cycloheptyl (C 7 ) and cyclooctyl (C 8 ).
  • each instance of a cycloalkyl group is independently unsubstituted (an "unsubstituted cycloalkyl") or substituted (a "substituted cycloalkyl”) with one or more substituents.
  • the cycloalkyl group is an unsubstituted C 3 _i 4 cycloalkyl.
  • the cycloalkyl group is a substituted C 3 _i 4 cycloalkyl.
  • heterocyclyl or “heterocyclic” refers to a radical of a 3- to 14- membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("3-14 membered heterocyclyl").
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • a heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and can be saturated or can contain one or more carbon- carbon double or triple bonds.
  • Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heterocyclyl also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system.
  • each instance of heterocyclyl is independently unsubstituted (an "unsubstituted heterocyclyl") or substituted (a "substituted heterocyclyl") with one or more substituents.
  • the heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-14 membered heterocyclyl.
  • a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heterocyclyl").
  • a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is
  • a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is
  • the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azirdinyl, oxiranyl, and thiiranyl.
  • Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl.
  • Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl,
  • Exemplary 5- membered heterocyclyl groups containing 2 heteroatoms include, without limitation, dioxolanyl, oxathiolanyl and dithiolanyl.
  • Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl.
  • Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl.
  • Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl.
  • Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazinanyl.
  • Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl.
  • Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl.
  • Exemplary bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl,
  • decahydronaphthyridinyl decahydro-1 ,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, lH-benzo[e] [l,4]diazepinyl, 1 ,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro- 5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-lH- pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-
  • aryl refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 ⁇ electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ("Ce- 14 aryl").
  • an aryl group has 6 ring carbon atoms ("C 6 aryl”; e.g., phenyl).
  • an aryl group has 10 ring carbon atoms ("Cio aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl).
  • an aryl group has 14 ring carbon atoms ("Ci 4 aryl”; e.g., anthracyl).
  • Aryl also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system.
  • each instance of an aryl group is independently unsubstituted (an "unsubstituted aryl") or substituted (a "substituted aryl”) with one or more substituents.
  • the aryl group is an
  • the aryl group is a substituted Ce- 14 aryl.
  • alkyl is a subset of “alkyl” and refers to an alkyl group, as defined herein, substituted by an aryl group, as defined herein, wherein the point of attachment is on the alkyl moiety.
  • heteroaryl refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 ⁇ electrons shared in a cyclic array) having ring carbon atoms and 1 ⁇ 4- ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-14 membered heteroaryl").
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heteroaryl includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system.
  • Heteroaryl also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl/heteroaryl) ring system.
  • Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom e.g., indolyl, quinolinyl, carbazolyl, and the like
  • the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).
  • a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl").
  • a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl").
  • a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl").
  • the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • each instance of a heteroaryl group is independently unsubstituted (an "unsubstituted heteroaryl") or substituted (a "substituted heteroaryl") with one or more substituents.
  • the heteroaryl group is an unsubstituted 5-14 membered heteroaryl.
  • the heteroaryl group is a substituted 5-14 membered heteroaryl.
  • Exemplary 5-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl.
  • Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
  • Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.
  • 5- membered heteroaryl groups containing 4 heteroatoms include, without limitation, tetrazolyl.
  • Exemplary 6-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyridinyl.
  • Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • 6- membered heteroaryl groups containing 3 or 4 heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively.
  • Exemplary 7-membered heteroaryl groups containing 1 heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl.
  • Exemplary 5,6- bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl,
  • Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
  • Exemplary tricyclic heteroaryl groups include, without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl and phenazinyl.
  • Heteroaralkyl is a subset of “alkyl” and refers to an alkyl group, as defined herein, substituted by a heteroaryl group, as defined herein, wherein the point of attachment is on the alkyl moiety.
  • partially unsaturated refers to a ring moiety that includes at least one double or triple bond.
  • the term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic groups (e.g., aryl or heteroaryl moieties) as herein defined.
  • saturated refers to a ring moiety that does not contain a double or triple bond, i.e. , contains all single bonds.
  • suffix "-ene” indicates the group is a divalent moiety, e.g.
  • alkylene is the divalent moiety of alkyl
  • alkenylene is the divalent moiety of alkenyl
  • alkynylene is the divalent moiety of alkynyl
  • heteroalkylene is the divalent moiety of heteroalkyl
  • heteroalkenylene is the divalent moiety of heteroalkenyl
  • heteroalkynylene is the divalent moiety of heteroalkynyl
  • carbocyclylene is the divalent moiety of carbocyclyl
  • heterocyclylene is the divalent moiety of heterocyclyl
  • arylene is the divalent moiety of aryl
  • heteroarylene is the divalent moiety of heteroaryl.
  • Alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, as defined herein, are optionally substituted (e.g., "substituted” or “unsubstituted” alkyl, "substituted” or “unsubstituted” alkenyl, "substituted” or “unsubstituted” alkynyl, "substituted” or “unsubstituted” carbocyclyl, "substituted” or “unsubstituted” heterocyclyl, "substituted” or “unsubstituted” aryl or “substituted” or “unsubstituted” heteroaryl group).
  • substituted means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not
  • a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position.
  • heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety.
  • R aa is, independently, selected from Ci_io alkyl, Cuo perhaloalkyl, C 2 _io alkenyl, C 2 _io alkynyl, C 3 _io carbocyclyl, 3-14 membered heterocyclyl, C6-i 4 aryl, and 5-14 membered heteroaryl, or two R ⁇ groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, heterocycly
  • each instance of R cc is, independently, selected from hydrogen, Ci_io alkyl, Cuo perhaloalkyl, C 2 _io alkenyl, C 2 _io alkynyl, C 3 _io carbocyclyl, 3-14 membered heterocyclyl, Ce- 14 aryl, and 5-14 membered heteroaryl, or two R cc groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;
  • each instance of R ee is, independently, selected from Ci_6 alkyl, Ci_6 perhaloalkyl, C 2 6 alkenyl, C 2 _6 alkynyl, C 3 _io carbocyclyl, C6-10 aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups;
  • each instance of R ff is, independently, selected from hydrogen, Ci_6 alkyl, Ci_6 perhaloalkyl, C 2 _6 alkenyl, C 2 _6 alkynyl, C 3 _io carbocyclyl, 3-10 membered heterocyclyl, Ce- io aryl and 5-10 membered heteroaryl, or two R ff groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups; and
  • hydroxyl refers to the group -OH.
  • thiol refers to the group -SH.
  • amino refers to the group -NH 2 .
  • substituted amino by extension, refers to a mono substituted amino, a disubstituted amino, or a trisubstituted amino, as defined herein.
  • trisubstituted amino refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with three groups, and includes groups selected from -N(R bb ) 3 and -N(R bb ) 3 + X ⁇ , wherein R bb and X are as defined herein.
  • sulfonyl refers to a group selected from -S0 2 N(R bb ) 2 , - S0 2 R aa , and -S0 2 OR aa , wherein R ⁇ and R bb are as defined herein.
  • acyl or “carbonyl” refers a group wherein the carbon directly attached to the parent molecule is sp 2 hybridized, and is substituted with an oxygen, nitrogen or sulfur atom, e.g.
  • sil refers to the group -Si(R aa ) 3 , wherein R aa is as defined herein.
  • boronyl refers to boranes, boronic acids, boronic esters, borinic acids, and borinic esters, e.g. , boronyl groups of Formula -B(R aa ) 2 , -B(OR cc ) 2 , and - BR ⁇ COR 00 ), wherein R ⁇ and R cc are as defined herein.
  • halo refers to fluorine (fluoro, -F), chlorine (chloro, -CI), bromine (bromo, -Br), or iodine (iodo, -I).
  • a "counterion” is a negatively charged group associated with a positively charged quarternary amine in order to maintain electronic neutrality.
  • exemplary counterions include halide ions (e.g., F “ , Cl ⁇ , Br “ , ⁇ ), N0 3 , C10 4 ⁇ , OFT, H 2 P0 4 ⁇ , HS0 4 ⁇ , sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate, naphthalene-l-sulfonic acid-5-sulfonate, ethan-l-sulfonic acid-2-sulfonate, and the like), and carboxylate ions (e.g., acetate, ethanoate, prop
  • Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quarternary nitrogen atoms.
  • the substituent present on the nitrogen atom is an amino protecting group (also referred to herein as a "nitrogen protecting group").
  • Amino protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
  • Amino protecting groups such as carbamate groups include, but are not limited to, methyl carbamate, ethyl carbamante, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di- i-butyl-[9-( 10,10-dioxo-l 0, 10,10,10-tetrahydrothioxanthyl)] methyl carbamate (DBD- Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2- trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), l-(l-adamantyl)-
  • TBOC l-methyl-l-(4-biphenylyl)ethyl carbamate
  • Bpoc l-(3,5-di-i-butylphenyl)-l- methylethyl carbamate
  • Pyoc 2-(2'- and 4'-pyridyl)ethyl carbamate
  • 2-(N,N- dicyclohexylcarboxamido)ethyl carbamate i-butyl carbamate (BOC), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carb
  • amino protecting groups include, but are not limited to, phenothiazinyl- (10)-acyl derivative, N'-p-toluenesulfonylaminoacyl derivative, N'-phenylaminothioacyl derivative, N-benzoylphenylalanyl derivative, N-acetylmethionine derivative, 4,5-diphenyl- 3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-l, l,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted l,3-dimethyl-l,3,5-triazacyclohexan-2-one, 5-substituted 1 ,3-dibenzyl- l,3,5-triazacyclohexan-2-one, 5-sub
  • benzenesulfenamide o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide,
  • triphenylmethylsulfenamide triphenylmethylsulfenamide
  • 3-nitropyridinesulfenamide Npys
  • the substituent present on an oxygen atom is a hydroxyl or thiol protecting group (also respectively referred to herein as an "oxygen protecting group” or "sulfur protecting group”).
  • Hydroxyl and thiol protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
  • Exemplary hydroxyl and thiol protecting groups include, but are not limited to, methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), i-butylthiomethyl,
  • diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, i-butyldimethylsilyl (TBDMS), t- butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-/?-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), i-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, /?-chlorophenoxyacetate, 3-phenylpropionate, 4- oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, a
  • salt refers to any and all salts, including pharmaceutically acceptable salts.
  • the term "pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, Berge et ah, describes
  • Pharmaceutically acceptable salts include those derived from suitable inorganic and organic acids and bases.
  • suitable inorganic and organic acids and bases examples include those derived from suitable inorganic and organic acids and bases.
  • pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
  • a "subject" to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g, infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or other non-human animals, for example mammals (e.g. , primates (e.g., cynomolgus monkeys, rhesus monkeys); commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and/or dogs), birds (e.g.
  • humans i.e., a male or female of any age group, e.g., a pediatric subject (e.g, infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)
  • non-human animals for example mammals (e.g. , primates (e.g., cy
  • the non-human animal is a mammal.
  • the non-human animal may be a male or female and at any stage of development.
  • a non-human animal may be a transgenic animal.
  • the terms “treat,” “treating” and “treatment” contemplate an action that occurs while a subject is suffering from the specified infection which reduces the severity of the infection or retards or slows the progression of the infection (“therapeutic treatment”), and also contemplates an action that occurs before a subject begins to suffer from the specified infection and which inhibits or reduces the severity of the infection (“prophylactic treatment”).
  • the "effective amount" of a compound refers to an amount sufficient to elicit the desired biological response, i.e., treating an infection.
  • the effective amount of a compound may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age, health, and condition of the subject.
  • the effective amount of a compound with anti-bacterial activity is the amount that results in a sufficient concentration to inhibit the growth, reduce, or kill bacteria, or make bacteria less virulent.
  • An effective amount encompasses therapeutic and
  • a “therapeutically effective amount” of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a infection or to delay or minimize one or more symptoms associated with the infection.
  • a therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the infection.
  • the term "therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of infection, or enhances the therapeutic efficacy of another therapeutic agent.
  • a prophylactically effective amount of a compound is an amount sufficient to prevent an infection, or one or more symptoms associated with the infection or prevent its recurrence.
  • a prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the infection.
  • the term "prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.
  • virulence refers to the degree of pathogenicity within of a microorganism as indicated by case fatality rates and/or the ability of the organism to invade the issues of the subject; e.g., the ability of the organism to cause an infection.
  • a “reduction of virulence” refers to a reduction of this pathogenic capacity of the organism.
  • Figure 1 Structures of a bioactive ADEP and synthetic fragments thereof. Dose-dependent effects of fragments on the minimal inhibitory concentration (MIC) of the ADEP against S. coelicolor grown on Difco nutrient agar is provided in Table 1A of Example 1. The MIC of the ADEP alone is 16 ⁇ g/mL.
  • Figure 2 Assessment of analogs of compound 3, a potentiator of ADEP activity. Concentrations indicate the ADEP MIC when it is combined with analogs at a 20: 1 molar excess. Shown in parentheses is the fold-change in MIC relative to ADEP alone (degree of potentiation).
  • Figures 3A-3C Potentiation of ADEP activity in mycobacteria.
  • Figure 3 A
  • FIG. 4 Growth of S. coelicolor was assessed in the presence of either DMSO ( W i s or compound (14) (WT+SC-14) in Tryptone Soya Broth (TSB). Initially, an equal amount of colony forming units (CPU) were added to 50mL TSB with or without compound (14) (50ug/mL) in an Erlenmeyer flask appropriately fitted with a spring to prevent clumping. These cultures were incubated at 30° C with constant agitation. 1 mL aliquots were removed from the TSB culture periodically and centrifuged. The supernatant was removed and the pellet washed twice with PBS. The resulting pellet was dried for 45 min and weighed. These experiments were performed in triplicate.
  • DMSO W i s or compound (14) (WT+SC-14) in Tryptone Soya Broth (TSB). Initially, an equal amount of colony forming units (CPU) were added to 50mL TSB with or without
  • Figure 5 Fragments of a cyclic acyldepsipeptide have differential antibacterial activity against B. subtilis.
  • Figure 6 Structures and antibacterial activities of N-acyldifluorophenylalanine fragment analogs against B. subtilis.
  • Figures 7A-7B ClpP binding of key N-acyldifluorophenylalanine fragment analogs.
  • Figure 7 A Hydrolysis of a fluorogenic decapeptide substrate (15 ⁇ ) by B. subtilis ClpP (25 nM) was assayed in the presence of increasing concentrations of ADEP fragments, and activity was fit to a cooperative binding model (solid lines) to determine apparent binding constants (K ⁇ ) and Hill Coefficients. Error bars represent standard deviation among three replicates.
  • Figure 7B Calculated apparent dissociation constants (K app ) for ADEP fragment binding to B. subtilis ClpP. Error bars represent the standard error of the binding model fit.
  • Raw data for Figures 7A-7B is provided in Table 2A of Example 2.
  • FIGS 9A-9B ADEP1 bound to B. subtilis ClpP.
  • Figure 9A Cartoon view of a heptameric face of ClpP shows ADEP1 bound between ClpP protomers.
  • Figure 9B The N- acylphenylalanine substituent lies in a hydrophobic pocket between protomers, while the serine-methylproline ester and the rest of the peptidolactone ring are largely exposed to solvent.
  • Figures 10A-10B depict the effect of 200 ⁇ of various compounds (as depicted in Figure 10B) on ClpX-ClpPlP2 protease activity.
  • the ADEPs inhibit the capacity of the ClpX-ClpPlP2 from M. tuberculosis to degrade a protein.
  • certain fragments having antibacterial activity can enhance the capacity of the ClpX-ClpPlP2 from M. tuberculosis to degrade a protein.
  • Fragments that enhance the enhance the capacity of the ClpX-ClpPlP2 from M. tuberculosis to degrade a protein can be of either Formula (I) or Formula (II).
  • fragments that do not markedly affect the capacity of of the ClpX-ClpPlP2 from M. tuberculosis to degrade a protein are able to potentiate the activty of the ADEP by competitively interfering with ADEP efflux.
  • Cyclic acyldepsipeptide (ADEP) antibiotics also referred to as enopeptins, such as ADEP4 have garnered considerable attention because of their potent antibacterial activity against a broad range of bacterial pathogens. (compound 1)
  • ADEP cyclic acyldepsipeptide
  • fragments of the ADEP exemplified by Formula (I) have antibacterial activity, in some cases that is superior to the intact ADEP. While such fragments have the same target as the intact ADEP, they can enhance the capacity of ClpP to degrade a protein rather than inhibit this capacity like the intact ADEPs.
  • fragments retain the capacity to bind the ClpP enzyme from M. tuberculosis, but affect ClpP activity differently from the intact ADEPs.
  • the intact ADEPs inhibit the capacity of ClpX-ClpPlP2 to degrade a protein substrate.
  • certain fragments enhance the capacity of ClpX-ClpPlP2 to degrade a protein substrate.
  • fragments that minimally affect the the capacity of ClpX-ClpPlP2 to degrade a protein substrate can potentiate the activities of antibacterial agents, such as an ADEP4, against bacteria that are not susceptible due to efflux pumps by competitively interfering with ADEP efflux.
  • Enopeptin analogs contemplated herein comprise compounds of Formula (I) and
  • R 1 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • each instance of R 2A and R 3A is independently optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl,
  • R 3A groups are joined to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring;
  • R 4 is hydrogen, -OH, -SH, -NH 2 , substituted hydroxyl, substituted thiol, substituted amino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • R 5 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR 5A or -NHR 5A , wherein each instance of R 5A is independently optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • each instance of R 6 is independently halogen, -OH, -SH, -NH 2 , -CN, -N0 2 , -N 3 , - S0 2 H, -SO3H, substituted hydroxyl, substituted thiol, substituted amino, sulfonyl, sulfinyl, carbonyl, silyl, boronyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; m is 0 or an integer of between 1 and 5, inclusive;
  • Y is O, S, or NR Y wherein R Y is hydrogen, optionally substituted alkyl, or a nitrogen protecting group;
  • X is O, S, or NR xb ,
  • R is hydrogen, optionally substituted alkyl, or a nitrogen protecting group
  • R Xa is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • R Xa and R xb are joined to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring.
  • the compound of Formula (II) is not:
  • R 1 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • R 1 is hydrogen
  • R 1 is optionally substituted alkyl, e.g., optionally substituted C 1-6 alkyl, optionally substituted Ci-salkyl, optionally substituted Ci- 4 alkyl, optionally substituted Ci-3alkyl, optionally substituted C 1-2 alkyl, or optionally substituted Cialkyl.
  • the alkyl group is further substituted, e.g., with halogen groups.
  • the alkyl group is unsubstituted.
  • R 1 is optionally substituted alkenyl, e.g., optionally substituted C 2 - 6 alkenyl, optionally substituted C 2 _ 5 alkenyl, optionally substituted C 2 _ 4 alkenyl, optionally substituted C 2 - 3 alkenyl, or optionally substituted C 2 alkenyl.
  • the alkenyl group is further substituted, e.g., with halogen groups.
  • R 1 is alkenyl
  • the alkenyl group is unsubstituted.
  • R 1 is optionally substituted alkynyl, e.g., optionally substituted C 2-6 alkynyl, optionally substituted C 2 - 5 alkynyl, optionally substituted C 2 - 4 alkynyl, optionally substituted C 2 - 3 alkynyl, or optionally substituted C 2 alkynyl.
  • R 1 is optionally substituted alkynyl, e.g., optionally substituted C 2-6 alkynyl, optionally substituted C 2 - 5 alkynyl, optionally substituted C 2 - 4 alkynyl, optionally substituted C 2 - 3 alkynyl, or optionally substituted C 2 alkynyl.
  • R 1 is alkynyl
  • the alkynyl group is further substituted, e.g., with halogen groups.
  • the alkynyl group is unsubstituted.
  • R 1 is optionally substituted carbocyclyl (e.g., C 3- 6carbocyclyl) or optionally substituted heterocyclyl (e.g., a 3- to 6-membered heterocyclyl).
  • R 1 is optionally substituted aryl (e.g., phenyl) or optionally substituted heteroaryl (e.g., 5- to 6- membered heteroaryl).
  • aryl e.g., phenyl
  • heteroaryl e.g., 5- to 6- membered heteroaryl
  • R 1 is hydrogen or optionally substituted alkyl. In certain embodiments, R 1 is hydrogen. In certain embodiments, R 1 is optionally substituted alkyl, e.g., optionally substituted C 1-3 alkyl, such as -CH 3 , -CF 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3i or - CH(CH 3 ) 2 .
  • R 2A is optionally substituted alkyl, e.g., optionally substituted C 1-6 alkyl, optionally substituted Q.salkyl, optionally substituted Ci_ 4 alkyl, optionally substituted Ci_ 3 alkyl, optionally substituted Ci_ 2 alkyl, or optionally substituted Cialkyl.
  • R 2A is alkyl
  • the alkyl group is further substituted, e.g., with halogen or substituted amino groups.
  • R 2A is alkyl
  • the alkyl group is unsubstituted.
  • At least one instance of R 2A is optionally substituted alkenyl, e.g., optionally substituted C 2 -6alkenyl, optionally substituted C 2 - 5 alkenyl, optionally substituted C 2 . 4 alkenyl, optionally substituted C 2 - 3 alkenyl, or optionally substituted
  • R 2A is alkenyl
  • the alkenyl group is further substituted, e.g., with halogen groups.
  • the alkenyl group is unsubstituted.
  • R 2A is optionally substituted alkynyl, e.g., optionally substituted C 2-6 alkynyl, optionally substituted C 2 - 5 alkynyl, optionally substituted C 2 . 4 alkynyl, optionally substituted C 2 . 3 alkynyl, or optionally substituted C 2 alkynyl.
  • R 2A is alkynyl
  • the alkynyl group is further substituted, e.g., with halogen groups.
  • R 2A is alkynyl
  • the alkynyl group is unsubstituted.
  • At least one instance of R 2A is optionally substituted carbocyclyl (e.g., C 3 _ 6 carbocyclyl) or optionally substituted heterocyclyl (e.g., a 3- to 6- membered heterocyclyl).
  • carbocyclyl e.g., C 3 _ 6 carbocyclyl
  • heterocyclyl e.g., a 3- to 6- membered heterocyclyl
  • At least one instance of R 2A is optionally substituted aryl (e.g., phenyl) or optionally substituted heteroaryl (e.g., 5- to 6- membered heteroaryl).
  • aryl e.g., phenyl
  • heteroaryl e.g., 5- to 6- membered heteroaryl
  • R 3A is optionally substituted alkyl, e.g., optionally substituted C 1-6 alkyl, optionally substituted Ci-salkyl, optionally substituted Ci- 4 alkyl, optionally substituted Ci- 3 alkyl, optionally substituted Ci- 2 alkyl, or optionally substituted Cialkyl.
  • R 3A is alkyl
  • the alkyl group is further substituted, e.g., with halogen groups.
  • the alkyl group is unsubstituted.
  • At least one instance of R 3A is optionally substituted alkenyl, e.g., optionally substituted C 2 -6alkenyl, optionally substituted C 2 - 5 alkenyl, optionally substituted C 2 _ 4 alkenyl, optionally substituted C 2 _ 3 alkenyl, or optionally substituted
  • R 3A is alkenyl
  • the alkenyl group is further substituted, e.g., with halogen groups.
  • R 3A is alkenyl
  • the alkenyl group is unsubstituted.
  • at least one instance of R is optionally substituted alkynyl, e.g., optionally substituted C 2-6 alkynyl, optionally substituted C 2- salkynyl, optionally substituted C 2-4 alkynyl, optionally substituted C 2-3 alkynyl, or optionally substituted C 2 alkynyl.
  • R 3A is alkynyl
  • the alkynyl group is further substituted, e.g., with halogen groups.
  • the alkynyl group is unsubstituted.
  • At least one instance of R 3A is optionally substituted carbocyclyl (e.g., C3-6carbocyclyl) or optionally substituted heterocyclyl (e.g., a 3- to 6- membered heterocyclyl).
  • At least one instance of R 3A is optionally substituted aryl (e.g., phenyl) or optionally substituted heteroaryl (e.g., 5- to 6- membered heteroaryl).
  • aryl e.g., phenyl
  • heteroaryl e.g., 5- to 6- membered heteroaryl
  • R 2 is hydrogen
  • R 2 is -OH or -OR 2A wherein R 2A is as described herein. In certain embodiments, R 2 is -OH. In certain embodiments, R 2 is -OR 2A wherein R 2A is optionally substituted alkyl, e.g. , optionally substituted C 1-3 alkyl, such as -CH 3 , -CF 3 , - CH 2 CH 3 , -CH2CH2CH3, or -CH(CH 3 ) 2 .
  • R 2A is optionally substituted alkyl, e.g. , optionally substituted C 1-3 alkyl, such as -CH 3 , -CF 3 , - CH 2 CH 3 , -CH2CH2CH3, or -CH(CH 3 ) 2 .
  • R 2A is a substituted alkyl (e.g., a Q alkyl) group.
  • the alkyl group is substituted with at least one substituted amino group.
  • R 2 is a group of formula:
  • R is hydrogen and optionally substituted alkyl
  • R 2C is optionally substituted alkyl or -OR 2D wherein R 2D is optionally substituted alkyl.
  • R is hydrogen
  • R 2B is optionally substituted alkyl, e.g., straight chain or branched alkyl optionally substituted with hydroxyl, substituted hydroxyl, thiol, substituted thiol, amino, substituted amino, carbonyl, optionally substituted aryl, or optionally substituted heteroaryl groups.
  • R 2B optionally substituted alkyl moieties encompass amino acid side chains of formula:
  • R is an amino acid side chain selected from the group consisting of alanine, serine, threonine, cysteine, valine, leucine, isoleucine, methionine, and lysine side chains, as defined herein.
  • R 2C is optionally substituted alkyl, e.g., optionally substituted d- 3 alkyl, such as -CH 3 , -CF 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3, or -CH(CH 3 ) 2 .
  • R is -OR and R is optionally substituted alkyl, e.g., optionally substituted d- 3 alkyl, such as -CH 3 , -CF 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3, or -CH(CH 3 ) 2 .
  • Ci- 3 alkyl such as -CH 3 , -CF 3 , - CH 2 CH 3 , -CH 2 CH 2 CH 3i or -CH(CH 3 ) 2 , or two R 2A groups are joined to form an optionally substituted heterocyclic (e.g., a 3- to 6-membered heterocyclic) ring or optionally substituted heteroaryl (e.g., 5- to 6- membered heteroaryl) ring.
  • heterocyclic e.g., a 3- to 6-membered heterocyclic
  • heteroaryl e.g., 5- to 6- membered heteroaryl
  • R 2 is optionally substituted alkyl, e.g., optionally substituted C 1-6 alkyl, optionally substituted Ci-salkyl, optionally substituted Ci- 4 alkyl, optionally substituted Ci- 3 alkyl, optionally substituted Ci- 2 alkyl, or optionally substituted Cialkyl.
  • the alkyl group is further substituted, e.g., with halogen groups.
  • the alkyl group is unsubstituted.
  • R 2 is optionally substituted alkenyl, e.g., optionally substituted C 2 _ 6 alkenyl, optionally substituted C 2 _ 5 alkenyl, optionally substituted C 2 _ 4 alkenyl, optionally substituted C 2 . 3 alkenyl, or optionally substituted C 2 alkenyl.
  • optionally substituted C 2 _ 6 alkenyl e.g., optionally substituted C 2 _ 6 alkenyl, optionally substituted C 2 _ 5 alkenyl, optionally substituted C 2 _ 4 alkenyl, optionally substituted C 2 . 3 alkenyl, or optionally substituted C 2 alkenyl.
  • R 2 is alkenyl
  • the alkenyl group is further substituted, e.g., with halogen groups.
  • the alkenyl group is unsubstituted.
  • R 2 is optionally substituted alkynyl, e.g., optionally substituted C 2-6 alkynyl, optionally substituted C 2 - 5 alkynyl, optionally substituted C 2 . 4 alkynyl, optionally substituted C 2 . 3 alkynyl, or optionally substituted C 2 alkynyl.
  • R 2 is optionally substituted alkynyl, e.g., optionally substituted C 2-6 alkynyl, optionally substituted C 2 - 5 alkynyl, optionally substituted C 2 . 4 alkynyl, optionally substituted C 2 . 3 alkynyl, or optionally substituted C 2 alkynyl.
  • R 2 is alkynyl
  • the alkynyl group is further substituted, e.g., with halogen groups.
  • the alkynyl group is unsubstituted.
  • R 2 is optionally substituted carbocyclyl (e.g., C 3- 6 carbocyclyl) or optionally substituted heterocyclyl (e.g., a 3- to 6-membered heterocyclyl).
  • R 2 is optionally substituted aryl (e.g., phenyl) or optionally substituted heteroaryl (e.g., 5- to 6- membered heteroaryl).
  • R 2A is optionally substituted alkyl, e.g. , optionally substituted Cialkyl, such as -CH 3 , -CF 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3, or -CH(CH 3 ) 2 .
  • R 3A is optionally substituted alkyl, e.g., optionally substituted Cialkyl, such as -CH 3 , -CF 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3, or -CH(CH 3 ) 2 .
  • Ci- 3 alkyl such as -CH 3 , -CF 3 , - CH 2 CH 3 , -CH 2 CH 2 CH 3i or -CH(CH 3 ) 2 , or two R 3A groups are joined to form an optionally substituted heterocyclic (e.g., a 3- to 6-membered heterocyclic) ring or optionally substituted heteroaryl (e.g., 5- to 6- membered heteroaryl) ring.
  • heterocyclic e.g., a 3- to 6-membered heterocyclic
  • heteroaryl e.g., 5- to 6- membered heteroaryl
  • R 3 is optionally substituted alkyl, e.g., optionally substituted C 1-6 alkyl, optionally substituted Ci-salkyl, optionally substituted Ci_ 4 alkyl, optionally substituted Ci- 3 alkyl, optionally substituted Ci- 2 alkyl, or optionally substituted Cialkyl.
  • the alkyl group is further substituted, e.g., with halogen groups, hydroxyl, or substituted hydroxyl groups.
  • the alkyl group is unsubstituted.
  • R 3 is optionally substituted alkenyl, e.g., optionally substituted C 2 -6alkenyl, optionally substituted C 2 -salkenyl, optionally substituted C 2 . 4 alkenyl, optionally substituted C 2 . 3 alkenyl, or optionally substituted C 2 alkenyl.
  • optionally substituted C 2 -6alkenyl e.g., optionally substituted C 2 -6alkenyl, optionally substituted C 2 -salkenyl, optionally substituted C 2 . 4 alkenyl, optionally substituted C 2 . 3 alkenyl, or optionally substituted C 2 alkenyl.
  • R 3 is alkenyl
  • the alkenyl group is further substituted, e.g., with halogen groups.
  • the alkenyl group is unsubstituted.
  • R 3 is optionally substituted alkynyl, e.g., optionally substituted C 2-6 alkynyl, optionally substituted C 2 -salkynyl, optionally substituted C 2 _ 4 alkynyl, optionally substituted C 2 - 3 alkynyl, or optionally substituted C 2 alkynyl.
  • the alkynyl group is further substituted, e.g., with halogen groups.
  • the alkynyl group is unsubstituted.
  • R 3 is optionally substituted carbocyclyl (e.g., C 3 _
  • 6carbocyclyl or optionally substituted heterocyclyl (e.g., a 3- to 6-membered heterocyclyl).
  • R 3 is optionally substituted aryl (e.g., phenyl) or optionally substituted heteroaryl (e.g., 5- to 6- membered heteroaryl).
  • aryl e.g., phenyl
  • heteroaryl e.g., 5- to 6- membered heteroaryl
  • R 3A is optionally substituted alkyl, e.g., optionally substituted Ci -3 alkyl, such as -CH 3 , -CF 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3, or -CH(CH 3 ) 2 , or R 3 is substituted C 1-3
  • R 4 is hydrogen, -OH, -SH, -NH 2 , substituted hydroxyl, substituted thiol, substituted amino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • the stereochemistry of the carbon substituted with R 4 may be (R) or (S) when R 4 is a non-hydrogen group. In certain embodiments when R 4 is a non- hydrogen group, the stereochemistry of the carbon substituted with R 4 is (R). In certain embodiments when R 4 is a non-hydrogen group, the stereochemistry of the carbon substituted with R 4 is (S).
  • R 4 is hydrogen
  • R 4 is -OH, -SH, -NH 2 , substituted hydroxyl, substituted thiol, or substituted amino, as defined herein.
  • R 4 is optionally substituted alkyl, e.g., optionally substituted C 1-6 alkyl, optionally substituted Ci-salkyl, optionally substituted C 1-4 alkyl, optionally substituted C 1-3 alkyl, optionally substituted C 1-2 alkyl, or optionally substituted Q alkyl.
  • the alkyl group is further substituted, e.g., with halogen groups.
  • the alkyl group is unsubstituted.
  • R 4 is optionally substituted alkenyl, e.g., optionally substituted C 2-6 alkenyl, optionally substituted C 2- salkenyl, optionally substituted C 2-4 alkenyl, optionally substituted C 2 - 3 alkenyl, or optionally substituted C 2 alkenyl.
  • the alkenyl group is further substituted, e.g., with halogen groups.
  • the alkenyl group is unsubstituted.
  • R 4 is optionally substituted alkynyl, e.g., optionally substituted C 2-6 alkynyl, optionally substituted C 2 - 5 alkynyl, optionally substituted C 2 - 4 alkynyl, optionally substituted C 2 - 3 alkynyl, or optionally substituted C 2 alkynyl.
  • R 4 is optionally substituted alkynyl, e.g., optionally substituted C 2-6 alkynyl, optionally substituted C 2 - 5 alkynyl, optionally substituted C 2 - 4 alkynyl, optionally substituted C 2 - 3 alkynyl, or optionally substituted C 2 alkynyl.
  • R 4 is alkynyl
  • the alkynyl group is further substituted, e.g., with halogen groups.
  • the alkynyl group is unsubstituted.
  • R 4 is optionally substituted carbocyclyl (e.g., C 3- 6carbocyclyl) or optionally substituted heterocyclyl (e.g., a 3- to 6-membered heterocyclyl).
  • R 4 is optionally substituted aryl (e.g., phenyl) or optionally substituted heteroaryl (e.g., 5- to 6- membered heteroaryl).
  • aryl e.g., phenyl
  • heteroaryl e.g., 5- to 6- membered heteroaryl
  • R 4 is hydrogen or optionally substituted alkyl, e.g. , optionally substituted Ci -3 alkyl, such as -CH 3 , -CF 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3, or -CH(CH 3 ) 2 .
  • R 4 is -CH 3 .
  • the stereochemistry of the carbon substituted with R 4 is (R).
  • R 4 is optionally substituted alkyl the stereochemistry of the carbon substituted with R 4 is (S).
  • Y is O, S, or NR Y wherein R Y is hydrogen, optionally substituted alkyl, or a nitrogen protecting group.
  • Y is O.
  • Y is S.
  • Y is NR Y wherein R Y is hydrogen or optionally substituted Ci -3 alkyl, e.g., -CH 3 , -CF 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3, or -CH(CH 3 ) 2 .
  • Y is O or NR Y wherein R Y is hydrogen or -CH 3 .
  • X is O, S, or NR xb , wherein R xb is hydrogen, optionally substituted alkyl, or a nitrogen protecting group; and R Xa is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or R Xa and R xb are joined to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring.
  • X is O.
  • X is S.
  • X is NR , whereinR is hydrogen, optionally substituted alkyl (e.g., -CH 3 ), or a nitrogen protecting group.
  • X is O, wherein R Xa is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • X is S, wherein R Xa is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • X is NR xb , wherein R xb is hydrogen, optionally substituted alkyl (e.g., -CH 3 ), or a nitrogen protecting group, and R Xa is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or R Xa and R xb are joined to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring.
  • R xb is hydrogen, optionally substituted alkyl (e.g., -CH 3 ), or a nitrogen protecting group
  • R Xa is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted hetero
  • R Xa is optionally substituted alkyl, e.g., optionally substituted C 1-6 alkyl, optionally substituted Ci-salkyl, optionally substituted C 1-4 alkyl, optionally substituted Q. 3 alkyl, optionally substituted C 1-2 alkyl, or optionally substituted Q alkyl.
  • the alkyl group is further substituted, e.g., with optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl groups.
  • R Xa is alkyl
  • the alkyl group is unsubstituted.
  • R Xa is optionally substituted alkenyl, e.g., optionally substituted C 2- 6 alkenyl, optionally substituted C 2 - 5 alkenyl, optionally substituted C 2-4 alkenyl, optionally substituted C 2-3 alkenyl, or optionally substituted C 2 alkenyl.
  • R Xa is alkenyl
  • the alkenyl group is further substituted, e.g., with halogen groups.
  • R Xa is alkenyl
  • the alkenyl group is unsubstituted.
  • R Xa is optionally substituted alkynyl, e.g., optionally substituted C 2- 6 alkynyl, optionally substituted C 2- salkynyl, optionally substituted C 2-4 alkynyl, optionally substituted C 2 - 3 alkynyl, or optionally substituted C 2 alkynyl.
  • R Xa is alkynyl
  • the alkynyl group is further substituted, e.g., with halogen groups.
  • R Xa is alkynyl
  • the alkynyl group is unsubstituted.
  • R Xa is optionally substituted carbocyclyl (e.g., C 3 _ 6 carbocyclyl) or optionally substituted he terocyclyl (e.g., a 3- to 6-membered heterocyclyl).
  • R Xa is optionally substituted aryl (e.g., phenyl) or optionally substituted heteroaryl (e.g., 5- to 6- membered heteroaryl).
  • R Xa and R xb are joined to form an optionally substituted heterocyclic (e.g., optionally substituted 3- to 6- membered heterocyclic) ring or optionally substituted heteroaryl (e.g., optionally substituted 5- to 6-membered heteroaryl) ring.
  • optionally substituted heterocyclic e.g., optionally substituted 3- to 6- membered heterocyclic
  • optionally substituted heteroaryl e.g., optionally substituted 5- to 6-membered heteroaryl
  • X is O or NR xb , wherein R xb is hydrogen or optionally substituted alkyl (e.g., -CH 3 ).
  • X is O or NR xb , wherein R xb is hydrogen or optionally substituted alkyl (e.g., -CH 3 ) and R Xa is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl.
  • X is O, wherein R Xa is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl.
  • X is O, wherein R Xa is hydrogen.
  • X is O, wherein R Xa is optionally substituted alkyl, e.g., optionally substituted Ci- 3 alkyl.
  • R Xa is optionally substituted Cialkyl (e.g., -CH 3 , or Ciaralkyl such as benzyl), optionally substituted C 2 alkyl, or optionally substituted C 3 alkyl.
  • X is O, wherein R Xa is optionally substituted alkenyl, e.g., optionally substituted C 3 -salkenyl. In certain embodiments, R Xa is optionally substituted C 3 alkenyl, optionally substituted C 4 alkenyl, or optionally substituted Csalkenyl.
  • X is O, wherein R Xa is optionally substituted alkynyl, e.g., optionally substituted C 3 -salkynyl. In certain embodiments, R Xa is optionally substituted C 3 alkynyl, optionally substituted Qalkynyl, or optionally substituted Csalkynyl.
  • X is NR , wherein R is hydrogen or optionally substituted alkyl (e.g., -CH 3 ) and R Xa is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl.
  • X is NR xb , wherein each of R Xa and R xb is hydrogen.
  • X is NR xb , wherein R xb is hydrogen or optionally substituted alkyl (e.g., -CH 3 ) and wherein R Xa is optionally substituted Cialkyl (e.g., -CH 3 , or Ciaralkyl such as benzyl), optionally substituted C 2 alkyl, or optionally substituted C 3 alkyl.
  • R xb is hydrogen or optionally substituted alkyl (e.g., -CH 3 ) and wherein R Xa is optionally substituted Cialkyl (e.g., -CH 3 , or Ciaralkyl such as benzyl), optionally substituted C 2 alkyl, or optionally substituted C 3 alkyl.
  • X is NR xb , wherein R xb is hydrogen or optionally substituted alkyl (e.g., -CH 3 ) and wherein R Xa is optionally substituted alkenyl, e.g., optionally substituted C 3 -salkenyl. In certain embodiments, R Xa is optionally substituted C 3 alkenyl, optionally substituted C 4 alkenyl, or optionally substituted Csalkenyl.
  • X is NR xb , wherein R xb is hydrogen or optionally substituted alkyl (e.g., -CH 3 ) and wherein R Xa is optionally substituted alkynyl, e.g., optionally substituted C 3 -salkynyl. In certain embodiments, R Xa is optionally substituted C 3 alkynyl, optionally substituted C 4 alkynyl, or optionally substituted Csalkynyl.
  • R xb is hydrogen or optionally substituted alkyl (e.g., -CH 3 ) and wherein R Xa is optionally substituted alkynyl, e.g., optionally substituted C 3 -salkynyl.
  • R Xa is optionally substituted C 3 alkynyl, optionally substituted C 4 alkynyl, or optionally substituted Csalkynyl.
  • R Xa is an optionally alkenyl group of formula (b):
  • z is 1, 2, 3, or 4;
  • R 12a and R 12b are independently hydrogen or optionally substituted alkyl
  • R 13 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • z is 1. In certain embodiments, z is 2. In certain embodiments, z is 3. In certain embodiments, z is 4.
  • At least one of R 12a and R 12b is hydrogen. In certain embodiments, at least one of R 12a and R 12b is optionally substituted alkyl (e.g., -CH 3 ). [00173] In certain embodiments, R a and R are both hydrogen, i.e., to provide a trans alkenyl group. In certain embodiments, R 12a and R 13 are both hydrogen, i.e., to provide a cis alkenyl group.
  • R 13 is optionally substituted alkyl, e.g., optionally substituted C 1-6 alkyl, optionally substituted Ci-salkyl, optionally substituted Ci_ 4 alkyl, optionally substituted Ci-3alkyl, optionally substituted C 1-2 alkyl, optionally substituted Cialkyl, optionally substituted C 2 alkyl, optionally substituted C 3 alkyl, optionally substituted C 4 alkyl, optionally substituted C 5 alkyl, or optionally substituted Cealkyl.
  • the alkyl group is further substituted, e.g., with halogen groups, or branched (e.g., with -CH 3 groups). However, in certain embodiments, wherein R 13 is alkyl, the alkyl group is unsubstituted. In certain embodiments, wherein R 13 is alkyl, the alkyl group is branched.
  • R 13 is optionally substituted alkenyl, e.g., optionally substituted C 2 _ 6 alkenyl, optionally substituted C 2 _ 5 alkenyl, optionally substituted C 2 _ 4 alkenyl, optionally substituted C 2 . 3 alkenyl, or optionally substituted C 2 alkenyl.
  • optionally substituted C 2 _ 6 alkenyl e.g., optionally substituted C 2 _ 6 alkenyl, optionally substituted C 2 _ 5 alkenyl, optionally substituted C 2 _ 4 alkenyl, optionally substituted C 2 . 3 alkenyl, or optionally substituted C 2 alkenyl.
  • R 13 is alkenyl
  • the alkenyl group is further substituted, e.g., with halogen groups.
  • the alkenyl group is unsubstituted.
  • R 13 is optionally substituted alkynyl, e.g., optionally substituted C 2-6 alkynyl, optionally substituted C 2 - 5 alkynyl, optionally substituted C 2 . 4 alkynyl, optionally substituted C 2 . 3 alkynyl, or optionally substituted C 2 alkynyl.
  • R 13 is optionally substituted alkynyl, e.g., optionally substituted C 2-6 alkynyl, optionally substituted C 2 - 5 alkynyl, optionally substituted C 2 . 4 alkynyl, optionally substituted C 2 . 3 alkynyl, or optionally substituted C 2 alkynyl.
  • R 13 is alkynyl
  • the alkynyl group is further substituted, e.g., with halogen groups.
  • the alkynyl group is unsubstituted.
  • R 13 is optionally substituted carbocyclyl (e.g.,
  • R 13 is optionally substituted aryl (e.g., phenyl) or optionally substituted heteroaryl (e.g., 5- to 6- membered heteroaryl).
  • aryl e.g., phenyl
  • heteroaryl e.g., 5- to 6- membered heteroaryl
  • the alkenyl group of formula (b) is: [00180] In certain embodiments of Formula (II), R a is an optionally alkynyl group of formula (c):
  • w is 1, 2, 3, or 4;
  • R 11 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • w is 1. In certain embodiments, w is 2. In certain embodiments, w is 3. In certain embodiments, w is 4.
  • R 11 is hydrogen
  • R 11 is optionally substituted alkyl, e.g., optionally substituted C 1-6 alkyl, optionally substituted Ci-salkyl, optionally substituted Ci- 4 alkyl, optionally substituted Ci-3alkyl, optionally substituted C 1-2 alkyl, optionally substituted Cialkyl, optionally substituted C 2 alkyl, optionally substituted C 3 alkyl, optionally substituted C 4 alkyl, optionally substituted C 5 alkyl, or optionally substituted Cealkyl.
  • the alkyl group is further substituted, e.g., with halogen groups, or branched (e.g., with -CH 3 groups). However, in certain embodiments, wherein R 11 is alkyl, the alkyl group is unsubstituted. In certain embodiments, wherein R 11 is alkyl, the alkyl group is branched.
  • R 11 is optionally substituted alkenyl, e.g., optionally substituted C 2 -6alkenyl, optionally substituted C 2 -salkenyl, optionally substituted C 2 . 4 alkenyl, optionally substituted C 2 . 3 alkenyl, or optionally substituted C 2 alkenyl.
  • optionally substituted alkenyl e.g., optionally substituted C 2 -6alkenyl, optionally substituted C 2 -salkenyl, optionally substituted C 2 . 4 alkenyl, optionally substituted C 2 . 3 alkenyl, or optionally substituted C 2 alkenyl.
  • R 11 is alkenyl
  • the alkenyl group is further substituted, e.g., with halogen groups.
  • the alkenyl group is unsubstituted.
  • R 11 is optionally substituted alkynyl, e.g., optionally substituted C 2-6 alkynyl, optionally substituted C 2 - 5 alkynyl, optionally substituted C 2 . 4 alkynyl, optionally substituted C 2 _ 3 alkynyl, or optionally substituted C 2 alkynyl.
  • R 11 is optionally substituted alkynyl, e.g., optionally substituted C 2-6 alkynyl, optionally substituted C 2 - 5 alkynyl, optionally substituted C 2 . 4 alkynyl, optionally substituted C 2 _ 3 alkynyl, or optionally substituted C 2 alkynyl.
  • R 11 is alkynyl
  • the alkynyl group is further substituted, e.g., with halogen groups.
  • R 11 is alkynyl
  • the alkynyl group is unsubstituted.
  • R 11 is optionally substituted carbocyclyl (e.g., Cscarbocyclyl, C 4 carbocyclyl, Cscarbocyclyl, or Cecarbocyclyl,) or optionally substituted heterocyclyl (e.g., a 3- to 6-membered heterocyclyl).
  • R 11 is optionally substituted aryl (e.g., phenyl) or optionally substituted heteroaryl (e.g., 5- to 6- membered heteroaryl).
  • aryl e.g., phenyl
  • heteroaryl e.g., 5- to 6- membered heteroaryl
  • R 11 is hydrogen, and w is 1, 2, or 3.
  • the alkynyl group of formula (c) is:
  • R 5 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR 5A or -NHR 5A ; wherein each instance of R 5A is independently optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • R 5 is optionally substituted alkyl. In certain embodiments, R 5 is unsubstituted alkyl. In certain embodiments, R 5 is substituted alkyl. In certain embodiments, R 5 is optionally substituted C 1-3 oalkyl. In certain embodiments, R 5 is optionally substituted C 1-2 salkyl. In certain embodiments, R 5 is optionally substituted Q. l salkyl. In certain embodiments, R 5 is optionally substituted Ci-ioalkyl. In certain
  • R 5 is optionally substituted C 2-1 oalkyl. In certain embodiments, R 5 is optionally substituted C 3- 8alkyl. In certain embodiments, R 5 is optionally substituted C 5- i 5 alkyl.
  • R 5 is optionally substituted alkyl of formula:
  • R 5 is optionally substituted alkenyl.
  • R 5 is an unsubstituted alkenyl. In certain embodiments, R 5 is a substituted alkenyl. In certain embodiments, R 5 is optionally substituted C2-30 alkenyl. In certain embodiments, R 5 is optionally substituted C 2 - 25 alkenyl. In certain embodiments, R 5 is optionally substituted C 2- 15 alkenyl. In certain embodiments, R 5 is optionally substituted C 2-1 o alkenyl. In certain embodiments, R 5 is optionally substituted C3-8 alkenyl. In certain embodiments, R 5 is optionally substituted C 5 -15 alkenyl.
  • R 5 is optionally substituted C 5 , C 6 , C 7 , C 8 , C9, or C 10 alkenyl. In certain embodiments, R 5 is optionally substituted Ce alkenyl. In certain embodiments, R 5 is unsubstituted Ce alkenyl. In certain embodiments, R 5 is optionally substituted C 7 alkenyl. In certain embodiments, R 5 is unsubstituted C 7 alkenyl. In certain embodiments, R 5 is optionally substituted C 8 alkenyl. In certain embodiments, R 5 is unsubstituted C 8 alkenyl.
  • R 5 is a C 7 - 3 oalkyl or C 7-3 oalkenyl.
  • these groups may also collectively be referred to as "hydrocarbon tails.”
  • Hydrocarbon tails can be saturated and unsaturated, depending on whether or not the hydrocarbon tail comprises double bonds.
  • the hydrocarbon tail can also comprise different lengths, often categorized as medium (i.e. , with tails between 7- 12 carbons, e.g., C 7-12 alkyl or C 7-12 alkenyl), long (i.e. , with tails greater than 12 carbons and up to 22 carbons, e.g., Ci 3 . 22 alkyl or Ci 3 . 22 alkenyl), or very long (i.e. , with tails greater than 22 carbons, e.g., C 23 - 30 alkyl or C 23 _ 30 alkenyl).
  • Exemplary unsaturated hydrocarbon tails include, but are not limited to:
  • Myristoleic -(CH 2 ) 7 CH CH(CH 2 ) 3 CH 3 ,
  • Palmitoliec -(CH 2 ) 7 CH CH(CH 2 ) 5 CH 3 ,
  • Oleic -(CH 2 ) 7 CH CH(CH 2 ) 7 CH 3 ,
  • Exemplary saturated hydrocarbon tails include, but are not limited to:
  • R 5 is an optionally substituted alkenyl group of formula
  • x is an integer between 1 and 10, inclusive
  • R 10a and R 10b are independently hydrogen or optionally substituted alkyl
  • R 9 is hydrogen, halogen, -OH, -SH, -NH 2 , -CN, -N0 2 , -N 3 , -S0 2 H, -S0 3 H, substituted hydroxyl, substituted thiol, substituted amino, sulfonyl, sulfinyl, carbonyl, silyl, boronyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • x is an integer between 1 and 8, inclusive. In certain embodiments, x is an integer between 1 and 6, inclusive. In certain embodiments, x is an integer between 1 and 5, inclusive. In certain embodiments, x is an integer between 1 and 4, inclusive. In certain embodiments, x is an integer between 1 and 3, inclusive. In certain embodiments, x is an integer between 1 and 2, inclusive. In certain embodiments, x is 1. In certain embodiments, x is 2. In certain embodiments, x is 3. In certain embodiments, x is 4. In certain embodiments, x is 5.
  • R 10a and R 10b are both hydrogen. In certain embodiments, R 10a and R 10b are independently selected from hydrogen and -CH 3 .
  • R 9 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • R 9 is optionally substituted alkyl, e.g., optionally substituted C 1-6 alkyl, optionally substituted Ci-salkyl, optionally substituted Ci_ 4 alkyl, optionally substituted Ci- 3 alkyl, optionally substituted Ci- 2 alkyl, optionally substituted Cialkyl, optionally substituted C 2 alkyl, optionally substituted C 3 alkyl, optionally substituted C 4 alkyl, optionally substituted C 5 alkyl, or optionally substituted Cealkyl.
  • R 9 is alkyl
  • the alkyl group is further substituted, e.g., with aryl or halogen groups, or branched (e.g., with -CH 3 groups).
  • R 9 is alkyl
  • the alkyl group is unsubstituted.
  • the alkyl group is branched.
  • R 9 is optionally substituted alkenyl, e.g., optionally substituted C 2 -6alkenyl, optionally substituted C 2 -5alkenyl, optionally substituted C 2 . 4 alkenyl, optionally substituted C 2 . 3 alkenyl, or optionally substituted C 2 alkenyl.
  • optionally substituted alkenyl e.g., optionally substituted C 2 -6alkenyl, optionally substituted C 2 -5alkenyl, optionally substituted C 2 . 4 alkenyl, optionally substituted C 2 . 3 alkenyl, or optionally substituted C 2 alkenyl.
  • R 9 is alkenyl
  • the alkenyl group is further substituted, e.g., with halogen groups.
  • the alkenyl group is unsubstituted.
  • R 9 is optionally substituted alkynyl, e.g., optionally substituted C 2-6 alkynyl, optionally substituted C 2 - 5 alkynyl, optionally substituted C 2-4 alkynyl, optionally substituted C 2 _ 3 alkynyl, or optionally substituted C 2 alkynyl.
  • optionally substituted alkynyl e.g., optionally substituted C 2-6 alkynyl, optionally substituted C 2 - 5 alkynyl, optionally substituted C 2-4 alkynyl, optionally substituted C 2 _ 3 alkynyl, or optionally substituted C 2 alkynyl.
  • R 9 is alkynyl
  • the alkynyl group is further substituted, e.g., with halogen groups.
  • the alkynyl group is unsubstituted.
  • R 9 is optionally substituted carbocyclyl (e.g.,
  • R 9 is optionally substituted aryl (e.g., phenyl) or optionally substituted heteroaryl (e.g., 5- to 6- membered heteroaryl).
  • R 5 is an optionally substituted alkenyl group of formula (al) wherein x is 1, R 10a and R 10b are each hydrogen, and R 9 is optionally substituted C 4 -6alkyl or optionally substituted C 3-6 carbocyclyl, as described herein.
  • the optionally substituted alkenyl group of formula (al) is selected from the group consisting of:
  • R 5 is optionally substituted alkynyl.
  • R 5 is an unsubstituted alkynyl. In certain embodiments, R 5 is a substituted alkynyl. In certain embodiments, R 5 is optionally substituted C 2 -30 alkynyl. In certain embodiments, R 5 is optionally substituted C 2 - 25 alkynyl. In certain embodiments, R 5 is optionally substituted C 2- 15 alkynyl. In certain embodiments, R 5 is optionally substituted C 2- 10 alkynyl. In certain embodiments, R 5 is optionally substituted C3-8 alkynyl. In certain embodiments, R 5 is optionally substituted C5-15 alkynyl.
  • R 5 is optionally substituted carbocyclyl (e.g.,
  • Cscarbocyclyl C 4 carbocyclyl, Cscarbocyclyl, or Cecarbocyclyl,) or optionally substituted heterocyclyl (e.g., a 3- to 6-membered heterocyclyl).
  • R 5 is optionally substituted aryl (e.g., phenyl) or optionally substituted heteroaryl (e.g., 5- to 6- membered heteroaryl).
  • aryl e.g., phenyl
  • heteroaryl e.g., 5- to 6- membered heteroaryl
  • R 5 is -OR 5A or -NHR 5A ; wherein R 5A is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • R 5 is -OR 5A . In certain embodiments, R 5 is-NHR 5A .
  • R 5 is -OR 5A or -NHR 5A , and R 5A is optionally substituted alkyl.
  • R 5A is unsubstituted alkyl.
  • R 5A is substituted alkyl.
  • R 5A is optionally substituted Ci- 30 alkyl.
  • R 5A is optionally substituted C 1-2 5alkyl.
  • R 5A is optionally substituted Ci-isalkyl.
  • R 5A is optionally substituted Ci- l oalkyl.
  • R 5A is optionally substituted C 2-1 oalkyl.
  • R 5A is optionally substituted C 3 _ 8 alkyl.
  • R 5A is optionally substituted Cs-isalkyl.
  • R 5 is -OR 5A or -NHR 5A and R 5A is an optionally substituted alkyl, provided is a group of formula:
  • R 5 is -OR 5A or -NHR 5A , and R 5A is optionally substituted alkenyl.
  • R 5A is an unsubstituted alkenyl.
  • R 5A is a substituted alkenyl.
  • R 5A is optionally substituted C 2 -30 alkenyl.
  • R 5A is optionally substituted C 2 - 25 alkenyl.
  • R 5A is optionally substituted C 2-15 alkenyl.
  • R 5A is optionally substituted C 2- 1 o alkenyl.
  • R 5A is optionally substituted C 3- 8 alkenyl.
  • R 5A is optionally substituted C 5 -15 alkenyl. In certain embodiments, R 5A is optionally substituted C 5 , C 6 , C 7 , C 8 , C9, or C 10 alkenyl. In certain embodiments, R 5A is optionally substituted Ce alkenyl. In certain embodiments, R 5A is unsubstituted Ce alkenyl. In certain embodiments, R 5A is optionally substituted C 7 alkenyl. In certain embodiments, R 5 is unsubstituted C 7 alkenyl. In certain embodiments, R 5A is optionally substituted C 8 alkenyl. In certain embodiments, R 5A is unsubstituted C 8 alkenyl.
  • R 5A is optionally substituted alkynyl. In certain embodiments, R 5A is an unsubstituted alkynyl. In certain embodiments, R 5 is a substituted alkynyl. In certain embodiments, R 5A is optionally substituted C 2 _ 30 alkynyl. In certain embodiments, R 5A is optionally substituted C 2 - 25 alkynyl. In certain embodiments, R 5A is optionally substituted C 2- 15 alkynyl. In certain embodiments, R 5A is optionally substituted C 2- 10 alkynyl. In certain embodiments, R 5A is optionally substituted C 3 . 8 alkynyl. In certain embodiments, R 5A is optionally substituted C 5 -15 alkynyl.
  • R 5A is optionally substituted carbocyclyl (e.g.,
  • R 5A is optionally substituted aryl (e.g., phenyl) or optionally substituted heteroaryl (e.g., 5- to 6- membered heteroaryl).
  • aryl e.g., phenyl
  • heteroaryl e.g., 5- to 6- membered heteroaryl
  • R 5A is an optionally substituted aryl or optionally substituted heteroaryl group of formulae:
  • q 0, 1, or 2;
  • each instance of R is independently selected from the group consisting of halogen, d_ 4 alkyl, Ci_ 4 haloalkyl, -OR 5D , or -NHR 5D , wherein R 5D is Ci_ 4 alkyl or Ci_
  • R 5C is hydrogen or Ci- 4 alkyl.
  • q is 0. In certain embodiments, q is 1. In certain embodiments, q is 2.
  • q is 1 or 2
  • at least one instance of R 5B is halogen, e.g., at least one instance of R is -CI.
  • q is 1 or 2
  • at least one instance of R 5B is Ci- 4 alkyl or Ci_ 4 haloalkyl, e.g., at least one instance of R 5B is -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , or - CF 3 .
  • q is 1 or 2
  • at least one instance of R 5B is -OR 5D wherein R 5D is Ci- 4 alkyl or e.g. , e.g., at least one instance of R 5B is -OCH 3 , - OCH 2 CH 3 , -OCH(CH 3 ) 2 , -OC(CH 3 ) 3 , or -OCF 3 .
  • q is 1 or 2
  • at least one instance of R 5B is -NHR 5D wherein R 5D is Ci- 4 alkyl or e.g. , e.g., at least one instance of R 5B is -NHCH 3 , -
  • R 5 is -OR 5A or -NHR 5A and R 5A is an optionally substituted group of formula (a2):
  • x is 0 or an integer between 1 and 10, inclusive;
  • R 10a and R 10b are independently hydrogen or optionally substituted alkyl
  • R 9 is hydrogen, halogen, -OH, -SH, -NH 2 , -CN, -N0 2 , -N 3 , -S0 2 H, -S0 3 H, substituted hydroxyl, substituted thiol, substituted amino, sulfonyl, sulfinyl, carbonyl, silyl, boronyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • x is 0.
  • x is an integer between 1 and 8, inclusive. In certain embodiments, x is an integer between 1 and 6, inclusive. In certain embodiments, x is an integer between 1 and 5, inclusive. In certain embodiments, x is an integer between 1 and 4, inclusive. In certain embodiments, x is an integer between 1 and 3, inclusive. In certain embodiments, x is an integer between 1 and 2, inclusive. In certain embodiments, x is 1. In certain embodiments, x is 2. In certain embodiments, x is 3. In certain embodiments, x is 4. In certain embodiments, x is 5.
  • R 10a and R 10b are both hydrogen. In certain embodiments, R 10a and R 10b are independently selected from hydrogen and -CH 3 .
  • R 9 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • R 9 is optionally substituted alkyl, e.g., optionally substituted optionally substituted Ci-salkyl, optionally substituted Ci_ 4 alkyl, optionally substituted Ci- 3 alkyl, optionally substituted Ci- 2 alkyl, optionally substituted Cialkyl, optionally substituted C 2 alkyl, optionally substituted C 3 alkyl, optionally substituted C 4 alkyl, optionally substituted C 5 alkyl, or optionally substituted Cealkyl.
  • the alkyl group is further substituted, e.g., with aryl or halogen groups, or branched (e.g., with -CH 3 groups).
  • R 9 is alkyl
  • the alkyl group is unsubstituted.
  • the alkyl group is branched.
  • R 9 is optionally substituted alkenyl, e.g., optionally substituted C 2 -6alkenyl, optionally substituted C 2 -5alkenyl, optionally substituted C 2 - 4 alkenyl, optionally substituted C 2 - 3 alkenyl, or optionally substituted C 2 alkenyl.
  • optionally substituted alkenyl e.g., optionally substituted C 2 -6alkenyl, optionally substituted C 2 -5alkenyl, optionally substituted C 2 - 4 alkenyl, optionally substituted C 2 - 3 alkenyl, or optionally substituted C 2 alkenyl.
  • R 9 is alkenyl
  • the alkenyl group is further substituted, e.g., with halogen groups.
  • the alkenyl group is unsubstituted.
  • R 9 is optionally substituted alkynyl, e.g., optionally substituted C 2 -6alkynyl, optionally substituted C 2 - 5 alkynyl, optionally substituted C 2 . 4 alkynyl, optionally substituted C 2 . 3 alkynyl, or optionally substituted C 2 alkynyl.
  • optionally substituted C 2 -6alkynyl e.g., optionally substituted C 2 -6alkynyl, optionally substituted C 2 - 5 alkynyl, optionally substituted C 2 . 4 alkynyl, optionally substituted C 2 . 3 alkynyl, or optionally substituted C 2 alkynyl.
  • R 9 is alkynyl
  • the alkynyl group is further substituted, e.g., with halogen groups.
  • the alkynyl group is unsubstituted.
  • R 9 is optionally substituted carbocyclyl (e.g.,
  • Qcarbocyclyl C 4 carbocyclyl, Cscarbocyclyl, or Cecarbocyclyl,) or optionally substituted heterocyclyl (e.g., a 3- to 6-membered heterocyclyl).
  • R 9 is optionally substituted aryl (e.g., phenyl) or optionally substituted heteroaryl (e.g., 5- to 6- membered heteroaryl).
  • aryl e.g., phenyl
  • heteroaryl e.g., 5- to 6- membered heteroaryl
  • each instance of R 6 is independently selected from the group consisting of halogen, -OH, -SH, -NH 2 , -CN, -N0 2 , -N 3 , -S0 2 H, -S0 3 H, substituted hydroxyl, substituted thiol, substituted amino, sulfonyl, sulfinyl, carbonyl, silyl, boronyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; and m is 0 or an integer of between 1 and 5, inclusive.
  • m is 0. In certain embodiments, m is an integer of between 1 and 5, inclusive. In certain embodiments, m is an integer of between 1 and 4, inclusive. In certain embodiments, m is an integer of between 1 and 3, inclusive. In certain embodiments, m is an integer of between 1 and 2, inclusive. In certain embodiments, m is 1, i.e., to provide a mono substituted phenyl. In certain embodiments, m is 2, i.e., to provide a disubstituted phenyl. In certain embodiments, m is 3, i.e., to provide a trisubstituted phenyl.
  • m is 4, i.e., to provide a tetrasubstituted phenyl. In certain embodiments, m is 5, i.e., to provide a pentasubstituted phenyl. [00237] In certain preferred embodiments, m is 1, 2, or 3 to provide a mono substituted, disubstituted, or trisubstituted phenyl. In this instance, all possible positional mono-, di-, and tri- substituted isomers are contemplated herein, i.e. :
  • m is 1, i.e., to provide a mono substituted phenyl.
  • R 6 may be an ortho-, meta- or para- sub stituent relative to the point of attachment to the parent molecule.
  • R 6 is an ort/zosubstituent.
  • R 6 is a meto-substituent.
  • R 6 is a para- substituent.
  • m is 2, i.e., to provide a disubstituted phenyl.
  • the two R 6 substituents are 1,2-substituents, 1,3 -substituents, 1,4-substituents, 1,5- substituents, 2,3-substituents, or 2,4-substituents, relative to the point of attachment to the parent molecule.
  • the two R 6 substituents are 1,2- substituents.
  • the two R 6 substituents are 1,3-substituents.
  • the two R 6 substituents are 1,4-substituents.
  • the two R 6 substituents are 1,5-substituents. In certain embodiments, the two R 6 substituents are 2,3-substituents. In certain embodiments, the two R 6 substituents are 2,4-substituents.
  • m is 3, i.e., to provide a trisubstituted phenyl.
  • the three R 6 substituents are 1,2,3-substituents, 2,3,4-substituents, 1,2,5-substituents, 1, 2,4-substituents, 2,3,5-substituents, relative to the point of attachment to the parent molecule.
  • the three R 6 substituents are 2,3,4-substituents.
  • m is 1, 2, or 3, optionally wherein at least one instance of R 6 is halogen (e.g.
  • fluoro (-F), chloro (-C1), bromo (-Br), or iodo (-1)), -OH, -SH, -NH 2 , - N0 2 , carbonyl (e.g., -C0 2 H) or optionally substituted alkyl (e.g., -CH 3 ).
  • at least one instance of R 6 is halogen, -OH, -SH, or -NH 2 .
  • m is 1, 2, or 3 and at least one instance of R 6 is halogen, e.g., fluoro.
  • m is 1 and R 6 is fluoro.
  • n is 1 and R 6 is a meta fluoro substituent. In certain embodiments, m is 2 and each R 6 is fluoro. In certain embodiments, m is 2 and the two R 6 groups are 2,4-fluoro substituents.
  • a compound of Formula (I) and (II) or pharmaceutically acceptable salt thereto may comprise a combination of two ore more of the below recited embodiments, e.g., wherein:
  • R 1 is hydrogen or optionally substituted alkyl, e.g. , optionally substituted Q.
  • 3alkyl such as -CH 3 , -CF 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3, or -CH(CH 3 ) 2 ;
  • R 4 is hydrogen or optionally substituted alkyl, e.g. , optionally substituted Ci- 3alkyl, such as -CH 3 , -CF 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3, or -CH(CH 3 ) 2 ;
  • Y is O or NR Y wherein R Y is hydrogen or -CH 3 ;
  • X is O or NR , wherein R is hydrogen or optionally
  • substituted alkyl e.g., -CH 3
  • X is O or or NR , wherein R is hydrogen or optionally substituted alkyl (e.g., -CH 3 ) and R Xa is hydrogen, optionally substituted alkyl (e.g., -CH 3 , or aralkyl such as benzyl), optionally substituted alkenyl (e.g., of formula (b)), or optionally substituted alkynyl (e.g., of formula (c)); h.
  • R is hydrogen or optionally substituted alkyl (e.g., -CH 3 ) and R Xa is hydrogen, optionally substituted alkyl (e.g., -CH 3 , or aralkyl such as benzyl), optionally substituted alkenyl (e.g., of formula (b)), or optionally substituted alkynyl (e.g., of formula (c)); h.
  • R 5 is an optionally substituted alkenyl group of formula (al), wherein x is 1, R 10a and R 10b are each hydrogen, and R 9 is optionally substituted C 4 - 6 alkyl or optionally substituted C3- 6 carbocyclyl;
  • R 5 is -OR 5A or -NHR 5A , wherein R 5A is optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, or a group of formula (a2); and/or
  • j. m is 1, 2, or 3, optionally wherein at least one instance of R 6 is halogen (e.g., fluoro (-F), chloro (-C1), bromo (-Br), or iodo (-1)), -OH, -SH, -NH 2 , -N0 2 , carbonyl (e.g., -C0 2 H) or optionally substituted alkyl (e.g., -CH 3 ); e.g., for example, wherein m is 2 and the two R 6 groups are 2,4-fluoro substituents.
  • halogen e.g., fluoro (-F), chloro (-C1), bromo (-Br), or iodo (-1)
  • -OH e.g., fluoro (-F), chloro (-C1), bromo (-Br), or iodo (-1)
  • -OH e.g., fluoro (-F),
  • R 1 is hydrogen or optionally substituted alkyl, e.g. , optionally substituted Ci- 3 alkyl, such as -CH 3 , -CF 3 , - CH 2 CH 3 , -CH 2 CH 2 CH 3, or -CH(CH 3 ) 2 .
  • Ci- 3 alkyl such as -CH 3 , -CF 3 , - CH 2 CH 3 , -CH 2 CH 2 CH 3, or -CH(CH 3 ) 2 .
  • Ci- 3 alkyl such as -CH 3 , -CF 3 , - CH 2 CH 3 , -CH 2 CH 2 CH 3, or -CH(CH 3 ) 2
  • R 3 is substituted Ci -3 alkyl, wherein the alkyl group is further substituted with hydroxyl or substituted hydroxyl group.
  • R 4 is hydrogen or optionally substituted alkyl, e.g. , optionally substituted Ci- 3 alkyl, such as - CH 3 , -CF 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3, or -CH(CH 3 ) 2 .
  • R 5 is an optionally substituted alkenyl group of formula (al) wherein x is 1, R 10a and R 10b are each hydrogen, and R 9 is optionally substituted C 4 -6alkyl or optionally substituted C 3 -6carbocyclyl.
  • R 5 is -OR 5A or -NHR 5A , wherein R 5A is optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl.
  • R 5A is a group of formula (a2).
  • m is 1, 2, or 3, optionally wherein at least one instance of R 6 is halogen (e.g.
  • fluoro (-F), chloro (-C1), bromo (-Br), or iodo (-1)), -OH, -SH, -NH 2 , -N0 2 , carbonyl (e.g., -C0 2 H) or optionally substituted alkyl (e.g., -CH 3 ).
  • m is 2 and the two R 6 groups are 2,4-fluoro substituents.
  • R is hydrogen or optionally substituted alkyl (e.g., -CH 3 ).
  • R 1 is hydrogen or optionally substituted alkyl, e.g. , optionally substituted C 1-3 alkyl, such as -CH 3 , -CF 3 , - CH2CH3, -CH2CH2CH3, or -CH(CH 3 ) 2 .
  • R 3 is substituted Ci_ 3 alkyl, wherein the alkyl group is further substituted with hydroxyl or substituted hydroxyl group.
  • R 4 is hydrogen or optionally substituted alkyl, e.g. , optionally substituted Ci- 3 alkyl, such as - CH 3 , -CF 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3, or -CH(CH 3 ) 2 .
  • R 5A is optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • R 5A is a group of formula (a2).
  • m is 1, 2, or 3, optionally wherein at least one instance of R 6 is halogen (e.g. , fluoro (-F), chloro (-C1), bromo (-Br), or iodo (-1)), -OH, -SH, -NH 2 , -N0 2 , carbonyl (e.g., -C0 2 H) or optionally substituted alkyl (e.g., -CH 3 ).
  • m is 2 and the two R 6 groups are 2,4-fluoro substituents.
  • R is hydrogen or optionally substituted alkyl (e.g., - CH 3 ).
  • R 1 is hydrogen or optionally substituted alkyl, e.g. , optionally substituted Ci-3alkyl, such as -CH 3 , -CF 3 , - CH 2 CH 3 , -CH 2 CH 2 CH 3, or -CH(CH 3 ) 2 .
  • Ci_ 3 alkyl such as -CH 3 , -CF 3 , - CH 2 CH 3 , -CH 2 CH 2 CH 3, or -CH(CH 3 ) 2 .
  • Ci- 3 alkyl such as -CH 3 , -CF 3 , - CH 2 CH 3 , -CH 2 CH 2 CH 3i or -CH(CH 3 ) 2
  • R 3 is substituted Ci_ 3 alkyl, wherein the alkyl group is further substituted with hydroxyl or substituted hydroxyl group.
  • R 4 is hydrogen or optionally substituted alkyl, e.g. , optionally substituted Ci- 3 alkyl, such as - CH 3 , -CF 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3, or -CH(CH 3 ) 2 .
  • x is 1, R 10a and R 10b are each hydrogen, and R 9 is optionally substituted C 4 _ 6 alkyl or optionally substituted C 3 _ 6carbocyclyl.
  • at least one instance of R 6 is halogen (e.g. , fluoro (-F), chloro (-C1), bromo (-Br), or iodo (-1)), -OH, -SH, -NH 2 , -N0 2 , carbonyl (e.g., -C0 2 H) or optionally substituted alkyl (e.g., -CH 3 ).
  • the two R 6 groups are 2,4- fluoro substituents.
  • R is hydrogen or optionally substituted alkyl (e.g., -CH 3 ).
  • R 1 is hydrogen or optionally substituted alkyl, e.g., optionally substituted Ci-3alkyl, such as -CH 3 , -CF 3 , - CH 2 CH 3 , -CH 2 CH 2 CH 3i or -CH(CH 3 ) 2 .
  • R is optionally substituted alkyl, e.g., optionally substituted Ci- 3 alkyl, such as -CH 3 , -CF 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3i or - CH(CH 3 ) 2 .
  • R 3A is optionally substituted alkyl, e.g.
  • Ci -3 alkyl such as -CH 3 , -CF 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3, or -CH(CH 3 ) 2 .
  • R 4 is hydrogen or optionally substituted alkyl, e.g. , optionally substituted Q. 3 alkyl, such as -CH 3 , -CF 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3, or -CH(CH 3 ) 2 .
  • x is 1, R 10a and R 10b are each hydrogen, and R 9 is optionally substituted C 4 - 6 alkyl or optionally substituted C 3 - 6 carbocyclyl.
  • At least one instance of R 6 is halogen (e.g. , fluoro (-F), chloro (-C1), bromo (-Br), or iodo (-1)), -OH, -SH, -NH 2 , -N0 2 , carbonyl (e.g., -C0 2 H) or optionally substituted alkyl (e.g., -CH 3 ).
  • halogen e.g. , fluoro (-F), chloro (-C1), bromo (-Br), or iodo (-1)
  • -OH e.g. , fluoro (-F), chloro (-C1), bromo (-Br), or iodo (-1)
  • -OH e.g. , fluoro (-F), chloro (-C1), bromo (-Br), or iodo (-1)
  • R is hydrogen or optionally substituted alkyl (e.g., -CH 3 ).
  • R 5 is an optionally substituted alkenyl group of formula (al) wherein x is 1, R 10a and R 10b are each hydrogen, and R 9 is optionally substituted C 4 - 6 alkyl or optionally substituted C 3 - 6 carbocyclyl.
  • R 5 is -OR 5A or -NHR 5A , wherein R 5A is optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • R 5A is a group of formula (a2).
  • m is 1, 2, or 3, optionally wherein at least one instance of R 6 is halogen (e.g.
  • fluoro (-F), chloro (-C1), bromo (-Br), or iodo (-1)), -OH, -SH, -NH 2 , -N0 2 , carbonyl (e.g., -C0 2 H) or optionally substituted alkyl (e.g., -CH 3 ).
  • m is 2 and the two R 6 groups are 2,4-fluoro substituents.
  • R is hydrogen or optionally substituted alkyl (e.g., -CH 3 ).
  • R Xa is hydrogen, optionally substituted alkyl (e.g., -CH 3 , or aralkyl such as benzyl), optionally substituted alkenyl (e.g., of formula (b)), or optionally substituted alkynyl (e.g., of formula (c)).
  • R 5 is -OR 5A or - 5A
  • R 5 is an optionally substituted alkenyl group of formula (al) wherein x is 1, R 10a and R 10b are each hydrogen, and R 9 is optionally substituted C 4 -6alkyl or optionally substituted C3-6carbocyclyl.
  • R 5A is optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • R 5A is a group of formula (a2).
  • m is 1, 2, or 3, optionally wherein at least one instance of R 6 is halogen (e.g.
  • m is 2 and the two R 6 groups are 2,4-fluoro substituents.
  • R xb is hydrogen or optionally substituted alkyl (e.g., -CH 3 ).
  • R Xa is hydrogen, optionally substituted alkyl (e.g., -CH 3 , or aralkyl such as benzyl), optionally substituted alkenyl (e.g., of formula (b)), or optionally substituted alkynyl (e.g., of formula (c)).
  • optionally substituted alkyl e.g., -CH 3 , or aralkyl such as benzyl
  • optionally substituted alkenyl e.g., of formula (b)
  • optionally substituted alkynyl e.g., of formula (c)
  • R 5 is an optionally substituted alkenyl group of formula (al) wherein x is 1, R 10a and R 10b are each hydrogen, and R 9 is optionally substituted C 4 -6alkyl or optionally substituted C 3 -6carbocyclyl.
  • R 5 is -OR 5A or -NHR 5A , wherein R 5A is optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • R 5A is a group of formula (a2).
  • m is 1, 2, or 3, optionally wherein at least one instance of R is halogen (e.g.
  • fluoro (-F), chloro (-C1), bromo (-Br), or iodo (-1)), -OH, -SH, -NH 2 , -NO 2 , carbonyl (e.g., -C0 2 H) or optionally substituted alkyl (e.g., -CH 3 ).
  • m is 2 and the two R 6 groups are 2,4-fluoro substituents.
  • R is hydrogen or optionally substituted alkyl (e.g., -CH 3 ).
  • R 5 is an optionally substituted alkenyl group of formula (al) wherein x is 1, R 10a and R 10b are each hydrogen, and R 9 is optionally substituted C 4 -6alkyl or optionally substituted C 3 -6carbocyclyl.
  • R 5 is -OR 5A or -NHR 5A , wherein R 5A is optionally substituted alkyl, ptionally substituted aryl, or optionally substituted heteroaryl.
  • R 5A is a group of formula (a2).
  • m is 1, 2, or 3, optionally wherein at least one instance of R 6 is halogen (e.g.
  • fluoro (-F), chloro (-C1), bromo (-Br), or iodo (-1)), -OH, -SH, -NH 2 , -NO 2 , carbonyl (e.g., -C0 2 H) or optionally substituted alkyl (e.g., -CH 3 ).
  • m is 2 and the two R 6 groups are 2,4-fluoro substituents.
  • R is hydrogen or optionally substituted alkyl (e.g., -CH 3 ).
  • R 10a and R 1 are each hydrogen, and R 9 is optionally substituted C 4 -6alkyl or optionally substituted C 3 . 6 carbocyclyl.
  • at least one instance of R 6 is halogen (e.g. , fluoro (-F), chloro (-C1), bromo (-Br), or iodo (-1)), -OH, -SH, -NH 2 , -N0 2 , carbonyl (e.g., -C0 2 H) or optionally substituted alkyl (e.g., -CH 3 ).
  • the two R 6 groups are 2,4-
  • R is hydrogen or optionally substituted alkyl (e.g., -CH 3 ).
  • R Xa is hydrogen, optionally substituted alkyl (e.g., - CH 3 , or aralkyl such as benzyl), optionally substituted alkenyl (e.g., of formula (b)), or optionally substituted alkynyl (e.g., of formula (c)).
  • R 10a and R 10b are each hydrogen, and R 9 is optionally substituted C 4 _ 6 alkyl or optionally substituted C 3 _ 6carbocyclyl.
  • at least one instance of R 6 is halogen (e.g. , fluoro (-F), chloro (-C1), bromo (-Br), or iodo (-1)), -OH, -SH, -NH 2 , -N0 2 , carbonyl (e.g., -C0 2 H) or optionally substituted alkyl (e.g., -CH 3 ).
  • the two R 6 groups are 2,4-
  • R is hydrogen or optionally substituted alkyl (e.g., -CH 3 ).
  • R 6 is halogen (e.g. , fluoro (-F), chloro (-C1), bromo (-Br), or iodo (-1)), -OH, -SH, -NH 2 , -N0 2 , carbonyl (e.g., -C0 2 H) or optionally substituted alkyl (e.g., -CH 3 ).
  • the two R 6 groups are 2,4- fluoro substituents.
  • R is hydrogen or optionally substituted alkyl (e.g., -CH 3 ).
  • Exemplary compounds of Formula (I) include, but are not limited to:
  • Compounds of Formula (I) and (II) may further be substituted with a label, optionally tethered to the compound via a divalent linker moiety, such as an optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkenylene, optionally substituted heteroalkynylene, optionally substituted carbocyclylene, optionally substituted heterocycylene, optionally substituted arylene, optionally substituted heteroarylene divalent moiety, or a divalent moiety comprising a combination of two or more of such groups sequentially linked together.
  • a divalent linker moiety such as an optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkenylene, optionally substituted heteroalkynylene, optionally substituted carbocyclylene, optionally substituted heteroc
  • a “label,” as used herein, refers to a detectable moiety, i.e., a moiety which provides a detectable (e.g., visually detectable) analytical signal.
  • detectable moieties include, but are not limited to, (a) a molecule which contains isotopic moieties, e.g., for use in radioimmunoassays, which may be radioactive and/or isotopic and include, but not limited to, 2 H, 3 H, 13 C, 14 C, 15 N, 31 P, 32 P, 35 S, 67 Ga, "mTc (Tc-"m), m In, 123 1, 125 1, 169 Yb, and 186 Re), (b) an enzyme or coenzyme; (c) a molecule which is colored (chromophore), fluorescent, phosphorescent, or chemiluminescent dyes; (d) a molecule which has one or more photo affinity moieties; (e) a molecule which has one or more photo
  • DNP dinitrophenol
  • digoxigenin digoxigenin
  • latex and magnetic particles gold, silver, and selenium colloidal particles
  • metal chelates metal chelates
  • oligonucleotides A wide variety of detectable moieties can be used, with the choice of label depending on the sensitivity required, stability requirements, and available instrumentation and disposal provisions. All of above can be used as label, and by attaching to the compound, they can be located with different detection method, e.g., for example, using Halo tag.
  • the label is biotin.
  • the biotin moiety allows the compound of Formula (I) or (II) to bind to certain surface such as, for example, beads, glass, or metal surface.
  • the label is a fluorescent moiety.
  • a "fluorescent moiety" or label as used herein refer to a moiety that absorbs light energy at a defined excitation wavelength and emit light energy at a different wavelength.
  • fluorescent labels include, but are not limited to: Alexa Fluor dyes (Alexa Fluor 350, Alexa Fluor 488, Alexa Fluor 532, Alexa Fluor 546, Alexa Fluor 568, Alexa Fluor 594, Alexa Fluor 633, Alexa Fluor 660 and Alexa Fluor 680), AMCA, AMCA-S, BODIPY dyes (BODIPY FL, BODIPY R6G, BODIPY TMR, BODIPY TR, BODIPY 493/503, BODIPY 530/550, BODIPY 558/568, BODIPY 564/570, BODIPY 576/589, BODIPY 581/591, BODIPY 630/650, BODIPY 650/665), Car
  • Exemplary labeled compounds include compounds of Formula:
  • w 1, 2, 3, or 4;
  • L is a divalent linker moiety as defined herein;
  • Label is a lable moiety as defined herein.
  • Exemplary labeled compounds of Formula (II-al-label) include, but are not limited to, the below biotin-labled compound:
  • Such compounds may be synthesized, for example, from “click chemistry” coupling of the corresponding alkynyl compound of Formula:
  • compositions comprising a compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the compound is provided in an effective amount in the pharmaceutical composition, e.g., a therapeutically effective amount and/or a prophylactically effective amount, depending upon the intended method of treatment.
  • compositions agents include any and all solvents, diluents or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • solvents diluents or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • compositions described herein can be prepared by any method known in the art of pharmacology.
  • preparatory methods include the steps of bringing the compound of Formula (I) or (II) or pharmaceutically acceptable salt thereof (the "active ingredient") into association with a carrier and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping and/or packaging the product into a desired single- or multi-dose unit.
  • compositions can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses.
  • a "unit dose" is discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient.
  • the amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage.
  • Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and/or any additional ingredients in a pharmaceutical composition will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the composition is to be administered.
  • the pharmaceutical composition may comprise between 0.1% and 100% (w/w) active ingredient.
  • compositions used in the manufacture of provided pharmaceutical compositions include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.
  • Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, etc., and combinations thereof.
  • Exemplary granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross- linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, etc. , and combinations thereof.
  • Exemplary surface active agents and/or emulsifiers include natural emulsifiers (e.g. acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g.
  • carboxymethylcellulose sodium powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g. polyoxyethylene sorbitan monolaurate (Tween 20),
  • polyoxyethylene sorbitan Teween 60
  • polyoxyethylene sorbitan monooleate Teween 80
  • sorbitan monopalmitate Span 40
  • sorbitan monostearate Span 60
  • sorbitan tristearate Span 65
  • polyoxyethylene esters e.g.
  • polyoxyethylene monostearate Myrj 45
  • polyoxyethylene hydrogenated castor oil polyethoxylated castor oil
  • polyoxymethylene stearate polyethoxylated castor oil
  • polyoxymethylene stearate and Solutol
  • sucrose fatty acid esters polyethylene glycol fatty acid esters (e.g. Cremophor)
  • polyoxyethylene ethers e.g.
  • polyoxyethylene lauryl ether (Brij 30)), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F-68, Poloxamer P188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, etc. and/or combinations thereof.
  • Exemplary binding agents include starch (e.g. cornstarch and starch paste), gelatin, sugars (e.g. sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g. acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose,
  • starch e.g. cornstarch and starch paste
  • gelatin e.g. cornstarch and starch paste
  • sugars e.g. sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.
  • natural and synthetic gums e.g. acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage
  • Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives.
  • antioxidants include alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.
  • Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g. , citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof.
  • EDTA ethylenediaminetetraacetic acid
  • salts and hydrates thereof e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like
  • citric acid and salts and hydrates thereof e.g. , citric
  • antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.
  • Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.
  • Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.
  • Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta- carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.
  • preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT),
  • the preservative is an anti-oxidant. In other embodiments, the preservative is a chelating agent.
  • Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D- gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic s
  • Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, etc., and combinations thereof.
  • Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury,
  • Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and combinations thereof.
  • Liquid dosage forms for oral and parenteral administration include
  • the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils ⁇ e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate,
  • the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • the active ingredient is mixed with solubilizing agents such as Cremophor, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and combinations thereof.
  • Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation can be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that can be employed are water, Ringer's solution, U.S. P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing the active ingredient with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and
  • Solid compositions of a similar type can be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
  • Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
  • the active ingredients can be in micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active ingredient can be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may comprise buffering agents. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • Dosage forms for topical and/or transdermal administration of the active ingredient may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants and/or patches.
  • the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier and/or any needed preservatives and/or buffers as can be required.
  • the transdermal patches are contemplated, which often have the added advantage of providing controlled delivery of an active ingredient to the body.
  • dosage forms can be prepared, for example, by dissolving and/or dispensing the active ingredient in the proper medium.
  • the rate can be controlled by either providing a rate controlling membrane and/or by dispersing the active ingredient in a polymer matrix and/or gel.
  • Suitable devices for use in delivering intradermal pharmaceutical compositions described herein include short needle devices such as those described in U.S. Patents 4,886,499; 5,190,521; 5,328,483; 5,527,288; 4,270,537; 5,015,235; 5,141,496; and
  • Intradermal compositions can be administered by devices which limit the effective penetration length of a needle into the skin, such as those described in PCT publication WO 99/34850 and functional equivalents thereof. Jet injection devices which deliver liquid vaccines to the dermis via a liquid jet injector and/or via a needle which pierces the stratum corneum and produces a jet which reaches the dermis are suitable. Jet injection devices are described, for example, in U.S. Patents 5,480,381 ; 5,599,302; 5,334,144;
  • Ballistic powder/particle delivery devices which use compressed gas to accelerate vaccine in powder form through the outer layers of the skin to the dermis are suitable.
  • conventional syringes can be used in the classical mantoux method of intradermal administration.
  • Formulations suitable for topical administration include, but are not limited to, liquid and/or semi liquid preparations such as liniments, lotions, oil in water and/or water in oil emulsions such as creams, ointments and/or pastes, and/or solutions and/or suspensions.
  • Topically-administrable formulations may, for example, comprise from about 1% to about 10% (w/w) active ingredient, although the concentration of the active ingredient can be as high as the solubility limit of the active ingredient in the solvent.
  • Formulations for topical administration may further comprise one or more of the additional ingredients described herein.
  • a pharmaceutical composition can be prepared, packaged, and/or sold in a formulation suitable for pulmonary administration via the buccal cavity.
  • Such a formulation may comprise dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 to about 7 nanometers or from about 1 to about 6 nanometers.
  • Such compositions are conveniently in the form of dry powders for administration using a device comprising a dry powder reservoir to which a stream of propellant can be directed to disperse the powder and/or using a self propelling solvent/powder dispensing container such as a device comprising the active ingredient dissolved and/or suspended in a low-boiling propellant in a sealed container.
  • Such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers.
  • Dry powder compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.
  • Low boiling propellants generally include liquid propellants having a boiling point of below 65 °F at atmospheric pressure.
  • the propellant may constitute 50 to 99.9% (w/w) of the composition, and the active ingredient may constitute 0.1 to 20% (w/w) of the composition.
  • the propellant may further comprise additional ingredients such as a liquid non-ionic and/or solid anionic surfactant and/or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient).
  • compositions formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and/or suspension.
  • Such formulations can be prepared, packaged, and/or sold as aqueous and/or dilute alcoholic solutions and/or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization and/or atomization device.
  • Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and/or a preservative such as methylhydroxybenzoate.
  • the droplets provided by this route of administration may have an average diameter in the range from about 0.1 to about 200 nanometers.
  • Formulations described herein as being useful for pulmonary delivery are useful for intranasal delivery of a pharmaceutical composition.
  • Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is administered by rapid inhalation through the nasal passage from a container of the powder held close to the nares.
  • Formulations for nasal administration may, for example, comprise from about as little as 0.1% (w/w) and as much as 100% (w/w) of the active ingredient, and may comprise one or more of the additional ingredients described herein.
  • a pharmaceutical composition can be prepared, packaged, and/or sold in a formulation for buccal administration.
  • Such formulations may, for example, be in the form of tablets and/or lozenges made using conventional methods, and may contain, for example, 0.1 to 20% (w/w) active ingredient, the balance comprising an orally dissolvable and/or degradable composition and, optionally, one or more of the additional ingredients described herein.
  • formulations for buccal administration may comprise a powder and/or an aerosolized and/or atomized solution and/or suspension comprising the active ingredient.
  • Such powdered, aerosolized, and/or aerosolized formulations when dispersed, may have an average particle and/or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein.
  • a pharmaceutical composition can be prepared, packaged, and/or sold in a formulation for ophthalmic administration.
  • Such formulations may, for example, be in the form of eye drops including, for example, a 0.1/1.0% (w/w) solution and/or suspension of the active ingredient in an aqueous or oily liquid carrier.
  • Such drops may further comprise buffering agents, salts, and/or one or more other of the additional ingredients described herein.
  • Other opthalmically-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and/or in a liposomal preparation. Ear drops and/or eye drops are contemplated as being within the scope of this disclosure.
  • compositions are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation. [00302] Still further contemplated are kits (e.g. , pharmaceutical packs).
  • kits provided may comprise a pharmaceutical composition or compound of Formula (I) or (II) or pharmaceutically acceptable salt thereof and a container (e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container).
  • a container e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container.
  • provided kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of a pharmaceutical composition or compound of Formula (I) or (II) or pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition or compound of Formula (I) or (II) or pharmaceutically acceptable salt thereof provided in the container and the second container are combined to form one unit dosage form.
  • a single container may comprise one or more compartments for containing a pharmaceutical composition or compound of Formula (I) or (II) or
  • a single container can be appropriate for modification such that the container may receive a physical modification so as to allow combination of compartments and/or components of individual compartments.
  • a foil or plastic bag may comprise two or more compartments separated by a perforated seal which can be broken so as to allow combination of contents of two individual compartments once the signal to break the seal is generated.
  • a kit may thus comprise such multicompartment containers providing a pharmaceutical composition or compound of Formula (I) or (II) or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
  • instructions for use are additionally provided in such kits.
  • Such instructions may provide, generally, for example, instructions for dosage and administration.
  • instructions may further provide additional detail relating to specialized instructions for particular containers and/or systems for administration.
  • instructions may provide specialized instructions for use in conjunction and/or in combination with an additional therapeutic agent.
  • kits for treating a microbial infection in a subject comprising administering an effective amount of a compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof to the subject in need thereof.
  • a method of treating microbial virulence can be conducted by contacting the compound of Formula (I) or (II) or a
  • a method of treating microbial virulence comprising contacting an effective amount of the a compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof with a microorganism.
  • an in vitro method of treating microbial virulence comprising contacting an effective amount of a compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof with a microorganism in a cell culture.
  • an in vivo method of treating microbial virulence comprising administering an effective amount of a compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof to a subject with a microbial infection.
  • compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof blocks virulence factor production.
  • the microbial virulence is bacterial virulence
  • the microorganism is a bacterium.
  • a method of potentiating the anti-bacterial activity of an anti-bacterial agent against a bacterium comprising delivering the anti-bacterial agent in combination with a compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof in vivo (i.e., by administration to a subject) or in vitro (e.g., upon contact with the microorganism in a cell culture) to the bacterium.
  • provided is a method of potentiating the activity of an anti-bacterial agent against a bacterium comprising contacting the anti-bacterial agent in combination with a compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof with a bacterium.
  • a method of potentiating the activity of an anti-bacterial agent against a bacterium comprising contacting the anti-bacterial agent in combination with a compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof with a bacterium in a cell culture.
  • an in vivo method of potentiating the activity of an anti-bacterial agent against a bacterium comprising adminstering the anti-bacterial agent in combination with a compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof to a subject with a bacterial infection.
  • the fragment used in the potentiation therapy is a compound of Formula (II) or a pharmaceutically acceptable salt thereof.
  • potentiate refers to the ability of the compound of Formula (I) or (II) to improve (i.e., increase) the effectiveness of the anti-bacterial agent against a bacterium.
  • the potentiation is synergistic (i.e., the combination results in a non-linear increase in effectiveness).
  • the potentiation is additive.
  • the effectiveness is measured by a reduction of MIC of the anti-bacterial agent, e.g., by about 1 ug/mL and about 50 ug/mL, inclusive, compared to the MIC of the anti-bacterial agent administered alone.
  • the potentiation is a result of the compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof competitively interfering with the efflux pumps of the bacterium.
  • the ratio of the compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof to the anti-bacterial agent (molar excess) is between about 1: 1 and about 100: 1, inclusive; e.g., between about 1: 1 and about 90: 1, between about 1: 1 and about 80: 1, between about 1: 1 and about 70: 1, between about 1: 1 and about 60: 1, between about 1: 1 and about 50: 1, between about 1: 1 and about 40: 1, between about 1: 1 and about 30:1, between about 1: 1 and about 20: 1, between about 1: 1 and about 10: 1, between about 2: 1 and about 50: 1, between about 2: 1 and about 40: 1 between about 2: 1 and about 30: 1, between about 2: 1 and about 20: 1, between about 5: 1 and about 50: 1, between about 5: 1 and
  • the anti-bacterial agent is any one of the agents described herein as additional therapeutically effective anti-bacterial agents. See infra.
  • the anti-baterial agent used in combination with a compound of Formula (I) or (II) or pharmaceutically acceptable salt thereof is reserpine.
  • the anti-bacterial agent used in combination with a compound of Formula (I) or (II) or pharmaceutically acceptable salt thereof is an enopeptin (ADEP) compound, e.g., as described in PCT Publication Application No. WO/2012/135615.
  • the anti-bacterial agent is an enopeptin (ADEP) compound, e.g., of Formula (A):
  • R 1 , R 4 , R 5 , R 6 , and m are as defined herein; further wherein:
  • R 21 is hydrogen, and R 31 and R 41 are joined to form an optionally substituted heterocyclyl; or
  • R 21 and R 31 are joined to form a spiro-fused optionally substituted carbocyclyl or spiro-fused optionally substituted heterocyclyl, and R 41 is hydrogen, optionally substituted alkyl, or an amino protecting group;
  • R 21 and R 31 are independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, provided that R 21 and R 31 are not both hydrogen; and R 41 is hydrogen, optionally substituted alkyl, or an amino protecting group;
  • R is hydrogen, -OH, -SH, -NH 2 , substituted hydroxyl, substituted thiol, substituted amino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • Exemplary ADEPs of Formula (A) contemplated useful in and potentiated by the combination with a com ound of Formula (I) or (II) include, but are not limited to:
  • microbial infection refers to an infection with a
  • the microbial infection is an infection with a fungus, i.e., a fungal infection.
  • the microbial infection is an infection with a virus, i.e., a viral infection.
  • the microbial infection is an infection with a bacteria, i.e., a bacterial infection.
  • Various microbial infections include, but are not limited to, skin infections, GI infections, urinary tract infections, genito-urinary infections, sepsis, blood infections, and systemic infections.
  • the microbial infection is an infection with a bacteria, i.e., a bacterial infection.
  • a compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof exhibits anti-bacterial activity.
  • a compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof has a mean inhibitory concentration (MIC), with respect to a particular bacterium, of less than 50 ⁇ g/mL, less than 25 ⁇ g/mL, less than 10 ⁇ g/mL, less than 5 ⁇ g/mL, less than 3 ⁇ g/mL, or less than 1 ⁇ g/mL.
  • MIC mean inhibitory concentration
  • Exemplary bacterial infections include, but are not limited to, infections with a gram positive bacteria (e.g., of the phylum Actinobacteria, phylum Firmicutes, or phylum Tenericutes); gram negative bacteria (e.g., of the phylum Aquificae, phylum Deinococcus- Thermus, phylum Fibrobacteres/Chlorobi/Bacteroidetes (FCB), phylum Fusobacteria, phylum Gemmatimonadest, phylum Ntrospirae, phylum
  • a gram positive bacteria e.g., of the phylum Actinobacteria, phylum Firmicutes, or phylum Tenericutes
  • gram negative bacteria e.g., of the phylum Aquificae, phylum Deinococcus- Thermus, phylum Fibrobacteres/Chlorobi/Bacteroidetes (FCB), phylum Fus
  • Planctomycetes/Verrucomicrobia/Chlamydiae PVC
  • phylum Proteobacteria phylum Spirochaetes
  • phylum Synergistetes e.g., of the phylum Acidobacteria, phylum Chlroflexi, phylum Chrystiogenetes, phylum Cyanobacteria, phylum
  • the bacterial infection is an infection with a gram positive bacteria.
  • the gram positive bacteria is a bacteria of the phylum
  • the bacteria is a member of the phylum Actinobacteria and the genus Mycobacteriium, i.e., the bacterial infection is a Mycobacteriium infection.
  • Exemplary Mycobacteriium bacteria include, but are not limited to, M. tuberculosis, M. bovis, M. africanum, M. canetti, M. caprae, M. microti, and . pinnipedii.
  • the Mycobacteriium infection is an M. tuberculosis infection.
  • the bacteria is a member of the phylum Actinobacteria and the genus Streptomyces, i.e., the bacterial infection is a Streptomyces infection.
  • the bacteria is a member of the phylum Actinobacteria and the genus Streptomyces, i.e., the bacterial infection is a Streptomyces infection.
  • Streptomyces bacteria include, but are not limited to, S. coelicolor.
  • the gram positive bacteria is a bacteria of the phylum
  • the bacteria is a member of the phylum Firmicutes and the genus Enterococcus, i.e., the bacterial infection is an Enterococcus infection.
  • Exemplary Enterococci bacteria include, but are not limited to, E. avium, E. durans, E. faecalis, E. faecium, E. gallinarum, E. solitarius, E. casseliflavus, and E. raffinosus.
  • the Enterococcus infection is an E. faecalis infection.
  • the Enterococcus infection is an E. faecium infection.
  • the bacteria is a member of the phylum Firmicutes and the genus Staphylococcus, i.e., the bacterial infection is a Staphylococcus infection.
  • Exemplary Staphylococci bacteria include, but are not limited to, S. arlettae, S. aureus, S. auricularis, S. capitis, S. caprae, S. carnous, S. chromogenes, S. cohii, S. condimenti, S. croceolyticus, S. delphini, S. devriesei, S. epidermis, S. equorum, S. felis, S. fluroettii, S. gallinarum, S.
  • the Staphylococcus infection is an S. aureus infection.
  • the Staphylococcus infection is an S. aureus infection.
  • Staphylococcus infection is an S. epidermis infection.
  • the bacteria is a member of the phylum Firmicutes and the genus Bacillus, i.e., the bacterial infection is a Bacillus infection.
  • Bacillus bacteria include, but are not limited to, B. alcalophilus, B. alvei, B. aminovorans, B.
  • amyloliquefaciens B. aneurinolyticus, B. anthracis, B. aquaemaris, B. atrophaeus, B.
  • boroniphilus B. brevis, B. caldolyticus, B. centrosporus, B. cereus, B. circulans, B.
  • coagulans B. firmus, B. flavothermus, B. fusiformis, B. globigii, B. infernus, B. larvae, B. laterosporus, B. lentus, B. licheniformis, B. megaterium, B. mesentericus, B. mucilaginosus, B. mycoides, B. natto, B. pantothenticus, B. polymyxa, B. pseudo anthracis, B. pumilus, B. schlegelii, B. sphaericus, B. sporothermodurans, B. stearothermophilus, B. subtilis, B.
  • thermoglucosidasius B. thuringiensis, B. vulgatis, and B. weihenstephanensis.
  • Bacillus infection is a B. subtilis infection.
  • the bacteria is a member of the phylum Firmicutes and the genus Strepococcus, i.e., the bacterial infection is a Strepococcus infection.
  • Strepococcus bacteria include, but are not limited to, S. agalactiae, S. anginosus, S. bovis, S. canis, S. constellatus, S. dysgalactiae, S. equinus, S. iniae, S. intermedius, S. mitis, S. mutans, S. oralis, S. parasanguinis, S. peroris, S. pneumoniae, S. pyogenes, S. ratti, S. salivarius, S. thermophilus, S. sanguinis, S. sobrinus, S. suis, S. uberis, S. vestibularis, S. viridans, and S. zooepidemicus.
  • the Strepococcus infection is an S. pyogenes infection. In certain embodiments, the Strepococcus infection is an S. pneumoniae infection. [00326] In certain embodiments, the bacterial infection is an infection with a Gram negative bacteria.
  • the Gram negtive bacteria is a bacteria of the phylum Proteobacteria and the genus Escherichia, i.e., the bacterial infection is an Escherichia infection.
  • Exemplary Escherichia bacteria include, but are not limited to, E. albertii, E. blattae, E. coli, E. fergusonii, E. hermannii, and E. vulneris.
  • the Escherichia infection is an E. coli infection.
  • the Gram negtive bacteria is a bacteria of the phylum Proteobacteria and the genus Haemophilus, i.e., the bacterial infection is an Haemophilus infection.
  • Exemplary Haemophilus bacteria include, but are not limited to, H. aegyptius, H. aphrophilus, H. avium, H. ducreyi, H. felis, H. haemolyticus, H. influenzae, H.
  • the Escherichia infection is an H. influenzae infection.
  • the bacterial infection is resistant to other antibiotic therapy.
  • the bacterial infection is vancomycin resistant (VR).
  • the bacterial infection is a methicillin-resistant (MR).
  • the bacterial infection is a methicillin-resistant S. aureus (MRSA) infection.
  • a method of treating bacterial infection and/or virulence including the treatment of bacteria or infection caused by bacteria that are resistent to other treatments, are multi-drug tolerant or resistent and/or that neither grow nor die in the presence of or as a result of other treatments.
  • Such a method can be conducted in vivo (i.e., by administration to a subject) or in vitro (e.g., upon contact with bacteria in a cell culture).
  • a method of treating bacterial virulence comprising administering an effective amount of a compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof, to a subject with a bacterial infection.
  • the compound blocks virulence factor production.
  • a compound of Formula (I) or (II) or pharmaceutically acceptable salt thereof may inhibit the growth of or kill rapidly dividing cells such as stimulated inflammatory cells.
  • methods of treating a disease, disorder, or condition associated with abnormal cellular proliferation such as cancer, autoimmune diseases, inflammatory diseases, and diabetic retinopathy.
  • a method of treating cancer comprising administering an effective amount of a compound of Formula (I) or (II) or pharmaceutically acceptable salt thereof to a subject.
  • a method of treating an autoimmune disease comprising administering an effective amount of a compound of Formula (I) or (II) or pharmaceutically acceptable salt thereof to a subject.
  • a method of treating an inflammatory disease comprising administering a compound of Formula (I) or (II) or pharmaceutically acceptable salt thereof to a subject.
  • a method of treating diabetic retinopathy comprising administering an effective amount of a compound of Formula (I) or (II) or pharmaceutically acceptable salt thereof to a subject.
  • compositions provided herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease, disorder, or condition being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.
  • the compounds and compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops), mucosal, nasal, bucal, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation; and/or as an oral spray, nasal spray, and/or aerosol.
  • enteral e.g., oral
  • parenteral intravenous
  • intramuscular intra-arterial
  • intramedullary intrathecal
  • subcutaneous intraventricular
  • transdermal transdermal
  • interdermal interdermal
  • rectal intravaginal
  • topical as by powders, ointments, creams, and/or drops
  • the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g. , its stability in the environment of the gastrointestinal tract), the condition of the subject (e.g., whether the subject is able to tolerate oral administration), etc.
  • the exact amount of a compound required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound(s), mode of administration, and the like.
  • the desired dosage can be delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks.
  • the desired dosage can be delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).
  • an effective amount of a compound for administration one or more times a day to a 70 kg adult human may comprise about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1 mg to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about 1000 mg, or about 100 mg to about 1000 mg, of a compound per unit dosage form.
  • the compound may be administered orally or parenterally at dosage levels sufficient to deliver from about 0.001 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, preferably from about 0.1 mg/kg to about 40 mg/kg, preferably from about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, and more preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
  • dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult.
  • the amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.
  • compositions as described herein, can be administered in combination with one or more additional therapeutically active agents.
  • additional therapeutically active agents can be administered in combination with additional therapeutically active agents.
  • the compounds or compositions can be administered in combination with additional therapeutically active agents.
  • therapeutically active agents that improve and/or potentiate their bioavailability, reduce and/or modify their metabolism, inhibit their excretion, and/or modify their distribution within the body. It will also be appreciated that the therapy employed may achieve a desired effect for the same disorder, and/or it may achieve different effects.
  • the compound of Formula (I) or (II) or pharmaceutically acceptable salt thereof or composition can be administered concurrently with, prior to, or subsequent to, one or more additional therapeutically active agents.
  • each agent will be administered at a dose and/or on a time schedule determined for that agent.
  • the additional therapeutically active agent utilized in this combination can be administered together in a single composition or administered separately in different compositions.
  • the particular combination to employ in a regimen will take into account compatibility of the active ingredient with the additional therapeutically active agent and/or the desired therapeutic effect to be achieved.
  • additional therapeutically active agents utilized in combination be utilized at levels that do not exceed the levels at which they are utilized individually.
  • Exemplary additional therapeutically active agents include, but are not limited to, antibiotics, anti-viral agents, anesthetics, anti-coagulants, inhibitors of an enzyme, steroidal agents, steroidal or non-steroidal anti-inflammatory agents, antihistamine,
  • immunosuppressant agents antigens, vaccines, antibodies, decongestant, sedatives, opioids, pain-relieving agents, analgesics, anti-pyretics, hormones, and prostaglandins, etc.
  • Therapeutically active agents include small organic molecules such as drug compounds (e.g. , compounds approved by the US Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides,
  • drug compounds e.g. , compounds approved by the US Food and Drug Administration as provided in the Code of Federal Regulations (CFR)
  • CFR Code of Federal Regulations
  • oligosaccharides polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins and cells.
  • the additional therapeutically agent is an anti-bacterial agent (an antibiotic).
  • antibiotics include, but are not limited to, penicillins (e.g., penicillin, amoxicillin), cephalosporins (e.g. , cephalexin), macrolides (e.g. , erythromycin, clarithormycin, azithromycin, troleandomycin), fluoroquinolones (e.g. , ciprofloxacin, levofloxacin, ofloxacin), sulfonamides (e.g. , co-trimoxazole, trimethoprim), tetracyclines (e.g.
  • tetracycline chlortetracycline, oxytetracycline, demeclocycline, methacycline, sancycline, doxycline, aureomycin, terramycin, minocycline, 6-deoxytetracycline, lymecycline, meclocycline, methacycline, rolitetracycline, and glycylcycline antibiotics (e.g., tigecycline)), aminoglycosides (e.g., gentamicin, tobramycin, paromomycin), aminocyclitol (e.g., spectinomycin), chloramphenicol, sparsomycin, quinupristin/dalfoprisin (SyndercidTM), reserpine, or an enopeptin (e.g., ADEP4).
  • aminoglycosides e.g., gentamicin, tobramycin, paromomycin
  • the antibiotic is a ribosome-targeting antibiotic.
  • Antibiotics target ribosomes at distinct locations within functionally relevant sites. They exert their inhibitory action by diverse modes, including competing with substrate binding, interfering with ribosomal dynamics, minimizing ribosomal mobility, facilitating miscoding, hampering the progression of the mRNA chain, and blocking the nascent protein exit tunnel.
  • antibiotics that reveal novel ribosomal properties or enforced otherwise observed findings include the following: decoding (paromomycin); mRNA progression (spectinomycin); A-site binding to the small (tetracycline antibiotic) and the large (chloramphenicol) subunits; PTC mobility (sparsomycin); tRNA rotatory motion (quinupristin/dalfoprisin), and tunnel gating (troleandomycin); see, e.g., Yonath, Annu. Rev. Biochem. (2005) 74:649-679.
  • the ribosome-targeting antibiotic is a tetracycline antibiotic.
  • tetracycline antibiotics include, but are not limited to, tetracycline, chlortetracycline, oxytetracycline, demeclocycline, methacycline, sancycline, doxycline, aureomycin, terramycin, minocycline, 6-deoxytetracycline, lymecycline, meclocycline, methacycline, rolitetracycline, and glycylcycline antibiotics (e.g., tigecycline).
  • Example 1 A Fragment-Based Strategy for Investigating and Suppressing the Efflux of Bioactive Small Molecules
  • Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus, and Mycobacterium tuberculosis can be ascribed to genes encoding these proteins.
  • 3 ' 4 ' 8 ' 9 ' 11 Remarkably, some efflux pumps exhibit high specificity for a particular molecule, while others act upon molecules of disparate structural classes. 1 ' 5 ' 7 ' 12 16 Those in the latter category underly a worrisome phenomenon wherein the acquisition of a single gene renders a tumor or pathogen multi-drug resistant.
  • S. coelicolor was selected because it is a non-pathogenic relative of M. tuberculosis and the ADEP resistance of streptomycetes has likewise been linked to efflux pumps.
  • 46 N-E- 2-heptenoyldifluorophenylalanine methyl ester (3) (i.e., the ADEP side chain moiety) potentiated the activity of ADEP against S. coelicolor in a dose- dependent fashion.
  • ADEP fragments such as the peptidolactone (2), the peptidolactone with a truncated side chain (5), or simply the N- acetyl difluorophenylalanine methyl ester (4) did not display any efficacy as ADEP potentiators.
  • tuberculosis by reserpine was lower than that reported by Parrish and co-workers (2.5-fold), 34 the design principle that yielded compound 14 and its superior efficacy as a potentiator of ADEP activity are truly noteworthy and bode well for the use of ADEPs in treating tuberculosis.
  • Streptomyces coelicolor M145 was grown at 30 °C on mannitol soya flour medium (SFM), Difco nutrient agar medium (DNA), Tryptone Soya Broth (TSB), yeast extract-malt extract medium (YEME), or minimal liquid medium (NMMP).
  • SFM mannitol soya flour medium
  • DNA Difco nutrient agar medium
  • TLB Tryptone Soya Broth
  • YEME yeast extract-malt extract medium
  • NMMP minimal liquid medium
  • Mycobacterium smegmatis MC2155 was grown in Luria-Bertani medium supplemented with 0.2% (v/v) glycerol at 37 °C.
  • Mycobacterium tuberculosis H37Rv was maintained in Middlebrook 7H9 broth supplemented with 0.2% (v/v) glycerol, 0.05% Tween 80, and 10% (v/v) oleic acid-albumin-dextrose-catalase.
  • MIC assays S. coelicolor M145 MIC assays were performed on Difco nutrient agar medium supplemented with the indicated concentrations of compound. Growth was assessed after incubation at 30°C for 48 h. The lowest drug concentration that inhibited >90% growth was considered to be the MIC. All experiments were performed in triplicate,
  • Mycobacterium smegmatis MIC assays were performed on Difco nutrient agar medium supplemented with 0.2% glycerol and the indicated concentrations of compound. Growth was assessed after incubation at 30°C for 72 h. The lowest drug concentration that inhibited >90% growth was considered to be the MIC. All experiments were performed in triplicate.
  • Flamme E Sangalang J, She M, Yen R, Gannon C, Griffith D, Chamberland S, Lomovskaya O, Hecker S, Lee V, Ohta T, Nakayama K. J Med Chem.
  • fragments 6A and 3 exhibited antibacterial activity, albeit with much lower potency than intact ADEP ( Figure 4).
  • the N-acyldifluorophenylalanine moiety is necessary and sufficient for antibacterial activity.
  • fragment 6A which has an acyclic portion of the ADEP peptidolactone, is less active than fragment 3, which is composed only of the N- acyldifluorophenylalanine moiety.
  • fragment 6A kills Mycobacterium tuberculosis (Mtb) with an MIC of about 25 ug/mL. This compares quite favorably to ADEP (compound 1) which has an Mtb MIC of about 150 ug/mL.
  • ADEP compound 1
  • Mtb Mycobacterium tuberculosis
  • S6 substitution of the serine in 6A with either ⁇ /to-threonine (6B) or threonine (6C) ( Figure 6) would yield more rigid and bioactive fragments.
  • ADEPs and N-acyldifluorophenylalanine fragments have the same mechanism of killing bacteria in a series of genetic and biochemical experiments.
  • an ADEP (1) and fragments 6A and 3 were tested for antibacterial activity against two engineered strains of B. subtilis- a spx null strain (AG 1927 spxv.neo) and a strain lacking both spx and clpP (AG 1246 spxv.neo and clpP::cat).
  • the clpP-spx null strain was selected because the spx null mutation suppresses the slow growth defect exhibited by a B.
  • subtilis strain lacking clpP lacking clpP.
  • S7 The spx null and wild-type strains of B. subtilis, both of which contain a functional ClpP, were equally susceptible to each of the three compounds. Importantly, neither intact ADEP nor fragments 6A and 3 were toxic to the spx-clpP null strain (MIC > 128 ⁇ g/mL). The essentiality of a functional clpP gene for the toxicity of both compounds indicates that the fragments share the same mechanism as the ADEPs.
  • N-acyldifluorophenylalanine moiety is highly amenable to structural elaboration as it possesses a reactive carboxylate functionality that can be easily coupled to a wide array of scaffolds and rapidly diversified. Work to develop more potent antibacterial agents using this strategy is underway in these laboratories.
  • Glyl27 is located in the equatorial interface between ClpP heptamers and is adjacent to the substrate-binding site. Mutation to valine may result in loss of ClpP function by decreasing oligomer stability and may sterically interfere with substrate binding. Finally, two of the mutants resistant to the ADEP and one of the mutants resistant to compound 3 did not harbor mutations in their clpP loci. It is possible that these resistant strains harbor mutations in proteins that perturb clpP expression.
  • subtillis mutants 5 mL liquid cultures (LB broth) were inoculated with a single colony of B. subtillis. After 4 hours of growth ( ⁇ ⁇ 0.4) ⁇ of culture were plated on LB Agar plates containing either compound 1 (1 ⁇ g/mL) or compound 17 (100 ⁇ g/mL). A dilution series was also carried out to determine colony-forming unit count. After 24 hours of growth, the resistant colonies were placed into fresh LB Broth maintaining selection for resistance by adding compound 1 or compound 17 at the same compound concentration. After 5 hours of growth, 3 mL fresh LB Broth cultures containing double the concentration of compound were inoculated with 1% of 5 h culture.
  • gDNA total genomic DNA
  • Qiagen blood and tissue purification kit following manufacturer's protocol for bacterial cells. DNA concentrations were measured using a NanoDrop ND-1000 spectrophotometer [00380]
  • the isolated gDNA was subjected to PCR to amplify the clpP locus with 250 base pairs (bp) upstream and 250 bp downstream. PCRs were performed with Pfu polymerase enzyme according to the manufacturer's protocol. An equal quantity of total gDNA was employed in all PCRs. A 1094 bp band corresponding to the clpP locus was obtained.
  • the PCR program used to amplify the clpP locus was 94°C for 2 min, 30 cycles of 94 °C for 45 s, 57 °C for 45 s, and 72 °C for 60 s, and a final elongation at 72 °C for 10 min.
  • the ClpP coding region was amplified by PCR from Bacillus subtilis strain 168 genomic DNA (ATCC) and cloned into plasmid pET-22b (EMD Millipore) in frame with a C-terminal 6xHis tag. ClpP was overexpressed in the clpP ' E. coli strain JK10 (J. Kenniston, T. A. Baker, R. Sauer. PNAS, 2005, 102, 1390-1395) at room temperature for 5 h, following induction with 0.5 mM isopropyl ⁇ -D-l-thiogalactopyranoside. ClpP was purified from clarified lysates by metal affinity (Ni-NTA; Thermo), anion exchange (MonoQ; GE
  • Activation assays were performed at 30°C in 25 mM HEPES pH 7.5, 5 mM MgCl 2 , 100 mM KC1, 10% glycerol, 1 mM DTT, 0.1 mM EDTA.
  • ClpP was incubated with various concentrations of ADEP or fragment and an internally quenched fluorogenic peptide substrate incorporating a 2-aminobenzoic acid (Abz) fluorophore and 3-nitrotyrosine ( ⁇ ⁇ ° 2 ) quencher.
  • Abz 2-aminobenzoic acid
  • ⁇ ⁇ ° 2 3-nitrotyrosine
  • Fragment activation assays incorporated 25 nM ClpP and the substrate Abz-DFAPKMALVPY N ° 2 (SEQ ID NO: 8). Hydrolysis of fluorogenic peptides was followed by the increase in 420 nm fluorescence upon 320 nm excitation in a SpectraMax M5 microplate reader (Molecular Devices).
  • the N-acyldifluorophenylalanine - Biotin conjugate was mixed with avidin- agarose beads for 30 minutes. Following incubation, the agarose beads with N- acyldifluorophenylalanine bound were added to the cell lysates and incubated on a nutating shaker for lh at RT. Controls in which no N-acyldifluorophenylalanine - Biotin conjugate was added were carried out in parallel. The beads were washed 3x with PBS and the supernatant was combined and saved. Next, the beads were washed twice with free N- acyldifluorophenylalanine in PBS and the supernatant collected and saved.
  • identifications to 1% FDR.
  • trypsin specificity with two missed cleavage sites was allowed and the MS mass tolerance was 7 ppm while the MS-MS tolerance was 0.5 Daltons.
  • Identifications were contingent on at least one unique peptide spectrum match (PSM) in the molecular weight search with a protein score cut-off of 32.8. Proteins that were nonspecifically eluted from the beads with PBS washes and proteins that were eluted from the no ZV-acyldifluorophenylalanine controls were subtracted from the compound washes, resulting in a list of specific binders.
  • PSM unique peptide spectrum match
  • Cbz ADEP peptidolactone (58 mg, 0.10 mmol) was dissolved in MeOH (1 mL) and treated with 10% Pd/C (13 mg) and 1 M HC1 (0.10 mL). The reaction flask was sealed with a septum through which H 2 was delivered from a balloon. Upon complete conversion of the starting material, the reaction was filtered through celite, rinsing with methanol. The crude product was then concentrated and subsequently dissolved in DCM (0.33 mL) and treated with acetic anhydride (20 ⁇ , 0.20 mmol) and triethylamine (28 ⁇ , .20 mmol).
  • Cbz ADEP peptidolactone (58 mg, 0.10 mmol) was dissolved in MeOH (1 mL) and treated with 10% Pd/C (13 mg) and 1 M HC1 (0.10 mL). The reaction flask was sealed with a septum through which H 2 was delivered from a balloon. Upon complete conversion of the starting material, the reaction was filtered through celite, rinsing with methanol. The crude product was then concentrated and subsequently dissolved in DMF (0.33 mL) and combined with Boc-3,5-difluorophenylalanine.
  • reaction solution was treated with HATU (38 mg, 0.10 mmol) and DIPEA (35 ⁇ L, 0.20 mmol) and allowed to react over night.
  • the reaction was then diluted with ethyl acetate (3 mL) and extracted: 3x 1M HC1, 3x sat NaHC0 3 , lx brine, and then dried over sodium sulfate. After removal of the solvent, the crude Boc-3,5-difluorophenylalanyl ADEP peptidolactone was used without further purification.
  • N-Cbz amino acid methyl ester (1 equivalent) and Boc proline (1.1 equivalent) were dissolved in DCM at a concentration of 0.2 M with respect to the N-Cbz amino acid.
  • the solution was treated with DMAP (0.1 equivalents) and EDC-HCl (1.5-2.0 equivalents), which was added in portions until the staring material was completely consumed (monitoring with TLC 1: 1 EtOAc/Hexanes). After 24 hours the reaction was concentrated in vacuo and then diluted with ethyl acetate (50 mL).
  • the ethyl acetate solution was extracted 3 x 1M HCl aq , 3 x saturated NaHC0 3aq , and 1 x Brine then dried over sodium sulfate.
  • the proline ester products were isolated by silica gel chromatography using a 30-50% ethyl acetate in hexanes solvent gradient.
  • Boc-proline esters (1 equivalent) were deprotected by treatment with 40% TFA in DCM. Upon complete conversion of the starting material, the reaction was concentrated first by blowing with a stream of nitrogen and then by placing the residue under high vacuum. Once dry, the residue was dissolved in DCM to a concentration of 0.2 M and treated with triethylamine (2 equivalents) and acetic anhydride (2 equivalents). The reactions were allowed to proceed for 16 hours after which the solvent was removed in vacuo. The N-acetyl proline esters were isolated by silica gel chromatography 100% ethyl acetate.
  • Cbz removal The CBZ protected proline ester was dissolved in methanol at a concentration of 0.14 M. Once the solution was homogeneous, 10% Pd/C (130 mg / mmol peptidolactone) was added followed by 1M HC1 (1 equivalent with respect to proline ester). With the reaction flask septum sealed, hydrogen gas was delivered to the reaction by a balloon affixed to a syringe. The reaction was allowed to proceed for 90 minutes after which it was filtered through celite in order to remove the Pd/C. Removal of solvent revealed the proline hydrochloride salt as an off white foam, which is used without further purification.
  • Boc-DifluoroPhe acylation The proline ester hydrochloride salt was dissolved in DMF at a concentration of 0.25 M. Once the solution was homogeneous, Boc- difluorophenylalanine (1.1 equivalents) was added followed by HATU (1.1 equivalents). The reaction was initiated by the addition of DIPEA (2.2 equivalents) and allowed to proceed for 2 hours. After the reaction, the DMF solution was diluted -10 x the reaction volume with ethyl acetate, and extracted 3x 1M HC1, 3x saturated NaHC0 3 , lx brine, then dried over sodium sulfate.
  • Boc-difluorophenylalanine acylated proline esters were isolated by silica gel chromatography using an ethyl acetate / acetone solvent gradient. Final removal of the solvent revealed a fine white powder, which was used without further purification.
  • Boc group removal The Boc-difluorophenylalanyl proline esters were treated with 40% TFA in DCM at a concentration of 0.3 M. Upon complete conversion of the starting material, the reaction was concentrated by blowing with a stream of nitrogen then by evaporation under high vacuum. The deprotected product was used without further purification.
  • E-2-Heptenoate Coupling The difluorophenylalanyl proline ester TFA salts were dissolved in DMF at a concentration of 0.2 M. Once the solution was homogeneous, E-2- heptenoic acid (1.1 equivalents) was dissolved in DMF at a concentration of 0.2 M. The acid was then treated with HATU (1.1 equivalents) and DIPEA (1.1 equivalents) and allowed to stir for 15 minutes. The preactivated acid was then added to a solution of the
  • a Boc-amino acid (1 equivalent) and either 7 M ammonia in methanol (1 equivalent), 2 M methyl amine in methanol (1 equivalent), or dimethylamine hydrochloride (1 equivalent) were dissolved in dichloromethane at a concentration of 0.1 M with respect to the Boc-amino acid.
  • the solution was then treated with EDC (1.1 equivalents), HOBt (1.1 equivalents), and TEA (1.1 equicalents for free base amines, 2.1 equivalents for dimethyl amine HC1).
  • the coupling reactions were allowed to run over night after which solvent was removed and the residue was diluted in ethyl acetate to twice the original reaction volume.
  • the ethyl acetate solution was extracted 3x 1M HC1, 3x sat NaHC03, lx brine, and then dried over sodium sulfate.
  • the concentrated crude Boc-amino amides were advanced without further purification.

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Abstract

L'invention concerne des analogues d'enopeptine répondant à la Formule (I) ou (II) : et des sels pharmaceutiquement acceptables de ceux-ci, et des compositions pharmaceutiques de ceux-ci, dans laquelle R1, R2, R3, R4, R5, R6, m, X, RXa et Y sont tels que définis aux présentes. Ces composés ont montré une activité antibactérienne, interfèrent de façon concurrentielle avec la pompe à efflux bactérien, et/ou potentialisent les activités d'autres agents antibactériens, tel qu'un ADEP4, contre des bactéries qui ne sont pas sensibles du fait des pompes d'efflux. L'invention concerne en outre des méthodes de traitement et des procédés d'utilisation de tels composés.
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