WO2015061467A1 - Lipid formulations for delivery of messenger rna - Google Patents

Lipid formulations for delivery of messenger rna Download PDF

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Publication number
WO2015061467A1
WO2015061467A1 PCT/US2014/061793 US2014061793W WO2015061467A1 WO 2015061467 A1 WO2015061467 A1 WO 2015061467A1 US 2014061793 W US2014061793 W US 2014061793W WO 2015061467 A1 WO2015061467 A1 WO 2015061467A1
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optionally substituted
alkyl
alkynyl
alkenyl
group
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English (en)
French (fr)
Inventor
Michael Heartlein
Daniel Anderson
Yizhou Dong
Frank Derosa
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Shire Human Genetics Therapies Inc
Massachusetts Institute of Technology
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Shire Human Genetics Therapies Inc
Massachusetts Institute of Technology
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Priority to BR112016009077A priority Critical patent/BR112016009077A2/pt
Priority to NZ718817A priority patent/NZ718817A/en
Priority to KR1020167012277A priority patent/KR101988552B1/ko
Priority to MX2016005238A priority patent/MX2016005238A/es
Priority to CA2928078A priority patent/CA2928078C/en
Priority to KR1020197016134A priority patent/KR102096796B1/ko
Priority to EA201690576A priority patent/EA201690576A1/ru
Priority to CN201480063947.5A priority patent/CN105813656B/zh
Priority to EP21158237.4A priority patent/EP3871696B1/en
Priority to AU2014340155A priority patent/AU2014340155B2/en
Priority to EP14792713.1A priority patent/EP3060257B1/en
Priority to JP2016526008A priority patent/JP6525435B2/ja
Application filed by Shire Human Genetics Therapies Inc, Massachusetts Institute of Technology filed Critical Shire Human Genetics Therapies Inc
Priority to SG11201602943PA priority patent/SG11201602943PA/en
Priority to ES14792713T priority patent/ES2865699T3/es
Publication of WO2015061467A1 publication Critical patent/WO2015061467A1/en
Priority to IL245030A priority patent/IL245030A0/en
Anticipated expiration legal-status Critical
Priority to AU2019200474A priority patent/AU2019200474B2/en
Priority to AU2021200980A priority patent/AU2021200980B2/en
Priority to AU2023206132A priority patent/AU2023206132A1/en
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers
    • A61K9/1272—Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers comprising non-phosphatidyl surfactants as bilayer-forming substances, e.g. cationic lipids or non-phosphatidyl liposomes coated or grafted with polymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/482—Serine endopeptidases (3.4.21)
    • A61K38/4846—Factor VII (3.4.21.21); Factor IX (3.4.21.22); Factor Xa (3.4.21.6); Factor XI (3.4.21.27); Factor XII (3.4.21.38)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/53—Ligases (6)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A61K48/0008—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition
    • A61K48/0025—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition wherein the non-active part clearly interacts with the delivered nucleic acid
    • A61K48/0033—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition wherein the non-active part clearly interacts with the delivered nucleic acid the non-active part being non-polymeric
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A61K48/005—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy

Definitions

  • RNA interference has been the subject of significant research and clinical development. While RNAi, such as short interfering RNA (siRNA), may have therapeutic potential, it is of little use in treating diseases involving deficiency of one or more proteins, messenger RNA (mRNA) therapy has become an increasingly important option for treatment of various diseases, in particular, for those associated with deficiency of one or more proteins.
  • siRNA short interfering RNA
  • mRNA messenger RNA
  • the present invention provides improved methods and compositions for highly efficient delivery and expression of mRNA and encoded protein in vivo.
  • the invention is based, in part, on the surprising discovery that liposomes based on a particular class of cationic lipids, such as, those having a structure of formula I-c described herein, are unexpectedly effective in delivering mRNA and producing encoded protein in vivo, more effective even as compared to those cationic lipids that were considered to be among the best in delivering mRNA in the prior art.
  • cationic lipids have been extensively explored as an important component of liposomes typically used to encapsulate nucleic acids including mRNA for in vivo delivery.
  • cationic lipids used in the liposomes typically play two roles. First, cationic lipids promote interaction with negatively charged mRNA during encapsulation, circulation and endocytosis, thereby capturing and protecting the mRNA. Then, once inside cytosol, cationic lipids need to be able to release the mRNA so that the mRNA can be translated to produce encoded protein. Some cationic lipids, in particular, those known as titratable cationic lipids are particularly effective in delivering mRNA. One example of such cationic lipids known to be capable of efficient delivery of mRNA is CI 2-200.
  • cationic lipids described herein can be even more effective in delivering various mRNA in vivo, than those best known in the prior art including C 12-200.
  • liposome particles incorporating a cationic lipid described herein e.g., cK -E12
  • cK -E12 a cationic lipid described herein
  • the plasma residence time of different proteins expressed from mRNA delivered by cKK-E12 based liposomes is sustained up to 7 days or longer post a single administration.
  • this class of cationic lipids having a structure of formula I-c described herein can be uniquely useful in delivering mRNA for highly efficient and sustained production of protein (e.g., therapeutic protein) in vivo.
  • the present invention therefore permits an improved mRNA therapy that can significantly reduce required amount of mRNA and associated lipids, administration frequency, and possible side effects, providing more potent, safer, and patient friendly mRNA therapy for various diseases.
  • the present invention provides methods of delivering messenger
  • RNA (mRNA) in vivo including administering to a subject in need of delivery a composition comprising an mRNA encoding a protein, encapsulated within a liposome such that the administering of the composition results in the expression of the protein encoded by the mRNA in vivo, wherein the liposome comprises a cationic lipid of formula I-c:
  • p is an integer of between 1 and 9, inclusive; each instance of R 2 is independently hydrogen or optionally substituted Ci_ 6 alkyl; each instance of R 6 and R 7 is independently a group of the formula (i), (ii), or (iii); Formulae (i), (ii), and (iii) are:
  • each instance of R' is independently hydrogen or optionally substituted alkyl
  • R P is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted
  • heterocyclyl optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, or a nitrogen protecting group when attached to a nitrogen atom;
  • R L is optionally substituted Ci_ 5 o alkyl, optionally substituted C 2 -50 alkenyl, optionally substituted C 2 -50 alkynyl, optionally substituted heteroCi_so alkyl, optionally substituted heteroC2-5o alkenyl, optionally substituted heteroC2-so alkynyl, or a polymer.
  • the present invention provides methods of treating a disease or disorder including administering to subject in need of treatment a composition comprising an mRNA encoding a therapeutic protein encapsulated within a liposome such that the
  • administering of the composition results in the expression of the protein encoded by the mRNA in one or more tissues affected by the disease or disorder, wherein the liposome comprises a cationic lipid having a structure of formula I-c.
  • the present invention provides compositions for delivery of messenger RNA (mRNA) comprising an mRNA encoding a protein encapsulated within a liposome, wherein the liposome comprises a cationic lipid having a structure of formula I-c.
  • mRNA messenger RNA
  • a suitable cationic lipid is cK -E12:
  • a suitable liposome further comprises one or more non- cationic lipids, one or more cholesterol-based lipids and/or one or more PEG-modified lipids.
  • the one or more non-cationic lipids are selected from
  • DSPC distearoylphosphatidylcholine
  • DOPC dioleoylphosphatidylcholine
  • DPPC dipalmitoylphosphatidylcholine
  • DOPG dioleoylphosphatidylglycerol
  • dipalmitoylphosphatidylglycerol DPPG
  • dioleoylphosphatidylethanolamine DOPE
  • palmitoyloleoylphosphatidylcholine POPC
  • palmitoyloleoyl-phosphatidylethanolamine POPE
  • dipalmitoyl phosphatidyl ethanolamine DPPE
  • dimyristoylphosphoethanolamine DMPE
  • distearoyl-phosphatidyl-ethanolamine DSPE
  • 16-O-monomethyl PE 16-O-dimethyl PE
  • 18-1 -trans PE l-stearoyl-2-oleoyl-phosphatidyethanolamine
  • SOPE l-stearoyl-2-oleoyl-phosphatidyethanolamine
  • a suitable liposome further comprises one or more cholesterol-based lipids.
  • the one or more cholesterol-based lipids are selected from cholesterol, PEGylated cholesterol and DC-Choi (N,N-dimethyl-N- ethylcarboxamidocholesterol), l,4-bis(3-N-oleylamino-propyl)piperazine.
  • a suitable liposome further comprises one or more PEG- modified lipids.
  • the one or more PEG-modified lipids comprise a poly(ethylene) glycol chain of up to 5 kDa in length covalently attached to a lipid with alkyl chain(s) of C 6 -C 2 o length.
  • a PEG-modified lipid is a derivatized ceramide such as N-Octanoyl-Sphingosine-l-[Succinyl(Methoxy Polyethylene Glycol)-2000].
  • a PEG-modified or PEGylated lipid is PEGylated cholesterol or
  • DMG Dimyristoylglycerol
  • a suitable liposome comprises cK -E12, DOPE, cholesterol and DMG-PEG2K.
  • the cationic lipid (e.g., cK -E12) constitutes about 30-50
  • the cationic lipid e.g., cK -E12
  • the cationic lipid constitutes about 30%), about 35%, about 40 %, about 45%, or about 50%> of the liposome by molar ratio.
  • PEG2K is approximately 40:30:20: 10 by molar ratio. In particular embodiments, the ratio of cK -E12:DOPE:cholesterol:DMG-PEG2K is approximately 40:30:25:5 by molar ratio. In particular embodiments, the ratio of cK -E12:DOPE:cholesterol:DMG-PEG2K is approximately 40:32:25:3 by molar ratio.
  • a suitable liposome has a size of or less than about 500nm
  • a composition according to the invention is administered intravenously.
  • a composition according to the invention is administered via pulmonary delivery.
  • the pulmonary delivery is by aerosolization, inhalation, nebulization or instillation.
  • a composition according to the invention is administered intrathecally.
  • the composition is formulated as respirable particles, nebulizable lipid, or inhalable dry powder.
  • the expression of the protein encoded by the mRNA is detectable in liver, kidney, heart, spleen, serum, brain, skeletal muscle, lymph nodes, skin, and/or cerebrospinal fluid.
  • the expression of the protein encoded by the mRNA is detectable 6, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66, and/or 72 hours after the administration. In some embodiments, the expression of the protein encoded by the mRNA is detectable 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, and/or 7 days after the administration. In some embodiments, the expression of the protein encoded by the mRNA is detectable 1 week, 2 weeks, 3 weeks, and/or 4 weeks after the administration. In some embodiments, the expression of the protein encoded by the mRNA is detectable after a month after the administration.
  • the protein encoded by the mRNA is a cytosolic protein.
  • the protein encoded by the mRNA is a secreted protein. In some embodiments, the protein encoded by the mRNA is an enzyme. In some embodiments, the mRNA has a length of or greater than about 0.5kb, 1 kb, 1.5 kb, 2 kb, 2.5 kb, 3 kb, 3.5 kb, 4 kb, 4.5 kb, or 5 kb. In some embodiments, the protein encoded by the mRNA is Argininosuccinate Synthetase (ASS1), Factor IX, survival of motor neuron 1, or phenylalanine hydroxylase.
  • ASS1 Argininosuccinate Synthetase
  • Factor IX survival of motor neuron 1, or phenylalanine hydroxylase.
  • the mRNA is administered at a dose ranging from about
  • 0.1 - 5.0 mg /kg body weight for example about 0.1 - 4.5, 0.1 - 4.0, 0.1 - 3.5, 0.1 - 3.0, 0.1 - 2.5, 0.1 - 2.0, 0.1 - 1.5, 0.1 - 1.0, 0.1 - 0.5, 0.1 - 0.3, 0.3 - 5.0, 0.3 - 4.5, 0.3 - 4.0, 0.3 - 3.5, 0.3
  • the mRNA is administered at a dose of or less than about 5.0, 4.5, 4.0, 3.5, 3.0, 2.5, 2.0, 1.5, 1.0, 0.8, 0.6, 0.5, 0.4, 0.3, 0.2, or 0.1 mg/kg body weight.
  • the mRNA comprises one or more modified nucleotides.
  • the one or more modified nucleotides comprise pseudouridine, N-l- methyl-pseudouridine, 2-aminoadenosine, 2-thiothymidine, inosine, pyrrolo-pyrimidine, 3- methyl adenosine, 5-methylcytidine, C-5 propynyl-cytidine, C-5 propynyl-uridine, 2- aminoadenosine, C5-bromouridine, C5-fluorouridine, C5-iodouridine, C5-propynyl-uridine, C5- propynyl-cytidine, C5-methylcytidine, 2-aminoadenosine, 7-deazaadenosine, 7-deazaguanosine, 8-oxoadenosine, 8-oxoguanosine, 0(6)-methylguanine, and/or 2-thiocytidine.
  • Figure 1 shows an exemplary graph of the levels of human factor IX (FIX) detected in the serum of treated mice 24 hours after administration of CI 2-200 or cK -E12 liposomes containing FIX mRNA.
  • FIX human factor IX
  • Figure 2 shows an exemplary graph of FIX detected in the plasma of mice treated with 0.1, 0.3, 0.6, 1.0, or 3.0 mg/kg of one of two ratios of FIX mRNA containing cK -E12 liposomes either 6 or 24 hours after administration.
  • Figure 3 shows an exemplary graph of the level of ASSl protein detected in the livers of mice treated with 0.1, 0.3, 0.6, 1.0, or 3.0 mg/kg of ASSl mRNA-containing cK -E12 liposomes 24 hours after administration.
  • Figure 4 shows exemplary western blot analyses of ASSl protein levels in the liver 24 hours post administration of 0.1, 0.3, 0.6, 1.0, or 3.0 mg/kg of cK -E12 liposomes containing ASSl mRNA.
  • Figure 5 shows an exemplary graph of ASSl protein levels in the liver of mice
  • ASSl mRNA containing cK -E12 liposomes (1 mg/kg). Also shown is the level of ASSl protein 7 days after administration.
  • Figure 6 shows exemplary western blot analyses of ASSl protein levels in the liver 0.5, 3, 6, 12, 24, 48, 72 hours after a single IV injection of lmg/kg ASSl mRNA containing cK -E12 liposomes. Also shown is the level of ASSl protein 7 days after administration.
  • Figure 7 - shows detection of human ASSl messenger RNA via in situ hybridization in the livers of treated mice. Exogenous mRNA is observable for at least 72 hr post-administration after a single dose (1.0 mg/kg) of ASSl mRNA-loaded MDl-based lipid nanoparticles. Human ASSl mRNA is detectable in sinusoidal cells as well as hepatocytes.
  • Figure 8 - shows exemplary immunohistochemical staining of ASSl protein levels in mouse liver 24 hours after administration of 1 mg/kg ASSl mRNA containing cK - E12 lipid nanoparticles.
  • Human ASSl protein is detectable in sinusoidal cells as well as hepatocytes.
  • Figure 9 shows low magnification (4x) immunohistochemical staining of ASSl protein levels in mouse liver 24 hours after administration of 1 mg/kg ASSl mRNA containing cK -E12 liposomes.
  • a comparison to untreated mouse liver (left) demonstrates the widespread distribution of human ASSl protein throughout the liver.
  • Figure 10 shows exemplary results illustrating that cK -E12 lipid nanoparticles efficiently delivered FL mRNA via nebulization. Mice were exposed to milligram of encapsulated FL mRNA and analysis was performed 24 hours post-exposure.
  • Figure 11 illustrates detection via western blot of human SMN-1 protein derived from exogenous hSMN-1 mRNA that was trans fected into BHK-21 cells.
  • Various antibodies specific to human SMN were employed: (A) anti-SMN 4F 11 antibody at 1 : 1 ,000 dilution; (B) Pierce PA5-27309 a-SMN antibody at 1 : 10,000 dilution; and (C) LSBio C138149 a- SMN antibody at 1 : 10,000 dilution.
  • Figure 12A-C illustrates multiplex nucleic acid in situ detection of human
  • Figure 13 illustrates positive detection of human SMN-1 protein produced in the spinal cord of a rat 24 hours post-intrathecal administration of human SMN-1 mRNA- loaded lipid nanoparticles.
  • Anti-human SMN 4F11 antibody was employed at 1 : 2500 dilution.
  • Panel A represents treated rat spinal cord tissue and panel B represents untreated rat spinal cord tissue.
  • FIG. 14 In vivo transfection of CFTR knockout mice with C-terminal Hisio tagged (SEQ ID NO: 11) codon-optimized human CFTR mRNA encapsulated within either a lipid (cK -E12) or polymeric (PEI) nanoparticle formulation. Following nebulized delivery of each respective mRNA formulation, Right and Left lung tissue lysate was collected and analyzed for CFTR expression by Western blot using anti-His antibody 1187. Control CFTR knockout lung tissue and CFTR-Hisio HEK293 lysate ("Hisio" disclosed as SEQ ID NO: 11) was used as a negative and positive controls respectively.
  • Figure 15 illustrates positive detection of active firefly luciferase (FFL) protein in a treated pig lung via luminescence upon exposure to FFL/CO-CFTR-C-Hisio mRNA ("His 10 " disclosed as SEQ ID NO: 11) encapsulated cK -E12 lipid nanoparticles.
  • Pigs were treated with 1 mg FFL + 9 mg CO-CFTR-C-Hisio mRNA ("Hisio" disclosed as SEQ ID NO: 11)
  • amino acid in its broadest sense, refers to any compound and/or substance that can be incorporated into a polypeptide chain.
  • an amino acid has the general structure H E N-C(H)(R)-COHO.
  • an amino acid is a naturally occurring amino acid.
  • an amino acid is a synthetic amino acid; in some embodiments, an amino acid is a d-amino acid; in some embodiments, an amino acid is an 1-amino acid.
  • Standard amino acid refers to any of the twenty standard 1-amino acids commonly found in naturally occurring peptides.
  • Nonstandard amino acid refers to any amino acid, other than the standard amino acids, regardless of whether it is prepared synthetically or obtained from a natural source.
  • synthetic amino acid encompasses chemically modified amino acids, including but not limited to salts, amino acid derivatives (such as amides), and/or substitutions.
  • Amino acids, including carboxyl- and/or amino-terminal amino acids in peptides, can be modified by methylation, amidation, acetylation, protecting groups, and/or substitution with other chemical groups that can change the peptide's circulating half-life without adversely affecting their activity. Amino acids may participate in a disulfide bond.
  • Amino acids may comprise one or posttranslational modifications, such as association with one or more chemical entities (e.g., methyl groups, acetate groups, acetyl groups, phosphate groups, formyl moieties, isoprenoid groups, sulfate groups, polyethylene glycol moieties, lipid moieties, carbohydrate moieties, biotin moieties, etc.).
  • chemical entities e.g., methyl groups, acetate groups, acetyl groups, phosphate groups, formyl moieties, isoprenoid groups, sulfate groups, polyethylene glycol moieties, lipid moieties, carbohydrate moieties, biotin moieties, etc.
  • amino acid is used interchangeably with "amino acid residue,” and may refer to a free amino acid and/or to an amino acid residue of a peptide. It will be apparent from the context in which the term is used whether it refers to a free amino acid or a residue of a
  • animal refers to any member of the animal kingdom. In some embodiments, “animal” refers to humans, at any stage of development. In some embodiments, “animal” refers to non-human animals, at any stage of development. In certain embodiments, the non-human animal is a mammal (e.g., a rodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat, a sheep, cattle, a primate, and/or a pig). In some embodiments, animals include, but are not limited to, mammals, birds, reptiles, amphibians, fish, insects, and/or worms. In some embodiments, an animal may be a transgenic animal, genetically-engineered animal, and/or a clone.
  • mammal e.g., a rodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat, a sheep, cattle, a primate, and/or a pig.
  • delivery encompasses both local and systemic delivery.
  • delivery of mRNA encompasses situations in which an mRNA is delivered to a target tissue and the encoded protein is expressed and retained within the target tissue (aslo referred to as “local distribution” or “local delivery”), and situations in which an mRNA is delivered to a target tissue and the encoded protein is expressed and secreted into patient's circulation system (e.g., serum) and systematically distributed and taken up by other tissues (also referred to as “systemic distribution” or “systemic delivery).
  • patient's circulation system e.g., serum
  • expression refers to translation of an mRNA into a polypeptide, assemble multiple polypeptides (e.g., heavy chain or light chain of antibody) into an intact protein (e.g., antibody) and/or post-translational modification of a polypeptide or fully assembled protein (e.g., antibody).
  • expression and “production,” and grammatical equivalent, are used inter-changeably.
  • a "functional" biological molecule is a biological molecule in a form in which it exhibits a property and/or activity by which it is characterized.
  • Half-life As used herein, the term "half-life" is the time required for a quantity such as nucleic acid or protein concentration or activity to fall to half of its value as measured at the beginning of a time period.
  • “reduce,” or grammatical equivalents indicate values that are relative to a baseline measurement, such as a measurement in the same individual prior to initiation of the treatment described herein, or a measurement in a control subject (or multiple control subject) in the absence of the treatment described herein.
  • a “control subject” is a subject afflicted with the same form of disease as the subject being treated, who is about the same age as the subject being treated.
  • in vitro refers to events that occur in an artificial environment, e.g., in a test tube or reaction vessel, in cell culture, etc., rather than within a multi-cellular organism.
  • in vivo refers to events that occur within a multi-cellular organism, such as a human and a non-human animal. In the context of cell-based systems, the term may be used to refer to events that occur within a living cell (as opposed to, for example, in vitro systems).
  • Isolated refers to a substance and/or entity that has been (1) separated from at least some of the components with which it was associated when initially produced (whether in nature and/or in an experimental setting), and/or (2) produced, prepared, and/or manufactured by the hand of man. Isolated substances and/or entities may be separated from about 10%, about 20%>, about 30%>, about 40%>, about 50%>, about 60%>, about 70%, about 80%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%o, about 97%, about 98%>, about 99%, or more than about 99% of the other components with which they were initially associated.
  • isolated agents are about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%), about 98%>, about 99%, or more than about 99% pure.
  • a substance is "pure” if it is substantially free of other components.
  • calculation of percent purity of isolated substances and/or entities should not include excipients (e.g., buffer, solvent, water, etc.).
  • tissue specific delivery or distribution refers to tissue specific delivery or distribution.
  • mR protein encoded by mR As
  • messenger RNA As used herein, the term "messenger RNA (mR A)" refers to a polynucleotide that encodes at least one polypeptide. mRNA as used herein encompasses both modified and unmodified RNA. mRNA may contain one or more coding and non-coding regions. mRNA can be purified from natural sources, produced using recombinant expression systems and optionally purified, chemically synthesized, etc. Where appropriate, e.g., in the case of chemically synthesized molecules, mRNA can comprise nucleoside analogs such as analogs having chemically modified bases or sugars, backbone modifications, etc. An mRNA sequence is presented in the 5' to 3' direction unless otherwise indicated.
  • an mRNA is or comprises natural nucleosides ⁇ e.g., adenosine, guanosine, cytidine, uridine); nucleoside analogs ⁇ e.g., 2-aminoadenosine, 2-thiothymidine, inosine, pyrrolo-pyrimidine, 3- methyl adenosine, 5-methylcytidine, C-5 propynyl-cytidine, C-5 propynyl-uridine, 2- aminoadenosine, C5-bromouridine, C5-fluorouridine, C5-iodouridine, C5-propynyl-uridine, C5- propynyl-cytidine, C5-methylcytidine, 2-aminoadenosine, 7-deazaadenosine, 7-deazaguanosine, 8-oxoadenosine, 8-oxoguanosine, 0(6)
  • the mRNA comprises one or more nonstandard nucleotide residues.
  • the nonstandard nucleotide residues may include, e.g., 5-methyl-cytidine ("5mC"), pseudouridine (“ ⁇
  • the mR A may be R A, which is defined as R A in which 25% of U residues are 2-thio-uridine and 25% of C residues are 5-methylcytidine.
  • RNA is disclosed US Patent Publication US20120195936 and internation publication WO2011012316, both of which are hereby incorporated by reference in their entirety.
  • the presence of nonstandard nucleotide residues may render an mRNA more stable and/or less immunogenic than a control mRNA with the same sequence but containing only standard residues.
  • the mRNA may comprise one or more nonstandard nucleotide residues chosen from isocytosine, pseudoisocytosine, 5-bromouracil, 5-propynyluracil, 6-aminopurine, 2-aminopurine, inosine, diaminopurine and 2-chloro-6-aminopurine cytosine, as well as combinations of these modifications and other nucleobase modifications.
  • Certain embodiments may further include additional modifications to the furanose ring or nucleobase. Additional modifications may include, for example, sugar modifications or substitutions (e.g., one or more of a 2'-0-alkyl modification, a locked nucleic acid (LNA)).
  • LNA locked nucleic acid
  • the RNAs may be complexed or hybridized with additional polynucleotides and/or peptide polynucleotides (PNA).
  • PNA polypeptide polynucleotides
  • the sugar modification is a 2'-0-alkyl modification
  • such modification may include, but are not limited to a 2'-deoxy-2'-fluoro modification, a 2'-0-methyl
  • any of these modifications may be present in 0-100% of the nucleotides— for example, more than 0%, 1%, 10%, 25%, 50%, 75%, 85%, 90%, 95%, or 100% of the constituent nucleotides individually or in combination.
  • nucleic acid refers to any compound and/or substance that is or can be incorporated into a polynucleotide chain.
  • a nucleic acid is a compound and/or substance that is or can be incorporated into a polynucleotide chain via a phosphodiester linkage.
  • nucleic acid refers to individual nucleic acid residues (e.g., nucleotides and/or nucleosides).
  • nucleic acid refers to a polynucleotide chain comprising individual nucleic acid residues.
  • nucleic acid encompasses RNA as well as single and/or double-stranded DNA and/or cDNA.
  • patient refers to any organism to which a provided composition may be administered, e.g., for experimental, diagnostic, prophylactic, cosmetic, and/or therapeutic purposes. Typical patients include animals ⁇ e.g., mammals such as mice, rats, rabbits, non-human primates, and/or humans). In some
  • a patient is a human.
  • a human includes pre and post natal forms.
  • compositions that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • systemic delivery refers to a delivery or distribution mechanism or approach that affect the entire body or an entire organism.
  • systemic distribution or delivery is accomplished via body's circulation system, e.g., blood stream.
  • Subject refers to a human or any non-human animal (e.g., mouse, rat, rabbit, dog, cat, cattle, swine, sheep, horse or primate).
  • a human includes pre- and post-natal forms.
  • a subject is a human being.
  • a subject can be a patient, which refers to a human presenting to a medical provider for diagnosis or treatment of a disease.
  • the term "subject” is used herein interchangeably with “individual” or "patient.”
  • a subject can be afflicted with or is susceptible to a disease or disorder but may or may not display symptoms of the disease or disorder.
  • Target tissues refers to any tissue that is affected by a disease to be treated. In some embodiments, target tissues include those tissues that display disease-associated pathology, symptom, or feature.
  • therapeutically effective amount As used herein, the term "therapeutically effective amount" of a therapeutic agent means an amount that is sufficient, when administered to a subject suffering from or susceptible to a disease, disorder, and/or condition, to treat, diagnose, prevent, and/or delay the onset of the symptom(s) of the disease, disorder, and/or condition. It will be appreciated by those of ordinary skill in the art that a therapeutically effective amount is typically administered via a dosing regimen comprising at least one unit dose.
  • Treating refers to any method used to partially or completely alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of and/or reduce incidence of one or more symptoms or features of a particular disease, disorder, and/or condition. Treatment may be administered to a subject who does not exhibit signs of a disease and/or exhibits only early signs of the disease for the purpose of decreasing the risk of developing pathology associated with the disease.
  • the present invention provides, among other things, methods and compositions for delivering mR A in vivo using improved liposomes incorporating cationic lipids described herein.
  • liposome refers to any lamellar, multilamellar, or solid lipid nanoparticle vesicle.
  • a liposome as used herein can be formed by mixing one or more lipids or by mixing one or more lipids and polymer(s).
  • liposome as used herein encompasses both lipid and polymer based nanoparticles.
  • a liposome according to the present invention incorporates a cationic lipid described herein.
  • a cationic lipid suitable for the present invention is cK -E12, or (3,6-bis(4- (bis(2-hydroxydodecyl)amino)butyl)piperazine-2,5-dione), as described in more detail below.
  • a suitable liposome may also contain second or additional cationic lipids, helper lipids (e.g., non- cationic lipids and/or cholesterol-based lipids), PEG-modified lipids, and/or polymers.
  • cationic lipid(s) constitute(s) about 30-50
  • the cationic lipid e.g., cK -E12
  • the cationic lipid constitutes about 30%), about 35%, about 40 %, about 45%, or about 50%> of the liposome by molar ratio.
  • provided liposomes or compositions provided comprise a cationic lipid according to formula I:
  • p is an integer of between 1 and 9, inclusive; each instance of Q is independently O, S, or NR Q ;
  • R Q is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group, or a group of the formula (i), (ii) or (iii); each instance of R 1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, halogen, -OR A1 , -N(R A1 ) 2 , -SR A1 , or a group of formula (iv):
  • L is an optionally substituted ; alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkenylene, optionally substituted heteroalkynylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene, or combination thereof, and each of R 6 and R 7 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group, or a group of formula (i), (ii) or (iii); each occurrence of R A1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted hetero
  • each instance of R' is independently hydrogen or optionally substituted alkyl;
  • X is O, S, or NR x ;
  • R x is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group;
  • Y is O, S, or NR Y ;
  • R Y is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group;
  • R P is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, or a nitrogen protecting group when attached to a nitrogen atom;
  • R L is optionally substituted Ci_ 5 o alkyl, optionally substituted C 2 -50 alkenyl, optionally substituted C 2 -50 alkynyl, optionally substituted heteroCi_so alkyl, optionally substituted heteroC2_5o alkenyl, optionally substituted heteroC2_5o alkynyl, or a polymer; provided that at least one instance of R ⁇ , R 2 , R 6 , or R 7 is a group of the formula (i), (ii), or (iii).
  • a cationic lipid in a provided composition or method is a compound of formula I. In some embodiments, a cationic lipid in a provided composition or method is a compound of formula I, wherein the compound comprises one or more basic groups. In some embodiments, a cationic lipid in a provided composition or method is a compound of formula I, wherein the compound comprises one or more amino groups.
  • a group of formula (i) represents a group of formula (i-a) or a group of formula (i-b):
  • a group of formula (i) is a group of formula (i-a). In some embodiments, a group of formula (i) is a group of formula (i-b).
  • At least one instance of R 1 is a group of formula (iv). In some embodiments, at least one instance of R 1 is a group of formula (iv), wherein at least one of R 6 and R 7 is a group of formula (i), (ii) or (iii). In some embodiments, at least one instance of R is a group of formula (iv), wherein each of R 6 and R 7 is independently a group of formula (i), (ii) or (iii). [0070] In some embodiments, each R 1 is independently a group of formula (iv).
  • each R 1 is independently a group of formula (iv), wherein at least one of R 6 and R 7 is a group of formula (i), (ii) or (iii). In some embodiments, each R 1 is independently a group of formula (iv), wherein each of R 6 and R 7 is independently a group of formula (i), (ii) or (iii). In some embodiments, each R 1 is independently a group of formula (iv), wherein each of R 6 and R 7 is independently a group of formula (i). In some embodiments, each R 1 is independently a group of formula (iv), wherein each of R 6 and R 7 is independently a group of formula (ii).
  • each R 1 is independently a group of formula (iv), wherein each of R 6 and R 7 is independently a group of formula (iii). In some embodiments, each R 1 is independently a group of formula (iv), wherein each of R 6 and R 7 is independently a group of formula (i-a). In some embodiments, each R 1 is independently a group of formula (iv), wherein each of R 6 and R 7 is independently a group of formula (i-b).
  • each instance of R' is hydrogen.
  • L is an optionally substituted alkylene.
  • a group of formula (iv) is of formula , wherein q is an integer between 1 and 50, inclusive, and each of R 6 and R 7 is independently as defined above and described herein.
  • p is an integer of between 1 and 9, inclusive. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3. In certain embodiments, p is 4. In certain embodiments, p is 5. In certain embodiments, p is 6. In certain embodiments, p is 7. In certain embodiments, p is 8. In certain embodiments, p is 9.
  • p is 1.
  • a compound of formula I is a compound of formula (I-a):
  • a compound of formula I is a compound of formula (I-p2):
  • p is 3.
  • a compound of formula I is a compound of formula (I-p3):
  • a compound of formula I is a compound of formula (I-p4):
  • p is 5.
  • a compound of formula I is a compound of formula (I-p5):
  • a compound of formula I is a compound of formula (I-p6):
  • p is 7.
  • a compound of formula I is a compound of formula (I-p7):
  • p is 8.
  • a compound of formula I is a compound of formula (I-p8):
  • p is 9.
  • a compound of formula I is a compound of formula (I-p9):
  • each instance of Q is independently O, S, or NR Q , wherein R Q is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group, or a group of the formula (i), (ii), or (iii).
  • At least one instance of Q is O. In certain embodiments, each instance of Q is O. In certain embodiments, at least one instance of Q is S. In certain embodiments, each instance of Q is S. In certain embodiments, at least one instance of Q is NR ⁇ , wherein R ⁇ is as defined above and described herein. In certain embodiments, each instance of Q is NR ⁇ , wherein each R ⁇ is independently as defined above and described herein. In certain embodiments, each instance of R Q is independently hydrogen or a group of the formula (i), (ii), or (iii).
  • R Q is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group, or a group of the formula (i), (ii) or (iii).
  • R Q is hydrogen. In some embodiments, R Q is optionally substituted alkyl. In some embodiments, R Q is optionally substituted alkenyl. In some embodiments, R ⁇ is optionally substituted alkynyl. In some embodiments, R ⁇ is carbocyclyl. In some embodiments, R Q is optionally substituted heterocyclyl. In some embodiments, R Q is optionally substituted aryl. In some embodiments, R ⁇ is optionally substituted heteroaryl. In some embodiments, R Q is a nitrogen protecting group. In some embodiments, R Q is a group of formula (i), (ii) or (iii). In some embodiments, R ⁇ is a group of formula (i). In some embodiments,
  • R ⁇ is a group of formula (ii). In some embodiments, R ⁇ is a group of formula (iii).
  • each instance of R 1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, halogen, -OR ⁇ , -N(R A1 ) 2 , or -SR A1 , or a group of formula (iv), wherein each of R A1 and formula (iv) is independently as defined above and described herein.
  • R 1 is hydrogen.
  • R 1 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In certain embodiments, at least one instance of R 1 is 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 optionally substituted alkyl; e.g., optionally substituted Ci_ 6 alkyl, optionally substituted C 2 _ 6 alkyl, optionally substituted C 3 _ 6 alkyl, optionally substituted C 4 _ 6 alkyl, optionally substituted C 4 _ 5 alkyl, or optionally substituted C 3 _ 4 alkyl.
  • R 1 is optionally substituted alkyl; e.g., optionally substituted Ci_ 6 alkyl, optionally substituted C 2 _ 6 alkyl, optionally substituted C 3 _ 6 alkyl, optionally substituted C 4 _ 6 alkyl, optionally substituted C 4 _ 5 alkyl, or optionally substituted C 3 _ 4 alkyl.
  • R 1 is optionally substituted alkenyl, e.g., optionally substituted C 2 _ 6 alkenyl, optionally substituted C 3 _ 6 alkenyl, optionally substituted C 4 _ 6 alkenyl, optionally substituted C 4 _ 5 alkenyl, or optionally substituted C 3 _ 4 alkenyl.
  • At least one instance of R 1 is optionally substituted alkenyl, e.g., optionally substituted C 2 _ 6 alkenyl, optionally substituted C 3 _ 6 alkenyl, optionally substituted C 4 _ 6 alkenyl, optionally substituted C 4 _ 5 alkenyl, or optionally substituted C 3 _ 4 alkenyl.
  • R 1 is optionally substituted alkynyl, e.g., optionally substituted C 2 _ 6 alkynyl, optionally substituted C 3 _ 6 alkynyl, optionally substituted C 4 _ 6 alkynyl, optionally substituted C 4 _ 5 alkynyl, or optionally substituted C 3 _ 4 alkynyl.
  • At least one instance of R 1 is optionally substituted alkynyl, e.g., optionally substituted C 2 _ 6 alkynyl, optionally substituted C 3 _ 6 alkynyl, optionally substituted C 4 _ 6 alkynyl, optionally substituted C 4 _ 5 alkynyl, or optionally substituted C 3 _ 4 alkynyl.
  • R 1 is optionally substituted carbocyclyl, e.g., optionally substituted C 3 _i 0 carbocyclyl, optionally substituted C 5 _ 8 carbocyclyl, optionally substituted C 5 _ 6 carbocyclyl, optionally substituted C 5 carbocyclyl, or optionally substituted C 6 carbocyclyl.
  • At least one instance of R 1 is optionally substituted carbocyclyl, e.g., optionally substituted C 3-10 carbocyclyl, optionally substituted C5-8 carbocyclyl, optionally substituted C 5 _ 6 carbocyclyl, optionally substituted C 5 carbocyclyl, or optionally substituted C 6 carbocyclyl.
  • R 1 is optionally substituted heterocyclyl, e.g., optionally substituted 3-14 membered heterocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted 5-8 membered heterocyclyl, optionally substituted 5-6 membered heterocyclyl, optionally substituted 5 -membered heterocyclyl, or optionally substituted 6- membered heterocyclyl.
  • At least one instance of R 1 is optionally substituted heterocyclyl, e.g., optionally substituted 3-14 membered heterocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted 5-8 membered heterocyclyl, optionally substituted 5-6 membered heterocyclyl, optionally substituted 5-membered
  • heterocyclyl or optionally substituted 6-membered heterocyclyl.
  • R 1 is optionally substituted aryl. In some embodiments,
  • R 1 is optionally substituted phenyl. In some embodiments, R 1 is phenyl. In some embodiments, R 1 is substituted phenyl. In certain embodiments, at least one instance of R 1 is optionally substituted aryl, e.g., optionally substituted phenyl.
  • R 1 is optionally substituted heteroaryl, e.g., optionally substituted 5-14 membered heteroaryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 5-6 membered heteroaryl, optionally substituted 5 membered heteroaryl, or optionally substituted 6 membered heteroaryl.
  • at least one instance of R 1 is optionally substituted heteroaryl, e.g., optionally substituted 5-14 membered heteroaryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 5-6 membered heteroaryl, optionally substituted 5 membered heteroaryl, or optionally substituted 6 membered heteroaryl.
  • R 1 is halogen. In some embodiments, R 1 is -F. In some embodiments, R 1 is -CI. In some embodiments, R 1 is -Br. In some embodiments, R 1 is -I.
  • R 1 is -OR A1 , wherein R A1 is as defined above and described herein.
  • R 1 is -N(R A1 ) 2 , wherein each R A1 is independently as defined above and described herein.
  • R 1 is -SR A1 , wherein R A1 is as defined above and described herein.
  • an R 1 alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl group may be substituted.
  • an R 1 alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl group may be substituted with an optionally substituted amino group.
  • an R 1 alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl group may be substituted with an optionally substituted hydroxyl group.
  • an R 1 alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl group may be substituted with an optionally substituted thiol group.
  • an R 1 alkyl, alkenyl, alkynyl, carbocyclyl, or heteroaryl group may be substituted with an optionally substituted thiol group.
  • heterocyclyl, aryl, or heteroaryl group may be substituted, for example, with an optionally substituted amino group (e.g., -NR 6 R 7 ), an optionally substituted hydroxyl group (e.g., -OR 6 ), an optionally substituted thiol group (e.g., -SR 6 ), or with a group of formula (i), (ii), or (iii), wherein each instance of R 6 and R 7 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom, or a group of formula (i), (ii), or (iii).
  • an optionally substituted amino group e
  • R 1 is an optionally substituted natural amino acid side chain. In some embodiments, R 1 is a natural amino acid side chain. In some embodiments, R 1 is an optionally substituted unnatural amino acid side chain. In some embodiments, R 1 is an unnatural amino acid side chain.
  • each instance of R 1 is the same. In certain embodiments, at least one R 1 group is different. In certain embodiments, each R 1 group is different.
  • R 1 is an alkyl, alkenyl, alkynyl, carbocyclyl,
  • R 1 is a group of formula (iv): wherein:
  • L is an optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkenylene, optionally substituted heteroalkynylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted
  • each of R 6 and R 7 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group, or a group of formula (i), (ii) or (iii):
  • R', Y, R P , R L and X is independently as defined above and described herein.
  • At least one instance of R 1 is an alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl group substituted with an amino group of the formula -NR 6 R 7 .
  • at least one instance of R is a group of formula (iv).
  • at least one instance of R 1 is a group of formula (iv), wherein at least one instance of R 6 and R 7 is a group of the formula (i), (ii) or (iii).
  • At least one instance of R 1 is a group of formula (iv), wherein each instance of R 6 and R 7 is a group of the formula (i), (ii) or (iii). In some embodiments, at least one instance of R 1 is a group of formula (iv), wherein each instance of R 6 and R 7 is a group of the formula (i). In some embodiments, at least one instance of R 1 is a group of formula (iv), wherein each instance of R 6 and R 7 is a group of the formula (ii). In some embodiments, at least one instance of R is a group of formula (iv), wherein each instance of R 6 and R 7 is a group of the formula (iii).
  • each instance of R 1 is a group of formula (iv). In some embodiments, each instance of R 1 is a group of formula (iv), wherein each instance of R 6 and R 7 is a group of the formula (i), (ii) or (iii). In some embodiments, each instance of R 1 is a group of formula (iv), wherein each instance of R 6 and R 7 is a group of the formula (i), (ii) or (iii). In some embodiments, each instance of R 1 is a group of formula (iv), wherein each instance of R 6 and R 7 is a group of the formula (i).
  • each instance of R is a group of formula (iv), wherein each instance of R 6 and R 7 is a group of the formula (ii).
  • each instance of R 1 is a group of formula (iv), wherein each instance of R 6 and R 7 is a group of the formula (iii).
  • At least two instances of R 1 is a group of formula (iv). In certain embodiments, at least three instances of R 1 is a group of formula (iv). In certain embodiments, at least four instances of R 1 is a group of formula (iv). In certain embodiments, at least five instances of R 1 is a group of formula (iv). In certain embodiments, at least six instances of R 1 is a group of formula (iv). In certain embodiments, at least seven instances of R 1 is a group of formula (iv). In certain embodiments, at least eight instances of R 1 is a group of formula (iv). In certain embodiments, at least nine instances of R 1 is a group of formula (iv). In certain embodiments, each instance of R 1 is a group of formula (iv).
  • L is an optionally substituted alkylene; e.g., optionally substituted Ci_ 5 oalkylene, optionally substituted Ci_ 4 oalkylene, optionally substituted Ci_ 30 alkylene, optionally substituted Ci_ 2 oalkylene, optionally substituted C 4 _ 2 oalkylene, optionally substituted C 6 _ 2 oalkylene, optionally substituted C 8 _ 2 oalkylene, optionally substituted C 10- 20 alkylene, optionally substituted Ci_ 6 alkylene, optionally substituted C 2 _ 6 alkylene, optionally substituted C 3 _ 6 alkylene, optionally substituted C 4 - 6 alkylene, optionally substituted C 4 - 5 alkylene, or optionally substituted C 3 _ 4 alkylene.
  • L is optionally substituted Ci alkylene. In some embodiments, L is optionally substituted C 2 alkylene. In some embodiments, L is optionally substituted C 3 alkylene. In some embodiments, L is optionally substituted C 4 alkylene. In some embodiments, L is optionally substituted C 5 alkylene. In some embodiments, L is optionally substituted C 6 alkylene. In some embodiments, L is optionally substituted C 7 alkylene. In some embodiments, L is optionally substituted Cg alkylene. In some embodiments, L is optionally substituted C 9 alkylene. In some embodiments, L is optionally substituted C 10 alkylene. In some embodiments, L is -CH 2 -.
  • L is -(CH 2 ) 2 - In some embodiments, L is -(CH 2 ) 3 -. In some embodiments, L is -(CH 2 ) 4 -. In some embodiments, L is -(CH 2 ) 5 -. In some embodiments, L is -(CH 2 ) 6 - In some embodiments, L is -(CH 2 ) 7 -. In some embodiments, L is -(CH 2 ) 8 -. In some embodiments, L is -(CH 2 ) 9 - In some embodiments, L is -(CH 2 ) 10 -.
  • L is an optionally substituted alkenylene, e.g., optionally substituted C 2 _ 5 oalkenylene, optionally substituted C 2 _ 4 oalkenylene, optionally substituted C 2 _ 30 alkenylene, optionally substituted C 2 _ 20 alkenylene, optionally substituted C 4 _ 20 alkenylene, optionally substituted C 6 - 2 oalkenylene, optionally substituted Cg_ 2 oalkenylene, optionally substituted Cio- 2 oalkenylene, optionally substituted C 2 _ 6 alkenylene, optionally substituted C 3 _ 6 alkenylene, optionally substituted C 4 _6alkenylene, optionally substituted C 4 -5alkenylene, or optionally substituted C 3 _ 4 alkenylene.
  • optionally substituted alkenylene e.g., optionally substituted C 2 _ 5 oalkenylene, optionally substituted C 2 _ 4 oalkeny
  • L is an optionally substituted alkynylene, e.g., optionally substituted C 2 _ 5 oalkynylene, optionally substituted C 2 _ 4 oalkynylene, optionally substituted C 2 _ 30 alkynylene, optionally substituted C 2 _ 2 oalkynylene, optionally substituted C 4 _ 2 oalkynylene, optionally substituted C 6 _ 2 oalkynylene, optionally substituted C 8 _ 20 alkynylene, optionally substituted Ci 0 _ 2 oalkynylene, optionally substituted C 2 _ 6 alkynylene, optionally substituted C 3 _ 6 alkynylene, optionally substituted C 4 _6alkynylene, optionally substituted C 4 _5alkynylene, or optionally substituted C 3 _ 4 alkynylene.
  • optionally substituted alkynylene e.g., optionally substituted C 2 _ 5
  • L is an optionally substituted heteroalkylene; e.g., optionally substituted heteroCi_ 50 alkylene, optionally substituted heteroCi_ 40 alkylene, optionally substituted heteroCi_ 3 oalkylene, optionally substituted heteroCi_ 2 oalkylene, optionally substituted heteroC 4 - 2 oalkylene, optionally substituted heteroC6- 2 oalkylene, optionally substituted heteroCg.
  • optionally substituted heteroalkylene e.g., optionally substituted heteroCi_ 50 alkylene, optionally substituted heteroCi_ 40 alkylene, optionally substituted heteroCi_ 3 oalkylene, optionally substituted heteroCi_ 2 oalkylene, optionally substituted heteroC 4 - 2 oalkylene, optionally substituted heteroC6- 2 oalkylene, optionally substituted heteroCg.
  • L is optionally substituted
  • L is optionally substituted heteroC 2 alkylene.
  • L is optionally substituted heteroC 3 alkylene.
  • L is optionally substituted heteroC 4 alkylene.
  • L is optionally substituted heteroC 5 alkylene.
  • L is optionally substituted heteroCealkylene.
  • L is optionally substituted heteroCyalkylene.
  • L is optionally substituted heteroCgalkylene.
  • L is optionally substituted heteroCgalkylene.
  • L is optionally substituted heteroC l oalkylene.
  • L is an optionally substituted heteroalkenylene, e.g., optionally substituted heteroC 2 _5oalkenylene, optionally substituted heteroC 2 - 4 oalkenylene, optionally substituted heteroC 2 _ 3 oalkenylene, optionally substituted heteroC 2 _ 2 oalkenylene, optionally substituted heteroC 4 _ 2 oalkenylene, optionally substituted heteroC 6 _ 2 oalkenylene, optionally substituted heteroCg- 2 oalkenylene, optionally substituted heteroCio- 2 oalkenylene, optionally substituted heteroC 2 _6alkenylene, optionally substituted heteroC 3 _6alkenylene, optionally substituted heteroC 4 _6alkenylene, optionally substituted heteroC 4 _5alkenylene, or optionally substituted heteroC 3 _ 4 alkenylene.
  • optionally substituted heteroalkenylene e.g., optionally substituted heteroC 2
  • L is an optionally substituted heteroalkynylene, e.g., optionally substituted heteroC 2 _5oalkynylene, optionally substituted heteroC 2 _ 4 oalkynylene, optionally substituted heteroC 2 _ 3 oalkynylene, optionally substituted heteroC 2 _ 2 oalkynylene, optionally substituted heteroC 4 _ 2 oalkynylene, optionally substituted heteroC 6 _ 2 oalkynylene, optionally substituted heteroC 8 _ 2 oalkynylene, optionally substituted heteroCi 0 - 2 oalkynylene, optionally substituted heteroC 2 _6alkynylene, optionally substituted heteroC 3 _6alkynylene, optionally substituted heteroC 4 _6alkynylene, optionally substituted heteroC 4 _5alkynylene, or optionally substituted heteroC 3 _ 4 alkynylene.
  • L is an optionally substituted carbocyclylene, e.g., optionally substituted C 3 _iocarbocyclylene, optionally substituted Cs-scarbocyclylene, optionally substituted Cs-ecarbocyclylene, optionally substituted C 5 carbocyclylene, or optionally substituted C 6 carbocyclylene.
  • L is an optionally substituted heterocyclylene, e.g., optionally substituted 3-14 membered heterocyclylene, optionally substituted 3-10 membered heterocyclylene, optionally substituted 5-8 membered heterocyclylene, optionally substituted 5-6 membered heterocyclylene, optionally substituted 5-membered heterocyclylene, or optionally substituted 6-membered heterocyclylene.
  • optionally substituted heterocyclylene e.g., optionally substituted 3-14 membered heterocyclylene, optionally substituted 3-10 membered heterocyclylene, optionally substituted 5-8 membered heterocyclylene, optionally substituted 5-6 membered heterocyclylene, optionally substituted 5-membered heterocyclylene, or optionally substituted 6-membered heterocyclylene.
  • L is an optionally substituted arylene, e.g., optionally substituted phenylene. In some embodiments, L is optionally substituted phenylene. In some embodiments, L is substituted phenylene. In some embodiments, L is unsubstituted phenylene.
  • L is an optionally substituted heteroarylene, e.g., optionally substituted 5-14 membered heteroarylene, optionally substituted 5-10 membered heteroarylene, optionally substituted 5-6 membered heteroarylene, optionally substituted 5- membered heteroarylene, or optionally substituted 6-membered heteroarylene.
  • group of formula (iv) is a group of the formula , wherein q is an integer between 1 and 50, inclusive, and each of R 6 and R 7 is independently as defined above and described herein.
  • q is an integer between 1 and 40, inclusive. In certain embodiments, q is an integer between 1 and 30, inclusive. In certain embodiments, q is an integer between 1 and 20, inclusive. In certain embodiments, q is an integer between 1 and 10, inclusive. In certain embodiments, q is an integer between 4 and 20, inclusive. In certain embodiments, q is an integer between 6 and 20, inclusive. In certain embodiments, q is an integer between 2 and 10, inclusive. In certain embodiments, q is an integer between 2 and 9, inclusive. In certain embodiments, q is an integer between 2 and 8, inclusive. In certain embodiments, q is an integer between 2 and 7, inclusive. In certain embodiments, q is an integer between 2 and 6, inclusive.
  • q is an integer between 2 and 5, inclusive. In certain embodiments, q is an integer between 2 and 4, inclusive. In certain embodiments, q is an integer between 3 and 10, inclusive. In certain embodiments, q is an integer between 3 and 8, inclusive. In certain embodiments, q is an integer between 3 and 7, inclusive. In certain embodiments, q is an integer between 3 and 6, inclusive. In certain embodiments, q is an integer between 3 and 5, inclusive. In certain embodiments, q is 3 or 4. In certain embodiments, q is an integer between 3 and 9, inclusive. In certain embodiments, q is an integer between 8 and 20, inclusive. In certain embodiments, q is 1. In certain embodiments, q is 2. In certain embodiments, q is 3. In certain embodiments, q is 4. In certain embodiments, q is 5. In certain embodiments, q is 6. In certain embodiments, q is 7. In certain embodiments, q is 8. In certain embodiments, q is 9. In certain embodiments, q is 10.
  • each R 6 is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group, or a group of formula (i), (ii) or (iii).
  • R 6 is hydrogen
  • R 6 is optionally substituted alkyl. In some embodiments,
  • R 6 is optionally substituted C2-50 alkyl. In some embodiments, R 6 is optionally substituted C2-40 alkyl. In some embodiments, R 6 is optionally substituted C2-30 alkyl. In some embodiments, R 6 is optionally substituted C2-20 alkyl. In some embodiments, R 6 is optionally substituted C2-19 alkyl. In some embodiments, R 6 is optionally substituted C 2-18 alkyl. In some embodiments, R 6 is optionally substituted C 2-17 alkyl. In some embodiments, R 6 is optionally substituted C 2-16 alkyl. In some embodiments, R 6 is optionally substituted C 2-15 alkyl. In some embodiments, R 6 is optionally substituted C 2-14 alkyl.
  • R 6 is optionally substituted C 2-13 alkyl. In some embodiments, R 6 is optionally substituted C 2-12 alkyl. In some embodiments, R 6 is optionally substituted C 2 -n alkyl. In some embodiments, R 6 is optionally substituted C 2-10 alkyl. In some embodiments, R 6 is optionally substituted C2-9 alkyl. In some embodiments, R 6 is optionally substituted C2-8 alkyl. In some embodiments, R 6 is optionally substituted C2-7 alkyl. In some embodiments, R 6 is optionally substituted C2-6 alkyl.
  • R 6 is optionally substituted C 4 _ 50 alkyl. In some embodiments, R 6 is optionally substituted C 4 - 4 o alkyl. In some embodiments, R 6 is optionally substituted C4-30 alkyl. In some embodiments, R 6 is optionally substituted C4-20 alkyl. In some embodiments, R 6 is optionally substituted C4-19 alkyl. In some embodiments, R 6 is optionally substituted C 4 _i 8 alkyl. In some embodiments, R 6 is optionally substituted C 4 _i 7 alkyl. In some embodiments, R 6 is optionally substituted C 4-16 alkyl. In some embodiments, R 6 is optionally substituted C 4-15 alkyl.
  • R 6 is optionally substituted C 4-14 alkyl. In some embodiments, R 6 is optionally substituted C 4-13 alkyl. In some embodiments, R 6 is optionally substituted C 4 _i 2 alkyl. In some embodiments, R 6 is optionally substituted C 4 _n alkyl. In some embodiments, R 6 is optionally substituted C 4 _io alkyl. In some embodiments, R 6 is optionally substituted C 4 _g alkyl. In some embodiments, R 6 is optionally substituted C 4 _g alkyl. In some embodiments, R 6 is optionally substituted C 4 _ 7 alkyl. In some embodiments, R 6 is optionally substituted C 4 _ 6 alkyl.
  • R 6 is optionally substituted C 6 -5o alkyl. In some embodiments, R 6 is optionally substituted C 6 - 4 o alkyl. In some embodiments, R 6 is optionally substituted C 6 -3o alkyl. In some embodiments, R 6 is optionally substituted C 6 - 2 o alkyl. In some embodiments, R 6 is optionally substituted C 6 _i9 alkyl. In some embodiments, R 6 is optionally substituted C 6-1 8 alkyl. In some embodiments, R 6 is optionally substituted C 6 -i 7 alkyl. In some embodiments, R 6 is optionally substituted C 6-1 6 alkyl.
  • R 6 is optionally substituted C 6-15 alkyl. In some embodiments, R 6 is optionally substituted C 6-14 alkyl. In some embodiments, R 6 is optionally substituted C 6-13 alkyl. In some embodiments, R 6 is optionally substituted C 6-12 alkyl. In some embodiments, R 6 is optionally substituted C 6-11 alkyl. In some embodiments, R 6 is optionally substituted C 6-1 o alkyl. In some embodiments, R 6 is optionally substituted C 6 -9 alkyl. In some embodiments, R 6 is optionally substituted C 6 -8 alkyl. In some embodiments, R 6 is optionally substituted C 6 _ 7 alkyl.
  • R 6 is optionally substituted C 8 _5o alkyl. In some embodiments, R 6 is optionally substituted Cg- 4 o alkyl. In some embodiments, R 6 is optionally substituted Cg-30 alkyl. In some embodiments, R 6 is optionally substituted Cg_ 2 o alkyl. In some embodiments, R 6 is optionally substituted Cg_ig alkyl. In some embodiments, R 6 is optionally substituted C 8 _i 8 alkyl. In some embodiments, R 6 is optionally substituted C 8-17 alkyl. In some embodiments, R 6 is optionally substituted C 8-16 alkyl. In some embodiments, R 6 is optionally substituted C 8-15 alkyl.
  • R 6 is optionally substituted C 8-14 alkyl. In some embodiments, R 6 is optionally substituted C 8-13 alkyl. In some embodiments, R 6 is optionally substituted C 8-12 alkyl. In some embodiments, R 6 is optionally substituted C 8-11 alkyl. In some embodiments, R 6 is optionally substituted C 8-10 alkyl. In some embodiments, R 6 is optionally substituted Cg_9 alkyl. [0126] In some embodiments, R 6 is optionally substituted C9-50 alkyl. In some embodiments, R 6 is optionally substituted C 9 _ 40 alkyl. In some embodiments, R 6 is optionally substituted C9-30 alkyl.
  • R 6 is optionally substituted C9-20 alkyl. In some embodiments, R 6 is optionally substituted C9-19 alkyl. In some embodiments, R 6 is optionally substituted C9-18 alkyl. In some embodiments, R 6 is optionally substituted C9-17 alkyl. In some embodiments, R 6 is optionally substituted C 9 _i 6 alkyl. In some embodiments, R 6 is optionally substituted C9-15 alkyl. In some embodiments, R 6 is optionally substituted Cg-i 4 alkyl. In some embodiments, R 6 is optionally substituted C9-13 alkyl. In some embodiments, R 6 is optionally substituted C9-12 alkyl. In some embodiments, R 6 is optionally substituted C9-11 alkyl. In some embodiments, R 6 is optionally substituted C 9 _i 0 alkyl.
  • R 6 is optionally substituted Cio-50 alkyl. In some embodiments, R 6 is optionally substituted Cio- 4 o alkyl. In some embodiments, R 6 is optionally substituted Cio-30 alkyl. In some embodiments, R 6 is optionally substituted Cio-20 alkyl. In some embodiments, R 6 is optionally substituted C 10-19 alkyl. In some embodiments, R 6 is optionally substituted C10-18 alkyl. In some embodiments, R 6 is optionally substituted C10-17 alkyl. In some embodiments, R 6 is optionally substituted C10-16 alkyl. In some embodiments, R 6 is optionally substituted Cio-15 alkyl.
  • R 6 is optionally substituted Cio-i 4 alkyl. In some embodiments, R 6 is optionally substituted C 10-13 alkyl. In some embodiments, R 6 is optionally substituted Cio-12 alkyl. In some embodiments, R 6 is optionally substituted Cio-n alkyl.
  • R 6 is optionally substituted Cn_5o alkyl. In some embodiments, R 6 is optionally substituted Cn.40 alkyl. In some embodiments, R 6 is optionally substituted Cn_3o alkyl. In some embodiments, R 6 is optionally substituted Cn_2o alkyl. In some embodiments, R 6 is optionally substituted Cn_i 9 alkyl. In some embodiments, R 6 is optionally substituted Cn_ig alkyl. In some embodiments, R 6 is optionally substituted Cn_i7 alkyl. In some embodiments, R 6 is optionally substituted Cn_i6 alkyl. In some embodiments, R 6 is optionally substituted Cn_is alkyl. In some embodiments, R 6 is optionally substituted Cn_i 4 alkyl. In some embodiments, R 6 is optionally substituted Cn_i 3 alkyl. In some embodiments, R 6 is optionally substituted Cn_i2 alkyl.
  • R 6 is optionally substituted C12-50 alkyl. In some embodiments, R 6 is optionally substituted Ci2- 4 o alkyl. In some embodiments, R 6 is optionally substituted C12-30 alkyl. In some embodiments, R 6 is optionally substituted C12-20 alkyl. In some embodiments, R 6 is optionally substituted C 12-1 alkyl. In some embodiments, R 6 is optionally substituted C 12-18 alkyl. In some embodiments, R 6 is optionally substituted C 12-17 alkyl. In some embodiments, R 6 is optionally substituted C 12-16 alkyl. In some embodiments, R 6 is optionally substituted C 12-15 alkyl. In some embodiments, R 6 is optionally substituted C 12-14 alkyl. In some embodiments, R 6 is optionally substituted C 12-13 alkyl.
  • R 6 is optionally substituted C 6 alkyl.
  • R 6 is optionally substituted C 7 alkyl. In some embodiments, R 6 is optionally substituted Cg alkyl. In some embodiments, R 6 is optionally substituted C9 alkyl. In some embodiments, R 6 is optionally substituted C 10 alkyl. In some embodiments, R 6 is optionally substituted Cn alkyl. In some embodiments, R 6 is optionally substituted C 12 alkyl. In some embodiments, R 6 is optionally substituted C 13 alkyl. In some embodiments, R 6 is optionally substituted C 14 alkyl. In some embodiments, R 6 is optionally substituted C 15 alkyl. In some embodiments, R 6 is optionally substituted C 16 alkyl.
  • R 6 is optionally substituted C 17 alkyl. In some embodiments, R 6 is optionally substituted C 18 alkyl. In some embodiments, R 6 is optionally substituted C19 alkyl. In some embodiments, R 6 is optionally substituted C20 alkyl.
  • R 6 is a substituted alkyl group. In some embodiments, R 6 is an unsubstituted alkyl group. In some embodiments, R 6 is an optionally substituted straight-chain alkyl group. In some embodiments, R 6 is a substituted straight-chain alkyl group. In some embodiments, R 6 is an unsubstituted straight-chain alkyl group. In some embodiments, R 6 is an optionally substituted branched alkyl group. In some embodiments, R 6 is a substituted branched alkyl group. In some embodiments, R 6 is an unsubstituted branched alkyl group.
  • R 6 is optionally substituted alkenyl.
  • R 6 is optionally substituted C2-50 alkenyl. In some embodiments, R 6 is optionally substituted C 2 -4o alkenyl. In some embodiments, R 6 is optionally substituted C2-30 alkenyl. In some embodiments, R 6 is optionally substituted C2-20 alkenyl. In some embodiments, R 6 is optionally substituted C2-19 alkenyl. In some embodiments, R 6 is optionally substituted C 2-18 alkenyl. In some embodiments, R 6 is optionally substituted C 2-17 alkenyl. In some embodiments, R 6 is optionally substituted C 2-16 alkenyl. In some embodiments, R 6 is optionally substituted C 2 _ 15 alkenyl. In some embodiments, R 6 is optionally substituted C 2 _i 4 alkenyl. In some
  • R 6 is optionally substituted C 2 _i 3 alkenyl. In some embodiments, R 6 is optionally substituted C 2 _i 2 alkenyl. In some embodiments, R 6 is optionally substituted C 2 _n alkenyl. In some embodiments, R 6 is optionally substituted C 2 _io alkenyl. In some embodiments, R 6 is optionally substituted C 2 _ 9 alkenyl. In some embodiments, R 6 is optionally substituted C 2 _ 8 alkenyl. In some embodiments, R 6 is optionally substituted C 2 _ 7 alkenyl. In some embodiments, R 6 is optionally substituted C 2 _ 6 alkenyl.
  • R 6 is optionally substituted C 4 _ 5 o alkenyl. In some embodiments, R 6 is optionally substituted C 4 _ 40 alkenyl. In some embodiments, R 6 is optionally substituted C 4 _ 3 o alkenyl. In some embodiments, R 6 is optionally substituted C 4 _ 2 o alkenyl. In some embodiments, R 6 is optionally substituted C 4 _ig alkenyl. In some embodiments, R 6 is optionally substituted C 4 _ig alkenyl. In some embodiments, R 6 is optionally substituted C 4 _i 7 alkenyl. In some embodiments, R 6 is optionally substituted C 4 _i 6 alkenyl.
  • R 6 is optionally substituted C 4 _i 5 alkenyl. In some embodiments, R 6 is optionally substituted C 4 _ 14 alkenyl. In some embodiments, R 6 is optionally substituted C 4 _i 3 alkenyl. In some
  • R 6 is optionally substituted C 4 _i 2 alkenyl. In some embodiments, R 6 is optionally substituted C 4 _n alkenyl. In some embodiments, R 6 is optionally substituted C 4 _i 0 alkenyl. In some embodiments, R 6 is optionally substituted C 4 _ 9 alkenyl. In some embodiments, R 6 is optionally substituted C 4 _g alkenyl. In some embodiments, R 6 is optionally substituted C 4 _ 7 alkenyl. In some embodiments, R 6 is optionally substituted C 4 _ 6 alkenyl.
  • R 6 is optionally substituted C 6 -5o alkenyl. In some embodiments, R 6 is optionally substituted C 6 _ 4 o alkenyl. In some embodiments, R 6 is optionally substituted C 6 - 3 o alkenyl. In some embodiments, R 6 is optionally substituted C 6 - 2 o alkenyl. In some embodiments, R 6 is optionally substituted C 6 -i9 alkenyl. In some embodiments, R 6 is optionally substituted C 6-1 8 alkenyl. In some embodiments, R 6 is optionally substituted C 6 -i 7 alkenyl. In some embodiments, R 6 is optionally substituted C 6 _i6 alkenyl. In some embodiments, R 6 is optionally substituted C 6-15 alkenyl. In some embodiments, R 6 is optionally substituted C 6- 14 alkenyl. In some embodiments, R 6 is optionally substituted C 6-13 alkenyl. In some embodiments, R 6 is optionally substituted C 6
  • R 6 is optionally substituted C 6-12 alkenyl. In some embodiments, R 6 is optionally substituted C 6 -n alkenyl. In some embodiments, R 6 is optionally substituted C 6 -io alkenyl. In some embodiments, R 6 is optionally substituted C 6 _9 alkenyl. In some embodiments, R 6 is optionally substituted C 6 _g alkenyl. In some embodiments, R 6 is optionally substituted C 6 - 7 alkenyl.
  • R 6 is optionally substituted Cg-so alkenyl. In some embodiments, R 6 is optionally substituted C 8 _ 40 alkenyl. In some embodiments, R 6 is optionally substituted Cg- 3 o alkenyl. In some embodiments, R 6 is optionally substituted Cg_ 2 o alkenyl. In some embodiments, R 6 is optionally substituted Cg-i9 alkenyl. In some embodiments, R 6 is optionally substituted Cg_ig alkenyl. In some embodiments, R 6 is optionally substituted Cg_i 7 alkenyl. In some embodiments, R 6 is optionally substituted C 8 _i 6 alkenyl.
  • R 6 is optionally substituted C 8-15 alkenyl. In some embodiments, R 6 is optionally substituted Cg_ 14 alkenyl. In some embodiments, R 6 is optionally substituted Cg_i 3 alkenyl. In some
  • R 6 is optionally substituted Cg_i 2 alkenyl. In some embodiments, R 6 is optionally substituted C 8-11 alkenyl. In some embodiments, R 6 is optionally substituted C 8 _i 0 alkenyl. In some embodiments, R 6 is optionally substituted Cg-9 alkenyl.
  • R 6 is optionally substituted C 9 -50 alkenyl. In some embodiments, R 6 is optionally substituted C 9 -40 alkenyl. In some embodiments, R 6 is optionally substituted C 9 _ 3 o alkenyl. In some embodiments, R 6 is optionally substituted C 9 _ 2 o alkenyl. In some embodiments, R 6 is optionally substituted C 9 _i9 alkenyl. In some embodiments, R 6 is optionally substituted Cg-ig alkenyl. In some embodiments, R 6 is optionally substituted Cg.n alkenyl. In some embodiments, R 6 is optionally substituted C 9 -16 alkenyl.
  • R 6 is optionally substituted C 9 -15 alkenyl. In some embodiments, R 6 is optionally substituted C 9 - 14 alkenyl. In some embodiments, R 6 is optionally substituted Cg_i 3 alkenyl. In some
  • R 6 is optionally substituted C 9 -12 alkenyl. In some embodiments, R 6 is optionally substituted C 9 -11 alkenyl. In some embodiments, R 6 is optionally substituted C 9 -10 alkenyl.
  • R 6 is optionally substituted Cio-50 alkenyl. In some embodiments, R 6 is optionally substituted C 10-40 alkenyl. In some embodiments, R 6 is optionally substituted Cio- 3 o alkenyl. In some embodiments, R 6 is optionally substituted Cio-20 alkenyl. In some embodiments, R 6 is optionally substituted C 10-19 alkenyl. In some embodiments, R 6 is optionally substituted Cio-ig alkenyl. In some embodiments, R 6 is optionally substituted Cio-i 7 alkenyl. In some embodiments, R 6 is optionally substituted C 10-1 6 alkenyl. In some embodiments, R 6 is optionally substituted C 10-15 alkenyl.
  • R 6 is optionally substituted C 10-14 alkenyl. In some embodiments, R 6 is optionally substituted C 10-13 alkenyl. In some embodiments, R 6 is optionally substituted C 10-12 alkenyl. In some embodiments, R 6 is optionally substituted C 10-11 alkenyl.
  • R 6 is optionally substituted C 11-50 alkenyl. In some embodiments, R 6 is optionally substituted C 11-40 alkenyl. In some embodiments, R 6 is optionally substituted C 11-30 alkenyl. In some embodiments, R 6 is optionally substituted C 11-20 alkenyl. In some embodiments, R 6 is optionally substituted Cn_i9 alkenyl. In some embodiments, R 6 is optionally substituted C 11-18 alkenyl. In some embodiments, R 6 is optionally substituted C 11-17 alkenyl. In some embodiments, R 6 is optionally substituted C 11-16 alkenyl. In some embodiments, R 6 is optionally substituted C 11-50 alkenyl. In some embodiments, R 6 is optionally substituted C 11-40 alkenyl. In some embodiments, R 6 is optionally substituted C 11-30 alkenyl. In some embodiments, R 6 is optionally substituted C 11-20 alkenyl. In some embodiments, R 6 is optionally substituted Cn_i9
  • R 6 is optionally substituted C 11-15 alkenyl. In some embodiments, R 6 is optionally substituted C 11-14 alkenyl. In some embodiments, R 6 is optionally substituted C 11-13 alkenyl. In some embodiments, R 6 is optionally substituted C 11-12 alkenyl.
  • R 6 is optionally substituted C12-50 alkenyl. In some embodiments, R 6 is optionally substituted C 12-40 alkenyl. In some embodiments, R 6 is optionally substituted C12-30 alkenyl. In some embodiments, R 6 is optionally substituted C12-20 alkenyl. In some embodiments, R 6 is optionally substituted C 12-1 alkenyl. In some embodiments, R 6 is optionally substituted C 12-18 alkenyl. In some embodiments, R 6 is optionally substituted C 12-17 alkenyl. In some embodiments, R 6 is optionally substituted C 12-16 alkenyl. In some embodiments,
  • R 6 is optionally substituted C 12-15 alkenyl. In some embodiments, R 6 is optionally substituted C 12-14 alkenyl. In some embodiments, R 6 is optionally substituted C 12-13 alkenyl.
  • R 6 is optionally substituted C 6 alkenyl. In some embodiments, R 6 is optionally substituted C 7 alkenyl. In some embodiments, R 6 is optionally substituted Cg alkenyl. In some embodiments, R 6 is optionally substituted C9 alkenyl. In some embodiments, R 6 is optionally substituted C 10 alkenyl. In some embodiments, R 6 is optionally substituted Cn alkenyl. In some embodiments, R 6 is optionally substituted C 12 alkenyl. In some embodiments, R 6 is optionally substituted C 13 alkenyl. In some embodiments, R 6 is optionally substituted C 14 alkenyl.
  • R 6 is optionally substituted C 15 alkenyl. In some embodiments, R 6 is optionally substituted C 16 alkenyl. In some embodiments, R 6 is optionally substituted C 17 alkenyl. In some embodiments, R 6 is optionally substituted C 18 alkenyl. In some embodiments, R 6 is optionally substituted C19 alkenyl. In some embodiments, R 6 is optionally substituted C20 alkenyl.
  • R 6 is a substituted alkenyl group.
  • R 6 is an unsubstituted alkenyl group.
  • R 6 is an optionally substituted straight-chain alkenyl group.
  • R 6 is a substituted straight-chain alkenyl group. In some embodiments, R 6 is an unsubstituted straight-chain alkenyl group. In some embodiments, R 6 is an optionally substituted branched alkenyl group. In some embodiments, R 6 is a substituted branched alkenyl group. In some embodiments, R 6 is an unsubstituted branched alkenyl group.
  • R 6 is optionally substituted alkynyl.
  • R 6 is optionally substituted C 2 _ 5 o alkynyl. In some embodiments, R 6 is optionally substituted C 2 _ 4 o alkynyl. In some embodiments, R 6 is optionally substituted C 2 _ 3 o alkynyl. In some embodiments, R 6 is optionally substituted C 2 _ 20 alkynyl. In some embodiments, R 6 is optionally substituted C 2 _i9 alkynyl. In some embodiments, R 6 is optionally substituted C 2 _ig alkynyl. In some embodiments, R 6 is optionally substituted C 2 _i 7 alkynyl. In some embodiments,
  • R 6 is optionally substituted C 2 _i 6 alkynyl. In some embodiments, R 6 is optionally substituted C 2 _i 5 alkynyl. In some embodiments, R 6 is optionally substituted C 2 _i 4 alkynyl. In some embodiments, R 6 is optionally substituted C 2 _i 3 alkynyl. In some embodiments, R 6 is optionally substituted C 2 _i 2 alkynyl. In some embodiments, R 6 is optionally substituted C 2 _n alkynyl. In some embodiments, R 6 is optionally substituted C 2 _io alkynyl. In some
  • R 6 is optionally substituted C 2 _9 alkynyl. In some embodiments, R 6 is optionally substituted C 2 _ 8 alkynyl. In some embodiments, R 6 is optionally substituted C 2 _ 7 alkynyl. In some embodiments, R 6 is optionally substituted C 2 _ 6 alkynyl.
  • R 6 is optionally substituted C 4 _ 5 o alkynyl. In some embodiments, R 6 is optionally substituted C 4 _ 4 o alkynyl. In some embodiments, R 6 is optionally substituted C 4 _ 30 alkynyl. In some embodiments, R 6 is optionally substituted C 4 _ 20 alkynyl. In some embodiments, R 6 is optionally substituted C 4 _i9 alkynyl. In some embodiments, R 6 is optionally substituted C 4 _ig alkynyl. In some embodiments, R 6 is optionally substituted C 4 _i 7 alkynyl.
  • R 6 is optionally substituted C 4 _i 6 alkynyl. In some embodiments, R 6 is optionally substituted C 4-15 alkynyl. In some embodiments, R 6 is optionally substituted C 4 _i 4 alkynyl. In some embodiments, R 6 is optionally substituted C _i 3 alkynyl. In some embodiments, R 6 is optionally substituted C 4 _i 2 alkynyl. In some embodiments, R 6 is optionally substituted C 4 _n alkynyl. In some embodiments, R 6 is optionally substituted C 4 _io alkynyl. In some embodiments, R 6 is optionally substituted C 4 _9 alkynyl.
  • R 6 is optionally substituted C _ 8 alkynyl. In some embodiments, R 6 is optionally substituted C _ 7 alkynyl. In some embodiments, R 6 is optionally substituted C 4 _ 6 alkynyl.
  • R 6 is optionally substituted C 6 -5o alkynyl. In some embodiments, R 6 is optionally substituted C 6 - 4 o alkynyl. In some embodiments, R 6 is optionally substituted C 6 _ 3 o alkynyl. In some embodiments, R 6 is optionally substituted C 6 _ 2 o alkynyl. In some embodiments, R 6 is optionally substituted C 6 -i9 alkynyl. In some embodiments, R 6 is optionally substituted C 6-1 8 alkynyl. In some embodiments, R 6 is optionally substituted C 6 -i 7 alkynyl. In some embodiments, R 6 is optionally substituted C 6-1 6 alkynyl. In some embodiments, R 6 is optionally substituted C 6 -5o alkynyl. In some embodiments, R 6 is optionally substituted C 6 - 4 o alkynyl. In some embodiments, R 6 is optionally substituted C 6 _ 3 o alky
  • R 6 is optionally substituted C 6-15 alkynyl. In some embodiments, R 6 is optionally substituted C 6-14 alkynyl. In some embodiments, R 6 is optionally substituted C 6-13 alkynyl. In some embodiments, R 6 is optionally substituted C 6-12 alkynyl. In some embodiments, R 6 is optionally substituted C 6-11 alkynyl. In some embodiments, R 6 is optionally substituted C 6-1 o alkynyl. In some embodiments, R 6 is optionally substituted C 6 _9 alkynyl. In some embodiments, R 6 is optionally substituted C 6 _8 alkynyl. In some embodiments, R 6 is optionally substituted C 6 _ 7 alkynyl.
  • R 6 is optionally substituted Cg-so alkynyl. In some embodiments, R 6 is optionally substituted Cg- 4 o alkynyl. In some embodiments, R 6 is optionally substituted C 8 _ 3 o alkynyl. In some embodiments, R 6 is optionally substituted C 8 _ 2 o alkynyl. In some embodiments, R 6 is optionally substituted Cg-i9 alkynyl. In some embodiments, R 6 is optionally substituted C 8-18 alkynyl. In some embodiments, R 6 is optionally substituted C 8-17 alkynyl. In some embodiments, R 6 is optionally substituted C 8-1 6 alkynyl. In some
  • R 6 is optionally substituted C 8-15 alkynyl. In some embodiments, R 6 is optionally substituted C 8-14 alkynyl. In some embodiments, R 6 is optionally substituted C 8-13 alkynyl. In some embodiments, R 6 is optionally substituted C 8-12 alkynyl. In some embodiments, R 6 is optionally substituted Cg-n alkynyl. In some embodiments, R 6 is optionally substituted Cg-io alkynyl. In some embodiments, R 6 is optionally substituted Cg_9 alkynyl.
  • R 6 is optionally substituted C9-50 alkynyl. In some embodiments, R 6 is optionally substituted C9-40 alkynyl. In some embodiments, R 6 is optionally substituted C9-30 alkynyl. In some embodiments, R 6 is optionally substituted C9-20 alkynyl. In some embodiments, R 6 is optionally substituted C 9 _i9 alkynyl. In some embodiments, R 6 is optionally substituted C9-18 alkynyl. In some embodiments, R 6 is optionally substituted C9-17 alkynyl. In some embodiments, R 6 is optionally substituted C9_i 6 alkynyl. In some
  • R 6 is optionally substituted C9-15 alkynyl. In some embodiments, R 6 is optionally substituted C 9 _i 4 alkynyl. In some embodiments, R 6 is optionally substituted C 9 _i 3 alkynyl. In some embodiments, R 6 is optionally substituted C9-12 alkynyl. In some embodiments, R 6 is optionally substituted C9-11 alkynyl. In some embodiments, R 6 is optionally substituted C9-10 alkynyl.
  • R 6 is optionally substituted Cio-50 alkynyl. In some embodiments, R 6 is optionally substituted C 10-40 alkynyl. In some embodiments, R 6 is optionally substituted Cio-30 alkynyl. In some embodiments, R 6 is optionally substituted Cio-20 alkynyl. In some embodiments, R 6 is optionally substituted C 10-19 alkynyl. In some embodiments, R 6 is optionally substituted Cio-is alkynyl. In some embodiments, R 6 is optionally substituted Cio-17 alkynyl. In some embodiments, R 6 is optionally substituted C10-16 alkynyl. In some embodiments,
  • R 6 is optionally substituted C10-15 alkynyl. In some embodiments, R 6 is optionally substituted Cio-14 alkynyl. In some embodiments, R 6 is optionally substituted Cio-i 3 alkynyl. In some embodiments, R 6 is optionally substituted C 10-12 alkynyl. In some embodiments, R 6 is optionally substituted Cio-n alkynyl.
  • R 6 is optionally substituted Cn_5o alkynyl. In some embodiments, R 6 is optionally substituted Cn_ 4 o alkynyl. In some embodiments, R 6 is optionally substituted Cn_ 3 o alkynyl. In some embodiments, R 6 is optionally substituted Cn_2o alkynyl. In some embodiments, R 6 is optionally substituted Cn_i 9 alkynyl. In some embodiments, R 6 is optionally substituted Cn_ig alkynyl. In some embodiments, R 6 is optionally substituted Cn_i7 alkynyl. In some embodiments, R 6 is optionally substituted Cn_i6 alkynyl. In some embodiments,
  • R 6 is optionally substituted Cn_is alkynyl. In some embodiments, R 6 is optionally substituted C 11-14 alkynyl. In some embodiments, R 6 is optionally substituted C 11-13 alkynyl. In some embodiments, R 6 is optionally substituted C 11-12 alkynyl.
  • R 6 is optionally substituted C 12 -50 alkynyl. In some embodiments, R 6 is optionally substituted C 12 -40 alkynyl. In some embodiments, R 6 is optionally substituted C 12 -30 alkynyl. In some embodiments, R 6 is optionally substituted C 12 - 20 alkynyl. In some embodiments, R 6 is optionally substituted C 12 -1 alkynyl. In some embodiments, R 6 is optionally substituted C 12-18 alkynyl. In some embodiments, R 6 is optionally substituted C 12-17 alkynyl. In some embodiments, R 6 is optionally substituted C 12-16 alkynyl. In some
  • R 6 is optionally substituted C 12-15 alkynyl. In some embodiments, R 6 is optionally substituted C 12-14 alkynyl. In some embodiments, R 6 is optionally substituted C 12-13 alkynyl.
  • R 6 is optionally substituted C 6 alkynyl. In some embodiments, R 6 is optionally substituted C 7 alkynyl. In some embodiments, R 6 is optionally substituted Cg alkynyl. In some embodiments, R 6 is optionally substituted C9 alkynyl. In some embodiments, R 6 is optionally substituted C 10 alkynyl. In some embodiments, R 6 is optionally substituted Cn alkynyl. In some embodiments, R 6 is optionally substituted C 12 alkynyl. In some embodiments, R 6 is optionally substituted C 13 alkynyl. In some embodiments, R 6 is optionally substituted C 14 alkynyl.
  • R 6 is optionally substituted C 15 alkynyl. In some embodiments, R 6 is optionally substituted C 16 alkynyl. In some embodiments, R 6 is optionally substituted C 17 alkynyl. In some embodiments, R 6 is optionally substituted C 18 alkynyl. In some embodiments, R 6 is optionally substituted C19 alkynyl. In some embodiments, R 6 is optionally substituted C 20 alkynyl.
  • R 6 is a substituted alkynyl group.
  • R 6 is an unsubstituted alknyl group.
  • R 6 is an optionally substituted straight-chain alkynyl group.
  • R 6 is a substituted straight-chain alkynyl group. In some embodiments, R 6 is an unsubstituted straight-chain alkynyl group. In some embodiments, R 6 is an optionally substituted branched alkynyl group. In some embodiments, R 6 is a substituted branched alkynyl group. In some embodiments, R 6 is an unsubstituted branched alkynyl group. [0152] In some embodiments, R 6 is optionally substituted carbocyclyl. In some embodiments, R 6 is optionally substituted heterocyclyl. In some embodiments, R 6 is optionally substituted aryl. In some embodiments, R 6 is optionally substituted heteroaryl. In some embodiments, R 6 is a nitrogen protecting group.
  • R 6 is a group of formula (i). In some embodiments, R 6 is
  • R 6 is a group of formula (i _ai )- I n some embodiments, R 6 is a group of formula (i-b). In some embodiments, R 6 is a group of formula (ii). In some embodiments, R 6 is a group of formula (iii).
  • R 6 is substituted with one or more hydroxyl groups. In some embodiments, R 6 is substituted with one hydroxyl group. In some embodiments, R 6 is substituted with one 2-hydroxyl group (CI is the carbon atom directly bonded to the nitrogen atom depicted in formula (iv)).
  • each R 7 is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group, or a group of formula (i), (ii) or (iii).
  • R 7 is hydrogen
  • R 7 is optionally substituted alkyl. In some embodiments,
  • R 7 is optionally substituted C 2 -50 alkyl. In some embodiments, R 7 is optionally substituted C 2 -40 alkyl. In some embodiments, R 7 is optionally substituted C 2 -30 alkyl. In some embodiments, R 7 is optionally substituted C 2 - 20 alkyl. In some embodiments, R 7 is optionally substituted C 2 -19 alkyl. In some embodiments, R 7 is optionally substituted C 2-18 alkyl. In some embodiments, R 7 is optionally substituted C 2-17 alkyl. In some embodiments, R 7 is optionally substituted C 2-16 alkyl. In some embodiments, R 7 is optionally substituted C 2-15 alkyl. In some embodiments, R 7 is optionally substituted C 2-14 alkyl.
  • R 7 is optionally substituted C 2-13 alkyl. In some embodiments, R 7 is optionally substituted C 2-12 alkyl. In some embodiments, R 7 is optionally substituted C 2-11 alkyl. In some embodiments, R 7 is optionally substituted C 2-10 alkyl. In some embodiments, R is optionally substituted C 2 -9 alkyl. In some embodiments, R is optionally substituted C 2 _8 alkyl. In some embodiments, R 7 is optionally substituted C 2 _7 alkyl. In some embodiments, R 7 is optionally substituted C 2 -6 alkyl.
  • R 7 is optionally substituted C4-50 alkyl. In some embodiments, R 7 is optionally substituted C4-40 alkyl. In some embodiments, R 7 is optionally substituted C 4 _ 30 alkyl. In some embodiments, R 7 is optionally substituted C 4 _ 2 o alkyl. In some embodiments, R 7 is optionally substituted C4-19 alkyl. In some embodiments, R 7 is optionally substituted C 4-18 alkyl. In some embodiments, R 7 is optionally substituted C 4-17 alkyl. In some embodiments, R 7 is optionally substituted C 4-16 alkyl. In some embodiments, R 7 is optionally substituted C 4 _i 5 alkyl.
  • R 7 is optionally substituted C 4 _i 4 alkyl. In some embodiments, R 7 is optionally substituted C 4-13 alkyl. In some embodiments, R 7 is optionally substituted C 4-12 alkyl. In some embodiments, R 7 is optionally substituted C4-11 alkyl. In some embodiments, R 7 is optionally substituted C4-10 alkyl. In some embodiments, R 7 is optionally substituted C 4 _ 9 alkyl. In some embodiments, R 7 is optionally substituted C 4 _ 8 alkyl. In some embodiments, R 7 is optionally substituted C4-7 alkyl. In some embodiments, R 7 is optionally substituted C 4 -6 alkyl.
  • R 7 is optionally substituted C 6 -5o alkyl. In some embodiments, R 7 is optionally substituted C 6 _ 4 o alkyl. In some embodiments, R 7 is optionally substituted C 6 _ 3 o alkyl. In some embodiments, R 7 is optionally substituted C 6 _ 2 o alkyl. In some embodiments, R 7 is optionally substituted C 6 -i9 alkyl. In some embodiments, R 7 is optionally substituted C 6-18 alkyl. In some embodiments, R 7 is optionally substituted C 6 -i7 alkyl. In some embodiments, R 7 is optionally substituted C 6-1 6 alkyl.
  • R 7 is optionally substituted C 6-15 alkyl. In some embodiments, R 7 is optionally substituted C 6-14 alkyl. In some embodiments, R 7 is optionally substituted C 6-13 alkyl. In some embodiments, R 7 is optionally substituted C 6-12 alkyl. In some embodiments, R 7 is optionally substituted C 6-11 alkyl. In some embodiments, R 7 is optionally substituted C 6-1 o alkyl. In some embodiments, R 7 is optionally substituted C 6 _9 alkyl. In some embodiments, R 7 is optionally substituted C 6 _8 alkyl. In some embodiments, R 7 is optionally substituted C 6 -7 alkyl.
  • R 7 is optionally substituted Cg-so alkyl. In some embodiments, R 7 is optionally substituted Cg- 4 o alkyl. In some embodiments, R 7 is optionally substituted Cg- 3 o alkyl. In some embodiments, R is optionally substituted Cg- 2 o alkyl. In some embodiments, R 7 is optionally substituted C 8 _i9 alkyl. In some embodiments, R 7 is optionally substituted Cg-is alkyl. In some embodiments, R 7 is optionally substituted Cg-n alkyl. In some embodiments, R 7 is optionally substituted Cg_i 6 alkyl.
  • R 7 is optionally substituted Cg_i 5 alkyl. In some embodiments, R 7 is optionally substituted Cg_i 4 alkyl. In some embodiments, R 7 is optionally substituted C 8 _i 3 alkyl. In some embodiments, R 7 is optionally substituted C 8-12 alkyl. In some embodiments, R 7 is optionally substituted C 8-11 alkyl. In some embodiments, R 7 is optionally substituted C 8-10 alkyl. In some embodiments, R 7 is optionally substituted Cg-9 alkyl.
  • R 7 is optionally substituted C 9 _ 50 alkyl. In some embodiments, R 7 is optionally substituted Cg- 4 o alkyl. In some embodiments, R 7 is optionally substituted C9-30 alkyl. In some embodiments, R 7 is optionally substituted C9-20 alkyl. In some embodiments, R 7 is optionally substituted C9-19 alkyl. In some embodiments, R 7 is optionally substituted C 9 _i 8 alkyl. In some embodiments, R 7 is optionally substituted C 9 _i7 alkyl. In some embodiments, R 7 is optionally substituted C9-16 alkyl. In some embodiments, R 7 is optionally substituted C9-15 alkyl.
  • R 7 is optionally substituted Cg-i 4 alkyl. In some embodiments, R 7 is optionally substituted Cg-i 3 alkyl. In some embodiments, R 7 is optionally substituted C 9 _i 2 alkyl. In some embodiments, R 7 is optionally substituted C 9 _n alkyl. In some embodiments, R 7 is optionally substituted C 9 _i 0 alkyl.
  • R 7 is optionally substituted Cio-50 alkyl. In some embodiments, R 7 is optionally substituted Cio- 4 o alkyl. In some embodiments, R 7 is optionally substituted Cio- 3 o alkyl. In some embodiments, R 7 is optionally substituted Cio- 20 alkyl. In some embodiments, R 7 is optionally substituted C 10 -19 alkyl. In some embodiments, R 7 is optionally substituted Cio-ig alkyl. In some embodiments, R 7 is optionally substituted C 10 -17 alkyl. In some embodiments, R 7 is optionally substituted C 10 -16 alkyl. In some embodiments, R 7 is optionally substituted Cio-15 alkyl.
  • R 7 is optionally substituted Cio-i 4 alkyl. In some embodiments, R 7 is optionally substituted Ci 0 _i 3 alkyl. In some embodiments, R 7 is optionally substituted Cio- 12 alkyl. In some embodiments, R 7 is optionally substituted Cio- 11 alkyl.
  • R 7 is optionally substituted Cn_so alkyl. In some embodiments, R 7 is optionally substituted Cn.40 alkyl. In some embodiments, R 7 is optionally substituted Cii_3o alkyl. In some embodiments, R is optionally substituted C 11-20 alkyl. In some embodiments, R 7 is optionally substituted Cn_i 9 alkyl. In some embodiments, R 7 is optionally substituted C 11-18 alkyl. In some embodiments, R 7 is optionally substituted C 11-17 alkyl. In some embodiments, R 7 is optionally substituted C 11-16 alkyl. In some embodiments, R 7 is optionally substituted C 11-15 alkyl. In some embodiments, R 7 is optionally substituted C 11-14 alkyl. In some embodiments, R 7 is optionally substituted C 11-13 alkyl. In some embodiments, R 7 is optionally substituted C 11-12 alkyl.
  • R 7 is optionally substituted C12-50 alkyl. In some embodiments, R 7 is optionally substituted C 12-40 alkyl. In some embodiments, R 7 is optionally substituted C12-30 alkyl. In some embodiments, R 7 is optionally substituted C12-20 alkyl. In some embodiments, R 7 is optionally substituted C 12-19 alkyl. In some embodiments, R 7 is optionally substituted C 12-18 alkyl. In some embodiments, R 7 is optionally substituted C 12-17 alkyl. In some embodiments, R 7 is optionally substituted C 12-16 alkyl. In some embodiments, R 7 is optionally substituted C 12-15 alkyl. In some embodiments, R 7 is optionally substituted C 12-14 alkyl. In some embodiments, R 7 is optionally substituted C 12-13 alkyl.
  • R 7 is optionally substituted C 6 alkyl.
  • R 7 is optionally substituted C 7 alkyl. In some embodiments, R 7 is optionally substituted C 8 alkyl. In some embodiments, R 7 is optionally substituted C 9 alkyl. In some embodiments, R 7 is optionally substituted C 10 alkyl. In some embodiments, R 7 is optionally substituted Cn alkyl. In some embodiments, R 7 is optionally substituted C 12 alkyl. In some embodiments, R 7 is optionally substituted C 13 alkyl. In some embodiments, R 7 is optionally substituted C 14 alkyl. In some embodiments, R 7 is optionally substituted C 15 alkyl. In some embodiments, R 7 is optionally substituted C 16 alkyl.
  • R 7 is optionally substituted C 17 alkyl. In some embodiments, R 7 is optionally substituted C 18 alkyl. In some embodiments, R 7 is optionally substituted C19 alkyl. In some embodiments, R 7 is optionally substituted C20 alkyl.
  • R 7 is a substituted alkyl group. In some embodiments, R 7 is an unsubstituted alkyl group. In some embodiments, R 7 is an optionally substituted straight-chain alkyl group. In some embodiments, R 7 is a substituted straight-chain alkyl group. In some embodiments, R 7 is an unsubstituted straight-chain alkyl group. In some embodiments, R is an optionally substituted branched alkyl group. In some embodiments, R 7 is a substituted branched alkyl group. In some embodiments, R 7 is an unsubstituted branched alkyl group.
  • R 7 is optionally substituted alkenyl.
  • R 7 is optionally substituted C 2 -50 alkenyl. In some embodiments, R 7 is optionally substituted C 2 - 4 o alkenyl. In some embodiments, R 7 is optionally substituted C 2 -30 alkenyl. In some embodiments, R 7 is optionally substituted C 2 - 20 alkenyl. In some embodiments, R 7 is optionally substituted C 2 -19 alkenyl. In some embodiments, R 7 is optionally substituted C 2-18 alkenyl. In some embodiments, R 7 is optionally substituted C 2-17 alkenyl. In some embodiments, R 7 is optionally substituted C 2-16 alkenyl. In some embodiments, R 7 is optionally substituted C 2 _ 15 alkenyl. In some embodiments, R 7 is optionally substituted C 2-14 alkenyl. In some embodiments, R 7 is optionally substituted C 2 -50 alkenyl. In some embodiments, R 7 is optionally substituted C 2 - 4 o alkenyl. In some embodiment
  • R 7 is optionally substituted C 2-13 alkenyl. In some embodiments, R 7 is optionally substituted C 2-12 alkenyl. In some embodiments, R 7 is optionally substituted C 2 -n alkenyl. In some embodiments, R 7 is optionally substituted C 2-10 alkenyl. In some embodiments, R 7 is optionally substituted C 2 -9 alkenyl. In some embodiments, R 7 is optionally substituted C 2 _8 alkenyl. In some embodiments, R 7 is optionally substituted C 2 -7 alkenyl. In some embodiments, R 7 is optionally substituted C 2 - 6 alkenyl.
  • R 7 is optionally substituted C 4 _ 50 alkenyl. In some embodiments, R 7 is optionally substituted C 4 _ 40 alkenyl. In some embodiments, R 7 is optionally substituted C 4 -30 alkenyl. In some embodiments, R 7 is optionally substituted C 4 - 20 alkenyl. In some embodiments, R 7 is optionally substituted C 4 -19 alkenyl. In some embodiments, R 7 is optionally substituted C 4-18 alkenyl. In some embodiments, R 7 is optionally substituted C 4-17 alkenyl. In some embodiments, R 7 is optionally substituted C 4 _i 6 alkenyl.
  • R 7 is optionally substituted C 4-15 alkenyl. In some embodiments, R 7 is optionally substituted C 4- 14 alkenyl. In some embodiments, R 7 is optionally substituted C 4 _i3 alkenyl. In some
  • R 7 is optionally substituted C 4-12 alkenyl. In some embodiments, R 7 is optionally substituted C 4-11 alkenyl. In some embodiments, R 7 is optionally substituted C 4 _i 0 alkenyl. In some embodiments, R 7 is optionally substituted C 4 -9 alkenyl. In some embodiments, R 7 is optionally substituted C 4 _8 alkenyl. In some embodiments, R 7 is optionally substituted C 4 -7 alkenyl. In some embodiments, R 7 is optionally substituted C 4 _ 6 alkenyl. [0169] In some embodiments, R is optionally substituted C 6 -5o alkenyl.
  • R 7 is optionally substituted C 6 _4o alkenyl. In some embodiments, R 7 is optionally substituted C 6 -3o alkenyl. In some embodiments, R 7 is optionally substituted C 6 -2o alkenyl. In some embodiments, R 7 is optionally substituted C 6 -i9 alkenyl. In some embodiments, R 7 is optionally substituted C 6-1 8 alkenyl. In some embodiments, R 7 is optionally substituted C 6-1 7 alkenyl. In some embodiments, R 7 is optionally substituted C 6 _i6 alkenyl. In some embodiments, R 7 is optionally substituted C 6-15 alkenyl. In some embodiments, R 7 is optionally substituted C 6- 14 alkenyl. In some embodiments, R 7 is optionally substituted C 6-13 alkenyl. In some embodiments, R 7 is optionally substituted C 6 _4o alkenyl. In some embodiments, R 7 is optionally substituted C 6 -3o alkenyl
  • R 7 is optionally substituted C 6-12 alkenyl. In some embodiments, R 7 is optionally substituted C 6 -n alkenyl. In some embodiments, R 7 is optionally substituted C 6 _io alkenyl. In some embodiments, R 7 is optionally substituted C 6 -9 alkenyl. In some embodiments, R 7 is optionally substituted C 6 _g alkenyl. In some embodiments, R 7 is optionally substituted C 6 -7 alkenyl.
  • R 7 is optionally substituted Cg_ 50 alkenyl. In some embodiments, R 7 is optionally substituted Cg-40 alkenyl. In some embodiments, R 7 is optionally substituted Cg_3o alkenyl. In some embodiments, R 7 is optionally substituted Cg_ 2 o alkenyl. In some embodiments, R 7 is optionally substituted Cg-i9 alkenyl. In some embodiments, R 7 is optionally substituted C 8 _i 8 alkenyl. In some embodiments, R 7 is optionally substituted C 8-17 alkenyl. In some embodiments, R 7 is optionally substituted C 8-16 alkenyl. In some embodiments, R 7 is optionally substituted C 8-15 alkenyl. In some embodiments, R 7 is optionally substituted Cg_ 14 alkenyl. In some embodiments, R 7 is optionally substituted C 8-13 alkenyl. In some embodiments, R 7 is optionally substituted Cg_ 50 alkenyl. In some embodiments, R
  • R 7 is optionally substituted C 8-12 alkenyl. In some embodiments, R 7 is optionally substituted C 8-11 alkenyl. In some embodiments, R 7 is optionally substituted C 8-10 alkenyl. In some embodiments, R 7 is optionally substituted Cg_g alkenyl.
  • R 7 is optionally substituted C 9 -50 alkenyl. In some embodiments, R 7 is optionally substituted C 9 -40 alkenyl. In some embodiments, R 7 is optionally substituted C 9 _3 0 alkenyl. In some embodiments, R 7 is optionally substituted C 9 _ 2 o alkenyl. In some embodiments, R 7 is optionally substituted C 9 -19 alkenyl. In some embodiments, R 7 is optionally substituted Cg-ig alkenyl. In some embodiments, R 7 is optionally substituted C 9 -17 alkenyl. In some embodiments, R 7 is optionally substituted C 9 -16 alkenyl.
  • R is optionally substituted C9-15 alkenyl. In some embodiments, R is optionally substituted C9- 14 alkenyl. In some embodiments, R 7 is optionally substituted Cg_i3 alkenyl. In some embodiments, R 7 is optionally substituted C9-12 alkenyl. In some embodiments, R 7 is optionally substituted C9-11 alkenyl. In some embodiments, R 7 is optionally substituted C9-10 alkenyl.
  • R 7 is optionally substituted Cio-50 alkenyl. In some embodiments, R 7 is optionally substituted C 10-40 alkenyl. In some embodiments, R 7 is optionally substituted Cio-30 alkenyl. In some embodiments, R 7 is optionally substituted Cio-20 alkenyl. In some embodiments, R 7 is optionally substituted C 10-19 alkenyl. In some embodiments, R 7 is optionally substituted C10-18 alkenyl. In some embodiments, R 7 is optionally substituted C10-17 alkenyl. In some embodiments, R 7 is optionally substituted C10-16 alkenyl. In some embodiments,
  • R 7 is optionally substituted C10-15 alkenyl. In some embodiments, R 7 is optionally substituted Cio-14 alkenyl. In some embodiments, R 7 is optionally substituted C10-13 alkenyl. In some embodiments, R 7 is optionally substituted C 10-12 alkenyl. In some embodiments, R 7 is optionally substituted Cio-n alkenyl.
  • R 7 is optionally substituted Cn_5o alkenyl. In some embodiments, R 7 is optionally substituted Cn_4o alkenyl. In some embodiments, R 7 is optionally substituted Cn_3o alkenyl. In some embodiments, R 7 is optionally substituted Cn_2o alkenyl. In some embodiments, R 7 is optionally substituted Cn_i 9 alkenyl. In some embodiments, R 7 is optionally substituted Cn_i 8 alkenyl. In some embodiments, R 7 is optionally substituted Cn_i 7 alkenyl. In some embodiments, R 7 is optionally substituted Cn_i6 alkenyl. In some embodiments, R 7 is optionally substituted Cn_5o alkenyl. In some embodiments, R 7 is optionally substituted Cn_4o alkenyl. In some embodiments, R 7 is optionally substituted Cn_3o alkenyl. In some embodiments, R 7 is optionally substituted Cn_2o
  • R 7 is optionally substituted Cn_is alkenyl. In some embodiments, R 7 is optionally substituted Cn_i4 alkenyl. In some embodiments, R 7 is optionally substituted Cn_i3 alkenyl. In some embodiments, R 7 is optionally substituted Cn_i 2 alkenyl.
  • R 7 is optionally substituted C12-50 alkenyl. In some embodiments, R 7 is optionally substituted C 12-40 alkenyl. In some embodiments, R 7 is optionally substituted C12-30 alkenyl. In some embodiments, R 7 is optionally substituted C12-20 alkenyl. In some embodiments, R 7 is optionally substituted C 12-19 alkenyl. In some embodiments, R 7 is optionally substituted C12-18 alkenyl. In some embodiments, R 7 is optionally substituted C 12-17 alkenyl. In some embodiments, R 7 is optionally substituted C 12-16 alkenyl. In some embodiments, R is optionally substituted C 12-15 alkenyl. In some embodiments, R is optionally substituted C 12-14 alkenyl. In some embodiments, R 7 is optionally substituted C 12-13 alkenyl.
  • R 7 is optionally substituted C 6 alkenyl. In some embodiments, R 7 is optionally substituted C 7 alkenyl. In some embodiments, R 7 is optionally substituted Cg alkenyl. In some embodiments, R 7 is optionally substituted C9 alkenyl. In some embodiments, R 7 is optionally substituted C 10 alkenyl. In some embodiments, R 7 is optionally substituted Cn alkenyl. In some embodiments, R 7 is optionally substituted C 12 alkenyl. In some embodiments, R 7 is optionally substituted C 13 alkenyl. In some embodiments, R 7 is optionally substituted C 14 alkenyl.
  • R 7 is optionally substituted C 15 alkenyl. In some embodiments, R 7 is optionally substituted C 16 alkenyl. In some embodiments, R 7 is optionally substituted C 17 alkenyl. In some embodiments, R 7 is optionally substituted C 18 alkenyl. In some embodiments, R 7 is optionally substituted C19 alkenyl. In some embodiments, R 7 is optionally substituted C 20 alkenyl.
  • R 7 is a substituted alkenyl group.
  • R 7 is an unsubstituted alkenyl group.
  • R 7 is an optionally substituted straight-chain alkenyl group.
  • R 7 is a substituted straight-chain alkenyl group. In some embodiments, R 7 is an unsubstituted straight-chain alkenyl group. In some embodiments, R 7 is an optionally substituted branched alkenyl group. In some embodiments, R 7 is a substituted branched alkenyl group. In some embodiments, R 7 is an unsubstituted branched alkenyl group.
  • R 7 is optionally substituted alkynyl.
  • R 7 is optionally substituted C 2 -50 alkynyl. In some embodiments, R 7 is optionally substituted C 2 _4o alkynyl. In some embodiments, R 7 is optionally substituted C 2 -30 alkynyl. In some embodiments, R 7 is optionally substituted C 2 - 20 alkynyl. In some embodiments, R 7 is optionally substituted C 2 -19 alkynyl. In some embodiments, R 7 is optionally substituted C 2-18 alkynyl. In some embodiments, R 7 is optionally substituted C 2-17 alkynyl. In some
  • R 7 is optionally substituted C 2-16 alkynyl. In some embodiments, R 7 is optionally substituted C 2-15 alkynyl. In some embodiments, R 7 is optionally substituted C 2-14 alkynyl. In some embodiments, R 7 is optionally substituted C 2-13 alkynyl. In some embodiments, R 7 is optionally substituted C 2-12 alkynyl. In some embodiments, R 7 is optionally substituted C 2-11 alkynyl. In some embodiments, R is optionally substituted C 2-10 alkynyl. In some embodiments, R 7 is optionally substituted C 2 _ 9 alkynyl. In some embodiments, R 7 is optionally substituted C 2 _g alkynyl. In some embodiments, R 7 is optionally substituted C 2 _ 7 alkynyl. In some embodiments, R 7 is optionally substituted C 2 _ 6 alkynyl.
  • R 7 is optionally substituted C4-50 alkynyl. In some embodiments, R 7 is optionally substituted C 4 _ 40 alkynyl. In some embodiments, R 7 is optionally substituted C 4 _ 3 o alkynyl. In some embodiments, R 7 is optionally substituted C 4 _ 2 o alkynyl. In some embodiments, R 7 is optionally substituted C 4 _ig alkynyl. In some embodiments, R 7 is optionally substituted C 4 _ig alkynyl. In some embodiments, R 7 is optionally substituted C 4 _i 7 alkynyl. In some embodiments, R 7 is optionally substituted C 4 _i 6 alkynyl. In some embodiments,
  • R 7 is optionally substituted C 4 _i 5 alkynyl. In some embodiments, R 7 is optionally substituted C 4 _i 4 alkynyl. In some embodiments, R 7 is optionally substituted C 4 _i 3 alkynyl. In some embodiments, R 7 is optionally substituted C 4 _i 2 alkynyl. In some embodiments, R 7 is optionally substituted C _n alkynyl. In some embodiments, R 7 is optionally substituted C _i 0 alkynyl. In some embodiments, R 7 is optionally substituted C 4 _9 alkynyl. In some embodiments, R 7 is optionally substituted C 4 _g alkynyl. In some embodiments, R 7 is optionally substituted C 4 _ 7 alkynyl. In some embodiments, R 7 is optionally substituted C 4 _ 6 alkynyl.
  • R 7 is optionally substituted C 6 _5o alkynyl. In some embodiments, R 7 is optionally substituted C 6 _ 4 o alkynyl. In some embodiments, R 7 is optionally substituted C 6 - 3 o alkynyl. In some embodiments, R 7 is optionally substituted C 6 - 2 o alkynyl. In some embodiments, R 7 is optionally substituted C 6 -i9 alkynyl. In some embodiments, R 7 is optionally substituted C 6-1 8 alkynyl. In some embodiments, R 7 is optionally substituted C 6 -i 7 alkynyl. In some embodiments, R 7 is optionally substituted C 6 _i6 alkynyl. In some embodiments,
  • R 7 is optionally substituted C 6-15 alkynyl. In some embodiments, R 7 is optionally substituted C 6-14 alkynyl. In some embodiments, R 7 is optionally substituted C 6-13 alkynyl. In some embodiments, R 7 is optionally substituted C 6-12 alkynyl. In some embodiments, R 7 is optionally substituted C 6 _n alkynyl. In some embodiments, R 7 is optionally substituted C 6 _io alkynyl. In some embodiments, R 7 is optionally substituted C 6 _9 alkynyl. In some embodiments, R 7 is optionally substituted C 6 -8 alkynyl.
  • R 7 is optionally substituted C 6 - 7 alkynyl. [0180] In some embodiments, R is optionally substituted Cg-so alkynyl. In some embodiments, R 7 is optionally substituted C 8 _4o alkynyl. In some embodiments, R 7 is optionally substituted Cg- 3 o alkynyl. In some embodiments, R 7 is optionally substituted Cg_ 2 o alkynyl. In some embodiments, R 7 is optionally substituted Cg-i9 alkynyl. In some embodiments, R 7 is optionally substituted Cg_ig alkynyl. In some embodiments, R 7 is optionally substituted Cg_i 7 alkynyl. In some embodiments, R 7 is optionally substituted Cg_i 7 alkynyl. In some embodiments, R 7 is optionally substituted C 8 _i 6 alkynyl. In some embodiments, R is optionally substituted Cg-so alkynyl.
  • R 7 is optionally substituted C 8-15 alkynyl. In some embodiments, R 7 is optionally substituted C 8-14 alkynyl. In some embodiments, R 7 is optionally substituted C 8-13 alkynyl. In some embodiments, R 7 is optionally substituted C 8-12 alkynyl. In some embodiments, R 7 is optionally substituted C 8 _n alkynyl. In some embodiments, R 7 is optionally substituted C 8-10 alkynyl. In some embodiments, R 7 is optionally substituted Cg_9 alkynyl.
  • R 7 is optionally substituted C9-50 alkynyl. In some embodiments, R 7 is optionally substituted C9-40 alkynyl. In some embodiments, R 7 is optionally substituted C 9 _3 0 alkynyl. In some embodiments, R 7 is optionally substituted C 9 _ 2 o alkynyl. In some embodiments, R 7 is optionally substituted C9-19 alkynyl. In some embodiments, R 7 is optionally substituted C9-18 alkynyl. In some embodiments, R 7 is optionally substituted Cg.n alkynyl. In some embodiments, R 7 is optionally substituted C9_i 6 alkynyl. In some
  • R 7 is optionally substituted C 9 _i 5 alkynyl. In some embodiments, R 7 is optionally substituted C 9 _i 4 alkynyl. In some embodiments, R 7 is optionally substituted C 9 _i 3 alkynyl. In some embodiments, R 7 is optionally substituted C9-12 alkynyl. In some embodiments, R 7 is optionally substituted C9-11 alkynyl. In some embodiments, R 7 is optionally substituted C9-10 alkynyl.
  • R 7 is optionally substituted Cio-50 alkynyl. In some embodiments, R 7 is optionally substituted C 10-40 alkynyl. In some embodiments, R 7 is optionally substituted Cio-30 alkynyl. In some embodiments, R 7 is optionally substituted Cio-20 alkynyl. In some embodiments, R 7 is optionally substituted C 10-19 alkynyl. In some embodiments, R 7 is optionally substituted C 10-18 alkynyl. In some embodiments, R 7 is optionally substituted C 10-17 alkynyl. In some embodiments, R 7 is optionally substituted C10-16 alkynyl. In some embodiments,
  • R 7 is optionally substituted C 10-15 alkynyl. In some embodiments, R 7 is optionally substituted C 10-14 alkynyl. In some embodiments, R 7 is optionally substituted C 10-13 alkynyl. In some embodiments, R is optionally substituted C 10-12 alkynyl. In some embodiments, R is optionally substituted C 10-11 alkynyl.
  • R 7 is optionally substituted C 11-50 alkynyl. In some embodiments, R 7 is optionally substituted C 11-40 alkynyl. In some embodiments, R 7 is optionally substituted C 11-30 alkynyl. In some embodiments, R 7 is optionally substituted C 11-20 alkynyl. In some embodiments, R 7 is optionally substituted Cn_i 9 alkynyl. In some embodiments, R 7 is optionally substituted C 11-18 alkynyl. In some embodiments, R 7 is optionally substituted C 11-17 alkynyl. In some embodiments, R 7 is optionally substituted C 11-16 alkynyl. In some embodiments, R 7 is optionally substituted C 11-50 alkynyl. In some embodiments, R 7 is optionally substituted C 11-40 alkynyl. In some embodiments, R 7 is optionally substituted C 11-30 alkynyl. In some embodiments, R 7 is optionally substituted C 11-20 alkynyl. In some embodiments,
  • R 7 is optionally substituted C 11-15 alkynyl. In some embodiments, R 7 is optionally substituted C 11-14 alkynyl. In some embodiments, R 7 is optionally substituted C 11-13 alkynyl. In some embodiments, R 7 is optionally substituted C 11-12 alkynyl.
  • R 7 is optionally substituted C12-50 alkynyl. In some embodiments, R 7 is optionally substituted C 12-40 alkynyl. In some embodiments, R 7 is optionally substituted C12-30 alkynyl. In some embodiments, R 7 is optionally substituted C12-20 alkynyl. In some embodiments, R 7 is optionally substituted C 12-19 alkynyl. In some embodiments, R 7 is optionally substituted C 12-18 alkynyl. In some embodiments, R 7 is optionally substituted C 12-17 alkynyl. In some embodiments, R 7 is optionally substituted C 12-16 alkynyl. In some embodiments,
  • R 7 is optionally substituted C 12-15 alkynyl. In some embodiments, R 7 is optionally substituted C 12-14 alkynyl. In some embodiments, R 7 is optionally substituted C 12-13 alkynyl.
  • R 7 is optionally substituted C 6 alkynyl. In some embodiments, R 7 is optionally substituted C 7 alkynyl. In some embodiments, R 7 is optionally substituted Cg alkynyl. In some embodiments, R 7 is optionally substituted C9 alkynyl. In some embodiments, R 7 is optionally substituted C 10 alkynyl. In some embodiments, R 7 is optionally substituted Cn alkynyl. In some embodiments, R 7 is optionally substituted C 12 alkynyl. In some embodiments, R 7 is optionally substituted C 13 alkynyl. In some embodiments, R 7 is optionally substituted C 14 alkynyl.
  • R 7 is optionally substituted C 15 alkynyl. In some embodiments, R 7 is optionally substituted C 16 alkynyl. In some embodiments, R 7 is optionally substituted C 17 alkynyl. In some embodiments, R 7 is optionally substituted C 18 alkynyl. In some embodiments, R 7 is optionally substituted C19 alkynyl. In some embodiments, R 7 is optionally substituted C20 alkynyl. [0186] In some embodiments, for example, in any of the above embodiments, R is a substituted alkynyl group. In some embodiments, R 7 is an unsubstituted alkynyl group. In some embodiments, R 7 is an optionally substituted straight-chain alkynyl group. In some
  • R 7 is a substituted straight-chain alkynyl group. In some embodiments, R 7 is an unsubstituted straight-chain alkynyl group. In some embodiments, R 7 is an optionally substituted branched alkynyl group. In some embodiments, R 7 is a substituted branched alkynyl group. In some embodiments, R 7 is an unsubstituted branched alkynyl group.
  • R 7 is optionally substituted carbocyclyl. In some embodiments, R 7 is optionally substituted heterocyclyl. In some embodiments, R 7 is optionally substituted aryl. In some embodiments, R 7 is optionally substituted heteroaryl. In some embodiments, R 7 is a nitrogen protecting group.
  • R 7 is a group of formula (i). In some embodiments, R 7 is a
  • R 7 is a group of formula (i _ai )- I n some embodiments, R 7 is a group of formula (i-b). In some embodiments, R 7 is a group of formula (ii). In some embodiments, R 7 is a group of formula (iii).
  • At least one instance of R 6 and R 7 is a group of the formula
  • each instance of R 6 and R 7 is independently a group of the formula (i), (ii) or (iii). In some embodiments, each instance of R 6 and R 7 is independently a group of the formula (i). In some embodiments, each instance of R 6 and R 7 is independently a group of the formula (i-a). In some embodiments, each instance of R 6 and R 7 is independently a group of the formula (i-b). In some embodiments, each instance of R 6 and R 7 is independently a group of the formula (ii). In some embodiments, each instance of R 6 and R 7 is independently a group of the formula (iii). In some embodiments, each instance of R 6 and R 7 is independently a group of the formula (iii).
  • R 6 and R 7 are the same. In some embodiments, R 6 and R 7 are different.
  • both R 6 and R 7 are hydrogen. In certain embodiments,
  • R 6 is hydrogen and R 7 is a group of the formula (i), (ii), or (iii). In certain embodiments, R 6 is hydrogen and R 7 is a group of the formula (i). In certain embodiments, R 6 is hydrogen and R 7 is a group of the formula (ii). In certain embodiments, R 6 is hydrogen and R 7 is a group of the formula (iii). In certain embodiments, each of R 6 and R 7 is independently a group of the formula
  • each of R 6 and R 7 is independently a group of the formula (i). In certain embodiments, each of R 6 and R 7 is independently a group of the formula
  • each of R 6 and R 7 is independently a group of the formula (iii). In certain embodiments, R 6 and R 7 are the same group, which is selected from formulas (i), (ii), and
  • R 6 and R 7 are the same group of formula (i). In some embodiments, R 6 and R 7 are the same group of formula (i-a). In some embodiments, R 6 and R 7 are the same group of formula (i-al). In some embodiments, R 6 and R 7 are the same group of formula (i-b).
  • R 6 and R 7 are the same group of formula (i-al), wherein R L is as defined above and described herein. In some embodiments, R 6 and R 7 are the
  • R L is optionally substituted Ci_ 5 oalkyl, optionally substituted C 2 _ 5 oalkenyl, optionally substituted C 2 _ 5 oalkynyl, optionally substituted heteroCi_ 50 alkyl, optionally substituted heteroC 2 _ 50 alkenyl, or optionally substituted heteroC 2 _
  • R 6 and R 7 are the same group of formula (i-al), wherein R L is optionally substituted C 5 - 5 oalkyl, optionally substituted C 5 - 5 oalkenyl, optionally substituted C 5 - 5 oalkynyl, optionally substituted heteroCs-soalkyl, optionally substituted heteroCs- 50 alkenyl, or optionally substituted heteroCs_ 5 oalkynyl. In some embodiments, R 6 and R 7 are the
  • R L is optionally substituted C 5 - 4 oalkyl, optionally substituted C 5 - 4 oalkenyl, optionally substituted C 5 - 4 oalkynyl, optionally substituted heteroC 5 _ 4 oalkyl, optionally substituted heteroCs- 4 oalkenyl, or optionally substituted heteroCs-
  • R 6 and R 7 are the same group of formula (i-al), wherein R L is optionally substituted C 5 - 3 oalkyl, optionally substituted C 5 - 3 oalkenyl, optionally substituted C 5 - 3 oalkynyl, optionally substituted heteroC 5 - 3 oalkyl, optionally substituted heteroCs- 3 0 alkenyl, or optionally substituted heteroC 5 _ 3 oalkynyl. In some embodiments, R 6 and R 7 are the same group of formula (i-al), wherein R L is optionally substituted C 5 - 3 oalkyl, optionally substituted C 5 - 3 oalkenyl, optionally substituted C 5 - 3 oalkynyl, optionally substituted heteroC 5 - 3 oalkyl, optionally substituted heteroCs- 3 0 alkenyl, or optionally substituted heteroC 5 _ 3 oalkynyl. In some embodiments, R 6 and R
  • R L is optionally substituted C 5-25 alkyl, optionally substituted Cs ⁇ alkenyl, optionally substituted Cs ⁇ alkynyl, optionally substituted heteroC 5 _ 25 alkyl, optionally substituted heteroCs ⁇ alkenyl, or optionally substituted heteroCs-
  • R 6 and R 7 are the same group of formula (i-al), wherein R L is optionally substituted C 5 - 2 oalkyl, optionally substituted C 5 - 2 oalkenyl, optionally substituted C 5 - 2 oalkynyl, optionally substituted heteroCs- 2 oalkyl, optionally substituted heteroCs- 2oalkenyl, or optionally substituted heteroC 5 _ 2 oalkynyl. In some embodiments, R 6 and R 7 are the same group of formula (i-al), wherein R L is optionally substituted C 5 - 2 oalkyl, optionally substituted C 5 - 2 oalkenyl, optionally substituted C 5 - 2 oalkynyl, optionally substituted heteroCs- 2 oalkyl, optionally substituted heteroCs- 2oalkenyl, or optionally substituted heteroC 5 _ 2 oalkynyl. In some embodiments, R 6 and R 7 are the
  • R L is optionally substituted Cs-isalkyl, optionally substituted Cs-isalkenyl, optionally substituted Cs-isalkynyl, optionally substituted heteroC 5 _i 5 alkyl, optionally substituted heteroCs-isalkenyl, or optionally substituted heteroCs-
  • R 6 and R 7 are the same group of formula (i-al), wherein R L is optionally substituted C 5 alkyl, optionally substituted C 5 alkenyl, optionally substituted C 5 alkynyl, optionally substituted heteroC 5 alkyl, optionally substituted
  • R 6 and R 7 are
  • R L is optionally substituted C 6 alkyl, optionally substituted C 6 alkenyl, optionally substituted C 6 alkynyl, optionally substituted heteroC 6 alkyl, optionally substituted heteroCealkenyl, or optionally substituted heteroCealkynyl.
  • R 6 and R 7 are the same group of formula (i-al), wherein R L is optionally substituted C 7 alkyl, optionally substituted C 7 alkenyl, optionally substituted C 7 alkynyl, optionally substituted heteroC 7 alkyl, optionally substituted heteroC 7 alkenyl, or optionally substituted heteroCvalkynyl. In some embodiments, R 6 and R 7 are the same group of
  • R L is optionally substituted Cg alkyl, optionally substituted Cg alkenyl, optionally substituted Cg alkynyl, optionally substituted heteroCgalkyl, optionally substituted heteroCgalkenyl, or optionally substituted heteroCgalkynyl.
  • R 6 and R 7 are the same group of formula wherein R L is optionally substituted
  • Cg alkyl optionally substituted Cg alkenyl, optionally substituted Cg alkynyl, optionally substituted heteroCgalkyl, optionally substituted heteroCgalkenyl, or optionally substituted
  • R 6 and R 7 are the same group of formula (i- al), wherein R L is optionally substituted Cio alkyl, optionally substituted Cio alkenyl, optionally substituted Cio alkynyl, optionally substituted heteroCi 0 alkyl, optionally substituted
  • R 6 and R 7 are independently substituted heteroCioalkenyl, or optionally substituted heteroCioalkynyl.
  • R 6 and R 7 are independently substituted heteroCioalkynyl.
  • R L is optionally substituted Cn alkyl, optionally substituted Cn alkenyl, optionally substituted Cn alkynyl, optionally substituted heteroC 11 alkyl, optionally substituted heteroCn alkenyl, or optionally substituted
  • R 6 and R 7 are the same group of formula al), wherein R L is optionally substituted C 12 alkyl, optionally substituted C 12 alkenyl, optionally substituted C 12 alkynyl, optionally substituted heteroCgalkyl, optionally substituted
  • R 6 and R 7 are independently substituted heteroCgalkenyl, or optionally substituted heteroCvalkynyl.
  • R 6 and R 7 are independently substituted heteroCvalkynyl.
  • R L is optionally substituted C 13 alkyl, optionally substituted C 13 alkenyl, optionally substituted C 13 alkynyl, optionally substituted heteroCgalkyl, optionally substituted heteroCgalkenyl, or optionally substituted heteroCi 3 alkynyl.
  • R 6 and R 7 are the same group of formula (i- al), wherein R L is optionally substituted C 14 alkyl, optionally substituted C 14 alkenyl, optionally substituted C 14 alkynyl, optionally substituted heteroC ⁇ alkyl, optionally substituted
  • R 6 and R 7 are heteroC ⁇ alkenyl, or optionally substituted heteroCualkynyl.
  • R 6 and R 7 are optionally substituted heteroCualkynyl.
  • R L is optionally substituted C 15 alkyl, optionally substituted C 15 alkenyl, optionally substituted C 15 alkynyl, optionally substituted heteroC 15 alkyl, optionally substituted heteroC 15 alkenyl, or optionally substituted
  • R 6 and R 7 are the same
  • R L is as defined above and described herein.
  • R 6 and R 7 are the same
  • R L is optionally substituted C 1-50 alkyl.
  • R 6 and R 7 are the same group of formula ⁇ ⁇ (i-al), wherein R L is optionally substituted C 5-50 alkyl. In some embodiments, R 6 and R 7 are the same group of
  • R 6 and R 7 are the same group of formula ( -al), wherein R L is optionally substituted
  • R 6 and R 7 are the same
  • R L is optionally substituted C 5-25 alkyl.
  • R 6 and R 7 are the same group of formula (i-al), wherein R L is optionally substituted C 5 _ 2 oalkyl.
  • R 6 and R 7 are the same group of formula (i-al), wherein R L is optionally substituted Cs-isalkyl. In some embodiments, R 6 and R 7 are the same group of
  • R 6 and R 7 are the same group of formula (i-al), wherein R L is optionally substituted
  • R 6 and R 7 are the same group of formula (i-al), wherein R L is optionally substituted C 7 alkyl. In some embodiments, R 6 and R 7 are the same
  • R 6 and R 7 are the same group of formula (i-al), wherein R L is optionally substituted C9 alkyl. In some embodiments, R 6 and R 7 are the same group of formula
  • R 6 and R 6 are optionally substituted C 10 alkyl.
  • R 6 and R 6 are optionally substituted C 10 alkyl.
  • R are the same group of formula 3 ⁇ 4 (i-al), wherein R is optionally substituted Cn alkyl.
  • R 6 and R 7 are the same group of formula (i-al), wherein R L is optionally substituted C 12 alkyl. In some embodiments, R 6 and R 7 are the same group of formula
  • R L is optionally substituted C 13 alkyl.
  • R 6 and R are the same group of formula substituted C 14 alkyl.
  • R 6 and R 7 are the same group of formula (i-al), wherein R L is optionally substituted C 15 alkyl.
  • each occurrence of R A1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to an sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R A1 groups, together with the nitrogen atom to which they are attached, are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring.
  • R A1 is hydrogen. In some embodiments, R A1 is optionally substituted alkyl. In some embodiments, R A1 is optionally substituted alkenyl. In some embodiments, R A1 is optionally substituted alkynyl. In some embodiments, R A1 is optionally substituted carbocyclyl. In some embodiments, R A1 is optionally substituted heterocyclyl. In some embodiments, R A1 is optionally substituted aryl. In some embodiments, R A1 is optionally substituted heteroaryl. In some embodiments, R A1 is an oxygen protecting group when attached to an oxygen atom. In some embodiments, R A1 is a sulfur protecting group when attached to a sulfur atom.
  • R A1 is a nitrogen protecting group when attached to a nitrogen atom.
  • two R A1 groups, together with the nitrogen atom to which they are attached, are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring.
  • each instance of R 2 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group, or a group of the formula (i), (ii), or (iii):
  • R 2 is hydrogen. In some embodiments, at least one instance of R 2 is hydrogen. In some embodiments, each instance of R 2 is hydrogen.
  • R 2 is optionally substituted alkyl; e.g., optionally substituted Ci_ 6 alkyl, optionally substituted C 2 _ 6 alkyl, optionally substituted C 3 _ 6 alkyl, optionally substituted C 4 _ 6 alkyl, optionally substituted C 4 _ 5 alkyl, or optionally substituted C 3 _ 4 alkyl.
  • R 2 is optionally substituted alkyl; e.g., optionally substituted Ci_ 6 alkyl, optionally substituted C 2 _ 6 alkyl, optionally substituted C 3 _ 6 alkyl, optionally substituted C 4 _ 6 alkyl, optionally substituted C 4 _ 5 alkyl, or optionally substituted C 3 - 4 alkyl.
  • R 2 is optionally substituted alkenyl, e.g., optionally substituted C 2 _ 6 alkenyl, optionally substituted C 3 _ 6 alkenyl, optionally substituted C 4 _ 6 alkenyl, optionally substituted C 4 _ 5 alkenyl, or optionally substituted C 3 _ 4 alkenyl.
  • At least one instance of R 2 is optionally substituted alkenyl, e.g., optionally substituted C 2 _ 6 alkenyl, optionally substituted C 3 _ 6 alkenyl, optionally substituted C 4 _ 6 alkenyl, optionally substituted C 4 _ 5 alkenyl, or optionally substituted C 3 _ 4 alkenyl.
  • R 2 is optionally substituted alkynyl, e.g., optionally substituted C 2 _ 6 alkynyl, optionally substituted C 3 _ 6 alkynyl, optionally substituted C 4 _ 6 alkynyl, optionally substituted C 4 _ 5 alkynyl, or optionally substituted C 3 _ 4 alkynyl.
  • At least one instance of R 2 is optionally substituted alkynyl, e.g., optionally substituted C 2 _ 6 alkynyl, optionally substituted C 3 _ 6 alkynyl, optionally substituted C 4 _ 6 alkynyl, optionally substituted C 4 _ 5 alkynyl, or optionally substituted C 3 _ 4 alkynyl.
  • R 2 is optionally substituted carbocyclyl, e.g., optionally substituted C 3 _iocarbocyclyl, optionally substituted Cs-scarbocyclyl, optionally substituted C 5 - 6 carbocyclyl, optionally substituted C 5 carbocyclyl, or optionally substituted C 6 carbocyclyl.
  • At least one instance of R 2 is optionally substituted carbocyclyl, e.g., optionally substituted C3_iocarbocyclyl, optionally substituted Cs-scarbocyclyl, optionally substituted C 5 -6carbocyclyl, optionally substituted C 5 carbocyclyl, or optionally substituted C 6 carbocyclyl.
  • R 2 is optionally substituted heterocyclyl, e.g., optionally substituted 3-14 membered heterocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted 5-8 membered heterocyclyl, optionally substituted 5-6 membered heterocyclyl, optionally substituted 5-membered heterocyclyl, or optionally substituted 6- membered heterocyclyl.
  • At least one instance of R 2 is optionally substituted heterocyclyl, e.g., optionally substituted 3-14 membered heterocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted 5-8 membered heterocyclyl, optionally substituted 5-6 membered heterocyclyl, optionally substituted 5-membered heterocyclyl, or optionally substituted 6-membered heterocyclyl.
  • R 2 is optionally substituted aryl, e.g., optionally substituted phenyl. In some embodiments, R 2 is optionally substituted phenyl. In some embodiments, R 2 is substituted phenyl. In some embodiments, R 2 is unsubstituted phenyl. In certain embodiments, at least one instance of R 2 is optionally substituted aryl, e.g., optionally substituted phenyl. In some embodiments, at least one instance of R 2 is optionally substituted phenyl. In some embodiments, at least one instance of R 2 is substituted phenyl. In some embodiments, at least one instance of R 2 is unsubstituted phenyl.
  • R 2 is optionally substituted heteroaryl, e.g., optionally substituted 5-14 membered heteroaryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 5-6 membered heteroaryl, optionally substituted 5-membered heteroaryl, or optionally substituted 6-membered heteroaryl.
  • at least one instance of R 2 is optionally substituted heteroaryl, e.g., optionally substituted 5-14 membered heteroaryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 5-6 membered heteroaryl, optionally substituted 5-membered heteroaryl, or optionally substituted 6-membered heteroaryl.
  • R 2 is a nitrogen protecting group. In some embodiments, at least one R 2 is a nitrogen protecting group.
  • R 2 is a group of the formula (i). In certain embodiments,
  • R 2 is a group of the formula (ii). In certain embodiments, R 2 is a group of the formula (iii). In certain embodiments, at least one instance of R 2 is a group of the formula (i). In certain embodiments, at least one instance of R 2 is a group of the formula (ii). In certain embodiments, at least one instance of R 2 is a group of the formula (iii).
  • each instance of R 2 is a group other than formula (i), (ii), or (iii); in that instance, it follows that at least one R Q is a group of the formula (i), (ii), or (iii), or at least one R 1 is a group of formula (iv), and at least one of R 6 or R 7 encompassed by R 1 is a group of the formula (i), (ii), or (iii).
  • both instances of R 2 are hydrogen, and thus at least one R Q is a group of the formula (i), (ii), or (iii), or at least one R is a group of formula (iv), and at least one of R 6 or R 7 encompassed by R 1 is a group of the formula (i), (ii), or (iii).
  • each instance of R' is independently hydrogen or optionally substituted alkyl.
  • R' is hydrogen.
  • R' is substituted alkyl.
  • at least one instance of R' is hydrogen.
  • at least two instances of R' is hydrogen.
  • each instance of R' is hydrogen.
  • at least one instance of R' is optionally substituted alkyl, e.g., methyl.
  • at least two instances of R' is optionally substituted alkyl, e.g., methyl.
  • at least one instance of R' is hydrogen, and at least one instance of R' is optionally substituted alkyl.
  • one instance of R' is optionally substituted alkyl, and the rest are hydrogen.
  • X is O, S, or NR X .
  • X is O.
  • X is S.
  • X is NR X , wherein R x is as defined above and described herein.
  • R x is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group.
  • R is hydrogen.
  • R x is optionally substituted alkyl.
  • R x is optionally substituted alkenyl.
  • R x is optionally substituted alkynyl.
  • R x is optionally substituted carbocyclyl.
  • R x is optionally substituted heterocyclyl.
  • R x is optionally substituted aryl.
  • R x is optionally substituted heteroaryl.
  • R x is a nitrogen protecting group.
  • Y is O, S, or NR Y .
  • Y is O.
  • Y is S.
  • Y is NR Y , wherein R Y is as defined above and described herein.
  • R Y is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group.
  • R Y is hydrogen.
  • R Y is optionally substituted alkyl.
  • R Y is optionally substituted alkenyl.
  • R Y is optionally substituted alkynyl.
  • R Y is optionally substituted carbocyclyl.
  • R Y is optionally substituted heterocyclyl.
  • R Y is optionally substituted aryl.
  • R Y is optionally substituted heteroaryl.
  • R Y is a nitrogen protecting group.
  • R P is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, or a nitrogen protecting group when attached to a nitrogen atom.
  • R P is hydrogen.
  • R P is optionally substituted alkyl.
  • R P is optionally substituted alkenyl.
  • R P is optionally substituted alkynyl.
  • R P is optionally substituted carbocyclyl. In some embodiments, R P is optionally substituted heterocyclyl. In some embodiments, R P is optionally substituted aryl. In some embodiments, R P is optionally substituted heteroaryl. In some embodiments, R P is an oxygen protecting group when attached to an oxygen atom. In some embodiments, R P is a sulfur protecting group when attached to a sulfur atom. In some embodiments, R P is a nitrogen protecting group when attached to a nitrogen atom.
  • R L is optionally substituted Ci_ 5 o alkyl, optionally substituted C2-50 alkenyl, optionally substituted C2-50 alkynyl, optionally substituted heteroCi_ 5 o alkyl, optionally substituted heteroC2_5o alkenyl, optionally substituted heteroC2_5o alkynyl, or a polymer.
  • R L is optionally substituted Ci_ 5 o alkyl. In some embodiments, R L is optionally substituted C 2 -50 alkyl. In some embodiments, R L is optionally substituted C 2 -40 alkyl. In some embodiments, R L is optionally substituted C 2 -30 alkyl. In some embodiments, R L is optionally substituted C 2 - 20 alkyl. In some embodiments, R L is optionally substituted C 2 -19 alkyl. In some embodiments, R L is optionally substituted C 2-18 alkyl. In some embodiments, R L is optionally substituted C 2-17 alkyl. In some embodiments, R L is optionally substituted C 2-16 alkyl.
  • R L is optionally substituted C 2-15 alkyl. In some embodiments, R L is optionally substituted C 2-14 alkyl. In some embodiments, R L is optionally substituted C 2-13 alkyl. In some embodiments, R L is optionally substituted C 2-12 alkyl. In some embodiments, R L is optionally substituted C 2-11 alkyl. In some embodiments, R L is optionally substituted C 2-10 alkyl. In some embodiments, R L is optionally substituted C 2 -9 alkyl. In some embodiments, R L is optionally substituted C 2 _8 alkyl. In some embodiments, R L is optionally substituted C 2 -7 alkyl. In some embodiments, R L is optionally substituted C 2 _6 alkyl.
  • R L is optionally substituted C 4 -50 alkyl. In some embodiments, R L is optionally substituted C 4 -40 alkyl. In some embodiments, R L is optionally substituted C 4 -30 alkyl. In some embodiments, R L is optionally substituted C 4 - 20 alkyl. In some embodiments, R L is optionally substituted C 4 _i 9 alkyl. In some embodiments, R L is optionally substituted C 4-18 alkyl. In some embodiments, R L is optionally substituted C 4-17 alkyl. In some embodiments, R L is optionally substituted C 4-16 alkyl. In some embodiments, R L is optionally substituted C 4-15 alkyl.
  • R L is optionally substituted C 4-14 alkyl. In some embodiments, R L is optionally substituted C 4 _i 3 alkyl. In some embodiments, R L is optionally substituted C 4-12 alkyl. In some embodiments, R L is optionally substituted C 4-11 alkyl. In some embodiments, R L is optionally substituted C 4 -10 alkyl. In some embodiments, R L is optionally substituted C 4 -9 alkyl. In some embodiments, R L is optionally substituted C 4 -8 alkyl. In some embodiments, R L is optionally substituted C4-7 alkyl. In some embodiments, R L is optionally substituted C 4 _ 6 alkyl.
  • R L is optionally substituted C 6 -5o alkyl. In some embodiments, R L is optionally substituted C 6 -4o alkyl. In some embodiments, R L is optionally substituted C 6 -3o alkyl. In some embodiments, R L is optionally substituted C 6 -2o alkyl. In some embodiments, R L is optionally substituted C 6 _i9 alkyl. In some embodiments, R L is optionally substituted C 6-1 8 alkyl. In some embodiments, R L is optionally substituted C 6-17 alkyl. In some embodiments, R L is optionally substituted C 6-1 6 alkyl. In some embodiments, R L is optionally substituted C 6-15 alkyl.
  • R L is optionally substituted Cg-so alkyl. In some embodiments, R L is optionally substituted Cg- 4 o alkyl. In some embodiments, R L is optionally substituted Cg-30 alkyl. In some embodiments, R L is optionally substituted Cg_ 2 o alkyl. In some embodiments, R L is optionally substituted C 8 _i9 alkyl. In some embodiments, R L is optionally substituted C 8-18 alkyl. In some embodiments, R L is optionally substituted C 8-17 alkyl. In some embodiments, R L is optionally substituted C 8-16 alkyl. In some embodiments, R L is optionally substituted C 8-15 alkyl.
  • R L is optionally substituted C 8-14 alkyl. In some embodiments, R L is optionally substituted C 8-13 alkyl. In some embodiments, R L is optionally substituted C 8-12 alkyl. In some embodiments, R L is optionally substituted C 8 _n alkyl. In some embodiments, R L is optionally substituted C 8-10 alkyl. In some embodiments, R L is optionally substituted Cg-9 alkyl.
  • R L is optionally substituted C9-50 alkyl. In some embodiments, R L is optionally substituted C 9 _ 40 alkyl. In some embodiments, R L is optionally substituted C9-30 alkyl. In some embodiments, R L is optionally substituted C9-20 alkyl. In some embodiments, R L is optionally substituted C9-19 alkyl. In some embodiments, R L is optionally substituted C9-18 alkyl. In some embodiments, R L is optionally substituted C9-17 alkyl. In some embodiments, R L is optionally substituted C9-16 alkyl. In some embodiments, R L is optionally substituted C 9 _i 5 alkyl.
  • R L is optionally substituted C 9 _i 4 alkyl. In some embodiments, R L is optionally substituted C 9 -13 alkyl. In some embodiments, R L is optionally substituted C 9 -12 alkyl. In some embodiments, R L is optionally substituted C9-11 alkyl. In some embodiments, R L is optionally substituted C9-10 alkyl.
  • R L is optionally substituted Cio-50 alkyl. In some embodiments, R L is optionally substituted Cio- 4 o alkyl. In some embodiments, R L is optionally substituted C 10-30 alkyl. In some embodiments, R L is optionally substituted C 10-20 alkyl. In some embodiments, R L is optionally substituted C 10-19 alkyl. In some embodiments, R L is optionally substituted C10-18 alkyl. In some embodiments, R L is optionally substituted Cio-17 alkyl. In some embodiments, R L is optionally substituted C10-16 alkyl. In some embodiments, R L is optionally substituted Cio-15 alkyl.
  • R L is optionally substituted Cio-i 4 alkyl. In some embodiments, R L is optionally substituted C 10-13 alkyl. In some embodiments, R L is optionally substituted C 10-12 alkyl. In some embodiments, R L is optionally substituted Cio-n alkyl.
  • R L is optionally substituted Cn_5o alkyl. In some embodiments, R L is optionally substituted Cn_ 4 o alkyl. In some embodiments, R L is optionally substituted Cn_3o alkyl. In some embodiments, R L is optionally substituted Cn_2o alkyl. In some embodiments, R L is optionally substituted Cn_i9 alkyl. In some embodiments, R L is optionally substituted Cn_i 8 alkyl. In some embodiments, R L is optionally substituted Cn_i 7 alkyl. In some embodiments, R L is optionally substituted Cn_i6 alkyl.
  • R L is optionally substituted Cn_is alkyl. In some embodiments, R L is optionally substituted Cn_i 4 alkyl. In some embodiments, R L is optionally substituted Cn_i3 alkyl. In some embodiments, R L is optionally substituted Cn_i 2 alkyl.
  • R L is optionally substituted C12-50 alkyl. In some embodiments, R L is optionally substituted Ci2- 4 o alkyl. In some embodiments, R L is optionally substituted C 12-30 alkyl. In some embodiments, R L is optionally substituted C 12-20 alkyl. In some embodiments, R L is optionally substituted C 12-19 alkyl. In some embodiments, R L is optionally substituted C12-18 alkyl. In some embodiments, R L is optionally substituted C 12-17 alkyl. In some embodiments, R L is optionally substituted C 12-16 alkyl. In some embodiments, R L is optionally substituted C 12-15 alkyl. In some embodiments, R L is optionally substituted C 12-14 alkyl. In some embodiments, R L is optionally substituted C 12 -13 alkyl.
  • R L is optionally substituted C 6 alkyl.
  • R L is optionally substituted C 7 alkyl. In some embodiments, R L is optionally substituted Cg alkyl. In some embodiments, R L is optionally substituted C9 alkyl. In some embodiments, R L is optionally substituted C 10 alkyl. In some embodiments, R L is optionally substituted Cn alkyl. In some embodiments, R L is optionally substituted C 12 alkyl. In some embodiments, R L is optionally substituted C 13 alkyl. In some embodiments, R L is optionally substituted C 14 alkyl. In some embodiments, R L is optionally substituted C 15 alkyl. In some embodiments, R L is optionally substituted C 16 alkyl.
  • R L is optionally substituted C 17 alkyl. In some embodiments, R L is optionally substituted C 18 alkyl. In some embodiments, R L is optionally substituted C19 alkyl. In some embodiments, R L is optionally substituted C 20 alkyl.
  • R L is a substituted alkyl group.
  • R L is an unsubstituted alkyl group.
  • R L is an optionally substituted straight-chain alkyl group.
  • R L is a substituted straight-chain alkyl group.
  • R L is an unsubstituted straight-chain alkyl group.
  • R L is an optionally substituted branched alkyl group.
  • R L is a substituted branched alkyl group.
  • R L is an unsubstituted branched alkyl group.
  • At least one instance of R L is an unsubstituted alkyl.
  • Exemplary unsubstituted alkyl groups include, but are not limited to, -CH 3 , -C 2 H 5 , -C 3 H 7 , - C4H9, -C 5 H 11 , -C 6 Hi3, -C 7 Hi 5 , -C 8 H 17 , -C9H19, -C10H21, -C11H23, -C12H25, -Ci 3 H 27 , -C14H29, - C 15 H 31 , -Ci 6 H 33 , -Ci 7 H 3 5, -Ci 8 H 37 , -Ci9H 3 9, -C 20 H 41 , -C 2 iH4 3 , -C22H45, -C 23 H4 7 , -C24H49, and -
  • At least one instance of R L is a substituted alkyl.
  • at least one instance of R L is an alkyl substituted with one or more fluorine substituents.
  • exemplary fluorinated alkyl groups include, but are not limited to:
  • R is optionally substituted C 2 -50 alkenyl. In some embodiments, R is optionally substituted C 2 -40 alkenyl. In some embodiments, R is optionally substituted C 2 -30 alkenyl. In some embodiments, R L is optionally substituted C 2 _ 2 o alkenyl. In some embodiments, R L is optionally substituted C 2 -19 alkenyl. In some embodiments, R L is optionally substituted C 2-18 alkenyl. In some embodiments, R L is optionally substituted C 2-17 alkenyl. In some embodiments, R L is optionally substituted C 2-16 alkenyl. In some
  • R L is optionally substituted C 2-15 alkenyl. In some embodiments, R L is optionally substituted C 2-14 alkenyl. In some embodiments, R L is optionally substituted C 2-13 alkenyl. In some embodiments, R L is optionally substituted C 2-12 alkenyl. In some embodiments, R L is optionally substituted C 2-11 alkenyl. In some embodiments, R L is optionally substituted C 2-10 alkenyl. In some embodiments, R L is optionally substituted C 2 -9 alkenyl. In some embodiments, R L is optionally substituted C 2 -8 alkenyl. In some embodiments, R L is optionally substituted C 2 -7 alkenyl. In some embodiments, R L is optionally substituted C 2 - 6 alkenyl.
  • R L is optionally substituted C 4 -50 alkenyl. In some embodiments, R L is optionally substituted C 4 -40 alkenyl. In some embodiments, R L is optionally substituted C 4 -30 alkenyl. In some embodiments, R L is optionally substituted C4-20 alkenyl. In some embodiments, R L is optionally substituted C 4 _i 9 alkenyl. In some embodiments, R L is optionally substituted C 4-18 alkenyl. In some embodiments, R L is optionally substituted C 4-17 alkenyl. In some embodiments, R L is optionally substituted C4_i 6 alkenyl. In some embodiments,
  • R L is optionally substituted C 4-15 alkenyl. In some embodiments, R L is optionally substituted C 4 _i 4 alkenyl. In some embodiments, R L is optionally substituted C 4 _i 3 alkenyl. In some embodiments, R L is optionally substituted C 4-12 alkenyl. In some embodiments, R L is optionally substituted C 4-11 alkenyl. In some embodiments, R L is optionally substituted C 4-10 alkenyl. In some embodiments, R L is optionally substituted C4_9 alkenyl. In some embodiments, R L is optionally substituted C 4 _ 8 alkenyl. In some embodiments, R L is optionally substituted C 4 _ 7 alkenyl. In some embodiments, R L is optionally substituted C4_ 6 alkenyl.
  • R L is optionally substituted C 6 -5o alkenyl. In some embodiments, R L is optionally substituted C 6 -4o alkenyl. In some embodiments, R L is optionally substituted C 6 - 3 o alkenyl. In some embodiments, R L is optionally substituted C 6 -2o alkenyl. In some embodiments, R L is optionally substituted C 6 _i9 alkenyl. In some embodiments, R L is optionally substituted C 6-18 alkenyl. In some embodiments, R L is optionally substituted C 6-17 alkenyl. In some embodiments, R L is optionally substituted C 6-1 6 alkenyl. In some
  • R L is optionally substituted C 6-15 alkenyl. In some embodiments, R L is optionally substituted C 6-14 alkenyl. In some embodiments, R L is optionally substituted C 6-13 alkenyl. In some embodiments, R L is optionally substituted C 6-12 alkenyl. In some embodiments, R L is optionally substituted C 6-11 alkenyl. In some embodiments, R L is optionally substituted C 6 -io alkenyl. In some embodiments, R L is optionally substituted C 6 -9 alkenyl. In some embodiments, R L is optionally substituted C 6 -8 alkenyl. In some embodiments, R L is optionally substituted C 6 - 7 alkenyl.
  • R L is optionally substituted Cg-so alkenyl. In some embodiments, R L is optionally substituted Cg-40 alkenyl. In some embodiments, R L is optionally substituted Cg-30 alkenyl. In some embodiments, R L is optionally substituted Cg_ 2 o alkenyl. In some embodiments, R L is optionally substituted C 8 _i9 alkenyl. In some embodiments, R L is optionally substituted C 8-18 alkenyl. In some embodiments, R L is optionally substituted C 8-17 alkenyl. In some embodiments, R L is optionally substituted C 8-16 alkenyl. In some embodiments,
  • R L is optionally substituted C 8-15 alkenyl. In some embodiments, R L is optionally substituted C 8-14 alkenyl. In some embodiments, R L is optionally substituted C 8-13 alkenyl. In some embodiments, R L is optionally substituted C 8-12 alkenyl. In some embodiments, R L is optionally substituted C 8-11 alkenyl. In some embodiments, R L is optionally substituted C 8-10 alkenyl. In some embodiments, R L is optionally substituted Cs-9 alkenyl.
  • R L is optionally substituted C 9 _ 50 alkenyl. In some embodiments, R L is optionally substituted C9-40 alkenyl. In some embodiments, R L is optionally substituted C9-30 alkenyl. In some embodiments, R L is optionally substituted Cg- 2 o alkenyl. In some embodiments, R L is optionally substituted C9-19 alkenyl. In some embodiments, R L is optionally substituted C 9 _i 8 alkenyl. In some embodiments, R L is optionally substituted C 9 _i 7 alkenyl. In some embodiments, R L is optionally substituted Cc>_i6 alkenyl. In some embodiments,
  • R L is optionally substituted C9-15 alkenyl. In some embodiments, R L is optionally substituted C9-14 alkenyl. In some embodiments, R L is optionally substituted C9-13 alkenyl. In some embodiments, R L is optionally substituted Cg-i 2 alkenyl. In some embodiments, R L is optionally substituted C 9 _n alkenyl. In some embodiments, R L is optionally substituted C 9 _i 0 alkenyl.
  • R L is optionally substituted Cio-50 alkenyl. In some embodiments, R L is optionally substituted C 10-40 alkenyl. In some embodiments, R L is optionally substituted Cio-30 alkenyl. In some embodiments, R L is optionally substituted Ci 0 _ 2 o alkenyl. In some embodiments, R L is optionally substituted C10-19 alkenyl. In some embodiments, R L is optionally substituted C 10-18 alkenyl. In some embodiments, R L is optionally substituted C 10-17 alkenyl. In some embodiments, R L is optionally substituted C10-16 alkenyl. In some embodiments, R L is optionally substituted C 10-15 alkenyl.
  • R L is optionally substituted C 10-14 alkenyl. In some embodiments, R L is optionally substituted C 10-13 alkenyl. In some embodiments, R L is optionally substituted C 10-12 alkenyl. In some embodiments, R L is optionally substituted C 10-11 alkenyl.
  • R L is optionally substituted C 11-50 alkenyl. In some embodiments, R L is optionally substituted C 11-40 alkenyl. In some embodiments, R L is optionally substituted C 11-30 alkenyl. In some embodiments, R L is optionally substituted C 11-20 alkenyl. In some embodiments, R L is optionally substituted Cn_i9 alkenyl. In some embodiments, R L is optionally substituted C 11-18 alkenyl. In some embodiments, R L is optionally substituted C 11-17 alkenyl. In some embodiments, R L is optionally substituted C 11-16 alkenyl. In some embodiments, R L is optionally substituted C 11-50 alkenyl. In some embodiments, R L is optionally substituted C 11-40 alkenyl. In some embodiments, R L is optionally substituted C 11-30 alkenyl. In some embodiments, R L is optionally substituted C 11-20 alkenyl. In some embodiments, R L is optionally substituted Cn_i9
  • R L is optionally substituted C 11-15 alkenyl. In some embodiments, R L is optionally substituted C 11-14 alkenyl. In some embodiments, R L is optionally substituted C 11-13 alkenyl. In some embodiments, R L is optionally substituted C 11-12 alkenyl.
  • R L is optionally substituted C12-50 alkenyl. In some embodiments, R L is optionally substituted C 12-40 alkenyl. In some embodiments, R L is optionally substituted C12-30 alkenyl. In some embodiments, R L is optionally substituted C12-20 alkenyl. In some embodiments, R L is optionally substituted C12-19 alkenyl. In some embodiments, R L is optionally substituted C 12-18 alkenyl. In some embodiments, R L is optionally substituted C 12-17 alkenyl. In some embodiments, R L is optionally substituted C 12-16 alkenyl. In some embodiments,
  • R L is optionally substituted C 12-15 alkenyl. In some embodiments, R L is optionally substituted C 12-14 alkenyl. In some embodiments, R L is optionally substituted C 12-13 alkenyl.
  • R L is optionally substituted C 6 alkenyl. In some embodiments, R L is optionally substituted C 7 alkenyl. In some embodiments, R L is optionally substituted Cg alkenyl. In some embodiments, R L is optionally substituted C9 alkenyl. In some embodiments, R L is optionally substituted C 10 alkenyl. In some embodiments, R L is optionally substituted Cn alkenyl. In some embodiments, R L is optionally substituted C 12 alkenyl. In some embodiments, R L is optionally substituted C 13 alkenyl. In some embodiments, R L is optionally substituted C 14 alkenyl.
  • R L is optionally substituted C 15 alkenyl. In some embodiments, R L is optionally substituted C 16 alkenyl. In some embodiments, R L is optionally substituted C 17 alkenyl. In some embodiments, R L is optionally substituted C 18 alkenyl. In some embodiments, R L is optionally substituted C 19 alkenyl. In some embodiments, R L is optionally substituted C 2 o alkenyl.
  • R L is a substituted alkyl group.
  • R L is an unsubstituted alkyl group.
  • R L is an optionally substituted straight-chain alkenyl group.
  • R L is a substituted straight-chain alkenyl group. In some embodiments, R L is an unsubstituted straight-chain alkenyl group. In some embodiments, R L is an optionally substituted branched alkenyl group. In some embodiments, R L is a substituted branched alkenyl group. In some embodiments, R L is an unsubstituted branched alkenyl group.
  • Exemplary unsubstituted alkenyl group include, but are not limited to:
  • R L is defined as a C 6 - 5 oalkyl or C 6 - 5 oalkenyl groups
  • such groups are meant to encompass lipophilic groups (also referred to as a "lipid tail").
  • Lipophilic groups comprise a group of molecules that include fats, waxes, oils, fatty acids, and the like. Lipid tails present in these lipid groups can be saturated and unsaturated, depending on whether or not the lipid tail comprises double bonds.
  • the lipid tail can also comprise different lengths, often categorized as medium (i.e., with tails between 7-12 carbons, e.g., C 7 _i 2 alkyl or C 7 _i 2 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 2 3_3o alkyl or C 2 3_3o alkenyl).
  • medium i.e., with tails between 7-12 carbons, e.g., C 7 _i 2 alkyl or C 7 _i 2 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
  • very long i.e., with tail
  • R L is optionally substituted C 2 _ 5 o alkynyl. In some embodiments, R L is optionally substituted C 2 _ 4 o alkynyl. In some embodiments, R L is optionally substituted C 2 _3o alkynyl. In some embodiments, R L is optionally substituted C 2 _ 2 o alkynyl. In some embodiments, R L is optionally substituted C 2 _i 9 alkynyl. In some embodiments, R L is optionally substituted C 2 _ig alkynyl. In some embodiments, R L is optionally substituted C 2 _i 7 alkynyl. In some embodiments, R L is optionally substituted C 2 _i 6 alkynyl. In some embodiments,
  • R L is optionally substituted C 2 _i 5 alkynyl. In some embodiments, R L is optionally substituted C 2 _i 4 alkynyl. In some embodiments, R L is optionally substituted C 2 _i 3 alkynyl. In some embodiments, R L is optionally substituted C 2 _i 2 alkynyl. In some embodiments, R L is optionally substituted C 2-11 alkynyl. In some embodiments, R L is optionally substituted C 2-10 alkynyl. In some embodiments, R L is optionally substituted C 2 -9 alkynyl. In some embodiments, R L is optionally substituted C 2 -8 alkynyl. In some embodiments, R L is optionally substituted C 2 -7 alkynyl. In some embodiments, R L is optionally substituted C 2 -6 alkynyl.
  • R L is optionally substituted C4-50 alkynyl. In some embodiments, R L is optionally substituted C 4 _ 40 alkynyl. In some embodiments, R L is optionally substituted C 4 _ 3 o alkynyl. In some embodiments, R L is optionally substituted C 4 _2o alkynyl. In some embodiments, R L is optionally substituted C 4 _ig alkynyl. In some embodiments, R L is optionally substituted C 4 _ig alkynyl. In some embodiments, R L is optionally substituted C 4 _i 7 alkynyl. In some embodiments, R L is optionally substituted C 4 _i 6 alkynyl. In some embodiments,
  • R L is optionally substituted C 4 _i 5 alkynyl. In some embodiments, R L is optionally substituted C 4 _i 4 alkynyl. In some embodiments, R L is optionally substituted C 4 _i 3 alkynyl. In some embodiments, R L is optionally substituted C 4 _i2 alkynyl. In some embodiments, R L is optionally substituted C _n alkynyl. In some embodiments, R L is optionally substituted C _i 0 alkynyl. In some embodiments, R L is optionally substituted C 4 _9 alkynyl. In some embodiments, R L is optionally substituted C 4 _g alkynyl. In some embodiments, R L is optionally substituted C 4 _ 7 alkynyl. In some embodiments, R L is optionally substituted C 4 _ 6 alkynyl.
  • R L is optionally substituted C 6 _5o alkynyl. In some embodiments, R L is optionally substituted C 6 _ 4 o alkynyl. In some embodiments, R L is optionally substituted C 6 - 3 o alkynyl. In some embodiments, R L is optionally substituted C 6 -2o alkynyl. In some embodiments, R L is optionally substituted C 6-1 9 alkynyl. In some embodiments, R L is optionally substituted C 6-1 8 alkynyl. In some embodiments, R L is optionally substituted C 6-17 alkynyl. In some embodiments, R L is optionally substituted C 6 _i6 alkynyl. In some
  • R L is optionally substituted C 6-15 alkynyl. In some embodiments, R L is optionally substituted C 6-14 alkynyl. In some embodiments, R L is optionally substituted C 6-13 alkynyl. In some embodiments, R L is optionally substituted C 6-12 alkynyl. In some embodiments, R L is optionally substituted C 6 _n alkynyl. In some embodiments, R L is optionally substituted C 6 _io alkynyl. In some embodiments, R L is optionally substituted C 6 -9 alkynyl. In some embodiments, R L is optionally substituted C 6 -8 alkynyl.
  • R L is optionally substituted C 6 - 7 alkynyl. [0242] In some embodiments, R L is optionally substituted Cg-so alkynyl. In some embodiments, R L is optionally substituted C 8 _4o alkynyl. In some embodiments, R L is optionally substituted Cg- 3 o alkynyl. In some embodiments, R L is optionally substituted Cg_ 2 o alkynyl. In some embodiments, R L is optionally substituted C 8-1 9 alkynyl. In some embodiments, R L is optionally substituted C 8-18 alkynyl. In some embodiments, R L is optionally substituted C 8-17 alkynyl. In some embodiments, R L is optionally substituted C 8-16 alkynyl. In some embodiments, R L is optionally substituted Cg-so alkynyl. In some embodiments, R L is optionally substituted Cg-so alkynyl. In some embodiments, R
  • R L is optionally substituted C 8-15 alkynyl. In some embodiments, R L is optionally substituted C 8-14 alkynyl. In some embodiments, R L is optionally substituted C 8-13 alkynyl. In some embodiments, R L is optionally substituted C 8-12 alkynyl. In some embodiments, R L is optionally substituted C 8 _n alkynyl. In some embodiments, R L is optionally substituted C 8-10 alkynyl. In some embodiments, R L is optionally substituted Cg_9 alkynyl.
  • R L is optionally substituted C9-50 alkynyl. In some embodiments, R L is optionally substituted C9-40 alkynyl. In some embodiments, R L is optionally substituted C 9 _3 0 alkynyl. In some embodiments, R L is optionally substituted C 9 _ 2 o alkynyl. In some embodiments, R L is optionally substituted C9-19 alkynyl. In some embodiments, R L is optionally substituted C9-18 alkynyl. In some embodiments, R L is optionally substituted C9-17 alkynyl. In some embodiments, R L is optionally substituted C9_i 6 alkynyl. In some embodiments,
  • R L is optionally substituted C 9 _i 5 alkynyl. In some embodiments, R L is optionally substituted C 9 _i 4 alkynyl. In some embodiments, R L is optionally substituted C 9 _i 3 alkynyl. In some embodiments, R L is optionally substituted C9-12 alkynyl. In some embodiments, R L is optionally substituted C9-11 alkynyl. In some embodiments, R L is optionally substituted C9-10 alkynyl.
  • R L is optionally substituted Cio-50 alkynyl. In some embodiments, R L is optionally substituted C 10-40 alkynyl. In some embodiments, R L is optionally substituted Cio-30 alkynyl. In some embodiments, R L is optionally substituted Cio-20 alkynyl. In some embodiments, R L is optionally substituted C10-19 alkynyl. In some embodiments, R L is optionally substituted C 10-18 alkynyl. In some embodiments, R L is optionally substituted C 10-17 alkynyl. In some embodiments, R L is optionally substituted C10-16 alkynyl. In some embodiments,
  • R L is optionally substituted C 10-15 alkynyl. In some embodiments, R L is optionally substituted C 10-14 alkynyl. In some embodiments, R L is optionally substituted C 10-13 alkynyl. In some embodiments, R L is optionally substituted C 10-12 alkynyl. In some embodiments, R L is optionally substituted C 10-11 alkynyl.
  • R L is optionally substituted C 11-50 alkynyl. In some embodiments, R L is optionally substituted C 11-40 alkynyl. In some embodiments, R L is optionally substituted C 11-30 alkynyl. In some embodiments, R L is optionally substituted C 11-20 alkynyl. In some embodiments, R L is optionally substituted Cn_i 9 alkynyl. In some embodiments, R L is optionally substituted C 11-18 alkynyl. In some embodiments, R L is optionally substituted C 11-17 alkynyl. In some embodiments, R L is optionally substituted C 11-16 alkynyl. In some embodiments, R L is optionally substituted C 11-50 alkynyl. In some embodiments, R L is optionally substituted C 11-40 alkynyl. In some embodiments, R L is optionally substituted C 11-30 alkynyl. In some embodiments, R L is optionally substituted C 11-20 alkynyl. In some embodiments,
  • R L is optionally substituted C 11-15 alkynyl. In some embodiments, R L is optionally substituted C 11-14 alkynyl. In some embodiments, R L is optionally substituted C 11-13 alkynyl. In some embodiments, R L is optionally substituted C 11-12 alkynyl.
  • R L is optionally substituted C12-50 alkynyl. In some embodiments, R L is optionally substituted C 12-40 alkynyl. In some embodiments, R L is optionally substituted C12-30 alkynyl. In some embodiments, R L is optionally substituted C12-20 alkynyl. In some embodiments, R L is optionally substituted C12-19 alkynyl. In some embodiments, R L is optionally substituted C 12-18 alkynyl. In some embodiments, R L is optionally substituted C 12-17 alkynyl. In some embodiments, R L is optionally substituted C 12-16 alkynyl. In some embodiments,
  • R L is optionally substituted C 12-15 alkynyl. In some embodiments, R L is optionally substituted C 12-14 alkynyl. In some embodiments, R L is optionally substituted C 12-13 alkynyl.
  • R L is optionally substituted C 6 alkynyl. In some embodiments, R L is optionally substituted C 7 alkynyl. In some embodiments, R L is optionally substituted Cg alkynyl. In some embodiments, R L is optionally substituted C9 alkynyl. In some embodiments, R L is optionally substituted C 10 alkynyl. In some embodiments, R L is optionally substituted Cn alkynyl. In some embodiments, R L is optionally substituted C 12 alkynyl. In some embodiments, R L is optionally substituted C 13 alkynyl. In some embodiments, R L is optionally substituted C 14 alkynyl.
  • R L is optionally substituted C 15 alkynyl. In some embodiments, R L is optionally substituted C 16 alkynyl. In some embodiments, R L is optionally substituted C 17 alkynyl. In some embodiments, R L is optionally substituted C 18 alkynyl. In some embodiments, R L is optionally substituted C19 alkynyl. In some embodiments, R L is optionally substituted C20 alkynyl. [0248] In some embodiments, for example, in any of the above embodiments, R L is a substituted alkynyl group. In some embodiments, R L is an unsubstituted alkynyl group.
  • R L is an optionally substituted straight-chain alkyl group. In some embodiments, R L is an optionally substituted straight-chain alkynyl group. In some embodiments, R L is a substituted straight-chain alkynyl group. In some embodiments, R L is an unsubstituted straight- chain alkynyl group. In some embodiments, R L is an optionally substituted branched alkynyl group. In some embodiments, R L is a substituted branched alkynyl group. In some embodiments, R L is a substituted branched alkynyl group. In some embodiments,
  • R L is an unsubstituted branched alkynyl group.
  • R L is optionally substituted heteroCi_5oalkyl. In some embodiments, R L is optionally substituted heteroC 2 _ 5 oalkyl. In some embodiments, R L is optionally substituted heteroC 2 _ 4 oalkyl. In some embodiments, R L is optionally substituted heteroC 2 _ 3 oalkyl. In some embodiments, R L is optionally substituted heteroC 2 _ 2 oalkyl. In some embodiments, R L is optionally substituted heteroC 2 _i9alkyl. In some embodiments, R L is optionally substituted heteroC 2 _i 8 alkyl. In some embodiments, R L is optionally substituted heteroC 2 _i 7 alkyl.
  • R L is optionally substituted heteroC 2 _i 6 alkyl. In some embodiments, R L is optionally substituted heteroC 2 _i5alkyl. In some embodiments, R L is optionally substituted heteroC 2 _i 4 alkyl. In some embodiments, R L is optionally substituted heteroC 2 _i 3 alkyl. In some embodiments, R L is optionally substituted heteroC 2 _i 2 alkyl. In some embodiments, R L is optionally substituted heteroC 2 _nalkyl. In some embodiments, R L is optionally substituted heteroC 2 _ioalkyl. In some embodiments, R L is optionally substituted heteroC 2 _ 9 alkyl.
  • R L is optionally substituted heteroC 2 _ 8 alkyl. In some embodiments, R L is optionally substituted heteroC 2 _7alkyl. In some embodiments, R L is optionally substituted heteroC 2 _ 6 alkyl.
  • R L is optionally substituted heteroC 4 _5oalkyl. In some embodiments, R L is optionally substituted heteroC 4 _ 4 oalkyl. In some embodiments, R L is optionally substituted heteroC 4 - 3 oalkyl. In some embodiments, R L is optionally substituted heteroC 4 _ 20 alkyl. In some embodiments, R L is optionally substituted heteroC 4 _i 9 alkyl. In some embodiments, R L is optionally substituted heteroC 4 _i8alkyl. In some embodiments, R L is optionally substituted heteroC 4 -i7alkyl. In some embodiments, R L is optionally substituted heteroC 4 -i 6 alkyl.
  • R L is optionally substituted heteroC 4 -isalkyl. In some embodiments, R L is optionally substituted heteroC 4 -i 4 alkyl. In some embodiments, R L is optionally substituted heteroC 4 _i 3 alkyl. In some embodiments, R L is optionally substituted heteroC 4 _i 2 alkyl. In some embodiments, R L is optionally substituted heteroC 4 _nalkyl. In some embodiments, R L is optionally substituted heteroC 4 -ioalkyl. In some embodiments, R L is optionally substituted heteroC 4 -9alkyl. In some embodiments, R L is optionally substituted heteroC 4 _ 8 alkyl. In some embodiments, R L is optionally substituted heteroC 4 _ 7 alkyl. In some embodiments, R L is optionally substituted heteroC 4 -6alkyl.
  • R L is optionally substituted heteroCe-soalkyl. In some embodiments, R L is optionally substituted heteroC6- 4 oalkyl. In some embodiments, R L is optionally substituted heteroC 6 _ 3 oalkyl. In some embodiments, R L is optionally substituted heteroC 6 - 2 oalkyl. In some embodiments, R L is optionally substituted heteroC 6 -i 9 alkyl. In some embodiments, R L is optionally substituted heteroCe-igalkyl. In some embodiments, R L is optionally substituted heteroCe-nalkyl. In some embodiments, R L is optionally substituted heteroC 6 -i 6 alkyl.
  • R L is optionally substituted heteroC 6 -i 5 alkyl. In some embodiments, R L is optionally substituted heteroC6-i 4 alkyl. In some embodiments, R L is optionally substituted heteroC6-i3alkyl. In some embodiments, R L is optionally substituted heteroC 6 -i 2 alkyl. In some embodiments, R L is optionally substituted heteroCe-iialkyl. In some embodiments, R L is optionally substituted heteroC 6 _ioalkyl. In some embodiments, R L is optionally substituted heteroC 6 _ 9 alkyl. In some embodiments, R L is optionally substituted heteroC 6 - 8 alkyl. In some embodiments, R L is optionally substituted heteroC 6 - 7 alkyl.
  • R L is optionally substituted heteroCg-soalkyl. In some embodiments, R L is optionally substituted heteroCg_ 4 oalkyl. In some embodiments, R L is optionally substituted heteroC 8 - 3 oalkyl. In some embodiments, R L is optionally substituted heteroC 8 - 2 oalkyl. In some embodiments, R L is optionally substituted heteroCg-igalkyl. In some embodiments, R L is optionally substituted heteroCg_igalkyl. In some embodiments, R L is optionally substituted heteroCg-nalkyl. In some embodiments, R L is optionally substituted heteroC 8 -i 6 alkyl.
  • R L is optionally substituted heteroCg_i 5 alkyl. In some embodiments, R L is optionally substituted heteroCg_i 4 alkyl. In some embodiments, R L is optionally substituted heteroCg_i3alkyl. In some embodiments, R L is optionally substituted heteroCg_i 2 alkyl. In some embodiments, R L is optionally substituted heteroCg_nalkyl. In some embodiments, R L is optionally substituted heteroCg-ioalkyl. In some embodiments, R L is optionally substituted heteroC 8 - 9 alkyl.
  • R L is optionally substituted heteroCg-soalkyl. In some embodiments, R L is optionally substituted heteroC9_ 4 oalkyl. In some embodiments, R L is optionally substituted heteroCg-soalkyl. In some embodiments, R L is optionally substituted heteroC 9 _ 2 oalkyl. In some embodiments, R L is optionally substituted heteroCg.igalkyl. In some embodiments, R L is optionally substituted heteroCg-isalkyl. In some embodiments, R L is optionally substituted heteroCg-nalkyl. In some embodiments, R L is optionally substituted heteroCc)-i 6 alkyl.
  • R L is optionally substituted heteroCg-isalkyl. In some embodiments, R L is optionally substituted heteroCg.nalkyl. In some embodiments, R L is optionally substituted heteroCg-isalkyl. In some embodiments, R L is optionally substituted heteroCc)_i 2 alkyl. In some embodiments, R L is optionally substituted heteroC 9 _nalkyl. In some embodiments, R L is optionally substituted heteroCg-ioalkyl.
  • R L is optionally substituted heteroCio-soalkyl. In some embodiments, R L is optionally substituted heteroCio- 4 oalkyl. In some embodiments, R L is optionally substituted heteroCio-3oalkyl. In some embodiments, R L is optionally substituted heteroC 10-20 alkyl. In some embodiments, R L is optionally substituted heteroCio-i9alkyl. In some embodiments, R L is optionally substituted heteroCio-isalkyl. In some embodiments, R L is optionally substituted heteroCio-nalkyl. In some embodiments, R L is optionally substituted heteroC io-i 6 alkyl.
  • R L is optionally substituted heteroCio-isalkyl. In some embodiments, R L is optionally substituted heteroCio-walkyl. In some embodiments, R L is optionally substituted heteroCio-i3alkyl. In some embodiments, R L is optionally substituted heteroC io-i 2 alkyl. In some embodiments, R L is optionally substituted heteroCio-nalkyl.
  • R L is optionally substituted heteroCn_5oalkyl. In some embodiments, R L is optionally substituted heteroCn_ 4 oalkyl. In some embodiments, R L is optionally substituted heteroCn_3oalkyl. In some embodiments, R L is optionally substituted heteroC 11-20 alkyl. In some embodiments, R L is optionally substituted heteroCn.igalkyl. In some embodiments, R L is optionally substituted heteroCn-igalkyl. In some embodiments, R L is optionally substituted heteroCii-nalkyl. In some embodiments, R L is optionally substituted heteroC n_i 6 alkyl.
  • R L is optionally substituted heteroCn-isalkyl. In some embodiments, R L is optionally substituted heteroCn_i 4 alkyl. In some embodiments, R L is optionally substituted heteroCii_i 3 alkyl. In some embodiments, R L is optionally substituted heteroCn_i 2 alkyl.
  • R L is optionally substituted heteroCi 2 -5oalkyl. In some embodiments, R L is optionally substituted heteroCi 2 - 4 oalkyl. In some embodiments, R L is optionally substituted heteroCioalkyl. In some embodiments, R L is optionally substituted heteroCi 2 - 2 oalkyl. In some embodiments, R L is optionally substituted heteroCi 2 -i 9 alkyl. In some embodiments, R L is optionally substituted heteroCi 2 -i8alkyl. In some embodiments, R L is optionally substituted heteroCi 2 -i7alkyl.
  • R L is optionally substituted heteroCi 2 -i 6 alkyl. In some embodiments, R L is optionally substituted heteroCi 2 -i 5 alkyl. In some embodiments, R L is optionally substituted heteroCi 2 -i 4 alkyl. In some embodiments, R L is optionally substituted heteroCi 2 -i 3 alkyl.
  • R L is optionally substituted heteroCealkyl. In some embodiments, R L is optionally substituted heteroCyalkyl. In some embodiments, R L is optionally substituted heteroCsalkyl. In some embodiments, R L is optionally substituted heteroCgalkyl. In some embodiments, R L is optionally substituted heteroCioalkyl. In some embodiments, R L is optionally substituted heteroCnalkyl. In some embodiments, R L is optionally substituted heteroCealkyl. In some embodiments, R L is optionally substituted heteroCealkyl. In some embodiments, R L is optionally substituted heteroCealkyl. In some embodiments, R L is optionally substituted heteroCealkyl. In some embodiments, R L is optionally substituted heteroCealkyl. In some embodiments, R L is optionally substituted heteroCealkyl.
  • R L is optionally substituted heteroCisalkyl. In some embodiments, R L is optionally substituted heteroCi 6 alkyl. In some embodiments, R L is optionally substituted heteroCnalkyl. In some embodiments, R L is optionally substituted heteroCigalkyl. In some embodiments, R L is optionally substituted heteroCigalkyl. In some embodiments, R L is optionally substituted heteroC 2 oalkyl.
  • R L is a substituted heteroalkyl group.
  • R L is an unsubstituted heteroalkyl group.
  • R L is an optionally substituted straight-chain heteroalkyl group.
  • R L is a substituted straight-chain heteroalkyl group.
  • R L is an unsubstituted straight-chain heteroalkyl group.
  • R L is an optionally substituted branched heteroalkyl group.
  • R L is a substituted branched heteroalkyl group.
  • R L is an unsubstituted branched heteroalkyl group.
  • Exemplary unsubstituted heteroalkyl groups include, but are not limited to:
  • R L is optionally substituted heteroC 2 -5oalkenyl. In some embodiments, R L is optionally substituted heteroC 2 _ 4 oalkenyl. In some embodiments, R L is optionally substituted heteroC 2 -3oalkenyl. In some embodiments, R L is optionally substituted heteroC 2 - 2 oalkenyl. In some embodiments, R L is optionally substituted heteroC 2 -i 9 alkenyl. In some embodiments, R L is optionally substituted heteroC 2 -i8alkenyl. In some embodiments, R L optionally substituted heteroC 2 _i 7 alkenyl.
  • R L is optionally substituted heteroC 2 -i 6 alkenyl. In some embodiments, R L is optionally substituted heteroC 2 -i 5 alkenyl. In some embodiments, R L is optionally substituted heteroC 2 -i 4 alkenyl. In some embodiments, R L optionally substituted heteroC 2 -i3alkenyl. In some embodiments, R L is optionally substituted heteroC 2 -i 2 alkenyl. In some embodiments, R L is optionally substituted heteroC 2 -nalkenyl. In some embodiments, R L is optionally substituted heteroC 2 -ioalkenyl. In some embodiments, R L optionally substituted heteroC 2 -9alkenyl.
  • R L is optionally substituted heteroC 2 - 8 alkenyl. In some embodiments, R L is optionally substituted heteroC 2 - 7 alkenyl. In some embodiments, R L is optionally substituted heteroC 2 - 6 alkenyl.
  • R L is optionally substituted heteroC 4 _5oalkenyl. In some embodiments, R L is optionally substituted heteroC 4 _ 4 oalkenyl. In some embodiments, R L is optionally substituted heteroC 4 _3oalkenyl. In some embodiments, R L is optionally substituted heteroC 4 _ 2 oalkenyl. In some embodiments, R L is optionally substituted heteroC 4 _i 9 alkenyl. In some embodiments, R L is optionally substituted heteroC 4 -i8alkenyl. In some embodiments, R L optionally substituted heteroC 4 -i7alkenyl.
  • R L is optionally substituted heteroC 4 _i 6 alkenyl. In some embodiments, R L is optionally substituted heteroC 4 _i 5 alkenyl. In some embodiments, R L is optionally substituted heteroC 4 _i 4 alkenyl. In some embodiments, R L optionally substituted heteroC 4 -i3alkenyl. In some embodiments, R L is optionally substituted heteroC 4 _i 2 alkenyl. In some embodiments, R L is optionally substituted heteroC 4 _nalkenyl. In some embodiments, R L is optionally substituted heteroC 4 -ioalkenyl. In some embodiments, R L optionally substituted heteroC 4 _ 9 alkenyl.
  • R L is optionally substituted heteroC 4 _ 8 alkenyl. In some embodiments, R L is optionally substituted heteroC 4 _ 7 alkenyl. In some embodiments, R L is optionally substituted heteroC 4 -6alkenyl.
  • R L is optionally substituted heteroCe-soalkenyl. In some embodiments, R L is optionally substituted heteroC 6 _ 4 oalkenyl. In some embodiments, R L is optionally substituted heteroC 6 _ 3 oalkenyl. In some embodiments, R L is optionally substituted heteroC 6 - 2 oalkenyl. In some embodiments, R L is optionally substituted heteroC 6 -i 9 alkenyl. In some embodiments, R L is optionally substituted heteroCe-isalkenyl. In some embodiments, R L optionally substituted heteroCe-nalkenyl.
  • R L is optionally substituted heteroC 6 -i 6 alkenyl. In some embodiments, R L is optionally substituted heteroC 6 -i 5 alkenyl. In some embodiments, R L is optionally substituted heteroCe-nalkenyl. In some embodiments, R L optionally substituted heteroC6-i3alkenyl. In some embodiments, R L is optionally substituted heteroC 6 -i 2 alkenyl. In some embodiments, R L is optionally substituted heteroCe-nalkenyl. In some embodiments, R L is optionally substituted heteroC 6 -ioalkenyl. In some embodiments, R L optionally substituted heteroC6-9alkenyl.
  • R L is optionally substituted heteroC 6 - 8 alkenyl. In some embodiments, R L is optionally substituted heteroC 6 - 7 alkenyl. [0263] In some embodiments, R L is optionally substituted heteroCg-soalkenyl. In some embodiments, R L is optionally substituted heteroC 8 - 4 oalkenyl. In some embodiments, R L is optionally substituted heteroCg-soalkenyl. In some embodiments, R L is optionally substituted heteroC 8 - 2 oalkenyl. In some embodiments, R L is optionally substituted heteroCg.igalkenyl. In some embodiments, R L is optionally substituted heteroCg_igalkenyl.
  • R L is optionally substituted heteroCg_i 7 alkenyl. In some embodiments, R L is optionally substituted heteroCg-iealkenyl. In some embodiments, R L is optionally substituted heteroCg-isalkenyl. In some embodiments, R L is optionally substituted heteroCg-ualkenyl. In some embodiments, R L is optionally substituted heteroCg_i3alkenyl. In some embodiments, R L is optionally substituted heteroC 8 _i 2 alkenyl. In some embodiments, R L is optionally substituted heteroC 8 _nalkenyl. In some embodiments, R L is optionally substituted heteroCg-ioalkenyl. In some embodiments, R L is optionally substituted heteroCg.galkenyl.
  • R L is optionally substituted heteroCg-soalkenyl. In some embodiments, R L is optionally substituted heteroC 9 _ 40 alkenyl. In some embodiments, R L is optionally substituted heteroCg-soalkenyl. In some embodiments, R L is optionally substituted heteroC 9 _ 2 oalkenyl. In some embodiments, R L is optionally substituted heteroC 9 _i 9 alkenyl. In some embodiments, R L is optionally substituted heteroCg-igalkenyl. In some embodiments, R L is optionally substituted heteroCg.nalkenyl. In some embodiments, R L is optionally substituted heteroCg-iealkenyl.
  • R L is optionally substituted heteroCg.isalkenyl. In some embodiments, R L is optionally substituted heteroCg-ualkenyl. In some embodiments, R L is optionally substituted heteroCg-isalkenyl. In some embodiments, R L is optionally substituted heteroC 9 _i 2 alkenyl. In some embodiments, R L is optionally substituted heteroC 9 _nalkenyl. In some embodiments, R L is optionally substituted heteroCg-ioalkenyl.
  • R L is optionally substituted heteroCio-soalkenyl. In some embodiments, R L is optionally substituted heteroCio- 4 oalkenyl. In some embodiments, R L is optionally substituted heteroCio-3oalkenyl. In some embodiments, R L is optionally substituted heteroC io- 2 oalkenyl. In some embodiments, R L is optionally substituted heteroCi 0 -i 9 alkenyl. In some embodiments, R L is optionally substituted heteroCio-igalkenyl. In some embodiments, R L is optionally substituted heteroC 10-17 alkenyl.
  • R L is optionally substituted heteroC io-i 6 alkenyl. In some embodiments, R L is optionally substituted heteroCio-isalkenyl. In some embodiments, R L is optionally substituted heteroCio-nalkenyl. In some embodiments, R L is optionally substituted heteroCi 0 -i 3 alkenyl. In some embodiments, R L is optionally substituted heteroCio-i 2 alkenyl. In some embodiments, R L is optionally substituted heteroCio-nalkenyl.
  • R L is optionally substituted heteroCn-soalkenyl. In some embodiments, R L is optionally substituted heteroCn_ 4 oalkenyl. In some embodiments, R L is optionally substituted heteroCn_3 0 alkenyl. In some embodiments, R L is optionally substituted heteroCn_ 2 oalkenyl. In some embodiments, R L is optionally substituted heteroCn-igalkenyl. In some embodiments, R L is optionally substituted heteroCn-igalkenyl. In some embodiments, R L is optionally substituted heteroCn-nalkenyl. In some embodiments, R L is optionally substituted heteroCn_i 6 alkenyl.
  • R L is optionally substituted heteroCn_i 5 alkenyl. In some embodiments, R L is optionally substituted heteroCn-ualkenyl. In some embodiments, R L is optionally substituted heteroCn_i 3 alkenyl. In some embodiments, R L is optionally substituted hetero C 11 _ 1 2 alkeny 1.
  • R L is optionally substituted heteroCn-soalkenyl. In some embodiments, R L is optionally substituted heteroCi 2 - 4 oalkenyl. In some embodiments, R L is optionally substituted heteroCi 2 - 3 oalkenyl. In some embodiments, R L is optionally substituted heteroCi 2 - 2 oalkenyl. In some embodiments, R L is optionally substituted heteroCi 2 -i 9 alkenyl. In some embodiments, R L is optionally substituted In some embodiments, R L is optionally substituted In some embodiments, R L is optionally substituted heteroCi 2 -i 7 alkenyl. In some embodiments, R L is optionally substituted heteroCi 2 -i 6 alkenyl.
  • R L is optionally substituted heteroCn-isalkenyl. In some embodiments, R L is optionally substituted heteroCi 2 -i 4 alkenyl. In some embodiments, R L is optionally substituted heteroCi 2 -i 3 alkenyl.
  • R L is optionally substituted heteroC 6 alkenyl. In some embodiments, R L is optionally substituted heteroCyalkenyl. In some embodiments, R L is optionally substituted heteroCgalkenyl. In some embodiments, R L is optionally substituted heteroCgalkenyl. In some embodiments, R L is optionally substituted heteroCioalkenyl. In some embodiments, R L is optionally substituted heteroCnalkenyl. In some embodiments, R L is optionally substituted heteroCnalkenyl. In some embodiments, R L is optionally substituted heteroCnalkenyl. In some embodiments, R L is optionally substituted heteroCnalkenyl. In some embodiments, R L is optionally substituted heteroCnalkenyl. In some embodiments, R L is optionally substituted heteroCnalkenyl. In some embodiments, R L is optionally substituted heteroCnalkenyl. In some embodiments, R L is optionally substituted heteroCnalkenyl.
  • R L is optionally substituted heteroCisalkenyl. In some embodiments, R L is optionally substituted heteroCi6alkenyl. In some embodiments, R L is optionally substituted heteroCnalkenyl. In some embodiments, R L is optionally substituted heteroCigalkenyl. In some embodiments, R L is optionally substituted heteroCigalkenyl. In some embodiments, R L is optionally substituted heteroC 2 oalkenyl.
  • R L is a substituted heteroalkenyl group.
  • R L is an unsubstituted heteroalkenyl group.
  • R L is an optionally substituted straight-chain heteroalkenyl group.
  • R L is a substituted straight-chain heteroalkenyl group.
  • R L is an unsubstituted straight-chain heteroalkenyl group.
  • R L is an optionally substituted branched heteroalkenyl group.
  • R is a substituted branched heteroalkenyl group.
  • R L is an unsubstituted branched heteroalkenyl group.
  • R L is optionally substituted heteroC 2 -5oalkynyl. In some embodiments, R L is optionally substituted heteroC 2 _ 4 oalkynyl. In some embodiments, R L is optionally substituted heteroC 2 -3oalkynyl. In some embodiments, R L is optionally substituted heteroC 2 - 2 oalkynyl. In some embodiments, R L is optionally substituted heteroC 2 -i 9 alkynyl. In some embodiments, R L is optionally substituted heteroC 2 -i8alkynyl. In some embodiments, R L is optionally substituted heteroC 2 _i 7 alkynyl.
  • R L is optionally substituted heteroC 2 -i 6 alkynyl. In some embodiments, R L is optionally substituted heteroC 2 -i 5 alkynyl. In some embodiments, R L is optionally substituted heteroC 2 -i 4 alkynyl. In some embodiments, R L is optionally substituted heteroC 2 -i3alkynyl. In some embodiments, R L is optionally substituted heteroC 2 -i 2 alkynyl. In some embodiments, R L is optionally substituted heteroC 2 -nalkynyl. In some embodiments, R L is optionally substituted heteroC 2 -ioalkynyl.
  • R L is optionally substituted heteroC 2 -9alkynyl. In some embodiments, R L is optionally substituted heteroC 2 - 8 alkynyl. In some embodiments, R L is optionally substituted heteroC 2 - 7 alkynyl. In some embodiments, R L is optionally substituted heteroC 2 -6alkynyl.
  • R L is optionally substituted heteroC 4 _ 5 oalkynyl. In some embodiments, R L is optionally substituted heteroC 4 - 4 oalkynyl. In some embodiments, R L is optionally substituted heteroC 4 -3oalkynyl. In some embodiments, R L is optionally substituted heteroC 4 _ 2 oalkynyl. In some embodiments, R L is optionally substituted heteroC 4 _i 9 alkynyl. In some embodiments, R L is optionally substituted heteroC 4 -i8alkynyl. In some embodiments, R L optionally substituted heteroC 4 _i 7 alkynyl.
  • R L is optionally substituted heteroC 4 _i 6 alkynyl. In some embodiments, R L is optionally substituted heteroC 4 _i 5 alkynyl. In some embodiments, R L is optionally substituted heteroC 4 -i 4 alkynyl. In some embodiments, R L optionally substituted heteroC 4 -i3alkynyl. In some embodiments, R L is optionally substituted heteroC 4 _i 2 alkynyl. In some embodiments, R L is optionally substituted heteroC 4 _nalkynyl. In some embodiments, R L is optionally substituted heteroC 4 -ioalkynyl.
  • R L optionally substituted heteroC 4 -9alkynyl. In some embodiments, R L is optionally substituted heteroC 4 _ 8 alkynyl. In some embodiments, R L is optionally substituted heteroC 4 _ 7 alkynyl. In some embodiments, R L is optionally substituted heteroC 4 _ 6 alkynyl.
  • R L is optionally substituted heteroCe-soalkynyl. In some embodiments, R L is optionally substituted heteroC6- 4 oalkynyl. In some embodiments, R L is optionally substituted heteroC6_3oalkynyl. In some embodiments, R L is optionally substituted heteroC 6 - 2 oalkynyl. In some embodiments, R L is optionally substituted heteroC 6 -i 9 alkynyl. In some embodiments, R L is optionally substituted heteroCe-igalkynyl. In some embodiments, R L optionally substituted heteroCe-nalkynyl.
  • R L is optionally substituted heteroC 6 -i 6 alkynyl. In some embodiments, R L is optionally substituted heteroCe-isalkynyl. In some embodiments, R L is optionally substituted heteroC 6 -i 4 alkynyl. In some embodiments, R L optionally substituted heteroC 6 _i 3 alkynyl. In some embodiments, R L is optionally substituted heteroC 6 -i 2 alkynyl. In some embodiments, R L is optionally substituted heteroCe-nalkynyl. In some embodiments, R L is optionally substituted heteroCe-ioalkynyl. In some embodiments, R L optionally substituted heteroC6_9alkynyl. In some embodiments, R L is optionally substituted heteroC 6 - 8 alkynyl. In some embodiments, R L is optionally substituted heteroC 6 - 7 alkynyl.
  • R L is optionally substituted heteroCg-soalkynyl. In some embodiments, R L is optionally substituted heteroCg_ 4 oalkynyl. In some embodiments, R L is optionally substituted heteroCg-soalkynyl. In some embodiments, R L is optionally substituted heteroCg_ 2 oalkynyl. In some embodiments, R L is optionally substituted heteroCg_i 9 alkynyl. In some embodiments, R L is optionally substituted heteroCg_igalkynyl. In some embodiments, R L optionally substituted heteroCg.nalkynyl.
  • R L is optionally substituted heteroCg_i 6 alkynyl. In some embodiments, R L is optionally substituted heteroCg-isalkynyl. In some embodiments, R L is optionally substituted heteroCg-nalkynyl. In some embodiments, R L is optionally substituted heteroC 8 -i 3 alkynyl. In some embodiments, R L is optionally substituted heteroC 8 -i 2 alkynyl. In some embodiments, R L is optionally substituted heteroCg-nalkynyl. In some embodiments, R L is optionally substituted heteroCg-ioalkynyl. In some embodiments, R L is optionally substituted heteroCg.galkynyl.
  • R L is optionally substituted heteroC 9 _ 50 alkynyl. In some embodiments, R L is optionally substituted heteroC9_ 4 oalkynyl. In some embodiments, R L is optionally substituted heteroCg-soalkynyl. In some embodiments, R L is optionally substituted heteroC 9 _ 2 oalkynyl. In some embodiments, R L is optionally substituted heteroC 9 _i 9 alkynyl. In some embodiments, R L is optionally substituted heteroCg-igalkynyl. In some embodiments, R L is optionally substituted heteroCg-nalkynyl.
  • R L is optionally substituted heteroC 9 _i 6 alkynyl. In some embodiments, R L is optionally substituted heteroCg-isalkynyl. In some embodiments, R L is optionally substituted heteroCg-nalkynyl. In some embodiments, R L is optionally substituted heteroC 9 _i 3 alkynyl. In some embodiments, R L is optionally substituted heteroCg-nalkynyl. In some embodiments, R L is optionally substituted heteroC 9 _nalkynyl. In some embodiments, R L is optionally substituted heteroCg-ioalkynyl.
  • R L is optionally substituted heteroCio-soalkynyl. In some embodiments, R L is optionally substituted heteroCi 0 - 4 oalkynyl. In some embodiments, R L is optionally substituted heteroCi 0 - 3 oalkynyl. In some embodiments, R L is optionally substituted heteroC 10-20 alkynyl. In some embodiments, R L is optionally substituted heteroCio-i9alkynyl. In some embodiments, R L is optionally substituted heteroCio-igalkynyl. In some embodiments, R L is optionally substituted heteroC 10-17 alkynyl.
  • R L is optionally substituted heteroC io-i 6 alkynyl. In some embodiments, R L is optionally substituted heteroCio-isalkynyl. In some embodiments, R L is optionally substituted heteroC io-i 4 alkynyl. In some embodiments, R L is optionally substituted heteroC io-i 3 alkynyl. In some embodiments, R L is optionally substituted heteroC io-i 2 alkynyl. In some embodiments, R L is optionally substituted heteroCio-nalkynyl.
  • R L is optionally substituted heteroCn_ 5 oalkynyl. In some embodiments, R L is optionally substituted heteroCn_ 4 oalkynyl. In some embodiments, R L is optionally substituted heteroCn_ 3 oalkynyl. In some embodiments, R L is optionally substituted heteroC n_ 2 oalkynyl. In some embodiments, R L is optionally substituted heteroCn-igalkynyl. In some embodiments, R L is optionally substituted heteroCn-igalkynyl. In some embodiments, R L is optionally substituted heteroCn_i 7 alkynyl.
  • R L is optionally substituted heteroCn_i 6 alkynyl. In some embodiments, R L is optionally substituted heteroCn-isalkynyl. In some embodiments, R L is optionally substituted heteroCn-ualkynyl. In some embodiments, R L is optionally substituted heteroCn_i3alkynyl. In some embodiments, R L is optionally substituted heteroC i i_i 2 alkynyl.
  • R L is optionally substituted heteroCi 2 -5oalkynyl. In some embodiments, R L is optionally substituted heteroCi 2 - 4 oalkynyl. In some embodiments, R L is optionally substituted heteroCi 2 -3oalkynyl. In some embodiments, R L is optionally substituted heteroCi 2 - 2 oalkynyl. In some embodiments, R L is optionally substituted heteroCi 2 -i 9 alkynyl. In some embodiments, R L is optionally substituted heteroCi 2 -i8alkynyl. In some embodiments, R L is optionally substituted heteroCi 2 -i 7 alkynyl.
  • R L is optionally substituted heteroCi 2 -i 6 alkynyl. In some embodiments, R L is optionally substituted heteroCi 2 -i 5 alkynyl. In some embodiments, R L is optionally substituted heteroCn-ualkynyl. In some embodiments, R L is optionally substituted heteroCi 2 -i 3 alkynyl.
  • R L is optionally substituted heteroCealkynyl. In some embodiments, R L is optionally substituted heteroC 7 alkynyl. In some embodiments, R L is optionally substituted heteroC 8 alkynyl. In some embodiments, R L is optionally substituted heteroCgalkynyl. In some embodiments, R L is optionally substituted heteroCioalkynyl. In some embodiments, R L is optionally substituted heteroCnalkynyl. In some embodiments, R L is optionally substituted heteroCnalkynyl. In some embodiments, R L is optionally substituted heteroCi 3 alkynyl.
  • R L is optionally substituted heteroCnalkynyl. In some embodiments, R L is optionally substituted heteroCi 5 alkynyl. In some embodiments, R L is optionally substituted heteroCi6alkynyl. In some embodiments, R L is optionally substituted heteroCnalkynyl. In some embodiments, R L is optionally substituted heteroCisalkynyl. In some embodiments, R L is optionally substituted heteroCigalkynyl. In some embodiments, R L is optionally substituted heteroC 2 oalkynyl.
  • R L is a substituted heteroalkynyl group.
  • R L is an unsubstituted heteroalkynyl group.
  • R L is an optionally substituted straight-chain heteroalkynyl group.
  • R L is a substituted straight-chain heteroalkynyl group.
  • R L is an unsubstituted straight-chain heteroalkynyl group.
  • R L is an optionally substituted branched heteroalkynyl group.
  • R L is a substituted branched heteroalkynyl group.
  • R L is an unsubstituted branched heteroalkynyl group.
  • R L is a polymer.
  • a polymer in some embodiments, refers to a compound comprised of at least 3 (e.g., at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, etc.) repeating covalently bound structural units.
  • the polymer is in certain embodiments biocompatible (i.e., non-toxic).
  • Exemplary polymers include, but are not limited to, cellulose polymers (e.g., hydroxyethylcellulose, ethylcellulose, carboxymethylcellulose, methylc cellulose, hydroxypropylmethylcellulose (HPMC)), dextran polymers, polymaleic acid polymers, poly(acrylic acid) polymers, poly(vinylalcohol) polymers, polyvinylpyrrolidone (PVP) polymers, and polyethyleneglycol (PEG) polymers, and combinations thereof.
  • cellulose polymers e.g., hydroxyethylcellulose, ethylcellulose, carboxymethylcellulose, methylc cellulose, hydroxypropylmethylcellulose (HPMC)
  • dextran polymers e.g., cellulose polymers (e.g., hydroxyethylcellulose, ethylcellulose, carboxymethylcellulose, methylc cellulose, hydroxypropylmethylcellulose (HPMC)), dextran polymers, polymaleic acid polymers, poly(acrylic
  • R L is a lipophilic, hydrophobic and/or non-polar group. In some embodiments, R L is a lipophilic group. In some embodiments, R L is a hydrophobic group. In some embodiments, R L is a non-polar group.
  • R L group when an R L group is depicted as bisecting a carbon-carbon bond, e.g., of the formula (i), it is understood that R L may be bonded to either carbon.
  • At least one instance of R ⁇ , R 2 , R 6 , or R 7 is a group of the formula (i), (ii), or (iii). In some embodiments, at least one instance of R 6 or R 7 of R 1 is a group of formula (i), (ii) or (iii). In some embodiments, at least one instance of R 6 or R 7 of R 1 is a group of formula (i). In some embodiments, at least one instance of R 6 or R 7 of R 1 is a group of formula (i-a). In some embodiments, at least one instance of R 6 or R 7 of R 1 is a group of formula (i-al).
  • At least one instance of R 6 or R 7 of R 1 is a group of formula (i-b). In some embodiments, at least one instance of R 6 or R 7 of R 1 is a group of formula (ii). In some embodiments, at least one instance of R 6 or R 7 of R 1 is a group of formula (iii).
  • I is a compound of formula I-a:
  • At least one R 1 is a group of formula (iv). In certain embodiments, each instance of R 1 is a group of formula (iv). In certain embodiments, each instance of R 2 is independently hydrogen or optionally substituted Ci_ 6 alkyl. In certain embodiments, each instance of R 2 is hydrogen. In certain embodiments, at least one instance of R 2 is a group of formula (i). In certain embodiments, at least one instance of R 2 is a group of formula (ii). In certain embodiments, at least one instance of R 2 is a group of formula (iii). In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3.
  • a compound of formula I is a compound of formula I-b:
  • each instance of R 1 is a group of formula (iv).
  • each instance of R 2 is independently hydrogen or optionally substituted Ci_ 6 alkyl. In certain embodiments, each instance of R 2 is hydrogen. In certain embodiments, at least one instance of R 2 is a group of formula (i). In certain embodiments, at least one instance of R 2 is a group of formula (ii). In certain embodiments, at least one instance of R 2 is a group of formula (iii). In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3. In certain embodiments, L is an optionally substituted alkylene. In certain embodiments, R 6 is a group of formula (i). In certain embodiments, R 6 is a group of formula (ii). In certain embodiments, R 6 is a group of formula (iii). In certain embodiments, R 7 is a group of formula
  • R 7 is a group of formula (ii). In certain embodiments, R 7 is a group of formula (iii). In certain embodiments, both R 6 and R 7 are independently groups of formula (i),
  • a compound of Formula I is a compound of formula I-c:
  • each instance of R 2 is independently hydrogen or optionally substituted Ci_ 6 alkyl. In certain embodiments, each instance of R 2 is hydrogen. In certain embodiments, at least one instance of R 2 is a group of formula (i). In certain
  • At least one instance of R 2 is a group of formula (ii). In certain embodiments, at least one instance of R 2 is a group of formula (iii). In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3. In certain embodiments, L is an optionally substituted alkylene. In certain embodiments, R 6 is a group of formula (i). In certain embodiments,
  • R 6 is a group of formula (ii). In certain embodiments, R 6 is a group of formula (iii). In certain embodiments, R 7 is a group of formula (i). In certain embodiments, R 7 is a group of formula (ii). In certain embodiments, R 7 is a group of formula (iii). In certain embodiments, both R 6 and R 7 are independently groups of formula (i), (ii), or (iii).
  • a compound of formula I-c is a compound of formula I-cl:
  • each instance of R 2 is independently hydrogen or optionally substituted Ci_ 6 alkyl. In certain embodiments, each instance of R 2 is hydrogen. In certain embodiments, at least one instance of R 2 is a group of formula (i). In certain
  • At least one instance of R 2 is a group of formula (ii). In certain embodiments, at least one instance of R 2 is a group of formula (iii). In certain embodiments, L is an optionally substituted alkylene.
  • R 6 is a group of formula (i). In certain embodiments, R 6 is a group of formula (ii). In certain embodiments, R 6 is a group of formula (iii). In certain embodiments, R 7 is a group of formula (i). In certain embodiments, R 7 is a group of formula (ii). In certain embodiments, R 7 is a group of formula (iii). In certain embodiments, R 7 is a group of formula (iii). In certain embodiments, both R 6 and R 7 are independently groups of formula (i), (ii), or (iii).
  • R 6 and R 7 are the same group of formula (i). In some embodiments, R 6 and R 7 are the same group of formula (i-a). In some embodiments, R 6 and R 7 are the same group of formula (i-al). In some embodiments, R 6 and R 7 are the same group of formula (i-b). In some embodiments, R 6 and R 7 are the same group of formula (ii). In some embodiments, R 6 and R 7 are the same group of formula (iii).
  • each instance of R 2 is hydrogen.
  • a compound of formula I-c is a compound of formula I-c2:
  • L is an optionally substituted alkylene.
  • R 6 is a group of formula (i). In certain embodiments, R 6 is a group of formula (ii). In certain embodiments, R 6 is a group of formula (iii). In certain embodiments, R 7 is a group of formula (i). In certain embodiments, R 7 is a group of formula (ii). In certain embodiments, R 7 is a group of formula (iii). In certain embodiments, both R 6 and R 7 are independently groups of formula (i), (ii), or (iii). In some embodiments, R 6 and R 7 are the same group of formula (i). In some embodiments, R 6 and R 7 are the same group of formula (i-a).
  • R 6 and R 7 are the same group of formula (i-al). In some embodiments, R 6 and R 7 are the same group of formula (i-b). In some embodiments, R 6 and R 7 are the same group of formula (ii). In some embodiments, R 6 and R 7 are the same group of formula (iii).
  • L is an optionally substituted alkylene.
  • a compound of formula I-c is a compound of formula I-c3:
  • q is an integer between 1 and 10, inclusive.
  • R 6 is a group of formula (i). In certain embodiments, R 6 is a group of formula (ii). In certain embodiments, R 6 is a group of formula (iii). In certain embodiments, R 7 is a group of formula (i). In certain embodiments, R 7 is a group of formula (ii). In certain embodiments, R 7 is a group of formula (iii). In certain embodiments, both R 6 and R 7 are independently groups of formula (i), (ii), or (iii). In some embodiments, R 6 and R 7 are the same group of formula (i). In some embodiments, R 6 and R 7 are the same group of formula (i-a).
  • R 6 and R 7 are the same group of formula (i-al). In some embodiments, R 6 and R 7 are the same group of formula (i-b). In some embodiments, R 6 and R 7 are the same group of formula (ii). In some embodiments, R 6 and R 7 are the same group of formula (iii). [0297] In some embodiments, a compound of formula I is a compound of formula I-d:
  • a compound of formula I is a compound of formula I-e:
  • a compound of formula I is a compound of formula I-f:
  • R 2 and R L are independently as defined above and described herein.
  • provided liposomes include a cationic lipid described in
  • a compound of formula I is a compound of formula I-cl-a:
  • each R 2 independently is hydrogen or Ci_ 3 alkyl; each q independently is 2 to 6; each R independently is hydrogen or Ci_ 3 alkyl; and each R L independently is C 8-12 alkyl.
  • each R 2 independently is hydrogen, methyl or ethyl. In some embodiments, each R 2 independently is hydrogen or methyl. In some embodiments, each R 2 is hydrogen.
  • each q independently is 3 to 6. In some embodiments, each q independently is 3 to 5. In some embodiments, each q is 4.
  • each R independently is hydrogen, methyl or ethyl. In some embodiments, each R independently is hydrogen or methyl. In some embodiments, each R independently is hydrogen.
  • each R L independently is C 8-12 alkyl. In some embodiments, each R L independently is C 8-12 alkyl. In some
  • each R L independently is «-C 8-12 alkyl. In some embodiments, each R L independently is C9_n alkyl. In some embodiments, each R L independently is n-Cg-n alkyl. In some embodiments, each R L independently is C 10 alkyl. In some embodiments, each R L independently is n-C 10 alkyl.
  • each R 2 independently is hydrogen or methyl; each q independently is 3 to 5; each R independently is hydrogen or methyl; and each R L independently is C 8 -i2 alkyl.
  • each R 2 is hydrogen; each q independently is 3 to 5; each
  • R is hydrogen; and each R L independently is C 8-12 alkyl.
  • each R 2 is hydrogen; each q is 4; each R' is hydrogen; and each R L independently is C 8-12 alkyl.
  • a compound of formula I is a compound of formula I-g:
  • a compound of formula I is a compound of formula X:
  • a compound of formula I is a compound of formula X-l :
  • a compound of formula I is
  • 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 performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley).
  • CI -6 alkyl is intended to encompass, CI, C2, C3, C4, C5, C6, CI -6, Cl-5, Cl -4, Cl-3, Cl -2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl.
  • alkyl refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 50 carbon atoms ("CI -50 alkyl”). In some embodiments, an alkyl group has 1 to 40 carbon atoms ("CI -40 alkyl”). In some embodiments, an alkyl group has 1 to 30 carbon atoms ("CI -30 alkyl”). In some embodiments, an alkyl group has 1 to 20 carbon atoms (“CI -20 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“CI- 10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms ("CI -9 alkyl”).
  • an alkyl group has 1 to 8 carbon atoms ("CI -8 alkyl”). In some embodiments, 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 ("CI -4 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”).
  • an alkyl group has 1 carbon atom (“CI alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6 alkyl”).
  • CI -6 alkyl groups include, without limitation, methyl (CI), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec- butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2- butanyl (C5), tertiary amyl (C5), and n-hexyl (C6).
  • alkyl groups include n- heptyl (C7), n-octyl (C8) and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an "unsubstituted alkyl") or substituted (a "substituted alkyl") with one or more substituents. In certain embodiments, the alkyl group is an unsubstituted CI -50 alkyl. In certain embodiments, the alkyl group is a substituted CI -50 alkyl.
  • heteroalkyl refers to an alkyl group as defined herein which further includes at least one heteroatom (e.g., 1 to 25, e.g., 1 , 2, 3, or 4 heteroatoms) selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus 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 50 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroCl -50 alkyl").
  • a heteroalkyl group refers to a saturated group having from 1 to 40 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroCl -40 alkyl"). In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 30 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroCl - 30 alkyl”). In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 20 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1 -20 alkyl").
  • a heteroalkyl group refers to a saturated group having from 1 to 10 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroC 1 - 10 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroCl -9 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCl -8 alkyl").
  • a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroC 1 -7 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroCl -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 (“heteroCl -5 alkyl"). In some
  • a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms within the parent chain ("heteroCl -4 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain ("heteroCl -3 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and
  • a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroCl 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 ("heteroC2-6 alkyl”). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl") or substituted (a "substituted heteroalkyl”) with one or more substituents. In certain embodiments, the heteroalkyl group is an unsubstituted heteroCl -50 alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroCl -50 alkyl.
  • alkenyl refers to a radical of a straight-chain or branched
  • an alkenyl group having from 2 to 50 carbon atoms and one or more carbon-carbon double bonds (e.g., 1 , 2, 3, or 4 double bonds) ("C2-50 alkenyl”).
  • an alkenyl group has 2 to 40 carbon atoms ("C2-40 alkenyl”).
  • an alkenyl group has 2 to 30 carbon atoms ("C2-30 alkenyl”).
  • an alkenyl group has 2 to 20 carbon atoms (“C2-20 alkenyl”).
  • an alkenyl group has 2 to 10 carbon atoms (“C2-10 alkenyl”).
  • an alkenyl group has 2 to 9 carbon atoms (“C2-9 alkenyl”).
  • an alkenyl group has 2 to 8 carbon atoms (“C2-8 alkenyl”).
  • an alkenyl group has
  • an alkenyl group has 2 to 6 carbon atoms ("C2-6 alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C2-5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C2-4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C2 alkenyl”).
  • the one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl).
  • Examples of C2-4 alkenyl groups include, without limitation, ethenyl (C2), 1 -propenyl (C3), 2-propenyl (C3), 1 -butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like.
  • Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like.
  • each instance of an alkenyl group is independently unsubstituted (an "unsubstituted alkenyl") or substituted (a "substituted alkenyl") with one or more substituents.
  • the alkenyl group is an unsubstituted C2-50 alkenyl.
  • the alkenyl group is a substituted C2-50 alkenyl.
  • heteroalkenyl refers to an alkenyl group as defined herein which further includes at least one heteroatom (e.g., 1 to 25, e.g., 1 , 2, 3, or 4 heteroatoms) selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus 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 50 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain ("heteroC2-50 alkenyl").
  • a heteroalkenyl group refers to a group having from 2 to 40 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain ("heteroC2-40 alkenyl"). In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 30 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain ("heteroC2-30 alkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 20 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-20 alkenyl").
  • a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain ("heteroC2-10 alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain ("heteroC2-9 alkenyl"). In 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 (“heteroC2- 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 (“heteroC2-7 alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 9 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2
  • a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain ("heteroC2-6 alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain ("heteroC2-5 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and for 2 heteroatoms within the parent chain (“heteroC2-4 alkenyl").
  • a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain ("heteroC2-3 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double, bond, and 1 or 2 heteroatoms within the parent chain ("heteroC2-6 alkenyl”). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an "unsubstituted heteroalkenyl") or substituted (a "substituted heteroalkenyl") with one or more substituents. In certain embodiments, the heteroalkenyl group is an unsubstituted heteroC2-50 alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC2-50 alkenyl.
  • alkynyl refers to a radical of a straight-chain or branched
  • hydrocarbon group having from 2 to 50 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) and optionally one or more double bonds (e.g., 1 , 2, 3, or 4 double bonds) ("C2-50 alkynyl").
  • An alkynyl group that has one or more triple bonds and one or more double bonds is also referred to as an "ene-yne”.
  • an alkynyl group has 2 to 40 carbon atoms (“C2-40 alkynyl”).
  • an alkynyl group has 2 to 30 carbon atoms (“C2-30 alkynyl”).
  • an alkynyl group has 2 to 20 carbon atoms ("C2-20 alkynyl”). In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C2- 10 alkynyl”). In some
  • an alkynyl group has 2 to 9 carbon atoms ("C2-9 alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms ("C2-8 alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms ("C2-7 alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms ("C2-6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2-5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms ("C2-4 alkynyl”).
  • an alkynyl group has 2 to 3 carbon atoms ("C2-3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms ("C2 alkynyl”).
  • the one or more carbon— carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl).
  • Examples of C2-4 alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like.
  • C2-6 alkenyl groups include the aforementioned C2-4 alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (CI), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is
  • the alkynyl group is an unsubstituted C2-50 alkynyl. In certain embodiments, the alkynyl group is a substituted C2-50 alkynyl.
  • heteroalkynyl refers to an alkynyl group as defined herein which further includes at least one heteroatom (e.g., 1 to 25, e.g., 1 , 2, 3, or 4 heteroatoms) selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus 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 50 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain ("heteroC2-50 alkynyl").
  • a heteroalkynyl group refers to a group having from 2 to 40 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain ("heteroC2-40 alkynyl"). In certain embodiments, a heteroalkynyl group refers to a group having from 2 to 30 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain ("heteroC2-30 alkynyl"). In certain embodiments, a heteroalkynyl group refers to a group having from 2 to 20 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-20 alkynyl").
  • a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain ("heteroC2-10 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain ("heteroC2-9 alkynyl"). In 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 (“heteroC2-8 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 (“heteroC2-7 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms
  • a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain ("heteroC2-6 alkynyl"). In 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 ("heteroC2-5 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and for 2 heteroatoms within the parent chain (“heteroC2-4 alkynyl").
  • a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain ("heteroC2-3 alkynyl"). In 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 ("heteroC2-6 alkynyl"). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an "unsubstituted heteroalkynyl") or substituted (a "substituted heteroalkynyl") with one or more substituents. In certain embodiments, the heteroalkynyl group is an unsubstituted heteroC2-50 alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC2-50 alkynyl.
  • carbocyclyl or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms ("C3- 10 carbocyclyl") and zero heteroatoms in the non-aromatic ring system.
  • a carbocyclyl group has 3 to 8 ring carbon atoms ("C3-8 carbocyclyl”).
  • a carbocyclyl group has 3 to 7 ring carbon atoms (“C3-7 carbocyclyl”).
  • a carbocyclyl group has 3 to 6 ring carbon atoms ("C3-6 carbocyclyl”).
  • a carbocyclyl group has 4 to 6 ring carbon atoms ("C4-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms ("C5-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C5- 10 carbocyclyl”).
  • Exemplary C3-6 carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like.
  • Exemplary C3-8 carbocyclyl groups include, without limitation, the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (CI), cycloheptenyl (CI), cycloheptadienyl (CI), cycloheptatrienyl (CI), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1 ]heptanyl (CI), bicyclo[2.2.2]octanyl (C8), and the like.
  • CI cycloheptyl
  • CI cycloheptenyl
  • CI cycloheptadienyl
  • CI cycloheptatrienyl
  • C8 cyclooctyl
  • C8 cyclooctenyl
  • bicyclo[2.2.2]octanyl (C8) and the like.
  • Exemplary C3- 10 carbocyclyl groups include, without limitation, the aforementioned C3-8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C I O), cyclodecenyl (C I O), octahydro- lH-indenyl (C9), decahydronaphthalenyl (C I O), spiro[4.5]decanyl (C I O), 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 C3- 10 carbocyclyl.
  • the carbocyclyl group is a substituted C3- 10 carbocyclyl.
  • “carbocyclyl” or “carbocyclic” is referred to as a "cycloalkyl", i.e., a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms ("C3- 10 cycloalkyl”).
  • a cycloalkyl group has 3 to 8 ring carbon atoms ("C3-8 cycloalkyl”).
  • a cycloalkyl group has 3 to 6 ring carbon atoms ("C3-6, cycloalkyl”).
  • a cycloalkyl group has 4 to 6 ring carbon atoms ("C4-6 cycloalkyl”).
  • a cycloalkyl group has 5 to 6 ring carbon atoms ("C5-6 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 C3-6 cycloalkyl groups include the aforementioned C5-6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4).
  • C3-8 cycloalkyl groups include the aforementioned C3-6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8).
  • 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 C3- 10 cycloalkyl.
  • the cycloalkyl group is a substituted C3- 10 cycloalkyl.
  • heterocyclyl refers to a radical of a 3- to 14- membered non-aromatic ring system having ring carbon atoms and 1 or more (e.g., 1, 2, 3, or 4) ring heteroatoms, wherein each heteroatom is independently selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus ("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
  • a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1 or more (e.g., 1, 2, 3, or 4) ring heteroatoms, wherein each heteroatom is independently selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus ("5-10 membered heterocyclyl").
  • a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1 or more (e.g., 1, 2, 3, or 4) ring heteroatoms, wherein each heteroatom is independently selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus ("5-8 membered heterocyclyl").
  • a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1 or more (e.g., 1, 2, 3, or 4) ring heteroatoms, wherein each heteroatom is independently selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus ("5-6 membered heterocyclyl").
  • the 5-6 membered heterocyclyl has 1 or more (e.g., 1, 2, or 3) ring heteroatoms selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus.
  • the 5-6 membered heterocyclyl has 1 or 2 ring heteroatoms selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus.
  • the 5-6 membered heterocyclyl has 1 ring heteroatom selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus.
  • Exemplary 3 -membered heterocyclyl groups containing 1 heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl.
  • 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,
  • 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 2 heteroatoms include, without limitation, triazinanyl.
  • Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl.
  • Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl.
  • bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl,
  • octahydrochromenyl octahydroisochromenyl, decahydronaphthyridinyl, decahydro-l,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H- benzo[e][l,4]diazepinyl, l,4,5,7-tetrahydropyrano[3,4-b] pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7- dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro- lH-pyrrolo[2,3-b ]pyridinyl, 2,3
  • 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 ("C6-14 aryl”).
  • aromatic ring system e.g., having 6, 10, or 14 ⁇ electrons shared in a cyclic array
  • an aryl group has 6 ring carbon atoms (“C6 aryl”; e.g., phenyl).
  • an aryl group has 10 ring carbon atoms ("CIO aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl).
  • 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 unsubstituted C6-14 aryl.
  • the aryl group is a substituted C6- 14 aryl.
  • 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 or more (e.g., 1, 2, 3, or 4 ring heteroatoms) ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus ("5-14 membered heteroaryl").
  • heteroaryl groups that contain one or more nitrogen atoms
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heteroaryl includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system.
  • Heteroaryl also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl/heteroaryl) ring system.
  • Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom e.g., indolyl, quinolinyl, carbazolyl, and the like
  • the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).
  • a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1 or more (e.g., 1, 2, 3, or 4) ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus ("5-10 membered heteroaryl").
  • a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1 or more (e.g., 1, 2, 3, or 4) ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus ("5-8 membered heteroaryl").
  • a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1 or more (e.g., 1, 2, 3, or 4) ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus ("5-6 membered heteroaryl").
  • the 5-6 membered heteroaryl has 1 or more (e.g., 1, 2, or 3) ring heteroatoms selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus. In some embodiments, the 5-6 membered heteroaryl has 1 or 2 ring heteroatoms selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted (an "unsubstituted heteroaryl") or substituted (a "substituted heteroaryl") with one or more substituents. In certain embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments,
  • the heteroaryl group is a substituted 5-14 membered heteroaryl.
  • Exemplary 5-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl.
  • Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
  • Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.
  • Exemplary 5-membered heteroaryl groups containing 4 heteroatoms include, without limitation, tetrazolyl.
  • Exemplary 6-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyridinyl.
  • Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • Exemplary 6-membered heteroaryl groups containing 3 or 4 heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively.
  • Exemplary 7-membered heteroaryl groups containing 1 heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl.
  • Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl,
  • benzisoxazolyl benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl.
  • Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
  • Exemplary tricyclic heteroaryl groups include, without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl and phenazinyl.
  • 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., the ring 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, in certain embodiments, optionally substituted.
  • Optionally substituted refers to a group which may be substituted or unsubstituted (e.g., "substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, "substituted” or “unsubstituted” alkynyl, "substituted” or “unsubstituted” heteroalkyl, “substituted” or “unsubstituted” heteroalkenyl, "substituted” or . 'unsubstituted” heteroalkynyl. "substituted" or
  • substituted means that at least one hydrogen present on a group is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
  • a "substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position.
  • substituted is contemplated to include substitution with all permissible substituents of organic compounds, any of the substituents described herein that results in the formation of a stable compound.
  • heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety.
  • Exemplary carbon atom substituents include, but are not limited to, halogen, -CN, -
  • each instance of Raa is, independently, selected from Cl-50 alkyl, C2-50 alkenyl, C2-50 alkynyl, C3-10 carbocyclyl, 3- 14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Raa groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups;
  • each instance of Rbb is, independently, selected from hydrogen, -OH, -ORaa, - N(Rcc)2,
  • each instance of Rcc is, independently, selected from hydrogen, Cl-50 alkyl, C2-50 alkenyl, C2-50 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5- 14 membered heteroaryl, or two Rcc groups, together with the heteroatom to which they are attached, 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 Rdd groups; [0341] each instance of Rdd is, independently, selected from halogen, -CN, -N02, -N3, - S02H,
  • each instance of Ree is, independently, selected from Cl-50 alkyl, C2-50 alkenyl, C2-50 alkynyl, C3-10 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 Rgg groups;
  • each instance of Rff is, independently, selected from hydrogen, Cl-50 alkyl, C2-50 alkenyl, C2-50 alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, C6-10 aryl and 5-10 membered heteroaryl, or two Rff groups, together with the heteroatom to which they are attached, 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 Rgg groups; and
  • each instance of Rgg is, independently, halogen, -CN, -N02, -N3, -S02H, -S03H, -
  • 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-, C1-, Br-, I-), N03-, C104-, OH-, H2P04-, HS04-, 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, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, and the like).
  • carboxylate ions e.g., acetate, ethanoate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, and the like.
  • Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quarternary nitrogen atoms.
  • Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quarternary nitrogen atoms.
  • the substituent present on a nitrogen atom is a nitrogen protecting group (also referred to as an amino protecting group).
  • Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
  • Nitrogen protecting groups such as carbamate groups include, but are not limited to, methyl carbamate, ethyl carbamante, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t- butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4- methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2- trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1- (l-adamantyl)-l- methylethyl
  • Nitrogen protecting groups such as sulfonamide groups include, but are not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6,-trimethyl- 4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl- 4-methoxybenzenesulfonamide (Pme), 2,3 ,5 ,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6- trimethylbenzenesulfonamide (Mts), 2,6- dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), me
  • Ts p-toluenesulfonamide
  • nitrogen protecting groups include, but are not limited to, phenothiazinyl-
  • Mpt dimethylthiophosphinamide
  • Ppt diphenylthiophosphinamide
  • dialkyl phosphoramidates dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o- nitrobenzenesulfenamide (Nps), 2,4- dinitrobenzenesulfenamide,
  • triphenylmethylsulfenamide triphenylmethylsulfenamide
  • 3-nitropyridinesulfenamide Npys
  • the substituent present on an oxygen atom is an oxygen protecting group (also referred to as a hydroxyl protecting group).
  • Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
  • oxygen protecting groups include, but are not limited to, methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl,
  • IPDMS dimethylisopropylsilyl
  • DEIPS diethylisopropylsilyl
  • TDMS t-butyldimethylsilyl
  • TDPS t-butyldiphenylsilyl
  • tribenzylsilyl tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS)
  • formate benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3- phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate
  • the substituent present on an sulfur atom is an sulfur protecting group (also referred to as a thiol protecting group).
  • Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
  • a "leaving group” is an art-understood term referring to a molecular fragment that departs with a pair of electrons in heterolytic bond cleavage, wherein the molecular fragment is an anion or neutral molecule. See, for example, Smith, March's Advanced Organic Chemistry 6th ed. (501-502).
  • Exemplary leaving groups include, but are not limited to, halo (e.g., chloro, bromo, iodo) and sulfonyl substituted hydroxyl groups (e.g., tosyl, mesyl, besyl).
  • At least one instance refers to one instance, but also encompasses more than one instance, e.g., for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 instances, and up to 100 instances.
  • a "polymer” refers to a compound comprised of at least 3 (e.g., at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, etc.) repeating covalently bound structural units.
  • lipophilic refers to the ability of a group to dissolve in fats, oils, lipids, and lipophilic non-polar solvents such as hexane or toluene.
  • a lipophilic group refers to an unsubstituted n-alkyl or unsubstituted n-alkenyl group having 6 to 50 carbon atoms, e.g., 6 to 40, 6 to 30, 6 to 20, 8 to 20, 8 to 19, 8 to 18, 8 to 17, 8 to 16, or 8 to 15 carbon atoms.
  • salt or “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, S. M. Berge et al., describes
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
  • suitable inorganic and organic acids and bases include those derived from suitable inorganic and organic acids and bases.
  • pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or rnalonic acid or by using other methods used in the art such as ion exchange.
  • Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate,
  • benzenesulfonate benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate.
  • digluconate dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pival
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(Cl-4alkyl)4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, sulfonate and aryl sulfonate.
  • Further pharmaceutically acceptable salts include salts formed from the quartemization of an amine using an appropriate electrophile, e.g., an alkyl halide, to form a quarternized alkylated amino salt.
  • liposomes may comprise a second or additional cationic lipid.
  • cationic lipid refers to any of a number of lipid species that have a net positive charge at a selected pH, such as physiological pH.
  • Particularly suitable cationic lipids for use in the compositions and methods of the invention include those described in international patent publications WO 2010/053572 (and particularly, C12-200 described at paragraph [00225]) and WO 2012/170930, both of which are incorporated herein by reference.
  • compositions and methods of the invention employ a lipid nanoparticles comprising an ionizable cationic lipid described in U.S. provisional patent application 61/617,468, filed March 29, 2012 (incorporated herein by reference), such as, e.g, (15Z, 18Z)-N,N-dimethyl-6-(9Z, 12Z)-octadeca-9, 12-dien-l -yl)tetracosa- 15,18-dien- 1 -amine (HGT5000), ( 15Z, 18Z)-N,N-dimethyl-6-((9Z, 12Z)-octadeca-9, 12-dien- 1 -yl)tetracosa- 4,15,18-trien-l -amine (HGT5001), and (15Z,18Z)-N,N-dimethyl-6-((9Z, 12Z)-octadeca-9, 12- dien- 1 -yl)tetracosa-5
  • the second or additional cationic lipid N-[l-(2,3- dioleyloxy)propyl]-N,N,N-trimethylammonium chloride or "DOTMA" is used.
  • DOTMA cationic lipid N-[l-(2,3- dioleyloxy)propyl]-N,N,N-trimethylammonium chloride
  • DOTMA can be formulated alone or can be combined with the neutral lipid, dioleoylphosphatidyl-ethanolamine or "DOPE" or other cationic or non-cationic lipids into a liposomal transfer vehicle or a lipid nanoparticle, and such liposomes can be used to enhance the delivery of nucleic acids into target cells.
  • suitable cationic lipids include, for example, 5-carboxyspermylglycinedioctadecylamide or "DOGS,” 2,3-dioleyloxy-N-[2(spermine-carboxamido)ethyl]-N,N-dimethyl-l-propanaminium or "DOSPA" (Behr et al. Proc.
  • Additional exemplary cationic lipids also include l,2-distearyloxy-N,N-dimethyl-3-aminopropane or "DSDMA", l,2-dioleyloxy-N,N-dimethyl-3- aminopropane or "DODMA", 1 ,2-dilinoleyloxy-N,N-dimethyl-3-aminopropane or "DLinDMA", l,2-dilinolenyloxy-N,N-dimethyl-3-aminopropane or "DLenDMA", N-dioleyl-N,N- dimethylammonium chloride or "DODAC", N,N-distearyl-N,N-dimethylarnrnonium bromide or "DDAB", N-(l,2-dimyristyloxyprop-3-yl)-N,N-dimethyl-N-hydroxyethyl ammonium bromide or "DMRIE", 3-dimethylamino-2-
  • one or more of the cationic lipids comprise at least one of an imidazole, dialkylamino, or guanidinium moiety.
  • the second or additional cationic lipid may be chosen from
  • provided liposomes contain one or more non-cationic amino acids
  • non-cationic lipid refers to any neutral, zwitterionic or anionic lipid.
  • anionic lipid refers to any of a number of lipid species that carry a net negative charge at a selected H, such as physiological pH.
  • Non- cationic lipids include, but are not limited to, distearoylphosphatidylcholine (DSPC),
  • DOPC dioleoylphosphatidylcholine
  • DPPC dipalmitoylphosphatidylcholine
  • DOPG dioleoylphosphatidylglycerol
  • DPPG dipalmitoylphosphatidylglycerol
  • dioleoylphosphatidylethanolamine DOPE
  • palmitoyloleoylphosphatidylcholine POPC
  • palmitoyloleoyl-phosphatidylethanolamine POPE
  • dioleoyl-phosphatidylethanolamine 4-(N- maleimidomethyl)-cyclohexane-l-carboxylate DOPE-mal
  • dipalmitoyl phosphatidyl ethanolamine DPPE
  • dimyristoylphosphoethanolamine DMPE
  • distearoyl-phosphatidyl- ethanolamine DSPE
  • 16-O-monomethyl PE 16-O-dimethyl PE
  • 18-1 -trans PE l-stearoyl-2- oleoyl-phosphatidyethanolamine
  • SOPE l-stearoyl-2- oleoyl-phosphatidyethanolamine
  • non-cationic lipids may be used alone, but are preferably used in combination with other excipients, for example, cationic lipids.
  • the non-cationic lipid may comprise a molar ratio of about 5% to about 90%, or about 10 % to about 70% of the total lipid present in a liposome.
  • a non- cationic lipid is a neutral lipid, i.e., a lipid that does not carry a net charge in the conditions under which the composition is formulated and/or administered.
  • the percentage of non-cationic lipid in a liposome may be greater than 5%, greater than 10%, greater than 20%, greater than 30%, or greater than 40%.
  • provided liposomes comprise one or more cholesterol- based lipids.
  • suitable cholesterol-based cationic lipids include, for example, DC- Choi (N,N-dimethyl-N-ethylcarboxamidocholesterol), l,4-bis(3-N-oleylamino-propyl)piperazine (Gao, et al. Biochem. Biophys. Res. Comm. 179, 280 (1991); Wolf et al. BioTechniques 23, 139 (1997); U.S. Pat. No. 5,744,335), or ICE.
  • the cholesterol-based lipid may comprise a molar ration of about 2% to about 30%, or about 5% to about 20% of the total lipid present in a liposome. In some embodiments, The percentage of cholesterol-based lipid in the lipid nanoparticle may be greater than 5, %, 10%, greater than 20%, greater than 30%, or greater than 40%.
  • provided liposomes comprise one or more PEGylated lipids.
  • PEG polyethylene glycol
  • derivatized lipids such as derivatized ceramides (PEG-CER), including N-Octanoyl- Sphingosine-l-[Succinyl(Methoxy Polyethylene Glycol)-2000] (C8 PEG-2000 ceramide) is also contemplated by the present invention in combination with one or more of the cationic and, in some embodiments, other lipids together which comprise the liposome.
  • Contemplated PEG- modified lipids include, but are not limited to, a polyethylene glycol chain of up to 5 kDa in length covalently attached to a lipid with alkyl chain(s) of C6-C20 length.
  • a PEG-modified or PEGylated lipid is PEGylated cholesterol or PEG-2K.
  • the addition of such components may prevent complex aggregation and may also provide a means for increasing circulation lifetime and increasing the delivery of the lipid-nucleic acid composition to the target cell, (Klibanov et al. (1990) FEBS Letters, 268 (1): 235-237), or they may be selected to rapidly exchange out of the formulation in vivo (see U.S. Pat. No. 5,885,613).
  • particularly useful exchangeable lipids are PEG-ceramides having shorter acyl chains (e.g., Ci 4 or Cig).
  • the PEG-modified phospholipid and derivitized lipids of the present invention may comprise a molar ratio from about 0% to about 15%, about 0.5%) to about 15%), about 1%> to about 15%>, about 4%> to about 10%>, or about 2%> of the total lipid present in the liposome.
  • the selection of second or additional cationic lipids, non-cationic lipids and/or PEG-modified lipids which comprise the lipid nanoparticle, as well as the relative molar ratio of such lipids to each other is based upon the characteristics of the selected lipid(s), the nature of the intended target cells, the characteristics of the mRNA to be delivered. Additional considerations include, for example, the saturation of the alkyl chain, as well as the size, charge, pH, pKa, fusogenicity and toxicity of the selected lipid(s). Thus the molar ratios may be adjusted accordingly. In some embodiments, the percentage of PEG- modified lipid in a liposome may be greater than 1%, greater than 2%, greater than 5%, greater than 10%, or greater than 15%.
  • a suitable liposome according to the present invention further includes a polymer, in combination with one or more cationic lipids as described and, in some embodiments, other carriers including various lipids described herein.
  • liposomal delivery vehicles as used herein, also encompass polymer containing nanoparticles. Suitable polymers may include, for example, polyacrylates,
  • PEI polyethylenimine
  • polyalkycyanoacrylates polylactide, polylactide-polyglycolide copolymers, polycaprolactones, dextran, albumin, gelatin, alginate, collagen, chitosan, cyclodextrins, protamine, PEGylated protamine, PLL, PEGylated PLL and polyethylenimine (PEI).
  • PEI polyethylenimine
  • it may be branched PEI of a molecular weight ranging from 10 to 40 kDA, e.g., 25 kDa branched PEI (Sigma #408727).
  • a suitable liposome formulation contains a combination of one or more cationic lipids, one or more non-cationic lipids, one or more cholesterol-based lipids one or more PEG-modified lipids, and/or one or more polymers.
  • a suitable liposome comprises cK -E12, DOPE, cholesterol and DMG-PEG2K.
  • the ratio of cationic lipid to non-cationic lipid to cholesterol-based lipid to PEGylated lipid may be between about 30-50:25-35:20-30: 1-15, respectively.
  • the ratio of cationic lipid to non-cationic lipid to cholesterol-based lipid to PEGylated lipid is approximately 40:30:20: 10, respectively. In some embodiments, the ratio of cationic lipid to non-cationic lipid to cholesterol-based lipid to PEGylated lipid is approximately 40:30:25:5, respectively. In some embodiments, the ratio of cationic lipid to non-cationic lipid to cholesterol-based lipid to PEGylated lipid is approximately 40:32:25:3, respectively.
  • the present invention can be used to deliver any mRNA.
  • mRNA is typically thought of as the type of RNA that carries information from DNA to the ribosome.
  • the existence of mRNA is usually very brief and includes processing and translation, followed by degradation.
  • mRNA processing comprises the addition of a "cap” on the N-terminal (5') end, and a "tail” on the C-terminal (3') end.
  • a typical cap is a 7- methylguanosine cap, which is a guanosine that is linked through a 5 '-5 '-triphosphate bond to the first transcribed nucleotide.
  • the presence of the cap is important in providing resistance to nucleases found in most eukaryotic cells.
  • the tail is typically a polyadenylation event whereby a polyadenylyl moiety is added to the 3' end of the mRNA molecule.
  • the presence of this "tail” serves to protect the mRNA from exonuclease degradation.
  • Messenger RNA typically is translated by the ribosomes into a series of amino acids that make up a protein.
  • any mRNA capable of being translated into one or more peptides (e.g., proteins) or peptide fragments is contemplated as within the scope of the present invention.
  • an mRNA encodes one or more naturally occurring peptides.
  • an mRNA encodes one or more modified or non-natural peptides.
  • an mRNA encodes an intracellular protein. In some embodiments, an mRNA encodes a cytosolic protein. In some embodiments, an mRNA encodes a protein associated with the actin cytoskeleton. In some embodiments, an mRNA encodes a protein associated with the plasma membrane. In some specific embodiments, an mRNA encodes a transmembrane protein. In some specific embodiments an mRNA encodes an ion channel protein. In some embodiments, an mRNA encodes a perinuclear protein. In some embodiments, an mRNA encodes a nuclear protein. In some specific embodiments, an mRNA encodes a transcription factor. In some embodiments, an mRNA encodes a chaperone protein.
  • an mRNA encodes an intracellular enzyme (e.g., mRNA encoding an enzyme associated with urea cycle or lysosomal storage metabolic disorders).
  • an mRNA encodes a protein involved in cellular metabolism, DNA repair, transcription and/or translation.
  • an mRNA encodes an extracellular protein.
  • an mRNA encodes a protein associated with the extracellular matrix.
  • an mRNA encodes a secreted protein.
  • an mRNA used in the composition and methods of the invention may be used to express functional proteins or enzymes that are excreted or secreted by one or more target cells into the surrounding extracellular fluid (e.g., mRNA encoding hormones and/or neurotransmitters).
  • compositions and methods of the invention provide for delivery of mRNA encoding a secreted protein.
  • the compositions and methods of the invention provide for delivery of mRNA encoding one or more secreted proteins listed in Table 1 ; thus, compositions of the invention may comprise an mRNA encoding a protein listed in Table 1 (or a homolog thereof) along with other components set out herein, and methods of the invention may comprise preparing and/or administering a composition comprising an mRNA encoding a protein listed in Table 1 (or a homolog thereof) along with other components set out herein.
  • J3KNZ1 Choriogonadotropin subunit beta variant 1 CGB1
  • J3KP00 Choriogonadotropin subunit beta CGB7

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PCT/US2014/061793 2013-10-22 2014-10-22 Lipid formulations for delivery of messenger rna Ceased WO2015061467A1 (en)

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Application Number Priority Date Filing Date Title
ES14792713T ES2865699T3 (es) 2013-10-22 2014-10-22 Formulaciones de lípidos para la administración de ARN mensajero
EP14792713.1A EP3060257B1 (en) 2013-10-22 2014-10-22 Lipid formulations for delivery of messenger rna
KR1020167012277A KR101988552B1 (ko) 2013-10-22 2014-10-22 메신저 rna의 전달을 위한 지질 제형
MX2016005238A MX2016005238A (es) 2013-10-22 2014-10-22 Formulaciones de lipidos para la administracion de acido ribonucleico mensajero.
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EA201690576A EA201690576A1 (ru) 2013-10-22 2014-10-22 Липидные композиции для доставки матричной рнк
CN201480063947.5A CN105813656B (zh) 2013-10-22 2014-10-22 用于递送信使rna的脂质制剂
EP21158237.4A EP3871696B1 (en) 2013-10-22 2014-10-22 Lipid formulations for delivery of messenger rna
BR112016009077A BR112016009077A2 (pt) 2013-10-22 2014-10-22 Formulações lipídicas para fornecimento de rna mensageiro
JP2016526008A JP6525435B2 (ja) 2013-10-22 2014-10-22 メッセンジャーｒｎａの送達のための脂質製剤
NZ718817A NZ718817A (en) 2013-10-22 2014-10-22 Lipid formulations for delivery of messenger rna
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