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  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7088—Compounds having three or more nucleosides or nucleotides
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  • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
  • C07C229/24—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having more than one carboxyl group bound to the carbon skeleton, e.g. aspartic acid
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  • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
  • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
  • C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
  • C07C229/12—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of acyclic carbon skeletons
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  • C07C219/02—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
  • C07C219/04—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
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  • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
  • C07C275/04—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms
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  • C07C275/14—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an acyclic and saturated carbon skeleton being further substituted by nitrogen atoms not being part of nitro or nitroso groups
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  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
  • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D207/24—Oxygen or sulfur atoms
  • C07D207/26—2-Pyrrolidones
  • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
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  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
  • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
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  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
  • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
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  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/62—Oxygen or sulfur atoms
  • C07D213/63—One oxygen atom
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  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
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  • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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Definitions

• the present disclosure recognizes that structural features of compositions, preparations, nanoparticles, and/or nanomaterials impact functional responses in vivo, in vitro, and ex vivo.
• the present disclosure describes, among other things, that selection and combination of one or more components described herein influence functional activity of lipid nanoparticles.
• functional activity can refer to desired tropisms, stabilization, and/or drug delivery efficacy.
• the present disclosure describes that different ratios of one of more components influence one or more functional activities of compositions, preparations, nanoparticles, and/or nanomaterials described herein.
• the present disclosure recognizes that chemical structures of lipids confer improved properties compared to reference lipid structures.
• the present disclosure describes compounds of Formula A’:
• the present disclosure describes compounds of Formula II”: II” or its N-oxide, or a pharmaceutically acceptable salt thereof, wherein each of L, L 1 , L 2 , L 3 , X 2 , R, and R 1 is as defined herein.
• the present disclosure describes compounds of Formula III’: III’ or its N-oxide, or a pharmaceutically acceptable salt thereof, wherein each of L, L 1 , L 2 , L 3 , X 2 , R, and R 1 is as defined herein.
• the present disclosure demonstrates surprising attributes of ionizable lipids (e.g., unexpected tropism, stabilization, and delivery efficacy of cargos such as therapeutic or prophylactic agents) comprising an ester-linked acetal feature, and compositions, preparations, nanoparticles, and/or nanomaterials (e.g., LNPs and/or LNP- containing compositions, preparations, nanoparticles, and/or nanomaterials) thereof, and methods of their use.
• ionizable lipids e.g., unexpected tropism, stabilization, and delivery efficacy of cargos such as therapeutic or prophylactic agents
• compositions, preparations, nanoparticles, and/or nanomaterials e.g., LNPs and/or LNP- containing compositions, preparations, nanoparticles, and/or nanomaterials
• the present disclosure demonstrates particularly surprising attributes of ionizable lipids (e.g., unexpected tropism, stabilization, and delivery efficacy of cargos such as therapeutic or prophylactic agents) comprising at least two ester-linked acetal features, and compositions, preparations, nanoparticles, and/or nanomaterials (e.g., LNPs and/or LNP-containing compositions, preparations, nanoparticles, and/or nanomaterials), and methods of their use.
• provided lipids include two symmetrical (e.g., identical) ester- linked acetal features; in some embodiments provided lipids include two or more different ester- linked acetal features.
• lipid nanoparticle (LNP) compositions comprising one or more ionizable lipids.
• LNP compositions and/or preparations comprising one or more of the disclosed ionizable lipids conferred unexpected tropisms.
• provided compositions, preparations, nanoparticles, and/or nanomaterials are for use in methods of treatment, delivery, producing polypeptides, or delaying/arresting progression of a disease or disorder.
• provided compositions, preparations, nanoparticles, and/or nanomaterials are for use in methods of manufacturing.
• compositions, preparations, nanoparticles, and/or nanomaterials are for use in methods of characterization.
• Elements of embodiments involving one aspect of the invention e.g., methods
• FIG.1 depicts an exemplary mRNA screening system of LNP preparations, in accordance with an embodiment of the present disclosure.
• FIG.2 depicts an exemplary siRNA screening system of LNP preparations, in accordance with an embodiment of the present disclosure.
• FIG.1 depicts an exemplary mRNA screening system of LNP preparations, in accordance with an embodiment of the present disclosure.
• FIG.2 depicts an exemplary siRNA screening system of LNP preparations, in accordance with an embodiment of the present disclosure.
• FIG. 3 depicts a bar graph that shows overall potency of three exemplary LNP screens (Screen 33, Screen 35, Screen 36) across various cell types (splenic B cells, splenic T cells, bone marrow B cells, bone marrow T cells, liver endothelial cells, hepatocytes, liver Kuppfer cells (liver macrophages)).
• FIG. 4 depicts a bar graph that shows potent delivery of exemplary LNP preparations (Exemplary Lipid 7, Exemplary Lipid 5, Exemplary Lipid 6, Exemplary Lipid 1, each having been characterized as an LNP preparation comprising an ester-linked acetal feature, and MC3 control) with potent delivery to various cell-types such as splenic B cells and T cells.
• FIG. 5 depicts a bar graph that shows potent delivery of exemplary LNP preparations (Exemplary Lipid 1, Exemplary Lipid 2, Exemplary Lipid 3, Exemplary Lipid 4, and saline control) with potent delivery to various cell-types such as bone marrow B cells, bone marrow memory B cells, bone marrow T cells, bone marrow monocytes, spleen monocytes, spleen T cells, spleen B cells, and spleen memory B cells.
• FIG. 1 shows potent delivery of exemplary LNP preparations (Exemplary Lipid 1, Exemplary Lipid 2, Exemplary Lipid 3, Exemplary Lipid 4, and saline control) with potent delivery to various cell-types such as bone marrow B cells, bone marrow memory B cells, bone marrow T cells, bone marrow monocytes, spleen monocytes, spleen T cells, spleen B cells, and spleen memory B cells.
• FIG. 1 shows potent delivery
• FIG. 6 depicts a bar graph that shows functional delivery of mRNA payloads encoding hEPO in vivo using exemplary LNP preparations (Exemplary Lipid 7, Exemplary Lipid 5, Exemplary Lipid 1) in mice. Amount of hEPO in plasma (ng/mL) was measured at 6 hours post- injection of exemplary LNP preparations in mice.
• FIG. 7 depicts a bar graph showing tolerability of two exemplary LNP preparations (Exemplary Lipid 5, Exemplary Lipid 1) delivering hEPO in rats at 24 hour post-injection. Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) levels (U/L) were measured at 24 hours post-injection.
• ALT Alanine Aminotransferase
• AST Aspartate Aminotransferase
• FIG. 8 depicts a bar graph showing tolerability of two exemplary LNP preparations (Exemplary Lipid 5, Exemplary Lipid 1) delivering hEPO in rats. Monocyte Chemoattractant Protein-1 (MCP-1) (ng/mL) was measured at 6 hours post injection.
• FIG. 9 depicts a bar graph showing efficacy of two exemplary LNP preparations (Exemplary Lipid 5, Exemplary Lipid 1) delivering hEPO in a rat model. hEPO was measured in plasma (ng/mL) across various time points (0, 2, 4, 6, 24, 48, and 72 hours).
• FIG.10 depicts a bar graph that shows functional delivery of mRNA payloads encoding a reporter in vivo using six exemplary LNP preparations (Exemplary Lipid 1, Exemplary Lipid 8, Exemplary Lipid 4, Exemplary Lipid 9, Exemplary Lipid 10, and Exemplary Lipid 11) in C57BL6 mice across a variety of HSC cell types (Lin-, Sca-1+, LSK cells, LT-HSCs (CD34-Flk2-), and LT-HSCs (CD150+CD48-)), with each LNP preparation containing 1.0 mg/kg reporter mRNA compared to a saline control (vehicle).
• LNP preparations Exemplary Lipid 1, Exemplary Lipid 8, Exemplary Lipid 4, Exemplary Lipid 9, Exemplary Lipid 10, and Exemplary Lipid 11
• HSC cell types Long-, Sca-1+, LSK cells, LT-HSCs (CD34-Flk2-), and LT-HSCs (CD150+CD48-)
• FIG.11 depicts a bar graph that shows functional delivery of mRNA payloads encoding a reporter in vivo using six exemplary LNP preparations (Exemplary Lipid 1, Exemplary Lipid 8, Exemplary Lipid 4, Exemplary Lipid 9, Exemplary Lipid 10, and Exemplary Lipid 11) in C57BL6 mice across a variety of bone marrow (BM) cell types (Live, T cells, B cells, CD11b, Macrophages, NK cells, CD11c), with each LNP preparation containing 1.0 mg/kg reporter mRNA compared to a saline control (vehicle).
• BM bone marrow
• FIG. 12 depicts a bar graph that shows functional delivery of mRNA payloads encoding reporter in vivo using six exemplary LNP preparations (Exemplary Lipid 1, Exemplary Lipid 8, Exemplary Lipid 4, Exemplary Lipid 9, Exemplary Lipid 10, and Exemplary Lipid 11) to C57BL6 mice across a variety of spleen cell types (T cells, B cells, CD11b, Macrophages, NK cells, CD11c), with each LNP preparation containing 1.0 mg/kg reporter mRNA compared to a saline control (vehicle).
• exemplary LNP preparations Exemplary Lipid 1, Exemplary Lipid 8, Exemplary Lipid 4, Exemplary Lipid 9, Exemplary Lipid 10, and Exemplary Lipid 11
• FIG.13 depicts a bar graph that shows functional delivery of mRNA payloads encoding a reporter in vivo using six exemplary LNP preparations (Exemplary Lipid 1, Exemplary Lipid 8, Exemplary Lipid 4, Exemplary Lipid 9, Exemplary Lipid 10, and Exemplary Lipid 11) to C57BL6 mice across a variety of liver cell types (CD31, Hepatocytes, CD45, CD11b, Kupffer cells, NK cells, T cells, B cells), with each LNP preparation containing 1.0 mg/kg reporter mRNA compared to a saline control (vehicle).
• LNP preparations Exemplary Lipid 1, Exemplary Lipid 8, Exemplary Lipid 4, Exemplary Lipid 9, Exemplary Lipid 10, and Exemplary Lipid 11
• FIG.14 depicts heat maps showing median fluorescence of a variety of LNP preparations containing different ionizable lipids normalized to the median fluorescence of an LNP preparation containing Exemplary Lipid 1 across a variety of cell types (bone marrow dendritic cells, splenic B cells, and splenic dendritic cells).
• Bottom left schematic shows experimental layout of each heat map for a variety of LNP preparations using exemplary lipids described in accordance with embodiments of the present disclosure.
• “X” in the bottom left schematic indicates a variety of different exemplary lipids that were tested in a variety of experiments accordance with the embodiments of the present disclosure.
• FIG.15 depicts two heat maps showing normalized average % reporter expression (left) or normalized average median fluorescence (right) of a variety of LNP preparations containing different ionizable lipids. Average % reporter and median average fluorescence values were normalized to average % reporter expression or median average fluorescence (right), respectively, of an LNP preparation containing Exemplary Lipid 1 delivered to T cells (bone marrow cells). Stars indicate LNP formulations that resulted in greater average % reporter expression compared to average % reporter expression using an LNP preparation containing Exemplary Lipid 1. The design layout of exemplary LNP preparations tested a variety of experiments is depicted in the bottom left schematic of FIG.14.
• FIG.16 depicts two heat maps showing normalized average % reporter expression (left) or median average fluorescence (right) of a variety of LNP preparations containing different ionizable lipids. Average % reporter and median average fluorescence values were normalized to % reporter expression (left) or median fluorescence (right), respectively, of an LNP preparation containing Exemplary Lipid 1 delivered to LSK (Lin-Sca-1+c-Kit+) cells. Stars indicate LNP formulations that resulted in greater average % reporter expression compared to average % reporter expression using an LNP preparation containing Exemplary Lipid 1. The design layout of exemplary LNP preparations tested a variety of experiments is depicted in the bottom left schematic of FIG.14. [0029] FIG.
• FIG. 17 depicts plots showing reporter expression of Exemplary Lipid 1 compared to Exemplary Lipid 11 in HSPCs and mouse LT-HSCs.
• FIG. 18 shows bar graphs that each depict delivery of mRNA using exemplary LNP preparations described herein to bone marrow cells (left) and blood cells (right) in humanized (NSG-CD34+) mice.
• FIG. 19 shows bar graphs that each depict delivery of mRNA using exemplary LNP preparations described herein to blood cells (left), bone marrow (live cells) (middle), and bone marrow (LSK cells) in two mouse strains (Balb/C, C57BL6J mice).
• FIG. 18 shows bar graphs that each depict delivery of mRNA using exemplary LNP preparations described herein to blood cells (left), bone marrow (live cells) (middle), and bone marrow (LSK cells) in two mouse strains (Balb/C, C57BL6J mice).
• FIG. 20 shows a bar graph of relative luminescence intensity after intramuscular administration of a variety of LNP preparations containing Trilink Fluc mRNA. Images of luminescence intensity also are shown in FIG.20.
• FIGS.21-23 show bar graphs depicting base editing in bone marrow cells, spleen cells, and liver cells using a variety of LNP preparations containing different exemplary lipids described herein.
• FIG. 24 depicts a bar graph that shows dose-dependent delivery of an exemplary LNP preparation comprising Exemplary Lipid 1 to mouse HSPCs.
• FIG.25A and FIG.25B depict bar graphs that show durability of delivery of an exemplary LNP preparation comprising Exemplary Lipid 1 to mouse HSPCs.
• FIG.25C and FIG.25D depict bar graphs that show reconstitution of immune and hematopoietic lineages by transfected HSPCs.
• FIG. 26A and FIG. 26B depict bar graphs that show delivery of an exemplary LNP preparation comprising Exemplary Lipid 1 to human CD34+ HSPCs in vitro.
• FIG. 27 depicts a bar graph that shows delivery of an exemplary LNP preparation comprising Exemplary Lipid 1 to non-human primate (NHP) HSPCs. Definitions [0038] About: As used herein, the term “about” or “approximately,” when used herein in reference to a value, refers to a value that is similar, in context to the referenced value.
• the term “about” may encompass a range of values that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or in either direction (greater than or less than) of the reference value unless otherwise stated or otherwise evident from the context (except where such number would exceed 100% of a possible value).
• Administration typically refers to the administration of a composition to a subject or system.
• routes that may, in appropriate circumstances, be utilized for administration to a subject, for example a human.
• administration may be ocular, oral, parenteral, topical, etc.
• administration may be bronchial (e.g., by bronchial instillation), buccal, dermal (which may be or comprise, for example, one or more of topical to the dermis, intradermal, interdermal, transdermal, etc), enteral, intra- arterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intraventricular, within a specific organ (e. g. intrahepatic), mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (e.g., by intratracheal instillation), vaginal, vitreal, etc.
• bronchial e.g., by bronchial instillation
• buccal which may be or comprise, for example, one or more of topical to the dermis, intradermal, interdermal, transdermal, etc
• enteral intra- arterial, intradermal, intragastric, intramedull
• administration may involve dosing that is intermittent (e.g., a plurality of doses separated in time) and/or periodic (e.g., individual doses separated by a common period of time) dosing. In some embodiments, administration may involve continuous dosing (e.g., perfusion) for at least a selected period of time.
• a pharmaceutical composition comprising lipid nanoparticles can be formulated for administration by parenteral (intramuscular, intraperitoneal, intravenous (IV) or subcutaneous injection), transdermal (either passively or using iontophoresis or electroporation), or transmucosal (nasal, vaginal, rectal, or sublingual) routes of administration or using bioerodible inserts and can be formulated in dosage forms appropriate for each route of administration.
• Aliphatic means a straight- chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocycle,” “carbocyclic”, “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule.
• aliphatic groups contain 1-6 aliphatic carbon atoms.
• aliphatic groups contain 1-5 carbon atoms. In some embodiments, aliphatic groups contain 1-4 carbon atoms. In some embodiments, aliphatic groups contain 1-3 carbon atoms, and in some embodiments, aliphatic groups contain 1-2 carbon atoms.
• “carbocyclic” refers to an optionally substituted monocyclic C3-C8 hydrocarbon, or an optionally substituted C6-C12 bicyclic hydrocarbon, that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule.
• Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
• Alkenyl As used herein, the term “alkenyl” refers to an alkyl group, as defined herein, having one or more double bonds.
• alkenyl refers to an optionally substituted straight or branched hydrocarbon chain having at least one double bond and having (unless otherwise specified) 2-20, 2-18, 2-16, 2-14, 2- 12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C 2-20 , C 2-18 , C 2-16 , C 2-14 , C 2-12 , C 2-10 , C 2-8 , C2-6, C 2-4 , or C 2-3 ).
• alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, and heptenyl.
• Alkenylene refers to a bivalent alkenyl group.
• a substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
• Alkyl As used herein, the term “alkyl” is given its ordinary meaning in the art and may include saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.
• alkyl has 1-100 carbon atoms.
• a straight chain or branched chain alkyl has about 1-20 carbon atoms in its backbone (e.g., C1-C20 for straight chain, C2-C20 for branched chain), and alternatively, about 1-10.
• a cycloalkyl ring has from about 3-10 carbon atoms in their ring structure where such rings are monocyclic or bicyclic, and alternatively about 5, 6 or 7 carbons in the ring structure.
• an alkyl group may be a lower alkyl group, wherein a lower alkyl group comprises 1-4 carbon atoms (e.g., C 1 -C 4 for straight chain lower alkyls).
• Alkylenyl refers to a bivalent alkyl group (i.e., a bivalent saturated hydrocarbon chain) that is a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted. Any of the above mentioned monovalent alkyl groups may be an alkylenyl by abstraction of a second hydrogen atom from the alkyl.
• an “alkylenyl” is a polymethylene group, i.e., –(CH 2 )n–, wherein n is a positive integer, preferably from 1 to 10, from 1 to 9, from 1 to 8, from 1 to 7, from 1 to 6, from 1 to 5, from 1 to 4, from 1 to 3, from 1 to 2, from 2 to 5, or from 4 to 8.
• a substituted alkylenyl is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
• alkynyl refers to an alkyl group, as defined herein, having one or more triple bonds.
• alkynyl used alone or as part of a larger moiety, refers to an optionally substituted straight or branched chain hydrocarbon group having at least one triple bond and having (unless otherwise specified) 2-20, 2-18, 2-16, 2-14, 2- 12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C 2-20 , C 2-18 , C 2-16 , C 2-14 , C 2-12 , C 2-10 , C 2-8 , C 2-6 , C2-4, or C2-3).
• alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and heptynyl.
• Amino acid in its broadest sense, as used herein, refers to any compound and/or substance that can be incorporated into a polypeptide chain, e.g., through formation of one or more peptide bonds.
• an amino acid has the general structure H2N–C(H)(R)–COOH.
• an amino acid is a naturally-occurring amino acid.
• an amino acid is a non-natural amino acid; in some embodiments, an amino acid is a D-amino acid; in some embodiments, an amino acid is an L-amino acid.
• Standard amino acid refers to any of the twenty standard L-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.
• an amino acid, including a carboxy- and/or amino-terminal amino acid in a polypeptide can contain a structural modification as compared with the general structure above.
• an amino acid may be modified by methylation, amidation, acetylation, pegylation, glycosylation, phosphorylation, and/or substitution (e.g., of the amino group, the carboxylic acid group, one or more protons, and/or the hydroxyl group) as compared with the general structure.
• such modification may, for example, alter the circulating half-life of a polypeptide containing the modified amino acid as compared with one containing an otherwise identical unmodified amino acid.
• such modification does not significantly alter a relevant activity of a polypeptide containing the modified amino acid, as compared with one containing an otherwise identical unmodified amino acid.
• amino acid may be used to refer to a free amino acid; in some embodiments it may be used to refer to an amino acid residue of a polypeptide.
• Animal as used herein refers to any member of the animal kingdom. In some embodiments, “animal” refers to humans, of either sex and at any stage of development. In some embodiments, “animal” refers to non-human animals, at any stage of development.
• 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).
• animals include, but are not limited to, mammals, birds, reptiles, amphibians, fish, insects, and/or worms.
• an animal may be a transgenic animal, genetically engineered animal, and/or a clone.
• aptamer refers to a macromolecule composed of nucleic acid (e.g., RNA, DNA) that binds tightly to a specific molecular target (e.g., an umbrella topology glycan).
• a particular aptamer may be described by a linear nucleotide sequence and is typically about 15-60 nucleotides in length.
• the chain of nucleotides in an aptamer form intramolecular interactions that fold the molecule into a complex three-dimensional shape, and this three-dimensional shape allows the aptamer to bind tightly to the surface of its target molecule.
• aptamers may be obtained for a wide array of molecular targets, including proteins and small molecules.
• aptamers typically have very high affinities for their targets (e.g., affinities in the picomolar to low nanomolar range for proteins).
• aptamers are chemically stable and can be boiled or frozen without loss of activity. Because they are synthetic molecules, aptamers are amenable to a variety of modifications, which can optimize their function for particular applications. For example, aptamers can be modified to dramatically reduce their sensitivity to degradation by enzymes in the blood for use in in vivo applications.
• Aryl refers to monocyclic and bicyclic ring systems having a total of six to fourteen ring members (e.g., C 6-14 ), wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members.
• the term “aryl” may be used interchangeably with the term “aryl ring”.
• “aryl” refers to an aromatic ring system which includes, but is not limited to, phenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Unless otherwise specified, “aryl” groups are hydrocarbons.
• Two events or entities are “associated” with one another, as that term is used herein, if the presence, level, degree, type and/or form of one is correlated with that of the other.
• a particular entity e.g., polypeptide, genetic signature, metabolite, microbe, etc
• two or more entities are physically “associated” with one another if they interact, directly or indirectly, so that they are and/or remain in physical proximity with one another.
• two or more entities that are physically associated with one another are covalently linked to one another; in some embodiments, two or more entities that are physically associated with one another are not covalently linked to one another but are non-covalently associated, for example by means of hydrogen bonds, van der Waals interaction, hydrophobic interactions, magnetism, and combinations thereof.
• Biocompatible refers to materials that do not cause significant harm to living tissue when placed in contact with such tissue, e.g., in vivo. In certain embodiments, materials are “biocompatible” if they are not toxic to cells.
• materials are “biocompatible” if their addition to cells in vitro results in less than or equal to 20% cell death, and/or their administration in vivo does not induce significant inflammation or other such adverse effects.
• Biodegradable refers to materials that, when introduced into cells, are broken down (e.g., by cellular machinery, such as by enzymatic degradation, by hydrolysis, and/or by combinations thereof) into components that cells can either reuse or dispose of without significant toxic effects on the cells.
• components generated by breakdown of a biodegradable material are biocompatible and therefore do not induce significant inflammation and/or other adverse effects in vivo.
• biodegradable polymer materials break down into their component monomers.
• breakdown of biodegradable materials involves hydrolysis of ester bonds.
• breakdown of biodegradable materials involves cleavage of urethane linkages.
• biodegradable polymers include, for example, polymers of hydroxy acids such as lactic acid and glycolic acid, including but not limited to poly(hydroxyl acids), poly(lactic acid)(PLA), poly(glycolic acid)(PGA), poly(lactic-co-glycolic acid)(PLGA), and copolymers with PEG, polyanhydrides, poly(ortho)esters, polyesters, polyurethanes, poly(butyric acid), poly(valeric acid), poly(caprolactone), poly(hydroxyalkanoates, poly(lactide-co-caprolactone), blends and copolymers thereof.
• Biodegradable including, for example, proteins such as albumin, collagen, gelatin and prolamines, for example, zein, and polysaccharides such as alginate, cellulose derivatives and polyhydroxyalkanoates, for example, polyhydroxybutyrate blends and copolymers thereof.
• proteins such as albumin, collagen, gelatin and prolamines, for example, zein
• polysaccharides such as alginate, cellulose derivatives and polyhydroxyalkanoates, for example, polyhydroxybutyrate blends and copolymers thereof.
• Biologically active refers to an observable biological effect or result achieved by an agent or entity of interest.
• a specific binding interaction is a biological activity.
• modulation (e.g., induction, enhancement, or inhibition) of a biological pathway or event is a biological activity.
• presence or extent of a biological activity is assessed through detection of a direct or indirect product produced by a biological pathway or event of interest.
• Biological sample typically refers to a sample obtained or derived from a biological source (e.g., a tissue or organism or cell culture) of interest, as described herein.
• a source of interest comprises an organism, such as an animal or human.
• a biological sample is or comprises biological tissue or fluid.
• a biological sample may be or comprise bone marrow; blood; blood cells; ascites; tissue or fine needle biopsy samples; cell-containing body fluids; free floating nucleic acids; sputum; saliva; urine; cerebrospinal fluid, peritoneal fluid; pleural fluid; feces; lymph; gynecological fluids; skin swabs; vaginal swabs; oral swabs; nasal swabs; washings or lavages such as a ductal lavages or broncheoalveolar lavages; aspirates; scrapings; bone marrow specimens; tissue biopsy specimens; surgical specimens; feces, other body fluids, secretions, and/or excretions; and/or cells therefrom, etc.
• a biological sample is or comprises cells obtained from an individual.
• obtained cells are or include cells from an individual from whom the sample is obtained.
• a sample is a “primary sample” obtained directly from a source of interest by any appropriate means.
• a primary biological sample is obtained by methods selected from the group consisting of biopsy (e.g., fine needle aspiration or tissue biopsy), surgery, collection of body fluid (e.g., blood, lymph, feces etc.), etc.
• sample refers to a preparation that is obtained by processing (e.g., by removing one or more components of and/or by adding one or more agents to) a primary sample. For example, filtering using a semi-permeable membrane.
• a “processed sample” may comprise, for example nucleic acids or proteins extracted from a sample or obtained by subjecting a primary sample to techniques such as amplification or reverse transcription of mRNA, isolation and/or purification of certain components, etc.
• Bivalent refers to a chemical moiety with two points of attachment.
• a “bivalent C1-8 (or C1-6) saturated or unsaturated, straight or branched, hydrocarbon chain” refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.
• Bridged bicyclic As used herein, the term “bridged bicyclic” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge.
• a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen).
• a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
• Such bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups.
• any substitutable nitrogen of a bridged bicyclic group is optionally substituted.
• exemplary bridged bicyclics include but are not limited to: [0057] Cancer: The terms “cancer”, “malignancy”, “neoplasm”, “tumor”, and “carcinoma”, are used herein to refer to cells that exhibit relatively abnormal, uncontrolled, and/or autonomous growth, so that they exhibit an aberrant growth phenotype characterized by a significant loss of control of cell proliferation.
• a tumor may be or comprise cells that are precancerous (e.g., benign), malignant, pre-metastatic, metastatic, and/or non-metastatic.
• precancerous e.g., benign
• malignant pre-metastatic
• metastatic metastatic
• non-metastatic e.g., metastatic
• the present disclosure specifically identifies certain cancers to which its teachings may be particularly relevant.
• a relevant cancer may be characterized by a solid tumor.
• a relevant cancer may be characterized by a hematologic tumor.
• examples of different types of cancers known in the art include, for example, hematopoietic cancers including leukemias, lymphomas (Hodgkin’s and non-Hodgkin’s), myelomas and myeloproliferative disorders; sarcomas, melanomas, adenomas, carcinomas of solid tissue, squamous cell carcinomas of the mouth, throat, larynx, and lung, liver cancer, genitourinary cancers such as prostate, cervical, bladder, uterine, and endometrial cancer and renal cell carcinomas, bone cancer, pancreatic cancer, skin cancer, cutaneous or intraocular melanoma, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, head and neck cancers, breast cancer, gastro-intestinal cancers and nervous system
• Carrier refers to a diluent, adjuvant, excipient, or vehicle with which a composition is administered.
• carriers can include sterile liquids, such as, for example, water and oils, including oils of petroleum, animal, vegetable or synthetic origin, such as, for example, peanut oil, soybean oil, mineral oil, sesame oil and the like.
• carriers are or include one or more solid components.
• Carbocyclyl The terms “carbocyclyl,” “carbocycle,” and “carbocyclic ring” as used herein, refer to saturated or partially unsaturated cyclic aliphatic monocyclic, bicyclic, or polycyclic ring systems, as described herein, having from 3 to 14 members, wherein the aliphatic ring system is optionally substituted as described herein.
• Carbocyclic groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, norbornyl, adamantyl, and cyclooctadienyl.
• “carbocyclyl” refers to an optionally substituted monocyclic C3-C8 hydrocarbon, or an optionally substituted C6-C12 bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule.
• the term “cycloalkyl” refers to an optionally substituted saturated ring system of about 3 to about 10 ring carbon atoms. In some embodiments, cycloalkyl groups have 3–6 carbons.
• Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
• cycloalkenyl refers to an optionally substituted non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and having about 3 to about 10 carbon atoms.
• Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, and cycloheptenyl.
• Comparable refers to two or more agents, entities, situations, sets of conditions, etc., that may not be identical to one another but that are sufficiently similar to permit comparison therebetween so that one skilled in the art will appreciate that conclusions may reasonably be drawn based on differences or similarities observed.
• comparable sets of conditions, circumstances, individuals, or populations are characterized by a plurality of substantially identical features and one or a small number of varied features.
• composition may be used to refer to a discrete physical entity that comprises one or more specified components.
• a composition may be of any form – e.g., gas, gel, liquid, solid, etc.
• composition or method described herein as “comprising” one or more named elements or steps is open-ended, meaning that the named elements or steps are essential, but other elements or steps may be added within the scope of the composition or method.
• any composition or method described as “comprising” (or which "comprises") one or more named elements or steps also describes the corresponding, more limited composition or method “consisting essentially of” (or which "consists essentially of") the same named elements or steps, meaning that the composition or method includes the named essential elements or steps and may also include additional elements or steps that do not materially affect the basic and novel characteristic(s) of the composition or method.
• composition or method described herein as “comprising” or “consisting essentially of” one or more named elements or steps also describes the corresponding, more limited, and closed-ended composition or method “consisting of” (or “consists of”) the named elements or steps to the exclusion of any other unnamed element or step.
• known or disclosed equivalents of any named essential element or step may be substituted for that element or step.
• an appropriate reference measurement may be or comprise a measurement in a particular system (e.g., in a single individual) under otherwise comparable conditions absent presence of (e.g., prior to and/or after) a particular agent or treatment, or in presence of an appropriate comparable reference agent.
• an appropriate reference measurement may be or comprise a measurement in comparable system known or expected to respond in a particular way, in presence of the relevant agent or treatment.
• determining involves manipulation of a physical sample. In some embodiments, determining involves consideration and/or manipulation of data or information, for example utilizing a computer or other processing unit adapted to perform a relevant analysis. In some embodiments, determining involves receiving relevant information and/or materials from a source. In some embodiments, determining involves comparing one or more features of a sample or entity to a comparable reference.
• Encapsulated The term “encapsulated” is used herein to refer to substances that are completely surrounded by another material.
• Excipient refers to a non-therapeutic agent that may be included in a pharmaceutical composition, for example to provide or contribute to a desired consistency or stabilizing effect.
• Suitable pharmaceutical excipients include, for example, starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
• expression As used herein, the term “expression” of a nucleic acid sequence refers to the generation of any gene product from the nucleic acid sequence.
• a gene product can be a transcript.
• a gene product can be a polypeptide.
• expression of a nucleic acid sequence involves one or more of the following: (1) production of an RNA template from a DNA sequence (e.g., by transcription); (2) processing of an RNA transcript (e.g., by splicing, editing, 5’ cap formation, and/or 3’ end formation); (3) translation of an RNA into a polypeptide or protein; and/or (4) post-translational modification of a polypeptide or protein.
• Haloaliphatic refers to an aliphatic group substituted by one or more halogen atoms (e.g., one, two, three, four, five, six, or seven halo, such as fluoro, iodo, bromo, or chloro). In some embodiments, haloaliphatic groups contain 1-7 halogen atoms. In some embodiments, haloaliphatic groups contain 1-5 halogen atoms. In some embodiments, haloaliphatic groups contain 1-3 halogen atoms.
• Haloalkyl refers to an alkyl group substituted by one or more halogen atoms (e.g., one, two, three, four, five, six, or seven halo, such as fluoro, iodo, bromo, or chloro). In some embodiments, haloalkyl groups contain 1-7 halogen atoms. In some embodiments, haloalkyl groups contain 1-5 halogen atoms. In some embodiments, haloalkyl groups contain 1-3 halogen atoms.
• Heteroalkylenyl denotes an optionally substituted straight–chain (i.e., unbranched), or branched bivalent alkyl group (i.e., bivalent saturated hydrocarbon chain) having, in addition to carbon atoms, from one to five heteroatoms.
• heteroatom is described below.
• heteroalkylenyl groups contain 2–10 carbon atoms wherein 1–3 carbon atoms are optionally and independently replaced with heteroatoms selected from oxygen, nitrogen, and sulfur.
• heteroalkylenyl groups contain 2–8 carbon atoms wherein 1–3 carbon atoms are optionally and independently replaced with heteroatoms selected from oxygen, nitrogen, and sulfur. In some embodiments, heteroalkylenyl groups contain 4-8 carbon atoms, wherein 1–3 carbon atoms are optionally and independently replaced with heteroatoms selected from oxygen, nitrogen, and sulfur. In some embodiments, heteroalkylenyl groups contain 2-5 carbon atoms, wherein 1–2 carbon atoms are optionally and independently replaced with heteroatoms selected from oxygen, nitrogen, and sulfur.
• heteroalkylenyl groups contain 1–3 carbon atoms, wherein 1 carbon atom is optionally and independently replaced with a heteroatom selected from oxygen, nitrogen, and sulfur.
• Suitable heteroalkylenyl groups include, but are not limited to -CH 2 O-, -(CH 2 ) 2 O-, -CH 2 OCH 2 -, -O(CH 2 ) 2 -, -(CH 2 ) 3 O-, -(CH 2 ) 2 OCH 2 -, -CH 2 O(CH 2 ) 2 -, -O(CH 2 ) 3 -, -(CH 2 )4O-, -(CH 2 ) 3 OCH 2 -, -CH 2 O(CH 2 ) 3 -, -(CH 2 ) 2 O(CH 2 ) 2 -, -O(CH 2 )4-.
• C x heteroalkylenyl refers to heteroalkylenyl having x number of carbon atoms prior to replacement with heteroatoms.
• Heteroaryl The terms “heteroaryl” and “heteroar—”, used alone or as part of a larger moiety, e.g., “heteroaralkyl”, or “heteroaralkoxy”, refer to monocyclic or bicyclic ring groups having 5 to 10 ring atoms (e.g., 5- to 6-membered monocyclic heteroaryl or 9- to 10-membered bicyclic heteroaryl); having 6, 10, or 14 ⁇ electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms.
• heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridonyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, imidazo[1,2- a]pyrimidinyl, imidazo[1,2-a]pyridinyl, thienopyrimidinyl, triazolopyridinyl, and benzoisoxazolyl.
• heteroaryl and “heteroar—”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring (i.e., a bicyclic heteroaryl ring having 1 to 3 heteroatoms).
• Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H– quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrido[2,3–b]–1,4–oxazin–3(4H)–one, and benzoisoxazolyl.
• heteroaryl may be used interchangeably with the terms “heteroaryl ring”, “heteroaryl group”, or “heteroaromatic”, any of which terms include rings that are optionally substituted.
• Heteroatom means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl)).
• Heterocycle The terms “heterocycle”, “heterocyclyl”, “heterocyclic radical”, and “heterocyclic ring” are used interchangeably herein, and refer to a stable 3- to 8-membered monocyclic, a 7- to 12-membered bicyclic, or a 10- to 16-membered polycyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, such as one to four, heteroatoms, as defined above.
• nitrogen includes a substituted nitrogen.
• the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (as in N-substituted pyrrolidinyl).
• a heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted.
• saturated or partially unsaturated heterocyclic radicals include, without limitation, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, tetrahydropyranyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, thiamorpholinyl, and .
• a heterocyclyl group may be mono-, bi-, tri-, or polycyclic, preferably mono-, bi-, or tricyclic, more preferably mono- or bicyclic.
• heterocyclylalkyl refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.
• a bicyclic heterocyclic ring also includes groups in which the heterocyclic ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings.
• bicyclic heterocyclic groups include indolinyl, isoindolinyl, benzodioxolyl, 1,3-dihydroisobenzofuranyl, 2,3- dihydrobenzofuranyl, and tetrahydroquinolinyl.
• a bicyclic heterocyclic ring can also be a spirocyclic ring system (e.g., 7- to 11-membered spirocyclic fused heterocyclic ring having, in addition to carbon atoms, one or more heteroatoms as defined above (e.g., one, two, three or four heteroatoms)).
• a bicyclic heterocyclic ring can also be a bridged ring system (e.g., 7- to 11- membered bridged heterocyclic ring having one, two, or three bridging atoms.
• Inhibitory agent refers to an entity, condition, or event whose presence, level, or degree correlates with decreased level or activity of a target).
• an inhibitory agent may be act directly (in which case it exerts its influence directly upon its target, for example by binding to the target); in some embodiments, an inhibitory agent may act indirectly (in which case it exerts its influence by interacting with and/or otherwise altering a regulator of the target, so that level and/or activity of the target is reduced).
• an inhibitory agent is one whose presence or level correlates with a target level or activity that is reduced relative to a particular reference level or activity (e.g., that observed under appropriate reference conditions, such as presence of a known inhibitory agent, or absence of the inhibitory agent in question, etc).
• a particular reference level or activity e.g., that observed under appropriate reference conditions, such as presence of a known inhibitory agent, or absence of the inhibitory agent in question, etc.
• 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) designed, 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%, 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.
• a substance may still be considered “isolated” or even “pure”, after having been combined with certain other components such as, for example, one or more carriers or excipients (e.g., buffer, solvent, water, etc.); in such embodiments, percent isolation or purity of the substance is calculated without including such carriers or excipients.
• a biological polymer such as a polypeptide or polynucleotide that occurs in nature is considered to be "isolated” when, a) by virtue of its origin or source of derivation is not associated with some or all of the components that accompany it in its native state in nature; b) it is substantially free of other polypeptides or nucleic acids of the same species from the species that produces it in nature; c) is expressed by or is otherwise in association with components from a cell or other expression system that is not of the species that produces it in nature.
• a polypeptide that is chemically synthesized or is synthesized in a cellular system different from that which produces it in nature is considered to be an "isolated” polypeptide.
• a polypeptide that has been subjected to one or more purification techniques may be considered to be an "isolated” polypeptide to the extent that it has been separated from other components a) with which it is associated in nature; and/or b) with which it was associated when initially produced.
• In vivo refers to events that occur within a multi-cellular organism, such as a human and a non-human animal.
• Linker is used to refer to that portion of a multi-element agent that connects different elements to one another.
• a polypeptide whose structure includes two or more functional or organizational domains often includes a stretch of amino acids between such domains that links them to one another.
• a polypeptide comprising a linker element “L’” has an overall structure of the general form S1-L’-S2, wherein S1 and S2 may be the same or different and represent two domains associated with one another by the linker.
• a polyptide linker is at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 or more amino acids in length.
• a linker is characterized in that it tends not to adopt a rigid three-dimensional structure, but rather provides flexibility to the polypeptide.
• linker elements that can appropriately be used when engineering polypeptides (e.g., fusion polypeptides) known in the art (see e.g., Holliger, P., et al. (1993) Proc. Natl. Acad. Sci.
• Nanoparticle refers to a particle having a diameter of less than 1000 nanometers (nm). In some embodiments, a nanoparticle has a diameter of less than 300 nm, as defined by the National Science Foundation. In some embodiments, a nanoparticle has a diameter of less than 100 nm as defined by the National Institutes of Health.
• nanoparticles are micelles in that they comprise an enclosed compartment, separated from the bulk solution by a micellar membrane, typically comprised of amphiphilic entities which surround and enclose a space or compartment (e.g., to define a lumen).
• a micellar membrane is comprised of at least one polymer, such as for example a biocompatible and/or biodegradable polymer.
• lipid nanoparticles described herein can have an average hydrodynamic diameter from about 30 to about 170 nm.
• lipid nanoparticles described herein can have an average hydrodynamic diameter that is about 30 nm, 35 nm,40 nm, 45 nm, 50 nm, 55 nm, 60 nm, 65 nm, 70 nm, 75 nm, 80 nm, 85 nm, 90 nm, 95 nm, 100 nm, 105 nm, 110 nm, 115 nm, 120 nm, 125 nm, 130 nm, 135 nm, 140 nm, 145 nm, 150 nm, 155 nm, 160 nm, 165 nm, 170 nm, or any range having endpoints defined by any two of the aforementioned values.
• Nanoparticle composition refers to a composition that contains at least one nanoparticle and at least one additional agent or ingredient. In some embodiments, a nanoparticle composition contains a substantially uniform collection of nanoparticles as described herein.
• Nucleic acid As used herein, in its broadest sense, refers to any compound and/or substance that is or can be incorporated into an oligonucleotide chain.
• a nucleic acid is a compound and/or substance that is or can be incorporated into an oligonucleotide chain via a phosphodiester linkage.
• nucleic acid refers to an individual nucleic acid residue (e.g., a nucleotide and/or nucleoside); in some embodiments, “nucleic acid” refers to an oligonucleotide chain comprising individual nucleic acid residues.
• a "nucleic acid” is or comprises RNA; in some embodiments, a "nucleic acid” is or comprises DNA.
• a nucleic acid is, comprises, or consists of one or more natural nucleic acid residues. In some embodiments, a nucleic acid is, comprises, or consists of one or more nucleic acid analogs. In some embodiments, a nucleic acid analog differs from a nucleic acid in that it does not utilize a phosphodiester backbone. For example, in some embodiments, a nucleic acid is, comprises, or consists of one or more "peptide nucleic acids", which are known in the art and have peptide bonds instead of phosphodiester bonds in the backbone, are considered within the scope of the present invention.
• a nucleic acid has one or more phosphorothioate and/or 5'-N- phosphoramidite linkages rather than phosphodiester bonds.
• a nucleic acid is, comprises, or consists of one or more natural nucleosides (e.g., adenosine, thymidine, guanosine, cytidine, uridine, deoxyadenosine, deoxythymidine, deoxy guanosine, and deoxycytidine).
• a nucleic acid is, comprises, or consists of one or more 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, O(6)-methylguanine, 2-thiocytidine, methylated bases, intercalated bases, and
• a nucleic acid comprises one or more modified sugars (e.g., 2'-fluororibose, ribose, 2'-deoxyribose, arabinose, and hexose) as compared with those in natural nucleic acids.
• a nucleic acid has a nucleotide sequence that encodes a functional gene product such as an RNA or protein.
• a nucleic acid includes one or more introns.
• nucleic acids are prepared by one or more of isolation from a natural source, enzymatic synthesis by polymerization based on a complementary template (in vivo or in vitro), reproduction in a recombinant cell or system, and chemical synthesis.
• a nucleic acid is at least 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 1 10, 120, 130, 140, 150, 160, 170, 180, 190, 20, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 600, 700, 800, 900, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000 or more residues long.
• a nucleic acid is partly or wholly single stranded; in some embodiments, a nucleic acid is partly or wholly double stranded.
• a nucleic acid has a nucleotide sequence comprising at least one element that encodes, or is the complement of a sequence that encodes, a polypeptide. In some embodiments, a nucleic acid has enzymatic activity.
• Operably linked refers to a juxtaposition wherein the components described are in a relationship permitting them to function in their intended manner.
• a control element "operably linked" to a functional element is associated in such a way that expression and/or activity of the functional element is achieved under conditions compatible with the control element.
• control elements are contiguous (e.g., covalently linked) with the coding elements of interest; in some embodiments, control elements act in trans to or otherwise at a from the functional element of interest.
• the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Ed. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5 th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.
• Parenteral administration and “administered parenterally” as used herein have their art-understood meaning referring to modes of administration other than enteral and topical administration, usually by injection, and include, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion.
• the term “patient” refers to any organism to which a provided composition is or 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 embodiments, a patient is a human. In some embodiments, a patient is suffering from or susceptible to one or more disorders or conditions. In some embodiments, a patient displays one or more symptoms of a disorder or condition. In some embodiments, a patient has been diagnosed with one or more disorders or conditions. In some embodiments, the disorder or condition is or includes cancer, or presence of one or more tumors.
• the patient is receiving or has received certain therapy to diagnose and/or to treat a disease, disorder, or condition.
• pharmaceutical composition refers to an active agent, formulated together with one or more pharmaceutically acceptable carriers.
• active agent is present in unit dose amount appropriate for administration in a therapeutic regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population.
• compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin, lungs, or oral cavity; intravaginally or intrarectally, for example, as a pessary, cream, or foam; sublingually; ocularly; transdermally; or nasally, pulmonary, and to other mucosal surfaces.
• oral administration for example, drenches (aqueous or non-aqueous solutions or suspension
• compositions or vehicles which are, within the scope of sound medical judgment, 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.
• pharmaceutically acceptable carrier means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body.
• Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
• materials which can serve as pharmaceutically-acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydrox
• compositions that are appropriate for use in pharmaceutical contexts, i.e., 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 in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977).
• pharmaceutically acceptable salts include, but are not limited to, nontoxic acid addition salts, which 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, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
• nontoxic acid addition salts which 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, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
• pharmaceutically acceptable salts include, but are not limited to, 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, palm
• 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, alkyl having from 1 to 6 carbon atoms, sulfonate and aryl sulfonate.
• Prevent or prevention refers to reducing the risk of developing the disease, disorder and/or condition and/or to delaying onset of one or more characteristics or symptoms of the disease, disorder or condition. Prevention may be considered complete when onset of a disease, disorder or condition has been delayed for a predefined period of time.
• Protein refers to a polypeptide (i.e., a string of at least two amino acids linked to one another by peptide bonds).
• Proteins may include moieties other than amino acids (e.g., may be glycoproteins, proteoglycans, etc.) and/or may be otherwise processed or modified.
• a “protein” can be a complete polypeptide chain as produced by a cell (with or without a signal sequence), or can be a characteristic portion thereof.
• a protein can sometimes include more than one polypeptide chain, for example linked by one or more disulfide bonds or associated by other means.
• Polypeptides may contain L-amino acids, D-amino acids, or both and may contain any of a variety of amino acid modifications or analogs known in the art.
• proteins may comprise natural amino acids, non-natural amino acids, synthetic amino acids, and combinations thereof.
• the term “peptide” is generally used to refer to a polypeptide having a length of less than about 100 amino acids, less than about 50 amino acids, less than 20 amino acids, or less than 10 amino acids.
• proteins are antibodies, antibody fragments, biologically active portions thereof, and/or characteristic portions thereof.
• Polypeptide The term “polypeptide”, as used herein, generally has its art-recognized meaning of a polymer of at least three amino acids.
• polypeptide is intended to be sufficiently general as to encompass not only polypeptides having a complete sequence recited herein, but also to encompass polypeptides that represent functional fragments (i.e., fragments retaining at least one activity) of such complete polypeptides. Moreover, those of ordinary skill in the art understand that protein sequences generally tolerate some substitution without destroying activity.
• Polypeptides may contain L-amino acids, D-amino acids, or both and may contain any of a variety of amino acid modifications or analogs known in the art.
• proteins may comprise natural amino acids, non-natural amino acids, synthetic amino acids, and combinations thereof.
• the term “peptide” is generally used to refer to a polypeptide having a length of less than about 100 amino acids, less than about 50 amino acids, less than 20 amino acids, or less than 10 amino acids.
• proteins are antibodies, antibody fragments, biologically active portions thereof, and/or characteristic portions thereof.
• prevention is assessed on a population basis such that an agent is considered to “prevent” a particular disease, disorder or condition if a statistically significant decrease in the development, frequency, and/or intensity of one or more symptoms of the disease, disorder or condition is observed in a population susceptible to the disease, disorder, or condition. Prevention may be considered complete when onset of a disease, disorder or condition has been delayed for a predefined period of time.
• Protecting Group refers to temporary substituents which protect a potentially reactive functional group from undesired chemical transformations.
• Si protecting group is a protecting group comprising a Si atom, such as Si-trialkyl (e.g., trimethylsilyl, tributylsilyl, t-butyldimethylsilyl), Si-triaryl, Si-alkyl-diphenyl (e.g., t-butyldiphenylsilyl), or Si- aryl-dialkyl (e.g., Si-phenyldialkyl).
• Si-trialkyl e.g., trimethylsilyl, tributylsilyl, t-butyldimethylsilyl
• Si-triaryl Si-alkyl-diphenyl (e.g., t-butyldiphenylsilyl)
• Si-aryl-dialkyl e.g., Si-phenyldialkyl
• a Si protecting group is attached to an oxygen atom.
• suitably protected hydroxyl groups further include, but are not limited to, esters, carbonates, sulfonates, allyl ethers, ethers, silyl ethers, alkyl ethers, arylalkyl ethers, and alkoxyalkyl ethers.
• suitable esters include formates, acetates, proprionates, pentanoates, crotonates, and benzoates.
• esters include formate, benzoyl formate, chloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, p-chlorophenoxyacetate, 3- phenylpropionate, 4-oxopentanoate, 4,4-(ethylenedithio)pentanoate, pivaloate (trimethylacetate), crotonate, 4-methoxy-crotonate, benzoate, p-benzylbenzoate, 2,4,6-trimethylbenzoate.
• Examples of suitable carbonates include 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2- (trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, vinyl, allyl, and p-nitrobenzyl carbonate.
• Examples of suitable silyl ethers include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t- butyldiphenylsilyl, triisopropylsilyl ether, and other trialkylsilyl ethers.
• alkyl ethers examples include methyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, trityl, t-butyl, and allyl ether, or derivatives thereof.
• Alkoxyalkyl ethers include acetals such as methoxymethyl, methylthiomethyl, (2-methoxyethoxy)methyl, benzyloxymethyl, beta- (trimethylsilyl)ethoxymethyl, and tetrahydropyran-2-yl ether.
• Suitable arylalkyl ethers include benzyl, p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, O-nitrobenzyl, p- nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, 2- and 4-picolyl ethers.
• Protected amines are well known in the art and include those described in detail in Greene (1999). Suitable mono-protected amines further include, but are not limited to, aralkylamines, carbamates, allyl amines, amides, and the like.
• Suitable mono-protected amino moieties include t-butyloxycarbonylamino (—NHBOC), ethyloxycarbonylamino, methyloxycarbonylamino, trichloroethyloxycarbonylamino, allyloxycarbonylamino (—NHAlloc), benzyloxocarbonylamino (–NHCBZ), allylamino, benzylamino (–NHBn), fluorenylmethylcarbonyl (–NHFmoc), formamido, acetamido, chloroacetamido, dichloroacetamido, trichloroacetamido, phenylacetamido, trifluoroacetamido, benzamido, t- butyldiphenylsilyl, and the like.
• Suitable di-protected amines include amines that are substituted with two substituents independently selected from those described above as mono-protected amines, and further include cyclic imides, such as phthalimide, maleimide, succinimide, and the like. Suitable di-protected amines also include pyrroles and the like, 2,2,5,5-tetramethyl- [1,2,5]azadisilolidine and the like, and azide. [0097] Protected aldehydes are well known in the art and include those described in detail in Greene (1999).
• Suitable protected aldehydes further include, but are not limited to, acyclic acetals, cyclic acetals, hydrazones, imines, and the like.
• Examples of such groups include dimethyl acetal, diethyl acetal, diisopropyl acetal, dibenzyl acetal, bis(2-nitrobenzyl) acetal, 1,3-dioxanes, 1,3- dioxolanes, semicarbazones, and derivatives thereof.
• Protected carboxylic acids are well known in the art and include those described in detail in Greene (1999).
• Suitable protected carboxylic acids further include, but are not limited to, optionally substituted C1–6 aliphatic esters, optionally substituted aryl esters, silyl esters, activated esters, amides, hydrazides, and the like.
• ester groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, benzyl, and phenyl ester, wherein each group is optionally substituted.
• Additional suitable protected carboxylic acids include oxazolines and ortho esters. [0099] Protected thiols are well known in the art and include those described in detail in Greene (1999).
• Suitable protected thiols further include, but are not limited to, disulfides, thioethers, silyl thioethers, thioesters, thiocarbonates, and thiocarbamates, and the like. Examples of such groups include, but are not limited to, alkyl thioethers, benzyl and substituted benzyl thioethers, triphenylmethyl thioethers, and trichloroethoxycarbonyl thioester, to name but a few.
• Protein The term “protein” as used herein refers to one or more polypeptides that function as a discrete unit.
• polypeptide and “protein” may be used interchangeably. If the discrete functional unit is comprised of more than one polypeptide that physically associate with one another, the term “protein” may be used to refer to the multiple polypeptides that are physically associated and function together as the discrete unit. In some embodiments, proteins may include moieties other than amino acids (e.g., may be glycoproteins, proteoglycans, etc.) and/or may be otherwise processed or modified.
• protein may refer to a complete polypeptide chain as produced by a cell (e.g., with or without a signal sequence), and/or to a form that is active within a cell (e.g., a truncated or complexed form).
• a protein may be covalently associated with one another, for example by one or more disulfide bonds, or may be associated by other means.
• an agent or entity is “pure” if it is substantially free of other components. For example, a preparation that contains more than about 90% of a particular agent or entity is typically considered to be a pure preparation.
• an agent or entity is at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% pure.
• Reference As used herein describes a standard or control relative to which a comparison is performed. For example, in some embodiments, an agent, animal, individual, population, sample, sequence or value of interest is compared with a reference or control agent, animal, individual, population, sample, sequence or value. In some embodiments, a reference or control is tested and/or determined substantially simultaneously with the testing or determination of interest. In some embodiments, a reference or control is a historical reference or control, optionally embodied in a tangible medium.
• sample typically refers to an aliquot of material obtained or derived from a source of interest, as described herein.
• a source of interest is a biological or environmental source.
• a source of interest may be or comprise a cell or an organism, such as a microbe, a plant, or an animal (e.g., a human).
• a source of interest is or comprises biological tissue or fluid.
• a biological tissue or fluid may be or comprise amniotic fluid, aqueous humor, ascites, bile, bone marrow, blood, breast milk, cerebrospinal fluid, cerumen, chyle, chime, ejaculate, endolymph, exudate, feces, gastric acid, gastric juice, lymph, mucus, pericardial fluid, perilymph, peritoneal fluid, pleural fluid, pus, rheum, saliva, sebum, semen, serum, smegma, sputum, synovial fluid, sweat, tears, urine, vaginal secreations, vitreous humour, vomit, and/or combinations or component(s) thereof.
• a biological fluid may be or comprise an intracellular fluid, an extracellular fluid, an intravascular fluid (blood plasma), an interstitial fluid, a lymphatic fluid, and/or a transcellular fluid.
• a biological fluid may be or comprise a plant exudate.
• a biological tissue or sample may be obtained, for example, by aspirate, biopsy (e.g., fine needle or tissue biopsy), swab (e.g., oral, nasal, skin, or vaginal swab), scraping, surgery, washing or lavage (e.g., brocheoalvealar, ductal, nasal, ocular, oral, uterine, vaginal, or other washing or lavage).
• a biological sample is or comprises cells obtained from an individual.
• a sample is a “primary sample” obtained directly from a source of interest by any appropriate means.
• the term “sample” refers to a preparation that is obtained by processing (e.g., by removing one or more components of and/or by adding one or more agents to) a primary sample. For example, filtering using a semi-permeable membrane.
• processing e.g., by removing one or more components of and/or by adding one or more agents to
• a primary sample e.g., filtering using a semi-permeable membrane.
• Such a “processed sample” may comprise, for example nucleic acids or proteins extracted from a sample or obtained by subjecting a primary sample to one or more techniques such as amplification or reverse transcription of nucleic acid, isolation and/or purification of certain components, etc.
• Stable nanoparticle composition means that the compositions maintain one or more aspects of their physical structure (e.g., size range and/or distribution of particles) over a period of time.
• a stable nanoparticle composition is one for which the average particle size, the maximum particle size, the range of particle sizes, and/or the distribution of particle sizes (i.e., the percentage of particles above a designated size and/or outside a designated range of sizes) is maintained for a period of time under specified conditions.
• a stable provided composition is one for which a biologically relevant activity is maintained for a period of time.
• the period of time is at least about one hour; in some embodiments the period of time is about 5 hours, about 10 hours, about one (1) day, about one (1) week, about two (2) weeks, about one (1) month, about two (2) months, about three (3) months, about four (4) months, about five (5) months, about six (6) months, about eight (8) months, about ten (10) months, about twelve (12) months, about twenty-four (24) months, about thirty-six (36) months, or longer. In some embodiments, the period of time is within the range of about one (1) day to about twenty-four (24) months, about two (2) weeks to about twelve (12) months, about two (2) months to about five (5) months, etc.
• a stable composition is stable at ambient conditions.
• a stable composition is stable under biologic conditions (i.e.37 oC in phosphate buffered saline).
• Sterolyl refers to a 17-membered fused polycyclic ring moiety that is either saturated or partially unsaturated and substituted with at least one hydroxyl group, and has a single point of attachment to the rest of the molecule at any substitutable carbon or oxygen atom.
• a sterolyl group is a cholesterolyl group, or a variant or derivative thereof.
• a cholesterolyl group is modified.
• a cholesterolyl group is an oxidized cholesterolyl group (e.g., oxidized on the beta- ring structure or on the hydrocarbon tail structure).
• a cholesterolyl group is an esterified cholesterolyl group.
• a sterolyl group is a phytosterolyl group.
• Exemplary sterolyl groups include but are not limited to 25-hydroxycholesterolyl (25-OH), 20 ⁇ -hydroxycholesterolyl (20 ⁇ -OH), 27-hydroxycholesterolyl, 6-keto-5 ⁇ -hydroxycholesterolyl, 7-ketocholesterolyl, 7 ⁇ -hydroxycholesterolyl, 7 ⁇ -hydroxycholesterolyl, 7 ⁇ -25- dihydroxycholesterolyl, beta-sitosterolyl, stigmasterolyl, brassicasterolyl, and campesterolyl.
• Subject refers an organism, typically a mammal (e.g., a human, in some embodiments including prenatal human forms).
• a subject is suffering from a relevant disease, disorder or condition.
• a subject is susceptible to a disease, disorder, or condition.
• a subject displays one or more symptoms or characteristics of a disease, disorder or condition.
• a subject does not display any symptom or characteristic of a disease, disorder, or condition.
• a subject is someone with one or more features characteristic of susceptibility to or risk of a disease, disorder, or condition.
• a subject is a patient.
• a subject is an individual to whom diagnosis and/or therapy is and/or has been administered.
• Substantially refers to the qualitative condition of exhibiting total or near-total extent or degree of a characteristic or property of interest.
• One of ordinary skill in the biological arts will understand that biological and chemical phenomena rarely, if ever, go to completion and/or proceed to completeness or achieve or avoid an absolute result. The term “substantially” is therefore used herein to capture the potential lack of completeness inherent in many biological and chemical phenomena.
• Substituted or optionally substituted As described herein, compounds of this disclosure may contain optionally substituted and/or substituted moieties.
• substituted means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. “Substituted” applies to one or more hydrogens that are either explicit or implicit from the structure (e.g., refers to at least otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this disclosure are preferably those that result in the formation of stable or chemically feasible compounds.
• stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.
• Groups described as being “substituted” preferably have between 1 and 4 substituents, more preferably 1 or 2 substituents.
• Groups described as being “optionally substituted” may be unsubstituted or be “substituted” as described above.
• Suitable monovalent substituents on R° are independently halogen, —(CH 2 ) 0–2 R ⁇ , –(haloR ⁇ ), –(CH 2 ) 0–2 OH, –(CH 2 ) 0–2 OR ⁇ , –(CH 2 ) 0–2 CH(OR ⁇ ) 2 ; –O(haloR ⁇ ), –CN, –N 3 , –(CH 2 ) 0– 2 C(O)R ⁇ , –(CH 2 ) 0–2 C(O)OH, –(CH 2 ) 0–2 C(O)OR ⁇ , –(CH 2 ) 0–2 C(O)NH 2 , –(CH 2 ) 0–2 C(O)NHR ⁇ , – (CH 2 )0–2C(O)NR
• Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: –O(CR * 2) 2 –3O–, wherein each independent occurrence of R * is selected from hydrogen, C1–6 aliphatic which may be substituted as defined below, or an unsubstituted 5– 6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
• Suitable substituents on the aliphatic group of R * include halogen, –R ⁇ , -(haloR ⁇ ), –OH, – OR ⁇ , –O(haloR ⁇ ), –CN, –C(O)OH, –C(O)OR ⁇ , –NH 2 , –NHR ⁇ , –NR ⁇ 2 , or –NO 2 , wherein each R ⁇ is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C 1–4 aliphatic, –CH 2 Ph, –O(CH 2 )0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
• suitable substituents on a substitutable nitrogen include —R ⁇ , –NR ⁇ 2, –C(O)R ⁇ , –C(O)OR ⁇ , –C(O)C(O)R ⁇ , –C(O)CH 2 C(O)R ⁇ , –S(O) 2 R ⁇ , –S(O) 2 NR ⁇ 2, –C(S)NR ⁇ 2, – C(NH)NR ⁇ 2 , or –N(R ⁇ )S(O) 2 R ⁇ ; wherein each R ⁇ is independently hydrogen, C 1–6 aliphatic which may be substituted as defined below, unsubstituted –OPh, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R ⁇
• Suitable substituents on the aliphatic group of R ⁇ are independently halogen, – R ⁇ , -(haloR ⁇ ), –OH, –OR ⁇ , –O(haloR ⁇ ), –CN, –C(O)OH, –C(O)OR ⁇ , –NH2, –NHR ⁇ , –NR ⁇ 2, or – NO2, wherein each R ⁇ is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C 1–4 aliphatic, –CH 2 Ph, –O(CH 2 ) 0–1 Ph, or a 5–6– membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
• structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
• structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
• compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this invention.
• Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention.
• Susceptible to An individual who is “susceptible to” a disease, disorder, or condition is at risk for developing the disease, disorder, or condition.
• an individual who is susceptible to a disease, disorder, or condition does not display any symptoms of the disease, disorder, or condition. In some embodiments, an individual who is susceptible to a disease, disorder, or condition has not been diagnosed with the disease, disorder, and/or condition. In some embodiments, an individual who is susceptible to a disease, disorder, or condition is an individual who has been exposed to conditions associated with development of the disease, disorder, or condition. In some embodiments, a risk of developing a disease, disorder, and/or condition is a population-based risk (e.g., family members of individuals suffering from the disease, disorder, or condition).
• Systemic The phrases “systemic administration,” “administered systemically,” “peripheral administration,” and “administered peripherally” as used herein have their art- understood meaning referring to administration of a compound or composition such that it enters the recipient’s system.
• Tautomeric forms The phrase “tautomeric forms,” as used herein, is used to describe different isomeric forms of organic compounds that are capable of facile interconversion. Tautomers may be characterized by the formal migration of a hydrogen atom or proton, accompanied by a switch of a single bond and adjacent double bond. In some embodiments, tautomers may result from prototropic tautomerism (i.e., the relocation of a proton).
• tautomers may result from valence tautomerism (i.e., the rapid reorganization of bonding electrons). All such tautomeric forms are intended to be included within the scope of the present disclosure.
• tautomeric forms of a compound exist in mobile equilibrium with each other, so that attempts to prepare the separate substances results in the formation of a mixture.
• tautomeric forms of a compound are separable and isolatable compounds.
• chemical compositions may be provided that are or include pure preparations of a single tautomeric form of a compound.
• chemical compositions may be provided as mixtures of two or more tautomeric forms of a compound.
• such mixtures contain equal amounts of different tautomeric forms; in certain embodiments, such mixtures contain different amounts of at least two different tautomeric forms of a compound.
• chemical compositions may contain all tautomeric forms of a compound. In some embodiments of the disclosure, chemical compositions may contain less than all tautomeric forms of a compound. In some embodiments of the disclosure, chemical compositions may contain one or more tautomeric forms of a compound in amounts that vary over time as a result of interconversion. In some embodiments of the disclosure, the tautomerism is keto-enol tautomerism.
• keto-enol tautomer can be “trapped” (i.e., chemically modified such that it remains in the “enol” form) using any suitable reagent known in the chemical arts in to provide an enol derivative that may subsequently be isolated using one or more suitable techniques known in the art. Unless otherwise indicated, the present disclosure encompasses all tautomeric forms of relevant compounds, whether in pure form or in admixture with one another.
• therapeutic agent refers to an agent that, when administered to a subject, has a therapeutic effect and/or elicits a desired biological and/or pharmacological effect.
• a therapeutic agent is any substance that can be used to alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of, and/or reduce incidence of one or more symptoms or features of a disease, disorder, and/or condition.
• Therapeutically effective amount means an amount of a substance (e.g., a therapeutic agent, composition, and/or formulation) that elicits a desired biological response when administered as part of a therapeutic regimen.
• a therapeutically effective amount of a substance is an amount that is sufficient, when administered to a subject suffering from or susceptible to a disease, disorder, and/or condition, to treat, diagnose, inhibit, alleviate, prevent, and/or delay the onset of the disease, disorder, and/or condition.
• the effective amount of a substance may vary depending on such factors as the desired biological endpoint, the substance to be delivered, the target cell or tissue, etc.
• the effective amount of compound in a formulation to treat a disease, disorder, and/or condition is the amount that alleviates, ameliorates, relieves, inhibits, prevents, delays onset of, reduces severity of and/or reduces incidence of one or more symptoms or features of the disease, disorder, and/or condition.
• a therapeutically effective amount is administered in a single dose; in some embodiments, multiple unit doses are required to deliver a therapeutically effective amount.
• the precise dosage will vary according to a variety of factors such as subject-dependent variables (e.g., age, immune system health, etc.), the disease, and the treatment being effected.
• tissue and/or “organ” refers to viable cellular materials in an aggregate form, e.g., small portions of an organ, as well as dispersed cells, e.g., cells dispersed, isolated and/or grown from muscle, heart muscle, liver or kidney, including bone marrow cells and progeny cells, blood born stem cells and progeny, and the various other blood elements, unless otherwise specified.
• the tissue and/or organ refers to kidney, heart liver, stomach, spleen, pancreas, lung, brain, eye, intestines, bladder, skin or dermal tissue, blood vessel, veins, arteries, heart valves, sperm, and oocyte(s).
• organ encompasses both solid organs, e.g., kidney, heart, liver, lung, as well as functional parts of organs, e.g., segments of skin, sections of artery, veins, transplantable lobes of a liver, kidney, lung, and the like.
• treatment refers to administration of a therapy that partially or completely alleviates, ameliorates, relives, inhibits, delays onset of, reduces severity of, and/or reduces incidence of one or more symptoms, features, and/or causes of a particular disease, disorder, and/or condition.
• such treatment may be of a subject who does not exhibit signs of the relevant disease, disorder and/or condition and/or of a subject who exhibits only early signs of the disease, disorder, and/or condition.
• such treatment may be of a subject who exhibits one or more established signs of the relevant disease, disorder and/or condition.
• treatment may be of a subject who has been diagnosed as suffering from the relevant disease, disorder, and/or condition.
• treatment may be of a subject known to have one or more susceptibility factors that are statistically correlated with increased risk of development of the relevant disease, disorder, and/or condition.
• treatment may be prophylactic; in some embodiments, treatment may be therapeutic.
• the present invention provides compositions, preparations, nanoparticles, and/or nanomaterials for delivery of therapeutic and/or prophylactic agents to target cells and/or tissue.
• the present disclosure describes lipid compounds for use in compositions, preparations, nanoparticles, and/or nanomaterials.
• compositions, preparations, and/or nanomaterials comprise LNPs carrying cargo to designated target cells, tissue, and/or organs.
• LNPs Lipid nanoparticles
• the present invention provides for compositions, preparations, and/or nanomaterials that comprise lipid nanoparticles.
• lipid nanoparticles comprise one or more components.
• lipid nanoparticles comprise one or more components such as compounds, ionizable lipids, sterols, conjugate-linker lipids, and phospholipids.
• selection and combination of one or more of the components as described herein impacts characteristics of lipid nanoparticles such as diameter, pKa, stabilization, and ionizability.
• selection and combination of one or more of the components as described herein impacts functional activity of lipid nanoparticles such as tropism, stabilization, and drug delivery efficacy.
• a combination of components may better suit delivery of siRNA.
• lipid nanoparticles comprise one or more compounds as described herein.
• lipid nanoparticles comprise one or more ionizable lipids as described herein.
• lipid nanoparticles comprise one or more sterols as described herein.
• lipid nanoparticles comprise one or more conjugate- linker lipids as described herein.
• lipid nanoparticles comprise one or more phospholipids as described herein. A.
• the present disclosure describes compositions, preparations, nanoparticles, and/or nanomaterials that comprise one or more compounds as described herein.
• the present disclosure provides a compound of Formula A’: A’ or its N-oxide, or a pharmaceutically acceptable salt thereof, wherein L 1 is absent, C1-6 alkylenyl, or C2-6 heteroalkylenyl; each L 2 is independently optionally substituted C2-15 alkylenyl, or optionally substituted C3-15 heteroalkylenyl; L is C1-10 alkylenyl, or C2-10 heteroalkylenyl; X 2 is -OC(O)-, -C(O)O-, or -OC(O)O-; X is absent, -OC(O)-, -C(O)O-, or -OC(O)O-; R” is hydrogen, optionally substituted group selected from C 6-20 aliphatic, 3- to
• the present disclosure provides a compound of Formula A: A or its N-oxide, or a pharmaceutically acceptable salt thereof, wherein L 1 is absent, C 1-6 alkylenyl, or C 2-6 heteroalkylenyl; each L 2 is independently C2-10 alkylenyl, or C3-10 heteroalkylenyl; L is C 1-10 alkylenyl, or C 2-10 heteroalkylenyl; each L 3 is independently absent, C 1-10 alkylenyl, or C 2-10 heteroalkylenyl; X 2 is -OC(O)-, -C(O)O-, or -OC(O)O-; X is absent, -OC(O)-, -C(O)O-, or -OC(O)O-; each R is independently hydrogen, , or an optionally substituted group selected from C6-20 aliphatic, C6-20 haloaliphatic, a 3- to 7-membered cycl
• the present disclosure provides a compound of Formula I”: I” or its N-oxide, or a pharmaceutically acceptable salt thereof, wherein L 1 is absent, C1-6 alkylenyl, or C2-6 heteroalkylenyl; each L 2 is independently optionally substituted C 2-15 alkylenyl, or optionally substituted C 3-15 heteroalkylenyl; L is C1-10 alkylenyl, or C2-10 heteroalkylenyl; X 2 is -OC(O)-, -C(O)O-, or -OC(O)O-; X is absent, -OC(O)-, -C(O)O-, or -OC(O)O-; each L 3 is independently absent, optionally substituted C1-10 alkylenyl, or optionally substituted C2-10 heteroalkylenyl; R” is hydrogen, optionally substituted group selected from C 6-20 aliphatic, 3- to 12-membered cyclo
• the present disclosure provides a compound of Formula I’: or its N-oxide, or a pharmaceutically acceptable salt thereof, wherein L 1 is absent, C1-6 alkylenyl, or C2-6 heteroalkylenyl; each L 2 is independently C 2-10 alkylenyl, or C 3-10 heteroalkylenyl; L is C 1-10 alkylenyl, or C 2-10 heteroalkylenyl; each L 3 is independently absent, C1-10 alkylenyl, or C2-10 heteroalkylenyl; X 2 is -OC(O)-, -C(O)O-, or -OC(O)O-; X is absent, -OC(O)-, -C(O)O-, or -OC(O)O-; each R is independently hydrogen, , or an optionally substituted group selected from C 6-20 aliphatic, C 6-20 haloaliphatic, a 3- to 7-membered cyclo
• the present disclosure provides a compound of Formula I: I or its N-oxide, or a salt thereof, wherein L 1 is absent, C 1-6 alkylenyl, or C 2-6 heteroalkylenyl; each L 2 is independently C2-10 alkylenyl, or C3-10 heteroalkylenyl; L is C1-10 alkylenyl, or C2-10 heteroalkylenyl; each L 3 is independently absent, C 1-10 alkylenyl, or C 2-10 heteroalkylenyl; X 2 is -OC(O)-, -C(O)O-, or -OC(O)O-; X is absent, -OC(O)-, -C(O)O-, or -OC(O)O-; each R is independently hydrogen, , or an optionally substituted group selected from C6-20 aliphatic, C6-20 haloaliphatic, a 3- to 7-membered cycloalipha
• the present disclosure provides a compound of Formula II”: II” or its N-oxide, or a pharmaceutically acceptable salt thereof, wherein L 1 is absent, C1-6 alkylenyl, or C2-6 heteroalkylenyl; each L 2 is independently optionally substituted C2-15 alkylenyl, or optionally substituted C3-15 heteroalkylenyl; L is C1-10 alkylenyl, or C2-10 heteroalkylenyl; X 2 is -OC(O)-, -C(O)O-, or -OC(O)O-; each L 3 is independently absent, optionally substituted C 1-10 alkylenyl, or optionally substituted C 2-10 heteroalkylenyl; each R is independently hydrogen, or an optionally substituted group selected from C6-20 aliphatic, 3- to 12-membered cycloaliphatic, 7- to 12-membered bridged bicyclic comprising 0-4 heteroatoms independently selected from nitrogen,
• the present disclosure provides a compound of Formula II’: II’ or its N-oxide, or a pharmaceutically acceptable salt thereof, wherein L 1 is absent, C1-6 alkylenyl, or C2-6 heteroalkylenyl; each L 2 is independently C 2-10 alkylenyl, or C 3-10 heteroalkylenyl; L is C 1-10 alkylenyl, or C 2-10 heteroalkylenyl; each L 3 is independently absent, C1-10 alkylenyl, or C2-10 heteroalkylenyl; X 2 is -OC(O)-, -C(O)O-, or -OC(O)O-; each R is independently hydrogen, , or an optionally substituted group selected from C 6-20 aliphatic, C 6-20 haloaliphatic, a 3- to 7-membered cycloaliphatic ring, 1-adamantyl, 2-adamantyl, sterolyl, and pheny
• the present disclosure provides a compound of Formula II: II or its N-oxide, or a salt thereof, wherein L 1 is absent, C 1-6 alkylenyl, or C 2-6 heteroalkylenyl; each L 2 is independently C 2-10 alkylenyl, or C 3-10 heteroalkylenyl; L is C1-10 alkylenyl, or C2-10 heteroalkylenyl; each L 3 is independently absent, C1-10 alkylenyl, or C2-10 heteroalkylenyl; X 2 is -OC(O)-, -C(O)O-, or -OC(O)O-; each R is independently hydrogen, , or an optionally substituted group selected from C6-20 aliphatic, C6-20 haloaliphatic, a 3- to 7-membered cycloaliphatic ring, 1-adamantyl, 2-adamantyl, sterolyl, and phenyl; R 1
• the present disclosure provides a compound of Formula III’: III’ or its N-oxide, or a pharmaceutically acceptable salt thereof, wherein L 1 is absent, C1-6 alkylenyl, or C2-6 heteroalkylenyl; each L 2 is independently optionally substituted C2-15 alkylenyl, or optionally substituted C3-15 heteroalkylenyl; each L is independently C1-10 alkylenyl, or C2-10 heteroalkylenyl; each X 2 is independently -OC(O)-, -C(O)O-, or -OC(O)O-; each L 3 is independently absent, optionally substituted C 1-10 alkylenyl, or optionally substituted C 2-10 heteroalkylenyl; each R is independently hydrogen, or an optionally substituted group selected from C6-20 aliphatic, 3- to 12-membered cycloaliphatic, 7- to 12-membered bridged bicyclic comprising 0-4 heteroatoms independently
• the present disclosure provides a compound of Formula III: III or its N-oxide, or a pharmaceutically acceptable salt thereof, wherein L 1 is absent, C1-6 alkylenyl, or C2-6 heteroalkylenyl; each L 2 is independently C 2-10 alkylenyl, or C 3-10 heteroalkylenyl; each L is independently C1-10 alkylenyl, or C2-10 heteroalkylenyl; each L 3 is independently absent, C1-10 alkylenyl, or C2-10 heteroalkylenyl; each X 2 is independently -OC(O)-, -C(O)O-, or -OC(O)O-; each R is independently hydrogen, , or an optionally substituted group selected from C 6-20 aliphatic, C 6-20 haloaliphatic, a 3- to 7-membered cycloaliphatic ring, 1-adamantyl, 2-adamantyl, sterolyl, and
• L 1 is absent, C1-6 alkylenyl, or C2-6 heteroalkylenyl. In some embodiments, L 1 is absent, C1-5 alkylenyl, or C2-5 heteroalkylenyl. In some embodiments, L 1 is absent, C1-4 alkylenyl, or C 2-4 heteroalkylenyl. In some embodiments, L 1 is absent. In some embodiments, L 1 is C 1-6 alkylenyl, or C 2-6 heteroalkylenyl.
• L 1 is C 1-5 alkylenyl, or C 2-5 heteroalkylenyl. In some embodiments, L 1 is C1-5 alkylenyl. In some embodiments, L 1 is C2-5 alkylenyl, or C 2-5 heteroalkylenyl. In some embodiments, L 1 is C 2-5 alkylenyl. In some embodiments, L 1 is C 2-5 heteroalkylenyl. In some embodiments, L 1 is C 1-4 alkylenyl, or C 2-4 heteroalkylenyl. In some embodiments, L 1 is C1-4 alkylenyl. In some embodiments, L 1 is C2-4 heteroalkylenyl.
• L 1 is C1 alkylenyl. In some embodiments, L 1 is C2 alkylenyl. In some embodiments, L 1 is C 3 alkylenyl. In some embodiments, L 1 is C 4 alkylenyl. In some embodiments, L 1 is C5 alkylenyl. In some embodiments, L 1 is C6 alkylenyl. In some embodiments, L 1 is -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, or -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -.
• L 1 is -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, or -CH 2 CH 2 CH 2 CH 2 CH 2 -. In some embodiments, L 1 is -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, or -CH 2 CH 2 CH 2 CH 2 -. In some embodiments, L 1 is -CH 2 -, -CH 2 CH 2 -, or -CH 2 CH 2 CH 2 -. In some embodiments, L 1 is -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, or -CH 2 CH 2 CH 2 CH 2 -.
• L 1 is -CH 2 CH 2 - or -CH 2 CH 2 CH 2 -. In some embodiments, L 1 is -CH 2 -. In some embodiments, L 1 is -CH 2 CH 2 -. In some embodiments, L 1 is -CH 2 CH 2 CH 2 -. In some embodiments, L 1 is -CH 2 CH 2 CH 2 CH 2 -. In some embodiments, L 1 is -CH 2 CH 2 CH 2 CH 2 -. In some embodiments, L 1 is -CH 2 CH 2 CH 2 CH 2 CH 2 -. In some embodiments, L 1 is -CH 2 CH 2 CH 2 CH 2 CH 2 -. In some embodiments, L 1 is C 2 heteroalkylenyl. In some embodiments, L 1 is C 3 heteroalkylenyl.
• L 1 is C4 heteroalkylenyl. In some embodiments, L 1 is C5 heteroalkylenyl. In some embodiments, L 1 is C6 heteroalkylenyl. In some embodiments, L 1 is C2 heteroalkylenyl comprising 1 heteroatom. In some embodiments, L 1 is C 3 heteroalkylenyl comprising 1 heteroatom. In some embodiments, L 1 is C 4 heteroalkylenyl comprising 1 heteroatom. In some embodiments, L 1 is C5 heteroalkylenyl comprising 1-2 heteroatoms. In some embodiments, L 1 is C 6 heteroalkylenyl comprising 1-2 heteroatoms.
• L 1 is C 2 heteroalkylenyl comprising 1 oxygen atom. In some embodiments, L 1 is C 3 heteroalkylenyl comprising 1 oxygen atom. In some embodiments, L 1 is C4 heteroalkylenyl comprising 1 oxygen atom. In some embodiments, L 1 is -CH 2 OCH 2 CH 2 -. In some embodiments, L 1 is C5 heteroalkylenyl comprising 1-2 oxygen atoms. In some embodiments, L 1 is C 6 heteroalkylenyl comprising 1-2 oxygen atoms.
• each L 2 is independently optionally substituted C2-15 alkylenyl, or optionally substituted C3-15 heteroalkylenyl. In some embodiments, each L 2 is independently optionally substituted C 2-12 alkylenyl, or optionally substituted C3-12 heteroalkylenyl. In some embodiments, each L 2 is independently optionally substituted C2-10 alkylenyl, or optionally substituted C3-10 heteroalkylenyl. In some embodiments, each L 2 is independently optionally substituted C 2-9 alkylenyl, or optionally substituted C 3-9 heteroalkylenyl.
• each L 2 is independently optionally substituted C5-10 alkylenyl, or optionally substituted C5-10 heteroalkylenyl. In some embodiments, each L 2 is independently optionally substituted C5-9 alkylenyl, or optionally substituted C 5-9 heteroalkylenyl. In some embodiments, each L 2 is independently optionally substituted C6-8 alkylenyl, or optionally substituted C6-8 heteroalkylenyl. In some embodiments, each L 2 is independently optionally substituted C5-8 alkylenyl, or optionally substituted C5-8 heteroalkylenyl.
• each L 2 is independently optionally substituted C 5-7 alkylenyl, or optionally substituted C 5-7 heteroalkylenyl. In some embodiments, each L 2 is independently optionally substituted C 4-8 alkylenyl, or optionally substituted C4-8 heteroalkylenyl. In some embodiments, each L 2 is independently optionally substituted C2-15 alkylenyl. In some embodiments, each L 2 is independently optionally substituted C 3-15 heteroalkylenyl. In some embodiments, each L 2 is independently optionally substituted C 2- 12 alkylenyl. In some embodiments, each L 2 is independently optionally substituted C3-12 heteroalkylenyl.
• each L 2 is independently optionally substituted C2- 10 alkylenyl. In some embodiments, each L 2 is independently optionally substituted C3-10 heteroalkylenyl. In some embodiments, each L 2 is independently optionally substituted C2-9 alkylenyl. In some embodiments, each L 2 is independently optionally substituted C 3-9 heteroalkylenyl. In some embodiments, each L 2 is independently optionally substituted C 5-10 alkylenyl. In some embodiments, each L 2 is independently optionally substituted C5-10 heteroalkylenyl. In some embodiments, each L 2 is independently optionally substituted C5-9 alkylenyl.
• each L 2 is independently optionally substituted C 5-9 heteroalkylenyl. In some embodiments, each L 2 is independently optionally substituted C 6-8 alkylenyl. In some embodiments, each L 2 is independently optionally substituted C6-8 heteroalkylenyl. In some embodiments, each L 2 is independently optionally substituted C5-8 alkylenyl. In some embodiments, each L 2 is independently optionally substituted C5-8 heteroalkylenyl. In some embodiments, each L 2 is independently optionally substituted C5-7 alkylenyl. In some embodiments, each L 2 is independently optionally substituted C 5-7 heteroalkylenyl.
• each L 2 is independently optionally substituted C 4-8 alkylenyl. In some embodiments, each L 2 is independently optionally substituted C4-8 heteroalkylenyl. [0140] In some embodiments, each L 2 is independently C 6-8 alkylenyl substituted with –R ⁇ or –OR ⁇ . In some embodiments, each L 2 is independently C 6-8 alkylenyl substituted with –R ⁇ ⁇ In some embodiments, each L 2 is independently C 6-8 alkylenyl substituted with –OR ⁇ .
• each L 2 is independently C 6-8 alkylenyl substituted with one or two –R ⁇ s ⁇ In some embodiments, each L 2 is independently C6-8 alkylenyl substituted with one –R ⁇ ⁇ In some embodiments, each L 2 is independently C6-8 alkylenyl substituted with two –R ⁇ s ⁇ In some embodiments, each L 2 is independently C6-8 alkylenyl substituted with one –OR ⁇ .
• each L 2 is independently C6-8 alkylenyl substituted with one or two C1–6 aliphatics ⁇ In some embodiments, each L 2 is independently C6-8 alkylenyl substituted with one C1–6 aliphatic ⁇ In some embodiments, each L 2 is independently C6-8 alkylenyl substituted with two C1–6 aliphatics ⁇ In some embodiments, each L 2 is independently C6-8 alkylenyl substituted with one or two methyls ⁇ In some embodiments, each L 2 is independently C6-8 alkylenyl substituted with one methyl ⁇ In some embodiments, each L 2 is independently C6-8 alkylenyl substituted with two methyls ⁇ ⁇ ⁇ In some embodiments, each L 2 is independently C6-8 alkylenyl substituted with one –OH.
• each L 2 is independently , , or .
• one L 2 is C 6-8 alkylenyl substituted with one – OR ⁇ , and the other L 2 is C6-8 alkylenyl.
• one L 2 is C6-8 alkylenyl substituted with one –OH, and the other L 2 is C 6-8 alkylenyl.
• one L 2 is C 7 alkylenyl substituted with one –OR ⁇ , and the other L 2 is C6 alkylenyl.
• one L 2 is C7 alkylenyl substituted with one –OH, and the other L 2 is C6 alkylenyl.
• each L 2 is independently C 2-15 alkylenyl, or C 3-15 heteroalkylenyl. In some embodiments, each L 2 is independently C 2-12 alkylenyl, or C 3-12 heteroalkylenyl. In some embodiments, each L 2 is independently C 2-15 alkylenyl. In some embodiments, each L 2 is independently C3-15 heteroalkylenyl. In some embodiments, each L 2 is independently C2-12 alkylenyl.
• each L 2 is independently C 3-12 heteroalkylenyl.
• each L 2 is independently C2-10 alkylenyl, or C3-10 heteroalkylenyl. In some embodiments, each L 2 is independently C 2-9 alkylenyl, or C 3-9 heteroalkylenyl. In some embodiments, each L 2 is independently C 5-10 alkylenyl, or C 5-10 heteroalkylenyl. In some embodiments, each L 2 is independently C5-9 alkylenyl, or C5-9 heteroalkylenyl.
• each L 2 is independently C 6-8 alkylenyl, or C 6-8 heteroalkylenyl. In some embodiments, each L 2 is independently C 5-8 alkylenyl, or C 5-8 heteroalkylenyl. In some embodiments, each L 2 is independently C4-8 alkylenyl, or C4-8 heteroalkylenyl. In some embodiments, each L 2 is independently C 2-10 alkylenyl. In some embodiments, each L 2 is independently C 3-10 heteroalkylenyl. In some embodiments, each L 2 is independently C 2-9 alkylenyl. In some embodiments, each L 2 is independently C3-9 heteroalkylenyl.
• each L 2 is independently C 5-10 alkylenyl. In some embodiments, each L 2 is independently C 5-10 heteroalkylenyl. In some embodiments, each L 2 is independently C 5-9 alkylenyl. In some embodiments, each L 2 is independently C5-9 heteroalkylenyl. In some embodiments, each L 2 is independently C6-8 alkylenyl. In some embodiments, each L 2 is independently C 6-8 heteroalkylenyl. In some embodiments, each L 2 is independently C 5-8 alkylenyl. In some embodiments, each L 2 is independently C5-8 heteroalkylenyl. In some embodiments, each L 2 is independently C4-8 alkylenyl.
• each L 2 is independently C 4-8 heteroalkylenyl. In some embodiments, each L 2 is independently C 5-7 alkylenyl, or C 5-7 heteroalkylenyl. In some embodiments, each L 2 is independently C 5-7 alkylenyl. In some embodiments, each L 2 is independently C5-7 heteroalkylenyl. [0143] In some embodiments, each L 2 is independently C 2 alkylenyl. In some embodiments, each L 2 is independently C 3 alkylenyl. In some embodiments, each L 2 is independently C 4 alkylenyl. In some embodiments, each L 2 is independently C5 alkylenyl. In some embodiments, each L 2 is independently C6 alkylenyl.
• each L 2 is independently C7 alkylenyl. In some embodiments, each L 2 is independently C 8 alkylenyl. In some embodiments, each L 2 is independently C9 alkylenyl. In some embodiments, each L 2 is independently C10 alkylenyl.
• each L 2 is independently -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, or -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -.
• each L 2 is independently - CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, or -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -.
• each L 2 is independently -CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, or -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -.
• each L 2 is independently - CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, or -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -.
• each L 2 is independently -CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, or -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -.
• each L 2 is independently -CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, or -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -.
• each L 2 is independently -CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 -, or -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -. In some embodiments, each L 2 is independently -CH 2 CH 2 CH 2 CH 2 CH 2 - or -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -. In some embodiments, each L 2 is -CH 2 CH 2 CH 2 CH 2 -. In some embodiments, each L 2 is -CH 2 CH 2 CH 2 CH 2 CH 2 -. In some embodiments, each L 2 is -CH 2 CH 2 CH 2 CH 2 CH 2 -. In some embodiments, each L 2 is -CH 2 CH 2 CH 2 CH 2 CH 2 -.
• each L 2 is -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -. In some embodiments, each L 2 is -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -. In some embodiments, each L 2 is -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -. In some embodiments, each L 2 is -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -. In some embodiments, the two L 2 groups are the same.
• the two L 2 groups are the same and are selected from the group consisting of -CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, and -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -.
• the two L 2 groups are the same and are selected from the group consisting of -CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, and -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -.
• the two L 2 groups are the same and are selected from the group consisting of -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, and -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -.
• the two L 2 groups are the same and are selected from the group consisting of -CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, and -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -.
• the two L 2 groups are the same and are selected from the group consisting of -CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, and -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -.
• the two L 2 groups are the same and are selected from the group consisting of -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 - and -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -. In some embodiments, the two L 2 groups are different. In some embodiments, one L 2 is -CH 2 CH 2 -, and the other L 2 is - CH 2 CH 2 CH 2 CH 2 CH 2 -. In some embodiments, one L 2 is -CH 2 CH 2 CH 2 -, and the other L 2 is - CH 2 CH 2 CH 2 CH 2 CH 2 -.
• one L 2 is -CH 2 CH 2 CH 2 CH 2 -, and the other L 2 is - CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -. In some embodiments, one L 2 is -CH 2 CH 2 CH 2 CH 2 CH 2 -, and the other L 2 is -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -. In some embodiments, one L 2 is -CH 2 CH 2 CH 2 CH 2 CH 2 -, and the other L 2 is -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -.
• one L 2 is -CH 2 CH 2 CH 2 CH 2 CH 2 -, and the other L 2 is - CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -. In some embodiments, one L 2 is -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 - , and the other L 2 is -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -. In some embodiments, one L 2 is - CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, and the other L 2 is -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -.
• one L 2 is -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 - , and the other L 2 is -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -. In some embodiments, one L 2 is -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, and the other L 2 is -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -. In some embodiments, one L 2 is -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, and the other L 2 is -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -. [0144] In some embodiments, each L 2 is independently C4 heteroalkylenyl.
• each L 2 is independently C 5 heteroalkylenyl. In some embodiments, each L 2 is independently C6 heteroalkylenyl. In some embodiments, each L 2 is independently C7 heteroalkylenyl. In some embodiments, each L 2 is independently C8 heteroalkylenyl. In some embodiments, each L 2 is independently C 4 heteroalkylenyl comprising 1 heteroatom. In some embodiments, each L 2 is independently C5 heteroalkylenyl comprising 1 heteroatom. In some embodiments, each L 2 is independently C6 heteroalkylenyl comprising 1 or 2 heteroatoms. In some embodiments, each L 2 is independently C 7 heteroalkylenyl comprising 1 or 2 heteroatoms.
• each L 2 is independently C 8 heteroalkylenyl comprising 1 or 2 heteroatoms. In some embodiments, each L 2 is independently C4 heteroalkylenyl comprising 1 oxygen atom. In some embodiments, each L 2 is independently C5 heteroalkylenyl comprising 1 oxygen atom. In some embodiments, each L 2 is independently C 6 heteroalkylenyl comprising 1 or 2 oxygen atoms. In some embodiments, each L 2 is independently C7 heteroalkylenyl comprising 1 or 2 oxygen atoms. In some embodiments, each L 2 is independently C8 heteroalkylenyl comprising 1 or 2 oxygen atoms.
• each L is independently C1-10 alkylenyl, or C2-10 heteroalkylenyl. In some embodiments, each L is independently C 1-8 alkylenyl, or C 2-8 heteroalkylenyl. In some embodiments, each L is independently C 1-10 alkylenyl. In some embodiments, each L is independently C2-10 heteroalkylenyl. In some embodiments, each L is independently C1-8 alkylenyl. In some embodiments, each L is independently C 2-8 heteroalkylenyl.
• each L is independently C 1-5 alkylenyl, or C 2-5 heteroalkylenyl. In some embodiments, each L is independently C1-5 alkylenyl. In some embodiments, each L is independently C2-5 heteroalkylenyl. In some embodiments, each L is independently C1-4 alkylenyl, or C 2-4 heteroalkylenyl. In some embodiments, each L is independently C 1-4 alkylenyl. In some embodiments, each L is independently C 2-4 heteroalkylenyl. In some embodiments, each L is independently C1 alkylenyl. In some embodiments, each L is independently C2 alkylenyl.
• each L is independently C 3 alkylenyl. In some embodiments, each L is independently C 4 alkylenyl. In some embodiments, each L is independently C 5 alkylenyl. In some embodiments, each L is independently -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, or -CH 2 CH 2 CH 2 CH 2 CH 2 -. In some embodiments, each L is independently -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, or -CH 2 CH 2 CH 2 CH 2 -.
• each L is independently -CH 2 CH 2 - , -CH 2 CH 2 CH 2 -, or -CH 2 CH 2 CH 2 CH 2 -. In some embodiments, each L is independently -CH 2 CH 2 - or -CH 2 CH 2 CH 2 -. In some embodiments, each L is -CH 2 -. In some embodiments, each L is - CH 2 CH 2 -. In some embodiments, each L is -CH 2 CH 2 CH 2 -. In some embodiments, each L is - CH 2 CH 2 CH 2 CH 2 -. In some embodiments, each L is -CH 2 CH 2 CH 2 -. In some embodiments, each L is -CH 2 CH 2 CH 2 -. In some embodiments, each L is -CH 2 CH 2 CH 2 CH 2 -. In some embodiments, each L is -CH 2 CH 2 CH 2 CH 2 -. In some embodiments, each L is -CH 2 CH 2 CH 2 CH 2 -. In some embodiments, each L is -CH 2 CH
• one L is -CH 2 CH 2 -, and the other L is - CH 2 CH 2 CH 2 -. In some embodiments, one L is -CH 2 CH 2 -, and the other L is -CH 2 CH 2 CH 2 CH 2 -. In some embodiments, one L is -CH 2 CH 2 CH 2 -, and the other L is -CH 2 CH 2 CH 2 CH 2 -. In some embodiments, each L is independently C2 heteroalkylenyl. In some embodiments, each L is independently C3 heteroalkylenyl. In some embodiments, each L is independently C4 heteroalkylenyl. In some embodiments, each L is independently C 5 heteroalkylenyl.
• each L is independently C2 heteroalkylenyl comprising 1 heteroatom. In some embodiments, each L is independently C3 heteroalkylenyl comprising 1 heteroatom. In some embodiments, each L is independently C4 heteroalkylenyl comprising 1 heteroatom. In some embodiments, each L is independently C 2 heteroalkylenyl comprising 1 oxygen atom. In some embodiments, each L is independently C 3 heteroalkylenyl comprising 1 oxygen atom. In some embodiments, each L is independently C4 heteroalkylenyl comprising 1 oxygen atom. In some embodiments, each L is independently C 5 heteroalkylenyl comprising 1 oxygen atom.
• each L is independently C 5 heteroalkylenyl comprising 2 oxygen atoms. [0146] In some embodiments, each L is independently C6-10 alkylenyl, or C6-10 heteroalkylenyl. In some embodiments, each L is independently C6-10 alkylenyl. In some embodiments, each L is independently C 6-10 heteroalkylenyl. In some embodiments, each L is independently C 6 alkylenyl. In some embodiments, each L is independently C7 alkylenyl. In some embodiments, each L is independently C8 alkylenyl. In some embodiments, each L is independently C9 alkylenyl. In some embodiments, each L is independently C 10 alkylenyl.
• each L is independently -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, or -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -.
• each L is -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -.
• each L is -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -.
• each L is -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -. In some embodiments, each L is -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -. In some embodiments, each L is -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -. In some embodiments, each L is independently C 6 heteroalkylenyl. In some embodiments, each L is independently C7 heteroalkylenyl. In some embodiments, each L is independently C8 heteroalkylenyl. In some embodiments, each L is independently C 9 heteroalkylenyl. In some embodiments, each L is independently C 10 heteroalkylenyl.
• each L is independently C6 heteroalkylenyl comprising 1 or 2 heteroatoms. In some embodiments, each L is independently C7 heteroalkylenyl comprising 1-3 heteroatoms. In some embodiments, each L is independently C 8 heteroalkylenyl comprising 1-3 heteroatoms. In some embodiments, each L is independently C 9 heteroalkylenyl comprising 1-3 heteroatoms. In some embodiments, each L is independently C10 heteroalkylenyl comprising 1-3 heteroatoms. In some embodiments, each L is independently C6 heteroalkylenyl comprising 1 or 2 oxygen atoms. In some embodiments, each L is independently C 7 heteroalkylenyl comprising 1-3 oxygen atoms.
• each L is independently C8 heteroalkylenyl comprising 1-3 oxygen atoms. In some embodiments, each L is independently C9 heteroalkylenyl comprising 1-3 oxygen atoms. In some embodiments, each L is independently C10 heteroalkylenyl comprising 1-3 oxygen atoms. [0147] As described above, in some embodiments of any of Formulae A’, I”, II”, and III’, each L 3 is independently absent, optionally substituted C1-10 alkylenyl, or optionally substituted C2-10 heteroalkylenyl. In some embodiments, each L 3 is independently optionally substituted C 1-10 alkylenyl, or optionally substituted C 2-10 heteroalkylenyl.
• each L 3 is independently optionally substituted C1-8 alkylenyl, or optionally substituted C 2-8 heteroalkylenyl. In some embodiments, each L 3 is independently optionally substituted C1-10 alkylenyl. In some embodiments, each L 3 is independently optionally substituted C 2-10 heteroalkylenyl. In some embodiments, each L 3 is independently optionally substituted C1-8 alkylenyl. In some embodiments, each L 3 is independently optionally substituted C 2-8 heteroalkylenyl. In some embodiments, each L 3 is independently optionally substituted C 1-5 alkylenyl, or optionally substituted C 2-5 heteroalkylenyl.
• each L 3 is independently optionally substituted C1-5 alkylenyl. In some embodiments, each L 3 is independently optionally substituted C 2-5 heteroalkylenyl. In some embodiments, each L 3 is independently optionally substituted C 1-4 alkylenyl, or optionally substituted C 2-4 heteroalkylenyl. In some embodiments, each L 3 is independently optionally substituted C1-4 alkylenyl. In some embodiments, each L 3 is independently optionally substituted C2-4 heteroalkylenyl. In some embodiments, each L 3 is independently optionally substituted C 6-10 alkylenyl, or optionally substituted C 6-10 heteroalkylenyl.
• each L 3 is independently optionally substituted C6-10 alkylenyl. In some embodiments, each L 3 is independently optionally substituted C6-10 heteroalkylenyl. [0148] In some embodiments of any of Formulae A’, A, I”, I’, I, II”, II’, II, III’, and III, each L 3 is independently absent, C1-10 alkylenyl, or C2-10 heteroalkylenyl. In some embodiments, each L 3 is absent. In some embodiments, each L 3 is independently C 1-10 alkylenyl, or C 2-10 heteroalkylenyl. In some embodiments, each L 3 is independently C 1-8 alkylenyl, or C 2-8 heteroalkylenyl.
• each L 3 is independently C1-10 alkylenyl. In some embodiments, each L 3 is independently C2-10 heteroalkylenyl. In some embodiments, each L 3 is independently C1-8 alkylenyl. In some embodiments, each L 3 is independently C 2-8 heteroalkylenyl. In some embodiments, each L 3 is independently C1-5 alkylenyl, or C2-5 heteroalkylenyl. In some embodiments, each L 3 is independently C1-5 alkylenyl. In some embodiments, each L 3 is independently C2-5 heteroalkylenyl. In some embodiments, each L 3 is independently C1-4 alkylenyl, or C 2-4 heteroalkylenyl.
• each L 3 is independently C 1-4 alkylenyl. In some embodiments, each L 3 is independently C 2-4 heteroalkylenyl. In some embodiments, each L 3 is independently C1 alkylenyl. In some embodiments, each L 3 is independently C2 alkylenyl. In some embodiments, each L 3 is independently C 3 alkylenyl. In some embodiments, each L 3 is independently C 4 alkylenyl. In some embodiments, each L 3 is independently C 5 alkylenyl.
• each L 3 is independently -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, or -CH 2 CH 2 CH 2 CH 2 CH 2 -. In some embodiments, each L 3 is independently -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, or -CH 2 CH 2 CH 2 CH 2 -. In some embodiments, each L 3 is independently -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, or -CH 2 CH 2 CH 2 CH 2 -. In some embodiments, each L 3 is independently -CH 2 CH 2 - or -CH 2 CH 2 CH 2 -.
• each L 3 is -CH 2 -. In some embodiments, each L 3 is -CH 2 CH 2 -. In some embodiments, each L 3 is -CH 2 CH 2 CH 2 -. In some embodiments, each L 3 is -CH 2 CH 2 CH 2 CH 2 -. In some embodiments, each L 3 is - CH 2 CH 2 CH 2 CH 2 -. In some embodiments, each L 3 is independently C2 heteroalkylenyl. In some embodiments, each L 3 is independently C 3 heteroalkylenyl. In some embodiments, each L 3 is independently C 4 heteroalkylenyl. In some embodiments, each L 3 is independently C 2 heteroalkylenyl comprising 1 heteroatom.
• each L 3 is independently C3 heteroalkylenyl comprising 1 heteroatom. In some embodiments, each L 3 is independently C4 heteroalkylenyl comprising 1 heteroatom. In some embodiments, each L 3 is independently C 2 heteroalkylenyl comprising 1 oxygen atom. In some embodiments, each L 3 is independently C3 heteroalkylenyl comprising 1 oxygen atom. In some embodiments, each L 3 is independently C4 heteroalkylenyl comprising 1 oxygen atom. In some embodiments, each L 3 is independently C 5 heteroalkylenyl comprising 1 oxygen atom. In some embodiments, each L 3 is independently C5 heteroalkylenyl comprising 2 oxygen atoms.
• each L 3 is independently C 6-10 alkylenyl, or C 6-10 heteroalkylenyl. In some embodiments, each L 3 is independently C 6-10 alkylenyl. In some embodiments, each L 3 is independently C6-10 heteroalkylenyl. In some embodiments, each L 3 is independently C6 alkylenyl. In some embodiments, each L 3 is independently C7 alkylenyl. In some embodiments, each L 3 is independently C 8 alkylenyl. In some embodiments, each L 3 is independently C 9 alkylenyl. In some embodiments, each L 3 is independently C10 alkylenyl.
• each L 3 is independently is -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, or -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -.
• each L 3 is independently is -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, or -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -.
• each L 3 is independently is -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 - or -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -. In some embodiments, each L 3 is independently is -CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 - or -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -. In some embodiments, each L 3 is -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -. In some embodiments, each L 3 is -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -.
• each L 3 is -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -. In some embodiments, each L 3 is -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -. In some embodiments, each L 3 is -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -. In some embodiments, each L 3 is independently C 6 heteroalkylenyl. In some embodiments, each L 3 is independently C 7 heteroalkylenyl. In some embodiments, each L 3 is independently C8 heteroalkylenyl. In some embodiments, each L 3 is independently C 9 heteroalkylenyl.
• each L 3 is independently C 10 heteroalkylenyl. In some embodiments, each L 3 is independently C 6 heteroalkylenyl comprising 1 or 2 heteroatoms. In some embodiments, each L 3 is independently C7 heteroalkylenyl comprising 1-3 heteroatoms. In some embodiments, each L 3 is independently C8 heteroalkylenyl comprising 1-3 heteroatoms. In some embodiments, each L 3 is independently C 9 heteroalkylenyl comprising 1-3 heteroatoms. In some embodiments, each L 3 is independently C10 heteroalkylenyl comprising 1-3 heteroatoms. In some embodiments, each L 3 is independently C6 heteroalkylenyl comprising 1 or 2 oxygen atoms.
• each L 3 is independently C 7 heteroalkylenyl comprising 1-3 oxygen atoms. In some embodiments, each L 3 is independently C8 heteroalkylenyl comprising 1-3 oxygen atoms. In some embodiments, each L 3 is independently C 9 heteroalkylenyl comprising 1-3 oxygen atoms. In some embodiments, each L 3 is independently C 10 heteroalkylenyl comprising 1-3 oxygen atoms. [0150] As described above, in some embodiments of Formulae A’, each L 3a is independently absent, optionally substituted C1-10 alkylenyl, or optionally substituted C2-10 heteroalkylenyl.
• each L 3a is independently optionally substituted C 1-10 alkylenyl, or optionally substituted C2-10 heteroalkylenyl. In some embodiments, each L 3a is independently optionally substituted C1-8 alkylenyl, or optionally substituted C 2-8 heteroalkylenyl. In some embodiments, each L 3a is independently optionally substituted C1-10 alkylenyl. In some embodiments, each L 3a is independently optionally substituted C 2-10 heteroalkylenyl. In some embodiments, each L 3a is independently optionally substituted C 1-8 alkylenyl. In some embodiments, each L 3a is independently optionally substituted C 2-8 heteroalkylenyl.
• each L 3a is independently optionally substituted C 1-5 alkylenyl, or optionally substituted C 2-5 heteroalkylenyl. In some embodiments, each L 3a is independently optionally substituted C 1-5 alkylenyl. In some embodiments, each L 3a is independently optionally substituted C2-5 heteroalkylenyl. In some embodiments, each L 3a is independently optionally substituted C1-4 alkylenyl, or optionally substituted C 2-4 heteroalkylenyl. In some embodiments, each L 3a is independently optionally substituted C1-4 alkylenyl. In some embodiments, each L 3a is independently optionally substituted C2-4 heteroalkylenyl.
• each L 3a is independently optionally substituted C6- 10 alkylenyl, or optionally substituted C 6-10 heteroalkylenyl. In some embodiments, each L 3a is independently optionally substituted C 6-10 alkylenyl. In some embodiments, each L 3a is independently optionally substituted C6-10 heteroalkylenyl. [0151] in some embodiments of Formula A’ or A, each L 3a is independently absent, C 1-10 alkylenyl, or C 2-10 heteroalkylenyl. In some embodiments, each L 3a is absent. In some embodiments, each L 3a is independently C1-10 alkylenyl, or C2-10 heteroalkylenyl.
• each L 3a is independently C1-8 alkylenyl, or C 2-8 heteroalkylenyl. In some embodiments, each L 3a is independently C 1-10 alkylenyl. In some embodiments, each L 3a is independently C2-10 heteroalkylenyl. In some embodiments, each L 3a is independently C1-8 alkylenyl. In some embodiments, each L 3a is independently C 2-8 heteroalkylenyl. In some embodiments, each L 3a is independently C 1-5 alkylenyl, or C 2-5 heteroalkylenyl. In some embodiments, each L 3a is independently C1-5 alkylenyl.
• each L 3a is independently C2-5 heteroalkylenyl. In some embodiments, each L 3a is independently C1-4 alkylenyl, or C 2-4 heteroalkylenyl. In some embodiments, each L 3a is independently C 1-4 alkylenyl. In some embodiments, each L 3a is independently C 2-4 heteroalkylenyl. In some embodiments, each L 3a is independently C1 alkylenyl. In some embodiments, each L 3a is independently C2 alkylenyl. In some embodiments, each L 3a is independently C3 alkylenyl. In some embodiments, each L 3a is independently C 4 alkylenyl.
• each L 3a is independently C 5 alkylenyl. In some embodiments, each L 3a is independently -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, or -CH 2 CH 2 CH 2 CH 2 CH 2 -. In some embodiments, each L 3a is independently -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, or -CH 2 CH 2 CH 2 CH 2 -. In some embodiments, each L 3a is independently -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, or -CH 2 CH 2 CH 2 CH 2 -.
• each L 3a is independently -CH 2 CH 2 - or -CH 2 CH 2 CH 2 -. In some embodiments, each L 3a is -CH 2 -. In some embodiments, each L 3a is -CH 2 CH 2 -. In some embodiments, each L 3a is -CH 2 CH 2 CH 2 -. In some embodiments, each L 3a is -CH 2 CH 2 CH 2 CH 2 -. In some embodiments, each L 3a is - CH 2 CH 2 CH 2 CH 2 -. In some embodiments, each L 3a is independently C 2 heteroalkylenyl. In some embodiments, each L 3a is independently C3 heteroalkylenyl.
• each L 3a is independently C4 heteroalkylenyl. In some embodiments, each L 3a is independently C2 heteroalkylenyl comprising 1 heteroatom. In some embodiments, each L 3a is independently C 3 heteroalkylenyl comprising 1 heteroatom. In some embodiments, each L 3a is independently C4 heteroalkylenyl comprising 1 heteroatom. In some embodiments, each L 3a is independently C2 heteroalkylenyl comprising 1 oxygen atom. In some embodiments, each L 3a is independently C 3 heteroalkylenyl comprising 1 oxygen atom. In some embodiments, each L 3a is independently C 4 heteroalkylenyl comprising 1 oxygen atom.
• each L 3a is independently C5 heteroalkylenyl comprising 1 oxygen atom. In some embodiments, each L 3a is independently C 5 heteroalkylenyl comprising 2 oxygen atoms. [0152] In some embodiments, each L 3a is independently C6-10 alkylenyl, or C6-10 heteroalkylenyl. In some embodiments, each L 3a is independently C6-10 alkylenyl. In some embodiments, each L 3a is independently C 6-10 heteroalkylenyl. In some embodiments, each L 3a is independently C 6 alkylenyl. In some embodiments, each L 3a is independently C7 alkylenyl.
• each L 3a is independently C8 alkylenyl. In some embodiments, each L 3a is independently C9 alkylenyl. In some embodiments, each L 3a is independently C 10 alkylenyl. In some embodiments, each L 3a is independently is -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, or -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -.
• each L 3a is independently is -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, or -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -. In some embodiments, each L 3a is independently is -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 - or -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -.
• each L 3a is independently is -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 - or -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -. In some embodiments, each L 3a is -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -. In some embodiments, each L 3a is -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -. In some embodiments, each L 3a is -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -.
• each L 3a is -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -. In some embodiments, each L 3a is -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -. In some embodiments, each L 3a is independently C 6 heteroalkylenyl. In some embodiments, each L 3a is independently C 7 heteroalkylenyl. In some embodiments, each L 3a is independently C8 heteroalkylenyl. In some embodiments, each L 3a is independently C9 heteroalkylenyl. In some embodiments, each L 3a is independently C10 heteroalkylenyl.
• each L 3a is independently C 6 heteroalkylenyl comprising 1 or 2 heteroatoms. In some embodiments, each L 3a is independently C7 heteroalkylenyl comprising 1-3 heteroatoms. In some embodiments, each L 3a is independently C8 heteroalkylenyl comprising 1-3 heteroatoms. In some embodiments, each L 3a is independently C 9 heteroalkylenyl comprising 1-3 heteroatoms. In some embodiments, each L 3a is independently C 10 heteroalkylenyl comprising 1-3 heteroatoms. In some embodiments, each L 3a is independently C6 heteroalkylenyl comprising 1 or 2 oxygen atoms.
• each L 3a is independently C 7 heteroalkylenyl comprising 1-3 oxygen atoms. In some embodiments, each L 3a is independently C8 heteroalkylenyl comprising 1-3 oxygen atoms. In some embodiments, each L 3a is independently C9 heteroalkylenyl comprising 1-3 oxygen atoms. In some embodiments, each L 3a is independently C 10 heteroalkylenyl comprising 1-3 oxygen atoms. [0153] As described above, in some embodiments of any of Formulae A’, A, I”, I’, I, II”, I’, II, III’, and III, each X 2 is independently -OC(O)-, -C(O)O-, or -OC(O)O-.
• each X 2 is independently -OC(O)-. In some embodiments, each X 2 is independently -C(O)O-. In some embodiments, each X 2 is independently -OC(O)O-. [0154] As described above, in some embodiments of any of Formulae A’, A, I”, I’, and I, X is absent, -OC(O)-, -C(O)O-, or -OC(O)O-. In some embodiments, X is absent. In some embodiments, X is -OC(O)-, -C(O)O-, or -OC(O)O-. In some embodiments, X is -OC(O)-.
• X is -C(O)O-. In some embodiments, X is -OC(O)O-.
• R is hydrogen, , , or an optionally substituted group selected from C6-20 aliphatic, 3- to 12- membered cycloaliphatic, 7- to 12-membered bridged bicyclic comprising 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 1-adamantyl, 2-adamantyl, sterolyl, and phenyl.
• R is hydrogen, , or an optionally substituted group selected from C 6-20 aliphatic, 3- to 12-membered cycloaliphatic, 7- to 12- membered bridged bicyclic comprising 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 1-adamantyl, 2-adamantyl, sterolyl, and phenyl.
• R is hydrogen, optionally substituted group selected from C6-20 aliphatic, 3- to 12-membered cycloaliphatic, 1-adamantyl, and phenyl.
• R is hydrogen, optionally substituted group selected from C 6-20 aliphatic, 3- to 12-membered cycloaliphatic, 1-adamantyl, and phenyl. [0157] In some embodiments, R” is hydrogen. In some embodiments, R” is . In some embodiments, . [0158] In some embodiments, R” is optionally substituted C6-20 aliphatic. In some embodiments, R” is optionally substituted C 6-12 aliphatic. In some embodiments, R” is optionally substituted C 8- 11 aliphatic. In some embodiments, R” is optionally substituted C 9-10 aliphatic. In some embodiments, R” is optionally substituted C6 aliphatic.
• R” is optionally substituted C 7 aliphatic. In some embodiments, R” is optionally substituted C 8 aliphatic. In some embodiments, R” is optionally substituted C 9 aliphatic. In some embodiments, R” is optionally substituted C10 aliphatic. In some embodiments, R” is optionally substituted C11 aliphatic. In some embodiments, R” is optionally substituted C12 aliphatic. In some embodiments, R” is optionally substituted C 13-20 aliphatic. In some embodiments, R” is optionally substituted C 15-20 aliphatic. In some embodiments, R” is optionally substituted C13 aliphatic. In some embodiments, R” is optionally substituted C14 aliphatic.
• R” is optionally substituted C15 aliphatic. In some embodiments, R” is optionally substituted C 16 aliphatic. In some embodiments, R” is optionally substituted C 17 aliphatic. In some embodiments, R” is optionally substituted C 18 aliphatic. In some embodiments, R” is optionally substituted C19 aliphatic. In some embodiments, R” is optionally substituted C 20 aliphatic. [0159] In some embodiments, R” is optionally substituted straight-chain C 6-20 aliphatic. In some embodiments, R” is optionally substituted straight-chain C6-12 aliphatic. In some embodiments, R” is optionally substituted straight-chain C8-11 aliphatic.
• R” is optionally substituted straight-chain C 9-10 aliphatic. In some embodiments, R” is optionally substituted straight-chain C6 aliphatic. In some embodiments, R” is optionally substituted straight-chain C7 aliphatic. In some embodiments, R” is optionally substituted straight-chain C8 aliphatic. In some embodiments, R” is optionally substituted straight-chain C 9 aliphatic. In some embodiments, R” is optionally substituted straight-chain C 10 aliphatic. In some embodiments, R” is optionally substituted straight-chain C11 aliphatic. In some embodiments, R” is optionally substituted straight-chain C12 aliphatic.
• R” is optionally substituted straight-chain C13- 20 aliphatic. In some embodiments, R” is optionally substituted straight-chain C 15-20 aliphatic. In some embodiments, R” is optionally substituted straight-chain C 13 aliphatic. In some embodiments, R” is optionally substituted straight-chain C14 aliphatic. In some embodiments, R” is optionally substituted straight-chain C 15 aliphatic. In some embodiments, R” is optionally substituted straight-chain C 16 aliphatic. In some embodiments, R” is optionally substituted straight-chain C17 aliphatic. In some embodiments, R” is optionally substituted straight-chain C18 aliphatic.
• R” is optionally substituted straight-chain C19 aliphatic. In some embodiments, R” is optionally substituted straight-chain C 20 aliphatic. [0160] In some embodiments, R” is optionally substituted branched C6-20 aliphatic. In some embodiments, R” is optionally substituted branched C6-12 aliphatic. In some embodiments, R” is optionally substituted branched C 8-11 aliphatic. In some embodiments, R” is optionally substituted branched C 9-10 aliphatic. In some embodiments, R” is optionally substituted branched C 6 aliphatic. In some embodiments, R” is optionally substituted branched C7 aliphatic.
• R” is optionally substituted branched C 8 aliphatic. In some embodiments, R” is optionally substituted branched C 9 aliphatic. In some embodiments, R” is optionally substituted branched C10 aliphatic. In some embodiments, R” is optionally substituted branched C11 aliphatic. In some embodiments, R” is optionally substituted branched C12 aliphatic. In some embodiments, R” is optionally substituted branched C 13-20 aliphatic. In some embodiments, R” is optionally substituted branched C15-20 aliphatic. In some embodiments, R” is optionally substituted branched C13 aliphatic.
• R” is optionally substituted branched C14 aliphatic. In some embodiments, R” is optionally substituted branched C 15 aliphatic. In some embodiments, R” is optionally substituted branched C16 aliphatic. In some embodiments, R” is optionally substituted branched C17 aliphatic. In some embodiments, R” is optionally substituted branched C18 aliphatic. In some embodiments, R” is optionally substituted branched C 19 aliphatic. In some embodiments, R” is optionally substituted branched C 20 aliphatic. [0161] In some embodiments, R” is C6-20 aliphatic. In some embodiments, R” is C6-12 aliphatic.
• R” is C8-11 aliphatic. In some embodiments, R” is C9-10 aliphatic. In some embodiments, R” is C 6 aliphatic. In some embodiments, R” is C 7 aliphatic. In some embodiments, R” is C8 aliphatic. In some embodiments, R” is C9 aliphatic. In some embodiments, R” is C10 aliphatic. In some embodiments, R” is C11 aliphatic. In some embodiments, R” is C12 aliphatic. In some embodiments, R” is C13-20 aliphatic. In some embodiments, R” is C15-20 aliphatic. In some embodiments, R” is C 13 aliphatic.
• R” is C 14 aliphatic. In some embodiments, R” is C 15 aliphatic. In some embodiments, R” is C 16 aliphatic. In some embodiments, R” is C17 aliphatic. In some embodiments, R” is C18 aliphatic. In some embodiments, R” is C 19 aliphatic. In some embodiments, R” is C 20 aliphatic. [0162] In some embodiments, R” is straight-chain C 6-20 aliphatic. In some embodiments, R” is straight-chain C6-12 aliphatic. In some embodiments, R” is straight-chain C8-11 aliphatic. In some embodiments, R” is straight-chain C9-10 aliphatic.
• R” is straight-chain C6 aliphatic. In some embodiments, R” is straight-chain C 7 aliphatic. In some embodiments, R” is straight-chain C8 aliphatic. In some embodiments, R” is straight-chain C9 aliphatic. In some embodiments, R” is straight-chain C10 aliphatic. In some embodiments, R” is straight-chain C11 aliphatic. In some embodiments, R” is straight-chain C 12 aliphatic. In some embodiments, R” is straight-chain C 13-20 aliphatic. In some embodiments, R” is straight-chain C 15-20 aliphatic. In some embodiments, R” is straight-chain C13 aliphatic.
• R” is straight-chain C14 aliphatic. In some embodiments, R” is straight-chain C 15 aliphatic. In some embodiments, R” is straight-chain C 16 aliphatic. In some embodiments, R” is straight-chain C 17 aliphatic. In some embodiments, R” is straight-chain C18 aliphatic. In some embodiments, R” is straight-chain C19 aliphatic. In some embodiments, R” is straight-chain C20 aliphatic. [0163] In some embodiments, R” is branched C 6-20 aliphatic. In some embodiments, R” is branched C6-12 aliphatic. In some embodiments, R” is branched C8-11 aliphatic.
• R” is branched C9-10 aliphatic. In some embodiments, R” is branched C6 aliphatic. In some embodiments, R” is branched C 7 aliphatic. In some embodiments, R” is branched C 8 aliphatic. In some embodiments, R” is branched C9 aliphatic. In some embodiments, R” is branched C10 aliphatic. In some embodiments, R” is branched C11 aliphatic. In some embodiments, R” is branched C 12 aliphatic. In some embodiments, R” is branched C 13-20 aliphatic. In some embodiments, R” is branched C 15-20 aliphatic.
• R” is branched C 13 aliphatic. In some embodiments, R” is branched C14 aliphatic. In some embodiments, R” is branched C15 aliphatic. In some embodiments, R” is branched C16 aliphatic. In some embodiments, R” is branched C 17 aliphatic. In some embodiments, R” is branched C 18 aliphatic. In some embodiments, R” is branched C19 aliphatic. In some embodiments, R” is branched C20 aliphatic. [0164] In some embodiments, R” is optionally substituted C6-20 alkyl. In some embodiments, R” is optionally substituted C 6-12 alkyl.
• R” is optionally substituted C 8-11 alkyl. In some embodiments, R” is optionally substituted C 9-10 alkyl. In some embodiments, R” is optionally substituted C6 alkyl. In some embodiments, R” is optionally substituted C7 alkyl. In some embodiments, R” is optionally substituted C 8 alkyl. In some embodiments, R” is optionally substituted C 9 alkyl. In some embodiments, R” is optionally substituted C 10 alkyl. In some embodiments, R” is optionally substituted C11 alkyl. In some embodiments, R” is optionally substituted C12 alkyl. In some embodiments, R” is optionally substituted C13-20 alkyl.
• R” is optionally substituted C 15-20 alkyl. In some embodiments, R” is optionally substituted C13 alkyl. In some embodiments, R” is optionally substituted C14 alkyl. In some embodiments, R” is optionally substituted C15 alkyl. In some embodiments, R” is optionally substituted C 16 alkyl. In some embodiments, R” is optionally substituted C 17 alkyl. In some embodiments, R” is optionally substituted C 18 alkyl. In some embodiments, R” is optionally substituted C19 alkyl. In some embodiments, R” is optionally substituted C20 alkyl. [0165] In some embodiments, R” is C 6-20 alkyl.
• R” is C 6-12 alkyl. In some embodiments, R” is C 8-11 alkyl. In some embodiments, R” is C 9-10 alkyl. In some embodiments, R” is C6 alkyl. In some embodiments, R” is C7 alkyl. In some embodiments, R” is C8 alkyl. In some embodiments, R” is C9 alkyl. In some embodiments, R” is C10 alkyl. In some embodiments, R” is C 11 alkyl. In some embodiments, R” is C 12 alkyl. In some embodiments, R” is C 13-20 alkyl. In some embodiments, R” is C15-20 alkyl. In some embodiments, R” is C13 alkyl.
• R” is C14 alkyl. In some embodiments, R” is C15 alkyl. In some embodiments, R” is C 16 alkyl. In some embodiments, R” is C 17 alkyl. In some embodiments, R” is C 18 alkyl. In some embodiments, R” is C19 alkyl. In some embodiments, R” is C20 alkyl. [0166] In some embodiments, R” is straight-chain C6-20 alkyl. In some embodiments, R” is straight-chain C 6-12 alkyl. In some embodiments, R” is straight-chain C 8-11 alkyl. In some embodiments, R” is straight-chain C 9-10 alkyl. In some embodiments, R” is straight-chain C 6 alkyl.
• R” is straight-chain C7 alkyl. In some embodiments, R” is straight-chain C8 alkyl. In some embodiments, R” is straight-chain C9 alkyl. In some embodiments, R” is straight-chain C 10 alkyl. In some embodiments, R” is straight-chain C 11 alkyl. In some embodiments, R” is straight-chain C12 alkyl. In some embodiments, R” is straight-chain C13-20 alkyl. In some embodiments, R” is straight-chain C15-20 alkyl. In some embodiments, R” is straight-chain C13 alkyl. In some embodiments, R” is straight-chain C14 alkyl. In some embodiments, R” is straight-chain C 15 alkyl.
• R” is straight-chain C 16 alkyl. In some embodiments, R” is straight-chain C 17 alkyl. In some embodiments, R” is straight-chain C18 alkyl. In some embodiments, R” is straight-chain C19 alkyl. In some embodiments, R” is straight-chain C 20 alkyl. [0167] In some embodiments, R” is branched C 6-20 alkyl. In some embodiments, R” is branched C6-12 alkyl. In some embodiments, R” is branched C8-11 alkyl. In some embodiments, R” is branched C9-10 alkyl. In some embodiments, R” is branched C6 alkyl.
• R” is branched C 7 alkyl. In some embodiments, R” is branched C 8 alkyl. In some embodiments, R” is branched C9 alkyl. In some embodiments, R” is branched C10 alkyl. In some embodiments, R” is branched C11 alkyl. In some embodiments, R” is branched C12 alkyl. In some embodiments, R” is branched C 13-20 alkyl. In some embodiments, R” is branched C 15-20 alkyl. In some embodiments, R” is branched C 13 alkyl. In some embodiments, R” is branched C 14 alkyl. In some embodiments, R” is branched C15 alkyl.
• R” is branched C16 alkyl. In some embodiments, R” is branched C 17 alkyl. In some embodiments, R” is branched C 18 alkyl. In some embodiments, R” is branched C 19 alkyl. In some embodiments, R” is branched C 20 alkyl. [0168] In some embodiments, R” is optionally substituted C6-20 alkenyl. In some embodiments, R” is optionally substituted C6-12 alkenyl. In some embodiments, R” is optionally substituted C8- 11 alkenyl. In some embodiments, R” is optionally substituted C 9-10 alkenyl. In some embodiments, R” is optionally substituted C6 alkenyl.
• R” is optionally substituted C7 alkenyl. In some embodiments, R” is optionally substituted C8 alkenyl. In some embodiments, R” is optionally substituted C 9 alkenyl. In some embodiments, R” is optionally substituted C10 alkenyl. In some embodiments, R” is optionally substituted C11 alkenyl. In some embodiments, R” is optionally substituted C12 alkenyl. In some embodiments, R” is optionally substituted C 13-20 alkenyl. In some embodiments, R” is optionally substituted C 15-20 alkenyl. In some embodiments, R” is optionally substituted C 13 alkenyl. In some embodiments, R” is optionally substituted C14 alkenyl.
• R” is optionally substituted C15 alkenyl. In some embodiments, R” is optionally substituted C16 alkenyl. In some embodiments, R” is optionally substituted C 17 alkenyl. In some embodiments, R” is optionally substituted C 18 alkenyl. In some embodiments, R” is optionally substituted C19 alkenyl. In some embodiments, R” is optionally substituted C20 alkenyl. [0169] In some embodiments, R” is C6-20 alkenyl. In some embodiments, R” is C6-12 alkenyl. In some embodiments, R” is C 8-11 alkenyl. In some embodiments, R” is C 9-10 alkenyl.
• R” is C 6 alkenyl. In some embodiments, R” is C 7 alkenyl. In some embodiments, R” is C8 alkenyl. In some embodiments, R” is C9 alkenyl. In some embodiments, R” is C10 alkenyl. In some embodiments, R” is C 11 alkenyl. In some embodiments, R” is C 12 alkenyl. In some embodiments, R” is C 13-20 alkenyl. In some embodiments, R” is C 15-20 alkenyl. In some embodiments, R” is C13 alkenyl. In some embodiments, R” is C14 alkenyl. In some embodiments, R” is C15 alkenyl.
• R” is C16 alkenyl. In some embodiments, R” is C17 alkenyl. In some embodiments, R” is C 18 alkenyl. In some embodiments, R” is C 19 alkenyl. In some embodiments, R” is C20 alkenyl. [0170] In some embodiments, R” is straight-chain C6-20 alkenyl. In some embodiments, R” is straight-chain C 6-12 alkenyl. In some embodiments, R” is straight-chain C 8-11 alkenyl. In some embodiments, R” is straight-chain C 9-10 alkenyl. In some embodiments, R” is straight-chain C 6 alkenyl. In some embodiments, R” is straight-chain C7 alkenyl.
• R” is straight-chain C 8 alkenyl. In some embodiments, R” is straight-chain C 9 alkenyl. In some embodiments, R” is straight-chain C 10 alkenyl. In some embodiments, R” is straight-chain C 11 alkenyl. In some embodiments, R” is straight-chain C12 alkenyl. In some embodiments, R” is straight-chain C13-20 alkenyl. In some embodiments, R” is straight-chain C15-20 alkenyl. In some embodiments, R” is straight-chain C 13 alkenyl. In some embodiments, R” is straight-chain C 14 alkenyl. In some embodiments, R” is straight-chain C15 alkenyl.
• R” is straight-chain C16 alkenyl. In some embodiments, R” is straight-chain C17 alkenyl. In some embodiments, R” is straight-chain C 18 alkenyl. In some embodiments, R” is straight-chain C 19 alkenyl. In some embodiments, R” is straight-chain C20 alkenyl. [0171] In some embodiments, R” is branched C6-20 alkenyl. In some embodiments, R” is branched C 6-12 alkenyl. In some embodiments, R” is branched C 8-11 alkenyl. In some embodiments, R” is branched C 9-10 alkenyl. In some embodiments, R” is branched C 6 alkenyl.
• R” is branched C7 alkenyl. In some embodiments, R” is branched C8 alkenyl. In some embodiments, R” is branched C9 alkenyl. In some embodiments, R” is branched C10 alkenyl. In some embodiments, R” is branched C 11 alkenyl. In some embodiments, R” is branched C 12 alkenyl. In some embodiments, R” is branched C13-20 alkenyl. In some embodiments, R” is branched C15-20 alkenyl. In some embodiments, R” is branched C13 alkenyl. In some embodiments, R” is branched C14 alkenyl.
• R” is branched C15 alkenyl. In some embodiments, R” is branched C 16 alkenyl. In some embodiments, R” is branched C 17 alkenyl. In some embodiments, R” is branched C 18 alkenyl. In some embodiments, R” is branched C19 alkenyl. In some embodiments, R” is branched C20 alkenyl. [0172] In some embodiments, R” is optionally substituted C 6-20 alkynyl. In some embodiments, R” is optionally substituted C 6-12 alkynyl. . In some embodiments, R” is optionally substituted C8-11 alkynyl.
• R” is optionally substituted C9-10 alkynyl. In some embodiments, R” is optionally substituted C6 alkynyl. In some embodiments, R” is optionally substituted C 7 alkynyl. In some embodiments, R” is optionally substituted C 8 alkynyl. In some embodiments, R” is optionally substituted C9 alkynyl. In some embodiments, R” is optionally substituted C10 alkynyl. In some embodiments, R” is optionally substituted C11 alkynyl. In some embodiments, R” is optionally substituted C 12 alkynyl. In some embodiments, R” is optionally substituted C 13-20 alkynyl.
• R” is optionally substituted C 15-20 alkynyl. In some embodiments, R” is optionally substituted C13 alkynyl. In some embodiments, R” is optionally substituted C 14 alkynyl. In some embodiments, R” is optionally substituted C 15 alkynyl. In some embodiments, R” is optionally substituted C 16 alkynyl. In some embodiments, R” is optionally substituted C17 alkynyl. In some embodiments, R” is optionally substituted C18 alkynyl. In some embodiments, R” is optionally substituted C19 alkynyl. In some embodiments, R” is optionally substituted C 20 alkynyl.
• R” is C6-20 alkynyl. In some embodiments, R” is C6-12 alkynyl. In some embodiments, R” is C8-11 alkynyl. In some embodiments, R” is C9-10 alkynyl. In some embodiments, R” is C 6 alkynyl. In some embodiments, R” is C 7 alkynyl. In some embodiments, R” is C8 alkynyl. In some embodiments, R” is C9 alkynyl. In some embodiments, R” is C10 alkynyl. In some embodiments, R” is C11 alkynyl. In some embodiments, R” is C12 alkynyl.
• R” is C 13-20 alkynyl. In some embodiments, R” is C 15-20 alkynyl. In some embodiments, R” is C 13 alkynyl. In some embodiments, R” is C 14 alkynyl. In some embodiments, R” is C15 alkynyl. In some embodiments, R” is C16 alkynyl. In some embodiments, R” is C17 alkynyl. In some embodiments, R” is C18 alkynyl. In some embodiments, R” is C19 alkynyl. In some embodiments, R” is C 20 alkynyl. [0174] In some embodiments, R” is straight-chain C6-20 alkynyl.
• R” is straight-chain C6-12 alkynyl. In some embodiments, R” is straight-chain C8-11 alkynyl. In some embodiments, R” is straight-chain C9-10 alkynyl. In some embodiments, R” is straight-chain C6 alkynyl. In some embodiments, R” is straight-chain C 7 alkynyl. In some embodiments, R” is straight-chain C 8 alkynyl. In some embodiments, R” is straight-chain C 9 alkynyl. In some embodiments, R” is straight-chain C10 alkynyl. In some embodiments, R” is straight-chain C11 alkynyl.
• R” is straight-chain C 12 alkynyl. In some embodiments, R” is straight-chain C 13-20 alkynyl. In some embodiments, R” is straight-chain C 15-20 alkynyl. In some embodiments, R” is straight-chain C13 alkynyl. In some embodiments, R” is straight-chain C14 alkynyl. In some embodiments, R” is straight-chain C15 alkynyl. In some embodiments, R” is straight-chain C 16 alkynyl. In some embodiments, R” is straight-chain C 17 alkynyl. In some embodiments, R” is straight-chain C18 alkynyl. In some embodiments, R” is straight-chain C19 alkynyl.
• R is straight-chain C20 alkynyl. [0175] In some embodiments, R” is C 6-20 haloaliphatic. In some embodiments, R” is C 6-12 haloaliphatic. In some embodiments, R” is C 6-10 haloaliphatic. In some embodiments, R” is C 6 haloaliphatic. In some embodiments, R” is C7 haloaliphatic. In some embodiments, R” is C8 haloaliphatic. In some embodiments, R” is C 9 haloaliphatic. In some embodiments, R” is C 10 haloaliphatic. In some embodiments, R” is C 15-20 haloaliphatic.
• R” is C 15 haloaliphatic. In some embodiments, R” is C16 haloaliphatic. In some embodiments, R” is C17 haloaliphatic. In some embodiments, R” is C18 haloaliphatic. In some embodiments, R” is C19 haloaliphatic. In some embodiments, R” is C 20 haloaliphatic. [0176] In some embodiments, R” is straight-chain C6-20 haloaliphatic. In some embodiments, R” is straight-chain C6-12 haloaliphatic. In some embodiments, R” is straight-chain C6-10 haloaliphatic. In some embodiments, R” is straight-chain C 6 haloaliphatic.
• R” is straight- chain C7 haloaliphatic. In some embodiments, R” is straight-chain C8 haloaliphatic. In some embodiments, R” is straight-chain C9 haloaliphatic. In some embodiments, R” is straight-chain C 10 haloaliphatic. In some embodiments, R” is straight-chain C 15-20 haloaliphatic. In some embodiments, R” is straight-chain C 15 haloaliphatic. In some embodiments, R” is straight-chain C16 haloaliphatic. In some embodiments, R” is straight-chain C17 haloaliphatic. In some embodiments, R” is straight-chain C18 haloaliphatic.
• R” is straight-chain C 19 haloaliphatic. In some embodiments, R” is straight-chain C 20 haloaliphatic. [0177] In some embodiments, R” is C6-20 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, R” is C6-20 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, R” is C6-20 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, R” is C6-12 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, R” is C 6-12 haloalkyl comprising 1-5 fluorine atoms.
• R” is C 6-12 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, R” is C6-10 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, R” is C 6-10 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, R” is C 6-10 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, R” is C 6 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, R” is C6 haloalkyl comprising 1-5 fluorine atoms.
• R” is C6 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, R” is C7 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, R” is C 7 haloalkyl comprising 1- 5 fluorine atoms. In some embodiments, R” is C7 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, R” is C8 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, R” is C 8 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, R” is C 8 haloalkyl comprising 1-3 fluorine atoms.
• R” is C 9 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, R” is C9 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, R” is C 9 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, R” is C 10 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, R” is C 10 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, R” is C10 haloalkyl comprising 1-3 fluorine atoms.
• R” is C15-20 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, R” is C 15-20 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, R” is C15-20 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, R” is C15 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, R” is C15 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, R” is C 15 haloalkyl comprising 1-3 fluorine atoms.
• R” is C16 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, R” is C16 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, R” is C16 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, R” is C 17 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, R” is C 17 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, R” is C17 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, R” is C18 haloalkyl comprising 1-7 fluorine atoms.
• R” is C18 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, R” is C 18 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, R” is C19 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, R” is C19 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, R” is C19 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, R” is C20 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, R” is C 20 haloalkyl comprising 1-5 fluorine atoms.
• R” is C 20 haloalkyl comprising 1-3 fluorine atoms. [0179] In some embodiments, R” is straight-chain C6-20 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, R” is straight-chain C 6-20 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, R” is straight-chain C 6-20 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, R” is straight-chain C6-12 haloalkyl comprising 1-7 fluorine atoms. some embodiments, R” is straight-chain C6-12 haloalkyl comprising 1-5 fluorine atoms.
• R” is straight-chain C 6-12 haloalkyl comprising 1-3 fluorine atoms. some embodiments, R” is straight-chain C6-10 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, R” is straight-chain C6-10 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, R” is straight-chain C 6-10 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, is straight-chain C 6 haloalkyl comprising 1-7 fluorine atoms. some embodiments, is straight-chain C6 haloalkyl comprising 1-5 fluorine atoms.
• R” is straight-chain C 6 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, R” is straight-chain C 7 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, R” is straight-chain C7 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, is straight-chain C7 haloalkyl comprising 1-3 fluorine atoms. some embodiments, is straight-chain C 8 haloalkyl comprising 1-7 fluorine atoms. some embodiments, R” is straight-chain C8 haloalkyl comprising 1-5 fluorine atoms.
• R is straight-chain C8 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, is straight-chain C 9 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, is straight-chain C9 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, is straight-chain C9 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, is straight-chain C 10 haloalkyl comprising 1-7 fluorine atoms. some embodiments, R” is straight-chain C 10 haloalkyl comprising 1-5 fluorine atoms.
• R” is straight-chain C10 haloalkyl comprising 1-3 fluorine atoms. [0180] In some embodiments, R” is straight-chain C15-20 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, R” is straight-chain C 15-20 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, R” is straight-chain C15-20 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, R” is straight-chain C15 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, R” is straight-chain C15 haloalkyl comprising 1-5 fluorine atoms.
• R” is straight-chain C 15 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, R” is straight-chain C 16 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, R” is straight-chain C16 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, R” is straight-chain C 16 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, R” is straight-chain C 17 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, R” is straight-chain C17 haloalkyl comprising 1-5 fluorine atoms.
• R” is straight-chain C17 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, R” is straight-chain C 18 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, R” is straight-chain C18 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, R” is straight-chain C18 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, R” is straight-chain C 19 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, R” is straight-chain C 19 haloalkyl comprising 1-5 fluorine atoms.
• R” is straight-chain C19 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, R” is straight-chain C 20 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, R” is straight-chain C 20 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, R” is straight-chain C20 haloalkyl comprising 1-3 fluorine atoms. [0181] In some embodiments, R” is optionally substituted 3- to 12-membered cycloaliphatic. In some embodiments, R” is optionally substituted 3- to 7-membered cycloaliphatic.
• R” is optionally substituted 4- to 7-membered cycloaliphatic. In some embodiments, R” is optionally substituted 5- to 7-membered cycloaliphatic. In some embodiments, R” is optionally substituted 6- to 7-membered cycloaliphatic. In some embodiments, R” is optionally substituted cyclopentyl. In some embodiments, R” is optionally substituted cyclohexyl.
• R is cyclohexyl substituted with R ⁇ ⁇ ⁇ ⁇
• R is cyclohexyl substituted with a 5- or 6-membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which is further substituted with –(CH 2 ) 0–2 R ⁇ .
• R” is cyclohexyl substituted with cyclohexyl, which is further substituted with C1-6 aliphatic.
• R” is optionally substituted cycloheptyl.
• R” is optionally substituted 7- to 12-membered bridged bicyclic comprising 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
• R is optionally substituted 1-adamantyl.
• R is optionally substituted 2-adamantyl.
• R is optionally substituted sterolyl.
• R” is optionally substituted cholesterolyl.
• R is optionally substituted phenyl.
• R is phenyl substituted with R ⁇ .
• R” is phenyl substituted with C1-6 aliphatic.
• each R is independently hydrogen, or an optionally substituted group selected from C 6-20 aliphatic, 3- to 12-membered cycloaliphatic, 7- to 12-membered bridged bicyclic comprising 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 1-adamantyl, 2-adamantyl, sterolyl, and phenyl.
• each R is independently hydrogen, , , or an optionally substituted group selected from C 6-20 aliphatic, C 6-20 haloaliphatic, a 3- to 7-membered cycloaliphatic ring, 1-adamantyl, 2-adamantyl, sterolyl, and phenyl.
• each R is independently hydrogen, optionally substituted group selected from C 6-20 aliphatic, C 6-20 haloaliphatic, a 3- to 7-membered cycloaliphatic ring, 1-adamantyl, 2-adamantyl, sterolyl, and phenyl.
• each R is independently hydrogen, or an optionally substituted group selected from C 6-20 aliphatic, 3- to 12-membered cycloaliphatic, 1-adamantyl, and phenyl. In some embodiments, each R is independently hydrogen, optionally substituted group selected from C 6-20 aliphatic, 3- to 7-membered cycloaliphatic, 1- adamantyl, and phenyl. In some embodiments, each R is independently hydrogen, , or an optionally substituted group selected from C 6-20 aliphatic, 3- to 7-membered cycloaliphatic, 1-adamantyl, and phenyl. [0185] In some embodiments, each R is hydrogen.
• each R is independently . , p y .
• each R is independently optionally substituted C6-20 aliphatic. In some embodiments, each R is independently optionally substituted C 6-12 aliphatic. In some embodiments, each R is independently optionally substituted C 8-11 aliphatic. In some embodiments, each R is independently optionally substituted C9-10 aliphatic. In some embodiments, each R is independently optionally substituted C6 aliphatic. In some embodiments, each R is independently optionally substituted C 7 aliphatic. In some embodiments, each R is independently optionally substituted C8 aliphatic. In some embodiments, each R is independently optionally substituted C9 aliphatic.
• each R is independently optionally substituted C 10 aliphatic. In some embodiments, each R is independently optionally substituted C 11 aliphatic. In some embodiments, each R is independently optionally substituted C 12 aliphatic. In some embodiments, each R is independently optionally substituted C13-20 aliphatic. In some embodiments, each R is independently optionally substituted C 15-20 aliphatic. In some embodiments, each R is independently optionally substituted C 13 aliphatic. In some embodiments, each R is independently optionally substituted C14 aliphatic. In some embodiments, each R is independently optionally substituted C15 aliphatic. In some embodiments, each R is independently optionally substituted C 16 aliphatic.
• each R is independently optionally substituted C17 aliphatic. In some embodiments, each R is independently optionally substituted C18 aliphatic. In some embodiments, each R is independently optionally substituted C19 aliphatic. In some embodiments, each R is independently optionally substituted C 20 aliphatic. [0187] In some embodiments, each R is independently optionally substituted straight-chain C6-20 aliphatic. In some embodiments, each R is independently optionally substituted straight-chain C 6-12 aliphatic. In some embodiments, each R is independently optionally substituted straight- chain C8-11 aliphatic. In some embodiments, each R is independently optionally substituted straight-chain C 9-10 aliphatic.
• each R is independently optionally substituted straight-chain C 6 aliphatic. In some embodiments, each R is independently optionally substituted straight-chain C7 aliphatic. In some embodiments, each R is independently optionally substituted straight-chain C8 aliphatic. In some embodiments, each R is independently optionally substituted straight-chain C 9 aliphatic. In some embodiments, each R is independently optionally substituted straight-chain C10 aliphatic. In some embodiments, each R is independently optionally substituted straight-chain C11 aliphatic. In some embodiments, each R is independently optionally substituted straight-chain C 12 aliphatic. In some embodiments, each R is independently optionally substituted straight-chain C 13-20 aliphatic.
• each R is independently optionally substituted straight-chain C15-20 aliphatic. In some embodiments, each R is independently optionally substituted straight-chain C 13 aliphatic. In some embodiments, each R is independently optionally substituted straight-chain C 14 aliphatic. In some embodiments, each R is independently optionally substituted straight-chain C15 aliphatic. In some embodiments, each R is independently optionally substituted straight-chain C16 aliphatic. In some embodiments, each R is independently optionally substituted straight-chain C 17 aliphatic. In some embodiments, each R is independently optionally substituted straight-chain C18 aliphatic. In some embodiments, each R is independently optionally substituted straight-chain C19 aliphatic.
• each R is independently optionally substituted straight-chain C 20 aliphatic. [0188] In some embodiments, each R is independently optionally substituted branched C6-20 aliphatic. In some embodiments, each R is independently optionally substituted branched C 6-12 aliphatic. In some embodiments, each R is independently optionally substituted branched C 8-11 aliphatic. In some embodiments, each R is independently optionally substituted branched C9-10 aliphatic. In some embodiments, each R is independently optionally substituted branched C6 aliphatic. In some embodiments, each R is independently optionally substituted branched C7 aliphatic. In some embodiments, each R is independently optionally substituted branched C 8 aliphatic.
• each R is independently optionally substituted branched C9 aliphatic. In some embodiments, each R is independently optionally substituted branched C10 aliphatic. In some embodiments, each R is independently optionally substituted branched C11 aliphatic. In some embodiments, each R is independently optionally substituted branched C 12 aliphatic. In some embodiments, each R is independently optionally substituted branched C 13-20 aliphatic. In some embodiments, each R is independently optionally substituted branched C15-20 aliphatic. In some embodiments, each R is independently optionally substituted branched C 13 aliphatic. In some embodiments, each R is independently optionally substituted branched C 14 aliphatic.
• each R is independently optionally substituted branched C15 aliphatic. In some embodiments, each R is independently optionally substituted branched C16 aliphatic. In some embodiments, each R is independently optionally substituted branched C 17 aliphatic. In some embodiments, each R is independently optionally substituted branched C18 aliphatic. In some embodiments, each R is independently optionally substituted branched C19 aliphatic. In some embodiments, each R is independently optionally substituted branched C 20 aliphatic. [0189] In some embodiments, each R is independently C6-20 aliphatic. In some embodiments, each R is independently C 6-12 aliphatic.
• each R is independently C 8-11 aliphatic. In some embodiments, each R is independently C 9-10 aliphatic. In some embodiments, each R is independently C6 aliphatic. In some embodiments, each R is independently C7 aliphatic. In some embodiments, each R is independently C8 aliphatic. In some embodiments, each R is independently C 9 aliphatic. In some embodiments, each R is independently C 10 aliphatic. In some embodiments, each R is independently C11 aliphatic. In some embodiments, each R is independently C12 aliphatic. In some embodiments, each R is independently C13-20 aliphatic. In some embodiments, each R is independently C 15-20 aliphatic.
• each R is independently C13 aliphatic. In some embodiments, each R is independently C14 aliphatic. In some embodiments, each R is independently C15 aliphatic. In some embodiments, each R is independently C 16 aliphatic. In some embodiments, each R is independently C 17 aliphatic. In some embodiments, each R is independently C 18 aliphatic. In some embodiments, each R is independently C19 aliphatic. In some embodiments, each R is independently C20 aliphatic. [0190] In some embodiments, each R is independently straight-chain C6-20 aliphatic. In some embodiments, each R is independently straight-chain C 6-12 aliphatic. In some embodiments, each R is independently straight-chain C8-11 aliphatic.
• each R is independently straight-chain C9-10 aliphatic. In some embodiments, each R is independently straight-chain C6 aliphatic. In some embodiments, each R is independently straight-chain C7 aliphatic. In some embodiments, each R is independently straight-chain C 8 aliphatic. In some embodiments, each R is independently straight-chain C 9 aliphatic. In some embodiments, each R is independently straight-chain C10 aliphatic. In some embodiments, each R is independently straight-chain C11 aliphatic. In some embodiments, each R is independently straight-chain C 12 aliphatic. In some embodiments, each R is independently straight-chain C 13-20 aliphatic.
• each R is independently straight-chain C15-20 aliphatic. In some embodiments, each R is independently straight-chain C13 aliphatic. In some embodiments, each R is independently straight-chain C14 aliphatic. In some embodiments, each R is independently straight-chain C 15 aliphatic. In some embodiments, each R is independently straight-chain C16 aliphatic. In some embodiments, each R is independently straight-chain C17 aliphatic. In some embodiments, each R is independently straight-chain C 18 aliphatic. In some embodiments, each R is independently straight-chain C 19 aliphatic. In some embodiments, each R is independently straight-chain C 20 aliphatic.
• each R is independently branched C6-20 aliphatic. In some embodiments, each R is independently branched C 6-12 aliphatic. In some embodiments, each R is independently branched C 8-11 aliphatic. In some embodiments, each R is independently branched C9-10 aliphatic. In some embodiments, each R is independently branched C6 aliphatic. In some embodiments, each R is independently branched C7 aliphatic. In some embodiments, each R is independently branched C 8 aliphatic. In some embodiments, each R is independently branched C 9 aliphatic. In some embodiments, each R is independently branched C10 aliphatic.
• each R is independently branched C11 aliphatic. In some embodiments, each R is independently branched C 12 aliphatic. In some embodiments, each R is independently branched C13-20 aliphatic. In some embodiments, each R is independently branched C15-20 aliphatic. In some embodiments, each R is independently branched C13 aliphatic. In some embodiments, each R is independently branched C 14 aliphatic. In some embodiments, each R is independently branched C 15 aliphatic. In some embodiments, each R is independently branched C 16 aliphatic. In some embodiments, each R is independently branched C17 aliphatic. In some embodiments, each R is independently branched C18 aliphatic.
• each R is independently branched C 19 aliphatic. In some embodiments, each R is independently branched C 20 aliphatic. [0192] In some embodiments, each R is independently optionally substituted C6-20 alkyl. In some embodiments, each R is independently optionally substituted C6-12 alkyl. In some embodiments, each R is independently optionally substituted C8-11 alkyl. In some embodiments, each R is independently optionally substituted C 9-10 alkyl. In some embodiments, each R is independently optionally substituted C 6 alkyl. In some embodiments, each R is independently optionally substituted C7 alkyl. In some embodiments, each R is independently optionally substituted C8 alkyl.
• each R is independently optionally substituted C 9 alkyl. In some embodiments, each R is independently optionally substituted C 10 alkyl. In some embodiments, each R is independently optionally substituted C11 alkyl. In some embodiments, each R is independently optionally substituted C12 alkyl. In some embodiments, each R is independently optionally substituted C 13-20 alkyl. In some embodiments, each R is independently optionally substituted C15-20 alkyl. In some embodiments, each R is independently optionally substituted C13 alkyl. In some embodiments, each R is independently optionally substituted C14 alkyl. In some embodiments, each R is independently optionally substituted C 15 alkyl. In some embodiments, each R is independently optionally substituted C 16 alkyl.
• each R is independently optionally substituted C17 alkyl. In some embodiments, each R is independently optionally substituted C 18 alkyl. In some embodiments, each R is independently optionally substituted C 19 alkyl. In some embodiments, each R is independently optionally substituted C 20 alkyl. [0193] In some embodiments, each R is independently C6-20 alkyl. In some embodiments, each R is independently C 6-12 alkyl. In some embodiments, each R is independently C 8-11 alkyl. In some embodiments, each R is independently C9-10 alkyl. In some embodiments, each R is independently C6 alkyl. In some embodiments, each R is independently C7 alkyl. In some embodiments, each R is independently C 8 alkyl.
• each R is independently C 9 alkyl. In some embodiments, each R is independently C10 alkyl. In some embodiments, each R is independently C11 alkyl. In some embodiments, each R is independently C12 alkyl. In some embodiments, each R is independently C 13-20 alkyl. In some embodiments, each R is independently C 15-20 alkyl. In some embodiments, each R is independently C 13 alkyl. In some embodiments, each R is independently C14 alkyl. In some embodiments, each R is independently C15 alkyl. In some embodiments, each R is independently C16 alkyl. In some embodiments, each R is independently C 17 alkyl. In some embodiments, each R is independently C 18 alkyl.
• each R is independently C19 alkyl. In some embodiments, each R is independently C20 alkyl. [0194] In some embodiments, each R is independently straight-chain C6-20 alkyl. In some embodiments, each R is independently straight-chain C 6-12 alkyl. In some embodiments, each R is independently straight-chain C 8-11 alkyl. In some embodiments, each R is independently straight-chain C9-10 alkyl. In some embodiments, each R is independently straight-chain C6 alkyl. In some embodiments, each R is independently straight-chain C 7 alkyl. In some embodiments, each R is independently straight-chain C 8 alkyl. In some embodiments, each R is independently straight-chain C9 alkyl.
• each R is independently straight-chain C10 alkyl. In some embodiments, each R is independently straight-chain C11 alkyl. In some embodiments, each R is independently straight-chain C 12 alkyl. In some embodiments, each R is independently straight-chain C13-20 alkyl. In some embodiments, each R is independently straight-chain C15-20 alkyl. In some embodiments, each R is independently straight-chain C13 alkyl. In some embodiments, each R is independently straight-chain C 14 alkyl. In some embodiments, each R is independently straight-chain C 15 alkyl. In some embodiments, each R is independently straight- chain C16 alkyl. In some embodiments, each R is independently straight-chain C17 alkyl.
• each R is independently straight-chain C 18 alkyl. In some embodiments, each R is independently straight-chain C 19 alkyl. In some embodiments, each R is independently straight- chain C20 alkyl. [0195] In some embodiments, each R is independently branched C6-20 alkyl. In some embodiments, each R is independently branched C 6-12 alkyl. In some embodiments, each R is independently branched C8-11 alkyl. In some embodiments, each R is independently branched C9- 10 alkyl. In some embodiments, each R is independently branched C6 alkyl. In some embodiments, each R is independently branched C 7 alkyl. In some embodiments, each R is independently branched C8 alkyl.
• each R is independently branched C9 alkyl. In some embodiments, each R is independently branched C10 alkyl. In some embodiments, each R is independently branched C 11 alkyl. In some embodiments, each R is independently branched C 12 alkyl. In some embodiments, each R is independently branched C 13-20 alkyl. In some embodiments, each R is independently branched C15-20 alkyl. In some embodiments, each R is independently branched C13 alkyl. In some embodiments, each R is independently branched C14 alkyl. In some embodiments, each R is independently branched C 15 alkyl. In some embodiments, each R is independently branched C16 alkyl.
• each R is independently branched C17 alkyl. In some embodiments, each R is independently branched C18 alkyl. In some embodiments, each R is independently branched C19 alkyl. In some embodiments, each R is independently branched C 20 alkyl. [0196] In some embodiments, each R is independently optionally substituted C 6-20 alkenyl. In some embodiments, each R is independently optionally substituted C6-12 alkenyl. In some embodiments, each R is independently optionally substituted C 8-11 alkenyl. In some embodiments, each R is independently optionally substituted C 9-10 alkenyl. In some embodiments, each R is independently optionally substituted C6 alkenyl.
• each R is independently optionally substituted C7 alkenyl. In some embodiments, each R is independently optionally substituted C 8 alkenyl. In some embodiments, each R is independently optionally substituted C 9 alkenyl. In some embodiments, each R is independently optionally substituted C10 alkenyl. In some embodiments, each R is independently optionally substituted C11 alkenyl. In some embodiments, each R is independently optionally substituted C 12 alkenyl. In some embodiments, each R is independently optionally substituted C 13-20 alkenyl. In some embodiments, each R is independently optionally substituted C15-20 alkenyl. In some embodiments, each R is independently optionally substituted C 13 alkenyl.
• each R is independently optionally substituted C 14 alkenyl. In some embodiments, each R is independently optionally substituted C15 alkenyl. In some embodiments, each R is independently optionally substituted C16 alkenyl. In some embodiments, each R is independently optionally substituted C17 alkenyl. In some embodiments, each R is independently optionally substituted C 18 alkenyl. In some embodiments, each R is independently optionally substituted C19 alkenyl. In some embodiments, each R is independently optionally substituted C20 alkenyl. [0197] In some embodiments, each R is independently C 6-20 alkenyl. In some embodiments, each R is independently C6-12 alkenyl.
• each R is independently C8-11 alkenyl. In some embodiments, each R is independently C9-10 alkenyl. In some embodiments, each R is independently C 6 alkenyl. In some embodiments, each R is independently C 7 alkenyl. In some embodiments, each R is independently C 8 alkenyl. In some embodiments, each R is independently C9 alkenyl. In some embodiments, each R is independently C10 alkenyl. In some embodiments, each R is independently C11 alkenyl. In some embodiments, each R is independently C12 alkenyl. In some embodiments, each R is independently C 13-20 alkenyl. In some embodiments, each R is independently C15-20 alkenyl.
• each R is independently C13 alkenyl. In some embodiments, each R is independently C14 alkenyl. In some embodiments, each R is independently C15 alkenyl. In some embodiments, each R is independently C16 alkenyl. In some embodiments, each R is independently C 17 alkenyl. In some embodiments, each R is independently C 18 alkenyl. In some embodiments, each R is independently C 19 alkenyl. In some embodiments, each R is independently C20 alkenyl. [0198] In some embodiments, each R is independently straight-chain C 6-20 alkenyl. In some embodiments, each R is independently straight-chain C 6-12 alkenyl. In some embodiments, each R is independently straight-chain C8-11 alkenyl.
• each R is independently straight-chain C9-10 alkenyl. In some embodiments, each R is independently straight-chain C6 alkenyl. In some embodiments, each R is independently straight-chain C 7 alkenyl. In some embodiments, each R is independently straight-chain C8 alkenyl. In some embodiments, each R is independently straight-chain C9 alkenyl. In some embodiments, each R is independently straight-chain C 10 alkenyl. In some embodiments, each R is independently straight-chain C 11 alkenyl. In some embodiments, each R is independently straight-chain C 12 alkenyl. In some embodiments, each R is independently straight-chain C13-20 alkenyl. In some embodiments, each R is independently straight-chain C 15-20 alkenyl.
• each R is independently straight-chain C 13 alkenyl. In some embodiments, each R is independently straight-chain C 14 alkenyl. In some embodiments, each R is independently straight-chain C15 alkenyl. In some embodiments, each R is independently straight-chain C16 alkenyl. In some embodiments, each R is independently straight-chain C 17 alkenyl. In some embodiments, each R is independently straight-chain C18 alkenyl. In some embodiments, each R is independently straight-chain C19 alkenyl. In some embodiments, each R is independently straight-chain C20 alkenyl. [0199] In some embodiments, each R is independently branched C 6-20 alkenyl.
• each R is independently branched C6-12 alkenyl. In some embodiments, each R is independently branched C8-11 alkenyl. In some embodiments, each R is independently branched C 9-10 alkenyl. In some embodiments, each R is independently branched C 6 alkenyl. In some embodiments, each R is independently branched C 7 alkenyl. In some embodiments, each R is independently branched C8 alkenyl. In some embodiments, each R is independently branched C9 alkenyl. In some embodiments, each R is independently branched C10 alkenyl. In some embodiments, each R is independently branched C 11 alkenyl.
• each R is independently branched C12 alkenyl. In some embodiments, each R is independently branched C13-20 alkenyl. In some embodiments, each R is independently branched C15-20 alkenyl. In some embodiments, each R is independently branched C13 alkenyl. In some embodiments, each R is independently branched C 14 alkenyl. In some embodiments, each R is independently branched C 15 alkenyl. In some embodiments, each R is independently branched C 16 alkenyl. In some embodiments, each R is independently branched C17 alkenyl. In some embodiments, each R is independently branched C 18 alkenyl. In some embodiments, each R is independently branched C 19 alkenyl.
• each R is independently branched C 20 alkenyl. [0200] In some embodiments, each R is independently optionally substituted C6-20 alkynyl. In some embodiments, each R is independently optionally substituted C6-12 alkynyl. In some embodiments, each R is independently optionally substituted C 8-11 alkynyl. In some embodiments, each R is independently optionally substituted C9-10 alkynyl. In some embodiments, each R is independently optionally substituted C6 alkynyl. In some embodiments, each R is independently optionally substituted C 7 alkynyl. In some embodiments, each R is independently optionally substituted C 8 alkynyl.
• each R is independently optionally substituted C 9 alkynyl. In some embodiments, each R is independently optionally substituted C10 alkynyl. In some embodiments, each R is independently optionally substituted C 11 alkynyl. In some embodiments, each R is independently optionally substituted C 12 alkynyl. In some embodiments, each R is independently optionally substituted C13-20 alkynyl. In some embodiments, each R is independently optionally substituted C15-20 alkynyl. In some embodiments, each R is independently optionally substituted C 13 alkynyl. In some embodiments, each R is independently optionally substituted C14 alkynyl. In some embodiments, each R is independently optionally substituted C15 alkynyl.
• each R is independently optionally substituted C16 alkynyl. In some embodiments, each R is independently optionally substituted C 17 alkynyl. In some embodiments, each R is independently optionally substituted C18 alkynyl. In some embodiments, each R is independently optionally substituted C19 alkynyl. In some embodiments, each R is independently optionally substituted C 20 alkynyl. [0201] In some embodiments, each R is independently C 6-20 alkynyl. In some embodiments, each R is independently C6-12 alkynyl. In some embodiments, each R is independently C8-11 alkynyl. In some embodiments, each R is independently C9-10 alkynyl.
• each R is independently C 6 alkynyl. In some embodiments, each R is independently C 7 alkynyl. In some embodiments, each R is independently C8 alkynyl. In some embodiments, each R is independently C9 alkynyl. In some embodiments, each R is independently C10 alkynyl. In some embodiments, each R is independently C11 alkynyl. In some embodiments, each R is independently C12 alkynyl. In some embodiments, each R is independently C 13-20 alkynyl. In some embodiments, each R is independently C 15-20 alkynyl. In some embodiments, each R is independently C 13 alkynyl. In some embodiments, each R is independently C14 alkynyl.
• each R is independently C 15 alkynyl. In some embodiments, each R is independently C 16 alkynyl. In some embodiments, each R is independently C 17 alkynyl. In some embodiments, each R is independently C18 alkynyl. In some embodiments, each R is independently C19 alkynyl. In some embodiments, each R is independently C20 alkynyl. [0202] In some embodiments, each R is independently straight-chain C 6-20 alkynyl. In some embodiments, each R is independently straight-chain C6-12 alkynyl. In some embodiments, each R is independently straight-chain C8-11 alkynyl. In some embodiments, each R is independently straight-chain C 9-10 alkynyl.
• each R is independently straight-chain C 6 alkynyl. In some embodiments, each R is independently straight-chain C 7 alkynyl. In some embodiments, each R is independently straight-chain C8 alkynyl. In some embodiments, each R is independently straight-chain C 9 alkynyl. In some embodiments, each R is independently straight-chain C 10 alkynyl. In some embodiments, each R is independently straight-chain C 11 alkynyl. In some embodiments, each R is independently straight-chain C12 alkynyl. In some embodiments, each R is independently straight-chain C13-20 alkynyl. In some embodiments, each R is independently straight-chain C 15-20 alkynyl.
• each R is independently straight-chain C13 alkynyl. In some embodiments, each R is independently straight-chain C14 alkynyl. In some embodiments, each R is independently straight-chain C15 alkynyl. In some embodiments, each R is independently straight-chain C 16 alkynyl. In some embodiments, each R is independently straight-chain C17 alkynyl. In some embodiments, each R is independently straight-chain C18 alkynyl. In some embodiments, each R is independently straight-chain C19 alkynyl. In some embodiments, each R is independently straight-chain C 20 alkynyl. [0203] In some embodiments, each R is independently optionally substituted C 6-20 haloaliphatic.
• each R is independently optionally substituted C6-12 haloaliphatic. In some embodiments, each R is independently optionally substituted C6-10 haloaliphatic. In some embodiments, each R is independently optionally substituted C 6 haloaliphatic. In some embodiments, each R is independently optionally substituted C7 haloaliphatic. In some embodiments, each R is independently optionally substituted C8 haloaliphatic. In some embodiments, each R is independently optionally substituted C9 haloaliphatic. In some embodiments, each R is independently optionally substituted C 10 haloaliphatic. In some embodiments, each R is independently optionally substituted C 15-20 haloaliphatic.
• each R is independently optionally substituted C15 haloaliphatic. In some embodiments, each R is independently optionally substituted C 16 haloaliphatic. In some embodiments, each R is independently optionally substituted C 17 haloaliphatic. In some embodiments, each R is independently optionally substituted C18 haloaliphatic. In some embodiments, each R is independently optionally substituted C19 haloaliphatic. In some embodiments, each R is independently optionally substituted C 20 haloaliphatic. [0204] In some embodiments, each R is independently optionally substituted straight-chain C6-20 haloaliphatic. In some embodiments, each R is independently optionally substituted straight-chain C 6-12 haloaliphatic.
• each R is independently optionally substituted straight- chain C 6-10 haloaliphatic. In some embodiments, each R is independently optionally substituted straight-chain C6 haloaliphatic. In some embodiments, each R is independently optionally substituted straight-chain C 7 haloaliphatic. In some embodiments, each R is independently optionally substituted straight-chain C 8 haloaliphatic. In some embodiments, each R is independently optionally substituted straight-chain C9 haloaliphatic. In some embodiments, each R is independently optionally substituted straight-chain C10 haloaliphatic. In some embodiments, each R is independently optionally substituted straight-chain C 15-20 haloaliphatic.
• each R is independently optionally substituted straight-chain C15 haloaliphatic. In some embodiments, each R is independently optionally substituted straight-chain C16 haloaliphatic. In some embodiments, each R is independently optionally substituted straight-chain C17 haloaliphatic. In some embodiments, each R is independently optionally substituted straight- chain C18 haloaliphatic. In some embodiments, each R is independently optionally substituted straight-chain C 19 haloaliphatic. In some embodiments, each R is independently optionally substituted straight-chain C 20 haloaliphatic. [0205] In some embodiments, each R is independently optionally substituted branched C6-20 haloaliphatic.
• each R is independently optionally substituted branched C 6-12 haloaliphatic. In some embodiments, each R is independently optionally substituted branched C6-10 haloaliphatic. In some embodiments, each R is independently optionally substituted branched C6 haloaliphatic. In some embodiments, each R is independently optionally substituted branched C7 haloaliphatic. In some embodiments, each R is independently optionally substituted branched C 8 haloaliphatic. In some embodiments, each R is independently optionally substituted branched C 9 haloaliphatic. In some embodiments, each R is independently optionally substituted branched C10 haloaliphatic.
• each R is independently optionally substituted branched C 15-20 haloaliphatic. In some embodiments, each R is independently optionally substituted branched C 15 haloaliphatic. In some embodiments, each R is independently optionally substituted branched C16 haloaliphatic. In some embodiments, each R is independently optionally substituted branched C17 haloaliphatic. In some embodiments, each R is independently optionally substituted branched C 18 haloaliphatic. In some embodiments, each R is independently optionally substituted branched C19 haloaliphatic. In some embodiments, each R is independently optionally substituted branched C20 haloaliphatic.
• each R is independently C 6-20 haloaliphatic. In some embodiments, each R is independently C 6-12 haloaliphatic. In some embodiments, each R is independently C 6-10 haloaliphatic. In some embodiments, each R is independently C6 haloaliphatic. In some embodiments, each R is independently C 7 haloaliphatic. In some embodiments, each R is independently C 8 haloaliphatic. In some embodiments, each R is independently C 9 haloaliphatic. In some embodiments, each R is independently C10 haloaliphatic. In some embodiments, each R is independently C15-20 haloaliphatic. In some embodiments, each R is independently C15 haloaliphatic.
• each R is independently C 16 haloaliphatic. In some embodiments, each R is independently C17 haloaliphatic. In some embodiments, each R is independently C18 haloaliphatic. In some embodiments, each R is independently C19 haloaliphatic. In some embodiments, each R is independently C 20 haloaliphatic. [0207] In some embodiments, each R is independently straight-chain C6-20 haloaliphatic. In some embodiments, each R is independently straight-chain C6-12 haloaliphatic. In some embodiments, each R is independently straight-chain C 6-10 haloaliphatic. In some embodiments, each R is independently straight-chain C 6 haloaliphatic.
• each R is independently straight-chain C7 haloaliphatic. In some embodiments, each R is independently straight-chain C8 haloaliphatic. In some embodiments, each R is independently straight-chain C9 haloaliphatic. In some embodiments, each R is independently straight-chain C 10 haloaliphatic. In some embodiments, each R is independently straight-chain C15-20 haloaliphatic. In some embodiments, each R is independently straight-chain C15 haloaliphatic. In some embodiments, each R is independently straight-chain C16 haloaliphatic. In some embodiments, each R is independently straight-chain C 17 haloaliphatic. In some embodiments, each R is independently straight-chain C 18 haloaliphatic.
• each R is independently straight-chain C 19 haloaliphatic. In some embodiments, each R is independently straight-chain C20 haloaliphatic. [0208] In some embodiments, each R is independently optionally substituted C 6-20 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, each R is independently optionally substituted C6-20 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R is independently optionally substituted C6-20 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R is independently optionally substituted C 6-12 haloalkyl comprising 1-7 fluorine atoms.
• each R is independently optionally substituted C6-12 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R is independently optionally substituted C 6-12 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R is independently optionally substituted C 6-10 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, each R is independently optionally substituted C6-10 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, R is independently optionally substituted C 6-10 haloalkyl comprising 1-3 fluorine atoms.
• each R is independently optionally substituted C6 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, each R is independently optionally substituted C6 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R is independently optionally substituted C 6 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R is independently optionally substituted C7 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, each R is independently optionally substituted C 7 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R is independently optionally substituted C7 haloalkyl comprising 1-3 fluorine atoms.
• each R is independently optionally substituted C8 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, each R is independently optionally substituted C 8 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R is independently optionally substituted C8 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R is independently optionally substituted C9 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, each R is independently optionally substituted C 9 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R is independently optionally substituted C9 haloalkyl comprising 1-3 fluorine atoms.
• each R is independently optionally substituted C10 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, each R is independently optionally substituted C 10 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R is independently optionally substituted C 10 haloalkyl comprising 1-3 fluorine atoms. [0209] In some embodiments, each R is independently optionally substituted C 15-20 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, each R is independently optionally substituted C15-20 haloalkyl comprising 1-5 fluorine atoms.
• each R is independently optionally substituted C15-20 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R is independently optionally substituted C 15 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, each R is independently optionally substituted C15 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R is independently optionally substituted C 15 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R is independently optionally substituted C 16 haloalkyl comprising 1-7 fluorine atoms.
• each R is independently optionally substituted C16 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R is independently optionally substituted C 16 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R is independently optionally substituted C17 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, each R is independently optionally substituted C17 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R is independently optionally substituted C 17 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R is independently optionally substituted C18 haloalkyl comprising 1-7 fluorine atoms.
• each R is independently optionally substituted C 18 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R is independently optionally substituted C18 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R is independently optionally substituted C19 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, each R is independently optionally substituted C 19 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R is independently optionally substituted C19 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R is independently optionally substituted C20 haloalkyl comprising 1-7 fluorine atoms.
• each R is independently optionally substituted C 20 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R is independently optionally substituted C20 haloalkyl comprising 1-3 fluorine atoms. [0210] In some embodiments, each R is independently C6-20 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, each R is independently C 6-20 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R is independently C 6-20 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R is independently C6-12 haloalkyl comprising 1-7 fluorine atoms.
• each R is independently C 6-12 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R is independently C 6-12 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R is independently C6-10 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, each R is independently C6-10 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R is independently C 6-10 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R is independently C6 haloalkyl comprising 1-7 fluorine atoms.
• each R is independently C6 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R is independently C 6 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R is independently C 7 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, each R is independently C7 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R is independently C 7 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R is independently C 8 haloalkyl comprising 1-7 fluorine atoms.
• each R is independently C8 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R is independently C8 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R is independently C 9 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, each R is independently C9 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R is independently C9 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R is independently C 10 haloalkyl comprising 1-7 fluorine atoms.
• each R is independently C10 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R is independently C10 haloalkyl comprising 1-3 fluorine atoms. [0211] In some embodiments, each R is independently C 15-20 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, each R is independently C15-20 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R is independently C15-20 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R is independently C 15 haloalkyl comprising 1-7 fluorine atoms.
• each R is independently C15 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R is independently C15 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R is independently C16 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, each R is independently C 16 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R is independently C 16 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R is independently C17 haloalkyl comprising 1-7 fluorine atoms.
• each R is independently C 17 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R is independently C 17 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R is independently C18 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, each R is independently C18 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R is independently C 18 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R is independently C19 haloalkyl comprising 1-7 fluorine atoms.
• each R is independently C19 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R is independently C 19 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R is independently C 20 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, each R is independently C20 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R is independently C 20 haloalkyl comprising 1-3 fluorine atoms. [0212] In some embodiments, each R is independently straight-chain C6-20 haloalkyl comprising 1-7 fluorine atoms.
• each R is independently straight-chain C6-20 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R is independently straight-chain C 6- 20 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R is independently straight-chain C6-12 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, each R is independently straight-chain C 6-12 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R is independently straight-chain C6-12 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R is independently straight-chain C6-10 haloalkyl comprising 1-7 fluorine atoms.
• each R is independently straight-chain C 6-10 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R is independently straight-chain C 6- 10 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R is independently straight-chain C6 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, each R is independently straight-chain C 6 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R is independently straight-chain C6 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R is independently straight-chain C7 haloalkyl comprising 1-7 fluorine atoms.
• each R is independently straight-chain C7 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R is independently straight-chain C 7 haloalkyl comprising 1- 3 fluorine atoms. In some embodiments, each R is independently straight-chain C 8 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, each R is independently straight-chain C8 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R is independently straight- chain C 8 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R is independently straight-chain C9 haloalkyl comprising 1-7 fluorine atoms.
• each R is independently straight-chain C9 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R is independently straight-chain C 9 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R is independently straight-chain C10 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, each R is independently straight-chain C10 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R is independently straight-chain C 10 haloalkyl comprising 1-3 fluorine atoms. [0213] In some embodiments, each R is independently straight-chain C15-20 haloalkyl comprising 1-7 fluorine atoms.
• each R is independently straight-chain C 15-20 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R is independently straight-chain C 15- 20 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R is independently straight-chain C15 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, each R is independently straight-chain C 15 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R is independently straight-chain C15 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R is independently straight-chain C16 haloalkyl comprising 1-7 fluorine atoms.
• each R is independently straight-chain C 16 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R is independently straight-chain C16 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R is independently straight-chain C17 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, each R is independently straight- chain C 17 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R is independently straight-chain C17 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R is independently straight-chain C18 haloalkyl comprising 1-7 fluorine atoms.
• each R is independently straight-chain C 18 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R is independently straight-chain C18 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R is independently straight-chain C19 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, each R is independently straight-chain C19 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R is independently straight-chain C 19 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R is independently straight- chain C20 haloalkyl comprising 1-7 fluorine atoms.
• each R is independently straight-chain C 20 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R is independently straight-chain C 20 haloalkyl comprising 1-3 fluorine atoms. [0214] In some embodiments, each R is independently optionally substituted 3- to 12-membered cycloaliphatic. In some embodiments, each R is independently optionally substituted 3- to 7- membered cycloaliphatic. In some embodiments, each R is independently optionally substituted 4- to 7-membered cycloaliphatic. In some embodiments, each R is independently optionally substituted 5- to 7-membered cycloaliphatic.
• each R is independently optionally substituted 6- to 7-membered cycloaliphatic. In some embodiments, each R is independently optionally substituted cyclopentyl. In some embodiments, each R is independently optionally substituted cyclohexyl. In some embodiments, each R is independently cyclohexyl substituted with R ⁇ ⁇ ⁇ ⁇ In some embodiments, each R is independently cyclohexyl substituted with a 5- or 6-membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which is further substituted with –(CH 2 ) 0– 2R ⁇ .
• each R is independently cyclohexyl substituted with cyclohexyl, which is further substituted with C1-6 aliphatic. In some embodiments, each R is independently optionally substituted cycloheptyl. [0215] In some embodiments, each R is independently optionally substituted 7- to 12-membered bridged bicyclic comprising 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, each R is independently optionally substituted 1-adamantyl. In some embodiments, each R is independently optionally substituted 2-adamantyl. In some embodiments, each R is independently optionally substituted sterolyl. In some embodiments, each R is independently optionally substituted cholesterolyl.
• each R is independently optionally substituted phenyl. In some embodiments, each R is independently phenyl substituted with R ⁇ . In some embodiments, each R is independently phenyl substituted with C1-6 aliphatic. [0216] In some embodiments of any of Formulae A’, A, I”, I’, and I, two Rs are optionally substituted C 6-20 alkyl, and the third R is optionally substituted C 6-20 alkenyl. In some embodiments, two Rs are optionally substituted C6-20 alkenyl, and the third R is optionally substituted C 6-20 alkynyl.
• two Rs are optionally substituted C 6-20 alkyl, and the third R is optionally substituted C 6-20 alkynyl. In some embodiments, two Rs are optionally substituted C6-20 alkenyl, and the third R is optionally substituted C6-20 alkyl. In some embodiments, two Rs are optionally substituted C 6-20 alkynyl, and the third R is optionally substituted C 6-20 alkyl. In some embodiments, two Rs are optionally substituted C 6-20 aliphatic, and the third R is optionally substituted C6-20 haloaliphatic. In some embodiments, two Rs are optionally substituted C6-20 haloaliphatic, and the third R is optionally substituted C6-20 aliphatic.
• two Rs are optionally substituted C 6-20 alkyl, and the third R is optionally substituted C6-20 haloalkyl. In some embodiments, two Rs are optionally substituted C6-20 alkenyl, and the third R is optionally substituted C6-20 haloalkyl. In some embodiments, two Rs are optionally substituted C 6-20 alkynyl, and the third R is optionally substituted C 6-20 haloalkyl. In some embodiments, two Rs are optionally substituted C 6-20 haloalkyl, and the third R is optionally substituted C6-20 alkyl.
• two Rs are optionally substituted C6-20 haloalkyl, and the third R is optionally substituted C 6-20 alkenyl. In some embodiments, two Rs are optionally substituted C 6-20 haloalkyl, and the third R is optionally substituted C 6-20 alkynyl. [0217] In some embodiments of any of Formulae II”, II’, II, III’, and III, two Rs are optionally substituted C6-20 alkyl, and the other two Rs are optionally substituted C6-20 alkenyl. In some embodiments, two Rs are optionally substituted C 6-20 alkenyl, and the other two Rs are optionally substituted C6-20 alkynyl.
• two Rs are optionally substituted C6-20 alkyl, and the other two Rs are optionally substituted C6-20 alkynyl. In some embodiments, two Rs are optionally substituted C 6-20 aliphatic, and the other two Rs are optionally substituted C 6-20 haloaliphatic. In some embodiments, two Rs are optionally substituted C6-20 alkyl, and the other two Rs are optionally substituted C6-20 haloalkyl. In some embodiments, two Rs are optionally substituted C 6-20 alkenyl, and the other two Rs are optionally substituted C 6-20 haloalkyl.
• each R a is independently hydrogen, or an optionally substituted group selected from C 6-20 aliphatic, 3- to 12-membered cycloaliphatic, 7- to 12-membered bridged bicyclic comprising 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 1-adamantyl, 2-adamantyl, sterolyl, and phenyl.
• each R a is independently hydrogen, optionally substituted group selected from C 6-20 aliphatic, C 6-20 haloaliphatic, a 3- to 7-membered cycloaliphatic ring, 1-adamantyl, 2-adamantyl, sterolyl, and phenyl. [0219] In some embodiments, each R a is independently hydrogen, or an optionally substituted group selected from C 6-20 aliphatic, 3- to 12-membered cycloaliphatic, 1-adamantyl, and phenyl.
• each R a is independently hydrogen, , or an optionally substituted group selected from C 6-20 aliphatic, 3- to 7-membered cycloaliphatic, 1-adamantyl, and phenyl.
• each R a is hydrogen.
• each R a is independently .
• each R a is independently optionally substituted C 6-20 aliphatic.
• each R a is independently optionally substituted C6-12 aliphatic.
• each R a is independently optionally substituted C 8-11 aliphatic.
• each R a is independently optionally substituted C 9-10 aliphatic.
• each R a is independently optionally substituted C6 aliphatic. In some embodiments, each R a is independently optionally substituted C7 aliphatic. In some embodiments, each R a is independently optionally substituted C 8 aliphatic. In some embodiments, each R a is independently optionally substituted C9 aliphatic. In some embodiments, each R a is independently optionally substituted C10 aliphatic. In some embodiments, each R a is independently optionally substituted C 11 aliphatic. In some embodiments, each R a is independently optionally substituted C 12 aliphatic. In some embodiments, each R a is independently optionally substituted C13-20 aliphatic.
• each R a is independently optionally substituted C15-20 aliphatic. In some embodiments, each R a is independently optionally substituted C 13 aliphatic. In some embodiments, each R a is independently optionally substituted C 14 aliphatic. In some embodiments, each R a is independently optionally substituted C15 aliphatic. In some embodiments, each R a is independently optionally substituted C 16 aliphatic. In some embodiments, each R a is independently optionally substituted C 17 aliphatic. In some embodiments, each R a is independently optionally substituted C18 aliphatic. In some embodiments, each R a is independently optionally substituted C19 aliphatic.
• each R a is independently optionally substituted C 20 aliphatic.
• each R a is independently optionally substituted straight-chain C6-20 aliphatic.
• each R a is independently optionally substituted straight-chain C 6-12 aliphatic.
• each R a is independently optionally substituted straight- chain C 8-11 aliphatic.
• each R a is independently optionally substituted straight-chain C9-10 aliphatic.
• each R a is independently optionally substituted straight-chain C 6 aliphatic.
• each R a is independently optionally substituted straight-chain C 7 aliphatic.
• each R a is independently optionally substituted straight-chain C8 aliphatic. In some embodiments, each R a is independently optionally substituted straight-chain C9 aliphatic. In some embodiments, each R a is independently optionally substituted straight-chain C 10 aliphatic. In some embodiments, each R a is independently optionally substituted straight-chain C11 aliphatic. In some embodiments, each R a is independently optionally substituted straight-chain C12 aliphatic. In some embodiments, each R a is independently optionally substituted straight-chain C 13-20 aliphatic. In some embodiments, each R a is independently optionally substituted straight-chain C15-20 aliphatic.
• each R a is independently optionally substituted straight-chain C13 aliphatic. In some embodiments, each R a is independently optionally substituted straight-chain C 14 aliphatic. In some embodiments, each R a is independently optionally substituted straight-chain C 15 aliphatic. In some embodiments, each R a is independently optionally substituted straight-chain C16 aliphatic. In some embodiments, each R a is independently optionally substituted straight-chain C17 aliphatic. In some embodiments, each R a is independently optionally substituted straight-chain C 18 aliphatic. In some embodiments, each R a is independently optionally substituted straight-chain C19 aliphatic.
• each R a is independently optionally substituted straight-chain C20 aliphatic. [0223] In some embodiments, each R a is independently optionally substituted branched C6-20 aliphatic. In some embodiments, each R a is independently optionally substituted branched C 6-12 aliphatic. In some embodiments, each R a is independently optionally substituted branched C8-11 aliphatic. In some embodiments, each R a is independently optionally substituted branched C 9-10 aliphatic. In some embodiments, each R a is independently optionally substituted branched C 6 aliphatic. In some embodiments, each R a is independently optionally substituted branched C 7 aliphatic.
• each R a is independently optionally substituted branched C8 aliphatic. In some embodiments, each R a is independently optionally substituted branched C9 aliphatic. In some embodiments, each R a is independently optionally substituted branched C 10 aliphatic. In some embodiments, each R a is independently optionally substituted branched C11 aliphatic. In some embodiments, each R a is independently optionally substituted branched C12 aliphatic. In some embodiments, each R a is independently optionally substituted branched C 13-20 aliphatic. In some embodiments, each R a is independently optionally substituted branched C 15-20 aliphatic.
• each R a is independently optionally substituted branched C13 aliphatic. In some embodiments, each R a is independently optionally substituted branched C 14 aliphatic. In some embodiments, each R a is independently optionally substituted branched C 15 aliphatic. In some embodiments, each R a is independently optionally substituted branched C16 aliphatic. In some embodiments, each R a is independently optionally substituted branched C17 aliphatic. In some embodiments, each R a is independently optionally substituted branched C 18 aliphatic. In some embodiments, each R a is independently optionally substituted branched C19 aliphatic.
• each R a is independently optionally substituted branched C20 aliphatic.
• each R a is independently C6-20 aliphatic. In some embodiments, each R a is independently C6-12 aliphatic. In some embodiments, each R a is independently C8-11 aliphatic. In some embodiments, each R a is independently C 9-10 aliphatic. In some embodiments, each R a is independently C 6 aliphatic. In some embodiments, each R a is independently C 7 aliphatic. In some embodiments, each R a is independently C8 aliphatic. In some embodiments, each R a is independently C9 aliphatic.
• each R a is independently C10 aliphatic. In some embodiments, each R a is independently C 11 aliphatic. In some embodiments, each R a is independently C12 aliphatic. In some embodiments, each R a is independently C13-20 aliphatic. In some embodiments, each R a is independently C15-20 aliphatic. In some embodiments, each R a is independently C13 aliphatic. In some embodiments, each R a is independently C14 aliphatic. In some embodiments, each R a is independently C 15 aliphatic. In some embodiments, each R a is independently C 16 aliphatic. In some embodiments, each R a is independently C 17 aliphatic.
• each R a is independently C18 aliphatic. In some embodiments, each R a is independently C 19 aliphatic. In some embodiments, each R a is independently C 20 aliphatic. [0225] In some embodiments, each R a is independently straight-chain C6-20 aliphatic. In some embodiments, each R a is independently straight-chain C6-12 aliphatic. In some embodiments, each R a is independently straight-chain C 8-11 aliphatic. In some embodiments, each R a is independently straight-chain C9-10 aliphatic. In some embodiments, each R a is independently straight-chain C6 aliphatic. In some embodiments, each R a is independently straight-chain C7 aliphatic.
• each R a is independently straight-chain C 8 aliphatic. In some embodiments, each R a is independently straight-chain C 9 aliphatic. In some embodiments, each R a is independently straight-chain C10 aliphatic. In some embodiments, each R a is independently straight-chain C11 aliphatic. In some embodiments, each R a is independently straight-chain C 12 aliphatic. In some embodiments, each R a is independently straight-chain C 13-20 aliphatic. In some embodiments, each R a is independently straight-chain C15-20 aliphatic. In some embodiments, each R a is independently straight-chain C13 aliphatic. In some embodiments, each R a is independently straight-chain C14 aliphatic.
• each R a is independently straight-chain C 15 aliphatic. In some embodiments, each R a is independently straight-chain C16 aliphatic. In some embodiments, each R a is independently straight-chain C17 aliphatic. In some embodiments, each R a is independently straight-chain C 18 aliphatic. In some embodiments, each R a is independently straight-chain C 19 aliphatic. In some embodiments, each R a is independently straight-chain C20 aliphatic. [0226] In some embodiments, each R a is independently branched C6-20 aliphatic. In some embodiments, each R a is independently branched C 6-12 aliphatic.
• each R a is independently branched C 8-11 aliphatic. In some embodiments, each R a is independently branched C9-10 aliphatic. In some embodiments, each R a is independently branched C6 aliphatic. In some embodiments, each R a is independently branched C7 aliphatic. In some embodiments, each R a is independently branched C 8 aliphatic. In some embodiments, each R a is independently branched C9 aliphatic. In some embodiments, each R a is independently branched C10 aliphatic. In some embodiments, each R a is independently branched C11 aliphatic. In some embodiments, each R a is independently branched C12 aliphatic.
• each R a is independently branched C 13-20 aliphatic. In some embodiments, each R a is independently branched C 15-20 aliphatic. In some embodiments, each R a is independently branched C 13 aliphatic. In some embodiments, each R a is independently branched C14 aliphatic. In some embodiments, each R a is independently branched C 15 aliphatic. In some embodiments, each R a is independently branched C 16 aliphatic. In some embodiments, each R a is independently branched C 17 aliphatic. In some embodiments, each R a is independently branched C18 aliphatic. In some embodiments, each R a is independently branched C19 aliphatic.
• each R a is independently branched C 20 aliphatic. [0227] In some embodiments, each R a is independently optionally substituted C6-20 alkyl. In some embodiments, each R a is independently optionally substituted C6-12 alkyl. In some embodiments, each R a is independently optionally substituted C 8-11 alkyl. In some embodiments, each R a is independently optionally substituted C 9-10 alkyl. In some embodiments, each R a is independently optionally substituted C6 alkyl. In some embodiments, each R a is independently optionally substituted C 7 alkyl. In some embodiments, each R a is independently optionally substituted C 8 alkyl.
• each R a is independently optionally substituted C 9 alkyl. In some embodiments, each R a is independently optionally substituted C10 alkyl. In some embodiments, each R a is independently optionally substituted C11 alkyl. In some embodiments, each R a is independently optionally substituted C 12 alkyl. In some embodiments, each R a is independently optionally substituted C13-20 alkyl. In some embodiments, each R a is independently optionally substituted C15-20 alkyl. In some embodiments, each R a is independently optionally substituted C13 alkyl. In some embodiments, each R a is independently optionally substituted C 14 alkyl. In some embodiments, each R a is independently optionally substituted C15 alkyl.
• each R a is independently optionally substituted C16 alkyl. In some embodiments, each R a is independently optionally substituted C 17 alkyl. In some embodiments, each R a is independently optionally substituted C 18 alkyl. In some embodiments, each R a is independently optionally substituted C19 alkyl. In some embodiments, each R a is independently optionally substituted C20 alkyl. [0228] In some embodiments, each R a is independently C 6-20 alkyl. In some embodiments, each R a is independently C6-12 alkyl. In some embodiments, each R a is independently C8-11 alkyl. In some embodiments, each R a is independently C9-10 alkyl.
• each R a is independently C6 alkyl. In some embodiments, each R a is independently C7 alkyl. In some embodiments, each R a is independently C 8 alkyl. In some embodiments, each R a is independently C 9 alkyl. In some embodiments, each R a is independently C 10 alkyl. In some embodiments, each R a is independently C11 alkyl. In some embodiments, each R a is independently C12 alkyl. In some embodiments, each R a is independently C 13-20 alkyl. In some embodiments, each R a is independently C 15-20 alkyl. In some embodiments, each R a is independently C 13 alkyl. In some embodiments, each R a is independently C14 alkyl.
• each R a is independently C15 alkyl. In some embodiments, each R a is independently C16 alkyl. In some embodiments, each R a is independently C 17 alkyl. In some embodiments, each R a is independently C 18 alkyl. In some embodiments, each R a is independently C19 alkyl. In some embodiments, each R a is independently C20 alkyl. [0229] In some embodiments, each R a is independently straight-chain C 6-20 alkyl. In some embodiments, each R a is independently straight-chain C 6-12 alkyl. In some embodiments, each R a is independently straight-chain C8-11 alkyl. In some embodiments, each R a is independently straight-chain C 9-10 alkyl.
• each R a is independently straight-chain C 6 alkyl. In some embodiments, each R a is independently straight-chain C 7 alkyl. In some embodiments, each R a is independently straight-chain C8 alkyl. In some embodiments, each R a is independently straight-chain C9 alkyl. In some embodiments, each R a is independently straight-chain C10 alkyl. In some embodiments, each R a is independently straight-chain C 11 alkyl. In some embodiments, each R a is independently straight-chain C12 alkyl. In some embodiments, each R a is independently straight-chain C13-20 alkyl. In some embodiments, each R a is independently straight-chain C15-20 alkyl.
• each R a is independently straight-chain C 13 alkyl. In some embodiments, each R a is independently straight-chain C14 alkyl. In some embodiments, each R a is independently straight-chain C15 alkyl. In some embodiments, each R a is independently straight- chain C 16 alkyl. In some embodiments, each R a is independently straight-chain C 17 alkyl. In some embodiments, each R a is independently straight-chain C 18 alkyl. In some embodiments, each R a is independently straight-chain C19 alkyl. In some embodiments, each R a is independently straight- chain C20 alkyl. [0230] In some embodiments, each R a is independently branched C 6-20 alkyl.
• each R a is independently branched C6-12 alkyl. In some embodiments, each R a is independently branched C8-11 alkyl. In some embodiments, each R a is independently branched C9- 10 alkyl. In some embodiments, each R a is independently branched C6 alkyl. In some embodiments, each R a is independently branched C 7 alkyl. In some embodiments, each R a is independently branched C 8 alkyl. In some embodiments, each R a is independently branched C 9 alkyl. In some embodiments, each R a is independently branched C10 alkyl. In some embodiments, each R a is independently branched C 11 alkyl.
• each R a is independently branched C 12 alkyl. In some embodiments, each R a is independently branched C 13-20 alkyl. In some embodiments, each R a is independently branched C15-20 alkyl. In some embodiments, each R a is independently branched C13 alkyl. In some embodiments, each R a is independently branched C 14 alkyl. In some embodiments, each R a is independently branched C 15 alkyl. In some embodiments, each R a is independently branched C16 alkyl. In some embodiments, each R a is independently branched C17 alkyl. In some embodiments, each R a is independently branched C18 alkyl.
• each R a is independently branched C 19 alkyl. In some embodiments, each R a is independently branched C 20 alkyl. [0231] In some embodiments, each R a is independently optionally substituted C6-20 alkenyl. In some embodiments, each R a is independently optionally substituted C 6-12 alkenyl. In some embodiments, each R a is independently optionally substituted C 8-11 alkenyl. In some embodiments, each R a is independently optionally substituted C9-10 alkenyl. In some embodiments, each R a is independently optionally substituted C6 alkenyl. In some embodiments, each R a is independently optionally substituted C 7 alkenyl.
• each R a is independently optionally substituted C8 alkenyl. In some embodiments, each R a is independently optionally substituted C9 alkenyl. In some embodiments, each R a is independently optionally substituted C 10 alkenyl. In some embodiments, each R a is independently optionally substituted C 11 alkenyl. In some embodiments, each R a is independently optionally substituted C12 alkenyl. In some embodiments, each R a is independently optionally substituted C13-20 alkenyl. In some embodiments, each R a is independently optionally substituted C 15-20 alkenyl. In some embodiments, each R a is independently optionally substituted C 13 alkenyl.
• each R a is independently optionally substituted C14 alkenyl. In some embodiments, each R a is independently optionally substituted C15 alkenyl. In some embodiments, each R a is independently optionally substituted C 16 alkenyl. In some embodiments, each R a is independently optionally substituted C17 alkenyl. In some embodiments, each R a is independently optionally substituted C18 alkenyl. In some embodiments, each R a is independently optionally substituted C19 alkenyl. In some embodiments, each R a is independently optionally substituted C 20 alkenyl. [0232] In some embodiments, each R a is independently C 6-20 alkenyl.
• each R a is independently C6-12 alkenyl. In some embodiments, each R a is independently C8-11 alkenyl. In some embodiments, each R a is independently C 9-10 alkenyl. In some embodiments, each R a is independently C 6 alkenyl. In some embodiments, each R a is independently C 7 alkenyl. In some embodiments, each R a is independently C8 alkenyl. In some embodiments, each R a is independently C9 alkenyl. In some embodiments, each R a is independently C10 alkenyl. In some embodiments, each R a is independently C 11 alkenyl. In some embodiments, each R a is independently C12 alkenyl.
• each R a is independently C13-20 alkenyl. In some embodiments, each R a is independently C15-20 alkenyl. In some embodiments, each R a is independently C 13 alkenyl. In some embodiments, each R a is independently C 14 alkenyl. In some embodiments, each R a is independently C 15 alkenyl. In some embodiments, each R a is independently C16 alkenyl. In some embodiments, each R a is independently C17 alkenyl. In some embodiments, each R a is independently C 18 alkenyl. In some embodiments, each R a is independently C 19 alkenyl. In some embodiments, each R a is independently C 20 alkenyl.
• each R a is independently straight-chain C6-20 alkenyl. In some embodiments, each R a is independently straight-chain C6-12 alkenyl. In some embodiments, each R a is independently straight-chain C 8-11 alkenyl. In some embodiments, each R a is independently straight-chain C9-10 alkenyl. In some embodiments, each R a is independently straight-chain C6 alkenyl. In some embodiments, each R a is independently straight-chain C7 alkenyl. In some embodiments, each R a is independently straight-chain C 8 alkenyl. In some embodiments, each R a is independently straight-chain C9 alkenyl.
• each R a is independently straight-chain C10 alkenyl. In some embodiments, each R a is independently straight-chain C11 alkenyl. In some embodiments, each R a is independently straight-chain C 12 alkenyl. In some embodiments, each R a is independently straight-chain C 13-20 alkenyl. In some embodiments, each R a is independently straight-chain C15-20 alkenyl. In some embodiments, each R a is independently straight-chain C13 alkenyl. In some embodiments, each R a is independently straight-chain C14 alkenyl. In some embodiments, each R a is independently straight-chain C 15 alkenyl. In some embodiments, each R a is independently straight-chain C16 alkenyl.
• each R a is independently straight-chain C17 alkenyl. In some embodiments, each R a is independently straight-chain C18 alkenyl. In some embodiments, each R a is independently straight-chain C19 alkenyl. In some embodiments, each R a is independently straight-chain C 20 alkenyl. [0234] In some embodiments, each R a is independently branched C 6-20 alkenyl. In some embodiments, each R a is independently branched C6-12 alkenyl. In some embodiments, each R a is independently branched C 8-11 alkenyl. In some embodiments, each R a is independently branched C 9-10 alkenyl.
• each R a is independently branched C 6 alkenyl. In some embodiments, each R a is independently branched C7 alkenyl. In some embodiments, each R a is independently branched C8 alkenyl. In some embodiments, each R a is independently branched C9 alkenyl. In some embodiments, each R a is independently branched C 10 alkenyl. In some embodiments, each R a is independently branched C11 alkenyl. In some embodiments, each R a is independently branched C12 alkenyl. In some embodiments, each R a is independently branched C 13-20 alkenyl. In some embodiments, each R a is independently branched C 15-20 alkenyl.
• each R a is independently branched C 13 alkenyl. In some embodiments, each R a is independently branched C14 alkenyl. In some embodiments, each R a is independently branched C 15 alkenyl. In some embodiments, each R a is independently branched C 16 alkenyl. In some embodiments, each R a is independently branched C 17 alkenyl. In some embodiments, each R a is independently branched C18 alkenyl. In some embodiments, each R a is independently branched C19 alkenyl. In some embodiments, each R a is independently branched C20 alkenyl.
• each R a is independently optionally substituted C 6-20 alkynyl. In some embodiments, each R a is independently optionally substituted C6-12 alkynyl. In some embodiments, each R a is independently optionally substituted C8-11 alkynyl. In some embodiments, each R a is independently optionally substituted C 9-10 alkynyl. In some embodiments, each R a is independently optionally substituted C6 alkynyl. In some embodiments, each R a is independently optionally substituted C7 alkynyl. In some embodiments, each R a is independently optionally substituted C 8 alkynyl. In some embodiments, each R a is independently optionally substituted C 9 alkynyl.
• each R a is independently optionally substituted C10 alkynyl. In some embodiments, each R a is independently optionally substituted C11 alkynyl. In some embodiments, each R a is independently optionally substituted C12 alkynyl. In some embodiments, each R a is independently optionally substituted C 13-20 alkynyl. In some embodiments, each R a is independently optionally substituted C15-20 alkynyl. In some embodiments, each R a is independently optionally substituted C13 alkynyl. In some embodiments, each R a is independently optionally substituted C14 alkynyl. In some embodiments, each R a is independently optionally substituted C 15 alkynyl.
• each R a is independently optionally substituted C 16 alkynyl. In some embodiments, each R a is independently optionally substituted C17 alkynyl. In some embodiments, each R a is independently optionally substituted C 18 alkynyl. In some embodiments, each R a is independently optionally substituted C 19 alkynyl. In some embodiments, each R a is independently optionally substituted C 20 alkynyl. [0236] In some embodiments, each R a is independently C6-20 alkynyl. In some embodiments, each R a is independently C6-12 alkynyl. In some embodiments, each R a is independently C8-11 alkynyl.
• each R a is independently C 9-10 alkynyl. In some embodiments, each R a is independently C6 alkynyl. In some embodiments, each R a is independently C7 alkynyl. In some embodiments, each R a is independently C8 alkynyl. In some embodiments, each R a is independently C 9 alkynyl. In some embodiments, each R a is independently C 10 alkynyl. In some embodiments, each R a is independently C 11 alkynyl. In some embodiments, each R a is independently C12 alkynyl. In some embodiments, each R a is independently C13-20 alkynyl. In some embodiments, each R a is independently C 15-20 alkynyl.
• each R a is independently C 13 alkynyl. In some embodiments, each R a is independently C 14 alkynyl. In some embodiments, each R a is independently C15 alkynyl. In some embodiments, each R a is independently C16 alkynyl. In some embodiments, each R a is independently C17 alkynyl. In some embodiments, each R a is independently C 18 alkynyl. In some embodiments, each R a is independently C19 alkynyl. In some embodiments, each R a is independently C20 alkynyl. [0237] In some embodiments, each R a is independently straight-chain C6-20 alkynyl.
• each R a is independently straight-chain C 6-12 alkynyl. In some embodiments, each R a is independently straight-chain C8-11 alkynyl. In some embodiments, each R a is independently straight-chain C9-10 alkynyl. In some embodiments, each R a is independently straight-chain C6 alkynyl. In some embodiments, each R a is independently straight-chain C 7 alkynyl. In some embodiments, each R a is independently straight-chain C 8 alkynyl. In some embodiments, each R a is independently straight-chain C9 alkynyl. In some embodiments, each R a is independently straight-chain C10 alkynyl.
• each R a is independently straight-chain C11 alkynyl. In some embodiments, each R a is independently straight-chain C 12 alkynyl. In some embodiments, each R a is independently straight-chain C13-20 alkynyl. In some embodiments, each R a is independently straight-chain C15-20 alkynyl. In some embodiments, each R a is independently straight-chain C13 alkynyl. In some embodiments, each R a is independently straight-chain C14 alkynyl. In some embodiments, each R a is independently straight-chain C 15 alkynyl. In some embodiments, each R a is independently straight-chain C 16 alkynyl.
• each R a is independently straight-chain C17 alkynyl. In some embodiments, each R a is independently straight-chain C 18 alkynyl. In some embodiments, each R a is independently straight-chain C 19 alkynyl. In some embodiments, each R a is independently straight-chain C 20 alkynyl. [0238] In some embodiments, each R a is independently optionally substituted C6-20 haloaliphatic. In some embodiments, each R a is independently optionally substituted C6-12 haloaliphatic. In some embodiments, each R a is independently optionally substituted C 6-10 haloaliphatic. In some embodiments, each R a is independently optionally substituted C6 haloaliphatic.
• each R a is independently optionally substituted C7 haloaliphatic. In some embodiments, each R a is independently optionally substituted C 8 haloaliphatic. In some embodiments, each R a is independently optionally substituted C 9 haloaliphatic. In some embodiments, each R a is independently optionally substituted C10 haloaliphatic. In some embodiments, each R a is independently optionally substituted C 15-20 haloaliphatic. In some embodiments, each R a is independently optionally substituted C 15 haloaliphatic. In some embodiments, each R a is independently optionally substituted C16 haloaliphatic. In some embodiments, each R a is independently optionally substituted C17 haloaliphatic.
• each R a is independently optionally substituted C 18 haloaliphatic. In some embodiments, each R a is independently optionally substituted C19 haloaliphatic. In some embodiments, each R a is independently optionally substituted C20 haloaliphatic. [0239] In some embodiments, each R a is independently optionally substituted straight-chain C 6-20 haloaliphatic. In some embodiments, each R a is independently optionally substituted straight- chain C6-12 haloaliphatic. In some embodiments, each R a is independently optionally substituted straight-chain C 6-10 haloaliphatic. In some embodiments, each R a is independently optionally substituted straight-chain C 6 haloaliphatic.
• each R a is independently optionally substituted straight-chain C7 haloaliphatic. In some embodiments, each R a is independently optionally substituted straight-chain C8 haloaliphatic. In some embodiments, each R a is independently optionally substituted straight-chain C 9 haloaliphatic. In some embodiments, each R a is independently optionally substituted straight-chain C10 haloaliphatic. In some embodiments, each R a is independently optionally substituted straight-chain C15-20 haloaliphatic. In some embodiments, each R a is independently optionally substituted straight-chain C15 haloaliphatic. In some embodiments, each R a is independently optionally substituted straight- chain C 16 haloaliphatic.
• each R a is independently optionally substituted straight-chain C17 haloaliphatic. In some embodiments, each R a is independently optionally substituted straight-chain C 18 haloaliphatic. In some embodiments, each R a is independently optionally substituted straight-chain C 19 haloaliphatic. In some embodiments, each R a is independently optionally substituted straight-chain C20 haloaliphatic. [0240] In some embodiments, each R a is independently optionally substituted branched C 6-20 haloaliphatic. In some embodiments, each R a is independently optionally substituted branched C6-12 haloaliphatic.
• each R a is independently optionally substituted branched C6-10 haloaliphatic. In some embodiments, each R a is independently optionally substituted branched C 6 haloaliphatic. In some embodiments, each R a is independently optionally substituted branched C 7 haloaliphatic. In some embodiments, each R a is independently optionally substituted branched C8 haloaliphatic. In some embodiments, each R a is independently optionally substituted branched C 9 haloaliphatic. In some embodiments, each R a is independently optionally substituted branched C 10 haloaliphatic. In some embodiments, each R a is independently optionally substituted branched C15-20 haloaliphatic.
• each R a is independently optionally substituted branched C15 haloaliphatic. In some embodiments, each R a is independently optionally substituted branched C 16 haloaliphatic. In some embodiments, each R a is independently optionally substituted branched C17 haloaliphatic. In some embodiments, each R a is independently optionally substituted branched C18 haloaliphatic. In some embodiments, each R a is independently optionally substituted branched C 19 haloaliphatic. In some embodiments, each R a is independently optionally substituted branched C20 haloaliphatic. [0241] In some embodiments, each R a is independently C6-20 haloaliphatic.
• each R a is independently C 6-12 haloaliphatic. In some embodiments, each R a is independently C 6- 10 haloaliphatic. In some embodiments, each R a is independently C 6 haloaliphatic. In some embodiments, each R a is independently C7 haloaliphatic. In some embodiments, each R a is independently C8 haloaliphatic. In some embodiments, each R a is independently C9 haloaliphatic. In some embodiments, each R a is independently C 10 haloaliphatic. In some embodiments, each R a is independently C15-20 haloaliphatic. In some embodiments, each R a is independently C15 haloaliphatic.
• each R a is independently C16 haloaliphatic. In some embodiments, each R a is independently C17 haloaliphatic. In some embodiments, each R a is independently C 18 haloaliphatic. In some embodiments, each R a is independently C 19 haloaliphatic. In some embodiments, each R a is independently C 20 haloaliphatic. [0242] In some embodiments, each R a is independently straight-chain C6-20 haloaliphatic. In some embodiments, each R a is independently straight-chain C 6-12 haloaliphatic. In some embodiments, each R a is independently straight-chain C 6-10 haloaliphatic.
• each R a is independently straight-chain C6 haloaliphatic. In some embodiments, each R a is independently straight-chain C7 haloaliphatic. In some embodiments, each R a is independently straight-chain C8 haloaliphatic. In some embodiments, each R a is independently straight-chain C 9 haloaliphatic. In some embodiments, each R a is independently straight-chain C10 haloaliphatic. In some embodiments, each R a is independently straight-chain C15-20 haloaliphatic. In some embodiments, each R a is independently straight-chain C 15 haloaliphatic. In some embodiments, each R a is independently straight-chain C 16 haloaliphatic.
• each R a is independently straight-chain C17 haloaliphatic. In some embodiments, each R a is independently straight-chain C 18 haloaliphatic. In some embodiments, each R a is independently straight-chain C 19 haloaliphatic. In some embodiments, each R a is independently straight-chain C 20 haloaliphatic. [0243] In some embodiments, each R a is independently optionally substituted C6-20 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, each R a is independently optionally substituted C 6-20 haloalkyl comprising 1-5 fluorine atoms.
• each R a is independently optionally substituted C6-20 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R a is independently optionally substituted C6-12 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, each R a is independently optionally substituted C 6-12 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R a is independently optionally substituted C6-12 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R a is independently optionally substituted C 6-10 haloalkyl comprising 1-7 fluorine atoms.
• each R a is independently optionally substituted C 6-10 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, R a is independently optionally substituted C6-10 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R a is independently optionally substituted C 6 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, each R a is independently optionally substituted C6 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R a is independently optionally substituted C6 haloalkyl comprising 1-3 fluorine atoms.
• each R a is independently optionally substituted C7 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, each R a is independently optionally substituted C 7 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R a is independently optionally substituted C7 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R a is independently optionally substituted C 8 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, each R a is independently optionally substituted C 8 haloalkyl comprising 1-5 fluorine atoms.
• each R a is independently optionally substituted C8 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R a is independently optionally substituted C 9 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, each R a is independently optionally substituted C9 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R a is independently optionally substituted C9 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R a is independently optionally substituted C 10 haloalkyl comprising 1-7 fluorine atoms.
• each R a is independently optionally substituted C10 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R a is independently optionally substituted C 10 haloalkyl comprising 1-3 fluorine atoms. [0244] In some embodiments, each R a is independently optionally substituted C15-20 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, each R a is independently optionally substituted C 15-20 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R a is independently optionally substituted C15-20 haloalkyl comprising 1-3 fluorine atoms.
• each R a is independently optionally substituted C15 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, each R a is independently optionally substituted C 15 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R a is independently optionally substituted C15 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R a is independently optionally substituted C 16 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, each R a is independently optionally substituted C 16 haloalkyl comprising 1-5 fluorine atoms.
• each R a is independently optionally substituted C16 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R a is independently optionally substituted C 17 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, each R a is independently optionally substituted C17 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R a is independently optionally substituted C17 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R a is independently optionally substituted C18 haloalkyl comprising 1-7 fluorine atoms.
• each R a is independently optionally substituted C 18 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R a is independently optionally substituted C18 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R a is independently optionally substituted C 19 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, each R a is independently optionally substituted C 19 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R a is independently optionally substituted C19 haloalkyl comprising 1-3 fluorine atoms.
• each R a is independently optionally substituted C 20 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, each R a is independently optionally substituted C20 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R a is independently optionally substituted C20 haloalkyl comprising 1-3 fluorine atoms. [0245] In some embodiments, each R a is independently C 6-20 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, each R a is independently C6-20 haloalkyl comprising 1-5 fluorine atoms.
• each R a is y C 6-20 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R a is independently C 6-12 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, each R a is independently C6-12 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R a is independently C6-12 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R a is independently C 6-10 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, each R a is independently C6-10 haloalkyl comprising 1-5 fluorine atoms.
• each R a is independently C6-10 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R a is independently C 6 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, each R a is independently C6 haloalkyl comprising 1-5 fluorine atoms. some embodiments, each R a is independently C6 haloalkyl comprising 1-3 fluorine atoms. some embodiments, each R a is independently C 7 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, each R a is independently C 7 haloalkyl comprising 1-5 fluorine atoms.
• each R a is independently C7 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R a is independently C8 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, each R a is independently C 8 haloalkyl comprising 1-5 fluorine atoms. some embodiments, each R a is independently C8 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R a is independently C9 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, each R a is independently C9 haloalkyl comprising 1-5 fluorine atoms.
• each R a is independently C 9 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R a is independently C 10 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, each R a is independently C10 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R a is independently C 10 haloalkyl comprising 1-3 fluorine atoms. [0246] In some embodiments, each R a is independently C15-20 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, each R a is independently C15-20 haloalkyl comprising 1-5 fluorine atoms.
• each R a is independently C 15-20 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R a is independently C15 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, each R a is independently C15 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R a is independently C 15 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R a is independently C 16 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, each R a is independently C16 haloalkyl comprising 1-5 fluorine atoms.
• each R a is independently C 16 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R a is independently C 17 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, each R a is independently C17 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R a is independently C17 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R a is independently C 18 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, each R a is independently C18 haloalkyl comprising 1-5 fluorine atoms.
• each R a is independently C18 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R a is independently C 19 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, each R a is independently C19 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R a is independently C19 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R a is independently C 20 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, each R a is independently C 20 haloalkyl comprising 1-5 fluorine atoms.
• each R a is independently C20 haloalkyl comprising 1-3 fluorine atoms. [0247] In some embodiments, each R a is independently straight-chain C 6-20 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, each R a is independently straight-chain C6-20 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R a is independently straight-chain C6- 20 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R a is independently straight-chain C 6-12 haloalkyl comprising 1-7 fluorine atoms.
• each R a is independently straight-chain C 6-12 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R a is independently straight-chain C6-12 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R a is independently straight-chain C 6-10 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, each R a is independently straight-chain C 6-10 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R a is independently straight-chain C6- 10 haloalkyl comprising 1-3 fluorine atoms.
• each R a is independently straight-chain C 6 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, each R a is independently straight-chain C6 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R a is independently straight-chain C6 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R a is independently straight-chain C 7 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, each R a is independently straight-chain C 7 haloalkyl comprising 1-5 fluorine atoms.
• each R a is independently straight-chain C7 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R a is independently straight-chain C 8 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, each R a is independently straight- chain C8 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R a is independently straight-chain C8 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R a is independently straight-chain C 9 haloalkyl comprising 1-7 fluorine atoms.
• each R a is independently straight-chain C9 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R a is independently straight-chain C9 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R a is independently straight-chain C 10 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, each R a is independently straight-chain C10 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R a is independently straight-chain C10 haloalkyl comprising 1-3 fluorine atoms.
• each R a is independently straight-chain C 15-20 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, each R a is independently straight-chain C15-20 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R a is independently straight-chain C 15-20 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R a is independently straight-chain C15 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, each R a is independently straight-chain C15 haloalkyl comprising 1-5 fluorine atoms.
• each R a is independently straight-chain C15 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R a is independently straight-chain C 16 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, each R a is independently straight-chain C 16 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R a is independently straight-chain C16 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R a is independently straight-chain C 17 haloalkyl comprising 1-7 fluorine atoms.
• each R a is independently straight- chain C17 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R a is independently straight-chain C17 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R a is independently straight-chain C 18 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, each R a is independently straight-chain C18 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R a is independently straight-chain C18 haloalkyl comprising 1-3 fluorine atoms.
• each R a is independently straight-chain C 19 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, each R a is independently straight-chain C 19 haloalkyl comprising 1-5 fluorine atoms. In some embodiments, each R a is independently straight- chain C 19 haloalkyl comprising 1-3 fluorine atoms. In some embodiments, each R a is independently straight-chain C 20 haloalkyl comprising 1-7 fluorine atoms. In some embodiments, each R a is independently straight-chain C20 haloalkyl comprising 1-5 fluorine atoms.
• each R a is independently straight-chain C20 haloalkyl comprising 1-3 fluorine atoms. [0249] In some embodiments, each R a is independently optionally substituted 3- to 12-membered cycloaliphatic. In some embodiments, each R a is independently optionally substituted 3- to 7- membered cycloaliphatic. In some embodiments, each R a is independently optionally substituted 4- to 7-membered cycloaliphatic. In some embodiments, each R a is independently optionally substituted 5- to 7-membered cycloaliphatic. In some embodiments, each R a is independently optionally substituted 6- to 7-membered cycloaliphatic.
• each R a is optionally substituted cyclopentyl. In some embodiments, each R a is optionally substituted cyclohexyl. In some embodiments, each R a is independently cyclohexyl substituted with R ⁇ ⁇ ⁇ ⁇ In some embodiments, each R a is independently cyclohexyl substituted with a 5- or 6-membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which is further substituted with –(CH 2 ) 0–2 R ⁇ .
• each R a is independently cyclohexyl substituted with cyclohexyl, which is further substituted with C 1-6 aliphatic. In some embodiments, each R a is optionally substituted cycloheptyl. [0250] In some embodiments, each R a is optionally substituted 1-adamantyl. In some embodiments, each R a is optionally substituted 2-adamantyl. In some embodiments, each R a is independently optionally substituted sterolyl. In some embodiments, each R a is independently optionally substituted cholesterolyl. In some embodiments, each R a is optionally substituted phenyl. In some embodiments, each R a is independently phenyl substituted with R ⁇ .
• each R a is independently phenyl substituted with C1-6 aliphatic.
• each of -L 3 -R”, -L 3 -R, and -L 3a -R a is independently .
• R 7 is optionally substituted C 4-10 aliphatic or C 4-10 haloaliphatic. In some embodiments, R 7 is optionally substituted C4-10 aliphatic.
• R 7 is optionally substituted C4-8 aliphatic. In some embodiments, R 7 is optionally substituted C 4-6 aliphatic. In some embodiments, R 7 is optionally substituted C 4 aliphatic. In some embodiments, R 7 is optionally substituted C 5 aliphatic. In some embodiments, R 7 is optionally substituted C6 aliphatic. In some embodiments, R 7 is optionally substituted C7 aliphatic. In some embodiments, R 7 is optionally substituted C8 aliphatic. In some embodiments, R 7 is optionally substituted C 9 aliphatic. In some embodiments, R 7 is optionally substituted C10 aliphatic.
• R 7 is optionally substituted C4-10 haloaliphatic. In some embodiments, R 7 is optionally substituted C 4-8 haloaliphatic. In some embodiments, R 7 is optionally substituted C 4-6 haloaliphatic. In some embodiments, R 7 is optionally substituted C 4 haloaliphatic. In some embodiments, R 7 is optionally substituted C5 haloaliphatic. In some embodiments, R 7 is optionally substituted C 6 haloaliphatic. In some embodiments, R 7 is optionally substituted C 7 haloaliphatic. In some embodiments, R 7 is optionally substituted C 8 haloaliphatic.
• R 7 is optionally substituted C9 haloaliphatic. In some embodiments, R 7 is optionally substituted C10 haloaliphatic.
• R 8 is optionally substituted C 2-8 aliphatic or C 2-8 haloaliphatic. In some embodiments, R 8 is optionally substituted C 2-8 aliphatic. In some embodiments, R 8 is optionally substituted C2-6 aliphatic. In some embodiments, R 8 is optionally substituted C2-4 aliphatic. In some embodiments, R 8 is optionally substituted C 2 aliphatic.
• R 8 is optionally substituted C 3 aliphatic. In some embodiments, R 8 is optionally substituted C 4 aliphatic. In some embodiments, R 8 is optionally substituted C5 aliphatic. In some embodiments, R 8 is optionally substituted C6 aliphatic. In some embodiments, R 8 is optionally substituted C 7 aliphatic. In some embodiments, R 8 is optionally substituted C 8 aliphatic. [0255] In some embodiments, R 8 is optionally substituted C 2-8 haloaliphatic. In some embodiments, R 8 is optionally substituted C2-6 haloaliphatic. In some embodiments, R 8 is optionally substituted C 2-4 haloaliphatic.
• R 8 is optionally substituted C 2 haloaliphatic. In some embodiments, R 8 is optionally substituted C3 haloaliphatic. In some embodiments, R 8 is optionally substituted C4 haloaliphatic. In some embodiments, R 8 is optionally substituted C 5 haloaliphatic. In some embodiments, R 8 is optionally substituted C 6 haloaliphatic. In some embodiments, R 8 is optionally substituted C 7 haloaliphatic. In some embodiments, R 8 is optionally substituted C8 haloaliphatic. [0256] In some embodiments of any of Formulae A’, A, I”, I’, I, II”, II’, II, III’, and III, p is 0 or 1.
• each of -L 3 -R”, -L 3 -R, and -L 3a -R a is independently selected from the group consisting of , , [0258] In some embodiments of any of Formulae A’, A, I”, I’, I, II”, II’, II, III’ and III, each of --L 3 -R”, L 3 -R, and -L 3a -R a is independently selected from the group consisting of , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,
• any of Formulae A, I’, I, II”, II’, II, III’, and III all of -L 3 -R moieties are the same. In some embodiments of any of Formulae A, I’, and I, two of -L 3 -R moieties are the same, both of which are different from the third -L 3 -R moiety. In some embodiments of any of Formulae II”, II’, II, III’, and III, two of -L 3 -R moieties are the same, both of which are different from the other two -L 3 -R moieties. [0260] In some embodiments of any of Formulae A’, A, I”, I’, I, II”, II’, II, III’, and III, each of a is independently selected from the group consisting of
• any of Formulae A’, A, I”, I’, I, II”, II’, II, III’, and III each of is independently selected from the group consisting of , , , , , , , , .
• the two moieties are the same. In some embodiments, the two moieties are different.
• R 1 is hydrogen, optionally substituted phenyl, optionally substituted 3- to 7-membered cycloaliphatic, optionally substituted 3- to 7-membered heterocyclyl comprising 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 5- to 6-membered monocyclic heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 8- to 10-membered bicyclic heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, -OR 2 , -C(O)OR 2 , -C(O)SR 2 , -OC(O)R 2 , -OC(O)OR 2 , -CN, -N(R 2 ) 2 , -C(O)N(R 2 ) 2 , -S(O) 2 N(R 2 ) 2 , -NR 2
• R 1 is hydrogen, optionally substituted phenyl, an optionally substituted 3- to 7-membered cycloaliphatic ring, an optionally substituted 3- to 7-membered heterocyclic ring comprising 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 5- to 6-membered monocyclic heteroaryl ring comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 8- to 10-membered bicyclic heteroaryl ring comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, -OR 2 , -C(O)OR 2 , -C(O)SR 2 , -OC(O)R 2 , -OC(O)OR 2 , -CN, -N(R 2 ) 2 , -C(O)N(R 2 ) 2 , -S(O) 2 N(R 2 )
• R 1 is hydrogen, a 3- to 7-membered cycloaliphatic ring, a 3- to 7-membered heterocyclic ring comprising 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, -OR 2 , -C(O)OR 2 , -C(O)SR 2 , -OC(O)R 2 , -OC(O)OR 2 , -CN, -N(R 2 ) 2 , -C(O)N(R 2 ) 2 , -NR 2 C(O)R 2 , -OC(O)N(R 2 ) 2 , -N(R 2 )C(O)OR 2 , -NR 2 S(O) 2 R 2 , -NR 2 C(O)N(R 2 ) 2 , -NR 2 C(S)N(R 2 ) 2 , -NR 2 C(NR 2 )N(R 2 ) 2 ,
• R 1 is hydrogen, optionally substituted phenyl, optionally substituted 3- to 7-membered cycloaliphatic, optionally substituted 3- to 7-membered heterocyclyl comprising 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 5- to 6-membered monocyclic heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 8- to 10-membered bicyclic heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, -OR 2 , -C(O)OR 2 , -C(O)SR 2 , -OC(O)R 2 , -OC(O)OR 2 , -CN, -N(R 2 ) 2 , -C(O)N(R 2 ) 2 , -S(O) 2 N(R 2 ) 2 , -NR 2 C(O)R 2 , -OC(O)N(R 2 , -NR 2 C(O
• cycloaliphatic or heterocyclyl ring is optionally substituted with 1-4 R 2 or R 3 groups.
• R 1 is hydrogen, optionally substituted phenyl, optionally substituted 5- to 6-membered monocyclic heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 8- to 10-membered bicyclic heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, -OR 2 , -C(O)OR 2 , -C(O)SR 2 , -OC(O)R 2 , -OC(O)OR 2 , -CN, -N(R 2 ) 2 , -C(O)N(R 2 ) 2 , -S(O) 2 N(R 2 ) 2 , -NR 2 C(O)R 2 , -OC(O)N(R 2 ) 2 , -N(R 2 )C(O)OR 2 , -NR 2 S(O) 2 R 2 , -NR 2 C(O)N(R 2 ) 2 , -NR 2 C(O)
• R 1 is hydrogen. [0271] In some embodiments, R 1 is optionally substituted phenyl. In some embodiments, R 1 is phenyl substituted with one or more -OR°, -C(O)N(R°) 2 , or C 1-4 alkyl optionally substituted with one or more –OH, -OR ⁇ , –C(O)NH 2 , –C(O)NHR ⁇ , or –C(O)NR ⁇ 2 . In some embodiments, R 1 is phenyl substituted with -C(O)N(R°) 2 , wherein one R° is further substituted with –C(O)NH2.
• R 1 is phenyl substituted with C 1-4 alkyl. [0272] In some embodiments, R 1 is optionally substituted 3- to 7-membered cycloaliphatic. In some embodiments, R 1 is optionally substituted 4- to 7-membered cycloaliphatic. In some embodiments, R 1 is optionally substituted 5- to 6-membered cycloaliphatic. In some embodiments, R 1 is optionally substituted 3-membered cycloaliphatic. In some embodiments, R 1 is optionally substituted 4-membered cycloaliphatic. In some embodiments, R 1 is optionally substituted 5-membered cycloaliphatic.
• R 1 is optionally substituted 6- membered cycloaliphatic. In some embodiments, R 1 is optionally substituted 7-membered cycloaliphatic. In some embodiments, R 1 is optionally substituted cyclopentyl. In some embodiments, R 1 is optionally substituted cyclohexyl. In some embodiments, R 1 is optionally substituted cycloheptyl. [0273] In some embodiments, R 1 is optionally substituted 3- to 7-membered heterocyclyl comprising 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 1 is optionally substituted 4- to 7-membered heterocyclyl comprising 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
• R 1 is optionally substituted 3-membered heterocyclyl comprising 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, R 1 is optionally substituted 4-membered heterocyclyl comprising 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, R 1 is optionally substituted 5-membered heterocyclyl comprising 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 1 is optionally substituted 5-membered heterocyclyl comprising 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
• R 1 is optionally substituted 5- membered heterocyclyl comprising 1 heteroatom selected from nitrogen, oxygen, and sulfur.
• R 1 is optionally substituted 6-membered heterocyclyl comprising 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
• R 1 is optionally substituted 6-membered heterocyclyl comprising 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
• R 1 is optionally substituted 6-membered heterocyclyl comprising 1 heteroatom selected from nitrogen, oxygen, and sulfur.
• R 1 is optionally substituted 7-membered heterocyclyl comprising 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
• R 1 is optionally substituted 7-membered heterocyclyl comprising 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
• R 1 is optionally substituted 7- membered heterocyclyl comprising 1 heteroatom selected from nitrogen, oxygen, and sulfur.
• R 1 is an optionally substituted group selected from morpholinyl, pyrrolidinyl, thiomorpholinyl, piperidinyl, piperazinyl, and imidazolidinyl.
• R 1 is optionally substituted morpholinyl.
• R 1 is optionally substituted pyrrolidinyl.
• R 1 is optionally substituted thiomorpholinyl.
• R 1 is an optionally substituted piperidinyl.
• R 1 is optionally substituted piperazinyl.
• R 1 is optionally substituted imidazolidinyl.
• R 1 is optionally substituted 5- to 6-membered monocyclic heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
• R 1 is optionally substituted 5-membered monocyclic heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
• R 1 is optionally substituted 5-membered monocyclic heteroaryl comprising 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
• R 1 is optionally substituted 5-membered monocyclic heteroaryl comprising 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
• R 1 is optionally substituted 5- membered monocyclic heteroaryl comprising 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, R 1 is optionally substituted 6-membered monocyclic heteroaryl comprising 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 1 is optionally substituted 6-membered monocyclic heteroaryl comprising 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 1 is optionally substituted 6-membered monocyclic heteroaryl comprising 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, R 1 is optionally substituted pyridinyl or triazolyl.
• R 1 is optionally substituted pyridinyl. In some embodiments, R 1 is optionally substituted triazolyl. [0275] In some embodiments, R 1 is optionally substituted 8- to 10-membered bicyclic heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 1 is optionally substituted 8-membered bicyclic heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 1 is optionally substituted 8-membered bicyclic heteroaryl comprising 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
• R 1 is optionally substituted 8-membered bicyclic heteroaryl comprising 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 1 is optionally substituted 8-membered bicyclic heteroaryl comprising 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, R 1 is optionally substituted 9-membered bicyclic heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
• R 1 is 9-membered bicyclic heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with one or more -OR°, -C(O)N(R°) 2 , or C1-4 alkyl optionally substituted with one or more -OH or -OR ⁇ .
• R 1 is optionally substituted 9-membered bicyclic heteroaryl comprising 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
• R 1 is optionally substituted 9-membered bicyclic heteroaryl comprising 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
• R 1 is optionally substituted 9-membered bicyclic heteroaryl comprising 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, R 1 is optionally substituted 10-membered bicyclic heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 1 is optionally substituted 10- membered bicyclic heteroaryl comprising 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 1 is optionally substituted 10-membered bicyclic heteroaryl comprising 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 1 is optionally substituted 10-membered bicyclic heteroaryl comprising 1 heteroatom selected from nitrogen, oxygen, and sulfur.
• R 1 is optionally substituted indazolyl.
• R 1 is hydrogen, optionally substituted phenyl, optionally substituted 3- to 7-membered cycloaliphatic, optionally substituted 3- to 7-membered heterocyclyl comprising 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 5- to 6-membered monocyclic heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 8- to 10-membered bicyclic heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, -OR 2 , -C(O)OR 2 , -C(O)SR 2 , -N(R 2 ) 2 , -C(O)N(R 2 ) 2 , -S(O) 2 N(R 2 ) 2 , -NR 2 C(O)R 2 , -NR 2 S(O) 2 R 2 , -NR 2
• R 1 is hydrogen, optionally substituted phenyl, optionally substituted 5- to 6-membered monocyclic heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 8- to 10-membered bicyclic heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, -OR 2 , -C(O)OR 2 , -C(O)SR 2 , -N(R 2 ) 2 , -C(O)N(R 2 ) 2 , -S(O) 2 N(R 2 ) 2 , -NR 2 C(O)R 2 , -NR 2 S(O) 2 R 2 , -NR 2 C(O)N(R 2 ) 2 , -CR 2 (R 3 ) 2 , -OP(O)(OR 2 ) 2 , -P(O)(OR 2 ) 2 , or a ring selected from 3- to 7- membered
• R 1 is -OR 2 , -OC(O)OR 2 , -C(O)OR 2 , -C(O)SR 2 , -N(R 2 ) 2 , -C(O)N(R 2 ) 2 , -S(O) 2 N(R 2 ) 2 , -NR 2 C(O)R 2 , -NR 2 S(O) 2 R 2 , -NR 2 C(O)N(R 2 ) 2 , -NR 2 C(S)N(R 2 ) 2 , -NR 2 C(NR 2 )N(R 2 ) 2 , or -CR 2 (OR 2 )R 3 .
• R 1 is -C(O)OR 2 , -C(O)SR 2 , -N(R 2 ) 2 , -C(O)N(R 2 ) 2 , -S(O) 2 N(R 2 ) 2 , -NR 2 C(O)R 2 , or -CR 2 (OR 2 )R 3 .
• R 1 is some embodiments, R 1 is -OR 2 .
• R 1 is -OC(O)OR 2 .
• R 1 is -C(O)OR 2 .
• R 1 is -C(O)SR 2 .
• R 1 is -N(R 2 ) 2 .
• R 1 is -C(O)N(R 2 ) 2 . In some embodiments, R 1 is -S(O) 2 N(R 2 ) 2 . In some embodiments, R 1 is -NR 2 C(O)R 2 . In some embodiments, R 1 is -NR 2 S(O) 2 R 2 . In some embodiments, R 1 is -NR 2 C(O)N(R 2 ) 2 . In some embodiments, R 1 is -NR 2 C(S)N(R 2 ) 2 . In some embodiments, R 1 is -NR 2 C(NR 2 )N(R 2 ) 2 . In some embodiments, . In some embodiments, R 1 is -CR 2 (R 3 ) 2 .
• R 1 is -CR 2 (OR 2 )R 3 . In some embodiments, R 1 is -OP(O)(OR 2 ) 2 . In some embodiments, R 1 is -P(O)(OR 2 ) 2 . In some embodiments, R 1 is . In some embodiments, R 1 is . In some embodiments, R 1 is . In some embodiments, R 1 is . In some embodiments, R 1 is . In some embodiments, . ., . . .
• R 1 is selected from the group consisting of , , , , , [ , , , , , , , , [0281]
• each R 2 is independently hydrogen, oxo, -CN, -NO 2 , -OR 4 , -S(O) 2 R 4 , -S(O) 2 N(R 4 ) 2 , -(CH 2 )n-R 4 , or an optionally substituted group selected from C1-6 aliphatic, phenyl, 3- to 7- membered cycloaliphatic, 5- to 6-membered monocyclic heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered heterocyclyl comprising 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two occurrences of R 2 , taken together with the atom(s) to which they
• each R 2 is independently hydrogen, -CN, -NO2, -OR 4 , -S(O) 2 R 4 , -S(O) 2 N(R 4 ) 2 , -(CH 2 )n-R 4 , or an optionally substituted group selected from C 1-6 aliphatic, phenyl, 3- to 7-membered cycloaliphatic, 5- to 6-membered monocyclic heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered heterocyclyl comprising 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two occurrences of R 2 , taken together with the atom(s) to which they are attached, form optionally substituted 4- to 7-membered heterocyclyl comprising 0- 1 additional heteroatom selected from nitrogen, oxygen, and sulfur.
• each R 2 is independently hydrogen, -CN, -NO2, -OR 4 , -S(O) 2 R 4 , -S(O) 2 N(R 4 ) 2 , -(CH 2 )n-R 4 , or an optionally substituted group selected from C 1-6 aliphatic, a 3- to 7-membered cycloaliphatic ring, and a 3- to 7-membered heterocyclic ring comprising 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two occurrences of R 2 , taken together with the atom(s) to which they are attached, form an optionally substituted 4- to 7-membered heterocyclic ring comprising 0-1 additional heteroatom selected from nitrogen, oxygen, and sulfur.
• each R 2 is independently hydrogen, oxo, -CN, -NO2, -OR 4 , -S(O) 2 R 4 , -S(O) 2 N(R 4 ) 2 , -(CH 2 )n-R 4 , or an optionally substituted group selected from phenyl, 3- to 7-membered cycloaliphatic, 5- to 6-membered monocyclic heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered heterocyclyl comprising 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two occurrences of R 2 , taken together with the atom(s) to which they are attached, form optionally substituted 4- to 7-membered heterocyclyl comprising 0-1 additional heteroatom selected from nitrogen, oxygen, and sulfur.
• each R 2 is independently hydrogen, -(CH 2 )n-R 4 , or an optionally substituted group selected from C 1-6 aliphatic, phenyl, and 5- to 6-membered monocyclic heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two occurrences of R 2 , taken together with the atom(s) to which they are attached, form optionally substituted 4- to 7-membered heterocyclyl comprising 0-1 additional heteroatom selected from nitrogen, oxygen, and sulfur.
• each R 2 is independently hydrogen, oxo, -(CH 2 )n-R 4 , or an optionally substituted group selected from phenyl, and 5- to 6- membered monocyclic heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two occurrences of R 2 , taken together with the atom(s) to which they are attached, form optionally substituted 4- to 7-membered heterocyclyl comprising 0-1 additional heteroatom selected from nitrogen, oxygen, and sulfur.
• each R 2 is independently hydrogen, -(CH 2 ) n -R 4 , or optionally substituted C1-6 aliphatic.
• each R 2 is independently hydrogen, or -(CH 2 )n-R 4 . [0287] In some embodiments, each R 2 is hydrogen. In some embodiments, each R 2 is oxo. In some embodiments, each R 2 is -CN. [0288] In some embodiments, each R 2 is independently -(CH 2 ) n -R 4 . In some embodiments, each R 2 is independently -(CH 2 )-R 4 , -(CH 2 ) 2 -R 4 , or -(CH 2 ) 3 -R 4 . In some embodiments, each R 2 is independently -(CH 2 ) 2 -R 4 or -(CH 2 ) 3 -R 4 .
• each R 2 is independently -(CH 2 )-R 4 . In some embodiments, each R 2 is independently -(CH 2 ) 2 -R 4 . In some embodiments, each R 2 is independently -(CH 2 ) 3 -R 4 . In some embodiments, each R 2 is independently -(CH 2 )4-R 4 . [0289] In some embodiments, each R 2 is independently optionally substituted C 1-6 aliphatic. In some embodiments, each R 2 is independently optionally substituted C1-4 aliphatic. In some embodiments, each R 2 is independently optionally substituted C1 aliphatic. In some embodiments, each R 2 is independently optionally substituted C 2 aliphatic.
• each R 2 is independently optionally substituted C 3 aliphatic. In some embodiments, each R 2 is independently optionally substituted C4 aliphatic. In some embodiments, each R 2 is independently optionally substituted C 5 aliphatic. In some embodiments, each R 2 is independently optionally substituted C 6 aliphatic. In some embodiments, each R 2 is methyl. In some embodiments, each R 2 is ethyl. [0290] In some embodiments, each R 2 is optionally substituted phenyl.
• R 2 is phenyl substituted with one or more -OR ⁇ , -C(O)N(R ⁇ ) 2 , or C 1-4 alkyl optionally substituted with one or more -OH or -OR ⁇ . In some embodiments, R 2 is phenyl substituted with C1-4 alkyl. [0291] In some embodiments, R 2 is optionally substituted 5- to 6-membered monocyclic heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 is optionally substituted 5-membered monocyclic heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
• R 2 is optionally substituted 5-membered monocyclic heteroaryl comprising 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 is optionally substituted 5-membered monocyclic heteroaryl comprising 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 is optionally substituted 5- membered monocyclic heteroaryl comprising 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 is optionally substituted 6-membered monocyclic heteroaryl comprising 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 is optionally substituted 6-membered monocyclic heteroaryl comprising 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
• R 2 is optionally substituted 6-membered monocyclic heteroaryl comprising 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 is optionally substituted pyridinyl. [0292] In some embodiments, two occurrences of R 2 , taken together with the atom(s) to which they are attached, form optionally substituted 4- to 7-membered heterocyclyl comprising 0-1 additional heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, two occurrences of R 2 , taken together with the atom(s) to which they are attached, form optionally substituted 5- to 6-membered heterocyclyl comprising 0-1 additional heteroatom selected from nitrogen, oxygen, and sulfur.
• two occurrences of R 2 taken together with the atom(s) to which they are attached, form 5- to 6-membered heterocyclyl comprising 0-1 additional heteroatom selected from nitrogen, oxygen, and sulfur substituted with one or more - OR°, -C(O)N(R°) 2 , or C 1-4 alkyl optionally substituted with one or more -OH or -OR ⁇ .
• two occurrences of R 2 taken together with the atom(s) to which they are attached, form optionally substituted 4-membered heterocyclyl comprising 0 additional heteroatom selected from nitrogen, oxygen, and sulfur.
• two occurrences of R 2 taken together with the atom(s) to which they are attached, form optionally substituted 5-membered heterocyclyl comprising 0-1 additional heteroatom selected from nitrogen, oxygen, and sulfur.
• two occurrences of R 2 taken together with the atom(s) to which they are attached, form optionally substituted 6-membered heterocyclyl comprising 0-1 additional heteroatom selected from nitrogen, oxygen, and sulfur.
• two occurrences of R 2 taken together with the atom(s) to which they are attached, form 6-membered heterocyclyl comprising 0-1 additional heteroatom selected from nitrogen, oxygen, and sulfur substituted with one or more -OR°, -C(O)N(R°) 2 , or C1-4 alkyl optionally substituted with one or more -OH or -OR ⁇ .
• two occurrences of R 2 taken together with the atom(s) to which they are attached, form optionally substituted 7-membered heterocyclyl comprising 0-1 additional heteroatom selected from nitrogen, oxygen, and sulfur.
• each R 3 is independently -(CH 2 ) n -R 4 ; or two occurrences of R 3 , taken together with the atom(s) to which they are attached, form optionally substituted 5- to 6-membered heterocyclyl comprising 0-1 additional heteroatom selected from nitrogen, oxygen, and sulfur.
• each R 3 is independently R 4 .
• each R 3 is independently -(CH 2 )-R 4 . In some embodiments, each R 3 is independently -(CH 2 ) 2 -R 4 . In some embodiments, each R 3 is independently -(CH 2 ) 3 -R 4 . In some embodiments, each R 3 is independently -(CH 2 )4-R 4 . [0295] In some embodiments, two occurrences of R 3 , taken together with the atom(s) to which they are attached, form optionally substituted 5- to 6-membered heterocyclyl comprising 0-1 additional heteroatom selected from nitrogen, oxygen, and sulfur.
• two occurrences of R 3 taken together with the atom(s) to which they are attached, form optionally substituted 5-membered heterocyclyl comprising 0-1 additional heteroatom selected from nitrogen, oxygen, and sulfur.
• two occurrences of R 3 taken together with the atom(s) to which they are attached, form optionally substituted 6-membered heterocyclyl comprising 0-1 additional heteroatom selected from nitrogen, oxygen, and sulfur.
• each R 4 is independently hydrogen, -OR 5 , -N(R 5 ) 2 , -OC(O)R 5 , -OC(O)OR 5 , -CN, -C(O)N(R 5 ) 2 , -NR 5 C(O)R 5 , -OC(O)N(R 5 ) 2 , -N(R 5 )C(O)OR 5 , -NR 5 S(O) 2 R 5 , -NR 5 C(O)N(R 5 ) 2 , -NR 5 C(S)N(R 5 ) 2 , -NR 5 C(NR 5 )N(R 5 ) 2 , .
• each R 4 is independently -OR 5 or -N(R 5 ) 2 .
• each R 4 is hydrogen.
• each R 4 is independently -OR 5 .
• each R 4 is independently -N(R 5 ) 2 .
• each R 4 is independently -C(O)N(R 5 ) 2 .
• each R 4 is independently -NR 5 C(O)R 5 .
• each R 4 is independently -NR 5 C(S)N(R 5 ) 2 .
• each R 4 is independently .
• each R 5 is independently hydrogen, or optionally substituted C 1-6 aliphatic; or two occurrences of R 5 , taken together with the atom(s) to which they are attached, form optionally substituted 4- to 7-membered heterocyclyl comprising 0-1 additional heteroatom selected from nitrogen, oxygen, and sulfur.
• each R 5 is independently hydrogen, or optionally substituted C 1-6 aliphatic.
• each R 5 is hydrogen.
• each R 5 is independently optionally substituted C1-6 aliphatic.
• each R 5 is independently optionally substituted C 1-4 aliphatic. In some embodiments, each R 5 is independently optionally substituted C 1 aliphatic. In some embodiments, each R 5 is independently optionally substituted C2 aliphatic. In some embodiments, each R 5 is independently optionally substituted C3 aliphatic. In some embodiments, each R 5 is independently optionally substituted C 4 aliphatic. In some embodiments, each R 5 is independently optionally substituted C5 aliphatic. In some embodiments, each R 5 is independently optionally substituted C6 aliphatic. In some embodiments, each R 5 is methyl. In some embodiments, each R 5 is ethyl.
• two occurrences of R 5 taken together with the atom(s) to which they are attached, form optionally substituted 4- to 7-membered heterocyclyl comprising 0-1 additional heteroatom selected from nitrogen, oxygen, and sulfur.
• two occurrences of R 5 taken together with the atom(s) to which they are attached, form optionally substituted 5- to 6-membered heterocyclyl comprising 0-1 additional heteroatom selected from nitrogen, oxygen, and sulfur.
• two occurrences of R 5 , taken together with the atom(s) to which they are attached form optionally substituted 4-membered heterocyclyl comprising 0 additional heteroatom selected from nitrogen, oxygen, and sulfur.
• two occurrences of R 5 taken together with the atom(s) to which they are attached, form optionally substituted 5-membered heterocyclyl comprising 0-1 additional heteroatom selected from nitrogen, oxygen, and sulfur.
• two occurrences of R 5 taken together with the atom(s) to which they are attached, form optionally substituted 6-membered heterocyclyl comprising 0-1 additional heteroatom selected from nitrogen, oxygen, and sulfur.
• two occurrences of R 5 , taken together with the atom(s) to which they are attached form optionally substituted morpholinyl.
• each R 6 is independently C4-12 aliphatic. In some embodiments, each R 6 is independently C 4-8 aliphatic. In some embodiments, each R 6 is independently C 6-12 aliphatic. In some embodiments, each R 6 is independently C6-8 aliphatic. In some embodiments, each R 6 is independently C4 aliphatic. In some embodiments, each R 6 is independently C5 aliphatic. In some embodiments, each R 6 is independently C6 aliphatic. In some embodiments, each R 6 is independently C 7 aliphatic.
• each R 6 is independently C 8 aliphatic. In some embodiments, each R 6 is independently C 9 aliphatic. In some embodiments, each R 6 is independently C10 aliphatic. In some embodiments, each R 6 is independently C11 aliphatic. In some embodiments, each R 6 is independently C 12 aliphatic. [0303] As described above, in some embodiments of any of Formulae A’, A, I”, I’, I, II”, II’, II, III’, and III, each n is independently 0 to 4. In some embodiments, each n is independently 1 to 4. In some embodiments, each n is independently 1 to 3. In some embodiments, each n is independently 2 or 3. In some embodiments, each n is 0.
• each n is 1. In some embodiments, each n is 2. In some embodiments, each n is 3. In some embodiments, each n is 4. [0304] In some embodiments, the present disclosure provides a compound of Formula I”-a: I”-a or its N-oxide, or a pharmaceutically acceptable salt thereof, wherein each of R, R”, R 1 , L, L 1 , L 2 , and L 3 is as defined above for any of Formulae A’ and I”, and described in classes and subclasses above and herein, both singly and in combination.
• the present disclosure provides a compound of Formula I’-a: I’-a or its N-oxide, or a pharmaceutically acceptable salt thereof, wherein each of R, R 1 , L, L 1 , L 2 , and L 3 is as defined above for any of Formulae A and I’, and described in classes and subclasses above and herein, both singly and in combination.
• the present disclosure provides a compound of Formula I-a: I-a or its N-oxide, or a salt thereof, wherein each of R, R 1 , L, L 1 , L 2 , and L 3 is as defined above for Formula I and described in classes and subclasses above and herein, both singly and in combination.
• the present disclosure provides a compound of Formula I”-a-i: I”-a-i or its N-oxide, or a pharmaceutically acceptable salt thereof, wherein each of R, R”, R 1 , L, L 1 , L 2 , and L 3 is as defined above for any of Formulae A’ and I”, and described in classes and subclasses above and herein, both singly and in combination.
• the present disclosure provides a compound of Formula I”-a-ii: I”-a-ii or its N-oxide, or a pharmaceutically acceptable salt thereof, wherein each of R, R”, R 1 , L, L 1 , L 2 , and L 3 is as defined above for any of Formulae A’ and I”, and described in classes and subclasses above and herein, both singly and in combination.
• the present disclosure provides a compound of Formula I”-a-iii: I”-a-iii or its N-oxide, or a pharmaceutically acceptable salt thereof, wherein each of R, R”, R 1 , L, L 1 , and L 2 is as defined above for any of Formulae A’ and I”, and described in classes and subclasses above and herein, both singly and in combination.
• the present disclosure provides a compound of Formula I”-b: I”-b or its N-oxide, or a pharmaceutically acceptable salt thereof, wherein each of R, R”, R 1 , L, L 1 , L 2 , and L 3 is as defined above for any of Formulae A’ and I”, and described in classes and subclasses above and herein, both singly and in combination.
• the present disclosure provides a compound of Formula I’-b: I’-b or its N-oxide, or a pharmaceutically acceptable salt thereof, wherein each of R, R 1 , L, L 1 , L 2 , and L 3 is as defined above for any of Formulae A and I’, and described in classes and subclasses above and herein, both singly and in combination.
• the present disclosure provides a compound of Formula I-b: I-b or its N-oxide, or a salt thereof, wherein each of R, R 1 , L, L 1 , L 2 , and L 3 is as defined above for Formula I and described in classes and subclasses above and herein, both singly and in combination.
• the present disclosure provides a compound of Formula I”-b-i: I”-b-i or its N-oxide, or a pharmaceutically acceptable salt thereof, wherein each of R, R”, R 1 , L, L 1 , L 2 , and L 3 is as defined above for any of Formulae A’ and I”, and described in classes and subclasses above and herein, both singly and in combination.
• the present disclosure provides a compound of Formula I”-b-ii: I”-b-ii or its N-oxide, or a pharmaceutically acceptable salt thereof, wherein each of R, R”, R 1 , L, L 1 , L 2 , and L 3 is as defined above for any of Formulae A’ and I”, and described in classes and subclasses above and herein, both singly and in combination.
• the present disclosure provides a compound of Formula I”-b-iii: I”-b-iii or its N-oxide, or a pharmaceutically acceptable salt thereof, wherein each of R, R”, R 1 , L, L 1 , and L 2 is as defined above for any of Formulae A’ and I”, and described in classes and subclasses above and herein, both singly and in combination.
• the present disclosure provides a compound of Formula I”-c: I”-c or its N-oxide, or a pharmaceutically acceptable salt thereof, wherein each of R, R”, R 1 , L, L 1 , L 2 , L 3 is as defined above for any of Formulae A’ and I”, and described in classes and subclasses above and herein, both singly and in combination.
• the present disclosure provides a compound of Formula I’-c: I’-c or its N-oxide, or a pharmaceutically acceptable salt thereof, wherein each of R, R 1 , L, L 1 , L 2 , L 3 is as defined above for any of Formulae A and I’ and described in classes and subclasses above and herein, both singly and in combination.
• the present disclosure provides a compound of Formula I-c: I-c or its N-oxide, or a salt thereof, wherein each of R, R 1 , L, L 1 , L 2 , L 3 is as defined above for Formula I and described in classes and subclasses above and herein, both singly and in combination.
• the present disclosure provides a compound of Formula I”-c-i: or its N-oxide, or a pharmaceutically acceptable salt thereof, wherein each of R, R”, R 1 , L, L 1 , L 2 , and L 3 is as defined above for any of Formulae A’ and I”, and described in classes and subclasses above and herein, both singly and in combination.
• the present disclosure provides a compound of Formula I”-c-ii: I”-c-ii or its N-oxide, or a pharmaceutically acceptable salt thereof, wherein each of R, R”, R 1 , L, L 1 , L 2 , and L 3 is as defined above for any of Formulae A’ and I”, and described in classes and subclasses above and herein, both singly and in combination.
• the present disclosure provides a compound of Formula I”-c-iii: I”-c-iii or its N-oxide, or a pharmaceutically acceptable salt thereof, wherein each of R, R”, R 1 , L, L 1 , and L 2 is as defined above for any of Formulae A’ and I”, and described in classes and subclasses above and herein, both singly and in combination.
• the present disclosure provides a compound of Formula I’-d: I’-d or its N-oxide, or a pharmaceutically acceptable salt thereof, wherein each of R, R 1 , L, L 1 , L 2 , L 3 is as defined above for any of Formulae A’, A, I”, and I’ and described in classes and subclasses above and herein, both singly and in combination.
• the present disclosure provides a compound of Formula I-d: I-d or its N-oxide, or a salt thereof, wherein each of R, R 1 , L, L 1 , L 2 , L 3 is as defined above for Formula I and described in classes and subclasses above and herein, both singly and in combination.
• the present disclosure provides a compound of Formula I’-d-i: I’-d-i or its N-oxide, or a pharmaceutically acceptable salt thereof, wherein each of R, R 1 , L, L 1 , L 2 , and L 3 is as defined above for any of Formulae A’, A, I”, I’ and I, and described in classes and subclasses above and herein, both singly and in combination.
• the present disclosure provides a compound of Formula II-a: II-a or its N-oxide, or a pharmaceutically acceptable salt thereof, wherein each of R, R 1 , L, L 1 , L 2 , and L 3 is as defined above for any of Formulae A’, A, II”, II’ and II, and described in classes and subclasses above and herein, both singly and in combination.
• the present disclosure provides a compound of Formula II-a-i: II-a-i or its N-oxide, or a pharmaceutically acceptable salt thereof, wherein each of R, R 1 , L, L 1 , and L 2 is as defined above for any of Formulae A’, A, II”, II’ and II, and described in classes and subclasses above and herein, both singly and in combination.
• the present disclosure provides a compound of Formula III-a: III-a or its N-oxide, or a pharmaceutically acceptable salt thereof, wherein each of R, R 1 , L, L 1 , L 2 , L 3 is as defined above for any of Formulae A’, A, III’, and III, and described in classes and subclasses above and herein, both singly and in combination.
• the present disclosure provides a compound of Formula III-a-i: III-a-i or its N-oxide, or a pharmaceutically acceptable salt thereof, wherein each of R, R 1 , L, L 1 , and L 2 is as defined above for any of Formulae A’, A, III’, and III, and described in classes and subclasses above and herein, both singly and in combination.
• R, R 1 , L, L 1 , and L 2 is as defined above for any of Formulae A’, A, III’, and III, and described in classes and subclasses above and herein, both singly and in combination.
• “[compound/formula] or its N-oxide, or a pharmaceutically acceptable salt thereof”, as used herein refers to pharmaceutically acceptable salts of i) the respective compound or formula or ii) N-oxides of such compound or formula.
• the present disclosure provides a compound selected from Table 1. Table 1.
• provided compounds are provided and/or utilized in a salt form (e.g., a pharmaceutically acceptable salt form).
• Reference to a compound provided herein is understood to include reference to salts thereof, unless otherwise indicated.
• reference to a compound of Formula A’ is intended to also include A, I”, I’, I, II”, II’, II, III’, III, I”-a, I’-a, I-a, I”-a-i, I”-a-ii, I”-a-iii, I”-b, I’-b, I”-b-i, I”-b-iii, I”-cii, I”-c-i, I”-c-ii, I”-c-ii, I”-c-ii, I’-d, I-d, I’-d-i, II-a, II-a-i, III
• a salt thereof is a pharmaceutically acceptable salt thereof.
• the present disclosure encompasses the recognition that provided compounds display certain desirable characteristics, e.g., as compared to reference compounds or other known compounds. For example, in some embodiments, provided compounds exhibit more potent delivery to various cell types in one or more experiments described herein, and/or have one or more other characteristics that make them more suitable for delivery of cargos such as therapeutic or prophylactic agents than other known compounds.
• the present disclosure encompasses the recognition that provided compounds characterized as including at least one ester-linked acetal feature display certain more desirable characteristics (e.g., more potent delivery to various cell types in one or more experiments described herein) than corresponding compounds lacking the same ester-linked acetal feature.
• Provided compounds may generally be made by the processes described in the ensuing schemes and examples.
• provided compounds are prepared according to the following Scheme: , wherein each of L, L 1 , L 2 , L 3 , X, X 2 , R, R”, and R 1 is as defined above for Formula I”, and described in classes and subclasses herein, both singly and in combination.
• intermediate I-3 is prepared by a process comprising contacting compounds of Formulae I-1 and I-2 in the presence of an acid reagent (e.g., PPTS).
• acid reagent e.g., PPTS
• intermediate I-4 is prepared by a process comprising contacting intermediate I-3 with a base reagent (e.g., KOH).
• intermediate I-6 is prepared by a process comprising contacting intermediate I-4 and compounds of Formula I-5 in the presence of a coupling reagent (e.g., EDC).
• intermediate I-9 is prepared by a process comprising contacting compounds of Formulae I-7 and I-8 in the presence of a coupling reagent (e.g., EDC).
• intermediate I-11 is prepared by a process comprising contacting intermediate I-9 with compounds of Formula I-10 under suitable conditions.
• compounds of Formula I” are prepared by a process comprising contacting intermediates I-11 and I-6 under suitable conditions.
• provided compounds are prepared according to the following Scheme: , wherein each of L, L 1 , L 2 , L 3 , X 2 , R, and R 1 is as defined above for any of Formulae III’ and III, and described in classes and subclasses herein, both singly and in combination.
• intermediate III-3 is prepared by a process comprising contacting compounds of Formulae III-1 and III-2 in the presence of an acid reagent (e.g., PPTS).
• acid reagent e.g., PPTS
• intermediate III-4 is prepared by a process comprising contacting intermediate III-3 with a base reagent (e.g., KOH).
• intermediate III-6 is prepared by a process comprising contacting compounds of Formulae III-4 and III-5 in the presence of a coupling reagent (e.g., EDC).
• a coupling reagent e.g., EDC
• compounds of any of Formulae III’ and III are prepared by a process comprising contacting intermediate III-6 with compounds of Formula III-7 under suitable conditions.
• C. Ionizable lipids [0339] Among other things, the present disclosure describes compositions, preparations, nanoparticles, and/or nanomaterials that comprise one or more ionizable lipids as described herein.
• compositions, preparations, nanoparticles, and/or nanomaterials described herein are important to and/or influence one or more functional activities of compositions, preparations, nanoparticles, and/or nanomaterials described herein.
• compositions, preparations, nanoparticles, and/or nanomaterials having an ionizable lipid that is at about 50 mol percent or less, based on total moles of components of the lipid nanoparticle was found to be useful and/or critical to functional activity of lipid nanoparticles such as desired tropisms, stabilization, and drug delivery efficacy as described herein.
• an ionizable lipid may include an amine-containing group on the head group.
• an ionizable lipid is or comprises a compound described herein (e.g., a compound of any of Formulae A’, A, I”, I’, I, II”, II’, II, III’, III, I”-a, I’-a, I-a, I”-a-i, I”-a-iii, I”-a-iii, I”-b, I’-b, I”-b-i, I”-b-ii, I”-b-iii, I”-c, I’-c, I-c, I”-c-i, I”-c-ii, I”-c-iii, I’-d, I-d, I’-d- i, II-a, II-a-i, III-a, and III-a-i).
• an ionizable lipid is present in a lipid nanoparticle (LNP) preparation from about 30 mole percent to about 70 mole percent, based on total moles of components of the lipid nanoparticle. In some embodiments, an ionizable lipid is present from about 33 mol percent to about 60 mole percent, based on total moles of components of the lipid nanoparticle. In some embodiments, an ionizable lipid is present from about 34 mol percent to about 55 mole percent, based on total moles of components of the lipid nanoparticle. In some embodiments, an ionizable lipid is present from about 33 mol percent to about 51 mole percent, based on total moles of components of the lipid nanoparticle.
• LNP lipid nanoparticle
• an ionizable lipid is present at about 34.7 mole percent, based on total moles of components of the lipid nanoparticle. In some embodiments, an ionizable lipid is present at about 50 mole percent, based on total moles of components of the lipid nanoparticle.
• a lipid nanoparticle composition comprises an ionizable lipid. In some embodiments, a lipid nanoparticle preparation comprises an ionizable lipid; a phospholipid; a conjugate-linker lipid; and a cholesterol.
• an ionizable lipid is or comprises a structure according to a compound described herein (e.g., a compound of any of Formulae A’, A, I”, I’, I, II”, II’, II, III’, III, I”-a, I’-a, I-a, I”-a-i, I”-a-ii, I”-a- iii, I”-b, I’-b, I-b, I”-b-i, I”-b-ii, I”-b-iii, I”-ci, I’-c, I-c, I”-c-i, I”-c-ii, I”-c-iii, I’-d, I-d, I’-d-i, II-a, II-a-i, III-a, and III-a-i).
• a compound described herein e.g., a compound of any of Formulae A’, A, I”, I’, I, II”, II’, II,
• an ionizable lipid is present in a LNP preparation from about 30 mole percent to about 70 mole percent, based on total moles of components of the lipid nanoparticle.
• D. Sterols [0343] Among other things, the present disclosure describes compositions, preparations, nanoparticles, and/or nanomaterials that comprise one or more sterols as described herein. [0344] In some embodiments, a sterol is a cholesterol, or a variant or derivative thereof. In some embodiments, a cholesterol is modified. In some embodiments, a cholesterol is an oxidized cholesterol. In some embodiments, a cholesterol is esterified cholesterol.
• Unmodified cholesterol can be acted upon by enzymes to form variants that are side-chain or ring oxidized.
• a cholesterol can be oxidized on the beta-ring structure or on the hydrocarbon tail structure.
• a sterol is a phytosterol.
• Exemplary sterols that are considered for use in the disclosed lipid nanoparticles include but are not limited to 25-hydroxycholesterol (25-OH), 20 ⁇ -hydroxycholesterol (20 ⁇ -OH), 27-hydroxycholesterol, 6-keto-5 ⁇ - hydroxycholesterol, 7-ketocholesterol, 7 ⁇ -hydroxycholesterol, 7 ⁇ -hydroxycholesterol, 7 ⁇ -25- dihydroxycholesterol, beta-sitosterol, stigmasterol, brassicasterol, campesterol, or combinations thereof.
• a side-chain oxidized cholesterol can enhance cargo delivery relative to other cholesterol variants.
• a cholesterol is an unmodified cholesterol.
• a LNP composition comprises from about 20 mol percent to about 50 mol percent sterol. In some embodiments, a LNP composition comprises about 38 mol percent sterol. In some embodiments, a LNP composition comprises about 38.5 mol percent sterol. In some embodiments, a LNP composition comprises about 33.8 mol percent cholesterol.
• Conjugate-linker lipids [0346] Among other things, the present disclosure describes compositions, preparations, nanoparticles, and/or nanomaterials that comprise one or more conjugate-linker lipids as described herein. [0347] In some embodiments, a conjugate-linker lipid is or comprises a polyethylene glycol (PEG)-lipid or PEG-modified lipid.
• PEG or PEG-modified lipids may be alternately referred to as PEGylated lipids or PEG-lipids.
• Inclusion of a PEGylating lipid can be used to enhance lipid nanoparticle colloidal stability in vitro and circulation time in vivo.
• the PEGylation is reversible in that the PEG moiety is gradually released in blood circulation.
• Exemplary PEG-lipids include but are not limited to PEG conjugated to saturated or unsaturated alkyl chains having a length of C6-C20.
• a PEG lipid may be PEG-c-DOMG, PEG- DMG, PEG-DLPE, PEG-DMPE, PEG-DPPE, PEG-DSG or a PEG-DSPE lipid.
• a conjugate-linker lipid comprises a polyethylene glycol lipid.
• the conjugate-linker lipid comprises DiMystyrlGlycerol (DMG), 1,2- Dipalmitoyl-rac-glycerol, methoxypolyethylene Glycol (DPG-PEG), or 1,2-Distearoyl-rac- glycero-3-methylpolyoxyethylene (DSG – PEG).
• DMG DiMystyrlGlycerol
• DPG-PEG methoxypolyethylene Glycol
• DSG – PEG 1,2-Distearoyl-rac- glycero-3-methylpolyoxyethylene
• a conjugate-linker lipid has an average molecular mass from about 500 Da to about 5000 Da.
• a conjugate-linker lipid has an average molecular mass of about 2000 Da.
• a LNP composition comprises from about 0 mol percent to about 5 mol percent conjugate-linker lipid.
• a LNP composition comprises about 1.5 mol percent conjugate-linker lipid. In some embodiments, a LNP composition comprises about 3 mol percent conjugate-linker lipid.
• F. Phospholipids [0349] Among other things, the present disclosure describes compositions, preparations, nanoparticles, and/or nanomaterials that comprise one or more phospholipids as described herein. In some embodiments, the present disclosure describes compositions, preparations, nanoparticles, and/or nanomaterials that comprise one or more (poly)unsaturated lipids. [0350] In some embodiments, one or more phospholipids may assemble into one or more lipid bilayers.
• one or more phospholipids may include a phospholipid moiety. In some embodiments, one or more phospholipids may include one or more fatty acid moieties. In some embodiments, one or more phospholipids may include a phospholipid moiety and one or more fatty acid moieties. In some embodiments, a phospholipid moiety includes but is not limited to phosphatidyl choline, phosphatidyl ethanolamine, phosphatidyl glycerol, phosphatidyl serine, phosphatidic acid, 2-lysophosphatidyl choline, and sphingomyelin.
• a fatty acid moiety includes but is not limited to lauric acid, myristic acid, myristoleic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, linoleic acid, alphalinolenic acid, erucic acid, phytanic acid, arachidic acid, arachidonic acid, eicosapentaenoic acid, behenic acid, docosapentaenoic acid, and docosahexaenoic acid.
• Non-natural species including natural species with modifications and substitutions including branching, oxidation, cyclization, and alkynes are also contemplated.
• a phospholipid may be functionalized with or cross-linked to one or more alkynes (e.g., an alkenyl group in which one or more double bonds is replaced with a triple bond).
• alkynes e.g., an alkenyl group in which one or more double bonds is replaced with a triple bond.
• an alkyne group may undergo a copper-catalyzed cycloaddition upon exposure to an azide.
• Such reactions may be useful in functionalizing a lipid bilayer of a nanoparticle composition to facilitate membrane permeation or cellular recognition or in conjugating a nanoparticle composition to a useful component such as a targeting or imaging moiety (e.g., a dye).
• Exemplary phospholipids include but are not limited to 1,2-distearoyl-snglycero-3- phosphocholine (DSPC), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 1,2- dilinoleoyl-sn-glycero-3-phosphocholine (DLPC), 1,2-dimyristoyl-sn-glycerophosphocholine (DMPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dipalmitoyl-sn-glycero-3- phosphocholine (DPPC), 1,2-diundecanoyl-sn-glycerophosphocholine (DUPC), l-palmitoyl-2- oleoyl-sn-glycero-3-phosphocholine (POPC), 1,2-di-O-octadecenyl-sn-glycero-3-phosphocholine (PO
• a phospholipid is DSPC. In some embodiments, a phospholipid is DMPC. [0352] In some embodiments, the phospholipid comprises 1,2-dioleoyl-sn-glycero-3- phosphoethanolamine-N-(succinyl) (succinyl PE), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), cholesterol, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), 1,2-dipalmitoyl- sn-glycero-3-phosphoethanolamine-N-(succinyl) (succinyl-DPPE), 1,2-dioleoyl-sn-glycero-3- phosphoethanolamine (DOPE), 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2- dipalmitoyl-sn-glycero-3-phosphocholine (DPPC)
• compositions, preparations, nanoparticles, and/or nanomaterials that have an average hydrodynamic diameter from about 30 to about 220 nm.
• compositions, preparations, nanoparticles, and/or nanomaterials described herein have an average hydrodynamic diameter that is about 30 nm, 35 nm,40 nm, 45 nm, 50 nm, 55 nm, 60 nm, 65 nm, 70 nm, 75 nm, 80 nm, 85 nm, 90 nm, 95 nm, 100 nm, 105 nm, 110 nm, 115 nm, 120 nm, 125 nm, 130 nm, 135 nm, 140 nm, 145 nm, 150 nm, 155 nm, 160 nm, 165 nm, 170 nm, 175 nm, 180 nm, 185 nm
• compositions, preparations, nanoparticles, and/or nanomaterials described herein have an average hydrodynamic diameter from between 50 nm to 200 nm.
• lipid nanoparticles described herein have an average hydrodynamic diameter from about 30 to about 220 nm.
• lipid nanoparticles described herein have an average hydrodynamic diameter that is about 30 nm, 35 nm,40 nm, 45 nm, 50 nm, 55 nm, 60 nm, 65 nm, 70 nm, 75 nm, 80 nm, 85 nm, 90 nm, 95 nm, 100 nm, 105 nm, 110 nm, 115 nm, 120 nm, 125 nm, 130 nm, 135 nm, 140 nm, 145 nm, 150 nm, 155 nm, 160 nm, 165 nm, 170 nm, 175 nm, 180 nm, 185 nm, 190 nm, 195 nm, 200 nm, 205 nm, 210 nm, 215 nm, 220 nm, or any range having endpoints defined by any two of the aforementioned values.
• lipid nanoparticles described herein have an average hydrodynamic diameter from between 50 nm to 200 nm.
• H. Polydispersity [0355]
• the present disclosure describes compositions, preparations, nanoparticles, and/or nanomaterials that have a polydispersity index (PDI) of about 0.01 to about 0.3.
• compositions, preparations, nanoparticles, and/or nanomaterials described herein have a PDI that is about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.15, 0.2, 0.25, 0.3, or any range having endpoints defined by any two of the aforementioned values.
• compositions, preparations, nanoparticles, and/or nanomaterials described herein have a PDI from about 0.05 to about 0.2, about 0.06 to about 0.1, or about 0.07 to about 0.09.
• lipid nanoparticles described herein have a PDI from about 0.01 to about 0.3.
• lipid nanoparticles described herein have a PDI that is about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.15, 0.2, 0.25, 0.3, or any range having endpoints defined by any two of the aforementioned values.
• lipid nanoparticles described herein have a PDI from about 0.05 to about 0.2, about 0.06 to about 0.1, or about 0.07 to about 0.09.
• Encapsulation efficiency [0357] Among other things, the present disclosure describes compositions, preparations, nanoparticles, and/or nanomaterials, wherein encapsulation effiency of provided compositions, preparations, nanoparticles, and/or nanomaterials is from about 80% to about 100%.
• encapsulation effiency of compositions, preparations, nanoparticles, and/or nanomaterials described herein is about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5%, 99%, 99.5%, 100%, or any range having endpoints defined by any two of the aforementioned values.
• encapsulation effiency of compositions, preparations, nanoparticles, and/or nanomaterials described herein is from about 90% to about 100%, about 95% to about 100%, about 95% to about 98%, or about 95.5% to about 97.5%.
• encapsulation effiency of compositions, preparations, nanoparticles, and/or nanomaterials described herein is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%. [0358] In some embodiments, encapsulation effiency of lipid nanoparticles described herein is from about 80% to about 100%.
• encapsulation effiency of lipid nanoparticles described herein is about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5%, 99%, 99.5%, 100%, or any range having endpoints defined by any two of the aforementioned values.
• encapsulation effiency of lipid nanoparticles described herein is from about 90% to about 100%, about 95% to about 100%, about 95% to about 98%, or about 95.5% to about 97.5%.
• encapsulation effiency of lipid nanoparticles described herein is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%.
• J. pKa [0359] Among other things, the present disclosure describes compositions, preparations, nanoparticles, and/or nanomaterials that have a pKa from about 5 to about 9. In some embodiments, compositions, preparations, nanoparticles, and/or nanomaterials described herein have a pKa that is about 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, or any range having endpoints defined by any two of the aforementioned values.
• compositions, preparations, nanoparticles, and/or nanomaterials described herein have a pKa that is about 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, or any range having endpoints defined by any two of the aforementioned values.
• lipid nanoparticles described herein have a pKa from about 5 to about 9.
• lipid nanoparticles described herein have a pKa that is about 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, or any range having endpoints defined by any two of the aforementioned values. In some embodiments, lipid nanoparticles described herein have a pKa that is about 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, or any range having endpoints defined by any two of the aforementioned values.
• lipid nanoparticle preparation comprises about 30 mole percent to about 70 mole percent ionizable lipid, about 5 mole percent to about 25 mole percent phospholipid, about 25 mole percent to about 45 mole percent cholesterol, and about 0 mole percent to about 5 mole percent conjugate-linker lipid.
• a lipid nanoparticle preparation comprises about 45 mole percent ionizable lipid, about 9 mole percent phospholipid, about 44 mole percent cholesterol, and about 2 mole percent conjugate-linker lipid.
• a lipid nanoparticle preparation comprises about 50 mole percent ionizable lipid, about 9 mole percent phospholipid, about 38 mole percent cholesterol, and about 3 mole percent conjugate-linker lipid. [0363] In some embodiments, a lipid nanoparticle preparation comprises about 40 mole percent to about 60 mole percent ionizable lipid of any of Formulae A’, A, I”, I’, I, II”, II’, II, III’, III, I”-a, I’-a, I-a, I”-a-i, I”-a-ii, I”-a-iii, I”-b, I’-b, I”-b-i, I”-b-iii, I”-b-iii, I”-c, I’-c, I-c, I”-c-i, I”-c-ii, I”-c-iii, I’-d, I-d, I’-d-i, II-a
• a lipid nanoparticle (LNP) preparation comprises a mass ratio of (ionizable lipid, cholesterol, lipid-PEG, and phospholipid):mRNA from about 2:1 and 50:1.
• a LNP preparation comprises a mass ratio of (ionizable lipid, cholesterol, lipid-PEG, and phospholipid):mRNA of about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 11:1, about 12:1, about 13:1, about 14:1, about 15:1, about 16:1, about 17:1, about 18:1, about 19:1, about 20:1, about 21:1, about 22:1, about 23:1, about 24:1, about 25:1, about 26:1, about 27:1, about 28:1, about 29:1, about 30:1, about 31:1, about 32:1, about 33:1, about 34:1, about 35:1, about 36:1, about 37:1, about 38:1, about 39:1, about 40:1, about 41:
• a lipid nanoparticle (LNP) preparation comprises a mass ratio of (ionizable lipid, cholesterol, lipid-PEG, and phospholipid):mRNA of about 11.7:1 and 19:1.
• a lipid nanoparticle preparation comprises a mass ratio of (ionizable lipid, cholesterol, lipid-PEG, and phospholipid):siRNA from about 2:1 and 50:1.
• a LNP preparation comprises a mass ratio of (ionizable lipid, cholesterol, lipid-PEG, and phospholipid):mRNA of about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 11:1, about 12:1, about 13:1, about 14:1, about 15:1, about 16:1, about 17:1, about 18:1, about 19:1, about 20:1, about 21:1, about 22:1, about 23:1, about 24:1, about 25:1, about 26:1, about 27:1, about 28:1, about 29:1, about 30:1, about 31:1, about 32:1, about 33:1, about 34:1, about 35:1, about 36:1, about 37:1, about 38:1, about 39:1, about 40:1, about 41:1, about 42:1, about 43:1, about 44:1, about 45:1, about 46:1, about 47:1, about 48:1, about 49:1, about 50:1.
• a lipid nanoparticle (LNP) preparation comprises a mass ratio of (ionizable lipid, cholesterol, lipid-PEG, and phospholipid):mRNA of about 11.7:1 and 19:1.
• pharmaceutical compositions comprise lipid nanoparticles and lipid nanoparticle preparations described herein.
• lipid nanoparticles and lipid nanoparticle preparations described herein can be formulated in whole or in part as pharmaceutical compositions.
• pharmaceutical compositions may include one or more nanoparticle compositions described herein.
• a pharmaceutical composition may comprise one or more nanoparticle compositions including one or more different therapeutic and/or prophylactics including but not limited to one or more nucleic acids of different types or encode different agents.
• a pharmaceutical composition comprises one or more pharmaceutically acceptable excipients or accessory ingredients including but not limited to a pharmaceutically acceptable carrier.
• a pharmaceutical composition may be administered to a subject.
• a pharmaceutical composition is administered as described herein.
• the nanoparticle compositions disclosed herein are administered to a subject in a therapeutically effective amount as described herein.
• a selected dosage depends upon the desired therapeutic effect, on the route of administration, and on the duration of the treatment desired.
• generally dosage levels of about 0.001 mg to about 5 mg of nucleic acid per kg of body weight are administered each dosage to mammals. More specifically, in some embodiments, a preferential dose for nucleic acids within the disclosed nanoparticles is about 0.1 mg / kg to about 1.0 mg/kg.
• a pharmaceutical composition described herein is administered locally, for example by injection directly into a site to be treated. Typically, the injection causes an increased localized concentration of the composition which is greater than that which can be achieved by systemic administration.
• a pharmaceutical composition described herein can be combined with a matrix as described herein to assist in creating an increased localized concentration of the polypeptide compositions by reducing the passive diffusion of the polypeptides out of the site to be treated.
• A. Preparations for parenteral administration [0371]
• the compositions, preparations, nanoparticles, and/or nanomaterials disclosed herein, including those containing lipid nanoparticles, are administered in an aqueous solution, by parenteral injection.
• a preparation may also be in the form of a suspension or emulsion.
• compositions including effective amounts of a lipid nanoparticle, and optionally include pharmaceutically acceptable diluents, preservatives, solubilizers, emulsifiers, adjuvants and/or carriers.
• Such compositions optionally include one or more for the following: diluents, sterile water, buffered saline of various buffer content (e.g., Tris-HCl, acetate, phosphate), pH and ionic strength; and additives such as detergents and solubilizing agents (e.g., TWEEN 20 (polysorbate-20), TWEEN 80 (polysorbate- 80)), anti-oxidants (e.g., ascorbic acid, sodium metabisulfite), and preservatives (e.g., Thimersol, benzyl alcohol) and bulking substances (e.g., lactose, mannitol).
• diluents sterile water, buffered saline of various buffer content (e.
• non-aqueous solvents or vehicles examples include propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate.
• Formulations may be lyophilized and redissolved/resuspended immediately before use.
• a formulation may be sterilized by, for example, filtration through a bacteria retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions.
• B. Controlled delivery polymeric matrices [0372]
• the compositions, preparations, nanoparticles, and/or nanomaterials disclosed herein can also be administered in controlled release formulations.
• controlled release polymeric devices can be made for long term release systemically following implantation of a polymeric device (such as a rod, cylinder, film, disk) or injection (such as microparticles).
• a matrix can be in the form of microparticles such as microspheres.
• an agent is dispersed within a solid polymeric matrix or microcapsules.
• a core is of a different material than a polymeric shell of any of the described compositions, preparations, nanoparticles, and/or nanomaterials.
• a peptide is dispersed or suspended in a core, which may be liquid or solid in nature, of any of the described compositions, preparations, nanoparticles, and/or nanomaterials. Unless specifically defined herein, microparticles, microspheres, and microcapsules are used interchangeably.
• a polymer may be cast as a thin slab or film, ranging from nanometers to four centimeters, a powder produced by grinding or other standard techniques, or even a gel such as a hydrogel.
• non-biodegradable matrices are used for delivery of the described compositions, preparations, nanoparticles, and/or nanomaterials.
• biodegradable matrices are used for delivery of the described compositions, preparations, nanoparticles, and/or nanomaterials. In some embodiments, biodegradable matrices are preferred. In some embodiments, biodegradable matrices comprise natural or synthetic polymers. In some embodiments, synthetic polymers are preferred due to the better characterization of degradation and release profiles. In some embodiments, a polymer is selected based on the period over which release is desired. In some embodiments, linear release may be most useful, although in others a pulse release or “bulk release” may provide more effective results.
• a polymer may be in the form of a hydrogel (typically in absorbing up to about 90% by weight of water), and can optionally be crosslinked with multivalent ions or polymers.
• the matrices can be formed by solvent evaporation, spray drying, solvent extraction and other methods known to those skilled in the art.
• Bioerodible microspheres can be prepared using any of the methods developed for making microspheres for drug delivery, for example, as described by Mathiowitz and Langer, J. Controlled Release, 5:13-22 (1987); Mathiowitz, et al., Reactive Polymers, 6:275-283 (1987); and Mathiowitz, et al., J. Appl.
• compositions, preparations, nanoparticles, and/or nanomaterials can be formulated for local release to treat the area of implantation or injection – which will typically deliver a dosage that is much less than the dosage for treatment of an entire body – or systemic delivery. These can be implanted or injected subcutaneously, into the muscle, fat, or swallowed.
• the present invention provides for compositions, preparations, nanoparticles, and/or nanomaterials that comprise cargo as described herein.
• compositions, preparations, nanoparticles, and/or nanomaterials include a therapeutic or prophylactic agent for delivery to a subject.
• a therapeutic or prophylactic agent is encapsulated by a lipid nanoparticle.
• a lipid nanoparticle is loaded with one or more nucleic acids.
• Therapeutic and/or prophylactic agents [0377]
• Cargo delivered via a LNP composition may be a biologically active agent.
• the cargo is or comprises one or more biologically active agents, such as mRNA, guide RNA (gRNA), nucleic acid, RNA-guided DNA-binding agent, expression vector, template nucleic acid, antibody (e.g.
• RNAi agent short interfering nucleic acid (siNA), short interfering RNA (siRNA), double-stranded RNA (dsRNA), micro-RNA (miRNA), short hairpin RNA (shRNA) and “self-replicating RNA” (encoding a replicase enzyme activity and capable
• Cargo delivered via a LNP composition may be an RNA, such as an mRNA molecule encoding a protein of interest.
• RNA such as an mRNA molecule encoding a protein of interest.
• GFP green fluorescent protein
• RNA-guided DNA-binding agent such as an RNA-guided DNA-binding agent
• Cas nuclease a Cas nuclease
• LNP compositions that include a Cas nuclease mRNA, for example a Class 2 Cas nuclease mRNA that allows for expression in a cell of a Class 2 Cas nuclease such as a Cas9 or Cpfl protein are provided.
• cargo may contain one or more guide RNAs or nucleic acids encoding guide RNAs.
• a template nucleic acid e.g., for repair or recombination, may also be included in the composition or a template nucleic acid may be used in the methods described herein.
• cargo comprises an mRNA that encodes a Streptococcus pyogenes Cas9, optionally and an S. pyogenes gRNA.
• cargo comprises an mRNA that encodes a Neisseria meningitidis Cas9, optionally and an nme gRNA.
• mRNA refers to a polynucleotide and comprises an open reading frame that can be translated into a polypeptide (i.e., can serve as a substrate for translation by a ribosome and amino- acylated tRNAs).
• mRNA can comprise a phosphate-sugar backbone including ribose residues or analogs thereof, e.g., 2’-methoxy ribose residues.
• the sugars of an mRNA phosphate-sugar backbone consist essentially of ribose residues, 2’-methoxy ribose residues, or a combination thereof.
• mRNAs do not contain a substantial quantity of thymidine residues (e.g., 0 residues or fewer than 30, 20, 10, 5, 4, 3, or 2 thymidine residues; or less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 4%, 3%, 2%, 1%, 0.5%, 0.2%, or 0.1% thymidine content).
• An mRNA can contain modified uridines at some or all of its uridine positions.
• the disclosed compositions, preparations, nanoparticles, and/or nanomaterials comprise an mRNA encoding an RNA-guided DNA-binding agent, such as a Cas nuclease.
• the disclosed compositions, preparations, nanoparticles, and/or nanomaterials comprise an mRNA encoding a Class 2 Cas nuclease, such as S. pyogenes Cas9.
• RNA-guided DNA binding agent means a polypeptide or complex of polypeptides having RNA and DNA binding activity, or a DNA-binding subunit of such a complex, wherein the DNA binding activity is sequence-specific and depends on the sequence of the RNA.
• RNA-guided DNA binding agents include Cas cleavases/nickases and inactivated forms thereof (“dCas DNA binding agents”).
• dCas DNA binding agents encompasses Cas cleavases, Cas nickases, and dCas DNA binding agents.
• Cas cleavases/nickases and dCas DNA binding agents include a Csm or Cmr complex of a type III CRISPR system, the CaslO, Csml, or Cmr2 subunit thereof, a Cascade complex of a type I CRISPR system, the Cas3 subunit thereof, and Class 2 Cas nucleases.
• a“Class 2 Cas nuclease” is a single chain polypeptide with RNA-guided DNA binding activity.
• Class 2 Cas nucleases include Class 2 Cas cleavases/nickases (e.g., H840A, D10A, or N863 A variants), which further have RNA-guided DNA cleavases or nickase activity, and Class 2 dCas DNA binding agents, in which cleavase/nickase activity is inactivated.
• Class 2 Cas cleavases/nickases e.g., H840A, D10A, or N863 A variants
• Class 2 dCas DNA binding agents in which cleavase/nickase activity is inactivated.
• Class 2 Cas nucleases include, for example, Cas9, Cpfl, C2cl, C2c2, C2c3, HF Cas9 (e.g., N497A, R661A, Q695A, Q926A variants), HypaCas9 (e.g., N692A, M694A, Q695A, H698A variants), eSPCas9(1.0) (e.g., K810A, K1003A, R1060A variants), and eSPCas9(1.1) (e.g., K848A, K1003A, R1060A variants) proteins and modifications thereof.
• Cas9, Cpfl, C2cl, C2c2, C2c3, HF Cas9 e.g., N497A, R661A, Q695A, Q926A variants
• HypaCas9 e.g., N692A, M694A, Q69
• Cpfl protein Zetsche et al., Cell, 163: 1-13 (2015), is homologous to Cas9, and contains a RuvC-like nuclease domain.
• Cpfl sequences of Zetsche are incorporated by reference in their entirety herein. See, e.g., Zetsche, Tables Sl and S3. See, e.g, Makarova et al., Nat Rev Microbiol, 13(11): 722-36 (2015); Shmakov et al., Molecular Cell, 60:385-397 (2015), the contents of which are hereby incorporated in its entirety herein.
• ribonucleoprotein or “RNP complex” refers to a guide RNA together with an RNA-guided DNA binding agent, such as a Cas nuclease, e.g., a Cas cleavase, Cas nickase, or dCas DNA binding agent (e.g., Cas9).
• a Cas nuclease e.g., a Cas cleavase, Cas nickase, or dCas DNA binding agent (e.g., Cas9).
• the guide RNA guides the RNA-guided DNA binding agent such as Cas9 to a target sequence, and the guide RNA hybridizes with and the agent binds to the target sequence; in cases where the agent is a cleavase or nickase, binding can be followed by cleaving or nicking.
• cargo for a LNP composition includes at least one guide RNA comprising guide sequences that direct an RNA-guided DNA binding agent, which can be a nuclease (e.g., a Cas nuclease such as Cas9), to a target DNA.
• a nuclease e.g., a Cas nuclease such as Cas9
• gRNA may guide the Cas nuclease or Class 2 Cas nuclease to a target sequence on a target nucleic acid molecule.
• a gRNA binds with and provides specificity of cleavage by a Class 2 Cas nuclease.
• a gRNA and a Cas nuclease may form a ribonucleoprotein (RNP), e.g., a CRISPR/Cas complex such as a CRISPR/Cas9 complex.
• a CRISPR/Cas complex may be a Type-II CRISPR/Cas9 complex.
• a CRISPR/Cas complex may be a Type-V CRISPR/Cas complex, such as a Cpfl/guide RNA complex.
• Cas nucleases and cognate gRNAs may be paired.
• a gRNA scaffold structures that pair with each Class 2 Cas nuclease vary with the specific CRISPR/Cas system.
• RNA refers to either a crRNA (also known as CRISPR RNA), or the combination of a crRNA and a trRNA (also known as tracrRNA).
• Guide RNAs can include modified RNAs as described herein.
• the crRNA and trRNA may be associated as a single RNA molecule (single guide RNA, sgRNA) or in two separate RNA molecules (dual guide RNA, dgRNA).
• sgRNA single guide RNA
• dgRNA dual guide RNA
• “Guide RNA” or “gRNA” refers to each type.
• trRNA may be a naturally-occurring sequence, or a trRNA sequence with modifications or variations compared to naturally-occurring sequences.
• a “guide sequence” refers to a sequence within a guide RNA that is complementary to a target sequence and functions to direct a guide RNA to a target sequence for binding or modification (e.g., cleavage) by an RNA-guided DNA binding agent.
• a “guide sequence” may also be referred to as a “targeting sequence,” or a “spacer sequence.”
• a guide sequence can be 20 base pairs in length, e.g., in the case of Streptococcus pyogenes (i.e., Spy Cas9) and related Cas9 homologs/orthologs.
• a target sequence is in a gene or on a chromosome, for example, and is complementary to a guide sequence.
• a degree of complementarity or identity between a guide sequence and its corresponding target sequence may be about or at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100%.
• a guide sequence and the target region may be 100% complementary or identical over a region of at least 15, 16, 17, 18, 19, or 20 contiguous nucleotides.
• a guide sequence and a target region may contain at least one mismatch.
• a guide sequence and a target sequence may contain 1, 2, 3, or 4 mismatches, where the total length of the target sequence is at least 17, 18, 19, 20 or more base pairs.
• a guide sequence and a target region may contain 1-4 mismatches where a guide sequence comprises at least 17, 18, 19, 20 or more nucleotides.
• a guide sequence and the target region may contain 1, 2, 3, or 4 mismatches where the guide sequence comprises 20 nucleotides.
• Target sequences for RNA-guided DNA binding proteins include both the positive and negative strands of genomic DNA (i.e., the sequence given and the sequence’s reverse compliment), as a nucleic acid substrate for a Cas protein is a double stranded nucleic acid. Accordingly, where a guide sequence is said to be “complementary to a target sequence”, it is to be understood that the guide sequence may direct a guide RNA to bind to the reverse complement of a target sequence.
• the guide sequence binds the reverse complement of a target sequence
• the guide sequence is identical to certain nucleotides of the target sequence (e.g., the target sequence not including the PAM) except for the substitution of U for T in the guide sequence.
• the length of the targeting sequence may depend on the CRISPR/Cas system and components used. For example, different Class 2 Cas nucleases from different bacterial species have varying optimal targeting sequence lengths. Accordingly, the targeting sequence may comprise 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, or more than 50 nucleotides in length.
• the targeting sequence length is 0, 1, 2, 3, 4, or 5 nucleotides longer or shorter than the guide sequence of a naturally-occurring nucleotide sequence.
• CRISPR/Cas system In certain embodiments, a Cas nuclease and gRNA scaffold will be derived from the same CRISPR/Cas system.
• a targeting sequence may comprise or consist of 18-24 nucleotides. In some embodiments, a targeting sequence may comprise or consist of 19-21 nucleotides. In some embodiments, the targeting sequence may comprise or consist of 20 nucleotides.
• a sgRNA is a “Cas9 sgRNA” capable of mediating RNA-guided DNA cleavage by a Cas9 protein.
• a sgRNA is a “Cpfl sgRNA” capable of mediating RNA-guided DNA cleavage by a Cpfl protein.
• a gRNA comprises a crRNA and tracr RNA sufficient for forming an active complex with a Cas9 protein and mediating RNA-guided DNA cleavage.
• a gRNA comprises a crRNA sufficient for forming an active complex with a Cpfl protein and mediating RNA-guided DNA cleavage. See Zetsche 2015.
• Certain embodiments of the invention also provide nucleic acids, e.g., expression cassettes, encoding the gRNA described herein.
• a “guide RNA nucleic acid” is used herein to refer to a guide RNA (e.g. an sgRNA or a dgRNA) and a guide RNA expression cassette, which is a nucleic acid that encodes one or more guide RNAs.
• Certain embodiments of the present disclosure also provide delivery of adenine base editors (“ABEs”) using the LNPs compositions, preparations, nanoparticles, and/or nanomaterials described herein. ABEs and methods of their use are described, e.g. in U.S.
• Patent No.10,113,163 and U.S. Patent Publication No. 2021/0130805 the contents of each of which are hereby incorporated by reference in their entireties.
• Certain embodiments of the present disclosure also provide delivery of cytosine base editors (“CBEs”) using the LNPs compositions, preparations, nanoparticles, and/or nanomaterials described herein. ABEs and methods of their use are described, e.g. in U.S. Patent Nos.10,167,457 and 9,840,699, the contents of each of which are hereby incorporated by reference in their entireties.
• CBEs cytosine base editors
• base editor refers to an agent comprising a polypeptide that is capable of making a modification to a base (e.g., A, T, C, G, or U) within a nucleic acid sequence (e.g., DNA or RNA).
• a base e.g., A, T, C, G, or U
• a nucleic acid sequence e.g., DNA or RNA.
• the base editor is capable of deaminating a base within a nucleic acid.
• the base editor is capable of deaminating a base within a DNA molecule.
• the base editor is capable of deaminating an adenine (A) in DNA. .
• the deaminase is a cytosine deaminase or a cytidine deaminase.
• the base editor is a fusion protein comprising a nucleic acid programmable DNA binding protein (napDNAbp) fused to an adenosine deaminase.
• napDNAbp nucleic acid programmable DNA binding protein
• the base editor is a Cas9 protein fused to an adenosine deaminase.
• the base editor is a Cas9 nickase (nCas9) fused to an adenosine deaminase.
• the base editor is a nuclease-inactive Cas9 (dCas9) fused to an adenosine deaminase.
• the base editor is fused to an inhibitor of base excision repair, for example, a UGI domain, or a dISN domain.
• the fusion protein comprises a Cas9 nickase fused to a deaminase and an inhibitor of base excision repair, such as a UGI or dISN domain.
• nucleic acid programmable DNA binding protein refers to a protein that associates with a nucleic acid (e.g., DNA or RNA), such as a guide nuclic acid, that guides the napDNAbp to a specific nucleic acid sequence.
• a Cas9 protein can associate with a guide RNA that guides the Cas9 protein to a specific DNA sequence that has complementary to the guide RNA.
• the napDNAbp is a class 2 microbial CRISPR-Cas effector.
• the napDNAbp is a Cas9 domain, for example a nuclease active Cas9, a Cas9 nickase (nCas9), or a nuclease inactive Cas9 (dCas9).
• nucleic acid programmable DNA binding proteins include, without limitation, Cas9 (e.g., dCas9 and nCas9), CasX, CasY, Cpf1, C2c1, C2c2, C2C3, and Argonaute. It should be appreciated, however, that nucleic acid programmable DNA binding proteins also include nucleic acid programmable proteins that bind RNA.
• the napDNAbp may be associated with a nucleic acid that guides the napDNAbp to an RNA.
• Other nucleic acid programmable DNA binding proteins are also within the scope of this disclosure, though they may not be specifically listed in this disclosure.
• F. Modified RNAs [0394] In certain embodiments, the disclosed compositions, preparations, nanoparticles, and/or nanomaterials comprise modified nucleic acids, including modified RNAs. [0395] Modified nucleosides or nucleotides can be present in an RNA, for example a gRNA or mRNA.
• a gRNA or mRNA comprising one or more modified nucleosides or nucleotides, for example, is called a “modified” RNA to describe the presence of one or more non-naturally and/or naturally occurring components or configurations that are used instead of or in addition to the canonical A, G, C, and U residues.
• a modified RNA is synthesized with a non-canonical nucleoside or nucleotide, here called “modified.”
• Modified nucleosides and nucleotides can include one or more of: (i) alteration, e.g., replacement, of one or both of the non-linking phosphate oxygens and/or of one or more of the linking phosphate oxygens in the phosphodiester backbone linkage (an exemplary backbone modification); (ii) alteration, e.g., replacement, of a constituent of the ribose sugar, e.g.
• RNA can contain 5' end and 3' end modifications.
• a modified RNA can contain one or more modified residues at non-terminal locations.
• a gRNA includes at least one modified residue.
• an mRNA includes at least one modified residue.
• Unmodified nucleic acids can be prone to degradation by, e.g., intracellular nucleases or those found in serum.
• nucleases can hydrolyze nucleic acid phosphodiester bonds.
• the RNAs (e.g. mRNAs, gRNAs) described herein can contain one or more modified nucleosides or nucleotides, e.g., to introduce stability toward intracellular or serum- based nucleases.
• the modified gRNA molecules described herein can exhibit a reduced innate immune response when introduced into a population of cells, both in vivo and ex vivo.
• RNA or nucleic acids in the disclosed the disclosed compositions, preparations, nanoparticles, and/or nanomaterials comprise at least one modification which confers increased or enhanced stability to the nucleic acid, including, for example, improved resistance to nuclease digestion in vivo.
• the terms “modification” and “modified” as such terms relate to the nucleic acids provided herein, include at least one alteration which preferably enhances stability and renders the RNA or nucleic acid more stable (e.g., resistant to nuclease digestion) than the wild-type or naturally occurring version of the RNA or nucleic acid.
• the terms “stable” and “stability” as such terms relate to the nucleic acids of the present invention, and particularly with respect to the RNA, refer to increased or enhanced resistance to degradation by, for example nucleases (i.e., endonucleases or exonucleases) which are normally capable of degrading such RNA.
• Increased stability can include, for example, less sensitivity to hydrolysis or other destruction by endogenous enzymes (e.g., endonucleases or exonucleases) or conditions within the target cell or tissue, thereby increasing or enhancing the residence of such RNA in the target cell, tissue, subject and/or cytoplasm.
• endogenous enzymes e.g., endonucleases or exonucleases
• the stabilized RNA molecules provided herein demonstrate longer half-lives relative to their naturally occurring, unmodified counterparts (e.g. the wild-type version of the mRNA).
• RNA or nucleic acid of the disclosed compositions, preparations, nanoparticles, and/or nanomaterials disclosed herein have undergone a chemical or biological modification to render it more stable.
• RNA modifications include the depletion of a base (e.g., by deletion or by the substitution of one nucleotide for another) or modification of a base, for example, the chemical modification of a base.
• the phrase “chemical modifications” as used herein includes modifications which introduce chemistries which differ from those seen in naturally occurring RNA, for example, covalent modifications such as the introduction of modified nucleotides, (e.g., nucleotide analogs, or the inclusion of pendant groups which are not naturally found in such RNA molecules).
• the phosphate group of a modified residue can be modified by replacing one or more of the oxygens with a different substituent.
• modified residue e.g., modified residue present in a modified nucleic acid
• the backbone modification of the phosphate backbone can include alterations that result in either an uncharged linker or a charged linker with unsymmetrical charge distribution.
• modified phosphate groups include, phosphorothioate, phosphoroselenates, borano phosphates, borano phosphate esters, hydrogen phosphonates, phosphoroamidates, alkyl or aryl phosphonates and phosphotriesters.
• the phosphorous atom in an unmodified phosphate group is achiral.
• the stereogenic phosphorous atom can possess either the “R” configuration (herein Rp) or the “S” configuration (herein Sp).
• the backbone can also be modified by replacement of a bridging oxygen, (i.e., the oxygen that links the phosphate to the nucleoside), with nitrogen (bridged phosphoroamidates), sulfur (bridged phosphorothioates) and carbon (bridged methylenephosphonates). The replacement can occur at either linking oxygen or at both of the linking oxygens.
• the phosphate group can be replaced by non-phosphorus containing connectors in certain backbone modifications.
• the charged phosphate group can be replaced by a neutral moiety.
• moieties which can replace the phosphate group can include, without limitation, e.g., methyl phosphonate, hydroxylamino, siloxane, carbonate, carboxymethyl, carbamate, amide, thioether, ethylene oxide linker, sulfonate, sulfonamide, thioformacetal, formacetal, oxime, methyleneimino, methylenemethylimino, methylenehydrazo, methylenedimethylhydrazo and methyleneoxymethylimino.
• the disclosed compositions, preparations, nanoparticles, and/or nanomaterials comprise an mRNA comprising an open reading frame (ORF) encoding an RNA- guided DNA binding agent, such as a Cas nuclease, or Class 2 Cas nuclease as described herein.
• an mRNA comprising an ORF encoding an RNA-guided DNA binding agent, such as a Cas nuclease or Class 2 Cas nuclease is provided, used, or administered.
• An mRNA may comprise one or more of a 5' cap, a 5' untranslated region (UTR), a 3' UTRs, and a polyadenine tail.
• the mRNA may comprise a modified open reading frame, for example to encode a nuclear localization sequence or to use alternate codons to encode the protein.
• mRNA in the disclosed compositions, preparations, nanoparticles, and/or nanomaterials may encode, for example, a secreted hormone, enzyme, receptor, polypeptide, peptide or other protein of interest that is normally secreted.
• the mRNA may optionally have chemical or biological modifications which, for example, improve the stability and/or half-life of such mRNA or which improve or otherwise facilitate protein production.
• suitable modifications include alterations in one or more nucleotides of a codon such that the codon encodes the same amino acid but is more stable than the codon found in the wild-type version of the mRNA.
• C's cyti dines
• U's uridines
• the number of C and/or U residues in an mRNA sequence is reduced. In another embodiment, the number of C and/or U residues is reduced by substitution of one codon encoding a particular amino acid for another codon encoding the same or a related amino acid.
• Contemplated modifications to the mRNA nucleic acids of the present invention also include the incorporation of pseudouridines. The incorporation of pseudouridines into the mRNA nucleic acids of the present invention may enhance stability and translational capacity, as well as diminishing immunogenicity in vivo. See, e.g., Kariko, K., et al., Molecular Therapy 16 (11): 1833-1840 (2008), the contents of which is hereby incorporated by reference herein in its entirety.
• modification also includes, for example, the incorporation of non-nucleotide linkages or modified nucleotides into the mRNA sequences of the present invention (e.g., modifications to one or both the 3' and 5' ends of an mRNA molecule encoding a functional secreted protein or enzyme).
• Such modifications include the addition of bases to an mRNA sequence (e.g., the inclusion of a poly A tail or a longer poly A tail), the alteration of the 3' UTR or the 5' UTR, complexing the mRNA with an agent (e.g., a protein or a complementary nucleic acid molecule), and inclusion of elements which change the structure of an mRNA molecule (e.g., which form secondary structures).
• the poly A tail is thought to stabilize natural messengers. Therefore, in one embodiment a long poly A tail can be added to an mRNA molecule thus rendering the mRNA more stable.
• Poly A tails can be added using a variety of art-recognized techniques.
• long poly A tails can be added to synthetic or in vitro transcribed mRNA using poly A polymerase (Yokoe, et al. Nature Biotechnology. 1996; 14: 1252-1256, the contents of which is hereby incorporated by reference herein in its entirety).
• a transcription vector can also encode long poly A tails.
• poly A tails can be added by transcription directly from PCR products.
• the length of the poly A tail is at least about 90, 200, 300, 400 at least 500 nucleotides.
• the length of the poly A tail is adjusted to control the stability of a modified mRNA molecule of the invention and, thus, the transcription of protein.
• the length of the poly A tail can influence the half-life of an mRNA molecule
• the length of the poly A tail can be adjusted to modify the level of resistance of the mRNA to nucleases and thereby control the time course of protein expression in a cell.
• the stabilized mRNA molecules are sufficiently resistant to in vivo degradation (e.g., by nucleases), such that they may be delivered to the target cell without a transfer vehicle.
• an mRNA can be modified by the incorporation 3' and/or 5' untranslated (UTR) sequences which are not naturally found in the wild-type mRNA.
• 3' and/or 5' flanking sequence which naturally flanks an mRNA and encodes a second, unrelated protein can be incorporated into the nucleotide sequence of an mRNA molecule encoding a therapeutic or functional protein in order to modify it.
• 3' or 5' sequences from mRNA molecules which are stable e.g., globin, actin, GAPDH, tubulin, histone, or citric acid cycle enzymes
• compositions, preparations, nanoparticles, and/or nanomaterials and methods disclosed herein may include a template nucleic acid.
• a template may be used to alter or insert a nucleic acid sequence at or near a target site for an RNA-guided DNA binding protein such as a Cas nuclease, e.g., a Class 2 Cas nuclease.
• the methods comprise introducing a template to the cell.
• a single template may be provided.
• two or more templates may be provided such that editing may occur at two or more target sites.
• different templates may be provided to edit a single gene in a cell, or two different genes in a cell.
• a template may be used in homologous recombination.
• the homologous recombination may result in the integration of the template sequence or a portion of the template sequence into the target nucleic acid molecule.
• a template may be used in homology-directed repair, which involves DNA strand invasion at the site of the cleavage in the nucleic acid.
• homology-directed repair may result in including the template sequence in the edited target nucleic acid molecule.
• a template may be used in gene editing mediated by non-homologous end joining.
• a template sequence has no similarity to the nucleic acid sequence near the cleavage site.
• a template or a portion of the template sequence is incorporated.
• a template includes flanking inverted terminal repeat (ITR) sequences.
• ITR flanking inverted terminal repeat
• a template sequence may correspond to, comprise, or consist of an endogenous sequence of a target cell. It may also or alternatively correspond to, comprise, or consist of an exogenous sequence of a target cell.
• endogenous sequence refers to a sequence that is native to the cell.
• exogenous sequence refers to a sequence that is not native to a cell, or a sequence whose native location in the genome of the cell is in a different location.
• the endogenous sequence may be a genomic sequence of the cell.
• the endogenous sequence may be a chromosomal or extrachromosomal sequence.
• an endogenous sequence may be a plasmid sequence of the cell.
• a template contains ssDNA or dsDNA containing flanking invert- terminal repeat (ITR) sequences.
• a template is provided as a vector, plasmid, minicircle, nanocircle, or PCR product.
• a nucleic acid is purified.
• a nucleic acid is purified using a precipitation method (e.g., LiCl precipitation, alcohol precipitation, or an equivalent method, e.g., as described herein).
• a nucleic acid is purified using a chromatography-based method, such as an HPLC-based method or an equivalent method (e.g., as described herein).
• a nucleic acid is purified using both a precipitation method (e.g, LiCl precipitation) and an HPLC-based method.
• the nucleic acid is purified by tangential flow filtration (TFF). IV.
• Methods of manufacturing lipid nanoparticles are known in the art.
• the described compositions, preparations, nanoparticles, and/or nanomaterials are manufactured using microfluidics.
• exemplary methods of using microfluidics to form lipid nanoparticles are described by Leung, A.K.K, et al., J Phys Chem, 116:18440-18450 (2012), Chen, D., et al., J Am Chem Soc, 134:6947-6951 (2012), and Belliveau, N.M., et al., Molecular Therapy- Nucleic Acids, 1: e37 (2012), the disclosures of which are hereby incorporated by reference in their entireties.
• a cargo such as a cargo described herein, is prepared in a first buffer solution.
• the other lipid nanoparticle components (such as ionizable lipid, conjugate-linker lipids, cholesterol, and phospholipid) are prepared in a second buffer solution.
• a syringe pump introduces the two solutions into a microfluidic device. The two solutions come into contact within the microfluidic device to form lipid nanoparticles encapsulating the cargo.
• Methods of screening the disclosed lipid nanoparticles are described in International Patent Application No. PCT/US2018/058171, which is incorporated by reference in its entirety herein.
• the screening methods characterize vehicle delivery preparations to identify preparations with a desired tropism and that deliver functional cargo to the cytoplasm of specific cells.
• the screening method uses a reporter that has a functionality that can be detected when delivered to the cell. For example, detecting a functional reporter in a cell indicates that the LNP preparation delivers functional cargo to the cell.
• a chemical composition identifier is included in each different delivery vehicle formulation to keep track of the chemical composition specific for each different delivery vehicle formulation.
• a chemical composition identifier is a nucleic acid barcode.
• a sequence of the nucleic acid barcode is paired to which chemical components were used to formulate the LNP preparation in which it is loaded so that when the nucleic acid barcode is sequenced, the chemical composition of the delivery vehicle that delivered the barcode is identified.
• Representative barcodes include, but are not limited to, barcodes described by Sago, 2018 PNAS, Sago, JACS 2018, the disclosure of which is hereby incorporated by reference in its entirety.
• Representative reporters include, but are not limited to siRNA, mRNA, nuclease protein, nuclease mRNA, small molecules, epigenetic modifiers, and phenotypic modifiers.
• DNA can be isolated using QuickExtract (Lucigen) and sequenced using Illumina MiniSeq as described by Sago et al. PNAS 2018, Sago et al. JACs 2018, Sago, Lokugamage et al. Nano Letters 2018, the disclosures of which are hereby incorporated by reference in their entireties).
• V. Methods of use [0417] Among other things, the present disclosure describes methods of using compositions, preparations, nanoparticles, and/or nanomaterials described herein. For example, in some embodiments, the present disclosure describes methods of using compositions, preparations, nanoparticles, and/or nanomaterials to deliver cargo to specific cells, tissues, or organs, as described herein.
• compositions, preparations, nanoparticles, and/or nanomaterials described herein are for use in medicine.
• compositions, preparations, nanoparticles, and/or nanomaterials described herein deliver therapeutic or prophylactic agents to specific cells or organs in a subject in need thereof.
• the compositions, preparations, nanoparticles, and/or nanomaterials deliver therapeutic or prophylactic agents to specific cells or organs in a subject in need thereof in the absence of a targeting ligand.
• compositions, preparations, nanoparticles, and/or nanomaterials are useful to treat or prevent diseases in a subject in need thereof.
• A. Methods of delivering cargo to cells, tissue, or organs target a particular type or class of cells (e.g., cells of a particular organ or system thereof), tissues, and/organs.
• the present disclosure provides methods of delivering one or more cargos described herein to a subject in need thereof. In some embodiments, such methods comprise in vivo and/or in vitro delivery. In some embodiments, such methods comprise in vivo delivery.
• such methods comprise in vitro delivery.
• the present disclosure provides for methods of delivering one or more therapeutic and/or prophylactic nucleic acids to a subject in need thereof are described herein.
• a composition, preparation, nanoparticle, and/or nanomaterial comprises a therapeutic and/or prophylactic of interest that may be specifically delivered to liver cells in the subject. Exemplary liver cells include but are not limited to hepatocytes.
• a composition, preparation, nanoparticle, and/or nanomaterial comprises a therapeutic and/or prophylactic of interest that may be specifically delivered to spleen cells in the subject.
• Exemplary spleen cells include but are not limited to splenic monocytes, splenic T cells, splenic memory B cells, or splenic B cells.
• a composition, preparation, nanoparticle, and/or nanomaterial comprises a therapeutic and/or prophylactic of interest that may be specifically delivered to bone marrow cells in the subject.
• Exemplary bone marrow cells include but are not limited to bone marrow monocytes, bone marrow B cells, bone marrow memory B cells, or bone marrow T cells.
• a composition, preparation, nanoparticle, and/or nanomaterial comprises a therapeutic and/or prophylactic of interest that may be specifically delivered to immune cells in the subject.
• exemplary immune cells include but are not limited to CD8+, CD4+, or CD8+CD4+ cells.
• a composition, preparation, nanoparticle, and/or nanomaterial comprises a therapeutic and/or prophylactic of interest that may be specifically delivered to hematopoietic stem cells in the subject.
• HSCs hematopoietic stem cells
• HSPCs hematopoietic stem and progenitor cells
• the lipid nanoparticles can be formulated to be delivered in the absence of a targeting ligand to a mammalian liver hepatocytes, liver immune cells, spleen T cells, or lung endothelial cells.
• Specific delivery to a particular class or type of cells indicates that a higher proportion of lipid nanoparticles are delivered to target type or class of cells.
• specific delivery may result in a greater than 2 fold, 5 fold, 10 fold, 15 fold, or 20 fold compared to delivery using a conventional nanoparticle system (e.g., MC3-containing LNPs).
• a conventional nanoparticle system e.g., MC3-containing LNPs
• compositions, preparations, nanoparticles, and/or nanomaterials disclosed herein are used for methods of producing a polypeptide.
• lipid nanoparticles described herein can be used for producing a polypeptide in a target cell in a subject in need thereof.
• lipid nanoparticles described herein can be used for producing a polypeptide in a target cell in a subject in need thereof.
• compositions, preparations, nanoparticles, and/or nanomaterials disclosed herein comprise one or more nucleic sequences to be delivered to a cell.
• one or more nucleic acids are expressed in a cell.
• expression of a nucleic acid sequence involves one or more of the following: (1) production of an RNA template from a DNA sequence (e.g., by transcription); (2) processing of an RNA transcript (e.g., by splicing, editing, 5’ cap formation, and/or 3’ end formation); (3) translation of an RNA into a polypeptide or protein; and/or (4) post-translational modification of a polypeptide or protein.
• Methods of gene regulation [0428] Among other things, in some embodiments, methods of using compositions, preparations, nanoparticles, and/or nanomaterials disclosed herein are used for gene regulation.
• lipid nanoparticles described herein can be used for reducing and/or increasing gene expression in a target cell in a subject in need thereof.
• lipid nanoparticles described herein can deliver one or more nucleic acids to a target cell in the subject without a targeting ligand.
• a nucleic acid is an inhibitor nucleic acid.
• an inhibitory nucleic acid is an siRNA.
• a nucleic acid is a nucleic acid described herein.
• lipid nanoparticles described herein can deliver cargo to a target cell in the subject without a targeting ligand.
• a cell that is targeted for gene regulation is an immune cell.
• the immune cell can be a T cell, such as CD8+ T cell, CD4+ T cell, or T regulatory cell.
• Other exemplary immune cells for gene editing include but are not limited to macrophages, dendritic cells, B cells or natural killer cells.
• the cell that is targeted for gene regulation in a hepatocyte is not limited to macrophages, dendritic cells, B cells or natural killer cells.
• genes that can be targeted include but are not limited to T cell receptors, B cell receptors, CTLA4, PD1, FOXO1, FOXO3, AKTs, CCR5, CXCR4, LAG3, TIM3, Killer immunoglobulin-like receptors, GITR, BTLA, LFA-4, T4, LFA-1, Bp35, CD27L receptor, TNFRSF8, TNFRSF5, CD47, CD52, ICAM-1, LFA-3, L-selectin, Ki-24, MB1, B7, B70, M- CSFR, TNFR-II, IL-7R, OX-40, CD137, CD137L, CD30L, CD40L, FasL, TRAIL, CD257, LIGHT, TRAIL-R1, TRAILR2, TRAIL-R4, TWEAK-R, TNFR, BCMA, B7DC, BTLA, B7-H1, B7-H2, B7-H3, ICOS, VEGFR2, NKG2
• exemplary genes that can be targeted include but are not limited to OCT, G6Pase, Mut, PCCA, PCCB, PCSK9, ALAS1, and PAH.
• exemplary tumor-associated antigens that can be recognized by T cells and are contemplated for targeting include but are not limited to MAGE1, MAGE3, MAGE6, BAGE, GAGE, NYESO- 1, MART1/Melan A, MC1R, GP100, tyrosinase, TRP-1, TRP-2, PSA, CEA, Cyp-B, Her2/Neu, hTERT, MUC1, PRAME, WT1, RAS, CDK-4, MUM-1, KRAS, MSLN and ⁇ -catenin. D.
• subjects who are treated are mammals experiencing cancer, autoimmune disease, infections disease, organ transplant, organ failure, protein deficiency, or a combination thereof.
• a subject is a human.
• methods described herein may cause hepatocytes to translate certain proteins.
• methods described herein may be used to deliver one or more DNA, mRNA, sgRNA, or siRNA to a hepatocyte.
• methods described herein may be used to deliver one or more DNA, mRNA, sgRNA, or siRNA to a splenic T cell.
• methods described herein may be used to deliver one or more DNA, mRNA, sgRNA, or siRNA to a splenic B cell. In some embodiments, methods described herein may be used to deliver one or more DNA, mRNA, sgRNA, or siRNA to a splenic monocyte. In some embodiments, methods described herein may be used to deliver one or more DNA, mRNA, sgRNA, or siRNA to a bone marrow cell. [0433] It should be understood that the order of steps or order for performing certain action is immaterial so long as the invention remains operable. Moreover, two or more steps or actions may be conducted simultaneously.
• a compound of Formula A’ A’ or its N-oxide, or a pharmaceutically acceptable salt thereof, wherein L 1 is absent, C 1-6 alkylenyl, or C 2-6 heteroalkylenyl; each L 2 is independently optionally substituted C2-15 alkylenyl, or optionally substituted C3-15 heteroalkylenyl; L is C 1-10 alkylenyl, or C 2-10 heteroalkylenyl; X 2 is -OC(O)-, -C(O)O-, or -OC(O)O-; X is absent, -OC(O)-, -C(O)O-, or -OC(O)O-; R” is hydrogen, optionally substituted group selected from C6-20 aliphatic, 3- to 12-membered cycloaliphatic, 7- to 12-membered bridged bicyclic comprising 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 1- adamantyl, 2-adamantyl,
• a compound of Formula A or its N-oxide, or a pharmaceutically acceptable salt thereof, wherein L 1 is absent, C1-6 alkylenyl, or C2-6 heteroalkylenyl; each L 2 is independently C 2-10 alkylenyl, or C 3-10 heteroalkylenyl; L is C1-10 alkylenyl, or C2-10 heteroalkylenyl; each L 3 is independently absent, C1-10 alkylenyl, or C2-10 heteroalkylenyl; X 2 is -OC(O)-, -C(O)O-, or -OC(O)O-; X is absent, -OC(O)-, -C(O)O-, or -OC(O)O-; each R is independently hydrogen, optionally substituted group selected from C 6-20 aliphatic, C 6-20 haloaliphatic, a 3- to 7-membered cycloaliphatic ring, 1-adamantyl, 2-adamantyl
• a compound of Formula I I” or its N-oxide, or a pharmaceutically acceptable salt thereof, wherein L 1 is absent, C 1-6 alkylenyl, or C 2-6 heteroalkylenyl; each L 2 is independently optionally substituted C2-15 alkylenyl, or optionally substituted C3-15 heteroalkylenyl; L is C 1-10 alkylenyl, or C 2-10 heteroalkylenyl; X 2 is -OC(O)-, -C(O)O-, or -OC(O)O-; X is absent, -OC(O)-, -C(O)O-, or -OC(O)O-; each L 3 is independently absent, optionally substituted C 1-10 alkylenyl, or optionally substituted C 2-10 heteroalkylenyl; R” is hydrogen, optionally substituted group selected from C6-20 aliphatic, 3- to 12-membered cycloaliphatic, 7- to 12-membered bridge
• a compound of Formula I’ or its N-oxide, or a pharmaceutically acceptable salt thereof, wherein L 1 is absent, C 1-6 alkylenyl, or C 2-6 heteroalkylenyl; each L 2 is independently C 2-10 alkylenyl, or C 3-10 heteroalkylenyl; L is C1-10 alkylenyl, or C2-10 heteroalkylenyl; each L 3 is independently absent, C 1-10 alkylenyl, or C 2-10 heteroalkylenyl; X 2 is -OC(O)-, -C(O)O-, or -OC(O)O-; X is absent, -OC(O)-, -C(O)O-, or -OC(O)O-; each R is independently hydrogen, , or an optionally substituted group selected from C 6-20 aliphatic, C 6-20 haloaliphatic, a 3- to 7-membered cycloaliphatic ring, 1-adamantyl
• a compound of Formula I or its N-oxide, or a salt thereof, wherein L 1 is absent, C 1-6 alkylenyl, or C 2-6 heteroalkylenyl; each L 2 is independently C2-10 alkylenyl, or C3-10 heteroalkylenyl; L is C 1-10 alkylenyl, or C 2-10 heteroalkylenyl; each L 3 is independently absent, C 1-10 alkylenyl, or C 2-10 heteroalkylenyl; X 2 is -OC(O)-, -C(O)O-, or -OC(O)O-; X is absent, -OC(O)-, -C(O)O-, or -OC(O)O-; each R is independently hydrogen, , or an optionally substituted group selected from C6-20 aliphatic, C6-20 haloaliphatic, a 3- to 7-membered cycloaliphatic ring, 1-adamantyl, 2-adam
• a compound of Formula II II” or its N-oxide, or a pharmaceutically acceptable salt thereof, wherein L 1 is absent, C1-6 alkylenyl, or C2-6 heteroalkylenyl; each L 2 is independently optionally substituted C 2-15 alkylenyl, or optionally substituted C 3-15 heteroalkylenyl; L is C1-10 alkylenyl, or C2-10 heteroalkylenyl; X 2 is -OC(O)-, -C(O)O-, or -OC(O)O-; each L 3 is independently absent, optionally substituted C 1-10 alkylenyl, or optionally substituted C2-10 heteroalkylenyl; each R is independently hydrogen, or an optionally substituted group selected from C6-20 aliphatic, 3- to 12-membered cycloaliphatic, 7- to 12-membered bridged bicyclic comprising 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 1-adamantyl, 2-
• a compound of Formula II’ II’ or its N-oxide, or a pharmaceutically acceptable salt thereof, wherein L 1 is absent, C1-6 alkylenyl, or C2-6 heteroalkylenyl; each L 2 is independently C 2-10 alkylenyl, or C 3-10 heteroalkylenyl; L is C1-10 alkylenyl, or C2-10 heteroalkylenyl; each L 3 is independently absent, C1-10 alkylenyl, or C2-10 heteroalkylenyl; X 2 is -OC(O)-, -C(O)O-, or -OC(O)O-; each R is independently hydrogen, , or an optionally substituted group selected from C6-20 aliphatic, C6-20 haloaliphatic, a 3- to 7-membered cycloaliphatic ring, 1-adamantyl, 2-adamantyl, sterolyl, and phenyl; R 1 is hydrogen, optionally substituted pheny
• a compound of Formula II II or its N-oxide, or a salt thereof, wherein L 1 is absent, C 1-6 alkylenyl, or C 2-6 heteroalkylenyl; each L 2 is independently C2-10 alkylenyl, or C3-10 heteroalkylenyl; L is C1-10 alkylenyl, or C2-10 heteroalkylenyl; each L 3 is independently absent, C 1-10 alkylenyl, or C 2-10 heteroalkylenyl; X 2 is -OC(O)-, -C(O)O-, or -OC(O)O-; each R is independently hydrogen, , or an optionally substituted group selected from C 6-20 aliphatic, C 6-20 haloaliphatic, a 3- to 7-membered cycloaliphatic ring, 1-adamantyl, 2-adamantyl, sterolyl, and phenyl; R 1 is hydrogen, a 3- to 7-membered cycl
• each R 2 is independently hydrogen, -CN, -NO 2 , -OR 4 , -S(O) 2 R 4 , -S(O) 2 N(R 4 ) 2 , -(CH 2 ) n -R 4 , or an optionally substituted group selected from C1-6 aliphatic, a 3- to 7-membered cycloaliphatic ring, and a 3- to 7-membered heterocyclic ring comprising 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two occurrences of R 2 , taken together with the atom(s) to which they are attached, form an optionally substituted 4- to 7-membered heterocyclic ring comprising 0-1 additional heteroatom selected from nitrogen, oxygen, and sulfur; each R 3 is independently -(CH 2 ) n -R 4 , or two occurrences of R 3 , taken together with the atoms to which they are attached, form an optionally substituted 5- to 6-membered heterocyclic ring comprising
• a compound of Formula III III or its N-oxide, or a pharmaceutically acceptable salt thereof, wherein L 1 is absent, C 1-6 alkylenyl, or C 2-6 heteroalkylenyl; each L 2 is independently C 2-10 alkylenyl, or C 3-10 heteroalkylenyl; each L is independently C1-10 alkylenyl, or C2-10 heteroalkylenyl; each L 3 is independently absent, C 1-10 alkylenyl, or C 2-10 heteroalkylenyl; each X 2 is independently -OC(O)-, -C(O)O-, or -OC(O)O-; each R is independently hydrogen, , or an optionally substituted group selected from C 6-20 aliphatic, C 6-20 haloaliphatic, a 3- to 7-membered cycloaliphatic ring, 1-adamantyl, 2-adamantyl, sterolyl, and phenyl; R 1 is hydrogen, optionally substituted
• each L 2 is independently -CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, or -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -.
• each L 2 is independently C4-8 heteroalkylenyl.
• each L 2 is independently optionally substituted C2-9 alkylenyl, or optionally substituted C3-9 heteroalkylenyl. 55.
• each L 2 is independently optionally substituted C 2-9 alkylenyl.
• each L 2 is independently optionally substituted C 3-9 heteroalkylenyl.
• 59. The compound according to any one of embodiments 1-57, wherein each L is independently C1-5 alkylenyl, or C2-5 heteroalkylenyl. 60.
• each L is independently C1-5 alkylenyl.
• each L is independently -CH 2 - , -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, or -CH 2 CH 2 CH 2 CH 2 CH 2 -.
• each L is independently C 2-10 heteroalkylenyl.
• each L is independently C 2-5 heteroalkylenyl. 64.
• each of L 3 and L 3a is independently absent, optionally substituted C 1-10 alkylenyl, or optionally substituted C2-10 heteroalkylenyl.
• 65. The compound according to any one of embodiments 1-42 and 44-64, wherein each of L 3 and L 3a is independently absent, C 1-10 alkylenyl, or C 2-10 heteroalkylenyl.
• 66. The compound according to embodiment 65, wherein each of L 3 and L 3a is absent.
• each of L 3 and L 3a is independently C1-10 alkylenyl.
• each L 3 and L 3a is independently C 2- 10 heteroalkylenyl.
• the compound according to embodiment 65, wherein each of L 3 and L 3a is independently C 1-5 alkylenyl, or C 2-5 heteroalkylenyl.
• the compound according to embodiment 69, wherein each of L 3 and L 3a is independently C 1-5 alkylenyl.
• the compound according to embodiment 69, wherein each of L 3 and L 3a is independently C 2-5 heteroalkylenyl. 72.
• R is hydrogen, optionally substituted group selected from C6-20 aliphatic, 3- to 12-membered cycloaliphatic, 7- to 12-membered bridged bicyclic comprising 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 1- adamantyl, 2-adamantyl, sterolyl, and phenyl. 73.
• R is hydrogen, an optionally substituted group selected from C 6-20 aliphatic, 3- to 12-membered cycloaliphatic, 7- to 12-membered bridged bicyclic comprising 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 1-adamantyl, 2-adamantyl, sterolyl, and phenyl.
• R is hydrogen, an optionally substituted group selected from C 6-20 aliphatic, 3- to 12-membered cycloaliphatic, 1- adamantyl, and phenyl.
• R is hydrogen, or an optionally substituted group selected from C 6-20 aliphatic, 3- to 12-membered cycloaliphatic, 1-adamantyl, and phenyl.
• R is hydrogen, or an optionally substituted group selected from C 6-20 aliphatic, 3- to 12-membered cycloaliphatic, 1-adamantyl, and phenyl.
• R is hydrogen, or an optionally substituted group selected from C 6-20 aliphatic, 3- to 12-membered cycloaliphatic, 1-adamantyl, and phenyl.
• each of R and R a is independently hydrogen, or an optionally substituted group selected from C6-20 aliphatic, 3- to 12-membered cycloaliphatic, 7- to 12-membered bridged bicyclic comprising 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 1-adamantyl, 2-adamantyl, sterolyl, and phenyl. 90.
• each of R, and R a is independently hydrogen, or an optionally substituted group selected from C 6-20 aliphatic, 3- to 12-membered cycloaliphatic, 1-adamantyl, and phenyl.
• each of R and R a is independently hydrogen, optionally substituted group selected from C 6-20 aliphatic, 3- to 7-membered cycloaliphatic, 1-adamantyl, and phenyl.
• each of R and R a is hydrogen.
• each of R and R a is independently , wherein each R 6 is independently C 4-12 aliphatic.
• each of R and R a is independently optionally substituted C 6-20 aliphatic.
• each of R and R a is independently optionally substituted C 6-20 alkyl.
• each of R and R a is independently optionally substituted C 6-20 alkenyl.
• 98 The compound according to embodiment 95, wherein each of R and R a is independently optionally substituted C6-20 alkynyl.
• 99 The compound according to any one of embodiments 89-92 and 95, wherein each of R and R a is independently optionally substituted C6-20 haloaliphatic. 100.
• the compound according to embodiment 99, wherein each of R and R a is independently C6-20 haloaliphatic. 101.
• each of R and R a is independently optionally substituted C6-20 haloalkyl comprising 1-7 fluorine atoms.
• each of R and R a is independently C6-20 haloalkyl comprising 1-7 fluorine atoms.
• 103 The compound according to any one of embodiments 89-92, wherein each of R and R a is independently optionally substituted 3- to 12-membered cycloaliphatic.
• 104 The compound according to embodiment 103, wherein each of R and R a is independently optionally substituted 3- to 7-membered cycloaliphatic. 105.
• each of R and R a is independently optionally substituted cyclohexyl.
• 106 The compound according to any one of embodiments 89-92, wherein each of R and R a is independently optionally substituted 1-adamantyl.
• 107 The compound according to any one of embodiments 89-92, wherein each of R and R a is independently optionally substituted phenyl.
• 108 The compound according to any one of embodiments 1-107, wherein each of -L 3 -R”, -L 3 -R, and -L 3a -R a is independently selected from the group consisting of , . 109.
• each of -L 3 -R”, -L 3 -R, and -L 3a -R a is independently selected from the group consisting of , , , , , , , , , , , , , , , , , , , , , , . 110.
• each R 4 is independently -OR 5 . 129.
• each R 4 is independently -NR 5 C(S)N(R 5 ) 2 . 135.
• R 1 is optionally substituted 3- to 7-membered cycloaliphatic. 140.
• R 1 is optionally substituted 3- to 7-membered heterocyclyl comprising 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
• R 1 is optionally substituted 5- to 6-membered monocyclic heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
• R 1 is optionally substituted 8- to 10-membered bicyclic heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
• R 1 is -OR 2 , -OC(O)OR 2 , -C(O)OR 2 , -C(O)SR 2 , -N(R 2 ) 2 , -C(O)N(R 2 ) 2 , -S(O) 2 N(R 2 ) 2 , -NR 2 C(O)R 2 , -NR 2 S(O) 2 R 2 , -NR 2 C(O)N(R 2 ) 2 , -NR 2 C(S)N(R 2 ) 2 , -NR 2 C(NR 2 )N(R 2 ) 2 , or -CR 2 (OR 2 )R 3 .
• R 1 is -OR 2 , -OC(O)OR 2 , -C(O)OR 2 , -C(O)SR 2 , -N(R 2 ) 2 , -C(O)N(R 2 ) 2 , -S(O) 2 N(R 2 ) 2
• R 1 is -CR 2 (OR 2 )R 3 , . 145.
• R 1 is hydrogen, optionally substituted phenyl, optionally substituted 3- to 7-membered cycloaliphatic, optionally substituted 3- to 7-membered heterocyclyl comprising 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 5- to 6-membered monocyclic heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 8- to 10-membered bicyclic heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, -OR 2 , -C(O)OR 2 , -C(O)SR 2 , -N(R 2 ) 2 , -C(O)N(R 2 ) 2 , -S(O) 2 N(R 2 ) 2 , -NR 2 C(O
• R 1 is hydrogen, optionally substituted phenyl, optionally substituted 5- to 6-membered monocyclic heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 8- to 10-membered bicyclic heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, -OR 2 , -C(O)OR 2 , -C(O)SR 2 , -N(R 2 ) 2 , -C(O)N(R 2 ) 2 , -S(O) 2 N(R 2 ) 2 , -NR 2 C(O)R 2 , -NR 2 S(O) 2 R 2 , -NR 2 C(O)N(R 2 ) 2 , -CR 2 (R 3 ) 2 , -OP(O)(OR 2 ) 2 , -P(O)(OR 2 ) 2 , or a ring selected from
• each R 2 is independently hydrogen, oxo, -(CH 2 )n-R 4 , or an optionally substituted group selected from phenyl, and 5- to 6-membered monocyclic heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two occurrences of R 2 , taken together with the atom(s) to which they are attached, form optionally substituted 4- to 7-membered heterocyclyl comprising 0- 1 additional heteroatom selected from nitrogen, oxygen, and sulfur.
• each R 2 is independently hydrogen, oxo, -(CH 2 )n-R 4 , or an optionally substituted group selected from phenyl, and 5- to 6-membered monocyclic heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two occurrences of R 2 , taken together with the atom(s) to which they are attached, form optionally substituted 4- to 7-membered heterocyclyl comprising 0- 1 additional heteroatom selected from nitrogen, oxygen, and
• each R 3 is independently -(CH 2 )n-R 4 . 151.
• the compound according to embodiment 151, wherein each R 5 is independently hydrogen, or optionally substituted C1-6 aliphatic. 153.
• R 1 is selected from the group consisting of , , , , , 155.
• R 1 is selected from the group consisting of , , , , , , 156.
• 158. The compound according to embodiment 1, wherein the compound is selected from Table 1, or a pharmaceutically acceptable salt thereof. 159.
• a lipid nanoparticle (LNP) preparation comprising an ionizable lipid according to any one of embodiments 1-158.
• a lipid nanoparticle (LNP) preparation comprising: an ionizable lipid according to any one of embodiments 1-158; a phospholipid; a sterol; and a conjugate-linker lipid (e.g., polyethylene glycol lipid). 161.
• the LNP preparation of embodiment 160 further comprising one or more contaminants and/or degradants.
• the LNP preparation of embodiment 160 excluding one or more contaminants and/or degradants.
• the LNP preparation of embodiment 159 or 160 further comprising a therapeutic and/or prophylactic agent. 164.
• the LNP preparation of embodiment 164, wherein the one or more nucleic acids is or comprises DNA.
• the LNP preparation of any one of embodiments 164-167, wherein the one or more nucleic acids comprises both RNA and DNA. 169.
• the target cells are or comprise spleen cells (e.g., splenic B cells, splenic T cells, splenic monocytes), liver cells (e.g., hepatocytes), bone marrow cells (e.g., bone marrow monocytes), immune cells, kidney cells, muscle cells, heart cells, or cells in the central nervous system. 171.
• the LNP preparation of embodiment 169, wherein the target cells are or comprise hematopoietic stem cells (HSCs). 172.
• HSCs hematopoietic stem cells
• the phospholipid comprises 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-(succinyl) (succinyl PE), 1,2- distearoyl-sn-glycero-3-phosphocholine (DSPC), cholesterol, 1,2-distearoyl-sn-glycero-3- phosphoethanolamine (DSPE), 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-(succinyl) (succinyl-DPPE), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 1,2-dimyristoyl-sn- glycero-3-phosphocholine (DMPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), or a combination thereof.
• the phospholipid comprises 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-(
• DMG DiMystyrlGlycerol
• 1,2-Dipalmitoyl-rac-glycerol 1,2-Dipalmitoyl-rac- glycerol
• methoxypolyethylene Glycol DPG-PEG
• 1,2-Distearoyl-rac-glycero-3- methylpolyoxyethylene DSG
• a method for administering a therapeutic and/or prophylactic agent to a subject in need thereof comprising administering the LNP preparation of any one of embodiments 159-198, or the pharmaceutical composition of embodiment 199, to the subject.
• a method for treating a disease or a disorder in a subject in need thereof comprising administering the LNP preparation of any one of embodiments 159-198, or the pharmaceutical composition of embodiment 199, to the subject, wherein the therapeutic and/or prophylactic agent is effective to treat the disease.
• a method for delaying and/or arresting progression a disease or a disorder in a subject in need thereof comprising administering the LNP preparation of any one of embodiments 159-198, or the pharmaceutical composition of embodiment 199, to the subject, wherein the therapeutic and/or prophylactic agent is effective to treat the disease.
• a method of delivering a therapeutic and/or prophylactic agent to a mammalian cell derived from a subject the method comprising contacting the cell of the subject having been administered the LNP preparation of any one of embodiments 159-198, or the pharmaceutical composition of embodiment 199.
• the method of embodiment 205 comprising administering to the subject the LNP preparation of any one of embodiments 159-198, or the pharmaceutical composition of embodiment 199.
• a method of producing a polypeptide of interest in a mammalian cell comprising contacting the cell with the LNP preparation of any one of embodiments 159-198, or the pharmaceutical composition of embodiment 199, wherein the therapeutic and/or prophylactic agent is or comprises an mRNA, and wherein the mRNA encodes the polypeptide of interest, whereby the mRNA is capable of being translated in the cell to produce the polypeptide of interest.
• the therapeutic and/or prophylactic agent is or comprises an mRNA, and wherein the mRNA encodes the polypeptide of interest, whereby the mRNA is capable of being translated in the cell to produce the polypeptide of interest.
• a method of inhibiting production of a polypeptide of interest in a mammalian cell comprising contacting the cell with the LNP preparation of any one of embodiments 159- 198, or the pharmaceutical composition of embodiment 199, wherein the therapeutic and/or prophylactic agent is or comprises an RNA, whereby the RNA is capable of inhibiting production of the polypeptide of interest.
• the RNA comprises an antisense RNA, a miRNA, a shRNA, a siRNA, or a gRNA. 210.
• a method of specifically delivering a therapeutic and/or prophylactic agent to a mammalian organ comprising contacting a mammalian organ with the LNP preparation of any one of embodiments 159-198, or the pharmaceutical composition of embodiment 199, whereby the therapeutic and/or prophylactic agent is delivered to the organ.
• the method of embodiment 210 comprising administering to a subject the LNP preparation of any one of embodiments 159-198, or the pharmaceutical composition of embodiment 199 to the subject.
• a method of manufacturing an intermediate e.g., any intermediate that may be stored or shipped
• a method of inducing an adaptive immune response in a subject comprising administering to the subject an effective amount of a composition comprising at least one RNA; wherein the composition comprises a LNP preparation comprising a compound of any of Formulae A’, A, I”, I’, I, II”, II’, II, III’, III, I”-a, I’-a, I-a, I”-a-i, I”-a-ii, I”-a-iii, I”-b, I’-b, I”-b-i, I”-b-ii, I”-b-iii, I”-c, I’-c, I-c, I”-c-i, I”-c-ii, I”-c-iii, I’-d, I-d, I’-d-i, II-a, II-a-i, III-a, and III-a-i, or any one of embodiments 1-158, or a pharmaceutically acceptable salt thereof.
• the present disclosure exemplifies compositions, preparations, formulations, nanoparticles, and/or nanomaterials described herein.
• the present disclosure also exemplifies methods of preparing, characterizing, and validating compositions, preparations, formulations, nanoparticles, and/or nanomaterials described herein.
• Example 1 Materials and Methods [0437]
• the present Example provides exemplary materials and methods of preparing, characterizing, and validating compositions, preparations, nanoparticles, and/or nanomaterials described herein.
• LNP preparations [0438] Among other things, the present Example provides for exemplary LNP preparations. [0439] Lipid nanoparticle components were dissolved in 100% ethanol at specified lipid component molar ratios.
• NA cargo was dissolved in 10 mM citrate, 100 mM NaCl, pH 4.0, resulting in a concentration of NA cargo of approximately 0.22 mg/mL.
• NA cargos include both a functional NA and a reporter DNA barcode mixed at mass ratios of 1:10 to 10:1 functional NA to barcode.
• a NA can be a siRNA, an anti-sense, an expressing DNA, or mRNA.
• LNPs were prepared with a total lipid to NA mass ratio of 11.7. LNPs were formed by microfluidic mixing of the lipid and NA solutions using a Precision Nanosystems NanoAssemblr Spark or Benchtop series Instruments, according to the manufacturers protocol.
• a ratio of aqueous to organic solvent of approximately 2:1 or 3:1 was maintained during mixing using differential flow rates.
• LNPs were collected, diluted in PBS (approximately 1:1 v/v). Further buffer exchange was conducted using dialysis in PBS at 4°C for 4 to 24 hours against a 20kDa filter. After this initial dialysis, each individual LNP preparation was characterized via dynamic light scattering (DLS) to measure the size (e.g., diameter) and polydispersity.
• pKa of a subpopulation of LNPs was measured via a 2-(p-toluidino)-6-napthalene sulfonic acid (TNS) assay.
• LNPs falling within specific diameter and polydispersity ranges were pooled, and further dialyzed against phosphate buffer saline (PBS) at 4°C for 1 to 4 hours against a 100kDa dialysis cassette. After the second dialysis, LNPs were sterile filtered using 0.22 ⁇ M filter and stored at 4°C for further use.
• LNP characterization [0441] DLS - LNP hydrodynamic diameter and polydispersity index (PDI) were measured using high throughput dynamic light scattering (DLS) (DynaPro plate reader II, Wyatt). LNPs were diluted 1X PBS to an appropriate concentration and analyzed.
• DLS high throughput dynamic light scattering
• Concentration of NA was determined by Qubit microRNA kit (for siRNA) or HS RNA kit (for mRNA) per manufacturer’s instructions. Encapsulation efficiency was determined by measuring nucleic acid concentration in unlysed and lysed LNPs.
• pKa A stock solution of 10 mM HEPES (Sigma Aldrich), 10 mM MES (Sigma Aldrich), 10 mM sodium acetate (Sigma), and 140 nM sodium chloride (Sigma Aldrich) was prepared, and pH was adjusted using hydrogen chloride and sodium hydroxide to a range of about pH 4-10.
• mice were temporarily restrained, and pooled LNP was administered intravenously (IV) via tail vein injection in up to five animals per experiment.
• Age- matched mice were also used to administer vehicle (1X PBS) via tail vein injection in up to three animals per experiment.
• tissues including liver, spleen, bone marrow, kidney, lung, muscle, and blood were collected for analysis.
• Flow [0445] Liver, kidney, lung, and muscle tissues were mechanically, and then enzymatically digested using a mixture of proteinases, then passed through a 70uM filter to generate single cell suspensions. Spleen tissues were mechanically digested to generate single cell suspensions.
• gating structure is size ⁇ singlet cells ⁇ live cells ⁇ cells of interest. T cells were defined as CD45+CD3+, monocytes are defined as CD45+CD11b+, and B cells are defined as CD45+CD19+.
• Endothelial cells were defined as CD31+, monocytes and Kupffer cells as CD45+CD11b+ and hepatocytes as CD31-/CD45-.
• siRNA studies downregulation of the target gene was gated.
• upregulation of the target gene was gated. Tissues from vehicle-dosed mice were used to set the gates for sorting. Up to 1 million cells of each cell subset with the correct phenotype were sorted into PBS. After sorting, cells were pelleted via centrifugation and DNA is extracted using Quick Extract DNA Extraction Solution (Lucigen) according to manufacturer’s protocol. Following DNA extraction, DNA was stored at -20°C.
• NA cargo was dissolved in 10 mM citrate, 100 mM NaCl, pH 4.0, resulting in a concentration of NA cargo of approximately 0.22 mg/mL.
• NA cargos include both a functional NA and a reporter DNA barcode mixed at mass ratios of 1:10 to 10:1 functional NA to barcode.
• LNPs were formulated with a total lipid to NA mass ratio of 11.7. LNPs were formed by microfluidic mixing of the lipid and NA solutions using a Precision Nanosystems NanoAssemblr Spark or Benchtop series Instruments, according to the manufacturers protocol. A 2:1 or 3:1 ratio of aqueous to organic solvent was maintained during mixing using differential flow rates.
• LNPs were collected, diluted in PBS (approximately 1:1 v/v), and further buffer exchange was conducted using dialysis in PBS at 4°C for 8 to 24 hours against a 20kDa filter. After this initial dialysis, each individual LNP formulation was characterized via DLS to measure the size and polydispersity, and the pKa of a subpopulation of LNPs was measured via TNS assay. A fter dialysis, LNPs are sterile filtered using 0.22 micron sterile filter and stored at 4°C for further use.
• LNP Characterization DLS LNP hydrodynamic diameter and polydispersity index (PDI) were measured using high throughput dynamic light scattering (DLS) (DynaPro plate reader II, Wyatt). LNPs were diluted 1X PBS to an appropriate concentration and analyzed. Concentration & Encapsulation Efficiency [0450] Concentration of NA was determined by Qubit microRNA kit (for siRNA) or HS RNA kit (for mRNA) per manufacturer’s instructions. Encapsulation efficiency was determined by measuring unlysed and lysed LNPs.
• a stock solution of 10 mM HEPES (Sigma Aldrich), 10 mM MES (Sigma Aldrich), 10 mM sodium acetate (Sigma), and 140 nM sodium chloride (Sigma Aldrich) was prepared and pH adjusted using hydrogen chloride and sodium hydroxide to a range of about pH 4-10. Using four replicates for each pH, 140 ⁇ L pH-adjusted buffer was added to a 96-well plate, followed by the addition 5 ⁇ L of 2-(p-toluidino)-6- napthalene sulfonic acid (60 ⁇ g/ mL). 5 ⁇ L of LNP was added to each well.
• mice Male and female mice aged approximately 8-12 weeks were used for studies described by the present Example. Each mouse was temporarily restrained, and pooled LNP was administered IV via tail vein injection in up to five animals per experiment. Age-matched mice was also used to administer vehicle (1X PBS) via tail vein injection in up to three animals per experiment.
• Additional routes of administration can also be conducted including intracerebral ventricular (ICV), intracisterna manga (ICM), intrathecal (IT), intramuscular (IM), nebulization, intranasal (IN), subcutaneous (SC), intraarticular, and intradermal (ID).
• ICV intracerebral ventricular
• ICM intracisterna manga
• IT intrathecal
• IM intramuscular
• nebulization intranasal
• SC subcutaneous
• intraarticular intradermal
• ID intradermal
• tissues including liver, spleen, bone marrow and blood were collected for analysis.
• Liver, kidney, lung, and muscle (e.g. skeletal and cardiac) tissues were mechanically, and then enzymatically digested using a mixture of proteinases, then passed through a 70uM filter to generate single cell suspensions. Spleen tissues were mechanically digested to generate single cell suspensions.
• Tissues were treated with ACK buffer to lyse red blood cells, and then stained with fluorescently-labeled antibodies for flow cytometry and fluorescence-activated cell sorting (FACS).
• FACS fluorescence-activated cell sorting
• Commercially available antibodies were used in the present example.
• samples were acquired via flow cytometry to generate gates prior to sorting.
• the gating structure was size singlet cells live cells cells of interest. T cells were defined as CD45+CD3+, monocytes are defined as CD45+CD11b+, and B cells are defined as CD45+CD19+.
• Endothelial cells were defined as CD31+, monocytes and Kupffer cells as CD45+CD11b+ and hepatocytes and myocytes were defined as CD31-/CD45- in the liver and muscle, respectively. Tissues from vehicle-dosed mice were used to set the gates for sorting.
• hEPO Expression For human EPO (hEPO) protein expression, mice were temporarily restrained and bled at 6 hours post-administration (via tail vein). Blood was collected in heparin tubes, processed to plasma, and stored at -80°C until ready to use. Appropriate dilutions of plasma were used to measure hEPO protein using R&D systems ELISA kit (DuoSet; DY286-05) according to manufacturer’s instructions.
• ALT / AST Quantification For rat Aspartate Transaminase (AST) and Alanine Transaminase (ALT) quantification, rats were temporarily restrained and bled at 2, 4, 6, 24, 48, and 72 hrs hours post-administration. Blood was collected in heparin tubes, processed to plasma, and stored at -80°C until ready to use. AST is quantified using AST/GOT reagent (ThermoFisher, TR70121) and ALT is quantified using ALT/GPT reagent (ThermoFisher, TR71121) according to manufacturer’s instructions.
• Rat MCP-1 ELISA For Rat Monocype Chemoattractant Protein-1 (MCP-1) protein expression, rats were temporarily restrained and bled at 2, 4, 6, 24, 48, and 72 hrs hours post-administration. Blood was collected in heparin tubes, processed to plasma, and stored at -80°C until ready to use. Appropriate dilutions of plasma were used to measure MCP-1 protein using R&D systems ELISA kit (DuoSet; DY3144-05) according to manufacturer’s instructions. Screening Experiments [0457] As described herein, a plurality of LNPs (for example, more than 300 LNP preparations) can be simultaneously tested in a single screening experiment.
• MCP-1 ELISA Rat Monocype Chemoattractant Protein-1
• each LNP preparation was formulated to carry Cre mRNA and a barcode as described herein.
• Each LNP preparation was administered to LSL-tdTom mouse (Ai14) (see FIG.1) in accordance with the methods described herein (see also FIG.1). Referring to FIG. 1, a library of LNP preparations each comprising one or more components, a barcode sequence, and Cre mRNA was administered into a Cre-LoxP reporter mouse.
• each LNP preparation was formulated to carry siGFP and barcodes, as described herein.
• Each LNP preparation was administered to a GFP mouse (see FIG. 2) in accordance with the methods described herein (see also FIG.2).
• a library of LNP preparations each comprising one or more components, a barcode sequence, and siGFP was administered into a GFP reporter mouse.
• cells were sorted using FACS based on GFP expression. Sorted cells were then sequenced as descried herein.
• LNP preparations were formulated using compounds described herein and compounds developed by Applicant that are described in U.S. Provisional Application Nos. 63/128,685 and 63/128,682.
• About 20 LNP preparations were formulated using MC3 as a control. The following measurements were made: LNP preparation diameter, LNP preparation polydispersity, “normalized delivery efficiency” to any combination of cell- and tissue- types (e.g., about 27 per screen), LNP preparation pKA (which is related to, but not the same as lipid pKA), lipid pKA, and LNP preparation ionizability. Encapsulation efficiency and delivery potency were also measured for each pool of LNP preparations. hEPO expression and Cre expression measurements were performed as described herein.
• Example 2 Potency per screen
• the present Example provides exemplary compositions, preparations, nanoparticles, and/or nanomaterials, and materials and methods for screening potency of such compositions, preparations, nanoparticles, and/or nanomaterials described herein.
• FIG.3 depicts a bar graph that shows overall potency of three exemplary LNP screens as described in Example 1 (Screen 33, Screen 35, Screen 36). Screen 33 contains compounds of the present disclosure, while Screens 35 and 36 contain compounds described in U.S. Provisional Application Nos.63/128,685 and 63/128,682.
• Example 3 Exemplary LNP preparations with potent delivery to various cell types [0463]
• the present Example provides exemplary LNP compositions, preparations, nanoparticles, and/or nanomaterials for potent delivery to various cell types described herein.
• lipids exemplary LNP preparations (Exemplary Lipid 7, Exemplary Lipid 5, Exemplary Lipid 6, Exemplary Lipid 1, which are exemplary compounds of any of Formulae A’, A, I”, I’, and I, and exemplary compounds of compounds 7-1 to 7-16) were identified for use in splenic delivery, and in particular, for use in B cell delivery. These identified lipids were formulated into LNP preparations and screened using a Cre reporter system described herein. Three Ai14 mice were used per group. Payloads comprised 0.3 mg/kg Cre mRNA. Data was collected at 168 hours post-injection. Results were compared to an MC3-LNP preparation as a control (see FIG. 4).
• Exemplary Lipids 7, 5, 6, and 1 are exemplary compounds of any of Formulae A’, A, I”, I’, and I, and exemplary compounds of compounds 7-1 to 7-16. Accordingly, the present example demonstrates that in some embodiments, lipids characterized by including an ester-linked acetal feature show potent delivery to various cell-types, for example splenic B cells and T cells.
• Example 4 Exemplary LNP preparations are delivered to various cell types
• the present Example provides exemplary LNP compositions, preparations, nanoparticles, and/or nanomaterials with potent delivery to various cell types as described herein.
• LNP preparations Example 1
• Four LNP preparations Example 1
• FIG.5 also includes data for Exemplary Lipids 2, 3, and 4, which are exemplary compounds described in U.S. Provisional Application Nos.63/128,685 and 63/128,682.
• FIG.5 shows % tdTomato+ cells across a variety of cell-types (bone marrow B cells, bone marrow memory B cells, bone marrow T cells, bone marrow monocytes, spleen monocytes, spleen T cells, spleen B cells, and spleen memory B cells) using four exemplary LNP preparations (Exemplary Lipid 1, Exemplary Lipid 2, Exemplary Lipid 3, Exemplary Lipid 4) containing 1 mg/kg Cre mRNA compared to a saline control. Data was also collected for liver delivery but is not shown. Three Ai14 mice per group were used in each experiment. Data was collected 72 hours post-injection. Unexpectedly, representative data in FIG.
• Exemplary Lipid 1 is an exemplary compound of any of Formulae A’, A, I”, I’, and I, and one of compounds 7-1 to 7-16. Accordingly, in some embodiments, the present example demonstrates that lipids characterized by having an ester-linked acetal feature show potent delivery across various cell types, including bone marrow B cells, bone marrow memory B cells, bone marrow monocytes, spleen monocytes, spleen B cells, and spleen memory B cells.
• Example 5 Exemplary LNP preparations deliver functional mRNA
• the present Example provides exemplary LNP compositions, preparations, nanoparticles, and/or nanomaterials that deliver functional mRNA to various cell types.
• Three exemplary LNP preparations (Exemplary Lipid 7, Exemplary Lipid 5, Exemplary Lipid 1, which are exemplary compounds of any of Formulae A’, A, I”, I’, and I, and exemplary compounds of compounds 7-1 to 7-16) were selected to determine each preparation’s ability to deliver functional mRNA in mice.
• LNP preparations each carried 0.15 mg/kg hEPO mRNA and was administered at a mass ratio of 11.7 and 19 in 2-3 C57BL6 mice.
• Exemplary Lipids 7, 5, and 1 are exemplary compounds of any of Formulae A’, A, I”, I’, and I, and exemplary compounds of compounds 7-1 to 7-16. Accordingly, in some embodiments, the present example demonstrates lipids characterized by having an ester-linked acetal are able to deliver functional mRNA in mice.
• Example 6 Tolerability and efficacy experiments
• the present Example provides exemplary materials and methods of preparing, characterizing, and validating compositions, preparations, nanoparticles, and/or nanomaterials described herein.
• LNP preparations Two exemplary LNP preparations (Exemplary Lipid 5 and Exemplary Lipid 1, which are exemplary compounds of any of Formulae A’, A, I”, I’, and I, and exemplary compounds of compounds 7-1 to 7-16) were selected to determine tolerability and efficacy of hEPO mRNA delivery in rats as described herein.
• FIG.7 shows amount of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) collected from rat plasma (U/L) at 24 hours post- injection for each exemplary LNP preparation.
• ALT alanine aminotransferase
• AST aspartate aminotransferase
• FIG.8 shows amount of monocyte chemoattractant protein-1 (MCP-1) collected from rat plasma (ng/mL) at 6 hours post-injection for each LNP preparation. Saline was used as a control.
• FIG. 9 shows amount of hEPO collected from rat plasma (ng/mL) after administering a vehicle (control) and the two exemplary LNP preparations across various time points post-injection (0, 2, 4, 6, 24, 48, 96 hours).
• Exemplary Lipids 1 and 5 are exemplary compounds of any of Formulae A’, A, I”, I’, and I, and exemplary compounds of compounds 7-1 to 7-16.
• the present example demonstrates that lipids characterized by having an ester-linked acetal feature are able to deliver functional mRNA in mice.
• Example 7 Synthesis of Ionizable lipids [0475]
• the present Example provides exemplary materials and methods of preparing, characterizing, and validating ionizable lipids as described herein.
• compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds of the present disclosure, the following general methods and other methods known to one of ordinary skill in the art can be applied to all compounds and subclasses and species of each of these compounds, as described herein.
• Ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) was performed using a Waters Acquity UPLC H-class Plus with QDa detector (ESI + ) using one of the following methods.
• Method A 6 min run, Column: BEH C18 (2.1 x 50 mm), 1.7 ⁇ M, mobile phase: initially 90% [0.1% HCOOH in water] and 10% ACN; then to 5% [0.1% HCOOH in water] and 95% ACN over 3 min, held this mobile phase composition for 2 min, and finally back to initial condition over 1 min, i.e; 90% [0.1% HCOOH in water] and 10% ACN.
• Flow 0.5 mL/min.
• Method C 12 min run, Column: XTERRA RP 18 (4.6 x 50 mm), 5 ⁇ m, (mobile phase: initially 80% [0.1% HCOOH in water] and 20% [0.1% HCOOH in (70:30) ACN: THF]; held this initial condition for 0.75 min; then to 65% [0.1% HCOOH in water] and 35% [0.1% HCOOH in (70:30) ACN: THF] in 3.0 min, then to 2% [0.1% HCOOH in water] and 98% [0.1% HCOOH in (70:30) ACN: THF] in 6.0 min, held this mobile phase composition up to 9.0 min, and finally back to initial condition, i.e.; 80% [0.1% HCOOH in WATER] and 20% [0.1% HCOOH in (70:30) ACN: THF] in 11.00 min, held this mobile phase composition up to 12.10 min.
• Example 7-1 nonyl 8-((6-((4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanoyl)oxy)hexyl)(2- hydroxyethyl)amino)octanoate
• Step 1 4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanenitrile
• General Procedure A [0481] To a vial containing pyridinium p-toluene sulfonate (0.12 g, 0.48 mmol, 0.05 Eq) was added 4,4-diethoxybutanenitrile (1.5 g, 9.5 mmol, 1 Eq) and cis-5-octen-1-ol (3.7 g, 29 mmol, 3 Eq).
• the vial was tightly capped, and the resulting mixture was heated at 105 oC for 72 h. After this time, the mixture was allowed to cool to room temperature.
• the crude material was purified by flash column chromatography (100 g silica, 0 to 100% dichloromethane in hexanes over 20 minutes). Obtained 4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanenitrile (1.14 g, 37%) as a colorless oil.
• Step 2 4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanoic acid
• Procedure B [0482] To a vial containing 4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanenitrile (1.14 g, 3.54 mmol, 1 Eq) was added potassium hydroxide (0.60 g, 10.6 mmol, 3 Eq) followed by ethanol (3.5 mL) and water (3.5 mL). The vial was tightly capped, and the reaction mixture was heated to 110 oC for 18 h. After this time, the mixture was allowed to cool to room temperature.
• Step 3 6-bromohexyl 4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanoate
• General Procedure C [0483] To a solution of 4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanoic acid (508 mg, 1 Eq, 1.49 mmol) in DCM (13 mL) was added 6-bromohexan-1-ol (270 mg, 195 ⁇ L, 1 Eq, 1.49 mmol), DIPEA (964 mg, 1.29 mL, 5 Eq, 7.46 mmol) , and DMAP (36.4 mg, 0.2 Eq, 298 ⁇ mol).
• Step 4 nonyl 8-bromooctanoate
• DCM dimethyl methacrylate
• Step 5 nonyl 8-((2-hydroxyethyl)amino)octanoate
• ACN/THF (1:1) 0.5 mL
• ethanolamine 1.7 mL, 28.04 mmol, 30 eq
• the reaction mixture was concentrated in vacuo and diluted with water (20 mL) and extracted with ethyl acetate (20 mL ⁇ 3).
• Step 6 nonyl 8-((6-((4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanoyl)oxy)hexyl)(2- hydroxyethyl)amino)octanoate (Example 7-1)
• General Procedure F [0486] To a solution of 6-bromohexyl 4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanoate (305 mg, 1 Eq, 606 ⁇ mol) in ACN (3 mL) and THF (3 mL) was added potassium carbonate (251 mg, 3 Eq, 1.82 mmol), potassium iodide (121 mg, 1.2 Eq, 727 ⁇ mol), and nonyl 8-((2- hydroxyethyl)amino)octanoate (200 mg, 1 Eq, 606 ⁇ mol).
• the resulting mixture was stirred at 85oC for 18 h. After this time, the mixture was filtered through a pad of celite and concentrated. The residue was partitioned between ethyl acetate and water, and the organic layer washed twice with water and once with brine. The organics were combined, dried over sodium sulfate and concentrated. The resulting residue was purified by flash column chromatography (50 g silica, 0 to 10% methanol in DCM).
• Step 2 (Z)-oct-5-en-1-yl 8-((2-hydroxyethyl)amino)octanoate [0488] Prepared according to General Procedure E, substituting (Z)-oct-5-en-1-yl 8- bromooctanoate for nonyl 8-bromooctanoate. Isolated 210 mg, 57%. UPLC-MS (Method A): Rt 2.38 min, m/z calculated [M+H]: 314.26, found 314.41.
• Step 3 (Z)-oct-5-en-1-yl 8-((6-((4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanoyl)oxy)hexyl)(2- hydroxyethyl)amino)octanoate (Example 7-2) [0489] Prepared according to General Procedure F, substituting (Z)-oct-5-en-1-yl 8-((2- hydroxyethyl)amino)octanoate for nonyl 8-((2-hydroxyethyl)amino)octanoate. Isolated 63 mg, 36%.
• Step 3 7,7,8,8,8-pentafluorooctyl 8-((6-((4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanoyl)oxy)hexyl)(2- hydroxyethyl)amino)octanoate (Example 7-3) [0492] Prepared according to General Procedure F, substituting 7,7,8,8,8-pentafluorooctyl 8-((2- hydroxyethyl)amino)octanoate for nonyl 8-((2-hydroxyethyl)amino)octanoate. Isolated 99 mg, 65%.
• Step 3 3,7-dimethyloct-6-en-1-yl 8-((6-((4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanoyl)oxy)hexyl)(2- hydroxyethyl)amino)octanoate (Example 7-4) [0495] Prepared according to General Procedure F, substituting 3,7-dimethyloct-6-en-1-yl 8-((2- hydroxyethyl)amino)octanoate for nonyl 8-((2-hydroxyethyl)amino)octanoate. Isolated 40 mg, 24%.
• Step 3 6-bromohexyl 4,4-bis(octyloxy)butanoate [0498] Prepared according to General Procedure C, substituting 4,4-bis(octyloxy)butanoic acid for 4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanoic acid. Isolated 878 mg, 63%.
• Step 4 nonyl 8-((6-((4,4-bis(octyloxy)butanoyl)oxy)hexyl)(2-hydroxyethyl)amino)octanoate (Example 7-5) [0499] Prepared according to General Procedure F, substituting 6-bromohexyl 4,4- bis(octyloxy)butanoate for 6-bromohexyl 4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanoate. Isolated 87 mg, 51%. UPLC-MS (Method A): Rt 3.83 min, m/z calculated [M+H]: 756.66, found 756.65.
• Example 7-6 (Z)-oct-5-en-1-yl 8-((6-((4,4-bis(octyloxy)butanoyl)oxy)hexyl)(2- hydroxyethyl)amino)octanoate [0500] Prepared according to General Procedure F, substituting 6-bromohexyl 4,4- bis(octyloxy)butanoate for 6-bromohexyl 4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanoate and (Z)-oct-5- en-1-yl 8-((2-hydroxyethyl)amino)octanoate for nonyl 8-((2-hydroxyethyl)amino)octanoate. Isolated 104 mg, 59%. UPLC-MS (Method A): Rt 3.65 min, m/z calculated [M+H]: 740.63, found 740.
• Example 7-7 7,7,8,8,8-pentafluorooctyl 8-((6-((4,4-bis(octyloxy)butanoyl)oxy)hexyl)(2- hydroxyethyl)amino)octanoate [0501] Prepared according to General Procedure F, substituting 6-bromohexyl 4,4- bis(octyloxy)butanoate for 6-bromohexyl 4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanoate and 7,7,8,8,8- pentafluorooctyl 8-((2-hydroxyethyl)amino)octanoate for nonyl 8-((2- hydroxyethyl)amino)octanoate.
• Example 7-9 nonyl 8-((6-((4,4-bis((7,7,8,8,8-pentafluorooctyl)oxy)butanoyl)oxy)hexyl)(2- hydroxyethyl)amino)octanoate
• Step 1 4,4-bis((7,7,8,8,8-pentafluorooctyl)oxy)butanenitrile [0503] Prepared according to General Procedure A, substituting 7,7,8,8,8-pentafluoro-1-octanol for cis-5-octen-1-ol. Isolated 4.74 g, 40%.
• Step 2 4,4-bis((7,7,8,8,8-pentafluorooctyl)oxy)butanoic acid [0504] Prepared according to General Procedure B, substituting 4,4-bis((7,7,8,8,8- pentafluorooctyl)oxy)butanenitrile for 4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanenitrile. Isolated 1.6 g, 96%.
• Step 3 6-bromohexyl 4,4-bis((7,7,8,8,8-pentafluorooctyl)oxy)butanoate [0505] Prepared according to General Procedure C, substituting 4,4-bis((7,7,8,8,8- pentafluorooctyl)oxy)butanoic acid for 4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanoic acid.
• Example 7-11 7,7,8,8,8-pentafluorooctyl 8-((6-((4,4-bis((7,7,8,8,8- pentafluorooctyl)oxy)butanoyl)oxy)hexyl)(2-hydroxyethyl)amino)octanoate [0508] Prepared according to General Procedure F, substituting 6-bromohexyl 4,4-bis((7,7,8,8,8- pentafluorooctyl)oxy)butanoate for 6-bromohexyl 4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanoate and 7,7,8,8,8-pentafluorooctyl 8-((2-hydroxyethyl)amino)octanoate for nonyl 8-((2- hydroxyethyl)amino)octanoate.
• Step 3 6-bromohexyl 4,4-bis((3,7-dimethyloct-6-en-1-yl)oxy)butanoate [0512] Prepared according to General Procedure C, substituting 4,4-bis((3,7-dimethyloct-6-en-1- yl)oxy)butanoic acid for 4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanoic acid. Isolated 596 mg, 66%.
• Step 4 nonyl 8-((6-((4,4-bis((3,7-dimethyloct-6-en-1-yl)oxy)butanoyl)oxy)hexyl)(2- hydroxyethyl)amino)octanoate (Example 7-13) [0513] Prepared according to General Procedure F, substituting 6-bromohexyl 4,4-bis((3,7- dimethyloct-6-en-1-yl)oxy)butanoate for 6-bromohexyl 4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanoate. Isolated 65 mg, 45%.
• Step 2 nonyl 8-((6-((4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanoyl)oxy)hexyl)(3- hydroxypropyl)amino)octanoate (Example 7-17) [0518] Prepared according to General Procedure F, substituting nonyl 8-((3- hydroxypropyl)amino)octanoate for nonyl 8-((2-hydroxyethyl)amino)octanoate. Isolated 75 mg, 51%.
• Step 2 6-((2-hydroxyethyl)amino)hexyl 4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanoate [0520] Prepared according to General Procedure E, substituting 6-bromohexyl 4,4-bis(((Z)-oct-5- en-1-yl)oxy)butanoate for nonyl 8-bromooctanoate. Isolated 2.1 g, 83%.
• Step 3 (Z)-non-2-en-1-yl 8-((6-((4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanoyl)oxy)hexyl)(2- hydroxyethyl)amino)octanoate (Example 7-18) [0521] Prepared according to General Procedure F, substituting (Z)-non-2-en-1-yl 8- bromooctanoate for 6-bromohexyl 4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanoate and 6-((2- hydroxyethyl)amino)hexyl 4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanoate for nonyl 8-((2- hydroxyethyl)amino)octanoate.
• Step 2 nonyl 8-((7-((4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanoyl)oxy)heptyl)(2- hydroxyethyl)amino)octanoate (Example 7-19) [0523] Prepared according to General Procedure F, substituting 7-bromoheptyl 4,4-bis(((Z)-oct- 5-en-1-yl)oxy)butanoate for 6-bromohexyl 4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanoate. Isolated 66 mg, 63%.
• Step 2 nonyl 8-((7-((4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanoyl)oxy)heptyl)(4- hydroxybutyl)amino)octanoate (Example 7-21) [0526] Prepared according to General Procedure F, substituting nonyl 8-((4- hydroxybutyl)amino)octanoate for nonyl 8-((2-hydroxyethyl)amino)octanoate. Isolated 71 mg, 71%. UPLC-MS (Method A): Rt 3.51 min, m/z calculated [M+H]: 794.68, found 794.80.
• Example 7-22 nonyl 8-((6-((5,5-bis(((Z)-oct-5-en-1-yl)oxy)pentanoyl)oxy)hexyl)(2- hydroxyethyl)amino)octanoate
• Step 1 ethyl 5-hydroxypentanoate
• Step 4 5,5-bis(((Z)-oct-5-en-1-yl)oxy)pentanoic acid [0530] To a stirred solution of ethyl 5,5-bis(((Z)-oct-5-en-1-yl)oxy)pentanoate (700 mg, 1.83 mmol) in THF (6 mL), and added NaOH (147 mg, 3.66 mmol) was dissolved in water (2 mL). The reaction mixture was stirred at 25 °C for 6 h.
• Step 5 6-bromohexyl 5,5-bis(((Z)-oct-5-en-1-yl)oxy)pentanoate [0531] Prepared according to General Procedure C, substituting 5,5-bis(((Z)-oct-5-en-1- yl)oxy)pentanoic acid for 4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanoic acid. Isolated 110 mg, 65%.
• Step 6 nonyl 8-((6-((5,5-bis(((Z)-oct-5-en-1-yl)oxy)pentanoyl)oxy)hexyl)(2- hydroxyethyl)amino)octanoate (Example 7-22) [0532] Prepared according to General Procedure F, substituting 6-bromohexyl 5,5-bis(((Z)-oct-5- en-1-yl)oxy)pentanoate for 6-bromohexyl 4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanoate. Isolated 43 mg, 43%.
• Step 2 2-(trimethylsilyl)ethyl (3-aminopropyl)carbamate
• Phenyl (2-(trimethylsilyl)ethyl) carbonate (200.0 mg, 0.84 mmol) was added to a stirring solution of 1,3-propanediamine (0.07 mL, 0.84 mmol) in absolute ethanol (3.0 mL) at 25 °C. After stirring for 12h, ethanol was evaporated and the reaction mixture was diluted with water (10 mL ⁇ 2). Then the pH of the solution was adjusted to 2-3 with 2N HCl and the aqueous phase was extracted with DCM (20 mL ⁇ 2). The organic layer was separated and the aqueous phase was made with 2N NaOH solution.
• Step 3 nonyl 2,2-dimethyl-6-oxo-5-oxa-7,11-diaza-2-silanonadecan-19-oate
• 2-(trimethylsilyl)ethyl (3-aminopropyl)carbamate 50 mg, 0.3 mmol
• TEA 0.07 mL, 0.458 mmol
• nonyl 8-bromooctanoate 40.0 mg, 0.115 mmol
• Step 4 nonyl 11-(6-((4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanoyl)oxy)hexyl)-2,2-dimethyl-6-oxo-5- oxa-7,11-diaza-2-silanonadecan-19-oate [0536] Prepared according to General Procedure F, substituting 2,2-dimethyl-6-oxo-5-oxa-7,11- diaza-2-silanonadecan-19-oate for nonyl 8-((2-hydroxyethyl)amino)octanoate. Isolated 250 mg, 67%.
• Step 5 nonyl 8-((3-aminopropyl)(6-((4,4-bis(((Z)-oct-5-en-1- yl)oxy)butanoyl)oxy)hexyl)amino)octanoate
• Step 6 nonyl 8-((6-((4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanoyl)oxy)hexyl)(3-(3- methylureido)propyl)amino)octanoate (Example 7-23) [0538] To a stirred solution of 8-((3-aminopropyl)(6-((4,4-bis(((Z)-oct-5-en-1- yl)oxy)butanoyl)oxy)hexyl)amino)octanoate (41 mg, 0.053 mmol, 1.0 eqv) in DCM (2.0 mL), methylcarbamic chloride (5 mg, 0.053 mmol, 1.0 eqv), TEA (11 mg, 0.11 mmol, 2.0 eqv) and DMAP (11 mg, 0.01 mmol, 0.2 eqv) were added to the solution
• Step 2 4,4-bis(((Z)-non-2-en-1-yl)oxy)butanoic acid [0542] Prepared according to General Procedure B, substituting 4,4-bis(((Z)-non-2-en-1- yl)oxy)butanenitrile for 4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanenitrile. Isolated 410 mg, 83%.
• Step 3 6-bromohexyl 4,4-bis(((Z)-non-2-en-1-yl)oxy)butanoate [0543] Prepared according to General Procedure C, substituting 4,4-bis(((Z)-non-2-en-1- yl)oxy)butanoic acid for 4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanoic acid. Isolated 230 mg, 64%.
• Step 4 nonyl 8-((6-((4,4-bis(((Z)-non-2-en-1-yl)oxy)butanoyl)oxy)hexyl)(2- hydroxyethyl)amino)octanoate (Example 7-26) [0544] Prepared according to General Procedure F, substituting 6-bromohexyl 4,4-bis(((Z)-non- 2-en-1-yl)oxy)butanoate for 6-bromohexyl 4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanoate. Isolated 28 mg, 25%.
• Step 2 4,4-bis(((Z)-non-3-en-1-yl)oxy)butanoic acid [0546] Prepared according to General Procedure B, substituting 4,4-bis(((Z)-non-3-en-1- yl)oxy)butanenitrile for 4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanenitrile. Isolated 450 mg, 86%.
• Step 3 6-bromohexyl 4,4-bis(((Z)-non-3-en-1-yl)oxy)butanoate [0547] Prepared according to General Procedure C, substituting 4,4-bis(((Z)-non-3-en-1- yl)oxy)butanoic acid for 4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanoic acid. Isolated 210 mg, 58%.
• Step 4 nonyl 8-((6-((4,4-bis(((Z)-non-3-en-1-yl)oxy)butanoyl)oxy)hexyl)(2- hydroxyethyl)amino)octanoate (Example 7-27) [0548] Prepared according to General Procedure F, substituting 6-bromohexyl 4,4-bis(((Z)-non-3- en-1-yl)oxy)butanoate for 6-bromohexyl 4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanoate. Isolated 34 mg, 29%.
• Step 2 4,4-bis(((Z)-hept-3-en-1-yl)oxy)butanoic acid [0550] Prepared according to General Procedure B, substituting 4,4-bis(((Z)-hept-3-en-1- yl)oxy)butanenitrile for 4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanenitrile. Isolated 440 mg, 91%.
• Step 3 6-bromohexyl 4,4-bis(((Z)-hept-3-en-1-yl)oxy)butanoate [0551] Prepared according to General Procedure C, substituting 4,4-bis(((Z)-hept-3-en-1- yl)oxy)butanoic acid for 4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanoic acid. Isolated 200 mg, 52%.
• Step 4 nonyl 8-((6-((4,4-bis(((Z)-hept-3-en-1-yl)oxy)butanoyl)oxy)hexyl)(2- hydroxyethyl)amino)octanoate (Example 7-28) [0552] Prepared according to General Procedure F, substituting 6-bromohexyl 4,4-bis(((Z)-hept- 3-en-1-yl)oxy)butanoate for 6-bromohexyl 4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanoate. Isolated 28 mg, 27%.
• Step 2 4,4-bis(((Z)-hex-3-en-1-yl)oxy)butanoic acid [0554] Prepared according to General Procedure B, substituting 4,4-bis(((Z)-hex-3-en-1- yl)oxy)butanenitrile for 4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanenitrile. Isolated 310 mg, 93%.
• Step 3 6-bromohexyl 4,4-bis(((Z)-hex-3-en-1-yl)oxy)butanoate [0555] Prepared according to General Procedure C, substituting 4,4-bis(((Z)-hex-3-en-1- yl)oxy)butanoic acid for 4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanoic acid. Isolated 210 mg, 53%.
• Step 4 nonyl 8-((6-((4,4-bis(((Z)-hex-3-en-1-yl)oxy)butanoyl)oxy)hexyl)(2- hydroxyethyl)amino)octanoate (Example 7-29) [0556] Prepared according to General Procedure F, substituting 6-bromohexyl 4,4-bis(((Z)-hex-3- en-1-yl)oxy)butanoate for 6-bromohexyl 4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanoate. Isolated 44 mg, 42%.
• Step 2 4,4-bis(hexyloxy)butanoic acid [0558] Prepared according to General Procedure B, substituting 4,4-bis(hexyloxy)butanenitrile for 4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanenitrile. Isolated 440 mg, 93%.
• Step 3 6-bromohexyl 4,4-bis(hexyloxy)butanoate [0559] Prepared according to General Procedure C, substituting 4,4-bis(hexyloxy)butanoic acid for 4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanoic acid. Isolated 76 mg, 85%.
• Step 3 6-bromohexyl 4,4-bis(decyloxy)butanoate [0563] Prepared according to General Procedure C, substituting 4,4-bis(decyloxy)butanoic acid for 4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanoic acid. Isolated 210 mg, 75%.
• Step 4 nonyl 8-((6-((4,4-bis(decyloxy)butanoyl)oxy)hexyl)(2-hydroxyethyl)amino)octanoate (Example 7-31) [0564] Prepared according to General Procedure F, substituting 6-bromohexyl 4,4- bis(decyloxy)butanoate for 6-bromohexyl 4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanoate. Isolated 29 mg, 32%.
• UPLC-MS Method B: Rt 2.41 min, m/z calculated [M+H]: 812.7, found 813.5.
• Example 7-32 nonyl 8-((6-((4,4-bis(hex-2-yn-1-yloxy)butanoyl)oxy)hexyl)(2- hydroxyethyl)amino)octanoate
• Step 1 4,4-bis(hex-2-yn-1-yloxy)butanenitrile [0565] Prepared according to General Procedure A, substituting hex-2-yn-1-ol for cis-5-octen-1- ol. Isolated 250 mg, 39%.
• Step 2 4,4-bis(hex-2-yn-1-yloxy)butanoic acid [0566] Prepared according to General Procedure B, substituting 4,4-bis(hex-2-yn-1- yloxy)butanenitrile for 4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanenitrile. Isolated 180 mg, 73%.
• Step 3 6-bromohexyl 4,4-bis(hex-2-yn-1-yloxy)butanoate [0567] Prepared according to General Procedure C, substituting 4,4-bis(hex-2-yn-1- yloxy)butanoic acid for 4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanoic acid. Isolated 105 mg, 37%.
• Step 4 nonyl 8-((6-((4,4-bis(hex-2-yn-1-yloxy)butanoyl)oxy)hexyl)(2- hydroxyethyl)amino)octanoate (Example 7-32) [0568] Prepared according to General Procedure F, substituting 6-bromohexyl 4,4-bis(hex-2-yn- 1-yloxy)butanoate for 6-bromohexyl 4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanoate. Isolated 35 mg, 33%.
• Step 2 4,4-bis(hept-2-yn-1-yloxy)butanoic acid [0570] Prepared according to General Procedure B, substituting 4,4-bis(hept-2-yn-1- yloxy)butanenitrile for 4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanenitrile. Isolated 325 mg, 92%.
• Step 3 6-bromohexyl 4,4-bis(hept-2-yn-1-yloxy)butanoate [0571] Prepared according to General Procedure C, substituting 4,4-bis(hept-2-yn-1- yloxy)butanoic acid for 4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanoic acid. Isolated 195 mg, 45%.
• Step 4 nonyl 8-((6-((4,4-bis(hept-2-yn-1-yloxy)butanoyl)oxy)hexyl)(2- hydroxyethyl)amino)octanoate (Example 7-33) [0572] Prepared according to General Procedure F, substituting 6-bromohexyl 4,4-bis(hept-2-yn- 1-yloxy)butanoate for 6-bromohexyl 4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanoate. Isolated 57 mg, 56%.
• Step 2 4,4-bis(hept-3-yn-1-yloxy)butanoic acid [0574] Prepared according to General Procedure B, substituting 4,4-bis(hept-3-yn-1- yloxy)butanenitrile for 4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanenitrile. Isolated 493 mg, 86%.
• Step 3 6-bromohexyl 4,4-bis(hept-3-yn-1-yloxy)butanoate [0575] Prepared according to General Procedure C, substituting 4,4-bis(hept-3-yn-1- yloxy)butanoic acid for 4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanoic acid. Isolated 165 mg, 39%.
• Step 4 nonyl 8-((6-((4,4-bis(hept-3-yn-1-yloxy)butanoyl)oxy)hexyl)(2- hydroxyethyl)amino)octanoate (Example 7-34) [0576] Prepared according to General Procedure F, substituting 6-bromohexyl 4,4-bis(hept-3-yn- 1-yloxy)butanoate for 6-bromohexyl 4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanoate. Isolated 80 mg, 53%.
• Step 2 4,4-bis(non-3-yn-1-yloxy)butanoic acid [0578] Prepared according to General Procedure B, substituting 4,4-bis(non-3-yn-1- yloxy)butanenitrile for 4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanenitrile. Isolated 453 mg, 92%.
• Step 3 6-bromohexyl 4,4-bis(non-3-yn-1-yloxy)butanoate [0579] Prepared according to General Procedure C, substituting 4,4-bis(non-3-yn-1- yloxy)butanoic acid for 4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanoic acid. Isolated 91 mg, 46%.
• Step 4 nonyl 8-((6-((4,4-bis(non-3-yn-1-yloxy)butanoyl)oxy)hexyl)(2- hydroxyethyl)amino)octanoate (Example 7-35) [0580] Prepared according to General Procedure F, substituting 6-bromohexyl 4,4-bis(non-3-yn- 1-yloxy)butanoate for 6-bromohexyl 4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanoate. Isolated 76 mg, 54%.
• Step 2 4,4-bis(((E)-hex-2-en-1-yl)oxy)butanoic acid [0582] Prepared according to General Procedure B, substituting 4,4-bis(((E)-hex-2-en-1- yl)oxy)butanenitrile for 4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanenitrile. Isolated 352 mg, 85%.
• Step 3 6-bromohexyl 4,4-bis(((E)-hex-2-en-1-yl)oxy)butanoate [0583] Prepared according to General Procedure C, substituting 4,4-bis(((E)-hex-2-en-1- yl)oxy)butanoic acid for 4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanoic acid. Isolated 134 mg, 43%.
• Step 4 nonyl 8-((6-((4,4-bis(((E)-hex-2-en-1-yl)oxy)butanoyl)oxy)hexyl)(2- hydroxyethyl)amino)octanoate (Example 7-36) [0584] Prepared according to General Procedure F, substituting 6-bromohexyl 4,4-bis(((E)-hex-2- en-1-yl)oxy)butanoate for 6-bromohexyl 4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanoate. Isolated 80 mg, 53%.
• Step 2 4,4-bis(((E)-hept-2-en-1-yl)oxy)butanoic acid [0586] Prepared according to General Procedure B, substituting 4,4-bis(((E)-hept-2-en-1- yl)oxy)butanenitrile for 4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanenitrile. Isolated 321 mg, 84%.
• Step 3 6-bromohexyl 4,4-bis(((E)-hept-2-en-1-yl)oxy)butanoate [0587] Prepared according to General Procedure C, substituting 4,4-bis(((E)-hept-2-en-1- yl)oxy)butanoic acid for 4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanoic acid. Isolated 54 mg, 65%.
• Step 4 nonyl 8-((6-((4,4-bis(((E)-hept-2-en-1-yl)oxy)butanoyl)oxy)hexyl)(2- hydroxyethyl)amino)octanoate (Example 7-37) [0588] Prepared according to General Procedure F, substituting 6-bromohexyl 4,4-bis(((E)-hept- 2-en-1-yl)oxy)butanoate for 6-bromohexyl 4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanoate. Isolated 24 mg, 32%.
• Step 2 4,4-bis(((E)-non-2-en-1-yl)oxy)butanoic acid [0590] Prepared according to General Procedure B, substituting 4,4-bis(((E)-non-2-en-1- yl)oxy)butanenitrile for 4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanenitrile. Isolated 295 mg, 93%.
• Step 3 6-bromohexyl 4,4-bis(((E)-non-2-en-1-yl)oxy)butanoate [0591] Prepared according to General Procedure C, substituting 4,4-bis(((E)-non-2-en-1- yl)oxy)butanoic acid for 4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanoic acid. Isolated 231 mg, 49%.
• Step 4 nonyl 8-((6-((4,4-bis(((E)-non-2-en-1-yl)oxy)butanoyl)oxy)hexyl)(2- hydroxyethyl)amino)octanoate (Example 7-38) [0592] Prepared according to General Procedure F, substituting 6-bromohexyl 4,4-bis(((E)-non- 2-en-1-yl)oxy)butanoate for 6-bromohexyl 4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanoate. Isolated 87 mg, 61%.
• Example 7-39 nonyl 8-((6-((4,4-bis((4-butylbenzyl)oxy)butanoyl)oxy)hexyl)(2- hydroxyethyl)amino)octanoate
• Step 1 4,4-bis((4-butylbenzyl)oxy)butanenitrile [0593] Prepared according to General Procedure A, substituting (4-butylphenyl)methanol for cis- 5-octen-1-ol. Isolated 634 mg, 36%.
• Step 2 4,4-bis((4-butylbenzyl)oxy)butanoic acid [0594] Prepared according to General Procedure B, substituting 4,4-bis((4- butylbenzyl)oxy)butanenitrile for 4,4-bis(((Z)-oct-5-en-1-yl)oxy)butanenitrile. Isolated 305 mg, 97%.

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