WO2025088570A1 - Ionizable lipids and ionizable lipid nanoparticles - Google Patents

Abstract

A compound having the following structure of Formula (I) or a stereoisomer of the compound, tautomer of the compound, pharmaceutically acceptable salt thereof, wherein A¹, A², A³, R^1a, R^1b, R^2a, R^2b, m¹, m², m³, and X are as defined herein. Pharmaceutical composition comprising the compounds, and their use in methods of treating diseases are also described.

Description

Attorney Docket No.: CRISP-43327.601 IONIZABLE LIPIDS AND IONIZABLE LIPID NANOPARTICLES CROSS-REFERENCE TO RELATED APPLCIATIONS This application claims the benefit if U.S. Prov. Appl.63/593,416, filed October 26, 2023, the entire contents of which are incorporated herein by reference. TECHNICAL FIELD The disclosure relates to ionizable lipids and ionizable lipid nanoparticles. The disclosure also provides compounds of formula (I) and pharmaceutically acceptable salts thereof and uses of the compounds for the treatment of abnormal cell growth, such as cancer, in a subject. The disclosure further provides lipid-nanoparticle compositions comprising such lipids towards delivery of therapeutic molecules, particularly therapeutic nucleic acids. BACKGROUND Nucleic acids-based therapies have attracted attention in the recent years as there is an enormous potential to treat diseases by targeting their genetic blueprints in vivo. Nucleic acids-based therapeutics can achieve long-lasting or even curative effects via gene inhibition, addition, replacement or editing. However, their clinical translation of both nucleic acid medicines and other therapeutic molecules depends on delivery technologies that improve stability, facilitate internalization and/or increase target affinity. A lipid-based delivery system such as, but not limited to lipid nanoparticles (LNP) may provide an approach to stabilize and deliver nucleic acids and other therapeutic molecules, and there remains a significant need towards improving this technology. Design features, such as optimal particle size, encapsulation efficiencies, robust manufacturing process, different lipophilicity and neutral surface charge, can be further advanced to provide efficient lipid-based delivery systems for nucleic acids and other therapeutic molecules. BRIEF SUMMARY In brief, the present disclosure provides compounds, including stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, which can be used alone or in combination with other therapeutic agents. In one embodiment, a compound having a structure of Formula (I) is provided:

Attorney Docket No.: CRISP-43327.601 or a stereoisomer of the compound, tautomer of the compound, pharmaceutically acceptable salt thereof, wherein A¹, A², A³, R^1a, R^1b, R^2a, R^2b, m¹, m², m³, and X are as defined herein. Pharmaceutical compositions comprising one or more of the foregoing compounds of Formula (I), (IA), (IB), (IA-a), (IA-b), (IB-a), (IB-b), (IA-a1), (IA-b1), (IB-a1), or (IB-b1) and an additional therapeutic agent are also provided. In other embodiments, methods of treatment by administering the foregoing compounds of Formula (I), (IA), (IB), (IA-a), (IA-b), (IB-a), (IB-b), (IA-a1), (IA-b1), (IB- a1), or (IB-b1) or the pharmaceutical compositions comprising a compound of Formula (I), (IA), (IB), (IA-a), (IA-b), (IB-a), (IB-b), (IA-a1), (IA-b1), (IB-a1), or (IB-b1), to a subject in need thereof to treat a disease are provided. In some embodiments, the compounds have the following structure of Formula (I): or a tautomer of the salt thereof, wherein: 1 ²

A , A , and A³ are, or X is -NR^3aR^3b or –OR⁴; R^1a, R^1b, R^2a, and R^2b are, each independently, C4-C18 alkyl, C4-C18 alkenyl, or , wherein R⁵ is C4-C18 alkyl or C4-C18 alkenyl, and n is an integer between 1

R^3a and R^3b are, each independently, C1-C18 alkyl, C2-C18 , or R^3a and R^3b, together with the nitrogen to which they are attached,

heterocycle or heteroaryl; , wherein R^4a and R^4b are, each independently, H, C1-C8 alkyl,

with the nitrogen they are attached to, form a 5-8 membered heterocycle, and p is an integer between 1 and 6; and m¹, m², and m³ are, each independently, an integer between 1 and 6, wherein each alkyl, alkenyl, heterocycle, and heteroaryl is independently unsubstituted or substituted with 1 or 2 substituents independently selected from hydroxy, Attorney Docket No.: CRISP-43327.601 methyl, and cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with 1-3 methyl groups. In some embodiments, A¹, A², and A³ are each O. In some embodiments, A¹, A², and A³ are each NH. In some embodiments, the compound has the following structures of Formula (IA):

Formula (IB): In some

structures of Formula (IA-a)-(IA-b) or (IB-a)-(IB-b): , , or

Attorney Docket No.: CRISP-43327.601 .

In some embodiments, R^1a, R^1b, R^2a, R^2b, R^3a, and R^3b are, each independently, C₆-C₁₆ alkyl, C₆-C₁₆ . In some alkyl of R^1a, R^1b, R^2a, R^2b, R^3a, or R^3b is, each

independently, - - - -C₁₀H₂₁, -C₁₁H₂₃, -C₁₂H₂₅, -C₁₃H₂₇, -C₁₄H₂₉, or - C16H33. In some embodiments, the C₆-C₁₆ alkenyl of R^1a, R^1b, R^2a, R^2b, R^3a, or R^3b has one, two, or three alkene moieties. In some embodiments, the C₆-C₁₆ alkenyl of R^1a, R^1b, R^2a, R^2b, R^3a, or R^3b is, each independently, C10 alkenyl, C11 alkenyl, or C12 alkenyl. In some embodiments, the C₆-C₁₆ alkenyl of R^1a, R^1b, R^2a, R^2b, R^3a, or R^3b is, each independently, . In

alkyl or C7-C14 alkenyl. In some embodiments, the C₇-C₁₄ alkyl of R⁵ is -C₈H₁₇, -C₉H₁₉, -C₁₀H₂₁, -C₁₁H₂₃, - C12H25, -C13H27, or -C14H29. In some embodiments, the C₇-C₁₄ alkenyl of R⁵ has one, two, or three alkene moieties. In some embodiments, the C₇-C₁₄ alkenyl of R⁵ is C₁₀ alkenyl, C₁₁ alkenyl, or C₁₂ alkenyl. In some embodiments, the C7-C14 alkenyl of R⁵ is . In some embodiments, n

In some embodiments, n is an integer of 1, 2, or 3. In some embodiments, n is an integer of 1. In some embodiments, R^3a and R^3b are, each independently, C1-C3 alkyl, each of which is independently unsubstituted or substituted with one hydroxy group. In some embodiments, R^3a and R^3b, together with the nitrogen to which they are attached, form a 5-8 membered heterocycle or heteroaryl selected from imidazolyl, piperidinyl, morpholinyl, pyrrolidinyl, and piperazinyl, each of which is independently Attorney Docket No.: CRISP-43327.601 unsubstituted or substituted with 1 or 2 substituents independently selected from methyl and hydroxy. In some embodiments, R⁴ is H. In some embodiments, R⁴ , wherein R^4a and R^4b are, each independently, H, C1-C8 alkyl, 1 and 4.

In some embodiments, R⁴ , wherein R^4a and R^4b are, each independently, H, C1-C6 alkyl, 1 and 4.

In some embodiments, the 5-8 membered heterocycle formed with R^4a and R^4b is further substituted with C1-C4 alkyl, C1-C4 heteroalkyl, -OH, or halo. In some embodiments, the 5-8 membered heterocycle formed with R^4a and R^4b is mono-, di-, or tri-substituted with C1-C4 alkyl, C1-C4 heteroalkyl, -OH, or halo. In some embodiments, R⁴ , wherein R^4a and R^4b together with the nitrogen they are attached to form

heterocycle and p is an integer between 1 and 4. In some embodiments, R⁴ , wherein R^4a and R^4b together with the nitrogen they are attached to form

and p is an integer of 1. In some embodiments, the 6 membered heterocycle formed with R^4a and R^4b is substituted with C₁ alkyl. In some embodiments, the 6 membered heterocycle formed with R^4a and R^4b . In

and m³ are, each independently, an integer between 1 and 3. In some embodiments, m¹, m², and m³ are, each independently, an integer of 1, 2, or 3. In some embodiments, the compound is a compound listed in Table 1. In some embodiments, the present disclosure provides a composition comprising the compound as described in any embodiments above and a nucleic acid. In some Attorney Docket No.: CRISP-43327.601 embodiments, the composition is a lipid nanoparticle (LNP) composition. In some embodiments, the compositions further comprise one or more additional lipids selected from the group consisting of helper lipids, cholesterol, and polymer conjugated lipids. In some embodiments, the nucleic acid comprises RNA, DNA, or mixtures thereof. In some embodiments, the RNA comprises mRNA, gRNA, or mixtures thereof. In some embodiments, the composition comprises a gene editing system. In some embodiments, the gene editing system comprises one or more components selected from the group consisting of a gRNA or sgRNA, a nucleic acid encoding an RNA-directed nuclease, and a donor polynucleotide. In some embodiments, the helper lipid is 1,2-dilinoleoyl-sn-glycero-3- phosphocholine (DLPC), 1,2-dimyristoyl-sn-glycero-phosphocholine (DMPC), 1,2-dioleoyl- sn-glycero-3-phosphocholine (DOPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-diundecanoyl-sn-glycero- phosphocholine (DUPC), l-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1,2-di- O-octadecenyl-sn-glycero-3-phosphocholine (18:0 Diether PC), l-oleoyl-2- cholesterylhemisuccinoyl-sn-glycero-3-phosphocholine (OChemsPC), 1-hexadecyl-sn- glycero-3-phosphocholine (C16 Lyso PC), 1,2-dilinolenoyl-sn-glycero-3-phosphocholine, 1,2-diarachidonoyl-sn-glycero-3-phosphocholine, 1,2-didocosahexaenoyl-sn-glycero-3- phosphocholine, 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 1,2-diphytanoyl- sn-glycero-3-phosphoethanolamine (ME 16.0 PE), l,2-distearoyl-sn-glycero-3- phosphoethanolamine, 1,2-dilinoleoyl-sn-glycero-3-phosphoethanolamine, 1,2-dilinolenoyl- sn-glycero-3-phosphoethanolamine, 1,2-diarachidonoyl-sn-glycero-3-phosphoethanolamine, 1,2-didocosahexaenoyl-sn-glycero-3-phosphoethanolamine, 1,2-dioleoyl-sn-glycero-3- phospho-rac-(1-glycerol) sodium salt (DOPG), or mixtures thereof. In some embodiments, the helper lipid is DSPC or DOPE. In some embodiments, the molar ratio of the compound to the helper lipid ranges from about 7:1 to about 1:7. In some embodiments, the molar ratio of the compound to the helper lipid ranges from about 5:1 to about 1:5. In some embodiments, the molar ratio of the compound to the helper lipid ranges from about 3:1 to about 1:3. In some embodiments, the composition further comprises cholesterol and the molar ratio of the compound to cholesterol ranges from 3:1 to 1:3. In some embodiments, the present invention provides a method for administering a nucleic acid or gene editing system to a subject in need thereof or cells of the patient, the method comprising administering the composition as described above, such as an LNP composition, to the subject or to the cells of the subject. In some embodiments, the subject is Attorney Docket No.: CRISP-43327.601 an animal. In some embodiments, the subject is a human. Various aspects and embodiments now will be described more fully hereinafter. Such aspects and embodiments may take many different forms, and the exemplary ones disclosed herein should not be construed as limiting; rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey its scope to those skilled in the art. DESCRIPTION OF THE FIGURES FIGs.1A and 1B provide graphs for containing results for editing efficiency (TIDE analysis, FIG.1A) and toxicity (FIG.1B) in liver HEP3B cells of LNPs comprising selected ionizable lipids disclosed herein at different LNP dosages. FIGs.2A and 2B provide graphs for containing results for editing efficiency (TIDE analysis, FIG.2A) and toxicity (FIG.2B) in liver HEP3B cells of LNPs comprising selected ionizable lipids disclosed herein at different dosages and pH and also with different buffers. FIGs.3A and 3B provide bar graphs summarizing the editing efficiency for FIGs 1A (FIG.3A) and 2A (FIG.3B) at a LNP dosage of 0.0156 ng/ul. FIGs.4A and 4B provide graphs containing results for editing efficiency (TIDE analysis, FIG.4A) and toxicity (FIG.4B) in liver HEP3B cells of LNPs comprising selected ionizable lipids under optimized conditions. FIGs.5A and 5B provide graphs containing results for editing efficiency (TIDE analysis, FIG.4A) and toxicity (FIG.4B) in AML-12 cells of LNPs comprising selected ionizable lipids. FIG.6 provides a graph showing results for editing efficiency (TIDE analysis) of liver cells in vivo using LNPs comprising selected ionizable lipids as disclosed herein. FIGs.7A and 7B provide editing efficiency (TIDE analysis) and toxicity data for editing in Hep3B cell at different LNP dosages. FIGs.8A and 8B provide editing efficiency (TIDE analysis) and toxicity data for editing in Hep3B cell at different LNP dosages. DETAILED DESCRIPTION I. Definitions For convenience, certain terms employed in the specification, examples and claims are collected here. Unless defined otherwise, all technical and scientific terms used in this disclosure have the same meanings as commonly understood by one of ordinary skill in the Attorney Docket No.: CRISP-43327.601 art to which this disclosure belongs. Where a range of values is provided, it is intended that each intervening value between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the disclosure. For example, if a range of 1 mM to 8 mM is stated, it is intended that 2 mM, 3 mM, 4 mM, 5 mM, 6 mM, and 7 mM are also explicitly disclosed, as well as the range of non-integer values greater than or equal to 1 mM and the range of non-integer values less than or equal to 8 mM. The singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a "polymer" includes a single polymer as well as two or more of the same or different polymers, reference to an "excipient" includes a single excipient as well as two or more of the same or different excipients, and the like. The term “about”, particularly in reference to a given quantity, is meant to encompass deviations of plus or minus five percent. The compositions of the present disclosure can comprise, consist essentially of, or consist of, the components disclosed. All percentages, parts and ratios are based upon the total weight of the compositions and all measurements made are at about 25 ºC., unless otherwise specified. As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated: "Amino" refers to the -NH2, -NHR, or -NR2 radical, "Cyano" refers to the -CN radical, "Hydroxyl" refers to the -OH radical, "Imino" refers to the =NH or =NR substituent, "Nitro" refers to the -NO2 radical, "Oxo" refers to the =O substituent, "Thio" refers to the =S substituent, "Trifluoromethyl" refers to the -CF₃ radical, Hydrazido or hydrazino refers to N-N substituent, wherein each R of “amino” or “imino” is a compatible substituent as described in this disclosure and wherein an R group is chiral, isomers are contemplated and included herein. "Alkyl" refers to a linear, saturated, acyclic, monovalent hydrocarbon radical or branched, saturated, acyclic, monovalent hydrocarbon radical, having from one to 30 carbon atoms, for example one to 24 carbon atoms, for example one to twelve carbon atoms, preferably one to eight carbon atoms or one to six carbon atoms, and which is attached to the Attorney Docket No.: CRISP-43327.601 rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl and the like. An optionally substituted alkyl radical is an alkyl radical that is optionally substituted, valence permitting, by one, two, three, four, or five substituents independently selected from the group consisting of halo, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, trimethylsilyl, -OR^′, -OC(O)R^′, -N(R^′)2, C(O)R′′, -C(O)OR^′, -C(O)N(R^′)2, - N(R^′)C(O)OR′′′, N(R^′)C(O)R′′′, -N(R^′)S(O)_tR′′′ (where t is 1 or 2), -S(O)_tOR′′′ (where t is 1 or 2), -S(O)pR′′′ (where p is 0, 1, or 2) and -S(O)tN(R^′)2 (where t is 1 or 2), where each R^′ is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, or heteroaryl; each R′′ is independently hydrogen, cycloalkyl, aryl, heterocyclyl, or heteroaryl; and each R′′′ is independently alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl. "Alkoxy" refers to a radical of the formula -OR_a where R_a is an alkyl radical as defined above containing one to twelve carbon atoms. The alkyl part of the optionally substituted alkoxy radical is optionally substituted as defined above for an alkyl radical. “Alkylene” refers to a bivalent saturated aliphatic radical. The alkylene is formed from an alkyl group by removal of one hydrogen. “Alkenyl” refers to a linear, saturated, acyclic, monovalent hydrocarbon radical or branched, saturated, acyclic, monovalent hydrocarbon radical having at least one carbon- carbon double bond and no triple bonds. The double bond(s) may be located at any position(s) with the hydrocarbon chain. The alkenyl group can be optionally substituted as defined above for an alkyl radical. In some embodiments, an alkenyl group refers to a radical of the formula -CnH2n-1, where n is an integer between 1 and 30. The alkenyl is a monovalent group formed from an alkene by removal of one hydrogen atoms from any carbon atom. "Alkoxyalkyl" refers to a radical of the formula -R_a-O-R_b where R_a is alkylene and R_b is alkyl as defined above. Alkyl and alkylene parts of the optionally substituted alkoxyalkyl radical are optionally substituted as defined above for an alkyl radical and alkylene chain, respectively. “Aralkyl” refers to a radical of the formula -R_a-R_b, where R_a is alkylene and R_b is aryl as described herein. Alkylene and aryl portions of optionally substituted aralkyl are optionally substituted as described herein for alkylene and aryl, respectively. "Aryl" refers to an aromatic monocyclic or multicyclic hydrocarbon ring system radical containing from 6 to 18 carbon atoms, where the multicyclic aryl ring system is a bicyclic, tricyclic, or tetracyclic ring system. Aryl radicals include, but are not limited to, Attorney Docket No.: CRISP-43327.601 groups such as fluorenyl, phenyl and naphthyl. An optionally substituted aryl is an aryl radical that is optionally substituted by one, two, three, four, or five substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, cyano, nitro, aryl, heteroaryl, heteroarylalkyl, -R′′-OR^′, -R′′-OC(O)-R^′, - R′′-N(R^′)₂, -R′′-C(O)R^′, -R′′-C(O)OR^′, -R′′-C(O)N(R^′)₂, -R′′-N(R^′)C(O)OR′′′, - R′′-N(R^′)C(O)R′′′, -R′′-N(R^′)S(O)tR′′′ (where t is 1 or 2), -R′′-S(O)tOR′′′ (where t is 1 or 2), - R′′-S(O)_pR′′′ (where p is 0, 1, or 2), and -R′′-S(O)_tN(R^′)₂ (where t is 1 or 2), where each R^′ is independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl; each R′′ is independently a direct bond or a linear or branched alkylene or alkenylene chain; and each R′′′ is independently alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, heterocyclyl, or heteroaryl. “Arylalkoxy” refers to a group of formula –O-R, where R is aralkyl. An optionally substituted arylalkoxy is an arylalkoxy that is optionally substituted as described herein for aralkyl. In some embodiments, arylalkoxy is benzyloxy. "Cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical having from three to fifteen carbon atoms, preferably having from three to ten carbon atoms, and which is saturated or unsaturated, and which attaches to the rest of the molecule by a single bond. A polycyclic hydrocarbon radical is bicyclic, tricyclic, or tetracyclic ring system. An unsaturated cycloalkyl contains one, two, or three carbon-carbon double bonds and/or one carbon-carbon triple bond. Monocyclic cycloalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl radicals include, for example, adamantyl, norbornyl, decalinyl, and the like. An optionally substituted cycloalkyl is a cycloalkyl radical that is optionally substituted by one, two, three, four, or five substituents independently selected from the group consisting of alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, nitro, oxo, aryl, aralkyl, cycloalkyl, heterocyclyl, heteroaryl, -R′′-OR^′, -R′′-OC(O)-R^′, -R′′-N(R^′)₂, -R′′-C(O)R^′, - R′′-C(O)OR^′, -R′′-C(O)N(R^′)2, -R′′-N(R^′)C(O)OR′′′, -R′′-N(R^′)C(O)R′′′, -R′′-N(R^′)S(O)tR′′′ (where t is 1 or 2), -R′′-S(O)_tOR′′′ (where t is 1 or 2), -R′′-S(O)_pR′′′ (where p is 0, 1, or 2) and -R′′-S(O)tN(R^′)2 (where t is 1 or 2) where each R^′ is independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl; each R′′ is independently a direct bond or a linear or branched alkylene or alkenylene chain; and each R′′′ is independently alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, or heteroaryl. “Deuterated compounds” are compounds where one or more hydrogen atoms have been replaced with a deuterium atom. Deuterated drugs may be derivatives of an active compound. Deuterated drugs may be prodrugs. Deuteration may alter the physical Attorney Docket No.: CRISP-43327.601 properties, metabolic properties, activity or safety of a drug. “Derivatives” are related chemical species that can be derived from a similar compound via chemical reactions. They may encompass slight chemical modifications, substitution of atoms with deuterated atoms, substitution of atoms with stable or radioactive isotopes or other modifications that imbue a compound with desirable properties. "Fused" refers to any ring system described herein which is fused to an existing ring structure in the compounds of the invention. When the fused ring system is a heterocyclyl or a heteroaryl, any carbon atom on the existing ring structure which becomes part of the fused ring system may be replaced with a nitrogen atom. "Halo" refers to the halogen substituents: bromo, chloro, fluoro, and iodo. "Haloalkyl" refers to an alkyl radical, as defined above, that is further substituted by one or more halogen substituents. The number of halo substituents included in haloalkyl is from one and up to the total number of the hydrogen atoms available for replacement with the halo substituents (e.g., perfluoroalkyl). Non-limiting examples of haloalkyl include trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl, 2- fluoroethyl, 3-bromo 2-fluoropropyl, 1-bromomethyl, 2-bromoethyl and the like. For an optionally substituted haloalkyl, the hydrogen atoms bonded to the carbon atoms of the alkyl part of the haloalkyl radical may be optionally replaced with substituents as defined above for an optionally substituted alkyl. "Haloalkenyl" refers to an alkenyl radical, as defined above, that is further substituted by one or more halo substituents. The number of halo substituents included in haloalkenyl is from one and up to the total number of the hydrogen atoms available for replacement with the halo substituents (e.g., perfluoroalkenyl). Non-limiting examples of haloalkenyl include 2,2-difluoroethenyl, 3-chloroprop-1-enyl, and the like. For an optionally substituted haloalkenyl, the hydrogen atoms bonded to the carbon atoms of the alkenyl part of the haloalkenyl radical may be optionally replaced with substituents as defined above for an optionally substituted alkenyl group. "Haloalkynyl" refers to an alkynyl radical, as defined above, that is further substituted by one or more halo substituents. The number of halo substituents included in haloalkynyl is from one and up to the total number of the hydrogen atoms available for replacement with the halo substituents (e.g., perfluoroalkynyl). Non-limiting examples of haloalkynyl include 3-chloroprop-1-ynyl and the like. The alkynyl part of the haloalkynyl radical may be additionally optionally substituted as defined above for an alkynyl group. “Heteroarylalkyl” refers to a radical of the formula -Ra-Rb, where Ra is alkylene and R_b is heteroaryl as described herein. Alkylene and heteroaryl portions of optionally Attorney Docket No.: CRISP-43327.601 substituted heteroarylalkyl are optionally substituted as described herein for alkylene and heteroaryl, respectively. "Heterocyclyl" refers to a stable 3- to 18--membered nonaromatic ring system radical having the carbon count of two to twelve and containing a total of one to six heteroatoms independently selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur. A heterocyclyl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system. A bicyclic, tricyclic, or tetracyclic heterocyclyl is a fused, spiro, and/or bridged ring system. The heterocyclyl radical may be saturated or unsaturated. An unsaturated heterocyclyl contains one, two, or three carbon-carbon double bonds and/or one carbon-carbon triple bond. An optionally substituted heterocyclyl is a heterocyclyl radical that is optionally substituted by one, two, three, four, or five substituents independently selected from the group consisting of alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, oxo, thioxo, nitro, aryl, aralkyl, cycloalkyl, heterocyclyl-, heteroaryl, -R′′-OR^′, -R′′-OC(O)-R^′, -R′′-N(R^′)₂, - R′′-C(O)R^′, -R′′-C(O)OR^′, -R′′-C(O)N(R^′)2, -R′′-N(R^′)C(O)OR′′′, -R′′-N(R^′)C(O)R′′′, - R′′-N(R^′)S(O)tR′′′ (where t is 1 or 2), -R′′-S(O)tOR′′′ (where t is 1 or 2), -R′′-S(O)pR′′′ (where p is 0, 1, or 2), and -R′′-S(O)tN(R^′)2 (where t is 1 or 2), where each R^′ is independently hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl; each R′′ is independently a direct bond or a linear or branched alkylene or alkenylene chain; and each R′′′ is independently alkyl, alkenyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl. The nitrogen, carbon, or sulfur atoms in the heterocyclyl radical may be optionally oxidized (when the substituent is oxo and is present on the heteroatom); the nitrogen atom may be optionally quaternized (when the substituent is alkyl, alkenyl, aryl, aralkyl, cycloalkyl, heterocyclyl, heteroaryl, -R′′-OR^′, -R′′-OC(O)-R^′, -R′′-N(R^′)2, -R′′-C(O)R^′, -R′′-C(O)OR^′, - R′′-C(O)N(R^′)₂, -R′′-N(R^′)C(O)OR′′′, -R′′-N(R^′)C(O)R′′′, -R′′-N(R^′)S(O)_tR′′′ (where t is 1 or 2), -R′′-S(O)tOR′′′ (where t is 1 or 2), -R′′-S(O)pR′′′ (where p is 0, 1, or 2), and - R′′-S(O)_tN(R^′)₂ (where t is 1 or 2), where R′′ is a linear or branched alkylene or alkenylene chain, and R^′ and R′′′ are as defined above). Examples of optionally substituted heterocyclyl radicals include, but are not limited to, azetidinyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2oxopyrrolidinyl, oxazolidinyl-, piperidinyl, piperazinyl, 4piperidonyl, pyrrolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1---oxothiomorpholinyl, and 1,1---dioxo-thiomorpholinyl. “Heterocyclylene” refers to a heterocyclyl in which one hydrogen atom is replaced with a valency. An optionally substituted heterocyclylene is optionally substituted as Attorney Docket No.: CRISP-43327.601 described herein for heterocyclyl. "Heteroaryl" refers to a 5- to 18-membered ring system radical containing at least one aromatic ring, having the carbon count of one to seventeen carbon atoms, and containing a total of one to ten heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. The heteroaryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system. The bicyclic, tricyclic, or tetracyclic heteroaryl radical is a fused and/or bridged ring system. An optionally substituted heteroaryl is a heteroaryl radical that is optionally substituted by one, two, three, four, or five substituents independently selected from the group consisting of alkyl, alkenyl, alkoxy, halo, haloalkyl, haloalkenyl, cyano, oxo, thioxo, nitro, oxo, aryl, aralkyl, cycloalkyl, heterocyclyl, heteroaryl, or heteroarylalkyl-, -R′′-OR^′, - R′′-OC(O)-R^′, -R′′-N(R^′)₂, -R′′-C(O)R^′, -R′′-C(O)OR^′, -R′′-C(O)N(R^′)₂, - R′′-N(R^′)C(O)OR′′′, -R′′-N(R^′)C(O)R′′′, -R′′-N(R^′)S(O)tR′′′ (where t is 1 or 2), -R′′-S(O)tOR′′′ (where t is 1 or 2), -R′′-S(O)_tR′′′ (where p is 0, 1, or 2), and -R′′-S(O)_tN(R^′)₂ (where t is 1 or 2), where each R^′ is independently hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl; each R′′ is independently a direct bond or a linear or branched alkylene or alkenylene chain; and each R′′′ is alkyl, alkenyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl. The nitrogen, carbon, or sulfur atoms in the heterocyclyl radical may be optionally oxidized (when the substituent is oxo and is present on the heteroatom), provided that at least one ring in heteroaryl remains aromatic; the nitrogen atom may be optionally quaternized (when the substituent is alkyl, alkenyl, aryl, aralkyl, cycloalkyl, heterocyclyl, heteroaryl, -R′′-OR^′, -R′′-OC(O)-R^′, -R′′-N(R^′)2, -R′′-C(O)R^′, -R′′-C(O)OR^′, - R′′-C(O)N(R^′)₂, -R′′-N(R^′)C(O)OR′′′, -R′′-N(R^′)C(O)R′′′, -R′′-N(R^′)S(O)_tR′′′ (where t is 1 or 2), -R′′-S(O)tOR′′′ (where t is 1 or 2), -R′′-S(O)pR′′′ (where p is 0, 1, or 2), and - R′′-S(O)_tN(R^′)₂ (where t is 1 or 2), where R′′ is a linear or branched alkylene or alkenylene chain, and R^′ and R′′′ are as defined above), provided that at least one ring in heteroaryl remains aromatic. Examples of optionally substituted heteroaryl radicals include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzthiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo-[1,2a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyl, naphthyridinyl, oxadiazolyl-, 2oxoazepinyl, oxazolyl, oxiranyl-, 1-phenyl-1Hpyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, Attorney Docket No.: CRISP-43327.601 purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl and thiophenyl- (i.e., thienyl). The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, salts, compositions, dosage forms, etc., which are--within the scope of sound medical judgment--suitable for use in contact with the tissues of human beings and/or other mammals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. In some aspects, "pharmaceutically acceptable" means approved by a regulatory agency of the federal or a state government, or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals (e.g., mammals), and more particularly, in humans. “Prodrugs” are compounds that after administration are metabolized or otherwise chemically transformed into an active moiety. Prodrugs may be derivatives of an active compound. Prodrugs may or may not be active prior to conversion into an active form in vivo. The term "treating" is used herein, for instance, in reference, for example, to methods of treating inflammatory diseases or to a gastrointestinal disease, and generally includes the administration of a compound or composition which reduces the frequency of, or delays the onset of, symptoms of a medical condition (e.g., autoimmune disease, inflammatory disorder, gastrointestinal disorder) in a subject relative to a subject not receiving the compound or composition. This can include reversing, reducing, or arresting the symptoms, clinical signs, and underlying pathology of a condition in a manner to improve or stabilize a subject's condition (e.g., regression of symptoms of an autoimmune or inflammatory disease such as improvement in the MAYO score in the treatment of ulcerative colitis). The embodiments disclosed herein encompass all pharmaceutically acceptable compounds of the compound of (I), (IA), (IB), (IA-a), (IA-b), (IB-a), (IB-b), (IA-a1), (IA- b1), (IB-a1), or (IB-b1) being isotopically-labeled by having one or more atoms replaced by an atom having a different atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I, and ¹²⁵I, respectively. These radiolabeled compounds could be useful to help determine or measure the effectiveness of the compounds, by characterizing, for example, the site or mode of action, or binding affinity to pharmacologically important site of action. Certain isotopically-labeled compounds of (I), (IA), (IB), (IA-a), (IA-b), (IB-a), (IB-b), (IA-a1), (IA-b1), (IB-a1), or (IB-b1), for example, Attorney Docket No.: CRISP-43327.601 those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e., ³H, and carbon-14, i.e., ¹⁴C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier isotopes such as deuterium, i.e., ²H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and ¹³N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds of (I), (IA), (IB), (IA-a), (IA-b), (IB-a), (IB-b), (IA-a1), (IA-b1), (IB-a1), or (IB-b1) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Preparations and Examples as set out below using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed. The embodiments disclosed herein encompass the in vivo metabolic products of the disclosed compounds. Such products may result from, for example, the oxidation, reduction, hydrolysis, amidation, esterification, and the like of the administered compound, primarily due to enzymatic processes. Accordingly, the disclosure includes compounds produced by a process comprising administering a compound of this disclosure to a mammal for a period of time sufficient to yield a metabolic product thereof. Such products are typically identified by administering a radiolabeled compound of the disclosure in a detectable dose to an animal, such as rat, mouse, guinea pig, monkey, or to human, allowing sufficient time for metabolism to occur, and isolating its conversion products from the urine, blood or other biological samples. "Pharmaceutically acceptable salt" includes both acid and base addition salts. "Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2- Attorney Docket No.: CRISP-43327.601 hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo- glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4- aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p- toluenesulfonic acid, trifluoroacetic acid (TFA), undecylenic acid, and the like. "Pharmaceutically acceptable base addition salt" refers to those salts which retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2- diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N ethylpiperidine, polyamine resins and the like. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. A "pharmaceutical composition" refers to a formulation of a compound of the disclosure and a medium generally accepted in the art for the delivery of the biologically active compound to mammals, e.g., humans. Such a medium includes all pharmaceutically acceptable carriers, diluents and excipients therefor. "Effective amount" or "therapeutically effective amount" refers to that amount of a compound of the disclosure which, when administered to a mammal, preferably a human, is sufficient to effect treatment in the mammal, preferably a human. The amount of a compound which constitutes a "therapeutically effective amount" will vary depending on the compound, the condition and its severity, the manner of administration, and the age of the Attorney Docket No.: CRISP-43327.601 mammal to be treated, but can be determined routinely by one of ordinary skill in the art having regard to his own knowledge and to this disclosure. A "stereoisomer" refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The present disclosure contemplates various stereoisomers and mixtures thereof and includes "enantiomers", which refers to two stereoisomers whose molecules are nonsuperimposeable mirror images of one another. The present disclosure also contemplates "diastereomers", which refers to non-mirror image of non-identical stereoisomers. Diastereomers occur when two or more stereoisomers of a compound have different configurations at one or more of the equivalent stereocenters and are not mirror images of each other. A "tautomer" refers to a proton shift from one atom of a molecule to another atom of the same molecule. The present disclosure includes tautomers of any said compounds. “Abnormal cell growth”, as used herein, unless otherwise indicated, means cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition). Abnormal cell growth may be benign (not cancerous) or malignant (cancerous). The term “neutral lipid” refers to any of a number of lipid species that exist either in an uncharged or neutral zwitterionic form at a selected pH. At physiological pH, such lipids include, but are not limited to, phosphotidylcholines such as 1,2-Distearoyl-sn-glycero-3- phosphocholine (DSPC), 1,2-Dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2- Dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1-Palmitoyl-2-oleoyl-sn-glycero-3- phosphocholine (POPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), phophatidylethanolamines such as 1,2-Dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), sphingomyelins (SM), ceramides, steroids such as sterols and their derivatives. Neutral lipids may be synthetic or naturally derived. The term “lipid nanoparticle” refers to particles having at least one dimension on the order of nanometers (e.g., 1-1,000 nm) which include one or more of the compounds of structure (I) or other specified cationic lipids. In some embodiments, lipid nanoparticles are included in a formulation that can be used to deliver an active agent or therapeutic agent, such as a nucleic acid (e.g., mRNA) to a target site of interest (e.g., cell, tissue, organ, tumor, and the like). In some embodiments, the lipid nanoparticles of the invention comprise a nucleic acid. Such lipid nanoparticles typically comprise a compound of structure Formula (I), (IA), (IB), (IA-a), (IA-b), (IB-a), (IB-b), (IA-a1), (IA-b1), (IB-a1), or (IB-b1) and one or more excipient selected from neutral lipids, charged lipids, steroids and polymer conjugated lipids. In some embodiments, the active agent or therapeutic agent, such as a nucleic acid, may be encapsulated in the lipid portion of the lipid nanoparticle or an aqueous space Attorney Docket No.: CRISP-43327.601 enveloped by some or all of the lipid portion of the lipid nanoparticle, thereby protecting it from enzymatic degradation or other undesirable effects induced by the mechanisms of the host organism or cells e.g. an adverse immune response. In various embodiments, the lipid nanoparticles have a mean diameter of from about 30 nm to about 150 nm, from about 40 nm to about 150 nm, from about 50 nm to about 150 nm, from about 60 nm to about 130 nm, from about 70 nm to about 110 nm, from about 70 nm to about 100 nm, from about 80 nm to about 100 nm, from about 90 nm to about 100 nm, from about 70 to about 90 nm, from about 80 nm to about 90 nm, from about 70 nm to about 80 nm, or 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, or 150 nm, and are substantially non-toxic. In certain embodiments, nucleic acids, when present in the lipid nanoparticles, are resistant in aqueous solution to degradation with a nuclease. Lipid nanoparticles comprising nucleic acids and their method of preparation are disclosed in, e.g., U.S. Patent Publication Nos. 2004/0142025, 2007/0042031 and PCT Pub. Nos. WO 2013/016058 and WO 2013/086373, the full disclosures of which are herein incorporated by reference in their entirety for all purposes. The term “polymer conjugated lipid” refers to a molecule comprising both a lipid portion and a polymer portion. An example of a polymer conjugated lipid is a pegylated lipid. The term “pegylated lipid” refers to a molecule comprising both a lipid portion and a polyethylene glycol portion. Pegylated lipids are known in the art and include 1- (monomethoxy-polyethyleneglycol)-2,3-dimyristoylglycerol (PEG-DMG) and the like. The terms “lipid,” “compound,” and “lipid compound” may be used interchangeably to refer to the ionizable lipids disclosed herein. By reserving the right to proviso out or exclude any individual members of any such group, including any sub-ranges or combinations of sub-ranges within the group, that can be claimed according to a range or in any similar manner, less than the full measure of this disclosure can be claimed for any reason. Further, by reserving the right to proviso out or exclude any individual substituents, analogs, compounds, ligands, structures, or groups thereof, or any members of a claimed group, less than the full measure of this disclosure can be claimed for any reason. Throughout this disclosure, various patents, patent applications and publications are referenced. The disclosures of these patents, patent applications and publications in their entireties are incorporated into this disclosure by reference in order to more fully describe the state of the art as known to those skilled therein as of the date of this disclosure. This Attorney Docket No.: CRISP-43327.601 disclosure will govern in the instance that there is any inconsistency between the patents, patent applications and publications cited and this disclosure. II. Compounds The compounds described herein are ionizable lipids. In one embodiment, a compound (i.e., a lipid compound) having a structure of Formula (I), or a stereoisomer, tautomer of the compound, or a pharmaceutically acceptable salt thereof is provided: wherein A¹, A², O; X is -NR^3aR^3b or –OR⁴; 1^{a 1b 2}

R , R , R ^a, and R^2b are, C18 alkenyl, or , wherein R⁵ is C4-C18 alkyl or C4-C18 alkenyl and n is an integer between 1

and 7; R^3a and R^3b are, each independently, C1-C18 alkyl, C2-C18 alkenyl, or , or R^3a and R^3b, together with the nitrogen to which they are attached,

heterocycle or heteroaryl; R⁴ is H , wherein R^4a and R^4b are, each independently, H, C₁-C₈ alkyl, or

with the nitrogen they are attached to form a 5-8 membered heterocycle and p is an integer between 1 and 6; and m¹, m², and m³ are, each independently, an integer between 1 and 6; wherein each alkyl, alkenyl, heterocycle, and heteroaryl is independently unsubstituted or substituted with 1 or 2 substituents independently selected from hydroxy, methyl, and cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with 1-3 methyl groups. In some embodiments, A¹, A², and A³ are, each independently, NH or O; X is - NR^3aR^3b or –OR⁴; R^1a, R^1b, R^2a, R^2b, R^3a, and R^3b are, each independently, C₄-C₁₈ alkyl, C₄- C₁₈ , wherein R⁵ is C₄-C₁₈ alkyl or C₄-C₁₈ alkenyl and n is an

integer , wherein R^4a and R^4b are, each independently,

with the nitrogen they are attached to Attorney Docket No.: CRISP-43327.601 form a 5-8 membered heterocycle and p is an integer between 1 and 6; and m¹, m², and m³ are, each independently, an integer between 1 and 6. In one embodiment, A¹, A², and A³ are each NH. In some embodiments, one of A¹, A², or A³ is NH. In some other embodiments, two of A¹, A², or A³ are NH. When A¹, A², and A³ are each NH, the compound has the following structure of Formula (IA): . In one embodiments, one of A¹, A², or A³ is O. In some

are O. When A¹, A², and A³ are each O, the compound has the following structure of Formula (IB): . In one X is –OR⁴. In some embodiments, X is -

the following Formula (IA-a)- (IA-b): or . In one (IA-a). In some

embodiments, the compound has the structure of Formula (IA-b). In some embodiments, the compound has one of the following Formula (IB-a)-(IB- b): Attorney Docket No.: CRISP-43327.601 or . In one (IB-a). In some embodiments, the

. In one embodiment, R^1a, R^1b, R^2a, R^2b, R^3a, and R^3b are, each independently, C4-C18 alkyl, C4-C18 alkenyl, or . For example, the C4-C18 alkyl of R^1a, R^1b, R^2a, R^2b, R^3a, or R^3b includes a

C4-C18 alkyl. In another example, the C4-C18 alkenyl of R^1a, R^1b, R^2a, R^2b, R^3a, or R^3b includes a linear or branched C₄-C₁₈ alkenyl. The C4-C18 alkenyl of R^1a, R^1b, R^2a, R^2b, R^3a, or R^3b includes one, two, or three alkene moieties. In some embodiments, R^1a, R^1b, R^2a, R^2b, R^3a, and R^3b are, each independently, C₆-C₁₆ alkyl, C₆-C₁₆ alkenyl, or . For example, the C₆-C₁₆ alkyl of R^1a, R^1b, R^2a, R^2b, R^3a, or R^3b is, each

-C8H17, -C9H19, -C10H21, -C11H23, -C12H25, - C₁₃H₂₇, -C₁₄H₂₉, or -C₁₆H₃₃. In some embodiments, the C₆-C₁₆ alkyl of R^1a, R^1b, R^2a, and R^2b, are, each independently -C6H13, -C8H17, -C9H19, -C10H21, -C11H23, -C12H25, -C13H27, - C₁₄H₂₉, or -C₁₆H₃₃. In some embodiments, the C₆-C₁₆ alkyl of R^1a, R^1b, R^2a, and R^2b, are - C6H13. In some embodiments, the C6-C16 alkyl of R^1a, R^1b, R^2a, and R^2b, are -C8H17. In some embodiments, the C₆-C₁₆ alkyl of R^1a, R^1b, R^2a, and R^2b, are -C₉H₁₉. In some embodiments, the C6-C16 alkyl of R^1a, R^1b, R^2a, and R^2b, are -C10H21. In some embodiments, the C6-C16 alkyl of R^1a, R^1b, R^2a, and R^2b, are -C11H23. In some embodiments, the C6-C16 alkyl of R^1a, R^1b, R^2a, and R^2b, are -C12H25. In some embodiments, the C6-C16 alkyl of R^1a, R^1b, R^2a, and R^2b, are -C13H27. In some embodiments, the C6-C16 alkyl of R^1a, R^1b, R^2a, and R^2b, are - C₁₄H₂₉. In some embodiments, the C₆-C₁₆ alkyl of R^1a, R^1b, R^2a, and R^2b, are -C₁₆H₃₃. In some embodiments, the C6-C16 alkenyl of R^1a, R^1b, R^2a, R^2b, R^3a, or R^3b has one, two, or three double bonds. In some embodiments, the C₆-C₁₆ alkenyl of R^1a, R^1b, R^2a, R^2b, R^3a, or R^3b has one double bond. In some embodiments, the C6-C16 alkenyl of R^1a, R^1b, R^2a, Attorney Docket No.: CRISP-43327.601 R^2b, R^3a, or R^3b has two double bonds. In some embodiments, the C₆-C₁₆ alkenyl of R^1a, R^1b, R^2a, R^2b, R^3a, or R^3b has three double bonds. In some embodiments, double bonds are present at any positions on the alkenyl group. For example, in some embodiments, a double bond is present at a terminal position. In another example, a double bond is present in the middle section. The numbers and locations of double bonds present in the alkenyl group may vary. In some embodiments, the C6-C16 alkenyl of R^1a, R^1b, R^2a, R^2b, R^3a, or R^3b is, each independently, C₁₀ alkenyl, C₁₁ alkenyl, or C₁₂ alkenyl. In some embodiments, the C₆-C₁₆ alkenyl of R^1a, R^1b, R^2a, R^2b, R^3a, and R^3b are, each independently, C10 alkenyl, C11 alkenyl, or C₁₂ alkenyl. In some embodiments, the C₆-C₁₆ alkenyl of R^1a, R^1b, R^2a, R^2b, R^3a, and R^3b are C10 alkenyl. In some embodiments, the C6-C16 alkenyl of R^1a, R^1b, R^2a, R^2b, R^3a, and R^3b are C₁₁ alkenyl. In some embodiments, the C₆-C₁₆ alkenyl of R^1a, R^1b, R^2a, R^2b, R^3a, and R^3b are C12 alkenyl. In some embodiments, the C6-C16 alkenyl of R^1a, R^1b, R^2a, and R^2b, are C10 alkenyl. In some embodiments, the C₆-C₁₆ alkenyl of R^1a, R^1b, R^2a, and R^2b, are C₁₁ alkenyl. In some embodiments, the C6-C16 alkenyl of R^1a, R^1b, R^2a, and R^2b, are C12 alkenyl. In some embodiments, the C6-C16 alkenyl of R^1a, R^1b, R^2a, R^2b, R^3a, or R^3b is, each independently, . In some embodiments, the C₆-C₁₆ alkenyl of R^1a, R^1b, R^2a, R^2b,

. In some embodiments, the C6-C16 alkenyl of R^1a, R^1b,

.

In one embodiment, when R^1a, R^1b, R^2a, R^2b, R^3a, or R^3b is , wherein R⁵ is C4-C18 alkyl or C4-C18 alkenyl and n is an integer between

embodiments, R⁵ is C7-C14 alkyl or C7-C14 alkenyl. The C7-C14 alkyl of R⁵ is -C7H15, -C8H17, -C9H19, -C10H21, -C11H23, -C12H25, -C13H27, or -C14H29. In some embodiments, C7-C14 alkyl of R⁵ is -C8H17, -C9H19, -C10H21, -C11H23, -C12H25, -C13H27, or -C14H29. In some embodiments, R⁵ is -C₈H₁₇. In some embodiments, R⁵ is -C₉H₁₉. In some embodiments, R⁵ is -C10H21. In some embodiments, R⁵ is -C11H23. In some embodiments, R⁵ is -C12H25. In some embodiments, R⁵ is -C₁₃H₂₇. In some embodiments, R⁵ is -C₁₄H₂₉. In some is

of

Attorney Docket No.: CRISP-43327.601 R^1a, R^1b, R^2a, R^2b, R^3a, or R^3b is . In some embodiments,

moieties. In some particular embodiments, the C₇-C₁₄ alkenyl of R⁵ has one alkene moiety. In some embodiments, the C7-C14 alkenyl of R⁵ is C7 alkenyl, C8 alkenyl, C9 alkenyl, C₁₀ alkenyl, C₁₁ alkenyl, C₁₂ alkenyl, C₁₃ alkenyl, or C₁₄ alkenyl. In some particular embodiments, the C7-C14 alkenyl of R⁵ is C10 alkenyl, C11 alkenyl, or C12 alkenyl. For example, the C₇-C₁₄ alkenyl of R⁵ is . In some other

In some is

.

In one embodiment, n is an integer between 1 and 7. In some

Attorney Docket No.: CRISP-43327.601 embodiments, n in is an integer between 1 and 4. In some embodiments, n in

is an integer of 1, 2, or 3. In some embodiments, n in is an

integer of 1. In some embodiments, n in is an integer of 2. In some

integer of 3. In R^3b are, each independently, C1-C3 alkyl, each of

which is substituted with one hydroxy group. In some embodiments, R^3a and R^3b are each methyl. In some embodiments, R^3a and R^3b are each ethyl. In some embodiments, R^3a is ethyl and R^3b is 2-hydroxyethyl. In some embodiments, R^3a is methyl and R^3b is 2-hydroxyethyl. In some embodiments, R^3a and R^3b, together with the nitrogen to which they are attached, form a 5-8 membered heterocycle or heteroaryl. In some embodiments, R^3a and R^3b, together with the nitrogen to which they are attached, form a 5-8 membered heterocycle or heteroaryl selected from imidazolyl, piperidinyl, morpholinyl, pyrrolidinyl, and piperazinyl, each of which is independently unsubstituted or substituted with 1 or 2 substituents independently selected from methyl and hydroxy. In some embodiments, R^3a and R^3b, together with the nitrogen to which they are attached, form an imidazolyl group. In some embodiments, R^3a and R^3b, together with the nitrogen to which they are attached, form a piperidinyl group, which is unsubstituted or substituted with a hydroxy group. In some embodiments, R^3a and R^3b, together with the nitrogen to which they are attached, form a morpholinyl group. In some embodiments, R^3a and R^3b, together with the nitrogen to which they are attached, form a pyrrolidinyl group, which is unsubstituted or substituted with a methyl group. In some embodiments, R^3a and R^3b, together with the nitrogen to which they are attached, form a piperazinyl group, which is unsubstituted or substituted with a methyl group. In some embodiments, the compound has one of the following structures of Formula (IA-a), (IA-b), (IB-a), or (IB-b): ,

Attorney Docket No.: CRISP-43327.601 (IA-a1) , . In some

(IA-a1): . In some

(IA-b1): .

In some (IB-a1): Attorney Docket No.: CRISP-43327.601 . In some

(IB-b1): .

In one embodiment, R⁴ is H . In some embodiments, R⁴ is H. In

some embodiments, R⁴ , wherein R^4a and R^4b are, each independently, H, C1-C8 alkyl, or R^4a and

the nitrogen they are attached to form a 5-8 membered heterocycle. In some embodiments, R⁴ , wherein R^4a and R^4b are, each independently, H, C₁-C₈ alkyl, and p is

1 and 4. In some embodiments, R⁴ is , wherein R^4a and R^4b are, each independently, H, C1-C6 alkyl, and p is an integer between 1 and 4. In some embodiments, the C₁-C₆ alkyl of R^4a or R^4b is methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, or n- hexane. In some embodiments, the 5-8 membered heterocycle formed with R^4a and R^4b is further substituted with C₁-C₄ alkyl, C₁-C₄ heteroalkyl, -OH, or halo. In some embodiments, the 5-8 membered heterocycle formed with R^4a and R^4b is mono-, di-, or tri-substituted with C₁-C₄ alkyl, C₁-C₄ heteroalkyl, -OH, or halo. In some embodiments, the 5-8 membered heterocycle formed with R^4a and R^4b is mono-substituted with C1-C4 alkyl. In some embodiments, the 5-8 membered heterocycle formed with R^4a and R^4b is mono-substituted with C1-C4 heteroalkyl. In some embodiments, the 5-8 membered heterocycle formed with Attorney Docket No.: CRISP-43327.601 R^4a and R^4b is mono--substituted with -OH. In some embodiments, the 5-8 membered heterocycle formed with R^4a and R^4b is mono-substituted with halo. In one embodiment, R^4a and R^4b together with the nitrogen they are attached to form a 5-8 membered heterocycle. In some embodiments, the 5-8 membered heterocycle formed by R^4a and R^4b together with the nitrogen they are attached to includes one, two , or three heteroatoms. In some embodiments, the 5-8 membered heterocycle formed by R^4a and R^4b together with the nitrogen they are attached to includes one, two, or three nitrogen (N), oxygen (O), or sulfur (O) atoms. In some embodiments, for example, the 5-8 membered heterocycle formed by R^4a and R^4b together with the nitrogen they are attached to is pyrrolidine, pyrrole, tetrahydrofuran, furan, tetrahydrothiophene, thiophene, imidazolidine, pyrazolidine, imidazole, pyrazole, oxazoline, isoxazoline, oxazole, isoxazole, thiazolidine, thiazole, isothiazole, dioxolane, dithiolane, piperidine, pyridine, oxane, pyran, thiane, thiopyran, diazinane, diazine, morpholine, oxazine, dioxane, dioxine, thiomorpholine, thiazine, oxathiane, dithiane, dithiin, triazinane, triazine, trioxane, trithiane, azepane, azepine, oxepane, oxepine, thiepane, thiepine, azocane, or azocine. In some embodiments, the 5-8 membered heterocycle formed by R^4a and R^4b together with the nitrogen they are attached to is pyrrolidine. In some embodiments, the 5-8 membered heterocycle formed by R^4a and R^4b together with the nitrogen they are attached to is pyrrole. In some embodiments, the 5-8 membered heterocycle formed by R^4a and R^4b together with the nitrogen they are attached to is tetrahydrofuran. In some embodiments, the 5-8 membered heterocycle formed by R^4a and R^4b together with the nitrogen they are attached to is furan. In some embodiments, the 5-8 membered heterocycle formed by R^4a and R^4b together with the nitrogen they are attached to is imidazolidine. In some embodiments, the 5-8 membered heterocycle formed by R^4a and R^4b together with the nitrogen they are attached to is pyrazolidine. In some embodiments, the 5-8 membered heterocycle formed by R^4a and R^4b together with the nitrogen they are attached to is imidazole. In some embodiments, the 5-8 membered heterocycle formed by R^4a and R^4b together with the nitrogen they are attached to is pyrazole. In some embodiments, the 5-8 membered heterocycle formed by R^4a and R^4b together with the nitrogen they are attached to is oxazoline. In some embodiments, the 5-8 membered heterocycle formed by R^4a and R^4b together with the nitrogen they are attached to is isooxazoline. In some embodiments, the 5-8 membered heterocycle formed by R^4a and R^4b together with the nitrogen they are attached to is oxazole. In some embodiments, the 5-8 membered heterocycle formed by R^4a and R^4b together with the nitrogen they are attached to is isoxazole. In some embodiments, the 5-8 membered heterocycle formed by R^4a and R^4b together with the nitrogen they are attached to is dioxolane. In some embodiments, the 5-8 Attorney Docket No.: CRISP-43327.601 membered heterocycle formed by R^4a and R^4b together with the nitrogen they are attached to is piperidine. In some embodiments, the 5-8 membered heterocycle formed by R^4a and R^4b together with the nitrogen they are attached to is pyridine. In some embodiments, the 5-8 membered heterocycle formed by R^4a and R^4b together with the nitrogen they are attached to is oxane. In some embodiments, the 5-8 membered heterocycle formed by R^4a and R^4b together with the nitrogen they are attached to is pyran. In some embodiments, the 5-8 membered heterocycle formed by R^4a and R^4b together with the nitrogen they are attached to is diazinane. In some embodiments, the 5-8 membered heterocycle formed by R^4a and R^4b together with the nitrogen they are attached to is diazine. In some embodiments, the 5-8 membered heterocycle formed by R^4a and R^4b together with the nitrogen they are attached to is morpholine. In some embodiments, the 5-8 membered heterocycle formed by R^4a and R^4b together with the nitrogen they are attached to is oxazine. In some embodiments, the 5-8 membered heterocycle formed by R^4a and R^4b together with the nitrogen they are attached to is dioxane. In some embodiments, the 5-8 membered heterocycle formed by R^4a and R^4b together with the nitrogen they are attached to is dioxine. In some embodiments, the 5-8 membered heterocycle formed by R^4a and R^4b together with the nitrogen they are attached to is triazinane. In some embodiments, the 5-8 membered heterocycle formed by R^4a and R^4b together with the nitrogen they are attached to is triazine. In some embodiments, the 5-8 membered heterocycle formed by R^4a and R^4b together with the nitrogen they are attached to is trioxane. In some embodiments, the 5-8 membered heterocycle formed by R^4a and R^4b together with the nitrogen they are attached to is azepane. In some embodiments, the 5-8 membered heterocycle formed by R^4a and R^4b together with the nitrogen they are attached to is azepine. In some embodiments, the 5-8 membered heterocycle formed by R^4a and R^4b together with the nitrogen they are attached to is oxepane. In some embodiments, the 5-8 membered heterocycle formed by R^4a and R^4b together with the nitrogen they are attached to is oxepine. In some embodiments, the 5-8 membered heterocycle formed by R^4a and R^4b together with the nitrogen they are attached to is azocane. In some embodiments, the 5-8 membered heterocycle formed by R^4a and R^4b together with the nitrogen they are attached to is azocine. In some embodiments, R^4a and R^4b together with the nitrogen they are attached to form a 5-6 membered heterocycle. In some embodiments, the 5-8 membered heterocycle formed by R^4a and R^4b together with the nitrogen they are attached to is tetrahydrothiophene. In some embodiments, the 5-8 membered heterocycle formed by R^4a and R^4b together with the nitrogen they are attached to is thiophene. In some embodiments, the 5-8 membered heterocycle formed by R^4a and R^4b together with the nitrogen they are attached to is thiazolidine. In some embodiments, the 5-8 membered heterocycle formed by R^4a and R^4b Attorney Docket No.: CRISP-43327.601 together with the nitrogen they are attached to is thiazole. In some embodiments, the 5-8 membered heterocycle formed by R^4a and R^4b together with the nitrogen they are attached to is isothiazole. In some embodiments, the 5-8 membered heterocycle formed by R^4a and R^4b together with the nitrogen they are attached to is dithiolane. In some embodiments, the 5-8 membered heterocycle formed by R^4a and R^4b together with the nitrogen they are attached to is thiane. In some embodiments, the 5-8 membered heterocycle formed by R^4a and R^4b together with the nitrogen they are attached to is thiopyran. In some embodiments, the 5-8 membered heterocycle formed by R^4a and R^4b together with the nitrogen they are attached to is thiomorpholine. In some embodiments, the 5-8 membered heterocycle formed by R^4a and R^4b together with the nitrogen they are attached to is thiazine. In some embodiments, the 5-8 membered heterocycle formed by R^4a and R^4b together with the nitrogen they are attached to is oxathiane. In some embodiments, the 5-8 membered heterocycle formed by R^4a and R^4b together with the nitrogen they are attached to is dithiane. In some embodiments, the 5-8 membered heterocycle formed by R^4a and R^4b together with the nitrogen they are attached to is dithiin. In some embodiments, the 5-8 membered heterocycle formed by R^4a and R^4b together with the nitrogen they are attached to is trithiane. In some embodiments, the 5-8 membered heterocycle formed by R^4a and R^4b together with the nitrogen they are attached to is thiepane. In some embodiments, the 5-8 membered heterocycle formed by R^4a and R^4b together with the nitrogen they are attached to is thiepine. In some embodiments, R⁴ , wherein R^4a and R^4b together with the nitrogen they are attached to form

heterocycle and p is an integer between 1 and 4. In some particular embodiments, R⁴ , wherein R^4a and R^4b together with the nitrogen they are attached to form a

and p is an integer of 1. In some embodiments, the 6 membered heterocycle formed with R^4a and R^4b is substituted with C₁ alkyl. In some embodiments, the 6 membered heterocycle formed with R^4a and R^4b is diazinane. In some embodiments, the 6 membered heterocycle formed with R^4a and R^4b is 1,4-diazinane. In some embodiments, the 6 membered heterocycle formed with R^4a and R^4b is substituted with a methyl (-CH3). In some embodiments, the 6 membered heterocycle formed with R^4a and R^4b substituted with C₁ alkyl . In some

Attorney Docket No.: CRISP-43327.601 embodiments, R⁴ . In some embodiments, R⁴ . In one between 1 and 6. In is an

integer between 1 between 1 and 4. p is an 3. In some embodiments, p is an integer of 1. In some embodiments, p is an integer of 2. In some embodiments, p is an integer of 3. In some embodiments, p is an integer of 4. In some embodiments, p is an integer of 5. In some embodiments, p is an integer of 6. In one embodiment, m¹, m², and m³ are, each independently, an integer between 1 and 6. In some embodiments, m¹, m², and m³ are, each independently, an integer between 1 and 4. In some embodiments, m¹, m², and m³ are, each independently, an integer between 1 and 3. In some embodiments, m¹, m², and m³ are, each independently, 1, 2, or 3. In one embodiment, the compound of formula (I), (IA), (IB), (IA-a), (IA-b), (IB-a), (IB-b), (IA-a1), (IA-b1), (IB-a1), or (IB-b1) has one of the following structures shown in Table 1 below. The exemplary compounds are designated Lipids 1-54 and 56-65. Lipids 1-54 and 56-65 were prepared according to the procedures described in Examples 6-88 as designated in Table 1. Table 1: A list of Lipids. Example Structure Lipid # # OH HN N N 6 1 C₁₁H₂₃ C H N N N N N _{11 23} C₁₁H H H 2₃ C₁₁H₂₃ OH HN N N 7 2 C₁₂H₂₅ C H N N N N N _{12 25} H H C₁₂H₂₅ C₁₂H₂₅ 8 3 Attorney Docket No.: CRISP-43327.601 OH HN 9 4 N N C₁₁H₂₃ C H N N N N N _{11 23} H H C₁₁H₂₃ C₁₁H₂₃ OH HN 10 5 N N C₁₂H₂₅ C H N N N N N _{12 25} H H C₁₂H₂₅ C₁₂H₂₅ 11 6 12 7 13 8 14 9 15 10 Attorney Docket No.: CRISP-43327.601 16 11 17 12 18 13 19 14 20 15 21 16 22 17 Attorney Docket No.: CRISP-43327.601 23 18 24 19 25 20 26 21 27 22 28 23 Attorney Docket No.: CRISP-43327.601 29 24 30 25 31 26 32 27

Attorney Docket No.: CRISP-43327.601 34 29 35 30 36 31 37 32 38 33 Attorney Docket No.: CRISP-43327.601 39 34 40 35 N O N HN O N N 41 36 ^C12H25 C N N N _N N ₁₂H₂₅ H H C₁₂H₂₅ C₁₂H₂₅ N O N O O HN O CH O N N CH 42 37 O O N N N N N O ^{C H} H H O CH O 43 38 N O N O HN O C₈H₁₇ O O N N C O ₈H₁₇ 44 39 O N N N N H H N O C₈H₁₇ O C₈H O ₁₇ Attorney Docket No.: CRISP-43327.601 45 40 HO O NH O C 63 41 1₂H₂₅ C H O N N O _{12 25} O N O N O N O ^C12H25 _O O ^C12H25 64 42 65 43 66 44 Attorney Docket No.: CRISP-43327.601 67 45 O N O HN O C₁₂H₂₅ C H 68 46 O N N O _{12 25} O N N N N N O H H C₁₂H_{25 O} O ^C12^H25 69 47 N O HN O C₁₂H₂₅ C H 70 48 O N N O _{12 25} O N N N N N O H H C₁₂H_{25 O} O ^C12H25 71 49

Attorney Docket No.: CRISP-43327.601 72 50 N N O HN O C₁₂H₂₅ C H 73 51 O N N O _{12 25} O N N N N N O H H C₁₂H_{25 O} O ^C12^H25 74 52 76 53 77 54 Attorney Docket No.: CRISP-43327.601 78 56 79 57 80 58 81 59 82 60 Attorney Docket No.: CRISP-43327.601 83 61 N O HN O C₈H₁₇ CH 84 62 O N N O _{8 17} O N N N N N O H H C₈H_{17 O} O ^C8^H17 85 63 86 64 87 65 As can be appreciated, the compounds described herein enable the development of new therapies for disease without the need for exotic chemistry or specialized reagents or Attorney Docket No.: CRISP-43327.601 manufacturing techniques. III. Pharmaceutical compositions Other embodiments are directed to pharmaceutical compositions. In an embodiment, the pharmaceutical composition comprises any one (or more) of the foregoing compounds and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition is formulated for oral administration. In other embodiments, the pharmaceutical composition is formulated for injection. In still more embodiments, the pharmaceutical compositions comprise a compound as disclosed herein and an additional therapeutic agent (e.g., anticancer agent). Non-limiting examples of such additional therapeutic agents are described herein below. In certain embodiments, a compound as described herein is administered in a local rather than systemic manner, for example, via injection of the compound directly into an organ, often in a depot preparation or sustained release formulation. In specific embodiments, long acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, in other embodiments, the compound is delivered in a targeted drug delivery system, for example, in a liposome coated with an organ specific antibody. In such embodiments, the liposomes are targeted to and taken up selectively by the organ. In yet other embodiments, the compound as described herein is provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation. In yet other embodiments, the compound described herein is administered topically. In treatment methods according to embodiments of the disclosure, an effective amount of at least one compound of Formula (I), (IA), (IB), (IA-a), (IA-b), (IB-a), (IB-b), (IA-a1), (IA-b1), (IB-a1), or (IB-b1) is administered to a subject suffering from or diagnosed as having such a disease, disorder, or medical condition. Effective amounts or doses may be ascertained by methods such as modeling, dose escalation studies or clinical trials, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the disease, disorder, or condition, the subject's previous or ongoing therapy, the subject's health status and response to drugs, and the judgment of the treating physician. The compounds according to the disclosure are effective over a wide dosage range. For example, in the treatment of adult humans, dosages from about 0.001 to 0.1 mg, 0.01 to 0.1 mg, 0.5 to 5 mg, 0.5 to 10 mg, 0.01 to 10 mg, 0.1 to 10 mg, 10 to 5000 mg, 100 to 5000 mg, 1000 mg to 4000 mg per day, or 1000 to 3000 mg per day are examples of dosages that are used in some embodiments. The exact dosage will depend upon the route of Attorney Docket No.: CRISP-43327.601 administration, the form in which the compound is administered, the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician. In some embodiments, compounds of the disclosure are administered in a single dose. In an embodiment, the single dose is administered orally. In another embodiment, the single dose is administered by injection. However, other routes are used as appropriate. In some embodiments, compounds of the disclosure are administered in multiple doses. In some embodiments, dosing is about once, twice, three times, four times, five times, six times, or more than six times per day. In other embodiments, dosing is about once a month, once every two weeks, once a week, or once every other day. In another embodiment compounds of the disclosure and another agent (e.g., an additional anti-cancer agent) are administered together about once per day to about 6 times per day. In another embodiment the administration of compounds of the disclosure and an agent continues for less than about 7 days. In yet another embodiment the administration continues for more than about 6, 10, 14, 28 days, two months, six months, or one year. In some cases, continuous dosing is achieved and maintained as long as necessary. Administration of compounds of the disclosure may continue as long as necessary. In some embodiments, compounds of the disclosure are administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, compounds of the disclosure are administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, compounds of the disclosure are administered chronically on an ongoing basis, e.g., for the treatment of chronic effects. In some embodiments, the compounds of the disclosure are administered in individual dosage forms. It is known in the art that due to intersubject variability in compound pharmacokinetics, individualization of dosing regimen is necessary for optimal therapy. In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. In specific embodiments, pharmaceutical compositions are formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the disclosed compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any pharmaceutically acceptable techniques, carriers, and excipients are used as suitable to formulate the pharmaceutical compositions described herein: Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Attorney Docket No.: CRISP-43327.601 Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins1999). Provided herein are pharmaceutical compositions comprising one or more compounds of Formula (I), (IA), (IB), (IA-a), (IA-b), (IB-a), (IB-b), (IA-a1), (IA-b1), (IB- a1), or (IB-b1), and a pharmaceutically acceptable carrier. Also provided herein are pharmaceutical compositions comprising one or more compounds selected from compounds of Formula (I), (IA), (IB), (IA-a), (IA-b), (IB-a), (IB-b), (IA-a1), (IA-b1), (IB-a1), or (IB-b1) and pharmaceutically acceptable diluent(s), excipient(s), and carrier(s). In certain embodiments, the compounds described are administered as pharmaceutical compositions in which one or more compounds selected from compounds of Formula (I), (IA), (IB), (IA-a), (IA-b), (IB-a), (IB-b), (IA-a1), (IA-b1), (IB-a1), or (IB-b1) are mixed with other active ingredients, as in combination therapy. Encompassed herein are all combinations of actives set forth in the combination therapies section below and throughout this disclosure. In specific embodiments, the pharmaceutical compositions include one or more compounds of Formula (I), (IA), (IB), (IA-a), (IA-b), (IB-a), (IB-b), (IA-a1), (IA-b1), (IB-a1), or (IB-b1). A pharmaceutical composition, as used herein, refers to a mixture of one or more compounds selected from compounds of Formula (I), (IA), (IB), (IA-a), (IA-b), (IB-a), (IB- b), (IA-a1), (IA-b1), (IB-a1), or (IB-b1) with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients. In certain embodiments, the pharmaceutical composition facilitates administration of the compound to an organism. In some embodiments, therapeutically effective amounts of one or more compounds selected from compounds of Formula (I), (IA), (IB), (IA-a), (IA-b), (IB-a), (IB-b), (IA-a1), (IA-b1), (IB-a1), or (IB-b1) provided herein are administered in a pharmaceutical composition to a mammal having a disease, disorder or medical condition to be treated. In specific embodiments, the mammal is a human. In certain embodiments, therapeutically effective amounts vary depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. The compounds described herein are used singly or in combination with one or more therapeutic agents as components of mixtures. In one embodiment, one or more compounds selected from compounds of Formula (I), (IA), (IB), (IA-a), (IA-b), (IB-a), (IB-b), (IA-a1), (IA-b1), (IB-a1), or (IB-b1) are formulated in aqueous solutions. In specific embodiments, the aqueous solution is selected from, by way of example only, a physiologically compatible buffer, such as Hank’s solution, Ringer’s solution, or physiological saline buffer. In other embodiments, one or more Attorney Docket No.: CRISP-43327.601 compounds selected from compounds of Formula (I), (IA), (IB), (IA-a), (IA-b), (IB-a), (IB- b), (IA-a1), (IA-b1), (IB-a1), or (IB-b1) are formulated for transmucosal administration. In specific embodiments, transmucosal formulations include penetrants that are appropriate to the barrier to be permeated. In still other embodiments wherein the compounds described herein are formulated for other parenteral injections, appropriate formulations include aqueous or non-aqueous solutions. In specific embodiments, such solutions include physiologically compatible buffers and/or excipients. In another embodiment, compounds described herein are formulated for oral administration. Compounds described herein are formulated by combining the active compounds with, e.g., pharmaceutically acceptable carriers or excipients. In various embodiments, the compounds described herein are formulated in oral dosage forms that include, by way of example only, tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions and the like. In certain embodiments, pharmaceutical preparations for oral use are obtained by mixing one or more solid excipient with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as: for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. In specific embodiments, disintegrating agents are optionally added. Disintegrating agents include, by way of example only, cross linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a pharmaceutically acceptable salt thereof such as sodium alginate. In one embodiment, the oral dosage forms, such as a pill, capsule or tablet, comprises one or more suitable layers or coatings. In specific embodiments, concentrated sugar solutions are used for coating the dosage form. The sugar solutions, optionally contain additional components, such as by way of example only, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs and/or pigments are also optionally added to the coatings for identification purposes. Additionally, the dyestuffs and/or pigments are optionally utilized to characterize different combinations of active compound doses. In certain embodiments, therapeutically effective amounts of at least one of the Attorney Docket No.: CRISP-43327.601 compounds described herein are formulated into other oral dosage forms. Oral dosage forms include push fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. In specific embodiments, push fit capsules contain the active ingredients in admixture with one or more filler. Fillers include, by way of example only, lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In other embodiments, soft capsules, contain one or more active compound that is dissolved or suspended in a suitable liquid. Suitable liquids include, by way of example only, one or more fatty oil, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers are optionally added. In still other embodiments, the compounds described herein are formulated for parental injection, including formulations suitable for bolus injection or continuous infusion. In specific embodiments, formulations for injection are presented in unit dosage form (e.g., in ampoules) or in multi dose containers. Preservatives are, optionally, added to the injection formulations. In still other embodiments, the pharmaceutical compositions are formulated in a form suitable for parenteral injection as sterile suspensions, solutions or emulsions in oily or aqueous vehicles. Parenteral injection formulations optionally contain formulatory agents such as suspending, stabilizing and/or dispersing agents. In specific embodiments, pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water soluble form. In additional embodiments, suspensions of one or more compounds selected from compounds of Formula (I), (IA), (IB), (IA-a), (IA-b), (IB-a), (IB-b), (IA-a1), (IA-b1), (IB-a1), or (IB-b1) are prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles for use in the pharmaceutical compositions described herein include, by way of example only, fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. In certain specific embodiments, aqueous injection suspensions contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension contains suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, in other embodiments, the active ingredient is in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. Pharmaceutical compositions include at least one pharmaceutically acceptable carrier, diluent or excipient, and one or more compounds selected from compounds of Formula (I), (IA), (IB), (IA-a), (IA-b), (IB-a), (IB-b), (IA-a1), (IA-b1), (IB-a1), or (IB-b1) as an active ingredient. The active ingredient is in free-acid or free-base form, or in a pharmaceutically acceptable salt form. In addition, the methods and pharmaceutical Attorney Docket No.: CRISP-43327.601 compositions described herein include the use of N-oxides, crystalline forms (also known as polymorphs), as well as active metabolites of these compounds having the same type of activity. All tautomers of the compounds described herein are included within the scope of the compounds presented herein. Additionally, the compounds described herein encompass unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein. In addition, the pharmaceutical compositions optionally include other medicinal or pharmaceutical agents, carriers, adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, pharmaceutically acceptable salts for regulating the osmotic pressure, buffers, and/or other therapeutically valuable substances. Methods for the preparation of compositions comprising the compounds described herein include formulating the compound(s) with one or more inert, pharmaceutically acceptable excipients or carriers to form a solid, semi-solid or liquid composition. Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories. Liquid compositions include solutions in which a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles, or nanoparticles comprising a compound as disclosed herein. Semi-solid compositions include, but are not limited to, gels, ointments, suspensions and creams. The form of the pharmaceutical compositions described herein include liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to use, or as emulsions. These compositions also optionally contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and so forth. In some embodiments, pharmaceutical compositions comprising one or more compounds selected from compounds of Formula (I), (IA), (IB), (IA-a), (IA-b), (IB-a), (IB- b), (IA-a1), (IA-b1), (IB-a1), or (IB-b1) illustratively takes the form of a liquid where the agents are present in solution, in suspension or both. Typically when the composition is administered as a suspension, a first portion of the agent is present in solution and a second portion of the agent is present in particulate form, in suspension in a liquid matrix. In some embodiments, a liquid composition includes a gel formulation. In other embodiments, the liquid composition is aqueous. In certain embodiments, aqueous suspensions contain one or more polymers as suspending agents. Polymers include water-soluble polymers such as cellulosic polymers, e.g., hydroxypropyl methylcellulose, and water-insoluble polymers such as cross-linked carboxyl-containing polymers. Certain pharmaceutical compositions described herein Attorney Docket No.: CRISP-43327.601 comprise a mucoadhesive polymer, selected for example from carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylic acid/butyl acrylate copolymer, sodium alginate and dextran. Pharmaceutical compositions also, optionally, include solubilizing agents to aid in the solubility of one or more compounds selected from compounds of Formula (I), (IA), (IB), (IA-a), (IA-b), (IB-a), (IB-b), (IA-a1), (IA-b1), (IB-a1), or (IB-b1). The term "solubilizing agent" generally includes agents that result in formation of a micellar solution or a true solution of the agent. Certain acceptable nonionic surfactants, for example polysorbate 80, are useful as solubilizing agents, as can ophthalmically acceptable glycols, polyglycols, e.g., polyethylene glycol 400, and glycol ethers. Furthermore, pharmaceutical compositions optionally include one or more pH adjusting agents or buffering agents, including acids such as acetic, boric, citric, lactic, phosphoric and hydrochloric acids; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris- hydroxymethylaminomethane; and buffers such as citrate/dextrose, sodium bicarbonate and ammonium chloride. Such acids, bases and buffers are included in an amount required to maintain pH of the composition in an acceptable range. Compositions also, optionally, include one or more pharmaceutically acceptable salts in an amount required to bring osmolality of the composition into an acceptable range. Such pharmaceutically acceptable salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable pharmaceutically acceptable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate. Other pharmaceutical compositions optionally include one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridinium chloride. Compositions may include one or more surfactants to enhance physical stability or for other purposes. Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, e.g., polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10, octoxynol 40. Compositions may include one or more antioxidants to enhance chemical stability where required. Suitable antioxidants include, by way of example only, ascorbic acid and Attorney Docket No.: CRISP-43327.601 sodium metabisulfite. In certain embodiments, aqueous suspension compositions are packaged in single- dose non-reclosable containers. Alternatively, multiple-dose reclosable containers are used, in which case it is typical to include a preservative in the composition. In alternative embodiments, other delivery systems for hydrophobic pharmaceutical compounds are employed. Liposomes and emulsions are examples of delivery vehicles or carriers useful herein. In certain embodiments, organic solvents such as N- methylpyrrolidone are also employed. In additional embodiments, the compounds described herein are delivered using a sustained release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained release materials are useful herein. In some embodiments, sustained release capsules release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization are employed. In certain embodiments, the formulations described herein comprise one or more antioxidants, metal chelating agents, thiol containing compounds and/or other general stabilizing agents. Examples of such stabilizing agents, include, but are not limited to: (a) about 0.5% to about 2% w/v glycerol, (b) about 0.1% to about 1% w/v methionine, (c) about 0.1% to about 2% w/v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w/v ascorbic acid, (f) 0.003% to about 0.02% w/v polysorbate 80, (g) 0.001% to about 0.05% w/v. polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrins, (l) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc; or (n) combinations thereof. In some embodiments, the concentration of one or more compounds selected from compounds of Formula (I), (IA), (IB), (IA-a), (IA-b), (IB-a), (IB-b), (IA-a1), (IA-b1), (IB- a1), or (IB-b1) provided in the pharmaceutical compositions is greater than 90%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25% 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%, 17.25% 17%, 16.75%, 16.50%, 16.25% 16%, 15.75%, 15.50%, 15.25% 15%, 14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25% 13%, 12.75%, 12.50%, 12.25% 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25% 10%, 9.75%, 9.50%, 9.25% 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25%, 7%, 6.75%, 6.50%, 6.25% 6%, 5.75%, 5.50%, 5.25%, 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 1.25% , 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, Attorney Docket No.: CRISP-43327.601 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w/w, w/v, or v/v. In another embodiment, the amount of a compound selected from compounds of (I), (IA), (IB), (IA-a), (IA-b), (IB-a), (IB-b), (IA-a1), (IA-b1), (IB-a1), or (IB- b1) in the pharmaceutical compositions is an amount between about any two of the values recited in the preceding sentence, for example, between about 2-70 w/w%, 3.5-80 w/w%, 1- 30 w/w%, etc. In some embodiments, the concentration of one or more compounds selected from compounds of Formula (I), (IA), (IB), (IA-a), (IA-b), (IB-a), (IB-b), (IA-a1), (IA-b1), (IB- a1), or (IB-b1) provided in the pharmaceutical compositions of the present disclosure is in the range from approximately 0.0001% to approximately 50%, approximately 0.001% to approximately 40 %, approximately 0.01% to approximately 30%, approximately 0.02% to approximately 29%, approximately 0.03% to approximately 28%, approximately 0.04% to approximately 27%, approximately 0.05% to approximately 26%, approximately 0.06% to approximately 25%, approximately 0.07% to approximately 24%, approximately 0.08% to approximately 23%, approximately 0.09% to approximately 22%, approximately 0.1% to approximately 21%, approximately 0.2% to approximately 20%, approximately 0.3% to approximately 19%, approximately 0.4% to approximately 18%, approximately 0.5% to approximately 17%, approximately 0.6% to approximately 16%, approximately 0.7% to approximately 15%, approximately 0.8% to approximately 14%, approximately 0.9% to approximately 12%, approximately 1% to approximately 10% w/w, w/v or v/v. In some embodiments, the amount the one or more compounds selected from compounds of Formula (I), (IA), (IB), (IA-a), (IA-b), (IB-a), (IB-b), (IA-a1), (IA-b1), (IB- a1), or (IB-b1) provided in the pharmaceutical compositions of the present disclosure is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g, 0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g, 0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g, or 0.0001 g. In some embodiments, the amount of the one or more compounds selected from compounds of Formula (I), (IA), (IB), (IA-a), (IA-b), (IB-a), (IB-b), (IA-a1), (IA-b1), (IB- a1), or (IB-b1) provided in the pharmaceutical compositions of the present disclosure is in the range of 0.0001-10 g, 0.0005-9 g, 0.001-8 g, 0.005-7 g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5-4 g, or 1-3 g. Packaging materials for use in packaging pharmaceutical compositions described Attorney Docket No.: CRISP-43327.601 herein include those found in, e.g., U.S. Pat. Nos.5,323,907, 5,052,558 and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment. For example, the container(s) includes one or more compounds described herein, optionally in a composition or in combination with another agent as disclosed herein. The container(s) optionally have a sterile access port (for example the container is an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). Such kits optionally comprise a compound with an identifying description or label or instructions relating to its use in the methods described herein. For example, a kit typically includes one or more additional containers, each with one or more of various materials (such as reagents, optionally in concentrated form, and/or devices) desirable from a commercial and user standpoint for use of a compound described herein. Non-limiting examples of such materials include, but not limited to, buffers, diluents, filters, needles, syringes; carrier, package, container, vial and/or tube labels listing contents and/or instructions for use, and package inserts with instructions for use. A set of instructions will also typically be included. A label is optionally on or associated with the container. For example, a label is on a container when letters, numbers or other characters forming the label are attached, molded or etched into the container itself, a label is associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert. In addition, a label is used to indicate that the contents are to be used for a specific therapeutic application. In addition, the label indicates directions for use of the contents, such as in the methods described herein. In certain embodiments, the pharmaceutical compositions are presented in a pack or dispenser device which contains one or more unit dosage forms containing a compound provided herein. The pack for example contains metal or plastic foil, such as a blister pack. Alternatively, the pack or dispenser device is accompanied by instructions for administration, or the pack or dispenser is accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, is the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. In some embodiments, compositions containing a compound provided herein formulated in a compatible pharmaceutical carrier are prepared, placed in an appropriate container, and Attorney Docket No.: CRISP-43327.601 labeled for treatment of an indicated condition. In some embodiments, a pharmaceutical composition has a compound described above and a pharmaceutically acceptable carrier including, for example, any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals. In one embodiment, a pharmaceutical composition comprising the compound of Formula (I), (IA), (IB), (IA-a), (IA-b), (IB-a), (IB-b), (IA-a1), (IA-b1), (IB-a1), or (IB-b1) and an additional therapeutic agent is disclosed. IV. Lipid Nanoparticles Disclosed herein are various LNP compositions for delivering biologically active agents, such as nucleic acids, e.g., DNA, mRNAs and gRNAs, including CRISPR/Cas cargoes. Such LNP compositions include an “ionizable amine lipid”, along with, for example, cholesterol, a polymer conjugated lipid, and a helper lipid. “Lipid nanoparticle” or “LNP” refers to, without limiting the meaning, a particle that comprises a plurality of (i.e., more than one) LNP components physically associated with each other by intermolecular forces. In some embodiments, the LNP composition comprises a compound of Formula (I), (IA), (IB), (IA-a), (IA-b), (IB-a), (IB-b), (IA-a1), (IA-b1), (IB-a1), or (IB-b1) or a combination of one or more of the compounds and one or more additional lipid components selected from the group consisting of neutral lipids and/or helper lipids (collectively helper lipids), polymer conjugated lipids, and cholesterol or a derivative thereof. While cholesterol can be considered to be a neutral or helper lipid in LNP compositions, for the purposes of the description herein the percentage of the composition of cholesterol in the LNP composition is listed separately from that of the designated helper lipids. In some embodiments, the composition further comprises a helper lipid and cholesterol or a derivative thereof. In some embodiments, the composition further comprises a helper lipid and a polymer conjugated lipid. In some embodiments, the composition further comprises a helper lipid, cholesterol or a derivative thereof, and a polymer conjugated lipid. In some embodiments, the helper lipid is selected from the group consisting of 1,2- dilinoleoyl-sn-glycero-3-phosphocholine (DLPC), 1,2-dimyristoyl-sn-glycero- phosphocholine (DMPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2- dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-distearoyl-sn-glycero-3- phosphocholine (DSPC), 1,2-diundecanoyl-sn-glycero-phosphocholine (DUPC), l-palmitoyl- Attorney Docket No.: CRISP-43327.601 2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1,2-di-O-octadecenyl-sn-glycero-3- phosphocholine (18:0 Diether PC), l-oleoyl-2-cholesterylhemisuccinoyl-sn-glycero-3- phosphocholine (OChemsPC), 1-hexadecyl-sn-glycero-3-phosphocholine (C16 Lyso PC), 1,2-dilinolenoyl-sn-glycero-3-phosphocholine, 1,2-diarachidonoyl-sn-glycero-3- phosphocholine, 1,2-didocosahexaenoyl-sn-glycero-3-phosphocholine, 1,2-dioleoyl-sn- glycero-3-phosphoethanolamine (DOPE), 1,2-diphytanoyl-sn-glycero-3- phosphoethanolamine (ME 16.0 PE), l,2-distearoyl-sn-glycero-3-phosphoethanolamine, 1,2- dilinoleoyl-sn-glycero-3-phosphoethanolamine, 1,2-dilinolenoyl-sn-glycero-3- phosphoethanolamine, 1,2-diarachidonoyl-sn-glycero-3-phosphoethanolamine, 1,2- didocosahexaenoyl-sn-glycero-3-phosphoethanolamine, 1,2-dioleoyl-sn-glycero-3-phospho- rac-(1-glycerol) sodium salt (DOPG), and mixtures thereof. In some embodiments, the helper lipid is DOPE or DSPC. In some embodiments, the helper lipid is a lipid other than cholesterol. Embodiments of the present disclosure provide lipid compositions described according to the respective molar ratios of the component lipids in the composition. All mol-% numbers are given as a fraction of the lipid component of the lipid composition or, more specifically, the LNP compositions. In certain embodiments, the mol-% of the compound of Formula (I), (IA), (IB), (IA-a), (IA-b), (IB-a), (IB-b), (IA-a1), (IA-b1), (IB-a1), or (IB-b1) may be from about 10 mol-% to about 70 mol-%. In certain embodiments, the mol-% of the compound of Formula (I), (IA), (IB), (IA-a), (IA-b), (IB-a), (IB-b), (IA-a1), (IA-b1), (IB-a1), or (IB-b1) may be from about 20 mol-% to about 70 mol-%. In certain embodiments, the mol-% of the compound of Formula (I), (IA), (IB), (IA-a), (IA-b), (IB-a), (IB-b), (IA-a1), (IA-b1), (IB-a1), or (IB-b1) may be at least 10 mol-%, at least 20 mol-%, at least 30 mol-%, at least 40 mol-%, or at least 50 mol-%. In certain embodiments, the mol-% of the helper lipid may be from about 0 mol-% to about 60 mol-%. In certain embodiments, the mol-% of the helper lipid may be from about 20 mol-% to about 60 mol-%. In certain embodiments, the mol-% of the helper lipid may be from about 20 mol-% to about 50 mol-%. In certain embodiments, the mol-% of the helper lipid may be about 40 mol-%. In certain embodiments, the mol-% of the helper lipid may be about 30 mol-%. In certain embodiments, the mol-% of cholesterol or a derivative thereof may be from about 0 mol-% to about 80 mol-%. In certain embodiments, the mol-% of cholesterol or a derivative thereof may be from about 20 mol-% to about 60 mol-%. In certain embodiments, the mol-% of cholesterol or a derivative thereof may be from about 30 mol-% to about 50 mol-%. In certain embodiments, the mol-% of cholesterol or a derivative thereof may be Attorney Docket No.: CRISP-43327.601 from 30 mol-% to about 40 mol-% or from about 35% mol-% to about 45 mol-%. In certain embodiments, the mol-% of cholesterol or a derivative thereof is adjusted based on compound of Formula (I), (IA), (IB), (IA-a), (IA-b), (IB-a), (IB-b), (IA-a1), (IA-b1), (IB-a1), or (IB-b1), helper lipid and/or PEG lipid concentrations to bring the lipid component to 100 mol-%. In certain embodiments, the mol-% of the PEG lipid may be from about 0.5 mol-% to about 10 mol-%. In certain embodiments, the mol-% of the PEG lipid may be from about 0.5 mol-% to about 4 mol-%. In certain embodiments, the mol-% of the PEG lipid may be about 0.5 mol-% to about 2 mol-%. In certain embodiments, the mol-% of the PEG lipid may be about 1.5 mol-%. In certain embodiments, the mol-% of the PEG lipid may be about 1.0 mol-%. In certain embodiments, the mol-% of the PEG lipid may be about 0.5 mol-%. In one embodiment, the molar ratio of the compound of Formula (I), (IA), (IB), (IA- a), (IA-b), (IB-a), (IB-b), (IA-a1), (IA-b1), (IB-a1), or (IB-b1) to the helper lipid ranges from about 1:7 to about 7:1. In another embodiment, the molar ratio of the compound of Formula (I), (IA), (IB), (IA-a), (IA-b), (IB-a), (IB-b), (IA-a1), (IA-b1), (IB-a1), or (IB-b1) to the helper lipid ranges from about 1:5 to about 5:1. In another embodiment, the molar ratio of the compound of Formula (I), (IA), (IB), (IA-a), (IA-b), (IB-a), (IB-b), (IA-a1), (IA-b1), (IB- a1), or (IB-b1) to the helper lipid ranges from about 1:4 to about 4:1. In another embodiment, the molar ratio of the compound of Formula (I), (IA), (IB), (IA-a), (IA-b), (IB- a), (IB-b), (IA-a1), (IA-b1), (IB-a1), or (IB-b1) to the helper lipid ranges from about 1:3 to about 3:1. In another embodiment, the molar ratio of the compound of Formula (I), (IA), (IB), (IA-a), (IA-b), (IB-a), (IB-b), (IA-a1), (IA-b1), (IB-a1), or (IB-b1) to the helper lipid ranges from about 1:2.5 to about 2.5:1. In another embodiment, the molar ratio of the compound of Formula (I), (IA), (IB), (IA-a), (IA-b), (IB-a), (IB-b), (IA-a1), (IA-b1), (IB-a1), or (IB-b1) to the helper lipid ranges from about 1:2 to about 2:1. In another embodiment, the molar ratio of the compound of Formula (I), (IA), (IB), (IA-a), (IA-b), (IB-a), (IB-b), (IA- a1), (IA-b1), (IB-a1), or (IB-b1) to the helper lipid ranges from about 1:1 to about 1:3. In another embodiment, the molar ratio of the compound of Formula (I), (IA), (IB), (IA-a), (IA- b), (IB-a), (IB-b), (IA-a1), (IA-b1), (IB-a1), or (IB-b1) to the helper lipid ranges from about 1:1 to about 1:2. In one embodiment, the molar ratio of the compound of Formula (I), (IA), (IB), (IA- a), (IA-b), (IB-a), (IB-b), (IA-a1), (IA-b1), (IB-a1), or (IB-b1) to cholesterol ranges from 3:1 to 1:3. In another embodiment, the molar ratio of the compound of Formula (I), (IA), (IB), (IA-a), (IA-b), (IB-a), (IB-b), (IA-a1), (IA-b1), (IB-a1), or (IB-b1) to cholesterol ranges from 2:1 to 1:2. In another embodiment, the molar ratio of the compound of Formula (I), (IA), Attorney Docket No.: CRISP-43327.601 (IB), (IA-a), (IA-b), (IB-a), (IB-b), (IA-a1), (IA-b1), (IB-a1), or (IB-b1) to cholesterol ranges from 1:1 to 1:3. In another embodiment, the molar ratio of the compound of Formula (I), (IA), (IB), (IA-a), (IA-b), (IB-a), (IB-b), (IA-a1), (IA-b1), (IB-a1), or (IB-b1) to cholesterol ranges from 1:1 to 1: 2. In some embodiments, an exemplary formulation molar ratio is: Ionizable lipid/helper lipid (DOPE)/ neutral lipid Cholesterol/PEG2K-DMG = 22/33.1/43.4/1.5. In some embodiments, an exemplary formulation molar ratio is: Ionizable lipid/helper lipid (DOPE)/ neutral lipid Cholesterol/PEG2K-DMG = 22/33/43/2. In some embodiments, an exemplary formulation molar ratio is: Ionizable lipid/helper lipid (DOPE)/ neutral lipid Cholesterol/PEG2K-DMG = 49/38.5/10/2.5. In some embodiments, an exemplary formulation molar ratio is: Ionizable lipid/helper lipid (DOPE)/ neutral lipid Cholesterol/PEG2K-DMG = 42.5/40/15/2.5. In one embodiment, a composition comprising the compound of Formula (I), (IA), (IB), (IA-a), (IA-b), (IB-a), (IB-b), (IA-a1), (IA-b1), (IB-a1), or (IB-b1) and a nucleic acid is disclosed. In some embodiments, the composition is an LNP composition as described above. In some embodiments, the nucleic acid comprises RNA, DNA, or mixtures thereof. In some embodiments, the RNA comprises messenger RNA (mRNA), guide RNA (gRNA), interfering RNA (RNAi), such as small interfering RNA (siRNA), small activating RNA (saRNA), circular RNA (circRNA), or mixtures thereof. In some particular embodiments, the nucleic acid is messenger RNA (mRNA). In some other particular embodiments, the nucleic acid is DNA. In some other particular embodiments, the nucleic acid is a guide RNA (gRNA). In some embodiments, the RNA encodes a nuclease. In some embodiments, the nuclease is an RNA-directed nuclease or site-directed nuclease such as a Cas nuclease. In another embodiment, a composition comprising the compound of Formula (I), (IA), (IB), (IA-a), (IA-b), (IB-a), (IB-b), (IA-a1), (IA-b1), (IB-a1), or (IB-b1) and a gene editing system is disclosed. In some embodiments, the composition is an LNP composition as described above. In these embodiments, the components of the gene editing system are nucleic acids or encoded by nucleic acids as is known in the art. The disclosure contemplates any genome editing system known to the skilled artisan, including clustered regularly interspaced short palindromic repeats (CRISPR)/Cas nuclease gene editing systems, base editing systems, reverse transcriptase (RT) editing systems, Attorney Docket No.: CRISP-43327.601 transcription activator-like effector nuclease (TALEN) gene editing systems, and zinc finger nuclease (ZFN) gene editing systems. The gene editing systems, base editing systems, and RT editing systems described herein use a site-directed polypeptide such as a nuclease that is directed by a genome-targeting nucleic acid to modify a target nucleotide sequence of a genome in a precise or pre-determined manner. The base editing, gene editing, and RT editing systems described herein comprise site-directed polypeptides that associate and/or complex with a genome-targeting nucleic acid to edit a genome of a cell in vitro, ex vivo, or in vivo (e.g., in a human subject). In the context of a CRISPR/Cas,CRISPR/Cpf1 system, or base editing system, the site-directed polypeptide can bind to a gRNA that, in turn, specifies the site in the target DNA to which the polypeptide is directed. In the context of an RT editing system, the site-directed polypeptide can bind to a template armed guide RNA (tagRNA) that, in turn, specifies the site in the target DNA to which the polypeptide is directed. A site-directed polypeptide of a base editing system, gene editing system, and/or RT editing system disclosed herein can comprise one or more nuclease domains (e.g., a domain having endonuclease activity). The site-directed polypeptide can be engineered to have one or more domains having endonuclease activity or a wild-type polypeptide with one or more domains having endonuclease activity (e.g., Cas9 from S. pyogenes). In the gene editing (e.g., CRISPR/Cas or CRISPR/Cpf1 systems), base editing, and RT editing systems disclosed herein, the site-directed polypeptide can be an endonuclease, such as a DNA endonuclease. Exemplary Cas proteins (e.g., DNA nucleases) include, without limitation, Cas1, Cas1B, Cas2, Cas3, Cas4, Cas5, Cas5d, Cas5t, Cas5h, Cas5a, Cas6, Cas7, Cas8, Cas8a, Cas8b, Cas8c, Cas9 (also known as Csn1 and Csx12), Cas10, Cas11, Casl2a/Cpfl, Casl2b/C2cl, Casl2c/C2c3, Casl2d/CasY, Casl2e/CasX, Cas 12g, Casl2h, Casl2i, Csy1, Csy2, Csy3, Csy4, Cse1 , Cse2, Cse3, Cse4, Cse5e, Csc1 , Csc2, Csa5, Csnl, Csn2, Csml, Csm2, Csm3, Csm4, Csm5, Csm6, Cmr1 , Cmr3, Cmr4, Cmr5, Cmr6, Csb1 , Csb2, Csb3, Csx17, Csx14, Csx10, Csx16, CsaX, Csx3, Csx1, CsxlS, Csx15, Csf1 , Csf2, Csf3, Csf4, Cpf1, Csdl, Csd2, Cstl, Cst2, Cshl, Csh2, Csal, Csa2, Csa3, Csa4, Csa5, SluCas9, Type II Cas effector proteins, Type V Cas effector proteins, Type VI Cas effector proteins, CARF, DinG, Cpfl, Casl2b/C2cl, Casl2c/C2c3, Casl2b/C2cl, Casl2c/C2c3, SpCas9(K855A), eSpCas9(l.l), SpCas9-HFl, hyper accurate Cas9 variant (HypaCas9), CasB, and homologs, modified or engineered variants, mutants, and/or functional fragments thereof. In some embodiments, the site-directed polypeptide of a base editing system, gene editing system, and/or RT editing system is encoded by an RNA. The base editing, gene editing and RT editing systems described herein use a Attorney Docket No.: CRISP-43327.601 genome-targeting nucleic acid that can direct a site-directed polypeptide to a target nucleic acid sequence to edit a target gene in the genome of a cell, tissue, or organism (e.g., human subject). The disclosure is not limited to any particular type of genome-targeting nucleic acid. The skilled artisan will appreciate that the genome-targeting nucleic acid can depend on the type of genomic editing used. The genome-targeting nucleic acid can be an RNA. A guide RNA can comprise at least a spacer sequence that hybridizes to a target nucleic acid sequence of interest, and a CRISPR repeat sequence. In Type II systems, the gRNA also comprises a second RNA called the trans-activating RNA (tracrRNA) sequence. In the Type II guide RNA (gRNA), the CRISPR repeat sequence and tracrRNA sequence hybridize to each other to form a duplex. In the Type V guide RNA (gRNA), the crRNA forms a duplex. In both systems, the duplex can bind a site-directed polypeptide, such that the guide RNA and site-direct polypeptide form a complex. The genome-targeting nucleic acid can provide target specificity to the complex by virtue of its association with the site-directed polypeptide. The genome-targeting nucleic acid thus can direct the activity of the site-directed polypeptide. The genome-targeting nucleic acid can be a single-molecule guide RNA (sgRNA). A single-molecule guide RNA (sgRNA) in a Type II system can comprise, in the 5′ to 3′ direction, an optional spacer extension sequence, a spacer sequence, a minimum CRISPR repeat sequence, a single-molecule guide linker, a minimum tracrRNA sequence, a 3′ tracrRNA sequence and an optional tracrRNA extension sequence. The optional tracrRNA extension can comprise elements that contribute additional functionality (e.g., stability) to the guide RNA. The single-molecule guide linker can link the minimum CRISPR repeat and the minimum tracrRNA sequence to form a hairpin structure. The optional tracrRNA extension can comprise one or more hairpins. A single-molecule guide RNA (sgRNA) in a Type V system can comprise, in the 5′ to 3′ direction, a minimum CRISPR repeat sequence and a spacer sequence. The genome-targeting nucleic acid can be an RT editing guide RNA (tagRNA) molecule. A tagRNA can comprise an RNA scaffold, a guide sequence (spacer), a flap binding site (FBS) and an editing template (ET). The tagRNA uses the spacer to direct a site- directed RT-editor polypeptide to a target nucleic acid sequence in a genome (protospacer) and initiates a nuclease- or nickase-mediated strand nick at a nick site, resulting in 3’ end hybridization to the FBS and initiation of reverse transcription by the ET to form a pair of redundant single-stranded DNA flaps. Equilibrium between the edited 3’ flap and unedited 5’ flap mediates cleavage, ligation, DNA repair, and the incorporation of the desired edit Attorney Docket No.: CRISP-43327.601 encoded in the ET into the genome of a cell. The gene editing system may further comprise a donor polynucleotide or sequence. In some embodiments, the donor template is DNA molecule that has homology to a target sequence. The donor template is an exogenous polynucleotide sequence that can be inserted into a target nucleic acid cleavage site. The donor polynucleotide, a portion of the donor polynucleotide, a copy of the donor polynucleotide, or a portion of a copy of the donor polynucleotide can be inserted into the target nucleic acid cleavage site. In some embodiments, the gene editing systems described herein include using site- directed nucleases to cut deoxyribonucleic acid (DNA) at precise target locations in the genome, thereby creating single-strand or double-strand DNA breaks at particular locations within the genome. Such breaks can be and regularly are repaired by natural, endogenous cellular processes, such as homology-directed repair (HDR) and NHEJ, as reviewed in Cox et al., Nature Medicine 21(2), 121-31 (2015). These two main DNA repair processes consist of a family of alternative pathways. NHEJ directly joins the DNA ends resulting from a double-strand break, sometimes with the loss or addition of nucleotide sequence, which may disrupt or enhance gene expression. HDR utilizes a homologous sequence, or donor sequence, as a template for inserting a defined DNA sequence at the break point. The homologous sequence can be in the endogenous genome, such as a sister chromatid. Alternatively, the donor can be an exogenous nucleic acid, such as a plasmid, a single-strand oligonucleotide, a double-stranded oligonucleotide, a duplex oligonucleotide or a virus, that has regions of high homology with the nuclease-cleaved locus, but which can also contain additional sequence or sequence changes including deletions that can be incorporated into the cleaved target locus. A third repair mechanism can be microhomology-mediated end joining (MMEJ), also referred to as “Alternative NHEJ,” in which the genetic outcome is similar to NHEJ in that small deletions and insertions can occur at the cleavage site. MMEJ can make use of homologous sequences of a few base pairs flanking the DNA break site to drive a more favored DNA end joining repair outcome, and recent reports have further elucidated the molecular mechanism of this process; see, e.g., Cho and Greenberg, Nature 518, 174-76 (2015); Kent et al., Nature Structural and Molecular Biology, Adv. Online doi:10.1038/nsmb.2961(2015); Mateos-Gomez et al., Nature 518, 254-57 (2015); Ceccaldi et al., Nature 528, 258-62 (2015). In some instances it may be possible to predict likely repair outcomes based on analysis of potential microhomologies at the site of the DNA break. V. Methods of Treatment In still another embodiment, a method for administering a nucleic acid or gene Attorney Docket No.: CRISP-43327.601 editing system to a patient in need thereof or to the cells of patient in thereof is disclosed. In these methods, a lipid formulation, preferably an LNP comprising a compound of Formula (I), (IA), (IB), (IA-a), (IA-b), (IB-a), (IB-b), (IA-a1), (IA-b1), (IB-a1), or (IB-b1), in association with a nucleic acid or gene editing system, is administered to the subject or the cells of the subject. In some embodiments, the subject is an animal. In some embodiments, the subject is a human. VI. Methods of Preparation Preparation methods for the above compounds and compositions are described herein below and/or known in the art. It will be appreciated by those skilled in the art that in the process described herein the functional groups of intermediate compounds may need to be protected by suitable protecting groups. Such functional groups include hydroxy, amino, mercapto and carboxylic acid. Suitable protecting groups for hydroxy include trialkylsilyl or diarylalkylsilyl (for example, t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitable protecting groups for amino, amidino and guanidino include t- butoxycarbonyl, benzyloxycarbonyl, and the like. Suitable protecting groups for mercapto include —C(O)—R″ (where R″ is alkyl, aryl or arylalkyl), p-methoxybenzyl, trityl and the like. Suitable protecting groups for carboxylic acid include alkyl, aryl or arylalkyl esters. Protecting groups may be added or removed in accordance with standard techniques, which are known to one skilled in the art and as described herein. The use of protecting groups is described in detail in Green, T. W. and P. G. M. Wutz, Protective Groups in Organic Synthesis (1999), 3rd Ed., Wiley. As one of skill in the art would appreciate, the protecting group may also be a polymer resin such as a Wang resin, Rink resin or a 2-chlorotrityl- chloride resin. It will also be appreciated by those skilled in the art, although such protected derivatives of compounds of this invention may not possess pharmacological activity as such, they may be administered to a mammal and thereafter metabolized in the body to form compounds of the invention which are pharmacologically active. Such derivatives may therefore be described as “prodrugs”. All prodrugs of compounds of this invention are included within the scope of the invention. In some embodiments, for example, a phosphate bearing compound of (I), (IA), (IB), (IA-a), (IA-b), (IB-a), (IB-b), (IA-a1), (IA-b1), (IB-a1), or (IB-b1) is a prodrug and the structure of such example is described in the disclosure. Furthermore, all compounds of the invention which exist in free base or acid form can be converted to their pharmaceutically acceptable salts by treatment with the appropriate inorganic or organic base or acid by methods known to one skilled in the art. Salts of the Attorney Docket No.: CRISP-43327.601 compounds of the invention can be converted to their free base or acid form by standard techniques. EXAMPLES The following section describes abbreviations used in the examples and includes examples for making intermediate compounds (Examples 1-5, 46-62, and 75), examples for making Lipids 1-54 and 56-64 (Examples 6-45, 63-74, and 76-87), and examples for making LNPs using the compounds and using the LNPs in gene editing (Examples 88-92). Abbreviations: Sat.: Saturated Aq.: Aqueous DIPEA: N,N-Diisopropylethylamine MeCN: Acetonitrile TFA: 2,2,2-Trifluoroacetic acid DCM: Dichloromethane Pd/C: Palladium on activated carbon Pt/C: Platinum on activated carbon DMF: N,N-Dimethylformamide DMA: N,N-Dimethylacetamide IPA: Isopropyl alcohol MeOH: Methanol Quant.: Quantitative HATU: 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) Attorney Docket No.: CRISP-43327.601 K₂CO₃: Potassium Carbonate Cs2CO3: Cesium Carbonate Na2SO4: Sodium Sulfate MgSO₄: Magnesium Sulfate Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium(0) SPhos: 2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenyl LCMS: Liquid chromatography mass spectrometry EtOAc: Ethyl acetate THF: Tetrahydrofuran MeI: Methyl iodide KOAc: Potassium acetate DMSO: Dimethyl sulfoxide HPLC: High-performance liquid chromatography PEPPSI-IPr: [1,3-Bis(2,6-Diisopropylphenyl)imidazol-2-ylidene](3- chloropyridyl)palladium(II) dichloride DBU: 1,8-Diazabicyclo[5.4.0]undec-7-ene PhMe: toluene PPh₃: Triphenylphosphine DIAD: Diisopropyl azodicarboxylate Synthesis Example 1 Intermediate A (di-tert-butyl (((6-chloro-1,3,5-triazine-2,4-diyl)bis(azanediyl))bis(propane- Attorney Docket No.: CRISP-43327.601 3,1-diyl))dicarbamate) Cl O N N O Intermediate A (di- )bis(propane- 3,1-diyl))

1 eq, 368.84 mg) with N-boc-1,3-diaminopropane (4.8 mm, 2.4 eq, 835.37 mg) in 25 ml of chloroform and 1.741 mL of DIPEA. The reaction was performed in a pressure vessel starting at 0℃ and after 30 minutes was heated to 50℃ before being left to run overnight. The next day a dry load cartridge was prepared by concentrating the reaction mixture with silica gel in vacuo. Flash chromatography (Teledyne) was used to purify the reaction mixture (hexanes/ethyl acetate, 0% – 100%, 30 minutes). The product eluted at around 60% ethyl acetate yielding 710 mg of product (71% yield). M+1 = 460.24. Example 2 Intermediate B (di-tert-butyl (((6-((2-hydroxyethyl)amino)-1,3,5-triazine-2,4- diyl)bis(azanediyl))bis(propane-3,1-diyl))dicarbamate) Intermediate B

2,4 diyl)bis(azanediyl))bis(propane-3,1-diyl))dicarbamate) was prepared by mixing Intermediate A (di-tert-butyl (((6-chloro-1,3,5-triazine-2,4-diyl)bis(azanediyl))bis(propane-3,1- diyl))dicarbamate) (8.9 mM, 1 eq, 4100 mg) with aminoethanol (13.35 mM, 1.5 eq, 836 mg) in 75 ml of 1,4 dioxane with 15.56 mL (10 eq) of DIPEA. The reaction was prepared in a pressure vessel and heated at 80℃ for 72 hours. Upon completion the reaction was concentrated in vacuo with silica gel to form a dry load cartridge. The cartridge was used to purify the reaction via flash chromatography (Teledyne, DCM/Methanol + 0.2% NH₃ ⁺, 0%- 20%, 30 minutes). The product eluted at around 7% methanol + NH3⁺ yielding 2995 mg (67% yield). M+1 = 485.31. Example 3 Intermediate C (di-tert-butyl (((6-((3-hydroxypropyl)amino)-1,3,5-triazine-2,4- Attorney Docket No.: CRISP-43327.601 diyl)bis(azanediyl))bis(propane-3,1-diyl))dicarbamate) Intermediate C (di- 2,4- diyl)bis(azanediyl)

in a similar manner as described in Example 2.1.5 eq of 3-aminopropanol was used in place of aminoethanol and the reaction yielded 3107 mg of product (70% yield) with a M+1 = 499.33. Example 4 Intermediate D (di-tert-butyl (((6-((4-hydroxybutyl)amino)-1,3,5-triazine-2,4- diyl)bis(azanediyl))bis(propane-3,1-diyl))dicarbamate) Intermediate D

2,4- diyl)bis(azanediyl))bis(propane-3,1-diyl))dicarbamate) can be prepared in a similar manner as described in Example 2.1.5 eq of 4-aminobutanol was used in place of aminoethanol and the reaction yielded 3219 mg (62% yield) with a M+1 = 513.34. Example 5 Intermediate E (tri-tert-butyl (((1,3,5-triazine-2,4,6-triyl)tris(azanediyl))tris(propane-3,1- diyl))tricarbamate) Intermediate E

)tris(propane-3,1- Attorney Docket No.: CRISP-43327.601 diyl))tricarbamate) can be prepared by mixing cyanuric chloride (17.5 mM, 1 eq, 3221 mg) with N-boc-1,3-diaminopropane (70 mM, 4 eq, 12101 mg) in 350 mL of 1,4 dioxane and 60 mL of DIPEA. The reaction was prepared at room temperature and then left under reflux at 80℃ for 72 hours. Upon completion the reaction was concentrated in vacuo with silica gel to form a dry load cartridge. Flash chromatography (Teledyne, DCM/Methanol + 0.2% NH₃ ⁺, 0-20%, 45 mins) was used to purify the material. The product eluted around 5% methanol yielding 5.2 g (51% yield). M+1 = 598.4. Example 6 2-((4,6-bis((3-(diundecylamino)propyl)amino)-1,3,5-triazin-2-yl)amino)ethan-1-ol (Lipid 1) (2-((4,6-bis((3- ethan-1-ol) can be

prepared by performing a reductive amination with Intermediate B (di-tert-butyl (((6-((2- hydroxyethyl)amino)-1,3,5-triazine-2,4-diyl)bis(azanediyl))bis(propane-3,1- diyl))dicarbamate).150 mg (1 eq) of intermediate B (di-tert-butyl (((6-((2- hydroxyethyl)amino)-1,3,5-triazine-2,4-diyl)bis(azanediyl))bis(propane-3,1- diyl))dicarbamate) was first deprotected overnight using 5 mL of DCM and 1 mL of 4N HCl in 1,4 dioxane in a 40 mL vial. The next day the solvent and acids were evaporated off leaving a while solid remaining. The deprotected solid was mixed with 20 mL of dichloroethane/0.5 ml triethylamine, undecanal (1.85 mM, 315 mg, 6 eq), and sodium triacetoxyborohydride (1.85 mM, 391 mg, 6 eq). The reaction was allowed to proceed overnight in the same 40 mL vial the deprotection was performed in. The next day, methanol was added to the reaction mixture until the solution was clear and gas bubbles were no longer forming. The mixture was concentrated in vacuo with silica to form a dry load plug before being purified via flash chromatography (Teledyne, DCM/Methanol + 0.2% NH₃ ⁺, 0- 15%, 35 minutes). This yielded 170 mg (60.9% yield) of product with a M+1 = 901.9. Example 7 2-((4,6-bis((3-(didodecylamino)propyl)amino)-1,3,5-triazin-2-yl)amino)ethan-1-ol (Lipid 2) Attorney Docket No.: CRISP-43327.601 OH HN 2₅ (2-((4,6-bis((3- ethan-1-ol) can be prepared in a similar

was replaced with 6 eq of dodecanal yielding 12.5 mg (4.2% yield) of product. M+1 = 957.91. Example 8 2-((4,6-bis((3-(di(undec-10-en-1-yl)amino)propyl)amino)-1,3,5-triazin-2-yl)amino)ethan-1- ol (Lipid 3)

yl)amino)ethan-1-ol) can be prepared in a similar manner as Example 6. In this case the undecanal was replaced with 6eq of undecylenic aldehyde yielding 60 mg (21.6% yield) of product. M+1 = 893.83. Example 9 3-((4,6-bis((3-(diundecylamino)propyl)amino)-1,3,5-triazin-2-yl)amino)propan-1-ol (Lipid 4) OH 2₃ (3-((4,6-bis((3-

propan-1-ol) can be prepared by performing a reductive amination with Intermediate C (di-tert-butyl (((6-((3- hydroxypropyl)amino)-1,3,5-triazine-2,4-diyl)bis(azanediyl))bis(propane-3,1- diyl))dicarbamate).200 mg (1 eq, 0.4 mM) of intermediate C (di-tert-butyl (((6-((3- Attorney Docket No.: CRISP-43327.601 hydroxypropyl)amino)-1,3,5-triazine-2,4-diyl)bis(azanediyl))bis(propane-3,1- diyl))dicarbamate) was first deprotected overnight using 5 mL of DCM and 1 mL of 4N HCl in 1,4 dioxane in a 40 mL vial. The next day the solvent and acids were evaporated off leaving a while solid remaining. The deprotected solid was mixed with 20mL of dichloroethane/0.5ml triethylamine, undecanal (2.8 mM, 473 mg, 7 eq), and sodium triacetoxyborohydride (2.8 mM, 594 mg, 7 eq). The reaction was allowed to proceed overnight in the same 40 mL vial the deprotection was performed in. The next day, methanol was added to the reaction mixture until the solution was clear and gas bubbles were no longer forming. The mixture was concentrated in vacuo with silica to form a dry load plug before being purified via flash chromatography (Teledyne, DCM/Methanol + 0.2% NH3⁺, 0- 15%, 35 minutes). This yielded 307 mg (83.5% yield) of product with a M+1 = 915.9. Example 10 3-((4,6-bis((3-(didodecylamino)propyl)amino)-1,3,5-triazin-2-yl)amino)propan-1-ol (Lipid 5) (3-((4,6-bis((3-

propan-1-ol) can be prepared in a similar manner as Example 9. In this case the undecanal was replaced with 7 eq of dodecanal yielding 75.9 mg (25.9% yield) of product. M+1 = 971.97. Example 11 3-((4,6-bis((3-(di(undec-10-en-1-yl)amino)propyl)amino)-1,3,5-triazin-2-yl)amino)propan-1- ol (Lipid 6)

1-ol) can be prepared in a similar manner as Example 9. In this case the undecanal was Attorney Docket No.: CRISP-43327.601 replaced with 7 eq of undecylenic aldehyde yielding 67 mg (24.52% yield) of product. M+1 = 907.85. Example 12 4-((4,6-bis((3-(dioctylamino)propyl)amino)-1,3,5-triazin-2-yl)amino)butan-1-ol (Lipid 7) (4-((4,6-bis((3- butan-1-ol) can be

prepared by (di-tert-butyl (((6-((4- hydroxybutyl)amino)-1,3,5-triazine-2,4-diyl)bis(azanediyl))bis(propane-3,1- diyl))dicarbamate).150 mg (1 eq, 0.3 mM) of intermediate D (di-tert-butyl (((6-((4- hydroxybutyl)amino)-1,3,5-triazine-2,4-diyl)bis(azanediyl))bis(propane-3,1- diyl))dicarbamate) was first deprotected overnight using 5 mL of DCM and 1mL of 4N HCl in 1,4 dioxane in a 40 mL vial. The next day the solvent and acids were evaporated off leaving a while solid remaining. The deprotected solid was mixed with 20 mL of dichloroethane/0.5ml triethylamine, octanal (1.8 mM, 228 mg, 6 eq), and sodium triacetoxyborohydride (1.8 mM, 370.89 mg, 6 eq). The reaction was allowed to proceed overnight in the same 40 mL vial the deprotection was performed in. The next day, methanol was added to the reaction mixture until the solution was clear and gas bubbles were no longer forming. The mixture was concentrated in vacuo with silica to form a dry load plug before being purified via flash chromatography (Teledyne, DCM/Methanol + 0.2% NH3⁺, 0- 15%, 35 minutes). This yielded 123 mg of product (55.17% yield) with a M+1 = 761.74. Example 13 4-((4,6-bis((3-(dinonylamino)propyl)amino)-1,3,5-triazin-2-yl)amino)butan-1-ol (Lipid 8) (4-((4,6-bis((3-

butan-1-ol) can be prepared in a similar manner as Example 12. In this case the octanal was replaced with 6 eq of nonanal yielding 3 mg (1.25% yield) of product. M+1 = 817.8. Attorney Docket No.: CRISP-43327.601 Example 14 4-((4,6-bis((3-(didecylamino)propyl)amino)-1,3,5-triazin-2-yl)amino)butan-1-ol (Lipid 9) (4-((4,6-bis((3- butan-1-ol) can be prepared in a similar

was replaced with 6 eq of decanal yielding 216 mg (84.45% yield) of product. M+1 = 873.8. Example 15 4-((4,6-bis((3-(diundecylamino)propyl)amino)-1,3,5-triazin-2-yl)amino)butan-1-ol (Lipid 10) (4-((4,6-bis((3- butan-1-ol) can be

prepared in a similar manner as Example 12. In this case the octanal was replaced with 6 eq of undecanal yielding 84 mg (30.8% yield) of product. M+1 = 929.9. Example 16 4-((4,6-bis((3-(didodecylamino)propyl)amino)-1,3,5-triazin-2-yl)amino)butan-1-ol (Lipid 11) (4-((4,6-bis((3-

butan-1-ol) can be prepared in a similar manner as Example 12. In this case the octanal was replaced with 6 eq of undecanal yielding 135 mg (46.7% yield) of product. M+1 = 986.0. Example 17 4-((4,6-bis((3-(ditetradecylamino)propyl)amino)-1,3,5-triazin-2-yl)amino)butan-1-ol (Lipid 12) Attorney Docket No.: CRISP-43327.601 (4-((4,6-bis((3- amino)butan-1-ol) can be prepared in a

was replaced with 6 eq of tetradecanal yielding 203 mg (63.11% yield) of product. M+1 = 1098.17. Example 18 N2,N4,N6-tris(3-(dinonylamino)propyl)-1,3,5-triazine-2,4,6-triamine (Lipid 13) (N2,N4,N6-tris(3- can be prepared by

performing a reductive amination with Intermediate E (tri-tert-butyl (((1,3,5-triazine-2,4,6- triyl)tris(azanediyl))tris(propane-3,1-diyl))tricarbamate).150 mg (1 eq, 0.25 mM) of intermediate C (tri-tert-butyl (((1,3,5-triazine-2,4,6-triyl)tris(azanediyl))tris(propane-3,1- diyl))tricarbamate) was first deprotected overnight using 5 mL of DCM and 1mL of 4N HCl in 1,4 dioxane in a 40 mL vial. The next day the solvent and acids were evaporated off leaving a while solid remaining. The deprotected solid was mixed with 20 mL of dichloroethane/0.5 ml triethylamine, undecanal (2 mM, 285 mg, 8 eq), and sodium triacetoxyborohydride (2 mM, 423 mg, 8 eq). The reaction was allowed to proceed overnight in the same 40 mL vial the deprotection was performed in. The next day, methanol was added to the reaction mixture until the solution was clear and gas bubbles were no longer forming. The mixture was concentrated in vacuo with silica to form a dry load plug before being purified via flash chromatography (Teledyne, DCM/Methanol + 0.2% NH3⁺, 0-15%, 35 minutes). This yielded 42 mg (15.94% yield) of product with a M+1 = 1055.08. Example 19 N2,N4,N6-tris(3-(diundecylamino)propyl)-1,3,5-triazine-2,4,6-triamine (Lipid 14) Attorney Docket No.: CRISP-43327.601 (N2,N4,N6-tris(3- can be prepared in a similar manner as

with 8 eq of undecanal yielding 110 mg (35.89% yield) of product. M+1 = 1227.12. Example 20 N2,N4,N6-tris(3-(didodecylamino)propyl)-1,3,5-triazine-2,4,6-triamine (Lipid 15) (N2,N4,N6-tris(3- can be prepared in

a similar manner as Example 18. In this case the nonanal was replaced with 8 eq of dodecanal yielding 120 mg (36.73% yield) of product. M+1 = 1307.37. Example 21 N2,N4,N6-tris(3-(ditridecylamino)propyl)-1,3,5-triazine-2,4,6-triamine (Lipid 16) (N2,N4,N6-tris(3-

can be prepared in a similar manner as Example 18. In this case the nonanal was replaced with 8 eq of tridecanal yielding 112 mg (32.21% yield) of product. M+1 = 1391.47. Example 22 N2,N4,N6-tris(3-(di(undec-10-en-1-yl)amino)propyl)-1,3,5-triazine-2,4,6-triamine (Lipid 17) Attorney Docket No.: CRISP-43327.601 be

8 eq of undecylenic aldehyde yielding 100 mg (32.76% yield) of product. M+1 = 1211.18. Example 23 tetrahexyl 3,3',3'',3'''-((((6-((2-hydroxyethyl)amino)-1,3,5-triazine-2,4- diyl)bis(azanediyl))bis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate (Lipid 18) (tetrahexyl

diyl)bis(azanediyl))bis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate) can be prepared by a Michaels Addition of Intermediate B (di-tert-butyl (((6-((2-hydroxyethyl)amino)-1,3,5- triazine-2,4 diyl)bis(azanediyl))bis(propane-3,1-diyl))dicarbamate) with hexyl acrylate.135 mg of di-tert-butyl (((6-((2-hydroxyethyl)amino)-1,3,5-triazine-2,4 diyl)bis(azanediyl))bis(propane-3,1-diyl))dicarbamate (1eq) was first deprotected overnight in 5 mL of DCM and 1 mL of 4N HCl in 1,4 dioxane. The solvent and acid were evaporated off prior to the addition of 0.5 mL of TEA and 5mL of ethanol. Lastly hexyl acrylate (1.75 mM, 6 eq, 273 mg) was added and the reaction was left to stir overnight. The next day a dry load cartridge was prepared by concentrating the reaction in vacuo with silica gel. The reaction was purified by flash chromatography (Teledyne, DCM/Methanol + 0.2% NH3⁺, 0- 20% MeOH + NH3+, 30 minutes) yielding 124 mg (48.9% yield) of product. M+1 = 909.67. Example 24 tetraoctyl 3,3',3'',3'''-((((6-((2-hydroxyethyl)amino)-1,3,5-triazine-2,4- diyl)bis(azanediyl))bis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate (Lipid 19) Attorney Docket No.: CRISP-43327.601 (tetraoctyl diyl)bis

be prepared in a similar manner as example 23. In this case hexyl acrylate was replaced with 6 eq of octyl acrylate yielding 178 mg (62.5% yield) of product. M+1 = 1021.03. Example 25 tetradodecyl 3,3',3'',3'''-((((6-((2-hydroxyethyl)amino)-1,3,5-triazine-2,4- diyl)bis(azanediyl))bis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate (Lipid 20) (tetradodecyl

diyl)bis(azanediyl))bis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate) can be prepared in a similar manner as example 23. In this case hexyl acrylate was replaced with 6 eq of dodecyl acrylate yielding 184 mg (52.94% yield) of product. M+1 = 1246.03. Example 26 tetrakis(tetradecyl) 3,3',3'',3'''-((((6-((2-hydroxyethyl)amino)-1,3,5-triazine-2,4- diyl)bis(azanediyl))bis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate (Lipid 21) (tetrakis

2,4- diyl)bis(azanediyl))bis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate) can be prepared in a similar manner as example 23. In this case hexyl acrylate was replaced with 6eq of Attorney Docket No.: CRISP-43327.601 tetradecyl acrylate yielding 125 mg (33.02% yield) of product. M+1 = 1358.17. Example 27 tetrahexadecyl 3,3',3'',3'''-((((6-((2-hydroxyethyl)amino)-1,3,5-triazine-2,4- diyl)bis(azanediyl))bis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate (Lipid 22)

diyl)bis can be prepared in a similar manner as example 23. In this case hexyl acrylate was replaced with 6 eq of hexadecyl acrylate yielding 156 mg (38.04% yield) of product. M+1 = 1470.29. Example 28 tetrahexyl 3,3',3'',3'''-((((6-((3-hydroxypropyl)amino)-1,3,5-triazine-2,4- diyl)bis(azanediyl))bis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate (Lipid 23) (tetrahexyl

diyl)bis(azanediyl))bis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate) can be prepared by a Michaels Addition of Intermediate C (di-tert-butyl (((6-((3-hydroxypropyl)amino)-1,3,5- triazine-2,4-diyl)bis(azanediyl))bis(propane-3,1-diyl))dicarbamate) with hexyl acrylate. 150mg of di-tert-butyl (((6-((3-hydroxypropyl)amino)-1,3,5-triazine-2,4- diyl)bis(azanediyl))bis(propane-3,1-diyl))dicarbamate (1 eq) was first deprotected overnight in 5mL of DCM and 1 mL of 4N HCl in 1,4 dioxane. The solvent and acid were evaporated off prior to the addition of 0.5 mL of TEA and 5mL of ethanol. Lastly hexyl acrylate (1.75 mM, 6 eq, 273 mg) was added and the reaction was left to stir overnight. The next day a dry load cartridge was prepared by concentrating the reaction in vacuo with silica gel. The reaction was purified by flash chromatography (Teledyne, DCM/Methanol + 0.2% NH₃ ⁺, 0- Attorney Docket No.: CRISP-43327.601 20% MeOH + NH₃ ⁺, 30 minutes) yielding 89 mg (35.57% yield) of product. M+1 = 923.06. Example 29 tetraoctyl 3,3',3'',3'''-((((6-((3-hydroxypropyl)amino)-1,3,5-triazine-2,4- diyl)bis(azanediyl))bis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate (Lipid 24) (tetraoctyl

diyl)bis can be prepared in a similar manner as example 28. In this case hexyl acrylate was replaced with 6 eq of octyl acrylate yielding 101 mg (35.99% yield) of product. M+1 = 1035.81. Example 30 tetradodecyl 3,3',3'',3'''-((((6-((3-hydroxypropyl)amino)-1,3,5-triazine-2,4- diyl)bis(azanediyl))bis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate (Lipid 25) (tetradodecyl

diyl)bis(azanediyl))bis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate) can be prepared in a similar manner as example 28. In this case hexyl acrylate was replaced with 6 eq of dodecyl acrylate yielding 181 mg (52.99% yield) of product. M+1 = 1260.06. Example 31 tetrakis(tetradecyl) 3,3',3'',3'''-((((6-((3-hydroxypropyl)amino)-1,3,5-triazine-2,4- diyl)bis(azanediyl))bis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate (Lipid 26) Attorney Docket No.: CRISP-43327.601 (tetrakis 2,4- diyl)bis

be prepared in a similar manner as example 28. In this case hexyl acrylate was replaced with 6 eq of tetradecyl acrylate yielding 115 mg (30.91% yield) of product. M+1 = 1372.29. Example 32 tetrahexadecyl 3,3',3'',3'''-((((6-((3-hydroxypropyl)amino)-1,3,5-triazine-2,4- diyl)bis(azanediyl))bis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate (Lipid 27)

diyl)bis(azanediyl))bis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate) can be prepared in a similar manner as example 28. In this case hexyl acrylate was replaced with 6 eq of hexadecyl acrylate yielding 88 mg (21.87% yield) of product. M+1 = 1484.31. Example 33 tetrahexyl 3,3',3'',3'''-((((6-((4-hydroxybutyl)amino)-1,3,5-triazine-2,4- diyl)bis(azanediyl))bis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate (Lipid 28) (tetrahexyl

Attorney Docket No.: CRISP-43327.601 diyl)bis(azanediyl))bis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate) can be prepared by a Michaels Addition of Intermediate D (di-tert-butyl (((6-((4-hydroxybutyl)amino)-1,3,5- triazine-2,4-diyl)bis(azanediyl))bis(propane-3,1-diyl))dicarbamate) with hexyl acrylate.135 mg of di-tert-butyl (((6-((4-hydroxybutyl)amino)-1,3,5-triazine-2,4- diyl)bis(azanediyl))bis(propane-3,1-diyl))dicarbamate (1 eq) was first deprotected overnight in 5mL of DCM and 1 mL of 4N HCl in 1,4 dioxane. The solvent and acid were evaporated off prior to the addition of 0.5mL of TEA and 5 mL of ethanol. Lastly hexyl acrylate (1.6 mM, 6 eq, 273 mg) was added and the reaction was left to stir overnight. The next day a dry load cartridge was prepared by concentrating the reaction in vacuo with silica gel. The reaction was purified by flash chromatography (Teledyne, DCM/Methanol + 0.2% NH3⁺, 0- 20% MeOH + NH₃ ⁺, 30 minutes) yielding 121 mg (49.03% yield) of product. M+1 = 937.7. Example 34 tetraoctyl 3,3',3'',3'''-((((6-((4-hydroxybutyl)amino)-1,3,5-triazine-2,4- diyl)bis(azanediyl))bis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate (Lipid 29) (tetraoctyl

diyl)bis(azanediyl))bis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate) can be prepared in a similar manner as example 33. In this case hexyl acrylate was replaced with 6 eq of octyl acrylate yielding 156 mg (56.4% yield) of product. M+1 = 1049.82. Example 35 tetranonyl 3,3',3'',3'''-((((6-((4-hydroxybutyl)amino)-1,3,5-triazine-2,4- diyl)bis(azanediyl))bis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate (Lipid 30) Attorney Docket No.: CRISP-43327.601 (tetranonyl diyl)bis

be prepared in a similar manner as example 33. In this case hexyl acrylate was replaced with 6 eq of nonyl acrylate yielding 210 mg (72.07% yield) of product. M+1 = 1105.89. Example 36 tetrakis(decyl) 3,3',3'',3'''-((((6-((4-hydroxybutyl)amino)-1,3,5-triazine-2,4- diyl)bis(azanediyl))bis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate (Lipid 31) (tetrakis

diyl)bis(azanediyl))bis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate) can be prepared in a similar manner as example 33. In this case hexyl acrylate was replaced with 6 eq of decyl acrylate yielding 176 mg (57.49% yield) of product. M+1 = 1161.05. Example 37 tetradodecyl 3,3',3'',3'''-((((6-((4-hydroxybutyl)amino)-1,3,5-triazine-2,4- diyl)bis(azanediyl))bis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate (Lipid 32) Attorney Docket No.: CRISP-43327.601 (tetradodecyl 3,3',3'',3'''-((((6-((4-hydroxybutyl)amino)-1,3,5-triazine-2,4- diyl)bis(azanediyl))bis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate) can be prepared in a similar manner as example 33. In this case hexyl acrylate was replaced with 6 eq of dodecyl acrylate yielding 169 mg of product (50.31% yield). M+1 = 1274.07. Example 38 tetrakis(tetradecyl) 3,3',3'',3'''-((((6-((4-hydroxybutyl)amino)-1,3,5-triazine-2,4- diyl)bis(azanediyl))bis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate (Lipid 33) (tetrakis 2,4-

diyl)bis(azanediyl))bis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate) can be prepared in a similar manner as example 33. In this case hexyl acrylate was replaced with 6 eq of tetradecyl acrylate yielding 178 mg (48.71% yield) of product. M+1 = 1386.2. Example 39 tetrahexadecyl 3,3',3'',3'''-((((6-((4-hydroxybutyl)amino)-1,3,5-triazine-2,4- diyl)bis(azanediyl))bis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate (Lipid 34)

diyl)bis(azanediyl))bis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate) can be prepared in a similar manner as example 33. In this case hexyl acrylate was replaced with 6 eq of hexadecyl acrylate yielding 110 mg (27.85% yield) of product. M+1 = 1498.32. Example 40 Attorney Docket No.: CRISP-43327.601 hexadodecyl 3,3',3'',3''',3'''',3'''''-((((1,3,5-triazine-2,4,6-triyl)tris(azanediyl))tris(propane-3,1- diyl))tris(azanetriyl))hexapropionate (Lipid 35) (hexadodecyl tris(propane-3,1-

diyl))tris of Intermediate E (tri-tert-butyl (((1,3,5-triazine-2,4,6-triyl)tris(azanediyl))tris(propane-3,1- diyl))tricarbamate) with dodecyl acrylate.150mg of tri-tert-butyl (((1,3,5-triazine-2,4,6- triyl)tris(azanediyl))tris(propane-3,1-diyl))tricarbamate (1 eq) was first deprotected overnight in 5 mL of DCM and 1 mL of 4N HCl in 1,4 dioxane. The solvent and acid were evaporated off prior to the addition of 0.5 mL of TEA and 5mL of ethanol. Lastly dodecyl acrylate (2 mM, 8 eq, 424 mg) was added and the reaction was left to stir overnight. The next day a dry load cartridge was prepared by concentrating the reaction in vacuo with silica gel. The reaction was purified by flash chromatography (Teledyne, DCM/Methanol + 0.2% NH₃ ⁺, 0- 20% MeOH + NH3⁺, 30 minutes) yielding 148mg (33.86% yield) of product. M+1 = 1739.49. Example 41 4-((4,6-bis((3-(didodecylamino)propyl)amino)-1,3,5-triazin-2-yl)amino)butyl 3-(4- methylpiperazin-1-yl)propanoate (Lipid 36) N (4-((4,6-bis((3-

butyl 3-(4- methylpiperazin-1-yl)propanoate) can be prepared via an EDC coupling between Example 16 (4-((4,6-bis((3-(didodecylamino)propyl)amino)-1,3,5-triazin-2-yl)amino)butan-1-ol) and 3-(4-methylpiperazin-1-yl)propanoic acid.100 mg (0.1 mM, 1 eq) of 4-((4,6-bis((3- (didodecylamino)propyl)amino)-1,3,5-triazin-2-yl)amino)butan-1-ol was weighed and Attorney Docket No.: CRISP-43327.601 transferred to an 8 ml vial and dissolved in 5ml of anhydrous dichloromethane. Next the 3- (4-methylpiperazin-1-yl)propanoic acid (0.25 mM, 2.5 eq, 51.2 mg) was weighed out and added to the mixture. Lastly the EDC (0.2 mM, 2 eq, 32 mg) and DMAP (1mg/catalytic amount) were added to the reaction before letting the mixture stir overnight. The next day, a dry load cartridge was made by concentrating the reaction in vacuo with silica gel. The reaction was purified by flash chromatography (Teledyne, DCM/Methanol + 0.2% NH3⁺, 0- 20% MeOH + NH₃ ⁺, 30 minutes) yielding 10.5 mg of product (9.1% yield). M+1 = 1140.40. Example 42 tetraoctyl 3,3',3'',3'''-((((6-((4-((3-(4-methylpiperazin-1-yl)propanoyl)oxy)butyl)amino)- 1,3,5-triazine-2,4-diyl)bis(azanediyl))bis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate (Lipid 37) N O N (tetraoctyl 3,3',3'',3'''-(( oxy)butyl)amino)-

1,3,5-triazine-2,4-diyl)bis(azanediyl))bis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate) can be prepared in a similar manner as example 41. In this case the 1eq of 4-((4,6-bis((3- (didodecylamino)propyl)amino)-1,3,5-triazin-2-yl)amino)butan-1-ol was replaced with 1eq of tetraoctyl 3,3',3'',3'''-((((6-((4-hydroxybutyl)amino)-1,3,5-triazine-2,4- diyl)bis(azanediyl))bis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate (example 38) and the equivalence of EDC and 3-(4-methylpiperazin-1-yl)propanoic acid were increased to 5 eq each (added in 2 intervals) yielding 78 mg (76.5% yield). M+1 = 1203.93. Example 43 tetrakis(tetradecyl) 3,3',3'',3'''-((((6-((3-((3-(4-methylpiperazin-1- yl)propanoyl)oxy)propyl)amino)-1,3,5-triazine-2,4-diyl)bis(azanediyl))bis(propane-3,1- diyl))bis(azanetriyl))tetrapropionate (Lipid 38) (tetrakis(tetradecyl)

Attorney Docket No.: CRISP-43327.601 yl)propanoyl)oxy)propyl)amino)-1,3,5-triazine-2,4-diyl)bis(azanediyl))bis(propane-3,1- diyl))bis(azanetriyl))tetrapropionate) can be prepared in a similar manner as example 41. In this case the 1eq of 4-((4,6-bis((3-(didodecylamino)propyl)amino)-1,3,5-triazin-2- yl)amino)butan-1-ol was replaced with 1eq of tetrakis(tetradecyl) 3,3',3'',3'''-((((6-((3- hydroxypropyl)amino)-1,3,5-triazine-2,4-diyl)bis(azanediyl))bis(propane-3,1- diyl))bis(azanetriyl))tetrapropionate (example 32) yielding 17.5 mg (20.97% yield). M+1 = 1526.29. Example 44 tetraoctyl 3,3',3'',3'''-((((6-((2-((3-(4-methylpiperazin-1-yl)propanoyl)oxy)ethyl)amino)-1,3,5- triazine-2,4-diyl)bis(azanediyl))bis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate (Lipid 39) N O N O HN 1_{7 17} (tetraoctyl ethyl)amino)- 1,3,5-triazine-2,4-

)tetrapropionate) can be prepared in a similar manner as example 41. In this case the 1 eq of 4-((4,6-bis((3- (didodecylamino)propyl)amino)-1,3,5-triazin-2-yl)amino)butan-1-ol was replaced with 1eq of tetraoctyl 3,3',3'',3'''-((((6-((2-hydroxyethyl)amino)-1,3,5-triazine-2,4- diyl)bis(azanediyl))bis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate (example 24) yielding 82 mg (80.05% yield). M+1 = 1175.49. Example 45 4-((4,6-bis((3-(bis((2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona- 2,4,6,8-tetraen-1-yl)amino)propyl)amino)-1,3,5-triazin-2-yl)amino)butan-1-ol (Lipid 40)

Attorney Docket No.: CRISP-43327.601 (4-((4,6- 1-yl)nona-

2,4,6,8- - can be prepared in a similar manner as Example 12. In this case the octanal was replaced with 6eq of retinal yielding 112mg (27.58% yield) of product. M+1 = 1386.12. Example 46 Intermediate F (di-tert-butyl (((6-chloro-1,3,5-triazine-2,4-diyl)bis(oxy))bis(propane-3,1- diyl))dicarbamate) Intermediate F (di-

)bis(propane-3,1- diyl))dicarbamate) was prepared by mixing cyanuric chloride (1eq, 5000mg) with N-boc- 1,3-aminopropanol (2.4eq, 11413mg) in 150ml of chloroform and 10mL of DIPEA. The reaction was performed in a pressure vessel starting at 0C and after 30 minutes was heated to 50C before being left to run overnight. The next day a dry load cartridge was prepared by concentrating the reaction mixture with silica gel in vacuo. Flash chromatography (Teledyne) was used to purify the reaction mixture (hexanes/ethyl acetate, 0% – 100%, 30 minutes). The product eluted at around 40% ethyl acetate yielding 4g of product (32% yield). M+22 = 483.4/484.4 Example 47 Intermediate G (Di-tert-butyl (((6-((3-(1H-imidazol-1-yl)propyl)amino)-1,3,5-triazine-2,4- diyl)bis(azanediyl))bis(propane-3,1-diyl))dicarbamate) Attorney Docket No.: CRISP-43327.601 Intermediate G (Di-tert- amino)-1,3,5-triazine-2,4- diyl)bis(azanediyl))bis

in a similar manner as described in Example 2.1.5eq of 3-(1H-imidazol-1-yl)propan-1-amine was used in place of aminoethanol and the reaction yielded 620mg of product (47.3% yield) with a M+1 = 449.7. H1-NMR (500mHz, MeOH-d4): 7.68 (s, 1 H), 7.16 (s, 1H), 6.99 (s, 1H), 4.11 (t, d=0.02, 2H), 3.32-3.37 (m, 4 or 6 H), 3.11 (t, d=0.01, 4H), 2.07 (t, d=0.02, 2H), 1.70 (m, 4H), 1.45 (s, 18H). Example 48 Intermediate H (di-tert-butyl (((6-((3-(dimethylamino)propyl)amino)-1,3,5-triazine-2,4- diyl)bis(azanediyl))bis(propane-3,1-diyl))dicarbamate) Intermediate H (di-tert-

-1,3,5-triazine-2,4- diyl)bis(azanediyl))bis(propane-3,1-diyl))dicarbamate) can be prepared in a similar manner as described in Example 2.1.5eq of N1,N1-dimethylpropane-1,3-diamine was used in place of aminoethanol and the reaction yielded 300mg of product (23.8% yield) with a M+1 = 526.7¹H NMR (400 MHz, MeOD) δ 3.58 – 3.28 (m, 11H), 3.12 (t, J = 6.7 Hz, 5H), 2.05 (s, 2H), 1.86 (t, J = 7.4 Hz, 2H), 1.71 (t, J = 6.5 Hz, 4H), 1.45 (s, 18H). Example 49 Intermediate I (di-tert-butyl (((6-((2-(piperidin-1-yl)ethyl)amino)-1,3,5-triazine-2,4- diyl)bis(azanediyl))bis(propane-3,1-diyl))dicarbamate) Attorney Docket No.: CRISP-43327.601 Intermediate I (di-tert- -1,3,5-triazine-2,4- diyl)bis(azanediyl))bis

in a similar manner as described in Example 2.1.5eq of 2-(piperidin-1-yl)ethan-1-amine was used in place of aminoethanol and the reaction yielded 501mg of product (37.8% yield) with a M+1 = 552.7 ¹H NMR (400 MHz, MeOD) δ 3.39 (s, 2H), 3.33 (d, J = 1.7 Hz, 6H), 3.12 (t, J = 6.7 Hz, 4H), 2.70 (s, 5H), 1.69 (s, 8H), 1.45 (s, 18H). Example 50 Intermediate J (di-tert-butyl (((6-((2-morpholinoethyl)amino)-1,3,5-triazine-2,4- diyl)bis(azanediyl))bis(propane-3,1-diyl))dicarbamate) Intermediate J (di-tert-

triazine-2,4- diyl)bis(azanediyl))bis(propane-3,1-diyl))dicarbamate) can be prepared in a similar manner as described in Example 2.1.5eq of 2-morpholinoethan-1-amine was used in place of aminoethanol and the reaction yielded 500mg of product (37.8% yield) with a M+1 = 554.8 ¹H NMR (500 MHz, MeOD) δ 3.71 (t, J = 4.7 Hz, 4H), 3.32 (p, J = 1.7 Hz, 6H), 3.11 (t, J = 6.7 Hz, 4H), 2.56 (d, J = 15.7 Hz, 6H), 1.70 (t, J = 7.0 Hz, 4H), 1.45 (s, 18H).   Example 51 Intermediate K (di-tert-butyl (((6-((2-(1-methylpyrrolidin-2-yl)ethyl)amino)-1,3,5-triazine- 2,4-diyl)bis(azanediyl))bis(propane-3,1-diyl))dicarbamate) Intermediate K (di-tert-

amino)-1,3,5-triazine- 2,4-diyl)bis(azanediyl))bis(propane-3,1-diyl))dicarbamate) can be prepared in a similar Attorney Docket No.: CRISP-43327.601 manner as described in Example 2.1.5eq of 2-(1-methylpyrrolidin-2-yl)ethan-1-amine was used in place of aminoethanol and the reaction yielded 720mg of product (54.05% yield) with a M+1 = 552.9.¹H NMR (500 MHz, MeOD) δ 3.32 (p, J = 1.7 Hz, 14H), 3.14 – 3.00 (m, 7H), 2.53 (s, 4H), 1.70 (s, 4H), 1.44 (s, 18H). Example 52 Intermediate L (di-tert-butyl (((6-((2-(diethylamino)ethyl)amino)-1,3,5-triazine-2,4- diyl)bis(azanediyl))bis(propane-3,1-diyl))dicarbamate) N Intermediate L (di-tert- -1,3,5-triazine-2,4-

diyl)bis(azanediyl))bis can in a similar manner as described in Example 2.1.5eq of N1,N1-diethylethane-1,2-diamine was used in place of aminoethanol and the reaction yielded 540mg of product (41.9% yield) with a M+1 = 541.0 ¹H NMR (500 MHz, MeOD) δ 3.45 (s, 2H), 3.25 (p, J = 1.7 Hz, 10H), 3.04 (t, J = 6.7 Hz, 4H), 1.63 (s, 4H), 1.37 (s, 18H), 1.10 (s, 6H). Example 53 Intermediate M (di-tert-butyl (((6-((2-(dimethylamino)ethyl)amino)-1,3,5-triazine-2,4- diyl)bis(azanediyl))bis(propane-3,1-diyl))dicarbamate) Intermediate M (di-tert-

-1,3,5-triazine-2,4- diyl)bis(azanediyl))bis(propane-3,1-diyl))dicarbamate) can be prepared in a similar manner as described in Example 2.1.5eq of N1,N1-dimethylethane-1,2-diamine was used in place of aminoethanol and the reaction yielded 385mg of product (28.5% yield) with a M+1 = 513.1 Example 54 Intermediate N (di-tert-butyl (((6-((2-(pyrrolidin-1-yl)ethyl)amino)-1,3,5-triazine-2,4- diyl)bis(azanediyl))bis(propane-3,1-diyl))dicarbamate) Attorney Docket No.: CRISP-43327.601 Intermediate N (di-tert- -1,3,5-triazine-2,4- diyl)bis(azanediyl))bis

in a similar manner as described in Example 2.1.5eq of 2-(pyrrolidin-1-yl)ethan-1-amine was used in place of aminoethanol and the reaction yielded 430mg of product (33.5% yield) with a M+1 = 539.1 Example 55 Intermediate O (di-tert-butyl (((6-((2-(4-methylpiperazin-1-yl)ethyl)amino)-1,3,5-triazine- 2,4-diyl)bis(azanediyl))bis(propane-3,1-diyl))dicarbamate) Intermediate O (di-tert- amino)-1,3,5-triazine-

2,4-diyl)bis(azanediyl))bis(propane-3,1-diyl))dicarbamate) can be prepared in a similar manner as described in Example 2.1.5eq of 2-(4-methylpiperazin-1-yl)ethan-1-amine was used in place of aminoethanol and the reaction yielded 330mg of product (24.4% yield) with a M+1 = 568.2 Example 56 Intermediate P (di-tert-butyl (((6-((2-(4-hydroxypiperidin-1-yl)ethyl)amino)-1,3,5-triazine- 2,4-diyl)bis(azanediyl))bis(propane-3,1-diyl))dicarbamate) Intermediate P (di-tert-

amino)-1,3,5-triazine- 2,4-diyl)bis(azanediyl))bis(propane-3,1-diyl))dicarbamate) can be prepared in a similar manner as described in Example 2.1.5eq of 1-(2-aminoethyl)piperidin-4-ol was used in place of aminoethanol and the reaction yielded 660mg of product (48.6% yield) with a M+1 Attorney Docket No.: CRISP-43327.601 = 568.3 Example 57 Intermediate Q (di-tert-butyl (((6-((2-(ethyl(2-hydroxyethyl)amino)ethyl)amino)-1,3,5- triazine-2,4-diyl)bis(azanediyl))bis(propane-3,1-diyl))dicarbamate) OH Intermediate Q (di-tert- ethyl)amino)-1,3,5-

triazine-2,4-diyl)bis can be prepared in a similar manner as described in Example 2.1.5eq of 2-((2-aminoethyl)(ethyl)amino)ethan-1- ol was used in place of aminoethanol and the reaction yielded 480mg of product (36.1% yield) with a M+1 = 555.9 Example 58 Intermediate R (di-tert-butyl (((6-((2-((2-hydroxyethyl)(methyl)amino)ethyl)amino)-1,3,5- triazine-2,4-diyl)bis(azanediyl))bis(propane-3,1-diyl))dicarbamate) OH Intermediate R (di-tert-

ethyl)amino)-1,3,5- triazine-2,4-diyl)bis(azanediyl))bis(propane-3,1-diyl))dicarbamate) can be prepared in a similar manner as described in Example 2.1.5eq of 2-((2-aminoethyl)(methyl)amino)ethan- 1-ol was used in place of aminoethanol and the reaction yielded 500mg of product (38.9% yield) with a M+1 = 542.0 Example 59 Intermediate S (di-tert-butyl (((6-((2-((2-hydroxyethyl)(methyl)amino)ethyl)amino)-1,3,5- triazine-2,4-diyl)bis(oxy))bis(propane-3,1-diyl))dicarbamate) Attorney Docket No.: CRISP-43327.601 Intermediate S (di-tert- ethyl)amino)-1,3,5- triazine-2,4-diyl)bis

be prepared in a similar manner as described in Example 58.1eq of intermediate F was used in place of intermediate A and the reaction yielded 630mg of product (50.8% yield) with a M+1 = 544.5 Example 60 Intermediate T (tert-butyl (3-((4-(3-(3,3-dimethylbutanamido)propoxy)-6-((4- hydroxybutyl)amino)-1,3,5-triazin-2-yl)oxy)propyl)carbamate) Intermediate T

-6-((4- hydroxybutyl)amino)-1,3,5-triazin-2-yl)oxy)propyl)carbamate) can be prepared as described. After purification and analysis, intermediate F (1eq) was returned to the pressure vessel. The material was dissolved in 1,4 dioxane and 4-hydroxybutylamine (2eq) was added. DIPEA was added last before the reaction vessel was closed and heated to 80C for 4 days. The reaction was concentrated and purified via flash chromatography (DCM/Methanol, 0-20% over 30 minutes). The product eluted at around 10% methanol yielding 2g (45%) of tert- butyl (3-((4-(3-(3,3-dimethylbutanamido)propoxy)-6-((4-hydroxybutyl)amino)-1,3,5-triazin- 2-yl)oxy)propyl)carbamate. M/Z: M+1 = 513.3 Example 61 Intermediate U (di-tert-butyl (((6-((2-(diethylamino)ethyl)amino)-1,3,5-triazine-2,4- diyl)bis(oxy))bis(propane-3,1-diyl))dicarbamate) Attorney Docket No.: CRISP-43327.601 Intermediate U (di-tert- -1,3,5-triazine-2,4- diyl)bis(oxy))bis(propane-

in a similar manner as described in Example 60.1.5eq of N1,N1-diethylethane-1,2-diamine was used in place of 4- hydroxybutylamine and the reaction yielded 220mg of product (25% yield) with a M+1 = 542.0 Example 62 Intermediate V (di-tert-butyl (((6-((2-(pyrrolidin-1-yl)ethyl)amino)-1,3,5-triazine-2,4- diyl)bis(oxy))bis(propane-3,1-diyl))dicarbamate) Intermediate V (di-tert- -1,3,5-triazine-2,4-

diyl)bis(oxy))bis(propane-3,1-diyl))dicarbamate) can be prepared in a similar manner as described in Example 60.1.5eq of 2-(pyrrolidin-1-yl)ethan-1-amine was used in place of 4- hydroxybutylamine and the reaction yielded 420mg of product (32.58% yield) with a M+1 = 539.9 Example 63 tetradodecyl 3,3',3'',3'''-((((6-((4-hydroxybutyl)amino)-1,3,5-triazine-2,4- diyl)bis(oxy))bis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate (Lipid 41) Lipid 41 can

of intermediate T was used in place of intermediate B and the reaction yielded 38mg of product Attorney Docket No.: CRISP-43327.601 (12.7% yield) with a M+1 = 1277.1 Example 64 tetraoctyl 3,3',3'',3'''-((((6-((4-hydroxybutyl)amino)-1,3,5-triazine-2,4- diyl)bis(oxy))bis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate (Lipid 42) Lipid 42 can of octyl

acrylate was of product (31.4% yield) with a M+1 = 1052.0 Example 65 Tetradodecyl 3,3',3'',3'''-((((6-((3-(1H-imidazol-1-yl)propyl)amino)-1,3,5-triazine-2,4- diyl)bis(azanediyl))bis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate (Lipid 43) Lipid 43 can

of intermediate G was used in place of intermediate B and the reaction yielded 63.7mg of product (22.4% yield) with a M+1 = 1310.1 Example 66 Tetradodecyl 3,3',3'',3'''-((((6-((2-(piperidin-1-yl)ethyl)amino)-1,3,5-triazine-2,4- diyl)bis(azanediyl))bis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate (Lipid 44) Attorney Docket No.: CRISP-43327.601 Lipid 44 can of intermediate

120mg of product (40.8% yield) with a M+1 = 1288.1 Example 67 tetradodecyl 3,3',3'',3'''-((((6-((3-(dimethylamino)propyl)amino)-1,3,5-triazine-2,4- diyl)bis(azanediyl))bis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate (Lipid 45) N Lipid 45 can

of intermediate I was used in place of intermediate B and the reaction yielded 63.7mg of product (22.4% yield) with a M+1 = 1313.5 Example 68 tetradodecyl 3,3',3'',3'''-((((6-((2-morpholinoethyl)amino)-1,3,5-triazine-2,4- diyl)bis(azanediyl))bis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate (Lipid 46) O 2₅ Lipid 46 can

of intermediate J was used in place of intermediate B and the reaction yielded 112mg of product (39.16% yield) with a M+1 = 1315.6 Attorney Docket No.: CRISP-43327.601 Example 69 tetradodecyl 3,3',3'',3'''-((((6-((2-(1-methylpyrrolidin-2-yl)ethyl)amino)-1,3,5-triazine-2,4- diyl)bis(azanediyl))bis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate (Lipid 47) Lipid 47 can of

intermediate was 88.6mg of product (34.1% yield) with a M+1 = 1313.9 Example 70 tetradodecyl 3,3',3'',3'''-((((6-((2-(diethylamino)ethyl)amino)-1,3,5-triazine-2,4- diyl)bis(azanediyl))bis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate (Lipid 48) N 2₅ Lipid 48 can

of intermediate L was used in place of intermediate B and the reaction yielded 122mg of product (41.5% yield) with a M+1 = 1301.8¹H NMR (500 MHz, CDCl3) δ 4.06 (t, J = 6.8 Hz, 8H), 3.74 – 3.64 (m, 2H), 3.50 (s, 3H), 3.40 – 3.32 (m, 4H), 2.78 (t, J = 7.2 Hz, 8H), 2.51 (t, J = 6.5 Hz, 4H), 2.47 (t, J = 7.1 Hz, 8H), 1.71 (p, J = 6.7 Hz, 4H), 1.67 – 1.58 (m, 9H), 1.37 – 1.27 (m, 72H), 0.89 (t, J = 6.9 Hz, 12H). Example 71 tetradodecyl 3,3',3'',3'''-((((6-((2-(dimethylamino)ethyl)amino)-1,3,5-triazine-2,4- diyl)bis(azanediyl))bis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate (Lipid 49) Attorney Docket No.: CRISP-43327.601 Lipid 49 can of intermediate

105mg of product (35.15% yield) with a M+1 = 1272.9 Example 72 tetradodecyl 3,3',3'',3'''-((((6-((2-(pyrrolidin-1-yl)ethyl)amino)-1,3,5-triazine-2,4- diyl)bis(azanediyl))bis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate (Lipid 50) Lipid 50 can

of intermediate N was used in place of intermediate B and the reaction yielded 95.1mg of product (32.7% yield) with a M+1 = 1298.9¹H NMR (500 MHz, CDCl₃) δ 4.07 (t, J = 6.8 Hz, 8H), 3.77 (d, J = 9.4 Hz, 3H), 3.51 (s, 3H), 3.45 – 2.97 (m, 10H), 2.78 (t, J = 7.2 Hz, 8H), 2.49 (dt, J = 20.0, 6.8 Hz, 12H), 1.67 (dp, J = 43.3, 6.7 Hz, 13H), 1.52 – 1.08 (m, 65H), 0.90 (t, J = 6.9 Hz, 12H). Example 73 tetradodecyl 3,3',3'',3'''-((((6-((2-(4-methylpiperazin-1-yl)ethyl)amino)-1,3,5-triazine-2,4- diyl)bis(azanediyl))bis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate (Lipid 51) N 2₅

Attorney Docket No.: CRISP-43327.601 Lipid 51 can be prepared in a similar manner as described in Example 25.1eq of intermediate O was used in place of intermediate B and the reaction yielded 100.9mg of product (35.8% yield) with a M+1 = 1328.9 Example 74 tetradodecyl 3,3',3'',3'''-((((6-((2-(4-hydroxypiperidin-1-yl)ethyl)amino)-1,3,5-triazine-2,4- diyl)bis(azanediyl))bis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate (Lipid 52) Lipid 52 can of

intermediate was of product (18.48% yield) with a M+1 = 1328.9 Example 75 Intermediate W (di-tert-butyl (((6-((2-(ethyl(2-hydroxyethyl)amino)ethyl)amino)-1,3,5- triazine-2,4-diyl)bis(oxy))bis(propane-3,1-diyl))dicarbamate) Intermediate W can be

in Example 57.1eq of Intermediate F was used in place of intermediate A and the reaction yielded 440mg of product (32.48%) with a M+1 = 566.5 Example 76 tetradodecyl 3,3',3'',3'''-((((6-((2-(ethyl(2-hydroxyethyl)amino)ethyl)amino)-1,3,5-triazine- 2,4-diyl)bis(azanediyl))bis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate (Lipid 53) Attorney Docket No.: CRISP-43327.601 Lipid 53 can of

intermediate 54.3mg of product (22.9% yield) with a M+1 = 1316.9 Example 77 tetradodecyl 3,3',3'',3'''-((((6-((2-((2-hydroxyethyl)(methyl)amino)ethyl)amino)-1,3,5- triazine-2,4-diyl)bis(azanediyl))bis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate (Lipid 54) Lipid 54 can

of intermediate S was used in place of intermediate B and the reaction yielded 56.4mg of product (23.5% yield) with a M+1 = 1302.9 Example 78 tetranonyl 3,3',3'',3'''-((((6-((3-(dimethylamino)propyl)amino)-1,3,5-triazine-2,4- diyl)bis(azanediyl))bis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate (Lipid 56) Attorney Docket No.: CRISP-43327.601 Lipid 56 can be prepared in a similar manner as described in Example 66.6eq of nonyl acrylate was used in place of dodecyl acrylate and the reaction yielded 110mg of product (43.04% yield) with a M+1 = 1119.0 Example 79 Tetranonyl 3,3',3'',3'''-((((6-((3-(dimethylamino)propyl)amino)-1,3,5-triazine-2,4- diyl)bis(azanediyl))bis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate (Lipid 57) Lipid 57 can of nonyl

acrylate was of product (11.6% yield) with a M+1 = 1147.1 Example 80 Tetranonyl 3,3',3'',3'''-((((6-((2-(pyrrolidin-1-yl)ethyl)amino)-1,3,5-triazine-2,4- diyl)bis(azanediyl))bis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate (Lipid 58) Lipid 58 can

of nonyl acrylate was used in place of dodecyl acrylate and the reaction yielded 103mg of product (40.8% yield) with a M+1 = 1130.4 Example 81 Tetranonyl 3,3',3'',3'''-((((6-((2-(4-methylpiperazin-1-yl)ethyl)amino)-1,3,5-triazine-2,4- diyl)bis(azanediyl))bis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate (Lipid 59) Attorney Docket No.: CRISP-43327.601 Lipid 59 can of nonyl acrylate was

of product (35.34% yield) with a M+1 = 1160.1 Example 82 Tetraoctyl 3,3',3'',3'''-((((6-((3-(dimethylamino)propyl)amino)-1,3,5-triazine-2,4- diyl)bis(azanediyl))bis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate (Lipid 60) Lipid 60 can

of octyl acrylate was used in place of dodecyl acrylate and the reaction yielded 95mg of product (39.5% yield) with a M+1 = 1064.0 Example 83 Tetraoctyl 3,3',3'',3'''-((((6-((2-(1-methylpyrrolidin-2-yl)ethyl)amino)-1,3,5-triazine-2,4- diyl)bis(azanediyl))bis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate (Lipid 61) Lipid 61 can

of octyl acrylate was used in place of dodecyl acrylate and the reaction yielded 132mg of product (55.6% yield) with a M+1 = 1089.6 Attorney Docket No.: CRISP-43327.601 Example 84 Tetraoctyl 3,3',3'',3'''-((((6-((2-(diethylamino)ethyl)amino)-1,3,5-triazine-2,4- diyl)bis(azanediyl))bis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate (Lipid 62) N 1₇ Lipid 62 can of octyl

acrylate was of product (72% yield) with a M+1 = 1133.0 Example 85 4-((4,6-bis(3-(didecylamino)propoxy)-1,3,5-triazin-2-yl)amino)butan-1-ol (Lipid 63) Lipid 63 can be

14.1eq of Intermediate T was used in place of Intermediate D and the reaction yielded 35mg of product (11.2% yield) with a M+1 = 876.0.¹H NMR (500 MHz, CDCl₃) δ 4.48 (t, J = 5.9 Hz, 2H), 4.40 (t, J = 5.9 Hz, 2H), 3.72 (t, J = 6.0 Hz, 2H), 3.48 (dd, J = 13.4, 6.9 Hz, 3H), 3.05 (s, 2H), 2.94 – 2.85 (m, 7H), 2.29 (dd, J = 14.6, 7.1 Hz, 4H), 1.77 – 1.71 (m, 6H), 1.71 – 1.62 (m, 6H), 1.45 (s, 2H), 1.36 – 1.26 (m, 56H), 0.90 (t, J = 6.9 Hz, 12H). Example 86 Tetradodecyl 3,3',3'',3'''-((((6-((2-(diethylamino)ethyl)amino)-1,3,5-triazine-2,4- diyl)bis(oxy))bis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate (Lipid 64) Attorney Docket No.: CRISP-43327.601 Lipid 64 can of Intermediate

10mg of product (3.5% yield) with a M+1 = 1303.1¹H NMR (500 MHz, CDCl₃) δ 4.42 – 3.36 (m, 18H), 2.94 – 2.30 (m, 24H), 2.10 – 1.53 (m, 20H), 1.50 – 1.00 (m, 68H), 0.90 (t, J = 6.8 Hz, 12H). Example 87 Tetradodecyl 3,3',3'',3'''-((((6-((2-(pyrrolidin-1-yl)ethyl)amino)-1,3,5-triazine-2,4- diyl)bis(oxy))bis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate (Lipid 65) Lipid 65 can

of Intermediate V was used in place of Intermediate N and the reaction yielded 12mg of product (4% yield) with a M+1 = 1300.6¹H NMR (500 MHz, CDCl3) δ 4.06 (t, J = 6.8 Hz, 8H), 2.79 (q, J = 9.5 Hz, 10H), 2.69 – 2.56 (m, 8H), 2.45 (t, J = 7.2 Hz, 8H), 1.96 – 1.79 (m, 9H), 1.62 (p, J = 6.9 Hz, 8H), 1.37 – 1.30 (m, 20H), 1.29 (d, J = 5.7 Hz, 20H), 1.28 (s, 31H), 0.90 (t, J = 6.9 Hz, 12H). Example 88 LNP preparation method One volume of lipid mixtures (ionizable lipid, cholesterol, DOPE or DSPC, and DMG-PEG at 22/33/43/2 or 49/38.5/10/2.5 or 42.5/40/15/2.5 -mole ratio) in ethanol and three volumes of biologically active agents (DNA, mRNA, guideRNA) containing 50mM acetate buffer solutions were mixed through the micromixer at a combined flow rate of 12 mL /min. The resultant mixture underwent buffer exchange via amicon or dialysis to remove ethanol. Post dialysis the collected LNP were sterilely filter and mixed with a cryoprotectant. Attorney Docket No.: CRISP-43327.601 The amount of biologically active agents (DNA, mRNA, guideRNA) encapsulated was calculated by Ribogreen assay. Example 89 In vitro editing of human Hep3 Cells Several of the ionizable lipids described above were selected for use in experiments examining in vitro editing in Hep3B cells. The selected lipid and their structures are provided in Table 2. Table 2. Lipid identifier Compound number, see Table 1 CC10-L2-T14 44 CC14-L2-T14 48 CC16-L2-T14 50 CC17-L2-T14 51 CC3-L5-T3 63 LNPs incorporating the ionizable lipids were produced as described in Example 88 above. Briefly, the LNPs were formulated to deliver Cas9 mRNA and gRNA targeting human ANGPTL3 gene. FIGs.1A and 1B provide editing efficiency (TIDE analysis) and toxicity data for editing in Hep3B cell at different LNP dosages. FIGs.2A and 2B provide data for editing efficiency (TIDE analysis) and toxicity for LNPs comprising selected ionizable lipids at different dosages, pH and buffers. FIGs.3A and 3B provide bar graphs that summarize the editing efficiency from FIGs.1A and 2A at the 0.0156 ng/ul dosage. FIGs 4A and 4B provide data for editing efficiency (TIDE analysis) and toxicity for LNP formulations using selected ionizable lipids as indicated. Together, these data show different LNPs formulated based on specific ionizable lipids and formulation methods demonstrate various but highly dose-dependent in vitro editing efficiency and cell toxicity, and Lipid 48 is one of the top performing ionizable lipids in terms of in vitro gene editing efficiency. Example 90 In vitro editing of mice AML12 Cells Several of the ionizable lipids described above were selected for use in experiments examining in vitro editing in mice AML-12 cells. Briefly, the LNPs were formulated to deliver Cas9 mRNA and gRNA targeting mice PCSK9 gene. FIGs.5A and 5B provide Attorney Docket No.: CRISP-43327.601 editing efficiency (TIDE analysis) and toxicity data for editing in AML-12 cells cell at different LNP dosages. These data show LNP formulated with Lipid 63, Lipid 48 and Lipid 50 are also able to edit the target genes in mice AML12 cells in a dose-dependent manner. Example 91 In vivo editing of liver cells Several of the ionizable lipids described above were selected for use in experiments examining in vivo editing of liver cells in a wildtype mouse model. Briefly, the LNPs were formulated to deliver CRISPR Cas9 mRNA and mice PCSK9 guide RNA at a ratio of 1:3 and intravenously injected into wildtype mice at a dose of 1mg/kg. One week post dosing, the mice were sacrificed, and the livers of the treated mice were collected. Genomic DNA was extracted from the collected livers using Quick Extract ^TM DNA Extraction Solution (QE0905T) and following the manufacturer’s protocol. Editing efficiency in the extracted genomic DNA was determined by TIDE analysis. FIG.6 provides editing efficiency (TIDE analysis) data. These data show a 37.2% editing efficiency in mice dosed with CC3L5T3 and a 16.2% and 13.5% editing efficiency in mice dosed with CC14-L2-T14 and CC16-L2-T14 respectively. Example 92 In Vitro Editing of Human HEP3 Cells LNPs incorporating the ionizable lipids were produced as described in Example 88 above. Briefly, the LNPs were formulated to deliver Cas9 mRNA and gRNA targeting the human ANGPTL3 gene. FIGs.7A and B and 8A and B provide editing efficiency (TIDE analysis) and toxicity data for editing in Hep3B cells at different LNP dosages with LNPs comprising the specified lipids.

Claims

Attorney Docket No.: CRISP-43327.601 Listing of Claims: 1. A compound having the following structure of Formula (I): or a tautomer of the salt thereof, wherein: A¹, A², and A³ are,

X is -NR^3aR^3b or –OR⁴; R^1a, R^1b, R^2a, and R^2b are, each independently, C4-C18 alkyl, C4-C18 alkenyl, or , wherein R⁵ is C₄-C₁₈ alkyl or C₄-C₁₈ alkenyl, and n is an integer between 1

R^3a and R^3b are, each independently, C1-C18 alkyl, C2-C18 alkenyl, or , or R^3a and R^3b, together with the nitrogen to which they are attached, form

heterocycle or heteroaryl; , wherein R^4a and R^4b are, each independently, H, C₁-C₈ alkyl,

with the nitrogen they are attached to, form a 5-8 membered heterocycle, and p is an integer between 1 and 6; and m¹, m², and m³ are, each independently, an integer between 1 and 6, wherein each alkyl, alkenyl, heterocycle, and heteroaryl is independently unsubstituted or substituted with 1 or 2 substituents independently selected from hydroxy, methyl, and cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with 1-3 methyl groups. 2. The compound of claim 1, wherein A¹, A², and A³ are each O. 3. The compound of claim 1, wherein A¹, A², and A³ are each NH. 4. The compound of claim 1 or 3, wherein the compound has the following structures of Formula (IA): Attorney Docket No.: CRISP-43327.601 Formula (IB):

5. The compound of

has one of the following structures of Formula (IA-a)-(IA-b) or (IB-a)-(IB-b): , , or .

Attorney Docket No.: CRISP-43327.601 (IB-b) 6. The compound of any one of claims 1-5, wherein R^1a, R^1b, R^2a, R^2b, R^3a, and R^3b are, each independently, C₆-C₁₆ alkyl, C₆-C₁₆ alkenyl, or . 7. The compound of claim 6, wherein the

R^1b, R^2a, R^2b, R^3a, or R^3b is, each independently, -C6H13, -C8H17, -C9H19, -C10H21, -C11H23, -C12H25, -C13H27, -C14H29, or -C16H33. 8. The compound of claim 6, wherein the C6-C16 alkenyl of R^1a, R^1b, R^2a, R^2b, R^3a, or R^3b has one, two, or three alkene moieties. 9. The compound of claim 6 or 8, wherein the C₆-C₁₆ alkenyl of R^1a, R^1b, R^2a, R^2b, R^3a, or R^3b is, each independently, C10 alkenyl, C11 alkenyl, or C12 alkenyl. 10. The compound of any one of claim 6, wherein the C6-C16 alkenyl of R^1a, R^1b, R^2a, R^2b, R^3a, or R^3b is, each independently, .

11. The compound of any one of claims 1-10, wherein R⁵ is C7-C14 alkyl or C7-C14 alkenyl. 12. The compound of claim 11, wherein the C₇-C₁₄ alkyl of R⁵ is -C₈H₁₇, -C₉H₁₉, - C10H21, -C11H23, -C12H25, -C13H27, or -C14H29. 13. The compound of claim 11, wherein the C7-C14 alkenyl of R⁵ has one, two, or three alkene moieties. 14. The compound of any one of claims 11-13, wherein the C₇-C₁₄ alkenyl of R⁵ is C₁₀ alkenyl, C11 alkenyl, or C12 alkenyl. 15. The compound of any one of claims 11-14, wherein the C7-C14 alkenyl of R⁵ is .

Attorney Docket No.: CRISP-43327.601 16. The compound of any one of claims 1-15, wherein n is an integer between 1 and 4. 17. The compound of any one of claims 1-16, wherein n is an integer of 1, 2, or 3. 18. The compound of any one of claims 1-17, wherein n is an integer of 1. 19. The compound of any one of claims 1-5, wherein R^3a and R^3b are, each independently, C1-C3 alkyl, each of which is independently unsubstituted or substituted with one hydroxy group. 20. The compound of any one of claims 1-5, wherein R^3a and R^3b, together with the nitrogen to which they are attached, form a 5-8 membered heterocycle or heteroaryl selected from imidazolyl, piperidinyl, morpholinyl, pyrrolidinyl, and piperazinyl, each of which is independently unsubstituted or substituted with 1 or 2 substituents independently selected from methyl and hydroxy. 21. The compound of any one of claims 1-20, wherein R⁴ is H. 22. The compound of any one of claims 1-21, wherein R⁴ , wherein R^4a and R^4b are, each independently, H, C1-C8 alkyl, and p is

1 and 4. 23. The compound of any one of claims 1-22, wherein R⁴ is , wherein R^4a and R^4b are, each independently, H, C₁-C₆ alkyl, and p is an integer between 1 and 4. 24. The compound of any one of claims 1-23, wherein the 5-8 membered heterocycle formed with R^4a and R^4b is further substituted with C1-C4 alkyl, C1-C4 heteroalkyl, -OH, or halo. 25. The compound of any one of claims 1-24, wherein the 5-8 membered heterocycle formed with R^4a and R^4b is mono-, di-, or tri-substituted with C1-C4 alkyl, C1-C4 heteroalkyl, -OH, or halo. Attorney Docket No.: CRISP-43327.601 26. The compound of any one of claims 1-25, wherein R⁴ , wherein R^4a and R^4b together with the nitrogen they are attached to heterocycle

and p is an integer between 1 and 4. 27. The compound of any one of claims 1-26, wherein R⁴ is , wherein R^4a and R^4b together with the nitrogen they are attached to form a 6 membered heterocycle and p is an integer of 1. 28. The compound of any one of claims 1-27, wherein the 6 membered heterocycle formed with R^4a and R^4b is substituted with C₁ alkyl. 29. The compound of claim 28, wherein the 6 membered heterocycle formed with R^4a and R^4b .

30. The compound of any one of claims 1-29, wherein m¹, m², and m³ are, each independently, an integer between 1 and 3. 31. The compound of any one of claims 1-30, wherein m¹, m², and m³ are, each independently, an integer of 1, 2, or 3. 32. The compound of claim 1, wherein the compound has one of the following structures: OH 2₃ ,

Attorney Docket No.: CRISP-43327.601 OH HN , ,

Attorney Docket No.: CRISP-43327.601 , , , , , , ,

Attorney Docket No.: CRISP-43327.601 , 5

Attorney Docket No.: CRISP-43327.601 , , , , ,

Attorney Docket No.: CRISP-43327.601 , , , , 5 ,

Attorney Docket No.: CRISP-43327.601 , , , , 5

Attorney Docket No.: CRISP-43327.601 N O N O 2₅ , ,

Attorney Docket No.: CRISP-43327.601 , , , , ,

Attorney Docket No.: CRISP-43327.601 N , , , , ,

Attorney Docket No.: CRISP-43327.601 , , , , 5 ,

Attorney Docket No.: CRISP-43327.601 , , , ₁₇ , Attorney Docket No.: CRISP-43327.601 or

33. A composition comprising the compound of claim 1 and a nucleic acid. 34. The composition of claim 33, further comprising one or more additional lipids selected from the group consisting of helper lipids, cholesterol, and polymer conjugated lipids. 35. The composition of claim 33, wherein the nucleic acid comprises RNA, DNA, or mixtures thereof. 36. The composition of claim 35, wherein the RNA comprises mRNA, gRNA, or mixtures thereof. 37. The composition of any one of claims 33 to 34, wherein the composition comprises a gene editing system. 38. The composition of any one of claim 37, wherein the gene editing system comprises one or more components selected from the group consisting of a gRNA or sgRNA, a nucleic acid encoding a nuclease, and a donor polynucleotide. Attorney Docket No.: CRISP-43327.601 39. The composition of anyone of claims 34-38, wherein the helper lipid is 1,2- dilinoleoyl-sn-glycero-3-phosphocholine (DLPC), 1,2-dimyristoyl-sn-glycero- phosphocholine (DMPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2- dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-distearoyl-sn-glycero-3- phosphocholine (DSPC), 1,2-diundecanoyl-sn-glycero-phosphocholine (DUPC), l-palmitoyl- 2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1,2-di-O-octadecenyl-sn-glycero-3- phosphocholine (18:0 Diether PC), l-oleoyl-2-cholesterylhemisuccinoyl-sn-glycero-3- phosphocholine (OChemsPC), 1-hexadecyl-sn-glycero-3-phosphocholine (C16 Lyso PC), 1,2-dilinolenoyl-sn-glycero-3-phosphocholine, 1,2-diarachidonoyl-sn-glycero-3- phosphocholine, 1,2-didocosahexaenoyl-sn-glycero-3-phosphocholine, 1,2-dioleoyl-sn- glycero-3-phosphoethanolamine (DOPE), 1,2-diphytanoyl-sn-glycero-3- phosphoethanolamine (ME 16.0 PE), l,2-distearoyl-sn-glycero-3-phosphoethanolamine, 1,2- dilinoleoyl-sn-glycero-3-phosphoethanolamine, 1,2-dilinolenoyl-sn-glycero-3- phosphoethanolamine, 1,2-diarachidonoyl-sn-glycero-3-phosphoethanolamine, 1,2- didocosahexaenoyl-sn-glycero-3-phosphoethanolamine, 1,2-dioleoyl-sn-glycero-3-phospho- rac-(1-glycerol) sodium salt (DOPG), or mixtures thereof. 40. The composition of claim 39, wherein the helper lipid is DSPC or DOPE. 41. The composition of any one of claims 34-40, wherein the molar ratio of the compound to the helper lipid ranges from about 7:1 to about 1:7. 42. The composition of any one of claims 34-40, wherein the molar ratio of the compound to the helper lipid ranges from about 5:1 to about 1:5. 43. The composition of any one of claims 34-40, wherein the molar ratio of the compound to the helper lipid ranges from about 3:1 to about 1:3. 44. The composition of any one of claims 34-43, wherein the composition further comprises cholesterol and the molar ratio of the compound to cholesterol ranges from 3:1 to 1:3. 45. The composition of any one of claims 34 to 44, wherein the composition is a lipid nanoparticle. Attorney Docket No.: CRISP-43327.601 46. A method for administering a nucleic acid or gene editing system to a subject in need thereof or cells of the patient, the method comprising administering the composition of any one of claims 33 to 45 to the subject or to the cells of the subject. 47. The method of claim 46, wherein the subject is an animal. 48. The method of claim 46, wherein the subject is a human. 49. Composition of any one of claims 33-45 for administration or delivery of a nucleic acid or gene editing to a subject in need thereof or the cells of a subject in need thereof.