Asymmetric piperazine-based cationic lipids

Abstract

The present invention provides, in part, an asymmetric piperazine lipid compound of formula (I') and its subformulas or a pharma- ceutically acceptable salt thereof.The compounds provided herein may be useful for the delivery and expression of mRNA and encoded proteins, for example as a component of liposomal delivery vehicles, and thus may be useful for the treatment of various diseases, disorders and conditions, such as those associated with deficiencies of one or more proteins.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 320,503, filed March 16, 2022, the disclosure of which is hereby incorporated by reference. [Background technology]

[0002] Nucleic acid delivery is being widely investigated as a potential therapeutic option for certain disease states. In particular, messenger RNA (mRNA) therapy is becoming an increasingly important option for the treatment of various diseases, including those associated with deficiencies of one or more proteins.

[0003] How to efficiently deliver nucleic acids encapsulated in liposomes remains an active area of ​​research. During liposome loading, cationic lipid components play an important role in promoting effective encapsulation of nucleic acids. In addition, cationic lipids may play an important role in the efficient release of nucleic acid cargo from liposomes into the cytoplasm of target cells. A variety of cationic lipids suitable for in vivo use have been discovered. However, there remains a need to identify lipids that can be synthesized efficiently and inexpensively without the formation of potentially toxic by-products. Summary of the Invention [Means for solving the problem]

[0004] The present invention provides, inter alia, cationic lipid compounds for the in vivo delivery of therapeutic agents, such as nucleic acids. It is contemplated that such compounds have highly effective in vivo delivery capabilities while maintaining a favorable toxicity profile.

[0005] The cationic lipid of the present invention can be synthesized from easily available starting reagents.The cationic lipid of the present invention also has unexpectedly high encapsulation efficiency.The cationic lipid of the present invention also comprises cleavable groups (for example, esters and disulfides), which are intended to improve biodegradability and thus contribute to its favorable toxicity profile.

[0006] In some embodiments, provided herein are cationic lipids having a structure according to formula (I'): [ka] or a pharmaceutically acceptable salt thereof [wherein: A 1 teeth, [ka] and -SS-, where the left side of each structure depicted is -(CH2) a -bonded to; Z 1 teeth, [ka] and -SS-, where the right side of each structure depicted is selected from -(CH2) a -bonded to; A 1 and Z 1 Unlike; Each R is [ka] (In the formula, each R 1 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -optionally substituted alkyl-(C=O)-O-optionally substituted alkyl, and -optionally substituted alkyl-O-(C=O)-optionally substituted alkyl; and [ka] (In the formula, each R 2 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl; each a is independently selected from 2, 3, 4, and 5; and each b is independently selected from 2, 3, 4, 5, 6 and 7].

[0007] In certain aspects, provided herein are cationic lipids of formula (I'z), which correspond to compounds of formula (I'), but where a is independently selected from 2, 3, 4, 5, and 6.

[0008] In some embodiments, provided herein are cationic lipids having a structure according to formula (II'): [ka] or a pharmaceutically acceptable salt thereof [wherein: A 1 teeth, [ka] and -SS-, where the left side of each structure depicted is -(CH2) a -bonded to; Z 1 teeth, [ka] and -SS-, where the right side of each structure depicted is selected from -(CH2) a -bonded to; Each R is [ka] (In the formula, each R 1are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -optionally substituted alkyl-(C=O)-O-optionally substituted alkyl, and -optionally substituted alkyl-O-(C=O)-optionally substituted alkyl; and [ka] (In the formula, each R 2 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl; each a is independently selected from 2, 3, 4, and 5; each b is independently selected from 2, 3, 4, 5, 6, and 7; and and c is 3 or 4.

[0009] In certain aspects, provided herein are cationic lipids of formula (II'z), which correspond to compounds of formula (II'), where a is independently selected from 2, 3, 4, 5, and 6.

[0010] In some embodiments, provided herein are cationic lipids having a structure according to formula (III'): [ka] or a pharmaceutically acceptable salt thereof [wherein: A 1 teeth, [ka] and -SS-, where the left side of each structure depicted is -(CH2) a -bonded to; Z 1 teeth, [ka] and -SS-, where the right side of each structure depicted is selected from -(CH2) a -bonded to; Each R A , R B , R C and R D teeth, [ka] (In the formula, each R 1 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -optionally substituted alkyl-(C=O)-O-optionally substituted alkyl, and -optionally substituted alkyl-O-(C=O)-optionally substituted alkyl; and [ka] (In the formula, each R 2 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl; R A , R B , R C and R D At least one of the A , R B , R C and R D are not all the same); each a is independently selected from 2, 3, 4, and 5; and each b is independently selected from 2, 3, 4, 5, 6 and 7].

[0011] In certain aspects, provided herein are cationic lipids of formula (III'z), which correspond to compounds of formula (III'), where a is independently selected from 2, 3, 4, 5, and 6.

[0012] In some embodiments, provided herein are cationic lipids having a structure according to formula (IV'): [ka] or a pharmaceutically acceptable salt thereof [wherein: A 1 teeth, [ka] and -SS-, where the left side of each structure depicted is -(CH2) a -bonded to; Z 1 teeth, [ka] and -SS-, where the right side of each structure depicted is selected from -(CH2) a -bonded to; A 1 and Z 1 Unlike; Each R is [ka] (In the formula, each R 1 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -optionally substituted alkyl-(C=O)-O-optionally substituted alkyl, and -optionally substituted alkyl-O-(C=O)-optionally substituted alkyl; and [ka] (In the formula, each R 2 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl; each a is independently selected from 2, 3, 4, and 5; each b is independently selected from 2, 3, 4, 5, 6, and 7; and and c is 3 or 4.

[0013] In certain aspects, provided herein are cationic lipids of formula (IV'z), which correspond to compounds of formula (IV'), where a is independently selected from 2, 3, 4, 5, and 6.

[0014] In some embodiments, provided herein are cationic lipids having a structure according to formula (V'): [ka] or a pharmaceutically acceptable salt thereof [wherein: A 1 teeth, [ka] and -SS-, where the left side of each structure depicted is -(CH2) a -bonded to; Z 1 teeth, [ka] and -SS-, where the right side of each structure depicted is selected from -(CH2) a -bonded to; A 1 and Z 1 Unlike; Each R A , R B , R C and R D teeth, [ka] (In the formula, each R 1 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -optionally substituted alkyl-(C=O)-O-optionally substituted alkyl, and -optionally substituted alkyl-O-(C=O)-optionally substituted alkyl; and [ka] (In the formula, each R 2 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl; R A , R B , R C and R D At least one of the A , R B , R C and R D are not all the same); each a is independently selected from 2, 3, 4, and 5; and each b is independently selected from 2, 3, 4, 5, 6 and 7].

[0015] In certain aspects, provided herein are cationic lipids of formula (V'z), which correspond to compounds of formula (V'), where a is independently selected from 2, 3, 4, 5, and 6.

[0016] In some embodiments, provided herein are cationic lipids having a structure according to formula (VI'): [ka] or a pharmaceutically acceptable salt thereof [wherein: A 1 teeth, [ka] and -SS-, where the left side of each structure depicted is -(CH2) a -bonded to; Z 1 teeth, [ka] and -SS-, where the right side of each structure depicted is selected from -(CH2) a-bonded to; Each R A , R B , R C and R D teeth, [ka] (In the formula, each R 1 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -optionally substituted alkyl-(C=O)-O-optionally substituted alkyl, and -optionally substituted alkyl-O-(C=O)-optionally substituted alkyl; and [ka] (In the formula, each R 2 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl; R A , R B , R C and R D At least one of the A , R B , R C and R D are not all the same); each a is independently selected from 2, 3, 4, and 5; each b is independently selected from 2, 3, 4, 5, 6, and 7; and and c is 3 or 4.

[0017] In certain aspects, provided herein are cationic lipids of formula (VI'z), which correspond to compounds of formula (VI'), where a is independently selected from 2, 3, 4, 5, and 6.

[0018] In some embodiments, provided herein are cationic lipids having a structure according to formula (VII'): [ka] or a pharmaceutically acceptable salt thereof [wherein: A 1 teeth, [ka] and -SS-, where the left side of each structure depicted is -(CH2) a -bonded to; Z 1 teeth, [ka] and -SS-, where the right side of each structure depicted is selected from -(CH2) a -bonded to; A 1 and Z 1 Unlike; Each R A , R B , R C and R D teeth, [ka] (In the formula, each R 1 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -optionally substituted alkyl-(C=O)-O-optionally substituted alkyl, and -optionally substituted alkyl-O-(C=O)-optionally substituted alkyl; and [ka] (In the formula, each R 2 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl; R A , R B , R C and R DAt least one of the A , R B , R C and R D are not all the same); each a is independently selected from 2, 3, 4, and 5; each b is independently selected from 2, 3, 4, 5, 6, and 7; and and c is 3 or 4.

[0019] In certain aspects, provided herein are cationic lipids of formula (VII'z), which correspond to compounds of formula (VII'), where a is independently selected from 2, 3, 4, 5, and 6.

[0020] In some embodiments, provided herein are cationic lipids having a structure according to formula (I): [ka] or a pharmaceutically acceptable salt thereof [wherein: A 1 teeth, [ka] and -SS-, where the left side of each structure depicted is -(CH2) a -bonded to; Z 1 teeth, [ka] and -SS-, where the right side of each structure depicted is selected from -(CH2) a -bonded to; A 1 and Z 1 Unlike; Each R is [ka] (In the formula, each R 1are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -optionally substituted alkyl-(C=O)-O-optionally substituted alkyl, and -optionally substituted alkyl-O-(C=O)-optionally substituted alkyl; and [ka] (In the formula, each R 2 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl; and each a is independently selected from 2, 3, 4, and 5.

[0021] In certain aspects, provided herein are cationic lipids of formula (Iz), which correspond to compounds of formula (I), wherein a is independently selected from 2, 3, 4, 5, and 6.

[0022] In some embodiments, provided herein are cationic lipids having a structure according to formula (II): [ka] or a pharmaceutically acceptable salt thereof [wherein: A 1 teeth, [ka] and -SS-, where the left side of each structure depicted is -(CH2) a -bonded to; Z 1 teeth, [ka] and -SS-, where the right side of each structure depicted is selected from -(CH2) a -bonded to; Each R is [ka] (In the formula, each R 1 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -optionally substituted alkyl-(C=O)-O-optionally substituted alkyl, and -optionally substituted alkyl-O-(C=O)-optionally substituted alkyl; and [ka] (In the formula, each R 2 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl; each a is independently selected from 2, 3, 4, and 5; and and c is 3 or 4.

[0023] In certain aspects, provided herein are cationic lipids of formula (IIz), which correspond to compounds of formula (II), where a is independently selected from 2, 3, 4, 5, and 6.

[0024] In some embodiments, provided herein are cationic lipids having a structure according to formula (III): [ka] or a pharmaceutically acceptable salt thereof [wherein: A 1 teeth, [ka] and -SS-, where the left side of each structure depicted is -(CH2) a -bonded to; Z 1 teeth, [ka] and -SS-, where the right side of each structure depicted is selected from -(CH2) a -bonded to; Each R A , R B , R C and R D teeth, [ka] (In the formula, each R 1 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -optionally substituted alkyl-(C=O)-O-optionally substituted alkyl, and -optionally substituted alkyl-O-(C=O)-optionally substituted alkyl; and [ka] (In the formula, each R 2 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl; R A , R B , R C and R D At least one of the A , R B , R C and R D are not all the same); each a is independently selected from 2, 3, 4, and 5.

[0025] In certain aspects, provided herein are cationic lipids of formula (IIIz), which correspond to compounds of formula (III), where a is independently selected from 2, 3, 4, 5, and 6.

[0026] In some embodiments, provided herein are cationic lipids having a structure according to formula (IV): [ka] or a pharmaceutically acceptable salt thereof [wherein: A 1 teeth, [ka] and -SS-, where the left side of each structure depicted is -(CH2) a -bonded to; Z 1 teeth, [ka] and -SS-, where the right side of each structure depicted is selected from -(CH2) a -bonded to; A 1 and Z 1 Unlike; Each R is [ka] (In the formula, each R 1 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -optionally substituted alkyl-(C=O)-O-optionally substituted alkyl, and -optionally substituted alkyl-O-(C=O)-optionally substituted alkyl; and [ka] (In the formula, each R 2 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl; each a is independently selected from 2, 3, 4, and 5; and and c is 3 or 4.

[0027] In certain aspects, provided herein are cationic lipids of formula (IVz), which correspond to compounds of formula (IV), where a is independently selected from 2, 3, 4, 5, and 6.

[0028] In some embodiments, provided herein are cationic lipids having a structure according to formula (V): [ka] or a pharmaceutically acceptable salt thereof [wherein: A 1 teeth, [ka] and -SS-, where the left side of each structure depicted is -(CH2) a -bonded to; Z 1 teeth, [ka] and -SS-, where the right side of each structure depicted is selected from -(CH2) a -bonded to; A 1 and Z 1 Unlike; Each R A , R B , R C and R D teeth, [ka] (In the formula, each R 1 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -optionally substituted alkyl-(C=O)-O-optionally substituted alkyl, and -optionally substituted alkyl-O-(C=O)-optionally substituted alkyl; and [ka] (In the formula, each R2 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl; R A , R B , R C and R D At least one of the A , R B , R C and R D are not all the same); each a is independently selected from 2, 3, 4, and 5.

[0029] In certain aspects, provided herein are cationic lipids of formula (Vz), which correspond to compounds of formula (V), where a is independently selected from 2, 3, 4, 5, and 6.

[0030] In some embodiments, provided herein are cationic lipids having a structure according to formula (VI): [ka] or a pharmaceutically acceptable salt thereof [wherein: A 1 teeth, [ka] and -SS-, where the left side of each structure depicted is -(CH2) a -bonded to; Z 1 teeth, [ka] and -SS-, where the right side of each structure depicted is selected from -(CH2) a -bonded to; Each R A , R B , R C and R D teeth, [ka] (In the formula, each R 1 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -optionally substituted alkyl-(C=O)-O-optionally substituted alkyl, and -optionally substituted alkyl-O-(C=O)-optionally substituted alkyl; and [ka] (In the formula, each R 2 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl; R A , R B , R C and R D At least one of the A , R B , R C and R D are not all the same); each a is independently selected from 2, 3, 4, and 5; and and c is 3 or 4.

[0031] In certain aspects, provided herein are cationic lipids of formula (VIz), which correspond to compounds of formula (VI), where a is independently selected from 2, 3, 4, 5, and 6.

[0032] In some embodiments, provided herein are cationic lipids having a structure according to formula (VII): [ka] or a pharmaceutically acceptable salt thereof [wherein: A 1 teeth, [ka] and -SS-, where the left side of each structure depicted is -(CH2) a -bonded to; Z 1 teeth, [ka] and -SS-, where the right side of each structure depicted is selected from -(CH2) a -bonded to; A 1 and Z 1 Unlike; Each R A , R B , R C and R D teeth, [ka] (In the formula, each R 1 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -optionally substituted alkyl-(C=O)-O-optionally substituted alkyl, and -optionally substituted alkyl-O-(C=O)-optionally substituted alkyl; and [ka] (In the formula, each R 2 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl; R A , R B , R C and R D At least one of the A , R B , R C and R D are not all the same); each a is independently selected from 2, 3, 4, and 5; and and c is 3 or 4.

[0033] In certain aspects, provided herein are cationic lipids of formula (VIIz), which correspond to compounds of formula (VII), where a is independently selected from 2, 3, 4, 5, and 6.

[0034] In some embodiments, provided herein are cationic lipids that are pharmaceutically acceptable salts of formula (I'). In some embodiments, provided herein are cationic lipids that are pharmaceutically acceptable salts of formula (II'). In some embodiments, provided herein are cationic lipids that are pharmaceutically acceptable salts of formula (III'). In some embodiments, provided herein are cationic lipids that are pharmaceutically acceptable salts of formula (IV'). In some embodiments, provided herein are cationic lipids that are pharmaceutically acceptable salts of formula (V'). In some embodiments, provided herein are cationic lipids that are pharmaceutically acceptable salts of formula (VI'). In some embodiments, provided herein are cationic lipids that are pharmaceutically acceptable salts of formula (VII').

[0035] In some embodiments, provided herein are cationic lipids that are pharmaceutically acceptable salts of formula (I'z). In some embodiments, provided herein are cationic lipids that are pharmaceutically acceptable salts of formula (II'z). In some embodiments, provided herein are cationic lipids that are pharmaceutically acceptable salts of formula (III'z). In some embodiments, provided herein are cationic lipids that are pharmaceutically acceptable salts of formula (IV'z). In some embodiments, provided herein are cationic lipids that are pharmaceutically acceptable salts of formula (V'z). In some embodiments, provided herein are cationic lipids that are pharmaceutically acceptable salts of formula (VI'z). In some embodiments, provided herein are cationic lipids that are pharmaceutically acceptable salts of formula (VII'z).

[0036] In some embodiments, provided herein are cationic lipids that are pharmaceutically acceptable salts of formula (I). In some embodiments, provided herein are cationic lipids that are pharmaceutically acceptable salts of formula (II). In some embodiments, provided herein are cationic lipids that are pharmaceutically acceptable salts of formula (III). In some embodiments, provided herein are cationic lipids that are pharmaceutically acceptable salts of formula (IV). In some embodiments, provided herein are cationic lipids that are pharmaceutically acceptable salts of formula (V). In some embodiments, provided herein are cationic lipids that are pharmaceutically acceptable salts of formula (VI). In some embodiments, provided herein are cationic lipids that are pharmaceutically acceptable salts of formula (VII).

[0037] In some embodiments, provided herein are cationic lipids that are pharmaceutically acceptable salts of formula (Iz). In some embodiments, provided herein are cationic lipids that are pharmaceutically acceptable salts of formula (IIz). In some embodiments, provided herein are cationic lipids that are pharmaceutically acceptable salts of formula (IIIz). In some embodiments, provided herein are cationic lipids that are pharmaceutically acceptable salts of formula (IVz). In some embodiments, provided herein are cationic lipids that are pharmaceutically acceptable salts of formula (Vz). In some embodiments, provided herein are cationic lipids that are pharmaceutically acceptable salts of formula (VIz). In some embodiments, provided herein are cationic lipids that are pharmaceutically acceptable salts of formula (VIIz).

[0038] In some embodiments, the present invention provides a composition comprising a cationic lipid of the present invention, one or more non-cationic lipids, one or more cholesterol-based lipids, and one or more PEG-modified lipids. In some embodiments, the composition is a lipid nanoparticle, optionally a liposome.

[0039] In certain embodiments, compositions comprising the cationic lipids of the present invention may be used in therapy. [Brief explanation of the drawings]

[0040] [Figure 1] 1 illustrates the in vivo protein production resulting from the delivery of mRNA (i.e., hEPO mRNA) using lipid nanoparticles containing compounds B1 or C1 as described herein. As shown in this figure, the use of these compounds results in high in vivo protein production (i.e., hEPO protein) after administration. [Figure 1-1] Same as above. [Figure 1-2] Same as above. [Figure 2] Illustrates Scheme 24A. [Figure 2-1] Same as above. [Figure 3] Scheme 24B is illustrated. [Figure 3-1] Same as above. [Figure 4] Illustrates Scheme 25A. [Figure 4-1] Same as above. [Figure 5] Illustrates Scheme 25B. [Figure 5-1] Same as above. [Figure 6] Scheme 26A is illustrated. [Figure 6-1] Same as above. [Figure 7] Scheme 26B is illustrated. [Figure 7-1] Same as above. [Figure 8] Illustrates Scheme 27A. [Figure 8-1] Same as above. [Figure 9] Scheme 27B is illustrated. [Figure 9-1] Same as above. [Figure 10] Scheme 28A is illustrated. [Figure 10-1] Same as above. [Figure 11] Scheme 28B is illustrated. [Figure 11-1] Same as above. [Figure 12] Illustrates Scheme 29A. [Figure 13] Scheme 29B is illustrated. [Figure 13-1] Same as above. [Figure 14] Illustrates Scheme 29C. [Figure 14-1] Same as above. DETAILED DESCRIPTION OF THE INVENTION

[0041] definition To facilitate understanding of the present invention, certain terms are first defined below. Additional definitions for these and other terms are set forth throughout the specification. Publications and other reference materials mentioned herein to describe the background of the invention or to provide additional details regarding its practice are hereby incorporated by reference.

[0042] Amino Acid: As used herein, the term "amino acid" in its broadest sense refers to any compound and / or substance that can be incorporated into a polypeptide chain. In some embodiments, an amino acid has the general structure HN-C(H)(R)-COOH. In some embodiments, an amino acid is a naturally occurring amino acid. In some embodiments, an amino acid is a synthetic amino acid; in some embodiments, an amino acid is a d-amino acid; in some embodiments, an amino acid is an l-amino acid. A "standard amino acid" refers to any of the 20 standard l-amino acids commonly found in naturally occurring peptides. A "non-standard amino acid" refers to any amino acid that is not a standard amino acid, whether it is synthetically prepared or obtained from a natural source. As used herein, "synthetic amino acid" encompasses chemically modified amino acids, including, but not limited to, salts, amino acid derivatives (such as amides), and / or substitutions. Amino acids, including carboxy- and / or amino-terminal amino acids in a peptide, can be modified by methylation, amidation, acetylation, protecting groups, and / or substitution with other chemical groups that can alter the circulating half-life of the peptide without adversely affecting its activity. Amino acids can participate in disulfide bonds. Amino acids can include single or post-translational modifications, such as association with one or more chemical entities (e.g., methyl groups, acetate groups, acetyl groups, phosphate groups, formyl moieties, isoprenoid groups, sulfate groups, polyethylene glycol moieties, lipid moieties, carbohydrate moieties, biotin moieties, etc.). The term "amino acid" is used interchangeably with "amino acid residue" and can refer to a free amino acid and / or an amino acid residue of a peptide. Whether a free amino acid or a residue of a peptide is referred to will be clear from the context in which the term is used.

[0043] Animal: As used herein, the term "animal" refers to any member of the animal kingdom. In some embodiments, "animal" refers to humans at any stage of development. In some embodiments, "animal" refers to non-human animals at any stage of development. In certain embodiments, the non-human animal is a mammal (e.g., a rodent, mouse, rat, rabbit, monkey, dog, cat, sheep, cow, primate, and / or pig). In some embodiments, animals include, but are not limited to, mammals, birds, reptiles, amphibians, fish, insects, and / or worms. In some embodiments, the animal may be a transgenic animal, a genetically engineered animal, and / or a clone.

[0044] Approximately or About: As used herein, the term "approximately" or "about," when applied to one or more values ​​of interest, refers to a value similar to the stated reference value. In certain embodiments, the term "approximately" or "about," unless otherwise specified or otherwise clear from the context, refers to a range of values ​​that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater or less than) the stated reference value (except where such number exceeds 100% of possible values).

[0045] Biologically active: As used herein, the term "biologically active" refers to the property of any agent that has activity in a biological system, particularly an organism. For example, an agent that, upon administration to an organism, has a biological effect on that organism is considered to be biologically active.

[0046] Delivery: As used herein, the term "delivery" encompasses both local and systemic delivery. For example, delivery of mRNA encompasses a situation in which the mRNA is delivered to a target tissue, where the encoded protein is expressed and remains within the target tissue (also referred to as "local distribution" or "local delivery"), and a situation in which the mRNA is delivered to a target tissue, where the encoded protein is expressed and secreted into the patient's circulatory system (e.g., serum), where it is systemically distributed, and where it is absorbed by other tissues (also referred to as "systemic distribution" or "systemic delivery").

[0047] Expression: As used herein, "expression" of a nucleic acid sequence refers to the translation of mRNA into polypeptides, the assembly of multiple polypeptides into an intact protein (e.g., an enzyme), and / or the post-translational modification of a polypeptide or fully assembled protein (e.g., an enzyme). In this application, the terms "expression" and "production," and their grammatical equivalents, are used interchangeably.

[0048] Functional: As used herein, a "functional" biomolecule is a biomolecule in a form in which it exhibits a property and / or activity that characterizes it.

[0049] Half-life: As used herein, the term "half-life" is the time required for a quantity, such as a nucleic acid or protein concentration or activity, to fall to half of its value as measured at the beginning of a period of time.

[0050] Helper lipid: The term "helper lipid," as used herein, refers to any neutral or zwitterionic lipid material, including cholesterol. Without wishing to be bound by theory, helper lipids may add stability, rigidity, and / or fluidity within the lipid bilayer / nanoparticle.

[0051] Improve, increase, or decrease: As used herein, the terms "improve," "increase," or "decrease," or grammatical equivalents, refer to a relative value compared to a baseline measurement, such as a measurement in the same individual before initiating a treatment described herein, or a measurement in a control subject (or control subjects), which may be in the absence of a treatment described herein. A "control subject" is a subject suffering from the same form of disease as the subject under treatment and who is approximately the same age as the subject under treatment.

[0052] In vitro: As used herein, the term "in vitro" refers to events that take place not within a multicellular organism, but rather in an artificial environment, such as in a test tube or reaction vessel, in cell culture, etc.

[0053] In vivo: As used herein, the term "in vivo" refers to events that occur within a multicellular organism, such as a human or non-human animal. In the context of cell-based systems, the term may be used to refer to events that occur within a living cell (as opposed to, for example, in an in vitro system).

[0054] Isolated: As used herein, the term "isolated" refers to a substance and / or entity that (1) has been separated from at least some of the components with which it was originally associated (whether produced in nature or in an experimental setting) and / or (2) has been produced, prepared, and / or manufactured by the hand of man. An isolated substance and / or entity may be separated from about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or more than about 99% of other components with which it was originally associated. In some embodiments, the isolated agent is about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or greater than about 99% pure. As used herein, a substance is "pure" if it is substantially free of other components. As used herein, excipients (e.g., buffers, solvents, water, etc.) should not be included in the calculation of percent purity of an isolated substance and / or entity.

[0055] Liposome: As used herein, the term "liposome" refers to any lamellar, multilamellar, or solid nanoparticle-like vesicle. Typically, liposomes, as used herein, can be formed by mixing one or more lipids, or by mixing one or more lipids and a polymer. In some embodiments, liposomes suitable for the present invention contain one or more cationic lipids and optionally one or more non-cationic lipids, optionally one or more cholesterol-based lipids, and / or optionally one or more PEG-modified lipids.

[0056] Messenger RNA (mRNA): As used herein, the term "messenger RNA (mRNA)" or "mRNA" refers to a polynucleotide that encodes at least one polypeptide. As used herein, mRNA encompasses both modified and unmodified RNA. The term "modified mRNA" refers to an mRNA that contains at least one chemically modified nucleotide. An mRNA may contain one or more coding and non-coding regions. mRNA can be purified from natural sources, produced using recombinant expression systems and optionally purified, chemically synthesized, etc. Where appropriate, e.g., in the case of chemically synthesized molecules, mRNA can contain nucleoside analogs, such as analogs with chemically modified bases or sugars, backbone modifications, etc. The mRNA sequence is presented in the 5' to 3' direction unless otherwise indicated. In some embodiments, the mRNA is selected from natural nucleosides (e.g., adenosine, guanosine, cytidine, uridine); nucleoside analogs (e.g., 2-aminoadenosine, 2-thiothymidine, inosine, pyrrolo-pyrimidine, 3-methyladenosine, 5-methylcytidine, C-5 propynyl-cytidine, C-5 propynyl-uridine, 2-aminoadenosine, C5-bromouridine, C5-fluorouridine, C5-iodouridine, C5-propynyl-uridine, C5-propynyl-cytidine, C5-methylcyt ...bromouridine, C5-bromouridine, C5-fluorouridine, C5-iodouridine, C5-bromouridine, C5-bromouridine, C5-bromouridine, C5-bromouridine, C5-bromouridine, C5-bromouridine, C5-bromouridine, C5-bromouridine, C5-bromouridine, C5-bromouridine, C5- adenosine, 7-deazaadenosine, 7-deazaguanosine, 8-oxoadenosine, 8-oxoguanosine, O(6)-methylguanine, and 2-thiocytidine; chemically modified bases; biologically modified bases (e.g., methylated bases); intercalated bases; modified sugars (e.g., 2'-fluororibose, ribose, 2'-deoxyribose, arabinose, and hexose); and / or modified phosphate groups (e.g., phosphorothioate linkages and 5'-N-phosphoramidite linkages).

[0057] Nucleic Acid: As used herein, the term "nucleic acid" in its broadest sense refers to any compound and / or substance that is or can be incorporated into a polynucleotide chain. In some embodiments, a nucleic acid is a compound and / or substance that is or can be incorporated into a polynucleotide chain via a phosphodiester bond. In some embodiments, "nucleic acid" refers to individual nucleic acid residues (e.g., nucleotides and / or nucleosides). In some embodiments, "nucleic acid" refers to a polynucleotide chain comprising individual nucleic acid residues. In some embodiments, "nucleic acid" includes RNA and single- and / or double-stranded DNA and / or cDNA. In some embodiments, "nucleic acid" includes ribonucleic acid (RNA), including, but not limited to, any one or more of interfering RNA (RNAi), small interfering RNA (siRNA), short hairpin RNA (shRNA), antisense RNA (aRNA), messenger RNA (mRNA), modified messenger RNA (mmRNA), long non-coding RNA (lncRNA), microRNA (miRNA), multimeric coding nucleic acid (MCNA), polymeric coding nucleic acid (PCNA), guide RNA (gRNA), and CRISPR RNA (crRNA). In some embodiments, "nucleic acid" includes deoxyribonucleic acid (DNA), including, but not limited to, any one or more of single-stranded DNA (ssDNA), double-stranded DNA (dsDNA), and complementary DNA (cDNA). In some embodiments, "nucleic acid" includes both RNA and DNA. In embodiments, the DNA may be in the form of antisense DNA, plasmid DNA, a portion of plasmid DNA, pre-condensed DNA, a product of polymerase chain reaction (PCR), a vector (e.g., P1, PAC, BAC, YAC, artificial chromosome), an expression cassette, a chimeric sequence, chromosomal DNA, or derivatives of these groups.In embodiments, the RNA may be a messenger RNA (mRNA), ribosomal RNA (rRNA), signal recognition particle RNA (7SL RNA or SRP RNA), transfer RNA (tRNA), transfer messenger RNA (tmRNA), small nuclear RNA (snRNA), small nucleolar RNA (snoRNA), SmY RNA, small Cajal body-specific RNA (scaRNA), guide RNA (gRNA), ribonuclease P (RNase P), Y RNA, telomerase RNA component (TERC), spliced ​​leader RNA (SL RNA), antisense RNA (aRNA or asRNA), cis-natural antisense transcript (cis-NAT), CRISPR RNA (crRNA), long non-coding RNA (lncRNA), microRNA (miRNA), piwi-interacting RNA (piRNA), small interfering RNA (siRNA), trans-acting siRNA (tasiRNA), repeat-associated siRNA (rasiRNA), 73K It can be in the form of RNA, retrotransposons, viral genomes, viroids, satellite RNA, or derivatives of these groups. In some embodiments, the nucleic acid is an mRNA that encodes a protein, such as an enzyme.

[0058] Patient: As used herein, the term "patient" or "subject" refers to any organism that may receive provided compositions, e.g., for experimental, diagnostic, prophylactic, cosmetic, and / or therapeutic purposes. Typical patients include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and / or humans). In some embodiments, the patient is a human. Humans include prenatal and postnatal forms.

[0059] Pharmaceutically acceptable: The term "pharmaceutically acceptable," as used herein, refers to substances that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit-to-risk ratio.

[0060] Pharmaceutically acceptable salts: Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al. provide a detailed description of pharmaceutically acceptable salts in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, and 2-hydroxy-ethanesulfonate. Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N-methyl-N ... + (C 1~4Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations, formed, where appropriate, using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, sulfonates, and arylsulfonates. Further pharmaceutically acceptable salts include salts formed from the quarternization of amines with electrophiles, e.g., alkyl halides, suitable for forming quarternized alkylated amino salts.

[0061] Systemic distribution or delivery: As used herein, the term "systemic distribution" or "systemic delivery," or its grammatical equivalents, refers to a delivery or distribution mechanism or technique that affects the entire body or organism. Typically, systemic distribution or delivery is achieved via the body's circulatory system, e.g., the bloodstream. Compare the definition of "local distribution or delivery."

[0062] Subject: As used herein, the term "subject" refers to a human or any non-human animal (e.g., a mouse, rat, rabbit, dog, cat, cow, pig, sheep, horse, or primate). Human includes prenatal and postnatal forms. In many embodiments, a subject is a human being. A subject may be a patient, which refers to a human who visits a health care provider for diagnosis or treatment of a disease. The term "subject" is used interchangeably herein with "individual" or "patient." A subject may be suffering from or susceptible to a disease or disorder, which may or may not exhibit symptoms of the disease or disorder.

[0063] Substantially: As used herein, the term "substantially" refers to the qualitative state of exhibiting the full or nearly full extent or degree of a characteristic or property of interest. Those skilled in the art of biology will understand that biological and chemical phenomena rarely, if ever, proceed to completion and / or perfection, or achieve or avoid absolute results. Thus, the term "substantially" is used herein to capture the possible lack of completeness inherent in many biological and chemical phenomena.

[0064] Target tissue: As used herein, the term "target tissue" refers to any tissue affected by a disease to be treated. In some embodiments, the target tissue includes tissue that exhibits a pathological condition, symptom, or characteristic associated with the disease.

[0065] Therapeutically effective amount: As used herein, the term "therapeutically effective amount" of a therapeutic agent means an amount sufficient, when administered to a subject suffering from or susceptible to a disease, disorder, and / or condition, to treat, diagnose, prevent, and / or delay the onset of one or more symptoms of the disease, disorder, and / or condition. Those skilled in the art will understand that a therapeutically effective amount is typically administered in a titration regimen comprising at least one unit dose.

[0066] Treating: As used herein, the terms "treat," "treatment," or "treating" refer to any method used to partially or completely alleviate, ameliorate, relieve, inhibit, prevent, delay the onset of, reduce the severity of, and / or reduce the incidence of one or more symptoms or characteristics of a particular disease, disorder, and / or condition. Treatment may be administered to a subject who does not exhibit signs of the disease and / or who exhibits only early signs of the disease, with the aim of reducing the risk of developing morbidity associated with the disease.

[0067] chemical definition Acyl: As used herein, the term “acyl” refers to a group consisting of R Z-(C=O)-(wherein, R Z refers to, for example, any alkyl, alkenyl, alkynyl, heteroalkyl, or heteroalkylene.

[0068] Aliphatic: As used herein, the term aliphatic refers to C1-C 50 Aliphatic refers to hydrocarbons, including both saturated and unsaturated hydrocarbons. Aliphatic groups can be linear, branched, or cyclic. For example, C1-C 20 Aliphatic groups include C1 to C 20 Alkyl (e.g., linear or branched C1-C 20 saturated alkyl), C2-C 20 Alkenyl (e.g., linear or branched C4-C 20 Dienyl, linear or branched C6-C 20 trienyl, etc.), and C2-C 20 Alkynyl (e.g., linear or branched C-C 20 alkynyl) may be included. 20 Aliphatic groups include C3 to C 20 Cycloaliphatic (e.g., C3-C 20 Cycloalkyl, C4-C 20 Cycloalkenyl, or C8-C 20 In certain embodiments, an aliphatic group may include one or more cycloaliphatic groups and / or one or more heteroatoms such as oxygen, nitrogen, or sulfur, and may be optionally substituted with one or more substituents such as alkyl, halo, alkoxyl, hydroxy, amino, aryl, ether, ester, or amide. An aliphatic group is unsubstituted or substituted with one or more substituents as described herein. For example, an aliphatic group may be selected from the group consisting of halogen, -COR", -COH, -COR", -CN, -OH, -OR", -OCOR', -OCOR", -NH, -NHR", -N(R"), -SR", or -SOR", where each instance of R is independently selected from C1 to C6. 20 Aliphatic (e.g., C1-C 20 Alkyl, C1-C 15 Alkyl, C1-C 10In embodiments, R" is independently substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents) of an unsubstituted alkyl (e.g., an unsubstituted C1-C alkyl, or a C1-C3 alkyl). 20 Alkyl, C1-C 15 Alkyl, C1-C 10 In embodiments, R" is independently an unsubstituted C1-C3 alkyl. In embodiments, the aliphatic is unsubstituted. In embodiments, the aliphatic does not contain any heteroatoms. Alkyl: As used herein, the term "alkyl" refers to acyclic linear and branched hydrocarbon groups, such as "C1-C 30 "Alkyl" refers to an alkyl group having 1 to 30 carbon atoms. The alkyl group can be linear or branched. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl tert-pentylhexyl, isohexyl, and the like. The term "lower alkyl" refers to an alkyl group having 1 to 6 carbon atoms, either straight chain or branched. Other alkyl groups will be readily apparent to those of ordinary skill in the art given the benefit of this disclosure. Alkyl groups can be unsubstituted or substituted with one or more substituents as described herein. For example, alkyl groups can be selected from the group consisting of halogen, -COR", -COH, -COR", -CN, -OH, -OR", -OCOR', -OCOR", -NH, -NHR", -N(R"), -SR", or -SOR", where each instance of R is independently selected from the group consisting of C1 to C2. 20 Aliphatic (e.g., C1-C 20 Alkyl, C1-C 15 Alkyl, C1-C 10 In embodiments, R" is independently substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents) of an unsubstituted alkyl (e.g., an unsubstituted C1-C alkyl, or a C1-C3 alkyl). 20 Alkyl, C1-C 15 Alkyl, C1-C 10In embodiments, R" is independently an unsubstituted C1-C3 alkyl. In embodiments, the alkyl is substituted (e.g., with 1, 2, 3, 4, 5, or 6 substituents as described herein). In embodiments, the alkyl is substituted with an -OH group, and may also be referred to herein as a "hydroxyalkyl" group, where the prefix represents the -OH group and "alkyl" is as described herein.

[0069] As used herein, "alkyl" also refers to a group of straight-chain or branched saturated hydrocarbon groups having 1 to 50 carbon atoms ("C1-C 50 In some embodiments, an alkyl group has 1 to 40 carbon atoms ("C1-C 40 In some embodiments, an alkyl group has 1 to 30 carbon atoms ("C1-C 30 In some embodiments, an alkyl group has 1 to 20 carbon atoms ("C1-C 20 In some embodiments, an alkyl group has 1 to 10 carbon atoms ("C1-C 10In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C1-C9 alkyl"). In some embodiments, an alkyl group has 1 to 8 carbon atoms ("C1-C8 alkyl"). In some embodiments, an alkyl group has 1 to 7 carbon atoms ("C1-C7 alkyl"). In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C1-C6 alkyl"). In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C1-C5 alkyl"). In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C1-C4 alkyl"). In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C1-C3 alkyl"). In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C1-C2 alkyl"). In some embodiments, an alkyl group has 1 carbon atom ("C1 alkyl"). In some embodiments, an alkyl group has 2 to 6 carbon atoms ("C2-C6 alkyl"). Examples of C1-C6 alkyl groups include, without limitation, methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6). Further examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents ("substituted alkyl"). In certain embodiments, an alkyl group is an unsubstituted C1-C6 alkyl group. 50 In certain embodiments, the alkyl group is a substituted C1-C 50 It is alkyl.

[0070] The suffix "-ene" added to a group indicates that the group is a divalent moiety; for example, an arylene is a divalent moiety of an aryl, and a heteroarylene is a divalent moiety of a heteroaryl.

[0071] Alkylene: The term "alkylene," as used herein, represents a saturated divalent straight- or branched-chain hydrocarbon group and is exemplified by methylene, ethylene, isopropylene, and the like. Similarly, the term "alkenylene," as used herein, represents an unsaturated divalent straight- or branched-chain hydrocarbon group having one or more unsaturated carbon-carbon double bonds that may occur at any stable point along the chain, and the term "alkynylene," as used herein, represents an unsaturated divalent straight- or branched-chain hydrocarbon group having one or more unsaturated carbon-carbon triple bonds that may occur at any stable point along the chain. In certain embodiments, alkylene, alkenylene, or alkynylene groups may contain one or more cyclic aliphatic and / or one or more heteroatoms such as oxygen, nitrogen, or sulfur, and may be optionally substituted with one or more substituents such as alkyl, halo, alkoxyl, hydroxy, amino, aryl, ether, ester, or amide. For example, alkylene, alkenylene, or alkynylene can be selected from halogen, —COR″, —COH, —COR″, —CN, —OH, —OR″, —OCOR″, —OCOR″, —NH2, —NHR″, —N(R″), —SR″, or —SOR″, where each instance of R″ is independently selected from C1 to C6 20 Aliphatic (e.g., C1-C 20 Alkyl, C1-C 15 Alkyl, C1-C 10 In embodiments, R" is independently substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents) of an unsubstituted alkyl (e.g., an unsubstituted C1-C alkyl, or a C1-C3 alkyl). 20 Alkyl, C1-C 15 Alkyl, C1-C 10In certain embodiments, R" is independently an unsubstituted C1-C3 alkyl. In certain embodiments, the alkylene, alkenylene, or alkynylene is unsubstituted. In certain embodiments, the alkylene, alkenylene, or alkynylene does not contain any heteroatoms. Alkenyl: As used herein, "alkenyl" refers to any linear or branched hydrocarbon chain with one or more unsaturated carbon-carbon double bonds that may occur at any stable point along the chain, e.g., "C2-C 30 "Alkenyl" refers to an alkenyl group having 2 to 30 carbons. For example, alkenyl groups include prop-2-enyl, but-2-enyl, but-3-enyl, 2-methylprop-2-enyl, hex-2-enyl, hex-5-enyl, 2,3-dimethylbut-2-enyl, and the like. In embodiments, an alkenyl has 1, 2, or 3 carbon-carbon double bonds. In embodiments, an alkenyl contains a single carbon-carbon double bond. In embodiments, multiple double bonds (e.g., 2 or 3) are conjugated. An alkenyl group can be unsubstituted or substituted with one or more substituents as described herein. For example, an alkenyl group can be a halogen, —COR″, —COH, —COR″, —CN, —OH, —OR″, —OCOR″, —OCOR″, —NH2, —NHR″, —N(R″), —SR″, or —SOR″, where each instance of R″ is independently C1 to C6 20 Aliphatic (e.g., C1-C 20 Alkyl, C1-C 15 Alkyl, C1-C 10 In embodiments, R" is independently substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents) of an unsubstituted alkyl (e.g., an unsubstituted C1-C alkyl, or a C1-C3 alkyl). 20 Alkyl, C1-C 15 Alkyl, C1-C 10In embodiments, R" is independently an unsubstituted C1-C3 alkyl. In embodiments, the alkenyl is unsubstituted. In embodiments, the alkenyl is substituted (e.g., with 1, 2, 3, 4, 5, or 6 substituents as described herein). In embodiments, the alkenyl group is substituted with an -OH group and may also be referred to herein as a "hydroxyalkenyl" group, where the prefix represents the -OH group and "alkenyl" is as described herein.

[0072] As used herein, "alkenyl" also refers to a group of straight-chain or branched hydrocarbon groups having 2 to 50 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds) ("C2-C 50 In some embodiments, an alkenyl group has 2 to 40 carbon atoms (“C2-C 40 In some embodiments, an alkenyl group has 2 to 30 carbon atoms (“C-C 30 In some embodiments, an alkenyl group has 2 to 20 carbon atoms (“C-C 20 In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C-C 10In some embodiments, an alkenyl group has 2 to 9 carbon atoms ("C2-C9 alkenyl"). In some embodiments, an alkenyl group has 2 to 8 carbon atoms ("C2-C8 alkenyl"). In some embodiments, an alkenyl group has 2 to 7 carbon atoms ("C2-C7 alkenyl"). In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C2-C6 alkenyl"). In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C2-C5 alkenyl"). In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C2-C4 alkenyl"). In some embodiments, an alkenyl group has 2 to 3 carbon atoms ("C2-C3 alkenyl"). In some embodiments, an alkenyl group has 2 carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (as in 2-butenyl) or terminal (as in 1-butenyl). Examples of C2-C4 alkenyl groups include, without limitation, ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-C6 alkenyl groups include the aforementioned C2-C4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Further examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an "unsubstituted alkenyl") or substituted with one or more substituents (a "substituted alkenyl"). In certain embodiments, the alkenyl group is an unsubstituted C-C 50 In certain embodiments, the alkenyl group is a substituted C-C 50 It is alkenyl.

[0073] Alkynyl: As used herein, "alkynyl" refers to any hydrocarbon chain of either linear or branched configuration with one or more carbon-carbon triple bonds occurring at any stable point along the chain, e.g., "C2-C 30"Alkynyl" refers to an alkynyl group having 2 to 30 carbons. Examples of alkynyl groups include prop-2-ynyl, but-2-ynyl, but-3-ynyl, pent-2-ynyl, 3-methylpent-4-ynyl, hex-2-ynyl, hex-5-ynyl, and the like. In embodiments, an alkynyl group contains one carbon-carbon triple bond. An alkynyl group can be unsubstituted or substituted with one or more substituents as described herein. For example, an alkynyl group can be a halogen, -COR", -COH, -COR", -CN, -OH, -OR", -OCOR", -OCOR", -NH, -NHR", -N(R"), -SR", or -SOR", where each instance of R is independently C1 to C2. 20 Aliphatic (e.g., C1-C 20 Alkyl, C1-C 15 Alkyl, C1-C 10 In embodiments, R" is independently substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents) of an unsubstituted alkyl (e.g., an unsubstituted C1-C alkyl, or a C1-C3 alkyl). 20 Alkyl, C1-C 15 Alkyl, C1-C 10 In embodiments, R" is independently an unsubstituted C1-C3 alkyl. In embodiments, the alkynyl is unsubstituted. In embodiments, the alkynyl is substituted (e.g., with 1, 2, 3, 4, 5, or 6 substituents as described herein).

[0074] As used herein, "alkynyl" also refers to a group of straight-chain or branched hydrocarbon groups having 2 to 50 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) and optionally one or more double bonds (e.g., 1, 2, 3, or 4 double bonds) ("C2-C 50 Alkynyl groups with one or more triple bonds and one or more double bonds are also referred to as "ene-ynes." In some embodiments, alkynyl groups have 2 to 40 carbon atoms ("C2-C40 In some embodiments, an alkynyl group has 2 to 30 carbon atoms (“C2-C 30 In some embodiments, an alkynyl group has 2 to 20 carbon atoms (“C-C 20 In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C-C 10 In some embodiments, an alkynyl group has 2 to 9 carbon atoms ("C2-C9 alkynyl"). In some embodiments, an alkynyl group has 2 to 8 carbon atoms ("C2-C8 alkynyl"). In some embodiments, an alkynyl group has 2 to 7 carbon atoms ("C2-C7 alkynyl"). In some embodiments, an alkynyl group has 2 to 6 carbon atoms ("C2-C6 alkynyl"). In some embodiments, an alkynyl group has 2 to 5 carbon atoms ("C2-C5 alkynyl"). In some embodiments, an alkynyl group has 2 to 4 carbon atoms ("C2-C4 alkynyl"). In some embodiments, an alkynyl group has 2 to 3 carbon atoms ("C2-C3 alkynyl"). In some embodiments, an alkynyl group has 2 carbon atoms ("C2 alkynyl"). The one or more carbon-triple bonds can be internal (as in 2-butynyl) or terminal (as in 1-butynyl). Examples of C2-C4 alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C2-C6 alkenyl groups include the aforementioned C2-C4 alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Further examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an "unsubstituted alkynyl") or substituted with one or more substituents (a "substituted alkynyl"). In certain embodiments, an alkynyl group is an unsubstituted C2-C6 alkenyl group. 50 In certain embodiments, the alkynyl group is a substituted C-C 50It is alkynyl.

[0075] Aryl: The term "aryl," used alone or as part of a larger moiety, as in "aralkyl," refers to a monocyclic, bicyclic, or tricyclic carbocyclic ring system having a total of 6 to 14 ring members, wherein the ring system has a single point of attachment to the rest of the molecule, at least one ring in the system is aromatic, and wherein each ring in the system contains 4 to 7 ring members. In embodiments, an aryl group has 6 ring carbon atoms ("C6 aryl," e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 aryl," e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms ("C 14 "Aryl," e.g., anthracen. "Aryl" also includes ring systems in which an aryl ring, as defined above, is fused to one or more carbocyclyl or heterocyclyl groups, where the groups or points of attachment are on the aryl ring, and in such cases the number of carbon atoms continues to refer to the number of carbon atoms in the aryl ring system. Exemplary aryls include phenyl, naphthyl, and anthracene.

[0076] As used herein, "aryl" also refers to a group of monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring systems (e.g., having 6, 10, or 14 shared pi electrons in the cyclic arrangement), wherein the aromatic ring system has 6 to 14 ring carbon atoms and 0 heteroatoms ("C6-C 14 In some embodiments, an aryl group has 6 ring carbon atoms ("C aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 Aryl"; e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms ("C 14"Aryl"; e.g., anthracyl). "Aryl" also includes ring systems in which an aryl ring, as defined above, is fused to one or more carbocyclyl or heterocyclyl groups, where the groups or points of attachment are on the aryl ring, and in such cases, the number of carbon atoms continues to refer to the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In certain embodiments, an aryl group is an unsubstituted C6-C6 14 In certain embodiments, the aryl group is a substituted C-C 14 It is aryl.

[0077] Arylene: The term "arylene," as used herein, refers to a divalent (i.e., having two points of attachment to the molecule) aryl group. Exemplary arylenes include phenylene (e.g., unsubstituted phenylene or substituted phenylene).

[0078] Carbocyclyl: As used herein, "carbocyclyl" or "carbocyclic" refers to a ring system having 3 to 10 ring carbon atoms ("C3-C6"). 10 "C-C carbocyclyl" refers to a group of non-aromatic cyclic hydrocarbon groups having 3 to 8 ring carbon atoms ("C-C carbocyclyl"). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms ("C-C carbocyclyl"). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C-C carbocyclyl"). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms ("C-C carbocyclyl"). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms ("C-C carbocyclyl"). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C-C 10carbocyclyl). Exemplary C3-C6 carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3-C8 carbocyclyl groups include, without limitation, the aforementioned C3-C6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C3~C 10 Carbocyclyl groups include, without limitation, the aforementioned C3 to C8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 As the foregoing examples illustrate, in certain embodiments, carbocyclyl groups are either monocyclic ("monocyclic carbocyclyl") or polycyclic (including, for example, fused, bridged, or spiro ring systems such as bicyclic ("bicyclic carbocyclyl") or tricyclic ("tricyclic carbocyclyl") ring systems) and may be saturated or contain one or more carbon-carbon double or triple bonds. "Carbocyclyl" also includes ring systems in which a carbocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, where the points of attachment are on the carbocyclyl ring, and in such cases, the number of carbons continues to refer to the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted ("unsubstituted carbocyclyl") or substituted with one or more substituents ("substituted carbocyclyl"). In certain embodiments, the carbocyclyl group is an unsubstituted C-C 10In certain embodiments, the carbocyclyl group is a substituted C-C 10 It is a carbocyclyl.

[0079] In some embodiments, a "carbocyclyl" or "carbocyclic" is referred to as a "cycloalkyl," i.e., a monocyclic saturated carbocyclyl group having 3 to 10 ring carbon atoms ("C3-C 10 In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C3-C8 cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C3-C6 cycloalkyl"). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms ("C4-C6 cycloalkyl"). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C5-C6 cycloalkyl"). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C5-C6 cycloalkyl"). 10 Examples of C5-C6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-C6 cycloalkyl groups include the aforementioned C5-C6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-C8 cycloalkyl groups include the aforementioned C3-C6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an "unsubstituted cycloalkyl") or substituted with one or more substituents (a "substituted cycloalkyl"). In certain embodiments, a cycloalkyl group is an unsubstituted C3-C6 10 In certain embodiments, the cycloalkyl group is a substituted C-C 10 It is cycloalkyl.

[0080] Halogen: As used herein, the term "halogen" means fluorine, chlorine, bromine, or iodine.

[0081] Heteroalkyl: The term "heteroalkyl" refers to a branched or unbranched alkyl, alkenyl, or alkynyl group having 1 to 14 carbon atoms in addition to 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, S, and P. Heteroalkyls include tertiary amines, secondary amines, ethers, thioethers, amides, thioamides, carbamates, thiocarbamates, hydrazones, imines, phosphate diesters, phosphoramidates, sulfonamides, and disulfides. Heteroalkyl groups can optionally include monocyclic, bicyclic, or tricyclic rings, each ring desirably having 3 to 6 members. Examples of heteroalkyls include polyethers such as methoxymethyl and ethoxyethyl.

[0082] Heteroalkylene: The term "heteroalkylene," as used herein, represents a divalent form of a heteroalkyl group, as described herein.

[0083] Heteroaryl: The term "heteroaryl," as used herein, refers to a fully unsaturated heteroatom-containing ring in which at least one ring atom is a heteroatom, such as, but not limited to, nitrogen and oxygen.

[0084] As used herein, "heteroaryl" also refers to a group of 5-14 membered monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring systems (e.g., having 6, 10, or 14 shared π electrons in the cyclic arrangement) in which ring carbon atoms and one or more (e.g., 1, 2, 3, or 4 ring heteroatoms) ring heteroatoms (where each heteroatom is independently selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus) are provided in the aromatic ring system ("5-14 membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom as valency allows. Heteroaryl polycyclic ring systems can contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring, as defined above, is fused to one or more carbocyclyl or heterocyclyl groups, where the point of attachment is on the heteroaryl ring, and in such cases, the number of ring members continues to refer to the number of ring members within the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring, as defined above, is fused to one or more aryl groups, where the point of attachment is on either the aryl ring or the heteroaryl ring, and in such cases, the number of ring members refers to the number of ring members within the fused polycyclic (aryl / heteroaryl) ring system. Polycyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.) can have the point of attachment on either ring, i.e., a ring with a heteroatom (e.g., 2-indolyl) or a ring without a heteroatom (e.g., 5-indolyl).

[0085] In some embodiments, heteroaryl groups are 5- to 10-membered aromatic ring systems ("5- to 10-membered heteroaryl") in which the aromatic ring system is provided with ring carbon atoms and one or more (e.g., 1, 2, 3, or 4) ring heteroatoms (wherein each heteroatom is independently selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus). In some embodiments, heteroaryl groups are 5- to 8-membered aromatic ring systems ("5- to 8-membered heteroaryl") in which the aromatic ring system is provided with ring carbon atoms and one or more (e.g., 1, 2, 3, or 4) ring heteroatoms (wherein each heteroatom is independently selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus). In some embodiments, a heteroaryl group is a 5- to 6-membered aromatic ring system ("5- to 6-membered heteroaryl"), comprising ring carbon atoms and one or more (e.g., 1, 2, 3, or 4) ring heteroatoms (wherein each heteroatom is independently selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus) provided in the aromatic ring system. In some embodiments, a 5- to 6-membered heteroaryl has one or more (e.g., 1, 2, or 3) ring heteroatoms selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus. In some embodiments, a 5- to 6-membered heteroaryl has one or two ring heteroatoms selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus. In some embodiments, a 5- to 6-membered heteroaryl has one ring heteroatom selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"). In certain embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.

[0086] Exemplary 5-membered heteroaryl groups having one heteroatom include, without limitation, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups having two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups having three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups having four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups having one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups having two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups having three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups having one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include, without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.

[0087] As used herein, "heterocyclyl" or "heterocyclic" refers to a radical of a 3- to 14-membered non-aromatic ring system ("3- to 14-membered heterocyclyl") having ring carbon atoms and one or more (e.g., 1, 2, 3, or 4) ring heteroatoms (where each heteroatom is independently selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus). In heterocyclyl groups having one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valence allows. Heterocyclyl groups can be either monocyclic ("monocyclic heterocyclyl") or polycyclic (e.g., fused, bridged, or spiro ring systems, such as a bicyclic ring system ("bicyclic heterocyclyl") or a tricyclic ring system ("tricyclic heterocyclyl")) and can be saturated or contain one or more carbon-carbon double or triple bonds. Heterocyclyl polycyclic ring systems can contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring, as defined above, is fused to one or more carbocyclyl groups, with the points of attachment being on either the carbocyclyl or heterocyclyl ring, or in which a heterocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, with the points of attachment being on the heterocyclyl ring, and in such cases, the number of ring members continues to refer to the number of ring members within the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, a heterocyclyl group is an unsubstituted 3- to 14-membered heterocyclyl. In certain embodiments, a heterocyclyl group is a substituted 3- to 14-membered heterocyclyl.

[0088] In some embodiments, a heterocyclyl group is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and one or more (e.g., 1, 2, 3, or 4) ring heteroatoms (wherein each heteroatom is independently selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus) (a "5- to 10-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and one or more (e.g., 1, 2, 3, or 4) ring heteroatoms (wherein each heteroatom is independently selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus) (a "5- to 8-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 6-membered non-aromatic ring system ("5- to 6-membered heterocyclyl") having ring carbon atoms and one or more (e.g., 1, 2, 3, or 4) ring heteroatoms (where each heteroatom is independently selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus). In some embodiments, a 5- to 6-membered heterocyclyl has one or more (e.g., 1, 2, or 3) ring heteroatoms selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus. In some embodiments, a 5- to 6-membered heterocyclyl has one or two ring heteroatoms selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus. In some embodiments, a 5- to 6-membered heterocyclyl has one ring heteroatom selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus.

[0089] Exemplary 3-membered heterocyclyl groups having one heteroatom include, without limitation, azirdinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups having one heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups having one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups having two heteroatoms include, without limitation, dioxolanyl, oxathiolanyl, and dithiolanyl. Exemplary 5-membered heterocyclyl groups having three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups having one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups having two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups having two heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups having one heteroatom include, without limitation, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups having one heteroatom include, without limitation, azocanyl, oxecanyl, and thiocanyl.Exemplary bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepin ... Examples include 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo-[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, and 1,2,3,4-tetrahydro-1,6-naphthyridinyl.

[0090] Heterocycloalkyl: The term "heterocycloalkyl," as used herein, refers to a non-aromatic ring in which at least one atom is a heteroatom, such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus, and the remaining atoms are carbon. Heterocycloalkyl groups can be substituted or unsubstituted.

[0091] As will be understood from the above, alkyl, alkenyl, alkynyl, acyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups as defined herein are, in certain embodiments, optionally substituted. Optionally substituted refers to a group that may be substituted or unsubstituted (e.g., a "substituted" or "unsubstituted" alkyl group, a "substituted" or "unsubstituted" alkenyl group, a "substituted" or "unsubstituted" alkynyl group, a "substituted" or "unsubstituted" heteroalkyl group, a "substituted" or "unsubstituted" heteroalkenyl group, a "substituted" or "unsubstituted" heteroalkynyl group, a "substituted" or "unsubstituted" carbocyclyl group, a "substituted" or "unsubstituted" heterocyclyl group, a "substituted" or "unsubstituted" aryl group, or a "substituted" or "unsubstituted" heteroaryl group). In general, the term "substituted" refers to a group in which at least one hydrogen present on a group is replaced by an acceptable substituent, e.g., a substituent that upon substitution results in a stable compound, e.g., by rearrangement, cyclization, elimination, or means replaced with a substituent that results in a compound that does not spontaneously undergo transformation, such as by other reactions. Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituents are either the same or different at each position. The term "substituted" is intended to include substitution with all permissible substituents of organic compounds, any of those substituents described herein, that result in the formation of a stable compound. The present invention contemplates any and all such combinations that result in stable compounds. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituents, as described herein, that satisfy the valence of the heteroatom and result in the formation of a stable moiety.

[0092] Exemplary carbon atom substituents include, but are not limited to, halogen, -CN, -NO2, -N3, -SO2, -SO3H, -OH, -OR aa , -ON(R bb )2, -N(Rbb )2、-N(R bb )3+X - 、-N(OR cc )R bb 、-SeH、-SeR aa 、-SH、-SR aa 、-SSR cc 、-C(=O)R aa 、-CO2H、-CHO、-C(OR cc )2、-CO2R aa 、-OC(=O)R aa 、-OCO2R aa 、-C(=O)N(R bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa 、-NR bb CO2R aa 、-NR bb C(=O)N(R bb )2、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3-OSi(R aa )3-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SRaa , -SC(=S)SR aa , -SC(=O)SR aa , -OC(=O)SR aa , -SC(=O)OR aa , -SC(=O)R aa , -P(=O)2R aa , -OP(=O)2R aa , -P(=O)(R aa )2, -OP(=O)(R aa )2, -OP(=O)(OR cc )2, -P(=O)2N(R bb )2, -OP(=O)2N(R bb )2, -P(=O)(NR bb )2, -OP(=O)(NR bb )2, -NR bb P(=O)(OR cc )2, -NR bb P(=O)(NR bb )2, -P(R cc )2, -P(R cc )3, -OP(R cc )2, -OP(R cc )3, -B(R aa )2, -B(OR cc )2, -BR aa (OR cc ), C1~C 50 Alkyl, C2-C 50 Alkenyl, C2-C 50 Alkynyl, C3-C 14 Carbocyclyl, 3-14 membered heterocyclyl, C6-C 14 and 5- to 14-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd Is it substituted with a group? Or two geminal hydrogens on a carbon atom are groups =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , =NNR bb S(=O)2Raa , =NR bb , or =NOR cc has been replaced by; R aa Each example is independently C1 to C 50 Alkyl, C2-C 50 Alkenyl, C2-C 50 Alkynyl, C3-C 10 Carbocyclyl, 3-14 membered heterocyclyl, C6-C 14 aryl, and 5- to 14-membered heteroaryl, or two R aa groups joined to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently contains 0, 1, 2, 3, 4, or 5 R dd substituted with a group; R bb Each example is independently hydrogen, —OH, —OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, C1~C 50 Alkyl, C2-C 50 Alkenyl, C2-C 50 Alkynyl, C3-C 10Carbocyclyl, 3-14 membered heterocyclyl, C6-C 14 aryl, and 5- to 14-membered heteroaryl, or two R bb groups, taken together with the heteroatom to which they are attached, form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently contains 0, 1, 2, 3, 4, or 5 R dd substituted with a group; R cc Each example is independently hydrogen, C1-C 50 Alkyl, C2-C 50 Alkenyl, C2-C 50 Alkynyl, C3-C 10 Carbocyclyl, 3-14 membered heterocyclyl, C6-C 14 aryl, and 5- to 14-membered heteroaryl, or two R cc groups, taken together with the heteroatom to which they are attached, form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently contains 0, 1, 2, 3, 4, or 5 R dd substituted with a group; R dd Each example is independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2, -N(R ff )3+X - , -N(OR ee )R ff , -SH, -SR ee , -SSR ee , -C(=O)R ee , -CO2H, -CO2R ee , -OC(=O)R ee , -OCO2R ee , -C(=O)N(R ff )2, -OC(=O)N(R ff )2, -NR ff C(=O)Ree , -NR ff CO2R ee , -NR ff C(=O)N(R ff )2, -C(=NR ff ) OR ee , -OC(=NR ff )R ee , -OC(=NR ff ) OR ee , -C(=NR ff )N(R ff )2, -OC(=NR ff )N(R ff )2, -NR ff C(=NR ff )N(R ff )2, -NR ff SO2R ee , -SO2N(R ff )2, -SO2R ee , -SO2OR ee , -OSO2R ee , -S(=O)R ee , -Si(R ee )3, -OSi(R ee )3, -C(=S)N(R ff )2, -C(=O)SR ee , -C(=S)SR ee , -SC(=S)SR ee , -P(=O)2R ee , -P(=O)(R ee )2, -OP(=O)(R ee )2, -OP(=O)(OR ee )2, C1~C 50 Alkyl, C2-C 50 Alkenyl, C2-C 50 Alkynyl, C3-C 10 Carbocyclyl, 3-10 membered heterocyclyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R gg group or two geminal R dd the substituents can be joined to form =O or =S; R ee Each example is independently C1 to C 50 Alkyl, C2-C 50 Alkenyl, C2-C 50 Alkynyl, C3-C 10 Carbocyclyl, C6-C 10 aryl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R gg substituted with a group; R ff Each example is independently hydrogen, C1-C 50 Alkyl, C2-C 50 Alkenyl, C2-C 50 Alkynyl, C3-C 10 Carbocyclyl, 3-10 membered heterocyclyl, C6-C 10 aryl and 5- to 10-membered heteroaryl, or two R ff groups, taken together with the heteroatom to which they are attached, form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently contains 0, 1, 2, 3, 4, or 5 R gg is substituted with a group; and R gg Each example is independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC1-C 50 Alkyl, -ON(C1-C 50 alkyl)2, -N(C1-C 50 alkyl)2, -N(C1-C 50 Alkyl)3+X - , -NH(C1~C 50 alkyl)2+X - , -NH2(C1~C 50 alkyl) + X - , -NH3+X - , -N(OC1~C 50 Alkyl) (C1-C 50alkyl), -N(OH)(C1-C 50 alkyl), -NH(OH), -SH, -SC1~C 50 Alkyl, -SS(C1-C 50 alkyl), -C(=O)(C1-C 50 alkyl), -CO2H, -CO2(C1-C 50 alkyl), -OC(=O)(C1-C 50 alkyl), -OCO2(C1-C 50 alkyl), -C(=O)NH2, -C(=O)N(C1-C 50 alkyl)2, -OC(=O)NH(C1-C 50 alkyl), -NHC(=O)(C1-C 50 alkyl), -N(C1-C 50 Alkyl)C(=O)(C1-C 50 alkyl), -NHCO2(C1-C 50 alkyl), -NHC(=O)N(C1-C 50 alkyl)2, -NHC(=O)NH(C1-C 50 alkyl), -NHC(=O)NH2, -C(=NH)O(C1-C 50 alkyl), -OC(=NH)(C1-C 50 alkyl), -OC(=NH)OC1~C 50 Alkyl, -C(=NH)N(C1-C 50 alkyl)2, -C(=NH)NH(C1-C 50 alkyl), -C(=NH)NH2, -OC(=NH)N(C1-C 50 alkyl)2, -OC(NH)NH(C1-C 50 alkyl), -OC(NH)NH2, -NHC(NH)N(C1-C 50 alkyl)2, -NHC(=NH)NH2, -NHSO2(C1-C 50 alkyl), -SO2N(C1-C 50 alkyl)2, -SO2NH(C1-C 50 alkyl), -SO2NH2, -SO2(C1-C 50 alkyl), -SO2O(C1-C 50 alkyl), -OSO2(C1-C6 alkyl), -SO(C1-C6 alkyl), -Si(C1-C 50alkyl)3, -OSi(C1-C6 alkyl)3, -C(=S)N(C1-C 50 alkyl)2, C(=S)NH(C1-C 50 alkyl), C(=S)NH2, -C(=O)S(C1-C6 alkyl), -C(=S)S(C1-C6 alkyl), -SC(=S)S(C1-C6 alkyl), -P(=O)2(C1-C 50 alkyl), -P(=O)(C1-C 50 alkyl)2, -OP(=O)(C1-C 50 alkyl)2, -OP(=O)(OC1~C 50 Alkyl)2, C1-C 50 Alkyl, C2-C 50 Alkenyl, C2-C 50 Alkynyl, C3-C 10 Carbocyclyl, C6-C 10 aryl, 3- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl; or two geminal R gg The substituents can be joined to form =O or =S; - is the counterion.

[0093] As used herein, the term "halo" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0094] As used herein, a "counterion" is a negatively charged group that is associated with a positively charged quaternary amine to maintain electronic neutrality. Exemplary counterions include halide ions (e.g., F - , Cl - , Br - , I - ), NO3 - , ClO4 - , O.H. - , H2PO4 - , HSO4 -, sulfonate ions (e.g., methanesulfonate ion, trifluoromethanesulfonate ion, p-toluenesulfonate ion, benzenesulfonate ion, 10-camphorsulfonate ion, naphthalene-2-sulfonate ion, naphthalene-1-sulfonic acid-5-sulfonate ion, ethane-1-sulfonic acid-2-sulfonate ion, etc.), and carboxylate ions (e.g., acetate ion, propanoate ion, benzoate ion, glycerate ion, lactate ion, tartrate ion, glycolate ion, etc.).

[0095] Nitrogen atoms may be substituted or unsubstituted as valence allows, including primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substitutents include, but are not limited to, hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR bb )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, C1~C 50 Alkyl, C2-C 50 Alkenyl, C2-C 50 Alkynyl, C3-C 10Carbocyclyl, 3-14 membered heterocyclyl, C6-C 14 aryl, and 5- to 14-membered heteroaryl, or two R cc groups, together with the N atom to which they are attached, form a 3- to 14-membered heterocyclyl ring or a 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently contains 0, 1, 2, 3, 4, or 5 R dd group, and wherein R aa , R bb , R cc and R dd is as defined above.

[0096] In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to as an amino protecting group). Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Butts, 3rd edition, John Wiley & Sons, 1999 (incorporated herein by reference).

[0097] For example, an amide group (e.g., —C(═O)R aaNitrogen protecting groups such as acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N'-dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine derivatives, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0098] Carbamate groups (e.g., -C(=O)OR aaNitrogen protecting groups such as, but not limited to, methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluorenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-Trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bume oc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate, Benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitrobenzyl carbamate (nitobenzyl), p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methyl (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chromonyl carbamate Methyl (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, o-nitrophenylmethyl phenyl carbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate, 2,2-dimethicone Benzyl o-(N,N-dimethylcarboxamido)carbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isobornyl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p'-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, carbamate 1-methylcyclohexyl carbamate, 1-methyl-l-cyclopropylmethyl carbamate, 1-methyl-1(3,5-dimethoxyphenyl)ethyl carbamate, 1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-l-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl.

[0099] Sulfonamide groups (e.g., -S(=O)R aa Nitrogen protecting groups such as, but not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide, anthracenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0100] Other nitrogen protecting groups include, but are not limited to, phenothiazinyl-(10)-acyl derivatives, N'-p-toluenesulfonylaminoacyl derivatives, N'-phenylaminothioacyl derivatives, N-benzoylphenylalanyl derivatives, N-acetylmethionine derivatives, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldiphenylamine, N-methyl-2,3-diphenylpropanol ... Aryl azacyclopentane adducts (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-ones, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-ones, 1-substituted 3,5-dinitro-4-pyridones, N-methylamines, N-allylamines, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyrroline) in)-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-picolylamino N'-oxide, N-1,1-dimethylamine N-methylthiomethyleneamine, N-benzylideneamine, Np-methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N',N'-dimethylaminomethylene)amine, N,N'-isopropylidenediamine, Np-nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivatives, N-diphenylborinic acid derivatives, N-[phenyl(pentaacylchromium or tungsten)acyl]amine, N-copper chelate, N-zinc chelate, N-nitroamine, N-nitrosamine, amine N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridine sulfenamide (Npys).

[0101] In certain embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also referred to as a hydroxyl protecting group).Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Butts, 3rd edition, John Wiley & Sons, 1999 (incorporated herein by reference).

[0102] Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (gum), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl ( MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4 -Methoxypiperidin-4-yl (y1) (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-l-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloro Ethyl, 2-trimethylsilylethyl, 2-(phenylselenenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxide, diphenylmethyl, p,p'-Dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4'-bromophenacyloxyphenyl)diphenylmethyl, 4,4',4"-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4"-tris(levulinoyloxyphenyl)methyl, 4,4',4"-tris(benzoyloxyphenyl)methyl nyl)methyl, 3-(imidazol-1-yl)bis(4',4"-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodisulfuran-2-yl, benzisothiazolyl S,S-dioxide, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS) ), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, pheno oxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyl dithioacetal), pivalic acid, adamantoic acid, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), alkyl methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl 2,2,2-Trichloroethyl (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphonio)ethyl carbonate (Peoc), alkyl isobutyl carbonate, alkyl vinyl carbonate, alkyl allyl carbonate, alkyl p-nitrophenyl carbonate, alkyl benzyl carbonate, alkyl p-methoxybenzyl carbonate, alkyl 3,4-dimethoxybenzyl carbonate, alkyl o-nitrobenzyl carbonate, alkyl p-nitrobenzyl carbonate, alkyl S-benzyl thiocarbonate, 4-ethoxy-1-naphthyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4 -methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinate, (E)-2-methyl-2-butenoate, o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N',N'-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).

[0103] In certain embodiments, the substituent present on the sulfur atom is a sulfur protecting group (also referred to as a thiol protecting group). Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Butts, 3rd edition, John Wiley & Sons, 1999 (incorporated herein by reference).

[0104] Exemplary sulfur protecting groups include, but are not limited to, alkyl, benzyl, p-methoxybenzyl, 2,4,6-trimethylbenzyl, 2,4,6-trimethoxybenzyl, o-hydroxybenzyl, p-hydroxybenzyl, o-acetoxybenzyl, p-acetoxybenzyl, p-nitrobenzyl, 4-picolyl, 2-quinolinylmethyl, 2-picolyl N-oxide, 9-anthrylmethyl, 9-fluorenylmethyl, xanthenyl, ferrocenylmethyl, diphenylmethyl, bis(4-methoxyphenyl)methyl, 5-dibenzosuberyl, triphenylmethyl, diphenyl-4-pyridylmethyl, phenyl, 2,4-dinitrophenyl, t-butyl, 1-adamantyl, methoxymethyl (MOM), isobutoxymethyl, benzyloxymethyl, 2-tetrahydropyranyl, benzylthiomethyl, phenylthiomethyl, thiazolidino, acetamidomethyl, trimethylacetamidomethyl, benzamidomethyl, allyloxycarbonylmethyl, and the like. Aminomethyl, phenylacetamidomethyl, phthalimidomethyl, acetylmethyl, carboxymethyl, cyanomethyl, (2-nitro-1-phenyl)ethyl, 2-(2,4-dinitrophenyl)ethyl, 2-cyanoethyl, 2-(trimethylsilyl)ethyl, 2,2-bis(carboethoxy)ethyl, (1-m-nitrophenyl-2-benzoyl)ethyl (othyl), 2-phenylsulfonylethyl, 2-(4-methylphenylsulfonyl)-2-methylprop-2 -yl, acetyl, benzoyl, trifluoroacetyl, N-[[(p-biphenylyl)isopropoxy]carbonyl]-N-methyl]-γ-aminothiobutyrate, 2,2,2-trichloroethoxycarbonyl, t-butoxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, N-ethyl, N-methoxymethyl, sulfonate, sulfenyl thiocarbonate, 3-nitro-2-pyridinesulfenyl sulfide, and oxathiolone.

[0105] Compounds of the Invention Liposome-based vehicles are considered attractive carriers for therapeutic drugs and are still the subject of ongoing development efforts. Although liposome-based vehicles containing certain lipid components have shown promising results in terms of encapsulation, stability, and site localization, there is still a great need for improved liposome-based delivery systems. For example, a significant drawback of liposome delivery systems relates to the construction of liposomes with sufficient cell culture or in vivo stability to reach desired target cells and / or intracellular compartments, and the ability of such liposome delivery systems to efficiently release their encapsulated materials into such target cells.

[0106] In particular, there remains a need for improved lipid compounds that demonstrate, for example, improved pharmacokinetic properties and have the ability to deliver macromolecules, such as nucleic acids, to a wide variety of cell types and tissues with increased efficiency. Importantly, there also remains a need for novel lipid compounds, particularly those that are characterized, for example, as exhibiting reduced toxicity and that have the ability to efficiently deliver encapsulated nucleic acids and polynucleotides to target cells, tissues, and organs.

[0107] Described herein are cationic lipid compounds for improved in vivo delivery of therapeutic agents, such as nucleic acids. Specifically, the cationic lipids described herein, optionally in conjunction with other lipids, can be used to formulate lipid-based nanoparticles (e.g., liposomes) for encapsulating therapeutic agents, such as nucleic acids (e.g., DNA, siRNA, mRNA, and / or microRNA) for therapeutic use.

[0108] In embodiments, the compounds of the present invention as described herein can provide one or more desirable features or properties. That is, in certain embodiments, the compounds of the present invention as described herein can be characterized as having one or more properties that provide such compounds with advantages over other similarly classified lipids. For example, the compounds disclosed herein allow for the control and adjustment of the properties of the liposome compositions (e.g., lipid nanoparticles) of which they are components. In particular, the compounds disclosed herein can be characterized by their improved transfection efficiency and their ability to induce specific biological outcomes. Such outcomes can include, for example, improved cellular uptake, endosome / lysosome disruption, and / or enhanced intracellular release of encapsulated materials (e.g., polynucleotides). In addition, the compounds disclosed herein have advantageous pharmacokinetic properties, biodistribution, and efficacy (e.g., due to different dissociation rates of the polymer groups used).

[0109] This application demonstrates that the cationic lipid of the present invention is not only easy to handle in synthesis from readily available starting materials, but also has unexpectedly high encapsulation efficiency.

[0110] In addition, the cationic lipids of the present invention have cleavable groups, such as ester groups and disulfides. It is contemplated that such cleavable groups (e.g., esters and disulfides) improve biodegradability and thus contribute to their favorable toxicity profile.

[0111] Provided herein are compounds that are cationic lipids. For example, cationic lipids of the present invention include compounds having a structure according to formula (I'z): [ka] or a pharmaceutically acceptable salt thereof [wherein: A 1 teeth, [ka] and -SS-, where the left side of each structure depicted is -(CH2) a -bonded to; Z 1 teeth, [ka] and -SS-, where the right side of each structure depicted is selected from -(CH2) a -bonded to; A 1 and Z 1 Unlike; Each R is [ka] (In the formula, each R 1 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkyl-(C=O)-O-optionally substituted alkyl, and -optionally substituted alkyl-O-(C=O)-optionally substituted alkyl; and [ka] (In the formula, each R 2 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl; each a is independently selected from 2, 3, 4, 5, and 6; and each b is independently selected from 2, 3, 4, 5, 6, and 7.

[0112] For example, cationic lipids of the present invention include compounds having a structure according to formula (II'z): [ka] or a pharmaceutically acceptable salt thereof [wherein: A 1 teeth, [ka] and -SS-, where the left side of each structure depicted is -(CH2) a -bonded to; Z 1 teeth, [ka] and -SS-, where the right side of each structure depicted is selected from -(CH2) a -bonded to; Each R is [ka] (In the formula, each R 1 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -optionally substituted alkyl-(C=O)-O-optionally substituted alkyl, and -optionally substituted alkyl-O-(C=O)-optionally substituted alkyl; and [ka] (In the formula, each R 2 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl; each a is independently selected from 2, 3, 4, 5, and 6; each b is independently selected from 2, 3, 4, 5, 6, and 7; and and c is 3 or 4.

[0113] For example, cationic lipids of the present invention include compounds having a structure according to formula (III'z): [ka] or a pharmaceutically acceptable salt thereof [wherein: A 1 teeth, [ka] and -SS-, where the left side of each structure depicted is -(CH2) a -bonded to; Z 1 teeth, [ka] and -SS-, where the right side of each structure depicted is selected from -(CH2) a -bonded to; Each R A , R B , R C and R D teeth, [ka] (In the formula, each R 1 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -optionally substituted alkyl-(C=O)-O-optionally substituted alkyl, and -optionally substituted alkyl-O-(C=O)-optionally substituted alkyl; and [ka] (In the formula, each R 2 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl; R A , R B , R C and R D At least one of the A , R B , R C and R D are not all the same); each a is independently selected from 2, 3, 4, 5, and 6; and each b is independently selected from 2, 3, 4, 5, 6, and 7.

[0114] For example, cationic lipids of the present invention include compounds having a structure according to formula (IV'z): [ka] or a pharmaceutically acceptable salt thereof [wherein: A 1 teeth, [ka] and -SS-, where the left side of each structure depicted is -(CH2) a -bonded to; Z 1 teeth, [ka] and -SS-, where the right side of each structure depicted is selected from -(CH2) a -bonded to; A 1 and Z 1 Unlike; Each R is [ka] (In the formula, each R 1 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -optionally substituted alkyl-(C=O)-O-optionally substituted alkyl, and -optionally substituted alkyl-O-(C=O)-optionally substituted alkyl; and [ka] (In the formula, each R 2are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl; each a is independently selected from 2, 3, 4, 5, and 6; each b is independently selected from 2, 3, 4, 5, 6, and 7; and and c is 3 or 4.

[0115] For example, cationic lipids of the present invention include compounds having a structure according to formula (V'z): [ka] or a pharmaceutically acceptable salt thereof [wherein: A 1 teeth, [ka] and -SS-, where the left side of each structure depicted is -(CH2) a -bonded to; Z 1 teeth, [ka] and -SS-, where the right side of each structure depicted is selected from -(CH2) a -bonded to; A 1 and Z 1 Unlike; Each R A , R B , R C and R D teeth, [ka] (In the formula, each R 1are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -optionally substituted alkyl-(C=O)-O-optionally substituted alkyl, and -optionally substituted alkyl-O-(C=O)-optionally substituted alkyl; and [ka] (In the formula, each R 2 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl; R A , R B , R C and R D At least one of the A , R B , R C and R D are not all the same); each a is independently selected from 2, 3, 4, 5, and 6; and each b is independently selected from 2, 3, 4, 5, 6, and 7.

[0116] For example, cationic lipids of the present invention include compounds having a structure according to formula (VI'z): [ka] or a pharmaceutically acceptable salt thereof [wherein: A 1 teeth, [ka] and -SS-, where the left side of each structure depicted is -(CH2) a -bonded to; Z 1 teeth, [ka] and -SS-, where the right side of each structure depicted is selected from -(CH2) a -bonded to; Each R A , R B , R C and R D teeth, [ka] (In the formula, each R 1 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -optionally substituted alkyl-(C=O)-O-optionally substituted alkyl, and -optionally substituted alkyl-O-(C=O)-optionally substituted alkyl; and [ka] (In the formula, each R 2 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl; R A , R B , R C and R D At least one of the A , R B , R C and R D are not all the same); each a is independently selected from 2, 3, 4, 5, and 6; each b is independently selected from 2, 3, 4, 5, 6, and 7; and and c is 3 or 4.

[0117] For example, cationic lipids of the present invention include compounds having a structure according to formula (VII'z): [ka] or a pharmaceutically acceptable salt thereof [wherein: A 1 teeth, [ka] and -SS-, where the left side of each structure depicted is -(CH2) a -bonded to; Z 1 teeth, [ka] and -SS-, where the right side of each structure depicted is selected from -(CH2) a -bonded to; A 1 and Z 1 Unlike; Each R A , R B , R C and R D teeth, [ka] (In the formula, each R 1 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -optionally substituted alkyl-(C=O)-O-optionally substituted alkyl, and -optionally substituted alkyl-O-(C=O)-optionally substituted alkyl; and [ka] (In the formula, each R 2 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl; R A , R B , R C and R D At least one of the A , R B , R C and RD are not all the same); each a is independently selected from 2, 3, 4, 5, and 6; each b is independently selected from 2, 3, 4, 5, 6, and 7; and and c is 3 or 4.

[0118] For example, cationic lipids of the present invention include compounds having a structure according to formula (Iz): [ka] or a pharmaceutically acceptable salt thereof [wherein: A 1 teeth, [ka] and -SS-, where the left side of each structure depicted is -(CH2) a -bonded to; Z 1 teeth, [ka] and -SS-, where the right side of each structure depicted is selected from -(CH2) a -bonded to; A 1 and Z 1 Unlike; Each R is [ka] (In the formula, each R 1 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -optionally substituted alkyl-(C=O)-O-optionally substituted alkyl, and -optionally substituted alkyl-O-(C=O)-optionally substituted alkyl; and [ka] (In the formula, each R 2are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl; and each a is independently selected from 2, 3, 4, 5 and 6.

[0119] For example, cationic lipids of the present invention include compounds having a structure according to formula (IIz): [ka] or a pharmaceutically acceptable salt thereof [wherein: A 1 teeth, [ka] and -SS-, where the left side of each structure depicted is -(CH2) a -bonded to; Z 1 teeth, [ka] and -SS-, where the right side of each structure depicted is selected from -(CH2) a -bonded to; Each R is [ka] (In the formula, each R 1 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -optionally substituted alkyl-(C=O)-O-optionally substituted alkyl, and -optionally substituted alkyl-O-(C=O)-optionally substituted alkyl; and [ka] (In the formula, each R 2are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl; each a is independently selected from 2, 3, 4, 5, and 6; and and c is 3 or 4.

[0120] For example, cationic lipids of the present invention include compounds having a structure according to formula (IIIz): [ka] or a pharmaceutically acceptable salt thereof [wherein: A 1 teeth, [ka] and -SS-, where the left side of each structure depicted is -(CH2) a -bonded to; Z 1 teeth, [ka] and -SS-, where the right side of each structure depicted is selected from -(CH2) a -bonded to; Each R A , R B , R C and R D teeth, [ka] (In the formula, each R 1 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -optionally substituted alkyl-(C=O)-O-optionally substituted alkyl, and -optionally substituted alkyl-O-(C=O)-optionally substituted alkyl; and (iv) [ka] (In the formula, each R 2 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl; R A , R B , R C and R D At least one of the A , R B , R C and R D are not all the same); each a is independently selected from 2, 3, 4, 5 and 6.

[0121] For example, cationic lipids of the present invention include compounds having a structure according to formula (IVz): [ka] or a pharmaceutically acceptable salt thereof [wherein: A 1 teeth, [ka] and -SS-, where the left side of each structure depicted is -(CH2) a -bonded to; Z 1 teeth, [ka] and -SS-, where the right side of each structure depicted is selected from -(CH2) a -bonded to; A 1 and Z 1 Unlike; Each R is [ka] (In the formula, each R 1are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -optionally substituted alkyl-(C=O)-O-optionally substituted alkyl, and -optionally substituted alkyl-O-(C=O)-optionally substituted alkyl; and [ka] (In the formula, each R 2 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl; each a is independently selected from 2, 3, 4, 5, and 6; and and c is 3 or 4.

[0122] For example, cationic lipids of the present invention include compounds having a structure according to formula (Vz): [ka] or a pharmaceutically acceptable salt thereof [wherein: A 1 teeth, [ka] and -SS-, where the left side of each structure depicted is -(CH2) a -bonded to; Z 1 teeth, [ka] and -SS-, where the right side of each structure depicted is selected from -(CH2) a -bonded to; A 1 and Z 1 Unlike; Each R A , R B , R C and R D teeth, [ka] (In the formula, each R 1 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -optionally substituted alkyl-(C=O)-O-optionally substituted alkyl, and -optionally substituted alkyl-O-(C=O)-optionally substituted alkyl; and [ka] (In the formula, each R 2 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl; R A , R B , R C and R D At least one of the A , R B , R C and R D are not all the same); each a is independently selected from 2, 3, 4, 5 and 6.

[0123] For example, cationic lipids of the present invention include compounds having a structure according to formula (VIz): [ka] or a pharmaceutically acceptable salt thereof [wherein: A 1 teeth, [ka] and -SS-, where the left side of each structure depicted is -(CH2) a -bonded to; Z 1 teeth, [ka] and -SS-, where the right side of each structure depicted is selected from -(CH2) a -bonded to; Each R A , R B , R C and R D teeth, [ka] (In the formula, each R 1 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -optionally substituted alkyl-(C=O)-O-optionally substituted alkyl, and -optionally substituted alkyl-O-(C=O)-optionally substituted alkyl; and [ka] (In the formula, each R 2 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl; R A , R B , R C and R D At least one of the A , R B , R C and R D are not all the same); each a is independently selected from 2, 3, 4, 5, and 6; and and c is 3 or 4.

[0124] For example, cationic lipids of the present invention include compounds having a structure according to formula (VIIz): [ka] or a pharmaceutically acceptable salt thereof [wherein: A 1 teeth, [ka] and -SS-, where the left side of each structure depicted is -(CH2) a -bonded to; Z 1 teeth, [ka] and -SS-, where the right side of each structure depicted is selected from -(CH2) a -bonded to; A 1 and Z 1 Unlike; Each R A , R B , R C and R D teeth, [ka] (In the formula, each R 1 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -optionally substituted alkyl-(C=O)-O-optionally substituted alkyl, and -optionally substituted alkyl-O-(C=O)-optionally substituted alkyl; and [ka] (In the formula, each R 2 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl; R A , R B , R C and R D At least one of the A , R B , R C and RD are not all the same); each a is independently selected from 2, 3, 4, 5, and 6; and and c is 3 or 4.

[0125] In embodiments, the cationic lipids of the present invention include a compound having a structure according to formula (Iaz): [ka] or a pharmaceutically acceptable salt thereof [wherein A 1 , Z 1 , R 2 and a is as defined for formula (Iz).

[0126] In embodiments, the cationic lipids of the present invention include a compound having a structure according to formula (IIaz): [ka] or a pharmaceutically acceptable salt thereof [wherein A 1 , Z 1 , R 2 , a and c are as defined for formula (IIz).

[0127] In embodiments, the cationic lipids of the present invention include a compound having a structure according to formula (IIIaz): [ka] or a pharmaceutically acceptable salt thereof [wherein A 1 , Z 1 and a are as defined for formula (IIIz), and each R 2A , R 2B , R 2C and R 2D are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl, where R 2A , R 2B , R 2Cand R 2D At least one of the 2A , R 2B , R 2C and R 2D (These are not all the same).

[0128] In embodiments, the cationic lipids of the present invention include a compound having a structure according to formula (IVaz): [ka] or a pharmaceutically acceptable salt thereof [wherein A 1 , Z 1 , R 2 , a and c are as defined for formula (IVz).

[0129] In embodiments, the cationic lipids of the present invention include a compound having a structure according to formula (Vaz): [ka] or a pharmaceutically acceptable salt thereof [wherein A 1 , Z 1 and a are as defined for formula (Vz), and each R 2A , R 2B , R 2C and R 2D are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl, where R 2A , R 2B , R 2C and R 2D At least one of the 2A , R 2B , R 2C and R 2D (These are not all the same).

[0130] In embodiments, the cationic lipids of the present invention include a compound having a structure according to formula (VIaz): [ka] or a pharmaceutically acceptable salt thereof [wherein A 1 , Z 1 , a and c are as defined for formula (VIz), and each R 2A , R 2B , R 2C and R 2D are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl, where R 2A , R 2B , R 2C and R 2D At least one of the 2A , R 2B , R 2C and R 2D (These are not all the same).

[0131] In embodiments, the cationic lipids of the present invention include a compound having a structure according to formula (VIIaz): [ka] or a pharmaceutically acceptable salt thereof [wherein A 1 , Z 1 , a and c are as defined for formula (VIIz), and each R 2A , R 2B , R 2C and R 2D are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl, where R 2A , R 2B , R 2C and R 2D At least one of the 2A , R 2B , R 2C and R 2D (These are not all the same).

[0132] In embodiments, the cationic lipids of the present invention include a compound having a structure according to formula (IIbz): [ka] or a pharmaceutically acceptable salt thereof [wherein R 2 , a and c are as defined for formula (IIz).

[0133] In embodiments, the cationic lipids of the present invention include a compound having a structure according to formula (IIIbz): [ka] or a pharmaceutically acceptable salt thereof, wherein a is as defined for formula (IIIz), and each R 2A , R 2B , R 2C and R 2D are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl, where R 2A , R 2B , R 2C and R 2D At least one of the 2A , R 2B , R 2C and R 2D (These are not all the same).

[0134] In embodiments, the cationic lipids of the present invention include a compound having a structure according to formula (VIbz): [ka] or a pharmaceutically acceptable salt thereof, wherein a and c are as defined for formula (VIz), and each R 2A , R 2B , R 2C and R 2Dare independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl, where R 2A , R 2B , R 2C and R 2D At least one of the 2A , R 2B , R 2C and R 2D (These are not all the same).

[0135] In embodiments, the cationic lipids of the present invention include compounds having a structure according to formula (Icz): [ka] or a pharmaceutically acceptable salt thereof [wherein R 2 and a is as defined for formula (Iz).

[0136] In embodiments, the cationic lipids of the present invention include a compound having a structure according to formula (IIcz): [ka] or a pharmaceutically acceptable salt thereof [wherein R 2 , a and c are as defined for formula (IIz).

[0137] In embodiments, the cationic lipids of the present invention include a compound having a structure according to formula (IIIcz): [ka] or a pharmaceutically acceptable salt thereof, wherein a is as defined for formula (IIIz), and each R 2A , R 2B , R 2C and R 2Dare independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl, where R 2A , R 2B , R 2C and R 2D At least one of the 2A , R 2B , R 2C and R 2D (These are not all the same).

[0138] In embodiments, the cationic lipids of the present invention include a compound having a structure according to formula (IVcz): [ka] or a pharmaceutically acceptable salt thereof [wherein R 2 , a and c are as defined for formula (IVz).

[0139] In embodiments, the cationic lipids of the present invention include a compound having a structure according to formula (Vcz): [ka] or a pharmaceutically acceptable salt thereof, wherein a is as defined for formula (Vz), and each R 2A , R 2B , R 2C and R 2D are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl, where R 2A , R 2B , R 2C and R 2D At least one of the 2A , R 2B , R 2C and R 2D (These are not all the same).

[0140] In embodiments, the cationic lipids of the present invention include a compound having a structure according to formula (VIcz): [ka] or a pharmaceutically acceptable salt thereof, wherein a and c are as defined for formula (VIz), and each R 2A , R 2B , R 2C and R 2D are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl, where R 2A , R 2B , R 2C and R 2D At least one of the 2A , R 2B , R 2C and R 2D (These are not all the same).

[0141] In embodiments, the cationic lipids of the present invention include a compound having a structure according to formula (VIIcz): [ka] or a pharmaceutically acceptable salt thereof, wherein a and c are as defined for formula (VIIz), and each R 2A , R 2B , R 2C and R 2D are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl, where R 2A , R 2B , R 2C and R 2D At least one of the 2A , R 2B , R 2C and R 2D (These are not all the same).

[0142] For example, cationic lipids of the present invention include compounds having a structure according to formula (I'): [ka] or a pharmaceutically acceptable salt thereof [wherein: A 1 teeth, [ka] and -SS-, where the left side of each structure depicted is -(CH2) a -bonded to; Z 1 teeth, [ka] and -SS-, where the right side of each structure depicted is selected from -(CH2) a -bonded to; A 1 and Z 1 Unlike; Each R is [ka] (In the formula, each R 1 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -optionally substituted alkyl-(C=O)-O-optionally substituted alkyl, and -optionally substituted alkyl-O-(C=O)-optionally substituted alkyl; and [ka] (In the formula, each R 2 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl; each a is independently selected from 2, 3, 4, and 5; and each b is independently selected from 2, 3, 4, 5, 6, and 7.

[0143] For example, the cationic lipids of the present invention include compounds having a structure according to formula (II'): [ka] or a pharmaceutically acceptable salt thereof [wherein: A 1 teeth, [ka] and -SS-, where the left side of each structure depicted is -(CH2) a -bonded to; Z 1 teeth, [ka] and -SS-, where the right side of each structure depicted is selected from -(CH2) a -bonded to; Each R is [ka] (In the formula, each R 1 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -optionally substituted alkyl-(C=O)-O-optionally substituted alkyl, and -optionally substituted alkyl-O-(C=O)-optionally substituted alkyl; and [ka] (In the formula, each R 2 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl; each a is independently selected from 2, 3, 4, and 5; each b is independently selected from 2, 3, 4, 5, 6, and 7; and and c is 3 or 4.

[0144] For example, the cationic lipids of the present invention include compounds having a structure according to formula (III'): [ka] or a pharmaceutically acceptable salt thereof [wherein: A 1 teeth, [ka] and -SS-, where the left side of each structure depicted is -(CH2) a -bonded to; Z 1 teeth, [ka] and -SS-, where the right side of each structure depicted is selected from -(CH2) a -bonded to; Each R A , R B , R C and R D teeth, [ka] (In the formula, each R 1 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -optionally substituted alkyl-(C=O)-O-optionally substituted alkyl, and -optionally substituted alkyl-O-(C=O)-optionally substituted alkyl; and [ka] (In the formula, each R 2are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl; R A , R B , R C and R D At least one of the A , R B , R C and R D are not all the same); each a is independently selected from 2, 3, 4, and 5; and each b is independently selected from 2, 3, 4, 5, 6, and 7.

[0145] For example, cationic lipids of the present invention include compounds having a structure according to formula (IV'): [ka] or a pharmaceutically acceptable salt thereof [wherein: A 1 teeth, [ka] and -SS-, where the left side of each structure depicted is -(CH2) a -bonded to; Z 1 teeth, [ka] and -SS-, where the right side of each structure depicted is selected from -(CH2) a -bonded to; A 1 and Z 1 Unlike; Each R is [ka] (In the formula, each R 1are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -optionally substituted alkyl-(C=O)-O-optionally substituted alkyl, and -optionally substituted alkyl-O-(C=O)-optionally substituted alkyl; and [ka] (In the formula, each R 2 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl; each a is independently selected from 2, 3, 4, and 5; each b is independently selected from 2, 3, 4, 5, 6, and 7; and and c is 3 or 4.

[0146] For example, cationic lipids of the present invention include compounds having a structure according to formula (V'): [ka] or a pharmaceutically acceptable salt thereof [wherein: A 1 teeth, [ka] and -SS-, where the left side of each structure depicted is -(CH2) a -bonded to; Z 1 teeth, [ka] and -SS-, where the right side of each structure depicted is selected from -(CH2) a -bonded to; A 1 and Z 1 Unlike; Each R A , R B, R C and R D teeth, [ka] (In the formula, each R 1 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -optionally substituted alkyl-(C=O)-O-optionally substituted alkyl, and -optionally substituted alkyl-O-(C=O)-optionally substituted alkyl; and [ka] (In the formula, each R 2 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl; R A , R B , R C and R D At least one of the A , R B , R C and R D are not all the same); each a is independently selected from 2, 3, 4, and 5; and each b is independently selected from 2, 3, 4, 5, 6, and 7.

[0147] For example, cationic lipids of the present invention include compounds having a structure according to formula (VI'): [ka] or a pharmaceutically acceptable salt thereof [wherein: A 1 teeth, [ka] and -SS-, where the left side of each structure depicted is -(CH2)a -bonded to; Z 1 teeth, [ka] and -SS-, where the right side of each structure depicted is selected from -(CH2) a -bonded to; Each R A , R B , R C and R D teeth, (i) [ka] (In the formula, each R 1 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -optionally substituted alkyl-(C=O)-O-optionally substituted alkyl, and -optionally substituted alkyl-O-(C=O)-optionally substituted alkyl; and (ii) [ka] (In the formula, each R 2 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl; R A , R B , R C and R D At least one of the A , R B , R C and R D are not all the same); each a is independently selected from 2, 3, 4, and 5; each b is independently selected from 2, 3, 4, 5, 6, and 7; and and c is 3 or 4.

[0148] For example, cationic lipids of the present invention include compounds having a structure according to formula (VII'): [ka] or a pharmaceutically acceptable salt thereof [wherein: A 1 teeth, [ka] and -SS-, where the left side of each structure depicted is -(CH2) a -bonded to; Z 1 teeth, [ka] and -SS-, where the right side of each structure depicted is selected from -(CH2) a -bonded to; A 1 and Z 1 Unlike; Each R A , R B , R C and R D teeth, [ka] (In the formula, each R 1 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -optionally substituted alkyl-(C=O)-O-optionally substituted alkyl, and -optionally substituted alkyl-O-(C=O)-optionally substituted alkyl; and [ka] (In the formula, each R 2are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl; R A , R B , R C and R D At least one of the A , R B , R C and R D are not all the same); each a is independently selected from 2, 3, 4, and 5; each b is independently selected from 2, 3, 4, 5, 6, and 7; and and c is 3 or 4.

[0149] In embodiments, the cationic lipids of the present invention include a compound having a structure according to formula (I): [ka] or a pharmaceutically acceptable salt thereof [wherein: A 1 teeth, [ka] and -SS-, where the left side of each structure depicted is -(CH2) a -bonded to; Z 1 teeth, [ka] and -SS-, where the right side of each structure depicted is selected from -(CH2) a -bonded to; A 1 and Z 1 Unlike; Each R is [ka] (In the formula, each R 1are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -optionally substituted alkyl-(C=O)-O-optionally substituted alkyl, and -optionally substituted alkyl-O-(C=O)-optionally substituted alkyl; and [ka] (In the formula, each R 2 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl; and each a is independently selected from 2, 3, 4, and 5.

[0150] In embodiments, the cationic lipids of the present invention include a compound having a structure according to formula (II): [ka] or a pharmaceutically acceptable salt thereof [wherein: A 1 teeth, [ka] and -SS-, where the left side of each structure depicted is -(CH2) a -bonded to; Z 1 teeth, [ka] and -SS-, where the right side of each structure depicted is selected from -(CH2) a -bonded to; Each R is [ka] (In the formula, each R 1are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -optionally substituted alkyl-(C=O)-O-optionally substituted alkyl, and -optionally substituted alkyl-O-(C=O)-optionally substituted alkyl; and [ka] (In the formula, each R 2 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl; each a is independently selected from 2, 3, 4, and 5; and and c is 3 or 4.

[0151] In embodiments, the cationic lipids of the present invention include a compound having a structure according to formula (III): [ka] or a pharmaceutically acceptable salt thereof [wherein: A 1 teeth, [ka] and -SS-, where the left side of each structure depicted is -(CH2) a -bonded to; Z 1 teeth, [ka] and -SS-, where the right side of each structure depicted is selected from -(CH2) a -bonded to; Each R A , R B , R C and R D teeth, [ka] (In the formula, each R 1 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -optionally substituted alkyl-(C=O)-O-optionally substituted alkyl, and -optionally substituted alkyl-O-(C=O)-optionally substituted alkyl; and [ka] (In the formula, each R 2 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl; R A , R B , R C and R D At least one of the A , R B , R C and R D are not all the same); each a is independently selected from 2, 3, 4, and 5.

[0152] In embodiments, the cationic lipids of the present invention include a compound having a structure according to formula (IV): [ka] or a pharmaceutically acceptable salt thereof [wherein: A 1 teeth, [ka] and -SS-, where the left side of each structure depicted is -(CH2) a -bonded to; Z 1 teeth, [ka] and -SS-, where the right side of each structure depicted is selected from -(CH2) a -bonded to; A 1 and Z 1 Unlike; Each R is [ka] (In the formula, each R 1 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -optionally substituted alkyl-(C=O)-O-optionally substituted alkyl, and -optionally substituted alkyl-O-(C=O)-optionally substituted alkyl; and [ka] (In the formula, each R 2 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl; each a is independently selected from 2, 3, 4, and 5; and and c is 3 or 4.

[0153] In embodiments, the cationic lipids of the present invention include a compound having a structure according to formula (V): [ka] or a pharmaceutically acceptable salt thereof [wherein: A 1 teeth, [ka] and -SS-, where the left side of each structure depicted is -(CH2) a -bonded to; Z 1 teeth, [ka] and -SS-, where the right side of each structure depicted is selected from -(CH2) a -bonded to; A 1 and Z 1 Unlike; Each R A , R B , R C and R D teeth, [ka] (In the formula, each R 1 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -optionally substituted alkyl-(C=O)-O-optionally substituted alkyl, and -optionally substituted alkyl-O-(C=O)-optionally substituted alkyl; and [ka] (In the formula, each R 2 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl; R A , R B , R C and R D At least one of the A , R B , R C and R D are not all the same); each a is independently selected from 2, 3, 4, and 5.

[0154] In embodiments, the cationic lipids of the present invention include a compound having a structure according to formula (VI): [ka] or a pharmaceutically acceptable salt thereof [wherein: A 1 teeth, [ka] and -SS-, where the left side of each structure depicted is -(CH2) a -bonded to; Z 1 teeth, [ka] and -SS-, where the right side of each structure depicted is selected from -(CH2) a -bonded to; Each R A , R B , R C and R D teeth, [ka] (In the formula, each R 1 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -optionally substituted alkyl-(C=O)-O-optionally substituted alkyl, and -optionally substituted alkyl-O-(C=O)-optionally substituted alkyl; and [ka] (In the formula, each R 2 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl; R A , R B , R C and R D At least one of the A , R B , R C and R Dare not all the same); each a is independently selected from 2, 3, 4, and 5; and and c is 3 or 4.

[0155] In embodiments, the cationic lipids of the present invention include a compound having a structure according to formula (VII): [ka] or a pharmaceutically acceptable salt thereof [wherein: A 1 teeth, [ka] and -SS-, where the left side of each structure depicted is -(CH2) a -bonded to; Z 1 teeth, [ka] and -SS-, where the right side of each structure depicted is selected from -(CH2) a -bonded to; A 1 and Z 1 Unlike; Each R A , R B , R C and R D teeth, [ka] (In the formula, each R 1 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -optionally substituted alkyl-(C=O)-O-optionally substituted alkyl, and -optionally substituted alkyl-O-(C=O)-optionally substituted alkyl; and [ka] (In the formula, each R2 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl; R A , R B , R C and R D At least one of the A , R B , R C and R D are not all the same); each a is independently selected from 2, 3, 4, and 5; and and c is 3 or 4.

[0156] In embodiments, the cationic lipids of the present invention include a compound having a structure according to formula (Ia): [ka] or a pharmaceutically acceptable salt thereof [wherein A 1 , Z 1 , R 2 and a is as defined for formula (I).

[0157] In embodiments, the cationic lipids of the present invention include a compound having a structure according to formula (IIa): [ka] or a pharmaceutically acceptable salt thereof [wherein A 1 , Z 1 , R 2 , a and c are as defined for formula (II).

[0158] In embodiments, the cationic lipids of the present invention include a compound having a structure according to formula (IIIa): [ka] or a pharmaceutically acceptable salt thereof [wherein A1 , Z 1 and a are as defined for formula (III), and each R 2A , R 2B , R 2C and R 2D are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl, where R 2A , R 2B , R 2C and R 2D At least one of the 2A , R 2B , R 2C and R 2D (These are not all the same).

[0159] In embodiments, the cationic lipids of the present invention include a compound having a structure according to formula (IVa): [ka] or a pharmaceutically acceptable salt thereof [wherein A 1 , Z 1 , R 2 , a and c are as defined for formula (IV).

[0160] In embodiments, the cationic lipids of the present invention include a compound having a structure according to formula (Va): [ka] or a pharmaceutically acceptable salt thereof [wherein A 1 , Z 1 and a are as defined for formula (V), and each R 2A , R 2B , R 2C and R 2D are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl, where R 2A , R 2B, R 2C and R 2D At least one of the 2A , R 2B , R 2C and R 2D (These are not all the same).

[0161] In embodiments, the cationic lipids of the present invention include a compound having a structure according to formula (VIa): [ka] or a pharmaceutically acceptable salt thereof [wherein A 1 , Z 1 , a and c are as defined for formula (VI), and each R 2A , R 2B , R 2C and R 2D are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl, where R 2A , R 2B , R 2C and R 2D At least one of the 2A , R 2B , R 2C and R 2D (These are not all the same).

[0162] In embodiments, the cationic lipids of the present invention include a compound having a structure according to formula (VIIa): [ka] or a pharmaceutically acceptable salt thereof [wherein A 1 , Z 1 , a and c are as defined for formula (VII), and each R 2A , R 2B , R 2C and R 2Dare independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl, where R 2A , R 2B , R 2C and R 2D At least one of the 2A , R 2B , R 2C and R 2D (These are not all the same).

[0163] In embodiments, the cationic lipids of the present invention include a compound having a structure according to formula (IIb): [ka] or a pharmaceutically acceptable salt thereof [wherein R 2 , a and c are as defined for formula (II).

[0164] In embodiments, the cationic lipids of the present invention include a compound having a structure according to formula (IIIb): [ka] or a pharmaceutically acceptable salt thereof, wherein a is as defined for formula (III), and each R 2A , R 2B , R 2C and R 2D are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl, where R 2A , R 2B , R 2C and R 2D At least one of the 2A , R 2B , R 2C and R 2D (These are not all the same).

[0165] In embodiments, the cationic lipids of the present invention include a compound having a structure according to formula (VIb): [ka] or a pharmaceutically acceptable salt thereof, wherein a and c are as defined for formula (VI), and each R 2A , R 2B , R 2C and R 2D are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl, where R 2A , R 2B , R 2C and R 2D At least one of the 2A , R 2B , R 2C and R 2D (These are not all the same).

[0166] In embodiments, the cationic lipids of the present invention include a compound having a structure according to formula (Ic): [ka] or a pharmaceutically acceptable salt thereof [wherein R 2 and a is as defined for formula (I).

[0167] In embodiments, the cationic lipids of the present invention include a compound having a structure according to formula (IIc): [ka] or a pharmaceutically acceptable salt thereof [wherein R 2 , a and c are as defined for formula (II).

[0168] In embodiments, the cationic lipids of the present invention include a compound having a structure according to formula (IIIc): [ka] or a pharmaceutically acceptable salt thereof, wherein a is as defined for formula (III), and each R 2A , R 2B , R 2C and R 2D are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl, where R 2A , R 2B , R 2C and R 2D At least one of the 2A , R 2B , R 2C and R 2D (These are not all the same).

[0169] In embodiments, the cationic lipids of the present invention include a compound having a structure according to formula (IVc): [ka] or a pharmaceutically acceptable salt thereof [wherein R 2 , a and c are as defined for formula (IV).

[0170] In embodiments, the cationic lipids of the present invention include a compound having a structure according to formula (Vc): [ka] or a pharmaceutically acceptable salt thereof, wherein a is as defined for formula (V), and each R 2A , R 2B , R 2C and R 2D are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl, where R 2A , R 2B , R 2C and R 2DAt least one of the 2A , R 2B , R 2C and R 2D (These are not all the same).

[0171] In embodiments, the cationic lipids of the present invention include a compound having a structure according to formula (VIc): [ka] or a pharmaceutically acceptable salt thereof, wherein a and c are as defined for formula (VI), and each R 2A , R 2B , R 2C and R 2D are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl, where R 2A , R 2B , R 2C and R 2D At least one of the 2A , R 2B , R 2C and R 2D (These are not all the same).

[0172] In embodiments, the cationic lipids of the present invention include a compound having a structure according to formula (VIIc): [ka] or a pharmaceutically acceptable salt thereof, wherein a and c are as defined for formula (VII), and each R 2A , R 2B , R 2C and R 2D are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl, where R 2A , R 2B , R 2C and R2D At least one of the 2A , R 2B , R 2C and R 2D (These are not all the same).

[0173] In embodiments, the cationic lipids of the present invention include compounds having a structure according to formula (Id): [ka] or a pharmaceutically acceptable salt thereof [wherein each a and R 2 is as defined in formula (I) or formula (Iz).

[0174] In embodiments, the cationic lipids of the present invention include a compound having a structure according to formula (IId): [ka] or a pharmaceutically acceptable salt thereof [wherein each of a, c, and R 2 is as defined in formula (II) or formula (IIz).

[0175] In embodiments, the cationic lipids of the present invention include a compound having a structure according to formula (IIId): [ka] or a pharmaceutically acceptable salt thereof, wherein each a is as defined in Formula (III) or Formula (IIIz), and each R 2A , R 2B , R 2C and R 2D are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl, where R 2A , R 2B , R 2C and R 2D At least one of the 2A , R2B , R 2C and R 2D (These are not all the same).

[0176] In embodiments, the cationic lipids of the present invention include a compound having a structure according to formula (IVd): [ka] or a pharmaceutically acceptable salt thereof [wherein each of a, c, and R 2 is as defined in formula (IV) or formula (IVz).

[0177] In embodiments, the cationic lipids of the present invention include a compound having a structure according to formula (Vd): [ka] or a pharmaceutically acceptable salt thereof, wherein each a is as defined in Formula (V) or Formula (Vz), and each R 2A , R 2B , R 2C and R 2D are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl, where R 2A , R 2B , R 2C and R 2D At least one of the 2A , R 2B , R 2C and R 2D (These are not all the same).

[0178] In embodiments, the cationic lipids of the present invention include compounds having a structure according to formula (VId): [ka] or a pharmaceutically acceptable salt thereof, wherein each a and c is as defined in Formula (VI) or Formula (VIz), and each R2A , R 2B , R 2C and R 2D are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl, where R 2A , R 2B , R 2C and R 2D At least one of the 2A , R 2B , R 2C and R 2D (These are not all the same).

[0179] In embodiments, the cationic lipids of the present invention include a compound having a structure according to formula (VIId): [ka] or a pharmaceutically acceptable salt thereof, wherein each a and c is as defined in formula (VII) or formula (VIIz), and each R 2A , R 2B , R 2C and R 2D are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl, where R 2A , R 2B , R 2C and R 2D At least one of the 2A , R 2B , R 2C and R 2D (These are not all the same).

[0180] In embodiments, the cationic lipids of the present invention include a compound having a structure according to formula (I'a): [ka] or a pharmaceutically acceptable salt thereof [wherein each A 1 , Z1 , a, b, R 1 , and R 2 is as defined in formula (I') or formula (I'z), optionally in which A 1 teeth, [ka] and the left side of the structure depicted here is -(CH2) a - and Z 1 is -SS-].

[0181] In embodiments, the cationic lipids of the present invention include a compound having a structure according to formula (II'a): [ka] or a pharmaceutically acceptable salt thereof [wherein each A 1 , Z 1 , a, b, c, R 1 , and R 2 is as defined in formula (II') or formula (II'z), optionally in which A 1 teeth, [ka] and the left side of the structure depicted here is -(CH2) a - and Z 1 is -SS-].

[0182] In embodiments, the cationic lipids of the present invention include a compound having a structure according to formula (III'a): [ka] or a pharmaceutically acceptable salt thereof [wherein each A 1 , Z 1 , a, b, and R 1 is as defined in formula (III') or formula (III'z), and each R 2A and R 2Bare independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl, and optionally 1 teeth, [ka] and the left side of the structure depicted here is -(CH2) a - and Z 1 is -SS-].

[0183] (e.g., a) formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc), or b) formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II'a), (III'a) , (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, each a is independently selected from 2, 3, and 4.

[0184] (e.g., a) formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc), or b) formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II'a), (III'a), ), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, each a is independently selected from 3 and 4.

[0185] The compounds of the present invention are (e.g., a) compounds of formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc), or b) compounds of formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II'a), In an embodiment of (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, each a is different.

[0186] The compounds of the present invention are (e.g., a) compounds of formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc), or b) compounds of formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II'a), (III'a), (I'z), (I In embodiments of (I'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, the value of a on the left side of the depicted formula is less than the value of a on the right side of the depicted formula.

[0187] (e.g., a) formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc), or b) formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II'a), (III'a), (I'z), (II' In an embodiment of (Iz), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, the value of a on the left side of the depicted formula is 3 and the value of a on the right side of the depicted formula is 4.

[0188] of the present invention (for example, formulas (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II'a), (III'a), (I'z), (II'z), (II I'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), ( In an embodiment of (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, the value of a on the left side of the depicted formula is 3 and the value of a on the right side of the depicted formula is 6.

[0189] The compounds of the present invention are (e.g., a) compounds of formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc), or b) compounds of formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II'a), ( In embodiments of III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, each a is the same.

[0190] The compounds of the present invention are (e.g., a) compounds of formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc), or b) compounds of formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II'a), In embodiments of (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, each a is 3.

[0191] (e.g., formula a) (II'), (IV'), (VI'), (VII'), (II), (IV), (VI), (VII), (IIa) (IIa), (IVa), (VIa), (VIIa), (IIb), (VIb), (IIc), (IVc), (VIc) or (VIIc), or b) formula (IId), (IVd), (VId), (VIId), (II'a) In an embodiment of (II'z), (IV'z), (VI'z), (VII'z), (IIz), (IVz), (VIz), (VIIz), (IIaz), (IVaz), (VIaz), (VIIaz), (IIbz), (VIbz), (IIcz), (IVcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, c is 3.

[0192] The compounds of the present invention are (e.g., a) compounds of formula (II'), (IV'), (VI'), (VII'), (II), (IV), (VI), (VII), (IIa), (IVa), (VIa), (VIIa), (IIb), (VIb), (IIc), (IVc), (VIc) or (VIIc), or b) compounds of formula (IId), (IVd), (VId), (VIId), (II'a), ( In an embodiment of (II'z), (IV'z), (VI'z), (VII'z), (IIz), (IVz), (VIz), (VIIz), (IIaz), (IVaz), (VIaz), (VIIaz), (IIbz), (VIbz), (IIcz), (IVcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, c is 4.

[0193] The compounds of the present invention are (e.g., a) compounds of formula (II'), (IV'), (VI'), (VII'), (II), (IV), (VI), (VII), (IIa), (IVa), (VIa), (VIIa), (IIb), (VIb), (IIc), (IVc), (VIc) or (VIIc), or b) compounds of formula (IId), (IVd), (VId), (VIId), (II'a), (II'z), (IV'z), (VI'z), (V In embodiments of (II'z), (IIz), (IVz), (VIz), (VIIz), (IIaz), (IVaz), (VIaz), (VIIaz), (IIbz), (VIbz), (IIcz), (IVcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, c is 3, the value of a on the left side of the depicted formula is 3, and the value of a on the right side of the depicted formula is 4.

[0194] The compounds of the present invention are (e.g., a) compounds of formula (II'), (IV'), (VI'), (VII'), (II), (IV), (VI), (VII), (IIa), (IVa), (VIa), (VIIa), (IIb), (VIb), (IIc), (IVc), (VIc) or (VIIc), or b) compounds of formula (IId), (IVd), (VId), (VIId), (II'a), (II'z), (IV'z), (VI'z), (V In embodiments of (II'z), (IIz), (IVz), (VIz), (VIIz), (IIaz), (IVaz), (VIaz), (VIIaz), (IIbz), (VIbz), (IIcz), (IVcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, c is 4, the value of a on the left side of the depicted formula is 3, and the value of a on the right side of the depicted formula is 4.

[0195] The compounds of the present invention are (e.g., a) compounds of formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc), or b) compounds of formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II' In embodiments of (I'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, R 2 Or each R 2A , R 2B , R 2C and R 2Dare independently selected from optionally substituted alkyl. In an embodiment of the present invention, R 2 Or each R 2A , R 2B , R 2C and R 2D is optionally substituted C5-C 50 In any of the above embodiments, R 2 Or each R 2A , R 2B , R 2C and R 2D is optionally substituted C5-C 40 In any of the above embodiments, R 2 Or each R 2A , R 2B , R 2C and R 2D is optionally substituted C5-C 30 In any of the above embodiments, R 2 Or each R 2A , R 2B , R 2C and R 2D is optionally substituted C5-C 25 In any of the above embodiments, R 2 Or each R 2A , R 2B , R 2C and R 2D is optionally substituted C5-C 20 alkyl.

[0196] The compounds of the present invention are (e.g., a) compounds of formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc), or b) compounds of formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II' In embodiments of (I'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, R 2 Or each R 2A , R 2B , R 2C and R 2D is C8H 17 , C 10 H 21 , C 12 H 25 , C 14 H 29 , C 16 H 33 , C 16 H 31 , C 16 H 29 , and C 16 H 27 are independently selected from

[0197] The compounds of the present invention are (e.g., a) compounds of formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc), or b) compounds of formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II'a), (II'a), In some embodiments, R 2 Or each R 2A , R 2B , R 2C and R 2D is an optionally substituted alkyl. In some embodiments, the optionally substituted alkyl is —OC(═O)R aa wherein each R aa is independently selected from optionally substituted alkyl. In some embodiments, the optionally substituted alkyl is —OC(═O)R aa C is replaced by 1~20 alkyl, wherein each R aa are optionally substituted C1 to C 50 In some embodiments, the optionally substituted alkyl is independently selected from -OC(=O)R aa C is replaced by 1~10 alkyl, wherein each R aa are optionally substituted C1 to C 50In some embodiments, the optionally substituted alkyl is independently selected from -OC(=O)R aa C is replaced by 1~5 alkyl, wherein each R aa are optionally substituted C1 to C 50 alkyl.

[0198] The compounds of the present invention are (e.g., a) compounds of formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc), or b) compounds of formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II In some embodiments of (III'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, R 2 Or each R 2A , R 2B , R 2C and R 2D is an optionally substituted alkyl. In some embodiments, the optionally substituted alkyl is —COR aa wherein each R aa is independently selected from optionally substituted alkyl. In some embodiments, the optionally substituted alkyl is —COR aa C is replaced by 1~20 alkyl, wherein each R aaare optionally substituted C1 to C 50 In some embodiments, the optionally substituted alkyl is independently selected from -COR aa C is replaced by 1~10 alkyl, wherein each R aa are optionally substituted C1 to C 50 In some embodiments, the optionally substituted alkyl is independently selected from -COR aa C is replaced by 1~5 alkyl, wherein each R aa are optionally substituted C1 to C 50 alkyl.

[0199] In any of the above embodiments, R aa are optionally substituted C1 to C 40 In any of the above embodiments, R aa are optionally substituted C1 to C 30 In any of the above embodiments, R aa are optionally substituted C1 to C 25 In any of the above embodiments, R aa are optionally substituted C1 to C 20 In any of the above embodiments, R aa are optionally substituted C1 to C 15 In any of the above embodiments, R aa are optionally substituted C1 to C 10 In any of the above embodiments, R aa are independently selected from optionally substituted C2-C8 alkyl. In any of the above embodiments, R aa are independently selected from optionally substituted C3-C7 alkyl.

[0200] The compounds of the present invention are (e.g., a) compounds of formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IVa), (IIb), (Ic), (IIc) or (IVc), or b) compounds of formula (Id), (IId), (IVd), (I'a), (II'a), ( In embodiments of (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IVaz), (IIbz), (Icz), (IIcz), or (IVcz), or a pharmaceutically acceptable salt thereof, each R 2 is the same.

[0201] In embodiments of the invention (e.g., of a) Formula (IIIa), (Va), (VIa), (VIIa), (IIIb), (VIb), (IIIc), (Vc), (VIc) or (VIIc), or b) Formula (IIId), (Vd), (VId), (VIId), (IIIaz), (Vaz), (VIaz), (VIIaz), (IIIbz), (VIbz), (IIIcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof), R 2A and R 2B are the same, and R 2C and R 2D is the same.

[0202] In embodiments of the invention (e.g., of a) Formula (IIIa), (Va), (VIa), (VIIa), (IIIb), (VIb), (IIIc), (Vc), (VIc) or (VIIc), or b) Formula (IIId), (Vd), (VId), (VIId), (IIIaz), (Vaz), (VIaz), (VIIaz), (IIIbz), (VIbz), (IIIcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof), R 2A and R 2C are the same, and R 2B and R 2Dis the same.

[0203] The compounds of the present invention are (e.g., a) compounds of formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc), or b) compounds of formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II In embodiments of (I'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz) or a pharmaceutically acceptable salt thereof, each R 2 or R 2A , R 2B , R 2C and R 2D At least one of the 10 H 21 is.

[0204] In embodiments of the invention (e.g., of a) Formula (IIIa), (Va), (VIa), (VIIa), (IIIb), (VIb), (IIIc), (Vc), (VIc) or (VIIc), or b) Formula (IIId), (Vd), (VId), (VIId), (III'a), (IIIaz), (Vaz), (VIaz), (VIIaz), (IIIbz), (VIbz), (IIIcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof), R 2A and R 2B is C 10 H 21 is.

[0205] In embodiments of the invention (e.g., of a) Formula (IIIa), (Va), (VIa), (VIIa), (IIIb), (VIb), (IIIc), (Vc), (VIc) or (VIIc), or b) Formula (IIId), (Vd), (VId), (VIId), (IIIaz), (Vaz), (VIaz), (VIIaz), (IIIbz), (VIbz), (IIIcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof), R 2C and R 2D is C 10 H 21 is.

[0206] In embodiments of the invention (e.g., of a) Formula (IIIa), (Va), (VIa), (VIIa), (IIIb), (VIb), (IIIc), (Vc), (VIc) or (VIIc), or b) Formula (IIId), (Vd), (VId), (VIId), (III'a), (IIIaz), (Vaz), (VIaz), (VIIaz), (IIIbz), (VIbz), (IIIcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof), R 2A and R 2B is C 16 H 31 is.

[0207] In embodiments of the invention (e.g., of a) Formula (IIIa), (Va), (VIa), (VIIa), (IIIb), (VIb), (IIIc), (Vc), (VIc) or (VIIc), or b) Formula (IIId), (Vd), (VId), (VIId), (IIIaz), (Vaz), (VIaz), (VIIaz), (IIIbz), (VIbz), (IIIcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof), R 2C and R 2D is C 16 H 31 is.

[0208] In embodiments of the invention (e.g., of a) Formula (IIIa), (Va), (VIa), (VIIa), (IIIb), (VIb), (IIIc), (Vc), (VIc) or (VIIc), or b) Formula (IIId), (Vd), (VId), (VIId), (IIIaz), (Vaz), (VIaz), (VIIaz), (IIIbz), (VIbz), (IIIcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof), R 2A and R 2B is C 10 H 21 and R 2C and R 2D is C 16 H 31 is.

[0209] In embodiments of the invention (e.g., of a) Formula (IIIa), (Va), (VIa), (VIIa), (IIIb), (VIb), (IIIc), (Vc), (VIc) or (VIIc), or b) Formula (IIId), (Vd), (VId), (VIId), (IIIaz), (Vaz), (VIaz), (VIIaz), (IIIbz), (VIbz), (IIIcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof), R 2A and R 2B is C 16 H 31 and R 2C and R 2D is C 10 H 21 is.

[0210] In embodiments of the invention (e.g., of a) Formula (IIIa), (Va), (VIa), (VIIa), (IIIb), (VIb), (IIIc), (Vc), (VIc) or (VIIc), or b) Formula (IIId), (Vd), (VId), (VIId), (IIIaz), (Vaz), (VIaz), (VIIaz), (IIIbz), (VIbz), (IIIcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof), R 2A and R 2C teeth, [ka] is.

[0211] In embodiments of the invention (e.g., of a) Formula (IIIa), (Va), (VIa), (VIIa), (IIIb), (VIb), (IIIc), (Vc), (VIc) or (VIIc), or b) Formula (IIId), (Vd), (VId), (VIId), (IIIaz), (Vaz), (VIaz), (VIIaz), (IIIbz), (VIbz), (IIIcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof), R 2B and R 2D teeth, [ka] is.

[0212] In embodiments of the invention (e.g., of a) Formula (IIIa), (Va), (VIa), (VIIa), (IIIb), (VIb), (IIIc), (Vc), (VIc) or (VIIc), or b) Formula (IIId), (Vd), (VId), (VIId), (IIIaz), (Vaz), (VIaz), (VIIaz), (IIIbz), (VIbz), (IIIcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof), R 2A and R 2C is C 16 H 31 is.

[0213] In embodiments of the invention (e.g., of a) Formula (IIIa), (Va), (VIa), (VIIa), (IIIb), (VIb), (IIIc), (Vc), (VIc) or (VIIc), or b) Formula (IIId), (Vd), (VId), (VIId), (IIIaz), (Vaz), (VIaz), (VIIaz), (IIIbz), (VIbz), (IIIcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof), R 2B and R2D is C 16 H 31 is.

[0214] In embodiments of the invention (e.g., of a) Formula (IIIa), (Va), (VIa), (VIIa), (IIIb), (VIb), (IIIc), (Vc), (VIc) or (VIIc), or b) Formula (IIId), (Vd), (VId), (VIId), (IIIaz), (Vaz), (VIaz), (VIIaz), (IIIbz), (VIbz), (IIIcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof), R 2A and R 2C teeth [ka] and R 2B and R 2D is C 16 H 31 is.

[0215] In embodiments of the invention (e.g., of a) Formula (IIIa), (Va), (VIa), (VIIa), (IIIb), (VIb), (IIIc), (Vc), (VIc) or (VIIc), or b) Formula (IIId), (Vd), (VId), (VIId), (IIIaz), (Vaz), (VIaz), (VIIaz), (IIIbz), (VIbz), (IIIcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof), R 2A and R 2C is C 16 H 31 and R 2B and R 2D teeth, [ka] is.

[0216] In embodiments of the invention (e.g., of a) Formula (IIIa), (Va), (VIa), (VIIa), (IIIb), (VIb), (IIIc), (Vc), (VIc) or (VIIc), or b) Formula (IIId), (Vd), (VId), (VIId), (IIIaz), (Vaz), (VIaz), (VIIaz), (IIIbz), (VIbz), (IIIcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof), R 2A and R 2B is optionally substituted alkyl, and R 2C and R 2D is an optionally substituted alkenyl.

[0217] In embodiments of the invention (e.g., of a) Formula (IIIa), (Va), (VIa), (VIIa), (IIIb), (VIb), (IIIc), (Vc), (VIc) or (VIIc), or b) Formula (IIId), (Vd), (VId), (VIId), (IIIaz), (Vaz), (VIaz), (VIIaz), (IIIbz), (VIbz), (IIIcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof), R 2A and R 2B is optionally substituted alkenyl, and R 2C and R 2D is optionally substituted alkyl.

[0218] In embodiments of the invention (e.g., of a) Formula (IIIa), (Va), (VIa), (VIIa), (IIIb), (VIb), (IIIc), (Vc), (VIc) or (VIIc), or b) Formula (IIId), (Vd), (VId), (VIId), (IIIaz), (Vaz), (VIaz), (VIIaz), (IIIbz), (VIbz), (IIIcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof), R 2A and R 2Cis -optionally substituted alkyl-(C=O)-O-optionally substituted alkyl, and R 2B and R 2D is an optionally substituted alkenyl.

[0219] In embodiments of the invention (e.g., of a) Formula (IIIa), (Va), (VIa), (VIIa), (IIIb), (VIb), (IIIc), (Vc), (VIc) or (VIIc), or b) Formula (IIId), (Vd), (VId), (VIId), (IIIaz), (Vaz), (VIaz), (VIIaz), (IIIbz), (VIbz), (IIIcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof), R 2A and R 2C is optionally substituted alkenyl, and R 2B and R 2D is -optionally substituted alkyl-(C=O)-O-optionally substituted alkyl.

[0220] In embodiments of the invention (e.g., of a) Formula (IIIa), (Va), (VIa), (VIIa), (IIIb), (VIb), (IIIc), (Vc), (VIc) or (VIIc), or b) Formula (IIId), (Vd), (VId), (VIId), (III'a), (IIIaz), (Vaz), (VIaz), (VIIaz), (IIIbz), (VIbz), (IIIcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof), each R 2A , R 2B , R 2C and R 2D teeth, [ka] are independently selected from

[0221] The compounds of the present invention (e.g., a) formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc), b) formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II'a) ), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, 2 or R 2A , R 2B , R 2C and R 2D At least one of the groups is -OC(=O)R aa C is replaced by 1~20 alkyl, wherein each R aa are optionally substituted C1 to C 20 alkyl.

[0222] The compounds of the present invention are (e.g., a) compounds of formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc), or b) compounds of formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II' In embodiments of (I'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, each R 2 or R 2A , R 2B , R 2C and R 2D At least one of the aa C is replaced by 1~20 alkyl, wherein each R aa are optionally substituted C1 to C 20 alkyl.

[0223] The compounds of the present invention are (e.g., a) compounds of formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc), or b) compounds of formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II'a), (III'a), In an embodiment of (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, each a is independently selected from 2, 3, and 4, and R 2 Or each R 2A , R 2B , R 2C and R 2D is independently selected from optionally substituted alkyl. In any of the above embodiments, R 2 Or each R 2A , R 2B , R 2C and R 2D is optionally substituted C5-C 50 In any of the above embodiments, R 2 Or each R 2A , R 2B , R 2C and R 2D is optionally substituted C5-C 40 In any of the above embodiments, R 2 Or each R 2A , R 2B , R 2C and R2D is optionally substituted C5-C 30 In any of the above embodiments, R 2 Or each R 2A , R 2B , R 2C and R 2D is optionally substituted C5-C 25 In any of the above embodiments, R 2 Or each R 2A , R 2B , R 2C and R 2D is optionally substituted C5-C 20 alkyl.

[0224] The compounds of the present invention are (e.g., a) compounds of formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc), or b) compounds of formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II'a), (III'a), In an embodiment of (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, each a is independently selected from 2, 3, and 4, and R 2 Or each R 2A , R 2B , R 2C and R 2Dare independently selected from optionally substituted alkyl, where optionally substituted alkyl is selected from -OC(=O)R aa wherein each R aa is independently selected from optionally substituted alkyl. In some embodiments, the optionally substituted alkyl is —OC(═O)R aa C is replaced by 1~20 alkyl, wherein each R aa are optionally substituted C1 to C 50 In some embodiments, the optionally substituted alkyl is independently selected from -OC(=O)R aa C is replaced by 1~10 alkyl, wherein each R aa are optionally substituted C1 to C 50 In some embodiments, the optionally substituted alkyl is independently selected from -OC(=O)R aa C is replaced by 1~5 alkyl, wherein each R aa are optionally substituted C1 to C 50 alkyl.

[0225] The compounds of the present invention are (e.g., a) compounds of formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc), or b) compounds of formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II'a), (III'a), In an embodiment of (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, each a is independently selected from 2, 3, and 4, and R 2 Or each R 2A , R 2B , R 2C and R 2D is independently selected from optionally substituted alkyl, where optionally substituted alkyl is —COR aa wherein each R aa is independently selected from optionally substituted alkyl. In some embodiments, the optionally substituted alkyl is —COR aa C is replaced by 1~20 alkyl, wherein each R aa are optionally substituted C1 to C 50 In some embodiments, the optionally substituted alkyl is independently selected from -COR aa C is replaced by 1~10 alkyl, wherein each R aa are optionally substituted C1 to C 50In some embodiments, the optionally substituted alkyl is independently selected from -COR aa C is replaced by 1~5 alkyl, wherein each R aa are optionally substituted C1 to C 50 alkyl.

[0226] In any of the above embodiments, R aa are optionally substituted C1 to C 40 In any of the above embodiments, R aa are optionally substituted C1 to C 30 In any of the above embodiments, R aa are optionally substituted C1 to C 25 In any of the above embodiments, R aa are optionally substituted C1 to C 20 In any of the above embodiments, R aa are optionally substituted C1 to C 15 In any of the above embodiments, R aa are optionally substituted C1 to C 10 In any of the above embodiments, R aa are independently selected from optionally substituted C2-C8 alkyl. In any of the above embodiments, R aa are independently selected from optionally substituted C3-C7 alkyl.

[0227] The compounds of the present invention are (e.g., a) compounds of formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc), or b) compounds of formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II'a), (III'a), In an embodiment of (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, each a is independently selected from 2, 3, and 4, and R 2 Or each R 2A , R 2B , R 2C and R 2D is C8H 17 , C 10 H 21 , C 12 H 25 , C 14 H 29 , C 16 H 33 , C 16 H 31 , C 16 H 29 , and C 16 H 27 are independently selected from

[0228] The compounds of the present invention are (e.g., a) compounds of formula (II'), (IV'), (VI'), (VII'), (II), (IV), (VI), (VII), (IIa), (IVa), (VIa), (VIIa), (IIb), (VIb), (IIc), (IVc), (VIc) or (VIIc), or b) compounds of formula (IId), (IVd), (VId), (VIId), (II'a), (II'z), (IV' In embodiments of (IIz), (VI'z), (VII'z), (IIz), (IVz), (VIz), (VIIz), (IIaz), (IVaz), (VIaz), (VIIaz), (IIbz), (VIbz), (IIcz), (IVcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, each a is independently selected from 3 and 4; c is 3; and R 2 Or each R 2A , R 2B , R 2C and R 2D is C8H 17 , C 10 H 21 , C 12 H 25 , C 14 H 29 , C 16 H 33 , C 16 H 31 , C 16 H 29 , and C 16 H 27 are independently selected from

[0229] The compounds of the present invention are (e.g., a) compounds of formula (II'), (IV'), (VI'), (VII'), (II), (IV), (VI), (VII), (IIa), (IVa), (VIa), (VIIa), (IIb), (VIb), (IIc), (IVc), (VIc) or (VIIc), or b) compounds of formula (IId), (IVd), (VId), (VIId), (II'a), (II'z), (IV' In embodiments of (IIz), (VI'z), (VII'z), (IIz), (IVz), (VIz), (VIIz), (IIaz), (IVaz), (VIaz), (VIIaz), (IIbz), (VIbz), (IIcz), (IVcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, each a is independently selected from 3 and 4; c is 4; and R 2 Or each R 2A , R 2B , R 2C and R 2D is C8H 17 , C 10 H 21 , C 12 H 25 , C 14 H 29 , C 16 H 33 , C 16 H 31 , C 16 H 29 , and C 16 H 27 are independently selected from

[0230] The compounds of the present invention are (e.g., a) compounds of formula (II'), (IV'), (VI'), (VII'), (II), (IV), (VI), (VII), (IIa), (IVa), (VIa), (VIIa), (IIb), (VIb), (IIc), (IVc), (VIc) or (VIIc), or b) compounds of formula (IId), (IVd), (VId), (VIId), (II'a), (II'z), (IV'z), (VI'z), (VI In an embodiment of (IIz), (IIz), (IVz), (VIz), (VIIz), (IIaz), (IVaz), (VIaz), (VIIaz), (IIbz), (VIbz), (IIcz), (IVcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, the value of a on the left side of the depicted formula is 3 and the value of a on the right side of the depicted formula is 4, c is 3, and R 2 Or each R 2A , R 2B , R 2C and R 2D is C8H 17 , C 10 H 21 , C 12 H 25 , C 14 H 29 , C 16 H 33 , C 16 H 31 , C 16 H 29 , and C 16 H 27 are independently selected from

[0231] The compounds of the present invention are (e.g., a) compounds of formula (II'), (IV'), (VI'), (VII'), (II), (IV), (VI), (VII), (IIa), (IVa), (VIa), (VIIa), (IIb), (VIb), (IIc), (IVc), (VIc) or (VIIc), or b) compounds of formula (IId), (IVd), (VId), (VIId), (II'a), (II'z), (IV'z), (VI'z), (VI In an embodiment of (IIz), (IIz), (IVz), (VIz), (VIIz), (IIaz), (IVaz), (VIaz), (VIIaz), (IIbz), (VIbz), (IIcz), (IVcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, the value of a on the left side of the depicted formula is 3 and the value of a on the right side of the depicted formula is 4, c is 4, and R 2 Or each R 2A , R 2B , R 2C and R 2D is C8H 17 , C 10 H 21 , C 12 H 25 , C 14 H 29 , C 16 H 33 , C 16 H 31 , C 16 H 29 , and C 16 H 27 are independently selected from

[0232] (e.g., a) formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc), or b) formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II'a), (I In embodiments of II'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, each a is 3 and R 2 Or each R 2A , R 2B , R 2C and R 2D is C8H 17 , C 10 H 21 , C 12 H 25 , C 14 H 29 , C 16 H 33 , C 16 H 31 , C 16 H 29 , and C 16 H 27 are independently selected from

[0233] (e.g., a) formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc), or b) formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II'a), (I In embodiments of II'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, each a is 3 and R 2 Or each R 2A , R 2B , R 2C and R 2D are independently selected from optionally substituted alkyl, where optionally substituted alkyl is —OC(═O)R aa wherein each R aa is independently selected from optionally substituted alkyl. In some embodiments, the optionally substituted alkyl is —OC(═O)R aa C is replaced by 1~20 alkyl, wherein each R aa are optionally substituted C1 to C 50 In some embodiments, the optionally substituted alkyl is independently selected from -OC(=O)R aa C is replaced by 1~10 alkyl, wherein each R aa are optionally substituted C1 to C 50In some embodiments, the optionally substituted alkyl is independently selected from -OC(=O)R aa C is replaced by 1~5 alkyl, wherein each R aa are optionally substituted C1 to C 50 alkyl.

[0234] (e.g., a) formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc), or b) formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II'a), (I In embodiments of II'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (Ivz), (Vz), (Viz), (VIIz), (Iaz), (Iiaz), (IIIaz), (Ivaz), (Vaz), (Viaz), (VIIaz), (Iibz), (IIIbz), (Vibz), (Icz), (Iicz), (IIIcz), (Ivcz), (Vcz), (Vicz), or (VIIcz), or a pharmaceutically acceptable salt thereof, each a is 3 and R 2 Or each R 2A , R 2B , R 2C and R 2D is independently selected from optionally substituted alkyl, where optionally substituted alkyl is —COR aa wherein each R aa is independently selected from optionally substituted alkyl. In some embodiments, the optionally substituted alkyl is —COR aa C is replaced by 1~20 alkyl, wherein each R aaare optionally substituted C1 to C 50 In some embodiments, the optionally substituted alkyl is independently selected from -COR aa C is replaced by 1~10 alkyl, wherein each R aa are optionally substituted C1 to C 50 In some embodiments, the optionally substituted alkyl is independently selected from -COR aa C is replaced by 1~5 alkyl, wherein each R aa are optionally substituted C1 to C 50 alkyl.

[0235] In any of the above embodiments, R aa are optionally substituted C1 to C 40 In any of the above embodiments, R aa are optionally substituted C1 to C 30 In any of the above embodiments, R aa are optionally substituted C1 to C 25 In any of the above embodiments, R aa are optionally substituted C1 to C 20 In any of the above embodiments, R aa are optionally substituted C1 to C 15 In any of the above embodiments, R aa are optionally substituted C1 to C 10 In any of the above embodiments, R aa are independently selected from optionally substituted C2-C8 alkyl. In any of the above embodiments, R aa are independently selected from optionally substituted C3-C7 alkyl.

[0236] The present invention relates to a compound of formula (e.g., a) formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IVa), (IIb), (Ic), (IIc) or (IVc), or b) formula (Id), (Iid), (Ivd), (I'a), (II'a), (I'z), In an embodiment of (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IVaz), (IIbz), (Icz), (IIcz), or (IVcz), or a pharmaceutically acceptable salt thereof, each a is the same and each R 2 is the same.

[0237] (e.g., a) formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc), or b) formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II'a), (I In embodiments of II'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, each a is 3 and each R 2 or R 2A , R 2B , R 2C and R 2DAt least one of the 10 H 21 is.

[0238] (e.g., a) formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc), or b) formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II'a), (I In embodiments of II'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, each a is 3 and each R 2 or R 2A , R 2B , R 2C and R 2D At least one of the groups is -OC(=O)R aa C is replaced by 1~20 alkyl, wherein each R aa are optionally substituted C1 to C 20 alkyl.

[0239] (e.g., a) formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc), or b) formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II'a), (I In embodiments of II'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, each a is 3 and each R 2 or R 2A , R 2B , R 2C and R 2D At least one of the aa C is replaced by 1~20 alkyl, wherein each R aa are optionally substituted C1 to C 20 alkyl.

[0240] In embodiments, the cationic lipids of the present invention have the structure: [ka] or a pharmaceutically acceptable salt thereof.

[0241] In embodiments, the cationic lipids of the present invention have the structure: [ka] or a pharmaceutically acceptable salt thereof.

[0242] In embodiments, the cationic lipids of the present invention have the structure: [ka] or a pharmaceutically acceptable salt thereof.

[0243] In embodiments, the cationic lipids of the present invention have the structure: [ka] or a pharmaceutically acceptable salt thereof.

[0244] In embodiments, the cationic lipids of the present invention have the structure: [ka] or a pharmaceutically acceptable salt thereof.

[0245] In embodiments, the cationic lipids of the present invention have the structure: [ka] or a pharmaceutically acceptable salt thereof.

[0246] In embodiments, the cationic lipids of the present invention have the structure: [ka] or a pharmaceutically acceptable salt thereof.

[0247] In embodiments, the cationic lipids of the present invention have the structure: [ka] or a pharmaceutically acceptable salt thereof.

[0248] In embodiments, the cationic lipids of the present invention have the structure: [ka] or a pharmaceutically acceptable salt thereof.

[0249] In embodiments, the cationic lipids of the present invention have the structure: [ka] or a pharmaceutically acceptable salt thereof.

[0250] In embodiments, the cationic lipids of the present invention have the structure: [ka] or a pharmaceutically acceptable salt thereof.

[0251] In embodiments, the cationic lipids of the present invention have the structure: [ka] or a pharmaceutically acceptable salt thereof.

[0252] In embodiments, the cationic lipids of the present invention have the structure: [ka] or a pharmaceutically acceptable salt thereof.

[0253] In embodiments, the cationic lipids of the present invention have the structure: [ka] or a pharmaceutically acceptable salt thereof.

[0254] In embodiments, the cationic lipids of the present invention have the structure: [ka] or a pharmaceutically acceptable salt thereof.

[0255] In embodiments, the cationic lipids of the present invention have the structure: [ka] or a pharmaceutically acceptable salt thereof.

[0256] In embodiments, the cationic lipids of the present invention have the structure: [ka] or a pharmaceutically acceptable salt thereof.

[0257] In embodiments, the cationic lipids of the present invention have the structure: [ka] or a pharmaceutically acceptable salt thereof.

[0258] In embodiments, the cationic lipids of the present invention have the structure: [ka] or a pharmaceutically acceptable salt thereof.

[0259] In embodiments, the cationic lipids of the present invention have the structure: [ka] or a pharmaceutically acceptable salt thereof.

[0260] In embodiments, the cationic lipids of the present invention have the structure: [ka] or a pharmaceutically acceptable salt thereof.

[0261] In embodiments, the cationic lipids of the present invention have the structure: [ka] or a pharmaceutically acceptable salt thereof.

[0262] In embodiments, the cationic lipids of the present invention have the structure: [ka] or a pharmaceutically acceptable salt thereof.

[0263] In embodiments, the cationic lipids of the present invention have the structure: [ka] or a pharmaceutically acceptable salt thereof.

[0264] (e.g., a) formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc), or b) formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II'a), (III'a) , (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, each a is independently selected from 2, 3, and 4.

[0265] (e.g., a) formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc), or b) formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II'a), (III'a), ), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, each a is independently selected from 3 and 4.

[0266] The compounds of the present invention are (e.g., a) compounds of formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc), or b) compounds of formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II'a), In an embodiment of (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, each a is different.

[0267] The compounds of the present invention are (e.g., a) compounds of formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc), or b) compounds of formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II'a), (III'a), (I'z), (I In embodiments of (I'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, the value of a on the left side of the depicted formula is less than the value of a on the right side of the depicted formula.

[0268] (e.g., a) formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc), or b) formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II'a), (III'a), (I'z), (II' In an embodiment of (Iz), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, the value of a on the left side of the depicted formula is 3 and the value of a on the right side of the depicted formula is 4.

[0269] The compounds of the present invention are (e.g., a) compounds of formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc), or b) compounds of formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II'a), ( In embodiments of III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, each a is the same.

[0270] The compounds of the present invention are (e.g., a) compounds of formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc), or b) compounds of formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II'a), In embodiments of (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, each a is 3.

[0271] In embodiments of the present invention (e.g., of a) Formula (I'), (II'), (III'), (IV'), (V'), (VI') or (VII'), or b) Formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), or a pharmaceutically acceptable salt thereof), each b is independently selected from 2, 3, 4, 5, 6, and 7.

[0272] In embodiments of the present invention (e.g., of a) Formula (I'), (II'), (III'), (IV'), (V'), (VI') or (VII'), or b) Formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), or a pharmaceutically acceptable salt thereof), each b is the same.

[0273] In embodiments of the present invention (e.g., of a) Formula (I'), (II'), (III'), (IV'), (V'), (VI') or (VII'), or b) Formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), or a pharmaceutically acceptable salt thereof), each b is 3.

[0274] In embodiments of the present invention (e.g., of a) Formula (I'), (II'), (III'), (IV'), (V'), (VI') or (VII'), or b) Formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), or a pharmaceutically acceptable salt thereof), each b is 7.

[0275] The compounds of the present invention are (e.g., a) compounds of formula (II'), (IV'), (VI'), (VII'), (II), (IV), (VI), (VII), (IIa), (IVa), (VIa), (VIIa), (IIb), (VIb), (IIc), (IVc), (VIc) or (VIIc), or b) compounds of formula (IId), (IVd), (VId), (VIId), (II'a), ( In embodiments of (II'z), (IV'z), (VI'z), (VII'z), (IIz), (IVz), (VIz), (VIIz), (IIaz), (IVaz), (VIaz), (VIIaz), (IIbz), (VIbz), (IIcz), (IVcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, c is 3.

[0276] The compounds of the present invention are (e.g., a) compounds of formula (II'), (IV'), (VI'), (VII'), (II), (IV), (VI), (VII), (IIa), (IVa), (VIa), (VIIa), (IIb), (VIb), (IIc), (IVc), (VIc) or (VIIc), or b) compounds of formula (IId), (IVd), (VId), (VIId), (II'a), ( In an embodiment of (II'z), (IV'z), (VI'z), (VII'z), (IIz), (IVz), (VIz), (VIIz), (IIaz), (IVaz), (VIaz), (VIIaz), (IIbz), (VIbz), (IIcz), (IVcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, c is 4.

[0277] The compounds of the present invention are (e.g., a) compounds of formula (II'), (IV'), (VI'), (VII'), (II), (IV), (VI), (VII), (IIa), (IVa), (VIa), (VIIa), (IIb), (VIb), (IIc), (IVc), (VIc) or (VIIc), or b) compounds of formula (IId), (IVd), (VId), (VIId), (II'a), (II'z), (IV'z), (VI'z), (V In embodiments of (II'z), (IIz), (IVz), (VIz), (VIIz), (IIaz), (IVaz), (VIaz), (VIIaz), (IIbz), (VIbz), (IIcz), (IVcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, c is 3, the value of a on the left side of the depicted formula is 3, and the value of a on the right side of the depicted formula is 4.

[0278] The compounds of the present invention are (e.g., a) compounds of formula (II'), (IV'), (VI'), (VII'), (II), (IV), (VI), (VII), (IIa), (IVa), (VIa), (VIIa), (IIb), (VIb), (IIc), (IVc), (VIc) or (VIIc), or b) compounds of formula (IId), (IVd), (VId), (VIId), (II'a), (II'z), (IV'z), (VI'z), (V In embodiments of (II'z), (IIz), (IVz), (VIz), (VIIz), (IIaz), (IVaz), (VIaz), (VIIaz), (IIbz), (VIbz), (IIcz), (IVcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, c is 4, the value of a on the left side of the depicted formula is 3, and the value of a on the right side of the depicted formula is 4.

[0279] In embodiments of the present invention (e.g., of a) Formula (III'), (V'), (VI'), (VII'), (III), (V), (VI) or (VII), or b) Formula (III'z), (V'z), (VI'z), (VII'z), (IIIz), (Vz), (VIz) or (VIIz), or a pharmaceutically acceptable salt thereof), R A and R B are the same, and R C and R D is the same.

[0280] In embodiments of the present invention (e.g., of a) Formula (III'), (V'), (VI'), (VII'), (III), (V), (VI) or (VII), or b) Formula (III'z), (V'z), (VI'z), (VII'z), (IIIz), (Vz), (VIz) or (VIIz), or a pharmaceutically acceptable salt thereof), R A and R C are the same, and R B and R D is the same.

[0281] In embodiments of the invention (e.g., of a) Formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI) or (VII), or b) Formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz) or (VIIz), or a pharmaceutically acceptable salt thereof), R 1 is independently selected from optionally substituted alkyl. In any of the above embodiments, R 1 is optionally substituted C5-C 50 In any of the above embodiments, R 1 is optionally substituted C5-C 40 In any of the above embodiments, R 1 is optionally substituted C5-C 30 In any of the above embodiments, R 1 is optionally substituted C5-C 25 In any of the above embodiments, R 1 is optionally substituted C5-C 20 alkyl.

[0282] In embodiments of the invention (e.g., of a) Formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI) or (VII), or b) Formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz) or (VIIz), or a pharmaceutically acceptable salt thereof), each R 1 is the same.

[0283] In embodiments of the invention (e.g., of a) Formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI) or (VII), or b) Formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz) or (VIIz), or a pharmaceutically acceptable salt thereof), each R 1 is optionally substituted C5-C 20 It is alkyl.

[0284] In embodiments of the present invention (e.g., of a) Formula (I'), (II'), (III'), (IV'), (V'), (VI') or (VII'), or b) Formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), or a pharmaceutically acceptable salt thereof), each a is independently selected from 2, 3, and 4; each b is independently selected from 2, 3, 4, 5, 6, and 7; and R 1 is independently selected from optionally substituted alkyl. In any of the above embodiments, R 1 is optionally substituted C5-C 50 In any of the above embodiments, R 1 is optionally substituted C5-C 40 In any of the above embodiments, R 1 is optionally substituted C5-C 30 In any of the above embodiments, R 1 is optionally substituted C5-C 25 In any of the above embodiments, R 1 is optionally substituted C5-C 20 alkyl.

[0285] In embodiments of the invention (e.g., of a) Formula (I'), (II'), (III'), (IV'), (V'), (VI') or (VII'), or b) Formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), or a pharmaceutically acceptable salt thereof), each a is 3 and each b is independently selected from 2, 3, 4, 5, 6, and 7, and R 1 is independently selected from optionally substituted alkyl. In any of the above embodiments, R 1 is optionally substituted C5-C 50 In any of the above embodiments, R 1 is optionally substituted C5-C 40 In any of the above embodiments, R 1 is optionally substituted C5-C 30 In any of the above embodiments, R 1 is optionally substituted C5-C 25 In any of the above embodiments, R 1 is optionally substituted C5-C 20 alkyl.

[0286] In embodiments of the invention (e.g., of a) Formula (I'), (II'), (III'), (IV'), (V'), (VI') or (VII'), or b) Formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), or a pharmaceutically acceptable salt thereof), each a is 3, each b is independently selected from 2, 3, 4, 5, 6, and 7, and each R 1 is optionally substituted C5-C 20 It is alkyl.

[0287] In an embodiment of the present invention (e.g., a) Formula (I'), (II'), (III'), (IV'), (V'), (VI') or (VII'), or b) Formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), or a pharmaceutically acceptable salt thereof, each a is 3, each b is 3, and each R 1 is optionally substituted C5-C 20 It is alkyl.

[0288] In embodiments of the invention (e.g., of a) Formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI) or (VII), or b) Formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (V)z, (VIz) or (VIIz), or a pharmaceutically acceptable salt thereof), R 1 is independently selected from optionally substituted alkenyl. In any of the above embodiments, R 1 is optionally substituted C5-C 50 In any of the above embodiments, R 1 is optionally substituted C5-C 40 In any of the above embodiments, R 1 is optionally substituted C5-C 30 In any of the above embodiments, R 1 is optionally substituted C5-C 25 In any of the above embodiments, R 1 is optionally substituted C5-C 20 alkenyl.

[0289] In embodiments of the invention (e.g., of a) Formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI) or (VII), or b) Formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (V), (VIz) or (VIIz), or a pharmaceutically acceptable salt thereof), each R 1 is the same.

[0290] In embodiments of the invention (e.g., of a) Formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI) or (VII), or b) Formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz) or (VIIz), or a pharmaceutically acceptable salt thereof), each R 1 is optionally substituted C5-C 20 It is alkenyl.

[0291] In embodiments of the present invention (e.g., of a) Formula (I'), (II'), (III'), (IV'), (V'), (VI') or (VII'), or b) Formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), or a pharmaceutically acceptable salt thereof), each a is independently selected from 2, 3, and 4; each b is independently selected from 2, 3, 4, 5, 6, and 7; and R 1 is independently selected from optionally substituted alkenyl. In any of the above embodiments, R 1 is optionally substituted C5-C 50 In any of the above embodiments, R 1is optionally substituted C5-C 40 In any of the above embodiments, R 1 is optionally substituted C5-C 30 In any of the above embodiments, R 1 is optionally substituted C5-C 25 In any of the above embodiments, R 1 is optionally substituted C5-C 20 alkenyl.

[0292] In embodiments of the invention (e.g., of a) Formula (I'), (II'), (III'), (IV'), (V'), (VI') or (VII'), or b) Formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), or a pharmaceutically acceptable salt thereof), each a is 3 and each b is independently selected from 2, 3, 4, 5, 6, and 7, and R 1 is independently selected from optionally substituted alkenyl. In any of the above embodiments, R 1 is optionally substituted C5-C 50 In any of the above embodiments, R 1 is optionally substituted C5-C 40 In any of the above embodiments, R 1 is optionally substituted C5-C 30 In any of the above embodiments, R 1 is optionally substituted C5-C 25 In any of the above embodiments, R 1 is optionally substituted C5-C 20 alkenyl.

[0293] In embodiments of the invention (e.g., of a) Formula (I'), (II'), (III'), (IV'), (V'), (VI') or (VII'), or b) Formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), or a pharmaceutically acceptable salt thereof), each a is 3, each b is independently selected from 2, 3, 4, 5, 6, and 7, and each R 1 is optionally substituted C5-C 20 It is alkenyl.

[0294] In an embodiment of the present invention (e.g., a) Formula (I'), (II'), (III'), (IV'), (V'), (VI') or (VII'), or b) Formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), or a pharmaceutically acceptable salt thereof, each a is 3, each b is 7, and each R 1 is optionally substituted C5-C 20 It is alkenyl.

[0295] In some embodiments (e.g., a) a compound of formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc) or b) a compound of formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II'a) , (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof).In some embodiments (e.g., a) a compound of formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc) or b) a compound of formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II'a) , (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof).In some embodiments (e.g., a) a compound of formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc) or b) a compound of formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II'a) , (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof).

[0296] In the above embodiments (e.g., a) a compound of formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc) or b) a compound of formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II'a), (I In any of the compounds of formula II'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, each a is the same.

[0297] In the above embodiments (e.g., a) a compound of formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc) or b) a compound of formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II'a), ( In any of the compounds of formula III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, each a is different.

[0298] In any of the above embodiments (e.g., a) a compound of Formula (I'), (II'), (III'), (IV'), (V'), (VI') or (VII') or b) a compound of Formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), or a pharmaceutically acceptable salt thereof), each b is independently selected from 2, 3, 4, 5, 6 and 7.

[0299] In some embodiments (e.g., a) a compound of Formula (I'), (II'), (III'), (IV'), (V'), (VI') or (VII') or b) a compound of Formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), or a pharmaceutically acceptable salt thereof), each b is 2. In some embodiments (e.g., a) a compound of Formula (I'), (II'), (III'), (IV'), (V'), (VI') or (VII') or b) a compound of Formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), or a pharmaceutically acceptable salt thereof), each b is 3. In some embodiments (e.g., a) a compound of Formula (I'), (II'), (III'), (IV'), (V'), (VI') or (VII') or b) a compound of Formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), or a pharmaceutically acceptable salt thereof), each b is 4. In some embodiments (e.g., a) a compound of Formula (I'), (II'), (III'), (IV'), (V'), (VI') or (VII') or b) a compound of Formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), or a pharmaceutically acceptable salt thereof), each b is 5. In some embodiments (e.g., a) a compound of Formula (I'), (II'), (III'), (IV'), (V'), (VI'), or (VII') or b) a compound of Formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), or a pharmaceutically acceptable salt thereof), each b is 6. In some embodiments (e.g., a) a compound of Formula (I'), (II'), (III'), (IV'), (V'), (VI'), or (VII') or b) a compound of Formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), or a pharmaceutically acceptable salt thereof), each b is 7.

[0300] In any of the above embodiments (e.g., a) a compound of formula (I'), (II'), (III'), (IV'), (V'), (VI') or (VII') or b) a compound of formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), or a pharmaceutically acceptable salt thereof), each b is the same.

[0301] In any of the above embodiments (e.g., a) a compound of formula (I'), (II'), (III'), (IV'), (V'), (VI') or (VII') or b) a compound of formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), or a pharmaceutically acceptable salt thereof), each b is different.

[0302] In the embodiment, A 1 teeth, [ka] The left side of each structure depicted here is selected from -(CH2) a - is bonded to.

[0303] In the embodiment, A 1 teeth [ka] The left side of each structure shown here is -(CH2) a In one embodiment, A 1 teeth [ka] The left side of each structure shown here is -(CH2) a In one embodiment, A 1 is -SS-.

[0304] In the embodiment, Z1 teeth, [ka] The right side of each structure depicted here is selected from -(CH2) a - is bonded to.

[0305] In the embodiment, Z 1 teeth [ka] and the right side of each structure shown here is -(CH2) a In embodiments, Z 1 teeth [ka] and the right side of each structure shown here is -(CH2) a In embodiments, Z 1 is -SS-.

[0306] In the embodiment, A 1 teeth [ka] The left side of each structure shown here is -(CH2) a - and Z 1 teeth [ka] and the right side of each structure shown here is -(CH2) a - is bonded to.

[0307] In the embodiment, A 1 teeth [ka] The left side of each structure shown here is -(CH2) a - and Z 1 teeth [ka] and the right side of each structure shown here is -(CH2) a - is bonded to.

[0308] In the embodiment, A 1 teeth [ka] The left side of each structure shown here is -(CH2) a - and Z 1 is -SS-.

[0309] In the embodiment, A 1 and Z 1 are each -SS-.

[0310] In embodiments of the present invention (e.g., of a) Formula (III'), (V'), (VI'), (VII'), (III), (V), (VI) or (VII), or b) Formula (III'z), (V'z), (VI'z), (VII'z), (IIIz), (Vz), (VIz) or (VIIz), or a pharmaceutically acceptable salt thereof), R A and R B are the same, and R C and R D is the same.

[0311] In embodiments of the present invention (e.g., of a) Formula (III'), (V'), (VI'), (VII'), (III), (V), (VI) or (VII), or b) Formula (III'z), (V'z), (VI'z), (VII'z), (IIIz), (Vz), (VIz) or (VIIz), or a pharmaceutically acceptable salt thereof), R A and R C are the same, and R B and R D is the same.

[0312] In any of the above embodiments (e.g., a) a compound of Formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI) or (VII); or b) a compound of Formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz) or (VIIz), or a pharmaceutically acceptable salt thereof), each R 1 is the same.

[0313] In any of the above embodiments (e.g., a) a compound of Formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI) or (VII); or b) a compound of Formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz) or (VIIz), or a pharmaceutically acceptable salt thereof), each R 1 is different.

[0314] In any of the above embodiments (e.g., a) a compound of Formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI) or (VII); or b) a compound of Formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz) or (VIIz), or a pharmaceutically acceptable salt thereof), each R 1 teeth, [ka] are independently selected from

[0315] In any of the above embodiments (e.g., a) a compound of Formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI) or (VII); or b) a compound of Formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz) or (VIIz), or a pharmaceutically acceptable salt thereof), each R 1 teeth, [ka] are independently selected from

[0316] In any of the above embodiments (e.g., a) a compound of Formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI) or (VII); or b) a compound of Formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz) or (VIIz), or a pharmaceutically acceptable salt thereof), each R 1 teeth, [ka] are independently selected from

[0317] In any of the above embodiments (e.g., a) a compound of Formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI) or (VII); or b) a compound of Formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz) or (VIIz), or a pharmaceutically acceptable salt thereof), each R 1 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, -optionally substituted alkyl-(C═O)—O-optionally substituted alkyl, or -optionally substituted alkyl-O—(C═O)-optionally substituted alkyl.

[0318] In any of the above embodiments (e.g., a) a compound of Formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI) or (VII); or b) a compound of Formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz) or (VIIz), or a pharmaceutically acceptable salt thereof), each R 1 is optionally substituted C5-C 50 Alkyl, optionally substituted C5-C 50 Alkenyl, optionally substituted C5-C 50 Alkynyl, optionally substituted C-C 25 Alkyl-(C=O)-O-optionally substituted C2-C 25 alkyl, or optionally substituted C-C 25 Alkyl-O-(C=O)-optionally substituted C2-C 25 alkyl.

[0319] In any of the above embodiments (e.g., a) a compound of Formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI) or (VII); or b) a compound of Formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz) or (VIIz), or a pharmaceutically acceptable salt thereof), each R 1 is optionally substituted C5-C 40 Alkyl, optionally substituted C5-C 40 Alkenyl, optionally substituted C5-C 40 Alkynyl, optionally substituted C-C 20 Alkyl-(C=O)-O-optionally substituted C2-C 20 alkyl, or optionally substituted C-C 20 Alkyl-O-(C=O)-optionally substituted C2-C 20 alkyl.

[0320] In any of the above embodiments (e.g., a) a compound of Formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI) or (VII); or b) a compound of Formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz) or (VIIz), or a pharmaceutically acceptable salt thereof), each R 1 is optionally substituted C5-C 30 Alkyl, optionally substituted C5-C 30 Alkenyl, optionally substituted C5-C 30 Alkynyl, optionally substituted C-C 15 Alkyl-(C=O)-O-optionally substituted C2-C15 alkyl, or optionally substituted C-C 15 Alkyl-O-(C=O)-optionally substituted C2-C 15 alkyl.

[0321] In any of the above embodiments (e.g., a) a compound of Formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI) or (VII); or b) a compound of Formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz) or (VIIz), or a pharmaceutically acceptable salt thereof), each R 1 is optionally substituted C5-C 25 Alkyl, optionally substituted C5-C 25 Alkenyl, optionally substituted C5-C 25 Alkynyl, optionally substituted C-C 15 Alkyl-(C=O)-O-optionally substituted C2-C 15 alkyl, or optionally substituted C-C 15 Alkyl-O-(C=O)-optionally substituted C2-C 15 alkyl.

[0322] In any of the above embodiments (e.g., a) a compound of Formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI) or (VII); or b) a compound of Formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz) or (VIIz), or a pharmaceutically acceptable salt thereof), each R 1 is optionally substituted C5-C20 Alkyl, optionally substituted C5-C 20 Alkenyl, optionally substituted C5-C 20 Alkynyl, optionally substituted C-C 10 Alkyl-(C=O)-O-optionally substituted C2-C 10 alkyl, or optionally substituted C-C 10 Alkyl-O-(C=O)-optionally substituted C2-C 10 alkyl.

[0323] In any of the above embodiments (e.g., a) a compound of Formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI) or (VII); or b) a compound of Formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz) or (VIIz), or a pharmaceutically acceptable salt thereof), each R 1 is independently selected from optionally substituted alkyl. In any of the above embodiments (e.g., a) a compound of Formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI) or (VII), or b) a compound of Formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz) or (VIIz), or a pharmaceutically acceptable salt thereof), each R 1 is optionally substituted C5-C 50In any of the above embodiments (e.g., a) a compound of Formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI) or (VII), or b) a compound of Formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz) or (VIIz), or a pharmaceutically acceptable salt thereof), each R 1 is optionally substituted C5-C 40 In any of the above embodiments (e.g., a) a compound of Formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI) or (VII), or b) a compound of Formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz) or (VIIz), or a pharmaceutically acceptable salt thereof), each R 1 is optionally substituted C5-C 30 In any of the above embodiments (e.g., a) a compound of Formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI) or (VII), or b) a compound of Formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz) or (VIIz), or a pharmaceutically acceptable salt thereof), each R 1 is optionally substituted C5-C 25In any of the above embodiments (e.g., a) a compound of Formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI) or (VII), or b) a compound of Formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz) or (VIIz), or a pharmaceutically acceptable salt thereof), each R 1 is optionally substituted C5-C 20 alkyl.

[0324] In any of the above embodiments (e.g., a) a compound of Formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI); or b) a compound of Formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz) or (VIIz), or (VII), or a pharmaceutically acceptable salt thereof), each R 1 is independently selected from optionally substituted alkenyl. In any of the above embodiments (e.g., a) a compound of Formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI) or (VII), or b) a compound of Formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz) or (VIIz), or a pharmaceutically acceptable salt thereof), each R 1 is optionally substituted C5-C 50In any of the above embodiments (e.g., a) a compound of Formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI) or (VII), or b) a compound of Formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz) or (VIIz), or a pharmaceutically acceptable salt thereof), each R 1 is optionally substituted C5-C 40 In any of the above embodiments (e.g., a) a compound of Formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI) or (VII), or b) a compound of Formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz) or (VIIz), or a pharmaceutically acceptable salt thereof), each R 1 is optionally substituted C5-C 30 In any of the above embodiments (e.g., a) a compound of Formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI) or (VII), or b) a compound of Formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz) or (VIIz), or a pharmaceutically acceptable salt thereof), each R 1 is optionally substituted C5-C 25In any of the above embodiments (e.g., a) a compound of Formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI) or (VII), or b) a compound of Formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz) or (VIIz), or a pharmaceutically acceptable salt thereof), each R 1 is optionally substituted C5-C 20 alkenyl.

[0325] In any of the above embodiments (e.g., a) a compound of Formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI) or (VII); or b) a compound of Formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz) or (VIIz), or a pharmaceutically acceptable salt thereof), each R 1 is independently selected from optionally substituted alkynyl. In any of the above embodiments (e.g., a) a compound of Formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI) or (VII), or b) a compound of Formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz) or (VIIz), or a pharmaceutically acceptable salt thereof), each R 1 is optionally substituted C5-C 50In any of the above embodiments (e.g., a) a compound of Formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI) or (VII), or b) a compound of Formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz) or (VIIz), or a pharmaceutically acceptable salt thereof), each R 1 is optionally substituted C5-C 40 In any of the above embodiments (e.g., a) a compound of Formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI) or (VII), or b) a compound of Formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz) or (VIIz), or a pharmaceutically acceptable salt thereof), each R 1 is optionally substituted C5-C 30 In any of the above embodiments (e.g., a) a compound of Formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI) or (VII), or b) a compound of Formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz) or (VIIz), or a pharmaceutically acceptable salt thereof), each R 1 is optionally substituted C5-C 25In any of the above embodiments (e.g., a) a compound of Formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI) or (VII), or b) a compound of Formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz) or (VIIz), or a pharmaceutically acceptable salt thereof), each R 1 is optionally substituted C5-C 20 alkynyl.

[0326] In any of the above embodiments (e.g., a) a compound of Formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI) or (VII); or b) a compound of Formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz) or (VIIz), or a pharmaceutically acceptable salt thereof), each R 1 is independently selected from -optionally substituted alkyl-(C═O)—O-optionally substituted alkyl. In any of the above embodiments (e.g., a) a compound of Formula (I′), (II′), (III′), (IV′), (V′), (VI′), (VII′), (I), (II), (III), (IV), (V), (VI) or (VII), or b) a compound of Formula (I′a), (II′a), (III′a), (I′z), (II′z), (III′z), (IV′z), (V′z), (VI′z), (VII′z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz) or (VIIz), or a pharmaceutically acceptable salt thereof), each R 1 -Optionally substituted C2 to C 25 Alkyl-(C=O)-O-optionally substituted C2-C25 In any of the above embodiments (e.g., a) a compound of Formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI) or (VII), or b) a compound of Formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz) or (VIIz), or a pharmaceutically acceptable salt thereof), each R 1 -Optionally substituted C2 to C 20 Alkyl-(C=O)-O-optionally substituted C2-C 20 In any of the above embodiments (e.g., a) a compound of Formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI) or (VII), or b) a compound of Formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz) or (VIIz), or a pharmaceutically acceptable salt thereof), each R 1 -Optionally substituted C2 to C 15 Alkyl-(C=O)-O-optionally substituted C2-C 15 In any of the above embodiments (e.g., a) a compound of Formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI) or (VII), or b) a compound of Formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz) or (VIIz), or a pharmaceutically acceptable salt thereof), each R 1 -Optionally substituted C2 to C10 Alkyl-(C=O)-O-optionally substituted C2-C 10 alkyl.

[0327] In any of the above embodiments (e.g., a) a compound of Formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI) or (VII); or b) a compound of Formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz) or (VIIz), or a pharmaceutically acceptable salt thereof), each R 1 is independently selected from -optionally substituted alkyl-O-(C=O)-optionally substituted alkyl. In any of the above embodiments (e.g., a) a compound of Formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI) or (VII), or b) a compound of Formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz) or (VIIz), or a pharmaceutically acceptable salt thereof), each R 1 -Optionally substituted C2 to C 25 Alkyl-O-(C=O)-optionally substituted C2-C 25In any of the above embodiments (e.g., a) a compound of Formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI) or (VII), or b) a compound of Formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz) or (VIIz), or a pharmaceutically acceptable salt thereof), each R 1 -Optionally substituted C2 to C 20 Alkyl-O-(C=O)-optionally substituted C2-C 20 In any of the above embodiments (e.g., a) a compound of Formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI) or (VII), or b) a compound of Formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz) or (VIIz), or a pharmaceutically acceptable salt thereof), each R 1 -Optionally substituted C2 to C 15 Alkyl-O-(C=O)-optionally substituted C2-C 15 In any of the above embodiments (e.g., a) a compound of Formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI) or (VII), or b) a compound of Formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz) or (VIIz), or a pharmaceutically acceptable salt thereof), each R 1 -Optionally substituted C2 to C 10Alkyl-O-(C=O)-optionally substituted C2-C 10 alkyl.

[0328] In any of the above embodiments (e.g., a) a compound of Formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI) or (VII); or b) a compound of Formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz) or (VIIz), or a pharmaceutically acceptable salt thereof), each R 1 is C8H 17 , C 10 H 21 , C 12 H 25 , C 14 H 29 , C 16 H 33 , C 18 H 37 , C 18 H 35 , C 18 H 33 , and C 18 H 31 are independently selected from

[0329] In any of the above embodiments (e.g., a) a compound of formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI) or (VII); or b) a compound of formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz) or (VIIz), or a pharmaceutically acceptable salt thereof), R 1 is C8H 17 is.

[0330] In any of the above embodiments (e.g., a) a compound of formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI) or (VII); or b) a compound of formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz) or (VIIz), or a pharmaceutically acceptable salt thereof), R 1 is C 10 H 21 is.

[0331] In any of the above embodiments (e.g., a) a compound of formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI) or (VII); or b) a compound of formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz) or (VIIz), or a pharmaceutically acceptable salt thereof), R 1 is C 12 H 25 is.

[0332] In any of the above embodiments (e.g., a) a compound of formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI) or (VII); or b) a compound of formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz) or (VIIz), or a pharmaceutically acceptable salt thereof), R 1 is C 14 H 29 is.

[0333] In any of the above embodiments (e.g., a) a compound of formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI) or (VII); or b) a compound of formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz) or (VIIz), or a pharmaceutically acceptable salt thereof), R 1 is C 16 H 33 is.

[0334] In any of the above embodiments (e.g., a) a compound of formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI) or (VII); or b) a compound of formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz) or (VIIz), or a pharmaceutically acceptable salt thereof), R 1 is C 18 H 37 is.

[0335] In any of the above embodiments (e.g., a) a compound of formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI) or (VII); or b) a compound of formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz) or (VIIz), or a pharmaceutically acceptable salt thereof), R 1 is C 18 H 35 is.

[0336] In any of the above embodiments (e.g., a) a compound of formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI) or (VII); or b) a compound of formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz) or (VIIz), or a pharmaceutically acceptable salt thereof), R 1 is C 18 H 33 is.

[0337] In any of the above embodiments (e.g., a) a compound of formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI) or (VII); or b) a compound of formula (I'a), (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz) or (VIIz), or a pharmaceutically acceptable salt thereof), R 1 is C 18 H 31 is.

[0338] The above embodiments (e.g., a) formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IVa), (IIb), (Ic), (IIc) or (IVc), or b) formula (Id), (IId), (IVd), (I'a), (II'a), ( In any of the compounds of formula (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IVaz), (IIbz), (Icz), (IIcz), or (IVcz), or a pharmaceutically acceptable salt thereof, each R 2 is the same.

[0339] The above embodiments (e.g., a) formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IVa), (IIb), (Ic), (IIc) or (IVc), or b) formula (Id), (IId), (IVd), (I'a), (II'a), ( In any of the compounds of formula (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IVaz), (IIbz), (Icz), (IIcz), or (IVcz), or a pharmaceutically acceptable salt thereof, each R 2 is different.

[0340] The above embodiments (e.g., a) formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IVa), (IIb), (Ic), (IIc) or (IVc), or b) formula (Id), (IId), (IVd), (I'a), (II'a), ( In any of the compounds of formula (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IVaz), (IIbz), (Icz), (IIcz), or (IVcz), or a pharmaceutically acceptable salt thereof), R 2 At least two of them are the same.

[0341] In embodiments of the present invention (e.g., of a) Formula (IIIa), (Va), (VIa), (VIIa), (IIIb), (VIb), (IIIc), (Vc), (VIc) or (VIIc), or b) Formula (IIId), (Vd), (VId), (VIId), (IIIaz), (Vaz), (VIaz), (VIIaz), (IIIbz), (VIbz), (IIIcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof), R 2A and R 2B are the same, and R 2C and R 2D is the same.

[0342] In embodiments of the present invention (e.g., of a) Formula (IIIa), (Va), (VIa), (VIIa), (IIIb), (VIb), (IIIc), (Vc), (VIc) or (VIIc), or b) Formula (IIId), (Vd), (VId), (VIId), (IIIaz), (Vaz), (VIaz), (VIIaz), (IIIbz), (VIbz), (IIIcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof), R 2A and R 2B are the same, and R 2C and R2D is different.

[0343] In embodiments of the present invention (e.g., of a) Formula (IIIa), (Va), (VIa), (VIIa), (IIIb), (VIb), (IIIc), (Vc), (VIc) or (VIIc), or b) Formula (IIId), (Vd), (VId), (VIId), (IIIaz), (Vaz), (VIaz), (VIIaz), (IIIbz), (VIbz), (IIIcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof), R 2A and R 2B is different, and R 2C and R 2D is the same.

[0344] In embodiments of the present invention (e.g., of a) Formula (IIIa), (Va), (VIa), (VIIa), (IIIb), (VIb), (IIIc), (Vc), (VIc) or (VIIc), or b) Formula (IIId), (Vd), (VId), (VIId), (IIIaz), (Vaz), (VIaz), (VIIaz), (IIIbz), (VIbz), (IIIcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof), R 2A and R 2C are the same, and R 2B and R 2D is the same.

[0345] The above embodiments (e.g., a) formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc), or b) formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II'a), (II'a), ), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof), each R 2 Or each R 2A , R 2B , R 2C and R 2D teeth, [ka] are independently selected from

[0346] The above embodiments (e.g., a) formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc), or b) formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II'a), (II'a), ), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof), each R 2 Or each R 2A , R 2B , R 2C and R 2D teeth, [ka] are independently selected from

[0347] The above embodiments (e.g., a) formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc), or b) formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II'a), (II'a), ), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof), each R 2 Or each R 2A , R 2B , R 2C and R 2D teeth, [ka] are independently selected from

[0348] The above embodiments (for example, a) formula (I’), (II’), (III’), (IV’), (V’), (VI’), (VII’), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc), or b) formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I’a), (II’a), (III’a), (I’z), (II’z), (III’z), (IV’z), (V’z), (VI’z), (VII’z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz) or (VIIcz), and their pharmaceutically acceptable salts), R 2 or each R 2A , R 2B , R 2C and R 2Dare independently selected from optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl. The above embodiments (e.g., a) formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc), or b) formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II' In any of the compounds of formula (I), (II'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, R 2 Or each R 2A , R 2B , R 2C and R 2Dis independently selected from optionally substituted alkyl. In embodiments (e.g., a) formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc), or b) formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II (II'a), (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof), 2 Or each R 2A , R 2B , R 2C and R 2D is optionally substituted C5-C 50and b) a group selected from the group consisting of alkyl, alkyl, and alkyl groups ... In any of the compounds of formula (I), (II'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, R 2 Or each R 2A , R 2B , R 2C and R 2D is optionally substituted C5-C 40and b) a group selected from the group consisting of alkyl, alkyl, and alkyl groups ... In any of the compounds of formula (I), (II'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, R 2 Or each R 2A , R 2B , R 2C and R 2D is optionally substituted C5-C 30and b) a group selected from the group consisting of alkyl, alkyl, and alkyl groups ... In any of the compounds of formula (I), (II'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, R 2 Or each R 2A , R 2B , R 2C and R 2D is optionally substituted C5-C 25 In any of the above embodiments, R 2 Or each R 2A , R 2B , R 2C and R 2D is optionally substituted C5-C 20 alkyl.

[0349] The above embodiments (e.g., a) formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc), or b) formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II' In any of the compounds of formula (I), (II'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, R 2 Or each R 2A , R 2B , R 2C and R 2Dis independently selected from optionally substituted alkenyl. The above embodiments (e.g., a) formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc), or b) formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II' In any of the compounds of formula (I), (II'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, R 2 Or each R 2A , R 2B , R 2C and R 2D is optionally substituted C5-C 50alkenyl. In the above embodiments (e.g., a) formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc), or b) formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II' In any of the compounds of formula (I), (II'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, R 2 Or each R 2A , R 2B , R 2C and R 2D is optionally substituted C5-C 40alkenyl. In the above embodiments (e.g., a) formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc), or b) formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II' In any of the compounds of formula (I), (II'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, R 2 Or each R 2A , R 2B , R 2C and R 2D is optionally substituted C5-C 30alkenyl. In the above embodiments (e.g., a) formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc), or b) formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II' In any of the compounds of formula (I), (II'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, R 2 Or each R 2A , R 2B , R 2C and R 2D is optionally substituted C5-C 25alkenyl. In the above embodiments (e.g., a) formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc), or b) formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II' In any of the compounds of formula (I), (II'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, R 2 Or each R 2A , R 2B , R 2C and R 2D is optionally substituted C5-C 20 alkenyl.

[0350] The above embodiments (e.g., a) formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc), or b) formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II' In any of the compounds of formula (I), (II'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, R 2 Or each R 2A , R 2B , R 2C and R 2Dis independently selected from optionally substituted alkynyl. The above embodiments (e.g., a) formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc), or b) formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II' In any of the compounds of formula (I), (II'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, R 2 Or each R 2A , R 2B , R 2C and R 2D is optionally substituted C5-C 50alkynyl. In the above embodiments (e.g., a) formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc), or b) formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II' In any of the compounds of formula (I), (II'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, R 2 Or each R 2A , R 2B , R 2C and R 2D is optionally substituted C5-C 40alkynyl. In the above embodiments (e.g., a) formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc), or b) formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II' In any of the compounds of formula (I), (II'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, R 2 Or each R 2A , R 2B , R 2C and R 2D is optionally substituted C5-C 30alkynyl. In the above embodiments (e.g., a) formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc), or b) formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II' In any of the compounds of formula (I), (II'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, R 2 Or each R 2A , R 2B , R 2C and R 2D is optionally substituted C5-C 25alkynyl. In the above embodiments (e.g., a) formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc), or b) formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II' In any of the compounds of formula (I), (II'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, R 2 Or each R 2A , R 2B , R 2C and R 2D is optionally substituted C5-C 20 alkynyl.

[0351] The above embodiments (e.g., a) formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc), or b) formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II' In any of the compounds of formula (I), (II'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, R 2 Or each R 2A , R 2B , R 2C and R 2Dis independently selected from optionally substituted acyl. The above embodiments (e.g., a) formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc), or b) formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II' In any of the compounds of formula (I), (II'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, R 2 Or each R 2A , R 2B , R 2C and R 2D is optionally substituted C5-C 50In the above embodiments (e.g., a) formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc), or b) formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II' In any of the compounds of formula (I), (II'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, R 2 Or each R 2A , R 2B , R 2C and R 2D is optionally substituted C5-C 40In the above embodiments (e.g., a) formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc), or b) formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II' In any of the compounds of formula (I), (II'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, R 2 Or each R 2A , R 2B , R 2C and R 2D is optionally substituted C5-C 30In the above embodiments (e.g., a) formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc), or b) formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II' In any of the compounds of formula (I), (II'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, R 2 Or each R 2A , R 2B , R 2C and R 2D is optionally substituted C5-C 25In the above embodiments (e.g., a) formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc), or b) formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II' In any of the compounds of formula (I), (II'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, R 2 Or each R 2A , R 2B , R 2C and R 2D is optionally substituted C5-C 20 acyl.

[0352] The above embodiments (e.g., a) formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc), or b) formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II' In any of the compounds of formula (I), (II'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, R 2 Or each R 2A , R 2B , R 2C and R 2D is C8H 17 , C 10 H 21 , C 12 H 25 , C 14 H 29 , C 16 H 33 , C 16 H 31 , C 16 H 29 , and C 16 H 27 are independently selected from

[0353] The above embodiments (e.g., a) formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc), or b) formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II' In any of the compounds of formula (I), (II'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, R 2 or R 2A , R 2B , R 2C and R 2D At least one of the 17 is.

[0354] The above embodiments (e.g., a) formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc), or b) formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II' In any of the compounds of formula (I), (II'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, R 2 or R 2A , R 2B , R 2C and R 2D At least one of the 10 H 21 is.

[0355] The above embodiments (e.g., a) formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc), or b) formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II' In any of the compounds of formula (I), (II'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, R 2 or R 2A , R 2B , R 2C and R 2D At least one of the 12 H 25 is.

[0356] The above embodiments (e.g., a) formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc), or b) formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II' In any of the compounds of formula (I), (II'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, R 2 or R 2A , R 2B , R 2C and R 2D At least one of the 14 H 29 is.

[0357] The above embodiments (e.g., a) formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc), or b) formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II' In any of the compounds of formula (I), (II'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, R 2 or R 2A , R 2B , R 2C and R 2D At least one of the 16 H 33 is.

[0358] The above embodiments (e.g., a) formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc), or b) formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II' In any of the compounds of formula (I), (II'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, R 2 or R 2A , R 2B , R 2C and R 2D At least one of the 16 H 31 is.

[0359] The above embodiments (e.g., a) formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc), or b) formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II'a) , (III'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof), R or R 2A , R 2B , R 2C and R 2D At least one of the 16 H 29 is.

[0360] The above embodiments (e.g., a) formula (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (I), (II), (III), (IV), (V), (VI), (VII), (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (IIb), (IIIb), (VIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc) or (VIIc), or b) formula (Id), (IId), (IIId), (IVd), (Vd), (VId), (VIId), (I'a), (II' In any of the compounds of formula (I), (II'a), (I'z), (II'z), (III'z), (IV'z), (V'z), (VI'z), (VII'z), (Iz), (IIz), (IIIz), (IVz), (Vz), (VIz), (VIIz), (Iaz), (IIaz), (IIIaz), (IVaz), (Vaz), (VIaz), (VIIaz), (IIbz), (IIIbz), (VIbz), (Icz), (IIcz), (IIIcz), (IVcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof, R 2 or R 2A , R 2B , R 2C and R 2D At least one of the 16 H 27 is.

[0361] In embodiments of the invention (e.g., of a) Formula (IIIa), (Va), (VIa), (VIIa), (IIIb), (VIb), (IIIc), (Vc), (VIc) or (VIIc), or b) Formula (IIId), (Vd), (VId), (VIId), (III'a), (IIIaz), (Vaz), (VIaz), (VIIaz), (IIIbz), (VIbz), (IIIcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof), R 2A and R 2B is C 10 H 21 is.

[0362] In embodiments of the invention (e.g., of a) Formula (IIIa), (Va), (VIa), (VIIa), (IIIb), (VIb), (IIIc), (Vc), (VIc) or (VIIc), or b) Formula (IIId), (Vd), (VId), (VIId), (III'a), (IIIaz), (Vaz), (VIaz), (VIIaz), (IIIbz), (VIbz), (IIIcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof), R 2A teeth [ka] and R 2B teeth [ka] is.

[0363] In embodiments of the invention (e.g., of a) Formula (IIIa), (Va), (VIa), (VIIa), (IIIb), (VIb), (IIIc), (Vc), (VIc) or (VIIc), or b) Formula (IIId), (Vd), (VId), (VIId), (IIIaz), (Vaz), (VIaz), (VIIaz), (IIIbz), (VIbz), (IIIcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof), R 2C and R 2D is C 10 H 21 is.

[0364] In embodiments of the invention (e.g., of a) Formula (IIIa), (Va), (VIa), (VIIa), (IIIb), (VIb), (IIIc), (Vc), (VIc) or (VIIc), or b) Formula (IIId), (Vd), (VId), (VIId), (IIIaz), (Vaz), (VIaz), (VIIaz), (IIIbz), (VIbz), (IIIcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof), R 2C and R 2D teeth, [ka] is.

[0365] In embodiments of the invention (e.g., of a) Formula (IIIa), (Va), (VIa), (VIIa), (IIIb), (VIb), (IIIc), (Vc), (VIc) or (VIIc), or b) Formula (IIId), (Vd), (VId), (VIId), (IIIaz), (Vaz), (VIaz), (VIIaz), (IIIbz), (VIbz), (IIIcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof), R 2C teeth [ka] and R 2D teeth [ka] is.

[0366] In embodiments of the invention (e.g., of a) Formula (IIIa), (Va), (VIa), (VIIa), (IIIb), (VIb), (IIIc), (Vc), (VIc) or (VIIc), or b) Formula (IIId), (Vd), (VId), (VIId), (III'a), (IIIaz), (Vaz), (VIaz), (VIIaz), (IIIbz), (VIbz), (IIIcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof), R 2A and R 2B is C 16 H 31 is.

[0367] In embodiments of the invention (e.g., of a) Formula (IIIa), (Va), (VIa), (VIIa), (IIIb), (VIb), (IIIc), (Vc), (VIc) or (VIIc), or b) Formula (IIId), (Vd), (VId), (VIId), (IIIaz), (Vaz), (VIaz), (VIIaz), (IIIbz), (VIbz), (IIIcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof), R 2C and R 2D is C 16 H 31 is.

[0368] In embodiments of the invention (e.g., of a) Formula (IIIa), (Va), (VIa), (VIIa), (IIIb), (VIb), (IIIc), (Vc), (VIc) or (VIIc), or b) Formula (IIId), (Vd), (VId), (VIId), (IIIaz), (Vaz), (VIaz), (VIIaz), (IIIbz), (VIbz), (IIIcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof), R 2A and R 2B is C 10 H 21 and R 2C and R 2D is C 16 H 31 is.

[0369] In embodiments of the invention (e.g., of a) Formula (IIIa), (Va), (VIa), (VIIa), (IIIb), (VIb), (IIIc), (Vc), (VIc) or (VIIc), or b) Formula (IIId), (Vd), (VId), (VIId), (IIIaz), (Vaz), (VIaz), (VIIaz), (IIIbz), (VIbz), (IIIcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof), R 2A and R 2B is C 16 H 31 and R 2C and R 2D is C10 H 21 is.

[0370] In embodiments of the invention (e.g., of a) Formula (IIIa), (Va), (VIa), (VIIa), (IIIb), (VIb), (IIIc), (Vc), (VIc) or (VIIc), or b) Formula (IIId), (Vd), (VId), (VIId), (IIIaz), (Vaz), (VIaz), (VIIaz), (IIIbz), (VIbz), (IIIcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof), R 2A and R 2C teeth, [ka] is.

[0371] In embodiments of the invention (e.g., of a) Formula (IIIa), (Va), (VIa), (VIIa), (IIIb), (VIb), (IIIc), (Vc), (VIc) or (VIIc), or b) Formula (IIId), (Vd), (VId), (VIId), (IIIaz), (Vaz), (VIaz), (VIIaz), (IIIbz), (VIbz), (IIIcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof), R 2B and R 2D teeth, [ka] is.

[0372] In embodiments of the invention (e.g., of a) Formula (IIIa), (Va), (VIa), (VIIa), (IIIb), (VIb), (IIIc), (Vc), (VIc) or (VIIc), or b) Formula (IIId), (Vd), (VId), (VIId), (IIIaz), (Vaz), (VIaz), (VIIaz), (IIIbz), (VIbz), (IIIcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof), R 2A and R2C teeth [ka] is.

[0373] In embodiments of the invention (e.g., of a) Formula (IIIa), (Va), (VIa), (VIIa), (IIIb), (VIb), (IIIc), (Vc), (VIc) or (VIIc), or b) Formula (IIId), (Vd), (VId), (VIId), (IIIaz), (Vaz), (VIaz), (VIIaz), (IIIbz), (VIbz), (IIIcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof), R 2B and R 2D teeth [ka] is.

[0374] In embodiments of the invention (e.g., of a) Formula (IIIa), (Va), (VIa), (VIIa), (IIIb), (VIb), (IIIc), (Vc), (VIc) or (VIIc), or b) Formula (IIId), (Vd), (VId), (VIId), (IIIaz), (Vaz), (VIaz), (VIIaz), (IIIbz), (VIbz), (IIIcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof), R 2A and R 2C is C 16 H 31 is.

[0375] In embodiments of the invention (e.g., of a) Formula (IIIa), (Va), (VIa), (VIIa), (IIIb), (VIb), (IIIc), (Vc), (VIc) or (VIIc), or b) Formula (IIId), (Vd), (VId), (VIId), (IIIaz), (Vaz), (VIaz), (VIIaz), (IIIbz), (VIbz), (IIIcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof), R2B and R 2D is C 16 H 31 is.

[0376] In embodiments of the invention (e.g., of a) Formula (IIIa), (Va), (VIa), (VIIa), (IIIb), (VIb), (IIIc), (Vc), (VIc) or (VIIc), or b) Formula (IIId), (Vd), (VId), (VIId), (IIIaz), (Vaz), (VIaz), (VIIaz), (IIIbz), (VIbz), (IIIcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof), R 2A and R 2C teeth [ka] and R 2B and R 2D is C 16 H 31 is.

[0377] In embodiments of the invention (e.g., of a) Formula (IIIa), (Va), (VIa), (VIIa), (IIIb), (VIb), (IIIc), (Vc), (VIc) or (VIIc), or b) Formula (IIId), (Vd), (VId), (VIId), (IIIaz), (Vaz), (VIaz), (VIIaz), (IIIbz), (VIbz), (IIIcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof), R 2A and R 2C teeth [ka] and R 2B and R 2D teeth [ka] is.

[0378] In embodiments of the invention (e.g., of a) Formula (IIIa), (Va), (VIa), (VIIa), (IIIb), (VIb), (IIIc), (Vc), (VIc) or (VIIc), or b) Formula (IIId), (Vd), (VId), (VIId), (IIIaz), (Vaz), (VIaz), (VIIaz), (IIIbz), (VIbz), (IIIcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof), R 2A and R 2C is C 16 H 31 and R 2B and R 2D teeth, [ka] is.

[0379] In embodiments of the invention (e.g., of a) Formula (IIIa), (Va), (VIa), (VIIa), (IIIb), (VIb), (IIIc), (Vc), (VIc) or (VIIc), or b) Formula (IIId), (Vd), (VId), (VIId), (IIIaz), (Vaz), (VIaz), (VIIaz), (IIIbz), (VIbz), (IIIcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof), R 2A and R 2B teeth [ka] and R 2C teeth [ka] and R 2D teeth [ka] is.

[0380] In embodiments of the invention (e.g., of a) Formula (IIIa), (Va), (VIa), (VIIa), (IIIb), (VIb), (IIIc), (Vc), (VIc) or (VIIc), or b) Formula (IIId), (Vd), (VId), (VIId), (IIIaz), (Vaz), (VIaz), (VIIaz), (IIIbz), (VIbz), (IIIcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof), R 2A teeth [ka] and R 2B teeth [ka] and R 2C and R 2D teeth [ka] is.

[0381] In embodiments of the invention (e.g., of a) Formula (IIIa), (Va), (VIa), (VIIa), (IIIb), (VIb), (IIIc), (Vc), (VIc) or (VIIc), or b) Formula (IIId), (Vd), (VId), (VIId), (IIIaz), (Vaz), (VIaz), (VIIaz), (IIIbz), (VIbz), (IIIcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof), R 2A and R 2B is optionally substituted alkyl, and R 2C and R 2D is an optionally substituted alkenyl.

[0382] In embodiments of the invention (e.g., of a) Formula (IIIa), (Va), (VIa), (VIIa), (IIIb), (VIb), (IIIc), (Vc), (VIc) or (VIIc), or b) Formula (IIId), (Vd), (VId), (VIId), (IIIaz), (Vaz), (VIaz), (VIIaz), (IIIbz), (VIbz), (IIIcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof), R 2A and R 2B is optionally substituted alkenyl, and R 2C and R 2D is optionally substituted alkyl.

[0383] In embodiments of the invention (e.g., of a) Formula (IIIa), (Va), (VIa), (VIIa), (IIIb), (VIb), (IIIc), (Vc), (VIc) or (VIIc), or b) Formula (IIId), (Vd), (VId), (VIId), (IIIaz), (Vaz), (VIaz), (VIIaz), (IIIbz), (VIbz), (IIIcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof), R 2A and R 2C is -optionally substituted alkyl-(C=O)-O-optionally substituted alkyl, and R 2B and R 2D is an optionally substituted alkenyl.

[0384] In embodiments of the invention (e.g., of a) Formula (IIIa), (Va), (VIa), (VIIa), (IIIb), (VIb), (IIIc), (Vc), (VIc) or (VIIc), or b) Formula (IIId), (Vd), (VId), (VIId), (IIIaz), (Vaz), (VIaz), (VIIaz), (IIIbz), (VIbz), (IIIcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof), R 2A and R 2Cis optionally substituted alkenyl, and R 2B and R 2D is -optionally substituted alkyl-(C=O)-O-optionally substituted alkyl.

[0385] In embodiments of the invention (e.g., of a) Formula (IIIa), (Va), (VIa), (VIIa), (IIIb), (VIb), (IIIc), (Vc), (VIc) or (VIIc), or b) Formula (IIId), (Vd), (VId), (VIId), (III'a), (IIIaz), (Vaz), (VIaz), (VIIaz), (IIIbz), (VIbz), (IIIcz), (Vcz), (VIcz), or (VIIcz), or a pharmaceutically acceptable salt thereof), each R 2A , R 2B , R 2C and R 2D teeth, [ka] are independently selected from

[0386] In embodiments, the optionally substituted alkyl is alkyl substituted with -CO2R" or -OCOR" where each instance of R" is independently C1-C 20 Aliphatic (e.g., a) C1-C 20 Alkyl, C1-C 15 Alkyl, C1-C 10 alkyl, or C1-C3 alkyl; or b) C2-C 20 alkenyl).

[0387] In an embodiment, the optionally substituted alkyl is alkyl substituted with —COR″, where each instance of R″ is independently C1-C 20 Aliphatic (e.g., a) C1-C 20 Alkyl, C1-C 15 Alkyl, C1-C 10 alkyl, or C1-C3 alkyl; or b) C2-C 20 alkenyl).

[0388] In embodiments, the cationic lipids of the present invention include a compound selected from those depicted in Tables A-C, or a pharmaceutically acceptable salt thereof.

[0389] In embodiments, there is provided a composition comprising the cationic lipid of any one of the preceding embodiments, one or more non-cationic lipids, one or more cholesterol-based lipids, and one or more PEG-modified lipids. In embodiments, the composition is a lipid nanoparticle. In embodiments, the one or more cationic lipids account for approximately 30 mol% to 60 mol% of the lipid nanoparticle. In embodiments, the one or more non-cationic lipids account for 10 mol% to 50 mol% of the lipid nanoparticle. In embodiments, the one or more PEG-modified lipids account for 1 mol% to 10 mol% of the lipid nanoparticle. In embodiments, the cholesterol-based lipids account for 10 mol% to 50 mol% of the lipid nanoparticle. In embodiments, the lipid nanoparticles encapsulate a nucleic acid, optionally an mRNA encoding a peptide or protein. In embodiments, the lipid nanoparticles have an encapsulation rate of at least 70% for mRNA. In embodiments, the lipid nanoparticles have an encapsulation rate of at least 75% for mRNA. In embodiments, the lipid nanoparticles have an encapsulation rate of at least 80% for mRNA. In embodiments, the lipid nanoparticles have an encapsulation rate of at least 85% for mRNA. In embodiments, the lipid nanoparticles have an encapsulation rate of at least 90% for mRNA. In embodiments, the lipid nanoparticles have an encapsulation rate of at least 95% for mRNA.

[0390] In embodiments, the composition of any one of the preceding embodiments is for use in therapy.

[0391] In embodiments, the composition of any one of the preceding embodiments is for use in a method for treating or preventing a disease amenable to treatment or prevention by a peptide or protein encoded by the mRNA, and optionally the disease is (a) a protein deficiency (optionally the protein deficiency affects the liver, lung, brain, or muscle), (b) an autoimmune disease, (c) an infectious disease, or (d) cancer.

[0392] In embodiments, the compositions are administered intravenously, intrathecally, or intramuscularly, or by pulmonary delivery, optionally via nebulization.

[0393] Exemplary Compounds Exemplary compounds include those set forth in Tables A-C, or pharmaceutically acceptable salts thereof.

[0394] [Table 1]

[0395] [Table 2]

[0396] [Table 3]

[0397] [Table 4]

[0398] [Table 5]

[0399] [Table 6]

[0400] [Table 7]

[0401] [Table 8]

[0402] [Table 9]

[0403] Any of the compounds identified in Tables A-C above may be provided in the form of a pharmaceutically acceptable salt, and such salts are intended to be encompassed by the present invention.

[0404] Compounds of the invention as described herein can be prepared by methods known in the art, including the exemplary syntheses of the Examples provided herein.

[0405] nucleic acid The compounds of the invention as described herein can be used to prepare compositions useful for the delivery of nucleic acids.

[0406] Nucleic acid synthesis The nucleic acids of the present invention can be synthesized by any known method. For example, the mRNA of the present invention can be synthesized by in vitro transcription (IVT). Briefly, IVT is typically carried out with a linear or circular DNA template containing a promoter, a pool of ribonucleotide triphosphates, a buffer system that may contain DTT and magnesium ions, and an appropriate RNA polymerase (e.g., T3, T7, mutant T7, or SP6 RNA polymerase), DNase I, pyrophosphatase, and / or RNase inhibitor. The exact conditions will vary depending on the specific application.

[0407] In some embodiments, a DNA template is transcribed in vitro to prepare mRNA of the present invention. A suitable DNA template typically has a promoter for in vitro transcription, such as a T3, T7, mutant T7, or SP6 promoter, followed by the desired nucleotide sequence for the desired mRNA and a termination signal.

[0408] One or more desired mRNA sequences according to the present invention can be determined using standard methods and incorporated into a DNA template. For example, starting from the desired amino acid sequence (e.g., an enzyme sequence), a virtual reverse translation based on the degenerate genetic code can be performed. An optimization algorithm can then be used to select suitable codons. Typically, the G / C content can be optimized, taking into account the highest possible G / C content on the one hand, and the highest possible frequency of tRNAs according to codon usage on the other hand. The optimized RNA sequence can be constructed and displayed, for example, with the aid of a suitable display device, and compared with the original (wild-type) sequence. By analyzing the secondary structure, the stabilizing and destabilizing properties or regions of the RNA, respectively, can also be calculated.

[0409] Modified mRNA In some embodiments, the mRNA of the present invention may be synthesized as unmodified mRNA or modified mRNA. Modified mRNA includes nucleotide modifications in the RNA. Thus, modified mRNA of the present invention may include nucleotide modifications, such as backbone modifications, sugar modifications, or base modifications. In some embodiments, the mRNA is synthesized from naturally occurring nucleotides and / or nucleotide analogs (modified nucleotides), including, but not limited to, purines (adenine (A), guanine (G)) or pyrimidines (thymine (T), cytosine (C), uracil (U)), and modified nucleotides, analogs or derivatives of purines and pyrimidines, such as 1-methyl-adenine, 2-methyl-adenine, 2-methylthio-N-6-isothiazol-1-yl (N-methyl-adenine), ... Isopentenyl-adenine, N6-methyl-adenine, N6-isopentenyl-adenine, 2-thio-cytosine, 3-methyl-cytosine, 4-acetyl-cytosine, 5-methyl-cytosine, 2,6-diaminopurine, 1-methyl-guanine, 2-methyl-guanine, 2,2-dimethyl-guanine, 7-methyl-guanine, inosine, 1-methyl-inosine, pseudouracil (5-uracil), dihydro-uracil, 2-thio-uracil, 4- Thio-uracil, 5-carboxymethylaminomethyl-2-thio-uracil, 5-(carboxyhydroxymethyl)-uracil, 5-fluoro-uracil, 5-bromo-uracil, 5-carboxymethylaminomethyl-uracil, 5-methyl-2-thio-uracil, 5-methyl-uracil, N-uracil-5-oxyacetic acid methyl ester, 5-methylaminomethyl-uracil, 5-methoxyaminomethyl-2-thio-uracil, 5'-methoxy Uracil may also be synthesized as dicarbonylmethyl-uracil, 5-methoxy-uracil, uracil-5-oxyacetic acid methyl ester, uracil-5-oxyacetic acid (v), 1-methyl-pseudouracil, queuosine, β-D-mannosyl-queuosine, wybutoxosine, and as phosphoramidates, phosphorothioates, peptide nucleotides, methylphosphonates, 7-deazaguanosine, 5-methylcytosine, and inosine.The preparation of such analogs is known to those skilled in the art from, for example, U.S. Pat. Nos. 4,373,071, 4,401,796, 4,415,732, 4,458,066, 4,500,707, 4,668,777, 4,973,679, 5,047,524, 5,132,418, 5,153,319, 5,262,530, and 5,700,642, the disclosures of which are incorporated by reference in their entireties. Nos. 4,373,071, 4,401,796, 4,415,732, 4,458,066, 4,500,707, 4,668,777, 4,973,679, 5,047,524, 5,132,418, 5,153,319, 5,262,530 and 5,700,642, the disclosures of which are incorporated by reference in their entirety.

[0410] Pharmaceutical formulations of cationic lipids and nucleic acids In certain embodiments, the compounds of the present invention as described herein, and pharmaceutical and liposomal compositions comprising such lipids, can be used in formulations to facilitate delivery of an encapsulated material (e.g., one or more polynucleotides, such as mRNA) to one or more target cells and subsequent transfection thereof. For example, in certain embodiments, the cationic lipids described herein (and compositions, such as liposomal compositions, comprising such lipids) are characterized as producing one or more of the following properties: receptor-mediated endocytosis, clathrin- and caveolae-mediated endocytosis, phagocytosis and macropinocytosis, membrane fusion activity, endosomal or lysosomal disruption and / or releasability, conferring advantages to such compounds over other similarly classified lipids.

[0411] According to the present invention, a nucleic acid, e.g., mRNA, encoding a protein as described herein (e.g., full-length, a fragment, or a portion of the protein) may be delivered by a delivery vehicle comprising a compound of the present invention as described herein.

[0412] As used herein, the terms "delivery vehicle," "transfer vehicle," "nanoparticle," or their grammatical equivalents are used interchangeably.

[0413] For example, the present invention provides compositions (e.g., pharmaceutical compositions) comprising a compound described herein and one or more polynucleotides. The compositions (e.g., pharmaceutical compositions) may further comprise one or more cationic lipids, one or more non-cationic lipids, one or more cholesterol-based lipids, and / or one or more PEG-modified lipids.

[0414] In certain embodiments, the composition exhibits improved (e.g., increased) ability to transfect one or more target cells. Accordingly, methods of transfecting one or more target cells are also provided herein. Such methods generally include contacting one or more target cells with the cationic lipids and / or pharmaceutical compositions disclosed herein (e.g., liposome formulations comprising the compounds described herein encapsulating one or more polynucleotides), thereby causing the encapsulated material (e.g., one or more polynucleotides) to be transfected into the one or more target cells. As used herein, the term "transfect" or "transfection" refers to the intracellular introduction of one or more encapsulated materials (e.g., nucleic acids and / or polynucleotides) into a cell (e.g., into a target cell). The introduced polynucleotides may be stably or transiently maintained in the target cell. The term "transfection efficiency"...

Claims

1. Compounds having the structure of formula (II'z): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof [in the formula, A 1 teeth, 【Chemistry 2】 And selected from -S-S-, the left side of each structure shown here is -(CH 2 ) a - is connected to; Z 1 teeth, 【Transformation 3】 And selected from -S-S-, the right side of each structure shown here is -(CH 2 ) a - is connected to; Each R is, 【Chemistry 4】 (In the formula, each R 1 (which are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -optionally substituted alkyl-(C=O)-O-optionally substituted alkyl, and -optionally substituted alkyl-O-(C=O)-optionally substituted alkyl); and 【Transformation 5】 (In the formula, each R 2 (which is independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl); Each a is independently selected from 2, 3, 4, 5, and 6; Each b is independently selected from 2, 3, 4, 5, 6, and 7; and c is 3 or 4.

2. Compounds having the structure of formula (III'z): 【Transformation 6】 or a pharmaceutically acceptable salt thereof [in the formula, A 1 is 【Transformation 7】 And selected from -S-S-, the left side of each structure shown here is -(CH 2 ) a - is connected to; Z 1 teeth, 【Transformation 8】 And selected from -S-S-, the right side of each structure shown here is -(CH 2 ) a - is connected to; Each R A , R B , R C , and R D teeth, 【Chemistry 9】 (In the formula, each R 1 (which are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -optionally substituted alkyl-(C=O)-O-optionally substituted alkyl, and -optionally substituted alkyl-O-(C=O)-optionally substituted alkyl); and 【Chemistry 10】 (In the formula, each R 2 (which is independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl); R A , R B , R C , and R D They are not all identical; Each a is independently selected from 2, 3, 4, 5, and 6; and Each b is independently selected from 2, 3, 4, 5, 6, and 7.

3. Compounds having the structure of formula (I'z): 【Chemistry 11】 or a pharmaceutically acceptable salt thereof [in the formula, A 1 teeth, 【Chemistry 12】 And selected from -S-S-, the left side of each structure shown here is -(CH 2 ) a - is connected to; Z 1 teeth, 【Chemistry 13】 And selected from -S-S-, the right side of each structure shown here is -(CH 2 ) a - is connected to; A 1 and Z 1 Unlike; Each R is, 【Chemistry 14】 (In the formula, each R 1 (which are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -optionally substituted alkyl-(C=O)-O-optionally substituted alkyl, and -optionally substituted alkyl-O-(C=O)-optionally substituted alkyl); and 【Chemistry 15】 (In the formula, each R 2 (which is independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted acyl); Each a is independently selected from 2, 3, 4, 5, and 6; and Each b is independently selected from 2, 3, 4, 5, 6, and 7.

4. Formula (Iaz): 【Chemistry 16】 A compound according to claim 3 or a pharmaceutically acceptable salt thereof having the structure relating to the above.

5. Formula (IIaz): 【Chemistry 17】 A compound according to claim 1 or a pharmaceutically acceptable salt thereof having the structure relating to the above.

6. Formula (IIIaz): [Chemistry 18] A compound according to claim 2 having the structure relating to the formula, or a pharmaceutically acceptable salt thereof [wherein R 2A , R 2B , R 2C , and R 2D Each of these is independently selected from optionally substituted alkyls, optionally substituted alkenyls, optionally substituted alkynyls, and optionally substituted acyls, where R 2A , R 2B , R 2C , and R 2D They are not all identical.

7. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein c is 3.

8. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein c is 4.

9. A 1 but, 【Chemistry 19】 Therefore, the left side of the illustrated structure is - (CH 2 ) a - is bonded to the compound according to claim 1 A substance or a pharmaceutically acceptable salt thereof.

10. Z 1 but, 【Chemistry 20】 Therefore, the right side of the illustrated structure is - (CH 2 ) a A compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is bonded to -.

11. Z 1 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is -S-S-.

12. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein the value of a on the left side of the illustrated formula is 3, and the value of a on the right side of the illustrated formula is 6.

13. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the value of a on the left side of the illustrated formula is 3, and the value of a on the right side of the illustrated formula is 4.

14. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein each a is 3.

15. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 14, wherein each alkyl group, alkenyl group, and alkynyl group is independently substituted.

16. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 14, wherein each alkyl group, alkenyl group, and alkynyl group is independently unsubstituted.

17. Each alkyl group, alkenyl group, and alkynyl group can independently be a halogen, -COR'', or -CO 2 H, -CO 2 R'', -CN, -OH, -OR'', -OCOR'', -OCO 2 R'', -NH 2 , -NHR'', -N(R'') 2 , -SR'' or -SO 2 Substituted by one or more R'', each example of R'' independently, C 1 -C 20 A compound or pharmaceutically acceptable salt according to any one of claims 1 to 14, wherein the compound is an aliphatic group.

18. Each R 2 However, independently, the following: 【Chemistry 21】 A compound or pharmaceutically acceptable salt according to any one of claims 1 to 14, selected from the group consisting of the above.

19. A compound, or a pharmaceutically acceptable salt thereof, selected from those listed in Tables A to C.

20. The aforementioned compound, 【Chemistry 22】 A compound or pharmaceutically acceptable salt according to claim 19, selected from the group consisting of the following.

21. A composition comprising a cationic lipid or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, 19, or 20, one or more non-cationic lipids, one or more cholesterol-based lipids, and one or more PEG-modified lipids.

22. The composition according to claim 21, wherein lipid nanoparticles, optionally liposomes.

23. The composition according to claim 22, wherein the lipid nanoparticles encapsulate mRNA encoding a peptide or protein.

24. Use of the composition according to claim 23 in the manufacture of a therapeutic agent.

25. The drug is a treatment by the peptide or protein encoded by the mRNA. The use according to claim 24, for treating or preventing a disease suitable for treatment or prevention, wherein the disease is optionally (a) a protein deficiency (optionally occurring in the liver, lungs, brain, or muscles), (b) an autoimmune disease, (c) an infectious disease, or (d) cancer.

26. The use according to claim 25, wherein the drug is administered via spray therapy, optionally by intravenous, subarachnoid, intramuscular, or intrapulmonary delivery.

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