Lipid nanoparticles containing encoding RNA molecules for use in gene editing, as well as for use as vaccines and therapeutic agents.

Abstract

This disclosure describes improved LNP-based RNA vaccines, nucleic acid editing systems, and therapeutic agents for use in the treatment of diseases and / or acquisition of immunity to diseases. In particular, this disclosure describes improved LNPs comprising novel and improved ionizable lipids for constructing LNPs that enhance the targeted delivery of linear and / or circular mRNA-based LNP-based RNA vaccines and therapeutic agents. The improved LNPs protect the linear and / or circular mRNA payload from degradation and loss while achieving improved targeted systemic or local delivery for use as vaccines and / or therapeutic agents.

Description

[Technical Field]

[0001] This disclosure generally relates to the field of nucleic acid lipid nanoparticle (LNP) compositions and their delivery for use as vaccines and / or therapeutic agents for the treatment of diseases. This disclosure further relates to compositions comprising LNPs formulated with encoding RNA, including linear and / or cyclic mRNA, for the delivery of encoded vaccine antigens and / or therapeutic proteins for vaccination against infectious agents and / or for the treatment of diseases including infectious diseases and cancer.

[0002] Sequence List This application includes a sequence listing submitted electronically in XML format, which is incorporated in its entirety by reference. The XML copy created on February 15, 2024, is named RNG025-WO1.xml and has a size of 44,129 bytes. [Background technology]

[0003] Many challenges exist in the delivery of nucleic acids to influence desired responses in biological systems such as epidemic reactions, or in the production of therapeutically beneficial proteins to treat diseases. While nucleic acid-based therapeutics and vaccines have great potential, more effective delivery of nucleic acids to the appropriate sites within cells or organisms is still needed to realize this potential.

[0004] Nucleic acid-based therapeutics and vaccines are typically composed of DNA or RNA. While DNA is known to be relatively stable and easy to handle, its use carries the risk of undesirable insertions into the cellular genome, potentially leading to mutagenic events. Further concerns include the association of DNA delivery with unwanted immunogenicity and the generation of anti-DNA antibodies. Yet another concern with the use of DNA is the limitation on the achievable expression levels of the encoded peptide or protein, stemming from the condition that it must first enter the nucleus to undergo transcription before being translated into the desired protein product (e.g., an antigen or therapeutic protein).

[0005] In contrast to DNA, RNA does not carry the risk of being incorporated into the genome of transfected cells, making its use virtually safe and thus eliminating concerns that the introduced genetic material may interfere with the normal function of essential genes or cause mutations. Furthermore, RNA-based drugs do not require exogenous promoter sequences for the effective expression of the encoded protein, and because RNA has a relatively shorter half-life than DNA, it is less immunogenic than DNA-based drugs. Additionally, while DNA must enter a nuclease to exert its function, RNA functions outside the nucleus, making it more efficient.

[0006] Despite the advantages of using RNA-based therapeutics and vaccines, the stability of RNA (e.g., mRNA) is far lower than that of DNA, especially when it reaches the cytoplasm of a cell and is exposed to RNA-degrading enzymes. Furthermore, the presence of a hydroxyl group on the second carbon of the sugar moiety in RNA causes steric hindrance, preventing RNA from forming the more stable double-helix structure as DNA does; thus, RNA is more prone to hydrolysis than DNA.

[0007] To circumvent these challenges, the delivery of RNA vaccines (e.g., mRNA vaccines) and therapeutics has recently focused on the use of lipid nanoparticles (LNPs). Indeed, LNPs have emerged as the most promising nonviral delivery vehicle for exogenous mRNA (see, e.g., Guan et al., “Nanotechnologies in delivery of mRNA therapeutics using nonviral vector-based delivery systems,” Gene Ther, 24(2017), pp.133-143). LNPs are complex nanostructures that facilitate intracellular delivery while providing protection for the encapsulated payload RNA molecule from the harsh degradation nuclease environment in vivo. LNPs are formed via self-assembly by combining the RNA payload with several lipid components, including ionizable lipids that play a central role in delivery efficacy (e.g., Miao et al., “Delivery of mRNA vaccines with heterocyclic lipids increases anti-tumor efficacy by STING-mediated immune cell activation,” Nat. Biotechnol., 27(2019), pp.1174-1185). RNA capture is achieved by mixing the RNA with the lipids at an acidic pH where the ionizable lipids are positively charged, thereby ensuring charge-induced interactions with the negatively charged RNA molecule (e.g., Mindy et al., “Mechanism of macromolecular structure evolution in self-assembled lipid nanoparticles for siRNA delivery,” Langmuir, 20(2014), pp.4613-4622). The pH is then adjusted to exceed the pKa of the ionizable lipids, which yields the desired nearly neutral surface charge for clinical administration (see ibid.). Furthermore, the incorporation of PEGylated lipids into the mixture achieves sterically stabilized core-shell nanoparticles useful for clinical applications as vaccines and / or therapeutic agents.

[0008] Despite advancements in LNPs, the targeted delivery of RNA payloads to cells in vivo, which also allows for sufficient levels of protein synthesis (e.g., the production of vaccine antigens or therapeutic proteins), remains a critical challenge.

[0009] Genome editing tools encompass a diverse set of technologies capable of performing many types of genome modifications in various contexts. These technologies have evolved over the past 20 years to provide a variety of user-programmable editing tools, including ZFN (zinc finger) nuclease editing systems, meganuclease editing systems, and TALENs (transcriptional activator-like effector nucleases). Over the past decade, we have seen an explosive growth in a new generation of genome editing systems based on components from bacterial immune pathways, including CRISPR (Clustered Regular Interval Short Palindromic Repeat) and related CRISPR-related proteins (e.g., CRISPR-Cas9) (Jinek et al., “A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity,” Science, Vol.337(6096), pp.816-821), meganuclease editors (Boissel et al., “megaTALs: a rare-cleaving nuclease architecture for therapeutic genome engineering,” Nucleic Acids Research 42: pp.2591-2601), and bacterial retron systems (Schubert et al., “High-throughput functional variant screens via in vivo production of single-stranded DNA,” PNAS, April 27, 2021, Vol.118(18), pp.1-10). In particular, CRISPR-Cas9 has been found to be useful in base editing (Komor et al.) by discovering alternative CRISPR Cas nuclease enzymes with different PAM requirements and cleavage characteristics (e.g., engineered Cas9 proteins and other naturally occurring Cas9 homologs (including, but not limited to, Cas12a, Cas12f, Cas13a, and Cas13b, and their engineered variants)).,“Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage,” Nature, May 19, 2016, 533(7603); pp. 420-424 [cytosine base edit or CBE] and Gaudelli et al., “Programmable base editing of AT to GC in genomic DNA without DNA cleavage,” Nature, Vol. 551, pp. 464-471 [adenine base edit or ABE]), prime editing (Anzalone et al., “Search-and-replace genome editing without double-strand breaks or donor DNA,” Nature, Dec 2019, 576(7789): pp. 149-157), twin prime editing (Anzalone et al., “Programmable deletion, replacement, integration and inversion of large DNA sequences with twin prime editing,” Nature Biotechnology, Dec 9, 2021, vol.40, pp.731-740), Epigenetic editing (Kungulovski and Jeltsch, “Epigenome Editing: State of the Art, Concepts, and Perspective,” Trends in Genetics, Vol.32, 206, pp.101-113), CRISPR-induced integrase editing (Yarnell et al.It has been derivatized in numerous ways to extend its guide RNA-based programmable double-strand cleavage activity to form systems ranging from "Drag-and-drop genome insertion of large sequences without double-stranded DNA cleavage using CRISPR-directed integrases," Nature Biotechnology, Nov 24, 2022, ("PASTE")).

[0010] While the expansion of genome editing tools has exploded, the development of safe and effective gene editing tool delivery systems has lagged behind. Numerous challenges remain in achieving safe and effective therapeutic applications of such tools in cells and patients (including, but not limited to, CRISPR-Cas9 and alternative Cas nuclease editors, retron editors, base editors, prime editors, twin-prime editors, epigenetic editors, and integrase editors) to treat diseases and / or otherwise modify the nucleotide sequence of target nucleic acid molecules (e.g., genes or genomes) (particularly since it relates to in vivo delivery). Nevertheless, the use of lipid nanoparticles (LNPs) has emerged as a major delivery option for safe and effective targeted delivery of gene editing tools to target tissues and cells. However, improved LNPs, including better-performing ionizable lipids, are still needed to enhance the targeted delivery of LNP-based gene editing tools. Preferably, such improved LNPs protect the payload from degradation and loss while achieving targeted delivery, are suitable for systemic or topical delivery, and provide delivery of RNA cargo, including those relating to a variety of gene editing tools such as those described above. Furthermore, such improved LNP-based therapeutics should exhibit low toxicity and provide an appropriate therapeutic index so that patient treatment at an effective dose of LNP minimizes risk to the patient while maximizing therapeutic benefit. Therefore, improved LNPs that enhance the delivery of LNP-based RNA vaccines and therapeutics to cells, tissues, and body parts, and that better protect the RNA payload, will advance the art. Preferably, such improved LNPs will protect the RNA payload from degradation and loss while achieving delivery, be suitable for ex vivo or in vivo delivery, and will provide delivery of any target, including linear and / or cyclic and / or modified forms of RNA. Furthermore, such improved LNP-based RNA vaccines and therapeutics should exhibit low toxicity and provide an appropriate therapeutic index so that patient treatment at an effective dose of LNP minimizes risk to the patient while maximizing therapeutic benefits. This disclosure provides these and related advantages. [Prior art documents] [Non-patent literature]

[0011] [Non-Patent Document 1] Guan et al., “Nanotechnologies in delivery of mRNA therapeutics using nonviral vector-based delivery systems,” Gene Ther, 24(2017), pp. 133-143 [Non-Patent Document 2] Miao et al., “Delivery of mRNA vaccines with heterocyclic lipids increases anti-tumor efficacy by STING-mediated immune cell activation,” Nat.Biotechnol.,27(2019),pp.1174-1185 [Non-Patent Document 3] Mindy et al.,“Mechanism of macromolecular structure evolution in self-assembled lipid nanoparticles for siRNA delivery,” Langmuir,20(2014),pp.4613-4622

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[0012] This specification describes compositions, methods, processes, kits and devices for the selection, design, preparation, manufacture, formulation and / or use of LNP-based RNA drugs (e.g., vaccines and gene-editing therapeutics). In particular, this specification describes compositions, methods, processes, kits and devices for the selection, design, preparation, manufacture, formulation and / or use of LNP-based RNA drugs (e.g., vaccines and gene-editing therapeutics) for the delivery of one or more coding and / or non-coding RNA molecules. In various embodiments, the non-coding RNA may comprise one or more guide RNAs relating to a gene-editing system, such as those based on CRISPR-Cas9 or CRISPR-Cas12a, each of which requires complexation with the guide RNA to facilitate the localization of the protein-RNA complex to a target sequence having an enzyme-specific PAM site (protospacer-adjacent motif (recognized by the CRISPR enzyme)) and a target nucleotide sequence (i.e., protospacer) complementary to a portion of the guide RNA (i.e., to the spacer region). In other embodiments, the coding RNA may code for any protein component of the LNP-based RNA drug, e.g., a viral antigen (e.g., viral envelope spike protein), a therapeutic protein (e.g., a functional version of a defect protein), or one or more gene editing components (e.g., a programmable nuclease or other effector protein, e.g., deaminase or reverse transcriptase). Furthermore, this specification describes compositions, methods, processes, kits and devices for the selection, design, preparation, manufacture, formulation and / or use of LNP-based RNA drugs (e.g., vaccines and / or gene editing therapeutics) for the delivery of one or more RNA molecules, e.g., coding RNA encoding one or more therapeutic proteins for the prophylactic and / or therapeutic treatment of one or more diseases or symptoms thereof, or non-coding RNA, e.g., guide RNA for gene editing systems, but not limited to these, for the delivery of such RNAs. In various embodiments, the RNA molecules delivered by the LNPs disclosed herein may be linear mRNA. In other embodiments, the RNA molecules delivered by the LNPs disclosed herein may be circular mRNA.In further embodiments, the RNA molecules delivered by the LNPs disclosed herein may include both linear and cyclic forms of mRNA. In further embodiments, the RNA may include one or more modifications, including chemical modifications (e.g., ribonucleotide analogs, alternative phosphate chain linkers), sequence modifications (e.g., relative to the wild-type sequence), and / or structural modifications (e.g., secondary folding structures, e.g., stem-loops, hairpins, and G quadruples, and tertiary structural elements, e.g., helical double-stranded and triple-stranded structures, but not limited to these). In various other embodiments, the disclosure provides novel lipid components of the LNPs disclosed herein, including but not limited to novel ionizable lipids.

[0013] This disclosure describes improved LNP-based RNA agents (e.g., vaccines and therapeutics) for use in the treatment of diseases and / or in acquiring immunity to diseases. In particular, this disclosure describes improved LNPs containing better-performing ionizable lipids that enhance the targeted delivery of LNP-based RNA vaccines and therapeutics based on linear and / or circular mRNA. The improved LNPs protect the linear and / or circular mRNA cargo (i.e., the circular and / or linear mRNA molecules encapsulated by the LNP) from degradation and loss, while achieving improved targeted systemic or topical delivery for use as vaccines and / or therapeutics.

[0014] In aspects of this disclosure, the formulas (S-A'), (SA), (SB), (SC), (SD), (SE), (SF), (SG), (SH), (SI), (S-Ia), (S-Ib), (S-J), (SK), (SL), (AT), (AT-A), (AT-A1), (AT-A2), (AT-B), (AT-B'), (AT-C), (AT-D), (AT-D'), (AT-D'a), (AT-D'b), (AT-E), (AT-E''), (AT-F), (AT-F'), (AT-F''), (AT-F'''), (AT-F''''), (AT- F'''''), (AT-G), (AT-G'), (AT-H), (AT-H'), (AT-H''), (AT-H'''), (AT-I), (AT-J), (AT-J'), (AT-K), (AT-K'), (AT-L), (AT-L'), (AT-L''), (AT-L '''), (AT-M), (AT-N), (AT-N'), (AT-O), (AT-O'), (AT-P), (AT-P'), (AT-P''), (AT-P'''), (AT-Q), (AT-Q1), (AT-Q2), (AT-R), (AT-R'), (AT-S), (AT -S'), (AT-S''), (AT-T), (AT-T'), (AT-T''), (AT-T'''), (AT-T''''), (AT-T'''''), (AC'), (AC), (AC-A), (AC-B), (AC-C), (AC-D), (AC-D1), (AC-D 2), (AC-E), (AC-F), (AC-G), (AC-H), (AC-I), (CO'), (CO), (CO-A), (CO-B), (CO-C), (CO-D), (CO-E), (CO-F), (CO-G), (CO-G'), (CO-H), (CO-H'), (C Compounds having any of the following structures: (O-I), (CO-I'), (CO-J), (CO-K), (CO-L), (CO-L'), (CO-M), (CO-M'), (CO-N), (CO-N'), (CO-O), (CO-O'), (CC'), (CC), (CC-A), (CC-B), (CC-C), (CC-D), (CC-E), (CC-F), (CC-F'), (CC-G), (CC-H), (CC-I), (CC-J), (CC-K), (CC-L), (CC-M), or pharmaceutically acceptable salts thereof, or Table (IA), (IB), (IC),Any lipid in (ID) or (IE), or its pharmaceutically acceptable salts, solvates, stereoisomers, or enantiomers (see below), are provided and collectively referred to as “Lipids of the Disclosure,” and each of them is individually referred to as “Lipids of the Disclosure.”

[0015] In aspects of this disclosure, the Specified herein provides a pharmaceutical composition comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0016] In one embodiment, as used herein, a) formulas (S-A'), (SA), (SB), (SC), (SD), (SE), (SF), (SG), (SH), (SI), (S-Ia), (S-Ib), (S-J), (SK), (SL), (AT), (AT-A), (AT-A1), (AT-A2), (AT-B), (AT-B'), (AT-C), (AT-D), (AT-D'), (AT-D'a), (AT-D'b), (AT-E), (AT-E''), (AT-F), (AT-F'), (AT-F''), (AT-F'''), (AT-F''''), (AT- F'''''), (AT-G), (AT-G'), (AT-H), (AT-H'), (AT-H''), (AT-H'''), (AT-I), (AT-J), (AT-J'), (AT-K), (AT-K'), (AT-L), (AT-L'), (AT-L''), (AT-L '''), (AT-M), (AT-N), (AT-N'), (AT-O), (AT-O'), (AT-P), (AT-P'), (AT-P''), (AT-P'''), (AT-Q), (AT-Q1), (AT-Q2), (AT-R), (AT-R'), (AT-S), (A T-S'), (AT-S''), (AT-T), (AT-T'), (AT-T''), (AT-T'''), (AT-T''''), (AT-T'''''), (AC'), (AC), (AC-A), (AC-B), (AC-C), (AC-D), (AC-D1), (AC- D2), (AC-E), (AC-F), (AC-G), (AC-H), (AC-I), (CO'), (CO), (CO-A), (CO-B), (CO-C), (CO-D), (CO-E), (CO-F), (CO-G), (CO-G'), (CO-H), (CO-H'), ( At least one compound having any of the following structures: (CO-I), (CO-I'), (CO-J), (CO-K), (CO-L), (CO-L'), (CO-M), (CO-M'), (CO-N), (CO-N'), (CO-O), (CO-O'), (CC'), (CC), (CC-A), (CC-B), (CC-C), (CC-D), (CC-E), (CC-F), (CC-F'), (CC-G), (CC-H), (CC-I), (CC-J), (CC-K), (CC-L), (CC-M), or a pharmaceutically acceptable salt thereof, or Table (IA),(IB), (IC), (ID), or (IE) any lipid, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable salt, solvate thereof, stereoisomer, or enantiomer thereof, or at least one lipid nanoparticle comprising any lipid, or a pharmaceutically acceptable salt, solvate thereof, stereoisomer, or enantiomer thereof, as defined in Table (IA), (IB), (IC), (ID), or (IE); and b) a pharmaceutical composition comprising at least one nucleic acid base editing system.

[0017] In one embodiment, the Specified provides a method for delivering a nucleic acid base editing system to a subject requiring it, the method comprising administering a pharmaceutical composition disclosed herein to the subject.

[0018] In aspects of this disclosure, the formulas (S-A'), (SA), (SB), (SC), (SD), (SE), (SF), (SG), (SH), (SI), (S-Ia), (S-Ib), (S-J), (SK), (SL), (AT), (AT-A), (AT-A1), (AT-A2), (AT-B), (AT-B'), (AT-C), (AT-D), (AT-D'), (AT-D'a), (AT-D'b), (AT-E), (AT-E''), (AT-F), (AT-F'), (AT-F''), (AT-F'''), (AT-F''''), (AT- F'''''), (AT-G), (AT-G'), (AT-H), (AT-H'), (AT-H''), (AT-H'''), (AT-I), (AT-J), (AT-J'), (AT-K), (AT-K'), (AT-L), (AT-L'), (AT-L''), (AT-L '''), (AT-M), (AT-N), (AT-N'), (AT-O), (AT-O'), (AT-P), (AT-P'), (AT-P''), (AT-P'''), (AT-Q), (AT-Q1), (AT-Q2), (AT-R), (AT-R'), (AT-S), (AT -S'), (AT-S''), (AT-T), (AT-T'), (AT-T''), (AT-T'''), (AT-T''''), (AT-T'''''), (AC'), (AC), (AC-A), (AC-B), (AC-C), (AC-D), (AC-D1), (AC-D 2), (AC-E), (AC-F), (AC-G), (AC-H), (AC-I), (CO'), (CO), (CO-A), (CO-B), (CO-C), (CO-D), (CO-E), (CO-F), (CO-G), (CO-G'), (CO-H), (CO-H'), (C Compounds having any of the following structures: (O-I), (CO-I'), (CO-J), (CO-K), (CO-L), (CO-L'), (CO-M), (CO-M'), (CO-N), (CO-N'), (CO-O), (CO-O'), (CC'), (CC), (CC-A), (CC-B), (CC-C), (CC-D), (CC-E), (CC-F), (CC-F'), (CC-G), (CC-H), (CC-I), (CC-J), (CC-K), (CC-L), (CC-M), or pharmaceutically acceptable salts thereof, or Table (IA), (IB), (IC),Lipid nanoparticles (LNPs) are provided that contain any lipid in (ID) or (IE), or a pharmaceutically acceptable salt, solvate, stereoisomer, or enantiomer thereof, or any lipid in Table (I), or a salt, solvate, stereoisomer, or enantiomer thereof.

[0019] In another aspect of this disclosure, the Specified provides a method for delivering nucleic acids to cells, comprising contacting the cells with LNPs disclosed herein or pharmaceutical compositions disclosed herein.

[0020] In another aspect of the present disclosure, the Specified provides a method for treating a disease characterized by a functional protein deficiency, the method comprising administering an LNP formulation comprising LNPs disclosed herein to a subject having the disease, wherein the mRNA encodes a functional protein or a protein having the same biological activity as the functional protein.

[0021] In another aspect of the present disclosure, the Specified provides a method for treating a disease characterized by the overexpression of a polypeptide, comprising administering an LNP formulation comprising the LNP and siRNA disclosed herein to a subject having the disease, wherein the siRNA targets the expression of the overexpressed polypeptide. [Brief explanation of the drawing]

[0022] [Figure 1] This diagram illustrates LNP-based RNA vaccines and therapeutic agents disclosed herein, which contain an RNA payload (e.g., linear and / or circular mRNA).

[0023] [Figure 2] This diagram illustrates the originator polynucleotide construct of the present disclosure, which may be linear or cyclic. [Modes for carrying out the invention]

[0024] I. Introduction This specification describes compositions, methods, processes, kits, and devices for the selection, design, preparation, manufacture, formulation, and / or use of LNP-based RNA drugs (e.g., vaccines, gene therapies, or gene-editing therapeutics). In various embodiments, the LNP-based RNA drug comprises an LNP delivery system (as described in detail herein) and an encapsulated cargo / payload (e.g., RNA in the case of an RNA drug).

[0025] As described in various embodiments and further herein, the LNP delivery vehicle is a complex nanostructure that provides protection for an encapsulated RNA payload (i.e., one or more RNA molecules) against environmental damage (e.g., the intracellular environment). The LNP is formed via the self-assembly of several lipid components, including (i) ionizable lipids (e.g., ALC-0315 as in COMIRNATY® (Pfizer-BioNTech), SM-102 as in SPIKEVAX® (Moderna), or MC3 as in ONPATTRO® (Alnylam), or those ionizable lipids described herein), (ii) helper lipids (e.g., but not limited to 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC)), (iii) sterols (e.g., cholesterol), and (iv) PEG-lipids (e.g., PEG-DSPE).

[0026] As described in various embodiments and further herein, the RNA payload in the LNP-based drugs described herein may include coding and / or non-coding RNA, and / or mixtures thereof. The specific RNA payload components will typically reflect the drug. For example, an LNP-based vaccine or therapeutic agent may include only coding RNA for expressing a vaccine antigen or therapeutic protein, respectively. However, an LNP-based gene-editing drug may include a combination of coding RNA (e.g., encoding a CRISPR nuclease) and non-coding RNA (e.g., guide RNA). In various embodiments, the RNA molecule delivered by the LNP disclosed herein may be linear mRNA. In other embodiments, the RNA molecule delivered by the LNP disclosed herein may be circular mRNA. In yet another embodiment, the RNA molecule delivered by the LNP disclosed herein may include both linear and circular forms of mRNA. In further embodiments, the RNA may include one or more modifications, including chemical modifications (e.g., ribonucleotide analogs, alternative phosphate chain linkers), sequence modifications (e.g., relative to the wild-type sequence), and / or structural modifications (e.g., secondary folding structures, e.g., stem-loops, hairpins, and G quadruples, and tertiary structural elements, e.g., helical double-stranded and triple-stranded structures, but not limited to these).

[0027] A LNP-based RNA vaccine In certain embodiments, improved LNP-based RNA vaccines for use in acquiring immunity to disease are described herein. In various embodiments, this disclosure describes improved LNPs comprising better-performing ionizable lipids that enhance the targeted delivery of LNP-based RNA vaccines and therapeutic agents based on linear and / or circular mRNA. The improved LNPs protect the linear and / or circular mRNA cargo (i.e., the circular and / or linear mRNA molecules encapsulated by the LNP) from degradation and loss, while achieving targeted systemic or topical delivery for use as an improved vaccine.

[0028] This specification describes compositions, methods, processes, kits, and devices for the selection, design, preparation, manufacture, formulation, and / or use of LNP-based RNA vaccines. In particular, this specification describes compositions, methods, processes, kits, and devices for the selection, design, preparation, manufacture, formulation, and / or use of LNP-based RNA vaccines for the delivery of RNA molecules encoding one or more immunogenic viral antigens for use as vaccines and / or immunogenic compositions. In various embodiments, the RNA molecules delivered by LNPs disclosed herein may be linear mRNA. In other embodiments, the RNA molecules delivered by LNPs disclosed herein may be circular mRNA. In yet another embodiment, the RNA molecules delivered by LNPs disclosed herein may include both linear and circular forms of mRNA. In further embodiments, the RNA may include one or more modifications, including chemical modifications (e.g., ribonucleotide analogs, alternative phosphate chain linkers), sequence modifications (e.g., relative to the wild-type sequence), and / or structural modifications (e.g., secondary folding structures, e.g., stem-loops, hairpins, and G quadruples, and tertiary structural elements, e.g., helical double-stranded and triple-stranded structures, but not limited to these). In various other embodiments, the Disclosure provides novel lipid components of LNPs disclosed herein, including but not limited to novel ionizable lipids.

[0029] B.LNP-based RNA therapeutic agents In certain embodiments, improved LNP-based RNA therapeutics for use in treating a disease or its symptoms are described herein. In various embodiments, this disclosure describes improved LNPs comprising better-functioning ionizable lipids that enhance the targeted delivery of LNP-based RNA therapeutics based on linear and / or circular mRNA. The improved LNPs protect the linear and / or circular mRNA cargo (i.e., the circular and / or linear mRNA molecules encapsulated by the LNP) from degradation and loss, while achieving targeted systemic or topical delivery for use as an improved therapeutic agent.

[0030] This specification describes compositions, methods, processes, kits, and devices for the selection, design, preparation, manufacture, formulation, and / or use of LNP-based RNA therapeutics. In particular, compositions, methods, processes, kits, and devices for the selection, design, preparation, manufacture, formulation, and / or use of LNP-based RNA therapeutics for the delivery of one or more RNA molecules encoding therapeutic proteins for use in treating a disease or its symptoms are described herein. Furthermore, compositions, methods, processes, kits, and devices for the selection, design, preparation, manufacture, formulation, and / or use of LNP-based RNA therapeutics for the administration of one or more RNA molecules encoding therapeutic proteins for prophylactic and / or therapeutic treatment of one or more diseases or its symptoms are described herein. In various embodiments, the RNA molecules delivered by LNPs disclosed herein may be linear mRNA. In other embodiments, the RNA molecules delivered by LNPs disclosed herein may be circular mRNA. In yet another embodiment, the RNA molecules delivered by LNPs disclosed herein may include both linear and circular forms of mRNA. In further embodiments, the RNA may include one or more modifications, including chemical modifications (e.g., ribonucleotide analogs, alternative phosphate chain linkers), sequence modifications (e.g., relative to the wild-type sequence), and / or structural modifications (e.g., secondary folding structures, e.g., stem-loops, hairpins, and G quadruples, and tertiary structural elements, e.g., helical double-stranded and triple-stranded structures, but not limited to these). In various other embodiments, the Disclosure provides novel lipid components of LNPs disclosed herein, including but not limited to novel ionizable lipids.

[0031] C-LNP-based gene editing therapies Furthermore, LNP compositions comprising gene editing systems for use in treating diseases and / or otherwise modifying the sequence and / or expression of target nucleotide sequences are described herein. This disclosure provides LNPs capable of delivering gene editing systems to target organs, tissues, and / or cells. Gene editing systems can be delivered to cells under in vitro or ex vivo conditions and to organs, tissues, or cells under in vivo conditions (e.g., administered to a target in an effective dose).

[0032] This disclosure also provides, in various embodiments, therapeutic or pharmaceutical compositions comprising LNPs containing a gene editing system or one or more components thereof. The gene editing system may include DNA components, RNA components, protein components, nucleoprotein components, polysaccharide components, or combinations thereof. In other embodiments, this disclosure provides nucleic acid molecules (e.g., RNA or DNA) that encode and / or constitute various components of the deliverable gene editing system envisioned herein. Other embodiments of this disclosure also provide nucleic acid molecules as components of the gene editing system envisioned herein, including, but are not limited to, plasmids or vectors encoding one or more components of the gene editing system, RNA encoding one or more components of the gene editing system (e.g., mRNA encoding the nuclease domain of the gene editing system), and non-coding RNA (e.g., guide RNA or retron ncRNA capable of complexing with a nucleic acid programmable DNA-binding domain and targeting it to a specific target nucleotide sequence).

[0033] In further embodiments, the nucleic acid component (e.g., RNA) may include one or more modifications, including chemical modifications (e.g., ribonucleotide analogs, alternative phosphate chain linkers), sequence modifications (e.g., relative to the wild-type sequence), and / or structural modifications (e.g., secondary folding structures, e.g., stem-loops, hairpins, and G quadruples, and tertiary structural elements, e.g., helical double-stranded and triple-stranded structures, but not limited to these).

[0034] In other aspects of this disclosure, we describe various protein components (which may be encoded by nucleic acid components described herein) of the various gene editing systems envisioned herein, including but not limited to, DNA-binding proteins and various effector proteins that can be programmed by the user, such as nucleases, polymerases, reverse transcriptases, recombinases, integrases, endonucleases, exonucleases, transposases, and deaminases.

[0035] This disclosure also describes, but is not limited to, nuclear protein components of gene editing systems contemplated herein, such as nuclease-guide RNA complexes. This disclosure also provides methods for modifying the sequence and / or expression level of a target nucleic acid molecule via delivery and / or administration of LNPs described herein, including a gene editing system or its components. Furthermore, this disclosure provides methods for treating a disease by administering a therapeutically effective dose of an LNP-based gene editing system that results in modification of the sequence and / or expression level of a target nucleic acid molecule (e.g., a disease-related gene or regulatory sequence, e.g., a promoter, transcription factor binding site, or gene enhancer site).

[0036] The gene editing systems deliverable by LNPs disclosed herein may be any type of gene editing system. Gene editing systems contemplated herein may include, but are not limited to, (A) nucleic acid base gene editing systems that result in one or more changes to the sequence of a target nucleic acid molecule (e.g., a gene or gene regulatory sequence) (sequence modifications may include, but are not limited to, insertion of one or more base pairs, deletion of one or more base pairs, substitution of one or more base pairs, conversion of one base pair to another base pair (e.g., a G:C pair being converted to an A:T pair), inversion, or translocation); (B) epigenetic editing systems that result in one or more modifications to the epigenome to produce an effect on gene expression without altering the sequence of the nucleic acid molecule; and (C) gene editing systems that combine features of nucleic acid base editing systems and epigenetic editing systems (e.g., combining components from both types of systems to alter sequence and epigenomic components in a single system).

[0037] Nucleic acid base editing systems include a diverse range of configurations having various combinations of protein functionality and / or nucleic acid molecular components, all of which are contemplated herein. Typically, a nucleic acid base editing system includes at least (i) a user-programmable DNA-binding domain to target a specific sequence in a nucleic acid molecule and optionally (ii) one or more effector domains that facilitate modification of the nucleic acid molecule's sequence. User programmability may include amino acid sequence-programmable DNA-binding domains (e.g., TALEN, zinc finger-binding domain, meganuclease (or homing endonuclease)) or nucleic acid sequence-programmable DNA-binding domains or proteins ("naspDBP") (e.g., CRISPR-Cas9, CRISPR-Cas12a, CRISPR-Cas12f, CRISPR-Cas13a, CRISPR-Cas13b, or TnpB).

[0038] Similarly, an epigenetic editing system includes at least (i) a DNA-binding domain that targets a specific sequence in a nucleic acid molecule, and (ii) one or more effector domains that facilitate the modification of one or more epigenomic features of the nucleic acid molecule.

[0039] A gene editing system may include a fusion protein comprising one or more effector domains that provide various functionalities to facilitate alterations of nucleotide sequences and / or gene expression, such as, but not limited to, single-stranded DNA-binding proteins, nucleases, endonucleases, exonucleases, deaminases (e.g., cytidine deaminase or adenosine deaminase), polymerases (e.g., reverse transcriptase), integrases, recombinases, and one or more functional domains linked together.

[0040] Furthermore, gene editing systems utilizing nucleic acid sequence programmable DNA-binding domains or proteins (naspDBPs) may also include one or more non-coding nucleic acids, such as one or more guide RNAs, which complex with the nucleic acid programmable DNA-binding protein (naspDBP) and target the complex to a specific nucleotide sequence. In the case of prime editing, the guide RNA may be a prime editing guide RNA ("pegRNA") containing a specialized RNA template molecule that provides a template or coding sequence for the reverse transcriptase of the prime editing system. In some embodiments, the RNA template molecule may be coupled to the guide RNA as an elongation arm at the 5' or 3' end of the guide RNA. In other embodiments, the RNA template molecule may be provided trans as a separate molecule such that the RNA template molecule itself is localized at the editing site and associated with the target sequence and / or gene editing system. In some embodiments, co-localization of the trans RNA template molecule may be achieved using an aptamer or other RNA structure that is coupled to the editing complex and integrates with it, or otherwise binds to an associated binding partner.

[0041] For editing systems containing nucleic acid sequence programmable DNA-binding proteins (naspDBPs), such as CRISPR-Cas9 or CRISPR-Cas12a nucleases, suitable guides can be designed and synthesized using methods, software, and commercial sources well known to those skilled in the art, so that guide RNA for any given naspDBP can be obtained without excessive experimentation.

[0042] The following references may be consulted for information and tools for the design, synthesis, modification, and structural construction of guide RNAs: (1) Mohr SE, Hu Y, Ewen-Campen B, Houston BE, Viswanatha R, Perrimon N. CRISPR guide RNA design for research applications. FEBS J. 2016 Sep;283(17):3232-8. doi:10.1111 / febs.13777. Epub 2016 Jun 22. PMID:27276584; PMCID:PMC5014588; (2) Hoberecht L, Perampalam P, Lun A, Fortin JP. A comprehensive Bioconductor ecosystem for the design of CRISPR guide RNAs across nucleases and technologies. Nat Commun. 2022 Nov 2;13(1):6568.doi:10.1038 / s41467-022-34320-7.PMID:36323688;PMCID:PMC9630310;(3)Cram D,Kulkarni M,Buchwaldt M,Rajagopalan N,Bhowmik P,Rozwadowski K,Parkin IAP,Sharpe AG,Kagale S.WheatCRISPR:a web-based guide RNA design tool for CRISPR / Cas9-mediated genome editing in wheat.BMC Plant Biol.2019 Nov 6;19(1):474.doi:10.1186 / s12870-019-2097-z.PMID:31694550;PMCID:PMC6836449;(4)Pliatsika V, Rigoutsos I. “Off-Spotter”: very fast and exhaustive enumeration of genomic lookalikes for designing CRISPR / Cas guide RNAs.Biol Direct.2015 Jan 29;10:4.doi:10.1186 / s13062-015-0035-z.PMID:25630343;PMCID:PMC4326336;(5)Hoof JB,Nodvig CS,Mortensen UH.Genome Editing:CRISPR-Cas9.Methods Mol Biol.2018;1775:119-132.doi:10.1007 / 978-1-4939-7804-5_11.PMID:29876814;(6)Labun K,Krause M,Torres Cleuren Y,Valen E.CRISPR Genome Editing Made Easy Through the CHOPCHOP Website.Curr Protoc.2021 Apr;1(4):e46.doi:10.1002 / cpz1.46.PMID:33905612;(7)Lee CM,Davis TH,Bao G.Examination of CRISPR / Cas9 design tools and the effect of target site accessibility on Cas9 activity.Exp Physiol.2018 Apr 1;103(4):456-460.doi:10.1113 / EP086043.Epub 2017 Apr 12.PMID:28303677;PMCID:PMC7266697;(8)Ma S,Lv J,Feng Z,Rong Z,Lin Y.Get ready for the CRISPR / Cas system:A beginner’s guide to the engineering and design of guide RNAs.J Gene Med.2021 Nov;23(11):e3377.doi:10.1002 / jgm.3377.Epub 2021 Jul 28.PMID:34270141;(9)Hiranniramol K,Chen Y,Wang X.CRISPR / Cas9 Guide RNA Design Rules for Predicting Activity.Methods Mol Biol.2020;2115:351-364.doi:10.1007 / 978-1-0716-0290-4_19.PMID:32006410;(10)Wiles MV,Qin W,Cheng AW,Wang H.CRISPR-Cas9-mediated genome editing and guide RNA design.Mamm Genome.2015 Oct;26(9-10):501-10.doi:10.1007 / s00335-015-9565-z.Epub 2015 May 20.PMID:25991564;PMCID:PMC4602062;(11)Creutzburg SCA,Wu WY,Mohanraju P,Swartjes T,Alkan F,Gorodkin J,Staals RHJ,van der Oost J.Good guide,bad guide:spacer sequence-dependent cleavage efficiency of Cas12a.Nucleic Acids Res.2020 Apr 6;48(6):3228-3243.doi:10.1093 / nar / gkz1240.PMID:31989168;PMCID:PMC7102956;(12)Heigwer F,Boutros M.Cloud-Based Design of Short Guide RNA(sgRNA)Libraries for CRISPR Experiments.Methods Mol Biol.2021;2162:3-22.doi:10.1007 / 978-1-0716-0687-2_1.PMID:32926374;(13)Dronina J,Samukaite-Bubniene U,Ramanavicius A.Towards application of CRISPR-Cas12a in the design of modern viral DNA detection tools(Review).J Nanobiotechnology.2022 Jan 21;20(1):41.doi:10.1186 / s12951-022-01246-7.PMID:35062978;PMCID:PMC8777428;(14)Krysler AR,Cromwell CR,Tu T,Jovel J,Hubbard BP.Guide RNAs containing universal bases enable Cas9 / Cas12a recognition of polymorphic sequences.Nat Commun.2022 Mar 25;13(1):1617.doi:10.1038 / s41467-022-29202-x.PMID:35338140;PMCID:PMC8956631;(15)Shin HR,Kweon J,Kim Y.Gene Manipulation Using Fusion Guide RNAs for Cas9 and Cas12a.Methods Mol Biol.2021;2162:185-193.doi:10.1007 / 978-1-0716-0687-2_10.PMID:32926383;(16)Schubert MS,Thommandru B,Woodley J,Turk R,Yan S,Kurgan G,McNeill MS,Rettig GR.Optimized design parameters for CRISPR Cas9 and Cas12a homology-directed repair.Sci Rep.2021 Sep 30;11(1):19482.doi:10.1038 / s41598-021-98965-y.PMID:34593942;PMCID:PMC8484621;(17)Crone MA,MacDonald JT,Freemont PS,Siciliano V.gDesigner:computational design of synthetic gRNAs for Cas12a-based transcriptional repression in mammalian cells.NPJ Syst Biol Appl.2022 Sep 16;8(1):34.doi:10.1038 / s41540-022-00241-w.PMID:36114193;PMCID:PMC9481559;(18)Konstantakos V,Nentidis A,Krithara A,Paliouras G.CRISPR-Cas9 gRNA efficiency prediction: an overview of predictive tools and the role of deep learning.Nucleic Acids Res.2022 Apr 22;50(7):3616-3637.doi:10.1093 / nar / gkac192.PMID:35349718;PMCID:PMC9023298;(19)Wang J, Zhang X, Cheng L,Luo Y.An overview and metanalysis of machine and deep learning-based CRISPR gRNA design tools.RNA Biol.2020 Jan;17(1):13-22.doi:10.1080 / 15476286.2019.1669406.Epub 2019 Sep 27.PMID:31533522;PMCID:PMC6948960;and (20)Cram D, Kulkarni M, Buchwaldt M, Rajagopalan N, Bhowmik P, Rozwadowski K, Parkin IAP, Sharpe AG, Kagale S. WheatCRISPR: a web-based guide RNA design tool for CRISPR / Cas9-mediated genome editing in wheat. BMC Plant Biol. 2019 Nov 6;19(1):474. doi:10.1186 / s12870-019-2097-z. PMID:31694550; PMCID:PMC6836449 (Each of these is incorporated herein by reference in whole).

[0043] For prime editing, the following references may be further consulted, particularly those providing information and tools for the design, synthesis, modification, and structural configuration of egRNAs: (1) Hsu JY, Gruenewald J, Szalay R, Shih J, Anzalone AV, Lam KC, Shen MW, Petri K, Liu DR, Joung JK, Pinello L. PrimeDesign software for rapid and simplified design of prime editing guide RNAs. Nat Commun. 2021 Feb 15;12(1):1034.doi:10.1038 / s41467-021-21337-7.PMID:33589617;PMCID:PMC7884779; (2) Li Y, Chen J, Tsai SQ, Cheng Y. Easy-Prime: a machine learning-based prime editor design tool. Genome Biol. 2021 Aug 19;22(1):235.doi:10.1186 / s13059-021-02458-0.PMID:34412673;PMCID:PMC8377858;(3)Zhang W,Petri K,Ma J,Lee H,Tsai CL,Joung JK,Yeh JJ.Enhancing CRISPR prime editing by reducing misfolded pegRNA interactions.bioRxiv [Preprint].2023 Aug 15:2023.08.14.553324.doi:10.1101 / 2023.08.14.553324.PMID:37645936;PMCID:PMC10462064;(4)Jin S,Lin Q,Gao Q,Gao C.Optimized prime editing in monocot plants using PlantPegDesigner and engineered plant prime editors(ePPEs).Nat Protoc.2023 Mar;18(3):831-853.doi:10.1038 / s41596-022-00773-9.Epub 2022 Nov 25.PMID:36434096;(5)Lin Q,Jin S,Zong Y,Yu H,Zhu Z,Liu G,Kou L,Wang Y,Qiu JL,Li J,Gao C.High-efficiency prime editing with optimized,paired pegRNAs in plants.Nat Biotechnol.2021 Aug;39(8):923-927.doi:10.1038 / s41587-021-00868-w.Epub 2021 Mar 25.PMID:33767395;(6)Standage-Beier K, Tekel SJ, Brafman DA, Wang X. Prime Editing Guide RNA Design Automation Using PINE-CONE.ACS Synth Biol.2021 Feb 19;10(2):422-427.doi:10.1021 / acssynbio.0c00445.Epub 2021 Jan 19.PMID:33464043;PMCID:PMC7901017;(7)Zhang W,Petri K,Ma J,Lee H,Tsai CL,Joung JK,Yeh JJ.Enhancing CRISPR prime editing by reducing misfolded pegRNA interactions.bioRxiv [Preprint].2023 Aug 15:2023.08.14.553324.doi:10.1101 / 2023.08.14.553324.PMID:37645936;PMCID:PMC10462064;(8)Chow RD,Chen JS,Shen J,Chen SA web tool for the design of prime-editing guide RNAs. Nat Biomed Eng. 2021 Feb;5(2):190-194. doi:10.1038 / s41551-020-00622-8. Epub 2020 Sep 28. PMID:32989284; PMCID:PMC7882013 (each of these is incorporated herein by reference in whole).

[0044] The following commercial vendors also sell guide RNAs for CRISPR editing applications (including base editing and prime editing) and provide a variety of tools and instructions for ordering, designing, synthesizing, modifying, and structurally constructing guide RNAs: in particular, GENSCRIPT, SYNTHEGO, TAKARA BIO, INTEGRATED DNA TECHNOLOGIES, LC SCIENCES, HORIZON DISCOVERY; SIGMA-ALDRICH; ORIGENE, and TWIST BIOSCIENCES.

[0045] Furthermore, guide RNA can be modified with chemical and / or structural modifications to improve various properties, including specificity and stability, and to limit off-target activity. Those skilled in the art will be able to modify guide RNA with any known modifications without excessive experimentation. Guide modification is discussed in the following references: (1) Ke Y, Ghalandari B, Huang S, Li S, Huang C, Zhi X, Cui D, Ding X. 2'-O-Methyl modified guide RNA promotes the single nucleotide polymorphism (SNP) discrimination ability of CRISPR-Cas12a systems. Chem Sci. 2022 Feb 1;13(7):2050-2061. doi:10.1039 / d1sc06832f. PMID:35308857; PMCID:PMC8848812; (2) Allen D, Rosenberg M, Hendel A. Using Synthetically Engineered Guide RNAs to Enhance CRISPR Genome Editing Systems in Mammalian Cells. Front Genome Ed. 2021 Jan 28;2:617910.doi:10.3389 / fgeed.2020.617910.PMID:34713240;PMCID:PMC8525374;(3)Basila M,Kelley ML,Smith AVB.Minimal 2'-O-methyl phosphorothioate linkage modification pattern of synthetic guide RNAs for increased stability and efficient CRISPR-Cas9 gene editing avoiding cellular toxicity.PLoS One.2017 Nov 27;12(11):e0188593.doi:10.1371 / journal.pone.0188593.PMID:29176845;PMCID:PMC5703482;(4)Sakovina L,Vokhtantsev I,Vorobyeva M,Vorobyev P,Novopashina D.Improving Stability and Specificity of CRISPR / Cas9 System by Selective Modification of Guide RNAs with 2’-fluoro and Locked Nucleic Acid Nucleotides.Int J Mol Sci.2022 Nov 3;23(21):13460.doi:10.3390 / ijms232113460.PMID:36362256;PMCID:PMC9655745;(5)Shapiro J,Tovin A,Iancu O,Allen D,Hendel A.Chemical Modification of Guide RNAs for Improved CRISPR Activity in CD34+Human Hematopoietic Stem and Progenitor Cells.Methods Mol Biol.2021;2162:37-48.doi:10.1007 / 978-1-0716-0687-2_3.PMID:32926376;(6)Filippova J,Matveeva A,Zhuravlev E,Stepanov G.Guide RNA modification as a way to improve CRISPR / Cas9-based genome-editing systems.Biochimie.2019 Dec;167:49-60.doi:10.1016 / j.biochi.2019.09.003.Epub 2019 Sep 4.PMID:31493470;(7)Hendel A,Bak RO,Clark JT,Kennedy AB,Ryan DE,Roy S,Steinfeld I,Lunstad BD,Kaiser RJ,Wilkens AB,Bacchetta R,Tsalenko A,Dellinger D,Bruhn L,Porteus MH.Chemically modified guide RNAs enhance CRISPR-Cas genome editing in human primary cells.Nat Biotechnol.2015 Sep;33(9):985-989.doi:10.1038 / nbt.3290.Epub 2015 Jun 29.PMID:26121415;PMCID:PMC4729442;(8)_ Ryan DE,Taussig D,Steinfeld I,Phadnis SM,Lunstad BD,Singh M,Vuong X,Okochi KD,McCaffrey R,Olesiak M,Roy S,Yung CW,Curry B,Sampson JR,Bruhn L,Dellinger DJ.Improving CRISPR-Cas specificity with chemical modifications in single-guide RNAs.Nucleic Acids Res.2018 Jan 25;46(2):792-803.doi:10.1093 / nar / gkx1199.Erratum in:Nucleic Acids Res.2022 Mar 21;50(5):2986.PMID:29216382;PMCID:PMC5778453;(9)Palumbo CM,Gutierrez-Bujari JM,O’Geen H,Segal DJ,Beal PA.Versatile 3’ Functionalization of CRISPR Single Guide RNA.Chembiochem.2020 Jun 2;21(11):1633-1640.doi:10.1002 / cbic.201900736.Epub 2020 Mar 5.PMID:31943634;PMCID:PMC7323579;(10)Mullally G,van Aelst K,Naqvi MM,Diffin FM,Karvelis T,Gasiunas G,Siksnys V,Szczelkun MD.5' modifications to CRISPR-Cas9 gRNA can change the dynamics and size of R-loops and inhibit DNA cleavage. Nucleic Acids Res. 2020 Jul 9;48(12):6811-6823.doi:10.1093 / nar / gkaa477.PMID:32496535;PMCID:PMC7337959;(12)Lu S, Zhang Y, Yin H. Chimeric DNA-RNA Guide RNA Designs. Methods Mol Biol. 2021;2162:79-85.doi:10.1007 / 978-1-0716-0687-2_6.PMID:32926379 (Each of these is incorporated herein by reference in whole).

[0046] In certain cases of prime editing, pegRNA may be modified with chemical and / or structural modifications to improve various properties, including specificity and stability, and to limit off-target activity. Those skilled in the art will be able to modify pegRNA for prime editing with any known modifications without excessive experimentation. PegRNA modification is discussed in the following references: (1) Nelson JW, Randolph PB, Shen SP, Everette KA, Chen PJ, Anzalone AV, An M, Newby GA, Chen JC, Hsu A, Liu DR. Engineered pegRNAs improve prime editing efficiency. Nat Biotechnol.2022 Mar;40(3):402-410.doi:10.1038 / s41587-021-01039-7.Epub 2021 Oct 4.Erratum in:Nat Biotechnol.2021 Dec 8;:PMID:34608327;PMCID:PMC8930418;(2)Liu B, Dong X, Cheng H, Zheng C, Chen Z, Rodriguez TC, Liang SQ, Xue W, Sontheimer EJ. A split prime editor with untethered reverse transcriptase and circular RNA template. Nat Biotechnol. 2022 Sep;40(9):1388-1393. doi:10.1038 / s41587-022-01255-9. Epub 2022 Apr 4. PMID:35379962 (Each of these is incorporated herein by reference in whole).

[0047] Depending on the requirements and / or characteristics of the gene editing system and the corresponding nucleic acid programmable protein, other specialized guide RNAs may be included. For example, the TnpB enzyme requires a specialized guide RNA called reRNA. The guide RNA also has different characteristics (e.g., PAM preference, spacer length, and skeletal portion that binds to the nuclease protein) depending on the requirements of the programmable nuclease.

[0048] The gene editing systems envisioned herein may introduce a variety of changes, including (A) alterations to the sequence of a target nucleic acid molecule, for example, (i) nucleic acid base substitutions (e.g., purine to pyrimidine), (ii) deletion of one or more nucleic acid bases, (iii) insertion of one or more nucleic acid bases, (iv) combinations of one or more deletions and insertions of nucleic acid bases, (v) inversion of the nucleic acid sequence, (vi) translocation of the nucleic acid sequence, and (vii) combinations of two or more such modifications, and (B) one or more modifications to the epigenome to produce an effect on gene expression without altering the sequence of the nucleic acid molecule (the epigenetic changes result in altered gene expression via an altered chromatin structure or accessibility).

[0049] The LNP compositions and / or gene editing systems described herein may include a variety of coding RNA molecules encoding various components of a gene edit. In various embodiments, the coding RNA may be linear mRNA. In other embodiments, the coding RNA may be circular mRNA. In various embodiments, the improved LNPs protect linear and / or circular mRNA cargoes from degradation and loss while achieving targeted systemic or local delivery for use as an improved gene editing platform and / or therapeutic agent.

[0050] In various other embodiments, the LNP compositions and / or gene editing systems described herein may also include repair templates, such as homologous recombination repair (HDR)-dependent repair templates (or HDR templates). Such HDR templates are well known in the art and may include single-stranded or double-stranded DNA (e.g., oligonucleotides) or RNA. Further information regarding HDR and HDR templates for use in editing systems for various applications such as gene knock-in can be found in Fu YW, Dai XY, Wang WT, Yang ZX, Zhao JJ, Zhang JP, Wen W, Zhang F, Oberg KC, Zhang L, Cheng T, Zhang XB. Dynamics and competition of CRISPR-Cas9 ribonucleoproteins and AAV donor-mediated NHEJ, MMEJ and HDR editing. Nucleic Acids Res. 2021 Jan 25;49(2):969-985.doi:10.1093 / nar / gkaa1251.PMID:33398341;PMCID:PMC7826255;Iyer S, Mir A, Vega-Badillo J, Roscoe BP, Ibraheim R, Zhu LJ, Lee J, Liu P, Luk K, Mintzer E, Guo D, Soares de Brito J, Emerson CP Jr, Zamore PD, Sontheimer EJ, Wolfe SA. Efficient Homology-Directed Repair with Circular Single-Stranded DNA Donors.CRISPR J.2022 Oct;5(5):685-701.doi:10.1089 / crispr.2022.0058.Epub 2022 Sep 7. PMID:36070530; PMCID:PMC9595650; and Richardson CD, Ray GJ, DeWitt MA, Curie GL, Corn JE.Enhancing homology-directed genome editing by catalytically active and inactive CRISPR-Cas9 using asymmetric donor DNA. Nat Biotechnol. 2016 Mar;34(3):339-44. doi:10.1038 / nbt.3481. Epub 2016 Jan 20. PMID:26789497 (Each of these is incorporated herein by reference in whole).

[0051] Accordingly, this specification describes compositions, methods, processes, kits and devices for the selection, design, preparation, manufacture, formulation and / or use of LNP-based gene editing systems as therapeutic compositions. Furthermore, this specification describes compositions, methods, processes, kits and devices for the selection, design, preparation, manufacture, formulation and / or use of LNP-based gene editing therapeutic agents for the prophylactic and / or therapeutic treatment of one or more diseases or their symptoms. Components that can be encapsulated or otherwise incorporated by the LNPs described herein may be referred to as LNP “payloads” and may include all of the above-mentioned biological substances, including DNA molecules, RNA molecules (coding and / or non-coding), proteins and nucleoproteins (e.g., Cas / guide RNA complexes).

[0052] II. LNP Delivery System The RNA payloads described herein (e.g., linear and cyclic mRNAs) may be encapsulated in and delivered in compositions and / or formulations comprising lipid nanoparticles (LNPs) and RNA-encapsulated LNPs.

[0053] The following describes LNPs that can be used as RNA payload delivery vehicles as intended herein, as well as various ionizable lipids, structural lipids, PEGylated lipids, and phospholipids that can be used to construct the LNPs described herein for the delivery of RNA payloads to cells. The following also describes additional LNP components that may be intended, such as targeting sites and other lipid components.

[0054] A. Lipid nanoparticle composition In one embodiment, the Disclosure further provides a delivery system for the delivery of the therapeutic payloads disclosed herein (e.g., a polypeptide of interest, e.g., an RNA payload described herein that may encode an antigen or therapeutic protein). In some embodiments, a suitable delivery system for the delivery of the therapeutic payloads disclosed herein includes a lipid nanoparticle (LNP) formulation.

[0055] In some embodiments, the LNPs of the Disclosure comprise ionizable lipids, structural lipids, PEGylated lipids (also known as PEG lipids), and phospholipids. In alternative embodiments, the LNPs comprise ionizable lipids, structural lipids, PEGylated lipids (also known as PEG lipids), and zwitterionic amino acid lipids. In some embodiments, the LNPs further comprise a fifth lipid in addition to any of the aforementioned lipid components. In some embodiments, the LNPs encapsulate one or more elements of the activators of the Disclosure. In some embodiments, the LNPs further comprise targeting sites covalently or noncovalently bound to the outer surface of the LNP. In some embodiments, the targeting sites are targeting sites that bind to cells in a particular organ system, or otherwise facilitate uptake by those cells.

[0056] In some embodiments, the LNP has a diameter of at least about 20 nm, 30 nm, 40 nm, 50 nm, 60 nm, 70 nm, 80 nm, or 90 nm. In some embodiments, the LNP has a diameter of less than about 100 nm, 110 nm, 120 nm, 130 nm, 140 nm, 150 nm, or 160 nm. In some embodiments, the LNP has a diameter of less than about 120 nm. In some embodiments, the LNP has a diameter of less than about 100 nm. In some embodiments, the LNP has a diameter of less than about 90 nm. In some embodiments, the LNP has a diameter of less than about 80 nm. In some embodiments, the LNP has a diameter of about 60 to 100 nm. In some embodiments, the LNP has a diameter of about 50 to 120 nm. In some embodiments, the LNP has a diameter of about 75 to 80 nm.

[0057] In some embodiments, the lipid nanoparticle compositions of this disclosure are described according to the respective molar ratios of component lipids in the formulation. In some non-limiting examples, the mol% of ionizable lipids may be about 10 mol% to about 80 mol%. In some non-limiting examples, the mol% of ionizable lipids may be about 20 mol% to about 70 mol%. In some non-limiting examples, the mol% of ionizable lipids may be about 30 mol% to about 60 mol%. In some non-limiting examples, the mol% of ionizable lipids may be about 35 mol% to about 55 mol%. In some non-limiting examples, the mol% of ionizable lipids may be about 40 mol% to about 50 mol%. In some non-limiting examples, the mol% of ionizable lipids may be about 30 mol% to about 40 mol%. In some non-limiting examples, the mol% of ionizable lipids may be about 25 mol% to about 35 mol%. In some embodiments, the mol% of ionizable lipids is about 10 mol%. In some embodiments, the mol% of ionizable lipids is about 15 mol%. In some embodiments, the mol% of ionizable lipids is about 20 mol%. In some embodiments, the mol% of ionizable lipids is about 25 mol%. In some embodiments, the mol% of ionizable lipids is about 30 mol%. In some embodiments, the mol% of ionizable lipids is about 33 mol%. In some embodiments, the mol% of ionizable lipids is about 35 mol%. In some embodiments, the mol% of ionizable lipids is about 40 mol%. In some embodiments, the mol% of ionizable lipids is about 45 mol%. In some embodiments, the mol% of ionizable lipids is about 55 mol%. In some embodiments, the mol% of ionizable lipids is about 60 mol%.

[0058] In some embodiments, the mol% of phospholipids can be about 1 mol% to about 50 mol%. In some embodiments, the mol% of phospholipids can be about 2 mol% to about 45 mol%. In some embodiments, the mol% of phospholipids can be about 3 mol% to about 40 mol%. In some embodiments, the mol% of phospholipids can be about 4 mol% to about 35 mol%. In some embodiments, the mol% of phospholipids can be about 5 mol% to about 30 mol%. In some embodiments, the mol% of phospholipids can be about 10 mol% to about 20 mol%. In some embodiments, the mol% of phospholipids can be about 5 mol% to about 20 mol%. In some embodiments, the mol% of phospholipids is about 30 mol% to about 60 mol%. In some embodiments, the mol% of phospholipids is about 35 mol% to about 55 mol%. In some embodiments, the mol% of phospholipids is about 35 mol% to about 45 mol%. In some embodiments, the mol% of phospholipids is about 10 mol%. In some embodiments, the mol% of phospholipids is about 15 mol%. In some embodiments, the mol% of phospholipids is about 20 mol%. In some embodiments, the mol% of phospholipids is about 25 mol%. In some embodiments, the mol% of phospholipids is about 30 mol%. In some embodiments, the mol% of phospholipids is about 35 mol%. In some embodiments, the mol% of phospholipids is about 40 mol%. In some embodiments, the mol% of phospholipids is about 45 mol%. In some embodiments, the mol% of phospholipids is about 55 mol%. In some embodiments, the mol% of phospholipids is about 60 mol%.

[0059] In some embodiments, the mol% of phospholipids described above includes two or more phospholipids in individual mol% amounts that are totaled in the aforementioned amounts. In a given embodiment, the mol% of phospholipids is about 20 mol% for each of the two phospholipids. In a given embodiment, the mol% of phospholipids is about 15 mol% for each of the two phospholipids. In a given embodiment, the mol% of phospholipids is about 25 mol% for each of the two phospholipids. In a given embodiment, the mol% of phospholipids is about 30 mol% for each of the two phospholipids. In a given embodiment, the mol% of phospholipids is about 15 mol% of a first phospholipid and about 20 mol% of a second phospholipid. In a given embodiment, the mol% of phospholipids is about 30 mol% of a first phospholipid and about 10 mol% of a second phospholipid. In a given embodiment, the mol% of phospholipids is about 25 mol% of a first phospholipid and about 10 mol% of a second phospholipid. In a given embodiment, the mol% of phospholipids is approximately 25 mol% of a first phospholipid and approximately 20 mol% of a second phospholipid. In another given embodiment, the mol% of phospholipids is approximately 15 mol% of a first phospholipid and approximately 20 mol% of a second phospholipid.

[0060] In some embodiments, the mol% of structural lipids can be about 10 mol% to about 80 mol%. In some embodiments, the mol% of structural lipids can be about 20 mol% to about 70 mol%. In some embodiments, the mol% of structural lipids can be about 30 mol% to about 60 mol%. In some embodiments, the mol% of structural lipids can be about 35 mol% to about 55 mol%. In some embodiments, the mol% of structural lipids can be about 40 mol% to about 50 mol%.

[0061] In some embodiments, the mol% of PEG lipids can be about 0.1 mol% to about 10 mol%. In some embodiments, the mol% of PEG lipids can be about 0.2 mol% to about 5 mol%. In some embodiments, the mol% of PEG lipids can be about 0.5 mol% to about 3 mol%. In some embodiments, the mol% of PEG lipids can be about 1 mol% to about 2 mol%. In some embodiments, the mol% of PEG lipids can be about 1.5 mol%. In some embodiments, the mol% of PEG lipids can be about 2.5 mol%. In some embodiments, the mol% of PEG lipids can be about 3 mol%. In some embodiments, the mol% of PEG lipids can be about 3.5 mol%.

[0062] Where "mol-%" or "mol%" is mentioned above, the amount of the described LNP component is intended to be a mol% of the specific component compared to the total lipid component content of the lipid nanoparticles.

[0063] i. Ionizable lipids In some embodiments, the LNP disclosed herein comprises an ionizable lipid. In some embodiments, the LNP comprises two or more ionizable lipids.

[0064] Series "S" Numerous exemplary ionizable lipids of this disclosure are listed below.

[0065] Formula (S-A') In some embodiments, the lipids of this disclosure have the structure of formula (SA): [ka] or a pharmaceutically acceptable salt thereof (in the formula, A is -N(-X 1 R 1 )-,-C(R ’ )(-L 1 -N(R'')R 6 )-, -C(R')(-OR 7a)-, -C(R’)(-N(R’’)R 8a )-, -C(R’)(-C(=O)OR 9a )-, -C(R’)(-OC(=O)R 9a )-, -C(R’)(-C(=O)N(R’’)R 10a )-, or -C(=N-R 11a )-; T is -X 2a -Y 1a -Q 1a or -X 3 -C(=O)OR 4 ; X 1 is optionally substituted C2-C6 alkenylenyl; R 1 is -OH, -N(R 3 )2,

Chemical formula

[0066] Formula (S-A) In some embodiments, the lipid of the present disclosure has the structure of formula (S-A):

Chemical formula

[0067] Formula (SB) In some embodiments, the lipids of the Disclosure have the structure of formula (SA) or (S-A'), and the lipids of the Disclosure have the structure of formula (SB): [ka] or a pharmaceutically acceptable salt thereof.

[0068] Formula (SC) In some embodiments, the lipids of the Disclosure have the structure of formula (SA) or (S-A'), and the lipids of the Disclosure have the structure of formula (SC): [ka] or a pharmaceutically acceptable salt thereof.

[0069] In some embodiments, the lipids of the present disclosure have a structure of formula (SA) or (S-A') (wherein A is -N(-X 1 R 1 )-- has ).

[0070] In some embodiments, the lipids of this disclosure have a structure of formula (SA) or (S-A') (wherein T is -X). 2a -Y 1a-Q 1a It has (is).

[0071] In some embodiments, the lipids of this disclosure have a structure of formula (SA) or (S-A') (wherein T is -X). 3 -C(=O)OR 4 It has (is).

[0072] In some embodiments, the lipids of this disclosure have a structure of formula (SA), (S-A'), (SB), or (SC) (wherein X 2 and / or X 2a This is an arbitrarily substituted C2-C 14 Alkyrenyl (e.g., C4-C 10 The lipids have an alkylenyl (C5-C7 alkylenyl, C5, C6, or C7 alkylenyl). In some embodiments, the lipids of the present disclosure have a structure of formula (SA), (S-A'), (SB), or (SC) (wherein X 2 C4-C 10 The lipids of this disclosure have the structure of formula (SA), (S-A'), (SB), or (SC) (wherein X 2a C4-C 10 The lipids of this disclosure have the structure of formula (SA), (S-A'), (SB), or (SC) (wherein X 2 (wherein X is a C5 alkylenyl molecule). In some embodiments, the lipids of the present disclosure have a structure of formula (SA), (S-A'), (SB), or (SC) (wherein X is a C5 alkylenyl molecule). 2 (wherein X is a C6 alkylenyl molecule). In some embodiments, the lipids of the present disclosure have a structure of formula (SA), (S-A'), (SB), or (SC) (wherein X is a C6 alkylenyl molecule). 2a (wherein X is a C5 alkylenyl molecule). In some embodiments, the lipids of the present disclosure have a structure of formula (SA), (S-A'), (SB), or (SC) (wherein X is a C5 alkylenyl molecule). 2a It has a C6 alkylenyl compound.

[0073] In some embodiments, the lipids of this disclosure have a structure of formula (SA), (S-A'), (SB), or (SC) (wherein Y, Y 1 and / or Y 1a teeth, [ka] In some embodiments, the lipids of the present disclosure have a structure of formula (SA), (S-A'), (SB), or (SC) (wherein Y 1 teeth, [ka] In some embodiments, the lipids of the present disclosure have a structure of formula (SA), (S-A'), (SB), or (SC) (wherein Y 1a teeth, [ka] In some embodiments, the lipids of the present disclosure have a structure of formula (SA), (S-A'), (SB), or (SC) (wherein Y 1 and / or Y 1a teeth, [ka] In some embodiments, the lipids of the present disclosure have a structure of formula (SA), (S-A'), (SB), or (SC) (wherein Y 1 teeth, [ka] In some embodiments, the lipids of the present disclosure have a structure of formula (SA), (S-A'), (SB), or (SC) (wherein Y 1a teeth, [ka] In some embodiments, the lipids of the present disclosure have a structure of formula (SA), (S-A'), (SB), or (SC) (wherein Y 1and / or Y 1a teeth, [ka] And Z 2 (wherein Y is hydrogen). In some embodiments, the lipids of the present disclosure have a structure of formula (SA), (S-A'), (SB), or (SC) (wherein Y is hydrogen). 1 teeth, [ka] And Z 2 (wherein Y is hydrogen). In some embodiments, the lipids of the present disclosure have a structure of formula (SA), (S-A'), (SB), or (SC) (wherein Y is hydrogen). 1a teeth, [ka] And Z 2 (wherein Y is hydrogen). In some embodiments, the lipids of the present disclosure have a structure of formula (SA), (S-A'), (SB), or (SC) (wherein Y is hydrogen). 1 and / or Y 1a teeth, [ka] And Z 2 (wherein Y is hydrogen). In some embodiments, the lipids of the present disclosure have a structure of formula (SA), (S-A'), (SB), or (SC) (wherein Y is hydrogen). 1 teeth, [ka] And Z 2 (wherein Y is hydrogen). In some embodiments, the lipids of the present disclosure have a structure of formula (SA), (S-A'), (SB), or (SC) (wherein Y is hydrogen). 1a teeth, [ka] And Z 2(wherein Y is hydrogen). In some embodiments, the lipids of the present disclosure have a structure of formula (SA), (S-A'), (SB), or (SC) (wherein Y is hydrogen). 1 and Y 1a Independently, [ka] In some embodiments, the lipids of the present disclosure have a structure of formula (SA), (S-A'), (SB), or (SC) (wherein Y 1 Independently, [ka] In some embodiments, the lipids of the present disclosure have a structure of formula (SA), (S-A'), (SB), or (SC) (wherein Y 1a Independently, [ka] In some embodiments, the lipids of the present disclosure have a structure of formula (SA), (S-A'), (SB), or (SC) (wherein X 3 This is an arbitrarily substituted C2-C 14 Alkyrenyl (e.g., C4-C 10 The lipids have an alkylenyl (C5-C7 alkylenyl, C5, C6, or C7 alkylenyl). In some embodiments, the lipids of the present disclosure have a structure of formula (SA), (S-A'), (SB), or (SC) (wherein X 3 (wherein X is a C5-C7 alkylenyl). In some embodiments, the lipids of the present disclosure have a structure of formula (SA), (S-A'), (SB), or (SC) (wherein X is a C5-C7 alkylenyl). 3 It has a C5 alkylenyl compound.

[0074] In some embodiments, the lipids of the present disclosure have a structure of formula (SA), (S-A'), (SB), or (SC) (wherein R 2 , R 3 , R 2’ , and / or R 3’(wherein R is hydrogen). In some embodiments, the lipids of the present disclosure have a structure of formula (SA), (S-A'), (SB), or (SC) (wherein R is hydrogen). 2 (wherein R is hydrogen). In some embodiments, the lipids of the present disclosure have a structure of formula (SA), (S-A'), (SB), or (SC) (wherein R is hydrogen). 3 (wherein R is hydrogen). In some embodiments, the lipids of the present disclosure have a structure of formula (SA), (S-A'), (SB), or (SC) (wherein R is hydrogen). 2’ (wherein R is hydrogen). In some embodiments, the lipids of the present disclosure have a structure of formula (SA), (S-A'), (SB), or (SC) (wherein R is hydrogen). 3’ It has (which is hydrogen).

[0075] In some embodiments, the lipids of the present disclosure have a structure of formula (SA), (S-A'), (SB), or (SC) (wherein R 2 , R 3 , R 2’ , and / or R 3’ This is an arbitrarily substituted C1-C 14 Alkyl (for example, C5-C 14 , C5-C 10 , C6-C9, C5, C6, C7, C8, C9, C 10 (is alkyl). In some embodiments, the lipids of the present disclosure have a structure of formula (SA), (S-A'), (SB), or (SC) (wherein R 2 C5-C 10 (is alkyl). In some embodiments, the lipids of the present disclosure have a structure of formula (SA), (S-A'), (SB), or (SC) (wherein R 3 C5-C 10 (is alkyl). In some embodiments, the lipids of the present disclosure have a structure of formula (SA), (S-A'), (SB), or (SC) (wherein R 2’ C5-C 10 (is alkyl). In some embodiments, the lipids of the present disclosure have a structure of formula (SA), (S-A'), (SB), or (SC) (wherein R 3’ C5-C10 (is alkyl). In some embodiments, the lipids of the present disclosure have a structure of formula (SA), (S-A'), (SB), or (SC) (wherein R 2 (wherein R is a C8 alkyl group). In some embodiments, the lipids of the present disclosure have a structure of formula (SA), (S-A'), (SB), or (SC) (wherein R is a C8 alkyl group). 3 (wherein R is a C8 alkyl group). In some embodiments, the lipids of the present disclosure have a structure of formula (SA), (S-A'), (SB), or (SC) (wherein R is a C8 alkyl group). 2’ (wherein R is a C8 alkyl group). In some embodiments, the lipids of the present disclosure have a structure of formula (SA), (S-A'), (SB), or (SC) (wherein R is a C8 alkyl group). 3’ It has a C8 alkyl group.

[0076] In some embodiments, the lipids of the present disclosure have a structure of formula (SA) or (SC) (wherein R 4 This is an arbitrarily substituted C4-C 14 Alkyl (for example, C6-C 12 , C8-C 12 , C6, C7, C8, C9, C 10 , C 11 , C 12 It has an alkyl structure. In some embodiments, the lipids of the present disclosure have a structure of formula (SA) or (SC) (wherein R 4 C6-C 12 (is alkyl). In some embodiments, the lipids of the present disclosure have a structure of formula (SA), (S-A'), (SB), or (SC) (wherein R 4 C 11 It has (being alkyl).

[0077] In some embodiments, the lipids of the present disclosure have a structure of formula (SA), (S-A'), (SB), or (SC) (wherein R 1 It has (which is OH).

[0078] In some embodiments, the lipids of this disclosure have a structure of formula (SA), (S-A'), (SB), or (SC) (wherein X 1 C 2-4 The lipids of this disclosure have an alkylenyl structure (e.g., C2, C3, or C4 alkylenyl). In some embodiments, the lipids of this disclosure have a structure of formula (SA), (S-A'), (SB), or (SC) (wherein X 1 (wherein X is a C2 alkylenyl). In some embodiments, the lipids of the present disclosure have a structure of formula (SA), (S-A'), (SB), or (SC) (wherein X is a C2 alkylenyl). 1 It has a C4 alkylenyl compound.

[0079] Formula (SD) In some embodiments, the lipids of this disclosure have the structure of formula (SD): [ka] or a pharmaceutically acceptable salt thereof (in the formula, A is -C(R ’ )(-L 1 -N(R'')R 6 )-, -C(R')(-OR 7a )-,-C(R')(-N(R'')R 8a )-, -C(R')(-C(=O)OR 9a )-, -C(R')(-C(=O)N(R'')R 10a )-, or -C(=NR 11a )-and; T is -X 2a -Y 1a -Q 1a or -X 3 -C(=O)OR 4 and; X 2 and X 2a This is an independently and arbitrarily substituted C2-C 14 Alkyrenyl or optionally substituted C2-C 14 It is alkenylenyl; X 3 This is an arbitrarily substituted C1-C 14 Alkyrenyl or optionally substituted C2-C14 It is alkenylenyl; Y 1 teeth, [ka] And, The combination marked with "*" is X 2 Joined; Y 1a teeth, [ka] And, The combination marked with "*" is X 2a Joined; each Z 3 These are independently of any substituted C1-C6 alkylenyl or any substituted C2-C 14 It is alkenylenyl; Q 1 -CH(SR 2 )(SR 3 ) and; Q 1a -CH(SR 2’ )(SR 3’ ) and; R 2 , and R 3 These are, independently, hydrogen, and optionally substituted C1-C 14 Alkyl, optionally substituted C2-C 14 Alkenylenyl, or -(CH2) m -G-(CH2) n H is; R 2’ and R 3’ These are, independently, hydrogen, and optionally substituted C1-C 14 Alkyl, optionally substituted C2-C 14 Alkenylenyl, or -(CH2) m -G-(CH2) n H is; G is a C3-C8 cycloalkylenyl; Each m is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; Each n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; X 3 This is an arbitrarily substituted C2-C 14 It is an alkylenyl; R 4 This is an arbitrarily substituted C4-C 14 It is alkyl; L 1 It is a C1-C8 alkylenyl; R 6 is a (hydroxy)C1-C6 alkyl or (amino)C1-C6 alkyl, R 7a is -C(=O)N(R''')R 7b , -C(=S)N(R''')R 7b -N=C(R 7b )(R 7c ), [ka] and; Z 1 is an optionally substituted C1-C6 alkyl group; R 10 It is a C1-C6 alkylenyl; R 7b These are C1-C6 alkyl, (hydroxy)C1-C6 alkyl, or (amino)C1-C6 alkyl; R 7c is hydrogen or a C1-C6 alkyl group; R 8a is -C(=O)N(R''')R 8b , -C(=S)N(R''')R 8b -N=C(R 8b )(R 8c ), [ka] and; R 8b These are C1-C6 alkyl, (hydroxy)C1-C6 alkyl, or (amino)C1-C6 alkyl; R 8cis hydrogen or a C1-C6 alkyl group; R 9a -N=C(R 9b )(R 9c ) and; R 9b These are C1-C6 alkyl, (hydroxy)C1-C6 alkyl, or (amino)C1-C6 alkyl; R 9c is hydrogen or a C1-C6 alkyl group; R 10a -N=C(R 10b )(R 10c ) and; R 10b These are C1-C6 alkyl, (hydroxy)C1-C6 alkyl, or (amino)C1-C6 alkyl; R 10c is hydrogen or a C1-C6 alkyl group; R 11a is -OR 11b ,-N(R'')R 11b -OC(=O)R 11b , or -N(R'')C(=O)R 11b and; R 11b These are C1-C6 alkyl, (hydroxy)C1-C6 alkyl, or (amino)C1-C6 alkyl; R' is either hydrogen or a C1-C6 alkyl group; R'' is either hydrogen or a C1-C6 alkyl group; R''' is either hydrogen or a C1-C6 alkyl group. It has.

[0080] In some embodiments, the lipids of this disclosure have the structure of formula (SD) (wherein A is -C(R ’ )(-L 1 N(R'')R 6 )-- has ).

[0081] In some embodiments, the lipids of this disclosure have the structure of formula (SD) (wherein A is -C(R')(-OR 7a )-- has ).

[0082] In some embodiments, the lipids of this disclosure have the structure of formula (SD) (wherein A is -C(R')(-N(R'')R 8a ) has )

[0083] In some embodiments, the lipids of this disclosure have the structure of formula (SD) (wherein A is C(R')(C(=O)OR 9a ) has )

[0084] In some embodiments, the lipids of this disclosure have the structure of formula (SD) (wherein A is C(R')(-C(=O)N(R'')R 10a )-- has ).

[0085] In some embodiments, the lipids of this disclosure have the structure of formula (SD) (wherein A is C(=NR)). 11a )-- has ).

[0086] In some embodiments, the lipids of this disclosure have the structure of formula (SD) (wherein T is -X 2a -Y 1a -Q 1a It has (is).

[0087] In some embodiments, the lipids of this disclosure have the structure of formula (SD) (wherein T is -X 3 -C(=O)OR 4 It has (is).

[0088] In some embodiments, the lipids of this disclosure have the structure of formula (SD) (wherein X 2 and / or X 2a This is an arbitrarily substituted C2-C 14 Alkyrenyl (e.g., C2-C 10 The lipids have an alkylenyl (C2-C8 alkylenyl, C2, C3, C4, C5, C6, C7, or C8 alkylenyl) structure (wherein X 2 C2-C 14The lipids have the structure of formula (SD) (wherein X 2a C2-C 14 The lipids have the structure of formula (SD) (wherein Y 1 and / or Y 1a teeth, [ka] In some embodiments, the lipids of this disclosure have the structure of formula (SD) (wherein Y 1 teeth, [ka] In some embodiments, the lipids of this disclosure have the structure of formula (SD) (wherein Y 1a teeth, [ka] In some embodiments, the lipids of this disclosure have the structure of formula (SD) (wherein Y 1 and / or Y 1a teeth, [ka] In some embodiments, the lipids of this disclosure have the structure of formula (SD) (wherein Y 1 teeth, [ka] In some embodiments, the lipids of this disclosure have the structure of formula (SD) (wherein Y 1a teeth, [ka] In some embodiments, the lipids of this disclosure have the structure of formula (SD) (wherein Y 1 and / or Y 1a teeth, [ka] In some embodiments, the lipids of this disclosure have the structure of formula (SD) (wherein Y 1 teeth, [ka] In some embodiments, the lipids of this disclosure have the structure of formula (SD) (wherein Y 1a teeth, [ka] In some embodiments, the lipids of this disclosure have the structure of formula (SD) (wherein Y 1 and / or Y 1a teeth, [ka] In some embodiments, the lipids of this disclosure have the structure of formula (SD) (wherein Y 1 teeth, [ka] In some embodiments, the lipids of this disclosure have the structure of formula (SD) (wherein Y 1a teeth, [ka] It has (is).

[0089] In some embodiments, the lipids of this disclosure have the structure of formula (SD) (wherein X 3 This is an arbitrarily substituted C1-C 14 The lipids have an alkylenyl (e.g., C1-C6, C1-C4 alkylenyl). In some embodiments, the lipids of this disclosure have the structure of formula (SD) (wherein X 3 C1-C 14 It has an alkylenyl compound.

[0090] In some embodiments, the lipids of this disclosure have the structure of formula (SD) (wherein R 2, R 3 , R 2’ , and / or R 3’ (wherein R is hydrogen). In some embodiments, the lipids of the present disclosure have the structure of formula (SD) (wherein R is hydrogen). 2 (wherein R is hydrogen). In some embodiments, the lipids of the present disclosure have the structure of formula (SD) (wherein R is hydrogen). 3 (wherein R is hydrogen). In some embodiments, the lipids of the present disclosure have the structure of formula (SD) (wherein R is hydrogen). 2’ (wherein R is hydrogen). In some embodiments, the lipids of the present disclosure have the structure of formula (SD) (wherein R is hydrogen). 3’ It has (which is hydrogen).

[0091] In some embodiments, the lipids of this disclosure have the structure of formula (SD) (wherein R 2 , R 3 , R 2’ , and / or R 3’ This is an arbitrarily substituted C1-C 14 Alkyl (for example, C4-C 10 It has alkyl, C5, C6, C7, C8, C9 alkyl) structures. In some embodiments, the lipids of the present disclosure have the structure of formula (SD) (wherein R 2 C4-C 10 It has an alkyl structure. In some embodiments, the lipids of the present disclosure have a structure of formula (SD) (wherein R 3 C4-C 10 It has an alkyl structure. In some embodiments, the lipids of the present disclosure have a structure of formula (SD) (wherein R 2’ C4-C 10 It has an alkyl structure. In some embodiments, the lipids of the present disclosure have a structure of formula (SD) (wherein R 3’ C4-C 10 It has (being alkyl).

[0092] In some embodiments, the lipids of this disclosure have the structure of formula (SD) (wherein R 4 This is an arbitrarily substituted C4-C 14 Alkyl (for example, C8-C 14 Alkyl, linear C8-C14 Alkyl, C8, C9, C 10 , C 11 , C 12 , C 13 , or C 14 It has an alkyl structure. In some embodiments, the lipids of the present disclosure have a structure of formula (SD) (wherein R 4 Linear C8-C 14 It has an alkyl structure. In some embodiments, the lipids of the present disclosure have a structure of formula (SD) (wherein R 4 Linear C 11 It has (being alkyl).

[0093] In some embodiments, the lipids of this disclosure have the structure of formula (SD) (wherein L 1 It has a C1-C3 alkylenyl compound.

[0094] In some embodiments, the lipids of this disclosure have the structure of formula (SD) (wherein R 6 It has (hydroxy)C1-C6 alkyl.

[0095] In some embodiments, the lipids of this disclosure have the structure of formula (SD) (wherein R 7a teeth, [ka] In some embodiments, the lipids of this disclosure have the structure of formula (SD) (wherein R 7a teeth, [ka] In some embodiments, the lipids of this disclosure have the structure of formula (SD) (wherein R 7a teeth, [ka] It has (is).

[0096] In some embodiments, the lipids of this disclosure have the structure of formula (SD) (wherein R 7ais -C(=O)N(R''')R 7b , -C(=S)N(R''')R 7b , and -N=C(R 7b )(R 7c The lipid has a structure of formula (SD) (wherein R 7a is -C(=O)N(R''')R 7b In some embodiments, the lipids of this disclosure have the structure of formula (SD) (wherein R 7a is -C(=S)N(R''')R 7b In some embodiments, the lipids of this disclosure have the structure of formula (SD) (wherein R 7a -N=C(R 7b )(R 7c ) has )

[0097] In some embodiments, the lipids of this disclosure have the structure of formula (SD) (wherein R 8a is -C(=O)N(R''')R 8b , -C(=S)N(R''')R 8b , and -N=C(R 8b )(R 8c The lipid has a structure of formula (SD) (wherein R 8a is -C(=O)N(R''')R 8b In some embodiments, the lipids of this disclosure have the structure of formula (SD) (wherein R 8a is -C(=S)N(R''')R 8b In some embodiments, the lipids of this disclosure have the structure of formula (SD) (wherein R 8a -N=C(R 8b )(R 8c ) has )

[0098] In some embodiments, the lipids of this disclosure have the structure of formula (SD) (wherein R 8a teeth, [ka] It has (is).

[0099] In some embodiments, the lipids of this disclosure have the structure of formula (SD) (wherein R 9b It has (hydroxy)C1-C6 alkyl.

[0100] In some embodiments, the lipids of this disclosure have the structure of formula (SD) (wherein R 10b It has (amino)C1-C6 alkyl.

[0101] In some embodiments, the lipids of this disclosure have the structure of formula (SD) (wherein R 11a is -OR 11b Or -OC(=O)R 11b In some embodiments, the lipids of this disclosure have the structure of formula (SD) (wherein R 11a is -OR 11b In some embodiments, the lipids of this disclosure have the structure of formula (SD) (wherein R 11a is -OC(=O)R 11b It has (is).

[0102] In some embodiments, the lipids of this disclosure have the structure of formula (SD) (wherein R 11a is -N(R'')R 11b Or -N(R'')C(=O)R 11b In some embodiments, the lipids of this disclosure have the structure of formula (SD) (wherein R 11a is -N(R'')R 11b In some embodiments, the lipids of this disclosure have the structure of formula (SD) (wherein R 11a is -N(R'')C(=O)R 11b It has (is).

[0103] In some embodiments, the lipids of this disclosure have the structure of formula (SD) (wherein R 11b It has (amino)C1-C6 alkyl.

[0104] Formula (SE) In some embodiments, the lipids of this disclosure have the structure of formula (SE): [ka] or a pharmaceutically acceptable salt thereof (in the formula, A is -N(-X 1 R 1 )-and; T is -X 2a -Y 1a -Q 1a or -X 3 -C(=O)OR 4 and; (i)X 1 is an arbitrarily substituted C2-C3 alkylenyl; R 1 teeth, [ka] , -NR''C(O)OR 20 , or -NR''R 21 is; or (ii)X 1 It is a C4-C6 alkylenyl, R 1 teeth, [ka] , -NR''C(O)OR 20 , or -NR''R 21 and; Z 1 is an optionally substituted C1-C6 alkyl group; Z 1a is a hydrogen- or optionally substituted C1-C6 alkyl group; R 20 is an optionally substituted C1-C6 alkyl group; R 21 It is -(C2 alkylenyl)-OH; X 2 and X 2a This is an independently and arbitrarily substituted C2-C 14 Alkyrenyl or optionally substituted C2-C 14 It is alkenylenyl; X 3 This is an arbitrarily substituted C2-C 14 Alkyrenyl or optionally substituted C2-C 14 It is alkenylenyl; Y 1 is to combine, [ka] And, The combination marked with "*" is X 2 Joined; Y 1a teeth, [ka] and; The combination marked with "*" is X 2a Joined; Y 1 and Y 1a teeth, [ka] And R 1 teeth, [ka] and; each Z 2 These are independently H or optionally substituted C1-C8 alkyl groups; each Z 3 These are independently of any substituted C1-C6 alkylenyl or any substituted C2-C 14 It is alkenylenyl; Q 1 -CH(SR 2 )(SR 3 ) and; Q 1a -CH(SR 2’ )(SR 3’ ) and; R 2 and R 3 These are, independently, hydrogen, and optionally substituted linear C1-C 14 Alkyl, optionally substituted C2-C 14Alkenylenyl, or -(CH2) m -G-(CH2) n H is; R 2’ and R 3’ These are, independently, hydrogen, and optionally substituted linear C1-C 14 Alkyl or optionally substituted C2-C 14 It is alkenylenyl; X 3 This is an arbitrarily substituted C2-C 14 It is an alkylenyl; R 4 This is an arbitrarily substituted C4-C 14 It is alkyl; (R'' is hydrogen or a C1-C6 alkyl group.) It has.

[0105] In some embodiments, the lipids of this disclosure have the structure of formula (SE) (wherein R 1 teeth, [ka] And Z 1 It is methyl, and Z 1a It has (which is hydrogen or methyl).

[0106] In some embodiments, the lipids of this disclosure have the structure of formula (SE) (wherein R 1 teeth, [ka] And Z 1 It has (which is methyl).

[0107] In some embodiments, the lipids of this disclosure have the structure of formula (SE) (wherein R 1 is -NR''C(O)OR 20 It has (is).

[0108] In some embodiments, the lipids of this disclosure have the structure of formula (SE) (wherein R 1 -NR''R 21 It has (is).

[0109] In some embodiments, the lipids of this disclosure have the structure of formula (SE) (wherein R 20 It contains (t-butyl or benzyl).

[0110] In some embodiments, the lipids of this disclosure have the structure of formula (SE) (wherein X 2 and / or X 2a This is an arbitrarily substituted C2-C 14 The lipids have an alkylenyl structure (e.g., C4-C8 alkylenyl, C4, C5, C6, C7, C8 alkylenyl). In some embodiments, the lipids of this disclosure have a structure of formula (SE) (wherein X 2 (wherein X is a C4-C8 alkylenyl). In some embodiments, the lipids of the present disclosure have the structure of formula (SE) (wherein X is a C4-C8 alkylenyl). 2a It has a C4-C8 alkylenyl compound.

[0111] In some embodiments, the lipids of this disclosure have the structure of formula (SE) (wherein Y 1 and / or Y 1a teeth, [ka] In some embodiments, the lipids of this disclosure have the structure of formula (SE) (wherein Y 1 teeth, [ka] In some embodiments, the lipids of this disclosure have the structure of formula (SE) (wherein Y 1a teeth, [ka] In some embodiments, the lipids of this disclosure have the structure of formula (SE) (wherein Y 1 and / or Y 1a teeth, [ka] In some embodiments, the lipids of this disclosure have the structure of formula (SE) (wherein Y 1 teeth, [ka] In some embodiments, the lipids of this disclosure have the structure of formula (SE) (wherein Y 1a teeth, [ka] In some embodiments, the lipids of this disclosure have the structure of formula (SE) (wherein Y 1 and / or Y 1a teeth, [ka] And Z 3 (wherein Y is a C2 alkylenyl). In some embodiments, the lipids of the present disclosure have the structure of formula (SE) (wherein Y is a C2 alkylenyl). 1 teeth, [ka] And Z 3 (wherein Y is a C2 alkylenyl). In some embodiments, the lipids of the present disclosure have the structure of formula (SE) (wherein Y is a C2 alkylenyl). 1a teeth, [ka] And Z 3 (wherein Y is a C2 alkylenyl). In some embodiments, the lipids of the present disclosure have the structure of formula (SE) (wherein Y is a C2 alkylenyl). 1 and / or Y 1a teeth, [ka] And Z 3 (wherein Y is a C2 alkylenyl). In some embodiments, the lipids of the present disclosure have the structure of formula (SE) (wherein Y is a C2 alkylenyl). 1 teeth, [ka] And Z 3 (wherein Y is a C2 alkylenyl). In some embodiments, the lipids of the present disclosure have the structure of formula (SE) (wherein Y is a C2 alkylenyl). 1a teeth, [ka] And Z 3 (wherein R is a C2 alkylenyl). In some embodiments, the lipids of the present disclosure have the structure of formula (SE) (wherein R is a C2 alkylenyl). 2 , R 3 , R 2’ , and R 3’ These are, independently, hydrogen, and optionally substituted linear C1-C 14 Alkyl (for example, C4-C 10 The lipids have the structure of formula (SE) (wherein R 2 (wherein R is hydrogen). In some embodiments, the lipids of the present disclosure have the structure of formula (SE) (wherein R is hydrogen). 3 (wherein R is hydrogen). In some embodiments, the lipids of the present disclosure have the structure of formula (SE) (wherein R is hydrogen). 2’ (wherein R is hydrogen). In some embodiments, the lipids of the present disclosure have the structure of formula (SE) (wherein R is hydrogen). 3’ (wherein R is hydrogen). In some embodiments, the lipids of the present disclosure have the structure of formula (SD) (wherein R is hydrogen). 2 is linear C4-C 10 It has an alkyl structure. In some embodiments, the lipids of the present disclosure have a structure of formula (SD) (wherein R 3 is linear C4-C 10 It has an alkyl structure. In some embodiments, the lipids of the present disclosure have a structure of formula (SD) (wherein R 2’ is linear C4-C 10 It has an alkyl structure. In some embodiments, the lipids of the present disclosure have a structure of formula (SD) (wherein R 3’ is linear C4-C 10 It has (being alkyl).

[0112] Formula (SF) In some embodiments, the lipids of this disclosure have the structure of formula (SF): [ka] or a pharmaceutically acceptable salt thereof (in the formula, R 1 teeth, [ka] and; Z 1 is an optionally substituted C1-C6 alkyl group; X 1 is an arbitrarily substituted C2-C6 alkylenyl; X 2 and X 2a This is an independently and arbitrarily substituted C2-C 14 It is an alkylenyl; Y 1 and Y 1a Independently, [ka] And, Z 3 These are independently and arbitrarily substituted C2-C6 alkylenyl compounds; R 2 and R 3 This is independently and arbitrarily substituted C4-C 14 It is alkyl; R 2’ and R 3’ This is independently and arbitrarily substituted C4-C 14 (It is alkyl.) It has.

[0113] In some embodiments, the lipids of the present disclosure have the structure of formula (SF) (wherein R 1 teeth, [ka] And Z 1It has (which is methyl).

[0114] In some embodiments, the lipids of this disclosure have a structure of formula (SF) (wherein X 1 (wherein X is a C2-C4 alkylenyl molecule). In some embodiments, the lipids of this disclosure have the structure of formula (SF) (wherein X is a C2-C4 alkylenyl molecule). 1 It has a C3 alkylenyl compound.

[0115] In some embodiments, the lipids of this disclosure have a structure of formula (SF) (wherein X 2 C4-C 10 The lipids of this disclosure have the structure of formula (SF) (wherein X 2 It has a C6 alkyl group.

[0116] In some embodiments, the lipids of the present disclosure have the structure of formula (SF) (wherein R 2 and R 3 This is independently and arbitrarily substituted C4-C 10 It has an alkyl group (for example, a C8 alkyl group). In some embodiments, the lipids of the present disclosure have a structure of formula (SF) (wherein R 2 and R 3 It independently has a C8 alkyl group.

[0117] Formula (SG) In some embodiments, the lipids of this disclosure have the structure of formula (SG): [ka] or a pharmaceutically acceptable salt thereof (in the formula, R 20 C1-C6 alkylenyl-NR 20’ C(O)OR 20’’ and; R 20’ is a hydrogen- or optionally substituted C1-C6 alkyl group; R 20’’is optionally substituted C1-C6 alkyl, phenyl, or benzyl; Z 1 is an optionally substituted C1-C6 alkyl group; X 2 and X 2a This is an independently and arbitrarily substituted C2-C 14 It is an alkylenyl; Y 1 and Y 1a Independently, [ka] and; The combination marked with "*" is X 2 or X 2a Joined; Z 3 These are independently and arbitrarily substituted C2-C6 alkylenyl compounds; R 2 and R 3 This is independently and arbitrarily substituted C4-C 14 It is alkyl; R 2’ and R 3’ This is independently and arbitrarily substituted C4-C 14 (It is alkyl.) It has.

[0118] In some embodiments, the lipids of this disclosure have the structure of formula (SG) (wherein R 20 (is -CH2CH2CH2NHC(O)Ot-butyl or -CH2CH2CH2NHC(O)O-benzyl). In some embodiments, the lipids of the present disclosure have the structure of formula (SG) (wherein R 20 (wherein R is -CH2CH2CH2NHC(O)Ot-butyl). In some embodiments, the lipids of the present disclosure have the structure of formula (SG) (wherein R is R). 20 It has -CH2CH2CH2NHC(O)O-benzyl.

[0119] In some embodiments, the lipids of this disclosure have a structure of formula (SG) (wherein X 2 and X2a The molecules independently have C4-C8 alkylenyl (e.g., C5, C6, C7 alkylenyl). In some embodiments, the lipids of the present disclosure have the structure of formula (SG) (wherein X 2 (wherein X is a C6 alkyl group). In some embodiments, the lipids of the present disclosure have the structure of formula (SG) (wherein X is a C6 alkyl group). 2a It has a C6 alkyl group.

[0120] In some embodiments, the lipids of this disclosure have a structure of formula (SG) (wherein Y 1 and Y 1a teeth, [ka] And Z 3 (wherein Y is a C2-C4 alkylenyl molecule). In some embodiments, the lipids of this disclosure have the structure of formula (SG) (wherein Y is a C2-C4 alkylenyl molecule). 1 teeth, [ka] And Z 3 (wherein Y is a C2-C4 alkylenyl molecule). In some embodiments, the lipids of this disclosure have the structure of formula (SG) (wherein Y is a C2-C4 alkylenyl molecule). 1a teeth, [ka] And Z 3 It has a C2-C4 alkylenyl (for example, a C2 alkylenyl).

[0121] In some embodiments, the lipids of this disclosure have the structure of formula (SG) (wherein R 2 , R 3 , R 2’ and R 3’ This is independently and arbitrarily substituted C4-C 10 The molecule has an alkyl group (e.g., C6-C9 alkyl, C6, C7, C8, C9 alkyl). In some embodiments, the lipids of this disclosure have a structure of formula (SG) (wherein R2 The molecule has a C6-C9 alkyl group. In some embodiments, the lipids of this disclosure have a structure of formula (SG) (wherein R 3 The molecule has a C6-C9 alkyl group. In some embodiments, the lipids of this disclosure have a structure of formula (SG) (wherein R 2’ The molecule has a C6-C9 alkyl group. In some embodiments, the lipids of this disclosure have a structure of formula (SG) (wherein R 3’ It has a C6-C9 alkyl group.

[0122] Formula (SH) In some embodiments, the lipids of this disclosure have the structure of formula (SH): [ka] or a pharmaceutically acceptable salt thereof (in the formula, R 1 is -OH or [ka] and; X 1 is an arbitrarily substituted C4 alkylenyl; X 2 and X 2a This is an independently and arbitrarily substituted C2-C 14 It is an alkylenyl; Y 1 and Y 1a Independently, [ka] and; Z 3 These are independently and arbitrarily substituted C2-C6 alkylenyl compounds; R 2 and R 3 This is independently and arbitrarily substituted C4-C 14 C1-C2 alkyl groups substituted with alkyl or optionally substituted cyclopropyl groups; or R 2’ and R 3’This is independently and arbitrarily substituted C4-C 14 (C1-C2 alkyl groups substituted with alkyl or optionally substituted cyclopropyl groups) It has.

[0123] In some embodiments, the lipids of this disclosure have a structure of formula (SH) (wherein X 1 It has a C4 alkylenyl compound.

[0124] In some embodiments, the lipids of this disclosure have a structure of formula (SH) (wherein X 2 and X 2a This is independently and arbitrarily substituted C4-C 10 Alkyrenyl (e.g., C5, C6, C7, C8, C9, or C 10 In some embodiments, the lipids of the present disclosure have the structure of formula (SH) (wherein X 2 C4-C 10 In some embodiments, the lipids of the present disclosure have the structure of formula (SH) (wherein X 2a C4-C 10 It has an alkylenyl compound.

[0125] In some embodiments, the lipids of the present disclosure have a structure of formula (SH) (wherein Y 1 and Y 1a Independently, [ka] And Z 3 It independently has a C2-C4 alkylenyl (e.g., a C2, C4 alkylenyl).

[0126] In some embodiments, the lipids of this disclosure have the structure of formula (SH) (wherein R 2 , R 3 , R 2’ and R 3’ It is independently, C6-C 14 Alkyl (e.g., C6, C7, C8, C9, C 10 , C 11 , C12 , C 13 , or C 14 The lipids have an alkyl group (or a C1-C2 alkyl group substituted with an optionally substituted cyclopropyl group). In some embodiments, the lipids of the present disclosure have a structure of formula (SH) (wherein R 2 , R 3 , R 2’ and R 3’ It is independently, C6-C 14 Alkyl (e.g., C6, C7, C8, C9, C 10 , C 11 , C 12 , C 13 , or C 14 It has an alkyl structure. In some embodiments, the lipids of the present disclosure have a structure of formula (SH) (wherein R 2 C6-C 14 It has an alkyl structure. In some embodiments, the lipids of the present disclosure have a structure of formula (SH) (wherein R 3 C6-C 14 It has an alkyl structure. In some embodiments, the lipids of the present disclosure have a structure of formula (SH) (wherein R 2’ C6-C 14 It has an alkyl structure. In some embodiments, the lipids of the present disclosure have a structure of formula (SH) (wherein R 3’ C6-C 14 It has an alkyl structure. In some embodiments, the lipids of the present disclosure have a structure of formula (SH) (wherein R 2 (wherein R is a C1-C2 alkyl substituted with a substituted cyclopropyl). In some embodiments, the lipids of the present disclosure have the structure of formula (SH) (wherein R is a C1-C2 alkyl substituted with a substituted cyclopropyl). 3 (wherein R is a C1-C2 alkyl substituted with a substituted cyclopropyl). In some embodiments, the lipids of the present disclosure have the structure of formula (SH) (wherein R is a C1-C2 alkyl substituted with a substituted cyclopropyl). 2’ (wherein R is a C1-C2 alkyl substituted with a substituted cyclopropyl). In some embodiments, the lipids of the present disclosure have the structure of formula (SH) (wherein R is a C1-C2 alkyl substituted with a substituted cyclopropyl). 3’ It has a substituted cyclopropyl-substituted C1-C2 alkyl group.

[0127] In some embodiments, the lipids of this disclosure have the structure of formula (SH) (wherein R 2 , R 3 , R 2’ and R 3’ This is independently a C1-C6 alkyl-substituted cyclopropylene, optionally substituted with C1-C6 alkyl. 6 The lipids have a structure of formula (SH) (wherein R 2 The molecule has a cyclopropylene-(C1-C6 alkylenyl optionally substituted with a C1-C6 alkyl) C1-C2 alkyl group. In some embodiments, the lipids of this disclosure have a structure of formula (SH) (wherein R 3 This is a cyclopropylene-(C1-C6 alkyl-substituted cyclopropylene, optionally substituted with C1-C 6 The lipids have a structure of formula (SH) (wherein R 2’ This is a cyclopropylene-(C1-C6 alkyl-substituted cyclopropylene, optionally substituted with C1-C 6 The lipids have a structure of formula (SH) (wherein R 3’ This is a cyclopropylene-(C1-C6 alkyl-substituted cyclopropylene, optionally substituted with C1-C 6 It has a C1-C2 alkyl group substituted with an alkylenyl group.

[0128] Formula (SJ) In some embodiments, the lipids of this disclosure have the structure of formula (SJ): [ka] or a pharmaceutically acceptable salt thereof (in the formula, R 1 is -OH or [ka] and; X 1 It is a branched C2-C8 alkylenyl, X 2 and X 2a This is an independently and arbitrarily substituted C2-C 14 It is an alkylenyl; Y 1 and Y 1a Independently, [ka] and; Z 3 These are independently and arbitrarily substituted C2-C6 alkylenyl compounds; R 2 and R 3 This is independently and arbitrarily substituted C4-C 14 It is alkyl; R 2’ and R 3’ This is independently and arbitrarily substituted C4-C 14 (It is alkyl.) It has.

[0129] In some embodiments, the lipids of this disclosure have the structure of formula (SJ) (wherein X 1 It has a branched C6 alkylenyl group.

[0130] In some embodiments, the lipids of this disclosure have the structure of formula (SJ) (wherein X 2 and X 2a It is independently, C4-C 10 The lipids have an alkylenyl (e.g., C6, C7, C8 alkylenyl). In some embodiments, the lipids of this disclosure have the structure of formula (SJ) (wherein X 2 C4-C 10 In some embodiments, the lipids of this disclosure have the structure of formula (SJ) (wherein X 2a C4-C 10 It has an alkylenyl compound.

[0131] In some embodiments, the lipids of this disclosure have the structure of formula (SJ) (wherein Y 1 and Y 1a teeth, [ka] And Z 3 (is independently an optionally substituted C2 alkylenyl). In some embodiments, the lipids of the present disclosure have the structure of formula (SJ) (wherein Y 1 teeth, [ka] And Z 3 (is independently an optionally substituted C2 alkylenyl). In some embodiments, the lipids of the present disclosure have the structure of formula (SJ) (wherein Y 1a teeth, [ka] And Z 3 It independently has an optionally substituted C2 alkylenyl compound.

[0132] In some embodiments, the lipids of this disclosure have the structure of formula (SJ) (wherein R 2 , R 3 , R 2’ and R 3’ It is independently, C6-C 12 C4-C4 is optionally substituted with alkyl (e.g., C9 alkyl) or C2-C8 alkenylene (e.g., C4, C6 alkenylene). 10 The lipids have an alkyl group (e.g., C4, C6 alkyl). In some embodiments, the lipids of the present disclosure have a structure of formula (SJ) (wherein R 2 C6-C 12 It has an alkyl structure. In some embodiments, the lipids of the present disclosure have a structure of formula (SJ) (wherein R 3 C6-C 12 It has an alkyl structure. In some embodiments, the lipids of the present disclosure have a structure of formula (SJ) (wherein R 2’ C6-C 12It has an alkyl structure. In some embodiments, the lipids of the present disclosure have a structure of formula (SJ) (wherein R 3’ C6-C 12 It has an alkyl structure. In some embodiments, the lipids of the present disclosure have a structure of formula (SJ) (wherein R 2 This is a C4-C compound optionally substituted with a C2-C8 alkenylene. 10 It has an alkyl structure. In some embodiments, the lipids of the present disclosure have a structure of formula (SJ) (wherein R 3 This is a C4-C compound optionally substituted with a C2-C8 alkenylene. 10 It has an alkyl structure. In some embodiments, the lipids of the present disclosure have a structure of formula (SJ) (wherein R 2’ This is a C4-C compound optionally substituted with a C2-C8 alkenylene. 10 It has an alkyl structure. In some embodiments, the lipids of the present disclosure have a structure of formula (SJ) (wherein R 3’ This is a C4-C compound optionally substituted with a C2-C8 alkenylene. 10 It has (being alkyl).

[0133] Formula (SK) In some embodiments, the lipids of this disclosure have the structure of formula (SK): [ka] or a pharmaceutically acceptable salt thereof (in the formula, R 1 is -OH; X 1 is an arbitrarily substituted C2-C6 alkylenyl; X 2 and X 2a This is an independently and arbitrarily substituted C2-C 14 It is an alkylenyl; Y 1 and Y 1a Each of them is a combination; R 2 and R 3 This is independently and arbitrarily substituted C4-C 14 It is alkyl; R 2’and R 3’ This is independently and arbitrarily substituted C4-C 14 (It is alkyl.) It has.

[0134] In some embodiments, the lipids of this disclosure have a structure of formula (SK) (wherein X 1 It has a C4 alkylenyl compound.

[0135] In some embodiments, the lipids of this disclosure have a structure of formula (SK) (wherein X 2 and X 2a It is independently, C4-C 10 The lipids have an alkylenyl structure (e.g., C6-C8 alkylenyl, C6, C7, C8 alkylenyl). In some embodiments, the lipids of the present disclosure have a structure of formula (SK) (wherein X 2 C4-C 10 In some embodiments, the lipids of this disclosure have the structure of formula (SK) (wherein X 2a C4-C 10 It has an alkylenyl compound.

[0136] In some embodiments, the lipids of this disclosure have the structure of formula (SK) (wherein R 2 , R 3 , R 2’ and R 3’ It is independently, C6-C 10 Alkyl (for example, C 7. In some embodiments, the lipids of the present disclosure have the structure of formula (SK) (wherein R 2 C6-C 10 It has an alkyl structure. In some embodiments, the lipids of the present disclosure have a structure of formula (SK) (wherein R 3 C6-C 10 It has an alkyl structure. In some embodiments, the lipids of the present disclosure have a structure of formula (SK) (wherein R 2’ C6-C 10 It has an alkyl structure. In some embodiments, the lipids of the present disclosure have a structure of formula (SK) (wherein R 3’ C6-C10 It has (being alkyl).

[0137] Expression (SL) In some embodiments, the lipids of this disclosure have the structure of formula (SL): [ka] or a pharmaceutically acceptable salt thereof (in the formula, R 1 -OH, -R 1a And, X 1 is an arbitrarily substituted C2-C6 alkylenyl; (i)Y 1 teeth, [ka] and; Z 3 is an arbitrarily substituted C2-C6 alkylenyl; R 2 and R 3 This is independently and arbitrarily substituted C4-C 14 It is alkyl; X 2 and X 3 is a C5 alkylenyl; or (ii)Y 1 It is a combination, R 2 and R 3 These are independently C4-C7 alkyl groups; X 2 This is an arbitrarily substituted C2-C 14 It is an alkylenyl; X 3 is an arbitrarily substituted C5 alkylenyl; R 4 This is an arbitrarily substituted C4-C 14 It is alkyl; R 1a teeth, [ka] and; R2a , R 2b , and R 2c These are independently hydrogen and C1-C6 alkyl; R 3a , R 3b , and R 3c These are independently hydrogen and C1-C6 alkyl; R 4a , R 4b , and R 4c These are independently hydrogen and C1-C6 alkyl; R 5a , R 5b , and R 5c (These are independently hydrogen and C1-C6 alkyl.) It has.

[0138] In some embodiments, the lipids of this disclosure have the structure of formula (SL) (wherein R 1 It has (which is OH).

[0139] In some embodiments, the lipids of this disclosure have the structure of formula (SL) (wherein X 1 It has a C2 alkylenyl compound.

[0140] In some embodiments, the lipids of this disclosure have the structure of formula (SL) (wherein Y 1 teeth, [ka] And Z 3 It has a C2 alkylenyl compound.

[0141] In some embodiments, the lipids of this disclosure have the structure of formula (SL) (wherein R 2 and R 3 It is independently, C6-C 12 Alkyl (C7, C8, C9, C 10 , C 11 It has an alkyl structure. In some embodiments, the lipids of the present disclosure have a structure of formula (SL) (wherein R 2 C6-C 12It has an alkyl structure. In some embodiments, the lipids of the present disclosure have a structure of formula (SL) (wherein R 3 C6-C 12 It has (being alkyl).

[0142] In some embodiments, the lipids of this disclosure have the structure of formula (SL) (wherein Y 1 It has a bond.

[0143] In some embodiments, the lipids of this disclosure have the structure of formula (SL) (wherein R 2 and R 3 R is a C4-C7 alkyl (e.g., C7 alkyl). In some embodiments, the lipids of the present disclosure have the structure of formula (SL) (wherein R is a C4-C7 alkyl). 2 The molecule has a C4-C7 alkyl group. In some embodiments, the lipids of this disclosure have a structure of formula (SL) (wherein R 3 It has a C4-C7 alkyl group.

[0144] In some embodiments, the lipids of this disclosure have the structure of formula (SL) (wherein X 2 C6-C 12 Alkyrenyl (e.g., C7, C8, C9, C 10 It has an alkylenyl compound.

[0145] Formula (S-I') In some embodiments, the lipids of this disclosure have the structure of formula (S-I'): [ka] or a pharmaceutically acceptable salt thereof (in the formula, X is either N or CH; Y is a combination, [ka] And the combinations indicated by "**" are joined to X; Each Z is, [ka] The combinations independently selected from the group consisting of "*" are joined to L; Each L is independently C2-C 10 It is an alkylenyl; R 1 OH, -N(R 3 )2, [ka] and; Each R is independently either -H or C1-C6 aliphatic; R Z is NR2 or OH; X Z This is an arbitrarily substituted C2-C 14 Alkyrenyl or optionally substituted C2-C 14 It is alkenylenyl; Each R 2 is an arbitrarily substituted C 2-14 Alkyl and C 2-14 Selected independently from Alkenil, C2-C 14 Any -(CH2)2- in the alkyl group can be optionally replaced with a C3-C6 cycloalkylenyl group; Each R 3 H and C 1-6 Selected independently of alkyl; n is selected from 0 to 6; (Each p is independently selected from 1 to 6) It has.

[0146] Equation (SI) In some embodiments, the lipids of this disclosure have the structure of formula (SI): [ka] or a pharmaceutically acceptable salt thereof (in the formula, X is either N or CH; Y is a combination, [ka] And the combinations indicated by "**" are joined to X; Each Z is, [ka] The combinations independently selected from the group consisting of "*" are joined to L; Each L is independently C2-C 10 It is an alkylenyl; R 1 OH, N(R 3 )2, [ka] and; Each R is independently either -H or C1-C6 aliphatic; Each R 2 is an arbitrarily substituted C 2-14 Alkyl and C 2-14 Selected independently from Alkenil, C2-C 14 Any -(CH2)2- in the alkyl group can be optionally replaced with a C3-C6 cycloalkylenyl group; Each R 3 H and C 1-6 Selected independently of alkyl; n is selected from 1 to 6; (Each p is independently selected from 1 to 6) It has.

[0147] X In some embodiments, the lipids of the Disclosure have a structure of formula (SI), or (S-I'), or (SI) (wherein X is N). In some embodiments, the lipids of the Disclosure have a structure of formula (SI), or (S-I'), or (SI) (wherein X is CH).

[0148] Y In some embodiments, the lipids of the Disclosure have a structure of formula (SI), or (S-I'), or (SI) (wherein Y is a bond). [ka] The bonds indicated by "**" are bonded to X). In some embodiments, the lipids of the present disclosure have a structure of formula (SI) or (S-I') (wherein Y is [ka] The bond indicated by "**" is bonded to X). In some embodiments, the lipids of the present disclosure have a structure of formula (SI) or (S-I') (wherein Y is [ka] The combinations indicated by "**" are joined to X.

[0149] Z In some embodiments, the lipids of this disclosure have a structure of formula (SI) or (S-I') (wherein Z is [ka] The bond indicated by "*" is bonded to X). In some embodiments, the lipids of the present disclosure have the structure of formula (SI) or (S-I') (wherein Z is [ka] The bond indicated by "*" is bonded to X). In some embodiments, the lipids of the present disclosure have the structure of formula (SI) or (S-I') (wherein Z is [ka] The bond indicated by "*" is bonded to X). In some embodiments, the lipids of the present disclosure have the structure of formula (SI) or (S-I') (wherein Z is [ka] The bond indicated by "*" is bonded to X). In some embodiments, the lipids of the present disclosure have the structure of formula (SI) or (S-I') (wherein Z is [ka] The bond indicated by "*" is bonded to X). In some embodiments, the lipids of the present disclosure have the structure of formula (SI) or (S-I') (wherein Z is [ka] The bond indicated by "*" is bonded to X). In some embodiments, the lipids of the present disclosure have the structure of formula (SI) or (S-I') (wherein Z is [ka] The combinations marked with "*" have the following properties (they are joined to X).

[0150] L In some embodiments, the lipids of the present disclosure have a structure of formula (SI) or (S-I') (wherein L is C2-C 10 In some embodiments, the lipids of the Disclosure have a structure of formula (SI) or (S-I') (wherein L is a C5-C8 alkylenyl). In some embodiments, the lipids of the Disclosure have a structure of formula (SI) or (S-I') (wherein L is a C5 alkylenyl). In some embodiments, the lipids of the Disclosure have a structure of formula (SI) or (S-I') (wherein L is a C6 alkylenyl). In some embodiments, the lipids of the Disclosure have a structure of formula (SI) or (S-I') (wherein L is a C7 alkylenyl). In some embodiments, the lipids of the Disclosure have a structure of formula (SI) or (S-I') (wherein L is a C8 alkylenyl).

[0151] R 1 In some embodiments, the lipid of the present disclosure has the structure of formula (S-I) or (S-I') (wherein R 1 is OH). In some embodiments, the lipid of the present disclosure has the structure of formula (S-I) or (S-I') (wherein R 1 is N(R 3 )2). In some embodiments, the lipid of the present disclosure has the structure of formula (S-I) or (S-I') (wherein R 1 is

Chemical formula

Chemical formula

Chemical formula

[0152] In some embodiments, the lipid of the present disclosure has the structure of formula (S-I) or (S-I') (wherein R 1 is OH, -N(R 3 )2,

Chemical formula

[0153] In some embodiments, the lipid of the present disclosure has the structure of formula (S-I) or (S-I') (wherein R 1 is OH, N(R 3 )2, and

Chemical formula

Chemical formula

[0154] In some embodiments, the lipid of the present disclosure has the structure of formula (S-Ia):

Chemical formula

[0155] In some embodiments, the lipid of the present disclosure has the structure of formula (S-Ib):

Chemical formula

[0156] In some embodiments, the lipids of this disclosure have the structure of formula (S-Ic): [ka] or a pharmaceutically acceptable salt thereof (in the formula, Each R 2 is an arbitrarily substituted C 2-14 Alkyl and C 2-14 Selected independently from Alkenil, C2-C 14 Any -(CH2)2- in the alkyl group can be optionally replaced with a C3-C6 cycloalkylenyl group; n is selected from 1 to 4; Each m is independently selected from 2 to 10; Each p is independently selected from 2 to 6. It has.

[0157] R 2 In some embodiments, the lipids of the present disclosure have the structure of formula (SI), formula (S-I'), formula (S-Ia), or formula (S-Ib) (wherein R 2 is an arbitrarily substituted C 2-14 (is alkyl). In some embodiments, the lipids of the present disclosure have a structure of formula (SI), formula (S-I'), formula (S-Ia), or formula (S-Ib) (wherein R 2 is an arbitrarily substituted C 7-12 (is alkyl). In some embodiments, the lipids of the present disclosure have a structure of formula (SI), formula (S-I'), formula (S-Ia), or formula (S-Ib) (wherein R 2 teeth, [ka] (Selected independently from the group consisting of)

[0158] In some embodiments, the lipids of the present disclosure have the structure of formula (SI), formula (S-I'), formula (S-Ia), or formula (S-Ib) (wherein R 2 teeth, [ka] In some embodiments, the lipids of the present disclosure have a structure of formula (SI), formula (S-I'), formula (S-Ia), or formula (S-Ib) (wherein R 2 teeth, [ka] In some embodiments, the lipids of the present disclosure have a structure of formula (SI), formula (S-I'), formula (S-Ia), or formula (S-Ib) (wherein R 2 teeth, [ka] In some embodiments, the lipids of the present disclosure have a structure of formula (SI), formula (S-I'), formula (S-Ia), or formula (S-Ib) (wherein R 2 teeth, [ka] In some embodiments, the lipids of the present disclosure have a structure of formula (SI), formula (S-I'), formula (S-Ia), or formula (S-Ib) (wherein R 2 is an arbitrarily substituted C 2-14 The lipids of this disclosure have the structure of formula (SI), formula (S-I'), formula (S-Ia), or formula (S-Ib) (wherein R 2 teeth, [ka] (Selected independently from) In some embodiments, the lipids of the present disclosure have a structure of formula (SI), formula (S-I'), formula (S-Ia), or formula (S-Ib) (wherein R 2 teeth, [ka] It has (is).

[0159] In some embodiments, the lipids of the present disclosure have the structure of formula (SI), formula (S-I'), formula (S-Ia), or formula (S-Ib) (wherein R 2 is an arbitrarily substituted C 8-9 The lipids of this disclosure have the structure of formula (SI), formula (S-I'), formula (S-Ia), or formula (S-Ib) (wherein R 2 teeth, [ka] In some embodiments, the lipids of the present disclosure have a structure of formula (SI), formula (S-I'), formula (S-Ia), or formula (S-Ib) (wherein R 2 teeth, [ka] In some embodiments, the lipids of the present disclosure have a structure of formula (SI), formula (S-I'), formula (S-Ia), or formula (S-Ib) (wherein R 2 teeth, [ka] It has (is).

[0160] R 3 In some embodiments, the lipids of the present disclosure have a structure of formula (SI) or formula (S-Ib) (wherein R 3 It has (which is hydrogen).

[0161] In some embodiments, the lipids of the present disclosure have the structure of formula (SI), formula (S-I'), formula (S-Ia), or formula (S-Ib) (wherein R 3 C 1-6 The lipids have the structure of formula (SI) or (S-I') (wherein each R 3(The elements are C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, or C6 alkyl.)

[0162] n In some embodiments, the lipids of the Disclosure have the structure of formula (SI), formula (S-I'), formula (S-Ia), or formula (S-Ib) (wherein n is 3). In some embodiments, the lipids of the Disclosure have the structure of formula (SI), formula (S-I'), formula (S-Ia), or formula (S-Ib) (wherein n is 4). In some embodiments, the lipids of the Disclosure have the structure of formula (SI), formula (S-I'), formula (S-Ia), or formula (S-Ib) (wherein n is 1, 2, 5, or 6).

[0163] m In some embodiments, the lipids of the Disclosure have the structure of formula (S-Ia) or formula (S-Ib) (wherein m is selected from 5 to 8). In some embodiments, the lipids of the Disclosure have the structure of formula (S-Ia) or formula (S-Ib) (wherein m is 5). In some embodiments, the lipids of the Disclosure have the structure of formula (S-Ia) or formula (S-Ib) (wherein m is 6). In some embodiments, the lipids of the Disclosure have the structure of formula (S-Ia) or formula (S-Ib) (wherein m is 7). In some embodiments, the lipids of the Disclosure have the structure of formula (S-Ia) or formula (S-Ib) (wherein m is 8). In some embodiments, the lipids of the Disclosure have the structure of formula (S-Ia) or formula (S-Ib) (wherein m is 2, 3, 4, 9, or 10).

[0164] p In some embodiments, the lipids of the Disclosure have the structure of formula (SI), formula (S-I'), formula (S-Ia), or formula (S-Ib) (wherein p is independently selected from 2 to 4). In some embodiments, the lipids of the Disclosure have the structure of formula (SI), formula (S-I'), formula (S-Ia), or formula (S-Ib) (wherein p is 2). In some embodiments, the lipids of the Disclosure have the structure of formula (SI), formula (S-I'), formula (S-Ia), or formula (S-Ib) (wherein p is 3). In some embodiments, the lipids of the Disclosure have the structure of formula (SI), formula (S-I'), formula (S-Ia), or formula (S-Ib) (wherein p is 4). In some embodiments, the lipids of the Disclosure have the structure of formula (SI), formula (S-I'), formula (S-Ia), or formula (S-Ib) (wherein p is 5 or 6). In some embodiments, the lipids of the Disclosure have the structure of formula (SI) or (S-I'), where p is 1.

[0165] Formula (S-M') In some embodiments, the lipids of this disclosure have the structure of formula (S-M'): [ka] or a pharmaceutically acceptable salt thereof (in the formula, X is either N or CH; Y is a combination, [ka] And the combinations indicated by "**" are joined to X; Each Z is, [ka] The combinations independently selected from the group consisting of "*" are joined to L; Each L is independently C2-C 10 It is an alkylenyl; R 1 OH, -N(R 3 )2, [ka] and; Each R is independently either -H or C1-C6 aliphatic; R Z is NR2 or OH; X Z This is an arbitrarily substituted C2-C 14 Alkyrenyl or optionally substituted C2-C 14 It is an alkenylenyl; each R 3 H and C 1-6 Selected independently of alkyl; R 4 -CH(SR 6 )(SR 7 ) and; R 5 is -CH(OR 8 )(OR 9 );-CH(SR 8 )(SR 9 );-CH(R 8 )(R 9 ) or optionally replaced C1-C 14 Aliphatic (one or more methylene bonds, each optionally and independently, optionally substituted C3-C8 cycloalkylenyl, optionally substituted bridging bicyclic or polycyclic C5-C 12 (It is replaced by cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-); R 6 and R 7 These are, independently, arbitrarily substituted C1-C 14 Aliphatic (one or more methylene bonds, each optionally and independently, optionally substituted C3-C8 cycloalkylenyl, optionally substituted bridging bicyclic or polycyclic C5-C 12 (It is replaced by cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-); R 8 and R 9is, independently of each other, optionally substituted C1-C 14 aliphatic (one or more methylene bonds are each optionally and independently optionally substituted C3-C8 cycloalkylenyl, optionally substituted bridged bicyclic or polycyclic C5-C 12 cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-); n is selected from 0 to 6; each p is independently selected from 1 to 6) having.

[0166] Formula (S-M) In some embodiments, the lipid of the present disclosure has the structure of formula (S-M):

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0167] In some embodiments, the lipids of this disclosure have the structure of formula (S-Ma): [ka] or a pharmaceutically acceptable salt thereof (in the formula, n is selected from 1 to 4; Each R 4 and R 5 This is as described in formula SM or S-M'; Each m is independently selected from 2 to 10; Each p is independently selected from 2 to 6. It has.

[0168] In some embodiments, the lipids of this disclosure have the structure of formula (S-Mb): [ka] or a pharmaceutically acceptable salt thereof (in the formula, Each R 3 H and C 1-6 Selected independently of alkyl; n is selected from 1 to 4; Each R 4 and R 5 This is as described in formula SM or S-M'; Each m is independently selected from 2 to 10; Each p is independently selected from 2 to 6. It has.

[0169] R 1 In some embodiments, the lipids of the present disclosure have a structure of formula (SM) or (S-M') (wherein R 1 The structure is OH. In some embodiments, the lipids of the present disclosure have a structure of formula (SM) or (S-M') (wherein R 1 N(R) 3)2) has. In some embodiments, the lipids of the present disclosure have a structure of formula (SM) or (S-M') (wherein R 1 teeth, [ka] In some embodiments, the lipids of the present disclosure have a structure of formula (SM) or (S-M') (wherein R 1 teeth, [ka] Each R independently has either -H or C1-C6 aliphatic. In a given embodiment, R 1 teeth, [ka] That is the case.

[0170] In some embodiments, the lipids of the present disclosure have a structure of formula (SM) or (S-M') (wherein R 1 OH, -N(R 3 )2, [ka] It has (selected from the group consisting of).

[0171] In some embodiments, the lipids of this disclosure have a structure of formula (S-M') (wherein R 1 OH, N(R 3 )2, and [ka] The lipid has a structure (selected from the group consisting of ). In some embodiments, the lipid of the present disclosure has a structure of formula (S-M') (wherein R 1 teeth, [ka] It has (is).

[0172] n In some embodiments, the lipids of the Disclosure have the structure of formula (SM), formula (S-M'), formula (S-Ma), or formula (S-Mb) (wherein n is 3). In some embodiments, the lipids of the Disclosure have the structure of formula (SM), formula (S-M'), formula (S-Ma), or formula (S-Mb) (wherein n is 4). In some embodiments, the lipids of the Disclosure have the structure of formula (SM), formula (S-M'), formula (S-Ma), or formula (S-Mb) (wherein n is 1, 2, 5, or 6).

[0173] p In some embodiments, the lipids of the Disclosure have the structure of formula (SM), formula (S-M'), formula (S-Ma), or formula (S-Mb) (wherein p is independently selected from 2 to 4). In some embodiments, the lipids of the Disclosure have the structure of formula (SM), formula (S-M'), formula (S-Ma), or formula (S-Mb) (wherein p is 2). In some embodiments, the lipids of the Disclosure have the structure of formula (SM), formula (S-M'), formula (S-Ma), or formula (S-Mb) (wherein p is 3). In some embodiments, the lipids of the Disclosure have the structure of formula (SM), formula (S-M'), formula (S-Ma), or formula (S-Mb) (wherein p is 4). In some embodiments, the lipids of the Disclosure have the structure of formula (SM), formula (S-M'), formula (S-Ma), or formula (S-Mb) (wherein p is 5 or 6). In some embodiments, the lipids of the Disclosure have the structure of formula (SM) or (S-M') (wherein p is 1).

[0174] R 4 As disclosed in formula (SM), in a given embodiment, R 4 -CH(SR 6 )(SR 7 ) In a given embodiment, R 4 teeth, [ka] Selected from.

[0175] R 5 As disclosed in formula (SM), in a given embodiment, R 5 is -CH(OR 8 )(OR 9 );-CH(SR 8 )(SR 9 );-CH(R 8 )(R 9 ); or optionally replaced C1-C 14 Aliphatic (one or more methylene bonds, each optionally and independently, optionally substituted C3-C8 cycloalkylenyl, optionally substituted bridging bicyclic or polycyclic C5-C 12 (It is replaced by cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-). In certain embodiments, R 5 This is an arbitrarily substituted C1-C 14 Aliphatic (one or more methylene bonds, each optionally and independently, optionally substituted C3-C8 cycloalkylenyl, optionally substituted bridging bicyclic or polycyclic C5-C 12 (It is replaced by cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-). In certain embodiments, R 5 This is an arbitrarily substituted C1-C 14 It is aliphatic. In a given embodiment, R 5 is -CH(OR 8 )(OR 9 ) In a given embodiment, R 5 is -CH(R 8 )(R 9 ) In a given embodiment, R 5 -CH(SR 8 )(SR 9 )

[0176] In a predetermined embodiment, R 4 and R 5 They are the same. In a given embodiment, R 4and R 5 They are different.

[0177] In a predetermined embodiment, R 5 teeth, [ka] Selected from.

[0178] R 6 and R 7 As disclosed in formula (SM), in a given embodiment, R 6 and R 7 These are, independently, arbitrarily substituted C1-C 14 Aliphatic (one or more methylene bonds, each optionally and independently, optionally substituted C3-C8 cycloalkylenyl, optionally substituted bridging bicyclic or polycyclic C5-C 12 It is replaced by cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-.

[0179] In a predetermined embodiment, R 6 and R 7 They are the same. In a given embodiment, R 6 and R 7 They are different.

[0180] In a predetermined embodiment, R 6 This is an arbitrarily substituted C1-C 14 It is aliphatic. In a given embodiment, R 6 This is an arbitrarily substituted C1-C 14 It is an alkylene. In a given embodiment, R 6 This is an arbitrarily substituted C1-C 14 It is a branched alkylene. In a given embodiment, R 6 This is an arbitrarily substituted C1-C 14 It is a linear alkylene. In a given embodiment, R 6 This is an arbitrarily substituted C1-C 14It is an alkenylene. In a given embodiment, R 6 This is an arbitrarily substituted C1-C 14 It is a branched alkenylene. In a given embodiment, R 6 This is an arbitrarily substituted C1-C 14 It is a linear alkenylene. In a given embodiment, R 6 This is an arbitrarily substituted C6-C 10 It is an alkylene. In a given embodiment, R 6 R is an arbitrarily substituted -(CH2)5CH3. In a given embodiment, R 6 is an arbitrarily substituted -(CH2)6CH3. In a given embodiment, R 6 R is an arbitrarily substituted -(CH2)7CH3. In a given embodiment, R 6 R is an arbitrarily substituted -(CH2)8CH3. In a given embodiment, R 6 This is an arbitrarily substituted -(CH2)9CH3.

[0181] In a predetermined embodiment, R 6 One of the methylene bonds is optionally substituted with a C3-C8 cycloalkylenyl or optionally substituted with a bridging bicyclic or polycyclic C5-C 12 It is replaced with cycloalkylenyl. In certain embodiments, it is optionally substituted with a bridging bicyclic or polycyclic C5-C. 12 Cycloalkylenyl is [ka] Selected from.

[0182] In a predetermined embodiment, R 7 This is an arbitrarily substituted C1-C 14 It is aliphatic. In a given embodiment, R 7 This is an arbitrarily substituted C1-C 14 It is an alkylene. In a given embodiment, R 7 This is an arbitrarily substituted C1-C 14 It is a branched alkylene. In a given embodiment, R 7 This is an arbitrarily substituted C1-C 14It is a linear alkylene. In a given embodiment, R 7 This is an arbitrarily substituted C1-C 14 It is an alkenylene. In a given embodiment, R 7 This is an arbitrarily substituted C1-C 14 It is a branched alkenylene. In a given embodiment, R 7 This is an arbitrarily substituted C1-C 14 It is a linear alkenylene. In a given embodiment, R 7 This is an arbitrarily substituted C6-C 10 It is an alkylene. In a given embodiment, R 7 R is an arbitrarily substituted -(CH2)5CH3. In a given embodiment, R 7 is an arbitrarily substituted -(CH2)6CH3. In a given embodiment, R 7 R is an arbitrarily substituted -(CH2)7CH3. In a given embodiment, R 7 R is an arbitrarily substituted -(CH2)8CH3. In a given embodiment, R 6 This is an arbitrarily substituted -(CH2)9CH3.

[0183] In a predetermined embodiment, R 7 One of the methylene bonds is optionally substituted with a C3-C8 cycloalkylenyl or optionally substituted with a bridging bicyclic or polycyclic C5-C 12 It is replaced with cycloalkylenyl. In certain embodiments, it is optionally substituted with a bridging bicyclic or polycyclic C5-C. 12 Cycloalkylenyl is [ka] Selected from.

[0184] In a predetermined embodiment, R 6 and R 7 teeth, [ka] Selected from.

[0185] In a predetermined method, each R6 and R 7 These are each arbitrarily substituted bridged biring C5-C 12 Selected independently from cycloalkylenyl. In a given embodiment, R 6 This is an arbitrarily substituted, bridging polycyclic C5-C 12 It is a cycloalkylenyl. In a given embodiment, R 7 This is a optionally substituted bridged biring C5-C 12 It is a cycloalkylenyl. In a given embodiment, it is optionally substituted with a bridging bicyclic or polycyclic C5-C 12 The cycloalkylenyl is selected from adamantyl, bicyclo[2.2.2]octyl, cubenyl, bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, and bicyclo[3.2.1]octyl. In a given embodiment, optionally substituted bridging bicyclic or polycyclic C5-C 12 Cycloalkylenyl is [ka] Selected from. In a given embodiment, a substituted bridging bicyclic or polycyclic C5-C 12 Cycloalkylenyl is [ka] The structure is selected from the following, and one or more CH bonds are substituted.

[0186] In a predetermined embodiment, R 6 and R 7 These are bridging bi-ring or poly-ring C5-C that are arbitrarily replaced together. 12 It forms a cycloalkylenyl. In a given embodiment, it optionally has a substituted cross-linked bicyclic or polycyclic C5-C 12 Cycloalkylenyl is [ka] Selected from.

[0187] R 8 and R9 As disclosed in formula (SM), in a given embodiment, R 8 and R 9 These are, independently, arbitrarily substituted C1-C 14 Aliphatic (one or more methylene bonds, each optionally and independently, optionally substituted C3-C8 cycloalkylenyl, optionally substituted bridging bicyclic or polycyclic C5-C 12 It is replaced by cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-.

[0188] In a predetermined embodiment, R 8 and R 9 They are the same. In a given embodiment, R 8 and R 9 They are different.

[0189] In a predetermined embodiment, R 8 This is an arbitrarily substituted C1-C 14 It is aliphatic. In a given embodiment, R 8 This is an arbitrarily substituted C1-C 14 It is an alkylene. In a given embodiment, R 8 This is an arbitrarily substituted C1-C 14 It is a branched alkylene. In a given embodiment, R 8 This is an arbitrarily substituted C1-C 14 It is a linear alkylene. In a given embodiment, R 8 This is an arbitrarily substituted C1-C 14 It is an alkenylene. In a given embodiment, R 8 This is an arbitrarily substituted C1-C 14 It is a branched alkenylene. In a given embodiment, R 8 This is an arbitrarily substituted C1-C 14 It is a linear alkenylene. In a given embodiment, R 8 This is an arbitrarily substituted C6-C 10 It is an alkylene. In a given embodiment, R 8R is an arbitrarily substituted -(CH2)5CH3. In a given embodiment, R 8 is an arbitrarily substituted -(CH2)6CH3. In a given embodiment, R 8 R is an arbitrarily substituted -(CH2)7CH3. In a given embodiment, R 8 R is an arbitrarily substituted -(CH2)8CH3. In a given embodiment, R 8 This is an arbitrarily substituted -(CH2)9CH3.

[0190] In a predetermined embodiment, R 8 One of the methylene bonds is optionally substituted with a C3-C8 cycloalkylenyl or optionally substituted with a bridging bicyclic or polycyclic C5-C 12 It is replaced with cycloalkylenyl. In certain embodiments, it is optionally substituted with a bridging bicyclic or polycyclic C5-C. 12 Cycloalkylenyl is [ka] Selected from.

[0191] In a predetermined embodiment, R 9 This is an arbitrarily substituted C1-C 14 It is aliphatic. In a given embodiment, R 9 This is an arbitrarily substituted C1-C 14 It is an alkylene. In a given embodiment, R 9 This is an arbitrarily substituted C1-C 14 It is a branched alkylene. In a given embodiment, R 9 This is an arbitrarily substituted C1-C 14 It is a linear alkylene. In a given embodiment, R 9 This is an arbitrarily substituted C1-C 14 It is an alkenylene. In a given embodiment, R 9 This is an arbitrarily substituted C1-C 14 It is a branched alkenylene. In a given embodiment, R 9 This is an arbitrarily substituted C1-C 14 It is a linear alkenylene. In a given embodiment, R 9This is an arbitrarily substituted C6-C 10 It is an alkylene. In a given embodiment, R 9 R is an arbitrarily substituted -(CH2)5CH3. In a given embodiment, R 9 is an arbitrarily substituted -(CH2)6CH3. In a given embodiment, R 9 R is an arbitrarily substituted -(CH2)7CH3. In a given embodiment, R 9 R is an arbitrarily substituted -(CH2)8CH3. In a given embodiment, R 9 This is an arbitrarily substituted -(CH2)9CH3.

[0192] In a predetermined embodiment, R 9 One of the methylene bonds is optionally substituted with a C3-C8 cycloalkylenyl or optionally substituted with a bridging bicyclic or polycyclic C5-C 12 It is replaced with cycloalkylenyl. In certain embodiments, it is optionally substituted with a bridging bicyclic or polycyclic C5-C. 12 Cycloalkylenyl is [ka] Selected from.

[0193] In a predetermined embodiment, R 8 and R 9 teeth, [ka] Selected from.

[0194] In some embodiments, R 8 and R 9 These are bridging bicyclic or polycyclic C4-C4s that are arbitrarily substituted together. 14 They form cycloalkyl or optionally substituted cross-linked bicyclic or polycyclic 4-14 membered heterocyclines.

[0195] In a predetermined method, each R 8 and R 9 These are each arbitrarily substituted bridged biring C5-C12 Selected independently from cycloalkylenyl. In a given embodiment, R 8 This is an arbitrarily substituted, bridging polycyclic C5-C 12 It is a cycloalkylenyl. In a given embodiment, R 9 This is a optionally substituted bridged biring C5-C 12 It is a cycloalkylenyl. In a given embodiment, it is optionally substituted with a bridging bicyclic or polycyclic C5-C 12 The cycloalkylenyl is selected from adamantyl, bicyclo[2.2.2]octyl, cubenyl, bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, and bicyclo[3.2.1]octyl. In a given embodiment, optionally substituted bridging bicyclic or polycyclic C5-C 12 Cycloalkylenyl is [ka] Selected from. In a given embodiment, a substituted bridging bicyclic or polycyclic C5-C 12 Cycloalkylenyl is [ka] The structure is selected from the following, and one or more CH bonds are substituted.

[0196] In a predetermined embodiment, R 8 and R 9 These are bridging bi-ring or poly-ring C5-C that are arbitrarily replaced together. 12 It forms a cycloalkylenyl. In a given embodiment, it optionally has a substituted cross-linked bicyclic or polycyclic C5-C 12 Cycloalkylenyl is [ka] Selected from.

[0197] In some embodiments, the lipids of the Disclosure include an acyclic core. In some embodiments, the lipids of the Disclosure are selected from any of the lipids or pharmaceutically acceptable salts thereof in the following Table (IA): [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4]

[0198] The "AT" series Numerous exemplary ionizable lipids of this disclosure are listed below.

[0199] Formula (AT) In some embodiments, the lipids of this disclosure have the structure of formula (AT): [ka] or a pharmaceutically acceptable salt thereof (In the formula, i) A is N; Z is a combination; X 1 is an optionally substituted C1-C6 aliphatic, where any substituent is X 1 If it is a C1 aliphatic, then it is not oxo; R 1 teeth, [ka] Selected from the group consisting of; or ii) A is CH; Z is [ka] And; combinations marked with "*" are X 1 Joined; X 1These are C1-C6 aliphatic atoms that are bonded or optionally substituted; R 1 teeth, [ka] Selected from the group consisting of; X 4 These are C1-C6 aliphatic atoms that are bonded or optionally substituted; R Z is NR2 or OH; Each R is independently either -H or C1-C6 aliphatic; X 2 and X 3 These are, independently, arbitrarily substituted C1-C 12 It is aliphatic; Y 1 and Y 2 teeth, [ka] Independently selected from the group consisting of; The combination marked with "*" is Y 1 Regarding X 2 or Y 2 Regarding X 3 Joined; R 2 is an arbitrarily substituted C1-C6 aliphatic; R 3 is an arbitrarily substituted C1-C6 aliphatic; R 4 is -CH(OR 6 )(OR 7 ), -CH(SR 6 )(SR 7 ), -CH(R 6 )(R 7 ), or optionally substituted C1-C 14 Aliphatic (one or more methylene bonds, each optionally and independently, optionally substituted C3-C8 cycloalkylenyl, optionally substituted bridging bicyclic or polycyclic C5-C 12(It is replaced by cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-); R 5 is -CH(OR 8 )(OR 9 ), -CH(SR 8 )(SR 9 ), -CH(R 8 )(R 9 ), or optionally substituted C1-C 14 Aliphatic (one or more methylene bonds, each optionally and independently, optionally substituted C3-C8 cycloalkylenyl, optionally substituted bridging bicyclic or polycyclic C5-C 12 (It is replaced by cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-); R 6 and R 7 These are, independently, arbitrarily substituted C1-C 14 Aliphatic (one or more methylene bonds, each optionally and independently, optionally substituted C3-C8 cycloalkylenyl, optionally substituted bridging bicyclic or polycyclic C5-C 12 (It is replaced by cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-); R 8 and R 9 These are, independently, arbitrarily substituted C1-C 14 Aliphatic (one or more methylene bonds, each optionally and independently, optionally substituted C3-C8 cycloalkylenyl, optionally substituted bridging bicyclic or polycyclic C5-C 12 (It is replaced by cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-) It has.

[0200] Formula (AT-A) In a given embodiment, the lipid of the Disclosure has the structure of formula (AT), and the lipid of the Disclosure has the structure of formula (AT-A): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 Z, X 2 , X 3 , X 4 , R Z , Y 1 , Y 2 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 This is as described in formula (AT) or as otherwise described in any of the following embodiments.

[0201] Formula (AT-A1) In a given embodiment, the lipid of the Disclosure has the structure of formula (AT), and the lipid of the Disclosure has the structure of formula (AT-A1): [ka] or a pharmaceutically acceptable salt thereof (in the formula, Z is [ka] And the combination marked with "*" is X 1 Joined; Y 1 and Y 2 teeth, [ka] Independently selected from the group consisting of; The combination marked with "*" is Y 1 Regarding R 2 or Y 2 Regarding R 3Joined; R 1 , R, X 1 , X 2 , X 3 , X 4 , R Z , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 (This is as described in formula (AT) or as otherwise described in any of the following embodiments.) It has.

[0202] Formula (AT-A2) In a given embodiment, the lipid of the Disclosure has the structure of formula (AT), and the lipid of the Disclosure has the structure of formula (AT-A2): [ka] or a pharmaceutically acceptable salt thereof (in the formula, Z is [ka] And the combination marked with "*" is X 1 Joined; Y 1 and Y 2 These are, [ka] And the combination marked with "*" is Y 1 Regarding R 2 or Y 2 Regarding R 3 Joined; R 1 , R, X 1 , X 2 , X 3 , X 4 , R Z , R 2 , R 3 , R 4 , R 5 , R 6, R 7 , R 8 , and R 9 (This is as described in formula (AT) or as otherwise described in any of the following embodiments.) It has.

[0203] Formula (AT-B) In a given embodiment, the lipid of the Disclosure has the structure of formula (AT), and the lipid of the Disclosure has the structure of formula (AT-B): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 Z, X 2 , X 3 , X 4 , R Z , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 It has the following characteristics (as described in formula (AT) or as otherwise described in any embodiment below):

[0204] Formula (AT-B') In a given embodiment, the lipid of the Disclosure has the structure of formula (AT), and the lipid of the Disclosure has the structure of formula (AT-B'): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 Z, X 2 , X 3 , X 4 , R Z , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9It has the following characteristics (as described in formula (AT) or as otherwise described in any embodiment below):

[0205] Formula (AT-C) In a given embodiment, the lipid of the Disclosure has the structure of formula (AT), and the lipid of the Disclosure has the structure of formula (AT-C): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 , X 2 , X 3 , X 4 , R Z , Y 1 , Y 2 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 It has the following characteristics (as described in formula (AT) or as otherwise described in any embodiment below):

[0206] Formula (AT-D) In a given embodiment, the lipid of the Disclosure has the structure of formula (AT), and the lipid of the Disclosure has the structure of formula (AT-D): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 , X 2 , X 3 , X 4 , R Z , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9It has the following characteristics (as described in formula (AT) or as otherwise described in any embodiment below):

[0207] Formula (AT-D') In a given embodiment, the lipid of the Disclosure has the structure of formula (AT), and the lipid of the Disclosure has the structure of formula (AT-D'): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 , X 2 , X 3 , X 4 , R Z , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 It has the following characteristics (as described in formula (AT) or as otherwise described in any embodiment below):

[0208] Formula (AT-D'a) In a given embodiment, the lipid of the Disclosure has the structure of formula (AT), and the lipid of the Disclosure has the structure of formula (AT-D'a): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 2 , X 3 , X 4 , R Z , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 It has the following characteristics (as described in formula (AT) or as otherwise described in any embodiment below):

[0209] Formula (AT-D'b) In a given embodiment, the lipid of the Disclosure has the structure of formula (AT), and the lipid of the Disclosure has the structure of formula (AT-D'b): [ka] It has.

[0210] Formula (AT-E) In a given embodiment, the lipid of the Disclosure has the structure of formula (AT), and the lipid of the Disclosure has the structure of formula (AT-E): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 Z, X 2 , X 3 , X 4 , R Z , Y 1 , Y 2 , R 2 , R 3 , R 6 , R 7 , R 8 , and R 9 It has the following characteristics (as described in formula (AT) or as otherwise described in any embodiment below):

[0211] Formula (AT-E') In a given embodiment, the lipid of the Disclosure has the structure of formula (AT), and the lipid of the Disclosure has the structure of formula (AT-E'): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 Z, X 2 , X 3 , X 4 , R Z , Y 1 , Y 2 , R 2 , R 3 , R 6 , R 7, R 8 , and R 9 It has the following characteristics (as described in formula (AT) or as otherwise described in any embodiment below):

[0212] Formula (AT-E'') In a given embodiment, the lipid of the Disclosure has the structure of formula (AT), and the lipid of the Disclosure has the structure of formula (AT-E''): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 Z, X 2 , X 3 , X 4 , R Z , Y 1 , Y 2 , R 2 , R 3 , R 6 , R 7 , R 8 , and R 9 It has the following characteristics (as described in formula (AT) or as otherwise described in any embodiment below):

[0213] Formula (AT-F) In a given embodiment, the lipid of the Disclosure has the structure of formula (AT), and the lipid of the Disclosure has the structure of formula (AT-F): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 Z, X 2 , X 3 , X 4 , R Z , R 2 , R 3 , R 6 , R 7 , R 8 , and R 9 It has the following characteristics (as described in formula (AT) or as otherwise described in any embodiment below):

[0214] Formula (AT-F') In a given embodiment, the lipid of the Disclosure has the structure of formula (AT), and the lipid of the Disclosure has the structure of formula (AT-F'): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 Z, X 2 , X 3 , X 4 , R Z , R 2 , R 3 , R 6 , R 7 , R 8 , and R 9 It has the following characteristics (as described in formula (AT) or as otherwise described in any embodiment below):

[0215] Formula (AT-F'') In a given embodiment, the lipid of the Disclosure has the structure of formula (AT), and the lipid of the Disclosure has the structure of formula (AT-F''): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 Z, X 2 , X 3 , X 4 , R Z , R 2 , R 3 , R 6 , R 7 , R 8 , and R 9 It has the following characteristics (as described in formula (AT) or as otherwise described in any embodiment below):

[0216] Formula (AT-F''') In a given embodiment, the lipid of the Disclosure has the structure of formula (AT), and the lipid of the Disclosure has the structure of formula (AT-F'''): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 Z, X 2 , X 3 , X 4 , R Z , R 2 , R 3 , R 6 , R 7 , R 8 , and R 9 It has the following characteristics (as described in formula (AT) or as otherwise described in any embodiment below):

[0217] Formula(AT-F'''') In a given embodiment, the lipid of the Disclosure has the structure of formula (AT), and the lipid of the Disclosure has the structure of formula (AT-F''''): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 Z, X 2 , X 3 , X 4 , R Z , R 2 , R 3 , R 6 , R 7 , R 8 , and R 9 It has the following characteristics (as described in formula (AT) or as otherwise described in any embodiment below):

[0218] Formula(AT-F''''') In a given embodiment, the lipid of the Disclosure has the structure of formula (AT), and the lipid of the Disclosure has the structure of formula (AT-F'''''): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 Z, X 2 , X 3, X 4 , R Z , R 2 , R 3 , R 6 , R 7 , R 8 , and R 9 It has the following characteristics (as described in formula (AT) or as otherwise described in any embodiment below):

[0219] Formula (AT-G) In a given embodiment, the lipid of the Disclosure has the structure of formula (AT), and the lipid of the Disclosure has the structure of formula (AT-G): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 , X 2 , X 3 , Y 1 , Y 2 , X 4 , R Z , R 2 , R 3 , R 6 , R 7 , R 8 , and R 9 It has the following characteristics (as described in formula (AT) or as otherwise described in any embodiment below):

[0220] Formula (AT-G') In a given embodiment, the lipid of the Disclosure has the structure of formula (AT), and the lipid of the Disclosure has the structure of formula (AT-G'): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 , X 2 , X 3 , Y 1 , Y 2 , X 4 , R Z , R 2 , R 3 , R 6 , R7 , R 8 , and R 9 It has the following characteristics (as described in formula (AT) or as otherwise described in any embodiment below):

[0221] Formula (AT-H) In a given embodiment, the lipid of the Disclosure has the structure of formula (AT), and the lipid of the Disclosure has the structure of formula (AT-H): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 , X 2 , X 3 , R 2 , R 3 , X 4 , R Z , R 6 , R 7 , R 8 , and R 9 It has the following characteristics (as described in formula (AT) or as otherwise described in any embodiment below):

[0222] Formula (AT-H') In a given embodiment, the lipid of the Disclosure has the structure of formula (AT), and the lipid of the Disclosure has the structure of formula (AT-H'): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 , X 2 , X 3 , R 2 , R 3 , X 4 , R Z , R 6 , R 7 , R 8 , and R 9 It has the following characteristics (as described in formula (AT) or as otherwise described in any embodiment below):

[0223] Formula (AT-H'') In a given embodiment, the lipid of the Disclosure has the structure of formula (AT), and the lipid of the Disclosure has the structure of formula (AT-H''): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 , X 2 , X 3 , R 2 , R 3 , X 4 , R Z , R 6 , R 7 , R 8 , and R 9 It has the following characteristics (as described in formula (AT) or as otherwise described in any embodiment below):

[0224] Formula (AT-H''') In a given embodiment, the lipid of the Disclosure has the structure of formula (AT), and the lipid of the Disclosure has the structure of formula (AT-H'''): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 , X 2 , X 3 , R 2 , R 3 , X 4 , R Z , R 6 , R 7 , R 8 , and R 9 It has the following characteristics (as described in formula (AT) or as otherwise described in any embodiment below):

[0225] Formula (AT-I) In a given embodiment, the lipid of the Disclosure has the structure of formula (AT), and the lipid of the Disclosure has the structure of formula (AT-I): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 , X 2 , X 3 , X 4 , R Z , Y 1 , Y 2 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 It has the following characteristics (as described in formula (AT) or as otherwise described in any embodiment below):

[0226] Formula (AT-J) In a given embodiment, the lipid of the Disclosure has the structure of formula (AT), and the lipid of the Disclosure has the structure of formula (AT-J): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 , X 2 , X 3 , X 4 , R Z , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 It has the following characteristics (as described in formula (AT) or as otherwise described in any embodiment below):

[0227] Formula (AT-J') In a given embodiment, the lipid of the Disclosure has the structure of formula (AT), and the lipid of the Disclosure has the structure of formula (AT-J'): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1, R, X 1 , X 2 , X 3 , X 4 , R Z , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 It has the following characteristics (as described in formula (AT) or as otherwise described in any embodiment below):

[0228] Formula (AT-K) In a given embodiment, the lipid of the Disclosure has the structure of formula (AT), and the lipid of the Disclosure has the structure of formula (AT-K): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 , X 2 , X 3 , Y 1 , Y 2 , X 4 , R Z , R 2 , R 3 , R 6 , R 7 , R 8 , and R 9 It has the following characteristics (as described in formula (AT) or as otherwise described in any embodiment below):

[0229] Formula (AT-K') In a given embodiment, the lipid of the Disclosure has the structure of formula (AT), and the lipid of the Disclosure has the structure of formula (AT-K'): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 , X 2 , X 3 , Y 1 , Y 2, X 4 , R Z , R 2 , R 3 , R 6 , R 7 , R 8 , and R 9 It has the following characteristics (as described in formula (AT) or as otherwise described in any embodiment below):

[0230] Formula (AT-L) In a given embodiment, the lipid of the Disclosure has the structure of formula (AT), and the lipid of the Disclosure has the structure of formula (AT-L): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 , X 2 , X 3 , R 2 , R 3 , X 4 , R Z , R 6 , R 7 , R 8 , and R 9 It has the following characteristics (as described in formula (AT) or as otherwise described in any embodiment below):

[0231] Formula (AT-L') In a given embodiment, the lipid of the Disclosure has the structure of formula (AT), and the lipid of the Disclosure has the structure of formula (AT-L'): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 , X 2 , X 3 , R 2 , R 3 , X 4 , R Z , R 6 , R 7 , R 8 , and R 9It has the following characteristics (as described in formula (AT) or as otherwise described in any embodiment below):

[0232] Formula (AT-L'') In a given embodiment, the lipid of the Disclosure has the structure of formula (AT), and the lipid of the Disclosure has the structure of formula (AT-L''): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 , X 2 , X 3 , R 2 , R 3 , X 4 , R Z , R 6 , R 7 , R 8 , and R 9 It has the following characteristics (as described in formula (AT) or as otherwise described in any embodiment below):

[0233] Formula (AT-L''') In a given embodiment, the lipid of the Disclosure has the structure of formula (AT), and the lipid of the Disclosure has the structure of formula (AT-L'''): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 , X 2 , X 3 , R 2 , R 3 , X 4 , R Z , R 6 , R 7 , R 8 , and R 9 It has the following characteristics (as described in formula (AT) or as otherwise described in any embodiment below):

[0234] Formula (AT-M) In a given embodiment, the lipid of the Disclosure has the structure of formula (AT), and the lipid of the Disclosure has the structure of formula (AT-M): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 2 , X 3 , X 4 , R Z , Y 1 , Y 2 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 It has the following characteristics (as described in formula (AT) or as otherwise described in any embodiment below):

[0235] Formula (AT-N) In a given embodiment, the lipid of the Disclosure has the structure of formula (AT), and the lipid of the Disclosure has the structure of formula (AT-N): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 , X 2 , X 3 , X 4 , R Z , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 It has the following characteristics (as described in formula (AT) or as otherwise described in any embodiment below):

[0236] Formula (AT-N') In a given embodiment, the lipid of the Disclosure has the structure of formula (AT), and the lipid of the Disclosure has the structure of formula (AT-N'): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 , X 2 , X 3 , X 4 , R Z , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 It has the following characteristics (as described in formula (AT) or as otherwise described in any embodiment below):

[0237] Formula (AT-O) In a given embodiment, the lipid of the Disclosure has the structure of formula (AT), and the lipid of the Disclosure has the structure of formula (AT-O): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 , X 2 , X 3 , Y 1 , Y 2 , X 4 , R Z , R 2 , R 3 , R 6 , R 7 , R 8 , and R 9 It has the following characteristics (as described in formula (AT) or as otherwise described in any embodiment below):

[0238] Formula (AT-O') In a given embodiment, the lipid of the Disclosure has the structure of formula (AT), and the lipid of the Disclosure has the structure of formula (AT-O'): [ka] or a pharmaceutically acceptable salt thereof (wherein R1 , R, X 1 , X 2 , X 3 , Y 1 , Y 2 , X 4 , R Z , R 2 , R 3 , R 6 , R 7 , R 8 , and R 9 It has the following characteristics (as described in formula (AT) or as otherwise described in any embodiment below):

[0239] Formula (AT-P) In a given embodiment, the lipid of the Disclosure has the structure of formula (AT), and the lipid of the Disclosure has the structure of formula (AT-P): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 , X 2 , X 3 , R 2 , R 3 , X 4 , R Z , R 6 , R 7 , R 8 , and R 9 It has the following characteristics (as described in formula (AT) or as otherwise described in any embodiment below):

[0240] Formula (AT-P') In a given embodiment, the lipid of the Disclosure has the structure of formula (AT), and the lipid of the Disclosure has the structure of formula (AT-P'): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 , X 2 , X 3 , R 2 , R 3 , X 4 , RZ , R 6 , R 7 , R 8 , and R 9 has (as described in formula (AT) or as separately described in any of the following embodiments).

[0241] Formula (AT-P’’) In certain embodiments, the lipid of the present disclosure has the structure of formula (AT), and the lipid of the present disclosure has the structure of formula (AT-P’’): [Chemical formula] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 , X 2 , X 3 , R 2 , R 3 , X 4 , R Z , R 6 , R 7 , R 8 , and R 9 has (as described in formula (AT) or as separately described in any of the following embodiments).

[0242] Formula (AT-P’’’) In certain embodiments, the lipid of the present disclosure has the structure of formula (AT), and the lipid of the present disclosure has the structure of formula (AT-P’’’): [Chemical formula] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 , X 2 , X 3 , R 2 , R 3 , X 4 , R Z , R 6 , R 7 , R 8 , and R 9 has (as described in formula (AT) or as separately described in any of the following embodiments).

[0243] Formula (AT-Q) In a given embodiment, the lipid of the Disclosure has the structure of formula (AT), and the lipid of the Disclosure has the structure of formula (AT-Q): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 , X 2 , X 3 , X 4 , R Z , Y 1 , Y 2 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 It has the following characteristics (as described in formula (AT) or as otherwise described in any embodiment below):

[0244] Formula (AT-Q1) In a given embodiment, the lipid of the Disclosure has the structure of formula (AT), and the lipid of the Disclosure has the structure of formula (AT-Q1): [ka] or a pharmaceutically acceptable salt thereof (in the formula, Y 1 and Y 2 teeth, [ka] Independently selected from the group consisting of; The combination marked with "*" is Y 1 Regarding R 2 or Y 2 Regarding R 3 Joined; R 1 , R, X 1 , X 2 , X 3 , X4 , R Z , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 (This is as described in formula (AT) or as otherwise described in any of the following embodiments.) It has.

[0245] Formula (AT-Q2) In a given embodiment, the lipid of the Disclosure has the structure of formula (AT), and the lipid of the Disclosure has the structure of formula (AT-Q2): [ka] or a pharmaceutically acceptable salt thereof (in the formula, R 1 teeth, [ka] and; Y 1 and Y 2 teeth, [ka] and; The combination marked with "*" is Y 1 Regarding R 2 or Y 2 Regarding R 3 Joined; R, Right 1 , X 2 , X 3 , X 4 , R Z , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 (This is as described in formula (AT) or as otherwise described in any of the following embodiments.) It has.

[0246] Model (AT-R) In a given embodiment, the lipid of the Disclosure has the structure of formula (AT), and the lipid of the Disclosure has the structure of formula (AT-R): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 , X 2 , X 3 , X 4 , R Z , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 It has the following characteristics (as described in formula (AT) or as otherwise described in any embodiment below):

[0247] Formula (AT-R') In a given embodiment, the lipid of the Disclosure has the structure of formula (AT), and the lipid of the Disclosure has the structure of formula (AT-R'): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 , X 2 , X 3 , X 4 , R Z , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 It has the following characteristics (as described in formula (AT) or as otherwise described in any embodiment below):

[0248] Formula (AT-S) In a given embodiment, the lipid of the Disclosure has the structure of formula (AT), and the lipid of the Disclosure has the structure of formula (AT-S): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 , X 2 , X 3 , X 4 , R Z , Y 1 , Y 2 , R 2 , R 3 , R 6 , R 7 , R 8 , and R 9 It has the following characteristics (as described in formula (AT) or as otherwise described in any embodiment below):

[0249] Formula (AT-S') In a given embodiment, the lipid of the Disclosure has the structure of formula (AT), and the lipid of the Disclosure has the structure of formula (AT-S'): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 , X 2 , X 3 , X 4 , R Z , Y 1 , Y 2 , R 2 , R 3 , R 6 , R 7 , R 8 , and R 9 It has the following characteristics (as described in formula (AT) or as otherwise described in any embodiment below):

[0250] Formula (AT-S'') In a given embodiment, the lipid of the Disclosure has the structure of formula (AT), and the lipid of the Disclosure has the structure of formula (AT-S''): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 , X 2 , X 3 , X 4 , R Z , Y 1 , Y 2 , R 2 , R 3 , R 6 , R 7 , R 8 , and R 9 It has the following characteristics (as described in formula (AT) or as otherwise described in any embodiment below):

[0251] Formula (AT-T) In a given embodiment, the lipid of the Disclosure has the structure of formula (AT), and the lipid of the Disclosure has the structure of formula (AT-T): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 , X 2 , X 3 , X 4 , R Z , R 2 , R 3 , R 6 , R 7 , R 8 , and R 9 It has the following characteristics (as described in formula (AT) or as otherwise described in any embodiment below):

[0252] Formula (AT-T') In a given embodiment, the lipid of the Disclosure has the structure of formula (AT), and the lipid of the Disclosure has the structure of formula (AT-T'): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 , X 2, X 3 , X 4 , R Z , R 2 , R 3 , R 6 , R 7 , R 8 , and R 9 It has the following characteristics (as described in formula (AT) or as otherwise described in any embodiment below):

[0253] Equation (AT-T'') In a given embodiment, the lipid of the Disclosure has the structure of formula (AT), and the lipid of the Disclosure has the structure of formula (AT-T''): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 , X 2 , X 3 , X 4 , R Z , R 2 , R 3 , R 6 , R 7 , R 8 , and R 9 It has the following characteristics (as described in formula (AT) or as otherwise described in any embodiment below):

[0254] Formula (AT-T''') In a given embodiment, the lipid of the Disclosure has the structure of formula (AT), and the lipid of the Disclosure has the structure of formula (AT-T'''): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 , X 2 , X 3 , X 4 , R Z , R 2 , R 3 , R 6 , R 7 , R 8 , and R9 It has the following characteristics (as described in formula (AT) or as otherwise described in any embodiment below):

[0255] Formula (AT-T'''') In a given embodiment, the lipid of the Disclosure has the structure of formula (AT), and the lipid of the Disclosure has the structure of formula (AT-T''''): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 , X 2 , X 3 , X 4 , R Z , R 2 , R 3 , R 6 , R 7 , R 8 , and R 9 It has the following characteristics (as described in formula (AT) or as otherwise described in any embodiment below):

[0256] Formula (AT-T''''') In a given embodiment, the lipid of the Disclosure has the structure of formula (AT), and the lipid of the Disclosure has the structure of formula (AT-T'''''): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 , X 2 , X 3 , X 4 , R Z , R 2 , R 3 , R 6 , R 7 , R 8 , and R 9 It has the following characteristics (as described in formula (AT) or as otherwise described in any embodiment below):

[0257] A As disclosed in formula (AT), in a given embodiment, A is CH or N. In a given embodiment, A is CH. In a given embodiment, A is N.

[0258] Z As disclosed in formula (AT), in a given embodiment where A is CH, Z is [ka] And; combinations marked with "*" are X 1 It is coupled to. In a predetermined embodiment where A is CH, Z is [ka] In a predetermined embodiment where A is CH, Z is [ka] In a given embodiment, Z is [ka] In a given embodiment, Z is [ka] In a given embodiment, Z is [ka] In a given embodiment, Z is [ka] In a given embodiment, Z is [ka] In a given embodiment, Z is [ka] In a given embodiment, Z is [ka] In a given embodiment, Z is [ka] In a given embodiment, Z is [ka] In a given embodiment, Z is [ka] In a given embodiment, Z is [ka] In a given embodiment where A is N, as disclosed in formula (AT), Z is a combination.

[0259] X 1 In a certain embodiment where A is N, as disclosed in formula (AT), X 1 is an arbitrarily substituted C1-C6 aliphatic. In a given embodiment where A is N, X 1 is an unsubstituted C1-C6 aliphatic. In a given embodiment, X 1 is an optionally substituted C1-C6 alkylene. In a given embodiment, X 1 is an unsubstituted C1-C6 alkylene. In a given embodiment, X 1 is an unsubstituted C2-C6 alkylene. In a given embodiment, X 1 R is an optionally substituted methylene. In a given embodiment, R 2 is an optionally substituted C2 alkylene. In a given embodiment, X 1 is an optionally substituted C3 alkylene. In a given embodiment, X 1 is an optionally substituted C4 alkylene. In a given embodiment, X 1 is an optionally substituted C5 alkylene. In a given embodiment, X 1is an optionally substituted C6 alkylene. In a given embodiment, X 1 is -(CH2)-. In a given embodiment, X 1 is -(CH2)2-. In a given embodiment, X 1 is -(CH2)3-. In a given embodiment, X 1 is -(CH2)4-. In a given embodiment, X 1 is -(CH2)5-. In a given embodiment, X 1 It is -(CH2)6-.

[0260] In a certain embodiment where A is CH, as disclosed in formula (AT), X 1 is a C1-C6 aliphatic that is bonded or optionally substituted. In a given embodiment, X 1 This is a combination. In a given embodiment, X 1 is an optionally substituted C1-C6 alkylene. In a given embodiment, X 1 is an unsubstituted C1-C6 alkylene. In a given embodiment, X 1 is an unsubstituted C2-C6 alkylene. In a given embodiment, X 1 R is an optionally substituted methylene. In a given embodiment, R 2 is an optionally substituted C2 alkylene. In a given embodiment, X 1 is an optionally substituted C3 alkylene. In a given embodiment, X 1 is an optionally substituted C4 alkylene. In a given embodiment, X 1 is an optionally substituted C5 alkylene. In a given embodiment, X 1 is an optionally substituted C6 alkylene. In a given embodiment, X 1 is -(CH2)-. In a given embodiment, X 1 is -(CH2)2-. In a given embodiment, X 1 is -(CH2)3-. In a given embodiment, X 1 is -(CH2)4-. In a given embodiment, X 1 is -(CH2)5-. In a given embodiment, X1 It is -(CH2)6-.

[0261] R 1 In a certain embodiment where A is N, as disclosed in formula (AT), R 1 teeth, [ka] Selected from the group consisting of . In a certain embodiment where A is CH, as disclosed in formula (AT), R 1 teeth, [ka] It is selected from the group consisting of the following.

[0262] In a predetermined embodiment, R 1 teeth, [ka] In a given embodiment, R 1 teeth, [ka] In a given embodiment, R 1 teeth, [ka] In a given embodiment, R 1 teeth, [ka] In a given embodiment, R 1 teeth, [ka] In a given embodiment, R 1 teeth, [ka] In a given embodiment, R 1teeth, [ka] In a given embodiment, R 1 teeth, [ka] In a given embodiment, R 1 teeth, [ka] That is the case.

[0263] In a predetermined embodiment, R 1 teeth, [ka] In a given embodiment, R 1 teeth, [ka] In a given embodiment, R 1 teeth, [ka] In a given embodiment, R 1 teeth, [ka] That is the case.

[0264] X 2 and X 3 As disclosed in formula (AT), in a given embodiment, X 2 and X 3 These are, independently, arbitrarily substituted C1-C 12 It is aliphatic. In a given embodiment, X 2 and X 3 They are the same. In a given embodiment, X 2 and X 3 They are different.

[0265] In a predetermined embodiment, X 2 This is an arbitrarily substituted C1-C 12 It is an alkylene. In a given embodiment, X 2 This is an arbitrarily substituted C1-C 12 It is an alkenylene. In a given embodiment, X 2 This is an arbitrarily substituted C1-C 10 It is aliphatic. In a given embodiment, X 2 This is an arbitrarily substituted C1-C 10 It is an alkylene. In a given embodiment, X 2 This is an arbitrarily substituted C1-C 10 It is an alkenylene. In a given embodiment, X 2 is an optionally substituted C1-C8 aliphatic. In a given embodiment, X 2 is an optionally substituted C1-C8 alkylene. In a given embodiment, X 2 is an optionally substituted C1-C8 alkenylene. In a given embodiment, X 2 is an optionally substituted C1-C6 aliphatic. In a given embodiment, X 2 is an optionally substituted C1-C6 alkylene. In a given embodiment, X 2 is an optionally substituted C1-C6 alkenylene. In a given embodiment, X 2 This is an arbitrarily substituted C2-C 12 It is aliphatic. In a given embodiment, X 2 This is an arbitrarily substituted C2-C 12 It is an alkylene. In a given embodiment, X 2 This is an arbitrarily substituted C2-C 12 It is an alkenylene. In a given embodiment, X 2 This is an arbitrarily substituted C4-C 12 It is aliphatic. In a given embodiment, X 2 This is an arbitrarily substituted C4-C 12 It is an alkylene. In a given embodiment, X 2 This is an arbitrarily substituted C4-C 12 It is an alkenylene. In a given embodiment, X 2 This is an arbitrarily substituted C4-C10 It is aliphatic. In a given embodiment, X 2 This is an arbitrarily substituted C4-C 10 It is an alkylene. In a given embodiment, X 2 This is an arbitrarily substituted C4-C 10 It is an alkenylene. In a given embodiment, X 2 is an optionally substituted C6-C8 aliphatic. In a given embodiment, X 2 is an optionally substituted C6-C8 alkylene. In a given embodiment, X 2 is an optionally substituted C6-C8 alkenylene. In a given embodiment, X 2 is -(CH2)-. In a given embodiment, X 2 is -(CH2)2-. In a given embodiment, X 2 is -(CH2)3-. In a given embodiment, X 2 is -(CH2)4-. In a given embodiment, X 2 is -(CH2)5-. In a given embodiment, X 2 is -(CH2)6-. In a given embodiment, X 2 is -(CH2)7-. In a given embodiment, X 2 is -(CH2)8-. In a given embodiment, X 2 is -(CH2)9-. In a given embodiment, X 2 is, -(CH2) 10 - is

[0266] In a predetermined embodiment, X 3 This is an arbitrarily substituted C1-C 12 It is an alkylene. In a given embodiment, X 3 This is an arbitrarily substituted C1-C 12 It is an alkenylene. In a given embodiment, X 3 This is an arbitrarily substituted C1-C 10 It is aliphatic. In a given embodiment, X 3 This is an arbitrarily substituted C1-C 10 It is an alkylene. In a given embodiment, X 3 This is an arbitrarily substituted C1-C 10It is an alkenylene. In a given embodiment, X 3 is an optionally substituted C1-C8 aliphatic. In a given embodiment, X 3 is an optionally substituted C1-C8 alkylene. In a given embodiment, X 3 is an optionally substituted C1-C8 alkenylene. In a given embodiment, X 3 is an optionally substituted C1-C6 aliphatic. In a given embodiment, X 3 is an optionally substituted C1-C6 alkylene. In a given embodiment, X 3 is an optionally substituted C1-C6 alkenylene. In a given embodiment, X 3 This is an arbitrarily substituted C2-C 12 It is aliphatic. In a given embodiment, X 3 This is an arbitrarily substituted C2-C 12 It is an alkylene. In a given embodiment, X 3 This is an arbitrarily substituted C2-C 12 It is an alkenylene. In a given embodiment, X 3 This is an arbitrarily substituted C4-C 12 It is aliphatic. In a given embodiment, X 3 This is an arbitrarily substituted C4-C 12 It is an alkylene. In a given embodiment, X 3 This is an arbitrarily substituted C4-C 12 It is an alkenylene. In a given embodiment, X 3 This is an arbitrarily substituted C4-C 10 It is aliphatic. In a given embodiment, X 3 This is an arbitrarily substituted C4-C 10 It is an alkylene. In a given embodiment, X 3 This is an arbitrarily substituted C4-C 10 It is an alkenylene. In a given embodiment, X 3 is an optionally substituted C6-C8 aliphatic. In a given embodiment, X 3 is an optionally substituted C6-C8 alkylene. In a given embodiment, X 3 is an optionally substituted C6-C8 alkenylene. In a given embodiment, X 3is -(CH2)-. In a given embodiment, X 3 is -(CH2)2-. In a given embodiment, X 3 is -(CH2)3-. In a given embodiment, X 3 is -(CH2)4-. In a given embodiment, X 3 is -(CH2)5-. In a given embodiment, X 3 is -(CH2)6-. In a given embodiment, X 3 is -(CH2)7-. In a given embodiment, X 3 is -(CH2)8-. In a given embodiment, X 3 is -(CH2)9-. In a given embodiment, X 3 is, -(CH2) 10 - is

[0267] In a predetermined embodiment, X 2 and X 3 Both are -(CH2)8-. In a given embodiment, X 2 and X 3 Both are -(CH2)6-.

[0268] X 4 As disclosed in formula (AT), in a given embodiment, X 4 is a bond or C2-C6 aliphatic. In a given embodiment, X 4 This is a combination. In a given embodiment, X 4 is a C2-C6 aliphatic. In a given embodiment, X 4 is a C2 aliphatic. In a given embodiment, X 4 is a C3 aliphatic. In a given embodiment, X 4 is a C4 aliphatic. In a given embodiment, X 4 is a C5 aliphatic. In a given embodiment, X 4 It is a C6 aliphatic.

[0269] Y 1 and Y 2 As disclosed in formula (AT), in a given embodiment, Y 1 and Y 2 Each of them operates independently. [ka] (In the formula, combinations marked with "*" are Y 1 Regarding X 2 or Y 2 Regarding X 3 (is coupled to) In a given embodiment, Y 1 and Y 2 They are the same. In a given embodiment, Y 1 and Y 2 They are different.

[0270] In a predetermined embodiment, Y 1 and Y 2 Each of them operates independently. [ka] In a given embodiment, Y 1 and Y 2 Each of them operates independently. [ka] In a given embodiment, Y 1 teeth, [ka] In a given embodiment, Y 1 teeth, [ka] In a given embodiment, Y 1 teeth, [ka] In a given embodiment, Y 1 teeth, [ka] In a given embodiment, Y 1 teeth, [ka] In a given embodiment, Y 1 teeth, [ka] In a given embodiment, Y 1 teeth, [ka] In a given embodiment, Y 1 teeth, [ka] In a given embodiment, Y 2 teeth, [ka] In a given embodiment, Y 2 teeth, [ka] In a given embodiment, Y 2 teeth, [ka] In a given embodiment, Y 2 teeth, [ka] In a given embodiment, Y 2 teeth, [ka] In a given embodiment, Y 2 teeth, [ka] In a given embodiment, Y2 teeth, [ka] In a given embodiment, Y 2 teeth, [ka] In a given embodiment, Y 1 and Y 2 Both are [ka] In a given embodiment, Y 1 and Y 2 Both are [ka] That is the case.

[0271] R 2 As disclosed in formula (AT), in a given embodiment, R 2 is an optionally substituted C1-C6 aliphatic. In a given embodiment, R 2 is an optionally substituted C1-C6 alkylene. In a given embodiment, R 2 R is an optionally substituted methylene. In a given embodiment, R 2 is an optionally substituted C2 alkylene. In a given embodiment, R 2 R is an optionally substituted C3 alkylene. In a given embodiment, R 2 R is an optionally substituted C4 alkylene. In a given embodiment, R 2 R is an optionally substituted C5 alkylene. In a given embodiment, R 2 is an optionally substituted C6 alkylene. In a given embodiment, R 2 is -(CH2)-. In a given embodiment, R 2 is -(CH2)2-. In a given embodiment, R 2 is -(CH2)3-. In a given embodiment, R 2is -(CH2)4-. In a given embodiment, R 2 is -(CH2)5-. In a given embodiment, R 2 It is -(CH2)6-.

[0272] R 3 As disclosed in formula (AT), in a given embodiment, R 3 is an optionally substituted C1-C6 aliphatic. In a given embodiment, R 3 is an optionally substituted C1-C6 alkylene. In a given embodiment, R 3 R is an optionally substituted methylene. In a given embodiment, R 3 is an optionally substituted C2 alkylene. In a given embodiment, R 3 R is an optionally substituted C3 alkylene. In a given embodiment, R 3 R is an optionally substituted C4 alkylene. In a given embodiment, R 3 R is an optionally substituted C5 alkylene. In a given embodiment, R 3 is an optionally substituted C6 alkylene. In a given embodiment, R 3 is -(CH2)-. In a given embodiment, R 3 is -(CH2)2-. In a given embodiment, R 3 is -(CH2)3-. In a given embodiment, R 3 is -(CH2)4-. In a given embodiment, R 3 is -(CH2)5-. In a given embodiment, R 3 It is -(CH2)6-.

[0273] In a predetermined embodiment, R 2 and R 3 They are the same. In a given embodiment, R 2 and R 3 They are different.

[0274] R 4 As disclosed in formula (AT), in a given embodiment, R 4is -CH(OR 6 )(OR 7 ), -CH(SR 6 )(SR 7 ), -CH(R 6 )(R 7 ), or optionally substituted C1-C 14 Aliphatic (one or more methylene bonds, each optionally and independently, optionally substituted C3-C8 cycloalkylenyl, optionally substituted bridging bicyclic or polycyclic C5-C 12 (It is replaced by cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-). In certain embodiments, R 4 This is an arbitrarily substituted C1-C 14 Aliphatic (one or more methylene bonds, each optionally and independently, optionally substituted C3-C8 cycloalkylenyl, optionally substituted bridging bicyclic or polycyclic C5-C 12 (It is replaced by cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-). In certain embodiments, R 4 This is an arbitrarily substituted C1-C 14 It is aliphatic. In a given embodiment, R 4 is -CH(OR 6 )(OR 7 ) In a given embodiment, R 4 is -CH(R 6 )(R 7 ) In a given embodiment, R 4 -CH(SR 6 )(SR 7 )

[0275] In a predetermined embodiment, R 4 One of the methylene bonds is optionally substituted with a C3-C8 cycloalkylenyl or optionally substituted with a bridging bicyclic or polycyclic C5-C 12 It is replaced with cycloalkylenyl. In certain embodiments, it is optionally substituted with a bridging bicyclic or polycyclic C5-C.12 Cycloalkylenyl is [ka] Selected from.

[0276] In a predetermined embodiment, R 4 teeth, [ka] Selected from.

[0277] In a predetermined embodiment, R 4 teeth, [ka] Selected from.

[0278] R 5 As disclosed in formula (AT), in a given embodiment, R 5 is -CH(OR 8 )(OR 9 ), -CH(SR 8 )(SR 9 ), -CH(R 8 )(R 9 ), or optionally substituted C1-C 14 Aliphatic (one or more methylene bonds, each optionally and independently, optionally substituted C3-C8 cycloalkylenyl, optionally substituted bridging bicyclic or polycyclic C5-C 12 (It is replaced by cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-). In certain embodiments, R 5 This is an arbitrarily substituted C1-C 14 Aliphatic (one or more methylene bonds, each optionally and independently, optionally substituted C3-C8 cycloalkylenyl, optionally substituted bridging bicyclic or polycyclic C5-C 12(It is replaced by cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-). In certain embodiments, R 5 This is an arbitrarily substituted C1-C 14 It is aliphatic. In a given embodiment, R 5 is -CH(OR 8 )(OR 9 ) In a given embodiment, R 5 is -CH(R 8 )(R 9 ) In a given embodiment, R 5 -CH(SR 8 )(SR 9 )

[0279] In a predetermined embodiment, R 5 One of the methylene bonds is optionally substituted with a C3-C8 cycloalkylenyl or optionally substituted with a bridging bicyclic or polycyclic C5-C 12 It is replaced with cycloalkylenyl. In certain embodiments, it is optionally substituted with a bridging bicyclic or polycyclic C5-C. 12 Cycloalkylenyl is [ka] Selected from.

[0280] In a predetermined embodiment, R 4 and R 5 They are the same. In a given embodiment, R 4 and R 5 They are different.

[0281] In a predetermined embodiment, R 5 teeth, [ka] Selected from.

[0282] In a predetermined embodiment, R 5 teeth, [ka] Selected from.

[0283] R 6 and R 7 As disclosed in formula (AT), in a given embodiment, R 6 and R 7 These are, independently, arbitrarily substituted C1-C 14 Aliphatic (one or more methylene bonds, each optionally and independently, optionally substituted C3-C8 cycloalkylenyl, optionally substituted bridging bicyclic or polycyclic C5-C 12 It is replaced by cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-.

[0284] In a predetermined embodiment, R 6 and R 7 They are the same. In a given embodiment, R 6 and R 7 They are different.

[0285] In a predetermined embodiment, R 6 This is an arbitrarily substituted C1-C 14 It is aliphatic. In a given embodiment, R 6 This is an arbitrarily substituted C1-C 14 It is alkyl. In a given embodiment, R 6 This is an arbitrarily substituted C1-C 14 It is a branched alkyl group. In a given embodiment, R 6 This is an arbitrarily substituted C1-C 14 It is a linear alkyl group. In a given embodiment, R 6 This is an arbitrarily substituted C1-C 14 It is an alkenylene. In a given embodiment, R 6 This is an arbitrarily substituted C1-C 14 It is a branched alkenyl. In a given embodiment, R 6 This is an arbitrarily substituted C1-C 14It is a linear alkenyl. In a given embodiment, R 6 This is an arbitrarily substituted C6-C 10 It is alkyl. In a given embodiment, R 6 R is an arbitrarily substituted -(CH2)5CH3. In a given embodiment, R 6 is an arbitrarily substituted -(CH2)6CH3. In a given embodiment, R 6 R is an arbitrarily substituted -(CH2)7CH3. In a given embodiment, R 6 R is an arbitrarily substituted -(CH2)8CH3. In a given embodiment, R 6 This is an arbitrarily substituted -(CH2)9CH3.

[0286] In a predetermined embodiment, R 6 One of the methylene bonds is optionally substituted with a C3-C8 cycloalkylenyl or optionally substituted with a bridging bicyclic or polycyclic C5-C 12 It is replaced with cycloalkylenyl. In certain embodiments, it is optionally substituted with a bridging bicyclic or polycyclic C5-C. 12 Cycloalkylenyl is [ka] Selected from.

[0287] In a predetermined embodiment, R 7 This is an arbitrarily substituted C1-C 14 It is aliphatic. In a given embodiment, R 7 This is an arbitrarily substituted C1-C 14 It is alkyl. In a given embodiment, R 7 This is an arbitrarily substituted C1-C 14 It is a branched alkyl group. In a given embodiment, R 7 This is an arbitrarily substituted C1-C 14 It is a linear alkyl group. In a given embodiment, R 7 This is an arbitrarily substituted C1-C 14 It is an alkenylene. In a given embodiment, R 7 This is an arbitrarily substituted C1-C 14It is a branched alkenyl. In a given embodiment, R 7 This is an arbitrarily substituted C1-C 14 It is a linear alkenyl. In a given embodiment, R 7 This is an arbitrarily substituted C6-C 10 It is alkyl. In a given embodiment, R 7 R is an arbitrarily substituted -(CH2)5CH3. In a given embodiment, R 7 is an arbitrarily substituted -(CH2)6CH3. In a given embodiment, R 7 R is an arbitrarily substituted -(CH2)7CH3. In a given embodiment, R 7 R is an arbitrarily substituted -(CH2)8CH3. In a given embodiment, R 6 This is an arbitrarily substituted -(CH2)9CH3.

[0288] In a predetermined embodiment, R 7 One of the methylene bonds is optionally substituted with a C3-C8 cycloalkylenyl or optionally substituted with a bridging bicyclic or polycyclic C5-C 12 It is replaced with cycloalkylenyl. In certain embodiments, it is optionally substituted with a bridging bicyclic or polycyclic C5-C. 12 Cycloalkylenyl is [ka] Selected from.

[0289] In a predetermined method, each R 6 and R 7 teeth, [ka] Selected from.

[0290] In a predetermined method, each R 6 and R 7 These are each arbitrarily substituted bridged biring C5-C 12 Selected independently from cycloalkylenyl. In a given embodiment, R 6 This is an arbitrarily substituted, bridging polycyclic C5-C12 It is a cycloalkylenyl. In a given embodiment, R 7 This is a optionally substituted bridged biring C5-C 12 It is a cycloalkylenyl. In a given embodiment, it is optionally substituted with a bridging bicyclic or polycyclic C5-C 12 The cycloalkylenyl is selected from adamantyl, bicyclo[2.2.2]octyl, cubenyl, bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, and bicyclo[3.2.1]octyl. In a given embodiment, optionally substituted bridging bicyclic or polycyclic C5-C 12 Cycloalkylenyl is [ka] Selected from. In a given embodiment, a substituted bridging bicyclic or polycyclic C5-C 12 Cycloalkylenyl is [ka] The structure is selected from the following, and one or more CH bonds are substituted.

[0291] In a predetermined embodiment, R 6 and R 7 These are bridging bi-ring or poly-ring C5-C that are arbitrarily replaced together. 12 It forms a cycloalkylenyl. In a given embodiment, it optionally has a substituted cross-linked bicyclic or polycyclic C5-C 12 Cycloalkylenyl is [ka] Selected from.

[0292] R 8 and R 9

[0293] As disclosed in formula (AT), in a given embodiment, R 8 and R 9 These are, independently, arbitrarily substituted C1-C14 Aliphatic (one or more methylene bonds, each optionally and independently, optionally substituted C3-C8 cycloalkylenyl, optionally substituted bridging bicyclic or polycyclic C5-C 12 It is replaced by cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-.

[0294] In a predetermined embodiment, R 8 and R 9 They are the same. In a given embodiment, R 8 and R 9 They are different.

[0295] In a predetermined embodiment, R 8 This is an arbitrarily substituted C1-C 14 It is aliphatic. In a given embodiment, R 8 This is an arbitrarily substituted C1-C 14 It is alkyl. In a given embodiment, R 8 This is an arbitrarily substituted C1-C 14 It is a branched alkyl group. In a given embodiment, R 8 This is an arbitrarily substituted C1-C 14 It is a linear alkyl group. In a given embodiment, R 8 This is an arbitrarily substituted C1-C 14 It is an alkenyl. In a given embodiment, R 8 This is an arbitrarily substituted C1-C 14 It is a branched alkenyl. In a given embodiment, R 8 This is an arbitrarily substituted C1-C 14 It is a linear alkenyl. In a given embodiment, R 8 This is an arbitrarily substituted C6-C 10 It is alkyl. In a given embodiment, R 8 R is an arbitrarily substituted -(CH2)5CH3. In a given embodiment, R 8 is an arbitrarily substituted -(CH2)6CH3. In a given embodiment, R 8R is an arbitrarily substituted -(CH2)7CH3. In a given embodiment, R 8 R is an arbitrarily substituted -(CH2)8CH3. In a given embodiment, R 8 This is an arbitrarily substituted -(CH2)9CH3.

[0296] In a predetermined embodiment, R 8 One of the methylene bonds is optionally substituted with a C3-C8 cycloalkylenyl or optionally substituted with a bridging bicyclic or polycyclic C5-C 12 It is replaced with cycloalkylenyl. In certain embodiments, it is optionally substituted with a bridging bicyclic or polycyclic C5-C. 12 Cycloalkylenyl is [ka] Selected from.

[0297] In a predetermined embodiment, R 9 This is an arbitrarily substituted C1-C 14 It is aliphatic. In a given embodiment, R 9 This is an arbitrarily substituted C1-C 14 It is alkyl. In a given embodiment, R 9 This is an arbitrarily substituted C1-C 14 It is a branched alkyl group. In a given embodiment, R 9 This is an arbitrarily substituted C1-C 14 It is a linear alkyl group. In a given embodiment, R 9 This is an arbitrarily substituted C1-C 14 It is an alkenyl. In a given embodiment, R 9 This is an arbitrarily substituted C1-C 14 It is a branched alkenyl. In a given embodiment, R 9 This is an arbitrarily substituted C1-C 14 It is a linear alkenyl. In a given embodiment, R 9 This is an arbitrarily substituted C6-C 10 It is alkyl. In a given embodiment, R 9 R is an arbitrarily substituted -(CH2)5CH3. In a given embodiment, R9 is an arbitrarily substituted -(CH2)6CH3. In a given embodiment, R 9 R is an arbitrarily substituted -(CH2)7CH3. In a given embodiment, R 9 R is an arbitrarily substituted -(CH2)8CH3. In a given embodiment, R 9 This is an arbitrarily substituted -(CH2)9CH3.

[0298] In a predetermined embodiment, R 9 One of the methylene bonds is optionally substituted with a C3-C8 cycloalkylenyl or optionally substituted with a bridging bicyclic or polycyclic C5-C 12 It is replaced with cycloalkylenyl. In certain embodiments, it is optionally substituted with a bridging bicyclic or polycyclic C5-C. 12 Cycloalkylenyl is [ka] Selected from.

[0299] In a predetermined method, each R 8 and R 9 teeth, [ka] Selected from.

[0300] In some embodiments, R 8 and R 9 These are bridging bicyclic or polycyclic C4-C4s that are arbitrarily substituted together. 14 They form cycloalkyl or optionally substituted cross-linked bicyclic or polycyclic 4-14 membered heterocyclines.

[0301] In a predetermined method, each R 8 and R 9 These are each arbitrarily substituted bridged biring C5-C 12 Selected independently from cycloalkylenyl. In a given embodiment, R 8 This is an arbitrarily substituted, bridging polycyclic C5-C 12It is a cycloalkylenyl. In a given embodiment, R 9 This is a optionally substituted bridged biring C5-C 12 It is a cycloalkylenyl. In a given embodiment, it is optionally substituted with a bridging bicyclic or polycyclic C5-C 12 The cycloalkylenyl is selected from adamantyl, bicyclo[2.2.2]octyl, cubenyl, bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, and bicyclo[3.2.1]octyl. In a given embodiment, optionally substituted bridging bicyclic or polycyclic C5-C 12 Cycloalkylenyl is [ka] Selected from. In a given embodiment, a substituted bridging bicyclic or polycyclic C5-C 12 Cycloalkylenyl is [ka] The structure is selected from the following, and one or more CH bonds are substituted.

[0302] In a predetermined embodiment, R 8 and R 9 These are bridging bi-ring or poly-ring C5-C that are arbitrarily replaced together. 12 It forms a cycloalkylenyl. In a given embodiment, it optionally has a substituted cross-linked bicyclic or polycyclic C5-C 12 Cycloalkylenyl is [ka] Selected from.

[0303] In some embodiments, the lipids of this disclosure are selected from any of the lipids or pharmaceutically acceptable salts thereof in the following Table (IB): [Table 2-1] [Table 2-2]

[0304] Series "AC" Numerous exemplary ionizable lipids of this disclosure are listed below.

[0305] Formula (AC') In some embodiments, the lipids of this disclosure have the structure of formula (AC'). [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 -NR2, [ka] Selected from the group consisting of; Each R is independently either -H or C1-C6 aliphatic; R Z is NR2 or OH; X Z This is an arbitrarily substituted C2-C 14 Alkyrenyl or optionally substituted C2-C 14 It is an alkenylenyl; each R 3 H and C 1-6 Selected independently of alkyl; X 1 These are C2-C6 aliphatic atoms that are bonded or optionally substituted; Z is [ka] And; combinations marked with "*" are X 1 Joined; X 2 and X 3 These are, independently, arbitrarily substituted C1-C 12 It is aliphatic; X 4 It is a conjugate or C2-C6 aliphatic; Y 1 and Y 2 teeth, [ka] Independently selected from the group consisting of; The combination marked with "*" is Y 1 Regarding X 2 or Y 2 Regarding X 3 Joined; R 2 is an arbitrarily substituted C1-C6 aliphatic; R 3 is an arbitrarily substituted C1-C6 aliphatic; (a)R 4 is -CH(OR 6 )(OR 7 ) and; or (b)R 1 but [ka] If R 4 is -CH(OR 6 )(OR 7 ), or -CH(R 6 )(R 7 ) and; R 5 is -CH(OR 8 )(OR 9 ), -CH(R 8 )(R 9 ), or optionally substituted C1-C 14 Aliphatic (one or more methylene bonds, each optionally and independently, optionally substituted C3-C8 cycloalkylenyl, optionally substituted bridging bicyclic or polycyclic C5-C 12 (It is replaced by cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-); R 6 and R 7 These are, independently, arbitrarily substituted C1-C 14Aliphatic (one or more methylene bonds, each optionally and independently, optionally substituted C3-C8 cycloalkylenyl, optionally substituted bridging bicyclic or polycyclic C5-C 12 (It is replaced by cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-); R 8 and R 9 These are, independently, arbitrarily substituted C1-C 14 Aliphatic (one or more methylene bonds, each optionally and independently, optionally substituted C3-C8 cycloalkylenyl, optionally substituted bridging bicyclic or polycyclic C5-C 12 (It is replaced by cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-) It has.

[0306] Formula (AC) In some embodiments, the lipids of this disclosure have the structure of formula (AC). [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 -NR2, [ka] Selected from the group consisting of; Each R is independently either -H or C1-C6 aliphatic; X 1 These are C2-C6 aliphatic atoms that are bonded or optionally substituted; Z is [ka] And; combinations marked with "*" are X 1 Joined; X 2 and X3 These are, independently, arbitrarily substituted C1-C 12 It is aliphatic; X 4 It is a conjugate or C2-C6 aliphatic; Y 1 and Y 2 teeth, [ka] Independently selected from the group consisting of; The combination marked with "*" is Y 1 Regarding X 2 or Y 2 Regarding X 3 Joined; R 2 is an arbitrarily substituted C1-C6 aliphatic; R 3 is an arbitrarily substituted C1-C6 aliphatic; R 4 is -CH(OR 6 )(OR 7 ) and; R 5 is -CH(OR 8 )(OR 9 ), -CH(R 8 )(R 9 ), or optionally substituted C1-C 14 Aliphatic (one or more methylene bonds, each optionally and independently, optionally substituted C3-C8 cycloalkylenyl, optionally substituted bridging bicyclic or polycyclic C5-C 12 (It is replaced by cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-); R 6 and R 7 These are, independently, arbitrarily substituted C1-C 14 Aliphatic (one or more methylene bonds, each optionally and independently, optionally substituted C3-C8 cycloalkylenyl, optionally substituted bridging bicyclic or polycyclic C5-C 12(It is replaced by cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-); R 8 and R 9 These are, independently, arbitrarily substituted C1-C 14 Aliphatic (one or more methylene bonds, each optionally and independently, optionally substituted C3-C8 cycloalkylenyl, optionally substituted bridging bicyclic or polycyclic C5-C 12 (It is replaced by cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-) It has.

[0307] Equation (AC-A) In a given embodiment, the lipid of the Disclosure has the structure of formula (AC), and the lipid of the Disclosure has the structure of formula (AC-A): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 Z, X 2 , X 3 , Y 1 , Y 2 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 (The element has the properties described in formula (AC) or (AC') or as otherwise described in any embodiment below.)

[0308] Equation (AC-B) In a given embodiment, the lipid of the Disclosure has the structure of formula (AC), and the lipid of the Disclosure has the structure of formula (AC-B): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 Z, X 2 , X 3 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 (The element has the properties described in formula (AC) or (AC') or as otherwise described in any embodiment below.)

[0309] Formula (AC-C) In a given embodiment, the lipid of the Disclosure has the structure of formula (AC), and the lipid of the Disclosure has the structure of formula (AC-C): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 , X 2 , X 3 , Y 1 , Y 2 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 (The element has the properties described in formula (AC) or (AC') or as otherwise described in any embodiment below.)

[0310] Equation (AC-D) In a given embodiment, the lipid of the Disclosure has the structure of formula (AC), and the lipid of the Disclosure has the structure of formula (AC-D): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 , X 2 , X 3, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 (The element has the properties described in formula (AC) or (AC') or as otherwise described in any embodiment below.)

[0311] Formula (AC-D1) In a given embodiment, the lipid of the Disclosure has the structure of formula (AC), and the lipid of the Disclosure has the structure of formula (AC-D1): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 (The element has the properties described in formula (AC) or (AC') or as otherwise described in any embodiment below.)

[0312] Formula (AC-D2) In a given embodiment, the lipid of the Disclosure has the structure of formula (AC), and the lipid of the Disclosure has the structure of formula (AC-D2): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9(The element has the properties described in formula (AC) or (AC') or as otherwise described in any embodiment below.)

[0313] Equation (AC-E) In a given embodiment, the lipid of the Disclosure has the structure of formula (AC), and the lipid of the Disclosure has the structure of formula (AC-E): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 Z, X 2 , X 3 , Y 1 , Y 2 , R 2 , R 3 , R 6 , R 7 , R 8 , and R 9 (The element has the properties described in formula (AC) or (AC') or as otherwise described in any embodiment below.)

[0314] Formula (AC-F) In a given embodiment, the lipid of the Disclosure has the structure of formula (AC), and the lipid of the Disclosure has the structure of formula (AC-F): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 Z, X 2 , X 3 , R 2 , R 3 , R 6 , R 7 , R 8 , and R 9 (The element has the properties described in formula (AC) or (AC') or as otherwise described in any embodiment below.)

[0315] Formula (AC-G) In a given embodiment, the lipid of the Disclosure has the structure of formula (AC), and the lipid of the Disclosure has the structure of formula (AC-G): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 , X 2 , X 3 , Y 1 , Y 2 , R 2 , R 3 , R 6 , R 7 , R 8 , and R 9 (The element has the properties described in formula (AC) or (AC') or as otherwise described in any embodiment below.)

[0316] Formula (AC-H) In a given embodiment, the lipid of the Disclosure has the structure of formula (AC), and the lipid of the Disclosure has the structure of formula (AC-H): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 , X 2 , X 3 , R 2 , R 3 , R 6 , R 7 , R 8 , and R 9 (The element has the properties described in formula (AC) or (AC') or as otherwise described in any embodiment below.)

[0317] Equation (AC-I) In a given embodiment, the lipid of the Disclosure has the structure of formula (AC), and the lipid of the Disclosure has the structure of formula (AC-I): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1, R, X 1 Z, X 2 , X 3 , X 4 , R 2 , R 3 , R 6 , R 7 , R 8 , and R 9 (The element has the properties described in formula (AC) or (AC') or as otherwise described in any embodiment below.)

[0318] R 1 In a predetermined embodiment, R 1 -NR2, [ka] It is selected from the group consisting of the following.

[0319] In some embodiments, R 1 -NR2, [ka] It is selected from the group consisting of the following.

[0320] In a predetermined embodiment, R 1 -NR2, [ka] It is selected from the group consisting of the following.

[0321] In a predetermined embodiment, R 1 is -NR2. In a given embodiment, R 1 teeth, [ka] In a given embodiment, R 1 teeth, [ka] In a given embodiment, R 1 teeth, [ka] In a given embodiment, R 1 teeth, [ka] In a given embodiment, R 1 teeth, [ka] In a given embodiment, R 1 teeth, [ka] In a given embodiment, R 1 teeth, [ka] In a given embodiment, R 1 teeth, [ka] In a given embodiment, R 1 teeth, [ka] In a given embodiment, R 1 teeth, [ka] In a given embodiment, R 1 teeth, [ka] In a given embodiment, R 1 -N(Et)2, -N(Me)(Et), [ka] , and [ka] Selected from the group consisting of. In a given embodiment, R 1 is -N(Et)². In a given embodiment, R 1 R is -N(Me)2. In a given embodiment, R 1 is -N(Me)(Et). In a given embodiment, R 1 is -NH2. In a given embodiment, R 1 is -N(nPr)². In a given embodiment, R 1 is -N(iPr)2. In a given embodiment, R 1 is -N(Me)(Et). In a given embodiment, R 1 teeth, [ka] In a given embodiment, R 1 teeth, [ka] In a given embodiment, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] That is the case.

[0322] X 1

[0323] In a predetermined embodiment, X 1 is an optionally substituted C2-C6 aliphatic. In a given embodiment, X 1 is an optionally substituted C2-C6 alkylene. In a given embodiment, R 2 is an optionally substituted C2 alkylene. In a given embodiment, X 1 is an optionally substituted C3 alkylene. In a given embodiment, X1 is an optionally substituted C4 alkylene. In a given embodiment, X 1 is an optionally substituted C5 alkylene. In a given embodiment, X 1 is an optionally substituted C6 alkylene. In a given embodiment, X 1 is -(CH2)2-. In a given embodiment, X 1 is -(CH2)3-. In a given embodiment, X 1 is -(CH2)4-. In a given embodiment, X 1 is -(CH2)5-. In a given embodiment, X 1 is -(CH2)6-. In a given embodiment, X 1 It is a combination.

[0324] Z In a given embodiment, the lipids of this disclosure have the structure of formula (AC), (AC-A), (AC-B), (AC-E), (AC-F), or (AC-I), where Z is [ka] And the combination marked with "*" is X 1 It is bound to. In a given embodiment, the lipid of the present disclosure has the structure of formula (AC), (AC-A), (AC-B), (AC-E), (AC-F), or (AC-I), where Z is [ka] In a given embodiment, the lipids of this disclosure have the structure of formula (AC), (AC-A), (AC-B), (AC-E), (AC-F), or (AC-I), where Z is [ka] In a given embodiment, the lipids of this disclosure have the structure of formula (AC), (AC-A), (AC-B), (AC-E), (AC-F), or (AC-I), where Z is [ka] In a given embodiment, the lipids of this disclosure have the structure of formula (AC), (AC-A), (AC-B), (AC-E), (AC-F), or (AC-I), where Z is [ka] In a given embodiment, the lipids of this disclosure have the structure of formula (AC), (AC-A), (AC-B), (AC-E), (AC-F), or (AC-I), where Z is [ka] In a given embodiment, the lipids of this disclosure have the structure of formula (AC), (AC-A), (AC-B), (AC-E), (AC-F), or (AC-I), and Y 1 teeth, [ka] In a given embodiment, the lipids of this disclosure have the structure of formula (AC), (AC-A), (AC-B), (AC-E), (AC-F), or (AC-I), where Z is [ka] In a given embodiment, the lipids of this disclosure have the structure of formula (AC), (AC-A), (AC-B), (AC-E), (AC-F), or (AC-I), where Z is [ka] That is the case.

[0325] X 2 and X 3 In a predetermined embodiment, X 2 and X 3 These are, independently, arbitrarily substituted C1-C 12 It is aliphatic. In a given embodiment, X 2 and X 3 They are the same. In a given embodiment, X 2 and X 3 They are different.

[0326] In a predetermined embodiment, X 2 This is an arbitrarily substituted C1-C 12 It is an alkylene. In a given embodiment, X 2 This is an arbitrarily substituted C1-C 12 In a given embodiment, X 2 This is an arbitrarily substituted C1-C 10 It is aliphatic. In a given embodiment, X 2 This is an arbitrarily substituted C1-C 10 It is an alkylene. In a given embodiment, X 2 This is an arbitrarily substituted C1-C 10 It is an alkenylene. In a given embodiment, X 2 is an optionally substituted C1-C8 aliphatic. In a given embodiment, X 2 is an optionally substituted C1-C8 alkylene. In a given embodiment, X 2 is an optionally substituted C1-C8 alkenylene. In a given embodiment, X 2 is an optionally substituted C1-C6 aliphatic. In a given embodiment, X 2 is an optionally substituted C1-C6 alkylene. In a given embodiment, X 2 is an optionally substituted C1-C6 alkenylene. In a given embodiment, X 2 This is an arbitrarily substituted C2-C 12 It is aliphatic. In a given embodiment, X 2 This is an arbitrarily substituted C2-C 12 It is an alkylene. In a given embodiment, X 2 This is an arbitrarily substituted C2-C 12 It is an alkenylene. In a given embodiment, X 2 This is an arbitrarily substituted C4-C 12 It is aliphatic. In a given embodiment, X 2 This is an arbitrarily substituted C4-C 12 It is an alkylene. In a given embodiment, X 2 This is an arbitrarily substituted C4-C 12 It is an alkenylene. In a given embodiment, X2 This is an arbitrarily substituted C4-C 10 It is aliphatic. In a given embodiment, X 2 This is an arbitrarily substituted C4-C 10 It is an alkylene. In a given embodiment, X 2 This is an arbitrarily substituted C4-C 10 It is an alkenylene. In a given embodiment, X 2 is an optionally substituted C6-C8 aliphatic. In a given embodiment, X 2 is an optionally substituted C6-C8 alkylene. In a given embodiment, X 2 is an optionally substituted C6-C8 alkenylene. In a given embodiment, X 2 is -(CH2)-. In a given embodiment, X 2 is -(CH2)2-. In a given embodiment, X 2 is -(CH2)3-. In a given embodiment, X 2 is -(CH2)4-. In a given embodiment, X 2 is -(CH2)5-. In a given embodiment, X 2 is -(CH2)6-. In a given embodiment, X 2 is -(CH2)7-. In a given embodiment, X 2 is -(CH2)8-. In a given embodiment, X 2 is -(CH2)9-. In a given embodiment, X 2 is, -(CH2) 10 - is

[0327] In a predetermined embodiment, X 3 This is an arbitrarily substituted C1-C 12 It is an alkylene. In a given embodiment, X 3 This is an arbitrarily substituted C1-C 12 It is an alkenylene. In a given embodiment, X 3 This is an arbitrarily substituted C1-C 10 It is aliphatic. In a given embodiment, X 3 This is an arbitrarily substituted C1-C 10 It is an alkylene. In a given embodiment, X 3This is an arbitrarily substituted C1-C 10 It is an alkenylene. In a given embodiment, X 3 is an optionally substituted C1-C8 aliphatic. In a given embodiment, X 3 is an optionally substituted C1-C8 alkylene. In a given embodiment, X 3 is an optionally substituted C1-C8 alkenylene. In a given embodiment, X 3 is an optionally substituted C1-C6 aliphatic. In a given embodiment, X 3 is an optionally substituted C1-C6 alkylene. In a given embodiment, X 3 is an optionally substituted C1-C6 alkenylene. In a given embodiment, X 3 This is an arbitrarily substituted C2-C 12 It is aliphatic. In a given embodiment, X 3 This is an arbitrarily substituted C2-C 12 It is an alkylene. In a given embodiment, X 3 This is an arbitrarily substituted C2-C 12 It is an alkenylene. In a given embodiment, X 3 This is an arbitrarily substituted C4-C 12 It is aliphatic. In a given embodiment, X 3 This is an arbitrarily substituted C4-C 12 It is an alkylene. In a given embodiment, X 3 This is an arbitrarily substituted C4-C 12 It is an alkenylene. In a given embodiment, X 3 This is an arbitrarily substituted C4-C 10 It is aliphatic. In a given embodiment, X 3 This is an arbitrarily substituted C4-C 10 It is an alkylene. In a given embodiment, X 3 This is an arbitrarily substituted C4-C 10 It is an alkenylene. In a given embodiment, X 3 is an optionally substituted C6-C8 aliphatic. In a given embodiment, X 3 is an optionally substituted C6-C8 alkylene. In a given embodiment, X 3is an optionally substituted C6-C8 alkenylene. In a given embodiment, X 3 is -(CH2)-. In a given embodiment, X 3 is -(CH2)2-. In a given embodiment, X 3 is -(CH2)3-. In a given embodiment, X 3 is -(CH2)4-. In a given embodiment, X 3 is -(CH2)5-. In a given embodiment, X 3 is -(CH2)6-. In a given embodiment, X 3 is -(CH2)7-. In a given embodiment, X 3 is -(CH2)8-. In a given embodiment, X 3 is -(CH2)9-. In a given embodiment, X 3 is, -(CH2) 10 - is

[0328] In a predetermined embodiment, X 2 and X 3 Both are -(CH2)8-. In a given embodiment, X 2 and X 3 Both are -(CH2)6-.

[0329] X 4 In a given embodiment, the lipid of this disclosure has a structure of formula (AC) or (AC-I) (wherein X 4 X has a bond or is C2-C6 aliphatic. In a given embodiment, the lipid of the present disclosure has a structure of formula (AC) or (AC-I) (wherein X 4 X is a bond. In a given embodiment, the lipid of the present disclosure has a structure of formula (AC) or (AC-I) (wherein X is a bond). 4 (is C2-C6 aliphatic). In a given embodiment, the lipid of the present disclosure has a structure of formula (AC) or (AC-I) (wherein X 4 (is C2 aliphatic). In a given embodiment, the lipid of the present disclosure has a structure of formula (AC) or (AC-I) (wherein X 4(is C3 aliphatic). In a given embodiment, the lipid of the present disclosure has a structure of formula (AC) or (AC-I) (wherein X 4 (is C4 aliphatic). In a given embodiment, the lipid of the present disclosure has a structure of formula (AC) or (AC-I) (wherein X 4 (is C5 aliphatic). In a given embodiment, the lipid of the present disclosure has a structure of formula (AC) or (AC-I) (wherein X 4 It has (C6 aliphatic) properties.

[0330] Y 1 and Y 2 In a predetermined embodiment, Y 1 and Y 2 Each of them operates independently. [ka] (In the formula, combinations marked with "*" are Y 1 Regarding X 2 or Y 2 Regarding X 3 It has (which is coupled to). In a predetermined embodiment, Y 1 and Y 2 They are the same. In a given embodiment, Y 1 and Y 2 They are different.

[0331] In a predetermined embodiment, Y 1 teeth, [ka] In a given embodiment, Y 1 teeth, [ka] In a given embodiment, Y 1 teeth, [ka] In a given embodiment, Y 1 teeth, [Chemical formula] is. In a predetermined embodiment, Y 1 is [Chemical formula] is. In a predetermined embodiment, Y 1 is [Chemical formula] is. In a predetermined embodiment, Y <00028​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​ In a given embodiment, Y 2 teeth, [ka] In a given embodiment, Y 2 teeth, [ka] In a given embodiment, Y 1 and Y 2 Both are [ka] In a given embodiment, Y 1 and Y 2 Both are [ka] That is the case.

[0332] R 2 In a predetermined embodiment, R 2 is an optionally substituted C1-C6 aliphatic. In a given embodiment, R 2 is an optionally substituted C1-C6 alkylene. In a given embodiment, R 2 R is an optionally substituted methylene. In a given embodiment, R 2 is an optionally substituted C2 alkylene. In a given embodiment, R 2 R is an optionally substituted C3 alkylene. In a given embodiment, R 2 R is an optionally substituted C4 alkylene. In a given embodiment, R 2 R is an optionally substituted C5 alkylene. In a given embodiment, R 2 is an optionally substituted C6 alkylene. In a given embodiment, R 2 is -(CH2)-. In a given embodiment, R 2 is -(CH2)2-. In a given embodiment, R 2is -(CH2)3-. In a given embodiment, R 2 is -(CH2)4-. In a given embodiment, R 2 is -(CH2)5-. In a given embodiment, R 2 It is -(CH2)6-.

[0333] R 3 In a predetermined embodiment, R 3 is an optionally substituted C1-C6 aliphatic. In a given embodiment, R 3 is an optionally substituted C1-C6 alkylene. In a given embodiment, R 3 R is an optionally substituted methylene. In a given embodiment, R 3 is an optionally substituted C2 alkylene. In a given embodiment, R 3 R is an optionally substituted C3 alkylene. In a given embodiment, R 3 R is an optionally substituted C4 alkylene. In a given embodiment, R 3 R is an optionally substituted C5 alkylene. In a given embodiment, R 3 is an optionally substituted C6 alkylene. In a given embodiment, R 3 is -(CH2)-. In a given embodiment, R 3 is -(CH2)2-. In a given embodiment, R 3 is -(CH2)3-. In a given embodiment, R 3 is -(CH2)4-. In a given embodiment, R 3 is -(CH2)5-. In a given embodiment, R 3 It is -(CH2)6-.

[0334] In a predetermined embodiment, R 2 and R 3 They are the same. In a given embodiment, R 2 and R 3 They are different.

[0335] R 4 In a predetermined embodiment, R4 is -CH(OR 6 )(OR 7 ). In certain embodiments, R 4 is -CH(R 6 )(R 7 ).

[0336] In certain embodiments, R 4 is

Chemical Formula

[0337] R 5 In certain embodiments, R 5 is optionally substituted C1-C 14 aliphatic, -CH(OR 8 )(OR 9 ); or -CH(R 8 )(R 9 ). In certain embodiments, R 5 is optionally substituted C1-C 14 aliphatic (one or more methylene bonds are each optionally and independently replaced by optionally substituted C3-C8 cycloalkenyl, optionally substituted bridged bicyclic or polycyclic C5-C 12 cycloalkenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-). In certain embodiments, R 5 is optionally substituted C1-C 14 aliphatic. In certain embodiments, R 5 is -CH(OR 8 )(OR 9 ). In certain embodiments, R 5 is -CH(R 8 )(R 9 ).

[0338] In certain embodiments, R 5One of the methylene bonds is optionally substituted with a C3-C8 cycloalkylenyl or optionally substituted with a bridging bicyclic or polycyclic C5-C 12 It is replaced with cycloalkylenyl. In certain embodiments, it is optionally substituted with a bridging bicyclic or polycyclic C5-C. 12 Cycloalkylenyl is

[0339] [ka] Selected from.

[0340] In a predetermined embodiment, R 4 and R 5 They are the same. In a given embodiment, R 4 and R 5 They are different.

[0341] In a predetermined embodiment, R 5 teeth, [ka] Selected from.

[0342] In a predetermined embodiment, R 5 teeth, [ka] Selected from.

[0343] R 6 and R 7 In a predetermined embodiment, R 6 and R 7 These are, independently, arbitrarily substituted C1-C 14 Aliphatic (one or more methylene bonds, each optionally and independently, optionally substituted C3-C8 cycloalkylenyl, optionally substituted bridging bicyclic or polycyclic C5-C 12It is replaced by cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-.

[0344] In a predetermined embodiment, R 6 and R 7 They are the same. In a given embodiment, R 6 and R 7 They are different.

[0345] In a predetermined embodiment, R 6 This is an arbitrarily substituted C1-C 14 It is aliphatic. In a given embodiment, R 6 This is an arbitrarily substituted C1-C 14 It is an alkylene. In a given embodiment, R 6 This is an arbitrarily substituted C1-C 14 It is a branched alkylene. In a given embodiment, R 6 This is an arbitrarily substituted C1-C 14 It is a linear alkylene. In a given embodiment, R 6 This is an arbitrarily substituted C1-C 14 It is an alkenylene. In a given embodiment, R 6 This is an arbitrarily substituted C1-C 14 It is a branched alkenylene. In a given embodiment, R 6 This is an arbitrarily substituted C1-C 14 It is a linear alkenylene. In a given embodiment, R 6 This is an arbitrarily substituted C6-C 10 It is an alkylene. In a given embodiment, R 6 R is an arbitrarily substituted -(CH2)5CH3. In a given embodiment, R 6 is an arbitrarily substituted -(CH2)6CH3. In a given embodiment, R 6 R is an arbitrarily substituted -(CH2)7CH3. In a given embodiment, R 6 R is an arbitrarily substituted -(CH2)8CH3. In a given embodiment, R 6 This is an arbitrarily substituted -(CH2)9CH3.

[0346] In a predetermined embodiment, R 6 One of the methylene bonds is optionally substituted with a C3-C8 cycloalkylenyl or optionally substituted with a bridging bicyclic or polycyclic C5-C 12 It is replaced with cycloalkylenyl. In certain embodiments, it is optionally substituted with a bridging bicyclic or polycyclic C5-C. 12 Cycloalkylenyl is [ka] Selected from.

[0347] In a predetermined embodiment, R 7 This is an arbitrarily substituted C1-C 14 It is aliphatic. In a given embodiment, R 7 This is an arbitrarily substituted C1-C 14 It is an alkylene. In a given embodiment, R 7 This is an arbitrarily substituted C1-C 14 It is a branched alkylene. In a given embodiment, R 7 This is an arbitrarily substituted C1-C 14 It is a linear alkylene. In a given embodiment, R 7 This is an arbitrarily substituted C1-C 14 It is an alkenylene. In a given embodiment, R 7 This is an arbitrarily substituted C1-C 14 It is a branched alkenylene. In a given embodiment, R 7 This is an arbitrarily substituted C1-C 14 It is a linear alkenylene. In a given embodiment, R 7 This is an arbitrarily substituted C6-C 10 It is an alkylene. In a given embodiment, R 7 R is an arbitrarily substituted -(CH2)5CH3. In a given embodiment, R 7 is an arbitrarily substituted -(CH2)6CH3. In a given embodiment, R 7 R is an arbitrarily substituted -(CH2)7CH3. In a given embodiment, R 7R is an arbitrarily substituted -(CH2)8CH3. In a given embodiment, R 6 This is an arbitrarily substituted -(CH2)9CH3.

[0348] In a predetermined embodiment, R 7 One of the methylene bonds is optionally substituted with a C3-C8 cycloalkylenyl or optionally substituted with a bridging bicyclic or polycyclic C5-C 12 It is replaced with cycloalkylenyl. In certain embodiments, it is optionally substituted with a bridging bicyclic or polycyclic C5-C. 12 Cycloalkylenyl is [ka] Selected from.

[0349] In a predetermined embodiment, R 6 and R 7 teeth, [ka] Selected from.

[0350] R 8 and R 9 In a predetermined embodiment, R 8 and R 9 These are, independently, arbitrarily substituted C1-C 14 Aliphatic (one or more methylene bonds, each optionally and independently, optionally substituted C3-C8 cycloalkylenyl, optionally substituted bridging bicyclic or polycyclic C5-C 12 It is replaced by cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-.

[0351] In a predetermined embodiment, R 8 and R 9 They are the same. In a given embodiment, R 8 and R 9 They are different.

[0352] In a predetermined embodiment, R 8 This is an arbitrarily substituted C1-C 14 It is aliphatic. In a given embodiment, R 8 This is an arbitrarily substituted C1-C 14 It is an alkylene. In a given embodiment, R 8 This is an arbitrarily substituted C1-C 14 It is a branched alkylene. In a given embodiment, R 8 This is an arbitrarily substituted C1-C 14 It is a linear alkylene. In a given embodiment, R 8 This is an arbitrarily substituted C1-C 14 It is an alkenylene. In a given embodiment, R 8 This is an arbitrarily substituted C1-C 14 It is a branched alkenylene. In a given embodiment, R 8 This is an arbitrarily substituted C1-C 14 It is a linear alkenylene. In a given embodiment, R 8 This is an arbitrarily substituted C6-C 10 It is an alkylene. In a given embodiment, R 8 R is an arbitrarily substituted -(CH2)5CH3. In a given embodiment, R 8 is an arbitrarily substituted -(CH2)6CH3. In a given embodiment, R 8 R is an arbitrarily substituted -(CH2)7CH3. In a given embodiment, R 8 R is an arbitrarily substituted -(CH2)8CH3. In a given embodiment, R 8 This is an arbitrarily substituted -(CH2)9CH3.

[0353] In a predetermined embodiment, R 8 One of the methylene bonds is optionally substituted with a C3-C8 cycloalkylenyl or optionally substituted with a bridging bicyclic or polycyclic C5-C 12 It is replaced with cycloalkylenyl. In certain embodiments, it is optionally substituted with a bridging bicyclic or polycyclic C5-C. 12 Cycloalkylenyl is [ka] Selected from.

[0354] In a predetermined embodiment, R 9 This is an arbitrarily substituted C1-C 14 It is aliphatic. In a given embodiment, R 9 This is an arbitrarily substituted C1-C 14 It is an alkylene. In a given embodiment, R 9 This is an arbitrarily substituted C1-C 14 It is a branched alkylene. In a given embodiment, R 9 This is an arbitrarily substituted C1-C 14 It is a linear alkylene. In a given embodiment, R 9 This is an arbitrarily substituted C1-C 14 It is an alkenylene. In a given embodiment, R 9 This is an arbitrarily substituted C1-C 14 It is a branched alkenylene. In a given embodiment, R 9 This is an arbitrarily substituted C1-C 14 It is a linear alkenylene. In a given embodiment, R 9 This is an arbitrarily substituted C6-C 10 It is an alkylene. In a given embodiment, R 9 R is an arbitrarily substituted -(CH2)5CH3. In a given embodiment, R 9 is an arbitrarily substituted -(CH2)6CH3. In a given embodiment, R 9 R is an arbitrarily substituted -(CH2)7CH3. In a given embodiment, R 9 R is an arbitrarily substituted -(CH2)8CH3. In a given embodiment, R 9 This is an arbitrarily substituted -(CH2)9CH3.

[0355] In a predetermined embodiment, R 9 One of the methylene bonds is optionally substituted with a C3-C8 cycloalkylenyl or optionally substituted with a bridging bicyclic or polycyclic C5-C 12It is replaced with cycloalkylenyl. In certain embodiments, it is optionally substituted with a bridging bicyclic or polycyclic C5-C. 12 Cycloalkylenyl is [ka] Selected from.

[0356] In a predetermined embodiment, R 8 and R 9 teeth, [ka] Selected from.

[0357] In some embodiments, the lipids of this disclosure are selected from any of the lipids or pharmaceutically acceptable salts thereof in the following table (IC): [Table 3-1] [Table 3-2] [Table 3-3]

[0358] Series "CO" Numerous exemplary ionizable lipids of this disclosure are listed below.

[0359] This disclosure relates to compounds of formula (CO'). [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 -OH, -N(R)2, [ka] Selected from the group consisting of; Each R is independently either -H or C1-C6 aliphatic; R Z is NR2 or OH; X Z This is an arbitrarily substituted C2-C 14 Alkyrenyl or optionally substituted C2-C 14 It is an alkenylenyl; each R 3 H and C 1-6 Selected independently of alkyl; Each R is independently either -H or C1-C6 aliphatic; X 1 is an optionally substituted C2-C6 aliphatic (where one or more methylene bonds are optionally and independently replaced by -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)-, or -C(O)O-); X 2 It is selected from the group consisting of bonds, -CH2-, and -CH2CH2-; X 3 It is selected from the group consisting of bonds, -CH2-, and -CH2CH2-; X 4 and X 5 These are, independently, arbitrarily substituted C1-C 10 It is aliphatic; Y 1 and Y 2 Each of them operates independently. [ka] and; The combination marked with "*" is X 4 or X 5 Joined; R 2 is an arbitrarily substituted C1-C6 aliphatic; R 3 is an arbitrarily substituted C1-C6 aliphatic; R 4 is -CH(OR 6 )(OR 7 );-CH(SR 6 )(SR 7 );-CH(R 6 )(R 7); or optionally replaced C1-C 14 Aliphatic (one or more methylene bonds, each optionally and independently, optionally substituted C3-C8 cycloalkylenyl, optionally substituted bridging bicyclic or polycyclic C5-C 12 (It is replaced by cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-); R 5 is -CH(OR 8 )(OR 9 );-CH(SR 8 )(SR 9 );-CH(R 8 )(R 9 ) or optionally replaced C1-C 14 Aliphatic (one or more methylene bonds, each optionally and independently, optionally substituted C3-C8 cycloalkylenyl, optionally substituted bridging bicyclic or polycyclic C5-C 12 (It is replaced by cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-); R 6 and R 7 These are, independently, arbitrarily substituted C1-C 14 Aliphatic (one or more methylene bonds, each optionally and independently, optionally substituted C3-C8 cycloalkylenyl, optionally substituted bridging bicyclic or polycyclic C5-C 12 (It is replaced by cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-); R 8 and R 9 These are, independently, arbitrarily substituted C1-C 14 Aliphatic (one or more methylene bonds, each optionally and independently, optionally substituted C3-C8 cycloalkylenyl, optionally substituted bridging bicyclic or polycyclic C5-C 12(It is replaced by cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-) To provide.

[0360] This disclosure relates to compounds of formula (CO). [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 -NR2, [ka] Selected from the group consisting of; Each R is independently either -H or C1-C6 aliphatic; X 1 is an optionally substituted C2-C6 aliphatic (where one or more methylene bonds are optionally and independently replaced by -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)-, or -C(O)O-); X 2 It is selected from the group consisting of bonds, -CH2-, and -CH2CH2-; X 3 It is selected from the group consisting of bonds, -CH2-, and -CH2CH2-; X 4 and X 5 These are, independently, arbitrarily substituted C1-C 10 It is aliphatic; Y 1 and Y 2 Each of them operates independently. [ka] and; The combination marked with "*" is X 4 or X 5 Joined; R 2is an arbitrarily substituted C1-C6 aliphatic; R 3 is an arbitrarily substituted C1-C6 aliphatic; R 4 is -CH(OR 6 )(OR 7 );-CH(SR 6 )(SR 7 );-CH(R 6 )(R 7 ); or optionally replaced C1-C 14 Aliphatic (one or more methylene bonds, each optionally and independently, optionally substituted C3-C8 cycloalkylenyl, optionally substituted bridging bicyclic or polycyclic C5-C 12 (It is replaced by cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-); R 5 is -CH(OR 8 )(OR 9 );-CH(SR 8 )(SR 9 );-CH(R 8 )(R 9 ) or optionally replaced C1-C 14 Aliphatic (one or more methylene bonds, each optionally and independently, optionally substituted C3-C8 cycloalkylenyl, optionally substituted bridging bicyclic or polycyclic C5-C 12 (It is replaced by cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-); R 6 and R 7 These are, independently, arbitrarily substituted C1-C 14 Aliphatic (one or more methylene bonds, each optionally and independently, optionally substituted C3-C8 cycloalkylenyl, optionally substituted bridging bicyclic or polycyclic C5-C 12(It is replaced by cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-); R 8 and R 9 These are, independently, arbitrarily substituted C1-C 14 Aliphatic (one or more methylene bonds, each optionally and independently, optionally substituted C3-C8 cycloalkylenyl, optionally substituted bridging bicyclic or polycyclic C5-C 12 (It is replaced by cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-) To provide.

[0361] In a given embodiment, the compound of formula (CO) is the compound of formula (CO-A): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 , X 2 , X 3 , X 4 , X 5 , Y 1 , Y 2 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 (This is as described in formula (CO) or (CO') or as otherwise described in any embodiment below.)

[0362] In a given embodiment, the compound of formula (CO) is the compound of formula (CO-B): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1, R, X 1 , X 4 , X 5 , Y 1 , Y 2 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 (This is as described in formula (CO) or (CO') or as otherwise described in any embodiment below.)

[0363] In a given embodiment, the compound of formula (CO) is the compound of formula (CO-C): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 , X 4 , X 5 , Y 1 , Y 2 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 (This is as described in formula (CO) or (CO') or as otherwise described in any embodiment below.)

[0364] In a given embodiment, the compound of formula (CO) is the compound of formula (CO-D): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 , Y 1 , Y 2 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7, R 8 , and R 9 (This is as described in formula (CO) or (CO') or as otherwise described in any embodiment below.)

[0365] In a given embodiment, the compound of formula (CO) is the compound of formula (CO-E): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 , X 2 , X 3 , X 4 , X 5 , Y 1 , Y 2 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 (This is as described in formula (CO) or (CO') or as otherwise described in any embodiment below.)

[0366] In a given embodiment, the compound of formula (CO) is the compound of formula (CO-F): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 , X 4 , X 5 , Y 1 , Y 2 , R 2 , R 3 , R 6 , R 7 , R 8 , and R 9 (This is as described in formula (CO) or (CO') or as otherwise described in any embodiment below.)

[0367] In a given embodiment, the compound of formula (CO) is the compound of formula (CO-F'): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 , X 4 , X 5 , Y 1 , Y 2 , R 2 , R 3 , R 6 , R 7 , R 8 , and R 9 (This is as described in formula (CO) or (CO') or as otherwise described in any embodiment below.)

[0368] In a given embodiment, the compound of formula (CO) is the compound of formula (CO-G): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 , X 4 , X 5 , Y 1 , Y 2 , R 2 , R 3 , R 6 , R 7 , R 8 , and R 9 (This is as described in formula (CO) or (CO') or as otherwise described in any embodiment below.)

[0369] In a given embodiment, the compound of formula (CO) is the compound of formula (CO-G'): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 , X 4 , X 5 , Y 1, Y 2 , R 2 , R 3 , R 6 , R 7 , R 8 , and R 9 (This is as described in formula (CO) or (CO') or as otherwise described in any embodiment below.)

[0370] In a given embodiment, the compound of formula (CO) is the compound of formula (CO-H): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 , Y 1 , Y 2 , R 2 , R 3 , R 6 , R 7 , R 8 , and R 9 (This is as described in formula (CO) or (CO') or as otherwise described in any embodiment below.)

[0371] In a given embodiment, the compound of formula (CO) is the compound of formula (CO-H'): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 , Y 1 , Y 2 , R 2 , R 3 , R 6 , R 7 , R 8 , and R 9 (This is as described in formula (CO) or (CO') or as otherwise described in any embodiment below.)

[0372] In a given embodiment, the compound of formula (CO) is the compound of formula (CO-I): [ka] or a pharmaceutically acceptable salt thereof (wherein R, X) 1 , X 4 , X 5 , Y 1 , Y 2 , R 2 , R 3 , R 6 , R 7 , R 8 , and R 9 (This is as described in formula (CO) or (CO') or as otherwise described in any embodiment below.)

[0373] In a given embodiment, the compound of formula (CO) is the compound of formula (CO-I'): [ka] or a pharmaceutically acceptable salt thereof (wherein R, X) 1 , X 4 , X 5 , Y 1 , Y 2 , R 2 , R 3 , R 6 , R 7 , R 8 , and R 9 (This is as described in formula (CO) or (CO') or as otherwise described in any embodiment below.)

[0374] In a given embodiment, the compound of formula (CO) is the compound of formula (CO-J): [ka] or a pharmaceutically acceptable salt thereof (wherein R, X) 1 , Y 1 , Y 2 , R 2 , R 3 , R 6 , R 7 , R 8 , and R 9(This is as described in formula (CO) or (CO') or as otherwise described in any embodiment below.)

[0375] In a given embodiment, the compound of formula (CO) is the compound of formula (CO-J'): [ka] or a pharmaceutically acceptable salt thereof (wherein R, X) 1 , Y 1 , Y 2 , R 2 , R 3 , R 6 , R 7 , R 8 , and R 9 (This is as described in formula (CO) or (CO') or as otherwise described in any embodiment below.)

[0376] In a given embodiment, the compound of formula (CO) is the compound of formula (CO-K): [ka] or a pharmaceutically acceptable salt thereof (wherein R, X) 1 , Y 1 , Y 2 , R 2 , R 3 , R 6 , R 7 , R 8 , and R 9 (This is as described in formula (CO) or (CO') or as otherwise described in any embodiment below.)

[0377] In a given embodiment, the compound of formula (CO) is the compound of formula (CO-L): [ka] or a pharmaceutically acceptable salt thereof (wherein R, X) 1 , Y 1 , Y 2 , R 2 , R3 , R 6 , R 7 , R 8 , and R 9 (This is as described in formula (CO) or (CO') or as otherwise described in any embodiment below.)

[0378] In a given embodiment, the compound of formula (CO) is the compound of formula (CO-L'): [ka] or a pharmaceutically acceptable salt thereof (wherein R, X) 1 , Y 1 , Y 2 , R 2 , R 3 , R 6 , R 7 , R 8 , and R 9 (This is as described in formula (CO) or (CO') or as otherwise described in any embodiment below.)

[0379] In a given embodiment, the compound of formula (CO) is the compound of formula (CO-M): [ka] or a pharmaceutically acceptable salt thereof (wherein R, X) 1 , Y 1 , Y 2 , R 2 , R 3 , R 6 , R 7 , R 8 , and R 9 (This is as described in formula (CO) or (CO') or as otherwise described in any embodiment below.)

[0380] In a given embodiment, the compound of formula (CO) is the compound of formula (CO-M'): [ka] or a pharmaceutically acceptable salt thereof (wherein R, X) 1 , Y 1 , Y 2 , R 2 , R 3 , R 6 , R 7 , R 8 , and R 9 (This is as described in formula (CO) or (CO') or as otherwise described in any embodiment below.)

[0381] In a given embodiment, the compound of formula (CO) is the compound of formula (CO-N): [ka] or a pharmaceutically acceptable salt thereof (wherein R, X) 1 , X 4 , X 5 , Y 1 , Y 2 , R 2 , R 3 , R 6 , R 7 , R 8 , and R 9 (This is as described in formula (CO) or (CO') or as otherwise described in any embodiment below.)

[0382] In a given embodiment, the compound of formula (CO) is the compound of formula (CO-N'): [ka] or a pharmaceutically acceptable salt thereof (wherein R, X) 1 , X 4 , X 5 , Y 1 , Y 2 , R 2 , R 3 , R 6 , R 7 , R 8 , and R 9 (This is as described in formula (CO) or (CO') or as otherwise described in any embodiment below.)

[0383] In a given embodiment, the compound of formula (CO) is the compound of formula (CO-O): [ka] or a pharmaceutically acceptable salt thereof (wherein R, X) 4 , X 5 , Y 1 , Y 2 , R 2 , R 3 , R 6 , R 7 , R 8 , and R 9 (This is as described in formula (CO) or (CO') or as otherwise described in any embodiment below.)

[0384] In a given embodiment, the compound of formula (CO) is the compound of formula (CO-O'): [ka] or a pharmaceutically acceptable salt thereof (wherein R, X) 4 , X 5 , Y 1 , Y 2 , R 2 , R 3 , R 6 , R 7 , R 8 , and R 9 (This is as described in formula (CO) or (CO') or as otherwise described in any embodiment below.)

[0385] R 1 As disclosed in formula (CO), in a given embodiment, R 1 -NR2, [ka] It is selected from the group consisting of the following.

[0386] As disclosed in formula (CO'), in a given embodiment, R 1 is selected from the group consisting of . In a given embodiment, R 1 is -NR2. In a given embodiment, R 1 teeth, [ka] In a given embodiment, R 1 teeth, [ka] In a given embodiment, R 1 teeth, [ka] In a given embodiment, R 1 teeth, [ka] In a given embodiment, R 1 teeth, [ka] In a given embodiment, R 1 teeth, [ka] In a given embodiment, R 1 teeth, [ka] In a given embodiment, R 1 teeth, [ka] In a given embodiment, R 1 teeth, [ka] In a given embodiment, R 1 teeth, [ka] In a given embodiment, R 1 teeth, [ka] That is the case.

[0387] In a predetermined embodiment, R 1 is -N(Et)². In a given embodiment, R 1 R is -N(Me)2. In a given embodiment, R 1 is -NH2. In a given embodiment, R 1 is -N(nPr)². In a given embodiment, R 1 is -N(iPr)2. In a given embodiment, R 1 is -N(Me)(Et). In a given embodiment, R 1 teeth, [ka] That is the case.

[0388] X 1 As disclosed in formula (CO), in a given embodiment, X 1 X is an optionally substituted C2-C6 aliphatic (one or more methylene bonds are optionally and independently replaced by -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -NHC(O)-, or -C(O)O-). In a given embodiment, X 1 is an optionally substituted C2-C6 aliphatic. In a given embodiment, X 1 is an optionally substituted C2-C6 alkylene. In a given embodiment, X 1 is an optionally substituted C2 alkylene. In a given embodiment, X 1 is an optionally substituted C3 alkylene. In a given embodiment, X 1 is an optionally substituted C4 alkylene. In a given embodiment, X 1is an optionally substituted C5 alkylene. In a given embodiment, X 1 is an optionally substituted C6 alkylene. In a given embodiment, X 1 is -(CH2)2-. In a given embodiment, X 1 is -(CH2)3-. In a given embodiment, X 1 is -(CH2)4-. In a given embodiment, X 1 is -(CH2)5-. In a given embodiment, X 1 It is -(CH2)6-.

[0389] X 2 As disclosed in formula (CO), in a given embodiment, X 2 X is selected from the group consisting of bonds, -CH2- and -CH2CH2-. In a given embodiment, X 2 This is a combination. In a given embodiment, X 2 is -CH2-. In a given embodiment, X 2 It is -CH2CH2-.

[0390] X 3 As disclosed in formula (CO), in a given embodiment, X 3 X is selected from the group consisting of bonds, -CH2- and -CH2CH2-. In a given embodiment, X 3 This is a combination. In a given embodiment, X 3 is -CH2-. In a given embodiment, X 3 is -CH2CH2-. In a given embodiment, X 2 and X 3 Both are -CH2-. In a given embodiment, X 2 and X 3 Both are -CH2CH2-. In a given embodiment, X 2 It is a combination, X 3 is -CH2-. In a given embodiment, X 2 It is a combination, X 3 is -CH2CH2-. In a given embodiment, X 3It is a combination, X 2 is -CH2-. In a given embodiment, X 3 It is a combination, X 2 It is -CH2CH2-.

[0391] X 4 and X 5 As disclosed in formula (CO), in a given embodiment, X 4 and X 5 These are, independently, arbitrarily substituted C1-C 10 It is aliphatic. In a given embodiment, X 4 and X 5 They are the same. In a given embodiment, X 4 and X 5 They are different.

[0392] In a predetermined embodiment, X 4 This is an arbitrarily substituted C1-C 10 It is an alkylene. In a given embodiment, X 4 This is an arbitrarily substituted C1-C 10 It is an alkenylene. In a given embodiment, X 4 is an optionally substituted C1-C6 alkylene. In a given embodiment, X 4 is an optionally substituted C1-C6 alkenylene. In a given embodiment, X 4 is -(CH2)-. In a given embodiment, X 4 is -(CH2)2-. In a given embodiment, X 4 is -(CH2)3-. In a given embodiment, X 4 is -(CH2)4-. In a given embodiment, X 4 is -(CH2)5-. In a given embodiment, X 4 It is -(CH2)6-.

[0393] In a predetermined embodiment, X 5 This is an arbitrarily substituted C1-C 10 It is an alkylene. In a given embodiment, X 5 This is an arbitrarily substituted C1-C 10It is an alkenylene. In a given embodiment, X 5 is an optionally substituted C1-C6 alkylene. In a given embodiment, X 5 is an optionally substituted C1-C6 alkenylene. In a given embodiment, X 5 is -(CH2)-. In a given embodiment, X 5 is -(CH2)2-. In a given embodiment, X 5 is -(CH2)3-. In a given embodiment, X 5 is -(CH2)4-. In a given embodiment, X 5 is -(CH2)5-. In a given embodiment, X 5 It is -(CH2)6-.

[0394] In a predetermined embodiment, X 4 and X 5 Both are -(CH2)-. In a given embodiment, X 4 and X 5 Both are -(CH2)2-.

[0395] Y 1 and Y 2 As disclosed in formula (CO), in a given embodiment, Y 1 and Y 2 Each of them operates independently. [ka] (In the formula, combinations marked with "*" are X 4 or X 5 (is coupled to) In a given embodiment, Y 1 and Y 2 They are the same. In a given embodiment, Y 1 and Y 2 They are different.

[0396] In a predetermined embodiment, Y 1 teeth, [ka] In a given embodiment, Y 1 teeth, [ka] In a given embodiment, Y 1 teeth, [ka] In a given embodiment, Y 1 teeth, [ka] In a given embodiment, Y 1 teeth, [ka] In a given embodiment, Y 1 teeth, [ka] In a given embodiment, Y 1 teeth, [ka] In a given embodiment, Y 1 teeth, [ka] In a given embodiment, Y 2 teeth, [ka] In a given embodiment, Y 2 teeth, [ka] In a given embodiment, Y 2 teeth, [ka] In a given embodiment, Y2 teeth, [ka] In a given embodiment, Y 2 teeth, [ka] In a given embodiment, Y 2 teeth, [ka] In a given embodiment, Y 2 teeth, [ka] In a given embodiment, Y 2 teeth, [ka] In a given embodiment, Y 1 and Y 2 Both are [ka] In a given embodiment, Y 1 and Y 2 Both are [ka] That is the case.

[0397] R 2 As disclosed in formula (CO), in a given embodiment, R 2 is an optionally substituted C1-C6 aliphatic. In a given embodiment, R 2 is an optionally substituted C1-C6 alkylene. In a given embodiment, R 2 R is an optionally substituted methylene. In a given embodiment, R 2 is an optionally substituted C2 alkylene. In a given embodiment, R 2R is an optionally substituted C3 alkylene. In a given embodiment, R 2 R is an optionally substituted C4 alkylene. In a given embodiment, R 2 R is an optionally substituted C5 alkylene. In a given embodiment, R 2 is an optionally substituted C6 alkylene. In a given embodiment, R 2 is -(CH2)-. In a given embodiment, R 2 is -(CH2)2-. In a given embodiment, R 2 is -(CH2)3-. In a given embodiment, R 2 is -(CH2)4-. In a given embodiment, R 2 is -(CH2)5-. In a given embodiment, R 2 It is -(CH2)6-.

[0398] R 3 As disclosed in formula (CO), in a given embodiment, R 3 is an optionally substituted C1-C6 aliphatic. In a given embodiment, R 3 is an optionally substituted C1-C6 alkylene. In a given embodiment, R 3 R is an optionally substituted methylene. In a given embodiment, R 3 is an optionally substituted C2 alkylene. In a given embodiment, R 3 R is an optionally substituted C3 alkylene. In a given embodiment, R 3 R is an optionally substituted C4 alkylene. In a given embodiment, R 3 R is an optionally substituted C5 alkylene. In a given embodiment, R 3 is an optionally substituted C6 alkylene. In a given embodiment, R 3 is -(CH2)-. In a given embodiment, R 3 is -(CH2)2-. In a given embodiment, R 3 is -(CH2)3-. In a given embodiment, R 3 is -(CH2)4-. In a given embodiment, R 3is -(CH2)5-. In a given embodiment, R 3 It is -(CH2)6-.

[0399] In a predetermined embodiment, R 2 and R 3 They are the same. In a given embodiment, R 2 and R 3 They are different. In a given embodiment, R 2 and R 3 Both are -(CH2)2-.

[0400] R 4 As disclosed in formula (CO), in a given embodiment, R 4 is -CH(OR 6 )(OR 7 );-CH(SR 6 )(SR 7 );-CH(R 6 )(R 7 ); or optionally replaced C1-C 14 Aliphatic (one or more methylene bonds, each optionally and independently, optionally substituted C3-C8 cycloalkylenyl, optionally substituted bridging bicyclic or polycyclic C5-C 12 (It is replaced by cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-). In certain embodiments, R 4 This is an arbitrarily substituted C1-C 14 Aliphatic (one or more methylene bonds, each optionally and independently, optionally substituted C3-C8 cycloalkylenyl, optionally substituted bridging bicyclic or polycyclic C5-C 12 (It is replaced by cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-). In certain embodiments, R 4 This is an arbitrarily substituted C1-C 14 It is aliphatic. In a given embodiment, R 4 is -CH(OR6 )(OR 7 ) In a given embodiment, R 4 is -CH(R 6 )(R 7 ) In a given embodiment, R 4 -CH(SR 6 )(SR 7 )

[0401] In a predetermined embodiment, R 4 teeth, [ka] Selected from.

[0402] In a predetermined embodiment, R 4 teeth, [ka] Selected from.

[0403] R 5 As disclosed in formula (CO), in a given embodiment, R 5 is -CH(OR 8 )(OR 9 );-CH(SR 8 )(SR 9 );-CH(R 8 )(R 9 ); or optionally replaced C1-C 14 Aliphatic (one or more methylene bonds, each optionally and independently, optionally substituted C3-C8 cycloalkylenyl, optionally substituted bridging bicyclic or polycyclic C5-C 12 (It is replaced by cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-). In certain embodiments, R 5 This is an arbitrarily substituted C1-C 14Aliphatic (one or more methylene bonds are each optionally and independently optionally substituted C3-C8 cycloalkylenyl, optionally substituted bridged bicyclic or polycyclic C5-C 12 cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-). In certain embodiments, R 5 is optionally substituted C1-C 14 aliphatic. In certain embodiments, R 5 is -CH(OR 8 )(OR 9 ). In certain embodiments, R 5 is -CH(R 8 )(R 9 ). In certain embodiments, R 5 is -CH(SR 8 )(SR 9 ).

[0404] In certain embodiments, R 4 and R 5 are the same. In certain embodiments, R 4 and R 5 are different.

[0405] In certain embodiments, R 5 is

Chemical formula

[0406] In certain embodiments, R 5 is

Chemical formula

[0407] R 6 and R 7 As disclosed in formula (CO), in certain embodiments, R[[ID=7​​These are, independently, arbitrarily substituted C1-C 14 Aliphatic (one or more methylene bonds, each optionally and independently, optionally substituted C3-C8 cycloalkylenyl, optionally substituted bridging bicyclic or polycyclic C5-C 12 It is replaced by cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-.

[0408] In a predetermined embodiment, R 6 and R 7 They are the same. In a given embodiment, R 6 and R 7 They are different.

[0409] In a predetermined embodiment, R 6 This is an arbitrarily substituted C1-C 14 It is aliphatic. In a given embodiment, R 6 This is an arbitrarily substituted C1-C 14 It is alkyl. In a given embodiment, R 6 This is an arbitrarily substituted C1-C 14 It is a branched alkyl group. In a given embodiment, R 6 This is an arbitrarily substituted C1-C 14 It is a linear alkyl group. In a given embodiment, R 6 This is an arbitrarily substituted C1-C 14 It is an alkenyl. In a given embodiment, R 6 This is an arbitrarily substituted C1-C 14 It is a branched alkenyl. In a given embodiment, R 6 This is an arbitrarily substituted C1-C 14 It is a linear alkenyl. In a given embodiment, R 6 This is an arbitrarily substituted C6-C 10 It is alkyl. In a given embodiment, R 6 R is an arbitrarily substituted -(CH2)5CH3. In a given embodiment, R 6 is an arbitrarily substituted -(CH2)6CH3. In a given embodiment, R 6R is an arbitrarily substituted -(CH2)7CH3. In a given embodiment, R 6 R is an arbitrarily substituted -(CH2)8CH3. In a given embodiment, R 6 This is an arbitrarily substituted -(CH2)9CH3.

[0410] In a predetermined embodiment, R 6 One of the methylene bonds is optionally substituted with a C3-C8 cycloalkylenyl or optionally substituted with a bridging bicyclic or polycyclic C5-C 12 It is replaced with cycloalkylenyl. In certain embodiments, it is optionally substituted with a bridging bicyclic or polycyclic C5-C. 12 Cycloalkylenyl is [ka] Selected from.

[0411] In a predetermined embodiment, R 7 This is an arbitrarily substituted C1-C 14 It is aliphatic. In a given embodiment, R 7 This is an arbitrarily substituted C1-C 14 It is alkyl. In a given embodiment, R 7 This is an arbitrarily substituted C1-C 14 It is a branched alkyl group. In a given embodiment, R 7 This is an arbitrarily substituted C1-C 14 It is a linear alkyl group. In a given embodiment, R 7 This is an arbitrarily substituted C1-C 14 It is an alkenyl. In a given embodiment, R 7 This is an arbitrarily substituted C1-C 14 It is a branched alkenyl. In a given embodiment, R 7 This is an arbitrarily substituted C1-C 14 It is a linear alkenyl. In a given embodiment, R 7 This is an arbitrarily substituted C6-C 10 It is alkyl. In a given embodiment, R 7 R is an arbitrarily substituted -(CH2)5CH3. In a given embodiment, R7 is an arbitrarily substituted -(CH2)6CH3. In a given embodiment, R 7 R is an arbitrarily substituted -(CH2)7CH3. In a given embodiment, R 7 R is an arbitrarily substituted -(CH2)8CH3. In a given embodiment, R 6 This is an arbitrarily substituted -(CH2)9CH3.

[0412] In a predetermined embodiment, R 7 One of the methylene bonds is optionally substituted with a C3-C8 cycloalkylenyl or optionally substituted with a bridging bicyclic or polycyclic C5-C 12 It is replaced with cycloalkylenyl. In certain embodiments, it is optionally substituted with a bridging bicyclic or polycyclic C5-C. 12 Cycloalkylenyl is [ka] Selected from.

[0413] In a predetermined embodiment, R 6 and R 7 teeth, [ka] Selected from.

[0414] In a predetermined method, each R 6 and R 7 These are each arbitrarily substituted bridged biring C5-C 12 Selected independently from cycloalkylenyl. In a given embodiment, R 6 This is an arbitrarily substituted, bridging polycyclic C5-C 12 It is a cycloalkylenyl. In a given embodiment, R 7 This is a optionally substituted bridged biring C5-C 12 It is a cycloalkylenyl. In a given embodiment, it is optionally substituted with a bridging bicyclic or polycyclic C5-C 12The cycloalkylenyl is selected from adamantyl, bicyclo[2.2.2]octyl, cubenyl, bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, and bicyclo[3.2.1]octyl. In a given embodiment, optionally substituted bridging bicyclic or polycyclic C5-C 12 Cycloalkylenyl is [ka] Selected from. In a given embodiment, a substituted bridging bicyclic or polycyclic C5-C 12 Cycloalkylenyl is [ka] The structure is selected from the following, and one or more CH bonds are substituted.

[0415] In a predetermined embodiment, R 6 and R 7 These are bridging bi-ring or poly-ring C5-C that are arbitrarily replaced together. 12 It forms a cycloalkylenyl. In a given embodiment, it optionally has a substituted cross-linked bicyclic or polycyclic C5-C 12 Cycloalkylenyl is [ka] Selected from.

[0416] R 8 and R 9 As disclosed in formula (CO), in a given embodiment, R 8 and R 9 These are, independently, arbitrarily substituted C1-C 14 Aliphatic (one or more methylene bonds, each optionally and independently, optionally substituted C3-C8 cycloalkylenyl, optionally substituted bridging bicyclic or polycyclic C5-C 12It is replaced by cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-.

[0417] In a predetermined embodiment, R 8 and R 9 They are the same. In a given embodiment, R 8 and R 9 They are different.

[0418] In a predetermined embodiment, R 8 This is an arbitrarily substituted C1-C 14 It is aliphatic. In a given embodiment, R 8 This is an arbitrarily substituted C1-C 14 It is alkyl. In a given embodiment, R 8 This is an arbitrarily substituted C1-C 14 It is a branched alkyl group. In a given embodiment, R 8 This is an arbitrarily substituted C1-C 14 It is a linear alkyl group. In a given embodiment, R 8 This is an arbitrarily substituted C1-C 14 It is an alkenyl. In a given embodiment, R 8 This is an arbitrarily substituted C1-C 14 It is a branched alkenyl. In a given embodiment, R 8 This is an arbitrarily substituted C1-C 14 It is a linear alkenyl. In a given embodiment, R 8 This is an arbitrarily substituted C6-C 10 It is alkyl. In a given embodiment, R 8 R is an arbitrarily substituted -(CH2)5CH3. In a given embodiment, R 8 is an arbitrarily substituted -(CH2)6CH3. In a given embodiment, R 8 R is an arbitrarily substituted -(CH2)7CH3. In a given embodiment, R 8 R is an arbitrarily substituted -(CH2)8CH3. In a given embodiment, R 8 This is an arbitrarily substituted -(CH2)9CH3.

[0419] In a predetermined embodiment, R 8 One of the methylene bonds is optionally substituted with a C3-C8 cycloalkylenyl or optionally substituted with a bridging bicyclic or polycyclic C5-C 12 It is replaced with cycloalkylenyl. In certain embodiments, it is optionally substituted with a bridging bicyclic or polycyclic C5-C. 12 Cycloalkylenyl is [ka] Selected from.

[0420] In a predetermined embodiment, R 9 This is an arbitrarily substituted C1-C 14 It is aliphatic. In a given embodiment, R 9 This is an arbitrarily substituted C1-C 14 It is alkyl. In a given embodiment, R 9 This is an arbitrarily substituted C1-C 14 It is a branched alkyl group. In a given embodiment, R 9 This is an arbitrarily substituted C1-C 14 It is a linear alkyl group. In a given embodiment, R 9 This is an arbitrarily substituted C1-C 14 It is an alkenyl. In a given embodiment, R 9 This is an arbitrarily substituted C1-C 14 It is a branched alkenyl. In a given embodiment, R 9 This is an arbitrarily substituted C1-C 14 It is a linear alkenyl. In a given embodiment, R 9 This is an arbitrarily substituted C6-C 10 It is alkyl. In a given embodiment, R 9 R is an arbitrarily substituted -(CH2)5CH3. In a given embodiment, R 9 is an arbitrarily substituted -(CH2)6CH3. In a given embodiment, R 9 R is an arbitrarily substituted -(CH2)7CH3. In a given embodiment, R 9 R is an arbitrarily substituted -(CH2)8CH3. In a given embodiment, R9 This is an arbitrarily substituted -(CH2)9CH3.

[0421] In a predetermined embodiment, R 9 One of the methylene bonds is optionally substituted with a C3-C8 cycloalkylenyl or optionally substituted with a bridging bicyclic or polycyclic C5-C 12 It is replaced with cycloalkylenyl. In certain embodiments, it is optionally substituted with a bridging bicyclic or polycyclic C5-C. 12 Cycloalkylenyl is [ka] Selected from.

[0422] In a predetermined embodiment, R 8 and R 9 teeth, [ka] Selected from.

[0423] In some embodiments, R 8 and R 9 These are bridging bicyclic or polycyclic C4-C4s that are arbitrarily substituted together. 14 They form cycloalkyl or optionally substituted cross-linked bicyclic or polycyclic 4-14 membered heterocyclines.

[0424] In a predetermined method, each R 8 and R 9 These are each arbitrarily substituted bridged biring C5-C 12 Selected independently from cycloalkylenyl. In a given embodiment, R 8 This is an arbitrarily substituted, bridging polycyclic C5-C 12 It is a cycloalkylenyl. In a given embodiment, R 9 This is a optionally substituted bridged biring C5-C 12 It is a cycloalkylenyl. In a given embodiment, it is optionally substituted with a bridging bicyclic or polycyclic C5-C 12The cycloalkylenyl is selected from adamantyl, bicyclo[2.2.2]octyl, cubenyl, bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, and bicyclo[3.2.1]octyl. In a given embodiment, optionally substituted bridging bicyclic or polycyclic C5-C 12 Cycloalkylenyl is [ka] Selected from. In a given embodiment, a substituted bridging bicyclic or polycyclic C5-C 12 Cycloalkylenyl is [ka] The structure is selected from the following, and one or more CH bonds are substituted.

[0425] In a predetermined embodiment, R 8 and R 9 These are bridging bi-ring or poly-ring C5-C that are arbitrarily replaced together. 12 It forms a cycloalkylenyl. In a given embodiment, it optionally has a substituted cross-linked bicyclic or polycyclic C5-C 12 Cycloalkylenyl is [ka] Selected from.

[0426] In some embodiments, the lipids of this disclosure are selected from any of the lipids or pharmaceutically acceptable salts thereof in the following table (ID): [Table 4-1] [Table 4-2] [Table 4-3]

[0427] Series "CC" In some embodiments, the LNP disclosed herein comprises an ionizable lipid. In some embodiments, the LNP comprises two or more ionizable lipids.

[0428] Numerous exemplary ionizable lipids of this disclosure are listed below.

[0429] In a given embodiment, the present disclosure relates to a compound of formula (CC'). [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 -OH, -OAc, -NR2, [ka] Selected from the group consisting of; Each R is independently either -H or C1-C6 aliphatic; R Z is NR2 or OH; X Z This is an arbitrarily substituted C2-C 14 Alkyrenyl or optionally substituted C2-C 14 It is an alkenylenyl; each R 3 H and C 1-6 Selected independently of alkyl; X 1 is an optionally substituted C2-C6 aliphatic (where one or more methylene bonds are optionally and independently replaced by -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)-, or -C(O)O-); X 2 It is selected from the group consisting of bonds, -CH2-, and -CH2CH2-; X 2’ It is selected from the group consisting of bonds, -CH2-, and -CH2CH2-; X 3It is selected from the group consisting of bonds, -CH2-, and -CH2CH2-; X 3’ It is selected from the group consisting of bonds, -CH2-, and -CH2CH2-; X 4 and X 5 These are independently and arbitrarily substituted C1-C 10 It is aliphatic; Y 1 and Y 2 teeth, [ka] Independently selected from the group consisting of; The combination marked with "*" is X 4 or X 5 Joined; R 2 is an arbitrarily substituted C1-C6 aliphatic; R 3 is an arbitrarily substituted C1-C6 aliphatic; R 4 is -CH(OR 6 )(OR 7 );-CH(SR 6 )(SR 7 );-CH(SR 8 )(SR 9 );-CH(R 6 )(R 7 );-R 10 ; or optionally substituted C1-C 14 Aliphatic-R 10 (Each of the methylene bonds is optionally and independently replaced by an optionally substituted C3-C8 cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)-, or -C(O)O-); R 5 is -CH(OR 8 )(OR 9 );-CH(SR 8 )(SR 9 );-CH(R 8 )(R 9 ); C1-C arbitrarily substituted 14Aliphatic (one or more methylene bonds are replaced by optionally substituted C3-C8 cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-);-R 11 ; or optionally substituted C1-C 14 Aliphatic-R 11 (Each of the methylene bonds is optionally and independently replaced by an optionally substituted C3-C8 cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)-, or -C(O)O-); (a)R 6 and R 7 These are, independently, -R 10 ; Arbitrarily substituted -C1-C 14 Aliphatic-R 10 (Each of the methylene bonds is optionally and independently replaced by an optionally substituted C3-C8 cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-); or (b)R 1 but [ka] If R 6 and R 7 These are, independently, arbitrarily substituted -C1-C 14 Aliphatic (one or more methylene bonds are replaced by optionally substituted C3-C8 cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-);-R 10 ; Arbitrarily substituted -C1-C 14 Aliphatic-R 10(Each of the methylene bonds is optionally and independently replaced by an optionally substituted C3-C8 cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)-, or -C(O)O-); R 8 and R 9 These are, independently, -R 11 ; Arbitrarily substituted -C1-C 14 Aliphatic (one or more methylene bonds are optionally and independently replaced by optionally substituted C3-C8 cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-); or optionally substituted -C1-C 14 Aliphatic-R 11 (Each of the methylene bonds is optionally and independently replaced by an optionally substituted C3-C8 cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)-, or -C(O)O-); Each R 10 and R 11 This is independently and optionally substituted with a bicyclic or polycyclic C5-C bridge. 12 It is a cycloalkylenyl, or two R 10 or two R's 11 These are bridging bi-ring or poly-ring C5-C that are arbitrarily replaced together. 12 Forming cycloalkylenyl; or Each R 10 and R 11 These are independently and optionally substituted ring, biring, bridging biring, polyring, or bridging polyring C4-C 14 It is a cycloalkyl or optionally substituted cyclic, bicyclic, bridged bicyclic, polycyclic, or bridged polycyclic 4-14 member heterocyclil, or two R 10 or two R's 11 These are bridging bicyclic or polycyclic C4-C4s that are arbitrarily substituted together. 14(Forms cycloalkyl or optionally substituted cross-linked bicyclic or polycyclic 4-14 member heterocyclines.) To provide.

[0430] In certain embodiments, the disclosure also relates to compounds of formula (CC). [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 -OH, -OAc, -NR2, [ka] Selected from the group consisting of; Each R is independently either -H or C1-C6 aliphatic; X 1 is an optionally substituted C2-C6 aliphatic (where one or more methylene bonds are optionally and independently replaced by -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)-, or -C(O)O-); X 2 It is selected from the group consisting of bonds, -CH2-, and -CH2CH2-; X 2’ It is selected from the group consisting of bonds, -CH2-, and -CH2CH2-; X 3 It is selected from the group consisting of bonds, -CH2-, and -CH2CH2-; X 3’ It is selected from the group consisting of bonds, -CH2-, and -CH2CH2-; X 4 and X 5 These are independently and arbitrarily substituted C1-C 10 It is aliphatic; Y 1 and Y 2 teeth, [ka] Independently selected from the group consisting of; The combination marked with "*" is X 4 or X 5 Joined; R 2 is an arbitrarily substituted C1-C6 aliphatic; R 3 is an arbitrarily substituted C1-C6 aliphatic; R 4 is -CH(OR 6 )(OR 7 );-CH(SR 6 )(SR 7 );-CH(SR 8 )(SR 9 );-CH(R 6 )(R 7 );-R 10 ; or optionally substituted C1-C 14 Aliphatic-R 10 (Each of the methylene bonds is optionally and independently replaced by an optionally substituted C3-C8 cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)-, or -C(O)O-); R 5 is -CH(OR 8 )(OR 9 );-CH(SR 8 )(SR 9 );-CH(R 8 )(R 9 ); C1-C arbitrarily substituted 14 Aliphatic (one or more methylene bonds are replaced by optionally substituted C3-C8 cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-);-R 11 ; or optionally substituted C1-C 14 Aliphatic-R 11(Each of the methylene bonds is optionally and independently replaced by an optionally substituted C3-C8 cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)-, or -C(O)O-); R 6 and R 7 These are, independently, -R 10 ; Arbitrarily substituted -C1-C 14 Aliphatic-R 10 (Each of the methylene bonds is optionally and independently replaced by an optionally substituted C3-C8 cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)-, or -C(O)O-); R 8 and R 9 These are, independently, -R 11 ; Arbitrarily substituted -C1-C 14 Aliphatic (one or more methylene bonds are optionally and independently replaced by optionally substituted C3-C8 cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-); or optionally substituted -C1-C 14 Aliphatic-R 11 (Each of the methylene bonds is optionally and independently replaced by an optionally substituted C3-C8 cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)-, or -C(O)O-); Each R 10 and R 11 This is independently and optionally substituted with a bicyclic or polycyclic C5-C bridge. 12 It is a cycloalkylenyl, or two R 10 or two R's 11 These are bridging bi-ring or poly-ring C5-C that are arbitrarily replaced together. 12 Forming cycloalkylenyl; or Each R10 and R 11 These are independently and optionally substituted ring, biring, bridging biring, polyring, or bridging polyring C4-C 14 It is a cycloalkyl or optionally substituted cyclic, bicyclic, bridged bicyclic, polycyclic, or bridged polycyclic 4-14 member heterocyclil, or two R 10 or two R's 11 These are bridging bicyclic or polycyclic C4-C4s that are arbitrarily substituted together. 14 (Forms cycloalkyl or optionally substituted cross-linked bicyclic or polycyclic 4-14 member heterocyclines.) To provide.

[0431] In a given embodiment, the compound of formula (CC) is the compound of formula (CC-A): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 , X 4 , X 5 , Y 1 , Y 2 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 (This is as described in formula (CC) or (CC') or as otherwise described in any embodiment below.)

[0432] In a given embodiment, the compound of formula (CC) is the compound of formula (CC-B): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 , X 4 , X 5 , Y 1 , Y 2, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 (This is as described in formula (CC) or (CC') or as otherwise described in any embodiment below.)

[0433] In a given embodiment, the compound of formula (CC) is the compound of formula (CC-C): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 , Y 1 , Y 2 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 (This is as described in formula (CC) or (CC') or as otherwise described in any embodiment below.)

[0434] In a given embodiment, the compound of formula (CC) is the compound of formula (CC-D): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 , Y 1 , Y 2 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R11 (This is as described in formula (CC) or (CC') or as otherwise described in any embodiment below.)

[0435] In a given embodiment, the compound of formula (CC) is the compound of formula (CC-E): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 , X 4 , X 5 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 (This is as described in formula (CC) or (CC') or as otherwise described in any embodiment below.)

[0436] In a given embodiment, the compound of formula (CC) is the compound of formula (CC-F): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 , X 4 , X 5 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , R 9 , R 10 , R 11 (This is as described in formula (CC) or (CC') or as otherwise described in any embodiment below.)

[0437] In a given embodiment, the compound of formula (CC) is the compound of formula (CC-F'): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 , X 4 , X 5 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , R 9 , R 10 , R 11 (This is as described in formula (CC) or (CC') or as otherwise described in any embodiment below.)

[0438] In a given embodiment, the compound of formula (CC) is the compound of formula (CC-G): [ka] or a pharmaceutically acceptable salt thereof (wherein X 1 , X 4 , X 5 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 (This is as described in formula (CC) or (CC') or as otherwise described in any embodiment below.)

[0439] In a given embodiment, the compound of formula (CC) is the compound of formula (CC-H): [ka] or a pharmaceutically acceptable salt thereof (wherein X 1 , X 4 , X 5 , R 2 , R 3 , R 4 , R5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 (This is as described in formula (CC) or (CC') or as otherwise described in any embodiment below.)

[0440] In a given embodiment, the compound of formula (CC) is the compound of formula (CC-I): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 , X 4 , X 5 , Y 1 , Y 2 , R 2 , R 3 , R 8 , R 9 , R 11 (This is as described in formula (CC) or (CC') or as otherwise described in any embodiment below.)

[0441] In a given embodiment, the compound of formula (CC) is the compound of formula (CC-J): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 , X 4 , X 5 , R 2 , R 3 , R 8 , R 9 , R 11 (This is as described in formula (CC) or (CC') or as otherwise described in any embodiment below.)

[0442] In a given embodiment, the compound of formula (CC) is the compound of formula (CC-K): [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R, X 1 , X 4 , X 5 , R 2 , R 3 , R 8 , R 9 , R 11 (This is as described in formula (CC) or (CC') or as otherwise described in any embodiment below.)

[0443] In a given embodiment, the compound of formula (CC) is the compound of formula (CC-L): [ka] or a pharmaceutically acceptable salt thereof (wherein X 1 , X 4 , X 5 , R 2 , R 3 , R 8 , R 9 , R 11 (This is as described in formula (CC) or (CC') or as otherwise described in any embodiment below.)

[0444] In a given embodiment, the compound of formula (CC) is the compound of formula (CC-M): [ka] or a pharmaceutically acceptable salt thereof (wherein X 1 , X 4 , X 5 , R 2 , R 3 , R 8 , R 9 , R 11 (This is as described in formula (CC) or (CC') or as otherwise described in any embodiment below.)

[0445] R 1 In some embodiments, the lipids of the present disclosure have the structure of formula (CC') and R 1 -OH, -OAc, -NR2, [ka] It is selected from the group consisting of the following.

[0446] As disclosed in formula (CC), in a given embodiment, R 1 -OH, -OAc, -NR2, [ka] It is selected from the group consisting of the following.

[0447] In a predetermined embodiment, R 1 is -OH. In a given embodiment, R 1 is -OAc. In a given embodiment, R 1 is -NR2. In a given embodiment, R 1 teeth, [ka] In a given embodiment, R 1 teeth, [ka] In a given embodiment, R 1 teeth, [ka] In a given embodiment, R 1 teeth, [ka] In a given embodiment, R 1 teeth, [ka] In a given embodiment, R 1 teeth, [ka] In a given embodiment, R 1 teeth, [ka] In a given embodiment, R 1 teeth, [ka] In a given embodiment, R 1 teeth, [ka] In a given embodiment, R 1 teeth, [ka] In a given embodiment, R 1 teeth, [ka] That is the case.

[0448] In a predetermined embodiment, R 1 is -N(Et)². In a given embodiment, R 1 R is -N(Me)2. In a given embodiment, R 1 is -NH2. In a given embodiment, R 1 is -N(nPr)². In a given embodiment, R 1 is -N(iPr)2. In a given embodiment, R 1 is -N(Me)(Et). In a given embodiment, R 1 is OH. In a given embodiment, R 1 teeth, [ka] That is the case.

[0449] X 1 As disclosed in formula (CC), in a given embodiment, X 1 X is an optionally substituted C2-C6 aliphatic (one or more methylene bonds are optionally and independently replaced by -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -NHC(O)-, or -C(O)O-). In a given embodiment, X 1 is an optionally substituted C2-C6 aliphatic. In a given embodiment, X 1 is an optionally substituted C2-C6 alkylene. In a given embodiment, X 1 is an optionally substituted C2 alkylene. In a given embodiment, X 1 is an optionally substituted C3 alkylene. In a given embodiment, X 1 is an optionally substituted C4 alkylene. In a given embodiment, X 1 is an optionally substituted C5 alkylene. In a given embodiment, X 1 is an optionally substituted C6 alkylene. In a given embodiment, X 1 is -(CH2)2-. In a given embodiment, X 1 is -(CH2)3-. In a given embodiment, X 1 is -(CH2)4-. In a given embodiment, X 1 is -(CH2)5-. In a given embodiment, X 1 It is -(CH2)6-.

[0450] X 2 As disclosed in formula (CC), in a given embodiment, X 2 X is selected from the group consisting of bonds, -CH2- and -CH2CH2-. In a given embodiment, X 2 This is a combination. In a given embodiment, X 2 is -CH2-. In a given embodiment, X 2 It is -CH2CH2-.

[0451] X 2’ As disclosed in formula (CC), in a given embodiment, X 2’ X is selected from the group consisting of bonds, -CH2- and -CH2CH2-. In a given embodiment, X 2’ This is a combination. In a given embodiment, X 2’ is -CH2-. In a given embodiment, X 2’ It is -CH2CH2-.

[0452] X 3 As disclosed in formula (CC), in a given embodiment, X 3 X is selected from the group consisting of bonds, -CH2- and -CH2CH2-. In a given embodiment, X 3 This is a combination. In a given embodiment, X 3 is -CH2-. In a given embodiment, X 3 It is -CH2CH2-.

[0453] X 3’ As disclosed in formula (CC), in a given embodiment, X 3’ X is selected from the group consisting of bonds, -CH2- and -CH2CH2-. In a given embodiment, X 3’ This is a combination. In a given embodiment, X 3’ is -CH2-. In a given embodiment, X 3’ It is -CH2CH2-.

[0454] In a predetermined embodiment, X 2 , X 2’ , X 3 and X 3’ Each of these is -CH2-. In a given embodiment, X 2 and X 3 Both are -CH2-;X 3’ It is a combination, X 2’ It is -CH2CH2-.

[0455] X 4 and X 5 As disclosed in formula (CC), in a given embodiment, X 4 and X 5 These are, independently, arbitrarily substituted C1-C 10 It is aliphatic. In a given embodiment, X 4 and X 5 They are the same. In a given embodiment, X 4 and X 5 They are different.

[0456] In a predetermined embodiment, X 4 This is an arbitrarily substituted C1-C 10 It is an alkylene. In a given embodiment, X 4 This is an arbitrarily substituted C1-C 10 It is an alkenylene. In a given embodiment, X 4 is an optionally substituted C1-C6 alkylene. In a given embodiment, X 4 is an optionally substituted C1-C6 alkenylene. In a given embodiment, X 4 is -(CH2)-. In a given embodiment, X 4 is -(CH2)2-. In a given embodiment, X 4 is -(CH2)3-. In a given embodiment, X 4 is -(CH2)4-. In a given embodiment, X 4 is -(CH2)5-. In a given embodiment, X 4 It is -(CH2)6-.

[0457] In a predetermined embodiment, X 5 This is an arbitrarily substituted C1-C 10 It is an alkylene. In a given embodiment, X 5 This is an arbitrarily substituted C1-C 10 It is an alkenylene. In a given embodiment, X 5 is an optionally substituted C1-C6 alkylene. In a given embodiment, X 5 is an optionally substituted C1-C6 alkenylene. In a given embodiment, X 5 is -(CH2)-. In a given embodiment, X 5is -(CH2)2-. In a given embodiment, X 5 is -(CH2)3-. In a given embodiment, X 5 is -(CH2)4-. In a given embodiment, X 5 is -(CH2)5-. In a given embodiment, X 5 It is -(CH2)6-.

[0458] In a predetermined embodiment, X 4 and X 5 Both are -(CH2)-. In a given embodiment, X 4 and X 5 Both are -(CH2)2-.

[0459] Y 1 and Y 2 As disclosed in formula (CC), in a given embodiment, Y 1 and Y 2 Each of them operates independently. [ka] (In the formula, combinations marked with "*" are X 4 or X 5 (is coupled to) In a given embodiment, Y 1 and Y 2 They are the same. In a given embodiment, Y 1 and Y 2 They are different.

[0460] In a predetermined embodiment, Y 1 teeth, [ka] In a given embodiment, Y 1 teeth, [ka] In a given embodiment, Y 1 teeth, [ka] In a given embodiment, Y 1 teeth, [ka] In a given embodiment, Y 1 teeth, [ka] In a given embodiment, Y 1 teeth, [ka] In a given embodiment, Y 1 teeth, [ka] In a given embodiment, Y 1 teeth, [ka] In a given embodiment, Y 2 teeth, [ka] In a given embodiment, Y 2 teeth, [ka] In a given embodiment, Y 2 teeth, [ka] In a given embodiment, Y 2 teeth, [ka] In a given embodiment, Y 2 teeth, [ka] In a given embodiment, Y 2 teeth, [ka] In a given embodiment, Y 2 teeth, [ka] In a given embodiment, Y 2 teeth, [ka] In a given embodiment, Y 1 and Y 2 Both are [ka] In a given embodiment, Y 1 and Y 2 Both are [ka] That is the case.

[0461] R 2 As disclosed in formula (CC), in a given embodiment, R 2 is an optionally substituted C1-C6 aliphatic. In a given embodiment, R 2 is an optionally substituted C1-C6 alkylene. In a given embodiment, R 2 R is an optionally substituted methylene. In a given embodiment, R 2 is an optionally substituted C2 alkylene. In a given embodiment, R 2 R is an optionally substituted C3 alkylene. In a given embodiment, R 2 R is an optionally substituted C4 alkylene. In a given embodiment, R 2 R is an optionally substituted C5 alkylene. In a given embodiment, R 2is an optionally substituted C6 alkylene. In a given embodiment, R 2 is -(CH2)-. In a given embodiment, R 2 is -(CH2)2-. In a given embodiment, R 2 is -(CH2)3-. In a given embodiment, R 2 is -(CH2)4-. In a given embodiment, R 2 is -(CH2)5-. In a given embodiment, R 2 It is -(CH2)6-.

[0462] R 3 As disclosed in formula (CC), in a given embodiment, R 3 is an optionally substituted C1-C6 aliphatic. In a given embodiment, R 3 is an optionally substituted C1-C6 alkylene. In a given embodiment, R 3 R is an optionally substituted methylene. In a given embodiment, R 3 is an optionally substituted C2 alkylene. In a given embodiment, R 3 R is an optionally substituted C3 alkylene. In a given embodiment, R 3 R is an optionally substituted C4 alkylene. In a given embodiment, R 3 R is an optionally substituted C5 alkylene. In a given embodiment, R 3 is an optionally substituted C6 alkylene. In a given embodiment, R 3 is -(CH2)-. In a given embodiment, R 3 is -(CH2)2-. In a given embodiment, R 3 is -(CH2)3-. In a given embodiment, R 3 is -(CH2)4-. In a given embodiment, R 3 is -(CH2)5-. In a given embodiment, R 3 It is -(CH2)6-.

[0463] In a predetermined embodiment, R 2 and R 3They are the same. In a given embodiment, R 2 and R 3 They are different. In a given embodiment, R 2 and R 3 Both are -(CH2)2-.

[0464] R 4 As disclosed in formula (CC), in a given embodiment, R 4 is -CH(OR 6 )(OR 7 );-CH(SR 6 )(SR 7 );-CH(SR 8 )(SR 9 );-CH(R 6 )(R 7 );-R 10 ; or optionally substituted C1-C 14 Aliphatic-R 10 (One or more methylene bonds are each optionally and independently replaced by optionally substituted C3-C8 cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)-, or -C(O)O-). In a given embodiment, R 4 This is an arbitrarily substituted C1-C 14 Aliphatic-R 10 (One or more methylene bonds are optionally and independently substituted with optionally substituted C3-C8 cycloalkylenyl, optionally substituted with bridging bicyclic or polycyclic C5-C 12 (It is replaced by cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-). In certain embodiments, R 4 This is an arbitrarily substituted C1-C 14 Aliphatic-R 10 In a given embodiment, R 4 is -CH(OR 6 )(OR 7 ) In a given embodiment, R 4 is -CH(R 6 )(R7 ) In a given embodiment, R 4 -CH(SR 6 )(SR 7 ) In a given embodiment, R 4 -CH(SR 8 )(SR 9 ) In a given embodiment, R 4 R 10 That is the case.

[0465] In a predetermined embodiment, R 4 teeth, [ka] Selected from.

[0466] In a predetermined embodiment, R 4 teeth, [ka] Selected from.

[0467] R 5 As disclosed in formula (CC), in a given embodiment, R 5 is -CH(OR 8 )(OR 9 );-CH(SR 8 )(SR 9 );-CH(R 8 )(R 9 ); C1-C arbitrarily substituted 14 Aliphatic (one or more methylene bonds are replaced by optionally substituted C3-C8 cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-);-R 11 ; or optionally substituted C1-C 14 Aliphatic-R 11(One or more methylene bonds are each optionally and independently replaced by optionally substituted C3-C8 cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)-, or -C(O)O-). In a given embodiment, R 5 This is an arbitrarily substituted C1-C 14 It is aliphatic. In a given embodiment, R 5 is -CH(OR 8 )(OR 9 ) In a given embodiment, R 5 is -CH(R 8 )(R 9 ) In a given embodiment, R 5 -CH(SR 8 )(SR 9 ) In a given embodiment, R 5 R 11 That is the case.

[0468] In a predetermined embodiment, R 4 and R 5 They are the same. In a given embodiment, R 4 and R 5 They are different.

[0469] In a predetermined embodiment, R 5 teeth, [ka] Selected from.

[0470] In a predetermined embodiment, R 5 teeth, [ka] Selected from.

[0471] R 6 and R 7 As disclosed in formula (CC), in a given embodiment, R 6 and R 7 These are, independently, -R10 ; Arbitrarily substituted -C1-C 14 Aliphatic-R 10 (Each of the methylene bonds is optionally and independently replaced by an optionally substituted C3-C8 cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)-, or -C(O)O-).

[0472] In a predetermined embodiment, R 6 and R 7 They are the same. In a given embodiment, R 6 and R 7 They are different.

[0473] In a predetermined embodiment, R 6 R 10 In a given embodiment, R 6 This is an arbitrarily substituted C1-C 14 Aliphatic-R 10 In a given embodiment, R 6 This is an arbitrarily substituted C1-C 14 Alkyl-R 10 In a given embodiment, R 6 This is an arbitrarily substituted C1-C 14 Branched alkyl-R 10 In a given embodiment, R 6 This is an arbitrarily substituted C1-C 14 Linear alkyl-R 10 In a given embodiment, R 6 This is an arbitrarily substituted C1-C 14 Alkenil-R 10 In a given embodiment, R 6 This is an arbitrarily substituted C1-C 14 Branched alkenyl-R 10 In a given embodiment, R 6 This is an arbitrarily substituted C1-C 14 Linear alkenyl-R 10 In a given embodiment, R 6 This is an optionally substituted C1-C5 alkyl-R 10In a given embodiment, R 6 This is an arbitrarily substituted -(CH2)-R 10 In a given embodiment, R 6 This is an arbitrarily substituted -(CH2)2-R 10 In a given embodiment, R 6 This is an arbitrarily substituted -(CH2)3-R 10 In a given embodiment, R 6 This is an arbitrarily substituted -(CH2)4-R 10 In a given embodiment, R 6 This is an arbitrarily substituted -(CH2)5-R 10 That is the case.

[0474] In a predetermined embodiment, R 7 R 10 In a given embodiment, R 7 This is an arbitrarily substituted C1-C 14 Aliphatic-R 10 In a given embodiment, R 7 This is an arbitrarily substituted C1-C 14 Alkyl-R 10 In a given embodiment, R 7 This is an arbitrarily substituted C1-C 14 Branched alkyl-R 10 In a given embodiment, R 7 This is an arbitrarily substituted C1-C 14 Linear alkyl-R 10 In a given embodiment, R 7 This is an arbitrarily substituted C1-C 14 Alkenil-R 10 In a given embodiment, R 7 This is an arbitrarily substituted C1-C 14 Branched alkenyl-R 10 In a given embodiment, R 7 This is an arbitrarily substituted C1-C 14 Linear alkenyl-R 10 In a given embodiment, R 7 This is an optionally substituted C1-C5 alkyl-R 10 In a given embodiment, R 7This is an arbitrarily substituted -(CH2)-R 10 In a given embodiment, R 7 This is an arbitrarily substituted -(CH2)2-R 10 In a given embodiment, R 7 This is an arbitrarily substituted -(CH2)3-R 10 In a given embodiment, R 7 This is an arbitrarily substituted -(CH2)4-R 10 In a given embodiment, R 7 This is an arbitrarily substituted -(CH2)5-R 10 That is the case.

[0475] In a predetermined embodiment, R 6 and R 7 teeth, [ka] Selected from.

[0476] R 8 and R 9 As disclosed in formula (CC), in a given embodiment, R 8 and R 9 Each of them is independent of R 11 ; Arbitrarily substituted -C1-C 14 Aliphatic (one or more methylene bonds are optionally and independently replaced by optionally substituted C3-C8 cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-); or optionally substituted -C1-C 14 Aliphatic-R 11 (Each of the methylene bonds is optionally and independently replaced by an optionally substituted C3-C8 cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)-, or -C(O)O-).

[0477] In a predetermined embodiment, R 8 and R9 They are the same. In a given embodiment, R 8 and R 9 They are different.

[0478] In a predetermined embodiment, R 8 R 11 In a given embodiment, R 8 This is an arbitrarily substituted C1-C 14 It is aliphatic. In a given embodiment, R 8 This is an arbitrarily substituted C1-C 14 It is alkyl. In a given embodiment, R 8 This is an arbitrarily substituted C1-C 14 It is a branched alkyl group. In a given embodiment, R 8 This is an arbitrarily substituted C1-C 14 It is a linear alkyl group. In a given embodiment, R 8 This is an arbitrarily substituted C1-C 14 It is an alkenyl. ...

Claims

1. Compounds of formula (CC): 【Chemical 846】 or a pharmaceutically acceptable salt thereof (In the formula, R １ -OH, -OAc, -NR ２ , 【Chemical 847】 Selected from the group consisting of; Each R is independently -H or C １ -C ６ It is aliphatic; X １ is an arbitrarily substituted C ２ -C ６ Aliphatic (one or more methylene bonds are replaced by -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)-, or -C(O)O-, each arbitrarily and independently); X ２ is selected from the group consisting of a bond, -CH ２ -, and -CH ２ CH ２ -; X ２’ The bond is -CH ２ - and -CH ２ CH ２ Selected from the group consisting of: X ３ The bond is -CH ２ - and -CH ２ CH ２ Selected from the group consisting of: X ３’ The bond is -CH ２ - and -CH ２ CH ２ Selected from the group consisting of: X ４ and X ５ This is an independently and arbitrarily substituted C １ -C １０ It is aliphatic; Y １ and Y ２ teeth, 【Chemical 848】 Independently selected from the group consisting of; The combination marked with "*" is X ４ or X ５ Joined; R ２ is an arbitrarily substituted C １ -C ６ It is aliphatic; R ３ is an arbitrarily substituted C １ -C ６ It is aliphatic; R ４ is -CH(OR ６ ) ( OR ７ ); -CH(SR ６ ) (SR ７ ); -CH(SR ８ ) (SR ９ ); -CH(R ６ ) (Caution ７ ); -R １０ ; or optionally replaced C １ -C １４ Aliphatic-R １０ (One or more methylene bonds may be optionally and independently substituted with any C ３ -C ８ (Substituted with cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-); R ５ is -CH(OR ８ ) ( OR ９ ); -CH(SR ８ ) (SR ９ ); -CH(R ８ ) (Caution ９ ); C as arbitrarily substituted １ -C １４ Aliphatic (one or more methylene bonds, each optionally and independently, optionally substituted with C ３ -C ８ (Substituted with cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-); -R １１ ; or optionally replaced C １ -C １４ Aliphatic-R １１ (One or more methylene bonds may be optionally and independently substituted with any C ３ -C ８ (Substituted with cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-); R ６ and R ７ Each of these is independently of -R １０ ; or optionally replaced with -C １ -C １４ Aliphatic-R １０ (One or more methylene bonds may be optionally and independently substituted with any C ３ -C ８ (Substituted with cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-); R ８ and R ９ Each of these is independently of -R １１ ; Arbitrarily substituted -C １ -C １４ Aliphatic (one or more methylene bonds, each optionally and independently, optionally substituted with C ３ -C ８ (Substituted with cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-); or optionally substituted with -C １ -C １４ Aliphatic-R １１ (One or more methylene bonds may be optionally and independently substituted with any C ３ -C ８ (Substituted with cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-); Each R １０ and R １１ is, independently, an optionally substituted crosslinked bicyclic or polycyclic C ４ -C １２ cycloalkenylenyl, or two Rs １０ or two Rs １１ together form an optionally substituted crosslinked bicyclic or polycyclic C ４ -C １２ cycloalkenylenyl). 【Request Item 2】 【Chemistry 849】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

3. The aforementioned compound is of formula (CC-B): 【Chemical 850】 The compound according to claim 1, which is either the compound or a pharmaceutically acceptable salt thereof.

4. The aforementioned compound is of formula (CC-C): 【Chemical 851】 The compound according to claim 1, which is either the compound or a pharmaceutically acceptable salt thereof.

5. The aforementioned compound is of formula (CC-D): 【Chemical 852】 The compound according to claim 1, which is either the compound or a pharmaceutically acceptable salt thereof.

6. The aforementioned compound is of formula (CC-E): 【Chemical 853】 The compound according to claim 1, which is either the compound or a pharmaceutically acceptable salt thereof.

7. The aforementioned compound is of formula (CC-F): 【Chemical 854】 The compound according to claim 1, which is either the compound or a pharmaceutically acceptable salt thereof.

8. The aforementioned compound is of formula (CC-F'): 【Chemical 855】 The compound according to claim 1, which is either the compound or a pharmaceutically acceptable salt thereof.

9. The aforementioned compound is of formula (CC-G): 【Chemical 856】 The compound according to claim 1, which is either the compound or a pharmaceutically acceptable salt thereof.

10. The aforementioned compound is of formula (CC-H): 【Chemical 857】 The compound according to claim 1, which is either the compound or a pharmaceutically acceptable salt thereof.

11. The aforementioned compound is of formula (CC-I): 【Chemical Formula 858】 The compound according to claim 1, which is either the compound or a pharmaceutically acceptable salt thereof.

12. The aforementioned compound is of formula (CC-J): 【Chemical 859】 The compound according to claim 1, which is either the compound or a pharmaceutically acceptable salt thereof.

13. The aforementioned compound is of formula (CC-K): 【Chemical 860】 The compound according to claim 1, which is either the compound or a pharmaceutically acceptable salt thereof.

14. The aforementioned compound is of formula (CC-L): 【Chemistry 861】 The compound according to claim 1, which is either the compound or a pharmaceutically acceptable salt thereof.

15. The aforementioned compound is of formula (CC-M): 【Chemical 862】 The compound according to claim 1, which is either the compound or a pharmaceutically acceptable salt thereof.

16. R １ is -OH or 【Chemical 863】 The compound according to any one of claims 1 to 9, 11 to 14.

17. R １ The compound according to claim 16, wherein is -OH.

18. R １ teeth, 【Chemical 864】 The compound according to claim 16.

19. R １ teeth, 【Chemistry 865】 The compound according to claim 16.

20. X １ is an arbitrarily substituted C ２ -C ６ The compound according to any one of claims 1 to 19, which is an alkylene.

21. X １ is an arbitrarily substituted C ２ -C ４ The compound according to claim 20, which is an alkylene.

22. X １ is, -(CH ２ ) ２ -, - (CH ２ ) ３ - and - (CH ２ ) ４ A compound according to claim 20, selected from the group consisting of -.

23. X １ is, -(CH ２ ) ２ - The compound according to claim 22.

24. X １ is, -(CH ２ ) ３ - The compound according to claim 22.

25. X １ is, -(CH ２ ) ４ - The compound according to claim 22.

26. X ４ is an arbitrarily substituted C ２ -C ７ The compound according to any one of claims 1 to 3, 6 to 12, or 15 to 25, which is aliphatic.

27. X ４ is an arbitrarily substituted C ２ -C ３ The compound according to claim 26, which is an alkylene.

28. X ４ is, -(CH ２ ) ２ - The compound according to claim 27.

29. X ４ is, -(CH ２ ) ３ - The compound according to claim 27.

30. X ５ is an arbitrarily substituted C ２ -C ７ The compound according to any one of claims 1 to 3, 6 to 12, or 15 to 29, wherein the compound is aliphatic.

31. X ５ is an arbitrarily substituted C ２ -C ３ The compound according to claim 30, which is an alkylene.

32. X ５ is, -(CH ２ ) ２ - The compound according to claim 31.

33. X ５ is, -(CH ２ ) ３ - The compound according to claim 31.

34. Y １ teeth, 【Chemical 866】 And the combination marked with "*" is X ４ A compound according to any one of claims 1 to 5, 11, or 16 to 33, which is bonded to.

35. Y ２ teeth, 【Chemical 867】 And the combination marked with "*" is X ５ A compound according to any one of claims 1 to 5, 11, or 16 to 34, which is bonded to.

36. R ２ is an arbitrarily substituted C １ -C ３ The compound according to any one of claims 1 to 35, which is an alkylene.

37. R ２ is an arbitrarily substituted C １ The compound according to any one of claims 1 to 35, which is an alkylene.

38. R ２ is, -(CH ２ The compound according to claim 37, which is:

39. R ３ is an arbitrarily substituted C ２ The compound according to any one of claims 1 to 35, which is an alkylene.

40. R ２ is, -(CH ２ ) ２ - The compound according to claim 39.

41. R ３ is an arbitrarily substituted C １ -C ３ The compound according to any one of claims 1 to 40, which is an alkylene.

42. R ３ is an arbitrarily substituted C １ The compound according to any one of claims 1 to 41, which is an alkylene.

43. R ３ is, -(CH ２ The compound according to claim 42, wherein the compound is as follows:

44. R ３ is an arbitrarily substituted C ２ The compound according to any one of claims 1 to 41, which is an alkylene.

45. R ３ is, -(CH ２ ) ２ - The compound according to claim 44.

46. R ４ is -CH(OR ６ ) ( OR ７ The compound according to any one of claims 1 to 10 or 16 to 45, which is the compound described above.

47. R ４ is -CH(SR ６ ) (SR ７ The compound according to any one of claims 1 to 10 or 16 to 45, which is the compound described above.

48. R ４ is, -R １０ The compound according to any one of claims 1 to 10 or 16 to 45.

49. R ４ teeth, 【Chemical 868】 Any of claims 1 to 10 or 16 to 45, selected from the group consisting of the above.

50. R ４ teeth, 【Chemical 869】 The compound according to any one of claims 1 to 10 or 16 to 45.

51. R ５ is -CH(OR ６ ) ( OR ７ The compound according to any one of claims 1 to 10 or 16 to 50, which is:

52. R ５ is -CH(OR ８ ) ( OR ９ The compound according to any one of claims 1 to 10 or 16 to 50, which is:

53. R ５ is -CH(SR ６ ) (SR ７ The compound according to any one of claims 1 to 10 or 16 to 50, which is:

54. R ５ is -CH(OR ８ ) ( OR ９ The compound according to any one of claims 1 to 10 or 16 to 50, which is:

55. R ５ is, -R １１ The compound according to any one of claims 1 to 10 or 16 to 50.

56. R ５ teeth, 【Chemical 870】 A compound selected from any of claims 1 to 10 or 16 to 50.

57. R ５ teeth, 【Chemistry 871】 A compound selected from any of claims 1 to 10 or 16 to 50.

58. R ６ is, -R １０ or optionally replaced with -C １ -C １４ Aliphatic-R １０ The compound according to any one of claims 1 to 55.

59. R ６ This is an arbitrarily substituted -C １ -C １４ Aliphatic-R １０ The compound according to claim 58.

60. R ６ is, -CH ２ R １０ The compound according to claim 58.

61. R ６ is, -R １０ The compound according to claim 58.

62. R ７ is, -R １０ or optionally replaced with -C １ -C １４ Aliphatic-R １０ The compound according to any one of claims 1 to 61.

63. R ７ This is an arbitrarily substituted -C １ -C １４ Aliphatic-R １０ The compound according to claim 62.

64. R ７ is, -CH ２ R １０ The compound according to claim 62.

65. R ７ is, -R １０ The compound according to claim 62.

66. R １０ This is a substituted bridged biring type C ５ -C １０ A compound according to any one of claims 1 to 65, wherein the compound is a cycloalkylenyl.

67. R １０ The compound according to claim 66, wherein is an optionally substituted group selected from bicyclo[2.2.2]octyl or adamantyl.

68. R １０ teeth, 【Chemical 872】 A compound according to claim 66, selected from the group consisting of the following.

69. R ８ This is an arbitrarily substituted -C １ -C １４ The compound according to any one of claims 1 to 68, which is aliphatic.

70. R ８ This is an arbitrarily substituted -C ７ -C １０ The compound according to claim 69, which is aliphatic.

71. R ８ teeth, 【Chemical 873】 A compound according to claim 69, selected from the group consisting of the following.

72. R ９ This is an arbitrarily substituted -C １ -C １４ The compound according to any one of claims 1 to 71, which is aliphatic.

73. R ９ This is an arbitrarily substituted -C ７ -C １０ The compound according to claim 72, which is aliphatic.

74. R ９ teeth, 【Chemistry 874】 A compound according to claim 72, selected from the group consisting of the following.

75. R １１ This is a substituted bridged biring type C ５ -C １０ A compound according to any one of claims 1 to 74, wherein the compound is a cycloalkylenyl.

76. R １１ The compound according to claim 75, wherein is an optionally substituted group selected from bicyclo[2.2.2]octyl or adamantyl.

77. R １１ teeth, 【Chemical 875】 A compound according to claim 76, selected from the group consisting of the following.

78. A compound selected from the group consisting of those disclosed in Table (I-E) or pharmaceutically acceptable salts thereof.

79. A pharmaceutical composition, a) at least one lipid nanoparticle comprising at least one compound according to any one of claims 1 to 78; and b) At least one nucleic acid base editing system The pharmaceutical composition comprising the above.

80. The pharmaceutically acceptable composition according to claim 79, wherein the nucleic acid base editing system comprises a CRISPR-Cas gene editing system.

81. The pharmaceutically acceptable composition according to claim 79, wherein the nucleic acid base editing system comprises a prime editing system or a component thereof.

82. The pharmaceutically acceptable composition according to claim 79, wherein the nucleic acid base editing system includes a retron editing system.

83. The pharmaceutically acceptable composition according to claim 79, wherein the nucleic acid base editing system comprises a TnpB editing system.

84. The pharmaceutically acceptable composition according to claim 79, wherein the nucleic acid base editing system comprises an integrase editing system.

85. The pharmaceutically acceptable composition according to claim 79, wherein the nucleic acid base editing system comprises an integrase editing system.

86. The pharmaceutical composition according to claim 79, wherein the nucleic acid base editing system includes an epigenetic editing system.

87. The pharmaceutical composition according to claim 79, wherein the nucleic acid base editing system includes a gene writing system.

88. The pharmaceutically acceptable composition according to claim 79, wherein the nucleic acid base editing system comprises a gene inactivation system.

89. The pharmaceutically acceptable composition according to claim 79, wherein the nucleic acid base editing system comprises a zinc finger nuclease.

90. The pharmaceutically acceptable composition according to claim 79, wherein the nucleic acid base editing system comprises a TALE nuclease, a TALE nickase, a zinc finger (ZF) nuclease, a ZF nickase, a meganuclease, or a combination thereof.

91. The pharmaceutically acceptable composition according to claim 79, wherein the nucleic acid base editing system comprises a meganuclease.

92. The at least one lipid nanoparticle is i) at least one structural lipid; ii) at least one phospholipid; and iii) At least one PEGylated lipid A pharmaceutical composition according to any one of claims 79 to 91, further comprising the above.

93. The pharmaceutical composition according to any one of claims 79 to 92, wherein the at least one structural lipid is selected from cholesterol, fecosterol, fucosterol, beta-sitosterol, sitosterol, ergosterol, campesterol, stigmasterol, brassicasterol, tomatidine, cholic acid, sitostanol, lithocholic acid, tomatine, ursolic acid, alpha-tocopherol, vitamin D3, vitamin D2, calcipotriol, botulinum, lupeol, oleanolic acid, beta-sitosterol acetate, and any combination thereof.

94. The at least one phospholipid is 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC), 1,2-dimyristoyl-sn-glycero-phosphocholine (DMPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-diundecanoyl-sn-glycero-phosphocholine (DUPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1,2-di-O-octadecenyl-sn-glycero-3-phosphocholine (18:0 diether PC), 1-oleoyl-2-cholesterylhemisuccinoyl-sn-glycero-3-phosphocholine (OChemsPC), 1-hexadecyl-sn-glycero-3-phosphocholine (C16 Lyso PC), 1,2-dilinolenoyl-sn-glycero-3-phosphocholine, 1,2-diarachidonoyl-sn-glycero-3-phosphocholine, 1,2-didocosahexaenoyl-sn-glycero-3-phosphocholine, 1,2-difytanoyl-sn-glycero-3-phosphoethanolamine (ME 16.0 PE), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, 1,2-dilinoleoyl-sn-glycero-3-phosphoethanolamine, 1,2-dilinolenoyl-sn-glycero-3-phosphoethanolamine, 1,2-diarachidonoyl-sn-glycero-3-phosphoethanolamine, 1,2-didocosahexaenoyl-sn-glycero-3-phosphoethanolamine, 1,2-dioleoyl-sn-glycero-3-phospho-rac-(1-glycerol) sodium salt (DOPG), sodium (S)-2-ammonio-3-((((R)-2-(oleoyloxy)-3-(stearoyloxy)propoxy)oxide phosphoryl)oxy)propanoate (L-α-phosphatidylserine;Brain PS), dimyristoyl phosphatidylcholine (DMPC), dimyristoyl phosphoethanolamine (DMPE), dimyristoyl phosphatidylglycerol (DMPG), dioleoyl-phosphatidylethanolamine 4-(N-maleimidomethyl)-cyclohexane-1-carboxylate (DOPE-mal), dioleoyl phosphatidylglycerol (DOPG), 1,2-dioleoyl-sn-glycero-3-(phospho-L-serine) (DOPS), acetyl-fusion phospholipid (DPhPE), dipalmitoyl phosphatidylethanolamine (DPPE) , 1,2-dierydoyl-sn-phosphatidylethanolamine (DEPE), dipalmitoylphosphatidylglycerol (DPPG), dipalmitoylphosphatidylserine (DPPS), distearoylphosphatidylcholine (DSPC), distearoyl-phosphatidyl-ethanolamine (DSPE), distearoylphosphoethanolamineimidazole (DSPEI), 1,2-diundecanoyl-sn-glycero-phosphocholine (DUPC), egg yolk phosphatidylcholine (EPC), 1,2-dioleoyl-sn-glycero-3-phosphate (18:1 PA; DOPA), ammonium bis((S)-2-hydroxy-3-(oleoyloxy)propyl) phosphate (18:1 DMP; LBPA), 1,2-dioleoyl-sn-glycero-3-phospho-(1'-myo-inositol) (DOPI; 18:1 PI), 1,2-distearoyl-sn-glycero-3-phospho-L-serine (18:0 PS), 1,2-dilinoleoyl-sn-glycero-3-phospho-L-serine (18:2 PS), 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-L-serine (16:0-18:1 PS;A pharmaceutical composition according to any one of claims 79 to 93, selected from POPs), 1-stearoyl-2-oleoyl-sn-glycero-3-phospho-L-serine (18:0-18:1 PS), 1-stearoyl-2-linoleoyl-sn-glycero-3-phospho-L-serine (18:0-18:2 PS), 1-oleoyl-2-hydroxy-sn-glycero-3-phospho-L-serine (18:1 Lyso PS), 1-stearoyl-2-hydroxy-sn-glycero-3-phospho-L-serine (18:0 Lyso PS), and sphingomyelin.

95. The at least one PEG-modified lipid is (R)-2,3-bis(octadecyloxy)propyl-1-(methoxypoly(ethylene glycol)2000)propylcarbamate, PEG-S-DSG, PEG-S-DMG, PEG-PE, PEG-PAA, PEG-OH DSPE C18, PEG-DSPE, PEG-DSG, PEG-DPG, PEG-DOMG, PEG-DMPE Na, PEG-DMPE, PEG-DMG2000, PEG-DMG C14, PEG-DMG 2000, PEG-DMG, PEG-DMA, PEG-Ceramide C16, PEG-C-DOMG, PEG-c-DMOG, PEG-c-DMA, PEG-cDMA, PEG, PEG750-C-DMA, PEG400, PEG2k-DMG, PEG2k-C11, PEG2000-PE, PEG2000P, PEG2000-DSPE, PEG2000-DOMG, PEG2000-DMG, PEG2000-C-DMA, PEG2000, PEG200, PEG(2k)-DMG, PEG DSPE C18, PEG DMPE C14, PEG DLPE C12, PEG Click DMG C14, PEG-C12, PEG-C10, N(carbonyl-methoxypolyethylene glycol-2000)-l,2-distearoyl-sn-glycero-3-phosphoethanolamine, Myrj52, mPEG-PLA, MPEG-DSPE, mPEG3000-DMPE, MPEG-2000-DSPE, MPEG2000-DSPE, mPEG2000-DPPE, mPEG2000-DMPE, mPEG2000-DMG, mDPPE-PEG2000, l,2-Distearoyl-sn-glycero-3-phosphoethanolamine-PEG2000, HPEG-2K-LiPD, Folic Acid PEG-DSPE, DSPE-PEGMA 500, DSPE-PEGMA, DSPE-PEG6000, DSPE-PEG5000, DSPE-PEG2K-NAG, DSPE-PEG2k, DSPE-PEG2000 Maleimide, DSPE-PEG2000, DSPE-PEG, DSG-PEGMA, DSG-PEG5000, DPPE-PEG-2K, DPPE-PEG, DPPE-mPEG2000, DPPE-mPEG, DPG-PEGMA, DOPE-PEG2000, DMPE-PEGMA, DMPE-PEG2000, DMPE-PEG, DMPE-mPEG2000, DMG-PEGMA, DMG-PEG2000, DMG-PEG, Distearoyl-Glycerol-Polyethylene Glycol, Cl8PEG750, Cl8PEG5000, Cl8PEG3000, CI8PEG2000, CI6PEG2000, CI4PEG2000, C18-PEG5000, C18PEG, C16PEG, C16 A pharmaceutical composition according to any one of claims 79 to 94, selected from mPEG (polyethylene glycol) 2000 ceramide, C14-PEG-DSPE200, C14-PEG2000, C14PEG2000, C14-PEG 2000, C14-PEG, C14PEG, 14:0-PEG2KPE, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-PEG2000, (R)-2,3-bis(octadecyloxy)propyl-1-(methoxypoly(ethylene glycol)2000)propylcarbamate, (PEG)-C-DOMG, PEG-C-DMA, and DSPE-PEG-X.

96. The aforementioned LNPs are 1,2-di-O-octadecenyl-sn-glycero-3-phosphocholine (18:0 diether PC), 1,2-dilinolenoyl-sn-glycero-3-phosphocholine (18:3 PC), acylcarnosine (AC), and 1-hexadecyl-sn-glycero-3-phosphocholine (C16 Lyso). PC), N-oleoyl-sphingomyelin (SPM) (C18:1), N-lignoceryl SPM (C24:0), N-noivernol-sphingomyelin (C24:1), cardiolipin (CL), l,2-bis(tricosa-10,12-diinoyl)-sn-glycero-3-phosphocholine (DC8-9PC), dicetyl phosphate (DCP), dihexadecyl phosphate (DCP1), 1,2-dipalmitoylglycerol- 3-hemisuccinate (DGSucc), short-chain bis-n-heptadecanoylphosphatidylcholine (DHPC), dihexadecoil-phosphoethanolamine (DHPE), 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC), l,2-dilauroyl-sn-glycero-3-PE (DLPE), dimyristoylglycerol hemisuccinate (DMGS), dimyristoylphosphatidylcholine (DMPC), dimy Listylphosphoethanolamine (DMPE), dimyristoylphosphatidylglycerol (DMPG), dioleyloxybenzyl alcohol (DOBA), 1,2-diol ethylglyceryl-3-hemisuccinate (DOGHEMS), N-[2-(2-{2-[2-(2,3-bis-octades-9-enyloxy-propoxy)-ethoxy]-ethoxy}-ethoxy)-ethyl]-3-(3,4,5-1-dihydroxy-6 -Hydroxymethyl-1-etrahydropyran-2-ylsulfanyl)-propionamide (DOGP4αMan), dioleoylphosphatidylcholine (DOPC), dioleylphosphatidylethanolamine (DOPE), dioleoylphosphatidylethanolamine 4-(N-maleimidemethyl)-cyclohexane-1-carboxylate (DOPE-mal), dioleoylphosphatidylglycerol (DOPG), 1,2-Dioleoyl-sn-glycero-3-(phospho-L-serine) (DOPS), Acell-fusion phospholipid (DPhPE), Dipalmitoylphosphatidylethanolamine (DPPE), Dipalmitoylphosphatidylglycerol (DPPG), Dipalmitoylphosphatidylserine (DPPS), Distearoylphosphatidylcholine (DSPC), Distearoyl-phosphatidyl-ethanolamine (DSPE), Distearoylphosphoethanolamineimidazole (DSPEI), 1,2-Diundecanoyl-sn-glycero-phosphocholine (DUPC), Egg yolk phosphatidylcholine (EPC), Histamine distearoylglycerol (HDSG), 1,2-Dipalmitoylglycerol-hemisuccinate-Nα-histidinyl-hemis Succinate (HistSuccDG), N-(5'-hydroxy-3'-oxypentyl)-10-12-pentacosadiinamide (h-Pegi-PCDA), 2-[l-hexyloxyethyl]-2-devinylpyropheophorbide-a (HPPH), hydrogenated soybean phosphatidylcholine (HSPC), 1,2-dipalmitoylglycerol-O-α-histidinyl-Nα-hemi Succinate (IsohistsuccDG), mannosylated dipalmitoylphosphatidylethanolamine (ManDOG), l,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-[4-(p-maleimidomethyl)cyclohexane-carboxamide] (MCC-PE), 1,2-difitanoyl-sn-glycero-3-phosphoethanolamine (ME 16:0 PE), 1-myristoyl-2-hydroxy-sn-glycero-phosphocholine (MHPC), thiol-reactive maleimide head lipids, e.g., 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-[4-(p-maleimidophenyl)butyramide (MPB-PE), nervonic acid (NA), sodium cholate (NaChol), l,2-Dioleoyl-sn-glycero-3-[phosphoethanolamine-N-dodecanoyl (NC12-DOPE), 1-oleoyl-2-cholesterylhemisuccinoyl-sn-glycero-3-phosphocholine (OChemsPC), phosphatidylethanolamine lipid (PE), PE lipid conjugated with polyethylene glycol (PEG) (e.g., polyethylene glycol-distearoylphosphatidylethanolamine lipid (PEG-PE)), phosphatidylglycerol (PG), partially hydrogenated soybean phosphatidylchlorin (PHS) PC), phosphatidylinositol lipid (PI), phosphotidylinositol-4-phosphate (PIP), palmitoyloleoylphosphatidylcholine (POPC), phosphatidylethanolamine (POPE), palmitoyloleyolphosphatidylglycerol (POPG), phosphatidylserine (PS), lysamine rhodamine B-phosphatidylethanolamine lipid (Rh-PE), purified soybean-derived phospholipid mixture (SIOO), phosphatidylcholine (SM), 18-1-trans-PE, 1-stearoyl-2-oleoyl-H Sphatidylethanolamine (SOPE), soy phosphatidylcholine (SPC), sphingomyelin (SPM), alpha,alpha-trehalose-6,6'-dibehenate (TDB), l,2-dieryloidyl-sn-glycero-3-foethanolamine (transDOPE), ((23S,5R)-3-(bis(hexadecyloxy)methoxy)-5-(5-methyl-2,4-dioxo-3,4-dihydropyrimidine-1(2H)-yl)tetrahydrofuran-2-yl)methylmethylphosphate, 1,2-diarachidonoyl-sn-g Lysero-3-phosphocholine, 1,2-diarachidonoyl-sn-glycero-3-phosphoethanolamine, 1,2-didocosahexaenoyl-sn-glycero-3-phosphocholine, 1,2-didocosahexaenoyl-sn-glycero-3-phosphoethanolamine, 1,2-dilinolenoyl-sn-glycero-3-phosphocholine, 1,2-dilinolenoyl-sn-glycero-3-phosphoethanolamine, 1,2-dilinoleoyl-sn-glycero-3-phosphoethanolamine, 1,2-dioleyl-sn-glycero-3-phosphoethanolamine, 1,The pharmaceutical composition according to any one of claims 79 to 95, further comprising at least one additional lipid component selected from 2-distearoyl-sn-glycero-3-phosphoethanolamine, 16-O-monomethylPE, 16-O-dimethylPE, and dioleylphosphatidylethanolamine.

97. A method for delivering a nucleic acid base editing system to a subject requiring it, the method comprising administering a pharmaceutical composition according to any one of claims 79 to 96 to the subject.

98. A pharmaceutical composition according to any one of claims 79 to 97 for use as a pharmaceutical.

99. Use of the pharmaceutical composition according to any one of claims 79 to 97 for the manufacture of a drug for the delivery of a nucleic acid base editing system.

100. Lipid nanoparticles (LNPs) comprising the compound according to any one of claims 1 to 78, or a pharmaceutically acceptable salt thereof.

101. (a) PEG-lipids (b) Structural lipids; and (c) Non-ionizable lipids and / or zwitterionic lipids The LNP according to claim 100, further comprising:

102. The LNP according to claim 101, wherein the lipid nanoparticles further comprise an additional ionizable lipid in addition to the compound of formula (CC).

103. The LNP according to claim 101 or 102, wherein the PEG-lipid is selected from the group consisting of PEG-c-DOMG, PEG-DMG, PEG-DLPE, PEG-DMPE, PEG-DPPC, and PEG-DSPE.

104. The LNP according to any one of claims 101 to 103, wherein the structural lipid is selected from the group consisting of cholesterol, fecosterol, sitosterol, ergosterol, campesterol, stigmasterol, brassicasterol, tomatidine, ursolic acid, and alpha-tocopherol.

105. The non-ionizable lipids are 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC), 1,2-dimyristoyl-sn-glycero-phosphocholine (DMPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-diundecanoyl-sn-glycero-3-phosphocholine (DUPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), and 1,2-di-O-octadecenyl-sn-glycero-3-phosphocholine (18:0 diether). PC), 1-oleoyl-2-cholesterylhemisuccinoyl-sn-glycero-3-phosphocholine (OChemsPC), 1-hexadecyl-sn-glycero-3-phosphocholine (C16 Lyso PC), 1,2-dilinolenoyl-sn-glycero-3-phosphocholine, 1,2-diarachidonoyl-sn-glycero-3-phosphocholine, 1,2-didocosahexaenoyl-sn-glycero-3-phosphocholine, 1,2-difytanoyl-sn-glycero-3-phosphoethanolamine (ME 16.0 PE), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, 1,2-dilinoleoyl-sn-glycero-3-phosphoethanolamine, 1,2-dilinolenoyl-sn-glycero-3-phosphoethanolamine, 1,2-diarachidonoyl-sn-glycero-3-phosphoethanolamine, 1,2-didocosahexaenoyl-sn-glycero-3-phosphoethanolamine, 1,2-dioleoyl-sn-glycero-3-phospho-rac-(1-glycerol) sodium salt (DOPG), sodium (S)-2-ammonio-3-((((R)-2-(oleoyloxy)-3-(stearoyloxy)propoxy)oxide phosphoryl)oxy)propanoate (L-α-phosphatidylserine;Brain PS), dimyristoyl phosphatidylcholine (DMPC), dimyristoyl phosphoethanolamine (DMPE), dimyristoyl phosphatidylglycerol (DMPG), dioleoyl-phosphatidylethanolamine 4-(N-maleimidomethyl)-cyclohexane-1-carboxylate (DOPE-mal), dioleoyl phosphatidylglycerol (DOPG), 1,2-dioleoyl-sn-glycero-3-(phospho-L-serine) (DOPS), acetyl-fusion phospholipid (DPhPE), dipalmitoyl phosph Phosphatidylethanolamine (DPPE), dipalmitoylphosphatidylglycerol (DPPG), dipalmitoylphosphatidylserine (DPPS), distearoylphosphatidylcholine (DSPC), distearoyl-phosphatidyl-ethanolamine (DSPE), distearoylphosphoethanolamineimidazole (DSPEI), 1,2-diundecanoyl-sn-glycero-phosphocholine (DUPC), egg yolk phosphatidylcholine (EPC), 1,2-dioleoyl-sn-glycero-3-phosphate (18:1 PA; DOPA), ammonium bis((S)-2-hydroxy-3-(oleoyloxy)propyl) phosphate (18:1 DMP; LBPA), 1,2-dioleoyl-sn-glycero-3-phospho-(1'-myo-inositol) (DOPI; 18:1 PI), 1,2-distearoyl-sn-glycero-3-phospho-L-serine (18:0 PS), 1,2-dilinoleoyl-sn-glycero-3-phospho-L-serine (18:2 PS), 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-L-serine (16:0-18:1 PS;An LNP according to any one of claims 101 to 104, which is a phospholipid selected from the group consisting of POPs), 1-stearoyl-2-oleoyl-sn-glycero-3-phospho-L-serine (18:0-18:1 PS), 1-stearoyl-2-linoleoyl-sn-glycero-3-phospho-L-serine (18:0-18:2 PS), 1-oleoyl-2-hydroxy-sn-glycero-3-phospho-L-serine (18:1 Lyso PS), 1-stearoyl-2-hydroxy-sn-glycero-3-phospho-L-serine (18:0 Lyso PS), and sphingomyelin.

106. The LNP according to any one of claims 101 to 105, further comprising a targeting site.

107. The LNP according to claim 106, wherein the targeting site is an antibody or a fragment thereof.

108. The LNP according to any one of claims 101 to 107, further comprising an activator.

109. The LNP according to claim 108, wherein the activator is a nucleic acid.

110. The LNP according to claim 109, wherein the nucleic acid is ribonucleic acid.

111. The LNP according to claim 110, wherein the ribonucleic acid is at least one ribonucleic acid selected from the group consisting of small interfering RNA (siRNA), asymmetric interfering RNA (aiRNA), microRNA (miRNA), Dicer-substrate (dsRNA), small hairpin RNA (shRNA), messenger RNA (mRNA), and long non-coding RNA (lncRNA).

112. The LNP according to claim 111, wherein the nucleic acid is messenger RNA (mRNA) or circular RNA.

113. The LNP according to claim 112, wherein the mRNA includes an open reading frame encoding a cancer antigen.

114. The LNP according to claim 112, wherein the mRNA includes an open reading frame encoding an immune checkpoint modulator.

115. The LNP according to any one of claims 112 to 114, wherein the mRNA includes at least one motif selected from the group consisting of a stem-loop, a strand termination nucleoside, a poly(A) sequence, a polyadenylation signal, and a 5' cap structure.

116. The nucleic acid is suitable for genome editing technology, as described in claim 109.

117. The LNP according to claim 116, wherein the genome editing technology is a clustered regular interval short palindromic repeat (CRISPR) or a transcription activator-like effector nuclease (TALEN).

118. The LNP according to claim 109, wherein the nucleic acid is at least one nucleic acid suitable for genome editing technology, selected from the group consisting of CRISPR RNA (crRNA), transactivating crRNA (tracrRNA), single guide RNA (sgRNA), and DNA repair templates.

119. The LNP according to claim 112, wherein the mRNA has a length of at least 30 nucleotides.

120. The LNP according to claim 112, wherein the mRNA has a length of at least 300 nucleotides.

121. A pharmaceutical composition comprising an LNP according to any one of claims 101 to 120 and a pharmaceutically acceptable carrier.

122. The pharmaceutical composition according to claim 121, formulated for intravenous or intramuscular administration.

123. The pharmaceutical composition according to claim 121, formulated for intravenous administration.

124. A method for delivering nucleic acids to cells, comprising contacting the cells with an LNP according to any one of claims 101 to 120 or a pharmaceutical composition according to any one of claims 99 to 101.

125. A method for treating a disease characterized by a functional protein deficiency, the method comprising administering an LNP preparation comprising the LNP described in any one of claims 101 to 120 to a subject having the disease, wherein the mRNA encodes the functional protein or a protein having the same biological activity as the functional protein.

126. A method for treating a disease characterized by the overexpression of a polypeptide, comprising administering an LNP preparation comprising the LNP and siRNA described in any one of claims 101 to 120 to a subject having the disease, wherein the siRNA targets the expression of the overexpressed polypeptide.

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