Novel ionizable cationic lipids

Abstract

In particular, novel ionizable cationic lipids, lipid nanoparticles comprising novel ionizable cationic lipids, and the method of using said nanoparticles are provided herein.Despite the abundance of cationic lipids, there is still a need in the art for improved lipid therapeutic nucleic acid compositions that are suitable for general therapeutic use.The present invention provides a means to solve this problem, for example, provides novel ionizable cationic lipids with enhanced efficiency of in vivo delivery.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 313,648, filed February 24, 2022, which is incorporated by reference in its entirety for all purposes.

[0002] Throughout this application, various publications, patents, and / or patent applications are referenced. The disclosures of the publications, patents, and / or patent applications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this disclosure pertains.

[0003] Technical Field The present disclosure provides novel ionizable cationic lipids that can be used to form lipid nanoparticles, for example, to facilitate delivery of intracellular payloads (e.g., delivery of mRNA, DNA, siRNA, oligonucleotides, amplified RNA, plasmids, ribozymes, aptamers, etc.). [Background technology]

[0004] Introduction and Overview Many macromolecules, such as nucleic acid molecules, cannot easily cross cell membranes due to their size, charge, and / or hydrophilicity.Therefore, delivery is one of the main challenges for such therapeutic agents, such as antisense payload and mRNA technology.The formulation containing the molecule must not only (1) protect the payload from enzymatic and non-enzymatic degradation and (2) provide suitable biodistribution of the formulation, but also (3) allow the formulation to be taken up or internalized into cells, and (4) facilitate the delivery of nucleic acid payload to the cytoplasm of cells.

[0005] Cationic lipid is an amphiphilic molecule that generally contains a lipophilic region that contains one or more hydrocarbon groups and a hydrophilic region that contains at least one polar head group that is positively charged or ionizable.Cationic lipid can form a positively charged (total charge) complex with macromolecule, thereby facilitating macromolecule, such as nucleic acid, to enter cell plasma through cell plasma membrane.This process, which is carried out in vitro and in vivo, is known as transfection.

[0006] Typically, cationic lipids are used alone or in combination with other lipids, such as phospholipids and / or neutral lipids, such as cholesterol, and / or polyethylene glycol (PEG)-functionalized lipids (PEG lipids) (Meng, C. et al., 2021, Adv. Ther. 4:2000099). These lipids can improve nanoparticle properties, such as particle stability, delivery efficacy, tolerance, and biodistribution (Hajj, KA et al., 2017, Nat. Rev. Mater. 2:17056; Kim, J. et al., 2021, Adv. Drug Deliv. Rev. 170:83-112). For example, 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) is a phosphatidylcholine with saturated tails, with a melting temperature of about 54°C and a cylindrical shape that allows DSPC molecules to form lamellar phases, which stabilize the structure of lipid nanoparticles (Koltover, I. et al., 1998, Science 281:78-81). By combining cationic lipids with neutral lipids, vesicles containing aligned lipid bilayers can be easily formed. Vesicles and liposomes formed with cationic lipids alone or in combination with neutral lipids have many positive charges on the surface, which can be used to form complexes with polynucleotides or other anionic molecules, such as negatively charged proteins. The remaining total cationic charges on the surface of the polynucleotide / cationic lipid / neutral lipid complex can cause strong interactions with cell membranes, mainly with the negative charges on the surface of cell membranes.

[0007] Many different types of cationic lipids have been synthesized for use in transfection and are currently commercially available, including, for example, Lipofectin, Lipofectin ACE, Lipofect AMINE, Transfeactam, and DOTAP.

[0008] Despite the abundance of cationic lipids, there is still a need in the art for improved lipid therapeutic nucleic acid compositions that are suitable for general therapeutic use.Preferably, these compositions encapsulate nucleic acid with high efficiency, have a high drug to lipid ratio, protect the encapsulated nucleic acid from degradation and clearance in serum, are suitable for systemic delivery, and / or provide intracellular delivery of the encapsulated nucleic acid.In addition, these nucleic acid-lipid particles should preferably be well tolerated and / or provide a sufficient therapeutic index, for example, so that the treatment of patients with effective doses of nucleic acid is not accompanied by significant toxicity and / or risk to patients. The present disclosure aims to meet one or more of these needs, provide other advantages, or at least provide the public with a useful choice. For example, provided herein are novel ionizable cationic lipids that have enhanced efficiency for delivery in vivo. [Prior art documents] [Non-patent literature]

[0009] [Non-Patent Document 1] Meng, C. et al., 2021, Adv. Ther. 4:2000099 [Non-Patent Document 2] Hajj, KA et al., 2017, Nat. Rev. Mater. 2:17056 [Non-Patent Document 3] Kim, J. et al., 2021, Adv. Drug Deliv. Rev. 170:83-112 [Non-Patent Document 4] Koltover, I. et al., 1998, Science 281:78-81 Summary of the Invention [Means for solving the problem]

[0010] In one embodiment, the cationic lipid of formula (I) [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, stereoisomer, or prodrug thereof provided herein. R 1 H, -OR 1A , -YOR 1A , -NR 1A R 1B , -YNR 1A R 1B , -SR 1A , -YSR 1A , -(C=O)R 1A , -Y(C=O)R 1A , -(C=O)OR 1A , -Y(C=O)OR 1A , -O(C=O)R 1A , -YO(C=O)R 1A , -O(C=O)OR 1A , -YO(C=O)OR 1A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. Y is a substituted or unsubstituted C0-C 12 It is alkylene or substituted or unsubstituted 0-12 membered heteroalkylene. R 2 H, -OR 2A , -SR 2A , -(C=O)R 2A , -(C=O)OR 2A , -O(C=O)R 2A , -O(C=O)OR 2A , -(C=O)NHR 2A , -NH(C=O)R 2A , substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. R 3 H, -OR 3A , -SR 3A , -(C=O)R 3A , -(C=O)OR 3A , -O(C=O)R 3A, -O(C=O)OR 3A , -(C=O)NHR 3A , -NH(C=O)R 3A , substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. R 4 H, -OR 4A , -SR 4A , -(C=O)R 4A , -(C=O)OR 4A , -O(C=O)R 4A , -O(C=O)OR 4A , -(C=O)NHR 4A , -NH(C=O)R 4A , substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. R 5 H, -OR 5A , -SR 5A , -(C=O)R 5A , -(C=O)OR 5A , -O(C=O)R 5A , -O(C=O)OR 5A , -(C=O)NHR 5A , -NH(C=O)R 5A , substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. B 1 is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. B 2 and B. 3 are each independently a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. L 1 is a bond, -O(C=O)-, -(C=O)O-, -O(C=O)O-, -C(=O)-, -O-, -O(CR 101 R 102 ) s O-, -S-, -C(=O)S-, -SC(=O)-, -NR 101 C(=O)-, -C(=O)NR101 -, -NR 101 C(=S)-, -C(=S)NR 101 -, -NR 101 C(=O)NR 102 -, -NR 101 C(=S)NR 102 -, -OC(=O)NR 101 -, -NR 101 C(=O)O-, -SC(=O)NR 101 -OR-NR 101 C(=O)S-. L 2 is a bond, -O(C=O)-, -(C=O)O-, -O(C=O)O-, -C(=O)-, -O-, -O(CR 201 R 202 ) s O-, -S-, -C(=O)S-, -SC(=O)-, -NR 201 C(=O)-, -C(=O)NR 201 -, -NR 201 C(=O)NR 202 -, -NR 201 C(=S)-, -C(=S)NR 201 -, -NR 201 C(=S)NR 202 -, -OC(=O)NR 201 -, -NR 201 C(=O)O-, -SC(=O)NR 201 -OR-NR 201 C(=O)S-. L 3 is a bond, -O(C=O)-, -(C=O)O-, -O(C=O)O-, -C(=O)-, -O-, -O(CR 301 R 302 ) s O-, -S-, -C(=O)S-, -SC(=O)-, -NR 301 C(=O)-, -C(=O)NR 301 -, -NR 301 C(=O)NR 302 -, -NR 301 C(=S)-, -C(=S)NR 301 -, -NR 301 C(=S)NR 302 -, -OC(=O)NR 301 -, -NR 301C(=O)O-, -SC(=O)NR 301 -OR-NR 301 C(=O)S-. L 4 is a bond, -O(C=O)-, -(C=O)O-, -O(C=O)O-, -C(=O)-, -O-, -O(CR 401 R 402 ) s O-, -S-, -C(=O)S-, -SC(=O)-, -NR 401 C(=O)-, -C(=O)NR 401 -, -NR 401 C(=O)NR 402 -, -NR 401 C(=S)-, -C(=S)NR 401 -, -NR 401 C(=S)NR 402 -, -OC(=O)NR 401 -, -NR 401 C(=O)O-, -SC(=O)NR 401 -OR-NR 401 C(=O)S-. L 5 is a bond, -O(C=O)-, -(C=O)O-, -O(C=O)O-, -C(=O)-, -O-, -O(CR 501 R 502 ) s O-, -S-, -C(=O)S-, -SC(=O)-, -NR 501 C(=O)-, -C(=O)NR 501 -, -NR 501 C(=O)NR 502 -, -NR 501 C(=S)-, -C(=S)NR 501 -, -NR 501 C(=S)NR 502 -, -OC(=O)NR 501 -, -NR 501 C(=O)O-, -SC(=O)NR 501 -OR-NR 501 C(=O)S-. L 6 is a bond, -O(C=O)-, -(C=O)O-, -O(C=O)O-, -C(=O)-, -O-, -O(CR 601 R 602 ) sO-, -S-, -C(=O)S-, -SC(=O)-, -NR 601 C(=O)-, -C(=O)NR 601 -, -NR 601 C(=O)NR 602 -, -NR 601 C(=S)-, -C(=S)NR 601 -, -NR 601 C(=S)NR 602 -, -OC(=O)NR 601 -, -NR 601 C(=O)O-, -SC(=O)NR 601 -OR-NR 601 C(=O)S-. L 7 is a bond, -O(C=O)-, -(C=O)O-, -O(C=O)O-, -C(=O)-, -O-, -O(CR 701 R 702 ) s O-, -S-, -C(=O)S-, -SC(=O)-, -NR 701 C(=O)-, -C(=O)NR 701 -, -NR 701 C(=O)NR 702 -, -NR 701 C(=S)-, -C(=S)NR 701 -, -NR 701 C(=S)NR 702 -, -OC(=O)NR 701 -, -NR 701 C(=O)O-, -SC(=O)NR 701 -OR-NR 701 C(=O)S-. L a1 and L a2 are each independently [ka] wherein each X is independently O, S, or CH. W 1 , W 2 , W 3 , W 4 , W 5 , and W 6 are each independently a bond or a substituted or unsubstituted C1-C12 It is alkylene, or a substituted or unsubstituted 2- to 12-membered heteroalkylene. Each R 1A and R 1B are independently H, substituted or unsubstituted C1-C 12 alkyl, or substituted or unsubstituted 2-12 membered heteroalkyl. Each R 2A , R 3A , R 4A , and R 5A are independently H, substituted or unsubstituted C1-C 30 alkyl, or substituted or unsubstituted 2-30 membered heteroalkyl. Each R 101 , R 102 , R 201 , R 202 , R 301 , R 302 , R 401 , R 402 , R 501 , R 502 , R 601 , R 602 , R 701 , and R 702 are independently H, substituted or unsubstituted C1-C 12 alkyl, or substituted or unsubstituted 2-12 membered heteroalkyl. Each s is independently an integer from 1 to 4.

[0011] In one embodiment, a cationic lipid of formula (II) [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, stereoisomer, or prodrug thereof provided herein. B 4 W 7 -L a3 -W 8 And W 7 and W 8 are each independently a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; L a3is a bond, -O(C=O)-, -(C=O)O-, -O(C=O)O-, -C(=O)-, -O-, -O(CR a31 R a32 ) s O-, -S-, -C(=O)S-, -SC(=O)-, -NR a31 C(=O)-, -C(=O)NR a31 -, -NR a31 C(=O)NR a32 -, -NR a31 C(=S)-, -C(=S)NR a31 -, -NR a31 C(=S)NR a32 -, -OC(=O)NR a31 -, -NR a31 C(=O)O-, -SC(=O)NR a31 -OR-NR a31 C(=O)S-. R 10 and R 11 are each independently H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or R 10 and R 11 together with the nitrogen atom to which they are attached form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. B 5 , B 6 , and B. 7 are each independently a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. L 8 is a bond, -O(C=O)-, -(C=O)O-, -O(C=O)O-, -C(=O)-, -O-, -O(CR 801 R 802 ) s O-, -S-, -C(=O)S-, -SC(=O)-, -NR 801 C(=O)-, -C(=O)NR 801 -, -NR 801 C(=O)NR 802 -, -NR 801 C(=S)-, -C(=S)NR 801 -, -NR 801 C(=S)NR 802-, -OC(=O)NR 801 -, -NR 801 C(=O)O-, -SC(=O)NR 801 -OR-NR 801 C(=O)S-. L 9 is a bond, -O(C=O)-, -(C=O)O-, -O(C=O)O-, -C(=O)-, -O-, -O(CR 901 R 902 ) s O-, -S-, -C(=O)S-, -SC(=O)-, -NR 901 C(=O)-, -C(=O)NR 901 -, -NR 901 C(=O)NR 902 -, -NR 901 C(=S)-, -C(=S)NR 901 -, -NR 901 C(=S)NR 902 -, -OC(=O)NR 901 -, -NR 901 C(=O)O-, -SC(=O)NR 901 -OR-NR 901 C(=O)S-. L 10 is a bond, -O(C=O)-, -(C=O)O-, -O(C=O)O-, -C(=O)-, -O-, -O(CR 110 R 111 ) s O-, -S-, -C(=O)S-, -SC(=O)-, -NR 110 C(=O)-, -C(=O)NR 110 -, -NR 110 C(=O)NR 111 -, -NR 110 C(=S)-, -C(=S)NR 110 -, -NR 110 C(=S)NR 111 -, -OC(=O)NR 110 -, -NR 110 C(=O)O-, -SC(=O)NR 110 -OR-NR 110 C(=O)S-. R 7 , R 8 , and R 9are each independently H, substituted or unsubstituted C1-C 30 alkyl, or substituted or unsubstituted 2-30 membered heteroalkyl. Each R a31 and R a32 are independently H, substituted or unsubstituted C1-C 12 alkyl, or substituted or unsubstituted 2-12 membered heteroalkyl. Each R 801 , R 802 , R 901 , R 902 , R 110 , and R 111 are independently H, substituted or unsubstituted C1-C 12 alkyl, or substituted or unsubstituted 2-12 membered heteroalkyl. Each s is independently an integer from 1 to 4.

[0012] In one embodiment, a cationic lipid of formula (III) [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, stereoisomer, or prodrug thereof provided herein. L 11 teeth, [ka] It is. Q is substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene. V is substituted or unsubstituted alkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted arylene. B 8 , B 9 , B 10 , and B. 11 are each independently a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. L12 is a bond, -O(C=O)-, -(C=O)O-, -O(C=O)O-, -C(=O)-, -O-, -O(CR 210 R 211 ) s O-, -S-, -C(=O)S-, -SC(=O)-, -NR 210 C(=O)-, -C(=O)NR 210 -, -NR 210 C(=O)NR 211 -, -NR 210 C(=S)-, -C(=S)NR 210 -, -NR 210 C(=S)NR 211 -, -OC(=O)NR 210 -, -NR 210 C(=O)O-, -SC(=O)NR 210 -OR-NR 210 C(=O)S-. L 13 is a bond, -O(C=O)-, -(C=O)O-, -O(C=O)O-, -C(=O)-, -O-, -O(CR 310 R 311 ) s O-, -S-, -C(=O)S-, -SC(=O)-, -NR 310 C(=O)-, -C(=O)NR 310 -, -NR 310 C(=O)NR 311 -, -NR 310 C(=S)-, -C(=S)NR 310 -, -NR 310 C(=S)NR 311 -, -OC(=O)NR 310 -, -NR 310 C(=O)O-, -SC(=O)NR 310 -OR-NR 310 C(=O)S-. R 12 H, -OR 12A , -SR 12A , -NR 12A , -CN, -(C=O)R 12A , -O(C=O)R 12A , -(C=O)OR 12A , -NR 12A (C=O)-R 12B, -(C=O)NR 12A R 12B It is. R 13 H, -OR 13A , -SR 13A , -NR 13A , -CN, -(C=O)R 13A , -O(C=O)R 13A , -(C=O)OR 13A , -NR 13A (C=O)-R 13B , -(C=O)NR 13A R 13B It is. R 14 and R 15 are each independently substituted or unsubstituted C2 to C 30 alkyl, or substituted or unsubstituted 2-30 membered heteroalkyl. R 12A , R 12B , R 13A , and R 13B are each independently H, substituted or unsubstituted C1-C 20 alkyl, or substituted or unsubstituted 2- to 20-membered heteroalkyl. Each R 210 , R 211 , R 310 , and R 311 are independently H, substituted or unsubstituted C1-C 12 alkyl, or substituted or unsubstituted 2-12 membered heteroalkyl. each n is independently an integer from 0 to 8; Each s is independently an integer from 1 to 4.

[0013] In one embodiment, a cationic lipid of formula (IV) R 17 -W 10 -L 14 -B 12 -L 15 -W 9 -R 16 (IV) or a pharma- ceutically acceptable salt, solvate, hydrate, stereoisomer, or prodrug thereof provided herein. B12 -W 7 -L a3 -W 8 -It is. W 7 and W 8 are each independently a bond or a substituted or unsubstituted C1-C 12 It is alkylene, or a substituted or unsubstituted 2- to 12-membered heteroalkylene. L a3 is a bond, -SS-, -O-(CHO) m -, [ka] It is. W 9 and W 10 are each independently a bond or a substituted or unsubstituted C1-C 12 It is alkylene, substituted or unsubstituted 2-12 membered heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, or any combination thereof. L 14 is a bond, -O(C=O)-, -(C=O)O-, -O(C=O)O-, -C(=O)-, -O-, -O(CR 410 R 411 ) s O-, -S-, -C(=O)S-, -SC(=O)-, -NR 410 C(=O)-, -C(=O)NR 410 -, -NR 410 C(=O)NR 411 -, -NR 410 C(=S)-, -C(=S)NR 410 -, -NR 410 C(=S)NR 411 -, -OC(=O)NR 410 -, -NR 410 C(=O)O-, -SC(=O)NR 410 -OR-NR 410 C(=O)S-. L 15 is a bond, -O(C=O)-, -(C=O)O-, -O(C=O)O-, -C(=O)-, -O-, -O(CR 510 R 511 )s O-, -S-, -C(=O)S-, -SC(=O)-, -NR 510 C(=O)-, -C(=O)NR 510 -, -NR 510 C(=O)NR 511 -, -NR 510 C(=S)-, -C(=S)NR 510 -, -NR 510 C(=S)NR 511 -, -OC(=O)NR 510 -, -NR 510 C(=O)O-, -SC(=O)NR 510 -OR-NR 510 C(=O)S-. R 16 and R 17 are each independently [ka] A fragment of a cationic lipid of formula (I): [ka] A fragment of a cationic lipid of formula (II): [ka] A fragment of a cationic lipid of formula (II): [ka] A fragment of a cationic lipid of formula (III), or [ka] A fragment of a cationic lipid of formula (III). Each R 410 , R 411 , R 510 , and R 511 are independently H, substituted or unsubstituted C1-C 12 alkyl, or substituted or unsubstituted 2-12 membered heteroalkyl. each m is independently an integer from 0 to 8; Each s is independently an integer from 1 to 4.

[0014] In one aspect, provided herein are lipid nanoparticles comprising a cationic lipid of Formulas I-IV as described herein.

[0015] In one aspect, provided herein is a pharmaceutical composition comprising a lipid nanoparticle comprising a cationic lipid of Formulas I-IV as described herein, and a pharma- ceutically acceptable carrier.

[0016] In one aspect, provided herein is a method for in vivo delivery of a therapeutic agent, the method comprising administering lipid nanoparticles comprising a cationic lipid of Formulas I-IV as described herein.

[0017] In one aspect, provided herein is a method for treating a disease in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of lipid nanoparticles comprising a cationic lipid of Formulas I-IV as described herein. [Brief description of the drawings]

[0018] [Figure 1A-B] 1A-D show the amount of anti-spike antibodies (SARS-CoV-2 antibodies) produced in mice in response to injection of lipid nanoparticles containing spike mRNA. FIG. 1A shows the amount of anti-spike antibodies (SARS-CoV-2 antibodies) produced in mice in response to injection of lipid nanoparticles containing spike mRNA Washington (WA) wild type. FIG. 1B shows the amount of anti-spike antibodies (SARS-CoV-2 antibodies) produced in mice in response to injection of lipid nanoparticles containing spike mRNA WA furin. FIG. 1C shows the amount of anti-spike antibodies (SARS-CoV-2 antibodies) produced in mice in response to injection of lipid nanoparticles containing spike mRNA beta-furin. FIG. 1D shows the amount of anti-spike antibodies (SARS-CoV-2 antibodies) produced in mice in response to injection of lipid nanoparticles containing spike mRNA beta-furin. [Figure 1C-D] Same as above.

[0019] [Diagram 2] FIG. 2 shows the composition of the lipid nanoparticles used to generate the graphs shown in FIGS. 1A-D. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS definition Unless otherwise defined, technical and scientific terms used herein have the meaning commonly understood by those skilled in the art. In general, the terms related to cell and tissue culture, molecular biology, immunology, microbiology, genetics, transgenic cell production, protein chemistry and nucleic acid chemistry, and hybridization techniques described herein are well known and commonly used in the art. The methods and techniques provided herein are generally carried out according to conventional procedures well known in the art, and as described in various general and more specific references cited and discussed herein, unless otherwise indicated. For example, see Sambrook et al. Molecular Cloning: A Laboratory Manual, 2d ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY (1989) and Ausubel et al., Current Protocols in Molecular Biology, Greene Publishing Associates (1992).Several basic texts describe the standard antibody production process, including Borrebaeck (ed) Antibody Engineering, 2nd Edition Freeman and Company, NY, 1995;McCafferty et al. Antibody Engineering, A Practical Approach IRL at Oxford Press, Oxford, England, 1996; and Paul (1995) Antibody Engineering Protocols Humana Press, Towata, NJ, 1995;Paul (ed.), Fundamental Immunology, Raven Press, NY, 1993;Coligan (1991) Current Protocols in Immunology Wiley / Greene, NY;Harlow and Lane (1989) Antibodies: A Laboratory Manual Cold Spring Harbor Press, NY;Stites et al. (eds.) Basic and Clinical Immunology (4th ed.) Lange Medical Publications, Los Altos, Calif. and references cited therein;Coding Monoclonal Antibodies: Principles and Practice (2nd ed.) Academic Press, New York, NY, 1986, and Kohler and Milstein Nature 256: 495-497, 1975. All references cited herein are incorporated by reference in their entirety. Enzymatic reactions and concentration / purification techniques are also well known and performed according to manufacturer's specifications as commonly accomplished in the art or as described herein. The terminology used in connection with and the laboratory procedures and techniques of analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are well known and commonly used in the art.Standard techniques can be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients.

[0021] The section headings used herein are for organizational purposes only and shall not be construed as limiting the desired subject matter in any way. In the event that any document incorporated by reference conflicts with any term defined herein, the present specification shall control. Although the teachings of the present invention are described in conjunction with various embodiments, it is not intended that the teachings of the present invention be limited to such embodiments. On the contrary, the teachings of the present invention encompass various alternatives, modifications, and equivalents as would be recognized by one skilled in the art. The features of any embodiment described herein may be combined with the features of any one or more of the other embodiments described herein, provided that the embodiments are not mutually inconsistent.

[0022] Before describing the teachings of the present invention in detail, it is to be understood that the present disclosure is not limited to specific compositions or process steps, which may vary. It should be noted that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "a conjugate" includes a plurality of conjugates, reference to "a cell" includes a plurality of cells, and so forth.

[0023] It is to be understood that the use of the alternative (eg, "or") herein is intended to mean either one or both of the alternatives or any combination thereof.

[0024] The term "and / or" as used herein is intended to mean the specific disclosure of each of the specified features or components, together with or without other features or components. For example, the term "and / or" as used herein in phrases such as "A and / or B" is intended to include "A and B", "A or B", "A" (alone), and "B" (alone). Similarly, the term "and / or" as used in phrases such as "A, B, and / or C" is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0025] As used herein, the term "about" refers to a value or composition that is within an acceptable error range for a particular value or composition as determined by one of ordinary skill in the art, which error range depends in part on the manner in which the value or composition is measured or determined, i.e., the limitations of the measurement system. For example, "about" or "approximately" can mean within one or more standard deviations per one practice in the art. Alternatively, "about" or "approximately" can mean a range of up to 10% (i.e., ±10%) or greater, depending on the limitations of the measurement system. For example, about 5 mg can include any number between 4.5 mg and 5.5 mg. Furthermore, particularly with respect to biological systems or processes, these terms can mean up to an order of magnitude or up to 5-fold difference from a value. When a particular value or composition is provided in this disclosure, unless otherwise stated, the meaning of "about" or "approximately" should be assumed to be within an acceptable error range for the particular value or composition. In some embodiments, "about" encompasses a variation within 10%, 5%, 2%, 1%, or 0.5% of the stated value.

[0026] Numerical ranges are inclusive of the numbers that define the range. Measured and measurable values ​​are believed to be approximations taking into account significant digits and errors associated with measurement. Also, all ranges are to be construed as including the endpoints unless there is an explicit exclusion, e.g., "not including the endpoints." Thus, for example, a "range of 1 to 10" includes the values ​​1 and 10, as well as all integer and (where appropriate) non-integer values ​​greater than 1 and less than 10.

[0027] The term "coronavirus infection" refers to a human or animal having cells infected with coronavirus. Infection can be confirmed by performing detection and / or virus titration from respiratory samples or by assaying for coronavirus-specific antibodies circulating in the blood. Detection of individuals infected with coronavirus is performed by conventional diagnostic methods, such as molecular biology (e.g., PCR), which are known to those skilled in the art.

[0028] The use of "comprise," "comprises," "comprising," "contain," "contains," "containing," "include," "includes," and "including," as well as grammatical variations thereof, as used herein, is intended to be non-limiting, such that one item or a number of items in a list do not exclude other items that may replace or be in addition to the listed items. It is to be understood that both the foregoing general and detailed descriptions are merely exemplary and explanatory and are not limiting teachings. Unless specifically noted in the specification above, embodiments herein that are described as "comprising" various components are also contemplated as "consisting of" or "consisting essentially of" the listed components. Embodiments herein that are described as "consisting of" various components are also contemplated as "comprising" or "consisting essentially of" the listed components. Additionally, embodiments herein that state that they "consist essentially of" various components are also envisioned to "consist of" or "comprise" the recited components (this interchangeability does not apply to the use of these terms in the claims).

[0029] The terms "effective amount", "therapeutically effective amount" or "effective dose" or related terms may be used interchangeably and refer to an amount of a therapeutic agent sufficient to affect, for example, a measurable improvement or prevention of a disease or disorder associated with a coronavirus infection when administered to a subject. For example, administering an effective dose is sufficient to inhibit the growth and / or replication of coronavirus in a subject and / or the development of a viral infection. The therapeutically effective amount of a therapeutic agent provided herein, when used alone or in combination with another drug, will vary depending on the relative activity of the therapeutic agent, as well as the subject and condition being treated, the subject's weight and age and sex, the severity of the condition in the subject, the mode of administration, etc., and the therapeutically effective amount can be readily determined by one of skill in the art. In one embodiment, the therapeutically effective amount depends on certain aspects of the subject to be treated and the disorder to be treated, and can be ascertained by one of skill in the art using known techniques. In addition, adjustments may be required for age, as well as weight, general health, sex, diet, time of administration, drug interactions, and severity of the disease, as is known in the art.

[0030] The terms "subject" and "patient" as used herein refer to humans and non-human animals, including vertebrates, mammals and non-mammals. In one embodiment, the subject may be a human, a non-human primate, monkey, ape, murine (e.g., mouse and rat), cow, pig, horse, dog, cat, goat, wolf, frog or fish.

[0031] The terms "administering" and "administered", and grammatical variations thereof, refer to the physical introduction of a therapeutic agent into a subject using any of a variety of methods and delivery systems known to those skilled in the art. Exemplary routes of administration for the formulations disclosed herein include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral routes of administration, such as administration by injection or infusion. The phrase "parenteral administration", as used herein, means a mode of administration other than enteral and topical administration, usually administration by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion, and electroporation in vivo. In one embodiment, the formulation is administered via a route other than parenteral, for example, orally. Other non-parenteral routes include topical, epidermal or mucosal routes of administration, such as intranasal, vaginal, rectal, sublingual or topical routes of administration. Administration can also be performed, for example, once, multiple times, and / or over one or more extended periods of time.

[0032] "Treating" is understood broadly and includes any beneficial effect, including, for example, delaying, slowing, or preventing the worsening of symptoms associated with pulmonary inflammatory disease, or at least partially ameliorating such symptoms. Treating also includes resulting in any form of improvement in patient function, as discussed in detail below. In some embodiments, treating also means prolonging life compared to expected survival if not receiving treatment. Those in need of treatment include those who already have a disease or disorder, as well as those who are prone to have a disease or disorder, or those in whom a disease or disorder is to be prevented. In embodiments, the terms "treatment" and "treating" refer to combating coronavirus infection in a human or animal subject. By administration of at least one embodiment of the compositions described herein, the viral infection rate (infectious titer) in the subject is reduced, and the virus may be completely eliminated from the subject. The terms "treatment" and "treating" also refer to attenuating symptoms associated with viral infection (e.g., respiratory syndrome, kidney failure, fever, and other symptoms associated with coronavirus infection).

[0033] The term "synergy" refers to a situation in which the combination of two or more agents produces an effect that is greater than the sum of the effects of each of the individual agents. This term encompasses not only a reduction in the symptoms of the disorder being treated, but also an improved side effect profile, improved tolerability, improved patient compliance, improved efficacy, or any other improvement in clinical outcome.

[0034] The term "sub-therapeutic amount" of a drug or therapy refers to an amount that is less than the effective amount for that drug or therapy as a single agent, but when combined with an effective or sub-therapeutic amount of another drug or therapy, can produce the result desired by the physician, e.g., by synergy in the resulting effective action, or by reduced side effects.

[0035] Combination therapy or "in combination with" refers to the use of more than one therapeutic agent to treat a particular disorder or condition. "In combination with" is not intended to mean that the therapeutic agents must be administered at the same time and / or formulated to be delivered together, although these delivery methods are within the scope of this disclosure. Therapeutic agents can be administered concurrently with one or more other additional agents, either before (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12 weeks, or 16 weeks), or after (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12 weeks, or 16 weeks) the other additional agents. The therapeutic agents of the combination therapy can also be administered on an alternating dosing schedule, with or without holiday periods (e.g., no therapeutic agent is administered on certain days of the schedule). Administration of a therapeutic agent "in combination with" another therapeutic agent includes, but is not limited to, sequential and simultaneous administration of the two agents. Generally, each therapeutic agent will be administered at a dosage and / or on a time schedule determined for that particular agent.

[0036] The terms "nucleic acid", "polynucleotide" and "oligonucleotide" as well as other related terms used herein are used interchangeably and refer to a polymer of nucleotides and are not limited to any particular length. The term refers to a polymer containing at least two deoxyribonucleotides or ribonucleotides in either single-stranded or double-stranded form, including DNA, RNA, and hybrids thereof. Nucleic acids include recombinant and chemically synthesized forms. Nucleic acids include DNA molecules (cDNA or genomic DNA), RNA molecules (e.g., mRNA, siRNA, dsRNA, shRNA, miRNA, tRNA, rRNA, vRNA), analogs of DNA or RNA generated using nucleotide analogs (e.g., peptide nucleic acids and non-naturally occurring nucleotide analogs), and hybrids thereof. Nucleic acid molecules can be single-stranded or double-stranded. In some embodiments, the nucleic acid molecules of the present disclosure comprise a continuous open reading frame encoding an Fc-coronavirus antigen fusion protein, or a derivative, mutein, or variant thereof. In one embodiment, the nucleic acid comprises one type of polynucleotide or a mixture of two or more different types of polynucleotides.

[0037] "Antigen-binding protein" and related terms used herein refer to a protein that includes a portion that binds to an antigen, and optionally a scaffold or framework portion that allows the antigen-binding portion to adopt a structure that promotes binding of the antigen-binding protein to an antigen. Examples of antigen-binding proteins include antibodies, antibody fragments (e.g., antigen-binding portions of antibodies), antibody derivatives, and antibody analogs. Antigen-binding proteins can include, for example, alternative protein scaffolds or artificial scaffolds with grafted CDRs or CDR derivatives. Such scaffolds include, but are not limited to, antibody-derived scaffolds, including, for example, mutations introduced to stabilize the three-dimensional structure of the antigen-binding protein, as well as fully synthetic scaffolds, including, for example, biocompatible polymers. See, for example, Korndorfer et al., 2003, Proteins: Structure, Function, and Bioinformatics, Volume 53, Issue 1:121-129;Roque et al., 2004, Biotechnol. Prog. 20:639-654. Additionally, peptide antibody mimetics ("PAMs") can be used, as well as antibody mimetic-based scaffolds that utilize fibronectin components as the scaffold.

[0038] An antigen-binding protein can have the structure of, for example, an immunoglobulin. In one embodiment, an "immunoglobulin" refers to a tetrameric molecule composed of two identical pairs of polypeptide chains, each pair having one "light" chain (about 25 kDa) and one "heavy" chain (about 50-70 kDa). The amino-terminal portion of each chain contains a variable region of about 100-110 or more amino acids that are primarily responsible for antigen recognition. The carboxy-terminal portion of each chain defines a constant region that is primarily responsible for effector function. Human light chains are classified as kappa or lambda light chains. Heavy chains are classified as mu, delta, gamma, alpha, or epsilon, which define the antibody's isotype as IgM, IgD, IgG, IgA, and IgE, respectively. Within the light and heavy chains, the variable and constant regions are joined by a "J" region of about 12 or more amino acids, with the heavy chain also containing a "D" region of about 10 more amino acids. See generally, Fundamental Immunology Ch. 7 (Paul, W., ed., 2nd ed. Raven Press, NY (1989)), incorporated by reference in its entirety for all purposes. The variable regions of each light / heavy chain pair form the antibody binding site such that an intact immunoglobulin has two antigen binding sites. In one embodiment, the antigen binding protein can be a synthetic molecule that has a different structure than a tetrameric immunoglobulin molecule but still binds to a target antigen, or that binds to two or more target antigens. For example, the synthetic antigen binding protein can include an antibody fragment, one to six or more polypeptide chains, an asymmetric assembly of polypeptides, or other synthetic molecules.

[0039] "Antibody" and "antibodies" and related terms used herein refer to an intact immunoglobulin or an antigen-binding portion thereof (or antigen-binding fragment thereof) that specifically binds to an antigen. Antigen-binding portions (or antigen-binding fragments) can be produced by recombinant DNA techniques or by enzymatic or chemical cleavage of intact antibodies. Antigen-binding portions (or antigen-binding fragments) include, among others, Fab, Fab', F(ab')2, Fv, domain antibodies (dAbs), and complementarity determining region (CDR) fragments, single chain antibodies (scFv), chimeric antibodies, diabodies, triabodies, tetrabodies, and polypeptides that contain at least a portion of an immunoglobulin sufficient to confer specific antigen-binding properties to the polypeptide.

[0040] Antibodies include recombinantly produced antibodies and antigen-binding portions. Antibodies include non-human, chimeric, humanized and fully human antibodies. Antibodies include monospecific, multispecific (e.g., bispecific, trispecific and higher order specificities). Antibodies include tetrameric antibodies, light chain monomers, heavy chain monomers, light chain dimers, heavy chain dimers. Antibodies include F(ab')2 fragments, Fab' fragments and Fab fragments. Antibodies include single domain antibodies, monovalent antibodies, single chain antibodies, single chain variable element fragments (scFv), camelized antibodies, affinity antibodies, disulfide-linked Fvs (sdFv), anti-idiotypic antibodies (anti-Id), miniantibodies. Antibodies include monoclonal and polyclonal populations.

[0041] "Neutralizing antibody" and related terms refer to an antibody that is capable of specifically binding to a neutralizing epitope of its target antigen (e.g., coronavirus spike protein) and substantially inhibiting or eliminating the biological activity of the target antigen (e.g., coronavirus spike protein). A neutralizing antibody can reduce the biological activity of the target antigen by at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater reduction in biological activity.

[0042] "Antigen-binding domain," "antigen-binding region," or "antigen-binding site," and other related terms as used herein, refer to a portion of an antigen-binding protein that contains the amino acid residues (or other moieties) that interact with an antigen and contribute to the specificity and affinity of the antigen-binding protein for the antigen. For an antibody that specifically binds to its antigen, this portion will include at least a portion of at least one of its CDR domains.

[0043] The terms "specific binding," "specifically binds," or "specifically bound," and other related terms, as used herein in the context of an antibody or antigen-binding protein or antibody fragment, refer to preferential non-covalent or covalent binding to an antigen relative to other molecules or moieties (e.g., an antibody that specifically binds to a particular antigen relative to other available antigens). In one embodiment, an antibody is -5 M or less, or 10 -6 M or less, or 10 -7 M or less, or 10 -8 M or less, or 10 -9 M or less, or 10 -10 M or a dissociation constant K D An antibody specifically binds to a target antigen when the antibody binds to the antigen at

[0044] The term "human antibody" refers to an antibody having one or more variable and constant regions derived from human immunoglobulin sequences. In one embodiment, all variable and constant domains are derived from human immunoglobulin sequences (e.g., a fully human antibody). These antibodies can be prepared in a variety of ways, examples of which are described below, including via recombinant methodologies or via immunization with the antigen of interest in mice that have been genetically modified to express antibodies from genes encoding human heavy and / or light chains.

[0045] The term "lipid" or "lipid moiety" is used according to its ordinary meaning in chemistry and generally refers to a hydrophobic molecule characterized by an aliphatic hydrocarbon chain. In embodiments, the lipid moiety comprises a carbon chain of 3-100 carbons. In embodiments, the lipid moiety comprises a carbon chain of 5-50 carbons. In embodiments, the lipid moiety comprises a carbon chain of 5-25 carbons. In embodiments, the lipid moiety comprises a carbon chain of 8-525 carbons. The lipid moiety can comprise a saturated or unsaturated carbon chain, and may be optionally substituted. In embodiments, the lipid moiety is optionally substituted at the terminus with a charged moiety. In embodiments, the lipid moiety is an alkyl or heteroalkyl optionally substituted at the terminus with a carboxylic acid moiety. Lipids also include, but are not limited to, esters of fatty acids and are a group of organic compounds characterized by being insoluble in water but soluble in many organic solvents. Lipids are commonly divided into at least three classes: (1) "simple lipids", which include fats and oils as well as waxes; (2) "complex lipids", which include phospholipids and glycolipids; and (3) "derived lipids", such as steroids.

[0046] The terms "cationic lipid" or "ionizable cationic lipid" are used interchangeably herein and refer to lipids that are protonated (e.g., >50% protonated) at low pH (e.g., pH 4), which causes the lipid to become positively charged, but allows the lipid to remain neutral at physiological pH (e.g., pH 7.4).

[0047] "Lipid nanoparticles" include lipid formulations that can be used to deliver active or therapeutic agents, such as nucleic acids (e.g., mRNA), to a target site of interest (e.g., cells, tissues, organs, etc.). In embodiments, the lipid particles described herein are nucleic acid-lipid particles formed, for example, from cationic lipids, non-cationic lipids, and conjugated lipids that, if necessary, prevent particle aggregation. In some embodiments, the active or therapeutic agent, such as nucleic acid, is encapsulated in the lipid portion of the particle, which can protect the nucleic acid from enzymatic degradation.

[0048] The term "lipid conjugate" refers to the conjugated lipid that inhibits lipid particle aggregation.Such lipid conjugate includes, but is not limited to, PEG-lipid conjugate, for example, PEG coupled to dimyristoylglycerol (for example, PEG-DMG conjugate), PEG coupled to diacylglycerol (for example, PEG-DAG conjugate), PEG coupled to cholesterol, PEG coupled to phosphatidylethanolamine, and PEG coupled to ceramide.

[0049] The term "diacylglycerol" or "DAG" refers to a diacylglycerol that is composed of two fatty acyl chains (R 1 and R 2 Both independently have between 2 and 30 carbons attached by an ester linkage to the 1- and 2-positions of glycerol. The acyl groups can be saturated or have different degrees of unsaturation. Suitable acyl groups include, but are not limited to, lauroyl (C 12 ), myristoyl (C 14 ), palmitoyl (C 16 ), stearoyl (C 18 ), and Icosoil (C 20 In a preferred embodiment, R 1 and R 2 are the same, i.e., R 1 and R 2 are both myristoyl (i.e., dimyristoyl), and R 1 and R 2 are both stearoyl (i.e., distearoyl). Diacylglycerols have the general formula: [ka]

[0050] The term "dialkyloxypropyl" or "DAA" refers to a compound that has two alkyl chains (R 1 Also 2and both independently have between 2 and 30 carbons. The alkyl groups can be saturated or have different degrees of unsaturation. Dialkyloxypropyl has the general formula: [ka]

[0051] "Pharmaceutically acceptable excipient" and "pharmaceutically acceptable carrier" refer to substances that aid in the administration and absorption of active agents by a subject, and can be included in the compositions of the present disclosure without causing significant adverse toxicological effects to the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, saline, lactated Ringer's solution, standard sucrose, standard glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings, salt solutions (e.g., Ringer's solution), alcohol, oils, gelatin, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine, and coloring agents. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring agents, and / or aromatic substances that do not adversely react with the compounds of the present disclosure. Those of skill in the art will recognize that other pharmaceutical excipients are useful in the present disclosure.

[0052] The abbreviations used herein have their conventional meanings within the chemical and biological arts. The chemical structures and formulas described herein are constructed according to the standard rules of chemical valence known in the chemical arts. The description of the compounds of the present disclosure is limited by the principles of chemical bonding known to those skilled in the art. Thus, when a group may be substituted with one or more of several substituents, such substitutions are selected to comply with the principles of chemical bonding and to obtain a compound that is not inherently unstable and / or known to those skilled in the art to be unstable under environmental conditions such as aqueous, neutral, and some known physiological conditions. For example, a heterocycloalkyl or heteroaryl is bonded to the rest of the molecule via a ring heteroatom according to the principles of chemical bonding known to those skilled in the art, thus avoiding compounds that are inherently unstable.

[0053] Where substituents are specified in accordance with these conventional chemical formulas written from left to right, these substituents equally encompass the chemically identical substituents that result from writing the structures from right to left. For example, -CH2O- is equivalent to -OCH2-.

[0054] The term "alkyl," by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched carbon chain (or carbons), or combinations thereof, which may be fully saturated, monounsaturated, or polyunsaturated, and can include monovalent, divalent, and polyvalent groups. An alkyl can contain a specified number of carbons (e.g., C1-C6). 10means 1-10 carbons). An alkyl is a non-cyclized chain. Examples of saturated hydrocarbon groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, methyl, such as homologs and isomers of n-pentyl, n-hexyl, n-heptyl, n-octyl. An unsaturated alkyl group is a group having one or more double or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers. An alkoxy is one in which the alkyl is attached to the remainder of the molecule via an oxygen linker (-O-). The alkyl moiety may be an alkenyl moiety. The alkyl moiety may be an alkynyl moiety. The alkyl moiety may be fully saturated. An alkenyl may contain, in addition to one or more double bonds, one or more double bonds and / or one or more triple bonds. An alkynyl may contain, in addition to one or more triple bonds, one or more triple bonds and / or one or more double bonds.

[0055] The term "alkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent group derived from alkyl, exemplified but not limited to, by -CH2CH2CH2CH2-. Typically, alkyl (or alkylene) groups have from 1 to 30 carbon atoms, although these groups are preferred herein to have 10 or fewer carbon atoms. A "lower alkyl" or "lower alkylene" is a shorter chain alkyl or alkylene group, generally having 8 or fewer carbon atoms. The term "alkenylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent group derived from alkene.

[0056] The term "heteroalkyl", by itself or in combination with another term, means, unless otherwise stated, a stable linear or branched chain, or combination thereof, containing at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, B, Se, and S), where the nitrogen and sulfur atoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. The heteroatom(s) (e.g., O, N, S, Si, B, Se, or P) may be located at either an interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Heteroalkyl is a non-cyclized chain. Examples include, but are not limited to: -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-S-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, -O-CH2-CH3, and -CN. Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. The heteroalkyl moiety may contain one heteroatom (e.g., O, N, S, Si, B, Se, or P). A heteroalkyl moiety can optionally contain two different heteroatoms (e.g., O, N, S, Si, B, Se, or P). A heteroalkyl moiety can optionally contain three different heteroatoms (e.g., O, N, S, Si, B, Se, or P). A heteroalkyl moiety can optionally contain four different heteroatoms (e.g., O, N, S, Si, B, Se, or P). A heteroalkyl moiety can optionally contain five different heteroatoms (e.g., O, N, S, Si, B, Se, or P). A heteroalkyl moiety can optionally contain up to eight different heteroatoms (e.g., O, N, S, Si, B, Se, or P).The term "heteroalkenyl", by itself or in combination with another term, means a heteroalkyl containing at least one double bond, unless otherwise stated. In addition to one or more double bonds, a heteroalkenyl can optionally contain one or more double bonds and / or one or more triple bonds. The term "heteroalkynyl", by itself or in combination with another term, means a heteroalkyl containing at least one triple bond, unless otherwise stated. In addition to one or more triple bonds, a heteroalkynyl can optionally contain one or more triple bonds and / or one or more double bonds.

[0057] Similarly, the term "heteroalkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, exemplified, but not limited to, -CH-CH-S-CH-CH- and -CH-S-CH-CH-NH-CH-. For heteroalkylene groups, heteroatoms can occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Furthermore, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(O)R'- represents both -C(O)R'- and -R'C(O)-. As described above, heteroalkyl groups, as used herein, include those groups that are attached to the remainder of the molecule via a heteroatom, e.g., -C(O)R', -C(O)NR', ​​-NR'R'', -OR', -SR', and / or -SOR'. When "heteroalkyl" is recited followed by a list of specific heteroalkyl groups, e.g., -NR'R'', etc., it is understood that the terms heteroalkyl and -NR'R'' are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to provide further clarity. Thus, the term "heteroalkyl" should not be construed herein to exclude specific heteroalkyl groups, e.g., -NR'R'', etc.

[0058] The terms "cycloalkyl" and "heterocycloalkyl", by themselves or in combination with other terms, refer to cyclic versions of "alkyl" and "heteroalkyl", respectively, unless otherwise stated. Cycloalkyls and heterocycloalkyls are not aromatic. Additionally, for heterocycloalkyls, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyls include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. A "cycloalkylene" and a "heterocycloalkylene," alone or as part of another substituent, mean a divalent radical derived from a cycloalkyl and heterocycloalkyl, respectively.

[0059] In embodiments, the term "cycloalkyl" refers to a monocyclic, bicyclic, or polycyclic cycloalkyl ring system. In embodiments, a monocyclic ring system is a cyclic hydrocarbon group containing 3-8 carbon atoms, and such groups can be saturated or unsaturated, but cannot be aromatic. In embodiments, a cycloalkyl group is fully saturated. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. A bicyclic cycloalkyl ring system is a bridged monocyclic ring or a fused bicyclic ring. In embodiments, a bridged monocyclic ring contains a monocyclic cycloalkyl ring in which two non-adjacent carbon atoms of the monocyclic ring are joined by an alkylene bridge of between 1-3 additional carbon atoms (i.e., (CH2) wA bridged group of the form (wherein w is 1, 2, or 3). Representative examples of bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane. In embodiments, the fused bicyclic cycloalkyl ring system contains a monocyclic cycloalkyl ring fused to a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. In embodiments, the bridged or fused bicyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkyl ring. In embodiments, the cycloalkyl group is optionally substituted with one or two groups that are independently oxo or thia. In embodiments, the fused bicyclic cycloalkyl is a 5- or 6-membered monocyclic cycloalkyl ring fused to a phenyl ring, a 5- or 6-membered monocyclic cycloalkyl, a 5- or 6-membered monocyclic cycloalkenyl, a 5- or 6-membered monocyclic heterocyclyl, or a 5- or 6-membered monocyclic heteroaryl, where the fused bicyclic cycloalkyl is optionally substituted with one or two groups which are independently oxo or thia. In embodiments, the polycyclic cycloalkyl ring system is a monocyclic cycloalkyl ring (base ring) fused to either: (i) one ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclyl; or (ii) the other two ring systems independently selected from the group consisting of phenyl, bicyclic aryl, monocyclic or bicyclic heteroaryl, monocyclic or bicyclic cycloalkyl, monocyclic or bicyclic cycloalkenyl, and monocyclic or bicyclic heterocyclyl. In embodiments, the polycyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the base ring.In embodiments, the polycyclic cycloalkyl ring system is a monocyclic cycloalkyl ring (base ring) fused to either: (i) one ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclyl; or (ii) the other two ring systems independently selected from the group consisting of phenyl, monocyclic heteroaryl, monocyclic cycloalkyl, monocyclic cycloalkenyl, and monocyclic heterocyclyl. Examples of polycyclic cycloalkyl groups include, but are not limited to, tetradecahydrophenanthrenyl, perhydrophenothiazin-1-yl, and perhydrophenoxazin-1-yl.

[0060] In embodiments, cycloalkyl is cycloalkenyl. The term "cycloalkenyl" is used according to its plain ordinary meaning. In embodiments, cycloalkenyl is a monocyclic, bicyclic, or polycyclic cycloalkenyl ring system. In embodiments, a monocyclic cycloalkenyl ring system is a cyclic hydrocarbon group containing 3 to 8 carbon atoms, such group being unsaturated (i.e., containing at least one cyclic carbon-carbon double bond) but not aromatic. Examples of monocyclic cycloalkenyl ring systems include cyclopentenyl and cyclohexenyl. In embodiments, a bicyclic cycloalkenyl ring is a bridged monocyclic ring or a fused bicyclic ring. In embodiments, a bridged monocyclic ring contains a monocyclic cycloalkenyl ring in which two non-adjacent carbon atoms of the monocyclic ring are joined by an alkylene bridge of between 1 and 3 additional carbon atoms (i.e., (CH2) w(wherein w is 1, 2, or 3). Representative examples of bicyclic cycloalkenyls include, but are not limited to, norbornenyl and bicyclo[2.2.2]oct2enyl. In embodiments, the fused bicyclic cycloalkenyl ring system contains a monocyclic cycloalkenyl ring fused to a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. In embodiments, the bridged or fused bicyclic cycloalkenyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkenyl ring. In embodiments, the cycloalkenyl group is optionally substituted with one or two groups that are independently oxo or thia. In embodiments, the polycyclic cycloalkenyl ring contains a monocyclic cycloalkenyl ring (base ring) fused to either: (i) one ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclyl; or (ii) two ring systems independently selected from the group consisting of phenyl, bicyclic aryl, monocyclic or bicyclic heteroaryl, monocyclic or bicyclic cycloalkyl, monocyclic or bicyclic cycloalkenyl, and monocyclic or bicyclic heterocyclyl. In embodiments, the polycyclic cycloalkenyl is attached to the parent molecular moiety through any carbon atom contained within the base ring. In embodiments, the polycyclic cycloalkenyl ring contains a monocyclic cycloalkenyl ring (base ring) fused to either: (i) one ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclyl; or (ii) two ring systems independently selected from the group consisting of phenyl, monocyclic heteroaryl, monocyclic cycloalkyl, monocyclic cycloalkenyl, and monocyclic heterocyclyl.

[0061] In an embodiment, the heterocycloalkyl is heterocyclyl. The term "heterocyclyl" as used herein means a monocyclic, bicyclic, or polycyclic heterocycle. A heterocyclyl monocyclic heterocycle is a 3-, 4-, 5-, 6-, or 7-membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S, and the ring is saturated or unsaturated, but not aromatic. A 3- or 4-membered ring contains one heteroatom selected from the group consisting of O, N, and S. A 5-membered ring can contain zero or one double bond and one, two, or three heteroatoms selected from the group consisting of O, N, and S. A 6- or 7-membered ring contains zero, one, or two double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. A heterocyclyl monocyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heterocyclyl monocyclic heterocycle. Representative examples of heterocyclyl monocyclic heterocycles include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolyl, and the like. The heterocyclyl bicyclic heterocycle includes diphenyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidethiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and trithianyl. Heterocyclyl bicyclic heterocycle is a monocyclic heterocycle fused to phenyl, monocyclic cycloalkyl, monocyclic cycloalkenyl, monocyclic heterocycle, or monocyclic heteroaryl. Heterocyclyl bicyclic heterocycle is linked to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the monocyclic heterocycle portion of the bicyclic system.Representative examples of bicyclic heterocyclyl include, but are not limited to, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzofuran-3-yl, indolin-1-yl, indolin-2-yl, indolin-3-yl, 2,3-dihydrobenzothien-2-yl, decahydroquinolinyl, decahydroisoquinolinyl, octahydro-1H-indolyl, and octahydrobenzofuranyl. In embodiments, the heterocyclyl group is optionally substituted with one or two groups that are independently oxo or thia. In certain embodiments, the bicyclic heterocyclyl is a 5- or 6-membered monocyclic heterocyclyl ring fused to a phenyl ring, a 5- or 6-membered monocyclic cycloalkyl, a 5- or 6-membered monocyclic cycloalkenyl, a 5- or 6-membered monocyclic heterocyclyl, or a 5- or 6-membered monocyclic heteroaryl, and the bicyclic heterocyclyl is optionally substituted with one or two groups that are independently oxo or thia. A polycyclic heterocyclyl ring system is a monocyclic heterocyclyl ring (base ring) fused to either: (i) one ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclyl; or (ii) two other ring systems independently selected from the group consisting of phenyl, bicyclic aryl, monocyclic or bicyclic heteroaryl, monocyclic or bicyclic cycloalkyl, monocyclic or bicyclic cycloalkenyl, and monocyclic or bicyclic heterocyclyl. The polycyclic heterocyclyl is attached to the parent molecular moiety through any carbon or nitrogen atom contained within the base ring. In embodiments, the polycyclic heterocyclyl ring system is a monocyclic heterocyclyl ring (base ring) fused to either: (i) one ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclyl; or (ii) two other ring systems independently selected from the group consisting of phenyl, monocyclic heteroaryl, monocyclic cycloalkyl, monocyclic cycloalkenyl, and monocyclic heterocyclyl.Examples of polycyclic heterocyclyl groups include, but are not limited to, 10H-phenothiazin-10-yl, 9,10-dihydroacridin-9-yl, 9,10-dihydroacridin-10-yl, 10H-phenoxazin-10-yl, 10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl, 1,2,3,4-tetrahydropyrido[4,3-g]isoquinolin-2-yl, 12H-benzo[b]phenoxazin-12-yl, and dodecahydro-1H-carbazol-9-yl.

[0062] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl" are intended to include monohaloalkyl and polyhaloalkyl. For example, the term "halo(C1-C4)alkyl" includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0063] The term "acyl," unless otherwise stated, means -C(O)R, in which R is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0064] The term "aryl", unless otherwise stated, means a polyunsaturated aromatic hydrocarbon substituent, which may be a single ring or multiple rings (preferably 1-3 rings) fused together (i.e., fused-ring aryl) or covalently linked. Fused-ring aryl refers to multiple rings fused together, where at least one of the fused rings is an aryl ring. The term "heteroaryl" refers to an aryl group (or ring) containing at least one heteroatom, e.g., N, O, or S, where the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom(s) are optionally quaternized. Thus, the term "heteroaryl" includes fused-ring heteroaryl groups (i.e., multiple rings fused together, where at least one of the fused rings is an aromatic heterocycle). 5,6-fused-ring heteroarylene refers to two rings fused together, where one ring has 5 members and the other ring has 6 members, and where at least one ring is a heteroaryl ring. Similarly, a 6,6-fused ring heteroarylene refers to two rings fused together, one having 6 members and the other having 6 members, with at least one ring being a heteroaryl ring. Additionally, a 6,5-fused ring heteroarylene refers to two rings fused together, one having 6 members and the other having 5 members, with at least one ring being a heteroaryl ring. The heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom.Non-limiting examples of aryl and heteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, benzoxazoyl, benzimidazolyl, benzofuran, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl, isoquinolyl, quinoxalinyl, quinolyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-pyrrolyl, 1 ... -imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of the above described aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. An "arylene" and a "heteroarylene," alone or as part of another substituent, mean a divalent radical derived from an aryl and heteroaryl, respectively. A heteroaryl group substituent may be -O-bonded to a ring heteroatom nitrogen.

[0065] A fused ring heterocycloalkyl-aryl is an aryl fused to a heterocycloalkyl. A fused ring heterocycloalkyl-heteroaryl is a heteroaryl fused to a heterocycloalkyl. A fused ring heterocycloalkyl-cycloalkyl is a heterocycloalkyl fused to a cycloalkyl. A fused ring heterocycloalkyl-heterocycloalkyl is a heterocycloalkyl fused to another heterocycloalkyl. A fused ring heterocycloalkyl-aryl, a fused ring heterocycloalkyl-heteroaryl, a fused ring heterocycloalkyl-cycloalkyl, or a fused ring heterocycloalkyl-heterocycloalkyl can each independently be unsubstituted or substituted with one or more of the substituents described herein.

[0066] A spirocyclic ring is two or more rings in which adjacent rings are linked through a single atom. The individual rings in a spirocyclic ring may be the same or different. The individual rings in a spirocyclic ring may be substituted or unsubstituted and may have different substituents than the other individual rings in the series of spirocyclic rings. The possible substituents for the individual rings in a spirocyclic ring are the possible substituents for the same ring when it is not part of a spirocyclic ring (e.g., a substituent for a cycloalkyl or heterocycloalkyl ring). A spirocylic ring may be a substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heterocycloalkylene, and the individual rings in a spirocyclic ring group may be any of the preceding list, including those in which all rings are one type (e.g., all rings are substituted heterocycloalkylene, and each ring may be the same or different substituted heterocycloalkylene). When referring to a spirocyclic ring system, a heterocyclic spirocyclic ring means a spirocyclic ring in which at least one ring is a heterocyclic ring, and each ring may be different. When referring to a spirocyclic ring system, a substituted spirocyclic ring means that at least one ring is substituted, and each substituent may be optionally different.

[0067] symbol [ka] represents the point of attachment of the chemical moiety to the rest of the molecule or to a chemical formula.

[0068] The term "oxo," as used herein, means an oxygen that is double bonded to a carbon atom.

[0069] The term "alkylsulfonyl," as used herein, means a moiety having the formula -S(O2)-R', where R' is a substituted or unsubstituted alkyl group as defined above. R' can have the specified number of carbon atoms (e.g., "C1-C4 alkylsulfonyl").

[0070] The term "alkylarylene" as an arylene moiety covalently linked to an alkylene moiety (also referred to herein as an alkylene linker). In embodiments, the alkylarylene group has the formula: [ka] has.

[0071] The alkylarylene moiety may be substituted (e.g., in a substituent group) on the alkylene portion or on the arylene linker (e.g., on carbons 2, 3, 4, or 6) with halogen, oxo, -N3, -CF3, -CCl3, -CBr3, -CI3, -CN, -CHO, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO2CH3-SO3H, -OSO3H, -SON2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, substituted or unsubstituted C1-C5 alkyl, or substituted or unsubstituted 2-5 membered heteroalkyl. In an embodiment, the alkylarylene is unsubstituted.

[0072] Each of the above terms (e.g., "alkyl," "heteroalkyl," "cycloalkyl," "heterocycloalkyl," "aryl," and "heteroaryl") includes both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.

[0073] Substituents for the alkyl and heteroalkyl groups (including those groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) include, but are not limited to, -OR', ═O, ═NR', ═N-OR', -NR'R'', -SR', -halogen, -SiR'R''R''', -OC(O)R', -C(O)R', -COR', -CONR'R'', -O and n is 0 or 1. It may be one or more of a variety of groups selected from C(O)NR'R'', -NR''C(O)R', -NR'-C(O)NR''R''', -NR''C(O)2R', -NR-C(NR'R''R'')=NR'''', -NR-C(NR'R'')=NR''', -S(O)R', -S(O)2R', -S(O)2NR'R'', -NRSO2R', -NR'NR''R''', -ONR'R'', -NR'C(O)NR''NR''R'''', -CN, -NO2, -NR'S02R'', -NR'C(O)R'', -NR'C(O)-OR'', -NR'OR''. R, R', R'', R''', and R'''' each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups. For example, when a compound described herein includes more than one R group, each of the R groups is independently selected such that each R', R'', R''', and R'''' group is selected when more than one of these groups is present. When R' and R'' are attached to the same nitrogen atom, they can combine with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, -NR'R'' includes, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl.From the above discussion of substituents, one of skill in the art will understand that the term "alkyl" is intended to include groups that contain carbon atoms bonded to groups other than hydrogen groups, such as haloalkyl (e.g., -CF and -CHCF) and acyls (e.g., -C(O)CH, -C(O)CF, -C(O)CHOCH, etc.).

[0074] Similar to the substituents described for the alkyl group, substituents for the aryl and heteroaryl groups are varied and range in number from zero to the total number of open valences on the aromatic ring system, and include, for example: -OR', -NR'R'', -SR', -halogen, -SiR'R''R''', -OC(O)R', -C(O)R', -CO2R', -CONR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'-C(O)NR''R''', -NR''C(O)2R', -NR-C(NR'R''R'')=NR'''', -NR-C(NR'R'')=NR''', -S(O)R', -S(O)2R', -S(O)2NR'R'', -NRSO2R', and R', R'', R''', and R'''' are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. For example, when a compound described herein includes more than one R group, each of the R groups is independently selected such that each R', R'', R''', and R'''' group is selected when more than one of these groups is present.

[0075] Substituents for a ring (e.g., cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene) may be illustrated as substituents on the ring rather than on a specific atom of the ring (commonly referred to as floating substituents). In such cases, the substituent may be attached to any of the ring atoms (according to the rules of chemical valence), and in the case of a fused or spirocyclic ring, a substituent shown as being attached to one member of the fused or spirocyclic ring (floating substituent on a single ring) may be a substituent on either of the fused or spirocyclic rings (floating substituent on a polycyclic ring). When a substituent is attached to a ring but not to a specific atom (floating substituent), and the subscript for the substituent is an integer greater than 1, the multiple substituents may be on the same atom, the same ring, different atoms, different fused rings, different spirocyclic rings, and each substituent may be different as appropriate. If the point of attachment of the ring to the rest of the molecule is not limited to a single atom (floating substituent), the point of attachment may be any atom of the ring, or, in the case of a fused or spirocyclic ring, any atom of any of the fused or spirocyclic rings, in accordance with the rules of chemical valence. If a ring, fused or spirocyclic ring contains one or more ring heteroatoms and the ring, fused or spirocyclic ring is shown to have another floating substituent (including but not limited to the point of attachment to the rest of the molecule), the floating substituent may be attached to the heteroatom. In a structure or formula having a floating substituent, if a ring heteroatom is shown to be attached to one or more hydrogens (e.g., a ring nitrogen with two bonds to ring atoms and a third bond to a hydrogen), if a heteroatom is attached to the floating substituent, the substituent is considered to replace a hydrogen in accordance with the rules of chemical valence.

[0076] Two or more substituents can be linked together to form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group, if desired. Such so-called ring-forming substituents are usually, but not always, found attached to a cyclic base structure. In one embodiment, the ring-forming substituents are attached to adjacent members of the base structure. For example, two ring-forming substituents attached to adjacent members of a cyclic base structure create a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single member of the base structure. For example, two ring-forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure. In yet another embodiment, the ring-forming substituents are attached to non-adjacent members of the base structure.

[0077] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring optionally have the formula -TC(O)-(CRR') q Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form a ring of the formula -A-(CH2) r A and B may be independently replaced with a substituent of -B-, -CRR'-, -O-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'-, or a single bond, and r is an integer from 1 to 4. One of the single bonds of the new ring thus formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CRR') s -X'-(C''R''R'') dwherein s and d are independently an integer from 0 to 3, and X' is -O-, -NR'-, -S-, -S(O)-, -S(O)2-, or -S(O)2NR'-. The substituents R, R', R'', and R''' are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0078] As used herein, the term "heteroatom" or "ring heteroatom" is meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

[0079] "Substituent," as used herein, means a group selected from the following moieties: (A) oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -N3, unsubstituted alkyl (e.g., C1-C 30 alkyl, C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2-30 membered heteroalkyl, 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C10 Aryl, C 10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl), and

[0080] (B) an alkyl group (e.g., C1 to C2) substituted with at least one substituent selected from the following: 30 alkyl, C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl (e.g., 2-30 membered heteroalkyl, 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl):

[0081] (i) oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -N3, unsubstituted alkyl (e.g., C1-C 30alkyl, C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2-30 membered heteroalkyl, 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl), and

[0082] (ii) an alkyl group (e.g., C1 to C6) substituted with at least one substituent selected from the following: 30 alkyl, C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl (e.g., 2-30 membered heteroalkyl, 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl):

[0083] (a) oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -N3, unsubstituted alkyl (e.g., C1-C 30 alkyl, C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2-30 membered heteroalkyl, 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl), and

[0084] (b) an alkyl group (e.g., C1 to C6) substituted with at least one substituent selected from the following: 30 alkyl, C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl (e.g., 2-30 membered heteroalkyl, 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), aryl (e.g., C6-C 10Aryl, C 10 aryl, or phenyl), heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl): oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2 , -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -N3, unsubstituted alkyl (e.g., C1-C 30 alkyl, C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2-30 membered heteroalkyl, 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl).

[0085] "Size-limited substituent" or "size-limited substituent group" as used herein means a group selected from all of the substituents listed above for "substituent", where each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C 30each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2-30 membered heteroalkyl; each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl; each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3-8 membered heterocycloalkyl; and each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C8 10 aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5-10 membered heteroaryl.

[0086] A "lower substituent" or "lower substituent group", as used herein, means a group selected from all of the substituents described above for "substituent", wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2-8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3-7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted phenyl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5-6 membered heteroaryl.

[0087] In some embodiments, each substituted group described in the compounds herein is substituted with at least one substituent.More specifically, in some embodiments, each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene described in the compounds herein is substituted with at least one substituent.In other embodiments, at least one or all of these groups are substituted with at least one size-limited substituent.In other embodiments, at least one or all of these groups are substituted with at least one lower substituent.

[0088] In other embodiments of the compounds herein, each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C 30 each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2-30 membered heteroalkyl; each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl; each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3-8 membered heterocycloalkyl; and each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C8 10 aryl, and / or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5-10 membered heteroaryl. In some embodiments of the compounds herein, each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C 30 each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2-30 membered heteroalkylene; each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C8 cycloalkylene; each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3-8 membered heterocycloalkylene; and each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C8 10arylene, and / or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5- to 10-membered heteroarylene.

[0089] In some embodiments, each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C 30 each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2-30 membered heteroalkyl; each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl; each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3-7 membered heterocycloalkyl; and each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C 10 In some embodiments, each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C6 alkylene. 30 each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2-30 membered heteroalkylene; each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C7 cycloalkylene; each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3-7 membered heterocycloalkylene; and each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C 10 and / or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5- to 9-membered heteroarylene. In some embodiments, the compound is a species described in the Examples section, Figures, or Tables below.

[0090] In embodiments, a substituted or unsubstituted moiety (e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and / or substituted or unsubstituted heteroarylene) is unsubstituted (e.g., unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted alkylene, unsubstituted heteroalkylene, unsubstituted cycloalkylene, unsubstituted heterocycloalkylene, unsubstituted arylene, and / or unsubstituted heteroarylene, respectively). In embodiments, a substituted or unsubstituted moiety (e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and / or substituted or unsubstituted heteroarylene) is substituted (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene, respectively).

[0091] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one substituent, and when a substituted moiety is substituted with multiple substituents, each substituent can be optionally different. In embodiments, when a substituted moiety is substituted with multiple substituents, each substituent is different.

[0092] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one size-limiting substituent, and when a substituted moiety is substituted with multiple size-limiting substituents, each size-limiting substituent can optionally be different. In embodiments, when a substituted moiety is substituted with multiple size-limiting substituents, each size-limiting substituent is different.

[0093] In embodiments, a substituted moiety (e.g., a substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one lower substituent, and when a substituted moiety is substituted with multiple lower substituents, each lower substituent can optionally be different. In embodiments, when a substituted moiety is substituted with multiple lower substituents, each lower substituent is different.

[0094] In embodiments, a substituted moiety (e.g., a substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one substituent, size-limiting substituent, or lower substituent, and when the substituted moiety is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may be different, if desired. In embodiments, when the substituted moiety is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent is different.

[0095] Certain compounds of the present disclosure possess asymmetric carbon atoms (optical or chiral centers) or double bonds; enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomeric forms that may be defined in terms of absolute stereochemistry as (R)- or (S)-, or (D)- or (L)-, relative to amino acids, and individual isomers are encompassed within the scope of the present disclosure. The compounds of the present disclosure do not include compounds known in the art to be too unstable to synthesize and / or isolate. The present disclosure is intended to include compounds in racemic and optically pure form. Optically active (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. Where compounds described herein contain olefinic bonds or other centers of geometric asymmetry, and unless otherwise specified, the compounds are intended to include both E and Z geometric isomers.

[0096] As used herein, the term "isomers" refers to compounds having the same number and kinds of atoms, and therefore the same molecular weight, but differing with respect to the structural or configuration of the atoms.

[0097] The term "tautomer," as used herein, refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another.

[0098] It will be apparent to one of ordinary skill in the art that certain compounds of the present disclosure may exist in tautomeric forms, and all such tautomeric forms of the compounds are contemplated within the scope of the present disclosure.

[0099] Unless otherwise stated, structures depicted herein are also intended to include all stereochemical forms of the structure, i.e., R and S configurations for each asymmetric center. Accordingly, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure.

[0100] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, a hydrogen is replaced by deuterium or tritium, or a carbon is replaced by 13 C- or 14 Compounds having the structures of the present invention except for the replacement with a C-enriched carbon are within the scope of the present disclosure.

[0101] "Analog" or "analogue" is used according to its plain ordinary meaning within chemistry and biology to refer to a chemical compound that is structurally similar to another compound (i.e., a so-called "reference" compound) but differs in composition, e.g., in the replacement of one atom by an atom of a different element, or in the presence of a particular functional group, or in the replacement of one functional group by another, or in the absolute stereochemistry of one or more chiral centers of the reference compound. Thus, an analog is a compound that is similar or equivalent to the reference compound in function and appearance, but is not similar or equivalent in structure or origin to the reference compound.

[0102] As used herein, the term "salt" refers to an acid or base salt of the compound used in the method of the present invention. Illustrative examples of acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, etc.) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid, etc.) salts, and quaternary ammonium (methyl iodide, ethyl iodide, etc.) salts.

[0103] The term "pharmaceutically acceptable salts" is intended to include salts of active compounds prepared with relatively non-toxic acids or bases, depending on the specific substituents found in the compounds described herein.When a compound of the present disclosure contains a relatively acidic functional group, a base addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of the desired base, either neat or in a suitable inert solvent.Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or similar salts.When a compound of the present disclosure contains a relatively basic functional group, an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharma- ceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, hydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, or phosphorous acid, as well as those derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, oxalic acid, methanesulfonic acid, etc. Also included are salts of amino acids, such as alginates, and salts of organic acids such as glucuronic acid or galacturonic acid (see, for example, Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0104] Thus, the compounds of the present disclosure can exist as salts with, for example, pharma- ceutically acceptable acids. The present disclosure includes such salts. Non-limiting examples of such salts include hydrochlorides, hydrobromides, phosphates, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, proprionates, tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof, including racemic mixtures), succinates, benzoates, and salts with amino acids, such as glutamic acid, and quaternary ammonium salts (e.g., methyl iodide, ethyl iodide, etc.). These salts can be prepared by methods known to those skilled in the art.

[0105] The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound may differ from the various salt forms in certain physical properties, for example, solubility in polar solvents.

[0106] In addition to salt forms, the present disclosure provides compounds in prodrug form. Prodrugs of the compounds described herein are compounds that can easily undergo chemical changes under physiological conditions to obtain the compounds of the present disclosure. Prodrugs of the compounds described herein may be converted in vivo after administration. In addition, prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment, for example, when contacted with suitable enzymes or chemical reagents.

[0107] Certain compounds of the present disclosure can exist in unsolvated form as well as solvated form, including hydrated form.Generally, solvated form is equivalent to unsolvated form and is included within the scope of the present disclosure.Certain compounds of the present disclosure can exist in multiple crystalline or amorphous forms.Generally, all physical forms are equivalent for the use envisioned by the present disclosure and are intended to be within the scope of the present disclosure. compound

[0108] In one embodiment, the cationic lipid of formula (I): [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, stereoisomer, or prodrug thereof provided herein. R 1 H, -OR 1A , -YOR 1A , -NR 1A R 1B , -YNR 1A R 1B , -SR 1A , -YSR 1A , -(C=O)R 1A , -Y(C=O)R 1A , -(C=O)OR 1A , -Y(C=O)OR 1A , -O(C=O)R 1A , -YO(C=O)R 1A , -O(C=O)OR 1A , -YO(C=O)OR 1A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. Y is a substituted or unsubstituted C0-C 12 It is alkylene or substituted or unsubstituted 0-12 membered heteroalkylene. R 2 H, -OR 2A , -SR 2A , -(C=O)R 2A , -(C=O)OR 2A , -O(C=O)R 2A , -O(C=O)OR 2A , -(C=O)NHR 2A , -NH(C=O)R 2A , substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. R 3 H, -OR 3A , -SR 3A, -(C=O)R 3A , -(C=O)OR 3A , -O(C=O)R 3A , -O(C=O)OR 3A , -(C=O)NHR 3A , -NH(C=O)R 3A , substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. R 4 H, -OR 4A , -SR 4A , -(C=O)R 4A , -(C=O)OR 4A , -O(C=O)R 4A , -O(C=O)OR 4A , -(C=O)NHR 4A , -NH(C=O)R 4A , substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. R 5 H, -OR 5A , -SR 5A , -(C=O)R 5A , -(C=O)OR 5A , -O(C=O)R 5A , -O(C=O)OR 5A , -(C=O)NHR 5A , -NH(C=O)R 5A , substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. B 1 is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. B 2 and B. 3 are each independently a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. L 1 is a bond, -O(C=O)-, -(C=O)O-, -O(C=O)O-, -C(=O)-, -O-, -O(CR 101 R 102 ) sO-, -S-, -C(=O)S-, -SC(=O)-, -NR 101 C(=O)-, -C(=O)NR 101 -, -NR 101 C(=S)-, -C(=S)NR 101 -, -NR 101 C(=O)NR 102 -, -NR 101 C(=S)NR 102 -, -OC(=O)NR 101 -, -NR 101 C(=O)O-, -SC(=O)NR 101 -OR-NR 101 C(=O)S-. L 2 is a bond, -O(C=O)-, -(C=O)O-, -O(C=O)O-, -C(=O)-, -O-, -O(CR 201 R 202 ) s O-, -S-, -C(=O)S-, -SC(=O)-, -NR 201 C(=O)-, -C(=O)NR 201 -, -NR 201 C(=O)NR 202 -, -NR 201 C(=S)-, -C(=S)NR 201 -, -NR 201 C(=S)NR 202 -, -OC(=O)NR 201 -, -NR 201 C(=O)O-, -SC(=O)NR 201 -OR-NR 201 C(=O)S-. L 3 is a bond, -O(C=O)-, -(C=O)O-, -O(C=O)O-, -C(=O)-, -O-, -O(CR 301 R 302 ) s O-, -S-, -C(=O)S-, -SC(=O)-, -NR 301 C(=O)-, -C(=O)NR 301 -, -NR 301 C(=O)NR 302 -, -NR 301 C(=S)-, -C(=S)NR 301 -, -NR 301C(=S)NR 302 -, -OC(=O)NR 301 -, -NR 301 C(=O)O-, -SC(=O)NR 301 -OR-NR 301 C(=O)S-. L 4 is a bond, -O(C=O)-, -(C=O)O-, -O(C=O)O-, -C(=O)-, -O-, -O(CR 401 R 402 ) s O-, -S-, -C(=O)S-, -SC(=O)-, -NR 401 C(=O)-, -C(=O)NR 401 -, -NR 401 C(=O)NR 402 -, -NR 401 C(=S)-, -C(=S)NR 401 -, -NR 401 C(=S)NR 402 -, -OC(=O)NR 401 -, -NR 401 C(=O)O-, -SC(=O)NR 401 -OR-NR 401 C(=O)S-. L 5 is a bond, -O(C=O)-, -(C=O)O-, -O(C=O)O-, -C(=O)-, -O-, -O(CR 501 R 502 ) s O-, -S-, -C(=O)S-, -SC(=O)-, -NR 501 C(=O)-, -C(=O)NR 501 -, -NR 501 C(=O)NR 502 -, -NR 501 C(=S)-, -C(=S)NR 501 -, -NR 501 C(=S)NR 502 -, -OC(=O)NR 501 -, -NR 501 C(=O)O-, -SC(=O)NR 501 -OR-NR 501 C(=O)S-. L 6is a bond, -O(C=O)-, -(C=O)O-, -O(C=O)O-, -C(=O)-, -O-, -O(CR 601 R 602 ) s O-, -S-, -C(=O)S-, -SC(=O)-, -NR 601 C(=O)-, -C(=O)NR 601 -, -NR 601 C(=O)NR 602 -, -NR 601 C(=S)-, -C(=S)NR 601 -, -NR 601 C(=S)NR 602 -, -OC(=O)NR 601 -, -NR 601 C(=O)O-, -SC(=O)NR 601 -OR-NR 601 C(=O)S-. L 7 is a bond, -O(C=O)-, -(C=O)O-, -O(C=O)O-, -C(=O)-, -O-, -O(CR 701 R 702 ) s O-, -S-, -C(=O)S-, -SC(=O)-, -NR 701 C(=O)-, -C(=O)NR 701 -, -NR 701 C(=O)NR 702 -, -NR 701 C(=S)-, -C(=S)NR 701 -, -NR 701 C(=S)NR 702 -, -OC(=O)NR 701 -, -NR 701 C(=O)O-, -SC(=O)NR 701 -OR-NR 701 C(=O)S-. L a1 and L a2 are each independently [ka] wherein each X is independently O, S, or CH. W 1 , W 2 , W3 , W 4 , W 5 , and W 6 are each independently a bond or a substituted or unsubstituted C1-C 12 It is alkylene, or a substituted or unsubstituted 2- to 12-membered heteroalkylene. Each R 1A and R 1B are independently H, substituted or unsubstituted C1-C 12 alkyl, or substituted or unsubstituted 2-12 membered heteroalkyl. Each R 2A , R 3A , R 4A , and R 5A are independently H, substituted or unsubstituted C1-C 30 alkyl, or substituted or unsubstituted 2-30 membered heteroalkyl. Each R 101 , R 102 , R 201 , R 202 , R 301 , R 302 , R 401 , R 402 , R 501 , R 502 , R 601 , R 602 , R 701 , and R 702 are independently H, substituted or unsubstituted C1-C 12 alkyl, or substituted or unsubstituted 2-12 membered heteroalkyl. Each s is independently an integer from 1 to 4.

[0109] In embodiments, R 1 are independently H, -OR 1A , -YOR 1A , -NR 1A R 1B , -YNR 1A R 1B , -SR 1A , -YSR 1A , -(C=O)R 1A , -Y(C=O)R 1A , -(C=O)OR 1A , -Y(C=O)OR1A , -O(C=O)R 1A , -YO(C=O)R 1A , -O(C=O)OR 1A , -YO(C=O)OR 1A , substituted (e.g., substituted with a substituent, a size-limited substituent or a lower substituent) or unsubstituted alkyl (e.g., C1-C 30 alkyl, C1-C8 alkyl, or C1-C4 alkyl), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl (e.g., 2-30 membered heteroalkyl, 2-8 membered heteroalkyl, or 2-4 membered heteroalkyl), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl) or substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl). 1 is substituted with one or more substituents. In embodiments, R 1 is substituted with one or more size-limited substituents. In embodiments, R 1 is substituted with one or more lower substituents.

[0110] In embodiments, R 1 is independently a substituted (e.g., substituted, size-limited or lower substituted) alkyl (e.g., C1-C 30 alkyl, C1-C8 alkyl, or C1-C4 alkyl).1 are independently unsubstituted alkyl (e.g., C1-C 30 alkyl, C1-C8 alkyl, or C1-C4 alkyl). 1 is independently a substituted (e.g., substituted, size-limited or lower substituted) heteroalkyl (e.g., 2-30 membered heteroalkyl, 2-8 membered heteroalkyl, or 2-4 membered heteroalkyl). 1 is independently an unsubstituted heteroalkyl (e.g., a 2- to 30-membered heteroalkyl, a 2- to 8-membered heteroalkyl, or a 2- to 4-membered heteroalkyl). 1 is independently a substituted (e.g., substituted, size-limited or lower substituted) cycloalkyl (e.g., C-C cycloalkyl, C-C cycloalkyl, or C-C cycloalkyl). 1 is independently unsubstituted cycloalkyl (e.g., C-C cycloalkyl, C-C cycloalkyl, or C-C cycloalkyl). 1 is independently a substituted (e.g., substituted, size-limited or lower substituted) heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl). 1 is independently an unsubstituted heterocycloalkyl (e.g., a 3- to 8-membered heterocycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkyl). 1 are independently substituted (e.g., substituted, size-limited or lower substituted) aryl (e.g., C 10 Aryl, C 10 aryl, or phenyl). In embodiments, R 1 are independently unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl). In embodiments, R 1is independently a substituted (e.g., substituted, size-limited or lower substituted) heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl). 1 is independently unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0111] In embodiments, R 1 are independently H, -OR 1A 、 or substituted or unsubstituted heteroalkyl. In embodiments, R 1 are independently H, -OR 1A 、 or substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl (e.g., 2-30 membered heteroalkyl, 2-8 membered heteroalkyl, or 2-4 membered heteroalkyl). 1 is independently H. In embodiments, R 1 are independently -OR 1A In an embodiment, R 1 is independently substituted or unsubstituted heteroalkyl. In embodiments, R 1 is independently substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl (e.g., 2-30 membered heteroalkyl, 2-8 membered heteroalkyl, or 2-4 membered heteroalkyl).

[0112] In embodiments, R 1 is independently H, -OH, methoxy, ethoxy, or substituted or unsubstituted heteroalkyl. 1 is independently -OH or methoxy.

[0113] In embodiments, R 1 is independently H. In embodiments, R 1 is independently -OH. In embodiments, R 1is independently methoxy. In embodiments, R 1 is independently ethoxy.

[0114] In embodiments, R 2 H, -OR 2A , -SR 2A , -(C=O)R 2A , -(C=O)OR 2A , -O(C=O)R 2A , -O(C=O)OR 2A , -(C=O)NHR 2A , -NH(C=O)R 2A , substituted (e.g., substituted with a substituent, a size-limited substituent or a lower substituent) or unsubstituted alkyl (e.g., C1-C 30 alkyl, C1-C8 alkyl, or C1-C4 alkyl), or substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl (e.g., 2-30 membered heteroalkyl, 2-8 membered heteroalkyl, or 2-4 membered heteroalkyl). 2 is substituted with one or more substituents. In embodiments, R 2 is substituted with one or more size-limited substituents. In embodiments, R 2 is substituted with one or more lower substituents.

[0115] In embodiments, R 2 is a substituted (e.g., substituted, size-limited or lower substituted) alkyl (e.g., C1-C 30 alkyl, C1-C8 alkyl, or C1-C4 alkyl). 2 is an unsubstituted alkyl (e.g., C1-C 30 alkyl, C1-C8 alkyl, or C1-C4 alkyl). 2 is a substituted (e.g., substituted, size-limited or lower substituted) heteroalkyl (e.g., 2-30 membered heteroalkyl, 2-8 membered heteroalkyl, or 2-4 membered heteroalkyl). 2is an unsubstituted heteroalkyl (e.g., a 2- to 30-membered heteroalkyl, a 2- to 8-membered heteroalkyl, or a 2- to 4-membered heteroalkyl).

[0116] In embodiments, R 2 is H or substituted or unsubstituted alkyl. In embodiments, R 2 is H or substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C1-C 12 alkyl, C1-C8 alkyl, or C1-C4 alkyl). 2 is H. In embodiments, R 2 is a substituted (e.g., substituted, size-limited or lower substituted) alkyl (e.g., C1-C 12 alkyl, C1-C8 alkyl, or C1-C4 alkyl). 2 is an unsubstituted alkyl (e.g., C1-C 12 alkyl, C1-C8 alkyl, or C1-C4 alkyl).

[0117] In embodiments, R 2 is H or substituted or unsubstituted C1-C 12 In embodiments, R 2 is substituted (e.g., substituted with a substituent, size-limited substituent or lower substituent) C1-C 12 In embodiments, R 2 is unsubstituted C1-C 12 It is an alkyl.

[0118] In embodiments, R 3 H, -OR 3A , -SR 3A , -(C=O)R 3A , -(C=O)OR 3A , -O(C=O)R 3A , -O(C=O)OR 3A , -(C=O)NHR 3A , -NH(C=O)R 3A, substituted (e.g., substituted with a substituent, a size-limited substituent or a lower substituent) or unsubstituted alkyl (e.g., C1-C 30 alkyl, C1-C8 alkyl, or C1-C4 alkyl), or substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl (e.g., 2-30 membered heteroalkyl, 2-8 membered heteroalkyl, or 2-4 membered heteroalkyl). 3 is substituted with one or more substituents. In embodiments, R 3 is substituted with one or more size-limited substituents. In embodiments, R 3 is substituted with one or more lower substituents.

[0119] In embodiments, R 3 is a substituted (e.g., substituted, size-limited or lower substituted) alkyl (e.g., C1-C 30 alkyl, C1-C8 alkyl, or C1-C4 alkyl). 3 is an unsubstituted alkyl (e.g., C1-C 30 alkyl, C1-C8 alkyl, or C1-C4 alkyl). 3 is a substituted (e.g., substituted, size-limited or lower substituted) heteroalkyl (e.g., 2-30 membered heteroalkyl, 2-8 membered heteroalkyl, or 2-4 membered heteroalkyl). 3 is an unsubstituted heteroalkyl (e.g., a 2- to 30-membered heteroalkyl, a 2- to 8-membered heteroalkyl, or a 2- to 4-membered heteroalkyl).

[0120] In embodiments, R 3 is H or substituted or unsubstituted alkyl. In embodiments, R 3 is H or substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C1-C 12 alkyl, C1-C8 alkyl, or C1-C4 alkyl). 3is H. In embodiments, R 3 is a substituted (e.g., substituted, size-limited or lower substituted) alkyl (e.g., C1-C 12 alkyl, C1-C8 alkyl, or C1-C4 alkyl). 3 is unsubstituted alkyl (e.g., C1-C 12 alkyl, C1-C8 alkyl, or C1-C4 alkyl).

[0121] In embodiments, R 3 is H or substituted or unsubstituted C1-C 12 In embodiments, R 3 is substituted (e.g., substituted with a substituent, size-limited substituent or lower substituent) C1-C 12 In embodiments, R 3 is unsubstituted C1~C 12 It is an alkyl.

[0122] In embodiments, R 4 H, -OR 4A , -SR 4A , -(C=O)R 4A , -(C=O)OR 4A , -O(C=O)R 4A , -O(C=O)OR 4A , -(C=O)NHR 4A , -NH(C=O)R 4A , substituted (e.g., substituted with a substituent, a size-limited substituent or a lower substituent) or unsubstituted alkyl (e.g., C1-C 30 alkyl, C1-C8 alkyl, or C1-C4 alkyl), or substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl (e.g., 2-30 membered heteroalkyl, 2-8 membered heteroalkyl, or 2-4 membered heteroalkyl). 4 is substituted with one or more substituents. In embodiments, R 4 is substituted with one or more size-limited substituents. In embodiments, R 4 is substituted with one or more lower substituents.

[0123] In embodiments, R 4 is a substituted (e.g., substituted, size-limited or lower substituted) alkyl (e.g., C1-C 30 alkyl, C1-C8 alkyl, or C1-C4 alkyl). 4 is unsubstituted alkyl (e.g., C1-C 30 alkyl, C1-C8 alkyl, or C1-C4 alkyl). 4 is a substituted (e.g., substituted, size-limited or lower substituted) heteroalkyl (e.g., 2-30 membered heteroalkyl, 2-8 membered heteroalkyl, or 2-4 membered heteroalkyl). 4 is an unsubstituted heteroalkyl (e.g., a 2- to 30-membered heteroalkyl, a 2- to 8-membered heteroalkyl, or a 2- to 4-membered heteroalkyl).

[0124] In embodiments, R 4 is H or substituted or unsubstituted alkyl. In embodiments, R 4 is H or substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C1-C 12 alkyl, C1-C8 alkyl, or C1-C4 alkyl). 4 is H. In embodiments, R 4 is a substituted (e.g., substituted, size-limited or lower substituted) alkyl (e.g., C1-C 12 alkyl, C1-C8 alkyl, or C1-C4 alkyl). 4 is unsubstituted alkyl (e.g., C1-C 12 alkyl, C1-C8 alkyl, or C1-C4 alkyl).

[0125] In embodiments, R 4 is H or substituted or unsubstituted C1-C 12 In embodiments, R 4is substituted (e.g., substituted with a substituent, size-limited substituent or lower substituent) C1-C 12 In embodiments, R 4 is unsubstituted C1~C 12 It is an alkyl.

[0126] In embodiments, R 5 H, -OR 5A , -SR 5A , -(C=O)R 5A , -(C=O)OR 5A , -O(C=O)R 5A , -O(C=O)OR 5A , -(C=O)NHR 5A , -NH(C=O)R 5A , substituted (e.g., substituted with a substituent, a size-limited substituent or a lower substituent) or unsubstituted alkyl (e.g., C1-C 30 alkyl, C1-C8 alkyl, or C1-C4 alkyl), or substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl (e.g., 2-30 membered heteroalkyl, 2-8 membered heteroalkyl, or 2-4 membered heteroalkyl). 5 is substituted with one or more substituents. In embodiments, R 5 is substituted with one or more size-limited substituents. In embodiments, R 5 is substituted with one or more lower substituents.

[0127] In embodiments, R 5 is a substituted (e.g., substituted, size-limited or lower substituted) alkyl (e.g., C1-C 30 alkyl, C1-C8 alkyl, or C1-C4 alkyl). 5 is unsubstituted alkyl (e.g., C1-C 30 alkyl, C1-C8 alkyl, or C1-C4 alkyl). 5is a substituted (e.g., substituted, size-limited or lower substituted) heteroalkyl (e.g., 2-30 membered heteroalkyl, 2-8 membered heteroalkyl, or 2-4 membered heteroalkyl). 5 is an unsubstituted heteroalkyl (e.g., a 2- to 30-membered heteroalkyl, a 2- to 8-membered heteroalkyl, or a 2- to 4-membered heteroalkyl).

[0128] In embodiments, R 5 is H or substituted or unsubstituted alkyl. In embodiments, R 5 is H or substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C1-C 12 alkyl, C1-C8 alkyl, or C1-C4 alkyl). 5 is H. In embodiments, R 5 is a substituted (e.g., substituted, size-limited or lower substituted) alkyl (e.g., C1-C 12 alkyl, C1-C8 alkyl, or C1-C4 alkyl). 5 is unsubstituted alkyl (e.g., C1-C 12 alkyl, C1-C8 alkyl, or C1-C4 alkyl).

[0129] In embodiments, R 5 is H or substituted or unsubstituted C1-C 12 In embodiments, R 5 is substituted (e.g., substituted with a substituent, size-limited substituent or lower substituent) C1-C 12 In embodiments, R 5 is unsubstituted C1~C 12 It is an alkyl.

[0130] In embodiments, Y is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted C0-C 12Alkylene or substituted (e.g., substituted with a substituent, a size-limiting substituent or a lower substituent) or unsubstituted 0-12 membered heteroalkylene. In embodiments, Y is substituted with one or more substituents. In embodiments, Y is substituted with one or more size-limiting substituents. In embodiments, Y is substituted with one or more lower substituents.

[0131] In embodiments, Y is a substituted (e.g., substituted, size-limited or lower substituted) C0-C 12 In an embodiment, Y is an unsubstituted C0-C 12 In an embodiment, Y is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) 0-12 membered heteroalkylene. In an embodiment, Y is an unsubstituted 0-12 membered heteroalkylene.

[0132] In an embodiment, Y is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) C1-C8 alkylene. In an embodiment, Y is an unsubstituted C1-C8 alkylene. In an embodiment, Y is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) 1-8 membered heteroalkylene. In an embodiment, Y is an unsubstituted 1-8 membered heteroalkylene.

[0133] In an embodiment, Y is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) C1-C4 alkylene. In an embodiment, Y is an unsubstituted C1-C4 alkylene. In an embodiment, Y is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) 1-4 membered heteroalkylene. In an embodiment, Y is an unsubstituted 1-4 membered heteroalkylene.

[0134] In embodiments, Y is substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) methylene, ethylene, or propylene. In embodiments, Y is unsubstituted methylene, ethylene, or propylene.

[0135] In an embodiment, B 1 is a bond, a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkylene (e.g., C1-C 30 alkylene, C1-C8 alkylene, or C1-C4 alkylene), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkylene (e.g., 2-30 membered heteroalkylene, 2-8 membered heteroalkylene, or 2-4 membered heteroalkylene), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted cycloalkylene (e.g., C3-C8 cycloalkylene, C3-C6 cycloalkylene, or C5-C6 cycloalkylene), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heterocycloalkylene (e.g., 3-8 membered heterocycloalkylene, 3-6 membered heterocycloalkylene, or 5-6 membered heterocycloalkylene), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted arylene (e.g., C6-C 10 Arylene, C 10 arylene, or phenylene), or substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroarylene (e.g., 5-10 membered heteroarylene, 5-9 membered heteroarylene, or 5-6 membered heteroarylene). 1 is substituted with one or more substituents. In embodiments, B 1 is substituted with one or more size-limited substituents. In embodiments, B 1 is substituted with one or more lower substituents. In embodiments, B 1 is a bond.

[0136] In an embodiment, B 1 is a substituted (e.g., substituted with a substituent, a size-limited substituent or a lower substituent) alkylene (e.g., C1-C 30 alkylene, C1-C8 alkylene, or C1-C4 alkylene). 1 is unsubstituted alkylene (e.g., C1-C30 alkylene, C1-C8 alkylene, or C1-C4 alkylene). 1 is a substituted (e.g., substituted, size-limited or lower substituted) heteroalkylene (e.g., 2-30 membered heteroalkylene, 2-8 membered heteroalkylene, or 2-4 membered heteroalkylene). 1 is unsubstituted heteroalkylene (e.g., 2- to 30-membered heteroalkylene, 2- to 8-membered heteroalkylene, or 2- to 4-membered heteroalkylene). 1 is a substituted (e.g., substituted, size-limited or lower substituted) cycloalkylene (e.g., C3-C8 cycloalkylene, C3-C6 cycloalkylene, or C5-C6 cycloalkylene). 1 is unsubstituted cycloalkylene (e.g., C3-C8 cycloalkylene, C3-C6 cycloalkylene, or C5-C6 cycloalkylene). 1 is a substituted (e.g., substituted, size-limited or lower substituted) heterocycloalkylene (e.g., 3-8 membered heterocycloalkylene, 3-6 membered heterocycloalkylene, or 5-6 membered heterocycloalkylene). 1 is unsubstituted heterocycloalkylene (e.g., 3- to 8-membered heterocycloalkylene, 3- to 6-membered heterocycloalkylene, or 5- to 6-membered heterocycloalkylene). 1 is a substituted (e.g., substituted with a substituent, a size-limited substituent or a lower substituent) arylene (e.g., C 10 Arylene, C 10 arylene, or phenylene). In an embodiment, B 1 is unsubstituted arylene (e.g., C6-C 10 Arylene, C 10 arylene, or phenylene). In an embodiment, B 1is a substituted (e.g., substituted, size-limited or lower substituted) heteroarylene (e.g., 5-10 membered heteroarylene, 5-9 membered heteroarylene, or 5-6 membered heteroarylene). 1 is unsubstituted heteroarylene (eg, 5- to 10-membered heteroarylene, 5- to 9-membered heteroarylene, or 5- to 6-membered heteroarylene).

[0137] In an embodiment, B 1 is a bond or substituted or unsubstituted alkylene. In embodiments, B 1 is a bond or a substituted (e.g., substituted with a substituent, a size-limited substituent or a lower substituent) or unsubstituted alkylene (e.g., C1-C 30 alkylene, C1-C8 alkylene, or C1-C4 alkylene).

[0138] In an embodiment, B 1 is a bond or unsubstituted alkylene. In embodiments, B 1 is a bond or unsubstituted C1-C8 alkylene. 1 is unsubstituted alkylene. In embodiments, B 1 is unsubstituted C1-C8 alkylene. 1 is a bond.

[0139] In an embodiment, B 2 and B. 3 Each is independently a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. 2 and B. 3 are each independently a bond, a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkylene (e.g., C1-C 30alkylene, C1-C8 alkylene, or C1-C4 alkylene), or substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkylene (e.g., 2-30 membered heteroalkylene, 2-8 membered heteroalkylene, or 2-4 membered heteroalkylene). 2 is substituted with one or more substituents. In embodiments, B 2 is substituted with one or more size-limited substituents. In embodiments, B 2 is substituted with one or more lower substituents. In embodiments, B 2 is a bond. In embodiments, B 3 is substituted with one or more substituents. In embodiments, B 3 is substituted with one or more size-limited substituents. In embodiments, B 3 is substituted with one or more lower substituents. In embodiments, B 3 is a bond.

[0140] In an embodiment, B 2 is a substituted (e.g., substituted with a substituent, a size-limited substituent or a lower substituent) alkylene (e.g., C1-C 30 alkylene, C1-C8 alkylene, or C1-C4 alkylene). 2 is unsubstituted alkylene (e.g., C1-C 30 alkylene, C1-C8 alkylene, or C1-C4 alkylene). 2 is a substituted (e.g., substituted, size-limited or lower substituted) heteroalkylene (e.g., 2-30 membered heteroalkylene, 2-8 membered heteroalkylene, or 2-4 membered heteroalkylene). 2 is unsubstituted heteroalkylene (eg, 2- to 30-membered heteroalkylene, 2- to 8-membered heteroalkylene, or 2- to 4-membered heteroalkylene).

[0141] In an embodiment, B 3is a substituted (e.g., substituted with a substituent, a size-limited substituent or a lower substituent) alkylene (e.g., C1-C 30 alkylene, C1-C8 alkylene, or C1-C4 alkylene). 3 is unsubstituted alkylene (e.g., C1-C 30 alkylene, C1-C8 alkylene, or C1-C4 alkylene). 3 is a substituted (e.g., substituted, size-limited or lower substituted) heteroalkylene (e.g., 2-30 membered heteroalkylene, 2-8 membered heteroalkylene, or 2-4 membered heteroalkylene). 3 is unsubstituted heteroalkylene (eg, 2- to 30-membered heteroalkylene, 2- to 8-membered heteroalkylene, or 2- to 4-membered heteroalkylene).

[0142] In an embodiment, B 2 and B. 3 are each independently a bond or substituted or unsubstituted alkylene. 2 and B. 3 are each independently a bond or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkylene (e.g., C1-C 30 alkylene, C1-C8 alkylene, or C1-C4 alkylene).

[0143] In an embodiment, B 2 and B. 3 are each independently a bond or a substituted or unsubstituted C1-C8 alkylene. 2 and B. 3 are each independently a bond or substituted (eg, substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted C1-C8 alkylene.

[0144] In an embodiment, B 2 is a bond. In embodiments, B 2 is a substituted C1-C8 alkylene.2 is unsubstituted C1-C8 alkylene. 3 is a bond. In embodiments, B 3 is a substituted C1-C8 alkylene. 3 is unsubstituted C1-C8 alkylene.

[0145] In an embodiment, B 2 is butylene. In an embodiment, B 2 is propylene. In an embodiment, B 2 is ethylene. In an embodiment, B 2 is methylene. In embodiments, B 3 is butylene. In an embodiment, B 3 is propylene. In an embodiment, B 3 is ethylene. In an embodiment, B 3 is methylene.

[0146] In an embodiment, L 2 is a bond, -O(C=O)-, -(C=O)O-, -O(C=O)O-, -C(=O)-, -O-, or -S-. 2 is a bond, -O(C=O)-, -(C=O)O-, or -C(=O)-. In embodiments, L 2 is a bond, -O(C=O)- or -(C=O)O-.

[0147] In an embodiment, L 1 is a bond, -NR 101 C(=S)-, -C(=S)NR 101 In an embodiment, L is -, -O(C=O)-, -(C=O)O-, or -O-. 1 is a bond, -NR 101 C(=S)- or -C(=S)NR 101 -It is.

[0148] In an embodiment, L 1 is a bond. In embodiments, L 1 -NR 101 C(=S)-. In an embodiment, L 1 is -C(=S)NR101 In an embodiment, L 1 is -O(C=O)-. In embodiments, L 1 is -(C=O)O-. In embodiments, L 1 In embodiments, L is -O-. 1 is -C(=S)NR 101 and in formula (I) the carbon atom is linked to a nitrogen atom. 1 is -C(=S)NH, where the carbon atom is linked to the nitrogen atom in formula (I).

[0149] In an embodiment, each R 101 are independently H, substituted or unsubstituted C1-C 12 In an embodiment, each R 101 are independently H, substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted C-C 12 In an embodiment, each R 101 is substituted with one or more substituents. In embodiments, each R 101 is substituted with one or more size-limited substituents. In embodiments, each R 101 is substituted with one or more lower substituents.

[0150] In an embodiment, each R 101 is independently H or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted 2-12 membered heteroalkyl. 101 is independently substituted (eg, substituted with a substituted group, a size-limited substituent, or a lower substituent) or unsubstituted 2-12 membered heteroalkyl.

[0151] In an embodiment, each R 101 is independently H. In an embodiment, each R 101is independently a substituted (e.g., substituted, size-limited or lower substituted) 2-12 membered heteroalkyl. 101 is independently unsubstituted 2-12 membered heteroalkyl.

[0152] In an embodiment, L 2 is a bond. In embodiments, L 2 is -O(C=O)-. In embodiments, L 2 is -(C=O)O-. In embodiments, L 2 is -C(=O)-. In embodiments, L 2 is -O(C=O)O-. In embodiments, L 2 In embodiments, L is -S-. 2 is -O-.

[0153] In an embodiment, L 3 is a bond, -O(C=O)-, -(C=O)O-, -O(C=O)O-, -C(=O)-, -O-, or -S-. 3 is a bond, -O(C=O)-, -(C=O)O-, or -C(=O)-. In embodiments, L 3 is a bond, -O(C=O)- or -(C=O)O-.

[0154] In an embodiment, L 3 is a bond. In embodiments, L 3 is -O(C=O)-. In embodiments, L 3 is -(C=O)O-. In embodiments, L 3 is -C(=O)-. In embodiments, L 3 is -O(C=O)O-. In embodiments, L 3 In embodiments, L is -S-. 3 is -O-.

[0155] In an embodiment, L 4 is a bond, -O(C=O)-, -(C=O)O-, -O(C=O)O-, -C(=O)-, -O-, or -S-. 4is a bond, -O(C=O)-, -(C=O)O-, or -C(=O)-. In embodiments, L 4 is a bond, -O(C=O)- or -(C=O)O-.

[0156] In an embodiment, L 4 is a bond. In embodiments, L 4 is -O(C=O)-. In embodiments, L 4 is -(C=O)O-. In embodiments, L 4 is -C(=O)-. In embodiments, L 4 is -O(C=O)O-. In embodiments, L 4 In embodiments, L is -S-. 4 is -O-.

[0157] In an embodiment, L 5 is a bond, -O(C=O)-, -(C=O)O-, -O(C=O)O-, -C(=O)-, -O-, or -S-. 5 is a bond, -O(C=O)-, -(C=O)O-, or -C(=O)-. In embodiments, L 5 is a bond, -O(C=O)- or -(C=O)O-.

[0158] In an embodiment, L 5 is a bond. In embodiments, L 5 is -O(C=O)-. In embodiments, L 5 is -(C=O)O-. In embodiments, L 5 is -C(=O)-. In embodiments, L 5 is -O(C=O)O-. In embodiments, L 5 In embodiments, L is -S-. 5 is -O-.

[0159] In an embodiment, L 6 is a bond, -O(C=O)-, -(C=O)O-, -O(C=O)O-, -C(=O)-, -O-, or -S-. 6is a bond, -O(C=O)-, -(C=O)O-, or -C(=O)-. In embodiments, L 6 is a bond, -O(C=O)- or -(C=O)O-.

[0160] In an embodiment, L 6 is a bond. In embodiments, L 6 is -O(C=O)-. In embodiments, L 6 is -(C=O)O-. In embodiments, L 6 is -C(=O)-. In embodiments, L 6 is -O(C=O)O-. In embodiments, L 6 In embodiments, L is -S-. 6 is -O-.

[0161] In an embodiment, L 7 is a bond, -O(C=O)-, -(C=O)O-, -O(C=O)O-, -C(=O)-, -O-, or -S-. 7 is a bond, -O(C=O)-, -(C=O)O-, or -C(=O)-. In embodiments, L 7 is a bond, -O(C=O)- or -(C=O)O-.

[0162] In an embodiment, L 7 is a bond. In embodiments, L 7 is -O(C=O)-. In embodiments, L 7 is -(C=O)O-. In embodiments, L 7 is -C(=O)-. In embodiments, L 7 is -O(C=O)O-. In embodiments, L 7 In embodiments, L is -S-. 7 is -O-.

[0163] In an embodiment, L a1 and L a2 are each independently [ka] wherein each X is independently O or S. In embodiments, L a1 and L a2 are each independently [ka] wherein each X is independently O or S. In embodiments, L a1 and L a2 are each independently [ka] wherein each X is independently O.

[0164] In an embodiment, L a1 and L a2 are each independently [ka] In an embodiment, L a1 and L a2 are each independently [ka] In an embodiment, L a1 and L a2 are each independently [ka] In an embodiment, L a1 and L a2 are each independently [ka] In an embodiment, L a1 and L a2 are each independently [ka] In an embodiment, L a1 and L a2 are each independently [ka] In an embodiment, L a1 and L a2 are each independently [ka] In an embodiment, L a1 and L a2 are each independently [ka] It is.

[0165] In the embodiment, W 1 , W 2 , W 3 , W 4 , W 5 , and W 6 are each independently a bond, a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted C1-C 12 alkylene, or substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted 2-12 membered heteroalkylene. 1 , W 2 , W 3 , W 4 , W 5 , and W 6 is each independently substituted with one or more substituents. 1 , W 2 , W 3 , W 4 , W 5 , and W 6 is each independently substituted with one or more size-limited substituents. 1 , W 2 , W 3 , W 4 , W 5 , and W 6 is each independently substituted with one or more lower substituents.

[0166] In the embodiment, W 1 , W 2 , W 3 , W 4 , W 5 , and W 6 are each independently a bond or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted C1-C 12 In embodiments, W is an alkylene. 1 , W 2 , W 3 , W 4 , W 5 , and W 6 are each independently a bond. 1 , W 2 , W 3 , W 4 , W 5 , and W 6 are each independently substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) C1-C 12 In embodiments, W is an alkylene. 1 , W 2 , W 3 , W 4 , W 5 , and W 6 are each independently unsubstituted C1 to C 12 It is alkylene.

[0167] In an embodiment, each R 1A and R 1B are independently H, substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted C-C 12 alkyl, or substituted (e.g., substituted, size-limited or lower substituted) or unsubstituted 2-12 membered heteroalkyl. 1A and R 1B is independently substituted with one or more substituents. In embodiments, each R 1A and R 1B is independently substituted with one or more size-limited substituents. In embodiments, each R 1Aand R 1B is independently substituted with one or more lower substituents.

[0168] In an embodiment, R 1A and R 1B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered) or a substituted or unsubstituted heteroaryl (e.g., 5-12 membered, 5-10 membered, 5-9 membered, or 5-6 membered). In embodiments, R 1A and R 1B The substituted heterocycloalkyl or substituted heteroaryl formed by linking the substituents is substituted with at least one substituent, size-limiting substituent, or lower-rank substituent, and the substituted heterocycloalkyl or substituted heteroaryl is substituted with multiple groups selected from substituents, size-limiting substituents, and lower-rank substituents, and each substituent, size-limiting substituent, and / or lower-rank substituent may be optionally different. In an embodiment, R 1A and R 1B When the heterocycloalkyl formed by linking the substituents is substituted, the heterocycloalkyl is substituted with at least one substituent. In an embodiment, R 1A and R 1B If the heterocycloalkyl formed by linking the substituents is substituted, the heterocycloalkyl is substituted with at least one size-limited substituent. In embodiments, R 1A and R 1B When the heterocycloalkyl formed by linking the substituents is substituted, the heterocycloalkyl is substituted with at least one lower substituent. In an embodiment, R 1A and R 1B When the heteroaryl formed by linking the substituents is substituted, the heteroaryl is substituted with at least one substituent. In an embodiment, R1A and R 1B If the heteroaryl formed by linking the substituents is substituted, the heteroaryl is substituted with at least one size-limited substituent. In embodiments, R 1A and R 1B When the heteroaryl formed by linking the substituents is substituted, the heteroaryl is substituted with at least one lower substituent.

[0169] In an embodiment, each R 1A are independently H or substituted or unsubstituted C1-C 12 In embodiments, each R 1A are independently H or substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted C1-C 12 In embodiments, each R 1A is independently H. In an embodiment, each R 1A are independently substituted (e.g., substituted with a substituent, a size-limited substituent or a lower substituent) C1-C 12 In embodiments, each R 1A are independently unsubstituted C1 to C 12 It is an alkyl.

[0170] In embodiments, R 1 H, -OR 1A Or substituted or unsubstituted heteroalkyl. L 1 is a bond, -NR 101 C(=S)-, -C(=S)NR 101 -, -O(C=O)-, -(C=O)O-, or -O-. B 1 is a bond or substituted or unsubstituted alkylene. B 2 and B. 3 are each independently a bond or substituted or unsubstituted alkylene. L 2is a bond, -O(C=O)-, -(C=O)O-, -O(C=O)O-, -C(=O)-, -O-, or -S-. L 4 is a bond, -O(C=O)-, -(C=O)O-, -O(C=O)O-, -C(=O)-, -O-, or -S-. W 1 , W 2 , W 3 , W 4 , W 5 , and W 6 each independently represents a bond or a substituted or unsubstituted C1-C 12 It is alkylene. L a1 and L a2 are each independently [ka] wherein each X is independently O or S. L 3 is a bond, -O(C=O)-, -(C=O)O-, -O(C=O)O-, -C(=O)-, -O-, or -S-. L 5 is a bond, -O(C=O)-, -(C=O)O-, -O(C=O)O-, -C(=O)-, -O-, or -S-. L 6 is a bond, -O(C=O)-, -(C=O)O-, -O(C=O)O-, -C(=O)-, -O-, or -S-. L 7 is a bond, -O(C=O)-, -(C=O)O-, -O(C=O)O-, -C(=O)-, -O-, or -S-. R 2 is H or substituted or unsubstituted alkyl. R 3 is H or substituted or unsubstituted alkyl. R 4 is H or substituted or unsubstituted alkyl. R 5 is H or substituted or unsubstituted alkyl. Each R 1Aare independently H or substituted or unsubstituted C1-C 12 is alkyl, Each R 101 is independently H or substituted or unsubstituted 2-12 membered heteroalkyl.

[0171] In embodiments, R 1 is H, --OH, methoxy, ethoxy, or substituted or unsubstituted heteroalkyl. L 1 is a bond, -NR 101 C(=S)- or -C(=S)NR 101 -It is. B 1 is a bond or unsubstituted C1-C8 alkylene. B 2 and B. 3 are each independently a bond or a substituted or unsubstituted C1 to C8 alkylene. L 2 is a bond, -O(C=O)-, or -(C=O)O-. L 4 is a bond, -O(C=O)-, or -(C=O)O-. W 1 , W 2 , W 3 , W 4 , W 5 , and W 6 each independently represents a bond or a substituted or unsubstituted C1-C 12 It is alkylene. L a1 and L a2 are each independently [ka] wherein each X is independently O or S. L 3 is a bond, -O(C=O)-, or -(C=O)O-. L 5 is a bond, -O(C=O)-, or -(C=O)O-. L 6is a bond, -O(C=O)-, or -(C=O)O-. L 7 is a bond, -O(C=O)-, or -(C=O)O-. R 2 is H or substituted or unsubstituted C1-C 12 It is an alkyl. R 3 is H or substituted or unsubstituted C1-C 12 It is an alkyl. R 4 is H or substituted or unsubstituted C1-C 12 It is an alkyl. R 5 is H or substituted or unsubstituted C1-C 12 is alkyl, Each R 101 is independently substituted or unsubstituted 2-12 membered heteroalkyl.

[0172] In embodiments, R 1 is -OH or methoxy. 1 is a bond. B 1 is unsubstituted C1-C8 alkylene. B 2 and B. 3 are each independently a bond or a substituted or unsubstituted C1 to C8 alkylene. L 2 is a bond. L 4 is a bond. W 1 , W 2 , W 3 , W 4 , W 5 , and W 6 each independently represents a bond or a substituted or unsubstituted C1-C 12 It is alkylene. L a1 and L a2 are each independently [ka] wherein each X is independently O. L 3 is a bond. L 5 is a bond. L 6 is a bond. L 7 is a bond. R 2 is H or substituted or unsubstituted C1-C 12 It is an alkyl group. 3 is H or substituted or unsubstituted C1-C 12 It is an alkyl. R 4 is H or substituted or unsubstituted C1-C 12 is alkyl, R 5 is H or substituted or unsubstituted C1-C 12 It is an alkyl.

[0173] In embodiments, R 1 is a substituted or unsubstituted heteroalkyl. L 1 is -C(=S)NR 101 -, in which the carbon atom is linked to the nitrogen atom in formula (I). B 1 is a bond. B 2 and B. 3 Each of L is independently a bond or a substituted or unsubstituted C1 to C8 alkylene. 2 is a bond, -O(C=O)-, or -(C=O)O-. 4 is a bond, -O(C=O)-, or -(C=O)O-. W 1 , W 2 , W 3 , W 4 , W 5 , and W 6 each independently represents a bond or a substituted or unsubstituted C1-C 12 It is alkylene. L a1 and L a2 are each independently [ka] (wherein each X is independently O). 3 is a bond. L 5 is a bond. L 6 is a bond. L 7 is a bond. R 2 is H or substituted or unsubstituted C1-C 12 It is an alkyl. R 3 is H or substituted or unsubstituted C1-C 12 It is an alkyl group. 4 is H or substituted or unsubstituted C1-C 12 is alkyl, R 5 is H or substituted or unsubstituted C1-C 12 It is an alkyl.

[0174] In an embodiment, each R 2A , R 3A , R 4A , and R 5A are independently H, substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted C-C 30 alkyl, or substituted (e.g., substituted, size-limited or lower substituted) or unsubstituted 2-30 membered heteroalkyl. 2A , R 3A , R 4A , and R 5A is independently H. In an embodiment, each R 2A , R 3A , R 4A , and R 5A are independently substituted (e.g., substituted with a substituent, a size-limited substituent or a lower substituent) C1-C 30 In embodiments, each R 2A , R 3A , R 4A , and R 5A are independently unsubstituted C1 to C 30 In embodiments, each R 2A , R 3A , R 4A , and R 5Ais independently a substituted (e.g., substituted, size-limited or lower substituted) 2-30 membered heteroalkyl. 2A , R 3A , R 4A , and R 5A is independently unsubstituted 2-30 membered heteroalkyl.

[0175] In an embodiment, each R 102 , R 201 , R 202 , R 301 , R 302 , R 401 , R 402 , R 501 , R 502 , R 601 , R 602 , R 701 , and R 702 are independently H, substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted C-C 12 alkyl, or substituted (e.g., substituted, size-limited or lower substituted) or unsubstituted 2-12 membered heteroalkyl. 102 , R 201 , R 202 , R 301 , R 302 , R 401 , R 402 , R 501 , R 502 , R 601 , R 602 , R 701 , and R 702 is independently H. In an embodiment, each R 102 , R 201 , R 202 , R 301 , R 302 , R 401 , R 402 , R 501 , R 502 , R 601 , R 602 , R 701 , and R 702 are independently substituted (e.g., substituted with a substituent, a size-limited substituent or a lower substituent) C1-C12 In embodiments, each R 102 , R 201 , R 202 , R 301 , R 302 , R 401 , R 402 , R 501 , R 502 , R 601 , R 602 , R 701 , and R 702 are independently unsubstituted C1 to C 12 In embodiments, each R 102 , R 201 , R 202 , R 301 , R 302 , R 401 , R 402 , R 501 , R 502 , R 601 , R 602 , R 701 , and R 702 is independently a substituted (e.g., substituted, size-limited or lower substituted) 2-12 membered heteroalkyl. 102 , R 201 , R 202 , R 301 , R 302 , R 401 , R 402 , R 501 , R 502 , R 601 , R 602 , R 701 , and R 702 is independently unsubstituted 2-12 membered heteroalkyl.

[0176] In an embodiment, each s is an integer from 1 to 4. In an embodiment, each s is 1. In an embodiment, each s is 2. In an embodiment, each s is 3. In an embodiment, each s is 4.

[0177] In embodiments, the cationic lipid of formula (I) is [ka] or a pharma- ceutically acceptable salt thereof.

[0178] In one embodiment, a cationic lipid of formula (II): [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, stereoisomer, or prodrug thereof provided herein. B 4 W 7 -L a3 -W 8 And W 7 and W 8 are each independently a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; L a3 is a bond, -O(C=O)-, -(C=O)O-, -O(C=O)O-, -C(=O)-, -O-, -O(CR a31 R a32 ) s O-, -S-, -C(=O)S-, -SC(=O)-, -NR a31 C(=O)-, -C(=O)NR a31 -, -NR a31 C(=O)NR a32 -, -NR a31 C(=S)-, -C(=S)NR a31 -, -NR a31 C(=S)NR a32 -, -OC(=O)NR a31 -, -NR a31 C(=O)O-, -SC(=O)NR a31 -OR-NR a31 C(=O)S-. R 10 and R 11 are each independently H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or R 10 and R 11 together with the nitrogen atom to which they are attached form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. B 5 , B 6 , and B.7 are each independently a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. L 8 is a bond, -O(C=O)-, -(C=O)O-, -O(C=O)O-, -C(=O)-, -O-, -O(CR 801 R 802 ) s O-, -S-, -C(=O)S-, -SC(=O)-, -NR 801 C(=O)-, -C(=O)NR 801 -, -NR 801 C(=O)NR 802 -, -NR 801 C(=S)-, -C(=S)NR 801 -, -NR 801 C(=S)NR 802 -, -OC(=O)NR 801 -, -NR 801 C(=O)O-, -SC(=O)NR 801 -OR-NR 801 C(=O)S-. L 9 is a bond, -O(C=O)-, -(C=O)O-, -O(C=O)O-, -C(=O)-, -O-, -O(CR 901 R 902 ) s O-, -S-, -C(=O)S-, -SC(=O)-, -NR 901 C(=O)-, -C(=O)NR 901 -, -NR 901 C(=O)NR 902 -, -NR 901 C(=S)-, -C(=S)NR 901 -, -NR 901 C(=S)NR 902 -, -OC(=O)NR 901 -, -NR 901 C(=O)O-, -SC(=O)NR 901 -OR-NR 901 C(=O)S-. L 10 is a bond, -O(C=O)-, -(C=O)O-, -O(C=O)O-, -C(=O)-, -O-, -O(CR 110 R 111 )s O-, -S-, -C(=O)S-, -SC(=O)-, -NR 110 C(=O)-, -C(=O)NR 110 -, -NR 110 C(=O)NR 111 -, -NR 110 C(=S)-, -C(=S)NR 110 -, -NR 110 C(=S)NR 111 -, -OC(=O)NR 110 -, -NR 110 C(=O)O-, -SC(=O)NR 110 -OR-NR 110 C(=O)S-. R 7 , R 8 , and R 9 are each independently H, substituted or unsubstituted C1-C 30 alkyl, or substituted or unsubstituted 2-30 membered heteroalkyl. Each R a31 and R a32 are independently H, substituted or unsubstituted C1-C 12 alkyl, or substituted or unsubstituted 2-12 membered heteroalkyl. Each R 801 , R 802 , R 901 , R 902 , R 110 , and R 111 are independently H, substituted or unsubstituted C1-C 12 alkyl, or substituted or unsubstituted 2-12 membered heteroalkyl. Each s is independently an integer from 1 to 4.

[0179] In the embodiment, W 7 and W 8 are each independently a bond or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkylene (e.g., C1-C 30alkylene, C1-C8 alkylene, or C1-C4 alkylene), or substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkylene (e.g., 2-30 membered heteroalkylene, 2-8 membered heteroalkylene, or 2-4 membered heteroalkylene). 7 and W 8 is each independently substituted with one or more substituents. 7 and W 8 is each independently substituted with one or more size-limited substituents. 7 and W 8 is each independently substituted with one or more lower substituents.

[0180] In the embodiment, W 7 and W 8 are each independently a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) alkylene (e.g., C 30 alkylene, C1-C8 alkylene, or C1-C4 alkylene). 7 and W 8 are each independently an unsubstituted alkylene (e.g., C1-C 30 alkylene, C1-C8 alkylene, or C1-C4 alkylene). 7 and W 8 are each independently a substituted (e.g., substituted, size-limited or lower) heteroalkylene (e.g., 2-30 membered heteroalkylene, 2-8 membered heteroalkylene, or 2-4 membered heteroalkylene). 7 and W 8 are each independently unsubstituted heteroalkylene (e.g., 2- to 30-membered heteroalkylene, 2- to 8-membered heteroalkylene, or 2- to 4-membered heteroalkylene). 7 and W 8 are each independently a bond.

[0181] In the embodiment, W 7 and W 8 are each independently a bond or a substituted or unsubstituted C1-C8 alkylene. 7 and W 8 are each independently a substituted (e.g., substituted, size-limited or lower) C1-C8 alkylene. 7 and W 8 are each independently unsubstituted C1 to C8 alkylene.

[0182] In the embodiment, W 7 and W 8 are each independently a bond or a substituted or unsubstituted C2-C4 alkylene. 7 and W 8 are each independently a substituted (e.g., substituted, size-limited or lower) C2-C4 alkylene. 7 and W 8 are each independently unsubstituted C2 to C4 alkylene.

[0183] In the embodiment, W 7 and W 8 are each independently a bond or an unsubstituted C2-C4 alkylene. 7 and W 8 are each independently a bond, ethylene, propylene, butylene, substituted ethylene (e.g., substituted with a substituent, a size-limiting substituent or a lower substituent), substituted propylene (e.g., substituted with a substituent, a size-limiting substituent or a lower substituent), or substituted butylene (e.g., substituted with a substituent, a size-limiting substituent or a lower substituent).

[0184] In an embodiment, L a3 is a bond, -O(C=O)-, -(C=O)O-, -O(C=O)O-, or -C(=O)-. In embodiments, L a3 is a bond. In embodiments, L a3 is -O(C=O)-. In embodiments, La3 is -(C=O)O-. In embodiments, L a3 is -O(C=O)O-. In embodiments, L a3 is -C(=O)-.

[0185] In embodiments, R 10 and R 11 are each independently H, substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C1-C 30 alkyl, C1-C8 alkyl, or C1-C4 alkyl), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl (e.g., 2-30 membered heteroalkyl, 2-8 membered heteroalkyl, or 2-4 membered heteroalkyl), or 10 and R 11 are taken together with the nitrogen atom to which they are attached to form a substituted (e.g., substituted with a substituent, size-limited substituent or lower substituent) or unsubstituted heterocycloalkyl (e.g., a 3- to 8-membered heterocycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkyl) or a substituted (e.g., substituted with a substituent, size-limited substituent or lower substituent) or unsubstituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). In embodiments, R 10 and R 11 is each independently substituted with one or more substituents. 10 and R 11 are each independently substituted with one or more size-limited substituents. 10 and R 11 is each independently substituted with one or more lower substituents.

[0186] In embodiments, R 10 and R 11 are each independently a substituted (e.g., substituted, size-limited or lower substituted) alkyl (e.g., C1-C 30alkyl, C1-C8 alkyl, or C1-C4 alkyl). 10 and R 11 are each independently an unsubstituted alkyl (e.g., C1-C 30 alkyl, C1-C8 alkyl, or C1-C4 alkyl). 10 and R 11 are each independently a substituted (e.g., substituted, size-limited or lower substituted) heteroalkyl (e.g., 2-30 membered heteroalkyl, 2-8 membered heteroalkyl, or 2-4 membered heteroalkyl). 10 and R 11 are each independently an unsubstituted heteroalkyl (e.g., a 2- to 30-membered heteroalkyl, a 2- to 8-membered heteroalkyl, or a 2- to 4-membered heteroalkyl). 10 and R 11 The substituted heterocycloalkyl or substituted heteroaryl formed by linking groups is substituted with at least one substituent, size-limiting substituent, or lower-class substituent. When the substituted heterocycloalkyl or substituted heteroaryl is substituted with multiple groups selected from substituents, size-limiting substituents, and lower-class substituents, each substituent, size-limiting substituent, and / or lower-class substituent may be different, if desired. In an embodiment, R 1 and R 2 bound to the same nitrogen atom are substituted with at least one of the following: 10 and R 11 When the heterocycloalkyl formed by linking the groups is substituted, the heterocycloalkyl is substituted with at least one substituent. In embodiments, R 10 and R 11 If the heterocycloalkyl formed by linking the groups is substituted, the heterocycloalkyl is substituted with at least one size-limited substituent. In embodiments, R 10 and R 11When the heterocycloalkyl formed by linking the groups is substituted, the heterocycloalkyl is substituted with at least one lower substituent. In embodiments, R 10 and R 11 When the heteroaryl formed by linking the groups is substituted, the heteroaryl is substituted with at least one substituent. In embodiments, R 10 and R 11 If the heteroaryl formed by linking the groups is substituted, the heteroaryl is substituted with at least one size-limited substituent. In embodiments, R 10 and R 11 When the heteroaryl formed by linking the groups is substituted, the heteroaryl is substituted with at least one lower substituent.

[0187] In embodiments, R 10 and R 11 together with the nitrogen atom to which they are attached form a substituted (e.g., substituted, size-limited or lower substituted) heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl). 10 and R 11 together with the nitrogen atom to which they are attached form an unsubstituted heterocycloalkyl (e.g., a 3- to 8-membered heterocycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkyl). 10 and R 11 taken together with the nitrogen atom to which they are attached form a substituted (e.g., substituted, size-limited or lower substituted) heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl). 10 and R 11together with the nitrogen atom to which they are attached form an unsubstituted heteroaryl (eg, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl).

[0188] In embodiments, R 10 and R 11 are each independently H, substituted or unsubstituted alkyl, or R 10 and R 11 taken together with the nitrogen atom to which they are attached form a substituted or unsubstituted heterocycloalkyl. 10 and R 11 are each independently H, substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C1-C 30 alkyl, C1-C8 alkyl, or C1-C4 alkyl) or R 10 and R 11 taken together with the nitrogen atom to which they are attached form a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heterocycloalkyl. In embodiments, R 10 and R 11 are each independently H.

[0189] In embodiments, R 10 and R 11 are each independently substituted or unsubstituted alkyl, or R 10 and R 11 taken together with the nitrogen atom to which they are attached form a substituted or unsubstituted heterocycloalkyl. 10 and R 11 are each independently substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C1-C 30 alkyl, C1-C8 alkyl, or C1-C4 alkyl) or R 10 and R 11together with the nitrogen atom to which they are attached form a substituted or unsubstituted heterocycloalkyl (eg, a 3- to 8-membered heterocycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkyl).

[0190] In embodiments, R 10 and R 11 are each independently substituted or unsubstituted methyl, ethyl, propyl, isopropyl, butyl, pentyl, or hexyl. 10 and R 11 are each independently substituted or unsubstituted methyl, ethyl, or propyl.

[0191] In embodiments, R 10 and R 11 are each independently substituted or unsubstituted methyl, ethyl, propyl, isopropyl, or R 10 and R 11 together with the nitrogen atom to which they are attached form a substituted or unsubstituted 3- to 8-membered heterocycloalkyl.

[0192] In embodiments, R 10 and R 11 are each independently substituted or unsubstituted methyl, ethyl, propyl, isopropyl, or R 10 and R 11 together with the nitrogen atom to which they are attached form a substituted (eg, substituted with a substituted group, a size-limited substituent or a lower substituent) or unsubstituted 3-8 membered heterocycloalkyl.

[0193] In embodiments, R 10 and R 11 are each independently substituted or unsubstituted methyl, ethyl, propyl, isopropyl, or R 10 and R 11 together with the nitrogen atom to which they are attached form a substituted or unsubstituted 5- to 6-membered heterocycloalkyl.

[0194] In embodiments, R 10 and R 11 are each independently substituted or unsubstituted methyl, ethyl, propyl, isopropyl, or R 10 and R 11 taken together with the nitrogen atom to which they are attached form a substituted (eg, substituted with a substituted group, a size-limited substituent or a lower substituent) or unsubstituted 5-6 membered heterocycloalkyl.

[0195] In embodiments, R 10 and R 11 taken together with the nitrogen atom to which they are attached form a substituted (e.g., substituted, size-limited or lower substituted) 5-6 membered heterocycloalkyl. 10 and R 11 taken together with the nitrogen atom to which they are attached form an unsubstituted 5-6 membered heterocycloalkyl.

[0196] In an embodiment, B 5 , B 6 , and B. 7 are each independently a bond, a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkylene (e.g., C1-C 30 alkylene, C1-C8 alkylene, or C1-C4 alkylene), or substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkylene (e.g., 2-30 membered heteroalkylene, 2-8 membered heteroalkylene, or 2-4 membered heteroalkylene). 5 , B 6 , and B. 7 is each independently substituted with one or more substituents. 5 , B 6 , and B. 7 is each independently substituted with one or more size-limited substituents. 5 , B 6 , and B. 7is each independently substituted with one or more lower substituents.

[0197] In an embodiment, B 5 , B 6 , and B. 7 are each independently a bond. 5 , B 6 , and B. 7 are each independently a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) alkylene (e.g., C 30 alkylene, C1-C8 alkylene, or C1-C4 alkylene). 5 , B 6 , and B. 7 are each independently an unsubstituted alkylene (e.g., C1-C 30 alkylene, C1-C8 alkylene, or C1-C4 alkylene). 5 , B 6 , and B. 7 are each independently a substituted (e.g., substituted, size-limited or lower) heteroalkylene (e.g., 2-30 membered heteroalkylene, 2-8 membered heteroalkylene, or 2-4 membered heteroalkylene). 5 , B 6 , and B. 7 are each independently unsubstituted heteroalkylene (eg, 2- to 30-membered heteroalkylene, 2- to 8-membered heteroalkylene, or 2- to 4-membered heteroalkylene).

[0198] In an embodiment, B 5 is a bond.

[0199] In an embodiment, B 6 and B. 7 are each independently a bond or substituted or unsubstituted alkylene. 6 and B. 7are each independently a bond or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkylene (e.g., C1-C 30 alkylene, C1-C8 alkylene, or C1-C4 alkylene).

[0200] In an embodiment, B 6 and B. 7 are each independently a bond or a substituted or unsubstituted C1-C8 alkylene. 6 and B. 7 are each independently a bond or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted C1-C8 alkylene. 6 and B. 7 are each independently a bond. 6 and B. 7 are each independently a substituted (e.g., substituted, size-limited or lower) C1-C8 alkylene. 6 and B. 7 are each independently unsubstituted C1 to C8 alkylene.

[0201] In an embodiment, B 6 and B. 7 are each independently a bond or a substituted or unsubstituted C2-C4 alkylene. 6 and B. 7 are each independently a bond or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted C2-C4 alkylene. 6 and B. 7 are each independently a substituted (e.g., substituted, size-limited or lower) C2-C4 alkylene. 6 and B. 7 are each independently unsubstituted C2 to C4 alkylene.

[0202] In an embodiment, B6 and B. 7 are each independently a bond or an unsubstituted C2-C4 alkylene. 6 and B. 7 are each independently a bond, ethylene, propylene, or butylene. 6 and B. 7 are each independently a bond. 6 and B. 7 are each independently ethylene. 6 and B. 7 are each independently propylene. 6 and B. 7 are each independently butylene.

[0203] In an embodiment, L 8 is a bond, -O(C=O)-, -(C=O)O-, or -C(=O)-. In embodiments, L 8 is a bond. In embodiments, L 8 is -O(C=O)-. In embodiments, L 8 is -(C=O)O-. In embodiments, L 8 is -C(=O)-.

[0204] In an embodiment, L 9 is a bond, -O(C=O)-, -(C=O)O-, or -C(=O)-. In embodiments, L 9 is -O(C=O)- or -(C=O)O-. In embodiments, L 9 is a bond. In embodiments, L 9 is -O(C=O)-. In embodiments, L 9 is -(C=O)O-. In embodiments, L 9 is -C(=O)-.

[0205] In an embodiment, L 10 is a bond, -O(C=O)-, -(C=O)O-, or -C(=O)-. In embodiments, L 10is -O(C=O)- or -(C=O)O-. In embodiments, L 10 is a bond. In embodiments, L 10 is -O(C=O)-. In embodiments, L 10 is -(C=O)O-. In embodiments, L 10 is -C(=O)-.

[0206] In embodiments, R 7 , R 8 , and R 9 are each independently H, a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted C1-C 30 alkyl, or substituted (e.g., substituted, size-limited or lower substituted) or unsubstituted 2-30 membered heteroalkyl. 7 , R 8 , and R 9 is each independently substituted with one or more substituents. 7 , R 8 , and R 9 are each independently substituted with one or more size-limited substituents. 7 , R 8 , and R 9 is each independently substituted with one or more lower substituents.

[0207] In embodiments, R 7 , R 8 , and R 9 are each independently H. In an embodiment, R 7 , R 8 , and R 9 are each independently substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) C1-C 30 In embodiments, R 7 , R 8 , and R 9 are each independently unsubstituted C1 to C 30 In embodiments, R 7 , R8 , and R 9 are each independently a substituted (e.g., substituted, size-limited or lower substituted) 2-30 membered heteroalkyl. 7 , R 8 , and R 9 are each independently unsubstituted 2-30 membered heteroalkyl.

[0208] In embodiments, R 7 , R 8 , and R 9 are each independently H or a substituted or unsubstituted C1-C 30 In embodiments, R 7 , R 8 , and R 9 are each independently H or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted C1-C 30 In embodiments, R 7 , R 8 , and R 9 are each independently a substituted (e.g., substituted with a substituent, a size-limited substituent or a lower substituent) or unsubstituted C1-C 30 It is an alkyl.

[0209] In embodiments, R 7 , R 8 , and R 9 are each independently substituted or unsubstituted C1-C 20 In embodiments, R 7 , R 8 , and R 9 are each independently a substituted (e.g., substituted with a substituent, a size-limited substituent or a lower substituent) or unsubstituted C1-C 20 In embodiments, R 7 , R 8 , and R 9 are each independently substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) C1-C 20 In embodiments, R 7 , R8 , and R 9 are each independently unsubstituted C1 to C 20 It is an alkyl.

[0210] In an embodiment, each R a31 and R a32 are independently H, substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted C-C 12 alkyl, or substituted (e.g., substituted, size-limited or lower substituted) or unsubstituted 2-12 membered heteroalkyl. a31 and R a32 is independently H. In an embodiment, each R a31 and R a32 are independently substituted (e.g., substituted with a substituent, a size-limited substituent or a lower substituent) C1-C 12 In embodiments, each R a31 and R a32 are independently unsubstituted C1 to C 12 In embodiments, each R a31 and R a32 is independently a substituted (e.g., substituted, size-limited or lower substituted) 2-12 membered heteroalkyl. a31 and R a32 is independently unsubstituted 2-12 membered heteroalkyl.

[0211] In an embodiment, each R 801 , R 802 , R 901 , R 902 , R 110 , and R 111 are independently H, substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted C-C 12 alkyl, or substituted (e.g., substituted, size-limited or lower substituted) or unsubstituted 2-12 membered heteroalkyl. 801 , R 802 , R 901 , R902 , R 110 , and R 111 is independently H. In an embodiment, each R 801 , R 802 , R 901 , R 902 , R 110 , and R 111 are independently substituted (e.g., substituted with a substituent, a size-limited substituent or a lower substituent) C1-C 12 In embodiments, each R 801 , R 802 , R 901 , R 902 , R 110 , and R 111 are independently unsubstituted C1 to C 12 In embodiments, each R 801 , R 802 , R 901 , R 902 , R 110 , and R 111 is independently a substituted (e.g., substituted, size-limited or lower substituted) 2-12 membered heteroalkyl. 801 , R 802 , R 901 , R 902 , R 110 , and R 111 is independently unsubstituted 2-12 membered heteroalkyl.

[0212] In embodiments, each s is independently an integer from 1 to 4. In embodiments, each s is 1. In embodiments, each s is 2. In embodiments, each s is 3. In embodiments, each s is 4.

[0213] In the embodiment, W 7 and W 8 Each of L is independently a bond or substituted or unsubstituted alkylene. a3 is a bond. R 10 and R 11 are each independently H, substituted or unsubstituted alkyl, or R 10 and R11 together with the nitrogen atom to which they are attached form a substituted or unsubstituted heterocycloalkyl. 5 is a bond. B 6 and B. 7 Each of L is independently a bond or substituted or unsubstituted alkylene. 8 is a bond. L 9 is a bond, -O(C=O)-, -(C=O)O-, or -C(=O)-. L 10 is a bond, -O(C=O)-, -(C=O)O-, or -C(=O)-, and R 7 , R 8 , and R 9 are each independently H or a substituted or unsubstituted C1-C 30 It is an alkyl.

[0214] In the embodiment, W 7 and W 8 Each of L is independently a bond or a substituted or unsubstituted C1 to C8 alkylene. a3 is a bond. R 10 and R 11 are each independently substituted or unsubstituted alkyl, or R 10 and R 11 together with the nitrogen atom to which they are attached form a substituted or unsubstituted heterocycloalkyl. 5 is a bond. B 6 and B. 7 Each of L is independently a bond or a substituted or unsubstituted C1 to C8 alkylene. 8 is a bond. L 9 is -O(C=O)- or -(C=O)O-. 10 is -O(C=O)- or -(C=O)O-, and R 7 , R 8 , and R 9 are each independently substituted or unsubstituted C1-C 20 It is an alkyl.

[0215] In the embodiment, W7 and W 8 Each of L is independently a bond or a substituted or unsubstituted C2 to C4 alkylene. a3 is a bond. R 10 and R 11 are each independently substituted or unsubstituted methyl, ethyl, propyl, isopropyl, or R 10 and R 11 together with the nitrogen atom to which they are attached, form a substituted or unsubstituted 3- to 8-membered heterocycloalkyl. 5 is a bond. B 6 and B. 7 Each of L is independently a bond or a substituted or unsubstituted C2 to C4 alkylene. 8 is a bond. L 9 is -O(C=O)- or -(C=O)O-. L 10 is -O(C=O)- or -(C=O)O-. 7 is H or methyl, R 8 , and R 9 are each independently substituted or unsubstituted C1-C 20 It is an alkyl.

[0216] In the embodiment, W 7 and W 8 are each independently a bond or an unsubstituted C2-C4 alkylene. a3 is a bond. R 10 and R 11 are each independently substituted or unsubstituted methyl, ethyl, propyl, isopropyl, or R 10 and R 11 together with the nitrogen atom to which they are attached, form a substituted or unsubstituted 5- to 6-membered heterocycloalkyl. 5 is a bond. B 6 and B. 7 are each independently a bond or an unsubstituted C2-C4 alkylene. 8 is a bond. L 9is -O(C=O)- or -(C=O)O-. 10 is -O(C=O)- or -(C=O)O-. R 7 is H or methyl, R 8 and R 9 are each independently substituted or unsubstituted C1-C 20 It is an alkyl.

[0217] In the embodiment, W 7 and W 8 are each independently a bond or an unsubstituted C2-C4 alkylene. a3 is a bond. R 10 and R 11 are each independently substituted or unsubstituted methyl, ethyl, propyl, isopropyl, or R 10 and R 11 together with the nitrogen atom to which they are attached, form a substituted or unsubstituted 5- to 6-membered heterocycloalkyl. 5 , B 6 , and B. 7 are each independently a bond. 8 is a bond. L 9 is a bond. L 10 is a bond. R 7 is H or methyl, R 8 and R 9 are each independently substituted or unsubstituted C1-C 30 It is an alkyl.

[0218] In embodiments, the cationic lipid of formula (II) is [ka] [ka] [ka] or a pharma- ceutically acceptable salt thereof.

[0219] In one embodiment, a cationic lipid of formula (III): [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, stereoisomer, or prodrug thereof provided herein. L 11 teeth, [ka] Q is substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene. V is substituted or unsubstituted alkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted arylene. B 8 , B 9 , B 10 , and B. 11 are each independently a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. L 12 is a bond, -O(C=O)-, -(C=O)O-, -O(C=O)O-, -C(=O)-, -O-, -O(CR 210 R 211 ) s O-, -S-, -C(=O)S-, -SC(=O)-, -NR 210 C(=O)-, -C(=O)NR 210 -, -NR 210 C(=O)NR 211 -, -NR 210 C(=S)-, -C(=S)NR 210 -, -NR 210 C(=S)NR 211 -, -OC(=O)NR 210 -, -NR 210 C(=O)O-, -SC(=O)NR 210 -OR-NR 210 C(=O)S-. L 13is a bond, -O(C=O)-, -(C=O)O-, -O(C=O)O-, -C(=O)-, -O-, -O(CR 310 R 311 ) s O-, -S-, -C(=O)S-, -SC(=O)-, -NR 310 C(=O)-, -C(=O)NR 310 -, -NR 310 C(=O)NR 311 -, -NR 310 C(=S)-, -C(=S)NR 310 -, -NR 310 C(=S)NR 311 -, -OC(=O)NR 310 -, -NR 310 C(=O)O-, -SC(=O)NR 310 -OR-NR 310 C(=O)S-. R 12 H, -OR 12A , -SR 12A , -NR 12A , -CN, -(C=O)R 12A , -O(C=O)R 12A , -(C=O)OR 12A , -NR 12A (C=O)-R 12B , -(C=O)NR 12A R 12B It is. R 13 H, -OR 13A , -SR 13A , -NR 13A , -CN, -(C=O)R 13A , -O(C=O)R 13A , -(C=O)OR 13A , -NR 13A (C=O)-R 13B , -(C=O)NR 13A R 13B It is. R 14 and R 15 are each independently substituted or unsubstituted C2 to C 30 alkyl, or substituted or unsubstituted 2-30 membered heteroalkyl. R 12A , R 12B , R13A , and R 13B are each independently H, substituted or unsubstituted C1-C 20 alkyl, or substituted or unsubstituted 2- to 20-membered heteroalkyl. Each R 210 , R 211 , R 310 , and R 311 are independently H, substituted or unsubstituted C1-C 12 alkyl, or substituted or unsubstituted 2-12 membered heteroalkyl. each n is independently an integer from 0 to 8; Each s is independently an integer from 1 to 4.

[0220] In an embodiment, L 11 teeth, [ka] (wherein n is an integer of 0 to 8, V is a substituted or unsubstituted alkylene, and Q is a substituted or unsubstituted alkylene).

[0221] In an embodiment, L 11 teeth, [ka] wherein V is a substituted or unsubstituted alkylene. In embodiments, L 11 teeth, [ka] [Wherein, V is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkylene (e.g., C1-C 30 alkylene, C1-C8 alkylene, or C1-C4 alkylene).

[0222] In an embodiment, L 11 teeth, [ka] [Wherein, V is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) alkylene (e.g., C1-C 30 In an embodiment, L is an alkylene, a C1-C8 alkylene, or a C1-C4 alkylene. 11 teeth, [ka] [Wherein, V is an unsubstituted alkylene (e.g., C1-C 30 alkylene, C1-C8 alkylene, or C1-C4 alkylene).

[0223] In an embodiment, L 11 teeth, [ka] (wherein n is an integer of 0 to 8). In an embodiment, L 11 teeth, [ka] (wherein n is an integer of 0 to 4).

[0224] In an embodiment, L 11 teeth, [ka] wherein n is 0. In an embodiment, L 11 teeth, [ka] (wherein n is 1).

[0225] In an embodiment, L 11 teeth, [ka] (wherein n is 2).

[0226] In an embodiment, L 11 teeth, [ka] (wherein n is 3).

[0227] In an embodiment, L 11 teeth, [ka] (wherein n is 4).

[0228] In an embodiment, L 11 teeth, [ka] wherein Q is a substituted or unsubstituted alkylene. In embodiments, L 11 teeth, [ka] [wherein Q is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkylene (e.g., C1-C 30 alkylene, C1-C8 alkylene, or C1-C4 alkylene).

[0229] In an embodiment, L 11 teeth, [ka] [wherein Q is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) alkylene (e.g., C1-C 30 In an embodiment, L is an alkylene, a C1-C8 alkylene, or a C1-C4 alkylene. 11 teeth, [ka] [In the formula, Q is an unsubstituted alkylene (e.g., C1-C 30 alkylene, C1-C8 alkylene, or C1-C4 alkylene).

[0230] In an embodiment, L 11 teeth, [ka] It is.

[0231] In embodiments, Q is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkylene (e.g., C1-C 30 alkylene, C1-C8 alkylene, or C1-C4 alkylene), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkylene (e.g., 2-30 membered heteroalkylene, 2-8 membered heteroalkylene, or 2-4 membered heteroalkylene), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted cycloalkylene (e.g., C3-C8 cycloalkylene, C3-C6 cycloalkylene, or C5-C6 cycloalkylene), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heterocycloalkylene (e.g., 3-8 membered heterocycloalkylene, 3-6 membered heterocycloalkylene, or 5-6 membered heterocycloalkylene), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted arylene (e.g., C6-C 10 Arylene, C 10 In embodiments, Q is substituted with one or more substituents. In embodiments, Q is substituted with one or more size-limiting substituents. In embodiments, Q is substituted with one or more lower substituents.

[0232] In embodiments, Q is a substituted (e.g., substituted, size-limited or lower substituted) alkylene (e.g., C1-C 30In embodiments, Q is an unsubstituted alkylene (e.g., C1-C alkylene, C1-C alkylene, or C1-C alkylene). 30 In an embodiment, Q is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) heteroalkylene (e.g., a 2-30 membered heteroalkylene, a 2-8 membered heteroalkylene, or a 2-4 membered heteroalkylene). In an embodiment, Q is an unsubstituted heteroalkylene (e.g., a 2-30 membered heteroalkylene, a 2-8 membered heteroalkylene, or a 2-4 membered heteroalkylene). In an embodiment, Q is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) cycloalkylene (e.g., a C3-C8 cycloalkylene, a C3-C6 cycloalkylene, or a C5-C6 cycloalkylene). In an embodiment, Q is an unsubstituted cycloalkylene (e.g., a C3-C8 cycloalkylene, a C3-C6 cycloalkylene, or a C5-C6 cycloalkylene). In embodiments, Q is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) heterocycloalkylene (e.g., a 3-8 membered heterocycloalkylene, a 3-6 membered heterocycloalkylene, or a 5-6 membered heterocycloalkylene). In embodiments, Q is an unsubstituted heterocycloalkylene (e.g., a 3-8 membered heterocycloalkylene, a 3-6 membered heterocycloalkylene, or a 5-6 membered heterocycloalkylene). In embodiments, Q is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) arylene (e.g., a C6-C 10 Arylene, C 10 In embodiments, Q is an unsubstituted arylene (e.g., C-C 10 Arylene, C 10In embodiments, Q is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) heteroarylene (e.g., a 5- to 10-membered heteroarylene, a 5- to 9-membered heteroarylene, or a 5- to 6-membered heteroarylene). In embodiments, Q is an unsubstituted heteroarylene (e.g., a 5- to 10-membered heteroarylene, a 5- to 9-membered heteroarylene, or a 5- to 6-membered heteroarylene).

[0233] In embodiments, Q is a substituted or unsubstituted alkylene. In embodiments, Q is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) alkylene (e.g., C1-C 30 alkylene, C1-C8 alkylene, or C1-C4 alkylene).

[0234] In embodiments, V is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkylene (e.g., C1-C 30 alkylene, C1-C8 alkylene, or C1-C4 alkylene), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted cycloalkylene (e.g., C3-C8 cycloalkylene, C3-C6 cycloalkylene, or C5-C6 cycloalkylene), or substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted arylene (e.g., C6-C 10 Arylene, C 10 arylene, or phenylene). In embodiments, V is substituted with one or more substituents. In embodiments, V is substituted with one or more size-limited substituents. In embodiments, V is substituted with one or more lower substituents.

[0235] In embodiments, V is a substituted (e.g., substituted, size-limited or lower substituted) alkylene (e.g., C1-C 30 In embodiments, V is an unsubstituted alkylene (e.g., C1-C alkylene, C1-C alkylene, or C1-C alkylene).30 In an embodiment, V is an alkylene, C1-C8 alkylene, or C1-C4 alkylene. In an embodiment, V is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) cycloalkylene (e.g., C3-C8 cycloalkylene, C3-C6 cycloalkylene, or C5-C6 cycloalkylene). In an embodiment, V is an unsubstituted cycloalkylene (e.g., C3-C8 cycloalkylene, C3-C6 cycloalkylene, or C5-C6 cycloalkylene). In an embodiment, V is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) arylene (e.g., C6-C 10 Arylene, C 10 In an embodiment, V is an unsubstituted arylene (e.g., C6-C 10 Arylene, C 10 arylene, or phenylene).

[0236] In embodiments, V is a substituted or unsubstituted alkylene. In embodiments, V is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) alkylene (e.g., C1-C 30 alkylene, C1-C8 alkylene, or C1-C4 alkylene).

[0237] In an embodiment, B 8 , B 9 , B 10 , and B. 11 are each independently a bond, a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkylene (e.g., C1-C 30 alkylene, C1-C8 alkylene, or C1-C4 alkylene), or substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkylene (e.g., 2-30 membered heteroalkylene, 2-8 membered heteroalkylene, or 2-4 membered heteroalkylene). 8 , B 9 , B 10 , and B. 11is each independently substituted with one or more substituents. 8 , B 9 , B 10 , and B. 11 is each independently substituted with one or more size-limited substituents. 8 , B 9 , B 10 , and B. 11 is each independently substituted with one or more lower substituents.

[0238] In an embodiment, B 8 , B 9 , B 10 , and B. 11 are each independently a bond. 8 , B 9 , B 10 , and B. 11 are each independently a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) alkylene (e.g., C 30 alkylene, C1-C8 alkylene, or C1-C4 alkylene). 8 , B 9 , B 10 , and B. 11 are each independently an unsubstituted alkylene (e.g., C1-C 30 alkylene, C1-C8 alkylene, or C1-C4 alkylene). 8 , B 9 , B 10 , and B. 11 are each independently a substituted (e.g., substituted, size-limited or lower) heteroalkylene (e.g., 2-30 membered heteroalkylene, 2-8 membered heteroalkylene, or 2-4 membered heteroalkylene). 8 , B 9 , B 10 , and B. 11 are each independently unsubstituted heteroalkylene (eg, 2- to 30-membered heteroalkylene, 2- to 8-membered heteroalkylene, or 2- to 4-membered heteroalkylene).

[0239] In an embodiment, B 8 , B 9 , B 10 , and B. 11 Each is independently a substituted or unsubstituted alkylene. 8 , B 9 , B 10 , and B. 11 are each independently substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted alkylene (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent).

[0240] In an embodiment, B 8 , B 9 , B 10 , and B. 11 are each independently substituted or unsubstituted C1-C 20 In an embodiment, B is an alkylene. 8 , B 9 , B 10 , and B. 11 are each independently a substituted (e.g., substituted with a substituent, a size-limited substituent or a lower substituent) or unsubstituted C1-C 20 In an embodiment, B is an alkylene. 8 , B 9 , B 10 , and B. 11 are each independently substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) C1-C 20 In an embodiment, B is an alkylene. 8 , B 9 , B 10 , and B. 11 are each independently unsubstituted C1 to C 20 It is alkylene.

[0241] In an embodiment, B 8 , B 9 , B 10 , and B. 11 are each independently a substituted or unsubstituted C1-C8 alkylene.8 , B 9 , B 10 , and B. 11 are each independently substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted C1-C8 alkylene. 8 , B 9 , B 10 , and B. 11 are each independently a substituted (e.g., substituted, size-limited or lower) C1-C8 alkylene. 8 , B 9 , B 10 , and B. 11 are each independently unsubstituted C1 to C8 alkylene.

[0242] In an embodiment, L 12 is a bond, -O(C=O)-, -(C=O)O-, -O(C=O)O-, -C(=O)-, or -O-. In embodiments, L 12 is a bond. In embodiments, L 12 is -O(C=O)-. In embodiments, L 12 is -(C=O)O-. In embodiments, L 12 is -O(C=O)O-. In embodiments, L 12 is -C(=O)-. In embodiments, L 12 is -O-.

[0243] In an embodiment, L 12 is -O(C=O)- or -(C=O)O-.

[0244] In an embodiment, L 13 is a bond, -O(C=O)-, -(C=O)O-, -O(C=O)O-, -C(=O)-, or -O-. In embodiments, L 13 is a bond. In embodiments, L 13 is -O(C=O)-. In embodiments, L 13 is -(C=O)O-. In embodiments, L 13 is -O(C=O)O-. In embodiments, L 13is -C(=O)-. In embodiments, L 13 is -O-.

[0245] In an embodiment, L 13 is -O(C=O)- or -(C=O)O-.

[0246] In embodiments, R 12 H, -OR 12A , -SR 12A , -NR 12A , -CN, or -(C=O)R 12A In an embodiment, R 12 H, -OR 12A , or -NR 12A In an embodiment, R 12 is H or -OR 12A It is.

[0247] In embodiments, R 12 is H. In embodiments, R 12 -OR 12A In an embodiment, R 12 Ha-SR 12A In an embodiment, R 12 -NR 12A In an embodiment, R 12 is CN. In embodiments, R 12 -(C=O)R 12A It is.

[0248] In embodiments, R 12 is -OH, methoxy, or ethoxy.

[0249] In embodiments, R 13 H, -OR 13A , -SR 13A , -NR 13A , -CN, or -(C=O)R 13A In an embodiment, R 13 H, -OR 13A , or -NR 13A In an embodiment, R 13 is H or -OR 13A It is.

[0250] In embodiments, R 13 is H. In embodiments, R 13 -OR 13A In an embodiment, R 13 Ha-SR 13A In an embodiment, R 13 -NR 13A In an embodiment, R 13 is CN. In embodiments, R 13 -(C=O)R 13A It is.

[0251] In embodiments, R 13 is -OH, methoxy, or ethoxy.

[0252] In embodiments, R 12A and R 13A are each independently H, a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted C1-C 20 alkyl, or substituted (e.g., substituted, size-limited or lower substituted) or unsubstituted 2-30 membered heteroalkyl. 12A and R 13A is each independently substituted with one or more substituents. 12A and R 13A are each independently substituted with one or more size-limited substituents. 12A and R 13A is each independently substituted with one or more lower substituents.

[0253] In embodiments, R 12A and R 13A are each independently H. In an embodiment, R 12A and R 13A are each independently substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) C1-C 20 In embodiments, R 12A and R 13Aare each independently unsubstituted C1 to C 20 In embodiments, R 12A and R 13A are each independently a substituted (e.g., substituted, size-limited or lower substituted) 2-30 membered heteroalkyl. 12A and R 13A are each independently unsubstituted 2-30 membered heteroalkyl.

[0254] In embodiments, R 12A and R 13A are each independently H, substituted or unsubstituted C1-C 20 In embodiments, R 12A and R 13A are each independently H, substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted C1-C 20 In embodiments, R 12A and R 13A are each independently substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) C1-C 20 In embodiments, R 12A and R 13A are each independently unsubstituted C1 to C 20 It is an alkyl.

[0255] In embodiments, R 12A and R 13A are each independently H, a substituted or unsubstituted C1-C8 alkyl. 12A and R 13A are each independently H, a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted C1-C8 alkyl. 12A and R 13A are each independently a substituted (e.g., substituted, size-limited or lower) C1-C8 alkyl. 12A and R 13Aare each independently unsubstituted C1-C8 alkyl.

[0256] In embodiments, R 12B and R 13B are each independently H, a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted C1-C 20 It is an alkyl, or a substituted (eg, substituted with a substituent, a size-limited substituent or a lower substituent) or unsubstituted 2-30 membered heteroalkyl.

[0257] In embodiments, R 12B and R 13B are each independently H. In an embodiment, R 12B and R 13B are each independently substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) C1-C 20 In embodiments, R 12B and R 13B are each independently unsubstituted C1 to C 20 In embodiments, R 12B and R 13B are each independently a substituted (e.g., substituted, size-limited or lower substituted) 2-30 membered heteroalkyl. 12B and R 13B are each independently unsubstituted 2-30 membered heteroalkyl.

[0258] In embodiments, R 14 and R 15 are each independently a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted C-C 30 alkyl, or substituted (e.g., substituted, size-limited or lower substituted) or unsubstituted 2-30 membered heteroalkyl. 14 and R 15 is each independently substituted with one or more substituents. 14 and R 15are each independently substituted with one or more size-limited substituents. 14 and R 15 is each independently substituted with one or more lower substituents.

[0259] In embodiments, R 14 and R 15 are each independently a substituted (e.g., substituted with a substituent, a size-limited substituent or a lower substituent) C2-C 30 In embodiments, R 14 and R 15 are each independently unsubstituted C2 to C 30 In embodiments, R 14 and R 15 are each independently a substituted (e.g., substituted, size-limited or lower substituted) 2-30 membered heteroalkyl. 14 and R 15 are each independently unsubstituted 2-30 membered heteroalkyl.

[0260] In embodiments, R 14 and R 15 are each independently substituted or unsubstituted C2 to C 30 In embodiments, R 14 and R 15 are each independently a substituted (e.g., substituted with a substituent, a size-limited substituent or a lower substituent) or unsubstituted C-C 30 It is an alkyl.

[0261] In an embodiment, each R 210 , R 211 , R 310 , and R 311 are independently H, substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted C-C 12 alkyl, or substituted (e.g., substituted, size-limited or lower substituted) or unsubstituted 2-12 membered heteroalkyl. 210 , R211 , R 310 , and R 311 is independently substituted with one or more substituents. In embodiments, each R 210 , R 211 , R 310 , and R 311 is independently substituted with one or more size-limited substituents. In embodiments, each R 210 , R 211 , R 310 , and R 311 is independently substituted with one or more lower substituents.

[0262] In an embodiment, each R 210 , R 211 , R 310 , and R 311 is independently H. In an embodiment, each R 210 , R 211 , R 310 , and R 311 are independently substituted (e.g., substituted with a substituent, a size-limited substituent or a lower substituent) C1-C 12 In embodiments, each R 210 , R 211 , R 310 , and R 311 are independently unsubstituted C1 to C 12 In embodiments, each R 210 , R 211 , R 310 , and R 311 is independently a substituted (e.g., substituted, size-limited or lower substituted) 2-12 membered heteroalkyl. 210 , R 211 , R 310 , and R 311 is independently unsubstituted 2-12 membered heteroalkyl.

[0263] In an embodiment, each n is independently an integer from 0 to 8. In an embodiment, each n is independently an integer from 0 to 4. In an embodiment, each n is independently 8. In an embodiment, each n is independently 7. In an embodiment, each n is independently 6. In an embodiment, each n is independently 5. In an embodiment, each n is independently 4. In an embodiment, each n is independently 3. In an embodiment, each n is independently 2. In an embodiment, each n is independently 1. In an embodiment, each n is independently 0.

[0264] In an embodiment, each s is an integer from 1 to 4. In an embodiment, each s is 4. In an embodiment, each s is 3. In an embodiment, each s is 2. In an embodiment, each s is 1.

[0265] In an embodiment, L 11 teeth, [ka] (wherein Q is substituted or unsubstituted alkylene, V is substituted or unsubstituted alkylene, and each n is independently an integer from 0 to 8). B 8 , B 9 , B 10 , and B. 11 are each independently substituted or unsubstituted alkylene. L 12 is -O(C=O)- or -(C=O)O-. 13 is -O(C=O)- or -(C=O)O-. 12 H, -OR 12A , or -NR 12A It is. R 13 H, -OR 13A , or -NR 13A R 14 and R 15 are each independently substituted or unsubstituted C2 to C 30 It is an alkyl group. 12A and R 13Aare each independently H, substituted or unsubstituted C1-C 20 It is an alkyl.

[0266] In an embodiment, L 11 teeth, [ka] (wherein V is substituted or unsubstituted alkylene, and each n is independently an integer from 0 to 4). B 8 , B 9 , B 10 , and B. 11 are each independently substituted or unsubstituted C1-C 20 It is alkylene. L 12 is -O(C=O)- or -(C=O)O-. 13 is -O(C=O)- or -(C=O)O-. 12 is H or -OR 12A R 13 is H or -OR 13A R 14 and R 15 are each independently substituted or unsubstituted C2 to C 20 It is an alkyl. R 12A and R 13A are each independently H or a substituted or unsubstituted C1-C8 alkyl.

[0267] In an embodiment, L 11 teeth, [ka] (wherein V is substituted or unsubstituted alkylene, and each n is independently an integer from 0 to 4). B 8 , B 9 , B 10 , and B. 11 are each independently substituted or unsubstituted C1 to C8 alkylene. L12 is -O(C=O)- or -(C=O)O-. 13 is -O(C=O)- or -(C=O)O-. 12 is -OH, methoxy, or ethoxy. R 13 is -OH, methoxy, or ethoxy. 14 and R 15 are each independently substituted or unsubstituted C2 to C 20 It is an alkyl.

[0268] In embodiments, the cationic lipid of formula (III) is [ka] or a pharma- ceutically acceptable salt thereof.

[0269] In one embodiment, a cationic lipid of formula (IV): R 17 -W 10 -L 14 -B 12 -L 15 -W 9 -R 16 (IV) or a pharma- ceutically acceptable salt, solvate, hydrate, stereoisomer, or prodrug thereof provided herein. B 12 -W 7 -L a3 -W 8 -It is. W 7 and W 8 are each independently a bond or a substituted or unsubstituted C1-C 12 It is alkylene, or a substituted or unsubstituted 2- to 12-membered heteroalkylene. L a3 is a bond, -SS-, -O-(CHO) m -, [ka] It is. W 9 and W10 are each independently a bond or a substituted or unsubstituted C1-C 12 It is alkylene, substituted or unsubstituted 2-12 membered heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, or any combination thereof. L 14 is a bond, -O(C=O)-, -(C=O)O-, -O(C=O)O-, -C(=O)-, -O-, -O(CR 410 R 411 ) s O-, -S-, -C(=O)S-, -SC(=O)-, -NR 410 C(=O)-, -C(=O)NR 410 -, -NR 410 C(=O)NR 411 -, -NR 410 C(=S)-, -C(=S)NR 410 -, -NR 410 C(=S)NR 411 -, -OC(=O)NR 410 -, -NR 410 C(=O)O-, -SC(=O)NR 410 -OR-NR 410 C(=O)S-. L 15 is a bond, -O(C=O)-, -(C=O)O-, -O(C=O)O-, -C(=O)-, -O-, -O(CR 510 R 511 ) s O-, -S-, -C(=O)S-, -SC(=O)-, -NR 510 C(=O)-, -C(=O)NR 510 -, -NR 510 C(=O)NR 511 -, -NR 510 C(=S)-, -C(=S)NR 510 -, -NR 510 C(=S)NR 511 -, -OC(=O)NR 510 -, -NR 510 C(=O)O-, -SC(=O)NR 510 -OR-NR 510 C(=O)S-. R 16 and R 17are each independently [ka] A fragment of a cationic lipid of formula (I): [ka] A fragment of a cationic lipid of formula (II): [ka] A fragment of a cationic lipid of formula (II): [ka] A fragment of a cationic lipid of formula (III), or [ka] A fragment of a cationic lipid of formula (III). Each R 410 , R 411 , R 510 , and R 511 are independently H, substituted or unsubstituted C1-C 12 alkyl, or substituted or unsubstituted 2-12 membered heteroalkyl. each m is independently an integer from 0 to 8; Each s is independently an integer from 1 to 4.

[0270] In the embodiment, W 7 and W 8 are each independently a bond, a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted C1-C 12 alkylene, or substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted 2-12 membered heteroalkylene. 7 and W 8 is each independently substituted with one or more substituents. 7 and W 8is each independently substituted with one or more size-limited substituents. 7 and W 8 is each independently substituted with one or more lower substituents.

[0271] In the embodiment, W 7 and W 8 are each independently a bond. 7 and W 8 are each independently substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) C1-C 12 In embodiments, W is an alkylene. 7 and W 8 are each independently unsubstituted C1 to C 12 In embodiments, W is an alkylene. 7 and W 8 are each independently a substituted (e.g., substituted, size-limited or lower substituted) 2-12 membered heteroalkylene. 7 and W 8 are each independently unsubstituted 2- to 12-membered heteroalkylene.

[0272] In the embodiment, W 7 and W 8 each independently represents a bond or a substituted or unsubstituted C1-C 12 It is an alkylene. 7 and W 8 are each independently a bond or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted C1-C 12 It is alkylene.

[0273] In the embodiment, W 7 and W 8 are each independently a bond or an unsubstituted C 12 It is alkylene.

[0274] In the embodiment, W 7 and W 8are each independently a bond or an unsubstituted C1-C8 alkylene. 7 and W 8 are each independently unsubstituted C1 to C8 alkylene.

[0275] In an embodiment, L a3 is the bond, -SS-, [ka] In an embodiment, L a3 is a bond. In embodiments, L a3 In an embodiment, L is -SS-. a3 teeth, [ka] In an embodiment, L a3 teeth, [ka] It is.

[0276] In the embodiment, W 9 and W 10 are each independently a bond, a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted C1-C 12 alkylene, substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted 2-12 membered heteroalkylene, substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted cycloalkylene (e.g., C3-C8 cycloalkylene, C3-C6 cycloalkylene, or C5-C6 cycloalkylene), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heterocycloalkylene (e.g., 3-8 membered heterocycloalkylene, 3-6 membered heterocycloalkylene, or 5-6 membered heterocycloalkylene), or any combination thereof. In an embodiment, W 9 and W 10is each independently substituted with one or more substituents. 9 and W 10 is each independently substituted with one or more size-limited substituents. 9 and W 10 is each independently substituted with one or more lower substituents.

[0277] In the embodiment, W 9 and W 10 are each independently a bond. 9 and W 10 are each independently substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) C1-C 12 In embodiments, W is an alkylene. 9 and W 10 are each independently unsubstituted C1 to C 12 In embodiments, W is an alkylene. 9 and W 10 are each independently a substituted (e.g., substituted, size-limited or lower substituted) 2-12 membered heteroalkylene. 9 and W 10 are each independently an unsubstituted 2- to 12-membered heteroalkylene. 9 and W 10 are each independently a substituted (e.g., substituted, size-limited or lower substituted) cycloalkylene (e.g., C3-C8 cycloalkylene, C3-C6 cycloalkylene, or C5-C6 cycloalkylene). 9 and W 10 are each independently unsubstituted cycloalkylene (e.g., C3-C8 cycloalkylene, C3-C6 cycloalkylene, or C5-C6 cycloalkylene). 9 and W 10are each independently a substituted (e.g., substituted, size-limited or lower substituted) heterocycloalkylene (e.g., 3-8 membered heterocycloalkylene, 3-6 membered heterocycloalkylene, or 5-6 membered heterocycloalkylene). 9 and W 10 are each independently unsubstituted heterocycloalkylene (eg, 3- to 8-membered heterocycloalkylene, 3- to 6-membered heterocycloalkylene, or 5- to 6-membered heterocycloalkylene).

[0278] In the embodiment, W 9 and W 10 each independently represents a bond or a substituted or unsubstituted C1-C 12 In embodiments, W is an alkylene. 9 and W 10 are each independently a bond or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted C1-C 12 In embodiments, W is an alkylene. 9 and W 10 are each independently substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) C1-C 12 In embodiments, W is an alkylene. 9 and W 10 are each independently unsubstituted C1 to C 12 It is alkylene.

[0279] In the embodiment, W 9 and W 10 are each independently a bond or an unsubstituted C1-C8 alkylene. 9 and W 10 are each independently unsubstituted C1 to C8 alkylene.

[0280] In an embodiment, L 14 -O(C=O)-, -(C=O)O-, -C(=O)-, -NR 410 C(=O)-, -C(=O)NR 410 -, -NR 410C(=S)-, -C(=S)NR 410 -, -OC(=O)NR 410 -, or -NR 410 In an embodiment, L 14 -O(C=O)-, -(C=O)O-, -NR 410 C(=S)-, -C(=S)NR 410 -, -OC(=O)NR 410 -, or -NR 410 C(=O)O-.

[0281] In an embodiment, L 14 is -O(C=O)-. In embodiments, L 14 is -(C=O)O-. In embodiments, L 14 is -C(=O)-. In embodiments, L 14 -NR 410 In one embodiment, L 14 is -C(=O)NR 410 In an embodiment, L 14 -NR 410 C(=S)-. In an embodiment, L 14 is -C(=S)NR 410 In an embodiment, L 14 -OC(=O)NR 410 In an embodiment, L 14 -NR 410 C(=O)O-.

[0282] In an embodiment, L 15 -O(C=O)-, -(C=O)O-, -C(=O)-, -NR 510 C(=O)-, -C(=O)NR 510 -, -NR 510 C(=S)-, -C(=S)NR 510 -, -OC(=O)NR 510 -, or -NR 510 In an embodiment, L 15 -O(C=O)-, -(C=O)O-, -NR 510 C(=S)-, -C(=S)NR 510 -, -OC(=O)NR 510-, or -NR 510 C(=O)O-.

[0283] In an embodiment, L 15 is -O(C=O)-. In embodiments, L 15 is -(C=O)O-. In embodiments, L 15 is -C(=O)-. In embodiments, L 15 -NR 510 In one embodiment, L 15 is -C(=O)NR 510 In an embodiment, L 15 -NR 510 C(=S)-. In an embodiment, L 15 is -C(=S)NR 510 In an embodiment, L 15 -OC(=O)NR 510 In an embodiment, L 5 -NR 510 C(=O)O-.

[0284] In an embodiment, each R 410 , R 411 , R 510 , and R 511 are independently H, substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted C-C 12 alkyl, or substituted (e.g., substituted, size-limited or lower substituted) or unsubstituted 2-12 membered heteroalkyl. 410 , R 411 , R 510 , and R 511 is independently substituted with one or more substituents. In embodiments, each R 410 , R 411 , R 510 , and R 511 is independently substituted with one or more size-limited substituents. In embodiments, each R 410 , R 411 , R 510 , and R 511 is independently substituted with one or more lower substituents.

[0285] In an embodiment, each R 410 , R 411 , R 510 , and R 511 is independently H. In an embodiment, each R 410 , R 411 , R 510 , and R 511 are independently substituted (e.g., substituted with a substituent, a size-limited substituent or a lower substituent) C1-C 12 In embodiments, each R 410 , R 411 , R 510 , and R 511 are independently unsubstituted C1 to C 12 In embodiments, each R 410 , R 411 , R 510 , and R 511 is independently a substituted (e.g., substituted, size-limited or lower substituted) 2-12 membered heteroalkyl. 410 , R 411 , R 510 , and R 511 is independently unsubstituted 2-12 membered heteroalkyl.

[0286] In an embodiment, each R 410 and R 510 are independently H or substituted or unsubstituted C1-C 12 In embodiments, each R 410 and R 510 are independently H or substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted C1-C 12 It is an alkyl.

[0287] In an embodiment, each R 410 and R 510 is independently H or unsubstituted C1-C8 alkyl. In an embodiment, each R 410 and R 510 is independently unsubstituted C1-C8 alkyl.

[0288] In an embodiment, each R 410 and R 510 is independently H, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl. 410 and R 510 is independently H or methyl. In an embodiment, each R 410 and R 510 is independently H. In an embodiment, each R 410 and R 510 is independently methyl.

[0289] In embodiments, R 16 and R 17 are each independently [ka] A fragment of a cationic lipid of formula (I): [ka] A fragment of a cationic lipid of formula (II): [ka] A fragment of a cationic lipid of formula (II): [ka] A fragment of a cationic lipid of formula (III), or [ka] A fragment of a cationic lipid of formula (III) 2 , B 3 , B 4 , B 5 , B 6 , B 7 , B 8 , B 9 , B 10 , B 11 , L 9 , L 2 , L 3 , L4 , L 5 , L 6 , L 7 , L 8 , L 9 , L 10 , L 12 , L 13 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , and R 15 as described herein, including the embodiments thereof).

[0290] In embodiments, R 16 and R 17 are each independently [ka] A fragment of a cationic lipid of formula (II) 6 , B 7 , L 9 , L 10 , R 8 , and R 9 is as described herein, including the embodiments.

[0291] In embodiments, R 16 and R 17 are each independently [ka] It is.

[0292] In embodiments, R 16 and R 17 are each independently [ka] It is.

[0293] In embodiments, R 16 and R 17 are each independently [ka] It is.

[0294] In an embodiment, each m is independently an integer from 0 to 8. In an embodiment, each m is independently 8. In an embodiment, each m is independently 7. In an embodiment, each m is independently 6. In an embodiment, each m is independently 5. In an embodiment, each m is independently 4. In an embodiment, each m is independently 3. In an embodiment, each m is independently 2. In an embodiment, each m is independently 1. In an embodiment, each m is independently 0.

[0295] In an embodiment, each s is an integer from 1 to 4. In an embodiment, each s is 4. In an embodiment, each s is 3. In an embodiment, each s is 2. In an embodiment, each s is 1.

[0296] In embodiments, the cationic lipid of formula (IV) is [ka] [ka] [ka] or a pharma- ceutically acceptable salt thereof. Lipid Nanoparticles

[0297] In one aspect, lipid nanoparticles are provided herein that comprise one or more of the ionizable cationic lipids described herein or salts thereof.In an embodiment, the lipid nanoparticles described herein further comprise one or more non-cationic lipids.In an embodiment, the lipid nanoparticles described herein further comprise one or more conjugated lipids that can reduce or inhibit particle aggregation.In another embodiment, the lipid nanoparticles described herein further comprise one or more therapeutic agents, such as nucleic acids (e.g., mRNA).

[0298] In embodiments, lipid nanoparticles comprising one or more ionizable cationic lipids described herein are used to encapsulate nucleic acids (e.g., mRNA) within the lipid nanoparticles.

[0299] In embodiments, the lipid nanoparticles comprise a therapeutic agent, e.g., a nucleic acid (e.g., mRNA), a cationic lipid (one or more ionizable cationic lipids of Formulas I-IV described herein or a salt thereof, or a cationic lipid known in the art), a non-cationic lipid (e.g., a mixture of one or more phospholipids and cholesterol), and a conjugated lipid that inhibits particle aggregation (e.g., one or more PEG-lipid conjugates).

[0300] In embodiments, non-cationic lipids that can be used in the lipid nanoparticles described herein include, without limitation, neutral, zwitterionic or anionic lipids, such as: Phospholipids, such as lecithin, phosphatidylethanolamine, lysolecithin, lysophosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, sphingomyelin, egg sphingomyelin (ESM), cephalin, cardiolipin, phosphatidic acid, cerebrosides, dicetyl phosphate, distearoylphosphatidylcholine (DSPC), dioleoylphosphatidylcholine (DOPC), dipalmitoylphosphatidylcholine (DPPC), dioleoylphosphatidylglycerol (DOPG), dipalmitoylphosphatidylglycerol (DPPG), dioleoylphosphatidylethanolamine (DOPE), palmitoyloleoyl-phosphatidylcholine (POPC), palmitoyloleoyl-phosphatidylethanolamine (POPE), palmitoyl Palmitoyloleoylphosphatidylglycerol (POPG), dioleoylphosphatidylethanolamine 4-(N-maleimidomethyl)-cyclohexane-1-carboxylate (DOPE-mal), dipalmitoyl-phosphatidylethanolamine (DPPE), dimyristoyl-phosphatidylethanolamine (DMPE), distearoyl-phosphatidylethanolamine (DSPE), monomethyl-phosphatidylethanolamine, dimethyl-phosphatidylethanolamine, dielaidoyl-phosphatidylethanolamine (DEPE), stearoyloleoyl-phosphatidylethanolamine (SOPE), lysophosphatidylcholine, dilinoleoylphosphatidylcholine, and mixtures thereof. Other diacylphosphatidylcholine and diacylphosphatidylethanolamine phospholipids can also be used. The acyl groups in these lipids are preferably C 10 ~C 24 The acyl group is derived from a fatty acid having a carbon chain, for example, lauroyl, myristoyl, palmitoyl, stearoyl, or oleoyl.

[0301] In embodiments, non-cationic lipids can be sterols, such as cholesterol and its derivatives.Non-limiting examples of cholesterol derivatives include polar analogs, such as 5α-cholestanol, 5β-coprostanol, cholesteryl-(2'-hydroxy)-ethyl ether, cholesteryl-(4'-hydroxy)-butyl ether, and 6-ketocholestanol; non-polar analogs, such as 5α-cholestan, cholestenone, 5α-cholestanone, 5β-cholestanone, and cholesteryl decanoate; and mixtures thereof.In embodiments, cholesterol derivatives are polar analogs, such as cholesteryl-(4'-hydroxy)-butyl ether.

[0302] In embodiments, the non-cationic lipids included in the lipid nanoparticles comprise a mixture of one or more phospholipids and cholesterol or a derivative thereof.

[0303] In embodiments, non-cationic lipids suitable for use in lipid nanoparticles include stearylamine, dodecylamine, hexadecylamine, acetyl palmitate, glycerol ricinoleate, hexadecyl stereate, isopropyl myristate, amphoteric acrylic polymers, triethanolamine-lauryl sulfate, alkylaryl sulfates, polyethyloxylated fatty acid amides, dioctadecyldimethylammonium bromide, ceramides, sphingomyelin, and the like.

[0304] In embodiments, lipid conjugates that can be used in the lipid nanoparticles described herein include, without limitation, PEG-lipid conjugates, POZ-lipid conjugates, ATTA-lipid conjugates, cationic polymer-lipid conjugates (CPLs), and mixtures thereof. In embodiments, the nanoparticles comprise PEG-lipid conjugates.

[0305] In embodiments, lipid conjugates that can be used in the lipid nanoparticles described herein include PEG coupled to dialkyloxypropyl (PEG-DAA), PEG coupled to diacylglycerol (PEG-DAG), PEG coupled to phospholipids, such as phosphatidylethanolamine (PEG-PE), PEG conjugated to ceramide, mPEG2000-1,2-di-O-alkyl-sn3-carbomoylglyceride (PEG-C-DOMG), 1-[8'-(1,2-dimyristoyl-3-propanoxy)-carboxamido-3',6'-dioxaotanyl]carbamoyl-co-methyl-poly(ethylene glycol) (2KPEG-DMG), 1,2-dimyristoyl-rac-glycero-3-methylpolyoxyethylene (DMG-PEG), PEG conjugated to cholesterol or derivatives thereof, and mixtures thereof.

[0306] In embodiments, the lipid nanoparticles described herein are useful for the introduction of therapeutic agents, such as nucleic acids (eg, mRNA), into cells.

[0307] In one aspect, provided herein is a method for in vivo delivery of a therapeutic agent, the method comprising administering to a mammal lipid nanoparticles comprised of ionizable cationic lipids of Formulas I-IV as described herein.

[0308] In embodiments, lipid nanoparticles described herein can be administered alone or in mixture with pharmaceutically acceptable carrier.Non-limiting examples of pharmaceutically acceptable carrier include water, NaCl, saline, lactated Ringer's, standard sucrose, standard glucose, binder, filler, disintegrant, lubricant, coating, sweetener, flavoring, salt solution (e.g. Ringer's solution), alcohol, oil, gelatin, carbohydrates such as lactose, amylose or starch, fatty acid ester, hydroxymethycellulose, polyvinylpyrrolidine, and coloring agent.

[0309] The pharma- ceutically acceptable carrier is usually added after the formation of the lipid nanoparticles, thus, after the lipid nanoparticles are formed, the nanoparticles can be diluted into a pharma- ceutically acceptable carrier, for example, standard buffered saline.

[0310] For in vivo administration, administration can be by any method known in the art, for example, by injection, oral administration, inhalation (eg, intranasal or intratracheal), transdermal application, or rectal administration.

[0311] In embodiments, the pharmaceutical compositions may be administered parenterally, i.e., intraarticularly, intravenously, intraperitoneally, subcutaneously, or intramuscularly, hi embodiments, the pharmaceutical compositions are administered by intravenous or intraperitoneal bolus injection.

[0312] In one aspect, provided herein is a method for preventing or treating a disease in a mammal in need thereof by administering to the mammal a therapeutically effective amount of lipid nanoparticles comprised of ionizable cationic lipids of formulas I-IV as described herein. In an embodiment, provided herein is a method for preventing a disease in a mammal by administering to the mammal a therapeutically effective amount of lipid nanoparticles comprised of ionizable cationic lipids of formulas I-IV as described herein. In an embodiment, provided herein is a method for treating a disease in a mammal in need thereof by administering to the mammal a therapeutically effective amount of lipid nanoparticles comprised of ionizable cationic lipids of formulas I-IV as described herein.

[0313] In embodiments, the mammal is a dog, a cat or a human. In embodiments, the mammal is a dog. In embodiments, the mammal is a cat. In embodiments, the mammal is a human.

[0314] The present disclosure will be further understood from the following non-limiting examples. EXAMPLES

[0315] As used herein, the symbols and conventions employed in these processes, schemes, and examples are consistent with those used in the contemporary scientific literature, e.g., the Journal of the American Chemical Society, the Journal of Medicinal Chemistry, or the Journal of Biological Chemistry, regardless of whether a particular abbreviation is specifically defined.

[0316] The following examples are intended to be illustrative and can be used to further understand the embodiments of the present disclosure, and should not be construed as limiting the scope of the present teachings in any way.

[0317] The chemical reactions described in the examples can be easily adapted to prepare some other compounds of the present disclosure, and alternative methods for preparing compounds of the present disclosure are considered to be within the scope of the present disclosure. For example, the synthesis of compounds not exemplified according to the present disclosure can be successfully carried out by modifications obvious to those skilled in the art, such as by utilizing other suitable reagents known in the art other than those described, or by modifying the routing of reaction conditions, reagents, and starting materials. Instead, other reactions disclosed herein or known in the art are recognized to have applicability for the preparation of other compounds of the present disclosure.

[0318] Definitions of abbreviations used: AcN Acetonitrile AcOH Acetic acid aq. Water-based Boc tert-Butyloxycarbonyl CSA Camphorsulfonic Acid CSCl2 Thiophosgene DCM Dichloromethane DMF N,N'-Dimethylformamide DMAP Dimethylaminopyridine EDC 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Et Ethyl Eq equivalent g grams hr time HCl Hydrochloric acid HPLC High Performance Liquid Chromatography LC / MS Liquid Chromatography-Mass Spectrometry Me Methyl mg milligram MeOH Methanol mL Milliliters μL / μL microliter mol mmol μmol / umol micromol MS mass spectrometry NaBH(OAc)3 Sodium triacetoxyborohydride PCC Pyridinium Chlorochromate rt room temperature t-Bu tert-Butyl TEA or Et3N Triethylamine TFA Trifluoroacetic acid THF Tetrahydrofuran TLC Thin Layer Chromatography Synthesis Examples

[0319] (Example S1) Synthesis of compound KT-001 (compound of formula (I)).

[0320] Compound KT-001 was prepared as shown in Scheme 1 below. [ka]

[0321] Compound 2. To a mixture of compound 1 (1.00 g, 4.16 mmol) and 1,2,6-hexanetriol (1.12 g, 8.32 mmol) in anhydrous acetonitrile (20 mL) was added camphorsulfonic acid (CSA) (290 mg, 1.25 mmol). The resulting solution was refluxed for 16 hr until TLC showed the reaction was complete. Compound 2 (650 mg) was obtained by silica gel chromatography.

[0322] Compound 3. Pyridinium chlorochromate (PCC) (785 mg, 3.64 mmol) was added to a solution of compound 2 (650 mg, 1.82 mmol) in dichloromethane (30 mL). The reaction was stirred at room temperature for 2 hr until TLC showed the reaction was complete. Compound 3 (320 mg) was obtained by silica gel chromatography.

[0323] Compound KT-001. Acetic acid (4 μL, 0.068 mmol) was added to a mixture of compound 3 (300 mg, 0.846 mmol) and 4-amino-1-butanol (30 mg, 0.338 mmol) in dichloromethane (5 mL). The resulting mixture was stirred at rt for 15 min, followed by the addition of sodium triacetoxyborohydride (NaBH(OAc)3) (215 mg, 1.01 mmol) and stirring at rt for another 4 h. Compound KT-001 (165 mg) was obtained by silica gel chromatography. 1 HNMR (500 MHz, CDCl3): δ = 0.85-0.91 (m, 12H), 1.20-1.44 (m, 48H), 1.46-1.72 (m, 20H), 2.31-2.61 (br, 6H), 3.40-3.47 (m, 2H), 3.52-3.60 (m, 2H), 3.99-4.07 (m, 4H).

[0324] (Example S2) Synthesis of compound TU-001 (compound of formula (II)).

[0325] Compound TU-001 was prepared as shown in Scheme 2 below. [ka]

[0326] A solution of compound 4 (510 mg, 5.0 mmol) in DCM (10 mL) was cooled to 0° C. Thiophosgene (CSCl2, 862 mg, 575 μL, 7.5 mmol) and TEA (1.4 mL, 10.0 mmol) were added to the solution. The resulting mixture was stirred at rt for 16 hr and then washed with sat. NaHCO3. Compound 5 (720 mg) was used crude in the next step.

[0327] TEA (1 mL) was added to a mixture of 5 (720 mg, 5.0 mmol) and bis(2-hydroxypropyl)amine (400 mg, 3.0 mmol) in MeOH (10 mL). The resulting mixture was stirred at rt for 16 hr until TLC showed the reaction was complete. Compound 6 (540 mg) was obtained by silica gel chromatography.

[0328] EDC·HCl (221 mg, 1.15 mmol) and DMAP (141 mg, 1.15 mmol) were added to a mixture of compound 6 (80 mg, 0.29 mmol) and 2-hexyldecanoic acid (296 mg, 338 μL, 1.15 mmol) in DCM (5 mL). The resulting mixture was stirred at rt for 16 hr until TLC showed the reaction was complete. Compound TU-001 (171 mg) was obtained by silica gel chromatography. 1 HNMR (500 MHz, CDCl3): δ = 0.88 (t, 12 H, J = 6.5 Hz), 1.15-1.65 (m, 54H), 1.93-2.05 (m, 6H), 2.26-2.40 (m, 4H), 3.62-3.81 (m, 6H), 4.13 (t, 4H, J = 6.5 Hz).

[0329] (Example S3) Synthesis of compound TU-002 (compound of formula (II)).

[0330] Compound TU-002 was prepared as shown in Scheme 3 below. [ka]

[0331] A solution of compound 7 (720 mg, 5.0 mmol) in DCM (10 mL) was cooled to 0° C. Thiophosgene (CSCl2, 862 mg, 575 μL, 7.5 mmol) and TEA (1.4 mL, 10.0 mmol) were added to the solution. The resulting mixture was stirred at rt for 16 hr and then washed with sat. NaHCO3. Compound 8 (930 mg) was used as crude product for the next step.

[0332] TEA (1 mL) was added to a mixture of compound 8 (930 mg, 5.0 mmol) and bis(2-hydroxypropyl)amine (400 mg, 3.0 mmol) in MeOH (10 mL). The resulting mixture was stirred at rt for 16 hr until TLC showed the reaction was complete. Compound 9 (630 mg) was obtained by silica gel chromatography.

[0333] EDC·HCl (192 mg, 1.00 mmol) and DMAP (122 mg, 1.00 mmol) were added to a mixture of compound 9 (80 mg, 0.25 mmol) and 2-hexyldecanoic acid (256 mg, 293 μL, 1.00 mmol) in DCM (5 mL). The resulting mixture was stirred at rt for 16 hr until TLC showed the reaction was complete. Compound TU-002 (158 mg) was obtained by silica gel chromatography.

[0334] 1HNMR (500 MHz, CDCl3): δ = 0.88 (t, 12H, J = 7.0 Hz), 1.18-1.33 (m, 40 H), 1.40-1.50 (m, 4H), 1.52-1.65 (m, 8H), 1.95-2.06 (m, 4H), 2.27-2.37 (m, 2H), 2.42-2.68 (m, 4H), 3.54-3.90 (m, 10H), 4.13 (t, 4H, J = 6.5 Hz).

[0335] (Example S4) Synthesis of compound TU-003 (compound of formula (II)).

[0336] Compound TU-003 was prepared as shown in Scheme 4 below. [ka]

[0337] A solution of compound 10 (780 mg, 5.0 mmol) in DCM (10 mL) was cooled to 0° C. Thiophosgene (CSCl2, 862 mg, 575 μL, 7.5 mmol) and TEA (1.4 mL, 10.0 mmol) were added to the solution. The resulting mixture was stirred at rt for 16 hr and then washed with sat. NaHCO3. Compound 11 (990 mg) was used as crude product for the next step.

[0338] TEA (1 mL) was added to a mixture of compound 11 (990 mg, 5.0 mmol) and bis(2-hydroxypropyl)amine (400 mg, 3.0 mmol) in MeOH (10 mL). The resulting mixture was stirred at rt for 16 hr until TLC showed the reaction was complete. Compound 12 (670 mg) was obtained by silica gel chromatography.

[0339] EDC·HCl (174 mg, 0.91 mmol) and DMAP (111 mg, 0.91 mmol) were added to a mixture of compound 12 (75 mg, 0.23 mmol) and 2-hexyldecanoic acid (232 mg, 265 μL, 0.91 mmol) in DCM (5 mL). The resulting mixture was stirred at rt for 16 hr until TLC showed the reaction was complete. Compound TU-003 (133 mg) was obtained by silica gel chromatography. 1 HNMR (500 MHz, CDCl3): δ = 0.87 (t, 12H, J = 7.0 Hz), 1.06 (d, 3H, J = 6.5 Hz), 1.19-1.33 (m, 45H). 1.40-1.50 (m, 5H), 1.54-1.68 (m, 10H), 1.96-2.04 (m, 4H), 2.27-2.37 (m, 3H), 3.55-3.84 (m, 6H), 4.12 (t, 4H, J = 6.5 Hz).

[0340] (Example S5) Synthesis of compound TU-004 (compound of formula (II)).

[0341] Compound TU-004 was prepared as shown in Scheme 5 below. [ka]

[0342] A solution of compound 13 (785 mg, 5.0 mmol) in DCM (10 mL) was cooled to 0° C. Thiophosgene (CSCl2, 862 mg, 575 μL, 7.5 mmol) and TEA (1.4 mL, 10.0 mmol) were added to the solution. The resulting mixture was stirred at rt for 16 hr and then washed with sat. NaHCO3. Compound 14 (995 mg) was used as crude product for the next step.

[0343] TEA (1 mL) was added to a mixture of compound 14 (995 mg, 5.0 mmol) and bis(2-hydroxypropyl)amine (400 mg, 3.0 mmol) in MeOH (10 mL). The resulting mixture was stirred at rt for 16 hr until TLC showed the reaction was complete. Compound 15 (630 mg) was obtained by silica gel chromatography.

[0344] EDC·HCl (173 mg, 0.90 mmol) and DMAP (110 mg, 0.90 mmol) were added to a mixture of compound 15 (75 mg, 0.23 mmol) and 2-hexyldecanoic acid (231 mg, 264 μL, 0.90 mmol) in DCM (5 mL). The resulting mixture was stirred at rt for 16 hr until TLC showed the reaction was complete. Compound TU-004 (127 mg) was obtained by silica gel chromatography. 1 HNMR (500 MHz, CDCl3): δ = 0.87 (t, 12H, J = 7.0 Hz), 1.19-1.32 (m, 40 H), 1.39-1.49 (m, 4H), 1.53-1.68 (m, 6H), 1.76-1.83 (m, 2H), 1.96-2.05 (m, 4H), 2.28 (s, 3H), 2.29-2.58 (m, 10H), 3.64-3.76 (m, 6H), 4.12 (t, 4H, J = 6.5 Hz).

[0345] (Example S6) Synthesis of compound TU-005 (compound of formula (II)).

[0346] Compound TU-005 was prepared as shown in Scheme 6 below. [ka]

[0347] A solution of compound 16 (870 mg, 5.0 mmol) in DCM (10 mL) was cooled to 0° C. Thiophosgene (CSCl2, 862 mg, 575 μL, 7.5 mmol) and TEA (1.4 mL, 10.0 mmol) were added to the solution. The resulting mixture was stirred at rt for 16 hr and then washed with sat. NaHCO3. Compound 17 (1.08 g) was used as crude product in the next step.

[0348] TEA (1 mL) was added to a mixture of compound 17 (1.08 g, 5.0 mmol) and bis(2-hydroxypropyl)amine (400 mg, 3.0 mmol) in MeOH (10 mL). The resulting mixture was stirred at rt for 16 hr until TLC showed the reaction was complete. Compound 18 (895 mg) was obtained by silica gel chromatography.

[0349] EDC·HCl (1.54 g, 8.00 mmol) and DMAP (978 mg, 8.00 mmol) were added to a mixture of compound 18 (700 mg, 2.00 mmol) and 2-hexyldecanoic acid (2.05 g, 2.34 mL, 8.00 mmol) in DCM (35 mL). The resulting mixture was stirred at rt for 16 hr until TLC showed the reaction was complete. Compound 19 (1.26 g) was obtained by silica gel chromatography.

[0350] A solution of compound 19 (1.20 g, 1.45 mmol) in DCM (20 mL) was cooled to 0° C. TFA (2 mL) was added and the mixture was stirred at rt for 16 hr. The reaction mixture was then concentrated and purified via silica gel chromatography to produce compound TU-005 (970 mg). 1HNMR (500 MHz, CD3OD): δ = 0.92 (t, 12H, J = 7.0 Hz), 1.24-1.40 (m, 40H), 1.44-1.69 (m, 8H), 1.92-2.06 (m, 6H), 2.35-2.44 (m, 2H), 3.00 (t, 2H, J = 7.0 Hz), 3.77 (t, 4H, J = 7.5 Hz), 3.82 (t, 2H, J = 6.5 Hz), 4.15 (t, 4H, J = 6.5 Hz).

[0351] (Example S7) Synthesis of compound TU-006 (compound of formula (II)).

[0352] Compound TU-006 was prepared as shown in Scheme 7 below. [ka]

[0353] AcOH (3 μL, 0.04 mmol) was added to a mixture of compound TU-005 (120 mg, 0.16 mmol) and acetaldehyde (70 mg, 1.6 mmol, 89 μL) in DCM (10 mL), and the resulting solution was stirred at rt for 15 min. After addition of NaBH(OAc)3 (260 mg, 1.23 mmol), stirring was continued for another 4 hr until TLC showed the reaction was complete. Compound TU-006 (98 mg) was obtained by silica gel chromatography. 1 HNMR (500 MHz, CD3OD): δ = 0.92 (t, 12H, J = 7.0 Hz), 1.24-1.40 (m, 46H), 1.45-1.55 (m, 4H), 1.58-1.69 (m, 4H), 1.96-2.13 (m, 6H), 2.35-2.44 (m, 2H), 3.19 (t, 2H, J = 7.5 Hz), 3.28 (q, 4H, J = 7.0 Hz), 3.73-3.83 (m, 6H), 4.15 (t, 4H, J = 6.5 Hz).

[0354] (Example S8) Synthesis of compound TU-007 (compound of formula (II)).

[0355] Compound TU-007 was prepared as shown in Scheme 8 below. [ka]

[0356] AcOH (3 μL, 0.04 mmol) was added to a mixture of compound TU-005 (120 mg, 0.16 mmol) and propionaldehyde (93 mg, 1.6 mmol, 115 μL) in DCM (10 mL), and the resulting solution was stirred at rt for 15 min. After addition of NaBH(OAc)3 (260 mg, 1.23 mmol), stirring was continued for another 4 hr until TLC showed the reaction was complete. Compound TU-007 (76 mg) was obtained by silica gel chromatography. 1 HNMR (500 MHz, CD3OD): δ = 0.92 (t, 12H, J = 7.0 Hz), 1.06 (t, 6H, J = 7.0 Hz), 1.23-1.38 (m, 40H), 1.46-1.67 (m, 8H), 1.72-1.84 (m, 4H), 2.00-2.19 (m, 6H), 2.35-2.45 (m, 2H), 3.09-3.19 (m, 4H), 3.22-3.29 (m, 2H), 3.52-3.67 (m, 6H), 4.11-4.24 (m, 4H).

[0357] (Example S9) Synthesis of compound TU-008 (compound of formula (II)).

[0358] Compound TU-008 was prepared as shown in Scheme 9 below. [ka]

[0359] AcOH (5 μL, 0.08 mmol) was added to a mixture of compound TU-005 (250 mg, 0.34 mmol) and acetone (400 μL) in DCM (10 mL), and the resulting solution was stirred at rt for 15 min. After addition of NaBH(OAc)3 (260 mg, 1.23 mmol), stirring was continued for another 4 hr until TLC showed the reaction was complete. Compound TU-008 (206 mg) was obtained by silica gel chromatography. 1 HNMR (500 MHz, CDCl3): δ = 0.92 (t, 12H, J = 7.0 Hz), 1.23-1.40 (m, 46H), 1.45-1.55 (m, 4H), 1.57-1.68 (m, 4H), 1.93-2.06 (m, 6H), 2.35-2.44 (m, 2H), 3.06 (t, 2H, J = 7.0 Hz), 3.36-3.44 (m, 1H), 3.78 (t, 4H, J = 7.5 Hz), 3.84 (t, 2H, J = 6.5 Hz), 4.15 (t, 4H, J = 6.5 Hz).

[0360] (Example S10) Synthesis of compound TU-009 (compound of formula (II)).

[0361] Compound TU-009 was prepared as shown in Scheme 10 below. [ka]

[0362] AcOH (3 μL, 0.04 mmol) was added to a mixture of compound TU-005 (120 mg, 0.16 mmol) and butyraldehyde (115 mg, 1.6 mmol, 144 μL) in DCM (10 mL), and the resulting solution was stirred at rt for 15 min. After addition of NaBH(OAc)3 (260 mg, 1.23 mmol), stirring was continued for another 4 hr until TLC showed the reaction was complete. Compound TU-009 (94 mg) was obtained by silica gel chromatography. 1HNMR (500 MHz, CD3OD): δ = 0.92 (t, 12H, J = 7.0 Hz), 1.04 (t, 6H, J = 7.5 Hz), 1.24-1.38 (m, 40H), 1.41-1.55 (m, 8H), 1.58-1.77 (m, 8H), 1.97-2.11 (m, 6H), 2.36-2.43 (m, 2H), 3.15-3.24 (m, 6H), 3.73-3.81 (m, 6H), 4.15 (t, 4H, J = 6.0 Hz).

[0363] (Example S11) Synthesis of compound BAE-001 (compound of formula (III)).

[0364] Compound BAE-001 was prepared as shown in Scheme 11 below. [ka]

[0365] 4-Amino-1-butanol (450 mg, 5.04 mmol) was added to a solution of compound 20 (500 mg, 2.52 mmol) in anhydrous THF (10 mL), and the resulting mixture was stirred at rt for 16 hr. Compound 21 (658 mg) was obtained by silica gel chromatography.

[0366] AcOH (5 μL, 0.08 mmol) was added to a mixture of compound 21 (154 mg, 0.41 mmol) and 6-(2'-hexyldecanoyloxy)hexanal (362 mg, 1.02 mmol) in DCM (10 mL), and the resulting solution was stirred at rt for 15 min. After addition of NaBH(OAc)3 (260 mg, 1.23 mmol), stirring was continued for another 4 hr until TLC showed the reaction was complete. Compound BAE-001 (98 mg) was obtained by silica gel chromatography. 1HNMR (500 MHz, CDCl3): δ = 0.87 (t, 12H, J = 7.0 Hz), 1.17-1.80 (m, 76H), 2.27-2.34 (m, 2H), 2.36-2.62 (br, 12H), 2.75-2.97 (m, 4H), 3.52-3.61 (m, 4H), 4.05 (t, 4H, J = 6.5 Hz), 4.08-4.15 (m, 4H).

[0367] (Example S12) Synthesis of compound BAA-001 (compound of formula (III)).

[0368] Compound BAA-001 was prepared as shown in Scheme 12 below. [ka]

[0369] 4-Amino-1-butanol (450 mg, 5.04 mmol) was added to a solution of compound 22 (522 mg, 2.00 mmol) in anhydrous methanol (20 mL), and the resulting mixture was refluxed for 16 hr. Compound 23 (705 mg) was obtained by C18 gel chromatography.

[0370] AcOH (5 μL, 0.08 mmol) was added to a mixture of compound 23 (180 mg, 0.41 mmol) and 6-(2'-hexyldecanoyloxy)hexanal (362 mg, 1.02 mmol) in THF (10 mL), and the resulting solution was stirred at rt for 15 min. After addition of NaBH(OAc)3 (260 mg, 1.23 mmol), stirring was continued for another 4 hr until TLC showed the reaction was complete. Compound BAA-001 (213 mg) was obtained by silica gel chromatography. 1HNMR (500 MHz, CD3OD): δ = 0.92 (t, 12H, J = 7.0 Hz), 1.23-1.72 (m, 74H), 2.32-2.41 (m, 6H), 2.47-2.54 (m, 6H), 2.81 (t, 4H, J = 7.0 Hz), 2.85 (t, 4H, J = 7.0 Hz), 3.52 (t, 4H, J = 6.5 Hz), 3.58 (t, 4H, J = 6.0 Hz), 4.11 (t, 4H, J = 6.5 Hz).

[0371] (Example S13) Synthesis of compound DS-001 (compound of formula (IV)).

[0372] Compound DS-001 was prepared as shown in Scheme 13 below. [ka] [ka]

[0373] TEA (90 mg, 124 μL, 0.89 mmol) was added to a mixture of compound 24 (1.58 g, 4.45 mmol) and N-Boc-1,4-butanediammonium hydrochloride (400 mg, 1.78 mmol) in DCM (30 mL). The resulting solution was stirred at rt for 15 min, followed by the addition of NaBH(OAc)3 (1.13 g, 5.34 mmol) and stirring for another 4 hr until TLC showed the reaction was complete. Compound 25 (1.3 g) was obtained by silica gel chromatography.

[0374] TFA (3 mL) was added to a solution of compound 25 (400 mg, 0.46 mmol) in DCM (6 mL). The resulting mixture was stirred at rt for 16 hr until TLC showed the reaction was complete. Elution through a C-18 gel cartridge gave compound 26 (429 mg).

[0375] TEA (0.5 mL) was added to a mixture of compound 26 (200 mg, 0.21 mmol) and 2-imidazolylcarbonyloxyethyl disulfide (32.8 mg, 0.096 mmol) in DCM (6 mL). The resulting mixture was stirred at rt for 16 hr until TLC showed the reaction was complete. Elution through a C-18 gel cartridge afforded compound DS-001. 1 HNMR (500 MHz, CDCl3): δ = 0.84-0.90 (m, 24H), 1.19-1.66 (m, 136H), 2.26-2.34 (m, 4H), 2.34-2.42 (m, 12H), 2.88-2.96 (m, 4H), 3.12-3.21 (m, 4H), 4.06 (t, 8H, J = 7.0 Hz), 4.30 (t, 4H, J = 7.0 Hz).

[0376] Example 14 Characterization of KT-001, TU-001, TU-002, TU-003, TU-004, TU-005, TU-006, TU-007, TU-008, TU-009, BAE-001, BAA-001, and DS-001.

[0377] Lipid nanoparticles were prepared with the following composition: ALC-0315:DSPC:cholesterol:GM020=50:10:38.5:1.5 (and buffer) (positive control) TU-001:DSPC:cholesterol:GM020=50:10:38.5:1.5 (and buffer) TU-002:DSPC:cholesterol:GM020=50:10:38.5:1.5 (and buffer) TU-003:DSPC:cholesterol:GM020=50:10:38.5:1.5 (and buffer) TU-004:DSPC:cholesterol:GM020=50:10:38.5:1.5 (and buffer) TU-005:DSPC:cholesterol:GM020=50:10:38.5:1.5 (and buffer) TU-006:DSPC:cholesterol:GM020=50:10:38.5:1.5 (and buffer) TU-007:DSPC:cholesterol:GM020=50:10:38.5:1.5 (and buffer) TU-008:DSPC:cholesterol:GM020=50:10:38.5:1.5 (and buffer) TU-009:DSPC:cholesterol:GM020=50:10:38.5:1.5 (and buffer) BAE-001:DSPC:cholesterol:GM020=50:10:38.5:1.5 (and buffer) BAA-001:DSPC:cholesterol:GM020=50:10:38.5:1.5 (and buffer) DS-001: DSPC: cholesterol: GM020 = 25: 10: 38.5: 1.5 (and buffer) KT-001:DSPC:cholesterol:GM020=50:10:38.5:1.5 (and buffer) The buffer is water, trehalose, Tris base, sodium chloride. DSPC is 1,2-distearoyl-sn-glycero-3-phosphocholine. GM020 is DMG-PEG (1,2-dimyristoyl-rac-glycero-3-methylpolyoxyethylene).

[0378] Table 1 summarizes the characterization of lipid nanoparticles with respect to various parameters including nanoparticle size (Z avg), polydispersity index (PDI), charge (zeta potential), encapsulation efficiency and yield.

[0379] [Table 1-1] [Table 1-2] Biological Examples

[0380] (Example B1) In vivo efficacy of SARS-CoV-2 spike mRNA in lipid nanoparticle formulations

[0381] Eight formulations containing SARS-CoV-2 spike mRNA in lipid nanoparticles were prepared. All formulations had the same mRNA concentration of 0.02 μg / μL and the same volume (50 μL) was injected into each mouse. The specific formulation of each lipid nanoparticle is shown in Figure 2. The rsF352 formulation with ALC-0315 was the positive control or reference formulation.

[0382] All spiked mRNA LNP (lipid nanoparticle) formulations were administered to female Balb / c mice via intramuscular injection. Female Balb / c mice (6-8 weeks old, 16-20 g) were purchased from The Jackson Laboratory (USA). Each of the six formulations was administered to five mice (i.e., a total of 30 mice). Blood was collected from each mouse on days 7, 14, and 28 after injection.

[0383] Mouse serum samples were isolated using a benchtop refrigerated centrifuge (10k RCF, 4°C, 20 min). Samples were transferred to serum storage plates according to mouse ear tag number sequence and stored at -70°C prior to ELISA.

[0384] ELISA was performed according to standard techniques (e.g., https: / / www.sinobiological.com / antibodies / cov-spike-40592-mm117 ) following the Spike S1 mIgG ELISA Protocol.

[0385] 4PL curve fitting and interpolation were performed to calculate IgG concentrations in mouse serum samples using GraphPad Prism 9. Values ​​are presented as mean ± SEM.

[0386] Figures 1A-D show the amount of anti-spike antibodies (antibodies to SARS-CoV-2) produced in mice in response to injection of lipid nanoparticles containing spike mRNA. Figure 1A demonstrates that equivalent amounts of anti-spike antibodies (antibodies to SARS-CoV-2) were produced in mice 28 days after injection of lipid nanoparticles containing ALC-0315 lipid (positive control) and lipid nanoparticles containing TU-001 lipid (the remainder of the nanoparticle composition was the same) (see Figure 2) (lipid nanoparticles in Figure 1A contain Washington (WA) wild-type spike mRNA).

[0387] Figure 1C-D demonstrates that the highest amounts of anti-spike antibodies (antibodies to SARS-CoV-2) were produced in mice injected with lipid nanoparticles containing KT-001 lipid (28 days after injection; lipid nanoparticles in Figure 1C-D contain Beta-Furin Spike mRNA).

[0388] The complete disclosures of all publications cited herein are hereby incorporated by reference in their entirety as if each was individually set forth in full and incorporated herein.

[0389] Various modifications and alterations to the embodiments disclosed herein will be apparent to those skilled in the art without departing from the scope and spirit of the present disclosure. Illustrative embodiments and examples are provided by way of example only and are not intended to limit the scope of the present invention.

Claims

1. Cationic lipids of formula (I): 【Chemistry 91】 or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, or prodrug thereof, wherein: R １ is H, -OR １Ａ , -YOR １Ａ , -NR １Ａ R １Ｂ , -YNR １Ａ R １Ｂ , -SR １Ａ , -YSR １Ａ , -(C=O)R １Ａ , -Y(C=O)R １Ａ , -(C=O)OR １Ａ , -Y(C=O)OR １Ａ , —O(C═O)R １Ａ , -YO(C=O)R １Ａ , -O(C=O)OR １Ａ , -YO(C=O)OR １Ａ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Y is a substituted or unsubstituted C ０ ~C １２ alkylene or substituted or unsubstituted 0-12 membered heteroalkylene; R ２ is H, -OR ２Ａ , -SR ２Ａ , -(C=O)R ２Ａ , -(C=O)OR ２Ａ , —O(C═O)R ２Ａ , -O(C=O)OR ２Ａ , -(C=O)NHR ２Ａ , -NH(C=O)R ２Ａ , substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; R ３ is H, -OR ３Ａ , -SR ３Ａ , -(C=O)R ３Ａ , -(C=O)OR ３Ａ , —O(C═O)R ３Ａ , -O(C=O)OR ３Ａ , -(C=O)NHR ３Ａ , -NH(C=O)R ３Ａ , substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; R ４ is H, -OR ４Ａ , -SR ４Ａ , -(C=O)R ４Ａ , -(C=O)OR ４Ａ , —O(C═O)R ４Ａ , -O(C=O)OR ４Ａ , -(C=O)NHR ４Ａ , -NH(C=O)R ４Ａ , substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; R ５ is H, -OR ５Ａ , -SR ５Ａ , -(C=O)R ５Ａ , -(C=O)OR ５Ａ , —O(C═O)R ５Ａ , -O(C=O)OR ５Ａ , -(C=O)NHR ５Ａ , -NH(C=O)R ５Ａ , substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; B １ is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; B ２ and B ３ are each independently a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; L １ is a bond, -O(C=O)-, -(C=O)O-, -O(C=O)O-, -C(=O)-, -O-, -O(CR １０１ R １０２ ) ｓ O-, -S-, -C(=O)S-, -SC(=O)-, -NR １０１ C(=O)-, -C(=O)NR １０１ -, -NR １０１ C(=S)-, -C(=S)NR １０１ -, -NR １０１ C(=O)NR １０２ -, -NR １０１ C(=S)NR １０２ -, -OC(=O)NR １０１ -, -NR １０１ C(=O)O-, -SC(=O)NR １０１ -or-NR １０１ C(═O)S—, L ２ is a bond, -O(C=O)-, -(C=O)O-, -O(C=O)O-, -C(=O)-, -O-, -O(CR ２０１ R ２０２ ) ｓ O-, -S-, -C(=O)S-, -SC(=O)-, -NR ２０１ C(=O)-, -C(=O)NR ２０１ -, -NR ２０１ C(=O)NR ２０２ -, -NR ２０１ C(=S)-, -C(=S)NR ２０１ -, -NR ２０１ C(=S)NR ２０２ -, -OC(=O)NR ２０１ -, -NR ２０１ C(=O)O-, -SC(=O)NR ２０１ -or-NR ２０１ C(═O)S—, L ３ is a bond, -O(C=O)-, -(C=O)O-, -O(C=O)O-, -C(=O)-, -O-, -O(CR ３０１ R ３０２ ) ｓ O-, -S-, -C(=O)S-, -SC(=O)-, -NR ３０１ C(=O)-, -C(=O)NR ３０１ -, -NR ３０１ C(=O)NR ３０２ -, -NR ３０１ C(=S)-, -C(=S)NR ３０１ -, -NR ３０１ C(=S)NR ３０２ -, -OC(=O)NR ３０１ -, -NR ３０１ C(=O)O-, -SC(=O)NR ３０１ -or-NR ３０１ C(═O)S—, L ４ is a bond, -O(C=O)-, -(C=O)O-, -O(C=O)O-, -C(=O)-, -O-, -O(CR ４０１ R ４０２ ) ｓ O-, -S-, -C(=O)S-, -SC(=O)-, -NR ４０１ C(=O)-, -C(=O)NR ４０１ -, -NR ４０１ C(=O)NR ４０２ -, -NR ４０１ C(=S)-, -C(=S)NR ４０１ -, -NR ４０１ C(=S)NR ４０２ -, -OC(=O)NR ４０１ -, -NR ４０１ C(=O)O-, -SC(=O)NR ４０１ -or-NR ４０１ C(═O)S—, L ５ is a bond, -O(C=O)-, -(C=O)O-, -O(C=O)O-, -C(=O)-, -O-, -O(CR ５０１ R ５０２ ) ｓ O-, -S-, -C(=O)S-, -SC(=O)-, -NR ５０１ C(=O)-, -C(=O)NR ５０１ -, -NR ５０１ C(=O)NR ５０２ -, -NR ５０１ C(=S)-, -C(=S)NR ５０１ -, -NR ５０１ C(=S)NR ５０２ -, -OC(=O)NR ５０１ -, -NR ５０１ C(=O)O-, -SC(=O)NR ５０１ -or-NR ５０１ C(═O)S—, L ６ is a bond, -O(C=O)-, -(C=O)O-, -O(C=O)O-, -C(=O)-, -O-, -O(CR ６０１ R ６０２ ) ｓ O-, -S-, -C(=O)S-, -SC(=O)-, -NR ６０１ C(=O)-, -C(=O)NR ６０１ -, -NR ６０１ C(=O)NR ６０２ -, -NR ６０１ C(=S)-, -C(=S)NR ６０１ -, -NR ６０１ C(=S)NR ６０２ -, -OC(=O)NR ６０１ -, -NR ６０１ C(=O)O-, -SC(=O)NR ６０１ -or-NR ６０１ C(═O)S—, L ７ is a bond, -O(C=O)-, -(C=O)O-, -O(C=O)O-, -C(=O)-, -O-, -O(CR ７０１ R ７０２ ) ｓ O-, -S-, -C(=O)S-, -SC(=O)-, -NR ７０１ C(=O)-, -C(=O)NR ７０１ -, -NR ７０１ C(=O)NR ７０２ -, -NR ７０１ C(=S)-, -C(=S)NR ７０１ -, -NR ７０１ C(=S)NR ７０２ -, -OC(=O)NR ７０１ -, -NR ７０１ C(=O)O-, -SC(=O)NR ７０１ -or-NR ７０１ C(═O)S—, L ａ１ and L ａ２ are each independently 【Chemistry 92】 and Each X is independently O, S, or CH ２ and W １ , W ２ , W ３ , W ４ , W ５ , and W ６ are each independently a bond, a substituted or unsubstituted C １ ~C １２ alkylene, or substituted or unsubstituted 2- to 12-membered heteroalkylene; Each R １Ａ and R １Ｂ are independently H, substituted or unsubstituted C １ ~C １２ alkyl, or substituted or unsubstituted 2- to 12-membered heteroalkyl; Each R ２Ａ , R ３Ａ , R ４Ａ , and R ５Ａ are independently H, substituted or unsubstituted C １ ~C ３０ alkyl, or substituted or unsubstituted 2- to 30-membered heteroalkyl; Each R １０１ , R １０２ , R ２０１ , R ２０２ , R ３０１ , R ３０２ , R ４０１ , R ４０２ , R ５０１ , R ５０２ , R ６０１ , R ６０２ , R ７０１ , and R ７０２ are independently H, substituted or unsubstituted C １ ~C １２ alkyl, or substituted or unsubstituted 2- to 12-membered heteroalkyl; each s is independently an integer from 1 to 4;

2. R １ But H, -OR １Ａ or substituted or unsubstituted heteroalkyl; L １ is a bond, -NR １０１ C(=S)-, -C(=S)NR １０１ -, -O(C=O)-, -(C=O)O-, or -O-; B １ is a bond or substituted or unsubstituted alkylene; B ２ and B ３ are each independently a bond or substituted or unsubstituted alkylene; L ２ is a bond, —O(C═O)—, —(C═O)O—, —O(C═O)O—, —C(═O)—, —O—, or —S—; L ４ is a bond, —O(C═O)—, —(C═O)O—, —O(C═O)O—, —C(═O)—, —O—, or —S—; W １ , W ２ , W ３ , W ４ , W ５ , and W ６ each independently represents a bond or a substituted or unsubstituted C １ ~C １２ is alkylene, L ａ１ and L ａ２ However, each independently, 【Chemistry 93】 and each X is independently O or S; L ３ is a bond, —O(C═O)—, —(C═O)O—, —O(C═O)O—, —C(═O)—, —O—, or —S—; L ５ is a bond, —O(C═O)—, —(C═O)O—, —O(C═O)O—, —C(═O)—, —O—, or —S—; L ６ is a bond, —O(C═O)—, —(C═O)O—, —O(C═O)O—, —C(═O)—, —O—, or —S—; L ７ is a bond, —O(C═O)—, —(C═O)O—, —O(C═O)O—, —C(═O)—, —O—, or —S—; R ２ is H or substituted or unsubstituted alkyl; R ３ is H or substituted or unsubstituted alkyl; R ４ is H or substituted or unsubstituted alkyl; R ５ is H or substituted or unsubstituted alkyl; Each R １Ａ are independently H or substituted or unsubstituted C １ ~C １２ is alkyl, Each R １０１ is independently H or substituted or unsubstituted 2-12 membered heteroalkyl, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, or prodrug thereof.

3. R １ is H, —OH, methoxy, ethoxy, or substituted or unsubstituted heteroalkyl; L １ is a bond, -NR １０１ C(=S)- or -C(=S)NR １０１ - and B １ is a bond or an unsubstituted C １ ~C ８ is alkylene, B ２ and B ３ each independently represents a bond or a substituted or unsubstituted C １ ~C ８ is alkylene, L ２ is a bond, —O(C═O)—, or —(C═O)O—; L ４ is a bond, —O(C═O)—, or —(C═O)O—; W １ , W ２ , W ３ , W ４ , W ５ , and W ６ each independently represents a bond or a substituted or unsubstituted C １ ~C １２ is alkylene, L ａ１ and L ａ２ However, each independently, 【Chemical 94】 and each X is independently O or S; L ３ is a bond, —O(C═O)—, or —(C═O)O—; L ５ is a bond, —O(C═O)—, or —(C═O)O—; L ６ is a bond, —O(C═O)—, or —(C═O)O—; L ７ is a bond, —O(C═O)—, or —(C═O)O—; R ２ is H or substituted or unsubstituted C １ ~C １２ is alkyl, R ３ is H or substituted or unsubstituted C １ ~C １２ is alkyl, R ４ is H or substituted or unsubstituted C １ ~C １２ is alkyl, R ５ is H or substituted or unsubstituted C １ ~C １２ is alkyl, Each R １０１ is independently a substituted or unsubstituted 2- to 12-membered heteroalkyl, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, or prodrug thereof.

4. R １ is —OH or methoxy; L １ is the bond, B １ is unsubstituted C １ ~C ８ is alkylene, B ２ and B ３ each independently represents a bond or a substituted or unsubstituted C １ ~C ８ is alkylene, L ２ is the bond, L ４ is the bond, W １ , W ２ , W ３ , W ４ , W ５ , and W ６ each independently represents a bond or a substituted or unsubstituted C １ ~C １２ is alkylene, L ａ１ and L ａ２ However, each independently, 【Chemical 95】 and each X is independently O; L ３ is the bond, L ５ is the bond, L ６ is the bond, L ７ is the bond, R ２ is H or substituted or unsubstituted C １ ~C １２ is alkyl, R ３ is H or substituted or unsubstituted C １ ~C １２ is alkyl, R ４ is H or substituted or unsubstituted C １ ~C １２ is alkyl, R ５ is H or substituted or unsubstituted C １ ~C １２ 4. The cationic lipid of claim 3, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, or prodrug thereof, wherein R is alkyl.

5. R １ is substituted or unsubstituted heteroalkyl; L １ But -C(=S)NR １０１ -, wherein said carbon atom in formula (I) is linked to a nitrogen atom, B １ is a bond, B ２ and B ３ each independently represents a bond or a substituted or unsubstituted C １ ~C ８ is alkylene, L ２ is a bond, —O(C═O)—, or —(C═O)O—; L ４ is a bond, —O(C═O)—, or —(C═O)O—; W １ , W ２ , W ３ , W ４ , W ５ , and W ６ each independently represents a bond or a substituted or unsubstituted C １ ~C １２ is alkylene, L ａ１ and L ａ２ However, each independently, 【Chemistry 96】 and each X is independently O; L ３ is a bond, L ５ is a bond, L ６ is a bond, L ７ is a bond, R ２ is H or substituted or unsubstituted C １ ~C １２ is alkyl, R ３ is H or substituted or unsubstituted C １ ~C １２ is alkyl, R ４ is H or substituted or unsubstituted C １ ~C １２ is alkyl, R ５ is H or substituted or unsubstituted C １ ~C １２ 4. The cationic lipid of claim 3, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, or prodrug thereof, wherein R is alkyl.

6. The cationic lipid 【Chemistry 97-1】 【Chemistry 97-2】 2. The cationic lipid of claim 1, wherein the cationic lipid is:

7. Cationic lipids of formula (II): 【Chem.98】 or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, or prodrug thereof, wherein: B ４ Is W ７ -L ａ３ -W ８ and W ７ and W ８ are each independently a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; L ａ３ is a bond, -O(C=O)-, -(C=O)O-, -O(C=O)O-, -C(=O)-, -O-, -O(CR ａ３１ R ａ３２ ) ｓ O-, -S-, -C(=O)S-, -SC(=O)-, -NR ａ３１ C(=O)-, -C(=O)NR ａ３１ -, -NR ａ３１ C(=O)NR ａ３２ -, -NR ａ３１ C(=S)-, -C(=S)NR ａ３１ -, -NR ａ３１ C(=S)NR ａ３２ -, -OC(=O)NR ａ３１ -, -NR ａ３１ C(=O)O-, -SC(=O)NR ａ３１ -or-NR ａ３１ C(═O)S—, R １０ and R １１ are each independently H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or R １０ and R １１ together with the nitrogen atom to which they are attached form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; B ５ , B ６ , and B ７ are each independently a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; L ８ is a bond, -O(C=O)-, -(C=O)O-, -O(C=O)O-, -C(=O)-, -O-, -O(CR ８０１ R ８０２ ) ｓ O-, -S-, -C(=O)S-, -SC(=O)-, -NR ８０１ C(=O)-, -C(=O)NR ８０１ -, -NR ８０１ C(=O)NR ８０２ -, -NR ８０１ C(=S)-, -C(=S)NR ８０１ -, -NR ８０１ C(=S)NR ８０２ -, -OC(=O)NR ８０１ -, -NR ８０１ C(=O)O-, -SC(=O)NR ８０１ -or-NR ８０１ C(═O)S—, L ９ is a bond, -O(C=O)-, -(C=O)O-, -O(C=O)O-, -C(=O)-, -O-, -O(CR ９０１ R ９０２ ) ｓ O-, -S-, -C(=O)S-, -SC(=O)-, -NR ９０１ C(=O)-, -C(=O)NR ９０１ -, -NR ９０１ C(=O)NR ９０２ -, -NR ９０１ C(=S)-, -C(=S)NR ９０１ -, -NR ９０１ C(=S)NR ９０２ -, -OC(=O)NR ９０１ -, -NR ９０１ C(=O)O-, -SC(=O)NR ９０１ -or-NR ９０１ C(═O)S—, L １０ is a bond, -O(C=O)-, -(C=O)O-, -O(C=O)O-, -C(=O)-, -O-, -O(CR １１０ R １１１ ) ｓ O-, -S-, -C(=O)S-, -SC(=O)-, -NR １１０ C(=O)-, -C(=O)NR １１０ -, -NR １１０ C(=O)NR １１１ -, -NR １１０ C(=S)-, -C(=S)NR １１０ -, -NR １１０ C(=S)NR １１１ -, -OC(=O)NR １１０ -, -NR １１０ C(=O)O-, -SC(=O)NR １１０ -or-NR １１０ C(═O)S—, R ７ , R ８ , and R ９ are each independently H, substituted or unsubstituted C １ ~C ３０ alkyl, or substituted or unsubstituted 2- to 30-membered heteroalkyl; Each R ａ３１ and R ａ３２ are independently H, substituted or unsubstituted C １ ~C １２ alkyl, or substituted or unsubstituted 2- to 12-membered heteroalkyl; Each R ８０１ , R ８０２ , R ９０１ , R ９０２ , R １１０ , and R １１１ are independently H, substituted or unsubstituted C １ ~C １２ alkyl, or substituted or unsubstituted 2- to 12-membered heteroalkyl; each s is independently an integer from 1 to 4;

8. W ７ and W ８ are each independently a bond or substituted or unsubstituted alkylene; L ａ３ is the bond, R １０ and R １１ are each independently H, substituted or unsubstituted alkyl, or R １０ and R １１ together with the nitrogen atom to which they are attached form a substituted or unsubstituted heterocycloalkyl; B ５ is the bond, B ６ and B ７ are each independently a bond or substituted or unsubstituted alkylene; L ８ is the bond, L ９ is a bond, —O(C═O)—, —(C═O)O—, or —C(═O)—; L １０ is a bond, —O(C═O)—, —(C═O)O—, or —C(═O)—; R ７ , R ８ , and R ９ are each independently H or substituted or unsubstituted C １ ~C ３０ 8. The cationic lipid of claim 7, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, or prodrug thereof, wherein R is alkyl.

9. W ７ and W ８ each independently represents a bond or a substituted or unsubstituted C １ ~C ８ is alkylene, L ａ３ is the bond, R １０ and R １１ are each independently substituted or unsubstituted alkyl, or R １０ and R １１ together with the nitrogen atom to which they are attached form a substituted or unsubstituted heterocycloalkyl; B ５ is the bond, B ６ and B ７ each independently represents a bond or a substituted or unsubstituted C １ ~C ８ is alkylene, L ８ is the bond, L ９ is —O(C═O)— or —(C═O)O—, L １０ is —O(C═O)— or —(C═O)O—, R ７ , R ８ , and R ９ are each independently substituted or unsubstituted C １ ~C ２０ 9. The cationic lipid of claim 8, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, or prodrug thereof, wherein R is alkyl.

10. W ７ and W ８ each independently represents a bond or a substituted or unsubstituted C ２ ~C ４ is alkylene, L ａ３ is a bond, R １０ and R １１ are each independently substituted or unsubstituted methyl, ethyl, propyl, isopropyl, or R １０ and R １１ together with the nitrogen atom to which they are attached form a substituted or unsubstituted 3- to 8-membered heterocycloalkyl; B ５ is the bond, B ６ and B ７ each independently represents a bond or a substituted or unsubstituted C ２ ~C ４ is alkylene, L ８ is the bond, L ９ is —O(C═O)— or —(C═O)O—, L １０ is —O(C═O)— or —(C═O)O—, R ７ is H or methyl, R ８ and R ９ are each independently substituted or unsubstituted C １ ~C ２０ 9. The cationic lipid of claim 8, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, or prodrug thereof, wherein R is alkyl.

11. W ７ and W ８ each independently represents a bond or an unsubstituted C ２ ~C ４ is alkylene, L ａ３ is the bond, R １０ and R １１ are each independently substituted or unsubstituted methyl, ethyl, propyl, isopropyl, or R １０ and R １１ together with the nitrogen atom to which they are attached form a substituted or unsubstituted 5- to 6-membered heterocycloalkyl; B ５ is the bond, B ６ and B ７ each independently represents a bond or an unsubstituted C ２ ~C ４ is alkylene, L ８ is the bond, L ９ is —O(C═O)— or —(C═O)O—, L １０ is —O(C═O)— or —(C═O)O—, R ７ is H or methyl, R ８ and R ９ are each independently substituted or unsubstituted C １ ~C ２０ 9. The cationic lipid of claim 8, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, or prodrug thereof, wherein R is alkyl.

12. W ７ and W ８ each independently represents a bond or an unsubstituted C ２ ~C ４ is alkylene, L ａ３ is the bond, R １０ and R １１ are each independently substituted or unsubstituted methyl, ethyl, propyl, isopropyl, or R １０ and R １１ together with the nitrogen atom to which they are attached form a substituted or unsubstituted 5- to 6-membered heterocycloalkyl; B ５ , B ６ , and B ７ are each independently a bond, L ８ is the bond, L ９ is the bond, L １０ is the bond, R ７ is H or methyl, R ８ and R ９ are each independently substituted or unsubstituted C １ ~C ３０ 9. The cationic lipid of claim 8, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, or prodrug thereof, wherein R is alkyl.

13. The cationic lipid, 【Chemistry 99-1】 【Chemistry 99-2】 【Chemistry 99-3】 【Chemistry 99-4】 8. The cationic lipid of claim 7, or a pharmaceutically acceptable salt thereof, solvate, hydrate, stereoisomer, or prodrug thereof.

14. Cationic lipids of formula (III): 【Chemistry 100】 or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, or prodrug thereof, wherein: L １１ teeth, 【Chemistry 101】 and Q is substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene; V is substituted or unsubstituted alkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted arylene; B ８ , B ９ , B １０ , and B １１ are each independently a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; L １２ is a bond, -O(C=O)-, -(C=O)O-, -O(C=O)O-, -C(=O)-, -O-, -O(CR ２１０ R ２１１ ) ｓ O-, -S-, -C(=O)S-, -SC(=O)-, -NR ２１０ C(=O)-, -C(=O)NR ２１０ -, -NR ２１０ C(=O)NR ２１１ -, -NR ２１０ C(=S)-, -C(=S)NR ２１０ -, -NR ２１０ C(=S)NR ２１１ -, -OC(=O)NR ２１０ -, -NR ２１０ C(=O)O-, -SC(=O)NR ２１０ -or-NR ２１０ C(═O)S—, L １３ is a bond, -O(C=O)-, -(C=O)O-, -O(C=O)O-, -C(=O)-, -O-, -O(CR ３１０ R ３１１ ) ｓ O-, -S-, -C(=O)S-, -SC(=O)-, -NR ３１０ C(=O)-, -C(=O)NR ３１０ -, -NR ３１０ C(=O)NR ３１１ -, -NR ３１０ C(=S)-, -C(=S)NR ３１０ -, -NR ３１０ C(=S)NR ３１１ -, -OC(=O)NR ３１０ -, -NR ３１０ C(=O)O-, -SC(=O)NR ３１０ -or-NR ３１０ C(═O)S—, R １２ is H, -OR １２Ａ , -SR １２Ａ , -NR １２Ａ , -CN, -(C=O)R １２Ａ , —O(C═O)R １２Ａ , -(C=O)OR １２Ａ , -NR １２Ａ (C═O)—R １２Ｂ , —(C═O)NR １２Ａ R １２Ｂ and R １３ is H, -OR １３Ａ , -SR １３Ａ , -NR １３Ａ , -CN, -(C=O)R １３Ａ , —O(C═O)R １３Ａ , -(C=O)OR １３Ａ , -NR １３Ａ (C═O)—R １３Ｂ , —(C═O)NR １３Ａ R １３Ｂ and R １４ and R １５ are each independently substituted or unsubstituted C ２ ~C ３０ alkyl, or substituted or unsubstituted 2- to 30-membered heteroalkyl; R １２Ａ , R １２Ｂ , R １３Ａ , and R １３Ｂ are each independently H, substituted or unsubstituted C １ ~C ２０ alkyl, or substituted or unsubstituted 2- to 20-membered heteroalkyl; Each R ２１０ , R ２１１ , R ３１０ , and R ３１１ are independently H, substituted or unsubstituted C １ ~C １２ alkyl, or substituted or unsubstituted 2- to 12-membered heteroalkyl; each n is independently an integer from 0 to 8; each s is independently an integer from 1 to 4;

15. L １１ but, 【Chemical Engineering 102】 and Q is a substituted or unsubstituted alkylene; V is substituted or unsubstituted alkylene; B ８ , B ９ , B １０ , and B １１ are each independently substituted or unsubstituted alkylene; L １２ is —O(C═O)— or —(C═O)O—, L １３ is —O(C═O)— or —(C═O)O—, R １２ But H, -OR １２Ａ , or -NR １２Ａ and R １３ But H, -OR １３Ａ , or -NR １３Ａ and R １４ and R １５ are each independently substituted or unsubstituted C ２ ~C ３０ is alkyl, R １２Ａ and R １３Ａ are each independently H, substituted or unsubstituted C １ ~C ２０ is alkyl, 15. The cationic lipid of claim 14, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, or prodrug thereof, wherein each n is independently an integer from 0 to 8.

16. L １１ but, 【Chemistry 103】 and V is substituted or unsubstituted alkylene; B ８ , B ９ , B １０ , and B １１ are each independently substituted or unsubstituted C １ ~C ２０ is alkylene, L １２ is —O(C═O)— or —(C═O)O—, L １３ is —O(C═O)— or —(C═O)O—, R １２ is H or -OR １２Ａ and R １３ is H or -OR １３Ａ and R １４ and R １５ are each independently substituted or unsubstituted C ２ ~C ２０ is alkyl, R １２Ａ and R １３Ａ are each independently H, substituted or unsubstituted C １ ~C ８ is alkyl, 16. The cationic lipid of claim 15, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, or prodrug thereof, wherein each n is independently an integer from 0 to 4.

17. L １１ but, 【Chemical 104】 and V is unsubstituted alkylene; B ８ , B ９ , B １０ , and B １１ are each independently substituted or unsubstituted C １ ~C ８ is alkylene, L １２ is —O(C═O)— or —(C═O)O—, L １３ is —O(C═O)— or —(C═O)O—, R １２ is —OH, methoxy, or ethoxy; R １３ is —OH, methoxy, or ethoxy; R １４ and R １５ are each independently substituted or unsubstituted C ２ ~C ２０ is alkyl, 17. The cationic lipid of claim 16, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, or prodrug thereof, wherein each n is independently an integer from 0 to 4.

18. The cationic lipid is 【Chemistry 105】 15. The cationic lipid of claim 14, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, or prodrug thereof.

19. Cationic lipids of formula (IV): R １７ -W １０ -L １４ -B １２ -L １５ -W ９ -R １６ (IV) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, or prodrug thereof, wherein: B １２ Ha, -W ７ -L ａ３ -W ８ - and W ７ and W ８ are each independently a bond, a substituted or unsubstituted C １ ~C １２ alkylene, or substituted or unsubstituted 2- to 12-membered heteroalkylene; L ａ３ represents a bond, -S-S-, -O-(CH ２ O) ｍ -, 【Chemistry 106】 and W ９ and W １０ are each independently a bond, a substituted or unsubstituted C １ ~C １２ alkylene, substituted or unsubstituted 2- to 12-membered heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, or any combination thereof; L １４ is a bond, -O(C=O)-, -(C=O)O-, -O(C=O)O-, -C(=O)-, -O-, -O(CR ４１０ R ４１１ ) ｓ O-, -S-, -C(=O)S-, -SC(=O)-, -NR ４１０ C(=O)-, -C(=O)NR ４１０ -, -NR ４１０ C(=O)NR ４１１ -, -NR ４１０ C(=S)-, -C(=S)NR ４１０ -, -NR ４１０ C(=S)NR ４１１ -, -OC(=O)NR ４１０ -, -NR ４１０ C(=O)O-, -SC(=O)NR ４１０ -or-NR ４１０ C(═O)S—, L １５ is a bond, -O(C=O)-, -(C=O)O-, -O(C=O)O-, -C(=O)-, -O-, -O(CR ５１０ R ５１１ ) ｓ O-, -S-, -C(=O)S-, -SC(=O)-, -NR ５１０ C(=O)-, -C(=O)NR ５１０ -, -NR ５１０ C(=O)NR ５１１ -, -NR ５１０ C(=S)-, -C(=S)NR ５１０ -, -NR ５１０ C(=S)NR ５１１ -, -OC(=O)NR ５１０ -, -NR ５１０ C(=O)O-, -SC(=O)NR ５１０ -or-NR ５１０ C(═O)S—, R １６ and R １７ are each independently 【Chemistry 107】 A fragment of a cationic lipid of formula (I): 【Chemistry 108】 A cationic lipid fragment of formula (II): 【Chemistry 109】 A cationic lipid fragment of formula (II): 【Chemical 110】 a fragment of a cationic lipid of formula (III), or 【Chemistry 111】 A fragment of a cationic lipid of formula (III): Each R ４１０ , R ４１１ , R ５１０ , and R ５１１ are independently H, substituted or unsubstituted C １ ~C １２ alkyl, or substituted or unsubstituted 2- to 12-membered heteroalkyl; each m is independently an integer from 0 to 8; each s is independently an integer from 1 to 4;

20. L ａ３ The bond, -S-S-, 【Chemistry 112】 and W ７ and W ８ each independently represents a bond or a substituted or unsubstituted C １ ~C １２ is alkylene, L １４ is -O(C=O)-, -(C=O)O-, -C(=O)-, -NR ４１０ C(=O)-, -C(=O)NR ４１０ -, -NR ４１０ C(=S)-, -C(=S)NR ４１０ -, -OC(=O)NR ４１０ - or -NR ４１０ C(═O)O—, L １５ is -O(C=O)-, -(C=O)O-, -C(=O)-, -NR ５１０ C(=O)-, -C(=O)NR ５１０ -, -NR ５１０ C(=S)-, -C(=S)NR ５１０ -, -OC(=O)NR ５１０ - or -NR ５１０ C(═O)O—, W ９ and W １０ each independently represents a bond or a substituted or unsubstituted C １ ~C １２ is alkylene, R １６ and R １７ However, each independently, 【Chemistry 113】 A fragment of a cationic lipid of formula (II): Each R ４１０ and R ５１０ are independently H or substituted or unsubstituted C １ ~C １２ 20. The cationic lipid of claim 19, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, or prodrug thereof, wherein:

21. L ａ３ The bond, -S-S-, 【Chemistry 114】 and W ７ and W ８ each independently represents a bond or an unsubstituted C １ ~C １２ is alkylene, L １４ is -O(C=O)-, -(C=O)O-, -NR ４１０ C(=S)-, -C(=S)NR ４１０ -, -OC(=O)NR ４１０ - or -NR ４１０ C(═O)O—, L １５ is -O(C=O)-, -(C=O)O-, -NR ５１０ C(=S)-, -C(=S)NR ５１０ -, -OC(=O)NR ５１０ - or -NR ５１０ C(═O)O—, W ９ and W １０ each independently represents a bond or a substituted or unsubstituted C １ ~C １２ is alkylene, R １６ and R １７ However, each independently, 【Chemical 115】 A fragment of a cationic lipid of formula (II): Each R ４１０ and R ５１０ are independently H or substituted or unsubstituted C １ ~C １２ 21. The cationic lipid of claim 20, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, or prodrug thereof, wherein:

22. L ａ３ The bond, -S-S-, 【Chemistry 116】 and W ７ and W ８ each independently represents a bond or an unsubstituted C １ ~C ８ is alkylene, L １４ is -O(C=O)-, -(C=O)O-, -NR ４１０ C(=S)-, -C(=S)NR ４１０ -, -OC(=O)NR ４１０ - or -NR ４１０ C(═O)O—, L １５ is -O(C=O)-, -(C=O)O-, -NR ５１０ C(=S)-, -C(=S)NR ５１０ -, -OC(=O)NR ５１０ - or -NR ５１０ C(═O)O—, W ９ and W １０ each independently represents a bond or an unsubstituted C １ ~C ８ is alkylene, R １６ and R １７ However, each independently, 【Chemistry 117】 A fragment of a cationic lipid of formula (II): Each R ４１０ and R ５１０ are independently H or unsubstituted C １ ~C ８ 22. The cationic lipid of claim 21, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, or prodrug thereof, wherein:

23. L ａ３ The bond, -S-S-, 【Chemistry 118】 and W ７ and W ８ each independently represents a bond or an unsubstituted C １ ~C ８ is alkylene, L １４ is -O(C=O)-, -(C=O)O-, -NR ４１０ C(=S)-, -C(=S)NR ４１０ -, -OC(=O)NR ４１０ - or -NR ４１０ C(═O)O—, L １５ is -O(C=O)-, -(C=O)O-, -NR ５１０ C(=S)-, -C(=S)NR ５１０ -, -OC(=O)NR ５１０ - or -NR ５１０ C(═O)O—, W ９ and W １０ each independently represents a bond or an unsubstituted C １ ~C ８ is alkylene, R １６ and R １７ However, each independently, 【Chemical 119】 and Each R ４１０ and R ５１０ 20. The cationic lipid of claim 19, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, or prodrug thereof, wherein:

24. The cationic lipid, 【Chemical 120-1】 【Chemistry 120-2】 【Chemistry 120-3】 20. The cationic lipid of claim 19, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, or prodrug thereof.

25. 25. A lipid nanoparticle comprising the cationic lipid of any one of claims 1 to 24, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, or prodrug thereof.

26. The lipid nanoparticle of claim 25, further comprising a non-cationic lipid.

27. 27. The lipid nanoparticle of claim 26, wherein the non-cationic lipid is selected from the group consisting of a phospholipid, cholesterol, or a mixture of a phospholipid and cholesterol.

28. 26. The lipid nanoparticle of claim 25, further comprising a conjugated lipid that inhibits particle aggregation.

29. 29. The lipid nanoparticle of claim 28, wherein the conjugated lipid that inhibits particle aggregation comprises a polyethylene glycol (PEG) lipid conjugate.

30. 26. The lipid nanoparticle of claim 25, further comprising a therapeutic agent.

31. The lipid nanoparticle of claim 30, wherein the therapeutic agent is a nucleic acid.

32. The lipid nanoparticle of claim 31 , wherein the nucleic acid is mRNA.

33. 31. A pharmaceutical composition comprising the lipid nanoparticle of claim 30 and a pharmaceutically acceptable carrier.

34. 31. A composition for in vivo delivery of a therapeutic agent, comprising the lipid nanoparticles of claim 30, wherein the composition is administered to a mammal.

35. 35. The composition of claim 34, wherein the mammal is a human.

36. A composition for treating a disease in a mammal in need thereof, comprising the lipid nanoparticles of claim 30.

37. 37. The composition of claim 36, wherein the mammal is a human.

38. 31. A composition for use in therapy, comprising the lipid nanoparticles of claim 30.

39. 31. Use of lipid nanoparticles according to claim 30 for the manufacture of a medicament.

Images