Lipid nanoparticle composition and its use

Abstract

This application relates to lipid nanoparticles containing cationic steroid compounds, and to the preparation and use of such lipid nanoparticles. Such lipid nanoparticles are useful for delivering payloads, such as nucleic acids, in vivo to organs other than the liver (e.g., the lungs) for the treatment or prevention of certain diseases or disorders, particularly lung diseases.

Description

[Technical Field]

[0001] <Cross-reference of related applications> This application claims priority to Chinese Patent Application No. 202310400925.4 filed on 14 April 2023 and International Patent Application No. PCT / CN2023 / 143111 filed on 29 December 2023, both of which are incorporated herein by reference in their entirety. 1. Technical field

[0002] This application relates to pharmaceutical therapy, particularly to the field of lipid nanoparticles. This application also relates to the preparation of such lipid nanoparticles, and to the use of such lipid nanoparticles for targeted delivery of biologically active molecules, such as nucleic acids (e.g., mRNA, miRNA, siRNA, saRNA, ASO, DNA) and polypeptides (e.g., antibodies), to specific organs, particularly the lungs. 2. Background technology [Background technology]

[0003] Nucleic acid-based gene therapy has made rapid progress in various fields in recent years, including the treatment of infectious diseases and cancer. Lipid nanoparticles (LNPs) are one of the most advanced nonviral delivery platforms that can safely and efficiently deliver nucleic acid drugs (e.g., mRNA or siRNA) to specific target organs of interest while protecting them from degradation by nucleases and other factors. LNPs offer several advantages, including high encapsulation efficiency, excellent cell transfection efficiency, strong tissue permeability, and relatively low cytotoxicity and immunogenicity. Currently, LNPs are successfully applied in several commercial products. For example, FDA-approved drugs such as the mRNA COVID-19 vaccine developed by Moderna and Pfizer-BioNTech, and the siRNA drug Onpattro developed by Alnylam, all utilize the LNP drug delivery platform.

[0004] In vivo, after entering the circulatory system, PEGylated lipids are dissociated from LNP nanoparticles, resulting in ApoE adsorption to the LNP surface, forming a ligand effective for liver targeting. Subsequently, the LNPs bind to lipoprotein receptors on the surface of hepatocytes, inducing endocytosis. Therefore, current LNP delivery systems primarily exhibit passive liver targeting. To fully unleash the therapeutic potential of nucleic acid therapy, expand its application to various types of diseases, and minimize toxic side effects on healthy organs, it is necessary to develop LNP delivery systems that target organs other than the liver.

[0005] This application provides specific steroid compounds for targeted delivery of payloads to organs other than the liver, particularly the lungs. 3. Outline of the Invention [Overview of the project] [Means for solving the problem]

[0006] In one embodiment, this specification provides for lipid nanoparticles comprising an ionized lipid and a steroid compound, wherein the steroid compound is a compound of formula (I): [ka] or its stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt, in the formula, [ka] It is either a single bond or a double bond; Y is -C(O)O-, -O-, -NH-, -SC(O)O-, -OC(O)NR 2a -, -NR 2a C(O)NR 2a -, -OC(O)S-, -OC(O)O-, -NR 2a C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR 2a -, -C(O)NR 2a -, -NR 2a C(O)-, -NR 2aC(O)S-, -SC(O)NR 2a -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR 2a -, -NR 2a C(S)O-, or -S(O) 0-2 -, and the left-side bond is directed in the direction of V1; Y1 is absent or -C(O)O-, -O-, -NH-, -SC(O)O-, -OC(O)NR 2a -, -NR 2a C(O)NR 2a -, -OC(O)S-, -OC(O)O-, -NR 2a C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR 2a -, -C(O)NR 2a -, -NR 2a C(O)-, -NR 2a C(O)S-, -SC(O)NR 2a -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR 2a -, -NR 2a C(S)O-, or -S(O) 0-2 -, and the left-side bond is directed in the direction of V1; R 2a Each example of is independently H, C 1-10 alkyl, C 3-14 cycloalkyl, or 3- to 14-member heterocyclyl, where the alkyl, cycloalkyl, and heterocyclyl are independently C 1-10 alkyl, L 2b -OR 2b L b -SR 2b L 2b -NR 2b R’ 2b L 2b N + R 2b R’ 2b R’’ 2b L 2b -OC(O)R 2b or L 2b -C(O)OR 2b and is optionally substituted; R 201 R202 , R 203 , R 204 Each example independently represents H, OH, alkyl, alkoxy, and -L. 2b -NR 21 R 22 , -L 2b -N + R 21 R 22 R 23 , L 2b -OC(O)R 21 , or L 2b -C(O)OR 21 and; m is an integer between 1 and 12; m1 is an integer between 0 and 12; V1 is NR 21 R 22 , N + R 21 R 22 R 23 , imidazole, pyridine, pyrrole, pyrrolidine, pyrazole, (iso)thiazole, (iso)oxazole, oxadiazine, oxazoline, dithiourazole, (iso)triazole, tetrazole, pentasol, indole, dihydroindole, pyrimidine, pyrazine, quinazoline, piperazine, piperidine, morpholine, pyran, quinoxaline, quinoline, quinolinone, (iso)quinoline, amidine, guanidine, or urea; M is either absent or independently one or more anions selected from chloride, bromide, iodide, sulfate, nitrate, perchlorate, formate, citrate, sulfonate, methanesulfonate, triflate, trifluoroacetate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, pyrophosphate, monohydrogen phosphate, dihydrogen phosphate, acetate, propionate, decanoate, caprylate, acrylate, isobutyrate, caproate, heptanoate, oxalate, malonate, succinate, fumarate, maleate, benzoate, phthalate, phenylacetate, lactate, glycolate, tartrate, mandelate, mesylate, gluconate, aspartate, or glutamate; R 21 , R 22 , R23 Each example of 1-8 is independently H, optionally substituted C 2b alkyl, -L 2b , -L 2b -SR 2b , -L 2b -NR 2b R’ 2b R’’ 2b , L 2b -OC(O)R 2b , or L 2b -C(O)OR 2b ; L 2b is either absent or optionally substituted C 1-10 alkylene; R 2b , R’ 2b , and R’’ 2b each example of 1-10 is independently H or C alkyl; z1 R 1-14 is C 1-14 alkyl or C alkenyl, where the alkyl and alkenyl are optionally substituted; However, when Y is -NHC(O)-, (i) m is an integer from 5 to 12; or (ii) V1 is not N(CH3)2,

[0007] In one aspect, as described herein, lipid nanoparticles comprising an ionizable lipid and a steroid compound, wherein the steroid compound is a compound of formula (I-P): [Chemical formula] or a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt, wherein ​​​​​​Y1 is absent, -C(O)O-, -O-, -NH-, -SC(O)O-, -OC(O)NR 2a -, -NR 2a C(O)NR 2a -, -OC(O)S-, -OC(O)O-, -NR 2a C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR 2a -, -C(O)NR 2a -, -NR 2a C(O)-, -NR 2a C(O)S-, -SC(O)NR 2a -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR 2a -, -NR 2a C(S)O-, -S(O) 0-2 -, or -OPO3-, wherein the left-hand bond is directed in the direction of V1; R 2a Each instance of is, independently, H, C 1-10 alkyl, C 3-14 cycloalkyl, or 3- to 14-membered heterocyclyl, where the alkyl, cycloalkyl, and heterocyclyl are, independently, C 1-10 alkyl, L 2b -OR 2b L b -SR 2b L 2b -NR 2b R’ 2b L 2b N + R 2b R’ 2b R’’ 2b L 2b -OC(O)R 2b or L 2b -C(O)OR 2b and are optionally substituted; R 201 R 202 R 203 R 204 Each instance of is, independently, H, OH, alkyl, alkoxy, -L 2b -NR 21 [[ID=FIG=80]]R 22 -L 2b -N + R 21 R22 R 23 , L 2b -OC(O)R 21 , or L 2b -C(O)OR 21 and; R 205 is either absent, or a cation, H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, or C2-6 alkynyl, where alkyl, haloalkyl, alkenyl, and alkynyl are optionally substituted; m is an integer between 1 and 12; m1 is an integer between 0 and 12; V1 is NR 21 R 22 , N + R 21 R 22 R 23 , imidazole, pyridine, pyrrole, pyrrolidine, pyrazole, (iso)thiazole, (iso)oxazole, oxadiazine, oxazoline, dithiourazole, (iso)triazole, tetrazole, pentasol, indole, dihydroindole, pyrimidine, pyrazine, quinazoline, piperazine, piperidine, morpholine, pyran, quinoxaline, quinoline, quinolinone, (iso)quinoline, amidine, guanidine, or urea; M is either absent or independently one or more anions selected from chloride, bromide, iodide, sulfate, nitrate, perchlorate, formate, citrate, sulfonate, methanesulfonate, triflate, trifluoroacetate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, pyrophosphate, monohydrogen phosphate, dihydrogen phosphate, acetate, propionate, decanoate, caprylate, acrylate, isobutyrate, caproate, heptanoate, oxalate, malonate, succinate, fumarate, maleate, benzoate, phthalate, phenylacetate, lactate, glycolate, tartrate, mandelate, mesylate, gluconate, aspartate, or glutamate; R 21 , R 22 , R 23Each example independently involves H, with C optionally substituted. 1-8 Alkyl, -L 2b -OR 2b , -L 2b -SR 2b , -L 2b -NR 2b R' 2b R'' 2b , L 2b -OC(O)R 2b , or L 2b -C(O)OR 2b and; L 2b C is either non-existent or optionally replaced. 1-10 It is alkylene; R 2b , R' 2b , and R'' 2b Each of these examples is independent of H or C 1-10 It is alkyl; R z1 C 1-14 Alkyl or C 1-14 Lipid nanoparticles are provided, which are alkenyls, where the alkyl and alkenyls are optionally substituted.

[0008] In one embodiment, Y is -C(O)O-, -OC(O)-, -O-, -NHC(O)O-, -NCH3-C(O)O-, -OC(O)NH-, or -OC(O)O-, where the bond on the left side of the formula is directed towards V1. In one embodiment, Y1 is absent or is -C(O)O-, -OC(O)-, -O-, -S-, SO, S(O)2, -O(CO)O-, -NHC(O)-, or -C(O)NH-, where the bond on the left side of the formula is directed towards V1.

[0009] In one embodiment, the steroid compound is a compound of formula (I-A1), (I-A2), (I-A3), (I-A4), or (I-A5): [ka] , or its stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts.

[0010] In one embodiment, the steroid compound is a compound of formula (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), or (I-B8): [ka] , or its stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt, where m3 is an integer from 1 to 11.

[0011] In one embodiment, R 201 , R 202 , R 203 , and R 204 Each example is independently H, C 1-6 Alkyl, -NR 21 R 22 , -N + R 21 R 22 R 23 ,-(CH2) 0-6 -OC(O)R 21 , or -(CH2) 0-6 -C(O)OR 21 In one embodiment, R 201 , R 202 , R 203 , and R 204 Each example independently represents H, NH2, and NH3. + These are -CH2OC(O)CH3, -CH2C(O)OCH3, -OC(O)CH3, -CO(O)OCH3, or -CH2CO2H.

[0012] In one embodiment, m is an integer between 5 and 12.

[0013] In one embodiment, the steroid compound is a compound of formula (I-P1): [ka] or its stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt, where m3 is an integer from 1 to 11.

[0014] In one embodiment, V1 is NR 21 R 22 , N + R 21 R 22 R 23 or optionally substituted amidine, guanidine, or urea radicals. In one embodiment, R 21 , R 22 , R 23 These are H, hydroxyl, and C, respectively, independently. 1-3 Alkyl, or C 1-3 It is a hydroxyalkyl group. In one embodiment, V1 is NH2, NH3 + , N(CH3)2, N + (CH3)3, N + CH3(CH2CH2OH)2, N + (CH3)2(CH2CH2OH), NHC(=N + H2)NH2, NHC(O)NH2, CH2C(=NH)NH2, N(CH3)(CH2CH2CO2CH3), N + (CH3)2(CH2CH2CO2CH3), N(CH3)(CH2CO2CH3), or N + (CH3)2(CH2CO2CH3). In one embodiment, V1 is N + CH3(CH2CH2OH)2, N + (CH3)2(CH2CH2OH), or N + It is (CH3)3.

[0015] In one embodiment, M is either absent or one or more of bromides, chlorides, iodides, or trifluoroacetates.

[0016] In one embodiment, R z1 C 1-14 Alkyl or C 1-14 Alkenyl, where the alkyl and alkenyl are one or more hydroxyl, oxo, nitro, cyano, halogen, C 1-6 Alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C 10It is optionally substituted with an aryl, a 5-10 member heteroaryl, or a 3-8 member heterocycline. In one embodiment, R z1 C 6-12 Alkyl or C 6-12 The alkyl and alkenyl are optionally substituted with one or more hydroxyl, oxo, or halogen atoms. In one embodiment, R z1 teeth, [ka] That is the case.

[0017] In other embodiments, this specification provides for lipid nanoparticles comprising an ionized lipid and a steroid compound, wherein the steroid compound is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] Lipid nanoparticles are provided, which are stereoisomers thereof, mixtures of stereoisomers, or pharmaceutically acceptable salts thereof.

[0018] In another embodiment, the Specified Provision provides lipid nanoparticles for use in delivering or expressing a payload in the lungs of a subject, wherein the lipid nanoparticles are administered to the subject via a systemic route, and the lipid nanoparticles comprise an ionized lipid and a steroid compound, wherein the steroid compound comprises one or more cationic groups.

[0019] In one embodiment, the systemic administration route is intravenous, intra-arterial, or intraperitoneal.

[0020] In one embodiment, the cationic group is a tertiary amine, a quaternary ammonium, a primary amine, ammonium, imidazole, pyridine, pyrrole, pyrrolidine, pyrazole, isothiazole, isoxazole, oxadiazine, oxazoline, dithiourazole, isotriaazole, tetrazole, pentasol, indole, dihydroindole, isoxazole, pyrimidine, pyrazine, quinazoline, piperazine, piperidine, morpholine, pyran, quinoxaline, quinoline, quinolinone, isoquinoline, amidine, guanidine, or urea.

[0021] In one embodiment, the steroid compound comprises a Z1 portion, and the Z1 portion is [ka] , or its stereoisomer or mixture of stereoisomers, where one or more cyclic CC bonds in Z1 are independently and optionally replaced by C=C bonds as far as the valence allows, and Z1 is hydroxyl, halogen, and C 1-14 Alkyl or C 1-14 The alkyl group is optionally substituted with one or more groups selected from alkenyl groups, and the alkyl group is one or more hydroxyl, nitro, cyano, halogen, or C groups. 1-6 Alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C 10The Z1 portion is optionally substituted with an aryl, a 5-10 membered heteroaryl, or a 3-8 membered heterocycline, and the bond at Z1 is directed to the remainder of the steroid compound. In one embodiment, the Z1 portion is cholesterol, cholestane, campesterol, sitosterol, sitostanol, β-sitosterol, stigmasterol, stigmastanol, brassicasterol, avenasterol, ergosterol, ursolic acid, tocopherol, lumisterol, or a monovalent radical thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

[0022] In one embodiment, the steroid compound is a compound of formula (I): [ka] or its stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt, in the formula, [ka] It is either a single bond or a double bond; Y is -C(O)O-, -O-, -NH-, -SC(O)O-, -OC(O)NR 2a -, -NR 2a C(O)NR 2a -, -OC(O)S-, -OC(O)O-, -NR 2a C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR 2a -, -C(O)NR 2a -, -NR 2a C(O)-, -NR 2a C(O)S-, -SC(O)NR 2a -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR 2a -, -NR 2a C(S)O-, or -S(O) 0-2 - and in the equation, the left-side bond is directed towards V1; Y1 either does not exist, or is -C(O)O-, -O-, -NH-, -SC(O)O-, -OC(O)NR 2a -, -NR2a C(O)NR 2a -, -OC(O)S-, -OC(O)O-, -NR 2a C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR 2a -, -C(O)NR 2a -, -NR 2a C(O)-, -NR 2a C(O)S-, -SC(O)NR 2a -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR 2a -, -NR 2a C(S)O-, or -S(O) 0-2 - and in the equation, the left-side bond is directed towards V1; R 2a Each example is independently H, C 1-10 Alkyl, C 3-14 A cycloalkyl or a 3-14 membered heterocycline, where the alkyl, cycloalkyl, and heterocycline are independently C 1-10 Alkyl, L 2b -OR 2b , L b -SR 2b , L 2b -NR 2b R' 2b , L 2b N + R 2b R' 2b R'' 2b , L 2b -OC(O)R 2b , or L 2b -C(O)OR 2b It is optionally replaced by; R 201 , R 202 , R 203 , R 204 Each example independently represents H, OH, alkyl, alkoxy, and -L. 2b -NR 21 R 22 , -L 2b -N + R 21 R 22 R 23 , L 2b -OC(O)R 21 , or L2b -C(O)OR 21 and; m is an integer between 1 and 12; m1 is an integer between 0 and 12; V1 is NR 21 R 22 , N + R 21 R 22 R 23 , imidazole, pyridine, pyrrole, pyrrolidine, pyrazole, (iso)thiazole, (iso)oxazole, oxadiazine, oxazoline, dithiourazole, (iso)triazole, tetrazole, pentasol, indole, dihydroindole, pyrimidine, pyrazine, quinazoline, piperazine, piperidine, morpholine, pyran, quinoxaline, quinoline, quinolinone, (iso)quinoline, amidine, guanidine, or urea; M is either absent or independently one or more anions selected from chloride, bromide, iodide, sulfate, nitrate, perchlorate, formate, citrate, sulfonate, methanesulfonate, triflate, trifluoroacetate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, pyrophosphate, monohydrogen phosphate, dihydrogen phosphate, acetate, propionate, decanoate, caprylate, acrylate, isobutyrate, caproate, heptanoate, oxalate, malonate, succinate, fumarate, maleate, benzoate, phthalate, phenylacetate, lactate, glycolate, tartrate, mandelate, mesylate, gluconate, aspartate, or glutamate; R 21 , R 22 , R 23 Each example independently involves H, with C optionally substituted. 1-8 Alkyl, -L 2b -OR 2b , -L 2b -SR 2b , -L 2b -NR 2b R' 2b R'' 2b , L 2b -OC(O)R 2b , or L 2b-C(O)OR 2b and; L 2b C is either non-existent or optionally replaced. 1-10 It is alkylene; R 2b , R' 2b , and R'' 2b Each of these examples is independent of H or C 1-10 It is alkyl; R z1 C 1-14 Alkyl or C 1-14 The alkyl and alkenyl compounds are optionally substituted.

[0023] In one embodiment, the steroid compound is a compound of formula (IP): [ka] or its stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt, in the formula, [ka] It is either a single bond or a double bond; Y1 either does not exist, or is -C(O)O-, -O-, -NH-, -SC(O)O-, -OC(O)NR 2a -, -NR 2a C(O)NR 2a -, -OC(O)S-, -OC(O)O-, -NR 2a C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR 2a -, -C(O)NR 2a -, -NR 2a C(O)-, -NR 2a C(O)S-, -SC(O)NR 2a -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR 2a -, -NR 2a C(S)O-, -S(O) 0-2 -, or -OPO3-, where the bond on the left is directed towards V1; R 2aEach example is independently H, C 1-10 Alkyl, C 3-14 A cycloalkyl or a 3-14 membered heterocycline, where the alkyl, cycloalkyl, and heterocycline are independently C 1-10 Alkyl, L 2b -OR 2b , L b -SR 2b , L 2b -NR 2b R' 2b , L 2b N + R 2b R' 2b R'' 2b , L 2b -OC(O)R 2b , or L 2b -C(O)OR 2b It is optionally replaced by; R 201 , R 202 , R 203 , R 204 Each example independently represents H, OH, alkyl, alkoxy, and -L. 2b -NR 21 R 22 , -L 2b -N + R 21 R 22 R 23 , L 2b -OC(O)R 21 , or L 2b -C(O)OR 21 and; R 205 is either absent, or a cation, H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, or C2-6 alkynyl, where alkyl, haloalkyl, alkenyl, and alkynyl are optionally substituted; m is an integer between 1 and 12; m1 is an integer between 0 and 12; V1 is NR 21 R 22 , N + R 21 R 22 R 23, imidazole, pyridine, pyrrole, pyrrolidine, pyrazole, (iso)thiazole, (iso)oxazole, oxadiazine, oxazoline, dithiourazole, (iso)triazole, tetrazole, pentasol, indole, dihydroindole, pyrimidine, pyrazine, quinazoline, piperazine, piperidine, morpholine, pyran, quinoxaline, quinoline, quinolinone, (iso)quinoline, amidine, guanidine, or urea; M is either absent or independently one or more anions selected from chloride, bromide, iodide, sulfate, nitrate, perchlorate, formate, citrate, sulfonate, methanesulfonate, triflate, trifluoroacetate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, pyrophosphate, monohydrogen phosphate, dihydrogen phosphate, acetate, propionate, decanoate, caprylate, acrylate, isobutyrate, caproate, heptanoate, oxalate, malonate, succinate, fumarate, maleate, benzoate, phthalate, phenylacetate, lactate, glycolate, tartrate, mandelate, mesylate, gluconate, aspartate, or glutamate; R 21 , R 22 , R 23 Each example independently involves H, with C optionally substituted. 1-8 Alkyl, -L 2b -OR 2b , -L 2b -SR 2b , -L 2b -NR 2b R' 2b R'' 2b , L 2b -OC(O)R 2b , or L 2b -C(O)OR 2b and; L 2b C is either non-existent or optionally replaced. 1-10 It is alkylene; R 2b , R' 2b , and R'' 2b Each of these examples is independent of H or C 1-10It is alkyl; R z1 C 1-14 Alkyl or C 1-14 The alkyl and alkenyl compounds are optionally substituted.

[0024] In one embodiment, the amount of the steroid compound is about 15 mol% to about 80 mol%, about 20 mol% to about 60 mol%, about 20 mol% to about 50 mol%, about 20 mol% to about 40 mol%, or about 15 mol% to about 30 mol% of the total lipids present in the lipid nanoparticles. In one embodiment, the amount of the steroid compound is about 20 mol% to about 30 mol% of the total lipids present in the lipid nanoparticles.

[0025] In one embodiment, the ionized lipid comprises at least one ionizable head group and at least one biodegradable hydrophobic chain, wherein the ionized lipid has a logP of at least about 10.1 and a pKa of about 4 to about 11; and the biodegradable hydrophobic chain is of formula -R 16 -M0-R 17 It has; in the formula, R 16 C4- 14 Alkylene, C4- 14 Alkenylene, or C4- 14 It is alkynylene; R 17 C6- 20 It is an alkyl group; M0 is a biodegradable group, and the alkylene, alkenylene, alkylylene, and alkyl groups are optionally substituted.

[0026] In one embodiment, M0 is an ester group, amide group, thioester group, carbonate group, carbamate group, carbamothioester group, urea group, or disulfide group.

[0027] In one embodiment, the ionized lipid is a compound of formula (III): [ka] or its stereoisomer, mixture of stereoisomers, tautomers, isotopic molecular species, or pharmaceutically acceptable salt, in the formula, Examples R3 and R4 are independently C 1-10 Alkyl, C 2-10 Alkenil, C 2-10 Alkinyl, C3-C 14 Cycloalkyl, 3-14 member heterocyclyl, (C 1-10 Alkylene)-(C3-C 14 Cycloalkyl), or (C 1-10 The alkylene is a 3-14 member heterocycline, or R3 and R4, together with the nitrogen atom to which they are bonded, form a 3-14 member heterocycline, or one of R4 and R0', together with the atom connecting them, forms a 4-10 member heterocycline or a 5-10 member heteroaryl, where the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycline, heteroaryl, and alkylene are independently one or more R * It is optionally replaced by; Each example of R0' is independently and optionally substituted methylene, or two R0's, together with the carbons they are bonded to, form a 3- to 8-membered cycloalkylene, where the cycloalkylene is one or more R ** It is optionally replaced by; k is 0, 1, 2, 3, 4, 5, or 6; j is either 0 or 1; The dashed line connecting Q and W either does not exist or represents a connection; W is C, CH, or N, except when W is N, then j is 0, and there is no dashed connection between Q and W; G5 does not exist, or C 1-24 Alkilen, C 2-24 Alkenylene, C3-C8 cycloalkylene, C3-C8 cycloalkenylene, where the above alkylene, alkenylene, cycloalkylene, and cycloalkenylene are one or more R ** It is optionally replaced by; G1, G2, G3, and G4 are either not present or C 1-13 Alkilen, C2-13 Alkenylene, or C 2-13 Alkynylene, where the above alkylene, alkenylene, and alkynylene are one or more R s It is optionally replaced by; G1 and G2 have the full length of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 carbon atoms; G3 and G4 have the full length of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 carbon atoms; R5, R6, R7, and R8 are each independently replaced with hydrogen or optionally substituted with carbon. 1-8 It is alkyl; If there is no dashed line connecting Q and W, then Q either does not exist, or it is -C(O)O-, -O-, -NH-, -SC(O)O-, -OC(O)NR b -, -NR b C(O)NR b -, -OC(O)S-, -OC(O)O-, -NR b C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR b -, -C(O)NR b -, -NR b C(O)-, -NR b C(O)S-, -SC(O)NR b -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR b -, -NR b C(S)O-, -SS-, or -S(O) 0-2 - and in the equation, the bond to the right is directed towards W; If the dashed line connecting Q and W represents a bond, then G5 does not exist, and Q and W form a 5-10 membered monoring or fused ring, and optionally, the above ring has one or more R ** Replaced by; M1 and M2 are either non-existent, or -C(O)O-, -O-, -SC(O)O-, -OC(O)NR, respectively. a -, -NR a C(O)NR a -, -OC(O)S-, -OC(O)O-, -NR aC(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR a -, -C(O)NR a -, -NR a C(O)-, -NR a C(O)S-, -SC(O)NR a -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR a -, -NR a C(S)O-, -SS-, or -S(O) 0-2 -and; Each example of R0 is independently -(CRR')-; Examples R and R' are independently H, C 1-20 Alkyl, L a -OR a , -L a -SR a , or -L a -NR a R' a Either R and R' are, together with the carbon they are bonded to, C 3-8 Forms cycloalkylenes; Q3 and Q4 are independently H, -(CRR')-, and C, respectively. 6-10 It is an aryl or steroid part; Examples A1, A2, A3, and A4 are independent of each other, -(CR 18 R 18 -CR 18 =CR 18 )- or -(CR 18 R 18 -C≡C)- and; R 18 Each of these examples is independent of H or C 1-20 It is alkyl; Examples N1 and N2 are, independently, biodegradable groups; Z does not exist, or C 1-10 It is an alkylene, or -OP(O)(OH)-O-; The dashed lines between Z-Q3 or Z-Q4 are either independent, nonexistent, or combined; however, if Z is absent, neither dashed line exists. m, n, q, r, u, v, y, and z are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; o, p, w, and x are independently 0, 1, or 2; s and t are independently either 0 or 1; The number of carbon atoms between G1 and Q3, or between G3 and Q4, is between 8 and 30; L a and L e Each of these is independent, either nonexistent or C 1-20 It is alkylene; L b and L f Each of these is independent, either nonexistent or C 1-10 It is alkylene; L c It does not exist, or C 1-8 It is alkylene; L d It does not exist, or C 1-14 It is alkylene; R * is hydroxyl, halogen, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Hydroxyalkyl, -L b -OR b , -L b -SR b , or -L b -NR b R' b and; R ** is hydroxyl, halogen, C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, -L b -OR b , -L b -SR b , or -L b -NR b R' b and; R s C 1-14 Alkyl, -L b -OR b , -Lb -SR b , or -L b -NR b R' b and; R a and R' a These are H and C, respectively, independently. 1-20 Alkyl, C 3-14 The alkyl, cycloalkyl, and heterocyclyl are cycloalkyl, cycloalkyl, and heterocyclyl, respectively, and are hydroxyl, halogen, and C. 1-20 Alkyl, -L e -OR e , -L e -SR e , or -L e -NR e R' e Optionally substituted with one or more elements selected from; R b and R' b These are H and C, respectively, independently. 1-10 Alkyl, C 3-14 The alkyl, cycloalkyl, and heterocyclyl are cycloalkyl, cycloalkyl, and heterocyclyl, respectively, and are hydroxyl, halogen, and C. 1-10 Alkyl, -L f -OR f , -L f -SR f , or -L f -NR f R' f Optionally substituted with one or more elements selected from; R c and R' c Each of them independently consists of hydrogen or C 1-8 It is alkyl; R d and R' d Each of them independently consists of hydrogen or C 1-14 It is alkyl; R e and R' e Each of them independently consists of hydrogen or C 1-20 It is alkyl; R f and R' fEach of them independently consists of hydrogen or C 1-10 It is alkyl.

[0028] In one embodiment, the ionized lipid is a compound of formula (IV'): [ka] or its stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt, in the formula, j is either 0 or 1; W is either CH or N, except when W is N, then j is 0; k is 0, 1, 2, 3, 4, 5, 6, 7, or 8; Each example of R0' is independently and optionally substituted methylene, or two R0's, together with the carbons they are bonded to, form a 3- to 8-membered cycloalkylene, where the cycloalkylene is one or more R ** It is optionally replaced by; M1 and M2 are independently -C(O)O-, -O-, -SC(O)O-, and -OC(O)NR, respectively. a -, -NR a C(O)NR a -, -OC(O)S-, -OC(O)O-, -NR a C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR a -, -C(O)NR a -, -NR a C(O)-, -NR a C(O)S-, -SC(O)NR a -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR a -, -NR a C(S)O-, -SS-, or -S(O) 0-2 -and; Q does not exist, or -C(O)O-, -O-, -SC(O)O-, -OC(O)NR b -, -NR b C(O)NR b -, -OC(O)S-, -OC(O)O-, -NR bC(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR b -, -C(O)NR b -, -NR b C(O)-, -NR b C(O)S-, -SC(O)NR b -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR b -, -NR b C(S)O-, -SS-, or -S(O) 0-2 -and; R a and R b These are H and C, respectively, independently. 1-20 Alkyl, C 3-14 The alkyl, cycloalkyl, and heterocyclyl are cycloalkyl, cycloalkyl, and heterocyclyl, respectively, and are hydroxyl, halogen, and C. 1-20 Alkyl, -L e -OR e , -L e -SR e , or -L e -NR e R' e Optionally substituted with one or more elements selected from; G5 is either non-existent or optionally replaced by C. 1-8 It is alkylene; R1 and R2 are independent of each other, C 4-20 Alkyl, C 4-20 Alkenyl, or C 4-20 It is an alkynyl, and one or more methylene units in R1 and R2 are independently -NH- or -N(C 1-20 The alkyl, alkenyl, and alkynyl are optionally substituted; Examples R3 and R4 are independently H, C 1-10 Alkyl, C 2-10 Alkenil, C 2-10 Alkinyl, C3-C 14It is a cycloalkyl or a 3- to 14-membered heterocycline, or R3 and R4, together with the N atom to which they are bonded, form a 3- to 14-membered heterocycline, or one of R4 and R0', together with the atom connecting them, forms a 4- to 10-membered heterocycline, where the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycline is one or more R * It is optionally replaced by; R5, R6, R7, and R8 are each independently replaced with hydrogen or optionally substituted with carbon. 1-8 It is alkyl.

[0029] In one embodiment, the ionized lipid is a compound of formula (V'), (VI'), or (VII'): [ka] or its stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt, in the formula, k is 0, 1, 2, 3, 4, or 5; L1 and L2 are independently -(CRR')2-, -CH=CH-, -C≡C-, or -NR''-; One of L3 and L5 is -(CR s R s ')2-, -CH=CH-, or -C≡C-, and the other does not exist; One of L4 and L6 is -(CR s R s ')2-, -CH=CH-, or -C≡C-, and the other does not exist; G 1a , G 1b , G 2a , G 2b , G 3a , G 3b , G 4a , and G 4b Each of these is either non-existent or optionally replaced by C. 1-7 It is alkylene; G 1a , G 1b , G 2a , and G 2bIt has a total length of 1, 2, 3, 4, 5, 6, or 7 carbon atoms; G 3a , G 3b , G 4a , and G 4b It has a total length of 1, 2, 3, 4, 5, 6, or 7 carbon atoms; R5, R6, R7, and R8 are each independently replaced with hydrogen or optionally substituted with carbon. 1-6 It is alkyl; G7, G8, G9, and G 10 Each of these is either non-existent or optionally replaced by C. 1-12 They are alkylenes, however G7 and G8 have the full length of 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms, and G9 and G 10 It has the full length of 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms; R s and R s ' are H and C, respectively, independently. 1-10 Alkyl, -L d -OR d , or -L d -NR d R' d and; R' is H, C 1-14 Alkyl, -L a -OR a , or -L a -NR a R' a and; R'' is H or C 1-14 It is alkyl; L d It does not exist, or C 1-10 It is alkylene; L a It does not exist, or C 1-14 It is alkylene; R a and R' a These are H and C, respectively, independently. 1-14 Alkyl, C 3-10The alkyl, cycloalkyl, or heterocyclyl is optionally substituted; R d and R' d These are, independently, H or C 1-10 It is alkyl; a' and b are independently 0, 1, 3, 4, and 5, respectively, except that at least one of a' and b is not 0; g is 0, 1, 2, 3, 4, or 5; a'+g is 0, 1, 2, 3, 4, or 5; c, d, e, and f are independently 0, 1, 2, 3, 4, 5, 6, or 7, where c+d is an integer between 2 and 9, and e+f is an integer between 2 and 9.

[0030] In one embodiment, the ionized lipid is a compound of formula (VIII): [ka] or its stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts.

[0031] In one embodiment, R5, R6, R7, and R8 are each independently hydrogen or methyl.

[0032] In one embodiment, G1, G2, G3, and G4 are each independent of or are absent or C 1-8 It is alkylene.

[0033] In one embodiment, the ionized lipid is a compound of formula (IX): [ka] or its stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt, in the formula, G1 and G2 are independently joined, C 1-13 Linear alkylene, C 2-13 Linear alkenylenes, or C2-13 A linear alkynylene, where the alkylene, alkenylene, and alkynylene are one or more R G1 It is optionally replaced by; G1 and G2 have the full length of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 carbon atoms; R G1 Each example is independent of C 1-14 Alkyl, -L a -OR a , -L a -SR a , or -L a -NR a R' a and; G3 is C 4-14 Linear alkylene, C 4-14 Linear alkenylenes, or C 4-14 A linear alkynylene, where the alkylene, alkenylene, and alkynylene are one or more R G3 It is optionally replaced by; R G3 Each example is independently H, -L a -OR a , -L a -SR a , or -L a -NR a R' a and; L a These are, independently, combined or C 1-14 It is alkylene; R a and R' a These are H and C, respectively, independently. 1-14 Alkyl, C 3-14 It is a cycloalkyl or a 3- to 14-membered heterocycline; G4 is a bond, C 1-6 Alkilen, C 2-6 Alkenylene, or C 2-6 Alkynylene, where the above alkylene, alkenylene, and alkynylene are one or more R G4 It is optionally replaced by; R G4 Each example is independently H, C1-6 Alkyl, -L b -OR b , -L b -SR b , or -L b -NR b R' b and; L b These are, independently, combined or C 1-6 It is alkylene; R b and R' b H and C are independent of each other. 1-6 Alkyl, C 3-10 It is a cycloalkyl or a 3- to 10-membered heterocycline; or two R G4 C 3-14 It forms a cycloalkylene or a 3-14 membered heterocyclene, where the cycloalkylene and heterocyclene are one or more R 4g It is optionally replaced by; R 4g Each example independently involves halogen, cyano, and C. 1-8 Alkyl, C 1-8 Haloalkyl, -L e -OR e , -L e -SR e , or -L e -NR e R' e and; L e These are, independently, combined or C 1-8 It is alkylene; R e and R' e H and C are independent of each other. 1-8 Alkyl, C 3-14 It is a cycloalkyl or a 3- to 14-membered heterocycline; M1 and M2 are independently -C(O)O-, -OC(O)-, -O-, -SC(O)O-, -OC(O)NR-, -NRC(O)NR-, -OC(O)S-, -OC(O)O-, -NRC(O)O-, -SC(O)-, -C(O)S-, -NR-, -C(O)NR-, -NRC(O)-, -NRC(O)S-, -SC(O)NR-, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR-, -NRC(S)O-, -SS-, or -S(O) 0-2 -and; Q represents the bonds -C(O)O-, -O-, -SC(O)O-, and -OC(O)NR. f -, -NR f C(O)NR f -, -OC(O)S-, -OC(O)O-, -NR f C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR f -, -C(O)NR f -, -NR f C(O)-, -NR f C(O)S-, -SC(O)NR f -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR f -, -NR f C(S)O-, -SS-, -S(O) 0-2 -, phenylene, or pyridylidene, where the phenylene and pyridylidene are one or more R * It is optionally replaced by; R * These are, independently, halogen, cyano, and C 1-10 Alkyl, C 1-10 Haloalkyl, -L f -OR f , -L f -SR f , or -L f -NR f R' f and; L f These are, independently, combined or C 1-8 It is alkylene; R f and R' f H and C are independent of each other. 1-10 Alkyl, C3-14 It is a cycloalkyl or a 3- to 14-membered heterocycline; R1 and R2 are independent of C 4-20 Alkyl, C 4-20 Alkenyl, or C 4-20 The alkyl, alkenyl, or alkynyl is one or more R 1s The units are optionally replaced by -NR'-, where one or more methylene units are optionally and independently replaced by -NR'-; R 1s H and C are independent of each other. 1-20 Alkyl, -L c -OR c , -L c -SR c , or -L c -NR c R' c and; R and R' are independently H or C 1-20 It is alkyl; L c These are, independently, combined or C 1-20 It is alkylene; R c and R' c These are H and C, respectively, independently. 1-20 Alkyl, C 3-14 It is a cycloalkyl or a 3- to 14-membered heterocycline; R3 is -CN, -OR g , -C(O)R g ,-OC(O)R g ,-NR''C(O)R g , -NR g R' g ,-NR''C(O)NR g R' g ,-NR''C(O)R g -NR''S(O)2R g -OC(O)NR g R' g , -NR''C(O)OR g , -N(OR g )C(O)R g , -N(OR g )S(O)2R g , -N(ORg )C(O)OR g , -N(OR g )C(O)R g R' g , optionally substituted 3- to 14-membered heterocyclyls, or optionally substituted 5- to 14-membered heteroaryls; R g and R' g These are H and C, respectively, independently. 1-10 Alkyl, C 3-10 It is a cycloalkyl or a 3- to 10-membered heterocycline; R'' is independently H or C 1-6 It is alkyl; R5 and R6 are independently C 1-8 It is an alkyl group, where the alkyl group is one or more R 4s It is optionally replaced by; Alternatively, R5 and R6, along with the carbon atoms to which they are bonded, are C 3-14 It forms a cycloalkylene or a 3-14 membered heterocyclene, where the cycloalkylene and heterocyclene are one or more R 4s It is optionally replaced by; R 4s Each example independently represents H, halogen, cyano, and C. 1-8 Alkyl, C 1-8 Haloalkyl, -L d -OR d , -L d -SR d , or -L d -NR d R' d and; L d These are, independently, combined or C 1-8 It is alkylene; R d and R' d H and C are independent of each other. 1-8 Alkyl, C 3-14 They are cycloalkyl or 3- to 14-membered heterocyclines.

[0034] In one embodiment, the ionized lipid is a compound of formula (X): [ka] or its stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt, in the formula, a is 1, 2, 3, 4, 5, or 6; b is 4, 5, 6, 7, 8, 9, or 10; c is 1, 2, 3, 4, 5, or 6; d is 0, 1, 2, 3, or 4; c+d is 3, 4, 5, 6, 7, 8, or 9.

[0035] In one embodiment, the ionized lipid is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or its stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts.

[0036] In one embodiment, the ionized lipid is [ka] Selected from the group consisting of a , its stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt.

[0037] In one embodiment, the ionized lipid is [ka] [ka] [ka] Selected from the group consisting of a , its stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt.

[0038] In one embodiment, the ionized lipid is DODAP, DODMA, DLinDMA, DLin-KC2-DMA, DLin-MC3-DMA, SM-102, or ALC-0315, or a combination thereof, or a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

[0039] In one embodiment, the amount of ionized lipids is about 20 mol% to about 80 mol% of the total lipids present in the lipid nanoparticles. In another embodiment, the amount of ionized lipids is about 20 mol% to about 55 mol% of the total lipids present in the lipid nanoparticles.

[0040] In one embodiment, the lipid nanoparticles further comprise phospholipids. In one embodiment, the phospholipids are DSPC, DMPC, DOPC, DPPC, POPC, DOPE, DMPE, POPOE, or DPPE.

[0041] In one embodiment, the lipid nanoparticles either do not contain phospholipids, or contain phospholipids in an amount of about 50 mol%, about 40 mol%, about 30 mol%, about 20 mol%, about 10 mol%, or less than about 5 mol% of the total lipids present in the lipid nanoparticles.

[0042] In one embodiment, the lipid nanoparticles further comprise structural lipids. In one embodiment, the structural lipids are selected from the group consisting of cholesterol, campesterol, stigmasterol, sitosterol, brassicasterol, ergosterol, solanine, ursolic acid, α-tocopherol, β-sitosterol, avenasterol, and canolasterol. In one embodiment, the amount of the structural lipids is about 3 mol% to about 80 mol%, about 5 mol% to about 60 mol%, or about 10 mol% to about 60 mol% of the total lipids present in the lipid nanoparticles.

[0043] In one embodiment, the lipid nanoparticles further comprise polymer conjugate lipids. In one embodiment, the polymer conjugate lipids are PEGylated lipids. In one embodiment, the PEGylated lipids comprise PEGylated moieties having molecular weights of about 1000 Da to about 20,000 Da, about 1000 Da to about 5000 Da, or about 1000 Da to about 2000 Da. In one embodiment, the polymer conjugate lipids are ALC-0159, DMG-PEG2000, DMPE-PEG1000, DPPE-PEG1000, DSPE-PEG1000, DOPE-PEG1000, ceramide-PEG2000, DMPE-PEG2000, DPPE-PEG2000, DSPE-PEG2000, DSPE-PEG2000-mannose, ceramide-PEG5000, DSPE-PEG5000, or DSPE-PEG2000 amine. In one embodiment, the amount of polymer conjugate lipid is about 0.1 mol% to about 7.5 mol%, about 0.25 mol% to about 2 mol%, about 0.25 mol% to about 1.5 mol%, or about 1 mol% of the total lipids present in the lipid nanoparticles.

[0044] In one embodiment, the lipid nanoparticles comprise a payload, wherein the payload is a therapeutic agent, a prophylactic agent, or a diagnostic agent. In one embodiment, the payload is a nucleic acid. In one embodiment, the nucleic acid is an antisense oligonucleotide (ASO), DNA, or RNA, and optionally, the RNA is RNA interference (RNAi), small interfering RNA (siRNA), short hairpin RNA (shRNA), antisense RNA (aRNA), messenger RNA (mRNA), modified messenger RNA (mmRNA), long non-coding RNA (lncRNA), microRNA (miRNA), small activated RNA (saRNA), multicoding nucleic acid (MCNA), polymer-coded nucleic acid (PCNA), guide RNA (gRNA), CRISPR RNA (crRNA), or any other RNA within a ribozyme.

[0045] In one embodiment, the ratio of the total number of nitrogen atoms in the steroid compound and the ionized lipid to the total number of phosphates in the nucleic acid is about 1:1 to about 20:1, about 1:1 to about 20:1, about 2:1 to about 10:1, or about 4:1 to about 8:1.

[0046] In one embodiment, the lipid nanoparticles have an apparent pKa of about 7, about 8, about 9, about 10, about 7 to about 10, or about 10.

[0047] In one embodiment, when the lipid nanoparticles containing the payload are administered systemically to a subject, the amount of the payload delivered or expressed in the subject's lungs is higher than the amount of the payload delivered or expressed in the subject's liver.

[0048] In one embodiment, the amount of payload delivered or expressed in the lungs of the subject is at least 2 times, at least 5 times, at least 10 times, at least 20 times, at least 40 times, at least 60 times, or at least 100 times higher than the amount of payload delivered or expressed in the liver of the subject.

[0049] In one embodiment, this specification provides a group of lipid nanoparticles, including the lipid nanoparticles described herein.

[0050] In one embodiment, this specification provides a pharmaceutical composition comprising lipid nanoparticles or a group of lipid nanoparticles as described herein.

[0051] In one embodiment, this specification provides a method for treating or preventing a lung disease in a subject having the lung disease, the method comprising administering to the subject a therapeutically effective amount of lipid nanoparticles, a group of lipid nanoparticles, or a pharmaceutical composition described herein.

[0052] In one embodiment, this specification provides a method for preparing lipid nanoparticles or a group of lipid nanoparticles described herein, (i) A step of dissolving a mixture containing lipids in a first solution, wherein the lipid solution is formed in an organic solvent, (ii) The step of dissolving the payload in the second solution to form a payload solution, (iii) A method is provided which includes the step of mixing the lipid solution and the payload solution to form the lipid nanoparticles.

[0053] In one embodiment, the above mixing is performed using a microfluidizer system.

[0054] In another embodiment, the steroid compound of formula (II-A) is used herein: [ka] Or a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt is provided, in the formula, [ka] These are, independently, single or double bonds; Y is -C(O)O-, -O-, -NH-, -SC(O)O-, -OC(O)NR 2a -, -NR 2a C(O)NR 2a -, -OC(O)S-, -OC(O)O-, -NR 2a C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR 2a -, -C(O)NR 2a -, -NR 2a C(O)-, -NR 2a C(O)S-, -SC(O)NR 2a -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR 2a -, -NR 2a C(S)O-, or -S(O) 0-2 - and in the equation, the left-side bond is directed towards V1; Y1 either does not exist, or is -C(O)O-, -O-, -NH-, -SC(O)O-, -OC(O)NR 2a -, -NR 2a C(O)NR 2a -, -OC(O)S-, -OC(O)O-, -NR 2a C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR 2a -, -C(O)NR 2a -, -NR 2a C(O)-, -NR 2a C(O)S-, -SC(O)NR 2a -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR 2a -, -NR 2a C(S)O-, or -S(O) 0-2 - and in the equation, the left-side bond is directed towards V1; R 2a Each example is independently H, C 1-10 Alkyl, C3-14 A cycloalkyl or a 3-14 membered heterocycline, where the alkyl, cycloalkyl, and heterocycline are independently C 1-10 Alkyl, L 2b -OR 2b , L b -SR 2b , L 2b -NR 2b R' 2b , L 2b N + R 2b R' 2b R'' 2b , L 2b -OC(O)R 2b , or L 2b -C(O)OR 2b It is optionally replaced by; R 201 , R 202 , R 203 , R 204 Each example independently represents H, OH, alkyl, alkoxy, and -L. 2b -NR 21 R 22 , or -L 2b -N + R 21 R 22 R 23 , L 2b -OC(O)R 21 , or L 2b -C(O)OR 21 and; m is an integer between 3 and 12; m1 is an integer between 0 and 12; V1 is NR 21 R 22 , N + R 21 R 22 R 23, imidazole, pyridine, pyrrole, pyrrolidine, pyrazole, (iso)thiazole, (iso)oxazole, oxadiazine, oxazoline, dithiourazole, (iso)triazole, tetrazole, pentasol, indole, dihydroindole, pyrimidine, pyrazine, quinazoline, piperazine, piperidine, morpholine, pyran, quinoxaline, quinoline, quinolinone, (iso)quinoline, amidine, guanidine, or urea; M is either absent or independently one or more anions selected from chloride, bromide, iodide, sulfate, nitrate, perchlorate, formate, citrate, sulfonate, methanesulfonate, triflate, trifluoroacetate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, pyrophosphate, monohydrogen phosphate, dihydrogen phosphate, acetate, propionate, decanoate, caprylate, acrylate, isobutyrate, caproate, heptanoate, oxalate, malonate, succinate, fumarate, maleate, benzoate, phthalate, phenylacetate, lactate, glycolate, tartrate, mandelate, mesylate, gluconate, aspartate, or glutamate; R 21 , R 22 , R 23 Each example independently involves H, with C optionally substituted. 1-8 Alkyl, -L 2b -OR 2b , -L 2b -SR 2b , -L 2b -NR 2b R' 2b R'' 2b , L 2b -OC(O)R 2b , or L 2b -C(O)OR 2b and; L 2b C is either non-existent or optionally replaced. 1-10 It is alkylene; R 2b , R' 2b , and R'' 2b These are, independently, H or C 1-10is alkyl; R z1 is C 1-14 alkyl or C 1-14 alkenyl, where the alkyl and alkenyl are optionally substituted; provided that the compound is not [Chemical Formula] not.

[0055] In another aspect, as used herein, a steroid compound of formula (I-P): [Chemical Formula] or a stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt thereof is provided, wherein [Chemical Formula] is a single bond or a double bond; Y1 is absent or -C(O)O-, -O-, -NH-, -SC(O)O-, -OC(O)NR 2a -, -NR 2a C(O)NR 2a -, -OC(O)S-, -OC(O)O-, -NR 2a C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR​​​​​​​​​​​​​​​​​​​​​​​​1-10 Alkyl, L 2b -OR 2b , L b -SR 2b , L 2b -NR 2b R' 2b , L 2b N + R 2b R' 2b R'' 2b , L 2b -OC(O)R 2b , or L 2b -C(O)OR 2b It is optionally replaced by; R 201 , R 202 , R 203 , R 204 Each example independently represents H, OH, alkyl, alkoxy, and -L. 2b -NR 21 R 22 , -L 2b -N + R 21 R 22 R 23 , L 2b -OC(O)R 21 , or L 2b -C(O)OR 21 and; R 205 is either absent, or a cation, H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, or C2-6 alkynyl, where alkyl, haloalkyl, alkenyl, and alkynyl are optionally substituted; m is an integer between 1 and 12; m1 is an integer between 0 and 12; V1 is NR 21 R 22 , N + R 21 R 22 R 23, imidazole, pyridine, pyrrole, pyrrolidine, pyrazole, (iso)thiazole, (iso)oxazole, oxadiazine, oxazoline, dithiourazole, (iso)triazole, tetrazole, pentazole, indole, dihydroindole, pyrimidine, pyrazine, quinazoline, piperazine, piperidine, morpholine, pyran, quinoxaline, quinoline, quinolinone, (iso)quinoline, amidine, guanidine, or urea; M is absent or independently chloride, bromide, iodide, sulfate, nitrate, perchlorate, formate, citrate, sulfonate, methanesulfonate, triflate, trifluoroacetate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, pyrophosphate, monohydrogen phosphate, dihydrogen phosphate, acetate, propionate, decanoate, caprylate, acrylate, isobutyrate, caproate, heptanoate, oxalate, malonate, succinate, fumarate, maleate, benzoate, phthalate, phenylacetate, lactate, glycolate, tartrate, mandelate, mesylate, gluconate, aspartate, or glutamate, one or more anions selected from; R 21 R 22 R 23 Each example of, is independently H, optionally substituted C 1-8 alkyl, -L 2b 2b -OR 2b 2b -SR 2b 2b -NR 2b R’ 2b R’’ 2b 2b -OC(O)R 2b 2b -C(O)OR 2b 1-10 2b 2b 2b 1-10 and; L 2b is absent or optionally substituted C 1-10 alkylene; R 2b R’ 2b 2b and each example of R’’ is independently H or C 1-10It is alkyl; R z1 C 1-14 Alkyl or C 1-14 The alkyl and alkenyl compounds are optionally substituted.

[0056] In one embodiment, the steroid compound is [ka] [ka] [ka] [ka] or its stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts.

[0057] In another embodiment, the steroid compound of formula (II-B) is used herein: [ka] Or a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt is provided, in the formula, Y is -C(O)O-, -O-, -NH-, -SC(O)O-, -OC(O)NR 2a -, -NR 2a C(O)NR 2a -, -OC(O)S-, -OC(O)O-, -NR 2a C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR 2a -, -C(O)NR 2a -, -NR 2a C(O)-, -NR 2a C(O)S-, -SC(O)NR 2a -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR 2a -, -NR 2a C(S)O-, or -S(O) 0-2- and in the equation, the left-side bond is directed towards V1; Y1 either does not exist, or is -C(O)O-, -O-, -NH-, -SC(O)O-, -OC(O)NR 2a -, -NR 2a C(O)NR 2a -, -OC(O)S-, -OC(O)O-, -NR 2a C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR 2a -, -C(O)NR 2a -, -NR 2a C(O)-, -NR 2a C(O)S-, -SC(O)NR 2a -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR 2a -, -NR 2a C(S)O-, or -S(O) 0-2 - and in the equation, the left-side bond is directed towards V1; R 2a Each example is independently H, C 1-10 Alkyl, C 3-14 A cycloalkyl or a 3-14 membered heterocycline, where the alkyl, cycloalkyl, and heterocycline are independently C 1-10 Alkyl, L 2b -OR 2b , L b -SR 2b , L 2b -NR 2b R' 2b , L 2b N + R 2b R' 2b R'' 2b , L 2b -OC(O)R 2b , or L 2b -C(O)OR 2b It is optionally replaced by; R 201 , R 202 , R 203 , R 204 Each example independently represents H, OH, alkyl, alkoxy, and -L. 2b -NR 21 R 22 , or -L2b -N + R 21 R 22 R 23 , L 2b -OC(O)R 21 , or L 2b -C(O)OR 21 and; m is an integer between 5 and 12; m1 is an integer between 0 and 12; V1 is NR 21 R 22 , N + R 21 R 22 R 23 , imidazole, pyridine, pyrrole, pyrrolidine, pyrazole, (iso)thiazole, (iso)xazole, oxadiazine, oxazoline, dithiourazole, (iso)triazole, tetrazole, pentasol, indole, dihydroindole, pyrimidine, pyrazine, quinazoline, piperazine, piperidine, morpholine, pyran, quinoxaline, quinoline, quinolinone, (iso)quinoline, amidine, guanidine, or urea; however, V1 is -NH2 or -NH3 + Not; M is either absent or independently one or more anions selected from chloride, bromide, iodide, sulfate, nitrate, perchlorate, formate, citrate, sulfonate, methanesulfonate, triflate, trifluoroacetate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, pyrophosphate, monohydrogen phosphate, dihydrogen phosphate, acetate, propionate, decanoate, caprylate, acrylate, isobutyrate, caproate, heptanoate, oxalate, malonate, succinate, fumarate, maleate, benzoate, phthalate, phenylacetate, lactate, glycolate, tartrate, mandelate, mesylate, gluconate, aspartate, or glutamate; R 21 , R 22 , R 23 Each example independently involves H, with C optionally substituted. 1-8 Alkyl, -L 2b -OR 2b, -L 2b -SR 2b , -L 2b -NR 2b R' 2b R'' 2b , L 2b -OC(O)R 2b , or L 2b -C(O)OR 2b and; L 2b C is either non-existent or optionally replaced. 1-10 It is alkylene; R 2b , R' 2b , and R'' 2b These are, independently, H or C 1-10 It is alkyl.

[0058] In one embodiment of formula (II-B), Y1 is -C(O)O-, -OC(O)-, -O-, -S-, -NR 2a -, -OC(O)NR 2a -, or -NR 2a It is C(O)-.

[0059] In another embodiment, the steroid compound of formula (II-C1) is used herein: [ka] Or a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt is provided, in the formula, R z1 teeth, [ka] and; R 2a is CH3, -CH2C(O)OCH3, or -CH2C(O)OH; V1 is NR 21 R 22 or N + R 21 R 22 R 23 However, V1 is -NH2 or -NH3 + Not; R21 , R 22 , R 23 Each example independently involves H, with C optionally substituted. 1-8 Alkyl, -L 2b -OR 2b , -L 2b -SR 2b , -L 2b -NR 2b R' 2b R'' 2b , L 2b -OC(O)R 2b , or L 2b -C(O)OR 2b and; L 2b C is either non-existent or optionally replaced. 1-10 It is alkylene; R 2b , R' 2b , and R'' 2b These are, independently, H or C 1-10 It is alkyl; M is either absent or independently one or more anions selected from chloride, bromide, iodide, sulfate, nitrate, perchlorate, formate, citrate, sulfonate, methanesulfonate, triflate, trifluoroacetate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, pyrophosphate, monohydrogen phosphate, dihydrogen phosphate, acetate, propionate, decanoate, caprylate, acrylate, isobutyrate, caproate, heptanoate, oxalate, malonate, succinate, fumarate, maleate, benzoate, phthalate, phenylacetate, lactate, glycolate, tartrate, mandelate, mesylate, gluconate, aspartate, or glutamate; m is an integer between 2 and 12.

[0060] In another embodiment, the steroid compound of formula (II-C2) is used herein: [ka] Or a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt is provided, in the formula, R z1 teeth, [ka] and; V1 is NR 21 R 22 or N + R 21 R 22 R 23 However, V1 is -NH2, -NH3 + , not N(CH3)2, N(CH3)(C2H5), or N(C2H5)2; R 21 , R 22 , R 23 Each example independently involves H, with C optionally substituted. 1-8 Alkyl, -L 2b -OR 2b , -L 2b -SR 2b , -L 2b -NR 2b R' 2b R'' 2b , L 2b -OC(O)R 2b , or L 2b -C(O)OR 2b and; L 2b C is either non-existent or optionally replaced. 1-10 It is alkylene; R 2b , R' 2b , and R'' 2b These are, independently, H or C 1-10 It is alkyl; M is either absent or independently one or more anions selected from chloride, bromide, iodide, sulfate, nitrate, perchlorate, formate, citrate, sulfonate, methanesulfonate, triflate, trifluoroacetate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, pyrophosphate, monohydrogen phosphate, dihydrogen phosphate, acetate, propionate, decanoate, caprylate, acrylate, isobutyrate, caproate, heptanoate, oxalate, malonate, succinate, fumarate, maleate, benzoate, phthalate, phenylacetate, lactate, glycolate, tartrate, mandelate, mesylate, gluconate, aspartate, or glutamate; m is an integer between 2 and 12.

[0061] In another aspect, the following steroid compounds are used herein: [ka] [ka] [ka] [ka] Alternatively, stereoisomers thereof, mixtures of stereoisomers, or pharmaceutically acceptable salts are provided.

[0062] In one embodiment, this specification provides lipid nanoparticles comprising a steroid compound described herein. 4. Brief explanation of the drawing [Brief explanation of the drawing]

[0063] [Figure 1] This shows the luciferase expression levels in the liver and lungs of mice after administration of LNP, regardless of the presence or absence of BHEM-Chol and DOPE.

[0064] [Figure 2A] This shows the ratio of luciferase expression levels (lung / liver) in the lungs and livers of mice after administration of LNPs containing different ionized lipids, regardless of the presence or absence of BHEM-Chol.

[0065] [Figure 2B] This shows the luciferase expression levels in the liver and lungs of mice after administration of LNPs containing different ionized lipids, with or without the presence of BHEM-Chol.

[0066] [Figure 3A] This shows the expression levels of luciferase in the liver and lungs of mice after administration of LNPs containing different cationic steroid compounds.

[0067] [Figure 3B] This shows the ratio of luciferase expression levels (lung / liver) in the lungs and livers of mice after administration of LNPs containing different cationic steroid compounds.

[0068] [Figure 4] This shows the expression levels of luciferase in the liver and lungs of mice after administration of an LNP containing either BHEM-Chol or DOTAP. 5. Modes for Carrying Out the Invention [Modes for carrying out the invention]

[0069] This specification provides compositions, preparations, and uses of lipid nanoparticles.

[0070] In one embodiment, lipid nanoparticles (LNPs, e.g., LNPs as described in Section 5.2) are provided herein. In one embodiment, the LNP comprises a steroid compound having a cationic group (cationic steroid compound, Section 5.2.1). In one embodiment, the LNP comprises an ionized lipid (Section 5.2.2). In one embodiment, the LNP further comprises a phospholipid lipid (Section 5.2.3). In one embodiment, the LNP does not contain a phospholipid lipid. In one embodiment, the LNP further comprises a structural lipid (Section 5.2.4). In one embodiment, the LNP further comprises a PEGylated lipid (Section 5.2.5). In one embodiment, the LNP comprises a payload (Section 5.2.6).

[0071] In one embodiment, a population of lipid nanoparticles (Section 5.3) is provided herein.

[0072] In one embodiment, the LNP described herein, when administered to a subject, preferably delivers the payload to an organ other than the liver (e.g., the lungs). In one embodiment, an LNP composition for use in the treatment of lung disease is provided herein.

[0073] In another embodiment, this specification provides a pharmaceutical composition (Section 5.4) comprising an LNP provided herein.

[0074] Furthermore, this specification provides a method for producing the LNP compositions described herein (see Section 5.5). This specification also provides a method for treating a disease using the LNP compositions described herein (Section 5.6). In one embodiment, this specification provides a method for treating a lung disease.

[0075] One aspect of this application relates to the finding that incorporating a steroid compound (e.g., a cationic steroid compound provided in Section 5.2.1) into LNPs significantly improves the efficiency of delivery of LNPs and their payloads to the lungs. More specifically, cationic steroid compounds lead to higher delivery efficiency of LNPs and their payloads to the lungs compared with other cationic lipids (e.g., DOTAP). Cationic steroid compounds can exert their effects in relatively small amounts, which can lead to reduced toxicity and side effects. Another aspect of this application relates to the finding that the absence of phospholipids in steroid-cationic lipid-containing LNPs does not affect the efficient delivery of the payload to the lungs. 5.1 Definition

[0076] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art. All patents, applications, published applications, and other documents are incorporated by reference in their entirety. If there are multiple definitions of a term herein, the definition in this section shall prevail unless otherwise stated.

[0077] In this specification, the term "about" means approximately, roughly, about, or roughly within that range. When the term "about" is used with a numerical range, it modifies the range by extending the upper and lower limits of the numerical value being stated. Generally, unless otherwise stated or made clear from the context, the term "about" may modify a number above or below the numerical value being stated by, for example, 10 percent, up or down (higher or lower).

[0078] Please note that in the event of any discrepancy between the illustrated structure and its name, the illustrated structure shall take precedence.

[0079] When a range of values ​​is listed, it is intended to include each value and sub-range within that range. For example, "C 1-6"Alkyl" refers to C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 It is intended to include.

[0080] As used herein, unless otherwise specified, “alkyl” refers to the radical of a straight-chain or branched-chain saturated hydrocarbon group from which one hydrogen atom has been removed. For example, “C 1-24 "Alkyl" refers to a radical of a straight-chain or branched-chain saturated hydrocarbon group having 1 to 24 carbon atoms. 1-20 "Alkyl" refers to a radical of a straight-chain or branched-chain saturated hydrocarbon group having 1 to 20 carbon atoms. 24 "Alkyl" refers to a radical of a straight-chain or branched-chain saturated hydrocarbon group having 6 to 24 carbon atoms. 20 "Alkyl" refers to a linear or branched saturated hydrocarbon radical having 6 to 20 carbon atoms. In some embodiments, alkyl is C 1-24 Alkyl, C 4-20 Alkyl, C 6-20 Alkyl, C 8-20 Alkyl, C 10-20 Alkyl, C 6-18 Alkyl, C 6-16 Alkyl, C 6-14 Alkyl, C 6-12 Alkyl, C 8-10 Alkyl, C 2-8 Alkyl, C 7-9 Alkyl, C 4-6 Alkyl, C 1-16 Alkyl, C 1-14 Alkyl, C 2-14 Alkyl, C 1-13 Alkyl, C 1-12 Alkyl, C 1-10Alkyl, C 1-8 Alkyl, C 1-7 Alkyl, C 2-7 Alkyl, C 1-6 Alkyl, C 1-5 Alkyl, C5 alkyl, C 1-4 Alkyl, C 2-4 Alkyl, C 1-3 Alkyl, C 2-3 Alkyl, C 1-2 It is alkyl or methyl. 1-6 Examples of alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). The term "alkyl" also includes heteroalkyls in which one or more carbon atoms (e.g., 1, 2, 3, or 4) are substituted with heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). Alkyls may or may not be substituted. Alkyls may be optionally substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Common abbreviations for alkyl groups include Me(-CH3), Et(-CH2CH3), iPr(-CH(CH3)2), nPr(-CH2CH2CH3), n-Bu(-CH2CH2CH2CH3), or i-Bu(-CH2CH(CH3)2).

[0081] As used herein, unless otherwise specified, “alkenyl” refers to a radical of a straight-chain or branched-chain unsaturated hydrocarbon group having at least one carbon-carbon double bond. For example, “C 6-24 "Alkenyl" refers to a radical of a straight-chain or branched hydrocarbon group having 6 to 24 carbon atoms and at least one carbon-carbon double bond. 4-28 "Alkenyl" refers to a radical of a straight-chain or branched hydrocarbon group having 4 to 28 carbon atoms and at least one carbon-carbon double bond. 4-20"Alkenyl" refers to a radical of a straight-chain or branched hydrocarbon group having 4 to 20 carbon atoms and at least one carbon-carbon double bond. 2-14 An "alkenyl" refers to a radical of a linear or branched hydrocarbon group having 2 to 14 carbon atoms and at least one carbon-carbon double bond. In some embodiments, an alkenyl is C 4-24 Alkenil, C 6-24 Alkenil, C 8-24 Alkenil, C 10-24 Alkenil, C8 Alkenil, C9 Alkenil, C 10 Alkenil, C 11 Alkenil, C 12 Alkenil, C 13 Alkenil, C 14 Alkenil, C 15 Alkenil, C 16 Alkenil, C 2-13 Alkenil, C 2-10 Alkenil, C 2-6 Alkenyl, or C 2-4 It is alkenil. 2-6 Examples of alkenyls include vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), and hexenyl (C6). The term "alkenyl" also includes heteroalkenyls in which one or more carbon atoms (e.g., 1, 2, 3, or 4) are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). Alkenyls may or may not be substituted. Alkenyls may be optionally substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0082] As used herein, unless otherwise specified, “alkynyl” refers to a radical of a linear or branched hydrocarbon group having at least one carbon-carbon triple bond. For example, “C 4-20"Alkynyl" refers to a radical of a linear or branched hydrocarbon group having 2 to 20 carbon atoms and at least one carbon-carbon triple bond. In some embodiments, alkynyl is C 4-24 Alkinyl, C 6-20 Alkinyl, C 8-18 Alkinyl, C8 Alkinyl, C9 Alkinyl, C 10 Alkinyl, C 11 Alkinyl, C 12 Alkinyl, C 13 Alkinyl, C 14 Alkinyl, C 15 Alkinyl, C 16 Alkinyl, C 17 Alkinyl, C 2-13 Alkinyl, C 2-10 Alkinyl, C 2-6 Alkinyl, or C 2-4 It is alkinyl C 2-6 Examples of alkynyls include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), and hexynyl (C6). The term "alkynyl" also includes heteroalkynyls in which one or more carbon atoms (e.g., 1, 2, 3, or 4) are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). Alkynnyls may or may not be substituted. The alkynyl group may be substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0083] As used herein, unless otherwise specified, “alkylene” refers to a divalent group formed by removing another hydrogen atom from an alkyl group. For example, “C 1-24 "Alkylene" refers to C 1-24 This refers to a divalent group formed by removing another hydrogen atom from an alkyl group. In some embodiments, alkylene is C 1-24 Alkilen, C 4-24 Alkilen, C 1-20 Alkilen, C 8-20 Alkylene, C8 alkylene, C9 alkylene, C10 Alkilen, C 11 Alkilen, C 12 Alkilen, C 13 Alkilen, C 13 Alkilen, C 14 Alkilen, C 15 Alkilen, C 16 Alkilen, C 17 Alkilen, C 18 Alkilen, C 1-20 Alkilen, C 1-14 Alkilen, C 2-14 Alkilen, C 1-13 Alkilen, C 1-12 Alkilen, C 1-10 Alkilen, C 1-8 Alkilen, C 7-9 Alkilen, C 4-6 Alkilen, C 1-7 Alkilen, C 2-7 Alkilen, C 1-6 Alkilen, C 1-5 Alkylene, C5 Alkylene, C 1-4 Alkilen, C 2-4 Alkilen, C 1-3 Alkilen, C 2-3 Alkilen, C 1-2The alkylene is either alkylene or methylene. The alkylene may be substituted or unsubstituted. Examples of unsubstituted alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), and hexylene (-CH2CH2CH2CH2CH2CH2-). Examples of substituted alkylene groups, such as those substituted with one or more alkyl(methyl) groups, include, but are not limited to, substituted methylene (-CH(CH3)-, -C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3)2-), and substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-).

[0084] As used herein, unless otherwise specified, "alkenylene" refers to a divalent group formed by removing another hydrogen from an alkenyl. For example, "C 2-24 "Alkenylene" refers to C 2-24 This refers to a divalent alkenylene radical obtained by removing another hydrogen from an alkenyl group. In some embodiments, the alkenylene is C 4-24 Alkenylene, C 4-20 Alkenylene, C 8-20 Alkenylene, C 8-18 Alkenylene, C 8-16 Alkenylene, C 4-14 Alkenylene, C 2-13 Alkenylene, C 2-10 Alkenylene, C 2-6 Alkenylene, or C 2-4These are alkenylenes. Alkenylenes may or may not be substituted. Examples of unsubstituted alkenylene groups include, but are not limited to, ethenylene (-CH=CH-) and propenylene (e.g., -CH=CHCH2-, -CH2-CH=CH-). For example, examples of substituted alkenylene groups substituted with one or more alkyl (methyl) groups include, but are not limited to, substituted ethenylene (-C(CH3)=CH-, -CH=C(CH3)-), substituted propenylene (e.g., -C(CH3)=CHCH2-, -CH=C(CH3)CH2-, -CH=CHCH(CH3)-, -CH=CHC(CH3)2-, -CH(CH3)-CH=CH-, -C(CH3)2-CH=CH-, -CH2-C(CH3)=CH-, -CH2-CH=C(CH3)-).

[0085] As used herein, unless otherwise specified, "alkynylene" refers to a divalent group formed by removing another hydrogen from an alkynyl group. For example, "C 2-24 "Alkynylene" is C 2-24 This refers to a divalent alkynylene radical obtained by removing another hydrogen atom from an alkynyl group. 2-13 "Alkynylene" is C 2-13 This refers to a divalent alkynylene radical obtained by removing another hydrogen atom from an alkynyl group. 14 "Alkynylene" is C 4-14 This refers to a divalent alkynylene radical obtained by removing another hydrogen from an alkynyl group. In some embodiments, alkynylene is C 2-24 Alkinylene, C 2-20 Alkinylene, C 4-16 Alkinylene, C 8-16 Alkinylene, C 9-16 Alkinylene, C 10-16 Alkinylene, C 4-12 Alkinylene, C 2-10 Alkinylene, C 2-6 Alkynylene, or C 2-4It is an alkynylene. The alkynylene may be substituted or unsubstituted. Examples of alkynylene groups include, but are not limited to, ethynylene (-C≡C-) and substituted or unsubstituted propynylene (-C≡CCH2-).

[0086] "C 0-6 "Alkylene" refers to a chemical bond and the aforementioned "C 1-6 Refers to "alkylene" and "C 0-4 "Alkylene" refers to a chemical bond and the aforementioned "C 1-4 This refers to "alkylene".

[0087] The phrase "Variable A and Variable B have a total length of x carbon atoms" means that the sum of the number of carbon atoms in the main chain of the group represented by Variable A and the number of carbon atoms in the main chain of the group represented by Variable B is x.

[0088] "Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0089] "Haloalkyl" refers to an alkyl group that has been substituted with one or more halogens. For example, "C 1-10 "Haloalkyl" refers to the aforementioned "C 1-10 In the case of "alkyl," it refers to a halogen substituted with one or more halogens. In some embodiments, the haloalkyl is C 1-24 Haloalkyl, C 1-20 Haloalkyl, C 1-18 Haloalkyl, C 1-16 Haloalkyl, C 1-14 Haloalkyl, C 1-12 Haloalkyl, C 6-12 Haloalkyl, C 1-6 Haloalkyl, C 1-4 Haloalkyl, or C 1-2Haloalkyls are C1 haloalkyls, C2 haloalkyls, C3 haloalkyls, C4 haloalkyls, C5 haloalkyls, C6 haloalkyls, C7 haloalkyls, or C8 haloalkyls. Haloalkyls may optionally further contain one or more non-halogen substituents. Examples of haloalkyls include, but are not limited to, -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CF2CF3, -CCl3, -CH2Cl, -CHCl2, and 2,2,2-trifluoro-1,1-dimethylethyl. Haloalkyls may be substituted at any available bonding site with, for example, one to five substituents, one to three substituents, or one substituent.

[0090] As used herein, unless otherwise specified, “cycloalkyl” refers to a non-aromatic monocyclic or polycyclic hydrocarbon radical consisting only of carbon atoms and hydrogen atoms. For example, “C 3-14 "Cycloalkyl" or "3-14 membered cycloalkyl" refers to a radical of a non-aromatic cyclic hydrocarbon group having 3-14 ring carbon atoms and 0 heteroatoms, and optionally containing 1, 2, or 3 double or triple bonds. In some embodiments, cycloalkyl refers to a 3-10 membered cycloalkyl (C 3-10 Cycloalkyl), 5-10 member cycloalkyl (C 5-10 Cycloalkyl), 3-8 member cycloalkyl (C 3-8 Cycloalkyl), 3-7 member cycloalkyl (C 3-7 Cycloalkyl), 3-6 member cycloalkyl (C 3-6 Cycloalkyl), 5-7 member cycloalkyl (C 5-7 Cycloalkyl), 4-6 member cycloalkyl (C 4-6 Cycloalkyl), 5-6 member cycloalkyl (C 5-6These include cycloalkyls, 3-membered cycloalkyls (C3 cycloalkyls), 4-membered cycloalkyls (C4 cycloalkyls), 5-membered cycloalkyls (C5 cycloalkyls), and 6-membered cycloalkyls (C6 cycloalkyls), 7-membered cycloalkyls (C7 cycloalkyls), or 8-membered cycloalkyls (C8 cycloalkyls). Cycloalkyls also include ring systems (with bonding sites on the cycloalkyl ring) in which the above-mentioned cycloalkyl ring is fused with one or more aryl or heteroaryl groups, in which case the number of carbon atoms still represents the number of carbon atoms in the cycloalkyl system. Cycloalkyls further include the above-mentioned cycloalkyls in which substituents on any non-adjacent carbon atoms bond to form a bridging ring, forming a polycyclic alkane sharing two or more carbon atoms together. Cycloalkyls further include the above-mentioned cycloalkyls in which substituents on the same carbon atom bond to form a ring, forming a polycyclic alkane sharing one carbon atom together. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), and cycloheptatrielinyl (C7). Cycloalkyl groups may or may not be substituted. Cycloalkyl groups may be substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0091] As used herein, unless otherwise specified, "cycloalkylene" refers to a divalent group formed by removing another hydrogen atom from a cycloalkyl group. For example, "C 3-14 "Cycloalkylene" refers to C 3-14 This refers to a divalent radical formed by removing another hydrogen atom from a cycloalkyl group. In some embodiments, the cycloalkylene is C 3-12 Cycloalkylene, C 3-8 Cycloalkylene, C 3-6 Cycloalkylene, C3-5 Cycloalkylene, C 3-4 These are cycloalkylenes, C3-cycloalkylenes, C4-cycloalkylenes, C5-cycloalkylenes, or C6-cycloalkylenes. The cycloalkylenes may or may not be substituted. Examples of cycloalkylenes include cyclopropylene, cyclobutylene, cyclopentylene, or cyclohexylene.

[0092] As used herein, unless otherwise specified, “heterocyclyl” refers to a saturated or unsaturated radical of a non-aromatic ring system having a ring carbon atom and at least one ring heteroatom. For example, “3- to 14-membered heterocyclyl” refers to a saturated or unsaturated radical of a 3- to 14-membered non-aromatic ring system having at least one ring heteroatom (e.g., 1 to 5 heteroatoms) and optionally containing one, two, or three double or triple bonds. In some embodiments, the ring heteroatoms in the heterocyclyl are selected from one or more of nitrogen, oxygen, sulfur, boron, phosphorus, or silicon. In heterocyclyls containing one or more nitrogen atoms, the bonding sites to the rest of the molecule may be carbon atoms or nitrogen atoms, as long as the valence allows. In some embodiments, the heterocyclil is a 3- to 10-membered heterocyclil, a 5- to 10-membered heterocyclil, a 5- to 10-membered nitrogen-containing heterocyclil, a 3- to 8-membered heterocyclil, a 3- to 8-membered nitrogen-containing heterocyclil, a 3- to 7-membered heterocyclil, a 5- to 7-membered heterocyclil, a 3- to 6-membered heterocyclil, a 4- to 6-membered heterocyclil, a 5 or 6-membered heterocyclil, a 4-membered heterocyclil, a 5-membered heterocyclil, a 6-membered heterocyclil, or a 7-membered heterocyclil. The heterocyclil also includes a ring system in which the above-mentioned heterocyclil is fused with one or more cycloalkyl groups (with the bond site on the heterocyclil ring), or a ring system in which the above-mentioned heterocyclil is fused with one or more aryl or heteroaryl groups (with the bond site on the heterocyclil ring), in which case the number of ring members continues to represent the number of ring members in the heterocyclil ring system. The heterocyclyl may further include the heterocyclyl described above, wherein substituents on any non-adjacent carbon or nitrogen atom bond to form a bridging ring, forming a polycyclic heteroalkane that shares two or more carbon or nitrogen atoms. The heterocyclyl may further include the heterocyclyl described above, wherein substituents on the same carbon atom bond to form a ring, forming a polycyclic heteroalkane that shares one carbon atom. Examples of three-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxyranyl, and thiorenyl.Examples of four-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Examples of five-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Examples of five-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, pyrazolidyl, dioxolanyl, oxasulfuranil, disulfuranil, and oxazolidine-2-one. Examples of five-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Examples of six-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidyl, tetrahydropyranyl, dihydropyridyl, and thianyl. Examples of six-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanil. Examples of six-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazinyl. Examples of seven-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Examples of five-membered heterocyclyl groups condensed with a C6 aryl (also referred to herein as 5,6-bicyclic heterocyclyls) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, and benzoxazolinonyl. Examples of six-membered heterocyclyl groups condensed with a C6 aryl (also referred to herein as 6,6-bicyclic heterocyclyls) include, but are not limited to, tetrahydroquinolinyl and tetrahydroisoquinolinyl. The heterocyclyl further comprises the heterocyclyl described above, which, to the extent that its valence allows, shares one or two atoms with a cycloalkyl, heterocyclyl, aryl, or heteroaryl to form a bridging ring or spiro ring, where the shared atom may be a carbon atom or a nitrogen atom.The heterocyclil further comprises the heterocyclil described above, which may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0093] As used herein, unless otherwise specified, “aryl” refers to a monocyclic or polycyclic 4n+2 aromatic ring radical containing only carbon and hydrogen atoms. For example, “C 6-10 "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 shared π electrons in the cyclic arrangement) radical having 6 to 10 ring carbon atoms and 0 heteroatoms. In some embodiments, the aryl group has 6 ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl group has 10 ring carbon atoms ("C6 aryl"). 10 "Aryl" (e.g., naphthyl, e.g., 1-naphthyl and 2-naphthyl). The aryl group also includes ring systems (with the bonding site on the aryl ring) in which the aryl ring described above is fused with one or more cycloalkyl or heterocyclyl groups, in which case the number of carbon atoms still represents the number of carbon atoms in the aryl ring system. The aryl may or may not be substituted. The aryl may be substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0094] As used herein, unless otherwise specified, “heteroaryl” refers to a radical of a monocyclic or polycyclic 4n+2 aromatic ring system having at least one ring heteroatom. For example, “5-14 membered heteroaryl” refers to a radical of a monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6, 10, or 14 shared π electrons in the cyclic arrangement) of a 5-14 membered ring having a ring carbon atom and ring heteroatoms (e.g., 1-4 ring heteroatoms). In some embodiments, each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl groups having one or more nitrogen atoms, the bond site can be a carbon atom or a nitrogen atom, as long as the valence allows. Heteroaryl bicyclic systems may contain one or more heteroatoms in one or two rings. Heteroaryls also include ring systems (where the bond site is on the heteroaryl ring) in which the heteroaryl ring described above is fused with one or more cycloalkyl or heterocyclyl groups. In such cases, the number of carbon atoms still represents the number of carbon atoms in the heteroaryl ring system. In some embodiments, the heteroaryl group is a 5- to 10-membered heteroaryl, a 5- to 8-membered heteroaryl, a 5- to 6-membered heteroaryl, a 5-membered heteroaryl, or a 6-membered heteroaryl. Examples of a 5-membered heteroaryl group containing one heteroatom include, but are not limited to, pyrrolyl, furyl, and thienyl. Examples of a 5-membered heteroaryl group containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Examples of a 5-membered heteroaryl group containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl (such as 1,2,4-oxadiazolyl), and thiadiazolyl. Examples of a 5-membered heteroaryl group containing four heteroatoms include, but are not limited to, tetrazolyl. Examples of a 6-membered heteroaryl group containing one heteroatom include, but are not limited to, pyridyl or pyridonyl. Examples of six-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl.Examples of six-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetradinyl, respectively. Examples of seven-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Examples of 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranil, benzoisofuranil, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolidinyl, and purinyl. Examples of 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthylidinyl, pteridinyl, quinolyl, isoquinolyl, synnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Heteroaryls may or may not be substituted. Heteroaryls may be substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Unless otherwise specified, (iso)heteroaryls include both the heteroaryl group and its isomers. For example, in one embodiment, (iso)thiazole is isothiazole. In another embodiment, (iso)thiazole is thiazole. In one embodiment, (iso)xazole is isoxazole. In another embodiment, (iso)xazole is oxazole. In one embodiment, (iso)triazole is isothiazole. In another embodiment, (iso)triazole is triazole. In one embodiment, (iso)quinoline is isoquinoline. In another embodiment, (iso)quinoline is quinoline.

[0095] "Hydroxyalkyl" refers to an alkyl group that is substituted with one or more hydroxyl groups.

[0096] "Alkoxy" refers to the oxyether form of a linear or branched alkyl group, i.e., an -O-alkyl group. Similarly, "methoxy" refers to -O-CH3.

[0097] Divalent groups formed by removing another hydrogen from groups defined above, such as alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, are collectively called "-ylenes." Ring-forming groups such as cycloalkyl, heterocyclyl, aryl, and heteroaryl are collectively called "cyclic groups."

[0098] Where used herein, unless otherwise specified, the phrase "optionally substituted" means either unsubstituted or substituted. Substituents are independently selected, and substitutions can be induced at any chemically accessible position. Where used herein, the term "substitution" means that a hydrogen atom is removed and replaced by a substituent. A single divalent substituent (e.g., oxo) can replace two hydrogen atoms. It should be understood that substitutions at a particular atom are limited by their valence. Specific examples of substituents include, in addition to the exemplary compounds, groups, and embodiments disclosed herein, halogens, deuterium, OH, CN, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, heterocycloalkyl, cycloalkylalkyl, heterocyclylalkyl, or heteroarylalkyl. The substituents may be optionally further substituted with other substituents such as halogens, deuterium, OH, CN, alkyl, haloalkyl, alkoxy, cycloalkyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, heterocycloalkoxy, cycloalkylalkyloxy, heterocyclylalkyloxy, heteroarylalkyloxy, oxo(=O), amino, alkylamino, cycloalkylamino, heteroarylamino, guanidino, acylamino, sulfonylamino, urea, nitrourea, oxime, hydroxylamino, alkoxyamino, hydrazine, azide, nitro, thio(-SH), sulfonyl, aminosulfonyl, acyl, formyl, carboxy, ester, carbamate, amide, cyano, or isocyanate.

[0099] All alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups as defined herein are optionally substituted groups.

[0100] Examples of substituents on carbon atoms include halogens, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, and -OR aa , -ON(R bb)2、-N(R bb )2、-N(R bb )3 + X - 、-N(OR cc )R bb 、-SH、-SR aa 、-SSR cc 、-C(=O)R aa 、-CO2H、-CHO、-C(OR cc )2、-CO2R aa 、-OC(=O)R aa 、-OCO2R aa 、-C(=O)N(R bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa 、-NR bb CO2R aa 、-NR bb C(=O)N(R bb )2、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3、-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SRaa -SC(=S)SR aa -SC(=O)SR aa -OC(=O)SR aa , -SC(=O)OR aa -SC(=O)R aa -P(=O)2R aa -OP(=O)2R aa -P(=O)(R aa )2, -OP(=O)(R aa )2, -OP(=O)(OR cc )2, -P(=O)2N(R bb )2, -OP(=O)2N(R bb )2, -P(=O)(NR bb )2, -OP(=O)(NR bb )2, -NR bb P(=O)(OR cc )2, -NR bb P(=O)(NR bb )2, -P(R cc )2, -P(R cc )3, -OP(R cc )2, -OP(R cc )3, -B(R aa )2, -B(OR cc )2, -BR aa (OR cc Examples include, but are not limited to, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl compounds, where each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl compounds independently contains 0, 1, 2, 3, 4, or 5 R dd Substituted with a group; or, two geminal hydrogens on a carbon atom =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa ,=NNR bb C(=O)OR aa ,=NNR bb S(=O)2R aa ,=NR bb , or =NOR cc It can be replaced by the base.

[0101] R aa Each of these is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R aa The groups bond to form a heterocyclyl or heteroaryl ring, where the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups each independently have 0, 1, 2, 3, 4, or 5 R groups. dd It is replaced by the base.

[0102] R bb These are, independently, hydrogen, -OH, and -OR. aa , -N(R cc )2, -CN, -C(=O)R aa -C(=O)N(R cc )2, -CO2R aa , -SO2R aa -C(=NR cc )OR aa -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc -SOR aa -C(=S)N(R cc )2, -C(=O)SR cc -C(=S)SR cc -P(=O)2R aa -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R bb The groups bond to form a heterocyclyl or heteroaryl ring, where the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups each independently have 0, 1, 2, 3, 4, or 5 R groups. dd It is replaced by the base.

[0103] R cc Each of these is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R cc The groups bond to form a heterocyclyl or heteroaryl ring, where the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups each independently have 0, 1, 2, 3, 4, or 5 R groups. dd It is replaced by the base.

[0104] R dd These are, independently, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, and -OR. ee , -ON(R ff )2, -N(R ff )2, -N(R ff )3 + X - , -N(OR ee )R ff -SH, -SR ee -SSR ee -C(=O)R ee -CO2H, -CO2R ee -OC(=O)R ee , -OCO2R ee -C(=O)N(R ff )2, -OC(=O)N(R ff )2, -NR ff C(=O)R ee , -NR ff CO2R ee , -NR ff C(=O)N(R ff )2, -C(=NR ff )OR ee -OC(=NR ff )R ee -OC(=NR ff )OR ee -C(=NR ff )N(R ff )2, -OC(=NR ff )N(R ff )2, -NR ff C(=NR ff)N(R ff )2, -NR ff SO2R ee , -SO2N(R ff )2, -SO2R ee , -SO2OR ee , -OSO2R ee -S(=O)R ee , -Si(R ee )3, -OSi(R ee )3, -C(=S)N(R ff )2, -C(=O)SR ee -C(=S)SR ee -SC(=S)SR ee -P(=O)2R ee -P(=O)(R ee ) 2 -OP(=O)(R ee ) 2 , -OP(=O)(OR ee )2, selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, where each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups independently has 0, 1, 2, 3, 4, or 5 R gg Substituted by or two geminal R dd Substituents can bond to form =O or =S.

[0105] R ee Each of these is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, where each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently selected from 0, 1, 2, 3, 4, or 5 R gg It is replaced by the base.

[0106] R ff Each of these is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R ffThe groups bond to form a heterocyclyl or heteroaryl ring, where the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups each independently have 0, 1, 2, 3, 4, or 5 R groups. gg It is replaced by the base.

[0107] R gg These are, independently, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, and -OC. 1-6 Alkyl, -ON(C 1-6 Alkyl)2,-N(C 1-6 Alkyl)2,-N(C 1-6 Alkyl)3 + X - , -NH(C 1-6 Alkyl)2 + X - -NH2(C 1-6 Alkyl) + X - , -NH3 + X - , -N(OC 1-6 Alkyl)(C 1-6 Alkyl), -N(OH)(C 1-6 Alkyl), -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 Alkyl), -C(=O)(C 1-6 Alkyl), -CO2H, -CO2(C 1-6 Alkyl), -OC(=O)(C 1-6 Alkyl), -OCO2(C 1-6 Alkyl), -C(=O)NH2, -C(=O)N(C 1-6 Alkyl)2,-OC(=O)NH(C 1-6 Alkyl), -NHC(=O)(C 1-6 Alkyl), -N(C 1-6 Alkyl)C(=O)(C 1-6 Alkyl), -NHCO2(C 1-6 Alkyl), -NHC(=O)N(C 1-6 Alkyl)2,-NHC(=O)NH(C 1-6 Alkyl), -NHC(=O)NH2, -C(=NH)O(C 1-6Alkyl), -OC(=NH)(C 1-6 Alkyl), -OC(=NH)OC 1-6 Alkyl, -C(=NH)N(C 1-6 Alkyl)2,-C(=NH)NH(C 1-6 Alkyl), -C(=NH)NH2, -OC(=NH)N(C 1-6 Alkyl)2,-OC(NH)NH(C 1-6 Alkyl), -OC(NH)NH2, -NHC(NH)N(C 1-6 Alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 Alkyl), -SO2N(C 1-6 Alkyl)2,-SO2NH(C 1-6 Alkyl), -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si(C 1-6 Alkyl)3,-OSi(C 1-6 Alkyl)3,-C(=S)N(C 1-6 Alkyl)2, C(=S)NH(C 1-6 Alkyl), C(=S)NH2, -C(=O)S(C 1-6 Alkyl), -C(=S)SC 1-6 Alkyl, -SC(=S)SC 1-6 Alkyl, -P(=O)2(C 1-6 Alkyl), -P(=O)(C 1-6 Alkyl)2, -OP(=O)(C 1-6 Alkyl)2, -OP(=O)(OC 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C 10 Aryl, C3-C7 heterocyclyl, C5-C 10 Selected from heteroaryls; or two geminal Rs gg The substituents may bond to form =O or =S, where X - It is a counterion.

[0108] Examples of substituents on a nitrogen atom include hydrogen, -OH, and -OR. aa , -N(R cc )2, -CN, -C(=O)R aa -C(=O)N(R cc )2, -CO2R aa , -SO2R aa -C(=NR bb )R aa -C(=NR cc )OR aa -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc -SOR aa -C(=S)N(R cc )2, -C(=O)SR cc -C(=S)SR cc -P(=O)2R aa -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R atoms bonded to a nitrogen atom to form a heterocyclyl or heteroaryl ring together cc Examples of groups include, but are not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups, each independently having 0, 1, 2, 3, 4, or 5 R groups. dd Substituted with R aa , R bb , R cc , and R dd This is as described in this specification.

[0109] "Nucleic acid" refers to single-stranded or double-stranded deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) molecules and their heterozygous molecules. Examples of nucleic acid molecules include, but are not limited to, messenger RNA (mRNA), microRNA (miRNA), small interfering RNA (siRNA), self-amplifying RNA (saRNA), and antisense oligonucleotides (ASOs). Nucleic acids may be further chemically modified, and the chemical modifiers may be selected from one or a combination of pseudouridine, N1-methyl-psoidouridine, 5-methoxyuridine, and 5-methylcytosine. mRNA molecules include a protein-coding region and may further include regulatory expression sequences. Typical regulatory expression sequences include, but are not limited to, the 5' cap, 5' untranslated region (5'UTR), 3' untranslated region (3'UTR), polyadenylate sequence (PolyA), and miRNA binding site.

[0110] As used herein, the term "pKa" refers to the negative logarithm (p) of the acid dissociation constant (Ka) of an acid, and corresponds to the pH value at which the acid and its conjugate base are present in equiconcentrations in a solution. As used herein, the term "pKa" can be measured using water or dimethyl sulfoxide as the solvent. Measurements previously reported as pKa when using water as the solvent can be used herein as pKa. In some embodiments, pKa can be measured by experiments such as titration experiments using hydrochloric acid or sodium hydroxide. In some embodiments, pKa is measured by the 2-(p-toluidino)naphthalene-6-sulfonic acid (TNS) fluorescence method.

[0111] As used herein, the terms “ionizable” or “ionizing group” refer to a chemical group that is ionized or capable of ionization. Ionizing groups can exist as neutral groups, positively charged groups (cationic groups), or negatively charged groups (anionic groups). As used herein, “charged moiety” refers to a chemical moiety that carries a formal electronic charge, such as monovalent (+1 or -1), divalent (+2 or -2), or trivalent (+3 or -3).

[0112] As used herein, the term “treatment” relates to the disease or condition to which the term applies, or to reversing, alleviating, suppressing, or preventing the progression of one or more symptoms of such disease or condition. As used herein, the noun “treatment” relates to the verb “to treat,” the latter as defined above.

[0113] As used herein, the term “pharmaceutically acceptable salt” refers to carboxylate and amino acid addition salts of the compounds disclosed that are suitable for contact with patient tissue within the bounds of reliable medical judgment and do not cause inappropriate toxicity, irritation, allergy, etc. They are commensurate with a reasonable benefit / risk ratio and are effective for their intended use. This term includes, where possible, the zwitterionic forms of the compounds disclosed.

[0114] pharmaceutically acceptable base addition salts are formed from metals or amines such as alkali metals and alkaline earth metal hydroxides or organic amines. Examples of metals used as cations include sodium, potassium, magnesium, and calcium. Suitable amines include N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine.

[0115] Base addition salts of acidic compounds can be prepared by conventional methods by contacting the free acid form with a sufficient amount of the desired base to form a salt. The free acid can be regenerated by conventional methods by contacting the salt form with the acid and then isolating the free acid. The free acid forms differ somewhat from their respective salt forms in terms of physical properties, such as solubility in polar solvents. However, for the purposes of this disclosure, these salts are still equivalent to their respective free acids.

[0116] These salts can be prepared from inorganic acids and include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, and iodides. Examples of acids include hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, and phosphoric acid. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthalene, methanesulfonate, glucoheptonate, lactobionate, laurylsulfonate, and isethionate. These salts can also be produced from organic acids, including aliphatic monocarboxylic acids and dicarboxylic acids, phenyl-substituted alkanes, hydroxyalkanoates, alkanedioates, aromatic acids, and aliphatic and aromatic sulfonic acids. Typical salts include acetate, propionate, octanoate, isobutyrate, oxalate, malonate, succinate, suberinate, sebacinate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, naphthoate, besylate, tosylate, phenylacetate, citrate, lactate, maleate, tartrate, and methanesulfonate. Pharmaceutically acceptable salts include, but are not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine, as well as non-toxic ammonium, quaternary ammonium, and amine cations. Salts of amino acids also include arginine salts, gluconates, and galacturonic acid salts. (See, for example, Berge SMet al., “Pharmaceutical Salts,” J.Pharm.Sci., 1977;66:1-19).

[0117] The “subjects” receiving the administration include, but are not limited to, humans (e.g., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)) and / or non-human animals (e.g., mammals, e.g., primates (crab-eating macaques, rhesus macaques), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs). In some embodiments, the subject is human. In some embodiments, the subject is a non-human animal. The terms “human,” “patient,” and “subject” may be used interchangeably herein.

[0118] In this specification, the terms “disease,” “disorder,” and “medical condition” may be used interchangeably.

[0119] Unless otherwise specified, the term “treatment” as used herein includes any effect on a subject suffering from a particular disease, disorder, or condition that reduces the severity of the disease, disorder, or condition, or that delays or slows the progression of the disease, disorder, or condition (“therapeutic treatment”). This term also includes any effect that occurs before a subject develops a particular disease, disorder, or condition (“preventive treatment”).

[0120] Generally, the “effective dose” of a pharmaceutical composition refers to an amount sufficient to induce a target biological response. As those skilled in the art will understand, the effective dose of a pharmaceutical composition in this disclosure may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the pharmaceutical composition, the disease being treated, the method of administration, and the age, health status, and symptoms of the subject. Effective doses include therapeutic doses and prophylactic doses. Unless otherwise specified, the “therapeutic dose” of a pharmaceutical composition as used herein is an amount sufficient to produce a therapeutic effect in the course of treating a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. The therapeutic dose of a pharmaceutical composition refers to the amount of therapeutic agent that, when used alone or in combination with other therapeutic agents, produces a therapeutic effect in treating a disease, disorder, or condition. The term “therapeutic dose” may include an amount that improves overall treatment, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic effect of other therapeutic agents.

[0121] Unless otherwise specified, the term “cationic steroid compound” as used herein refers to any steroid compound containing at least one cationic moiety. As used herein, the term “steroid” refers to a type of compound having a tetracyclic, 17-carbon ring structure and may further contain one or more substituents, including but not limited to alkyl groups, alkoxy groups, hydroxyl groups, oxo groups, acyl groups, or double bonds between two or more carbon atoms. As used herein, the term “steroid” also includes steroid esters and sterols. As used herein, the term “steroid” also includes compounds belonging to or related to the exemplary family of corticosteroids, mineralicosteroids, and sex steroids (e.g., androgenic or estrogenic or antiandrogenic, and anti-estrogenic molecules). Non-limiting examples of steroids include cholesterol, cholestane, campesterol, sitosterol, sitostanol, β-sitosterol, stigmasterol, stigmastanol, brassicasterol, avenasterol, ergosterol, ursolic acid, tocopherol, lumisterol, or derivatives thereof. In one embodiment, the cationic steroid compound is an ionized steroid compound or a zwitterionic steroid compound that is positively charged at a specific pH. In one embodiment, the cationic steroid compound is a permanently cationic steroid compound. In one embodiment, the cationic steroid compound is a compound described in Section 5.2.1.

[0122] Unless otherwise specified, the term “biodegradable” as used herein refers to substances that are broken down under physiological conditions. In some embodiments, biodegradable substances are substances that are broken down by cellular mechanisms. In some embodiments of any aspect, biodegradable substances are substances that are broken down by chemical processes. As used herein, “biodegradable group” refers to a group containing one or more bonds that may undergo bond cleavage reactions within a biological environment, such as a living organism, organ, tissue, cell, or organelle. For example, a biodegradable group may be metabolizable in the body of a mammal such as a human (e.g., by hydrolysis). Some groups containing biodegradable bonds include, but are not limited to, esters, dithiols, and oximes. Non-limiting examples of biodegradable groups include -OC(O)-, -C(O)O-, -SC(O)-, -C(O)S-, -OC(S)-, -C(S)O-, -SS-, -C(R cc )=N-, -N=C(R cc )-,-C(R cc )=NO-, -ON=C(R cc )-,-C(O)(NR cc )-,-N(R cc )C(O)-, -C(S)(NR cc )-,-N(R cc )C(O)-, -N(R cc )C(O)N(R cc )-, -OC(O)O-, -OSi(R cc )2O-, -C(O)(CR cc R cc )C(O)O-, or -OC(O)(CR cc R cc )C(O)- is an example. The term "biodegradable lipid" refers to a lipid that has one or more biodegradable groups located in the intermediate or distal part of the lipid portion (e.g., the hydrophobic chain) of the lipid. Without being constrained by theory, incorporating biodegradable groups into lipids leads to faster metabolism of the lipid after payload delivery and removal from the body.

[0123] Unless otherwise specified, the term “structural lipids” refers to neutral sterols and lipids containing neutral sterol moieties. Without being constrained by theory, incorporating structural lipids into lipid nanoparticles may help mitigate the aggregation of other lipids within the particles. Structural lipids may be selected from the group including, but not limited to, cholesterol, fecosterol, sitosterol, ergosterol, campesterol, stigmasterol, brassicasterol, tomatidine, tomatine, ursolic acid, α-tocopherol, hopanoids, phytosterols, or mixtures thereof. In some embodiments, the structural lipids are sterols. As defined herein, “sterols” are a subgroup of steroids consisting of steroid alcohols. In certain embodiments, the structural lipids are cholesterol. In certain embodiments, the structural lipids are cholesterol analogues. In certain embodiments, the structural lipids are α-tocopherol. Unless otherwise specified, “structural lipids” as used herein are not the same as “steroid compounds” or “cationic steroid compounds” as used herein. In one embodiment, the "structural lipid" as used herein does not contain a cationic or ionizable moiety. In one embodiment, the "structural lipid" as used herein does not contain a quaternary ammonium group or a tertiary amine group.

[0124] Unless otherwise specified, the term “polymer-conjugated lipid” as used herein refers to a polymer conjugated with a lipid (e.g., polyethylene glycol (PEG), polypropylene glycol, polyvinylpyrrolidone (PVP), or poly(N-(2-hydroxypropyl)methacrylamide)). For example, PEG can be conjugated with myristoyl diglyceride to produce DMG-PEG-2000. Alternatively, PEG can be conjugated with DSPE to produce DSPE-PEG-2000. In one embodiment, the polymer-conjugated lipid is a PEGylated lipid. PEGylated lipids can incorporate various functionalized PEG terminal groups, including amines, carboxylic acids, azides, aldehydes, thiols, and hydroxyl moieties. Without being constrained by theory, polymer-conjugated lipids improve circulation time, drug stability, and adaptability to different administration routes, and contribute to achieving drug delivery. 5.2 Lipid Nanoparticles

[0125] In one embodiment, lipid nanoparticles (LNPs) are provided herein. In one embodiment, the LNP comprises a steroid compound having a cationic group (cationic steroid compound, Section 5.2.1). In one embodiment, the LNP comprises an ionized lipid (Section 5.2.2). In one embodiment, the LNP comprises a steroid compound having a cationic group (Section 5.2.1) and an ionized lipid (Section 5.2.2). In one embodiment, the LNP further comprises a phospholipid lipid (Section 5.2.3). In one embodiment, the LNP does not contain a phospholipid lipid. In one embodiment, the LNP further comprises a structural lipid (Section 5.2.4). In one embodiment, the LNP further comprises a polymer conjugate lipid (Section 5.2.5). In one embodiment, the LNP further comprises a payload (Section 5.2.6).

[0126] In one embodiment, the lipid nanoparticles described herein are not liposomes. In one embodiment, the lipid nanoparticles described herein either have essentially no aqueous internal cavities or have internal cavities of less than 10% of the total volume of the nanoparticles. In one embodiment, the lipid nanoparticles described herein comprise a single layer of lipid membrane. In one embodiment, the lipid nanoparticles described herein comprise smaller particles within the lipid nanoparticles, which bind to the payload described herein.

[0127] In one embodiment, lipid nanoparticles are provided herein for use in delivering or expressing a payload in the lungs of a subject. In one embodiment, the amount of payload delivered or expressed in the lungs of the subject is greater than the amount of payload delivered or expressed in the liver of the subject. In one embodiment, the payload is delivered by systemic administration. 5.2.1 Steroid compounds

[0128] In one embodiment, the lipid nanoparticles comprise a steroid compound containing one or more cationic groups.

[0129] In one embodiment, the cationic group of the steroid compound is a tertiary amine group, a quaternary ammonium group, or an ammonium group (NH3 + ), primary amine group (NH2), imidazole group, pyridine group, pyrrole group, pyrrolidine group, pyrazole group, (iso)thiazole group, (iso)oxazole group, oxadiazine group, oxazoline group, dithiourazole group, (iso)triazole group, tetrazole group, pentazole group, indole group, dihydroindole group, pyrimidine group, pyrazine group, quinazoline group, piperazine group, piperidine group, morpholine group, pyran group, quinoxaline group, quinoline group, quinolinone group, (iso)quinoline group, amidine group, guanidine group, or urea group.

[0130] In one embodiment, the cationic group of the steroid compound is a quaternary ammonium group. In one embodiment, the cationic group is a tertiary amine group. In one embodiment, the steroid compound comprises a quaternary ammonium group and a β-sitosterol moiety. In one embodiment, the cationic steroid compound comprises a tertiary amine group and a β-sitosterol moiety. In one embodiment, the cationic group is an amidine group, a guanidine group, or a urea group.

[0131] In one embodiment, the steroid compound is a permanently cationic steroid compound (i.e., positively charged regardless of pH). In one embodiment, the steroid compound is an ionizable cationic steroid compound (e.g., positively charged at a specific pH). In one embodiment, the steroid compound is a zwitterionic steroid compound.

[0132] In one embodiment, the steroid compound comprises a Z1 moiety containing three condensed cyclohexyl rings and one condensed cyclopentyl ring, wherein one or more CC bonds within the rings are optionally replaced with C=C double bonds. In one embodiment, Z1 comprises an optionally substituted perhydrocyclopentanophenanthrene moiety.

[0133] In one embodiment, the steroid compound comprises a Z1 portion, and the Z1 portion is [ka] , or its stereoisomer or mixture of stereoisomers, where one or more cyclic CC bonds in Z1 are independently and optionally replaced by C=C bonds as far as the valence allows, and Z1 is hydroxyl, halogen, and C 1-14 Alkyl or C 1-14 The alkyl group is optionally substituted with one or more groups selected from alkenyl groups, and the alkyl group is one or more hydroxyl, nitro, cyano, halogen, or C groups. 1-6 Alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C10 The molecule is optionally substituted with an aryl, a 5-10 member heteroaryl, or a 3-8 member heterocycline, and the bond at Z1 is directed towards the remainder of the steroid compound.

[0134] In one embodiment, the steroid compound comprises a Z1 portion, where the Z1 portion is a monovalent radical of cholesterol, cholestane, campesterol, sitosterol, sitostanol, β-sitosterol, stigmasterol, stigmastanol, brassicasterol, avenasterol, ergosterol, ursolic acid, tocopherol, lumisterol, or a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

[0135] In one embodiment, the steroid compound has a pKa of 5 to 8. In one embodiment, the steroid compound has a pKa of 5.5 to 6.5. In one embodiment, the steroid compound has a pKa greater than 8. In one embodiment, the steroid compound has a pKa greater than 10. In one embodiment, the steroid compound has a pKa greater than 10.

[0136] In one embodiment, the steroid compound is a compound of formula (C): M - V1-[-(R 20 ) a1 -Y1] n1 -Z1(C) or its stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt, in the formula, Z1 is a steroid that has been optionally substituted; Each example of Y1 is either nonexistent or -C(O)O-, -O-, -NH-, -SC(O)O-, -OC(O)NR 2a -, -NR 2a C(O)NR 2a -, -OC(O)S-, -OC(O)O-, -NR 2a C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR 2a -, -C(O)NR 2a-, -NR 2a C(O)-, -NR 2a C(O)S-, -SC(O)NR 2a -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR 2a -, -NR 2a C(S)O-, -SS-, or -S(O) 0-2 - and in the equation, the left-side bond is directed towards V1, and the right-side bond is directed towards Z1; R 2a Each example is independently H, C 1-10 Alkyl, C 3-14 A cycloalkyl or a 3-14 membered heterocycline, where the alkyl, cycloalkyl, and heterocycline are independently C 1-10 Alkyl, L 2b -OR 2b , L b -SR 2b , L 2b -NR 2b R' 2b , or L 2b N + R 2b R' 2b R'' 2b It is optionally replaced by; R 20 Each example is independent of -(CR 201 R 202 )- and in the formula, R 201 and R 202 Each example independently represents H, OH, alkyl, alkoxy, and -L. 2b -NR 21 R 22 , or -L 2b -N + R 21 R 22 R 23 and; a1 and n1 are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; V1 is NR 21 R 22 , N + R 21 R 22 R 23, or an optionally substituted nitrogen-containing heterocycline selected from the group consisting of imidazole, pyridine, pyrrole, pyrrolidine, pyrazole, (iso)thiazole, (iso)oxazole, oxadiazine, oxazoline, dithiourazole, (iso)triazole, tetrazole, pentasol, indole, dihydroindole, pyrimidine, pyrazine, quinazoline, piperazine, piperidine, morpholine, pyran, quinoxaline, quinoline, quinolinone, and (iso)quinoline, or a nitrogen-containing nonheterocyclic group selected from amidine, guanidine, and urea; M is either absent or an anion selected from chloride, bromide, iodide, sulfate, nitrate, perchlorate, formate, phosphate, pyrophosphate, citrate, sulfonate, methanesulfonate, triflate, and trifluoroacetate; R 21 , R 22 , R 23 Each example is independently H, C 1-8 Alkyl, -L 2b -OR 2b , -L 2b -SR 2b , or -L 2c -NR 2b R' 2b R'' 2b and; L 2b It does not exist, or C 1-10 It is alkylene; R 2b , R' 2b , and R'' 2b These are, independently, H or C 1-10 It is alkyl.

[0137] In one embodiment, a1 is 3, 4, 5, 6, 7, 8, 9, or 10.

[0138] In one embodiment, n1 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0139] In one embodiment, the steroid compound is a compound of formula (C1): M - V1-(R 20 ) 2-8 -Y1-Z1(C1)

[0140] In one embodiment, the steroid compound is a compound of formula (C2): M - V1-(R 20 ) 2-6 -Y1-(R 20 ) 2-6 -Y1-Z1(C2)

[0141] In one embodiment, R 20 is, -(CR 201 R 202 )- and in the formula, R 201 and R 202 Each example independently represents H, OH, alkyl, alkoxy, and -L. 2b -NR 21 R 22 , or -L 2b -N + R 21 R 22 R 23 In one embodiment, R 20 Ha, -(CR 201 R 202 )- and in the formula, R 201 and R 202 Each example is independently H, C 1-6 Alkyl, -NR 21 R 22 , or -N + R 21 R 22 R 23 That is the case.

[0142] In one embodiment, the steroid compound is a compound of formula (I): [ka] or its stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt, in the formula, [ka] It is either a single bond or a double bond; Y is -C(O)O-, -O-, -NH-, -SC(O)O-, -OC(O)NR 2a -, -NR 2a C(O)NR 2a -, -OC(O)S-, -OC(O)O-, -NR 2a C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR 2a -, -C(O)NR 2a -, -NR 2a C(O)-, -NR 2a C(O)S-, -SC(O)NR 2a -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR 2a -, -NR 2a C(S)O-, or -S(O) 0-2 - and in the equation, the left-side bond is directed towards V1; Y1 either does not exist, or is -C(O)O-, -O-, -NH-, -SC(O)O-, -OC(O)NR 2a -, -NR 2a C(O)NR 2a -, -OC(O)S-, -OC(O)O-, -NR 2a C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR 2a -, -C(O)NR 2a -, -NR 2a C(O)-, -NR 2a C(O)S-, -SC(O)NR 2a -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR 2a -, -NR 2a C(S)O-, or -S(O) 0-2 - and in the equation, the left-side bond is directed towards V1; R 2a Each example is independently H, C 1-10 Alkyl, C 3-14 A cycloalkyl or a 3-14 membered heterocycline, where the alkyl, cycloalkyl, and heterocycline are independently C 1-10 Alkyl, L 2b -OR 2b , L b -SR2b , L 2b -NR 2b R' 2b , L 2b N + R 2b R' 2b R'' 2b , L 2b -OC(O)R 2b , or L 2b -C(O)OR 2b It is optionally replaced by; R 201 , R 202 , R 203 , R 204 Each example independently represents H, OH, alkyl, alkoxy, and -L. 2b -NR 21 R 22 , -L 2b -N + R 21 R 22 R 23 , L 2b -OC(O)R 21 , or L 2b -C(O)OR 21 and; m is an integer between 1 and 12; m1 is an integer between 0 and 12; V1 is NR 21 R 22 , N + R 21 R 22 R 23 , imidazole, pyridine, pyrrole, pyrrolidine, pyrazole, (iso)thiazole, (iso)oxazole, oxadiazine, oxazoline, dithiourazole, (iso)triazole, tetrazole, pentasol, indole, dihydroindole, pyrimidine, pyrazine, quinazoline, piperazine, piperidine, morpholine, pyran, quinoxaline, quinoline, quinolinone, (iso)quinoline, amidine, guanidine, or urea; M is either absent or independently one or more anions selected from chloride, bromide, iodide, sulfate, nitrate, perchlorate, formate, citrate, sulfonate, methanesulfonate, triflate, trifluoroacetate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, pyrophosphate, monohydrogen phosphate, dihydrogen phosphate, acetate, propionate, decanoate, caprylate, acrylate, isobutyrate, caproate, heptanoate, oxalate, malonate, succinate, fumarate, maleate, benzoate, phthalate, phenylacetate, lactate, glycolate, tartrate, mandelate, mesylate, gluconate, aspartate, or glutamate; R 21 , R 22 , R 23 Each example independently involves H, with C optionally substituted. 1-8 Alkyl, -L 2b -OR 2b , -L 2b -SR 2b , -L 2b -NR 2b R' 2b R'' 2b , L 2b -OC(O)R 2b , or L 2b -C(O)OR 2b and; L 2b C is either non-existent or optionally replaced. 1-10 It is alkylene; R 2b , R' 2b , and R'' 2b Each of these examples is independent of H or C 1-10 It is alkyl; R z1 C 1-14 Alkyl or C 1-14 The alkyl and alkenyl compounds are optionally substituted.

[0143] In one embodiment, the steroid compound is a compound of formula (I): [ka] or its stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt, in the formula, [ka] It is either a single bond or a double bond; Y is -C(O)O-, -O-, -NH-, -SC(O)O-, -OC(O)NR 2a -, -NR 2a C(O)NR 2a -, -OC(O)S-, -OC(O)O-, -NR 2a C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR 2a -, -C(O)NR 2a -, -NR 2a C(O)-, -NR 2a C(O)S-, -SC(O)NR 2a -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR 2a -, -NR 2a C(S)O-, or -S(O) 0-2 - and in the equation, the left-side bond is directed towards V1; Y1 either does not exist, or is -C(O)O-, -O-, -NH-, -SC(O)O-, -OC(O)NR 2a -, -NR 2a C(O)NR 2a -, -OC(O)S-, -OC(O)O-, -NR 2a C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR 2a -, -C(O)NR 2a -, -NR 2a C(O)-, -NR 2a C(O)S-, -SC(O)NR 2a -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR 2a -, -NR 2a C(S)O-, or -S(O) 0-2 - and in the equation, the left-side bond is directed towards V1; R 2a Each example is independently H, C 1-10Alkyl, C 3-14 A cycloalkyl or a 3-14 membered heterocycline, where the alkyl, cycloalkyl, and heterocycline are independently C 1-10 Alkyl, L 2b -OR 2b , L b -SR 2b , L 2b -NR 2b R' 2b , L 2b N + R 2b R' 2b R'' 2b , L 2b -OC(O)R 2b , or L 2b -C(O)OR 2b It is optionally replaced by; R 201 , R 202 , R 203 , R 204 Each example independently represents H, OH, alkyl, alkoxy, and -L. 2b -NR 21 R 22 , -L 2b -N + R 21 R 22 R 23 , L 2b -OC(O)R 21 , or L 2b -C(O)OR 21 and; m is an integer between 1 and 12; m1 is an integer between 0 and 12; V1 is NR 21 R 22 , N + R 21 R 22 R 23, imidazole, pyridine, pyrrole, pyrrolidine, pyrazole, (iso)thiazole, (iso)oxazole, oxadiazine, oxazoline, dithiourazole, (iso)triazole, tetrazole, pentasol, indole, dihydroindole, pyrimidine, pyrazine, quinazoline, piperazine, piperidine, morpholine, pyran, quinoxaline, quinoline, quinolinone, (iso)quinoline, amidine, guanidine, or urea; M is either absent or independently one or more anions selected from chloride, bromide, iodide, sulfate, nitrate, perchlorate, formate, citrate, sulfonate, methanesulfonate, triflate, trifluoroacetate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, pyrophosphate, monohydrogen phosphate, dihydrogen phosphate, acetate, propionate, decanoate, caprylate, acrylate, isobutyrate, caproate, heptanoate, oxalate, malonate, succinate, fumarate, maleate, benzoate, phthalate, phenylacetate, lactate, glycolate, tartrate, mandelate, mesylate, gluconate, aspartate, or glutamate; R 21 , R 22 , R 23 Each example independently involves H, with C optionally substituted. 1-8 Alkyl, -L 2b -OR 2b , -L 2b -SR 2b , -L 2b -NR 2b R' 2b R'' 2b , L 2b -OC(O)R 2b , or L 2b -C(O)OR 2b and; L 2b C is either non-existent or optionally replaced. 1-10 It is alkylene; R 2b , R' 2b , and R'' 2b Each of these examples is independent of H or C 1-10It is alkyl; R z1 C 1-14 Alkyl or C 1-14 It is an alkenyl, where the alkyl and alkenyl are optionally substituted; However, if Y is -NHC(O)-, (i) m is an integer between 5 and 12; or (ii) V1 is not N(CH3)2. At least one of the following conditions is met.

[0144] In one embodiment of formula (I), V1 is NH2 or NH3 + No. In one embodiment of equation (III), Y is -NR 2a If it is C(O)-, then V1 is NH2 or NH3 + No. In one embodiment of formula (I), if Y is -NHC(O)-, then V1 is NH2 or NH3 + isn't it.

[0145] In one embodiment, Y is -C(O)O-, -OC(O)-, -O-, -NHC(O)O-, -OC(O)NH-, or -OC(O)O-. In one embodiment, Y is -C(O)O-. In one embodiment, Y is -O-. In one embodiment, Y is -NH-. In one embodiment, Y is -SC(O)O-. In one embodiment, Y is -OC(O)NR 2a -In one embodiment, Y is -NR 2a C(O)NR 2a In one embodiment, Y is -OC(O)S-. In one embodiment, Y is -OC(O)O-. In one embodiment, Y is -NR 2a It is C(O)O-. In one embodiment, Y is -OC(O)-. In one embodiment, Y is -SC(O)-. In one embodiment, Y is -C(O)S-. In one embodiment, Y is -NR 2a -In one embodiment, Y is -C(O)NR 2a -In one embodiment, Y is -NR2a It is C(O)-. In one embodiment, Y is -NR 2a It is C(O)S-. In one embodiment, Y is -SC(O)NR 2a -In one embodiment, Y is -C(O)-.In one embodiment, Y is -OC(S)-.In one embodiment, Y is -C(S)O-.In one embodiment, Y is -OC(S)NR 2a -In one embodiment, Y is -NR 2a It is C(S)O-. In one embodiment, Y is -S(O) 0-2 -(for example, -S-). In these embodiments, the left-side coupling is directed towards V1.

[0146] In one embodiment, Y1 is absent, or -C(O)O-, -OC(O)-, -O-, -S-, SO, S(O)2, -O(CO)O-, -NHC(O)-, or -C(O)NH-. In one embodiment, Y1 is absent. In one embodiment, Y1 is -SC(O)O-. In one embodiment, Y1 is -OC(O)NR 2a -In one embodiment, Y1 is -NR 2a C(O)NR 2a -In one embodiment, Y1 is -OC(O)S-.In one embodiment, Y1 is -OC(O)O-.In one embodiment, Y1 is -NR 2a It is C(O)O-. In one embodiment, Y1 is -NR 2a It is C(O)S-. In one embodiment, Y1 is -SC(O)NR 2a -In one embodiment, Y1 is -OC(S)NR 2a -In one embodiment, Y1 is -NR 2a It is C(S)O-. In one embodiment, Y1 is -NHC(O)-. In one embodiment, Y1 is -C(O)NH-. In one embodiment, Y1 is -O(CO)O-. In one embodiment, Y1 is -O-. In these embodiments, the bond on the left side is directed towards V1.

[0147] In one embodiment, the steroid compound is a compound of formula (IP): [ka] or its stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt, in the formula, [ka] It is either a single bond or a double bond; Y1 either does not exist, or is -C(O)O-, -O-, -NH-, -SC(O)O-, -OC(O)NR 2a -, -NR 2a C(O)NR 2a -, -OC(O)S-, -OC(O)O-, -NR 2a C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR 2a -, -C(O)NR 2a -, -NR 2a C(O)-, -NR 2a C(O)S-, -SC(O)NR 2a -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR 2a -, -NR 2a C(S)O-, -S(O) 0-2 -, or -OPO3-, where the bond on the left is directed towards V1; R 2a Each example is independently H, C 1-10 Alkyl, C 3-14 A cycloalkyl or a 3-14 membered heterocycline, where the alkyl, cycloalkyl, and heterocycline are independently C 1-10 Alkyl, L 2b -OR 2b , L b -SR 2b , L 2b -NR 2b R' 2b , L 2b N + R 2b R' 2b R'' 2b , L 2b -OC(O)R2b , or L 2b -C(O)OR 2b It is optionally replaced by; R 201 , R 202 , R 203 , R 204 Each example independently represents H, OH, alkyl, alkoxy, and -L. 2b -NR 21 R 22 , -L 2b -N + R 21 R 22 R 23 , L 2b -OC(O)R 21 , or L 2b -C(O)OR 21 and; R 205 is either absent, or a cation, H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, or C2-6 alkynyl, where alkyl, haloalkyl, alkenyl, and alkynyl are optionally substituted; m is an integer between 1 and 12; m1 is an integer between 0 and 12; V1 is NR 21 R 22 , N + R 21 R 22 R 23 , imidazole, pyridine, pyrrole, pyrrolidine, pyrazole, (iso)thiazole, (iso)oxazole, oxadiazine, oxazoline, dithiourazole, (iso)triazole, tetrazole, pentasol, indole, dihydroindole, pyrimidine, pyrazine, quinazoline, piperazine, piperidine, morpholine, pyran, quinoxaline, quinoline, quinolinone, (iso)quinoline, amidine, guanidine, or urea; M is either absent or independently one or more anions selected from chloride, bromide, iodide, sulfate, nitrate, perchlorate, formate, citrate, sulfonate, methanesulfonate, triflate, trifluoroacetate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, pyrophosphate, monohydrogen phosphate, dihydrogen phosphate, acetate, propionate, decanoate, caprylate, acrylate, isobutyrate, caproate, heptanoate, oxalate, malonate, succinate, fumarate, maleate, benzoate, phthalate, phenylacetate, lactate, glycolate, tartrate, mandelate, mesylate, gluconate, aspartate, or glutamate; R 21 , R 22 , R 23 Each example independently involves H, with C optionally substituted. 1-8 Alkyl, -L 2b -OR 2b , -L 2b -SR 2b , -L 2b -NR 2b R' 2b R'' 2b , L 2b -OC(O)R 2b , or L 2b -C(O)OR 2b and; L 2b C is either non-existent or optionally replaced. 1-10 It is alkylene; R 2b , R' 2b , and R'' 2b Each of these examples is independent of H or C 1-10 It is alkyl; R z1 C 1-14 Alkyl or C 1-14 The alkyl and alkenyl compounds are optionally substituted.

[0148] In one embodiment, the steroid compound of formula (IP) is the compound of formula (I-P1): [ka] or its stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt, where m3 is an integer from 1 to 11.

[0149] In one embodiment, the steroid compound is a pharmaceutically acceptable salt of formula (IP). In another embodiment, the steroid compound is a pharmaceutically acceptable salt of formula (I-P1).

[0150] In one embodiment, the steroid compound is a compound of formula (I-A1), (I-A2), (I-A3), (I-A4), or (I-A5): [ka] , or its stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts.

[0151] In one embodiment, the steroid compound is a compound of formula (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), or (I-B8): [ka] , or its stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt, where m3 is an integer from 1 to 11.

[0152] In one embodiment, m is an integer between 1 and 12. In one embodiment, m is an integer between 5 and 12. In one embodiment, m is 5. In one embodiment, m is 6. In one embodiment, m is 7. In one embodiment, m is 8. In one embodiment, m is 9. In one embodiment, m is 10. In one embodiment, m is 11. In one embodiment, m is 12. In one embodiment, m is an integer between 2 and 10. In one embodiment, m is an integer between 3 and 10. In one embodiment, m is an integer between 3 and 7. In one embodiment, m is an integer between 1 and 6. In one embodiment, m is an integer between 2 and 6. In one embodiment, m is an integer between 3 and 6. In one embodiment, m is an integer between 4 and 6. In one embodiment, m is 0. In one embodiment, m is 1. In one embodiment, m is 2. In one embodiment, m is 3. In one embodiment, m is 4.

[0153] In one embodiment, m1 is an integer between 0 and 12. In one embodiment, m1 is an integer between 0 and 6. In one embodiment, m1 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. In one embodiment, m1 is an integer between 0 and 4. In one embodiment, m1 is an integer between 0 and 3. In one embodiment, m1 is an integer between 1 and 2. In one embodiment, m1 is 0. In one embodiment, m1 is 1. In one embodiment, m1 is 2. In one embodiment, m1 is 3. In one embodiment, m1 is 4.

[0154] In one embodiment, m3 is an integer from 1 to 11. In one embodiment, m3 is an integer from 1 to 6. In one embodiment, m3 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11. In one embodiment, m3 is 1 or 2. In one embodiment, m3 is an integer from 2 to 4. In one embodiment, m3 is 3 or 4. In one embodiment, m3 is 1. In one embodiment, m3 is 2. In one embodiment, m3 is 3. In one embodiment, m3 is 4.

[0155] In one embodiment, R 2a H is H.

[0156] In one embodiment, R 2a C 1-10 It is alkyl. In one embodiment, R 2a C 1-6 It is alkyl. In one embodiment, R 2a C 1-3 It is alkyl. In one embodiment, R 2a is methyl. In one embodiment, R 2a The alkyl group is L 2b -OR 2b It is replaced by R 2a The alkyl group is not substituted. In one embodiment, R 2a The alkyl group is L b -SR 2b It is replaced by R 2a The alkyl group is L 2b -NR 2b R' 2b It is replaced by R 2a The alkyl group is L 2b N + R 2b R' 2b R'' 2b It will be replaced by this.

[0157] In one embodiment, R 2a C 3-14 It is cycloalkyl. In one embodiment, R 2aC 3-8 It is cycloalkyl. In one embodiment, R 2a C 3-6 It is cycloalkyl. In one embodiment, R 2a is a C3, C4, C5, or C6 cycloalkyl group. In one embodiment, R 2a The cycloalkyl group is unsubstituted. In one embodiment, R 2a The cycloalkyl group is C 1-10 It is substituted with alkyl. In one embodiment, R 2a The cycloalkyl group is L 2b -OR 2b It is replaced by R 2a The cycloalkyl group is L b -SR 2b It is replaced by R 2a The cycloalkyl group is L 2b -NR 2b R' 2b It is replaced by R 2a The cycloalkyl group is L 2b N + R 2b R' 2b R'' 2b It will be replaced by this.

[0158] In one embodiment, R 2a R is a 3-14 member heterocycline. In one embodiment, R 2a R is a 3-8 member heterocycline. In one embodiment, R 2a R is a 3-6 member heterocycline. In one embodiment, R 2a It is a 3-6 membered nitrogen-containing heterocycline. In one embodiment, R 2a It is a 3-6 member oxygen-containing heterocycline. In one embodiment, R 2a The heterocyclyl is not substituted. In one embodiment, R 2a The heterocyclyl is C 1-10 It is substituted with alkyl. In one embodiment, R 2a The heterocyclyl is L 2b -OR 2bIt is replaced by R 2a The heterocyclyl is L b -SR 2b It is replaced by R 2a The heterocyclyl is L 2b -NR 2b R' 2b It is replaced by R 2a The heterocyclyl is L 2b N + R 2b R' 2b R'' 2b It will be replaced by this.

[0159] In one embodiment, R 201 , R 202 , R 203 , and R 204 Each example is independently H, C 1-6 Alkyl, -NR 21 R 22 , -N + R 21 R 22 R 23 ,-(CH2) 0-6 -OC(O)R 21 , or -(CH2) 0-6 -C(O)OR 21 That is the case.

[0160] In one embodiment, R 201 , R 202 , R 203 , and R 204 Each example independently represents H, NH2, and NH3. + These are -CH2OC(O)CH3, -CH2C(O)OCH3, -OC(O)CH3, -CO(O)OCH3, or -CH2CO2H.

[0161] In one embodiment, V1 is NR 21 R 22 In one embodiment, V1 is N + R 21 R 22 R 23 That is the case.

[0162] In one embodiment, R 21 , R 22 , R 23 These are H, hydroxyl, and C, respectively, independently. 1-3 Alkyl, or C 1-3 It is a hydroxyalkyl group.

[0163] In one embodiment, V1 is an optionally substituted nitrogen-containing heterocycline. In one embodiment, V1 is an optionally substituted 3- to 8-membered nitrogen-containing heterocycline. In one embodiment, V1 is an optionally substituted nitrogen-containing heteroaryl. In one embodiment, V1 is an optionally substituted 5 or 6-membered nitrogen-containing heteroaryl. In one embodiment, V1 is selected from the group consisting of imidazole, pyridine, pyrrole, pyrrolidine, pyrazole, (iso)thiazole, (iso)xazole, oxadiazine, oxazoline, dithiourazole, (iso)triazole, tetrazole, pentazole, indole, dihydroindole, pyrimidine, pyrazine, quinazoline, piperazine, piperidine, morpholine, pyran, quinoxaline, quinoline, quinolinone, and (iso)quinoline. In one embodiment, (iso)thiazole is a thiazole. In one embodiment, (iso)thiazole is an isothiazole. In one embodiment, (iso)oxazole is an oxazole. In one embodiment, (iso)oxazole is an isoxazole. In one embodiment, (iso)quinoline is a quinoline. In one embodiment, (iso)quinoline is an isoquinoline.

[0164] In one embodiment, V1 is a nitrogen-containing nonheterocyclic group. In one embodiment, V1 is an optionally substituted amidine radical. In one embodiment, V1 is an optionally substituted guanidine radical. In one embodiment, V1 is an optionally substituted urea radical.

[0165] In one embodiment, V1 is N(CH3)2, N + (CH3)3, N +CH3(CH2CH2OH)2, N + (CH3)2(CH2CH2OH), NHC(=N + H2)NH2, NHC(O)NH2, CH2C(=NH)NH2, N(CH3)(CH2CH2CO2CH3), N + (CH3)2(CH2CH2CO2CH3), N(CH3)(CH2CO2CH3), or N + (CH3)2(CH2CO2CH3). In one embodiment, V1 is N + CH3(CH2CH2OH)2, N + (CH3)2(CH2CH2OH), or N + It is (CH3)3.

[0166] In one embodiment, V1 is N(CH3)2. In one embodiment, V1 is N + (CH3)3. In one embodiment, V1 is N + It is CH3(CH2CH2OH)2. In one embodiment, V1 is N + (CH3)2(CH2CH2OH). In one embodiment, V1 is NHC(=N + It is H2)NH2. In one embodiment, V1 is NHC(O)NH2. In one embodiment, V1 is CH2C(=NH)NH2.

[0167] In one embodiment, V1 is NH2. In one embodiment, V1 is NH3. + That is the case.

[0168] In one embodiment, R 21 , R 22 , R 23 These are H and C, respectively, independently. 1-8 Alkyl, -L 2b -OR 2b , -L 2b -SR 2b , or -L 2c -NR 2b R' 2b R'' 2b In one embodiment, R 21 , R 22 , R23 These are H and C, respectively, independently. 1-6 Alkyl, -OR 2b , -SR 2b , or -NR 2b R' 2b R'' 2b In one embodiment, R 21 , R 22 , R 23 These are H, hydroxyl, and C, respectively, independently. 1-3 Alkyl, or C 1-3 It is a hydroxyalkyl group.

[0169] In one embodiment, R 21 H is H. In one embodiment, R 21 C 1-8 It is alkyl. In one embodiment, R 21 C 1-6 It is alkyl. In one embodiment, R 21 C 1-3 It is alkyl. In one embodiment, R 21 is methyl. In one embodiment, R 21 is ethyl. In one embodiment, R 21 is propyl or isopropyl. In one embodiment, R 21 The alkyl group is not substituted. In one embodiment, R 21 The alkyl group is substituted with one or more halogens (i.e., F, Cl, Br, or I). In one embodiment, R 21 The alkyl group is L b -OR 2b It is replaced by R 21 The alkyl group is L b -SR 2b It is replaced by R 21 The alkyl group is L 2b -NR 2b R' 2b It is replaced by R 21 The alkyl group is L 2b N + R 2b R' 2b R'' 2bIt will be replaced by this.

[0170] In one embodiment, R 22 is, -L 2b -OR 2b In one embodiment, R 22 is, -L 2b -SR 2b In one embodiment, R 22 is, -L 2c -NR 2b R' 2b R'' 2b That is the case.

[0171] In one embodiment, R 22 H is H. In one embodiment, R 22 C 1-8 It is alkyl. In one embodiment, R 22 C 1-6 It is alkyl. In one embodiment, R 22 C 1-3 It is alkyl. In one embodiment, R 22 is methyl. In one embodiment, R 22 is ethyl. In one embodiment, R 22 is propyl or isopropyl. In one embodiment, R 22 The alkyl group is not substituted. In one embodiment, R 22 The alkyl group is substituted with one or more halogens (i.e., F, Cl, Br, or I). In one embodiment, R 22 The alkyl group is L b -OR 2b It is replaced by R 22 The alkyl group is L b -SR 2b It is replaced by R 22 The alkyl group is L 2b -NR 2b R' 2b It is replaced by R 22 The alkyl group is L 2b N + R 2b R' 2b R''2b It will be replaced by this.

[0172] In one embodiment, R 22 is, -L 2b -OR 2b In one embodiment, R 22 is, -L 2b -SR 2b In one embodiment, R 22 is, -L 2c -NR 2b R' 2b R'' 2b That is the case.

[0173] In one embodiment, R 23 H is H. In one embodiment, R 23 C 1-8 It is alkyl. In one embodiment, R 23 C 1-6 It is alkyl. In one embodiment, R 23 C 1-3 It is alkyl. In one embodiment, R 23 is methyl. In one embodiment, R 23 is ethyl. In one embodiment, R 23 is propyl or isopropyl. In one embodiment, R 23 The alkyl group is not substituted. In one embodiment, R 23 The alkyl group is substituted with one or more halogens (i.e., F, Cl, Br, or I). In one embodiment, R 23 The alkyl group is L b -OR 2b It is replaced by R 23 The alkyl group is L b -SR 2b It is replaced by R 23 The alkyl group is L 2b -NR 2b R' 2b It is replaced by R 23 The alkyl group is L 2b N + R 2b R'2b R'' 2b It will be replaced by this.

[0174] In one embodiment, R 23 is, -L 2b -OR 2b In one embodiment, R 23 is, -L 2b -SR 2b In one embodiment, R 23 is, -L 2c -NR 2b R' 2b R'' 2b That is the case.

[0175] In one embodiment, L 2b It does not exist. In one embodiment, L 2b This is C, which is optionally substituted. 1-10 It is alkylene. 2b This is C, which is optionally substituted. 1-6 It is alkylene. 2b This is C, which is optionally substituted. 1-3 It is alkylene. 2b The alkylene is not substituted. In one embodiment, L 2b The alkylene is one or more halogens, hydroxyl, or C 1-3 It is substituted with an alkoxy.

[0176] In one embodiment, R 2b H is H. In one embodiment, R 2b C 1-10 It is alkyl. In one embodiment, R 2b C 1-6 It is alkyl. In one embodiment, R 2b C 1-3 It is alkyl. In one embodiment, R 2b is methyl. In one embodiment, R 2b is ethyl. In one embodiment, R 2b is propyl or isopropyl. In one embodiment, R 2bThe alkyl group is not substituted. In one embodiment, R 2b The alkyl group is one or more halogens, hydroxyls, or C 1-3 It is substituted with an alkoxy.

[0177] In one embodiment, R' 2b is H. In one embodiment, R' 2b C 1-10 It is alkyl. In one embodiment, R' 2b C 1-6 It is alkyl. In one embodiment, R' 2b C 1-3 It is alkyl. In one embodiment, R' 2b is methyl. In one embodiment, R' 2b is ethyl. In one embodiment, R' 2b is propyl or isopropyl. In one embodiment, R' 2b The alkyl group is not substituted. In one embodiment, R' 2b The alkyl group is one or more halogens, hydroxyls, or C 1-3 It is substituted with an alkoxy.

[0178] In one embodiment, R'' 2b is H. In one embodiment, R'' 2b C 1-10 It is alkyl. In one embodiment, R'' 2b C 1-6 It is alkyl. In one embodiment, R'' 2b C 1-3 It is alkyl. In one embodiment, R'' 2b is methyl. In one embodiment, R'' 2b is ethyl. In one embodiment, R'' 2b is propyl or isopropyl. In one embodiment, R'' 2b The alkyl group is not substituted. In one embodiment, R'' 2b The alkyl group is one or more halogens, hydroxyls, or C 1-3 It is substituted with an alkoxy.

[0179] In one embodiment, M is one or more anions. In one embodiment, M is one or more pharmaceutically acceptable anions. In one embodiment, M is absent or independently one or more anions selected from chlorides, bromides, iodides, sulfates, nitrates, perchlorates, formates, citrates, sulfons, methanesulfons, triflates, trifluoroacetates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, pyrophosphates, monohydrogen phosphates, dihydrogen phosphates, acetates, propions, decanoates, caprylates, acrylates, isobutyrates, capronates, heptanoates, oxalates, malons, succinates, fumarates, maleates, benzoates, phthalates, phenylacetates, lactates, glycolates, tartrates, mandelates, mesylates, glucons, aspartates, or glutamates.

[0180] In one embodiment, M is a chloride, bromide, iodide, sulfate, nitrate, perchlorate, formate, phosphate, pyrophosphate, citrate, sulfonate, methanesulfonate, triflate, or trifluoroacetate. In one embodiment, M is absent or one or more of bromides, chlorides, or trifluoroacetates.

[0181] In one embodiment, R z1 C 1-14 Alkyl or C 1-14 Alkenyl, where the alkyl and alkenyl are one or more hydroxyl, oxo, nitro, cyano, halogen, C 1-6 Alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C 10 It is optionally substituted with an aryl, a 5-10 member heteroaryl, or a 3-8 member heterocycline. In one embodiment, R Z1 C 3-12 Alkyl or C 3-12 It is an alkenyl. In one embodiment, R Z1 C 7-10Alkyl or C 7-10 It is an alkenyl. In one embodiment, R Z1 is a C7 alkyl or C7 alkenyl. In one embodiment, R Z1 is a C8 alkyl or C8 alkenyl. In one embodiment, R Z1 is a C9 alkyl or C9 alkenyl. In one embodiment, R Z1 C 10 Alkyl or C 10 It is Alkenil.

[0182] In one embodiment, R Z1 C 6-12 It is alkyl. In one embodiment, R Z1 is unsubstituted C 6-12 It is alkyl. In one embodiment, R Z1 C is a C substituted with one or more oxo or hydroxyl groups. 6-12 It is alkyl.

[0183] In one embodiment, R Z1 C 6-12 It is an alkenyl. In one embodiment, R Z1 is unsubstituted C 6-12 It is an alkenyl. In one embodiment, R Z1 C is a C substituted with one or more oxo or hydroxyl groups. 6-12 It is Alkenil.

[0184] In one embodiment, R Z1 teeth, [ka] In one embodiment, R Z1 teeth, [ka] In one embodiment, R Z1 teeth, [ka] In one embodiment, RZ1 teeth, [ka] In one embodiment, R Z1 teeth, [ka] In one embodiment, R Z1 teeth, [ka] In one embodiment, R Z1 teeth, [ka] That is the case.

[0185] In one embodiment, the steroid compound is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or its stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts.

[0186] In one embodiment, the steroid compound is [ka] Or it is not a pharmaceutically acceptable salt.

[0187] In one embodiment, the steroid compound of formula (II-A) is used herein: [ka] Or a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt is provided, in the formula, [ka] These are, independently, single or double bonds; Y is -C(O)O-, -O-, -NH-, -SC(O)O-, -OC(O)NR 2a -, -NR 2a C(O)NR 2a -, -OC(O)S-, -OC(O)O-, -NR 2a C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR 2a -, -C(O)NR 2a -, -NR 2a C(O)-, -NR 2a C(O)S-, -SC(O)NR 2a -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR 2a -, -NR 2a C(S)O-, or -S(O) 0-2 - and in the equation, the left-side bond is directed towards V1; Y1 either does not exist, or is -C(O)O-, -O-, -NH-, -SC(O)O-, -OC(O)NR 2a -, -NR 2a C(O)NR 2a -, -OC(O)S-, -OC(O)O-, -NR 2a C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR 2a -, -C(O)NR 2a -, -NR 2a C(O)-, -NR 2aC(O)S-, -SC(O)NR 2a -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR 2a -, -NR 2a C(S)O-, or -S(O) 0-2 - and in the equation, the left-side bond is directed towards V1; R 2a Each example is independently H, C 1-10 Alkyl, C 3-14 A cycloalkyl or a 3-14 membered heterocycline, where the alkyl, cycloalkyl, and heterocycline are independently C 1-10 Alkyl, L 2b -OR 2b , L b -SR 2b , L 2b -NR 2b R' 2b , L 2b N + R 2b R' 2b R'' 2b , L 2b -OC(O)R 2b , or L 2b -C(O)OR 2b It is optionally replaced by; R 201 , R 202 , R 203 , R 204 Each example independently represents H, OH, alkyl, alkoxy, and -L. 2b -NR 21 R 22 , or -L 2b -N + R 21 R 22 R 23 , L 2b -OC(O)R 21 , or L 2b -C(O)OR 21 and; m is an integer between 3 and 12; m1 is an integer between 0 and 12; V1 is NR 21 R 22 , N + R 21 R 22R 23 , imidazole, pyridine, pyrrole, pyrrolidine, pyrazole, (iso)thiazole, (iso)oxazole, oxadiazine, oxazoline, dithiourazole, (iso)triazole, tetrazole, pentasol, indole, dihydroindole, pyrimidine, pyrazine, quinazoline, piperazine, piperidine, morpholine, pyran, quinoxaline, quinoline, quinolinone, (iso)quinoline, amidine, guanidine, or urea; M is either absent or independently one or more anions selected from chloride, bromide, iodide, sulfate, nitrate, perchlorate, formate, citrate, sulfonate, methanesulfonate, triflate, trifluoroacetate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, pyrophosphate, monohydrogen phosphate, dihydrogen phosphate, acetate, propionate, decanoate, caprylate, acrylate, isobutyrate, caproate, heptanoate, oxalate, malonate, succinate, fumarate, maleate, benzoate, phthalate, phenylacetate, lactate, glycolate, tartrate, mandelate, mesylate, gluconate, aspartate, or glutamate; R 21 , R 22 , R 23 Each example independently involves H, with C optionally substituted. 1-8 Alkyl, -L 2b -OR 2b , -L 2b -SR 2b , -L 2b -NR 2b R' 2b R'' 2b , L 2b -OC(O)R 2b , or L 2b -C(O)OR 2b and; L 2b C is either non-existent or optionally replaced. 1-10 It is alkylene; R 2b , R' 2b , and R'' 2b These are, independently, H or C1-10 It is alkyl; R z1 C 1-14 Alkyl or C 1-14 It is an alkenyl, where the alkyl and alkenyl are optionally substituted; however, the compound is [ka] isn't it.

[0188] In one embodiment of formula (II-A), V1 is NH2 or NH3 + No. In one embodiment of equation (II-A), Y is -NR 2a If it is C(O)-, then V1 is NH2 or NH3 + No. In one embodiment of formula (II-A), when Y is -NHC(O)-, V1 is NH2 or NH3 + isn't it.

[0189] In one embodiment, the steroid compound of formula (II-B) is used herein: [ka] Or a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt is provided, in the formula, Y is -C(O)O-, -O-, -NH-, -SC(O)O-, -OC(O)NR 2a -, -NR 2a C(O)NR 2a -, -OC(O)S-, -OC(O)O-, -NR 2a C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR 2a -, -C(O)NR 2a -, -NR 2a C(O)-, -NR 2a C(O)S-, -SC(O)NR 2a -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR 2a -, -NR 2a C(S)O-, or -S(O) 0-2- and in the equation, the left-side bond is directed towards V1; Y1 either does not exist, or is -C(O)O-, -O-, -NH-, -SC(O)O-, -OC(O)NR 2a -, -NR 2a C(O)NR 2a -, -OC(O)S-, -OC(O)O-, -NR 2a C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR 2a -, -C(O)NR 2a -, -NR 2a C(O)-, -NR 2a C(O)S-, -SC(O)NR 2a -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR 2a -, -NR 2a C(S)O-, or -S(O) 0-2 - and in the equation, the left-side bond is directed towards V1; R 2a Each example is independently H, C 1-10 Alkyl, C 3-14 A cycloalkyl or a 3-14 membered heterocycline, where the alkyl, cycloalkyl, and heterocycline are independently C 1-10 Alkyl, L 2b -OR 2b , L b -SR 2b , L 2b -NR 2b R' 2b , L 2b N + R 2b R' 2b R'' 2b , L 2b -OC(O)R 2b , or L 2b -C(O)OR 2b It is optionally replaced by; R 201 , R 202 , R 203 , R 204 Each example independently represents H, OH, alkyl, alkoxy, and -L. 2b -NR 21 R 22 , or -L 2b -N+ R 21 R 22 R 23 , L 2b -OC(O)R 21 , or L 2b -C(O)OR 21 and; m is an integer between 5 and 12; m1 is an integer between 0 and 12; V1 is NR 21 R 22 , N + R 21 R 22 R 23 , imidazole, pyridine, pyrrole, pyrrolidine, pyrazole, (iso)thiazole, (iso)xazole, oxadiazine, oxazoline, dithiourazole, (iso)triazole, tetrazole, pentasol, indole, dihydroindole, pyrimidine, pyrazine, quinazoline, piperazine, piperidine, morpholine, pyran, quinoxaline, quinoline, quinolinone, (iso)quinoline, amidine, guanidine, or urea; however, V1 is -NH2 or -NH3 + isn't it. M is either absent or independently one or more anions selected from chloride, bromide, iodide, sulfate, nitrate, perchlorate, formate, citrate, sulfonate, methanesulfonate, triflate, trifluoroacetate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, pyrophosphate, monohydrogen phosphate, dihydrogen phosphate, acetate, propionate, decanoate, caprylate, acrylate, isobutyrate, caproate, heptanoate, oxalate, malonate, succinate, fumarate, maleate, benzoate, phthalate, phenylacetate, lactate, glycolate, tartrate, mandelate, mesylate, gluconate, aspartate, or glutamate; R 21 , R 22 , R 23 Each example independently involves H, with C optionally substituted. 1-8 Alkyl, -L 2b -OR 2b , -L 2b-SR 2b , -L 2b -NR 2b R' 2b R'' 2b , L 2b -OC(O)R 2b , or L 2b -C(O)OR 2b and; L 2b C is either non-existent or optionally replaced. 1-10 It is alkylene; R 2b , R' 2b , and R'' 2b These are, independently, H or C 1-10 It is alkyl.

[0190] In one embodiment of formula (II-B), Y1 is -C(O)O-, -OC(O)-, -O-, -S-, -NR 2a -, -OC(O)NR 2a -, or -NR 2a It is C(O)-. In one embodiment of formula (II-B), Y1 is -C(O)O-, -OC(O)-, -O-, -S-, -NH-, -NCH3-, -OC(O)NH-, or -NCH(O)-. In one embodiment of formula (II-B), Y1 is -O-. In one embodiment of formula (II-B), Y1 is -S-.

[0191] In one embodiment, the steroid compound of formula (II-C1) is used herein: [ka] Or a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt is provided, in the formula, R z1 teeth, [ka] and; R 2a is CH3, -CH2C(O)OCH3, or -CH2C(O)OH; V1 is NR 21 R22 or N + R 21 R 22 R 23 However, V1 is -NH2 or -NH3 + Not; R 21 , R 22 , R 23 Each example independently involves H, with C optionally substituted. 1-8 Alkyl, -L 2b -OR 2b , -L 2b -SR 2b , -L 2b -NR 2b R' 2b R'' 2b , L 2b -OC(O)R 2b , or L 2b -C(O)OR 2b and; L 2b C is either non-existent or optionally replaced. 1-10 It is alkylene; R 2b , R' 2b , and R'' 2b These are, independently, H or C 1-10 It is alkyl; M is either absent or independently one or more anions selected from chloride, bromide, iodide, sulfate, nitrate, perchlorate, formate, citrate, sulfonate, methanesulfonate, triflate, trifluoroacetate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, pyrophosphate, monohydrogen phosphate, dihydrogen phosphate, acetate, propionate, decanoate, caprylate, acrylate, isobutyrate, caproate, heptanoate, oxalate, malonate, succinate, fumarate, maleate, benzoate, phthalate, phenylacetate, lactate, glycolate, tartrate, mandelate, mesylate, gluconate, aspartate, or glutamate; m is an integer between 2 and 12.

[0192] In one embodiment, as used herein, a steroid compound of formula (II-C2): [ka] Or a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt is provided, in the formula, R z1 teeth, [ka] and; V1 is NR 21 R 22 or N + R 21 R 22 R 23 However, V1 is -NH2, -NH3 + , not N(CH3)2, N(CH3)(C2H5), or N(C2H5)2; R 21 , R 22 , R 23 Each example independently involves H, with C optionally substituted. 1-8 Alkyl, -L 2b -OR 2b , -L 2b -SR 2b , -L 2b -NR 2b R' 2b R'' 2b , L 2b -OC(O)R 2b , or L 2b -C(O)OR 2b and; L 2b C is either non-existent or optionally replaced. 1-10 It is alkylene; R 2b , R' 2b , and R'' 2b These are, independently, H or C 1-10 It is alkyl; M is either absent or independently one or more anions selected from chloride, bromide, iodide, sulfate, nitrate, perchlorate, formate, citrate, sulfonate, methanesulfonate, triflate, trifluoroacetate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, pyrophosphate, monohydrogen phosphate, dihydrogen phosphate, acetate, propionate, decanoate, caprylate, acrylate, isobutyrate, caproate, heptanoate, oxalate, malonate, succinate, fumarate, maleate, benzoate, phthalate, phenylacetate, lactate, glycolate, tartrate, mandelate, mesylate, gluconate, aspartate, or glutamate; m is an integer between 2 and 12.

[0193] In one embodiment, the steroid compound is [ka] Or it is not a pharmaceutically acceptable salt.

[0194] In one embodiment, the following compounds are used herein: [ka] [ka] [ka] Alternatively, stereoisomers thereof, mixtures of stereoisomers, or pharmaceutically acceptable salts are provided.

[0195] In one embodiment, the following compounds are used herein: [ka] [ka] [ka] [ka] Alternatively, stereoisomers thereof, mixtures of stereoisomers, or pharmaceutically acceptable salts are provided.

[0196] In one embodiment, the amount of the steroid compound is approximately 15 mol% to approximately 80 mol%, approximately 20 mol% to approximately 60 mol%, approximately 20 mol% to approximately 50 mol%, approximately 20 mol% to approximately 40 mol%, or approximately 15 mol% to approximately 30 mol% of the total lipids present in the lipid nanoparticles.

[0197] In one embodiment, the amount of the steroid compound is about 20 mol% to about 80 mol%. In one embodiment, the amount of the steroid compound is about 20 mol% to about 60 mol%. In one embodiment, the amount of the steroid compound is about 20 mol% to about 50 mol%. In one embodiment, the amount of the steroid compound is about 20 mol% to about 40 mol%. In one embodiment, the amount of the steroid compound is about 20 mol% to about 30 mol%. In one embodiment, the amount of the steroid compound is less than about 30 mol%. In one embodiment, the amount of the steroid compound is less than about 20 mol%. In one embodiment, the amount of the steroid compound is about 10 mol%, about 15 mol%, about 20 mol%, about 25 mol%, about 30 mol%, about 35 mol%, about 40 mol%, about 45 mol%, about 50 mol%, about 55 mol%, about 60 mol%, about 65 mol%, about 70 mol%, about 75 mol%, or about 80 mol% of the total lipids present in the lipid nanoparticles.

[0198] In one embodiment, the amount of the steroid compound is about 50 mol%. In one embodiment, the amount of the steroid compound is 50 mol%. In one embodiment, the amount of the steroid compound is about 25.7 mol%. In one embodiment, the amount of the steroid compound is 25.7 mol%. In one embodiment, the amount of the steroid compound is about 28.5 mol%. In one embodiment, the amount of the steroid compound is 28.5 mol%.

[0199] In one embodiment, the amount of steroid compound is about 20 mol% to about 50 mol% of the total lipids present in the lipid nanoparticles, and the amount of ionized lipids (see Section 5.2.2) is about 20 mol% to about 80 mol% of the total lipids present in the lipid nanoparticles. 5.2.2 Ionized Lipids

[0200] In one embodiment, the lipid nanoparticles further comprise an ionized lipid. In one embodiment, the ionized lipid is different from the steroid compound described in Section 5.2.1. In one embodiment, the lipid nanoparticles comprise an ionized lipid and a steroid compound having a cationic group.

[0201] In one embodiment, the ionized lipid has a pKa of about 4 to about 14. In one embodiment, the ionized lipid has a pKa of about 5 to about 7. In one embodiment, the ionized lipid has a pKa of about 6 to about 7. In one embodiment, the ionized lipid has a pKa greater than 7. In one embodiment, the ionized lipid has a pKa of about 4, about 5, about 6, about 7, about 8, about 9, about 10, or about 11. In one embodiment, the ionized lipid has a pKa of 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, or greater than 11. In one embodiment, the ionized lipid is positively charged at physiological pH (i.e., pH 7.4).

[0202] In one embodiment, the ionized lipid contains one or more groups that are protonated at physiological pH, but are deprotonated and have no charge at pH greater than 8, pH greater than 9, or pH greater than 10. In one embodiment, the ionized lipid contains one or more tertiary amine groups. In one embodiment, the ionized lipid has 1, 2, 3, or 4 C6-C groups. 24 It contains alkyl or alkenyl lipid groups. These lipid groups may be bonded via functional groups (e.g., ester or amide groups) or further introduced via Michael addition to a sulfur atom.

[0203] In one embodiment, the ionized lipid comprises at least one ionizable head group and at least one biodegradable hydrophobic chain, wherein the ionized lipid has a logP of at least about 10.1 and a pKa of about 4 to about 11; and the biodegradable hydrophobic chain is of formula -R 16 -M0-R 17 It has; in the formula, R 16 C4- 14 Alkylene, C4- 14 Alkenylene, or C4- 14 It is alkynylene; R 17 C6- 20 The group is alkyl; M0 is a biodegradable group, and the alkylene, alkenylene, alkylylene, and alkyl groups are optionally substituted. In one embodiment, the ionizable head group is a tertiary amine group. In one embodiment, the tertiary amine group of the ionized lipid includes a -CH2CH2OH moiety.

[0204] In one embodiment, the ionized lipid comprises one tertiary amine group and two biodegradable hydrophobic chains, where each hydrophobic chain independently comprises -R 16 -C(O)OR 17 And R 16 It is bonded to the above tertiary amine group. In one embodiment, one R 17 This is a branched chain of C 6-20 It is alkyl, and the other R 17 is a linear C 6-20 It is alkyl.

[0205] In one embodiment, M0 is an ester group, an amide group, a thioester group, a carbonate group, a carbamate group, a carbamothioester group, a urea group, or an ether group. In one embodiment, M0 is an ester group.

[0206] In one embodiment, the ionized lipid is a compound of formula (III): [ka] or its stereoisomer, mixture of stereoisomers, tautomers, isotopic molecular species, or pharmaceutically acceptable salt, in the formula, Examples R3 and R4 are independently C 1-10 Alkyl, C 2-10 Alkenil, C 2-10 Alkinyl, C3-C 14 Cycloalkyl, 3-14 member heterocyclyl, (C 1-10 Alkylene)-(C3-C 14 Cycloalkyl), or (C 1-10 The alkylene is a 3-14 member heterocycline, or R3 and R4, together with the nitrogen atom to which they are bonded, form a 3-14 member heterocycline, or one of R4 and R0', together with the atom connecting them, forms a 4-10 member heterocycline or a 5-10 member heteroaryl, where the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycline, heteroaryl, and alkylene are independently one or more R * It is optionally replaced by; Each example of R0' is independently an optionally substituted methylene group, or two substituents of R0', together with the methylene group to which they are bonded, form a 3- to 8-membered cycloalkylene, where the cycloalkylene is one or more R ** It is optionally replaced by; k is 0, 1, 2, 3, 4, 5, or 6; j is either 0 or 1; The dashed line connecting Q and W either does not exist or represents a connection; W is C, CH, or N, except when W is N, then j is 0, and there is no dashed connection between Q and W; G5 does not exist, or C 1-24 Alkilen, C 2-24 Alkenylene, C3-C8 cycloalkylene, C3-C8 cycloalkenylene, where the above alkylene, alkenylene, cycloalkylene, and cycloalkenylene are one or more R ** It is optionally replaced by; G1, G2, G3, and G4 are either not present or C1-13 Alkilen, C 2-13 Alkenylene, or C 2-13 Alkynylene, where the above alkylene, alkenylene, and alkynylene are one or more R s It is optionally replaced by; G1 and G2 have the full length of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 carbon atoms; G3 and G4 have the full length of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 carbon atoms; R5, R6, R7, and R8 are each independently replaced with hydrogen or optionally substituted with carbon. 1-8 It is alkyl; If there is no dashed line connecting Q and W, then Q either does not exist, or it is -C(O)O-, -O-, -NH-, -SC(O)O-, -OC(O)NR b -, -NR b C(O)NR b -, -OC(O)S-, -OC(O)O-, -NR b C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR b -, -C(O)NR b -, -NR b C(O)-, -NR b C(O)S-, -SC(O)NR b -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR b -, -NR b C(S)O-, -SS-, or -S(O) 0-2 - and in the equation, the bond to the right is directed towards W; If the dashed line connecting Q and W represents a bond, then G5 does not exist, and Q and W form a 5-10 membered monoring or fused ring, and optionally, the above ring has one or more R ** Replaced by; M1 and M2 are either non-existent, or -C(O)O-, -O-, -SC(O)O-, -OC(O)NR, respectively. a -, -NR a C(O)NR a -, -OC(O)S-, -OC(O)O-, -NR aC(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR a -, -C(O)NR a -, -NR a C(O)-, -NR a C(O)S-, -SC(O)NR a -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR a -, -NR a C(S)O-, -SS-, or -S(O) 0-2 -and; Each example of R0 is independently -(CRR')-; Examples R and R' are independently H, C 1-20 Alkyl, L a -OR a , -L a -SR a , or -L a -NR a R' a Either R and R' are, together with the carbon they are bonded to, C 3-8 Forms cycloalkylenes; Q3 and Q4 are independently H, -(CRR')-, and C, respectively. 6-10 It is an aryl or steroid part; Examples A1, A2, A3, and A4 are independent of each other, -(CR 18 R 18 -CR 18 =CR 18 )- or -(CR 18 R 18 -C≡C)- and; R 18 Each of these examples is independent of H or C 1-20 It is alkyl; Examples N1 and N2 are, independently, biodegradable groups; Z does not exist, or C 1-10 It is an alkylene, or -OP(O)(OH)-O-; The dashed lines between Z-Q3 or Z-Q4 are either independent, nonexistent, or combined; however, if Z is absent, neither dashed line exists. m, n, q, r, u, v, y, and z are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; o, p, w, and x are independently 0, 1, or 2; s and t are independently either 0 or 1; The number of atoms between G1 and Q3, or between G3 and Q4, is between 8 and 30; L a and L e Each of these is independent, either nonexistent or C 1-20 It is alkylene; L b and L f Each of these is independent, either nonexistent or C 1-10 It is alkylene; L c It does not exist, or C 1-8 It is alkylene; L d It does not exist, or C 1-14 It is alkylene; R * is hydroxyl, halogen, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Hydroxyalkyl, -L b -OR b , -L b -SR b , or -L b -NR b R' b and; R ** is hydroxyl, halogen, C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, -L b -OR b , -L b -SR b , or -L b -NR b R' b and; R s C 1-14 Alkyl, -L b -OR b , -Lb -SR b , or -L b -NR b R' b and; R a and R' a These are H and C, respectively, independently. 1-20 Alkyl, C 3-14 The alkyl, cycloalkyl, and heterocyclyl are cycloalkyl, cycloalkyl, and heterocyclyl, respectively, and are hydroxyl, halogen, and C. 1-20 Alkyl, -L e -OR e , -L e -SR e , or -L e -NR e R' e Optionally substituted with one or more elements selected from; R b and R' b These are H and C, respectively, independently. 1-10 Alkyl, C 3-14 The alkyl, cycloalkyl, and heterocyclyl are cycloalkyl, cycloalkyl, and heterocyclyl, respectively, and are hydroxyl, halogen, and C. 1-10 Alkyl, -L f -OR f , -L f -SR f , or -L f -NR f R' f Optionally substituted with one or more elements selected from; R c and R' c Each of them independently consists of hydrogen or C 1-8 It is alkyl; R d and R' d Each of them independently consists of hydrogen or C 1-14 It is alkyl; R e and R' e Each of them independently consists of hydrogen or C 1-20 It is alkyl; R f and R' fEach of them independently consists of hydrogen or C 1-10 It is alkyl.

[0207] In one embodiment, m is 0. In one embodiment, m is 1. In one embodiment, m is 2. In one embodiment, m is 3. In one embodiment, m is 4. In one embodiment, m is 5. In one embodiment, m is 6. In one embodiment, m is 7. In one embodiment, m is 8. In one embodiment, m is 9. In one embodiment, m is 10.

[0208] In one embodiment, n is 0. In one embodiment, n is 1. In one embodiment, n is 2. In one embodiment, n is 3. In one embodiment, n is 4. In one embodiment, n is 5. In one embodiment, n is 6. In one embodiment, n is 7. In one embodiment, n is 8. In one embodiment, n is 9. In one embodiment, n is 10.

[0209] In one embodiment, q is 0. In one embodiment, q is 1. In one embodiment, q is 2. In one embodiment, q is 3. In one embodiment, q is 4. In one embodiment, q is 5. In one embodiment, q is 6. In one embodiment, q is 7. In one embodiment, q is 8. In one embodiment, q is 9. In one embodiment, q is 10.

[0210] In one embodiment, r is 0. In one embodiment, r is 1. In one embodiment, r is 2. In one embodiment, r is 3. In one embodiment, r is 4. In one embodiment, r is 5. In one embodiment, r is 6. In one embodiment, r is 7. In one embodiment, r is 8. In one embodiment, r is 9. In one embodiment, r is 10.

[0211] In one embodiment, u is 0. In one embodiment, u is 1. In one embodiment, u is 2. In one embodiment, u is 3. In one embodiment, u is 4. In one embodiment, u is 5. In one embodiment, u is 6. In one embodiment, u is 7. In one embodiment, u is 8. In one embodiment, u is 9. In one embodiment, u is 10.

[0212] In one embodiment, v is 0. In one embodiment, v is 1. In one embodiment, v is 2. In one embodiment, v is 3. In one embodiment, v is 4. In one embodiment, v is 5. In one embodiment, v is 6. In one embodiment, v is 7. In one embodiment, v is 8. In one embodiment, v is 9. In one embodiment, v is 10.

[0213] In one embodiment, y is 0. In one embodiment, y is 1. In one embodiment, y is 2. In one embodiment, y is 3. In one embodiment, y is 4. In one embodiment, y is 5. In one embodiment, y is 6. In one embodiment, y is 7. In one embodiment, y is 8. In one embodiment, y is 9. In one embodiment, y is 10.

[0214] In one embodiment, z is 0. In one embodiment, z is 1. In one embodiment, z is 2. In one embodiment, z is 3. In one embodiment, z is 4. In one embodiment, z is 5. In one embodiment, z is 6. In one embodiment, z is 7. In one embodiment, z is 8. In one embodiment, z is 9. In one embodiment, z is 10.

[0215] In one embodiment, m+q+u+y is an integer between 3 and 25. In one embodiment, m+q+u+y is an integer between 5 and 20. In one embodiment, m+q+u+y is an integer between 5 and 20. In one embodiment, m+q+u+y is an integer between 5 and 20. In one embodiment, m+q+u+y is an integer between 5 and 18. In one embodiment, m+q+u+y is an integer between 6 and 12. In one embodiment, m+q+u+y is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18.

[0216] In one embodiment, n+r+v+z is an integer between 3 and 25. In one embodiment, n+r+v+z is an integer between 5 and 20. In one embodiment, n+r+v+z is an integer between 5 and 20. In one embodiment, n+r+v+z is an integer between 5 and 20. In one embodiment, n+r+v+z is an integer between 5 and 18. In one embodiment, n+r+v+z is an integer between 6 and 12. In one embodiment, n+r+v+z is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18.

[0217] In one embodiment, o is 0. In one embodiment, o is 1. In one embodiment, o is 2.

[0218] In one embodiment, p is 0. In one embodiment, p is 1. In one embodiment, p is 2.

[0219] In one embodiment, w is 0. In one embodiment, w is 1. In one embodiment, w is 2.

[0220] In one embodiment, x is 0. In one embodiment, x is 1. In one embodiment, x is 2.

[0221] In one embodiment, o+p is 0. In one embodiment, o+p is 1. In one embodiment, o+p is 2. In one embodiment, w+x is 0. In one embodiment, w+x is 1. In one embodiment, w+x is 2. In one embodiment, o+p+w+x is 0. In one embodiment, o+p+w+x is 1. In one embodiment, o+p+w+x is 2. In one embodiment, o+p+w+x is 3. In one embodiment, o+p+w+x is 4.

[0222] In one embodiment, R0 is CH2. In one embodiment, R0 is CH(C 1-16 It is alkyl. In one embodiment, R0 is CH(C 1-14 It is alkyl. In one embodiment, R0 is CH(C 1-12 It is alkyl. In one embodiment, R0 is CH(C 1-6 It is alkyl. In one embodiment, R0 is CHCH3. In one embodiment, R0 is C(CH3)2. In one embodiment, R0 is C(C 1-12 It is alkyl)2. In one embodiment, R0 is CH(L a -OR a ) is. In one embodiment, R0 is CH(L a -SR a ) is. In one embodiment, R0 is CH(L a -NR a R' a ) is. In one embodiment, R0 is CH(OR a ) is. In one embodiment, R0 is CH(SR a ) is. In one embodiment, R0 is CH(NR a R' a ) is. In one embodiment, R0 is CHN(C 1-12 It is alkyl)2. In one embodiment, R0 is CH(CH2) 1-6 NR a R' a In one embodiment, R0 is CH(CH2) 1-6 N(C 1-12It is alkyl(2).

[0223] In one embodiment, Q3 is H. In one embodiment, Q3 is -(CRR')-. In one embodiment, Q3 is -(CH2)-. In one embodiment, Q4 is H. In one embodiment, Q4 is -(CRR')-. In one embodiment, Q4 is -(CH2)-.

[0224] In one embodiment, A1 does not exist. In one embodiment, A1 is -(CR 18 R 18 -CR 18 =CR 18 )-. In one embodiment, A1 is -(CHR 18 -CH=CH)-. In one embodiment, A1 is -(CH2-CH=CH)-. In one embodiment, the C=C bond of A1 is in a Z configuration. In one embodiment, the C=C bond of A1 is in an E configuration. In one embodiment, A1 is -(CR 18 R 18 -C≡C)-. In one embodiment, A1 is -(CHR 18 -C≡C)-. In one embodiment, A1 is -(CH2-C≡C)-.

[0225] In one embodiment, A2 does not exist. In one embodiment, A2 is -(CR 18 R 18 -CR 18 =CR 18 )-. In one embodiment, A2 is -(CHR 18 -CH=CH)-. In one embodiment, A2 is -(CH2-CH=CH)-. In one embodiment, the C=C bond of A2 is in a Z configuration. In one embodiment, the C=C bond of A2 is in an E configuration. In one embodiment, A2 is -(CR 18 R 18 -C≡C)-. In one embodiment, A2 is -(CHR 18 -C≡C)-. In one embodiment, A2 is -(CH2-C≡C)-.

[0226] In one embodiment, A3 does not exist. In one embodiment, A3 is -(CR 18 R 18 -CR 18 =CR 18 )-. In one embodiment, A3 is -(CHR 18 -CH=CH)-. In one embodiment, A3 is -(CH2-CH=CH)-. In one embodiment, the C=C bond of A3 is in a Z configuration. In one embodiment, the C=C bond of A3 is in an E configuration. In one embodiment, A3 is -(CR 18 R 18 -C≡C)-. In one embodiment, A3 is -(CHR 18 -C≡C)-. In one embodiment, A3 is -(CH2-C≡C)-.

[0227] In one embodiment, A4 does not exist. In one embodiment, A4 is -(CR 18 R 18 -CR 18 =CR 18 )-. In one embodiment, A4 is -(CHR 18 -CH=CH)-. In one embodiment, A4 is -(CH2-CH=CH)-. In one embodiment, the C=C bond of A4 is in a Z configuration. In one embodiment, the C=C bond of A4 is in an E configuration. In one embodiment, A4 is -(CR 18 R 18 -C≡C)-. In one embodiment, A4 is -(CHR 18 -C≡C)-. In one embodiment, A4 is -(CH2-C≡C)-.

[0228] In one embodiment, R 18 H is H. In one embodiment, R 18 C 1-20 It is alkyl. In one embodiment, R 18 C 1-16 It is alkyl. In one embodiment, R 18 C 1-12It is alkyl. In one embodiment, R 18 C 1-6 It is alkyl.

[0229] In one embodiment, s is 0. In one embodiment, s is 1. In one embodiment, t is 0. In one embodiment, t is 1.

[0230] In one embodiment, N1 is absent. In one embodiment, N1 is a biodegradable group. In one embodiment, N1 is an ester group. In one embodiment, N1 is an amide group. In one embodiment, N1 is a thioester group. In one embodiment, N1 is a carbonate group. In one embodiment, N1 is a carbamate group. In one embodiment, N1 is a carbamothioester group. In one embodiment, N1 is a urea group. In one embodiment, N1 is an imine group. In one embodiment, N1 is an oxime group. In one embodiment, N1 is a disulfide group.

[0231] In one embodiment, N2 is absent. In one embodiment, N2 is a biodegradable group. In one embodiment, N2 is an ester group. In one embodiment, N2 is an amide group. In one embodiment, N2 is a thioester group. In one embodiment, N2 is a carbonate group. In one embodiment, N2 is a carbamate group. In one embodiment, N2 is a carbamothioester group. In one embodiment, N2 is a urea group. In one embodiment, N2 is an imine group. In one embodiment, N2 is an oxime group. In one embodiment, N2 is a disulfide group.

[0232] In one embodiment, Z does not exist. In one embodiment, Z does not exist, and neither the dashed line between Q4 and Z nor the dashed line between Q3 and Z exists. In one embodiment, Z does not exist, and both Q4 and Q3 are H.

[0233] In one embodiment, Z is C 1-10 It is an alkylene. In one embodiment, Z is C 1-6 It is an alkylene. In one embodiment, Z is C 1-3 It is an alkylene. In one embodiment, Z is -OP(O)(OH)-O-.

[0234] In one embodiment, Z is absent, and the number of carbon atoms between G1 and Q3 is 8 to 30. In one embodiment, Z is absent, and the number of carbon atoms between G1 and Q3 is 10 to 25. In one embodiment, Z is absent, and the number of carbon atoms between G1 and Q3 is 10 to 20.

[0235] In one embodiment, Z is absent, and the number of carbon atoms between G3 and Q4 is 8 to 30. In one embodiment, Z is absent, and the number of carbon atoms between G3 and Q4 is 10 to 25. In one embodiment, Z is absent, and the number of carbon atoms between G3 and Q4 is 10 to 20.

[0236] In one embodiment, the ionized lipid is a compound of formula (IV'): [ka] or its stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt, in the formula, j is either 0 or 1; W is either CH or N, except when W is N, then j is 0; k is 0, 1, 2, 3, 4, 5, 6, 7, or 8; Each example of R0' is independently an optionally substituted methylene group, or two substituents of R0', together with the methylene group to which they are bonded, form a 3- to 8-membered cycloalkylene, where the cycloalkylene is one or more R ** It is optionally replaced by; M1 and M2 are independently -C(O)O-, -O-, -SC(O)O-, and -OC(O)NR, respectively. a -, -NR a C(O)NRa -, -OC(O)S-, -OC(O)O-, -NR a C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR a -, -C(O)NR a -, -NR a C(O)-, -NR a C(O)S-, -SC(O)NR a -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR a -, -NR a C(S)O-, -SS-, or -S(O) 0-2 -and; Q does not exist, or -C(O)O-, -O-, -SC(O)O-, -OC(O)NR b -, -NR b C(O)NR b -, -OC(O)S-, -OC(O)O-, -NR b C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR b -, -C(O)NR b -, -NR b C(O)-, -NR b C(O)S-, -SC(O)NR b -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR b -, -NR b C(S)O-, -SS-, or -S(O) 0-2 -and; R a and R b These are H and C, respectively, independently. 1-20 Alkyl, C 3-14 The alkyl, cycloalkyl, and heterocyclyl are cycloalkyl, cycloalkyl, and heterocyclyl, respectively, and are hydroxyl, halogen, and C. 1-20 Alkyl, -L e -OR e , -L e -SR e , or -L e -NR e R' e Optionally substituted with one or more elements selected from; G5 is either non-existent or optionally replaced by C. 1-8 It is alkylene; R1 and R2 are independent of each other, C 4-20 Alkyl, C 4-20 Alkenyl, or C 4-20 It is an alkynyl, and one or more methylene units in R1 and R2 are independently -NH- or -N(C 1-20 The alkyl, alkenyl, and alkynyl are optionally substituted; Examples R3 and R4 are independently H, C 1-10 Alkyl, C 2-10 Alkenil, C 2-10 Alkinyl, C3-C 14 It is a cycloalkyl or a 3- to 14-membered heterocycline, or R3 and R4, together with the N atom to which they are bonded, form a 3- to 14-membered heterocycline, or one of R4 and R0', together with the atom connecting them, forms a 4- to 10-membered heterocycline, where the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycline is one or more R * It is optionally replaced by; R5, R6, R7, and R8 are each independently replaced with hydrogen or optionally substituted with carbon. 1-8 It is alkyl.

[0237] In one embodiment, the ionized lipid is a compound of formula (IV'-A): [ka] or its stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts.

[0238] In one embodiment, the ionized lipid is a compound of formula (VIII): [ka] or its stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts.

[0239] In one embodiment, the ionized lipid is a compound of formula (V'), (VI'), or (VII'): [ka] or its stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt, in the formula, k is 0, 1, 2, 3, 4, or 5; L1 and L2 are independently -(CRR')2-, -CH=CH-, -C≡C-, or -NR''-; One of L3 and L5 is -(CR s R s ')2-, -CH=CH-, or -C≡C-, and the other does not exist; One of L4 and L6 is -(CR s R s ')2-, -CH=CH-, or -C≡C-, and the other does not exist; G 1a , G 1b , G 2a , G 2b , G 3a , G 3b , G 4a , and G 4b Each of these is either non-existent or optionally replaced by C. 1-7 It is alkylene; G 1a , G 1b , G 2a , and G 2b It has a total length of 1, 2, 3, 4, 5, 6, or 7 carbon atoms; G 3a , G 3b , G 4a , and G 4b It has a total length of 1, 2, 3, 4, 5, 6, or 7 carbon atoms; R5, R6, R7, and R8 are each independently replaced with hydrogen or optionally substituted with carbon. 1-6 It is alkyl; G7, G8, G9, and G 10 Each of these is either non-existent or optionally replaced by C. 1-12They are alkylenes, however G7 and G8 have the full length of 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms, and G9 and G 10 It has the full length of 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms; R s and R s ' are H and C, respectively, independently. 1-10 Alkyl, -L d -OR d , or -L d -NR d R' d and; R' is H, C 1-14 Alkyl, -L a -OR a , or -L a -NR a R' a and; R'' is H or C 1-14 It is alkyl; L d It does not exist, or C 1-10 It is alkylene; L a It does not exist, or C 1-14 It is alkylene; R a and R' a These are H and C, respectively, independently. 1-14 Alkyl, C 3-10 The alkyl, cycloalkyl, or heterocyclyl is optionally substituted; R d and R' d These are, independently, H or C 1-10 It is alkyl; a' and b are independently 0, 1, 3, 4, and 5, respectively, except that at least one of a' and b is not 0; g is 0, 1, 2, 3, 4, or 5; a'+g is 0, 1, 2, 3, 4, or 5; c, d, e, and f are independently 0, 1, 2, 3, 4, 5, 6, or 7, where c+d is an integer between 2 and 9, and e+f is an integer between 2 and 9.

[0240] In one embodiment, R1 is C 4-20 It is alkyl. In one embodiment, R1 is C 6-18 It is alkyl. In one embodiment, R1 is C 8-18 It is alkyl. In one embodiment, R1 is C8, C9, C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , or C 20 It is alkyl. In one embodiment, R1 is C 4-20 It is an alkenyl. In one embodiment, R1 is C 6-18 It is an alkenyl. In one embodiment, R1 is C 8-18 It is an alkenyl. In one embodiment, R1 is C8, C9, C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , or C 20 It is an alkenyl. In one embodiment, R1 is C 4-20 It is an alkynyl. In one embodiment, R1 is C 6-18 It is an alkynyl. In one embodiment, R1 is C 8-18 It is an alkynyl. In one embodiment, R1 is C8, C9, C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19, or C 20 It is alkinyl.

[0241] In one embodiment, one or more -CH2- groups in R1 are replaced with -NH-. In one embodiment, one or more -CH2- groups in R1 are replaced with -N(C 1-20 It is replaced by alkyl)-. In one embodiment, one or more -CH2- groups in R1 are -N(C 1-12 It can be replaced with alkyl(-).

[0242] In one embodiment, R1 is not substituted. In one embodiment, R1 is -L a -OR a It is replaced by -L a -SR a It is replaced by. In one embodiment, R1 is -L a -NR a R' a It will be replaced by this.

[0243] In one embodiment, R2 is C 4-20 It is alkyl. In one embodiment, R2 is C 6-18 It is alkyl. In one embodiment, R2 is C 8-18 It is alkyl. In one embodiment, R2 is C8, C9, C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , or C 20 It is alkyl. In one embodiment, R2 is C 4-20 It is an alkenyl. In one embodiment, R2 is C 6-18 It is an alkenyl. In one embodiment, R2 is C 8-18 It is an alkenyl. In one embodiment, R2 is C8, C9, C 10 , C 11 , C 12 , C 13 , C 14, C 15 , C 16 , C 17 , C 18 , C 19 , or C 20 It is an alkenyl. In one embodiment, R2 is C 4-20 It is an alkynyl. In one embodiment, R2 is C 6-18 It is an alkynyl. In one embodiment, R2 is C 8-18 It is an alkynyl. In one embodiment, R2 is C8, C9, C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , or C 20 It is alkinyl.

[0244] In one embodiment, one or more -CH2- groups in R2 are replaced with -NH-. In one embodiment, one or more -CH2- groups in R2 are replaced with -N(C 1-20 It is replaced by alkyl)-. In one embodiment, one or more -CH2- groups in R2 are -N(C 1-12 It can be replaced with alkyl(-).

[0245] In one embodiment, R2 is not replaced. In one embodiment, R2 is -L a -OR a It is replaced by -L a -SR a It is replaced by. In one embodiment, R2 is -L a -NR a R' a It will be replaced by this.

[0246] In one embodiment, L a It does not exist. In one embodiment, L a C 1-14 It is alkylene. a C 1-6It is alkylene. a L is methylene. In one embodiment, L a It is ethylene.

[0247] In one embodiment, R a C 1-14 It is alkyl. In one embodiment, R a C 3-10 It is cycloalkyl. In one embodiment, R a R is a 3-10 member heterocycline. In one embodiment, R a C 1-10 It is alkyl; in one embodiment, R a C 8-10 It is alkyl; in one embodiment, R a C 8-10 It is a linear alkyl group; in one embodiment, R a is -(CH2)8CH3; in one embodiment, R a The substituents are: H, C 1-20 Alkyl, -L e -OR e , -L e -SR e , and -L e -NR e R' e It is optionally replaced by one or more of the following.

[0248] In one embodiment, R' a C 1-14 It is alkyl. In one embodiment, R' a C 3-10 It is cycloalkyl. In one embodiment, R' a It has 3 to 10 members. In one embodiment, R' a C 8-10 It is alkyl; in one embodiment, R' a C 8-10 It is a linear alkyl group; in one embodiment, R' a is -(CH2)8CH3; in one embodiment, R' a The substituents are: H, C 1-20 Alkyl, -Le -OR e , -L e -SR e , and -L e -NR e R' e It is optionally replaced by one or more of the following.

[0249] In one embodiment, R a and R' a These, together with the nitrogen atoms to which they are bonded, form a 4-10 membered ring. In one embodiment, R a and R' a These, together with the nitrogen atoms to which they are bonded, form a 4-8 membered ring. In one embodiment, R a and R' a These, together with the nitrogen atoms to which they are bonded, form a 4-6 membered ring. In one embodiment, R a and R' a These, together with the nitrogen to which they are bound, form a 4-6 membered cycloalkyl group. In one embodiment, R a and R' a These, along with the nitrogen atoms to which they are bound, form 4-6 membered heterocyclines.

[0250] In one embodiment, R3 is H. In one embodiment, R3 is C. 1-10 It is alkyl. In one embodiment, R3 is C 1-10 It is a haloalkyl. In one embodiment, R3 is C 2-10 It is an alkenyl. In one embodiment, R3 is C 2-10 It is an alkynyl. In one embodiment, R3 is a 3-14 member cycloalkyl. In one embodiment, R3 is a 3-14 member heterocyclyl. In one embodiment, R3 is C6- 10 It is an aryl compound. In one embodiment, R3 is a 5- to 14-membered heteroaryl compound. In one embodiment, R3 is C 1-6 It is alkyl. In one embodiment, R3 is C 1-6It is a haloalkyl. In one embodiment, R3 is a 3- to 10-membered cycloalkyl. In one embodiment, R3 is a 3- to 10-membered heterocycline. In one embodiment, R3 is a 3- to 7-membered cycloalkyl. In one embodiment, R3 is a 3- to 7-membered heterocycline.

[0251] In one embodiment, R3 is not substituted. In one embodiment, R3 is one or more R * It is replaced by, here, each R * These are, independently, halogen, cyano, and C 1-10 Alkyl, C 1-10 Haloalkyl, -L b -OR b , -L b -SR b , or -L b -NR b R' b In one embodiment, R3 is 1, 2, 3, 4, or 5 R * It is optionally replaced, where each R * These are, independently, halogen, cyano, and C 1-10 Alkyl, C 1-10 Haloalkyl, -L b -OR b , -L b -SR b , or -L b -NR b R' b In one embodiment, R3 is Me. In one embodiment, R3 is -CH2CH3. In one embodiment, R3 is -CH(CH3)2.

[0252] In one embodiment, R3 is a C that is optionally substituted with OH. 1-6 It is alkyl. In one embodiment, R3 is -CH2CH2OH.

[0253] In one embodiment, R4 is H. In one embodiment, R4 is C. 1-10 It is alkyl. In one embodiment, R4 is C 1-10 It is a haloalkyl. In one embodiment, R4 is C2-10 It is an alkenyl. In one embodiment, R4 is C 2-10 It is an alkynyl. In one embodiment, R4 is a 3-14 member cycloalkyl. In one embodiment, R4 is a 3-14 member heterocyclyl. In one embodiment, R4 is C6- 10 It is an aryl compound. In one embodiment, R4 is a 5- to 14-membered heteroaryl compound. In one embodiment, R4 is C 1-6 It is alkyl. In one embodiment, R4 is C 1-6 It is a haloalkyl. In one embodiment, R4 is a 3- to 10-membered cycloalkyl. In one embodiment, R4 is a 3- to 10-membered heterocyclyl. In one embodiment, R4 is a 3- to 7-membered cycloalkyl. In one embodiment, R4 is a 3- to 7-membered heterocyclyl. In one embodiment, R4 is Me. In one embodiment, R3 is unsubstituted. In one embodiment, R3 is one or more R * It is replaced by one of five R3s. In one embodiment, R3 is one of five R3s. * It is optionally replaced.

[0254] In one embodiment, R3 and R'4, together with the N atom to which they are bound, form a 3- to 14-membered heterocycline. In one embodiment, R3 and R4, together with the N atom to which they are bound, form a 3- to 10-membered heterocycline; in one embodiment, R3 and R4, together with the N atom to which they are bound, form a 3- to 7-membered heterocycline; in one embodiment, R3 and R4, together with the N atom to which they are bound, form a 5- to 7-membered heterocycline; in one embodiment, R3 and R4, together with the N atom to which they are bound, form a 4- to 6-membered heterocycline; in one embodiment, R3 and R4, together with the N atom to which they are bound, form a 5-membered heterocycline; in one embodiment, R3 and R4, together with the N atom to which they are bound, [ka] Forming; in one embodiment, R3 and R4, together with the N atom to which they are bonded, [ka] Forming; in one embodiment, R3 and R4, together with the N atom to which they are bonded, [ka] Forming; in one embodiment, R3 and R4, together with the N atom to which they are bonded, [ka] In one embodiment, the heterocycline formed with R3 and R4 together with the N atoms to which they are bonded is one or more R * R3 and R4 are optionally substituted; in one embodiment, the heterocycline formed with R3 and R4 together with the N atom to which they are bonded is 1, 2, 3, 4, or 5 R * It is optionally replaced.

[0255] In one embodiment, R4, together with the nitrogen atom to which it is bound and one of the R0's, forms a 3- to 14-membered heterocycline. In one embodiment, R4, together with the nitrogen atom to which it is bound and one of the R0's, forms a 4- to 10-membered heterocycline. In one embodiment, R4, together with the nitrogen atom to which it is bound and one of the R0's, forms a 4- to 6-membered heterocycline. In one embodiment, R4, together with the nitrogen atom to which it is bound and one of the R0's, forms a 5- to 14-membered heteroaryl. In one embodiment, R4, together with the nitrogen atom to which it is bound and one of the R0's, forms a 5- to 10-membered heteroaryl. In one embodiment, R4, together with the nitrogen atom to which it is bound and one of the R0's, forms a 5 or 6-membered heteroaryl.

[0256] In one embodiment, R5 is H; in one embodiment, R5 is C 1-8 It is alkyl; in one embodiment, R5 is C 1-6It is alkyl; in one embodiment, R5 is C 1-3 It is alkyl; in one embodiment, R5 is Me; in one embodiment, R5 is one or more R * It is optionally replaced by; in one embodiment, R5 is 1, 2, 3, 4, or 5 R * It is optionally replaced by; in one embodiment, R5 is one or more R 4s It is optionally replaced by . In one embodiment, R5 is 1, 2, 3, 4, or 5 R 4s It is optionally replaced.

[0257] In one embodiment, R6 is H; in one embodiment, R6 is C 1-8 It is alkyl; in one embodiment, R6 is C 1-6 It is alkyl; in one embodiment, R6 is C 1-3 It is alkyl; in one embodiment, R6 is Me; in one embodiment, R6 is one or more R * It is optionally replaced by; in one embodiment, R6 is 1, 2, 3, 4, or 5 R * It is optionally replaced by one or more R. In one embodiment, R6 is one or more R 4s It is optionally replaced by 1, 2, 3, 4, or 5 R 4s It is optionally replaced.

[0258] In one embodiment, R5 and R6, along with the carbon atoms to which they are bonded, are C 3-14 It forms a cycloalkylene or a 3-14 membered heterocyclene, where the cycloalkylene and heterocyclene are one or more R 4s They are optionally substituted by. In one embodiment, R5 and R6, along with the carbon atoms to which they are bonded, are C 3-8 It forms a cycloalkylene. In one embodiment, R5 and R6, together with the carbon atom to which they are bonded, C 3-6They form cycloalkylenes. In one embodiment, R5 and R6, together with the carbon atoms to which they are bonded, form a C3 cycloalkylene, a C4 cycloalkylene, a C5 cycloalkylene, or a C6 cycloalkylene. In one embodiment, R5 and R6, together with the carbon atoms to which they are bonded, form a 3- to 8-membered heterocyclene. In one embodiment, R5 and R6, together with the carbon atoms to which they are bonded, form a 3- to 6-membered heterocyclene. In one embodiment, R5 and R6, together with the carbon atoms to which they are bonded, form a 3-membered heterocyclene, a 4-membered heterocyclene, a 5-membered heterocyclene, or a 6-membered heterocyclene. In one embodiment, the heterocyclene has one or more oxygen, sulfur, or nitrogen atoms on the ring. In one embodiment, the heterocyclene or cycloalkylene formed by R5 and R6 is unsubstituted. In one embodiment, the heterocyclene or cycloalkylene formed by R5 and R6 has 1, 2, 3, 4, or 5 R * It is replaced by R5 and R6. In one embodiment, the heterocyclylene or cycloalkylene formed by R5 and R6 is 1, 2, 3, 4, or 5 R 4s It will be replaced by this.

[0259] In one embodiment, R7 is H; in one embodiment, R7 is C 1-8 It is alkyl; in one embodiment, R7 is C 1-6 It is alkyl; in one embodiment, R7 is C 1-3 It is alkyl; in one embodiment, R7 is Me; in one embodiment, R7 is one or more R * It is optionally replaced by; in one embodiment, R7 is 1, 2, 3, 4, or 5 R * It is optionally replaced.

[0260] In one embodiment, R5, R6, R7, and R8 are each independently hydrogen or methyl. In one embodiment, R5 and R6 are each independently C 1-6In one embodiment, R5 and R6 are both methyl, and R7 and R8 are both hydrogen. In another embodiment, R5, R6, R7, and R8 are all hydrogen.

[0261] In one embodiment, R8 is H; in one embodiment, R8 is C 1-8 It is alkyl; in one embodiment, R8 is C 1-6 It is alkyl; in one embodiment, R8 is C 1-3 It is alkyl; in one embodiment, R8 is Me; in one embodiment, R8 is one or more R * It is optionally replaced by; in one embodiment, R8 is 1, 2, 3, 4, or 5 R * It is optionally replaced.

[0262] In one embodiment, R7 and R8, along with the carbon atoms to which they are bonded, are C 3-14 It forms a cycloalkylene or a 3-14 membered heterocyclene, where the cycloalkylene and heterocyclene are one or more R 4s They are optionally substituted by. In one embodiment, R7 and R8, along with the carbon atoms to which they are bonded, are C 3-8 It forms a cycloalkylene. In one embodiment, R7 and R8, together with the carbon atom to which they are bonded, C 3-6They form cycloalkylenes. In one embodiment, R7 and R8, together with the carbon atoms to which they are bonded, form C3 cycloalkylene, C4 cycloalkylene, C5 cycloalkylene, or C6 cycloalkylene. In one embodiment, R7 and R8, together with the carbon atoms to which they are bonded, form 3- to 8-membered heterocyclenes. In one embodiment, R7 and R8, together with the carbon atoms to which they are bonded, form 3- to 6-membered heterocyclenes. In one embodiment, R7 and R8, together with the carbon atoms to which they are bonded, form 3-membered heterocyclenes, 4-membered heterocyclenes, 5-membered heterocyclenes, or 6-membered heterocyclenes. In one embodiment, the heterocyclene has one or more oxygen, sulfur, or nitrogen atoms on the ring. In one embodiment, the heterocyclene or cycloalkylene formed by R7 and R8 is unsubstituted. In one embodiment, the heterocyclene or cycloalkylene formed by R7 and R8 has 1, 2, 3, 4, or 5 R * It is replaced by R7 and R8. In one embodiment, the heterocyclylene or cycloalkylene formed by R7 and R8 is 1, 2, 3, 4, or 5 R 4s It will be replaced by this.

[0263] In one embodiment, R * These are halogen, cyano, and C 1-6 Alkyl, C 1-6 Haloalkyl, -L b -OR b , or -L b -NR b R' b And; in one embodiment, R * C 1-6 Alkyl, C 1-6 Haloalkyl or -OR b And; in one embodiment, R * These are H, halogen, and C, independently. 1-6 Alkyl, or C 1-6 It is a haloalkyl; in one embodiment, R * C 1-6 Alkyl or C 1-6It is a haloalkyl; in one embodiment, R * is Me. In one embodiment, R * is OH. In one embodiment, R * is a halogen; in one embodiment, R * is cyano; in one embodiment, R * C 1-10 It is alkyl; in one embodiment, R * C 1-10 It is a haloalkyl; in one embodiment, R * is, -L b -OR b And; in one embodiment, R * is, -L b -SR b And; in one embodiment, R * is, -L b -NR b R' b And; in one embodiment, R * C 1-6 It is alkyl; in one embodiment, R * C 1-6 It is a haloalkyl; in one embodiment, R * is -OR b That is the case.

[0264] In one embodiment, L b It does not exist. In one embodiment, L b C 1-10 It is alkylene. b C 1-6 It is alkylene. b C 1-3 It is alkylene. b L is methylene. In one embodiment, L b It is ethylene.

[0265] In one embodiment, L f It does not exist. In one embodiment, L f C 1-10 It is alkylene.f C 1-6 It is alkylene. f C 1-3 It is alkylene. f L is methylene. In one embodiment, L f It is ethylene.

[0266] In one embodiment, L c It does not exist. In one embodiment, L c C 1-8 It is alkylene. c C 1-6 It is alkylene. c C 1-3 It is alkylene. c L is methylene. In one embodiment, L c It is ethylene.

[0267] In one embodiment, R b C 1-10 It is alkyl. In one embodiment, R b C 1-6 It is alkyl. In one embodiment, R b C 1-3 It is alkyl. In one embodiment, R b C 3-14 It is cycloalkyl. In one embodiment, R b C 3-8 It is cycloalkyl. In one embodiment, R b C 3-6 It is cycloalkyl. In one embodiment, R b R is a 3-14 member heterocycline. In one embodiment, R b R is a 3-8 member heterocycline. In one embodiment, R b R is a 3-6 member heterocycline. In one embodiment, R b It is a 3-6 membered nitrogen-containing heterocycline. In one embodiment, R b is not substituted. In one embodiment, R bC 1-10 Alkyl, -L f -OR f , -L f -SR f , or -L f -NR f R' f Substituted by one or more of the following, in the formula, R f and R' f These are, independently, H or C 1-10 It is alkyl.

[0268] In one embodiment, R' b C 1-10 It is alkyl. In one embodiment, R' b C 1-6 It is alkyl. In one embodiment, R' b C 1-3 It is alkyl. In one embodiment, R' b , C 3-14 It is cycloalkyl. In one embodiment, R' b C 3-8 It is cycloalkyl. In one embodiment, R' b , C 3-6 It is cycloalkyl. In one embodiment, R' b R' is a 3-14 member heterocycline. In one embodiment, R' b R' is a 3- to 8-membered heterocycline. In one embodiment, R' b R' is a 3-6 member heterocycline. In one embodiment, R' b It is a 3-6 membered nitrogen-containing heterocycline. In one embodiment, R' b is not substituted. In one embodiment, R' b C 1-10 Alkyl, -L f -OR f , -L f -SR f , or -L f -NR f R' f Substituted by one or more of the following, in the formula, R f and R' f These are, independently, H or C 1-10 It is alkyl.

[0269] In one embodiment, j is 0. In another embodiment, j is 1.

[0270] In one embodiment, W is CH. In another embodiment, W is N.

[0271] In one embodiment, k is 0. In one embodiment, k is 1. In one embodiment, k is 2. In one embodiment, k is 3. In one embodiment, k is 4. In one embodiment, k is 5. In one embodiment, k is 6. In one embodiment, k is 7. In one embodiment, k is 8.

[0272] In one embodiment, the two substituents of R'0, together with the methylene group to which they are bonded, form a 3- to 8-membered cycloalkyl group. In one embodiment, the two substituents of R'0, together with the methylene group to which they are bonded, form a 3- to 6-membered cycloalkyl group. In one embodiment, the two substituents of R'0, together with the methylene group to which they are bonded, form a 5 or 6-membered cycloalkyl group.

[0273] In one embodiment, M1 is -C(O)O-; in one embodiment, M1 is -O-; in one embodiment, M1 is -SC(O)O-; in one embodiment, M1 is -OC(O)NR a -and; in one embodiment, M1 is -NR a C(O)NR a -and; in one embodiment, M1 is -OC(O)S-; in one embodiment, M1 is -OC(O)O-; in one embodiment, M1 is -NR a C(O)O-; in one embodiment, M1 is -OC(O)-; in one embodiment, M1 is -SC(O)-; in one embodiment, M1 is -C(O)S-; in one embodiment, M1 is -NR a -and; in one embodiment, M1 is -C(O)NR a-and; in one embodiment, M1 is -NR a C(O)-; in one embodiment, M1 is -NR a C(O)S-; in one embodiment, M1 is -SC(O)NR a -and; in one embodiment, M1 is -C(O)-; in one embodiment, M1 is -OC(S)-; in one embodiment, M1 is -C(S)O-; in one embodiment, M1 is -OC(S)NR a -and; in one embodiment, M1 is -NR a It is C(S)O-; in one embodiment, M1 is -SS-; in one embodiment, M1 is -S(O) 0-2 - is

[0274] In one embodiment, M2 is -C(O)O-; in one embodiment, M2 is -O-; in one embodiment, M2 is -SC(O)O-; in one embodiment, M2 is -OC(O)NR a -and; in one embodiment, M2 is -NR a C(O)NR a -and; in one embodiment, M2 is -OC(O)S-; in one embodiment, M2 is -OC(O)O-; in one embodiment, M2 is -NR a C(O)O-; in one embodiment, M2 is -OC(O)-; in one embodiment, M2 is -SC(O)-; in one embodiment, M2 is -C(O)S-; in one embodiment, M2 is -NR a -and; in one embodiment, M2 is -C(O)NR a -and; in one embodiment, M2 is -NR a C(O)-; in one embodiment, M2 is -NR a C(O)S-; in one embodiment, M2 is -SC(O)NR a -and; in one embodiment, M2 is -C(O)-; in one embodiment, M2 is -OC(S)-; in one embodiment, M2 is -C(S)O-; in one embodiment, M2 is -OC(S)NRa -and; in one embodiment, M2 is -NR a It is C(S)O-; in one embodiment, M2 is -SS-; in one embodiment, M2 is -S(O) 0-2 - is

[0275] In one embodiment, M1 and M2 are independently -C(O)O-, -SC(O)O-, and -OC(O)NR a -, -NR a C(O)NR a -, -OC(O)S-, -OC(O)O-, -NR a C(O)O-, -C(O)S-, -C(O)NR a -, -NR a C(O)S-, -SC(O)NR a -, -C(S)O-, -OC(S)NR a -, and -NR a Selected from C(S)O-; in one embodiment, M1 and M2 are independently -C(O)O-, -C(O)S-, and -C(O)NR a -, or -C(S)O-; in one embodiment, M1 and M2 are independently -C(O)O-, -C(O)S-, or -C(O)NR a -In one embodiment, both M1 and M2 are -C(O)O-.

[0276] In one embodiment, Q is absent; in another embodiment, Q is -C(O)O-; in another embodiment, Q is -O-; in another embodiment, Q is -SC(O)O-; in another embodiment, Q is -OC(O)NR b -and; in other embodiments, Q is -NR b C(O)NR b -and; in other embodiments, Q is -OC(O)S-; in other embodiments, Q is -OC(O)O-; in other embodiments, Q is -NR bIn other embodiments, Q is C(O)O-; in other embodiments, Q is -OC(O)-; in other embodiments, Q is -SC(O)-; in other embodiments, Q is -C(O)S-; in other embodiments, Q is -NR b -and; in other embodiments, Q is -C(O)NR b -and; in other embodiments, Q is -NR b C(O)-; in other embodiments, Q is -NR b C(O)S-; in other embodiments, Q is -SC(O)NR b -and; in other embodiments, Q is -C(O)-; in other embodiments, Q is -OC(S)-; in other embodiments, Q is -C(S)O-; in other embodiments, Q is -OC(S)NR b -and; in other embodiments, Q is -NR b In other embodiments, Q is C(S)O-; in other embodiments, Q is -SS-; in other embodiments, Q is -S(O) 0-2 - is; in other embodiments, Q is phenylene; in other embodiments, Q is pyridylidene; in other embodiments, the phenylene or pyridylidene is one or more R * It is optionally replaced.

[0277] In one embodiment, Q is non-existent, -C(O)O-, -O-, -SC(O)O-, -OC(O)NR b -, -NR b C(O)NR b -, -OC(O)S-, -OC(O)O-, -NR b C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR b -, -C(O)NR b -, -NR b C(O)-, -NR b C(O)S-, -SC(O)NR b -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR b -, -NR b C(S)O-, -SS-, and -S(O)0-2 - is selected from; in one embodiment, Q is -C(O)O-, -O-, -SC(O)O-, -OC(O)NH-, -NHC(O)NH-, -OC(O)S-, -OC(O)O-, -NHC(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NH-, -C(O)NH-, -NHC(O)-, -NHC(O)S-, -SC(O)NH-, -C(O Q is selected from -OC(S)-, -C(S)O-, -OC(S)NH-, and -NHC(S)O-; in one embodiment, Q is selected from -C(O)O-, -O-, -SC(O)O-, -OC(O)NH-, -NHC(O)NH-, -OC(O)S-, -OC(O)O-, and -NHC(O)O-; in one embodiment, Q is -C(O)O-.

[0278] In one embodiment, R a H is; in other embodiments, R a C 1-20 It is alkyl; in other embodiments, R a is a 3-14 member cycloalkyl group; in other embodiments, R a R is a 3-14 member heterocycline; in other embodiments, R a C 1-14 It is alkyl; in other embodiments, R a C 1-10 It is alkyl; in other embodiments, R a C 8-10 It is alkyl; in other embodiments, R a C 8-10 It is a linear alkyl group; in other embodiments, R a is -(CH2)8CH3; in other embodiments, R a The substituents are: H, C 1-20 Alkyl, -L e -OR e , -L e -SR e , and -L e -NR e R' e It is optionally substituted with one or more of the following, in the formula, L e It does not exist, or C1-20 It is alkylene, R e and R' e H or C 1-20 It is alkyl.

[0279] In one embodiment, R' a H is; in other embodiments, R' a C 1-20 It is alkyl; in other embodiments, R' a is a 3- to 14-membered cycloalkyl group; in other embodiments, R' a R' is a 3-14 member heterocycline; in other embodiments, R' a C 1-14 It is alkyl; in other embodiments, R' a C 1-10 It is alkyl; in other embodiments, R' a C 8-10 It is alkyl; in other embodiments, R' a C 8-10 It is a linear alkyl group; in other embodiments, R' a is -(CH2)8CH3; in other embodiments, R' a The substituents are: H, C 1-20 Alkyl, -L e -OR e , -L e -SR e , and -L e -NR e R' e It is optionally substituted with one or more of the following, in the formula, L e It does not exist, or C 1-20 It is alkylene, R e and R' e H or C 1-20 It is alkyl.

[0280] In one embodiment, Le does not exist. In one embodiment, Le is C 1-20 It is an alkylene. In one embodiment, Le is C 1-16 It is an alkylene. In one embodiment, Le is C 1-12It is an alkylene. In one embodiment, Le is C 1-6 It is an alkylene. In one embodiment, Le is methylene. In one embodiment, Le is ethylene.

[0281] In one embodiment, R e is hydrogen. In one embodiment, R e C 1-20 It is alkyl. In one embodiment, R e C 1-16 It is alkyl. In one embodiment, R e C 1-12 It is alkyl. In one embodiment, R e C 1-6 It is alkyl. In one embodiment, R' e is hydrogen. In one embodiment, R' e C 1-20 It is alkyl. In one embodiment, R' e C 1-16 It is alkyl. In one embodiment, R' e C 1-12 It is alkyl. In one embodiment, R' e C 1-6 It is alkyl.

[0282] In one embodiment, R f is hydrogen. In one embodiment, R f C 1-10 It is alkyl. In one embodiment, R f C 1-6 It is alkyl. In one embodiment, R f C 1-3 It is alkyl. In one embodiment, R' f is hydrogen. In one embodiment, R' f C 1-10 It is alkyl. In one embodiment, R' f C 1-6 It is alkyl. In one embodiment, R' f C 1-3 It is alkyl.

[0283] In one embodiment, G1 is absent; in another embodiment, G1 is C 1-13 It is an alkylene; in other embodiments, G1 is C 2-13 It is an alkenylene; in other embodiments, G1 is C 2-6 It is an alkenylene; in other embodiments, G1 is C 2-13 It is an alkynylene; in other embodiments, G1 is C 2-6 It is an alkynylene; in other embodiments, G1 is one or more R s It is optionally replaced by R s H and C are independent of each other. 1-14 Alkyl, -L d -OR d , -L d -SR d , or -L d -NR d R' d And L d It does not exist, or C 1-14 It is alkylene; R d and R' d H or C 1-14 It is alkyl.

[0284] In one embodiment, G2 is absent; in another embodiment, G2 is C 2-13 It is an alkylene; in other embodiments, G2 is C 2-6 It is an alkenylene; in other embodiments, G2 is C 2-13 It is an alkenylene; in other embodiments, G2 is C 2-6 It is an alkynylene; in other embodiments, G2 is C 2-13 It is an alkynylene; in other embodiments, G2 is one or more R s It is optionally replaced by R s H and C are independent of each other. 1-14 Alkyl, -L d -OR d , -L d -SR d , or -L d -NR d R' dAnd L d It does not exist, or C 1-14 It is alkylene; R d and R' d H or C 1-14 It is alkyl.

[0285] In one embodiment, G1 and G2 have a total length of 3 carbon atoms; in another embodiment, G1 and G2 have a total length of 4 carbon atoms; in another embodiment, G1 and G2 have a total length of 5 carbon atoms; in another embodiment, G1 and G2 have a total length of 6 carbon atoms; in another embodiment, G1 and G2 have a total length of 7 carbon atoms; in another embodiment, G1 and G2 have a total length of 8 carbon atoms; in another embodiment, G1 and G2 have a total length of 9 carbon atoms; in another embodiment, G1 and G2 have a total length of 10 carbon atoms; in another embodiment, G1 and G2 have a total length of 11 carbon atoms; in another embodiment, G1 and G2 have a total length of 12 carbon atoms; in another embodiment, G1 and G2 have a total length of 13 carbon atoms.

[0286] In one embodiment, G3 is absent; in another embodiment, G3 is C 1-13 It is an alkylene; in other embodiments, G3 is C 2-13 It is an alkenylene; in other embodiments, G3 is C 2-6 It is an alkenylene; in other embodiments, G3 is C 2-13 It is an alkynylene; in other embodiments, G3 is C 2-6 It is an alkynylene; in other embodiments, G3 is one or more R s It is optionally replaced by R s H and C are independent of each other. 1-14 Alkyl, -L d -OR d , -L d -SR d , or -L d -NR d R' d And L dIt does not exist, or C 1-14 It is alkylene; R d and R' d H or C 1-14 It is alkyl.

[0287] In one embodiment, G3 is C 1-14 It is an alkylene. In one embodiment, G3 is C 4-14 It is an alkylene. In one embodiment, G3 is C 1-14 It is an alkenylene. In one embodiment, G3 is C 4-14 It is an alkenylene. In one embodiment, G3 is C 1-14 It is alkynylene. In one embodiment, G3 is C 4-14 It is alkynylene.

[0288] In one embodiment, G4 is absent; in another embodiment, G4 is C 2-13 It is an alkylene; in other embodiments, G4 is C 2-6 It is an alkenylene; in other embodiments, G4 is C 2-13 It is an alkenylene; in other embodiments, G4 is C 2-6 It is an alkynylene; in other embodiments, G4 is C 2-13 It is an alkynylene; in other embodiments, G4 is one or more R s It is optionally replaced by R s H and C are independent of each other. 1-14 Alkyl, -L d -OR d , -L d -SR d , or -L d -NR d R' d And L d It does not exist, or C 1-14 It is alkylene; R d and R' d H or C 1-14 It is alkyl.

[0289] In one embodiment, G1, G2, G3, and G4 are each independent of or are absent or C 1-8 It is alkylene.

[0290] In one embodiment, G3 and G4 have a total length of 3 carbon atoms; in another embodiment, G3 and G4 have a total length of 4 carbon atoms; in another embodiment, G3 and G4 have a total length of 5 carbon atoms; in another embodiment, G3 and G4 have a total length of 6 carbon atoms; in another embodiment, G3 and G4 have a total length of 7 carbon atoms; in another embodiment, G3 and G4 have a total length of 8 carbon atoms; in another embodiment, G3 and G4 have a total length of 9 carbon atoms; in another embodiment, G3 and G4 have a total length of 10 carbon atoms; in another embodiment, G3 and G4 have a total length of 11 carbon atoms; in another embodiment, G3 and G4 have a total length of 12 carbon atoms; in another embodiment, G3 and G4 have a total length of 13 carbon atoms.

[0291] In one embodiment, R s H is; in other embodiments, R s C 1-14 It is alkyl; in other embodiments, R s is, -L d -OR d In other embodiments, R s is, -L d -SR d In other embodiments, R s is, -L d -NR d R' d In other embodiments, R s C 1-10 It is alkyl; in other embodiments, R s C 1-6 It is alkyl. In one embodiment, R s H, C 1-10 Alkyl, -L d -OR, or -L d -NR d R'd In other more specific embodiments, R s H or C 1-6 It is alkyl.

[0292] In one embodiment, G5 is absent. In one embodiment, G5 is absent, j is 0, and R3 is CH2CH2OH.

[0293] In other embodiments, G5 is C 1-8 It is an alkylene; in other embodiments, G5 is C 1-6 It is an alkylene; in other embodiments, G5 is C 1-3 It is an alkylene; in other embodiments, G5 is one or more R ** It is optionally replaced, where each R ** Independently, C 1-8 Alkyl, -L c -OR c , -L c -SR c , or -L c -NR c R' c And R c and R' c H or C 1-8 It is alkyl, and Lc is either absent or C 1-6 It is alkylene.

[0294] In one embodiment, R ** C 1-8 It is alkyl; in other embodiments, R ** is, -L c -OR c In other embodiments, R ** is, -L c -SR c In other embodiments, R ** is, -L c -NR c R' c In other embodiments, R ** C 1-6 It is alkyl.

[0295] In one embodiment, L1 is -(CRR')2-. In one embodiment, L1 is -CH=CH-. In one embodiment, L1 is -C≡C-. In one embodiment, L1 is -NR''-.

[0296] In one embodiment, L2 is -(CRR')2-. In one embodiment, L2 is -CH=CH-. In one embodiment, L2 is -C≡C-. In one embodiment, L2 is -NR''-.

[0297] In one embodiment, L3 is -(CR s R s ')2- and L5 does not exist. In one embodiment, L3 is -CH=CH- and L5 does not exist. In one embodiment, L3 is -C≡C- and L5 does not exist. In one embodiment, L5 is -(CR s R s In one embodiment, L5 is -CH=CH- and L3 does not exist. In another embodiment, L5 is -C≡C- and L3 does not exist.

[0298] In one embodiment, L4 is -(CR s R s ')2- and L6 does not exist. In one embodiment, L4 is -CH=CH- and L6 does not exist. In one embodiment, L4 is -C≡C- and L6 does not exist. In one embodiment, L6 is -(CR s R s In one embodiment, L6 is -CH=CH- and L4 does not exist. In another embodiment, L6 is -C≡C- and L4 does not exist.

[0299] In one embodiment, G 1a It does not exist. In one embodiment, G 1a is methylene. In one embodiment, G 1a is ethylene. In one embodiment, G1a is a C3 alkylene. In one embodiment, G 1a is a C4 alkylene. In one embodiment, G 1a is a C5 alkylene. In one embodiment, G 1a is a C6 alkylene. In one embodiment, G 1a is a C7 alkylene. In one embodiment, G 1a is not substituted. In one embodiment, G 1a is replaced. In one embodiment, G 1a is one or more R s It is replaced by, here, each R s H and C are independent of each other. 1-14 Alkyl, -L d -OR d , -L d -SR d , or -L d -NR d R' d And L d It does not exist, or C 1-14 It is alkylene; R d and R' d H or C 1-14 It is alkyl.

[0300] In one embodiment, G 1b It does not exist. In one embodiment, G 1b is methylene. In one embodiment, G 1b is ethylene. In one embodiment, G 1b is a C3 alkylene. In one embodiment, G 1b is a C4 alkylene. In one embodiment, G 1b is a C5 alkylene. In one embodiment, G 1b is a C6 alkylene. In one embodiment, G 1b is a C7 alkylene. In one embodiment, G 1b is not substituted. In one embodiment, G 1b is replaced. In one embodiment, G 1b is one or more R sReplaced by each R s H and C are independent of each other. 1-14 Alkyl, -L d -OR d , -L d -SR d , or -L d -NR d R' d And L d It does not exist, or C 1-14 It is alkylene; R d and R' d H or C 1-14 It is alkyl.

[0301] In one embodiment, G 2a It does not exist. In one embodiment, G 2a is methylene. In one embodiment, G 2a is ethylene. In one embodiment, G 2a is a C3 alkylene. In one embodiment, G 2a is a C4 alkylene. In one embodiment, G 2a is a C5 alkylene. In one embodiment, G 2a is a C6 alkylene. In one embodiment, G 2a is a C7 alkylene. In one embodiment, G 2a is not substituted. In one embodiment, G 2a is replaced. In one embodiment, G 2a is one or more R s Replaced by each R s H and C are independent of each other. 1-14 Alkyl, -L d -OR d , -L d -SR d , or -L d -NR d R' d And L d It does not exist, or C 1-14 It is alkylene; R d and R' d H or C 1-14 It is alkyl.

[0302] In one embodiment, G 2b It does not exist. In one embodiment, G 2b is methylene. In one embodiment, G 2b is ethylene. In one embodiment, G 2b is a C3 alkylene. In one embodiment, G 2b is a C4 alkylene. In one embodiment, G 2b is a C5 alkylene. In one embodiment, G 2b is a C6 alkylene. In one embodiment, G 2b is a C7 alkylene. In one embodiment, G 2b is not substituted. In one embodiment, G 2b is replaced. In one embodiment, G 2b is one or more R s Replaced by each R s H and C are independent of each other. 1-14 Alkyl, -L d -OR d , -L d -SR d , or -L d -NR d R' d And L d It does not exist, or C 1-14 It is alkylene; R d and R' d H or C 1-14 It is alkyl.

[0303] In one embodiment, G 3a It does not exist. In one embodiment, G 3a is methylene. In one embodiment, G 3a is ethylene. In one embodiment, G 3a is a C3 alkylene. In one embodiment, G 3a is a C4 alkylene. In one embodiment, G 3a is a C5 alkylene. In one embodiment, G 3a is a C6 alkylene. In one embodiment, G3a is a C7 alkylene. In one embodiment, G 3a is not substituted. In one embodiment, G 3a is replaced. In one embodiment, G 3a is one or more R s Replaced by each R s H and C are independent of each other. 1-14 Alkyl, -L d -OR d , -L d -SR d , or -L d -NR d R' d And L d It does not exist, or C 1-14 It is alkylene; R d and R' d H or C 1-14 It is alkyl.

[0304] In one embodiment, G 3b It does not exist. In one embodiment, G 3b is methylene. In one embodiment, G 3b is ethylene. In one embodiment, G 3b is a C3 alkylene. In one embodiment, G 3b is a C4 alkylene. In one embodiment, G 3b is a C5 alkylene. In one embodiment, G 3b is a C6 alkylene. In one embodiment, G 3b is a C7 alkylene. In one embodiment, G 3b is not substituted. In one embodiment, G 3b is replaced. In one embodiment, G 3b is one or more R s Replaced by each R s H and C are independent of each other. 1-14 Alkyl, -L d -OR d , -L d -SR d , or -L d -NR d R'd And L d It does not exist, or C 1-14 It is alkylene; R d and R' d H or C 1-14 It is alkyl.

[0305] In one embodiment, G 4a It does not exist. In one embodiment, G 4a is methylene. In one embodiment, G 4a is ethylene. In one embodiment, G 4a is a C3 alkylene. In one embodiment, G 4a is a C4 alkylene. In one embodiment, G 4a is a C5 alkylene. In one embodiment, G 4a is a C6 alkylene. In one embodiment, G 4a is a C7 alkylene. In one embodiment, G 4a is not substituted. In one embodiment, G 4a is replaced. In one embodiment, G 4a is one or more R s Replaced by each R s H and C are independent of each other. 1-14 Alkyl, -L d -OR d , -L d -SR d , or -L d -NR d R' d And L d It does not exist, or C 1-14 It is alkylene; R d and R' d H or C 1-14 It is alkyl.

[0306] In one embodiment, G 4b It does not exist. In one embodiment, G 4b is methylene. In one embodiment, G 4b is ethylene. In one embodiment, G 4bis a C3 alkylene. In one embodiment, G 4b is a C4 alkylene. In one embodiment, G 4b is a C5 alkylene. In one embodiment, G 4b is a C6 alkylene. In one embodiment, G 4b is a C7 alkylene. In one embodiment, G 4b is not substituted. In one embodiment, G 4b is replaced. In one embodiment, G 4b is one or more R s Replaced by each R s H and C are independent of each other. 1-14 Alkyl, -L d -OR d , -L d -SR d , or -L d -NR d R' d And L d It does not exist, or C 1-14 It is alkylene; R d and R' d H or C 1-14 It is alkyl.

[0307] In one embodiment, G 1a , G 1b , G 2a , and G 2b It has a total length of 1, 2, 3, 4, 5, 6, or 7 carbon atoms; in other more specific embodiments, G 1a , G 1b , G 2a , and G 2b It has a total length of 1, 2, 3, 4, 5, or 6 carbon atoms. In one embodiment, G 1a , G 1b , G 2a , and G 2b It has the full length of one carbon atom. In one embodiment, G 1a , G 1b , G 2a , and G 2b It has the full length of two carbon atoms. In one embodiment, G 1a , G1b , G 2a , and G 2b It has the full length of three carbon atoms. In one embodiment, G 1a , G 1b , G 2a , and G 2b It has the full length of 4 carbon atoms. In one embodiment, G 1a , G 1b , G 2a , and G 2b It has a total length of 5 carbon atoms. In one embodiment, G 1a , G 1b , G 2a , and G 2b It has a total length of 6 carbon atoms.

[0308] In one embodiment, G 3a , G 3b , G 4a , and G 4b It has a total length of 1, 2, 3, 4, 5, 6, or 7 carbon atoms. In one embodiment, G 3a , G 3b , G 4a , and G 4b It has the full length of one carbon atom. In one embodiment, G 3a , G 3b , G 4a , and G 4b It has the full length of two carbon atoms. In one embodiment, G 3a , G 3b , G 4a , and G 4b It has the full length of three carbon atoms. In one embodiment, G 3a , G 3b , G 4a , and G 4b It has the full length of 4 carbon atoms. In one embodiment, G 3a , G 3b , G 4a , and G 4b It has a total length of 5 carbon atoms. In one embodiment, G 3a , G 3b , G 4a , and G 4bIt has the total length of 6 carbon atoms. In one embodiment, G 3a , G 3b , G 4a , and G 4b It has a total length of 7 carbon atoms.

[0309] In one embodiment, G7 is absent; in another embodiment, G7 is C 1-12 It is an alkylene; in other embodiments, G7 is C 1-6 It is an alkylene; in other embodiments, G7 is C 1-5 It is an alkylene; in other embodiments, G7 is C 1-5 It is a linear alkylene; in other embodiments, G7 is -CH2-; in other embodiments, G7 is -(CH2)2-; in other embodiments, G7 is -(CH2)4-; in other embodiments, G7 is -(CH2)5-; in other embodiments, G7 is optionally substituted with 1, 2, 3, 4, 5, or 6 Rs, where R is C 1-10 It is alkyl. In other embodiments, one, two, or three methylene groups in G7 are optionally and independently substituted with one R; in other embodiments, one or two methylene groups in G7 are optionally and independently substituted with one R; and in other embodiments, the methylene group bonded to M1 of G7 is not substituted with R.

[0310] In one embodiment, G8 is absent; in another embodiment, G8 is C 1-12 It is an alkylene; in other embodiments, G8 is C 1-10 It is an alkylene; in other embodiments, G8 is C 1-8 It is an alkylene; in other embodiments, G8 is C 1-8It is a linear alkylene; in other embodiments, G8 is -(CH2)2-; in other embodiments, G8 is -(CH2)4-; in other embodiments, G8 is -(CH2)6-; in other embodiments, G8 is -(CH2)7-; in other embodiments, G8 is -(CH2)8-; in other embodiments, G8 is optionally substituted with 1, 2, 3, 4, 5, or 6 Rs, where R is C 1-10 It is alkyl; in other embodiments, one, two, or three methylene groups in G8 are optionally and independently substituted with one R; in other embodiments, one or two alkylene groups in G8 are optionally and independently substituted with one R.

[0311] In one embodiment, G7 and G8 have a total length of 4 carbon atoms; in another embodiment, G7 and G8 have a total length of 5 carbon atoms; in another embodiment, G7 and G8 have a total length of 6 carbon atoms; in another embodiment, G7 and G8 have a total length of 7 carbon atoms; in another embodiment, G7 and G8 have a total length of 8 carbon atoms; in another embodiment, G7 and G8 have a total length of 9 carbon atoms; in another embodiment, G7 and G8 have a total length of 10 carbon atoms; in another embodiment, G7 and G8 have a total length of 11 carbon atoms; in another embodiment, G7 and G8 have a total length of 12 carbon atoms.

[0312] In one embodiment, G7 and G8 have a total length of 6, 7, 8, 9, or 10 carbon atoms.

[0313] In one embodiment, G9 is absent; in another embodiment, G9 is C 1-12 It is an alkylene; in other embodiments, G9 is C 1-6 It is an alkylene; in other embodiments, G9 is C 1-5 It is an alkylene; in other embodiments, G9 is C 1-5It is a linear alkylene; in other embodiments, G9 is -CH2-; in other embodiments, G9 is -(CH2)2-; in other embodiments, G9 is -(CH2)4-; in other embodiments, G9 is -(CH2)5-; in other embodiments, G9 is optionally substituted with 1, 2, 3, 4, 5, or 6 Rs, where R is C 1-10 It is alkyl; in other embodiments, one, two, or three methylene groups in G9 are optionally and independently substituted with one R; in other embodiments, one or two methylene groups in G9 are optionally and independently substituted with one R; in other embodiments, the methylene group of G9 bonded to M2 is not substituted with R.

[0314] In one embodiment, G 10 In other embodiments, G 10 C 1-12 It is an alkylene; in other embodiments, G 10 C 1-10 It is an alkylene; in other embodiments, G 10 C 1-8 It is an alkylene; in other embodiments, G 10 C 1-8 It is a linear alkylene; in other embodiments, G 10 is -(CH2)2-; in other embodiments, G 10 is -(CH2)4-; in other embodiments, G 10 is -(CH2)6-; in other embodiments, G 10 is -(CH2)7-; in other embodiments, G 10 is -(CH2)8-; in other embodiments, G 10 is optionally replaced by 1, 2, 3, 4, 5, or 6 Rs, where R is C 1-10 Alkyl; in other embodiments, G 10 In other embodiments, one, two, or three methylene groups are optionally and independently substituted with one R; in other embodiments, G 10 One or two methylene groups within the molecule are optionally and independently substituted by one R group.

[0315] In one embodiment, G9 and G 10 It has the full length of 4 carbon atoms; in other embodiments, G9 and G 10 It has a total length of 5 carbon atoms; in other embodiments, G9 and G 10 It has the full length of 6 carbon atoms; in other embodiments, G9 and G 10 It has a total length of 7 carbon atoms; in other embodiments, G9 and G 10 It has the full length of 8 carbon atoms; in other embodiments, G9 and G 10 It has the full length of 9 carbon atoms; in other embodiments, G9 and G 10 It has a total length of 10 carbon atoms; in other embodiments, G9 and G 10 It has the full length of 11 carbon atoms; in other embodiments, G9 and G 10 It has the full length of 12 carbon atoms.

[0316] In one embodiment, G9 and G 10 It has a total length of 6, 7, 8, 9, or 10 carbon atoms. In one embodiment, G9 and G 10 It has a total length of 6, 7, or 8 carbon atoms.

[0317] In one embodiment, R s H is H. In one embodiment, R s C 1-10 It is alkyl. In one embodiment, R s C 1-6 It is alkyl. In one embodiment, R s is methyl. In one embodiment, R s is ethyl. In one embodiment, R s is a C3 alkyl group. In one embodiment, R s is a C4 alkyl group. In one embodiment, R s is a C5 alkyl group. In one embodiment, R s is a C6 alkyl group. In one embodiment, R s is, -Ld -OR d In one embodiment, R s is, -L d -NR d R' d In one embodiment, R s is -OR d In one embodiment, R s -NR d R' d In one embodiment, R s is -CH2-OR d In one embodiment, R s -CH2-NR d R' d That is the case.

[0318] In one embodiment, R s’ H is H. In one embodiment, R s’ C 1-10 It is alkyl. In one embodiment, R s’ C 1-6 It is alkyl. In one embodiment, R s’ is methyl. In one embodiment, R s’ is ethyl. In one embodiment, R s’ is a C3 alkyl group. In one embodiment, R s’ is a C4 alkyl group. In one embodiment, R s’ is a C5 alkyl group. In one embodiment, R s’ is a C6 alkyl group. In one embodiment, R s’ is, -L d -OR d In one embodiment, R s’ is, -L d -NR d R' d In one embodiment, R s’ is -OR d In one embodiment, R s’ -NR d R' d In one embodiment, R s’ is -CH2-OR dIn one embodiment, R s’ -CH2-NR d R' d That is the case.

[0319] Examples R and R' are independently H, C 1-20 Alkyl, L a -OR a , -L a -SR a , or -L a -NR a R' a Either R and R' are, together with the carbon they are bonded to, C 3-8 It forms cycloalkylenes.

[0320] In one embodiment, R is H. In one embodiment, R is C. 1-20 It is alkyl. In one embodiment, R is C 1-14 It is alkyl. In one embodiment, R is C 1-8 It is alkyl. In one embodiment, R is C 1-6 It is alkyl. In one embodiment, R is -L a -OR a In one embodiment, R is -L a -NR a R' a In one embodiment, R is -OR a In one embodiment, R is -NR a R' a In one embodiment, R is -CH2-OR a In one embodiment, R is -CH2-NR a R' a That is the case.

[0321] In one embodiment, R ’ is H. In one embodiment, R' is C 1-20 It is alkyl. In one embodiment, R ’ C 1-14 It is alkyl. In one embodiment, R ’ C 1-8It is alkyl. In one embodiment, R ’ C 1-6 It is alkyl. In one embodiment, R ’ is, -L a -OR a In one embodiment, R ’ is, -L a -NR a R' a In one embodiment, R ’ is -OR a In one embodiment, R ’ -NR a R' a In one embodiment, R ’ is -CH2-OR a In one embodiment, R ’ -CH2-NR a R' a That is the case.

[0322] In one embodiment, R and R', along with the carbon to which they are bonded, are C 3-8 It forms a cycloalkylene. In one embodiment, R and R' together with the carbon to which they are bonded, C 3-6 A cycloalkylene is formed. In one embodiment, R and R', together with the carbon to which they are bonded, form a C3 cycloalkylene, a C4 cycloalkylene, a C5 cycloalkylene, or a C6 cycloalkylene.

[0323] In one embodiment, R ’’ H is H. In one embodiment, R ’’ C 1-14 It is alkyl. In one embodiment, R ’’ C 1-8 It is alkyl. In one embodiment, R ’’ C 1-6 It is alkyl. In one embodiment, R ’’ is methyl. In one embodiment, R ’’ is ethyl. In one embodiment, R ’’ is a C3 alkyl group. In one embodiment, R ’’is a C4 alkyl group. In one embodiment, R ’’ is a C5 alkyl group. In one embodiment, R ’’ It is a C6 alkyl group.

[0324] In one embodiment, L d It does not exist. In one embodiment, L d C 1-10 It is alkylene. d C 1-6 It is alkylene. d L is methylene. In one embodiment, L d is ethylene. In one embodiment, L d is a C3 alkylene. In one embodiment, L d is a C4 alkylene. In one embodiment, L d is a C5 alkylene. In one embodiment, L d It is a C6 alkylene.

[0325] In one embodiment, R c H is H. In one embodiment, R c C 1-8 It is alkyl. In one embodiment, R c C 1-6 It is alkyl. In one embodiment, R c is methyl. In one embodiment, R c is ethyl. In one embodiment, R c is a C3 alkyl group. In one embodiment, R c is a C4 alkyl group. In one embodiment, R c is a C5 alkyl group. In one embodiment, R c is a C6 alkyl group. In one embodiment, R c is a C7 alkyl group. In one embodiment, R c It is a C8 alkyl group.

[0326] In one embodiment, R' c is H. In one embodiment, R'c C 1-8 It is alkyl. In one embodiment, R' c C 1-6 It is alkyl. In one embodiment, R' c is methyl. In one embodiment, R' c is ethyl. In one embodiment, R' c is a C3 alkyl group. In one embodiment, R' c is a C4 alkyl group. In one embodiment, R' c is a C5 alkyl group. In one embodiment, R' c is a C6 alkyl group. In one embodiment, R' c is a C7 alkyl group. In one embodiment, R' c It is a C8 alkyl group.

[0327] In one embodiment, R d H is H. In one embodiment, R d C 1-10 It is alkyl. In one embodiment, R d C 1-8 It is alkyl. In one embodiment, R d C 1-6 It is alkyl. In one embodiment, R d is methyl. In one embodiment, R d is ethyl. In one embodiment, R d is a C3 alkyl group. In one embodiment, R d is a C4 alkyl group. In one embodiment, R d is a C5 alkyl group. In one embodiment, R d is a C6 alkyl group. In one embodiment, R d is a C7 alkyl group. In one embodiment, R d is a C8 alkyl group. In one embodiment, R d is a C9 alkyl group. In one embodiment, R d C 10 It is alkyl.

[0328] In one embodiment, R' d is H. In one embodiment, R' d C 1-10 It is alkyl. In one embodiment, R' d C 1-8 It is alkyl. In one embodiment, R' d C 1-6 It is alkyl. In one embodiment, R' d is methyl. In one embodiment, R' d is ethyl. In one embodiment, R' d is a C3 alkyl group. In one embodiment, R' d is a C4 alkyl group. In one embodiment, R' d is a C5 alkyl group. In one embodiment, R' d is a C6 alkyl group. In one embodiment, R' d is a C7 alkyl group. In one embodiment, R' d is a C8 alkyl group. In one embodiment, R' d is a C9 alkyl group. In one embodiment, R' d C 10 It is alkyl.

[0329] In one embodiment, a' is 0. In one embodiment, a' is 1. In one embodiment, a' is 2. In one embodiment, a' is 3. In one embodiment, a' is 4. In one embodiment, a' is 5.

[0330] In one embodiment, b is 0. In one embodiment, b is 1. In one embodiment, b is 2. In one embodiment, b is 3. In one embodiment, b is 4. In one embodiment, b is 5.

[0331] In one embodiment, g is 0. In one embodiment, g is 1. In one embodiment, g is 2. In one embodiment, g is 3. In one embodiment, g is 4. In one embodiment, g is 5.

[0332] In one embodiment, a' is 2 and b is 2. In one embodiment, a' is 0 and b is 2. In one embodiment, a' is 2 and b is 0. In one embodiment, a' is 1 and b is 2. In one embodiment, a' is 2 and b is 1.

[0333] In one embodiment, a'+g is equal to 2. In one embodiment, a'+g is equal to 3. In one embodiment, a'+g is equal to 0. In one embodiment, a'+g is equal to 1. In one embodiment, a'+g is equal to 4. In one embodiment, a'+g is equal to 5.

[0334] In one embodiment, c is 0. In one embodiment, c is 1. In one embodiment, c is 2. In one embodiment, c is 3. In one embodiment, c is 4. In one embodiment, c is 5. In one embodiment, c is 6. In one embodiment, c is 7.

[0335] In one embodiment, d is 0. In one embodiment, d is 1. In one embodiment, d is 2. In one embodiment, d is 3. In one embodiment, d is 4. In one embodiment, d is 5. In one embodiment, d is 6. In one embodiment, d is 7.

[0336] In one embodiment, e is 0. In one embodiment, e is 1. In one embodiment, e is 2. In one embodiment, e is 3. In one embodiment, e is 4. In one embodiment, e is 5. In one embodiment, e is 6. In one embodiment, e is 7.

[0337] In one embodiment, f is 0. In one embodiment, f is 1. In one embodiment, f is 2. In one embodiment, f is 3. In one embodiment, f is 4. In one embodiment, f is 5. In one embodiment, f is 6. In one embodiment, f is 7.

[0338] In one embodiment, c+d is equal to 2. In one embodiment, c+d is equal to 3. In one embodiment, c+d is equal to 0. In one embodiment, c+d is equal to 1. In one embodiment, c+d is equal to 4. In one embodiment, c+d is equal to 5. In one embodiment, c+d is equal to 6. In one embodiment, c+d is equal to 7. In one embodiment, c+d is equal to 8. In one embodiment, c+d is equal to 9.

[0339] In one embodiment, e+f is equal to 2. In one embodiment, e+f is equal to 3. In one embodiment, e+f is equal to 0. In one embodiment, e+f is equal to 1. In one embodiment, e+f is equal to 4. In one embodiment, e+f is equal to 5. In one embodiment, e+f is equal to 6. In one embodiment, e+f is equal to 7. In one embodiment, e+f is equal to 8. In one embodiment, e+f is equal to 9.

[0340] In one embodiment, [ka] It has a total length consisting of 4, 5, 6, 7, 8, or 9 carbon atoms.

[0341] In one embodiment, [ka] are independently -(CH2)3-C(CH3)2-, -(CH2)4-C(CH3)2-, -(CH2)5-C(CH3)2-, -(CH2)6-C(CH3)2-, -(CH2)7-C(CH3)2 -, -(CH2)8-C(CH3)2-, -(CH2)3-CH=CH-C(CH3)2-, -(CH2)3-C≡CC(CH3)2-, -(CH2)4-C(CH3)2-CH2-, -(CH2)3- Selected from C(CH3)2-(CH2)2-, -(CH2)2-C(CH3)2-(CH2)3-, -(CH2)2-CH=CH-C(CH3)2-CH2-, -(CH2)2-C(CH3)2-C≡C-CH2-, -(CH2)2-C(CH3)2-CH=CH-CH2-, -(CH2)2-C≡CC(CH3)2-CH2-, and -(CH2)3-C(CH3)2-C≡C-; in one embodiment, [ka] These are independently -(CH2)4-C(CH3)2-, -(CH2)5-C(CH3)2-, or -(CH2)6-C(CH3)2-; in one embodiment, [ka] It is -(CH2)5-C(CH3)2-. In one embodiment, [ka] It is -(CH2)6-C(CH3)2-, [ka] It is -(CH2)7-. In one embodiment, [ka] It is -(CH2)7-, [ka] It is -(CH2)7-.

[0342] In one embodiment, -G7-L1-G8-H or -G9-L2-G 10 -H is independent of -(CH2)5CH3, -(CH2)6CH3, -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3, -(CH2) 11 CH3, -CH2-C≡C-(CH2)5CH3, -CH2-C≡C-(CH2)6CH3, -(CH2)2-C≡C-(CH2)5CH3, -(CH2)4-C≡C-(CH2)3CH3, -CH2-CH=CH-( CH2)5CH3, -CH2-CH=CH-(CH2)6CH3, -(CH2)2-CH=CH-(CH2)5CH3, -(CH2)4-CH=CH-(CH2)3CH3, -(CH2)5-CH=CH-CH2CH3, [ka] Selected from.

[0343] In one embodiment, -G7-L1-G8-H or -G9-L2-G 10 -H is independently one of the following groups: -(CH2)5CH3, -(CH2)6CH3, -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3, -(CH2) 11 CH3, -CH2-C≡C-(CH2)5CH3, -CH2-C≡C-(CH2)6CH3, -(CH2)2-C≡C-(CH2)5CH3, -(CH2)4-C≡C-(CH2)3CH3, -CH2-CH=CH-( CH2)5CH3, -CH2-CH=CH-(CH2)6CH3, -(CH2)2-CH=CH-(CH2)5CH3, -(CH2)4-CH=CH-(CH2)3CH3, -(CH2)5-CH=CH-CH2CH3, [ka] Selected from.

[0344] In one embodiment, -G7-L1-G8-H or -G9-L2-G 10 -H is, [ka] In one embodiment, -G7-L1-G8-H or -G9-L2-G 10 -H is -(CH2)8CH3. In one embodiment, -G7-L1-G8-H and -G9-L2-G 10 - One of H is, [ka] The other is -(CH2)8CH3.

[0345] In one embodiment, the ionized lipid is a compound of formula (IX): [ka] or its stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt, in the formula, G1 and G2 are independently joined, C 1-13 Linear alkylene, C 2-13 Linear alkenylenes, or C 2-13 A linear alkynylene, where the alkylene, alkenylene, and alkynylene are one or more R G1 It is optionally replaced by; G1 and G2 have the full length of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 carbon atoms; R G1 Each example is independent of C 1-14 Alkyl, -L a -OR a , -L a -SR a , or -L a -NR a R' a and; G3 is C 4-14 Linear alkylene, C 4-14 Linear alkenylenes, or C 4-14 A linear alkynylene, where the alkylene, alkenylene, and alkynylene are one or more R G3 It is optionally replaced by; RG3 Each example is independently H, -L a -OR a , -L a -SR a , or -L a -NR a R' a and; L a These are, independently, combined or C 1-14 It is alkylene; R a and R' a These are H and C, respectively, independently. 1-14 Alkyl, C 3-14 It is a cycloalkyl or a 3- to 14-membered heterocycline; G4 is a bond, C 1-6 Alkilen, C 2-6 Alkenylene, or C 2-6 Alkynylene, where the above alkylene, alkenylene, and alkynylene are one or more R G4 It is optionally replaced by; R G4 Each example is independently H, C 1-6 Alkyl, -L b -OR b , -L b -SR b , or -L b -NR b R' b and; L b These are, independently, combined or C 1-6 It is alkylene; R b and R' b H and C are independent of each other. 1-6 Alkyl, C 3-10 It is a cycloalkyl or a 3- to 10-membered heterocycline; or two R G4 C 3-14 It forms a cycloalkylene or a 3-14 membered heterocyclene, where the cycloalkylene and heterocyclene are one or more R 4g It is optionally replaced by; R 4gEach example independently involves halogen, cyano, and C. 1-8 Alkyl, C 1-8 Haloalkyl, -L e -OR e , -L e -SR e , or -L e -NR e R' e and; L e These are, independently, combined or C 1-8 It is alkylene; R e and R' e H and C are independent of each other. 1-8 Alkyl, C 3-14 It is a cycloalkyl or a 3- to 14-membered heterocycline; M1 and M2 are independently -C(O)O-, -OC(O)-, -O-, -SC(O)O-, -OC(O)NR-, -NRC(O)NR-, -OC(O)S-, -OC(O)O-, -NRC(O)O-, -SC(O)-, -C(O)S-, -NR-, -C(O)NR-, -NRC(O)-, -NRC(O)S-, -SC(O)NR-, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR-, -NRC(S)O-, -SS-, or -S(O) 0-2 -and; Q represents the bonds -C(O)O-, -O-, -SC(O)O-, and -OC(O)NR. f -, -NR f C(O)NR f -, -OC(O)S-, -OC(O)O-, -NR f C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR f -, -C(O)NR f -, -NR f C(O)-, -NR f C(O)S-, -SC(O)NR f -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR f -, -NR f C(S)O-, -SS-, -S(O) 0-2-, phenylene, or pyridylidene, where the phenylene and pyridylidene are one or more R * It is optionally replaced by; R * These are, independently, halogen, cyano, and C 1-10 Alkyl, C 1-10 Haloalkyl, -L f -OR f , -L f -SR f , or -L f -NR f R' f and; L f These are, independently, combined or C 1-8 It is alkylene; R f and R' f H and C are independent of each other. 1-10 Alkyl, C 3-14 It is a cycloalkyl or a 3- to 14-membered heterocycline; R1 and R2 are independent of C 4-20 Alkyl, C 4-20 Alkenyl, or C 4-20 The alkyl, alkenyl, or alkynyl is one or more R 1s The units are optionally replaced by -NR'-, where one or more methylene units are optionally and independently replaced by -NR'-; R 1s H and C are independent of each other. 1-20 Alkyl, -L c -OR c , -L c -SR c , or -L c -NR c R' c and; R and R' are independently H or C 1-20 It is alkyl; L c These are, independently, combined or C 1-20 It is alkylene; R c and R' c These are H and C, respectively, independently. 1-20 Alkyl, C3-14 It is a cycloalkyl or a 3- to 14-membered heterocycline; R3 is -CN, -OR g , -C(O)R g ,-OC(O)R g ,-NR''C(O)R g , -NR g R' g ,-NR''C(O)NR g R' g ,-NR''C(O)R g -NR''S(O)2R g -OC(O)NR g R' g , -NR''C(O)OR g , -N(OR g )C(O)R g , -N(OR g )S(O)2R g , -N(OR g )C(O)OR g , -N(OR g )C(O)R g R' g , optionally substituted 3- to 14-membered heterocyclyls, or optionally substituted 5- to 14-membered heteroaryls; R g and R' g These are H and C, respectively, independently. 1-10 Alkyl, C 3-10 It is a cycloalkyl or a 3- to 10-membered heterocycline; R'' is independently H or C 1-6 It is alkyl; R5 and R6 are independently C 1-8 It is an alkyl group, where the alkyl group is one or more R 4s It is optionally replaced by; Alternatively, R5 and R6, along with the carbon atoms to which they are bonded, are C 3-14 It forms a cycloalkylene or a 3-14 membered heterocyclene, where the cycloalkylene and heterocyclene are one or more R 4s It is optionally replaced by; R 4s Each example independently represents H, halogen, cyano, and C.1-8 Alkyl, C 1-8 Haloalkyl, -L d -OR d , -L d -SR d , or -L d -NR d R' d and; L d These are, independently, combined or C 1-8 It is alkylene; R d and R' d H and C are independent of each other. 1-8 Alkyl, C 3-14 They are cycloalkyl or 3- to 14-membered heterocyclines.

[0346] In one embodiment, G1 and G2 are independently bonded, C 1-9 Linear alkylene, C 2-9 Linear alkenylenes, or C 2-9 It is a straight-chain alkynylene.

[0347] In one embodiment, G1 is C 1-6 Linear alkylene, C 2-6 Linear alkenylenes, or C 2-6 It is a linear alkynylene. In one embodiment, G1 is C 1-6 It is a linear alkylene. In one embodiment, G1 is C 2-6 It is a linear alkylene.

[0348] In one embodiment, G2 is bonded, C 1-6 Linear alkylene, C 2-6 Linear alkenylenes, or C 2-6 It is a linear alkynylene. In one embodiment, G2 is a bond or C 1-6 It is a linear alkylene. In one embodiment, G2 is a bond or C 1-4 It is a linear alkylene.

[0349] In one embodiment, G1 and G2 have a total length of 3, 4, 5, 6, 7, 8, or 9 carbon atoms. In one embodiment, G1 and G2 have a total length of 4, 5, or 6 carbon atoms. In one embodiment, G1 and G2 have a total length of 5 or 6 carbon atoms. In one embodiment, G1 and G2 have a total length of 5, 6, or 7 carbon atoms. In one embodiment, G1 and G2 have a total length of 6 or 7 carbon atoms. In one embodiment, G1 and G2 have 1, 2, 3, or 4 R G1 It is optionally replaced by [another term].

[0350] In one embodiment, R G1 Each of these examples is independent of H or C 1-10 It is alkyl. In one embodiment, R G1 Each of these examples is independent of H or C 1-6 It is alkyl.

[0351] In one embodiment, G3 is C 4-10 Linear alkylene, C 4-10 Linear alkenylenes, or C 4-10 It is a linear alkynylene. In one embodiment, G3 is C 4-9 It is a linear alkylene. In one embodiment, G3 is C 5-8 It is a linear alkylene. In one embodiment, G3 is 1, 2, 3, or 4 R G3 It is optionally replaced by [another term].

[0352] In one embodiment, L a These are, independently, combined or C 1-10 It is alkylene. a These are, independently, combined or C 1-6 It is alkylene.

[0353] In one embodiment, R a and R' a These are H and C, respectively, independently. 1-10 Alkyl, C 3-10 It is a cycloalkyl or a 3-10 membered heterocycline. In one embodiment, R aand R' a These are, independently, H or C 1-6 It is alkyl.

[0354] In one embodiment, G4 is C 1-4 Alkilen, C 2-4 Alkenylene, or C 2-4 It is an alkynylene. In one embodiment, G4 is C 2-4 It is an alkylene. In one embodiment, G4 is C 2-3 It is alkylene. In one embodiment, G4 is 1, 2, 3, or 4 R G4 It is optionally replaced by [another term].

[0355] In one embodiment, R G4 H or C 1-6 It is alkyl. In one embodiment, R G4 Independently, C 1-4 It is alkyl.

[0356] In one embodiment, two R G4 C 3-10 It forms a cycloalkylene or a 3-10 membered heterocyclene. In one embodiment, two R G4 C 3-7 They form cycloalkylenes or 3- to 7-membered heterocyclenes. In one embodiment, the cycloalkylenes and heterocyclenes have 1, 2, or 3 R 4g It is optionally replaced by [another term].

[0357] In one embodiment, R 4g These are independently H, halogen, cyano, and C. 1-6 Alkyl, or C 1-6 It is a haloalkyl group.

[0358] In one embodiment, L b These are, independently, combined or C 1-4 It is alkylene.

[0359] In one embodiment, R b and R' b H and C are independent of each other. 1-6 Alkyl, C 3-7 It is a cycloalkyl or a 3- to 7-membered heterocycline. In one embodiment, R b and R' b H or C 1-6 It is alkyl. In one embodiment, R b and R' b H or C 1-4 It is alkyl.

[0360] In one embodiment, M1 and M2 are independently -C(O)O-, -OC(O)-, -OC(O)O-, -SC(O)-, -C(O)S-, -C(O)NR-, or -NRC(O)-. In one embodiment, M1 and M2 are independently -C(O)O-, -OC(O)O-, -OC(O)-, -SC(O)-, or -C(O)S-. In one embodiment, M1 and M2 are independently -C(O)O-, -OC(O)-, -SC(O)-, or -C(O)S-. In one embodiment, M1 and M2 are independently -C(O)O- or -OC(O)-.

[0361] In one embodiment, R1 and R2 are independently C 6-14 Alkyl, C 6-14 Alkenyl, or C 6-14 It is an alkynyl. In one embodiment, R1 and R2 are independently C 6-14 It is alkyl. In one embodiment, R1 and R2 are independently C 7-12 It is alkyl. In one embodiment, R1 and R2 are independently C 8-12 It is alkyl. In one embodiment, R1 and R2 are independently C 7-12 Alkyl, C 7-12 Alkenyl, or C 7-12 It is alkinyl.

[0362] In one embodiment, R1 and R2 are 1, 2, 3, or 4 R 1sIt is optionally replaced by one R. In one embodiment, R1 and R2 are one R 1s It is optionally replaced by [another term].

[0363] In one embodiment, R1 and R2 are independently -(CH2)5CH3, -(CH2)6CH3, -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3, -(CH2) 11 CH3, -CH2-C≡C-(CH2)5CH3, -CH2-C≡C-(CH2)6CH3, -(CH2)2-C≡C-(CH2)5CH3, -(CH2)2-C≡C-(CH2)4CH3, -(CH2)3-C≡C-(CH2)3CH3, -(CH2)4-C≡C- (CH2)3CH3, -CH2-CH=CH-(CH2)5CH3, -CH2-CH=CH-(CH2)6CH3, -(CH2)2-CH=CH-(CH2)5CH3, -(CH2)4-CH=CH-(CH2)3CH3, -(CH2)5-CH=CH-CH2CH3, [ka] That is the case.

[0364] In one embodiment, R 1s H and C are independent of each other. 1-14 Alkyl, -L c -OR c , or -L c -NR c R' c In one embodiment, R 1s H or C 1-14 It is alkyl. In one embodiment, R 1s H or C 1-10 It is alkyl. In one embodiment, R 1s H or C 1-9 It is alkyl. In one embodiment, R 1s H or C 1-6 It is alkyl. In one embodiment, R 1s H or C 1-4 It is alkyl.

[0365] In one embodiment, R and R' are independently H or C 1-20 It is alkyl. In one embodiment, R and R' are independently H or C 1-14 It is alkyl. In one embodiment, R and R' are independently H or C 1-9 It is alkyl. In one embodiment, R and R' are independently H or C 1-6 It is alkyl. In one embodiment, R is H.

[0366] In one embodiment, L c These are, independently, combined or C 1-14 It is alkylene. c These are, independently, combined or C 1-10 It is alkylene. c These are, independently, combined or C 1-6 It is alkylene.

[0367] In one embodiment, R c and R' c H or C 1-14 It is alkyl. In one embodiment, R c and R' c H or C 1-10 It is alkyl. In one embodiment, R c and R' c H or C 1-6 It is alkyl.

[0368] In one embodiment, R3 is cyano, -OR g , or -NR g R' g In one embodiment, R3 is -OR g or -NR g R' g In one embodiment, R3 is -OR g In one embodiment, R3 is -OH.

[0369] In one embodiment, R3 is -OH or -N(CH3)2.

[0370] In one embodiment, R g and R' g H and C are independent of each other. 1-6 Alkyl, C 3-7 It is a cycloalkyl or a 3- to 7-membered heterocycline. In one embodiment, R g and R' g H or C 1-6 It is alkyl. In one embodiment, R g and R' g H or C 1-4 It is alkyl. In one embodiment, R g and R' g These are independently either H or -CH3.

[0371] In one embodiment, R5 and R6 are independently C 1-6 It is alkyl. In one embodiment, R5 and R6 are independently C 1-3 It is alkyl. In one embodiment, R5 and R6 are independently -CH3. In one embodiment, R5 and R6 are independently 1, 2, or 3 R 4s It is optionally replaced by [another term].

[0372] In one embodiment, R5 and R6, along with the carbon atoms to which they are bonded, are C 3-10 It forms a cycloalkylene or a 3- to 10-membered heterocyclene. In one embodiment, the cycloalkylene or heterocyclene has 1, 2, or 3 R 4s It is optionally replaced by [another term].

[0373] In one embodiment, R 4s These are independently H, halogen, cyano, and C. 1-6 Alkyl, C 1-6 Haloalkyl, -L d -OR d , -L d -SR d , or -L d -NRd R' d In one embodiment, R 4s These are independently H, halogen, cyano, and C. 1-6 Alkyl, or C 1-6 It is a haloalkyl. In one embodiment, R 4s H and C are independent of each other. 1-3 Alkyl, or C 1-3 It is a haloalkyl group.

[0374] In one embodiment, L d These are, independently, combined or C 1-6 It is alkylene. d These are, independently, combined or C 1-3 It is alkylene.

[0375] In one embodiment, R d and R' d H and C are independent of each other. 1-6 Alkyl, C 3-10 It is a cycloalkyl or a 3-10 membered heterocycline. In one embodiment, R d and R' d H or C 1-6 It is alkyl. In one embodiment, R d and R' d H or C 1-6 It is alkyl.

[0376] In one embodiment, L e These are, independently, combined or C 1-6 It is alkylene. e These are, independently, combined or C 1-4 It is alkylene.

[0377] In one embodiment, R e and R' e H and C are independent of each other. 1-6 Alkyl, C 3-10 It is a cycloalkyl or a 3-10 membered heterocycline. In one embodiment, R e and R' e H or C1-6 It is alkyl. In one embodiment, R e and R' e H or C 1-4 It is alkyl.

[0378] In one embodiment, L f These are, independently, combined or C 1-6 It is alkylene. f These are, independently, combined or C 1-4 It is alkylene.

[0379] In one embodiment, R f and R' f H and C are independent of each other. 1-6 Alkyl, C 3-10 It is a cycloalkyl or a 3-10 membered heterocycline. In one embodiment, R f and R' f H or C 1-6 It is alkyl. In one embodiment, R f and R' f H or C 1-4 It is alkyl.

[0380] In one embodiment, the compound of formula (IX) is the compound of formula (X): [ka] or its stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt, During the ceremony, a is 1, 2, 3, 4, 5, or 6; b is 4, 5, 6, 7, 8, 9, or 10; c is 1, 2, 3, 4, 5, or 6; d is 0, 1, 2, 3, or 4; c+d is 3, 4, 5, 6, 7, 8, or 9.

[0381] In one embodiment, M1 or M2 is on R1 or R2 1sIt is separated from the substitution site by 0 to 10 carbon atoms. In one embodiment, M1 or M2 is on R1 or R2 1s It is separated from the substitution site by 0 to 6 carbon atoms. In one embodiment, M1 or M2 is on R1 or R2 1s It is separated from the substitution site by 0 to 4 carbon atoms. In one embodiment, M1 or M2 is on R1 or R2 1s It is separated from the substitution site by 0 to 2 carbon atoms. In one embodiment, M1 or M2 is on R1 or R2 1s It is separated from the substitution site by zero carbon atoms.

[0382] In one embodiment, R2 is [ka] In one embodiment, R2 is [ka] In one embodiment, R2 is [ka] In one embodiment, R2 is [ka] That is the case.

[0383] In one embodiment, R1 is [ka] That is the case.

[0384] In one embodiment, the ionized lipid is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or its stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts.

[0385] In one embodiment, the ionized lipid is [ka] , or its stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts.

[0386] In one embodiment, the ionized lipid is [ka] [ka] [ka] , or its stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts.

[0387] A description of ionized lipids and their preparation processes can be found in CN115850104 A, which is incorporated herein by reference in its entirety.

[0388] In one embodiment, the ionized lipid is DODAP, DODMA, DLinDMA, DLin-KC2-DMA, DLin-MC3-DMA, SM-102, or ALC-0315, or a combination thereof, or a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

[0389] In one embodiment, the ionized lipid is compound 46 of the following formula: [ka] or its stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts.

[0390] In one embodiment, the ionized lipid is compound 132 of the following formula: [ka] or its stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts.

[0391] In one embodiment, the ionized lipid is [ka] or its stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts.

[0392] In one embodiment, the amount of ionized lipids is about 20 mol% to about 80 mol% of the total lipids present in the lipid nanoparticles. In one embodiment, the amount of ionized lipids is about 20 mol% to about 55 mol% of the total lipids present in the lipid nanoparticles. In one embodiment, the amount of ionized lipids is about 20 mol% to about 30 mol% of the total lipids present in the lipid nanoparticles.

[0393] In one embodiment, the amount of ionized lipids is approximately 50 mol% of the total lipids present in the lipid nanoparticles. In one embodiment, the amount of ionized lipids is 50 mol%. In one embodiment, the amount of ionized lipids is approximately 47.5 mol% of the total lipids present in the lipid nanoparticles. In one embodiment, the amount of ionized lipids is 47.5 mol%. In one embodiment, the amount of ionized lipids is approximately 46.3 mol%. In one embodiment, the amount of ionized lipids is 46.3 mol%. In one embodiment, the amount of ionized lipids is approximately 32 mol%. In one embodiment, the amount of ionized lipids is 32 mol%. In one embodiment, the amount of ionized lipids is approximately 24 mol%. In one embodiment, the amount of ionized lipids is 24 mol%. In one embodiment, the amount of ionized lipids is approximately 23.8 mol% of the total lipids present in the lipid nanoparticles. In one embodiment, the amount of ionized lipids is 23.8 mol%. 5.2.3 Phospholipids

[0394] As used herein, phospholipids refer to amphiphilic lipids having a negatively charged phosphate group and one or more hydrophobic moieties. Phospholipids may aggregate into one or more lipid bilayers. Phospholipids consist of two fatty acid tails (hydrophobic moieties) and a phosphate group head, linked via glycerol, and may be naturally occurring or synthetic. Non-limiting examples of phospholipids include soy lecithin, egg yolk lecithin, phosphatidylglycerol, phosphatidylinositol, phosphatidylethanolamine, phosphatidic acid, sphingomyelin, diphosphatidylglycerol, phosphatidylserine, phosphatidylcholine, dimyristoylphosphatidylcholine, dimyristoylphosphatidylglycerol, distearoylphosphatidylglycerol, dipalmitoylphosphatidylcholine, and hydrogenated or partially hydrogenated lecithin. In some embodiments, the phospholipid is phosphatidic acid (DMPA, DPPA, DSPA), phosphatidylcholine (DDPC, DLPC, DMPC, DPPC, DSPC, DOPC, POPC, DEPC), phosphatidylglycerol (DMPG, DPPG, DSPG, POPG), phosphatidylethanolamine (DMPE, DPPE, DSPE, DOPE), or phosphatidylserine (DOPS). The phospholipid may be a natural phospholipid, a non-natural phospholipid, or a synthetic phospholipid. The phospholipid may be modified or functionalized by various chemical reactions, such as conjugation with an azide group by binding to an alkyne. The phospholipid may be functionalized for targeting or imaging purposes.

[0395] In one embodiment, the lipid nanoparticles contain a phospholipid. In one embodiment, the phospholipid is distearoylphosphatidylcholine (DSPC). In one embodiment, the phospholipid is dioleoylphosphatidylethanolamine (DOPE). In one embodiment, the phospholipid is dimyristoylphosphatidylcholine (DMPC). In one embodiment, the phospholipid is 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC). In one embodiment, the phospholipid is dipalmitoylphosphatidylcholine (DPPC). In one embodiment, the phospholipid is 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC). In one embodiment, the phospholipid is 1,2-dimiristoyl-sn-glycero-3-phosphoethanolamine (DMPE). In one embodiment, the phospholipid is 1,2-dihexadecanoyl-sn-glycero-3-phosphoethanolamine (DPPE). In one embodiment, the phospholipid is dipalmitoylphosphatidylcholine (DPPC). In another embodiment, the phospholipid is hexadecanoyl-2-(9Z-octadecanoyl)-sn-glycero-3-phosphoethanolamine (POPE).

[0396] In one embodiment, the lipid nanoparticles either do not contain phospholipids, or contain phospholipids in an amount of about 50 mol%, about 40 mol%, about 30 mol%, about 20 mol%, about 15 mol%, about 10 mol%, or less than about 5 mol% of the total lipids present in the lipid nanoparticles.

[0397] In one embodiment, the amount of phospholipids is about 15 mol% of the total lipids present in the lipid nanoparticles. In one embodiment, the amount of phospholipids is about 15 mol% of the total lipids present in the lipid nanoparticles. In one embodiment, the amount of phospholipids is about 10 mol% of the total lipids present in the lipid nanoparticles. In one embodiment, the amount of phospholipids is about 9.4 mol% of the total lipids present in the lipid nanoparticles. In one embodiment, the amount of phospholipids is about 9.4 mol% of the total lipids present in the lipid nanoparticles. In one embodiment, the amount of phospholipids is about 7.5 mol% of the total lipids present in the lipid nanoparticles. In one embodiment, the amount of phospholipids is about 5 mol% of the total lipids present in the lipid nanoparticles. In one embodiment, the amount of phospholipids is about 5 mol% of the total lipids present in the lipid nanoparticles.

[0398] In one embodiment, the lipid nanoparticles are essentially phospholipid-free. In one embodiment, the lipid nanoparticles are phospholipid-free. In one embodiment, the lipid nanoparticles contain less than about 5 mol% of the total lipids present in the lipid nanoparticles. In one embodiment, the lipid nanoparticles contain about 4 mol% of the total lipids present in the lipid nanoparticles. In one embodiment, the lipid nanoparticles contain less than about 3 mol% of the total lipids present in the lipid nanoparticles. In one embodiment, the lipid nanoparticles contain about 3 mol% of the total lipids present in the lipid nanoparticles. In one embodiment, the lipid nanoparticles contain about 2 mol% of the total lipids present in the lipid nanoparticles. In one embodiment, the lipid nanoparticles contain about 1 mol% of the total lipids present in the lipid nanoparticles. In one embodiment, the lipid nanoparticles contain about 0.5 mol% of the total lipids present in the lipid nanoparticles. In one embodiment, the lipid nanoparticles contain about 0 mol% of the total lipids present in the lipid nanoparticles. 5.2.4 Structured lipids

[0399] In one embodiment, the lipid nanoparticles further comprise structural lipids. Unless otherwise specified, the structural lipids are neutral lipids different from the steroid compounds described in Section 5.2.1. In one embodiment, the structural lipids do not contain cationic groups. In one embodiment, the structural lipids do not contain tertiary amine groups or quaternary ammonium groups.

[0400] In one embodiment, the structural lipid is a sterol. In one embodiment, the structural lipid is a neutral sterol. In one embodiment, the structural lipid is cholesterol. In a specific embodiment, the structural lipid is a cholesterol analog. In one embodiment, the structural lipid is sitosterol or β-sitosterol. In one embodiment, the structural lipid is coprosterol. In one embodiment, the structural lipid is fucosterol. In one embodiment, the structural lipid is brassicasterol. In one embodiment, the structural lipid is ergosterol. In one embodiment, the structural lipid is tomatine. In one embodiment, the structural lipid is ursolic acid. In one embodiment, the structural lipid is α-tocopherol. In one embodiment, the structural lipid is stigmasterol. In one embodiment, the structural lipid is avenasterol. In one embodiment, the structural lipid is campesterol. In one embodiment, the structural lipid is solanine.

[0401] In one embodiment, the amount of the structural lipid is about 3 mol% to about 80 mol%, about 5 mol% to about 60 mol%, or about 10 mol% to about 60 mol% of the total lipids present in the lipid nanoparticles.

[0402] In one embodiment, the amount of structural lipids is about 5 mol% to about 60 mol% of the total lipids present in the lipid nanoparticles. In one embodiment, the amount of structural lipids is about 10 mol% to about 75 mol% of the total lipids present in the lipid nanoparticles. In one embodiment, the amount of structural lipids is about 10 mol% to about 50 mol%. In one embodiment, the amount of structural lipids is about 10 mol% to about 40 mol%. In one embodiment, the amount of structural lipids is about 20 mol% to about 30 mol%. In one embodiment, the amount of structural lipids is about 5 mol%, about 10 mol%, about 15 mol%, about 20 mol%, about 25 mol%, about 30 mol%, about 35 mol%, about 40 mol%, about 45 mol%, about 50 mol%, or about 55 mol%, about 60 mol%, about 65 mol%, about 70 mol%, or about 75 mol%.

[0403] In one embodiment, the amount of structural lipids is approximately 75 mol%. In one embodiment, the amount of structural lipids is 75 mol%. In one embodiment, the amount of structural lipids is approximately 45.5 mol%. In one embodiment, the amount of structural lipids is 45.5 mol%. In one embodiment, the amount of structural lipids is approximately 42.7 mol%. In one embodiment, the amount of structural lipids is 42.7 mol%. In one embodiment, the amount of structural lipids is approximately 38.5 mol%. In one embodiment, the amount of structural lipids is 38.5 mol%. In one embodiment, the amount of structural lipids is approximately 25 mol%. In one embodiment, the amount of structural lipids is 25 mol%. In one embodiment, the amount of structural lipids is approximately 17.8 mol%. In one embodiment, the amount of structural lipids is 17.8 mol%. In one embodiment, the amount of structural lipids is approximately 17 mol%. In one embodiment, the amount of structural lipids is 17 mol%. In one embodiment, the amount of structural lipids is approximately 14.2 mol%. In one embodiment, the amount of structural lipids is 14.2 mol%. In one embodiment, the amount of structural lipids is approximately 12.8 mol%. In one embodiment, the amount of ionized lipids is 12.8 mol%. In one embodiment, the amount of structural lipids is approximately 7.5 mol%. In one embodiment, the amount of structural lipids is 7.5 mol%.

[0404] In one embodiment, the Specified Information provides lipid nanoparticles comprising a steroid compound (e.g., Section 5.2.1), an ionized lipid (e.g., Section 5.2.2), and cholesterol. 5.2.5 Polymer-conjugated lipids

[0405] In one embodiment, the lipid nanoparticles include polymer-conjugated lipids. In one embodiment, the polymer-conjugated lipids are PEGylated lipids (PEG lipids). In one embodiment, the PEG lipids are diglycerides that also include PEG chains bonded to glycerol groups. In one embodiment, the PEG lipids are one or more C6-C chains bonded to a linker group having PEG chains. 24 Long-chain alkyl or alkenyl group or C6-C 24 These are compounds containing fatty acid groups. Non-limiting examples of PEG lipids include PEG-modified phosphatidylethanolamine and phosphatidic acid, PEG ceramide conjugate, PEG-modified dialkylamine and PEG-modified 1,2-diacyloxypropane-3-amine, PEG-modified diacylglycerol and dialkylglycerol. In one embodiment, PEG-modified distearoylphosphatidylethanolamine or PEG-modified dimyristoyl-sn-glycerol is used. In one embodiment, the PEG modification is measured by the molecular weight of the PEG component of the lipid. In one embodiment, the PEGylated lipid has a molecular weight of about 1,000 Da to about 10,000 Da. In one embodiment, the PEGylated lipid has a molecular weight of about 1,000 Da to about 5,000 Da. In one embodiment, the PEGylated lipid has a molecular weight of about 1,000 Da to about 2,000 Da.

[0406] In one embodiment, the PEGylated lipid is methoxypolyethylene glycol oxy(2000)-N,N-ditetradecylacetamide (ALC-0159). In one embodiment, the PEGylated lipid is 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000 (DMG-PEG2000). In one embodiment, the PEGylated lipid is 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine-polyethylene glycol 1000 (DMPE-PEG1000). In one embodiment, the PEGylated lipid is 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-polyethylene glycol 1000 (DPPE-PEG1000). In one embodiment, the PEGylated lipid is 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-polyethylene glycol 1000 (DSPE-PEG1000). In one embodiment, the PEGylated lipid is 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-polyethylene glycol 1000 (DOPE-PEG1000). In one embodiment, the PEGylated lipid is 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000 (ceramide-PEG2000). In one embodiment, the PEGylated lipid is 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine-polyethylene glycol 2000 (DMPE-PEG2000). In one embodiment, the PEGylated lipid is 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-polyethylene glycol 2000 (DPPE-PEG2000). In one embodiment, the PEGylated lipid is 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-polyethylene glycol 2000 (DSPE-PEG2000). In one embodiment, the PEGylated lipid is 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-(polyethylene glycol 2000)-mannose (DSPE-PEG2000-mannose).In one embodiment, the PEGylated lipid is 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-5000 (ceramide-PEG5000). In one embodiment, the PEGylated lipid is 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-polyethylene glycol 5000 (DSPE-PEG5000). In one embodiment, the PEGylated lipid is 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000 (DSPE-PEG2000amine)].

[0407] In one embodiment, the amount of PEGylated lipids is approximately 0.1 mol% to approximately 7.5 mol%, approximately 0.25 mol% to approximately 2 mol%, approximately 0.25 mol% to approximately 1.5 mol%, or approximately 1 mol% of the total lipids present in the lipid nanoparticles.

[0408] In one embodiment, the amount of PEGylated lipids is about 0.5 mol% of the total lipids present in the lipid nanoparticles. In one embodiment, the amount of PEGylated lipids is 0.5 mol%. In one embodiment, the amount of PEGylated lipids is about 0.05 mol% to about 5 mol% of the total lipids present in the lipid nanoparticles. In one embodiment, the amount of PEGylated lipids is about 0.1 mol% to about 3 mol% of the total lipids present in the lipid nanoparticles. In one embodiment, the amount of PEGylated lipids is about 0.25 mol% to about 2 mol% of the total lipids present in the lipid nanoparticles. In one embodiment, the amount of PEGylated lipids is about 0.5 mol% to about 1.5 mol% of the total lipids present in the lipid nanoparticles. In one embodiment, the amount of PEGylated lipids is about 0.1 mol%, about 0.5 mol%, about 1 mol%, about 1.5 mol%, about 2 mol%, about 2.5 mol%, or about 3 mol% of the total lipids present in the lipid nanoparticles.

[0409] In one embodiment, the amount of PEGylated lipids is about 0.9 mol% of the total lipids present in the lipid nanoparticles. In one embodiment, the amount of PEGylated lipids is 0.9 mol%. In one embodiment, the amount of PEGylated lipids is about 1 mol%. In one embodiment, the amount of PEGylated lipids is 1 mol%. In one embodiment, the amount of PEGylated lipids is about 1.5 mol%. In one embodiment, the amount of PEGylated lipids is 1.5 mol%. In one embodiment, the amount of PEGylated lipids is about 1.6 mol%. In one embodiment, the amount of PEGylated lipids is 1.6 mol%. In one embodiment, the amount of PEGylated lipids is about 2 mol%. In one embodiment, the amount of PEGylated lipids is 2 mol%.

[0410] In one embodiment, the Specified Provisions provide lipid nanoparticles comprising a steroid compound (e.g., Section 5.2.1), an ionized lipid (e.g., Section 5.2.2), cholesterol, and DMG-PEG2000. 5.2.6 Payload

[0411] In one embodiment, the lipid nanoparticles include a payload.

[0412] In one embodiment, the payload is a small molecule.

[0413] In one embodiment, the payload is nucleic acid.

[0414] In one embodiment, the payload includes psychoactive drugs such as anticancer agents, antifungal agents, analgesics, drugs that alter the level of consciousness such as anesthetics and hypnotics, nonsteroidal anti-inflammatory drugs (NSAIDs), anthelmintics, antiacids, antianginic agents, antiarrhythmics, antiasthmatics, antibacterial agents, benign prostatic hyperplasia treatments, anticoagulants, antidepressants, antidiabetic drugs, antiemetics, antiepileptics, antigout drugs, antihypertensives, anti-inflammatory drugs, antimalarial drugs, migraine treatments, antimuscarinic agents, antitumor agents, antiobesity agents, osteoporosis treatments, and antiparkinic agents. These include Son's disease agents, antiproliferative agents, antiparasitic agents, antithyroid agents, antitussives, urinary incontinence treatments, antiviral agents, anxiolytics, appetite suppressants, beta-blockers, cardiac stimulants, chemotherapy agents, cognitive function enhancers, contraceptives, corticosteroids, COX-2 inhibitors, diuretics, erectile dysfunction treatments, expectorants, gastrointestinal agents, histamine receptor antagonists, immunosuppressants, keratolytic agents, lipid regulators, leukotriene inhibitors, macrolides, muscle relaxants, antipsychotics, nutritional supplements, opioid analgesics, protease inhibitors, or sedatives.

[0415] In one embodiment, the payload is a protein. In one embodiment, the payload is a peptide. In one embodiment, the payload is an antibody. In one embodiment, the payload is a monoclonal antibody. In one embodiment, the payload is a bispecific antibody.

[0416] In one embodiment, the payload is an antisense oligonucleotide (ASO). In one embodiment, the ASO contains a naturally occurring nucleoside. In one embodiment, the ASO contains a modified nucleoside. In one embodiment, the ASO can regulate the expression of a target gene by hybridizing to a target nucleic acid, particularly a continuous sequence on the target nucleic acid. In one embodiment, the ASO is single-stranded.

[0417] In one embodiment, the payload is deoxyribonucleic acid (DNA). In one embodiment, the payload is plasmid DNA (pDNA). In one embodiment, the payload is double-stranded DNA (dsDNA). In one embodiment, the payload is single-stranded DNA (ssDNA).

[0418] In one embodiment, the payload is ribonucleic acid (RNA). In one embodiment, the payload is RNA interference (RNAi). In one embodiment, the payload is small interfering RNA (siRNA). In one embodiment, the payload is short hairpin RNA (shRNA). In one embodiment, the payload is antisense RNA (aRNA). In one embodiment, the payload is messenger RNA (mRNA). In one embodiment, the payload is modified messenger RNA (mmRNA). In one embodiment, the payload is long non-coding RNA (lncRNA). In one embodiment, the payload is microRNA (miRNA). In one embodiment, the payload is small activating RNA (saRNA). In one embodiment, the payload is multicoding nucleic acid (MCNA). In one embodiment, the payload is polymer-coding nucleic acid (PCNA). In one embodiment, the payload is any RNA within a ribozyme.

[0419] In one embodiment, the payload is clustered, regularly spaced, short, palindromic repeating (CRISPR)-associated nucleic acids. In one embodiment, the payload is guide RNA (gRNA). In one embodiment, the payload is CRISPR RNA (crRNA). In one embodiment, the payload comprises a first nucleic acid and a second nucleic acid. In one embodiment, the first nucleic acid is messenger RNA. In one embodiment, the second nucleic acid is a single guide RNA. In one embodiment, the first nucleic acid is messenger RNA (mRNA) and the second nucleic acid is a single guide RNA (sgRNA).

[0420] In one embodiment, the ratio (N:P ratio) of (total number of nitrogen atoms in the cationic steroid compound and ionized lipid) to (total number of phosphorus atoms in nucleic acid) is approximately 1:1 to approximately 15:1. In one embodiment, the N:P ratio is approximately 3:1 to approximately 12:1. In one embodiment, the N:P ratio is approximately 3:1 to approximately 8:1. In one embodiment, the N:P ratio is approximately 4:1 to approximately 9:1. In one embodiment, the N:P ratio is approximately 4:1, approximately 5:1, approximately 6:1, approximately 7:1, approximately 8:1, or approximately 9:1. In one embodiment, the N:P ratio is approximately 6:1. In one embodiment, the N:P ratio is 6:1. In one embodiment, the N:P ratio is approximately 8:1. In one embodiment, the N:P ratio is 8:1. In one embodiment, the N:P ratio is approximately 4:1. In one embodiment, the N:P ratio is 4:1. In one embodiment, the N:P ratio is approximately 5.5:1. In one embodiment, the N:P ratio is 5.5:1. In one embodiment, the N:P ratio is approximately 3:1. In one embodiment, the N:P ratio is 3:1.

[0421] In one embodiment, when lipid nanoparticles are administered to a subject, the amount of payload delivered or expressed in the subject's non-liver tissue by the lipid nanoparticles is higher than the amount of payload delivered or expressed in the subject's liver by the lipid nanoparticles. In one embodiment, when lipid nanoparticles are administered to a subject, the amount of payload delivered or expressed in the subject's lungs by the lipid nanoparticles is higher than the amount of payload delivered or expressed in the subject's liver by the lipid nanoparticles.

[0422] In one embodiment, the amount of payload delivered to or expressed in the subject's lungs is higher than the amount of payload delivered to or expressed in the subject's liver. In one embodiment, the amount of payload delivered to or expressed in the subject's lungs is at least twice as high as the amount of payload delivered to or expressed in the subject's liver. In one embodiment, the amount of payload delivered to or expressed in the subject's lungs is at least five times higher than the amount of payload delivered to or expressed in the subject's liver. In one embodiment, the amount of payload delivered to or expressed in the subject's lungs is at least ten times higher than the amount of payload delivered to or expressed in the subject's liver. In one embodiment, the amount of payload delivered to or expressed in the subject's lungs is at least twenty times higher than the amount of payload delivered to or expressed in the subject's liver. In one embodiment, the amount of payload delivered to or expressed in the subject's lungs is at least forty times higher than the amount of payload delivered to or expressed in the subject's liver. In one embodiment, the amount of payload delivered to or expressed in the subject's lungs is at least sixty times higher than the amount of payload delivered to or expressed in the subject's liver. In one embodiment, the amount of payload delivered to or expressed in the subject's lungs is at least 100 times higher than the amount of payload delivered to or expressed in the subject's liver.

[0423] In one embodiment, when lipid nanoparticles containing nucleic acids are administered to a subject, the amount of protein expressed in the subject's lungs by the nucleic acids is higher than the amount of protein expressed in the subject's liver by the nucleic acids. In another embodiment, when lipid nanoparticles containing mRNA are administered to a subject, the amount of protein expressed in the subject's lungs by the mRNA is higher than the amount of protein expressed in the subject's liver by the mRNA.

[0424] In one embodiment, the amount of protein expressed in the subject's lungs is higher than the amount of protein expressed in the subject's liver. In one embodiment, the amount of protein expressed in the subject's lungs is at least twice as high as the amount of protein expressed in the subject's liver. In one embodiment, the amount of protein expressed in the subject's lungs is at least five times higher than the amount of protein expressed in the subject's liver. In one embodiment, the amount of protein expressed in the subject's lungs is at least ten times higher than the amount of protein expressed in the subject's liver. In one embodiment, the amount of protein expressed in the subject's lungs is at least twenty times higher than the amount of protein expressed in the subject's liver. In one embodiment, the amount of protein expressed in the subject's lungs is at least forty times higher than the amount of protein expressed in the subject's liver. In one embodiment, the amount of protein expressed in the subject's lungs is at least sixty times higher than the amount of protein expressed in the subject's liver. In one embodiment, the amount of protein expressed in the subject's lungs is at least one hundred times higher than the amount of protein expressed in the subject's liver. 5.3 Population of lipid nanoparticles

[0425] In one embodiment, this specification provides a group of lipid nanoparticles comprising the lipid nanoparticles described in Section 5.2. In one embodiment, the group of lipid nanoparticles described herein comprises the steroid compounds described in Section 5.2.1 and the ionized lipids described in Section 5.2.2. In one embodiment, the group of lipid nanoparticles described herein comprises the phospholipids described in Section 5.2.3. In one embodiment, the group of lipid nanoparticles described herein does not contain phospholipids. In one embodiment, the group of lipid nanoparticles described herein comprises the structural lipids described in Section 5.2.4. In one embodiment, the group of lipid nanoparticles described herein comprises the polymer-conjugate lipids described in Section 5.2.5. In one embodiment, the group of lipid nanoparticles described herein comprises the payload described in Section 5.2.6.

[0426] In one embodiment, the lipid nanoparticle population has a polydispersity index (PDI) of less than 0.2. In one embodiment, the lipid nanoparticle population has a PDI of less than 0.1. In one embodiment, the lipid nanoparticle population has a PDI of about 0.01, about 0.02, about 0.03, about 0.04, about 0.05, about 0.06, about 0.07, about 0.08, about 0.09, or about 0.10.

[0427] In one embodiment, the lipid nanoparticle population has an apparent acid dissociation constant (pKa) greater than 7. In one embodiment, the lipid nanoparticle population has an apparent pKa of 8 to 13. In one embodiment, the lipid nanoparticle population has an apparent pKa greater than 8. In one embodiment, the lipid nanoparticle population has an apparent pKa greater than 9. In one embodiment, the lipid nanoparticle population has an apparent pKa greater than 10. In one embodiment, the lipid nanoparticle population has an apparent pKa greater than 11. In one embodiment, the lipid nanoparticle population has an apparent pKa greater than 12. In one embodiment, the lipid nanoparticle population has an apparent pKa greater than 13. In one embodiment, the lipid nanoparticle population has an apparent pKa of about 7, about 7.5, about 8, about 8.5, about 9, about 9.5, or 10, about 11, about 12, or about 13.

[0428] In one embodiment, a group of lipid nanoparticles has an apparent pKa of 6 to 7. In one embodiment, a group of lipid nanoparticles has an apparent pKa of about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, and about 7. In one embodiment, a group of lipid nanoparticles has an apparent pKa of less than 6. In one embodiment, a group of lipid nanoparticles has an apparent pKa of 4 to 6.

[0429] In one embodiment, the apparent pKa is measured by 2-(p-toluidino)-6-naphthalenesulfonic acid (TNS) fluorescence spectroscopy. The TNS fluorescence spectroscopy is described in the art, for example, in Jayaraman M, et al., Maximizing the potency of siRNA lipid nanoparticles for hepatic gene silencing in vivo. Angew Chem Int Ed, 2012. 51, 8529-8533, which is incorporated herein by reference. 5.4 Pharmaceutical Compositions

[0430] In one embodiment, this specification provides a pharmaceutical composition comprising lipid nanoparticles as described in Section 5.2 or a group of lipid nanoparticles as described in Section 5.3. In one embodiment, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0431] pharmaceutically acceptable carriers for use in this application include non-toxic carriers, adjuvants, or media that do not impair the pharmacological activity of the compounds formulated together. pharmaceutically acceptable carriers that may be used in the compositions of this disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffers (e.g., phosphates), glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol, and lanolin.

[0432] In one embodiment, the pharmaceutical composition is formulated for oral administration. In one embodiment, the pharmaceutical composition is formulated for intravenous administration. In one embodiment, the pharmaceutical composition is formulated for intramuscular administration. In one embodiment, the pharmaceutical composition is formulated for inhalation administration. In one embodiment, administration is intra-arterial. In one embodiment, administration is intraperitoneal.

[0433] Generally, the pharmaceutical compositions provided herein are administered in effective doses. The actual amount of pharmaceutical composition administered is usually determined by a physician, taking into account relevant circumstances such as the medical condition to be treated or prevented, the chosen route of administration, the actual pharmaceutical composition administered, the individual patient's age, weight and response, and the severity of the patient's symptoms.

[0434] When used to prevent the disorders described herein, the pharmaceutical compositions provided herein are typically administered to subjects at risk of developing such conditions, usually under the advice and supervision of a physician, at the dose levels described above. Subjects at risk of developing specific conditions generally include those with a family history of such conditions, or those identified as particularly susceptible to such conditions through genetic testing or screening.

[0435] The pharmaceutical compositions provided herein may also be administered chronically ("chronic administration"). Chronic administration refers to the administration of a compound or its pharmaceutical composition over a long period of time, such as over periods of 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, or indefinitely, for example, for the remainder of the subject's life. In certain embodiments, chronic administration is performed with the aim of maintaining a constant blood concentration of the compound within a therapeutic window over a long period of time.

[0436] The pharmaceutical compositions of this disclosure may be delivered by a variety of administration methods. For example, in certain embodiments, the pharmaceutical composition may be administered as a bolus to raise the blood concentration of the compound to an effective level. The location of the bolus administration depends on the desired systemic concentration of the active ingredient in the body. For example, intramuscular or subcutaneous bolus administration allows for the slow release of the active ingredient, while direct bolus delivery intravenously (e.g., via IV infusion) can rapidly raise the blood concentration of the active ingredient to an effective level. In other embodiments, the pharmaceutical composition may be administered by continuous infusion, such as IV infusion, to maintain a steady-state concentration of the active ingredient in the subject's body. Furthermore, in yet another embodiment, the pharmaceutical composition may be administered as a bolus first, followed by continuous infusion.

[0437] Compositions for oral administration may take the form of a bulk liquid solution or suspension, or a bulk powder. However, more generally, for the sake of facilitating precise administration, compositions are provided in unit dosage forms. The term "unit dosage form" refers to a physically distinct unit suitable for single administration to human subjects and other mammals, where each unit contains a predetermined amount of active material, calculated to produce the desired therapeutic effect, combined with appropriate pharmaceutical excipients. Typical unit dosage forms include pre-filled and measured ampoules or syringes for liquid compositions, and tablets, capsules, etc., for solid compositions. In such compositions, the active substance is usually a small component (about 0.1 to about 50% by weight, or about 1 to about 40% by weight), with the remainder being various media or excipients and formulation aids useful for forming the desired dosage form.

[0438] Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous medium, as well as buffers, suspending agents and dispersants, colorants, and flavorings. Solid forms may include, for example, binders such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients such as starch or lactose; disintegrants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate; flow enhancers such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; and flavorings such as peppermint, methyl salicylate, or orange flavor.

[0439] The injectable compositions are typically based on sterile saline for injection, phosphate-buffered saline, or other injectable excipients known in the art. As mentioned above, the active ingredient in such compositions is usually a small amount, often about 0.05 to 10% by weight, with the remainder being injectable excipients, etc.

[0440] The components of the oral, injectable, or topical compositions described above are merely representative. Other materials and processing techniques are described in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which are incorporated herein by reference.

[0441] Furthermore, this specification also provides kits (e.g., pharmaceutical packs) containing the pharmaceutical compositions described herein. The kits described herein may include the pharmaceutical compositions and other therapeutic, diagnostic, or preventive agents, as well as first and second containers (e.g., vials, ampoules, bottles, syringes, and / or dispersible packaging or other materials) for containing the pharmaceutical compositions or other therapeutic, diagnostic, or preventive agents. In some embodiments, the kits provided may optionally include a third container, which contains pharmaceutically acceptable excipients for diluting or suspending the nanoparticle compositions and / or other therapeutic, diagnostic, or preventive agents of this disclosure. In some embodiments, the nanoparticle compositions of this application provided in the first container and the other therapeutic, diagnostic, or preventive agents provided in the second container are combined to form a unit dose form. 5.5 Method for preparing or manufacturing lipid nanoparticles

[0442] This specification also states, (i) A step of dissolving a mixture containing lipids described herein in a first solution, wherein the lipid solution is formed in an organic solvent, (ii) The step of dissolving the payload in the second solution to form a payload solution, (iii) A method for producing lipid nanoparticles is also provided, comprising the step of mixing the lipid solution and the payload solution to form the lipid nanoparticles.

[0443] In one embodiment, the organic solvent is a water-miscible organic solvent. In one embodiment, the organic solvent is an alcohol. In one embodiment, the organic solvent is ethanol.

[0444] In one embodiment, the second solution is an aqueous solution. In one embodiment, the second solution is an aqueous solution with a pH of less than 7. In one embodiment, the second solution is an aqueous solution with a pH of 3 to 6. In one embodiment, the second solution is an aqueous solution with a pH of about 3.5, about 4, about 4.5, about 5, about 5.5, or about 6. In one embodiment, the second solution is a sodium acetate buffer solution with a pH of about 4.5. 5.6 Treatment method

[0445] In one embodiment, this specification provides a method for treating or preventing a disease or disorder in a subject. In one embodiment, the method comprises administering a subject to lipid nanoparticles as described in Section 5.2. In one embodiment, the method comprises administering a subject to a population of lipid nanoparticles as described in Section 5.3. In one embodiment, the method comprises administering a subject to a pharmaceutical composition as described in Section 5.4.

[0446] In one embodiment, this specification provides a method for treating or preventing a disease or disorder in a subject, comprising administering to the subject a therapeutically effective amount of lipid nanoparticles comprising (i) a steroid compound (see Section 5.2.1) and (ii) an ionized lipid (5.2.2).

[0447] In one embodiment, the Specified Information provides lipid nanoparticles for use in delivering or expressing a payload in the lungs of a subject, wherein the lipid nanoparticles are administered to the subject via a systemic route, and the lipid nanoparticles comprise an ionized lipid and a steroid compound, and the steroid compound (e.g., the steroid compound of Section 5.2.1) comprises one or more cationic groups.

[0448] In one embodiment, administration is systemic. In one embodiment, administration is intravenous. In one embodiment, administration is intra-arterial. In one embodiment, administration is intraperitoneal. In one embodiment, administration is oral. In one embodiment, administration is intramuscular.

[0449] In one embodiment, a method for treating a lung disease in a subject is provided herein. In one embodiment, a method for treating lung cancer in a subject is provided herein.

[0450] In one embodiment, the Specified herein provides a method for delivering or expressing a payload described in Section 5.2.6 to a subject, comprising administering to the subject a therapeutically effective amount of a population of lipid nanoparticles described in Section 5.2 or Section 5.3.

[0451] In one embodiment, the amount of payload delivered to or expressed in the subject's lungs is higher than the amount of payload delivered to or expressed in the subject's liver. In one embodiment, the amount of payload delivered to or expressed in the subject's lungs is at least twice as high as the amount of payload delivered to or expressed in the subject's liver. In one embodiment, the amount of payload delivered to or expressed in the subject's lungs is at least five times higher than the amount of payload delivered to or expressed in the subject's liver. In one embodiment, the amount of payload delivered to or expressed in the subject's lungs is at least ten times higher than the amount of payload delivered to or expressed in the subject's liver. In one embodiment, the amount of payload delivered to or expressed in the subject's lungs is at least twenty times higher than the amount of payload delivered to or expressed in the subject's liver. In one embodiment, the amount of payload delivered to or expressed in the subject's lungs is at least forty times higher than the amount of payload delivered to or expressed in the subject's liver. In one embodiment, the amount of payload delivered to or expressed in the subject's lungs is at least sixty times higher than the amount of payload delivered to or expressed in the subject's liver. In one embodiment, the amount of payload delivered to or expressed in the subject's lungs is at least 100 times higher than the amount of payload delivered to or expressed in the subject's liver.

[0452] In one embodiment, the amount of protein expressed in the lungs of a subject by LNP-encapsulated mRNA is higher than the amount of protein expressed in the liver of a subject by LNP-encapsulated mRNA. In one embodiment, the amount of protein expressed in the lungs of a subject by LNP-encapsulated mRNA is at least 5 times, at least 10 times, at least 20 times, at least 30 times, at least 40 times, at least 50 times, at least 60 times, at least 70 times, at least 80 times, at least 90 times, or at least 100 times higher than the amount of protein expressed in the liver of a subject by LNP-encapsulated mRNA.

[0453] In one embodiment, the ratio of the amount of payload delivered to or expressed in the lungs of the subject to the amount of payload delivered to or expressed in the liver of the subject (lung / liver ratio) is greater than 1. In one embodiment, the lung / liver ratio is greater than 2. In one embodiment, the lung / liver ratio is greater than 5. In one embodiment, the lung / liver ratio is greater than 10. In one embodiment, the lung / liver ratio is greater than 15. In one embodiment, the lung / liver ratio is greater than 20. In one embodiment, the lung / liver ratio is greater than 25. In one embodiment, the lung / liver ratio is greater than 30. In one embodiment, the lung / liver ratio is greater than 35. In one embodiment, the lung / liver ratio is greater than 40. In one embodiment, the lung / liver ratio is greater than 50. In one embodiment, the lung / liver ratio is greater than 60. In one embodiment, the lung / liver ratio is greater than 70. In one embodiment, the lung / liver ratio is greater than 80. In one embodiment, the lung / liver ratio is greater than 90. In one embodiment, the lung / liver ratio is greater than 100. 6. Examples

[0454] To make the technical solutions of this disclosure clearer and more specific, the disclosure is further described through the following examples. The following examples are intended solely to enable those skilled in the art to understand this application by illustrating specific embodiments of this disclosure, and are not intended to limit the scope of protection of this application. Technical means and methods not specifically described in the specific embodiments of this disclosure are prior art means or methods in the art. Materials, reagents, etc. used in the examples are commercially available unless otherwise specified.

[0455] [Table 1] Example 1.1: Synthesis of Compound 46 [ka]

[0456] Compounds 1-6 (959 mg, 2.8 mmol, 1.0 equivalent) and 3-1 (638 mg, 3.08 mmol, 1.1 equivalent) were dissolved in DMF, and potassium carbonate (1.55 g, 11.2 mmol, 4.0 equivalents) was added to the solution. The mixture was heated at 60°C for 4 hours, then cooled to room temperature and quenched with saturated sodium chloride aqueous solution. The resulting solution was extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was further purified by silica gel column chromatography to obtain compound 3-2 (682 mg).

[0457] Compound 3-2 (324 mg, 0.69 mmol, 1.0 equivalent) was dissolved in 5.0 mL of dichloromethane, and the reaction system was cooled to 0°C in an ice bath. Two drops of DMF were added, and then oxalyl chloride (0.24 mL, 2.8 mmol, 4.0 equivalents) was added dropwise to the reaction solution. After the addition was complete, the ice bath was removed, and the mixture was stirred at room temperature for 1 hour. The solvent was removed using a rotary evaporator to obtain the crude acyl chloride product (309 mg) as an oily substance, which was used directly in the next reaction step.

[0458] Compound 3-3 (407 mg, 1.9 mmol, 3.0 equivalents) was added to a solution of crude acyl chloride (309 mg) dissolved in DCE (3.0 mL), and the reaction mixture was heated to 70°C and allowed to react overnight. The reaction solution was cooled to room temperature, and the solvent was removed using a rotary evaporator to obtain the crude product, which was then purified using a silica gel column to obtain compound 3-4 (325 mg).

[0459] Compounds 3-4 were dissolved in 4.0 mL of methanol, and NaBH4 (28 mg, 0.73 mmol) was added at room temperature. TLC showed the disappearance of the starting material. The mixture was quenched with saturated NaCl aqueous solution, extracted with dichloromethane (×3), combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain crude product 3-5 (260 mg), which was used in the next step without purification.

[0460] Crude compound 3-5 (260 mg, 0.39 mmol, 1.0 equivalent) was dissolved in 5.0 mL of dichloromethane, and compounds 1-10 (77.4 mg, 0.59 mmol, 1.5 equivalent), EDCI (224 mg, 1.17 mmol, 3.0 equivalent), triethylamine (0.16 mL, 1.17 mmol, 3.0 equivalent), and DMAP (48 mg, 0.39 mmol, 1.0 equivalent) were added to the reaction system. The reaction solution was stirred at room temperature for 12 hours. The reaction solution was then quenched by adding saturated sodium chloride solution and extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was collected and concentrated to obtain the crude product, which was subjected to preparative high-performance liquid chromatography to obtain compound 46 (32.6 mg) as an oily product. 1 H NMR (400 MHz, CDCl3): δ ppm 0.88 (t, J = 7.2 Hz, 9H), 1.14 (s, 12H), 1.15-1.28 (m, 37H), 1.47-1.59 (m, 18H), 1.75-1.84 (m, 2H), 2.24-2.35 (m, 10H), 3.95 (d, J = 5.6 Hz, 2H), 4.03 (t, J = 6.8 Hz, 2H), 4.80-4.87 (m, 1H); MS m / z [M+H] + (ESI): 780.7. Example 1.2: Synthesis of Compound 132 [ka]

[0461] 1-nonanol (15 g, 104.0 mmol, 1.0 equivalent), compound 132-1 (25.5 g, 114.0 mmol, 1.1 equivalent), DMAP (2.54 g, 20.8 mmol, 0.2 equivalent), DIEA (40.3 g, 312.0 mmol, 3.0 equivalent), and EDCI (25.9 g, 135 mmol, 1.3 equivalent) were dissolved in 250 mL of DCM at room temperature. The reaction solution was stirred at room temperature for 4 hours, and then quenched with 200 mL of saturated sodium chloride aqueous solution. The resulting solution was extracted with DCM (3 × 100 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was further purified by silica gel column chromatography to obtain 21 g of yellow oily compound 132-2 (682 mg).

[0462] Compound 132-2 (21 g, 60.1 mmol, 1.0 equivalent) and 2-hydroxyethylamine (110 g, 1.80 mol, 30.0 equivalents) were dissolved in 100 mL of methanol at room temperature. The mixture was heated to 60 °C and stirred for 18 hours. The solvent was removed to obtain the crude product. The crude product was dissolved in saturated aqueous ammonium chloride and ethyl acetate, extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and further purified by silica gel column chromatography to obtain a yellow oily compound 132-3 (14 g).

[0463] 9-Heptadecanol (9.8 g, 38.2 mmol, 1.0 equivalent) and triethylamine (15.5 g, 152.8 mmol, 4.0 equivalents) were dissolved in 100 mL of DCM at room temperature. The reaction system was cooled in an ice bath, and isobutyryl chloride (9.8 g, 91.7 mmol, 2.4 equivalents) was gradually added. The resulting solution was stirred overnight at room temperature and then quenched with saturated ammonium chloride aqueous solution. The resulting solution was extracted with DCM, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was further purified by silica gel column chromatography to obtain a yellow oily compound 132-5 (8.7 g).

[0464] Compound 132-5 (8.7 g, 26.6 mmol, 1.0 equivalent) was dissolved in THF, cooled to -45°C, and LDA (13.1 mL, 26.2 mmol, 0.98 equivalents) was slowly added dropwise. The mixture was then stirred for 1 hour, and then 1,6-dibromohexane (9.03 g, 37.0 mmol, 1.39 equivalents) and DMPU (0.48 g, 3.73 mmol, 0.14 equivalents) were added. The reaction solution was stirred overnight at room temperature, then quenched with saturated ammonium chloride aqueous solution. The resulting solution was extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. This was further purified by silica gel column chromatography to obtain the yellow oily compound 132-6 (10.1 g).

[0465] Compound 132-6 (1.48 g, 3.04 mmol, 2.0 equivalents), compound 132-3 (500 mg, 1.52 mmol, 1.0 equivalent), K2CO3 (628.2 mg, 4.55 mmol, 3.0 equivalents), and KI (302.3 mg, 1.82 mmol, 1.2 equivalents) were dissolved in cyclopentyl methyl ether (7.5 mL) and acetonitrile (2.5 mL). The resulting mixture was heated to 80°C. After the reaction was complete, the reaction was quenched with saturated ammonium chloride ice solution and extracted with DCM. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was further purified by silica gel column chromatography to obtain oily compound 132 (96.98 mg). 1 H NMR (400 MHz, CDCl3) δ: 4.86-4.80 (m, 1H), 4.04 (t, J = 7.2 Hz, 2H), 3.57 (m, 2H), 2.62 (t, J = 7.2 Hz, 2H), 2.49 (t, J = 7.2 Hz, 4H), 2.29 (t, J = 7.2 Hz, 2H), 1.62 (m, 4H), 1.51-1.45 (m, 10H), 1.38-1.23 (m, 49H), 1.15 (s, 6H), 0.88 (t, J = 7.2 Hz, 9H); ESI-MS m / z: 738.60 [M+H] + . Example 2: Synthesis of the compound Lys-es-cholesterol [ka]

[0466] Cholesteryl chloroformate 2-1 (1.0 g, 2.2 mmol, 1.0 equivalent) and pyridine (18 μL, 0.22 mmol, 0.1 equivalent) were dissolved in 20 mL of dichloromethane. Then, 1,6-hexanediol 2-2 (1.1 mL, 8.8 mmol, 4.0 equivalents) was added to the reaction mixture and heated at 45°C for 12 hours. After the reaction, the reaction mixture was cooled to room temperature, quenched with saturated sodium chloride solution, extracted with dichloromethane, combined, and dried over anhydrous sodium sulfate. The solution was filtered and dried to obtain the crude product, which was purified by silica gel column chromatography to obtain intermediate compound 2-3 (879 mg).

[0467] Compound 2-4 (0.49 g, 2.0 mmol, 1.0 equivalent), pyridine (0.24 mL, 3.0 mmol, 1.5 equivalents), and DCC (0.62 g, 3.0 mmol, 1.5 equivalents) were dissolved in dichloromethane (20 mL). Then, compound 2-3 (879 mg, 1.7 mmol, 0.85 equivalents) prepared above was added to the reaction mixture. The reaction was carried out at room temperature until complete conversion was observed by TLC. The reaction mixture was quenched with saturated sodium chloride solution, extracted with dichloromethane, and the organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated to obtain the crude product, which was then purified by silica gel column chromatography to obtain intermediate compound 2-5 (641 mg).

[0468] Compound 2-5 (200 mg) was dissolved in a mixture of dichloromethane (4.0 mL) and trifluoroacetic acid (2.0 mL). The mixture was stirred at room temperature until the complete reaction of compound 2-5 was achieved. The organic solvent and trifluoroacetic acid were then removed by rotary evaporation to obtain a solid crude product dispersed in a mixture of methanol and n-hexane. The slurry was then filtered and dried to obtain the final product, Lys-es-cholesterol (62.2 mg).1 H NMR (400 MHz, CD3OD): δ 0.74 (s, 3H), 0.88 (d, J = 6.8 Hz, 6H), 0.90-1.68 (m, 38H), 1.75-2.18 (m, 8H), 2.28-2.38 (m, 2H), 2.96 (t, J = MS m / z [M+H] + (ESI): 659.5. Example 3: Synthesis of the compound Arg-es-cholesterol [ka]

[0469] Compounds 2-5 (200 ...

Claims

1. Lipid nanoparticles comprising an ionized lipid and a steroid compound, wherein the steroid compound is a compound of formula (I): 【Chemistry 1】 or its stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt, in the formula, 【Chemistry 2】 It is either a single bond or a double bond; Y is -C(O)O-, -O-, -NH-, -SC(O)O-, -OC(O)NR ２ａ -, -NR ２ａ C(O)NR ２ａ -, -OC(O)S-, -OC(O)O-, -NR ２ａ C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR ２ａ -, -C(O)NR ２ａ -, -NR ２ａ C(O)-, -NR ２ａ C(O)S-, -SC(O)NR ２ａ -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR ２ａ -, -NR ２ａ C(S)O-, or -S(O) ０－２ -, and the bond to the left is in the direction of V １ ; Y １ It does not exist, or -C(O)O-, -O-, -NH-, -SC(O)O-, -OC(O)NR ２ａ -, -NR ２ａ C(O)NR ２ａ -, -OC(O)S-, -OC(O)O-, -NR ２ａ C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR ２ａ -, -C(O)NR ２ａ -, -NR ２ａ C(O)-, -NR ２ａ C(O)S-, -SC(O)NR ２ａ -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR ２ａ -, -NR ２ａ C(S)O-, or -S(O) ０－２ - and in the formula, the combination to the left is V １ It is oriented in that direction; R ２ａ Each example is independently H, C １－１０ Alkyl, C ３－１４ A cycloalkyl or a 3- to 14-membered heterocycline, where the alkyl, cycloalkyl, and heterocycline are independently C １－１０ Alkyl, L ２ｂ -OR ２ｂ , L ｂ -SR ２ｂ , L ２ｂ -NR ２ｂ R' ２ｂ , L ２ｂ N ＋ R ２ｂ R' ２ｂ R'' ２ｂ , L ２ｂ -OC(O)R ２ｂ , or L ２ｂ -C(O)OR ２ｂ It is optionally replaced by; R ２０１ , R ２０２ , R ２０３ , R ２０４ Each example independently represents H, OH, alkyl, alkoxy, and -L. ２ｂ -NR ２１ R ２２ , -L ２ｂ -N ＋ R ２１ R ２２ R ２３ , L ２ｂ -OC(O)R ２１ , or L ２ｂ -C(O)OR ２１ And; m is an integer between 1 and 12; m1 is an integer between 0 and 12; V １ NR ２１ R ２２ , N ＋ R ２１ R ２２ R ２３ , imidazole, pyridine, pyrrole, pyrrolidine, pyrazole, (iso)thiazole, (iso)oxazole, oxadiazine, oxazoline, dithiourazole, (iso)triazole, tetrazole, pentasol, indole, dihydroindole, pyrimidine, pyrazine, quinazoline, piperazine, piperidine, morpholine, pyran, quinoxaline, quinoline, quinolinone, (iso)quinoline, amidine, guanidine, or urea; M is either absent or independently one or more anions selected from chlorides, bromides, iodides, sulfates, nitrates, perchlorates, formates, citrates, sulfons, methanesulfons, triflates, trifluoroacetates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, pyrophosphates, monohydrogen phosphates, dihydrogen phosphates, acetates, propions, decanoates, caprylates, acrylates, isobutyrates, capronates, heptanoates, oxalates, malons, succinates, fumarates, maleates, benzoates, phthalates, phenylacetates, lactates, glycolates, tartrates, mandelates, mesylates, glucons, aspartates, or glutamates; R ２１ , R ２２ , R ２３ Each example independently involves H, and C, which is optionally substituted. １－８ Alkyl, -L ２ｂ -OR ２ｂ , -L ２ｂ -SR ２ｂ , -L ２ｂ -NR ２ｂ R' ２ｂ R'' ２ｂ , L ２ｂ -OC(O)R ２ｂ , or L ２ｂ -C(O)OR ２ｂ And; L ２ｂ C is either non-existent or optionally replaced. １－１０ It is alkylene; R ２ｂ , R' ２ｂ , and R'' ２ｂ each example of which is, independently, H or C １－１０ alkyl; R ｚ１ C １－１４ Alkyl or C １－１４ It is an alkenyl, where the alkyl and alkenyl are optionally substituted; However, if Y is -NHC(O)-, (i) m is an integer between 5 and 12; or (ii) V １ is not N(CH ３ ) ２ ​ At least one of the following conditions is met: Lipid nanoparticles.

2. Lipid nanoparticles comprising an ionized lipid and a steroid compound, wherein the steroid compound is a compound of formula (I-P): 【Transformation 3】 or its stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt, in the formula, 【Chemistry 4】 It is either a single bond or a double bond; Y １ It does not exist, or -C(O)O-, -O-, -NH-, -SC(O)O-, -OC(O)NR ２ａ -, -NR ２ａ C(O)NR ２ａ -, -OC(O)S-, -OC(O)O-, -NR ２ａ C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR ２ａ -, -C(O)NR ２ａ -, -NR ２ａ C(O)-, -NR ２ａ C(O)S-, -SC(O)NR ２ａ -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR ２ａ -, -NR ２ａ C(S)O-, -S(O) ０－２ - or -OPO ３ - and in the formula, the combination to the left is V １ It is oriented in that direction; R ２ａ Each example is independently H, C １－１０ Alkyl, C ３－１４ A cycloalkyl or a 3- to 14-membered heterocycline, where the alkyl, cycloalkyl, and heterocycline are independently C １－１０ Alkyl, L ２ｂ -OR ２ｂ , L ｂ -SR ２ｂ , L ２ｂ -NR ２ｂ R' ２ｂ , L ２ｂ N ＋ R ２ｂ R' ２ｂ R'' ２ｂ , L ２ｂ -OC(O)R ２ｂ , or L ２ｂ -C(O)OR ２ｂ It is optionally replaced by; R ２０１ , R ２０２ , R ２０３ , R ２０４ Each example independently represents H, OH, alkyl, alkoxy, and -L. ２ｂ -NR ２１ R ２２ , -L ２ｂ -N ＋ R ２１ R ２２ R ２３ , L ２ｂ -OC(O)R ２１ , or L ２ｂ -C(O)OR ２１ And; R ２０５ is either absent, or a cation, H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, or C2-6 alkynyl, where alkyl, haloalkyl, alkenyl, and alkynyl are optionally substituted; m is an integer between 1 and 12; m1 is an integer between 0 and 12; V １ NR ２１ R ２２ , N ＋ R ２１ R ２２ R ２３ , imidazole, pyridine, pyrrole, pyrrolidine, pyrazole, (iso)thiazole, (iso)oxazole, oxadiazine, oxazoline, dithiourazole, (iso)triazole, tetrazole, pentasol, indole, dihydroindole, pyrimidine, pyrazine, quinazoline, piperazine, piperidine, morpholine, pyran, quinoxaline, quinoline, quinolinone, (iso)quinoline, amidine, guanidine, or urea; M is either absent or independently one or more anions selected from chlorides, bromides, iodides, sulfates, nitrates, perchlorates, formates, citrates, sulfons, methanesulfons, triflates, trifluoroacetates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, pyrophosphates, monohydrogen phosphates, dihydrogen phosphates, acetates, propions, decanoates, caprylates, acrylates, isobutyrates, capronates, heptanoates, oxalates, malons, succinates, fumarates, maleates, benzoates, phthalates, phenylacetates, lactates, glycolates, tartrates, mandelates, mesylates, glucons, aspartates, or glutamates; R ２１ , R ２２ , R ２３ Each example independently involves H, and C, which is optionally substituted. １－８ Alkyl, -L ２ｂ -OR ２ｂ , -L ２ｂ -SR ２ｂ , -L ２ｂ -NR ２ｂ R' ２ｂ R'' ２ｂ , L ２ｂ -OC(O)R ２ｂ , or L ２ｂ -C(O)OR ２ｂ And; L ２ｂ C is either non-existent or optionally replaced. １－１０ It is alkylene; R ２ｂ , R' ２ｂ , and R'' ２ｂ Each of these examples is independently H or C １－１０ It is alkyl; R ｚ１ C １－１４ Alkyl or C １－１４ It is an alkenyl, where the alkyl and alkenyl are optionally substituted. Lipid nanoparticles.

3. Y is -C(O)O-, -OC(O)-, -O-, -NHC(O)O-, -NCH ３ The formulas are -C(O)O-, -OC(O)NH-, or -OC(O)O-, where the bond on the left side is V. １ Lipid nanoparticles according to claim 1, which are oriented in the direction of [the specified direction].

4. Y １ It does not exist, or -C(O)O-, -OC(O)-, -O-, -S-, SO, S(O) ２ The compounds are -O(CO)O-, -NHC(O)-, or -C(O)NH-, and in the formula, the bond on the left side is V １ Lipid nanoparticles according to any one of claims 1 to 3, which are oriented in the direction of.

5. The steroid compound is a compound of formula (I-A1), (I-A2), (I-A3), (I-A4), or (I-A5): 【Transformation 5】 , or its stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts, Lipid nanoparticles according to claim 1.

6. The steroid compound is a compound of formula (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-B7), or (I-B8): 【Transformation 6】 , or its stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt, where m3 is an integer from 1 to 11. Lipid nanoparticles according to claim 5.

7. R ２０１ , R ２０２ , R ２０３ , and R ２０４ Each example is independently H, C １－６ Alkyl, -NR ２１ R ２２ , -N ＋ R ２１ R ２２ R ２３ ,-(CH ２ ) ０－６ -OC(O)R ２１ , or - (CH ２ ) ０－６ -C(O)OR ２１ Lipid nanoparticles according to any one of claims 1 to 6.

8. R ２０１ , R ２０２ , R ２０３ , and R ２０４ Each example is independently H, NH ２ NH ３ ＋ ien-CH ２ OC(O)CH ３ ien-CH ２ C(O)OCH ３ -OC(O)CH ３ , -CO(O)OCH ３ , or -CH ２ CO ２ The lipid nanoparticles according to claim 7, wherein H.

9. Lipid nanoparticles according to any one of claims 1 to 8, wherein m is an integer from 5 to 12.

10. The aforementioned steroid compound is a compound of formula (I-P1): 【Transformation 7】 or its stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt, where m3 is an integer from 1 to 11. Lipid nanoparticles according to claim 2.

11. V １ NR ２１ R ２２ , N ＋ R ２１ R ２２ R ２３ Lipid nanoparticles according to any one of claims 1 to 10, which are, or optionally substituted radicals of amidine, guanidine, or urea.

12. R ２１ , R ２２ , R ２３ These are H, hydroxyl, and C, respectively, independently. １－３ Alkyl, or C １－３ Lipid nanoparticles according to any one of claims 1 to 11, wherein the nanoparticle is a hydroxyalkyl group.

13. V １ NH ２ NH ３ ＋ , N (CH ３ ) ２ , N ＋ (CH ３ ) ３ , N ＋ CH ３ (CH ２ CH ２ OH) ２ , N ＋ (CH ３ ) ２ (CH ２ CH ２ OH), NHC (=N ＋ H2) NH ２ NHC(O)NH ２ ,CH ２ C(=NH)NH ２ , N (CH ３ ) (CH ２ CH ２ CO ２ CH ３ ), N ＋ (CH ３ ) ２ (CH ２ CH ２ CO ２ CH ３ ), N (CH ３ ) (CH ２ CO ２ CH ３ ), or N ＋ (CH ３ ) ２ (CH ２ CO ２ CH ３ Lipid nanoparticles according to any one of claims 1 to 12, wherein the lipid nanoparticles are as described in claim 1 to 12.

14. V １ is, N ＋ CH ３ (CH ２ CH ２ OH) ２ , N ＋ (CH ３ ) ２ (CH ２ CH ２ OH), or N ＋ (CH ３ ) ３ The lipid nanoparticles according to claim 13.

15. Lipid nanoparticles according to any one of claims 1 to 14, wherein M is absent or one or more of bromide, chloride, iodide, or trifluoroacetate.

16. R ｚ１ C １－１４ Alkyl or C １－１４ Alkenyl, where the alkyl and alkenyl are one or more hydroxyl, oxo, nitro, cyano, halogen, C １－６ Alkoxy, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C ３ -C ８ Cycloalkyl, C ６ -C １０ Lipid nanoparticles according to any one of claims 1 to 15, which are optionally substituted with an aryl, a 5- to 10-membered heteroaryl, or a 3- to 8-membered heterocycline.

17. R ｚ１ C ６－１２ Alkyl or C ６－１２ The lipid nanoparticle according to claim 16, wherein the alkyl and alkenyl are optionally substituted with one or more hydroxyl, oxo, or halogen atoms.

18. R ｚ１ teeth, 【Transformation 8】 The lipid nanoparticles according to claim 17.

19. Lipid nanoparticles comprising an ionized lipid and a steroid compound, wherein the steroid compound is 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 or its stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt, Lipid nanoparticles.

20. Lipid nanoparticles for use in delivering or expressing a payload in the lungs of a subject, wherein the lipid nanoparticles are administered to the subject via a systemic route, and the lipid nanoparticles comprise an ionized lipid and a steroid compound, and the steroid compound comprises one or more cationic groups.

21. The lipid nanoparticles according to claim 20, wherein the systemic administration route is intravenous, intra-arterial, or intraperitoneal administration.

22. The lipid nanoparticle according to claim 20 or 21, wherein the cationic group is a tertiary amine, a quaternary ammonium, a primary amine, ammonium, imidazole, pyridine, pyrrole, pyrrolidine, pyrazole, (iso)thiazole, (iso)oxazole, oxadiazine, oxazoline, dithiourazole, (iso)triazole, tetrazole, pentasol, indole, dihydroindole, pyrimidine, pyrazine, quinazoline, piperazine, piperidine, morpholine, pyran, quinoxaline, quinoline, quinolinone, (iso)quinoline, amidine, guanidine, or urea.

23. The aforementioned steroid compound is Z １ Including the portion and the Z １ teeth, [Chemistry 18] or its stereoisomer or mixture thereof, where Z １ In Z, one or more cyclic C-C bonds can be independently and optionally replaced by C=C bonds, as long as the valence allows. １ These are hydroxyl, halogen, and C １－１４ Alkyl or C １－１４ The alkyl group is optionally substituted with one or more groups selected from alkenyl groups, wherein the alkyl group is one or more hydroxyl, nitro, cyano, halogen, or C groups. １－６ Alkoxy, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C ３ -C ８ Cycloalkyl, C ６ -C １０ Optionally substituted with aryl, 5-10 membered heteroaryl, or 3-8 membered heterocyclyl, and Z １ The binding in this case is directed towards the remainder of the steroid compound. Lipid nanoparticles according to any one of claims 20 to 22.

24. Said Z １ The lipid nanoparticles according to any one of claims 20 to 23, wherein the portion is cholesterol, cholestane, campesterol, sitosterol, sitostanol, β-sitosterol, stigmasterol, stigmastanol, brassicasterol, avenasterol, ergosterol, ursolic acid, tocopherol, lumisterol monovalent radical, or a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

25. The steroid compound is a compound of formula (I): 【Chemistry 19】 or its stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt, in the formula, 【Chemistry 20】 It is either a single bond or a double bond; Y is -C(O)O-, -O-, -NH-, -SC(O)O-, -OC(O)NR ２ａ -, -NR ２ａ C(O)NR ２ａ -, -OC(O)S-, -OC(O)O-, -NR ２ａ C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR ２ａ -, -C(O)NR ２ａ -, -NR ２ａ C(O)-, -NR ２ａ C(O)S-, -SC(O)NR ２ａ -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR ２ａ -, -NR ２ａ C(S)O-, or -S(O) ０－２ - and in the formula, the combination to the left is V １ It is oriented in that direction; Y １ It does not exist, or -C(O)O-, -O-, -NH-, -SC(O)O-, -OC(O)NR ２ａ -, -NR ２ａ C(O)NR ２ａ -, -OC(O)S-, -OC(O)O-, -NR ２ａ C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR ２ａ -, -C(O)NR ２ａ -, -NR ２ａ C(O)-, -NR ２ａ C(O)S-, -SC(O)NR ２ａ -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR ２ａ -, -NR ２ａ C(S)O-, or -S(O) ０－２ - and in the formula, the combination to the left is V １ It is oriented in that direction; R ２ａ Each example is independently H, C １－１０ Alkyl, C ３－１４ A cycloalkyl or a 3- to 14-membered heterocycline, where the alkyl, cycloalkyl, and heterocycline are independently C １－１０ Alkyl, L ２ｂ -OR ２ｂ , L ｂ -SR ２ｂ , L ２ｂ -NR ２ｂ R' ２ｂ , L ２ｂ N ＋ R ２ｂ R' ２ｂ R'' ２ｂ , L ２ｂ -OC(O)R ２ｂ , or L ２ｂ -C(O)OR ２ｂ It is optionally replaced by; R ２０１ , R ２０２ , R ２０３ , R ２０４ Each example independently represents H, OH, alkyl, alkoxy, and -L. ２ｂ -NR ２１ R ２２ , -L ２ｂ -N ＋ R ２１ R ２２ R ２３ , L ２ｂ -OC(O)R ２１ , or L ２ｂ -C(O)OR ２１ And; m is an integer between 1 and 12; m1 is an integer between 0 and 12; V １ NR ２１ R ２２ , N ＋ R ２１ R ２２ R ２３ , imidazole, pyridine, pyrrole, pyrrolidine, pyrazole, (iso)thiazole, (iso)oxazole, oxadiazine, oxazoline, dithiourazole, (iso)triazole, tetrazole, pentasol, indole, dihydroindole, pyrimidine, pyrazine, quinazoline, piperazine, piperidine, morpholine, pyran, quinoxaline, quinoline, quinolinone, (iso)quinoline, amidine, guanidine, or urea; M is either absent or independently one or more anions selected from chlorides, bromides, iodides, sulfates, nitrates, perchlorates, formates, citrates, sulfons, methanesulfons, triflates, trifluoroacetates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, pyrophosphates, monohydrogen phosphates, dihydrogen phosphates, acetates, propions, decanoates, caprylates, acrylates, isobutyrates, capronates, heptanoates, oxalates, malons, succinates, fumarates, maleates, benzoates, phthalates, phenylacetates, lactates, glycolates, tartrates, mandelates, mesylates, glucons, aspartates, or glutamates; R ２１ , R ２２ , R ２３ Each example independently involves H, and C, which is optionally substituted. １－８ Alkyl, -L ２ｂ -OR ２ｂ , -L ２ｂ -SR ２ｂ , -L ２ｂ -NR ２ｂ R' ２ｂ R'' ２ｂ , L ２ｂ -OC(O)R ２ｂ , or L ２ｂ -C(O)OR ２ｂ And; L ２ｂ C is either non-existent or optionally replaced. １－１０ It is alkylene; R ２ｂ , R' ２ｂ , and R'' ２ｂ Each of these examples is independently H or C １－１０ It is alkyl; R ｚ１ C １－１４ Alkyl or C １－１４ It is an alkenyl, where the alkyl and alkenyl are optionally substituted. Lipid nanoparticles according to any one of claims 20 to 24.

26. The aforementioned steroid compound is a compound of formula (I-P): 【Chemistry 21】 or its stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt, in the formula, 【Chemistry 22】 It is either a single bond or a double bond; Y １ It does not exist, or -C(O)O-, -O-, -NH-, -SC(O)O-, -OC(O)NR ２ａ -, -NR ２ａ C(O)NR ２ａ -, -OC(O)S-, -OC(O)O-, -NR ２ａ C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR ２ａ -, -C(O)NR ２ａ -, -NR ２ａ C(O)-, -NR ２ａ C(O)S-, -SC(O)NR ２ａ -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR ２ａ -, -NR ２ａ C(S)O-, -S(O) ０－２ - or -OPO ３ - and in the formula, the combination to the left is V １ It is oriented in that direction; R ２ａ Each example is independently H, C １－１０ Alkyl, C ３－１４ A cycloalkyl or a 3- to 14-membered heterocycline, where the alkyl, cycloalkyl, and heterocycline are independently C １－１０ Alkyl, L ２ｂ -OR ２ｂ , L ｂ -SR ２ｂ , L ２ｂ -NR ２ｂ R' ２ｂ , L ２ｂ N ＋ R ２ｂ R' ２ｂ R'' ２ｂ , L ２ｂ -OC(O)R ２ｂ , or L ２ｂ -C(O)OR ２ｂ It is optionally replaced by; R ２０１ , R ２０２ , R ２０３ , R ２０４ Each example independently represents H, OH, alkyl, alkoxy, and -L. ２ｂ -NR ２１ R ２２ , -L ２ｂ -N ＋ R ２１ R ２２ R ２３ , L ２ｂ -OC(O)R ２１ , or L ２ｂ -C(O)OR ２１ And; R ２０５ is either absent, or a cation, H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, or C2-6 alkynyl, where alkyl, haloalkyl, alkenyl, and alkynyl are optionally substituted; m is an integer between 1 and 12; m1 is an integer between 0 and 12; V １ NR ２１ R ２２ , N ＋ R ２１ R ２２ R ２３ , imidazole, pyridine, pyrrole, pyrrolidine, pyrazole, (iso)thiazole, (iso)oxazole, oxadiazine, oxazoline, dithiourazole, (iso)triazole, tetrazole, pentasol, indole, dihydroindole, pyrimidine, pyrazine, quinazoline, piperazine, piperidine, morpholine, pyran, quinoxaline, quinoline, quinolinone, (iso)quinoline, amidine, guanidine, or urea; M is either absent or independently one or more anions selected from chlorides, bromides, iodides, sulfates, nitrates, perchlorates, formates, citrates, sulfons, methanesulfons, triflates, trifluoroacetates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, pyrophosphates, monohydrogen phosphates, dihydrogen phosphates, acetates, propions, decanoates, caprylates, acrylates, isobutyrates, capronates, heptanoates, oxalates, malons, succinates, fumarates, maleates, benzoates, phthalates, phenylacetates, lactates, glycolates, tartrates, mandelates, mesylates, glucons, aspartates, or glutamates; R ２１ , R ２２ , R ２３ Each example independently involves H, and C, which is optionally substituted. １－８ Alkyl, -L ２ｂ -OR ２ｂ , -L ２ｂ -SR ２ｂ , -L ２ｂ -NR ２ｂ R' ２ｂ R'' ２ｂ , L ２ｂ -OC(O)R ２ｂ , or L ２ｂ -C(O)OR ２ｂ And; L ２ｂ C is either non-existent or optionally replaced. １－１０ It is alkylene; R ２ｂ , R' ２ｂ , and R'' ２ｂ Each of these examples is independently H or C １－１０ It is alkyl; R ｚ１ C １－１４ Alkyl or C １－１４ It is an alkenyl, where the alkyl and alkenyl are optionally substituted. Lipid nanoparticles according to any one of claims 20 to 24.

27. The lipid nanoparticles according to any one of claims 1 to 26, wherein the amount of the steroid compound is about 15 mol% to about 80 mol%, about 20 mol% to about 60 mol%, about 20 mol% to about 50 mol%, about 20 mol% to about 40 mol%, or about 15 mol% to about 30 mol% of the total lipids present in the lipid nanoparticles.

28. The lipid nanoparticles according to claim 27, wherein the amount of the steroid compound is about 20 mol% to about 30 mol% of the total lipids present in the lipid nanoparticles.

29. The ionized lipid comprises at least one ionizable head group and at least one biodegradable hydrophobic chain, where, The ionized lipid has at least about 10.1 logP and about 4 to about 11 pKa; and The aforementioned biodegradable hydrophobic chain is, formula -R １６ -M ０ -R １７ It has; in the formula, R １６ C ４ - １４ Alkylene, C ４ - １４ Alkenylene, or C ４ - １４ It is alkynylene; R １７ C ６ - ２０ Alkyl; M ０ is a biodegradable group, and the alkylene, alkenylene, alkylylene, and alkyl are optionally substituted. Lipid nanoparticles according to any one of claims 1 to 28.

30. M ０ The lipid nanoparticles according to claim 29, wherein is an ester group, an amide group, a thioester group, a carbonate group, a carbamate group, a carbamothioester group, a urea group, or a disulfide group.

31. The ionized lipid is a compound of formula (III): 【Chemistry 23】 or its stereoisomer, mixture of stereoisomers, tautomers, isotopic molecular species, or pharmaceutically acceptable salt, in the formula, R ３ and R ４ Each example is independent of C １－１０ Alkyl, C ２－１０ Alkenil, C ２－１０ Alkinyl, C ３ -C １４ Cycloalkyl, 3-14 member heterocyclyl, (C １－１０ Alkylene) - (C ３ -C １４ Cycloalkyl), or (C １－１０ Alkilen)-(3-14 member heterocycline), or R ３ and R ４ They form 3- to 14-membered heterocyclines together with the nitrogen atoms to which they are bonded, or R ４ and R ０ One of them, together with the atoms connecting them, forms a 4-10 membered heterocycline or a 5-10 membered heteroaryl, where the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycline, heteroaryl, and alkylene are independently one or more R ＊ It is optionally replaced by; R ０ Each example of ' is independently and optionally substituted methylene or two R ０ ', together with the carbons to which they are bonded, form a 3- to 8-membered cycloalkylene, where the cycloalkylene is one or more R ＊＊ It is optionally replaced by; k is 0, 1, 2, 3, 4, 5, or 6; j is either 0 or 1; The dashed line connecting Q and W is either nonexistent or a combination; W is C, CH, or N, except when W is N, then j is 0, and there is no dashed connection between Q and W; G ５ It does not exist, or C １－２４ Alkylene, C ２－２４ Alkenylene, C ３ -C ８ Cycloalkylene, C ３ -C ８ It is a cycloalkenylene, where the alkylene, alkenylene, cycloalkylene, and cycloalkenylene are one or more R ＊＊ It is optionally replaced by; G １ G ２ G ３ and G ４ These are, independently, non-existent, or C １－１３ Alkylene, C ２－１３ Alkenylene, or C ２－１３ Alkynylene, where the alkylene, alkenylene, and alkynylene are one or more R ｓ It is optionally replaced by; G １ and G ２ It has the full length of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 carbon atoms; G ３ and G ４ It has the full length of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 carbon atoms; R ５ , R ６ , R ７ and R ８ Each of these is independently of hydrogen or optionally substituted C １－８ It is alkyl; If there is no dashed line connecting Q and W, then Q either does not exist, or it is -C(O)O-, -O-, -NH-, -SC(O)O-, -OC(O)NR ｂ -, -NR ｂ C(O)NR ｂ -, -OC(O)S-, -OC(O)O-, -NR ｂ C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR ｂ -, -C(O)NR ｂ -, -NR ｂ C(O)-, -NR ｂ C(O)S-, -SC(O)NR ｂ -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR ｂ -, -NR ｂ C(S)O-, -S-S-, or -S(O) ０－２ - and in the equation, the bond to the right is directed in the direction of W; If the dashed line connecting Q and W is a connection, then G ５ There are no R members present, and Q and W form a 5-10 membered monoring or fused ring, and optionally the ring has one or more R members. ＊＊ Replaced by; M １ and M ２ These are either nonexistent, or -C(O)O-, -O-, -SC(O)O-, -OC(O)NR ａ -, -NR ａ C(O)NR ａ -, -OC(O)S-, -OC(O)O-, -NR ａ C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR ａ -, -C(O)NR ａ -, -NR ａ C(O)-, -NR ａ C(O)S-, -SC(O)NR ａ -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR ａ -, -NR ａ C(S)O-, -S-S-, or -S(O) ０－２ - and; R ０ Each example is independently -(CRR')-; Examples R and R' are independently H, C １－２０ Alkyl, L ａ -OR ａ , -L ａ -SR ａ , or -L ａ -NR ａ R' ａ Either R and R' are, together with the carbon to which they are bonded, C ３－８ Forms cycloalkylene; Q ３ and Q ４ These are H, -(CRR')-, and C, respectively, independently. ６－１０ It is an aryl or steroid part; A １ A ２ A ３ A ４ Each example is independent of -(CR １８ R １８ -CR １８ =CR １８ ) - or - (CR １８ R １８ -C≡C)- and; R １８ Each of these examples is independently H or C １－２０ It is alkyl; N １ and N ２ Each of these examples is independently a biodegradable group; Z does not exist, or C １－１０ It is an alkylene, or -O-P(O)(OH)-O-; Z-Q ３ Or Z-Q ４ The dashed lines between them are either independent, nonexistent, or combined, except that if Z does not exist, neither dashed line exists; m, n, q, r, u, v, y, and z are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; o, p, w, and x are independently 0, 1, or 2; s and t are independently either 0 or 1; G １ and Q ３ During, or G ３ and Q ４ The number of carbon atoms between them is 8 to 30; L ａ and L ｅ Each of these is independent, either nonexistent or C １－２０ It is alkylene; L ｂ and L ｆ Each of these is independent, either nonexistent or C １－１０ It is alkylene; L ｃ It does not exist, or C １－８ It is alkylene; L ｄ It does not exist, or C １－１４ It is alkylene; R ＊ is hydroxyl, halogen, C １－１０ Alkyl, C １－１０ Haloalkyl, C １－１０ Hydroxyalkyl, -L ｂ -OR ｂ , -L ｂ -SR ｂ , or -L ｂ -NR ｂ R' ｂ And; R ＊＊ is hydroxyl, halogen, C １－８ Alkyl, C １－８ Haloalkyl, C １－８ Hydroxyalkyl, -L ｂ -OR ｂ , -L ｂ -SR ｂ , or -L ｂ -NR ｂ R' ｂ And; R ｓ C １－１４ Alkyl, -L ｂ -OR ｂ , -L ｂ -SR ｂ , or -L ｂ -NR ｂ R' ｂ And; R ａ and R' ａ These are H and C, which are independent of each other. １－２０ Alkyl, C ３－１４ The alkyl, cycloalkyl, and heterocyclyl are hydroxyl, halogen, and C. １－２０ Alkyl, -L ｅ -OR ｅ , -L ｅ -SR ｅ , or -L ｅ -NR ｅ R' ｅ Optionally substituted with one or more elements selected from; R ｂ and R' ｂ These are H and C, which are independent of each other. １－１０ Alkyl, C ３－１４ The alkyl, cycloalkyl, and heterocyclyl are hydroxyl, halogen, and C. １－１０ Alkyl, -L ｆ -OR ｆ , -L ｆ -SR ｆ , or -L ｆ -NR ｆ R' ｆ Optionally substituted with one or more elements selected from; R ｃ and R' ｃ Each of them independently consists of hydrogen or C １－８ It is alkyl; R ｄ and R' ｄ Each of them independently consists of hydrogen or C １－１４ It is alkyl; R ｅ and R' ｅ Each of them independently consists of hydrogen or C １－２０ It is alkyl; R ｆ and R' ｆ Each of them independently consists of hydrogen or C １－１０ It is alkyl. Lipid nanoparticles according to any one of claims 1 to 28.

32. The aforementioned ionized lipid is a compound of formula (IV'): 【Chemistry 24】 or its stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt, in the formula, j is either 0 or 1; W is either CH or N, except when W is N, then j is 0; k is 0, 1, 2, 3, 4, 5, 6, 7, or 8; R ０ Each example of ' is independently and optionally substituted methylene or two R ０ ', together with the carbons to which they are bonded, form a 3- to 8-membered cycloalkylene, where the cycloalkylene is one or more R ＊＊ It is optionally replaced by; M １ and M ２ These are independently -C(O)O-, -O-, -SC(O)O-, and -OC(O)NR ａ -, -NR ａ C(O)NR ａ -, -OC(O)S-, -OC(O)O-, -NR ａ C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR ａ -, -C(O)NR ａ -, -NR ａ C(O)-, -NR ａ C(O)S-, -SC(O)NR ａ -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR ａ -, -NR ａ C(S)O-, -S-S-, or -S(O) ０－２ - and; Q does not exist, or -C(O)O-, -O-, -SC(O)O-, -OC(O)NR ｂ -, -NR ｂ C(O)NR ｂ -, -OC(O)S-, -OC(O)O-, -NR ｂ C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR ｂ -, -C(O)NR ｂ -, -NR ｂ C(O)-, -NR ｂ C(O)S-, -SC(O)NR ｂ -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR ｂ -, -NR ｂ C(S)O-, -S-S-, or -S(O) ０－２ - and; R ａ and R ｂ These are H and C, which are independent of each other. １－２０ Alkyl, C ３－１４ The alkyl, cycloalkyl, and heterocyclyl are hydroxyl, halogen, and C. １－２０ Alkyl, -L ｅ -OR ｅ , -L ｅ -SR ｅ , or -L ｅ -NR ｅ R' ｅ Optionally substituted with one or more elements selected from; G ５ C is either non-existent or optionally replaced. １－８ It is alkylene; R １ and R ２ Each of them is independent of C ４－２０ Alkyl, C ４－２０ Alkenyl, or C ４－２０ It is alkinyl, R １ and R ２ One or more methylene units in this case are independently -NH- or -N(C) １－２０ The alkyl, alkenyl, and alkynyl are optionally substituted; R ３ and R ４ Each example is independently H, C １－１０ Alkyl, C ２－１０ Alkenil, C ２－１０ Alkinyl, C ３ -C １４ It is either a cycloalkyl or a 3- to 14-membered heterocycline, or R ３ and R ４ They form a 3- to 14-membered heterocycline together with the N atom to which they are bonded, or R ４ and R ０ One of them, together with the atoms connecting them, forms a 4- to 10-membered heterocycline, where the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycline is one or more R ＊ It is optionally replaced by; R ５ , R ６ , R ７ and R ８ Each of these is independently of hydrogen or optionally substituted C １－８ It is alkyl. Lipid nanoparticles according to claim 31.

33. The ionized lipid is a compound of formula (V'), (VI'), or (VII'): 【Chemistry 25】 or its stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt, in the formula, k is 0, 1, 2, 3, 4, or 5; L １ and L ２ These are, independently, -(CRR') ２ -, -CH=CH-, -C≡C-, or -NR''-; L ３ and L ５ One of them is -(CR ｓ R ｓ ') ２ -, -CH=CH-, or -C≡C-, and the other does not exist; L ４ and L ６ One of them is -(CR ｓ R ｓ ') ２ -, -CH=CH-, or -C≡C-, and the other does not exist; G １ａ G １ｂ G ２ａ G ２ｂ G ３ａ G ３ｂ G ４ａ , and G ４ｂ Each of these is either non-existent or optionally replaced by C. １－７ It is alkylene; G １ａ G １ｂ G ２ａ , and G ２ｂ It has the full length of 1, 2, 3, 4, 5, 6, or 7 carbon atoms; G ３ａ G ３ｂ G ４ａ , and G ４ｂ It has the full length of 1, 2, 3, 4, 5, 6, or 7 carbon atoms; R ５ , R ６ , R ７ and R ８ Each of these is independently of hydrogen or optionally substituted C １－６ It is alkyl; G ７ G ８ G ９ , and G １０ Each of these is either non-existent or optionally replaced by C. １－１２ It is alkylene, however, G ７ and G ８ It has a total length of 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms, G ９ and G １０ It has the full length of 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms; R ｓ and R ｓ ' are H and C, respectively, independently. １－１０ Alkyl, -L ｄ -OR ｄ , or -L ｄ -NR ｄ R' ｄ And; R' is H, C １－１４ Alkyl, -L ａ -OR ａ , or -L ａ -NR ａ R' ａ And; R'' is H or C １－１４ It is alkyl; L ｄ It does not exist, or C １－１０ It is alkylene; L ａ It does not exist, or C １－１４ It is alkylene; R ａ and R' ａ These are H and C, which are independent of each other. １－１４ Alkyl, C ３－１０ The alkyl, cycloalkyl, or 3- to 10-membered heterocyclyl is optionally substituted; R ｄ and R' ｄ These are, independently, H or C １－１０ It is alkyl; a' and b are independently 0, 1, 3, 4, and 5, respectively, except that at least one of a' and b is not 0; g is 0, 1, 2, 3, 4, or 5; a' + g is 0, 1, 2, 3, 4, or 5; c, d, e, and f are independently 0, 1, 2, 3, 4, 5, 6, or 7, where c + d is an integer between 2 and 9, and e + f is an integer between 2 and 9. Lipid nanoparticles according to claim 32.

34. The ionized lipid is a compound of formula (VIII): 【Chemistry 26】 or its stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt, Lipid nanoparticles according to claim 31 or 32.

35. R ５ , R ６ , R ７ , and R ８ The lipid nanoparticles according to claim 34, wherein each is independently hydrogen or methyl.

36. G １ G ２ G ３ , and G ４ Each of these is independent, either nonexistent or C １－８ Lipid nanoparticles according to claim 34 or 35, wherein the nanoparticles are alkylenes.

37. The aforementioned ionized lipid is a compound of formula (IX): 【Chemistry 27】 or its stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt, in the formula, G １ and G ２ Each is independent, combined, C １－１３ Linear alkylene, C ２－１３ Linear alkenylenes, or C ２－１３ A linear alkylene, where the alkylene, alkenylene, and alkylene are one or more R Ｇ１ It is optionally replaced by; G １ and G ２ It has the full length of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 carbon atoms; R Ｇ１ Each example is independent of C １－１４ Alkyl, -L ａ -OR ａ , -L ａ -SR ａ , or -L ａ -NR ａ R' ａ And; G ３ C ４－１４ Linear alkylene, C ４－１４ Linear alkenylenes, or C ４－１４ A linear alkylene, where the alkylene, alkenylene, and alkylene are one or more R Ｇ３ It is optionally replaced by; R Ｇ３ Each of these examples is independent of H, -L ａ -OR ａ , -L ａ -SR ａ , or -L ａ -NR ａ R' ａ And; L ａ These are, independently, combined or C １－１４ It is alkylene; R ａ and R' ａ These are H and C, which are independent of each other. １－１４ Alkyl, C ３－１４ It is a cycloalkyl or a 3- to 14-membered heterocycline; G ４ C １－６ Alkylene, C ２－６ Alkenylene, or C ２－６ Alkynylene, where the alkylene, alkenylene, and alkynylene are one or more R Ｇ４ It is optionally replaced by; R Ｇ４ Each example is independently H, C １－６ Alkyl, -L ｂ -OR ｂ , -L ｂ -SR ｂ , or -L ｂ -NR ｂ R' ｂ And; L ｂ is, independently, a bond or C １－６ alkylene; R ｂ and R' ｂ H and C are independent of each other. １－６ Alkyl, C ３－１０ It is a cycloalkyl or a 3- to 10-membered heterocycline; or two Rs Ｇ４ together with the same carbon atom to which they are attached form a C ３－１４ cycloalkylene or 3- to 14-membered heterocyclylene, where said cycloalkylene and heterocyclylene are optionally substituted by one or more Rs ４ｇ ; R ４ｇ Each example independently involves halogen, cyano, and C. １－８ Alkyl, C １－８ Haloalkyl, -L ｅ -OR ｅ , -L ｅ -SR ｅ , or -L ｅ -NR ｅ R' ｅ And; L ｅ These are, independently, combined or C １－８ It is alkylene; R ｅ and R' ｅ H and C are independent of each other. １－８ Alkyl, C ３－１４ It is a cycloalkyl or a 3- to 14-membered heterocycline; M １ and M ２ These are, independently, -C(O)O-, -OC(O)-, -O-, -SC(O)O-, -OC(O)NR-, -NRC(O)NR-, -OC(O)S-, -OC(O)O-, -NRC(O)O-, -SC(O)-, -C(O)S-, -NR-, -C(O)NR-, -NRC(O)-, -NRC(O)S-, -SC(O)NR-, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR-, -NRC(S)O-, -S-S-, or -S(O) ０－２ - and; Q represents the bond -C(O)O-, -O-, -SC(O)O-, -OC(O)NR ｆ -, -NR ｆ C(O)NR ｆ -, -OC(O)S-, -OC(O)O-, -NR ｆ C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR ｆ -, -C(O)NR ｆ -, -NR ｆ C(O)-, -NR ｆ C(O)S-, -SC(O)NR ｆ -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR ｆ -, -NR ｆ C(S)O-, -S-S-, -S(O) ０－２ -, phenylene, or pyridylidene, where the phenylene and pyridylidene are one or more R ＊ It is optionally replaced by; R ＊ These are, independently, halogen, cyano, and C １－１０ Alkyl, C １－１０ Haloalkyl, -L ｆ -OR ｆ , -L ｆ -SR ｆ , or -L ｆ -NR ｆ R' ｆ And; L ｆ These are, independently, combined or C １－８ It is alkylene; R ｆ and R' ｆ H and C are independent of each other. １－１０ Alkyl, C ３－１４ It is a cycloalkyl or a 3- to 14-membered heterocycline; R １ and R ２ Independently, C ４－２０ Alkyl, C ４－２０ Alkenyl, or C ４－２０ It is an alkynyl, and the alkyl, alkenyl, or alkynyl is one or more R １ｓ The units are optionally replaced by -NR'-, where one or more methylene units are optionally and independently replaced by -NR'-; R １ｓ is independently H, C １－２０ alkyl, -L ｃ -OR ｃ -L ｃ -SR ｃ or -L ｃ -NR ｃ R' ｃ wherein; R and R' are each independently H or C １－２０ It is alkyl; L ｃ These are, independently, combined or C １－２０ It is alkylene; R ｃ and R' ｃ These are H and C, which are independent of each other. １－２０ Alkyl, C ３－１４ It is a cycloalkyl or a 3- to 14-membered heterocycline; R ３ -CN, -OR ｇ , -C(O)R ｇ , -OC(O)R ｇ , -NR''C(O)R ｇ , -NR ｇ R' ｇ , -NR''C(O)NR ｇ R' ｇ , -NR''C(O)R ｇ , -NR''S(O) ２ R ｇ , -OC(O)NR ｇ R' ｇ , -NR''C(O)OR ｇ , -N(OR ｇ ) C(O)R ｇ , -N(OR ｇ ) S(O) ２ R ｇ , -N(OR ｇ ) C(O)OR ｇ , -N(OR ｇ ) C(O)R ｇ R' ｇ , optionally substituted 3- to 14-membered heterocyclyls, or optionally substituted 5- to 14-membered heteroaryls; R ｇ and R' ｇ These are H and C, which are independent of each other. １－１０ Alkyl, C ３－１０ It is a cycloalkyl or a 3- to 10-membered heterocycline; R'' is independently H or C １－６ It is alkyl; R ５ and R ６ Independently, C １－８ It is an alkyl group, where the alkyl group is one or more R ４ｓ It is optionally replaced by; or R ５ and R ６ C ３－１４ It forms a cycloalkylene or a 3- to 14-membered heterocyclene, where the cycloalkylene and heterocyclene are one or more R ４ｓ It is optionally replaced by; R ４ｓ Each example independently represents H, halogen, cyano, and C. １－８ Alkyl, C １－８ Haloalkyl, -L ｄ -OR ｄ , -L ｄ -SR ｄ , or -L ｄ -NR ｄ R' ｄ And; L ｄ These are, independently, combined or C １－８ It is alkylene; R ｄ and R' ｄ H and C are independent of each other. １－８ Alkyl, C ３－１４ It is a cycloalkyl or a 3- to 14-membered heterocycline. Lipid nanoparticles according to any one of claims 1 to 28.

38. The aforementioned ionized lipid is a compound of formula (X): 【Chemistry 28】 or its stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt, in the formula, a is 1, 2, 3, 4, 5, or 6; b is 4, 5, 6, 7, 8, 9, or 10; c is 1, 2, 3, 4, 5, or 6; d is 0, 1, 2, 3, or 4; c + d is 3, 4, 5, 6, 7, 8, or 9. Lipid nanoparticles according to claim 37.

39. The aforementioned ionized lipid is 【Chemistry 29】 【Transformation 30】 【Chemistry 31】 【Chemistry 32】 【Transformation 33】 【Transformation 34】 【Chemistry 35】 【Transformation 36】 【Chemistry 37】 or its stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt, Lipid nanoparticles according to any one of claims 1 to 28.

40. The aforementioned ionized lipid is 【Transformation 38】 【Chemistry 39】 or selected from the group consisting of stereoisomers thereof, mixtures of stereoisomers, or pharmaceutically acceptable salts, Lipid nanoparticles according to claim 37 or 38.

41. The aforementioned ionized lipid is 【Chemistry 40】 【Chemistry 41】 【Chemistry 42】 【Chemistry 43】 or selected from the group consisting of stereoisomers thereof, mixtures of stereoisomers, or pharmaceutically acceptable salts, Lipid nanoparticles according to claim 37 or 38.

42. The lipid nanoparticle according to any one of claims 1 to 28, wherein the ionized lipid is DODAP, DODMA, DLinDMA, DLin-KC2-DMA, DLin-MC3-DMA, SM-102, or ALC-0315, or a combination thereof, or a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

43. The lipid nanoparticles according to any one of claims 1 to 42, wherein the amount of the ionized lipid is about 20 mol% to about 80 mol% of the total lipids present in the lipid nanoparticles.

44. The lipid nanoparticles according to claim 43, wherein the amount of the ionized lipid is about 20 mol% to about 55 mol% of the total lipids present in the lipid nanoparticles.

45. Lipid nanoparticles according to any one of claims 1 to 44, further comprising phospholipids.

46. The lipid nanoparticle according to claim 45, wherein the phospholipid is DSPC, DMPC, DOPC, DPPC, POPPC, DOPE, DMPE, POPOE, or DPPE.

47. The lipid nanoparticles according to any one of claims 1 to 46, wherein the lipid nanoparticles do not contain phospholipids, or contain phospholipids in an amount of about 50 mol%, about 40 mol%, about 30 mol%, about 20 mol%, about 10 mol%, or less than about 5 mol% of the total lipids present in the lipid nanoparticles.

48. Lipid nanoparticles according to any one of claims 1 to 47, further comprising structural lipids.

49. The lipid nanoparticles according to claim 48, wherein the structural lipid is selected from the group consisting of cholesterol, campesterol, stigmasterol, sitosterol, brassicasterol, ergosterol, solanine, ursolic acid, α-tocopherol, β-sitosterol, avenasterol, and canolasterol.

50. The lipid nanoparticles according to claim 48 or 49, wherein the amount of the structural lipid is about 3 mol% to about 80 mol%, about 5 mol% to about 60 mol%, or about 10 mol% to about 60 mol% of the total lipids present in the lipid nanoparticles.

51. Lipid nanoparticles according to any one of claims 1 to 50, further comprising polymer-conjugated lipids.

52. The lipid nanoparticle according to claim 51, wherein the polymer conjugate lipid is a PEG-modified lipid.

53. The lipid nanoparticle according to claim 52, wherein the PEGylated lipid includes a PEGylated portion having a molecular weight of about 1,000 Da to about 20,000 Da, about 1,000 Da to about 5,000 Da, or about 1,000 Da to about 2,000 Da.

54. The lipid nanoparticle according to any one of claims 51 to 53, wherein the polymer conjugate lipid is ALC-0159, DMG-PEG2000, DMPE-PEG1000, DPPE-PEG1000, DSPE-PEG1000, DOPE-PEG1000, ceramide-PEG2000, DMPE-PEG2000, DPPE-PEG2000, DSPE-PEG2000, DSPE-PEG2000-mannose, ceramide-PEG5000, DSPE-PEG5000, or DSPE-PEG2000 amine.

55. The lipid nanoparticles according to any one of claims 51 to 54, wherein the amount of the polymer conjugate lipid is about 0.1 mol% to about 7.5 mol%, about 0.25 mol% to about 2 mol%, about 0.25 mol% to about 1.5 mol%, or about 1 mol% of the total lipid present in the lipid nanoparticles.

56. The lipid nanoparticles according to any one of claims 1 to 55, wherein the lipid nanoparticles include a payload, wherein the payload is a therapeutic agent, a preventive agent, or a diagnostic agent.

57. The lipid nanoparticles according to claim 56, wherein the payload is nucleic acid.

58. The lipid nanoparticle according to claim 57, wherein the nucleic acid is an antisense oligonucleotide (ASO), DNA, or RNA, and optionally, the RNA is RNA interference (RNAi), small interfering RNA (siRNA), short hairpin RNA (shRNA), antisense RNA (aRNA), messenger RNA (mRNA), modified messenger RNA (mmRNA), long non-coding RNA (lncRNA), microRNA (miRNA), small activating RNA (saRNA), multicoding nucleic acid (MCNA), polymer-coded nucleic acid (PCNA), guide RNA (gRNA), CRISPR RNA (crRNA), or any other RNA in a ribozyme.

59. Lipid nanoparticles according to claim 57 or 58, wherein the ratio of the total number of nitrogen atoms in the steroid compound and the ionized lipid to the total number of phosphates in the nucleic acid is about 1:1 to about 20:1, about 1:1 to about 20:1, about 2:1 to about 10:1, or about 4:1 to about 8:

1.

60. The lipid nanoparticles according to any one of claims 1 to 59, wherein the lipid nanoparticles have an apparent pKa of about 7, about 8, about 9, about 10, about 7 to about 10, or about 10.

61. The lipid nanoparticles according to any one of claims 56 to 60, wherein when the lipid nanoparticles containing the payload are administered systemically to a subject, the amount of the payload delivered or expressed in the lungs of the subject is higher than the amount of the payload delivered or expressed in the liver of the subject.

62. The lipid nanoparticle according to claim 61, wherein the amount of payload delivered or expressed in the lungs of the subject is at least 2 times, at least 5 times, at least 10 times, at least 20 times, at least 40 times, at least 60 times, or at least 100 times higher than the amount of payload delivered or expressed in the liver of the subject.

63. A group of lipid nanoparticles comprising the lipid nanoparticles described in any one of claims 1 to 62.

64. A pharmaceutical composition comprising lipid nanoparticles according to any one of claims 1 to 62 or a group of lipid nanoparticles according to claim 63, and a pharmaceutically acceptable carrier.

65. A method for treating or preventing a lung disease in a subject having a lung disease, comprising administering to the subject a therapeutically effective amount of lipid nanoparticles according to any one of claims 1 to 62, a group of lipid nanoparticles according to claim 63, or a pharmaceutical composition according to claim 64.

66. A method for preparing lipid nanoparticles according to any one of claims 1 to 62 or a group of lipid nanoparticles according to claim 63, (i) A step of dissolving a mixture containing lipids in a first solution, wherein the lipid solution is formed in an organic solvent, (ii) The step of dissolving the payload in the second solution to form a payload solution, (iii) The step of mixing the lipid solution and the payload solution to form the lipid nanoparticles, method.

67. The method according to claim 66, wherein the mixing is performed using a microfluidizer system.

68. Steroid compounds of formula (II-A): 【Chemistry 44】 or its stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt, wherein the formula, 【Chemistry 45】 These are independently single or double bonds; Y is -C(O)O-, -O-, -NH-, -SC(O)O-, -OC(O)NR ２ａ -, -NR ２ａ C(O)NR ２ａ -, -OC(O)S-, -OC(O)O-, -NR ２ａ C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR ２ａ -, -C(O)NR ２ａ -, -NR ２ａ C(O)-, -NR ２ａ C(O)S-, -SC(O)NR ２ａ -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR ２ａ -, -NR ２ａ C(S)O-, or -S(O) ０－２ - and in the formula, the combination to the left is V １ It is oriented in that direction; Y １ It does not exist, or -C(O)O-, -O-, -NH-, -SC(O)O-, -OC(O)NR ２ａ -, -NR ２ａ C(O)NR ２ａ -, -OC(O)S-, -OC(O)O-, -NR ２ａ C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR ２ａ -, -C(O)NR ２ａ -, -NR ２ａ C(O)-, -NR ２ａ C(O)S-, -SC(O)NR ２ａ -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR ２ａ -, -NR ２ａ C(S)O-, or -S(O) ０－２ - and in the formula, the combination to the left is V １ It is oriented in that direction; R ２ａ Each example is independently H, C １－１０ Alkyl, C ３－１４ A cycloalkyl or a 3- to 14-membered heterocycline, where the alkyl, cycloalkyl, and heterocycline are independently C １－１０ Alkyl, L ２ｂ -OR ２ｂ , L ｂ -SR ２ｂ , L ２ｂ -NR ２ｂ R' ２ｂ , L ２ｂ N ＋ R ２ｂ R' ２ｂ R'' ２ｂ , L ２ｂ -OC(O)R ２ｂ , or L ２ｂ -C(O)OR ２ｂ It is optionally replaced by; R ２０１ , R ２０２ , R ２０３ , R ２０４ Each example independently represents H, OH, alkyl, alkoxy, and -L. ２ｂ -NR ２１ R ２２ , or -L ２ｂ -N ＋ R ２１ R ２２ R ２３ , L ２ｂ -OC(O)R ２１ , or L ２ｂ -C(O)OR ２１ And; m is an integer between 3 and 12; m1 is an integer between 0 and 12; V １ NR ２１ R ２２ , N ＋ R ２１ R ２２ R ２３ , imidazole, pyridine, pyrrole, pyrrolidine, pyrazole, (iso)thiazole, (iso)oxazole, oxadiazine, oxazoline, dithiourazole, (iso)triazole, tetrazole, pentasol, indole, dihydroindole, pyrimidine, pyrazine, quinazoline, piperazine, piperidine, morpholine, pyran, quinoxaline, quinoline, quinolinone, (iso)quinoline, amidine, guanidine, or urea; M is either absent or independently one or more anions selected from chlorides, bromides, iodides, sulfates, nitrates, perchlorates, formates, citrates, sulfons, methanesulfons, triflates, trifluoroacetates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, pyrophosphates, monohydrogen phosphates, dihydrogen phosphates, acetates, propions, decanoates, caprylates, acrylates, isobutyrates, capronates, heptanoates, oxalates, malons, succinates, fumarates, maleates, benzoates, phthalates, phenylacetates, lactates, glycolates, tartrates, mandelates, mesylates, glucons, aspartates, or glutamates; R ２１ , R ２２ , R ２３ Each example independently involves H, and C, which is optionally substituted. １－８ Alkyl, -L ２ｂ -OR ２ｂ , -L ２ｂ -SR ２ｂ , -L ２ｂ -NR ２ｂ R' ２ｂ R'' ２ｂ , L ２ｂ -OC(O)R ２ｂ , or L ２ｂ -C(O)OR ２ｂ And; L ２ｂ C is either non-existent or optionally replaced. １－１０ It is alkylene; R ２ｂ , R' ２ｂ , and R'' ２ｂ These are, independently, H or C １－１０ It is alkyl; R ｚ１ C １－１４ Alkyl or C １－１４ The compound is an alkenyl, where the alkyl and alkenyl are optionally substituted; however, the compound is 【Chemistry 46】 isn't it, Steroid compounds, or their stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts.

69. Steroid compounds of formula (I-P): 【Chemistry 47】 or its stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt, wherein the formula, 【Chemistry 48】 It is either a single bond or a double bond; Y １ It does not exist, or -C(O)O-, -O-, -NH-, -SC(O)O-, -OC(O)NR ２ａ -, -NR ２ａ C(O)NR ２ａ -, -OC(O)S-, -OC(O)O-, -NR ２ａ C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR ２ａ -, -C(O)NR ２ａ -, -NR ２ａ C(O)-, -NR ２ａ C(O)S-, -SC(O)NR ２ａ -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR ２ａ -, -NR ２ａ C(S)O-, -S(O) ０－２ - or -OPO ３ - and in the formula, the combination to the left is V １ It is oriented in that direction; R ２ａ Each example is independently H, C １－１０ Alkyl, C ３－１４ A cycloalkyl or a 3- to 14-membered heterocycline, where the alkyl, cycloalkyl, and heterocycline are independently C １－１０ Alkyl, L ２ｂ -OR ２ｂ , L ｂ -SR ２ｂ , L ２ｂ -NR ２ｂ R' ２ｂ , L ２ｂ N ＋ R ２ｂ R' ２ｂ R'' ２ｂ , L ２ｂ -OC(O)R ２ｂ , or L ２ｂ -C(O)OR ２ｂ It is optionally replaced by; R ２０１ , R ２０２ , R ２０３ , R ２０４ Each example independently represents H, OH, alkyl, alkoxy, and -L. ２ｂ -NR ２１ R ２２ , -L ２ｂ -N ＋ R ２１ R ２２ R ２３ , L ２ｂ -OC(O)R ２１ , or L ２ｂ -C(O)OR ２１ And; R ２０５ is either absent, or a cation, H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, or C2-6 alkynyl, where alkyl, haloalkyl, alkenyl, and alkynyl are optionally substituted; m is an integer between 1 and 12; m1 is an integer between 0 and 12; V １ NR ２１ R ２２ , N ＋ R ２１ R ２２ R ２３ , imidazole, pyridine, pyrrole, pyrrolidine, pyrazole, (iso)thiazole, (iso)oxazole, oxadiazine, oxazoline, dithiourazole, (iso)triazole, tetrazole, pentasol, indole, dihydroindole, pyrimidine, pyrazine, quinazoline, piperazine, piperidine, morpholine, pyran, quinoxaline, quinoline, quinolinone, (iso)quinoline, amidine, guanidine, or urea; M is either absent or independently one or more anions selected from chlorides, bromides, iodides, sulfates, nitrates, perchlorates, formates, citrates, sulfons, methanesulfons, triflates, trifluoroacetates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, pyrophosphates, monohydrogen phosphates, dihydrogen phosphates, acetates, propions, decanoates, caprylates, acrylates, isobutyrates, capronates, heptanoates, oxalates, malons, succinates, fumarates, maleates, benzoates, phthalates, phenylacetates, lactates, glycolates, tartrates, mandelates, mesylates, glucons, aspartates, or glutamates; R ２１ , R ２２ , R ２３ Each example independently involves H, and C, which is optionally substituted. １－８ Alkyl, -L ２ｂ -OR ２ｂ , -L ２ｂ -SR ２ｂ , -L ２ｂ -NR ２ｂ R' ２ｂ R'' ２ｂ , L ２ｂ -OC(O)R ２ｂ , or L ２ｂ -C(O)OR ２ｂ And; L ２ｂ C is either non-existent or optionally replaced. １－１０ It is alkylene; R ２ｂ , R' ２ｂ , and R'' ２ｂ Each of these examples is independently H or C １－１０ It is alkyl; R ｚ１ C １－１４ Alkyl or C １－１４ It is an alkenyl, where the alkyl and alkenyl are optionally substituted. Steroid compounds, or their stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts.

70. The aforementioned steroid compound, 【Chemistry 49】 [Transformation 50] 【Chemistry 51】 or its stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt, The steroid compound according to claim 68 or 69.

71. Steroid compounds of formula (II-B): 【Chemistry 52】 or its stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt, wherein the formula, Y is -C(O)O-, -O-, -NH-, -SC(O)O-, -OC(O)NR ２ａ -, -NR ２ａ C(O)NR ２ａ -, -OC(O)S-, -OC(O)O-, -NR ２ａ C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR ２ａ -, -C(O)NR ２ａ -, -NR ２ａ C(O)-, -NR ２ａ C(O)S-, -SC(O)NR ２ａ -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR ２ａ -, -NR ２ａ C(S)O-, or -S(O) ０－２ - and in the formula, the combination to the left is V １ It is oriented in that direction; Y １ It does not exist, or -C(O)O-, -O-, -NH-, -SC(O)O-, -OC(O)NR ２ａ -, -NR ２ａ C(O)NR ２ａ -, -OC(O)S-, -OC(O)O-, -NR ２ａ C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR ２ａ -, -C(O)NR ２ａ -, -NR ２ａ C(O)-, -NR ２ａ C(O)S-, -SC(O)NR ２ａ -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR ２ａ -, -NR ２ａ C(S)O-, or -S(O) ０－２ - and in the formula, the combination to the left is V １ It is oriented in that direction; R ２ａ Each example is independently H, C １－１０ Alkyl, C ３－１４ A cycloalkyl or a 3- to 14-membered heterocycline, where the alkyl, cycloalkyl, and heterocycline are independently C １－１０ Alkyl, L ２ｂ -OR ２ｂ , L ｂ -SR ２ｂ , L ２ｂ -NR ２ｂ R' ２ｂ , L ２ｂ N ＋ R ２ｂ R' ２ｂ R'' ２ｂ , L ２ｂ -OC(O)R ２ｂ , or L ２ｂ -C(O)OR ２ｂ It is optionally replaced by; R ２０１ , R ２０２ , R ２０３ , R ２０４ Each example independently represents H, OH, alkyl, alkoxy, and -L. ２ｂ -NR ２１ R ２２ , or -L ２ｂ -N ＋ R ２１ R ２２ R ２３ , L ２ｂ -OC(O)R ２１ , or L ２ｂ -C(O)OR ２１ And; m is an integer between 5 and 12; m1 is an integer between 0 and 12; V １ NR ２１ R ２２ , N ＋ R ２１ R ２２ R ２３ , imidazole, pyridine, pyrrole, pyrrolidine, pyrazole, (iso)thiazole, (iso)oxazole, oxadiazine, oxazoline, dithiourazole, (iso)triazole, tetrazole, pentasol, indole, dihydroindole, pyrimidine, pyrazine, quinazoline, piperazine, piperidine, morpholine, pyran, quinoxaline, quinoline, quinolinone, (iso)quinoline, amidine, guanidine, or urea; however, V1 is -NH ２ or -NH ３ ＋ Rather; M is either absent or independently one or more anions selected from chlorides, bromides, iodides, sulfates, nitrates, perchlorates, formates, citrates, sulfons, methanesulfons, triflates, trifluoroacetates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, pyrophosphates, monohydrogen phosphates, dihydrogen phosphates, acetates, propions, decanoates, caprylates, acrylates, isobutyrates, capronates, heptanoates, oxalates, malons, succinates, fumarates, maleates, benzoates, phthalates, phenylacetates, lactates, glycolates, tartrates, mandelates, mesylates, glucons, aspartates, or glutamates; R ２１ , R ２２ , R ２３ Each example independently involves H, and C, which is optionally substituted. １－８ Alkyl, -L ２ｂ -OR ２ｂ , -L ２ｂ -SR ２ｂ , -L ２ｂ -NR ２ｂ R' ２ｂ R'' ２ｂ , L ２ｂ -OC(O)R ２ｂ , or L ２ｂ -C(O)OR ２ｂ And; L ２ｂ C is either non-existent or optionally replaced. １－１０ It is alkylene; R ２ｂ , R' ２ｂ , and R'' ２ｂ These are, independently, H or C １－１０ It is alkyl. Steroid compounds, or their stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts.

72. Y １ is -C(O)O-, -OC(O)-, -O-, -S-, -NR ２ａ -, -OC(O)NR ２ａ -, or -NR ２ａ The steroid compound according to claim 71, wherein it is C(O)-.

73. Steroid compounds of formula (II-C1): 【Chemistry 53】 or its stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt, wherein the formula, R ｚ１ teeth, 【Chemistry 54】 And; R ２ａ CH ３ ien-CH ２ C(O)OCH ３ , or -CH ２ It is C(O)OH; V １ NR ２１ R ２２ or N ＋ R ２１ R ２２ R ２３ And, however, V １ is, -NH ２ or -NH ３ ＋ Rather; R ２１ , R ２２ , R ２３ Each example independently involves H, and C, which is optionally substituted. １－８ Alkyl, -L ２ｂ -OR ２ｂ , -L ２ｂ -SR ２ｂ , -L ２ｂ -NR ２ｂ R' ２ｂ R'' ２ｂ , L ２ｂ -OC(O)R ２ｂ , or L ２ｂ -C(O)OR ２ｂ And; L ２ｂ C is either non-existent or optionally replaced. １－１０ It is alkylene; R ２ｂ , R' ２ｂ , and R'' ２ｂ These are, independently, H or C １－１０ It is alkyl; M is either absent or independently one or more anions selected from chlorides, bromides, iodides, sulfates, nitrates, perchlorates, formates, citrates, sulfons, methanesulfons, triflates, trifluoroacetates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, pyrophosphates, monohydrogen phosphates, dihydrogen phosphates, acetates, propions, decanoates, caprylates, acrylates, isobutyrates, capronates, heptanoates, oxalates, malons, succinates, fumarates, maleates, benzoates, phthalates, phenylacetates, lactates, glycolates, tartrates, mandelates, mesylates, glucons, aspartates, or glutamates; m is an integer between 2 and 12. Steroid compounds, or their stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts.

74. Steroid compounds of formula (II-C2): 【Transformation 55】 or its stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt, wherein the formula, R ｚ１ teeth, 【Transformation 56】 And; V １ NR ２１ R ２２ or N ＋ R ２１ R ２２ R ２３ And, however, V １ is, -NH ２ , -NH ３ ＋ , -N(CH ３ ) ２ , -N(CH ３ ) (C ２ H ５ ), or -N(C ２ H ５ ) ２ Rather; R ２１ , R ２２ , R ２３ Each example independently involves H, and C, which is optionally substituted. １－８ Alkyl, -L ２ｂ -OR ２ｂ , -L ２ｂ -SR ２ｂ , -L ２ｂ -NR ２ｂ R' ２ｂ R'' ２ｂ , L ２ｂ -OC(O)R ２ｂ , or L ２ｂ -C(O)OR ２ｂ And; L ２ｂ C is either non-existent or optionally replaced. １－１０ It is alkylene; R ２ｂ , R' ２ｂ , and R'' ２ｂ These are, independently, H or C １－１０ It is alkyl; M is either absent or independently one or more anions selected from chlorides, bromides, iodides, sulfates, nitrates, perchlorates, formates, citrates, sulfons, methanesulfons, triflates, trifluoroacetates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, pyrophosphates, monohydrogen phosphates, dihydrogen phosphates, acetates, propions, decanoates, caprylates, acrylates, isobutyrates, capronates, heptanoates, oxalates, malons, succinates, fumarates, maleates, benzoates, phthalates, phenylacetates, lactates, glycolates, tartrates, mandelates, mesylates, glucons, aspartates, or glutamates; m is an integer between 2 and 12. Steroid compounds, or their stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts.

75. The following steroid compounds: 【Chemistry 57】 【Chemistry 58】 【Chemistry 59】 【Transformation 60】 【Chemistry 61】 or its stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts.

76. Lipid nanoparticles comprising the compound described in any one of claims 68 to 75.

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