Lipid nanoparticles targeting the spleen

Abstract

This application relates to lipid nanoparticles containing steroid compounds, and to the manufacture and use of such lipid nanoparticles. Such lipid nanoparticles can be used to deliver a payload (e.g., nucleic acid) in vivo to organs other than the liver, such as the spleen, in order to treat or prevent certain diseases or conditions, particularly diseases related to the spleen.

Description

[Technical Field]

[0001] 1. Technical field This application relates to the field of pharmacotherapy, particularly to lipid nanoparticles. The application also relates to the production 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 spleen. [Background technology]

[0002] 2.Background technology In recent years, nucleic acid-based gene therapy has advanced rapidly in various fields, including the treatment of infectious diseases and cancer. Lipid nanoparticles (LNPs) are one of the most advanced non-viral delivery platforms, capable of safely and effectively delivering nucleic acid drugs (such as mRNA or siRNA) to specific target organs while simultaneously protecting them from degradation by nucleases. LNPs offer several advantages, including high encapsulation efficiency, good cell transfection efficiency, strong tissue permeability, and relatively low cytotoxicity and immunogenicity. Currently, LNPs are successfully applied in several commercially available 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, both utilize the LNP drug delivery platform.

[0003] Studies have shown that after entering in vivo circulation, polyethylene glycolated lipids dissociate from LNP nanoparticles, allowing for the adsorption of ApoE to the LNP surface and forming an effective ligand for liver targeting. The LNPs then induce endocytosis by binding to lipoprotein receptors on the surface of hepatocytes. Therefore, current LNP delivery systems primarily exhibit passive liver targeting. To fully unlock the therapeutic potential of nucleic acid therapy, extend its application to various types of diseases, and minimize toxic side effects on healthy organs, there is a need to develop LNP delivery systems that target organs other than the liver.

[0004] This invention provides specific steroid compounds that enable targeted delivery of a payload to organs other than the liver, particularly the spleen.

[0005] 3. Outline of the Invention This invention provides lipid nanoparticles that target the spleen, exhibiting superior delivery effects to the spleen compared to other organs such as the liver or lungs.

[0006] In one embodiment, the lipid nanoparticles include a steroid compound and an ionized lipid.

[0007] In one embodiment, the molar percentage of the steroid compound in the total lipids is 3 to 15 mol%, preferably 5 to 10 mol%, for example, 3 mol%, 4 mol%, 5 mol%, 6 mol%, 7 mol%, 8 mol%, 9 mol%, 10 mol%, 11 mol%, 12 mol%, 13 mol%, 14 mol%, or 15 mol%.

[0008] In one embodiment, the molar percentage of the ionized lipid is 35 to 70 mol%, more preferably 40 to 60 mol%, for example, 35 mol%, 40 mol%, 45 mol%, 50 mol%, 55 mol%, or 60 mol%.

[0009] In one embodiment, the lipid nanoparticles targeting the spleen further comprise phospholipids.

[0010] In one preferred embodiment, the phospholipid is DSPC, DMPC, DOPC, DPPC, POPC, DOPE, DMPE, POPOE, or DPPE.

[0011] In one preferred embodiment, the molar percentage of the phospholipid is 5 to 30 mol%, preferably 5 to 20 mol%, more preferably 5 to 15 mol%, for example, 5 mol%, 6 mol%, 7 mol%, 8 mol%, 9 mol%, 10 mol%, 11 mol%, 12 mol%, 13 mol%, 14 mol%, or 15 mol%.

[0012] In one embodiment, the lipid nanoparticles targeting the spleen further include structural lipids such as cholesterol.

[0013] In one preferred embodiment, 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 natanesterol.

[0014] In one preferred embodiment, the molar percentage of the structural lipid is 10 to 80 mol%, more preferably 15 to 70 mol%, even more preferably 30 to 50 mol%, and most preferably 30 to 40 mol%, for example, 30 mol%, 35 mol%, 40 mol%, 45 mol%, 50 mol%, 55 mol%, or 60 mol%.

[0015] In one embodiment, the lipid nanoparticles targeting the spleen further comprise polymer-conjugated lipids such as polyethylene glycolated lipids.

[0016] In one preferred embodiment, the polyethylene glycolated lipid includes a polyethylene glycolated portion having a molecular weight of approximately 1000 Da to approximately 20000 Da, approximately 1000 Da to approximately 5000 Da, or approximately 1000 Da to approximately 2000 Da.

[0017] In one preferred embodiment, 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.

[0018] In one preferred embodiment, the molar percentage of the polymer conjugate lipid is 0.25 to 10 mol%, more preferably 0.5 to 5 mol%, and even more preferably 0.5 to 3 mol%, for example 0.5 mol%, 0.6 mol%, 0.7 mol%, 0.8 mol%, 0.9 mol%, 1.0 mol%, 1.1 mol%, 1.2 mol%, 1.3 mol%, 1.4 mol%, 1.5 mol%, 1.6 mol%, and 1.7 mol%. %, 1.8mol%, 1.9mol%, 2.0mol%, 2.1mol%, 2.2mol%, 2.3mol%, 2.4mol%, 2.5mol%, 2.6mol%, 2.7mol%, 2.8mol%, 2.9mo 1%, 3.0mol%, 3.1mol%, 3.2mol%, 3.3mol%, 3.4mol%, 3.5mol%, 3.6mol%, 3.7mol%, 3.8mol%, 3.9mol% or 4.0mol%.

[0019] In one embodiment, the average particle size of the lipid nanoparticles targeting the spleen is 50 to 800 nm, more preferably 50 to 400 nm, and even more preferably 80 to 200 nm, for example, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 nm.

[0020] In one embodiment, the lipid nanoparticles include (1) a steroid compound, (2) an ionized lipid, (3) a phospholipid compound, (4) a structural lipid, and (5) a polymer conjugate lipid.

[0021] In one more preferred embodiment, the lipid nanoparticles further comprise a payload.

[0022] In one embodiment, the payload is a therapeutic agent, a preventive agent, or a diagnostic agent.

[0023] In one embodiment, the payload is nucleic acid.

[0024] In one preferred embodiment, the nucleic acid is an antisense oligonucleotide (ASO), DNA, or RNA, and optionally the RNA is any other RNA from among 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), multimer-coding nucleic acid (MCNA), polymer-coding nucleic acid (PCNA), guide RNA (gRNA), CRISPR RNA (crRNA), or ribozyme.

[0025] In one preferred embodiment, the lipid nanoparticles targeting the spleen are 1) 3-15 mol% steroid compound, 2) 35-70 mol% ionized lipids, 3) 5-30 mol% phospholipids, 4) 10-80 mol% structural lipids, and 5) Contains components in molar percentages, such as polymer conjugate lipids, at concentrations of 0.25 to 10 mol%.

[0026] In one preferred embodiment, the lipid nanoparticles targeting the spleen are 1) 5-10 mol% steroid compound, 2) 40-60 mol% ionized lipids, 3) 5-20 mol% phospholipids, 4) 15-70 mol% structural lipids, and 5) Contains components in molar percentages, such as polymer conjugate lipids, in amounts of 0.5 to 5 mol%.

[0027] In one preferred embodiment, the lipid nanoparticles targeting the spleen are 1) 5-10 mol% steroid compound, 2) 40-60 mol% ionized lipids, 3) 5-15 mol% phospholipids, 4) 30-50 mol% structural lipids, and 5) Contains components in molar percentages, such as polymer conjugate lipids, at a concentration of 0.5 to 3 mol%.

[0028] In one particularly preferred embodiment, the lipid nanoparticles targeting the spleen are 1) 5 mol% steroid compound, 2) 50 mol% ionized lipids, 3) 10 mol% phospholipids, 4) 33.5 mol% structural lipids, and 5) Contains components in molar percentages, such as 1.5 mol% polymer conjugate lipids.

[0029] In one embodiment, the particle size distribution (PDI) of the lipid nanoparticles is 0.2 or less, preferably 0.15 or less.

[0030] In one embodiment, after administration, the ratio of the amount distributed to the spleen to the amount distributed to the liver of the lipid nanoparticles is 1 or more, more preferably 2 or more, more preferably 3 or more, more preferably 4 or more, more preferably 5 or more, more preferably 10 or more, more preferably 20 or more, more preferably 30 or more, more preferably 40 or more, more preferably 50 or more, and more preferably 100 or more.

[0031] In one embodiment, after administration, the ratio of the amount of distribution to the spleen to the amount of distribution to the lung of the lipid nanoparticles is 1 or more, more preferably 2 or more, more preferably 3 or more, more preferably 4 or more, more preferably 5 or more, more preferably 10 or more, more preferably 20 or more, more preferably 30 or more, more preferably 40 or more, more preferably 50 or more, more preferably 100 or more.

[0032] In one aspect, the present specification provides lipid nanoparticles comprising an ionizable lipid and a steroid compound, wherein the steroid compound is a compound of formula (I),

Chemical formula

Chemical formula

[0033] In one embodiment, the present invention provides lipid nanoparticles comprising an ionizable lipid and a steroid compound, where the steroid compound is a compound of formula (I-P), [Chemical formula] or a stereoisomer, a mixture of stereoisomers or a pharmaceutically acceptable salt thereof, where [Chemical formula] is a single bond or a double bond, Y1 is either 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)NR2a -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR 2a -, -NR 2a C(S)O-, -S(O) 0-2 - or -OPO3-, and here the left bond is directed towards V1, R 2a Each example is independently H, C 1-10 Alkyl alkyl group, C 3-14 A cycloalkyl group or a 3-14 membered heterocyclyl group, wherein the alkyl group, cycloalkyl group and heterocyclyl group are independently and optionally 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 Replaced by, R 201 , R 202 , R 203 , R 204 Each example independently includes H, OH, alkyl group, alkoxy group, 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 It either does not exist, or it is a cation, H, C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 2-6 Alkenyl group or C 2-6It is an alkynyl group, and here the alkyl group, haloalkyl group, alkenyl group and alkynyl group can be 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 These are imidazole, pyridine, pyrrole, pyrrolidine, pyrazole, (iso)thiazole, (iso)oxazole, oxadiazine, oxazoline, dithioureazole, (iso)triazole, tetrazole, pentasol, indole, indoline, pyrimidine, pyrazine, quinazoline, piperazine, piperidine, morpholine, pyran, quinoxaline, quinoline, quinolinone, (iso)quinoline, amidine, guanidine, or urea. M is absent or one or more anions, and the above anions are independently selected from chloride, bromide, iodide, sulfate, nitrate, perchlorate, formate, citrate, sulfonate, methanesulfonate, trifluoromethanesulfonate, trifluoroacetate, pyrosulfate, bisulfite, sulfite, bisulfite, phosphate, pyrophosphate, monohydrogen phosphate, dihydrogen phosphate, acetate, propionate, caprine, octanoate, acrylate, isobutyrate, hexanoate, heptanoate, oxalate, malonate, succinate, fumarate, maleate, benzoate, phthalate, phenylacetate, lactate, glycolate, tartrate, mandelate, methanesulfonate, gluconate, aspartate, or glutamate. R 21 , R 22 , R 23 Each example is independently H, and optionally substituted C. 1-8 Alkyl, -L 2b -OR 2b , -L 2b -SR 2b , -L 2b -NR 2b R' 2b R'' 2b , L2b -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 an alkylene group, R 2b , R' 2b and R'' 2b Each example is independently H or C 1-10 It is an alkyl group, R z1 C 1-14 Alkyl alkyl group or C 1-14 This is an alkenyl group, where the alkyl group and alkenyl group can be optionally substituted.

[0034] In one embodiment, Y is -C(O)O-, -OC(O)-, -O-, -NHC(O)O-, -OC(O)NH-, or -OC(O)O-, where the leftward bond 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 leftward bond is directed towards V1.

[0035] In one embodiment, the steroid compound is a compound of formula (I-A1), (I-A2), (I-A3), (I-A4), or (I-A5), [ka] Alternatively, these may be stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts. 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] Alternatively, these are stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts, where m3 is an integer from 1 to 11.

[0036] In one embodiment, R 201 , R 202 , R 203 and R 204 Each example is independently H, C 1-6 Alkyl 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.

[0037] 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, or -C(O)OCH3.

[0038] In one embodiment, m is an integer between 5 and 12.

[0039] In one embodiment, the present invention provides lipid nanoparticles, where the steroid compound is a compound of formula (I-P1), [ka] Alternatively, it may be a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, where m3 is an integer from 1 to 11.

[0040] In one embodiment, V1 is NR 21 R 22 , N + R 21 R 22 R 23or a radical of amidine, guanidine, or urea that is optionally substituted. In one embodiment, R 21 , R 22 , R 23 These are H, hydroxyl group, and C, respectively, independently. 1-3 Alkyl alkyl group 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. In one embodiment, M is either absent or one or more of the following: bromide, chloride, iodide, or trifluoroacetate.

[0041] In one embodiment, R z1 C 1-14 Alkyl alkyl group or C 1-14 The group is an alkenyl group, where the alkyl group and alkenyl group can be optionally one or more hydroxyl groups, oxo groups, nitro groups, cyano groups, halogens, or C groups. 1-6 Alkoxy group, C2-C6 alkenyl group, C2-C6 alkynyl group, C3-C8 cycloalkyl group, C6-C 10 It is substituted with an aryl group, a 5-10 membered heteroaryl group, or a 3-8 membered heterocyclyl group. In one embodiment, R z1 C 6-12 Alkyl alkyl group or C 6-12The group is an alkenyl group, and the alkyl group and alkenyl group are optionally substituted with one or more hydroxyl groups, oxo groups, or halogens. In one embodiment, R z1 teeth, [ka] That is the case.

[0042] In another embodiment, the steroid compound is a compound of formula (II-A), [ka] Alternatively, it may be a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt, where, each [ka] These are independently single bonds 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 here the leftward connection 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 here the leftward connection is directed towards V1, R 2a Each example is independently H, C 1-10 Alkyl alkyl group, C 3-14 A cycloalkyl group or a 3-14 membered heterocyclyl group, wherein the alkyl group, cycloalkyl group and heterocyclyl group are independently and optionally 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 Replaced by, R 201 , R 202 , R 203 , R 204 Each example independently includes H, OH, alkyl group, alkoxy group, 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 21And, m is an integer between 3 and 12. m1 is an integer between 0 and 12. V1 is NR 21 , N + R 21 R 22 R 23 These are imidazole, pyridine, pyrrole, pyrrolidine, pyrazole, (iso)thiazole, (iso)oxazole, oxadiazine, oxazoline, dithioureazole, (iso)triazole, tetrazole, pentasol, indole, indoline, pyrimidine, pyrazine, quinazoline, piperazine, piperidine, morpholine, pyran, quinoxaline, quinoline, quinolinone, (iso)quinoline, amidine, guanidine, or urea. M is absent or one or more anions, and the above anions are independently selected from chloride, bromide, iodide, sulfate, nitrate, perchlorate, formate, citrate, sulfonate, methanesulfonate, trifluoromethanesulfonate, trifluoroacetate, pyrosulfate, bisulfite, sulfite, bisulfite, phosphate, pyrophosphate, monohydrogen phosphate, dihydrogen phosphate, acetate, propionate, caprine, octanoate, acrylate, isobutyrate, hexanoate, heptanoate, oxalate, malonate, succinate, fumarate, maleate, benzoate, phthalate, phenylacetate, lactate, glycolate, tartrate, mandelate, methanesulfonate, gluconate, aspartate, or glutamate. R 21 , R 22 , R 23 These are H independently 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 an alkylene group, R 2b , R' 2b and R'' 2b Each of these is independently H or C 1-10 It is an alkyl group, and R z1 C 1-14 Alkyl alkyl group or C 1-14 It is an alkenyl group, where the alkyl group and alkenyl group are optionally substituted, and the compound is assumed to be [ka] isn't it.

[0043] In one embodiment, the steroid compound is of formula (II-B), [ka] Alternatively, it may be a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt, where, 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 here the leftward connection 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 here the leftward connection is directed towards V1, R 2a Each example is independently H, C 1-10 Alkyl alkyl group, C 3-14 A cycloalkyl group or a 3-14 membered heterocyclyl group, wherein the alkyl group, cycloalkyl group and heterocyclyl group are independently and optionally 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 Replaced by, R 201 , R 202 , R 203 , R 204 Each example independently includes H, OH, alkyl group, alkoxy group, and -L. 2b -NR 21 R 22 or -L 2b -N + R 21 R22 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 These are imidazole, pyridine, pyrrole, pyrrolidine, pyrazole, (iso)thiazole, (iso)oxazole, oxadiazine, oxazoline, dithioureazole, (iso)triazole, tetrazole, pentasol, indole, indoline, pyrimidine, pyrazine, quinazoline, piperazine, piperidine, morpholine, pyran, quinoxaline, quinoline, quinolinone, (iso)quinoline, amidine, guanidine, or urea. M is absent or one or more anions, and the above anions are independently selected from chloride, bromide, iodide, sulfate, nitrate, perchlorate, formate, citrate, sulfonate, methanesulfonate, trifluoromethanesulfonate, trifluoroacetate, pyrosulfate, bisulfite, sulfite, bisulfite, phosphate, pyrophosphate, monohydrogen phosphate, dihydrogen phosphate, acetate, propionate, caprine, octanoate, acrylate, isobutyrate, hexanoate, heptanoate, oxalate, malonate, succinate, fumarate, maleate, benzoate, phthalate, phenylacetate, lactate, glycolate, tartrate, mandelate, methanesulfonate, gluconate, aspartate, or glutamate. R 21 , R 22 , R 23 These are H independently and C which is optionally substituted. 1-8 Alkyl, -L 2b -OR 2b , -L 2b -SR 2b , -L 2b -NR2b 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 an alkylene group, R 2b , R' 2b and R'' 2b Each of these is independently H or C 1-10 It is an alkyl group.

[0044] In the 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)-.

[0045] In another embodiment, the steroid compound is a compound of formula (II-C1), [ka] Alternatively, it may be a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt, where, R z1 teeth, [ka] And, R 2a H is replaced by C, which is optionally substituted. 1-8 Alkyl, -L 2b -OR 2b , L 2b -OC(O)R 2b or L 2b -C(O)OR 2b It is preferably H, -CH3, -CH2C(O)OCH3, or -CH2C(O)OH, V1 is NR 21 R22 or N + R 21 R 22 R 23 And here R 21 , R 22 , R 23 These are H independently 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 R 21 and R 22 It is not hydrogen at the same time, L 2b C is either non-existent or optionally replaced. 1-10 It is an alkylene group, R 2b , R' 2b and R'' 2b Each of these is independently H or C 1-10 It is an alkyl group, M is absent or one or more anions, and the above anions are independently selected from chloride, bromide, iodide, sulfate, nitrate, perchlorate, formate, citrate, sulfonate, methanesulfonate, trifluoromethanesulfonate, trifluoroacetate, pyrosulfate, bisulfite, sulfite, bisulfite, phosphate, pyrophosphate, monohydrogen phosphate, dihydrogen phosphate, acetate, propionate, caprine, octanoate, acrylate, isobutyrate, hexanoate, heptanoate, oxalate, malonate, succinate, fumarate, maleate, benzoate, phthalate, phenylacetate, lactate, glycolate, tartrate, mandelate, methanesulfonate, gluconate, aspartate, or glutamate. m is an integer between 1 and 10, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0046] In another embodiment, the steroid compound is a compound of formula (II-C2), [ka] Alternatively, it may be a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt, where, R z1 teeth, [ka] And, V1 is NR 21 R 22 or N + R 21 R 22 R 23 And here R 21 , R 22 , R 23 These are H independently 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 R 21 and R 22 It is not hydrogen at the same time, L 2b C is either non-existent or optionally replaced. 1-10 It is an alkylene group, R 2b , R' 2b and R'' 2b Each of these is independently H or C 1-10 It is an alkyl group, M is absent or one or more anions, and the above anions are independently selected from chloride, bromide, iodide, sulfate, nitrate, perchlorate, formate, citrate, sulfonate, methanesulfonate, trifluoromethanesulfonate, trifluoroacetate, pyrosulfate, bisulfite, sulfite, bisulfite, phosphate, pyrophosphate, monohydrogen phosphate, dihydrogen phosphate, acetate, propionate, caprine, octanoate, acrylate, isobutyrate, hexanoate, heptanoate, oxalate, malonate, succinate, fumarate, maleate, benzoate, phthalate, phenylacetate, lactate, glycolate, tartrate, mandelate, methanesulfonate, gluconate, aspartate, or glutamate. m is an integer between 1 and 10, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0047] In another aspect, this specification provides lipid nanoparticles comprising an ionized lipid and a steroid compound, wherein the steroid compound is [ka] JPEG2026515723000019.jpg200149 JPEG2026515723000020.jpg203149 JPEG2026515723000021.jpg176149 JPEG2026515723000022.jpg198149 JPEG2026515723000023.jpg166149 JPEG2026515723000024.jpg182149 JPEG2026515723000025.jpg63149 Alternatively, these may be stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts.

[0048] In another embodiment, the Specified provides lipid nanoparticles for delivering or expressing a payload in the spleen of a subject, wherein the lipid nanoparticles are administered to the subject via a systemic route, wherein the lipid nanoparticles comprise an ionized lipid and a steroid compound, and wherein the steroid compound comprises one or more cationic groups.

[0049] In one embodiment, the systemic administration route is intravenous, intra-arterial, or intraperitoneal.

[0050] 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, dithioureaoxazole, isotriazoline, tetrazole, pentasol, indole, indoline, isoxazole, pyrimidine, pyrazine, quinazoline, piperazine, piperidine, morpholine, pyran, quinoxaline, quinoline, quinolinone, isoquinoline, amidine, guanidine, or urea.

[0051] In one embodiment, the steroid compound comprises a Z1 portion, where Z1 is [ka] Or a stereoisomer thereof or a mixture of stereoisomers, where one or more ring-CC bonds in Z1 are independently and optionally substituted with C=C bonds where valence allows, and where Z1 is optionally a hydroxyl group, a halogen and C 1-14 Alkyl alkyl group or C 1-14 Substituted with one or more groups selected from alkenyl groups, where the alkyl group is optionally one or more hydroxyl groups, nitro groups, cyano groups, halogens, C 1-6 Alkoxy group, C2-C6 alkenyl group, C2-C6 alkynyl group, C3-C8 cycloalkyl group, C6-C 10The group is substituted with an aryl group, a 5-10 membered heteroaryl group, or a 3-8 membered heterocyclyl group, where the bond at Z1 is directed toward the rest of the steroid compound. In one embodiment, the Z1 portion is a monovalent group of cholesterol, cholestane, campesterol, sitosterol, sitostanol, β-sitosterol, stigmasterol, stigmasterol, brassicasterol, avenasterol, ergosterol, ursolic acid, tocopherol, lumisterol, or a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

[0052] In one embodiment, the steroid compound is a compound of formula (I), [ka] Alternatively, it may be a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt, where, [ka] These are 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 here the leftward connection is directed towards V1, Y1 either does not exist, or is -C(O)O-, -O-, -NH-, -SC(O)O-, -OC(O)NR2a -, -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 here the leftward connection is directed towards V1, R 2a Each example is independently H, C 1-10 Alkyl alkyl group, C 3-14 A cycloalkyl group or a 3-14 membered heterocyclyl group, wherein the alkyl group, cycloalkyl group and heterocyclyl group are independently and optionally C 1-10 Alkyl, L 2b -OR 2b Lb-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 Replaced by, R 201 , R 202 , R 203 , R 204 Each example independently includes H, OH, alkyl group, alkoxy group, and -L. 2b -NR 21 R 22 , -L 2b -N + R 21 R 22 R 23 , L 2b -OC(O)R 21or 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 These are imidazole, pyridine, pyrrole, pyrrolidine, pyrazole, isothiazole, isoxazole, oxadiazine, oxazoline, dithioureaoxazole, isotriaazole, tetrazole, pentasol, indole, indoline, isoxazole, pyrimidine, pyrazine, quinazoline, piperazine, piperidine, morpholine, pyran, quinoxaline, quinoline, quinolinone, isoquinoline, amidine, guanidine, or urea. M is absent or one or more anions, and the above anions are independently selected from chloride, bromide, iodide, sulfate, nitrate, perchlorate, formate, citrate, sulfonate, methanesulfonate, trifluoromethanesulfonate, trifluoroacetate, pyrosulfate, bisulfite, sulfite, bisulfite, phosphate, pyrophosphate, monohydrogen phosphate, dihydrogen phosphate, acetate, propionate, caprine, octanoate, acrylate, isobutyrate, hexanoate, heptanoate, oxalate, malonate, succinate, fumarate, maleate, benzoate, phthalate, phenylacetate, lactate, glycolate, tartrate, mandelate, methanesulfonate, gluconate, aspartate, or glutamate. R 21 , R 22 , R 23 Each example is independently H, and optionally substituted C. 1-8 Alkyl, -L 2b -OR 2b , -L 2b -SR 2b , -L 2b -NR 2b R' 2b R'' 2b , L 2b -OC(O)R2b or L 2b -C(O)OR 2b And, L 2b C is either non-existent or optionally replaced. 1-10 It is an alkylene group, R 2b , R' 2b and R'' 2b Each example is independently H or C 1-10 It is an alkyl group, and R z1 C 1-14 Alkyl alkyl group or C 1-14 This is an alkenyl group, where the alkyl group and alkenyl group can be optionally substituted.

[0053] In one embodiment, the amount of the steroid compound accounts for approximately 15 mol% to approximately 80 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 in the lipid nanoparticles. In one embodiment, the amount of the steroid compound accounts for approximately 20 mol% to approximately 30 mol% of the total lipids in the lipid nanoparticles.

[0054] In one embodiment, the ionized lipid comprises at least one ionized 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 structural formula of the biodegradable hydrophobic chain is -R 16 -M0-R 17 And here, R 16 is C 4-14 Alkylene group, C 4-14 Alkenylene group or C 4-14 It is an alkynylene group, R 17 is C 6-20 It is an alkyl group, and M0 is a biodegradable group, and the alkylene group, alkenylene group, alkylylene group and alkyl group can be optionally substituted.

[0055] In one embodiment, M0 is an ester group, amide group, thioester group, carbonate group, carbamate group, carbamoylthioester group, urea group, or disulfide group.

[0056] In one embodiment, the ionized lipid is a compound of formula (III), [ka] Alternatively, it may be a stereoisomer thereof, a mixture of stereoisomers, a tautomer, an isotope substitution, or a pharmaceutically acceptable salt, where, Examples R3 and R4 were independently C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C3-C 14 Cycloalkyl group, 3-14 member heterocyclyl group, (C 1-10 Alkylene group)-(C3-C 14 (Cycloalkyl group) or (C 1-10 The alkylene group is a 3-14 member heterocyclyl group, or R3 and R4, together with the nitrogen atom bonded to them, form a 3-14 member heterocyclyl group, or R4 and one R0', together with the atom bonded to them, form a 4-10 member heterocyclyl group or a 5-10 member heteroaryl group, and here the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, heteroaryl group and alkylene group are independently and optionally one or more R * Replaced by, Each example of R0' is an independently and optionally substituted methylene group, or two of these R0's together with the carbons bonded to them form a 3- to 8-membered cycloalkylene group, where the cycloalkylene group is optionally substituted with one or more R ** 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 represents a chemical bond. W is C, CH, or N, and the condition is that if W is N, then j is 0, and there is no dashed line connection between Q and W. G5 does not exist, or C 1-24 Alkylene group, C 2-24 The groups are alkenylene groups, C3-C8 cycloalkylene groups, and C3-C8 cycloalkenylene groups, where the above alkylene groups, alkenylene groups, cycloalkylene groups, and cycloalkenylene groups are optionally selected as one or more R groups. ** Replaced by, G1, G2, G3, and G4 do not exist independently of each other, or C 1-13 Alkylene group, C 2-13 Alkenylene group or C 2-13 The alkylene group is an alkylene group, where the alkylene group, alkenylene group and alkylene group can be optionally selected as one or more R groups. s Replaced by, The total length of G1 and G2 is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 carbon atoms. The total length of G3 and G4 is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 carbon atoms. R5, R6, R7, and R8 are each independently substituted with hydrogen or optionally substituted with carbon. 1-8 It is an alkyl group, If there is no dashed line connecting Q and W, then Q is either nonexistent, or -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 - is selected from, where the bond to the right is directed towards W, If the dashed line connecting Q and W represents a chemical bond, then G5 does not exist, and Q and W form a 5-10 membered monocyclic ring or a fused ring, and optionally the ring has one or more R ** Replaced by, M1 and M2 either do not exist independently of each other, or they are -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-, -SS-, or -S(O) 0-2 - Selected from, Each example of R0 is independently -(CRR')-, Examples R and R' are independently H and C 1-20 Alkyl, L a -OR a , -L a -SR a or -L a -NR a R' a And, or R and R' together with the carbons bonded to them, C 3-8 Forming a cycloalkylene group, Q3 and Q4 are independently H, -(CRR')-, and C, respectively. 6-10 It is an aryl group or a steroid group, Examples A1, A2, A3, and A4 are independently - (CR 18 R 18 -CR 18 =CR 18 )- or -(CR 18 R 18 -C≡C)- and R 18 Each example is independently C 1-20 It is an alkyl group, Examples N1 and N2 are independently biodegradable groups. Z does not exist, or C 1-10 It is an alkylene group or -OP(O)(OH)-O- The dashed lines between Z-Q3 and Z-Q4 either do not exist independently or represent a chemical bond. If Z is not present, then neither of the two dashed lines exists. m, n, q, r, u, v, y, and z are each independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. o, p, w, and x are each independently selected from 0, 1, or 2. s and t are each independently selected from 0 or 1. The number of carbon atoms between G1 and Q3 or between G3 and Q4 is 8 to 30. L a and L e They either do not exist independently of each other, or C 1-20 Selected from alkylene groups, L b and L f They either do not exist independently of each other, or C 1-10 Selected from alkylene groups, L c It does not exist, or C 1-8 Selected from alkylene groups, L d It does not exist, or C 1-14 Selected from alkylene groups, R * is a hydroxyl group, halogen, C 1-10 Alkyl alkyl group, C 1-10 Haloalkyl group, C 1-10 Hydroxyalkyl group, -L b -OR b , -L b -SR b or -L b -NR b R' b And, R **is a hydroxyl group, halogen, C 1-8 Alkyl alkyl group, C 1-8 Haloalkyl group, C 1-8 Hydroxyalkyl group, -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 H and C are independent of each other. 1-20 Alkyl alkyl group, C 3-14 The alkyl group is a cycloalkyl group or a 3-14 member heterocyclyl group, where the alkyl group, cycloalkyl group and heterocyclyl group can optionally be a hydroxyl group, a halogen, or C 1-20 Alkyl, -L e -OR e , -L e -SR e or -L e -NR e R' e Replaced by one or more groups selected from, R b and R' b H and C are independent of each other. 1-10 Alkyl alkyl group, C 3-14 The alkyl group is a cycloalkyl group or a 3-14 member heterocyclyl group, where the alkyl group, cycloalkyl group and heterocyclyl group can optionally be a hydroxyl group, a halogen, or C 1-10 Alkyl, -L f -OR f , -L f -SR f or -L f -NR f R' f Replaced by one or more groups selected from, R c and R' c These are, independently, hydrogen or C 1-8 It is an alkyl group, R d and R' d These are, independently, hydrogen or C 1-14 It is an alkyl group, R e and R' e These are, independently, hydrogen or C 1-20 It is an alkyl group, and R f and RR' f These are, independently, hydrogen or C 1-10 It is an alkyl group.

[0057] In one embodiment, the ionized lipid is a compound of formula (IV'), [ka] Or its stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt, where j is either 0 or 1. W is either CH or N, and assuming W is N, then j is 0. k is 0, 1, 2, 3, 4, 5, 6, 7, or 8. Each example of R0' is an independently and optionally substituted methylene group, or two of these R0's together with the carbons bonded to them form a 3- to 8-membered cycloalkylene group, where the cycloalkylene group is optionally substituted with one or more R ** 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 aC(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-, -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, R a and R b H and C are independent of each other. 1-20 Alkyl alkyl group, C 3-14 The alkyl group is a cycloalkyl group or a 3-14 member heterocyclyl group, where the alkyl group, cycloalkyl group and heterocyclyl group can optionally be a hydroxyl group, a halogen, or C 1-20 Alkyl, -L e -OR e , -L e -SR e or -L e -NReR' e Replaced by one or more groups selected from, G5 is either non-existent or optionally replaced by C. 1-8 It is an alkylene group, R1 and R2 are each independently C 4-20 Alkyl alkyl group, C 4-20 Alkenyl group or C 4-20It is an alkynyl group, where one or more methylene group units of R1 and R2 are independently and optionally -NH- or -N(C 1-20 Substituted with an alkyl group, where the alkyl group, alkenyl group, and alkynyl group are optionally substituted. Examples R3 and R4 are independently H, C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C3-C 14 R3 and R4 are cycloalkyl groups or 3-14 membered heterocyclyl groups, or R3 and R4, together with the N atom bonded to them, form a 3-14 membered heterocyclyl group, or R4 and one R0', together with the atom bonded to them, form a 4-10 membered heterocyclyl group, and here the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group may be one or more R groups of any choice. * Replaced with and R5, R6, R7, and R8 are each independently substituted with hydrogen or selectively substituted with carbon. 1-8 It is an alkyl group.

[0058] In one embodiment, the ionized lipid is a compound of formula (V'), (VI'), or (VII'), [ka] Alternatively, these are stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts, where, 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. G1a , G 1b , G 2a , G 2b , G 3a , G 3b , G 4a and G 4b Each of these either does not exist independently or is selectively substituted with C. 1-7 It is an alkylene group, G 1a , G 1b , G 2a and G 2b The total length is 1, 2, 3, 4, 5, 6, or 7 carbon atoms. G 3a , G 3b , G 4a and G 4b The total length is 1, 2, 3, 4, 5, 6, or 7 carbon atoms. R5, R6, R7, and R8 are each independently substituted with hydrogen or selectively substituted with carbon. 1-6 It is an alkyl group, G7, G8, G9 and G 10 These are either C elements that do not exist independently or are selectively substituted. 1-12 It is an alkylene group, and the conditions are that the total length of G7 and G8 is 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms, and G9 and G 10 The total length is 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 an alkyl group, L dIt does not exist, or C 1-10 It is an alkylene group, L a It does not exist, or C 1-14 It is an alkylene group, R a and R' a H and C are independent of each other. 1-14 Alkyl alkyl group, C 3-10 A cycloalkyl group or a 3-10 membered heterocyclyl group, wherein the alkyl group, cycloalkyl group and heterocyclyl group are optionally substituted. R d and R' d These are H or C, respectively, independently. 1-10 It is an alkyl group, a' and b are independently 0, 1, 3, 4, and 5, and the condition is 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, and c, d, e, and f are independently 0, 1, 2, 3, 4, 5, 6, or 7, and the conditions are that c+d is an integer between 2 and 9, and e+f is an integer between 2 and 9.

[0059] In one embodiment, the ionized lipid is a compound of formula (VIII), [ka] Alternatively, it may be a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

[0060] In one embodiment, R5, R6, R7, and R8 are each independently a hydrogen atom or a methyl group.

[0061] In one embodiment, G1, G2, G3, and G4 do not exist independently of each other, or C 1-8 It is an alkylene group.

[0062] In one embodiment, the ionized lipid is a compound of formula (IX), [ka] Or its stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt, where G1 and G2 are joined independently, C 1-13 Linear alkylene group, C 2-13 Linear alkenylene group or C 2-13 A linear alkylene group, where the alkylene group, alkenylene group, and alkylene group can be optionally selected as one or more R G1 Replaced by, The total length of G1 and G2 is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 carbon atoms. R G1 In various cases, H and C are independent. 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 group, C 4-14 Linear alkenylene group or C 4-14 A linear alkylene group, where the alkylene group, alkenylene group, and alkylene group can be optionally selected as one or more R G3 Replaced by, R G3 In various cases, H and -L are independent. 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 an alkylene group, R a and R' a H and C are independent of each other.1-14 Alkyl alkyl group, C 3-14 It is a cycloalkyl group or a 3-14 member heterocyclyl group. G4 is a bond, C 1-6 Alkylene group, C 2-6 Alkenylene group or C 2-6 The alkylene group is an alkylene group, where the alkylene group, alkenylene group and alkylene group can be optionally selected as one or more R groups. G4 Replaced by, R G4 In various cases, H and C are independent. 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 an alkylene group, R b and R' b H and C are independent of each other. 1-6 Alkyl alkyl group, C 3-10 It is a cycloalkyl group or a 3-10 membered heterocyclyl group. Alternatively, the two RG4 atoms, along with the same carbon atom bonded to them, are C 3-14 A cycloalkylene group or a 3-14 membered heterocyclene group is formed, where the cycloalkylene group and heterocyclene group are optionally one or more R groups. 4g Replaced by, R 4g In various cases, H, halogen, cyano group, and C are independently involved. 1-8 Alkyl alkyl group, C 1-8 Haloalkyl group, -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 an alkylene group, Re and R’ e is independently H, C 1-8 alkyl group, C 3-14 cycloalkyl group or a 3- to 14-membered heterocyclyl group, and 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-, -S-S- or -S(O) 0-2 - and Q is a 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 -, a phenylene group or a pyridinylene group, where the phenylene group or pyridinylene group is optionally substituted with one or more R * and R * is independently H, halogen, cyano group, C<​​​​​​​​​​​​​​​​​​​​is independently bonded or C 1-8 is an alkylene group, R f and R’ f are independently H, C 1-10 alkyl group, C 3-14 cycloalkyl group or a 3- to 14-member heterocyclyl group, R1 and R2 are independently C 4-20 alkyl group, C 4-20 alkenyl group or C 4-20 alkynyl group, optionally substituted by one or more R 1s and wherein one or more methylene group units are optionally independently substituted by -NR’-, R 1s is independently H, C 1-20 alkyl group, -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 alkyl group, L c is independently bonded or C 1-20 alkylene group, R c and R’ c are independently H, C 1-20 alkyl group, C 3-14 cycloalkyl group or a 3- to 14-member heterocyclyl group, 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(ORg )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 、 a 3- to 14-member heterocyclic group or a 5- to 14-member heteroaryl group, R g and R’ g are, independently, H, C 1-10 alkyl group, C 3-10 cycloalkyl group and a 3- to 10-member heterocyclic group, R’’ is, independently, H or C 1-6 alkyl group, R5 and R6 are, independently, C 1-8 alkyl group, where the alkyl group is optionally substituted with one or more R 4s s, or R5 and R6 together with the same carbon atom to which they are attached form a C 3-14 cycloalkylene group or a 3- to 14-member heterocyclylene group, where the cycloalkylene group and the heterocyclylene group are optionally substituted with one or more R 4s s, R 4s is, independently, H, halogen, cyano group, C 1-8 alkyl group, C 1-8 haloalkyl group, -L d -OR d 、 -L d -SR d or -L d -NR d R’ d , L d is, independently, a bond or C 1-8 alkylene group, R d and R’ d are, independently, H, C 1-8 alkyl group, C 3-14 cycloalkyl group or a 3- to 14-member heterocyclic group.

[0063] In one embodiment, the ionized lipid is a compound of formula (X), [ka] Or its stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt, where 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.

[0064] In one embodiment, the ionized lipid is [ka] JPEG2026515723000036.jpg192149 JPEG2026515723000037.jpg196149 JPEG2026515723000038.jpg82149 Alternatively, these may be stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts.

[0065] In one embodiment, the ionized lipid is [ka] JPEG2026515723000040.jpg176149 JPEG2026515723000041.jpg192149 JPEG2026515723000042.jpg99149 Alternatively, these may be stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts.

[0066] 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.

[0067] In one embodiment, the molar percentage of the ionized lipids in the total lipids is 35 to 70 mol%, more preferably 40 to 60 mol%, for example, 35 mol%, 40 mol%, 45 mol%, 50 mol%, 55 mol%, or 60 mol%.

[0068] In one embodiment, the lipid nanoparticles further comprise phospholipids. In one embodiment, the phospholipids are one or more selected from DSPC, DMPC, DOPC, DPPC, POPC, DOPE, DMPE, POPOE, or DPPE.

[0069] In one embodiment, the molar percentage of the phospholipid in the total lipids is 5 to 30 mol%, preferably 5 to 20 mol%, more preferably 5 to 15 mol%, for example, 5 mol%, 6 mol%, 7 mol%, 8 mol%, 9 mol%, 10 mol%, 11 mol%, 12 mol%, 13 mol%, 14 mol%, or 15 mol%.

[0070] 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 natanesterol.

[0071] In one embodiment, the molar percentage of the structural lipids in the total lipids is 10 to 80 mol%, more preferably 15 to 70 mol%, even more preferably 30 to 50 mol%, and most preferably 30 to 40 mol%, for example, 30 mol%, 35 mol%, 40 mol%, 45 mol%, 50 mol%, 55 mol%, or 60 mol%.

[0072] In one embodiment, the lipid nanoparticles further comprise polymer conjugate lipids. In one embodiment, the polymer conjugate lipids are polyethylene glycolated lipids. In one embodiment, the polyethylene glycolated lipids comprise polyethylene glycolated moieties having molecular weights of approximately 1000 Da to approximately 20,000 Da, approximately 1000 Da to approximately 5000 Da, or approximately 1000 Da to approximately 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-amino.

[0073] In one embodiment, the molar percentage of the polymer conjugate lipid in the total lipid is 0.25 to 10 mol%, more preferably 0.5 to 5 mol%, and even more preferably 0.5 to 3 mol%, for example 0.5 mol%, 0.6 mol%, 0.7 mol%, 0.8 mol%, 0.9 mol%, 1.0 mol%, 1.1 mol%, 1.2 mol%, 1.3 mol%, 1.4 mol%, 1.5 mol%, 1.6 mol%, 1.7 mol%. ol%, 1.8mol%, 1.9mol%, 2.0mol%, 2.1mol%, 2.2mol%, 2.3mol%, 2.4mol%, 2.5mol%, 2.6mol%, 2.7mol%, 2.8mol%, 2.9 mol%, 3.0mol%, 3.1mol%, 3.2mol%, 3.3mol%, 3.4mol%, 3.5mol%, 3.6mol%, 3.7mol%, 3.8mol%, 3.9mol%, 4.0mol%.

[0074] In one embodiment, the lipid nanoparticles contain a payload that serves as a therapeutic, prophylactic, or diagnostic agent. In one embodiment, the payload is nucleic acid. In one embodiment, the nucleic acid is antisense oligonucleotide (ASO), DNA, or RNA, and optionally the RNA is any other RNA from among 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), multimeric coding nucleic acid (MCNA), polymer coding nucleic acid (PCNA), guide RNA (gRNA), CRISPR RNA (crRNA), or ribozyme.

[0075] In one embodiment, the molar ratio of the total N atoms in the steroid compound and ionized lipid to the P atoms in the nucleic acid molecule is approximately 1:1 to approximately 20:1, approximately 1:1 to approximately 20:1, approximately 2:1 to approximately 10:1, or approximately 4:1 to approximately 8:1.

[0076] In one embodiment, when lipid nanoparticles containing a payload are administered systemically to a target, the delivery or expression level of the payload in the target spleen is higher than the delivery or expression level of the payload in the target liver.

[0077] In one embodiment, the delivery or expression level of the payload in the target spleen is at least 1-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 10-fold, at least 20-fold, at least 30-fold, at least 40-fold, at least 50-fold, or at least 100-fold higher than the delivery or expression level of the payload in the target liver.

[0078] In one embodiment, this specification provides a lipid nanoparticle composition comprising the lipid nanoparticles described herein.

[0079] In one embodiment, this specification provides a pharmaceutical composition comprising lipid nanoparticles or a lipid nanoparticle composition described herein.

[0080] In one embodiment, this specification provides a method for treating or preventing a splenic disease or splenic-related disease in a subject suffering from a splenic disease or splenic-related disease, the method comprising administering a therapeutically effective amount of lipid nanoparticles, lipid nanoparticle compositions, or pharmaceutical compositions described herein to the subject.

[0081] In one embodiment, this specification provides the use of lipid nanoparticles or lipid nanoparticle compositions described herein in the manufacture of a drug for preventing or treating spleen disease or spleen-related disease.

[0082] In one embodiment, this specification provides lipid nanoparticles, lipid nanoparticle compositions, or pharmaceutical compositions described herein for preventing or treating spleen diseases or spleen-related diseases.

[0083] In one preferred embodiment, the spleen disease or spleen-related disease described above includes blood disorders, infectious diseases, immune disorders, or cancer.

[0084] In one preferred embodiment, the splenic disease or splenic-related disease described above includes hemolytic anemia, thrombocytopenic purpura, chronic leukemia, lymphomas such as Hodgkin lymphoma or non-Hodgkin lymphoma, lipid metabolism disorders such as myelodysplastic syndrome, myelofibrosis, splenomegaly, glucocerebroside disease and sphingomyelinosis, and splenomegaly and hypersplenism associated with sepsis, typhus, infectious mononucleosis or subacute bacterial endocarditis, and splenomegaly and hypersplenism associated with malaria, tuberculosis, kala-azar, etc., congestive splenomegaly and hypersplenism resulting from portal hypertension due to liver cirrhosis, splenic cysts such as parasitic splenic cysts or pseudocysts, splenic abscesses, primary splenic tumors, splenic metastatic tumors, splenic artery aneurysms, splenic infarction, splenic purpura, and splenic rupture.

[0085] In one embodiment, this specification provides a method for producing lipid nanoparticles or lipid nanoparticle compositions 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 comprising the step of mixing a lipid solution and a payload solution to form lipid nanoparticles.

[0086] In one embodiment, mixing is performed using a microfluidic system.

[0087] In another embodiment, this specification refers to a steroid compound of formula (II-A), [ka] Alternatively, we provide stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts thereof, where, each [ka] These are independently single bonds 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 here the connection to the left 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 - is selected from and here the connection to the left is directed towards V1, R 2a Each example is independently H, C 1-10 Alkyl alkyl group, C 3-14A cycloalkyl group or a 3-14 membered heterocyclyl group, wherein the alkyl group, cycloalkyl group and heterocyclyl group are independently and optionally C 1-10 Alkyl, L 2b -OR 2b Lb-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 Replaced by, R 201 , R 202 , R 203 , R 204 Each example independently includes H, OH, alkyl group, alkoxy group, 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 , N + R 21 R 22 R 23 These are imidazole, pyridine, pyrrole, pyrrolidine, pyrazole, (iso)thiazole, (iso)oxazole, oxadiazine, oxazoline, dithioureazole, (iso)triazole, tetrazole, pentasol, indole, indoline, pyrimidine, pyrazine, quinazoline, piperazine, piperidine, morpholine, pyran, quinoxaline, quinoline, quinolinone, (iso)quinoline, amidine, guanidine, or urea. M is absent or one or more anions, and the above anions are independently selected from chloride, bromide, iodide, sulfate, nitrate, perchlorate, formate, citrate, sulfonate, methanesulfonate, trifluoromethanesulfonate, trifluoroacetate, pyrosulfate, bisulfite, sulfite, bisulfite, phosphate, pyrophosphate, monohydrogen phosphate, dihydrogen phosphate, acetate, propionate, caprine, octanoate, acrylate, isobutyrate, hexanoate, heptanoate, oxalate, malonate, succinate, fumarate, maleate, benzoate, phthalate, phenylacetate, lactate, glycolate, tartrate, mandelate, methanesulfonate, gluconate, aspartate, or glutamate. R 21 , R 22 , R 23 These are H independently 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 an alkylene group, R 2b , R' 2b and R'' 2b Each of these is independently H or C 1-10 It is an alkyl group, and R z1 C 1-14 Alkyl alkyl group or C 1-14 It is an alkenyl group, where the alkyl group and alkenyl group can be optionally substituted, and the condition is as follows: [ka] It is not that compound.

[0088] In one embodiment, the present invention provides a steroid compound of formula (II-B), [ka] Alternatively, it may be a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt, where, 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 here the leftward connection 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 here the leftward connection is directed towards V1, R 2a Each example is independently H, C 1-10 Alkyl alkyl group, C 3-14 A cycloalkyl group or a 3-14 membered heterocyclyl group, wherein the alkyl group, cycloalkyl group and heterocyclyl group are independently and optionally 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 Replaced by, R 201 , R 202 , R 203 , R 204 Each example independently includes H, OH, alkyl group, alkoxy group, 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 23These are imidazole, pyridine, pyrrole, pyrrolidine, pyrazole, (iso)thiazole, (iso)oxazole, oxadiazine, oxazoline, dithioureazole, (iso)triazole, tetrazole, pentasol, indole, indoline, pyrimidine, pyrazine, quinazoline, piperazine, piperidine, morpholine, pyran, quinoxaline, quinoline, quinolinone, (iso)quinoline, amidine, guanidine, or urea. M is absent or one or more anions, and the above anions are independently selected from chloride, bromide, iodide, sulfate, nitrate, perchlorate, formate, citrate, sulfonate, methanesulfonate, trifluoromethanesulfonate, trifluoroacetate, pyrosulfate, bisulfite, sulfite, bisulfite, phosphate, pyrophosphate, monohydrogen phosphate, dihydrogen phosphate, acetate, propionate, caprine, octanoate, acrylate, isobutyrate, hexanoate, heptanoate, oxalate, malonate, succinate, fumarate, maleate, benzoate, phthalate, phenylacetate, lactate, glycolate, tartrate, mandelate, methanesulfonate, gluconate, aspartate, or glutamate. R 21 , R 22 , R 23 These are H independently 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 an alkylene group, R 2b , R' 2b and R'' 2bEach of these is independently H or C 1-10 It is an alkyl group.

[0089] In one embodiment, the present invention provides a steroid compound of formula (IP), [ka] Alternatively, it may be a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt, where, [ka] These are single or double bonds, 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-, and here the left bond is directed towards V1, R 2a Each example is independently H, C 1-10 Alkyl alkyl group, C 3-14 A cycloalkyl group or a 3-14 membered heterocyclyl group, wherein the alkyl group, cycloalkyl group and heterocyclyl group are independently and optionally C 1-10 Alkyl, L 2b -OR 2b , L b -SR 2b , L 2b -NR 2bR' 2b , L 2b N + R 2b R' 2b R'' 2b , L 2b -OC(O)R 2b or L 2b -C(O)OR 2b Replaced by, R 201 , R 202 , R 203 , R 204 Each example independently includes H, OH, alkyl group, alkoxy group, 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 It either does not exist, or it is a cation, H, C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 2-6 Alkenyl group or C 2-6 It is an alkynyl group, and here the alkyl group, haloalkyl group, alkenyl group and alkynyl group can be 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 These are imidazole, pyridine, pyrrole, pyrrolidine, pyrazole, (iso)thiazole, (iso)oxazole, oxadiazine, oxazoline, dithioureazole, (iso)triazole, tetrazole, pentasol, indole, indoline, pyrimidine, pyrazine, quinazoline, piperazine, piperidine, morpholine, pyran, quinoxaline, quinoline, quinolinone, (iso)quinoline, amidine, guanidine, or urea. M is absent or one or more anions, and the above anions are independently selected from chloride, bromide, iodide, sulfate, nitrate, perchlorate, formate, citrate, sulfonate, methanesulfonate, trifluoromethanesulfonate, trifluoroacetate, pyrosulfate, bisulfite, sulfite, bisulfite, phosphate, pyrophosphate, monohydrogen phosphate, dihydrogen phosphate, acetate, propionate, caprine, octanoate, acrylate, isobutyrate, hexanoate, heptanoate, oxalate, malonate, succinate, fumarate, maleate, benzoate, phthalate, phenylacetate, lactate, glycolate, tartrate, mandelate, methanesulfonate, gluconate, aspartate, or glutamate. R 21 , R 22 , R 23 Each example is independently H, and optionally substituted C. 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 an alkylene group, R 2b , R' 2b and R'' 2b Each example is independently H or C 1-10 It is an alkyl group, R z1 C 1-14 Alkyl alkyl group or C 1-14 This is an alkenyl group, where the alkyl group and alkenyl group can be optionally substituted.

[0090] In one embodiment, this specification provides a steroid compound of formula (II-C1), [ka] Alternatively, it may be a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt, where, R z1 teeth, [ka] And, R 2a H is replaced by C, which is optionally substituted. 1-8 Alkyl, -L 2b -OR 2b , L 2b -OC(O)R 2b or L 2b -C(O)OR 2b It is preferably H, -CH3, -CH2C(O)OCH3, or -CH2C(O)OH, V1 is NR 21 R 22 or N + R 21 R 22 R 23 And here R 21 , R 22 , R 23 These are H independently 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 R 21 and R 22 It is not hydrogen at the same time, L 2b C is either non-existent or optionally replaced. 1-10 It is an alkylene group, R 2b , R' 2b and R'' 2b Each of these is independently H or C 1-10 It is an alkyl group, M is absent or one or more anions, and the above anions are independently selected from chloride, bromide, iodide, sulfate, nitrate, perchlorate, formate, citrate, sulfonate, methanesulfonate, trifluoromethanesulfonate, trifluoroacetate, pyrosulfate, bisulfite, sulfite, bisulfite, phosphate, pyrophosphate, monohydrogen phosphate, dihydrogen phosphate, acetate, propionate, caprine, octanoate, acrylate, isobutyrate, hexanoate, heptanoate, oxalate, malonate, succinate, fumarate, maleate, benzoate, phthalate, phenylacetate, lactate, glycolate, tartrate, mandelate, methanesulfonate, gluconate, aspartate, or glutamate. m is an integer between 1 and 10, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0091] In one embodiment, this specification provides a steroid compound of formula (II-C2), [ka] Alternatively, it may be a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt, where, R z1 teeth, [ka] And, V1 is NR 21 R 22 or N + R 21 R 22 R 23 And here R 21 , R 22 , R 23These are H independently 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 R 21 and R 22 It is not hydrogen at the same time, L 2b C is either non-existent or optionally replaced. 1-10 It is an alkylene group, R 2b , R' 2b and R'' 2b Each of these is independently H or C 1-10 It is an alkyl group, M is absent or one or more anions, and the above anions are independently selected from chloride, bromide, iodide, sulfate, nitrate, perchlorate, formate, citrate, sulfonate, methanesulfonate, trifluoromethanesulfonate, trifluoroacetate, pyrosulfate, bisulfite, sulfite, bisulfite, phosphate, pyrophosphate, monohydrogen phosphate, dihydrogen phosphate, acetate, propionate, caprine, octanoate, acrylate, isobutyrate, hexanoate, heptanoate, oxalate, malonate, succinate, fumarate, maleate, benzoate, phthalate, phenylacetate, lactate, glycolate, tartrate, mandelate, methanesulfonate, gluconate, aspartate, or glutamate. m is an integer between 1 and 10, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0092] In one embodiment, the steroid compound is [ka] JPEG2026515723000054.jpg134149 JPEG2026515723000055.jpg188149 JPEG2026515723000056.jpg180149 JPEG2026515723000057.jpg201149 JPEG2026515723000058.jpg187149 JPEG2026515723000059.jpg96149 Alternatively, they may be selected from their stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts.

[0093] In one embodiment, the steroid compound is [ka] JPEG2026515723000061.jpg196149 Alternatively, these may be stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts.

[0094] In another embodiment, this specification provides steroid compounds, [ka] JPEG2026515723000063.jpg197149 Alternatively, they may be selected from their stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts.

[0095] In one embodiment, this specification provides lipid nanoparticles containing the steroid compound described herein. [Brief explanation of the drawing]

[0096] [Figure 1]The expression levels in the liver, lungs, and spleen of mice after administration of LNP5 in Test Example 3 are shown, with the three rows in the figure representing the experimental results for three different mice. [Modes for carrying out the invention]

[0097] 5. Modes for Carrying Out the Invention This specification provides lipid nanoparticle compositions, as well as their production and use.

[0098] In one embodiment, this specification provides lipid nanoparticles (LNPs, e.g., LNPs as described in Section 0). In one embodiment, the LNP comprises a steroid compound having a cationic group, also called a steroid ionized lipid (cationic steroid compound, Section 0). In one embodiment, the LNP comprises an ionized lipid (Section 0). In one embodiment, the LNP further comprises a phospholipid (Section 0). In one embodiment, the LNP does not contain a phospholipid. In one embodiment, the LNP further comprises a structural lipid (Section 0). In one embodiment, the LNP further comprises a polymer conjugate lipid, such as a polyethylene glycolated lipid (Section 0). In one embodiment, the LNP comprises a payload (Section 0).

[0099] In one embodiment, this specification provides lipid nanoparticle compositions (Section 0).

[0100] In one embodiment, when the LNP described herein is administered to a target, the payload is preferably delivered to an organ other than the liver (e.g., the spleen). In one embodiment, this specification provides an LNP composition for treating splenic disease or spleen-related disease.

[0101] In another embodiment, this specification provides pharmaceutical compositions comprising LNPs provided herein (Section 0).

[0102] This specification further provides a method for producing the LNP compositions described herein (see Section 0). This specification further provides a method for treating a disease using the LNP compositions described herein (Section 0). In one embodiment, this specification provides a method for treating a spleen disease or a spleen-related disease.

[0103] One aspect of the present invention relates to the discovery that including a steroid compound (e.g., a cationic steroid compound provided in Section 0) in LNPs significantly increases the delivery efficiency of LNPs and their payloads to the spleen. More specifically, compared to other cationic lipids (e.g., DOTAP), cationic steroid compounds further improve the delivery efficiency of LNPs and their payloads to the lungs. Cationic steroid compounds are effective at relatively low amounts, which can reduce toxicity and side effects.

[0104] 5.1 Definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. All patents, applications, published applications and other publications are incorporated by reference in their entirety. If a term herein has more than one definition, the definition in this section shall prevail unless otherwise specified.

[0105] The term "approximately" in this specification means roughly, roughly, generally, or approximately. When used with a numerical range, the term "approximately" modifies the range by extending the boundary above or below the stated numerical value. Generally, unless otherwise stated or the context makes clear, the term "approximately" may modify numerical values ​​above or below the stated value by 10% upward or downward (higher or lower) variance.

[0106] It should be noted that if there is a difference between the described structure and the name of that structure, the described structure will be given greater weight.

[0107] When a range of values ​​is listed, it is intended to include each value and subrange 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 contain an alkyl group.

[0108] As used herein, and unless otherwise stated, “alkyl group” refers to a linear or branched saturated hydrocarbon group formed by removing one hydrogen atom. For example, “C 1-24 "Alkyl group" refers to a straight-chain or branched hydrocarbon having 1 to 24 carbon atoms. 1-20 "Alkyl group" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 20 carbon atoms. 6-24 "Alkyl group" refers to a straight-chain or branched saturated hydrocarbon group having 6 to 24 carbon atoms. 6-20 An alkyl group refers to a linear or branched saturated hydrocarbon radical having 6 to 20 carbon atoms. In some embodiments, the alkyl group is C 1-24 Alkyl alkyl group, C 4-20 Alkyl alkyl group, C 6-20 Alkyl alkyl group, C 8-20 Alkyl alkyl group, C 10-20 Alkyl alkyl group, C 6-18 Alkyl alkyl group, C 6-16 Alkyl alkyl group, C 6-14 Alkyl alkyl group, C 6-12 Alkyl alkyl group, C 8-10 Alkyl alkyl group, C 2-8 Alkyl alkyl group, C 7-9 Alkyl alkyl group, C 4-6 Alkyl alkyl group, C 1-16 Alkyl alkyl group, C 1-14 Alkyl alkyl group, C2-14 Alkyl alkyl group, C 1-13 Alkyl alkyl group, C 1-12 Alkyl alkyl group, C 1-10 Alkyl alkyl group, C 1-8 Alkyl alkyl group, C 1-7 Alkyl alkyl group, C 2-7 Alkyl alkyl group, C 1-6 Alkyl alkyl group, C 1-5 Alkyl alkyl group, C5 alkyl group, C 1-4 Alkyl alkyl group, C 2-4 Alkyl alkyl group, C 1-3 Alkyl alkyl group, C 2-3 Alkyl alkyl group, C 1-2 It is an alkyl group or a methyl group. 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 group" further includes heteroalkyl groups in which one or more (e.g., one, two, three, or four) carbon atoms are substituted with heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). Alkyl groups may be substituted or unsubstituted. Alkyl groups may be optionally substituted with one or more substituents, for example, with 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).

[0109] As used herein, and unless otherwise stated, “alkenyl group” refers to a straight-chain or branched unsaturated hydrocarbon group having at least one carbon-carbon double bond. For example, “C 6-24 An "alkenyl group" refers to a straight-chain or branched hydrocarbon group having 6 to 24 carbon atoms and at least one carbon-carbon double bond.4-28 An "alkenyl group" refers to a straight-chain or branched hydrocarbon group having 4 to 28 carbon atoms and at least one carbon-carbon double bond. 4-20 An "alkenyl group" refers to a linear or branched hydrocarbon group having 4 to 20 carbon atoms and at least one carbon-carbon double bond. A "C2-14 alkenyl group" refers to a linear, linear or branched hydrocarbon group having 2 to 14 carbon atoms and at least one carbon-carbon double bond. In some embodiments, the alkenyl group is C 4-24 Alkenyl group, C 6-24 Alkenyl group, C 8-24 Alkenyl group, C 10-24 Alkenyl group, C8 alkenyl group, C9 alkenyl group, C 10 Alkenyl group, C 11 Alkenyl group, C 12 Alkenyl group, C 13 Alkenyl group, C 14 Alkenyl group, C 15 Alkenyl group, C 16 Alkenyl group, C 2-13 Alkenyl group, C 2-10 Alkenyl group, C 2-6 Alkenyl group or C 2-4 It is an alkenyl group. 2-6 Examples of alkenyl groups include ethenyl (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 group" further includes heteroalkenyl groups in which one or more (e.g., one, two, three, or four) carbon atoms are substituted with heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). Alkenyl groups may be substituted or unsubstituted. Alkenyl groups may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0110] As used herein, and unless otherwise stated, “alkynyl group” refers to a linear or branched hydrocarbon group having at least one carbon-carbon triple bond. For example, “C 4-20 An "alkynyl group" refers to a linear or branched hydrocarbon group having 2 to 20 carbon atoms and at least one carbon-carbon triple bond. In some embodiments, the alkynyl group is C 4-24 Alkynyl group, C 6-20 Alkynyl group, C 8-18 Alkynyl group, C8 alkynyl group, C9 alkynyl group, C 10 Alkynyl group, C 11 Alkynyl group, C 12 Alkynyl group, C 13 Alkynyl group, C 14 Alkynyl group, C 15 Alkynyl group, C 16 Alkynyl group, C 17 Alkynyl group, C 2-13 Alkynyl group, C 2-10 Alkynyl group, C 2-6 Alkynyl group or C 2-4 It is an alkynyl group. 2-6 Examples of alkynyl groups 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 group" further includes heteroalkynyl groups in which one or more (e.g., one, two, three, or four) carbon atoms are substituted with heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). Alkynyl groups may be substituted or unsubstituted. Alkynyl groups may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0111] As used herein, and unless otherwise stated, “alkylene group” refers to a divalent group formed by removing another hydrogen atom from an alkyl group. For example, “C 1-24 The alkylene group is C 1-24This refers to a divalent group formed by removing another hydrogen atom from an alkyl group. In some embodiments, the alkylene group is C 1-24 Alkylene group, C 4-24 Alkylene group, C 1-20 Alkylene group, C 8-20 Alkylene group, C8 alkylene group, C9 alkylene group, C 10 Alkylene group, C 11 Alkylene group, C 12 Alkylene group, C 13 Alkylene group, C 13 Alkylene group, C 14 Alkylene group, C 15 Alkylene group, C 16 Alkylene group, C 17 Alkylene group, C 18 Alkylene group, C 1-20 Alkylene group, C 1-14 Alkylene group, C 2-14 Alkylene group, C 1-13 Alkylene group, C 1-12 Alkylene group, C 1-10 Alkylene group, C 1-8 Alkylene group, C 7-9 Alkylene group, C 4-6 Alkylene group, C 1-7 Alkylene group, C 2-7 Alkylene group, C 1-6 Alkylene group, C 1-5 Alkylene group, C5 alkylene group, C 1-4 Alkylene group, C 2-4 Alkylene group, C 1-3 Alkylene group, C 2-3 Alkylene group, C 1-2The group is either an alkylene group or a methylene group. The alkylene group may be substituted or unsubstituted. 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 (for example, alkylene groups substituted with one or more alkyl groups (methyl groups)) include, but are not limited to, substituted methylene groups (-CH(CH3)-, -C(CH3)2-), substituted ethylene groups (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3)2-), substituted propylene groups (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), etc.

[0112] As used herein, and unless otherwise stated, "alkenylene group" refers to a divalent group formed by removing another hydrogen from an alkenyl group. For example, "C 2-24 The "alkenylene group" is formed when another hydrogen atom is removed, resulting in a divalent C of the alkenylene group. 2-24 This refers to an alkenyl group. In some embodiments, the alkenylene group is C 4-24 Alkenylene group, C 4-20 Alkenylene group, C 8-20 Alkenylene group, C 8-18 Alkenylene group, C 8-16 Alkenylene group, C 4-14 Alkenylene group, C 2-13 Alkenylene group, C 2-10 Alkenylene group, C 2-6 Alkenylene group or C 2-4This is an alkenylene group. The alkenylene group may be substituted or unsubstituted. Exemplary unsubstituted alkenylene groups include, but are not limited to, ethenylene (-CH=CH-) and propenylene (e.g., -CH=CHCH2-, -CH2-CH=CH-). Exemplary substituted alkenylene groups (e.g., alkenylene groups substituted with one or more alkyl groups (methyl groups)) include, but are not limited to, substituted ethenylene groups (-C(CH3)=CH-, -CH=C(CH3)-), substituted propenylene groups (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)-), etc.

[0113] As used herein, and unless otherwise stated, “alkynylene group” refers to a divalent group formed by removing another hydrogen from an alkynyl group. For example, “C 2-24 The "alkylylene group" is formed when another hydrogen atom is removed, resulting in a divalent C atom of the alkylylene group. 2-24 This refers to the alkynyl group. 2-13 The "alkylene group" is formed when another hydrogen atom is removed, resulting in a divalent radical of the alkylene group. 2-13 This refers to the alkynyl group. 4-14 The "alkylene group" is formed when another hydrogen atom is removed, resulting in a divalent radical of the alkylene group. 4-14 This refers to an alkynyl group. In some embodiments, the alkynylene group is C 2-24 Alkynylene group, C 2-20 Alkynylene group, C 4-16 Alkynylene group, C 8-16 Alkynylene group, C 9-16 Alkynylene group, C 10-16 Alkynylene group, C 4-12 Alkynylene group, C 2-10 Alkynylene group, C 2-6 Alkynylene group or C 2-4This is an alkynylene group. The alkynylene group may be substituted or unsubstituted. Exemplary alkynylene groups include, but are not limited to, ethynylene groups (-C≡C-) and substituted or unsubstituted propynylene groups (-C≡CCH2-).

[0114] "C 0-6 The alkylene group is a chemical bond as described above and C 1-6 This refers to the "alkylene group" and "C 0-4 The alkylene group is a chemical bond as described above and C 1-4 This refers to the "alkylene group".

[0115] The phrase "the combined length of variable A and variable B is x carbon atoms" means that the total 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 are both x.

[0116] "Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0117] A "haloalkyl group" refers to an alkyl group that is substituted with one or more halogens. For example, "C 1-10 "Haloalkyl group" is the above "C" which is substituted with one or more halogens. 1-10 This refers to an alkyl group. In some embodiments, the haloalkyl group is C 1-24 Haloalkyl group, C 1-20 Haloalkyl group, C 1-18 Haloalkyl group, C 1-16 Haloalkyl group, C 1-14 Haloalkyl group, C 1-12 Haloalkyl group, C 6-12 Haloalkyl group, C 1-6 Haloalkyl group, C 1-4 Haloalkyl group or C 1-2Haloalkyl groups are C1 haloalkyl groups, C2 haloalkyl groups, C3 haloalkyl groups, C4 haloalkyl groups, C5 haloalkyl groups, C6 haloalkyl groups, C7 haloalkyl groups, or C8 haloalkyl groups. Haloalkyl groups may optionally further include one or more non-halogenated substitutions. Exemplary haloalkyl groups include, but are not limited to, -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CF2CF3, -CCl3, -CH2Cl, -CHCl2, 2,2,2-trifluoro-1,1-dimethylethyl, etc. Haloalkyl groups may be substituted at any available bond point, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0118] As used herein, and unless otherwise stated, “cycloalkyl group” refers to a non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon atoms and hydrogen atoms. For example, “C 3-14 "Cycloalkyl group" or "3-14 membered cycloalkyl group" refers to 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, the cycloalkyl group is a 3-10 membered cycloalkyl group (C 3-10 Cycloalkyl groups), 5-10 member cycloalkyl groups (C 5-10 Cycloalkyl groups), 3-8 membered cycloalkyl groups (C 3-8 Cycloalkyl groups), 3-7 membered cycloalkyl groups (C 3-7 Cycloalkyl groups), 3-6 membered cycloalkyl groups (C 3-6 Cycloalkyl groups), 5-7 membered cycloalkyl groups (C 5-7 Cycloalkyl groups), 4-6 membered cycloalkyl groups (C 4-6 Cycloalkyl groups), 5-6 membered cycloalkyl groups (C 5-6These are cycloalkyl groups (C3 cycloalkyl groups), 3-membered cycloalkyl groups (C4 cycloalkyl groups), 4-membered cycloalkyl groups (C4 cycloalkyl groups), 5-membered cycloalkyl groups (C5 cycloalkyl groups), and 6-membered cycloalkyl groups (C6 cycloalkyl groups), 7-membered cycloalkyl groups (C7 cycloalkyl groups), or 8-membered cycloalkyl groups (C8 cycloalkyl groups). A cycloalkyl group further comprises a ring system, where the cycloalkyl ring described above is condensed with one or more aryl or heteroaryl groups having bonding sites on the cycloalkyl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the cycloalkyl system. A cycloalkyl group further comprises the cycloalkyl ring described above, wherein substituents on any non-adjacent carbon atoms are bonded to form a bridging ring, thereby forming a polycycloalkane sharing two or more carbon atoms. A cycloalkyl group further comprises the cycloalkyl ring described above, wherein substituents on the same carbon atom are bonded to form a ring, thereby forming a polycycloalkane sharing one carbon atom. Exemplary 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 be substituted or unsubstituted. Cycloalkyl groups may be substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0119] As used herein, and unless otherwise stated, “cycloalkylene group” refers to a divalent radical formed by removing another hydrogen from a cycloalkyl group. For example, “C 3-14 The "cycloalkylene group" is C 3-10This refers to a divalent group formed by removing another hydrogen from a cycloalkyl group. In some embodiments, the cycloalkylene group is C 3-12 Cycloalkylene group, C 3-8 Cycloalkylene group, C 3-6 Cycloalkylene group, C 3-5 Cycloalkylene group, C 3-4 The group is a cycloalkylene group, a C3 cycloalkylene group, a C4 cycloalkylene group, a C5 cycloalkylene group, or a C6 cycloalkylene group. The cycloalkylene group may be substituted or unsubstituted. Exemplary cycloalkylene groups include a cyclopropylene group, a cyclobutylene group, a cyclopentylene group, or a cyclohexylene group.

[0120] As used herein, and unless otherwise stated, “heterocyclyl group” 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, “3-14 membered heterocyclyl group” refers to a saturated or unsaturated radical of a 3-14 membered non-aromatic ring system having at least one ring heteroatom (e.g., 1-5 heteroatoms) and optionally containing 1, 2, or 3 double or triple bonds. In some embodiments, the ring heteroatoms in the heterocyclyl group are one or more selected from nitrogen, oxygen, sulfur, boron, phosphorus, or silicon. In a heterocyclyl group containing one or more nitrogen atoms, the bonding sites with the rest of the molecule may be carbon atoms or nitrogen atoms, as long as the valence allows. In some embodiments, the heterocyclyl group is a 3-10 membered heterocyclyl group, a 5-10 membered heterocyclyl group, a 5-10 membered nitrogen-containing heterocyclyl group, a 3-8 membered heterocyclyl group, a 3-8 membered nitrogen-containing heterocyclyl group, a 3-7 membered heterocyclyl group, a 5-7 membered heterocyclyl group, a 3-6 membered heterocyclyl group, a 4-6 membered heterocyclyl group, a 5 or 6 membered heterocyclyl group, a 4 membered heterocyclyl group, a 5 membered heterocyclyl group, a 6 membered heterocyclyl group, or a 7 membered heterocyclyl group. The heterocyclyl group further comprises a ring system, where the heterocyclyl group described above is condensed with one or more cycloalkyl groups having a bonding site on the heterocyclyl ring, or with one or more aryl or heteroaryl groups having a bonding site on the heterocyclyl ring, in which case the number of ring members continues to represent the number of ring members in the heterocyclyl ring system. The heterocyclyl group may further include the heterocyclyl ring described above, wherein substituents on any non-adjacent carbon or nitrogen atom are bonded to form a bridging ring, thereby forming a polycyclic heteroalkane sharing two or more carbon or nitrogen atoms. The heterocyclyl group may further include the heterocyclyl ring described above, wherein substituents on the same carbon atom are bonded to form a ring, thereby forming a polycyclic heteroalkane sharing one carbon atom. Exemplary three-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxyranyl, and thyranyl groups.Exemplary four-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl groups. Exemplary five-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary five-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, pyrazolidinyl, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidine-2-one. Five-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl groups. Exemplary six-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridyl, and tetrahydrothiopyranyl (thianyl) groups. Exemplary six-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl groups. Exemplary six-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazinanyl. Exemplary seven-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl groups. Exemplary five-membered heterocyclyl groups fused with a C6 aryl ring (also referred to herein as 5,6-biscycloheterocyclyl groups) include, but are not limited to, indolinyl groups, isoindolinyl groups, dihydrobenzofuranyl groups, dihydrobenzothienyl groups, and benzoxazolinonyl groups. Exemplary six-membered heterocyclyl groups fused with a C6 aryl ring (also referred to herein as 6,6-biscycloheterocyclyl groups) include, but are not limited to, tetrahydroquinolinyl groups and tetrahydroisoquinolinyl groups.To the extent that the valence allows, the heterocyclyl group further comprises the heterocyclyl ring described above, sharing one or two atoms with a cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group to form a bridging ring or spiro ring, wherein the shared atoms may be carbon atoms or nitrogen atoms. The heterocyclyl group further comprises the heterocyclyl ring described above, which may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0121] As used herein, and unless otherwise stated, “aryl group” refers to a monocyclic or polycyclic 4n+2 aromatic ring system group containing only carbon atoms and hydrogen atoms. For example, “C 6-10 An "aryl group" refers to a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system having 6 to 10 ring carbon atoms and 0 heteroatoms (e.g., having 6 or 10 shared π electrons in the cyclic arrangement). In some embodiments, the aryl group has 6 ring carbon atoms ("C6 aryl group," e.g., phenyl group). In some embodiments, the aryl group has 10 ring carbon atoms ("C6 aryl group"). 10 An aryl group is a naphthyl group, such as a 1-naphthyl group and a 2-naphthyl group. The aryl group further comprises a ring system, where the aryl ring described above is condensed with one or more cycloalkyl or heterocyclyl groups having bonding sites on the aryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system. The aryl group may be substituted or unsubstituted. The aryl group may be substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0122] As used herein, and unless otherwise stated, “heteroaryl group” refers to a monocyclic or polycyclic 4n+2 aromatic ring system having at least one ring heteroatom. For example, “5-14 membered heteroaryl group” refers to a radical of a 5-14 membered monocyclic or bicyclic 4n+2 aromatic ring system having a ring carbon atom and ring heteroatoms (e.g., 1-4 ring heteroatoms) (e.g., having 6, 10, or 14 π electrons shared in the cyclic arrangement). In some embodiments, each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In a heteroaryl group containing one or more nitrogen atoms, the bond site may be a carbon atom or a nitrogen atom, as long as the valence allows. A heteroaryl bicyclic system may contain one or more heteroatoms in one or two rings. The heteroaryl group further comprises a ring system, where the heteroaryl ring described above is condensed with one or more cycloalkyl or heterocyclyl groups having a bond site on the heteroaryl ring. In such cases, the number of carbon atoms continues to represent the number of carbon atoms in the heteroaryl ring system. In some embodiments, the heteroaryl group is a 5- to 10-membered heteroaryl group, a 5- to 8-membered heteroaryl group, a 5- to 6-membered heteroaryl group, a 5-membered heteroaryl group, or a 6-membered heteroaryl group. Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, a pyrrolyl group, a furanyl group, and a thienyl group. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, an imidazolyl group, a pyrazolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, and an isothiazolyl group. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, a triazolyl group, an oxadiazolyl group (e.g., 1,2,4-oxadiazolyl group), and a thiadiazolyl group. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, a tetraazolyl group. An exemplary six-membered heteroaryl group containing one heteroatom may include, but is not limited to, a pyridyl group or a pyridone group. An exemplary six-membered heteroaryl group containing two heteroatoms may include, but is not limited to, a pyridazinyl group, a pyrimidinyl group, and a pyrazinyl group.Exemplary six-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, a triazinyl group and a tetraazinyl group, respectively. Exemplary seven-membered heteroaryl groups containing one heteroatom include, but are not limited to, an azacycloheptatrienyl group, an oxacycloheptatrienyl group and a thiocycloheptatrienyl group. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, an indolyl group, an isoindolyl group, an indazolyl group, a benzotriazolyl group, a benzothienyl group, an isobenzothienyl group, a benzofuryl group, a benzoisofuryl group, a benzimidazolyl group, a benzoxazolyl group, a benzoisoxazolyl group, a benzoxadiazolyl group, a benzothiazolyl group, a benzoisothiazolyl group, a benzothiadiazolyl group, an indenazinyl group and a prynyl group. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthilidinyl, pteridinyl, quinolinyl, isoquinolinyl, synnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl groups. Heteroaryl groups may be substituted or unsubstituted. Heteroaryl groups may be substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0123] A "hydroxyalkyl group" refers to an alkyl group that is substituted with one or more hydroxyl groups.

[0124] An "alkoxy group" refers to a linear or branched alkyl group, i.e., the oxyether form of an -O-alkyl group. Similarly, a "methoxy group" refers to an -O-CH3 group.

[0125] Divalent groups formed by removing another hydrogen from the groups defined above (e.g., alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups) are collectively called "alkylene groups." Ring-forming groups such as cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups are collectively called "cyclyl groups."

[0126] As described herein, and unless otherwise stated, the term “optionally substituted” means unsubstituted or substituted. Substituents may be independently selected and substituted at any chemically acceptable position. As used herein, the term “substituted” means that a hydrogen atom is removed and replaced with a substituent. One divalent substituent (e.g., oxo) can substitute for two hydrogen atoms. It is understood that substitution at a given atom is limited by its valence. Exemplary examples of substituents are those found in the exemplary compounds, groups and embodiments disclosed herein, and halogens, deuterium, OH, CN, alkyl groups, haloalkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, aryl groups, heterocyclyl groups, heteroaryl groups, heterocycloalkyl groups, cycloalkylalkyl groups, heterocyclylalkyl groups, or heteroarylalkyl groups. The substitution may be further optionally substituted with another substitution, such as halogen, deuterium, OH, CN, alkyl group, haloalkyl group, alkoxy group, cycloalkyloxy group, aryloxy group, heterocyclyloxy group, heteroaryloxy group, heterocycloalkyloxy group, heterocyclylalkoxy group, heteroaryloxy group, oxo(-O), amino group, alkylamino group, cycloalkylamino group, heteroarylamino group, guanidino group, acylamino group, sulfonylamino group, urea, nitrourea, oxime, hydroxyamino group, alkoxyamino group, hydrazine, azide group, nitro group, thio(-SH), sulfonyl group, aminosulfonyl group, acyl group, formyl group, carboxyl group, ester, carbamate, amide group, cyano group, or isocyanate group.

[0127] All alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups as defined herein are all optionally substituted groups.

[0128] Exemplary substituents on carbon atoms include halogen, -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(Raa)3、-OSi(R aa )3、-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa-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)(ORcc)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)(ORcc)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 ), including, but not limited to, alkyl groups, haloalkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups, where each of the alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups may independently contain 0, 1, 2, 3, 4 or 5 R dd Substituted by 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 Substituted with the base, R aaEach of these is independently selected from alkyl groups, haloalkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, or two R aa The groups combine to form a heterocyclyl group or a heteroaryl ring, where each of the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group independently has 0, 1, 2, 3, 4, or 5 R groups. dd Substituted with the base, R bb Each of these is 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 groups, haloalkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups, or two R bb The groups combine to form a heterocyclyl group or a heteroaryl ring, where each of the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group independently has 0, 1, 2, 3, 4, or 5 R groups. dd Substituted with the base, R ccEach of these is independently selected from hydrogen, alkyl groups, haloalkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, or two R cc The groups combine to form a heterocyclyl group or a heteroaryl ring, where each of the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group independently has 0, 1, 2, 3, 4, or 5 R groups. dd Substituted with the base, R dd Each of these is independently halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2, -N(R ff )3 + X - , -N(OR ee )R ff -SH, -SR ee -SSR ee -C(=O)R ee -CO2H, -CO2R ee -OC(=O)R ee , -OCO2R ee -C(=O)N(R ff )2, -OC(=O)N(R ff )2, -NR ff C(=O)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, -NRff 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 groups, haloalkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups, where each of alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups is independently present in 0, 1, 2, 3, 4 or 5 R gg Substituted by or two geminal R dd The substituents may combine to form =O or =S. R ee Each of these is independently selected from alkyl groups, haloalkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, aryl groups, heterocyclyl groups, and heteroaryl groups, where each of the alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups is independently selected to have 0, 1, 2, 3, 4, or 5 R gg Substituted with the base, R ff Each of these is independently selected from hydrogen, alkyl groups, haloalkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, or two R ffThe groups combine to form a heterocyclyl group or a heteroaryl ring, where each of the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group independently has 0, 1, 2, 3, 4, or 5 R groups. gg Substituted with the base, R gg Each of these is independently halogen, -CN, -NO2, N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -ON(C 1-6 Alkyl)2,-N(C 1-6 Alkyl)2,-N(C 1-6 Alkyl)3 + X - -NH(C1-6 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 alkyl group, -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 1-6 Alkyl), -OC(=NH)(C1-6 Alkyl), -OC(=NH)OC 1-6 Alkyl group, -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 alkyl groups, -SO2OC 1-6 Alkyl alkyl group, -OSO2C 1-6 Alkyl alkyl groups, -SOC 1-6 Alkyl group, -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 group, -SC(=S)SC 1-6 Alkyl group, -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 alkyl group, C 1-6 Haloalkyl groups, C2-C6 alkenyl groups, C2-C6 alkynyl groups, C3-C7 cycloalkyl groups, C6-C 10 Aryl group, C3-C7 heterocyclyl group, C5-C 10 Selected from heteroaryl groups, or two geminal R groups gg The substituents combine to form =O or =S, where X- is the counterion.

[0129] Exemplary substituents on the nitrogen atom are 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, including but not limited to alkyl groups, haloalkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups, or two R groups bonded to a nitrogen atom cc The groups combine to form a heterocyclyl group or a heteroaryl ring, where each of the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group independently has 0, 1, 2, 3, 4, or 5 R groups. dd Substituted with the base, where R aa , R bb , R cc and R dd This is as described herein.

[0130] "Nucleic acid" refers to single-stranded or double-stranded deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) molecules and their hybrid 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 oligonucleotide (ASO). Nucleic acids may be further chemically modified, and the chemical modifiers may be 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, a 5' cap, a 5' untranslated region (5'UTR), a 3' untranslated region (3'UTR), a polyadenonucleotide sequence (PolyA), and a miRNA binding site.

[0131] As used herein, the term "pKa" refers to the negative logarithm (p) of the acid dissociation constant (Ka) of an acid, and is equal to the pH value when an equal concentration of the acid and its conjugate base are present in a solution. As used herein, the term "pKa" can be measured using water or dimethyl sulfoxide as a solvent. Observations previously reported as pKa when using water as a solvent can be used as pKa as used herein. In some embodiments, pKa can be determined by experiments such as titration experiments using hydrochloric acid or sodium hydroxide. In some embodiments, pKa is determined by the 2-(p-toluidino)naphthalene-6-sulfonic acid (TNS) fluorescence method.

[0132] As used herein, the terms “ionization” or “ionizing group” refer to a chemical group that is ionized or can be ionized. Ionizing groups can exist in the form of a neutral group, a positively charged group (cationic group), or a negatively charged group (anionic group). As used herein, “charged moiety” refers to a chemical moiety that carries a charge, such as monovalent (+1 or -1), divalent (+2 or -2), or trivalent (+3 or -3).

[0133] As used herein, the term “treatment” refers to reversing, mitigating, or inhibiting the progression of the disease or condition to which the above term applies, or preventing the disease or condition, or reversing, mitigating, or inhibiting the progression of one or more symptoms of such disease or condition, or preventing one or more symptoms. As used herein, the noun “treatment” refers to the act of treatment (verb), and treatment (verb) is as defined above.

[0134] As used herein, the term “pharmaceutically acceptable salt” refers to carboxylate and amino acid addition salts of the compounds disclosed, which are suitable for contact with patient tissues within the bounds of reliable medical judgment and do not produce inappropriate toxicity, irritation, allergic reactions, etc. They are commensurate with a reasonable benefit / risk ratio and are effective for their intended use. Where possible, the above term includes the amphoteric forms of the compounds disclosed.

[0135] pharmaceutically acceptable base addition salts are formed from metals or amines, such as hydroxides of alkali metals and alkaline earth metals or organic amines. Metals used as cations include sodium, potassium, magnesium, and calcium. Examples of suitable amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine.

[0136] 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 contacting the salt form with the acid and then isolating the free acid using conventional methods. The free acid form differs from its salt form in physical properties such as solubility in polar solvents. However, for the purposes of this disclosure, the salt is still equivalent to its free acid.

[0137] Salts can be produced from inorganic acids, which include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, and iodides. Examples of inorganic acids include hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, and phosphoric acid. Typical salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthalenedicarboxylate, methanesulfonate, glucoheptanoate, lactobionate, laurylsulfonate, and isethionate. Salts can also be produced from organic acids, which include aliphatic monocarboxylic acids and dicarboxylic acids, phenyl-substituted alkanes, hydroxyalkanoates, alkanedioates, aromatic acids, aliphatic sulfonic acids, and aromatic sulfonic acids. Typical salts include acetate, propionate, octanoate, isobutyrate, oxalate, malonate, succinate, suberinate, sebacinate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, naphthoate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, and methanesulfonate. Pharmaceutically acceptable salts include, but are not limited to, cations based on alkali metals and alkaline earth metals (such as sodium, lithium, potassium, calcium, and magnesium), as well as non-toxic ammonium, quaternary ammonium, and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine. Salts of amino acids, such as arginine salts, glucons, and galacturons, are also included (see, for example, Berge SM et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977;66:1-19).

[0138] The “subjects” to be administered 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 people, middle-aged or elderly)) and / or non-human animals, e.g., primates (e.g., cynomolgus macaques, rhesus macaques), mammals such as 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” are used interchangeably herein.

[0139] The terms "disease," "symptom," and "condition" are used interchangeably in this specification.

[0140] Unless otherwise stated herein, the term “treatment” includes, as used herein, an effect on an object suffering from a particular disease, condition, or illness that reduces the severity of the disease, condition, or illness, or that delays or mitigates the progression of the disease, condition, or illness (“therapeutic treatment”). The same term further includes an effect that occurs before the object suffers from a particular disease, condition, or illness (“preventive treatment”).

[0141] Generally, the “effective dose” of a pharmaceutical composition refers to an amount sufficient to induce a target biological response. As will be understood by those skilled in the art, 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 mode of administration, and the age, health status, and symptoms of the subject. The effective dose includes the therapeutic effective dose and the prophylactic effective dose. Unless otherwise indicated, as used herein, the “therapeutic effective dose” of a pharmaceutical composition is an amount sufficient to provide a therapeutic benefit in the course of treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. The therapeutic effective dose of a pharmaceutical composition refers to the amount of the therapeutic agent that provides a therapeutic benefit in the treatment of a disease, disorder, or condition, whether used alone or in combination with other therapies. The term “therapeutic effective 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.

[0142] Unless otherwise stated herein, the terms “steroid compound” or “cationic steroid compound” refer to any steroid compound comprising at least one cationic moiety. As used herein, the term “steroid” is a class of compounds having a tetracyclic 17-carbon cyclic structure, which may further include, but are not limited to, one or more substitutions comprising an alkyl group, alkoxy group, hydroxyl group, oxo group, acyl group, or a double bond between two or more carbon atoms. As used herein, the term “steroid” further includes steroid esters and sterols. As used herein, the term “steroid” further includes compounds belonging to or related to exemplary families of compounds such as corticosteroids, mineralocorticosteroids, and sex steroids (e.g., androgens or estrogens, or anti-androgen and anti-estrogen molecules). Non-limiting examples of steroids include cholesterol, cholestane, campesterol, sitosterol, sitostanol, β-sitosterol, stigmasterol, stigmasterol, brassicasterol, avenasterol, ergosterol, ursolic acid, tocopherol, lumisterol, or derivatives thereof. In one embodiment, the cationic steroid compound is an ionized steroid compound or an amphoteric steroid compound that changes to be positively charged at a certain pH. In one embodiment, the cationic steroid compound is a persistent cationic steroid compound. In one embodiment, the cationic steroid compound is a compound described in Section 0.

[0143] Unless otherwise stated herein, the term “biodegradable” means a substance that is broken down under physiological conditions. In some embodiments, a biodegradable substance is a substance that is broken down by cellular organelles. In some embodiments of any aspect, a biodegradable substance is a substance that is broken down by chemical processes. As used herein, the term “biodegradable group” means a group that contains one or more bonds that can undergo bond cleavage reactions in a biological environment such as a living organism, organ, tissue, cell or organelle. For example, a biodegradable group may be metabolized by the body of a mammal (e.g., 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 are -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)-. The term "biodegradable lipid" refers to a lipid that has one or more biodegradable groups at the intermediate or distal end of the lipid portion (e.g., the hydrophobic chain) of the lipid. Without being bound by theory, the incorporation of biodegradable groups into a lipid results in the lipid being metabolized more rapidly and removed from in vivo after the delivery of the payload.

[0144] Unless otherwise specified, the term “structural lipids” refers to neutral sterols, and also to lipids containing a neutral sterol moiety. Without being bound by theory, the incorporation of structural lipids into lipid nanoparticles helps to alleviate the aggregation of other lipids within the particles. Structural lipids may be selected from a group including, but not limited to, cholesterol, fecosterol, sitosterol, ergosterol, campesterol, stigmasterol, brassicasterol, tomatidine, tomatine, ursolic acid, α-tocopherol, hopanoids, plant sterols, or mixtures thereof. In some embodiments, the structural lipid is a sterol. As defined herein, “sterol” is a subgroup of steroids consisting of steroid alcohols. In certain embodiments, the structural lipid is cholesterol. In certain embodiments, the structural lipid is an analogue of cholesterol. In certain embodiments, the structural lipid is α-tocopherol. Unless otherwise stated, as used herein, “structural lipid” is not the same as “steroid compound” or “cationic steroid compound” as used herein. In one embodiment, as used herein, “structural lipid” does not contain a cationic or ionized moiety. In one embodiment, as used herein, “structural lipid” does not contain a quaternary ammonium group or a tertiary amine group.

[0145] Unless otherwise stated herein, the term “polymer-conjugated lipid” refers to a polymer that binds to a lipid (e.g., polyethylene glycol (PEG), polypropylene glycol, polyvinylpyrrolidone, or poly(N-(2-hydroxypropyl)methacrylamide)). For example, PEG can bind to myristoyl diglyceride to produce DMG-PEG-2000. Alternatively, PEG can bind to DSPE to produce DSPE-PEG-2000. In one embodiment, the polymer-conjugated lipid is a polyethylene glycolated lipid. The polyethylene glycolated lipid may incorporate various functionalized PEG-terminated groups, including amines, carboxylic acids, azides, aldehydes, thiols, and hydroxyl moieties. Without being limited by theory, polymer-conjugated lipids can help improve cycle time, drug stability, suitability for different administration routes, and achieve targeted drug delivery.

[0146] 5.2 Lipid Nanoparticles In one embodiment, this specification provides lipid nanoparticles (LNPs). In one embodiment, the LNP comprises a steroid compound (steroid compound, Section 0). In one embodiment, the LNP comprises an ionized lipid (Section 0). In one embodiment, the LNP comprises a steroid compound (Section 0) and an ionized lipid (Section 0). In one embodiment, the LNP further comprises a phospholipid (Section 0). In one embodiment, the LNP does not contain a phospholipid. In one embodiment, the LNP further comprises a structural lipid (Section 0). In one embodiment, the LNP further comprises a polymer conjugate lipid (Section 0). In one embodiment, the LNP further comprises a payload (Section 0).

[0147] In one embodiment, the lipid nanoparticles described herein are not liposomes. In one embodiment, the lipid nanoparticles described herein essentially do not contain an aqueous lumen, or have a lumen of less than 10% of the total volume of the nanoparticles. In one embodiment, the lipid nanoparticles described herein include a monolayer lipid membrane. In one embodiment, the lipid nanoparticles described herein contain relatively small particles inside the lipid nanoparticles, where these relatively small particles bind to the payload described herein.

[0148] In one embodiment, this specification provides lipid nanoparticles for delivering or expressing a payload in the spleen of a target. In one embodiment, the amount of payload delivered or expressed in the spleen of the target is higher than the amount in the liver of the target. In one embodiment, the payload is delivered by systemic administration.

[0149] In one embodiment, the lipid nanoparticles include a steroid compound and an ionized lipid.

[0150] In one embodiment, the molar percentage of the steroid compound in the total lipids is 3 to 15 mol%, preferably 5 to 10 mol%, for example, 3 mol%, 4 mol%, 5 mol%, 6 mol%, 7 mol%, 8 mol%, 9 mol%, 10 mol%, 11 mol%, 12 mol%, 13 mol%, 14 mol%, or 15 mol%.

[0151] In one embodiment, the molar percentage of the ionized lipid is 35 to 70 mol%, more preferably 40 to 60 mol%, for example, 35 mol%, 40 mol%, 45 mol%, 50 mol%, 55 mol%, or 60 mol%.

[0152] In one embodiment, the lipid nanoparticles targeting the spleen further comprise phospholipids.

[0153] In one preferred embodiment, the molar percentage of the phospholipid is 5 to 30 mol%, preferably 5 to 20 mol%, more preferably 5 to 15 mol%, for example 5 mol%, 6 mol%, 7 mol%, 8 mol%, 9 mol%, 10 mol%, 11 mol%, 12 mol%, 13 mol%, 14 mol%, 15 mol%, 16 mol%, 17 mol%, 18 mol%, 19 mol%, or 20 mol%.

[0154] In one embodiment, the lipid nanoparticles targeting the spleen further include structural lipids such as cholesterol.

[0155] In one preferred embodiment, the molar percentage of the structural lipid is 10 to 80 mol%, more preferably 15 to 70 mol%, even more preferably 30 to 50 mol%, and most preferably 30 to 40 mol%, for example, 30 mol%, 35 mol%, 40 mol%, 45 mol%, 50 mol%, 55 mol%, or 60 mol%.

[0156] In one embodiment, the lipid nanoparticles targeting the spleen further comprise polymer-conjugated lipids such as polyethylene glycolated lipids.

[0157] In one preferred embodiment, the molar percentage of the polymer conjugate lipid is 0.25 to 10 mol%, more preferably 0.5 to 5 mol%, and even more preferably 0.5 to 3 mol%, for example 0.5 mol%, 0.6 mol%, 0.7 mol%, 0.8 mol%, 0.9 mol%, 1.0 mol%, 1.1 mol%, 1.2 mol%, 1.3 mol%, 1.4 mol%, 1.5 mol%, 1.6 mol%, 1.7 mol%. l%, 1.8mol%, 1.9mol%, 2.0mol%, 2.1mol%, 2.2mol%, 2.3mol%, 2.4mol%, 2.5mol%, 2.6mol%, 2.7mol%, 2.8mol%, 2.9m ol%, 3.0mol%, 3.1mol%, 3.2mol%, 3.3mol%, 3.4mol%, 3.5mol%, 3.6mol%, 3.7mol%, 3.8mol%, 3.9mol%, 4.0mol%.

[0158] In one embodiment, the average particle size of the lipid nanoparticles targeting the spleen is 50 to 800 nm, more preferably 50 to 400 nm, and even more preferably 80 to 200 nm, for example, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 nm.

[0159] In one embodiment, the lipid nanoparticles include (1) a steroid compound, (2) an ionized lipid, (3) a phospholipid compound, (4) a structural lipid, and (5) a polymer conjugate lipid. In one more preferred embodiment, the lipid nanoparticles further include a payload.

[0160] In one preferred embodiment, the lipid nanoparticles targeting the spleen are 6) 3-15 mol% steroid compounds, 7) 35-70 mol% ionized lipids, 8) 5-30 mol% phospholipids, 9) 10-80 mol% structural lipids, and 10) Contains components in molar percentages, such as polymer conjugate lipids, at concentrations of 0.25 to 10 mol%.

[0161] In one preferred embodiment, the lipid nanoparticles targeting the spleen are 6) 5-10 mol% steroid compound, 7) 40-60 mol% ionized lipids, 8) 5-20 mol% phospholipids, 9) 15-70 mol% structural lipids, and 10) Contains components in molar percentages, such as polymer conjugate lipids, at a concentration of 0.5 to 5 mol%.

[0162] In one preferred embodiment, the lipid nanoparticles targeting the spleen are 6) 5-10 mol% steroid compound, 7) 40-60 mol% ionized lipids, 8) 5-15 mol% phospholipids, 9) 30-50 mol% structural lipids, and 10) Contains components in molar percentages, such as polymer conjugate lipids, at a concentration of 0.5 to 3 mol%.

[0163] In one particularly preferred embodiment, the lipid nanoparticles targeting the spleen are 6) 5 mol% steroid compound, 7) 50 mol% ionized lipids, 8) 10 mol% phospholipids, 9) 33.5 mol% structural lipids, and 10) Contains components in molar percentages, such as 1.5 mol% polymer conjugate lipids.

[0164] In one embodiment, the particle size distribution (PDI) of the lipid nanoparticles is 0.2 or less, preferably 0.15 or less.

[0165] In one embodiment, after administration, the ratio of the amount distributed to the spleen to the amount distributed to the liver of the lipid nanoparticles is 1 or more, more preferably 2 or more, more preferably 3 or more, more preferably 4 or more, more preferably 5 or more, more preferably 10 or more, more preferably 20 or more, more preferably 30 or more, more preferably 40 or more, more preferably 50 or more, and more preferably 100 or more.

[0166] In one embodiment, after administration, the ratio of the amount distributed to the spleen to the amount distributed to the lungs of the lipid nanoparticles is 1 or more, more preferably 2 or more, more preferably 3 or more, more preferably 4 or more, more preferably 5 or more, more preferably 10 or more, more preferably 20 or more, more preferably 30 or more, more preferably 40 or more, more preferably 50 or more, and more preferably 100 or more.

[0167] 5.2.1. Steroid Compounds In one embodiment, the lipid nanoparticles comprise a steroid compound containing one or more cationic groups.

[0168] 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), imidazolyl group, pyridyl group, pyrrolyl group, pyrrolidinyl group, pyrazolyl group, isothiazolyl group, isoxazolyl group, oxadiadinyl group, oxazolinyl group, dithioureazolyl group, isotriazolyl group, tetrazolyl group, pentazolyl group, indolyl group, indolinyl group, isoxazolyl group, pyrimidinyl group, pyrazinyl group, quinazolinyl group, piperazinyl group, piperidinyl group, morpholinyl group, pyranyl group, quinoxalinyl group, quinolinyl group, quinolinonyl group, isoquinolinyl group, amidino group, guanidino group, or urea group.

[0169] 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 includes a quaternary ammonium group and a β-sitosterol moiety. In one embodiment, the cationic steroid compound includes a tertiary amine group and a β-sitosterol moiety. In one embodiment, the cationic group is an amidino group, a guanidino group, or a urea group.

[0170] In one embodiment, the steroid compound is a persistent cationic steroid compound (i.e., positively charged regardless of pH). In one embodiment, the steroid compound is an ionized cationic steroid compound (e.g., positively charged at a certain pH). In one embodiment, the steroid compound is an amphoteric steroid compound.

[0171] In one embodiment, the steroid compound comprises a Z1 moiety containing three condensed cyclohexyl rings and one condensed cyclopentyl ring, where one or more of the CC bonds in the rings are optionally substituted with C=C double bonds. In one embodiment, Z1 comprises an optionally substituted cyclopentane polyhydrophenanthrene moiety.

[0172] In one embodiment, the steroid compound comprises a Z1 portion, where Z1 is [ka] Or a stereoisomer thereof or a mixture of stereoisomers, where one or more ring CC bonds of Z1 are independently and optionally substituted with C=C bonds where valence allows, and where Z1 is optionally a hydroxyl group, a halogen and C 1-14 Alkyl alkyl group or C 1-14 Substituted with one or more groups selected from alkenyl groups, where the alkyl group is optionally one or more hydroxyl groups, nitro groups, cyano groups, halogens, C 1-6 Alkoxy group, C2-C6 alkenyl group, C2-C6 alkynyl group, C3-C8 cycloalkyl group, C6-C 10 The group is substituted with an aryl group, a 5-10 membered heteroaryl group, or a 3-8 membered heterocyclyl group, and the bond at Z1 is directed toward the rest of the steroid compound.

[0173] 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, stigmasterol, brassicasterol, avenasterol, ergosterol, ursolic acid, tocopherol, lumisterol, or their stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts.

[0174] In one embodiment, the pKa of the steroid compound is between 5 and 8. In one embodiment, the pKa of the steroid compound is between 5.5 and 6.5. In one embodiment, the pKa of the steroid compound is greater than 8. In one embodiment, the pKa of the steroid compound is greater than 10. In one embodiment, the pKa of the steroid compound is greater than 10.

[0175] In one embodiment, the steroid compound is a compound of formula (C), M - V1-[-(R 20 ) a1 -Y1] n1 -Z1(C) Alternatively, it may be a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt, where, Z1 is a steroid that has been selectively substituted, Each example of Y1 either does not exist independently, 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-, -SS-, or -S(O) 0-2 -Therefore, the left connection is directed towards V1, and the right connection is directed towards Z1, R 2a Each example is independently H, C 1-10 Alkyl alkyl group, C 3-14 A cycloalkyl group or a 3-14 membered heterocyclyl group, wherein the alkyl group, cycloalkyl group and heterocyclyl group are independently and optionally C 1-10 Alkyl, L 2b -OR 2b Lb-SR 2b , L 2b -NR 2b R' 2b or L 2b N + R 2b R' 2b R'' 2b Replaced by, R20 Each example is independently -(CR 201 R 202 )- and here, R 201 and R 202 Each example independently includes H, OH, alkyl group, alkoxy group, 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 optionally substituted nitrogen-containing heterocyclyl groups selected from the group consisting of imidazole, pyridine, pyrrole, pyrrolidine, pyrazole, isothiazole, isoxazole, oxadiazine, oxazoline, dithioureaoxazole, isotriazole, tetrazole, pentazole, indole, indoline, isoxazole, pyrimidine, pyrazine, quinazoline, piperazine, piperidine, morpholine, pyran, quinoxaline, quinoline, quinolinone and isoquinoline, or nitrogen-containing non-heterocyclyl groups selected from amidine, guanidine or urea. M is either absent or selected from the anions of chloride, bromide, iodide, sulfate, nitrate, perchlorate, formate, phosphate, pyrophosphate, citrate, sulfonate, methanesulfonate, trifluoromethanesulfonate, 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 an alkylene group, and R 2b , R' 2b and R'' 2b Each of these is independently H or C 1-10 It is an alkyl group.

[0176] In one embodiment, a1 is 3, 4, 5, 6, 7, 8, 9, or 10.

[0177] In one embodiment, n1 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0178] In one embodiment, the steroid compound is a compound of formula (C1), M - V1-(R 20 ) 2-8 -Y1-Z1(C1) 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) In one embodiment, R 20 is, -(CR 201 R 202 )- and here, R 201 and R 202 Each example independently includes H, OH, alkyl group, alkoxy group, and -L. 2b -NR 21 R 22 or -L 2b -N + R 21 R 22 R 23 In one embodiment, R 20 is, -(CR 201 R 202 )- and here, R 201 and R 202 Each example is independently H, C 1-6Alkyl alkyl, -NR 21 R 22 or -N + R 21 R 22 R 23 And, In one embodiment, the steroid compound is a compound of formula (I), [ka] Alternatively, it may be a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt, where, [ka] These are 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 here the leftward connection 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)-, -NR2a 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 - is selected from and here the left connection is directed towards V1, R 2a Each example is independently H, C 1-10 Alkyl alkyl group, C 3-14 A cycloalkyl group or a 3-14 membered heterocyclyl group, wherein the alkyl group, cycloalkyl group and heterocyclyl group are independently and optionally C 1-10 Alkyl, L 2b -OR 2b Lb-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 Replaced by, R 201 , R 202 , R 203 , R 204 Each example independently includes H, OH, alkyl group, alkoxy group, 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 R22 R 23 These are imidazole, pyridine, pyrrole, pyrrolidine, pyrazole, isothiazole, isoxazole, oxadiazine, oxazoline, dithioureaoxazole, isotriaazole, tetrazole, pentasol, indole, indoline, isoxazole, pyrimidine, pyrazine, quinazoline, piperazine, piperidine, morpholine, pyran, quinoxaline, quinoline, quinolinone, isoquinoline, amidine, guanidine, or urea. M is absent or one or more anions, and the above anions are independently selected from chloride, bromide, iodide, sulfate, nitrate, perchlorate, formate, citrate, sulfonate, methanesulfonate, trifluoromethanesulfonate, trifluoroacetate, pyrosulfate, bisulfite, sulfite, bisulfite, phosphate, pyrophosphate, monohydrogen phosphate, dihydrogen phosphate, acetate, propionate, caprine, octanoate, acrylate, isobutyrate, hexanoate, heptanoate, oxalate, malonate, succinate, fumarate, maleate, benzoate, phthalate, phenylacetate, lactate, glycolate, tartrate, mandelate, methanesulfonate, gluconate, aspartate, or glutamate. R 21 , R 22 , R 23 Each example is independently H, and optionally substituted C. 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 an alkylene group, R 2b , R' 2band R'' 2b Each example is independently H or C 1-10 It is an alkyl group, and R z1 C 1-14 Alkyl alkyl group or C 1-14 This is an alkenyl group, where the alkyl group and alkenyl group can be optionally substituted.

[0179] In one embodiment, the steroid compound is a compound of formula (I), [ka] Alternatively, it may be a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt, where, [ka] These are 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 here the leftward connection 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 2aC(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 here the leftward connection is directed towards V1, R 2a Each example is independently H, C 1-10 Alkyl alkyl group, C 3-14 A cycloalkyl group or a 3-14 membered heterocyclyl group, wherein the alkyl group, cycloalkyl group and heterocyclyl group are independently and optionally C 1-10 Alkyl, L 2b -OR 2b Lb-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 Replaced by, R 201 , R 202 , R 203 , R 204 Each example independently includes H, OH, alkyl group, alkoxy group, 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 These are imidazole, pyridine, pyrrole, pyrrolidine, pyrazole, isothiazole, isoxazole, oxadiazine, oxazoline, dithioureaoxazole, isotriaazole, tetrazole, pentasol, indole, indoline, isoxazole, pyrimidine, pyrazine, quinazoline, piperazine, piperidine, morpholine, pyran, quinoxaline, quinoline, quinolinone, isoquinoline, amidine, guanidine, or urea. M is absent or one or more anions, and the above anions are independently selected from chloride, bromide, iodide, sulfate, nitrate, perchlorate, formate, citrate, sulfonate, methanesulfonate, trifluoromethanesulfonate, trifluoroacetate, pyrosulfate, bisulfite, sulfite, bisulfite, phosphate, pyrophosphate, monohydrogen phosphate, dihydrogen phosphate, acetate, propionate, caprine, octanoate, acrylate, isobutyrate, hexanoate, heptanoate, oxalate, malonate, succinate, fumarate, maleate, benzoate, phthalate, phenylacetate, lactate, glycolate, tartrate, mandelate, methanesulfonate, gluconate, aspartate, or glutamate. R 21 , R 22 , R 23 Each example is independently H, and optionally substituted C. 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 2bC is either non-existent or optionally replaced. 1-10 It is an alkylene group, R 2b , R' 2b and R'' 2b Each example is independently H or C 1-10 It is an alkyl group, R z1 C 1-14 Alkyl alkyl group or C 1-14 It is an alkenyl group, where the alkyl group and alkenyl group can be optionally substituted, and As a premise, if Y is -NHC(O)-, (i) m is an integer between 5 and 12, or (ii) V1 is not N(CH3)2, and at least one of these conditions is met.

[0180] In one embodiment, the steroid compound is a compound of formula (IP), [ka] Alternatively, it may be a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt, where, [ka] These are single or double bonds, 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 -, -NR2a C(S)O-, -S(O) 0-2 - or -OPO3-, and here the left bond is directed towards V1, R 2a Each example is independently H, C 1-10 Alkyl alkyl group, C 3-14 A cycloalkyl group or a 3-14 membered heterocyclyl group, wherein the alkyl group, cycloalkyl group and heterocyclyl group are independently and optionally 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 Replaced by, R 201 , R 202 , R 203 , R 204 Each example independently includes H, OH, alkyl group, alkoxy group, 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 It either does not exist, or it is a cation, H, C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 2-6 Alkenyl group or C 2-6 It is an alkynyl group, and here the alkyl group, haloalkyl group, alkenyl group and alkynyl group can be 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 These are imidazole, pyridine, pyrrole, pyrrolidine, pyrazole, (iso)thiazole, (iso)oxazole, oxadiazine, oxazoline, dithioureazole, (iso)triazole, tetrazole, pentasol, indole, indoline, pyrimidine, pyrazine, quinazoline, piperazine, piperidine, morpholine, pyran, quinoxaline, quinoline, quinolinone, (iso)quinoline, amidine, guanidine, or urea. M is absent or one or more anions, and the above anions are independently selected from chloride, bromide, iodide, sulfate, nitrate, perchlorate, formate, citrate, sulfonate, methanesulfonate, trifluoromethanesulfonate, trifluoroacetate, pyrosulfate, bisulfite, sulfite, bisulfite, phosphate, pyrophosphate, monohydrogen phosphate, dihydrogen phosphate, acetate, propionate, caprine, octanoate, acrylate, isobutyrate, hexanoate, heptanoate, oxalate, malonate, succinate, fumarate, maleate, benzoate, phthalate, phenylacetate, lactate, glycolate, tartrate, mandelate, methanesulfonate, gluconate, aspartate, or glutamate. R 21 , R 22 , R 23 Each example is independently H, and optionally substituted C. 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, L2b C is either non-existent or optionally replaced. 1-10 It is an alkylene group, R 2b , R' 2b and R'' 2b Each example is independently H or C 1-10 It is an alkyl group, R z1 C 1-14 Alkyl alkyl group or C 1-14 It is an alkenyl group, where the alkyl group and alkenyl group can be optionally substituted. In one embodiment of formula (I), V1 is NH2 or NH3 + No. In one embodiment of formula (I), Y is -NR 2a If it is C(O)-, then V1 is NH2 or NH3 + No. In one embodiment of formula (I), when Y is -NHC(O), V1 is NH2 or NH3 + isn't it.

[0181] The following embodiments apply to formulas (I) and (IP).

[0182] 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 -NR 2a 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 leftward coupling is directed towards V1.

[0183] 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 2aIt 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 to the left is directed towards V1.

[0184] In one embodiment, the steroid compound is a compound of formula (I-A1), (I-A2), (I-A3), (I-A4), or (I-A5), [ka] Alternatively, these may be stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts. 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] Alternatively, these are stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts, where m3 is an integer from 1 to 11.

[0185] In one embodiment, the steroid compound is a compound of formula (I-P1), [ka] Alternatively, it may be a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, where m3 is an integer from 1 to 11.

[0186] In one embodiment, m is an integer from 1 to 12. In one embodiment, m is an integer from 5 to 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.

[0187] In one embodiment, m1 is an integer from 0 to 12. In one embodiment, m1 is an integer from 0 to 6. In one embodiment, m1 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.

[0188] 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.

[0189] In one embodiment, R 2a H is H.

[0190] In one embodiment, R 2a C 1-10 It is an alkyl group. In one embodiment, R 2a C 1-6 It is an alkyl group. In one embodiment, R 2a C 1-3 It is an alkyl group. In one embodiment, R 2a is a methyl group. 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 Lb-SR 2b It is replaced by R 2a The alkyl group is L 2b -NR 2b R' 2bIt is replaced by R 2a The alkyl group is L 2b N + R 2b R' 2b R'' 2b It will be replaced by this.

[0191] In one embodiment, R 2a C 3-14 It is a cycloalkyl group. In one embodiment, R 2a C 3-8 It is a cycloalkyl group. In one embodiment, R 2a C 3-6 It is a cycloalkyl group. In one embodiment, R 2a is a C3, C4, C5, or C6 cycloalkyl group. In one embodiment, R 2a The cycloalkyl group is not substituted. In one embodiment, R 2a The cycloalkyl group is C 1-10 It is substituted with an alkyl group. In one embodiment, R 2a The cycloalkyl group is L 2b -OR 2b It is replaced by R 2a The cycloalkyl group is Lb-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.

[0192] In one embodiment, R 2a R is a 3-14 member heterocyclyl group. In one embodiment, R 2a R is a 3- to 8-membered heterocyclyl group. In one embodiment, R 2a R is a 3-6 membered heterocyclyl group. In one embodiment, R 2aThis is a 3-6 membered nitrogen-containing heterocyclyl group. In one embodiment, R 2a This is a 3-6 member oxygen-containing heterocyclyl group. In one embodiment, R 2a The heterocyclyl group is not substituted. In one embodiment, R 2a The heterocyclyl group is C 1-10 It is substituted with an alkyl group. In one embodiment, R 2a The heterocyclyl group is L 2b -OR 2b It is replaced by R 2a The heterocyclyl group is L b -SR 2b It is replaced by R 2a The heterocyclyl group is L 2b -NR 2b R' 2b It is replaced by R 2a The heterocyclyl group is L 2b N + R 2b R' 2b R'' 2b It will be replaced by this.

[0193] In one embodiment, R 201 , R 202 , R 203 and R 204 Each example is independently H, C 1-6 Alkyl 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.

[0194] 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, or -C(O)OCH3.

[0195] 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.

[0196] In one embodiment, R 21 , R 22 , R 23 Each of these is independently H, a hydroxyl group, a C1-3 alkyl group, or C 1-3 It is a hydroxyalkyl group.

[0197] In one embodiment, V1 is an optionally substituted nitrogen-containing heterocyclyl group. In one embodiment, V1 is an optionally substituted 3- to 8-membered nitrogen-containing heterocyclyl group. In one embodiment, V1 is an optionally substituted nitrogen-containing heteroaryl group. In one embodiment, V1 is an optionally substituted 5 or 6-membered nitrogen-containing heteroaryl group. In one embodiment, V1 is selected from the group consisting of imidazole, pyridine, pyrrole, pyrrolidine, pyrazole, isothiazole, isoxazole, oxadiazine, oxazoline, dithioureaoxazole, isotriazole, tetrazole, pentazole, indole, indoline, isoxazole, pyrimidine, pyrazine, quinazoline, piperazine, piperidine, morpholine, pyran, quinoxaline, quinoline, quinolinone, and isoquinoline.

[0198] In one embodiment, V1 is a nitrogen-containing non-heterocycline group. In one embodiment, V1 is an optionally substituted amidino group. In one embodiment, V1 is an optionally substituted guanidino group. In one embodiment, V1 is an optionally substituted urea group.

[0199] 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.

[0200] 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.

[0201] In one embodiment, V1 is NH2. In one embodiment, V1 is NH3. + That is the case.

[0202] In one embodiment, R 21 , R 22 , R 23 H and C are independent of each other. 1-8 Alkyl, -L 2b -OR 2b , -L 2b -SR 2b or -L 2c -NR 2b R' 2b R'' 2bIn one embodiment, R 21 , R 22 , R 23 H and C are independent of each other. 1-6 alkyl group, -OR 2b , -SR 2b or -NR 2b R' 2b R'' 2b In one embodiment, R 21 , R 22 , R 23 These are H, hydroxyl group, and C, respectively, independently. 1-3 Alkyl alkyl group or C 1-3 It is a hydroxyalkyl group.

[0203] In one embodiment, R 21 H is H. In one embodiment, R 21 C 1-8 It is an alkyl group. In one embodiment, R 21 C 1-6 It is an alkyl group. In one embodiment, R 21 C 1-3 It is an alkyl group. In one embodiment, R 21 is a methyl group. In one embodiment, R 21 is an ethyl group. In one embodiment, R 21 is a propyl group or an isopropyl group. 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 Lb-OR 2b It is replaced by R 21 The alkyl group is Lb-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 + R2b R' 2b R'' 2b It will be replaced by this.

[0204] 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.

[0205] In one embodiment, R 22 H is H. In one embodiment, R 22 C 1-8 It is an alkyl group. In one embodiment, R 22 C 1-6 It is an alkyl group. In one embodiment, R 22 C 1-3 It is an alkyl group. In one embodiment, R 22 is a methyl group. In one embodiment, R 22 is an ethyl group. In one embodiment, R 22 is a propyl group or an isopropyl group. 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 Lb-OR 2b It is replaced by R 22 The alkyl group is Lb-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 + R2b R' 2b R'' 2b It will be replaced by this.

[0206] 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 -L2c-NR 2b R' 2b R'' 2b That is the case.

[0207] In one embodiment, R 23 H is H. In one embodiment, R 23 C 1-8 It is an alkyl group. In one embodiment, R 23 C 1-6 It is an alkyl group. In one embodiment, R 23 C 1-3 It is an alkyl group. In one embodiment, R 23 is a methyl group. In one embodiment, R 23 is an ethyl group. In one embodiment, R 23 is a propyl group or an isopropyl group. 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 Lb-OR 2b It is replaced by R 23 The alkyl group is Lb-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.

[0208] 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.

[0209] 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 an alkylene group. 2b This is C, which is optionally substituted. 1-6 It is an alkylene group. 2b This is C, which is optionally substituted. 1-3 It is an alkylene group. 2b The alkylene group is not substituted. In one embodiment, L 2b The alkylene group is one or more halogens, hydroxyl groups, or C 1-3 It is substituted with an alkoxy group.

[0210] In one embodiment, R 2b H is H. In one embodiment, R 2b C 1-10 It is an alkyl group. In one embodiment, R 2b C 1-6 It is an alkyl group. In one embodiment, R 2b C 1-3 It is an alkyl group. In one embodiment, R 2b is a methyl group. In one embodiment, R 2b is an ethyl group. In one embodiment, R 2bis a propyl group or an isopropyl group. In one embodiment, R 2b The alkyl group is not substituted. In one embodiment, R 2b The alkyl group is one or more halogens, hydroxyl groups, or C 1-3 It is substituted with an alkoxy group.

[0211] In one embodiment, R' 2b is H. In one embodiment, R' 2b C 1-10 It is an alkyl group. In one embodiment, R' 2b C 1-6 It is an alkyl group. In one embodiment, R' 2b C 1-3 It is an alkyl group. In one embodiment, R' 2b R' is a methyl group. In one embodiment, R' 2b is an ethyl group. In one embodiment, R' 2b is a propyl group or an isopropyl group. In one embodiment, R' 2b The alkyl group is not substituted. In one embodiment, R' 2b The alkyl group is one or more halogens, hydroxyl groups, or C 1-3 It is substituted with an alkoxy group.

[0212] In one embodiment, R'' 2b is H. In one embodiment, R'' 2b C 1-10 It is an alkyl group. In one embodiment, R'' 2b C 1-6 It is an alkyl group. In one embodiment, R'' 2b C 1-3 It is an alkyl group. In one embodiment, R'' 2b is a methyl group. In one embodiment, R'' 2b is an ethyl group. In one embodiment, R'' 2b is a propyl group or an isopropyl group. In one embodiment, R'' 2b The alkyl group is not substituted. In one embodiment, R''2b The alkyl group is one or more halogens, hydroxyl groups, or C 1-3 It is substituted with an alkoxy group.

[0213] 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 one or more anions, the anions being independently selected from chlorides, bromides, iodides, sulfates, nitrates, perchlorates, formates, citrates, sulfons, methanesulfons, trifluoromethanesulfons, trifluoroacetates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, pyrophosphates, monohydrogen phosphates, dihydrogen phosphates, acetates, propions, caprinates, octanates, acrylates, isobutyrates, hexanoates, heptanoates, oxalates, malons, succinates, fumarates, maleates, benzoates, phthalates, phenylacetates, lactates, glycolates, tartrates, mandelates, methanesulfons, glucons, aspartates, or glutamates.

[0214] In one embodiment, M is a chloride, bromide, iodide, sulfate, nitrate, perchlorate, formate, phosphate, pyrophosphate, citrate, sulfonate, methanesulfonate, trifluoromethanesulfonate, or trifluoroacetate. In one embodiment, M is absent or is one or more of bromides, chlorides, or trifluoroacetates.

[0215] In one embodiment, R z1 C 1-14 Alkyl alkyl group or C 1-14 The group is an alkenyl group, where the alkyl group and alkenyl group can be optionally one or more hydroxyl groups, oxo groups, nitro groups, cyano groups, halogens, or C groups. 1-6 Alkoxy group, C2-C6 alkenyl group, C2-C6 alkynyl group, C3-C8 cycloalkyl group, C6-C 10It is substituted with an aryl group, a 5-10 membered heteroaryl group, or a 3-8 membered heterocyclyl group. In one embodiment, R z1 C 3-12 Alkyl alkyl group or C 3-12 It is an alkenyl group. z1 C 7-10 Alkyl alkyl group or C 7-10 It is an alkenyl group. z1 is a C7 alkyl group or a C7 alkenyl group. In one embodiment, R z1 is a C8 alkyl group or a C8 alkenyl group. In one embodiment, R z1 is a C9 alkyl group or a C9 alkenyl group. In one embodiment, R z1 C 10 Alkyl alkyl group or C 10 It is an alkenyl group.

[0216] In one embodiment, R z1 C 6-12 It is an alkyl group. In one embodiment, R z1 is the unsubstituted C 6-12 It is an alkyl group. In one embodiment, R z1 C is a C substituted with one or more oxo or hydroxyl groups. 6-12 It is an alkyl group.

[0217] In one embodiment, R z1 C 6-12 It is an alkenyl group. z1 is the unsubstituted C 6-12 It is an alkenyl group. z1 C is a C substituted with one or more oxo or hydroxyl groups. 6-12 It is an alkenyl group.

[0218] In one embodiment, Rz1 teeth, [ka] In one embodiment,Rz1 teeth, [ka] In one embodiment, Rz1 teeth, [ka] In one embodiment, Rz1 teeth, [ka] In one embodiment, Rz1 teeth, [ka] In one embodiment, Rz1 teeth, [ka] In one embodiment, Rz1 teeth, [ka] That is the case.

[0219] In one embodiment, the steroid compound is [ka] JPEG2026515723000082.jpg177149 JPEG2026515723000083.jpg175149 JPEG2026515723000084.jpg202149 JPEG2026515723000085.jpg203149 JPEG2026515723000086.jpg213149 JPEG2026515723000087.jpg182149 JPEG2026515723000088.jpg61149 Alternatively, these may be stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts.

[0220] In one embodiment, the steroid compound is [ka] Or they are not pharmaceutically acceptable salts.

[0221] In one embodiment, this specification describes a steroid compound of formula (II-A), [ka] Alternatively, it may be a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt, where, each [ka] These are independently single bonds 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 here the leftward connection 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 here the leftward connection is directed towards V1, R 2a Each example is independently H, C 1-10 Alkyl alkyl group, C 3-14 A cycloalkyl group or a 3-14 membered heterocyclyl group, wherein the alkyl group, cycloalkyl group and heterocyclyl group are independently and optionally C 1-10 Alkyl, L 2b -OR 2b Lb-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 Replaced by, R 201 , R 202 , R 203 , R 204 Each example independently includes H, OH, alkyl group, alkoxy group, and -L. 2b -NR 21 R 22 or -L 2b -N + R 21 R 22R 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 , N + R 21 R 22 R 23 These are imidazole, pyridine, pyrrole, pyrrolidine, pyrazole, (iso)thiazole, (iso)oxazole, oxadiazine, oxazoline, dithioureazole, (iso)triazole, tetrazole, pentasol, indole, indoline, pyrimidine, pyrazine, quinazoline, piperazine, piperidine, morpholine, pyran, quinoxaline, quinoline, quinolinone, (iso)quinoline, amidine, guanidine, or urea. M is absent or one or more anions, and the above anions are independently selected from chloride, bromide, iodide, sulfate, nitrate, perchlorate, formate, citrate, sulfonate, methanesulfonate, trifluoromethanesulfonate, trifluoroacetate, pyrosulfate, bisulfite, sulfite, bisulfite, phosphate, pyrophosphate, monohydrogen phosphate, dihydrogen phosphate, acetate, propionate, caprine, octanoate, acrylate, isobutyrate, hexanoate, heptanoate, oxalate, malonate, succinate, fumarate, maleate, benzoate, phthalate, phenylacetate, lactate, glycolate, tartrate, mandelate, methanesulfonate, gluconate, aspartate, or glutamate. R 21 , R 22 , R 23 These are H independently 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 an alkylene group, R 2b , R' 2b and R'' 2b Each of these is independently H or C 1-10 It is an alkyl group, and R z1 C 1-14 Alkyl alkyl group or C 1-14 It is an alkenyl group, where the alkyl group and alkenyl group can be optionally substituted, and is based on the premise that [ka] It is not that compound.

[0222] 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.

[0223] In one embodiment, the steroid compound is of formula (II-B), [ka] Alternatively, it may be a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt, where, 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 here the leftward connection 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 here the leftward connection is directed towards V1, R 2a Each example is independently H, C 1-10 Alkyl alkyl group, C 3-14 A cycloalkyl group or a 3-14 membered heterocyclyl group, wherein the alkyl group, cycloalkyl group and heterocyclyl group are independently and optionally C 1-10 Alkyl, L 2b -OR 2b , L b -SR 2b , L 2b -NR 2b R' 2b , L 2b N + R2b R' 2b R'' 2b , L 2b -OC(O)R 2b or L 2b -C(O)OR 2b Replaced by, R 201 , R 202 , R 203 , R 204 Each example independently includes H, OH, alkyl group, alkoxy group, 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 These are imidazole, pyridine, pyrrole, pyrrolidine, pyrazole, (iso)thiazole, (iso)oxazole, oxadiazine, oxazoline, dithioureazole, (iso)triazole, tetrazole, pentasol, indole, indoline, pyrimidine, pyrazine, quinazoline, piperazine, piperidine, morpholine, pyran, quinoxaline, quinoline, quinolinone, (iso)quinoline, amidine, guanidine, or urea. M is absent or one or more anions, and the above anions are independently selected from chloride, bromide, iodide, sulfate, nitrate, perchlorate, formate, citrate, sulfonate, methanesulfonate, trifluoromethanesulfonate, trifluoroacetate, pyrosulfate, bisulfite, sulfite, bisulfite, phosphate, pyrophosphate, monohydrogen phosphate, dihydrogen phosphate, acetate, propionate, caprine, octanoate, acrylate, isobutyrate, hexanoate, heptanoate, oxalate, malonate, succinate, fumarate, maleate, benzoate, phthalate, phenylacetate, lactate, glycolate, tartrate, mandelate, methanesulfonate, gluconate, aspartate, or glutamate. R 21 , R 22 , R 23 These are H independently 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 an alkylene group, R 2b , R' 2b and R'' 2b Each of these is independently H or C 1-10 It is an alkyl group.

[0224] In one embodiment, Y1 in the above formula (II-B) steroid compound is -C(O)O-, -OC(O)-, -O-, -S-, -NR 2a -, -OC(O)NR 2a - or -NR 2aIt is C(O)-. In one embodiment, Y1 in the above formula (II-B) steroid compound is -C(O)O-, -OC(O)-, -O-, -S-, -NH-, -NCH3-, -OC(O)NH-, or -NHC(O)-. In one embodiment, Y1 in the above formula (II-B) steroid compound is -O-. In one embodiment, Y1 in the above formula (II-B) steroid compound is -S-.

[0225] In another embodiment, the steroid compound is a compound of formula (II-C1), [ka] Alternatively, it may be a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt, where, R z1 teeth, [ka] And, R 2a H is replaced by C, which is optionally substituted. 1-8 Alkyl, -L 2b -OR 2b , L 2b -OC(O)R 2b or L 2b -C(O)OR 2b It is preferably H, -CH3, -CH2C(O)OCH3, or -CH2C(O)OH, V1 is NR 21 R 22 or N + R 21 R 22 R 23 And here R 21 , R 22 , R 23 These are H independently and C which is optionally substituted. 1-8 Alkyl, -L 2b -OR 2b , -L 2b -SR 2b , -L 2b -NR 2bR' 2b R'' 2b , L 2b -OC(O)R 2b or L 2b -C(O)OR 2b And R 21 and R 22 It is not hydrogen at the same time, L 2b C is either non-existent or optionally replaced. 1-10 It is an alkylene group, R 2b , R' 2b and R'' 2b Each of these is independently H or C 1-10 It is an alkyl group, M is absent or one or more anions, and the above anions are independently selected from chloride, bromide, iodide, sulfate, nitrate, perchlorate, formate, citrate, sulfonate, methanesulfonate, trifluoromethanesulfonate, trifluoroacetate, pyrosulfate, bisulfite, sulfite, bisulfite, phosphate, pyrophosphate, monohydrogen phosphate, dihydrogen phosphate, acetate, propionate, caprine, octanoate, acrylate, isobutyrate, hexanoate, heptanoate, oxalate, malonate, succinate, fumarate, maleate, benzoate, phthalate, phenylacetate, lactate, glycolate, tartrate, mandelate, methanesulfonate, gluconate, aspartate, or glutamate. m is an integer between 1 and 12, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.

[0226] In another embodiment, the steroid compound is a compound of formula (II-C2), [ka] Alternatively, it may be a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt, where, R z1 teeth, [ka] And, V1 is NR 21 R 22 or N + R 21 R 22 R 23 And here R 21 , R 22 , R 23 These are H independently 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 R 21 and R 22 It is not hydrogen at the same time, L 2b C is either non-existent or optionally replaced. 1-10 It is an alkylene group, R 2b , R' 2b and R'' 2b Each of these is independently H or C 1-10 It is an alkyl group, M is absent or one or more anions, and the above anions are independently selected from chloride, bromide, iodide, sulfate, nitrate, perchlorate, formate, citrate, sulfonate, methanesulfonate, trifluoromethanesulfonate, trifluoroacetate, pyrosulfate, bisulfite, sulfite, bisulfite, phosphate, pyrophosphate, monohydrogen phosphate, dihydrogen phosphate, acetate, propionate, caprine, octanoate, acrylate, isobutyrate, hexanoate, heptanoate, oxalate, malonate, succinate, fumarate, maleate, benzoate, phthalate, phenylacetate, lactate, glycolate, tartrate, mandelate, methanesulfonate, gluconate, aspartate, or glutamate. m is an integer between 1 and 12, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.

[0227] In one embodiment, the steroid compound is [ka] Or it is not a pharmaceutically acceptable salt.

[0228] In one embodiment, the Specified Name [ka] JPEG2026515723000100.jpg177149 JPEG2026515723000101.jpg58149 Alternatively, the present invention provides stereoisomers thereof, mixtures of stereoisomers, or pharmaceutically acceptable salts thereof.

[0229] In one embodiment, the Specified Name [ka] JPEG2026515723000103.jpg178149 JPEG2026515723000104.jpg177149 JPEG2026515723000105.jpg172149 JPEG2026515723000106.jpg73149 Alternatively, the present invention provides stereoisomers thereof, mixtures of stereoisomers, or pharmaceutically acceptable salts thereof.

[0230] In one embodiment, the molar percentage of the steroid compound in the total lipids is 3 to 15 mol%, preferably 5 to 10 mol%, for example, 3 mol%, 4 mol%, 5 mol%, 6 mol%, 7 mol%, 8 mol%, 9 mol%, 10 mol%, 11 mol%, 12 mol%, 13 mol%, 14 mol%, or 15 mol%.

[0231] 5.2.2. Ionized Lipids In one embodiment, the lipid nanoparticles further comprise ionized lipids. In one embodiment, the ionized lipids are different from the steroid compounds described in Section 0. In one embodiment, the lipid nanoparticles comprise ionized lipids and a steroid compound having a cationic group.

[0232] In one embodiment, the pKa of the ionized lipid is about 4 to about 14. In one embodiment, the pKa of the ionized lipid is about 5 to about 7. In one embodiment, the pKa of the ionized lipid is about 6 to about 7. In one embodiment, the pKa of the ionized lipid is greater than 7. In one embodiment, the pKa of the ionized lipid is about 4, about 5, about 6, about 7, about 8, about 9, about 10, or about 11. In one embodiment, the pKa of the ionized lipid is 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).

[0233] In one embodiment, the ionized lipid contains one or more groups that are protonated at physiological pH but deprotonated at pH greater than 8, greater than 9, or greater than 10 and have no charge. In one embodiment, the ionized lipid contains one or more tertiary amine groups. In one embodiment, the ionized lipid contains one, two, three, or four C6-C24 alkyl or alkenyl lipid groups. These lipid groups may be bonded via functional groups (e.g., ester or amide groups) or further added to a sulfur atom by Michael addition.

[0234] In one embodiment, the ionized lipid comprises at least one ionized 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 structural formula of the biodegradable hydrophobic chain is -R 16 -M0-R 17 And here, R 16 is C 4-14 Alkylene group, C 4-14 Alkenylene group or C 4-14 It is an alkynylene group, R 17 is C 6-20 The alkyl group is an alkyl group, and M0 is a biodegradable group, and the alkylene group, alkenylene group, alkylylene group and alkyl group can be optionally substituted. In one embodiment, the ionization head group is a tertiary amine group. In one embodiment, the tertiary amine group of the ionized lipid includes a -CH2CH2OH moiety.

[0235] In one embodiment, the ionized lipid comprises one tertiary amine group and two biodegradable hydrophobic chains, where each hydrophobic chain is independently -R 16 -C(O)OR 17 And here, R 16 It is bonded to a tertiary amine group. In one embodiment, R 17 One of them is branch C 6-20 It is an alkyl group, and the other R 17 is linear C 6-20 It is an alkyl group.

[0236] In one embodiment, M0 is an ester group, an amide group, a thioester group, a carbonate group, a carbamate group, a carbamoylthioester group, a urea group, or an ether group. In one embodiment, M0 is an ester group.

[0237] In one embodiment, the ionized lipid is a compound of formula (III), [ka] Or its stereoisomer, mixture of stereoisomers, tautomers, isotopic substitutions, or pharmaceutically acceptable salts, where, Examples R3 and R4 were independently C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C3-C 14 Cycloalkyl group, 3-14 member heterocyclyl group, (C 1-10 Alkylene group)-(C3-C 14 (Cycloalkyl group) or (C 1-10 The alkylene group is a 3-14 member heterocyclyl group, or R3 and R4, together with the nitrogen atom bonded to them, form a 3-14 member heterocyclyl group, or R4 and one R0', together with the atom bonded to them, form a 4-10 member heterocyclyl group or a 5-10 member heteroaryl group, and here the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, heteroaryl group and alkylene group are independently and optionally one or more R * Replaced by, Each example of R0' is an independently and optionally substituted methylene group, or the two substituents of R0' together with the methylene group attached to them form a 3- to 8-membered cycloalkylene group, where the cycloalkylene group is optionally one or more R ** 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 represents a connection. W is C, CH, or N, and assuming 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 Alkylene group, C 2-24 The groups are alkenylene groups, C3-C8 cycloalkylene groups, and C3-C8 cycloalkenylene groups, where the above alkylene groups, alkenylene groups, cycloalkylene groups, and cycloalkenylene groups are optionally selected as one or more R groups. ** Replaced by, G1, G2, G3, and G4 do not exist independently of each other, or C 1-13 Alkylene group, C 2-13 Alkenylene group or C 2-13 The alkylene group is an alkylene group, where the alkylene group, alkenylene group and alkylene group can be optionally selected as one or more R groups. s Replaced by, The total length of G1 and G2 is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 carbon atoms. The total length of G3 and G4 is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 carbon atoms. R5, R6, R7, and R8 are each independently substituted with hydrogen or optionally substituted with carbon. 1-8 It is an alkyl group, 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 - is selected from, where the bond to the right is directed towards W, If the dashed line connecting Q and W represents a chemical bond, then G5 does not exist, and Q and W form a 5-10 membered monocyclic ring or a fused ring, and optionally the above ring is one or more R ** Replaced by, M1 and M2 either do not exist independently of each other, or they are -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-, -SS-, or -S(O) 0-2 -and, Each example of R0 is independently -(CRR')-, Examples R and R' are independently H and C 1-20 Alkyl, L a -OR a , -L a -SR a or -L a -NR a R' a And, or R and R' together with the carbons bonded to them, C 3-8 Forming a cycloalkylene group, Q3 and Q4 are independently H, -(CRR')-, and C, respectively. 6-10 It is an aryl group or a steroid moiety. Examples A1, A2, A3, and A4 are independently - (CR 18 R 18 -CR 18 =CR 18 )- or -(CR 18 R 18 -C≡C)- and R 18 Each example is independently C 1-20 It is an alkyl group, Examples N1 and N2 are independently biodegradable groups. Z does not exist, or C 1-10 It is an alkylene group or -OP(O)(OH)-O- Each of the dashed lines between Z-Q3 and Z-Q4 either does not exist independently or is a chemical bond. If Z does not exist, then neither of the two dashed lines exists. m, n, q, r, u, v, y, and z are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. o, p, w, and x are each 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 8 to 30. L a and L e They either do not exist independently of each other, or C 1-20 It is an alkylene group, L b and L f They either do not exist independently of each other, or C 1-10 It is an alkylene group, L c It does not exist, or C 1-8 It is an alkylene group, L d It does not exist, or C 1-14 It is an alkylene group, R * is a hydroxyl group, halogen, C 1-10 Alkyl alkyl group, C 1-10 Haloalkyl group, C 1-10 Hydroxyalkyl group, -L b -OR b , -L b -SR b or -L b -NR b R' b And, R ** is a hydroxyl group, halogen, C1-8 Alkyl alkyl group, C 1-8 Haloalkyl group, C 1-8 Hydroxyalkyl group, -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 H and C are independent of each other. 1-20 Alkyl alkyl group, C 3-14 The alkyl group is a cycloalkyl group or a 3-14 member heterocyclyl group, where the alkyl group, cycloalkyl group and heterocyclyl group can optionally be a hydroxyl group, a halogen, or C 1-20 Alkyl, -L e -OR e , -L e -SR e or -L e -NR e R' e Replaced by one or more groups selected from, R b and R' b H and C are independent of each other. 1-10 Alkyl alkyl group, C 3-14 The alkyl group is a cycloalkyl group or a 3-14 member heterocyclyl group, where the alkyl group, cycloalkyl group and heterocyclyl group can optionally be a hydroxyl group, a halogen, or C 1-10 Alkyl, -L f -OR f , -L f -SR f or -L f -NR f R' f Replaced by one or more groups selected from, Rc and R' c Each is independently of hydrogen or C 1-8 It is an alkyl group, R d and R' d Each is independently of hydrogen or C 1-14 It is an alkyl group, R e and R' e Each is independently of hydrogen or C 1-20 It is an alkyl group, and R f and R' f Each is independently of hydrogen or C 1-10 It is an alkyl group.

[0238] 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.

[0239] 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.

[0240] 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.

[0241] 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.

[0242] 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.

[0243] 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.

[0244] 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.

[0245] 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.

[0246] 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.

[0247] 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.

[0248] In one embodiment, o is 0. In one embodiment, o is 1. In one embodiment, o is 2.

[0249] In one embodiment, p is 0. In one embodiment, p is 1. In one embodiment, p is 2.

[0250] In one embodiment, w is 0. In one embodiment, w is 1. In one embodiment, w is 2.

[0251] In one embodiment, x is 0. In one embodiment, x is 1. In one embodiment, x is 2.

[0252] 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.

[0253] 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 -ORa ) 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 1-12 It is alkyl(2).

[0254] 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)-.

[0255] 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 the Z configuration. In one embodiment, the C=C bond of A1 is in the 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)-.

[0256] 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 the Z configuration. In one embodiment, the C=C bond of A2 is in the 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)-.

[0257] 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 in A3 is in the Z configuration. In one embodiment, the C=C bond in A3 is in the 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)-.

[0258] 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 in A4 is in the Z configuration. In one embodiment, the C=C bond in A4 is in the 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)-.

[0259] In one embodiment, R 18 H is H. In one embodiment, R 18 C 1-20 It is an alkyl group. In one embodiment, R 18 C 1-16 It is an alkyl group. In one embodiment, R 18 C 1-12 It is an alkyl group. In one embodiment, R 18 C 1-6 It is an alkyl group.

[0260] In one embodiment, s is 0. In one embodiment, s is 1. In one embodiment, t is 0. In one embodiment, t is 1.

[0261] 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 carbamoylthioester 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.

[0262] 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 carbamoylthioester 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.

[0263] 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.

[0264] In one embodiment, Z is C 1-10 It is an alkylene group. In one embodiment, Z is C 1-6 It is an alkylene group. In one embodiment, Z is C 1-3 It is an alkylene group. In one embodiment, Z is -OP(O)(OH)-O-.

[0265] 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.

[0266] 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.

[0267] In one embodiment, the ionized lipid is a compound of formula (IV'), [ka] Or its stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt, where j is either 0 or 1. W is either CH or N, and assuming W is N, then j is 0. k is 0, 1, 2, 3, 4, 5, 6, 7, or 8. Each example of R0' is an independently and optionally substituted methylene group, or the two substituents of R0' together with the methylene group attached to them form a 3- to 8-membered cycloalkylene group, where the cycloalkylene group is optionally one or more R ** 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 either does not exist, or is either -C(O)O-, -O-, -NH-, -SC(O)O-, -OC(O)NRb-, -NRbC(O)NRb-, -OC(O)S-, -OC(O)O-, -NRbC(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NRb-, -C(O)NRb-, -NRbC(O)-, -NRbC(O)S-, -SC(O)NRb-, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NRb-, -NRbC(S)O-, -SS- or -S(O) 0-2 -and, R a and R b H and C are independent of each other. 1-20 Alkyl alkyl group, C 3-14 The alkyl group is a cycloalkyl group or a 3-14 member heterocyclyl group, where the alkyl group, cycloalkyl group and heterocyclyl group can optionally be a hydroxyl group, a halogen, or C 1-20 Alkyl, -L e -OR e , -L e -SR e or -L e -NR e R' e Replaced by one or more groups selected from, G5 is either non-existent or optionally replaced by C. 1-8 It is an alkylene group, R1 and R2 are each independently C 4-20 Alkyl alkyl group, C 4-20 Alkenyl group or C 4-20 It is an alkynyl group, where one or more methylene group units of R1 and R2 are independently and optionally -NH- or -N(C 1-20 Substituted with an alkyl group, where the alkyl group, alkenyl group, and alkynyl group are optionally substituted. Examples R3 and R4 are independently H, C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C3-C 14R3 and R4 are cycloalkyl groups or 3-14 membered heterocyclyl groups, or R3 and R4, together with the N atom bonded to them, form a 3-14 membered heterocyclyl group, or R4 and one R0', together with the atom bonded to them, form a 4-10 membered heterocyclyl group, and here the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group may be one or more R groups of any choice. * Replaced with and R5, R6, R7, and R8 are each independently substituted with hydrogen or optionally substituted with carbon. 1-8 It is an alkyl group.

[0268] In one embodiment, the ionized lipid is a compound of formula (IV'-A), [ka] Alternatively, it may be a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

[0269] In one embodiment, the ionized lipid is a compound of formula (VIII), [ka] Alternatively, it may be a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

[0270] In one embodiment, the ionized lipid is a compound of formula (V'), (VI'), or (VII'), [ka] Alternatively, these are stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts, where, 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 Rs ')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 either does not exist independently or is optionally replaced by C. 1-7 It is an alkylene group, G 1a , G 1b , G 2a and G 2b The total length is 1, 2, 3, 4, 5, 6, or 7 carbon atoms. G 3a , G 3b , G 4a and G 4b The total length is 1, 2, 3, 4, 5, 6, or 7 carbon atoms. R5, R6, R7, and R8 are each independently substituted with hydrogen or optionally substituted with carbon. 1-6 It is an alkyl group, G7, G8, G9 and G 10 Each of these either does not exist independently or is optionally replaced by C. 1-12 It is an alkylene group, and the premise is that the total length of G7 and G8 is 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms, and G9 and G 10 The total length is 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 1-14Alkyl, -L a -OR a or -L a -NR a R' a And, R'' is H or C 1-14 It is an alkyl group, L d It does not exist, or C 1-10 It is an alkylene group, L a It does not exist, or C 1-14 It is an alkylene group, R a and R' a H and C are independent of each other. 1-14 Alkyl alkyl group, C 3-10 A cycloalkyl group or a 3-10 membered heterocyclyl group, wherein the alkyl group, cycloalkyl group and heterocyclyl group are optionally substituted. R d and R' d These are H or C, respectively, independently. 1-10 It is an alkyl group, a' and b are independently 0, 1, 3, 4, and 5, respectively, and the premise is 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, and c, d, e, and f are independently 0, 1, 2, 3, 4, 5, 6, or 7, and it is assumed that c+d is an integer between 2 and 9, and e+f is an integer between 2 and 9.

[0271] In one embodiment, R1 is C 4-20 It is an alkyl group. In one embodiment, R1 is C 6-18 It is an alkyl group. In one embodiment, R1 is C 8-18 It is an alkyl group. In one embodiment, R1 is C8, C9, C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C16 , C 17 , C 18 , C 19 or C 20 It is an alkyl group. In one embodiment, R1 is C 4-20 It is an alkenyl group. In one embodiment, R1 is C 6-18 It is an alkenyl group. In one embodiment, R1 is C 8-18 It is an alkenyl group. 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 group. In one embodiment, R1 is C 4-20 It is an alkynyl group. In one embodiment, R1 is C 6-18 It is an alkynyl group. In one embodiment, R1 is C 8-18 It is an alkynyl group. 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 alkynyl group.

[0272] In one embodiment, one or more of the -CH2- groups in R1 are replaced with -NH-. In one embodiment, one or more of the -CH2- groups in R1 are replaced with -N(C 1-20 Substituted with alkyl)-. In one embodiment, one or more of the -CH2- groups in R1 are -N(C 1-12 It is replaced with alkyl(-).

[0273] In one embodiment, R1 is not substituted. In one embodiment, R1 is -L a -ORa It is replaced by -L a -SR a It is replaced by -L a -NR a R' a It will be replaced by this.

[0274] In one embodiment, R2 is C 4-20 It is an alkyl group. In one embodiment, R2 is C 6-18 It is an alkyl group. In one embodiment, R2 is C 8-18 It is an alkyl group. 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 alkyl group. In one embodiment, R2 is C 4-20 It is an alkenyl group. In one embodiment, R2 is C 6-18 It is an alkenyl group. In one embodiment, R2 is C 8-18 It is an alkenyl group. 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 group. In one embodiment, R2 is C 4-20 It is an alkynyl group. In one embodiment, R2 is C 6-18 It is an alkynyl group. In one embodiment, R2 is C 8-18 It is an alkynyl group. In one embodiment, R2 is C8, C9, C 10 , C 11 , C 12 , C 13 , C 14 , C15 , C 16 , C 17 , C 18 , C 19 or C 20 It is an alkynyl group.

[0275] In one embodiment, one or more of the -CH2- groups in R2 are replaced with -NH-. In one embodiment, one or more of the -CH2- groups in R2 are replaced with -N(C 1-20 Substituted with alkyl)-. In one embodiment, one or more of the -CH2- groups in R2 are -N(C 1-12 It is replaced with alkyl(-).

[0276] 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 -L a -NR a R' a It will be replaced by this.

[0277] In one embodiment, L a It does not exist. In one embodiment, L a C 1-14 It is an alkylene group. a C 1-6 It is an alkylene group. a is a methylene group. In one embodiment, L a This is an ethylene group.

[0278] In one embodiment, R a C 1-14 It is an alkyl group. In one embodiment, R a C 3-10 It is a cycloalkyl group. In one embodiment, R a R is a 3-10 membered heterocyclyl group. In one embodiment, R a C 1-10It is an alkyl group, and in one embodiment, R a C 8-10 It is an alkyl group, and in one embodiment, R a C 8-10 It is a linear alkyl group, and in one embodiment, R a is -(CH2)8CH3, and in one embodiment, R a H and C are chosen at will. 1-20 Alkyl, -L e -OR e , -L e -SR e and -L e -NR e R' e It is substituted with one or more of the substituents listed above.

[0279] In one embodiment, R' a C 1-14 It is an alkyl group. In one embodiment, R' a C 3-10 It is a cycloalkyl group. In one embodiment, R' a It has 3 to 10 members. In one embodiment, R' a C 8-10 It is an alkyl group, and in one embodiment, R' a C 8-10 It is a linear alkyl group, and in one embodiment, R' a is -(CH2)8CH3, and in one embodiment, R' a H and C are chosen at will. 1-20 Alkyl, -L e -OR e , -L e -SR e and -L e -NR e R' e It is substituted with one or more of the substituents listed above.

[0280] In one embodiment, R a and R' a These, together with the nitrogen atoms bonded to them, form a 4-10 membered ring. In one embodiment, R a and R' aThese, together with the nitrogen atoms bonded to them, form a 4-8 membered ring. In one embodiment, R a and R' a These, together with the nitrogen atoms bonded to them, form a 4-6 membered ring. In one embodiment, R a and R' a These, together with the nitrogen bonded to them, form a 4-6 membered cycloalkyl group. In one embodiment, R a and R' a These, along with the nitrogen atoms bonded to them, form a 4-6 membered heterocycline group.

[0281] In one embodiment, R3 is H. In one embodiment, R3 is C. 1-10 It is an alkyl group. In one embodiment, R3 is C 1-10 It is a haloalkyl group. In one embodiment, R3 is C 2-10 It is an alkenyl group. In one embodiment, R3 is C 2-10 It is an alkynyl group. In one embodiment, R3 is a 3-14 member cycloalkyl group. In one embodiment, R3 is a 3-14 member heterocyclyl group. In one embodiment, R3 is C 6-10 It is an alkyl group. In one embodiment, R3 is a 5-14 member heteroaryl group. In one embodiment, R3 is C 1-6 It is an alkyl group. In one embodiment, R3 is C 1-6 It is a haloalkyl group. In one embodiment, R3 is a 3- to 10-membered cycloalkyl group. In one embodiment, R3 is a 3- to 10-membered heterocyclyl group. In one embodiment, R3 is a 3- to 7-membered cycloalkyl group. In one embodiment, R3 is a 3- to 7-membered heterocyclyl group.

[0282] In one embodiment, R3 is not replaced. In one embodiment, R3 is one or more R * It is replaced by, and here each R * These are, independently, halogens, cyano groups, and C 1-10 Alkyl alkyl group, C 1-10 Haloalkyl group, -L b -OR b , -Lb -SR b or -L b -NR b R' b In one embodiment, R3 is optionally 1, 2, 3, 4, or 5 R * It is replaced by, and here each R * These are, independently, halogens, cyano groups, and C 1-10 Alkyl alkyl group, C 1-10 Haloalkyl group, -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.

[0283] In one embodiment, R3 is a C that is optionally substituted with OH. 1-6 It is an alkyl group. In one embodiment, R3 is -CH2CH2OH.

[0284] In one embodiment, R4 is H. In one embodiment, R4 is C. 1-10 It is an alkyl group. In one embodiment, R4 is C 1-10 It is a haloalkyl group. In one embodiment, R4 is C 2-10 It is an alkenyl group. In one embodiment, R4 is C 2-10 It is an alkynyl group. In one embodiment, R4 is a 3-14 membered cycloalkyl group. In one embodiment, R4 is a 3-14 membered heterocyclyl group. In one embodiment, R4 is C 6-10 It is an alkyl group. In one embodiment, R4 is a 5-14 member heteroaryl group. In one embodiment, R4 is C 1-6 It is an alkyl group. In one embodiment, R4 is C 1-6It is a haloalkyl group. In one embodiment, R4 is a 3- to 10-membered cycloalkyl group. In one embodiment, R4 is a 3- to 10-membered heterocyclyl group. In one embodiment, R4 is a 3- to 7-membered cycloalkyl group. In one embodiment, R4 is a 3- to 7-membered heterocyclyl group. 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, two, three, four, or five R3s. In one embodiment, R3 is optionally replaced by one, two, three, four, or five R3s. * It will be replaced by this.

[0285] In one embodiment, R3 and R4, together with the N atoms bonded to them, form a 3- to 14-membered heterocyclyl group. In one embodiment, R3 and R4, together with the N atoms bonded to them, form a 3- to 10-membered heterocyclyl group. In one embodiment, R3 and R4, together with the N atoms bonded to them, form a 3- to 7-membered heterocyclyl group. In one embodiment, R3 and R4, together with the N atoms bonded to them, form a 5- to 7-membered heterocyclyl group. In one embodiment, R3 and R4, together with the N atoms bonded to them, form a 4- to 6-membered heterocyclyl group. In one embodiment, R3 and R4, together with the N atoms bonded to them, form a 5-membered heterocyclyl group. In one embodiment, R3 and R4, together with the N atoms bonded to them, [ka] In one embodiment, R3 and R4, along with the N atoms bonded to them, form a structure. [ka] In one embodiment, R3 and R4, along with the N atoms bonded to them, form a structure. [ka] In one embodiment, R3 and R4, along with the N atoms bonded to them, form a structure. [ka] In one embodiment, the heterocyclyl groups formed by R3 and R4 together with the N atoms to which they are bonded may optionally consist of one or more R * Substituted with, in one embodiment, the heterocyclyl groups formed by R3 and R4 together with the N atoms to which they are bonded are optionally 1, 2, 3, 4, or 5 R * It will be replaced by this.

[0286] In one embodiment, R4, together with the nitrogen atom bonded to it and one R0', forms a 3- to 14-membered heterocyclyl group. In one embodiment, R4, together with the nitrogen atom bonded to it and one R0', forms a 4- to 10-membered heterocyclyl group. In one embodiment, R4, together with the nitrogen atom bonded to it and one R0', forms a 4- to 6-membered heterocyclyl group. In one embodiment, R4, together with the nitrogen atom bonded to it and one R0', forms a 5- to 14-membered heteroaryl group. In one embodiment, R4, together with the nitrogen atom bonded to it and one R0', forms a 5- to 10-membered heteroaryl group. In one embodiment, R4, together with the nitrogen atom bonded to it and one R0', forms a 5 or 6-membered heteroaryl group.

[0287] In one embodiment, R5 is H, and in one embodiment, R5 is C 1-8 It is an alkyl group, and in one embodiment, R5 is C 1-6 It is an alkyl group, and in one embodiment, R5 is C 1-3 It is an alkyl group, and in one embodiment, R5 is Me, and in one embodiment, R5 is optionally one or more R * It is replaced by, in one embodiment, R5 is optionally 1, 2, 3, 4 or 5 R * It will be replaced by this.

[0288] In one embodiment, R6 is H, and in one embodiment, R6 is C 1-8 It is an alkyl group, and in one embodiment, R6 is C1-6 It is an alkyl group, and in one embodiment, R6 is C 1-3 It is an alkyl group, and in one embodiment, R6 is Me, and in one embodiment, R6 is optionally one or more R * It is replaced by, in one embodiment, R6 is optionally 1, 2, 3, 4 or 5 R * It will be replaced by this.

[0289] In one embodiment, R5 and R6, along with the carbon atoms bonded to them, are C 3-14 A cycloalkylene group or a 3-14 membered heterocyclene group is formed, where the cycloalkylene group and heterocyclene group are optionally one or more R groups. 4s It is replaced by C. In one embodiment, R5 and R6 are C along with the carbon atoms bonded to them. 3-8 A cycloalkylene group is formed. In one embodiment, R5 and R6, together with the carbon atoms bonded to them, form a C 3-6 They form a cycloalkylene group. In one embodiment, R5 and R6, together with the carbon atoms bonded to them, form a C3 cycloalkylene group, a C4 cycloalkylene group, a C5 cycloalkylene group, or a C6 cycloalkylene group. In one embodiment, R5 and R6, together with the carbon atoms bonded to them, form a 3- to 8-membered heterocyclene group. In one embodiment, R5 and R6, together with the carbon atoms bonded to them, form a 3- to 6-membered heterocyclene group. In one embodiment, R5 and R6, together with the carbon atoms bonded to them, form a 3-membered heterocyclene group, a 4-membered heterocyclene group, a 5-membered heterocyclene group, or a 6-membered heterocyclene group. In one embodiment, the heterocyclene group has one or more oxygen, sulfur, or nitrogen atoms on the ring. In one embodiment, the heterocyclene group or cycloalkylene group formed by R5 and R6 is unsubstituted. In one embodiment, the heterocyclene group or cycloalkylene group formed by R5 and R6 has 1, 2, 3, 4, or 5 R * It is substituted with. In one embodiment, the heterocyclylene group or cycloalkylene group formed by R5 and R6 is substituted with 1, 2, 3, 4 or 5 R4s It will be replaced by this.

[0290] In one embodiment, R7 is H, and in one embodiment, R7 is C 1-8 It is an alkyl group, and in one embodiment, R7 is C 1-6 It is an alkyl group, and in one embodiment, R7 is C 1-3 It is an alkyl group, and in one embodiment, R7 is Me, and in one embodiment, R7 is optionally one or more R * It is replaced by, in one embodiment, R7 is optionally 1, 2, 3, 4 or 5 R * It will be replaced by this.

[0291] In one embodiment, R5, R6, R7, and R8 are each independently hydrogen or a methyl group. In one embodiment, R5 and R6 are each independently C 1-6 It is an alkyl group, and R7 and R8 are both hydrogen. In one embodiment, R5 and R6 are both methyl groups, and R7 and R8 are both hydrogen. In one embodiment, R5, R6, R7, and R8 are all hydrogen.

[0292] In one embodiment, R8 is H, and in one embodiment, R8 is C 1-8 It is an alkyl group, and in one embodiment, R8 is C 1-6 It is an alkyl group, and in one embodiment, R8 is C 1-3 It is an alkyl group, and in one embodiment, R8 is Me, and in one embodiment, R8 is optionally one or more R * It is replaced by, in one embodiment, R8 is optionally 1, 2, 3, 4 or 5 R * It will be replaced by this.

[0293] In one embodiment, R7 and R8, along with the carbon atoms bonded to them, are C 3-14 A cycloalkylene group or a 3-14 membered heterocyclene group is formed, where the cycloalkylene group and heterocyclene group are optionally one or more R groups. 4sIt is replaced by C. In one embodiment, R7 and R8 are C along with the carbon atoms bonded to them. 3-8 A cycloalkylene group is formed. In one embodiment, R7 and R8, together with the carbon atoms bonded to them, form a C 3-6 They form a cycloalkylene group. In one embodiment, R7 and R8, together with the carbon atoms bonded to them, form a C3 cycloalkylene group, a C4 cycloalkylene group, a C5 cycloalkylene group, or a C6 cycloalkylene group. In one embodiment, R7 and R8, together with the carbon atoms bonded to them, form a 3- to 8-membered heterocyclene group. In one embodiment, R7 and R8, together with the carbon atoms bonded to them, form a 3- to 6-membered heterocyclene group. In one embodiment, R7 and R8, together with the carbon atoms bonded to them, form a 3-membered heterocyclene group, a 4-membered heterocyclene group, a 5-membered heterocyclene group, or a 6-membered heterocyclene group. In one embodiment, the heterocyclene group has one or more oxygen, sulfur, or nitrogen atoms on the ring. In one embodiment, the heterocyclene group or cycloalkylene group formed by R7 and R8 is unsubstituted. In one embodiment, the heterocyclene group or cycloalkylene group 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 group or cycloalkylene group formed by R7 and R8 is substituted by 1, 2, 3, 4 or 5 R 4s It will be replaced by this.

[0294] In one embodiment, R * is a halogen, cyano group, C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, -L b -OR b or -L b -NR b R' b In one embodiment, R * C 1-6 Alkyl alkyl group, C 1-6 Halogen group or -OR b In one embodiment, R * These are H, halogen, and C independently.1-6 Alkyl alkyl group or C 1-6 It is a haloalkyl group, and in one embodiment, R * C 1-6 Alkyl alkyl group or C 1-6 It is a haloalkyl group, and in one embodiment, R * is Me. In one embodiment, R * is OH. In one embodiment, R * is a halogen, and in one embodiment, R * is a cyano group, and in one embodiment, R* is C 1-10 It is an alkyl group, and in one embodiment, R * C 1-10 It is a haloalkyl group, and in one embodiment, R * is, -L b -OR b In one embodiment, R * is, -L b -SR b In one embodiment, R * is, -L b -NR b R' b In one embodiment, R * C 1-6 It is an alkyl group, and in one embodiment, R * C 1-6 It is a haloalkyl group, and in one embodiment, R * is -OR b That is the case.

[0295] In one embodiment, L b It does not exist. In one embodiment, L b C 1-10 It is an alkylene group. b C 1-6 It is an alkylene group. b C 1-3 It is an alkylene group. b is a methylene group. In one embodiment, L b This is an ethylene group.

[0296] In one embodiment, L f It does not exist. In one embodiment, L f C 1-10 It is an alkylene group. f C 1-6 It is an alkylene group. f C 1-3 It is an alkylene group. f is a methylene group. In one embodiment, L f This is an ethylene group.

[0297] In one embodiment, L c It does not exist. In one embodiment, L c C 1-8 It is an alkylene group. c C 1-6 It is an alkylene group. c C 1-3 It is an alkylene group. c is a methylene group. In one embodiment, L c This is an ethylene group.

[0298] In one embodiment, R b C 1-10 It is an alkyl group. In one embodiment, R b C 1-6 It is an alkyl group. In one embodiment, R b C 1-3 It is an alkyl group. In one embodiment, R b C 3-14 It is a cycloalkyl group. In one embodiment, R b C 3-8 It is a cycloalkyl group. In one embodiment, R b C 3-6 It is a cycloalkyl group. In one embodiment, R b R is a 3-14 member heterocyclyl group. In one embodiment, R b R is a 3- to 8-membered heterocyclyl group. In one embodiment, Rb R is a 3-6 membered heterocyclyl group. In one embodiment, R b This is a 3-6 membered nitrogen-containing heterocyclyl group. 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 It is replaced with one or more of the following, where R f and R' f These are H or C, respectively, independently. 1-10 It is an alkyl group.

[0299] In one embodiment, R' b C 1-10 It is an alkyl group. In one embodiment, R' b C 1-6 It is an alkyl group. In one embodiment, R' b C 1-3 It is an alkyl group. In one embodiment, R' b C 3-14 It is a cycloalkyl group. In one embodiment, R' b C 3-8 It is a cycloalkyl group. In one embodiment, R' b C 3-6 It is a cycloalkyl group. In one embodiment, R' b R' is a 3- to 14-membered heterocyclyl group. In one embodiment, R' b R' is a 3- to 8-membered heterocyclyl group. In one embodiment, R' b R' is a 3-6 membered heterocyclyl group. In one embodiment, R' b R' is a 3-6 membered nitrogen-containing heterocyclyl group. In one embodiment, R' b is not substituted. In one embodiment, R' b C 1-10 Alkyl, -L f -OR f , -Lf -SR f or -L f -NR f R' f It is replaced with one or more of the following, where R f and R' f These are H or C, respectively, independently. 1-10 It is an alkyl group.

[0300] In one embodiment, j is 0. In another embodiment, j is 1.

[0301] In one embodiment, W is CH. In another embodiment, W is N.

[0302] In one embodiment, k is 0. In one embodiment, k is 1. In one embodiment, k is 2.

[0303] 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.

[0304] In one embodiment, the two substituents of R0', together with the methylene group attached to them, form a 3- to 8-membered cycloalkyl group. In one embodiment, the two substituents of R0', together with the methylene group attached to them, form a 3- to 6-membered cycloalkyl group. In one embodiment, the two substituents of R0', together with the methylene group attached to them, form a 5 or 6-membered cycloalkyl group.

[0305] In one embodiment, M1 is -C(O)O-, in one embodiment, M1 is -O-, in one embodiment, M1 is -SC(O)O-, and in one embodiment, M1 is -OC(O)NR a -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-, and in one embodiment, M1 is -NR a In one embodiment, M1 is 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-, and in one embodiment, M1 is -NR a -and in one embodiment, M1 is -C(O)NR a -In one embodiment, M1 is -NR a It is C(O)-, and in one embodiment, M1 is -NR a C(O)S-, and 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-, and in one embodiment, M1 is -OC(S)NR a -In one embodiment, M1 is -NR a It is C(S)O-, and in one embodiment, M1 is -SS-, and in one embodiment, M1 is -S(O) 0-2 - is

[0306] In one embodiment, M2 is -C(O)O-, in one embodiment, M2 is -O-, in one embodiment, M2 is -SC(O)O-, and 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-, and in one embodiment, M2 is -NR a In one embodiment, M2 is 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-, and 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)-, and in one embodiment, M2 is -NR a C(O)S-, and 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-, and in one embodiment, M2 is -OC(S)NR a -and in one embodiment, M2 is -NR a It is C(S)O-, and in one embodiment, M2 is -SS-, and in one embodiment, M2 is -S(O) 0-2 - is

[0307] In one embodiment, M1 and M2 are independently -C(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-, -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-, and 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-.

[0308] 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 another embodiment, Q is -NR b C(O)NR b -and in another embodiment, Q is -OC(O)S-, in another embodiment, Q is -OC(O)O-, and in another embodiment, Q is -NR b In another embodiment, Q is C(O)O-, in another embodiment, Q is -OC(O)-, in another embodiment, Q is -SC(O)-, in another embodiment, Q is -C(O)S-, in another embodiment, Q is -NR b -and in another embodiment, Q is -C(O)NR b -and in another embodiment, Q is -NR b C(O)-, and in another embodiment, Q is -NR b C(O)S-, and in another embodiment, Q is -SC(O)NR b -and in another embodiment, Q is -C(O)-, in another embodiment, Q is -OC(S)-, in another embodiment, Q is -C(S)O-, and in another embodiment, Q is -OC(S)NR b -and in another embodiment, Q is -NR b In another embodiment, Q is C(S)O-, and in yet another embodiment, Q is -SS-, and in yet another embodiment, Q is -S(O) 0-2 -In another embodiment, Q is a phenylene group, in another embodiment, Q is a pyridinylene group, and in another embodiment, the phenylene group or pyridinylene group is optionally one or more R * It will be replaced by this.

[0309] In one embodiment, Q is either nonexistent or -C(O)O-, -O-, -SC(O)O-, -OC(O)NR b -, -NR b C(O)NRb -, -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 -Selected from, in one method, 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 Q is selected from (O)-, -OC(S)-, -C(S)O-, -OC(S)NH- and -NHC(S)O-, and 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-, and in one embodiment Q is -C(O)O-.

[0310] In one embodiment, R a H is, in another embodiment, R a C 1-20 It is an alkyl group, and in another embodiment, R a is a 3-14 member cycloalkyl group, and in another embodiment, R a is a 3-14 member heterocyclyl group, and in another embodiment, R a C 1-14 It is an alkyl group, and in another embodiment, R a C 1-10 It is an alkyl group, and in another embodiment, R a C 8-10 It is an alkyl group, and in another embodiment, R a C 8-10It is a linear alkyl group, and in another embodiment, R a is -(CH2)8CH3, and in another embodiment, R a H and C are chosen at will. 1-20 Alkyl, -L e -OR e , -L e -SR e and -L e -NR e R' e It is substituted with one or more of the substituents, where L e It does not exist, or C 1-20 It is an alkylene group, and here, R e and R' e H or C 1-20 It is an alkyl group, In one embodiment, R' a H is, in another embodiment, R' a C 1-20 It is an alkyl group, and in another embodiment, R' a R' is a 3-14 membered cycloalkyl group, and in another embodiment, R' a R' is a 3-14 member heterocyclyl group, and in another embodiment, R' a C 1-14 It is an alkyl group, and in another embodiment, R' a C 1-10 It is an alkyl group, and in another embodiment, R' a C 8-10 It is an alkyl group, and in another embodiment, R' a C 8-10 It is a linear alkyl group, and in another embodiment, R' a is -(CH2)8CH3, and in another embodiment, R' a H and C are chosen at will. 1-20 Alkyl, -L e -OR e , -L e -SR e and -L e -NR e R' e It is substituted with one or more of the substituents, where L eIt does not exist, or C 1-20 It is an alkylene group, and here, R e and R' e H or C 1-20 It is an alkyl group.

[0311] In one embodiment, L e It does not exist. In one embodiment, L e C 1-20 It is an alkylene group. e C 1-16 It is an alkylene group. e C 1-12 It is an alkylene group. e C 1-6 It is an alkylene group. e is a methylene group. In one embodiment, L e This is an ethylene group.

[0312] In one embodiment, R e is hydrogen. In one embodiment, R e C 1-20 It is an alkyl group. In one embodiment, R e C 1-16 It is an alkyl group. In one embodiment, R e C 1-12 It is an alkyl group. In one embodiment, R e C 1-6 It is an alkyl group. In one embodiment, R' e is hydrogen. In one embodiment, R' e C 1-20 It is an alkyl group. In one embodiment, R' e C 1-16 It is an alkyl group. In one embodiment, R' e C 1-12 It is an alkyl group. In one embodiment, R' e C 1-6 It is an alkyl group.

[0313] In one embodiment, Rf is hydrogen. In one embodiment, R f C 1-10 It is an alkyl group. In one embodiment, R f C 1-6 It is an alkyl group. In one embodiment, R f C 1-3 It is an alkyl group. In one embodiment, R' f is hydrogen. In one embodiment, R' f C 1-10 It is an alkyl group. In one embodiment, R' f C 1-6 It is an alkyl group. In one embodiment, R' f C 1-3 It is an alkyl group.

[0314] In one embodiment, G1 is absent, and in another embodiment, G1 is C 1-13 It is an alkylene group, and in another embodiment, G1 is C 2-13 It is an alkenylene group, and in another embodiment, G1 is C 2-6 It is an alkenylene group, and in another embodiment, G1 is C 2-13 It is an alkynylene group, and in another embodiment, G1 is C 2-6 The group is an alkynylene group, and in another embodiment, G1 is optionally one or more R groups. s It is replaced by, here, 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 here L d It does not exist, or C 1-14 It is an alkylene group, and here, R d and R' d H or C 1-14 It is an alkyl group.

[0315] In one embodiment, G2 is absent, and in another embodiment, G2 is C 2-13 It is an alkylene group, and in another embodiment, G2 is C 2-6 It is an alkylene group, and in another embodiment, G2 is C 2-13 It is an alkenylene group, and in another embodiment, G2 is C 2-6 It is an alkenylene group, and in another embodiment, G2 is C 2-13 It is an alkynylene group, and in another embodiment, G2 is optionally one or more R s It is replaced by, here, 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 here L d It does not exist, or C 1-14 It is an alkylene group, and here, R d and R' d H or C 1-14 It is an alkyl group.

[0316] In one embodiment, the total length of G1 and G2 is 3 carbon atoms; in another embodiment, the total length of G1 and G2 is 4 carbon atoms; in another embodiment, the total length of G1 and G2 is 5 carbon atoms; in another embodiment, the total length of G1 and G2 is 6 carbon atoms; in another embodiment, the total length of G1 and G2 is 7 carbon atoms; in another embodiment, the total length of G1 and G2 is 8 carbon atoms; in another embodiment, the total length of G1 and G2 is 9 carbon atoms; in another embodiment, the total length of G1 and G2 is 10 carbon atoms; in another embodiment, the total length of G1 and G2 is 11 carbon atoms; in another embodiment, the total length of G1 and G2 is 12 carbon atoms; and in another embodiment, the total length of G1 and G2 is 13 carbon atoms.

[0317] In one embodiment, G3 is absent, and in another embodiment, G3 is C 1-13 It is an alkylene group, and in another embodiment, G3 is C 2-13 It is an alkenylene group, and in another embodiment, G3 is C 2-6 It is an alkenylene group, and in another embodiment, G3 is C 2-13 It is an alkynylene group, and in another embodiment, G3 is C 2-6 It is an alkynylene group, and in another embodiment, G3 is optionally one or more R s It is replaced by, here, 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 here L d It does not exist, or C 1-14 It is an alkylene group, and here, R d and R' d H or C 1-14 It is an alkyl group.

[0318] In one embodiment, G4 is absent, and in another embodiment, G4 is C 2-13 It is an alkylene group, and in another embodiment, G4 is C 2-6 It is an alkylene group, and in another embodiment, G4 is C 2-13 It is an alkenylene group, and in another embodiment, G4 is C 2-6 It is an alkenylene group, and in another embodiment, G4 is C 2-13 The group is an alkynylene group, and in another embodiment, G4 is optionally one or more R s It is replaced by, here, R s H and C are independent of each other. 1-14 Alkyl, -L d -OR d , -L d -SR d or -L d -NRd R' d And here L d It does not exist, or C 1-14 It is an alkylene group, and here, R d and R' d H or C 1-14 It is an alkyl group.

[0319] In one embodiment, G1, G2, G3, and G4 do not exist independently of each other, or C 1-8 It is an alkylene group.

[0320] In one embodiment, the total length of G3 and G4 is 3 carbon atoms; in another embodiment, the total length of G3 and G4 is 4 carbon atoms; in another embodiment, the total length of G3 and G4 is 5 carbon atoms; in another embodiment, the total length of G3 and G4 is 6 carbon atoms; in another embodiment, the total length of G3 and G4 is 7 carbon atoms; in another embodiment, the total length of G3 and G4 is 8 carbon atoms; in another embodiment, the total length of G3 and G4 is 9 carbon atoms; in another embodiment, the total length of G3 and G4 is 10 carbon atoms; in another embodiment, the total length of G3 and G4 is 11 carbon atoms; in another embodiment, the total length of G3 and G4 is 12 carbon atoms; and in another embodiment, the total length of G3 and G4 is 13 carbon atoms.

[0321] In one embodiment, R s H is, in another embodiment, R s C 1-14 It is an alkyl group, and in another embodiment, R s is, -L d -OR d And in another embodiment, R s is, -L d -SR d And in another embodiment, R s is, -L d -NR d R' dAnd in another embodiment, R s C 1-10 It is an alkyl group, and in another embodiment, R s C 1-6 It is an alkyl group. In one embodiment, R s H, C 1-10 Alkyl, -L d -OR d or -L d -NR d R' d And in another, more specific embodiment, R s H or C 1-6 It is an alkyl group.

[0322] In one embodiment, G5 is absent. In one embodiment, G5 is absent, j is 0, and R3 is CH2CH2OH.

[0323] In another embodiment, G5 is C 1-8 It is an alkylene group, and in another embodiment, G5 is C 1-6 It is an alkylene group, and in another embodiment, G5 is C 1-3 It is an alkylene group, and in another embodiment, G5 is optionally one or more R ** It is replaced by, and here each R ** C 1-8 Alkyl, -L c -OR c , -L c -SR c or -L c -NR c R' c And here, R c and R' c H or C 1-8 It is an alkyl group, and here L c It does not exist, or C 1-6 It is an alkylene group, In one embodiment, R ** C 1-8 It is an alkyl group, and in another embodiment, R ** is, -L c -OR cAnd in another embodiment, R ** is, -L c -SR c And in another embodiment, R ** is, -L c -NR c R' c And in another embodiment, R ** C 1-6 It is an alkyl group.

[0324] 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''-. 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''-. 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 one embodiment, L5 is -C≡C- and L3 does not exist.

[0325] 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 sIn one embodiment, L6 is -CH=CH- and L4 does not exist. In one embodiment, L6 is -C≡C- and L4 does not exist.

[0326] In one embodiment, G 1a It does not exist. In one embodiment, G 1a is a methylene group. In one embodiment, G 1a is an ethylene group. In one embodiment, G 1a This is a C3 alkylene group. In one embodiment, G 1a This is a C4 alkylene group. In one embodiment, G 1a is a C5 alkylene group. In one embodiment, G 1a This is a C6 alkylene group. In one embodiment, G 1a is a C7 alkylene group. 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, and 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 here L d It does not exist, or C 1-14 It is an alkylene group, and here, R d and R' d H or C 1-14 It is an alkyl group.

[0327] In one embodiment, G 1b It does not exist. In one embodiment, G 1b is a methylene group. In one embodiment, G 1b is an ethylene group. In one embodiment, G 1bThis is a C3 alkylene group. In one embodiment, G 1b This is a C4 alkylene group. In one embodiment, G 1b is a C5 alkylene group. In one embodiment, G 1b This is a C6 alkylene group. In one embodiment, G 1b is a C7 alkylene group. 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 s It is replaced by, and 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 here L d It does not exist, or C 1-14 It is an alkylene group, and here, R d and R' d H or C 1-14 It is an alkyl group.

[0328] In one embodiment, G 2a It does not exist. In one embodiment, G 2a is a methylene group. In one embodiment, G 2a is an ethylene group. In one embodiment, G 2a This is a C3 alkylene group. In one embodiment, G 2a This is a C4 alkylene group. In one embodiment, G 2a is a C5 alkylene group. In one embodiment, G 2a This is a C6 alkylene group. In one embodiment, G 2a is a C7 alkylene group. In one embodiment, G 2a is not substituted. In one embodiment, G 2a is replaced. In one embodiment, G 2ais one or more R s It is replaced by, and 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 here L d It does not exist, or C 1-14 It is an alkylene group, and here, R d and R' d H or C 1-14 It is an alkyl group.

[0329] In one embodiment, G 2b It does not exist. In one embodiment, G 2b is a methylene group. In one embodiment, G 2b is an ethylene group. In one embodiment, G 2b This is a C3 alkylene group. In one embodiment, G 2b This is a C4 alkylene group. In one embodiment, G 2b is a C5 alkylene group. In one embodiment, G 2b This is a C6 alkylene group. In one embodiment, G 2b is a C7 alkylene group. 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 It is replaced by, and 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 here L d It does not exist, or C 1-14 It is an alkylene group, and here, R dand R' d H or C 1-14 It is an alkyl group.

[0330] In one embodiment, G 3a It does not exist. In one embodiment, G 3a is a methylene group. In one embodiment, G 3a is an ethylene group. In one embodiment, G 3a This is a C3 alkylene group. In one embodiment, G 3a This is a C4 alkylene group. In one embodiment, G 3a is a C5 alkylene group. In one embodiment, G 3a This is a C6 alkylene group. In one embodiment, G 3a is a C7 alkylene group. 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 It is replaced by, and 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 here L d It does not exist, or C 1-14 It is an alkylene group, and here, R d and R' d H or C 1-14 It is an alkyl group.

[0331] In one embodiment, G 3b It does not exist. In one embodiment, G 3b is a methylene group. In one embodiment, G 3b is an ethylene group. In one embodiment, G 3b This is a C3 alkylene group. In one embodiment, G 3bThis is a C4 alkylene group. In one embodiment, G 3b is a C5 alkylene group. In one embodiment, G 3b This is a C6 alkylene group. In one embodiment, G 3b is a C7 alkylene group. 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 It is replaced by, and 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 here L d It does not exist, or C 1-14 It is an alkylene group, and here, R d and R' d H or C 1-14 It is an alkyl group.

[0332] In one embodiment, G 4a It does not exist. In one embodiment, G 4a is a methylene group. In one embodiment, G 4a is an ethylene group. In one embodiment, G 4a This is a C3 alkylene group. In one embodiment, G 4a This is a C4 alkylene group. In one embodiment, G 4a is a C5 alkylene group. In one embodiment, G 4a This is a C6 alkylene group. In one embodiment, G 4a is a C7 alkylene group. 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 It is replaced by, and here each Rs 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 here L d It does not exist, or C 1-14 It is an alkylene group, and here, R d and R' d H or C 1-14 It is an alkyl group.

[0333] In one embodiment, G 4b It does not exist. In one embodiment, G 4b is a methylene group. In one embodiment, G 4b is an ethylene group. In one embodiment, G 4b This is a C3 alkylene group. In one embodiment, G 4b This is a C4 alkylene group. In one embodiment, G 4b is a C5 alkylene group. In one embodiment, G 4b This is a C6 alkylene group. In one embodiment, G 4b is a C7 alkylene group. 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 It is replaced by, and 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 here L d It does not exist, or C 1-14 It is an alkylene group, and here, R d and R' d H or C1-14 It is an alkyl group.

[0334] In one embodiment, G 1a , G 1b , G 2a and G 2b The total length is 1, 2, 3, 4, 5, 6, or 7 carbon atoms, and in another more specific embodiment, G 1a , G 1b , G 2a and G 2b The total length of is 1, 2, 3, 4, 5, or 6 carbon atoms. In one embodiment, G 1a , G 1b , G 2a and G 2b The total length is one carbon atom. In one embodiment, G 1a , G 1b , G 2a and G 2b The total length is 2 carbon atoms. In one embodiment, G 1a , G 1b , G 2a and G 2b The total length is 3 carbon atoms. In one embodiment, G 1a , G 1b , G 2a and G 2b The total length is 4 carbon atoms. In one embodiment, G 1a , G 1b , G 2a and G 2b The total length is 5 carbon atoms. In one embodiment, G 1a , G 1b , G 2a and G 2b The total length is 6 carbon atoms.

[0335] In one embodiment, G 3a , G 3b , G 4a and G 4b The total length of is 1, 2, 3, 4, 5, 6, or 7 carbon atoms. In one embodiment, G 3a , G 3b , G 4a and G4b The total length is one carbon atom. In one embodiment, G 3a , G 3b , G 4a and G 4b The total length is 2 carbon atoms. In one embodiment, G 3a , G 3b , G 4a and G 4b The total length is 3 carbon atoms. In one embodiment, G 3a , G 3b , G 4a and G 4b The total length is 4 carbon atoms. In one embodiment, G 3a , G 3b , G 4a and G 4b The total length is 5 carbon atoms. In one embodiment, G 3a , G 3b , G 4a and G 4b The total length is 6 carbon atoms. In one embodiment, G 3a , G 3b , G 4a and G 4b The total length is 7 carbon atoms.

[0336] In one embodiment, G7 is absent, and in another embodiment, G7 is C 1-12 It is an alkylene group, and in another embodiment, G7 is C 1-6 It is an alkylene group, and in another embodiment, G7 is C 1-5 It is an alkylene group, and in another embodiment, G7 is C 1-5 It is a linear alkylene group, and in another embodiment, G7 is -CH2-, in another embodiment, G7 is -(CH2)2-, in another embodiment, G7 is -(CH2)4-, in another embodiment, G7 is -(CH2)5-, and in another embodiment, G7 is optionally substituted with 1, 2, 3, 4, 5 or 6 Rs, where R is C 1-10It is an alkyl group. In another embodiment, one, two, or three methylene groups of G7 are optionally and independently substituted with one R; in another embodiment, one or two methylene groups of G7 are optionally and independently substituted with one R; and in another embodiment, the methylene group bonded to M1 of G7 is not substituted with R.

[0337] In one embodiment, G8 is absent, and in another embodiment, G8 is C 1-12 It is an alkylene group, and in another embodiment, G8 is C 1-10 It is an alkylene group, and in another embodiment, G8 is C 1-8 It is an alkylene group, and in another embodiment, G8 is C 1-8 It is a linear alkylene group, and in another embodiment, G8 is -(CH2)2-, in another embodiment, G8 is -(CH2)4-, in another embodiment, G8 is -(CH2)6-, in another embodiment, G8 is -(CH2)7-, in another embodiment, G8 is -(CH2)8-, and in another embodiment, G8 is optionally substituted with 1, 2, 3, 4, 5 or 6 Rs, where R is C 1-10 It is an alkyl group, and in another embodiment, one, two, or three methylene groups of G8 are optionally and independently substituted with one R, and in another embodiment, one or two methylene groups of G8 are optionally and independently substituted with one R.

[0338] In one embodiment, the total length of G7 and G8 is 4 carbon atoms; in another embodiment, the total length of G7 and G8 is 5 carbon atoms; in another embodiment, the total length of G7 and G8 is 6 carbon atoms; in another embodiment, the total length of G7 and G8 is 7 carbon atoms; in another embodiment, the total length of G7 and G8 is 8 carbon atoms; in another embodiment, the total length of G7 and G8 is 9 carbon atoms; in another embodiment, the total length of G7 and G8 is 10 carbon atoms; in another embodiment, the total length of G7 and G8 is 11 carbon atoms; and in another embodiment, the total length of G7 and G8 is 12 carbon atoms.

[0339] In one embodiment, the total length of G7 and G8 is 6, 7, 8, 9, or 10 carbon atoms.

[0340] In one embodiment, G9 is absent, and in another embodiment, G9 is C 1-12 It is an alkylene group, and in another embodiment, G9 is C 1-6 It is an alkylene group, and in another embodiment, G9 is C 1-5 It is an alkylene group, and in another embodiment, G9 is C 1-5 It is a linear alkylene group, and in another embodiment, G9 is -CH2-, in another embodiment, G9 is -(CH2)2-, in another embodiment, G9 is -(CH2)4-, in another embodiment, G9 is -(CH2)5-, and in another embodiment, G9 is optionally substituted with 1, 2, 3, 4, 5 or 6 Rs, where R is C 1-10 It is an alkyl group, and in another embodiment, one, two, or three methylene groups of G9 are optionally and independently substituted with one R, in another embodiment, one or two methylene groups of G9 are optionally and independently substituted with one R, and in another embodiment, the methylene group bonded to M2 of G9 is not substituted with R.

[0341] In one embodiment, G 10 In another embodiment, G 10 C 1-12 It is an alkylene group, and in another embodiment, G 10 C 1-10 It is an alkylene group, and in another embodiment, G 10 C 1-8 It is an alkylene group, and in another embodiment, G 10 C 1-8 A linear alkylene group, and in another embodiment, G 10 is -(CH2)2-, and in another embodiment, G 10 is -(CH2)4-, and in another embodiment, G 10 is -(CH2)6-, and in another embodiment, G 10 is -(CH2)7-, and in another embodiment, G 10 is -(CH2)8-, and in another embodiment, G 10 R is optionally replaced with 1, 2, 3, 4, 5, or 6 Rs, where R is C 1-10 It is an alkyl group, and in another embodiment, G 10 One, two, or three methylene groups are optionally and independently substituted with one R, and in another embodiment, G 10 One or two methylene groups are optionally and independently substituted with one R.

[0342] In one embodiment, G9 and G 10 The total length of is 4 carbon atoms, and in another embodiment, G9 and G 10 The total length of is 5 carbon atoms, and in another embodiment, G9 and G 10 The total length of is 6 carbon atoms, and in another embodiment, G9 and G 10 The total length is 7 carbon atoms, and in another embodiment, G9 and G 10 The total length of is 8 carbon atoms, and in another embodiment, G9 and G 10 The total length of is 9 carbon atoms, and in another embodiment, G9 and G 10The total length is 10 carbon atoms, and in another embodiment, G9 and G 10 The total length is 11 carbon atoms, and in another embodiment, G9 and G 10 The total length is 12 carbon atoms.

[0343] In one embodiment, G9 and G 10 The total length of is 6, 7, 8, 9, or 10 carbon atoms. In one embodiment, G9 and G 10 The total length is 6, 7, or 8 carbon atoms.

[0344] In one embodiment, R s H is H. In one embodiment, R s C 1-10 It is an alkyl group. In one embodiment, R s C 1-6 It is an alkyl group. In one embodiment, R s is a methyl group. In one embodiment, R s is an ethyl group. 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 d In one embodiment, R s -CH2-NR d R' dThat is the case.

[0345] In one embodiment, R s ' is H. In one embodiment, R s ' is C 1-10 It is an alkyl group. In one embodiment, R s ' is C 1-6 It is an alkyl group. In one embodiment, R s ' is a methyl group. In one embodiment, R s ' is an ethyl group. 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 ' is -NR d R' d In one embodiment, R s ' is -CH2-OR d In one embodiment, R s ' is -CH2-NR d R' d That is the case.

[0346] Examples R and R' are independently H and C 1-20 Alkyl, L a -OR a , -L a -SR a or -L a -NR a R' a And, or R and R' together with the carbon atoms bonded to them, C 3-8Forming a cycloalkylene group, In one embodiment, R is H. In one embodiment, R is C. 1-20 It is an alkyl group. In one embodiment, R is C 1-14 It is an alkyl group. In one embodiment, R is C 1-8 It is an alkyl group. In one embodiment, R is C 1-6 It is an alkyl group. 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.

[0347] In one embodiment, R' is H. In one embodiment, R' is C 1-20 It is an alkyl group. In one embodiment, R' is C 1-14 It is an alkyl group. In one embodiment, R' is C 1-8 It is an alkyl group. In one embodiment, R' is C 1-6 It is an alkyl group. 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.

[0348] In one embodiment, R and R' are C along with the carbon atoms bonded to them. 3-8 A cycloalkylene group is formed. In one embodiment, R and R' together with the carbon atoms bonded to them are C 3-6 A cycloalkylene group is formed. In one embodiment, R and R' together with the carbon atoms bonded to them form a C3 cycloalkylene group, a C4 cycloalkylene group, a C5 cycloalkylene group, or a C6 cycloalkylene group. In one embodiment, R'' is H. In one embodiment, R'' is C 1-14 It is an alkyl group. In one embodiment, R'' is C 1-8 It is an alkyl group. In one embodiment, R'' is C 1-6 It is an alkyl group. In one embodiment, R'' is a methyl group. In one embodiment, R'' is an ethyl group. 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'' is a C6 alkyl group.

[0349] In one embodiment, L d It does not exist. In one embodiment, L d C 1-10 It is an alkylene group. d C 1-6 It is an alkylene group. d is a methylene group. In one embodiment, L d is an ethylene group. In one embodiment, L d is a C3 alkylene group. In one embodiment, L d is a C4 alkylene group. In one embodiment, L d is a C5 alkylene group. In one embodiment, L d This is a C6 alkylene group.

[0350] In one embodiment, R c H is H. In one embodiment, R c C1-8 It is an alkyl group. In one embodiment, R c C 1-6 It is an alkyl group. In one embodiment, R c is a methyl group. In one embodiment, R c is an ethyl group. 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.

[0351] In one embodiment, R' c is H. In one embodiment, R' c C 1-8 It is an alkyl group. In one embodiment, R' c C 1-6 It is an alkyl group. In one embodiment, R' c R' is a methyl group. In one embodiment, R' c is an ethyl group. 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.

[0352] In one embodiment, R d H is H. In one embodiment, R d C 1-10 It is an alkyl group. In one embodiment, R d C 1-8It is an alkyl group. In one embodiment, R d C 1-6 It is an alkyl group. In one embodiment, R d is a methyl group. In one embodiment, R d is an ethyl group. 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 an alkyl group.

[0353] In one embodiment, R' d is H. In one embodiment, R' d C 1-10 It is an alkyl group. In one embodiment, R' d C 1-8 It is an alkyl group. In one embodiment, R' d C 1-6 It is an alkyl group. In one embodiment, R' d R' is a methyl group. In one embodiment, R' d is an ethyl group. 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' dis a C9 alkyl group. In one embodiment, R' d C 10 It is an alkyl group.

[0354] 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.

[0355] 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.

[0356] 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.

[0357] 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.

[0358] 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.

[0359] 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.

[0360] 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.

[0361] 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.

[0362] 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.

[0363] 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.

[0364] 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.

[0365] In one embodiment, [ka] The total length is 4, 5, 6, 7, 8, or 9 carbon atoms.

[0366] 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- One embodiment is 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-, [ka] These are independently -(CH2)4-C(CH3)2-, -(CH2)5-C(CH3)2-, or -(CH2)6-C(CH3)2-, and in one embodiment, [ka] It is -(CH2)5-C(CH3)2-. In one embodiment, [ka] is -(CH2)6-C(CH3)2- and [ka] It is -(CH2)7-. In one embodiment, [ka] is -(CH2)7- and [ka] It is -(CH2)7-.

[0367] In one embodiment, -G7-L1-G8-H or -G9-L2-G 10 -H is 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)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] They are selected from among them.

[0368] In one embodiment, -G7-L1-G8-H or -G9-L2-G 10 -H is 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)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] It is a base selected from among them.

[0369] 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] And the other is -(CH2)8CH3.

[0370] In one embodiment, the ionized lipid is a compound of formula (IX), [ka] Or its stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt, where G1 and G2 are joined independently, C 1-13 Linear alkylene group, C 2-13 Linear alkenylene group or C 2-13 A linear alkylene group, where the alkylene group, alkenylene group, and alkylene group can be optionally selected as one or more R G1 Replaced by, The total length of G1 and G2 is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 carbon atoms. R G1 In various cases, H and C are independent. 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 group, C 4-14 Linear alkenylene group or C 4-14 A linear alkylene group, where the alkylene group, alkenylene group, and alkylene group can be optionally selected as one or more R G3 Replaced by, R G3 In various cases, H and -L are independent. 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 an alkylene group, R a and R' a H and C are independent of each other. 1-14 Alkyl alkyl group, C 3-14It is a cycloalkyl group or a 3-14 member heterocyclyl group. G4 is a bond, C 1-6 Alkylene group, C 2-6 Alkenylene group or C 2-6 The alkylene group is an alkylene group, where the alkylene group, alkenylene group and alkylene group can be optionally selected as one or more R groups. G4 Replaced by, R G4 In various cases, H and C are independent. 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 an alkylene group, R b and R' b H and C are independent of each other. 1-6 Alkyl alkyl group, C 3-10 It is a cycloalkyl group or a 3-10 membered heterocyclyl group. Alternatively, the two RG4 atoms, along with the same carbon atom bonded to them, are C 3-14 A cycloalkylene group or a 3-14 membered heterocyclene group is formed, where the cycloalkylene group and heterocyclene group are optionally one or more R groups. 4g Replaced by, R 4g In various cases, H, halogen, cyano group, and C are independently involved. 1-8 Alkyl alkyl group, C 1-8 Haloalkyl group, -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 an alkylene group, R e and R' e H and C are independent of each other.1-8 Alkyl alkyl group, C 3-14 It is a cycloalkyl group or a 3-14 member heterocyclyl group. 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 -, a phenylene group or a pyridinylene group, where the phenylene group or pyridinylene group is optionally one or more R * Replaced by, R * These are independently H, halogen, cyano group, and C 1-10 Alkyl alkyl group, C 1-10 Haloalkyl group, -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 an alkylene group, R f and R' f H and C are independent of each other. 1-10 Alkyl alkyl group, C 3-14 It is a cycloalkyl group or a 3-14 member heterocyclyl group. R1 and R2 are independently C 4-20 Alkyl alkyl group, C 4-20 Alkenyl group or C 4-20 It is an alkynyl group, and one or more R groups can be optionally selected. 1s Substituted with, and here one or more methylene group units are optionally and independently substituted with -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 an alkyl group, L c These are independently combined or C 1-20 It is an alkylene group, R c and R' c H and C are independent of each other. 1-20 Alkyl alkyl group, C 3-14 It is a cycloalkyl group or a 3-14 member heterocyclyl group. 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(ORg )S(O)2R g , -N(OR g )C(O)OR g , -N(OR g )C(O)R g R' g , a 3-14 member heterocyclyl group or a 5-14 member heteroaryl group, R g and R' g H and C are independent of each other. 1-10 Alkyl alkyl group, C 3-10 These are cycloalkyl groups and 3-10 membered heterocyclyl groups. R'' is independently H or C 1-6 It is an alkyl group, R5 and R6 are independently C 1-8 It is an alkyl group, where the alkyl group is optionally one or more R 4s Replaced by, Alternatively, R5 and R6, along with the same carbon atom bonded to them, are C 3-14 A cycloalkylene group or a 3-14 membered heterocyclene group is formed, where the cycloalkylene group and heterocyclene group are optionally one or more R groups. 4s Replaced by, R 4s These are independently H, halogen, cyano group, and C 1-8 Alkyl alkyl group, C 1-8 Haloalkyl group, -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 an alkylene group, R d and R' d H and C are independent of each other. 1-8 Alkyl alkyl group, C 3-14 It is a cycloalkyl group or a 3- to 14-membered heterocyclyl group.

[0371] In one embodiment, G1 and G2 are independently bonded, C1-9 Linear alkylene group, C 2-9 Linear alkenylene group or C 2-9 It is a linear alkynylene group.

[0372] In one embodiment, G1 is C 1-6 Linear alkylene group, C 2-6 Linear alkenylene group or C 2-6 It is a linear alkynylene group. In one embodiment, G1 is C 1-6 It is a linear alkylene group. In one embodiment, G1 is C 2-6 It is a linear alkylene group.

[0373] In one embodiment, G2 is bonded, C 1-6 Linear alkylene group, C 2-6 Linear alkenylene group or C 2-6 It is a linear alkynylene group. In one embodiment, G2 is a bond or C 1-6 It is a linear alkylene group. In one embodiment, G2 is a bond or C 1-4 It is a linear alkylene group.

[0374] 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 an optional 1, 2, 3, or 4 R G1 It will be replaced by this.

[0375] In one embodiment, in various cases, R G1 H or C 1-10 It is an alkyl group. In one embodiment, in various cases, R G1 H or C 1-6 It is an alkyl group.

[0376] In one embodiment, G3 is C 4-10 Linear alkylene group, C 4-10 Linear alkenylene group or C 4-10 It is a linear alkynylene group. In one embodiment, G3 is C 4-9 It is a linear alkylene group. In one embodiment, G3 is C 5-8 It is a linear alkylene group. In one embodiment, G3 optionally consists of 1, 2, 3, or 4 R G3 It will be replaced by this.

[0377] In one embodiment, L a These are independently combined or C 1-10 It is an alkylene group. a These are independently combined or C 1-6 It is an alkylene group.

[0378] In one embodiment, R a and R' a H and C are independent of each other. 1-10 Alkyl alkyl group, C 3-10 It is a cycloalkyl group or a 3-10 membered heterocyclyl group. In one embodiment, R a and R' a These are H or C, respectively, independently. 1-6 It is an alkyl group.

[0379] In one embodiment, G4 is C 1-4 Alkylene group, C 2-4 Alkenylene group or C 2-4 It is an alkynylene group. In one embodiment, G4 is C 2-4 It is an alkylene group. In one embodiment, G4 is C 2-3 It is an alkylene group. In one embodiment, G4 is optionally 1, 2, 3, or 4 R G4 It will be replaced by this.

[0380] In one embodiment, R G4 H or C 1-6 It is an alkyl group. In one embodiment, R G4 C 1-4It is an alkyl group.

[0381] In one embodiment, two R G4 C 3-10 It forms a cycloalkylene group or a 3-10 membered heterocyclylene group. In one embodiment, two R G4 C 3-7 A cycloalkylene group or a 3-7 membered heterocyclylene group is formed. In one embodiment, the cycloalkylene group and the heterocyclylene group optionally have 1, 2, or 3 R 4g Replaced by, In one embodiment, R 4g These are independently H, halogen, cyano group, and C 1-6 Alkyl alkyl group or C 1-6 It is a haloalkyl group.

[0382] In one embodiment, L b These are independently combined or C 1-4 It is an alkylene group.

[0383] In one embodiment, R b and R' b H and C are independent of each other. 1-6 Alkyl alkyl group, C 3-7 It is a cycloalkyl group or a 3- to 7-membered heterocyclyl group. In one embodiment, R b and R' b H or C 1-6 It is an alkyl group. In one embodiment, R b and R' b H or C 1-4 It is an alkyl group.

[0384] 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)-.

[0385] In one embodiment, R1 and R2 are independently C 6-14 Alkyl alkyl group, C 6-14 Alkenyl group or C 6-14 It is an alkynyl group. In one embodiment, R1 and R2 are independently C 6-14 It is an alkyl group. In one embodiment, R1 and R2 are independently C 7-12 It is an alkyl group. In one embodiment, R1 and R2 are independently C 8-12 It is an alkyl group. In one embodiment, R1 and R2 are independently C 7-12 Alkyl alkyl group, C 7-12 Alkenyl group or C 7-12 It is an alkynyl group.

[0386] In one embodiment, R1 and R2 are optionally 1, 2, 3, or 4 R 1s It is replaced by one R. In one embodiment, R1 and R2 are optionally replaced by one R 1s It will be replaced by this.

[0387] In one embodiment, R1 and R2 are independently -(CH2)5CH3, -(CH2)6CH3, -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3, -(CH2) 11CH3, -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.

[0388] 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 an alkyl group. In one embodiment, R 1s H or C 1-10 It is an alkyl group. In one embodiment, R 1s H or C 1-9 It is an alkyl group. In one embodiment, R 1s H or C 1-6 It is an alkyl group. In one embodiment, R 1s H or C 1-4 It is an alkyl group.

[0389] In one embodiment, R and R' are independently H or C 1-20 It is an alkyl group. In one embodiment, R and R' are independently H or C 1-14 It is an alkyl group. In one embodiment, R and R' are independently H or C 1-9 It is an alkyl group. In one embodiment, R and R' are independently H or C 1-6It is an alkyl group. In one embodiment, R is H.

[0390] In one embodiment, L c These are independently combined or C 1-14 It is an alkylene group. c These are independently combined or C 1-10 It is an alkylene group. c These are independently combined or C 1-6 It is an alkylene group.

[0391] In one embodiment, R c and R' c H or C 1-14 It is an alkyl group. In one embodiment, R c and R' c H or C 1-10 It is an alkyl group. In one embodiment, R c and R' c H or C 1-6 It is an alkyl group.

[0392] In one embodiment, R3 is a cyano group, -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.

[0393] In one embodiment, R3 is -OH or -N(CH3)2.

[0394] In one embodiment, R g and R' g H and C are independent of each other. 1-6 Alkyl alkyl group, C 3-7 It is a cycloalkyl group or a 3- to 7-membered heterocyclyl group. In one embodiment, R g and R' g H or C1-6 It is an alkyl group. In one embodiment, R g and R' g H or C 1-4 It is an alkyl group. In one embodiment, R g and R' g These are independently H or -CH3.

[0395] In one embodiment, R5 and R6 are independently C 1-6 It is an alkyl group. In one embodiment, R5 and R6 are independently C 1-3 It is an alkyl group. In one embodiment, R5 and R6 are independently -CH3. In one embodiment, R5 and R6 are independently and optionally 1, 2, or 3 R 4s It will be replaced by this.

[0396] In one embodiment, R5 and R6, along with the carbon atoms bonded to them, are C 3-10 A cycloalkylene group or a 3-10 membered heterocyclylene group is formed. In one embodiment, the cycloalkylene group or heterocyclylene group optionally has 1, 2, or 3 R 4s It will be replaced by this.

[0397] In one embodiment, R 4s These are independently H, halogen, cyano group, and C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, -L d -OR d , -L d -SR d or -L d -NR d R' d In one embodiment, R 4s These are independently H, halogen, cyano group, and C 1-6 Alkyl alkyl group or C 1-6 It is a haloalkyl group. In one embodiment, R 4s H and C are independent of each other. 1-3 Alkyl alkyl group or C 1-3 It is a haloalkyl group.

[0398] In one embodiment, L d These are independently combined or C 1-6 It is an alkylene group. d These are independently combined or C 1-3 It is an alkylene group.

[0399] In one embodiment, R d and R' d H and C are independent of each other. 1-6 Alkyl alkyl group, C 3-10 It is a cycloalkyl group or a 3-10 membered heterocyclyl group. In one embodiment, R d and R' d H or C 1-6 It is an alkyl group. In one embodiment, R d and R' d H or C 1-6 It is an alkyl group.

[0400] In one embodiment, L e These are independently combined or C 1-6 It is an alkylene group. e These are independently combined or C 1-4 It is an alkylene group.

[0401] In one embodiment, R e and R' e H and C are independent of each other. 1-6 Alkyl alkyl group, C 3-10 It is a cycloalkyl group or a 3-10 membered heterocyclyl group. In one embodiment, R e and R' e H or C 1-6 It is an alkyl group. In one embodiment, R e and R' e H or C 1-4 It is an alkyl group.

[0402] In one embodiment, L f These are independently combined or C 1-6 It is an alkylene group. f These are independently combined or C1-4 It is an alkylene group.

[0403] In one embodiment, R f and R' f H and C are independent of each other. 1-6 Alkyl alkyl group, C 3-10 It is a cycloalkyl group or a 3-10 membered heterocyclyl group. In one embodiment, R f and R' f H or C 1-6 It is an alkyl group. In one embodiment, R f and R' f H or C 1-4 It is an alkyl group.

[0404] In one embodiment, the ionized lipid is a compound of formula (X), [ka] Or its stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt, where 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.

[0405] In one embodiment, R in M1 or M2 and R1 or R2 1s The substitution site has a spacing of 0 to 10 carbon atoms. In one embodiment, the R in M1 or M2 and R1 or R2 1s The substitution site has a spacing of 0 to 6 carbon atoms. In one embodiment, the R in M1 or M2 and R1 or R2 1s The substitution site has a spacing of 0 to 4 carbon atoms. In one embodiment, the R in M1 or M2 and R1 or R2 1sThe substitution site has a spacing of 0 to 2 carbon atoms. In one embodiment, the R in M1 or M2 and R1 or R2 1s The substitution site has zero carbon atoms spaced apart.

[0406] 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.

[0407] In one embodiment, R1 is [ka] That is the case.

[0408] In one preferred embodiment, the ionized lipid is [ka] JPEG2026515723000137.jpg197149 JPEG2026515723000138.jpg187149 JPEG2026515723000139.jpg199149 JPEG2026515723000140.jpg188149 JPEG2026515723000141.jpg195149 JPEG2026515723000142.jpg186149 JPEG2026515723000143.jpg120149 JPEG2026515723000144.jpg171149 JPEG2026515723000145.jpg170149 JPEG2026515723000146.jpg186149 JPEG2026515723000147.jpg96149 Alternatively, these may be stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts.

[0409] For a description of ionized lipids, including their manufacturing process, see CN115850104A, and the entire contents of the above document are incorporated herein by reference.

[0410] 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.

[0411] In one embodiment, the ionized lipid is compound 46 of the following formula, [ka] Alternatively, it may be a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

[0412] In one embodiment, the ionized lipid is compound 132, [ka] Alternatively, it may be a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

[0413] In one embodiment, the ionized lipid is [ka] Alternatively, these may be stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts.

[0414] In one embodiment, the molar percentage of the ionized lipid in the total lipids of the lipid nanoparticles is 35 to 70 mol%, more preferably 40 to 60 mol%, for example, 35 mol%, 40 mol%, 45 mol%, 50 mol%, 55 mol%, or 60 mol%.

[0415] 5.2.3. Phospholipids As used herein, phospholipids refer to amphiphilic lipids having a negatively charged phosphate ester group and one or more hydrophobic moieties. Phospholipids may be assembled into one or more lipid bilayers. Phospholipids consist of two fatty acid tails (hydrophobic moieties) linked by glycerol and a phosphate ester group head, and may be natural or synthetic. Non-limiting examples of phospholipids include soy lecithin, egg 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 can be modified or functionalized by various chemical reactions, such as binding to an azide group by binding to an alkyne. The phospholipid can be functionalized for targeting or imaging purposes.

[0416] In one embodiment, the lipid nanoparticles contain phospholipids. 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-dimyristol-sn-glycero-3-phosphoethanolamine (DMPE). In one embodiment, the phospholipid is 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE). In one embodiment, the phospholipid is dipalmitoylphosphatidylcholine (DPPC). In another embodiment, the phospholipid is -2-(9Z-octadecanoyl)-sn-glycero-3-phosphoethanolamine (POPE).

[0417] In one embodiment, the lipid nanoparticles do not contain phospholipids, or the amount of phospholipids they contain is about 50 mol%, about 40 mol%, 30 mol%, 20 mol%, 15 mol%, 10 mol%, or less than 5 mol% of the total lipids present in the lipid nanoparticles.

[0418] In one embodiment, the molar percentage of the phospholipid in the total lipids of the lipid nanoparticles is 5 to 30 mol%, more preferably 5 to 20 mol%, and more preferably 5 to 15 mol%, for example, 5 mol%, 6 mol%, 7 mol%, 8 mol%, 9 mol%, 10 mol%, 11 mol%, 12 mol%, 13 mol%, 14 mol%, 15 mol%, 16 mol%, 17 mol%, 18 mol%, 19 mol%, or 20 mol%.

[0419] 5.2.4. Structural lipids In one embodiment, the lipid nanoparticles further comprise structural lipids. Unless otherwise stated, the structural lipids are neutral lipids distinct from the steroid compounds described in Section 0. 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.

[0420] 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.

[0421] In one embodiment, the molar percentage of the structural lipids in the total lipids of the lipid nanoparticles is 10 to 80 mol%, more preferably 15 to 70 mol%, even more preferably 30 to 50 mol%, and most preferably 30 to 40 mol%, for example, 30 mol%, 35 mol%, 40 mol%, 45 mol%, 50 mol%, 55 mol%, or 60 mol%.

[0422] 5.2.5. Polymer-conjugated lipids In one embodiment, the lipid nanoparticles include polymer-conjugated lipids. In one embodiment, the polymer-conjugated lipid is polyethylene glycolated lipid (PEG lipid). In one embodiment, the PEG lipid is a diglyceride further comprising a PEG chain bonded to a glycerol group. In one embodiment, the PEG lipid is a compound comprising one or more C6-C24 long-chain alkyl or alkenyl groups or C6-C24 fatty acid groups bonded to a linker group having a PEG chain. Non-limiting examples of PEG lipids include PEG-modified phosphatidylethanolamine and phosphatidic acid, PEG-modified dialkylamine and PEG-modified 1,2-diacyloxypropane-3-amine bonded to a PEG ceramide bond, PEG-modified diacylglycerol and dialkylglycerol. In one embodiment, it is PEG-modified distearoylphosphatidylethanolamine or PEG-modified dimyristoyl-sn-glycerol. In one embodiment, the PEG modification is measured according to the molecular weight of the PEG component of the lipid. In one embodiment, the molecular weight of the polyethylene glycolated lipid is approximately 1,000 Da to approximately 10,000 Da. In one embodiment, the molecular weight of the polyethylene glycolated lipid is approximately 1,000 Da to approximately 5,000 Da. In one embodiment, the molecular weight of the polyethylene glycolated lipid is approximately 1,000 Da to approximately 2,000 Da.

[0423] In one embodiment, the polyethylene glycolated lipid is methoxypolyethylene glycol oxy(2000)-N,N-bistetradecylacetamide (ALC-0159). In one embodiment, the polyethylene glycolated lipid is 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000 (DMG-PEG2000). In one embodiment, the polyethylene glycolated lipid is 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine-polyethylene glycol 1000 (DMPE-PEG1000). In one embodiment, the polyethylene glycolated lipid is 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-polyethylene glycol 1000 (DPPE-PEG1000). In one embodiment, the polyethylene glycolated lipid is 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-polyethylene glycol 1000 (DSPE-PEG1000). In one embodiment, the polyethylene glycolated lipid is 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-polyethylene glycol 1000 (DOPE-PEG1000).

[0424] In one embodiment, the polyethylene glycolated lipid is 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000 (ceramide-PEG2000). In one embodiment, the polyethylene glycolated lipid is 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine-polyethylene glycol 2000 (DMPE-PEG2000). In one embodiment, the polyethylene glycolated lipid is 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-polyethylene glycol 2000 (DPPE-PEG2000). In one embodiment, the polyethylene glycolated lipid is 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-polyethylene glycol 2000 (DSPE-PEG2000). In one embodiment, the polyethylene glycolated lipid is 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-(polyethylene glycol 2000)-mannose (DSPE-PEG2000-mannose). In one embodiment, the polyethylene glycolated lipid is 1,2-dimiristoyl-rac-glycero-3-methoxypolyethylene glycol-5000 (ceramide-PEG5000). In one embodiment, the polyethylene glycolated lipid is 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-polyethylene glycol 5000 (DSPE-PEG5000). In one embodiment, the polyethylene glycolated lipid is 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000 (DSPE-PEG2000amine)].

[0425] In one preferred embodiment, the molar percentage of the polymer conjugate lipid in the total lipid of the lipid nanoparticles is 0.25 to 10 mol%, more preferably 0.5 to 5 mol%, and more preferably 0.5 to 3 mol%, for example 0.5 mol%, 0.6 mol%, 0.7 mol%, 0.8 mol%, 0.9 mol%, 1.0 mol%, 1.1 mol%, 1.2 mol%, 1.3 mol%, 1.4 mol%, 1.5 mol%, and 1.6 mol%. %, 1.7mol%, 1.8mol%, 1.9mol%, 2.0mol%, 2.1mol%, 2.2mol%, 2.3mol%, 2.4mol%, 2.5mol%, 2.6mol%, 2.7mol%, 2.8mol%, 2.9mol%, 3.0mol%, 3.1mol%, 3.2mol%, 3.3mol%, 3.4mol%, 3.5mol%, 3.6mol%, 3.7mol%, 3.8mol%, 3.9mol%, 4.0mol%.

[0426] 5.2.6. Payload In one embodiment, the lipid nanoparticles include a payload.

[0427] In one embodiment, the payload is a small molecule.

[0428] In one embodiment, the payload is nucleic acid.

[0429] In one embodiment, the payload may include anticancer agents, antifungal agents, psychiatric preparations (e.g., analgesics), preparations that alter the level of consciousness (e.g., anesthetics or hypnotics), nonsteroidal anti-inflammatory drugs (NSAIDS), anthelmintic agents, antiacne agents, antianginic agents, antiarrhythmic agents, antiasthmatic agents, antibacterial agents, antibenign prostatic hyperplasia agents, anticoagulants, antidepressants, antidiabetic agents, antiemetics, antiepileptic agents, antigout agents, antihypertensive agents, anti-inflammatory agents, antimalarial agents, antimigraine agents, antimuscarinic agents, antitumor agents, antiobesity agents, antiosteoporosis agents, antiparkinson's disease agents, antiproliferative agents, antiparasitic agents, antithyroid agents, antitussives, antiurinal agents, antiurinal agents, antiviral agents, anxiolytics, appetite inhibitors, β-receptor blockers, and preparations that affect or control myocardial contraction (cardiac inotropic). These include agents, chemotherapeutic drugs, cognitive enhancers, contraceptives, corticosteroids, Cox-2 inhibitors, diuretics, erectile dysfunction medications, expectorants, gastrointestinal preparations, histamine receptor antagonists, immunosuppressants, exfoliants, lipid regulators, leukotriene inhibitors, macrolide drugs, muscle relaxants, nerve relaxants, nutritional preparations, opioid analgesics, protease inhibitors, or sedatives.

[0430] 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.

[0431] 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 with a target nucleic acid, particularly a continuous sequence on the target nucleic acid. In one embodiment, the ASO is single-stranded.

[0432] 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).

[0433] In one embodiment, the payload is ribonucleic acid (RNA). In another embodiment, the payload is RNA interference (RNAi). In one embodiment, the payload is a small interfering RNA (siRNA). In one embodiment, the payload is a short hairpin RNA (shRNA). In one embodiment, the payload is an antisense RNA (aRNA). In one embodiment, the payload is a messenger RNA (mRNA). In one embodiment, the payload is a modified messenger RNA (mmRNA). In one embodiment, the payload is a long non-coding RNA (lncRNA). In one embodiment, the payload is a microRNA (miRNA). In one embodiment, the payload is a small activated RNA (siRNA). In one embodiment, the payload is a multimer-coding nucleic acid (MCNA). In one embodiment, the payload is a polymer-coding nucleic acid (PCNA). In one embodiment, the payload is any RNA in a ribozyme.

[0434] In one embodiment, the payload is clustered, regularly spaced short palindromic repeats (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).

[0435] In one embodiment, the ratio of (total number of nitrogen atoms in the cationic steroid compound and ionized lipid) to (total number of phosphorus atoms in the nucleic acid) is approximately 1:1 to approximately 15:1 (N:P ratio). In one embodiment, the N:P ratio is approximately 3:1 to approximately 12:1. 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.

[0436] In one embodiment, when lipid nanoparticles are administered to a target, the amount of payload delivered or expressed in the target's non-liver tissue by the lipid nanoparticles is higher than the amount of payload delivered or expressed in the target's liver by the lipid nanoparticles. In another embodiment, when lipid nanoparticles are administered to a target, the amount of payload delivered or expressed in the target's spleen by the lipid nanoparticles is higher than the amount of payload delivered or expressed in the target's liver by the lipid nanoparticles.

[0437] In one embodiment, the amount of payload delivered or expressed in the target spleen is higher than the amount of payload delivered or expressed in the target liver. In one embodiment, the amount of payload delivered or expressed in the target spleen is at least twice as high as the amount of payload delivered or expressed in the target liver. In one embodiment, the amount of payload delivered or expressed in the target spleen is at least five times higher than the amount of payload delivered or expressed in the target liver. In one embodiment, the amount of payload delivered or expressed in the target spleen is at least ten times higher than the amount of payload delivered or expressed in the target liver. In one embodiment, the amount of payload delivered or expressed in the target spleen is at least twenty times higher than the amount of payload delivered or expressed in the target liver. In one embodiment, the amount of payload delivered or expressed in the target spleen is at least forty times higher than the amount of payload delivered or expressed in the target liver. In one embodiment, the amount of payload delivered or expressed in the target spleen is at least sixty times higher than the amount of payload delivered or expressed in the target liver. In one embodiment, the amount of payload delivered or expressed in the target spleen is at least one hundred times higher than the amount of payload delivered or expressed in the target liver.

[0438] In one embodiment, when lipid nanoparticles containing nucleic acids are administered to a subject, the amount of protein expressed in the subject's spleen 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 spleen by the mRNA is higher than the amount of protein expressed in the subject's liver by the mRNA.

[0439] In one embodiment, the amount of protein expressed in the target spleen is higher than the amount of protein expressed in the target liver. In one embodiment, the amount of protein expressed in the target spleen is at least twice as high as the amount of protein expressed in the target liver. In one embodiment, the amount of protein expressed in the target spleen is at least five times higher than the amount of protein expressed in the target liver. In one embodiment, the amount of protein expressed in the target spleen is at least ten times higher than the amount of protein expressed in the target liver. In one embodiment, the amount of protein expressed in the target spleen is at least twenty times higher than the amount of protein expressed in the target liver. In one embodiment, the amount of protein expressed in the target spleen is at least forty times higher than the amount of protein expressed in the target liver. In one embodiment, the amount of protein expressed in the target spleen is at least sixty times higher than the amount of protein expressed in the target liver. In one embodiment, the amount of protein expressed in the target spleen is at least one hundred times higher than the amount of protein expressed in the target liver.

[0440] 5.3 Lipid Nanoparticle Compositions In one embodiment, this specification provides a lipid nanoparticle composition comprising lipid nanoparticles as described in Section 0. In one embodiment, the lipid nanoparticle composition described herein comprises a steroid compound as described in Section 0 and an ionized lipid as described in Section 0. In one embodiment, the lipid nanoparticle composition described herein comprises a phospholipid as described in Section 0. In one embodiment, the lipid nanoparticle population described herein does not contain a phospholipid. In one embodiment, the lipid nanoparticle composition described herein comprises a structural lipid as described in Section 0. In one embodiment, the lipid nanoparticle composition described herein comprises a polymer conjugate lipid as described in Section 0. In one embodiment, the lipid nanoparticle composition described herein comprises a payload as described in Section 0.

[0441] In one embodiment, the polydispersity index (PDI) of the lipid nanoparticle composition is less than 0.2. In one embodiment, the PDI of the lipid nanoparticle composition is less than 0.15. In one embodiment, the PDI of the lipid nanoparticle composition is 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.

[0442] In one embodiment, the apparent pKa of the lipid nanoparticle composition is between 2 and 7. In one embodiment, the apparent pKa of the lipid nanoparticle composition is 2, 3, 4, 5, 6, or 7. In one embodiment, the apparent pKa of the lipid nanoparticle composition is less than 6. In one embodiment, the apparent pKa of the lipid nanoparticle composition is between 3 and 6.

[0443] In one embodiment, the apparent pKa is determined by 2-(p-toluidino)-6-naphthalenesulfonic acid (TNS) fluorescence spectroscopy. In the art, TNS fluorescence spectroscopy is described, for example, 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.

[0444] 5.4 Pharmaceutical Compositions In one embodiment, this specification provides a pharmaceutical composition comprising lipid nanoparticles or a lipid nanoparticle composition described in Section 0. In one embodiment, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0445] The pharmaceutically acceptable carriers used in this application include non-toxic carriers, adjuvants, or carriers that do not impair the pharmacological activity of the compounds prepared together. Pharmaceutically acceptable carriers usable in the compositions of this disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum prot...

Claims

1. Lipid nanoparticles comprising ionized lipids and steroid compounds, The steroid compound is a compound of formula (I), 【Chemistry 1】 Alternatively, it may be a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt, where, 【Chemistry 2】 These are 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 where the left bond is in the direction of V １ and is directed towards 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 here the connection to the left is V １ It is heading in that direction, R ２ａ Each example is independently H, C １－１０ Alkyl alkyl group, C ３－１４ A cycloalkyl group or a 3- to 14-membered heterocyclyl group, wherein the alkyl group, cycloalkyl group and heterocyclyl group are independently and optionally C １－１０ Alkyl 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 Replaced by, R ２０１ , R ２０２ , R ２０３ , R ２０４ Each example independently consists of H, OH, alkyl group, alkoxy group, 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, dithioureazole, (iso)triazole, tetrazole, pentasol, indole, indoline, pyrimidine, pyrazine, quinazoline, piperazine, piperidine, morpholine, pyran, quinoxaline, quinoline, quinolinone, (iso)quinoline, amidine, guanidine, or urea. M is absent or one or more anions, the anions being independently selected from chloride, bromide, iodide, sulfate, nitrate, perchlorate, formate, citrate, sulfonate, methanesulfonate, trifluoromethanesulfonate, trifluoroacetate, pyrosulfate, bisulfite, sulfite, bisulfite, phosphate, pyrophosphate, monohydrogen phosphate, dihydrogen phosphate, acetate, propionate, caprine, octanoate, acrylate, isobutyrate, hexanoate, heptanoate, oxalate, malonate, succinate, fumarate, maleate, benzoate, phthalate, phenylacetate, lactate, glycolate, tartrate, mandelate, methanesulfonate, gluconate, aspartate, or glutamate. R ２１ , R ２２ , R ２３ Each example independently involves H, and C is optionally substituted. １－８ Alkyl alkyl group, -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 an alkylene group, R ２ｂ , R' ２ｂ and R'' ２ｂ each example of which is independently H or a C １－１０ alkyl group, R ｚ１ C １－１４ Alkyl alkyl group or C １－１４ It is an alkenyl group, where the alkyl group and the alkenyl group are optionally substituted, and As a premise, if Y is -NHC(O)-, (i) m is an integer between 5 and 12, or (ii) V １ is not N(CH ３ ) ２ A lipid nanoparticle that satisfies at least one of the conditions such as.

2. Lipid nanoparticles comprising ionized lipids and steroid compounds, The aforementioned steroid compound is a compound of formula (I-P), 【Transformation 3】 Alternatively, it may be a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt, where, 【Chemistry 4】 These are single or double bonds, 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 here the connection to the left is V １ It is heading in that direction, R ２ａ Each example is independently H, C １－１０ Alkyl alkyl group, C ３－１４ A cycloalkyl group or a 3- to 14-membered heterocyclyl group, wherein the alkyl group, cycloalkyl group and heterocyclyl group are independently and optionally C １－１０ Alkyl 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 Replaced by, R ２０１ , R ２０２ , R ２０３ , R ２０４ Each example independently consists of H, OH, alkyl group, alkoxy group, 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 It either does not exist, or it is a cation, H, C １－６ Alkyl alkyl group, C １－６ Haloalkyl group, C ２－６ Alkenyl group or C ２－６ It is an alkynyl group, and here the alkyl group, haloalkyl group, alkenyl group and alkynyl group can be 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, dithioureazole, (iso)triazole, tetrazole, pentasol, indole, indoline, pyrimidine, pyrazine, quinazoline, piperazine, piperidine, morpholine, pyran, quinoxaline, quinoline, quinolinone, (iso)quinoline, amidine, guanidine, or urea. M is absent or one or more anions, the anions being independently selected from chloride, bromide, iodide, sulfate, nitrate, perchlorate, formate, citrate, sulfonate, methanesulfonate, trifluoromethanesulfonate, trifluoroacetate, pyrosulfate, bisulfite, sulfite, bisulfite, phosphate, pyrophosphate, monohydrogen phosphate, dihydrogen phosphate, acetate, propionate, caprine, octanoate, acrylate, isobutyrate, hexanoate, heptanoate, oxalate, malonate, succinate, fumarate, maleate, benzoate, phthalate, phenylacetate, lactate, glycolate, tartrate, mandelate, methanesulfonate, gluconate, aspartate, or glutamate. R ２１ , R ２２ , R ２３ Each example independently involves H, and C is optionally substituted. １－８ Alkyl alkyl group, -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 an alkylene group, R ２ｂ , R' ２ｂ and R'' ２ｂ Each example is independently H or C １－１０ It is an alkyl group, R ｚ１ C １－１４ Alkyl alkyl group or C １－１４ Lipid nanoparticles comprising an alkenyl group, wherein the alkyl group and alkenyl group are optionally substituted.

3. Y is -C(O)O-, -OC(O)-, -O-, -NHC(O)O-, -OC(O)NH-, or -OC(O)O-, and where the bond to the left 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 , -O(CO)O-, -NHC(O)-, or -C(O)NH-, and where the bond to the left is V １ Lipid nanoparticles according to any one of claims 1 to 3, which are oriented in the direction of [the specified direction].

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

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】 Alternatively, the lipid nanoparticles according to claim 5, which are stereoisomers thereof, mixtures of stereoisomers, or pharmaceutically acceptable salts thereof, where m3 is an integer from 1 to 11.

7. R ２０１ , R ２０２ , R ２０３ and R ２０４ Each example is independently H, C １－６ Alkyl 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 or -C(O)OCH ３ The lipid nanoparticles according to claim 7.

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】 Alternatively, the lipid nanoparticles according to claim 2, wherein m3 is an integer from 1 to 11, and the nanoparticles are stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts thereof.

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 optionally substituted radicals of amidine, guanidine, or urea.

12. R ２１ , R ２２ , R ２３ These are H, hydroxyl group, and C, respectively, independently. １－３ Alkyl alkyl group 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 ＋ H ２ ) 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 above.

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 bromides, chlorides, iodides, or trifluoroacetates.

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

17. R ｚ１ C ６－１２ Alkyl alkyl group or C ６－１２ The lipid nanoparticle according to claim 14, wherein the group is an alkenyl group, and the alkyl group and the alkenyl group are optionally substituted with one or more hydroxyl groups, oxo groups, or halogens.

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

19. Lipid nanoparticles comprising ionized lipids and steroid compounds, The aforementioned steroid compound, 【Chemistry 9】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 Alternatively, lipid nanoparticles that are stereoisomers thereof, mixtures of stereoisomers, or pharmaceutically acceptable salts thereof.

20. Lipid nanoparticles according to any one of claims 1 to 19, wherein the molar percentage of the steroid compound in the total lipid is 3 to 15 mol%, preferably 5 to 10 mol%, for example 3 mol%, 4 mol%, 5 mol%, 6 mol%, 7 mol%, 8 mol%, 9 mol%, 10 mol%, 11 mol%, 12 mol%, 13 mol%, 14 mol%, or 15 mol%.

21. The ionized lipid comprises at least one ionized 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 structural formula of the biodegradable hydrophobic chain is -R １６ -M ０ -R １７ And here R １６ C ４－１４ Alkylene group, C ４－１４ Alkenylene group or C ４－１４ It is an alkynylene group, R １７ is C ６－２０ It is an alkyl group and M ０ is a biodegradable group, and here the alkylene group, alkenylene group, alkylylene group and alkyl group are optionally substituted. Preferably, here, M ０ The lipid nanoparticle according to any one of claims 1 to 20, wherein is an ester group, an amide group, a thioester group, a carbonate group, a carbamate group, a carbamoylthioester group, a urea group, or a disulfide group.

22. The ionized lipid is a compound of formula (III), 【Chemistry 10】 Alternatively, it may be a stereoisomer thereof, a mixture of stereoisomers, a tautomer, an isotope substitution, or a pharmaceutically acceptable salt, where, R ３ and R ４ Each example is independently C １－１０ Alkyl alkyl group, C ２－１０ Alkenyl group, C ２－１０ Alkynyl group, C ３ -C １４ Cycloalkyl group, 3-14 member heterocyclyl group, (C １－１０ (alkylene group) - (C ３ -C １４ (Cycloalkyl group) or (C １－１０ Alkylene group) - (3-14 member heterocyclyl group), or R ３ and R ４ These, together with the nitrogen atoms bonded to them, form a 3- to 14-membered heterocyclyl group, or R ４ and one R ０ ' forms a 4-10 membered heterocyclyl group or a 5-10 membered heteroaryl group together with the atoms bonded to them, and here the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, heteroaryl group and alkylene group independently and optionally one or more R ＊ Replaced by, R ０ Each example of ' is a methylene group that is independently and optionally substituted, or here two R ０ ' forms a 3- to 8-membered cycloalkylene group together with the carbons bonded to them, and here the cycloalkylene group optionally has one or more R ＊＊ 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 represents a connection. W is C, CH, or N, and assuming 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 group, C ２－２４ Alkenylene group, C ３ -C ８ Cycloalkylene group, C ３ -C ８ A cycloalkenylene group, where the alkylene group, alkenylene group, cycloalkylene group, and cycloalkenylene group can be optionally selected as one or more R groups. ＊＊ Replaced by, G １ G ２ G ３ and G ４ They either do not exist independently of each other, or C １－１３ Alkylene group, C ２－１３ Alkenylene group or C ２－１３ The alkylene group is an alkylene group, where the alkylene group, alkenylene group, and alkylene group can be optionally selected as one or more R groups. ｓ Replaced by, G １ and G ２ The total length is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 carbon atoms. G ３ and G ４ The total length is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 carbon atoms. R ５ , R ６ , R ７ and R ８ Each is either hydrogen or optionally substituted C １－８ It is an alkyl group, 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 here 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 Rs, and Q and W form a 5-10 member monocyclic ring or fused ring, and optionally the ring is one or more Rs. ＊＊ Replaced by, M １ and M ２ These either do not exist independently of each other, or they are -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 alkyl, L ａ -OR ａ , -L ａ -SR ａ or -L ａ -NR ａ R' ａ And, or R and R' together with the carbons bonded to them, C ３－８ Forming a cycloalkylene group, Q ３ and Q ４ These are H, -(CRR')-, and C, respectively, independently. ６－１０ It is an aryl group or a steroid moiety. A １ A ２ A ３ A ４ Each example is independently - (CR １８ R １８ -CR １８ =CR １８ ) - or - (CR １８ R １８ -C≡C)-, R １８ Each example is independently H or C １－２０ It is an alkyl group, 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 group or -O-P(O)(OH)-O- Z-Q ３ Or Z-Q ４ Each of the dashed lines between them either does not exist independently or is combined, and if Z does not exist as a premise, neither of the two dashed lines exists. m, n, q, r, u, v, y, and z are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. o, p, w, and x are each independently 0, 1, or 2. s and t are independently either 0 or 1. G １ and Q ３ Between or G ３ and Q ４ The number of carbon atoms between them is 8 to 30. L ａ and L ｅ They either do not exist independently of each other, or C １－２０ It is an alkylene group, L ｂ and L ｆ They either do not exist independently of each other, or C １－１０ It is an alkylene group, L ｃ It does not exist, or C １－８ It is an alkylene group, L ｄ It does not exist, or C １－１４ It is an alkylene group, R ＊ is a hydroxyl group, halogen, C １－１０ Alkyl alkyl group, C １－１０ Haloalkyl group, C １－１０ Hydroxyalkyl group, -L ｂ -OR ｂ , -L ｂ -SR ｂ or -L ｂ -NR ｂ R' ｂ And, R ＊＊ is a hydroxyl group, halogen, C １－８ Alkyl alkyl group, C １－８ Haloalkyl group, C １－８ Hydroxyalkyl group, -L ｂ -OR ｂ , -L ｂ -SR ｂ or -L ｂ -NR ｂ R' ｂ And, R ｓ C １－１４ Alkyl alkyl group, -L ｂ -OR ｂ , -L ｂ -SR ｂ or -L ｂ -NR ｂ R' ｂ And, R ａ and R' ａ H and C are independent of each other. １－２０ Alkyl alkyl group, C ３－１４ The alkyl group is a cycloalkyl group or a 3- to 14-membered heterocyclyl group, where the alkyl group, cycloalkyl group and heterocyclyl group can be optionally a hydroxyl group, a halogen, or C １－２０ Alkyl alkyl group, -L ｅ -OR ｅ , -L ｅ -SR ｅ or -L ｅ -NR ｅ R' ｅ Substituted with one or more groups selected from, R ｂ and R' ｂ H and C are independent of each other. １－１０ Alkyl alkyl group, C ３－１４ The alkyl group is a cycloalkyl group or a 3- to 14-membered heterocyclyl group, where the alkyl group, cycloalkyl group and heterocyclyl group can be optionally a hydroxyl group, a halogen, or C １－１０ Alkyl alkyl group, -L ｆ -OR ｆ , -L ｆ -SR ｆ or -L ｆ -NR ｆ R' ｆ Substituted with one or more groups selected from, R ｃ and R' ｃ Each is independently of hydrogen or C １－８ It is an alkyl group, R ｄ and R' ｄ Each is independently of hydrogen or C １－１４ It is an alkyl group, R ｅ and R' ｅ Each is independently of hydrogen or C １－２０ It is an alkyl group, and R ｆ and R' ｆ Each is independently of hydrogen or C １－１０ Lipid nanoparticles according to any one of claims 1 to 21, wherein the molecule is an alkyl group.

23. The ionized lipid is a compound of formula (IV'), 【Chemistry 11】 Or its stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt, where j is either 0 or 1. W is either CH or N, and assuming 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 a methylene group that is independently and optionally substituted, or here two R ０ ' forms a 3- to 8-membered cycloalkylene group together with the carbons bonded to them, and here the cycloalkylene group optionally has one or more R ＊＊ 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 H and C are independent of each other. １－２０ Alkyl alkyl group, C ３－１４ The alkyl group is a cycloalkyl group or a 3- to 14-membered heterocyclyl group, where the alkyl group, cycloalkyl group and heterocyclyl group can be optionally a hydroxyl group, a halogen, or C １－２０ Alkyl alkyl group, -L ｅ -OR ｅ , -L ｅ -SR ｅ or -L ｅ -NR ｅ R' ｅ Substituted with one or more groups selected from, G ５ C is either non-existent or optionally replaced. １－８ It is an alkylene group, R １ and R ２ Each of them is independently C ４－２０ Alkyl alkyl group, C ４－２０ Alkenyl group or C ４－２０ It is an alkynyl group, and here, R １ and R ２ One or more of the methylene group units are independently and optionally -NH- or -N(C) １－２０ Substituted with an alkyl group, where the alkyl group, alkenyl group, and alkynyl group are optionally substituted. R ３ and R ４ Each example is independently H, C １－１０ Alkyl alkyl group, C ２－１０ Alkenyl group, C ２－１０ Alkynyl group, C ３ -C １４ It is a cycloalkyl group or a 3-14 member heterocyclyl group, or R ３ and R ４ These, together with the N atoms bonded to them, form a 3- to 14-membered heterocyclyl group, or R ４ and one R ０ ' forms a 4-10 membered heterocyclyl group together with the atoms bonded to them, and here the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group is optionally one or more R ＊ Replaced with and R ５ , R ６ , R ７ and R ８ Each is either hydrogen or optionally substituted C １－８ Lipid nanoparticles according to claim 22, wherein the nanoparticle is an alkyl group.

24. The ionized lipid is a compound of formula (V'), (VI'), or (VII'), 【Chemistry 12】 Alternatively, these are stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts, where, k is 0, 1, 2, 3, 4, or 5. L １ and L ２ These are each independent of each other - (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 either does not exist independently or is optionally replaced by C. １－７ It is an alkylene group, G １ａ G １ｂ G ２ａ and G ２ｂ The total length is 1, 2, 3, 4, 5, 6, or 7 carbon atoms. G ３ａ G ３ｂ G ４ａ and G ４ｂ The total length is 1, 2, 3, 4, 5, 6, or 7 carbon atoms. R ５ , R ６ , R ７ and R ８ Each is either hydrogen or optionally substituted C １－６ It is an alkyl group, G ７ G ８ G ９ and G １０ Each of these either does not exist independently or is optionally replaced by C. １－１２ It is an alkylene group, and the premise is G ７ and G ８ The total length is 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms, and G ９ and G １０ The total length is 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 alkyl group, -L ｄ -OR ｄ or -L ｄ -NR ｄ R' ｄ And, R' is H, C １－１４ Alkyl alkyl group, -L ａ -OR ａ or -L ａ -NR ａ R' ａ And, R'' is H or C １－１４ It is an alkyl group, L ｄ It does not exist, or C １－１０ It is an alkylene group, L ａ It does not exist, or C １－１４ It is an alkylene group, R ａ and R' ａ H and C are independent of each other. １－１４ Alkyl alkyl group, C ３－１０ A cycloalkyl group or a 3- to 10-membered heterocyclyl group, wherein the alkyl group, cycloalkyl group and heterocyclyl group are optionally substituted. R ｄ and R' ｄ These are H or C, respectively, independently. １－１０ It is an alkyl group, a' and b are independently 0, 1, 3, 4, and 5, respectively, and the premise is 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, and The lipid nanoparticles according to claim 23, wherein c, d, e, and f are each independently 0, 1, 2, 3, 4, 5, 6, or 7, and it is assumed that c + d is the integral between 2 and 9, and e + f is the integral between 2 and 9.

25. The ionized lipid is a compound of formula (VIII), 【Chemistry 13】 Lipid nanoparticles according to any one of claims 1 to 24, which are stereoisomers thereof, mixtures of stereoisomers, or pharmaceutically acceptable salts thereof.

26. R ５ , R ６ , R ７ and R ８ The lipid nanoparticle according to claim 25, wherein each is independently a hydrogen or a methyl group.

27. G １ G ２ G ３ and G ４ They either do not exist independently of each other, or C １－８ Lipid nanoparticles according to claim 25, wherein the group is alkylene.

28. The aforementioned ionized lipid is a compound of formula (IX), 【Chemistry 14】 Or its stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt, where G １ and G ２ Each is joined independently, C １－１３ Linear alkylene group, C ２－１３ Linear alkenylene group or C ２－１３ A linear alkylene group, where the alkylene group, alkenylene group, and alkylene group are optionally one or more R Ｇ１ Replaced by, G １ and G ２ The total length is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 carbon atoms. R Ｇ１ In various cases, H and C are independent. １－１４ Alkyl alkyl group, -L ａ -OR ａ , -L ａ -SR ａ or -L ａ -NR ａ R' ａ And, G ３ C ４－１４ Linear alkylene group, C ４－１４ Linear alkenylene group or C ４－１４ A linear alkylene group, where the alkylene group, alkenylene group, and alkylene group are optionally one or more R Ｇ３ Replaced by, R Ｇ３ In various cases, H and -L are independent. 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 an alkylene group, R ａ and R' ａ H and C are independent of each other. １－１４ Alkyl alkyl group, C ３－１４ It is a cycloalkyl group or a 3-14 membered heterocyclyl group. G ４ C １－６ Alkylene group, C ２－６ Alkenylene group or C ２－６ The alkylene group is an alkylene group, where the alkylene group, alkenylene group, and alkylene group can be optionally selected as one or more R groups. Ｇ４ Replaced by, R Ｇ４ In various cases, H and C are independent. １－６ Alkyl alkyl group, -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 an alkylene group, R ｂ and R' ｂ H and C are independent of each other. １－６ Alkyl alkyl group, C ３－１０ It is a cycloalkyl group or a 3- to 10-membered heterocyclyl group. Or two RG ４ C ３－１４ A cycloalkylene group or a 3- to 14-membered heterocyclene group is formed, where the cycloalkylene group and heterocyclene group are optionally one or more R groups. ４ｇ Replaced by, R ４ｇ In various cases, H, halogen, cyano group, and C are independently involved. １－８ Alkyl alkyl group, C １－８ Haloalkyl group, -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 an alkylene group, R ｅ and R' ｅ H and C are independent of each other. １－８ Alkyl alkyl group, C ３－１４ It is a cycloalkyl group or a 3-14 membered heterocyclyl group. 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 -, a phenylene group or a pyridinylene group, where the phenylene group or pyridinylene group is optionally one or more R ＊ Replaced by, R ＊ These are independently H, halogen, cyano group, and C １－１０ Alkyl alkyl group, C １－１０ Haloalkyl group, -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 an alkylene group, R ｆ and R' ｆ H and C are independent of each other. １－１０ Alkyl alkyl group, C ３－１４ It is a cycloalkyl group or a 3-14 membered heterocyclyl group. R １ and R ２ C ４－２０ Alkyl alkyl group, C ４－２０ Alkenyl group or C ４－２０ It is an alkynyl group, and optionally one or more R groups. １ｓ Substituted with, and here one or more methylene group units are optionally and independently substituted with -NR'-, R １ｓ H and C are independent of each other. １－２０ Alkyl alkyl group, -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 an alkyl group, L ｃ These are independently combined or C １－２０ It is an alkylene group, R ｃ and R' ｃ H and C are independent of each other. １－２０ Alkyl alkyl group, C ３－１４ It is a cycloalkyl group or a 3-14 membered heterocyclyl group. 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 , a 3-14 membered heterocyclyl group or a 5-14 membered heteroaryl group, R ｇ and R' ｇ H and C are independent of each other. １－１０ Alkyl alkyl group, C ３－１０ These are cycloalkyl groups and 3- to 10-membered heterocyclyl groups. R'' is independently H or C １－６ It is an alkyl group, R ５ and R ６ C １－８ It is an alkyl group, where the alkyl group is optionally one or more R ４ｓ Replaced by, Or R ５ and R ６ C ３－１４ A cycloalkylene group or a 3- to 14-membered heterocyclene group is formed, where the cycloalkylene group and heterocyclene group are optionally one or more R groups. ４ｓ Replaced by, R ４ｓ These are independently H, halogen, cyano group, and C １－８ Alkyl alkyl group, C １－８ Haloalkyl group, -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 an alkylene group, R ｄ and R' ｄ H and C are independent of each other. １－８ Alkyl alkyl group, C ３－１４ Lipid nanoparticles according to any one of claims 1 to 27, wherein the nanoparticle is a cycloalkyl group or a 3- to 14-membered heterocyclyl group.

29. The ionized lipid is a compound of formula (X), 【Chemistry 15】 Or its stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt, where 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. Lipid nanoparticles according to any one of claims 1 to 28, wherein c + d is 3, 4, 5, 6, 7, 8, or 9.

30. The aforementioned ionized lipid is 【Chemistry 16】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 Lipid nanoparticles according to any one of claims 1 to 29, which are stereoisomers thereof, mixtures of stereoisomers, or pharmaceutically acceptable salts thereof.

31. The lipid nanoparticle according to any one of claims 1 to 30, 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.

32. The lipid nanoparticles according to any one of claims 1 to 31, wherein the molar percentage of the ionized lipid is 35 to 70 mol%, more preferably 40 to 60 mol%, for example 35 mol%, 40 mol%, 45 mol%, 50 mol%, 55 mol%, or 60 mol%.

33. Lipid nanoparticles according to any one of claims 1 to 32, further comprising phospholipids.

34. The lipid nanoparticle according to claim 33, wherein the phospholipid is DSPC, DMPC, DOPC, DPPC, POPPC, DOPE, DMPE, POPOE, or DPPE.

35. The lipid nanoparticles according to any one of claims 1 to 34, wherein the molar percentage of the phospholipid is 5 to 30 mol%, preferably 5 to 20 mol%, more preferably 5 to 15 mol%, for example 5 mol%, 6 mol%, 7 mol%, 8 mol%, 9 mol%, 10 mol%, 11 mol%, 12 mol%, 13 mol%, 14 mol%, or 15 mol%.

36. Lipid nanoparticles according to any one of claims 1 to 35, further comprising structural lipids.

37. The lipid nanoparticles according to claim 36, 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 natanesterol.

38. The lipid nanoparticles according to any one of claims 1 to 37, wherein the molar percentage of the structural lipid is 10 to 80 mol%, more preferably 15 to 70 mol%, even more preferably 30 to 50 mol%, and most preferably 30 to 40 mol%, for example 30 mol%, 35 mol%, 40 mol%, 45 mol%, 50 mol%, 55 mol%, or 60 mol%.

39. Lipid nanoparticles according to any one of claims 1 to 38, further comprising polymer-conjugated lipids, such as polyethylene glycolated lipids.

40. The lipid nanoparticle according to claim 39, wherein the polyethylene glycolated lipid includes a polyethylene glycolated 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.

41. The lipid nanoparticles according to claim 39, 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.

42. The molar percentage of the polymer conjugate lipid is 0.25 to 10 mol%, more preferably 0.5 to 5 mol%, and even more preferably 0.5 to 3 mol%, for example 0.5 mol%, 0.6 mol%, 0.7 mol%, 0.8 mol%, 0.9 mol%, 1.0 mol%, 1.1 mol%, 1.2 mol%, 1.3 mol%, 1.4 mol%, 1.5 mol%, 1.6 mol%, 1.7 mol%, 1.8 mol%, 1.9 mol%, Lipid nanoparticles according to any one of claims 1 to 41, wherein the amounts are 2.0 mol%, 2.1 mol%, 2.2 mol%, 2.3 mol%, 2.4 mol%, 2.5 mol%, 2.6 mol%, 2.7 mol%, 2.8 mol%, 2.9 mol%, 3.0 mol%, 3.1 mol%, 3.2 mol%, 3.3 mol%, 3.4 mol%, 3.5 mol%, 3.6 mol%, 3.7 mol%, 3.8 mol%, 3.9 mol%, and 4.0 mol%.

43. Lipid nanoparticles according to any one of claims 1 to 42, wherein the lipid nanoparticles include (1) a steroid compound, (2) an ionized lipid, (3) a phospholipid compound, (4) a structural lipid, and (5) a polymer conjugate lipid.

44. The aforementioned lipid nanoparticles targeting the spleen are 1) 3 to 15 mol%, preferably 5 to 10 mol%, of a steroid compound. 2) 35 to 70 mol%, preferably 40 to 60 mol%, ionized lipids 3) 5 to 30 mol%, preferably 5 to 20 mol%, phospholipids 4) 10 to 80 mol%, preferably 15 to 70 mol%, more preferably 30 to 50 mol%, of structural lipids, 5) Lipid nanoparticles according to any one of claims 1 to 43, comprising a component in molar percentage of 0.25 to 10 mol%, preferably 0.5 to 5 mol%, and more preferably 0.5 to 3 mol%, such as polymer conjugate lipids.

45. The lipid nanoparticles according to any one of claims 1 to 44, further comprising a payload which is a therapeutic agent, a preventive agent, or a diagnostic agent.

46. The lipid nanoparticles according to claim 45, wherein the payload is nucleic acid.

47. The lipid nanoparticle according to claim 46, wherein the nucleic acid is an antisense oligonucleotide (ASO), DNA, or RNA, and optionally the RNA is any other RNA from among 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), multimer coding nucleic acid (MCNA), polymer coding nucleic acid (PCNA), guide RNA (gRNA), CRISPR RNA (crRNA), or ribozyme.

48. A lipid nanoparticle composition comprising lipid nanoparticles according to any one of claims 1 to 47.

49. A pharmaceutical composition comprising lipid nanoparticles according to any one of claims 1 to 47 or a lipid nanoparticle composition according to claim 48 and a pharmaceutically acceptable carrier.

50. A method for treating or preventing a spleen disease or spleen-related disease in a subject suffering from such a disease, comprising administering to the subject a therapeutically effective amount of lipid nanoparticles according to any one of claims 1 to 47, a lipid nanoparticle composition according to claim 48, or a pharmaceutical composition according to claim 49.

51. Use of lipid nanoparticles according to any one of claims 1 to 47 or a lipid nanoparticle composition according to claim 48 in the manufacture of a drug for preventing or treating spleen disease or spleen-related disease.

52. It is used to prevent or treat spleen diseases or spleen-related diseases, preferably the spleen disease or spleen-related disease includes hematological disorders, infectious diseases, immune diseases or cancer, and more preferably the spleen disease or spleen-related disease includes hemolytic anemia, thrombocytopenic purpura, chronic leukemia, lymphomas such as Hodgkin lymphoma or non-Hodgkin lymphoma, myelodysplastic syndrome, myelofibrosis, splenomegaly, lipid metabolism disorders such as glucocerebroside disease and sphingomyelinosis, and sepsis, typhus, infectious mononuclear cells Lipid nanoparticles according to any one of claims 1 to 47, a lipid nanoparticle composition according to claim 48, or a pharmaceutical composition according to claim 49, comprising splenomegaly and hypersplenism associated with disease or subacute bacterial endocarditis, splenomegaly and hypersplenism associated with malaria, tuberculosis, kala-azar, etc., congestive splenomegaly and hypersplenism caused by portal hypertension due to liver cirrhosis, splenic cysts such as parasitic splenic cysts or pseudosplenic cysts, splenic abscesses, primary splenic tumors, splenic metastatic tumors, splenic artery aneurysms, splenic infarctions, splenic purpura, splenic rupture, etc.

53. The use of the method of claim 50 or claim 51, wherein the spleen disease or spleen-related disease includes blood disorders, infectious diseases, immune diseases, or cancer.

54. The splenic disease or splenic-related disease includes hemolytic anemia, thrombocytopenic purpura, chronic leukemia, lymphoma such as Hodgkin lymphoma or non-Hodgkin lymphoma, myelodysplastic syndrome, myelofibrosis, splenomegaly, lipid metabolism disorders such as glucocerebroside disease and sphingomyelinosis, and splenomegaly and hypersplenism associated with sepsis, typhus, infectious mononucleosis or subacute bacterial endocarditis, and splenomegaly and hypersplenism associated with malaria, tuberculosis, kala-azar, etc., congestive splenomegaly and hypersplenism resulting from portal hypertension due to liver cirrhosis, splenic cysts such as parasitic splenic cysts or pseudosplenic cysts, splenic abscess, primary splenic tumor, splenic metastatic tumor, splenic artery aneurysm, splenic infarction, splenic purpura, splenic rupture, etc., as described in the method of claim 50 or use of claim 51.

55. A method for producing lipid nanoparticles according to any one of claims 1 to 47 or a lipid nanoparticle composition according to claim 48, (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 comprising the step of mixing the lipid solution and the payload solution to form the lipid nanoparticles.

56. The method according to claim 55, wherein the mixing is carried out using a microfluidic system.

57. Steroid compounds of formula (II-A), 【Chemistry 17】 Or a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, where, each [Chemistry 18] These are independently single bonds 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 here the connection to the left is V １ It is heading 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 here the connection to the left is V １ It is heading in that direction, R ２ａ Each example is independently H, C １－１０ Alkyl alkyl group, C ３－１４ A cycloalkyl group or a 3- to 14-membered heterocyclyl group, wherein the alkyl group, cycloalkyl group and heterocyclyl group are independently and optionally C １－１０ Alkyl 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 Replaced by, R ２０１ , R ２０２ , R ２０３ , R ２０４ Each example independently consists of H, OH, alkyl group, alkoxy group, 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 is NR ２１ R ２２ N ＋ R ２１ R ２２ R ２３ imidazole, pyridine, pyrrole, pyrrolidine, pyrazole, (iso)thiazole, (iso)oxazole, oxadiazine, oxazoline, dithioureazole, (iso)triazole, tetrazole, pentazole, indole, indoline, pyrimidine, pyrazine, quinazoline, piperazine, piperidine, morpholine, pyran, quinoxaline, quinoline, quinolinone, (iso)quinoline, amidine, guanidine or urea, and M is absent or independently chloride, bromide, iodide, sulfate, nitrate, perchlorate, formate, citrate, sulfonate, methanesulfonate, trifluoromethanesulfonate, trifluoroacetate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, pyrophosphate, monohydrogen phosphate, dihydrogen phosphate, acetate, propionate, caprylate, octanoate, acrylate, isobutyrate, hexanoate, heptanoate, oxalate, malonate, succinate, fumarate, maleate, benzoate, phthalate, phenylacetate, lactate, glycolate, tartrate, mandelate, methanesulfonate, gluconate, aspartate or glutamate, one or more anions selected from: R ２１ 、 R ２２ 、 R ２３ are each independently H, optionally substituted C １－８ alkyl group, -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 an alkylene group, R ２ｂ , R' ２ｂ and R'' ２ｂ Each of these is independently H or C １－１０ It is an alkyl group, and R ｚ１ C １－１４ Alkyl alkyl group or C １－１４ It is an alkenyl group, where the alkyl group and the alkenyl group are optionally substituted, and the compound is, 【Chemistry 19】 Not the steroid compound of formula (II-A), or its stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt.

58. The steroid compound is represented by formula (II-B), 【Chemistry 20】 Or a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, where, 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 here the connection to the left is V １ It is heading 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 here the connection to the left is V １ It is heading in that direction, R ２ａ Each example of １－１０ is independently H, C ３－１４ alkyl group, C １－１０ cycloalkyl group or a 3- to 14-member heterocyclyl group, and wherein said alkyl group, cycloalkyl group and heterocyclyl group are independently optionally C ２ｂ alkyl group, L ２ｂ -OR ｂ , L ２ｂ -SR ２ｂ , L 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 substituted, R ２０１ , R ２０２ , R ２０３ , R ２０４ Each example independently consists of H, OH, alkyl group, alkoxy group, 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, dithioureazole, (iso)triazole, tetrazole, pentasol, indole, indoline, pyrimidine, pyrazine, quinazoline, piperazine, piperidine, morpholine, pyran, quinoxaline, quinoline, quinolinone, (iso)quinoline, amidine, guanidine, or urea. M is absent or one or more anions, the anions being independently selected from chloride, bromide, iodide, sulfate, nitrate, perchlorate, formate, citrate, sulfonate, methanesulfonate, trifluoromethanesulfonate, trifluoroacetate, pyrosulfate, bisulfite, sulfite, bisulfite, phosphate, pyrophosphate, monohydrogen phosphate, dihydrogen phosphate, acetate, propionate, caprine, octanoate, acrylate, isobutyrate, hexanoate, heptanoate, oxalate, malonate, succinate, fumarate, maleate, benzoate, phthalate, phenylacetate, lactate, glycolate, tartrate, mandelate, methanesulfonate, gluconate, aspartate, or glutamate. R ２１ , R ２２ , R ２３ H is independent of C, which is optionally substituted. １－８ Alkyl alkyl group, -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 an alkylene group, R ２ｂ , R' ２ｂ and R'' ２ｂ Each of these is independently H or C １－１０ It is an alkyl group, Preferably, Y １ is -C(O)O-, -OC(O)-, -O-, -S-, -NR ２ａ -, -OC(O)NR ２ａ - or - NR ２ａ A steroid compound of formula (II-B) that is C(O)-, or a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

59. A steroid compound of formula (I-P), 【Chemistry 21】 Or a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, where, 【Chemistry 22】 These are single or double bonds, 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 here the connection to the left is V １ It is heading in that direction, R ２ａ Each example is independently H, C １－１０ Alkyl alkyl group, C ３－１４ A cycloalkyl group or a 3- to 14-membered heterocyclyl group, wherein the alkyl group, cycloalkyl group and heterocyclyl group are independently and optionally C １－１０ Alkyl 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 Replaced by, R ２０１ , R ２０２ , R ２０３ , R ２０４ Each example independently consists of H, OH, alkyl group, alkoxy group, 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 It either does not exist, or it is a cation, H, C １－６ Alkyl alkyl group, C １－６ Haloalkyl group, C ２－６ Alkenyl group or C ２－６ It is an alkynyl group, and here the alkyl group, haloalkyl group, alkenyl group and alkynyl group can be 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, dithioureazole, (iso)triazole, tetrazole, pentasol, indole, indoline, pyrimidine, pyrazine, quinazoline, piperazine, piperidine, morpholine, pyran, quinoxaline, quinoline, quinolinone, (iso)quinoline, amidine, guanidine, or urea. M is absent or one or more anions, the anions being independently selected from chloride, bromide, iodide, sulfate, nitrate, perchlorate, formate, citrate, sulfonate, methanesulfonate, trifluoromethanesulfonate, trifluoroacetate, pyrosulfate, bisulfite, sulfite, bisulfite, phosphate, pyrophosphate, monohydrogen phosphate, dihydrogen phosphate, acetate, propionate, caprine, octanoate, acrylate, isobutyrate, hexanoate, heptanoate, oxalate, malonate, succinate, fumarate, maleate, benzoate, phthalate, phenylacetate, lactate, glycolate, tartrate, mandelate, methanesulfonate, gluconate, aspartate, or glutamate. R ２１ , R ２２ , R ２３ Each example independently involves H, and C is optionally substituted. １－８ Alkyl alkyl group, -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 an alkylene group, R ２ｂ , R' ２ｂ and R'' ２ｂ Each example is independently H or C １－１０ It is an alkyl group, R ｚ１ C １－１４ Alkyl alkyl group or C １－１４ A steroid compound of formula (I-P), or a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein the alkyl group and the alkenyl group are optionally substituted.

60. A steroid compound of formula (II-C1), 【Chemistry 23】 Or a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, where, R ｚ１ teeth, 【Chemistry 24】 And, R ２ａ H is replaced by C, which is optionally substituted. １－８ Alkyl alkyl group, -L ２ｂ -OR ２ｂ , L ２ｂ -OC(O)R ２ｂ or L ２ｂ -C(O)OR ２ｂ Preferably H, -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 here, R ２１ , R ２２ , R ２３ H is independent of C, which is optionally substituted. １－８ Alkyl alkyl group, -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 R ２１ and R ２２ It is not hydrogen at the same time, L ２ｂ C is either non-existent or optionally replaced. １－１０ It is an alkylene group, R ２ｂ , R' ２ｂ and R'' ２ｂ Each of these is independently H or C １－１０ It is an alkyl group, M is absent or one or more anions, the anions being independently selected from chloride, bromide, iodide, sulfate, nitrate, perchlorate, formate, citrate, sulfonate, methanesulfonate, trifluoromethanesulfonate, trifluoroacetate, pyrosulfate, bisulfite, sulfite, bisulfite, phosphate, pyrophosphate, monohydrogen phosphate, dihydrogen phosphate, acetate, propionate, caprine, octanoate, acrylate, isobutyrate, hexanoate, heptanoate, oxalate, malonate, succinate, fumarate, maleate, benzoate, phthalate, phenylacetate, lactate, glycolate, tartrate, mandelate, methanesulfonate, gluconate, aspartate, or glutamate. A steroid compound of formula (II-C1), or a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, where m is an integer from 1 to 10, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

61. A steroid compound of formula (II-C2), 【Chemistry 25】 Or a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, where, R ｚ１ teeth, 【Chemistry 26】 And, V １ NR ２１ R ２２ or N ＋ R ２１ R ２２ R ２３ And here R ２１ , R ２２ , R ２３ H is independent of C, which is optionally substituted. １－８ Alkyl alkyl group, -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 R ２１ and R ２２ It is not hydrogen at the same time, L ２ｂ C is either non-existent or optionally replaced. １－１０ It is an alkylene group, R ２ｂ , R' ２ｂ and R'' ２ｂ Each of these is independently H or C １－１０ It is an alkyl group, M is absent or one or more anions, the anions being independently selected from chloride, bromide, iodide, sulfate, nitrate, perchlorate, formate, citrate, sulfonate, methanesulfonate, trifluoromethanesulfonate, trifluoroacetate, pyrosulfate, bisulfite, sulfite, bisulfite, phosphate, pyrophosphate, monohydrogen phosphate, dihydrogen phosphate, acetate, propionate, caprine, octanoate, acrylate, isobutyrate, hexanoate, heptanoate, oxalate, malonate, succinate, fumarate, maleate, benzoate, phthalate, phenylacetate, lactate, glycolate, tartrate, mandelate, methanesulfonate, gluconate, aspartate, or glutamate. A steroid compound of formula (II-C2), or a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, where m is an integer from 1 to 10, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

62. A steroid compound selected from the following compounds, 【Chemistry 27】 【change】 【change】 【change】 【change】 【change】 【change】 Or their stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts.

63. Lipid nanoparticles comprising the compound described in any one of claims 57 to 62.

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