Lipid nanoparticle compositions and uses thereof

A steroid compound, wherein the steroid compound has any one of the following definitions:

• i) which is a steroid compound of formula (II-A):
• or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof,
• wherein:
• each is independently a single bond or double bond;
• Y is —C(O)O—, —O—, —NH—, —SC(O)O—, —OC(O)NR2a—, —NR2aC(O)NR2a—, —OC(O)S—, —OC(O)O—, —NR2aC(O)O—, —OC(O)—, —SC(O)—, —C(O)S—, —NR2a—, —C(O)NR2a—, —NR2aC(O)—, —NR2aC(O)S—, —SC(O)NR2a—, —C(O)—, —OC(S)—, —C(S)O—, —OC(S)NR2a—, —NR2aC(S)O—, or —S(O)0-2—, and wherein the attachment to the left is to the direction of V1;
• Y1 is absent, —C(O)O—, —O—, —NH—, —SC(O)O—, —OC(O)NR2a—, —NR2aC(O)NR2a—, —OC(O)S—, —OC(O)O—, —NR2aC(O)O—, —OC(O)—, —SC(O)—, —C(O)S—, —NR2a—, —C(O)NR2a—, —NR2aC(O)—, —NR2aC(O)S—, —SC(O)NR2a—, —C(O)—, —OC(S)—, —C(S)O—, —OC(S)NR2a—, —NR2aC(S)O—, or —S(O)0-2—, and wherein the attachment to the left is to the direction of V1;
• each instance of R2a is independently H, C1-10 alkyl, C3-14 cycloalkyl, or 3 to 14-membered heterocyclyl, and wherein the alkyl, cycloalkyl, and heterocyclyl are independently optionally substituted with C1-10 alkyl, L2b-OR2b, Lb-SR2b, L2b-NR2bR′2b, L2bN+R2bR′2bR″2b, L2b-OC(O)R2b, or
• L2b-C(O)OR2b;
• each instance of R201, R202, R203, R204 are independently H, OH, alkyl, alkoxy, -L2b-NR21R22, or -L2b-N+R21R22R23, L2b-OC(O)R21, or L2b-C(O)OR21;
• m is an integer from 3 to 12;
• m1 is integer from 0 to 12;
• V1 is NR21R22, N+R21R22R23, imidazole, pyridine, pyrrole, pyrrolidine, pyrazole, (iso)thiazole, (iso)oxazole, oxadiazine, oxazoline, dithiourazole, (iso)triazole, tetrazole, pentazole, indole, dihydroindole, pyrimidine, pyrazine, quinazoline, piperazine, piperidine, morpholine, pyran, quinoxaline, quinoline, quinolinone, (iso)quinoline, amidine, guanidine, or urea;
• M is absent or one or more anions independently selected from chloride, bromide, iodide, sulfate, nitrate, perchlorate, formate, citrate, sulfonate, methanesulfonate, triflate, trifluoroacetate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, pyrophosphate, monohydrogen phosphate, dihydrogen phosphate, acetate, propionate, decanoate, caprylate, acrylate, isobutyrate, caproate, heptanoates, oxalate, malonate, succinate, fumarates, maleate, benzoates, phthalates, phenylacetate, lactate, glycolate, tartrate, mandelate, mesylate, gluconate, aspartate, or glutamate;
• each instance of R21, R22, R23 are independently H, optionally substituted C1-8 alkyl, -L2b-OR2b, -L2b-SR2b, -L2b-NR2bR′2bR″2b, L2b-OC(O)R2b, or L2b-C(O)OR2b;
• L2b is absent or optionally substituted C1-10 alkylene;
• each of R2b, R′2b and R″2b are independently H or C1-10 alkyl;
• and
• Rz1 is C1-14 alkyl or C1-14 alkenyl, wherein the alkyl and alkenyl are optionally substituted;
• and
• provided that the compound is not:
• ii) which is a steroid compound of formula (I-P):
• or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof,
• wherein:
• is a single bond or double bond;
• Y1 is absent, —C(O)O—, —O—, —NH—, —SC(O)O—, —OC(O)NR2a—, —NR2aC(O)NR2a—, —OC(O)S—, —OC(O)O—, —NR2aC(O)O—, —OC(O)—, —SC(O)—, —C(O)S—, —NR2a—, —C(O)NR2a—, —NR2aC(O)—, —NR2aC(O)S—, —SC(O)NR2a—, —C(O)—, —OC(S)—, —C(S)O—, —OC(S)NR2a—, —NR2aC(S)O—, —S(O)0-2—, or —OPO3—, and wherein the attachment to the left is to the direction of V1;
• each instance of R2a is independently H, C1-10 alkyl, C3-14 cycloalkyl, or 3 to 14-membered heterocyclyl, and wherein the alkyl, cycloalkyl, and heterocyclyl are independently optionally substituted with C1-10 alkyl, L2b-OR2b, Lb-SR2b, L2b-NR2bR′2b, L N+R2bR′2bR″2b, L2b-OC(O)R2b, or
• L2b-C(O)OR2b;
• each instance of R201, R202, R203, R204 are independently H, OH, alkyl, alkoxy, -L2b-NR21R22, -L2b-N+R21R22R23, L2b-OC(O)R21, or L2b-C(O)OR21;
• R205 is absent, a cationc, H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, or C2-6 alkynyl, and wherein alkyl, haloalkyl, alkenyl, and alkynyl, is optionally substituted;
• m is an integer from 1 to 12:
• m1 is an integer from 0 to 12;
• V1 is NR21R22, N+R21R22R23, imidazole, pyridine, pyrrole, pyrrolidine, pyrazole, (iso)thiazole, (iso)oxazole, oxadiazine, oxazoline, dithiourazole, (iso)triazole, tetrazole, pentazole, indole, dihydroindole, pyrimidine, pyrazine, quinazoline, piperazine, piperidine, morpholine, pyran, quinoxaline, quinoline, quinolinone, (iso)quinoline, amidine, guanidine, or urea;
• M is absent or one or more anions independently selected from chloride, bromide, iodide, sulfate, nitrate, perchlorate, formate, citrate, sulfonate, methanesulfonate, triflate, trifluoroacetate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, pyrophosphate, monohydrogen phosphate, dihydrogen phosphate, acetate, propionate, decanoate, caprylate, acrylate, isobutyrate, caproate, heptanoates, oxalate, malonate, succinate, fumarates, maleate, benzoates, phthalates, phenylacetate, lactate, glycolate, tartrate, mandelate, mesylate, gluconate, aspartate, or glutamate;
• each instance of R21, R22, R23 are independently H, optionally substituted C1-8 alkyl, -L2b-OR2b, -L2b-SR2b, L2b-NR2bR′2bR″2b, L2b-OC(O)R2b, or L2b-C(O)OR2b;
• L2b is absent or optionally substituted C1-10 alkylene;
• each instance of R2b, R′2b and R″2b are independently H or C1-10 alkyl;
• and
• Rz1 is C1-14 alkyl or C1-14 alkenyl, wherein the alkyl and alkenyl are optionally substituted;
• ii which is:
• or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof;
• iv) which is a steroid compound of formula (II-B):
• or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof,
• wherein:
• Y is —C(O)O—, —O—, —NH—, —SC(O)O—, —OC(O)NR2a—, —NR2aC(O)NR2a—, —OC(O)S—, —OC(O)O—, —NR2aC(O)O—, —OC(O)—, —SC(O)—, —C(O)S—, —NR2a—, —C(O)NR2a—, —NR2aC(O)—, —NR2aC(O)S—, —SC(O)NR2a—, —C(O)—, —OC(S)—, —C(S)O—, —OC(S)NR2a—, —NR2aC(S)O—, or —S(O)0-2—, and wherein the attachment to the left is to the direction of V1;
• Y1 is absent, —C(O)O—, —O—, —NH—, —SC(O)O—, —OC(O)NR2a—, —NR2aC(O)NR2a—, —OC(O)S—, —OC(O)O—, —NR2aC(O)O—, —OC(O)—, —SC(O)—, —C(O)S—, —NR2a—, —C(O)NR2a—, —NR2aC(O)—, —NR2aC(O)S—, —SC(O)NR2a—, —C(O)—, —OC(S)—, —C(S)O—, —OC(S)NR2a—, —NR2aC(S)O—, or —S(O)0-2—, and wherein the attachment to the left is to the direction of V1;
• or Y1 is —C(O)O—, —OC(O)—, —O—, —S—, —NRa—, —OC(O)NR2a—, or —NR2aC(O)—;
• each instance of R2a is independently H, C1-10 alkyl, C3-14 cycloalkyl, or 3 to 14-membered heterocyclyl, and wherein the alkyl, cycloalkyl, and heterocyclyl are independently optionally substituted with C1-10 alkyl, L2b-OR2b, Lb-SR2b, L2b-NR2bR′2b, L2bN+R2bR′2bR″2b, L2b-OC(O)R2b, or
• L2b-C(O)OR2b;
• each instance of R201, R202, R203, R204 are independently H, OH, alkyl, alkoxy, -L2b-NR21R22, or -L2b-N+R21R22R23, L2b-OC(O)R21, or L2b-C(O)OR21;
• m is an integer from 5 to 12;
• m1 is integer from 0 to 12;
• V1 is NR21R22, N+R21R22R23, imidazole, pyridine, pyrrole, pyrrolidine, pyrazole, (iso)thiazole, (iso)oxazole, oxadiazine, oxazoline, dithiourazole, (iso)triazole, tetrazole, pentazole, indole, dihydroindole, pyrimidine, pyrazine, quinazoline, piperazine, piperidine, morpholine, pyran, quinoxaline, quinoline, quinolinone, (iso)quinoline, amidine, guanidine, or urea;
• provided that V1 is not —NH2 or —NH3+;
• M is absent or one or more anions independently selected from chloride, bromide, iodide, sulfate, nitrate, perchlorate, formate, citrate, sulfonate, methanesulfonate, triflate, trifluoroacetate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, pyrophosphate, monohydrogen phosphate, dihydrogen phosphate, acetate, propionate, decanoate, caprylate, acrylate, isobutyrate, caproate, heptanoates, oxalate, malonate, succinate, fumarates, maleate, benzoates, phthalates, phenylacetate, lactate, glycolate, tartrate, mandelate, mesylate, gluconate, aspartate, or glutamate;
• each instance of R21, R22, R23 are independently H, optionally substituted C1-8 alkyl, -L2b-OR2b, -L2b-SRb L2b-NR2bR′2bR″2b, L2b-OC(O)R2b, or L2b-C(O)OR2b;
• L2b is absent or optionally substituted C1-10 alkylene;
• and
• each of R2b, R′2b and R″2b are independently H or C1-10 alkyl;
• v) which is a steroid compound of formula (II-C1):
• or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof,
• wherein:
• Rz1 is
• R2a is CH3—CH2C(O)OCH3, or —CH2C(O)OH;
• V1 is NR21R22 or N+R21R22R23, provided that V1 is not —NH2 or —NH3+;
• each instance of R21, R22, R23 are independently H, optionally substituted C1-8 alkyl, -L2b-OR2b, -L2b-SR2b, -L2b-NR2bR′2bR″2b, L2b-OC(O)R2b, or L2b-C(O)OR2b;
• L2b is absent or optionally substituted C1-10 alkylene;
• each of R2b, R′2b and R″2b are independently H or C1-10 alkyl;
• and
• M is absent or one or more anions independently selected from chloride, bromide, iodide, sulfate, nitrate, perchlorate, formate, citrate, sulfonate, methanesulfonate, triflate, trifluoroacetate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, pyrophosphate, monohydrogen phosphate, dihydrogen phosphate, acetate, propionate, decanoate, caprylate, acrylate, isobutyrate, caproate, heptanoates, oxalate, malonate, succinate, fumarates, maleate, benzoates, phthalates, phenylacetate, lactate, glycolate, tartrate, mandelate, mesylate, gluconate, aspartate, or glutamate;
• and
• m is an integer from 2 to 12:
• vi) which is a steroid compound of formula (II-C2):
• or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof,
• wherein:
• Rz1 is
• V1 is NR21R22 or N+R21R22R23, provided that V1 is not —NH2, —NH3+, —N(CH3)2, —N(CH3)(C2H5), or —N(C2H5)2;
• each instance of R21, R22, R23 are independently H, optionally substituted C1-8 alkyl, -L2b-OR2b, -L2b-SR2b, -L2b-NR2bR′2bR″2b, L2b-OC(O)R2b, or L2b-C(O)OR2b;
• L2b is absent or optionally substituted C1-10 alkylene;
• each of R2b, R′2b and R″2b are independently H or C1-10 alkyl;
• and
• M is absent or one or more anions independently selected from chloride, bromide, iodide, sulfate, nitrate, perchlorate, formate, citrate, sulfonate, methanesulfonate, triflate, trifluoroacetate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, pyrophosphate, monohydrogen phosphate, dihydrogen phosphate, acetate, propionate, decanoate, caprylate, acrylate, isobutyrate, caproate, heptanoates, oxalate, malonate, succinate, fumarates, maleate, benzoates, phthalates, phenylacetate, lactate, glycolate, tartrate, mandelate, mesylate, gluconate, aspartate, or glutamate;
• and
• m is an integer from 2 to 12;
• and
• vii) which is:
• or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.