Lipid compounds for delivering therapeutics, oligonucleotide delivery systems, and preparation methods and applications thereof

Abstract

The present disclosure belongs to the field of biomedical technology, and specifically relates to lipid compounds for delivery therapy, oligonucleotide delivery systems, and preparation methods and applications thereof. The present disclosure has the following advantages: the lipid compounds for delivery therapy disclosed herein or their pharmaceutically acceptable salts, isomers, solvates or prodrugs can be used to prepare siRNA delivery systems, further improving the target gene knockdown ability of siRNA in muscle, fat, peripheral nerve and other tissues. The lipid compounds for delivery therapy provided by the present disclosure or their pharmaceutically acceptable salts, isomers, solvates or prodrugs are expected to provide new strategies for delivering siRNA to muscle, fat, nervous system, etc.

Description

Technical Field

[0001] The present disclosure belongs to the field of biomedicine technology, and specifically relates to lipid compounds and oligonucleotide delivery systems for delivering therapeutics, as well as preparation methods and applications thereof. Background Art

[0002] At present, many different types of nucleic acids are being developed as therapeutic agents for the treatment of many diseases. Therapeutic nucleic acids include small interfering RNA (siRNA), microRNA (miRNA), antisense oligonucleotides, ribozymes, plasmids and immunostimulatory nucleic acids. In siRNA or miRNA, these nucleic acids can reduce the intracellular level of specific proteins by a process called RNA interference (RNAi). After siRNA or miRNA is introduced into the cytoplasm, these double-stranded RNA constructs can be combined with a protein called RISC. The sense strand of the siRNA or miRNA is replaced by the RISC complex, and a template is provided in RISC, which can recognize and combine with an mRNA with a sequence complementary to the sequence of the combined siRNA or miRNA. After combining with complementary mRNA, the RISC complex cleaves the mRNA and releases the cleaved chain. RNAi can provide a reduction in specific proteins by targeting the specific destruction of the mRNA synthesized by the corresponding coding protein.

[0003] The therapeutic applications of RNAi are very broad because siRNA and miRNA constructs can be synthesized with any nucleotide sequence for the target protein. To date, siRNA constructs have demonstrated the ability to specifically downregulate target proteins in both in vitro and in vivo models. In addition, siRNA constructs are currently being evaluated in clinical studies.

[0004] However, siRNA or miRNA constructs are currently facing two problems, the first, its sensitivity to nuclease digestion in blood plasma, and the second, when it is systemically applied with free siRNA or miRNA, its ability to enter the intracellular compartment is limited, in which it can be combined with RISC. These double-stranded constructs can be stabilized by intramolecularly combining chemically modified nucleotide linkers, such as thiophosphate groups of the chemically modified nucleotide linkers. However, these chemical modifications only provide limited protection to nuclease digestion, and may reduce the activity of the construct. Can be by using carrier systems such as polymers, lipid compounds or by constructs being chemically modified such as by covalently attached cholesterol molecules and promoting the intracellular delivery of siRNA or miRNA. Therefore, it is necessary to develop a novel delivery system to improve the effect of siRNA or miRNA molecules and reduce or eliminate the needs for chemical modification.

[0005] Therefore, the development of lipid compounds for delivering siRNA has important clinical significance. The present disclosure aims to propose lipid compounds, oligonucleotide delivery systems, and preparation methods and applications thereof for delivering therapeutics. Summary of the invention

[0006] The technical problem to be solved by the present disclosure is to develop a novel lipid compound for delivering treatment, which can be used to prepare an siRNA delivery system. The siRNA delivery system disclosed herein can improve the target gene knockdown ability of siRNA in muscle, fat, peripheral nerve and other tissues. The siRNA delivery system disclosed herein further improves the target gene knockdown ability of siRNA in muscle, fat, peripheral nerve, eye, heart, kidney, pancreas, uterus, placenta and other tissues.

[0007] In order to achieve the above technical objectives, the technical solution adopted by the present disclosure is:

[0008] In a first aspect, the present disclosure provides a lipid compound having a structure shown in the following formula (I) for delivery therapy or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof,

[0009] (I)

[0010] Wherein, in the formula (I),

[0011] R1 and R2 are each independently selected from C 1-25 Alkyl, C 2-25 Alkenyl or C 3-25 Cycloalkyl;

[0012] n1, n2, n3, m1 are each independently an integer from 0 to 10;

[0013] G1, G2 and G3 are each independently selected from *-C(=O)NH-**, *-CH2NH(C=O)-**, *-NH(C=O)-**, *-(CH2CH2O) m2 -**, *-CH2OPh-**, *-C(=O)-**; wherein m2 is an integer from 1 to 10; * indicates connection with R1, R2 or Q, ** indicates connection with (CH2) n1 、(CH2) n2 or (CH2) n3 Connected;

[0014] Q is CH or N;

[0015] D is H or a group containing an amide structure and ending in a carboxyl group.

[0016] In some preferred embodiments of the present disclosure, D is H or has a structure shown in formula (IA');

[0017] The structure shown in the formula (IA') is:

[0018] (IA')

[0019] in,

[0020] G does not exist or ; *L1 indicates connection with O or carbonyl; *L2 indicates connection with NH;

[0021] n4, n5, and n6 are each independently an integer from 0 to 10;

[0022] V is selected from or ; wherein n7 is an integer from 0 to 10; *L3 represents (CH2) n5 connected; *L4 means connected to O; R x -(CH2)n x -C(CH2ODMTr)H-(CH2)n y - or *L5-C(CH2ODMTr)H-(CH2)n z -CH-*L6;

[0023] n x 、n y 、n z Each independently represents an integer from 1 to 10;

[0024] R y For hydrogen, C 1-8 Alkylene, C 1-8 Alkyl or C 3-8 Cycloalkyl;

[0025] n4, n5, and n6 are each independently an integer from 0 to 10;

[0026] When R x *L5-C(CH2ODMTr)H-(CH2)n z -CH-*L6 and R y C 1-8 When it is alkylene, R x With R y connected to form a ring; *L5 indicates connection with N, *L6 indicates connection with O, R y are connected.

[0027] In some preferred embodiments of the present disclosure, D is H or has a structure shown in formula (IA');

[0028] The structure shown in the formula (IA') is:

[0029] (IA')

[0030] in,

[0031] G does not exist or ; *L1 indicates connection with O or carbonyl; *L2 indicates connection with NH;

[0032] n4, n5, and n6 are each independently an integer from 0 to 10;

[0033] V is selected from or ; wherein n7 is an integer from 0 to 10; *L3 represents (CH2) n5 connected; *L4 means connected to O;

[0034] R x *L5-C(CH2ODMTr)H-(CH2)n z -CH-*L6;n z is an integer from 1 to 10; *L5 indicates connection with N, *L6 indicates connection with O, R y Connected;

[0035] R y C 1-8 Alkylene;

[0036] R x With R y Connected into a ring.

[0037] In some preferred embodiments of the present disclosure, the lipid compound having the structure shown in the following formula (I) or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof,

[0038] (I)

[0039] Wherein, in the formula (I),

[0040] R1 and R2 are each independently selected from C 1-25 alkyl;

[0041] n1, n2, n3, m1 are each independently an integer from 0 to 10;

[0042] G1, G2 and G3 are each independently selected from *-C(=O)NH-**, *-CH2NH(C=O)-**, *-NH(C=O)-**, *-(CH2CH2O) m2 -**, *-CH2OPh-**, *-C(=O)-**; wherein m2 is an integer from 1 to 10; * indicates connection with R1, R2 or Q, ** indicates connection with (CH2)n1 、(CH2) n2 or (CH2) n3 Connected;

[0043] Q is CH or N;

[0044] D is H or has a structure represented by formula (IA');

[0045] The structure shown in the formula (IA') is:

[0046] (IA')

[0047] in,

[0048] G does not exist or ; *L1 indicates connection with O or carbonyl; *L2 indicates connection with NH;

[0049] n4, n5, and n6 are each independently an integer from 0 to 10;

[0050] V is selected from or ; wherein n7 is an integer from 0 to 10; *L3 represents (CH2) n5 connected; *L4 means connected to O;

[0051] R x *L5-C(CH2ODMTr)H-(CH2)n z -CH-*L6;n z is an integer from 1 to 10; *L5 indicates connection with N, *L6 indicates connection with O, R y Connected;

[0052] R y C 1-8 Alkylene;

[0053] R x With R y Connected into a ring.

[0054] In some preferred embodiments of the present disclosure, the lipid compound having the structure shown in the following formula (I) or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof,

[0055] (I)

[0056] Wherein, in the formula (I),

[0057] R1 and R2 are each independently selected from C 1-25 alkyl;

[0058] n1, n2, n3, m1 are each independently an integer from 0 to 10;

[0059] G1, G2 and G3 are each independently selected from *-C(=O)NH-**, *-CH2NH(C=O)-**, *-NH(C=O)-**, *-(CH2CH2O) m2 -**, *-CH2OPh-**, *-C(=O)-**; wherein m2 is an integer from 1 to 10; * indicates connection with R1, R2 or Q, ** indicates connection with (CH2) n1 、(CH2) n2 or (CH2) n3 Connected;

[0060] Q is CH;

[0061] D is H or has a structure represented by formula (IA');

[0062] The structure shown in the formula (IA') is:

[0063] (IA')

[0064] in,

[0065] G is ; *L1 indicates connection with O or carbonyl; *L2 indicates connection with NH;

[0066] n4, n5, and n6 are each independently an integer from 0 to 10;

[0067] V is selected from or ; wherein n7 is an integer from 0 to 10; *L3 represents (CH2) n5 connected; *L4 means connected to O;

[0068] R x *L5-C(CH2ODMTr)H-(CH2)n z -CH-*L6;n z is an integer from 1 to 10; *L5 indicates connection with N, *L6 indicates connection with O, R y Connected;

[0069] R y C 1-8 Alkylene;

[0070] R x With R y Connected into a ring.

[0071] In some preferred embodiments of the present disclosure, the lipid compound having the structure shown in the following formula (I) or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof,

[0072] (I)

[0073] Wherein, in the formula (I),

[0074] R1 and R2 are each independently selected from C 1-25 alkyl;

[0075] n1, n2, n3, m1 are each independently an integer from 0 to 10;

[0076] G1, G2 and G3 are each independently selected from *-C(=O)NH-**, *-CH2NH(C=O)-**, *-NH(C=O)-**, *-(CH2CH2O) m2 -**, *-CH2OPh-**, *-C(=O)-**; wherein m2 is an integer from 1 to 10; * indicates connection with R1, R2 or Q, ** indicates connection with (CH2) n1 、(CH2) n2 or (CH2) n3 Connected;

[0077] Q is N;

[0078] D has the structure shown in formula (IA');

[0079] The structure shown in the formula (IA') is:

[0080] (IA')

[0081] in,

[0082] G means not exist;

[0083] n5 and n6 are each independently an integer from 0 to 10;

[0084] V ; *L3 represents (CH2) n5 connected; *L4 means connected to O;

[0085] R x *L5-C(CH2ODMTr)H-(CH2)n z -CH-*L6;n z is an integer from 1 to 10; *L5 indicates connection with N, *L6 indicates connection with O, R y Connected;

[0086] R yC 1-8 Alkylene;

[0087] R x With R y Connected into a ring.

[0088] In some preferred embodiments of the present disclosure, R y C 1-6 Alkylene; preferably, R y C 1-5 Alkylene; preferably, R y C 1-4 Alkylene; preferably, R y C 1-3 Alkylene; preferably, R y C 1-2 Alkylene; preferably, R y It is -CH2-.

[0089] In some preferred embodiments of the present disclosure, n7 is an integer from 0 to 8; preferably, n7 is an integer from 0 to 6; preferably, n7 is an integer from 0 to 4; preferably, n7 is an integer from 0 to 3; preferably, n7 is an integer from 0 to 2; preferably, n7 is 1 or 2; preferably, n7 is 1.

[0090] In some preferred embodiments of the present disclosure, n4, n5, and n6 are each independently an integer from 1 to 8; preferably, n4, n5, and n6 are each independently an integer from 1 to 6.

[0091] In some preferred embodiments of the present disclosure, n4 is an integer from 0 to 10, preferably an integer from 1 to 8, preferably an integer from 1 to 6, preferably an integer from 1 to 5, preferably an integer from 1 to 4, preferably an integer from 1 to 3, preferably 1 or 2.

[0092] In some preferred embodiments of the present disclosure, n5 is an integer from 0 to 10, preferably an integer from 1 to 8, preferably an integer from 1 to 6, preferably an integer from 4 to 6, preferably 4 or 5.

[0093] In some preferred embodiments of the present disclosure, n6 is an integer from 0 to 10, preferably an integer from 1 to 8, preferably an integer from 1 to 6, preferably an integer from 1 to 5, preferably an integer from 1 to 4, preferably an integer from 1 to 3, preferably 1 or 2.

[0094] In some preferred embodiments of the present disclosure, n z is an integer from 0 to 8; preferably, n z is an integer from 0 to 6; preferably, n z is an integer from 0 to 4; preferably, n z is an integer from 0 to 3; preferably, nz is an integer from 0 to 2; preferably, n z is 1 or 2; preferably, n z is 1.

[0095] In some preferred embodiments of the present disclosure, V is selected from or ; wherein n7 is an integer from 0 to 10; *L3 represents (CH2) n5 connected; *L4 means connected to O.

[0096] In some preferred embodiments of the present disclosure, V is ; wherein n7 is an integer from 0 to 10; *L3 represents (CH2) n5 connected; *L4 means connected to O.

[0097] In some preferred embodiments of the present disclosure, n7 is an integer from 0 to 8; preferably, n7 is an integer from 0 to 6; preferably, n7 is an integer from 0 to 4; preferably, n7 is an integer from 0 to 3; preferably, n7 is 1 or 2; preferably, n7 is 1.

[0098] In some preferred embodiments of the present disclosure, V is ; *L3 represents (CH2) n5 connected; *L4 means connected to O.

[0099] The lipid compound for delivery therapy disclosed herein or its pharmaceutically acceptable salt, isomer, solvate or prodrug can be used to prepare a siRNA delivery system. The siRNA delivery system disclosed herein can improve the target gene knockdown ability of siRNA in muscle, fat, peripheral nerve and other tissues. The siRNA delivery system disclosed herein further improves the target gene knockdown ability of siRNA in muscle, fat, peripheral nerve, eye, heart, kidney, pancreas, uterus, placenta and other tissues.

[0100] In some preferred embodiments of the present disclosure, according to the aforementioned lipid compound or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof, when m1 is an integer from 1 to 10, D is H.

[0101] In some preferred embodiments of the present disclosure, according to the lipid compound or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof as described above, when m1 is an integer from 1 to 10 and Q is CH, D is H.

[0102] In some preferred embodiments of the present disclosure, when m1 is an integer from 1 to 10, the D has a structure represented by formula (IA2);

[0103] The structure shown in the formula (IA2) is:

[0104] (IA2)

[0105] in,

[0106] n4, n5, n6, n7 are each independently an integer from 0 to 10; preferably, n4, n5, n6 are each independently an integer from 1 to 8; preferably, n4, n5, n6 are each independently an integer from 1 to 6; preferably, n4 is an integer from 1 to 3, n5 is an integer from 4 to 6, and n6 is an integer from 1 to 3; preferably, n4 is 1 or 2, n5 is 4 or 5, and n6 is 1 or 2.

[0107] In some preferred embodiments of the present disclosure, when m1 is an integer from 1 to 10 and Q is CH, the D has a structure shown in formula (IA2);

[0108] The structure shown in the formula (IA2) is:

[0109] (IA2)

[0110] in,

[0111] n4, n5, n6, n7 are each independently an integer from 0 to 10; preferably, n4, n5, n6 are each independently an integer from 1 to 8; preferably, n4, n5, n6 are each independently an integer from 1 to 6; preferably, n4 is an integer from 1 to 3, n5 is an integer from 4 to 6, and n6 is an integer from 1 to 3; preferably, n4 is 1 or 2, n5 is 4 or 5, and n6 is 1 or 2.

[0112] In some preferred embodiments of the present disclosure, according to the lipid compound or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof as described above, when m1 is an integer from 1 to 10, the D has a structure shown in formula (IA);

[0113] The structure shown in the formula (IA) is:

[0114] (IA)

[0115] in,

[0116] R x -(CH2)n x -C(CH2ODMTr)H-(CH2)n y - or *L5-C(CH2ODMTr)H-(CH2)n z -CH-*L6;

[0117] n x 、ny 、n z Each independently represents an integer from 1 to 10;

[0118] R y For hydrogen, C 1-8 Alkylene, C 1-8 Alkyl or C 3-8 Cycloalkyl;

[0119] n4, n5, and n6 are each independently an integer from 0 to 10;

[0120] When R x -C(CH2ODMTr)H-(CH2)n z -CH- and R y C 1-8 When it is alkylene, R x With R y Connected into a ring.

[0121] In some preferred embodiments of the present disclosure, according to the lipid compound or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof as described above, when m1 is an integer from 1 to 10 and Q is CH, the D has a structure shown in formula (IA);

[0122] The structure shown in the formula (IA) is:

[0123] (IA)

[0124] in,

[0125] R x -(CH2)n x -C(CH2ODMTr)H-(CH2)n y - or *L5-C(CH2ODMTr)H-(CH2)n z -CH-*L6;

[0126] n x 、n y 、n z Each independently represents an integer from 1 to 10;

[0127] R y For hydrogen, C 1-8 Alkylene, C 1-8 Alkyl or C 3-8 Cycloalkyl;

[0128] n4, n5, and n6 are each independently an integer from 0 to 10;

[0129] When R x -C(CH2ODMTr)H-(CH2)n z-CH- and R y C 1-8 When it is alkylene, R x With R y Connected into a ring.

[0130] In some preferred embodiments of the present disclosure, n4, n5, and n6 are each independently an integer from 0 to 10; preferably, n4, n5, and n6 are each independently an integer from 1 to 8; preferably, n4, n5, and n6 are each independently an integer from 1 to 6; preferably, n4 is an integer from 1 to 3, n5 is an integer from 4 to 6, and n6 is an integer from 1 to 3; preferably, n4 is 1 or 2, n5 is 4 or 5, and n6 is 1 or 2.

[0131] In some preferred embodiments of the present disclosure, according to the lipid compound or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof as described above, it is characterized in that when m1 is an integer from 1 to 10, the D has a structure shown in formula (IA);

[0132] The structure shown in the formula (IA) is:

[0133] (IA)

[0134] in,

[0135] R x -(CH2)n x -C(CH2ODMTr)H-(CH2)n y -;n x 、n y are each independently an integer from 1 to 10; R y For hydrogen, C 1-8 Alkyl or C 3-8 Cycloalkyl; n4, n5, n6 are each independently an integer from 0 to 10.

[0136] In some preferred embodiments of the present disclosure, according to the lipid compound or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof as described above, it is characterized in that when m1 is an integer from 1 to 10 and Q is CH, the D has a structure shown in formula (IA);

[0137] The structure shown in the formula (IA) is:

[0138] (IA)

[0139] in,

[0140] R x -(CH2)n x -C(CH2ODMTr)H-(CH2)ny -;n x 、n y are each independently an integer from 1 to 10; R y For hydrogen, C 1-8 Alkyl or C 3-8 Cycloalkyl; n4, n5, n6 are each independently an integer from 0 to 10.

[0141] In some preferred embodiments of the present disclosure, according to the lipid compound or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof as described above, it is characterized in that when m1 is an integer from 1 to 10, the D has a structure shown in formula (IA);

[0142] The structure shown in the formula (IA) is:

[0143] (IA)

[0144] in,

[0145] R x -(CH2)n x -C(CH2ODMTr)H-(CH2)n y -;n x 、n y are each independently an integer from 1 to 8; R y For hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl; n4, n5, n6 are each independently an integer from 1 to 8.

[0146] In some preferred embodiments of the present disclosure, according to the lipid compound or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof as described above, it is characterized in that when m1 is an integer from 1 to 10 and Q is CH, the D has a structure shown in formula (IA);

[0147] The structure shown in the formula (IA) is:

[0148] (IA)

[0149] in,

[0150] R x -(CH2)n x -C(CH2ODMTr)H-(CH2)n y -;n x 、n y are each independently an integer from 1 to 8; R y For hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl; n4, n5, n6 are each independently an integer from 1 to 8.

[0151] In some preferred embodiments of the present disclosure, according to the lipid compound or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof as described above, it is characterized in that when m1 is an integer from 1 to 10, the D has a structure shown in formula (IA);

[0152] The structure shown in the formula (IA) is:

[0153] (IA)

[0154] in,

[0155] R x -(CH2)n x -C(CH2ODMTr)H-(CH2)n y -;n x 、n y Each independently represents an integer from 1 to 6; R y is hydrogen; n4, n5, and n6 are each independently an integer from 1 to 6.

[0156] In some preferred embodiments of the present disclosure, according to the lipid compound or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof as described above, it is characterized in that when m1 is an integer from 1 to 10 and Q is CH, the D has a structure shown in formula (IA);

[0157] The structure shown in the formula (IA) is:

[0158] (IA)

[0159] in,

[0160] R x -(CH2)n x -C(CH2ODMTr)H-(CH2)n y -;n x 、n y Each independently represents an integer from 1 to 6; R y is hydrogen; n4, n5, and n6 are each independently an integer from 1 to 6.

[0161] In some preferred embodiments of the present disclosure, according to the lipid compound or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof as described above, it is characterized in that when m1 is an integer from 1 to 10, the D has a structure shown in formula (IA);

[0162] The structure shown in the formula (IA) is:

[0163] (IA)

[0164] in,

[0165] R x *L5-C(CH2ODMTr)H-(CH2)n z -CH-*L6;n z is an integer from 1 to 10; R y C 1-8 Alkylene; n4, n5, n6 are each independently an integer from 0 to 10; Rx and R y connected to form a ring; *L5 indicates connection with N, *L6 indicates connection with O, R y are connected.

[0166] In some preferred embodiments of the present disclosure, according to the lipid compound or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof as described above, it is characterized in that when m1 is an integer from 1 to 10 and Q is CH, the D has a structure shown in formula (IA);

[0167] The structure shown in the formula (IA) is:

[0168] (IA)

[0169] in,

[0170] R x *L5-C(CH2ODMTr)H-(CH2)n z -CH-*L6;n z is an integer from 1 to 10; R y C 1-8 Alkylene; n4, n5, n6 are each independently an integer from 0 to 10; Rx and R y connected to form a ring; *L5 indicates connection with N, *L6 indicates connection with O, R y are connected.

[0171] In some preferred embodiments of the present disclosure, according to the lipid compound or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof as described above, it is characterized in that when m1 is an integer from 1 to 10, the D has a structure shown in formula (IA);

[0172] The structure shown in the formula (IA) is:

[0173] (IA)

[0174] in,

[0175] R x *L5-C(CH2ODMTr)H-(CH2)n z-CH-*L6;n z is an integer from 1 to 6; R y C 1-6 Alkylene; n4, n5, n6 are each independently an integer from 1 to 8; Rx and R y connected to form a ring; *L5 indicates connection with N, *L6 indicates connection with O, R y are connected.

[0176] In some preferred embodiments of the present disclosure, according to the lipid compound or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof as described above, it is characterized in that when m1 is an integer from 1 to 10 and Q is CH, the D has a structure shown in formula (IA);

[0177] The structure shown in the formula (IA) is:

[0178] (IA)

[0179] in,

[0180] R x *L5-C(CH2ODMTr)H-(CH2)n z -CH-*L6;n z is an integer from 1 to 6; R y C 1-6 Alkylene; n4, n5, n6 are each independently an integer from 1 to 8; Rx and R y connected to form a ring; *L5 indicates connection with N, *L6 indicates connection with O, R y are connected.

[0181] In some preferred embodiments of the present disclosure, according to the lipid compound or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof as described above, it is characterized in that when m1 is an integer from 1 to 10, the D has a structure shown in formula (IA);

[0182] The structure shown in the formula (IA) is:

[0183] (IA)

[0184] in,

[0185] R x *L5-C(CH2ODMTr)H-(CH2)n z -CH-*L6;n z is an integer from 1 to 3; R y C 1-3 Alkylene; n4, n5, n6 are each independently an integer from 1 to 6; Rx and R yconnected to form a ring; *L5 indicates connection with N, *L6 indicates connection with O, R y are connected.

[0186] In some preferred embodiments of the present disclosure, according to the lipid compound or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof as described above, it is characterized in that when m1 is an integer from 1 to 10 and Q is CH, the D has a structure shown in formula (IA);

[0187] The structure shown in the formula (IA) is:

[0188] (IA)

[0189] in,

[0190] R x *L5-C(CH2ODMTr)H-(CH2)n z -CH-*L6;n z is an integer from 1 to 3; R y C 1-3 Alkylene; n4, n5, n6 are each independently an integer from 1 to 6; Rx and R y connected to form a ring; *L5 indicates connection with N, *L6 indicates connection with O, R y are connected.

[0191] In some preferred embodiments of the present disclosure, n z is an integer from 0 to 8; preferably, n z is an integer from 0 to 6; preferably, n z is an integer from 0 to 4; preferably, n z is an integer from 0 to 3; preferably, n z is an integer from 0 to 2; preferably, n z is 1 or 2; preferably, n z is 1.

[0192] In some preferred embodiments of the present disclosure, R y C 1-6 Alkylene; preferably, R y C 1-5 Alkylene; preferably, R y C 1-4 Alkylene; preferably, R y C 1-3 Alkylene; preferably, R y C 1-2 Alkylene; preferably, R y It is -CH2-.

[0193] In some preferred embodiments of the present disclosure, when m1 is an integer from 1 to 10, D has a structure represented by formula (IA1):

[0194] (IA1)

[0195] in,

[0196] n4, n5, n6 are each independently an integer from 0 to 10; preferably, n4, n5, n6 are each independently an integer from 1 to 8; preferably, n4, n5, n6 are each independently an integer from 1 to 6; preferably, n4 is an integer from 1 to 3, n5 is an integer from 4 to 6, and n6 is an integer from 1 to 3; preferably, n4 is 1 or 2, n5 is 4 or 5, and n6 is 1 or 2.

[0197] In some preferred embodiments of the present disclosure, when m1 is an integer from 1 to 10 and Q is CH, the D has a structure shown in formula (IA1):

[0198] (IA1)

[0199] in,

[0200] n4, n5, n6 are each independently an integer from 0 to 10; preferably, n4, n5, n6 are each independently an integer from 1 to 8; preferably, n4, n5, n6 are each independently an integer from 1 to 6; preferably, n4 is an integer from 1 to 3, n5 is an integer from 4 to 6, and n6 is an integer from 1 to 3; preferably, n4 is 1 or 2, n5 is 4 or 5, and n6 is 1 or 2.

[0201] In some preferred embodiments of the present disclosure, according to the lipid compound or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof as described above, when m1 is 0, the D has a structure shown in formula (IB);

[0202] The structure shown in the formula (IB) is:

[0203] (IB)

[0204] in,

[0205] R x -(CH2)n x -C(CH2ODMTr)H-(CH2)n y - or *L5-C(CH2ODMTr)H-(CH2)n z -CH-*L6;

[0206] n x 、n y 、n zEach independently represents an integer from 1 to 10;

[0207] R y For hydrogen, C 1-8 Alkylene, C 1-8 Alkyl or C 3-8 Cycloalkyl;

[0208] n5 and n6 are each independently an integer from 0 to 10;

[0209] When R x *L5-C(CH2ODMTr)H-(CH2)n z -CH-*L6 and R y C 1-8 When it is alkylene, R x With R y Connected into a ring.

[0210] In some preferred embodiments of the present disclosure, according to the lipid compound or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof as described above, when m1 is 0 and Q is N, the D has a structure shown in formula (IB);

[0211] The structure shown in the formula (IB) is:

[0212] (IB)

[0213] in,

[0214] R x -(CH2)n x -C(CH2ODMTr)H-(CH2)n y - or *L5-C(CH2ODMTr)H-(CH2)n z -CH-*L6;

[0215] n x 、n y 、n z Each independently represents an integer from 1 to 10;

[0216] R y For hydrogen, C 1-8 Alkylene, C 1-8 Alkyl or C 3-8 Cycloalkyl;

[0217] n5 and n6 are each independently an integer from 0 to 10;

[0218] When R x *L5-C(CH2ODMTr)H-(CH2)n z -CH-*L6 and R y C1-8 When it is alkylene, R x With R y Connected into a ring.

[0219] In some preferred embodiments of the present disclosure, according to the lipid compound or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof as described above, it is characterized in that when m1 is 0, D has a structure shown in formula (IB);

[0220] The structure shown in the formula (IB) is:

[0221] (IB)

[0222] in,

[0223] R x -(CH2)n x -C(CH2ODMTr)H-(CH2)n y -;n x 、n y are each independently an integer from 1 to 10; R y For hydrogen, C 1-8 Alkyl or C 3-8 Cycloalkyl; n5 and n6 are each independently an integer from 0 to 10.

[0224] In some preferred embodiments of the present disclosure, according to the lipid compound or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof as described above, it is characterized in that when m1 is 0 and Q is N, the D has a structure shown in formula (IB);

[0225] The structure shown in the formula (IB) is:

[0226] (IB)

[0227] in,

[0228] R x -(CH2)n x -C(CH2ODMTr)H-(CH2)n y -;n x 、n y are each independently an integer from 1 to 10; R y For hydrogen, C 1-8 Alkyl or C 3-8 Cycloalkyl; n5 and n6 are each independently an integer from 0 to 10.

[0229] In some preferred embodiments of the present disclosure, according to the lipid compound or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof as described above, it is characterized in that when m1 is 0, D has a structure shown in formula (IB);

[0230] The structure shown in the formula (IB) is:

[0231] (IB)

[0232] in,

[0233] R x -(CH2)n x -C(CH2ODMTr)H-(CH2)n y -;n x 、n y Each independently represents an integer from 1 to 8; R y For hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl; n5 and n6 are each independently an integer from 1 to 8.

[0234] In some preferred embodiments of the present disclosure, according to the lipid compound or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof as described above, it is characterized in that when m1 is 0 and Q is N, the D has a structure shown in formula (IB);

[0235] The structure shown in the formula (IB) is:

[0236] (IB)

[0237] in,

[0238] R x -(CH2)n x -C(CH2ODMTr)H-(CH2)n y -;n x 、n y Each independently represents an integer from 1 to 8; R y For hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl; n5 and n6 are each independently an integer from 1 to 8.

[0239] In some preferred embodiments of the present disclosure, according to the lipid compound or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof as described above, it is characterized in that when m1 is 0, D has a structure shown in formula (IB);

[0240] The structure shown in the formula (IB) is:

[0241] (IB)

[0242] in,

[0243] R x -(CH2)n x -C(CH2ODMTr)H-(CH2)n y -;n x 、n y Each independently represents an integer from 1 to 6; R y is hydrogen; n5 and n6 are each independently an integer from 1 to 6.

[0244] In some preferred embodiments of the present disclosure, according to the lipid compound or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof as described above, it is characterized in that when m1 is 0 and Q is N, the D has a structure shown in formula (IB);

[0245] The structure shown in the formula (IB) is:

[0246] (IB)

[0247] in,

[0248] R x -(CH2)n x -C(CH2ODMTr)H-(CH2)n y -;n x 、n y Each independently represents an integer from 1 to 6; R y is hydrogen; n5 and n6 are each independently an integer from 1 to 6.

[0249] In some preferred embodiments of the present disclosure, according to the lipid compound or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof as described above, it is characterized in that when m1 is 0, D has a structure shown in formula (IB);

[0250] The structure shown in the formula (IB) is:

[0251] (IB)

[0252] in,

[0253] R x *L5-C(CH2ODMTr)H-(CH2)n z -CH-*L6; *L5 indicates connection with N, *L6 indicates connection with O, R y Connected; n z is an integer from 1 to 10; R y C 1-8Alkylene; n5, n6 are each independently an integer from 0 to 10; Rx and R y Connected into a ring.

[0254] In some preferred embodiments of the present disclosure, according to the lipid compound or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof as described above, it is characterized in that when m1 is 0 and Q is N, the D has a structure shown in formula (IB);

[0255] The structure shown in the formula (IB) is:

[0256] (IB)

[0257] in,

[0258] R x *L5-C(CH2ODMTr)H-(CH2)n z -CH-*L6; *L5 indicates connection with N, *L6 indicates connection with O, R y Connected; n z is an integer from 1 to 10; R y C 1-8 Alkylene; n5, n6 are each independently an integer from 0 to 10; Rx and R y Connected into a ring.

[0259] In some preferred embodiments of the present disclosure, according to the lipid compound or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof as described above, it is characterized in that when m1 is 0, D has a structure shown in formula (IB);

[0260] The structure shown in the formula (IB) is:

[0261] (IB)

[0262] in,

[0263] R x *L5-C(CH2ODMTr)H-(CH2)n z -CH-*L6; *L5 indicates connection with N, *L6 indicates connection with O, R y Connected; n z is an integer from 1 to 6; R y C 1-6 Alkylene; n5, n6 are each independently an integer from 1 to 8; Rx and R y Connected into a ring.

[0264] In some preferred embodiments of the present disclosure, according to the lipid compound or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof as described above, it is characterized in that when m1 is 0 and Q is N, the D has a structure shown in formula (IB);

[0265] The structure shown in the formula (IB) is:

[0266] (IB)

[0267] in,

[0268] R x *L5-C(CH2ODMTr)H-(CH2)n z -CH-*L6; *L5 indicates connection with N, *L6 indicates connection with O, R y Connected; n z is an integer from 1 to 6; R y C 1-6 Alkylene; n5, n6 are each independently an integer from 1 to 8; Rx and R y Connected into a ring.

[0269] In some preferred embodiments of the present disclosure, according to the lipid compound or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof as described above, it is characterized in that when m1 is 0, D has a structure shown in formula (IB);

[0270] The structure shown in the formula (IB) is:

[0271] (IB)

[0272] in,

[0273] R x *L5-C(CH2ODMTr)H-(CH2)n z -CH-*L6; *L5 indicates connection with N, *L6 indicates connection with O, R y Connected; n z is an integer from 1 to 3; R y C 1-3 Alkylene; n5, n6 are each independently an integer from 1 to 6; Rx and R y Connected into a ring.

[0274] In some preferred embodiments of the present disclosure, according to the lipid compound or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof as described above, it is characterized in that when m1 is 0 and Q is N, the D has a structure shown in formula (IB);

[0275] The structure shown in the formula (IB) is:

[0276] (IB)

[0277] in,

[0278] R x *L5-C(CH2ODMTr)H-(CH2)n z -CH-*L6; *L5 indicates connection with N, *L6 indicates connection with O, R y Connected; n z is an integer from 1 to 3; R y C 1-3 Alkylene; n5, n6 are each independently an integer from 1 to 6; Rx and R y Connected into a ring.

[0279] In some preferred embodiments of the present disclosure, n z is an integer from 0 to 8; preferably, n z is an integer from 0 to 6; preferably, n z is an integer from 0 to 4; preferably, n z is an integer from 0 to 3; preferably, n z is an integer from 0 to 2; preferably, n z is 1 or 2; preferably, n z is 1.

[0280] In some preferred embodiments of the present disclosure, R y C 1-6 Alkylene; preferably, R y C 1-5 Alkylene; preferably, R y C 1-4 Alkylene; preferably, R y C 1-3 Alkylene; preferably, R y C 1-2 Alkylene; preferably, R y It is -CH2-.

[0281] In some preferred embodiments of the present disclosure, when m1 is 0, the D has a structure represented by formula (IB1);

[0282] The structure shown in the formula (IB1) is:

[0283] (IB1)

[0284] wherein n5 and n6 are each independently an integer from 0 to 10; preferably, n5 and n6 are each independently an integer from 1 to 8; preferably, n5 and n6 are each independently an integer from 1 to 6; preferably, n5 is an integer from 4 to 6, and n6 is an integer from 1 to 3; preferably, n5 is 4 or 5, and n6 is 1 or 2.

[0285] In some preferred embodiments of the present disclosure, when m1 is 0 and Q is N, the D has a structure shown in formula (IB1);

[0286] The structure shown in the formula (IB1) is:

[0287] (IB1)

[0288] wherein n5 and n6 are each independently an integer from 0 to 10; preferably, n5 and n6 are each independently an integer from 1 to 8; preferably, n5 and n6 are each independently an integer from 1 to 6; preferably, n5 is an integer from 4 to 6, and n6 is an integer from 1 to 3; preferably, n5 is 4 or 5, and n6 is 1 or 2.

[0289] In some preferred embodiments of the present disclosure, according to the aforementioned lipid compound or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof, it is characterized in that Q is CH.

[0290] In some preferred embodiments of the present disclosure, according to the aforementioned lipid compound or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof, it is characterized in that Q is N.

[0291] The second aspect of the present disclosure provides a lipid compound having a structure shown in the following formula (II) for delivery therapy or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof,

[0292] (Ⅱ)

[0293] Wherein, in the formula (II),

[0294] R1 and R2 are each independently selected from C 1-25 Alkyl, C 2-25 Alkenyl or C 3-25 Cycloalkyl;

[0295] n1, n2, n3 are each independently an integer from 0 to 10;

[0296] m1 is an integer from 1 to 10;

[0297] G1, G2 and G3 are each independently selected from *-C(=O)NH-**, *-CH2NH(C=O)-**, *-NH(C=O)-**, *-(CH2CH2O) m2 -**, *-CH2OPh-**, *-C(=O)-**; wherein m2 is an integer from 1 to 10; * indicates connection with R1, R2 or CH, ** indicates connection with (CH2) n1 、(CH2) n2 or (CH2) n3 are connected.

[0298] The third aspect of the present disclosure provides a lipid compound having a structure shown in the following formula (III) for delivery therapy or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof,

[0299] (III)

[0300] Wherein, in the formula (III),

[0301] R1 and R2 are each independently selected from C 1-25 Alkyl, C 2-25 Alkenyl or C 3-25 Cycloalkyl;

[0302] n1, n2, n3 are each independently an integer from 0 to 10;

[0303] m1 is an integer from 1 to 10;

[0304] G1, G2 and G3 are each independently selected from *-C(=O)NH-**, *-CH2NH(C=O)-**, *-NH(C=O)-**, *-(CH2CH2O) m2 -**, *-CH2OPh-**, *-C(=O)-**; wherein m2 is an integer from 1 to 10; * indicates connection with R1, R2 or CH, ** indicates connection with (CH2) n1 、(CH2) n2 or (CH2) n3 Connected;

[0305] D has the structure shown in formula (IA');

[0306] The structure shown in the formula (IA') is:

[0307] (IA')

[0308] in,

[0309] G does not exist or ; *L1 indicates connection with O or carbonyl; *L2 indicates connection with NH;

[0310] n4, n5, and n6 are each independently an integer from 0 to 10;

[0311] V is selected from or ; wherein n7 is an integer from 0 to 10; *L3 represents (CH2) n5 connected; *L4 means connected to O;

[0312] R x -(CH2)n x -C(CH2ODMTr)H-(CH2)n y - or *L5-C(CH2ODMTr)H-(CH2)n z -CH-*L6; *L5 indicates connection with N, *L6 indicates connection with O, R y Connected;

[0313] n x 、n y 、n z Each independently represents an integer from 1 to 10;

[0314] R y For hydrogen, C 1-8 Alkylene, C 1-8 Alkyl or C 3-8 Cycloalkyl;

[0315] When R x -C(CH2ODMTr)H-(CH2)n z -CH- and R y C 1-8 When it is alkylene, R x With R y Connected into a ring.

[0316] In some preferred embodiments of the present disclosure, a lipid compound having a structure shown in the following formula (III) or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof for delivering therapy is provided.

[0317] (III)

[0318] Wherein, in the formula (III),

[0319] R1 and R2 are each independently selected from C 1-25 Alkyl, C 2-25 Alkenyl or C 3-25 Cycloalkyl;

[0320] n1, n2, n3 are each independently an integer from 0 to 10;

[0321] m1 is an integer from 1 to 10;

[0322] G1, G2 and G3 are each independently selected from *-C(=O)NH-**, *-CH2NH(C=O)-**, *-NH(C=O)-**, *-(CH2CH2O) m2 -**, *-CH2OPh-**, *-C(=O)-**; wherein m2 is an integer from 1 to 10; * indicates connection with R1, R2 or CH, ** indicates connection with (CH2) n1 、(CH2) n2 or (CH2) n3 Connected;

[0323] D has the structure shown in formula (IA');

[0324] The structure shown in the formula (IA') is:

[0325] (IA')

[0326] in,

[0327] G does not exist or ; *L1 indicates connection with O or carbonyl; *L2 indicates connection with NH;

[0328] n4, n5, and n6 are each independently an integer from 0 to 10;

[0329] V is selected from or ; wherein n7 is an integer from 0 to 10; *L3 represents (CH2) n5 connected; *L4 means connected to O;

[0330] R x *L5-C(CH2ODMTr)H-(CH2)n z -CH-*L6; *L5 indicates connection with N, *L6 indicates connection with O, R y Connected;

[0331] n z is an integer from 1 to 10;

[0332] R y C 1-8 Alkylene;

[0333] R x With R y Connected into a ring.

[0334] In some preferred embodiments of the present disclosure, V is selected from or ; Among them, *L3 represents (CH2) n5 connected; *L4 means connected to O.

[0335] In some preferred embodiments of the present disclosure, the lipid compound having the structure shown in the following formula (III) or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof is:

[0336] (III)

[0337] Wherein, in the formula (III),

[0338] R1 and R2 are each independently selected from C 1-25 alkyl;

[0339] n1, n2, n3 are each independently an integer from 0 to 10;

[0340] m1 is an integer from 1 to 10;

[0341] G1, G2 and G3 are each independently selected from *-C(=O)NH-**, *-CH2NH(C=O)-**, *-NH(C=O)-**, *-(CH2CH2O) m2 -**, *-CH2OPh-**, *-C(=O)-**; wherein m2 is an integer from 1 to 10; * indicates connection with R1, R2 or CH, ** indicates connection with (CH2) n1 、(CH2) n2 or (CH2) n3 Connected;

[0342] D has the structure shown in formula (IA');

[0343] The structure shown in the formula (IA') is:

[0344] (IA')

[0345] in,

[0346] G is ; *L1 indicates connection with O or carbonyl; *L2 indicates connection with NH;

[0347] n4, n5, and n6 are each independently an integer from 0 to 10;

[0348] V is selected from or ; n7 is an integer from 0 to 10; * L3 represents (CH2) n5 connected; *L4 means connected to O.

[0349] In a fourth aspect, the present disclosure provides a lipid compound having a structure shown in the following formula (IV) for delivery therapy or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof,

[0350] (IV)

[0351] Wherein, in the formula (IV),

[0352] R1 and R2 are each independently selected from C 1-25 Alkyl, C 2-25 Alkenyl or C 3-25 Cycloalkyl;

[0353] n1, n2, n3 are each independently an integer from 0 to 10;

[0354] G1, G2 and G3 are each independently selected from *-C(=O)NH-**, *-CH2NH(C=O)-**, *-NH(C=O)-**, *-(CH2CH2O) m2 -**, *-CH2OPh-**, *-C(=O)-**; wherein m2 is an integer from 1 to 10; * indicates connection with R1, R2 or CH, ** indicates connection with (CH2) n1 、(CH2) n2 or (CH2) n3 Connected;

[0355] D has the structure shown in formula (IB);

[0356] The structure shown in the formula (IB) is:

[0357] (IB)

[0358] in,

[0359] R x -(CH2)n x -C(CH2ODMTr)H-(CH2)n y - or *L5-C(CH2ODMTr)H-(CH2)n z -CH-*L6;

[0360] n x 、n y 、n z Each independently represents an integer from 1 to 10;

[0361] R y For hydrogen, C 1-8 Alkylene, C 1-8 Alkyl or C 3-8 Cycloalkyl;

[0362] n5 and n6 are each independently an integer from 0 to 10;

[0363] When R x *L5-C(CH2ODMTr)H-(CH2)n z -CH-*L6 and R y C 1-8 When it is alkylene, R x With R y connected to form a ring; *L5 indicates connection with N, *L6 indicates connection with O, R y are connected.

[0364] In some preferred embodiments of the present disclosure, the D has a structure shown in formula (IB1);

[0365] The structure shown in the formula (IB1) is:

[0366] (IB1)

[0367] wherein n5 and n6 are each independently an integer from 0 to 10; preferably, n5 and n6 are each independently an integer from 1 to 8; preferably, n5 and n6 are each independently an integer from 1 to 6; preferably, n5 is an integer from 4 to 6, and n6 is an integer from 1 to 3; preferably, n5 is 4 or 5, and n6 is 1 or 2.

[0368] In some preferred embodiments of the present disclosure, the lipid compound having the structure shown in the following formula (IV) or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof is:

[0369] (IV)

[0370] Wherein, in the formula (IV),

[0371] R1 and R2 are each independently selected from C 1-25 alkyl;

[0372] n1, n2, n3 are each independently an integer from 0 to 10;

[0373] G1, G2 and G3 are each independently selected from *-C(=O)NH-**, *-CH2NH(C=O)-**, *-NH(C=O)-**, *-(CH2CH2O) m2 -**, *-CH2OPh-**, *-C(=O)-**; wherein m2 is an integer from 1 to 10; * indicates connection with R1, R2 or CH, ** indicates connection with (CH2) n1 、(CH2) n2 or (CH2) n3 Connected;

[0374] The D has a structure shown in formula (IB1);

[0375] The structure shown in the formula (IB1) is:

[0376] (IB1)

[0377] Wherein, n5 and n6 are each independently an integer from 0 to 10.

[0378] In some preferred embodiments of the present disclosure, n x 、n y 、n z Each independently represents an integer from 1 to 10; preferably, n x 、n y 、n z Each independently represents an integer from 1 to 8; preferably, n x 、n y 、n z Each independently represents an integer from 1 to 6; preferably, n x 、n y 、n z Each independently represents an integer from 1 to 5; preferably, n x 、n y 、n z Each independently represents an integer from 1 to 4; preferably, n x is an integer from 1 to 4, n y is 1 or 2, n z Is 1 or 2.

[0379] In some preferred embodiments of the present disclosure, n x It is an integer of 1 to 10, preferably an integer of 1 to 8, preferably an integer of 1 to 6, preferably an integer of 1 to 5, and preferably an integer of 1 to 4.

[0380] In some preferred embodiments of the present disclosure, n y It is an integer from 1 to 10, preferably an integer from 1 to 8, preferably an integer from 1 to 6, preferably an integer from 1 to 5, preferably an integer from 1 to 4, preferably an integer from 1 to 3, preferably 1 or 2, and preferably 1.

[0381] In some preferred embodiments of the present disclosure, n z It is an integer from 1 to 10, preferably an integer from 1 to 8, preferably an integer from 1 to 6, preferably an integer from 1 to 5, preferably an integer from 1 to 4, preferably an integer from 1 to 3, preferably 1 or 2, and preferably 1.

[0382] In some preferred embodiments of the present disclosure, according to the lipid compound or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof as described above, R1 and R2 are each independently selected from C 5-25 Alkyl, C 5-25 Alkenyl or C 5-25 Cycloalkyl.

[0383] In some preferred embodiments of the present disclosure, according to the lipid compound or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof as described above, R1 and R2 are each independently selected from C 10-22 Alkyl, C 10-22 Alkenyl or C 10-22 Cycloalkyl.

[0384] In some preferred embodiments of the present disclosure, according to the lipid compound or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof as described above, R1 and R2 are each independently selected from C 10-22 Alkyl or C 10-22 Alkenyl.

[0385] In some preferred embodiments of the present disclosure, according to the lipid compound or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof as described above, R1 and R2 are each independently selected from C 5-25 Preferably, R1 and R2 are each independently selected from unsubstituted C 5-25 alkyl.

[0386] In some preferred embodiments of the present disclosure, according to the lipid compound or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof as described above, R1 and R2 are each independently selected from C 5-25 Preferably, R1 and R2 are each independently selected from unsubstituted C 5-25 Alkenyl.

[0387] In some preferred embodiments of the present disclosure, according to the lipid compound or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof as described above, R1 and R2 are each independently selected from C 5-25 Preferably, R1 and R2 are each independently selected from unsubstituted C 5-25 Cycloalkyl.

[0388] In some preferred embodiments of the present disclosure, according to the lipid compound or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof as described above, R1 and R2 are each independently selected from C 10-22 Preferably, R1 and R2 are each independently selected from unsubstituted C 10-22 Preferably, R1 and R2 are each independently selected from unsubstituted unbranched C 10-22Preferably, R1 and R2 are each independently selected from an unsubstituted, unbranched, saturated C 10-22 alkyl.

[0389] In some preferred embodiments of the present disclosure, according to the lipid compound or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof as described above, R1 and R2 are each independently selected from C 11-18 Preferably, R1 and R2 are each independently selected from unsubstituted C 11-18 Preferably, R1 and R2 are each independently selected from unsubstituted unbranched C 11-18 Preferably, R1 and R2 are each independently selected from an unsubstituted, unbranched, saturated C 11-18 alkyl.

[0390] In some preferred embodiments of the present disclosure, according to the lipid compound or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof as described above, R1 and R2 are each independently selected from C 12-16 Preferably, R1 and R2 are each independently selected from unsubstituted C 12-16 Preferably, R1 and R2 are each independently selected from unsubstituted unbranched C 12-16 Preferably, R1 and R2 are each independently selected from an unsubstituted, unbranched, saturated C 12-16 alkyl.

[0391] In some preferred embodiments of the present disclosure, according to the lipid compound or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof as described above, R1 and R2 are each independently selected from C 14-15 Preferably, R1 and R2 are each independently selected from unsubstituted C 14-15 Preferably, R1 and R2 are each independently selected from unsubstituted unbranched C 14-15 Preferably, R1 and R2 are each independently selected from an unsubstituted, unbranched, saturated C 14-15 alkyl.

[0392] In some preferred embodiments of the present disclosure, according to the lipid compound or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof as described above, R1 and R2 are each independently selected from C 10-22 Preferably, R1 and R2 are each independently selected from unsubstituted C 10-22 Preferably, R1 and R2 are each independently selected from unsubstituted unbranched C 10-22 Preferably, R1 and R2 are each independently selected from unsubstituted unbranched unsaturated C 10-22 Alkenyl.

[0393] In some preferred embodiments of the present disclosure, according to the lipid compound or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof as described above, R1 and R2 are each independently selected from C 14-22 Preferably, R1 and R2 are each independently selected from unsubstituted C 14-22 Preferably, R1 and R2 are each independently selected from unsubstituted unbranched C 14-22 Preferably, R1 and R2 are each independently selected from unsubstituted unbranched unsaturated C 14-22 Alkenyl.

[0394] In some preferred embodiments of the present disclosure, according to the lipid compound or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof as described above, R1 and R2 are each independently selected from C 14-15 Preferably, R1 and R2 are each independently selected from unsubstituted C 14-15 Preferably, R1 and R2 are each independently selected from unsubstituted unbranched C 14-15 Preferably, R1 and R2 are each independently selected from unsubstituted unbranched unsaturated C 14-15 Alkenyl.

[0395] In some preferred embodiments of the present disclosure, R1 and R2 are each independently selected from C 5-25 alkyl.

[0396] In some preferred embodiments of the present disclosure, R1 and R2 are each independently selected from C 10-22 alkyl.

[0397] In some preferred embodiments of the present disclosure, R1 and R2 are each independently selected from C 11-18 alkyl.

[0398] In some preferred embodiments of the present disclosure, according to the lipid compound or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof as described above, n1, n2, n3 are each independently an integer from 0 to 8.

[0399] In some preferred embodiments of the present disclosure, according to the lipid compound or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof as described above, n1, n2, n3 are each independently an integer from 0 to 6.

[0400] In some preferred embodiments of the present disclosure, according to the lipid compound or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof as described above, n1, n2, n3 are each independently an integer from 0 to 5.

[0401] In some preferred embodiments of the present disclosure, according to the lipid compound or its pharmaceutically acceptable salt, isomer, solvate or prodrug as described above, n1 is an integer from 0 to 3, n2 is an integer from 1 to 4, and n3 is an integer from 1 to 3.

[0402] In some preferred embodiments of the present disclosure, according to the lipid compound or its pharmaceutically acceptable salt, isomer, solvate or prodrug as described above, G1 is selected from *-C(=O)NH-**, *-CH2NH(C=O)-**; G2 is selected from *-C(=O)NH-**, *-CH2NH(C=O)-**, *-(CH2CH2O) m2 -**, *-CH2OPh-**; G3 is selected from *-C(=O)NH-**, *-NH(C=O)-**, *-C(=O)-**; wherein m2 is an integer from 1 to 10; * indicates connection with R1, R2 or Q, ** indicates connection with (CH2) n1 、(CH2) n2 or (CH2) n3 are connected.

[0403] In some preferred embodiments of the present disclosure, according to the lipid compound or its pharmaceutically acceptable salt, isomer, solvate or prodrug as described above, G1 is selected from *-C(=O)NH-**, *-CH2NH(C=O)-**; G2 is selected from *-C(=O)NH-**, *-CH2NH(C=O)-**, *-(CH2CH2O) m2 -**, *-CH2OPh-**; G3 is selected from *-C(=O)NH-**, *-NH(C=O)-**, *-C(=O)-**; wherein m2 is an integer from 1 to 6; * indicates connection with R1, R2 or Q, ** indicates connection with (CH2) n1 、(CH2) n2 or (CH2) n3 are connected.

[0404] In some preferred embodiments of the present disclosure, according to the lipid compound or its pharmaceutically acceptable salt, isomer, solvate or prodrug as described above, G1 is selected from *-C(=O)NH-**, *-CH2NH(C=O)-**; G2 is selected from *-C(=O)NH-**, *-CH2NH(C=O)-**, *-(CH2CH2O) m2 -**, *-CH2OPh-**; G3 is selected from *-C(=O)NH-**, *-NH(C=O)-**, *-C(=O)-**; wherein m2 is an integer from 1 to 3; * indicates connection with R1, R2 or Q, ** indicates connection with (CH2) n1 、(CH2)n2 or (CH2) n3 are connected.

[0405] In some preferred embodiments of the present disclosure, according to the lipid compound as described above or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof, the lipid compound is selected from the following compounds:

[0406] (DSC-001),

[0407] (DSC-002),

[0408] (DSC-003),

[0409] (DSC-004),

[0410] (DSC-005),

[0411] (DSC-006),

[0412] (DSC-007),

[0413] (DSC-008),

[0414] (DSC-009),

[0415] (DSC-0010),

[0416] (DSC-0011),

[0417] (DSC-0012),

[0418] (DSC-0013),

[0419] (DSC-0014).

[0420] In some preferred embodiments of the present disclosure, according to the lipid compound as described above or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof, the lipid compound is selected from the following compounds:

[0421] (DSC-001),

[0422] (DSC-002),

[0423] (DSC-003),

[0424] (DSC-004).

[0425] In some preferred embodiments of the present disclosure, according to the lipid compound as described above or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof, the lipid compound is selected from the following compounds:

[0426] (DSC-005).

[0427] In some preferred embodiments of the present disclosure, according to the lipid compound as described above or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof, the lipid compound is selected from the following compounds:

[0428] (DSC-006),

[0429] (DSC-007),

[0430] (DSC-008),

[0431] (DSC-009),

[0432] (DSC-0010).

[0433] In some preferred embodiments of the present disclosure, according to the lipid compound as described above or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof, the lipid compound is selected from the following compounds:

[0434] (DSC-0011),

[0435] (DSC-0012),

[0436] (DSC-0013),

[0437] (DSC-0014).

[0438] The fifth aspect of the present disclosure provides the use of the lipid compound as described above or its pharmaceutically acceptable salt, isomer, solvate or prodrug in the preparation of an oligonucleotide delivery system. The oligonucleotide includes but is not limited to siRNA, microRNA mimics, stem-loop structures, single-stranded siRNA, ribonuclease H oligonucleotide, anti-microRNA oligonucleotide, steric blocking oligonucleotide, CRISPR guide RNA or aptamer.

[0439] In some preferred embodiments of the present disclosure, the lipid compound as described above or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof is used in the preparation of a siRNA or miRNA delivery system.

[0440] In some preferred embodiments of the present disclosure, the lipid compound as described above or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof is used in the preparation of an siRNA delivery system.

[0441] A sixth aspect of the present disclosure provides an oligonucleotide delivery system, which comprises the lipid compound as described above or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof.

[0442] In some preferred embodiments of the present disclosure, a siRNA or miRNA delivery system comprises the lipid compound as described above or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof.

[0443] In some preferred embodiments of the present disclosure, a siRNA delivery system is provided, comprising the lipid compound as described above or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof.

[0444] A seventh aspect of the present disclosure provides a method for preparing an oligonucleotide delivery system, comprising the following steps: preparing an oligonucleotide sequence using the lipid compound as described above or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof.

[0445] In some preferred embodiments of the present disclosure, a method for preparing an oligonucleotide delivery system comprises the following steps: preparing the lipid compound as described above or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof into a solid phase carrier, and preparing an oligonucleotide sequence by an oligonucleotide synthesizer.

[0446] In some preferred embodiments of the present disclosure, a method for preparing an oligonucleotide delivery system comprises the following steps: preparing a lipid compound as described above or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof into a solid phase carrier, preparing an oligonucleotide sequence by an oligonucleotide synthesizer, wherein the lipid compound as described above or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof is located at the 3' end, 5' end or middle position of the oligonucleotide. For example, it is coupled to the 5' end, 3' end or middle position of the siRNA sense chain with a phosphate bond or a thiophosphate bond. Exemplary sequences in the technical scheme are as follows: The literature (Nature Biotechnology volume 40, pages 1500–1508 (2022) Expanding RNAitherapeutics to extrahepatic tissues with lipophilic conjugates https: / / doi.org / 10.1038 / s41587-022-01334-x) reports SDO1 modified sequences:

[0447] SS chain: Cm*Am*UmUmUmUmAfAmUfCfCfUmCmAmCmUmCmUmAm*Am*Am

[0448] AS chain: VPUm*Uf*UmAmGmAfGmUfGfAmGmGmAmUfUmAfAmAmAmUmGm*Am*Gm

[0449] The present disclosure has the following advantages:

[0450] (1) The lipid compound for delivery therapy disclosed herein or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof can be used to prepare a siRNA delivery system.

[0451] (2) The lipid compound for delivery therapy disclosed herein or its pharmaceutically acceptable salt, isomer, solvate or prodrug can be used to prepare siRNA delivery system to further improve the target gene knockdown ability of siRNA in muscle, fat, peripheral nerve and other tissues.

[0452] (3) The lipid compounds for delivery therapy provided by the present disclosure or their pharmaceutically acceptable salts, isomers, solvates or prodrugs are expected to provide a new strategy for delivering siRNA to muscle, fat, nervous system, etc. DETAILED DESCRIPTION

[0453] Definition and Description

[0454] In order to make it easier to understand the present disclosure, some technical and scientific terms are specifically defined below. In the present disclosure, unless otherwise stated, the scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. In addition, the cell and tissue culture, microbiology-related terms and laboratory operation steps used herein are terms and routine steps widely used in the corresponding fields. At the same time, in order to better understand the present disclosure, the definition and explanation of the relevant terms are provided below. It should be understood that the present disclosure is not limited to specific methods, reagents, compounds, compositions or biological systems, and of course the above can be changed. It should also be understood that the terms used in the present application are only for describing specific embodiments and are not intended to be limited.

[0455] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise.

[0456] As used herein, the terms "include" and "have" and any variations thereof are intended to cover non-exclusive inclusions. For example, a process, method, device, product or apparatus comprising a series of steps is not limited to the listed steps or modules, but may optionally include steps not listed, or may optionally include other steps inherent to these processes, methods, products or apparatuses.

[0457] In the description herein, reference is made to “some embodiments”, “some implementation schemes” or “some implementation plans”, which describe a subset of all possible embodiments, but it can be understood that “some embodiments” may be the same subset or different subsets of all possible embodiments and may be combined with each other without conflict.

[0458] As used herein and unless otherwise specified, the terms "comprising", "including", "having", "containing", including grammatical equivalents thereof, should generally be understood as open and non-limiting, for example, not excluding other unlisted elements or steps.

[0459] When a numerical range is listed, it is intended to include every value and sub-range within the stated range. For example, "C 1-6 "Alkyl" includes 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 , C4-5 and C 5-6 alkyl.

[0460] As used herein, the term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include variants of deuterium and hydrogen, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is an oxo group (i.e., =O), it means that two hydrogen atoms are replaced. The term "optionally substituted" or "optionally substituted" means that it may be substituted or not substituted, and unless otherwise specified, the type and number of the substituent can be arbitrary on the basis of chemically achievable.

[0461] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, and each occurrence of R is an independent choice. In addition, combinations of substituents and / or variants thereof are permitted only if such combinations result in stable compounds.

[0462] In any embodiment, any or all hydrogens present in the compound, or hydrogens in a specific group or moiety within the compound, may be replaced by deuterium or tritium. From one to the maximum number of hydrogens present in the compound may be replaced by deuterium. From one to the maximum number of hydrogens present in any group in the general compound or in the specific compound may be deuterated. For example, when describing a group as ethyl, the ethyl group may be C2H5 or C2H5 in which x (1 to 5) hydrogens are replaced by deuterium, such as C2D x H 5-x When describing a group as a deuterated ethyl group, the deuterated ethyl group may be C2H5 in which x (1 to 5) hydrogen atoms are replaced by deuterium, for example C2D x H 5-x The stable deuterated derivatives disclosed herein are preferably stable deuterated isotope derivatives obtained by replacing any deuterated hydrogen atom in each formula with 1 to a maximum number (e.g., 1 to 2, 1 to 3, 1 to 4, 1 to 5, 1 to 6, 1 to 7, etc.) of deuterium atoms.

[0463] The present disclosure mentions the compound of formula (I), which also includes its tautomers, stereoisomers, mixtures of stereoisomers, solvates or derivatives, etc.

[0464] The present disclosure "compounds" also include tautomeric forms. Tautomeric forms are derived from the exchange of a single bond with an adjacent double bond and the migration of a proton. The term "tautomer" or "tautomeric form" means that at room temperature, different functional group isomers are in dynamic equilibrium and can quickly convert to each other. It refers to one of two or more structural isomers that exist in equilibrium and are easily converted from one isomeric form to another isomeric form. This transformation results in the formal migration of hydrogen atoms and is accompanied by the conversion of adjacent conjugated double bonds. Tautomers exist as a mixture of tautomeric groups in solution. In solutions where tautomerism may occur, a chemical equilibrium of tautomers will be reached. The exact ratio of tautomers depends on several factors, including temperature, solvent and pH conditions. The concept of tautomers that can be converted to each other by tautomerization is called tautomerism.

[0465] When the present specification describes a compound that is susceptible to tautomerism, but only one of the tautomers is described, it should be understood that all tautomers are included as part of the chemical meaning described. It should be understood that when a compound has a tautomeric form, it is intended to include all tautomeric forms, and the naming of the compound does not exclude any tautomeric form.

[0466] Of the various types of tautomerism possible, two are commonly observed. In keto-enol tautomerism, both electrons and hydrogen atoms shift simultaneously.

[0467] Common tautomeric pairs are: keto-enol, amide-nitrile, lactam-lactam, amide-imidic acid tautomerism in heterocycles, imine-enamine, and enamine-enamine.

[0468] The term "isomer" refers to different compounds with the same molecular formula but different atomic arrangements and configurations. Depending on their structure, the compounds of the present disclosure may exist in different stereoisomeric forms. These forms include configurational isomers or optical conformers (enantiomers and / or diastereomers, including those of atropisomers). Therefore, the present disclosure includes enantiomers, diastereomers and mixtures thereof. The present disclosure further includes all mixtures of the above stereoisomers, regardless of the ratio, including racemates.

[0469] Depending on their structure, the compounds of the present disclosure may exist in various stable isotopic forms. These forms include those in which one or more hydrogen atoms have been replaced by deuterium atoms, those in which one or more nitrogen atoms have been replaced by 15N atoms, or those in which one or more carbon, fluorine, chlorine, bromine, sulfur or oxygen have been replaced by stable isotopes of the respective original atoms.

[0470] Some compounds and salts according to the present disclosure may exist in different crystalline forms (polymorphs), which are within the scope of the present disclosure.

[0471] In this disclosure, the term “ "and" "Denotes the absolute configuration of a stereocenter." " ” refers to the chemical bond connection.

[0472] When the ring appears ", and the connection position is uncertain, it means that the connection site is located at " "Any atom on the single ring where it is located, as long as the atomic valence permits.

[0473] The term "prodrug" refers to a precursor or derivative form of a pharmaceutically active substance that is less cytotoxic to tumor cells than the parent drug and can be activated or converted to a more active parent form by enzyme action. The prodrugs disclosed herein include, but are not limited to, phosphate-containing prodrugs, thiophosphate-containing prodrugs, sulfate-containing prodrugs, peptide-containing prodrugs, D-amino acid-modified prodrugs, glycosylated prodrugs, β-lactam-containing prodrugs, optionally substituted phenoxyacetamide-containing prodrugs or optionally substituted phenylacetamide-containing prodrugs, 5-fluorocytosine, and other 5-fluorouridine prodrugs that can be converted into more active cytotoxic free drugs. Examples of cytotoxic drugs that can be derived as prodrug forms for use in the present disclosure include, but are not limited to, those chemotherapeutic agents described above.

[0474] The term "alkyl" refers to a chain (straight or branched) saturated aliphatic hydrocarbon group. The term "alkyl" may be a straight or branched chain alkyl group (C 1-10 Alkyl), preferably an alkyl group containing 1 to 6 carbon atoms (C 1-6 Alkyl). Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and various branched chain isomers thereof. More preferred are lower alkyl (C 2-4-16-17) groups containing 1 to 3 carbon atoms. 1-3 Alkyl), non-limiting examples include methyl, ethyl, n-propyl, isopropyl, etc. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the groups described in the present application.

[0475] In one embodiment, the substituents are independently selected from oxo, halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, alkyl (including linear, branched and / or unsaturated alkyl), substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, fluoroalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkoxy, fluoroalkoxy, -S-alkyl, S(=O)2alkyl, -C(=O)NH(substituted or unsubstituted alkyl, or substituted or unsubstituted phenyl), -C(=O)N(H or alkyl)2, -OC(=O)N(substituted or unsubstituted alkyl)2, NHC(=O)NH(substituted or unsubstituted alkyl, or substituted or unsubstituted phenyl), -NHC(=O)alkyl, -N(substituted or unsubstituted alkyl)C(=O)(substituted or unsubstituted alkyl), -NHC(=O)(substituted or unsubstituted alkyl), -C(OH)(substituted or unsubstituted alkyl)2 and -C(NH2)(substituted or unsubstituted alkyl)2. In another embodiment, for example, the optional substituents are selected from oxo, fluoro, chloro, bromo, iodo, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CH(CH3)2, -CF3, -CH2CF3, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCF3, -OCH2CF3, -S(=O)2-CH3, -C(=O)NH2, -C(=O)-NHCH3, -NHC(=O)NHCH3, -C(=O)CH3, -ON(O)2, and C(=O)OH. In yet another embodiment, the substituents are independently selected from C 1-6 Alkyl, -OH, C 1-6 In yet another embodiment, the substituents are independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, halogen, acetamido and nitro. As used herein, when the substituent is an alkyl or alkoxy group, the carbon chain may be branched, linear or cyclic.

[0476] The term "alkylene" refers to a divalent group formed by removing another hydrogen of an alkyl group, which may be substituted or unsubstituted. The "alkylene" is preferably a divalent group of a straight or branched chain saturated aliphatic hydrocarbon containing 1 to 8 carbon atoms, more preferably a divalent alkyl group (C 2-6) containing 1 to 6 carbon atoms. 1-6 Examples of alkylene include, but are not limited to, -CH2-, -CH(CH3)-, -CH2CH2-, -CH(CH3)CH2-, -CH2CH2CH2-, or -(CH2)4- and stereoisomers thereof.

[0477] The term "heteroatom" is selected from nitrogen, oxygen or sulfur. Among them, the nitrogen can be optionally substituted; the sulfur can also be optionally substituted, for example, oxo, that is, forming S(O) t3 (where t3 is an integer from 0 to 2).

[0478] The term "aryl" means phenyl or naphthyl, or phenyl or naphthyl substituted by halogen, C 1-8 Alkyl, hydroxyl, nitro, trifluoromethyl, etc. Preferred is phenyl or monosubstituted phenyl; most preferred is phenyl.

[0479] The "solvate" mentioned in the present disclosure refers to a complex formed by the compound of the present disclosure and a solvent. They either react in a solvent or precipitate or crystallize from a solvent. For example, a complex formed with water is called a "hydrate". Solvates of the compound represented by formula (I) of the present disclosure belong to the scope of the present disclosure.

[0480] The present disclosure includes prodrugs of the above compounds. Prodrugs include known amino protecting groups and carboxyl protecting groups, which are hydrolyzed under physiological conditions or released via enzyme reactions to obtain parent compounds. Specific prodrug preparation methods can refer to (Saulnier, MG; Frennesson, DB; Deshpande, MS; Hansel, SB and Vysa, DM Bioorg. Med. Chem Lett. 1994, 4, 1985-1990; and Greenwald, RB; Choe, YH; Conover, CD; Shum, K.; Wu, D.; Royzen, MJ Med. Chem. 2000, 43, 475.).

[0481] As used herein, the term "hydroxy" refers to -OH.

[0482] As used herein, the term "oxo" refers to =0.

[0483] As used herein, the term "carboxy" refers to -C(=0)OH.

[0484] As used herein, the term "acetyl (Ac)" refers to -COCH3.

[0485] As used herein, the term "DMTr" refers to 4,4'-dimethoxytrityl.

[0486] As used herein, the term "Ph" refers to phenyl, ie, C6H5-.

[0487] As used herein, "treatment" refers to mitigation, slowing progression, attenuation, prevention, or maintenance of an existing disease or condition (e.g., cancer). Treatment also includes curing, preventing, or mitigating one or more symptoms of a disease or condition to a certain extent. As used herein, the term "treatment" or "treatment" is defined as administering or applying a therapeutic agent, i.e., a compound of the present disclosure (alone or in combination with another agent), to a patient, or administering or applying a therapeutic agent to a tissue or cell separated from a patient (e.g., for diagnosis or ex vivo application), the patient suffers from a disease or condition considered herein, a sign or symptom of a disease or condition considered herein, or has the potential to develop a disease or condition considered herein, with the purpose of curing, healing, alleviating, mitigating, altering, remedying, improving, improving, or affecting a disease or condition considered herein, a sign or symptom of a disease or condition considered herein, or the possibility of developing a disease or condition considered herein. Such treatments can be specifically customized or modified based on knowledge obtained from the field of pharmacogenomics. The term "treatment" disease used herein refers to reducing the frequency or severity of at least one sign or symptom of a disease or condition experienced by a subject.

[0488] "Therapeutic" treatment is treatment administered to a subject exhibiting signs or symptoms of a pathological disease or condition with the goal of reducing or eliminating those signs or symptoms.

[0489] Example

[0490] In order to make the purpose, technical solution and advantages of the embodiments of the present disclosure clearer, the technical solution in the embodiments of the present disclosure will be clearly and completely described below in combination with the chemical reaction formula in the embodiments of the present disclosure. Obviously, the described embodiments are part of the embodiments of the present disclosure, not all of the embodiments. The following is only a further description of the present disclosure, and the protection scope of the present disclosure is not limited thereto.

[0491] Example 1

[0492] Preparation of compound DSC-003:

[0493]

[0494]

[0495] Preparation of compound 3:

[0496]

[0497] Compound 1 (32 g, 124.8 mmol) was dissolved in 150 mL DMF, stirred, and DIPEA (40.3 g, 312.1 mmol) and HATU (71.2 pieces, 187.2 mmol) were added in sequence, stirred for 30 min, and compound 2 (5 g, 31.2 mmol) was added to the reaction system, stirred at 50 ° C for 16 hours, and the reaction was monitored by TLC. After the reaction was completed, the reaction solution was poured into 500 ml of dichloromethane, and the reaction solution was treated with 200 mL of water and 200 mL of saturated brine respectively, and the organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (DCM: MeOH = 50: 1) to obtain an off-white solid compound 3 (12.1 g, yield 61%). 1 HNMR (400MHz, CDCl3) δ: 6.19 (2, J=7.7Hz, 1H), 5.71 (S, 1H), 4.58 (td, J=8.1, 4.6Hz, 1H), 3.74 (ss, 3H), 3.26-3.21 (m, 2H), 2.27-2.21 (m, 2H), 2.19-2.13 (m, 2H), 1.66- 1.51 (m, 8H), 1.25 (s, 50H), 0.88 (t, J= 6.8Hz, 6H).

[0498] Preparation of compound 4:

[0499]

[0500] Compound 3 (11 g, 17.3 mmol) was dissolved in 100 ml MeOH / THF / H2O = 2 / 2 / 1, LiOH (1.24 g, 51.8 mmol) was added, and the mixture was reacted at 25 °C for 18 h. The reaction solution was poured into 150 ml 1 M dilute hydrochloric acid, stirred for 30 min under ice bath, extracted with 200 ml dichloromethane, concentrated, and the remaining residue was purified by slurrying with ethyl acetate: petroleum ether = 1:2 to obtain an off-white solid 4 (8.1 g, yield 94.8%).

[0501]

[0502] Preparation of compound 6:

[0503] Compound 5 (20 g, 99.4 mmol) was dissolved in 150 ml of dioxane, and potassium tert-butoxide (22.3 g, 198.7 mmol) was added under ice bath, and acrylonitrile (15.8 g, 298 mmol) was dissolved in 50 ml of dioxane, and added to the reaction system under nitrogen protection. The reaction was carried out at room temperature for 18 hours. 250 ml of dichloromethane and 200 ml of ice water were added to the reaction system, and the organic phase was collected, washed with 200 ml of saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE: EA = 5: 1) to obtain a light yellow solid compound 6 (15 g, yield 60%). MS: 199.0 (ESI, [M-56+H] + ).

[0504] Preparation of compound 7:

[0505] Compound 6 (14 g, 55.1 mmol) was dissolved in 50 ml of methanol / concentrated sulfuric acid (3:1) and reacted at 60 degrees Celsius for 18 hours. After the reaction was completed, the reaction solution was made alkaline with saturated sodium carbonate solution, extracted with dichloromethane, and the organic phase was collected. The organic phase was treated with 200 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain a light yellow oily compound 6 (7.4 g, yield 71.8%). 1 HNMR (400 MHz, DMSO-d6) δ: 3.62 (dd, 4.3Hz 2H), 3.59 (s, 3H), 3.28-3.23 (m1H), 2.53-2.48 (m, 4H), 2.43-2.35 (m 2H), 2.04-1.92 (m, 1), 1.77-1.73 (m, 2H), 1.22-1.14 (m, 2H).

[0506] Preparation of compound 9:

[0507] Compound 8 (11.4 g, 56.1 mmol) and HATU (28.3 g, 74.8 mmol) were dissolved in 150 ml of dichloromethane, DIPEA (14.5 g, 112.2 mmol) was added, stirred for 30 min, compound 7 (7 g, 37.4 mmol) was added, reacted for 16 hours, TLC (PE: EA = 2: 1) showed that a new substance was generated, saturated sodium bicarbonate solution 100 ml was added to the reaction mixture, the organic phase was collected, the organic phase was washed twice with saturated sodium chloride solution, and concentrated to obtain a crude product, which was purified by column chromatography (PE: EA = 2: 1) to obtain a yellow oil compound 9 (8.3 g, yield 59.6%). MS: 373.2 (ESI, M+H).

[0508] Preparation of compound 10:

[0509] Compound 9 (8 g, 21.5 mmol) was dissolved in 60 ml of dichloromethane, and 20 ml of trifluoroacetic acid was added. The mixture was stirred at room temperature for 3 hours, and the solvent was removed by distillation under reduced pressure. The residue was dissolved in 100 ml of dichloromethane, washed with saturated sodium bicarbonate solution, washed with saturated sodium chloride solution, and the organic phase was collected, dried with anhydrous sodium sulfate, and concentrated to obtain a yellow oil compound 10 (5.5 g, yield 94%). MS: 273.1 (ESI, [M+H] + )

[0510] Preparation of compound 11:

[0511] Compound 4 (8 g, 12.8 mmol) and HATU (8.1 g, 21.3 mmol) were dissolved in 50 ml of DMF, DIPEA (3.1 g, 32 mmol) was added, and the mixture was stirred at room temperature for 30 min. Compound 10 (2.9 g, 10.6 mmol) was added, and the mixture was reacted at room temperature for 18 hours. 250 ml of DCM and 200 ml of saturated sodium bicarbonate solution were added to the reaction mixture, and the organic phase was collected. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by column chromatography (DCM: MeOH = 10:1) to obtain an off-white solid compound 11 (5.5 g, yield 58.9%). l H NMR (400 MHz, CDCl3) δ: 7.07 (d, J=5.2Hz, lH), 6.43 (d, J=7.6Hz, lH), 5.92 (d, J=4.6Hz, lH), 4.35 (dd, J=12.9, 7.7 Hz, lH), 3.74 (d, J=6.3Hz, 2H), 3.70 (s, 3H), 3.62-3.56 (m, 2H), 3.25 (dq, J=19.1, 6.4Hz, 5H), 2.58 (t, J=6.2Hz, 2H), 2.39 (t, J= 6.8Hz, 2H), 2.22 (t, J= 7.6Hz, 2H), 2.18-2.13 (m, 2H), 1.87-1.76 (m, 5H), 1.56 (dd, J=21.2, 14.8Hz, l0H), 1.25 (s, 50H), 0.88 (t, J=6.8Hz, 6H).

[0512] Preparation of compound 12:

[0513] Compound 11 (5 g, 5.7 mmol) was dissolved in 50 ml MeOH / THF / H2O = 2 / 2 / 1, LiOH (0.6 g, 25 mmol) was added, and the mixture was reacted at 25 °C for 16 h. The reaction solution was poured into 50 ml 1 M dilute hydrochloric acid, extracted with 100 ml dichloromethane, and the organic phase was collected, concentrated, and slurried with PE:EA = 1:2 to obtain an off-white solid 12 (3.5 g, yield 71%).

[0514] Preparation of compound 14:

[0515] Compound 12 (3.5 g, 4.1 mmol), HATU (2.5 g, 6.5 mmol), and DIPEA (1.3 g, 10.1 mmol) were dissolved in 30 mL DMF and stirred for 30 min. 13 (3.4 g, 5.3 mmol) was added and reacted at room temperature for 16 hours. TLC (DMC: MeOH = 10:1) showed that the reaction was complete. DCM 150 ml and water 100 ml were added to the reaction mixture. The organic phase was collected and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (DCM: MeOH = 10:1) to obtain an off-white solid 14 (4.3 g, yield 71%). 1 H NMR (400MHz, CDCl3) δ: 7.44-7.32 (m, 2H), 7.27 (dd, J=11.9, 8.7Hz, 5H), 7.13 (d, J=8.6Hz, 2H), 6.79 (d, J=8.6Hz, 4H), 6.42 (s, 1H ), 6.19(s, 1H), 5.87(d, J=19.6Hz, 1H), 4.13(d, J=8.1Hz, 3H), 3.75(s, 6H), 3.52(d, J=4.6Hz, 2H), 3.21(dd, J=13.7, 6.4Hz, 8H), 3.00 (8, 1H), 2.58 (8, 3H), 2.50 (8, 1H), 2.37 (dd, J=9.9, 5.7Hz, 4H), 2.14 (dt, J=14.9, 7 .1Hz, 6H), 1.80 (d, J=5.4Hz, 8H), 1.53 (d, J=34.8Hz, 16H), 1.21 (s, 54H), 0.85 (d, J=6.0Hz, 6H), 0.00 (s, 9H).

[0516] Preparation of compound DSC-003:

[0517] Compound 14 (3.5 g, 2.3 mmol) was dissolved in 40 ml THF, and TBAF (23.4 ml, 23.4 mmol) solution was added, stirred at room temperature for 18 hours, and concentrated under reduced pressure to obtain a crude product. The crude product was slurried with 50 ml of isopropanol: water = 4:1 solution, filtered, and washed to obtain a white solid DSC-003 (2.4 g, yield 73.5%). MS: 1416.752 [M+Na] + ; 1 HNMR: (400MHz, CDCl3) δ: 7.40 (d, J=7.6Hz, 1H), 7.28 (dd, J=10.2, 6.1Hz, 6H), 7.19 (dd, J=14.1, 7.9Hz, 2H), 6.87-6.76 (m, 4H), 6.72-6.61 (m, 1H), 6.48 (s, 1H), 6. 02 (s, 1H), 4.36 (d, J=4.9Hz, 1H), 4.19 (ddd, J=25.5, 11.0, 5.4Hz, 2H), 3.79 (d, J=3.7Hz, 6H), 3.73 (dd, J=14.2, 8.4Hz, 2H), 3.63-3.51 (m, 2H ), 3.35-3.17(m, 9H), 3.l3-2.99(m, 2H), 2.57(d, J=3.0Hz, 2H), 2.43(t, J=5.3Hz, 2H), 2.38(d, J=6.7Hz, 2H), 2.22(t, J=7.4Hz, 2H), 2.18-2. l3 (m, 2H), 1.83 (s, 6H), 1.65 (dd, J=20.2, 12.6Hz, 7H), 1.47 (ddd, J=21.8, l3.4, 6.7Hz, 7H), 1.30 (d, J=37.3Hz, 54H), 0.88 (t, J=6.7Hz, 6H).

[0518] The lipid compound described in the present disclosure is prepared into a phosphoramidite monomer or a solid phase carrier such as CPG, PS, etc. by conventional methods, and finally an oligonucleotide synthesizer is used to prepare an oligonucleotide sequence containing the lipid compound described in the present disclosure. The above structure can be located at the 3' end, 5' end or middle position of the oligonucleotide. For example, it is coupled to the 5' end, 3' end or middle position of the siRNA sense chain by a phosphate bond or a phosphorothioate bond.

[0519] Exemplary sequences in the technical scheme are as follows: The literature (Nature Biotechnology volume 40, pages 1500–1508 (2022) Expanding RNAi therapeutics to extrahepatic tissues with lipophilic conjugates https: / / doi.org / 10.1038 / s41587-022-01334-x) reports SDO1 modification sequence:

[0520] SS chain: Cm*Am*UmUmUmUmAfAmUfCfCfUmCmAmCmUmCmUmAm*Am*Am

[0521] AS chain: VPUm*Uf*UmAmGmAfGmUfGfAmGmGmAmUfUmAfAmAmAmUmGm*Am*Gm

[0522] In Table 1, “SDO1 modified sequences”, m refers to methylation modification;

[0523] In Table 1, “SDO1 modified sequences”, f refers to 2′-fluoro modification;

[0524] In Table 1 "SDO1 modified sequences", * refers to phosphorothioate bonds.

[0525] Table 1. Exemplary SOD1 modified sequences

[0526]

[0527] Table 2 shows the abbreviations of nucleotide monomers or modified nucleotide monomers used in nucleic acid sequence representation (according to the st.26 sequence listing standard, the letter U in the abbreviations of uridine and modified uridine is T in the st.26 sequence listing file). It will be understood that these monomers, when present in an oligonucleotide, are interconnected by 5'-3' phosphodiester bonds unless otherwise specified. And it should be understood that when a nucleotide contains a 2'-fluorine modification, the fluorine replaces the hydroxyl group at that position in the parent nucleotide (i.e., it is a 2'-fluorine nucleotide).

[0528] Table 2. Nucleotide monomer abbreviations used in nucleic acid sequence representation

[0529]

[0530] VPUm is 2'-methoxy modified uridine, and its structure is as follows:

[0531] .

[0532] VP (vinylphosphonic acid) in VPUm refers to vinylphosphonic acid modification.

[0533] UC16 is 2'-hexadecyloxy modified uridine, and its structure is as follows: .

[0534] In the absence of specific information on the source of reagents, such reagents can be obtained from any molecular biology reagent supplier at quality / purity standards appropriate for molecular biology.

[0535] Example 2

[0536] Preparation of siRNA

[0537] The siRNA sequence is synthesized separately on a solid support via a sense strand (SS) and an antisense strand (AS), and is obtained after deprotection, cleavage, purification, annealing, purification, and lyophilization.

[0538] Solid phase synthesis: The sense strand and antisense strand are synthesized separately on a solid support using an oligonucleotide automatic synthesizer using phosphoramidite technology. The synthesizers include AKTA Oligopilot (Cytiva) and Dr.Oligo 192XLc (Kunshan Berleke Precision Instrument Co., Ltd.). Solid phase synthesis starts from the 3' end of the sequence and couples the monomers into the sequence in sequence. Each coupling of a phosphoramidite monomer includes four chemical steps: 1) unblocking or deprotection (dehydroxyl protecting group); 2) coupling; 3) oxidation; 4) end-capping. The phosphoramidite monomers, reagents, and purification consumables used are commercial circulating reagents and consumables, such as various phosphoramidite monomers purchased from Shanghai Zhaowei Technology Development Co., Ltd. (such as 5'-O-(4,4'-Dimethoxytrityl)-2'-O-methyl-Uridine-3'-CE-Phosphoramidite), and reaction reagents purchased from Sigma-Aldrich LLC (such as 40wt% methylamine aqueous solution, 28wt% ammonium hydroxide aqueous solution, etc.). The siRNA synthesis and purification methods used in this article are described in US20130178612A1, US2015100197A1, etc., the contents of which are incorporated herein by reference; the synthesis method of VPUm and APU structure sequences is described in J. Med. Chem. 2018, 61, 734-744, the contents of which are incorporated herein by reference.

[0539] (1) Synthesis of the positive chain

[0540] The solid phase phosphoramidite method is a mature oligonucleotide synthesis method. The reaction is carried out in a stainless steel synthesis column using a computer-controlled synthesizer. In the synthesis of the positive chain, a solid phase support loaded with a targeting ligand (such as DSC-001) is used as the starting point, or directly starting from the solid phase support. Different raw materials, reagents and solvents are injected in the order of sequence 3' to 5' through different pipelines controlled by the solid phase synthesizer to connect phosphoramidite nucleoside monomers one by one. The reaction process includes four cycles of DMT protection group removal reaction, condensation reaction, oxidation or thiolation reaction, and end-capping reaction. Each cycle connects a nucleotide unit to obtain an oligonucleotide sequence of 19 or 21 nucleotide units. After the synthesis is completed, the protecting group (2-cyanoethyl) is removed on the solid phase synthesis column, and the synthesized sequence is cut from the solid phase support by aminolysis reaction, filtered, the filter cake is washed with ethanol, the filtrate and washing liquid are collected, and concentrated to obtain the crude positive chain. The crude product is purified by chromatography (SOURCE 15Q) and freeze-dried to obtain the target product positive chain.

[0541] (2) Synthesis of antisense strand

[0542] The synthesis of the antisense strand is similar to that of the sense strand. Different raw materials, reagents and solvents are injected into different pipelines in the order of 3' to 5' of the sequence through the solid phase synthesizer to connect the phosphoramidite nucleoside monomers one by one. The reaction process includes four cycles of DMT protection group removal reaction, condensation reaction, oxidation or thiolation reaction, and end-capping reaction. Each cycle connects a nucleotide unit to obtain an oligonucleotide sequence of 21 or 23 nucleotide units. After the synthesis is completed, the protective group (2-cyanoethyl) is removed on the solid phase synthesis column, and then the synthesized sequence is cut from the solid phase support by aminolysis reaction, filtered, and the filter cake is washed with ethanol. The filtrate and washing liquid are collected and concentrated to obtain the crude antisense strand. The crude product is purified by chromatography (SOURCE 15Q), ultrafiltered, and dried or freeze-dried to obtain the target product antisense strand siRNA.

[0543] (3) Preparation of double-stranded siRNA

[0544] Dissolve the sense strand and antisense strand in injection water, mix them in a certain ratio (1.01:1.0~1.2:1.0), incubate at 30-50℃ for 30-90 min, cool to room temperature, and freeze-dry to obtain double-stranded siRNA products.

[0545] Example 3

[0546] Activity evaluation experiment of SOD1-siRNA in mice

[0547] The experiment used SPF male C57BL / 6J mice aged 6 to 8 weeks (Beijing Biotechnology Co., Ltd.), which were randomly divided into 5 groups. C57Bl / 6 mice were subcutaneously administered 24 mg / kg of SOD1-siRNA reagent (as shown in Table 1) and normal saline (NC, negative control) once. On the 14th day after administration, the mice were euthanized, and the sciatic nerve, tibial nerve and brachial plexus nerve samples were collected and stored in RNAlater. The mRNA in the above tissues was extracted and the mRNA content was detected and analyzed by RT-PCR.

[0548] The mRNA in the tissues was extracted using conventional methods, and the detection was performed using ChamQ SYBR qPCR Master Mix (Novozymes, Q311-02), qPCR, Forword primer (Robochem), Reverse primer (Robochem), Template cDNA, ddH2O, and qPCR instrument (ROCGENE, Archimed).

[0549] Export the data to EXCEL format and use CT SOD1 -CT GAPDH The control group was normalized. In order to calculate the fold change of relative silencing efficiency, the data were analyzed using the △△CT method, and the mean and standard deviation of the three parallel repeated data were calculated.

[0550] During the experiment, no animals showed death or dying symptoms. No obvious abnormalities were observed in all animals during clinical observation. The experimental data are shown in Table 3. As can be seen from Table 3, when the dosage is 24 mg / kg, the in vivo inhibition rate of SOD1 mRNA of the modified siRNA reagent can reach or approach 50%.

[0551] Table 3. Inhibition efficiency of exemplary sequences in mice

[0552]

[0553] Example 4

[0554] Experimental evaluation of the activity of SOD1-siRNA in rat eyes

[0555] SPF male SD rats (Beijing Biotechnology Co., Ltd.) were used in the experiment. According to the results of ophthalmological examination and body weight, they were randomly divided into the vehicle control group (N group), with 5 rats in each group. After the rats were anesthetized, 75ug / rat of SOD1-siRNA reagent (as shown in Table 1) and normal saline (NC, negative control) were injected into the right eye vitreous cavity. Levofloxacin eye drops were used twice a day for 3 days before injection and 5 days after injection. On the 14th day after administration, the mice were euthanized, and corneal samples were collected and stored in RNAlater. The mRNA in the above tissues was extracted and the mRNA content was detected and analyzed by RT-PCR.

[0556] The mRNA in the tissues was extracted using conventional methods, and the detection was performed using ChamQ SYBR qPCR Master Mix (Novozymes, Q311-02), qPCR, Forword primer (Robochem), Reverse primer (Robochem), Template cDNA, ddH2O, and qPCR instrument (ROCGENE, Archimed).

[0557] Export the data to EXCEL format and use CT SOD1 -CT GAPDH The control group was normalized. In order to calculate the fold change of relative silencing efficiency, the data were analyzed using the △△CT method, and the mean and standard deviation of the three parallel repeated data were calculated.

[0558] During the experiment, no animals showed death or dying symptoms. The experimental data are shown in Table 4. As shown in Table 4, when the dosage is 75ug / animal, the in vivo inhibition rate of SOD1 mRNA of the modified siRNA reagent can reach or approach 80%.

[0559] Table 4. Inhibition efficiency of exemplary sequences in rat retina

[0560]

[0561] The foregoing description of specific exemplary embodiments of the present disclosure is for the purpose of illustration and demonstration. These descriptions are not intended to limit the present disclosure to the precise form disclosed, and it is clear that many changes and variations can be made based on the above teachings. The purpose of selecting and describing the exemplary embodiments is to explain the specific principles of the present disclosure and its practical application, so that those skilled in the art can realize and utilize various different exemplary embodiments of the present disclosure and various different selections and changes. The scope of the present disclosure is intended to be defined by the claims and their equivalents.

Claims

1. A lipid compound having a structure represented by the following formula (III) or a pharmaceutically acceptable salt thereof, (Ⅲ) in, In the formula (III), R1 and R2 are each independently selected from C 1-25 alkyl; n1, n2, n3 are each independently an integer from 0 to 5; m1 is 1; G1 is selected from *-C(=O)NH-**, *-CH2NH(C=O)-**; G2 is selected from *-C(=O)NH-**, *-CH2NH(C=O)-**, *-(CH2CH2O) m2 -**, *-CH2OPh-**; G3 is selected from *-C(=O)NH-**, *-NH(C=O)-**, *-C(=O)-**; wherein m2 is an integer from 1 to 3; * represents connection with R1, R2 or CH, ** represents connection with (CH2) n1 、(CH2) n2 or (CH2) n3 Connected; D is H or has a structure represented by formula (IA'); The structure shown in the formula (IA') is: (IA') in, G is ; *L1 indicates connection with O; *L2 indicates connection with NH; n4, n5, and n6 are each independently an integer from 1 to 6; V is selected from or ; n7 is an integer from 0 to 4; * L3 represents (CH2) n5 connected; *L4 means connected to O.

2. The lipid compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The D is H, and the lipid compound has a structure shown in the following formula (II): (Ⅱ) Wherein, in the formula (II), R1, R2, G1, G2, G3, n1, n2, n3, and m1 are each defined as shown in the formula (III) in claim 1.

3. The lipid compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The D has a structure represented by formula (IA').

4. The lipid compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The D has a structure shown in formula (IA'); the V is .

5. The lipid compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The D has a structure shown in formula (IA'); the V is .

6. A lipid compound having a structure represented by the following formula (IV) or a pharmaceutically acceptable salt thereof, (Ⅳ) in, In the formula (IV), R1 and R2 are each independently selected from C 1-25 alkyl; n1, n2, n3 are each independently an integer from 0 to 5; G1 is selected from *-C(=O)NH-**, *-CH2NH(C=O)-**; G2 is selected from *-C(=O)NH-**, *-CH2NH(C=O)-**, *-(CH2CH2O) m2 -**, *-CH2OPh-**; G3 is selected from *-C(=O)NH-**, *-NH(C=O)-**, *-C(=O)-**; wherein m2 is an integer from 1 to 3; * represents connection with R1, R2 or N, ** represents connection with (CH2) n1 、(CH2) n2 or (CH2) n3 Connected; The D has a structure shown in formula (IB1); The structure shown in the formula (IB1) is: (IB1) Wherein, n5 and n6 are each independently an integer from 1 to 6.

7. The lipid compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, characterized in that: R1 and R2 are each independently selected from C 5-25 alkyl.

8. The lipid compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, characterized in that: R1 and R2 are each independently selected from C 10-22 alkyl.

9. The lipid compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, characterized in that: R1 and R2 are each independently selected from C 11-18 alkyl.

10. The lipid compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, characterized in that: n1 is an integer from 0 to 3, n2 is an integer from 1 to 4, and n3 is an integer from 1 to 3.

11. A lipid compound or a pharmaceutically acceptable salt thereof, characterized in that: The lipid compound is selected from the following compounds: 、 、 、 、 、 、 、 、 、 、 、 、 。 12. The lipid compound or pharmaceutically acceptable salt thereof according to claim 6, characterized in that: The lipid compound is the following compound: 。 13. Use of the lipid compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof in the preparation of an oligonucleotide delivery system.

14. Use of the lipid compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof in the preparation of a siRNA or miRNA delivery system.

15. Use of the lipid compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof in preparing a siRNA delivery system.

16. An oligonucleotide delivery system, characterized in that The oligonucleotide delivery system comprises the lipid compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof.

17. A siRNA or miRNA delivery system, characterized in that: The siRNA or miRNA delivery system comprises the lipid compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof.

18. A siRNA delivery system, characterized in that: The siRNA delivery system comprises the lipid compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof.

19. A method for preparing an oligonucleotide delivery system, characterized in that: The method comprises the following steps: preparing an oligonucleotide sequence using the lipid compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof.

20. The preparation method according to claim 19, characterized in that: The lipid compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12 is prepared into a solid phase carrier, and an oligonucleotide sequence is prepared by an oligonucleotide synthesizer.

21. The preparation method according to claim 19, characterized in that: The lipid compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 12 is prepared into a solid phase carrier, and an oligonucleotide sequence is prepared by an oligonucleotide synthesizer, wherein the lipid compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 12 is located at the 3' end, 5' end or middle position of the oligonucleotide.

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