Lipid compound for therapeutic delivery, oligonucleotide delivery system, and preparation method therefor and use thereof

Abstract

The present disclosure belongs to the technical field of biomedicine, and specifically relates to a lipid compound for therapeutic delivery, an oligonucleotide delivery system, and a preparation method therefor and the use thereof. The present disclosure has the following advantage: the lipid compound for therapeutic delivery or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof of the present disclosure can be used in the preparation of an siRNA delivery system, thereby further improving the ability of siRNA to knock down target genes in tissues such as muscle, adipose tissue, and peripheral nerves. The lipid compound for therapeutic delivery or the pharmaceutically acceptable salt, isomer, solvate or prodrug thereof provided in the present disclosure is expected to provide a new strategy for siRNA delivery to muscle, adipose tissue, nervous system, etc.

Description

Lipid compounds, oligonucleotide delivery systems for therapeutic delivery, their preparation methods and applications Technical Field

[0001] This disclosure belongs to the field of biomedical technology, specifically relating to lipid compounds for therapeutic delivery, oligonucleotide delivery systems, their preparation methods and applications. Background Technology

[0002] Currently, many different types of nucleic acids are being developed as therapeutic agents for treating a wide range of 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 downregulate the intracellular levels of specific proteins through a process called RNA interference (RNAi). After siRNA or miRNA is introduced into the cytoplasm, these double-stranded RNA constructs can bind to a protein called a RISC. The sense strand of the siRNA or miRNA is replaced by the RISC complex, which provides a template within the RISC that recognizes and binds to mRNAs with sequences complementary to the sequence of the bound siRNA or miRNA. Once the complementary mRNA has bound, the RISC complex cleaves the mRNA and releases the cleaved strand. RNAi can provide downregulation of specific proteins by specifically targeting and disrupting the mRNA encoding the corresponding protein.

[0003] RNAi has wide-ranging therapeutic applications because siRNA and miRNA constructs can be synthesized using any nucleotide sequence targeting the protein. To date, siRNA constructs have demonstrated the ability to specifically downregulate target proteins in both in vitro and in vivo models. Furthermore, siRNA constructs are currently being evaluated in clinical trials.

[0004] However, siRNA or miRNA constructs currently face two problems: first, their sensitivity to digestion by nucleases in plasma; and second, their limited ability to enter intracellular compartments where they can bind RISC when systemically administered as free siRNA or miRNA. These double-stranded constructs can be stabilized by binding chemically modified nucleotide linkers, such as phosphate thioester groups, intramolecularly. However, these modifications offer only limited protection against nuclease digestion and may reduce the activity of the construct. Intracellular delivery of siRNA or miRNA can be facilitated by using carrier systems such as polymers, lipid compounds, or by chemically modifying the construct, such as by covalently attaching cholesterol molecules. Therefore, there is a need to develop novel delivery systems to improve the efficacy of siRNA or miRNA molecules and reduce or eliminate the need for chemical modifications.

[0005] Therefore, the development of lipid compounds for siRNA delivery is of significant clinical importance. This disclosure aims to provide lipid compounds, oligonucleotide delivery systems, preparation methods, and applications for therapeutic delivery. Summary of the Invention

[0006] The technical problem this disclosure aims to solve is to develop novel lipid compounds for therapeutic delivery, which can be used to prepare siRNA delivery systems. The siRNA delivery system of this disclosure can enhance the target gene knockdown ability of siRNA in tissues such as muscle, fat, and peripheral nerves. The siRNA delivery system of this disclosure further enhances the target gene knockdown ability of siRNA in tissues such as muscle, fat, peripheral nerves, eye, heart, kidney, pancreas, uterus, and placenta.

[0007] To achieve the above-mentioned technical objectives, the technical solution adopted in this disclosure is as follows:

[0008] On the one hand, this disclosure provides a lipid compound having the structure shown in formula (I) for delivery of treatment, or a pharmaceutically acceptable salt, isomer, solvate, or prodrug thereof.

[0009] Wherein, in the above formula (I),

[0010] R1 and R2 are each independently selected from C 1-25 Alkyl, C 2-25 alkenyl or C 3-25 cycloalkyl;

[0011] n1, n2, n3, and m1 are each an independent integer from 0 to 10;

[0012] G1, G2, and G3 are each independently selected from *-C(=O)NH-**, *-CH2NH(C=O)-**, *-NH(C=O)-**, and *-(CH2CH2O). m2 -**、*-CH2OPh-**、*-C(=O)-**; where m2 is an integer from 1 to 10; * indicates connection to R1, R2 or Q, and ** indicates connection to (CH2) n1 (CH2) n2 Or (CH2) n3 Connected;

[0013] Q is CH or N;

[0014] D is H or a group containing an amide structure and ending with a carboxyl group.

[0015] The lipid compounds disclosed herein for delivering therapeutic effects, or their pharmaceutically acceptable salts, isomers, solvates, or prodrugs, can be used to prepare siRNA delivery systems. The siRNA delivery systems disclosed herein can enhance the target gene knockdown ability of siRNA in tissues such as muscle, adipose tissue, and peripheral nerves. The siRNA delivery systems disclosed herein further enhance the target gene knockdown ability of siRNA in tissues such as muscle, adipose tissue, peripheral nerves, eye, heart, kidney, pancreas, uterus, and placenta.

[0016] In some preferred embodiments of this disclosure, D has the structure shown in formula (IA2) when m1 is an integer from 1 to 10, based on the lipid compound or its pharmaceutically acceptable salt, isomer, solvate or prodrug as described above.

[0017] The structure shown in equation (IA2) is as follows:

[0018] in,

[0019] R x -(CH2)n x -C(CH2ODMTr)H-(CH2)n y -or-C(CH2ODMTr)H-(CH2)n z -CH-;

[0020] n y n z Each is an independent integer from 1 to 10;

[0021] n x Integers between 0 and 10;

[0022] R y For hydrogen, C 1-8 Alkylene, C 1-8 Alkyl or C 3-8 cycloalkyl;

[0023] n4, n5, and n6 are each independent integers from 0 to 10;

[0024] nh is 0 or 1;

[0025] When R x -C(CH2ODMTr)H-(CH2)n z -CH- and R y C 1-8 When alkylene, R x With R y They are connected to form a ring.

[0026] In some preferred embodiments of this disclosure, nh is 0.

[0027] In some preferred embodiments of this disclosure, nh is 1.

[0028] In some preferred embodiments of this disclosure, D is H or has the structure shown in formula (IA) when m1 is an integer from 1 to 10, based on the lipid compound or its pharmaceutically acceptable salt, isomer, solvate or prodrug as described above;

[0029] The structure shown in equation (IA) is as follows:

[0030] in,

[0031] R x -(CH2)n x -C(CH2ODMTr)H-(CH2)n y -or-C(CH2ODMTr)H-(CH2)n z -CH-;

[0032] n x n y n z Each is an independent integer from 1 to 10;

[0033] R y For hydrogen, C 1-8 Alkylene, C 1-8 Alkyl or C 3-8 cycloalkyl;

[0034] n4, n5, and n6 are each independent integers from 0 to 10;

[0035] When R x -C(CH2ODMTr)H-(CH2)n z -CH- and R y C 1-8 When alkylene, R x With R y They are connected to form a ring.

[0036] In some preferred embodiments of this disclosure, D is H when m1 is an integer from 1 to 10, based on the lipid compound as described above or its pharmaceutically acceptable salt, isomer, solvate or prodrug.

[0037] In some preferred embodiments of this disclosure, the lipid compound or its pharmaceutically acceptable salt, isomer, solvate or prodrug as described above is characterized in that, when m1 is an integer from 1 to 10, the D has the structure shown in formula (IA2).

[0038] The structure shown in equation (IA2) is as follows:

[0039] in,

[0040] R x -(CH2)n x -C(CH2ODMTr)H-(CH2)n y -;n y n is an integer from 1 to 8; x R is an integer from 0 to 8; y For hydrogen, C 1-8 Alkyl or C 3-8 Cycloalkyl; n4, n5, and n6 are each independent integers from 1 to 8;

[0041] nh is 0.

[0042] In some preferred embodiments of this disclosure, the lipid compound or its pharmaceutically acceptable salt, isomer, solvate or prodrug as described above is characterized in that, when m1 is an integer from 1 to 10, the D has the structure shown in formula (IA2).

[0043] The structure shown in equation (IA2) is as follows:

[0044] in,

[0045] R x -(CH2)n x -C(CH2ODMTr)H-(CH2)n y -;n y n is an integer from 1 to 6; x R is an integer from 0 to 6; y For hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl; n4, n5, and n6 are each independent integers from 1 to 6;

[0046] nh is 0.

[0047] In some preferred embodiments of this disclosure, the lipid compound or its pharmaceutically acceptable salt, isomer, solvate or prodrug as described above is characterized in that, when m1 is an integer from 1 to 10, the D has the structure shown in formula (IA2).

[0048] The structure shown in equation (IA2) is as follows:

[0049] in,

[0050] R x -(CH2)n x -C(CH2ODMTr)H-(CH2)n y -;ny n is an integer from 1 to 6; x =0; R y For hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl; n4, n5, and n6 are each independent integers from 1 to 6;

[0051] nh is 0.

[0052] In some preferred embodiments of this disclosure, D has the structure shown in formula (IA) when m1 is an integer from 1 to 10, based on the lipid compound or its pharmaceutically acceptable salt, isomer, solvate or prodrug as described above.

[0053] The structure shown in equation (IA) is as follows:

[0054] in,

[0055] R x -(CH2)n x -C(CH2ODMTr)H-(CH2)n y -or-C(CH2ODMTr)H-(CH2)n z -CH-;

[0056] n x n y n z Each is an independent integer from 1 to 10;

[0057] R y For hydrogen, C 1-8 Alkylene, C 1-8 Alkyl or C 3-8 cycloalkyl;

[0058] n4, n5, and n6 are each independent integers from 0 to 10;

[0059] When R x -C(CH2ODMTr)H-(CH2)n z -CH- and R y C 1-8 When alkylene, R x With R y They are connected to form a ring.

[0060] In some preferred embodiments of this disclosure, the lipid compound or its pharmaceutically acceptable salt, isomer, solvate or prodrug as described above is characterized in that, when m1 is an integer from 1 to 10, the D has the structure shown in formula (IA).

[0061] The structure shown in equation (IA) is as follows:

[0062] in,

[0063] R x -(CH2)n x -C(CH2ODMTr)H-(CH2)n y -;n x n y Each is an independent integer from 1 to 10; R y For hydrogen, C 1-8 Alkyl or C 3-8 Cycloalkyl; n4, n5, and n6 are each an integer from 0 to 10.

[0064] In some preferred embodiments of this disclosure, the lipid compound or its pharmaceutically acceptable salt, isomer, solvate or prodrug as described above is characterized in that, when m1 is an integer from 1 to 10, the D has the structure shown in formula (IA).

[0065] The structure shown in equation (IA) is as follows:

[0066] in,

[0067] R x -(CH2)n x -C(CH2ODMTr)H-(CH2)n y -;n x n y Each is an independent integer from 1 to 8; R y For hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl; n4, n5, n6 are each an integer from 1 to 8.

[0068] In some preferred embodiments of this disclosure, the lipid compound or its pharmaceutically acceptable salt, isomer, solvate or prodrug as described above is characterized in that, when m1 is an integer from 1 to 10, the D has the structure shown in formula (IA).

[0069] The structure shown in equation (IA) is as follows:

[0070] in,

[0071] R x -(CH2)n x -C(CH2ODMTr)H-(CH2)n y -;n x n y Each is an independent integer from 1 to 6; R yn is hydrogen; n4, n5, and n6 are each an independent integer from 1 to 6.

[0072] In some preferred embodiments of this disclosure, the lipid compound or its pharmaceutically acceptable salt, isomer, solvate or prodrug as described above is characterized in that, when m1 is an integer from 1 to 10, the D has the structure shown in formula (IA).

[0073] The structure shown in equation (IA) is as follows:

[0074] in,

[0075] R x -C(CH2ODMTr)H-(CH2)n z -CH-;n z R is an integer from 1 to 10; y C 1-8 Alkylene; n4, n5, n6 are each an independent integer from 0 to 10; Rx and Ry are linked to form a ring.

[0076] In some preferred embodiments of this disclosure, the lipid compound or its pharmaceutically acceptable salt, isomer, solvate or prodrug as described above is characterized in that, when m1 is an integer from 1 to 10, the D has the structure shown in formula (IA).

[0077] The structure shown in equation (IA) is as follows:

[0078] in,

[0079] R x -C(CH2ODMTr)H-(CH2)n z -CH-;n z R is an integer from 1 to 6; y C 1-6 Alkylene; n4, n5, n6 are each an integer from 1 to 8; Rx and Ry are linked to form a ring.

[0080] In some preferred embodiments of this disclosure, the lipid compound or its pharmaceutically acceptable salt, isomer, solvate or prodrug as described above is characterized in that, when m1 is an integer from 1 to 10, the D has the structure shown in formula (IA).

[0081] The structure shown in equation (IA) is as follows:

[0082] in,

[0083] R x -C(CH2ODMTr)H-(CH2)nz -CH-;n z R is an integer from 1 to 3; y C 1-3 Alkylene; n4, n5, n6 are each an integer from 1 to 6; Rx and Ry are linked to form a ring.

[0084] In some preferred embodiments of this disclosure, when m1 is 0, D has the structure shown in formula (IB) based on the lipid compound or its pharmaceutically acceptable salt, isomer, solvate or prodrug as described above.

[0085] The structure shown in equation (IB) is as follows:

[0086] in,

[0087] R x -(CH2)n x -C(CH2ODMTr)H-(CH2)n y -or-C(CH2ODMTr)H-(CH2)n z -CH-;

[0088] n x n y n z Each is an independent integer from 1 to 10;

[0089] R y For hydrogen, C 1-8 Alkylene, C 1-8 Alkyl or C 3-8 cycloalkyl;

[0090] n5 and n6 are each independent integers from 0 to 10;

[0091] When R x -C(CH2ODMTr)H-(CH2)n z -CH- and R y C 1-8 When alkylene, R x With R y They are connected to form a ring.

[0092] In some preferred embodiments of this disclosure, the lipid compound or its pharmaceutically acceptable salt, isomer, solvate or prodrug as described above is characterized in that, when m1 is 0, the D has the structure shown in formula (IB).

[0093] The structure shown in equation (IB) is as follows:

[0094] in,

[0095] R x -(CH2)n x -C(CH2ODMTr)H-(CH2)n y -;n x n y Each is an independent integer from 1 to 10; R y For hydrogen, C 1-8 Alkyl or C 3-8 Cycloalkyl; n5 and n6 are each an integer from 0 to 10.

[0096] In some preferred embodiments of this disclosure, the lipid compound or its pharmaceutically acceptable salt, isomer, solvate or prodrug as described above is characterized in that, when m1 is 0, the D has the structure shown in formula (IB).

[0097] The structure shown in equation (IB) is as follows:

[0098] in,

[0099] R x -(CH2)n x -C(CH2ODMTr)H-(CH2)n y -;n x n y Each is an independent integer from 1 to 8; R y For hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl; n5 and n6 are each an integer from 1 to 8.

[0100] In some preferred embodiments of this disclosure, the lipid compound or its pharmaceutically acceptable salt, isomer, solvate or prodrug as described above is characterized in that, when m1 is 0, the D has the structure shown in formula (IB).

[0101] The structure shown in equation (IB) is as follows:

[0102] in,

[0103] R x -(CH2)n x -C(CH2ODMTr)H-(CH2)n y -;n x n y Each is an independent integer from 1 to 6; R y n is hydrogen; n5 and n6 are each an independent integer from 1 to 6.

[0104] In some preferred embodiments of this disclosure, the lipid compound or its pharmaceutically acceptable salt, isomer, solvate or prodrug as described above is characterized in that, when m1 is 0, the D has the structure shown in formula (IB).

[0105] The structure shown in equation (IB) is as follows:

[0106] in,

[0107] R x -C(CH2ODMTr)H-(CH2)n z -CH-;n z R is an integer from 1 to 10; y C 1-8 Alkylene; n5 and n6 are each independent integers from 0 to 10; Rx and Ry are linked to form a ring.

[0108] In some preferred embodiments of this disclosure, the lipid compound or its pharmaceutically acceptable salt, isomer, solvate or prodrug as described above is characterized in that, when m1 is 0, the D has the structure shown in formula (IB).

[0109] The structure shown in equation (IB) is as follows:

[0110] in,

[0111] R x -C(CH2ODMTr)H-(CH2)n z -CH-;n z R is an integer from 1 to 6; y C 1-6 Alkylene; n5 and n6 are each an integer from 1 to 8; Rx and Ry are linked to form a ring.

[0112] In some preferred embodiments of this disclosure, the lipid compound or its pharmaceutically acceptable salt, isomer, solvate or prodrug as described above is characterized in that, when m1 is 0, the D has the structure shown in formula (IB).

[0113] The structure shown in equation (IB) is as follows:

[0114] in,

[0115] R x -C(CH2ODMTr)H-(CH2)n z -CH-;n z R is an integer from 1 to 3; y C 1-3Alkylene; n5 and n6 are each an integer from 1 to 6; Rx and Ry are linked to form a ring.

[0116] In some preferred embodiments of this disclosure, the lipid compound as described above, or its pharmaceutically acceptable salt, isomer, solvate, or prodrug, is characterized in that Q is CH.

[0117] In some preferred embodiments of this disclosure, the lipid compound as described above, or its pharmaceutically acceptable salt, isomer, solvate, or prodrug, is characterized in that Q is N.

[0118] On the other hand, this disclosure provides a lipid compound having the structure shown in formula (II) for delivery of treatment, or a pharmaceutically acceptable salt, isomer, solvate, or prodrug thereof.

[0119] In equation (II),

[0120] R1 and R2 are each independently selected from C 1-25 Alkyl, C 2-25 alkenyl or C 3-25 cycloalkyl;

[0121] n1, n2, and n3 are each independent integers from 0 to 10;

[0122] m1 is an integer from 1 to 10;

[0123] G1, G2, and G3 are each independently selected from *-C(=O)NH-**, *-CH2NH(C=O)-**, *-NH(C=O)-**, and *-(CH2CH2O). m2 -**、*-CH2OPh-**、*-C(=O)-**; where m2 is an integer from 1 to 10; * indicates connection to R1, R2 or CH, and ** indicates connection to (CH2). n1 (CH2) n2 Or (CH2) n3 Connected.

[0124] On the other hand, this disclosure provides a lipid compound having the structure shown in formula (Ⅲ) for delivery of treatment, or a pharmaceutically acceptable salt, isomer, solvate, or prodrug thereof.

[0125] In equation (Ⅲ),

[0126] R1 and R2 are each independently selected from C 1-25 Alkyl, C 2-25 alkenyl or C 3-25 cycloalkyl;

[0127] n1, n2, and n3 are each independent integers from 0 to 10;

[0128] m1 is an integer from 1 to 10;

[0129] G1, G2, and G3 are each independently selected from *-C(=O)NH-**, *-CH2NH(C=O)-**, *-NH(C=O)-**, and *-(CH2CH2O). m2 -**、*-CH2OPh-**、*-C(=O)-**; where m2 is an integer from 1 to 10; * indicates connection to R1, R2 or CH, and ** indicates connection to (CH2). n1 (CH2) n2 Or (CH2) n3 Connected;

[0130] D has the structure shown in equation (IA2);

[0131] The structure shown in equation (IA2) is as follows:

[0132] in,

[0133] R x -(CH2)n x -C(CH2ODMTr)H-(CH2)n y -or-C(CH2ODMTr)H-(CH2)n z -CH-;

[0134] n y n z Each is an independent integer from 1 to 10;

[0135] n x Integers between 0 and 10;

[0136] R y For hydrogen, C 1-8 Alkylene, C 1-8 Alkyl or C 3-8 cycloalkyl;

[0137] n4, n5, and n6 are each independent integers from 0 to 10;

[0138] nh is 0 or 1;

[0139] When R x -C(CH2ODMTr)H-(CH2)n z -CH- and R y C 1-8 When alkylene, R x With R y They are connected to form a ring.

[0140] According to this disclosure, a lipid compound having the structure shown in formula (Ⅲ) or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof for delivery of a therapeutic agent, wherein nh is 0.

[0141] According to this disclosure, a lipid compound having the structure shown in formula (Ⅲ) or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof for delivery of a therapeutic agent, wherein nh is 1.

[0142] According to this disclosure, a lipid compound having the structure shown in formula (Ⅲ) or a pharmaceutically acceptable salt, isomer, solvate, or prodrug thereof for delivery of therapeutic purposes, n x It is 0.

[0143] In some preferred embodiments of this disclosure, in formula (IA2), n x It is 0.

[0144] In some preferred embodiments of this disclosure, nh is 0 in formula (IA2), n x It is 0.

[0145] On the other hand, this disclosure provides a lipid compound having the structure shown in formula (Ⅲ) for delivery of treatment, or a pharmaceutically acceptable salt, isomer, solvate, or prodrug thereof.

[0146] In equation (Ⅲ),

[0147] R1 and R2 are each independently selected from C 1-25 Alkyl, C 2-25 alkenyl or C 3-25 cycloalkyl;

[0148] n1, n2, and n3 are each independent integers from 0 to 10;

[0149] m1 is an integer from 1 to 10;

[0150] G1, G2, and G3 are each independently selected from *-C(=O)NH-**, *-CH2NH(C=O)-**, *-NH(C=O)-**, and *-(CH2CH2O). m2 -**、*-CH2OPh-**、*-C(=O)-**; where m2 is an integer from 1 to 10; * indicates connection to R1, R2 or CH, and ** indicates connection to (CH2). n1 (CH2) n2 Or (CH2) n3 Connected;

[0151] D has the structure shown in equation (IA);

[0152] The structure shown in equation (IA) is as follows:

[0153] in,

[0154] R x -(CH2)n x -C(CH2ODMTr)H-(CH2)n y -or-C(CH2ODMTr)H-(CH2)n z -CH-;

[0155] n x n y n z Each is an independent integer from 1 to 10;

[0156] R y For hydrogen, C 1-8 Alkylene, C 1-8 Alkyl or C 3-8 cycloalkyl;

[0157] n4, n5, and n6 are each independent integers from 0 to 10;

[0158] When R x -C(CH2ODMTr)H-(CH2)n z -CH- and R y C 1-8 When alkylene, R x With R y They are connected to form a ring.

[0159] On the other hand, this disclosure provides a lipid compound having the structure shown in formula (Ⅲ) for delivery of treatment, or a pharmaceutically acceptable salt, isomer, solvate, or prodrug thereof.

[0160] Wherein, in the above formula (Ⅳ),

[0161] R1 and R2 are each independently selected from C 1-25 Alkyl, C 2-25 alkenyl or C 3-25 cycloalkyl;

[0162] n1, n2, and n3 are each independent integers from 0 to 10;

[0163] G1, G2, and G3 are each independently selected from *-C(=O)NH-**, *-CH2NH(C=O)-**, *-NH(C=O)-**, and *-(CH2CH2O). m2-**、*-CH2OPh-**、*-C(=O)-**; where m2 is an integer from 1 to 10; * indicates connection to R1, R2 or CH, and ** indicates connection to (CH2). n1 (CH2) n2 Or (CH2) n3 Connected;

[0164] D has the structure shown in equation (IB);

[0165] The structure shown in equation (IB) is as follows:

[0166] in,

[0167] R x -(CH2)n x -C(CH2ODMTr)H-(CH2)n y -or-C(CH2ODMTr)H-(CH2)n z -CH-;

[0168] n x n y n z Each is an independent integer from 1 to 10;

[0169] R y For hydrogen, C 1-8 Alkylene, C 1-8 Alkyl or C 3-8 cycloalkyl;

[0170] n5 and n6 are each independent integers from 0 to 10;

[0171] When R x -C(CH2ODMTr)H-(CH2)n z -CH- and R y C 1-8 When alkylene, R x With R y They are connected to form a ring.

[0172] In some preferred embodiments of this disclosure, R1 and R2 are each independently selected from C, based on the lipid compound as described above or its pharmaceutically acceptable salt, isomer, solvate, or prodrug. 5-25 Alkyl, C 5-25 alkenyl or C 5-25 Cycloalkyl.

[0173] In some preferred embodiments of this disclosure, R1 and R2 are each independently selected from C, based on the lipid compound as described above or its pharmaceutically acceptable salt, isomer, solvate, or prodrug. 10-22 Alkyl, C10-22 alkenyl or C 10-22 Cycloalkyl.

[0174] In some preferred embodiments of this disclosure, R1 and R2 are each independently selected from C, based on the lipid compound as described above or its pharmaceutically acceptable salt, isomer, solvate, or prodrug. 10-22 Alkyl or C 10-22 Alkenyl group.

[0175] In some preferred embodiments of this disclosure, R1 and R2 are each independently selected from C, based on the lipid compound as described above or its pharmaceutically acceptable salt, isomer, solvate, or prodrug. 5-25 Alkyl group; preferably, R1 and R2 are each independently selected from unsubstituted C14 groups. 5-25 alkyl.

[0176] In some preferred embodiments of this disclosure, R1 and R2 are each independently selected from C, based on the lipid compound as described above or its pharmaceutically acceptable salt, isomer, solvate, or prodrug. 5-25 Alkenyl; preferably, R1 and R2 are each independently selected from unsubstituted C. 5-25 Alkenyl group.

[0177] In some preferred embodiments of this disclosure, R1 and R2 are each independently selected from C, based on the lipid compound as described above or its pharmaceutically acceptable salt, isomer, solvate, or prodrug. 5-25 Cycloalkyl; preferably, R1 and R2 are each independently selected from unsubstituted C1 and C2. 5-25 Cycloalkyl.

[0178] In some preferred embodiments of this disclosure, R1 and R2 are each independently selected from C, based on the lipid compound as described above or its pharmaceutically acceptable salt, isomer, solvate, or prodrug. 10-22 Alkyl group; preferably, R1 and R2 are each independently selected from unsubstituted C14 groups. 10-22 Alkyl group; preferably, R1 and R2 are each independently selected from unsubstituted, unbranched C4 groups. 10-22 Alkyl group; preferably, R1 and R2 are each independently selected from unsubstituted, unbranched, saturated C4 alkyl groups. 10-22 alkyl.

[0179] In some preferred embodiments of this disclosure, R1 and R2 are each independently selected from C, based on the lipid compound as described above or its pharmaceutically acceptable salt, isomer, solvate, or prodrug. 11-18 Alkyl group; preferably, R1 and R2 are each independently selected from unsubstituted C14 groups. 11-18 Alkyl group; preferably, R1 and R2 are each independently selected from unsubstituted, unbranched C4 groups. 11-18Alkyl group; preferably, R1 and R2 are each independently selected from unsubstituted, unbranched, saturated C4 alkyl groups. 11-18 alkyl.

[0180] In some preferred embodiments of this disclosure, R1 and R2 are each independently selected from C, based on the lipid compound as described above or its pharmaceutically acceptable salt, isomer, solvate, or prodrug. 12-16 Alkyl group; preferably, R1 and R2 are each independently selected from unsubstituted C14 groups. 12-16 Alkyl group; preferably, R1 and R2 are each independently selected from unsubstituted, unbranched C4 groups. 12-16 Alkyl group; preferably, R1 and R2 are each independently selected from unsubstituted, unbranched, saturated C4 alkyl groups. 12-16 alkyl.

[0181] In some preferred embodiments of this disclosure, R1 and R2 are each independently selected from C, based on the lipid compound as described above or its pharmaceutically acceptable salt, isomer, solvate, or prodrug. 14-15 Alkyl group; preferably, R1 and R2 are each independently selected from unsubstituted C14 groups. 14-15 Alkyl group; preferably, R1 and R2 are each independently selected from unsubstituted, unbranched C4 groups. 14-15 Alkyl group; preferably, R1 and R2 are each independently selected from unsubstituted, unbranched, saturated C4 alkyl groups. 14-15 alkyl.

[0182] In some preferred embodiments of this disclosure, R1 and R2 are each independently selected from C, based on the lipid compound as described above or its pharmaceutically acceptable salt, isomer, solvate, or prodrug. 10-22 Alkenyl; preferably, R1 and R2 are each independently selected from unsubstituted C. 10-22 Alkenyl; preferably, R1 and R2 are each independently selected from unsubstituted, unbranched C. 10-22 Alkenyl; preferably, R1 and R2 are each independently selected from unsubstituted, unbranched, unsaturated C. 10-22 Alkenyl group.

[0183] In some preferred embodiments of this disclosure, R1 and R2 are each independently selected from C, based on the lipid compound as described above or its pharmaceutically acceptable salt, isomer, solvate, or prodrug. 14-22 Alkenyl; preferably, R1 and R2 are each independently selected from unsubstituted C. 14-22 Alkenyl; preferably, R1 and R2 are each independently selected from unsubstituted, unbranched C. 14-22 Alkenyl; preferably, R1 and R2 are each independently selected from unsubstituted, unbranched, unsaturated C. 14-22 Alkenyl group.

[0184] In some preferred embodiments of this disclosure, R1 and R2 are each independently selected from C, based on the lipid compound as described above or its pharmaceutically acceptable salt, isomer, solvate, or prodrug. 14-15 Alkenyl; preferably, R1 and R2 are each independently selected from unsubstituted C. 14-15 Alkenyl; preferably, R1 and R2 are each independently selected from unsubstituted, unbranched C. 14-15 Alkenyl; preferably, R1 and R2 are each independently selected from unsubstituted, unbranched, unsaturated C. 14-15 Alkenyl group.

[0185] In some preferred embodiments of this disclosure, n1, n2, and n3 are each independently an integer from 0 to 8, depending on the lipid compound as described above or its pharmaceutically acceptable salt, isomer, solvate, or prodrug.

[0186] In some preferred embodiments of this disclosure, n1, n2, and n3 are each independently integers from 0 to 6, depending on the lipid compound as described above or its pharmaceutically acceptable salt, isomer, solvate, or prodrug.

[0187] In some preferred embodiments of this disclosure, n1, n2, and n3 are each independently an integer from 0 to 5, depending on the lipid compound as described above or its pharmaceutically acceptable salt, isomer, solvate, or prodrug.

[0188] In some preferred embodiments of this disclosure, based on the lipid compound as described above or its pharmaceutically acceptable salt, isomer, solvate or prodrug, 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.

[0189] In some preferred embodiments of this disclosure, G1 is selected from *-C(=O)NH-**, *-CH2NH(C=O)-**, and G2 is selected from *-C(=O)NH-**, *-CH2NH(C=O)-**, *-(CH2CH2O) according to the lipid compound as described above or its pharmaceutically acceptable salt, isomer, solvate or prodrug. m2 -**、*-CH2OPh-**;G3 is selected from *-C(=O)NH-**、*-NH(C=O)-**、*-C(=O)-**;where 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.

[0190] In some preferred embodiments of this disclosure, G1 is selected from *-C(=O)NH-**, *-CH2NH(C=O)-**, and G2 is selected from *-C(=O)NH-**, *-CH2NH(C=O)-**, *-(CH2CH2O) according to the lipid compound as described above or its pharmaceutically acceptable salt, isomer, solvate or prodrug. m2 -**、*-CH2OPh-**;G3 is selected from *-C(=O)NH-**、*-NH(C=O)-**、*-C(=O)-**;where 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 Connected.

[0191] In some preferred embodiments of this disclosure, G1 is selected from *-C(=O)NH-**, *-CH2NH(C=O)-**, and G2 is selected from *-C(=O)NH-**, *-CH2NH(C=O)-**, *-(CH2CH2O) according to the lipid compound as described above or its pharmaceutically acceptable salt, isomer, solvate or prodrug. m2 -**、*-CH2OPh-**;G3 is selected from *-C(=O)NH-**、*-NH(C=O)-**、*-C(=O)-**;where 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 Connected.

[0192] In some preferred embodiments of this disclosure, the lipid compound is selected from the following compounds, based on the lipid compound as described above or a pharmaceutically acceptable salt, isomer, solvate, or prodrug thereof:

[0193] In some preferred embodiments of this disclosure, the lipid compound is selected from the following compounds, based on the lipid compound as described above or a pharmaceutically acceptable salt, isomer, solvate, or prodrug thereof:

[0194] In some preferred embodiments of this disclosure, the lipid compound is selected from the following compounds, based on the lipid compound as described above or a pharmaceutically acceptable salt, isomer, solvate, or prodrug thereof:

[0195] In some preferred embodiments of this disclosure, the lipid compound is selected from the following compounds, based on the lipid compound as described above or a pharmaceutically acceptable salt, isomer, solvate, or prodrug thereof:

[0196] In some preferred embodiments of this disclosure, the lipid compound is selected from the following compounds, based on the lipid compound as described above or a pharmaceutically acceptable salt, isomer, solvate, or prodrug thereof:

[0197] On the other hand, this disclosure provides the use of the lipid compounds as described above, or their pharmaceutically acceptable salts, isomers, solvates, or prodrugs, in the preparation of oligonucleotide delivery systems. The oligonucleotides include, but are not limited to, siRNA, microRNA mimics, stem-loop structures, single-stranded siRNA, ribonuclease H oligonucleotides, anti-microRNA oligonucleotides, steric-blocking oligonucleotides, CRISPR guide RNA, or aptamers.

[0198] In some preferred embodiments of this disclosure, the use of the lipid compound or its pharmaceutically acceptable salt, isomer, solvate or prodrug as described above in the preparation of siRNA or miRNA delivery systems is employed.

[0199] In some preferred embodiments of this disclosure, the use of the lipid compound or its pharmaceutically acceptable salt, isomer, solvate or prodrug as described above in the preparation of the siRNA delivery system.

[0200] On the other hand, this disclosure provides an oligonucleotide delivery system comprising a lipid compound as described above, or a pharmaceutically acceptable salt, isomer, solvate, or prodrug thereof.

[0201] In some preferred embodiments of this disclosure, an siRNA or miRNA delivery system is provided, the siRNA or miRNA delivery system comprising a lipid compound as described above or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof.

[0202] In some preferred embodiments of this disclosure, an siRNA delivery system comprises a lipid compound as described above, or a pharmaceutically acceptable salt, isomer, solvate, or prodrug thereof.

[0203] On the other hand, this disclosure provides a method for preparing an oligonucleotide delivery system, comprising the following steps: preparing an oligonucleotide sequence using a lipid compound as described above or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof.

[0204] In some preferred embodiments of this disclosure, a method for preparing an oligonucleotide delivery system includes the following steps: preparing a solid-phase carrier from a lipid compound as described above or its pharmaceutically acceptable salt, isomer, solvate or prodrug, and preparing an oligonucleotide sequence using an oligonucleotide synthesizer.

[0205] In some preferred embodiments of this disclosure, a method for preparing an oligonucleotide delivery system includes the following steps: preparing a solid-phase carrier from a lipid compound as described above or a pharmaceutically acceptable salt, isomer, solvate, or prodrug thereof; preparing an oligonucleotide sequence using 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 may be coupled to the 5' end, 3' end, or middle position of the siRNA positive strand by a phosphate ester bond or a thiophosphate ester bond. An exemplary sequence in the technical solution is 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 an SDO1 modified sequence:

[0206] SS chain: Cm*Am*UmUmUmUmAfAmUfCfCfUmCmAmCmUmCmUmAm*Am*Am

[0207] AS chain: VPUm*Uf*UmAmGmAfGmUfGfAmGmGmAmUfUmAfAmAmAmUmGm*Am*Gm

[0208] This disclosure has the following advantages:

[0209] (1) The lipid compounds disclosed herein for delivering therapeutic effects or their pharmaceutically acceptable salts, isomers, solvates or prodrugs may be used to prepare siRNA delivery systems.

[0210] (2) The lipid compounds disclosed herein for delivering therapy or their pharmaceutically acceptable salts, isomers, solvates or prodrugs can be used to prepare siRNA delivery systems to further enhance the ability of siRNA to knock down target genes in tissues such as muscle, fat, and peripheral nerves.

[0211] (3) The lipid compounds for delivering therapeutic effects provided in this disclosure, or their pharmaceutically acceptable salts, isomers, solvates or prodrugs, are expected to provide new strategies for delivering siRNA to muscles, fat, nervous system, etc. Detailed Implementation

[0212] Definitions and Explanations

[0213] To facilitate understanding of this disclosure, certain technical and scientific terms are specifically defined below. In this disclosure, unless otherwise stated, the scientific and technical terms used herein have meanings commonly understood by those skilled in the art. Furthermore, the cell and tissue culture, microbiology-related terms, and laboratory procedures used herein are all widely used terms and routine procedures in their respective fields. Meanwhile, to better understand this disclosure, definitions and explanations of relevant terms are provided below. It should be understood that this disclosure is not limited to specific methods, reagents, compounds, compositions, or biological systems, and variations thereof are certainly possible. It should also be understood that the terminology used in this application is for describing specific embodiments only and is not intended to be limiting.

[0214] Unless otherwise expressly stated, the terms “a,” “an,” and “the” as used in this specification and the appended claims cover one or more types.

[0215] As used herein, the terms “comprising” and “having”, and any variations thereof, are intended to cover non-exclusive inclusion. For example, a process, method, apparatus, product, or device that includes a series of steps is not limited to the steps or modules listed, but may optionally include steps not listed, or may optionally include other steps inherent to such process, method, product, or device.

[0216] In the description herein, references to “some embodiments,” “some implementations,” or “some implementation schemes” describe a subset of all possible embodiments. However, it is 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.

[0217] As used herein and unless otherwise stated, the terms “comprising,” “including,” “having,” “containing,” and their grammatical equivalents, including their grammatical equivalents, should generally be understood as open-ended and non-restrictive, e.g., not excluding other unlisted elements or steps.

[0218] When listing a range of values, it is assumed that each value and the subranges within that range are included. For example, "C 1-6 Alkyl groups include C1, C2, C3, C4, C5, C6, and C6. 1-6 C 1-5 C 1-4 C1-3 C 1-2 C 2-6 C 2-5 C 2-4 C 2-3 C 3-6 C 3-5 C 3-4 C 4-6 C 4-5 and C 5-6 alkyl.

[0219] As used herein, the term "substitution" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, provided that 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 terms "optional substitution" or "optionally substituted" mean that substitution is optional, and unless otherwise specified, the type and number of substituents can be arbitrary on a chemically feasible basis.

[0220] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Thus, for example, if a group is substituted by 0-2 Rs, the group can optionally be substituted by at most two Rs, and the Rs in each case have independent options. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce a stable compound.

[0221] In any embodiment, any or all hydrogen atoms present in the compound, or hydrogen atoms in a specific group or portion of the compound, may be replaced by deuterium or tritium. One to a maximum number of hydrogen atoms present in the compound may be replaced by deuterium. One to a maximum number of hydrogen atoms present in any group of the general formula compound or a specific compound may be replaced by deuterium. For example, when a group is described as ethyl, the ethyl group may be C2H5 or a C2H5 in which x (1 to 5) hydrogen atoms are replaced by deuterium, such as C2D. x H 5-x When a group is described as a deuterated ethyl group, the deuterated ethyl group can be a C2H5 with x (1 to 5) hydrogen atoms replaced by deuterium, such as C2D. x H 5-x The stable deuterated derivatives described in this disclosure 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.

[0222] This disclosure refers to compounds of formula (I), and also includes their tautomers, stereoisomers, mixtures of stereoisomers, solvates or derivatives.

[0223] This disclosure of "compounds" also includes tautomer forms. A tautomer form arises from the exchange of a single bond with an adjacent double bond, accompanied by the migration of a proton. The terms "tautomer" or "tautomer form" refer to isomers of different functional groups in dynamic equilibrium at room temperature that can rapidly interconvert. It refers to one of two or more structural isomers that exist in equilibrium and readily transform from one isomer form to another. This transformation results in the formal migration of a hydrogen atom, accompanied by the conversion of adjacent conjugated double bonds. Tautomers exist as a mixture of tautomer groups in solution. In solutions where tautomerization is possible, chemical equilibrium of the tautomers will be reached. The exact proportions of the tautomers depend on several factors, including temperature, solvent, and pH conditions. The concept of tautomers that can interconvert through tautomerization is called tautomerism.

[0224] When this specification describes a compound that is readily tautomerizable, but only one of its 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 tautomeric forms, it is intended to include all tautomeric forms, and the naming of the compound does not exclude any tautomeric form.

[0225] Of the various possible types of tautomerism, two are typically observed. In keto-enol tautomerism, both electrons and hydrogen atoms move simultaneously.

[0226] Common tautomer pairs are: keto-enol, amide-nitrile, lactam-lactam, amide-imine tautomer in heterocycles, imine-enamine, and enamine-enamine.

[0227] The term "isomer" refers to different compounds having the same molecular formula but different atomic arrangements and configurations. Depending on their structure, the compounds of this disclosure can exist in different stereoisomeric forms. These forms include configurational isomers or optical conformational isomers (enantiomers and / or diastereomers, including those that are blocked from rotation). Therefore, this disclosure includes enantiomers, diastereomers, and mixtures thereof. This disclosure further includes all mixtures of the above-described stereoisomers, regardless of proportions, including racemic mixtures.

[0228] Depending on their structure, the compounds disclosed herein can exist in various stable isotopic forms. These forms include those in which one or more hydrogen atoms are replaced by deuterium atoms, those in which one or more nitrogen atoms are replaced by 15N atoms, or those in which one or more carbon, fluorine, chlorine, bromine, sulfur, or oxygen are replaced by stable isotopes of their respective original atoms.

[0229] According to this disclosure, some compounds and salts can exist in different crystalline forms (polymorphs) within the scope of this disclosure.

[0230] In this disclosure, the following is used and It represents the absolute configuration of the center of a solid. In It refers to the junction of chemical bonds.

[0231] When the ring appears Furthermore, if the connection location is uncertain, it indicates that the connection site is located at... Any atom on the monocyclic ring, as long as its valence allows.

[0232] The term "prodrug" refers to a precursor or derivative of a pharmaceutically active substance that exhibits lower cytotoxicity to tumor cells compared to the parent drug and can be activated by enzymes or converted into a more active parent form. Prodrugs disclosed herein include, but are not limited to, phosphate (ester)-containing prodrugs, thiophosphate (ester)-containing prodrugs, sulfate (ester)-containing prodrugs, peptide-containing prodrugs, D-amino acid-modified prodrugs, glycosylated prodrugs, β-lactam-containing prodrugs, prodrugs containing optionally substituted phenoxyacetamide or phenylacetamide, 5-fluorocytosine, and other 5-fluorouridine prodrugs capable of being converted into more active cytotoxic free drugs. Examples of cytotoxic agents that can be derived into prodrug forms for use in the cytotoxic drugs of this disclosure include, but are not limited to, the aforementioned chemotherapeutic agents.

[0233] The term "alkyl" refers to a chain-like (straight-chain or branched) saturated aliphatic hydrocarbon group. The term "alkyl" can refer to a straight-chain or branched alkyl group containing 1 to 10 carbon atoms. 1-10 Alkyl groups, preferably alkyl groups containing 1 to 6 carbon atoms (C 1-6 Alkyl groups. 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 isomers thereof. More preferably are lower alkyl groups containing 1 to 3 carbon atoms (C... 1-3Alkyl groups, including methyl, ethyl, n-propyl, isopropyl, etc., are used in non-limiting embodiments. Alkyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups described in this application.

[0234] In one embodiment, the substituent is independently selected from oxo, halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, alkyl (including straight-chain, 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, fluorine, chlorine, bromine, iodine, -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 Alkyl, halogen, amino, acetamino, oxo, and nitro groups. In yet another embodiment, the substituents are independently selected from C10. 1-6 Alkyl, C 1-6 Alkoxy, halogen, acetamino, and nitro groups. As used herein, when the substituent is alkyl or alkoxy, the carbon chain can be branched, linear, or cyclic.

[0235] The term "alkylene" refers to a divalent group formed by removing one hydrogen atom from an alkyl group, which may be substituted or unsubstituted. The "alkylene" is preferably a divalent group of a straight-chain or branched saturated aliphatic hydrocarbon containing 1 to 8 carbon atoms, more preferably a divalent alkyl group containing 1 to 6 carbon atoms (C1 to C2). 1-6Alkylenes, examples of which include, but are not limited to, -CH2-, -CH(CH3)-, -CH2CH2-, -CH(CH3)CH2-, -CH2CH2CH2- or -(CH2)4- and their stereoisomers.

[0236] The term "heteroatom" is selected from nitrogen, oxygen, or sulfur. Nitrogen may optionally be substituted; sulfur may also optionally be substituted, for example, by oxidation, thus forming S(O). t3 (where t3 is an integer from 0 to 2).

[0237] The term "aryl" refers to phenyl or naphthyl, or phenyl or naphthyl substituted with the following groups: halogen, C 1-8 Alkyl, hydroxyl, nitro, trifluoromethyl, etc. Phenyl or monosubstituted phenyl groups are preferred; phenyl is the most preferred.

[0238] The term "solvent" as used in this disclosure refers to a complex formed by the compound of this disclosure with a solvent. These complexes either react in the solvent or precipitate or crystallize from the solvent. For example, a complex formed with water is called a "hydrate". Solvents of the compounds represented by formula (I) of this disclosure are within the scope of this disclosure.

[0239] This disclosure includes prodrugs of the aforementioned compounds. The prodrugs include known amino and carboxyl protecting groups, which are released under physiological conditions by hydrolysis or via enzymatic reactions to yield the parent compound. Specific methods for preparing the prodrugs can be found in (Saulnier, MG; Frenneson, DB; Deshpande, MS; Hansel, SB and Vysa, DMB 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.).

[0240] As used in this article, the term "hydroxyl group" refers to -OH.

[0241] As used in this article, the term "oxo" refers to =O.

[0242] As used in this article, the term "carboxyl group" refers to -C(=O)OH.

[0243] As used in this article, the term "acetyl (Ac)" refers to -COCH3.

[0244] As used in this article, the term "DMTr" refers to 4,4'-dimethoxytriphenylmethyl.

[0245] As used herein, “treatment” means to reduce, slow the progression of, attenuate, prevent, or maintain an existing disease or condition (e.g., cancer). Treatment also includes curing, preventing the development of, or reducing to some extent one or more symptoms of a disease or condition. As used herein, the term “treatment” or “treatment” is defined as the administration or application of a therapeutic agent, namely a compound of this disclosure (alone or in combination with another pharmaceutical agent), or the administration or application of a therapeutic agent to an isolated tissue or cell from a patient who 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 aim of curing, resolving, alleviating, reducing, altering, remedying, improving, ameliorating, or influencing the 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 tailored or modified based on knowledge obtained from the field of pharmacogenomics. As used herein, the term “treatment” for a disease refers to reducing the frequency or severity of at least one sign or symptom of a disease or condition experienced by a subject.

[0246] "Therapeutic" treatment refers to treatment applied to a subject who exhibits signs or symptoms of a pathological disease or condition, with the aim of reducing or eliminating those signs or symptoms.

[0247] Example

[0248] To make the objectives, technical solutions, and advantages of the embodiments of this disclosure clearer, the technical solutions of the embodiments of this disclosure will be clearly and completely described below in conjunction with the chemical reaction formulas in the embodiments of this disclosure. Obviously, the described embodiments are only some embodiments of this disclosure, and not all embodiments. The following is merely a further description of this disclosure, and the protection scope of this disclosure is not limited thereto.

[0249] Example 1

[0250] Preparation of compound DSC-003:

[0251] Preparation of compound 3:

[0252] Compound 1 (32 g, 124.8 mmol) was dissolved in 150 mL of DMF and stirred. DIPEA (40.3 g, 312.1 mmol) and HATU (71.2 g, 187.2 mmol) were added sequentially, and the mixture was stirred for 30 min. Compound 2 (5 g, 31.2 mmol) was then added to the reaction system, and the mixture was stirred at 50 °C for 16 h. The reaction was monitored by TLC. After the reaction was complete, the reaction solution was poured into 500 mL of dichloromethane and treated with 200 mL of water and then 200 mL of saturated saline solution. The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (DCM:MeOH = 50:1) to give a 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).

[0253] Preparation of compound 4:

[0254] Compound 3 (11 g, 17.3 mmol) was dissolved in 100 ml of MeOH / THF / H2O = 2 / 2 / 1, and LiOH (1.24 g, 51.8 mmol) was added. The mixture was reacted at 25 °C for 18 hours. The reaction solution was poured into 150 ml of 1 M dilute hydrochloric acid and stirred in an ice bath for 30 min. The mixture was extracted with 200 ml of dichloromethane, concentrated, and the residue was purified by slurry mixing with ethyl acetate:petroleum ether = 1:2 to give off-white solid 4 (8.1 g, yield 94.8%).

[0255] Preparation of compound 6:

[0256] Compound 5 (20 g, 99.4 mmol) was dissolved in 150 mL of dioxane. Potassium tert-butoxide (22.3 g, 198.7 mmol) and acrylonitrile (15.8 g, 298 mmol) dissolved in 50 mL of dioxane were added under nitrogen protection. The mixture was added to the reaction system and reacted at room temperature for 18 hours. Then, 250 mL of dichloromethane and 200 mL of ice water were added to the reaction mixture. 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 give a pale yellow solid, compound 6 (15 g, 60% yield). MS: 199.0 (ESI, [M-56+H)).+ ).

[0257] Preparation of compound 7:

[0258] Compound 6 (14 g, 55.1 mmol) was dissolved in 50 ml of methanol / concentrated sulfuric acid (3:1) and reacted at 60 °C for 18 hours. After the reaction was completed, the reaction solution was prepared to be 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 give a pale yellow oily compound 6 (7.4 g, yield 71.8%). 1 HNMR (400MHz, DMSO-d6) δ: 3.62 (dd, 4.3Hz 2H), 3.59 (s, 3H), 3.28-3.23 (m 1H), 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).

[0259] Preparation of compound 9:

[0260] 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, and the mixture was stirred for 30 min. Compound 7 (7 g, 37.4 mmol) was then added, and the reaction was allowed to proceed for 16 h. TLC (PE:EA = 2:1) showed the formation of a new substance. 100 mL of saturated sodium bicarbonate solution was added to the reaction mixture, and the organic phase was collected. The organic phase was washed twice with saturated sodium chloride solution and concentrated to obtain a crude product. The crude product was purified by column chromatography (PE:EA = 2:1) to give a yellow oily compound 9 (8.3 g, yield 59.6%). MS: 373.2 (ESI, M+H).

[0261] Preparation of compound 10:

[0262] 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 vacuum distillation. The residue was dissolved in 100 mL of dichloromethane, washed with saturated sodium bicarbonate solution, and then washed with saturated sodium chloride solution. The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated to give a yellow oily compound 10 (5.5 g, 94% yield). MS: 273.1 (ESI, [M+H]). + )

[0263] Preparation of compound 11:

[0264] 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 h. 250 mL of DCM and 200 mL of saturated sodium bicarbonate solution were added to the reaction mixture. The organic phase was collected, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by column chromatography (DCM:MeOH = 10:1) to obtain a white solid compound 11 (5.5 g, yield 58.9%). l H NMR (400MHz, CDCl3) δ: 7.07 (d, J = 5.2 Hz, lH), 6.43 (d, J = 7.6 Hz, lH), 5.92 (d, J = 4.6 Hz, lH), 4.3 5(dd,J=12.9,7.7Hz,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, 10H), 1.25 (s, 50H), 0.88 (t, J=6.8Hz, 6H).

[0265] Preparation of compound 12:

[0266] Compound 11 (5 g, 5.7 mmol) was dissolved in 50 ml of MeOH / THF / H2O = 2 / 2 / 1, and LiOH (0.6 g, 25 mmol) was added. The reaction was carried out at 25 °C for 16 hours. The reaction solution was poured into 50 ml of 1 M dilute hydrochloric acid and extracted with 100 ml of dichloromethane. The organic phase was collected, concentrated, and slurried with PE:EA = 1:2 to give off-white solid 12 (3.5 g, yield 71%).

[0267] Preparation of compound 14:

[0268] 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 of DMF and stirred for 30 min. Compound 13 (3.4 g, 5.3 mmol) was added, and the mixture was reacted at room temperature for 16 h. TLC (DMC:MeOH = 10:1) showed that the reaction was complete. 150 mL of DCM and 100 mL of water were added to the reaction mixture, and the organic phase was collected. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography (DCM:MeOH = 10:1) to give 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).

[0269] Preparation of compound DSC-003:

[0270] Compound 14 (3.5 g, 2.3 mmol) was added to 40 mL of THF, and a solution of TBAF (23.4 mL, 23.4 mmol) was added. The mixture was stirred at room temperature for 18 hours, then concentrated under reduced pressure to obtain the 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: 14 16.75 2 [M + Na] + ; 1HNMR: (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).

[0271] The lipid compound described in this disclosure is prepared into a phosphorus amide monomer or a solid-phase support such as CPG or PS using conventional methods. Finally, an oligonucleotide sequence containing the lipid compound described in this disclosure is prepared using an oligonucleotide synthesizer. The above structure can be located at the 3' end, 5' end, or middle position of the oligonucleotide. For example, it can be coupled to the 5' end, 3' end, or middle position of the siRNA positive strand by a phosphate ester bond or a thiophosphate ester bond.

[0272] Example sequences in the technical solution include: 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 the SDO1 modified sequence:

[0273] SS chain: Cm*Am*UmUmUmUmAfAmUfCfCfUmCmAmCmUmCmUmAm*Am*Am

[0274] AS chain: VPUm*Uf*UmAmGmAfGmUfGfAmGmGmAmUfUmAfAmAmAmUmGm*Am*Gm

[0275] In Table 1, “SDO1 Modification Sequence”, m refers to methylation modification;

[0276] In Table 1, “SDO1 Modification Sequence”, f refers to 2'-fluorine modification;

[0277] In Table 1, "SDO1 Modification Sequence", * refers to thiophosphate bonds.

[0278] Table 1. Exemplary SOD1 Modification Sequences

[0279] Table 2 shows the abbreviations for nucleotide monomers or modified nucleotide monomers used in nucleic acid sequence representation (in accordance with the st.26 sequence listing standard, where 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 oligonucleotides, are interconnected by 5'-3' phosphodiester bonds unless otherwise stated. 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).

[0280] Table 2. Abbreviations for nucleotide monomers used in nucleic acid sequence representation

[0281] VPUm is a 2'-methoxy-modified uridine, and its structure is as follows:

[0282] In VPUm, VP (vinylphosphonic acid) refers to vinylphosphonic acid modification.

[0283] UC16 is a 2'-hexadecyloxy-modified uridine, and its structure is as follows:

[0284] Unless otherwise specified in this article, such reagents can be obtained from any molecular biology reagent supplier, and their quality / purity standards are applicable to molecular biology.

[0285] Example 2

[0286] Preparation of siRNA

[0287] The siRNA sequence was synthesized separately on a solid support via the sense strand (SS) and antisense strand (AS), and was obtained after deprotection, cleavage, purification, annealing, purification and lyophilization.

[0288] Solid-phase synthesis: Sensitive and antisense oligonucleotides were synthesized separately on a solid support using an automated oligonucleotide synthesizer, employing phosphoramide technology. The synthesizer, such as the AKTA Oligopilot (Cytiva) or Dr. Oligo 192XLc (Kunshan Berlik Precision Instruments Co., Ltd.), was used. Solid-phase synthesis began at the 3' end of the sequence, with monomers sequentially coupled into the sequence. Each coupling of a phosphoramide monomer involved four chemical steps: 1) unblocking or deprotection (de-hydroxyl protecting group); 2) coupling; 3) oxidation; and 4) end-capping. All phosphoramidite monomers, reagents, and purification consumables used were commercially available. For example, various phosphoramidite monomers (such as 5'-O-(4,4'-Dimethoxytrityl)-2'-O-methyl-Uridine-3'-CE-Phosphoramidite) were purchased from Shanghai Zhaowei Technology Development Co., Ltd., and reaction reagents (such as 40wt% methylamine aqueous solution, 28wt% ammonium hydroxide aqueous solution, etc.) were purchased from Sigma-Aldrich LLC. The siRNA synthesis and purification methods used in this paper are described in US20130178612A1 and US2015100197A1, the contents of which are incorporated herein by reference. The synthesis methods containing VPUm and APU structural sequences are described in J.Med.Chem. 2018, 61, 734-744, the contents of which are incorporated herein by reference.

[0289] (1) The synthesis of the justice chain

[0290] Solid-phase phosphoramide synthesis is a mature method for synthesizing oligonucleotides. A computer-controlled synthesizer is used, and the reaction takes place in a stainless steel column. The positive chain synthesis begins with a solid support loaded with a targeting ligand (e.g., DSC-001), or directly with the solid support. Different starting materials, reagents, and solvents are injected sequentially from the 3' to 5' positions through different tubing lines controlled by the solid-phase synthesizer, linking phosphoramide nucleoside monomers one by one. The reaction process involves four cyclic steps: DMT protection removal, condensation, oxidation or thiolation, and end-capping. One nucleotide unit is linked in each cycle, yielding an oligonucleotide sequence of 19 or 21 nucleotides. After synthesis, the protecting group (2-cyanoethyl) is removed on the solid-phase column, and the synthesized sequence is cleaved from the solid support via ammonolysis. The sequence is filtered, the filter cake is washed with ethanol, and the filtrate and washings are collected and concentrated to obtain the crude positive chain. The crude product is purified by chromatography (SOURCE 15Q) and lyophilized to obtain the target product, the positive chain.

[0291] (2) Synthesis of antisense chains

[0292] Similar to the sense strand synthesis, the antisense strand is synthesized using a solid-phase synthesizer. Different starting materials, reagents, and solvents are injected sequentially from the 3' to 5' ends of the sequence through different tubing, linking phosphoramidine nucleoside monomers one by one. The reaction process involves four cyclic steps: DMT protection removal, condensation, oxidation or thiolation, and end-capping. One nucleotide unit is linked in each cycle, yielding an oligonucleotide sequence of 21 or 23 nucleotides. After synthesis, the protecting group (2-cyanoethyl) is removed on a solid-phase column, and the synthesized sequence is cleaved from the solid support via ammonolysis. The sequence is filtered, the filter cake is washed with ethanol, and the filtrate and washings are collected and concentrated to obtain the crude antisense strand. The crude product is purified by chromatography (SOURCE 15Q), ultrafiltered, and dried or lyophilized to obtain the target product, antisense siRNA.

[0293] (3) Preparation of double-stranded siRNA

[0294] The sense and antisense strands were dissolved separately in injection water and mixed in a defined ratio (1.01:1.0–1.2:1.0). The mixture was incubated at 30–50°C for 30–90 minutes and then cooled to room temperature. The double-stranded siRNA product was obtained by freeze-drying.

[0295] Example 3

[0296] SOD1-siRNA activity evaluation experiment in mice

[0297] SPF-grade male C57BL / 6J mice, aged 6–8 weeks (Speford (Beijing) Biotechnology Co., Ltd.), were randomly divided into groups of 5 mice each. C57BL / 6 mice were subcutaneously administered a single dose of 24 mg / kg SOD1-siRNA reagent (as shown in Table 1) and physiological saline (NC, negative control). On day 14 post-administration, the mice were euthanized, and sciatic nerve, tibial nerve, and brachial plexus nerve samples were collected and stored in RNAlater. mRNA was extracted from these tissues and analyzed for mRNA content using RT-PCR.

[0298] mRNA was extracted from tissues using conventional methods and detected using ChamQ SYBR qPCR Master Mix (Novizan, Q311-02) qPCR, Forward primer (Ruibokexing), Reverse primer (Ruibokexing), Template cDNA, ddH2O, and a qPCR instrument (ROCGENE, Archimed).

[0299] Export the data to Excel format using CT. SOD1 -CT GAPDH The control group was normalized. To calculate the fold change in relative silencing efficiency, the data were analyzed using the ΔΔCT method. The mean and standard deviation of the three parallel replicates were calculated.

[0300] During the experiment, no animals showed signs of death or near-death. Clinical observation revealed no significant abnormalities in any animal. Experimental data are shown in Table 3. As can be seen from Table 3, at a dosage of 24 mg / kg, the in vivo inhibition rate of SOD1 mRNA modified with the siRNA reagent reached or approached 50%.

[0301] Table 3. Inhibitory efficiency of exemplary sequences in mice

[0302] Example 4

[0303] Activity evaluation experiment of SOD1-siRNA in rat eyes

[0304] SPF-grade male SD rats (Speford (Beijing) Biotechnology Co., Ltd.) were used in the experiment. Based on ophthalmological examination results and body weight, they were randomly divided into a solvent control group (N group), with 5 rats in each group. After anesthesia, the rats were injected intravitreally into the right eye with 75 μg / rat of SOD1-siRNA reagent (as shown in Table 1) and physiological saline (NC, negative control). Levofloxacin eye drops were administered twice daily for 3 days before and 5 days after injection. On day 14 after administration, the mice were euthanized, and corneal samples were collected and stored in RNAlater. mRNA was extracted from these tissues and analyzed by RT-PCR.

[0305] mRNA was extracted from tissues using conventional methods and detected using ChamQ SYBR qPCR Master Mix (Novizan, Q311-02) qPCR, Forward primer (Ruibokexing), Reverse primer (Ruibokexing), Template cDNA, ddH2O, and a qPCR instrument (ROCGENE, Archimed).

[0306] Export the data to Excel format using CT. SOD1 -CT GAPDH The control group was normalized. To calculate the fold change in relative silencing efficiency, the data were analyzed using the ΔΔCT method. The mean and standard deviation of the three parallel replicates were calculated.

[0307] During the experiment, no animals showed signs of death or near-death. Experimental data are shown in Table 4. As can be seen from Table 4, at a dosage of 75 μg / animal, the in vivo inhibition rate of SOD1 mRNA modified with the siRNA reagent reached or approached 80%.

[0308] Table 4. Inhibition efficiency of exemplary sequences in the rat retina

[0309] The foregoing description of specific exemplary embodiments of this disclosure is for illustrative and explanatory purposes. These descriptions are not intended to limit this disclosure to the precise forms disclosed, and it will be apparent that many changes and variations can be made in accordance with the foregoing teachings. The exemplary embodiments were chosen and described in order to explain the specific principles of this disclosure and their practical application, thereby enabling those skilled in the art to implement and utilize various different exemplary embodiments of this disclosure, as well as various different choices and variations. The scope of this disclosure is intended to be defined by the claims and their equivalents.

Claims

1. A lipid compound having the structure shown in formula (I) or a pharmaceutically acceptable salt, isomer, solvate, or prodrug thereof, in, In the above formula (I), R1 and R2 are each independently selected from C 1-25 Alkyl, C 2-25 alkenyl or C 3-25 cycloalkyl; n1, n2, n3, and m1 are each an independent integer from 0 to 10; G1, G2, and G3 are each independently selected from *-C(=O)NH-**, *-CH2NH(C=O)-**, *-NH(C=O)-**, and *-(CH2CH2O). m2 -**、*-CH2OPh-**、*-C(=O)-**; where m2 is an integer from 1 to 10; * indicates connection to R1, R2 or Q, and ** indicates connection to (CH2) n1 (CH2) n2 Or (CH2) n3 Connected; Q is CH or N; D is H or a group containing an amide structure and ending with a carboxyl group.

2. The lipid compound according to claim 1, or a pharmaceutically acceptable salt, isomer, solvate, or prodrug thereof, characterized in that, When m1 is an integer from 1 to 10, D has the structure shown in equation (IA2); The structure shown in equation (IA2) is as follows: in, R x -(CH2)n x -C(CH2ODMTr)H-(CH2)n y -or-C(CH2ODMTr)H-(CH2)n z -CH-; n y n z Each is an independent integer from 1 to 10; n x Integers between 0 and 10; R y For hydrogen, C 1-8 Alkylene, C 1-8 Alkyl or C 3-8 cycloalkyl; n4, n5, and n6 are each independent integers from 0 to 10; nh is 0 or 1; When R x -C(CH2ODMTr)H-(CH2)n z -CH- and R y C 1-8 When alkylene, R x With R y Connected to form a ring; Preferably, when m1 is an integer from 1 to 10, D is H or has the structure shown in formula (IA); The structure shown in equation (IA) is as follows: in, R x -(CH2)n x -C(CH2ODMTr)H-(CH2)n y -or-C(CH2ODMTr)H-(CH2)n z -CH-; n x n y n z Each is an independent integer from 1 to 10; R y For hydrogen, C 1-8 Alkylene, C 1-8 Alkyl or C 3-8 cycloalkyl; n4, n5, and n6 are each independent integers from 0 to 10; When R x -C(CH2ODMTr)H-(CH2)n z -CH- and R y C 1-8 When alkylene, R x With R y They are connected to form a ring.

3. The lipid compound according to claim 1 or 2, or a pharmaceutically acceptable salt, isomer, solvate, or prodrug thereof, characterized in that, When m1 is an integer from 1 to 10, D is H.

4. The lipid compound according to claim 2, or a pharmaceutically acceptable salt, isomer, solvate, or prodrug thereof, characterized in that, When m1 is an integer from 1 to 10, in the structure shown in equation (IA2), R x -(CH2)n x -C(CH2ODMTr)H-(CH2)n y -or-C(CH2ODMTr)H-(CH2)n z -CH-; n y n z Each is an independent integer from 1 to 10; n x Integers between 0 and 10; R y For hydrogen, C 1-8 Alkylene, C 1-8 Alkyl or C 3-8 cycloalkyl; n4, n5, and n6 are each independent integers from 0 to 10; When R x -C(CH2ODMTr)H-(CH2)n z -CH- and R y C 1-8 When alkylene, R x With R y Connected to form a ring; Preferably, when m1 is an integer from 1 to 10, in the structure shown in equation (IA), R x -(CH2)n x -C(CH2ODMTr)H-(CH2)n y -or-C(CH2ODMTr)H-(CH2)n z -CH-; n x n y n z Each is an independent integer from 1 to 10; R y For hydrogen, C 1-8 Alkylene, C 1-8 Alkyl or C 3-8 cycloalkyl; n4, n5, and n6 are each independent integers from 0 to 10; When R x -C(CH2ODMTr)H-(CH2)n z -CH- and R y C 1-8 When alkylene, R x With R y They are connected to form a ring.

5. The lipid compound according to claim 4, or a pharmaceutically acceptable salt, isomer, solvate, or prodrug thereof, characterized in that, When m1 is an integer from 1 to 10, in the structure shown by equation (IA2) or (IA), R x -(CH2)n x -C(CH2ODMTr)H-(CH2)n y -;n y n is an integer from 1 to 10; x Integers between 0 and 10; R y For hydrogen, C 1-8 Alkyl or C 3-8 Cycloalkyl; n4, n5, and n6 are each independent integers from 0 to 10; Preferably, R x -(CH2)n x -C(CH2ODMTr)H-(CH2)n y -;n y n is an integer from 1 to 8; x Integers from 0 to 8; R y For hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl; n4, n5, and n6 are each independent integers from 1 to 8; Preferably, R x -(CH2)n x -C(CH2ODMTr)H-(CH2)n y -;n y n is an integer from 1 to 6; x Integers from 0 to 6; R y n is hydrogen; n4, n5, and n6 are each an independent integer from 1 to 6; Preferably, when m1 is an integer from 1 to 10, in the structure shown in equation (IA), R x -(CH2)n x -C(CH2ODMTr)H-(CH2)n y -;n x n y Each is an independent integer from 1 to 10; R y For hydrogen, C 1-8 Alkyl or C 3-8 Cycloalkyl; n4, n5, and n6 are each independent integers from 0 to 10; Preferably, R x -(CH2)n x -C(CH2ODMTr)H-(CH2)n y -;n x n y Each is an independent integer from 1 to 8; R y For hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl; n4, n5, and n6 are each independent integers from 1 to 8; Preferably, R x -(CH2)n x -C(CH2ODMTr)H-(CH2)n y -;n x n y Each is an independent integer from 1 to 6; R y n is hydrogen; n4, n5, and n6 are each an independent integer from 1 to 6.

6. The lipid compound according to claim 4, or a pharmaceutically acceptable salt, isomer, solvate, or prodrug thereof, characterized in that, When m1 is an integer from 1 to 10, in the structure shown by equation (IA2) or (IA), R x -C(CH2ODMTr)H-(CH2)n z -CH-;n z R is an integer from 1 to 10; y C 1-8 Alkylene; n4, n5, n6 are each an independent integer from 0 to 10; Rx and Ry are linked to form a ring; Preferably, R x -C(CH2ODMTr)H-(CH2)n z -CH-;n z R is an integer from 1 to 6; y C 1-6 Alkylene; n4, n5, n6 are each an independent integer from 1 to 8; Rx and Ry are linked to form a ring; Preferably, R x -C(CH2ODMTr)H-(CH2)n z -CH-;n z R is an integer from 1 to 3; y C 1-3 Alkylene; n4, n5, n6 are each an integer from 1 to 6; Rx and Ry are linked to form a ring.

7. The lipid compound according to claim 1, or a pharmaceutically acceptable salt, isomer, solvate, or prodrug thereof, characterized in that, When m1 is 0, D has the structure shown in equation (IB); The structure shown in equation (IB) is as follows: in, R x -(CH2)n x -C(CH2ODMTr)H-(CH2)n y -or-C(CH2ODMTr)H-(CH2)n z -CH-; n x n y n z Each is an independent integer from 1 to 10; R y For hydrogen, C 1-8 Alkylene, C 1-8 Alkyl or C 3-8 cycloalkyl; n5 and n6 are each independent integers from 0 to 10; When R x -C(CH2ODMTr)H-(CH2)n z -CH- and R y C 1-8 When alkylene, R x With R y They are connected to form a ring.

8. The lipid compound according to claim 7, or a pharmaceutically acceptable salt, isomer, solvate, or prodrug thereof, characterized in that, When m1 is 0, in the formula (IB), R x -(CH2)n x -C(CH2ODMTr)H-(CH2)n y -;n x n y Each is an independent integer from 1 to 10; R y For hydrogen, C 1-8 Alkyl or C 3-8 Cycloalkyl; n5 and n6 are each independent integers from 0 to 10; Preferably, R x -(CH2)n x -C(CH2ODMTr)H-(CH2)n y -;n x n y Each is an independent integer from 1 to 8; R y For hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl; n5 and n6 are each an integer from 1 to 8 independently; Preferably, R x -(CH2)n x -C(CH2ODMTr)H-(CH2)n y -;n x n y Each is an independent integer from 1 to 6; R y n is hydrogen; n5 and n6 are each an independent integer from 1 to 6.

9. The lipid compound according to claim 7, or a pharmaceutically acceptable salt, isomer, solvate, or prodrug thereof, characterized in that, When m1 is 0, in the structure shown by equation (IB), R x -C(CH2ODMTr)H-(CH2)n z -CH-;n z R is an integer from 1 to 10; y C 1-8 Alkylene; n5 and n6 are each independent integers from 0 to 10; Rx and Ry are linked to form a ring; Preferably, R x -C(CH2ODMTr)H-(CH2)n z -CH-;n z R is an integer from 1 to 6; y C 1-6 Alkylene; n5 and n6 are each independent integers from 1 to 8; Rx and Ry are linked to form a ring; Preferably, R x -C(CH2ODMTr)H-(CH2)n z -CH-;n z R is an integer from 1 to 3; y C 1-3 Alkylene; n5 and n6 are each an integer from 1 to 6; Rx and Ry are linked to form a ring.

10. The lipid compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, isomer, solvate, or prodrug thereof, characterized in that, Q stands for CH.

11. The lipid compound according to any one of claims 1, 7 to 9, or a pharmaceutically acceptable salt, isomer, solvate, or prodrug thereof, characterized in that, Q is N.

12. A lipid compound having the structure shown in formula (II) or a pharmaceutically acceptable salt, isomer, solvate, or prodrug thereof, in, In the above formula (II), R1 and R2 are each independently selected from C 1-25 Alkyl, C 2-25 alkenyl or C 3-25 cycloalkyl; n1, n2, and n3 are each independent integers from 0 to 10; m1 is an integer from 1 to 10; G1, G2, and G3 are each independently selected from *-C(=O)NH-**, *-CH2NH(C=O)-**, *-NH(C=O)-**, and *-(CH2CH2O). m2 -**、*-CH2OPh-**、*-C(=O)-**; where m2 is an integer from 1 to 10; * indicates connection to R1, R2 or CH, and ** indicates connection to (CH2). n1 (CH2) n2 Or (CH2) n3 Connected.

13. A lipid compound having the structure shown in formula (Ⅲ) or a pharmaceutically acceptable salt, isomer, solvate, or prodrug thereof, in, In the above formula (Ⅲ), R1 and R2 are each independently selected from C 1-25 Alkyl, C 2-25 alkenyl or C 3-25 cycloalkyl; n1, n2, and n3 are each independent integers from 0 to 10; m1 is an integer from 1 to 10; G1, G2, and G3 are each independently selected from *-C(=O)NH-**, *-CH2NH(C=O)-**, *-NH(C=O)-**, and *-(CH2CH2O). m2 -**、*-CH2OPh-**、*-C(=O)-**; where m2 is an integer from 1 to 10; * indicates connection to R1, R2 or CH, and ** indicates connection to (CH2). n1 (CH2) n2 Or (CH2) n3 Connected; The D has the structure shown in equation (IA2); The structure shown in equation (IA2) is as follows: in, R x -(CH2)n x -C(CH2ODMTr)H-(CH2)n y -or-C(CH2ODMTr)H-(CH2)n z -CH-; n y n z Each is an independent integer from 1 to 10; n x Integers between 0 and 10; R y For hydrogen, C 1-8 Alkylene, C 1-8 Alkyl or C 3-8 cycloalkyl; n4, n5, and n6 are each independent integers from 0 to 10; nh is 0 or 1; When R x -C(CH2ODMTr)H-(CH2)n z -CH- and R y C 1-8 When alkylene, R x With R y Connected to form a ring; Preferably, D has the structure shown in formula (IA); The structure shown in equation (IA) is as follows: in, R x -(CH2)n x -C(CH2ODMTr)H-(CH2)n y -or-C(CH2ODMTr)H-(CH2)n z -CH-; n x n y n z Each is an independent integer from 1 to 10; R y For hydrogen, C 1-8 Alkylene, C 1-8 Alkyl or C 3-8 cycloalkyl; n4, n5, and n6 are each independent integers from 0 to 10; When R x -C(CH2ODMTr)H-(CH2)n z -CH- and R y C 1-8 When alkylene, R x With R y They are connected to form a ring.

14. A lipid compound having the structure shown in formula (III) or a pharmaceutically acceptable salt, isomer, solvate, or prodrug thereof, in, In the above formula (Ⅳ), R1 and R2 are each independently selected from C 1-25 Alkyl, C 2-25 alkenyl or C 3-25 cycloalkyl; n1, n2, and n3 are each independent integers from 0 to 10; G1, G2, and G3 are each independently selected from *-C(=O)NH-**, *-CH2NH(C=O)-**, *-NH(C=O)-**, and *-(CH2CH2O). m2 -**、*-CH2OPh-**、*-C(=O)-**; where m2 is an integer from 1 to 10; * indicates connection to R1, R2 or CH, and ** indicates connection to (CH2). n1 (CH2) n2 Or (CH2) n3 Connected; D has the structure shown in equation (IB); The structure shown in equation (IB) is as follows: in, R x -(CH2)n x -C(CH2ODMTr)H-(CH2)n y -or-C(CH2ODMTr)H-(CH2)n z -CH-; n x n y n z Each is an independent integer from 1 to 10; R y For hydrogen, C 1-8 Alkylene, C 1-8 Alkyl or C 3-8 cycloalkyl; n5 and n6 are each independent integers from 0 to 10; When R x -C(CH2ODMTr)H-(CH2)n z -CH- and R y C 1-8 When alkylene, R x With R y They are connected to form a ring.

15. The lipid compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, isomer, solvate, or prodrug thereof, characterized in that, R1 and R2 are each independently selected from C 5-25 Alkyl, C 5-25 alkenyl or C 5-25 Cycloalkyl; preferably, R1 and R2 are each independently selected from C1 and C2. 10-22 Alkyl, C 10-22 alkenyl or C 10-22 Cycloalkyl; preferably, R1 and R2 are each independently selected from C1 and C2. 10-22 Alkyl or C 10-22 Alkenyl; preferably, R1 and R2 are each independently selected from C 10-22 Alkyl group; preferably, R1 and R2 are each independently selected from C1 and C2. 11-18 alkyl.

16. The lipid compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, isomer, solvate, or prodrug thereof, characterized in that, n1, n2, and n3 are each independently an integer from 0 to 8; preferably, n1, n2, and n3 are each independently an integer from 0 to 6; preferably, n1, n2, and n3 are each independently an integer from 0 to 5; preferably, 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.

17. The lipid compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, isomer, solvate, or prodrug thereof, characterized in that, G1 is selected from *-C(=O)NH-** and *-CH2NH(C=O)-**; G2 is selected from *-C(=O)NH-**, *-CH2NH(C=O)-**, and *-(CH2CH2O). m2 -**、*-CH2OPh-**;G3 is selected from *-C(=O)NH-**、*-NH(C=O)-**、*-C(=O)-**;where 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; Preferably, 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)-**;where 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 Connected; Preferably, 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)-**;where 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 Connected.

18. The following lipid compounds or their pharmaceutically acceptable salts, isomers, solvates or prodrugs, characterized in that, The lipid compound is selected from the following compounds:

19. The use of the lipid compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt, isomer, solvate, or prodrug thereof, in the preparation of an oligonucleotide delivery system; Preferably, the use of the lipid compound according to any one of claims 1 to 18 or its pharmaceutically acceptable salt, isomer, solvate or prodrug in the preparation of siRNA or miRNA delivery systems; Preferably, the use of the lipid compound according to any one of claims 1 to 18 or its pharmaceutically acceptable salt, isomer, solvate or prodrug in the preparation of an siRNA delivery system.

20. An oligonucleotide delivery system, characterized in that, The oligonucleotide delivery system comprises the lipid compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt, isomer, solvate, or prodrug thereof; Preferably, an siRNA or miRNA delivery system is characterized in that the siRNA or miRNA delivery system comprises a lipid compound as described in any one of claims 1 to 18 or a pharmaceutically acceptable salt, isomer, solvate, or prodrug thereof; Preferably, an siRNA delivery system is characterized in that the siRNA delivery system comprises a lipid compound as described in any one of claims 1 to 18, or a pharmaceutically acceptable salt, isomer, solvate, or prodrug thereof.

21. A method for preparing an oligonucleotide delivery system, characterized in that, The steps include: preparing an oligonucleotide sequence using the lipid compound of any one of claims 1 to 18 or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof; Preferably, the lipid compound according to any one of claims 1 to 18 or its pharmaceutically acceptable salt, isomer, solvate or prodrug is prepared as a solid-phase support, and an oligonucleotide sequence is prepared by an oligonucleotide synthesizer; Preferably, the lipid compound of any one of claims 1 to 18 or its pharmaceutically acceptable salt, isomer, solvate or prodrug is prepared as a solid-phase support, and an oligonucleotide sequence is prepared by an oligonucleotide synthesizer, wherein the lipid compound of any one of claims 1 to 18 or its pharmaceutically acceptable salt, isomer, solvate or prodrug is located at the 3' end, 5' end or middle position of the oligonucleotide.

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