Poly(β-amino ester) compound, composition comprising same and use thereof

Abstract

A poly(β-amino ester) compound, a composition comprising same and a use thereof, and in particular, a compound as shown in a formula I or a pharmaceutically acceptable salt thereof. The compound as shown in formula I can be used for preparing a delivery system. The prepared delivery system is capable of delivering a nucleic acid drug, and can be used for delivering a nucleic acid prophylactic and / or therapeutic agent to the lung and / or liver.

Description

A poly-β-amino lipid compound, its composition and application

[0001] This application claims the benefit of Chinese Patent Application No. 2023112753519, filed September 28, 2023. This application incorporates the entirety of the aforementioned Chinese Patent Application. Technical Field

[0002] The present invention relates to a poly-β-amino lipid compound, a composition and application thereof. Background Art

[0003] Gene therapy refers to the insertion of normal or therapeutic exogenous genes into target cells to repair or replace defective genes in the target cells, thereby achieving the purpose of treating the disease. Gene therapy has demonstrated excellent performance in areas such as genetic diseases, cancer, and infectious diseases, and has played a role that cannot be replaced by traditional drugs. Nucleic acid drugs have played an important role in the fields of vaccines and infectious diseases since the outbreak of the COVID-19 pandemic. For nucleic acid drugs, how to design suitable vectors to deliver them to target cells is one of the biggest challenges limiting the development of nucleic acid drugs. Currently, the vectors used for nucleic acid delivery include viral vectors and non-viral vectors. Although viral vectors have high delivery efficiency, due to the rapid clearance of antibodies in the body, limited vector size and other possible side effects, researchers have recently been committed to developing non-viral delivery vectors, such as liposomes, polymers, inorganic materials, etc. The success of Onpattro, the first non-viral vector siRNA drug, has also brought confidence in the design and development of non-viral nucleic acid delivery vectors.

[0004] Cationic polymers, poly(beta-amino esters), (PBAEs), have been studied in the field of nucleic acid delivery for over two decades and are one of the most common materials used for gene delivery. Their electrostatic interactions with negatively charged nucleic acids facilitate the formation of stable nanoparticles that deliver nucleic acids to target cells. PBAEs are typically prepared by step-growth polymerization (such as the Michael addition reaction) or ring-opening polymerization, with the Michael addition reaction being the most commonly used reaction. The tertiary amines on the PBAE backbone can be protonated, making the polymer positively charged and enabling lysosomal escape. The chemical structure and properties of PBAEs can be tuned by varying the diacrylate, side chains, and end-capping groups.

[0005] In addition to sharing the common properties of ionizable cationic lipids: effective nucleic acid coating, rapid cellular uptake, efficient endosomal escape, easy nucleic acid release into cells, and low cytotoxicity, PBAEs also offer unique advantages such as simple synthesis, strong modifiability, a wide range of cargo types, and high stability. Currently, PBAEs have achieved effective in vivo delivery of various nucleic acids, including mRNA, circular mRNA, shRNA, and plasmid DNA, with promising results in cancer therapy, tumor immunity, and gene editing.

[0006] However, despite the significant advantages of PBAE in nucleic acid delivery, we have found, based on literature review and previous laboratory research, that conventional PBAE-encapsulated nucleic acids injected into mice via the tail vein are generally limited to lung-targeted expression. Furthermore, in vivo mouse experimental results have shown a low lethal dose, a narrow safety window, and limited back-end applications. Furthermore, the expression level of conventional PBAE in the liver is very limited, far below the effectiveness of commercially available ionizable lipids.

[0007] Summary of the Invention

[0008] In order to solve the problems of low lethal doses in mice, narrow safety windows, or limited back-end applications of existing PBAE compounds, the present invention aims to provide a poly (β-amino) lipid compound, a composition, and an application thereof.

[0009] The present invention provides a compound as shown in Formula I or a pharmaceutically acceptable salt thereof,

[0010] wherein n is 2-20 (n represents the average degree of polymerization);

[0011] R is -(CH2)m- or is replaced by one or more R a Substituted -(CH2)m-, wherein 0 to 12 -CH2- in said -(CH2)m- are optionally independently replaced by O, S, -NR b -, Sub-C6-C 12 Aryl, C3-C6 cycloalkylene, 1 or more R c Substituted C6-C 12 Aryl and 9,9-diphenylfluorenyl are substituted, and m is 1-40;

[0012] Each R a are independently hydroxyl, -NR b R b , C1-C6 alkyl, halogen or C1-C4 heteroalkyl; the heteroatom species in the C1-C4 heteroalkyl is selected from one or more of O, S and N, and the number of heteroatoms is 1, 2 or 3;

[0013] Each R bare independently hydrogen, C1-C6 alkyl, C6-C 12 Aryl, 1 or more R c Substituted C6-C 12 Aryl or one or more R b1 Substituted C1-C6 alkyl;

[0014] Each R c are independently hydroxy, nitro, cyano, C1-C6 alkyl, halogen or amino;

[0015] Each R b1 are independently hydroxyl groups;

[0016] R 1 C1-C 22 Alkyl, C2-C 22 Alkenyl, C2-C 22 Alkynyl, one or more R 1-1 Substituted C1-C 22 Alkyl, one or more R 1-2 Substituted C2-C 22 Alkenyl or one or more R 1-3 Substituted C2-C 22 Alkynyl; the C1-C 22 0 to 8 -CH2- in the alkyl group are optionally independently replaced by O or S; 22 0 to 8 -CH2- in the alkenyl group are optionally independently replaced by O or S; 22 0 to 8 -CH2- in the alkynyl group are optionally independently replaced by O or S;

[0017] Each R 1-1 、R 1-2 and R 1-3 are independently -NR b R b , hydroxyl, C6-C 12 Aryl or C3-C6 cycloalkyl;

[0018] R 2 C1-C 22 Alkyl, C2-C 22 Alkenyl, C2-C 22 Alkynyl, one or more R 2-1 Substituted C1-C 22 Alkyl, one or more R 2-2 Substituted C2-C 22 Alkenyl, one or more R 2-3 Substituted C2-C 22 Alkynyl, C3-C6 cycloalkyl, 1 or more R 2eSubstituted C3-C6 cycloalkyl, "a 3-7 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S" or "a 3-7 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms ... 2f The substituted "heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3 3-membered heterocycloalkyl", the C2-C 22 0 to 8 -CH2- in the alkynyl group are optionally replaced by O or S;

[0019] Each R 2-1 、R 2-2 and R 2-3 are independently -NR b R b , hydroxyl, C6-C 12 Aryl, one or more R 2d3 Substituted C6-C 12 Aryl, C3-C6 cycloalkyl, one or more R 2d3 Substituted C3-C6 cycloalkyl, "a 5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S" or one or more R 2d3 Substituted "5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S";

[0020] Each R 2d3 are independently C1-C6 alkyl, halogen or halogenated C1-C6 alkyl;

[0021] Each R 2e and R 2f are independently halogen, C1-C6 alkyl or halogenated C1-C6 alkyl;

[0022] X is

[0023] R 3 is hydrogen, C1-C 22 Alkyl, C2-C 22 Alkenyl, C2-C 22 Alkynyl, one or more R 3-1 Substituted C1-C 22 Alkyl, one or more R 3-2 Substituted C2-C 22 Alkenyl, one or more R 3-3 Substituted C2-C 22 Alkynyl, C3-C6 cycloalkyl, C6-C 12 Aryl or "3-7 membered heterocycloalkyl group wherein the heteroatoms are 1, 2 or 3 selected from N, O and S";

[0024] Each R 3-1 、R 3-2 and R 3-3 are independently -NR b R b , C3-C6 cycloalkyl or hydroxyl.

[0025] In a preferred embodiment, the present invention provides a compound as shown in Formula I or a pharmaceutically acceptable salt thereof,

[0026] in,

[0027] n is 2-20 (n represents the average degree of polymerization);

[0028] R is -(CH2)m- or is replaced by one or more R a Substituted -(CH2)m-, wherein 0 to 10 -CH2- in said -(CH2)m- are optionally replaced by O, S, -NR b -, Sub-C6-C 12 Aryl, C3-C6 cycloalkylene and one or more R c Substituted C6-C 12 Aryl, m is 1-30;

[0029] Each R a are independently hydroxyl, -NR b R b , C1-C6 alkyl, halogen or C1-C4 heteroalkyl; the heteroatom species in the C1-C4 heteroalkyl is selected from one or more of O, S and N, and the number of heteroatoms is 1, 2 or 3;

[0030] Each R b are independently hydrogen, C1-C6 alkyl, C6-C 12 Aryl or one or more R c Substituted C6-C 12 aryl;

[0031] Each R c are independently hydroxy, nitro, cyano, C1-C6 alkyl, halogen or amino;

[0032] R 1 C1-C 22 Alkyl, C2-C 22 Alkenyl, C2-C 22 Alkynyl, one or more R 1-1 Substituted C1-C 22 Alkyl, one or more R 1-2 Substituted C2-C 22 Alkenyl or one or more R1-3 Substituted C2-C 22 Alkynyl;

[0033] Each R 1-1 、R 1-2 and R 1-3 are independently -NR b R b - or hydroxyl group;

[0034] R 2 C1-C 22 Alkyl, C2-C 22 Alkenyl, C2-C 22 Alkynyl, one or more R 2-1 Substituted C1-C 22 Alkyl, one or more R 2-2 Substituted C2-C 22 Alkenyl or one or more R 2-3 Substituted C2-C 22 Alkynyl;

[0035] Each R 2-1 、R 2-2 and R 2-3 are independently -NR b R b or hydroxyl;

[0036] X is

[0037] R 3 is hydrogen, C1-C 22 Alkyl, C2-C 22 Alkenyl, C2-C 22 Alkynyl, one or more R 3-1 Substituted C1-C 22 Alkyl, one or more R 3-2 Substituted C2-C 22 Alkenyl, one or more R 3-3 Substituted C2-C 22 Alkynyl, C3-C6 cycloalkyl, C6-C 12 Aryl or a 3-7 membered heterocycloalkyl group optionally substituted by 1, 2 or 3 heteroatoms, wherein the heteroatoms are optionally one or more of N, O and S; the number of heteroatoms is 1, 2 or 3;

[0038] Each R 3-1 、R 3-2 and R 3-3 are independently -NR b R b , C3-C6 cycloalkyl or hydroxyl.

[0039] Those skilled in the art will understand that the 0 to 10 -CH2- in the -(CH2)m- are optionally substituted by O, etc., which is equivalent to the 0 to 10 -CH2- in the -(CH2)m- being optionally substituted by O, etc., and the -(CH2)m- means "-(CH2)m-" and "substituted by one or more R a The "-(CH2)m-" in "substituted-(CH2)m-" does not specifically refer to unsubstituted-(CH2)m-.

[0040] In a preferred embodiment, such as in the compound of formula I, the definitions of certain groups may be as described below, and the definitions of other groups may be as described in any other embodiment (hereinafter referred to as "a preferred embodiment").

[0041] In a preferred embodiment, in R, in the -(CH2)m-, m can be 1-27, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 14, 15, 23 or 27.

[0042] In a preferred embodiment, in R, the one or more R a In the substituted -(CH2)m-, the plurality is 2-14, for example, 2, 3, 4, 5, 6, 7, 8 or 12.

[0043] In a preferred embodiment, in R, the one or more R a In the substituted -(CH2)m-, the plurality is 2-8, for example, 2, 3, 4, 5, 6, 7 or 8.

[0044] In a preferred embodiment, in R, 0 to 12 -CH2- in the -(CH2)m- are optionally independently replaced by O, S, -NR b -, Sub-C6-C 12 Aryl, C3-C6 cycloalkylene, 1 or more R c Substituted C6-C 12 Aryl and 9,9-diphenylfluorenyl are substituted with 1 to 13 -CH2- in the -(CH2)m- being optionally substituted with O, and m may be 5-36, for example

[0045] In a preferred embodiment, in R, 0 to 10 -CH2- in the -(CH2)m- are optionally replaced by O, S, -NR b -, Sub-C6-C 12 Aryl and 1 or more R c Substituted C6-C 12 Aryl is 1 to 6 -CH2- in the -(CH2)m- optionally substituted by O, and m can be 5-27, for example

[0046] In a preferred embodiment, in R, 0 to 12 -CH2- in the -(CH2)m- are optionally independently replaced by O, S, -NR b -, Sub-C6-C 12 Aryl, C3-C6 cycloalkylene, 1 or more R c Substituted C6-C 12 Aryl and 9,9-diphenylfluorenyl are substituted with 1 to 2 -CH2- in the -(CH2)m-, optionally substituted with S, and m may be 1-6, for example

[0047] In a preferred embodiment, in R, 0 to 10 -CH2- in the -(CH2)m- are optionally replaced by O, S, -NR b -, Sub-C6-C 12 Aryl and 1 or more R c Substituted C6-C 12 Aryl is one to two -CH2- in the -(CH2)m- group optionally substituted by S, and m can be 1-6, for example

[0048] In a preferred embodiment, in R, 0 to 12 -CH2- in the -(CH2)m- are optionally independently replaced by O, S, -NR b -, Sub-C6-C 12 Aryl, C3-C6 cycloalkylene, 1 or more R c Substituted C6-C 12 The aryl and 9,9-diphenylfluorenyl groups are replaced by 1 to 2 -CH2- in the -(CH2)m- group, which are optionally replaced by C6-C 12 Aryl or one or more R c Substituted C6-C 12 Aryl substitution, m can be 1-6, for example

[0049] In a preferred embodiment, in R, 0 to 10 -CH2- in the -(CH2)m- are optionally replaced by O, S, -NR b -, Sub-C6-C 12 Aryl and 1 or more R c Substituted C6-C 12 Aryl is 1 to 2 -CH2- in the -(CH2)m-, optionally replaced by C6-C 12 Aryl and / or 1 or more R c Substituted C6-C 12 Aryl substitution, m can be 1-6, for example

[0050] In a preferred embodiment, in R, 0 to 12 -CH2- in the -(CH2)m- are optionally independently replaced by O, S, -NR b -, Sub-C6-C 12 Aryl, C3-C6 cycloalkylene, 1 or more R c Substituted C6-C 12 The aryl and 9,9-diphenylfluorenyl groups are replaced by 1 to 6 -CH2- in the -(CH2)m- group, which are optionally replaced by O and C6-C 12 Aryl substitution, e.g.

[0051] In a preferred embodiment, in R, 0 to 10 -CH2- in the -(CH2)m- are optionally replaced by O, S, -NR b -, Sub-C6-C 12 Aryl and 1 or more R c Substituted C6-C 12 Aryl is 1 to 6 -CH2- in the -(CH2)m-, optionally replaced by O and C6-C 12 Aryl and / or 1 or more R c Substituted C6-C 12 Aryl substitution, e.g.

[0052] In a preferred embodiment, in R, the sub-C6-C 12 The aryl group is C6-C 10 An aryl group, for example, a phenylene group.

[0053] In a preferred embodiment, R a wherein the C1-C6 alkyl group is a C1-C4 alkyl group, for example, methyl or ethyl.

[0054] In a preferred embodiment, R a wherein the halogen is fluorine, chlorine, bromine or iodine, for example, fluorine.

[0055] In a preferred embodiment, each R a In the C1-C4 heteroalkyl group, the heteroatom type is O, S or N, such as O; the number of heteroatoms can be 2; for example

[0056] In a preferred embodiment, R a wherein the C1-C4 heteroalkyl group is a C4 heteroalkyl group.

[0057] In a preferred embodiment, Rb wherein the C1-C6 alkyl group is a C1-C4 alkyl group, for example, a methyl group or an ethyl group.

[0058] In a preferred embodiment, R b wherein the C1-C6 alkyl group is a C1-C4 alkyl group, for example, a methyl group.

[0059] In a preferred embodiment, R b In the C6-C 12 The aryl group is C6-C 10 An aryl group, for example, a phenyl group.

[0060] In a preferred embodiment, R b In the above, one or more R b1 The C1-C6 alkyl group in the substituted C1-C6 alkyl group is a C1-C4 alkyl group; for example, ethyl.

[0061] In a preferred embodiment, R c wherein the C1-C6 alkyl group is a C1-C4 alkyl group, for example, a methyl group.

[0062] In a preferred embodiment, R c wherein the halogen is fluorine, chlorine, bromine or iodine, for example, fluorine.

[0063] In a preferred embodiment, R 1 In the C1-C 22 The alkyl group is C2-C 20 Alkyl, preferably a straight chain C2-C 20 Alkyl groups, for example,

[0064] In a preferred embodiment, R 1 In the C2-C 22 Alkenyl is C 14 -C 22 Alkenyl, preferably a straight chain C 14 -C 22 Alkenyl, for example,

[0065] In a preferred embodiment, R 1 In the C2-C 22 Alkynyl is a straight-chain C2-C 20 Alkynyl groups, for example,

[0066] In a preferred embodiment, R 1 In the C2-C 22 0 to 8 -CH2- in the alkynyl group are optionally independently replaced by O or S to form the C2-C 220 to 8 -CH2- in the alkynyl group are optionally replaced by O; for example,

[0067] In a preferred embodiment, R 1-1 In the C6-C 12 Aryl is phenyl.

[0068] In a preferred embodiment, R 1-1 wherein the C3-C6 cycloalkyl group is a cyclohexyl group.

[0069] In a preferred embodiment, R 2 In the C1-C 22 The alkyl group is C2-C 20 Alkyl groups, for example,

[0070] In a preferred embodiment, R 2 In the C1-C 22 The alkyl group is C2-C 20 Alkyl, preferably a straight chain C2-C 20 Alkyl groups, for example,

[0071] In a preferred embodiment, R 2 In the C2-C 22 Alkenyl is independently C2-C 22 Alkenyl, preferably a straight chain C2-C 10 Alkenyl, for example,

[0072] In a preferred embodiment, R 2 In the C2-C 22 Alkenyl is C 14 -C 22 Alkenyl, preferably a straight chain C 14 -C 22 Alkenyl, for example,

[0073] In a preferred embodiment, R 2 In the C2-C 22 Alkynyl is a C2-C6 alkynyl, preferably a straight-chain C2-C6 alkynyl, for example,

[0074] In a preferred embodiment, R 2 In the C2-C 22 0 to 8 -CH2- in the alkynyl group are optionally replaced by O or S to form the C2-C 220 to 8 -CH2- in the alkynyl group are optionally replaced by O; for example,

[0075] In a preferred embodiment, R 2 In the above, one or more R 2-1 Substituted C1-C 22 The alkyl group may be separated by an R 2-1 Substituted C1-C6 alkyl, for example,

[0076] In a preferred embodiment, R 2 In the above, one or more R 2-1 Substituted C1-C 22 The alkyl group may be separated by an R 2-1 Substituted C3-C6 alkyl, for example,

[0077] In a preferred embodiment, R 2 wherein the C3-C6 cycloalkyl group is a cyclohexyl group.

[0078] In a preferred embodiment, R 2 wherein the heteroatom in the 3-7 membered heterocycloalkyl group is N or O; for example,

[0079] In a preferred embodiment, R 2-1 In the C6-C 12 Aryl is phenyl.

[0080] In a preferred embodiment, R 2-1 In the above, one or more R 2d3 Substituted C6-C 12 Aryl is an aryl group consisting of one or more R 2d3 Substituted C6-C 12 Aryl; for example,

[0081] In a preferred embodiment, R 2-1 wherein the C3-C6 cycloalkyl group is a cyclohexyl group.

[0082] In a preferred embodiment, R 2-1 In the above, the “5-10 membered heteroaryl group having one, two or three heteroatoms selected from N, O and S, and having one, two or three heteroatoms” is a 5-membered heteroaryl group substituted by O, for example,

[0083] In a preferred embodiment, R 2d3 wherein the halogen is fluorine, chlorine, bromine or iodine, for example, bromine.

[0084] In a preferred embodiment, R 2f wherein the C1-C6 alkyl group is independently a C1-C4 alkyl group; for example, methyl.

[0085] In a preferred embodiment, in the halogenated C1-C6 alkyl group, the halogenated group is halogen substituted, and the halogen is fluorine, chlorine, bromine or iodine; and the C1-C6 alkyl group is a C1-C4 alkyl group.

[0086] In a preferred embodiment, R 3 In the C1-C 22 The alkyl group may be a C1-C6 alkyl group, for example,

[0087] In a preferred embodiment, R 3 In the C1-C 22 The alkyl group may be a C1-C4 alkyl group, for example,

[0088] In a preferred embodiment, R 3 In the C2-C 22 Alkenyl is C2-C4 alkenyl, for example,

[0089] In a preferred embodiment, R 3 In the above, one or more R 3-1 Substituted C1-C 22 The alkyl group may be separated by an R 3-1 Substituted C1-C3 alkyl, for example,

[0090] In a preferred embodiment, R 3-1 In the embodiment, the C3-C6 cycloalkyl group may be

[0091] In a preferred embodiment, n is 5-12.

[0092] In a preferred embodiment, n may be 8-11.

[0093] In a preferred embodiment, R is -(CH2)m- or is replaced by one or more R a Substituted -(CH2)m-; 0 to 12 -CH2- in said -(CH2)m- are optionally replaced by O, S, C6-C 12 Aryl, 1 or more R c Substituted C6-C 12 Aryl and 9,9-diphenylfluorenyl are substituted, m is 1-27, for example, Preferably, R is -(CH2)m- or is replaced by one or more R a Substituted -(CH2)m-; said -(CH2)m- satisfies any of the following conditions: (1) 1 to 12 -CH2- in -(CH2)m- are optionally replaced by O; (2) 1 to 6 -CH2- in said -(CH2)m- are optionally replaced independently by O and C6-C 12 Aryl substitution; for example, R is For example, R is For example, R is

[0094] In a preferred embodiment, R is -(CH2)m-, and 0 -CH2- in said -(CH2)m- are substituted.

[0095] In a preferred embodiment, R is -(CH2)m- or is replaced by one or more R a Substituted -(CH2)m-; 0 to 10 -CH2- in said -(CH2)m- are optionally replaced by O, S, C6-C 12 Aryl and 1 or more R c Substituted C6-C 12 Aryl substituted, m is 1-27, for example, Preferably, R is -(CH2)m- or is replaced by 1-4 R a Substituted -(CH2)m-; 0 to 4 -CH2- in said -(CH2)m- are optionally replaced by O and C6-C 12 Aryl substituted, m is 3-11; for example, For example, For example, Further example,

[0096] In a preferred embodiment, each R a are independently hydroxyl, C1-C6 alkyl, halogen or C1-C4 heteroalkyl; the heteroatom species in the C1-C4 heteroalkyl is O, S or N, and the number of heteroatoms is 1, 2 or 3; preferably, each R a are independently hydroxy or C1-C6 alkyl.

[0097] In a preferred embodiment, each R c are independently nitro or C1-C6 alkyl.

[0098] In a preferred embodiment, R 1C1-C 22 Alkyl, C2-C 22 Alkenyl, C2-C 22 Alkynyl or one or more R 1-1 Substituted C1-C 22 Alkyl, the C2-C 22 0 to 5 -CH2- in the alkynyl group are optionally substituted by O; for example, Preferably, R 1 C8-C 18 Alkyl, C3-C 18 Alkenyl, C3-C 18 Alkynyl or one or more R 1-1 Substituted C1-C6 alkyl, the C2-C 22 0 to 5 -CH2- in the alkynyl group are optionally substituted by O; for example, More preferably, R 1 C8-C 18 Alkyl groups, such as R 1 for For example, R 1 for

[0099] In a preferred embodiment, R 1 C1-C 22 Alkyl or C2-C 22 Alkenyl, for example, Preferably, R 1 C8-C 18 Alkyl groups, e.g.

[0100] In a preferred embodiment, each R 1-1 -NR b R b , hydroxyl, C6-C 12 Aryl or C3-C6 cycloalkyl.

[0101] In a preferred embodiment, R 2 C1-C 22 Alkyl, C2-C 22 Alkenyl, C2-C 22 Alkynyl, one or more R 2-1 Substituted C1-C 22Alkyl, C3-C6 cycloalkyl, "heteroatoms selected from 1, 2 or 3 of N, O and S, 3-7 membered heterocycloalkyl" or one or more R 2f The substituted "heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3 3-membered heterocycloalkyl", the C2-C 22 0 to 5 -CH2- in the alkynyl group are optionally substituted by O; for example, Preferably, R 2 C1-C 18 Alkyl, C3-C 18 Alkenyl, C3-C 18 Alkynyl, with an R 2-1 Substituted C1-C6 alkyl, C3-C6 cycloalkyl, "3-7 membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from N, O and S" or substituted by one or more R 2f The substituted "heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3 3-membered heterocycloalkyl", the C2-C 22 0 to 5 -CH2- in the alkynyl group are optionally substituted by O; for example, More preferably, R 2 C1-C 22 Alkyl or one or more R 2-1 Substituted C1-C 22 Alkyl, each R 2-1 are independently hydroxyl.

[0102] In a preferred embodiment, R 2 C1-C 22 Alkyl, C2-C 22 Alkenyl or one or more R 2-1 Substituted C1-C 22 Alkyl groups, for example, Preferably, R 2 C4-C 18 Alkyl or an R 2- 1 Substituted C1-C5 alkyl groups, for example,

[0103] In a preferred embodiment, R 2-1 -NR b Rb , hydroxyl, C6-C 12 Aryl, one or more R 2d3 Substituted C6-C 12 Aryl, C3-C6 cycloalkyl or "a 5-10 membered heteroaryl group in which the heteroatoms are 1, 2 or 3 selected from the group consisting of N, O and S".

[0104] In a preferred embodiment, R 2-1 -NR b R b or hydroxyl groups.

[0105] In a preferred embodiment, each R b are independently hydrogen, C1-C6 alkyl, C6-C 12 Aryl or one or more R b1 Substituted C1-C6 alkyl.

[0106] In a preferred embodiment, each R b are independently hydrogen or C1-C6 alkyl.

[0107] In a preferred embodiment, each R 2d3 are independently halogen.

[0108] In a preferred embodiment, each R 2e and R 2f are independently C1-C6 alkyl.

[0109] In a preferred embodiment, X is For example, X is

[0110] In a preferred embodiment, X is Preferably, X is

[0111] In a preferred embodiment, R 3 is hydrogen, C1-C 22 Alkyl, one or more R 3-1 Substituted C1-C 22 Alkyl or C2-C 22 Alkenyl, for example, hydrogen, Preferably, R 3 is hydrogen, C1-C 22 Alkyl or C2-C 22 Alkenyl, for example, hydrogen,

[0112] In a preferred embodiment, R 3 is hydrogen, C1-C 22 Alkyl or one or more R 3-1 Substituted C1-C22 Alkyl groups, for example, For example, R 3 For hydrogen.

[0113] In a preferred embodiment, R 3-1 It is a C3-C6 cycloalkyl group.

[0114] In a preferred embodiment, n is 5-15, for example 8-15.

[0115] In a preferred embodiment, n is 5-12.

[0116] In a preferred embodiment, R is -(CH2)m- or is replaced by one or more R a Substituted -(CH2)m-; 0 to 12 -CH2- in said -(CH2)m- are optionally independently replaced by O, and m is 1-19, for example, For example, Preferably, R is -(CH2)m-; m is 1-6, for example, For example,

[0117] In a preferred embodiment, R is -(CH2)m-, wherein 0 to 3 -CH2- in said -(CH2)m- are optionally replaced by O, and m is 1-12; for example,

[0118] In a preferred embodiment, each R a are independently C1-C6 alkyl.

[0119] In a preferred embodiment, R is -(CH2)m- or is replaced by 1-4 R a Substituted -(CH2)m-; 0 to 4 -CH2- in said -(CH2)m- are optionally replaced by O and C6-C 12 Aryl substituted, m is 3-11; for example, For example,

[0120] In a preferred embodiment, R is -(CH2)m-; 0 to 3 -CH2- in said -(CH2)m- are optionally substituted by O, and m is 4-11; for example, For example,

[0121] In a preferred embodiment, R is -(CH2)m-; 0 to 3 -CH2- in said -(CH2)m- are optionally substituted by O, and m is 4-11; for example,

[0122] In a preferred embodiment, R 1 C1-C 22 Alkyl or C2-C 22 alkenyl; for example, For example, Further, for example, More example,

[0123] In a preferred embodiment, R 1 C 10 -C 16 Alkyl groups, for example,

[0124] In a preferred embodiment, R 2 C1-C 22 Alkyl, C2-C 22 Alkenyl, C2-C 22 Alkynyl, with an R 2-1 Substituted C1-C6 alkyl, C3-C6 cycloalkyl, "3-7 membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from N, O and S" or substituted by one or more R 2f Substituted "3-7 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S"; for example, Better, R 2 C1-C 12 Alkyl, C2-C 22 Alkenyl, C2-C 22 Alkynyl, with an R 2-1 Substituted C1-C6 alkyl, C3-C6 cycloalkyl or "a 3-7 membered heterocycloalkyl group wherein the heteroatoms are 1, 2 or 3 selected from N, O and S"; for example, For example,

[0125] In a preferred embodiment, R2 C1-C 22 Alkyl, C2-C 22 Alkenyl, C2-C 22 Alkynyl, with an R 2-1 Substituted C1-C 22 Alkyl, C3-C6 cycloalkyl or one or more R 2f Substituted "3-7 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S"; for example,

[0126] In a preferred embodiment, R 2 C1-C 22 Alkyl, C2-C 22 Alkenyl, with an R 2-1 Substituted C1-C6 alkyl or one or more R 2f Substituted "3-7 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S"; for example,

[0127] In a preferred embodiment, R 2 C1-C 22 Alkyl, C2-C 22 Alkenyl or one or more R 2-1 Substituted C1-C 22 Alkyl; for example,

[0128] In a preferred embodiment, R 2-1 -NR b R b , hydroxyl, C6-C 12 Aryl, one or more R 2d3 Substituted C6-C 12 Aryl or "a 5-10 membered heteroaryl group wherein the heteroatom is selected from 1, 2 or 3 of N, O and S"; for example, -NR b R b , hydroxyl, C6-C 12 Aryl or one or more R 2d3 Substituted C6-C 12 Aryl; also for example, -NR b R b .

[0129] In a preferred embodiment, each R b are independently C1-C6 alkyl.

[0130] In a preferred embodiment, R 2 C4-C 16 Alkyl or an R 2-1 Substituted C1-C5 alkyl groups, for example, For example,

[0131] In a preferred embodiment, R 2-1 It is a hydroxyl group.

[0132] In a preferred embodiment, R 2 C4-C 16 Alkyl or an R 2-1 Substituted C1-C5 alkyl groups, for example,

[0133] In a preferred embodiment, n is 8-9.

[0134] In a preferred embodiment, R is -(CH2)m-; m is 4-6; for example,

[0135] In a preferred embodiment, R 1 C 14 -C 16 Alkyl groups, for example,

[0136] In a preferred embodiment, R 2 C4-C 16 Alkyl or an R 2-1 Substituted C1-C5 alkyl groups, for example, For example, For example,

[0137] In a preferred embodiment, n is 9-10.

[0138] In a preferred embodiment, R is -(CH2)m-; 0 to 3 -CH2- in said -(CH2)m- are optionally substituted by O, and m is 4-11; for example,

[0139] In a preferred embodiment, R 1 C8-C 12 Alkyl groups, for example,

[0140] In a preferred embodiment, R 2 C4-C 10Alkyl or an R 2-1 Substituted C1-C5 alkyl groups, for example, For example,

[0141] In a preferred embodiment, the weight average molecular weight of the compound represented by Formula I is 1000-10000.

[0142] In a preferred embodiment,

[0143] R is -(CH2)m-, m is 1-6; for example,

[0144] R 1 C8-C 18 Alkyl groups, such as R 1 for

[0145] In one plan,

[0146] R is -(CH2)m-, wherein 0 to 6 -CH2- in said -(CH2)m- are optionally independently replaced by O, and m is 8-14, for example,

[0147] R 1 C8-C 18 Alkyl groups, such as R 1 for

[0148] In one scheme, n is 8-11;

[0149] R is -(CH2)m- or is replaced by one or more R a Substituted -(CH2)m-; 0 to 10 -CH2- in said -(CH2)m- are optionally replaced by O, S, C6-C 12 Aryl and 1 or more R c Substituted C6-C 12 Aryl substituted, m is 1-27, for example,

[0150] Each R a are independently hydroxyl, C1-C6 alkyl, halogen or C1-C4 heteroalkyl; the heteroatom species in the C1-C4 heteroalkyl is O, S or N, and the number of heteroatoms is 1, 2 or 3;

[0151] Each R c are independently nitro or C1-C6 alkyl;

[0152] R 1C1-C 22 Alkyl or C2-C 22 Alkenyl, for example,

[0153] R 2 C1-C 22 Alkyl, C2-C 22 Alkenyl or one or more R 2-1 Substituted C1-C 22 Alkyl groups, for example,

[0154] R 2-1 -NR b R b or hydroxyl;

[0155] Each R b are independently hydrogen or C1-C6 alkyl;

[0156] X is

[0157] R 3 is hydrogen, C1-C 22 Alkyl or one or more R 3-1 Substituted C1-C 22 Alkyl groups, for example,

[0158] R 3-1 is a C3-C6 cycloalkyl group;

[0159] Preferably, the weight average molecular weight of the compound represented by Formula I is 2030-5460, preferably 2600-4200, for example, 2600, 2700, 2900, 3000, 3100, 3400, 3500, 4100 or 4200.

[0160] In one scheme, n is 8-11;

[0161] R is -(CH2)m- or is replaced by 1-4 R a Substituted -(CH2)m-; 0 to 4 -CH2- in said -(CH2)m- are optionally replaced by O and C6-C 12 Aryl substituted, m is 3-11; for example,

[0162] Each R a are independently hydroxy or C1-C6 alkyl;

[0163] R1 C8-C 18 Alkyl groups, for example,

[0164] R 2 C4-C 18 Alkyl or an R 2-1 Substituted C1-C5 alkyl groups, for example,

[0165] R 2-1 -NR b R b or hydroxyl;

[0166] Each R b are independently hydrogen or C1-C6 alkyl;

[0167] X is

[0168] R 3 is hydrogen;

[0169] Preferably, the weight average molecular weight of the compound represented by Formula I is 2030-5460, preferably 2600-4200, for example, 2600, 2700, 2900, 3000, 3100, 3400, 3500, 4100 or 4200.

[0170] In one scheme, n is 8-11;

[0171] R is -(CH2)m- or is replaced by 1-4 R a Substituted -(CH2)m-; 0 to 4 -CH2- in said -(CH2)m- are optionally replaced by O and C6-C 12 Aryl substituted, m is 3-11; for example,

[0172] Each R a are independently hydroxy or C1-C6 alkyl;

[0173] R 1 C8-C 18 Alkyl groups, for example,

[0174] R 2 C4-C 18 Alkyl or an R 2-1 Substituted C1-C5 alkyl groups, for example,

[0175] R2-1 -NR b R b or hydroxyl;

[0176] Each R b are independently hydrogen or C1-C6 alkyl;

[0177] X is

[0178] R 3 is hydrogen;

[0179] Preferably, the weight average molecular weight of the compound represented by Formula I is 1890-5330, preferably 2700-4100, for example, 2700, 3100, 3500 or 4100.

[0180] In one scheme, n is 8-11;

[0181] R is -(CH2)m- or is replaced by 1-4 R a Substituted -(CH2)m-; 0 to 4 -CH2- in said -(CH2)m- are optionally replaced by O and C6-C 12 Aryl substituted, m is 3-11; for example,

[0182] Each R a are independently hydroxy or C1-C6 alkyl;

[0183] R 1 C8-C 18 Alkyl groups, for example,

[0184] R 2 C4-C 18 Alkyl or an R 2-1 Substituted C1-C5 alkyl groups, for example,

[0185] R 2-1 -NR b R b or hydroxyl;

[0186] Each R b are independently hydrogen or C1-C6 alkyl;

[0187] X is

[0188] R 3 is hydrogen;

[0189] Preferably, the weight average molecular weight of the compound represented by Formula I is 1890-4550, preferably 2700-3500, for example, 2700, 3100 or 3500.

[0190] In one scheme, n is 8-11;

[0191] R is -(CH2)m- or is replaced by 1-4 R a Substituted -(CH2)m-; 0 to 4 -CH2- in said -(CH2)m- are optionally replaced by O and C6-C 12 Aryl substituted, m is 3-11; for example,

[0192] Each R a are independently hydroxy or C1-C6 alkyl;

[0193] R 1 C8-C 18 Alkyl groups, for example,

[0194] R 2 C4-C 18 Alkyl or an R 2-1 Substituted C1-C5 alkyl groups, for example,

[0195] R 2-1 -NR b R b or hydroxyl;

[0196] Each R b are independently hydrogen or C1-C6 alkyl; X is

[0197] R 3 For hydrogen.

[0198] In one plan,

[0199] n is 8-11;

[0200] R is -(CH2)m- or is replaced by 1-4 R a Substituted -(CH2)m-; 0 to 4 -CH2- in said -(CH2)m- are optionally replaced by O and C6-C 12 Aryl substituted, m is 3-11; for example,

[0201] Each R a are independently hydroxy or C1-C6 alkyl;

[0202] R 1 C8-C 18 Alkyl groups, for example,

[0203] R 2 C4-C 18 Alkyl or an R 2-1 Substituted C1-C5 alkyl groups, for example,

[0204] R 2-1 -NR b R b or hydroxyl;

[0205] Each R b are independently hydrogen or C1-C6 alkyl;

[0206] X is

[0207] R 3 is hydrogen;

[0208] Preferably, the weight average molecular weight of the compound of Formula I is 2030-5460, preferably 2600-4200, for example, 2600, 2700, 2900, 3000, 3100, 3400, 3500 or 4200.

[0209] In one scheme, n is 8-11;

[0210] R is -(CH2)m- or is replaced by 1-4 R a Substituted -(CH2)m-; 0 to 4 -CH2- in said -(CH2)m- are optionally replaced by O and C6-C 12 Aryl substituted, m is 3-11; for example,

[0211] Each R a are independently hydroxy or C1-C6 alkyl;

[0212] R 1 C8-C 18 Alkyl groups, for example,

[0213] R 2 C4-C 18 Alkyl or an R 2-1 Substituted C1-C5 alkyl groups, for example,

[0214] R 2-1 -NR b R b or hydroxyl;

[0215] Each R b are independently hydrogen or C1-C6 alkyl;

[0216] X is

[0217] R 3 is hydrogen;

[0218] Preferably, the weight average molecular weight of the compound represented by Formula I is 2030-5460, preferably 2600-4200, for example, 2600, 2900, 3000, 3100, 3400 or 4200.

[0219] In one scheme, n is 8-11;

[0220] R is -(CH2)m-; 0 to 3 -CH2- in said -(CH2)m- are optionally substituted by O, and m is 4-11; for example,

[0221] R 1 C8-C 18 Alkyl groups, for example,

[0222] R 2 C4-C 18 Alkyl or an R 2-1 Substituted C1-C5 alkyl groups, for example,

[0223] R 2-1 -NR b R b or hydroxyl;

[0224] Each R b are independently hydrogen or C1-C6 alkyl;

[0225] X is

[0226] R 3 is hydrogen;

[0227] Preferably, the weight average molecular weight of the compound represented by Formula I is 1890-5330, preferably 2700-4100, for example, 2700, 3100, 3500 or 4100.

[0228] In one scheme, n is 8-11;

[0229] R is -(CH2)m-; 0 to 3 -CH2- in said -(CH2)m- are optionally substituted by O, and m is 4-11; for example,

[0230] R 1 C8-C 18 Alkyl groups, for example,

[0231] In a preferred embodiment, R 2 C4-C 18 Alkyl or an R 2-1 Substituted C1-C5 alkyl groups, for example,

[0232] R 2-1 -NR b R b or hydroxyl;

[0233] Each R b are independently hydrogen or C1-C6 alkyl;

[0234] X is

[0235] R 3 is hydrogen;

[0236] Preferably, the weight average molecular weight of the compound represented by Formula I is 1890-4500, preferably 2700-3500, for example, 2700, 3100 or 3500.

[0237] In one scheme, n is 8-10;

[0238] R is -(CH2)m-; 0 to 3 -CH2- in said -(CH2)m- are optionally substituted by O, and m is 4-11; for example,

[0239] R 1 C 10 -C 16 Alkyl groups, for example,

[0240] R 2 C4-C 16 Alkyl or an R 2-1 Substituted C1-C5 alkyl groups, for example,

[0241] R 2-1 -NR b R b or hydroxyl;

[0242] Each R b are independently hydrogen or C1-C6 alkyl;

[0243] X is

[0244] R 3 is hydrogen;

[0245] Preferably, the weight average molecular weight of the compound represented by Formula I is 2450-5330, preferably 3500-4100, for example, 3500 or 4100.

[0246] In one scheme, n is 8-10;

[0247] R is -(CH2)m-; 0 to 3 -CH2- in said -(CH2)m- are optionally substituted by O, and m is 4-11; for example,

[0248] R 1 C 10 -C 16 Alkyl groups, for example,

[0249] R 2 C4-C 16 Alkyl or an R 2-1 Substituted C1-C5 alkyl groups, for example,

[0250] R 2-1 is hydroxyl group;

[0251] X is

[0252] R 3 is hydrogen;

[0253] Preferably, the weight average molecular weight of the compound represented by Formula I is 2450-5330, preferably 3500-4100, for example, 3500 or 4100.

[0254] In one scheme, n is 8-10;

[0255] R is -(CH2)m-; 0 to 3 -CH2- in said -(CH2)m- are optionally substituted by O, and m is 4-11; for example,

[0256] R1 C 10 -C 16 Alkyl groups, for example,

[0257] R 2 C4-C 16 Alkyl or an R 2-1 Substituted C1-C5 alkyl groups, for example,

[0258] R 2-1 -NR b R b or hydroxyl;

[0259] Each R b are independently C1-C6 alkyl;

[0260] X is

[0261] R 3 is hydrogen;

[0262] Preferably, the weight average molecular weight of the compound represented by Formula I is 2450-5330, preferably 3500-4100, for example, 3500 or 4100.

[0263] In one scheme, n is 8-9;

[0264] R is -(CH2)m-; m is 4-6; for example,

[0265] R 1 C 14 -C 16 Alkyl groups, for example,

[0266] R 2 C4-C 16 Alkyl or an R 2-1 Substituted C1-C5 alkyl groups, for example,

[0267] R 2-1 -NR b R b or hydroxyl;

[0268] Each R b are independently hydrogen or C1-C6 alkyl;

[0269] X is

[0270] R 3 is hydrogen;

[0271] Preferably, the weight average molecular weight of the compound represented by Formula I is 2450-4550, for example, 3500.

[0272] In one scheme, n is 8-9;

[0273] R is -(CH2)m-; m is 4-6; for example,

[0274] R 1 C 14 -C 16 Alkyl groups, for example,

[0275] R 2 C4-C 16 Alkyl or an R 2-1 Substituted C1-C5 alkyl groups, for example,

[0276] R 2-1 -NR b R b or hydroxyl;

[0277] Each R b are independently hydrogen or C1-C6 alkyl;

[0278] X is

[0279] R 3 is hydrogen;

[0280] Preferably, the weight average molecular weight of the compound represented by Formula I is 2450-4550, for example, 3500.

[0281] In one scheme, n is 8-9;

[0282] R is -(CH2)m-; m is 4-6; for example,

[0283] R 1 C 14 -C 16 Alkyl groups, for example,

[0284] R 2 C4-C 16 Alkyl or an R 2-1 Substituted C1-C5 alkyl groups, for example,

[0285] R 2-1 is hydroxyl group;

[0286] Rb is hydrogen;

[0287] X is

[0288] R 3 is hydrogen;

[0289] Preferably, the weight average molecular weight of the compound represented by Formula I is 2450-4550, for example, 3500.

[0290] In one scheme, n is 9-10;

[0291] R is -(CH2)m-; 0 to 3 -CH2- in said -(CH2)m- are optionally substituted by O, and m is 4-11; for example,

[0292] R 1 C8-C 12 Alkyl groups, for example,

[0293] R 2 C4-C 10 Alkyl or an R 2-1 Substituted C1-C5 alkyl groups, for example,

[0294] R 2-1 -NR b R b or hydroxyl;

[0295] Each R b are independently hydrogen or C1-C6 alkyl; X is

[0296] R 3 is hydrogen;

[0297] Preferably, the weight average molecular weight of the compound represented by Formula I is 2870-5330, for example, 4100.

[0298] In one scheme, n is 9-10;

[0299] R is -(CH2)m-; 0 to 3 -CH2- in said -(CH2)m- are optionally substituted by O, and m is 4-11; for example,

[0300] R 1 C8-C 12 Alkyl groups, for example,

[0301] R 2 C4-C10 Alkyl groups, for example,

[0302] X is

[0303] R 3 is hydrogen;

[0304] Preferably, the weight average molecular weight of the compound represented by Formula I is 2870-5330, for example, 4100.

[0305] In a preferred embodiment, the compound represented by Formula I or a pharmaceutically acceptable salt thereof is any one of the compounds in the following table:

[0306] In a preferred embodiment, the compound represented by Formula I or a pharmaceutically acceptable salt thereof is any one of the compounds listed in Table 1:

[0307] Table 1

[0308] The present invention also provides a blank polymer-lipid nanoparticle, which includes an ionizable polymer PBAE, wherein the ionizable polymer PBAE is the compound shown in Formula I as described above or a pharmaceutically acceptable salt thereof.

[0309] In a preferred embodiment, the blank polymer-lipid nanoparticles further comprise a diluent, which can be an organic phase or an aqueous phase.

[0310] In a preferred embodiment, in the diluent, the organic phase can be selected from ethanol, acetone, tetrahydrofuran, acetonitrile, etc. that are miscible with water, preferably ethanol; the aqueous phase can be selected from sodium citrate buffer with pH=3 or sodium acetate buffer with pH=5, preferably sodium acetate.

[0311] In a preferred embodiment, in the diluent, the volume ratio of the organic phase to the aqueous phase may be 1:1-1:3, preferably 1:2 and 1:3.

[0312] In a preferred embodiment, the blank polymer-lipid nanoparticles further include auxiliary phospholipids.

[0313] In a preferred embodiment, the auxiliary phospholipid may be DSPC, DOPE, DOPC, DSPE and derivatives thereof, preferably DOPE.

[0314] In a preferred embodiment, the blank polymer-lipid nanoparticles further include sterol.

[0315] In a preferred embodiment, the sterol may be cholesterol and its derivatives, preferably cholesterol.

[0316] In a preferred embodiment, the blank polymer-lipid nanoparticles further comprise a lipid that inhibits particle aggregation. In a preferred embodiment, the lipid that inhibits particle aggregation can be polyethylene glycol and its derivatives, preferably DMG-PEG.

[0317] In a preferred embodiment, the molar ratio of the ionizable polymer PBAE to the auxiliary phospholipid is 1:0.03-2.5, preferably 1:1 or 1:0.48.

[0318] In a preferred embodiment, the molar ratio of the ionizable polymer PBAE to sterol is 1:0.67-6.5, preferably 1:2 or 1:2.40.

[0319] In a preferred embodiment, the molar ratio of the ionizable polymer PBAE to the particle aggregation inhibiting lipid is 1:0.01-1, preferably 1:0.20 or 1:0.12.

[0320] In the present invention, the molar ratio means the percentage of a substance in the mass of the ionizable polymer PBAE substance, and the sum of the molar contents of each component in the blank polymer-lipid nanoparticles does not exceed 100 mol%.

[0321] In a preferred embodiment, the blank polymer-lipid nanoparticles are composed of the ionizable polymer PBAE and common lipids, wherein the common lipids are auxiliary phospholipids, sterols and lipids that inhibit particle aggregation.

[0322] In a preferred embodiment, the blank polymer-lipid nanoparticles are composed of the ionizable polymer PBAE, DOPE, cholesterol and DMG-PEG, and the molar ratios of the ionizable polymer PBAE, DOPE, cholesterol and DMG-PEG are 23.8:23.8:47.6:4.8 and 25:12:60:3.

[0323] The present invention also provides a nucleic acid drug polymer-lipid nanoparticle, which comprises a nucleic acid drug and the aforementioned blank polymer-lipid nanoparticle.

[0324] In a preferred embodiment, the nucleic acid drug may be a conventional nucleic acid molecule in the art, and the nucleic acid molecule may be mRNA, saRNA, cirRNA, miRNA, shRNA, siRNA, dsDNA, pDNA, preferably mRNA.

[0325] In a preferred embodiment, the N / P ratio of the ionizable polymer PBAE and the nucleic acid molecule may be 5:1-50:1, preferably 25:1, 12.5:1 or 21:1.

[0326] In a preferred embodiment, the nucleic acid drug polymer-lipid nanoparticles further include a diluent, which can be an organic phase or an aqueous phase.

[0327] In a preferred embodiment, in the diluent, the organic phase can be selected from ethanol, acetone, tetrahydrofuran, acetonitrile, etc. that are miscible with water, preferably ethanol; the aqueous phase can be selected from sodium citrate buffer with pH=3 or sodium acetate buffer with pH=5, preferably sodium acetate.

[0328] In a preferred embodiment, in the diluent, the volume ratio of the organic phase to the aqueous phase may be 1:1-1:3.

[0329] The present invention provides a use of an ionizable polymer (PBAE) in preparing a delivery system, wherein the ionizable polymer (PBAE) is a compound represented by Formula I or a pharmaceutically acceptable salt thereof, and the delivery system is a system for delivering a therapeutic and / or prophylactic agent to the lungs and / or liver; the therapeutic and / or prophylactic agent is a nucleic acid drug.

[0330] In a preferred embodiment, the delivery is targeted delivery.

[0331] In a preferred embodiment, the delivery system is the blank polymer-lipid nanoparticles described above.

[0332] In a preferred embodiment, the ionizable polymer PBAE, blank polymer-lipid nanoparticles and nucleic acid drug are as described above.

[0333] The present invention provides a use of an ionizable polymer PBAE as a pharmaceutical excipient, wherein the ionizable polymer PBAE is a compound as shown in Formula I or a pharmaceutically acceptable salt thereof, and the functions of the pharmaceutical excipient include nucleic acid encapsulation, lung and / or liver targeted delivery, and promotion of effective cellular uptake or lysosomal escape.

[0334] The present invention provides a use of a composition A in preparing a delivery system or preparing a drug for treating and / or preventing a disease, wherein the disease is a lung or / and liver-related disease. The composition nucleic acid drug polymer-lipid nanoparticle includes an ionizable polymer PBAE, and the ionizable polymer PBAE is a compound shown in Formula I or a pharmaceutically acceptable salt thereof. The delivery system is as described above.

[0335] In a preferred embodiment, the composition A further comprises one or more of auxiliary phospholipids, sterols, lipids that inhibit particle aggregation and / or nucleic acid drugs, and the auxiliary phospholipids, sterols, lipids that inhibit particle aggregation and / or nucleic acid drugs in the composition A are as described above.

[0336] In a preferred embodiment, in the composition A, the ionizable polymer PBAE forms blank polymer-lipid nanoparticles as described above with one or more of the auxiliary phospholipids, sterols, and lipids that inhibit particle aggregation.

[0337] In a preferred embodiment, in the composition A, the blank polymer-lipid nanoparticles and the nucleic acid drug form the nucleic acid drug polymer-lipid nanoparticles as described above.

[0338] In a preferred embodiment, in the composition A, the average particle size of the blank polymer-lipid nanoparticles of the composition may be 30-200 nm, and the surface potential may be -20-+20 mV.

[0339] In a preferred embodiment, in the composition A, the average particle size of the nucleic acid drug polymer-lipid nanoparticles in the composition may be 50-300 nm, and the surface potential may be -20-+20 mV.

[0340] In the present invention, the -CH2- in the -(CH2)m- is optionally independently substituted, which has the same meaning as the -CH2- in (CH2)m- is optionally independently replaced; both represent that -CH2- is replaced.

[0341] Unless otherwise specified, the terms used in this invention have the following meanings:

[0342] The term "pharmaceutically acceptable" means relatively non-toxic, safe, and suitable for use by patients.

[0343] The term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable acid or base. When the compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, bismuth salts, and ammonium salts. When the compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochlorides, sulfates, and methanesulfonates. For details, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, Camille G. Wermuth, 2011, 2nd Revised Edition).

[0344] In the structure fragment It means that the structural fragment is connected to the rest of the molecule through this site.

[0345] A "-" at the end of a group means that the group is attached to the rest of the molecule through that site.

[0346] The term "alkyl" refers to a group having a specified number of carbon atoms (e.g., C1 to C 22 Examples of the alkyl group include, but are not limited to, ethyl, propyl, and butyl.

[0347] The term "alkenyl" refers to a linear or branched monovalent hydrocarbon radical (e.g., C2 to C4) of two to twenty-two carbon atoms having at least one unsaturated site, i.e., a carbon-carbon sp2 double bond. 22 Examples of which include, but are not limited to: wait.

[0348] The term "alkynyl" refers to a straight or branched monovalent hydrocarbon radical of two to twenty-two carbon atoms having at least one site of unsaturation, ie, a carbon-carbon sp triple bond.

[0349] The term "cycloalkyl" refers to a monovalent hydrocarbon group that is monocyclic or polycyclic (e.g., cyclic, spirocyclic or bridged) in which each carbon atom is saturated, and the C1 to C6 cycloalkyl group can be specifically a 3-, 4-, 5- or 6-membered cycloalkyl group, including cyclopropyl, cyclobutyl, cyclopentyl, etc.

[0350] The term "cycloalkylene" refers to a divalent group that is attached to the rest of the molecule by two single bonds, and otherwise has the same meaning as the term "cycloalkyl".

[0351] The term "heteroalkyl" refers to a group in which at least one carbon atom in an alkyl group is replaced by a heteroatom selected from N, O and S. The C1-C4 heteroalkyl group may specifically be a 1-, 2-, 3- or 4-membered heteroalkyl group.

[0352] The term "heterocycloalkyl" refers to a group in which at least one carbon atom in a cycloalkyl group is replaced by a heteroatom selected from N, O and S. The 3-7 membered heterocycloalkyl group may specifically be a 3-, 4-, 5-, 6- or 7-membered heterocycloalkyl group.

[0353] The term "aryl" refers to an aromatic carbon ring, wherein each ring is aromatic, C6 to C 12 Specifically, the aromatic ring may be a benzene ring or a naphthalene ring.

[0354] The term "arylene" refers to a divalent group connected to the rest of the molecule by two single bonds, and the rest is the same as the definition of the term "aryl".

[0355] On the basis of conforming to the common sense in this field, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0356] The reagents and raw materials used in the present invention are commercially available.

[0357] The positive improvement effect of the present invention is that the poly (β-amino) lipid compound of the present invention has at least any of the following advantages over the existing PBAE: (1) higher efficacy, (2) higher targeting and (3) higher safety. BRIEF DESCRIPTION OF THE DRAWINGS

[0358] FIG1 shows the body weight changes within 7 days after administration of 1C16X in Example 33;

[0359] FIG2 shows the body weight changes within 7 days after administration of 3C10X in Example 33. DETAILED DESCRIPTION

[0360] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0361] The present invention synthesizes the aforementioned compound of formula I by the following general reaction formula. The naming rule of the compound of formula I is as follows: the compound is abbreviated and named according to the structure number of the synthesized main chain B, side chain S and end cap E monomer (for example: the product obtained by the polymerization reaction of B1 main chain, S selected as C12 amine side chain and E selected as NH2 end cap group is named "1C12NH2").

[0362] Reaction Formula I

[0363] Main chain B and side chain S were added in a 1.1:1 ratio and reacted solvent-free at 65-90°C overnight, with the reaction monitored by H-NMR spectroscopy. After reaching the target degree of polymerization, heating was stopped, and B and S were dissolved in THF at a concentration of 200 mg / mL. A 10-fold equivalent of end-capping agent E was added and allowed to react at room temperature for 24 hours. After the end-capping reaction was complete, the polymer was precipitated using diethyl ether or ethanol and washed twice to obtain the product.

[0364] Where B is

[0365] Where S is

[0366] Where E is

[0367] The blank polymer-lipid nanoparticles disclosed in the present invention contain an ionizable polymer and common lipids, and are characterized by having an average particle size of 30-200 nm and a surface potential of -20-+20 mV. The ionizable polymer is PBAE, and the common lipids are divided into three types: auxiliary phospholipids, sterols, and lipids that inhibit particle aggregation.

[0368] The four components of blank polymer-lipid nanoparticles include:

[0369] a) Ionizable polymer PBAE

[0370] b) Auxiliary phospholipids: DSPC, DOPE, DOPC, DSPE and their derivatives, preferably DOPE

[0371] c) Sterols: cholesterol and its derivatives, preferably cholesterol

[0372] d) Lipids that inhibit particle aggregation: polyethylene glycol and its derivatives, preferably DMG-PEG

[0373] The molar ratio of ionizable polymer PBAE: auxiliary phospholipid: sterol: particle aggregation inhibiting lipid is: x:y:(100-xyz):z; wherein the range of x is 10-60mol%, the range of y is 2-20mol%, and the range of z is 0.5-10mol%.

[0374] The blank polymer-lipid nanoparticle preparation method disclosed in the present invention is an organic solvent injection method, and a microfluidic method is selected for amplified preparation.

[0375] The process of preparing blank polymer-lipid nanoparticles using the organic solvent injection method is as follows:

[0376] Weigh appropriate amounts of ionizable polymer PBAE, auxiliary phospholipid, cholesterol, and lipid-polyethylene glycol, and dilute them together in an organic solvent (e.g., water-miscible ethanol, acetone, tetrahydrofuran, acetonitrile, etc., preferably ethanol) according to the set molar ratio of the four components. Rapidly inject the organic phase into the aqueous phase (e.g., pH = 3 sodium citrate buffer or pH = 5 sodium acetate buffer, preferably sodium acetate) at a volume ratio of 1:1-1:3, mix well, and incubate the sample on ice for 2-10 minutes to allow the components to assemble into blank nanoparticles.

[0377] The nucleic acid drug polymer-lipid nanoparticles disclosed by the invention contain nucleic acid drugs and blank polymer-lipid nanoparticles, and are characterized by having an average particle size of 50-300 nm and a surface potential of -20-+20 mV.

[0378] The composition of nucleic acid drug polymer-lipid nanoparticles includes:

[0379] (1) Nucleic acid molecules. Including but not limited to mRNA, saRNA, cirRNA, miRNA, shRNA, siRNA, dsDNA, pDNA, preferably mRNA;

[0380] (2) Lipid composition.

[0381] The four components include:

[0382] a) Ionizable polymer PBAE

[0383] b) Auxiliary phospholipids: DSPC, DOPE, DOPC, DSPE and their derivatives, preferably DOPE

[0384] c) Sterols: cholesterol and its derivatives, preferably cholesterol

[0385] d) Lipids that inhibit particle aggregation: polyethylene glycol and its derivatives, preferably DMG-PEG

[0386] The molar ratio of the ionizable polymer PBAE: auxiliary phospholipid: sterol: particle aggregation inhibiting lipid is: x:y:(100-xyz):z, wherein x ranges from 10-60 mol%, y ranges from 2-25 mol%, and z ranges from 0.5-10 mol%. The N / P ratio of the ionizable polymer to the nucleic acid molecule is 5:1-50:1.

[0387] The process of preparing mRNA polymer-lipid nanoparticles using the organic solvent injection method is as follows:

[0388] Appropriate amounts of the ionizable polymer PBAE, auxiliary phospholipid, cholesterol, and lipid-PEG are weighed and diluted in an organic solvent (e.g., water-miscible ethanol, acetone, tetrahydrofuran, acetonitrile, etc., preferably ethanol) according to the pre-determined molar ratio of the four components. mRNA is diluted in an aqueous solution (e.g., sodium citrate buffer, pH 3, sodium acetate buffer, pH 5, preferably sodium acetate). The nitrogen-phosphorus ratio of the ionizable polymer to the mRNA is 5:1-50:1. The organic phase is rapidly injected into the mRNA-added aqueous solution at a volume ratio of 1:1-1:3, mixed thoroughly, and the sample is incubated on ice for 2-10 minutes to allow the components to assemble into mRNA polymer-lipid nanoparticles. For in vitro characterization, the nanoparticles can be used directly. For in vivo screening, the nanoparticles are dialyzed against 2000 volumes of PBS at 4°C for 2 hours to remove the organic solvent and form the final nanoparticles.

[0389] Example 1

[0390] Polymer PBAE:

[0391] According to the above general reaction formula, the reaction was carried out using propane-1,3-diyl diacrylate (202.6 mg, 1.1 mmol) and octylamine (129.2 mg, 1.0 mmol) as starting materials. After stirring at 65°C without solvent for approximately 30 hours, the reaction progress was monitored by proton nuclear magnetic resonance spectroscopy. Heating was stopped after the target degree of polymerization (dP) n was reached (dP = average degree of polymerization, n = 8-10 (actual n = 9.55) in subsequent examples). The calculated weight-average molecular weight of the polymer was approximately 2900, and the molar weight was 0.1144 mmol. The polymer was dissolved in THF at a concentration of 200 mg / mL, and a 10-fold molar amount of octylamine (147.8 mg, 1.144 mmol) was added for end-capping. The reaction was allowed to react at room temperature for 24 hours. After completion of the reaction, the polymer was precipitated with 10 volumes of ethanol and washed twice to obtain the product. The product was finally verified by proton nuclear magnetic resonance spectroscopy to yield 165 mg, 45.67%. 1 H NMR(500MHz,Chloroform-d)δ4.15(t,J=6.4Hz,38H),2.82(t,J=6.94Hz,38H),2.52(t,J=7.3Hz,38H),2.4 5(t,J=6.96Hz,21H),1.99–1.94(m,19H),1.47–1.37(m,21H),1.31–1.23(m,106H),0.88(t,J=7.0Hz,31H). Mn=3894.

[0392] Example 2

[0393] According to the above general reaction formula, the reaction was carried out using propane-1,3-diyl diacrylate (202.6 mg, 1.1 mmol) and octylamine (129.2 mg, 1.0 mmol) as starting materials. After solvent-free stirring at 65°C for approximately 30 hours, the reaction progress was monitored by H NMR spectroscopy. Heating was stopped after the target degree of polymerization (dP) of n=8-10 (actual n=9.55) was reached. The calculated weight-average molecular weight of the polymer was approximately 2900, and the molar weight was 0.1144 mmol. The polymer was dissolved in THF at a concentration of 200 mg / mL, and a 10-fold molar amount of dodecyl primary amine (212.0 mg, 1.144 mmol) was added for end-capping. The reaction was allowed to react at room temperature for 24 hours. After completion of the reaction, the polymer was precipitated with 10 volumes of ethanol and washed twice to obtain the product. The product was finally confirmed by H NMR spectroscopy to yield 170 mg of the product, with a yield of 45.43%.

[0394] Example 3

[0395] According to the above general reaction formula, the reaction was carried out using propane-1,3-diyl diacrylate (202.6 mg, 1.1 mmol) and octylamine (129.2 mg, 1.0 mmol) as starting materials. After solvent-free stirring at 65°C for approximately 30 hours, the reaction progress was monitored by proton nuclear magnetic resonance spectroscopy. Heating was stopped after the target degree of polymerization (dP) of n=8-10 (actual n=9.55) was reached. The calculated weight-average molecular weight of the polymer was approximately 2900, and the molar weight was 0.1144 mmol. The polymer was dissolved in THF at a concentration of 200 mg / mL, and end-capped with 10-fold molar amount of hexadecylamine (276.2 mg, 1.144 mmol). The reaction was allowed to proceed at room temperature for 24 hours. After completion, the polymer was precipitated with 10 volumes of ethanol and washed twice to obtain the product. Yield: 168 mg, 43.41%.

[0396] Example 4

[0397] According to the above general reaction formula, the reaction was carried out using propane-1,3-diyl diacrylate (202.6 mg, 1.1 mmol) and dodecyl primary amine (185.3 mg, 1.0 mmol) as starting materials. After solvent-free stirring at 65°C for approximately 30 hours, the reaction progress was monitored by proton nuclear magnetic resonance spectroscopy. Heating was stopped after the target degree of polymerization (dP) of n=8-10 (actual n=9) was reached. The calculated weight-average molecular weight of the polymer was approximately 3100, and the molar weight was 0.1251 mmol. The polymer was dissolved in THF at a concentration of 200 mg / mL, and a 10-fold molar amount of octylamine (161.6 mg, 1.251 mmol) was added for end-capping. The reaction was allowed to react at room temperature for 24 hours. After completion of the reaction, the polymer was precipitated with 10 volumes of ethanol and washed twice to obtain the product. Yield: 176 mg, 41.88%.

[0398] Example 5

[0399] According to the above general reaction formula, the reaction was carried out using propane-1,3-diyl diacrylate (202.6 mg, 1.1 mmol) and dodecylamine (185.3 mg, 1.0 mmol) as starting materials. After solvent-free stirring at 65°C for approximately 30 hours, the reaction progress was monitored by proton nuclear magnetic resonance spectroscopy. Heating was stopped after the target degree of polymerization (dP) of n=8-10 (actual n=9) was reached. The calculated weight-average molecular weight of the polymer was approximately 3100, and the molar weight was 0.1251 mmol. The polymer was dissolved in THF at a concentration of 200 mg / mL, and end-capped with 10-fold molar amount of dodecylamine (231.8 mg, 1.251 mmol). The reaction was allowed to react at room temperature for 24 hours. After completion, the polymer was precipitated with 10 volumes of ethanol and washed twice to obtain the product. Yield: 185 mg, 42.60%.

[0400] Example 6

[0401] According to the above general reaction formula, the reaction was carried out using propane-1,3-diyl diacrylate (202.6 mg, 1.1 mmol) and dodecyl primary amine (185.3 mg, 1.0 mmol) as starting materials. After solvent-free stirring at 65°C for approximately 30 hours, the reaction progress was monitored by proton nuclear magnetic resonance spectroscopy. Heating was stopped after the target degree of polymerization (dP) of n=8-10 (actual n=9) was reached. The calculated weight-average molecular weight of the polymer was approximately 3100, and the molar weight was 0.1251 mmol. The polymer was dissolved in THF at a concentration of 200 mg / mL, and end-capped with 10-fold molar amount of hexadecylamine (302.03 mg, 1.251 mmol). The reaction was allowed to react at room temperature for 24 hours. After completion, the polymer was precipitated with 10 volumes of ethanol and washed twice to obtain the product. Yield: 208 mg, 46.40%.

[0402] Example 7

[0403] According to the above general reaction formula, the reaction was carried out using propane-1,3-diyl diacrylate (202.6 mg, 1.1 mmol) and hexadecylamine (241.4 mg, 1.0 mmol) as starting materials. After solvent-free stirring at 65°C for approximately 30 hours, the reaction progress was monitored by proton nuclear magnetic resonance spectroscopy. Heating was stopped after the target degree of polymerization (dP) of n=8-10 (actual n=10.12) was reached. The calculated weight-average molecular weight of the polymer was approximately 4200, and the molar weight was 0.1057 mmol. The polymer was dissolved in THF at a concentration of 200 mg / mL, and a 10-fold molar amount of octylamine (136.6 mg, 1.057 mmol) was added for end-capping. The reaction was allowed to react at room temperature for 24 hours. After completion of the reaction, the polymer was precipitated with 10 volumes of ethanol and washed twice to obtain the product. Yield: 232 mg, 49.22%.

[0404] Example 8

[0405] According to the above general reaction formula, the reaction was carried out using propane-1,3-diyl diacrylate (202.6 mg, 1.1 mmol) and hexadecylamine (241.4 mg, 1.0 mmol) as starting materials. After solvent-free stirring at 65°C for approximately 30 hours, the reaction progress was monitored by proton nuclear magnetic resonance spectroscopy. Heating was stopped after the target degree of polymerization (dP) of n=8-10 (actual n=10.12) was reached. The calculated weight-average molecular weight of the polymer was approximately 4200, and the molar weight was 0.1057 mmol. The polymer was dissolved in THF at a concentration of 200 mg / mL, and end-capped with 10-fold molar amount of dodecyl primary amine (195.9 mg, 1.057 mmol). The reaction was allowed to react at room temperature for 24 hours. After completion, the polymer was precipitated with 10 volumes of ethanol and washed twice to obtain the product. Yield: 238 mg, 49.26%.

[0406] Example 9

[0407] According to the above general reaction formula, the reaction was carried out using propane-1,3-diyl diacrylate (202.6 mg, 1.1 mmol) and hexadecylamine (241.4 mg, 1.0 mmol) as starting materials. After solvent-free stirring at 65°C for approximately 30 hours, the reaction progress was monitored by proton nuclear magnetic resonance spectroscopy. Heating was stopped after the target degree of polymerization (dP) of n=8-10 (actual n=10.12) was reached. The calculated weight-average molecular weight of the polymer was approximately 4200, and the molar weight was 0.1057 mmol. The polymer was dissolved in THF at a concentration of 200 mg / mL, and a 10-fold molar amount of hexadecylamine (255.2 mg, 1.057 mmol) was added for end-capping. The reaction was allowed to react at room temperature for 24 hours. After completion of the reaction, the polymer was precipitated with 10 volumes of ethanol and washed twice to obtain the product. Yield: 249 mg, 50.30%. 1 H NMR(500MHz,Chloroform-d)δ4.14(t,J=6.4Hz,40H),2.82(t,J=6.95Hz,4.03+36.09H),2.52(t,J=6.95Hz,4.14+35.79H) ,2.46(t,J=6.85Hz,4.06+18.94H),1.99–1.94(m,20H),1.43–1.37(m,22H),1.31–1.23(m,289H),0.88(t,J=6.9Hz,33H).

[0408] Example 10

[0409] According to the above general reaction formula, 1,5-pentanediol diacrylate (233.5 mg, 1.1 mmol) and octylamine (129.2 mg, 1.0 mmol) were used as starting materials. After solvent-free stirring at 65°C for approximately 30 hours, the reaction progress was monitored by proton nuclear magnetic resonance spectroscopy. Heating was discontinued after the target degree of polymerization (dP) of n=8-10 (actual n=8.1) was reached. The calculated weight-average molecular weight of the polymer was approximately 2600, and the molar weight was 0.1395 mmol. The polymer was dissolved in THF at a concentration of 200 mg / mL, and end-capped with 10-fold molar amount of octylamine (180.2 mg, 1.395 mmol). The reaction was allowed to proceed at room temperature for 24 hours. After completion, the polymer was precipitated with 10 volumes of ethanol and washed twice to obtain the product. Yield: 142 mg, 35.61%. 1H NMR(500MHz,Chloroform-d)δ4.10–4.05(m,32H),2.83(t,J=6.9Hz,3.21+29.87H),2.52(t,J=7.2Hz,3.28+29.63H) ,2.47(t,J=7Hz,3.29+15.48H),1.69–1.63(m,32H),1.44–1.38(m,34H),1.31–1.23(m,91H),0.88(t,J=6.9Hz,27H). Mn:3987.

[0410] Example 11

[0411] According to the above general reaction formula, 1,5-pentanediol diacrylate (233.5 mg, 1.1 mmol) and octylamine (129.2 mg, 1.0 mmol) were used as starting materials. After solvent-free stirring at 65°C for approximately 30 hours, the reaction progress was monitored by proton nuclear magnetic resonance spectroscopy. Heating was stopped after the target degree of polymerization (dP) of n = 8-10 (actual n = 8.1) was reached. The calculated weight-average molecular weight of the polymer was approximately 2600, and the molar weight was 0.1395 mmol. The polymer was dissolved in THF at a concentration of 200 mg / mL, and end-capped with 10-fold molar amount of dodecyl primary amine (258.5.0 mg, 1.395 mmol). The reaction was allowed to react at room temperature for 24 hours. After completion, the polymer was precipitated with 10 volumes of ethanol and washed twice to obtain the product. Yield: 170 mg, 41.02%.

[0412] Example 12

[0413] According to the above general reaction formula, 1,5-pentanediol diacrylate (233.5 mg, 1.1 mmol) and octylamine (129.2 mg, 1.0 mmol) were used as starting materials. After solvent-free stirring at 65°C for approximately 30 hours, the reaction progress was monitored by proton nuclear magnetic resonance spectroscopy. Heating was stopped after the target degree of polymerization (dP) of n=8-10 (actual n=8.1) was reached. The calculated weight-average molecular weight of the polymer was approximately 2600, and the molar weight was 0.1395 mmol. The polymer was dissolved in THF at a concentration of 200 mg / mL, and a 10-fold molar amount of hexadecylamine (336.8 mg, 1.395 mmol) was added for end-capping. The reaction was allowed to react at room temperature for 24 hours. After completion of the reaction, the polymer was precipitated with 10 volumes of ethanol and washed twice to obtain the product. Yield: 178 mg, 41.39% yield.

[0414] Example 13

[0415] According to the above general reaction formula, 1,5-pentanediol diacrylate (233.5 mg, 1.1 mmol) and primary dodecylamine (185.3 mg, 1.0 mmol) were used as starting materials. After solvent-free stirring at 65°C for approximately 30 hours, the reaction progress was monitored by proton nuclear magnetic resonance spectroscopy. Heating was stopped after the target degree of polymerization (n=8-10) was reached (actual n=8). The calculated weight-average molecular weight of the polymer was approximately 3000, and the molar weight was 0.1396 mmol. The polymer was dissolved in THF at a concentration of 200 mg / mL, and a 10-fold molar amount of octylamine (180.4 mg, 1.396 mmol) was added for end-capping. The reaction was allowed to react at room temperature for 24 hours. After completion of the reaction, the polymer was precipitated with 10 volumes of ethanol and washed twice to obtain the product. Yield: 197 mg, 43.31%.

[0416] Example 14

[0417] According to the above reaction formula, 1,5-pentanediol diacrylate (233.5 mg, 1.1 mmol) and dodecylamine (185.3 mg, 1.0 mmol) were used as starting materials. After stirring at 65°C without solvent for approximately 30 hours, the reaction progress was monitored by proton nuclear magnetic resonance spectroscopy. Heating was stopped after the target degree of polymerization (n=8-10) was reached (actual n=8). The calculated weight-average molecular weight of the polymer was approximately 3000, and the molar weight was 0.1396 mmol. The polymer was dissolved in THF at a concentration of 200 mg / mL, and a 10-fold molar amount of dodecylamine (258.7 mg, 1.396 mmol) was added for end-capping. The reaction was allowed to react at room temperature for 24 hours. After completion of the reaction, the polymer was precipitated with 10 volumes of ethanol and washed twice to obtain the product. Yield: 184 mg, 39.10%.

[0418] Example 15

[0419] According to the above general reaction formula, 1,5-pentanediol diacrylate (233.5 mg, 1.1 mmol) and dodecyl primary amine (185.3 mg, 1.0 mmol) were used as starting materials. After solvent-free stirring at 65°C for approximately 30 hours, the reaction progress was monitored by proton nuclear magnetic resonance spectroscopy. Heating was stopped after the target degree of polymerization (n=8-10) was reached (actual n=8). The calculated weight-average molecular weight of the polymer was approximately 3000, and the molar weight was 0.1396 mmol. The polymer was dissolved in THF at a concentration of 200 mg / mL, and a 10-fold molar amount of hexadecylamine (337.0 mg, 1.396 mmol) was added for end-capping. The reaction was allowed to react at room temperature for 24 hours. After completion of the reaction, the polymer was precipitated with 10 volumes of ethanol and washed twice to obtain the product. Yield: 192 mg, 39.49%.

[0420] Example 16

[0421] According to the above general reaction formula, 1,5-pentanediol diacrylate (233.5 mg, 1.1 mmol) and hexadecylamine (241.4 mg, 1.0 mmol) were used as starting materials. After solvent-free stirring at 65°C for approximately 30 hours, the reaction progress was monitored by proton nuclear magnetic resonance spectroscopy. Heating was stopped after the target degree of polymerization (dP) of n=8-10 (actual n=8) was reached. The calculated weight-average molecular weight of the polymer was approximately 3400, and the molar weight was 0.1397 mmol. The polymer was dissolved in THF at a concentration of 200 mg / mL, and octylamine (180.5 mg, 1.397 mmol) was added to cap the end portions. The reaction was allowed to react at room temperature for 24 hours. After completion of the reaction, the polymer was precipitated with 10 volumes of ethanol and washed twice to obtain the product. Yield: 210 mg, 41.10%.

[0422] Example 17

[0423] According to the above general reaction formula, 1,5-pentanediol diacrylate (233.5 mg, 1.1 mmol) and hexadecylamine (241.4 mg, 1.0 mmol) were used as starting materials. After solvent-free stirring at 65°C for approximately 30 hours, the reaction progress was monitored by proton nuclear magnetic resonance spectroscopy. Heating was stopped after the target degree of polymerization (dP) of n=8-10 (actual n=8) was reached. The calculated weight-average molecular weight of the polymer was approximately 3400, and the molar weight was 0.1397 mmol. The polymer was dissolved in THF at a concentration of 200 mg / mL, and a 10-fold molar amount of dodecyl primary amine (258.9 mg, 1.397 mmol) was added for end-capping. The reaction was allowed to react at room temperature for 24 hours. After completion of the reaction, the polymer was precipitated with 10 volumes of ethanol and washed twice to obtain the product. Yield: 199 mg, 37.78%.

[0424] Example 18

[0425] According to the above general reaction formula, 1,5-pentanediol diacrylate (233.5 mg, 1.1 mmol) and hexadecylamine (241.4 mg, 1.0 mmol) were used as starting materials. After solvent-free stirring at 65°C for approximately 30 hours, the reaction progress was monitored by proton nuclear magnetic resonance spectroscopy. Heating was stopped after the target degree of polymerization (dP) of n=8-10 (actual n=8.19) was reached. The calculated weight-average molecular weight of the polymer was approximately 3400, and the molar weight was 0.1397 mmol. The polymer was dissolved in THF at a concentration of 200 mg / mL, and a 10-fold molar amount of hexadecylamine (377.3 mg, 1.397 mmol) was added for end-capping. The reaction was allowed to react at room temperature for 24 hours. After completion of the reaction, the polymer was precipitated with 10 volumes of ethanol and washed twice to obtain the product. Yield: 212 mg, 39.09%. 1 H NMR(500MHz,Chloroform-d)δ4.10-4.05(m,33H),2.83(t,J=7.0Hz,3.5+29.67H),2.52(t,J=7.3Hz,3.78+29.23H),2 .46(t,J=7.1Hz,3.92+15.05H),1.69–1.63(m,33H),1.45–1.37(m,35H),1.31–1.23(m,239H),0.88(t,J=6.9Hz,28H).

[0426] Example 19

[0427] According to the above general reaction formula, 1,4-butanediol diacrylate (218.0 mg, 1.1 mmol) and octylamine (129.2 mg, 1.0 mmol) were used as starting materials. After solvent-free stirring at 65°C for approximately 30 hours, the reaction progress was monitored by proton nuclear magnetic resonance spectroscopy. Heating was stopped after the target degree of polymerization (dP) of n = 8-10 (actual n = 8.63) was reached. The calculated weight-average molecular weight of the polymer was approximately 2700, and the molar weight was 0.1286 mmol. The polymer was dissolved in THF at a concentration of 200 mg / mL, and octylamine (147.8 mg, 1.286 mmol) was added for end-capping. The reaction was allowed to react at room temperature for 24 hours. After completion, the polymer was precipitated with 10 volumes of ethanol and washed twice to obtain the product. Yield: 159 mg, 41.79%. 1H NMR(500MHz,Chloroform-d)δ4.11–4.07(m,35H),2.83(t,J=7.00Hz,3.09+32.48H),2.53(t,J=7.2Hz,3.25+31.53H), 2.47(t,J=7.3Hz,3.16+17.12H),1.71–1.69(m,35H),1.44–1.38(m,19H),1.31–1.22(m,96H),0.88(t,J=6.9Hz,29H). Mn:4138.

[0428] Example 20

[0429] According to the above general reaction formula, 1,4-butanediol diacrylate (218.0 mg, 1.1 mmol) and octylamine (129.2 mg, 1.0 mmol) were used as starting materials. After solvent-free stirring at 65°C for approximately 30 hours, the reaction progress was monitored by proton nuclear magnetic resonance spectroscopy. Heating was stopped after the target degree of polymerization (dP) of n = 8-10 (actual n = 8.63) was reached. The calculated weight-average molecular weight of the polymer was approximately 2700, and the molar weight was 0.1286 mmol. The polymer was dissolved in THF at a concentration of 200 mg / mL, and a 10-fold molar amount of dodecyl primary amine (238.3 mg, 1.286 mmol) was added for end-capping. The reaction was allowed to react at room temperature for 24 hours. After completion of the reaction, the polymer was precipitated with 10 volumes of ethanol and washed twice to obtain the product. Yield: 158 mg, 40.01%.

[0430] Example 21

[0431] According to the above general reaction formula, 1,4-butanediol diacrylate (218.0 mg, 1.1 mmol) and octylamine (129.2 mg, 1.0 mmol) were used as starting materials. After solvent-free stirring at 65°C for approximately 30 hours, the reaction progress was monitored by proton nuclear magnetic resonance spectroscopy. Heating was stopped after the target degree of polymerization (dP) of n = 8-10 (actual n = 8.63) was reached. The calculated weight-average molecular weight of the polymer was approximately 2700, and the molar weight was 0.1286 mmol. The polymer was dissolved in THF at a concentration of 200 mg / mL, and end-capped with 10-fold molar amount of hexadecylamine (310.48 mg, 1.286 mmol). The reaction was allowed to react at room temperature for 24 hours. After completion, the polymer was precipitated with 10 volumes of ethanol and washed twice to obtain the product. Yield: 177 mg, 43.24%.

[0432] Example 22

[0433] According to the above general reaction formula, 1,4-butanediol diacrylate (218.0 mg, 1.1 mmol) and primary dodecylamine (185.3 mg, 1.0 mmol) were used as starting materials. After solvent-free stirring at 65°C for approximately 30 hours, the reaction progress was monitored by proton nuclear magnetic resonance spectroscopy. Heating was stopped after the target degree of polymerization (dP) of n = 8-10 (actual n = 8.63) was reached. The calculated weight-average molecular weight of the polymer was approximately 3100, and the molar weight was 0.07623 mmol. The polymer was dissolved in THF at a concentration of 200 mg / mL, and a 10-fold molar amount of octylamine (98.5 mg, 0.7623 mmol) was added for end-capping. The reaction was allowed to react at room temperature for 24 hours. After completion, the polymer was precipitated with 10 volumes of ethanol and washed twice to obtain the product. Yield: 189 mg, 44.68%.

[0434] Example 23

[0435] According to the above general reaction formula, 1,4-butanediol diacrylate (218.0 mg, 1.1 mmol) and dodecylamine (185.3 mg, 1.0 mmol) were used as starting materials. After stirring at 65°C without solvent for approximately 30 hours, the reaction progress was monitored by proton nuclear magnetic resonance spectroscopy. Heating was stopped after the target degree of polymerization (dP) of n = 8-10 (actual n = 8.63) was reached. The calculated weight-average molecular weight of the polymer was approximately 3100, and the molar weight was 0.07623 mmol. The polymer was dissolved in THF at a concentration of 200 mg / mL, and a 10-fold molar amount of dodecylamine (141.3 mg, 0.7623 mmol) was added for end-capping. The reaction was allowed to react at room temperature for 24 hours. After completion, the polymer was precipitated with 10 volumes of ethanol and washed twice to obtain the product. Yield: 187 mg, 43.33%. 1 H NMR(500MHz,Chloroform-d)δ4.12–4.06(m,35H),2.83(t,J=7.00Hz,3.08+31.8H),2.52(t,J=7.3Hz,3.05+30.56H),2 .46(t,J=7.05Hz,3.07+16.81H),1.71–1.69(m,35H),1.44–1.38(m,19H),1.31–1.23(m,174H),0.88(t,J=6.9Hz,29H).

[0436] Example 24

[0437] According to the above general reaction formula, 1,4-butanediol diacrylate (218.0 mg, 1.1 mmol) and primary dodecylamine (185.3 mg, 1.0 mmol) were used as starting materials. After solvent-free stirring at 65°C for approximately 30 hours, the reaction progress was monitored by proton nuclear magnetic resonance spectroscopy. Heating was stopped after the target degree of polymerization (dP) of n = 8-10 (actual n = 8.63) was reached. The calculated weight-average molecular weight of the polymer was approximately 3100, and the molar weight was 0.07623 mmol. The polymer was dissolved in THF at a concentration of 200 mg / mL, and end-capped with 10-fold molar amount of hexadecylamine (184.0 mg, 0.7623 mmol). The reaction was allowed to proceed at room temperature for 24 hours. After completion, the polymer was precipitated with 10 volumes of ethanol and washed twice to obtain the product. Yield: 185 mg, 42.04%.

[0438] Example 25

[0439] According to the above general reaction formula, 1,4-butanediol diacrylate (218.0 mg, 1.1 mmol) and hexadecylamine (241.4 mg, 1.0 mmol) were used as starting materials. After solvent-free stirring at 65°C for approximately 30 hours, the reaction progress was monitored by proton nuclear magnetic resonance spectroscopy. Heating was stopped after the target degree of polymerization (dP) of n = 8-10 (actual n = 8.49) was reached. The calculated weight-average molecular weight of the polymer was approximately 3500, and the molar weight was 0.1313 mmol. The polymer was dissolved in THF at a concentration of 200 mg / mL, and a 10-fold molar amount of octylamine (169.6 mg, 1.313 mmol) was added for end-capping. The reaction was allowed to react at room temperature for 24 hours. After completion of the reaction, the polymer was precipitated with 10 volumes of ethanol and washed twice to obtain the product. Yield: 193 mg, 39.12%.

[0440] Example 26

[0441] According to the above general reaction formula, 1,4-butanediol diacrylate (218.0 mg, 1.1 mmol) and hexadecylamine (241.4 mg, 1.0 mmol) were used as starting materials. After solvent-free stirring at 65°C for approximately 30 hours, the reaction progress was monitored by proton nuclear magnetic resonance spectroscopy. Heating was stopped after the target degree of polymerization (dP) of n = 8-10 (actual n = 8.49) was reached. The calculated weight-average molecular weight of the polymer was approximately 3500, and the molar weight was 0.1313 mmol. The polymer was dissolved in THF at a concentration of 200 mg / mL, and end-capped with 10-fold molar amount of dodecyl primary amine (243.3.0 mg, 1.313 mmol). The reaction was allowed to react at room temperature for 24 hours. After completion, the polymer was precipitated with 10 volumes of ethanol and washed twice to obtain the product. Yield: 200 mg, 40.55%.

[0442] Example 27

[0443] According to the above general reaction formula, 1,4-butanediol diacrylate (218.0 mg, 1.1 mmol) and hexadecylamine (241.4 mg, 1.0 mmol) were used as starting materials. After solvent-free stirring at 65°C for approximately 30 hours, the reaction progress was monitored by proton nuclear magnetic resonance spectroscopy. Heating was stopped after the target degree of polymerization (dP) of n=8-10 (actual n=8.49) was reached. The calculated weight-average molecular weight of the polymer was approximately 3500, and the molar weight was 0.1313 mmol. The polymer was dissolved in THF at a concentration of 200 mg / mL, and a 10-fold molar amount of hexadecylamine (317.0 mg, 1.313 mmol) was added for end-capping. The reaction was allowed to react at room temperature for 24 hours. After completion, the polymer was precipitated with 10 volumes of ethanol and washed twice to obtain the product. Yield: 222 mg, 42.46%. 1 H NMR(500MHz,Chloroform-d)δ4.12–4.07(m,34H),2.83(t,J=6.90Hz,4.29+28.95H),2.52(t,J=7.3Hz,4.56+28.14H),2.46 (t,J=7.0Hz,4.2+15.12H),1.71–1.69(m,34H),1.43–1.38(m,19H),1.31–1.23(m,246H),0.88(t,J=6.9Hz,28H).Mn:4032.

[0444] Example 28

[0445] According to the above general reaction formula, tetraethylene glycol diacrylate (332.55 mg, 1.1 mmol) and decylamine (157.3 mg, 1.0 mmol) were used as starting materials. After stirring at 65°C without solvent for approximately 24 hours, the reaction progress was monitored by proton nuclear magnetic resonance spectroscopy. Heating was stopped after the target degree of polymerization (dP) of n = 8-10 (actual n = 9.78) was reached. The calculated weight-average molecular weight of the polymer was approximately 4100, and the molar weight was 0.1195 mmol. The polymer was dissolved in THF at a concentration of 200 mg / mL, and a 10-fold molar amount of 1,3-propylenediamine (88.6 mg, 1.195 mmol) was added for end-capping. The reaction was allowed to react at room temperature for 24 hours. After completion of the reaction, the polymer was precipitated with 10 volumes of ethanol and washed twice to obtain the product. Yield: 210 mg, 36.30%.

[0446] Example 29

[0447] According to the above general reaction formula, tetraethylene glycol diacrylate (332.55 mg, 1.1 mmol) and decylamine (157.3 mg, 1.0 mmol) were used as starting materials. After solvent-free stirring at 65°C for approximately 24 hours, the reaction progress was monitored by proton nuclear magnetic resonance spectroscopy. Heating was stopped after the target degree of polymerization (dP) of n = 8-10 (actual n = 9.78) was reached. The calculated weight-average molecular weight of the polymer was approximately 4100, with a molar weight of 0.1195 mmol. The polymer was dissolved in THF at a concentration of 200 mg / mL, and end-capped with 10-fold molar amount of N-methyl-1,3-propylenediamine (105.3 mg, 1.195 mmol). The reaction was allowed to proceed at room temperature for 24 hours. After completion, the polymer was precipitated with 10 volumes of ethanol and washed twice to obtain the product. Yield: 239 mg, 40.16%.

[0448] Example 30

[0449] According to the above general reaction formula, tetraethylene glycol diacrylate (332.55 mg, 1.1 mmol) and decylamine (157.3 mg, 1.0 mmol) were used as starting materials. After stirring at 65°C without solvent for approximately 24 hours, the reaction progress was monitored by proton nuclear magnetic resonance spectroscopy. Heating was stopped after the target degree of polymerization (dP) of n = 8-10 (actual n = 9.78) was reached. The calculated weight-average molecular weight of the polymer was approximately 4100, and the molar weight was 0.1195 mmol. The polymer was dissolved in THF at a concentration of 200 mg / mL, and a 10-fold molar amount of 3-dimethylaminopropylamine (122.1 mg, 1.195 mmol) was added for end-capping. The reaction was allowed to react at room temperature for 24 hours. After completion of the reaction, the polymer was precipitated with 10 volumes of ethanol and washed twice to obtain the product. Yield: 225 mg, 36.77%.

[0450] Example 31

[0451] According to the above general reaction formula, tetraethylene glycol diacrylate (332.55 mg, 1.1 mmol) and decylamine (157.3 mg, 1.0 mmol) were used as starting materials. After stirring at 65°C without solvent for approximately 24 hours, the reaction progress was monitored by proton nuclear magnetic resonance spectroscopy. Heating was stopped after the target degree of polymerization (dP) of n=8-10 (actual n=9.78) was reached. The calculated weight-average molecular weight of the polymer was approximately 4100, and the molar weight was 0.1195 mmol. The polymer was dissolved in THF at a concentration of 200 mg / mL, and end-capped with 10-fold molar amount of n-butylamine (87.4 mg, 1.195 mmol). The reaction was allowed to proceed at room temperature for 24 hours. After completion, the polymer was precipitated with 10 volumes of ethanol and washed twice to obtain the product. Yield: 253 mg, 43.83%.

[0452] Example 32

[0453] According to the above general reaction formula, tetraethylene glycol diacrylate (332.55 mg, 1.1 mmol) and decylamine (157.3 mg, 1.0 mmol) were used as starting materials. After stirring at 65°C without solvent for approximately 24 hours, the reaction progress was monitored by proton nuclear magnetic resonance spectroscopy. Heating was stopped after the target degree of polymerization (dP) of n = 8-10 (actual n = 9.78) was reached. The calculated weight-average molecular weight of the polymer was approximately 4100, and the molar weight was 0.1195 mmol. The polymer was dissolved in THF at a concentration of 200 mg / mL, and a 10-fold molar amount of decylamine (188.0 mg, 1.195 mmol) was added for end-capping. The reaction was allowed to react at room temperature for 24 hours. After completion of the reaction, the polymer was precipitated with 10 volumes of ethanol and washed twice to obtain the product. Yield: 295 mg, 43.52%.

[0454] Example 33 7C8C8 n=5.3

[0455] According to the above reaction formula, the reaction was carried out using propane-1,3-diyl diacrylate (122.1 mg, 1.1 eq) and octylamine (78.0 mg, 1.0 eq) as raw materials. After solvent-free stirring at 75°C for approximately 3 hours, the reaction progress was monitored by proton nuclear magnetic resonance spectroscopy. After the reaction reached the target degree of polymerization n (the degree of polymerization n is the average degree of polymerization, and the meaning of n in subsequent examples remains the same, n = 5-6 (actual n = 5.36)), heating was stopped. The calculated weight-average molecular weight of the polymer was approximately 1549.552, and the molar weight was 0.129 mmol. The polymer was dissolved in THF at a concentration of 200 mg / mL, and octylamine (94.4 mg, 1.29 mmol) was added to cap the end. The reaction was allowed to react at room temperature for 24 hours. After completion of the reaction, the polymer was precipitated with 10 volumes of methanol and washed twice to obtain the product. 1 H NMR (500MHz, CDCl3) δ4.26-4.13(m,21H),2.82(t,J=7.5Hz,21H),2.53(t,J=7.5Hz,21H),2. 47(t,J=7.5Hz,12H),1.99–1.84(m,11H),1.43–1.23(m,73H),0.88(t,J=5Hz,19H).Mn:2957.

[0456] Example 34

[0457] 7C8C8 n=14.05

[0458] According to the above general reaction formula, a reaction was carried out using propane-1,3-diyl diacrylate (122.1 mg, 1.1 eq) and octylamine (78.0 mg, 1.0 eq) as starting materials. After solvent-free stirring at 75°C for approximately 40 hours, the reaction progress was monitored by proton nuclear magnetic resonance spectroscopy. Heating was stopped after the reaction reached the target degree of polymerization n (the degree of polymerization n is the average degree of polymerization, and in subsequent examples, n = 14-15 (actual n = 14.05)). The calculated weight-average molecular weight of the polymer was approximately 4271.26, and the molar weight was 0.047 mmol. The polymer was dissolved in THF at a concentration of 200 mg / mL, and a 10-fold molar amount of octylamine (60.5 mg, 0.47 mmol) was added for end-capping. The reaction was allowed to react at room temperature for 24 hours. After completion of the reaction, the polymer was precipitated with 10 volumes of ethanol and washed twice to obtain the product. 1 H NMR (500MHz, CDCl3) δ4.18-4.13(m,56H),2.82(t,J=7.5Hz,56H),2.52(t,J=7.5Hz,56H),2.4 6(t,J=7.5Hz,30H),1.99–1.94(m,28H),1.43–1.23(m,180H),0.88(t,J=5.0Hz,45H).Mn:5661

[0459] Example 35 7C8C4 n=9.6

[0460] According to the above reaction formula, the reaction was carried out using propane-1,3-diyl diacrylate (122.1 mg, 1.1 eq) and octylamine (78.0 mg, 1.0 eq) as raw materials. After solvent-free stirring at 75°C for approximately 7.5 hours, the reaction progress was monitored by proton nuclear magnetic resonance spectroscopy. After the reaction reached the target degree of polymerization n (the degree of polymerization n is the average degree of polymerization, and the meaning of n in subsequent examples remains the same, n = 9-10 (actual n = 9.6)), heating was stopped. The calculated weight-average molecular weight of the polymer was approximately 2890.048, and the molar weight was 0.069 mmol. The polymer was dissolved in THF at a concentration of 200 mg / mL, and butylamine (50.6 mg, 0.69 mmol) was added to cap the end. The reaction was allowed to react at room temperature for 24 hours. After completion of the reaction, the polymer was precipitated with 10 volumes of ethanol and washed twice to obtain the product. 1 H NMR (500MHz, CDCl3) δ4.18-4.13(m,39H),2.82(t,J=7.5Hz,38H),2.53(t,J=7.5Hz,38H),2.4 6(t,J=7.5Hz,21H),1.99–1.94(m,19H),1.43–1.22(m,112H),0.9(t,J=7.5Hz,31H).Mn:5321

[0461] Example 36 7C8C12 n=9.6

[0462] According to the above reaction formula, the reaction was carried out using propane-1,3-diyl diacrylate (122.1 mg, 1.1 eq) and octylamine (78.0 mg, 1.0 eq) as raw materials. After solvent-free stirring at 75°C for approximately 7.5 hours, the reaction progress was monitored by proton nuclear magnetic resonance spectroscopy. After the reaction reached the target degree of polymerization n (the degree of polymerization n is the average degree of polymerization, and the meaning of n in subsequent examples remains the same, n = 9-10 (actual n = 9.6)), heating was stopped. The calculated weight-average molecular weight of the polymer was approximately 2890.048, and the molar weight was 0.069 mmol. The polymer was dissolved in THF at a concentration of 200 mg / mL, and a 10-fold molar amount of dodecyl primary amine (128.27 mg, 0.69 mmol) was added for end-capping. The reaction was allowed to react at room temperature for 24 hours. After completion of the reaction, the polymer was precipitated with 10 volumes of ethanol and washed twice to obtain the product.

[0463] Example 37 7C8C16 n=9.6

[0464] According to the above reaction formula, the reaction was carried out using propane-1,3-diyl diacrylate (122.1 mg, 1.1 eq) and octylamine (78.0 mg, 1.0 eq) as raw materials. After solvent-free stirring at 75°C for approximately 7.5 hours, the reaction progress was monitored by proton nuclear magnetic resonance spectroscopy. After the reaction reached the target degree of polymerization n (the degree of polymerization n is the average degree of polymerization, and the meaning of n in subsequent examples remains the same, n = 9-10 (actual n = 9.6)), heating was stopped. The calculated weight-average molecular weight of the polymer was approximately 2890.048, and the molar weight was 0.069 mmol. The polymer was dissolved in THF at a concentration of 200 mg / mL, and a 10-fold molar amount of hexadecyl primary amine (167.1 mg, 0.69 mmol) was added for end-capping. The reaction was allowed to react at room temperature for 24 hours. After completion of the reaction, the polymer was precipitated with 10 volumes of ethanol and washed twice to obtain the product.

[0465] Example 38 7C4C8 n=9.34

[0466] According to the above general reaction formula, the reaction was carried out using propane-1,3-diyl diacrylate (221.62 mg, 1.1 eq) and butylamine (80.0 mg, 1.0 eq) as raw materials. After solvent-free stirring at 75°C for approximately 7.5 hours, the reaction progress was monitored by proton nuclear magnetic resonance spectroscopy. After the reaction reached the target degree of polymerization n (the degree of polymerization n is the average degree of polymerization, and the meaning of n in subsequent examples remains the same, n = 9-10 (actual n = 9.34)), heating was stopped. The calculated weight-average molecular weight of the polymer was approximately 2328.79, and the molar weight was 0.129 mmol. The polymer was dissolved in THF at a concentration of 200 mg / mL, and octylamine (166.6 mg, 1.29 mmol) was added to cap the end. The reaction was allowed to react at room temperature for 24 hours. After completion of the reaction, the polymer was precipitated with 10 volumes of ethanol and washed twice to obtain the product.

[0467] Example 39 7C12C8 n=9.96

[0468] According to the above reaction formula, the reaction was carried out using propane-1,3-diyl diacrylate (163.96 mg, 1.1 eq) and dodecyl primary amine (150 mg, 1.0 eq) as raw materials. After solvent-free stirring at 75°C for approximately 43 hours, the reaction progress was monitored by proton nuclear magnetic resonance spectroscopy. After the reaction reached the target degree of polymerization n (the degree of polymerization n is the average degree of polymerization, and the meaning of n in subsequent examples remains the same, n = 9-10 (actual n = 9.96)), heating was stopped. The calculated weight-average molecular weight of the polymer was approximately 3492.92, and the molar weight was 0.090 mmol. The polymer was dissolved in THF at a concentration of 200 mg / mL, and octylamine (116.23 mg, 0.9 mmol) was added to cap the end. The reaction was allowed to react at room temperature for 24 hours. After completion of the reaction, the polymer was precipitated with 10 volumes of ethanol and washed twice to obtain the product. 1 H NMR (500MHz, CDCl3) δ4.18-4.13(m,40H),2.82(t,J=7.5Hz,39H),2.52(t,J=7.5Hz,39H),2.4 6(t,J=7.5Hz,21H),1.99–1.94(m,20H),1.43-1.22(m,213H),0.88(t,J=5.0Hz,33H).Mn:3794

[0469] Example 40 7C16C8 n=10.44

[0470] According to the above reaction formula, a reaction was carried out using propane-1,3-diyl diacrylate (125.86 mg, 1.1 eq) and hexadecyl primary amine (150 mg, 1.0 eq) as starting materials. After solvent-free stirring at 90°C for approximately 32 hours, the reaction progress was monitored by proton nuclear magnetic resonance spectroscopy. Heating was stopped after the reaction reached the target degree of polymerization n (the degree of polymerization n is the average degree of polymerization, and the meaning of n in subsequent examples remains the same, n = 10-11 (actual n = 10.44)). The calculated weight-average molecular weight of the polymer was approximately 4199.384, and the molar weight was 0.066 mmol. The polymer was dissolved in THF at a concentration of 200 mg / mL, and octylamine (84.8 mg, 0.66 mmol) was added to cap the end portions. The reaction was allowed to react at room temperature for 24 hours. After completion of the reaction, the polymer was precipitated with 10 volumes of ethanol and washed twice to obtain the product. 1 H NMR(500MHz,CDCl3)δ 4.18–4.13(m,42H),2.82(t,J=7.5Hz,42H),2.52(t,J=7.5Hz,42H),2.46(t,J=7.5 Hz,23H),1.99–1.94(m,21H),1.43-1.23(m,296H),0.88(t,J=7.5Hz,35H).Mn:3855

[0471] Example 41 7C8G12 n=9.52

[0472] According to the above reaction formula, the reaction was carried out using propane-1,3-diyl diacrylate (122.1 mg, 1.1 eq) and octylamine (78 mg, 1.0 eq) as raw materials. After solvent-free stirring at 75°C for approximately 7.5 hours, the reaction progress was monitored by proton nuclear magnetic resonance spectroscopy. After the reaction reached the target degree of polymerization n (the degree of polymerization n is the average degree of polymerization, and the meaning of n in subsequent examples remains the same, n = 9-10 (actual n = 9.52)), heating was stopped. The calculated weight-average molecular weight of the polymer was approximately 2852.464, and the molar weight was 0.07 mmol. The polymer was dissolved in THF at a concentration of 200 mg / mL, and a 10-fold molar amount of N-dodecylmethylamine (139.8 mg, 0.7 mmol) was added for end-capping. The reaction was allowed to react at room temperature for 24 hours. After completion of the reaction, the polymer was precipitated with 10 volumes of ethanol and washed twice to obtain the product.

[0473] Example 42 7C8G14 n=9.52

[0474] According to the above reaction formula, the reaction was carried out using propane-1,3-diyl diacrylate (122.1 mg, 1.1 eq) and octylamine (78 mg, 1.0 eq) as raw materials. After solvent-free stirring at 75°C for approximately 7.5 hours, the reaction progress was monitored by proton nuclear magnetic resonance spectroscopy. After the reaction reached the target degree of polymerization n (the degree of polymerization n is the average degree of polymerization, and the meaning of n in subsequent examples remains the same, n = 9-10 (actual n = 9.52)), heating was stopped. The calculated weight-average molecular weight of the polymer was approximately 2852.464, and the molar weight was 0.07 mmol. The polymer was dissolved in THF at a concentration of 200 mg / mL, and a 10-fold molar amount of N-methylallylamine (49.8 mg, 0.7 mmol) was added for end-capping. The reaction was allowed to react at room temperature for 24 hours. After completion of the reaction, the polymer was precipitated with 10 volumes of ethanol and washed twice to obtain the product.

[0475] Example 43 7C8G15 n=9.52

[0476] According to the above general reaction formula, a reaction was carried out using propane-1,3-diyl diacrylate (122.1 mg, 1.1 eq) and octylamine (78 mg, 1.0 eq) as raw materials. After solvent-free stirring at 75°C for approximately 7.5 hours, the reaction progress was monitored by proton nuclear magnetic resonance spectroscopy. Heating was stopped after the reaction reached the target degree of polymerization n (the degree of polymerization n is the average degree of polymerization, and the meaning of n in subsequent examples remains the same, n = 9-10 (actual n = 9.52)). The calculated weight-average molecular weight of the polymer was approximately 2852.464, and the molar weight was 0.07 mmol. The polymer was dissolved in THF at a concentration of 200 mg / mL, and a 10-fold molar amount of N-methylpropargylamine (48.4 mg, 0.7 mmol) was added for end-capping. The reaction was allowed to react at room temperature for 24 hours. After completion of the reaction, the polymer was precipitated with 10 volumes of ethanol and washed twice to obtain the product.

[0477] Example 44 7C8G16 n=9.52

[0478] According to the above reaction formula, the reaction was carried out using propane-1,3-diyl diacrylate (122.1 mg, 1.1 eq) and octylamine (78 mg, 1.0 eq) as raw materials. After solvent-free stirring at 75°C for approximately 7.5 hours, the reaction progress was monitored by proton nuclear magnetic resonance spectroscopy. After the reaction reached the target degree of polymerization n (the degree of polymerization n is the average degree of polymerization, and the meaning of n in subsequent examples remains the same, n = 9-10 (actual n = 9.52)), heating was stopped. The calculated weight-average molecular weight of the polymer was approximately 2852.464, and the molar weight was 0.07 mmol. The polymer was dissolved in THF at a concentration of 200 mg / mL, and a 10-fold molar amount of N,N,N'-trimethylethylenediamine (71.5 mg, 0.7 mmol) was added for end-capping. The reaction was allowed to react at room temperature for 24 hours. After completion of the reaction, the polymer was precipitated with 10 volumes of ethanol and washed twice to obtain the product.

[0479] Example 45 7C8G17 n=9.52

[0480] According to the above general reaction formula, a reaction was carried out using propane-1,3-diyl diacrylate (122.1 mg, 1.1 eq) and octylamine (78 mg, 1.0 eq) as starting materials. After solvent-free stirring at 75°C for approximately 7.5 hours, the reaction progress was monitored by proton nuclear magnetic resonance spectroscopy. Heating was stopped after the target degree of polymerization (dP) n was reached (dP = average degree of polymerization, n = 9-10 (actual n = 9.52) in subsequent examples). The calculated weight-average molecular weight of the polymer was approximately 2852.464, with a molar weight of 0.07 mmol). The polymer was dissolved in THF at a concentration of 200 mg / mL and end-capped with 10-fold molar amount of N-methylphenethylamine (94.6 mg, 0.7 mmol). The reaction was allowed to react at room temperature for 24 hours. After completion of the reaction, the polymer was precipitated with 10 volumes of ethanol and washed twice to obtain the product. 1 H NMR (500MHz, CDCl3) δ7.30-7.27(m,6H),7.20–7.18(m,4H),4.18-4.13(m,38H),2.82(t,J=7.5Hz,40H),2.53(t,J=7.5Hz,40H),2 .54–2.47(m,4H),2.39(t,J=7.5Hz,18H),2.31(s,4H),1.99–1.94(m,19H),1.43–1.25(m,108H),0.88(t,J=5.0Hz,26H).Mn:3761

[0481] Example 46 7C8G18 n=9.52

[0482] According to the above reaction formula, the reaction was carried out using propane-1,3-diyl diacrylate (122.1 mg, 1.1 eq) and octylamine (78 mg, 1.0 eq) as raw materials. After solvent-free stirring at 75°C for approximately 7.5 hours, the reaction progress was monitored by proton nuclear magnetic resonance spectroscopy. After the reaction reached the target degree of polymerization n (the degree of polymerization n is the average degree of polymerization, and the meaning of n in subsequent examples remains the same, n = 9-10 (actual n = 9.52)), heating was stopped. The calculated weight-average molecular weight of the polymer was approximately 2852.464, and the molar weight was 0.07 mmol. The polymer was dissolved in THF at a concentration of 200 mg / mL, and a 10-fold molar amount of N-methyl-4-bromobenzylamine (140.05 mg, 0.7 mmol) was added for end-capping. The reaction was allowed to react at room temperature for 24 hours. After completion of the reaction, the polymer was precipitated with 10 volumes of ethanol and washed twice to obtain the product. 1 H NMR (500MHz, CDCl3) δ7.43 (d, J = 5Hz, 4H), 7.17 (d, J = 10Hz, 4H), 4.17-4.12 (m, 38H), 2.82 (t, J = 7.5Hz, 38H), 2.54 (t ,J=7.5Hz,27H),2.52(t,J=7.5Hz,38H),1.99–1.95(m,20H),1.43–1.25(m,112H),0.88(t,J=5.0Hz,26H).Mn:3322

[0483] Example 47 7C8G19 n=9.52

[0484] According to the above reaction formula, the reaction was carried out using propane-1,3-diyl diacrylate (122.1 mg, 1.1 eq) and octylamine (78 mg, 1.0 eq) as raw materials. After stirring at 75°C without solvent for approximately 7.5 hours, the reaction progress was monitored by proton nuclear magnetic resonance spectroscopy. After the reaction reached the target degree of polymerization n (the degree of polymerization n is the average degree of polymerization, and the meaning of n in subsequent examples remains the same, n = 9-10 (actual n = 9.52)), heating was stopped. The calculated weight-average molecular weight of the polymer was approximately 2852.464, and the molar weight was 0.07 mmol. The polymer was dissolved in THF at a concentration of 200 mg / mL, and a 10-fold molar amount of 4-n-butylamino-1-butanol (101.67 mg, 0.7 mmol) was added for end-capping. The reaction was allowed to react at room temperature for 24 hours. After completion of the reaction, the polymer was precipitated with 10 volumes of ethanol and washed twice to obtain the product. 1H NMR (500MHz, CDCl3) δ4.18-4.13(m,38H),2.82(t,J=7.5Hz,38H),2.57(t,J=7.5Hz,25H),2.5 2(t,J=7.5Hz,40H),1.99–1.94(m,19H),1.43–1.25(m,118H),0.9(t,J=5.0Hz,31H).Mn:4436

[0485] Example 48 7C8G20 n=9.52

[0486] According to the above reaction formula, the reaction was carried out using propane-1,3-diyl diacrylate (122.1 mg, 1.1 eq) and octylamine (78 mg, 1.0 eq) as raw materials. After solvent-free stirring at 75°C for approximately 7.5 hours, the reaction progress was monitored by proton nuclear magnetic resonance spectroscopy. After the reaction reached the target degree of polymerization n (the degree of polymerization n is the average degree of polymerization, and the meaning of n in subsequent examples remains the same, n = 9-10 (actual n = 9.52)), heating was stopped. The calculated weight-average molecular weight of the polymer was approximately 2852.464, and the molar weight was 0.07 mmol. The polymer was dissolved in THF at a concentration of 200 mg / mL, and a 10-fold molar amount of allylcyclohexylamine (97.46 mg, 0.7 mmol) was added for end-capping. The reaction was allowed to react at room temperature for 24 hours. After completion of the reaction, the polymer was precipitated with 10 volumes of ethanol and washed twice to obtain the product. 1 H NMR (500MHz, CDCl3) δ4.26–4.13(m,38H),2.83(t,J=7.5Hz,38H),2.52(t,J=7.5Hz,38H),2.46(t,J=7.5Hz,20H),2.06–1.94(m,19H), 1.43–1.25(m,118H),0.88(t,J=5.0Hz,27H).Mn:5235

[0487] Example 49 7C8G21 n=9.52

[0488] According to the above reaction formula, the reaction was carried out using propane-1,3-diyl diacrylate (122.1 mg, 1.1 eq) and octylamine (78 mg, 1.0 eq) as raw materials. After solvent-free stirring at 75°C for approximately 7.5 hours, the reaction progress was monitored by proton nuclear magnetic resonance spectroscopy. After the reaction reached the target degree of polymerization n (the degree of polymerization n is the average degree of polymerization, and the meaning of n in subsequent examples remains the same, n = 9-10 (actual n = 9.52)), heating was stopped. The calculated weight-average molecular weight of the polymer was approximately 2852.464, and the molar weight was 0.07 mmol. The polymer was dissolved in THF at a concentration of 200 mg / mL, and a 10-fold molar amount of N-ethyltetrahydro-2H-pyran-4-amine (90.44 mg, 0.7 mmol) was added for end-capping. The reaction was allowed to react at room temperature for 24 hours. After completion of the reaction, the polymer was precipitated with 10 volumes of ethanol and washed twice to obtain the product. 1 H NMR (500MHz, CDCl3) δ4.26–4.13(m,39H),2.83(t,J=7.5Hz,38H),2.55(t,J=7.5Hz,38H),2.4 8(t,J=7.5Hz,21H),2.06–1.94(m,19H),1.43–1.25(m,120H),0.88(t,J=5.0Hz,30H).Mn:5452

[0489] Example 50 7C8G22 n=9.52

[0490] According to the above general reaction formula, a reaction was carried out using propane-1,3-diyl diacrylate (122.1 mg, 1.1 eq) and octylamine (78 mg, 1.0 eq) as starting materials. After solvent-free stirring at 75°C for approximately 7.5 hours, the reaction progress was monitored by proton nuclear magnetic resonance spectroscopy. Heating was stopped after the target degree of polymerization (dP) n was reached (dP = average degree of polymerization, n = 9-10 (actual n = 9.52) in subsequent examples). The calculated weight-average molecular weight of the polymer was approximately 2852.464, with a molar weight of 0.07 mmol). The polymer was dissolved in THF at a concentration of 200 mg / mL, and a 10-fold molar amount of 1-methyl-4-(methylamino)piperidine (89.75 mg, 0.7 mmol) was added for end-capping. The reaction was allowed to react at room temperature for 24 hours. After completion of the reaction, the polymer was precipitated with 10 volumes of ethanol and washed twice to obtain the product.

[0491] Example 51 7C8G23 n=9.52

[0492] According to the above reaction formula, the reaction was carried out using propane-1,3-diyl diacrylate (122.1 mg, 1.1 eq) and octylamine (78 mg, 1.0 eq) as raw materials. After stirring at 75°C without solvent for approximately 7.5 hours, the reaction progress was monitored by hydrogen nuclear magnetic resonance spectroscopy. After the reaction reached the target degree of polymerization n (the degree of polymerization n is the average degree of polymerization, and the meaning of n in subsequent examples is the same as n = 9-10 (actual n = 9.52)), heating was stopped. The calculated weight-average molecular weight of the polymer was approximately 2852.464, and the molar weight was 0.07 mmol. The polymer was dissolved in THF at a concentration of 200 mg / mL, and 10-fold molar amount of octadecanethiol (200.59 mg, 0.7 mmol) was added for end-capping. The reaction was allowed to react at room temperature for 24 hours. After completion of the reaction, the polymer was precipitated with 10 volumes of ethanol and washed twice to obtain the product.

[0493] Example 52 7C8G24 n=9.52

[0494] According to the above reaction formula, the reaction was carried out using propane-1,3-diyl diacrylate (122.1 mg, 1.1 eq) and octylamine (78 mg, 1.0 eq) as raw materials. After stirring at 75°C without solvent for approximately 7.5 hours, the reaction progress was monitored by proton nuclear magnetic resonance spectroscopy. After the reaction reached the target degree of polymerization n (the degree of polymerization n is the average degree of polymerization, and the meaning of n in subsequent examples remains the same, n = 9-10 (actual n = 9.52)), heating was stopped. The calculated weight-average molecular weight of the polymer was approximately 2852.464, and the molar weight was 0.07 mmol. The polymer was dissolved in THF at a concentration of 200 mg / mL, and cyclohexanethiol (81.35 mg, 0.7 mmol) was added to cap the end. The reaction was allowed to react at room temperature for 24 hours. After completion of the reaction, the polymer was precipitated with 10 volumes of ethanol and washed twice to obtain the product.

[0495] Example 53 7C8G25 n=9.52

[0496] According to the above reaction formula, the reaction was carried out using propane-1,3-diyl diacrylate (122.1 mg, 1.1 eq) and octylamine (78 mg, 1.0 eq) as raw materials. After stirring at 75°C without solvent for approximately 7.5 hours, the reaction progress was monitored by proton nuclear magnetic resonance spectroscopy. After the reaction reached the target degree of polymerization n (the degree of polymerization n is the average degree of polymerization, and the meaning of n in subsequent examples is the same as n = 9-10 (actual n = 9.52)), heating was stopped. The calculated weight-average molecular weight of the polymer was approximately 2852.464, and the molar weight was 0.07 mmol. The polymer was dissolved in THF at a concentration of 200 mg / mL, and a 10-fold molar amount of furan-2-methylthiol (79.9 mg, 0.7 mmol) was added for end-capping. The reaction was allowed to react at room temperature for 24 hours. After completion of the reaction, the polymer was precipitated with 10 volumes of ethanol and washed twice to obtain the product.

[0497] Example 54 7G2G2 n=9.67

[0498] According to the above general reaction formula, a reaction was carried out using propane-1,3-diyl diacrylate (200.8 mg, 1.1 eq) and oleylamine (264.4 mg, 1.0 eq) as starting materials. After solvent-free stirring at 90°C for approximately 27 hours, the reaction progress was monitored by proton nuclear magnetic resonance spectroscopy. Heating was stopped after the target degree of polymerization (dP) n was reached (dP = average degree of polymerization, n = 9-10 (actual n = 9.67) in subsequent examples). The calculated weight-average molecular weight of the polymer was approximately 4097.4579, with a molar weight of 0.11 mmol). The polymer was dissolved in THF at a concentration of 200 mg / mL, and a 10-fold molar amount of oleylamine (294.2 mg, 1.1 mmol) was added for end-capping. The reaction was allowed to react at room temperature for 24 hours. After completion of the reaction, the polymer was precipitated with 10 volumes of ethanol and washed twice to obtain the product. 1 H NMR (500MHz, CDCl3) δ5.39–5.31(m,18H),4.18–4.13(m,39H),2.82(t,J=7.5Hz,39H),2.52(t,J=7.5Hz, 39H),2.46(t,J=7.5Hz,22H),1.98-1.94(m,22H),1.49–1.23(m,299H),0.88(t,J=5.0Hz,33H).Mn:4297

[0499] Example 55 7G3G3 n=8.45

[0500] According to the above general reaction formula, a reaction was carried out using propane-1,3-diyl diacrylate (199.5 mg, 1.1 eq) and propargylamine (54.2 mg, 1.0 eq) as starting materials. After solvent-free stirring at 75°C for approximately 60 hours, the reaction progress was monitored by proton nuclear magnetic resonance spectroscopy. Heating was stopped after the target degree of polymerization (dP) n was reached (dP = average degree of polymerization, n = 8-9 (actual n = 8.45) in subsequent examples). The calculated weight-average molecular weight of the polymer was approximately 1965.524, with a molar weight of 0.13 mmol). The polymer was dissolved in THF at a concentration of 200 mg / mL, and a 10-fold molar amount of propargylamine (71.6 mg, 1.3 mmol) was added for end-capping. The reaction was allowed to react at room temperature for 24 hours. After completion of the reaction, the polymer was precipitated with 10 volumes of ethanol and washed twice to obtain the product.

[0501] Example 56 7G4G4 n=10.86

[0502] According to the above reaction formula, the reaction was carried out using propane-1,3-diyl diacrylate (99.8 mg, 1.1 eq) and propyne-pentaethylene glycol-amine (136.3 mg, 1.0 eq) as raw materials. After solvent-free stirring at 90°C for approximately 25 hours, the reaction progress was monitored by proton nuclear magnetic resonance spectroscopy. Heating was stopped after the reaction reached the target degree of polymerization n (the degree of polymerization n is the average degree of polymerization, and the meaning of n in subsequent examples remains the same, n = 10-11 (actual n = 10.86)). The calculated weight-average molecular weight of the polymer was approximately 4711.9892, and the molar weight was 0.05 mmol. The polymer was dissolved in THF at a concentration of 200 mg / mL, and a 10-fold molar amount of propyne-pentaethylene glycol-amine (137.9 mg, 0.5 mmol) was added for end-capping. The reaction was allowed to react at room temperature for 24 hours. After completion of the reaction, the polymer was precipitated with 10 volumes of ethanol and washed twice to obtain the product.

[0503] Example 57 7G5G5 n=9.0

[0504] According to the above reaction formula, the reaction was carried out using propane-1,3-diyl diacrylate (200.3 mg, 1.1 eq) and 2-amino-5-diethylaminopentane (156.5 mg, 1.0 eq) as raw materials. After stirring at 75°C without solvent for approximately 50 hours, the reaction progress was monitored by proton nuclear magnetic resonance spectroscopy. After the reaction reached the target degree of polymerization n (the degree of polymerization n is the average degree of polymerization, and the meaning of n in subsequent examples is the same as n = 9-10 (actual n = 9.0)), heating was stopped. The calculated weight-average molecular weight of the polymer was approximately 2922.08 and the molar weight was 0.12 mmol. The polymer was dissolved in THF at a concentration of 200 mg / mL, and a 10-fold molar amount of 2-amino-5-diethylaminopentane (193.27 mg, 1.2 mmol) was added for end-capping. The reaction was allowed to react at room temperature for 24 hours. After the reaction was completed, the polymer was precipitated with 10 volumes of ethanol and washed twice to obtain the product.

[0505] Example 58 7G6G6 n=9.58

[0506] According to the above reaction formula, the reaction was carried out using propane-1,3-diyl diacrylate (199.9 mg, 1.1 eq) and N-(3-aminopropyl)-N-methylaniline (163.2 mg, 1.0 eq) as raw materials. After stirring at 75°C without solvent for approximately 25 hours and at 90°C for 1.5 hours, the reaction progress was monitored by hydrogen nuclear magnetic resonance spectroscopy. After the reaction reached the target degree of polymerization n (the degree of polymerization n is the average degree of polymerization, and the meaning of n in subsequent examples remains the same, n=9-10 (actual n=9.58)), heating was stopped. The calculated weight-average molecular weight of the polymer was approximately 3173.69, and the molar weight was 0.11 mmol. The polymer was dissolved in THF at a concentration of 200 mg / mL, and 10-fold molar amount of N-(3-aminopropyl)-N-methylaniline (187.9 mg, 1.1 mmol) was added for end-capping. The reaction was allowed to react at room temperature for 24 hours. After the reaction was completed, the polymer was precipitated with 10-fold volume of ethanol and washed twice to obtain the product.

[0507] Example 59 7G7G7 n=10.04

[0508] According to the above reaction formula, the reaction was carried out using propane-1,3-diyl diacrylate (200 mg, 1.1 eq) and N-(3-aminopropyl)diethanolamine (159.7 mg, 1.0 eq) as raw materials. After stirring at 75°C without solvent for approximately 4 hours, the reaction progress was monitored by proton nuclear magnetic resonance spectroscopy. After the reaction reached the target degree of polymerization n (the degree of polymerization n is the average degree of polymerization, and the meaning of n in subsequent examples is the same as n = 10-11 (actual n = 10.04)), heating was stopped. The calculated weight-average molecular weight of the polymer was approximately 3313.81, and the molar weight was 0.11 mmol. The polymer was dissolved in THF at a concentration of 200 mg / mL, and a 10-fold molar amount of N-(3-aminopropyl)diethanolamine (176.1 mg, 1.1 mmol) was added for end-capping. The reaction was allowed to react at room temperature for 24 hours. After completion of the reaction, the polymer was precipitated with 10 volumes of ethanol and washed twice to obtain the product.

[0509] Example 60 7G8G8 n=10.32

[0510] According to the above reaction formula, the reaction was carried out using propane-1,3-diyl diacrylate (200.5 mg, 1.1 eq) and 6-amino-1-hexanol (115.6 mg, 1.0 eq) as raw materials. After stirring at 75°C without solvent for approximately 7.5 hours, the reaction progress was monitored by nuclear magnetic resonance spectroscopy. After the reaction reached the target degree of polymerization n (the degree of polymerization n is the average degree of polymerization, and the meaning of n in subsequent examples is the same as n = 10-11 (actual n = 10.32)), heating was stopped. The calculated weight-average molecular weight of the polymer was approximately 2991.17 and the molar weight was 0.11 mmol. The polymer was dissolved in THF at a concentration of 200 mg / mL, and 10-fold molar amount of 6-amino-1-hexanol (123.6 mg, 1.1 mmol) was added for end-capping. The reaction was allowed to react at room temperature for 24 hours. After the reaction was completed, the polymer was precipitated with 10-fold volume of ethanol and washed twice to obtain the product.

[0511] Example 61 7G10G10 n=8.27

[0512] According to the above reaction formula, the reaction was carried out using propane-1,3-diyl diacrylate (200.3 mg, 1.1 eq) and cyclohexylmethylamine (111.8 mg, 1.0 eq) as raw materials. After stirring at 90°C without solvent for approximately 30 hours, the reaction progress was monitored by proton nuclear magnetic resonance spectroscopy. After the reaction reached the target degree of polymerization n (the degree of polymerization n is the average degree of polymerization, and the meaning of n in subsequent examples remains the same, n = 8-9 (actual n = 8.27)), heating was stopped. The calculated weight-average molecular weight of the polymer was approximately 2344.6513, and the molar weight was 0.13 mmol. The polymer was dissolved in THF at a concentration of 200 mg / mL, and a 10-fold molar amount of cyclohexylmethylamine (150.5 mg, 1.3 mmol) was added for end-capping. The reaction was allowed to react at room temperature for 24 hours. After completion of the reaction, the polymer was precipitated with 10 volumes of ethanol and washed twice to obtain the product.

[0513] Example 62 7G11G11 n=9.11

[0514] According to the above reaction formula, the reaction was carried out using propane-1,3-diyl diacrylate (204.6 mg, 1.1 eq) and 4-phenylbutylamine (150.7 mg, 1.0 eq) as raw materials. After stirring at 75°C without solvent for approximately 30 hours, the reaction progress was monitored by proton nuclear magnetic resonance spectroscopy. After the reaction reached the target degree of polymerization n (the degree of polymerization n is the average degree of polymerization, and the meaning of n in subsequent examples is the same as n = 9-10 (actual n = 9.11)), heating was stopped. The calculated weight-average molecular weight of the polymer was approximately 2886.25, and the molar weight was 0.12 mmol. The polymer was dissolved in THF at a concentration of 200 mg / mL, and a 10-fold molar amount of 4-phenylbutylamine (183.7 mg, 1.2 mmol) was added for end-capping. The reaction was allowed to react at room temperature for 24 hours. After completion of the reaction, the polymer was precipitated with 10 volumes of ethanol and washed twice to obtain the product.

[0515] Example 63B29C8C8 n=11.1

[0516] According to the above reaction formula, the reaction was carried out using 1,6-bis(acryloyloxy)-2,2,3,3,4,4,5,5-octafluorohexane (157.65 mg, 1.1 eq) and octylamine (50 mg, 1.0 eq) as raw materials. After solvent-free stirring at 90°C for approximately 9 hours, the reaction progress was monitored by proton nuclear magnetic resonance spectroscopy. After the reaction reached the target degree of polymerization n (the degree of polymerization n is the average degree of polymerization, and the meaning of n in subsequent examples remains the same, n = 11-12 (actual n = 11.1)), heating was stopped. The calculated weight-average molecular weight of the polymer was approximately 5413.524, and the molar weight was 0.04 mmol. The polymer was dissolved in THF at a concentration of 200 mg / mL, and octylamine (49.5 mg, 0.4 mmol) was added for end-capping. The reaction was allowed to react at room temperature for 24 hours. After completion of the reaction, the polymer was precipitated with 10 volumes of ethanol and washed twice to obtain the product.

[0517] Example 64B31C8C8 n=11.33

[0518] The reaction was carried out according to the above reaction formula, using α-(1-oxo-2-propenyl)-ω-[(1-oxo-2-propenyl)oxy]-poly[oxy(methyl-1,2-ethylene)] (298.1 mg, 1.1 eq) and octylamine (50 mg, 1.0 eq) as raw materials. After stirring at 90° C. without solvent for about 5.5 hours, the reaction progress was monitored by hydrogen nuclear magnetic resonance spectroscopy. After the reaction reached the target degree of polymerization n (the degree of polymerization n is the average degree of polymerization, and the subsequent examples have the same meaning of n=11-12 (actual n=11.33)), heating was stopped. The calculated weight average molecular weight of the polymer was approximately 9265.1195, and the molar weight was 0.04 mmol. The polymer was dissolved in THF at a concentration of 200 mg / mL, and 10-fold molar amount of octylamine (51.66 mg, 0.4 mmol) was added for end-capping. The reaction was allowed to react at room temperature for 24 hours. After the reaction was completed, the polymer was precipitated with 10-fold volume of ethanol and washed twice to obtain the product.

[0519] Example 65B33C8C8 n=11.78

[0520] According to the above general reaction formula, a reaction was carried out using polyethylene glycol diacrylate (244.87 mg, 1.1 eq) and octylamine (50 mg, 1.0 eq) as raw materials. After solvent-free stirring at 90°C for approximately 22 hours, the reaction progress was monitored by proton nuclear magnetic resonance spectroscopy. Heating was stopped after the reaction reached the target degree of polymerization n (the degree of polymerization n is the average degree of polymerization, and the meaning of n in subsequent examples remains the same, n = 11-12 (actual n = 11.78)). The calculated weight-average molecular weight of the polymer was approximately 8165.737, and the molar weight was 0.04 mmol. The polymer was dissolved in THF at a concentration of 200 mg / mL, and a 10-fold molar amount of octylamine (51.66 mg, 0.4 mmol) was added for end-capping. The reaction was allowed to react at room temperature for 24 hours. After completion of the reaction, the polymer was precipitated with 10 volumes of ethanol and washed twice to obtain the product.

[0521] Example 66

[0522] B34C8C8 n=9.18

[0523] According to the above reaction formula, the reaction was carried out using 9,9-bis[4-(2-acryloyloxyethoxy)phenyl]fluorene (232.78 mg, 1.1 eq) and octylamine (50 mg, 1.0 eq) as raw materials. After solvent-free stirring at 90°C for approximately 4.5 hours, the reaction progress was monitored by proton nuclear magnetic resonance spectroscopy. After the reaction reached the target degree of polymerization n (the degree of polymerization n is the average degree of polymerization, and the meaning of n in subsequent examples remains the same, n = 9-10 (actual n = 9.18)), heating was stopped. The calculated weight-average molecular weight of the polymer was approximately 6194.2968, and the molar weight was 0.04 mmol. The polymer was dissolved in THF at a concentration of 200 mg / mL, and octylamine (51.66 mg, 0.4 mmol) was added to cap the end. The reaction was allowed to react at room temperature for 24 hours. After completion of the reaction, the polymer was precipitated with 10 volumes of ethanol and washed twice to obtain the product.

[0524] Example 67

[0525] B35C8C8 n=11.55

[0526] According to the above general reaction formula, ethylene glycol diacrylate (72.45 mg, 1.1 eq) and octylamine (50 mg, 1.0 eq) were used as raw materials. After solvent-free stirring at 75°C for approximately 7 hours, the reaction progress was monitored by proton nuclear magnetic resonance spectroscopy. Heating was stopped after the target degree of polymerization (dP) n was reached (dP = average degree of polymerization, n = 11-12 (actual n = 11.55) in subsequent examples). The polymer had a weight-average molecular weight of approximately 3588.05 and a molar weight of 0.034 mmol). The polymer was dissolved in THF at a concentration of 200 mg / mL and capped with 10-fold molar amount of octylamine (45 mg, 0.34 mmol). The reaction was allowed to react at room temperature for 24 hours. After completion, the polymer was precipitated with 10 volumes of ethanol and washed twice to obtain the product.

[0527] Example 68

[0528] 3C8N n=10.62

[0529] According to the above general reaction formula, the reaction was carried out using tetraethylene glycol diacrylate (302.32 mg, 1.1 eq) and octylamine (117.4 mg, 1.0 eq) as raw materials. After stirring at 75°C without solvent for approximately 7 hours, the reaction progress was monitored by proton nuclear magnetic resonance spectroscopy. Heating was stopped after the reaction reached the target degree of polymerization n (the degree of polymerization n is the average degree of polymerization, and the meaning of n in subsequent examples remains the same, n = 10-11 (actual n = 10.62)). The polymer was dissolved in THF at a concentration of 200 mg / mL, and a 10-fold molar amount of N,N-dimethyl-1,3-diaminopropane (96.5 mg, 0.95 mmol) was added for end-capping. The reaction was allowed to react at room temperature for 24 hours. After completion of the reaction, the polymer was precipitated with 10 volumes of ethanol and washed twice to obtain the product. 1 H NMR (500MHz, CDCl3) δ4.41–4.08(m,42H),3.71–3.63(m,125H),2.88(td,J=6.5,2.7Hz,2H),2.77(t,J=7.3Hz,39H),2.71–2.50(m,7H),2.50–2.42( m,38H),2.42–2.35(m,19H),2.31(td,J=7.3,2.1Hz,2H),2.22(s,6H),1.4 0(p,J=7.6Hz,20H),1.33–1.18(m,122H),0.88(t,J=7.0Hz,31H).Mn=4489

[0530] Example 69

[0531] 3C12N n=8.95

[0532] According to the above reaction formula, the reaction was carried out using tetraethylene glycol diacrylate (302.32 mg, 1.1 eq) and dodecyl primary amine (168.5 mg, 1.0 eq) as raw materials. After stirring at 75°C without solvent for approximately 9 hours, the reaction progress was monitored by proton nuclear magnetic resonance spectroscopy. After the reaction reached the target degree of polymerization n (the degree of polymerization n is the average degree of polymerization, and the meaning of n in subsequent examples is the same as n = 8-9 (actual n = 8.95)), heating was stopped. The polymer was dissolved in THF at a concentration of 200 mg / mL, and a 10-fold molar amount of N,N-dimethyl-1,3-diaminopropane (115 mg, 1.14 mmol) was added for end-capping. The reaction was allowed to react at room temperature for 24 hours. After the reaction was completed, the polymer was precipitated with 10 volumes of ethanol and washed twice to obtain the product. 1 H NMR (500MHz, CDCl3) δ4.28–4.18(m,35H),3.71–3.64(m,109H),2.88(td,J= 6.4,4.0Hz,2H),2.77(t,J=7.4Hz,34H),2.71–2.50(m,7H),2.47(t,J=7.3H z,34H),2.43–2.35(m,18H),2.31(td,J=7.0,2.1Hz,2H),2.26–2.15(m,5H) ,1.42–1.38(m,15H),1.33–1.18(m,194H),0.88(t,J=7.0Hz,26H).Mn=4907.

[0533] Example 70

[0534] 3C16N n=9.00

[0535] According to the above reaction formula, the reaction was carried out using tetraethylene glycol diacrylate (302.32 mg, 1.1 eq) and hexadecylamine (219.5 mg, 1.0 eq) as raw materials. After stirring at 90°C without solvent for approximately 7 hours, the reaction progress was monitored by proton nuclear magnetic resonance spectroscopy. Heating was stopped after the reaction reached the target degree of polymerization n (the degree of polymerization n is the average degree of polymerization, and the meaning of n in subsequent examples is the same as n = 9-10 (actual n = 9.00)). The polymer was dissolved in THF at a concentration of 200 mg / mL and capped with 10-fold molar amount of N,N-dimethyl-1,3-diaminopropane (82.5 mg, 0.82 mmol). The reaction was allowed to react at room temperature for 24 hours. After completion of the reaction, the polymer was precipitated with 10-fold volume of ethanol and washed twice to obtain the product. 1H NMR (500MHz, CDCl3) δ4.29–4.18(m,36H),3.71–3.64(m,113H),2.88(td,J =6.6,3.1Hz,3H),2.77(t,J=7.4Hz,34H),2.71–2.51(m,7H),2.47(t,J=7. 3Hz,34H),2.39(t,J=7.5Hz,17H),2.35–2.27(m,2H),2.22(s,6H),1.40(p ,J=7.3Hz,20H),1.25(t,J=3.6Hz,281H),0.88(t,J=7.0Hz,28H).Mn=4862

[0536] Example 71

[0537] Preparation and Characterization of mRNA Polymer-Lipid Nanoparticles (PLNPs)

[0538] Preparation method:

[0539] Method 1: Appropriate amounts of the ionizable polymer PBAE, DOPE, cholesterol, and DMG-PEG were weighed and prepared into an ethanol solution. The ethanol organic phase was prepared at a molar ratio of PBAE:DOPE:cholesterol:DMG-PEG = 23.8:23.8:47.6:4.8. The mRNA was diluted in sodium citrate solution at pH 3 as the aqueous phase. The nitrogen-phosphorus ratio of the ionizable polymer to the mRNA was 25:1 for B1 and B3, and 12.5:1 for B2. The organic phase was rapidly injected into the mRNA-added aqueous phase at a volume ratio of 1:2, mixed thoroughly, and the sample was incubated on ice for 5 minutes. The components assembled to form mRNA polymer-lipid nanoparticles. For in vitro characterization, the nanoparticles can be used directly. For in vivo screening, the nanoparticles must be dialyzed against 2000 volumes of PBS at 4°C for 2 hours to remove the organic solvent and form the final nanoparticles.

[0540] Method 2: Appropriate amounts of the ionizable polymer PBAE, DOPE, cholesterol, and DMG-PEG are weighed and prepared into an ethanol solution. The ethanol organic phase is prepared at a molar ratio of PBAE:DOPE:cholesterol:DMG-PEG = 25:12:60:3. The mRNA is diluted in sodium acetate solution at pH 5 as the aqueous phase. The nitrogen-phosphorus ratio of the ionizable polymer to the mRNA is 21:1. The organic phase is rapidly injected into the mRNA-added aqueous phase at a volume ratio of 1:3. Mix thoroughly. After incubating the sample on ice for 5 minutes, the components assemble to form mRNA polymer-lipid nanoparticles. For in vitro characterization, the nanoparticles can be used directly. For in vivo screening, the nanoparticles must be dialyzed against 2000 volumes of PBS at 4°C for 2 hours to remove the organic solvent and form the final nanoparticles.

[0541] The particle size, potential and polydispersity index (PDI) of mRNA polymer-lipid nanoparticles prepared by method 1 are shown in Table 1

[0542] Table 1 Properties of the mRNA polymer-lipid nanoparticles of the present invention

[0543] The above data show that the particle size of the mRNA polymer-lipid nanoparticles of the present invention is between 50 and 200 nm, which meets the particle size requirements for nucleic acid delivery vectors; the polydispersity coefficients (PDI) are all less than 0.2, indicating that the mRNA polymer-lipid nanoparticles prepared by the ethanol injection method are uniform in size and have strong consistency; the Zeta potential is between -10 and +10 mV, indicating that the prepared mRNA polymer-lipid nanoparticles can effectively encapsulate nucleic acids while shielding excessive potential to prevent binding to various proteins in the blood circulation and being rapidly cleared.

[0544] Example 72

[0545] The polymer-lipid nanoparticles prepared by method 1 were used to mediate cell transfection of EGFP plasmid and green fluorescent protein mRNA (Suzhou Jinan Protein Technology Co., Ltd., product number MR008).

[0546] Experimental Methods: PLNPs were prepared using in vitro characterization methods for polymer-lipid nanoparticles. HEK 293T cells (purchased from the Institute of Cell Biology, Chinese Academy of Sciences) were transfected with 150 ng / well of pEGFP (purchased from Addgene) or mEGFP (purchased from Suzhou Jinan Protein Technology Co., Ltd.) in 96-well plates. Fluorescence expression was observed 24 hours after transfection.

[0547] Table 2 Quantification of EGFP green fluorescence expression in HEK 293T cells transfected with pDNA polymer-lipid nanoparticles of the present invention

[0548] The above results show that most of the three main chain molecules exhibited obvious green fluorescence signals, among which B2 had the highest expression efficiency, followed by B1, and B3 had the lowest. All of them showed stronger transfection effects under polar blocking groups, and the expression intensity also increased with the increase of hydrophobic side chain length, especially when transfecting mRNA. This rule is more obvious.

[0549] Table 3 Quantification of EGFP green fluorescence expression in HEK 293T cells transfected with polymer-lipid nanoparticles containing green fluorescent protein mRNA (Suzhou Jinan Protein Technology Co., Ltd., Cat. No. MR008)

[0550] The above results show that most of the six main chain molecules exhibited obvious green fluorescence signals. Among them, B5, B7, B8 and B2 had higher expression efficiency, followed by B1, and B3 had the lowest. They all showed stronger transfection effects under polar blocking groups. The expression intensity also increased with the increase of hydrophobic side chain length, especially when transfecting mRNA. This rule was more obvious.

[0551] Example 73

[0552] The polymer-lipid nanoparticles prepared by method 1 were used to mediate in vivo transfection of luciferase mRNA (Suzhou Jinan Protein Technology Co., Ltd., product number MR009).

[0553] Experimental Methods: PLNPs were prepared using a polymer-lipid nanoparticle method developed for in vivo screening. Dialyzed nanoparticles were diluted to 0.02 mg / mL in PBS and stored on ice. Luciferase mRNA was then injected into the tail vein of 3-week-old ICR male mice (n=3) at a dose of 0.2 mg / kg. Six hours after administration, luciferase substrate solution (15 mg / mL dissolved in DPBS) was injected intraperitoneally at a dose of 10 μL / g of mouse body weight. In vivo imaging was used to detect bioluminescent signals. The effectiveness and targeting of each PBAE were evaluated by bioluminescent signal intensity in vivo and expression distribution in various organs after dissection.

[0554] Table 4 Quantitative expression of mRNA polymer-lipid nanoparticles of the present invention in vivo

[0555] Table 4-1 Quantitative expression of mRNA polymer-lipid nanoparticles in various organs of the present invention

[0556] These experimental results demonstrate effective in vivo expression across all six main chain molecules, with B1, B5, B7, B8, and B35 showing the highest expression efficiencies, followed by B3, and B2 showing the lowest. Furthermore, expression efficacy correlated with side chains and end-capping groups: Within the same end-capping group, in vivo expression increased with increasing side chain length. Polymers with carbon chain lengths of 8-16 exhibited good in vivo expression, while carbon chain lengths of 18 or less were less effective. Within the same main chain and side chain, in vivo expression was partially enhanced with decreasing end-capping group polarity.

[0557] Example 74

[0558] Liver and lung specific targeting blank and mRNA polymer-lipid nanoparticles prepared by method 1 red blood cell hemolysis experiment

[0559] Experimental method: Blood was collected from C57BL / 6 mice through the eye socket and placed in a heparin-moistened EP tube. After centrifugation at 3500rpm and 4℃ for 10 minutes, the supernatant was discarded to obtain red blood cells. The red blood cells were then diluted to 5 times the volume of 10mM PBS (pH 7.4) and washed 5 times, and finally resuspended in 5 times the volume of PBS. 15μL of the diluted red blood cell suspension was added to 135μL of PBS containing different concentrations of unloaded PLNPs or mRNA-loaded PLNPs (PBAE 100ug / mL, 200ug / mL and 400ug / mL). After incubation at 37℃ for 1 hour, the sample was centrifuged at 3500rpm for 5 minutes, 100μL of the supernatant was taken and placed in a 96-well plate, and the absorbance at 545nm was read by a microplate reader. The degree of red blood cell hemolysis caused by PBAE is proportional to the absorbance. The percentage of red blood cell hemolysis was calculated using the following formula:

[0560] Table 5 Evaluation of the hemolytic activity of blank and mRNA polymer-lipid nanoparticles of the present invention

[0561] The above experimental results show that when erythrocytes were incubated with liver-targeted 1C16X PLNPs at different concentrations, regardless of whether they were loaded with nucleic acids, PBAE without terminal amino groups exhibited relatively weak erythrocyte hemolysis (<10%), while PBAE with amino termini significantly increased the probability of erythrocyte hemolysis. This contrast was even more pronounced in the lung-targeted 3C10X material. 3C10X with terminal amino groups caused high hemolysis rates of 30%-60% at low PBAE concentrations, while 3C10X without terminal amino groups did not experience significant hemolysis even at high concentrations (<10%).

[0562] Example 75

[0563] Cytotoxicity experiments of blank mRNA polymer-lipid nanoparticles with liver and lung specific targeting and those prepared by method 1

[0564] Experimental Methods: Unloaded PLNPs or mRNA-loaded PLNPs at varying concentrations were prepared using the polymer-lipid nanoparticle method. Cell viability was assessed using a CCK-8 assay after 24 hours of incubation of HEK 293T cells with either unloaded or mRNA-loaded PLNPs in the presence of PBAE at low doses of 40 μg / mL and high doses of 80 μg / mL.

[0565] Table 6 Cytotoxicity evaluation of blank and mRNA polymer-lipid nanoparticles transfected into HEK 293T cells

[0566] The above experimental results show that in the liver-targeted material 1C16X, PBAE without a terminal amino group showed little to no cell growth inhibition, while PBAE with a terminal amino group exhibited significant cytotoxicity, with toxicity increasing in a dose-dependent manner. However, the lung-targeted material 3C10X showed no significant end-capping-related differences in cytotoxicity, and the cell state remained essentially normal with and without nucleic acid encapsulation, as well as with high-dose PBAE.

[0567] Example 76

[0568] In vivo tolerance study of blank polymer-lipid nanoparticles specifically targeting the liver and lungs

[0569] Experimental Methods: Preliminary experiments determined the maximum tolerated doses of various PBAE structures. The 1C16X series exhibited a higher tolerated dose in mice than the 3C10X series. Based on this, a low, medium, and high PBAE dose gradient was established to reflect the in vivo toxicity of empty PLNPs with different structures. Each PLNP was injected into mice via the tail vein, and survival and weight changes were continuously observed and recorded over 7 days.

[0570] Table 7 In vivo tolerance dose determination of blank polymer-lipid nanoparticles 1C16X of the present invention

[0571] Table 8 In vivo tolerance dose determination of blank polymer-lipid nanoparticles 3C10X of the present invention

[0572] The above experimental results show that the presence of terminal amino groups significantly increased the mortality rate in mice, regardless of whether it was the liver-targeted 1C16X series or the lung-targeted 3C10X series. Compared to PBAEs without terminal amino groups, PBAEs with terminal amino groups caused mouse mortality at lower doses, and the mortality rate gradually increased with increasing doses. However, PBAEs without terminal amino groups maintained normal mouse health even at the highest dose.

[0573] Example 77

[0574] Body weight changes of mice within 7 days after administration of blank polymer-lipid nanoparticles 1C16X and 3C10X of the present invention at different doses

[0575] The weight changes of surviving mice were recorded within 7 days after administration. Basically, most mice (except 3C10C10) lost weight on the first day after administration, among which PBAE with an amino group at the end had a greater weight loss. Then the weight gradually recovered. All mice were able to basically return to their initial weight before administration within 7 days. The weight changes within 7 days after administration of 1C16X are shown in Figure 1, and the weight changes within 7 days after administration of 3C10X are shown in Figure 2.

Claims

1. A compound as shown in formula I or a pharmaceutically acceptable salt thereof, characterized in that: Wherein, n is 2-20; R is -(CH2)m- or is replaced by one or more R a Substituted -(CH2)m-, wherein 0 to 12 -CH2- in the -(CH2)m- are optionally independently replaced by O, S, -NR b -, Sub-C6-C 12 Aryl, C3-C6 cycloalkylene, 1 or more R c Substituted C6-C 12 Aryl and 9,9-diphenylfluorenyl are substituted, and m is 1-40; Each R a are independently hydroxyl, -NR b R b , C1-C6 alkyl, halogen or C1-C4 heteroalkyl; the heteroatom species in the C1-C4 heteroalkyl is selected from one or more of O, S and N, and the number of heteroatoms is 1, 2 or 3; Each R b are independently hydrogen, C1-C6 alkyl, C6-C 12 Aryl, 1 or more R c Substituted C6-C 12 Aryl or one or more R b1 Substituted C1-C6 alkyl; Each R c are independently hydroxy, nitro, cyano, C1-C6 alkyl, halogen or amino; Each R b1 are independently hydroxyl groups; R 1 C1-C 22 Alkyl, C2-C 22 Alkenyl, C2-C 22 Alkynyl, with one or more R 1-1 Substituted C1-C 22 Alkyl, with one or more R 1-2 Substituted C2-C 22 Alkenyl or one or more R 1-3 Substituted C2-C 22 Alkynyl; the C1-C 22 0 to 8 -CH2- in the alkyl group are optionally independently replaced by O or S; 22 0 to 8 -CH2- in the alkenyl group are optionally independently replaced by O or S; 22 0 to 8 -CH2- in the alkynyl group are optionally independently replaced by O or S; Each R 1-1 , R 1-2 and R 1-3 Independently -NR b R b , hydroxyl, C6-C 12 Aryl or C3-C6 cycloalkyl; R 2 C1-C 22 Alkyl, C2-C 22 Alkenyl, C2-C 22 Alkynyl, with one or more R 2-1 Substituted C1-C 22 Alkyl, with one or more R 2-2 Substituted C2-C 22 Alkenyl, one or more R 2-3 Substituted C2-C 22 Alkynyl, C3-C6 cycloalkyl, 1 or more R 2e Substituted C3-C6 cycloalkyl, "a 3-7 membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from N, O and S" or substituted by 1 or more R 2f The substituted "heteroatom is selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3 3-membered heterocycloalkyl", the C2-C 22 0 to 8 -CH2- in the alkynyl group are optionally replaced by O or S; Each R 2-1 , R 2-2 and R 2-3 Independently -NR b R b , hydroxyl, C6-C 12 Aryl, one or more R 2d3 Substituted C6-C 12 Aryl, C3-C6 cycloalkyl, one or more R 2d3 Substituted C3-C6 cycloalkyl, "a 5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S" or one or more R 2d3 Substituted "5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S"; Each R 2d3 are independently C1-C6 alkyl, halogen or halogenated C1-C6 alkyl; Each R 2e and R 2f are independently halogen, C1-C6 alkyl or halogenated C1-C6 alkyl; X is R 3 is hydrogen, C1-C 22 Alkyl, C2-C 22 Alkenyl, C2-C 22 Alkynyl, with one or more R 3-1 Substituted C1-C 22 Alkyl, with one or more R 3-2 Substituted C2-C 22 Alkenyl, one or more R 3-3 Substituted C2-C 22 Alkynyl, C3-C6 cycloalkyl, C6-C 12 Aryl or "3-7 membered heterocycloalkyl group whose heteroatoms are selected from 1, 2 or 3 of N, O and S, and whose heteroatoms are 1, 2 or 3"; Each R 3-1 , R 3-2 and R 3-3 Independently -NR b R b , C3-C6 cycloalkyl or hydroxy.

2. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: Wherein, n is 2-20; R is -(CH2)m- or is replaced by one or more R a Substituted -(CH2)m-, wherein 0 to 10 -CH2- in the -(CH2)m- are optionally replaced by O, S, -NR b -, Sub-C6-C 12 Aryl, C3-C6 cycloalkylene and 1 or more R c Substituted C6-C 12 Aryl, m is 1-30; Each R a are independently hydroxyl, -NR b R b , C1-C6 alkyl, halogen or C1-C4 heteroalkyl; the heteroatom species in the C1-C4 heteroalkyl is selected from one or more of O, S and N, and the number of heteroatoms is 1, 2 or 3; Each R b are independently hydrogen, C1-C6 alkyl, C6-C 12 Aryl or 1 or more R c Substituted C6-C 12 Aryl; Each R c are independently hydroxy, nitro, cyano, C1-C6 alkyl, halogen or amino; R 1 C1-C 22 Alkyl, C2-C 22 Alkenyl, C2-C 22 Alkynyl, with one or more R 1-1 Substituted C1-C 22 Alkyl, with one or more R 1-2 Substituted C2-C 22 Alkenyl or one or more R 1-3 Substituted C2-C 22 Alkynyl; Each R 1-1 , R 1-2 and R 1-3 Independently -NR b R b or hydroxyl; R 2 C1-C 22 Alkyl, C2-C 22 Alkenyl, C2-C 22 Alkynyl, with one or more R 2-1 Substituted C1-C 22 Alkyl, with one or more R 2-2 Substituted C2-C 22 Alkenyl or one or more R 2-3 Substituted C2-C 22 Alkynyl; Each R 2-1 , R 2-2 and R 2-3 Independently -NR b R b or hydroxyl; X is R 3 is hydrogen, C1-C 22 Alkyl, C2-C 22 Alkenyl, C2-C 22 Alkynyl, with one or more R 3-1 Substituted C1-C 22 Alkyl, with one or more R 3-2 Substituted C2-C 22 Alkenyl, one or more R 3-3 Substituted C2-C 22 Alkynyl, C3-C6 cycloalkyl, C6-C 12 Aryl or a 3-7-membered heterocycloalkyl group optionally substituted by 1, 2 or 3 heteroatoms, wherein the heteroatoms are optionally one or more of N, O and S; the number of heteroatoms is 1, 2 or 3; Each R 3-1 , R 3-2 and R 3-3 Independently -NR b R b , C3-C6 cycloalkyl or hydroxy.

3. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that: The compound as shown in formula I satisfies one or more of the following conditions: (1) In R, in the -(CH2)m-, m is 1-27, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 14, 15, 23 or 27; (2) In R, the one or more R a In the substituted -(CH2)m-, the plurality is 2-8, for example, 2, 3, 4, 5, 6, 7 or 8; (3) In R, 0 to 10 -CH2- in the -(CH2)m- are optionally replaced by O, S, -NR b -, Sub-C6-C 12 Aryl and 1 or more R c Substituted C6-C 12 Aryl means that 1 to 6 -CH2- in the -(CH2)m- are optionally substituted by O, and m can be 5-27, for example (4) In R, 0 to 10 -CH2- in the -(CH2)m- are optionally replaced by O, S, -NR b -, Sub-C6-C 12 Aryl and 1 or more R c Substituted C6-C 12 Aryl means that 1 to 2 -CH2- in the -(CH2)m- are optionally substituted by S, and m can be 1-6, for example (5) In R, 0 to 10 -CH2- in the -(CH2)m- are optionally replaced by O, S, -NR b -, Sub-C6-C 12 Aryl and 1 or more R c Substituted C6-C 12 Aryl is 1 to 2 -CH2- in the -(CH2)m-, which are optionally replaced by C6-C 12 Aryl and / or 1 or more R c Substituted C6-C 12 Aryl substitution, m can be 1-6, for example (6) In R, 0 to 10 -CH2- in the -(CH2)m- are optionally replaced by O, S, -NR b -, Sub-C6-C 12 Aryl and 1 or more R c Substituted C6-C 12 The aryl group is 1 to 6 -CH2- in the -(CH2)m- group, which are optionally replaced by O and C6-C 12 Aryl and / or 1 or more R c Substituted C6-C 12 Aryl substitution, e.g. (7) In R, the sub-C6-C 12 The aromatic group is C6-C 10 an aryl group, for example, phenylene; (8)R a wherein the C1-C6 alkyl group is a C1-C4 alkyl group, for example, methyl, ethyl; (9)R a wherein the halogen is fluorine, chlorine, bromine or iodine, for example, fluorine; (10) Each R a In the C1-C4 heteroalkyl group, the heteroatom type is O, S or N, such as O; the number of heteroatoms can be 2; for example (11)R a wherein the C1-C4 heteroalkyl group is a C4 heteroalkyl group; (12)R b wherein the C1-C6 alkyl group is a C1-C4 alkyl group, for example, a methyl group; (13)R b In the C6-C 12 The aryl group is C6-C 10 an aryl group, for example, a phenyl group; (14)R c wherein the C1-C6 alkyl group is a C1-C4 alkyl group, for example, a methyl group; (15)R c wherein the halogen is fluorine, chlorine, bromine or iodine, for example, fluorine; (16)R 1 In the above, C1-C 22 The alkyl group is C2-C 20 The alkyl group is preferably a straight chain C2-C 20 The alkyl group, for example, (17)R 1 In the C2-C 22 Alkenyl is C 14 -C 22 Alkenyl, preferably a straight chain C 14 -C 22 Alkenyl, for example, (18)R 2 In the above, C1-C 22 The alkyl group is C2-C 20 The alkyl group is preferably a straight chain C2-C 20 The alkyl group, for example, (19)R 2 In the C2-C 22 Alkenyl is C 14 -C 22 Alkenyl, preferably a straight chain C 14 -C 22 Alkenyl, for example, (20)R 2 In the above, the one or more R 2-1 Substituted C1-C 22 Alkyl is an R 2-1 Substituted C3-C6 alkyl, for example, (21)R 3 In the above, C1-C 22 The alkyl group is a C1-C4 alkyl group, for example, (22)R 3 In the above, the one or more R 3-1 Substituted C1-C 22 Alkyl is an R 3-1 Substituted C1-C3 alkyl, for example, and (23)R 3-1 In the formula (C3-C6), the C3-C6 cycloalkyl group is 4. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The compound as shown in formula I satisfies one or more of the following conditions: (1) R, wherein the a In the substituted -(CH2)m-, the plurality is 2-14, for example, 2, 3, 4, 5, 6, 7, 8 or 12; (2) In R, 0 to 12 -CH2- in the -(CH2)m- are optionally and independently replaced by O, S, -NR b -, Sub-C6-C 12 Aryl, C3-C6 cycloalkylene, 1 or more R c Substituted C6-C 12 The aryl group and the 9,9-diphenylfluorenyl group are replaced by 1 to 13 -CH2- in the -(CH2)m-, and m can be 5-36, for example (3) In R, 0 to 12 -CH2- in the -(CH2)m- are optionally and independently replaced by O, S, -NR b -, Sub-C6-C 12 Aryl, C3-C6 cycloalkylene, 1 or more R c Substituted C6-C 12 Aryl and 9,9-diphenylfluorenyl are substituted with 1 to 2 -CH2- in the -(CH2)m- being optionally substituted with S, and m can be 1-6, for example (4) In R, 0 to 12 -CH2- in the -(CH2)m- are optionally and independently replaced by O, S, -NR b -, Sub-C6-C 12 Aryl, ethylene C3-C6 cycloalkyl, 1 or more R c Substituted C6-C 12 The aryl and 9,9-diphenylfluorenyl groups are replaced by 1 to 2 -CH2- in the -(CH2)m- group, which are optionally replaced by C6-C 12 Aryl or 1 or more R c Substituted C6-C 12 Aryl substitution, m can be 1-6, for example (5) In R, 0 to 12 -CH2- in the -(CH2)m- are optionally and independently replaced by O, S, -NR b -, Sub-C6-C 12 Aryl, C3-C6 cycloalkylene, 1 or more R c Substituted C6-C 12 The aryl and 9,9-diphenylfluorenyl groups are substituted by 1 to 6 -CH2- in the -(CH2)m- group, which are optionally replaced by O and C6-C 12 Aryl substitution, e.g. (6)R b wherein the C1-C6 alkyl group is a C1-C4 alkyl group, for example, a methyl group or an ethyl group; (7) The one or more R b1 The C1-C6 alkyl in the substituted C1-C6 alkyl is a C1-C4 alkyl; for example, ethyl; (8)R 1 In the C2-C 22 Alkynyl is a straight chain C2-C 20 Alkynyl groups, for example, (9)R 1 In the C2-C 22 0 to 8 -CH2- in the alkynyl group are optionally independently replaced by O or S to form the C2-C 22 0 to 8 -CH2- in the alkynyl group are optionally replaced by O; for example, (10)R 1-1 In the C6-C 12 Aryl is phenyl; (11)R 1-1 wherein the C3-C6 cycloalkyl group is a cyclohexyl group; (12)R 2 In the above, C1-C 22 The alkyl group is C2-C 20 The alkyl group, for example, (13)R 2 In the C2-C 22 The alkenyl groups are independently C2-C 22 Alkenyl, preferably a straight chain C2-C 10 Alkenyl, for example, (14)R 2 In the C2-C 22 Alkynyl is C2-C6 alkynyl, preferably a straight-chain C2-C6 alkynyl, for example, (15)R 2 In the C2-C 22 0 to 8 -CH2- in the alkynyl group are optionally replaced by O or S to form the C2-C 22 0 to 8 -CH2- in the alkynyl group are optionally replaced by O; for example, (16)R 2 In the above, the one or more R 2-1 Substituted C1-C 22 The alkyl group may be 2-1 Substituted C1-C6 alkyl, for example, (17)R 2 wherein the C3-C6 cycloalkyl group is a cyclohexyl group; (18)R 2 In the heterocycloalkyl group of the 3-7 membered ring, the heteroatom is N or O; for example, (19)R 2-1 In the C6-C 12 Aryl is phenyl; (20)R 2-1 In the above, the one or more R 2d3 Substituted C6-C 12 Aryl is an aryl group consisting of one or more R 2d3 Substituted C6-C 12 Aryl; for example, (21)R 2-1 wherein the C3-C6 cycloalkyl group is a cyclohexyl group; (22)R 2-1 In the above, the "5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S" is a 5-membered heteroaryl group substituted by O, for example, (23)R 2d3 wherein the halogen is fluorine, chlorine, bromine or iodine, for example, bromine; (24)R 2f In the above, the C1-C6 alkyl group is independently a C1-C4 alkyl group; for example, a methyl group; (25) In the halogenated C1-C6 alkyl group, the halogenated group is substituted by halogen, and the halogenated group is fluorine, chlorine, bromine or iodine; the C1-C6 alkyl group is a C1-C4 alkyl group; (26)R 3 In the above, C1-C 22 The alkyl group may be a C1-C6 alkyl group, for example, and (27)R 3 In the C2-C 22 Alkenyl is C2-C4 alkenyl, for example, 5. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The compound as shown in formula I satisfies one or more of the following conditions: (1) n is 5-12; (2) R is -(CH2)m- or is replaced by one or more R a substituted -(CH2)m-; wherein 0 to 12 -CH2- in said -(CH2)m- are optionally replaced by O, S, sub-C6-C 12 Aryl, 1 or more R c Substituted C6-C 12 Aryl and 9,9-diphenylfluorenyl, m is 1- 27, for example, Preferably, R is -(CH2)m- or is replaced by one or more R a Substituted -(CH2)m-; the -(CH2)m- satisfies any of the following conditions: (1) 1 to 12 -CH2- in -(CH2)m- are optionally replaced by O; (2) 1 to 6 -CH2- in the -(CH2)m- are optionally and independently replaced by O and C6-C 12 Aryl substitution; for example, R is For example, R is For example, R is (3)R 1 C1-C 22 Alkyl, C2-C 22 Alkenyl, C2-C 22 Alkynyl or one or more R 1-1 Substituted C1-C 22 Alkyl, the C2-C 22 0 to 5 -CH2- in the alkynyl group are optionally substituted by O; for example, Preferably, R 1 For C8-C 18 Alkyl, C3-C 18 Alkenyl, C3-C 18 Alkynyl or one or more R 1-1 Substituted C1-C6 alkyl, the C2-C 22 0 to 5 -CH2- in the alkynyl group are optionally substituted by O; for example, More preferably, R 1 For C8-C 18 Alkyl groups, such as R 1 for For example, R 1 for (4) Each R 1-1 For-NR b R b , hydroxyl, C6-C 12 Aryl or C3-C6 cycloalkyl; (5)R 2 C1-C 22 Alkyl, C2-C 22 Alkenyl, C2-C 22 Alkynyl, with one or more R 2-1 Substituted C1-C 22 Alkyl, C3-C6 cycloalkyl, "3-7 membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from N, O and S" or "substituted by 1 or more R 2f The substituted "heteroatom is selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3 3-membered heterocycloalkyl", the C2-C 22 0 to 5 -CH2- in the alkynyl group are optionally substituted by O; for example, Preferably, R 2 C1-C 18 Alkyl, C3-C 18 Alkenyl, C3-C 18 Alkynyl, with one R 2-1 Substituted C1-C6 alkyl, C3-C6 cycloalkyl, "3-7 membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from N, O and S" or substituted by 1 or more R 2f The substituted heteroatom is selected from 1, 2 or 3 of N, O and S. A 3-7 membered heterocycloalkyl group having 1, 2 or 3 atoms", the C2-C 22 0 to 5 -CH2- in the alkynyl group are optionally substituted by O; for example, (6)R 2-1 For-NR b R b , hydroxyl, C6-C 12 Aryl, one or more R 2d3 Substituted C6-C 12 Aryl, C3-C6 cycloalkyl or "a 5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S"; (7) Each R b are independently hydrogen, C1-C6 alkyl, C6-C 12 Aryl or one or more R b1 Substituted C1-C6 alkyl; (8) Each R 2d3 are independently halogen; (9) Each R 2e and R 2f are independently C1-C6 alkyl; (10)X is For example, X is and (11)R 3 is hydrogen, C1-C 22 Alkyl, with one or more R 3-1 Substituted C1-C 22 Alkyl or C2-C 22 alkenyl, for example, hydrogen, Preferably, R 3 is hydrogen, C1-C 22 Alkyl or C2-C 22 alkenyl, for example, hydrogen, 6. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that: The compound as shown in formula I satisfies one or more of the following conditions: (1) n is 8-11; (2) R is -(CH2)m- or is replaced by one or more R a substituted -(CH2)m-; wherein 0 to 10 -CH2- in said -(CH2)m- are optionally replaced by O, S, sub-C6-C 12 Aryl and 1 or more R c Substituted C6-C 12 Aryl substituted, m is 1-27, for example, Preferably, R is -(CH2)m- or is replaced by 1-4 R a substituted -(CH2)m-; wherein 0 to 4 -CH22- in said -(CH2)m- are optionally replaced by O and C6-C 12 Aryl substitution, m is 3-11; for example, For example, For example, Further example, (3) Each R a are independently hydroxyl, C1-C6 alkyl, halogen or C1-C4 heteroalkyl; the heteroatom species in the C1-C4 heteroalkyl is O, S or N, and the number of heteroatoms is 1, 2 or 3; preferably, each R a are independently hydroxyl or C1-C6 alkyl; (4) Each R c are independently nitro or C1-C6 alkyl; (5)R 1 C1-C 22 Alkyl or C2-C 22 Alkenyl, for example, Preferably, R 1 For C8-C 18 Alkyl groups, for example, (6)R 2 C1-C 22 Alkyl, C2-C 22 Alkenyl or one or more R 2-1 Substituted C1-C 22 Alkyl groups, for example, Preferably, R 2 C4-C 18 Alkyl or an R 2- 1 Substituted C1-C5 alkyl, for example, (7)R 2-1 For-NR b R b or hydroxyl; (8) Each R b are independently hydrogen or C1-C6 alkyl; (9)X is Preferably, X is (10)R 3 is hydrogen, C1-C 22 Alkyl or one or more R 3-1 Substituted C1-C 22 Alkyl groups, for example, For example, R 3 is hydrogen; and (11)R 3-1 It is a C3-C6 cycloalkyl group.

7. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The compound as shown in formula I satisfies one or more of the following conditions: (1) n is 5-15, for example 8-15; (2) R is -(CH2)m-, and 0 -CH2- in said -(CH2)m- are substituted; and (3)R 2 C1-C 22 Alkyl or one or more R 2-1 Substituted C1-C 22 Alkyl, each R 2-1 are independently hydroxyl.

8. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The compound as shown in formula I satisfies one or more of the following conditions: (1) n is 5-12; (2) R is -(CH2)m- or is replaced by one or more R a Substituted -(CH2)m-; 0 to 12 -CH2- in said -(CH2)m- are optionally independently replaced by O, and m is 1-19, for example, For example, Preferably, R is -(CH2)m-; m is 1-6, for example, For example, (3) Each R a are independently C1-C6 alkyl; (4)R 1 C1-C 22 Alkyl or C2-C 22 Alkenyl; for example, For example, Further, for example, More for example, (5)R 2 C1-C 22 Alkyl, C2-C 22 Alkenyl, C2-C 22 Alkynyl, with one R 2-1 Substituted C1-C6 alkyl, C3-C6 cycloalkyl, "3-7 membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from N, O and S" or substituted by 1 or more R 2f Substituted "3-7 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S"; for example, Better, R 2 C1-C 12 Alkyl, C2-C 22 Alkenyl, C2-C 22 Alkynyl, with one R 2-1 Substituted C1-C6 alkyl, C3-C6 cycloalkyl or "3-7 membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from N, O and S"; for example, For example, (6)R 2-1 For-NR b R b , hydroxyl, C6-C 12 Aryl, one or more R 2d3 Substituted C6-C 12 Aryl or "a 5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S"; for example, -NR b R b , hydroxyl, C6-C 12 Aryl or one or more R 2d3 Substituted C6-C 12 Aryl; also for example, -NR b R b ; and (7) each R b are independently C1-C6 alkyl.

9. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The compound as shown in formula I satisfies one or more of the following conditions: (1) R is -(CH2)m-, wherein 0 to 3 -CH2- in said -(CH2)m- are optionally replaced by O, and m is 1-12; for example, (2)R 2 C1-C 22 Alkyl, C2-C 22 Alkenyl, C2-C 22 Alkynyl, with one R 2-1 Substituted C1-C 22 Alkyl, C3-C6 cycloalkyl or one or more R 2f Substituted "3-7 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S"; for example, (3) The weight average molecular weight of the compound represented by formula I is 1000-10000.

10. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The compound as shown in formula I satisfies one or both of the following conditions: (1)R 2 C1-C 22 Alkyl, C2-C 22 Alkenyl, with one R 2-1 Substituted C1-C6 alkyl or 1 or more R 2f Substituted "3-7 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S"; for example, and (2) R is -(CH2)m-, m is 1-6; for example, R 1 For C8-C 18 Alkyl groups, such as R 1 for 11. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The compound as shown in formula I satisfies one or both of the following conditions: (1)R 2 C1-C 22 Alkyl, C2-C 22 Alkenyl or one or more R 2-1 Substituted C1-C 22 Alkyl; for example, and (2) R is -(CH2)m-, wherein 0 to 6 -CH2- in said -(CH2)m- are optionally independently replaced by O, and m is 8-14, for example, R 1 For C8-C 18 Alkyl groups, such as R 1 for 12. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that: R is -(CH2)m- or 1-4 R a substituted -(CH2)m-; wherein 0 to 4 -CH2- in said -(CH2)m- are optionally replaced by O and C6-C 12 Aryl substituted, m is 3-11; for example, For example, 13. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that: The compound as shown in formula I satisfies one or both of the following conditions: (1) n is 8-11; and (2) R is -(CH2)m-; 0 to 3 -CH2- in said -(CH2)m- are optionally substituted by O, and m is 4-11; for example, For example, 14. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that: The compound of formula I satisfies one or more of the following conditions: (1) R is -(CH2)m-; 0 to 3 -CH2- in the -(CH2)m- are optionally substituted by O, and m is 4-11; for example, (2)R 1 C 10 -C 16 Alkyl groups, for example, (3)R 2 C4-C 16 Alkyl or an R 2-1 Substituted C1-C5 alkyl, for example, For example, and (4) R 2-1 It is hydroxyl.

15. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that: R 2 C4-C 16 Alkyl or an R 2-1 Substituted C1-C5 alkyl, for example, 16. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that: The compound as shown in Formula I satisfies one or more of the following conditions: (1) n is 8-9; (2) R is -(CH2)m-; m is 4-6; for example, (3)R 1 C 14 -C 16 Alkyl groups, for example, and (4) R 2 C4-C 16 Alkyl or an R 2-1 Substituted C1-C5 alkyl, for example, For example, For example, 17. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that: The compound as shown in Formula I satisfies one or more of the following conditions: (1) n is 9-10; (2) R is -(CH2)m-; 0 to 3 -CH2- in said -(CH2)m- are optionally substituted by O, and m is 4-11; for example, (3)R 1 For C8-C 12 Alkyl groups, for example, and (4) R 2 C4-C 10 Alkyl or an R 2-1 Substituted C1-C5 alkyl, for example, For example, 18. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that: The compound as shown in formula I satisfies any of the following schemes: Scenario 1: n is 8-11; R is -(CH2)m- or is replaced by one or more R a substituted -(CH2)m-; 0 to 10 -CH2- in said -(CH2)m- are optionally replaced by O, S, sub-C6-C 12 Aryl and 1 or more R c Substituted C6-C 12 Aryl substituted, m is 1-27, for example, Each R a are independently hydroxyl, C1-C6 alkyl, halogen or C1-C4 heteroalkyl; the heteroatom species in the C1-C4 heteroalkyl is O, S or N, and the number of heteroatoms is 1, 2 or 3; Each R c are independently nitro or C1-C6 alkyl; R 1 C1-C 22 Alkyl or C2-C 22 Alkenyl, for example, R 2 C1-C 22 Alkyl, C2-C 22 Alkenyl or one or more R 2-1 Substituted C1-C 22 Alkyl groups, for example, R 2-1 For-NR b R b or hydroxyl; Each R b are independently hydrogen or C1-C6 alkyl; X is R 3 is hydrogen, C1-C 22 Alkyl or one or more R 3-1 Substituted C1-C 22 Alkyl groups, for example, R 3-1 is a C3-C6 cycloalkyl group; Preferably, the weight average molecular weight of the compound as shown in Formula I is 2030-5460, preferably 2600-4200, for example, 2600, 2700, 2900, 3000, 3100, 3400, 3500, 4100 or 4200; Scenario 2: n is 8-11; R is -(CH2)m- or 1-4 R a substituted -(CH2)m-; wherein 0 to 4 -CH2- in said -(CH2)m- are optionally replaced by O and C6-C 12 Aryl substituted, m is 3-11; for example, Each R a are independently hydroxyl or C1-C6 alkyl; R 1 For C8-C 18 Alkyl groups, for example, R 2 C4-C 18 Alkyl or an R 2-1 Substituted C1-C5 alkyl, for example, R 2-1 For-NR b R b or hydroxyl; Each R b are independently hydrogen or C1-C6 alkyl; X is R 3 is hydrogen; Preferably, the weight average molecular weight of the compound as shown in Formula I is 2030-5460, preferably 2600-4200, for example, 2600, 2700, 2900, 3000, 3100, 3400, 3500, 4100 or 4200; Scenario 3: n is 8-11; R is -(CH2)m- or 1-4 R a substituted -(CH2)m-; wherein 0 to 4 -CH2- in said -(CH2)m- are optionally replaced by O and C6-C 12 Aryl substituted, m is 3-11; for example, Each R a are independently hydroxyl or C1-C6 alkyl; R 1 For C8-C 18 Alkyl groups, for example, R 2 C4-C 18 Alkyl or an R 2-1 Substituted C1-C5 alkyl, for example, R 2-1 For-NR b R b or hydroxyl; Each R b are independently hydrogen or C1-C6 alkyl; X is R 3 is hydrogen; Preferably, the weight average molecular weight of the compound as shown in Formula I is 1890-5330, preferably 2700-4100, for example, 2700, 3100, 3500 or 4100; Solution 4: n is 8-11; R is -(CH2)m- or 1-4 R a substituted -(CH2)m-; wherein 0 to 4 -CH2- in said -(CH2)m- are optionally replaced by O and C6-C 12 Aryl substituted, m is 3-11; for example, Each R a are independently hydroxyl or C1-C6 alkyl; R 1 For C8-C 18 Alkyl groups, for example, R 2 C4-C 18 Alkyl or an R 2-1 Substituted C1-C5 alkyl, for example, R 2-1 For-NR b R b or hydroxyl; Each R b are independently hydrogen or C1-C6 alkyl; X is R 3 is hydrogen; Preferably, the weight average molecular weight of the compound as shown in Formula I is 1890-4550, preferably 2700-3500, for example, 2700, 3100 or 3500; Solution 5: n is 8-11; R is -(CH2)m- or 1-4 R a substituted -(CH2)m-; wherein 0 to 4 -CH2- in said -(CH2)m- are optionally replaced by O and C6-C 12 Aryl substituted, m is 3-11; for example, Each R a are independently hydroxyl or C1-C6 alkyl; R 1 For C8-C 18 Alkyl groups, for example, R 2 C4-C 18 Alkyl or an R 2-1 Substituted C1-C5 alkyl, for example, R 2-1 For-NR b R b or hydroxyl; Each R b are independently hydrogen or C1-C6 alkyl; X is R 3 is hydrogen; Solution 6: n is 8-11; R is -(CH2)m- or 1-4 R a substituted -(CH2)m-; wherein 0 to 4 -CH2- in said -(CH2)m- are optionally replaced by O and C6-C 12 Aryl substituted, m is 3-11; for example, Each R a are independently hydroxyl or C1-C6 alkyl; R 1 For C8-C 18 Alkyl groups, for example, R 2 C4-C 18 Alkyl or an R 2-1 Substituted C1-C5 alkyl, for example, R 2-1 For-NR b R b or hydroxyl; Each R b are independently hydrogen or C1-C6 alkyl; X is R 3 is hydrogen; Preferably, the weight average molecular weight of the compound as shown in Formula I is 2030-5460, preferably 2600-4200, for example, 2600, 2700, 2900, 3000, 3100, 3400, 3500 or 4200; Solution 7: n is 8-11; R is -(CH2)m- or 1-4 R a substituted -(CH2)m-; wherein 0 to 4 -CH2- in said -(CH2)m- are optionally replaced by O and C6-C 12 Aryl substituted, m is 3-11; for example, Each R a are independently hydroxyl or C1-C6 alkyl; R 1 For C8-C 18 Alkyl groups, for example, R 2 C4-C 18 Alkyl or an R 2-1 Substituted C1-C5 alkyl, for example, R 2-1 For-NR b R b or hydroxyl; Each R b are independently hydrogen or C1-C6 alkyl; X is R 3 is hydrogen; Preferably, the weight average molecular weight of the compound as shown in Formula I is 2030-5460, preferably 2600-4200, for example, 2600, 2900, 3000, 3100, 3400 or 4200; Solution 8: n is 8-11; R is -(CH2)m-; 0 to 3 -CH2- in said -(CH2)m- are optionally substituted by O, and m is 4-11; for example, R 1 For C8-C 18 Alkyl groups, for example, R 2 C4-C 18 Alkyl or an R 2-1 Substituted C1-C5 alkyl, for example, R 2-1 For-NR b R b or hydroxyl; Each R b are independently hydrogen or C1-C6 alkyl; X is R 3 is hydrogen; Preferably, the weight average molecular weight of the compound as shown in Formula I is 1890-5330, preferably 2700-4100, for example, 2700, 3100, 3500 or 4100; Solution 9: n is 8-11; R is -(CH2)m-; 0 to 3 -CH2- in said -(CH2)m- are optionally substituted by O, and m is 4-11; for example, R 1 For C8-C 18 Alkyl groups, for example, R 2 C4-C 18 Alkyl or an R 2-1 Substituted C1-C5 alkyl, for example, R 2-1 For-NR b R b or hydroxyl; Each R b are independently hydrogen or C1-C6 alkyl; X is R 3 is hydrogen; Preferably, the weight average molecular weight of the compound as shown in Formula I is 1890-4500, preferably 2700-3500, for example, 2700, 3100 or 3500; Solution 10: n is 8-10; R is -(CH2)m-; 0 to 3 -CH2- in said -(CH2)m- are optionally substituted by O, and m is 4-11; for example, R 1 C 10 -C 16 Alkyl groups, for example, R 2 C4-C 16 Alkyl or an R 2-1 Substituted C1-C5 alkyl, for example, R 2-1 For-NR b R b or hydroxyl; Each R b are independently hydrogen or C1-C6 alkyl; X is R 3 is hydrogen; Preferably, the weight average molecular weight of the compound as shown in Formula I is 2450-5330, preferably, 3500-4100, for example, 3500 or 4100; Solution 11: n is 8-10; R is -(CH2)m-; 0 to 3 -CH2- in said -(CH2)m- are optionally substituted by O, and m is 4-11; for example, R 1 C 10 -C 16 Alkyl groups, for example, R 2 C4-C 16 Alkyl or an R 2-1 Substituted C1-C5 alkyl, for example, R 2-1 is hydroxyl group; X is R 3 is hydrogen; Preferably, the weight average molecular weight of the compound as shown in Formula I is 2450-5330, preferably, 3500-4100, for example, 3500 or 4100; Solution 12: n is 8-10; R is -(CH2)m-; 0 to 3 -CH2- in said -(CH2)m- are optionally substituted by O, and m is 4-11; for example, R 1 C 10 -C 16 Alkyl groups, for example, R 2 C4-C 16 Alkyl or an R 2-1 Substituted C1-C5 alkyl, for example, R 2-1 For-NR b R b or hydroxyl; Each R b are independently C1-C6 alkyl; X is R 3 is hydrogen; Preferably, the weight average molecular weight of the compound as shown in Formula I is 2450-5330, preferably 3500-4100, for example, 3500 or 4100; Solution 13: n is 8-9; R is -(CH2)m-; m is 4-6; for example, R 1 C 14 -C 16 Alkyl groups, for example, R 2 C4-C 16 Alkyl or an R 2-1 Substituted C1-C5 alkyl, for example, R 2-1 For-NR b R b or hydroxyl; Each R b are independently hydrogen or C1-C6 alkyl; X is R 3 is hydrogen; Preferably, the weight average molecular weight of the compound as shown in Formula I is 2450-4550, for example, 3500; Solution 14: n is 8-9; R is -(CH2)m-; m is 4-6; for example, R 1 C 14 -C 16 Alkyl groups, for example, R 2 C4-C 16 Alkyl or an R 2-1 Substituted C1-C5 alkyl, for example, R 2-1 For-NR b R b or hydroxyl; Each R b are independently hydrogen or C1-C6 alkyl; X is R 3 is hydrogen; Preferably, the weight average molecular weight of the compound as shown in Formula I is 2450-4550, for example, 3500; Solution 15: n is 8-9; R is -(CH2)m-; m is 4-6; for example, R 1 C 14 -C 16 Alkyl groups, for example, R 2 C4-C 16 Alkyl or an R 2-1 Substituted C1-C5 alkyl, for example, R 2-1 is hydroxyl group; X is R 3 is hydrogen; Preferably, the weight average molecular weight of the compound as shown in Formula I is 2450-4550, for example, 3500; Scheme 16: n is 9-10; R is -(CH2)m-; 0 to 3 -CH2- in said -(CH2)m- are optionally substituted by O, and m is 4-11; for example, R 1 For C8-C 12 Alkyl groups, for example, R 2 C4-C 10 Alkyl or an R 2-1 Substituted C1-C5 alkyl, for example, R 2-1 For-NR b R b or hydroxyl; Each R b are independently hydrogen or C1-C6 alkyl; X is R 3 is hydrogen; preferably, the weight average molecular weight of the compound as shown in Formula I is 2870-5330, for example, 4100; Solution 17: n is 9-10; R is -(CH2)m-; 0 to 3 -CH2- in said -(CH2)m- are optionally substituted by O, and m is 4-11; for example, R 1 For C8-C 12 Alkyl groups, for example, R 2 C4-C 10 Alkyl groups, for example, X is R 3 is hydrogen; Preferably, the weight average molecular weight of the compound as shown in Formula I is 2870-5330, for example, 4100.

19. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The compound as shown in formula I is any one of the compounds in the following table, 20. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that: The compound as shown in formula I is any one of the compounds in Table 1 below, Table 1 21. A blank polymer-lipid nanoparticle, characterized in that: It includes an ionizable polymer PBAE, and the ionizable polymer PBAE is a compound as shown in formula I as described in any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof.

22. The blank polymer-lipid nanoparticle of claim 21, wherein: The blank polymer-lipid nanoparticles satisfy one or more of the following conditions: (1) The blank polymer-lipid nanoparticles further include a diluent; (2) the blank polymer-lipid nanoparticles further include auxiliary phospholipids; (3) the blank polymer-lipid nanoparticles further include sterol; and (4) the blank polymer-lipid nanoparticles further include lipids that inhibit particle aggregation.

23. The blank polymer-lipid nanoparticle of claim 22, wherein: The blank polymer-lipid nanoparticles satisfy one or more of the following conditions: (1) The diluent is an organic phase and an aqueous phase. Preferably, the organic phase is ethanol, acetone, tetrahydrofuran or acetonitrile miscible with water, preferably ethanol; the aqueous phase can be sodium citrate buffer with a pH of 3 or sodium acetate buffer with a pH of 5, preferably sodium acetate; (2) The auxiliary phospholipid is DSPC, DOPE, DOPC, DSPE and its derivatives, preferably DOPE; (3) The sterol is cholesterol and its derivatives, preferably cholesterol; (4) The lipid that inhibits particle aggregation can be polyethylene glycol and its derivatives, preferably DMG-PEG; (5) In the diluent, the volume ratio of the organic phase to the aqueous phase may be 1:1-1:3, preferably 1:2 and 1:3; (6) In the blank polymer-lipid nanoparticles, the molar ratio of the ionizable polymer PBAE to the auxiliary phospholipid is 1:0.03-2.5, preferably 1:1 or 1:0.48; (7) In the blank polymer-lipid nanoparticles, the molar ratio of the ionizable polymer PBAE to sterol is 1:0.67-6.5, preferably 1:2 or 1:2.40; and (8) in the blank polymer-lipid nanoparticles, the molar ratio of the ionizable polymer PBAE to the particle aggregation inhibiting lipid is 1:0.01-1, preferably 1:0.20 or 1:0.

12.

24. The blank polymer-lipid nanoparticle of claim 23, wherein: The blank polymer-lipid nanoparticles are composed of the ionizable polymer PBAE and common lipids, wherein the common esters are auxiliary phospholipids, sterols and lipids that inhibit particle aggregation; preferably, the blank polymer-lipid nanoparticles are composed of the ionizable polymer PBAE, DOPE, cholesterol and DMG-PEG, and the molar ratios of the ionizable polymer PBAE, DOPE, cholesterol and DMG-PEG are 23.8:23.8:47.6:4.8 and 25:12:60:

3.

25. A nucleic acid drug polymer-lipid nanoparticle, characterized in that: It includes a nucleic acid drug and a blank polymer-lipid nanoparticle as described in any one of claims 21-24. Preferably, the nucleic acid drug may be a conventional nucleic acid molecule in the art; for example, the nucleic acid molecule may be mRNA, saRNA, cirRNA, miRNA, shRNA, siRNA, dsDNA, pDNA, preferably mRNA.

26. The nucleic acid drug polymer-lipid nanoparticle of claim 25, wherein: The nucleic acid drug polymer-lipid nanoparticles also include a diluent.

27. The nucleic acid drug polymer-lipid nanoparticle of claim 26, wherein: The nucleic acid drug polymer-lipid nanoparticles meet one or more of the following conditions: (1) The diluent may be an organic phase and an aqueous phase. Preferably, the organic phase is ethanol, acetone, tetrahydrofuran, acetonitrile miscible with water, preferably ethanol; the aqueous phase is sodium citrate buffer at pH=3 or sodium acetate buffer at pH=5, preferably sodium acetate; (2) In the diluent, the volume ratio of the organic phase to the aqueous phase is 1:1-1:3; and (3) in the nucleic acid drug polymer-lipid nanoparticles, the N / P ratio of the ionizable polymer PBAE and the nucleic acid molecule may be 5:1-50:1, preferably 25:1, 12.5:1 or 21:1; Preferably, the nucleic acid drug polymer-lipid nanoparticles consist of the nucleic acid drug and the blank polymer-lipid nanoparticles.

28. Use of an ionizable polymer PBAE in preparing a delivery system, characterized in that: The ionizable polymer PBAE is a compound as shown in formula I as described in any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, and the delivery system is a system for delivering a therapeutic agent and / or a preventive agent to the lungs and / or liver; the therapeutic agent and / or the preventive agent is a nucleic acid drug.

29. Use of the ionizable polymer PBAE according to claim 28 in preparing a delivery system, characterized in that: It satisfies one or more of the following conditions: (1) The delivery is targeted delivery; (2) The delivery system is a blank polymer-lipid nanoparticle as described in any one of claims 12 to 15; and (3) the ionizable polymer PBAE, blank polymer-lipid nanoparticles and nucleic acid drugs are as described in any one of claims 1-18.

30. An application of an ionizable polymer PBAE as a pharmaceutical excipient, characterized in that: The ionizable polymer PBAE is a compound of formula I as described in any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, and the functions of the pharmaceutical excipient include nucleic acid encapsulation, lung and / or liver targeted delivery, promoting effective cell uptake or promoting lysosomal escape.

31. Use of composition A in preparing a delivery system or a drug for treating and / or preventing a disease, characterized in that: The disease is a lung or / and liver-related disease, the composition nucleic acid drug polymer-lipid nanoparticle includes an ionizable polymer PBAE, the ionizable polymer PBAE is a compound shown in Formula I or a pharmaceutically acceptable salt thereof, and the delivery system is as described in claim 28 or 29.

32. Use of the composition A as claimed in claim 31 in preparing a delivery system or a drug for treating and / or preventing a disease, characterized in that: The composition A also includes one or more of auxiliary phospholipids, sterols, lipids that inhibit particle aggregation and / or nucleic acid drugs. In the composition A, the auxiliary phospholipids, sterols, lipids that inhibit particle aggregation and / or nucleic acid drugs are as described in any one of claims 21-27.

33. Use of the composition A as claimed in claim 32 in preparing a delivery system or a drug for treating and / or preventing a disease, characterized in that: The composition A satisfies at least one of the following conditions: (1) In the composition A, the ionizable polymer PBAE and one or more of the auxiliary phospholipids, sterols, and lipids that inhibit particle aggregation form blank polymer-lipid nanoparticles as described in any one of claims 12 to 15; (2) In the composition A, the blank polymer-lipid nanoparticles and the nucleic acid drug form the nucleic acid drug polymer-lipid nanoparticles according to any one of claims 16 to 18; (3) In the composition A, the average particle size of the blank polymer-lipid nanoparticles of the composition may be 30-200 nm, and the surface potential may be -20-+20 mV; (4) In the composition A, the average particle size of the nucleic acid drug polymer-lipid nanoparticles in the composition can be 50-300 nm, and the surface potential can be -20-+20 mV.

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