Novel lipid nanodelivery material, preparation therefore and use thereof

Abstract

Provided in the present invention is a functional material capable of self-assembling into nanoscale dimensions, with an amino acid or polypeptide as a core backbone, a hydrophobic segment at one end and a hydrophilic segment at the other end. The material can be used in fields such as drug delivery through self-assembly into nanoscale forms. Formula (I).

Description

A novel lipid nanodelivery material and its preparation and use

[0001] This application claims priority to Chinese Patent Application No. 2024106264473, filed on May 20, 2024. This application incorporates the entirety of the aforementioned Chinese Patent Application. TECHNICAL FIELD

[0002] The present application belongs to the field of nanomaterials and drug delivery, and relates to a novel lipid nanodelivery material and its preparation and use. BACKGROUND

[0003] In recent years, various forms of nanotechnology platforms in the field of medical biology have attracted widespread attention, especially the research and development of multifunctional nanoparticles as drug carriers have grown exponentially. The delivery principles of these nanoparticles (including nanoemulsions, nanomicelles, lipid nanoparticles, dendrimers, nanogold, liposomes, drug carrier conjugates, antibody drug complexes, and magnetic nanoparticles, etc.) are mainly based on the unique self-assembly forms of natural, artificially synthesized or biological components, and the materials involve small molecules, polymers, metals, and lipids, etc.

[0004] The success of lipid nanoparticle-delivered mRNA vaccines has led to great development in the field of drug delivery, and the core carriers have been extensively and deeply researched and developed by the nanomedicine and material fields. The success of these nanoparticles in the clinic depends on the selection and consideration of some important parameters, such as the manufacturing strategy of nanoparticles, the mode of action, the physical properties, the drug loading efficiency, the drug release potential, and the carrier toxicity, etc. Among them, the advantages of lipid-based nanoparticles are highlighted, such as less toxicity in vivo, lower immunogenicity, high drug loading capacity, and easier production of lipid nanocarriers, etc.

[0005] Self-assembly is a natural phenomenon that exists universally in biological systems and plays a crucial role in life activities, such as self-assembly at the structural level of proteins and nucleic acids, presenting different morphologies such as helical structures, and especially phospholipids with hydrophilic heads and hydrophobic tails self-assemble to form a phospholipid bilayer membrane structure with fluidity, etc. The minimum structure of proteins is polypeptides and amino acids, so the polypeptide or amino acid self-assembly technology has started to develop gradually and rapidly, especially the responsive self-assembly functional materials and drug carriers, which have caused great repercussions in the field of biological nanomaterials and medical applications, and have very great market potential.

[0006] The application provides a new type of lipid nanomaterial, a functional material which is combined by amino acids or polypeptides as a skeleton, a lipid hydrophobic segment as a hydrophobic part connected at one end, and a hydrophilic segment such as polysarcosine or PEG as a hydrophilic part connected at one end, can be self-assembled into nanometer size for drug delivery, and can have a modifiable functional group, so that drug delivery can be realized by drug coupling, and has a very large application prospect in the fields of materials and medicine. SUMMARY

[0007] The application provides a new type of nanomaterial and its preparation and use, which can be used for nano self-assembly and has the function of nano drug delivery.

[0008] The application provides a functional material which can be used for nano self-assembly and nano drug delivery, as shown in formula (I),

[0009] wherein:

[0010] A is an amino acid residue, a polypeptide or a derivative thereof;

[0011] L 1 , L 2 is absent or a connecting unit;

[0012] P 1 is a hydrophilic segment;

[0013] Y 2 is a branching center;

[0014] Q 2a and Q 2b are hydrophobic segments, Q 2a is T 2a -R 1 or absent, Q 2b is T 2b -R 2 or absent, Q 2a and Q 2b are at least one;

[0015] T 2a , T 2b is absent or a connecting unit;

[0016] R 1 , R 2 is a hydrophobic segment;

[0017] The hydrogen connected with carbon in the compound shown in formula (I), wherein one hydrogen or a plurality of hydrogens can be replaced by deuterium or any substituent.

[0018] In some embodiments, the functional materials useful for nano self-assembly and nanomedicine delivery provided by the present application are characterized by one or more of the following:

[0019] (1) L 1 , L 2 is absent or, when present, L 1 , L 2 is independently an alkane, a heterocyclic alkane, an aromatic hydrocarbon, a heterocyclic aromatic hydrocarbon, a substituted or unsubstituted amino acid or a polypeptide composed thereof, or a plurality of combinations thereof, wherein L 1 , L 2 is independently selected from the group consisting of:

[0020] wherein, L La , L Lb , L Lc , L Ld is independently selected from the group consisting of a hydroxyl group, a C1-C5 alkyl group, or a C1-C5 alkoxy group;

[0021] R Le is hydrogen, a hydroxyl group, a C1-C5 alkyl group, or a C1-C5 alkoxy group;

[0022] L 1a , L 1b is independently selected from the group consisting of O, NR Lf , S, S-S, or is absent, R Lf is hydrogen or a C1-C5 alkyl group;

[0023] (2) T 2a , T 2b is absent or, when present, T 2a , T 2b is independently an alkane, a heterocyclic alkane, an aromatic hydrocarbon, a heterocyclic aromatic hydrocarbon, a substituted or unsubstituted amino acid or a polypeptide composed thereof, or a plurality of combinations thereof, wherein T 2a , T 2b is independently selected from the group consisting of:

[0024] wherein, L 1a , L 1b is independently selected from the group consisting of O, NR Lf , S, S-S, a substituted or unsubstituted methylene group, or is absent, R Lf is hydrogen or a C1-C5 alkyl group;

[0025] (3) Y 2for a multifunctional branched center, selected from a multifunctional amino acid, a polypeptide, or the following structure:

[0026] wherein R y0 selected from hydrogen, deuterium, halogen, nitro, cyano, C1-C10 alkyl, C1-C10 alkoxy, C3-C10 alkenyl, C3-C10 alkynyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C10 aryl, C5-C10 heteroaryl, or a group containing primary amine, secondary amine, tertiary amine, hydroxyl, thiol, carboxyl, ester, amide, boronic acid, boronate ester, phosphonic acid, sulfonic acid, sulfoxide, aldehyde, ketone functional group;

[0027] R y1 selected from C1-C10 alkyl, C1-C10 alkoxy, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl;

[0028] R y2 selected from hydrogen, deuterium, halogen, hydroxyl, amino, nitro, cyano, C1-C10 alkyl, C1-C10 alkoxy, C3-C10 alkenyl, C3-C10 alkynyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C10 aryl, C5-C10 heteroaryl, or a group containing primary amine, secondary amine, tertiary amine, hydroxyl, thiol, carboxyl, ester, amide, boronic acid, boronate ester, phosphonic acid, sulfonic acid, sulfoxide, aldehyde, ketone functional group;

[0029] A 1 ring is C6-C 20 aryl or C5-C 20 heteroaryl; the heteroatom in the C5-C 20 heteroaryl is O, S or N, the number of the heteroatom is one or more, when more than one, the heteroatoms are the same or different;

[0030] E ring is C2-C8 heterocycloalkyl; the heteroatom in the heterocycloalkyl is O, S or N, the number of the heteroatom is one or more, when more than one, the heteroatoms are the same or different;

[0031] (4) P 1 is a hydrophilic moiety, selected from polyethylene glycol, sugar, oligosaccharide and polysaccharide (such as hyaluronic acid, chondroitin sulfate, chitosan, heparin, tea polysaccharide, dextran, polysialic acid, chitosan, dextran, sodium alginate, cellulose, polysucrose, cyclodextrin), polysarcosine, polyphosphoester, polyglycerol, polyvinylpyrrolidone, polyoxazoline, polyamino acid, polyacrylic acid residue, polymethacrylic acid residue, quaternary ammonium salt derivative, carboxyl-containing derivative, sulfonic acid group-containing derivative, phosphonic acid group-containing derivative, zwitterionic derivative or zwitterionic polymer;

[0032] (5) A is selected from natural amino acids and derivatives thereof, unnatural amino acids and derivatives thereof, or polypeptides or derivatives thereof consisting of them.

[0033] In some embodiments, the functional materials provided by the present application for nano self-assembly and nano drug delivery are characterized in that the core skeleton of the A moiety satisfies one or more of the following conditions:

[0034] (1) A is selected from natural amino acids and derivatives thereof, and the natural amino acids include but are not limited to glycine, alanine, valine, leucine, isoleucine, phenylalanine, proline, serine, threonine, histidine, tryptophan, cysteine, aspartic acid, glutamic acid, lysine, tyrosine, methionine, asparagine, glutamine, arginine, and citrulline; the amino acid configuration can be D or L type;

[0035] (2) A is selected from unnatural amino acids, and is selected from the following structures:

[0036] wherein R a1 , R a2 , R a6 , R a7 , R a8 are each independently selected from hydrogen, deuterium, hydroxyl, amino, halogen, cyano, C1-C10 alkyl, C1-C10 alkoxy, C3-C10 alkenyl, C3-C10 alkynyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C10 aryl, or C5-C10 heteroaryl; 10 1～ 10 10 10 10

[0037] R a3 , R a4 are each independently selected from hydrogen, deuterium, C1-C10 alkyl, C1-C10 alkoxy, C3-C10 alkenyl, C3-C10 alkynyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C10 aryl, or C5-C10 heteroaryl; 10 10 10 10 10 10

[0038] R a5 is selected from hydrogen, C1-C10 alkyl, C1-C10 alkoxy, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C10 aryl, or C5-C10 heteroaryl; 1～ 10 10 10 10 ​​​​​​​​​​​​​​​​​

[0039] or R a1 and R a2 , R a3 and R a4 , together with the carbon atom to which they are attached, form a C 3-7 monocyclic, bicyclic alkyl or heterocycloalkane, wherein the heteroatom is N, O, S, P or B;

[0040] or R a1 and R a3 , R a1 and R a4 , R a2 and R a3 , R a2 and R a4 , together with the carbon atom to which they are attached, form a C 3-7 monocyclic, bicyclic alkyl or heterocycloalkane, wherein the heteroatom is N, O, S, P or B;

[0041] m1, m2, m3, m4 are selected from an integer from 0 to 5;

[0042] (3) A is selected from a polypeptide structure, the polypeptide consisting of 2-10 amino acids and derivatives thereof, the amino acid residues including natural amino acids and unnatural amino acids, the natural amino acids including, for example, glycine, alanine, valine, leucine, isoleucine, phenylalanine, proline, serine, threonine, histidine, tryptophan, cysteine, aspartic acid, glutamic acid, lysine, tyrosine, methionine, asparagine, glutamine, arginine, citrulline, in the configuration of D or L type; the unnatural amino acids being as described in (2) above.

[0043] In some embodiments, the functional material useful for nano self-assembly and nanomedicine delivery provided by the present application is characterized in that P1 is selected from:

[0044] (1) the polyethylene glycol derivative residue is selected from the following structures:

[0045] wherein pa1 is selected from an integer from 5 to 250, pr1 is selected from an integer from 0 to 8, and R p1 is hydrogen, C1-C10 alkyl, C1-C10 heteroalkyl, C3-C10 cycloalkyl, C3-C10 alkenyl, C3-C10 alkynyl, or a hydroxyl protecting group;

[0046] Preferably, pa1 is selected from an integer from 5 to 150, pr1 is selected from an integer from 0 to 8, and R p1 is hydrogen, C1-C10 alkyl, or a hydroxyl protecting group;

[0047] More preferably, pa1 is selected from an integer from 10 to 60, pr1 is selected from an integer from 0 to 2, and R p1C1-C10 alkyl;

[0048] (2) The poly-muscimole derivative residue is selected from the following structures:

[0049] wherein pb1 is selected from an integer between 5 and 250, R p2 selected from hydrogen, C1-C10 alkyl, C1-C10 alkoxy, C3-C10 alkenyl, C3-C10 alkynyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C10 aryl, C5-C10 heteroaryl, or an amine protecting group; R p3 selected from OR p3a or NR p3b R p3c wherein R p3a selected from hydrogen, C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C10 aryl, or C5-C10 heteroaryl; R p3b , R p3c are each independently selected from hydrogen, C1-C10 alkyl, C1-C10 alkoxy, C3-C10 alkenyl, C3-C10 alkynyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C10 aryl, C5-C10 heteroaryl, an amine protecting group, or R p3b and R p3c form a C3-C10 cyclic structure with the nitrogen atom to which they are both attached;

[0050] R p4 selected from OR p5 , NR p6 R p7 , C1-C10 alkyl, C1-C10 alkoxy, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C10 aryl, C5-C10 heteroaryl; R p5 selected from hydrogen, C1-C10 alkyl, C1-C10 alkoxy, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C10 aryl, C5-C10 heteroaryl, or a hydroxyl protecting group; R p6 , R p7 selected from hydrogen, C1-C10 alkyl, C1-C10 alkoxy, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C10 aryl, C5-C10 heteroaryl, or an amino protecting group, R p6 , R p7 form a C3-C10 cyclic structure with the nitrogen atom to which they are both attached;

[0051] Preferably, pb1 is selected from an integer between 5 and 150;

[0052] (3) The quaternary ammonium salt derivative residue is selected from the following structures:

[0053] wherein, pc1 is an integer selected from 0-10, A- is selected from R p3 , R p4 , R p5 are each independently selected from C1-C10 alkyl, C1-C10 alkoxy, C3-C8 cycloalkyl, or C2-C8 heterocycloalkyl;

[0054] (4) Zwitterionic derivatives or Zwitterionic polymers:

[0055] wherein,

[0056] pd1 is an integer selected from 5-250;

[0057] R p6 is selected from:

[0058] pc1, pe1 is an integer selected from 0-10, A- is selected from R p3 , R p4 , R p5 are each independently selected from C1-C10 alkyl, C1-C10 alkoxy, C3-C8 cycloalkyl, or C2-C8 heterocycloalkyl; L p is absent or a linking unit selected from alkane, heterocycloalkane, aromatic hydrocarbon, heterocycloalkane, or various combinations thereof;

[0059] (5) Polysaccharide polymers:

[0060] wherein, pf1, pf2, pg1, pg2, ph1, ph2, pi1, pi2 are integers selected from 1-250.

[0061] In some embodiments, the present application provides functional materials useful for nano self-assembly and nanomedicine delivery, characterized in that:

[0062] L 1 , L 2 is selected from absent or present, when present, selected from:

[0063] wherein L a , L b is a linking moiety between A and a hydrophilic segment or a hydrophobic segment, selected from saturated carbon-carbon bond, unsaturated carbon-carbon bond, saturated carbon-nitrogen bond, unsaturated carbon-nitrogen bond, azo bond, carbon-sulfur bond, ether, ester, amide, sulfonamide, sulfilimine, hydrazone, oxime, phospholipid, triazole, acetal, hemiacetal; L 4alkanes, heterocyclic alkanes, aromatic hydrocarbons, heterocyclic aromatic hydrocarbons, substituted or unsubstituted amino acids or polypeptides composed thereof, or various combinations thereof;

[0064] preferably selected from saturated carbon-carbon bonds, saturated carbon-nitrogen bonds, carbon-sulfur bonds, ethers, esters or amides;

[0065] L 4 selected from C1-C10 saturated alkyl groups, C1-C10 unsaturated alkyl groups, C1-C10 alkoxy groups, C3-C10 alkenyl groups, C3-C10 alkynyl groups, C3-C8 cycloalkyl groups, C2-C8 heterocyclic alkyl groups, C6-C10 aryl groups, C5-C10 heteroaryl groups, or various combinations thereof;

[0066] Y 2 selected from,

[0067] preferably selected from

[0068] more preferably selected from L 2 terminal connection;

[0069] P 1 selected from polyethylene glycol derivative residues with a number of repeating units of pa1 and terminal groups of R p1 wherein pa1 is selected from integers between 10 and 60, preferably between 15 and 50, for example 21, 22, 44 or 45; R p1 is a C1-C6 alkyl group, preferably a C1-C3 alkyl group, for example methyl, ethyl, n-propyl or i-propyl;

[0070] or P 1 selected from poly-muscle acid derivative residues with a number of repeating units of pb1 and terminal groups of R p2

[0071] wherein pb1 is selected from integers between 10 and 60, preferably between 15 and 50; R p2 selected from hydrogen, C1-C10 alkyl groups, C1-C10 alkoxy groups, C3-C10 alkenyl groups, C3-C10 alkynyl groups, C3-C8 cycloalkyl groups, C2-C8 heterocyclic alkyl groups, C6-C10 aryl groups, C5-C10 heteroaryl groups or amine protecting groups;

[0072] Q 2a T 2a -R 1 Q 2b T 2b -R 2 T 2a T 2b are defined as described in the present invention, R​1 , R 2 selected from:

[0073] wherein r1a, r1b are selected from integers from 1 to 30.

[0074] In some embodiments, the present application provides functional materials useful for nano self-assembly and nano drug delivery, characterized in that:

[0075] (1) A is selected from the following structures:

[0076] Single amino acids:

[0077] or polypeptides:

[0078] wherein A a , A b is selected from glycine, alanine, valine, leucine, isoleucine, phenylalanine, proline, serine, threonine, histidine, tryptophan, cysteine, aspartic acid, glutamic acid, lysine, tyrosine, methionine, asparagine, glutamine, arginine, citrulline and derivatives thereof, or 2-8 short peptides combined by them;

[0079] (2) selected from the following structures:

[0080] wherein x, q are selected from integers from 10 to 60; pf1, pf2, ph1, ph2 are selected from integers between 1 and 100; x1 is selected from integers from 0 to 10;

[0081] (3) selected from the following structures:

[0082] wherein x1 is selected from integers from 0 to 10; y, z, y1, y2, z1, z2, z3 are selected from integers from 1 to 20.

[0083] In some embodiments, the functional materials useful for nano self-assembly and nanomedicine delivery provided herein are characterized in that the functional materials are selected from the group consisting of structures having Formula (II) or (III):

[0084] wherein R pa is selected from the group consisting of R p2 or R p2 , R p4 , Q 2a , Q 2b , Y 2 , L 1 , L 2 , A, pbl, R p3 are as defined herein.

[0085] In some embodiments, the functional materials useful for nano self-assembly and nanomedicine delivery provided herein are characterized in that the functional materials are selected from the group consisting of structures having Formula (IV):

[0086] wherein Q 2a , Q 2b , Y 2 , L 1 , L 2 , A, pal, R p1 are as defined herein.

[0087] In some embodiments, the functional materials useful for nano self-assembly and nanomedicine delivery provided herein are characterized in that, the structures are selected from the group consisting of:

[0088] In some embodiments, the functional materials useful for nano self-assembly and nanomedicine delivery provided herein are characterized in that the functional materials are selected from the group consisting of structures having Formula (IV):

[0089] In some embodiments, the functional material for nano self-assembly and nano drug delivery provided by the present application is characterized in that the functional material is selected from the following structures:

[0090] In some embodiments, the functional material for nano self-assembly and nano drug delivery provided by the present application is characterized in that the self-assembly nano size average particle size is in the range of 5-500 nm; preferably, the average particle size is in the range of 10-100 nm.

[0091] In some embodiments, the functional material for nano self-assembly and nano drug delivery provided by the present application is characterized in that small molecule drugs, polypeptide drugs, macromolecular drugs, proteins, antibodies, nucleic acid drugs, vaccines, gene drugs and nuclide drugs can be delivered by self-assembly.

[0092] In some embodiments, the functional material for nano self-assembly and nano drug delivery provided by the present application is characterized in that drug delivery, including small molecule drugs, polypeptide drugs, macromolecular drugs, proteins, antibodies, nucleic acid drugs, vaccines, gene drugs and nuclide drugs, can be carried out by covalent cleavable or non-cleavable coupling.

[0093] The terms used in the present application, unless otherwise stated, have the following meanings:

[0094] The amine protecting groups, hydroxyl protecting groups, carboxyl protecting groups of the present application are those known in the art to be suitable for the protection of amine groups, hydroxyl groups and carboxyl groups, see the various classes of protecting groups in "Protective Groups in Organic Synthesis", 5thEdition, P.G.M. Wuts and T.W. Greene, John Wiley & Sons, Inc., 2007. Th Ed. T. W. Greene & P. G. M. Wuts).

[0095] The term "alkyl" means a saturated aliphatic hydrocarbon group including straight-chain or branched-chain groups having 1 to 30 carbon atoms. Preferred are alkyl groups having 1 to 10 carbon atoms, more preferred are alkyl groups having 1 to 8 carbon atoms, non-limiting examples include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, isobutyl, t-butyl, sec-butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1,1,2-trimethylpropyl, 1-ethyl-2-methylpropyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 3,3-dimethylpentyl, 3,4-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, octyl, nonyl, decyl, undecyl, dodecyl, and the like. The "alkyl" group can be substituted or unsubstituted.

[0096] The term "cycloalkyl" means a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent including 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 10 carbon atoms, most preferably including 3 to 6 carbon atoms, non-limiting examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, and the like. Non-limiting examples of polycyclic cycloalkyl groups include, but are not limited to, spirocyclic, fused, and bridged cycloalkyl groups. The "cycloalkyl" group can be substituted or unsubstituted.

[0097] The term "alkenyl" means an alkyl group as defined in the present application consisting of at least two carbon atoms and at least one carbon-carbon double bond, preferably C2to C10alkenyl, more preferably C2to C6alkenyl, for example ethenyl, propenyl, 1-propenyl, and the like. The "alkenyl" group can be substituted or unsubstituted.

[0098] The term "alkynyl" denotes an alkyl group as defined in the present application consisting of at least two carbon atoms and at least one carbon-carbon triple bond, preferably a C2to C10alkynyl group, more preferably a C2to C6alkynyl group, such as ethynyl, 1-propynyl, 2-propynyl, and the like. The "alkynyl" group can be substituted or unsubstituted.

[0099] The term "heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, including 3 to 20 ring atoms, wherein one or more ring atoms are selected from N, O, Si, B, S(O) m m (wherein m is an integer from 0 to 2) heteroatoms, but not including a ring moiety of -O-O, -O-S-, or -S-S-, the remaining ring atoms being carbon. Preferably, 3 to 12 ring atoms, including 1 to 4 heteroatoms, non-limiting examples of monocyclic heterocycloalkyl groups include pyrrolyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, pyranyl, and the like. Polycyclic heterocycloalkyl groups include spiro, fused, and bridged ring heterocycloalkyl groups. The "heterocycloalkyl" group can be substituted or unsubstituted.

[0100] The term "alkoxy" refers to -O-(alkyl) and -O-(cycloalkyl), wherein alkyl, cycloalkyl are as defined in the present description. Non-limiting examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. The "alkoxy" group can be substituted or unsubstituted.

[0101] The term "alkylthio" refers to -S-(alkyl) and -S-(cycloalkyl), wherein alkyl, cycloalkyl are as defined in the present description. Non-limiting examples include, but are not limited to, methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, and the like. The "alkylthio" group can be substituted or unsubstituted.

[0102] The term "aryl" refers to any stable 6 to 18 carbon atom, preferably 6 to 10 carbon atom, conjugated hydrocarbon ring system group, which can be a monocyclic, bicyclic, tricyclic, or more ring aromatic radical, such as phenyl, naphthyl, and anthracene, and the like, which aryl group can include an aryl ring fused with a heterocycloalkyl or cycloalkyl ring. The "aryl" group can be substituted or unsubstituted.

[0103] ​The term "heteroaryl" refers to an aromatic ring system formed by replacement of at least one carbon atom on a ring with a heteroatom selected from N, O, or S, preferably a 5- to 7-membered monocyclic structure or a 7- to 12-membered bicyclic structure, more preferably a 5- to 6-membered heteroaryl, such as pyrrolyl, imidazolyl, pyridyl, pyrimidinyl, thiazolyl, thienyl, pyrazinyl, triazolyl, tetrazolyl, oxazolyl, indazolyl, and the like, which can include heteroaryl rings fused to heteroaryl, heterocycloalkyl, or cycloalkyl rings. The "heteroaryl" group can be substituted or unsubstituted.

[0104] The term "hydroxyl" refers to -OH.

[0105] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0106] The term "nitro" refers to -NO2.

[0107] The term "amino" refers to -NH2.

[0108] The term "cyano" refers to -CN.

[0109] The term "carboxylic acid" refers to -C(O)OH.

[0110] The term "mercapto" refers to -SH.

[0111] The term "substituted" refers to one or more hydrogen atoms on a group being independently replaced with a corresponding number of deuterium or a substituent.

[0112] The term "substituent" refers to a molecular group that replaces a hydrogen in a compound, which can include, but is not limited to, halogen, alkyl, alkoxy, nitro, cyano, hydroxyl, sulfone, sulfoxide, cycloalkyl, heterocycloalkyl, amino, substituted amino, azido, oxo, carboxyl, carboxylate, alkenyl, alkynyl, mercapto, alkylmercapto, aryl, heteroaryl, or a group formed by each of them in combination with each other.

[0113] The term "sulfone" refers to -S(O)2-alkyl, cycloalkyl, aryl, or heteroaryl, wherein alkyl, cycloalkyl, aryl, and heteroaryl are defined as described above.

[0114] The term "sulfoxide" refers to -SO-alkyl, cycloalkyl, aryl, or heteroaryl, wherein alkyl, cycloalkyl, aryl, and heteroaryl are defined as described above.

[0115] The term "carboxylate" refers to -C(O)O-alkyl, aryl, or cycloalkyl, wherein alkyl, aryl, and cycloalkyl are defined as described above.

[0116] The term "amino acid" includes those selected from naturally occurring a-L-amino acids such as alanine (Ala or A), cysteine (Cys or C), aspartic acid (Asp or D), glutamic acid (Glu or E), phenylalanine (Phe or F), glycine (Gly or G), histidine (His or H), isoleucine (lie or I), lysine (Lys or K), leucine (Leu or L), methionine (Met or M), asparagine (Asn or N), proline (Pro or P), glutamine (Gin or Q), arginine (Arg or R), serine (Ser or S), threonine (Thr or T), valine (Val or V), tryptophan (Trp or W), tyrosine (Tyr or Y), and citrulline (Cit), as well as D-amino acids, synthetic a, b or g amino acids, which can be substituted or unsubstituted.

[0117] The term "peptide" or "polypeptide" refers to both natural and synthetic peptides, which can comprise natural amino acids, unnatural amino acids, or a combination of natural and unnatural amino acids.

[0118] "Solvate" refers to an aggregate or complex of one or more solvent molecules with a compound of the present application. Solvents that form solvates include, but are not limited to, water, dimethylsulfoxide, methanol, ethanol, isopropanol, acetic acid, and the like.

[0119] "Isomer" refers to stereoisomers, including enantiomers and diastereomers, and cis- trans isomers are a type of diastereomers. Isomers of the compounds of the present disclosure can be enantiomers, diastereomers, and any mixture thereof, including free or salt forming forms.

[0120] The term "effective amount" or "therapeutically effective amount" refers to a nontoxic but sufficient amount of an agent to achieve a desired result. Determination of an effective amount is dependent on the age and general condition of the recipient, on the particular active agent, and appropriate effective amounts for a given case can be determined by one of ordinary skill in the art according to routine testing.

[0121] The abbreviations used for any protecting groups, amino acids and other compounds used in the present application are those commonly used and accepted abbreviations, unless otherwise indicated, or refer to the IUPAC-IUB Commission on Biochemical Nomenclature (see Biochem. 1972, 11, 942-944). BRIEF DESCRIPTION OF DRAWINGS

[0122] Figure 1 is a graph of the tumor inhibition curves of Example El and E2 in human small cell lung cancer cell NCI-H69 xenograft mouse model.

[0123] Figure 2. Graph of mRNA delivery transfection efficiency experiment of Example 1 and 19.

[0124] Figure 3. Tumor inhibition curve of the vaccine prepared in the present application in TC-1 cervical cancer model in mice. DETAILED DESCRIPTION

[0125] The present application is further illustrated by the following examples, which are not intended to limit the application in any way. The experimental methods in the following examples, where no specific conditions are indicated, were carried out according to conventional methods and conditions, or as specified in the commercial instructions.

[0126] The abbreviations used in the present application are shown in the following table:

[0127] Since the application has been described in terms of specific embodiments, it will be apparent to those of ordinary skill in the art that modifications and / or equivalents can be substituted for those described specifically without departing from the scope of the present application.

[0128] General analysis method of HPLC:

[0129] Chromatographic conditions:

[0130] Solvent gradient conditions:

[0131] The structure of all compounds of the present application can be determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). The NMR shift (δ) is recorded in units of 10 - 6 (ppm). The measuring instrument of NMR is Bruker AVANCE-400 spectrometer. The deuterated solvents tested are deuterated chloroform (CDCI3), deuterated methanol (MeOD), deuterated dimethyl sulfoxide (DMSO-D6), and the internal standard is tetramethylsilane (TMS).

[0132] Low resolution mass spectrometry (MS) is measured by Agilent 6120 quadruple LCMS mass spectrometer.

[0133] Example 1: Synthesis of compound 1

[0134] Synthesis of compound 1-1

[0135] To a solution of 1-SM1 (200 g, 0.1 mol) in DCM (800 mL) was added triethylamine (35.42 g, 0.35 mol) in one portion, stirred for 5 min, replaced by nitrogen, stirred to dissolve, the internal temperature was cooled to 0 °C, a solution of di(p-nitrophenyl) carbonate (30.2 g, 0.22 mol) in DCM (150 mL) was added, the temperature was increased to 20-25 °C and stirred for 1 h. The CAD-HPLC in-process control showed that the starting material was left 16.44%. The internal temperature was cooled to 0 °C, a solution of di(p-nitrophenyl) carbonate (10.1 g, 0.07 mol) in DCM (50 mL) was continuously added, the temperature was increased to 20-25 °C and stirred for 1.5 h. The CAD-HPLC in-process control showed that the reaction was complete, filtered, the filtrate was concentrated to dryness at 35 °C. To the concentrated solution was added MTBE (2.0 L), stirred magnetically. The temperature was decreased to 0 °C, stirred for 20 min. Filtered, the filter cake was transferred to a 2.0 L single-necked flask and 1.0 L THF was added, stirred for 0.5 h. Filtered, the filtrate was concentrated to dryness at 40 °C. 1.6 L MTBE was added, slurried for 0.5 h, filtered, the filter cake was washed with 0.4 L MTBE. The filter cake was placed in a 25 °C vacuum oven and dried overnight to give compound 1-1 as a white solid (203 g, yield 93.7%).

[0136] Synthesis of compound 1-2

[0137] Under nitrogen protection at room temperature, to a solution of L-glutamic acid-5-tert-butyl ester (37.5 g, 0.18 mmol) in DMF (2.0 L) was added triethylamine (23.36 g, 0.23 mol) and 1-1 (200 g, 0.09 mol), stirred for 16 h. The sampling TLC monitoring (quenched with saturated aqueous citric acid, extracted with DCM, spotted with DCM phase) showed that the starting material was completely reacted (DCM / MeOH = 8:1, iodine coloration). The temperature was decreased to 10 °C, 1.0 L saturated aqueous citric acid and 2.0 L DCM were added, stirred for 15 min. The solution was allowed to stand and separated, the aqueous phase was extracted with 1.0 L DCM once. The organic phases were combined, the organic phase was washed with 1.0 L saturated brine once. The solution was separated, the organic phase was concentrated to dryness at 40 °C. To the concentrated solution was added 200 mL DCM, stirred to dissolve, 3.0 L MTBE was added, and the temperature was increased to 20-25 °C and stirred for 1 h. The filter cake was transferred to a single-necked flask, dried in a vacuum oven at room temperature to give compound 1-2 as a white solid (215.8 g, yield >99%). The sampling CAD-HPLC showed that the purity was 99.66%.

[0138] Synthesis of compound 1-3

[0139] To compound 1-2 (200 g, 0.09 mol) in dichloromethane (2.0 L) was added HATU (68.2 g, 0.18 mol), DMAP (27.4 g, 0.22 mol) and DSG (84.1 g, 0.13 mol) and stirred at room temperature (15-20 °C) for 4 h. The sample point plate (0.5N HCl quench, DCM dilution spot plate) showed the reaction was complete (DCM / MeOH = 9: 1, iodine coloration). The temperature was lowered to 10 °C. 1.0 L of 0.5N aqueous hydrochloric acid and 1.0 L of DCM were added and stirred for 15 m min. The solution was partitioned, the organic phase was washed with 1.0 L of 0.5N hydrochloric acid three times and 1.0 L of saturated brine once. The solution was partitioned, the organic phase was dried with anhydrous sodium sulfate. The solution was filtered and the filtrate was concentrated at 40 °C. The sample was mixed with 100-200 mesh silica gel and columned (DCM / MeOH = 50: 1-20: 1). The product phase was collected and concentrated at 40 °C to dryness to give compound 1-3 as a light yellow solid (200 g, 78.6% yield). CAD-HPLC showed a purity of 99.61%.

[0140] 1 H NMR (400 MHz, Chloroform-d) δ 5.42 (d, J = 8.2 Hz, 1H), 5.28-5.23 (m, 1H), 4.43-4.26 (m, 3H), 4.24-4.10 (m, 4H), 3.88-3.42 (m, 196H), 3.37 (s, 3H), 2.47 (s, 2H), 2.40-2.24 (m, 4H), 2.18-2.04 (m, 1H), 1.99-1.84 (m, 1H), 1.69-1.55 (m, 4H), 1.43 (s, 9H), 1.25 (s, 60H), 0.87 (t, J = 6.7 Hz, 6H).

[0141] Synthesis of compound 1

[0142] To compound 1-3 (111.6 g, 39.17 mmol) in dichloromethane (223 mL) was added TFA (167 mL). Stirring at room temperature (20-25 °C) for 2 h, sampling and diluting TLC spot plate (DCM / MeOH = 9: 1, iodine coloration) showed that the starting material was not completely reacted. Added 56 mL of TFA, and continued to stir at room temperature for 3 h. TLC showed that the starting material was completely reacted. The reaction solution was concentrated to dryness at 35 °C. The residue was added to 840 mL of DCM, and stirred to dissolve and clarify. The temperature was lowered to 10-15 °C, and saturated aqueous sodium bicarbonate solution was added to adjust the pH to basic, and separated into two layers. The organic phase was washed with brine (1.0 L), 0.5N hydrochloric acid (560 mL x 3), and brine again (560 mL). The organic phase was dried over anhydrous sodium sulfate, and suction filtered, and concentrated to dryness under reduced pressure at 40 °C. To the concentrated residue was added 2.8 L of MTBE, heated to 40 °C, and stirred for 0.5 h to dissolve and clarify. The temperature was slowly lowered to 10-15 °C, and a large amount of white solid was precipitated. Stirring at room temperature for 1.0 h, suction filtration, and the filter cake was rinsed with 280 mL of MTBE. The filter cake was transferred to a vacuum oven, and dried at 35 °C for 16 h. The material was removed, and weighed to give compound 1 as a white solid (100.3 g, yield 92%). CAD-HPLC showed a purity of 99.50%.

[0143] 1 H NMR (400 MHz, Chloroform-d) δ 5.56 (d, J = 8.5 Hz, 1H), 5.34-5.19 (m, 1H), 4.48-4.37 (m, 3H), 4.31 (dd, J = 12.0, 4.2 Hz, 1H), 4.26-4.02 (m, 3H), 3.87-3.45 (m, 191H), 3.39 (s, 3H), 2.52-2.38 (m, 2H), 2.33 (td, J = 7.6, 2.8 Hz, 4H), 2.28-2.17 (m, 1H), 2.12-1.94 (m, 1H), 1.70-1.53 (m, 4H), 1.27 (s, 60H), 0.89 (t, J = 6.7 Hz, 6H).

[0144] Example 2: Synthesis of compound 2

[0145] Synthesis of compound 2-1

[0146] To a solution of D-valine benzyl ester phenylsulfonate (10.8 g, 28.5 mmol, 1.2 eq) in acetonitrile (160 mL) was added N-Boc glycine (4.2 g, 23.7 mmol, 1.0 eq), DIPEA (3.67 g, 28.5 mmol, 1.2 eq), TCFH (7.99 g, 28.5 mmol, 1.2 eq) and N-methylimidazole (4.9 g, 60.0 mmol, 2.1 eq) at 0 °C. After addition, the reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction was complete, and the mixture was concentrated under reduced pressure at low temperature. The residue was purified by silica gel column (PE / EA = 1:1) to give the crude product. The crude product was further purified by reverse phase column (CH3CN:H2O = 5-50%, 0.05% TFA) to give 8.2 g of pure white solid.

[0147] MS (ESI), m / z, 309.0 [M-55] + .

[0148] Synthesis of compound 2-2

[0149] To a solution of 2-1 (2.38 g, 6.54 mmol, 1.0 eq) in CH2Cl2(6 mL) was added TFA (6 mL) dropwise at room temperature 25 °C. The reaction mixture was stirred at room temperature for 2 h. The reaction was complete, and the mixture was concentrated. The residue was further concentrated by oil pump. CH3CN (500 mL) was added, and the mixture was concentrated under reduced pressure to give 2.1 g of yellow solid.

[0150] MS (ESI), m / z, 264.20 [M+H-TFA] +

[0151] Synthesis of compound 2-3

[0152] To a solution of 1-4 (3.0 g, 4.76 mmol, 1.0 eq) in CH2Cl2(80 mL) was added 2-2 (4.53 g, 11.9 mmol, 2.5 eq), EDCI.HCl (2.3 g, 11.9 mmol, 2.5 eq) and DMAP (1.16 g, 9.52 mmol, 2.0 eq) successively at room temperature 25 °C. The reaction mixture was stirred at room temperature for 2 h. The reaction was complete, and the mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column (PE / EA = 1:1) to give 2.9 g of pure product.

[0153] MS (ESI), m / z, 761.00 [M / 4+H] +

[0154] Synthesis of compound 2

[0155] To a solution of 2-3 (8.28 g, 2.80 mmol, 1.0 eq) in MeOH (200 mL) was added 10% Pd / C (800 mg) at room temperature 25 °C. H2was replaced (balloon), and stirred at room temperature for 2 h under H2atmosphere. After the reaction was completed, MeOH (200 mL) was added, and the mixture was filtered through celite, and the filtrate was concentrated under reduced pressure, and dried in vacuum to give 6.1 g of pure white solid.

[0156] MS (ESI), m / z, 735.30 [M / 4+H] + .

[0157] Example 3: Synthesis of compound 3

[0158] Synthesis of compound 3-1

[0159] To a solution of D-alanine benzyl ester phenylsulfonate (10 g, 28.5 mmol, 1.2 eq) in acetonitrile (160 mL) was added N-Boc glycine (4.2 g, 23.7 mmol, 1.0 eq), DIPEA (3.67 g, 28.5 mmol, 1.2 eq), TCFH (7.99 g, 28.5 mmol, 1.2 eq) and N-methylimidazole (4.9 g, 60.0 mmol, 2.1 eq) successively at 0 °C. After the addition, the mixture was allowed to warm to room temperature and stirred for 2 h. After the reaction was completed, the mixture was concentrated under reduced pressure at low temperature. The residue was purified by silica gel column chromatography (PE / EA = 1:1) to give a crude product. The crude product was further purified by C18 column (CH3CN:H2O = 5-50%, 0.05% TFA) to give 8.2 g of pure white solid.

[0160] MS (ESI), m / z, 281.0 [M-55] + .

[0161] Synthesis of compound 3-2

[0162] To a solution of 3-1 (2.2 g, 6.54 mmol, 1.0 eq) in CH2Cl2(6 mL) was added TFA (6 mL) dropwise at room temperature 25 °C. The mixture was stirred at room temperature for 2 h. After the reaction was completed, the mixture was concentrated, and the residue was further concentrated by oil pump. CH3CN (500 mL) was added, and the mixture was concentrated under reduced pressure to give 2.1 g of yellow solid.

[0163] MS (ESI), m / z, 236.20 [M+H-TFA] + .

[0164] Synthesis of compound 3-3

[0165] To a solution of 1-4 (3.0 g, 4.76 mmol, 1.0 eq) in CH2Cl2(80 mL) was added 3-2 (4.2 g, 11.9 mmol, 2.5 eq), EDCI.HCl (2.3 g, 11.9 mmol, 2.5 eq) and DMAP (1.16 g, 9.52 mmol, 2.0 eq) successively at room temperature 25 °C. Stirring at room temperature for 2 h. The reaction was completed, filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel column (PE / EA = 1:1 as eluent) to give 2.9 g of pure product.

[0166] MS (ESI), m / z, 754.00 [M / 4+H] + .

[0167] Synthesis of compound 3

[0168] To a solution of 3-3 (8.2 g, 2.80 mmol, 1.0 eq) in methanol (200 mL) was added 10% Pd / C (800 mg) at room temperature 25 °C. H2replacement (balloon), stirring at room temperature for 2 h under H2atmosphere. After the reaction was completed, MeOH (200 mL) was added, and the mixture was filtered through celite, and the filtrate was concentrated under reduced pressure and dried in vacuum to give 6.1 g of pure white solid.

[0169] MS (ESI), m / z, 731.30 [M / 4+H] + .

[0170] Example 4: Synthesis of compound 4

[0171] Synthesis of compound 4-1

[0172] To a solution of glycine benzyl ester hydrochloride (4.2 g, 20 mmol, 1.0 eq) in DMF (20 mL) was added BOC-glycine (3.5 g, 20 mmol, 1.0 eq) and HATU (11.4 g, 30 mmol, 1.5 eq) successively at 0 °C. DIPEA (7.74 g, 60 mmol, 3.0 eq) was added dropwise slowly. After addition, stirring at room temperature for 2 h. The reaction was completed, the reaction liquid was poured into water (150 mL), and EA was added to extract (100 mL x 2), and saturated brine was washed (100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column (PE / EA = 1:1) to give 4.8 g of pure white solid.

[0173] MS (ESI), m / z, 266.80 [M+H] + .

[0174] Synthesis of compound 4-2

[0175] To a solution of 4-1 (2.2 g, 6.82 mmol, 1.0 eq) in CH2Cl2(6 mL) was added TFA (6 mL) dropwise at room temperature 25 °C. Stirring at room temperature for 2 h. The reaction was completed, the reaction was concentrated, the residue was concentrated by oil pump. CH3CN (500 mL) was added and concentrated under reduced pressure to give 2.1 g of yellow solid.

[0176] MS (ESI), m / z, 223.20 [M+H-TFA] +

[0177] Synthesis of compound 4-3

[0178] To a solution of 4-2 (1.82 g, 5.39 mmol, 1.0 eq) in CH2Cl2(20 mL) was added 1-4 (2.5 g, 10.78 mmol, 2.0 eq), EDCI (3.1 g, 16.17 mmol, 3.0 eq) and DMAP (1.32 g, 10.78 mmol, 2.0 eq) successively at room temperature 25 °C. Stirring at room temperature for 2 h. The reaction was completed, concentrated under reduced pressure, purified by silica gel column (PE / EA = 2:1 ~ 1:1 as eluent) to give 2.0 g of yellow-green solid.

[0179] MS (ESI), m / z, 750.30 [M / 4+H] + .

[0180] Synthesis of compound 4

[0181] To a solution of 4-3 (5.0 g, 1.67 mmol, 1.0 eq) in methanol (100 mL) was added 10% Pd / C (500 mg) at room temperature 25 °C. H2replacement (balloon), stirring at room temperature under H2for 2 h. After the reaction was completed, MeOH (200 mL) was added, and the mixture was filtered through celite, and the filtrate was concentrated under reduced pressure, and purified by reverse phase column (THF:H2O = 5-70%) to give 3.0 g of white solid.

[0182] MS (ESI), m / z, 728.00 [M / 4+H] + .

[0183] Example 5: Synthesis of compound 5

[0184] Synthesis of compound 5-1

[0185] To a solution of cysteamine hydrochloride (1.50 g, 13.2 mmol, 1.0 eq) in methanol (18 mL) was added triethylamine (1.85 mL, 26.4 mmol, 2.0 eq), 2-hydroxyethyl disulfide (1.50 g, 13.2 mmol, 1.0 eq) in dichloromethane, and stirred at room temperature for 16 h under ice-water bath and nitrogen protection. The above solution was cooled to 0 °C, and di-tert-butyl dicarbonate (4.32 g, 19.8 mmol, 1.5 eq) was added. Stirring at room temperature for 4 h. The reaction was terminated by LCMS detection. The reaction solution was directly concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 3: 1) to give the compound as colorless oil (0.9 g, 26.9% yield).

[0186] MS (ESI), m / z, 154.00 [M-100] + .

[0187] Synthesis of compound 5-2

[0188] To a solution of 5-1 (2.2 g, 8.66 mmol, 1.0 eq) in CH2Cl2(6 mL) was added TFA (6 mL) dropwise at room temperature 25 °C. Stirring at room temperature for 2 h. The reaction was completed, and the reaction solution was concentrated, and the residue was fully concentrated by oil pump. CH3CN (500 mL) was added and continued to concentrate under reduced pressure to give 2.1 g of yellow solid.

[0189] MS (ESI), m / z, 154.00 [M+H-TFA] + .

[0190] Synthesis of compound 5

[0191] To a solution of 1-4 (360 mg, 0.129 mmol, 1.0 eq) in DMF (4 mL) was added HATU (98 mg, 0.258 mmol, 2.0 eq), DIPEA (50 mg, 0.387 mmol, 3.0 eq) and 5-2 (41 mg, 0.155 mmol, 1.2 eq) successively at room temperature. The reaction solution was continued to stir for 16 h, and the mixture was directly injected into a C8 reversed-phase column (80 g, 20-35 pm, THF / MeOH = 3: 1, H2O = 5-70%, flow rate: 60 mL / min) for purification. The product was collected and concentrated to give 620 mg of light yellow solid.

[0192] MS (ESI), m / z, 733.00 [M / 4+H] + .

[0193] Example 6: Synthesis of compound 6

[0194] Synthesis of compound 6-1

[0195] To a solution of 1-4 (1.4 g, 0.5 mmol) in DMF (25 mL) was added 6-SM (256 mg, 0.5 mmol, synthesized according to the method in WO2015155998A1 Example 12), HATU (0.7 g, 1.0 mmol) and DIPEA (0.33 g, 2.5 mmol). The reaction was stirred at room temperature for 12 h, HPLC showed the reaction was complete, precipitated in 100 mL MTBE, filtered, the crude was purified by silica gel column (DCM / MeOH) to give compound 6-1 as a white solid (1.2 g).

[0196] MS (ESI), m / z, 823.00 [M / 4+H] + .

[0197] Synthesis of compound 6

[0198] To a solution of 6-1 (5.0 g, 1.52 mmol, 1.0 eq) in methanol (100 mL) was added 10% Pd / C (500 mg) at room temperature 25 °C. H2replacement (balloon), stirred at room temperature for 2 h under H2environment. After the reaction was completed, MeOH (200 mL) was added, and the mixture was filtered through celite, and the filtrate was concentrated under reduced pressure, and purified by reverse phase column (THF:H2O = 5-70%) to give 3.0 g of white solid.

[0199] MS (ESI), m / z, 800.50 [M / 4+H] + .

[0200] Example 7: Synthesis of compound 7

[0201] Synthesis of compound 7-1

[0202] To a solution of (S)-(-)-methyl 2-chloropropionate 7-SM (10 g, 81.60 mmol, 1.0 eq) in DMF (50 mL) was added KSAc (11.2 g, 97.9 mmol, 1.2 eq) at room temperature 25 °C under nitrogen protection. The reaction mixture was stirred for 16 hours. LCMS detected that the reaction was complete, the reaction liquid was added to water, extracted with PE / EA = 5:1, washed with brine, dried over anhydrous sodium sulfate, rotary evaporation, and purified by silica gel column (PE:EA = 5:1) to give 7-1 as a colorless oil, 12.52 g, 95% yield.

[0203] MS (ESI), m / z, 163.0 [M+H] + .

[0204] Synthesis of compound 7-2

[0205] To a solution of LiAlH4(2.5 M, 60 mL, 4.0 eq) in THF was added a solution of 7-1 (6.0 g, 37 mmol, 1.0 eq) in THF (50 mL) at room temperature 0 °C under nitrogen protection. After the addition was completed, the reaction was warmed to 80 °C and refluxed for 2 h. The reaction was cooled to room temperature, EA (18.0 mL) was added, and the mixture was cooled to 0 °C in an ice bath. Hydrochloric acid solution (2 M, 24 mL) was slowly added, and the mixture was filtered. The filtrate was dried over anhydrous sodium sulfate, filtered, and the filtrate was used directly in the next step without further purification.

[0206] Synthesis of compound 7-3

[0207] To a solution of 7-2 (1.5 g, 5.23 mmol, 1.0 eq) in methanol (15 mL) was added 10-SM2 (CAS: 535943-48-7, 471 mg, 5.23 mmol, 1.0 eq) at room temperature 25 °C under nitrogen protection. The reaction mixture was stirred at room temperature for 16 h. LCMS showed the reaction was completed. The reaction was concentrated, and the residue was purified by C18 column (ACN / TFA 0.05% H2O) to give the product 7-3 as a colorless oil, 1.0 g, 72% yield.

[0208] MS (ESI), m / z, 290.0 [M+Na] + .

[0209] Synthesis of compound 7-4

[0210] To a solution of 7-3 (2.2 g, 8.23 mmol, 1.0 eq) in CH2Cl2(6 mL) was added TFA (6 mL) dropwise at room temperature 25 °C. The reaction was stirred at room temperature for 2 h. The reaction was concentrated, and the residue was concentrated by oil pump. CH3CN (500 mL) was added, and the mixture was concentrated under reduced pressure to give 2.1 g of yellow solid.

[0211] MS (ESI), m / z, 168.10 [M+H-TFA] + .

[0212] Synthesis of compound 7

[0213] To a solution of 1-4 (1.4 g, 0.5 mmol) in DMF (25 mL) was added 7-4 (141 mg, 0.5 mmol), HATU (0.7 g, 1.0 mmol), and DIPEA (0.33 g, 2.5 mmol). The reaction was stirred at room temperature for 12 h. HPLC showed the reaction was completed. The reaction was added to 100 mL MTBE for precipitation, filtered, and the crude product was purified by silica gel column (DCM / MeOH) to give compound 7 as a white solid (1.3 g).

[0214] Example 8: Synthesis of compound 8

[0215] Synthesis of compound 8-1

[0216] To a suspension of L-aspartic acid-4-tert-butyl ester (380 mg, 2.0 mmol, 2.0 eq) in DMF (20 mL) was added 1-1 (2.17 g, 1.0 mmol, 1.0 eq) and triethylamine (253 mg, 2.5 mmol, 2.5 eq) sequentially at 20 °C. After addition, the reaction was stirred at 20 °C for 16 h. The reaction was quenched by the addition of saturated aqueous citric acid solution. The reaction was extracted with DCM (100 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered through celite, and the clear filtrate was obtained. The filtrate was concentrated, dissolved in DCM (2 mL), and then MTBE (30 mL) was added. A large amount of white solid was precipitated upon stirring at 20 °C. The solid was collected by suction filtration and the filter cake was dried thoroughly under vacuum to give 2.1 g of pure white solid. TLC showed a single spot.

[0217] Synthesis of compound 8-2

[0218] To a solution of 8-1 (1.0 g, 0.449 mmol, 1.0 eq) in DCM (20 mL) was added HATU (341 mg, 0.898 mmol, 2.0 eq), DMAP (110 mg, 0.898 mmol, 2.0 eq), and DSG (337 mg, 0.539 mmol, 1.2 eq) sequentially at 15 °C. After addition, the reaction was stirred at 15 °C for 4 h. The reaction was quenched by the addition of 0.5 N aqueous HC1 (100 mL). The reaction was partitioned and the organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (DCM / MeOH = 98:2 to 95:5 to 94:6) to give 1.3 g of pure white solid.

[0219] 1H NMR (400 MHz, CDC13) δ 5.74 (d, J = 8.8 Hz, 1H), 5.28 - 5.22 (m, 1H), 5.01 (s, 1H), 4.57 (dt, J = 9.0, 4.5 Hz, 1H), 4.40 - 4.17 (m, 5H), 4.11 (dd, J = 12.0, 6.0 Hz, 1H), 3.65 (s, 179H), 3.38 (s, 3H), 2.99 - 2.84 (m, 1H), 2.73 (dd, J = 17.0, 4.5 Hz, 1H), 2.31 (dt, J = 7.6, 3.8 Hz, 4H), 1.66 - 1.55 (m, 6H), 1.43 (s, 15H), 1.29 - 1.22 (m, 64H), 0.88 (t, J = 6.7 Hz, 6H).

[0220] Synthesis of compound 8

[0221] To a solution of 8-2 (1.3 g, 0.455 mmol, 1.0 eq) in DCM (3 mL) was added TFA (4 mL) at 16 °C. After addition, the reaction was stirred at 16 °C for 2 h. The reaction solution was directly purified by silica gel column (DCM / MeOH = 10:0~10:1), and the collected solution was concentrated to give 1.0 g of white solid pure product.

[0222] 1 H NMR (400 MHz, CDC13) δ 5.74 (d, J = 8.8 Hz, 1H), 5.28 - 5.22 (m, 1H), 5.01 (s, 1H), 4.57 (dt, J = 9.0, 4.5 Hz, 1H), 4.40 - 4.17 (m, 5H), 4.11 (dd, J = 12.0, 6.0 Hz, 1H), 3.65 (s, 179H), 3.38 (s, 3H), 2.99 - 2.84 (m, 1H), 2.73 (dd, J = 17.0, 4.5 Hz, 1H), 2.31 (dt, J = 7.6, 3.8 Hz, 4H), 1.66 - 1.55 (m, 6H), 1.43 (s, 15H), 1.29 - 1.22 (m, 64H), 0.88 (t, J = 6.7 Hz, 6H).

[0223] Example 9: Synthesis of compound 9

[0224] Synthesis of compound 9-1

[0225] To a suspension of 1-1 (2.17 g, 1.0 mmol, 2.0 eq) in DMF (20 mL) was added S- triphenylmethyl-L-cysteine (0.72 g, 2.0 mmol, 2.0 eq) and triethylamine (0.25 g, 2.5 mmol, 2.5 eq) sequentially at 20 °C. After addition, the reaction was stirred at 20 °C for 16 h. The reaction was quenched by the addition of saturated aqueous citric acid solution. The reaction was extracted with DCM (100 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered through celite to give a clear filtrate. The filtrate was concentrated, and the residual DMF was concentrated with an oil pump. The concentrate was dissolved in DCM (2 mL). MTBE (30 mL) was added and stirred at 20 °C to precipitate a large amount of white solid. The solid was collected by suction filtration and dried thoroughly under vacuum to give a pure white solid 2.1 g. The solid was used directly in the next step.

[0226] Synthesis of compound 9-2

[0227] To a solution of compound 9-1 (0.5 g, 0.21 mmol, 1.0 eq) in DCM (10 mL) was added DSG (0.19 g, 0.31 mmol, 1.5 eq), HATU (0.16 g, 0.42 mmol, 2.0 eq) and DMAP (0.06 g, 0.52 mmol, 2.5 eq) under nitrogen at room temperature. The reaction was stirred for 16 h. The reaction was monitored by TLC (DCM:MeOH = 10:1). The reaction was concentrated and purified by reverse phase column chromatography (A = H2O, B = THF:MeOH = 3:1). The product fractions were concentrated to remove the organic solvent and the aqueous layer was extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give a white solid (1.1 g, 100% yield).

[0228] 1 H NMR (400 MHz, CDC13) δ 7.40 (d, J = 7.8 Hz, 6H), 7.32 (d, J = 7.2 Hz, 5H), 7.24 (t, J = 7.2 Hz, 3H), 7.00 (s, 2H), 5.32 - 5.15 (m, 2H), 5.03 (s, 1H), 4.35 (dd, J = 11.8, 4.2 Hz, 1H), 4.29 (dd, J = 11.8, 4.4 Hz, 2H), 4.24 - 4.15 (m, 3H), 4.10 (dd, J = 11.8, 5.9 Hz, 1H), 3.89 - 3.47 (s, 180H), 3.40 (s, 3H), 2.69 - 2.55 (m, 2H), 2.30 - 2.24 (m, 5H), 1.75 (dd, J = 11.6, 4.4 Hz, 5H), 1.28 (s, 72H), 0.86 (d, J = 1.6 Hz, 6H).

[0229] Synthesis of compound 9-3

[0230] TFA (25 mL) was cooled to 0 °C, and compound 9-2 (0.5 g, 0.166 mmol, 1.0 eq) and triethylsilane (1 mL) were added under nitrogen protection. The stirring was continued at 0 °C for 1 h. The reaction solution was concentrated, and methyl tert-butyl ether and petroleum ether were added to slurry, and centrifugation gave compound 9-3 as a white solid (0.36 g, 78.3% yield). Directly to the next reaction.

[0231] Synthesis of compound 9

[0232] To a solution of 9-3 (1.52 g, 0.55 mmol, 1.0 eq) in DMF (6 mL) was added 9-SM1 (174 mg, 0.82 mmol, 1.5 eq) and DIPEA (0.14 g, 1.1 mmol, 2.0 eq) at room temperature under nitrogen protection. The stirring was continued at room temperature for 16 h. LCMS detection showed that the reaction was complete. Filtration gave compound 9 as a white solid (0.44 g, 72.7% yield).

[0233] MS (ESI), m / z, 745.80 [M+H] + .

[0234] Example 10: Synthesis of compound 10

[0235] Synthesis of compound 10-1

[0236] To a suspension of N -Boc-L-lysine (493 mg, 2.0 mmol, 2.0 eq) in DMF (20 mL) was added 1-1 (2.17 g, 1.0 mmol, 1.0 eq) and triethylamine (253 mg, 2.5 mmol, 2.5 eq) successively at 20 °C. After addition, the stirring was continued at 20 °C for 16 h. After the reaction was completed, saturated aqueous citric acid was added to quench the reaction. DCM extraction (100 mL x 2). The combined organic phase was emulsified, and anhydrous sodium sulfate was added to dryness. The organic phase was still turbid emulsion, and diatomite was filtered to obtain a clear filtrate. The filtrate was rotary evaporated, and the residual DMF was concentrated by an oil pump. The concentrate was dissolved in DCM (2 mL), and then MTBE (30 mL) was added to slurry at 20 °C, and a large amount of white solid was precipitated. Filtration under suction, and the filter cake was fully vacuum dried to obtain a pure white solid 2.0 g. TLC showed a pure single point.

[0237] Synthesis of compound 10-2

[0238] To a solution of 10-1 (1.0 g, 0.437 mmol, 1.0 eq) in DCM (20 mL) was added HATU (332 mg, 0.874 mmol, 2.0 eq), DMAP (107 mg, 0.874 mmol, 2.0 eq) and DSG (355 mg, 0.568 mmol, 1.3 eq) successively at 15 °C. After addition, the reaction was stirred at 15 °C for 4 h. After the reaction was completed, the reaction was quenched by adding 0.5 N HCl (aq) (100 mL) aqueous solution. The organic phase was washed with saturated sodium chloride (200 mL), dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (DCM / MeOH = 98:2 ~ 95:5 ~ 94:6) to give 840 mg of pure white solid.

[0239] Synthesis of compound 10-3

[0240] To a solution of 10-2 (840 mg, 0.29 mmol, 1.0 eq) in DCM (8 mL) was added TFA (6 mL) at 16 °C. After addition, the reaction was stirred at 16 °C for 4 h. After the reaction was completed, the reaction was directly concentrated and purified by silica gel column chromatography (DCM / MeOH = 10:0 ~ 10:1). The collected fraction was concentrated to give 860 mg of pure white solid.

[0241] Synthesis of compound 10

[0242] To a solution of 10-3 (860 mg, 0.307 mmol, 1.0 eq) in DCM (6 mL) was added succinic anhydride (62 mg, 0.615 mmol, 2.0 eq) and DIPEA (119 mg, 0.921 mmol, 3.0 eq) at 16 °C. After addition, the reaction was stirred at 16 °C for 2 h. After the reaction was completed, the reaction was concentrated, added water and extracted with DCM (100 mL x 2), and the combined organic phase was dried over anhydrous sodium sulfate. The filtrate was concentrated to give 840 mg of pure white solid. TLC showed a single spot.

[0243] 1H NMR (400 MHz, CDC13) δ 6.99 (s, 1H), 6.30 (t, J = 6.0 Hz, 1H), 5.95 (d, J = 7.8 Hz, 1H), 5.33 - 5.26 (m, 1H), 4.43 (dd, J = 11.8, 4.2 Hz, 1H), 4.35 - 4.09 (m, 5H), 3.66 (s, 180H), 3.39 (s, 3H), 3.28 (q, J = 7.7, 6.8 Hz, 2H), 2.71 (dt, J = 8.3, 3.3 Hz, 2H), 2.64 (s, 1H), 2.47 (t, J = 6.2 Hz, 2H), 2.33 (td, J = 7.5, 3.6 Hz, 4H), 2.28 (d, J = 4.8 Hz, 2H), 1.35 - 1.20 (m, 68H), 0.89 (t, J = 6.7 Hz, 6H).

[0244] Example 11: Synthesis of compound 11

[0245] Synthesis of compound 11-1

[0246] To a suspension of Boc-Lys-OH (737 mg, 2.0 mmol, 2.0 eq) in DMF (20 mL) was added 1-1 (2.17 g, 1.0 mmol, 1.0 eq) and triethylamine (253 mg, 2.5 mmol, 2.5 eq) sequentially at 20 °C. After addition, the reaction was stirred at 20 °C for 16 h. After the reaction was completed, saturated aqueous citric acid was added to quench the reaction. DCM (100 mL x 2) was added to extract the reaction. The combined organic phase was emulsified. Anhydrous sodium sulfate was added to dry the organic phase. The mixture was filtered through celite to give a clear filtrate. The filtrate was concentrated, and the residual DMF was pumped off. The concentrate was dissolved in DCM (2 mL). MTBE (30 mL) was added to the solution to precipitate a large amount of white solid. The solid was collected by suction filtration and dried under vacuum to give 1.9 g of white solid.

[0247] Synthesis of compound 11-2

[0248] To a solution of 11-1 (1.0 g, 0.437 mmol, 1.0 eq) in DCM (20 mL) was added HATU (332 mg, 0.874 mmol, 2.0 eq), DMAP (107 mg, 0.874 mmol, 2.0 eq) and DSG (355 mg, 0.568 mmol, 1.3 eq) successively at 15 °C. After addition, the reaction was stirred at 15 °C for 4 h. After the reaction was completed, the reaction solution was quenched by adding 0.5 N aqueous HCl (100 mL). The organic phase was separated and washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (DCM / MeOH = 98:2 ~ 95:5 ~ 94:6) to obtain 1.1 g of a pure white solid.

[0249] 1 H NMR (400 MHz, Chloroform-d) δ 5.27 (tt, J = 5.9, 4.3 Hz, 1H), 5.07 (d, J = 8.3 Hz, 1H), 5.00 (d, J = 7.1 Hz, 2H), 4.43 - 4.35 (m, 1H), 4.32 - 4.10 (m, 6H), 3.65 (d, J = 1.9 Hz, 175H), 3.38 (s, 3H), 3.16 (q, J = 6.7 Hz, 2H), 2.31 (t, J = 7.6 Hz, 4H), 2.27 (s, 2H), 1.44 (d, J = 3.8 Hz, 20H), 1.34 - 1.20 (m, 72H), 0.88 (t, J = 6.8 Hz, 6H).

[0250] Synthesis of compound 11-3

[0251] To a solution of 11-2 (1.1 g, 0.38 mmol, 1.0 eq) in DCM (4 mL) was added TFA (4 mL) at 16 °C. After addition, the reaction was stirred at 16 °C for 4 h. After the reaction was completed, the reaction solution was directly purified by silica gel column chromatography (DCM / MeOH = 10:0 ~ 10:1), and the collected solution was concentrated to obtain 970 mg of a white solid pure product.

[0252] Synthesis of compound 11

[0253] To a solution of 11-3 (970 mg, 0.335 mmol, 1.0 eq) in DCM (6 mL) was added succinic anhydride (67 mg, 0.67 mmol, 2.0 eq) and DIPEA (129 mg, 1.005 mmol, 3.0 eq) successively at 16 °C. After addition, the reaction was stirred at 16 °C for 2 h. After the reaction was completed, the reaction solution was directly concentrated, water was added, and the organic phase was extracted with DCM (100 mL x 2), and the combined organic phase was dried over anhydrous sodium sulfate. The filtrate was concentrated to obtain 820 mg of a self-colored solid pure product.

[0254] 1 H NMR (400 MHz, DMSO-d6) δ 6.50 (d, J = 8.1 Hz, 1H), 5.63 (t, J = 5.8 Hz, 1H), 5.28 (td, J = 10.2, 9.7, 6.6 Hz, 1H), 4.74 - 4.58 (m, 1H), 4.41 (dd, J = 11.9, 4.1 Hz, 1H), 4.34 - 4.10 (m, 6H), 3.65 (s, 179H), 3.39 (s, 3H), 3.17 (dq, J = 24.3, 7.3, 6.7 Hz, 2H), 3.00 - 2.77 (m, 1H), 2.69 - 2.40 (m, 3H), 2.32 (t, J = 7.6 Hz, 4H), 2.27 (d, J = 5.7 Hz, 1H), 1.35 - 1.22 (s, 76H), 0.89 (t, J = 6.7 Hz, 6H).

[0255] Example 12: Synthesis of compound 12

[0256] Synthesis of compound 12-SM1

[0257] To a solution of glycine benzyl ester hydrochloride (2.21 g, 10.5 mmol, 1.05 eq) in DMF (20 mL) was added Fmoc-O-tert-butyl-L-glutamic acid (4.25 g, 10 mmol, 1.0 eq) and HATU (5.7 g, 15 mmol, 1.5 eq) at 0 °C. DIPEA (2.58 g, 20 mmol, 2.0 eq) was added dropwise slowly. After the addition, the reaction was stirred at room temperature for 2 h. After the reaction was completed, the reaction solution was poured into water (200 mL), extracted with ethyl acetate (150 mL x 2), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (PE / EA = 2:1) to give 5.4 g of pure white solid.

[0258] MS (ESI), m / z, 596.30 [M+Na] + .

[0259] Synthesis of compound 12-SM2

[0260] To a solution of 12-SM1 (5.4 g, 9.23 mmol, 1.0 eq) in methanol (150 mL) was added 10% Pd-C (1.0 g) at room temperature 25 °C. H2was replaced and stirred at room temperature for 4 h under hydrogen atmosphere. After the reaction was completed, MeOH (200 mL) was added, and the mixture was filtered through celite. The filtrate was concentrated to give the crude product, which was used directly in the next step.

[0261] MS (ESI), m / z, 505.20 [M+Na] + .

[0262] Synthesis of compound 12-SM3

[0263] To the reaction solution of 12-SM2 crude in DMF (30 mL) was added triethylamine (6.0 mL) at 25 °C, and the reaction was stirred for 6 h. After the reaction was completed, it was concentrated. A large amount of white solid was precipitated, and the filter cake was rinsed with acetonitrile until the filtrate was colorless. The filter cake was slurried with acetonitrile (60 mL) at 60 °C for 1 h. After cooling to room temperature, it was suction filtered, and the filter cake was thoroughly dried under vacuum to obtain 2.4 g of white solid.

[0264] MS (ESI), m / z, 261.20 [M+H] + .

[0265] Synthesis of compound 12-1

[0266] To the suspension of 12-SM3 (522 mg, 2.0 mmol, 2.0 eq) in DMF (20 mL) was sequentially added 1-1 (2.17 g, 1.0 mmol, 1.0 eq) and triethylamine (253 mg, 2.5 mmol, 2.5 eq) at 20 °C. After the addition was completed, the reaction was stirred at 20 °C for 16 h. After the reaction was completed, saturated aqueous citric acid was added to the reaction solution to quench the reaction. It was extracted with DCM (100 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, suction filtered through celite to obtain a clear filtrate. The filtrate was concentrated, and the residual DMF was pumped dry. DCM (2 mL) was added to dissolve the concentrate. It was slurried with MTBE (30 mL) at 20 °C to precipitate a large amount of white solid. It was suction filtered, and the filter cake was thoroughly dried under vacuum to obtain 2.2 g of pure white solid.

[0267] Synthesis of compound 12-2

[0268] To the solution of 12-1 (1.0 g, 0.434 mmol, 1.0 eq) in DCM (20 mL) was sequentially added HATU (330 mg, 0.868 mmol, 2.0 eq), DMAP (106 mg, 0.868 mmol, 2.0 eq), and DSG (326 mg, 0.521 mmol, 1.2 eq) at 15 °C. After the addition was completed, the reaction was stirred at 15 °C for 4 h. After the reaction was completed, 0.5 N aqueous HCl (100 mL) was added to the reaction solution to quench the reaction. It was separated, and the organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (DCM / MeOH = 98:2 ~ 95:5 ~ 94:6) to obtain 970 mg of pure white solid.

[0269] Synthesis of compound 12

[0270] To a solution of 12-2 (970 mg, 0.33 mmol, 1.0 eq) in DCM (4 mL) was added TFA (3 mL) at 16 °C. After addition, the reaction was stirred at 16 °C for 4 h. After the reaction was completed, the reaction solution was concentrated and purified by silica gel column chromatography (DCM / MeOH = 10:0~10:1). The collected solution was concentrated to give 820 mg of white solid product.

[0271] 1 H NMR (400 MHz, DMSO-d6) δ 5.26 (p, J = 5.1 Hz, 1H), 4.45 - 4.29 (m, 3H), 4.25 - 4.10 (m, 2H), 4.03 (br s, 2H), 3.65 (s, 180H), 3.38 (s, 3H), 2.66 - 2.41 (m, 2H), 2.32 (q, J = 7.0 Hz, 5H), 2.25 - 2.12 (m, 1H), 2.01 (dd, J = 15.9, 9.3 Hz, 1H), 1.70 - 1.50 (m, 5H), 1.50 - 1.10 (m, 56H), 0.88 (t, J = 6.7 Hz, 6H).

[0272] Example 13: Synthesis of compound 13

[0273] Synthesis of compound 13-SM1

[0274] To a suspension of L-glutamic acid-5-tert-butyl ester (2.03 g, 10 mmol, 1.0 eq) in THF (100 mL) was added Fmoc-Gly-OSu (4.73 g, 12 mmol, 1.2 eq) and Et3N (2.53 g, 25 mmol, 2.5 eq) successively at 25 °C. After addition, the reaction was stirred at room temperature for 4 h. After the reaction was completed, the reaction solution was concentrated, and the obtained crude product was directly used in the next step.

[0275] MS (ESI), m / z, 505.20 [M+Na] + .

[0276] Synthesis of compound 13-SM2

[0277] To a reaction solution of 13-SM1 crude product in DMF (30 mL) was added triethylamine (6.0 mL) at 25 °C, and the reaction was stirred for 6 h. After the reaction was completed, it was concentrated, and a large amount of white solid was precipitated. The filter cake was rinsed with acetonitrile until the filtrate was colorless. The filter cake was slurried with acetonitrile (60 mL) at 60 °C for 1 h. After cooling to room temperature, it was suction filtered, and the filter cake was thoroughly dried under vacuum to give 2.2 g of white solid.

[0278] MS (ESI), m / z, 205.20 [M+H-C4H8] +.

[0279] Synthesis of compound 13-1

[0280] To a suspension of 13-SM2 (522 mg, 2.0 mmol, 2.0 eq) in DMF (20 mL) was added 1-1 (2.17 g, 1.0 mmol, 1.0 eq) and triethylamine (253 mg, 2.5 mmol, 2.5 eq) sequentially at 20 °C. After addition, the reaction was stirred at 20 °C for 16 h. After completion of the reaction, the reaction was quenched by the addition of saturated aqueous citric acid solution. The reaction was extracted with DCM (100 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered through celite, and the filtrate was concentrated. The residual DMF was removed by oil pump. The concentrate was dissolved in DCM (2 mL). The solution was slurried with MTBE (30 mL) at 20 °C, and a large amount of white solid was precipitated. The solid was collected by suction filtration and dried thoroughly under vacuum to give 2.2 g of pure white solid.

[0281] Synthesis of compound 13-2

[0282] To a solution of 13-1 (1.0 g, 0.434 mmol, 1.0 eq) in DCM (20 mL) was added HATU (330 mg, 0.868 mmol, 2.0 eq), DMAP (106 mg, 0.868 mmol, 2.0 eq), and DSG (326 mg, 0.521 mmol, 1.2 eq) sequentially at 15 °C. After addition, the reaction was stirred at 15 °C for 4 h. After completion of the reaction, the reaction was quenched by the addition of 0.5 N aqueous HC1 solution (100 mL). The reaction was partitioned, and the organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (DCM / MeOH = 98:2 to 95:5 to 94:6) to give 850 mg of pure white solid.

[0283] Synthesis of compound 13

[0284] To a solution of 13-2 (770 mg, 0.265 mmol, 1.0 eq) in DCM (4 mL) was added TFA (4 mL) at 16 °C. After addition, the reaction was stirred at 16 °C for 4 h. After completion of the reaction, the reaction was concentrated, and the product was purified by silica gel column chromatography (DCM / MeOH = 10:0 to 10:1) to give 740 mg of pure white solid.

[0285] 1H NMR (400 MHz, Chloroform-d) δ 7.71 (s, 1H), 6.63 (s, 1H), 5.27 (s, 1H), 4.54 (br s, 1H), 4.43 - 4.09 (m, 6H), 3.67 (s, 180H), 3.39 (s, 3H), 2.45 (br s, 2H), 2.32 (q, J=7.1 Hz, 4H), 2.25 - 1.94 (m, 3H), 1.66 - 1.54 (m, 5H), 1.45 - 1.00 (m, 63H), 0.88 (t, J=6.9 Hz, 6H).

[0286] Example 14: Synthesis of compound 14

[0287] Synthesis of compound 14-SM1

[0288] Into a 250 mL single neck flask was added stearic acid (12.63 g, 0.044 mol), 1,3-dihydroxyacetone (2 g, 0.022 mol) and pyridine (67 mL), then a solution of DCC (9.16 g, 0.044 mmol) in DCM (22 mL) was added, replaced with nitrogen for three times and protected, the reaction was stirred at room temperature for 32 h, the reaction solution was filtered, the filter cake was washed with DCM, the filtrate was directly concentrated to get the crude product, the crude product was added into acetone (75 mL), dissolved at 70 °C, hot filtered, the filtrate was naturally warmed to room temperature to crystallize, filtered, the filter cake was washed with acetone and dried under vacuum to get white solid 6.36 g.

[0289] 1 H NMR (400 MHz, Chloroform-d) δ 4.75 (s, 4H), 2.42 (t, J=7.5 Hz, 4H), 1.66 (t, J=7.3 Hz, 5H), 1.26 (s, 56H), 0.88 (t, J=6.7 Hz, 6H).

[0290] Synthesis of compound 14-SM2

[0291] Into a 25 mL three neck flask was added 14-SM1 (2.5 g, 4.01 mmol) and THF (40 mL), stirred to dissolve at 25 °C, replaced with nitrogen for three times and protected, added borane dimethyl sulfide (2.5 mL, 1.003 mmol), stirred to react at 25 °C for 16 h, sampled for TLC detection, the raw material was completely reacted, the reaction solution was quenched by adding water (4 mL), directly concentrated to get the crude product, added acetone (60 mL), stirred to dissolve at 70 °C, then naturally cooled to room temperature, a large amount of solid was precipitated, filtered, the filter cake was washed with acetone and dried under vacuum to get white solid 1.59 g.

[0292] 1H NMR (400 MHz, Chloroform-d) δ 4.25-4.02 (m, 5H), 2.46 (s, 1H), 2.35 (t, J = 7.6 Hz, 4H), 1.63 (t, J = 7.3 Hz, 5H), 1.25 (s, 56H), 0.88 (t, J = 6.7 Hz, 6H).

[0293] Synthesis of compound 14-1

[0294] To a solution of 1-2 (1.0 g, 0.44 mmol, 1.0 eq) in DCM (20 mL) was added HATU (334 mg, 0.88 mmol, 2.0 eq), DMAP (107 mg, 0.88 mmol, 2.0 eq) and 14-SM2 (356 mg, 0.57 mmol, 1.3 eq) successively at 15 °C. After addition, the reaction was stirred at 15 °C for 4 h. After the reaction was completed, the reaction solution was quenched by adding 0.5 N aqueous HC1 (100 mL). The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (DCM / MeOH = 97:3~90:10) to give 1.3 g of colorless oil.

[0295] Synthesis of compound 14

[0296] To a solution of 14-1 (1.3 g, 0.456 mmol, 1.0 eq) in DCM (12 mL) was added TFA (6 mL) at 16 °C. After addition, the reaction was stirred at 16 °C for 2 h. After the reaction was completed, it was concentrated and dissolved in toluene (300 mL), and concentrated to remove the residual TFA. This was repeated three times to give 990 mg of pure product.

[0297] 1 H NMR (400 MHz, Chloroform-d) δ 5.73 (d, J = 8.3 Hz, 1H), 5.37-5.25 (m, 1H), 4.49-4.04 (m, 4H), 3.65 (s, 189H), 3.38 (s, 3H), 2.52-2.17 (m, 7H), 2.10-1.92 (m, 1H), 1.70-1.53 (m, 5H), 1.50-1.02 (m, 57H), 0.88 (t, J = 6.7 Hz, 6H).

[0298] Example 15: Synthesis of compound 15

[0299] Synthesis of compound 15-1

[0300] To a solution of 1-2 (1.0 g, 0.44 mmol, 1.0 eq) in DCM (20 mL) was added HATU (370 mg, 0.974 mmol, 2.2 eq), DMAP (118 mg, 0.974 mmol, 2.2 eq) and 11-undecanol (177 mg, 0.57 mmol, 1.3 eq) sequentially at 15 °C. After addition, the reaction was stirred at 15 °C for 4 h. After completion of the reaction, the reaction was quenched by the addition of 0.5 N aqueous HC1 (100 mL). The organic phase was washed with saturated brine (200 mL), dried over anhydrous Na2S04 and concentrated. The crude was purified by silica gel column chromatography (DCM / MeOH = 95:5 ~ 94:6 ~ 90:10, elution gradient: 90:10, flow rate: 60 mL / min) to give 650 mg of a white solid. Solid TLC showed one pure spot.

[0301] MS (ESI), m / z, 620.80 [(M-Boc) / 4+H] + .

[0302] Synthesis of compound 15

[0303] To a solution of 15-1 (600 mg, 0.236 mmol, 1.0 eq) in DCM (8 mL) was added TFA (4 mL) at 16 °C. After addition, the reaction was stirred at 16 °C for 2 h. After completion of the reaction, the reaction was concentrated, dissolved in toluene (300 mL) and concentrated again to remove the residual TFA. This was repeated three times to give 550 mg of a pure product.

[0304] MS (ESI), m / z, 620.80 [(M-Boc) / 4+H] + .

[0305] 1 H NMR (400 MHz, Chloroform-d) δ 5.60 (d, J = 8.4 Hz, 1H), 4.98 - 4.87 (m, 1H), 4.52 - 4.33 (m, 2H), 4.08 (t, J = 8.9 Hz, 1H), 3.66 (s, 180H), 3.40 (s, 3H), 2.47 - 2.22 (m, 4H), 2.03 - 1.95 (m, 1H), 1.36 - 1.20 (m, 37H), 0.89 (t, J = 6.7 Hz, 6H).

[0306] Example 16: Synthesis of compound 16

[0307] Synthesis of compound 16-1

[0308] To a solution of 1-2 (1.0 g, 0.44 mmol, 1.0 eq) in DMF (20 mL) was added HATU (330 mg, 0.88 mmol, 2.0 eq), DMAP (110 mg, 0.88 mmol, 2.0 eq) and ALC-0315 (440 mg, 0.58 mmol, 1.3 eq) successively at 15 °C. After addition, the reaction was stirred at 15 °C for 4 h. After the reaction was completed, the reaction solution was quenched by adding saturated aqueous NH4Cl (100 mL). The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (DCM / MeOH = 10:0 ~ 95:5 ~ 90:10) to give 1.3 g of pure white solid.

[0309] Synthesis of compound 16

[0310] To a solution of 16-1 (820 mg, 0.29 mmol, 1.0 eq) in DCM (8 mL) was added TFA (12 mL) at 11 °C. After addition, the reaction was stirred at 11 °C for 2 h. After the reaction was completed, it was concentrated and purified by silica gel column chromatography (60 g, 20 ~ 35 μm, DCM: [MeOH: (H2O: Et3N = 10:1, v:v) = 30:1, v:v] = (5.0 ~ 5.5%) ~ (6.5 ~ 10.0%), where the impurity eluted at 5.0 ~ 5.5% and the target product eluted at 6.5 ~ 10.0%). The collected fraction was concentrated to give 550 mg of pure white solid.

[0311] MS (ESI), m / z, 734.20 [M / 4+H] + .

[0312] 1 H NMR (400 MHz, Chloroform-d) δ 5.77 (d, J = 7.8 Hz, 1H), 4.41 - 3.98 (m, 8H), 3.64 (s, 180H), 3.38 (s, 3H), 3.17 - 2.72 (m, 8H), 2.46 - 1.99 (m, 6H), 1.96 - 1.50 (m, 14H), 1.48 - 1.15 (m, 66H), 0.88 (t, J = 6.7 Hz, 12H).

[0313] Example 17: Synthesis of compound 17

[0314] Synthesis of compound 17-SM1

[0315] To a solution of 17-SM1 (1.8 g, 3.66 mmol, 1.0 eq), stearic acid (1.04 g, 3.6 mmol, 1.0 eq) and DMAP (0.89 g, 7.32 mmol, 2.0 eq) in DCM (100 mL) was added DCC (1.51 g, 7.32 mmol, 2.0 eq) at room temperature under nitrogen protection. The reaction was stirred at room temperature for 16 h, quenched by saturated citric acid, separated, dried over anhydrous sodium sulfate, filtered and concentrated. Compound 17-SM2 was obtained as a white solid (2.1 g, 75.5% yield) by purification on a silica gel column.

[0316] MS (ESI), m / z, 514.4 [M+Na] + .

[0317] Synthesis of compound 17-SM3

[0318] To a solution of 17-SM1 (1.8 g, 3.66 mmol, 1.0 eq), stearic acid (1.04 g, 3.6 mmol, 1.0 eq) and DMAP (0.89 g, 7.32 mmol, 2.0 eq) in DCM (100 mL) was added DCC (1.51 g, 7.32 mmol, 2.0 eq) at room temperature under nitrogen protection. The reaction was stirred at room temperature for 16 h, quenched by saturated citric acid, separated, dried over anhydrous sodium sulfate, filtered and concentrated. Compound 17-SM2 was obtained as a white solid (2.1 g, 75.5% yield) by purification on a silica gel column.

[0319] 1 H NMR (400 MHz, CDC13) δ 7.37 - 7.22 (m, 5H), 5.48 (d, J = 8.0 Hz, 1H), 5.06 (s, 2H), 4.58 - 4.50 (m, 1H), 4.39 (d, J = 3.6 Hz, 1H), 4.34 - 4.21 (m, 1H), 4.08 (t, J = 6.4 Hz, 2H), 2.20 (t, J = 7.6 Hz, 2H), 1.60 - 1.45 (m, 6H), 1.19 (s, 58H), 0.81 (t, J = 6.8 Hz, 6H).

[0320] Synthesis of compound 17-SM3

[0321] To a solution of 17-SM2 (2.1 g, 2.77 mmol, 1.0 eq) in DCM / MeOH (1:1, 100 mL) was added Pd / C (10%, 0.21 g) under room temperature and nitrogen protection, hydrogen replacement, and the reaction solution was stirred under hydrogen environment (hydrogen balloon) for 16 h. The reaction solution was filtered, the filtrate was concentrated, and the compound 17-SM3 was obtained as a white solid (1.7 g, 100% yield) by slurry with methyl tert-butyl ether.

[0322] 1 H NMR (400 MHz, CDC13) δ 4.37 (t, J = 4.6 Hz, 2H), 4.15 (dd, J = 12.0, 6.4 Hz, 2H), 3.83 (s, 1H), 2.34 (d, J = 7.4 Hz, 2H), 1.73 - 1.53 (m, 4H), 1.19 (s, 53H), 0.88 (t, J = 6.7 Hz, 6H).

[0323] Synthesis of compound 17-1

[0324] To a solution of 17-SM3 (0.05 g, 0.08 mmol, 1.0 eq) and 1-2 (0.18 g, 0.08 mmol, 1.0 eq) in DMF (5 mL) was added HATU (0.061 g, 0.16 mmol, 2.0 eq) and DIPEA (0.031 g, 0.24 mmol, 3.0 eq) under room temperature and nitrogen protection. The reaction solution was stirred at room temperature for 16 h, concentrated, and citric acid water and dichloromethane were added. The dichloromethane was extracted, the organic phases were combined, washed with salt, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (DCM / MeOH) to obtain compound 17-1 as a white solid (90 mg, yield 39%).

[0325] 1 H NMR (400 MHz, CDC13) δ 4.37 (t, J = 4.6 Hz, 2H), 4.15 (dd, J = 12.0, 6.4 Hz, 2H), 3.83 (s, 1H), 2.34 (d, J = 7.4 Hz, 2H), 1.73 - 1.53 (m, 4H), 1.19 (s, 53H), 0.88 (t, J = 6.7 Hz, 6H).

[0326] Synthesis of compound 17

[0327] To a solution of 17-1 (820 mg, 0.29 mmol, 1.0 eq) in DCM (8 mL) was added TFA (12 mL) at 11 °C. After addition, the reaction was stirred at 11 °C for 2 h. After the reaction was completed, the reaction was concentrated and purified by silica gel column chromatography (60 g, 20-35 pm, DCM: [MeOH: (H2O: Et3N = 10:1, v:v) = 30:1, v:v] = (5.0-5.5%)~(6.5-10.0%), where the impurity eluted at 5.0-5.5% and the target product eluted at 6.5-10.0%). The collected fractions were concentrated to give 550 mg of the white solid of the pure product.

[0328] Example 18: Synthesis of compound 18

[0329] Synthesis of compound 18-1

[0330] To a solution of Z-Lys-OH (0.4 g, 1.43 mmol, 2.0 eq) in DMF (15 mL) was added 1-1 (1.56 g, 0.71 mmol, 1.0 eq) and triethylamine (0.14 g, 1.43 mmol, 2.0 eq) at room temperature under nitrogen protection, and the reaction was stirred for 16 h. The reaction was concentrated, saturated citric acid and dichloromethane were added, and the dichloromethane was extracted, dried over anhydrous sodium sulfate, filtered, concentrated, and slurried with methyl tert-butyl ether to give compound 18-1 as a white solid (1.5 g, 90.4% yield).

[0331] Synthesis of compound 18-2

[0332] To a solution of 18-1 (1.5 g, 0.646 mmol, 1.0 eq) and tert-butyl alcohol (0.095 g, 1.29 mmol, 2.0 eq) in DCM (20 mL) was added DMAP (0.16 g, 1.29 mmol, 2.0 eq) and DCC (0.26 g, 1.29 mmol, 2.0 eq) at room temperature under nitrogen protection. The reaction was stirred for 12 h, filtered, concentrated, and purified by column chromatography to give compound 18-2 as a white solid (0.7 g, 45% yield).

[0333] Synthesis of compound 18-3

[0334] To a solution of 18-2 (0.7 g, 0.029 mmol, 1.0 eq) in DCM / MeOH (1:1, 20 mL) was added palladium on carbon (10%, 0.07 g) at room temperature, and the reaction was stirred under hydrogen atmosphere at 20 °C for 16 h. The reaction was filtered, concentrated, and slurried with methyl tert-butyl ether to give compound 18-3 as a white solid (0.58 g, 86.2% yield).

[0335] Synthesis of compound 18-4

[0336] To a solution of 18-3 (0.58 g, 0.4 mmol, 1.0 eq) in DMF (10 mL) was added succinic anhydride (0.04 g, 0.4 mmol, 1.0 eq) and DIPEA (0.103 g, 0.802 mmol, 2.0 eq) at room temperature under nitrogen protection. The reaction was stirred at room temperature for 4 h. The reaction was quenched with saturated citric acid, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 18-4 as a white solid (0.65 g, crude, used directly in the next step).

[0337] Synthesis of compound 18-5

[0338] To a solution of 18-4 (0.5 g, 0.213 mmol, 1.0 eq) and DSG (0.26 g, 0.426 mmol, 2.0 eq) in DCM (15 mL) was added DCC (0.088 g, 0.426 mmol, 2.0 eq) and DMAP (0.05 g, 0.426 mmol, 2.0 eq) at room temperature under nitrogen protection. The reaction was stirred at room temperature for 16 h. The reaction was quenched with saturated citric acid, separated, extracted with dichloromethane, combined the organic phase, dried over anhydrous sodium sulfate, filtered, concentrated, and purified on a silica gel column to give compound 18-5 as a white solid (0.14 g, 22% yield).

[0339] 1 H NMR (400 MHz, CDC13) δ 4.23 (s, 6H), 3.88 - 3.46 (s, 180H), 3.40 (s, 4H), 3.18 (s, 3H), 2.78 - 2.47 (m, 5H), 2.30 (dd, J = 23.2, 15.8 Hz, 4H), 1.63 (dd, J = 112.0, 39.2 Hz, 31H), 1.43 - 1.12 (m, 52H), 0.90 (t, J = 6.7 Hz, 7H).

[0340] Synthesis of compound 18

[0341] To a solution of compound 18-5 (0.05 g, 0.016 mmol, 1.0 eq) in DCM (5 mL) was added TFA (2.5 mL) at room temperature under nitrogen protection. The reaction was stirred at room temperature for 16 h. The reaction was directly concentrated, and the compound 18 was obtained as a yellow solid (0.04 g, 80% yield) by slurry with methyl tert-butyl ether.

[0342] 1H NMR (400 MHz, Chloroform-d) δ 5.27 (ddd, J = 5.9, 4.2, 1.5 Hz, 1H), 5.08 (d, J = 8.4 Hz, 1H), 4.40 (dd, J = 11.9, 4.1 Hz, 1H), 4.37 - 4.26 (m, 2H), 4.25 - 4.09 (m, 2H), 2.37 - 2.24 (m, 6H), 2.16 - 2.05 (m, 1H), 1.96 - 1.85 (m, 1H), 1.66 - 1.56 (m, 4H), 1.44 (d, J = 3.2 Hz, 20H), 1.25 (s, 56H), 0.88 (t, J = 6.8 Hz, 6H).

[0343] Example 19: Synthesis of compound 19

[0344] Synthesis of compound 19-1

[0345] To DSG (2.5 g, 4.0 mmol, 1.0 eq) and tert-butoxycarbonyl-L-glutamic acid-5-tert-butyl ester (2.43 g, 8.0 mmol, 2.0 eq) in anhydrous DCM (20 mL) was added HATU (3.0 g, 8.0 mmol, 2.0 eq) and DMAP (1.22 g, 10.0 mmol, 2.5 eq) at room temperature under nitrogen protection. The reaction was stirred at room temperature for 15 h. TLC monitored the reaction, DSG was completely converted. The reaction was filtered to remove the insoluble, concentrated and purified by silica gel column (DCM / MeOH: 100:0~95:5) to give 3.81 g of white solid containing a small amount of solvent which was not dried.

[0346] 1 H NMR (400 MHz, Chloroform-d) δ 5.27 (ddd, J = 5.9, 4.2, 1.5 Hz, 1H), 5.08 (d, J = 8.4 Hz, 1H), 4.40 (dd, J = 11.9, 4.1 Hz, 1H), 4.37 - 4.26 (m, 2H), 4.25 - 4.09 (m, 2H), 2.37 - 2.24 (m, 6H), 2.16 - 2.05 (m, 1H), 1.96 - 1.85 (m, 1H), 1.66 - 1.56 (m, 4H), 1.44 (d, J = 3.2 Hz, 20H), 1.25 (s, 56H), 0.88 (t, J = 6.8 Hz, 6H).

[0347] Synthesis of compound 19-2

[0348] To 19-1 (1.0 g) was added DCM / TFA (2:1, 10 mL) sequentially at room temperature. The reaction was stirred at room temperature for 15 h, concentrated to give 731 mg of white solid.

[0349] 1H NMR (400 MHz, Chloroform-d) δ 5.30-5.25 (m, 1H), 4.50-4.37 (m, 1H), 4.36-4.11 (m, 4H), 2.68-2.57 (m, 2H), 2.37-2.11 (m, 6H), 1.67-1.53 (m, 4H), 1.25 (s, 56H), 0.88 (t, J = 6.7 Hz, 6H).

[0350] Synthesis of compound 19

[0351] To a solution of 19-2 (264.7 mg, 0.3 mmol, 1.0 eq) in DCM (60 mL) was added benzoic acid (183.2 mg, 1.5 mmol, 5.0 eq), DIPEA (52.3 μL, 0.3 mmol, 1.0 eq), and 3-methyl oxazolidine-2,5-dione (Sar-NCA) (1.38 g, 12 mmol, 40.0 eq) sequentially at room temperature. The reaction was stirred at room temperature for 1 h. DIPEA (0.26 mL, 1.5 mmol, 5.0 eq) and acetic anhydride (70.4 μL, 0.75 mmol, 2.5 eq) were added sequentially. The reaction was stirred at room temperature for 15 h. After the reaction was completed, the reaction was dropped into MTBE, and a white precipitate was formed. The supernatant was removed by centrifugation. The solid was dried under vacuum to give the product as a white solid, 1.05 g, with a degree of polymerization of about 39.

[0352] 1 H NMR (400 MHz, Chloroform-d) δ 5.30-5.22 (m, 1H), 4.40-3.83 (m, 83H), 3.16-2.80 (m, 117H), 2.31 (q, J = 7.3 Hz, 4H), 2.16-2.01 (m, 3H), 1.65-1.54 (m, 4H), 1.25 (s, 56H), 0.88 (t, J = 6.8 Hz, 6H).

[0353] Example 20: Synthesis of compound 20

[0354] Synthesis of compound 20-1

[0355] To a solution of ALC-0315 (1.53 g, 2.0 mmol, 1.0 eq) and tert-butoxycarbonyl-L-glutamic acid-5-tert-butyl ester (1.21 g, 4.0 mmol, 2.0 eq) in DCM (10 mL) was added HATU (1.52 g, 4.0 mmol, 2.0 eq) and DMAP (0.61 g, 5.0 mmol, 2.5 eq) at room temperature under nitrogen protection. The reaction was stirred at room temperature for 15 h. TLC monitored the reaction, the starting material was completely converted, the reaction was concentrated, and the product was purified by silica gel column (PE:EA = 100:0 ~ 50:50) to give yellow oil 2.51 g.

[0356] 1 H NMR (400 MHz, Chloroform-d) δ 5.26 (d, J = 8.1 Hz, 1H), 4.32 - 4.11 (m, 4H), 4.07 (t, J = 6.7 Hz, 4H), 3.17 - 3.01 (m, 6H), 2.44 - 2.23 (m, 5H), 2.22 - 2.08 (m, 2H), 2.00 - 1.88 (m, 2H), 1.88 - 1.52 (m, 17H), 1.51 - 1.36 (m, 41H), 1.27 (s, 42H), 0.89 (t, J = 6.7 Hz, 12H).

[0357] Synthesis of compound 20-2

[0358] A mixture of 20-1 (0.25 g) in DCM / TFA (3:1, 2 mL) was stirred at room temperature for 15 h. The reaction was directly concentrated to give white solid product 0.28 g.

[0359] 1 H NMR (400 MHz, Chloroform-d) δ 4.39 - 4.15 (m, 3H), 4.08 (t, J = 6.7 Hz, 4H), 3.20 - 2.99 (m, 6H), 2.71 - 2.60 (m, 2H), 2.39 - 2.21 (m, 4H), 1.92 - 1.52 (m, 16H), 1.51 - 1.36 (m, 12H), 1.27 (s, 42H), 0.89 (t, J = 6.8 Hz, 12H).

[0360] Synthesis of compound 20

[0361] To a 50 mL single necked flask was added N-Boc-N'-Cbz-L-lysine (876 mg, 2.3 mmol), HATU (1.46 g, 3.8 mmol), DMAP (586 mg, 4.8 mmol) and DCM (30 mL), then added DSG (1.2 g, 1.92 mmol), replaced with nitrogen for three times and protected, stirred the reaction at room temperature for 16 h, sampled TLC to monitor the reaction, the starting material was consumed completely, the reaction was directly concentrated to get the crude product, purified by silica gel column chromatography (DCM:MeOH = 100:0-95:5) to get white solid 1.89 g.

[0362] 1 H NMR (400 MHz, Chloroform-d) δ 4.37 - 3.84 (m, 106 H), 3.18 - 2.74 (m, 155 H), 2.41 (s, 2 H), 2.31 (dq, J=8.9, 4.5, 3.7 Hz, 2 H), 2.12 (d, J=17.6 Hz, 7 H), 1.76 - 1.51 (m, 14 H), 1.50 - 1.34 (m, 15 H), 1.25 (s, 42 H), 0.87 (t, J=6.7 Hz, 12 H).

[0363] Example 21: Synthesis of compound 21

[0364] Synthesis of compound 21-1

[0365] To a 50 mL single necked flask was added N-Boc-N'-Cbz-L-lysine (876 mg, 2.3 mmol), HATU (1.46 g, 3.8 mmol), DMAP (586 mg, 4.8 mmol) and DCM (30 mL), then added DSG (1.2 g, 1.92 mmol), replaced with nitrogen for three times and protected, stirred the reaction at room temperature for 16 h, sampled TLC to monitor the reaction, the starting material was consumed completely, the reaction was directly concentrated to get the crude product, purified by silica gel column chromatography (DCM:MeOH = 100:0-95:5) to get white solid 1.89 g.

[0366] Synthesis of compound 21-2

[0367] Into a 100 mL single neck flask was added 21-1 (1.89 g, 1.91 mmol), DCM (12 mL) and TFA (4 mL), dissolved, stirred at room temperature for 2 h, sampled TLC detection, the raw material reacted completely, the reaction solution was directly concentrated to obtain a crude product, which was purified by silica gel column chromatography (DCM:MeOH = 1:0-95:5) to obtain a white solid 1.91 g.

[0368] 1 H NMR (400 MHz, Chloroform-d) δ 7.32 (q, J = 7.3, 6.3 Hz, 5H), 5.35-5.19 (m, 1H), 5.07 (s, 2H), 4.47 (dd, J = 11.9, 4.1 Hz, 1H), 4.36-4.10 (m, 3H), 4.06 (t, J = 6.1 Hz, 1H), 3.18 (s, 2H), 2.30 (t, J = 7.6 Hz, 4H), 1.97 (s, 2H), 1.58 (t, J = 7.2 Hz, 8H), 1.25 (m, 56H), 0.88 (t, J = 6.8 Hz, 6H).

[0369] Synthesis of compound 21-3

[0370] Into a 50 mL single neck flask was added 21-2 (300 mg, 0.299 mmol), Sar-NCA (1.38 g, 11.98 mmol), benzoic acid (183 mg, 1.498 mmol) and DCM (8 mL), then DIPEA (39 mg, 0.299 mmol) was added, stirred at room temperature for 2 h, acetic anhydride (46 mg, 0.149 mmol) and DIPEA (116 mg, 0.899 mmol) were added, replaced with nitrogen for three times and protected, stirred at room temperature for 16 h, slowly dropped into ethyl acetate (80 mL), a solid precipitated, centrifuged, the supernatant was poured out, the lower solid was again added with ethyl acetate (30 mL) and stirred for 10 min, centrifuged, the supernatant was poured out, and the lower layer was dried under vacuum to obtain a white solid 1.14 g, and the degree of polymerization was about 40.

[0371] 1 H NMR (400 MHz, Chloroform-d) δ 7.34 (s, 4H), 5.28 (d, J = 17.2 Hz, 1H), 5.07 (d, J = 3.9 Hz, 2H), 4.44-3.79 (m, 85H), 3.22-2.75 (m, 120H), 2.37-2.23 (m, 4H), 2.13 (d, J = 4.1 Hz, 3H), 1.59 (s, 6H), 1.46 (m, 9H), 1.26 (d, J = 2.7 Hz, 56H), 0.88 (t, J = 6.7 Hz, 6H).

[0372] Synthesis of compound 21-4

[0373] Into a 100 mL single neck flask was placed 21-3 (680 mg, 0.23 mmol) and methanol (20 mL), dissolved, then Pd / C (68 mg, 10% wt) was added, replaced with hydrogen gas for three times and protected, the reaction was stirred at room temperature for 16 h, the reaction solution was filtered with celite, the filter cake was washed with methanol, the filtrate was further filtered with 0.45 pm nylon filter head, the filtrate was directly concentrated under reduced pressure and dried in vacuum to get 618 mg of gray solid.

[0374] 1 H NMR (400 MHz, Chloroform-d) d 5.25 (s, 1H), 4.56 - 3.70 (m, 85H), 3.16 - 2.78 (m, 120H), 2.38 - 2.23 (m, 4H), 2.11 (d, J = 18.7 Hz, 3H), 1.65 - 1.50 (m, 4H), 1.39 (s, 9H), 1.25 (s, 56H), 0.88 (t, J = 6.7 Hz, 6H).

[0375] Synthesis of compound 21

[0376] Into a 50 mL single neck flask was placed 21-4 (589 mg, 0.16 mmol), succinic anhydride (24.3 mg, 0.243 mmol) and dichloromethane (10 mL), dissolved, then DIPEA (63 mg, 0.486 mmol) was added, the reaction was stirred at room temperature for 3 h, sampled with Ksiser reagent at 100 °C for 3 min color development, colorless, the reaction solution was slowly added into ethyl acetate (100 mL), solid precipitated, centrifuged, the supernatant was poured out, the lower layer was added into ethyl acetate (40 mL) and swelled for 10 min before centrifuged again, the supernatant was poured out, the lower layer was dried in vacuum to get 368 mg of white solid crude product, the solid was dissolved with methanol / dichloromethane 1:1 (3 mL), purified with gel column (DCM:MeOH = 1:1) to get 368 mg of white solid.

[0377] 1 H NMR (400 MHz, Chloroform-d) d 5.27 (t, J = 5.2 Hz, 1H), 4.49 - 3.81 (m, 85H), 3.28 - 2.78 (m, 120H), 2.63 (s, 2H), 2.43 (s, 2H), 2.31 (td, J = 7.5, 4.9 Hz, 4H), 2.11 (d, J = 18.4 Hz, 3H), 1.78 (s, 2H), 1.67 - 1.54 (m, 5H), 1.52 - 1.40 (m, 6H), 1.25 (s, 56H), 0.88 (t, J = 6.8 Hz, 6H).

[0378] Example 22: Synthesis of compound 22

[0379] Synthesis of compound 22-1

[0380] Into a 50 mL single necked flask was placed 14-SM2 (481 mg, 1.585 mmol), Boc-L- glutamic acid-5-t-butyl ester (900 mg, 1.44 mmol), HATU (1.09 g, 2.88 mmol), DMAP (440 mg, 3.6 mmol) and DCM (30 mL), replaced with nitrogen for three times and protected, stirred the reaction at room temperature for 2 h, sampled TLC detection, the raw material reacted completely, the reaction liquid was purified by silica gel column chromatography (PE:EA = 1:0-9:1) to obtain 1.56 g of colorless transparent oil.

[0381] 1 H NMR (400 MHz, Chloroform-d) δ 5.30 (ddd, J = 6.0, 4.1, 1.9 Hz, 1H), 5.08 (d, J = 8.4 Hz, 1H), 4.31 (td, J = 12.0, 4.1 Hz, 3H), 4.15 (td, J = 11.9, 6.2 Hz, 2H), 2.37 - 2.25 (m, 6H), 2.11 (dtd, J = 14.6, 7.5, 5.0 Hz, 1H), 1.91 (dtd, J = 14.7, 8.3, 6.6 Hz, 1H), 1.61 (d, J = 10.8 Hz, 5H), 1.44 (d, J = 2.0 Hz, 18H), 1.25 (s, 56H), 0.88 (t, J = 6.8 Hz, 6H).

[0382] Synthesis of compound 22-2

[0383] Into a 50 mL single necked flask was placed 22-1 (1.18 g, 1.3 mmol), TFA (5 mL) and DCM (10 mL), replaced with nitrogen for three times and protected, stirred the reaction at room temperature for 16 h, sampled TLC detection, the raw material reacted completely, the reaction liquid was directly concentrated to obtain 1.45 g of self-color viscous solid.

[0384] 1 H NMR (400 MHz, Chloroform-d) δ 5.30 (ddd, J = 6.0, 4.1, 1.9 Hz, 1H), 5.08 (d, J = 8.4 Hz, 1H), 4.31 (td, J = 12.0, 4.1 Hz, 3H), 4.15 (td, J = 11.9, 6.2 Hz, 2H), 2.37 - 2.25 (m, 6H), 2.11 (dtd, J = 14.6, 7.5, 5.0 Hz, 1H), 1.91 (dtd, J = 14.7, 8.3, 6.6 Hz, 1H), 1.61 (d, J = 10.8 Hz, 5H), 1.44 (d, J = 2.0 Hz, 18H), 1.25 (s, 56H), 0.88 (t, J = 6.8 Hz, 6H).

[0385] Synthesis of compound 22

[0386] Into a 50 mL single neck flask was added 22-2 (200 mg, 0.23 mmol), Sar-NCA (1.06 g, 9.2 mmol), benzoic acid (141 mg, 1.15 mmol) and DCM (8 mL), followed by DIPEA (41 mg, 0.23 mmol), the reaction was stirred at room temperature for 2 h, then acetic anhydride (35 mg, 0.34 mmol) and DIPEA (89 mg, 0.69 mmol) were added, the reaction was stirred at room temperature for 16 h, then slowly added into ethyl acetate (80 mL), solid was precipitated, centrifuged, the supernatant was poured out, the lower solid was dried under vacuum, then dissolved in DCM (8 mL), slowly added into MTBE (80 mL), solid was precipitated, centrifuged, the supernatant was poured out, the lower solid was dried under vacuum to give white solid 806 mg, degree of polymerization 40.

[0387] 1 H NMR (400 MHz, Chloroform-d) δ 5.26 (s, 1H), 4.54 - 3.70 (m, 85H), 3.18 - 2.75 (m, 122H), 2.32 (d, J=6.8 Hz, 4H), 2.14 (s, 3H), 2.11 - 1.95 (m, 2H), 1.61 (s, 4H), 1.36 - 1.13 (m, 56H), 0.88 (t, J=6.6 Hz, 6H).

[0388] Example 23: Synthesis of compound 23

[0389] Synthesis of compound 23-1

[0390] Into a 50 mL single neck flask was added 22-2 (200 mg, 0.23 mmol), Sar-NCA (1.06 g, 9.2 mmol), benzoic acid (141 mg, 1.15 mmol) and DCM (8 mL), followed by DIPEA (41 mg, 0.23 mmol), the reaction was stirred at room temperature for 2 h, then acetic anhydride (35 mg, 0.34 mmol) and DIPEA (89 mg, 0.69 mmol) were added, the reaction was stirred at room temperature for 16 h, then slowly added into ethyl acetate (80 mL), solid was precipitated, centrifuged, the supernatant was poured out, the lower solid was dried under vacuum, then dissolved in DCM (8 mL), slowly added into MTBE (80 mL), solid was precipitated, centrifuged, the supernatant was poured out, the lower solid was dried under vacuum to give white solid 806 mg, degree of polymerization 40.

[0391] 1H NMR (400 MHz, Chloroform-d) δ 5.44 (d, J = 8.9 Hz, 1H), 5.28 - 5.20 (m, 1H), 4.59 - 4.47 (m, 1H), 4.41 - 4.27 (m, 2H), 4.27 - 4.19 (m, 1H), 4.17 - 4.09 (m, 1H), 2.93 - 2.83 (m, 1H), 2.77 - 2.67 (m, 1H), 2.37 - 2.24 (m, 4H), 1.66 - 1.58 (m, 4H), 1.45 (s, 9H), 1.44 (s, 9H), 1.25 (s, 56H), 0.87 (t, J = 6.8 Hz, 6H).

[0392] Synthesis of compound 23-2

[0393] To 23-1 (0.6 g) was added DCM and TFA (2: 1, 6 mL) sequentially at room temperature. The reaction was stirred at room temperature for 15 h. The mixture was concentrated to give the product 0.44 g as a white solid.

[0394] 1 H NMR (400 MHz, Chloroform-d) δ 5.31 - 5.17 (m, 1H), 4.48 - 4.05 (m, 5H), 3.12 - 2.79 (m, 2H), 2.38 - 2.20 (m, 4H), 1.68 - 1.50 (m, 4H), 1.25 (s, 56H), 0.88 (t, J = 6.6 Hz, 6H).

[0395] Synthesis of compound 23

[0396] To 23-2 (34.2 mg, 0.04 mmol, 1.0 eq) was added PhCOOH (24.4 mg, 0.2 mmol, 5.0 eq), DIPEA (7.2 μL, 0.04 mmol, 1.0 eq), Sar-NCA (184.2 mg, 1.6 mmol, 40.0 eq), DCM (8 mL) sequentially at room temperature. The reaction was stirred at room temperature for 1 h. DIPEA (43.7 μL, 0.24 mmol, 6.0 eq) and Ac20 (11.3 μL, 0.12 mmol, 3.0 eq) were added sequentially. The reaction was stirred at room temperature for 15 h. After the reaction was completed, the reaction was dropped into MTBE, and a white precipitate was precipitated. The supernatant was removed by centrifugation. The solid was dried under vacuum to give the product 55 mg as a white solid, and the degree of polymerization was about 43.

[0397] 1H NMR (400 MHz, Chloroform-d) δ 5.25 (s, 1H), 4.45-3.79 (m, 92H), 3.18-2.52 (m, 144H), 2.38-2.23 (m, 5H), 2.16-2.08 (m, 3H), 1.66-1.53 (m, 4H), 1.35-1.21 (m, 56H), 0.88 (t, J = 6.7 Hz, 6H).

[0398] Example 24: Synthesis of compound 24

[0399] Synthesis of compound 24-1

[0400] Glycine (0.9 g, 12 mmol, 1.2 eq), Boc-glu(OtBu)-OSU (4.0 g, 10 mmol, 1.0 eq), NaHC03(1.3 g, 15 mmol, 1.5 eq), MeCN (30 mL) and H20 (30 mL) were added successively at room temperature. The reaction was stirred at room temperature for 15 hours. The reaction was monitored by LCMS, and the starting material was completely converted. The reaction solution was concentrated, the system was adjusted to be acidic with 1 M HC1, the aqueous phase was extracted with DCM, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain an oil. The oil was purified by Prep-HPLC, and the product was obtained as a white solid after lyophilization, 2.6 g.

[0401] 1 H NMR (400 MHz, Chloroform-d) δ 7.25-7.17 (m, 1H), 5.56 (d, J = 8.7 Hz, 1H), 4.45-4.30 (m, 1H), 4.27-3.91 (m, 2H), 2.48-2.26 (m, 2H), 2.18-2.03 (m, 1H), 1.97-1.80 (m, 1H), 1.53-1.35 (m, 18H).

[0402] Synthesis of compound 24-2

[0403] DSG (1.0 g, 1.6 mmol, 1.0 eq), 24-1 (1.15 g, 3.2 mmol, 2.0 eq), HATU (1.22 g, 3.2 mmol, 2.0 eq), DMAP (0.49 g, 4.0 mmol, 2.5 eq) and DCM (8 mL) were added successively at room temperature under nitrogen protection. The reaction was stirred at room temperature for 15 hours. The reaction was monitored by TLC, and the starting material was completely converted. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (DCM:MeOH = 100:0~90:10) to obtain the product as a white solid, 1.6 g.

[0404] 1 H NMR (400 MHz, Chloroform-d) δ 6.96 - 6.83 (m, 1H), 5.38 (d, J = 7.9 Hz, 1H), 5.31 - 5.24 (m, 1H), 4.42 - 4.28 (m, 2H), 4.27 - 4.01 (m, 5H), 2.50 - 2.29 (m, 6H), 2.18 - 2.07 (m, 1H), 1.98 - 1.86 (m, 1H), 1.68 - 1.56 (m, 4H), 1.51 - 1.42 (m, 18H), 1.37 - 1.21 (m, 57H), 0.89 (t, J = 6.7 Hz, 6H).

[0405] Synthesis of compound 24-3

[0406] Compound 24-3 was synthesized by adding 24-2 (0.2 g), DCM and TFA (3: 1, 2 mL) successively at room temperature. The reaction was stirred at room temperature for 15 hours. The reaction solution was concentrated to obtain white solid product 0.22 g.

[0407] 1 H NMR (400 MHz, Chloroform-d) δ 8.29 (s, 1H), 5.32 - 5.25 (m, 1H), 4.48 - 4.29 (m, 3H), 4.29 - 4.19 (m, 1H), 4.19 - 4.11 (m, 1H), 4.11 - 3.98 (m, 2H), 2.74 - 2.63 (m, 2H), 2.34 (q, J = 7.4 Hz, 4H), 2.27 - 2.12 (m, 2H), 1.69 - 1.55 (m, 4H), 1.28 (s, 57H), 0.90 (t, J = 6.7 Hz, 6H).

[0408] Synthesis of compound 24

[0409] Compound 24 was synthesized by adding 24-3 (37.0 mg, 0.04 mmol, 1.0 eq), benzoic acid (24.4 mg, 0.2 mmol, 5.0 eq), DIPEA (7.2 μL, 0.04 mmol, 1.0 eq), Sar-NCA (184.2 mg, 1.6 mmol, 40.0 eq) and DCM (8 mL) successively at room temperature. The reaction was stirred at room temperature for 1 hour. DIPEA (43.7 μL, 0.24 mmol, 6.0 eq) and Ac2O (11.3 μL, 0.12 mmol, 3.0 eq) were added successively. The reaction was stirred at room temperature for 15 hours. After the reaction was completed, the reaction solution was dropped into MTBE, and white precipitate was precipitated. The supernatant was removed by centrifugation. The solid was dried under vacuum to obtain white solid product 118 mg, and the degree of polymerization was about 38.

[0410] 1 H NMR (400 MHz, Chloroform-d) δ 5.28 - 5.20 (m, 1H), 4.48 - 3.81 (m, 82H), 3.19 - 2.77 (m, 116H), 2.31 (q, J=7.4 Hz, 4H), 2.15 - 2.10 (m, 3H), 1.66 - 1.56 (m, 4H), 1.25 (s, 57H), 0.88 (t, J=6.7 Hz, 6H).

[0411] Example 25: Synthesis of compound 25

[0412] Synthesis of compound 25-1

[0413] L-glutamic acid-5-tert-butyl ester (2.44 g, 12 mmol, 1.2 eq), Boc-Gly-OSu (2.72 g, 10 mmol, 1.0 eq), NaHC03(1.26 g, 15 mmol, 1.5 eq), MeCN (30 mL) and H20 (30 mL) were added successively at room temperature. The reaction was stirred at room temperature for 15 hours. The reaction was monitored by LCMS, and the starting material was completely converted. The reaction solution was concentrated and the system was adjusted to be acidic with 1 M HC1, extracted with DCM, dried over anhydrous sodium sulfate, and concentrated to obtain an oil. The oil was purified by Prep-HPLC and lyophilized to obtain the white solid product 2.4 g.

[0414] 1 H NMR (400 MHz, Chloroform-d) δ 10.15 (s, 1H), 7.54 - 7.32 (m, 1H), 5.81 - 5.61 (m, 1H), 4.71 - 4.48 (m, 1H), 4.02 - 3.68 (m, 2H), 2.44 - 2.26 (m, 2H), 2.26 - 2.13 (m, 1H), 2.06 - 1.92 (m, 1H), 1.54 - 1.33 (m, 18H).

[0415] Synthesis of compound 25-2

[0416] DSG (1.0 g, 1.6 mmol, 1.0 eq), 25-1 (1.15 g, 3.2 mmol, 2.0 eq), HATU (1.22 g, 3.2 mmol, 2.0 eq), DMAP (0.49 g, 4.0 mmol, 2.5 eq) and DCM (8 mL) were added successively at room temperature under nitrogen protection. The reaction was stirred at room temperature for 15 hours. The reaction was monitored by TLC, and the starting material was completely converted. The reaction solution was concentrated and purified by silica gel column (PE:EA = 100:0~50:50) to obtain the white solid product 1.5 g.

[0417] 1 H NMR (400 MHz, Chloroform-d) δ 6.94 - 6.79 (m, 1H), 5.31 - 5.17 (m, 2H), 4.68 - 4.57 (m, 1H), 4.45 - 4.06 (m, 4H), 3.85 (qd, J = 16.9, 5.7 Hz, 2H), 2.42 - 2.24 (m, 6H), 2.20 - 2.11 (m, 1H), 2.03 - 1.91 (m, 1H), 1.68 - 1.57 (m, 4H), 1.47 (d, J = 9.8 Hz, 18H), 1.27 (s, 56H), 0.90 (t, J = 6.8 Hz, 6H).

[0418] Synthesis of compound 25-3

[0419] To 25-2 (0.2 g) was added DCM and TFA (3: 1, 2 mL) sequentially at room temperature. The reaction was stirred at room temperature for 15 hours. The reaction was concentrated to give the product 0.22 g as a colorless solid.

[0420] 1 H NMR (400 MHz, Chloroform-d) δ 5.33 - 5.23 (m, 1H), 4.80 - 4.64 (m, 1H), 4.48 - 3.86 (m, 6H), 2.52 - 2.40 (m, 2H), 2.39 - 2.28 (m, 4H), 2.28 - 2.16 (m, 1H), 2.03 - 1.87 (m, 1H), 1.67 - 1.54 (m, 4H), 1.28 (s, 57H), 0.90 (t, J = 6.6 Hz, 6H).

[0421] Synthesis of compound 25

[0422] To 25-3 (37.0 mg, 0.04 mmol, 1.0 eq) was added benzoic acid (24.4 mg, 0.2 mmol, 5.0 eq), DIPEA (7.2 μL, 0.04 mmol, 1.0 eq), Sar-NCA (184.2 mg, 1.6 mmol, 40.0 eq) and DCM (8 mL) sequentially at room temperature. The reaction was stirred at room temperature for 1 hour. DIPEA (43.7 μL, 0.24 mmol, 6.0 eq) and Ac20 (11.3 μL, 0.12 mmol, 3.0 eq) were added sequentially. The reaction was stirred at room temperature for 15 hours. After the reaction was completed, the reaction was dropped into MTBE, and a white precipitate was precipitated. The supernatant was removed by centrifugation. The solid was dried under vacuum to give the product 88 mg as a white solid, and the degree of polymerization was about 36.

[0423] 1H NMR (400 MHz, Chloroform-d) δ 5.29 - 5.22 (m, 1H), 4.38 - 3.86 (m, 78H), 3.15 - 2.84 (m, 108H), 2.36 - 2.27 (m, 4H), 2.16 - 2.09 (m, 3H), 1.67 - 1.53 (m, 5H), 1.53 - 1.37 (m, 8H), 1.34 - 1.22 (m, 56H), 0.88 (t, J=6.7 Hz, 6H).

[0424] Example 26: Synthesis of compound 26

[0425] Synthesis of compound 26-1

[0426] Compound 26-1 was synthesized according to the following procedure. 26-SM (5.0 g, 20.9 mmol, 1.0 eq), imidazole (2.85 g, 41.8 mmol, 2.0 eq) were dissolved in DMF (25 mL) at room temperature. TBSCl (3.15 g, 20.9 mmol, 1.0 eq) was added at 0 °C under argon protection, and stirred for 16 h. The reaction was completed. Water (100 mL), ethyl acetate (1000 mL) were added, and the mixture was separated. The ethyl acetate layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and rotary evaporated. The crude product was purified by normal phase column chromatography to give compound 26-1 as a white solid (3.0 g, 40.6% yield).

[0427] MS (ESI), m / z, 354.2 [M+H] + .

[0428] Synthesis of compound 26-2

[0429] Compound 26-2 was synthesized according to the following procedure. To a solution of 26-1 (0.5 g, 1.41 mmol, 1.0 eq) in DCM / MeOH (1:1, 20 mL) was added Pd / C (0.1 g) at room temperature. The reaction was stirred under hydrogen atmosphere at room temperature for 16 h. The reaction was completed. The reaction solution was filtered, and the filtrate was rotary evaporated to give compound 26-2 as a yellow oil (0.32 g, 100% yield).

[0430] MS (ESI), m / z, 220.2 [M+H] + .

[0431] Synthesis of compound 26-3

[0432] Compound 26-4 was synthesized by dissolving 26-3 (0.5 g, 0.22 mmol, 1.0 eq), DSG (0.14 g, 0.22 mmol, 1.0 eq) and DMAP (0.054 g, 0.44 mmol, 2.0 eq) in DCM (10 mL) at room temperature. DCC (0.09 g, 0.44 mmol, 2.0 eq) was added under argon protection. Stirring at room temperature for 6 h. TLC detection. The reaction was completed. Saturated aqueous citric acid was added, and the solution was separated. The organic phase was dried with anhydrous sodium sulfate and rotary evaporated. The obtained crude product was purified by silica gel column (DCM:MeOH = 4:1 ~ 3:1) to give compound 26-4 as a white solid (0.15 g, 23.6% yield).

[0433] 1 H NMR: (400 MHz, CDC13) δ 5.66 (d, J = 7.4 Hz, 1H), 4.44 - 3.96 (m, 5H), 3.92 - 3.45 (s, 180H), 3.38 (s, 3H), 1.11 - 0.68 (m, 9H), 0.13 - 0.00 (m, 6H).

[0434] Synthesis of compound 26-4

[0435] Compound 26-4 was synthesized by dissolving 26-3 (0.5 g, 0.22 mmol, 1.0 eq), DSG (0.14 g, 0.22 mmol, 1.0 eq) and DMAP (0.054 g, 0.44 mmol, 2.0 eq) in DCM (10 mL) at room temperature. DCC (0.09 g, 0.44 mmol, 2.0 eq) was added under argon protection. Stirring at room temperature for 6 h. TLC detection. The reaction was completed. Saturated aqueous citric acid was added, and the solution was separated. The organic phase was dried with anhydrous sodium sulfate and rotary evaporated. The obtained crude product was purified by silica gel column (DCM:MeOH = 4:1 ~ 3:1) to give compound 26-4 as a white solid (0.15 g, 23.6% yield).

[0436] 1 H NMR: (400 MHz, CDC13) δ 5.66 (d, J = 7.4 Hz, 1H), 4.44 - 3.96 (m, 5H), 3.92 - 3.45 (s, 180H), 3.38 (s, 3H), 1.11 - 0.68 (m, 9H), 0.13 - 0.00 (m, 6H).

[0437] Synthesis of compound 26

[0438] Compound 26-4 (0.05 g, 0.0017 mmol, 1.0 eq) was dissolved in DCM (3 mL) at room temperature. TFA (3.0 mL) was added under argon protection, stirred at 20 °C for 16 h. The reaction was terminated. Spinned to dryness, added methyl tert-butyl ether to slurry to get compound 26 as a white solid (0.03 g, 66.7% yield).

[0439] 1 H NMR (400 MHz, CDC13) δ 5.36 (s, 2H), 4.80 - 3.90 (m, 11H), 3.79 - 3.45 (s, 180H), 3.40 (s, 3H), 2.30 (ddd, J=32.0, 15.0, 7.6 Hz, 5H), 1.89 (s, 24H), 1.62 (s, 6H), 1.27 (s, 49H), 0.90 (t, J=6.8 Hz, 6H).

[0440] Example 27: Synthesis of compound 27

[0441] Synthesis of compound 27-1

[0442] Compound 27-1 (0.86 g, 0.55 mmol, 1.0 eq) was dissolved in DCM (5 mL) at room temperature. TFA (5.0 mL) was added under argon protection, stirred at 20 °C for 16 h. The reaction was terminated. Spinned to dryness, added methyl tert-butyl ether to slurry to get compound 27-2 as a white solid (0.45 g, 67.2% yield).

[0443] 1 H NMR (400 MHz, CDC13) δ 5.36 (s, 2H), 4.80 - 3.90 (m, 11H), 3.79 - 3.45 (s, 180H), 3.40 (s, 3H), 2.30 (ddd, J=32.0, 15.0, 7.6 Hz, 5H), 1.89 (s, 24H), 1.62 (s, 6H), 1.27 (s, 49H), 0.90 (t, J=6.8 Hz, 6H).

[0444] Synthesis of compound 27-2

[0445] Compound 27-2 was synthesized from 27-1 (0.5 g, 0.22 mmol, 1.0 eq), DSG (0.27 g, 0.44 mmol, 2.0 eq) and DMAP (0.053 g, 0.44 mmol, 2.0 eq) in DCM (10 mL) at room temperature. DCC (0.09 g, 0.44 mmol, 2.0 eq) was added under argon atmosphere. Stirring at room temperature for 16 h. TLC detection. The reaction was terminated. Sat. aq. citric acid was added. The mixture was partitioned between DCM and water. The organic phase was dried over anhydrous sodium sulfate. The crude product was purified by silica gel column (PE:EA = 4:1 ~ 3:1) to give compound 27-2 as a white solid (0.26 g, 41% yield).

[0446] 1 H NMR (400 MHz, CDC13) δ 7.46 - 7.29 (m, 6 H), 7.06 (dd, J = 14.0, 8.6 Hz, 2 H), 6.91 (dd, J = 8.2, 5.4 Hz, 2 H), 5.27 - 5.17 (m, 2 H), 5.03 (s, 2 H), 4.58 (d, J = 7.8 Hz, 1 H), 4.21 (dddd, J = 44.0, 18.0, 12.0, 5.0 Hz, 6 H), 3.85 - 3.44 (s, 180 H), 3.38 (s, 3 H), 3.03 (dd, J = 10.8, 5.9 Hz, 2 H), 2.31 (td, J = 7.6, 3.2 Hz, 3 H), 1.38 - 1.15 (m, 50 H), 0.88 (t, J = 6.8 Hz, 6 H).

[0447] Synthesis of compound 27

[0448] Compound 27 was synthesized from 27-2 (0.1 g, 0.034 mmol, 1.0 eq) in DCM / MeOH (1 : 1, 10 mL) at room temperature by adding Pd / C (0.05 g). Stirring at 20 °C for 16 h under hydrogen atmosphere (1 atm). TLC detection. The reaction was terminated. The mixture was filtered and the filtrate was concentrated. The crude product was slurry in methyl tert-butyl ether to give compound 27 as a white solid (0.09 g, 89% yield).

[0449] 1H NMR (400 MHz, CDC13) δ 6.97 (dd, J = 13.8, 8.4 Hz, 2H), 6.78 (d, J = 8.3 Hz, 2H), 5.32 - 5.16 (m, 2H), 4.56 (dd, J = 13.3, 7.0 Hz, 1H), 4.40 - 3.99 (m, 6H), 3.87 - 3.44 (s, 180H), 3.38 (s, 3H), 2.32 (td, J = 7.6, 4.2 Hz, 3H), 1.62 (s, 4H), 1.42 - 1.12 (m, 47H), 1.06 - 0.65 (m, 6H).

[0450] Example 28: Synthesis of compound 28

[0451] Synthesis of compound 28-1

[0452] Dissolve 28-SM (0.4 g, 1.01 mmol, 2.0 eq), 1-1 (1.08 g, 0.503 mmol, 1.0 eq) and TEA (0.101 g, 1.101 mmol, 2.0 eq) in DMF (10 mL) at room temperature. Stir for 16 h at 25 °C under argon protection. TLC detection. The reaction is complete. Add saturated aqueous citric acid solution. Extract with DCM, separate the liquid. Dry the organic phase with anhydrous sodium sulfate, and rotary evaporate. The obtained crude is slurried with methyl tert-butyl ether to give compound 28-1 as a white solid (1.1 g, 89% yield).

[0453] 1 H NMR (400 MHz, CDC13) δ 6.97 (dd, J = 13.8, 8.4 Hz, 2H), 6.78 (d, J = 8.3 Hz, 2H), 5.32 - 5.16 (m, 2H), 4.56 (dd, J = 13.3, 7.0 Hz, 1H), 4.40 - 3.99 (m, 6H), 3.87 - 3.44 (s, 180H), 3.38 (s, 3H), 2.32 (td, J = 7.6, 4.2 Hz, 3H), 1.62 (s, 4H), 1.42 - 1.12 (m, 47H), 1.06 - 0.65 (m, 6H).

[0454] Synthesis of compound 28-2

[0455] Compound 28-2 was obtained as a white solid (0.16 g, 25.6% yield) by dissolving 28-1 (0.5 g, 0.205 mmol, 1.0 eq), DSG (0.26 g, 0.41 mmol, 2.0 eq) and DMAP (0.05 g, 0.41 mmol, 2.0 eq) in DCM (10 mL) at room temperature. DCC (0.08 g, 0.41 mmol, 2.0 eq) was added under argon protection. Stirring at room temperature for 16 h. TLC detection showed the reaction was completed. Saturated aqueous citric acid solution was added. The organic phase was dried over anhydrous sodium sulfate. Rotary evaporation, and the crude product was purified by silica gel column (PE:EA = 4:1 ~ 3:1) to give compound 28-2 as a white solid (0.16 g, 25.6% yield).

[0456] 1 H NMR (400 MHz, CDC13) δ 7.32 (dd, J = 8.8, 6.0 Hz, 10H), 7.09 (dd, J = 6.6, 3.0 Hz, 7H), 6.58 (s, 1H), 5.16 - 5.08 (m, 1H), 4.58 - 4.52 (m, 1H), 4.28 - 4.00 (m, 7H), 3.85 - 3.43 (s, 180H), 3.38 (s, 3H), 3.01 (t, J = 5.3 Hz, 2H), 2.22 (dt, J = 20.0, 7.0 Hz, 5H), 1.56 (d, J = 6.9 Hz, 4H), 1.34 - 1.19 (m, 62H), 0.88 (t, J = 6.8 Hz, 6H).

[0457] Synthesis of compound 28

[0458] To a solution of 28-2 (0.1 g, 0.033 mmol, 1.0 eq) in DCM (10 mL) was added TFA (3 mL) at room temperature. Stirring at 20 °C for 16 h. Rotary evaporation after TLC detection showed the reaction was completed. The crude product was obtained. The obtained crude product was slurry with methyl tert-butyl ether to give compound 28 as a white solid (0.084 g, 82% yield).

[0459] 1 H NMR (400 MHz, CDC13) δ 7.32 (dd, J = 8.8, 6.0 Hz, 10H), 7.09 (dd, J = 6.6, 3.0 Hz, 7H), 6.58 (s, 1H), 5.16 - 5.08 (m, 1H), 4.58 - 4.52 (m, 1H), 4.28 - 4.00 (m, 7H), 3.85 - 3.43 (s, 180H), 3.38 (s, 3H), 3.01 (t, J = 5.3 Hz, 2H), 2.22 (dt, J = 20.0, 7.0 Hz, 5H), 1.56 (d, J = 6.9 Hz, 4H), 1.34 - 1.19 (m, 62H), 0.88 (t, J = 6.8 Hz, 6H).

[0460] Example 29: Synthesis of compound 29

[0461] Synthesis of compound 29

[0462] To a solution of DSG (584 mg, 1.53 mmol) in DCM (10 mL) was added EDCI (295 mg, 1.53 mmol), DMAP (47 mg, 0.38 mmol) and 29-SM1 (100 mg, 1.60 mmol) successively at room temperature. After addition, the reaction was stirred at room temperature for 16 h. TLC test showed the starting material was consumed completely. The reaction mixture was directly concentrated to give the crude product, which was separated by silica gel column chromatography (DCM:MeOH = 1:0-97:3) to give white solid 1.22 g.

[0463] 1 H NMR (400 MHz, Chloroform-d) δ 7.39 - 7.26 (m, 5H), 5.62 (d, J = 8.2 Hz, 1H), 5.16 (dd, J = 62.4, 5.1 Hz, 3H), 4.45 - 3.93 (m, 5H), 2.91 (s, 2H), 2.29 (t, J = 7.3 Hz, 4H), 1.91 - 1.36 (m, 11H), 1.25 (d, J = 2.4 Hz, 58H), 0.99 - 0.74 (m, 6H).

[0464] Synthesis of compound 29-2

[0465] To a solution of 29-1 (1.22 g, 1.23 mmol) in DCM (9 mL) was added TFA (3 mL) at room temperature. The reaction was stirred at room temperature for 2 h. TLC test showed the starting material was consumed completely. The reaction mixture was directly concentrated to give the crude product, which was separated by silica gel column chromatography (DCM:MeOH = 1:0-95:5) to give white solid 1.22 g.

[0466] 1 H NMR (400 MHz, Chloroform-d) δ 7.39 - 7.26 (m, 5H), 5.62 (d, J = 8.2 Hz, 1H), 5.16 (dd, J = 62.4, 5.1 Hz, 3H), 4.45 - 3.93 (m, 5H), 2.91 (s, 2H), 2.29 (t, J = 7.3 Hz, 4H), 1.91 - 1.36 (m, 11H), 1.25 (d, J = 2.4 Hz, 58H), 0.99 - 0.74 (m, 6H).

[0467] Synthesis of compound 29-3

[0468] Into a 10 mL vial was added 29-2 (120 mg, 0.12 mmol), NCA (552 mg, 4.79 mmol), benzoic acid (73 mg, 0.599 mmol) and DCM (2.5 mL), followed by DIPEA (15.5 mg, 0.119 mmol), the reaction was stirred at room temperature for 1.5 h, acetic anhydride (18.4 mg, 0.179 mmol) and DIPEA (465 mg, 0.359 mmol) were added, the reaction was stirred at room temperature for 2.5 h, the reaction was slowly added to ethyl acetate (30 mL), a solid was precipitated, centrifuged, the supernatant was poured out, ethyl acetate (30 mL) was added again, the mixture was ultrasonically treated for 2 min, centrifuged, the supernatant was poured out, and the lower layer was dried under vacuum to obtain a white solid 440 mg, and the degree of polymerization was 40.

[0469] 1 H NMR (400 MHz, Chloroform-d) δ 7.47-7.30 (m, 5H), 5.26 (s, 1H), 5.09 (d, J = 8.9 Hz, 2H), 4.40-3.76 (m, 85H), 3.67 (h, J = 6.7 Hz, 1H), 2.98 (dd, J = 37.3, 12.0 Hz, 121H), 2.31 (t, J = 7.6 Hz, 4H), 2.11 (d, J = 17.9 Hz, 4H), 1.60 (s, 5H), 1.40 (d, J = 6.7 Hz, 9H), 1.25 (s, 57H), 0.88 (t, J = 6.7 Hz, 6H).

[0470] Synthesis of compound 29

[0471] Into a 10 mL vial was added 29-3 (100 mg, 0.034 mmol) and methanol (3 mL) was dissolved, followed by Pd / C (10 mg, 10% wt), the reaction was stirred at room temperature for 16 h, the reaction solution was filtered with a 0.24 micron nylon filter, slowly added to MTBE (30 mL), a solid was precipitated, centrifuged, the supernatant was poured out, and the lower layer was dried under vacuum at 30°C to obtain a gray solid 21 mg.

[0472] Example 30: Synthesis of compound 30

[0473] Synthesis of compound 30-1

[0474] Into a 10 mL vial was added 30-SM (50 mg, 0.06 mmol), NCA (278 mg, 2.42 mmol), benzoic acid (37 mg, 0.303 mmol) and DCM (1.5 mL), the reaction was stirred at room temperature for 2 h, acetic anhydride (9.3 mg, 0.091 mmol) and DIPEA (24 mg, 0.18 mmol) were added, the reaction was protected by nitrogen for three times, the reaction was stirred at room temperature for 16 h, the reaction was slowly added into ethyl acetate (15 mL), solid was precipitated, centrifuged, the supernatant was poured out, the lower solid was added into MTBE (60 mL) and stirred for 10 min, centrifuged, the supernatant was poured out, the lower solid was dried under vacuum to obtain white solid 195 mg, the polymerization degree was 52.

[0475] 1 H NMR (400 MHz, Chloroform-d) δ 5.30-5.21 (m, 1H), 4.63 (d, J = 8.2 Hz, 1H), 4.39-3.70 (m, 112H), 3.16-2.74 (m, 162H), 2.31 (td, J = 7.6, 3.7 Hz, 4H), 2.03 (d, J = 15.0 Hz, 3H), 1.61 (d, J = 4.5 Hz, 4H), 1.26 (d, J = 5.3 Hz, 56H), 0.86 (s, 15H), 0.04 (d, J = 6.1 Hz, 6H).

[0476] Synthesis of compound 30

[0477] Into a 5 mL centrifuge tube was added 30-1 (30 mg, 0.0081 mmol), THF (1 mL) and DCM (1 mL), dissolved, then TBAF (0.012 mL, 0.012 mmol) was added, the reaction was stirred at room temperature for 3 h, then the reaction was slowly added into MTBE (20 mL), solid was precipitated, centrifuged, the supernatant was poured out, the lower solid was dried under vacuum to obtain white solid 24 mg.

[0478] 1 H NMR (400 MHz, Chloroform-d) δ 5.28 (d, J = 23.1 Hz, 1H), 4.47-3.65 (m, 113H), 3.17-2.75 (m, 162H), 2.30 (d, J = 8.3 Hz, 4H), 2.11 (d, J = 18.0 Hz, 3H), 1.65 (s, 4H), 1.26 (d, J = 7.1 Hz, 56H), 0.88 (s, 6H).

[0479] Example 31: Synthesis of compound 31

[0480] Synthesis of compound 31-1

[0481] Into a 10 mL single neck flask was added DSG (400 mg, 0.64 mmol), 31-SM (260 mg, 0.76 mmol), HATU (487 mg, 1.28 mmol), DMAP (196 mg, 1.6 mmol) and DCM (10 mL), replaced with nitrogen for three times and protected, stirred the reaction at room temperature for 3 h, sampled TLC detection, the raw material reacted completely, the reaction liquid was filtered, the filter cake was washed with DCM, the filtrate was concentrated to obtain a white solid 650 mg.

[0482] Synthesis of compound 31-2

[0483] Into a 10 mL single neck flask was added 31-1 (650 mg, 0.69 mmol), TFA (3 mL) and DCM (6 mL), dissolved, replaced with nitrogen for three times and protected, stirred the reaction at room temperature for 16 h, sampled TLC detection, the raw material reacted completely, the reaction liquid was directly concentrated to obtain a white solid 637 mg.

[0484] 1 H NMR (400 MHz, Chloroform-d) δ 7.00 (d, J = 7.8 Hz, 2H), 6.73 (d, J = 7.8 Hz, 2H), 5.24 (t, J = 5.0 Hz, 1H), 4.24 (dddd, J = 63.1, 51.2, 11.9, 5.2 Hz, 5H), 3.17 (ddd, J = 63.0, 14.8, 6.1 Hz, 2H), 2.33 (td, J = 7.5, 1.9 Hz, 4H), 1.60 (t, J = 7.2 Hz, 4H), 1.37 - 1.15 (m, 56H), 0.97 - 0.78 (m, 6H).

[0485] Synthesis of compound 31

[0486] Into a 10 mL single neck flask was added 31-2 (50 mg, 0.055 mmol), NCA (255 mg, 2.22 mmol), benzoic acid (34 mg, 0.277 mmol) and DCM (1.5 mL), then added DIPEA (7.2 mg, 0.055 mmol), stirred the reaction at room temperature for 2 h, added acetic anhydride (8.5 mg, 0.083 mmol) and DIPEA (22 mg, 0.166 mmol), replaced with nitrogen for three times and protected, stirred the reaction at room temperature for 16 h, the reaction liquid was slowly added to ethyl acetate (15 mL), a solid was precipitated, centrifuged, the supernatant was poured out, and the lower layer was dried under vacuum to obtain a white solid 205 mg, and the degree of polymerization was 40.

[0487] 1H NMR (400 MHz, Chloroform-d) δ 7.25 - 6.53 (m, 4H), 5.32 (s, 1H), 4.78 (s, 1H), 4.45 - 3.75 (m, 84H), 2.99 (dd, J = 39.5, 13.9 Hz, 122H), 2.33 (t, J = 7.7 Hz, 4H), 2.18 - 2.09 (m, 3H), 1.61 (t, J = 7.1 Hz, 4H), 1.37 - 1.14 (m, 56H), 0.89 (t, J = 6.7 Hz, 6H).

[0488] Example 32: Synthesis of compound 32

[0489] Synthesis of compound 32-SM1

[0490] Into a 50 mL single necked flask, was placed 32-SM (2 g, 6.91 mmol), TEA (1.05 g, 10.37 mmol) and methanol (30 mL), dissolved, then Boc20 (2.26 g, 10.37 mmol) was added, replaced with nitrogen for three times and protected, the reaction was stirred at room temperature for 4 h, sampled and detected by LCMS, the raw material was substantially completely reacted, the reaction solution was directly concentrated to obtain a crude product, which was separated by silica gel column chromatography (DCM:MeOH = 1:0-3:1) to obtain a white solid 2.82 g.

[0491] Synthesis of compound 32-1

[0492] Into a 10 mL single necked flask, was placed DSG (1.0 g, 1.6 mmol), 32-SM1 (748 mg, 1.92 mmol), HATU (1.22 g, 3.2 mmol), DMAP (489 mg, 3.99 mmol) and DCM (20 mL), replaced with nitrogen for three times and protected, the reaction was stirred at room temperature for 3 h, sampled and detected by TLC, the raw material was completely reacted, the reaction solution was filtered, the filter cake was washed with DCM, and the filtrate was concentrated to obtain a crude product, which was separated by silica gel column chromatography (PE:EA = 1:0-3:1) to obtain a white solid 1.6 g.

[0493] Synthesis of compound 32-2

[0494] Into a 100 mL single necked flask, was placed 32-1 (600 mg, 0.602 mmol) and methanol (10 mL), dissolved, then Pd / c (60 mg, 10%wt) was added, replaced with hydrogen for three times and protected, the reaction was stirred at room temperature for 4 h, then filtered with diatomite, the filter cake was washed with dichloromethane, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated by silica gel column chromatography (DCM:MeOH = 1:0-96:4) to obtain a white solid 437 mg.

[0495] 1H NMR (400 MHz, Chloroform-d) δ 8.01 (d, J = 1.3 Hz, 1H), 7.22 (s, 1H), 5.30 (s, 1H), 4.36 (ddd, J = 24.3, 11.9, 4.3 Hz, 2H), 4.20 (ddd, J = 27.9, 11.9, 5.9 Hz, 2H), 3.88 (dd, J = 7.7, 4.6 Hz, 1H), 3.04 (dd, J = 14.5, 4.5 Hz, 1H), 2.86 (dd, J = 14.6, 7.7 Hz, 1H), 2.33 (t, J = 7.5 Hz, 4H), 1.63 (s, 13H), 1.27 (s, 56H), 0.90 (t, J = 6.7 Hz, 6H).

[0496] Synthesis of compound 32-3

[0497] Into a 10 mL vial was placed 32-2 (50 mg, 0.058 mmol), NCA (266 mg, 2.32 mmol), benzoic acid (35 mg, 0.29 mmol) and DCM (2 mL), the reaction was stirred at room temperature for 2 h, acetic anhydride (8.9 mg, 0.087 mmol) and DIPEA (23 mg, 0.174 mmol) were added, the reaction was protected by nitrogen for 3 times, the reaction was stirred at room temperature for 16 h, the reaction solution was slowly added into ethyl acetate (305 mL), solid was precipitated, centrifuged, the supernatant was poured out, the lower layer was added into ethyl acetate (30 mL) and ultrasonic for 5 min, centrifuged, the supernatant was poured out, the lower layer was dried under vacuum to obtain white solid 112 mg, the degree of polymerization was 38.

[0498] 1 H NMR (400 MHz, Chloroform-d) δ 7.50 (d, J = 7.3 Hz, 1H), 7.22 (s, 1H), 5.23 (s, 1H), 4.80 (d, J = 12.0 Hz, 2H), 4.45 - 3.82 (m, 81H), 3.25 - 2.77 (m, 115H), 2.37 - 2.25 (m, 4H), 2.06 (s, 3H), 1.62 (s, 13H), 1.26 (d, J = 2.9 Hz, 56H), 0.89 (t, J = 6.7 Hz, 6H).

[0499] Synthesis of compound 32

[0500] Into a 10 mL vial was placed 32-3 (50 mg, 0.013 mmol), TsOH (4 mg, 0.02 mmol) and ethanol (2 mL), the reaction was stirred at 60 °C for 3.5 h, then naturally cooled to room temperature, the reaction solution was directly concentrated and dried under reduced pressure to obtain white solid 53 mg.

[0501] 1 H NMR (400 MHz, Chloroform-d) δ 7.57 (s, 1H), 7.26-7.19 (m, 1H), 5.23 (s, 1H), 4.86-4.71 (m, 2H), 4.53-3.82 (m, 81H), 3.19-2.61 (m, 115H), 2.69 (d, J = 27.8 Hz, 4H), 2.33 (s, 3H), 1.61 (d, J = 4.0 Hz, 4H), 1.38-1.11 (m, 56H), 0.88 (t, J = 6.7 Hz, 6H).

[0502] Example 33: Synthesis of compound 33

[0503] Synthesis of compound 33-1

[0504] Into a 10-mL single-necked flask, was placed DSG (800 mg, 1.28 mmol), succinic anhydride (154 mg, 1.53 mmol), DMAP (234 mg, 1.92 mmol) and DCM (15 mL), which was replaced with nitrogen for three times and protected, and stirred at room temperature for 16 h. TLC detection showed that the reaction was complete. The reaction solution was directly concentrated to obtain a crude product, which was separated by silica gel column chromatography (DCM:MeOH = 1:0-92:8) to obtain a white solid 1 g.

[0505] Synthesis of compound 33-2

[0506] Into a 10-mL single-necked flask, was placed 33-1 (900 mg, 1.24 mmol), 33-SM (505 mg, 1.49 mmol), HATU (944 mg, 2.48 mmol), DMAP (379 mg, 3.1 mmol) and DCM (30 mL). The flask was replaced with nitrogen for three times and protected, and stirred at room temperature for 16 h. TLC detection showed that the reaction was complete. The reaction solution was directly concentrated to obtain a crude product, which was separated by silica gel column chromatography (DCM:MeOH = 1:0-96:4) to obtain a white solid 1.51 g.

[0507] Synthesis of compound 33-3

[0508] Into a 50-mL single-necked flask, was placed 33-2 (1.28 g, 1.2 mmol), TFA (3 mL) and DCM (9 mL), which was stirred at room temperature for 16 h. TLC detection showed that the reaction was complete. The reaction solution was directly concentrated to obtain a crude product, which was separated by silica gel column chromatography (DCM:MeOH = 1:0-0:1) to obtain a white solid 451 mg.

[0509] 1H NMR (400 MHz, Chloroform-d) δ 5.30 - 5.18 (m, 1H), 4.49 - 4.00 (m, 5H), 2.96 (s, 2H), 2.57 (d, J = 25.5 Hz, 4H), 2.30 (q, J = 7.3 Hz, 4H), 1.87 - 1.51 (m, 6H), 1.50 - 1.35 (m, 3H), 1.25 (s, 56H), 0.88 (t, J = 6.8 Hz, 6H).

[0510] Synthesis of compound 33

[0511] Into a 10 mL single neck flask was added 33-3 (50 mg, 0.058 mmol), NCA (269 mg, 2.34 mmol), benzoic acid (36 mg, 0.293 mmol) and DCM (1.5 mL), then DIPEA (7.6 mg, 0.058 mmol) was added, the reaction was stirred at room temperature for 1.5 h, acetic anhydride (9 mg, 0.088 mmol) and DIPEA (23 mg, 0.176 mmol) were added, nitrogen was replaced for three times and protected, the reaction was stirred at room temperature for 16 h, slowly added dropwise into ethyl acetate (30 mL), solid precipitated, centrifuged, the supernatant was poured out, ethyl acetate (30 mL) was added again, ultrasonic was treated for 2 min, centrifuged, the supernatant was poured out, the lower layer was dried under vacuum to obtain white solid 213 mg, the degree of polymerization was 42.

[0512] 1 H NMR (400 MHz, Chloroform-d) δ 5.26 (d, J = 5.3 Hz, 1H), 4.49 - 3.79 (m, 85H), 2.98 (dd, J = 39.4, 16.4 Hz, 126H), 2.36 - 2.25 (m, 4H), 2.05 (s, 3H), 1.60 (s, 6H), 1.46 (d, J = 7.3 Hz, 3H), 1.25 (s, 56H), 0.88 (t, J = 6.7 Hz, 6H).

[0513] Example 34: Synthesis of compound 34

[0514] Synthesis of compound 34-1

[0515] Into a 25 mL single necked flask was placed 34-SM (400 mg, 1.28 mmol), N-Boc-L- glutamic acid tert-butyl ester (466 mg, 1.54 mmol), HATU (974 mg, 2.56 mmol), DMAP (391 mg, 3.79 mmol) and DCM (10 mL), replaced with nitrogen for three times and protected, stirred the reaction at room temperature for 3 h, TLC test by sampling, the raw material reacted completely, the reaction liquid was filtered, the filter cake was washed with DCM, the filtrate was concentrated to obtain a crude product, which was separated by silica gel column chromatography (DCM:MeOH = 1:0-95:5) to obtain colorless transparent oil 796 mg.

[0516] Synthesis of compound 34-2

[0517] Into a 50 mL single necked flask was placed 34-1 (796 mg, 1.33 mmol), TFA (3 mL) and DCM (6 mL). Stirring dissolution, replaced with nitrogen for three times and protected, stirred the reaction at room temperature for 16 h, TLC test by sampling, the raw material reacted completely, the reaction liquid was directly concentrated to obtain colorless transparent oil 813 mg.

[0518] 1 H NMR (400 MHz, Chloroform-d) δ 4.98 (t, J = 6.1 Hz, 1H), 4.20 (dd, J = 7.5, 3.9 Hz, 1H), 2.69 (ddd, J = 11.8, 7.8, 4.1 Hz, 2H), 2.27 (ddd, J = 30.8, 7.9, 4.3 Hz, 2H), 1.59 (s, 4H), 1.27 (d, J = 3.3 Hz, 32H), 0.90 (t, J = 6.7 Hz, 6H).

[0519] Synthesis of compound 34

[0520] Into a 10 mL single necked flask was placed 34-2 (30 mg, 0.054 mmol), NCA (248 mg, 2.16 mmol), benzoic acid (33 mg, 0.27 mmol) and DCM (1.5 mL), then DIPEA (7 mg, 0.054 mmol) was added. Stirred the reaction at room temperature for 2 h, acetic anhydride (8.3 mg, 0.081 mmol) and DIPEA (21 mg, 0.162 mmol) were added, replaced with nitrogen for three times and protected, stirred the reaction at room temperature for 16 h, the reaction liquid was slowly added dropwise into ethyl acetate (20 mL), solid was precipitated, centrifuged, the supernatant was poured out, the lower layer was dried under vacuum to obtain white solid 156 mg, degree of polymerization 37.

[0521] 1H NMR (400 MHz, Chloroform-d) δ 4.87 (d, J = 7.2 Hz, 1H), 4.42 - 3.81 (m, 71H), 3.25 - 2.77 (m, 107H), 2.15 (s, 2H), 2.09 (d, J = 17.4 Hz, 3H), 1.54 (s, 4H), 1.27 (d, J = 4.9 Hz, 32H), 0.89 (t, J = 6.7 Hz, 6H).

[0522] Example 35: Synthesis of compound 35

[0523] Synthesis of compound 35-1

[0524] To a solution of N-Cbz-L-serine (2.5 g, 7.5 mmol, 1.1 eq) in CH3CN / DMF (45 mL, 5 mL) was added KOH (0.42 g, 7.5 mmol, 1.1 eq) at room temperature. It was stirred at 80 °C for 1 h under argon protection. 1-Bromooctadecane (1.63 g, 6.82 mmol, 1.0 eq) was added and stirred at 80 °C for 16 h. LCMS detection. The filtrate was filtered under reduced pressure. Water (10 mL) and ethyl acetate (100 mL) were added to the filtrate. The organic phase was washed with saturated sodium chloride and dried over anhydrous sodium sulfate, rotary evaporation, normal phase separation to give a white solid (2 g, 59.7% yield).

[0525] MS (ESI), m / z, 514.4 [M+23] + .

[0526] Synthesis of compound 35-2

[0527] To a solution of 35-1 (1.8 g, 3.66 mmol, 1.0 eq) in DCM (100 mL) was added stearic acid (1.04 g, 3.6 mmol, 1.0 eq) and DMAP (0.89 g, 7.32 mmol, 2.0 eq) successively at room temperature. DCC (1.51 g, 7.32 mmol, 2.0 eq) was added under argon protection. It was stirred at room temperature for 16 h. TLC detection. The reaction was terminated. Saturated aqueous citric acid solution was added. The organic phase was dried over anhydrous sodium sulfate, rotary evaporation, normal phase separation to give compound 35-2 as a white solid (2.1 g, 75.5% yield).

[0528] 1H NMR (400 MHz, CDC13) δ 7.37 - 7.22 (m, 5H), 5.48 (d, J = 8.0 Hz, 1H), 5.06 (s, 2H), 4.58 - 4.50 (m, 1H), 4.39 (d, J = 3.6 Hz, 1H), 4.34 - 4.21 (m, 1H), 4.08 (t, J = 6.4 Hz, 2H), 2.20 (t, J = 7.6 Hz, 2H), 1.60 - 1.45 (m, 6H), 1.19 (s, 58H), 0.81 (t, J = 6.8 Hz, 6H).

[0529] Synthesis of compound 35-3

[0530] To a solution of 35-2 (2.1 g, 2.77 mmol, 1.0 eq) in DCM / MeOH (1 : 1, 100 mL) was added Pd / C (0.21 g) at room temperature. Stirring at 20 °C for 16 h under hydrogen balloon. TLC detection. The reaction was terminated. Filtration, rotary evaporation of the filtrate. The resulting crude was slurried with methyl tert-butyl ether to give compound 35-3 as a white solid (1.7 g, 100% yield).

[0531] 1 H NMR (400 MHz, CDC13) δ 7.37 - 7.22 (m, 5H), 5.48 (d, J = 8.0 Hz, 1H), 5.06 (s, 2H), 4.58 - 4.50 (m, 1H), 4.39 (d, J = 3.6 Hz, 1H), 4.34 - 4.21 (m, 1H), 4.08 (t, J = 6.4 Hz, 2H), 2.20 (t, J = 7.6 Hz, 2H), 1.60 - 1.45 (m, 6H), 1.19 (s, 58H), 0.81 (t, J = 6.8 Hz, 6H).

[0532] Synthesis of compound 35-4

[0533] To a solution of 35-3 (1.7 g, 2.72 mmol, 1.0 eq) in DCM (20 mL) was added N-Cbz-L-glutamic acid tert-butyl ester (0.92 g, 2.72 mmol, 1.0 eq), HATU (1.04 g, 2.72 mmol, 1.0 eq) and DIPEA (0.7 g, 5.45 mmol, 2.0 eq) successively at room temperature. Stirring at 20 °C for 16 h. TLC detection (DCM:MeOH = 50:1). The reaction was completed. Filtration, silica gel column, DCM:MeOH = 100:0~50:1, to give compound 35-4 as a white solid (1.85 g, 72% yield).

[0534] 1H NMR (400 MHz, CDC13) δ 7.33 (dt, J = 6.2, 3.8 Hz, 4H), 7.16 (d, J = 7.6 Hz, 1H), 5.64 (d, J = 7.4 Hz, 1H), 5.30 (s, 2H), 5.11 (s, 2H), 4.89 - 4.72 (m, 1H), 4.48 (d, J = 3.5 Hz, 1H), 4.42 - 4.25 (m, 2H), 4.15 (dd, J = 10.6, 6.4 Hz, 2H), 2.53 - 2.36 (m, 2H), 2.29 (t, J = 7.6 Hz, 2H), 2.15 - 2.05 (m, 1H), 1.95 (s, 1H), 1.69 - 1.51 (m, 8H), 1.44 (d, J = 6.0 Hz, 8H), 1.25 (s, 52H), 0.88 (t, J = 6.8 Hz, 6H).

[0535] Synthesis of compound 35-5

[0536] To a solution of 35-4 (1.85 g, 1.96 mmol, 1.0 eq) in MeOH / DCM (1:1, 100 mL) was added Pd / C (0.18 g) at room temperature. Stirring was continued under hydrogen balloon at 20 °C for 16 h. TLC detection (DCM:MeOH = 50:1). The reaction was terminated. Filtration, the filtrate was rotary evaporated. The resulting crude was slurry with methyl tert-butyl ether (50 mL). Filtration, the filter cake was dried thoroughly under vacuum to give compound 35-5 as a white solid (1.12 g, 70.4% yield).

[0537] 1 H NMR (400 MHz, CDC13) δ 8.38 (d, J = 8.0 Hz, 1H), 5.01 - 4.77 (m, 1H), 4.54 (d, J = 3.2 Hz, 1H), 4.43 (s, 2H), 4.26 - 3.92 (m, 2H), 3.51 (s, 6H), 2.83 (s, 8H), 2.67 (d, J = 8.6 Hz, 2H), 2.35 (dt, J = 15.8, 7.8 Hz, 4H), 1.62 (dd, J = 13.2, 7.0 Hz, 6H), 1.47 (s, 10H), 1.27 (s, 60H), 0.90 (t, J = 6.8 Hz, 6H).

[0538] Synthesis of compound 35-6

[0539] To a solution of 35-5 (210 mg) in DCM / TFA (3:1, 2 mL) was added at room temperature. The reaction was stirred at room temperature for 15 h. The solvent was rotary evaporated to give the product 220 mg as a white solid.

[0540] 1H NMR (400 MHz, Chloroform-d) δ 5.03-4.69 (m, 3H), 4.56-4.32 (m, 1H), 4.29-4.07 (m, 1H), 2.37-2.24 (m, 2H), 2.02-1.91 (m, 1H), 1.83-1.73 (m, 1H), 1.72-1.51 (m, 5H), 1.28 (s, 55H), 0.90 (t, J = 6.6 Hz, 6H).

[0541] Synthesis of compound 35

[0542] To 35-6 (34.7 mg, 0.04 mmol, 1.0 eq), PhCOOH (24.4 mg, 0.2 mmol, 5.0 eq), DIPEA (7.2 μL, 0.04 mmol, 1.0 eq), Sar-NCA (184.2 mg, 1.6 mmol, 40.0 eq) in DCM (8 mL) was added sequentially at room temperature. The reaction was stirred at room temperature for 1 h. DIPEA (43.7 μL, 0.24 mmol, 6.0 eq) and Ac20 (11.3 μL, 0.12 mmol, 3.0 eq) were added sequentially. The reaction was stirred at room temperature for 15 h. The reaction was complete. The reaction was dropped into MTBE, and white precipitate was formed. The supernatant was removed by centrifugation. The solid was pumped dry to give 108 mg of white solid product with a degree of polymerization of about 40.

[0543] 1 H NMR (400 MHz, Chloroform-d) δ 4.82-4.63 (m, 1H), 4.51-3.80 (m, 84H), 3.11-2.86 (m, 134H), 2.34-2.24 (m, 2H), 2.16-2.07 (m, 3H), 1.69-1.50 (m, 5H), 1.37-1.21 (m, 56H), 0.88 (t, J = 6.7 Hz, 6H).

[0544] Example 36: Synthesis of compound 36

[0545] Synthesis of compound 36-1

[0546] To a solution of 36-2 (0.3 g) in DCM / DEA (1 : 1, 10 mL) was added 36-1 (0.3 g) at room temperature. The reaction was stirred at room temperature for 15 h. TLC monitored the reaction, the starting material was completely converted. The reaction was concentrated and purified by silica gel column (PE / EA: 100:0~3: 1) to give white solid 0.26 g.

[0547] 1 H NMR (400 MHz, Chloroform-d) δ 7.83-7.74 (m, 2H), 7.70-7.59 (m, 2H), 7.47-7.37 (m, 6H), 7.37-7.26 (m, 10H), 7.26-7.20 (m, 2H), 7.11 (d, J=8.0 Hz, 2H), 5.29-5.17 (m, 2H), 4.47-4.06 (m, 8H), 2.77-2.59 (m, 2H), 2.36-2.23 (m, 7H), 1.59 (s, 7H), 1.27 (s, 56H), 0.91 (t, J=6.8 Hz, 6H).

[0548] Synthesis of compound 36-2

[0549] To a solution of 36-2 (0.3 g) in DCM / DEA (1 : 1, 10 mL) was added 36-1 (0.3 g) at room temperature. The reaction was stirred at room temperature for 15 h. TLC monitored the reaction, the starting material was completely converted. The reaction was concentrated and purified by silica gel column (PE / EA: 100:0~3: 1) to give white solid 0.26 g.

[0550] 1 H NMR (400 MHz, Chloroform-d) δ 7.83-7.74 (m, 2H), 7.70-7.59 (m, 2H), 7.47-7.37 (m, 6H), 7.37-7.26 (m, 10H), 7.26-7.20 (m, 2H), 7.11 (d, J=8.0 Hz, 2H), 5.29-5.17 (m, 2H), 4.47-4.06 (m, 8H), 2.77-2.59 (m, 2H), 2.36-2.23 (m, 7H), 1.59 (s, 7H), 1.27 (s, 56H), 0.91 (t, J=6.8 Hz, 6H).

[0551] Synthesis of compound 36-3

[0552] At room temperature, 36-2 (39.4 mg, 0.04 mmol, 1.0 eq), PhCOOH (24.4 mg, 0.2 mmol, 5.0 eq), Sar-NCA (184.2 mg, 1.6 mmol, 40.0 eq), DCM (8 mL) were added sequentially. The reaction was stirred at room temperature for 1 hour. Then DIPEA (43.7 μL, 0.24 mmol, 6.0 eq) and Ac20 (11.3 μL, 0.12 mmol, 3.0 eq) were added sequentially. The reaction was stirred at room temperature for 15 hours. After the reaction was completed, the reaction was dropped into MTBE, and a white precipitate was precipitated. The supernatant was removed by centrifugation. The solid was pumped dry to obtain a white solid product 103 mg, with a degree of polymerization of about 41.

[0553] 1 H NMR (400 MHz, Chloroform-d) δ 7.40 - 7.33 (m, 4H), 7.33 - 7.28 (m, 4H), 7.26 - 7.20 (m, 4H), 7.11 (d, J=7.9 Hz, 2H), 5.25 - 5.13 (m, 1H), 4.48 - 3.83 (m, 87H), 3.12 - 2.85 (m, 123H), 2.34 - 2.26 (m, 9H), 2.17 - 2.08 (m, 3H), 1.66 - 1.51 (m, 4H), 1.46 - 1.37 (m, 3H), 1.26 (s, 56H), 0.89 (t, J=6.7 Hz, 6H).

[0554] Synthesis of compound 36

[0555] At room temperature, 36-3 (30 mg), DCM / TFA / TIS (100:2.5:5, 0.3 mL) were added sequentially. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction was dropped into MTBE, and a white precipitate was precipitated. The supernatant was removed by centrifugation. The solid was pumped dry to obtain a white solid product 18 mg.

[0556] 1 H NMR (400 MHz, Chloroform-d) δ 7.40 - 7.33 (m, 4H), 7.33 - 7.28 (m, 4H), 7.26 - 7.20 (m, 4H), 7.11 (d, J=7.9 Hz, 2H), 5.25 - 5.13 (m, 1H), 4.48 - 3.83 (m, 87H), 3.12 - 2.85 (m, 123H), 2.34 - 2.26 (m, 9H), 2.17 - 2.08 (m, 3H), 1.66 - 1.51 (m, 4H), 1.46 - 1.37 (m, 3H), 1.26 (s, 56H), 0.89 (t, J=6.7 Hz, 6H).

[0557] Example 37: Synthesis of compound 37

[0558] Synthesis of compound 37-1

[0559] To a solution of 37-SM (10.1 g, 0.01 mol) in DCM (50 mL) was added triethylamine (3.52 g, 0.35 mol) in one portion at 0 °C under nitrogen protection, stirred for 5 min until the solution was clear, then di(p-nitrophenyl) carbonate (4.4 g, 0.022 mol) in DCM (20 mL) was added, and the reaction was continued at room temperature for 1 h. The reaction was filtered, and the filtrate was concentrated. MTBE (200 mL) was added, and the mixture was stirred magnetically. The solid was precipitated by cooling to 0 °C, and was filtered to give compound 37-1 as a white solid (10.3 g, 90% yield).

[0560] Synthesis of compound 37-2

[0561] To a solution of L-glutamic acid-5-tert-butyl ester (3.48 g, 0.017 mol) in DMF (50 mL) was added triethylamine (2.17 g, 0.02 mol) and 37-1 (10 g, 8.6 mmol) at room temperature under nitrogen protection, and the reaction was stirred for 12 h. The reaction was added to 50 mL of saturated aqueous citric acid and 100 mL of DCM, and the layers were separated. The aqueous phase was further extracted with dichloromethane, and the combined organic phases were washed with salt, dried over anhydrous sodium sulfate, concentrated, dissolved in 20 mL of dichloromethane, slurried with 200 mL of MTBE, filtered, and the filter cake was rinsed with 30 mL of MTBE. The solid was collected as compound 37-3, a white solid (9.8 g).

[0562] Synthesis of compound 37-3

[0563] To a solution of compound 37-2 (5.0 g, 4.1 mmol) in dichloromethane (100 mL) was added DSG (3.8 g, 6.1 mmol), HATU (3.1 g, 8.13 mmol), and DMAP (1.25 g, 10.2 mmol). The reaction was stirred at room temperature for 4 h. The reaction was quenched by adding 50 mL of 0.5 N aqueous hydrochloric acid, extracted with dichloromethane, and the combined organic phases were washed with salt, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (DCM-MeOH solvent system) to give 37-3 as a light yellow solid (6.5 g).

[0564] Synthesis of compound 37

[0565] To a solution of compound 37-3 (5.0 g) in dichloromethane (20 mL) was added TFA (20 mL), and the reaction was stirred at room temperature (20-25 °C) for 2 h. The reaction was concentrated, and the residue was added to 100 mL of DCM, stirred to dissolve and clarify, and concentrated repeatedly three times to give the crude product compound 37 (4.8 g) with a CAD-HPLC purity of 98.9%.

[0566] Examples 38-40: Synthesis of compounds 38-40

[0567] Refer to the synthesis method of example 1 or 37, synthesis was carried out according to different PEG molecular weight of polymer, the desired compounds 38-40 were obtained.

[0568] Examples 41-45: Synthesis of compounds 41-45

[0569] Refer to the synthesis method of example 19, synthesis was carried out according to different PEG molecular weight of polymer, the desired compounds 41-45 were obtained.

[0570] Example 46: Synthesis of compound 46

[0571] Synthesis of compound 46-1

[0572] To the solution of D-glutamic acid-5-tert-butyl ester (0.41 g, 2.0 mmol) in DMF (10 mL) was added triethylamine (0.15 g, 1.5 mmol) and 1-1 (2.18 g, 1.0 mmol) under nitrogen protection at room temperature, and the reaction was stirred for 12 h. The reaction solution was added to 10 mL of saturated aqueous citric acid and 20 mL of DCM, and the layers were separated. The aqueous phase was further extracted with dichloromethane, and the organic phases were combined, washed with salt, dried over anhydrous sodium sulfate, concentrated, dissolved in 5 mL of dichloromethane, added to 50 mL of MTBE to slurry, filtered, and the collected solid was compound 46-1, white solid (2.0 g).

[0573] Synthesis of compound 46-2

[0574] To the solution of D-glutamic acid-5-tert-butyl ester (0.41 g, 2.0 mmol) in DMF (10 mL) was added triethylamine (0.15 g, 1.5 mmol) and 1-1 (2.18 g, 1.0 mmol) under nitrogen protection at room temperature, and the reaction was stirred for 12 h. The reaction solution was added to 10 mL of saturated aqueous citric acid and 20 mL of DCM, and the layers were separated. The aqueous phase was further extracted with dichloromethane, and the organic phases were combined, washed with salt, dried over anhydrous sodium sulfate, concentrated, dissolved in 5 mL of dichloromethane, added to 50 mL of MTBE to slurry, filtered, and the collected solid was compound 46-1, white solid (2.0 g).

[0575] Synthesis of compound 46

[0576] To compound 46-2 (2.0 g) in dichloromethane (20 mL) was added TFA (20 mL), stirred at room temperature for 2 h, concentrated, the residue was dissolved in 50 mL DCM, stirred to clear, concentrated, repeated three times to get crude product compound 46 (1.9 g), CAD-HPLC purity 98.6%.

[0577] Example 47: Synthesis of compound 47

[0578] Synthesis of compound 47

[0579] The preparation of intermediate 47-1, 47-2 and final product 47 was based on starting material BOC-D-glutamic acid 5-tert-butyl ester, the product was obtained as 950 mg, CAD-HPLC purity 98.2%, degree of polymerization 40.

[0580] Example 48: Synthesis of compound 48

[0581] Synthesis of compound 48-1

[0582] To compound 1-2 (20 g, 8.9 mmol) in dichloromethane (200 mL) was added HATU (6.78 g, 0.018 mol), DMAP (2.74 g, 0.022 mol) and 48-SM (7.60 g, 0.013 mol) and stirred at room temperature for 4 h. Quenched with 100 mL 0.5 N aqueous hydrochloric acid and diluted with 100 mL DCM and stirred for 0.5 h. The solution was separated, the organic phase was washed with 100 mL 0.5 N hydrochloric acid three times, salted out, dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography (DCM-MeOH solvent system) to give compound 48-1 as a light yellow solid (20.1 g, yield 80.7%). CAD-HPLC showed purity 98.9%.

[0583] Synthesis of compound 48

[0584] To compound 48-1 (20 g) in dichloromethane (200 mL) was added TFA (150 mL). The reaction was stirred at room temperature (20-25 °C) for 2 h, concentrated, dissolved in dichloromethane and concentrated, repeated three times, the crude product was dissolved in dichloromethane, the pH was adjusted to basic with saturated aqueous sodium bicarbonate solution, the solution was separated, salted out, dried over anhydrous sodium sulfate, filtered, concentrated, and the compound 48 was obtained as a white solid (16.5 g, yield 84%). CAD-HPLC showed purity 98.9%.

[0585] Example 49-58: Synthesis of compounds 49-58

[0586] Refer to the synthesis method of Example 1 or 48, according to different glyceride or lipophilic fragment raw materials, the desired compounds 49-58 are synthesized.

[0587] Examples 59-69: Synthesis of compounds 59-69

[0588] Refer to the synthesis method of Example 19, according to different glyceride or lipophilic fragment raw materials, the desired compounds 59-69 are synthesized.

[0589] Application Example E1: Covalent coupling delivery drug SN38 of Example 1

[0590] Synthesis of compound E1

[0591] To the solution of 1 (2.8 g, 1.0 mmol) in DMF (25 mL), 1-SM2 (0.91 g, 1.0 mmol, refer to the synthesis of compound 10114 in WO2023078464A1), HATU (1.4 g, 2.0 mmol) and DIPEA (0.33 g, 2.5 mmol) were added. The reaction was stirred at room temperature for 6 h, HPLC showed that the reaction was complete, and was added to 200 mL MTBE for precipitation, filtration, the filter cake was rinsed with 30 mL MTBE, and was dried under vacuum at 30°C to give compound 1 as a white solid (2.2 g, yield 62%).

[0592] Application Example E2: Covalent coupling delivery drug SN38 of Example 19

[0593] Synthesis of compound E2

[0594] To the solution of 19 (300 mg, 0.086 mmol, 1.0 eq) and 1-SM2 (136.8 mg, 0.15 mmol, 1.75 eq) in DMF (3 mL), PyBOP (89.2 mg, 0.17 mmol, 2.0 eq), HOBt (23.2 mg, 0.17 mmol, 2.0 eq) and NMM (43.3 μl, 0.39 mmol, 4.5 eq) were added under room temperature and nitrogen protection. The reaction was stirred at room temperature for 15 hours. CAD monitored the reaction, and the raw material was completely converted. Concentration, gel column separation (DCM:MeOH=1:1), to give white solid product 230 mg.

[0595] 1H NMR (400 MHz, Chloroform-d) δ 8.15 (s, 1H), 7.80 (s, 1H), 7.64 (s, 2H), 7.51 (s, 2H), 7.23 (s, 1H), 5.72 (d, J = 16.4 Hz, 1H), 5.30-5.22 (m, 2H), 5.15-4.99 (m, 3H), 4.61-3.80 (m, 79H), 3.69-3.49 (m, 3H), 3.30-2.71 (m, 119H), 2.63-2.25 (m, 14H), 2.21-2.05 (m, 4H), 2.05-1.85 (m, 3H), 1.73-1.52 (m, 4H), 1.52-1.37 (m, 3H), 1.26 (s, 56H), 1.07-0.92 (m, 6H), 0.88 (t, J = 6.7 Hz, 6H).

[0596] Evaluation Example 1: Pharmacodynamic study of the compound of the present application using application examples E1 and E2 in human small cell lung cancer cell NCI-H69 xenograft mouse model

[0597] Experimental animals and inoculation method:

[0598] BALB / c nude mice, female, 4-5 weeks old, weighing 20-25 grams, after arrival, feed in the experimental environment for one week, subcutaneously inoculate NCI-H69 cancer cells in the right axillary, when the tumor growth reaches ~ 150mm 3 , start grouping and dosing, 6 mice in each group.

[0599] Preparation of test sample:

[0600] Weigh an appropriate amount of the compound of the present application, add a certain volume of normal saline, shake and dissolve, filter with a 0.2 μm membrane, and prepare for use.

[0601] Dosing of test drug:

[0602] The dosing amount and dosing regimen are shown in Table 1. The subcutaneous tumor volume of nude mice was measured 2-3 times a week (the calculation formula of tumor volume is: V = 0.5a x b 2 , a and b represent the long diameter and short diameter of the tumor, respectively), the mouse weight was weighed, and the data was recorded.

[0603] Table 1 Note: The dosing volume is 10 mg / mL.

[0604] Analysis and evaluation:

[0605] Experimental evaluation index: tumor growth inhibition rate TGI (%) or relative tumor proliferation rate T / C (%) were used for evaluation, where T is the experimental group and C is the control group.

[0606] Calculation of relative tumor proliferation rate T / C (%): if T > T0, T / C (%) = (T - T0) / (C - C0) x 100%, if T < T0, T / C (%) = (T - T0) / T0 x 100% wherein T, C are tumor volumes at the end of the experiment; T0, C0 are tumor volumes at the beginning of the experiment.

[0607] Calculation of tumor growth inhibition rate TGI (%): TGI (%) = (1 - T / C) x 100%.

[0608] Evaluation criteria: T / C (%) > 40 (i.e. TGI (%) < 60%) is invalid; T / C (%) ≤ 40 (i.e. TGI (%) ≥ 60%) is effective, and P < 0.05 after statistical processing is effective.

[0609] Pharmacodynamic experiment results:

[0610] The tumor inhibition effect of the relevant embodiments on the small cell lung cancer cell NCI-H69 tumor model is shown in Figure 1.

[0611] The results show that the application examples E1 and E2 of the compound of the application for covalently coupling delivery of the drug SN38 have a very strong tumor inhibition effect on the small cell lung cancer cell NCI-H69 tumor model, and the effect of the compound covalently coupled by the material of example 19 for delivery of the drug is better than that of example 1.

[0612] Evaluation example 2: mRNA delivery transfection efficiency experiment of the application examples 1 and 19

[0613] Experimental scheme:

[0614] 1. Experimental material preparation:

[0615] The commercially available 1.0 mg / mL EGFP mRNA (70 μL) (brand APExBIO) is diluted with sterile water to a volume of 3.5 mL, and the EGFP mRNA concentration is 2.0 μg / mL, ready for use;

[0616] The positive control PEI 25K is a commercially available reagent (brand APExBIO), and the concentration is 1 mg / mL, ready for use;

[0617] Example 1 (3.5 mg) is added to 3.5 mL of pure water, and ultrasonic oscillation is performed until it is clear, and then filtered with a sterile 0.22 μm needle filter to obtain 3.5 mL of a solution of example 1 with a concentration of 1.0 mg / mL, ready for use;

[0618] Example 19 (4 mg) is added to 4 mL of pure water, and ultrasonic oscillation is performed until it is clear, and then filtered with a sterile 0.22 μm needle filter to obtain 4.0 mL of a solution of example 19 with a concentration of 1.0 mg / mL, ready for use.

[0619] 2. Experimental steps:

[0620] a. Collect the cultured cells (Hela, from CAS, culture medium is DMEM + 10% FBS, and the plating number is 10000) and count the live cells with an automatic cell counter. After adjusting the cell suspension to the appropriate concentration with the culture medium, add 100 μL of the cell suspension to each well of a 96-well cell culture plate, and the final cell density is determined according to historical data.

[0621] b. Cell transfection:

[0622] (1) Dilute 1500 μL of 2 μg / mL mRNA stock solution with 1500 μL of serum-free medium to prepare 1 μg / mL mRNA working solution, and mix thoroughly;

[0623] (2) Blank control group: 1 μg / mL mRNA working solution, without adding transfection reagent;

[0624] (3) Transfection group: add 10 μL of the above prepared PEI 25k, Example 1 and Example 2 three kinds of transfection reagents to 100 μL of mRNA working solution respectively, vortex for 10 seconds, and mix thoroughly;

[0625] (4) Incubate at room temperature for 10-25 min to form a nucleic acid transfection reagent complex;

[0626] (5) Remove the culture medium from all wells of the 96-well cell culture plate, add the nucleic acid transfection reagent complex, shake the culture plate, and mix gently. Incubate the cells in a 37°C, 5% CO2, 95% air incubator for 24 hours.

[0627] c. Imaging:

[0628] After transfection for 24 hours, observe the cell morphology and take a fluorescent photo with blue light excitation.

[0629] Experimental results:

[0630] The relevant transfection imaging pictures are shown in FIG. 2.

[0631] The results show that the compound of Example 19 has a certain transfection efficiency on EGFP mRNA in the Hela cell model, and the cell transfection efficiency is stronger than that of Example 1.

[0632] Evaluation of Example 3: The drug efficacy of the micellar vaccine of the compound of the application on the TC-1 cervical cancer model in mice

[0633] Experimental animals and inoculation method:

[0634] C57BL / 6 female mice, female, 6-8 weeks old, weight 20-25 grams, after arrival, feed for one week in the experimental environment, 3x10 4 TC-1 cells are inoculated subcutaneously on the right side of the mice, 9-11 days after subcutaneous inoculation, when the tumor volume grows to 40-50mm 3 , start grouping and dosing, 6 mice per group.

[0635] Test sample preparation:

[0636] (1) Dissolve DSPE-PEG2K (PEG-PG) or Example 1 or Example 19, PAL-E7 peptide, MPLA (molar ratio 180:4:3) in 0.8 mL methanol-ethanol (1:1) respectively;

[0637] (2) Rotary evaporation to remove organic reagents, forming a lipid film on the inner wall of the beaker;

[0638] (3) Place the beaker with the formed lipid film and 0.9% NaCl injection in a 80°C water bath for preheating;

[0639] (4) Take 0.8 mL 0.9% NaCl and add it to the beaker, stir at maximum speed for 10 min to form a micellar vaccine.

[0640] Test drug administration:

[0641] The above grouped animals were treated with blank group, control group and vaccine group (PAL-E7, 0.2 mg / kg) respectively, once a week, for a total of three weeks. The tumor volume of the nude mice was measured 2-3 times a week (the formula for calculating the tumor volume is: V = 0.5a x b 2 , a and b represent the long diameter and short diameter of the tumor respectively), the mouse weight was measured, and the data was recorded.

[0642] Pharmacodynamic experiment results:

[0643] The antitumor effect of the vaccine prepared from the compound of the present application on the TC-1 cervical cancer tumor model in mice is shown in Figure 3.

[0644] The experimental results are shown in Figure 3. After 1 administration per week for a total of 3 administrations, and observation for 28 days, the vaccines prepared from Examples 1 and 19 have strong inhibitory effects on the TC-1 cervical cancer tumor model, with tumor inhibition rates of 78.25% and 87.91% respectively, which are superior to the vaccine prepared from PEG-PG (tumor inhibition rate is only 50.47%), and the tumor inhibition effect of the vaccine prepared from Example 19 is superior to that of Example 1.

[0645] Evaluation of Example 4: Pharmacodynamics of the micellar vaccine of the compound of the present application on the TC-1 cervical cancer model in mice

[0646] Experimental animals and inoculation method:

[0647] C57BL / 6 female mice, female, 6-8 weeks old, weight 20-25 grams, after arrival, feed for one week in the experimental environment, 3x10 4 TC-1 cells were inoculated subcutaneously on the right side of the mice, 9-11 days after subcutaneous inoculation, when the tumor volume grew to 40-45mm 3 , the mice were grouped and administered, 6 mice per group.

[0648] Test sample preparation: the preparation of compounds 1, 38, 40, 41, 44 and 45 is the same as in Evaluation Example 2.

[0649] Test drug administration:

[0650] The above grouped animals were treated with blank group, compound group and vaccine group (PAL-E7, 0.2mg / kg) respectively, once a week, for a total of three weeks. The tumor volume of the nude mice was measured 2-3 times a week (the formula for calculating the tumor volume is: V=0.5a×b 2 , a and b represent the long diameter and short diameter of the tumor respectively), the weight of the mice was measured, and the data was recorded.

[0651] Pharmacodynamic test results:

[0652] The tumor inhibition effect of the vaccines prepared from compounds 1, 38, 40, 41, 44 and 45 on the TC-1 cervical cancer tumor model in mice is shown in Table 2.

[0653] Table 2 Tumor inhibition effect of TC-1 cervical cancer tumor model

[0654] The experimental results show that the vaccines prepared from the patent compounds 1, 38, 40, 41, 44 and 45 have strong inhibition effect on the TC-1 cervical cancer tumor model, and are significantly better than the vaccine prepared from the control group PEG-PG, and the compounds in the polysarcosine series are better than the compounds in the PEG series.

Claims

1. A functional material as shown in formula (I) for nano self-assembly and nano drug delivery, wherein: A is an amino acid residue, a polypeptide or a derivative thereof; L 1 , L 2 is absent or a linking unit; P 1 is a hydrophilic moiety; Y 2 is a branching center; Q 2a and Q 2b is a hydrophobic moiety, Q 2a is T 2a -R 1 or is absent, Q 2b is T 2b -R 2 or is absent, Q 2a and Q 2b are present at least one; T 2a , T 2b is absent or a linking unit; R 1 , R 2 is a hydrophobic fragment; a hydrogen connected to carbon in the compound of formula (I), wherein one hydrogen or multiple hydrogens can be replaced by deuterium or any substituent.

2. The functional material for nano self-assembly and nano drug delivery according to claim 1, wherein, one or more of the following conditions are met: (1) L 1 , L 2 is absent or, when present, L 1 , L 2 each independently is an alkane, a heterocyclic alkane, an aromatic hydrocarbon, a heterocyclic aromatic hydrocarbon, a substituted or unsubstituted amino acid or a polypeptide composed thereof, or a plurality of combinations thereof, wherein L 1 , L 2 the functional group linking moiety at each of the two ends is selected from: wherein R La , R Lb , R Lc , R Ld are each independently selected from hydroxyl, C1-C5alkyl or C1-C5alkoxy; R Le is hydrogen, hydroxyl, C1-C5alkyl or C1-C5alkoxy; L 1a 、L 1b each independently is selected from O, NR Lf , S, S-S, or absent, R Lf is hydrogen or C1-C5alkyl; (2) T 2a , T 2b absent or, when present, T 2a , T 2b each independently is an alkane, a heterocyclic alkane, an aromatic hydrocarbon, a heterocyclic aromatic hydrocarbon, a substituted or unsubstituted amino acid or a polypeptide composed thereof, or a plurality of combinations thereof, wherein T 2a , T 2b the functional groups at each of the two ends of the linkage are selected from: wherein L 1a , L 1b are each independently selected from O, NR Lf , S, S-S, substituted or non-substituted methylene, or absent, R Lf is hydrogen or C1-C5alkyl; (3) Y 2 as a multifunctional branching center, selected from the group consisting of multifunctional amino acids, polypeptides, or the following structure: wherein R is selected from hydrogen, deuterium, halogen, nitro, cyano, C1-C10 alkyl, C1-C10 alkoxy, C3-C10 alkenyl, C3-C10 alkynyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C10 aryl, C5-C10 heteroaryl, or a group containing a primary, secondary, tertiary amine, hydroxyl, thiol, carboxyl, ester, amide, boronic acid, boronate ester, phosphonic acid, sulfonic acid, sulfoxide, aldehyde, ketone functional group; y0 selected from hydrogen, deuterium, halogen, nitro, cyano, C1-C10 alkyl, C1-C10 alkoxy, C3-C10 alkenyl, C3-C10 alkynyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C10 aryl, C5-C10 heteroaryl, or a group containing a primary, secondary, tertiary amine, hydroxyl, thiol, carboxyl, ester, amide, boronic acid, boronate ester, phosphonic acid, sulfonic acid, sulfoxide, aldehyde, ketone functional group; R y1 selected from the group consisting of C1-C10 alkyl, C1-C10 alkoxy, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl; R y2 selected from hydrogen, deuterium, halogen, hydroxyl, amino, nitro, cyano, C1-C10 alkyl, C1-C10 alkoxy, C3-C10 alkenyl, C3-C10 alkynyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C10 aryl, C5-C10 heteroaryl, or a group containing a primary, secondary, tertiary amine, hydroxyl, thiol, carboxyl, ester, amide, boronic acid, boronate ester, phosphonic acid, sulfonic acid, sulfoxide, aldehyde, ketone functional group; A1 ring is C6-C20 aryl or C5-C20 heteroaryl; the heteroatom in the C5-C20 heteroaryl is O, S or N, the number of the heteroatom is one or more, when multiple, the heteroatoms are the same or different; E ring is C2-C8 heterocycloalkyl; the heteroatom in the heterocycloalkyl is O, S or N, the number of the heteroatom is one or more, when multiple, the heteroatoms are the same or different; (4) P 1 polyglycerol, a sugar, an oligosaccharide, and a polysaccharide (such as hyaluronic acid, chondroitin sulfate, chitosan, heparin, tea polysaccharide, dextran, polysialic acid, chitosan, dextran, sodium alginate, cellulose, polysucrose, cyclodextrin), a poly sarcosine, a polyphosphoester, a polyglycerol, a polyvinylpyrrolidone, a polyoxazoline, a polyamino acid, a polyacrylic acid residue, a polymethacrylic acid residue, a quaternary ammonium salt derivative, a carboxyl group-containing derivative, a sulfonic acid group-containing derivative, a phosphoric acid group-containing derivative, a zwitterionic derivative, or a zwitterionic polymer; (5) A is selected from natural amino acids and derivatives thereof, unnatural amino acids and derivatives thereof, or polypeptides or derivatives thereof composed of them.

3. The functional material for nano self-assembly and nano drug delivery according to any one of claims 1-2, wherein, one or more of the following conditions are met for the core skeleton of A part: (1) A is selected from natural amino acids and derivatives thereof, natural amino acids include but are not limited to the following amino acids: glycine, alanine, valine, leucine, isoleucine, phenylalanine, proline, serine, threonine, histidine, tryptophan, cysteine, aspartic acid, glutamic acid, lysine, tyrosine, methionine, asparagine, glutamine, arginine, citrulline; the configuration of the amino acid can be D or L type; (2) A is selected from a non-natural amino acid selected from the following structures: wherein R a1 , R a2 , R a6 , R a7 , R a8 are each independently selected from hydrogen, deuterium, hydroxyl, amino, halogen, cyano, Ci-C 10 alkyl, Ci-C 10 alkoxy, C3-C 10 alkenyl, C3-C 10 alkynyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, C6-C 10 aryl, or C5-C 10 heteroaryl; R a3 , R a4 are each independently selected from the group consisting of hydrogen, deuterium, Ci-C 10 alkyl, Ci-C 10 alkoxy, C3-C 10 alkenyl, C3-C 10 alkynyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, C6-C 10 aryl, or C5-C 10 heteroaryl; R a5 selected from hydrogen, C1-C 10 alkyl, C1-C 10 alkoxy, C3-C8cycloalkyl, C2-C8heterocycloalkyl, C6-C 10 aryl or C5-C 10 heteroaryl; or R a1 and R a2 , R a3 and R a4 together with the carbon atom to which they are attached form a C 3-7 monocyclic, bicyclic alkyl or heteroalkane, wherein the heteroatom is N, O, S, P or B; Or R a1 and R a3 R a1 and R a4 R a2 and R a3 R a2 and R a4 Together they form C 3-7 Monocyclic, bicyclic alkyl or heterocyclic alkanes, wherein the heteroatom is N, O, S, P or B; m1, m2, m3, m4 are selected from integers from 0 to 5; (3) A is selected from polypeptide structure, polypeptide is composed of 2-10 amino acids and derivatives thereof, the amino acid residue includes natural amino acid and unnatural amino acid, natural amino acid includes, such as glycine, alanine, valine, leucine, isoleucine, phenylalanine, proline, serine, threonine, histidine, tryptophan, cysteine, aspartic acid, glutamic acid, lysine, tyrosine, methionine, asparagine, glutamine, arginine, citrulline, configuration is D type or L type; unnatural amino acid is as described above (2).

4. The functional material for nano self-assembly and nano drug delivery according to any one of claims 1-3, wherein, P1 is selected from: (1) The polyethylene glycol derivative residue is selected from the following structures: wherein pai is selected from an integer between 5 and 250, prl is selected from an integer between 0 and 8, R p1 is hydrogen, C1-C10alkyl, C1-C10heteroalkyl, C3-C10cycloalkyl, C3-C10alkenyl, C3-C10alkynyl, or a hydroxyl protecting group; Preferably, pai is selected from an integer between 5 and 150, prl is selected from an integer between 0 and 8, R p1 is hydrogen, C1-C10 alkyl or a hydroxyl protecting group; More preferably, pai is selected from an integer between 10 and 60, prl is selected from an integer between 0 and 2, R p1 is C1-C10 alkyl; (2) the poly-myo-inosinic acid derivative residue is selected from the group consisting of the following structures: wherein pb1 is selected from an integer between 5 and 250, R p2 selected from hydrogen, C1-C10 alkyl, C1-C10 alkoxy, C3-C10 alkenyl, C3-C10 alkynyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C10 aryl, C5-C10 heteroaryl or an amine protecting group; R p3 selected from OR p3a or NR p3b R p3c wherein R p3a selected from hydrogen, C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C10 aryl or C5-C10 heteroaryl; R p3b , R p3c are each independently selected from hydrogen, C1-C10 alkyl, C1-C10 alkoxy, C3-C10 alkenyl, C3-C10 alkynyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C10 aryl, C5-C10 heteroaryl, an amine protecting group or R p3b and R p3c form, with the nitrogen atom to which they are both attached, a C3-C10 cyclic structure; R p4 selected from OR p5 , NR p6 R p7 , C1-C10 alkyl, C1-C10 alkoxy, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C10 aryl, C5-C10 heteroaryl; R p5 is selected from hydrogen, C1-C10 alkyl, C1-C10 alkoxy, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C10 aryl, C5-C10 heteroaryl or a hydroxyl protecting group; R p6 , R p7 is selected from hydrogen, C1-C10 alkyl, C1-C10 alkoxy, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C10 aryl, C5-C10 heteroaryl or an amino protecting group, R p6 , R p7 and the nitrogen atom to which they are both attached form a C3-C10 cyclic structure; Preferably, pb1 is selected from an integer between 5 and 150; (3) the quaternary ammonium salt derivative residue is selected from the group consisting of the following structures: wherein pc1 is selected from an integer between 0 and 10, A- is selected from R p3 , R p4 , R p5 each independently is selected from C1-C10 alkyl, C1-C10 alkoxy, C3-C8 cycloalkyl or C2-C8 heterocycloalkyl; (4) Zwitterionic derivatives or zwitterionic polymers: wherein, pd1 is selected from an integer between 5 and 250; R p6 selected from: pc1, pe1 are selected from an integer between 0 and 10, A - selected from R p3 , R p4 , R p5 each independently is selected from C1-C10 alkyl, C1-C10 alkoxy, C3-C8 cycloalkyl, or C2-C8 heterocycloalkyl; L p is absent or is a linking unit selected from an alkane, a heterocycloalkane, an arene, a heterocycloalkane, or various combinations thereof. (5) Polysaccharide polymers: wherein, pf1, pf2, pg1, pg2, ph1, ph2, pi1, pi2 are selected from an integer between 1 and 250.

5. The functional material for nano self-assembly and nano drug delivery according to any one of claims 1-4, wherein: L 1 , L 2 is selected from the absence or, when present, is selected from: wherein L a , L b is a linking moiety between A and the hydrophilic or hydrophobic segment selected from a saturated carbon-carbon bond, an unsaturated carbon-carbon bond, a saturated carbon-nitrogen bond, an unsaturated carbon-nitrogen bond, an azo bond, a carbon-sulfur bond, an ether, an ester, an amide, a sulfonamide, a sulfinamide, a hydrazone, an oxime, a phospholipid, a triazole, an acetal, a hemiacetal; L 4 is an alkane, a heterocyclic alkane, an aromatic hydrocarbon, a heterocyclic aromatic hydrocarbon, a substituted or unsubstituted amino acid or a polypeptide composed thereof, or a plurality of combinations thereof. Preferably, selected from saturated carbon-carbon bond, saturated carbon-nitrogen bond, carbon-sulfur bond, ether, ester or amide; L 4 selected from C1-C10 saturated alkyl, C1-C10 unsaturated alkyl, C1-C10 alkoxy, C3-C10 alkenyl, C3-C10 alkynyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C10 aryl, C5-C10 heteroaryl, or multiple combinations thereof; Y 2 selected from, Preferably, selected from More preferably, selected from L 2 end connection; P 1 a polyethylene glycol derivative residue with a number of repeating units pa1 and an end group R p1 wherein pa1 is selected from the group consisting of integers from 10 to 60, preferably from 15 to 50, for example 21, 22, 44 or 45; R p1 is a C1-C6 alkyl group, preferably a C1-C3 alkyl group, for example methyl, ethyl, n-propyl or i-propyl; or P 1 selected from the group consisting of poly-methyl- alanine derivatives having a number of repeating units of pb1, an end group of R p2 and a residue of a poly-methyl-alanine derivative having a number of repeating units of pb1, an end group of R wherein pbl is selected from an integer between 10 and 60, preferably between 15 and 50; R p2 is selected from hydrogen, C1-C10alkyl, C1-C10alkoxy, C3-C10alkenyl, C3-C10alkynyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, C6-C10aryl, C5-C10heteroaryl, or an amine protecting group; Q 2a is T 2a -R 1 , Q 2b is T 2b -R 2 , T 2a , T 2b , R 1 , R 2 are selected from the group consisting of: wherein, r1a, r1b are selected from an integer from 1 to 30.

6. The functional material for nano self-assembly and nano drug delivery according to any one of claims 1-5, wherein: (1) A is selected from the following structure: Single amino acids: or polypeptides: wherein A a , A b is selected from glycine, alanine, valine, leucine, isoleucine, phenylalanine, proline, serine, threonine, histidine, tryptophan, cysteine, aspartic acid, glutamic acid, lysine, tyrosine, methionine, asparagine, glutamine, arginine, citrulline and derivatives thereof, or 2-8 short peptides in combination thereof; (2) selected from the group consisting of: wherein, x, q are selected from an integer from 10 to 60; pf1, pf2, ph1, ph2 are selected from an integer between 1 and 100; x1 is selected from an integer from 0 to 10; (3) selected from the group consisting of: wherein, x1 is selected from an integer from 0 to 10; y, z, y1, y2, z1, z2, z3 are selected from an integer from 1 to 20.

7. The functional material for nano self-assembly and nano drug delivery according to any one of claims 1-6, wherein, The functional material is selected from the group consisting of compounds having the structure of formula (II) or (III): wherein R pa selected from R p2 or Q 2a , Q 2b , Y 2 , L 1 , L 2 , A, pbl, R p3 are as defined in claims 1-6.

8. The functional material for nano self-assembly and nano drug delivery according to any one of claims 1-6, wherein, The functional material is selected from the group consisting of compounds having the structure of formula (IV) wherein Q 2a , Q 2b , Y 2 , L 1 , L 2 , A, pa1, R p1 are as defined in claims 1-6.

9. The functional material for nano self-assembly and nano drug delivery according to any one of claims 1-6, wherein, selected from the group consisting of:

10. The functional material for nano self-assembly and nano drug delivery according to any one of claims 1-7, wherein, The functional material is selected from the following structures:

11. The functional material for nano self-assembly and nano drug delivery according to any one of claims 1-6 or 8-10, wherein, The functional material is selected from the following structures:

12. The functional material for nano self-assembly and nano drug delivery according to any one of claims 1-11, wherein, The average particle size of the self-assembled nanometer is in the range of 5-500 nanometers; preferably, the average particle size is in the range of 10-100 nanometers.

13. The functional material for nano self-assembly and nano drug delivery according to any one of claims 1-12, wherein the functional material can deliver small molecule drugs, polypeptide drugs, macromolecule drugs, proteins, antibodies, nucleic acid drugs, vaccines, gene drugs and nuclide drugs through self-assembly.

14. The functional material for nano self-assembly and nano drug delivery according to claim 13, wherein the functional material can deliver small molecule drugs, polypeptide drugs, macromolecule drugs, proteins, antibodies, nucleic acid drugs, vaccines, gene drugs and nuclide drugs through covalent cleavable or non-cleavable coupling.

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