Star-shaped pAsp-oligoamine derivatives

Abstract

The present disclosure relates to three-arm star-shaped polycationic charged polymers consisting of a 1,3,5-benzenetricarboxamide related central core and three polypeptide backbone arms, and their use as carriers for the delivery of active agents such as nucleic acids.

Description

[Technical field]

[0001] This application claims the benefit of European patent application EP21382666.2, filed on July 22, 2021.

[0002] The present disclosure relates to three-arm star polypeptide derivatives capable of delivering active agents and / or imaging agents to target cells or tissues, more specifically, the present invention relates to three-arm star polycationic charged polymers and their use as carriers for the delivery of active agents such as nucleic acids and / or imaging agents. [Background technology]

[0003] Considerable effort has been expended on the development of novel polymeric structures with specific properties for use as delivery systems for targeted drugs, including large molecules such as polypeptides and nucleic acids.

[0004] Several polycationic charged polymers have been described that spontaneously form spherical micelles or nano-objects with anionic macromolecules due to electrostatic interactions acting between the two in aqueous / buffered media.

[0005] EP 3331937 discloses a family of three-arm star polypeptide derivatives consisting of a 1,3,5-benzenetricarboxamide-related central core used as an initiator for the ring-opening polymerization of N-carboxyanhydride monomers and three polypeptide backbone arms. The polypeptide backbone of the compounds described therein is different from that disclosed herein. According to EP 3331937, the three-arm star polypeptide derivatives undergo a self-assembly process to generate larger nanometric spherical structures with a rigid globular shape with outwardly directed branch points. In the three-arm star polypeptide derivatives according to formula (II) described in the above specification, only 0.01% to 50% of the glutamic acid units of St-PGA are modified.

[0006] It is well known that gene therapy requires an appropriate technique for the delivery of nucleic acid molecules to target cells due to their low in vivo stability.For example, a technique for the delivery of nucleic acid is known in the past, which uses a block copolymer having a hydrophilic polymer segment and a cationic polymer segment to form a complex (polyion complex) with nucleic acid through electrostatic interaction.

[0007] An example of a known cationic polyamino acid includes linear poly(N-[N-(2-aminoethyl)]aspartamide) (PAsp(DET)), which has an ethylenediamine structure in its side chain and a block copolymer containing PAsp(DET) as one block component. PAsp(DET) is known to form polyplexes with nucleic acids and facilitate the introduction of plasmid DNA into cells with high efficiency, thereby expressing genes encoded in the nucleic acid. Other linear PAsp(DET) derivatives are also known to form polyplexes.

[0008] From what is known in the art, there remains a need to discover new carriers for the specific and controlled delivery of active and / or imaging agents to target cells or tissues. Summary of the Invention

[0009] The present disclosure is made to solve the problems of the related art, and the main objective of the present disclosure is to provide a novel carrier for biomedical applications. In particular, the three-arm star polypeptide derivatives can deliver active agents and / or imaging agents to target cells or tissues.

[0010] The three-arm star polypeptide derivatives of the present disclosure are three-arm star polycationically charged polymers consisting of a 1,3,5-benzenetricarboxamide related central core and three polypeptide backbone arms.

[0011] In the context of the present invention, the term "cationically charged", "polycationically charged" or equivalent terms refer to polymers having amino protonatable (i.e. cationic) groups in the side chains, i.e. polymers that are already cationized by hydrogen ion coordination, but also contain amino groups that will become cationic upon gaining a hydrogen ion. Polypeptides having cationic groups in the side chains include polypeptides obtained by peptide linkage of known amino acids having basic side chains (e.g. lysine, arginine, histidine, ornithine, proline, etc.) as well as polypeptides obtained by peptide linkage of any amino acid and subsequent substitution in its side chain to have a cationically charged group.

[0012] The three-dimensional structuring and subsequent supramolecular organization of non-viral vectors have been shown to be key features for increasing the efficiency of the transfection process. Vectors based on liposomes, polymersomes, comb-like structures, or dendrimers have been shown to have better transfection efficiency than simple cationic polymer systems. This difference is mainly based on the higher density of the vector's surface, as well as its greater ability to condense DNA, facilitating fixation and enhancing its transfection capacity.

[0013] Among vectors that adopt three-dimensional structures, cationically charged star-shaped polymers have been investigated in recent years and shown to be very promising non-viral vectors. Polyplexes based on star systems exhibit well-defined structures with predictable structure and conformation (usually spherical, facilitating endocytosis and maximizing the transfection process), high homogeneity, high multivalency, multifunctionality, and responsiveness to stimuli, as well as greater encapsulation capacity, better solubility, and tunable physical properties in terms of rheological, mechanical, and thermal properties. Moreover, these structures allow for more precise control of the supramolecular morphology, which may result in improved biodistribution, pharmacokinetics, and improved penetration of biological barriers.

[0014] A first aspect of the present disclosure relates to any stereoisomer or mixture of stereoisomers of a compound of formula (I), a pharma- ceutically acceptable salt thereof, or any of the compounds of formula (I) or a pharma- ceutically acceptable salt thereof, including homopolypeptides or random or block or graft copolypeptides; [ka] wherein A, A', and A'' are each independently selected from radical groups of formula II; each of the A, A', and A'' subunits can be the same or different; [ka] where the wavy lines indicate the attachment points; Also, although the repeat units defined by the brackets and their numerical values ​​r, s, t, and u in Formula II are shown in a particular order for convenience of illustration, the repeat units can be present in any order, the repeat units can be present in blocks or randomly, and each of the repeat units can comprise blocks of monomer units which can be the same or different from one another; wherein K, K', and K'' are each independently selected from -O- and -NH-; L is selected from: [ka] where α, α', and α'' are integers from 0 to 1; each wavy line indicates a point of attachment to A, A', or A''; and "*" indicates a point of attachment to K, K', or K''; R2 is selected from -O- and -NH-; R1 is a biradical selected from the group consisting of (III) and (IV); [ka] where the wavy lines indicate the attachment points; where y and z are independently integers ranging from 1 to 20; X is -NH-, -NH(C 1 ~C6 )Alkyl-, -O-, -(C 1 ~C6) alkyl-COO-, linear or branched -(C 1 ~C 30 ) alkylene-, and a biradical selected from the group consisting of (V), (VI), (VII), (VIII), (IX), (X), (XI), and (XII); [ka] Here, * " indicates the attachment point; In the formula, X is -(C 1 ~C 30 ) Alkylene biradicals are -OH, -NR a R b , -SH, -NHNH 2 , -COOR c , -CF 3 , -OCF 3 and halogen; R a , R b and R c is H, -phenyl, -(C 1 ~C 30 ) alkyl, -(C 2 ~C 30 ) alkenyl, -(C 1 ~C 30 ) alkylphenyl, and -phenyl(C 1 ~C 30 ) alkyl; where a and a' are independently integers ranging from 0 to 1; r, s, t, and u are independently integers ranging from 0 to 500, and at least one of r or t is 1 or greater; wherein in the radical of formula (II), the repeat unit defined by the square brackets having the numerical value r is designated as PAA1; the repeat unit defined by the square brackets having the numerical value s is designated as PAA2; the repeat unit defined by the square brackets having the numerical value t is designated as PAA3; and the repeat unit defined by the square brackets having the numerical value u is designated as PAA4; wherein the molar ratio of PAA1 monomer to PAA2 is 100 / 0 to 60 / 40; wherein the molar ratio of PAA1 monomer to PAA4 is 100 / 0 to 60 / 40; wherein the molar ratio of PAA3 monomer to PAA4 is 100 / 0 to 60 / 40; wherein the molar ratio of PAA3 monomer to PAA2 is 100 / 0 to 60 / 40; the molar ratio of the sum of PAA1+PAA3 monomers to the sum of PAA2+PAA4 is 100 / 0 to 60 / 40; R 9 and R 17 is H, -(C 1 ~C 30 ) alkyl, -(C 2 ~C 30 ) alkenyl, -(C 1 ~C 30 ) Alkyl-R i1 , -(C 1 ~C 30 )Alkyl-COOR ii1 , -(C 1 ~C 30 )Alkyl-O Riii1 , -(C 1 ~C 30 )Alkyl-NR iv1 R v1 , -C(O)-R vi1 , -(C 1 ~C 12 )Alkyl-CO-NH 2 and a radical selected from the group consisting of (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), and (XXI); [ka] Here, * " indicates the attachment point; R i1 is H, -(C 1 ~C 30 ) alkyl, -(C 2 ~C 30 ) alkenyl, -(C 2 ~C 30 ) Alkynyl, halogen, -CF 3 , -OCF 3 , isoxazole, oxazole, furan, oxolane, thiol, thiophene, N-methylpyrrole, pyrrole, pyrrolidine, pyran, pyridine, piperidine, thiazole, dioxane, morpholine, pyrimidine, -NH 2 , -N((C 1 ~C 30 )Alkyl) 2 , -NH(C 1 ~C 30 ) alkyl, -NHC(O)-(C 1 ~C 30 ) alkyl, -NHC(O)O(C 1 ~C 30 ) alkyl, -NHC(O)NH 2 , -NHC(O)N(CH 3 ) 2 , -NHS(O) 2 (C 1 ~C 30 ) Alkyl, -NHSO 2 NH 2 , -C(O)(C 1 ~C 30 ) alkyl, -CON((C 1 ~C 30 )Alkyl) 2 ;-NO 2 , -CN, -OC(O)-(C 1 ~C 30 ) alkyl, -OC(O)O(C 1 ~C 30 ) alkyl, -OC(O)NH 2 , -OC(O)N((C 1 ~C30 )Alkyl) 2 , -SeH, -SH, -S(C 1 ~C 30 ) alkyl, -S(O)H, -S(O)(C 1 ~C 30 ) alkyl, and -SO 2 (C 1 ~C 30 ) alkyl; R vii1 is H, -(C 1 ~C 30 ) alkyl, -(C 2 ~C 30 ) alkenyl, -(C 2 ~C 30 )Alkynyl, -Oalkyl(C 1 ~C 12 ), F, Cl, Br, I, -CF 3 , -OCF 3 , -NO 2 , -CN, -NH 2 , -(C 1 ~C 30 ) AlkylNH 2 , -N((C 1 ~C 30 )Alkyl) 2 , and -NH(C 1 ~C 30 ) alkyl; R ii1 , R iii1 , R iv1 and R v1 is H, -OH, -(C 1 ~C 30 ) alkyl, -(C 1 ~C 30 ) AlkylNH 2 , -(C 1 ~C 30 )Alkyl-N((C 1 ~C 30 )Alkyl) 2 , and -(C 1 ~C 30 )Alkyl-NH(C 1 ~C 30 ) alkyl; Rvi1 is H, -OH, -(C 1 ~C 30 ) alkyl, -(C 2 ~C 30 ) alkenyl, -(C 1 ~C 30 ) AlkylNH 2 , -NH 2 , -(C 1 ~C 30 )Alkyl-N((C 1 ~C 30 )Alkyl) 2 , -NH(C 2 ~C 30 ) alkenyl, -(C 1 ~C 30 )Alkyl-NH(C 1 ~C 30 ) alkyl, -NH-oleic acid, -NH-noneic acid, and -NH-lipoic acid; In the formula, R i1 , R ii1 , R iii1 , R iv1 , R v1 , R vi1 , and R vii1 teeth, -OH, Halogen, -O(C 1 ~C 30 ) alkyl, -CF 3 , -OCF 3 , -NH 2 , -(C 1 ~C 30 ) Alkyl, -SH, -NHNH 2 , -NHCH 3 , -N(CH 3 ) 2 , -NCH(CH 3 ) 2 and -(C 1 ~C 30 ) alkyl-OH; b1, c1, d1, e1, f1, g1, h1, i1, and j1 are independently integers ranging from 1 to 20; wherein W1 and W2 are each independently selected from CH and N; R 6 , R 7 , R 14 , R 15 and R 19 is H, -(C 1 ~C 30 ) alkyl, -(C 2 ~C 30 ) alkenyl, -(C 2 ~C 30 ) alkynyl, -(C 1 ~C 30 ) Alkyl-R i2 , -(C 1 ~C 30 )Alkyl-OR iii2 , -(C 1 ~C 30 )Alkyl-NR iv2 R v2 , -C(O)-R vi2 and radicals selected from the group consisting of (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), and (XXXI); [ka] Here, * " indicates the attachment point; R i2 is H, -(C 1 ~C 30 ) alkyl, -(C 2 ~C 30 ) alkenyl, -(C 2 ~C 30 )Alkynyl, -Oalkyl(C 1 ~C 6 ), halogen, -CF 3 , -OCF 3 , isoxazole, oxazole, furan, oxolane, thiol, thiophene, N-methylpyrrole, pyrrole, pyrrolidine, pyran, pyridine, piperidine, thiazole, dioxane, morpholine, pyrimidine, -NO 2, -CN, -OC(O)-(C 1 ~C 30 ) alkyl, -OC(O)O(C 1 ~C 30 ) alkyl, -OC(O)NH 2 , -OC(O)N((C 1 ~C 30 )Alkyl) 2 , -SH, -S(C 1 ~C 30 ) alkyl, -S(O)H, -S(O)(C 1 ~C 30 ) alkyl, and -SO 2 (C 1 ~C 30 ) alkyl; R iii2 , R iv2 , and R v2 teeth, H, -(C 1 ~C 30 ) alkyl, -(C 2 ~C 30 ) alkenyl, -(C 1 ~C 30 ) AlkylNH 2 , -(C 1 ~C 30 )Alkyl-N((C 1 ~C 30 )Alkyl) 2 , -(C 1 ~C 30 )Alkyl-NH(C 1 ~C 30 ) alkyl, and a radical selected from the group consisting of (XXXII), (XXXIII), (XXXIV), (XXXV), (XXXVI), (XXXVII), (XXXVIII), (XXXIX), (XL), (XLI), (XLII), (XLIII), (XLIV), (XLV), and (XLVI); [ka] In the formula, R viii2 , R ix2 , Rviii2’ , and R ix2’’ teeth, H, -(C 1 ~C 12 ) alkyl, -(C 1 ~C 12 ) AlkylNH 2 , -(C 1 ~C 12 )Alkyl-N((C 1 ~C 12 )Alkyl) 2 , -(C 1 ~C 12 )Alkyl-NH(C 1 ~C 12 ) alkyl, -O(C 1 ~C 12 ) alkyl, -COH, -CO(C 1 ~C 12 ) alkyl, and -O(C 2 ~C 30 ) alkenyl; R vii2 and R vii2’ is H, -(C 1 ~C 30 ) alkyl, -(C 2 ~C 30 ) alkenyl, -(C 2 ~C 30 )Alkynyl, -Oalkyl(C 1 ~C 12 ), F, Cl, Br, I, -CF 3 , -OCF 3 , -NO 2 , -CN, -NH 2 , -(C 1 ~C 30 ) AlkylNH 2 , -N((C 1 ~C 30 )Alkyl) 2 , and -NH(C 1 ~C 30 ) alkyl; R vi2 teeth, H, -OH, -(C 1 ~C 30 ) alkyl, -(C 2 ~C30 ) alkenyl, -(C 1 ~C 30 ) alkyl-COOH, -(C 2 ~C 30 ) alkenyl-COOH, -(C 1 ~C 30 ) AlkylNH 2 , -NH 2 , -(C 1 ~C 30 )Alkyl-N((C 1 ~C 30 ) alkyl) 2, -O-(C 1 ~C 30 ) alkyl, -NH(C 2 ~C 30 ) alkenyl, -(C 1 ~C 30 )Alkyl-NH(C 1 ~C 30 ) alkyl, -NH-oleic acid, -NH-noneic acid, -NH-lipoic acid, and -CH=CH(COOH)-CH 2 -COOH; During the ceremony, Alk 2 , Alk 22 , Alk 2 ’ and Alk 22 ’ is a straight or branched chain -(C 1 ~C 30 ) alkyl and straight or branched chain -(C 2 ~C 30 ) alkenyl, 2 and β 2 ' are each independently an integer from 0 to 6; 2 and X 2’ are each independently selected from -NH-, -COO-, and O-; In the formula, R i2 , R iii2 , R iv2 , R v2 , R vi2 , R vii2 , R viii2 , R ix2 , Rviii2’ , and R ix2’ is H, OH, Halogen, -O(C 1 ~C 30 ) alkyl, -CF 3 , -OCF 3 , -NH 2 , -(C 1 ~C 30 ) alkyl, -(C 2 ~C 30 ) alkenyl, -(C 2 ~C 30 ) Alkynyl, -SH, -NHNH 2 , -NHCH 3 , -N(CH 3 ) 2 , -NCH(CH 3 ) 2 and -(C 1 ~C 30 ) alkyl-OH; b2, c2, d2, e2, h2, k2, l2, k2', l2', b2'', c2'', d2'', e2'', and h2'' are independently integers ranging from 1 to 20; b2', c2', d2', e2', and h2' are independently integers ranging from 0 to 20; m2, n2, m2', and n2' are independently integers ranging from 1 to 200; R 3 , R 4 , R 11 and R 13 is -(C 1 ~C 6 ) alkyl-, -(C 1 ~C 6 ) alkyl-SS-(C 1 ~C 6 ) alkyl-, -(C 1 ~C 6 )Alkyl-O-(C 1 ~C 6 ) alkyl-, and -(C 1 ~C 6 ) alkyl-NH-(C 1 ~C6 ) alkyl; Here, R 3 , R 4 , R 11 and R 13 is -NH 2 and -(C 1 ~C 6 )Alkyl-NH 2 optionally substituted with one or more substituents selected from the group consisting of: However, when a=1, R 3 does not exist, and if a'=1, then R 11 does not exist; R 5 , R 8 , R 10 , R 12 , R 16 and R 18 is H and -(C 1 ~C 6 ) alkyl; In the formula, R 9 and R 10 are optionally combined together to form a proline ring moiety; R17 and R18 are optionally combined together to form a proline ring moiety.

[0015] As stated above, each of the repeat units defined by the brackets, i.e., PAA1, PAA2, PAA3 and PAA4, respectively having numerical values ​​r, s, t and u, may comprise blocks of monomer units that may be the same or different from each other. Thus, formula I defined above encompasses compounds that may comprise repeat units defined by the brackets, where each of the monomer units may comprise the same or different substituents. When the monomer units present in the same repeat unit PAAn are the same, the repeat unit is a "homopolymer", and when the monomer units present in the same repeat unit PAAn comprise different substituents, the repeat unit is a "copolymer", which may be a "random copolymer" or a "block copolymer".

[0016] For purposes of the present invention, the term "homopolymer" refers to a polymer derived from a single monomer. The term "copolymer" as used herein refers to a polymer derived from two or more monomers. A copolymer may be a random or block copolymer. The term "random copolymer" as used herein refers to a copolymer in which the monomer units are randomly arranged in the polymer molecule. The term "block copolymer" as used herein refers to a copolymer that includes at least two different monomer units that upon polymerization form at least two chemically distinct regions, segments, or blocks that are chemically distinguishable from one another. The term block copolymer includes linear block copolymers, multiblock copolymers, and star block copolymers.

[0017] A second aspect of the present disclosure relates to a conjugate comprising a compound of formula (I) as defined above, which is covalently attached to at least one labeling or imaging agent or to at least one cell targeting agent.

[0018] A third aspect of the present disclosure relates to a polymer complex comprising a compound of formula (I) or a conjugate according to the second aspect as defined above, and one or more active agents selected from the group consisting of pharmaceutical active agents, veterinary active agents, cosmetic active agents, nucleic acids, peptides, proteins, antibodies, aptamers, and mixtures thereof.

[0019] The at least one active agent(s) may be covalently attached directly or through one or more linkers, or the at least one active agent(s) may be non-covalently attached to the compound.

[0020] A further embodiment relates to particles comprising a compound of formula (I) as defined herein, and optionally one or more active agents selected from the group consisting of pharma- ceutical active agents, cell targeting agents, labeling agents, imaging agents, penetration enhancers, cosmetic active agents, diagnostic active agents, nucleic acids, peptides, proteins, antibodies, aptamers, and mixtures thereof.

[0021] The term "non-covalent bonds" as used herein refers to bonds that do not involve the sharing of electrons, but rather a more diffuse variation of electromagnetic interactions between molecules. Non-covalent bonds can be classified into various categories, such as electrostatic interactions, π interactions, van der Waals forces, hydrogen bonds, and hydrophobic effects.

[0022] In a preferred embodiment, at least one active agent is covalently linked to the polypeptide backbone via an amino acid side residue via an amide, ester, anhydride bond, or via a linker containing one or more functional groups, including, but not limited to, alkyne, azide, reactive disulfide, maleimide, hydrazide, hydrazone, Schiff base, acetal, aldehyde, carbamate, and reactive ester. In an alternative embodiment, the covalent linkage is bioresponsive.

[0023] In another preferred embodiment, the active agent(s) is linked to the polypeptide backbone via electrostatic interaction.Thus, anionic compounds with more negative charges than positive charges can form polymer complexes with the compound of formula (I) via electrostatic interaction when mixed in aqueous medium.Examples of anionic compounds include proteins, polysaccharides, lipids, and nucleic acids.

[0024] The conditions for preparation, such as the aqueous medium, pH, temperature, ionic strength, etc., can be appropriately adjusted by those skilled in the art.

[0025] According to a particular embodiment, the polymer complex is obtained upon mixing in an aqueous medium at a pH in the range of 4 to 9, preferably in the range of 4.5 to 8.5, more preferably in the range of 5 to 7.5, and particularly preferably in the range of 6.5 to 7.4. The pH can be easily adjusted using a buffer as the solvent.

[0026] According to a specific embodiment, the ionic strength of the solution to be mixed can be appropriately adjusted within a range that does not destroy the structure of the nanoparticles or inhibit the inclusion of the substance to be encapsulated in the nanoparticles, and is preferably within the range of 0 to 1000 mM, preferably 0 to 300 mM, more preferably 0 to 150 mM, and particularly preferably 0 to 50 mM.

[0027] According to certain embodiments, the average molecular weight (Mw) of the compounds according to the invention is in the range of 400 Da to 500 kDa, preferably 1 kDa to 150 kDa, more preferably 5 kDa to 100 kDa, or 1 kDa to 50 kDa, as measured by gel permeation chromatography-refractive index-multi-angle light scattering-visible-ultraviolet (GPC-RI-MALS-UV).

[0028] According to certain embodiments, the at least one active agent is selected from the group consisting of low molecular weight drugs, peptides, antibodies, hormones, enzymes, nucleic acids, proteins, and combinations thereof.

[0029] According to certain embodiments, the polymer complex (also referred to herein as polyplex) comprises a compound of formula (I) according to the first aspect of the present disclosure and at least a nucleic acid. In certain embodiments, the polymer complex comprises a compound of formula (I) according to the first aspect of the present disclosure and one nucleic acid. In another particular embodiment, the polymer complex comprises a combination of a compound of formula (I) according to the first aspect of the present disclosure and two or more nucleic acids.

[0030] The compounds of formula (I) carry a positive charge from the cationic groups and are therefore capable of forming complexes with negatively charged nucleic acids through electrostatic interactions.

[0031] As used herein, the term "nucleic acid" refers to DNA or RNA.In certain embodiments, nucleic acid is DNA / RNA hybrid, short interfering RNA (siRNA), microRNA (miRNA), single-stranded RNA (sgRNA), donor DNA, self-amplifying / replicating RNA, circular RNA (oRNA), plasmid DNA (pDNA), closed linear DNA (clDNA), short hairpin RNA (shRNA), messenger RNA (mRNA), and antisense RNA (aRNA), messenger RNA (mRNA), CRISPR guide RNA, antisense nucleic acid, decoy nucleic acid, aptamer, and ribozyme, to name a few, and includes both nucleotide sequence and any structural aspect thereof, such as double-stranded, single-stranded, helical, hairpin, and may include modified or unmodified bases.

[0032] When separate nucleic acids are provided, they may be all DNA molecules or all RNA molecules, or may be molecules that contain a mixture of DNA and RNA molecules or an association of DNA and RNA strands.

[0033] The nucleic acid may be a poly or oligonucleotide, such as an oligo or poly double-stranded RNA, an oligo or poly double-stranded DNA, an oligo or poly single-stranded RNA, an oligo or poly single-stranded DNA, etc. Each of the nucleotides contained in the nucleic acid may be a naturally occurring nucleotide or a chemically modified non-natural nucleotide.

[0034] The length of the nucleic acid is not particularly limited, and the nucleic acid may have a short chain in the range of 10 to 200 bases, preferably 20 to 180 bases, preferably 25 to 100 bases, preferably 30 to 50 bases; or the nucleic acid may have a relatively long chain of 200 to 20,000 bases, more preferably 250 to about 15,000 bases.

[0035] According to certain embodiments, the nucleic acid is a closed linear DNA (clDNA), i.e. a molecule in which the double-stranded region is flanked and protected by two single-stranded loops, thereby generating a dumbbell-shaped molecule.

[0036] In a more particular embodiment, the clDNA consists of a stem region comprising a double-stranded DNA sequence of interest covalently closed at both ends by hairpin loops, wherein the clDNA comprises at least two modified nucleotides.

[0037] As used herein, the term "closed linear DNA" or "clDNA" refers to a single-stranded DNA molecule that is covalently closed, forming a "dumbbell" or "doggybone" shaped structure under conditions that allow nucleotide hybridization. Thus, clDNA is formed by a single-stranded DNA molecule, but the formation of the "dumbbell" structure by hybridization of two complementary sequences within the same molecule produces a structure consisting of a double-stranded intermediate segment flanked by two single-stranded loops. Those skilled in the art will recognize how to generate clDNA from open or closed double-stranded DNA using routine molecular biology techniques. For example, those skilled in the art will recognize that clDNA can be generated by attaching a hairpin DNA adaptor to both ends of an open double-stranded DNA, for example, by the action of a ligase. A "hairpin DNA adaptor" refers to a single-stranded DNA that forms a stem-loop structure by hybridization of two complementary sequences, the stem region formed being closed at one end by a single-stranded loop and open at the other end.

[0038] A "modified nucleotide" is any nucleotide (e.g., adenosine, guanosine, cytidine, uracil, and thymidine) that has been chemically modified by modification of the base, sugar, or phosphate group, or that incorporates a non-natural moiety into its structure. Thus, modified nucleotides can be naturally occurring or non-naturally occurring, depending on the modification.

[0039] The polymer complexes of the present disclosure constitute useful tools for therapeutic or diagnostic indications, the compounds of formula (I) as defined herein acting as non-viral vectors for the delivery of active agents, resulting in the improvement of certain properties such as; transfection efficiency into the desired cells, safety or toxicological profile, or release profile in physiological conditions.

[0040] The polymer complex may have a particle size in the range of 10 nm to 2000 nm, preferably 20 nm to 800 nm, more preferably 25 nm to 350 nm, 30 nm to 300 nm, or 30 nm to 200 nm.

[0041] The polymer complex may be prepared by mixing the compound of formula (I) or the conjugate according to the second aspect of the disclosure with the active ingredient in an optionally buffered aqueous solution.

[0042] According to some embodiments, the polymer complex is a nanoparticle, a micelle, a cylindrical micelle, a reverse micelle, a vesicle, or a liposome.

[0043] The compounds of the present invention can be formulated in various compositions, including pharmaceutical, veterinary, cosmetic and diagnostic compositions, together with excipients and carriers.Accordingly, an additional aspect of the present disclosure relates to a composition comprising at least one conjugate or polymer complex as defined herein together with one or more pharmaceutical, veterinary, cosmetic or diagnostic acceptable excipients or carriers.

[0044] The conjugates and polymers of the present invention can be used in pharmaceutical, cosmetic and diagnostic applications. Thus, a further aspect of the present disclosure relates to a conjugate, polymer complex or composition of the present disclosure for use as a medicament.

[0045] This aspect also relates to a pharmaceutical composition comprising: a) a conjugate as defined herein; in particular a conjugate comprising a radical derived from a compound of formula (I) as defined above, which is covalently attached to a cell targeting agent; or b) a polymer complex as defined herein; or c) a composition as defined herein The compound can be formulated as a therapeutic product comprising:

[0046] This aspect of the disclosure can be reformulated as the use of a conjugate, polymer complex, or pharmaceutical composition of the disclosure for the manufacture of a medicament.

[0047] This embodiment may also be formulated as a method for the treatment, diagnosis, prevention and / or theranostics of disease, comprising administering to a subject, including a human, in need thereof a therapeutically, diagnostically, prophylactically and / or theranostically effective amount of the polymer complex of the third aspect of the present disclosure, or the pharmaceutical composition of the fifth aspect of the present disclosure, together with one or more suitable pharma- ceutical , veterinarily or cosmetically acceptable excipients and / or carriers.

[0048] Another aspect of the invention relates to a diagnostic product which is: a) a conjugate comprising a radical derived from a compound of formula (I) as defined above, covalently attached to at least one labelling or imaging agent; or b) a diagnostic or therapeutic composition as defined above, for use in diagnosis.

[0049] Another aspect of the present invention relates to the use in cosmetics of a cosmetic product which is a) a polymer complex as defined above, in which the active agent is a cosmetically active agent, or b) a cosmetic composition as defined above.

[0050] Another aspect of the present invention relates to the use of a compound of formula (I) as defined herein, as a carrier.

[0051] In the present invention, the "subject" may be a mammal, including a human. The subject may be a healthy subject or a subject suffering from any disease.

[0052] In the present invention, "treatment" refers to curing, preventing or inducing remission of a disease or disorder, or slowing the rate of progression of a disease or disorder. Treatment can be achieved by administering a therapeutically effective amount of a pharmaceutical composition.

[0053] When the method refers to diagnosis, this embodiment can also be formulated as a method for diagnosing disease in an isolated sample of a subject, the method comprises administering an effective amount of any of the polymer complexes to said subject or to an isolated sample of a subject with a pharmaceutical composition having one or more imaging agents as defined above.The detection of these imaging agents can be performed by well-known techniques, such as imaging diagnostic techniques.Examples of imaging diagnostic techniques suitable for the present disclosure include, but are not limited to, ultrasound imaging, magnetic resonance imaging (MRI), fluoroscopy, X-ray, positron emission tomography (PET), single photon emission computed tomography (SPECT), fluorescence microscopy, and in vivo fluorescence.

[0054] Therefore, the present disclosure also relates to the use of the compound, the polymer complex or the pharmaceutical composition according to the first aspect of the present disclosure as a bioimaging tool, in particular for tracking the internalization and delivery of an active or imaging agent.

[0055] "Bioimaging tools" are to be understood by this description as reagents used in imaging techniques used in biology to track cells or certain compartments of a particular tissue. Examples of bioimaging tools include chemiluminescent compounds, fluorescent and phosphorescent compounds, compounds that emit X-rays or alpha, beta or gamma rays, etc.

[0056] A further aspect of the present disclosure relates to the use of the polymer complexes defined herein as non-viral vectors commonly used in biomedical applications, such as vaccines or gene therapy, which are effective for transfection of host eukaryotic cells in culture, in vivo or ex vivo, unicellular parasites and bacteria, including gene editing using the CRISPR / Cas9 approach.

[0057] In a particular embodiment, the present invention relates to the use of the polymer complexes defined herein as transfection reagents for delivering active agents (preferably nucleic acids, circular and linear nucleic acids, regardless of size and structure) to target cells in vivo, in vitro or ex vivo. In a particular embodiment, the active agent is selected from the group consisting of low molecular weight drugs, peptides, proteins, antibodies, nucleic acids, aptamers, and combinations thereof.

[0058] The above transfection reagents are also useful for co-transfection of two or more active agents, such as two or more nucleic acids, simultaneously.

[0059] Transfection compositions (such as kits) and methods of using the transfection reagents to deliver nucleic acids to target cells are also within the scope of the invention. Further embodiments will be apparent upon review of this disclosure.

[0060] The present invention also relates to methods for delivering active agents in vitro, ex vivo, and in vivo that involve using the polymer complexes disclosed herein.

[0061] The present invention also relates to a method of transfecting a cell comprising contacting the cell with a polymer complex disclosed herein. The present invention also relates to a polymer complex or pharmaceutical composition as defined herein for use in a method of delivering a nucleic acid into a target cell, comprising contacting an animal, including a human, with a solution comprising a polymer complex or pharmaceutical composition as defined herein along with a target cell, such that the complex may be introduced into the target cell; transferring the complex from an endosome to the cytoplasm; dissociating the complex in the cell; and releasing the nucleic acid into the cytoplasm.

[0062] The present invention also provides the composition for use as a pharmaceutical composition to induce a modulatory effect on the expression of one or more target proteins that cause or are involved in genetic inherited or complex genetic diseases, immune diseases, cancer, viral infections in various tissues / organs, or tumors.

[0063] The present invention also relates to the in vitro or ex vivo use of the composition according to the present invention in the manufacture of biological products, in particular biological products that code recombinant protein, peptide or antibody; or in the production of recombinant virus, such as adeno-associated virus (AAV), lentivirus (LV), adenovirus, oncolytic virus, baculovirus, or virus or virus-like particle, the composition comprises polymer complex as defined herein and comprises at least one nucleic acid molecule for transfection.As used herein, the term "biological product" refers to protein or nucleic acid or their combination, biological entity such as cell or virus, cell compartment, organoid, and tissue.

[0064] The present invention also relates to the in vitro or ex vivo use of the polymer complexes according to the invention for genome engineering, for cell reprogramming, for cell differentiation or gene editing.

[0065] Compositions for transfecting cells include a polymer complex as defined herein and an acceptable excipient, buffer, cell culture medium, or transfection medium.

[0066] The present invention also relates to the composition defined herein for use as a therapeutic or preventive vaccine against viral infection, or a therapeutic vaccine against cancer.Generally, in this aspect, the vaccine is delivered by direct administration, such as systemic administration, intramuscular administration, intradermal administration, intraperitoneal administration, intratumoral administration, oral administration, topical administration, or subcutaneous administration, in which the composition is combined with a pharmaceutically acceptable vehicle.In other words, the vaccine can be directly injected into the body, particularly into a human individual, to induce cellular and / or humoral response.

[0067] Cellular targeting is achieved through a variety of mechanisms and depends on the nature and characteristics of the transfection reagent, the composition or formulation of the method or protocol, and the route of administration.

[0068] In a more particular embodiment, the present invention relates to a polymer complex for use in the prevention and / or treatment of various diseases such as neurodegenerative diseases, neurological diseases, cancer, infectious diseases, ageing-related diseases, neuroinflammation, demyelinating diseases multiple sclerosis, ischemic disorders, immune disorders, inflammatory disorders, rare diseases, among others, depending on the active agent it carries.

[0069] The compounds described in the present disclosure, their pharma- ceutically acceptable salts and solvates, and pharmaceutical compositions containing them, can be combined with other additional drugs to provide combination therapy.These additional drugs can be part of the same pharmaceutical composition or can be provided in the form of separate compositions for simultaneous or non-simultaneous administration with the pharmaceutical composition containing the compound of formula (I), its pharma- ceutically acceptable salts, stereoisomers, or solvates.

[0070] A further aspect of the present disclosure relates to the use of a compound of formula (I) as defined herein as a carrier.

[0071] A further aspect of the present disclosure relates to a device, for example for delivering an active agent, preferably a nucleic acid, into a cell, which comprises a polymer complex of the present disclosure.

[0072] This embodiment may also be formulated as a device for use in a method of delivering a nucleic acid into a cell, the device comprising a polymer complex as defined herein.

[0073] As will be appreciated by those skilled in the art, the appropriate device for delivering active agent into cells will depend on the formulation of the selected composition or pharmaceutical composition and / or the desired administration site.For example, if the formulation of the composition is suitable for injection in a subject, the device can be a syringe.As another example, if the desired administration site is a cell culture medium, the device can be a sterile pipette.As yet another example, if the desired administration site is a vein or artery, the device can be a graft.As yet another example, if the desired administration site is a subcutaneous or organ-specific depot, the device can be a surgical implant.

[0074] The delivery device of the present invention can be utilized for therapy (gene therapy) in which a nucleic acid of interest is introduced into cells responsible for any of a variety of diseases.

[0075] Another aspect of the present disclosure relates to a method for delivering an active agent into a target cell, preferably a nucleic acid, comprising administering to an animal a solution containing a polymer complex as defined herein, such that the polymer complex may be introduced into the target cell; translocating the polymer complex from an endosome to the cytoplasm; dissociating the polymer complex in the cell; and releasing the active agent in the cytoplasm.

[0076] This embodiment can be reformulated as the use of a polymer complex or pharmaceutical composition disclosed herein in a method for delivering a nucleic acid into a target cell, the method comprising: contacting a solution containing the polymer complex or pharmaceutical composition with an animal, including a human, having a target cell, such that the complex can be introduced into the target cell; translocating the complex from an endosome to the cytoplasm; dissociating the complex in the cell; and releasing the nucleic acid into the cytoplasm.

[0077] In another aspect, the present disclosure relates to a process for synthesizing a compound of formula (I) of the first aspect of the present disclosure or any embodiment thereof, the process generally comprises polymerizing N-carboxyanhydrides (NCAs) of amino acids, protected or unprotected, known per se, to produce poly(amino acid) esters, and then performing aminolysis using a suitable amine. The different radicals present in the repeating units can be introduced in the desired ratio by varying the ratio of each amine used during aminolysis.

[0078] According to this aspect, there is provided a process for the synthesis of a compound of formula (I) of the first aspect of the disclosure or any embodiment thereof, the process comprising: i) reacting an amine or ammonium tetrafluoroboric acid or trifluoroacetate salt form of an initiator of formula (II) below; i.1) using a suitable N-carboxylic anhydride (NCA); or alternatively reacting the amine or ammonium tetrafluoroboric acid or trifluoroacetate salt form of the initiator of step i) sequentially with a suitable N-carboxylic anhydride to obtain a block copolymer; i.2) Alternatively, reacting the amine or tetrafluoroboric acid or trifluoroacetate ammonium salt form of the initiator of step i) with a suitable NCA mixture in a statistical manner to obtain a random copolymer; ii) Optionally, reacting the amine group at the N-terminal position with an amine-reactive group to form R 19 and; iii) optionally, orthogonally removing amino acid side chain protecting groups; iv) Optionally, reacting an amine group at a terminal position of the side chain with an amine reactive group to form R 7 , R 6 , R 15 or R 14 introducing structural extensions, conjugations, labels or shielding into the v) purifying the product obtained in step i), ii) or iii) optionally by fractionation, precipitation, ultrafiltration, dialysis, size exclusion chromatography, affinity chromatography or tangential flow filtration. Includes.

[0079] The above step i) may comprise: a) a ring-opening polymerization of amino acid N-carboxyanilide (NCA) monomers by reacting the amine or tetrafluoroborate or trifluoroacetate ammonium salt form of the initiator of formula (IV) above with the selected NCA, where the monomer / initiator ratio allows for control of the degree of polymerization (DP); b) a step-growth polymerization, where block copolypeptides are prepared after polymerization reaction a) in a sequential manner, allowing the initial NCA monomer to be consumed, and the resulting product may or may not be purified before adding the next monomer to build the next polypeptide block; or c) a statistical polymerization a), where random copolypeptides are prepared after polymerization reaction a) in a statistical manner, where all NCA monomers are mixed before initiating the polymerization by addition of the amine or tetrafluoroborate or trifluoroacetate ammonium salt form of the initiator.

[0080] Step ii) above corresponds to end-capping, where the amine group at the N-terminal position is reacted with an amine-reactive group to give R 19 Introduce the following.

[0081] Step iii) above corresponds to the deprotection, in which the amino acid side chain is orthogonally removed depending on the protecting group.

[0082] Step iv) corresponds to conjugation, in which an amine group at a side chain terminal position of the shielding polymer, active small molecule, targeting agent or imaging agent is reacted with an amine reactive group.

[0083] Any suitable amino protecting group known in the art may be used without limitation. Non-limiting examples of amino protecting groups include acyl-based groups, carbamate-based groups, imide-based groups, sulfonamide-based groups, and the like. In certain embodiments, the amino protecting group is selected from the group consisting of acetyl, methyloxycarbonyl, benzyloxycarbonyl (Cbz), p-methoxybenzyloxycarbonyl, t-butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), 2,2,2-trichloroethoxycarbonyl group (Troc), benzoyl (Bz), benzyl (Bn), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), tosyl (Ts), trimethylsilylethoxycarbonyl (Teoc), benzhydryl, triphenylmethyl (trityl), (4-methoxyphenyl)diphenylmethyl (MMT), dimethoxytrityl (DMT), and diphenylphosphino, and even more particularly, the amino protecting group is acetyl.

[0084] Introduction and removal of amino protecting groups can be carried out by standard methods, such as those described in TW Green and PGM Huts, Protective Groups in Organic Chemistry, Wiley, 3rd ed. 1999, Chapter 7 (pp. 495-653).

[0085] Any suitable carboxy protecting group known in the art may be used without limitation. Representative carboxy protecting groups include alkyl, aryl or benzyl esters, silyl esters, amides or hydrazides. In certain embodiments, the carboxy protecting group is selected from the group consisting of -(C1-C6) alkyl, benzyl, p-methoxyphenyl, trimethylsilyl and [2-(trimethylsilyl)ethoxy]methyl (SEM).

[0086] The introduction and removal of these protecting groups can be carried out by standard methods, such as those described in TW Green and PGM Huts, Protective Groups in Organic Chemistry, Wiley, 3rd ed. 1999, Chapter 5 (pp. 369-451).

[0087] As used herein, the term "initiator" refers to a chemical molecule used for initiation of the ring-opening polymerization (ROP) reaction of α-amino acid N-carboxylic anhydrides via a common amine mechanism, where the initiator is incorporated into the backbone of the resulting polyamino acid. The initiator may contain one or more nucleophilic groups capable of initiating the ROP reaction, and thus the initiator may be mono- or polyfunctional, respectively, resulting in one or several terminal X groups in the polymer of the invention, respectively.

[0088] The compounds of the present disclosure defined in any of the above embodiments or aspects of the present disclosure may include isomers depending on the presence of multiple bonds (e.g., Z, E), including optical isomers or enantiomers depending on the presence of chiral centers. In certain cases, amino acids may acquire L- or D-configuration. Polyaspartic acids obtained by aminolysis synthesis procedures and mechanisms may also acquire isomerization of α or β forms of aspartamide. Individual isomers, enantiomers or diastereoisomers, and mixtures thereof, are within the scope of the present disclosure. Individual enantiomers or diastereoisomers, and mixtures thereof, may be separated by any conventional technique well known to those skilled in the art.

[0089] The compounds of the present disclosure may be in crystalline form as free form or as solvates, and both forms are intended to be included within the scope of the present disclosure. In this respect, the term "solvate" as used herein includes both pharmaceutically acceptable solvates, i.e., solvates of the compounds of formula (I) that can be used in the preparation of pharmaceuticals, and pharmaceutically unacceptable solvates, which may be useful in the preparation of pharmaceutically acceptable solvates or salts. The nature of the pharmaceutically acceptable solvate is not important, so long as it is pharmaceutically acceptable. In certain embodiments, the solvate is a hydrate. The solvate can be obtained by conventional solvation methods well known to those skilled in the art. Unless otherwise specified, the compounds of the present disclosure also include compounds that differ only in the presence of one or more isotopically enriched atoms. Examples of isotopically enriched atoms are, but are not limited to, deuterium, tritium, 13C or 14C, or nitrogen atoms enriched with 15N.

[0090] According to another aspect of the present invention there is provided a process for preparing a compound structurally distinct from a compound of formula I as defined herein, said process comprising the steps of: i. using a compound of formula I as defined herein as a starting compound; ii. subjecting the compound of step (i) to a structural modification to obtain a compound structurally different from the compound of formula I; Includes.

[0091] In a further aspect of the invention there is provided the use of a compound of formula I as defined herein for the preparation of a compound which is structurally different to a compound of formula I. [Brief description of the drawings]

[0092] Non-limiting examples of the present disclosure are described below with reference to the accompanying drawings:

[0093] [Figure 1]The results of polyplexes PX5 (top left), PX13 (top right), PX21 (bottom left) and PX31 (bottom right) analyzed by agarose gel electrophoresis technique are shown. This technique shows in a qualitative way the ability of polyplexes to complex with DNA. It also shows the ability to release DNA in the presence of a polyanionic competitor (heparin) at low and high concentrations. In lane 1, free DNA is seeded and it can be seen that the free DNA shines under the UV transilluminator. In lanes 2, 3, and 4, polyplexes are seeded at different N / P ratios (5, 10, and 30) and it can be seen that when polycations are present and polyplexes are formed, DNA is captured and no signal can be observed. In lane 5, polyplexes at N / P=30 are seeded in the presence of a low concentration of heparin competitor, showing no release in these conditions. In lane 6, polyplexes with N / P=30 were seeded with a high concentration of anionic heparin competitor, in which case DNA release is observed. This behavior is ideal because polyplexes need to be stable at low concentrations to compete with molecules outside the cell, yet unstable enough to release cargo when an intracellular stimulus is applied. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0094] All terms used herein in this application are to be understood in their ordinary meaning as known in the art unless otherwise specified. Other more specific definitions of certain terms used in this application are as follows, and are intended to be applied uniformly throughout the specification and claims, unless a definition expressly set forth otherwise provides a broader definition.

[0095] As used herein, the indefinite articles "a" and "an" are equivalent to "at least one" or "one or more." Unless otherwise specified, as used herein, definite articles such as "the" also include the plural form of a noun.

[0096] The term "halogen" or "halo" as used herein means fluoro, chloro, bromo, and iodo, preferably fluoro, chloro, and bromo, more preferably fluoro and chloro.

[0097] The term "alkenyl" refers to an organic group composed of carbon and hydrogen atoms, including at least one double covalent bond between two carbons. Typically, "alkenyl" as used in this disclosure refers to an organic group containing 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 30 carbon atoms, or any range of carbon atoms between or including any two of the aforementioned values. In some cases, the alkenyl group is conjugated, in other cases, the alkenyl group is not conjugated, and in yet other cases, the alkenyl group may have conjugated and non-conjugated portions. Furthermore, when there are more than two carbons, the carbons may be connected in a linear fashion, or when there are more than three carbons, the carbons may be linked in a branched fashion, such that the parent chain includes one or more secondary, tertiary, or quaternary carbons. The alkenyl may be substituted or unsubstituted.

[0098] The term "alkyl" refers to an organic group composed of carbon and hydrogen atoms and containing a single covalent bond between the carbons. Typically, "alkyl" as used in this disclosure refers to an organic group containing 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 30 carbon atoms, or any range between or including any two of the aforementioned values. Examples of alkyl groups with 1 to 12 carbon atoms may include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, n-hexyl, decyl, and undecyl groups.

[0099] If there is more than one carbon, the carbons may be connected in a linear fashion, and if there are more than two carbons, the carbons may be linked in a branched fashion, such that the parent chain contains one or more secondary, tertiary, or quaternary carbons. Alkyl may be substituted or unsubstituted.

[0100] The term "alkynyl" refers to an organic group composed of carbon and hydrogen atoms, including a triple covalent bond between two carbons. Typically, "alkynyl" as used in this disclosure refers to an organic group containing 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 30 carbon atoms, or any range between or including any two of the aforementioned values. C2-alkynyl can form a triple bond to a carbon of the parent chain, while alkynyl groups of three or more carbons can contain multiple triple bonds. When there are more than three carbons, the carbons can be connected in a linear fashion, or when there are more than four carbons, the carbons can be linked in a branched fashion, such that the parent chain includes one or more secondary, tertiary, or quaternary carbons. Alkynyl can be substituted or unsubstituted.

[0101] Terms commonly represented by the notation "Cx-Cy" (where x and y are integers and y>x) before a functional group, such as "C1-C12 alkyl", refer to a range of numbers of carbon atoms. For purposes of this disclosure, the range designated by "Cx-Cy" (where x and y are integers and y>x) is not limited to the range designated, but includes the range designated by "Cx-Cy" and all possible ranges that fall within that range (where x and y are integers and y>x). For example, the term "C1-C4" provides explicit support of a range of 1-4 carbon atoms, but also provides implicit support of the range encompassed by 1-4 carbon atoms, such as 1-2 carbon atoms, 1-3 carbon atoms, 2-3 carbon atoms, 2-4 carbon atoms, and 3-4.

[0102] The term "moiety" refers to a specific segment or functional group of a molecule or compound.

[0103] As used herein, the term "subject" refers to any mammal, including both humans and other mammals.

[0104] The term "substituted" means that one or more hydrogen atoms on a specified atom or group are replaced with one selected from a specified group, provided that the normal valence of the specified atom under the present circumstances is not exceeded. Combinations of substituents and / or variables are permissible.

[0105] The term "optionally substituted" means that the number of substituents can be equal to or different from zero.Unless otherwise indicated, an optionally substituted group can be substituted with as many optional substituents as it can accommodate by replacing hydrogen atoms with non-hydrogen substituents on any available carbon or nitrogen atom.The group in the conjugate according to the present invention can be substituted with 1, 2, 3, 4 or 5 identical or different substituents, particularly 1, 2 or 3 substituents.

[0106] In those embodiments of the invention where the substitution or unsubstitution of a particular group is not specified, i.e., where no particular substitution for the group is indicated, nor is the group indicated as being unsubstituted, it is to be understood that the possible substitution of this group is in the broadest scope as defined herein.

[0107] As used herein, the term "protecting group" refers to a group of atoms that, when attached to a reactive group in a molecule, masks, reduces or prevents that reactivity.

[0108] Protective groups for carboxyl and amino groups are described, for example, in TW Green and PGM Wets, Protective Groups in Organic Chemistry (Wiley, 3rd ed. 1999), Chapter 5 (pp. 369-451) and Chapter 7 (pp. 495-653), respectively.

[0109] The term "disorder" as used herein is intended to be generally synonymous with, and is used interchangeably with, the terms "disease," "syndrome," and "condition" (as in medical condition), in that all reflect an abnormal condition of the human or animal body or one of its parts that impairs normal function and typically exhibit characteristic signs and symptoms.

[0110] As used herein, the terms "pharmaceutical acceptable carrier", "pharmaceutical acceptable excipient", "physiologically acceptable carrier", or "physiologically acceptable excipient" refer to a pharma- ceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulant. Each component must be "pharmaceutical acceptable" in the sense of being compatible with the other components of a pharmaceutical formulation. It must also be suitable for use in contact with the tissues or organs of humans and animals without undue toxicity, irritation, allergic response, immunogenicity, or other problems or complications, consistent with a reasonable benefit / risk ratio.

[0111] The terms "cosmetically acceptable carrier" or "dermatologically acceptable carrier", as used interchangeably herein, refer to excipients or carriers that are suitable for use in contact with human skin without undue toxicity, incompatibility, instability, or allergic response.

[0112] The term "therapeutically acceptable" refers to compounds that are suitable for use in contact with the tissues of a patient without undue toxicity, irritation, allergic response, or immunogenicity, and that are effective for their intended use, commensurate with a reasonable benefit / risk ratio.

[0113] The term "pharmaceutically, cosmetically, or diagnostically acceptable salts" includes commonly used non-toxic salts. The preparation of pharmaceutically, cosmetically, or diagnostically acceptable salts of the compounds of the present invention can be carried out by methods well known in the art. In general, such salts can be prepared by reacting the free acid or base form of the compounds of the present invention with a stoichiometric amount of a suitable base or acid, respectively, in a suitable solvent such as water, an organic solvent, or a mixture thereof.

[0114] Examples of pharma- ceutically , cosmetically , or diagnostically acceptable salts include those derived from inorganic acids, such as hydrochloric, hydrobromic, sulfuric, nitric, hydroiodic, metaphosphoric, or phosphoric acids, as well as organic acids, such as succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, trifluoroacetic, malic, lactic, formic, propionic, glycolic, gluconic, camphorsulfuric, isothionic, mucic, gentisic, isonicotinic, saccharic, glucuronic, furoic, glutamic, ascorbic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), ethanesulfonic, tauric ... Sulfonic acid, pantothenic acid, stearic acid, sulfinilic acid, alginic acid and galacturonic acid; and arylsulfonic acid, such as benzenesulfonic acid, p-toluenesulfonic acid, oxalic acid, methanesulfonic acid or naphthalenesulfonic acid; base addition salts formed with alkali metals and alkaline earth metals and organic bases, such as N,N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), lysine and procaine, as well as salts formed internally. The compounds of the present invention and their salts may differ in some physical properties, but for the purposes of the present invention they are equivalent.

[0115] As used herein, the term "pharmacologically active agent" refers to an agent that has pharmacological activity and is used to cure, alleviate, treat or prevent disease in mammals, particularly humans. The term "cosmetically active agent" refers to an agent that does not provide any medical treatment but is used for cosmetic purposes, such as improving the appearance, preserving, conditioning, cleaning, coloring or protecting the skin, nails or hair.

[0116] The term "diagnostic composition" refers to a composition suitable for use in diagnosis, particularly imaging diagnostic techniques. The term "diagnostically effective amount" as used herein refers to an effective amount of the detection polymer that, when administered, is sufficient for the diagnosis of a disease or disorder, particularly for imaging diagnostics as a contrast imaging agent. The dose of the detection polymer administered will, of course, be determined by the particular circumstances surrounding the case, including the polymer administered, the route of administration, the particular condition being diagnosed, and similar considerations. The diagnostic composition of the present invention includes one or more diagnostically acceptable excipients or carriers. The term "diagnostically acceptable" refers to an excipient or carrier suitable for use in diagnostic techniques to prepare a composition having diagnostic use, particularly by imaging diagnostic use. Detection of these diagnostic agents in the patient's body can be performed by well-known techniques used in imaging diagnostics, such as magnetic resonance imaging (MRI) and X-ray imaging diagnostics.

[0117] As used herein, the terms "treat," "treating," and "treatment" refer to ameliorating the symptoms associated with a disease or disorder, including preventing or delaying the onset of a symptom of a disease or disorder and / or reducing the severity or frequency of a symptom of a disease or disorder.

[0118] As used herein, the term "peptide" refers to a molecule that contains two or more consecutive amino acids linked together via peptide bonds. The term peptide includes oligopeptides and polypeptides. The term "protein" refers to large peptides, particularly peptides having at least about 50 amino acids. For purposes of the present invention, the terms peptide and protein are used interchangeably.

[0119] As used herein, the term "repeat unit" or "block" refers to a repeating monomer unit. A repeat unit or block may be composed of a single monomer, or may be composed of one or more monomers, either randomly or in blocks, resulting in a "mixed block."

[0120] One of ordinary skill in the art will recognize that repeating monomeric units are defined by brackets ("[]") drawn around the repeating monomeric unit. The number (or letter representing a numerical range) to the right of the brackets represents the number of monomeric units present in the polymer chain.

[0121] For ease of explanation only, in the radical of formula (II) shown above, the repeat unit defined by square brackets containing the number r (see (1) below) is represented as PAA1; the repeat unit defined by square brackets containing the number s (see (2) below) is represented as PAA2; the repeat unit defined by square brackets containing the number t (see (3) below) is represented as PAA3; and the repeat unit defined by square brackets containing the number u (see (4) below) is represented as PAA4. [ka]

[0122] In the context of the present disclosure, the term "conjugate" refers to a polymer complex comprising a polymeric compound of formula (I) and any moiety having inherent biological activity covalently attached to the polymer backbone. In this particular context, the moiety having inherent biological activity may be a shielding moiety, a cell targeting agent, or a labeling or imaging agent.

[0123] In the context of the present disclosure, the term "polyplex" or "polymer complex" refers to a compound formed by electrostatic interactions between a polycationic polymer of formula I or a conjugate according to the present disclosure and any of the polyanionic genetic material (preferably nucleic acid) described above or below. The polycationic polymer of formula I or a conjugate according to the present disclosure contains an opposite charge to the polyanionic genetic material at a given pH, resulting in the formation of multiple electrostatic bonds between the polyanionic genetic material and the polymer at a given pH. The driving force for the formation of the polymer complex is the multivalency of both the polyanionic nucleic acid and the polycationic polymer, which results in highly effective entropically driven condensation of the genetic material. Polymer complexes (polyplexes) containing nucleic acids are useful as non-viral synthetic vectors that can deliver nucleic acids to target cells. DNA or RNA delivery to target cells by non-viral synthetic vectors (such as polyplexes) is widely recognized as a promising alternative delivery method to using viral vectors, which face significant challenges and drawbacks. These include immunogenic responses (which may prevent re-administration), risk of insertional mutagenesis, difficulty in large-scale production at Good Manufacturing Practice grades, limited cargo size, and cost.

[0124] The compounds of the present disclosure provide an improvement as drug carriers or "nanovectors" due to their inherent ability to overcome many biological barriers. Moreover, their multifunctionality allows the incorporation of cell targeting groups, diagnostic agents, and multiple therapeutic agents in one delivery system. Polymer conjugates formed by molecular assembly of the polymers of the present disclosure with imaging agents, cell targeting groups, diagnostic agents, or any other therapeutic agents represent one noteworthy type of multifunctional nanovectors.

[0125] The compounds of the present disclosure are particularly attractive due to their ability to deliver large payloads of various active ingredients (e.g., small molecule, protein, and DNA / RNA therapeutics), their improved in vivo stability and tunable directionality compared to other colloidal carriers (e.g., liposomes), and their nanoscale size that allows for passive accumulation in diseased tissues such as solid tumors due to the enhanced permeation and retention (EPR) effect.

[0126] Using appropriate surface functional groups, the compounds of the present disclosure may be further modified with cell targeting groups and / or penetration enhancers that can actively target cells and aid in cell entry, resulting in conjugates with improved cell-specific delivery.

[0127] As used herein, the term "labeling or imaging" refers to a molecule that facilitates visualization and / or detection of a targeting molecule disclosed herein.

[0128] In the context of this disclosure, the expression "labeling agent or imaging agent" refers to any substance that is used as a label or enhances a particular structure in any imaging technique. Imaging agents therefore include optical imaging agents, magnetic resonance imaging agents, radioisotopes, and contrast agents. Imaging agents or labeling agents are well known in the art. Specific examples of imaging agents or labeling agents are gases such as sterile air, oxygen, argon, nitrogen, fluorine, perfluorocarbons, carbon dioxide, nitrogen dioxide, xenon, and helium; commercially available agents used in positron emission tomography (PET), computer-assisted tomography (CAT), single-photon emission computed tomography, X-ray, fluoroscopy, and magnetic resonance imaging (MRI). Examples of materials suitable for use as contrast agents in MRI include currently available gadolinium chelates such as diethylenetriaminepentaacetic acid (DTPA) and gadopentetate dimeglumine, as well as iron, magnesium, manganese, copper, and chromium. Examples of materials useful for CAT and X-ray include iodine-based materials for intravenous administration, ionic monomers such as diatrizoate and iothalamate, non-ionic monomers such as iopamidol, isohexol, and ioversol, non-ionic dimers such as iotrol and iodixanol, ionic dimers such as ioxagalte. Other useful materials include insoluble salts such as barium and zinc acetate for oral use. In some molecules, the imaging agent is a dye. In some molecules, the imaging agent is a fluorescent moiety. In some molecules, the fluorescent moiety is selected from a fluorescent protein, a fluorescent peptide, a fluorescent dye, a fluorescent substance, or a combination thereof.Examples of fluorescent dyes include, but are not limited to, xanthenes (e.g., rhodamine, rhodol, fluorescein, and their derivatives); bimanes; coumarins and their derivatives (e.g., umbelliferone and aminomethylcoumarin); aromatic amines (e.g., dansyl, squarate dyes); benzofurans; fluorescent cyanines; indocarbocyanines; carbazoles; dicyanomethylenepyrans; polymethines; oxabenthans; xanthenes; pyryliums; carbostils; perylenes; acridones; quinacridones; rubrenes; anthracenes; coronenes; phenanthrecenes; pyrenes; butadienes; stilbenes; porphyrins; phthalocyanines; lanthanide metal chelate complexes; rare earth metal chelate complexes; and derivatives of such dyes. Examples of fluorescein dyes include, but are not limited to, 5-carboxyfluorescein, fluorescein-5-isothiocyanate, fluorescein-6-isothiocyanate, and 6-carboxyfluorescein. Examples of rhodamine dyes include, but are not limited to, tetramethylrhodamine-6-isothiocyanate, 5-carboxytetramethylrhodamine, 5-carboxyrhodol derivatives, tetramethyl and tetraethylrhodamine, diphenyldimethyl and diphenyldiethylrhodamine, dinaphthylrhodamine, rhodamine 101 sulfonyl chloride (sold under the trade name TEXAS RED®). Examples of cyanine dyes include, but are not limited to, Cy3, Cy3B, Cy3.5, Cy5, Cy5.5, Cy7, IRDYE680, AlexaFluor750, IRDye800CW, ICG. Examples of fluorescent peptides include GFP (green fluorescent protein) or derivatives of GFP (e.g., EBFP, EBFP2, Azurite, mKalama1, ECFP, Cerulean, CyPet, YFP, Citrine, Venus, YPet). Fluorescent labels are detected by any suitable method.For example, fluorescent labels can be detected by exciting the fluorescent dye with light of an appropriate wavelength and detecting the resulting fluorescence, for example, by microscopy, visual inspection, photographic film, or by using electronic detectors such as charge-coupled devices (CCDs), photomultipliers, etc. In some molecules, imaging agents are labeled with positron-emitting isotopes (e.g., 18F) for positron emission tomography (PET), gamma-ray isotopes (e.g., 99mTc) for single-photon emission computed tomography (SPECT), or paramagnetic molecules or nanoparticles (e.g., Gd3+ chelates or coated magnetite nanoparticles) for magnetic resonance imaging (MRI). In some molecules, imaging agents are labeled with gadolinium chelates, iron oxide particles, superparamagnetic iron oxide particles, ultrasmall paramagnetic particles, manganese chelates, or gallium-containing agents. Examples of gadolinium chelates include, but are not limited to, diethylenetriaminepentaacetic acid (DTPA), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), and 1,4,7-triazacyclononane-N,N',N''-triacetic acid (NOTA). In some molecules, the imaging agent is a near-infrared fluorophore for near-infrared (near-IR) imaging, luciferase (firefly, bacteria, or coelenterate) or other luminescent molecules for bioluminescence imaging, or perfluorocarbon-filled vesicles for ultrasound. In some molecules, the imaging agent is a nuclear probe. In some molecules, the imaging agent is a SPECT or PET radionuclide probe. In some molecules, the radionuclide probe is selected from technetium chelates, copper chelates, radioactive fluorides, radioactive iodines, and indium chelates. Examples of Tc chelates include, but are not limited to, HYNIC, DTPA, and DOTA. In some molecules, the imaging agent is a radioactive moiety, as described by Lu et al., e.g. 211 At, 13 1I, 125 I, 90 Y, 186 Re, 188 Re, 153 Sm, 212 Bi, 32 P,64 Contains radioisotopes such as the Cu radioisotope.

[0129] As used herein, the term "cell targeting agent" refers to any molecule, macromolecule, or biopolymer that exhibits affinity for a (macro)molecule present in the human or animal body, which can be induced by directing the conjugate or its self-assembled particle to a therapeutic target site, for example because it selectively binds to a receptor expressed or overexpressed on a particular cell type. Cell targeting groups are well known in the art. In more specific embodiments, the cell targeting group is a moiety selected from the following: galactosamine, folic acid, Her-2 binding peptide, TLR agonist, β-D-glucose, Asn-Gly-Arg peptide, angiopep2, folic acid, aptamer (A-9, A10, anti-gp120, TTA1, sgc8, anti-MUC-1, AS1411), primaquine, zidovudine, superoxide dismutase, prednisolone, platinum, cisplatin, sulfamethoxazole. le, amoxicillin, etoposide, mesalidine, doxorubicin, paclitaxel, 5-aminosalicylic acid, denosumab, docetaxel, calcitonin, proanthocyanidins, methotrexate, camptothecin, galactose, glycyrrhetinic acid, lactose, hyaluronic acid, octeotolide, lactobionic acid, β-galactosyl moieties, arabino-galactan, chitosan, azo-based polyphosphazenes, azo groups and 4-amino-benzyl-carbamate, succinic acid, 4,4'-Dihydroxyazobenzene-3-carboxylic acid, cyclic RGD pentapeptide, aspartic acid octapeptide, alendronate, transferrin, bisphosphonate adendrone, monosialoganglioside GM1, glutathione, E-selectin thioaptamer, poloxamer-407, urokinase-type plasminogen activator receptor (uPAR) antagonist, CXCR4 chemokine receptor antagonist, GRP78 peptide antagonist, RGD peptide, RGD cyclic peptide, luteinizing hormone releasing hormone (LHRH) antagonist peptide, aminopeptidase targeting peptide, brain homing peptide, kidney homing peptide, heart homing peptide, gut homing peptide, integrin homing peptide, angiogenic tumor endothelium homing peptides, ovary homing peptides, uterus homing peptides, sperm homing peptides, microglia homing peptides, synovial membrane homing peptides, urothelium homing peptides, prostate homing peptides, lung homing peptides (RCPLSHSLICY), laminin receptor binding peptides (e.g., YIGSR), skin homing peptides, retina homing peptides, pancreatic homing peptides, liver homing peptides, lymph node homing peptides, adrenal gland homing peptides, thyroid homing peptides, bladder homing peptides, breast homing peptides, neuroblastoma homing peptides, lymphoma homing peptides, muscle homing peptides, wound vasculature homing peptides, adipose tissue homing peptides, virus binding peptides, or fusogenic peptides.

[0130] The compounds of the present disclosure may be used as "non-viral vectors" (NNVs) for preparing complexes with nucleic acids (also called polyplexes), which result in improved transfection efficiency of the nucleic acid into desired cells, or the release profile of the nucleic acid in physiological conditions.

[0131] According to a more specific embodiment, the N / P ratio in the polyplex of the present disclosure, defined as [total number of cationic groups in the block copolymer (N)] / [total number of phosphate groups in the nucleic acid (P)], is in the range of 1 to 200, preferably 2 to 100, and more preferably 2 to 50. The N / P ratio refers to the ratio of the molar concentration (N) of the protic amino groups derived from the side chains of the compound of formula (I) to the molar concentration (P) of the phosphate groups derived from the nucleic acid in the mixed solution.

[0132] In a more specific embodiment, the polymer complex as defined in the third aspect of the present disclosure or any embodiment thereof may comprise at least one active agent in an amount ranging from 1 to 80% w / w, based on the mass ratio of active agent to conjugate. In a preferred embodiment, the range is 1 to 70% w / w. In an even more preferred embodiment, the conjugate comprises an amount of agent ranging from 2 to 55% w / w. Other preferred ranges are 3 to 30% w / w, 4 to 25% w / w, and 7 to 24% w / w.

[0133] The pharmaceutical, diagnostic or theranostic compositions according to the present disclosure may be prepared in solid form or in aqueous suspension in a pharma- ceutically acceptable diluent. These preparations may be administered by any suitable route of administration, and thus the preparations are formulated in pharmaceutical forms suitable for the selected route of administration. In more particular embodiments, administration is by oral, topical, rectal or parenteral route (subcutaneous, intraperitoneal, intradermal, intramuscular, intravenous, etc.).

[0134] According to a more particular embodiment, in the compound of formula I, α, α' and α'' are 1, thus resulting in a six-arm star compound of formula Ia, in which the two -NH terminal moieties of radical L are linked to the A, A', or A'' moieties. [ka] In the formula, K, A, A' and A'' are as defined above.

[0135] According to a more particular embodiment, in the compound of formula I, α, α' and α'' are 0, thus giving rise to a three-arm star compound of formula Ib. [ka] In the formula, K, A, A' and A'' are as defined above.

[0136] According to a more specific embodiment, for both compounds of formula Ia or Ib, R1 is a biradical selected from the group consisting of: [ka] where the wavy lines indicate the attachment points; where y and z are independently integers ranging from 1 to 6; X is a linear or branched -(C 1 ~C 12 ) alkylene-, -(C 1 ~C 6 ) alkyl-COO-, and a biradical selected from the group consisting of (V), (VI), (VII), (VIII), (IX), (X), (XI), and (XII) as defined above; In the formula, X is a straight or branched chain -(C 1 ~C 12 ) Alkylene biradicals are -OH, -NR a R b , -SH, -NHNH 2 , -COOR c , -CF 3 , -OCF 3 and optionally substituted with one or more radicals selected from the group consisting of halogen; R a , R b and R c is H, -phenyl, -(C 1 ~C 12 ) alkyl, -(C 2 ~C 30 ) alkenyl, -(C 1 ~C 12) alkylphenyl, and -phenyl(C 1 ~C 12 ) alkyl.

[0137] According to a more particular embodiment, for both compounds of formula Ia or Ib, R1 is -CH 2 CH 2 -SS-CH 2 CH 2 -, -CH 2 CH 2 CH 2 -SS-CH 2 CH 2 CH 2 -, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 -, -CH 2 CH(CH 2 CH 3 )CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, -CH 2 COO-, -CH 2 CH 2 COO-, -CH 2 CHCH 3 COO-, -CH 2 CH 2 CH 3 CH 2 and a biradical selected from the group consisting of (V), (VI), (VII), (VIII), (IX), (X), (XI), and (XII) as defined above.

[0138] According to a more specific embodiment, for both compounds of formula Ia or Ib: In the formula, R 9 and R 17 is H, -(C 1 ~C 12) alkyl, -(C 2 ~C 30 ) alkenyl, -(C 1 ~C 12 ) Alkyl-R i1 , -(C 1 ~C 12 )Alkyl-OR iii1 , -(C 1 ~C 12 )Alkyl-NR iv1 R v1 , -C(O)-R vi1 , -(C 1 ~C 12 )Alkyl-CO-NH 2 and a radical selected from the group consisting of (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), and (XXI) as defined above; R i1 are H, F, Cl, Br, I, -CF 3 , -OCF 3 , isoxazole, oxazole, furan, oxolane, thiol, thiophene, N-methylpyrrole, pyrrole, pyrrolidine, pyran, pyridine, piperidine, thiazole, dioxane, morpholine, pyrimidine, -NH 2 , -N((C 1 ~C 12 )Alkyl) 2 , -NH(C 1 ~C 12 ) alkyl, -NHC(O)-(C 1 ~C 12 ) alkyl, -NHC(O)O(C 1 ~C 12 ) alkyl, -NHC(O)NH 2 , -NHC(O)N(CH 3 ) 2 , -NHS(O) 2 (C 1 ~C 12 ) Alkyl, -NHSO 2 NH 2 , -SH, -S(C 1 ~C12 ) alkyl, -S(O)H, -S(O)(C 1 ~C 12 ) Alkyl, -SO 2 (C 1 ~C 12 ) alkyl, -SeH, -C(O)(C 1 ~C 12 ) alkyl, and -CON((C 1 ~C 12 )Alkyl) 2 selected from the group consisting of; R vii1 is H, methyl, ethyl, propyl, isopropyl, butyl, -(C 2 ~C 30 ) alkenyl, (C 2 ~C 30 )Alkynyl, -Oalkyl(C 1 ~C 12 ), F, Cl, Br, I, -CF 3 , -OCF 3 , -NO 2 , -CN, -NH 2 , -(C 1 ~C 6 ) AlkylNH 2 , -N((C 1 ~C 6 )Alkyl) 2 , and -NH(C 1 ~C 6 ) alkyl; R iii1 , R iv1 and R v1 teeth, H, -(C 1 ~C 12 ) alkyl, -(C 1 ~C 12 ) AlkylNH 2 , -(C 1 ~C 12 )Alkyl-N((C 1 ~C 12 )Alkyl) 2 , and -(C 1 ~C 12 )Alkyl-NH(C 1 ~C12 ) alkyl; R vi1 is H, -(C 1 ~C 12 ) alkyl, -(C 2 ~C 30 ) alkenyl, -(C 1 ~C 12 ) AlkylNH 2 , -NH 2 , -(C 1 ~C 12 )Alkyl-N((C 1 ~C 12 )Alkyl) 2 , -NH(C 2 ~C 30 ) alkenyl, -(C1-C12) alkyl-NH(C 1 ~C 12 ) alkyl, -NH-oleic acid, -NH-noneic acid, and -NH-lipoic acid; In the formula, R i1 , R ii1 , R iii1 , R iv1 , R v1 , R vi1 , and R vii1 are -OH, F, Cl, Br, I, -O(C 1 ~C 6 ) alkyl, -CF 3 , -OCF 3 , -NH 2 , -(C 1 ~C 6 ) Alkyl, -SH, -NHNH 2 , -NHCH 3 , -N(CH 3 ) 2 , -NCH(CH 3 ) 2 and -(C 1 ~C 6 ) alkyl-OH; b1, c1, d1, e1, f1, g1, h1, i1, and j1 are independently integers ranging from 1 to 6; In the formula, R9 and R 10 are optionally combined together to form a proline ring moiety; R17 and R18 are optionally combined together to form a proline ring moiety.

[0139] In a more particular embodiment, for both compounds of formula Ia or Ib, R 9 and R 17 is H, methyl, ethyl, propyl, isopropyl, butyl, n-butyl, -(C 2 ~C 30 ) alkenyl, -CH 2 SCH 3 , -CH 2 CH 2 SCH 3 , -CH 2 CH 2 SCH 2 CH 3 , -CH 2 SCH 2 CH 3 , -CH 2 SH, -CH 2 -SeH, -CH 2 CH 2 SH, -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 CH 2 NH 2 , -CH 2 CH(CH 3 )CH 2 NH 2 , -CH 2 NHCH 3 , -CH 2 NHCH 2 CH 3 , -CH 2 CH 2 NHCH 3、-CH 2 CH 2 NHCH 2 CH 3 、 -CH 2 CH 2 CH 2 NHCH 3 、-CH 2 CH 2 CH 2 NHCH 2 CH 3 、-CH 2 CH(CH 3 )CH 2 NHCH 3 、 -CH 2 CH(CH 3 )CH 2 NHCH 2 CH 3 、-CH 2 CH 2 NHCH 2 CH 2 NH 2 、 -CH 2 CH 2 CH 2 NHCH 2 CH 2 CH 2 NH 2 、-CH 2 CH 2 N((CH(CH 3 ) 2 ))、 -CH 2 CH 2 CH 2 N((CH(CH 3 ) 2 ))、-CH 2 CH 2 NH(CH(CH 3 ) 2 )、 -CH 2 CH 2 CH 2 NH(CH(CH 3 ) 2 )、-C(O)H、-C(O)OCH 3 、-C(O)OCH 2 CH 3 、 -C(O)OCH(CH 3 ) 2 、-C(O)CH 2 NH 2 、-C(O)CH 2 CH 2 NH 2 、-C(O)CH(CH 3 )CH 2 NH 2 、 -C(O)CH 2 NHCH 3 、-C(O)CH 2 NHCH 2 CH 3 、-C(O)CH 2 CH 2 NHCH 2 CH 3 、 -C(O)CH 2 CH 2 CH 2 NHCH 2 CH 3 、-C(O)CH 2 CH 2 CH 2 NHCH 2 CH 2 CH 3 、 -C(O)CH 2 CH(CH 3 )CH 2 NHCH 3 、-C(O)CH 2 CH(CH 3 )CH 2 NHCH 2 CH 3 、 -C(O)CH 2 CH 2 NHCH 2 CH 2 NH 2 、-C(O)CH 2 CH 2 CH 2 NHCH 2 CH 2 CH 2 NH 2 、 -C(O)CH 2 CH 2 N((CH(CH 3 )2 )), -C(O)CH 2 CH 2 CH 2 N((CH(CH 3 ) 2 )) -C(O)CH 2 CH 2 NH(CH(CH 3 ) 2 ), -C(O)CH 2 CH 2 CH 2 NH(CH(CH 3 ) 2 ), -CH 2 COOCH 3 , -CH 2 CH 2 COOCH 3 , -CH 2 COOCH 2 CH 3 , -CH 2 CH 2 COOCH 2 CH 3 , -CH 2 COOCH(CH 3 ) 2 , -CH 2 CONH 2 , -CH 2 CH 2 CONH 2 , -CH 2 CH 2 CH 2 CONH 2 -CONH-oleic acid, -CONH-noneic acid, -CONH-lipoic acid, and radicals selected from the group consisting of (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), and (XXI) as defined above; In the formula, R vii1 is H, methyl, ethyl, propyl, isopropyl, butyl, -(C 2 ~C 30 ) alkenyl, -(C 2 ~C 30 )Alkynyl, -Oalkyl(C 1 ~C12 ), F, Cl, Br, I, -CF 3 , -OCF 3 , -NO 2 , -CN, -NH 2 , -(C 1 ~C6) alkyl NH 2 , -N((C 1 ~C 6 )Alkyl) 2 , and -NH(C 1 ~C 6 ) alkyl; where b1, c1, d1, e1, f1, g1, h1, i1, and j1 are independently integers ranging from 1 to 6; In the formula, R 9 and R 10 are optionally combined together to form a proline ring moiety; R17 and R18 are optionally combined together to form a proline ring moiety.

[0140] According to a more specific embodiment, for both compounds of formula Ia or Ib, R 9 and R 17 is H, methyl, ethyl, propyl, isopropyl, butyl, n-butyl, -CH 2 SCH 3 , -CH 2 CH 2 SCH 3 , -CH 2 CH 2 SCH 2 CH 3 , -CH 2 SCH 2 CH 3 , -CH 2 SH, -CH 2 CH 2 S.H., C.H. 2 SeH, -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 NH 2, -CH 2 CH 2 CH 2 CH 2 NH 2 and a radical selected from the group consisting of (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), and (XXI) as defined above; In the formula, R vii1 is H, methyl, ethyl, propyl, isopropyl, butyl, -(C 2 ~C 30 ) alkenyl, -(C 2 ~C 30 )Alkynyl, -Oalkyl(C 1 ~C 6 ), F, Cl, Br, I, -CF 3 , -OCF 3 , -NO 2 , -CN, -NH 2 , -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -CH(CH 3 )NH 2 , -CH 2 CH(CH 3 )NH 2 , -CH 2 CH 2 CH 2 NH 2 , -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -NCH(CH 3 ) 2 , -NHCH 3 , -NHCH 2 CH 3 , and -NHCH(CH 3 ) 2 Selected from; where b1, c1, d1, e1, f1, g1, h1, i1, and j1 are independently integers ranging from 1 to 4; In the formula, R 9and R 10 are optionally combined together to form a proline ring moiety; R17 and R18 are optionally combined together to form a proline ring moiety.

[0141] According to certain embodiments, W1 and W2 are each independently selected from CH and N, with the proviso that at least one of them is CH.

[0142] According to a particular embodiment, W1 and W2 are both CH.

[0143] According to a particular embodiment, W1 and W2 are both N.

[0144] According to a more specific embodiment, for both compounds of formula Ia or Ib: R 6 , R 7 , R 14 , R 15 and R 19 is H, -(C 1 ~C 30 ) alkyl, -(C 2 ~C 30 ) alkenyl, -(C 2 ~C 30 ) alkynyl, -(C 1 ~C 30 ) Alkyl-R i2 , -(C 1 ~C 30 )Alkyl-OR iii2 , -(C 1 ~C 30 )Alkyl-NR iv2 R v2 , -C(O)-R vi2 and radicals selected from the group consisting of (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), and (XXXI); R i2 is H, -(C 1 ~C 12) alkyl, -O alkyl (C 1 ~C 6 ), F, Cl, Br, I, -CF 3 , -OCF 3 , isoxazole, oxazole, furan, oxolane, thiol, thiophene, N-methylpyrrole, pyrrole, pyrrolidine, pyran, pyridine, piperidine, thiazole, dioxane, morpholine, pyrimidine, -NH 2 , -N((C 1 ~C 12 )Alkyl) 2 , -NH(C 1 ~C 12 ) alkyl, -OC(O)O(C 1 ~C 12 ) alkyl, -OC(O)NH2, -OC(O)N((C 1 ~C 12 )Alkyl) 2 , -SH, -S(C 1 ~C 12 ) alkyl, -S(O)H, -S(O)(C 1 ~C 12 ) Alkyl, -SO 2 (C 1 ~C 12 ) alkyl; R iii2 , R iv2 , and R v2 teeth, H, -(C 1 ~C 12 ) alkyl, -(C 2 ~C 30 ) alkenyl, -(C 1 ~C 30 ) AlkylNH 2 , -(C 1 ~C 12 )Alkyl-N((C 1 ~C 12 )Alkyl) 2 , -(C 1 ~C 12 )Alkyl-NH(C 1 ~C 12) alkyl, and radicals selected from the group consisting of (XXXII), (XXXIII), (XXXIV), (XXXV), (XXXVI), (XXXVII), (XXXVIII), (XXXIX), (XL), (XLI), (XLII), (XLIII), (XLIV), (XLV), and (XLVI), as defined above; In the formula, R viii2 , R ix2 , R viii2 ', and R ix2’’ teeth, H, -(C 1 ~C 6 ) alkyl, -(C 1 ~C 6 ) AlkylNH 2 , -(C 1 ~C 6 )Alkyl-N((C 1 ~C 6 )Alkyl) 2 , -(C 1 ~C 6 )Alkyl-NH(C 1 ~C 6 ) alkyl, -O(C 1 ~C 6 ) alkyl, -COH, -CO(C 1 ~C 6 ) alkyl, and -O(C 2 ~C 12 ) alkenyl; R vii2 and R vii2’ is H, -(C 1 ~C 12 ) alkyl, -(C 2 ~C 30 ) alkenyl, -(C 2 ~C 30 ) alkynyl, -O(C 1 ~C 6 ) Alkyl, F, Cl, Br, I, -CF 3 , -OCF 3 , -NO 2 , -CN, -NH 2 , -(C 1 ~C 12 ) AlkylNH 2, -N((C 1 ~C 12 )Alkyl) 2 , and -NH(C 1 ~C 12 ) alkyl; R vi2 teeth, H, -OH, -(C 1 ~C 1 ) alkyl, -(C 2 ~C 30 ) alkenyl, -(C 1 ~C 12 ) alkyl-COOH, -(C 2 ~C 30 ) alkenyl-COOH, -(C 1 ~C 12 ) AlkylNH 2 , -(C 1 ~C 12 )Alkyl-N((C 1 ~C 12 )Alkyl) 2 , -O-(C 1 ~C 12 ) alkyl, -NH(C 2 ~C 12 ) alkenyl, -(C 1 ~C 12 )Alkyl-NH(C 1 ~C 12 ) alkyl, -NH-oleic acid, -NH-noneic acid, -NH-lipoic acid and -CH=CH(COOH)-CH 2 -COOH; During the ceremony, Alk 2 , Alk 22 , Alk 2 ' and Alk 22 ' is a straight or branched -(C 1 ~C 12 ) alkyl and straight or branched -(C 2 ~C 30 ) alkenyl, 2 and β 2 ' are each independently an integer from 0 to 6; 2 and X 2’are each independently selected from the group consisting of -NH-, -COO-, and O-; In the formula, R i2 , R iii2 , R iv2 , R v2 , R vi2 , R vii2 , R viii2 , R ix2 , R viii2’ , and R ix2’ are OH, F, Cl, Br, I, -O(C 1 ~C 6 ) alkyl, -CF 3 , -OCF 3 , -NH 2 , -(C 1 ~C 6 )Alkyl-NHNH 2 , -NHCH 3 , -N(CH 3 ) 2 , -NCH(CH 3 ) 2 and -(C 1 ~C 6 ) alkyl-OH; b2, c2, d2, e2, h2, k2, l2, k2', l2', b2'', c2'', d2'', e2'', and h2'' are independently integers ranging from 1 to 6; b2', c2', d2', e2', and h2' are independently integers ranging from 0 to 6; m2, n2, m2', and n2' are independently integers ranging from 1 to 150.

[0145] According to a more specific embodiment, for both compounds of formula Ia or Ib: R 6 , R 7 , R 14 , R 15 and R 19 is H, methyl, ethyl, propyl, isopropyl, butyl, -CH 2 OCH 3 , -CH 2 CH 2 OCH 3、-CH 2 CH 2 OCH 2 CH 3 、-CH 2 CH 2 OCH(CH 3 ) 2 、 -CH 2 OCH 2 CH 3 、-CH 2 OCH(CH 3 ) 2 、-(C 2 ~C 30 )アルケニル、-(C 2 ~C 30 )アルキニル、-CH 2 SCH 3 、-CH 2 CH 2 SCH 3 、-CH 2 CH 2 SCH 2 CH 3 、-CH 2 SCH 2 CH 3 、-CH 2 NH 2 、-CH 2 CH 2 NH 2 、 -CH 2 CH 2 CH 2 NH 2 、-CH 2 CH(CH 3 )CH 2 NH 2 、-CH 2 NHCH 3 、-CH 2 NHCH 2 CH 3 、 -CH 2 CH 2 NHCH 3 、-CH 2 CH 2 NHCH 2 CH 3 、-CH 2 CH 2 CH 2 NHCH 3 、 -CH 2 CH 2 CH 2 NHCH 2 CH 3 、-CH 2 CH(CH 3 )CH 2 NHCH 3 、 -CH 2 CH(CH 3 )CH 2 NHCH 2 CH 3 、-CH 2 CH 2 NHCH 2 CH 2 NH 2 、 -CH 2 CH 2 CH 2 NHCH 2 CH 2 CH 2 NH 2 、-CH 2 CH 2 N((CH(CH 3 ) 2 ))、 -CH 2 CH 2 CH 2 N((CH(CH 3 ) 2 ))、-CH 2 CH 2 NH(CH(CH 3 ) 2 )、 -CH 2 CH 2 CH 2 NH(CH(CH 3 ) 2 )、-C(O)H、-C(O)OCH 3 、-C(O)OCH 2 CH 3 、 -C(O)OCH(CH 3 ) 2 、-C(O)CH 2 NH 2 、-C(O)CH 2 CH 2 NH 2 、-C(O)CH(CH3 )CH 2 NH 2 、 -C(O)CH 2 NHCH 3 、-C(O)CH 2 NHCH 2 CH 3 、-C(O)CH 2 CH 2 NHCH 2 CH 3 、 -C(O)CH 2 CH 2 CH 2 NHCH 2 CH 3 、-C(O)CH 2 CH 2 CH 2 NHCH 2 CH 2 CH 3 、 -C(O)CH 2 CH(CH 3 )CH 2 NHCH 3 、-C(O)CH 2 CH(CH 3 )CH 2 NHCH 2 CH 3 、 -C(O)CH 2 CH 2 NHCH 2 CH 2 NH 2 、-C(O)CH 2 CH 2 CH 2 NHCH 2 CH 2 CH 2 NH 2 、 -C(O)CH 2 CH 2 N((CH(CH 3 ) 2 ))、-C(O)CH 2 CH 2 CH 2 N((CH(CH 3 ) 2 ))、 -C(O)CH 2 CH2 NH(CH(CH 3 ) 2 ), -C(O)CH 2 CH 2 CH 2 NH(CH(CH 3 ) 2 ), -CH 2 COOH, -CH 2 CH 2 COOH, -CH 2 COOCH 3 , -CH 2 CH 2 COOCH 3 , -CH 2 COOCH 2 CH 3 , -CH 2 CH 2 COOCH 2 CH 3 , -CH 2 COOCH(CH 3 ) 2 , -(C 1 ~C 6 ) Alkyl-R i2 , -(C 1 ~C 6 )Alkyl-OR iii2 , -(C 1 ~C 6 )Alkyl-NRi v2 R v2 -CONH-oleic acid, -CONH-noneic acid, -CONH-lipoic acid, and radicals selected from the group consisting of (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), and (XXXI) as defined above; R i2 is imidazole, N-methylpyrrole, pyrrole, pyrrolidine, pyran, pyridine, piperidine, pyrimidine, -OC(O)NH 2 , -OC(O)N((C 1 ~C 6 )Alkyl) 2 selected from the group consisting of; Riii2 , R iv2 , and R v2 is -(C 2 ~C 30 ) alkenyl, -(C 2 ~C 30 ) alkynyl, -(C 1 ~C 6 )Alkyl-NH 2 , -(C 1 ~C 6 )Alkyl-N((C 1 ~C 6 )Alkyl) 2 , -(C 1 ~C 6 )Alkyl-NH(C 1 ~C 6 ) alkyl, and radicals selected from the group consisting of (XXXII), (XXXIII), (XXXIV), (XXXV), (XXXVI), (XXXVII), (XXXVIII), (XXXIX), (XL), (XLI), (XLII), (XLIII), (XLIV), (XLV), and (XLVI), as defined above; R vii2 and R vii2’ is H, methyl, ethyl, propyl, isopropyl, butyl, -Oalkyl(C 1 ~C 6 ), F, Cl, Br, I, -CF 3 , -OCF 3 , -NO 2 , -CN, -NH 2 , -(C 1 ~C 6 )Alkyl-NH 2 , -N((C 1 ~C 6 )Alkyl) 2 , -NH(C 1 ~C 6 ) alkyl; In the formula, R viii2 , R ix2 , R viii2’ , and R ix2’’ is H, -(C 1 ~C 6 ) alkyl, -(C 2 ~C6 ) alkenyl, -(C 2 ~C 6 ) alkynyl, -(C 1 ~C 6 ) AlkylNH 2 , -(C 1 ~C 6 )Alkyl-N((C 1 ~C 6 )Alkyl) 2 , -(C 1 ~C 6 )Alkyl-NH(C 1 ~C 6 ) alkyl; In the formula, R i2 , R iii2 , R iv2 , R v2 , R vi2 , R vii2 , R viii2 , R ix2 , R viii2’ , and R ix2’ are OH, F, Cl, Br, -OCH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 , -CF 3 , -OCF 3 , -NH 2 , -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 OH, -CH 2 CH 2 OH, and -CH 2 CH(OH)CH 3 optionally substituted with one or more substituents selected from the group consisting of: b2, c2, d2, e2, h2, k2, l2, k2', l2', b2'', c2'', d2'', e2'', and h2'' are independently integers ranging from 1 to 4; b2', c2', d2', e2', and h2' are independently integers ranging from 0 to 4; m2, n2, m2', and n2' are independently integers ranging from 1 to 120.

[0146] In a more specific embodiment, for both compounds of formula Ia or Ib: In the formula, R 1 -CH 2 CH 2 -SS-CH 2 CH 2 -, -CH 2 CH 2 CH 2 -SS-CH 2 CH 2 CH 2 -, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 -, -CH 2 CH(CH 2 CH 3 )CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, -CH 2 COO-, -CH 2 CH 2 COO-, -CH 2 CHCH 3 COO-, -CH 2 CH 2 CH 3 CH 2 a biradical selected from the group consisting of COO-, and a biradical selected from the group consisting of (V), (VI), (VII), (VIII), (IX), (X), (XI), and (XII) as defined above; R 9 and R 17 is H, methyl, ethyl, propyl, isopropyl, butyl, n-butyl, -CH 2 SCH 3 , -CH 2 CH 2 SCH 3 , -CH2 CH 2 SCH 2 CH 3 , -CH 2 SCH 2 CH 3 , -CH 2 SH, -CH 2 CH 2 SH, -CH 2 SeH, -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 CH 2 NH 2 and a radical selected from the group consisting of (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), and (XXI) as defined above; In the formula, R vii1 is H, methyl, ethyl, propyl, isopropyl, butyl, -(C 2 ~C 30 ) alkenyl, -(C 2 ~C 30 ) Alkynyl, -OCH 3 , -OCH 2 CH 3 , F, Cl, Br, I, -CF 3 , -OCF 3 , -NO 2 , -CN, -NH 2 , -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -CH(CH 3 )NH 2 , -CH 2 CH(CH 3 )NH 2 , -CH 2 CH 2 CH2 NH 2 , -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -NCH(CH 3 ) 2 , -NHCH 3 , -NHCH 2 CH 3 , and -NHCH(CH 3 ) 2 Selected from; where b1, c1, d1, e1, f1, g1, h1, i1, and j1 are independently integers ranging from 1 to 6; In the formula, R 9 and R 10 are optionally combined together to form a proline ring moiety; R17 and R18 are optionally combined together to form a proline ring moiety; r, s, t, and u are independently integers ranging from 0 to 250, and at least one of r or t is 1 or greater.

[0147] According to a more specific embodiment, for both compounds of formula Ia or Ib: In the formula, R1 is -CH 2 CH 2 -SS-CH 2 CH 2 -, -CH 2 CH 2 CH 2 -SS-CH 2 CH 2 CH 2 -, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 -, -CH 2 CH(CH 2 CH 3 )CH 2 -, --CH 2 CH 2 CH2 CH 2 -, -CH 2 COO-, -CH 2 CH 2 COO-, -CH 2 CHCH 3 COO-, -CH 2 CH 2 CH 3 CH 2 a biradical selected from the group consisting of COO-, and a biradical selected from the group consisting of (V), (VI), (VII), (VIII), (IX), (X), (XI), and (XII) as defined above; R 9 and R 17 is H, methyl, ethyl, propyl, isopropyl, butyl, n-butyl, -CH 2 SCH 3 , -CH 2 CH 2 SCH 3 , -CH 2 CH 2 SCH 2 CH 3 , -CH 2 SCH 2 CH 3 , -CH 2 SH, -CH 2 CH 2 S.H., C.H. 2 SeH, -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 CH 2 NH 2 and a radical selected from the group consisting of (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), and (XXI) as defined above; R vii1 is H, methyl, ethyl, propyl, isopropyl, butyl, -OCH 3 , -OCH 2 CH 3 , F, Cl, Br, I, -CF 3 , OCF 3 , -NO 2 , -CN, -NH 2 , -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -CH 2 CH(CH 3 )NH 2 , -CH 2 CH 2 CH 2 NH 2 , -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -NCH(CH 3 ) 2 , -NHCH 3 , -NHCH 2 CH 3 , and -NHCH(CH 3 ) 2 Selected from; b1, c1, d1, e1, f1, g1, h1, i1, and j1 are independently integers ranging from 1 to 6; In the formula, R 9 and R 10 are optionally combined together to form a proline ring moiety; R17 and R18 are optionally combined together to form a proline ring moiety; R 6 , R 7 , R 14 , R 15 and R 19 is H, methyl, ethyl, propyl, isopropyl, butyl, -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , -CH2 CH 2 OCH 2 CH 3 、 -CH 2 CH 2 OCH(CH 3 ) 2 、-CH 2 OCH 2 CH 3 、-CH 2 OCH(CH 3 )2、-(C 2 ~C 30 )アルケニル、 -(C 2 ~C 30 )アルキニル、-CH 2 SCH 3 、-CH 2 CH 2 SCH 3 、-CH 2 SH、CH 2 SeH-CH 2 CH 2 SH、 -CH 2 CH 2 SCH 2 CH 3 、-CH 2 SCH 2 CH 3 、-CH 2 NH 2 、-CH 2 CH 2 NH 2 、-CH 2 CH 2 CH 2 NH 2 、-CH 2 CH(CH 3 )CH 2 NH 2 、-CH 2 NHCH 3 、-CH 2 NHCH 2 CH 3 、-CH 2 CH 2 NHCH 3 、 -CH 2 CH 2 NHCH 2 CH 3、-CH 2 CH 2 CH 2 NHCH 3 、-CH 2 CH 2 CH 2 NHCH 2 CH 3 、 -CH 2 CH(CH 3 )CH 2 NHCH 3 、-CH 2 CH(CH 3 )CH 2 NHCH 2 CH 3 、 -CH 2 CH 2 NHCH 2 CH 2 NH 2 、-CH 2 CH 2 CH 2 NHCH 2 CH 2 CH 2 NH 2 、 -CH 2 CH 2 N((CH(CH 3 ) 2 ))、-CH 2 CH 2 CH 2 N((CH(CH 3 ) 2 ))、-CH 2 CH 2 NH(CH(CH 3 ) 2 )、 -CH 2 CH 2 CH 2 NH(CH(CH 3 ) 2 )、-C(O)H、-C(O)OCH 3 、-C(O)OCH 2 CH 3 、 -C(O)OCH(CH 3 ) 2 、-C(O)CH 2 NH 2 、-C(O)CH2 CH 2 NH 2 、-C(O)CH(CH 3 )CH 2 NH 2 、 -C(O)CH 2 NHCH 3 、-C(O)CH 2 NHCH 2 CH 3 、-C(O)CH 2 CH 2 NHCH 2 CH 3 、 -C(O)CH 2 CH 2 CH 2 NHCH 2 CH 3 、-C(O)CH 2 CH 2 CH 2 NHCH 2 CH 2 CH 3 、 -C(O)CH 2 CH(CH 3 )CH 2 NHCH 3 、-C(O)CH 2 CH(CH 3 )CH 2 NHCH 2 CH 3 、 -C(O)CH 2 CH 2 NHCH 2 CH 2 NH 2 、-C(O)CH 2 CH 2 CH 2 NHCH 2 CH 2 CH 2 NH 2 、 -C(O)CH 2 CH 2 N((CH(CH 3 ) 2 ))、-C(O)CH 2 CH 2 CH 2 N((CH(CH 3) 2 )) -C(O)CH 2 CH 2 NH(CH(CH 3 ) 2 ), -C(O)CH 2 CH 2 CH 2 NH(CH(CH 3 ) 2 ), -CH 2 COOH, -CH 2 CH 2 COOH, -CH 2 COOCH 3 , -CH 2 CH 2 COOCH 3 , -CH 2 COOCH 2 CH 3 , -CH 2 CH 2 COOCH 2 CH 3 , -CH 2 COOCH(CH 3 ) 2 , -(C 1 ~C 6 ) Alkyl-R i2 , -(C 1 ~C 6 )Alkyl-OR iii2 , -(C 1 ~C 6 )Alkyl-NR iv2 R v2 , independently selected from the group consisting of -CONH-oleic acid, -CONH-noneic acid, -CONH-lipoic acid, and radicals selected from the group consisting of (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), and (XXXI) as defined above; R i2 is imidazole, N-methylpyrrole, pyrrole, pyrrolidine, pyran, pyridine, piperidine, pyrimidine, -OC(O)NH 2 , -OC(O)N((C1 ~C 6 )Alkyl) 2 selected from the group consisting of; R iii2 , R iv2 , and R v2 is H, -(C 2 ~C 30 ) alkenyl, -(C 2 ~C 30 ) alkynyl, -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 NH 2 , -CH 2 CH(CH 3 )CH 2 NH 2 , -CH 2 NHCH 3 , -CH 2 NHCH 2 CH 3 , -CH 2 CH 2 NHCH 3 , -CH 2 CH 2 NHCH 2 CH 3 , -CH 2 CH 2 CH 2 NHCH 3 , -CH 2 CH 2 CH 2 NHCH 2 CH 3 , -CH 2 CH(CH 3 )CH 2 NHCH 3 , -CH 2 CH(CH 3 )CH 2 NHCH 2 CH 3 , -CH 2 CH 2 NHCH2 CH 2 NH 2 , -CH 2 CH 2 CH 2 NHCH 2 CH 2 CH 2 NH 2 , -CH 2 CH 2 N((CH(CH 3 ) 2 )), -CH 2 CH 2 CH 2 N((CH(CH 3 ) 2 )), -CH 2 CH 2 NH(CH(CH 3 ) 2 ), -CH 2 CH 2 CH 2 NH(CH(CH 3 ) 2 and radicals selected from the group consisting of (XXXII), (XXXIII), (XXXIV), (XXXV), (XXXVI), (XXXVII), (XXXVIII), (XXXIX), (XL), (XLI), (XLII), (XLIII), (XLIV), (XLV), and (XLVI), as defined above; R vii2 and R vii2’ is H, methyl, ethyl, propyl, isopropyl, butyl, F, Cl, Br, I, -CF 3 , -OCF 3 , -NO 2 , -CN, -NH 2 , and -(C 1 ~C 6 )Alkyl-NH 2 are independently selected from; R viii2 , R ix2 , R viii2’ , and R ix2’’ is H, methyl, ethyl, propyl, isopropyl, -CH 2 NH 2 , -CH 2CH 2 NH 2 、-CH 2 CH 2 CH 2 NH 2 、 -CH 2 CH(CH 3 )CH 2 NH 2 、-CH 2 NHCH 3 、-CH 2 NHCH 2 CH 3 、-CH 2 CH 2 NHCH 3 、 -CH 2 CH 2 NHCH 2 CH 3 、-CH 2 CH 2 CH 2 NHCH 3 、-CH 2 CH 2 CH 2 NHCH 2 CH 3 、 -CH 2 CH(CH 3 )CH 2 NHCH 3 、-CH 2 CH(CH 3 )CH 2 NHCH 2 CH 3 、 -CH 2 CH 2 NHCH 2 CH 2 NH 2 、-CH 2 CH 2 CH 2 NHCH 2 CH 2 CH 2 NH 2 、 -CH 2 CH 2 N((CH(CH 3 ) 2 ))、-CH 2 CH 2CH 2 N((CH(CH 3 ) 2 )), -CH 2 CH 2 NH(CH(CH 3 ) 2 ), -CH 2 CH 2 CH 2 NH(CH(CH 3 ) 2 ) are independently selected; In the formula, R i2 , R iii2 , R iv2 , R v2 , R vi2 , R vii2 , R viii2 , R ix2 , R viii2’ , and R ix2’ are OH, F, Cl, Br, -OCH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 , -CF 3 , -OCF 3 , -NH 2 , -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 OH, -CH 2 CH 2 OH, and -CH 2 CH(OH)CH 3 optionally substituted with one or more substituents selected from the group consisting of: b2, c2, d2, e2, h2, k2, l2, k2', l2', b2'', c2'', d2'', e2'', and h2'' are independently integers ranging from 1 to 4; b2', c2', d2', e2', and h2' are independently integers ranging from 0 to 4; m2, n2, m2', and n2' are independently integers ranging from 1 to 120.

[0148] According to a more specific embodiment, in formula (I), r, s, t, and u represent the number of repeats of the repeating unit, and are integers in the range of 0 to 400, preferably integers of 0 to 250, preferably integers of 0 to 200, more preferably integers of 0 to 150; particularly preferably integers of 0 to 100.

[0149] In a more specific embodiment, r+t is an integer from 2-400, preferably from 4-250, preferably from 10-200, preferably from 15-150, preferably from 20-100.

[0150] According to one embodiment, in a compound of formula (I) as defined herein, a) the molar ratio of PAA1 monomer to PAA2 is from 100 / 0 to 65 / 35, in particular from 100 / 0 to 70 / 30, more particularly from 100 / 0 to 75 / 25, even more particularly from 100 / 0 to 80 / 20, from 100 / 0 to 85 / 15, from 100 / 0 to 90 / 10, from 100 / 0 to 95 / 5; b) the molar ratio of PAA1 monomer to PAA4 is from 100 / 0 to 65 / 35, in particular from 100 / 0 to 70 / 30, more particularly from 100 / 0 to 75 / 25, even more particularly from 100 / 0 to 80 / 20, from 100 / 0 to 85 / 15, from 100 / 0 to 90 / 10, from 100 / 0 to 95 / 5; c) the molar ratio of PAA3 monomer to PAA4 is from 100 / 0 to 65 / 35, in particular from 100 / 0 to 70 / 30, more particularly from 100 / 0 to 75 / 25, even more particularly from 100 / 0 to 80 / 20, from 100 / 0 to 85 / 15, from 100 / 0 to 90 / 10, from 100 / 0 to 95 / 5; d) the molar ratio of PAA3 monomer to PAA2 is from 100 / 0 to 65 / 35, in particular from 100 / 0 to 70 / 30, more particularly from 100 / 0 to 75 / 25, even more particularly from 100 / 0 to 80 / 20, from 100 / 0 to 85 / 15, from 100 / 0 to 90 / 10, from 100 / 0 to 95 / 5; Here, the molar ratio of the sum of PAA1+PAA3 monomers to the sum of PAA2+PAA4 monomers is 100 / 0 to 65 / 35, particularly 100 / 0 to 70 / 30, more specifically 100 / 0 to 75 / 25, even more specifically 100 / 0 to 80 / 20, 100 / 0 to 85 / 15, 100 / 0 to 90 / 10, 100 / 0 to 95 / 5.

[0151] Particularly preferred compounds of formula I according to the present disclosure are as follows (their preparation processes, complete chemical structures, 1 Details regarding H NMR, DP, Mn and other properties are given in the examples below): [Table 1] TIFF2024528853000014.tif53159

[0152] It should be noted that the values ​​given in parentheses indicate the degree of polymerization (DP) of each monomer unit as a statistical value. The DP of a particular monomer unit contained in a copolymer is calculated by a combination of two techniques. First, the ratio of different monomers is evaluated by NMR spectroscopy, and then the DP of each repeating structural motif is calculated based on the absolute MW obtained by SEC-MALS technique by dividing the molecular weight of the polymer by the molecular weight of the monomer unit. The DP of a homopolymer is calculated directly by dividing the molecular weight of the polymer by the molecular weight of the monomer unit. The DP value is reported as the center value of a Gaussian distribution that includes polymers of various DP (depending on the inherent polydispersity). This DP value is also subject to a reasonable uncertainty due to the ring-opening polymerization mechanism, which in the context of the present invention is considered to be within ±20%, preferably ±15%, more preferably ±10%, even more preferably ±5%, and particularly preferably ±2% of the nominal DP value.

[0153] The term "polydispersity index" (PDI) is used as a measure of the broadness of the molecular weight distribution. The higher the PDI, the broader the molecular weight. The PDI of a polymer is calculated as the ratio of the weight average (MW) to the number average (Mn) molecular weight.

number

[0154] Thus, for example, compound 35 (CP35:St-SS-PAspDET(51) / DIIPA(20)-b-PSar(58)) is described as having a PAspDET DP of 51, a DIIPA DP of 20, and a PSar DP of 58; DP numbers quoted herein are subject to reasonable uncertainties within the ranges noted above.

[0155] The compound of formula (I) above has two or more different amino groups, and each of the amino groups shows a different pKa value.At pH 7.4, which is physiological condition, the amino group is in a partially protonated state, and therefore the compound can suitably form a complex (for example, a polyion complex) with nucleic acid through electrostatic interaction.When the complex is taken up into endosome (pH 5.5), the protonation of the amino group can further proceed, and can promote endosomal escape based on the buffer "proton sponge" effect.

[0156] All terms used herein in this application are to be understood in their ordinary meaning as known in the art unless otherwise specified. Other, more specific definitions of certain terms used in this application are set forth below and are intended to be applied uniformly throughout the specification and claims, unless a definition expressly set forth otherwise provides a broader definition.

[0157] Throughout the description and claims, the word "comprise" and variations of the word are not intended to exclude other technical features, additives, components, or steps. Furthermore, the word "comprise" also includes "consisting of". Additional objects, advantages, and features of the present disclosure will become apparent to those skilled in the art upon consideration of the detailed description or may be learned by practicing the present disclosure. The following examples and drawings are provided by way of illustration and are not intended to limit the present disclosure. Reference signs placed in parentheses in connection with the drawings and in the claims are intended only to enhance the completeness of the claims and are not to be construed as limiting the scope of the claims. Furthermore, the present disclosure includes all possible combinations of the specific preferred embodiments described herein.

[0158] While only a few examples are disclosed herein, other alternatives, modifications, uses and / or equivalents are possible. Moreover, all possible combinations of the described embodiments are covered. Thus, the scope of the disclosure should not be limited by the specific embodiments, but should be determined only by a fair reading of the following claims.

[0159] Working Example In the following examples, a and a′ are independently integers from 0 to 1, and R 3 does not exist when a = 1, and R 11 does not exist when a' = 1. Mixtures of compounds where a = 0 and a = 1, and where a' = 0 and a' = 1, may be obtained.

[0160] For ease of illustration only, in the examples that follow, the structures depicted represent only one isomer of the aspartic acid backbone (ie, when a=0 and a′=0).

[0161] Thus, for example, a compound of formula (1) may be represented, for ease of illustration only, as follows: [ka]

[0162] Nevertheless, compounds of formula (1) may contain a mixture of repeating aspartic acid backbone blocks, as shown in formula (1'): [ka]

[0163] Example 1. Preparation of compounds of formula (Ib1). [ka]

[0164] Generally, to synthesize the compounds of formula (Ib1) according to the present disclosure, a three-arm star initiator was first obtained within 2-3 steps. Such an initiator was used to polymerize γ-benzyl L-aspartic acid-NCA to produce a benzyl-protected star polymer (St-PAsp(Bz)). The benzyl group was removed by aminolysis reaction to obtain the corresponding Star-PAsp-oligoamine.

[0165] Scheme 1 shows a specific example of the polymerization and aminolysis steps: [ka]

[0166] Example 1A Synthesis of a 3-Arm Star Initiator Synthetic routes to two classes of three-arm star initiators are described below.

[0167] Example 1A.1: N1,N3,N5-tris(2-aminoethyl)benzene-1,3,5-tricarboxamide (St-initiator) (1) The title compound was synthesized according to the general procedure disclosed in Scheme 2. [ka]

[0168] Step (a): Synthesis of 1,3,5-tri-tert-butyl((benzenetricarbonyltris-(azanediyl))tris(ethane-2,1-diyl))tricarbamate (2): [ka]

[0169] Stir bar and N 2 In a two-necked round bottom flask equipped with an inlet and an outlet, 500 mg of 1,3,5-benzenetricarbonyl trichloride (1.88 mmol, 1 equiv.) was dissolved in 12 mL of anhydrous THF. N,N',N''-diisopropylethylenediamine (DIEA) (803.31 mg, 6.22 mmol, 3.3 equiv.) was added to the reaction mixture, followed by the dropwise addition of N-Boc-ethylenediamine (1.34 g, 6.22 mmol, 3.3 equiv.) over a period of 10 minutes. The reaction was then allowed to proceed for 2 hours. The solvent was then completely removed under vacuum. The product was redissolved in chloroform and washed with deionized water (ddH 2 The organic phase was then washed three times with 100 mL of 1.0 MgCl2 and three times with acidic water (pH approx. 3). Finally, the organic phase was isolated under vacuum and the product was recrystallized three times from THF / methanol / hexane to give a white crystalline solid. The product was then dried under high vacuum and stored at -20°C. Yield: 82%. 1 H NMR (300 MHz, DMSO) δ 8.68-8.65 (m, 3H), 8.41 (s, 3H), 6.92-6.88(m, 3H), 3.34-3.31 (m, 6H), 3.16-3.13 (m, 6H), 1.37 (s, 27H). 13 C NMR (75 MHz, CDCl 3 ) δ 166.80 (C=O), 156.84 (C=O), 134.58 (Car quaternary), 128.47 (CH Ar ), 79.57 (C quaternary), 40.93 (CH 2 ), 40.43 (CH 2), 28.45 (CH 3 ).

[0170] Step (b): Synthesis of 1,3,5-(benzenetricarbonyltris(azanediyl))-triethanemonium TFA salt (3): [ka]

[0171] In a round bottom flask equipped with a stir bar and stopper, 200 mg of 1,3,5-tri-tert-butyl((benzenetricarbonyltris(azanediyl))tris(ethane-2,1-diyl))tricarbamate (2) (0.33 mmol, 1 equiv.) was dissolved in 5 mL of anhydrous dichloromethane and 2.5 mL of TFA was added. The reaction was stirred under nitrogen atmosphere for 2 h and completion of the reaction was monitored by TLC. The solvent was evaporated in vacuum. The TFA salt of the initiator (220 mg) was obtained in quantitative yield and dried under vacuum. Yield: 98%. 1 H NMR (300 MHz, D 2 O) δ 8.36 (s, 3H), 3.75 (t, J= 5,9 Hz, 6H) 3.29 (t, J= 6,0 Hz, 6H). 19 F NMR (300 MHz, D 2 O) δ-75.84.

[0172] Step (c): N 1 ,N 3 ,N 5 Synthesis of -tris(2-aminoethyl)benzene-1,3,5-tricarboxamide (1): [ka]

[0173] 220 mg of 1,3,5-(benzenetricarbonyltris(azanediyl))triethanemonium TFA salt (3) was dissolved in 22 mL of HO:MeOH (7:3) mixture and stirred with excess of weakly basic Amberlyst ion exchange resin (1000 mol%) for 24 h. The mixture was then filtered and the filtrate was concentrated by removing methanol. The aqueous solution was lyophilized to give the free base amine in high purity. Yield: 98%. 1 H NMR (300 MHz, D 2 O) δ 8.13 (s, 3H), 3.45 (t, J= 6,3 Hz, 6H) 2.86 (t, J= 6,3 Hz, 6H).

[0174] Example 1A.2: Trifluoroacetate salt of N,N,N-tris(2-((2-aminoethyl)disulfanyl)ethyl)benzene-1,3,5-tricarboxamide (St-SS-initiator) (4) The trifluoroacetate salt of N,N,N-tris(2-((2-aminoethyl)disulfanyl)ethyl)benzene-1,3,5-tricarboxamide (St-SS-initiator) (4) was synthesized according to the general procedure disclosed in Scheme 3. [ka]

[0175] The synthesis of the trimeric amine initiator begins with a coupling reaction followed by deprotection of the amine.

[0176] Step (a) Synthesis of tri-tert-butyl((((benzenetricarbonyltris-(azanediyl))tris(ethane-2,1-diyl))tris(disulfanediyl))tris(ethane-2,1-diyl))-tricarbamate (5): [ka]

[0177] N-(tert-butyloxycarbonyl)cystamine (7.99, 27 mmol, 3.3 equiv.) was weighed into a flame-dried two-necked round-bottom flask and dissolved in 56 mL of anhydrous THF. Freshly distilled DIPEA (4.75 mL, 27 mmol, 3.3 equiv.) was added and stirred at room temperature for 15 min. 1,3,5-benzenetricarbonyl trichloride (2.25 g, 8.3 mmol, 1 equiv.) was weighed into a flame-dried two-necked round-bottom flask and dissolved in 28 mL of anhydrous THF. The trichloride solution was slowly added to the N-(tert-butyloxycarbonyl)cystamine mixture via syringe. The progress of the reaction was monitored by thin layer chromatography (TLC). After 4 h, the solvent was evaporated in vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed successively with Milli-Q water, 1 M hydrochloric acid and saturated sodium bicarbonate solution. The organic phase was dried over anhydrous magnesium sulfate and concentrated in vacuo to give tri-tert-butyl((((benzenetricarbonyltris-(azanediyl))tris(ethane-2,1-diyl))tris(disulfanediyl))tris(ethane-21-diyl))-tricarbamate (5) as a white foam (7.5 g, η=98%). 1 H NMR (CDCl 3 ): δ = 1.39 (brs, 27H, -C(CH 3 ) 3 ), 2.84 (t, J = 6.26 Hz, 6H, CH 2 ), 2.96 (t, J = 6.84 Hz, 6H.CH 2 ), 3.46 (m, 6H, CH 2 ), 3.79 (m, 6H, CH 2 ), 5.18 (brs, 3H, -NHBoc), 7.39 (brs, 3H, arylCH).

[0178] Step (b): Synthesis of the trifluoroacetate salt of N,N,N-tris(2-((2-aminoethyl)disulfanyl)ethyl)benzene-1,3,5-tricarboxamide (St-SS-initiator) (4): [ka]

[0179] 7.5 g (8.19 mmol) of initiator (5) was dissolved in anhydrous dichloromethane (180 mL) and 90 mL of TFA was added. The reaction was stirred under nitrogen atmosphere for 60 min and completion of the reaction was monitored by TLC. The solvent was evaporated under vacuum. The TFA salt of initiator (4) (7 g, 7.31 mmol) was obtained in quantitative yield and dried under vacuum. 1 H NMR (D 2 O): δ = 2.86 (m, 12 H), 3.25 (t, J = 6.49 Hz, 8H), 3.60 (t, J = 6.85 Hz, 8H), 8.02 (brs, 3H, aryl CH).

[0180] Example 1A.3: Trifluoroacetate salt of N1,N3,N5-tris(2-((R)-2-((R)-2-amino-3-methylbutanamido)propanamido)ethyl)benzene-1,3,5-tricarboxamide (1b). [ka]

[0181] The synthesis of the trimeric amine initiator begins with a coupling reaction followed by deprotection of the amine.

[0182] Synthesis of tri-tert-butyl ((2,2',2''R)-(((2,2',2''R)-(((benzenetricarbonyltris(azanediyl))tris(ethane-2,1-diyl))tris(azanediyl))tris(1-oxopropane-2,1-diyl))tris(azanediyl))tris(3-methyl-1-oxobutane-2,1-diyl))tricarbamate (2b). [ka]

[0183] Boc-Val-Ala-OH (1.5 g, 5.35 mmol) was added to a two-neck round-bottom flask equipped with a stir bar and stopper, then vacuum / N 2 The mixture was purged with 3 cycles of 0.1% hexanes and dissolved in 10 mL of DMF. CDI (4 eq., 5.8 mmol, 941 mg) was then added to the reaction mixture and stirred at room temperature for 30 min. After this time, N1,N3,N5-tris(2-aminoethyl)benzene-1,3,5-tricarboxamide (St-initiator: 500 mg, 1.488 mmol) dissolved in 5 mL of DMF and DIPE (3 eq., 0.772 mL) was added. The mixture was stirred at room temperature for 16 h. The reaction mixture was dried under vacuum and the product was purified using column chromatography (Rf: 0.3, DCM:MeOH 20%). The final product was isolated as a yellow sticky solid.

[0184] The product synthesis of tri-tert-butyl ((2,2',2''R)-(((2,2',2''R)-(((benzenetricarbonyltris(azanediyl))tris(ethane-2,1-diyl))tris(azanediyl))tris(1-oxopropane-2,1-diyl))tris(azanediyl))tris(3-methyl-1-oxobutane-2,1-diyl))tricarbamate exhibits rotamers due to the presence of carbamates in the molecule and NMR will be explained in the next step.

[0185] Synthesis of N1,N3,N5-tris(2-((R)-2-((R)-2-amino-3-methylbutanamido)propanamido)ethyl)benzene-1,3,5-tricarboxamide trifluoroacetate (1b). [ka]

[0186] The experimental procedure for acid deprotection of the Boc protecting group is the same as that described above for the trifluoroacetate salt of N,N,N-tris(2-((2-aminoethyl)disulfanyl)ethyl)benzene-1,3,5-tricarboxamide.

[0187] Yield: 97%. 1 H NMR (300 MHz, D 2 O) δ 8.30 (s, 3H), 4.36 (q, J= 7.1 Hz, CH), 3.82 (dd, J= 10.7, 6.1 Hz, CH), 3.58 (dd, J= 16.6, 4.6 Hz, CH 2 ), 2.19 (m, CH), 1.39 (dd, J= 7.1, 3.9 Hz, CH 3 ), 0.95 (d, J= 6.9 Hz, CH 3 ).

[0188] Example 1A.4: N1,N3,N5-Tris(2-(2,6-diaminohexanamido)ethyl)benzene-1,3,5-tricarboxamide TFA salt:. [ka]

[0189] The synthesis of the trimeric amine initiator begins with a coupling reaction followed by deprotection of the amine.

[0190] Synthesis of hexa-tert-butyl((((((benzene-1,3,5-tricarbonyl)tris(azanediyl))tris(ethane-2,1-diyl))tris(azanediyl))tris(2-oxoethane-2,1-diyl))tris(azanediyl))tris(5-oxopentane-5,1,4-triyl))hexacarbamate (2c) [ka]

[0191] Boc-Lys(Boc)OH (741 mg, 2.14 mmol, 6 equiv.) was weighed into a Schlenk flask along with N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uranium hexafluorophosphate (HBTU, 879 mg, 2.318 mmol, 6.5 equiv.) and 1-hydroxybenzotriazole (HOBt, 313 mg, 2.318 mmol, 7 equiv.) and dissolved in 2 mL of anhydrous DMF. DIPEA (617 μL, 10 equiv.) was added directly and the mixture was stirred at 0° C. for 30 min. In a separate Schlenk flask, butyl-based 3-arm initiator (120 mg, 0.356 mmol, 1 equiv.) was dissolved in 1.6 mL of anhydrous DMF. The di-Boc-lysine mixture was then added to the 3-arm initiator solution and stirred at room temperature for 2 days. The reaction mixture was then diluted with 0.5 M KHSO 4 The organic layers were combined and then washed with H2O and brine. 2 SO 4 After passing through a silica gel column, the organic layer was evaporated under reduced pressure. The residue was purified using column chromatography (Rf=0.45, EtOAc / MeOH 10%) to give 200 mg of pure product.

[0192] Yield: 42%. 1 H NMR (300 MHz, D 2 O) δ 8.43 (s, aryl CH), 4.02-3.91 (m, CH), 3.65-3.38 (m, CH2), 3.05-2.96 (m, CH2), 1.71 (m, CH2), 1.63-1.51 (m, CH2), 1.50-1.29 (m, CH3).

[0193] Synthesis of N1,N3,N5-tris(2-(2,6-diaminohexanamido)ethyl)benzene-1,3,5-tricarboxamide TFA salt [ka]

[0194] The experimental procedure for acid deprotection of the Boc protecting group is the same as that described above for the trifluoroacetate salt of N,N,N-tris(2-((2-aminoethyl)disulfanyl)ethyl)benzene-1,3,5-tricarboxamide. Yield:98 %.1H NMR (300 MHz, D2O) δ 8.28 (s, aryl CH), 3.97 (t, J= 6.6 Hz, CH), 3.68-3.44 (m, CH2), 2.91 (t, J=7.6 Hz, CH2), 1.98-1.78 (m, CH2), 1.71-1.56 (m, CH2), 1.46-1.36 (m, CH2), 1.34 (d, J= 6.4 Hz, CH2).

[0195] Example 1B: St-Poly(β-benzyl-L-aspartic acid) (Star-PAsp(Bz)) (6) The general procedure for the polymerization of St-PAsp(Bz) (6) is as follows: [ka]

[0196] β-Benzyl-L-aspartate-NCA (5 g, 2 mmol) was added to a Schlenk flask equipped with a stir bar and stopper, and vacuum / N 2 The reaction mixture was purged with 3 cycles of 0.1 mL of 100 mL of chloroform and dissolved in a mixture of anhydrous chloroform (100 mL) and DMF (6 mL). Next, star-shaped initiator (St) was dissolved in DMF (4 mL) and added to the reaction mixture. The mixture was stirred at 50° C. for 16 h. Upon completion, the reaction mixture became clear and complete conversion of the monomer could be detected by IR. The reaction mixture was poured into diethyl ether to precipitate the product. The precipitate was isolated by centrifugation (3750 rpm, 4 min) and dried under vacuum. St-poly(β-benzyl-L-aspartate) (Star-PAsp(Bz)) (6) was isolated as a white solid.

[0197] Yield: 70-90% 1 H NMR (TFA): δ = 2.92 (m, 2H, CH2 ), 4.85 (s, 1H, CH), 5.05 (m, 2H, benzyl CH 2 ), 7.13 (s, 5H, arylCH), 8.38 (s, arylCH).

[0198] Table 1 shows the different initiators used in the polymerization process and the different DP (degree of polymerization) obtained for different Star-PAsp(Bz) of formula (6), demonstrating the versatility and accuracy of the experimental procedure. [Table 2]

[0199] Example 1C. Aminolysis of Poly(β-benzyl-L-aspartic acid) (6) to Obtain St-PAsp-Oligoamine (7) General procedure for aminolysis reactions to produce polycationic homopolymers regardless of the nature of the initiator and amine used in the polymerization step: [ka]

[0200] St-PAsp(Bz) (6) (DP=50, 750 mg) was dissolved in NMP (15 mL) and cooled to 4 °C. This solution was added dropwise to a cooled oligoamine (50 equivalents of DET, TEP or imidazole amine per Asp unit) at 4 °C, and the mixture was stirred at the same temperature for 4 h. After this time, the reaction mixture was added dropwise to cold HCl 6 M for neutralization (pH 3.5). The polymer product was purified by centrifuge-assisted ultrafiltration. After filtration through a 0.22 μm PES filter, the remaining aqueous polymer solution was lyophilized to give the final product (370 mg, η=50%).

[0201] 1 H NMR [St-PAspDET] (D 2 O): δ 2.93 (brs, 2H, CH 2 ), 3.12-3.85 (m, 2H, CH2 ), 8.33 (s, 3H, arylCH).

[0202] 1 H NMR [St-SS-PAsp imidazolamine] (D 2 O): δ 2.02 (brs, 2H, CH 2 ), 2.76 (m, 2H, CH 2 ), 3.14 (brs, 2H, CH 2 ), 4.16 (m, 2H, CH 2 ), 4.60 (m, 1H, CH), 7.38 (s, 1H, imidazole CH), 7.43 (s, 1H, imidazole CH), 8.23 ​​(s, 3H, aryl CH), 8.61 (m, 1H, imidazole CH).

[0203] 1 H NMR [St-SS-PAspTEP] (D 2 O): δ 2.68-3.84 (m, 2H, CH2), 8.38 (s, 3H, arylCH).

[0204] Table 2 shows different St-PAsp-DET derivatives of formula (7). [Table 3]

[0205] Example 2. Synthesis of compounds of formula (Ib2). [ka]

[0206] Example 2A. Synthesis of polycationic polymer Star-PAspDET / (DIIPA or imidazole amine) (8). Star-PAspDET / (DIIPA or imidazole amine) (8) was designed to investigate how the number of amino protonatable groups affects toxicity and transfection efficiency, and showed that the presence of a second oligoamine (DIIPA) as a side chain along with DET significantly improved transfection efficiency without compromising toxicity. PAsp(DET / (DIIPA or imidazole amine) was prepared by aminolysis reaction on St-PAsp(Bz) (6) with DET and DIIPA or 1-(3 aminopropyl)imidazole. [ka]

[0207] General procedure for aminolysis of St-PAspDET / (DIIPA or imidazole amine) (8):

[0208] St-PAsp(Bz) (6) (DP = 67, 60 mg) was dissolved in NMP (3 mL) and cooled to 4 °C. The resulting St-PAsp(Bz) solution was added dropwise to a mixture of DET (1.58 mL) and a second primary amine (DIIIPA or imidazole amine) (molar ratio 1:3) cooled at 4 °C, and the mixture was stirred at the same temperature for 4 h. After this time, the reaction mixture was added dropwise to cold HCl 6 M for neutralization (pH 3.5). The polymer product was purified by centrifuge-assisted ultrafiltration. After filtration, the remaining aqueous polymer solution was lyophilized to obtain the final product (η = 70-60%).

[0209] 1 H NMR [St-PAspDET / DIIPA] (D 2 O): δ = 1.4 (d, J = 6.4 Hz, 3H, CH 3 ), 2.91 (brs, 2H, CH 2 ), 3.15-3.88 (m, 2H, CH 2 ), 8.34 (s, arylCH).

[0210] 1H NMR [St-PAspDET / imidazole amine] (D 2 O): δ = 2.14 (brs, 2H, CH 2 ), 2.87 (brs, 2H, CH2), 3.22 (m, 2H, CH 2 ), 4.30 (brs, 2H, CH 2 ), 7.52 (s, imidazole CH), 7.57 (s, imidazole CH), 8.34 (s, aryl CH), 8.78 (s, imidazole CH).

[0211] Different Star-PAspDET / (DIIPA or imidazole amine) of formula (8) were synthesized according to a similar procedure. The ratio of the repeat unit introduction was adjusted by changing the mixture ratio of the corresponding monomer units reacted.

[0212] Table 3 shows different cationic polymers of Star-PAspDET / (DIIPA or imidazole amine) according to formula (8). [Table 4]

[0213] CP10-CP14 are cationically charged polymers of Star-PAspDET / DIIPA according to formula (8), while CP48 and CP49 are cationically charged polymers of Star-PAspDET / imidazole amine according to formula (8).

[0214] The ratio of DET / DIIPA or imidazole amine (r / t) obtained in the final cationic polymer depends on the stoichiometric ratio of DET / second primary amine to the St-PAsp(Bz)(6) unit. For example, for the St-SS-PAspDET(78) / DIIPA(21) system, 20 equivalents of DET and 60 equivalents of DIEPA were required per unit of aspartic acid used (i.e., DET / DIIPA ratio 1:3). For the St-SS-PAspDET(91) / DIIPA(29) system, a DET / DIIPA ratio of 1:4 was required. For the St-SS-PAspDET (49) / imidazole amine (17) and St-SS-PAspDET (86) / imidazole amine (31) systems, 20 equivalents of DET and 40 equivalents of 1-(3-aminopropyl)imidazole were required for 66 and 100 units of aspartic acid.

[0215] Example 3. Synthesis of amphiphilic block copolymer having formula (Ib3). [ka] The presence of hydrophobic groups in the copolymer creates an amphiphilic system and can increase the transfection efficiency in cells.

[0216] Below are synthetic routes for the introduction of amphiphilic copolymers. In particular, this example discloses the preparation of St-Rn-PAsp(DET)-co-PLeu and St-SS-PAsp(DET)-co-PPhe.

[0217] Example 3A. Synthesis of Star-PAsp(Bz)(9) copolymers containing hydrophobic fragments. [ka]

[0218] To synthesize copolymers bearing hydrophobic residues, polymerizations were carried out via a ring-opening polymerization mechanism using the trifluoroacetate salt of N,N,N-tris(2-((2-aminoethyl)disulfanyl)ethyl)-benzene-1,3,5-tricarboxamide or N1,N3,N5-tris(2-((R)-2-((R)-2-amino-3-methylbutanamido)propanamido)ethyl)benzene-1,3,5-tricarboxamide as the initiator.

[0219] General procedure for the synthesis of St-SS-PAsp(Bz)(45)-co-PLeu (5):

[0220] β-Benzyl-L-aspartic acid-N-carboxyanhydride (3.5 g, 14.15 mmol) and L-leucine-N-carboxyanhydride (247 mg, 1.57 mmol) were added to a Schlenk tube equipped with a stir bar and stopper, purged with three cycles of vacuum / N2, and dissolved in a mixture of anhydrous chloroform (100 mL) and DMF (6 mL). The star-shaped initiator was then dissolved in DMF (4 mL) and added to the reaction mixture. The mixture was stirred at 50° C. for 16 h. Upon completion, the reaction mixture became clear and complete conversion of the monomers could be detected by IR. The reaction mixture was poured into diethyl ether to precipitate the product. The precipitate was isolated by centrifugation (3750 rpm, 4 min) and dried under vacuum. The copolymer was isolated as a white solid.

[0221] Yield: 70-90% 1H NMR (TFA): δ = 0.95 (s, 3H, CH 3 ), 3.05 (s, 2H, CH), 4.98 (brs, 1H, CH), 5.17 (m, 2H, benzyl CH 2 ), 7.26 (s, 5H, arylCH), 8.51 (s, arylCH).

[0222] Different St-Rn-PAsp(Bz)-co-PLeu of formula (9) were synthesized according to a similar procedure. The ratio of the repeating units introduced was adjusted by changing the mixture ratio of the corresponding monomer units reacted.

[0223] Table 4 shows the ratios of the copolymer St-Rn-PAsp(Bz)-co-PLeu according to formula (9). [Table 5]

[0224] In the table above, R 17 =Leu refers to the leucine side chain. Rn=-CH 2 CH 2 SSCH 2 CH 2 -

[0225] Similar systems were synthesized by replacing the phenylalanine with a leucine block, but with a hydrophobic residue consistent with the protecting group of polyaspartic acid by 1H-NMR. These systems were analyzed after aminolysis reactions.

[0226] The same experimental procedure is carried out for the synthesis of St-Ala-Val-PAspDET-co-PPhe as described above, but in this case using the trifluoroacetate salt of N1,N3,N5-tris(2-((R)-2-((R)-2-amino-3-methylbutanamido)propanamido)ethyl)benzene-1,3,5-tricarboxamide as the initiator. These systems are analyzed after the aminolysis reaction.

[0227] Example 3B. Synthesis of amphiphilic polyaspartamide derivative St-Rn-PAspDET-co-PR17(10). As shown in the synthetic pathway below, various St-Rn-PAspDET-co-PR17 (10), acting as amphiphilic polyamino acids, were prepared by simultaneous aminolysis of PBLA and DET. [ka]

[0228] As an example, in this specification, R 17 The synthesis method is described in which represents either a leucine or phenylalanine group. The copolymer of St-SS-PAsp(Bz)45-co-PLeu (5) (500 mg of copolymer, 470 mg of PBLA, DP: 45) was dissolved in NMP (10 mL) and cooled to 4 °C. The resulting copolymer solution was added dropwise to a mixture of DET (12 mL, 50 equivalents relative to the PAsp(Bz) unit) and the solution was stirred at 4 °C for 4 h under nitrogen atmosphere. After this time, the reaction mixture was added dropwise into cold HCl 6 M for neutralization (pH 3.5). The polymer product was purified by centrifuge-assisted ultrafiltration. After filtration, the remaining aqueous polymer solution was lyophilized to obtain the final product.

[0229] Yield: 65-80%. 1 H NMR (D 2 O) [Rn=-CH 2 CH 2 SSCH 2 CH 2 - R 17 = Leu side chain]: δ = 0.95 (d, J = 20.0 Hz, 3H, CH3), 1.64 (brs, 1H, CH), 3.07-2.77 (m, 2H, CH2), 3.79-3.14 (m, 8H, CH2), 8.33 (s, aryl CH).

[0230] Yield: 70-80%. 1 H NMR (D 2 O) [Rn=-CH 2 CH 2 SSCH 2 CH 2 - R 17 = Phe side chain]: δ = 2.91 (brs, 2H, CH2), 3.84-3.18 (m, 2H, CH2), 7.34 (brs, 5H, aryl CH of Phe), 8.33 (s, aryl CH).

[0231] Yield: 70-80%.1 H NMR (TFA) [Rn= -Ala-Val-, R 17 = Phe side chain]: δ = 1.30 (m,3H, CH 3 ), 1.52 (m, 3H, CH 3 ), 2.24 (m,1H, CH), 2.38 (d, J = 13.3 Hz, 2H, CH 2 ), 2.62-4.37 (m, 2H, CH 2 ) 4.8-5.59 (s,1H, CH), 6.96-7.50 (brs, 5H, aryl CH of Phe), 8.74 (s,aryl CH).

[0232] Different St-Rn-PAspDET-co-PR of formula (10) 17 was synthesized according to a similar procedure. The ratio of the repeating unit introduction was adjusted by changing the mixture ratio of the corresponding monomer units reacted. Table 5 refers to the amphiphilic copolymer St-Rn-PAspDET-co-R17 according to formula (10). [Table 6]

[0233] In the above table, R 17 =Leu and R 17 =Phe refers to the leucine or phenylalanine side chains, respectively.

[0234] Example 4. Synthesis of amphiphilic block copolymer having formula (Ib4) [ka]

[0235] Example 4A. Synthesis of polycationic polymer St-SS-PAspDET / (DIIPA or imidazole amine)-co-PR9 (11a)

[0236] To improve the transfection efficiency in the polymer system described in Example 3, two different amines were introduced into St-SS-PAsp(Bz)-co-PR9(9) by aminolysis reaction in the presence of DET and either DIIPA or 1-(3-aminopropyl)imidazole as the second primary amine. [ka]

[0237] As described above (Example 2A), the general procedure for the synthesis of amphiphilic copolymer St-SS-PAspDET / (DIIPA or imidazole amine)-co-PR9 begins by dissolving the copolymer (DP of PBLA=45, 300 mg) in NMP (10 mL) and cooling to 4° C. The resulting polymer solution was added dropwise to a mixture of DET (3 mL) and a second primary amine. In the case of DIIPA, the molar ratio to the DET equivalent is 1:4, and in the case of 1-(3 aminopropyl)imidazole, the molar ratio is 1:2. After cooling to 4° C., the mixture was stirred at this temperature for 4 hours. After this time, the reaction mixture was added dropwise into cold HCl 6M for neutralization (pH 3.5). The polymer product was purified by centrifuge-assisted ultrafiltration. After filtration, the remaining aqueous polymer solution was lyophilized to obtain the final product.

[0238] Yield: 70-80%. 1 H NMR (D 2 O) [R9= Leu side chain, Z= DIIPA]: δ = 1.01-0.81 (m, 3H, CH3), 1.47-1.25 (m, 3H, CH3), 1.64 (brs, 1H, CH), 2.94 (m, 2H, CH2), 3.95-3.19 (m, 2H, CH2), 4.39 (brs, 1H, CH), 8.35 (s, arylCH).

[0239] Yield: 70-80%. 1 H NMR (D 2O) [R9 = Phe side chain], Z = DIIPA: δ = 1.40 (m, 3H, CH3), 2.93 (m, 2H, CH2), 3.87-3.16 (m, 2 H, CH2), 7.38 (brs, 5H, aryl CH of Phe), 8.34 (s, aryl CH).

[0240] Yield: 70-80%. 1 H NMR (D 2 O) [R9 = Phe side chain, Z = aminopropylimidazole]: δ = 2.15 (brs, 2H, CH 2 ), 2.56-3.12 (brs, 2H, CH 2 ), 3.14-3.87 (m, 2H, CH 2 ), 4.30 (brs, 2H, CH 2 ), 7.34 (brs, phenyl CH), 7.52 (s, imidazole CH), 7.57 (s, imidazole CH), 8.33 (s, aryl CH), 8.75 (s, imidazole CH).

[0241] Different St-SS-PAspDET / Z-co-PR9 of formula (11a) were synthesized according to a similar procedure, and the ratio of the repeating units introduced was adjusted by changing the mixture ratio of the corresponding monomer units reacted.

[0242] Table 6 shows the amphiphilic copolymer St-SS-PAspDET / Z-co-PR9 according to formula (11a). [Table 7]

[0243] In the above table, R9=Leu and R9=Phe refer to the leucine side chain or phenylalanine, and Z refers to DIIPA or aminopropylimidazole side chain, respectively.

[0244] Example 4B. Synthesis of polycationic polymer St-SS-PAspDET-co-P (cyclic R9-R10) (11b) To improve the transfection efficiency in the polymer system described in Example 3, a new hydrophobic residue, polyproline, is introduced. The synthetic strategy consists of using St-SS-PAsp(Bz)(6) as initiator and polymerizing a terminal proline block. Once the diblock is generated, an aminolysis reaction is carried out using DET. [ka]

[0245] Different St-SS-Pasp(Bz)-b-Ppro were synthesized following similar procedures as described above or below for similar products.

[0246] Table 7 shows the proportions of the copolymer St-SS-Pasp(Bz)-b-Ppro according to formula (11b). [Table 8]

[0247] In the table above, R=Pro refers to the proline side chain.

[0248] Yield: 65-80%. 1 H NMR (DMSO)]: δ = 1.79 (brs, 2H, CH 2 ), 2.54-2.92 (m, 2H, CH 2 ), 3.56 (brs, H, CH), 4.62 (m, H, CH), 4.83-5.17 (m, 2H, benzyl CH 2 ), 7.10-7.45 (m, aryl CH), 7.82 (s, aryl CH)

[0249] As an example, a synthetic method is described herein in which R9 and R10 in diagram (Ib4) combine together to form a proline ring moiety. Copolymer of St-S-SPAsp(Bz)100-b-Ppro (10) (500 mg, DP: 100) was dissolved in NMP (7 mL) and cooled to 4°C. The resulting copolymer solution was added dropwise to a mixture of DET (13 mL, 50 equivalents relative to Pasp(Bz) unit) and the solution was stirred for 4 hours at 4°C under nitrogen atmosphere. After this time, the reaction mixture was added dropwise into cold HCl 6M for neutralization (pH 3.5). The polymer product was purified by centrifuge-assisted ultrafiltration. After filtration, the remaining aqueous polymer solution was lyophilized to obtain the final product. Yield: 70-90%. 1 H NMR (D 2 O) δ = 1.78-2.52 (m, 2H, CH 2 ), 2.93 (brs, 2H, CH 2 ), 3.18-3.88 (m, 2H, CH 2 ), 8.36 (s, arylCH).

[0250] Table 8 shows the amphiphilic copolymer St-SS-PAspDET-b-Ppro according to formula (11b). [Table 9]

[0251] Example 5. Synthesis of a masked compound having formula (Ib5). [ka]

[0252] To improve the stability of the systems described in the previous examples, hydrophilic polymers such as polysarcosine were introduced, where the use of sarcosine prevents aggregation and precipitation in complex media such as blood, thereby enhancing their in vivo circulation time.

[0253] Example 5A. Introduction of hydrophilic fragments in the synthesis of block copolymers. Polysarcosine was introduced as a hydrophilic block into all the polymers described in the previous examples. The polymerizations were carried out via a ring-opening polymerization mechanism using St-SS-Pasp(Bz) or St-SS-Pasp(Bz)-co-R9 as initiators. [ka]

[0254] General procedure for the synthesis of St-SS-Pasp(Bz)-b-Psar or St-SS-Pasp(Bz)-co-PR9-b-Psar:

[0255] St-SS-Pasp(Bz) or St-SS-Pasp(Bz)-co-PR9 (0.083 mmol, DP=47) was added to a Schlenk tube equipped with a stir bar and stopper, then purged with three cycles of vacuum / N2 and dissolved in anhydrous dichloromethane (22 mL). Sarcosine-NCA (450 mg, 3.91 mmol, DP=47) was then dissolved in DMF (2 mL) and added to the reaction mixture. The mixture was stirred at 10° C. for 16 h. Upon completion, the reaction mixture became clear and complete conversion of the monomer could be detected by IR. The reaction mixture was poured into diethyl ether to precipitate the product. The precipitate was isolated by centrifugation (3750 rpm, 4 min) and dried under vacuum. The copolymer was isolated as a white solid.

[0256] Yield: 60-80%.

[0257] St-SS-Pasp(Bz)-b-Psar: 1 H NMR (DMSO): δ = 2.91-2.55 (m, 2 H, CH 2 ), 4.45-3.81 (m, 2H, CH), 4.62 (brs, 1H, CH), 5.01 (brs, 2H, benzyl CH 2), 7.27 (brs, 5H, aryl CH), 8.16 (brs, 1H, amide), 8.41 (s, aryl CH).

[0258] St-SS-Pasp(Bz)-co-Pphe-b-Psar: 1 H NMR (TFA): δ = 3.40-2.92 (m, 2 H, CH 2 ), 4.75-4.41 (m, 2H, CH), 5.03 (brs, 1H, CH), 5.23 (brs, 2H, benzyl CH 2 ), 7.32 (brs, 5H, arylCH), 8.61 (s, 1H). St-SS-Pasp(Bz)-co-Pleu-b-Psar: 1 H NMR (TFA): δ = 0.84 (m, 3H, CH 3 ), 1.58 (m, 1H), 3.23-2.85 (m, 2H, CH 2 ), 4.57-4.18 (m, 2H, CH), 4.90 (brs, 1H, CH), 5.11 (brs, 2H, benzyl CH 2 ), 7.22 (brs, 5H, arylCH), 8.44 (s, 1H).

[0259] Different St-SS-Pasp(Bz)-co-PR9-b-Psar of formula (12) were synthesized according to the same procedure. The ratio of the repeating units introduced was adjusted by changing the mixture ratio of the corresponding monomer units reacted.

[0260] Table 9 shows the amphiphilic copolymer St-SS-Pasp(Bz)-co-PR9-b-Psar according to formula (12). [Table 10]

[0261] Compounds CP24 and CP25 correspond to compounds according to (12) with s = 0. R9 = Leu and R9 = Phe refer to the leucine and phenylalanine side chains, respectively.

[0262] Example 5B. Synthesis of polyaspartamide derivative (St-SS-PAspDET-co-PR9-b-Psar). Aminolysis reactions were carried out on the different block polymers synthesized in Example 5A. [ka]

[0263] General procedure for aminolysis of St-SS-PAspDET-co-PR9-b-Psar (13):

[0264] By way of example, we now describe a synthetic method in which R9 can carry either an anhydrous hydrophobic polymer, such as polyleucine or polyphenylalanine, or a polyaspartic acid polymer.

[0265] The polymer (200 mg of PBLA) was dissolved in NMP (4 mL) and cooled to 4° C. The resulting copolymer solution was added dropwise to a mixture of DET (5.3 mL, 50 equivalents per Pasp(Bz) unit) and the solution was stirred at 4° C. for 4 h under nitrogen atmosphere. After this time, the reaction mixture was added dropwise into cold HCl 6M for neutralization (pH 3.5). The polymer product was purified by centrifuge-assisted ultrafiltration. After filtration, the remaining aqueous polymer solution was lyophilized to obtain the final product.

[0266] Yield: 60-80%. St-SS-PAspDET-b-Psar 1 H NMR (D 2 O): δ = 3.18-2.60 (m, 2H, CH 2 Pasp + 3H, CH 3 Psar), 3.65-3.25 (m, 2H, CH 2 ), 4.40 (m, 2H, CH 2), 8.33 (s, 1H).

[0267] Yield: 60~80%. St-SS-PAspDET-co-Pleu-b-Psar 1 H NMR (D 2 O): δ =0.94 (d, J = 14,7 Hz, 3H, CH 3 ), 1.65 (brs, 1H, CH), 3.19-2.69 (m, 2H, CH 2 Pasp + 3H, CH 3 Psar), 3.73-3.23 (m, 2H, CH 2 ), 4.64-4.10 (m, 2H, CH 2 ), 8.34 (s, 1H).

[0268] Yield: 60~80%. St-SS-PAspDET-co-Pphe-b-Psar 1 H NMR (D 2 O): δ = 3.17-2.67 (m, 3H, CH 3 Psar) 3.72-3.19 (m, 2H, CH 2 ), 4.40 (m, 2H, CH 2 ),7.36 (brs, 5H, CH aryl), 8.33 (s, 1H).

[0269] Different St-SS-Pasp(DET)-co-PR9-b-Psar of formula (13) were synthesized according to a similar procedure, and the ratio of the repeating units introduced was adjusted by changing the mixture ratio of the corresponding monomer units reacted.

[0270] Table 10 refers to the amphiphilic copolymer St-SS-PAspDET-co-PR9-b-Psar according to formula (13). [Table 11]

[0271] *Compounds CP30 and CP31 correspond to the compounds according to (13) with s = 0. R9 = Leu and R9 = Phe refer to the leucine and phenylalanine side chains, respectively.

[0272] Example 5C. Synthesis of polyaspartamide derivative (St-SS-PAspDET / DIIPA-co-PR9-b-Psar) (14). As described above in Example 4, to improve the transfection efficiency in the polymer system, two types of amines were introduced into the amphiphilic system by aminolysis reaction in the presence of DET and DIIPA. [ka]

[0273] The strategy followed is similar to that described above for the aminolysis products of Example 4, point 4A.

[0274] Yield: 60~80%. St-SS-PAspDET / DIIPA-b-Psar 1 H NMR (D 2 O): δ = 1.41 (d, J = 6,4 Hz, 3H, CH 3 ), 3.19-2.73 (m, 3H, CH 3 ), 3.68-3.23 (m, 2H, CH 2 ), 3.93-3.73 (m, 2H, CH 2 ), 4.61-.4.08 (m, 2H, CH 2 ), 8.36 (s, 1H).

[0275] Yield: 60~80%. St-SS-PAspDET / DIIPA-co-Pleu-b-Psar 1 HNMR(DO): δ=0.95(brs, 3H, CH 3 ), 1.40(s,3H,CH 3 ), 3.02-2.76(m,3H,CH 3 ), 3.57-3.04(m,2H,CH 2 ), 3.78(m,2H,CH2 ), 4.57-4.10(m,2H,CH 2 ),8.35(s,1H).

[0276] Yield: 60~80%. St-SS-PAspDET / DIIPA-co-Pphe-b-Psar 1 HNMR(D2O): δ=1.40(brs,3H,CH3),2.94(m,3H,CH3),3.90-3.18(m,2H,CH2),4.40(m,2H,CH2),7.34(brs,5H,CH aryl),8.35(s,1H).

[0277] Different St-SS-PAspDET / DIIPA-co-PR9-b-Psar of formula (14) were synthesized according to a similar procedure, and the ratio of the repeating units introduced was adjusted by changing the mixture ratio of the corresponding monomer units reacted.

[0278] Table 11 refers to the amphiphilic copolymer St-SS-PAspDET / DIIPA-co-PR9-b-Psar according to formula (14). [Table 12]

[0279] *Compound CP35 corresponds to the compound according to (14) with s = 0. R9 = Leu and R9 = Phe refer to the leucine and phenylalanine side chains, respectively.

[0280] Example 6. Synthesis of a masked compound having formula (Ib6). As an alternative to the system described in Example 5, a hydrophilic block was introduced into the side chain of DET by grafting. [ka]

[0281] Example 6A. Synthesis of the shielded polyaspartamide derivative (-Succ-Psar-Q to St-SS-PAspDET / DIIPA-grafted) (15). Following this route, a variety of masked polyaspartamide derivatives were synthesized. [ka]

[0282] General procedure for peptide coupling using 1,1'-carbonyldiimidazole coupling reagent (CDI): Q-PSar-Succ (0.029 mmol, 6% conjugation) was added to a two-necked round-bottom flask equipped with a stir bar and stopper, then purged with three cycles of vacuum / N2, and dissolved in 2 mL of DMSO. CDI (3 eq., 0.089 mmol, 15 mg) was then added to the reaction mixture and stirred at room temperature for 30 min. After this time, the polymer (St-SS-PAspDET: 100 mg, 0.499 mmol) dissolved in 2 mL of DMSO was added. The mixture was stirred at room temperature for 16 h. The reaction mixture was poured into THF to precipitate the product. The precipitate was isolated by centrifugation (3750 rpm, 4 min) and dried under vacuum. The final product was isolated as a white solid.

[0283] Yield: 60-80%. St-SS-PAspDET-grafting into Succ-PSar 1 H NMR (D 2 O): δ = 3.18-2.60 (m, CH 2 + CH 3 ), 3.65-3.25 (m, 2H, CH 2 ), 4.40 (m, 2H, CH 2 ), 8.33 (s, 1H)

[0284] Different St-SS-PAspDET / DIIPA grafts into Succ-PSar-Q according to formula (15) were synthesized following a similar procedure. The ratio of the repeat unit introduction was adjusted by changing the mixture ratio of the corresponding monomer units reacted.

[0285] Table 12 shows the grafting of different St-SS-PAspDET into Succ-PSar-Q according to formula (15). [Table 13]

[0286] Example 6B. Synthesis of the masked detachable polyaspartamide derivative (St-SS-PAspDET-co-PPhe-grafted into -Succ-detachable-PSar-Q) (16). Design of a novel family of structures containing a cleavable shield that improves transfection without compromising the stability of the polymer in aqueous media:

[0287] Synthesis of cleavable shields based on bioreducible polymers: [ka]

[0288] To generate this type of structure, polysarcosines that can be cleaved by S-S bonds were synthesized according to this synthetic route: [ka]

[0289] PSar-COCH 3 General procedure for the polymerization of: [ka]

[0290] Sarcosine-NCA (1675 mg, 14.59 mmol) was added to a Schlenk tube equipped with a stir bar and stopper, then purged with three cycles of vacuum / N2, and dissolved in 5 mL of anhydrous DMF. 2-((2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)ethyl)disulfanyl)ethanaminium chloride was then dissolved in DMF (2 mL) and added to the reaction mixture. The mixture was stirred at 10° C. for 16 h. Upon completion, the reaction mixture became clear. Complete conversion of the monomer could be detected by IR.

[0291] DIPEA (1 eq., 84.20 mL) and acetic anhydride (10 eq., 460 mL) were then added and the mixture was stirred at the same temperature for 1 h. After this time, the reaction mixture was poured into diethyl ether to precipitate the product. The precipitate was isolated by centrifugation (3750 rpm, 4 min) and dried under vacuum. The final product was isolated as a white solid. Yield: 65% 1 H NMR (TFA): δ = 2.71 (s, 3H, CH 3 ), 2.85 (dd, J= 11,8;5,2 Hz, 2H), 3.16-2.97 (m, 2H, CH 2 ), 3.77-3.661 (m, 2H, CH 2 ), 3.97-3.87 (m,2H, CH 2 ), 4.63-4.18 (m, 2H, CH 2 ).

[0292] General procedure for Fmoc deprotection: [ka]

[0293] Polysarcosine (750 mg) was added to a round bottom flask equipped with a stir bar and stopper, purged with three cycles of vacuum / N2, and then dissolved in a mixture of 5 mL of anhydrous DMF and 1 mL of piperidine. The mixture was stirred at room temperature for 2 hours. After this time, the reaction mixture was poured into diethyl ether to precipitate the product. The precipitate was isolated by centrifugation (3750 rpm, 4 min) and dried under vacuum. The final product was isolated as a white solid.

[0294] Yield: 90%. 1 H NMR (D 2 O): δ = 2.01 (d, J = 9.7 Hz, 4H, CH 2 ), 2.22 (s, 3H, CH 3 ), 3.17-2.70 (m, 3H, CH 3 ), 4.63-4.01 (m, 2H, CH 2 ), 7.26 (m,1 H, CHaryl), 7.53 (s, 1H,aryl CH).

[0295] Succ-Ethyl-SS-PSar-COCH 3 General procedure for the synthesis of: [ka]

[0296] Polysarcosine (400 mg) was added to a round-bottom flask equipped with a stirrer and stopper, purged with three cycles of vacuum / N2, and then dissolved in 3 L of DMF. Succinic anhydride (10 equiv., 1.34 mmol, 144 mg) was added and the mixture was stirred at room temperature for 16 h. After this time, the reaction mixture was poured into diethyl ether to precipitate the product. The precipitate was isolated by centrifugation (3750 rpm, 4 min) and dried under vacuum. The final product was isolated as a white solid.

[0297] Yield: 75% 1 H NMR (D 2O): δ = 2.04 (d, J = 9.2 Hz, 2H, CH 2 ), 2.19 (s, 3H, CH 3 ), 2.65 (m, 2H, CH 2 ), 3.27-2.81 (m, 3H, CH 2 ), 3.58 (m,2H, CH 2 ), 4.32 (m,2H CH 2 ).

[0298] Once the cleavable polysarcosines were synthesized, coupling reactions were carried out for all polymer systems PAspDET contained herein following the procedure disclosed above for Example 6. This methodology produces novel cleavable polycation systems according to formula (16) above.

[0299] Different St-SS-PAspDET-PR9 / grafts into -[Succ-ethyl-SS-ethyl]-PSar according to formula (16) were synthesized following a similar procedure. The ratio of incorporation of repeat units was adjusted by changing the mixture ratio of the corresponding monomer units reacted.

[0300] Table 13 refers to different St-SS-PAspDET-PR9 / grafting into -[Succ-Ethyl-SS-Ethyl]-PSar according to formula (16). [Table 14]

[0301] Example 7. Synthesis of a biotagged compound having formula (Ib7). [ka]

[0302] The cationic polymers described in the previous examples were biotagged with sulfo cy5.5 in order to quantify the transfection efficiency and their biodistribution in organisms.

[0303] General procedure for biotagged St-SS-PAspDET: [ka]

[0304] St-SS-PAspDET(100) (100 mg, 0.36 mmol) was added to a two-necked round-bottom flask equipped with a stir bar and stopper, then purged with three cycles of vacuum / N2, and dissolved in 3 mL of DMSO. Sulfo-cy5.5 (0.1 equiv., 2.98 mg, 0.0036 mmol) was then dissolved in 1 mL of DMSO, added to the reaction mixture, and stirred at room temperature for 16 h. The reaction mixture was poured into THF to precipitate the product. The precipitate was isolated by centrifugation (3750 rpm, 4 min) and dried under vacuum. The final product was isolated as a white solid (η=95%).

[0305] The amount of sulfo-cy5.5 in the final product was determined by fluorescence.

[0306] Example 7A. Synthesis of a shielded biotagged polyaspartamide derivative (St-SS-PAspDET-sulfocy5.5--grafted into Succ-PSar-galactosamine) [ka]

[0307] Hydrophilic fragments are introduced into the biotagged compounds by coupling grafts as described in Example 6.

[0308] Yield: 60-80%. -St-SS-PAspDET-SulfoCy5.5-Grafting into Succ-PSar-Galactosamine 1 H NMR (D 2 O): δ = 3.18-2.60 (m, CH 2 + CH 3 ), 3.65-3.25 (m, 2H, CH 2), 4.40 (m, 2H, CH 2 ), 8.33 (s, 1H)

[0309] Table 14 shows the synthesis of St-SS-PAspDET-sulfocytidine in -Succ-PSar-galactosamine according to formula (18). 5.5 Refers to the graft. [Table 15]

[0310] Example 8. Synthesis of lipid polyaspartamide derivative (St-SS-PAspDET-grafted into lipoic acid) (19).

[0311] Following this route, lipid polyaspartamide derivatives were synthesized. [ka]

[0312] General procedure for peptide coupling using 1,1'-carbonyldiimidazole coupling reagent (CDI):

[0313] Lipoic acid (0.02 mmol, 5% conjugation) was added to a two-necked round-bottom flask equipped with a stir bar and stopper, then purged with three cycles of vacuum / N2, and dissolved in 2 mL of DMSO. CDI (3 eq., 0.06 mmol, 10 mg) was then added to the reaction mixture and stirred at room temperature for 30 min. After this time, the polymer (St-SS-PAspDET: 80 mg, 0.4 mmol) dissolved in 1 mL of DMSO was added. The mixture was stirred at room temperature for 16 h. The reaction mixture was poured into THF to precipitate the product. The precipitate was isolated by centrifugation (3750 rpm, 4 min) and dried under vacuum. The final product was isolated as a white solid.

[0314] Yield: 60-80%. St-SS-PAspDET(72)-Grafting into Lipoic Acid(5) 1 H NMR (D2 O): δ = 1.34-1.56 (m, 2H, CH 2 ), 1.61-1.84 (m, 2H, CH 2 ), 2.04 (td, J= 6.6, 13.3 Hz, 1 H, CH), 2.35 (t, J= 7.1 Hz, 2H, CH 2 ), 2.53 (dt, J= 6.1, 18.6 Hz, 2H, CH 2 ), 2.89 (brs, 2H, CH 2 ), 3.02-3.81 (m, 2H, CH 2 ), 8.36 (s, arylCH).

[0315] Table 15 refers to the St-SS-PAspDET (72)-grafted into lipoic acid (5) of formula (19). [Table 16]

[0316] Example 9. Synthesis of lipid polyaspartamide derivatives (St-SS-PAspDET / imidazoleamine-grafted into the lipid chain). Following this route, a variety of lipid polyaspartamide derivatives were synthesized. [ka]

[0317] General procedure for peptide coupling using 1,1'-carbonyldiimidazole coupling reagent (CDI):

[0318] The experimental procedure for the synthesis of the polymer St-SS-PAspDET / imidazole amine graft into the lipid chain consists of peptide coupling with CDI. The procedure is the same as that described in Example 7, in this case using other lipid acids such as oleic acid and nonanoic acid.

[0319] Yield: 60-80%. St-SS-PAspDET (65) / imidazoleamine (26)-grafted into oleic acid (5) 1 H NMR (D 2 O): δ = 0.89 (brs, 3H, CH 3 ), 1.29 (s, 2H, CH 2 ), 1.60 (s, 2H, CH 2 ), 2.03 (s, 2H, CH 2 ), 2.15 (s, 2H, CH 2 ), 2.30 (s, 2H, CH 2 ), 2.50-3.12 (brs, 2H, CH 2 ), 3.14-3.75 (m, 2H, CH 2 ), 4.29 (s, 2H, CH 2 ), 5.35 (m, CH), 7.51 (s, imidazole CH), 7.56 (s, 1H, imidazole CH);8.36 (s, aryl CH), 8.73 (s, 1H, imidazole CH).

[0320] Yield: 60-80%. Grafting of St-SS-PAspDET (65) / imidazole amine (26) into oleic acid (5) / nonanoic acid (13). 1 H NMR (D 2 O): δ = 0.89 (brs, 3H, CH 3 ), 1.29 (s, 2H, CH 2 ), 1.60 (s, 2H, CH 2 ), 2.03 (s, 2H, CH 2 ), 2.15 (s, 2H, CH 2 ), 2.30 (s, 2H, CH 2 ), 2.50-3.12 (brs, 2H, CH 2 ), 3.14-3.75 (m, 2H, CH 2 ), 4.29 (s, 2H, CH 2), 5.35 (m, CH), 7.51 (s, imidazole CH), 7.56 (s, 1H, imidazole CH);8.36 (s, aryl CH), 8.73 (s, 1H, imidazole CH).

[0321] Table 16 shows different St-SS-PAspDET / imidazole amine grafts into the lipid chain according to formula (20). [Table 17]

[0322] Example 10: Synthesis of 6-arm St-Lys(3)-polyaspartamide derivatives The general procedure for polymerization of 6-arm St-Lys(3)-PAsp(OBzl) is the same as that described in Example 1B. [ka]

[0323] Yield: 70-90% 1 H NMR[St-Lys(3)- PAspDET(100)] (TFA): δ = 1.51 (m, 3H, CH 3 ), 1.84-1.95 (m, 2H, CH 2 ), 2.80-3.26 (m, 2H, CH 2 ), 3.48 (m, 2H, CH 2 ), 4.97 (brs, 1H, CH), 5.15 (m, 2H, benzyl CH 2 ), 7.34 (brs, 5H, arylCH), 8.68 (s, arylCH).

[0324] Aminolysis of poly(β-benzyl-L-aspartate) (21) to give St-Lys(3)-PAsp-oligoamines (22)

[0325] General Procedure for Aminolysis Reactions to Generate Polycationic Homopolymers [ka]

[0326] St-[Lys(3)-PAsp(Bz) (21) (DP=100, 750 mg) was dissolved in NMP (15 mL) and cooled to 4 °C. This solution was added dropwise to oligoamine (50 equivalents of DET, per Asp unit) cooled at 4 °C, and the mixture was stirred at the same temperature for 4 h. After this time, the reaction mixture was added dropwise to cold HCl 6 M for neutralization (pH 3.5). The polymer product was purified by centrifuge-assisted ultrafiltration. After filtration through a 0.22 μm PES filter, the remaining aqueous polymer solution was lyophilized to give the final product (400 mg, η=60%).

[0327] 1 H NMR [St-Lys(3)-PAspDET] (D 2 O): δ 1.49 (m, 2H, CH 2 ), 2.28 (brs, 2H, CH 2 ), 3.13-3.76 (m, 2H, CH 2 ), 4.38 (brs, 2H, CH 2 ), 8.32 (s, 3H, arylCH).

[0328] Table 17 shows the properties obtained for the star-shaped 6-arm initiator of formula (22) -PAspDET. [Table 18]

[0329] Example 11. Potentiometric titration The pKa of the cationic polymer is determined by acid-base titration, measuring the pH of the solution throughout the process. The pKa is then obtained from the titration graph.

[0330] To perform the measurements, a 1 mg / mL solution of the cationic polymer is prepared in Milli-Q water and a known amount of 0.1 M HCl is added until the pH of the solution is approximately 2. At this point, a titration is performed with NaOH 0.2M using an automated Methrom 916 titouch potentiometer equipped with a Dosin 800 dispenser. The titration rate is set to 0.1 mL / min and the signal drift to 50 mV / min. The titration is complete when the pH reaches 12.

[0331] The relationship between pH and the degree of protonation of the polycation was calculated from the obtained titration curves, and the pK=pH+log[α / (1-α)] values ​​were plotted against 1-α, where K is the effective dissociation constant.

[0332] Example 12. Polyplex formation and analysis Example 12A. Polyplex Formulation Procedure 1 Polyplex formation is prepared in-situ (by pipette mixing) and added to the assay plate.

[0333] Polyplex formulations are referred to as "PX CPx_ratio nuc ", where "CPx" corresponds to the nomenclature of the compounds used to form the polyplexes, as described above; where "ratio" refers to the N / P ratio; where "nuc" refers to the type of nucleic acid: pDNA or clDNA.

[0334] In the examples, the sequence of the cIDNA according to SEQ ID NO: 1 is the sequence of Table 18. [Table 19] TIFF2024528853000079.tif194159TIFF2024528853000080.tif199159TIFF2024528853 000081.tif194159TIFF2024528853000082.tif198159TIFF2024528853000083.tif92159

[0335] In the following examples, pDNA (purchased from PlasmidFactory, reference PF461 (pCMV-luc)), containing 6233 bp expressing luciferase), commercially available mRNA (luc) (purchased from Trilink Biotechnologies), commercially available pDNA (GFP) (purchased from Akron Biotech) and clDNA according to SEQ ID NO: 1 obtained according to standard molecular biology methods, such as that disclosed in Heinrich, M. et al. "Linear closed mini DNA generated by the prokaryotic cleaving-joining enzyme TelN is functional in mammalian cells", J Mol Med, 2002, vol. 80, pp. 648-654, are used as nucleic acids of interest covering a range of sizes and protein expression.

[0336] Polyplex formulations for testing toxicity and transfection capacity were prepared in-situ (mixing with pipette) as follows: 100ng, 200ng or 1000ng of pDNA (pDNA was purchased from PlasmidFactory, reference number PF461 (pCMV-luc)) containing 6233bp expressing luciferase or clDNA as set forth in SEQ ID NO: 1 expressing luciferase and the calculated amount of polymer with the indicated charge ratio (+ / -) or amine to phosphate ratio (N / P) were diluted in 10μL of Hepes 20mM buffer in a separate tube. Only protonatable nitrogens, not amide nitrogens, were considered in the calculation of + / - and N / P ratios. For the formation of polyplexes, the nucleic acid and polymer solutions were mixed by rapid pipetting up and down (10 times) and incubated for 20 minutes at room temperature. The formed polyplexes were then characterized by DLS to determine the size and Z potential (Table 18).

[0337] Samples formulated by this first method were prepared in a similar way for in vitro testing, but with Hepes buffer replaced by NaCl 150 mM. After 48 hours of incubation, toxicity and transfection capacity are evaluated. The ratios examined for each polymer were N / P5 for 100 ng of clDNA, NP10, 30, and 100 for 200 ng of clDNA. As a positive control for transfection, jetPEI (Polyplus-transfection SA, Illkirch, France) (reference Polyplus:101-10N) was used at 100 ng of pDNA / clDNA with a nitrogen to phosphorus ratio (NP5) for HaCaT and 100 ng of pDNA / clDNA with NP8 for BJ cells. Cell transfection was performed using jetPEI® according to the manufacturer's instructions. JetPEI® is a powerful reagent that ensures robust, efficient and reproducible DNA transfection into mammalian cells with low toxicity. JetPEI® is composed primarily of linear polyethyleneimine produced in Polyplus-transfection. JetPEI® is provided as a 7.5 mM solution (expressed as the concentration of nitrogen residues) in sterile, non-pyrogenic water.

[0338] Example 12A.1. Polyplex size and Z potential. After 20 min stabilization, the size and Z potential of polyplexes formed with clDNA at N / P ratio = 30 were measured using a Malvern Zetasizer NanoZS instrument equipped with a 532 nm laser at a fixed scattering angle of 173°. After polyplex formation, the solution was allowed to stabilize for 20 min and 20 μl was measured using a quartz glass high performance cuvette (Hellma Analytics). The size distribution was measured (diameter, nm) by n>3 measurements and the results are shown in Table 19. [Table 20]

[0339] All polyplexes formed at this N / P ratio exhibited hydrodynamic diameter sizes of approximately 20–30 nm and Z potentials of 20–35 mV.

[0340] Example 12A.2. Complexation / decomposition experiments. Furthermore, the effectiveness of complex formation and the possible presence of free pDNA in the polyplexes were evaluated using electrophoretic gels as an initial screening method. An E-gel Power Snap Electrophoresis device and an E-Gel Power Snap Camera (Invitrogen) were used to perform the electrophoresis. A 1.2% agarose gel prepared to contain SYBR safe DNA marker (E-Gel® 1.2% with SYBR safe, Invitrogen) was used.

[0341] The complexation efficiency of polyplexes (20 μl) with different NPs (5, 10, 30) was evaluated, as was the disassembly of polyplexes in NP30 in the presence of low (0.075 IU / ml) and high (200 IU / ml) heparin concentrations (PanReacAppliChem, Spain). For the low concentration, 0.1 μl of 15 IU / ml heparin solution was added to 20 μl of already formed polyplexes, and for the high concentration, 0.8 μl of 5000 IU / ml heparin solution was added to 20 μl of polyplexes. Once the gel is loaded (20 μl / well), choose the protocol of the instrument depending on the type of gel used (in this case, the E-Gel 0.8-2% protocol of about 40 minutes, but the time can be modified depending on the sample).

[0342] [Table 21]

[0343] In all cases, no free pDNA is observed with the different NPs or at low concentrations of heparin, but at high concentrations of heparin, free pDNA signals are observed due to competition between heparin and pDNA for binding to the polymer, indicating the ability of the polymers to release their cargo (representative images of the gels can be seen in Figure 1).

[0344] Example 12B. Polyplex Formulation Procedure 2 The microfluidic device was placed in a laminar flow hood to avoid possible contamination of the samples, and all polymers used in this formulation step were pre-sterilized by passing through a 0.22 μm PES filter. In this first screening, the stability and formation of polyplexes was tested with different NP ratios (10 and 30) in PBS pH 7.4. For this test, 0.2 μg of pDNA and polymer compound (NVV) were used. For the formation of polyplexes, pDNA solution (100 μl, 0.2 μg) and polymer solution (100 μl, mass calculated as shown in the polyplex formation section) were placed in a 1 ml plastic syringe (BD Plastipak™, Spain). Two programmable injection syringe pumps (NE-4000, SyringePump, USA) were then used for fluid injection and control according to the desired flow rate ratio of the side and central streams (300 μl / min). The final polyplex solution was then collected and allowed to stabilize for 20 min. Based on these stability studies, optimal NP ratios were identified (30) and the corresponding polyplexes formed by NVV were formed.

[0345] For all microfluidic experiments, the microfluidic device was at room temperature. All additional details regarding polyplex size and stability, as well as complexation / disassembly experiments, are described below.

[0346] Example 12B.1. Microfluidic Device and Setup The microfluidic device was purchased at Little Things Factory GmbH (Germany). The system consists of two connected reactors made of borosilicate glass: the first reactor (LTF-MS) has two inlet channels (one for DNA, the other for polymer) and one outlet channel, volume 0.2 ml, channel size: 1 mm, 0.5-20 ml / min / channel, not sensitive to blockages. Size: 115x60x6 mm (l, w, h). The second reactor (LTF-VS) has one inlet channel (connected to the outlet channel of the first reactor) and one outlet channel, volume 1.1 ml, channel size: 1 mm. Size: 115x60x6 mm (l, w, h). The first reactor is used for mixing and formation of polyplexes, the second reactor is used to increase the residence time.

[0347] In addition, two programmable pumps control the fluid flow rate of the syringes (NE-4000 Programmable Two-Channel Syringe Pump, Syringe Pump, USA). The system accepts injection rates from 1.436 μL / h (1 mL syringe) to 7515 mL / h (60 mL syringe).

[0348] This methodology provides reproducibility in polyplex formation and the potential for scaling up the process.

[0349] Example 12B.2. Optimization of various parameters for microfluidic formulation Different speeds and reaction times (150, 300, and 600 μL / min) and different buffers with different ionic strengths (Hepes 20 mM, NaCl 150 mM, and a mixture of Hepes 20 mM and NaCl 130 mM) were evaluated. In this study, 1 ml syringes (BD Plastipak™, Spain) were used. As an example, a commercial reference polymer, end-capped acetyl n-butyl-poly-L-aspartic acid-diethylenetriamine (degree of polymerization of PAsp=50), was used (Sunbright AS50-DT-A (internal code: CXP15D_4) (obtained from NOF therapeutics) and pDNA (pCMV-luc, PlasmidFactory, Germany) with a nitrogen to phosphorus ratio (NP30). The polymer solution (100 μl) was introduced through one of the inlet channels of the first reactor and the DNA solution (100 μl) was introduced through the other inlet channel. The final polyplex solution was then collected and allowed to stabilize for 20 min before measuring the size by DLS (Malvern Panalytical, Spain).

[0350] It is observed that stable polyplexes are formed using the three flow rates, their size is appropriate, and their correlation coefficients show good signals. Optimization was performed by carefully observing the quality indicators of the measurement and the uniformity of the samples. The intermediate flow rate was selected for further formulation of polyplexes (300 μl / min) to adequately control the size and formation of polyplexes at room temperature. The hydrodynamic diameter (measured by DLS) of the polyplexes formed using this procedure was about 30 nm.

[0351] Example 12C. Polyplex stability. Polyplex stability is the most important aspect in developing an efficient therapeutic. After confirming the mid- to long-term stability of the pharmaceutical formulation, a panel assay is performed that mimics the physiological conditions met by the drug according to the route of administration that needs to be stable during circulation to the target site of action. It is well known that polyplexes exhibiting a positive surface charge undergo salt-induced aggregation, which can cause inaccurate cell biological evaluation and serious toxicity issues when applied systemically. Initial stability tests are currently being developed during this project, which aim to observe the properties (size) of the polyplex particles; in addition, more tests need to be further developed and performed to evaluate the DNA polymer concentration (complexed vs. free). This is an important measure to be implemented during the hit-to-lead stage and will become a routine QC assay. For stability measurements, polyplexes were kept in a refrigerator during the experiment, and the stability of polyplexes was measured at various times.

[0352] Example 12C.1 Stability in Biologically Relevant Media The stability and formation of polyplexes by microfluidics (as reported above) at different times was investigated using a NP=30 ratio in PBS pH 7.4. In this experiment, 3 μg of pDNAluc (pCMV-luc, PlasmidFactory, Germany) and polymers CP36 and CP19 were used. The final concentration of polymers in the polyplexes was 0.335 mg / ml for CP36 and 0.202 mg / ml for CP19. The final polyplex solution (200 μl) was allowed to stabilize for 20 min before the size was measured by DLS (MalvernPanalytical, Spain). Polyplexes were kept in a refrigerator during the experiment and the stability of the polyplexes was measured at different times.

[0353] As shown in Table 21, the presence of sarcosine in the structure of polymer CP36 provided stability to polyplexes in solution for up to one month, maintaining a constant size over time and avoiding aggregation. [Table 22]

[0354] Example 12C.2 Stability in Different Buffers: Effect of Salt on Polyplex Aggregation The stability of polyplexes in different buffers (pure water, Hepes 20 mM, and PBS pH 7.4) using a NP=30 ratio was investigated at different time points. In this experiment, 3 μg of pDNAluc (pCMV-luc, PlasmidFactory, Germany) and polymers CP38 and CP19 were used. The final concentration of polymers in the polyplexes was 0.335 mg / ml for CP38 and 0.202 mg / ml for CP19. The final polyplex solution (200 μl) was allowed to stabilize for 20 min before the size was measured by DLS (MalvernPanalytical, Spain). Polyplexes were kept in a refrigerator during the experiment and the stability of polyplexes was measured at different times.

[0355] As shown in Table 22, the presence of salt in the buffer (PBS pH 7.4) promoted the destabilization of polyplexes without sarcosine in their structure (CP19), whereas the polymers containing sarcosine (CP38) remained stable. However, in buffers with less salt or no salt (water and hepes 20 mM), all polyplexes maintained a constant size over time and avoided aggregation. [Table 23]

[0356] Example 13. In vitro biological test (I) Example 13A. Cell Culture The HaCaT cell line was obtained from CLS® (300493) and maintained in DMEM Glutamax (Gibco Ref: 6195-026) supplemented with 10% FBS (HyClone Ref: SV30160.03) using standard tissue culture conditions. The BJ cell line was obtained from ATCC® (CRL-2522) and maintained in EMEM (ATCC Ref: 30-2003) supplemented with 10% FBS (HyClone Ref: SV30160.03) using standard tissue culture conditions. In both cases, the cells were incubated at 4°C for 30 min at 20°C for 12 h at 5% CO 2 The cells were routinely maintained at 37 °C in a humidified atmosphere, medium was changed every 2-3 days, and passaged when the cells reached 80% cell confluence. Cell density (6000 cells / well for HaCat and 4500 cells / well for fibroblast BJ) was optimized to reach exponential growth and appropriate readouts.

[0357] To perform cytotoxicity and transfection efficiency experiments, cells were seeded in sterile 96-well white microtiter plates with clear bottom (ViewPlate TCRef: 6005181 Perkin-Elmer) in 80 μl complete medium at a density of 6000 cells / well and 4500 cells / well for HaCaT and BJ cells, respectively. After 24 hours of incubation, 20 μl of polyplexes were added to test cytotoxicity and cell transfection in separate plates.

[0358] Example 13B. ATP Evaluation for Cytotoxicity Assessment After 48 hours of incubation, cell viability was assessed by measuring intracellular ATP content using the ATP1Step kit (Perkin-Elmer #6016731) as described by the manufacturer. After the incubation period, 50 μl aliquots of cells were taken in duplicate into black 96-well plates and mixed with 50 μl of ATP quantification reagent. ATP concentrations were determined by reading chemiluminescence using a VictorNivo plate reader. Viability was expressed as a percentage of the signal relative to untreated cells.

[0359] Example 13C. Luciferase assay. After 48 hours of incubation, 20 μl of Bright-Glo Luciferase Assay System (Ref. E2610 Promega) was added to each well according to the manufacturer's instructions. After 2 minutes of incubation at room temperature, luciferase activity was measured using an Ensight Plate Reader (Perkin Elmer). Data were expressed as luminescence versus cell viability and as a percentage of transfection versus transfection positive control.

[0360] First, we performed primary screening of polyplexes in HaCaT cells, and then selected some polyplexes for further screening in other cell lines, such as fibroblast BJ cells.

[0361] The cIDNA sequence shown in this example, SEQ ID NO:1, is the sequence in Table 18 above.

[0362] Table 23 shows cell viability and transfection efficiency in HaCaT cells for representative synthesized polyplexes. [Table 24]

[0363] Table 24 shows cell viability and transfection efficiency in fibroblast BJ cells for selected polyplexes. [Table 25]

[0364] Example 14. Comparison of linear and star-shaped NVVs on cell viability and transfection efficiency Star-based selected polyplexes (PX 23CP2330 clDNA , PX18CP1830 clDNA , PX17 CP17 30 clDNA , PX7 CP7 30 clDNA and PX5 CP5 30 clDNA ) and standard linear-based PAsp-DET polyplexes (PX49 Nbu-PAsp-DET(46) clDNA , PX50 Nbu-PAsp-DET(43)30 clDNA and PX51 Nbu-PAsp-DET(38)30 clDNA*4 A direct comparison between the polyplexes was performed to illustrate the improvement in transfection efficiency driven by this structural modification in delivering clDNA(luc) in HeLa cells. The polyplexes were formulated in the same manner as described in the previous examples, and the bioactivity response was evaluated in the same manner.

[0365] The sequence of the cIDNA shown in this example, SEQ ID NO:1, is the sequence in Table 18 above. [Table 26]

[0366] As can be seen in the table above, the star-shaped polyplexes designed in the present invention show better results in terms of transfection efficiency and toxicity. As an example, PX18cp18 30clDNA shows a 6.5-fold increase in transfection efficiency when compared to polyplexes formed with the linear counterpart PX50Nbu-PAsp-DET(43)30clDNA*. Also, cell viability is improved when comparing star-shaped polymers with linear polymers. For PX18cp1830clDNA, cell viability is 88.6%, while for PX50Nbu-PAsp-DET(43)30clDNA*, cell viability is 63.7%.

[0367] Example 15. In vitro biological test (II) Example 15A. Cell Culture HeLa cells were cultured in high glucose DMEM with Glutamax (Gibco-ThermoFisher #61965-059) supplemented with 10% fetal bovine serum (Hyclone #SV30160.03HI, provided by GE Healthcare Europe GmbH). Transfections were performed in 96-well plates with 10000 cells / well in a final volume of 100 μl and cells were incubated for 24 h at 37°C and 5% CO2. After 24 h, the medium was removed and refreshed with 90 μl of complete medium. Transfection mixtures were prepared using PBS and, in the case of the positive control (JetPEI), 10 μl of each formulation was added to the cells after 20 min stabilization according to the manufacturer's guidelines (#101-10N, Polyplus Transfection). After 24 h, cells were harvested and processed.

[0368] HEK293 (human embryonic kidney) cells were cultured in high glucose DMEM (Gibcoref 61965-059) + 10% FBS (Hyclone #SV30160.03HI, provided by GE Healthcare Europe GmbH). Transfections were performed in 96-well plates with 10000 cells / well in a final volume of 100 μl and cells were incubated for 24 h at 37°C and 5% CO2. After 24 h, the medium was removed and refreshed with 90 μl of complete medium. Transfection mixtures were prepared using PBS and, in the case of the positive control (JetPEI), following the manufacturer's guidelines (#101-10N, Polyplus Transfection), 10 μl of each formulation was added to the cells after 20 min stabilization. After 24 h, cells were harvested and processed.

[0369] Example 15B. ATP evaluation for cytotoxicity assessment After 24 hours of incubation, the medium was aspirated and 50 μl / well of ATPLite reagent (ATPLite PerkinElmer #6016731) was added. The plate was incubated for 10 minutes at room temperature in the dark. Luminescence was read spectrophotometrically using VictorNivo (PerkinElmer) and data was expressed as a percentage of cell viability, using untreated control cells as 100%.

[0370] Example 15C. Luciferase assay After 24 hours of incubation, 100 μl of BrightGlo reagent (Promega #E2620) was added to each well according to the manufacturer's instructions. After 5 minutes of incubation at room temperature, luciferase activity was measured using VictorNivo (Perkin Elmer). Data was expressed as luminescence versus percentage of transfection relative to the transfection positive control.

[0371] Example 15D. Biological activity of polyplexes in HeLa cells The transfection efficiency and cell viability of polyplexes formed by CP46, CP53, CP50, and CP45 in HeLa cells are reported in the following table: Transfection data are expressed as % of the positive control jetPEI®, which is 100% after 24 hours of treatment, and cell viability is compared to untreated (NT) cells, with the readout of ATP content of NT cells being equal to 100%. [Table 27]

[0372] Example 15E. Biological activity of polyplexes in HEK293 cells The transfection efficiency and cell viability of polyplexes formed by CP46, CP53, CP50, and CP45 in HEK293 cells are reported in the following table: Transfection data are expressed as % of the positive control jetPEI®, which is 100% after 24 hours of treatment, and cell viability is compared to untreated (NT) cells, with the readout of ATP content of NT cells being equal to 100%. [Table 28]

[0373] Example 15F. Biological activity of polyplexes in HEK293 cells (100 ng, compared to Lipofectamine 2000®) Cell transfection was performed using Lipofectamine 2000® (ThermoFisher scientific, Spain. Reference number 11668019) as a positive control according to the manufacturer's instructions. Lipofectamine 2000® reagent delivers DNA or siRNA with excellent transfection performance in protein expression, gene silencing, and functional assays. The transfection efficiency and cell viability of polyplexes formed by CP58 (NP15 and NP30) and pDNA-GFP in HEK293 cells were tested at 24 h, 48 h, and 72 h. The results are reported in the following table. Transfection data are expressed as % of the positive control Lipofectamine 2000®, with the positive control being 100%. Cell viability was compared to untreated (NT) cells, with the ATP content reading of NT cells being equal to 100%. Table 28. Cell viability and transfection efficiency in HEK293 cells with pDNA-GFP (n=2) versus Lipofectamine 2000 [Table 29]

[0374] In all cases examined in this example, Polylex exceeded the transfection efficiency of Lipofectamine 2000 and had favorable cytotoxicity results. References EP3331937 J Mol Med, 2002, vol. 80, pp. 648-654 - TWGreen and PGM Wuts, Protective Groups in Organic Chemistry, Wiley, 3rd ed. 1999, Chapter 5 (pp. 369-451) - TWGreen and PGM Wuts, Protective Groups in Organic Chemistry, Wiley, 3rd ed. 1999, Chapter 7 (pp. 495-653)

[0375] Terms For reasons of completeness, the various aspects of the invention are set out in the following numbered clauses: Clause 1. Any stereoisomer or mixture of stereoisomers of the compound of formula (I), a pharma- ceutically acceptable salt thereof, or any of the compounds of formula (I) or a pharma- ceutically acceptable salt thereof, including homopolypeptides or random or block or graft copolypeptides; [ka] wherein A, A', and A'' are each independently selected from radical groups of formula II; each of the A, A', and A'' subunits can be the same or different; [ka] where the wavy lines indicate the attachment points; and although the repeat units defined by the brackets and their numerical values ​​r, s, t, and u in Formula II are shown in a particular order for convenience of illustration, the repeat units can be present in any order, the repeat units can be present in blocks or randomly, and each of the repeat units can include blocks of monomer units which can be the same or different from one another; wherein K, K', and K'' are each independently selected from -O- and -NH-; L is selected from: [ka] where α, α', and α'' are integers from 0 to 1; each wavy line indicates a point of attachment to A, A', or A''; and "*" indicates a point of attachment to K, K', or K''; R2 is selected from -O- and -NH-; R1 is a biradical selected from the group consisting of (III) and (IV); [ka] where the wavy lines indicate the attachment points; where y and z are independently integers ranging from 1 to 20; X is -NH-, -NH(C 1 ~C 6 )Alkyl-, -O-, -(C 1 ~C6) alkyl-COO-, linear or branched -(C 1 ~C 30 ) alkylene-, and a biradical selected from the group consisting of (V), (VI), (VII), (VIII), (IX), (X), (XI), and (XII); [ka] Here, * " indicates the attachment point; In the formula, X is -(C 1 ~C 30 ) Alkylene biradicals are -OH, -NR a R b, -SH, -NHNH 2 , -COOR c , -CF 3 , -OCF 3 and halogen; R a , R b and R c is H, -phenyl, -(C 1 ~C 30 ) alkyl, -(C 2 ~C 30 ) alkenyl, -(C 1 ~C 30 ) alkylphenyl, and -phenyl(C 1 ~C 30 ) alkyl; where a and a' are independently integers ranging from 0 to 1; r, s, t, and u are independently integers ranging from 0 to 500, and at least one of r or t is greater than or equal to 1; R 9 and R 17 is H, -(C 1 ~C 30 ) alkyl, -(C 2 ~C 30 ) alkenyl, -(C 1 ~C 30 ) Alkyl-R i1 , -(C 1 ~C 30 )Alkyl-O Riii1 , -(C 1 ~C 30 )Alkyl-NR iv1 R v1 , -C(O)-R vi1 , -(C 1 ~C 12 )Alkyl-CO-NH 2 and a radical selected from the group consisting of (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), and (XXI); [ka] Here, * " indicates the attachment point; R i1 is H, -(C 1 ~C 30 ) alkyl, -(C 2 ~C 30 ) alkenyl, -(C 2 ~C 30 ) Alkynyl, halogen, -CF 3 , -OCF 3 , isoxazole, oxazole, furan, oxolane, thiol, thiophene, N-methylpyrrole, pyrrole, pyrrolidine, pyran, pyridine, piperidine, thiazole, dioxane, morpholine, pyrimidine, -NH 2 , -N((C 1 ~C 30 )Alkyl) 2 , -NH(C 1 ~C 30 ) alkyl, -NHC(O)-(C 1 ~C 30 ) alkyl, -NHC(O)O(C 1 ~C 30 ) alkyl, -NHC(O)NH 2 , -NHC(O)N(CH 3 ) 2 , -NHS(O) 2 (C 1 ~C 30 ) Alkyl, -NHSO 2 NH 2 , -C(O)(C 1 ~C 30 ) alkyl, -CON((C 1 ~C 30 )Alkyl) 2 ;-NO 2 , -CN, -OC(O)-(C 1 ~C 30 ) alkyl, -OC(O)O(C 1 ~C 30 ) alkyl, -OC(O)NH 2 , -OC(O)N((C 1 ~C 30)Alkyl) 2 , -SeH, -SH, -S(C 1 ~C 30 ) alkyl, -S(O)H, -S(O)(C 1 ~C 30 ) alkyl, and -SO 2 (C 1 ~C 30 ) alkyl; R vii1 is H, -(C 1 ~C 30 ) alkyl, -(C 2 ~C 30 ) alkenyl, -(C 2 ~C 30 )Alkynyl, -Oalkyl(C 1 ~C 12 ), F, Cl, Br, I, -CF 3 , -OCF 3 , -NO 2 , -CN, -NH 2 , -(C 1 ~C 30 ) AlkylNH 2 , -N((C 1 ~C 30 )Alkyl) 2 , and -NH(C 1 ~C 30 ) alkyl; R iii1 , R iv1 and R v1 is H, -(C 1 ~C 30 ) alkyl, -(C 1 ~C 30 ) AlkylNH 2 , -(C 1 ~C 30 )Alkyl-N((C 1 ~C 30 )Alkyl) 2 , and -(C 1 ~C 30 )Alkyl-NH(C 1 ~C 30 ) alkyl; R vi1 is H, -(C 1 ~C30 ) alkyl, -(C 2 ~C 30 ) alkenyl, -(C 1 ~C 30 ) AlkylNH 2 , -NH 2 , -(C 1 ~C 30 )Alkyl-N((C 1 ~C 30 )Alkyl) 2 , -NH(C 2 ~C 30 ) alkenyl, -(C 1 ~C 30 )Alkyl-NH(C 1 ~C 30 ) alkyl, -NH-oleic acid, -NH-noneic acid, and -NH-lipoic acid; In the formula, R i1 , R ii1 , R iii1 , R iv1 , R v1 , R vi1 , and R vii1 is -OH, halogen, -O(C 1 ~C 30 ) alkyl, -CF 3 , -OCF 3 , -NH 2 , -(C 1 ~C 30 ) Alkyl, -SH, -NHNH 2 -NHCH 3 , -N(CH 3 ) 2 , -NCH(CH 3 ) 2 and -(C 1 ~C 30 ) alkyl-OH; b1, c1, d1, e1, f1, g1, h1, i1, and j1 are independently integers ranging from 1 to 20; wherein W1 and W2 are each independently selected from CH and N; R 6 , R 7 , R 14, R 15 and R 19 is H, -(C 1 ~C 30 ) alkyl, -(C 2 ~C 30 ) alkenyl, -(C 2 ~C 30 ) alkynyl, -(C 1 ~C 30 ) Alkyl-R i2 , -(C 1 ~C 30 )Alkyl-OR iii2 , -(C 1 ~C 30 )Alkyl-NR iv2 R v2 , -C(O)-R vi2 and radicals selected from the group consisting of (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), and (XXXI); [ka] Here, * " indicates the attachment point; R i2 is H, -(C 1 ~C 30 ) alkyl, -(C 2 ~C 30 ) alkenyl, -(C 2 ~C 30 )Alkynyl, -Oalkyl(C 1 ~C 6 ), halogen, -CF 3 , -OCF 3 , isoxazole, oxazole, furan, oxolane, thiol, thiophene, N-methylpyrrole, pyrrole, pyrrolidine, pyran, pyridine, piperidine, thiazole, dioxane, morpholine, pyrimidine, -NO2, -CN, -OC(O)-(C 1 ~C 30 ) alkyl, -OC(O)O(C 1 ~C 30 ) alkyl, -OC(O)NH2 , -OC(O)N((C 1 ~C 30 )Alkyl) 2 , -SH, -S(C 1 ~C 30 ) alkyl, -S(O)H, -S(O)(C 1 ~C 30 ) Alkyl, -SO 2 (C 1 ~C 30 ) alkyl; R iii2 , R iv2 , and R v2 teeth, H, -(C 1 ~C 30 ) alkyl, -(C 2 ~C 30 ) alkenyl, -(C 1 ~C 30 ) AlkylNH 2 , -(C 1 ~C 30 )Alkyl-N((C 1 ~C 30 )Alkyl) 2 , -(C 1 ~C 30 )Alkyl-NH(C 1 ~C 30 ) alkyl, and a radical selected from the group consisting of (XXXII), (XXXIII), (XXXIV), (XXXV), (XXXVI), (XXXVII), (XXXVIII), (XXXIX), (XL), (XLI), (XLII), (XLIII), (XLIV), (XLV), and (XLVI); [ka] In the formula, R viii2 , R ix2 , R viii2’ , and R ix2’’ teeth, H, -(C 1 ~C 12 ) alkyl, -(C 1 ~C 12 ) AlkylNH2 , -(C 1 ~C 12 )Alkyl-N((C 1 ~C 12 )Alkyl) 2 , -(C 1 ~C 12 )Alkyl-NH(C 1 ~C 12 ) alkyl, -O(C 1 ~C 12 ) alkyl, -COH, -CO(C 1 ~C 12 ) alkyl, and -O(C 2 ~C 30 ) alkenyl; R vii2 and R vii2’ is H, -(C 1 ~C 30 ) alkyl, -(C 2 ~C 30 ) alkenyl, -(C 2 ~C 30 )Alkynyl, -Oalkyl(C 1 ~C 12 ), F, Cl, Br, I, -CF 3 , -OCF 3 , -NO 2 , -CN, -NH 2 , -(C 1 ~C 30 ) AlkylNH 2 , -N((C 1 ~C 30 )Alkyl) 2 , and -NH(C 1 ~C 30 ) alkyl; R vi2 teeth, H, -OH, -(C 1 ~C 30 ) alkyl, -(C 2 ~C 30 ) alkenyl, -(C 1 ~C 30 ) alkyl-COOH, -(C 2 ~C 30 ) alkenyl-COOH, -(C1 ~C 30 ) AlkylNH 2 , -NH 2 , -(C 1 ~C 30 )Alkyl-N((C 1 ~C 30 )Alkyl) 2 , -O-(C 1 ~C 30 ) alkyl, -NH(C 2 ~C 30 ) alkenyl, -(C 1 ~C 30 )Alkyl-NH(C 1 ~C 30 ) alkyl, -NH-oleic acid, -NH-noneic acid, -NH-lipoic acid, and -CH=CH(COOH)-CH 2 -COOH; During the ceremony, Alk 2 , Alk 22 , Alk 2 ' and Alk 22 ' is a straight or branched -(C 1 ~C 30 ) alkyl and straight or branched -(C 2 ~C 30 ) alkenyl, 2 and β 2 ' are each independently an integer from 0 to 6; 2 and X 2 each ' is independently selected from -NH-, -COO-, and O-; In the formula, R i2 , R iii2 , R iv2 , R v2 , R vi2 , R vii2 , R viii2 , R ix2 , R viii2’ , and R ix2’ is H, OH, halogen, -O(C 1 ~C 30 ) alkyl, -CF 3 , -OCF 3 , -NH 2 , -(C1-C30) alkyl, -(C 2 ~C 30 ) alkenyl, -(C 2 ~C 30 ) Alkynyl, -SH, -NHNH 2 , -NHCH 3 , -N(CH 3 ) 2 , -NCH(CH 3 ) 2 and -(C 1 ~C 30 ) alkyl-OH; b2, c2, d2, e2, h2, k2, l2, k2', l2', b2'', c2'', d2'', e2'', and h2'' are independently integers ranging from 1 to 20; b2', c2', d2', e2', and h2' are independently integers ranging from 0 to 20; m2, n2, m2', and n2' are independently integers ranging from 1 to 200; R 3 , R 4 , R 11 and R 13 is -(C 1 ~C 6 ) alkyl-, -(C 1 ~C 6 ) alkyl-SS-(C 1 ~C 6 ) alkyl-, -(C 1 ~C 6 )Alkyl-O-(C 1 ~C 6 ) alkyl-, and -(C 1 ~C 6 ) alkyl-NH-(C 1 ~C 6 ) alkyl; R 3 , R 4 , R 11 and R 13 is -NH 2 and -(C 1 ~C 6)Alkyl-NH 2 optionally substituted with one or more substituents selected from the group consisting of: However, R 3 does not exist when a = 1, and R 11 does not exist if a' = 1; R 5 , R 8 , R 10 , R 12 , R 16 and R 18 is H and -(C 1 ~C 6 ) alkyl.

[0376] Clause 2. The compound of formula I according to clause 1, wherein α, α' and α'' are 0 and the compound of formula I is according to formula Ib. [ka]

[0377] Clause 3. A compound of formula I according to clause 1, wherein α, α' and α'' are 1 and the compound of formula I is according to formula Ib. [ka]

[0378] Clause 4. The compound of formula I according to any one of clauses 1 to 3, wherein R1 is a biradical selected from the group consisting of: [ka] where the wavy lines indicate the attachment points; wherein y and z are independently integers ranging from 1 to 6, in particular, y and z are independently 1, 2, 3, 4, 5, or 6; X is a linear or branched -(C 1 ~C 12 ) alkylene-, -(C 1 ~C 6) alkyl-COO-, and a biradical selected from the group consisting of (V), (VI), (VII), (VIII), (IX), (X), (XI), and (XII); In the formula, X is a linear or branched -(C 1 ~C 12 ) alkylene biradical is -OH, -NR a R b , -SH, -NHNH 2 , -COOR c , -CF 3 , -OCF 3 and halogen; R a , R b and R c is H, -phenyl, -(C 1 ~C 12 ) alkyl, -(C 2 ~C 30 ) alkenyl, -(C 1 ~C 12 ) alkylphenyl, and -phenyl(C 1 ~C 12 ) alkyl.

[0379] Clause 5. A compound of formula I according to any one of clauses 1 to 4: In the formula, R 9 and R 17 is H, -(C 1 ~C 12 ) alkyl, -(C 2 ~C 30 ) alkenyl, -(C 1 ~C 12 ) Alkyl-R i1、 -(C 1 ~C 12 )Alkyl-OR iii1 , -(C 1 ~C 12 )Alkyl-NR iv1 R v1 , -C(O)-R vi1 , -(C 1 ~C12 )Alkyl-CO-NH 2 and a radical selected from the group consisting of (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), and (XXI); R i1 are H, F, Cl, Br, I, -CF 3 , -OCF 3 , isoxazole, oxazole, furan, oxolane, thiol, thiophene, N-methylpyrrole, pyrrole, pyrrolidine, pyran, pyridine, piperidine, thiazole, dioxane, morpholine, pyrimidine, -NH 2 , -N((C 1 ~C 12 )Alkyl) 2 , -NH(C 1 ~C 12 ) alkyl, -NHC(O)-(C 1 ~C 12 ) alkyl, -NHC(O)O(C 1 ~C 12 ) alkyl, -NHC(O)NH 2 , -NHC(O)N(CH 3 ) 2 , -NHS(O) 2 (C 1 ~C 12 ) Alkyl, -NHSO 2 NH 2 , -SH, -S(C 1 ~C 12 ) alkyl, -S(O)H, -S(O)(C 1 ~C 12 ) Alkyl, -SO 2 (C 1 ~C 12 ) alkyl, -SeH, -C(O)(C 1 ~C 12 ) alkyl, and -CON((C 1 ~C 12 )Alkyl) 2 selected from the group consisting of; R vii1is H, methyl, ethyl, propyl, isopropyl, butyl, -(C 2 ~C 30 ) alkenyl, -(C 2 ~C 30 )Alkynyl, -Oalkyl(C 1 ~C 12 ), F, Cl, Br, I, -CF 3 , -OCF 3 , -NO 2 , -CN, -NH 2 , -(C 1 ~C6) alkyl NH 2 , -N((C 1 ~C 6 )Alkyl) 2 , and -NH(C 1 ~C 6 ) alkyl; R iii1 , R iv1 and R v1 teeth, H, -(C 1 ~C 12 ) alkyl, -(C 1 ~C 12 ) AlkylNH 2 , -(C 1 ~C 12 )Alkyl-N((C 1 ~C 12 )Alkyl) 2 , and -(C 1 ~C 12 )Alkyl-NH(C 1 ~C 12 ) alkyl; R vi1 is H, -(C 1 ~C 12 ) alkyl, -(C 2 ~C 30 ) alkenyl, -(C 1 ~C 12 ) AlkylNH 2 , -NH 2 , -(C 1 ~C 12 )Alkyl-N((C 1 ~C 12 )Alkyl) 2 , -NH(C2 ~C 30 ) alkenyl, -(C 1 ~C 12 )Alkyl-NH(C 1 ~C 12 ) alkyl, -NH-oleic acid, -NH-nonenoic acid, and -NH-lipoic acid; In the formula, R i1 , R ii1 , R iii1 , R iv1 , R v1 , R vi1 , and R vii1 are -OH, F, Cl, Br, I, -O(C 1 ~C 6 ) alkyl, -CF 3 , -OCF 3 , -NH 2 , -(C 1 ~C 6 ) Alkyl, -SH, -NHNH 2 , -NHCH 3 , -N(CH 3 ) 2 , -NCH(CH 3 ) 2 and -(C 1 ~C 6 ) alkyl-OH; b1, c1, d1, e1, f1, g1, h1, i1, and j1 are independently integers ranging from 1 to 6.

[0380] Clause 6. A compound of formula I according to any one of clauses 1 to 5: In the formula, R 9 and R 17 is H, methyl, ethyl, propyl, isopropyl, butyl, n-butyl, -(C 2 ~C 30 ) alkenyl, -CH 2 SCH 3 , -CH 2 CH 2 SCH 3 , -CH 2 CH 2 SCH2 CH 3 、-CH 2 SCH 2 CH 3 、-CH 2 SH、-CH 2 -SeH、-CH 2 CH 2 SH、 -CH 2 NH 2 、-CH 2 CH 2 NH 2 、-CH 2 CH 2 CH 2 NH 2 、-CH 2 CH 2 CH 2 CH 2 NH 2 、 -CH 2 CH(CH 3 )CH 2 NH 2 、-CH 2 NHCH 3 、-CH 2 NHCH 2 CH 3 、-CH 2 CH 2 NHCH 3 、 -CH 2 CH 2 NHCH 2 CH 3 、-CH 2 CH 2 CH 2 NHCH 3 、-CH 2 CH 2 CH 2 NHCH 2 CH 3 、 -CH 2 CH(CH 3 )CH 2 NHCH 3 、-CH 2 CH(CH 3 )CH 2 NHCH 2 CH 3 、 -CH2 CH 2 NHCH 2 CH 2 NH 2 、-CH 2 CH 2 CH 2 NHCH 2 CH 2 CH 2 NH 2 、 -CH 2 CH 2 N((CH(CH 3 ) 2 ))、-CH 2 CH 2 CH 2 N((CH(CH 3 ) 2 ))、-CH 2 CH 2 NH(CH(CH 3 ) 2 )、 -CH 2 CH 2 CH 2 NH(CH(CH 3 ) 2 )、-C(O)H、-C(O)OCH 3 、-C(O)OCH 2 CH 3 、 -C(O)OCH(CH 3 ) 2 、-C(O)CH 2 NH 2 、-C(O)CH 2 CH 2 NH 2 、-C(O)CH(CH 3 )CH 2 NH 2 、 -C(O)CH 2 NHCH 3 、-C(O)CH 2 NHCH 2 CH 3 、-C(O)CH 2 CH 2 NHCH 2 CH 3 、 -C(O)CH 2 CH 2 CH2 NHCH 2 CH 3 、-C(O)CH 2 CH 2 CH 2 NHCH 2 CH 2 CH 3 、 -C(O)CH 2 CH(CH 3 )CH 2 NHCH 3 、-C(O)CH 2 CH(CH 3 )CH 2 NHCH 2 CH 3 、 -C(O)CH 2 CH 2 NHCH 2 CH 2 NH 2 、-C(O)CH 2 CH 2 CH 2 NHCH 2 CH 2 CH 2 NH 2 、 -C(O)CH 2 CH 2 N((CH(CH 3 ) 2 ))、-C(O)CH 2 CH 2 CH 2 N((CH(CH 3 ) 2 ))、 -C(O)CH 2 CH 2 NH(CH(CH 3 ) 2 )、-C(O)CH 2 CH 2 CH 2 NH(CH(CH 3 ) 2 )、-CH 2 COOCH 3 、-CH 2 CH 2 COOCH 3 、 -CH 2 COOCH 2CH 3 , -CH 2 CH 2 COOCH 2 CH 3 , -CH 2 COOCH(CH 3 ) 2 , -CH 2 CONH 2 , -CH 2 CH 2 CONH 2 , -CH 2 CH 2 CH 2 CONH 2 , -CONH-oleic acid, -CONH-noneic acid, -CONH-lipoic acid, and a radical selected from the group consisting of (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), and (XXI); In the formula, R vii1 is H, methyl, ethyl, propyl, isopropyl, butyl, -(C 2 ~C 30 ) alkenyl, -(C 2 ~C 30 )Alkynyl, -Oalkyl(C 1 ~C 12 ), F, Cl, Br, I, -CF 3 , -OCF 3 , -NO 2 , -CN, -NH 2 , -(C 1 ~C6) alkyl NH 2 , -N((C 1 ~C 6 )Alkyl) 2 , and -NH(C 1 ~C 6 ) alkyl; Here, b1, c1, d1, e1, f1, g1, h1, i1, and j1 are independently integers ranging from 1 to 6.

[0381] Clause 7. A compound of formula I according to any one of clauses 1 to 6: In the formula, R 9 and R 17is H, methyl, ethyl, propyl, isopropyl, butyl, n-butyl, -CH 2 SCH 3 , -CH 2 CH 2 SCH 3 , -CH 2 CH 2 SCH 2 CH 3 , -CH 2 SCH 2 CH 3 , -CH 2 SH, -CH 2 CH 2 SH, -CH 2 SeH, -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 CH 2 NH 2 and a radical selected from the group consisting of (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), and (XXI); In the formula, R vii1 is H, methyl, ethyl, propyl, isopropyl, butyl, -(C2-C30)alkenyl, -(C 2 ~C 30 )Alkynyl, -Oalkyl(C 1 ~C 6 ), F, Cl, Br, I, -CF 3 , -OCF 3 , -NO 2 , -CN, -NH 2 , -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -CH(CH 3 )NH2 , -CH 2 CH(CH 3 )NH 2 , -CH 2 CH 2 CH 2 NH 2 , -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -NCH(CH 3 ) 2 , -NHCH 3 , -NHCH 2 CH 3 , and -NHCH(CH 3 ) 2 Selected from; Here, b1, c1, d1, e1, f1, g1, h1, i1, and j1 are independently integers ranging from 1 to 4.

[0382] Clause 8. A compound of formula I according to any one of clauses 1 to 7: In the formula, R 6 , R 7 , R 14 , R 15 and R 19 is H, -(C 1 ~C 30 ) alkyl, -(C 2 ~C 30 ) alkenyl, -(C 2 ~C 30 ) alkynyl, -(C 1 ~C 30 ) Alkyl-R i2 , -(C 1 ~C 30 )Alkyl-OR iii2 , -(C 1 ~C 30 )Alkyl-NR iv2 R v2 , -C(O)-R vi2and radicals selected from the group consisting of (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), and (XXXI); R i2 is H, -(C 1 ~C 12 ) alkyl, -O alkyl (C 1 ~C 6 ), F, Cl, Br, I, -CF 3 , -OCF 3 , isoxazole, oxazole, furan, oxolane, thiol, thiophene, N-methylpyrrole, pyrrole, pyrrolidine, pyran, pyridine, piperidine, thiazole, dioxane, morpholine, pyrimidine, -NH 2 , -N((C 1 ~C 12 )Alkyl) 2 , -NH(C 1 ~C 12 ) alkyl, -OC(O)O(C 1 ~C 12 ) alkyl, -OC(O)NH2, -OC(O)N((C 1 ~C 12 )Alkyl) 2 , -SH, -S(C 1 ~C 12 ) alkyl, -S(O)H, -S(O)(C 1 ~C 12 ) Alkyl, -SO 2 (C 1 ~C 12 ) alkyl; R iii2 , R iv2 , and R v2 teeth, H, -(C 1 ~C 12 ) alkyl, -(C 2 ~C 30 ) alkenyl, -(C 1 ~C 30 ) AlkylNH 2 , -(C 1 ~C12 )Alkyl-N((C 1 ~C 12 )Alkyl) 2 , -(C 1 ~C 12 )Alkyl-NH(C 1 ~C 12 ) alkyl, and a radical selected from the group consisting of (XXXII), (XXXIII), (XXXIV), (XXXV), (XXXVI), (XXXVII), (XXXVIII), (XXXIX), (XL), (XLI), (XLII), (XLIII), (XLIV), (XLV), and (XLVI); In the formula, R viii2 , R ix2 , R viii2 ', and R ix2’’ is H, -(C 1 ~C 6 ) alkyl, -(C 1 ~C 6 ) AlkylNH 2 , -(C 1 ~C 6 )Alkyl-N((C 1 ~C 6 )Alkyl) 2 , -(C 1 ~C 6 )Alkyl-NH(C 1 ~C 6 ) alkyl, -O(C 1 ~C 6 ) alkyl, -COH, -CO(C 1 ~C 6 ) alkyl, and -O(C 2 ~C 12 ) alkenyl; R vii2 and R vii2’ is H, -(C 1 ~C 12 ) alkyl, -(C 2 ~C 30 ) alkenyl, -(C 2 ~C 30 ) alkynyl, -O(C 1 ~C 6 ) Alkyl, F, Cl, Br, I, -CF3 , -OCF 3 , -NO 2 , -CN, -NH 2 , -(C 1 ~C 12 ) AlkylNH 2 , -N((C 1 ~C 12 )Alkyl) 2 , and -NH(C 1 ~C 12 ) alkyl; R vi2 is H, -OH, -(C 1 ~C 1 ) alkyl, -(C 2 ~C 30 ) alkenyl, -(C 1 ~C 12 ) alkyl-COOH, -(C 2 ~C 30 ) alkenyl-COOH, -(C 1 ~C 12 ) AlkylNH 2 , -(C 1 ~C 12 )Alkyl-N((C 1 ~C 12 )Alkyl) 2 , -O-(C 1 ~C 12 ) alkyl, -NH(C 2 ~C 12 ) alkenyl, -(C 1 ~C 12 )Alkyl-NH(C 1 ~C 12 ) alkyl, -NH-oleic acid, -NH-noneic acid, -NH-lipoic acid and -CH=CH(COOH)-CH 2 -COOH; During the ceremony, Alk 2 , Alk 22 , Alk 2 ' and Alk 22 ' is a straight or branched chain -(C 1 ~C 12 ) alkyl and straight or branched chain -(C 2 ~C 30) alkenyl, 2 and β 2 ' are each independently an integer from 0 to 6; 2 and X 2’ are each independently selected from the group consisting of -NH-, -COO-, and O-; In the formula, R i2 , R iii2 , R iv2 , R v2 , R vi2 , R vii2 , R viii2 , R ix2 , R viii2’ , and R ix2’ are OH, F, Cl, Br, I, -O(C 1 ~C 6 ) alkyl, -CF 3 , -OCF 3 , -NH 2 , -(C 1 ~C 6 )Alkyl-NHNH 2 , -NHCH 3 , -N(CH 3 ) 2 , -NCH(CH 3 ) 2 and -(C 1 ~C 6 ) alkyl-OH; b2, c2, d2, e2, h2, k2, l2, k2', l2', b2'', c2'', d2'', e2'', and h2'' are independently integers ranging from 1 to 6; b2', c2', d2', e2', and h2' are independently integers ranging from 0 to 6; m2, n2, m2', and n2' are independently integers ranging from 1 to 150.

[0383] Clause 9. A compound of formula I according to any one of clauses 1 to 8: In the formula, R 6 , R 7 , R 14 , R 15 and R 19is H, methyl, ethyl, propyl, isopropyl, butyl, -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 OCH 2 CH 3 , -CH 2 CH 2 OCH(CH 3 ) 2 , -CH 2 OCH 2 CH 3 , -CH 2 OCH(CH 3 ) 2 , -(C 2 ~C 30 ) alkenyl, -(C 2 ~C 30 ) alkynyl, -CH 2 SCH 3 , -CH 2 CH 2 SCH 3 , -CH 2 CH 2 SCH 2 CH 3 , -CH 2 SCH 2 CH 3 , -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 NH 2 , -CH 2 CH(CH 3 )CH 2 NH 2 , -CH 2 NHCH 3 , -CH 2 NHCH 2 CH 3 , -CH 2 CH 2 NHCH 3 , -CH2 CH 2 NHCH 2 CH 3 、-CH 2 CH 2 CH 2 NHCH 3 、-CH 2 CH 2 CH 2 NHCH 2 CH 3 、 -CH 2 CH(CH 3 )CH 2 NHCH 3 、-CH 2 CH(CH 3 )CH 2 NHCH 2 CH 3 、 -CH 2 CH 2 NHCH 2 CH 2 NH 2 、-CH 2 CH 2 CH 2 NHCH 2 CH 2 CH 2 NH 2 、 -CH 2 CH 2 N((CH(CH 3 ) 2 ))、-CH 2 CH 2 CH 2 N((CH(CH 3 ) 2 ))、-CH 2 CH 2 NH(CH(CH 3 ) 2 )、 -CH 2 CH 2 CH 2 NH(CH(CH 3 ) 2 )、-C(O)H、-C(O)OCH 3 、-C(O)OCH 2 CH 3 、 -C(O)OCH(CH 3 )2 、-C(O)CH 2 NH 2 、-C(O)CH 2 CH 2 NH 2 、-C(O)CH(CH 3 )CH 2 NH 2 、 -C(O)CH 2 NHCH 3 、-C(O)CH 2 NHCH 2 CH 3 、-C(O)CH 2 CH 2 NHCH 2 CH 3 、 -C(O)CH 2 CH 2 CH 2 NHCH 2 CH 3 、-C(O)CH 2 CH 2 CH 2 NHCH 2 CH 2 CH 3 、 -C(O)CH 2 CH(CH 3 )CH 2 NHCH 3 、-C(O)CH 2 CH(CH 3 )CH 2 NHCH 2 CH 3 、 -C(O)CH 2 CH 2 NHCH 2 CH 2 NH 2 、-C(O)CH 2 CH 2 CH 2 NHCH 2 CH 2 CH 2 NH 2 、 -C(O)CH 2 CH 2 N((CH(CH 3 ) 2 ))、-C(O)CH2 CH 2 CH 2 N((CH(CH 3 ) 2 )) -C(O)CH 2 CH 2 NH(CH(CH 3 ) 2 ), -C(O)CH 2 CH 2 CH 2 NH(CH(CH 3 ) 2 ), -CH 2 COOH, -CH 2 CH 2 COOH, -CH 2 COOCH 3 , -CH 2 CH 2 COOCH 3 , -CH 2 COOCH 2 CH 3 , -CH 2 CH 2 COOCH 2 CH 3 , -CH 2 COOCH(CH 3 ) 2 , -(C 1 ~C 6 ) Alkyl-R i2 , -(C 1 ~C 6 )Alkyl-OR iii2 , -(C 1 ~C 6 )Alkyl-NR iv2 R v2 , -CONH-oleic acid, -CONH-noneic acid, -CONH-lipoic acid, and radicals selected from the group consisting of (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), and (XXXI); R i2 is imidazole, N-methylpyrrole, pyrrole, pyrrolidine, pyran, pyridine, piperidine, pyrimidine, -OC(O)NH2 , -OC(O)N((C 1 ~C 6 )Alkyl) 2 selected from the group consisting of; R iii2 , R iv2 , and R v2 is -(C 2 ~C 30 ) alkenyl, -(C 2 ~C 30 ) alkynyl, -(C 1 ~C 6 )Alkyl-NH 2 , -(C 1 ~C 6 )Alkyl-N((C 1 ~C 6 )Alkyl) 2 , -(C 1 ~C 6 )Alkyl-NH(C 1 ~C 6 ) alkyl, and a radical selected from the group consisting of (XXXII), (XXXIII), (XXXIV), (XXXV), (XXXVI), (XXXVII), (XXXVIII), (XXXIX), (XL), (XLI), (XLII), (XLIII), (XLIV), (XLV), and (XLVI); R vii2 and R vii2’ is H, methyl, ethyl, propyl, isopropyl, butyl, -Oalkyl(C 1 ~C 6 ), F, Cl, Br, I, -CF 3 , -OCF 3 , -NO 2 , -CN, -NH 2 , -(C 1 ~C 6 )Alkyl-NH 2 , -N((C 1 ~C 6 )Alkyl) 2 , -NH(C 1 ~C 6 ) alkyl; In the formula, R viii2 , Rix2 , R viii2’ , and R ix2’’ is H, -(C 1 ~C 6 ) alkyl, -(C 2 ~C 6 ) alkenyl, -(C 2 ~C 6 ) alkynyl, -(C 1 ~C 6 ) AlkylNH 2 , -(C 1 ~C 6 )Alkyl-N((C 1 ~C 6 )Alkyl) 2 , -(C 1 ~C 6 )Alkyl-NH(C 1 ~C 6 ) alkyl; In the formula, R i2 , R iii2 , R iv2 , R v2 , R vi2 , R vii2 , R viii2 , R ix2 , R viii2’ , and R ix2’ are OH, F, Cl, Br, -OCH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 , -CF 3 , -OCF 3 , -NH 2 , -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 OH, -CH 2 CH 2 OH, and -CH 2 CH(OH)CH 3 optionally substituted with one or more substituents selected from the group consisting of: b2, c2, d2, e2, h2, k2, l2, k2', l2', b2'', c2'', d2'', e2'', and h2'' are independently integers ranging from 1 to 4; b2', c2', d2', e2', and h2' are independently integers ranging from 0 to 4; m2, n2, m2', and n2' are independently integers ranging from 1 to 120.

[0384] Clause 10. A compound of formula I according to any one of claims 1 to 9: In the formula, R 1 -CH 2 CH 2 -SS-CH 2 CH 2 -, -CH 2 CH 2 CH 2 -SS-CH 2 CH 2 CH 2 -, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 -, -CH 2 CH(CH 2 CH 3 )CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, -CH 2 COO-, -CH 2 CH 2 COO-, -CH 2 CHCH 3 COO-, -CH 2 CH 2 CH 3 CH 2 a biradical selected from the group consisting of COO-, and a biradical selected from the group consisting of (V), (VI), (VII), (VIII), (IX), (X), (XI), and (XII); R 9 and R17 is H, methyl, ethyl, propyl, isopropyl, butyl, n-butyl, -CH 2 SCH 3 , -CH 2 CH 2 SCH 3 , -CH 2 CH 2 SCH 2 CH 3 , -CH 2 SCH 2 CH 3 , -CH 2 S.H., -CH 2 CH 2 SH, -CH 2 SeH, -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 CH 2 NH 2 and a radical selected from the group consisting of (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), and (XXI); In the formula, R vii1 is H, methyl, ethyl, propyl, isopropyl, butyl, -(C 2 ~C 30 ) alkenyl, -(C 2 ~C 30 ) Alkynyl, -OCH 3 , -OCH 2 CH 3 , F, Cl, Br, I, -CF 3 , -OCF 3 , -NO 2 , -CN, -NH 2 , -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -CH(CH3 )NH 2 , -CH 2 CH(CH 3 )NH 2 , -CH 2 CH 2 CH 2 NH 2 , -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -NCH(CH 3 ) 2 , -NHCH 3 , -NHCH 2 CH 3 , and -NHCH(CH 3 ) 2 Selected from; where b1, c1, d1, e1, f1, g1, h1, i1, and j1 are independently integers ranging from 1 to 6; r, s, t, and u are independently integers ranging from 0 to 250, and at least one of r or t is 1 or greater.

[0385] Clause 11. A compound of formula I according to any one of claims 1 to 10: In the formula, R1 is -CH 2 CH 2 -SS-CH 2 CH 2 -, -CH 2 CH 2 CH 2 -SS-CH 2 CH 2 CH 2 -, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 -, -CH 2 CH(CH 2 CH 3 )CH 2 -, -CH 2 CH 2 CH 2 CH2 -, -CH 2 COO-, -CH 2 CH 2 COO-, -CH 2 CHCH 3 COO-, -CH 2 CH 2 CH 3 CH 2 a biradical selected from the group consisting of COO-, and a biradical selected from the group consisting of (V), (VI), (VII), (VIII), (IX), (X), (XI), and (XII); R 9 and R 17 is H, methyl, ethyl, propyl, isopropyl, butyl, n-butyl, -CH 2 SCH 3 , -CH 2 CH 2 SCH 3 , -CH 2 CH 2 SCH 2 CH 3 , -CH 2 SCH 2 CH 3 , -CH 2 SH, -CH 2 CH 2 S.H., -CH 2 SeH, -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 CH 2 NH 2 and a radical selected from the group consisting of (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), and (XXI); R vii1is H, methyl, ethyl, propyl, isopropyl, butyl, -OCH 3 , -OCH 2 CH 3 , F, Cl, Br, I, -CF 3 , OCF 3 , -NO 2 , -CN, -NH 2 , -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -CH 2 CH(CH 3 )NH 2 , -CH 2 CH 2 CH 2 NH 2 , -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -NCH(CH 3 ) 2 , -NHCH 3 , -NHCH 2 CH 3 , and -NHCH(CH 3 ) 2 Selected from; b1, c1, d1, e1, f1, g1, h1, i1, and j1 are independently integers ranging from 1 to 6; R 6 , R 7 , R 14 , R 15 and R 19 is H, methyl, ethyl, propyl, isopropyl, butyl, -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 OCH 2 CH 3 , -CH 2 CH 2 OCH(CH 3 ) 2 , -CH2 OCH 2 CH 3 、-CH 2 OCH(CH 3 )2、-(C 2 ~C 30 )アルケニル、 -(C 2 ~C 30 )アルキニル、-CH 2 SCH 3 、-CH 2 CH 2 SCH 3 、-CH 2 SH、CH 2 SeH-CH 2 CH 2 SH、 -CH 2 CH 2 SCH 2 CH 3 、-CH 2 SCH 2 CH 3 、-CH 2 NH 2 、-CH 2 CH 2 NH 2 、-CH 2 CH 2 CH 2 NH 2 、-CH 2 CH(CH 3 )CH 2 NH 2 、-CH 2 NHCH 3 、-CH 2 NHCH 2 CH 3 、-CH 2 CH 2 NHCH 3 、 -CH 2 CH 2 NHCH 2 CH 3 、-CH 2 CH 2 CH 2 NHCH 3 、-CH 2 CH 2 CH 2 NHCH 2 CH3 、 -CH 2 CH(CH 3 )CH 2 NHCH 3 、-CH 2 CH(CH 3 )CH 2 NHCH 2 CH 3 、 -CH 2 CH 2 NHCH 2 CH 2 NH 2 、-CH 2 CH 2 CH 2 NHCH 2 CH 2 CH 2 NH 2 、 -CH 2 CH 2 N((CH(CH 3 ) 2 ))、-CH 2 CH 2 CH 2 N((CH(CH 3 ) 2 ))、-CH 2 CH 2 NH(CH(CH 3 ) 2 )、 -CH 2 CH 2 CH 2 NH(CH(CH 3 ) 2 )、-C(O)H、-C(O)OCH 3 、-C(O)OCH 2 CH 3 、 -C(O)OCH(CH 3 ) 2 、-C(O)CH 2 NH 2 、-C(O)CH 2 CH 2 NH 2 、-C(O)CH(CH 3 )CH 2 NH 2 、 -C(O)CH 2NHCH 3 、-C(O)CH 2 NHCH 2 CH 3 、-C(O)CH 2 CH 2 NHCH 2 CH 3 、 -C(O)CH 2 CH 2 CH 2 NHCH 2 CH 3 、-C(O)CH 2 CH 2 CH 2 NHCH 2 CH 2 CH 3 、 -C(O)CH 2 CH(CH 3 )CH 2 NHCH 3 、-C(O)CH 2 CH(CH 3 )CH 2 NHCH 2 CH 3 、 -C(O)CH 2 CH 2 NHCH 2 CH 2 NH 2 、-C(O)CH 2 CH 2 CH 2 NHCH 2 CH 2 CH 2 NH 2 、 -C(O)CH 2 CH 2 N((CH(CH 3 ) 2 ))、-C(O)CH 2 CH 2 CH 2 N((CH(CH 3 ) 2 ))、 -C(O)CH 2 CH 2 NH(CH(CH 3 ) 2 )、-C(O)CH 2 CH2 CH 2 NH(CH(CH 3 ) 2 ), -CH 2 COOH, -CH 2 CH 2 COOH, -CH 2 COOCH 3 , -CH 2 CH 2 COOCH 3 , -CH 2 COOCH 2 CH 3 , -CH 2 CH 2 COOCH 2 CH 3 , -CH 2 COOCH(CH 3 ) 2 , -(C 1 ~C 6 ) Alkyl-R i2 , -(C 1 ~C 6 )Alkyl-OR iii2 , -(C 1 ~C 6 )Alkyl-NR iv2 R v2 , -CONH-oleic acid, -CONH-noneic acid, -CONH-lipoic acid, and radicals selected from the group consisting of (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), and (XXXI); R i2 is imidazole, N-methylpyrrole, pyrrole, pyrrolidine, pyran, pyridine, piperidine, pyrimidine, -OC(O)NH 2 , -OC(O)N((C 1 ~C 6 )Alkyl) 2 selected from the group consisting of; R iii2 , R iv2 , and R v2 is H, -(C 2~C 30 )アルケニル、-(C 2 ~C 30 )アルキニル、-CH 2 NH 2 、 -CH 2 CH 2 NH 2 、-CH 2 CH 2 CH 2 NH 2 、-CH 2 CH(CH 3 )CH 2 NH 2 、-CH 2 NHCH 3 、-CH 2 NHCH 2 CH 3 、-CH 2 CH 2 NHCH 3 、 -CH 2 CH 2 NHCH 2 CH 3 、-CH 2 CH 2 CH 2 NHCH 3 、-CH 2 CH 2 CH 2 NHCH 2 CH 3 、-CH 2 CH(CH 3 )CH 2 NHCH 3 、 -CH 2 CH(CH 3 )CH 2 NHCH 2 CH 3 、-CH 2 CH 2 NHCH 2 CH 2 NH 2 、-CH 2 CH 2 CH 2 NHCH 2 CH 2 CH 2 NH 2 、 -CH2 CH 2 N((CH(CH 3 ) 2 )), -CH 2 CH 2 CH 2 N((CH(CH 3 ) 2 )), -CH 2 CH 2 NH(CH(CH 3 ) 2 ), -CH 2 CH 2 CH 2 NH(CH(CH 3 ) 2 and radicals selected from the group consisting of (XXXII), (XXXIII), (XXXIV), (XXXV), (XXXVI), (XXXVII), (XXXVIII), (XXXIX), (XL), (XLI), (XLII), (XLIII), (XLIV), (XLV), and (XLVI); R vii2 and R vii2’ is H, methyl, ethyl, propyl, isopropyl, butyl, F, Cl, Br, I, -CF 3 , -OCF 3 , -NO 2 , -CN, -NH 2 , and -(C 1 ~C 6 )Alkyl-NH 2 are independently selected from; R viii2 , R ix2 , R viii2’ , and R ix2’’ is H, methyl, ethyl, propyl, isopropyl, -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 NH 2 , -CH 2 CH(CH 3 )CH 2 NH 2 , -CH 2NHCH 3 、 -CH 2 NHCH 2 CH 3 、-CH 2 CH 2 NHCH 3 、-CH 2 CH 2 NHCH 2 CH 3 、-CH 2 CH 2 CH 2 NHCH 3 、-CH 2 CH 2 CH 2 NHCH 2 CH 3 、 -CH 2 CH(CH 3 )CH 2 NHCH 3 、-CH 2 CH(CH 3 )CH 2 NHCH 2 CH 3 、-CH 2 CH 2 NHCH 2 CH 2 NH 2 、 -CH 2 CH 2 CH 2 NHCH 2 CH 2 CH 2 NH 2 、-CH 2 CH 2 N((CH(CH 3 ) 2 ))、-CH 2 CH 2 CH 2 N((CH(CH 3 ) 2 ))、 -CH 2 CH 2 NH(CH(CH 3 ) 2 )、-CH 2 CH 2 CH 2 NH(CH(CH 3) 2 ) are independently selected; In the formula, R i2 , R iii2 , R iv2 , R v2 , R vi2 , R vii2 , R viii2 , R ix2 , R viii2’ , and R ix2’ are OH, F, Cl, Br, -OCH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 , -CF 3 , -OCF 3 , -NH 2 , -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 OH, -CH 2 CH 2 OH, and -CH 2 CH(OH)CH 3 optionally substituted with one or more substituents selected from the group consisting of: b2, c2, d2, e2, h2, k2, l2, k2', l2', b2'', c2'', d2'', e2'', and h2'' are independently integers ranging from 1 to 4; b2', c2', d2', e2', and h2' are independently integers ranging from 0 to 4; m2, n2, m2', and n2' are independently integers ranging from 1 to 120.

[0386] Clause 12. A compound of formula I according to any one of clauses 1 to 11, selected from: [Table 30] TIFF2024528853000106.tif43159

Claims

1. Any stereoisomer or mixture of stereoisomers of a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising a compound of formula (I), a pharmaceutically acceptable salt thereof, or a homopolypeptide or a random or block or graft copolymer polypeptide; 【Chemical 1】 wherein A, A' and A'' are each independently selected from the radical groups of formula II; and each of the A, A' and A'' subunits may be the same or different; 【Chemical 2】 where the wavy line indicates the point of attachment; and the repeating units defined by the square brackets and their numerical values r, s, t and u in formula II are shown in a specific order for convenience of explanation, but the repeating units may be present in any order and the repeating units may be present in blocks or randomly, and each of the repeating units may comprise blocks of monomer units that may be the same or different from each other; wherein K, K' and K'' are each independently selected from -O- and -NH-; L is selected from the following; 【Chemical Formula 3】 wherein α, α', and α'' are integers from 0 to 1; each wavy line indicates the point of attachment to A, A' or A''; and "*" indicates the point of attachment to K, K' or K''; where R2 is selected from -O- and -NH-; where R1 is a biradical selected from the group consisting of (III) and (IV), 【Chemical Formula 4】 where the wavy line indicates the point of attachment; where y and z are independently integers in the range of 1 to 20; X is a biradical selected from the group consisting of -NH-, -NH(C １ ~C ６ ), alkyl-, -O-, -(C １ ~C6) alkyl-COO-, linear or branched -(C １ ~C ３０ ), alkylene-, and a biradical selected from the group consisting of (V), (VI), (VII), (VIII), (IX), (X), (XI) and (XII), and 【Chemical Formula 5】 Here, " ＊ " indicates the attachment point; wherein the -(C １ ~C ３０ ) alkylene biradical is optionally substituted with one or more radicals selected from the group consisting of -OH, -NR ａ R ｂ , -SH, -NHNH ２ , -COOR ｃ , -CF ３ , -OCF ３ , and halogen; R ａ 、 R ｂ and R ｃ are each independently selected from the group consisting of H, -phenyl, -(C １ ~C ３０ )alkyl, -(C ２ ~C ３０ )alkenyl, -(C １ ~C ３０ )alkylphenyl, and -phenyl(C １ ~C ３０ )alkyl; where a and a' are independently integers in the range of 0 to 1; r, s, t and u are independently integers in the range of 0 to 500, where at least one of r or t is 1 or more; where in the radical of formula (II), the repeating unit defined by the square brackets having the numerical value r is represented as PAA1; the repeating unit defined by the square brackets having the numerical value s is represented as PAA2; the repeating unit defined by the square brackets having the numerical value t is represented as PAA3; and the repeating unit defined by the square brackets having the numerical value u is represented as PAA4; where the molar ratio of PAA1 monomer to PAA2 is from 100 / 0 to 60 / 40; where the molar ratio of PAA1 monomer to PAA4 is from 100 / 0 to 60 / 40; where the molar ratio of PAA3 monomer to PAA4 is from 100 / 0 to 60 / 40; Here, the molar ratio of the PAA3 monomer to PAA2 is from 100 / 0 to 60 / 40; and here, the molar ratio of the total of the PAA1 + PAA3 monomers to the total of the PAA2 + PAA4 is from 100 / 0 to 60 / 40; R ９ and R １７ are H, -(C １ ~C ３０ ), alkyl, -(C ２ ~C ３０ ), alkenyl, -(C １ ~C ３０ ), alkyl-R ｉ１ , -(C １ ~C ３０ ), alkyl-COOR ｉｉ１ , -(C １ ~C ３０ )-alkyl - O - R ｉｉｉ１ 、-(C １ ~C ３０ )-alkyl - NR ｉｖ１ R ｖ１ 、-C(O)R ｖｉ１ 、 -(C １ ~C １２ )alkyl-CO-NH ２ a radical independently selected from the group consisting of, and a radical selected from the group consisting of (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), and (XXI); [Chemical Formula 6] Here, " ＊ " indicates the attachment point; R ｉ１ is H, -(C １ ~C ３０ )-alkyl, -(C ２ ~C ３０ )-alkenyl, -(C ２ ~C ３０ )-alkynyl, halogen, -CF ３ , -OCF ３ , isoxazole, oxazole, furan, oxolane, thiol, thiophene, N-methylpyrrole, pyrrole, pyrrolidine, pyran, pyridine, piperidine, thiazole, dioxane, morpholine, pyrimidine, -NH ２ , -N((C １ ~C ３０ )-alkyl) ２ , -NH(C １ ~C ３０ )-alkyl, -NHC(O)-(C １ ~C ３０ )-alkyl, -NHC(O)O(C １ ~C ３０ )alkyl, -NHC(O)NH ２ , -NHC(O)N(CH ３ ) ２ , -NHS(O) ２ (C １ ~C ３０ )alkyl, -NHSO ２ NH ２ , -C(O)(C １ ~C ３０ )alkyl, -CON((C １ ~C ３０ )alkyl) ２ ; -NO ２ , -CN, -OC(O)-(C １ ~C ３０ )alkyl, -OC(O)O(C １ ~C ３０ )alkyl, -OC(O)NH ２ , -OC(O)N((C １ ~C ３０ )(alkyl) ２ , -SeH, -SH, -S(C １ ~C ３０ )(alkyl), -S(O)H, -S(O)(C １ ~C ３０ )alkyl, and -SO ２ (C １ ~C ３０ )alkyl selected from the group consisting of; R ｖｉｉ１ is selected from the group consisting of H, -(C １ ~C ３０ ), alkyl, -(C ２ ~C ３０ ), alkenyl, -(C ２ ~C ３０ ), alkynyl, -O alkyl (C １ ~C １２ ), F, Cl, Br, I, -CF ３ , -OCF ３ , -NO ２ , -CN, -NH ２ , -(C １ ~C ３０ ), alkyl NH ２ , -N((C １ ~C ３０ ), alkyl) ２ , and -NH(C １ ~C ３０ ), alkyl R ｉｉ１ 、R ｉｉｉ１ 、R ｉｖ１ and R ｖ１ are independently selected from the group consisting of H, -OH, -(C １ ~C ３０ alkyl, -(C １ ~C ３０ alkylNH ２ , -(C １ ~C ３０ alkyl-N((C １ ~C ３０ alkyl)), ２ and -(C １ ~C ３０ alkyl-NH(C １ ~C ３０ alkyl); R ｖｉ１ is H, -OH, -(C １ ~C ３０ )-alkyl, -(C ２ ~C ３０ )-alkenyl, -(C １ ~C ３０ )-alkylNH ２ , -NH ２ , -(C １ ~C ３０ )-alkyl-N((C １ ~C ３０ )-alkyl) ２ , -NH(C ２ ~C ３０ )-alkenyl, -(C １ ~C ３０ )-alkyl-NH(C １ ~C ３０ )-alkyl, selected from the group consisting of -NH-oleic acid, -NH-nonanoic acid, and -NH-lipoic acid, wherein R ｉ１ , R ｉｉ１ , R ｉｉｉ１ , R ｉｖ１ , R ｖ１ , R ｖｉ１ , and R ｖｉｉ１ are -OH, halogen, -O(C １ ~C ３０ )alkyl, -CF ３ , -OCF ３ , -NH ２ , -(C １ ~C ３０ )alkyl, -SH, -NHNH ２ , -NHCH ３ 、-N(CH ３ ) ２ 、-NCH(CH ３ ) ２ and -(C １ ~C ３０ ) alkyl-OH and is optionally substituted with one or more substituents selected from the group consisting of; b1, c1, d1, e1, f1, g1, h1, i1, and j1 are independently integers in the range of 1 to 20; where W1 and W2 are independently selected from CH and N; R ６ , R ７ , R １４ , R １５ and R １９ is H, -(C １ ~C ３０ ) alkyl, -(C ２ ~C ３０ ) alkenyl, -(C ２ ~C ３０ ) alkynyl, -(C １ ~C ３０ ) alkyl-R ｉ２ , -(C １ ~C ３０ )alkyl - O - R ｉｉｉ２ 、-(C １ ~C ３０ )alkyl - NR ｉｖ２ R ｖ２ 、-C(O)-R ｖｉ２ from the group consisting of, and independently selected from the group consisting of radicals selected from the group consisting of (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), and (XXXI), 【Chemical Formula 7】 Here, " ＊ " indicates the attachment point; R ｉ２ is H, -(C １ ~C ３０ )alkyl, -(C ２ ~C ３０ )alkenyl, -(C ２ ~C ３０ ) alkynyl, -O alkyl (C １ ~C ６ ), halogen, -CF ３ , -OCF ３ , isoxazole, oxazole, furan, oxolane, thiol, thiophene, N-methylpyrrole, pyrrole, pyrrolidine, pyran, pyridine, piperidine, thiazole, dioxane, morpholine, pyrimidine, -NO ２ , -CN, -OC(O)-(C １ ~C ３０ ) alkyl, -OC(O)O(C １ ~C ３０ ) alkyl, -OC(O)NH ２ 、-OC(O)N((C １ ~C ３０ )alkyl) ２ 、-SH、-S(C １ ~C ３０ )alkyl、-S(O)H、 -S(O)(C １ ~C ３０ )alkyl, -SO ２ (C １ ~C ３０ )alkyl, and is selected from the group consisting of; R ｉｉｉ２ 、R ｉｖ２ 、and R ｖ２ are H, -(C １ ~C ３０ )alkyl, -(C ２ ~C ３０ )alkenyl, -(C １ ~C ３０ )alkylNH ２ , -(C １ ~C ３０ )alkyl-N((C １ ~C ３０ )alkyl) ２ 、-(C １ ~C ３０ )alkyl-NH(C １ ~C ３０ )alkyl, and independently selected from the group consisting of radicals selected from the group consisting of (XXXII), (XXXIII), (XXXIV), (XXXV), (XXXVI), (XXXVII), (XXXVIII), (XXXIX), (XL), (XLI), (XLII), (XLIII), (XLIV), (XLV), and (XLVI), [Chemical 8] wherein R ｖｉｉｉ２ , R ｉｘ２ , R ｖｉｉｉ２’ , and R ｉｘ２’’ are H, -(C １ ~C １２ ), alkyl, -(C １ ~C １２ ), alkylNH ２ , -(C １ ~C １２ )alkyl-N((C １ ~C １２ )alkyl) ２ 、-(C １ ~C １２ )alkyl-NH(C １ ~C １２ )alkyl、-O(C １ ~C １２ )alkyl、-COH、-CO(C １ ~C １２ )alkyl、and -O(C ２ ~C ３０ )alkenyl, independently selected from the group consisting of R ｖｉｉ２ and R ｖｉｉ２’ are each independently selected from the group consisting of H, -(C １ ~C ３０ )alkyl, -(C ２ ~C ３０ )alkenyl, -(C ２ ~C ３０ )alkynyl, -Oalkyl(C １ ~C １２ ), F, Cl, Br, I, -CF ３ , -OCF ３ , -NO ２ , -CN, -NH ２ , -(C １ ~C ３０ )alkylNH ２ , -N((C １ ~C ３０ )alkyl) ２ , and -NH(C １ ~C ３０ )alkyl R ｖｉ２ is H, -OH, -(C １ ~C ３０ )-alkyl, -(C ２ ~C ３０ )-alkenyl, -(C １ ~C ３０ )-alkyl-COOH, -(C ２ ~C ３０ )-alkenyl-COOH, -(C １ ~C ３０ )alkylNH ２ 、-NH ２ 、 -(C １ ~C ３０ )alkyl-N((C １ ~C ３０ )alkyl) ２ , -O-(C １ ~C ３０ )alkyl, -NH(C ２ ~C ３０ )alkenyl, -(C １ ~C ３０ )alkyl-NH(C １ ~C ３０ )alkyl, -NH-oleic acid, -NH-nonanoic acid, -NH-lipoic acid, and -CH=CH(COOH)-CH ２ -COOH, selected from the group consisting of, where Alk ２ , Alk ２２ , Alk ２ ’ and Alk ２２ ’ are each independently selected from the group consisting of linear or branched -(C １ ~C ３０ )alkyl and linear or branched -(C ２ ~C ３０ )alkenyl, β ２ and β ２ ’ are each independently an integer from 0 to 6, and X ２ and X ２ ’ are each independently selected from -NH-, -COO-, and O-; wherein R ｉ２ , R ｉｉｉ２ , R ｉｖ２ , R ｖ２ , R ｖｉ２ , R ｖｉｉ２ , R ｖｉｉｉ２ , R ｉｘ２ , R ｖｉｉｉ２’ , and R ｉｘ２’ are H, OH, halogen, -O(C １ ~C ３０ )alkyl, -CF ３ , -OCF ３ , -NH ２ , -(C １ ~C ３０ )alkyl, -(C １ ~C ３０ )alkyl, -(C ２ ~C ３０ )alkenyl, -(C ２ ~C ３０ )alkynyl, -SH, -NHNH ２ , -NHCH ３ , -N(CH ３ ) ２ , -NCH(CH ３ ) ２ and -(C １ ~C ３０ ) alkyl-OH; b2, c2, d2, e2, h2, k2, l2, k2', l2', b2'', c2'', d2'', e2'', and h2'' are independently integers in the range of 1 to 20; b2', c2', d2', e2', and h2' are independently integers in the range of 0 to 20; m2, n2, m2', and n2' are independently integers in the range of 1 to 200; Here, R ３ , R ４ , R １１ and R １３ are -(C １ ~C ６ )alkyl-, -(C １ ~C ６ )alkyl-S-S-(C １ ~C ６ )alkyl-, -(C １ ~C ６ )alkyl-O-(C １ ~C ６ )alkyl-, and -(C １ ~C ６ )alkyl-NH-(C １ ~C ６ )alkyl, which is a biradical independently selected from the group consisting of; R ３ 、R ４ 、R １１ and R １３ are optionally substituted by one or more substituents selected from the group consisting of -NH ２ and -(C １ ~C ６ )alkyl-NH ２ ; However, R ３ does not exist when a = 1, and R １１ does not exist when a' = 1; R ５ 、 R ８ 、 R １０ 、 R １２ 、 R １６ and R １８ are radicals independently selected from the group consisting of H and -(C １ ~C ６ )alkyl; wherein R ９ and R １０ are optionally combined together to form a proline ring moiety; and in the formula, R17 and R18 are optionally combined together to form a proline ring moiety.

2. The compound of formula I according to claim 1, wherein α, α' and α'' are 0.

3. The compound of formula I according to claim 1, wherein R1 is a biradical selected from the group consisting of: 【Chemical Formula 9】 where the wavy line indicates the attachment point; where y and z are independently integers in the range of 1 to 6; X is a linear or branched -(C １ ~C １２ ) alkylene-, -(C １ ~C ６ ) A radical selected from -alkyl-COO-, and a radical selected from the group consisting of (V), (VI), (VII), (VIII), (IX), (X), (XI) and (XII); wherein the linear or branched -(C １ ~C １２ ) alkylene biradical is optionally substituted with one or more radicals selected from the group consisting of -OH, -NR ａ R ｂ , -SH, -NHNH ２ , -COOR ｃ , -CF ３ , -OCF ３ , and halogen; R ａ , R ｂ and R ｃ are radicals independently selected from the group consisting of H, -phenyl, -(C １ ~C １２ )alkyl, -(C ２ ~C ３０ )alkenyl, -(C １ ~C １２ )alkylphenyl, and -phenyl(C １ ~C １２ ).

4. The compound of formula I according to claim 1: wherein R ９ and R １７ are H, -(C １ ~C １２ )alkyl, -(C ２ ~C ３０ )alkenyl, -(C １ ~C １２ )alkyl-R ｉ１ , -(C １ ~C １２ )alkyl - O Ｒｉｉｉ１ 、-(C １ ~C １２ )alkyl - NR ｉｖ１ R ｖ１ 、-C(O)-R ｖｉ１ 、 -(C １ ~C １２ )alkyl-CO-NH ２ a radical independently selected from the group consisting of, and a radical selected from the group consisting of (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), and (XXI); R ｉ１ is H, F, Cl, Br, I, -CF ３ , -OCF ３ , isoxazole, oxazole, furan, oxolane, thiol, thiophene, N-methylpyrrole, pyrrole, pyrrolidine, pyran, pyridine, piperidine, thiazole, dioxane, morpholine, pyrimidine, -NH ２ , -N((C １ ~C １２ )alkyl) ２ , -NH(C １ ~C １２ )alkyl -NHC(O)-(C １ ~C １２ ), -NHC(O)O(C １ ~C １２ ), -NHC(O)NH ２ , -NHC(O)N(CH ３ ) ２ 、-NHSO ２ (C １ ~C １２ )alkyl, -NHSONH ２ 、-SH, -S(C ２ ~C １ )alkyl, １２ -NHC(O)N(CH ３ ) ２ 、-NHSO ２ (C １ ~C １２ )alkyl, -NHSONH ２ 、-SH, -S(C ２ ~C １ )alkyl, １２ It should be noted that the text seems to be incomplete or contains some unclear notations, which may affect the full understanding of its exact chemical meaning. -NHC(O)N(CH ３ ) ２ , -NHSO ２ (C １ ~C １２ )alkyl, -NHSONH ２ , -SH, -S(C ２ ~C １ )alkyl, １２ -S(O)H, -S(O)(C １ ~C １２ )alkyl, -SO ２ (C １ ~C １２ )alkyl, -SeH, -C(O)(C １ ~C １２ )alkyl, and -CON((C １ ~C １２ )alkyl) ２ selected from the group consisting of; R ｖｉｉ１ is selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, butyl, -(C ２ ~C ３０ )-alkenyl, -(C ２ ~C ３０ )-alkynyl, -O-alkyl(C １ ~C １２ ), F, Cl, Br, I, -CF ３ ), -OCF ３ ), -NO ２ ), -CN, -NH ２ ), -(C １ ~C6)alkylNH ２ ), -N((C １ ~C ６ ))alkyl ２ ), and -NH(C １ ~C ６ ))alkyl; R ｉｉｉ１ 、 R ｉｖ１ and R ｖ１ are, H, -(C １ ~C １２ ), alkyl, -(C １ ~C １２ ), alkylNH ２ , -(C １ ~C １２ )alkyl-N((C １ ~C １２ )alkyl) ２ 、and -(C １ ~C １２ )alkyl-NH(C １ ~C １２ )alkyl, independently selected from the group consisting of; R ｖｉ１ is H, -(C １ ~C １２ )alkyl, -(C ２ ~C ３０ )alkenyl, -(C １ ~C １２ )alkylNH ２ , -NH ２ , -(C １ ~C １２ )alkyl-N((C １ ~C １２ )alkyl) ２ , -NH(C ２ ~C ３０ )alkenyl, -(C １ ~C １２ )alkyl-NH(C １ ~C １２ )alkyl, -NH-oleic acid, -NH-nonanoic acid, and -NH-lipoic acid; wherein R ｉ１ , R ｉｉ１ , R ｉｉｉ１ , R ｉｖ１ , R ｖ１ , R ｖｉ１ , and R ｖｉｉ１ are -OH, F, Cl, Br, I, -O(C １ ~C ６ )alkyl, CF ３ , OCF ３ , NH ２ , -(C １ ~C ６ )alkyl, -SH, -NHNH ２ , -NHCH ３ , -N(CH ３ ) ２ , -NCH(CH ３ ) ２ and -(C １ ~C ６ )alkyl-OH, and is optionally substituted with one or more substituents independently selected from the group consisting of; b1, c1, d1, e1, f1, g1, h1, i1, and j1 are independently integers in the range of 1 to 6; wherein R ９ and R １０ are optionally combined together to form a proline ring moiety; and in the formula, R17 and R18 are optionally combined together to form a proline ring moiety.

5. The compound of formula I according to claim 1: wherein R ９ and R １７ are H, methyl, ethyl, propyl, isopropyl, butyl, n-butyl, -(C ２ ~C ３０ ) alkenyl, -CH ２ SCH ３ , -CH ２ CH ２ SCH ３ , -CH ２ CH ２ SCH ２ CH ３ 、-CH ２ SCH ２ CH ３ 、-CH ２ 、-SH、CH ２ 、-SeH、-CH ２ CH ２ 、-SH、 -CH ２ NH ２ 、-CH ２ CH ２ NH ２ 、-CH ２ CH ２ CH ２ NH ２ 、-CH ２ CH ２ CH ２ CH ２ NH ２ 、 -CH ２ CH(CH ３ )CH ２ NH ２ 、-CH ２ NHCH ３ 、-CH ２ NHCH ２ CH ３ 、-CH ２ CH ２ NHCH ３ 、 -CH ２ CH ２ NHCH ２ CH ３ 、-CH ２ CH ２ CH ２ NHCH ３ 、-CH ２ CH ２ CH ２ NHCH ２ CH ３ 、 -CH ２ CH(CH ３ )CH ２ NHCH ３ 、-CH ２ CH(CH ３ )CH ２ NHCH ２ CH ３ 、 -CH ２ CH ２ NHCH ２ CH ２ NH ２ 、-CH ２ CH ２ CH ２ NHCH ２ CH ２ CH ２ NH ２ 、 -CH ２ CH ２ N((CH(CH ３ ))、-CH ２ CH ２ CH ２ CH ２ N((CH(CH ３ ))、-CH ２ CH ２ CH ２ NH(CH(CH ３ ))、 ２ ​ -CH ２ CH ２ CH ２ NH(CH(CH ３ ) ２ ), -C(O)H, -C(O)OCH ３ , -C(O)OCH ２ CH ３ , -C(O)OCH(CH ３ ) ２ , -C(O)CH ２ NH ２ , -C(O)CH ２ CH ２ NH ２ , -C(O)CH(CH ３ )CH ２ NH ２ , -C(O)CH ２ NHCH ３ 、-C(O)CH ２ NHCH ２ CH ３ 、-C(O)CH ２ CH ２ NHCH ２ CH ３ 、 -C(O)CH ２ CH ２ CH ２ NHCH ２ CH ３ 、-C(O)CH ２ CH ２ CH ２ NHCH ２ CH ２ CH ３ 、 -C(O)CH ２ CH(CH ３ )CH ２ NHCH ３ 、-C(O)CH ２ CH(CH ３ )CH ２ NHCH ２ CH ３ 、 -C(O)CH ２ CH ２ NHCH ２ CH ２ NH ２ 、-C(O)CH ２ CH ２ CH ２ NHCH ２ CH ２ CH ２ NH ２ 、 -C(O)CH ２ CH ２ N((CH(CH ３ ))、-C(O)CH ２ CH ２ CH ２ CH ２ N((CH(CH ３ )) ２ )、 -C(O)CH ２ CH ２ NH(CH(CH ３ ) ２ )、-C(O)CH ２ CH ２ CH ２ NH(CH(CH ３ ) ２ )、-CH ２ COOCH ３ 、-CH ２ CH ２ COOCH ３ 、-CH ２ COOCH ２ CH ３ 、 -CH ２ CH ２ COOCH ２ CH ３ 、-CH ２ COOCH(CH ３ ) ２ 、-CH ２ CONH ２ 、-CH ２ CH ２ CONH ２ 、 -CH ２ CH ２ CH ２ CONH ２ a radical independently selected from -CONH-oleic acid, -CONH-nonanoic acid, -CONH-lipoic acid, and a radical selected from the group consisting of (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), and (XXI); wherein R ｖｉｉ１ is selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, butyl, -(C ２ ~C ３０ )-alkenyl, -(C ２ ~C ３０ )-alkynyl, -Oalkyl(C １ ~C １２ ), F, Cl, Br, I, -CF ３ , -OCF ３ , -NO ２ , -CN, -NH ２ , -(C １ ~C6)alkylNH ２ , -N((C １ ~C ６ )alkyl) ２ , and -NH(C １ ~C ６ )alkyl; and here, b1, c1, d1, e1, f1, g1, h1, i1, and j1 are independently integers in the range of 1 to 6; wherein R ９ and R １０ are optionally combined together to form a proline ring moiety; and in the formula, R17 and R18 are optionally combined together to form a proline ring moiety.

6. The compound of formula I according to claim 1: wherein R ９ and R １７ are H, methyl, ethyl, propyl, isopropyl, butyl, n-butyl, -CH ２ SCH ３ , -CH ２ CH ２ SCH ３ , -CH ２ CH ２ SCH ２ CH ３ 、-CH ２ SCH ２ CH ３ 、-CH ２ SH、-CH ２ CH ２ SH、-CH ２ SeH、-CH ２ NH ２ 、-CH ２ CH ２ NH ２ 、-CH ２ CH ２ CH ２ NH ２ 、-CH ２ CH ２ CH ２ CH ２ NH ２ a radical independently selected from the group consisting of, and a radical selected from the group consisting of (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), and (XXI); wherein R ｖｉｉ１ is H, methyl, ethyl, propyl, isopropyl, butyl, -(C ２ ~C ３０ )-alkenyl, -(C ２ ~C ３０ )-alkynyl, -Oalkyl(C １ ~C ６ ), F, Cl, Br, I, -CF ３ , -OCF ３ , -NO ２ , -CN, -NH ２ , -CH ２ NH ２ , -CH ２ CH ２ NH ２ , -CH(CH ３ )NH ２ , -CH ２ CH(CH ３ )NH ２ 、-CH ２ CH ２ CH ２ NH ２ 、-N(CH ３ ) ２ 、-N(CH ２ CH ３ ) ２ 、-NCH(CH ３ ) ２ 、 -NHCH ３ 、 -NHCH ２ CH ３ 、 and -NHCH(CH ３ ) ２ selected from; and here, b1, c1, d1, e1, f1, g1, h1, i1, and j1 are independently integers in the range of 1 to 4; wherein R ９ and R １０ are optionally combined together to form a proline ring moiety; and wherein R17 and R18 are optionally combined together to form a proline ring moiety. **Claim 7** The compound of formula I according to claim 1: wherein R ６ , R ７ , R １４ , R １５ and R １９ are H, -(C １ ~C ３０ ) alkyl, -(C ２ ~C ３０ ) alkenyl, -(C ２ ~C ３０ ) alkynyl, -(C １ ~C ３０ ) alkyl-R ｉ２ , -(C １ ~C ３０ )-alkyl-O-R ｉｉｉ２ ,-(C １ ~C ３０ )-alkyl-NR ｉｖ２ R ｖ２ ,-C(O)-R ｖｉ２ and independently selected from the group consisting of radicals selected from the group consisting of (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), and (XXXI), R ｉ２ is H, -(C １ ~C １２ )alkyl, -Oalkyl(C １ ~C ６ ), F, Cl, Br, I, -CF ３ , -OCF ３ , isoxazole, oxazole, furan, oxolane, thiol, thiophene, N-methylpyrrole, pyrrole, pyrrolidine, pyran, pyridine, piperidine, thiazole, dioxane, morpholine, pyrimidine, -NH ２ , -N((C １ ~C １２ )alkyl) ２ , -NH(C １ ~C １２ )alkyl, -OC(O)O(C １ ~C １２ ), alkyl, -OC(O)NH2, -OC(O)N((C １ ~C １２ ), alkyl)), ２ , -SH, -S(C １ ~C １２ )alkyl, -S(O)H, -S(O)(C １ ~C １２ )alkyl, -SO ２ (C １ ~C １２ )alkyl and is selected from the group consisting of; R ｉｉｉ２ 、R ｉｖ２ 、and R ｖ２ are H, -(C １ ~C １２ ), alkyl, -(C ２ ~C ３０ ), alkenyl, -(C １ ~C ３０ ), alkylNH ２ , -(C １ ~C １２ )alkyl-N((C １ ~C １２ )alkyl) ２ ,-(C １ ~C １２ )alkyl-NH(C １ ~C １２ )alkyl, and independently selected from the group consisting of radicals selected from the group consisting of (XXXII), (XXXIII), (XXXIV), (XXXV), (XXXVI), (XXXVII), (XXXVIII), (XXXIX), (XL), (XLI), (XLII), (XLIII), (XLIV), (XLV), and (XLVI), wherein R ｖｉｉｉ２ , R ｉｘ２ , R ｖｉｉｉ２ ’, and R ｉｘ２’’ are H, -(C １ ~C ６ )alkyl, -(C １ ~C ６ )alkylNH ２ , -(C １ ~C ６ )alkyl-N((C １ ~C ６ )alkyl) ２ , -(C １ ~C ６ )alkyl-NH(C １ ~C ６ )alkyl, -O(C １ ~C ６ )alkyl, -COH, -CO(C １ ~C ６ )alkyl, and -O(C ２ ~C １２ )alkenyl, and is independently selected from the group consisting of R ｖｉｉ２ and R ｖｉｉ２’ are H, -(C １ ~C １２ ), alkyl, -(C ２ ~C ３０ ), alkenyl, -(C ２ ~C ３０ ), alkynyl, -O(C １ ~C ６ ), alkyl, F, Cl, Br, I, -CF ３ , -OCF ３ , -NO ２ , -CN, -NH ２ , -(C １ ~C １２ ), alkylNH ２ , -N((C １ ~C １２ ), alkyl) ２ , and -NH(C １ ~C １２ ), alkyl are independently selected from the group consisting of; R ｖｉ２ is H, -OH, -(C １ ~C １ )alkyl, -(C ２ ~C ３０ )alkenyl, -(C １ ~C １２ )alkyl-COOH, -(C ２ ~C ３０ ) alkenyl COOH, -(C １ ~C １２ ) alkyl NH ２ , -(C １ ~C １２ ) alkyl-N((C １ ~C １２ ) alkyl) ２ , -O-(C １ ~C １２ ), -NH(C ２ ~C １２ ), -(C １ ~C １２ )-alkyl-NH(C １ ~C １２ ), -NH-oleic acid, -NH-nonanoic acid, -NH-lipoic acid, and -CH=CH(COOH)-CH ２ -COOH; selected from the group consisting of wherein Alk ２ , Alk ２２ , Alk ２ ’, and Alk ２２ ’ are each independently selected from the group consisting of linear or branched -(C １ ~C １２ )alkyl and linear or branched -(C ２ ~C ３０ )alkenyl, β ２ and β ２ ’ are each independently an integer from 0 to 6, and X ２ and X ２ ’ are each independently selected from the group consisting of -NH-, -COO-, and -O-; wherein R ｉ２ , R ｉｉｉ２ , R ｉｖ２ , R ｖ２ , R ｖｉ２ , R ｖｉｉ２ , R ｖｉｉｉ２ , R ｉｘ２ , R ｖｉｉｉ２’ , and R ｉｘ２’ are OH, F, Cl, Br, I, -O(C １ ~C ６ ) alkyl, -CF ３ , -OCF ３ , -NH ２ , -(C １ ~C ６ )alkyl-NHNH ２ , -NHCH ３ , -N(CH ３ ) ２ , -NCH(CH ３ ) ２ and -(C １ ~C ６ )alkyl-OH and is optionally substituted by one or more substituents selected from the group consisting of; b2, c2, d2, e2, h2, k2, l2, k2’, l2’, b2’’, c2’’, d2’’, e2’’, and h2’’ are independently integers in the range of 1 to 6; b2’, c2’, d2’, e2’, and h2’ are independently integers in the range of 0 to 6; m2, n2, m2’, and n2’ are independently integers in the range of 1 to 150. **Claim 8** The compound of formula I according to claim 1: wherein R ６ , R ７ , R １４ , R １５ and R １９ are H, methyl, ethyl, propyl, isopropyl, butyl, -CH ２ OCH ３ , -CH ２ CH ２ OCH ３ , -CH ２ CH ２ OCH ２ CH ３ 、-CH ２ CH ２ OCH(CH ３ ) ２ 、-CH ２ OCH ２ CH ３ 、-CH ２ OCH(CH ３ ) ２ 、 -(C ２ ~C ３０ ) alkenyl, -(C ２ ~C ３０ ) alkynyl, -CH ２ SCH ３ , -CH ２ CH ２ SCH ３ , -CH ２ CH ２ SCH ２ CH ３ 、-CH ２ SCH ２ CH ３ 、-CH ２ NH ２ 、-CH ２ CH ２ NH ２ 、-CH ２ CH ２ CH ２ NH ２ 、-CH ２ CH(CH ３ )CH ２ NH ２ 、-CH ２ NHCH ３ 、-CH ２ NHCH ２ CH ３ 、-CH ２ CH ２ NHCH ３ 、 -CH ２ CH ２ NHCH ２ CH ３ 、-CH ２ CH ２ CH ２ NHCH ３ 、-CH ２ CH ２ CH ２ NHCH ２ CH ３ 、 -CH ２ CH(CH ３ )CH ２ NHCH ３ 、-CH ２ CH(CH ３ )CH ２ NHCH ２ CH ３ 、 -CH ２ CH ２ NHCH ２ CH ２ NH ２ 、-CH ２ CH ２ CH ２ NHCH ２ CH ２ CH ２ NH ２ 、 -CH ２ CH ２ N((CH(CH ３ ))、-CH ２ ))、-CH ２ CH ２ CH ２ N((CH(CH ３ ))、-CH ２ ))、-CH ２ CH ２ NH(CH(CH ３ ))、 ２ ))、 -CH ２ CH ２ CH ２ NH(CH(CH ３ ) ２ ), -C(O)H, -C(O)OCH ３ , -C(O)OCH ２ CH ３ , -C(O)OCH(CH ３ ) ２ , -C(O)CH ２ NH ２ , -C(O)CH ２ CH ２ NH ２ , -C(O)CH(CH ３ )CH ２ NH ２ , -C(O)CH ２ NHCH ３ 、-C(O)CH ２ NHCH ２ CH ３ 、-C(O)CH ２ CH ２ NHCH ２ CH ３ 、 -C(O)CH ２ CH ２ CH ２ NHCH ２ CH ３ 、-C(O)CH ２ CH ２ CH ２ NHCH ２ CH ２ CH ３ 、 -C(O)CH ２ CH(CH ３ )CH ２ NHCH ３ 、-C(O)CH ２ CH(CH ３ )CH ２ NHCH ２ CH ３ 、 -C(O)CH ２ CH ２ NHCH ２ CH ２ NH ２ 、-C(O)CH ２ CH ２ CH ２ NHCH ２ CH ２ CH ２ NH ２ 、 -C(O)CH ２ CH ２ N((CH(CH ３ ))、-C(O)CH ２ CH ２ CH ２ CH ２ N((CH(CH ３ )) ２ ))、 -C(O)CH ２ CH ２ NH(CH(CH ３ ) ２ ), -C(O)CH ２ CH ２ CH ２ NH(CH(CH ３ ) ２ ), -CH ２ COOH, -CH ２ CH ２ COOH, -CH ２ COOCH ３ 、-CH ２ CH ２ COOCH ３ 、-CH ２ COOCH ２ CH ３ 、 -CH ２ CH ２ COOCH ２ CH ３ 、-CH ２ COOCH(CH ３ ) ２ 、-(C １ ~C ６ )alkyl-R ｉ２ 、 -(C １ ~C ６ )alkyl - O - R ｉｉｉ２ 、-(C １ ~C ６ )alkyl - NR ｉｖ２ R ｖ２ 、 -CONH-oleic acid, -CONH-nonanoic acid, -CONH-lipoic acid, and independently selected from the group consisting of radicals selected from the group consisting of (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), and (XXXI), R ｉ２ is imidazole, N-methylpyrrole, pyrrole, pyrrolidine, pyran, pyridine, piperidine, pyrimidine, -OC(O)NH ２ , -OC(O)N((C １ ~C ６ )alkyl) ２ selected from the group consisting of; R ｉｉｉ２ , R ｉｖ２ , and R ｖ２ are independently selected from the group consisting of radicals selected from the group consisting of -(C ２ ~C ３０ ) alkenyl, -(C ２ ~C ３０ ) alkynyl, -(C １ ~C ６ ) alkyl-NH ２ , -(C １ ~C ６ ) alkyl-N((C １ ~C ６ ) alkyl) ２ , -(C １ ~C ６ ) alkyl-NH(C １ ~C ６ ) alkyl, and radicals selected from the group consisting of (XXXII), (XXXIII), (XXXIV), (XXXV), (XXXVI), (XXXVII), (XXXVIII), (XXXIX), (XL), (XLI), (XLII), (XLIII), (XLIV), (XLV), and (XLVI). R ｖｉｉ２ and R ｖｉｉ２’ are H, methyl, ethyl, propyl, isopropyl, butyl, -O alkyl (C １ ~C ６ ), F, Cl, Br, I, -CF ３ , -OCF ３ , -NO ２ , -CN, -NH ２ , -(C １ ~C ６ )alkyl-NH ２ , -N((C １ ~C ６ )alkyl) ２ , -NH(C １ ~C ６ )alkyl is independently selected from; wherein R ｖｉｉｉ２ , R ｉｘ２ , R ｖｉｉｉ２’ , and R ｉｘ２’’ are H, -(C １ ~C ６ )alkyl, -(C ２ ~C ６ )alkenyl, -(C ２ ~C ６ )alkynyl, -(C １ ~C ６ )alkylNH ２ , -(C １ ~C ６ )alkyl-N((C １ ~C ６ )alkyl) ２ 、-(C １ ~C ６ )alkyl-NH(C １ ~C ６ )alkyl are independently selected from; wherein R ｉ２ , R ｉｉｉ２ , R ｉｖ２ , R ｖ２ , R ｖｉ２ , R ｖｉｉ２ , R ｖｉｉｉ２ , R ｉｘ２ , R ｖｉｉｉ２’ , and R ｉｘ２’ are OH, F, Cl, Br, -OCH ３ , -OCH ２ CH ３ , -OCH(CH ３ )([[]] ２ , -CF ３ , -OCF ３ , -NH ２ , -CH ３ , -CH ２ CH ３ , -CH(CH ３ ) ２ , -CH ２ OH, -CH ２ CH ２ OH, and -CH ２ CH(OH)CH ３ optionally substituted by one or more substituents selected from the group consisting of; b2, c2, d2, e2, h2, k2, l2, k2’, l2’, b2’’, c2’’, d2’’, e2’’, and h2’’ are independently integers in the range of 1 to 4; b2’, c2’, d2’, e2’, and h2’ are independently integers in the range of 0 to 4; m2, n2, m2’, and n2’ are independently integers in the range of 1 to 120. **Claim 9** The compound of formula I according to claim 1: wherein R １ is, -CH ２ CH ２ -S-S-CH ２ CH ２ -, -CH ２ CH ２ CH ２ -S-S-CH ２ CH ２ CH ２ -、-CH ２ -、-CH ２ CH ２ -、-CH ２ CH(CH ３ )CH ２ -、 -CH ２ CH(CH ２ CH ３ )CH ２ -、-CH ２ CH ２ CH ２ CH ２ -、-CH ２ COO-、-CH ２ CH ２ COO-、 -CH ２ CHCH ３ COO-, -CH ２ CH ２ CH ３ CH ２ a biradical selected from the group consisting of COO-, -CHCHCHCHCHCHCHCOO-, and a biradical selected from the group consisting of (V), (VI), (VII), (VIII), (IX), (X), (XI), and (XII); R ９ and R １７ are H, methyl, ethyl, propyl, isopropyl, butyl, n-butyl, -CH ２ SCH ３ , -CH ２ CH ２ SCH ３ , -CH ２ CH ２ SCH ２ CH ３ 、 -CH ２ SCH ２ CH ３ 、 -CH ２ SH、 -CH ２ CH ２ SH、 -CH ２ SeH、 -CH ２ NH ２ 、 -CH ２ CH ２ NH ２ 、 -CH ２ CH ２ CH ２ NH ２ 、 -CH ２ CH ２ CH ２ CH ２ NH ２ A radical independently selected from the group consisting of, and a radical selected from the group consisting of (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), and (XXI); wherein R ｖｉｉ１ is H, methyl, ethyl, propyl, isopropyl, butyl, -(C ２ ~C ３０ -alkenyl, -(C ２ ~C ３０ -alkynyl, -OCH ３ -OCH ２ CH ３ F, Cl, Br, I, -CF ３ -OCF ３ -NO ２ -CN, -NH ２ -CH ２ NH ２ -CH ２ CH ２ NH ２ -CH(CH ３ )NH ２ , -CH ２ CH(CH ３ )NH ２ 、-CH ２ CH ２ CH ２ NH ２ 、-N(CH ３ ) ２ 、-N(CH ２ CH ３ ) ２ 、-NCH(CH ３ ) ２ 、 -NHCH ３ 、 -NHCH ２ CH ３ 、 and -NHCH(CH ３ ) ２ is selected from; wherein b1, c1, d1, e1, f1, g1, h1, i1, and j1 are independently integers in the range of 1 to 6; wherein R ９ and R １０ are optionally combined together to form a proline ring moiety; and wherein R17 and R18 are optionally combined together to form a proline ring moiety, wherein r, s, t and u are independently integers in the range of 0 to 250, wherein at least one of r or t is 1 or more. **Claim 10** The compound of formula I according to claim 1: wherein R1 is -CH ２ CH ２ -S-S-CH ２ CH ２ -, -CH ２ CH ２ CH ２ -S-S-CH ２ CH ２ CH ２ -, -CH ２ -,-CH ２ CH ２ - -CH ２ CH(CH ３ )CH ２ -、-CH ２ CH(CH ２ CH ３ )CH ２ -、-CH ２ CH ２ CH ２ CH ２ -、-CH ２ COO-、 -CH ２ CH ２ COO-, -CH ２ CHCH ３ COO-, -CH ２ CH ２ CH ３ CH ２ a biradical selected from the group consisting of COO-, and a biradical selected from the group consisting of ((V), (VI), (VII), (VIII), (IX), (X), (XI) and (XII); R ９ and R １７ are H, methyl, ethyl, propyl, isopropyl, butyl, n-butyl, -CH ２ SCH ３ , -CH ２ CH ２ SCH ３ , -CH ２ CH ２ SCH ２ CH ３ , -CH ２ SCH ２ CH ３ 、-CH ２ SH、-CH ２ CH ２ SH、CH ２ SeH、-CH ２ NH ２ 、-CH ２ CH ２ NH ２ 、 -CH ２ CH ２ CH ２ NH ２ 、-CH ２ CH ２ CH ２ CH ２ NH ２ a radical independently selected from, and a radical selected from the group consisting of (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), and (XXI); R ｖｉｉ１ is H, methyl, ethyl, propyl, isopropyl, butyl, -OCH ３ -, -OCH ２ CH ３ , F, Cl, Br, I, -CF ３ , OCF ３ , -NO ２ , -CN, -NH ２ , -CH ２ NH<00015" + "00>, It should be noted that there seems to be an error in the original text where the number in the tag ２ is split. I have made a correction in the translation accordingly. If this is not what you intended, please let me know. -CH ２ CH ２ NH ２ 、-CH ２ CH(CH ３ )NH ２ 、-CH ２ CH ２ CH ２ NH ２ 、-N(CH ３ ) ２ 、-N(CH ２ CH ３ ) ２ 、 -NCH(CH ３ ), -NHCH ２ , -NHCH ３ , -NHCH ２ CH ３ , and -NHCH(CH ３ ), ２ selected from; b1, c1, d1, e1, f1, g1, h1, i1, and j1 are independently integers in the range of 1 to 6; wherein R ９ and R １０ are optionally combined together to form a proline ring moiety; and wherein R17 and R18 are optionally combined together to form a proline ring moiety, R ６ , R ７ , R １４ , R １５ and R １９ is H, methyl, ethyl, propyl, isopropyl, butyl, -CH ２ OCH ３ , -CH ２ CH ２ OCH ３ , -CH ２ CH ２ OCH ２ CH ３ , -CH ２ CH ２ OCH(CH ３ ) ２ 、-CH ２ OCH ２ CH ３ 、-CH ２ OCH(CH ３ )2、-(C ２ ~C ３０ ) alkenyl, -(C ２ ~C ３０ ) alkynyl, -CH ２ SCH ３ , -CH ２ CH ２ SCH ３ , -CH ２ SH, -CH ２ SeH-CH ２ CH ２ SH, -CH ２ CH ２ SCH ２ CH ３ 、-CH ２ SCH ２ CH ３ 、-CH ２ NH ２ 、-CH ２ CH ２ NH ２ 、-CH ２ CH ２ CH ２ NH ２ 、-CH ２ CH(CH ３ )CH ２ NH ２ 、-CH ２ NHCH ３ 、-CH ２ NHCH ２ CH ３ 、-CH ２ CH ２ NHCH ３ 、 -CH ２ CH ２ NHCH ２ CH ３ 、-CH ２ CH ２ CH ２ NHCH ３ 、-CH ２ CH ２ CH ２ NHCH ２ CH ３ 、 -CH ２ CH(CH ３ )CH ２ NHCH ３ 、-CH ２ CH(CH ３ )CH ２ NHCH ２ CH ３ 、 -CH ２ CH ２ NHCH ２ CH ２ NH ２ 、-CH ２ CH ２ CH ２ NHCH ２ CH ２ CH ２ NH ２ 、 -CH ２ CH ２ N((CH(CH ３ ))、-CH ２ CH ２ CH ２ CH ２ N((CH(CH ３ ))、-CH ２ CH ２ CH ２ NH(CH(CH ３ ))、 ２ ​ -CH ２ CH ２ CH ２ NH(CH(CH ３ ) ２ ), -C(O)H, -C(O)OCH ３ , -C(O)OCH ２ CH ３ , -C(O)OCH(CH ３ ) ２ 、-C(O)CH ２ NH ２ 、-C(O)CH ２ CH ２ NH ２ 、-C(O)CH(CH ３ )CH ２ NH ２ 、 -C(O)CH ２ NHCH ３ 、-C(O)CH ２ NHCH ２ CH ３ 、-C(O)CH ２ CH ２ NHCH ２ CH ３ 、 -C(O)CH ２ CH ２ CH ２ NHCH ２ CH ３ 、-C(O)CH ２ CH ２ CH ２ NHCH ２ CH ２ CH ３ 、 -C(O)CH ２ CH(CH ３ )CH ２ NHCH ３ 、-C(O)CH ２ CH(CH ３ )CH ２ NHCH ２ CH ３ 、 -C(O)CH ２ CH ２ NHCH ２ CH ２ NH ２ 、-C(O)CH ２ CH ２ CH ２ NHCH ２ CH ２ CH ２ NH ２ 、 -C(O)CH ２ CH ２ N((CH(CH ３ ))、-C(O)CH ２ CH ２ CH ２ CH ２ N((CH(CH ３ )) ２ ))、 -C(O)CH ２ CH ２ NH(CH(CH ３ ) ２ ), -C(O)CH ２ CH ２ CH ２ NH(CH(CH ３ ) ２ ), -CH ２ COOH, -CH ２ CH ２ COOH, -CH ２ COOCH ３ 、-CH ２ CH ２ COOCH ３ 、-CH ２ COOCH ２ CH ３ 、 -CH ２ CH ２ COOCH ２ CH ３ 、-CH ２ COOCH(CH ３ ) ２ 、-(C １ ~C ６ )alkyl-R ｉ２ 、 -(C １ ~C ６ )alkyl - O - R ｉｉｉ２ 、-(C １ ~C ６ )alkyl - NR ｉｖ２ R ｖ２ 、 -CONH-oleic acid, -CONH-nonanoic acid, -CONH-lipoic acid, and independently selected from the group consisting of radicals selected from the group consisting of (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), and (XXXI), R ｉ２ is imidazole, N-methylpyrrole, pyrrole, pyrrolidine, pyran, pyridine, piperidine, pyrimidine, -OC(O)NH ２ , -OC(O)N((C １ ~C ６ )alkyl) ２ selected from the group consisting of; R ｉｉｉ２ 、 R ｉｖ２ 、 and R ｖ２ are H, -(C ２ ~C ３０ ) alkenyl,[ -(C ２ ~C ３０ ) alkynyl, -CH ２ NH ２ , -CH ２ CH ２ NH ２ , -CH ２ CH ２ CH ２ NH ２ , -CH ２ CH(CH ３ )CH ２ NH ２ 、-CH ２ NHCH ３ 、-CH ２ NHCH ２ CH ３ 、-CH ２ CH ２ NHCH ３ 、 -CH ２ CH ２ NHCH ２ CH ３ 、-CH ２ CH ２ CH ２ NHCH ３ 、-CH ２ CH ２ CH ２ NHCH ２ CH ３ 、 -CH ２ CH(CH ３ )CH ２ NHCH ３ 、-CH ２ CH(CH ３ )CH ２ NHCH ２ CH ３ 、 -CH ２ CH ２ NHCH ２ CH ２ NH ２ 、-CH ２ CH ２ CH ２ NHCH ２ CH ２ CH ２ NH ２ 、 -CH ２ CH ２ N((CH(CH ３ ))、-CH ２ CH ２ CH ２ CH ２ N((CH(CH ３ ))、-CH ２ CH ２ CH ２ NH(CH(CH ３ ))、 ２ ))、 -CH ２ CH ２ CH ２ NH(CH(CH ３ ) ２ ) and independently selected from radicals selected from the group consisting of (XXXII), (XXXIII), (XXXIV), (XXXV), (XXXVI), (XXXVII), (XXXVIII), (XXXIX), (XL), (XLI), (XLII), (XLIII), (XLIV), (XLV), and (XLVI); wherein R ｖｉｉ２ and R ｖｉｉ２’ are independently selected from H, methyl, ethyl, propyl, isopropyl, butyl, F, Cl, Br, I, -CF ３ , -OCF ３ , -NO ２ , -CN, -NH ２ , and -(C １ ~C ６ )alkyl-NH ２ ; and are independently selected from; wherein R ｖｉｉｉ２ , R ｉｘ２ , R ｖｉｉｉ２’ , and R ｉｘ２’’ are H, methyl, ethyl, propyl, isopropyl, -CH ２ NH ２ , -CH ２ CH ２ NH ２ , -CH ２ CH ２ CH ２ NH ２ , -CH ２ CH(CH ３ )CH ２ NH ２ 、-CH ２ NHCH ３ 、-CH ２ NHCH ２ CH ３ 、-CH ２ CH ２ NHCH ３ 、 -CH ２ CH ２ NHCH ２ CH ３ 、-CH ２ CH ２ CH ２ NHCH ３ 、-CH ２ CH ２ CH ２ NHCH ２ CH ３ 、 -CH ２ CH(CH ３ )CH ２ NHCH ３ 、-CH ２ CH(CH ３ )CH ２ NHCH ２ CH ３ 、 -CH ２ CH ２ NHCH ２ CH ２ NH ２ 、-CH ２ CH ２ CH ２ NHCH ２ CH ２ CH ２ NH ２ 、 -CH ２ CH ２ N((CH(CH ３ ))、-CH ２ CH ２ CH ２ CH ２ N((CH(CH ３ ))、-CH ２ CH ２ CH ２ NH(CH(CH ３ ))、 ２ ) -CH ２ CH ２ CH ２ NH(CH(CH ３ ) ２ is independently selected from; wherein R ｉ２ , R ｉｉｉ２ , R ｉｖ２ , R ｖ２ , R ｖｉ２ , R ｖｉｉ２ , R ｖｉｉｉ２ , R ｉｘ２ , R ｖｉｉｉ２’ , and R ｉｘ２’ are OH, F, Cl, Br, -OCH ３ , -OCH ２ CH ３ , -OCH(CH ３ ) ２ , -CF ３ , -OCF ３ , -NH ２ , -CH ３ , -CH ２ CH ３ , -CH(CH ３ ) ２ , -CH ２ OH, -CH ２ CH ２ OH, and -CH ２ CH(OH)CH ３ optionally substituted by one or more substituents selected from the group consisting of; b2, c2, d2, e2, h2, k2, l2, k2', l2', b2'', c2'', d2'', e2'', and h2'' are independently integers in the range of 1 to 4; b2', c2', d2', e2', and h2' are independently integers in the range of 0 to 4; m2, n2, m2', and n2' are independently integers in the range of 1 to 120. **Claim 11** A compound of formula I according to claim 1, selected from the following: 【Table 1】 **Claim 12** A conjugate comprising a radical derived from a compound of formula (I) according to claim 1, covalently attached to at least one labeling or imaging agent, or to a cell targeting agent. **Claim 13** A polymeric complex comprising a compound of formula (I) according to claim 1 or a conjugate according to claim 12, and one or more active agents selected from the group consisting of pharmaceutically active agents, veterinary active agents, cosmetically active agents, diagnostic active agents, nucleic acids, peptides, antibodies, aptamers, proteins, and mixtures thereof. **Claim 14** The polymeric complex according to claim 13, wherein at least one active agent is selected from the group consisting of low molecular weight drugs, peptides, proteins, antibodies, nucleic acids, aptamers, and combinations thereof. **Claim 15** The polymeric complex according to claim 14, wherein the nucleic acid is selected from the group consisting of DNA / RNA hybrids, short interfering RNAs (siRNAs), microRNAs (miRNAs), sgRNAs, donor DNAs, self-amplifying / replicating RNAs, circular RNAs (circRNAs), plasmid DNAs (pDNAs), closed circular linear DNAs (clDNAs), short hairpin RNAs (shRNAs), messenger RNAs (mRNAs), and antisense RNAs (aRNAs), messenger RNAs (mRNAs), CRISPR guide RNAs, antisense nucleic acids, decoy nucleic acids, aptamers, and ribozymes. **Claim 16** The polymeric complex according to claim 15, wherein the nucleic acid is clDNA. **Claim 17** A composition comprising the polymeric complex according to claim 13 together with at least one conjugate according to claim 12, or one or more pharmaceutically, diagnostically, veterinarily, or cosmetically acceptable excipients or carriers. **Claim 18** For use in a medicament, d) a conjugate as described in claim 12; or e) a polymeric complex as described in claim 13; or f) A therapeutic product which is a composition as claimed in claim 17. Claim 19 A device for use in a method of delivering nucleic acid into cells, the device comprising the polymer complex as claimed in claim 15. Claim 20 Contacting an animal, including a human, having said target cells with a solution comprising the polymer complex as claimed in claim 15 or the pharmaceutical composition as claimed in claim 17 such that the complex can be introduced into the target cells; moving the complex from an endosome to the cytoplasm; dissociating the complex in the cell; and releasing the nucleic acid into the cytoplasm, for use in a method of delivering nucleic acid into target cells, the polymer complex as claimed in claim 15, or the pharmaceutical composition as claimed in claim 17. Claim 21 A method of transfecting cells, comprising contacting the cells with the polymer complex as claimed in claim 13.

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