Compounds for stabilizing lipid nanoparticles

Abstract

The invention refers to a compound of Formula I, or pharmaceutically acceptable salts or solvates thereof and further to a lipid nanoparticle composition.

Description

COMPOUNDS FOR STABILIZING LIPID NANOPARTICLES FIELD[1] The present disclosure relates to novel compounds (including lipid-polymer conjugates), their use in lipid nanoparticles (LNPs) and lipid nanoparticle compositions including said compounds.BACKGROUND[2] Lipid nanoparticles (LNPs) have become a platform for the delivery of therapeutic agents, such as mRNA, siRNA, and DNA, due to their stability, ability to encapsulate and protect active agents while facilitating targeted delivery. Despite their advantages, LNPs are inherently unstable under physiological conditions and during manufacturing, storage, and transport, which can lead to aggregation, degradation, and loss of therapeutic efficacy. For the stability, prolongation of circulation time, reduction of immunogenicity and delivery efficacy of lipid nanoparticles, in addition to the molecular composition, parameters like particle size, charge, or grafting with molecular moieties, lipid-polymer conjugates such as polyethylene glycol (PEG) may play a role. Grafting with PEG is employed to reduce the interactions of proteins from blood serum, to increase stability in blood serum and to increase circulation time of LNP, which may be helpful for approaches.[3] Furthermore, PEGylation can be used for LNP engineering. For example, if lipid nanoparticles are manufactured by mixing an aqueous phase of the nucleic acid with an organic phase of the lipids, a certain fraction of PEG-conjugated lipid in the lipid mixture is required to avoid aggregation of the LNP. For techniques where LNPs are formed from an ethanolic and an aqueous phase, one role of PEG-lipids is to facilitate particle self-assembly by providing a steric barrier at the surface of nascent lipid nanoparticles formed when a nucleic acid is rapidly mixed in ethanol solutions comprising lipids to complex with the nucleic acid. In addition, control of particle size may be obtained by varying the parameter of PEG including higher PEG molecular weight or higher molar fraction of PEG-lipids in the nanoparticles lead to smaller nanoparticles.[4] However, there remains a need for efficient methods and new compositions for the internalization of nucleic acids into cells, which may use different compounds. These compounds may include PEG surrogates or PEG-conjugated lipid surrogates.BRIEF SUMMARY[5] The present disclosure provides novel compounds (including lipid-polymer conjugates), their use and methods comprising said compounds. The lipid-polymer conjugates of the present disclosure may form an outer shell of lipid nanoparticles and may be used in various applications. The disclosed compounds and / or methods may be useful for forming and stabilizing lipid nanoparticles and as a cryoprotectant during the lyophilization. The lipid-polymer conjugates of the present disclosure may also increase circulation time of lipid nanoparticles in blood and change their biodistribution. The nanoparticles comprising the disclosed compounds may be able to deliver various payloads into cells, tissue and organs. The compounds may be suitable as stabilizing agents of the lipid nanoparticles.[6] The present disclosure refers to lipid-polymer conjugates which may comprise a polymerized portion and at least one lipidic portion. The lipid-polymer conjugate may be a lipid-poly(JV-(2- hydroxypropyljmeth acrylamide) conjugate.[7] In some aspects, the disclosure relates to a compound of Formula I, or pharmaceutically acceptable salts or solvates thereof:OHFormula IQ5-N71 \6Y¹ is selected from the group consisting of -O-, -NH- and Q;J1is selected from the group consisting of C1-C15 alkylene chains, C2-C15 alkenylene chains and C2-C15 alkynylene chains, wherein in said C1-C15 alkylene chains, C2-C15 alkenylene chains or C2-C15 alkynylene chains one or more -CH2- groups may be replaced with-O- and / or -S-;direct bond between J1and M1or selected from the group consisting of° O O O°, O OO, O O and OH%HO, wherein δ₂ designates the bond to M¹;M1is selected from the group consisting ofQ1is direct bond between M1and Q3or selected from the group consisting ofwherein δ3 designates the bond to M1;Q2is direct bond between M1and Q4or selected from the group consisting ofwherein δ3 designates the bond to M1;Q3is selected from the group consisting of C5-C35 alkyl chains, C5-C35 alkenyl chains, C5-C35I / Q7|-HCalkynyl chains and Q, wherein said C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains may be linear or branched, wherein in said C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains one or more -CH2- groups may be replaced with groups selected from the group consisting of -CH(OH)-, -OC(=O)-, -C(=O)O-, -S-S-, -S-Se-, -Se-Se-, -Se-S-, -S- S-S-, -S-Se-S-, -C(=O)NH-, -NHC(=O)-, -O-, -O-C(=O)NH-, -NHC(=O)O-, -OC(=O)O-, -CF2-, -CHF- and -S-;Q4is selected from the group consisting of C5-C35 alkyl chains, C5-C35 alkenyl chains, C5-C35I 'Q7rH\ galkynyl chains and Q, wherein said C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains may be linear or branched, wherein in said C5-C35 alkyl chains, C5-C35 alkenylchains and C5-C35 alkynyl chains one or more -CH2- groups may be replaced with groups selected from the group consisting of -CH(OH)-, -OC(=O)-, -C(=O)O-, -S-S-, -S-Se-, -Se-Se-, -Se-S-, -S-S-S-, -S-Se-S-, -C(=O)NH-, -NHC(=O)-, -O-, -O-C(=O)NH-, -NHC(=O)O-, -OC(=O)O-, -CF2-, -CHF- and -S-;Q5is selected from the group consisting of C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains, wherein said C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains may be linear or branched, wherein in said C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains one or more -CH2- groups may be replaced with groups selected from the group consisting of -CH(OH)-, -OC(=O)-, -C(=O)O-, -S-S-, -S-Se-, -Se-Se-, -Se-S-, -S-S-S-, -S-Se-S-, -C(=O)NH-, -NHC(=O)-, -O-, -O-C(=O)NH-, -NHC(=O)O-, -OC(=O)O-, -CF2-, -CHF- and -S-;Q6is selected from the group consisting of C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains, wherein said C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains may be linear or branched, wherein in said C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains one or more -CH2- groups may be replaced with groups selected from the group consisting of -CH(OH)-, -OC(=O)-, -C(=O)O-, -S-S-, -S-Se-, -Se-Se-, -Se-S-, -S-S-S-, -S-Se-S-, -C(=O)NH-, -NHC(=O)-, -O-, -O-C(=O)NH-, -NHC(=O)O-, -OC(=O)O-, -CF2-, -CHF- and -S-;Q7is C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains, wherein said C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains may be linear or branched, wherein in said C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains one or more -CH2-groups may be replaced with groups selected from the group consisting of -CH(OH)-, -OC(=O)-, -C(=O)O-, -S-S-, -S-Se-, -Se-Se-, -Se-S-, -S-S-S-, -S-Se-S-, -C(=O)NH-, -NHC(=O)-, -O-, -O-C(=O)NH-, -NHC(=O)O-, -OC(=O)O-, -CF2-, -CHF- and -S-;Q8is C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains, wherein said C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains may be linear or branched, wherein in said C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains one or more -CH2-groups may be replaced with groups selected from the group consisting of -CH(OH)-, -OC(=O)-, -C(=O)O-, -S-S-, -S-Se-, -Se-Se-, -Se-S-, -S-S-S-, -S-Se-S-, -C(=O)NH-, -NHC(=O)-, -O-, -O-C(=O)NH-, -NHC(=O)O-, -OC(=O)O-, -CF2-, -CHF- and -S-;X2is selected from the group consisting of -OH, -H, -SH, -Cl, -Br, -NH2, -N3,N=N, wherein δ5designates the bond to Y2;Y2is direct bond between X2and J2or selected from the group consisting of -CH3, C1-C15 alkylene chains, C2-C15 alkenylene chains and C2-C15 alkynylene chains, wherein in said C1-C15 alkylene chains, C2-C15 alkenylene chains or C2-C15 alkynylene chains one or more -CH2- groups may be replaced with -O- and / or -S-;J2is selected from the group consisting ofO wherein δ₄ designates the bond to Y²;T2is direct bond between J2and M2or selected from the group consisting of C1-C15 alkylene chains, C2-C15 alkenylene chains and C2-C15 alkynylene chains, wherein in said C1-C15 alkylene chains, C2-C15 alkenylene chains or C2-C15 alkynylene chains one or more -CH2- groups may be replaced with -O- and / or -S-;PM2is selected from the group consisting of -CH3, -Cl, -SH, -OH,-NH2, H2NQ9is selected from the group consisting of C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains, wherein said C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains may be linear or branched;Q10is selected from the group consisting of C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains, wherein said C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains may be linear or branched;Q11is selected from the group consisting of C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains, wherein said C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains may be linear or branched;Q12is selected from the group consisting of C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains, wherein said C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains may be linear or branched;wherein y is an integer in the range of 2 to 200, i is an integer in the range of 0 to 3, p is an integer in the range of 2 to 4, e is an integer in the range of 1 to 4 and t is an integer in the range of 1 to 2;, wherein δ₅ designates the bond to Y², Y² is direct bond between X² and J² or selected from the group consisting of C1-C15 alkylene chains, C2-C15 alkenylene chains and C2-C15 alkynylene chains, wherein in said C1-C15 alkylene chains, C2-C15 alkenylene chains or C2-C15 alkynylene chains one or more -CH2- groups may be replaced with -O- and / or -S-, J2isselected from the group consisting ofO, O, \ and 0, wherein δ4designates the bond to Y2, T2is direct bond between J2and M2or selected from the group consisting of C1-C15 alkylene chains, C2-C15 alkenylene chains and C2-C15 alkynylene chains, wherein in said C1-C15 alkylene chains, C2-C15 alkenylene chains or C2-C15 alkynylene chains one or more -CH2- groups may be replaced with -O- and / or -S- and M2is selected from the groupconsisting of Q10selected from the group consisting of C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains, wherein said C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains may be linear or branched, Q10is selected from the group consisting of C5-C35 alkyl chains, C5- C35 alkenyl chains and C5-C35 alkynyl chains, wherein said C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains may be linear or branched, Q11is selected from the group consisting of C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains, wherein said C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains may be linear or branched and Q12is selected from the group consisting of C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains, wherein said C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains may be linear or branched;wherein if Y1isQ6, then J1, T1, M1, Q1, Q2, Q3and Q4are absent;\ / CNwherein if X2is -OH, -H, -Br, -Cl, -NH2, -SH,or N3, then Y2, J2, T2and M2are absent;wherein if Y2is -CH3, then J2, T2and M2are absent.[8] The following paragraphs provide additional aspects of the compounds of Formula I.[9] In some aspects, the disclosure relates to compounds of Formula I in whicho o oQ5Y1is selected from the group consisting of -O-, -NH- andQ6;J1is selected from the group consisting of C1-C15 alkylene chains, C2-C15 alkenylene chains and C2-C15 alkynylene chains, wherein in said C1-C15 alkylene chains, C2-C15 alkenylene chains or C2- C15 alkynylene chains, one or more -CH2- groups may be replaced with -O- and / or -S-;oT1is direct bond between J1and M1or is selected from the group consisting ofwherein δ2 designates the bond to M1;M1is selected from the group consisting ofQ1is direct bond between M1and Q3or selected from the group consisting ofOwherein δ3 designates the bond to M1;Q2is direct bond between M1and Q4or selected from the group consisting ofwherein δ3 designates the bond to M1;Q7h nupb / \8Q3is selected from the group consisting of C8-C20 alkyl chains and;Q7| — HC\-\8Q4is selected from the group consisting of C8-C20 alkyl chains andu;Q5is selected from the group consisting of C8-C20 alkyl chains, C8-C20 alkenyl chains and C8-C20 alkynyl chains, wherein said C8-C20 alkyl chains, C8-C20 alkenyl chains and C8-C20 alkynyl chains may be linear or branched;Q6is selected from the group consisting of C8-C20 alkyl chains, C8-C20 alkenyl chains and C8-C20 alkynyl chains, wherein said C8-C20 alkyl chains, C8-C20 alkenyl chains and C8-C20 alkynyl chains may be linear or branched;Q7is selected from the group consisting of C8-C20 alkyl chains, C8-C20 alkenyl chains and C8-C20 alkynyl chains, wherein said C8-C20 alkyl chains, C8-C20 alkenyl chains and C8-C20 alkynyl chains may be linear or branched;Q8is selected from the group consisting of C8-C20 alkyl chains, C8-C20 alkenyl chains and C8-C20 alkynyl chains, wherein said C8-C20 alkyl chains, C8-C20 alkenyl chains and C8-C20 alkynyl chains may be linear or branched;X2is selected from the group consisting of -OH, -H, -SH, -N3,and, wherein δ5designates the bond to Y2;Y2is direct bond between X2and J2or selected from the group consisting of -CH3 and C1-C5 alkylene chains;O, wherein δ₄ designates the bond to Y²;T2is direct bond between J2and M2or selected from the group consisting of C1-C8alkylene chains, wherein in said C1-C8alkylene chain, one or more -CH2- groups may be replaced with -O- or -S-Q9M2is selected from the group consisting of -CH3, -OH, Q10OQ9is selected from the group consisting of C5-C20 alkyl chains;Q10is selected from the group consisting of C5-C20 alkyl chains;Q11is selected from the group consisting of C5-C20 alkyl chains;Q12is selected from the group consisting of C5-C20 alkyl chains;wherein y is an integer in the range of 2 to 200;and Q4are absent and X2is selected from the group consisting ofand, wherein δ5designates the bond to Y2, Y2is direct bond between X2and J2or selected from the group consisting of Ci-C5 alkylene chains, J2is selected from the group consisting of, wherein δ4designates the bond to Y2, T2is direct bond between J2and M2or selected from the group consisting of C1-C8alkylene chains, wherein in said C1-C8alkylene chain, one or more -CH2- groups may be replaced with -O- or -S-, M2is selected from the groupselected from the group consisting of C5-C20 alkyl chains, Q10is selected from the group consisting of C5-C20 alkyl chains, Q11is selected from the group consisting of C5-C20 alkyl chains and wherein Q12is selected from the group consisting of C5-C20 alkyl chains;, / Q5wherein if Y1isQ6, then J1, T1, M1, Q1, Q2, Q3and Q4are absent;wherein if X2is -OH, -H, -SH,or N3, then Y2, J2, T2and M2are absent;wherein if Y2is -CH3, then J2, T2and M2are absent.

[0010] In some aspects, the disclosure relates to compounds of Formula I in whichX1is selected from the group consisting of, wherein δ1 designates the bond to Y1;Y1is selected from the group consisting of -O-, -NH- andJ1is selected from the group consisting of C1-C15 alkylene chains, C2-C15 alkenylene chains and C2-C15 alkynylene chains, wherein in said C1-C15 alkylene chains, C2-C15 alkenylene chains or C2- C15 alkynylene chains, one or more -CH2- groups may be replaced with -O- and / or -S-;T1is direct bond between J1and M1selected from the group consisting ofOHHO, wherein δ₂ designates the bond to M¹;M1is selected from the group consisting ofandQ1is direct bond between M1and Q3or selected from the group consisting of0V / X / C-j 63\ Y / and °, wherein δ3 designates the bond to M1;Q2is direct bond between M1and Q4selected from the group consisting of063\ Y / and O, wherein δ3 designates the bond to M1;Q7I— HCZV>8Q3is selected from the group consisting of C8-C20 alkyl chains andQQ7| — HCQ4is selected from the group consisting of C8-C20 alkyl chains andQ8Q5is selected from the group consisting of C8-C20 alkyl chains;Q6is selected from the group consisting of C8-C20 alkyl chains;Q7is C4-C12 alkyl chain;Q8is C4-C12 alkyl chain;X2is selected from the group consisting of -OH, -H, -SH, -N3,Y2is selected from the group consisting of -CH3 and C1-C5 alkylene chains;H 0.0 J2is selected from the group consisting of0O, wherein δ₄ designates the bond to Y²;T2is direct bond between J2and M2or selected from the group consisting of Ci-Cs alkylene chains, wherein in said Ci-Cs alkylene chains one or more -CH2- groups may be replaced with -O- and / or -S-;M2is selected from the group consisting ofQ9is selected from the group consisting of C8-C18alkyl chains;Q10is selected from the group consisting of C8-C18alkyl chains;Q11is selected from the group consisting of C8-C18alkyl chains;Q12is selected from the group consisting of C8-C18alkyl chains;wherein y is an integer in the range of 2 to 200;wherein if X1is, then Y1, J1, T1, M1, Q1, Q2, Q3and Q4are absent and X2is, Y2is selected from the group consisting of C1-C5 alkylene chains, J2is selected from the groupconsisting of O wherein δ4designates the bond to Y2, T2is direct bond between J2and M2or selected from the groupconsisting of direct bond and C1-C8alkylene chains, wherein in said C1-C8alkylene chains one or more -CH2- groups may be replaced with -O- and / or -S-, M2is selected from the group consisting o011^0Q9 Uof Q and O, Q9is selected from the group consisting of C10-C18alkyl chains, Q10is selected from the group consisting of C10-C18alkyl chains, Q11is selected from the group consisting of C10-C18alkyl chains and Q12is selected from the group consisting of C10-C18alkyl chains;, / Q5wherein if Y1isQ6, then J1, T1, M1, Q1, Q2, Q3and Q4are absent;wherein if X2is -OH, -H, -SH,or N3, then Y2, J2, T2and M2are absent;wherein if Y2is -CH3, then J2, T2and M2are absent.

[0011] In some aspects, the disclosure relates to compounds of Formula I in whichX1is selected from the group consisting of, wherein δ1 designates the bond to Y1;, / QSl-\Y1is selected from the group consisting of -0-, -NH- and Q6-J1is selected from the group consisting of C1-C15 alkylene chains, wherein in said C1-C15 alkylene chains, one or more -CH2- groups may be replaced with -O- and / or -S-;T1is direct bond between J1and M1or selected from the group consisting ofOHxIIwherein δ2 designates the bond to M1;M1is selected from the group consisting ofQ1is direct bond between M1and Q3or selected from the group consisting of O and Owherein δ3 designates the bond to M1;Q2is direct bond between M1and Q4or selected from the group consisting of OOwherein δ3 designates the bond to M1;|-HCQ3is selected from the group consisting of C11-C18alkyl chains andQ;I / Q7Q4is selected from the group consisting of C11-C18alkyl chains andQ8;Q5is selected from the group consisting of C12-C18 alkyl chains;Q6is selected from the group consisting of C12-C18 alkyl chains;Q7is C8alkyl chain;Q8is C8alkyl chain;X2is selected from the group consisting of -OH, -H, -SH, -N3,Y2is selected from the group consisting of -CH3 and C1-C2 alkylene chains;J2is selected from the group consisting ofO and O, wherein δ₄ designates the bond to Y²;T2is direct bond between J2and M2or selected from the group consisting of C1-C4 alkylene chains, wherein in said C1-C4 alkylene chains one or more -CH2- groups may be replaced with -S-;M2is selected from the group consisting ofQ9is a C 14 alkyl chain;Q10is a C14 alkyl chain;Q11is a C13 alkyl chain;Q12is a C13 alkyl chain;wherein y is an integer in the range of 2 to 200;wherein if X1is, then Y1, J1, T1, M1, Q1, Q2, Q3and Q4are absent and X2is, Y2is selected from the group consisting of C1-C2 alkylene chains, J2is selected from the groupconsisting of O and O, T2is direct bond between J2and M2or selected from the group consisting of C1-C4 alkylene chains, wherein in said C1-C4 alkylene chains one or more -CH2- groups may be replaced with -S-, M2is selected from the group consisting of Q10and6, Q9is C14 alkyl chain, Q10is C14 alkyl chain, Q11is C13 alkyl chain;, / Q5I \wherein if Y1is Q6, then J1, T1, M1, Q1, Q2, Q3and Q4are absent;wherein if X2is -OH, -H, -SH,or -N3, then Y2, J2, T2and M2are absent;wherein if Y2is -CH3, then J2, T2and M2are absent.

[0012] In some aspects, the disclosure relates to compounds of Formula I in whichO1, wherein δ1 designates the bond to Y1;Y1is selected from the group consisting of -O-, -NH- andJ1is selected from the group consisting of C1-C15 alkylene chains, wherein in said C1-C15 alkylene chains, one or more -CH2- groups may be replaced with -O- and / or -S-;T1is direct bond between J1and M1or selected from the group consisting of, wherein δ2 designates the bond to M1;M1is selected from the group consisting ofQ1is direct bond between M1and Q3or selected from the group consisting of O and Owherein δ3 designates the bond to M1;δ3 Q2is direct bond between M1and Q4or selected from the group consisting of O and Owherein δ3 designates the bond to M1;Q3is selected from the group consisting of C11-C15 alkyl chains;Q4is selected from the group consisting of C11-C15 alkyl chains;Q5is selected from the group consisting of C12-C16 alkyl chains;Q6is selected from the group consisting of C12-C16 alkyl chains;X2is -OH and Y2, J2, T2and M2are absent;wherein y is an integer in the range of 5 to 50;wherein if Y1isQ6, then J1, T1, M1, Q1, Q2, Q3and Q4are absent.

[0013] In some aspects, the disclosure relates to compounds of Formula I in which5l, wherein δ1 designates the bond to Y1;Y1is selected from the group consisting of -O- andQ6;J1is selected from the group consisting of -CH2-;T1is direct bond between J1and M1;Q1is selected from the group consisting ofand53, wherein δ3 designates the bond to M1;Q2is selected from the group consisting ofO and53, wherein δ3 designates the bond to M1;Q3is C13 alkyl chain;Q4is C13 alkyl chain;Q5is C14 alkyl chain;Q6is C14 alkyl chain;X2is -OH;Y2, J2, T2and M2are absent;wherein y is an integer in the range of 5 to 30;, Q5wherein if Y1isQ6, then J1, T1, M1, Q1, Q2, Q3and Q4are absent.

[0014] The following paragraphs provide additional aspects of the compounds of Formula I.

[0015] In some aspects, X1is selected from the group consisting ofwherein δ1 designates the bond to Y1;wherein if X1is, then Y1, J1, T1, M1, Q1, Q2, Q3and Q4are absent and X2isY2is selected from the group consisting of -CH3 and C1-C2 alkylene chains, J2is selected fromthe group consisting of ° and °, T2is direct bond between J2and M2or selected from the group consisting of C1-C4 alkylene chains, wherein in said C1-C4 alkylene chains one or Q9more -CH2- groups may be replaced with -S-, M2is selected from the group consisting of Q10Oand0, wherein Q9is C14 alkyl chain, Q10is C14 alkyl chain, Q11is C13 alkyl chain and Q12is C13 alkyl chain.Q5

[0016] In some aspects, Y¹ is selected from the group consisting of -O-, -NH- and Q;wherein Q5is selected from the group consisting of C12-C18 alkyl chains, and wherein Q6is selected from the group consisting of C12-C18 alkyl chains;Q5wherein if Y1isQ6, then J1, T1, M1, Q1, Q2, Q3and Q4are absent.

[0017] In some aspects, J1is selected from the group consisting of C1-C15 alkylene chains, wherein in said C1-C15 alkylene chains, one or more -CH2- groups may be replaced with -O- and / or -S-.

[0018] In some aspects, T1is direct bond between J1and M1or selected from the group consisting of, wherein δ2 designates the bond to M1.In some aspects, M1is selected from the group consisting of

[0020] In some aspects, Q1is direct bond between M1and Q3or selected from the group consistingof and, wherein δ3 designates the bond to M1.

[0021] In some aspects, Q2is direct bond between M1and Q4or selected from the group consistingwherein δ3 designates the bond to M1.Q7I — -HC

[0022] In some aspects, Q3is selected from the group consisting of Cn-Cis alkyl chains andu; wherein Q7is C8alkyl chain, and wherein Q8is C8alkyl chain.Q7hu rlp /

[0023] In some aspects, Q4is selected from the group consisting of C11-C18alkyl chains and Q8; wherein Q7is C8alkyl chain, and wherein Q8is C8alkyl chain.

[0024] In some aspects, X2is selected from the group consisting of -OH, -H, -SH, -N3,; wherein if X2is -OH, -H, -SH, or -N3, then Y2, J2, T2and M2are absent.

[0025] In some aspects, Y2is selected from the group consisting of -CH3 and C1-C2 alkylene chains;wherein if Y2is -CH3, then J2, T2and M2are absent.

[0026] In some aspects, J2is selected from the group consisting of, wherein δ4designates the bond to Y2.

[0027] In some aspects, T2is direct bond between Y2and M2or selected from the group consisting of C1-C4 alkylene chains, wherein in said C1-C4 alkylene chains one or more -CH2- groups may be replaced with -S-.

[0028] In some aspects, M2is selected from the group consisting of; wherein Q9is a C14 alkyl chain; wherein Q10is a C14 alkyl chain; wherein Q11is a C13 alkyl chain and wherein Q12is a C13 alkyl chain.

[0029] In some aspects, the disclosure relates to a compound of Formula II, or pharmaceutically acceptable salts or solvates thereof:Ylais selected from the group consisting of -N< and -0CH2CH<;R1is selected from the group consisting of -H, C10-C20 alkyl, C10-C20 alkenyl, C10-C20 alkynyl and -CH2OC(=O)CH2(CH2)7-17CH3;R2is selected from the group consisting of Cio-C2o alkyl, Cio-C2o alkenyl, Cio-C2o alkynyl,N (CH2)mCH3-OC(=O)CH2(CH2)7-17CH3, (CH2)mCH3 ^ndO(CH2)mCH30group consisting of-OH, -SH and -X2a-Y2a(R3)(R4);wherein X2ais selected from the group consisting ofOCNwherein Y2ais selected from the group consisting of -N< and -OCH2CH<;wherein R3is selected from the group consisting of -H, Cio-C2o alkyl, Cio-C2o alkenyl, Cio-C2o alkynyl and -CH2OC(=O)CH2(CH2)7-i7CH3;R4is selected from the group consisting of Cio-C2o alkyl, Cio-C2o alkenyl, Cio-C2o alkynyl,N (CH2)mCH3-OC(=O)CH2(CH2)7-17CH3, \cH2)mCH3O(CH2)mCH3and Owherein m is an integer in the range of 7 to 18;wherein n is an integer in the range of 2 to 200.

[0030] The following paragraphs provide additional aspects of the compounds of Formula II.

[0031] In some aspects, the disclosure relates to a compound of Formula II, or pharmaceutically acceptable salts or solvates thereof:Ylais selected from the group consisting of -N< and -OCH2CH<;R1is selected from the group consisting of -H, C10-C20 alkyl, C10-C20 alkenyl, C10-C20 alkynyl and -CH2OC(=O)CH2(CH2)7-17CH3;R2is selected from the group consisting of C10-C20 alkyl, C10-C20 alkenyl, C10-C20 alkynyl,Nx(CH2)mCH3-OC(=O)CH2(CH2)7-17CH3, (CHsimCHsanc[X^S'S^O^°^O'^ O'^ O^(CHd'"CH3O(CH2)mCH30 consisting of-OH, -SH and -X2a-Y2a(R3)(R4);wherein X2ais selected from the group consisting ofOCNwherein Y2ais selected from the group consisting of -N< and -0CH2CH<;wherein R3is selected from the group consisting of -H, C10-C20 alkyl, C10-C20 alkenyl, C10-C20 alkynyl and -CH2OC(=O)CH2(CH2)7-17CH3;R4is selected from the group consisting of C10-C20 alkyl, C10-C20 alkenyl, C10-C20 alkynyl,S' N (CH2)mCH3-OC(=O)CH2(CH2)7-17CH3, XCH2)mCH30 0O(CH2)mCH3and O wherein if R3is -H then R4is selected from the group consisting of X N XCH2)mCH3(CHsimCHsanc[0 0O(CH2)mCH30and Yla, R1and R2are absent;then Yla, R1and R2are absent and Z1is -X2a-Y2a(R3)(R4);Owherein if Xlais then Z1is not -X2a-Y2a(R3)(R4);wherein if R1is -H then R2is selected from the group consisting ofN \CH2)mCH3\cH2)mCH3andO(CH2)mCH30wherein m is an integer in the range of 7 to 18;wherein n is an integer in the range of 2 to 200.

[0032] In some aspects, in the compound of Formula II or pharmaceutically acceptable salt or solvate thereof:o o oH, -OH, and -SH;Ylais selected from the group consisting of -N< and -0CH2CH<;R1is selected from the group consisting of -H, C10-C20 alkyl, C10-C20 alkenyl, C10-C20 alkynyl and -CH2OC(=O)CH2(CH2)7-i7CH3;R2is selected from a group consisting of C10-C20 alkyl, Cio-Cis alkenyl, Cio-Cis alkynyl,Os-s\x^oO N '(CH2)mCH3-OC(=O)CH2(CH2)7-17CH3, (CH2)mCH3and 0 O S O O O Y^o / U^(CH2)mCH3O(CH2)mCH30-OH, -SH and -X2a-Y2a(R3)(R4);Owherein X2ais selected from the group consisting ofandOCNwherein Y2ais selected from the group consisting of -N< and -0CH2CH<;wherein R3is selected from the group consisting of -H, C10-C20 alkyl, C10-C20 alkenyl, C10-C20 alkynyl and -CH2OC(=O)CH2(CH2)7-17CH3;R4is selected from the group consisting of C10-C20 alkyl, C10-C20 alkenyl, C10-C20 alkynyl,H, -OH, or -SH and Yla, R1and R2are absent;-H, -OH, or -SH, then Yla, R1and R2are absent and Z1is -X2a-Y2a(R3)(R4);wherein if Xlais then Z1is not -X2a-Y2a(R3)(R4);wherein if R3is -H then R4is selected from the group consisting ofN (CH2)mCH3(CH2)mCH3 and A^(CH2)mCH3O(CH2)mCH30wherein if R4is selected from the group consisting of OS o O' N (CH2)mCH3(CH2)mCH3 ^ndO(CH2)mCH30, then R3is -H;wherein if R1is -H then R2is selected from the group consisting ofs^sN (CH2)mCH3(CH2)mCH3 and OoA^ / (CH2)mCH3O(CH2)mCH30wherein if R2is selected from the group consisting ofNx(CH2)mCH3(CH2)mCH3andX^S, S^O^°^O'^ O'^ O^(CH^CH3O(CH2)mCH30, then R1is -H;wherein m is an integer in the range of 7 to 18;wherein n is an integer in the range of 2 to 200.

[0033] In some aspects, in the compound of Formula II or a pharmaceutically acceptable salt or solvate thereof:Xlais selected the group consisting ofYlais selected from the group consisting of -N< and -0CH2CH<;R1is selected from the group consisting of -CH2(CH2)10-18CH3, and -CH2OC(=O)CH2(CH2)7-17CH3;R2is selected from the group consisting of -CH2(CH2)10-18CH3and -OC(=O)CH2(CH2)7-i7CH3;Z1is selected from the group consisting of -OH,and -X2a-Y2a(R3)(R4);Owherein X2ais CNwherein Y2ais N<;wherein R3is -CH2(CH2)8-18CH3;wherein R4is -CH2(CH2)8-18CH3;wherein if Z1is -X2a-Y2a(R3)(R4), then X1isand Yla, R1and R2are absent;wherein if Xlaisthen Yla, R1and R2are absent and Z1is -X2a-Y2a(R3)(R4);wherein if X1is / \ / then Z1is not -X2a-Y2a(R3)(R4);wherein n is an integer in the range of 2 to 200.

[0034] In some aspects, in the compound of Formula II or a pharmaceutically acceptable salt or solvate thereof:Xlais selected from the group consisting ofYlais selected from the group consisting of -N< and -OCH2CH<;R1is selected from the group consisting of -CH2(CH2)12CH3, -CH2(CH2)14CH3, -CH2(CH2)16CH3, -CH2OC(=O)CH2(CH2)11CH3, -CH2OC(=O)CH2(CH2)13CH3and -CH2OC(=O)CH2(CH2)15CH3;R2is selected from the group consisting of -CH2(CH2)12CH3, -CH2(CH2)14CH3, -CH2(CH2)16CH3, -OC(=O)CH2(CH2)11CH3, -OC(=O)CH2(CH2)13CH3and -OC(=O)CH2(CH2)15CH3;and -X2a-Y2a(R3)(R4);owherein X2ais CN;wherein Y2ais N<;wherein R3is -CH2(CH2)12CH3;wherein R4is -CH2(CH2)12CH3;OHwherein if Xlais, then Yla, R1and R2are absent and Z1is -X2a-Y2a(R3)(R4);Owherein if Xlais then Z1is not -X2a-Y2a(R3)(R4);wherein if Z1is -X2a-Y2a(R3)(R4) then if Xlaisand Yla, R1and R2are absent;wherein n is an integer in the range of 2 to 200.

[0035] In some aspects, in the compound of Formula II or a pharmaceutically acceptable salt or solvate thereof:Ylais selected from the group consisting of -N< and -OCH2CH<;R1is selected from the group consisting of -CH2(CH2)12CH3, -CH2(CH2)14CH3, -CH2(CH2)16CH3, -CH2OC(=O)CH2(CH2)11CH3, -CH2OC(=O)CH2(CH2)13CH3and -CH2OC(=O)CH2(CH2)15CH3;R2is selected from the group consisting of -CH2(CH2)12CH3, -CH2(CH2)14CH3, -CH2(CH2)16CH3, -OC(=O)CH2(CH2)11CH3, -OC(=O)CH2(CH2)13CH3and -OC(=O)CH2(CH2)15CH3;Z1is selected from the group consisting of -OH,-X2a-Y2a(R3)(R4);wherein X2ais CNwherein Y2ais N<;wherein R3is -CH2(CH2)12CH3;wherein R4is -CH2(CH2)12CH3;O AAQHwherein if Xlais A, then Yla, R1and R2are absent and Z1is -X2a-Y2a(R3)(R4);Owherein if Xlais then Z1is not -X2a-Y2a(R3)(R4);OX^OHwherein if Z1is -X2a-Y2a(R3)(R4), then Xlais A and Yla, R1and R2are absent;wherein n is an integer in the range of 2 to 200.

[0036] In some aspects, in the compound of Formula II or a pharmaceutically acceptable salt or solvate thereof:Ylais selected from the group consisting of -N<, and -OCH2CH<;R1is selected from the group consisting of -CH2(CH2)8-i8CH3 and -CH2OC(=O)CH2(CH2)7-17CH3;R2is selected from the group consisting of -CH2(CH2)8-i8CH3 and -OC(=O)CH2(CH2)7-i7CH3;o owherein n is an integer in the range of 2 to 200.

[0037] In some aspects, in the compound of Formula II or a pharmaceutically acceptable salt or solvate thereof:is selected from the group consisting of -N<, and -0CH2CH<;R1is selected from the group consisting of -CH2(CH2)12CH3, -CH2(CH2)14CH3, -CH2(CH2)ieCH3, -CH2OC(=O)CH2(CH2)11CH3, -CH2OC(=O)CH2(CH2)13CH3and -CH2OC(=O)CH2(CH2)15CH3;R2is selected from the group consisting of -CH2(CH2)12CH3, -CH2(CH2)i4CH3, -CH2(CH2)16CH3, -OC(=O)CH2(CH2)11CH3, -OC(=O)CH2(CH2)13CH3and -OC(=O)CH2(CH2)15CH3;from the group consisting of -OH, CN andwherein n is an integer in the range of 2 to 200.

[0038] In some aspects, in the compound of Formula II or a pharmaceutically acceptable salt or solvate thereof:Ylais absent;R1is absent;R2is absent;Z1is -X2a-Y2a(R3)(R4);wherein X2ais selected from the group consisting ofandOCNwherein Y2ais selected from the group consisting of -N< and -OCH2CH<;wherein R3is selected from the group consisting of -CH2(CH2)10-18CH3 and -CH2OC(=O)CH2(CH2)9-i7CH3;wherein R4is selected from the group consisting of -CH2(CH2)10-18CH3, and -OC(=O)CH2(CH2)9-i7CH3;wherein n is an integer in the range of 2 to 200.

[0039] In some aspects, in the compound of Formula II or a pharmaceutically acceptable salt or solvate thereof:X ■ is selected from the group consisting of, ZX / \^OH, -OH, -H and -SH;Ylais absent;R1is absent;R2is absent;Z1is -X2a-Y2a(R3)(R4);Owherein X2ais selected from the group consisting ofandOCN;wherein Y2ais selected from the group consisting of -N< and -0CH2CH<;wherein R3is selected from the group consisting of -CH2(CH2)8-i8CH3 and -CH2OC(=O)CH2(CH2)7-17CH3;wherein R4is selected from the group consisting of -CH2(CH2)8-i8CH3, and -OC(=O)CH2(CH2)7-17CH3;wherein n is an integer in the range of 2 to 200.

[0040] In some aspects, if Ylais -N<, then R1is selected from the group consisting of -H, C10-C20 alkyl, C10-C20 alkenyl and C10-C20 alkynyl and R2is selected from the group consisting of C10- C20 alkyl, C10-C20 alkenyl, C10-C20 alkynyl,s^sN (CH2)mCH3(CH2)mCH3,anc[A^(CH2)mCH 3S"O(CH2)mCH30

[0041] In some aspects, if Ylais -N<, then R1is -CH2(CH2)10-18CH3 and R2is -CH2(CH2)10-18CH3.

[0042] In some aspects, if Ylais -N<, then R1is selected from the group consisting of - CH2(CH2)i2CH3,-CH2(CH2)14CH3and -CH2(CH2)i6CH3 and R2is selected from the group consisting of -CH2(CH2)i2CH3, -CH2(CH2)i4CH3and -CH2(CH2)16CH3.

[0043] In some aspects, if Ylais -N<, then R1is -CH2(CH2)8-18CH3 and R2is -CH2(CH2)8-18CH3.

[0044] In some aspects, if Ylais -0CH2CH<, then R1is -CH2OC(=O)CH2(CH2)7-17CH3and R2is -OC(=O)CH2(CH2)7-17CH3.

[0045] In some aspects, if Ylais -OCH2CH<, then R1is selected from the group consisting of -CH2OC(=O)CH2(CH2)11CH3, -CH2OC(=O)CH2(CH2)13CH3 and -CH2OC(=O)CH2(CH2)i5CH3 and R2is selected from the group consisting of -OC(=O)CH2(CH2)IICH3, -OC(=O)CH2(CH2)13CH3and -OC(=O)CH2(CH2)i5CH3.

[0046] In some aspects, if Y2ais -N<, then R3is selected from the group consisting of -H, Cio-Cis alkyl, Cio-Cis alkenyl and Cio-Cis alkynyl and R4is selected from the group consisting of Cio-Cis alkyl, Cio-Cis alkenyl, Cio-Cis alkynyl,s^sN (CH2)mCH3(CH2)mCH30 O0 / -^0^^0A^(CH2)mCH3S" OO(CH2)mCH30

[0047] In some aspects, if Y2ais -N<, then R3is -CH2(CH2)10-18CH3and R4is -CH2(CH2)10-18CH3.

[0048] In some aspects, if wherein if Y2ais -N<, then R3is -CH2(CH2)8-i8CH3 and R4is -CH2(CH2)8-i8CH3 and R4IS -CH2(CH2)8-i8CH3.

[0049] In some aspects, if Y2ais -OCH2CH<, then R3is -CH2OC(=O)CH2(CH2)9-i7CH3 and R4is -OC(=O)CH2(CH2)9-i7CH3.

[0050] In some aspects, if Y2ais -OCH2CH< then R3is -CH2OC(=O)CH2(CH2)7-17CH3 and R4is - OC(=O)CH2(CH2)7-i7CH3.

[0051] In some aspects, if R4is selected from the group consisting ofN "(CH2)mCH3(CH2)rnCH3and0 00^^0^^0JV(CH2)mCH3S' 0O(CH2)mCH30, then R3is -H.

[0052] In some aspects, in the compound of Formula II or a pharmaceutically acceptable salt or solvate thereof:Ylais selected from the group consisting of -N< and -0CH2CH<;R1is selected from the group consisting of -H, C10-C20 alkyl, C10-C20 alkenyl, C10-C20 alkynyl and -CH2OC(=O)CH2(CH2)7-17CH3;R2is selected from the group consisting of C10-C20 alkyl, C10-C20 alkenyl, C10-C20 alkynyl,N ^(CH2)mCH3-OC(=O)CH2(CH2)7-17CH3, (CH2)mCH3anc[0 0 S'" 0O(CH2)mCH30the group consisting of -H, -OH, -SH,Owherein X2ais selected from the group consisting ofand oCNwherein Y2ais selected from the group consisting of -N< and -0CH2CH<;wherein R3is selected from the group consisting of -H, C10-C20 alkyl, C10-C20 alkenyl, C10-C20 alkynyl and -CH2OC(=O)CH2(CH2)7-i7CH3;wherein R4is selected from the group consisting of C10-C20 alkyl, C10-C20 alkenyl, C10-C20 alkynyl, -OC(=O)CH2(CH2)7-17CH3,N (CH2)mCH3(CH2)mCH3and O 00^A0^^0A / (CH2)mCH3Sx0O(CH2)mCH30wherein m is an integer in the range of 7 to 18;wherein if Y2ais -N<, then R3is selected from the group consisting of -H, C10-C20 alkyl, C10-C20 alkenyl and C10-C20 alkynyl and R4is selected from the group consisting of C10-C20 alkyl, C10-C20 alkenyl, C10-C20 alkynyl,s^sN (CH2)mCH3(CH2)mCH30 O0 / -^0^y^0A^(CH2)mCH3S" O O(CH2)mCH30wherein if Y23is -OCH2CH< then R3is -CH2OC(=O)CH2(CH2)7-17CH3and R4is -OC(=O)CH2(CH2)7-i7CH3;wherein if R3is -H then R4is selected from the group consisting ofN "(CH2)mCH3(CH2)mCH3andO(CH2)mCH30wherein if R4is selected from the group consisting ofN (CH2)mCH3(CH2)mCH3and o 00^^0^Y-^0A^ / (CH2)mCH3S" O O(CH2)mCH30, then R3isare absent;then Yla, R1and R2are absent and Z1is -X2a-Y2a(R3)(R4);wherein if Xlais then Z1is not -X2a-Y2a(R3)(R4);wherein if Ylais -N< then R1is selected from the group consisting of -H, C10-C20 alkyl, C10-C20 alkenyl and C10-C20 alkynyl and R2is selected from the group consisting of C10-C20 alkyl, C10-C20S N (CH2)mCH3alkenyl, C10-C20 alkynyl, (CH2)mCH3 anc[0 O0 / -^0^^0A^(CH2)mCH3S" OO(CH2)mCH30wherein if Ylais -OCH2CH<, then R1is -CH2OC(=O)CH2(CH2)7-17CH3and R2is -OC(=O)CH2(CH2)7-i7CH3;wherein if R1is -H then R2is selected from the group consisting ofN (CH2)mCH3(CH2)mCH3and0 00wherein if R2is selected from the group consisting ofN ^(CH2)mCH3(CH2)mCH3and 0 0 S" 0O(CH2)mCH30, then R1is -H;wherein n is an integer in the range of 2 to 200.

[0053] In some aspects, in the compound of Formula II or a pharmaceutically acceptable salt or solvate thereof:o o oH, -OH and -SH;Ylais selected from the group consisting of -N< and -0CH2CH<;R1is selected from the group consisting of -H, C10-C20 alkyl, C10-C20 alkenyl, C10-C20 alkynyl and -CH2OC(=O)CH2(CH2)7-17CH3;R2is selected from the group consisting of C10-C20 alkyl, Cio-Cis alkenyl, Cio-Cis alkynyl,N (CH2)mCH3-OC(=O)CH2(CH2)7-i7CH3, (CH2)mCH3 and0 0 / C^s. Sx^o^^O^^o^^o^^oJV(CH2)mCH3OY^(CH2)mCH300 and -X2a-Y2a(R3)(R4);Owherein X2ais selected from the group consisting ofandOCNwherein Y2ais selected from the group consisting of -N< and -0CH2CH<;wherein R3is selected from the group consisting of -H, C10-C20 alkyl, C10-C20 alkenyl, C10-C20 alkynyl and -CH2OC(=O)CH2(CH2)7-17CH3;R4is selected from the group consisting of C10-C20 alkyl, C10-C20 alkenyl, C10-C20 alkynyl,N \CH2)mCH3-OC(=O)CH2(CH2)7-17CH3, (CH2)mCH3andH, -OH or -SH, Ylaabsent and R1and R2are absent;are absent and Z1is -X2a-Y2a(R3)(R4);wherein if Xlais then Z1is not -X2a-Y2a(R3)(R4);wherein if Y2ais -N<, then R3is selected from the group consisting of -H, C10-C20 alkyl, C10- C20 alkenyl and C10-C20 alkynyl and R4is selected from the group consisting of C10-C20 alkyl, C10-C20 alkenyl, C10-C20 alkynyl,N (CH2)mCH3(CH2)mCH3anc[ 0 O0^^0 / -Y^0A^(CH2)mCH3S" O'O(CH2)mCH3Owherein if Y2ais -0CH2CH<, then R3is -CH2OC(=O)CH2(CH2)7-17CH3and R4is -OC(=O)CH2(CH2)7-i7CH3;wherein if R3is -H then R4is selected from the group consisting ofN (CH2)mCH3(CH2)mCH3andO(CH2)mCH30wherein if R4is selected from the group consisting ofN \CH2)mCH3(CH2)mCH3and0 0O(CH2)mCH30, then R3is -H;wherein m is an integer in the range of 7 to 18;wherein if Ylais -N< then R1is selected from the group consisting of -H, C10-C20 alkyl, C10-C20 alkenyl and C10-C20 alkynyl and R2is selected from the group consisting of C10-C20 alkyl, C10-C20N "(CH2)mCH3alkenyl, C10-C20 alkynyl, (CHzlmCHsan(-[0 0O(CH2)mCH3Owherein if Ylais -0CH2CH<, then R1is -CH2OC(=O)CH2(CH2)7-17CH3and R2is -OC(=O)CH2(CH2)7-17CH3;wherein if R1is -H then R2is selected from the group consisting ofN (CH2)mCH3(CH2)mCH3andA^(CH2)mCH 3 SO(CH2)mCH30wherein if R2is selected from the group consisting ofN ^(CH2)mCH3"(CH2)mCH3and0 0(CH2)mCH3O(CH2)mCH30, then R1is -H;wherein n is an integer in the range of 2 to 200.

[0054] In some aspects, in the compound of Formula II or a pharmaceutically acceptable salt or solvate thereof:O OXlais selected from the group consisting ofYlais selected from the group consisting of -N< and -0CH2CH<;R1is selected from the group consisting of -CH2(CH2)10-18CH3, and -CH2OC(=O)CH2(CH2)7-17CH3;R2is selected from the group consisting of -CH2(CH2)10-18CH3and -OC(=O)CH2(CH2)7-i7CH3;Z1is selected from the group consisting of -OH, CN,OCNHand -X2a-Y2a(R3)(R4);wherein X2ais CN;wherein Y2ais N<;wherein R3is -CH2(CH2)8-i8CH3;wherein R4is -CH2(CH2)8-18CH3;wherein if Ylais -N<, then R1is -CH2(CH2)10-18CH3and R2is -CH2(CH2)10-18CH3;wherein if Ylais -0CH2CH<, then R1is -CH2OC(=O)CH2(CH2)7-17CH3and R2is -OC(=O)CH2(CH2)7-i7CH3;wherein if Xlaisthen Yla, R1and R2are absent and Z1is -X2a-Y2a(R3)(R4);wherein if Xlais then Z1is not -X2a-Y2a(R3)(R4);wherein if Z1is -X2a-Y2a(R3)(R4), then Xlaisand Yla, R1and R2are absent; wherein n is an integer in the range of 2 to 200.

[0055] In some aspects, in the compound of Formula II or a pharmaceutically acceptable salt or solvate thereof:o oOHXlais selected from the group consisting ofandYlais selected from the group consisting of -N< and -0CH2CH<;R1is selected from the group consisting of -CH2(CH2)12CH3, -CH2(CH2)14CH3, -CH2(CH2)16CH3, -CH2OC(=O)CH2(CH2)11CH3, -CH2OC(=O)CH2(CH2)13CH3and -CH2OC(=O)CH2(CH2)i5CH3;R2is selected from the group consisting of -CH2(CH2)12CH3, -CH2(CH2)14CH3, -CH2(CH2)16CH3, -OC(=O)CH2(CH2)11CH3, -OC(=O)CH2(CH2)13CH3and -OC(=O)CH2(CH2)i5CH3;Z1is selected from the group consisting of -OH,and -X2a-Y2a(R3)(R4);Owherein X2ais CN;wherein Y2ais N<;wherein R3is -CH2(CH2)12CH3;wherein R4is -CH2(CH2)12CH3;wherein if Ylais -N<, then R1is selected from the group consisting of -CH2(CH2)12CH3, -CH2(CH2)14CH3and -CH2(CH2)ieCH3 and R2is selected from the group consisting of -CH2(CH2)i2CH3, -CH2(CH2)i4CH3and -CH2(CH2)16CH3;wherein if Ylais -0CH2CH<, then R1is selected from the group consisting of -CH2OC(=O)CH2(CH2)11CH3, -CH2OC(=O)CH2(CH2)13CH3 and-CH2OC(=O)CH2(CH2)ISCH3 and R2is selected from the group consisting of -OC(=O)CH2(CH2)IICH3, -OC(=O)CH2(CH2)13CH3and -OC(=O)CH2(CH2)i5CH3;owherein if Xlais A A H, then Yla, R1and R2are absent and Z1is -X2a-Y2a(R3)(R4);wherein if Xlais then Z1is not -X2a-Y2a(R3)(R4);Owherein if Z1is -X2a-Y2a(R3)(R4) then XlaisA and Yla, R1and R2are absent; wherein n is an integer in the range of 2 to 200.

[0056] In some aspects, in the compound of Formula II or a pharmaceutically acceptable salt or solvate thereof:O OXlais selected from the group consisting ofYlais selected from the group consisting of -N< and -OCH2CH<;R1is selected from the group consisting of -CH2(CH2)12CH3, -CH2(CH2)14CH3, -CH2(CH2)16CH3, -CH2OC(=O)CH2(CH2)11CH3, -CH2OC(=O)CH2(CH2)13CH3and -CH2OC(=O)CH2(CH2)15CH3;R2is selected from the group consisting of -CH2(CH2)12CH3, -CH2(CH2)14CH3, -CH2(CH2)i6CH3, -OC(=O)CH2(CH2)IICH3, -OC(=O)CH2(CH2)13CH3and -OC(=O)CH2(CH2)i5CH3;Z1is selected from the group consisting of -OH, CN,and -X2a-Y2a(R3)(R4);wherein X2ais CN;wherein Y2ais N<;wherein R3is -CH2(CH2)12CH3;wherein R4is -CH2(CH2)12CH3;wherein if Ylais -N<, then R1is selected from the group consisting of -CH2(CH2)12CH3, -CH2(CH2)14CH3and -CH2(CH2)ieCH3 and R2is selected from the group consisting of -CH2(CH2)i2CH3, -CH2(CH2)i4CH3 and -CH2(CH2)i6CH3;wherein if Ylais -0CH2CH<, then R1is selected from the group consisting of -CH2OC(=O)CH2(CH2)11CH3, -CH2OC(=O)CH2(CH2)13CH3 and -CH2OC(=O)CH2(CH2)ISCH3 and R2is selected from the group consisting of -OC(=O)CH2(CH2)IICH3, -OC(=O)CH2(CH2)13CH3and -OC(=O)CH2(CH2)i5CH3;Owherein if Xlais / \, then Yla, R1and R2are absent and Z1is -X2a-Y2a(R3)(R4);Owherein if Xlais then Z1is not -X2a-Y2a(R3)(R4);Owherein if Z1is -X2a-Y2a(R3)(R4), then Xlais / \ and Yla, R1and R2are absent; wherein n is an integer in the range of 2 to 200.

[0057] In some aspects, in the compound of Formula II or a pharmaceutically acceptable salt or solvate thereof:OYlais selected from the group consisting of -N<, and -OCH2CH<;R1is selected from the group consisting of -CH2(CH2)8-18CH3 and -CH2OC(=O)CH2(CH2)7-17CH3;R2is selected from the group consisting of -CH2(CH2)8-18CH3 and -OC(=O)CH2(CH2)7-i7CH3;wherein if Ylais -N<, then R1is -CH2(CH2)8-18CH3 and R2is -CH2(CH2)8-18CH3;wherein if Ylais -0CH2CH<, then R1is -CH2OC(=O)CH2(CH2)7-17CH3and R2is -OC(=O)CH2(CH2)7-i7CH3;wherein n is an integer in the range of 2 to 200.

[0058] In some aspects, in the compound of Formula II or a pharmaceutically acceptable salt or solvate thereof:OXlais;Ylais selected from the group consisting of -N<, and -OCH2CH<;R1is selected from the group consisting of -CH2(CH2)12CH3, -CH2(CH2)14CH3, -CH2(CH2)16CH3, -CH2OC(=O)CH2(CH2)11CH3, -CH2OC(=O)CH2(CH2)13CH3and -CH2OC(=O)CH2(CH2)15CH3;R2is selected from the group consisting of -CH2(CH2)12CH3, -CH2(CH2)14CH3, -CH2(CH2)16CH3, -OC(=O)CH2(CH2)11CH3, -OC(=O)CH2(CH2)13CH3and -OC(=O)CH2(CH2)i5CH3;Z1is selected from the group consisting of -OH, CNwherein if Ylais -N<, then R1is selected from the group consisting of -CH2(CH2)12CH3, -CH2(CH2)14CH3and -CH2(CH2)ieCH3 and R2is selected from the group consisting of -CH2(CH2)i2CH3, -CH2(CH2)i4CH3and -CH2(CH2)16CH3;wherein if Ylais -OCH2CH<, then R1is selected from the group consisting of -CH2OC(=O)CH2(CH2)11CH3, -CH2OC(=O)CH2(CH2)13CH3 and -CH2OC(=O)CH2(CH2)ISCH3 and R2is selected from the group consisting of -OC(=O)CH2(CH2)IICH3, -OC(=O)CH2(CH2)13CH3and -OC(=O)CH2(CH2)i5CH3; wherein n is an integer in the range of 2 to 200.

[0059] In some aspects, in the compound of Formula II or a pharmaceutically acceptable salt or solvate thereof:Xlais selected from the group consisting of-OH, -H, -SH,Ylais absent;R1is absent;R2is absent;Z1is -X2a-Y2a(R3)(R4);wherein X2ais selected from the group consisting of / \ and OCN;wherein Y2ais selected from the group consisting of -N< and -0CH2CH<;wherein R3is selected from the group consisting of -CH2(CH2)10-18CH3 and -CH2OC(=O)CH2(CH2)9-i7CH3;wherein R4is selected from the group consisting of -CH2(CH2)10-18CH3, and -OC(=O)CH2(CH2)9-i7CH3;wherein if Y2ais -N<, then R3is -CH2(CH2)10-18CH3 and R4is -CH2(CH2)10-18CH3;wherein if Y2ais -0CH2CH<, then R3is -CH2OC(=O)CH2(CH2)9-17CH3 and R4is -OC(=O)CH2(CH2)9-17CH3;wherein n is an integer in the range of 2 to 200.

[0060] In some aspects, in the compound of Formula II or a pharmaceutically acceptable salt or solvate thereof:Xlais selected from the group consisting of / \, -OH, -H and -SH;Ylais absent;R1is absent;R2is absent;Z1is -X2a-Y2a(R3)(R4);Owherein X2ais selected from the group consisting ofandOCN;wherein Y2ais selected from the group consisting of -N< and -OCH2CH<;wherein R3is selected from the group consisting of -CF^CFF isCHs and -CH2OC(=O)CH2(CH2)7-17CH3;wherein R4is selected from the group consisting of -CH2(CH2)s-i8CH3, and -OC(=O)CH2(CH2)7-17CH3;wherein if Y2ais -N<, then R3is -CH2(CH2)8-18CH3and R4is -CH2(CH2)8-18CH3and R4is -CH2(CH2)8-18CH3;wherein if Y2ais -0CH2CH<, then R3is -CH2OC(=O)CH2(CH2)7-17CH3and R4is -OC(=O)CH2(CH2)7-17CH3;wherein n is an integer in the range of 2 to 200.

[0061] In some aspects, the compound of Formula II is represented by Formula III or a pharmaceutically acceptable salt or solvate thereof:OHFormula IIIK1is -C(=0)- and -C(=O)OH;Ylais selected from the group consisting of -N< and -0CH2CH<;R1is selected from the group consisting of C10-C20 alkyl, C10-C20 alkenyl, C10-C20 alkynyl and -CH2OC(=O)CH2(CH2)7-17CH3;R2is selected from the group consisting of C10-C20 alkyl, C10-C20 alkenyl, C10-C20 alkynyl and -OC(=O)CH2(CH2)7-i7CH3;Z1is selected from the group consisting of -OH, CN,N (CH2)8-18CH3O(CH2)8-18CH3andwherein if K1is -C(=O)OH, then Yla, R1and R2are absent and Z1isoN (CH2)8-18CH3(CH2)8-18CH3N' '(CH2)8.18CH3Iwherein if Z1is, then K1is -C(=O)OH;wherein n is an integer in the range of 2 to 200.

[0062] In some aspects, subset of compounds of Formula III may include those in which if Ylais - N<, then R1is selected from the group consisting of C10-C20 alkyl, C10-C20 alkenyl andC10-C20 alkynyl and R2is selected from the group consisting of C10-C20 alkyl, C10-C20 alkenyl and C10-C20 alkynyl.

[0063] In some aspects, subset of compounds of Formula in may include those in which if Ylais - OCH2CH< then R1is -CH2OC(=O)CH2(CH2)7-17CH3and R2is-OC(=O)CH2(CH2)7-17CH3.

[0064] In some aspects, subset of compounds of Formula in may include those in whichK1is -C(=O)- and -C(=O)OH;Ylais selected from the group consisting of -N< and -OCH2CH<;R1is selected from the group consisting of C10-C20 alkyl, C10-C20 alkenyl, C10-C20 alkynyl and - CH2OC(=O)CH2(CH2)7-i7CH3;R2is selected from the group consisting of C10-C20 alkyl, C10-C20 alkenyl, C10-C20 alkynyl and -OC(=O)CH2(CH2)7-17CH3;selected from the group consisting of -OH, CN,(CH2)8-18CH3CN NHandwherein if Ylais -N<, then R1is selected from the group consisting of C10-C20 alkyl, C10-C20 alkenyl and C10-C20 alkynyl and R2is selected from the group consisting of C10-C20 alkyl, C10-C20 alkenyl and C10-C20 alkynyl;wherein if Ylais -OC FCI, then R1is -CH2OC(=O)CH2(CH2)7-17CH3and R2is -OC(=O)CH2(CH2)7-i7CH3;wherein if K1is -C(=O)OH, then R1and R2are absent and Z1is(CH2)8-18CH3oN (CH2)8-18CH3CN^(CH2)8.18CH3wherein if Z1is, then K1is -C(=O)OH;wherein n is an integer in the range of 2 to 200.

[0065] In some aspects, the compound of Formula II is represented by Formula IV or a pharmaceutically acceptable salt or solvate thereof:Formula IVYlais selected from the group consisting of -N<, -OCH2CH< and -OH;R1is selected from the group consisting of Cio-Cis alkyl, Cio-Cis alkenyl, Cio-Cis alkynyl and -CH2OC(=0)CH2(CH2)io-i6CH3;R2is selected from the group consisting of Cio-Cis alkyl, Cio-Cis alkenyl, Cio-Cis alkynyl and -OC(=0)CH2(CH2)io-i6CH3;Z1is selected from the group consisting of -OH, CN,ON '' ■(CH2)e.,3CH3CN^< CH2)8.18CH3CNHand;wherein if Ylais -OH, then R1and R2are absent and Z1isON / ^'(CH2)8. I8CH3(CH2)8.18CH3N ^(CH2)8.18CH3(CH2)8. I8CH3wherein if Z1is, then Ylais -OH;wherein n is an integer in the range of 2 to 200.

[0066] In some aspects, subset of compounds of Formula IV may include those in which if Ylais - N<, then R1is selected from the group consisting of Cio-Cis alkyl, Cio-Cis alkenyl andC10-C18 alkynyl and R2is selected from the group consisting of Cio-Cis alkyl, Cio-Cis alkenyl and Cio-Cis alkynyl.

[0067] In some aspects, subset of compounds of Formula IV may include those in which if Ylais - OCH2CH< then R1is -CH2OC(=0)CH2(CH2)io-i6CH3 and R2is-OC(=0)CH2(CH2)io-i6CH3.

[0068] In some aspects, subset of compounds of Formula IV may include those in whichYlais selected from the group consisting of -N<, -OCH2CH< and -OH;R1is selected from the group consisting of Cio-Cis alkyl, Cio-Cis alkenyl, Cio-Cis alkynyl and -CH2OC(=0)CH2(CH2)io-i6CH3;R2is selected from group the consisting of Cio-Cis alkyl, Cio-Cis alkenyl, Cio-Cis alkynyl and -OC(=0)CH2(CH2)io-i6CH3;Z1is selected from the group consisting of -OH, CN,(CH2)8.18CH3wherein if Ylais -N<, then R1is selected from the group consisting of Cio-Cis alkyl, Cio-Cis alkenyl and Cio-Cis alkynyl and R2is selected from the group consisting of Cio-Cis alkyl, Cio-Cis alkenyl and Cio-Cis alkynyl;wherein if Ylais -0CH2CH< then R1is -CH20C(=0)CH2(CH2)io-i6CH3 and R2is -OC(=0)CH2(CH2)io-i6CH3;wherein if Ylais -OH, then R1and R2are absent and Z1isoN (CH2)8-18CH3(CH2)8.18CH3N (CH2)8-18CH3(CH2)8.18CH3wherein if Z1is, then Ylais -OH;wherein n is an integer in the range of 2 to 200.

[0069] In some aspects, the disclosure relates to a compound of Formula V, or pharmaceutically acceptable salts or solvates thereof:o o wherein X1is selected from the group consisting ofwherein δ1 designates the bond to Y1;, / QSY1is selected from the group consisting of -O-, -NH- and Q6- J1is selected from the group consisting of C1-C15 alkylene chains, wherein in said C1-C15 alkylene chains, one or more -CH2- groups may be replaced with -O- and / or -S-;T1is direct bond between J1and M1or selected from the group consisting ofwherein δ2 designates the bond to M1;HC^ I - M1is selected from the group consisting of ■Y and -Y;Q1is direct bond between M1and Q3or selected from the group consisting of O and Owherein δ3 designates the bond to M1;δ3 Q2is direct bond between M1and Q4or selected from the group consisting of O and Owherein δ3 designates the bond to M1;Q3is selected from the group consisting of C11-C18alkyl chains and Q;i / Q?Q4s l c e f' \ a is e e t d rom the group consisting of C11-C18 alkyl chains and Q;Q5is selected from the group consisting of C12-C18 alkyl chains;Q6is selected from the group consisting of C12-C18 alkyl chains;Q7is C8alkyl chain;Q8is C8alkyl chain;X3is selected from the group consisting ofx°YsyS, wherein δ6 designates the bond to Y3;Y3is a direct bond between X3and J3or selected from the group consisting of C1-C13alkylene chains, wherein in said C1-C11alkylene chains, one or more -CH2- groups may be replaced withwherein y is an integer in the range of 2 to 200;wherein if X1is, then Y1, J1, T1, M1, Q1, Q2, Q3and Q4are absentwherein if Y1isQ6, then J1, T1, M1, Q1, Q2, Q3and Q4are absent.

[0070] In some aspects, the disclosure relates to compounds of Formula V in whichOH Formula VY1is selected from the group consisting of -O-, -NH- andJ1is selected from the group consisting of C1-C15 alkylene chains, C2-C15 alkenylene chains and C2-C15 alkynylene chains, wherein in said C1-C15 alkylene chains, C2-C15 alkenylene chains or C2- OHC15 alkynylene chains one or more -CH2- groups may be replaced withCH3H<CH3-O- and / or -S-;OT1is a direct bond between J1and M1or selected from the group consisting of?HOH.IIeO and OH1 / PII O, wherein δ₂ designates the bond to M¹;|— H( / M1is selected from the group consisting ofandQ1is direct bond between M1and Q3or selected from the group consisting of53'1O > HO, wherein δ3 designates the bond to M1;Q2is direct bond between M1and Q4or selected from the group consisting of53'e<^ O O > H OHH o O O andwherein δ3 designates the bond to M1;Q3is selected from the group consisting of C5-C35 alkyl chains, C5-C35 alkenyl chains, C5-C35 l |-_HC 'Q7alkynyl chains andQ, wherein said C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains may be linear or branched;Q4is selected from the group consisting of C5-C35 alkyl chains, C5-C35 alkenyl chains, C5-C351 |-HC 'Q7galkynyl chains and Q, wherein said C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains may be linear or branched;Q5is selected from the group consisting of C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains, wherein said C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains may be linear or branched;Q6is selected from the group consisting of C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains, wherein said C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains may be linear or branched;Q7is C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains, wherein said C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains may be linear or branched;Q8is C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains, wherein said C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains may be linear or branched;X3is selected from the group consisting of S s s andS, wherein δ6 designates the bond to Y3;Y3is a direct bond between X3and J3or selected from the group consisting of C1-C13alkylene chains, wherein in said C1-C11alkylene chains, one or more -CH2- groups may be replaced with CH3J3is selected from the group consisting of -CH3,wherein y is an integer in the range of 2 to 200, i is an integer in the range of 0 to 3, p is an integer in the range of 2 to 4, e is an integer in the range of 1 to 4 and t is an integer in the range of 1 to 2.

[0071] In some aspects, the disclosure relates to a compound of Formula 1A or a pharmaceutically acceptable salt or solvate thereof:Formula 1Awherein Xlais selected from the group consisting ofR1is selected from the group consisting of -H, C10-C20 alkyl, C10-C20 alkenyl, C10-C20 alkynyl andO; wherein f is an integer between 8 and 18;R2is selected from the group consisting of C10-C20 alkyl, C10-C20 alkenyl, C10-C20 alkynyl,O(CH2)mCH30 wherein q is an integer between 8 and 18; and wherein m is an integer between 7 and 17;wherein if R1is H then R2is selected from the group consisting of N(CH2)mCH3(CH2)mCH3ando owherein when Z1is selected from the group consisting of oXR1o N,R|I CNR2, and CN R2, then Xlais not selected the group consisting of 0O / •R1N o-VRR2and R2wherein n is an integer in the range of 2 to 200.

[0072] In some aspects, the disclosure relates to a compound of Formula A or a pharmaceutically acceptable salt or solvate thereof:Formula Awherein A is a polymerized portion;wherein the polymerized portion is poly(N-(2-hydroxypropyl)methacrylamide);B is a linking group;L1and L2are lipidic portions;wherein the lipidic portion consists of alkyl, alkenyl, alkynyl or fatty acid ester consisting of at least 10 carbon atoms, wherein in said alkyl, alkenyl, alkynyl or fatty acid ester one carbon atom may be substituted with O;C is a substituent consisting of a terminal group;wherein the terminal group is not (ethylthio)(λ1-sulfaneyl)methanethione, (methylthio)(λ1-sulfaneyl)methanethione and (propylthio)(λ1-sulfaneyl)methanethione;n is an integer within the range of 2 to 200.

[0073] In some aspects, subset of compounds of Formula A may include compounds of Formula B or a pharmaceutically acceptable salt or solvate thereof:Formula Bwherein A is a polymerized portion;wherein the polymerized portion is poly(N-(2-hydroxypropyl)methacrylamide);D is a part of the linker;L1and L2are lipid portions;wherein the lipidic portion consists of alkyl, alkenyl or alkynyl consisting of at least 10 carbon atoms, wherein in said alkyl, alkenyl or alkynyl one carbon atom may be substituted with O;C is a substituent consisting of a terminal group;wherein the terminal group is not (ethylthio)(λ1-sulfaneyl)methanethione, (methylthio)(λ1-sulfaneyl)methanethione and (propylthio)(λ1-sulfaneyl)methanethione;n is an integer within the range of 2 to 200.

[0074] In some aspects, Formula I, Formula II, Formula III, Formula IV, Formula V, Formula 1 A, Formula A and / or Formula B may comprise a linker.

[0075] In some aspects, Formula I may comprise a terminal group.

[0076] In some aspects, linker may comprise X1and Y1as defined above. Terminal group may comprise X2, Y2, J2, T2and M2as defined above.

[0077] In some aspects, linker may comprise X1, Y1, J1and T1as defined above. Terminal group may comprise X2, Y2, J2, T2and M2as defined above.

[0078] In some aspects, Formula I may comprise a spacer.

[0079] In some aspects, spacer may be part of a linker.

[0080] In some aspects, δ5designates the bond to Y2or J2, if Y2is a direct bond between X2and J2.

[0081] In some aspects, in Formula I, J1may be selected from the group consisting of C1-C20 alkylene chains, C2-C20 alkenylene chains, C2-C20 alkynylene chains, -(CH2)k-O-(CH2)k-, - (CH2)k-O-(CH2)k-O-(CH2)k-, -(CH2)k-O-(CH2)k-O-(CH2)k-O-(CH2)k-, -(CH2)k-O-(CH2)k-O- (CH2)k-O-(CH2)k-O-(CH2)k-, -(CH2)k-O-(CH2)k-O-(CH2)k-O-(CH2)k-O-(CH2)k-O-(CH2)k-, - (CH2)k-O-(CH2)k-O-(CH2)k-O-(CH2)k-O-(CH2)k-O-(CH2)k-O-(CH2)k-, -(CH2)k-S-S-(CH2)k-, - (CH2)k-S-S-(CH2)k-O-(CH2)k-, -(CH2)k-O-(CH2)k-S-S-(CH2)k-, -(CH2)k-S-S-(CH2)k-S-S-(CH2)k-, -(CH2)k-S-S-(CH2)k-O-(CH2)k-O-(CH2)k-, -(CH2)k-O-(CH2)k-S-S-(CH2)k-O-(CH2)k-, -(CH2)k-O- (CH2)k-O-(CH2)k-S-S-(CH2)k-, -(CH2)k-S-S-(CH2)k-S-S-(CH2)k-O-(CH2)k-, -(CH2)k-S-S-(CH2)k- O-(CH2)k-S-S-(CH2)k-, -(CH2)k-O-(CH2)k-S-S-(CH2)k-S-S-(CH2)k-, -(CH2)k-S-S-(CH2)k-S-S- (CH2)k-S-S-(CH2)k-, -(CH2)k-S-S-(CH2)k-O-(CH2)k-O-(CH2)k-O-(CH2)k-, -(CH2)k-O-(CH2)k-S-S- (CH2)k-O-(CH2)k-O-(CH2)k-, -(CH2)k-O-(CH2)k-O-(CH2)k-S-S-(CH2)k-O-(CH2)k-, -(CH2)k-S-S- (CH2)k-O-(CH2)k-O-(CH2)k-O-(CH2)k-O-(CH2)k-, -(CH2)k-S-S-(CH2)k-O-(CH2)k-O-(CH2)k-O- (CH2)k-O-(CH2)k-O-(CH2)k-, -(CH2)k-OC(=O)-(CH2)k-, -(CH2)k-C(=O)O-(CH2)k-, -(CH2)k- NHC(=O)-(CH2)k-, -(CH2)k-C(=O)NH-(CH2)k-, -(CH2)k-OC(=O)-(CH2)k-O-(CH2)k-, -(CH2)k- C(=O)O-(CH2)k-O-(CH2)k-, -(CH2)k-NHC(=O)-(CH2)k-O-(CH2)k-, -(CH2)k-C(=O)NH-(CH2)k-O- (CH2)k-, -(CH2)k-O-(CH2)k-OC(=O)-(CH2)k-, -(CH2)k-O-(CH2)k-C(=O)O-(CH2)k-, -(CH2)k-O- (CH2)k-NHC(=O)-(CH2)k-, -(CH2)k-O-(CH2)k-C(=O)NH-(CH2)k-, -(CH2)k-O-(CH2)k-OC(=O)- (CH2)k-O-(CH2)k-, -(CH2)k-O-(CH2)k-C(=O)O-(CH2)k-O-(CH2)k-, -(CH2)k-O-(CH2)k-NHC(=O)- (CH2)k-O-(CH2)k-, -(CH2)k-O-(CH2)k-C(=O)NH-(CH2)k-O-(CH2)k-, -(CH2)k-O-(CH2)k-O-(CH2)k- OC(=O)-(CH2)k-, -(CH2)k-O-(CH2)k-O-(CH2)k-C(=O)O-(CH2)k-, -(CH2)k-O-(CH2)k-O-(CH2)k-NHC(=O)-(CH2)k-, -(CH2)k-O-(CH2)k-O-(CH2)k-C(=O)NH-(CH2)k-, -(CH2)k-OC(=O)-(CH2)k-O- (CH2)k-O-(CH2)k-, -(CH2)k-C(=O)O-(CH2)k-O-(CH2)k-O-(CH2)k-, -(CH2)k-NHC(=O)-(CH2)k-O- (CH2)k-O-(CH2)k-, -(CH2)k-C(=O)NH-(CH2)k-O-(CH2)k-O-(CH2)k-, -(CH2)k-O-(CH2)k-OC(=O)- (CH2)k-OC(=O)-(CH2)k-, -(CH2)k-O-(CH2)k-C(=O)O-(CH2)k-OC(=O)-(CH2)k-, -(CH2)k-O- (CH2)k-C(=O)O-(CH2)k-C(=O)O-(CH2)k-, -(CH2)k-O-(CH2)k-OC(=O)-(CH2)k-C(=O)O-(CH2)k-, - (CH2)k-OC(=O)-(CH2)k-OC(=O)-(CH2)k-O-(CH2)k-, -(CH2)k-C(=O)O-(CH2)k-OC(=O)-(CH2)k- O-(CH2)k-, -(CH2)k-C(=O)O-(CH2)k-C(=O)O-(CH2)k-O-(CH2)k-, -(CH2)k-OC(=O)-(CH2)k- C(=O)O-(CH2)k-O-(CH2)k-, -(CH2)k-OC(=O)-(CH2)k-O-(CH2)k-OC(=O)-(CH2)k-, -(CH2)k- C(=O)O-(CH2)k-O-(CH2)k-OC(=O)-(CH2)k-, -(CH2)k-C(=O)O-(CH2)k-O-(CH2)k-C(=O)O- (CH2)k-, -(CH2)k-OC(=O)-(CH2)k-O-(CH2)k-C(=O)O-(CH2)k-, -(CH2)k-O-(CH2)k-OC(=O)- (CH2)k-OC(=O)-(CH2)k-O-(CH2)k-, -(CH2)k-O-(CH2)k-C(=O)O-(CH2)k-OC(=O)-(CH2)k-O- (CH2)k-, -(CH2)k-O-(CH2)k-C(=O)O-(CH2)k-C(=O)O-(CH2)k-O-(CH2)k-, -(CH2)k-O-(CH2)k- OC(=O)-(CH2)k-C(=O)O-(CH2)k-O-(CH2)k-, -(CH2)k-OC(=O)-(CH2)k-NHC(=O)-(CH2)k-, - (CH2)k-OC(=O)-(CH2)k-C(=O)NH-(CH2)k-, -(CH2)k-C(=O)O-(CH2)k-NHC(=O)-(CH2)k-, - (CH2)k-C(=O)O-(CH2)k-C(=O)NH-(CH2)k-, -(CH2)k-NHC(=O)-(CH2)k-OC(=O)-(CH2)k-, - (CH2)k-C(=O)NH-(CH2)k-OC(=O)-(CH2)k-, -(CH2)k-C(=O)NH-(CH2)k-C(=O)O-(CH2)k-, - (CH2)k-NHC(=O)-(CH2)k-C(=O)O-(CH2)k-, -(CH2)k-NHC(=O)-(CH2)k-NHC(=O)-(CH2)k-, - (CH2)k-C(=O)NH-(CH2)k-C(=O)NH-(CH2)k-, -(CH2)k-C(=O)NH-(CH2)k-NHC(=O)-(CH2)k-, - (CH2)k-NHC(=O)-(CH2)k-C(=O)NH-(CH2)k-, -(CH2)k-OC(=O)-(CH2)k-OC(=O)-(CH2)k-, - (CH2)k-C(=O)O-(CH2)k-OC(=O)-(CH2)k-, -(CH2)k-C(=O)O-(CH2)k-C(=O)O-(CH2)k-, -(CH2)k- OC(=O)-(CH2)k-C(=O)O-(CH2)k-, -(CH2)k-OC(=O)-(CH2)k-NHC(=O)-(CH2)k-, -(CH2)k- OC(=O)-(CH2)k-C(=O)NH-(CH2)k-, -(CH2)k-C(=O)O-(CH2)k-NHC(=O)-(CH2)k-, -(CH2)k- C(=O)O-(CH2)k-C(=O)NH-(CH2)k-, -(CH2)k-NHC(=O)-(CH2)k-OC(=O)-(CH2)k-, -(CH2)k- C(=O)NH-(CH2)k-OC(=O)-(CH2)k-, -(CH2)k-C(=O)NH-(CH2)k-C(=O)O-(CH2)k-, -(CH2)k- NHC(=O)-(CH2)k-C(=O)O-(CH2)k-, -(CH2)k-NHC(=O)-(CH2)k-NHC(=O)-(CH2)k-, -(CH2)k- C(=O)NH-(CH2)k-C(=O)NH-(CH2)k-, -(CH2)k-C(=O)NH-(CH2)k-NHC(=O)-(CH2)k- and - (CH2)k-NHC(=O)-(CH2)k-C(=O)NH-(CH2)k-, wherein k is an integer in the range of 1 to 10.

[0082] In some aspects, in Formula I, Y2may be selected from the group consisting of C1-C20alkylene chains, C2-C20alkenylene chains, C2-C20alkynylene chains, -(CH2)k-O-(CH2)k-, - (CH2)k-O-(CH2)k-O-(CH2)k-, -(CH2)k-O-(CH2)k-O-(CH2)k-O-(CH2)k-, -(CH2)k-O-(CH2)k-O- (CH2)k-O-(CH2)k-O-(CH2)k-, -(CH2)k-O-(CH2)k-O-(CH2)k-O-(CH2)k-O-(CH2)k-O-(CH2)k-, -(CH2)k-O-(CH2)k-O-(CH2)k-O-(CH2)k-O-(CH2)k-O-(CH2)k-O-(CH2)k-, -(CH2)k-S-S-(CH2)k-, -(CH2)k-S-S-(CH2)k-O-(CH2)k-, -(CH2)k-O-(CH2)k-S-S-(CH2)k-, -(CH2)k-S-S-(CH2)k-S-S-(CH2)k-, -(CH2)k-S-S-(CH2)k-O-(CH2)k-O-(CH2)k-, -(CH2)k-O-(CH2)k-S-S-(CH2)k-O-(CH2)k-, -(CH2)k-O-(CH2)k-O-(CH2)k-S-S-(CH2)k-, -(CH2)k-S-S-(CH2)k-S-S-(CH2)k-O-(CH2)k-, -(CH2)k-S-S-(CH2)k-O-(CH2)k-S-S-(CH2)k-, -(CH2)k-O-(CH2)k-S-S-(CH2)k-S-S-(CH2)k-, -(CH2)k-S-S-(CH2)k-S-S-(CH2)k-S-S-(CH2)k-, -(CH2)k-S-S-(CH2)k-O-(CH2)k-O-(CH2)k-O-(CH2)k-, -(CH2)k-O-(CH2)k-S-S-(CH2)k-O-(CH2)k-O-(CH2)k-, -(CH2)k-O-(CH2)k-O-(CH2)k-S-S-(CH2)k-O-(CH2)k-, -(CH2)k-S-S-(CH2)k-O-(CH2)k-O-(CH2)k-O-(CH2)k-O-(CH2)k-, -(CH2)k-S-S-(CH2)k-O-(CH2)k-O-(CH2)k-O-(CH2)k-O-(CH2)k-O-(CH2)k-, -(CH2)k-OC(=O)-(CH2)k-, -(CH2)k-C(=O)O-(CH2)k-, -(CH2)k-NHC(=O)-(CH2)k-, -(CH2)k-C(=O)NH-(CH2)k-, -(CH2)k-OC(=O)-(CH2)k-O-(CH2)k-, -(CH2)k-C(=O)O-(CH2)k-O-(CH2)k-, -(CH2)k-NHC(=O)-(CH2)k-O-(CH2)k-, -(CH2)k-C(=O)NH-(CH2)k-O-(CH2)k-, -(CH2)k-O-(CH2)k-OC(=O)-(CH2)k-, -(CH2)k-O-(CH2)k-C(=O)O-(CH2)k-, -(CH2)k-O-(CH2)k-NHC(=O)-(CH2)k-, -(CH2)k-O-(CH2)k-C(=O)NH-(CH2)k-, -(CH2)k-O-(CH2)k-OC(=O)-(CH2)k-O-(CH2)k-, -(CH2)k-O-(CH2)k-C(=O)O-(CH2)k-O-(CH2)k-, -(CH2)k-O-(CH2)k-NHC(=O)-(CH2)k-O-(CH2)k-, -(CH2)k-O-(CH2)k-C(=O)NH-(CH2)k-O-(CH2)k-, -(CH2)k-O-(CH2)k-O-(CH2)k-OC(=O)-(CH2)k-, -(CH2)k-O-(CH2)k-O-(CH2)k-C(=O)O-(CH2)k-, -(CH2)k-O-(CH2)k-O-(CH2)k-NHC(=O)-(CH2)k-, -(CH2)k-O-(CH2)k-O-(CH2)k-C(=O)NH-(CH2)k-, -(CH2)k-OC(=O)-(CH2)k-O-(CH2)k-O-(CH2)k-, -(CH2)k-C(=O)O-(CH2)k-O-(CH2)k-O-(CH2)k-, -(CH2)k-NHC(=O)-(CH2)k-O-(CH2)k-O-(CH2)k-, -(CH2)k-C(=O)NH-(CH2)k-O-(CH2)k-O-(CH2)k-, -(CH2)k-O-(CH2)k-OC(=O)-(CH2)k-OC(=O)-(CH2)k-, -(CH2)k-O-(CH2)k-C(=O)O-(CH2)k-OC(=O)-(CH2)k-, -(CH2)k-O-(CH2)k-C(=O)O-(CH2)k-C(=O)O-(CH2)k-, -(CH2)k-O-(CH2)k-OC(=O)-(CH2)k-C(=O)O-(CH2)k-, -(CH2)k-OC(=O)-(CH2)k-OC(=O)-(CH2)k-O-(CH2)k-, -(CH2)k-C(=O)O-(CH2)k-OC(=O)-(CH2)k-O-(CH2)k-, -(CH2)k-C(=O)O-(CH2)k-C(=O)O-(CH2)k-O-(CH2)k-, -(CH2)k-OC(=O)-(CH2)k-C(=O)O-(CH2)k-O-(CH2)k-, -(CH2)k-OC(=O)-(CH2)k-O-(CH2)k-OC(=O)-(CH2)k-, -(CH2)k-C(=O)O-(CH2)k-O-(CH2)k-OC(=O)-(CH2)k-, -(CH2)k-C(=O)O-(CH2)k-O-(CH2)k-C(=O)O-(CH2)k-, -(CH2)k-OC(=O)-(CH2)k-O-(CH2)k-C(=O)O-(CH2)k-, -(CH2)k-O-(CH2)k-OC(=O)-(CH2)k-OC(=O)-(CH2)k-O-(CH2)k-, -(CH2)k-O-(CH2)k-C(=O)O-(CH2)k-OC(=O)-(CH2)k-O-(CH2)k-, -(CH2)k-O-(CH2)k-C(=O)O-(CH2)k-C(=O)O-(CH2)k-O-(CH2)k-, -(CH2)k-O-(CH2)k-OC(=O)-(CH2)k-C(=O)O-(CH2)k-O-(CH2)k-, -(CH2)k-OC(=O)-(CH2)k-NHC(=O)-(CH2)k-, -(CH2)k-OC(=O)-(CH2)k-C(=O)NH-(CH2)k-, -(CH2)k-C(=O)O-(CH2)k-NHC(=O)-(CH2)k-, -(CH2)k-C(=O)O-(CH2)k-C(=O)NH-(CH2)k-, -(CH2)k-NHC(=O)-(CH2)k-OC(=O)-(CH2)k-, -(CH2)k-C(=O)NH-(CH2)k-OC(=O)-(CH2)k-, -(CH2)k-C(=O)NH-(CH2)k-C(=O)O-(CH2)k-, - (CH2)k-NHC(=O)-(CH2)k-C(=O)O-(CH2)k-, -(CH2)k-NHC(=O)-(CH2)k-NHC(=O)-(CH2)k-, - (CH2)k-C(=O)NH-(CH2)k-C(=O)NH-(CH2)k-, -(CH2)k-C(=O)NH-(CH2)k-NHC(=O)-(CH2)k-, - (CH2)k-NHC(=O)-(CH2)k-C(=O)NH-(CH2)k-, -(CH2)k-OC(=O)-(CH2)k-OC(=O)-(CH2)k-, - (CH2)k-C(=O)O-(CH2)k-OC(=O)-(CH2)k-, -(CH2)k-C(=O)O-(CH2)k-C(=O)O-(CH2)k-, -(CH2)k- OC(=O)-(CH2)k-C(=O)O-(CH2)k-, -(CH2)k-OC(=O)-(CH2)k-NHC(=O)-(CH2)k-, -(CH2)k- OC(=O)-(CH2)k-C(=O)NH-(CH2)k-, -(CH2)k-C(=O)O-(CH2)k-NHC(=O)-(CH2)k-, -(CH2)k- C(=O)O-(CH2)k-C(=O)NH-(CH2)k-, -(CH2)k-NHC(=O)-(CH2)k-OC(=O)-(CH2)k-, -(CH2)k- C(=O)NH-(CH2)k-OC(=O)-(CH2)k-, -(CH2)k-C(=O)NH-(CH2)k-C(=O)O-(CH2)k-, -(CH2)k- NHC(=O)-(CH2)k-C(=O)O-(CH2)k-, -(CH2)k-NHC(=O)-(CH2)k-NHC(=O)-(CH2)k-, -(CH2)k- C(=O)NH-(CH2)k-C(=O)NH-(CH2)k-, -(CH2)k-C(=O)NH-(CH2)k-NHC(=O)-(CH2)k- and - (CH2)k-NHC(=O)-(CH2)k-C(=O)NH-(CH2)k-, wherein k is an integer in the range of 1 to 10.

[0083] In some aspects, in Formula I, T2may be selected from the group consisting of C1-C20alkylene chains, C2-C20alkenylene chains, C2-C20alkynylene chains, -(CH2)k-O-(CH2)k-, - (CH2)k-O-(CH2)k-O-(CH2)k-, -(CH2)k-O-(CH2)k-O-(CH2)k-O-(CH2)k-, -(CH2)k-O-(CH2)k-O- (CH2)k-O-(CH2)k-O-(CH2)k-, -(CH2)k-O-(CH2)k-O-(CH2)k-O-(CH2)k-O-(CH2)k-O-(CH2)k-, - (CH2)k-O-(CH2)k-O-(CH2)k-O-(CH2)k-O-(CH2)k-O-(CH2)k-O-(CH2)k-, -(CH2)k-S-S-(CH2)k-, - (CH2)k-S-S-(CH2)k-O-(CH2)k-, -(CH2)k-O-(CH2)k-S-S-(CH2)k-, -(CH2)k-S-S-(CH2)k-S-S-(CH2)k-, -(CH2)k-S-S-(CH2)k-O-(CH2)k-O-(CH2)k-, -(CH2)k-O-(CH2)k-S-S-(CH2)k-O-(CH2)k-, -(CH2)k-O- (CH2)k-O-(CH2)k-S-S-(CH2)k-, -(CH2)k-S-S-(CH2)k-S-S-(CH2)k-O-(CH2)k-, -(CH2)k-S-S-(CH2)k- O-(CH2)k-S-S-(CH2)k-, -(CH2)k-O-(CH2)k-S-S-(CH2)k-S-S-(CH2)k-, -(CH2)k-S-S-(CH2)k-S-S- (CH2)k-S-S-(CH2)k-, -(CH2)k-S-S-(CH2)k-O-(CH2)k-O-(CH2)k-O-(CH2)k-, -(CH2)k-O-(CH2)k-S-S- (CH2)k-O-(CH2)k-O-(CH2)k-, -(CH2)k-O-(CH2)k-O-(CH2)k-S-S-(CH2)k-O-(CH2)k-, -(CH2)k-S-S- (CH2)k-O-(CH2)k-O-(CH2)k-O-(CH2)k-O-(CH2)k-, -(CH2)k-S-S-(CH2)k-O-(CH2)k-O-(CH2)k-O- (CH2)k-O-(CH2)k-O-(CH2)k-, -(CH2)k-OC(=O)-(CH2)k-, -(CH2)k-C(=O)O-(CH2)k-, -(CH2)k- NHC(=O)-(CH2)k-, -(CH2)k-C(=O)NH-(CH2)k-, -(CH2)k-OC(=O)-(CH2)k-O-(CH2)k-, -(CH2)k- C(=O)O-(CH2)k-O-(CH2)k-, -(CH2)k-NHC(=O)-(CH2)k-O-(CH2)k-, -(CH2)k-C(=O)NH-(CH2)k-O- (CH2)k-, -(CH2)k-O-(CH2)k-OC(=O)-(CH2)k-, -(CH2)k-O-(CH2)k-C(=O)O-(CH2)k-, -(CH2)k-O- (CH2)k-NHC(=O)-(CH2)k-, -(CH2)k-O-(CH2)k-C(=O)NH-(CH2)k-, -(CH2)k-O-(CH2)k-OC(=O)- (CH2)k-O-(CH2)k-, -(CH2)k-O-(CH2)k-C(=O)O-(CH2)k-O-(CH2)k-, -(CH2)k-O-(CH2)k-NHC(=O)- (CH2)k-O-(CH2)k-, -(CH2)k-O-(CH2)k-C(=O)NH-(CH2)k-O-(CH2)k-, -(CH2)k-O-(CH2)k-O-(CH2)k-OC(=O)-(CH2)k-, -(CH2)k-O-(CH2)k-O-(CH2)k-C(=O)O-(CH2)k-, -(CH2)k-O-(CH2)k-O-(CH2)k- NHC(=O)-(CH2)k-, -(CH2)k-O-(CH2)k-O-(CH2)k-C(=O)NH-(CH2)k-, -(CH2)k-OC(=O)-(CH2)k-O- (CH2)k-O-(CH2)k-, -(CH2)k-C(=O)O-(CH2)k-O-(CH2)k-O-(CH2)k-, -(CH2)k-NHC(=O)-(CH2)k-O- (CH2)k-O-(CH2)k-, -(CH2)k-C(=O)NH-(CH2)k-O-(CH2)k-O-(CH2)k-, -(CH2)k-O-(CH2)k-OC(=O)- (CH2)k-OC(=O)-(CH2)k-, -(CH2)k-O-(CH2)k-C(=O)O-(CH2)k-OC(=O)-(CH2)k-, -(CH2)k-O- (CH2)k-C(=O)O-(CH2)k-C(=O)O-(CH2)k-, -(CH2)k-O-(CH2)k-OC(=O)-(CH2)k-C(=O)O-(CH2)k-, - (CH2)k-OC(=O)-(CH2)k-OC(=O)-(CH2)k-O-(CH2)k-, -(CH2)k-C(=O)O-(CH2)k-OC(=O)-(CH2)k- O-(CH2)k-, -(CH2)k-C(=O)O-(CH2)k-C(=O)O-(CH2)k-O-(CH2)k-, -(CH2)k-OC(=O)-(CH2)k- C(=O)O-(CH2)k-O-(CH2)k-, -(CH2)k-OC(=O)-(CH2)k-O-(CH2)k-OC(=O)-(CH2)k-, -(CH2)k- C(=O)O-(CH2)k-O-(CH2)k-OC(=O)-(CH2)k-, -(CH2)k-C(=O)O-(CH2)k-O-(CH2)k-C(=O)O- (CH2)k-, -(CH2)k-OC(=O)-(CH2)k-O-(CH2)k-C(=O)O-(CH2)k-, -(CH2)k-O-(CH2)k-OC(=O)- (CH2)k-OC(=O)-(CH2)k-O-(CH2)k-, -(CH2)k-O-(CH2)k-C(=O)O-(CH2)k-OC(=O)-(CH2)k-O- (CH2)k-, -(CH2)k-O-(CH2)k-C(=O)O-(CH2)k-C(=O)O-(CH2)k-O-(CH2)k-, -(CH2)k-O-(CH2)k- OC(=O)-(CH2)k-C(=O)O-(CH2)k-O-(CH2)k-, -(CH2)k-OC(=O)-(CH2)k-NHC(=O)-(CH2)k-, - (CH2)k-OC(=O)-(CH2)k-C(=O)NH-(CH2)k-, -(CH2)k-C(=O)O-(CH2)k-NHC(=O)-(CH2)k-, - (CH2)k-C(=O)O-(CH2)k-C(=O)NH-(CH2)k-, -(CH2)k-NHC(=O)-(CH2)k-OC(=O)-(CH2)k-, - (CH2)k-C(=O)NH-(CH2)k-OC(=O)-(CH2)k-, -(CH2)k-C(=O)NH-(CH2)k-C(=O)O-(CH2)k-, - (CH2)k-NHC(=O)-(CH2)k-C(=O)O-(CH2)k-, -(CH2)k-NHC(=O)-(CH2)k-NHC(=O)-(CH2)k-, - (CH2)k-C(=O)NH-(CH2)k-C(=O)NH-(CH2)k-, -(CH2)k-C(=O)NH-(CH2)k-NHC(=O)-(CH2)k-, - (CH2)k-NHC(=O)-(CH2)k-C(=O)NH-(CH2)k-, -(CH2)k-OC(=O)-(CH2)k-OC(=O)-(CH2)k-, - (CH2)k-C(=O)O-(CH2)k-OC(=O)-(CH2)k-, -(CH2)k-C(=O)O-(CH2)k-C(=O)O-(CH2)k-, -(CH2)k- OC(=O)-(CH2)k-C(=O)O-(CH2)k-, -(CH2)k-OC(=O)-(CH2)k-NHC(=O)-(CH2)k-, -(CH2)k- OC(=O)-(CH2)k-C(=O)NH-(CH2)k-, -(CH2)k-C(=O)O-(CH2)k-NHC(=O)-(CH2)k-, -(CH2)k- C(=O)O-(CH2)k-C(=O)NH-(CH2)k-, -(CH2)k-NHC(=O)-(CH2)k-OC(=O)-(CH2)k-, -(CH2)k- C(=O)NH-(CH2)k-OC(=O)-(CH2)k-, -(CH2)k-C(=O)NH-(CH2)k-C(=O)O-(CH2)k-, -(CH2)k- NHC(=O)-(CH2)k-C(=O)O-(CH2)k-, -(CH2)k-NHC(=O)-(CH2)k-NHC(=O)-(CH2)k-, -(CH2)k- C(=O)NH-(CH2)k-C(=O)NH-(CH2)k-, -(CH2)k-C(=O)NH-(CH2)k-NHC(=O)-(CH2)k- and - (CH2)k-NHC(=O)-(CH2)k-C(=O)NH-(CH2)k-, wherein k is an integer in the range of 1 to 10.

[0084] In some aspects, in Formula I, y may be an integer in the range of 5 to 200.

[0085] In some aspects, in Formula I, y may be an integer in the range of 5 to 150.

[0086] In some aspects, in Formula I, y may be an integer in the range of 5 to 100.

[0087] In some aspects, in Formula I, y may be an integer in the range of 5 to 70.

[0088] In some aspects, in Formula I, y may be an integer in the range of 5 to 50.

[0089] In some aspects, in Formula I, y may be an integer in the range of 7 to 125.

[0090] In some aspects, in Formula I, y may be an integer in the range of 7 to 100.

[0091] In some aspects, in Formula I, y may be an integer in the range of 7 to 70.

[0092] In some aspects, in Formula I, y may be an integer in the range of 7 to 50.

[0093] In some aspects, in Formula I, y may be an integer in the range of 10 to 100.

[0094] In some aspects, in Formula I, y may be an integer in the range of 15 to 70.

[0095] In some aspects, in Formula I, y may be an integer in the range of 17 to 50.

[0096] In some aspects, the compound of Formula I, Formula II, Formula III, Formula IV Formula 1 A, Formula A or Formula B is selected from the group consisting of the following compounds and their pharmaceutically acceptable salts or solvates thereof:(CH2)ZCH3(CH2)ZCH3(CH2)ZCH3OH0 0 s's0 0 N (CH,)ZCH,(CH2)ZCH30 0 A^(CH2)ZCH3s °Y^(CH2)ZCH30 OHN^(CH2)ZCH3SCH2)ZCH3OH H3CZ(H2C)^ H3CZ(H2C)^Nwherein n is an integer in the range of 2 to 200,z is an integer in the range of 10 to 16, if applicable andR5is selected from the group consisting of -H, -OH and -SH.

[0097] In some other aspects, the compound of Formula I, Formula II, Formula III, Formula IV, Formula 1A, Formula A or Formula B is selected from the group consisting of the following compounds and pharmaceutically acceptable salts or solvates thereof:OJk / lCH^nCHsHO °Y^(CH2)11CH3oOHo (C H 2) 13c H3 HOO^I^O^^(CH2)i3CH3 o OH OA^(CH2)15CH3HO °YX^(CH2)I5CH3O OHOA^(CH2)13CH3(CH2)12CH3(CH2)I2CH3 OHOH(CH2)16CH3(CH2)16CH3(CH2)12CH3wherein n is an integer in the range of 2 to 200.

[0098] In some other aspects, the compound of Formula I, Formula II, Formula III, Formula IV, Formula 1A, Formula A or Formula B is selected from the group consisting of the following compounds and pharmaceutically acceptable salts or solvates thereof:oOHOA^(CH2)13CH3”T t ]f°X^ / O^^(CH2)13CH3HN" X) ° ° OH(CH2)12CH3(CH2)14CH3N^(CH2)14CH3(CH2)16CH3(CH2)16CH3HO □ OH HO '3 OH5CH3OHoOA^(CH2)13CH3OHOH(CH2)12CH3(CH2)12CH3

[0099] In some other aspects, the compound of Formula I, Formula II, Formula III, Formula IV, Formula 1A, Formula A or Formula B is selected from the group consisting of the following compounds and pharmaceutically acceptable salts or solvates thereof:C)OA^(CH2)„CH3HN 00OJ1^4CH2)MCH3110~ J' ° [ '%(CH2)t1CH5HlAo "0'> OH0>3 HOoJV-lCH^aCHj HOJx-'0Y^CH^CH, o0J^4CH2hCH3HO °'|^(CH2)13CH30OA / (CH2J13CH3'1XX°YXCH2)13CHSX30HtC XiOO. A^(CH2)15CH3HO ^°YXCH,)WCH3HNo01HO - * -1‘(CHgJlgCHg HN" X>O QA^WMCHS ~. ■ °xA^° Y^(CH2hCH3‘; Jv 4 hN ' 0bOH0A^(CH2h3CH3‘64 HNXO^(CH2)„CH3N^(CHZ)12CH3OH^(CH2)„CH3HO N^(CH2)„CH3OHN^4CH2)„CH3^(CH2)12CH3N^'(CHzh2CH3OH(CH2)12CH3OHx(CH2)tCH3N^(CH2)iaCH3OHHO(CH2)«CH3HO(CH2)12CH3 HO (CHZ)12CH3(CH2)12CH3(CH2)14CH3HO-r (CH2)14CH3HN(CH2)16CH3N^CHghsCHs^(CHg^gCHj HO N«.KX(CH2)ISCH3OH6Hr4CH2)14CH3[ -k --"SXI-s-uGH Iz110Z0HNX^O0QI Ion.W‘ft+3)^2‘(0zHto€H HOW’T’HOro0AV4CH2)„CH3I"'! OlrfJ"'““'’* o Ii" on HN^O N^(CH2>I2CH3OH^(CH2)ieCH3HO N^(CH2hsCH3KY'U"|^(CH2)i5CH3O ° OHWCH30OA^,4CH2)13CH3HNC\ \ / YN ss • r f” T [••0■0rCH1 Jx. «5 I 1 * 0 HH^O ° °OH(CH2)12CH3NCN > ■N^(CH2)12CH3HN^OOH(CH2)12CH3N^(CH2)12CH3I OHHS^(CH2)i2CH3NX / (CH2)12CH3Oil

[0100] In some other aspects, the compound of Formula V is selected from the group consisting of the following compounds and pharmaceutically acceptable salts or solvates thereof:9HO WWo)^0oHOO(CH^-iCHaO^(CH2hiCH3(CH2>t1CH32 A^x(CH2)t3CH3(CH2I13CH300A^(GH2h3CH3k 30 HN^O0A^(CH2h3CM3C" IW,3CH3I X 13 S HN^O 0 A^tCH^wCHaf1 i V n i n S S "* " T ■ w *<*‘W CM °Y: ' " lrf " H s HN^O '0° S ^XS X’‘’—“X-V-'f"' 11L 9 s HN ^OX(CH2)12CH3^x(CHa}j2CH3OH^-(CH2)l2CH3N^x(CH2)tCH3(CHJ«CH3N^(CH2)tCH3( C H g ) 121 H 3X(CH2)12CH3: CH ■ OH^-(CH2)l2CH3N^x(CH^tCH3(CHJtCHs^x(CH2)i2CH3N.X(CH2)„CH3OHs ^(Cl-y^Clla i^x(CH2)tCH3-(CH2h2CH3(CH2)12CH3S ^(CH2)«CH3• ' S S I -‘i ■ N^(CH2)14CH3• ' ) '10 / HN '0 OHOH^(CH2)16CH3N.^(CH2)1SCH30OA^(CH2),3CH3X-'XX’O j3OI 30OA^(CH2)15CH3,s '^°Y^'1CH2)15CH3(CH2)«CH3(CH2)12CH3(CH2)14CH3(CH2)14CH3(CHJ1BCH3(CH2)WCH3HN0A^CH2>WCH3T lCH2)tgCH3OJo OHo’■:ci.I H3C(H2C)12XOH

[0101] In some aspects, the compound of any of the Formula I- V, Formula 1A, Formula A or Formula B described within this application is suitable for preparation of lipid nanoparticles.

[0102] In some aspects, the compounds of Formula I, Formula 1A or Formula A may not comprise atoms protonatable in aqueous solution in pH in the range of 2 to 7. Therefore, compounds of Formula I-V, Formula 1 A or Formula A may be electroneutral in said conditions.

[0103] In some aspects, some compounds of Formula I, Formula 1A or Formula A may be protonatable in aqueous solution in pH in the range of 2 to 7. In some aspects, compounds comprising pyridyl moiety may be protonatable. For example, following compounds may be protonatable:(CH2)ZCH3(CH2)ZCH3(CH2)ZCH3(CH2)ZCH3OH

[0104] When the compounds of the disclosure comprise one or more chiral centers, the compound of Formula I-V, Formula 1A or Formula A may comprise pure enantiomers or mixture of enantiomers, including the racemate.J\ / x3

[0105] In some aspects, Y3' may be replaced with a terminal group, wherein said terminal group may comprise X2, Y2, J2, T2and M2as defined above.J\ / x3y

[0106] In some aspects, Y3 / may be replaced with a terminal group, wherein said terminal 2^T\|2group may be MJJ\ / X

[0107] In some aspects, replacing Y3 / with a terminal group may reduce toxicity.

[0108] Definitions

[0109] As used herein, the term “alkyl” means a saturated hydrocarbon chain which may be linear, branched or cyclic or cycle containing, wherein said hydrocarbon chain comprises one or more carbon atoms (e.g., one, two, three, four, or more carbon atoms), and which is derived from an alkane by removal of one hydrogen atom. The notation “C1-C14 alkyl” means a linear or branched or cyclic or cycle containing, saturated hydrocarbon chain including 1-14 carbon atoms. In some aspects, “C1-C14 alkyl” means a linear or branched, saturated hydrocarbon chain including 1-14 carbon atoms. Preferably, the “alkyl” means linear or branched hydrocarbon chain. More preferably, the “alkyl” means linear hydrocarbon chain.

[0110] As used herein, the term “alkenyl” means a hydrocarbon chain comprising at least one double bond between carbon atoms, and which is derived from an alkene by removal of one hydrogen atom. The hydrocarbon chain may be linear, branched or cyclic or cycle-containing. The hydrocarbon chain comprises two or more carbon atoms (e.g. two, three, four or more). The notation “C2-C14 alkenyl” means linear or branched or cyclic or cycle containing hydrocarbon chain including 2-14 carbon atoms and at least one double bond between two carbons. An alkenyl may comprise one, two or more carbon-carbon double bonds. In some aspects, “C2-C14 alkenyl” means linear or branched hydrocarbon chain including 2-14 carbon atoms and at least one double bond between two carbons.[Hl] As used herein, the term “alkynyl” means a hydrocarbon chain comprising at least one triple bond between carbon atoms, and which is derived from an alkyne by removal of one hydrogen atom. The hydrocarbon chain may be linear, branched or cyclic or cycle-containing. The hydrocarbon chain comprises two or more carbon atoms (e.g. two, three, four or more). The notation “C2-C14 alkynyl” means linear or branched or cyclic or cycle comprising hydrocarbon chain including 2-14 carbon atoms and at least one triple bond between two carbons. An alkynyl group may comprise one, two or more carbon-carbon triple bonds. In some aspects, “C2-C14 alkynyl” means linear or branched hydrocarbon chain including 2-14 carbon atoms and at least one triple bond between two carbons.

[0112] As used herein, the term “alkylene chain” means a saturated hydrocarbon chain, which may be linear, branched or cyclic or saturated cycle-containing. The alkylene chain has two valencies, i.e. it is derived from an alkane by removal of two hydrogen atoms from different carbon atoms, binds as a bridge via two bonds.

[0113] As used herein, the term “alkenylene chain” means a hydrocarbon chain comprising a double bond. The alkenylene chain may be linear, branched, cyclic or cycle-containing comprising the double bond. The alkenylene chain has two valencies, i.e. it binds as a bridge via two bonds.

[0114] As used herein, the term “alkynylene chain” means a hydrocarbon chain comprising a triple bond. The alkynylene chain may be linear, branched or cyclic or cycle- containing comprising the triple bond. The alkynylene chain has two valencies, i.e. it binds as a bridge via two bonds. The alkynylene chain comprises one or more -CH2- groups on each of its ends.

[0115] As used herein, the term “arylene comprising chain” means an aryl cycle with two substituents, wherein each substituent binds as a bridge via a bond.

[0116] As used herein, the term “compound” is meant to comprise all isomers and isotopes of the depicted structures of the disclosure.

[0117] As used herein, the term “contacting” means establishing a physical connection between two or more entities. For example, contacting a cell with a lipid nanoparticle composition and / or LNP means that the cell and the lipid nanoparticle composition and / or LNP are made to share a physical connection. Methods of contacting cells with external entities both in vivo and ex vivo are well known in the biological arts. For example, contacting the lipid composition or LNP and a mammalian cell disposed within a mammal may be performed by varied routes of administration (e.g., intravenous, intramuscular, intradermal, and subcutaneous) and may involve varied amounts of lipid composition and / or lipid nanoparticles (e.g., payload-free LNPs or loaded LNPs). Moreover, more than one cell may be contacted by the composition or LNP.

[0118] As used herein, “encapsulation efficiency" of a payload describes the amount of the pay load that is encapsulated or otherwise associated with a LNP after preparation, relative to the initial amount provided.

[0119] As used herein, “encapsulation”, “encapsulated”, “loaded”, and “associated” refers to complete, substantial, or partial enclosure, confinement, surrounding, or encasement. As used herein, “encapsulation” or “association” may refer to the process of confining an individual nucleic acid molecule within a nanoparticle and / or establishing a physicochemical relationship between an individual nucleic acid molecule and a nanoparticle.

[0120] As used herein, the term “ex vivo” refers to events that occur outside of an organism (e.g., animal, plant, or microbe or cell or tissue thereof). Ex vivo events may take place in an environment minimally altered from a natural (e.g., in vivo) environment.

[0121] As used used herein, the term “in vitro” refers to events that occur in an artificial environment, e.g., in a test tube or reaction vessel, in cell culture, in a Petri dish, etc., rather than within an organism (e.g., animal, plant, or microbe).

[0122] As used herein, the term “in vivo” refers to events that occur within an organism (e.g., animal, plant, or microbe or cell or tissue thereof).

[0123] As used herein, a “ionizable compound” refers to a chemical substance that can gain or lose protons under specific pH conditions, resulting in the formation of positively or negatively charged ions.

[0124] As used herein, the term “isomer” means any geometric isomer, tautomer, zwitterion, stereoisomer, enantiomer, or diastereomer of a compound.

[0125] As used herein, the term “linker” refers to a part of the molecule, which connects the polymerized portion to the lipidic portion

[0126] As used herein, the term “lipidic portion” refers to a portion, which consists of alkyl, alkenyl or alkynyl consisting of at least 10 carbon atoms, wherein in said alkyl, alkenyl or alkynyl one carbon atom may be replaced with -O-.

[0127] As used herein, a “lipid nanoparticle” refers to a particle formed from lipid composition e.g.by use of a microfluidic device. The nanoparticles may comprise loaded lipid nanoparticles or empty nanoparticles

[0128] As used herein, the “N: P ratio” is the molar ratio of ionizable (in the physiological pH range) nitrogen atoms in a lipid nanoparticle composition to phosphate groups in an RNA, e.g., in a lipid nanoparticle composition including an ionizable compound and an RNA.

[0129] As used herein, the term “nucleic acid” refers to ribonucleic acid (RNA), deoxyribonucleic acid (DNA), antisense oligonucleotides or peptide nucleic acid (PNA) that may be naturally or non-naturally occurring. DNA may be single-stranded DNA, double-stranded DNA, cDNA, plasmid DNA encoding a gene or genes. RNA may be messenger RNA (mRNA), transfer RNA (tRNA), small interfering RNA (siRNA), double-stranded RNA, circular RNA (circRNA), selfreplicating RNA, micro-RNA (miRNA), piwi-RNA (piRNA), antisense RNA (asRNA), guide RNA (gRNA) for the CRISPR system and their combinations (typically e.g. gRNA and mRNA encoding Cas9 nuclease, Casl3a / C2c2 and Casl3b, or analogous nucleases, suitable for use in CRISPR, CRISPRi and other variations and subsequent modification of the host cell or tissue genome or modification of the host cell or tissue transcriptome). The nucleic acid may comprise one or more modified and / or non-naturally occurring parts such as nucleobases, nucleosides and / or nucleotides. Such modifications may comprise phosphorylation at the 5' and / or 3' end of the strand,5-methylcytidine-5'-triphosphate, N1-methylpseudouridine-5'-triphosphate,P1-(5'-(3'-O-methyl)-7-methyl-guanosyl)-P3-(5'-(guanosyl))triphosphate, P1-(guanosyl)3-(5'-(guanosyl))tri -phosphate, P1-(5'-7-methyl-guanosyl)P3-(5'-(guanosyl))triphosphate, P1-(5'-2,2,7-trimethyl-guanosyl)P3-(5'-(guanosyl))triphosphate,N6-methyladenosine-5'-triphosphate, 2-thiouridine-5'-triphosphate,pseudo uridine-5 '-triphosphate, 5-methoxyuridine-5'-triphosphate,N1-methyladenosine-5'-triphosphate, N4-acetylcytidine-5'-triphosphate,2'-O-methyl, 2'-O-methoxy ethyl, 2'-fluoro, a methylene bridge between the 2'-oxygen and the 4'-carbon of the pentose ring (a so-called locked nucleic acid), boranophosphonates, or phosphorothioates.

[0130] As used herein term “payload” refers to any compound that, when administered to a subject, has a therapeutic, diagnostic, and / or prophylactic effect and / or elicits a desired biological and / or pharmacological effect. The payload is therapeutic agent, diagnostic agent and / or prophylactic agent. The payload may comprise naturally or non-naturally occurring compounds. Suchcompounds comprise, but are not limited to, antibody, cytotoxins, radioactive ions, chemotherapeutic agents, small molecule drugs, prodrugs, proteins, nucleotides, nucleosides, cyclic dinucleotides and nucleic acids.

[0131] As used herein, “pharmaceutically acceptable salts” refers to derivatives of the compounds wherein the compound is derived by converting its acid or base moiety to its salt form, e.g., by reacting a free base group with a suitable organic or inorganic acid. Representative acid salts comprise acetate, adipate, alginate, ascorbate, aspartate, benzenesuphonate, benzoate, besylate, bicarbonate, bitartrate, bisulphate, borate, bromide, butyrate, camsylate, carbonate, chloride, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, decanoate, digluconate, dodecylsulfate, edeate, esylate, ethanesulfonate, fumarate, gluceptate, glucoheptonate, gluconate, glutamate, glycerophosphate, glycolate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, iodide, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, mesylate, methansulphate, 2-naphthalenesulfonate, napsylate, nicotinate, nitrate, octanoate, oleate, oxalate, palmitate, palmoate, panthotenate, pectinate, persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, polygalacturonate, propionate, salicylate, stearate, succinate, sulphate, tartrate, thiocyanate, tosylate, toluenesulfonate, undecanoate, valerate salts, and the like. Other representative salts comprise sodium, lithium, potassium, calcium, magnesium. Yet other representative salts comprise salts including nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethyl ammonium, tetraethylammonium, methylammonium, dimethylammonium, trimethylammonium, triethylammonium, ethyl ammonium, and the like. The pharmaceutically acceptable salts of the present disclosure comprise the conventional non-toxic salts of the disclosed compound formed, for example, from non-toxic inorganic or organic acids.

[0132] As used herein, the “polydispersity index” or “PDi” is a ratio that describes the homogeneity of the particle size distribution of a system. A small value, e.g., less than 0.3, indicates a narrow particle size distribution.

[0133] As used herein, the term “polymerized portion” refers to the portion of a polymer that is formed by the polymerization of monomeric units

[0134] As used herein, the term “protein” refers to a chain of amino acid residues that may be naturally or non-naturally occurring.

[0135] As used herein, the term “mean size” in the context of lipid nanoparticles (e.g., payload-LNPs or loaded LNPs) refers to the mean diameter of a lipid nanoparticle composition.

[0136] As used herein, “sterol” refers to a compound comprising sterol core and is selected from group comprising cholesterol, β-sitosterol, stigmastanol, campesterol, fucosterol, avenasterol, fecosterol, brassicasterol, ergosterol, 7 -hydroxy cholesterol, coprostanol and 9,11- dehy droergo sterol.

[0137] As used herein, “structural lipid” refers to neutral, cationic and anionic lipids. Structural lipid is selected from group comprising: l,2-dioleoyl-sn-glycero-3 -phosphoethanolamine (DOPE), l-stearoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (SOPE), l-palmitoyl-2-oleoyl- sn-glycero-3 -phosphoethanolamine (POPE), l,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1.2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1, 2-dipalmitoyl-sn-gly cero-3 - phosphocholine (DPPC), l,2-dimyristoyl-sn-glycero-3 -phosphocholine (DMPC), and 1,2- dioleoyl-sn-glycero-3- phosphoethanolamine-N-(Cyanine 5), l,2-dioleoyl-3- dimethylammonium-propane (DODAP), l,2-dioleoyl-3-trimethylammonium-propane (DOTAP), 1.2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC), l,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-diundecanoyl-sn-glycero-phosphocholine (DUPC), l-palmitoyl-2-oleoyl-sn- glycero-3-phosphocholine (POPC), l,2-di-O-octadecenyl-sn-glycero-3-phosphocholine (18:0 di ether PC), l-oleoyl-2-cholesterylhemisuccinoyl-sn-glycero-3 -phosphocholine (OChemsPC), 1- hexadecyl-sn-glycero-3 -phosphocholine (CI 6 Lyso PC), 1,2-dilinolenoyl-sn-gly cero-3 - phosphocholine, 1,2-diarachidonoyl-sn-gly cero-3 -phosphocholine, 1, 2- di docosah exaenoyl-sn- glycero-3-phosphocholine, l,2-diphytanoyl-sn-glycero-3-phosphoethanolamine (ME 16.0 PE), 1.2-distearoyl-sn-glycero-3-phosphoethanolamine, 1,2-dilinoleoyl-sn-gly cero-3 - phosphoethanolamine, l,2-dilinolenoyl-sn-glycero-3 -phosphoethanolamine, 1,2-diarachidonoyl- sn-gly cero-3 -phosphoethanolamine, l,2-didocosahexaenoyl-sn-glycero-3-phosphoethanolamine, 1.2-dioleoyl-sn-gly cero-3 -phospho-rac-(l-glycerol) sodium salt (DOPG), diphytanoylphosphatidylcholine (DPhPC), dioleoyl-3 -trimethylammonium propane (DOAB), dierucoylphosphatidylcholine (DEPC), dilinoleoylphosphatidylcholine (DEPC) andsphingomyelin.

[0138] As used herein, “transfection” refers to the introduction of a payload (e.g., an RNA) into a cell. Transfection may occur, for example, in vitro, ex vivo, or in vivo.DETAILED DESCRIPTION

[0139] The present disclosure provides compounds that represent an important part of lipid nanoparticles. Lipid nanoparticles may be created by assembly, including self-assembly. Lipid nanoparticles may be engineered to be used as a vehicle, which may encapsulate a payload. Encapsulating therapeutic agents in LNPs ensures their stability and delivery into a specific site of action. In living systems lipid nanoparticles may be dispersed into the bloodstream and may circulate throughout and be taken up by cells. Once inside the cell, lipid nanoparticles may be trafficked through the endosomal pathway. The acidic environment within the endosome may trigger the release of the therapeutic agent from the LNPs. The lipid-polymer conjugates may play a crucial role in this process, as they can ensure the lipid nanoparticles stability.

[0140] The present disclosure refers to lipid-polymer conjugates. Lipid-polymer conjugates may act as stabilizing agents.

[0141] The present disclosure refers to compounds of Formula I, Formula II, Formula III, Formula IV, Formula V Formula 1 A, Formula A and Formula B.

[0142] Since compounds of Formula III and Formula IV are a subset of the compounds of Formula II, any aspect described in relation to Formula II may also apply to compounds of Formula III and compounds of Formula IV unless otherwise mentioned. Since compounds of Formula B are a subset of the compounds of Formula A, any aspects described in relation to Formula A may also apply to compounds of Formula B unless otherwise mentioned.

[0143] In some aspects, at least one compound of Formula I, Formula II, Formula V, Formula 1A or Formula A may have at least one same function in LNP as PEG-conjugated lipid. In some aspects, at least one compound of Formula I, Formula II, Formula 1 A or Formula A may avoid aggregation of lipid nanoparticles.

[0144] In some aspects, compound of Formula I or Formula II may be a lipid-polymer conjugate.

[0145] In some aspects, compound of Formula I or Formula II may comprise a polymerized portion and at least one lipidic portion.

[0146] In some aspects, compound of Formula I or Formula II may comprise a polymerized portion, a linker and at least one lipidic portion.

[0147] In some aspects, compound of Formula I or Formula II may comprise a polymerized portion, a linker and at least two lipidic portions.

[0148] In some aspects, compound of Formula I or Formula II may comprise a polymerized portion, at least one lipidic portion and a linker, wherein the at least one lipidic portion may be connected to the polymerized portion via a linker.

[0149] In some aspects, compound of Formula I or Formula II may comprise a polymerized portion, at least one lipidic portion, a linker and at least one other substituent.

[0150] In some aspects, compound of Formula I or Formula II may comprise a polymerized portion, at least one lipidic portion, a linker and at least one other substituent, wherein the substituent is covalently bound to the polymerized portion.

[0151] In some aspects, compound of Formula I or Formula II may comprise a polymerized portion, a linker, at least two lipidic portions and at least one other substituent, wherein the substituent is covalently bound to the polymerized portion.

[0152] In some aspects, compound of Formula I or Formula II may comprise a polymerized portion, a linker and at least one lipidic portions, wherein said polymerized portion and at least one lipidic portion may be connected to said linker.

[0153] In some aspects, compound of Formula I or Formula II may comprise a polymerized portion, a linker and at least two lipidic portions, wherein said polymerized portion and at least two lipidic portions may be connected to said linker.

[0154] In some aspects, the polymerized portion may comprise poly(N-(2-hydroxypropyl)methacrylamide) (HPMA).

[0155] In some aspects, lipid-polymer conjugates may comprise compounds of Formulas I-V.

[0156] The compounds of Formula I, Formula II, Formula III, Formula IV or Formula V may be obtained by reacting a chain transfer agent with a monomer.

[0157] In some aspects, the compounds of Formula I, Formula II, Formula III, Formula IV or Formula V may be obtained by reacting a chain transfer agent with a monomer, wherein the monomer may comprise N-(2-hydroxypropyl)methacrylamide.

[0158] In some aspects the lipidic portion may comprise C10-C20alkyl, C10-C20alkenyl or C10-C20alkynyl, wherein said C10-C20alkyl, C10-C20alkenyl or C10-C20alkynyl may be linear or branched and wherein said lipidic portion is covalently bound to a heteroatom (e.g. nitrogen, oxygen, phosphorus, sulphur).

[0159] In some aspects, the linker may comprise amide group or ester group.

[0160] The present disclosure also refers to compounds of Formula 1A, Formula A and Formula B.

[0161] Since compounds of Formula B are a subset of the compounds of Formula B, any aspect described in relation to Formula A may also apply to Formula B

[0162] In some aspects, compound of Formula 1A and / or Formula A may comprise a polymerized portion and at least two lipidic portions.

[0163] In some aspects, compound of Formula 1A and / or Formula A may comprise a polymerized portion, a linker and at least two lipidic portions.

[0164] In some aspects, compound of Formula 1A and / or Formula A may comprise a polymerized portion, at least two lipidic portions and a linker, wherein the at least two lipidic portions may be connected to the polymerized portion via a linker.

[0165] In some aspects, compound of Formula 1A and / or Formula A may comprise a polymerized portion, at least two lipidic portions, a linker and at least one other substituent comprising a terminal group.

[0166] In some aspects, compound of Formula 1A and / or Formula A may comprise a polymerized portion, at least two lipidic portions, a linker and at least one other substituent comprising a terminal group, wherein the substituent is covalently bound to the polymerized portion.

[0167] In some aspects, compound of Formula 1A and / or Formula A may comprise a polymerized portion, a linker and at least two lipidic portions, wherein said polymerized portion and at least two lipidic portion may be connected to said linker.

[0168] The present disclosure also refers to a composition.

[0169] In some aspects the composition refers to a lipid nanoparticle composition and / or lipid composition.

[0170] In some aspects, the lipid nanoparticle composition may comprise at least one compound of Formula I, Formula II, Formula 1 A or Formula A.

[0171] In some aspects, the lipid nanoparticle composition may comprise at least one ionizable compound and at least one compound of Formula I, Formula II, Formula 1 A or Formula A.

[0172] In some aspects, the lipid nanoparticle composition may comprise at least one structural lipid and at least one compound of Formula I, Formula II, Formula 1A or Formula A.

[0173] In some aspects, the lipid nanoparticle composition may comprise at least one ionizable compound, at least one structural lipid and at least one compound of Formula I, Formula II, Formula 1A or Formula A.

[0174] In some aspects, the lipid nanoparticle composition may comprise at least one lipid-polymer conjugate and at least one sterol, wherein the lipid-polymer conjugate is a compound comprising HPM A polymer.

[0175] In some aspects, the lipid nanoparticle composition may comprise at least one ionizable compound, at least one structural lipid, at least one sterol and at least one compound of Formula I, Formula II, Formula 1 A or Formula A.

[0176] In some other aspects, the lipid nanoparticle composition may comprise at least one ionizable compound, at least one structural lipid, at least one sterol and the compound of Formula I, Formula II, Formula 1 A or Formula A.

[0177] In some other aspects, the lipid nanoparticle composition may comprise at least one compound of Formula I, Formula II, Formula 1 A or Formula A and at least one nucleic acid.

[0178] In some other aspects, the lipid nanoparticle composition may comprise at least one compound of Formula I, Formula II, Formula 1A or Formula A and at least one nucleic acid and / or nucleic acid derivative.

[0179] In some other aspects, the lipid nanoparticle composition may comprise at least one compound of Formula I, Formula II, Formula 1 A or Formula A and at least one nucleic acid.

[0180] In some other aspects, the lipid nanoparticle composition may comprise at least one ionizable compound, at least one structural lipid, at least one sterol, at least one compound of Formula I, Formula II, Formula 1 A or Formula A and at least one nucleic acid.

[0181] In some aspects, the lipid nanoparticle composition may comprise at least one ionizable compound, DOPE, a sterol and at least one compound of Formula I, Formula II, Formula 1A or Formula A.

[0182] In some aspects, the lipid nanoparticle composition may comprise at least one ionizable compound, DOPE and / or DSPC, a sterol, at least one compound of Formula I, Formula II, Formula 1A or Formula A and combinations thereof.

[0183] In some aspects, the lipid nanoparticle composition may comprise at least one ionizable compound, at least one structural lipid, cholesterol and at least one compound of Formula I, Formula II, Formula 1A or Formula A.

[0184] In some aspects, the lipid nanoparticle composition may comprise at least one ionizable compound, at least one structural lipid, β-sitosterol and at least one compound of Formula I, Formula II, Formula 1A or Formula A.

[0185] In some aspects, the lipid nanoparticle composition may comprise at least one ionizable compound, at least one structural lipid, cholesterol, β-sitosterol and at least one compound of Formula I, Formula II, Formula 1 A or Formula A.

[0186] In some aspects, the lipid nanoparticle composition may comprise at least one ionizable compound, DOPE, β-sitosterol and at least one compound of Formula I, Formula II, Formula 1A or Formula A.

[0187] In some aspects, the lipid nanoparticle composition may comprise at least one ionizable compound, DSPC, β-sitosterol and at least one compound of Formula I, Formula II, Formula 1A or Formula A.

[0188] In some aspects, the lipid nanoparticle composition may comprise at least one ionizable compound, DOPE, DSPC, β-sitosterol and at least one compound of Formula I, Formula II, Formula 1A or Formula A.

[0189] In some aspects, the lipid nanoparticle composition may comprise at least one ionizable compound, at least one structural lipid, 7-hydroxycholesterol and at least one compound of Formula I, Formula II, Formula 1 A or Formula A.

[0190] In some aspects, the lipid nanoparticle composition may comprise at least one ionizable compound, at least one structural lipid, 7-hydroxycholesterol, cholesterol and at least one compound of Formula I, Formula II, Formula 1 A or Formula A.

[0191] In some aspects, the lipid nanoparticle composition may comprise at least one ionizable compound, DOPE and / or DSPC, 7-hydroxycholesterol and / or cholesterol and at least one compound of Formula I, Formula II, Formula 1 A or Formula A.

[0192] In some aspect, the lipid nanoparticle composition may comprise at least one ionizable compound and a lipid-polymer conjugate, wherein the lipid-polymer conjugate may be thecompound comprising HPMA polymer and wherein the lipid-polymer conjugate may comprise terminal group.

[0193] In some aspect, the lipid nanoparticle composition may comprise at least one ionizable compound and a lipid-polymer conjugate, wherein the lipid-polymer conjugate may be the compound comprising HPMA polymer, wherein the lipid-polymer conjugate may comprise terminal group and wherein the ionizable compound is selected form a group comprising: SM-102; N1,N3,N5,-Tris(5-(didodecylamino)pentyl)adamantane-1,3,5-tricarboxamide; N1,N3,N5,-Tris(6-(didodecylamino)hexyl)adamantane-1,3,5-tricarboxamide; MC-3; ALC-0159 and ALC-0315.

[0194] In some aspect, the lipid nanoparticle composition may comprise at least one ionizable compound and a lipid-polymer conjugate, wherein the lipid-polymer conjugate is the compound comprising HPMA polymer, and wherein the ionizable compound is selected form a group comprising: SM-102; N1,N3,N5-Tris(5-(didodecylamino)pentyl)adamantane-1,3,5-tricarboxamide; N1,N3,N5-Tris(6-(didodecylamino)hexyl)adamantane-1,3,5-tricarboxamide; MC-3; ALC-0159 and ALC-0315.

[0195] In some aspect, the lipid nanoparticle composition may comprise at least one ionizable compound and a lipid-polymer conjugate, wherein the lipid-polymer conjugate is a compound of Formula I, Formula II, Formula III, Formula IV, Formula 1 A or Formula A and wherein the ionizable compound is selected form a group comprising SM-102; N1, N3, N5,-Tris(5- (didodecylamino)pentyl)adamantane-l,3,5-tricarboxamide; N1, N3, N5,-Tris(6- (didodecylamino)hexyl)adamantane-l,3,5-tricarboxamide; MC-3; ALC-0159 and ALC-0315.

[0196] In some aspects, in the lipid nanoparticle composition ionizable compound may be in the range of 2.5 to 80 mol %, or in the range of 5 to 70 mol %, or in the range of 10 to 65 mol %, or in the range of 15 to 60 mol %, or in the range of 20 to 55 mol %, or in the range of 22 to 55 mol %, or in the range of 22 to 50 mol %, or in the range of 25 to 50 mol %, or in the range of 30 to 50 mol%, or in the range of 33 to 50 mol %.

[0197] In some aspects, in the lipid nanoparticle composition structural lipid may be in the range of 2.5 to 50 mol %, or in the range of 10 to 45 mol %, or in the range of 10 to 33 mol %, or in the range of 20 to 40 mol %, or in the range of 25 to 35 mol %, or in the range of 27 to 33 mol %.

[0198] In some aspects, in the lipid nanoparticle composition DOPE may be in the range of 2.5 to 80 mol % or 5 to 60 mol % or 5 to 50 mol % or 10 to 40 mol % or 10 to 30 mol % or 20 to 30 mol % or 10 to 15 mol %.

[0199] In some aspects, in the lipid nanoparticle composition DSPC may be in the range of 2.5 to 80 mol % or 5 to 60 mol % or 5 to 50 mol % or 10 to 40 mol % or 10 to 30 mol % or 20 to 30 mol % or 10 to 15 mol %.

[0200] In some aspects, in the lipid nanoparticle composition POPE may be in the range of 2.5 to 80 mol % or 5 to 60 mol % or 5 to 50 mol % or 10 to 40 mol % or 10 to 30 mol % or 20 to 30 mol % or 10 to 15 mol %.

[0201] In some aspects, in the lipid nanoparticle composition SOPE may be in the range of 2.5 to 80 mol % or 5 to 60 mol % or 5 to 50 mol % or 10 to 40 mol % or 10 to 30 mol % or 20 to 30 mol % or 10 to 15 mol %.

[0202] In some aspects, in the lipid nanoparticle composition sterol may be in the range of: 2.5 to 80 mol %, or in the range of 10 to 70 mol %, or in the range of 20 to 60 mol %, or in the range of 25 to 55 mol %, or in the range of 30 to 50 mol %, or in the range of 32 to 43.5 mol %, or in the range of 35 to 45 mol %, or in the range of 37 to 44 mol %, or in the range of 37.5 to 43.5 mol %

[0203] In some aspects, in the lipid nanoparticle composition cholesterol may be in the range of 2.5 to 80 mol % or 10 to 70 mol % or 20 to 60 mol % or 30 to 50 mol % or 35 to 45 mol %.

[0204] In some aspects, in the lipid nanoparticle composition β-sitosterol may be in the range of 2.5 to 80 mol % or 10 to 70 mol % or 20 to 60 mol % or 30 to 50 mol % or 35 to 45 mol %.

[0205] In some aspects, in the lipid nanoparticle composition 7-hydroxycholesterol may be in the range of 2.5 to 80 mol % or 10 to 70 mol % or 20 to 60 mol % or 30 to 50 mol % or 35 to 45 mol %.

[0206] In some aspects, in the lipid nanoparticle composition compound of Formula I, Formula II, Formula 1A or Formula A may be in the range of 0.001 to 80 mol %, or in the range of 0.005 to 40 mol %, or in the range of 0.01 to 30 mol %, or in the range of 0.1 to 20 mol %, or in the range of 0.5 to 15 mol %, or in the range of 1 to 10 mol %, or in the range of 1.2 to 10 mol %, or in therange of 1.5 to 10 mol %, or in the range of 1.5 to 8 mol %, or in the range of 1 to 5 mol% or in the range of 1.5 to 5 mol %.

[0207] The present disclosure also refers to a plurality of lipid nanoparticles, wherein each lipid nanoparticle comprises at least one lipid-poly(N-(2-hydroxypropyl)methacrylamide) conjugate according to Formula I, Formula II, Formula 1A, Formula A or Formula B.

[0208] The present disclosure also refers to a plurality of lipid nanoparticles, wherein each lipid nanoparticle comprises at least one ionizable compound, at least one structural lipid, at least one sterol and at least one lipid-poly mer conjugate.

[0209] The present disclosure also refers to a plurality of lipid nanoparticles, wherein each lipid nanoparticle comprises at least one ionizable compound, and at least one lipid-poly(N-(2-hydroxypropyl)methacrylamide) conjugate.

[0210] In some aspects, lipid nanoparticles may comprise a solid core. The solid core may be defined as a core which may lack any substantial aqueous content in its center.

[0211] In some aspects, lipid nanoparticles may not comprise liposomes.

[0212] Lipid nanoparticles may be characterized by a variety of methods. For example, NMR spectroscopy may be used to identify the molecular structure of a compound. Size exclusion chromatography may be used to determine the molecular weight of a lipid-polymer conjugate. Microscopy (e.g., transmission electron microscopy or scanning electron microscopy) may be used to examine the morphology and size distribution of a lipid nanoparticle. Dynamic light scattering or potentiometry (e.g., potentiometric titrations) may be used to measure zeta potentials. Dynamic light scattering may also be utilized to determine particle sizes. Instruments such as the Zetasizer Nano ZS (Malvern Instruments Ltd, Malvern, Worcestershire, UK) may also be used to measure multiple characteristics of a lipid nanoparticle, such as particle size, poly dispersity index, and zeta potential.

[0213] The mean size of the lipid nanoparticle, may be between tens of nm and hundreds of nm, as measured by e.g. dynamic light scattering (DLS). In some aspects the mean size of prepared LNPs may be in the range of 20 to 500 nm, or in the range of 25 to 300 nm, or in the range of 30 to 250nm, or in the range of 38 to 206 nm, or in the range of 40 to 200 nm, or in the range of 50 to 150 nm.

[0214] The lipid nanoparticle’s size distribution may be homogenous. A poly dispersity index may be used to indicate the homogeneity of lipid nanoparticles, e.g., the particle size distribution of the lipid nanoparticle. A small (e.g., less than 0.3) polydispersity index may generally indicate a narrow particle size distribution. Prepared lipid nanoparticles may have a polydispersity index in the range of 0.01 to 0.3, or in the range of 0.01 to 0.25, or in the range of 0.01 to 0.2, or in the range of 0.04 to 0.23, or in the range of 0.05 to 0.2, or in the range of 0.1 to 0.2.

[0215] The encapsulation efficiency may be desirably high (e.g. close to 100%). The encapsulation efficiency may be measured, for example, by comparing the amount of the payload in a solution comprising the LNP before and after breaking up the LNP with one or more organic solvents or detergents. Fluorescence may be used to measure the amount of free payload (e.g. RNA or DNA) in a solution. For the LNPs described herein, the encapsulation efficiency of the payload may be at least 40%, or at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%.

[0216] The lipid nanoparticle composition and / or LNPs of the present disclosure may be used in transfecting cells, tissues and / or organs with nucleic acid and / or any other therapeutic agent in vitro.

[0217] The lipid nanoparticle composition and / or LNPs of the present disclosure may also be used in transfecting cells and / or tissues and / or organs and / or any other part of living system with nucleic acid and / or any other therapeutic agent in vivo (excluding the transfection of human embryos for industrial or commercial use, and excluding the modification of human germ line). The lipid composition and / or LNPs may be administered to a living system by contacting the cell with the lipid composition and / or LNP, whereby the payload may be delivered to the cell.

[0218] The lipid nanoparticle composition and / or LNPs comprising lipid-polymer conjugates of the present disclosure may be used for therapeutic and / or prophylactic purposes in veterinary and human medicine. Said particles comprising nucleic acid and / or any other therapeutic agent may be administered to an animal and / or human to silence and / or activate chromosomal gene(s), to silence and / or activate immunogens, to inhibit and / or activate signaling pathways, to edit thegenome and / or the transcriptome and / or enable the expression of protein(s) encoded by the nucleic acid.

[0219] The lipid nanoparticle composition and / or LNPs comprising lipid-polymer conjugates of the present disclosure may also be used as medicaments for gene therapy. It may mean, that lipid nanoparticle composition and / or LNPs comprising lipid-polymer conjugates of the present disclosure may be used in the treatment of malignancies and / or genetic disorder (e.g. Duchenne Muscular dystrophy, Cystic Fibrosis, Hemophilia etc.) and / or infectious diseases (e.g. HIV, Hepatitis B etc.) and / or neurological disorders (e.g. Spinal Muscular Atrophy, Huntington’s Disease etc.) and / or eye diseases (e.g. Leber Congenital Amaurosis, wet age-related macular degeneration, retinitis pigmentosa etc.) and / or skin-related diseases (e.g. Epidermolysis Bullosa, Albinism, Psoriasis, Atopic Dermatisis, Diabetic Foot Ulcers, Netherton Syndrome).

[0220] Furthermore, the lipid nanoparticle composition and / or LNPs comprising lipid-polymer conjugates of the present disclosure may also be used for the purposes of the cosmetics industry in order to deliver the payload to a site of its action (for example, for wrinkle reduction, skin rejuvenation and / or to treat alopecia). The payload may comprise an active substance. The lipid composition and / or LNPs with payload may be prepared in the form of cream, gel, ointment, paste, balm, liquid or any other suitable form.

[0221] The lipid nanoparticle composition and / or LNPs may be formulated for therapeutic, cosmetic or biotechnological use in the form of preparations with pharmaceutically acceptable excipients. The formulations may be in liquid or solid form, or in other forms, such as an aerosol. Liquid forms may comprise solutions, suspensions, dispersions, adapted e.g. for injection or oral administration. Solid forms may comprise, for example, capsules, tablets, coated tablets, powders, suppositories, and other forms. The liquid formulations may be nebulized. Nebulized suspensions may be breathed in directly from the nebulizing device or the nebulizing device may be attached to a face mask tent, and / or intermittent positive pressure breathing machine. The solid dosage forms may also be administered via inhalation using dry -powder inhalers. Suspension and / or dry powder formulations may be administered orally or nasally from devices, which may deliver the pharmaceutical composition. In order to deliver the payload (e.g. including active substance) on the skin or mucous membranes, the lipid composition and / or LNPs may be also prepared in the form of a cream, gel, ointment, paste, balm, liquid. These topical forms may be applied directlyon the site of action or in the vicinity of the site of action. The site of action may comprise a skin, an internal organ, a blood vessel, a muscle, an adipose tissue, a dermis, a bone, a joint. Pharmaceutically acceptable excipients may comprise solvents, solubility control agents, pH adjusting agents, carriers, fillers, binders, glidants, disintegrants, preservatives, sorbents, viscosity control agents, agents that affect sensory properties such as taste, odor or the color of the formulation.

[0222] For clarity, it is noted that the terms "comprising", “including” and “containing” are intended to be identical and to be open and permits but does not require the inclusion of additional elements or steps. When the terms "comprising", “including” and “containing” is used herein, the terms "consisting essentially of’ and "consisting of’ are thus also encompassed and disclosed. Throughout the description, where compositions are described as having, including, or comprising specific components, it is contemplated that compositions also consist essentially of, or consist of, the recited components. Similarly, where methods or processes are described as having, including, or comprising specific process steps, the processes also consist essentially of, or consist of, the recited processing steps.

[0223] List of abbreviations:°C degree of Celsiusp microAc acetylAIBN 2,2'-azobis(2-methylpropionitrile) (CAS: 78-67-1)ALT alanine aminotransferaseAPI active pharmaceutical ingredientAST aspartate aminotransferaseBn benzylBoc tert-butyloxycarbonylBoc2O di-tert-butyl dicarbonate (CAS: 24424-99-5) CAD charged aerosol detectorcat. catalystCDCl3 deuterated chloroform (CAS: 865-49-6)cDNA complementary deoxyribonucleic acidCo. companycone. concentratedCRE creatinineCTA chain transfer agentd dayD dispersityDP degree of polymerizationDCM dichloromethane (CAS: 75-09-2)DIC A, A’-diisopropylcarbodiimide (CAS: 693-13-0) DIPEA N,N-diisopropylethylamine (CAS: 7087-68-5) DLS dynamic light scatteringDMAP 4-dimethylaminopyridine (CAS: 1122-58-3) DMF dimethylformamide (CAS: 68-12-2)DMSO dimethyl sulfoxide (CAS: 67-68-5)DMSO-d6 hexadeuterodimethyl sulfoxide (CAS: 2206-27-1)DNA deoxyribonucleic acidEE encapsulation efficiencyeq. equivalent(s)ESI electrospray ionizationEt ethylEtOAc ethyl acetate (CAS: 141-78-6)F100 30:1 (v / v) isopropanol-25% aqueous ammonia mixtureFBS fetal bovine serumFT-IR Fourier- transform infrared spectroscopyg gram(g) gaseoush hourHATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (CAS: 148893-10-1)HBTU 2-(lH-benzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (CAS: 94790-37-1)HPMA N-(2 -hydroxypropyl) methacrylamide / A-(2-hydroxypropyl)-2-methylprop-2-enamide (CAS: 21442-01-3)I initiatorIU International UnitsL literLC lipid compositionLNP lipid nanoparticleLYM lymphocytesLtd. limitedMALS multiangle light scattering detector mbar milibarmm milimetreM molarMHz megahertzMe methylmM milimolarm / z mass-to-charge ratioMeCN acetonitrile (CAS: 75-05-8) MEM minimum essential medium mRNA messenger ribonucleic acidMS mass spectrometryMwweight-average molecular weight Mnnumber-average molecular weight n nanoN: P nitrogen-to-phosphorus ratioNA nucleic acidND no dataNEU neutrophilsNMR nuclear magnetic resonanceNo. numberPBS phosphate-buffered salinePCR polymerase chain reactionPDI polydispersity indexPEG polyethylene glycolPh phenylppm parts per millionpsi pound per square inchPTFE polytetrafluoroethylene (CAS: 9002-84-0)PVDF poly vinylidene fluoride (CAS: 24937-79-9)PyBOP benzotriazole- 1 -yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (CAS: 128625-52-5)Rf retardation factorRNA ribonucleic acidRT room temperatureRT-PCR reverse transcription polymerase chain reactionSD standard deviationSEC size exclusion chromatographySEQ. sequenceTBAF Tetra-n-butylammonium fluoride (CAS: 429-41-4)TCE 1,1,2,2-tetrachloroethane (CAS: 79-34-5)TCM trichloromethane (CAS: 67-66-3)TEA triethylamine (CAS: 121-44-8)tert- tertiaryTf triflate, trifluoromethanesulfonateTFA trifluoracetic acid (CAS: 76-05-1)TFAA trifluoroacetanhydride (CAS: 407-25-0)TIC total ion currentTLC thin layer chromatographyTMS tetramethylsilane (CAS: 75-76-3)TNS 2-(p-toluidino)-6-napthalene sulfonic acid (CAS: 53313-85-2) Tris tris(hydroxymethyl)aminomethane (CAS: 77-86-1)Ts pp-toluenesulfonylUPLC ultra performance liquid chromatographyv / v volume per volumevac vacuumWBS whole blood serumw / w weight per weightwt% weight percentExamples

[0224] All reagents that are not coded and all solvents used were obtained commercially, unless otherwise specified. The NMR spectra were measured on Bruker AVANCE-III 600 MHz instrument (1H at 600 MHz and13C at 150.9 MHz) with a BBO probe in CDCl3, and DMSO-d6at 25 °C. Spectra were referenced to solvent peak and chemical shifts recalculated to d-scale using d(H) = 7.26 ppm and d(C) = 77.0 ppm. Some signals of carbon atoms may be missing because of possible overlapping. Flash chromatography purifications were carried out on silica gel (40-63 pm, Sigma- Aldrich) using ECOM Compact Preparative System. UPLC-MS spectra were obtained on a Waters ACQUITY UPLC H-Class PLUS system coupled with a single quadrupole mass detector (SQD2) in electrospray ionization mode and a charged aerosol detector (CAD). Chromatographic separations were performed using both an ACQUITY Premier CSH C18 (100 x 2.1 mm, 1.7 pm) and an ACQUITY Premier CSH Phenyl-Hexyl (100 x 2.1 mm, 1.7 pm) column. The column temperature was maintained at 40 °C. The mobile phase system consisted of water containing 0.1% formic acid (mobile phase A) and an isopropanol: acetonitrile mixture (25:75, v / v) containing 0.1% formic acid (mobile phase B). The flow rate was maintained at 0.4 mL / min.

[0225] The products were analyzed by size exclusion chromatography (SEC) in DMF containing 0.1 M LiBr at 60 °C using a Waters Agilent 1260 Infinity II High Performance Liquid Chromatography (HPLC) system equipped with two columns: Waters PSS GRAM Lux 100 A (8 x 300 mm, 10 pm) and a guard column, GRAM Lux (8 x 50 mm, 10 pm), along with a Variable Wavelength Detector (G7114A) detecting at wavelength of 254 and 280 nm. The system was operated at a flow rate of 1 mL / min. The weight-average molecular weight (A / w), number-average molecular weight (n), and dispersity ( =w / n) were determined with a DAWN 18-angleStatic Light Scattering (MALS) Detector (Wyatt). The specific refractive index increment (dn / dc = 0.104 mL / g) of the products was measured using an Optilab On-line Differential Refractometer (Wyatt). SEC data were processed with Astra 8.2 software (Wyatt Technology). The Fourier Transform Infrared (FT-IR) spectroscopy measurements were performed using a Nicolet iS5 spectrometer (Thermo Fisher Scientific, USA) equipped with a diamond ATR attachment. FT-IR spectra were recorded in the range of 4000-500 cm1with 20 scans per spectrum and a spectral resolution of 4 cm1.

[0226] It is noted that the term “removed under vacuum on a rotary vacuum evaporator” refers to a method, which is done at 35 °C for at least 20 minutes while under a pressure of 20 mbar.Precursors (Chain transfer agents, CTAs)Example 1 - 2-(((lsobutylthio)carbonothioyl)thio)-2-methylpropanoic acid ADA900020X.

[0227] In a IL round bottom flask equipped with a stirring bar and under argon atmosphere (kept by purging the flask with argon by using a needle which introduces argon into the closed tube through the septum), a NaOH aqueous solution (10 mL, 33 wt%, 125 mmol) was added dropwise to a solution of 2-methyl-l -propanethiol (12 mL, 111 mmol), methyltrioctylammonium chloride (4.5 g, 11.25 mmol) in acetone (140 mL) kept at 0°C in an ice bath. After the end of the addition, the reaction was stirred for 20 min at 0 °C. A solution of carbon disulfide (7 mL, 110 mmol) in acetone (20 mL) was then slowly added into the mixture (within 5 min) and the solution was stirred for another 30 min at 0 °C. Then, the cooling bath was removed, TCM (20 mL, 238 mmol) was added in one portion, and then aqueous NaOH solution (32.5 mL, 33 wt%, 407.5 mmol) was added dropwise. The reaction mixture was stirred overnight at RT. The day after, 1625 mL of distilled H2O was added to the resulting reaction mixture, followed by a very slow addition of 82.5 mL of concentrated HC1 (37 wt%), under cooling in ice-bath, to acidify the reaction mixture to pH = 1- 2. The remaining acetone was removed under vacuum on a rotary vacuum evaporator. The yellow solid was collected by filtration and then washed with H2O to remove inorganic salts.ADA900020X, as a bright yellow solid (12.7 g, 42% yield) was obtained by recrystallization from an acetone / pentane (1 / 10, v / v) solution. Product was analyzed by1H NMR (600 MHz, CDCl3) 8 11.26 (s br, 1H), 3.27 (d, J = 6.8 Hz, 2H), 2.05 - 1.95 (m, 1H), 1.72 (s, 6H), 1.02 (d, J = 6.8 Hz, 6H). UPLC-MS (TIC / ESI): m / z calculated for C9H17O2S3+[M + H]+253.04; found 253.28.1. Acetone, methyltrioctylamonium chloride2. NaOH 33 wt%, 0 °C3. Carbon disulfide in acetoneCOOH4. TCM 5. H2O, HCI (37 wt%), ice-bathADA900020XExample 2 - 3-((2-(((lsobutylthio)carbonothioyl)thio)-2-methylpropanoyl)oxy)propane-1,2-diyl ditetradecanoate ADA900021X.

[0228] ADA900020X (3.69 g, 14.6 mmol, 1.5 eq.) and 1,2-dimyristoyl glycerol (5 g, 9.8 mmol, 1 eq.) were dissolved in 50 mL of dry DCM in a 250mL round bottom flask under argon atmosphere. Following, DMAP (116 mg, 0.95 mmol, 0.1 eq.) was added, and the solution was cooled to 0 °C in an ice bath. Afterwards, DIC (2.41 mL, 15.6 mmol, 1.6 eq.) was added dropwise (1 drop / sec). The reaction mixture was stirred for 30 min at 0 °C and then slowly warmed up to RT overnight. The day after, the DCM was removed under vacuum on a rotary vacuum evaporator, the crude product was adsorbed onto silica gel, and the product was purified by flash chromatography with a gradient of 0-15 % of EtOAc in cyclohexane. The compound ADA900021X was obtained as a yellowish waxy solid (4.38 g, 71% yield). The product was analyzed by1H NMR (600 MHz, CDCl3) δ 5.30 – 5.23 (m, 1H), 4.32 -4.25 (m, 2H), 4.18 -4.08 (m, 2H), 3.18 (d, J = 6.8 Hz, 2H), 2.33 - 2.27 (m, 4H), 1.96 (-hept, J = 6.7 Hz, 1H), 1.68 (d, J = 4.0 Hz, 6H), 1.65 – 1.57 (m, 4H), 1.35 – 1.20 (m, 40H), 1.00 (d, J = 6.7 Hz, 6H), 0.90 – 0.85 (m, 6H). UPLC-MS (TIC / ESI): m / z calculated for C40H74O6S3Na+[M + Na]+769.45; found 769.98.°01,2-dimyristoyl glycerol1. DMAP, 0 °C2. DIC, dropwise, dry DCMADA900020X VExample 3 - 3-((2-(((lsobutylthio)carbonothioyl)thio)-2-methylpropanoyl)oxy)propane-1,2-diyl-dipalmitate ADA002004X.

[0229] ADA900020X (333 mg, 1.3 mmol, 1.5 eq.) and 1,2-dipalmitoyl glycerol (500 mg, 0.88 mmol, 1 eq.) were dissolved in 15 mL of dry DCM in a 50 mL round bottom flask under argon atmosphere. Following, DMAP (4.3 mg, 0.035 mmol, 0.04 eq.) was added, and the solution was cooled to 0 °C in an ice bath. Afterwards, DIC (221 pL, 1.4 mmol, 1.6 eq.) was added dropwise (1 drop / sec). The reaction mixture was stirred for 30 min at 0 °C and then slowly warmed up to RT overnight. Afterwards, extraDIC (111 pL, 0.7 mmol, 0.8 eq.) was added dropwise (1 drop / sec) and the reaction was left to react under stirring at RT for 3 days. In the end, the DCM was removed under vacuum on a rotary vacuum evaporator, the crude product was adsorbed onto silica gel, and the product was purified by flash chromatography with a gradient of 0-15 % of EtOAc in cyclohexane. The compound ADA002004X was obtained as a yellowish waxy solid (570 mg, 81% yield). The product was analyzed by1H NMR (600 MHz, CDCl3) δ 5.26 (-p, J= 5.1 Hz, 1H), 4.31 -4.26 (m, 2H), 4.17 -4.09 (m, 2H), 3.19 (d, J= 6.8 Hz, 2H), 2.33 -2.28 (m, 4H), 1.96 (pseudo-hept, J= 6.7 Hz, 1H), 1.68 (d, J= 6.1 Hz, 6H), 1.65 - 1.57 (m, 4H), 1.32 - 1.20 (m, 48H), 1.00 (d, J= 6.7 Hz, 6H), 0.88 (t, J= 6.9 Hz, 6H). UPLC-MS (TIC / ESI): m / z calculated for C44H82O6S3Na+[M + Na]+825.52; found 825.70.H°% OCH3(CK2)13^YO^'O^^(CH2)13CH3o1, 2-dipalmitoyl glycerol1. DMAP, 0 °C2. DIC, dropwise, dry DCMADA900020X VADA002004XExample 4 - 3-((2-(((lsobutylthio)carbonothioyl)thio)-2-methylpropanoyl)oxy)propane-1,2-diyl distearate ADA002005X.

[0230] ADA900020X (303 mg, 1.2 mmol, 1.5 eq.) and 1,2 -distearoyl glycerol (500 mg, 0.8 mmol, 1 eq.) were dissolved in 15 mL of a mixture of dry DCM / DMF (4 / 1, v / v) in a 50mL round bottom flask under argon atmosphere. Following, DMAP (3.9 mg, 0.032 mmol, 0.04 eq.) was added, and the solution was kept at RT. Afterwards, DIC (201 pL, 1.3 mmol, 1.6 eq.) was added dropwise (1 drop / sec). The reaction mixture was left to stir overnight. Afterwards, extra DIC (201 pL, 1.3 mmol, 1.6 eq.) was added dropwise (1 drop / sec) and the reaction was left to react under stirring at RT for 3 days. In the end, the solvents were removed under vacuum on a rotary vacuum evaporator, the crude product was adsorbed onto silica gel, and the product was purified by flash chromatography with a gradient of 50-90 % of DCM in cyclohexane. The compound ADA002005X was obtained as a yellowish waxy solid (310 mg, 45% yield). The product was analyzed by1H NMR (600 MHz, CDCl3) δ 5.26 (-p, J = 5.0 Hz, 1H), 4.32 - 4.25 (m, 2H), 4.17 - 4.09 (m, 2H), 3.19 (d, J= 6.8 Hz, 2H), 2.34 -2.27 (m, 4H), 1.96 (-hept, J = 6.7 Hz, 1H), 1.68 (d, J= 6.0 Hz, 6H), 1.64 - 1.57 (m, 4H), 1.34 - 1.21 (m, 56H), 1.00 (d, J= 6.7Hz, 6H), 0.88 (t, J = 7.0 Hz, 6H). UPLC-MS (TIC / ESI): m / z calculated for C48H90O6S3Na+[M + Na]+881.58; found 881.72H°% OCH3(CH2)15^Y°^O^^(CH2)15CH3o1,2-distearoyl glycerol1. DMAP, 0 °C2. DIC, dropwise, dry DCMADA900020X VADA002005XExample 5 - 1-(Ditetradecylamino)-2-methyl-1-oxopropan-2-yl isobutyl carbonotrithioate ADA900042X

[0231] In a 50mL round bottom flask, to a stirred solution of ADA900020X (250 mg, 991 pmol, 1.5 eq.) in dry DCM (10 mL) under argon atmosphere was added HATU (377 mg, 990 pmol, 1.5 eq.) and the reaction mixture was cooled down to 0 °C in an ice bath. Afterwards, TEA (368 pL, 2.6 mmol, 4 eq.) was added, and the mixture was stirred for 10 min at 0 °C, and then ditetradecylamine (271 mg, 660 pmol, 1 eq.), in 10 mL of dry DCM was added. The reaction mixture was stirred for 30 min at 0 °C and then slowly warmed up to RT overnight. The day after, the DCM was removed under vacuum on a rotary vacuum evaporator and the crude product was adsorbed onto silica gel. The product was purified by flash chromatography with a gradient of 66-100 % of DCM in cyclohexane. The compound ADA900042X was obtained as a yellow oil (200 mg, 47% yield). The yellow oil was stored at -20 °C and turned into a yellow waxy solid.1H NMR (600 MHz, CDCl3) δ 3.59 – 3.50 (m, 2H), 3.28 – 3.22 (m, 2H), 3.20 (d, J = 6.8 Hz, 2H), 1.95 (-hept, J = 6.7 Hz, 1H), 1.72 (s, 6H), 1.56 - 1.44 (m, 4H), 1.33 - 1.19 (m, 44H), 1.00 (d, J= 6.7Hz, 6H), 0.88 (t, J= 7.0 Hz, 6H). UPLC-MS (TIC / ESI): m / z calculated for C37H73NOS3Na+[M + Na]+666.48; found 666.67.1. HATU, 0 °C, dry DCM2. TEA, 10 min, 0 °C(CH2)12CH33. Ditetradecylamine N^(CH2)12CH3COOHADA900020X ADA900042XExample 6 - 1-(Dihexadecylamino)-2-methyl-1-oxopropan-2-yl isobutyl carbonotrithioate ADA000019X

[0232] In a 50mL round bottom flask, to a stirred solution of ADA900020X (500 mg, 2 mmol, 1.3 eq.) in dry DMF (5 mL) under argon was added HATU (753 mg, 2 mmol, 1.3 eq.) and the reaction mixture was cooled down to 0 °C in an ice bath. Afterwards, TEA (850 pL, 6.1 mmol, 4 eq.) was added, and the reaction mixture was stirred for 10 min at 0 °C, and then dihexadecylamine (710 mg, 1.5 mmol, 1 eq.) in 15 mL of mixture of dry DCM / DMF (2 / 1, v / v) was added. The suspension was stirred at RT, sonicated (in ultrasound bath) occasionally and left to react at RT overnight. The day after, the solvents were removed under vacuum on a rotary vacuum evaporator and the crude product was adsorbed onto silica gel. The product was purified by flash chromatography with a gradient of 66-100 % of DCM in cyclohexane. The compound ADA000019X was obtained as a yellow oil (280 mg, 26% yield). The yellow oil was stored at -20 °C and turned into yellow waxy solid. The product was analyzed by1H NMR (600 MHz, CDCl3) δ 3.58 – 3.49 (m, 2H), 3.28 – 3.22 (m, 2H), 3.20 (d, J = 6.8 Hz, 2H), 1.95 (-hept, J = 6.7 Hz, 1H), 1.72 (s, 6H), 1.56 - 1.44 (m, 4H), 1.33 - 1.19 (m, 60H), 1.00 (d, J= 6.7 Hz, 6H), 0.88 (t, J= 7.0 Hz, 6H). UPLC-MS (TIC / ESI): m / z calculated for C41H81NOS3Na+[M + Na]+722.54; found 722.68.1. HATU, 0 °C, DMF ^(CH2)14CH32. TEA, 0 °C to RT N.V,(CH2)14CH3COOH 3. Dihexadecylamine, DCM / DMFADA900020X ADA000019XExample 7 - 1-(Dioctadecylamino)-2-methyl-1-oxopropan-2-yl isobutyl carbonotrithioate ADA900041X.

[0233] In a 50mL round bottom flask, to a stirred solution of ADA900020X (500 mg, 2 mmol, 1.3 eq.) in dry DMF (5 mL) under argon atmosphere was added HATU (753 mg, 2 mmol, 1.3 eq.) andthe reaction mixture was cooled down to 0 °C in an ice bath. Afterwards, TEA (850 pL, 6.1 mmol, 4 eq.) was added, and the reaction mixture was stirred for 10 min at 0 °C, and then dioctadecylamine (795 mg, 1.5 mmol, 1 eq.) in 15 mL of mixture of dry DCM / DMF (2 / 1, v / v) was added. The suspension was stirred at RT and sonicated (in the ultrasound bath) occasionally and left to react at RT overnight. The day after, the solvents were removed under vacuum on a rotary vacuum evaporator and the crude product was adsorbed onto silica gel. The product was purified by flash chromatography with a gradient of 66-90 % of DCM in cyclohexane. The compound ADA900041X was obtained as yellow oil (80 mg, 7% yield). The yellow oil was stored at -20 °C and turned it to a brown waxy solid. The product was analyzed by1H NMR (600 MHz, CDC13) 83.58 - 3.49 (m, 2H), 3.28 - 3.22 (m, 2H), 3.20 (d, J= 6.8 Hz, 2H), 1.95 (-hept, J = 6.7 Hz, 1H), 1.72 (s, 6H), 1.56 – 1.44 (m, 4H), 1.33 – 1.19 (m, 60H), 1.00 (d, J = 6.7 Hz, 6H), 0.88 (t, J = 7.0 Hz, 6H). UPLC-MS (TIC / ESI): m / z calculated for C45H89NOS3+[M + H]+778.60; found 778.79.1. HATU, 0 °C, DMFg / (CH2)16CH32. TEA, 0 °C to RT. N^(CH2)16CH3COOH 3. Dioctadecylamine, DCM / DMF | JIADA900020X ADA900041XExample 8 - (E)-4,4'-(Diazene-1,2-diyl)bis(4-cyano-A / , A / -ditetradecylpentanamide) ADA002002X

[0234] In a 50mL round bottom flask, to a stirred suspension of 4,4'-azobis(4-cyanovaleric acid) (250 mg, 0.9 mmol, 1 eq.) in dry DCM (10 mL) under argon atmosphere was added HATU (687 mg, 1.81 mmol, 2 eq.) and the reaction mixture was cooled down to 0 °C in an ice bath. Afterwards, TEA (755 pL, 5.42 mmol, 6 eq.) was added, and the mixture was stirred for 10 min at 0 °C, and then ditetradecylamine (1.11 g, 2.71 mmol, 3 eq.), in 30 mL of dry DCM was added. The reaction mixture was stirred for 30 min at 0 °C and then slowly warmed up to RT overnight. The day after, the DCM was removed under vacuum on a rotary vacuum evaporator and the crude product was adsorbed onto silica gel. The product was purified by flash chromatography with a gradient of 15- 30 % of EtOAc in cyclohexane. The compound ADA002002X was obtained as white waxy solid (590 mg, 61% yield).1H NMR (600 MHz, CDCl3) δ 3.34 – 3.23 (m, 4H), 3.22 – 3.15 (m, 4H), 2.54 – 2.27 (m, 8H), 1.75 – 1.64 (m, 6H), 1.57 – 1.46 (m, 8H), 1.33 – 1.21 (m, 88H), 0.88 (t, J = 7.0 Hz, 12H). UPLC-MS (TIC / ESI): m / z calculated for C68H131N6O2+[M + H]+1064.03; found 1064.28.4,4'-Azobis(4-cyanovaleric acid)1. HATU, 0 °C, dry DCM2. TEA, 10 min, 0 °C3. DitetradecylamineV(CH2)12CH3ADA002002XExample 9 - ((4,4'-((E)-Diazene-1,2-diyl)bis(4-cyanopentanoyl))bis(oxy))bis(propane-3,1,2-triyl) tetratetradecanoate ADA002003X

[0235] 4,4'-Azobis(4-cyanovaleric acid) (250 mg, 0.9 mmol, 1 eq.) and 1,2-dimyristoyl glycerol (1.01 g, 1.96 mmol, 2.2 eq.) were dissolved in 20 mL of a mixture of dry DCM / DMF (1 / 1, v / v) in a 50mL round bottom flask under argon atmosphere. Then, DMAP (4.4 mg, 0.035 mmol, 0.04 eq.) was added, and the solution was cooled down to 0 °C in an ice bath. Afterwards, DIC (308 pL, 1.96 mmol, 2.2 eq.) was added dropwise (1 drop / sec). The reaction mixture was stirred for 30 min at 0 °C and then slowly warmed up to RT and left to stir overnight. Afterwards, extra DIC (154 pL, 0.98 mmol, 1.1 eq.) was added dropwise (1 drop / sec) and the reaction was left to react under stirring at RT for 3 days. In the end, the solvents were removed under vacuum on a rotary vacuum evaporator, the crude product was adsorbed onto silica gel, and the product was purified by flash chromatography with a gradient of 15-30 % of EtOAc in cyclohexane. The compound ADA002003X was obtained as a white waxy solid (390 mg, 34% yield). The product was analyzed by1H NMR (600 MHz, CDCl3) δ 5.29 – 5.25 (m, 2H), 4.38 – 4.26 (m, 4H), 4.22 – 4.10 (m, 4H),2.62 - 2.28 (m, 16H), 1.73 (s, 3H), 1.67 (s, 3H), 1.65 - 1.56 (m, 8H), 1.35 - 1.21 (m, 80H), 0.88 (t, J = 7.0 Hz, 12H). UPLC-MS (TIC / ESI): m / z calculated for C74H134N4O13+[M + H2O]+1286.99; found 1287.29.4,4'-Azobis(4-cyanovaleric acid)1. 1,2-dimyristoyl glycerol, dry DCM / DMF 2. DMAP, 0 °C 3. DIC, dropwise, dry DCM / DMFO CNADA002003XExample 10 - 2,7,7-Trimethyl-8,25-dioxo-5-thioxo-16,19,22,26-tetraoxa-4,6,12,13-tetrathia-9-azanonacosane-28,29-diyl ditetradecanoate ADA002013X.

[0236] ADA002013X was synthesized through a three-step synthetic pathway as follows: In a 25mL round bottom flask, to a stirred solution of ADA900020X (183 mg, 725 pmol, 1.5 eq.) in dry DMF (5 mL) under argon atmosphere was added HBTU (275 mg, 725 pmol, 1.5 eq.) and the reaction mixture was cooled down to 0 °C in an ice bath. Afterwards, TEA (270 pL, 1.93 mmol, 4 eq.) was added, and the mixture was stirred for 5 min at 0 °C, and then (5)-2-pyridylthio cysteamine hydrochloride (CAS: 106139-15-5) (90 mg, 483 pmol, 1 eq.), in 2 mL of dry DMF was added. The reaction mixture was stirred for 30 min at 0 °C and then slowly warmed up to RT overnight. The day after, the DMF was removed under vacuum on a rotary vacuum evaporator, and the crude product was adsorbed onto silica gel. The product was purified by flash chromatography with a gradient of 20-40 % of EtOAc in cyclohexane. The compound ADA002009X was obtained as a yellow oil (90 mg, 44% yield). 'H NMR (600 MHz, CDCh) 8 8.57 (d, J = 4.5 Hz, 1H), 7.99 -7.90 (m, 1H), 7.60 (t, J = 7.6 Hz, 1H), 7.49 (d, J= 8.0 Hz, 1H), 7.15 - 7.10 (m, 1H), 3.53 - 3.47 (m, 2H), 3.19 (d, J= 6.8 Hz, 2H), 2.89 - 2.83 (m, 2H), 1.96 (psew o-hept, J= 6.7 Hz, 1H), 1.74 (s, 6H), 0.97 (d, J= 6.7 Hz, 6H). UPLC-MS (TIC / ESI): m / z calculated for C16H24N2OS5+[M + H]+421.06; found 421.32.1. HBTU, 0 °C, dry DCM 2. TEA, 10 min, 0 °C COOH 3. 2-(Pyridin-2-yldisulfanyl)ethanamineADA002009XADA900020X

[0237] In a lOmL round bottom flask, to a stirred solution of ADA002009X (38 mg, 90 pmol, 1 eq.) in dry MeOH (2 mL) under argon atmosphere and at 0 °C was added dropwise a solution of 3-(2- (2-(2-mercaptoethoxy)ethoxy)ethoxy)propanoic acid (34 mg, 145 pmol, 1.6 eq.) in dry MeOH (1 mL) over 1 hour. The reaction mixture was stirred for 30 min at 0 °C and then slowly warmed up to RT overnight. The day after, MeOH was removed under vacuum on a rotary vacuum evaporator and the crude product was adsorbed onto silica gel. The product was purified by flash chromatography with a gradient of 0-25 % of MeOH in EtOAc. The compound ADA002012X was obtained as a yellow amorphous solid (35 mg, 71% yield). The product was analyzed by1H NMR (600 MHz, CDCh) 86.97 (t, J= 6.0 Hz, 1H), 3.81 - 3.77 (m, 2H), 3.73 (t, J= 6.4 Hz, 2H), 3.68 - 3.62 (m, 8H), 3.57 (q, J= 6.1 Hz, 2H), 3.20 (d, J= 6.8 Hz, 2H), 2.89 (t, J= 6.4 Hz, 2H), 2.79 (t, J= 6.2 Hz, 2H), 2.64 (t, J= 6.0 Hz, 2H), 1.98 (psew o-hept, J = 6.7 Hz, 1H), 1.69 (s, 6H), 1.01 (d, J = 6.7 Hz, 6H). UPLC-MS (TIC / ESI): m / z calculated for C20H38NO6S5+[M + H]+548.13; found 548.40.ADA002009XADA002012X

[0238] ADA002012X (35 mg, 64 pmol, 1 eq.) and 1,2-dimyristoyl glycerol (39 mg, 77 pmol, 1.2 eq.) were dissolved in 5 mL of dry DCM in a 25mL flask under argon atmosphere. Following, DMAP (312 pg, 3 pmol, 0.04 eq.) was added, and the solution was cooled to 0 °C in an ice bath. Afterwards, DIC (16 pL, 102 pmol, 1.6 eq.) was added dropwise (1 drop / sec). The reaction mixture was stirred for 30 min at 0 °C and then slowly warmed up to RT overnight. The day after, DCM was removed under vacuum on a rotary vacuum evaporator, the crude product was adsorbed onto silica gel, and the product was purified by flash chromatography with a gradient of 20-50 % of EtOAc in cyclohexane. The compound ADA002013X was obtained as a yellowish waxy solid (25 mg, 38% yield). The product was analyzed byJH NMR (600 MHz, CDCh) 86.91 (t, J = 5.7 Hz, 1H), 5.29 - 5.24 (m, 1H), 4.30 (dt, J= 11.9, 4.7 Hz, 2H), 4.16 (ddd, J = 20.3, 11.9, 6.0 Hz, 2H), 3.74 (t, J= 6.5 Hz, 2H), 3.71 (t, J = 6.6 Hz, 2H), 3.66 - 3.60 (m, 8H), 3.55 (q, J= 6.1 Hz, 2H), 3.20 (d, J= 6.8 Hz, 2H), 2.87 (t, J= 6.7 Hz, 2H), 2.77 (t, J= 6.2 Hz, 2H), 2.61 (t, J = 6.5 Hz, 2H), 2.31 (td, J= 7.6, 4.9 Hz, 4H), 2.02 - 1.94 (m, 1H), 1.69 (s, 6H), 1.64 - 1.58 (m, 4H), 1.35 - 1.19 (m, 40H), 1.01 (d, J= 6.7 Hz, 6H), 0.88 (t, J= 7.0 Hz, 6H). UPLC-MS (TIC / ESI): m / z calculated for C51H96NO10S5+[M + H]+1042.56; found 1042.75.ADA002012XoOA.^(CH2)IICH3 1. DMAP, 0 °C CH3(CH2)11^Y° 2. DIG, dropwise, dry DOM1,2-dimyristoyl glycerolADA002013XExample 11 - Bis(((1R,8S,9s)-bicyclo[6.1.0]non-4-yn-9-yl)methyl)((E)-13,16-dicyano-13,16-dimethyl-10,19-dioxo-3,6,23,26-tetraoxa-9,14,15,20-tetraazaoctacos-14-ene-1,28-diyl)dicarbamate ADA002000X

[0239] In a 25mL round bottom flask, to a stirred suspension of 4,4'-azobis(4-cyanovaleric acid) (102 mg, 0.36 mmol, 1 eq.) in dry DCM (5 mL) under argon atmosphere was added HATU (291 mg, 0.77 mmol, 2.1 eq.). Afterwards, TEA (305 pL, 2.19 mmol, 6 eq.) was added, and the mixture was stirred for 5 min at RT, and then cwc / -BCN-PEG2-NH2 (CAS: 1263166-93-3; 260 mg, 0.80 mmol, 2.2 eq.), in 5 mL of dry DCM was added. The reaction mixture was stirred at RT overnight. The day after, the DCM was removed from the reaction mixture under vacuum on a rotary vacuum evaporator and the crude product was adsorbed onto silica gel. The product was purified by flash chromatography with a gradient of 5-20 % of MeOH in EtOAc. The compound ADA002000X was obtained as colorless amorphous solid (209 mg, 64% yield).XH NMR (600 MHz, CDC13) 54.23 - 4.11 (m, 4H), 3.69 - 3.53 (m, 16H), 3.51 - 3.41 (m, 4H), 3.41 - 3.34 (m, 4H), 2.51 -2.35 (m, 4H), 2.33 - 2.18 (m, 12H), 1.73 - 1.68 (m, 6H), 1.66 - 1.53 (m, 10H), 0.99 - 0.90 (m, 4H). UPLC-MS (TIC / ESI): m / z calculated for C46H69N8O10+[M + H]+893.51; found 893.88.4,4'-Azobis(4-cyanovaleric acid)1. HATU, dry DCM 2. TEA 3. endo-BCN-PEG-2-NH2, dry DCMExample 12 - Bis((bicyclo[6.1.0]non-4-yn-9-yl)methyl) (13,16-dicyano-13,16-dimethyl-10,19-dioxo-3,6,23,26-tetraoxa-9,14,15,20-tetraazaoctacos-14-ene-1,28-diyl)dicarbamate ADA002056X

[0240] In a 25mL round bottom flask, to a stirred suspension of 4,4'-azobis(4-cyanovaleric acid) (102 mg, 0.36 mmol, 1 eq.) in dry DCM (5 mL) under argon atmosphere was added HATU (291 mg, 0.77 mmol, 2.1 eq.). Afterwards, TEA (305 pL, 2.19 mmol, 6 eq.) was added, and the mixture was stirred for 5 min at RT, and then BCN-PEG-2-NH2 (260 mg, 0.80 mmol, 2.2 eq.), in 5 mL of dry DCM was added. The reaction mixture was stirred at RT overnight. The day after, the DCM was removed from the reaction mixture under vacuum on a rotary vacuum evaporator and the crude product was adsorbed onto silica gel. The product was purified by flash chromatography with a gradient of 5-20 % of MeOH in EtOAc. The compound ADA002056X was obtained as colorless amorphous solid (209 mg, 64% yield).XH NMR (600 MHz, CDC13) 54.23 - 4.11 (m, 4H), 3.69 - 3.53 (m, 16H), 3.51 - 3.41 (m, 4H), 3.41 - 3.34 (m, 4H), 2.51 -2.35 (m, 4H), 2.33 -2.18 (m, 12H), 1.73 - 1.68 (m, 6H), 1.66 - 1.53 (m, 10H), 0.99 - 0.90 (m, 4H). UPLC-MS (TIC / ESI): m / z calculated for C46H69N8O10+[M + H]+893.51; found 893.88.4,4'-Azobis(4-cyanovaleric acid)1. HATU, dry DCM 2. TEA 3. BCN-PEG-2-NH2, dry DCMExample 13 - Isobutyl (2-methyl-3,20-dioxo-21-tetradecyl-11,14,17-trioxa-7,8-dithia-4,21-diazapentatriacontan-2-yl) carbonotrithioate ADA2016X

[0241] In a 25mL round bottom flask, to a stirred solution of ADA002012X (180 mg, 0.33 mmol, 1 eq.) in dry DCM (5 mL) under argon was added HATU (150 mg, 0.39 mmol, 1.2 eq.) and the reaction mixture was cooled down to 0 °C in an ice bath. Afterwards, TEA (137 pL, 0.99 mmol, 3 eq.) was added, the reaction mixture was stirred at 0 °C for 5 minutes, and then a solution of ditetradecyl amine (175 mg, 0.43 mmol, 1.3 eq.) in dry DCM (5 mL) was added. The reaction mixture was left to react at RT overnight. The day after, the DCM was removed under vacuum on a rotary vacuum evaporator and the crude product was adsorbed onto silica gel. The product was purified by flash chromatography with a gradient of 20-60 % of EtOAc in cyclohexane. The compound ADA002016X was obtained as yellow gel (240 mg, 78% yield).XH NMR (600 MHz, CDCh) 8 6.91 (t, J= 6.1 Hz, 1H), 3.79 (t, J= 7.1 Hz, 2H), 3.71 (t, J= 6.6 Hz, 2H), 3.65 - 3.62 (m, 8H), 3.55 (q, J= 6.1 Hz, 2H), 3.30 - 3.26 (m, 2H), 3.22 - 3.17 (m, 4H), 2.87 (t, J= 6.6 Hz, 2H), 2.77 (t, J= 6.2 Hz, 2H), 2.62 (t, J= 7.1 Hz, 2H), 1.98 (psew o-hept, J= 6.7 Hz, 1H), 1.69 (s, 6H), 1.32 - 1.21 (m, 48H), 1.01 (d, J = 6.7 Hz, 6H), 0.88 (t, J = 7.1 Hz, 6H). UPLC-MS (TIC / ESI): m / z calculated for C48H95N2O5S5+[M + H]+939.58; found 939.72.ADA002012X1. HATU, 0 °C, dry DCM2. TEA, 5 min, 0 °C3. Ditetradecylamine, dry DCMO H N O' O' N (CH2)12CH3(CH2)12CH3ADA002016XExample 14 - (E)-4,4'-(Diazene-1,2-diyl)bis(4-cyano-A / -(2-(pyridin-2-yldisulfaneyl)ethyl)pentanamide) ADA002021X

[0242] In a 25mL round bottom flask, to a stirred suspension of 4,4'-azobis(4-cyanovaleric acid) (150 mg, 0.54 mmol, 1 eq.) in dry DMF (5 mL) under argon atmosphere was added HBTU (447 mg, 1.18 mmol, 2.2 eq.). Afterwards, TEA (448 pL, 3.21 mmol, 6 eq.) was added, the mixture was stirred for 5 min at RT, and then (5)-2-pyridylthio cysteamine hydrochloride (CAS: 106139-15-5; 298 mg, 1.34 mmol, 2.5 eq.) in dry DMF (2 mL) was added. The reaction mixture turned opaque and was stirred at RT overnight. The day after, the DMF was removed under vacuum on a rotary vacuum evaporator and the crude product was adsorbed onto silica gel. The product was purified by flash chromatography with a gradient of 20-40 % of Fl 00 in cyclohexane. The compound ADA002021X was obtained as white wax (245 mg, 74% yield).‘HNMR (600 MHz, CDC13) 8 8.55 - 8.50 (m, 2H), 7.65 - 7.59 (m, 2H), 7.57 - 7.53 (m, 2H), 7.53 -7.48 (m, 2H), 7.19 - 7.14 (m, 2H), 3.63 - 3.47 (m, 4H), 2.97 - 2.87 (m, 4H), 2.54 - 2.38 (m, 6H), 2.34 - 2.23 (m, 2H), 1.75 - 1.68 (m, 6H). UPLC-MS (TIC / ESI): m / z calculated for C26H33N8O2S4+[M + H]+617.16; found 617.58.4,4'-Azobis(4-cyanovaleric acid)1. HBTU, dry DMF2. TEA 3. (S)-2-Pyridylthio cysteamine HCI, dry DMFADA002021XExample 15 - (E)-4,4'-(Diazene-1,2-diyl)bis(4-cyano-A / -(4-(6-methyl-1,2,4,5-tetrazin-3-yl)benzyl)pentanamide) ADA002023X

[0243] In a 25mL round bottom flask, to a stirred suspension of 4,4'-azobis(4-cyanovaleric acid) (54 mg, 0.19 mmol, 1 eq.) in dry DCM (10 mL) under argon atmosphere was added HBTU (152 mg, 0.40 mmol, 2.1 eq.). Afterwards, TEA (160 pL, 1.15 mmol, 6 eq.) was added, the mixture was stirred for 5 min at RT, and then (4-(6-methyl-l,2,4,5-tetrazin-3-yl)phenyl)methanamine hydrochloride (100 mg, 0.42 mmol, 2.2 eq.) was added. The flask containing the reaction mixture was wrapped in aluminum foil and stirred at RT overnight. The day after, the DCM was removed from the reaction mixture under vacuum on a rotary vacuum evaporator and the crude product was adsorbed onto silica gel. The product was purified by flash chromatography with a gradient of 0- 3.5 % of MeOH in DCM. Compound ADA002023X was obtained as violet powder (87 mg, 70% yield).'H NMR (600 MHz, DMSO-r / 6) 8 8.66 - 8.60 (m, 2H), 8.43 - 8.37 (m, 4H), 7.52 (t, J= 8.2 Hz, 4H), 4.45 - 4.34 (m, 4H), 3.00 - 2.97 (m, 6H), 2.44 - 2.32 (m, 6H), 2.30 - 2.17 (m, 2H), 1.72 (s, 3H), 1.69 (s, 3H). UPLC-MS (TIC / ESI): m / z calculated for C32H35N14O2+[M + H]+647.30; found 647.19.4,4'-Azobis(4-cyanovaleric acid)1. HBTU, dry DCM 2. TEA 3. (4-(6-Methyl-1,2,4,5-tetrazin-3-yl)phenyl)methanamine hydrochlorideExample 16 - (E)-4,4'-(Diazene-1,2-diyl)bis(A / -(4-(1,2,4,5-tetrazin-3-yl)benzyl)-4-cyanopentanamide) ADA002024X

[0244] In a 25mL round bottom flask, to a stirred suspension of 4,4'-azobis(4-cyanovaleric acid) (57 mg, 0.20 mmol, 1 eq.) in dry DCM (10 mL) under argon atmosphere was added HBTU (162 mg, 0.43 mmol, 2.1 eq.). Afterwards, TEA (170 pL, 1.22 mmol, 6 eq.) was added, the mixture was stirred for 5 min atRT, and then (4-(l, 2, 4, 5-tetrazin-3-yl)phenyl)methanamine hydrochloride (100 mg, 0.45 mmol, 2.2 eq.) was added. The reaction mixture was wrapped in aluminum foil and stirred at RT for 3 hours. Then, the DCM was removed from the reaction mixture under vacuum on a rotary vacuum evaporator and the crude product was adsorbed onto silica gel. The product was purified by flash chromatography with a gradient of 0-3.5 % of MeOH in DCM. Compound ADA002024X was obtained as pink powder (80 mg, 63% yield).'H NMR (600 MHz, DMSO-r / 6) 8 10.59 - 10.56 (m, 2H), 8.67 - 8.61 (m, 2H), 8.47 - 8.40 (m, 4H), 7.57 - 7.52 (m, 4H), 4.45 - 4.37 (m, 4H), 2.45 - 2.33 (m, 6H), 2.29 - 2.17 (m, 2H), 1.74 - 1.65 (m, 6H). UPLC-MS (TIC / ESI): m / z calculated for C30H31N14O2+[M + H]+619.27; found 619.18.4,4'-Azobis(4-cyanovaleric acid)1. HBTU, dry DCM2. TEA3. (4-(1,2,4,5-Tetrazin-3-yl)phenyl)methanamine hydrochlorideExample 17 - tert-Butyl (2-(2-(((isobutylthio)carbonothioyl)thio)-2-methylpropanamido)ethyl)carbamate ADA002037X

[0245] In a 50mL round bottom flask, to a stirred solution of ADA900020X (500 mg, 1.98 mmol, 1 eq.) in dry DMF (10 mL) under argon atmosphere was added HBTU (751 mg, 1.98 mmol, 1 eq.) and the reaction mixture was cooled down to 0 °C in an ice bath. Afterwards, TEA (828 pL, 5.94 mmol, 3 eq.) was added, and the mixture was stirred for 5 min at 0 °C, and then A-Boc-1,2- diaminoethane (317 mg, 1.98 mmol, 1 eq.), in 2 mL of dry DMF was added. The reaction mixture was stirred for 30 min at 0 °C and then slowly warmed up to RT overnight. The day after, the DMF was removed under vacuum on a rotary vacuum evaporator and the crude product was adsorbed onto silica gel. The product was purified by flash chromatography with a gradient of 20- 40 % of EtOAc in cyclohexane. The compound ADA002037X was obtained as a yellow crystalline solid (570 mg, 73% yield).'H NMR (600 MHz, CDCh) 86.88 (bs, 1H), 4.79 (bs, 1H), 3.35 - 3.29 (m, 2H), 3.27 - 3.22 (m, 2H), 3.20 (d, J= 6.8 Hz, 2H), 1.97 (psew o-hept, J = 6.7 Hz, 1H), 1.69 (s, 6H), 1.43 (s, 9H), 1.01 (d, J =6.7 Hz, 6H). UPLC-MS (TIC / ESI): m / z calculated for C16H31N2O3S3+[M + H]+395.15; found 395.44.1. HBTU, 0 °C, dry DMF2. TEA, 5 min, 0 °C3. A / -Boc-1,2-diaminoethane, dry DMF COOH NHBocADA900020X ADA002037XExample 18 - 2-(2-(3-(tert-Butoxy)-3-oxopropoxy)ethoxy)ethyl 2-(((isobutylthio)carbonothioyl)thio)-2-methylpropanoate ADA007000X

[0246] In a 25mL round bottom flask, to a stirred solution of ADA900020X (979 mg, 3.88 mmol, 1 eq.) in dry DCM (10 mL) under argon atmosphere were added tert-butyl 3-(2-(2- hydroxyethoxy)ethoxy)propanoate (1000 mg, 4.27 mmol, 1.1 eq.) and DMAP (47 mg, 0.388 mmol, 0.1 eq.), and the reaction mixture was cooled down to -10 °C in an ice bath (acetone, ice, NaCl). Afterwards, DIC (608 pL, 3.88 mmol, 1 eq.) was added dropwise (1 drop / sec). Then the flask containing the reaction mixture was removed from the ice bath and the reaction mixture was stirred at RT overnight. The day after, the solvents were removed under vacuum on a rotary vacuum evaporator, and the crude product was adsorbed onto silica gel. The product was purified by flash chromatography with a gradient of 5-20 % of EtOAc in cyclohexane. The compound ADA007000X was obtained as a yellow oil (1040 mg, 57% yield).1HNMR(600 MHz, CDCh) 84.27-4.22 (m, 2H), 3.71 (t, J= 6.6 Hz, 2H), 3.69 - 3.66 (m, 2H), 3.63 - 3.60 (m, 2H), 3.60 - 3.57 (m, 2H), 3.19 (d, J= 6.8 Hz, 2H), 2.50 (t, J= 6.6 Hz, 2H), 1.97 (pseudo-hept, J= 13.4, 6.8 Hz, 1H), 1.70 (s, 6H), 1.45 (s, 9H), 1.00 (d, J= 6.7 Hz, 6H). UPLC-MS (TIC / ESI): m / z calculated for C20H37O6S3+[M + H]+469.18; found 469.36.ADA900020X terf-butyl 3-(2-(2-hydroxyethoxy)ethoxy)propanoate1. DCM, DMAP, DIC, -10 °C - RTADA007000XExample 19 - 2,7,7-Trimethyl-8-oxo-5-thioxo-9,12,15-trioxa-4,6-dithiaoctadecan-18-oic acid ADA007001X

[0247] In a 50mL round bottom flask, 10 mL of TFA, 10 mL of DCM and 0.3 mL of H2O were added to ADA007000X (1040 mg, 2.22 mmol, 1 eq.). The solution was stirred for 3 h. The solution was then concentrated under vacuum on a rotary vacuum evaporator, and co -evaporated with toluene (3 x 30 mL) to yield ADA007001X in a quantitative yield (915 mg, quant.).1H NMR (600 MHz, CDCl₃) δ 4.26 (dd, J = 5.7, 4.2 Hz, 2H), 3.78 (t, J = 6.2 Hz, 2H), 3.73 – 3.67 (m, 2H), 3.64 (s, 4H), 3.19 (d, J = 6.8 Hz, 2H), 2.65 (t, J = 6.2 Hz, 2H), 1.96 (dt, J = 13.4, 6.7 Hz, 1H), 1.70 (s, 6H), 1.01 (s, 3H), 1.00 (s, 3H). UPLC-MS (TIC / ESI): m / z calculated for C₁₆H₂₇O₆S₃⁻ [M – H]⁻ 411.10; found 411.10.ADA007000X1. DCM. TFA, H2OADA007001XExample 20 - 2-(2-(3-((1,3-Dihydroxypropan-2-yl)amino)-3-oxopropoxy)ethoxy)ethyl 2-(((isobutylthio)carbonothioyl)thio)-2-methylpropanoate ADA002046X

[0248] In a 25mL round bottom flask, to a stirred solution of ADA007001X (150 mg, 0.36 mmol, 1 eq.) in dry DMF (3 mL) under argon atmosphere was added HBTU (110 mg, 0.44 mmol, 1.2 eq.) and the reaction mixture was cooled down to 0 °C in an ice bath. Afterwards, TEA (152 pL, 1.09 mmol, 3 eq.) was added, and the mixture was stirred for 5 min at 0 °C, and then serinol (CAS: 534-03-2; 166 mg, 1.82 mmol, 5 eq.), in 4 mL of dry DMF was added. The reaction mixture was stirred for 30 min at 0 °C and then slowly warmed up to RT. After 2 hours, the DMF was removed under vacuum on a rotary vacuum evaporator and the crude product was adsorbed onto silica gel. The product was purified by flash chromatography with a gradient of 5-10 % of MeOH in DCM. The compound ADA002046X was obtained as a yellow oil (125 mg, 71% yield).¹H NMR (600 MHz, CDCl₃) δ 7.03 (d, J = 7.1 Hz, 1H), 4.29 – 4.25 (m, 2H), 3.96 – 3.89 (m, 1H), 3.84 – 3.76 (m, 4H), 3.73 (t, J = 5.6 Hz, 2H), 3.71 – 3.68 (m, 2H), 3.67 – 3.64 (m, 2H), 3.63 – 3.60 (m, 2H), 3.19 (d, J = 6.8 Hz, 2H), 3.11 (t, J = 5.9 Hz, 2H), 2.52 (t, J = 5.6 Hz, 2H), 1.96 (pseudo-hept, J = 6.7 Hz, 1H), 1.70 (s, 6H), 1.01 (d, J = 6.7 Hz, 6H). UPLC-MS (TIC / ESI): m / z calculated for C₁₉H₃₆NO₇S₃⁺ [M + H]⁺ 486.16; found 486.21.ADA007001X1. HBTU, 0 °C, dry DMF2. TEA, 5 min, 0 °C3. Serinol, dry DMFADA002046XExample 21 - 2-(2,7,7-Trimethyl-8-oxo-5-thioxo-9,12,15-trioxa-4,6-dithiaoctadecan-18-amido)propane-1,3-diyl bis(2-octyldecanoate) ADA002049X

[0249] ADA002046X (57 mg, 117 pmol, 1 eq.), 2-octyldecanoic acid (100 mg, 352 pmol, 3 eq.) and DMAP (574 pg, 5 pmol, 0.04 eq.) were dissolved in 5 mL of dry DCM in a 25mL round bottom flask under argon atmosphere. Afterwards, DIC (55 pL, 352 pmol, 3 eq.) was added dropwise (1 drop / sec). The reaction mixture was stirred at RT overnight. The day after, the DCM was removed under vacuum on a rotary vacuum evaporator, the crude product was adsorbed onto silica gel, and the product was purified by flash chromatography with a gradient of 10-25 % of EtOAc in cyclohexane. The compound ADA002049X was obtained as a yellowish oil (82 mg, 69% yield).¹H NMR (600 MHz, CDCl₃) δ 6.45 (d, J = 8.4 Hz, 1H), 4.50 – 4.44 (m, 1H), 4.28 – 4.24 (m, 2H), 4.20 (dd, J = 11.3, 5.4 Hz, 2H), 4.06 (dd, J = 11.3, 5.8 Hz, 2H), 3.71 (t, J = 5.9 Hz, 2H), 3.70 – 3.68 (m, 2H), 3.64 – 3.59 (m, 4H), 3.19 (d, J = 6.8 Hz, 2H), 2.46 (t, J = 5.9 Hz, 2H), 2.37 – 2.29 (m, 2H), 1.96 (pseudo-hept, J = 6.7 Hz, 1H), 1.70 (s, 6H), 1.62 – 1.53 (m, 4H), 1.49 – 1.41 (m, 4H), 1.33 – 1.19 (m, 48H), 1.00 (d, J = 6.7 Hz, 6H), 0.88 (t, J = 7.0 Hz, 12H). UPLC-MS (TIC / ESI): m / z calculated for C₅₅H₁₀₄NO₉S₃⁺ [M + H]⁺ 1018.69; found 1018.68.Example 22 - 2-(2-(3-(Ditetradecylamino)-3-oxopropoxy)ethoxy)ethyl 2-(((isobutylthio)carbonothioyl)thio)-2-methylpropanoate ADA007002X

[0250] In a 25mL round bottom flask, to a stirred solution of ADA007001X (98 mg, 0.239 mmol, 1 eq.) in dry DCM (3 mL) under argon atmosphere was added HATU (100 mg, 0.263 mmol, 1.1 eq.), and the reaction mixture was cooled down to 0 °C in an ice bath. Afterwards, TEA (67 pL, 0.487 mmol, 2 eq.) was added, and the reaction mixture was stirred for 5 minutes, and then ditetradecyl amine (117 mg, 0.287 mmol, 1.2 eq.) was added. The reaction mixture was stirred at RT overnight. The day after, the solvents were removed under vacuum on a rotary vacuum evaporator, and the crude product was adsorbed onto silica gel. The product was purified by flash chromatography with a gradient of 7-35 % of EtOAc in cyclohexane. The compound ADA007002X was obtained as a yellow oil (156 mg, 81% yield).¹H NMR (600 MHz, CDCl₃) δ 4.29 – 4.21 (m, 2H), 3.78 (t, J = 7.1 Hz, 2H), 3.71 – 3.66 (m, 2H), 3.66 – 3.56 (m, 4H), 3.30 – 3.25 (m, 2H), 3.23 – 3.15 (m, 4H), 2.61 (t, J = 7.1 Hz, 2H), 1.96 (pseudo-hept, J = 6.7 Hz, 1H), 1.69 (s, 6H), 1.58 – 1.45 (m, 4H), 1.33 – 1.21 (m, 48H), 1.00 (s, 3H), 0.99 (s, 3H), 0.88 (t, J = 7.0 Hz, 6H). UPLC-MS (TIC / ESI): m / z calculated for C₄₄H₈₆NO₅S₃⁺ [M + H]⁺ 804.57; found 804.53.ADA007001X1. HATU, 0 °C, dry DCM2. TEA, 5 min, 0 °C3. ditetradecylamineExample 23 - 2,7,7-Trimethyl-8,18-dioxo-5-thioxo-9,12,15,19-tetraoxa-4,6-dithiadocosane-21,22-diyl ditetradecanoate ADA007003X

[0251] In a 25mL round bottom flask, to a stirred solution of ADA007001X (357 mg, 0.865 mmol, 1 eq.) in dry DCM (3 mL) under argon atmosphere were added 1,2-dimyristoyl-glycerol (532 mg, 1.04 mmol, 1.2 eq.), DMAP (11 mg, 0.086 mmol, 0.1 eq.), and the reaction mixture was cooled down to 0 °C in an ice bath. Afterwards, DIC (135 pL, 0.865 mmol, 1 eq.) was added, the flask containing reaction mixture was removed from the ice bath and the reaction mixture was stirred until RT was reached. The reaction mixture was then stirred at RT overnight. The day after, the solvents were removed under vacuum on a rotary vacuum evaporator, and the crude product was adsorbed onto silica gel. The product was purified by flash chromatography with a gradient of 4- 25 % of EtOAc in cyclohexane. The compound ADA007003X was obtained as a yellow oil (381 mg, 48% yield).¹H NMR (600 MHz, CDCl₃) δ 5.26 (tt, J = 5.9, 4.3 Hz, 1H), 4.30 (ddd, J = 11.5, 6.8, 4.3 Hz, 2H), 4.27 – 4.21 (m, 2H), 4.16 (ddd, J = 20.7, 11.9, 6.0 Hz, 2H), 3.74 (t, J = 6.5 Hz, 2H), 3.70 – 3.65 (m, 2H), 3.64 – 3.55 (m, 4H), 3.19 (d, J = 6.8 Hz, 2H), 2.61 (t, J = 6.4 Hz, 2H), 2.31 (td, J = 7.6, 4.8 Hz, 4H), 1.96 (pseudo-hept, J = 6.7 Hz, 1H), 1.70 (s, 6H), 1.64 – 1.58 (m, 4H), 1.37 – 1.17 (m, 44H), 1.00 (d, J = 6.7 Hz, 6H), 0.88 (t, J = 6.9 Hz, 6H). UPLC-MS (TIC / ESI): m / z calculated for C₄₇H₈₉O₁₁S₃⁺ [M + H₂O + H]⁺ 925.56; found 925.53.ADA007001X1. DMAP, 0 °C, dry DCM2. 1,2-dimyristoyl-glycerol3. DICExample 24 - 2-(2-(3-(Dihexadecylamino)-3-oxopropoxy)ethoxy)ethyl 2-(((isobutylthio)carbonothioyl)thio)-2-methylpropanoate ADA007004X

[0252] In a 25mL round bottom flask, to a stirred solution of ADA007001X (200 mg, 0.484 mmol, 1 eq.) in dry DCM (3 mL) under argon was added HATU (202 mg, 0.533 mmol, 1.1 eq.), and the reaction mixture was cooled down to 0 °C in an ice bath. Afterwards, TEA (135 pL, 0.969 mmol, 2 eq.) was added, and then dihexadecyl amine (271 mg, 0.581 mmol, 1.2 eq.) was added. The suspension was stirred at RT overnight. The day after, the solvents were removed under vacuum on a rotary vacuum evaporator, and the crude product was adsorbed onto silica gel. The product was purified by flash chromatography with a gradient of 5-30 % of EtOAc in cyclohexane. The compound ADA007004X was obtained as a yellow oil (350 mg, 84% yield). ¹H NMR (600 MHz, CDCl₃) δ 4.27 – 4.21 (m, 2H), 3.79 (t, J = 7.1 Hz, 2H), 3.70 – 3.65 (m, 2H), 3.64 – 3.58 (m, 4H), 3.30 – 3.24 (m, 2H), 3.23 – 3.15 (m, 4H), 2.61 (t, J = 7.1 Hz, 2H), 1.96 (pseudo-hept, J = 6.7 Hz, 1H), 1.69 (s, 6H), 1.50 (m, 4H), 1.33 – 1.19 (m, 56H), 1.01 (s, 3H), 1.00 (s, 3H), 0.88 (t, J = 7.0 Hz, 6H). UPLC-MS (TIC / ESI): m / z calculated for C₄₈H₉₄NO₅S₃⁺ [M + H]⁺ 860.63; found 860.45.ADA007001X1. HATU, 0 °C, dry DCM2. TEA, 5 min, 0 °C3. dihexadecylamineADA007004XExample 25 - 2-(2-(3-(Dioctadecylamino)-3-oxopropoxy)ethoxy)ethyl 2-(((isobutylthio)carbonothioyl)thio)-2-methylpropanoate ADA007005X

[0253] In a 50mL round bottom flask, to a stirred solution of ADA007001X (200 mg, 0.484 mmol, 1 eq.) in dry DCM (15 mL) under argon atmosphere was added HATU (202 mg, 0.533 mmol, 1.1 eq.) and the reaction mixture was cooled down to 0 °C in an ice bath. Afterwards, TEA (135 pL, 0.969 mmol, 2 eq.) was added, and then dioctadecylamine (304 mg, 0.582 mmol, 1.2 eq.) was added. The reaction mixture was stirred at RT overnight. The day after, the solvents were removed under vacuum on a rotary vacuum evaporator, and the crude product was adsorbed onto silica gel. The product was purified by flash chromatography with a gradient of 5-30 % of EtOAc in cyclohexane. The compound ADA007005X was obtained as a yellow oil (267 mg, 60% yield).¹H NMR (600 MHz, CDCl₃) δ 4.25 (dd, J = 5.7, 4.3 Hz, 2H), 3.79 (t, J = 7.1 Hz, 2H), 3.70 – 3.65 (m, 2H), 3.64 – 3.57 (m, 4H), 3.30 – 3.23 (m, 2H), 3.23 – 3.14 (m, 4H), 2.61 (t, J = 7.1 Hz, 2H), 1.96 (pseudo-hept, J = 6.7 Hz, 1H), 1.69 (s, 6H), 1.33 – 1.19 (m, 64H), 1.01 (s, 3H), 1.00 (s, 2H), 0.88 (t, J = 6.9 Hz, 6H). UPLC-MS (TIC / ESI): m / z calculated for C₅₂H₁₀₂NO₅S₃⁺ [M + H]⁺ 916.69; found 916.84.ADA007001X1. HATU, 0 °C, dry DCM2. TEA, 5 min, 0 °C3. dioctadecylamineADA007005XExample 26 - 2,7,7-Trimethyl-8,18-dioxo-5-thioxo-9,12,15,19-tetraoxa-4,6-dithiadocosane-21,22-diyl dipalmitate ADA007006X

[0254] In a 25mL round bottom flask, to a stirred solution of ADA007001X (200 mg, 0.485 mmol, 1 eq.) in dry DCM (10 mL) under argon atmosphere were added 1,2-dipalmitoyl-sn-glycerol (331 mg, 0.582 mmol, 1.2 eq.), DMAP (6 mg, 0.048 mmol, 0.1 eq.), and the reaction mixture was cooled down to 0 °C in an ice bath. Afterwards, DIC (76 pL, 0.484 mmol, 1 eq.) was added, the flask containing reaction mixture was removed from the ice bath and the reaction mixture was stirred until RT was reached. The reaction mixture was then stirred at RT overnight. The day after, the solvents were removed under vacuum on a rotary vacuum evaporator, and the crude product was adsorbed onto silica gel. The product was purified by flash chromatography with a gradient of 5-25 % of EtOAc in cyclohexane followed by flash chromatography in 10 % of EtOAc in DCM. The compound ADA007006X was obtained as a yellow solid (279 mg, 60% yield).¹H NMR (600 MHz, CDCl₃) δ 5.26 (tt, J = 6.0, 4.3 Hz, 1H), 4.30 (ddd, J = 11.3, 6.7, 4.3 Hz, 2H), 4.27 – 4.23 (m, 2H), 4.16 (m, 2H), 3.74 (t, J = 6.5 Hz, 2H), 3.70 – 3.65 (m, 2H), 3.63 – 3.56 (m, 4H), 3.19 (d, J = 6.8 Hz, 2H), 2.61 (t, J = 6.4 Hz, 2H), 2.31 (td, J = 7.5, 4.8 Hz, 4H), 1.96 (pseudo-hept, J = 6.7 Hz, 1H), 1.70 (s, 6H), 1.60 (m, 4H), 1.25 (s, 52H), 1.01 (s, 3H), 1.00 (s, 3H), 0.88 (t, J = 6.9 Hz, 6H). UPLC-MS (TIC / ESI): m / z calculated for C₅₁H₉₇O₁₁S₃⁺ [M + H₂O + H]⁺ 981.62; found 981.83.ADA007001X1. DMAP, 0 °C, dry DCM2. 1,2-dipalmitoyl-glycerol3. DICExample 27 - 2,7,7-Trimethyl-8,18-dioxo-5-thioxo-9,12,15,19-tetraoxa-4,6-dithiadocosane-21,22-diyl distearate ADA007007X

[0255] In a 25mL round bottom flask, to a stirred solution of ADA007001X (200 mg, 0.485 mmol, 1 eq.) in dry DCM (10 mL) under argon atmosphere were added 1,2-distearoyl-glycerol (364 mg, 0.582 mmol, 1.2 eq.), DMAP (6 mg, 0.048 mmol, 0.1 eq.), and the reaction mixture was cooled down to 0 °C in an ice bath. Afterwards, DIC (76 pL, 0.484 mmol, 1 eq.) was added, the flask containing the reaction mixture was removed from the ice bath and the reaction mixture was stirred until RT was reached. The reaction mixture was then stirred at RT overnight. The day after, the solvents were removed under vacuum on a rotary vacuum evaporator, and the crude product was adsorbed onto silica gel. The product was purified by flash chromatography with a gradient of 5- 25 % of EtOAc in cyclohexane followed by flash chromatography in 10 % of EtOAc in DCM. The compound ADA007007X was obtained as a yellow solid (217 mg, 44% yield).'H NMR (600 MHz, CDCh) 8 5.26 (tt, J= 6.1, 4.3 Hz, 1H), 4.30 (ddd, J= 12.0, 6.5, 4.3 Hz, 2H), 4.27 - 4.22 (m, 2H), 4.16 (m, 2H), 3.74 (t, J= 6.4 Hz, 2H), 3.70 - 3.64 (m, 2H), 3.64 - 3.54 (m, 4H), 3.19 (d, J= 6.8 Hz, 2H), 2.61 (t, J= 6.4 Hz, 2H), 2.31 (td, J= 7.6, 4.9 Hz, 4H), 1.96 (psewrfo-hept, J = 6.7 Hz, 1H), 1.70 (s, 6H), 1.64- 1.57 (m, 4H), 1.36 - 1.17 (m, 60H), 1.01 (s, 3H), 1.00 (s, 3H), 0.88 (t,.7=7,0 Hz, 6H). UPLC-MS (TIC / ESI): m / z calculated for CssHiosOnSs [M + H2O + H]+1037.68; found 1037.40.o ADA007001X1. DMAP, 0 °C, dry DCM2. 1,2-distearoyl-glycerol3. DICExample 28 - 2-Methyl-2-((((3-phenylpropyl)thio)carbonothioyl)thio)propanoic acid ADA007010X

[0256] In a 250mL round bottom flask equipped with a stirring bar and under argon atmosphere (kept by purging the flask with argon by using a needle which introduces argon into the closed flask through the septum), a NaOH aqueous solution (0.333 mL, 33 wt%, 1.1 eq.) was added dropwise to a solution of 3 -phenyl- 1 -propanethiol (0.563 mL, 3.7 mmol, 1 eq.), acetone (5 mL) and methyltrioctylammonium chloride (0.150 g, 0.357 mmol, 0.1 eq.) and kept in an ice bath. After the end of the addition, the reaction mixture was stirred for 20 min. A solution of carbon disulfide (0.233 mL, 3.86 mmol, 1.04 eq.) in acetone (0.7 mL) was slowly added into the reaction mixture (within 5 min.), and the solution was stirred for another 30 min. Chloroform (0.666 mL, 8.26 mmol, 2.2 eq.) was added in one portion, and 1.08 mL of an aqueous NaOH solution (33 wt%, 3.6 eq.) was added dropwise. The reaction mixture was stirred overnight at RT. The day after, 45 mL of distilled H2O was added to the resulting reaction mixture, followed by a very slow addition of 0.96 mL of concentrated HC1 (37%, wt%), while cooling in an ice-bath, to acidify the reaction to pH = 1 -2. The remaining acetone was removed under vacuum on a rotary vacuum evaporator. The reaction mixture was extracted with DCM (3 x 20 mL). The combined organic layer was dried over MgSCL, concentrated on a rotary vacuum evaporator, and the crude product was adsorbed onto silica gel. The product was purified by flash chromatography with a gradient of 4-25 % ofEtOAc (with 1% AcOH) in cyclohexane. The compound ADA007010X was obtained as a yellow oil (736 mg, 63% yield).'H NMR (600 MHz, CDCh) 87.28 (t, J = 7.6 Hz, 2H), 7.19 (t, J = 7.3 Hz, 1H), 7.18 - 7.14 (m, 2H), 3.30 (t, J= 7.3 Hz, 2H), 2.72 (t, J= 7.6 Hz, 2H), 2.01 (p, J= 7.5 Hz, 2H), 1.73 (s, 6H). UPLC-MS (TIC / ESI): m / z calculated for C14H17O2S3[M - H]" 313.04; found 312.88.1. Acetone, methyltrioctylamonium chloride2. NaOH 33 wt%, ice bath 3. Carbon disulfide in acetoneCOOH 4. CHCI3, NaOH 33 wt% 3-phenylpropane-1 -thiol5. H2O, HCI (37 wt%), ice-bath ADA007010XExample 29 - 2-(2-(3-(tert-Butoxy)-3-oxopropoxy)ethoxy)ethyl 2-methyl-2-((((3-phenylpropyl)thio)carbonothioyl)thio)propanoate ADA007009X

[0257] In a 50mL round bottom flask, to a stirred solution of ADA007010X (201 mg, 0.639 mmol, 1 eq.) in dry DCM (10 mL) under argon atmosphere were added tert-butyl 3-(2-(2- hydroxyethoxy)ethoxy)propanoate (164 mg, 0.703 mmol, 1.1 eq.), DMAP (15 mg, 0.127 mmol, 0.1 eq.), and the reaction mixture was cooled down to -10 °C in an ice bath (acetone, ice, NaCl). Afterwards, DIC (109 pL, 0.703 mmol, 1 eq.) was added, the flask containing the reaction mixture was removed from the ice bath and the reaction mixture was stirred until RT was reached. The reaction mixture was stirred at RT overnight. The day after, the solvents were removed under vacuum on a rotary vacuum evaporator, and the crude product was adsorbed onto silica gel. The product was purified by flash chromatography with a gradient of 0-20 % of EtOAc in cyclohexane. The compound ADA007009X was obtained as a yellow oil (274 mg, 81% yield).'H NMR (600 MHz, CDCh) 87.31 (t, J= 7.5 Hz, 2H), 7.22 (t, J= 7.4 Hz, 1H), 7.19 (d, J= 7.2 Hz, 2H), 4.32 - 4.21 (m, 2H), 3.76 - 3.67 (m, 4H), 3.64 - 3.61 (m, 2H), 3.61 - 3.55 (m, 2H), 3.31 (m, 2H), 2.74 (m, 2H), 2.52 (t, J= 6.6 Hz, 2H), 2.02 (p, J= 7.5 Hz, 2H), 1.72 (s, 6H), 1.47 (s, 9H). UPLC-MS (TIC / ESI): m / z calculated for C25H38NaO6S3+[M + Na]+553.17; found 553.12.O ADA007010X tert-butyl 3-(2-(2-hydroxyethoxy)ethoxy)propanoate1. DCM, DMAP, DIC, -10 °C - RTADA007009XExample 30 - 7,7-Dimethyl-8-oxo-1-phenyl-5-thioxo-9,12,15-trioxa-4,6-dithiaoctadecan-18-oic acid ADA007011X

[0258] In a 50mL round bottom flask, a solution of TFA, DCM, and H2O (3 mL TFA, 3 mL DCM, 0.1 mL H2O) was added to ADA007009X (274 mg, 0.516 mmol, 1 eq.). The reaction mixture was stirred for 3 h. The reaction mixture was concentrated under reduced pressure, and co-evaporated with toluene (3 x 30 mL) under reduced pressure to get the ADA007011X in a quantitative yield (244 mg, quant.).'H NMR (600 MHz, CDCh) 87.28 (t, J= 7.5 Hz, 2H), 7.20 (t, J= 7.4 Hz, 1H), 7.17 (d, J= 6.8 Hz, 2H), 4.28 - 4.23 (m, 2H), 3.76 (t, J= 6.2 Hz, 2H), 3.70 - 3.66 (m, 2H), 3.62 (s, 4H), 3.31 - 3.26 (m, 2H), 2.71 (m, 2H), 2.64 (t, J = 6.1 Hz, 2H), 2.00 (p, J = 7.6 Hz, 2H), 1.70 (s, 6H). UPLC-MS (TIC / ESI): m / z calculated for C21H29O6S3[M - H]-473.11; found 472.97.ADA007009X1. DCM. TFA, H2OADA007011XExample 31 - 2-(2-(3-(Ditetradecylamino)-3-oxopropoxy)ethoxy)ethyl 2-methyl-2-((((3-phenylpropyl)thio)carbonothioyl)thio)propanoate ADA007012X

[0259] In a 25mL round bottom flask, to a stirred solution of ADA007011X (220 mg, 0.463 mmol, 1 eq.) in dry DCM (10 mL) under argon atmosphere were added ditetradecylamine (208 mg, 0.509 mmol, 1.1 eq.), DMAP (6 mg, 0.046 mmol, 0.1 eq.), and the reaction mixture was cooled down to -10 °C in an ice bath (acetone, ice, NaCl). Afterwards, DIC (79 pL, 0.509 mmol, 1 eq.) was added, the flask containing reaction mixture was removed from the ice bath and the reaction mixture was stirred until RT was reached. The reaction mixture was then stirred at RT overnight. The day after, the solvents were removed under vacuum on a rotary vacuum evaporator, and the crude product was adsorbed onto silica gel. The product was purified by flash chromatography with a gradient of 0-25 % of EtOAc in cyclohexane. The compound ADA007012X was obtained as a yellow oil (220 mg, 55% yield).'H NMR (600 MHz, CDCh) 87.28 (t, J= 7.5 Hz, 2H), 7.19 (t, J= 7.3 Hz, 1H), 7.17 (d, J= 7.0 Hz, 2H), 4.25 (dd, J= 5.8, 4.1 Hz, 2H), 3.78 (t, J= 7.1 Hz, 2H), 3.68 (dd, J= 5.8, 4.2 Hz, 2H), 3.60 (m, 4H), 3.28 (td, J= 7.6, 4.6 Hz, 4H), 3.23 - 3.16 (m, 2H), 2.71 (m, 2H), 2.61 (t, J= 7.1 Hz, 2H), 2.00 (p, J= 7.5 Hz, 2H), 1.70 (s, 6H), 1.54 - 1.44 (m, 4H), 1.36 - 1.17 (m, 48H), 0.88 (t, J= 6.9 Hz, 6H).UPLC-MS (TIC / ESI): m / z calculated for C49H88NO5S3+[M + H]+866.58; found 866.58.SADA007011X1. DMAP, - 10 °C, dry DCM2. ditetradecylamine3. DICExample 32 - 3-((Hydroxy((15, 15,20-trimethyl-4, 14-dioxo-17-thioxo-7, 10,13-trioxa-16, 18-d ith ia-3-azahenicosyl)oxy)phosphoryl)oxy)propane-1,2-diyl distearate ADA007014X

[0260] In a 25mL round bottom flask, to a stirred solution of ADA007001X (30 mg, 0.073 mmol, 1 eq.) in dry DCM (20 mL) under argon atmosphere was added HATU (28 mg, 0.073 mmol, 1 eq.), and the reaction mixture was cooled down to -10 °C in an ice bath (acetone, ice, NaCl). Afterwards, TEA (20 pL, 0.145 mmol, 2 eq.) was added, and then l,2-distearoyl-glycero-3- phosphoethanolamine (54 mg, 0.073 mmol, 1 eq.) was added. The reaction mixture was removed from the ice bath and the reaction mixture was then stirred at RT overnight. The day after, the solvents were removed under vacuum on a rotary vacuum evaporator, and the crude product was adsorbed onto silica gel. The product was purified by flash chromatography with a gradient of 0- 25 % of MeOH in DCM. The product was further purified by crystallization from DCM / MeOH. The compound ADA007014X was obtained as a pale yellow solid (24 mg, 29% yield).'H NMR (600 MHz, CDCh) 8 5.22 (s, 1H), 4.41 (d, J= 13.5 Hz, 1H), 4.28 (s, 2H), 4.13 (t, J = 9.8 Hz, 1H), 3.90 (s, 4H), 3.84 - 3.60 (m, 8H), 3.59 - 3.40 (m, 2H), 3.19 (d, J= 6.8 Hz, 2H), 2.54 (s, 2H), 2.28 (q, J= 7.7 Hz, 4H), 1.96 (dt, J= 13.4, 6.7 Hz, 1H), 1.68 (d, J= 10.6 Hz, 6H), 1.25 (s, 60H), 1.01 (d, J= 6.7 Hz, 6H), 0.88 (t, J= Hz, 6H). UPLC-MS (TIC / ESI): m / z calculated for C57H107NO13PS3 [M-H]- 1140.66; found 1140.71.ADA007001X1. HATU,-10 °C, dry DCM2. TEA3. 1,2-distearoyl-glycero-3- phosphoethanolamineExample 33 - 3 -((Hydroxy (2-(2-(((isobutylthio)carbonothioyl)thi o)-2-methylpropanamido)ethoxy)phosphoryl)oxy)propane-l,2-diyl distearate ADA007015X

[0261] In a 25mL round bottom flask, to a stirred solution of ADA900020X (30 mg, 0.073 mmol, 1 eq.) in dry DCM (20 mL) under argon atmosphere was added HATU (28 mg, 0.073 mmol, 1 eq.), and the reaction mixture was cooled to -10 °C in an ice bath (acetone, ice, NaCl). Afterwards, TEA (20 pL, 0.145 mmol, 2 eq.) was added, and then l,2-distearoyl-glycero-3- phosphoethanolamine (54 mg, 0.073 mmol, 1 eq.) was added. The flask containing the reaction mixture was removed from the ice bath and the reaction mixture was then stirred at RT overnight. The day after, the solvents were removed under vacuum on a rotary vacuum evaporator, and the crude product was adsorbed onto silica gel. The product was purified by flash chromatography with a gradient of 0-25 % of MeOH in DCM. The product was further purified by crystallization from DCM / MeOH. The compound ADA007015X was obtained as a pale yellow solid (17 mg, 26% yield).'HNMR (600 MHz, CDCh) 8 5.22 (s, 1H), 4.37 (s, 1H), 4.13 (s, 1H), 3.93 (s, 2H), 3.18 (d, J= 6.8 Hz, 2H), 2.40 - 2.17 (m, 4H), 2.01 - 1.92 (m, 1H), 1.82 - 1.66 (m, 6H), 1.64 - 1.63 (m, 4H), 1.33 -1.14 (m, 60H), 1.01 (d, J = 6.8 Hz, 6H), 0.88 (t, J =. Q Hz, 6H). UPLC-MS (TIC / ESI): m / z calculated for C50H95NO9PS3 [M - H]-980.59; found 980.51.ADA900020X1. HATU, 0 °C, dry DCM2. TEA3. 1,2-distearoyl-glycero-3- phosphoethanolamineExample 34 - 15,15,20-Trimethyl-2-(((2-octyldecanoyl)oxy)methyl)-4,14-dioxo-17-thioxo-7,10,13-trioxa-16,18-dithia-3-azahenicosyl dodecanoate ADA002053X

[0262] ADA002046X (80 mg, 165 pmol, 1 eq.), 2-octyldecanoic acid (52 mg, 181 pmol, 1.1 eq.) and DMAP (805 pg, 7 pmol, 0.04 eq.) were dissolved in 4 mL of dry DCM in a 25mL round bottom flask under argon atmosphere. Afterwards, a solution of DIC (39 pL, 247 pmol, 1.5 eq.) in 1 mL of dry DCM was added dropwise (1 drop / sec). The reaction mixture was stirred at RT for 2 hours. Then, lauric acid (CAS: 143-07-7; 50 mg, 247 pmol, 1.5 eq.) and DIC (39 pL, 247 pmol, 1.5 eq.) were added. The reaction mixture was stirred at RT for 2 hours. Next, the DCM was removed from the reaction mixture under vacuum on a rotary vacuum evaporator, the crude product was adsorbed onto silica gel, and the product was purified by flash chromatography with a gradient of 20-50 % of EtOAc in cyclohexane. The compound ADA002053X was obtained as a yellowish oil (95 mg, 62% yield).'H NMR (600 MHz, CDCh) 86.48 (d, J= 8.5 Hz, 1H), 4.50 - 4.44 (m, 1H), 4.28 - 4.24 (m, 2H), 4.19 (dd, J= 11.2, 5.4 Hz, 2H), 4.11 -4.05 (m, 2H), 3.71 (t, J= 5.9 Hz, 2H), 3.70 - 3.67 (m, 2H),3.64 - 3.59 (m, 4H), 3.19 (d, J= 6.8 Hz, 2H), 2.47 (t, J= 5.8 Hz, 2H), 2.37 - 2.33 (m, 1H), 2.31 (t, J= 7.6 Hz, 2H), 1.96 (pseudo-hept, J= 6.7 Hz, 1H), 1.70 (s, 6H), 1.66 - 1.57 (m, 4H), 1.48 -1.41 (m, 2H), 1.36 - 1.19 (m, 40H), 1.01 (d, J= 6.7 Hz, 6H), 0.91 - 0.85 (m, 9H). UPLC-MS (TIC / ESI): m / z calculated for C49H92NO9S3+[M + H]+934.59; found 934.45.ADA002046X1. DMAP, dry DCM 2. DIC, DCM, dropwise 3. Lauric acid 4. DIC, dropwiseExample 35 - 2-(2,7,7-Trimethyl-8-oxo-5-thioxo-9,12,15-trioxa-4,6-dithiaoctadecan-18-amido)propane-1,3-diyl didodecanoate ADA002054X

[0263] ADA002046X (80 mg, 165 pmol, 1 eq.), 2-octyldecanoic acid (52 mg, 181 pmol, 1.1 eq.) and DMAP (805 pg, 7 pmol, 0.04 eq.) were dissolved in 4 mL of dry DCM in a 25mL round bottom flask under argon atmosphere. Afterwards, a solution of DIC (39 pL, 247 pmol, 1.5 eq.) in 1 mL of dry DCM was added dropwise (1 drop / sec). The reaction mixture was stirred at RT for 2 hours. Then, lauric acid (CAS: 143-07-7; 50 mg, 247 pmol, 1.5 eq.) and DIC (39 pL, 247 pmol, 1.5 eq.) were added. The reaction mixture was stirred at RT for 2 hours. Next, the DCM was removed under vacuum on a rotary vacuum evaporator, the crude product was adsorbed onto silica gel, and the product was purified by flash chromatography with a gradient of 20-50 % of EtOAc in cyclohexane. The compound ADA002054X was obtained as a yellowish oil (20 mg, 14% yield).'H NMR (600 MHz, CDCh) 86.51 (d, J= 8.7 Hz, 1H), 4.50 - 4.44 (m, 1H), 4.28 - 4.24 (m, 2H), 4.19 (dd, J= 11.3, 5.3 Hz, 2H), 4.09 (dd, J= 11.3, 5.6 Hz, 2H), 3.71 (t, J= 5.8 Hz, 2H), 3.70 - 3.67 (m, 2H), 3.65 - 3.58 (m, 4H), 3.19 (d, J= 6.8 Hz, 2H), 2.48 (t, J= 5.8 Hz, 2H), 2.31 (t, J = 7.6 Hz, 4H), 1.96 (pseudo-hept, J = 6.7 Hz, 1H), 1.70 (s, 6H), 1.64 - 1.58 (m, 4H), 1.37 - 1.19 (m, 32H), 1.00 (d, J= 6.7 Hz, 6H), 0.88 (t, J= Hz, 6H). UPLC-MS (TIC / ESI): m / z calculated for C43H80NO9S3+[M + H]+850.50; found 850.41.ADA002046X1. DMAP, dry DCM2. DIC, DCM, dropwise3. Lauric acid4. DIC, dropwisePolymers and lipid-polymer conjugates prepared by using glycerol-based CTAs Example 36 - Poly(A / -(2-hydroxypropyl)methacrylamide)-glycerol-based lipid conjugates

[0264] The polymerization of HPMA was carried out according to the [CTA]:[AIBN] ratio specified in Table 1. In the Figure 1 there is a general procedure for synthesizing the PHPMA-lipid conjugate: In a Schlenk tube, HPMA (200 mg, 1.4 mmol) and AIBN (amount of substance: refers to Table 1) were dissolved in 1.0 mL of dry solvent (as listed in Table 1) under stirring. The respective glycerol-based CTA (amount of substance: refers to Table 1) was then added in 1 mL of dry solvent (refers to Table 1). The polymerization mixture was purged with argon for 20 minutes by using a needle which introduces argon into the tube through the septum. Afterwards, the Schlenk tube with the reaction mixture was placed into a heating block at 75 °C to initiate the polymerization, which was allowed to proceed for 18 hours. The reaction was then quenched by exposing the mixture to air and liquid nitrogen (by opening the stopcock valve of the Schlenk tube and putting the Schlenk tube into the liquid nitrogen bath). To the polymerization solution, 3 mL of methanol (MeOH) was added, and the mixture was purified by flash chromatography using a Sephadex® LH-20 column, with methanol as the mobile phase. The collected polymer solution inMeOH was concentrated to 2 mL under vacuum on a rotary vacuum evaporator and then dialyzed against water for 24 hours and lyophilized. The glycerol-based lipid-polymer conjugates (Figure 1, listed in Table 1) were obtained as yellowish powders (yield, as indicated in Table 1) and characterized by size exclusion chromatography with multi-angle light scattering (SEC-MALS).HPMA Al BN, 75 °C, 18 h, solventoA^(CH2)nCH3O'^X / Ox( / X(CH2)nCH3OPolymerOHFigure 1. Synthetic pathway and structure of glycerol-based lipid-polymer conjugates. For list of CTAs and polymers, see Table 1.Table 1. Characteristics of lipid-polymer conjugates prepared from glycerol-based CTAs in 2 mL of solvent for 1.4 mmol (200 mg) of HPMA monomer.[CTA]: [I] Mw, SEC D Yield Yield Polymer Solvent n ymmol (g / mol)a(SEC)b(mg) (%) C14- [ADA900021X]:glycerols [AIBN]ADA000022P 0.054 : 0.006 DMF 11 7 1 900 1.10 132 55 ADA000041P 0.030 : 0.003 DMF 11 19 4 100 1.17 102 45 ADA000043P 0.023 : 0.002 DMF 11 30 6 000 1.18 115 57 ADA000045P 0.017 : 0.005 DMF 11 45 8 900 1.23 125 58ADA000024P 0.013: 0.003 DMF 11 50 9700 1.24 85 40ADA000083P 0.047: 0.005 DMF 11 17 3 600 1.15 120 51( 16- [ADA002004X]glycerols: [AIBN]ADA000079P 0.013: 0.003 i-PrOH 13 30 6 100 1.20 112 53ADA000080P 0.012: 0.002 i-PrOH 13 64 11 700 1.17 100 47ADA000084P 0.072: 0.007 i-PrOH 13 13 3 000 1.15 78 30ADA000090P 0.070: 0.007 i-PrOH 13 15 3 300 1.10 80 31 C18- [ADA002005X]glycerols: [AIBN]ADA000082P 0.012: 0.002 i-PrOH 15 76 12 900 1.10 100 47 ADA000091P 0.070: 0.007 i-PrOH 15 9 2 400 1.09 60 23“Determined by SEC-MALS in DMF / O.1 M LiBr;bDispersity as determined bySEC-MALS y = (Mnof polymer measured by SEC -wof CTA) / W\ of HPMA monomer.Example 37 - Hydroxylation of polymers obtained from glycerol-based CTAs

[0265] The terminal trithiocarbonate group of the lipid-polymer conjugates was converted to hydroxyl group as follows: In a 5mL Schlenk tube, 30 mg of starting polymer (refers to Table 2) were dissolved in 2 mL of water and the Schlenk tube including the reaction mixture was placed into a heating block at 75 °C for polymer complete solubilization (for about 5 min). Hydrogen peroxide (H2O2; molar ratio of H2O2 to polymer = 10.0, as specified in Table 2) was added to the solution. H₂O₂ was used as a 30% w / w aqueous solution. The Schlenk tube including the reaction mixture was sealed with a rubber septum and left to stir for 16 hours at 70 °C, exposed to air (with the stopcock valve open). The yellowish coloration of polymers completely disappeared after 16 hours as observed by visual inspection. Afterwards, 3 mL of MeOH were added to the polymer solution, and the polymer was purified by flash chromatography in a Sephadex® LH-20 column, with MeOH as the mobile phase. The collected polymer solution in MeOH was concentrated to 2 mL under vacuum on a rotary vacuum evaporator and then the polymerization solution was dialyzedagainst water for 24h and lyophilized. The glycerol-based hydroxyl-terminated lipid-polymer conjugate (Figure 2, see Table 2) was obtained as a white powder (yield shown in Table 2) and characterized by size exclusion chromatography (UV-SEC-MALS) by detecting at a fixed wavelength of 280 nm, corresponding to the absorption assigned to the trithiocarbonate group of the CTA end-group. The complete disappearance of the trithiocarbonate group signal in the SEC chromatogram confirmed the successful modification of the polymer end-group.1. H2O, 75 °C2. H2O2(30% W / W), 16 hVOOH hydroxyl-terminated polymerFigure 2. Synthetic pathway and structure of hydroxyl-terminated glycerol-based lipid-polymer conjugates. For list of starting polymers and hydroxyl-terminated polymers, see Table 2.Table 2. Characteristics of hydroxyl-terminated lipid-polymer conjugates prepared from glycerolbased CTAs.HydroxylYield Starting Added mmol of Yield terminated n y (%) polymer H2O2 (mg) polymerC14-glycerolsADA000023P ADA000022P 0.15 11 7 25 88 ADA000042P ADA000041P 0.07 11 19 23 79 ADA000044P ADA000043P 0.05 11 30 25 86 ADA000046P ADA000045P 0.03 11 45 24 82 ADA000025P ADA000024P 0.03 11 50 23 80 ADA000196P ADA000083P 0.08 11 17 21 75C16-glycerolsADA000088P ADA000080P 0.02 13 64 25 86 ADA000095P ADA000090P 0.09 13 15 21 75ADA000198P ADA000079P 0.05 13 30 25 86ADA000201P ADA000084P 0.10 13 13 21 75C18-glycerolsADA000089P ADA000082P 0.02 15 76 24 82 ADA000096P ADA000091P 0.12 15 9 22 79Example 38 - propargylation of polymers obtained from glycerol-based CTAs

[0266] The terminal tri thio carbonate group of the lipid-polymer conjugate was modified to propargyl group as follows: In a 5mL Schlenk tube, 15 mg of a starting polymer and ADA902085X (molar ratio of ADA902085X to polymer = 20.0, as specified in Table 3) were dissolved in 1 mL of dry DMSO. The solution was sealed with a rubber septum and purged with argon at RT for 20 min. The Schlenk tube was then placed into a heating block at 75 °C and let to react for 2 h. Afterwards, the solution was quenched by exposing the reaction mixture to air and liquid nitrogen. To the solution, 3 mL of MeOH were added and the mixture was then purified by flash chromatography in a Sephadex® LH-20 column using MeOH as mobile phase. The collected polymer solution in MeOH was concentrated to 2 mL under vacuum on a rotary vacuum evaporator and then dialyzed against water for 24 h and then lyophilized. The glycerol-based propargyl terminated lipidpolymer conjugate (Figure 3, Table 3) was obtained as a white powder (yield, as indicated in Table 3).starting polymerpropargyl-term i nated polymerFigure 3. Synthetic pathway and structure of propargyl -terminated glycerol-based lipid-polymer conjugates. For list of starting polymers and propargyl-terminated polymers, see Table 3.Table 3. Characteristics of propargyl -terminated lipid-polymer conjugates prepared from glycerolbased CTAs.Propargyl-terminated Starting Added µmol of Yieldn y Yield (%) polymer polymer ADA902085X (mg)C14-glycerolsADA000026P ADA000024P 32 11 50 11 73 C16-glycerolsADA000085P ADA000080P 26 13 64 12 80 C18-glycerolsADA000086P ADA000082P 23 15 76 12 80Example 39 - Poly(A / -(2-hydroxypropyl)methacrylamide)-glycerol-based lipid conjugates containing spacer

[0267] The polymerization of HPMA was carried out according to the [CTA]:[AIBN] ratio specified in Table 4. In Figure 4 there is a general procedure for synthesizing the PHPMA-lipid conjugate: In a Schlenk tube, HPMA (200 mg, 1.4 mmol) and AIBN (amount of substance: refers to Table 4) were dissolved in 1.0 mL of dry solvent (as listed in Table 4) under stirring. The respective glycerol-based CTA (amount of substance refers to Table 4) was then added in 1 mL of dry solvent (refers to Table 4). The polymerization mixture was purged with argon for 20 minutes by using a needle which introduces argon into the tube through the septum. Afterwards, the Schlenk tube with the reaction mixture was placed into a heating block at 75 °C to initiate the polymerization, which was allowed to proceed for 18 hours. The reaction was then quenched by exposing the mixture to air and liquid nitrogen (by opening the stopcock valve of the Schlenk tube and putting the Schlenk tube into a liquid nitrogen bath). To the polymerization solution, 3 mL of MeOH was added, and the mixture was purified by flash chromatography using a Sephadex® LH-20 column, with MeOH as the mobile phase. The collected polymer solution in MeOH was concentrated to 2 mL under vacuum on a rotary vacuum evaporator and then dialyzed against water for 24 hours and lyophilized. The glycerol-based lipid-polymer conjugates (Figure 4, listed in Table 4) were obtained as yellowish powders (yield, as indicated in Table 4) and characterized by size exclusion chromatography with multi-angle light scattering (SEC-MALS).13PolymerOHFigure 4. Synthetic pathway and structure of glycerol-based lipid-polymer conjugates containing spacer. For a list of CT As and polymers, see Table 4.Table 4. Characteristics of lipid-polymer conjugates prepared from glycerol -based CTAs in 2 mL of solvent for 1.4 mmol (200 mg) of HPMA monomer.Polymer [CTA]: [I] Solvent n y D Yield Yield Mw, SECmmol (SEC)b(mg) (%) (g / mol)aC14-glycerols [ADA007003X]: [AIBN]ADA000209P 0.033: 0.003 Dioxane 11 15 3 400 1.10 140 60C16-glycerols [ADA007006X]: [AIBN]ADA000217P 0.068: 0.008 Dioxane 13 11 2800 1.10 170 64C18-glycerols [ADA007007X]: [AIBN]ADA000218P 0.068: 0.008 Dioxane 15 10 2800 1.12 172 63aDetermined by SEC-MALS in DMF / 0.1 M LiBr; bDispersity as determined by SEC-MALS (Mw / Mn). y = (Mnof polymer measured by SEC – Mwof CTA) / Mwof HPMA monomer.Example 40 - Hydroxylation of polymers obtained from glycerol-based CTAs and containing spacer

[0268] The terminal trithiocarbonate group of the lipid-polymer conjugates was converted to hydroxyl groups as follows: In a 5mL Schlenk tube, 30 mg of starting polymer (refers to Table 5) were dissolved in 2 mL of water and the Schlenk tube including the reaction mixture was placed into a heating block at 75 °C for polymer complete solubilization (for about 5 min). Hydrogen peroxide (H2O2; molar ratio of H2O2 to polymer = 10.0, as specified in Table 5) was added to the solution. H₂O₂ was used as a 30% w / w aqueous solution. The Schlenk tube including the reaction mixturewas sealed with a rubber septum and left to stir for 16 hours at 70 °C, exposed to air (with the stopcock valve open). The yellowish coloration of polymers completely disappeared after 16 hours as observed by visual inspection. Afterwards, 3 mL of MeOH were added to the polymer solution, and the polymer was purified by flash chromatography in a Sephadex® LH-20 column, with MeOH as the mobile phase. The collected polymer solution in MeOH was concentrated to 2 mL under vacuum on a rotary vacuum evaporator and then the polymerization solution was dialyzed against water for 24 h and lyophilized. The glycerol-based hydroxyl-terminated lipid-poly mer conjugate (Figure 5, see Table 5) was obtained as a white powder (yield shown in Table 5) and characterized by size exclusion chromatography (UV-SEC-MALS) by detecting at a fixed wavelength of 280 nm, corresponding to the absorption assigned to the trithiocarbonate group of the RAFT end-group. The complete disappearance of the trithiocarbonate group signal in the SEC chromatogram confirmed the successful modification of the polymer end-group.hydroxyl-terminated polymerFigure 5. Synthetic pathway and structure of hydroxyl-terminated glycerol-based lipid-polymer conjugates containing spacer. For a list of starting polymers and hydroxyl-terminated polymers, see Table 5.Table 5. Characteristics of hydroxyl-terminated lipid-polymer conjugates prepared from glycerolbased CTAs and containing spacer.Hydroxyl-terminated Starting Added mmol n y Yiel Yield polymer polymer ofH2O2d (%) (mg)C14-glycerolsADA000214P ADA0002 0.09 11 15 23 8109PC16-glycerolsADA000236P ADA0002 0.11 13 11 24 8217PC18-glycerolsADA000237P ADA0002 0.11 15 10 25 8618PExample 41 - Azidation of polymers obtained from glycerol-based CTAsThe terminal tri thiocarbonate group of the lipid-polymer conjugate was modified to azide groups as follows: In a 5mL Schlenk tube, 15.0 mg of starting polymer (5.4 pmol, 1 eq.), p-toluenesulfonylazide (21.3 mg, 108 pmol, 20 eq.), potassium persulfate (21.9 mg, 81 pmol, 15 eq.) and sodium thiosulfate pentahydrate (20.1 mg, 81 pmol, 15 eq.) were dissolved in 1.0 mL of DMF and 1.0 mL of distilled water under stirring. The reaction mixture was purged with argon for 20 minutes by using a needle which introduces argon into the tube through the septum. Afterwards, the Schlenk tube with the reaction mixture was placed into a heating block at 50 °C to initiate the reaction, which was allowed to proceed for 14 hours. The yellowish coloration of polymer gradually became lighter and completely disappeared after 14 hours as observed by visual inspection. Afterwards, 3 mL of MeOH were added to the polymer solution, and the polymer was purified by flash chromatography in a Sephadex® LH-20 column, with MeOH as the mobile phase. The collected polymer solution in MeOH was concentrated to 2 mL under vacuum on a rotary vacuum evaporator and then the polymer solution was dialyzed against water for 24h and lyophilized. The glycerol-based azide -terminated lipid-polymer conjugate (Figure 6, see Table 6) was obtained as a white powder (yield shown in Table 6) and characterized by size exclusion chromatography (UV-SEC-MALS) by detecting at a fixed wavelength of 280 nm, corresponding to the absorption assigned to the trithiocarbonate group of the CTA end-group. The complete disappearance of the trithiocarbonate group signal in the SEC chromatogram, along with the appearance of the characteristic stretching vibration corresponding to the azido groups in the FT-IR (2000 - 2200 cm-1), confirmed the successful modification of the polymer end-group.Masting poiyme;GH2. C^F.-H2O {1:t v / y);5$4C6Hazide te natsM polynFigure 6. Synthetic pathway and structure of azido-terminated glycerol-based lipid-poly mer conjugate.Table 6. Characteristics of glycerol-based azido-terminated lipid-polymer conjugate.Azido- Starting Added pmol n y Yiel Yield terminated polymer of TsNs d (%) polymer (mg)C14-GlycerolADA000265P ADA000022P 108 11 7 10 72Example 42 - Pyridyl disulfide polymers obtained from glycerol-based CTAsThe terminal trithiocarbonate group of the lipid-polymer conjugate was modified to pyridyl disulfide group as follows: In a 5mL Schlenk tube, 15 mg of starting polymer and ADA002021X (molar ratio of ADA002021X to polymer = 20.0, as specified in Table 7) were dissolved in 1 mL of dry DMSO. The solution was sealed with a rubber septum and purged with argon at RT for 20 min. The Schlenk tube was then placed into a heating block at 75 °C and the reaction mixture was allowed to react for 2 h. Afterwards, the solution was quenched by exposing the reaction mixture to air and liquid nitrogen. To the solution, 3 mL of MeOH were added and the mixture was then purified by flash chromatography in a Sephadex® LH-20 column using MeOH as mobile phase. The collected polymer solution in MeOH was concentrated to 2 mL under vacuum on a rotary vacuum evaporator and then dialyzed against water for 24 h and then lyophilized. The glycerol-based pyridyl disulfide terminated lipid-polymer conjugate (Figure 7, Table 7) was obtained as a white powder (yield, as indicated in Table 7).iJ^(CH2)nCH3°^^(CH2)nCH3Ostarting polymerpyridyl disulfide-terminated polymerFigure 7. Synthetic pathway and structure of pyridyl disulfide-terminated glycerol-based lipid-polymer conjugate.Table 7. Characteristics of pyridyl-disulfide terminated glycerol-based lipid-polymer conjugates prepared from pyridyl-disulfide modified imitator ADA002021X.PyridylStarting Added µmol of n y Yield Yield disulfide - polymer (mg) (%)ADA002021XterminatedpolymerADA000174P ADA00 158 11 7 11 850022PADA000200P ADA00 91 13 15 10 770090PExample 43 - tetrazine terminated polymers obtained from glycerol-based CTAsThe terminal trithiocarbonate group of the lipid-polymer conjugate was modified to tetrazine groups as follows: In a 5mL Schlenk tube, 15 mg of starting polymer and ADA002024X (molar ratio of ADA002024Xto polymer = 20.0) were dissolved in 1 mL of dry DMSO. The solution was sealed with a rubber septum and purged with argon at RT for 20 min. The Schlenk tube was then placed into a heating block at 75 °C and the reaction mixture was allowed to react for 2 h. Afterwards, the solution was quenched by exposing the reaction mixture to air and liquid nitrogen. To the solution, 3 mL of MeOH were added and the mixture was then purified by flash chromatography in a Sephadex® LH-20 column using MeOH as mobile phase. The collected polymer solution in MeOH was concentrated to 2 mL under vacuum on a rotary vacuum evaporator and then dialyzed against water for 24 h and then lyophilized. The glycerol-based tetrazine terminated lipid-polymer conjugate (Figure 8, Table 8) was obtained as a pink powder (yield, as indicated in Table 8).Figure 8. Synthetic pathway and structure of tetrazine-terminated glycerol-based lipid-polymer conjugate.tetrazine-terminated polymerTable 8. Characteristics of tetrazine-terminated glycerol-based lipid-polymer conjugate prepared from tetrazine modified imitator ADA002024X.PyridylStarting Added n y Yield Yield disulfide - polymer pmol of (mg) (%)terminated ADA00202polymer IXADA000199P ADA0000 91 13 15 11 8590PPolymers prepared by using alkylamide-based CTAsExample 44 - Poly(A / -(2-hydroxypropyl)methacrylamide)-alkylamide-based lipid conjugates

[0269] The polymerization of HPMA was carried out according to the [CTA]:[AIBN] ratio specified in Table 9. In Figure 9 there is a general procedure for synthesizing the PHPMA-lipid conjugate: In a 5mL Schlenk tube, HPMA (200 mg, 1.4 mmol) and AIBN (refer to Table 9) were dissolved in 1.0 mL of dry DMF under stirring. The respective alkylamide-based CTA (see Table 9) was then added in a form of solution including 1 mL of dry DMF. The polymerization mixture was purged with argon for 20 minutes. Afterwards, the Schlenk tube was placed into a heating block at 75 °C to initiate the polymerization, which was allowed to proceed for 18 hours. The reaction was then quenched by exposing the reaction mixture to air and liquid nitrogen (by opening the valve of the Schlenk tube and putting the Schlenk tube into the liquid nitrogen bath). To the polymerization solution, 3 mL of MeOH were added, and the reaction mixture was purified by flash chromatography using a Sephadex® LH-20 column, with MeOH as the mobile phase. The collected polymer solution in MeOH was concentrated to 2 mL under vacuum on a rotary vacuum evaporator and then dialyzed against water for 24 hours and lyophilized. The alkylamide-based lipid-polymer conjugates (Figure 9, listed in Table 9) were obtained as yellowish powders (yield, as indicated in Table 9) and characterized by size exclusion chromatography with multi-angle light scattering (SEC-MALS).(CH2)nCH3N^(CH2)nCH3O CTA OH HPMA AIBN, 75 °C, 18 h, DMFOH polymerFigure 9. Synthetic pathway and structure of alkylamide-based lipid-polymer conjugate. For a list of CTAs and polymers, see Table 9.Table 9. Characteristics of lipid-polymer conjugates prepared from alkylamide-based CTAs in 2 mL ofDMF for 1.4 mmol (200 mg) of HPMA monomer.[CTA]: [I] Mw, SEC D Yield Yield Polymer n ymmol (g / mol)a(SEC)b(mg) (%) C14-alkylamides [ADA900042X]: [AIBN]ADA000002P 0.0275: 0.0027 12 28 5 300 1.14 81 37 ADA000004P 0.0240: 0.0024 12 46 8 200 1.13 85 37 ADA000008P 0.0763: 0.0076 12 17 3 100 1.12 68 27ADA000038P 0.0107: 0.0011 12 72 12600 1.15 108 52 ADA000039P 0.0114: 0.0012 12 74 11 300 1.11 69 33 ADA000060P 0.0092: 0.009 12 89 14800 1.10 60 29 ADA000054P 0.0065: 0.0006 12 125 18 500 1.19 72 35ADA000097P 0.0687: 0.0067 12 14 3 200 1.20 100 34ADA000098P 0.0610: 0.0061 12 20 4 300 1.20 96 34ADA000207P 0.0648: 0.007 12 18 3700 1.16 100 43C16-alkylamides [ADA000001X]: [AIBN]ADA000037P 0.0083: 0.0009 14 107 16 100 1.25 52 24C 18- alky lamides [ADA900041X]: [AIBN]ADA000047P 0.0109: 0.0011 16 81 12400 1.10 52 25 ADA000050P 0.0093: 0.0009 16 100 14600 1.12 54 26“Determined by SEC-MALS in DMF / O.1 M LiBr;bDispersity as determined by SEC-MALS y = (Mnof polymer measured by SEC - Mwof CTA) / Mwof HPMA monomer.Example 45 - Poly(A / -(2-hydroxypropyl)methacrylamide)-alkylamide-based lipid conjugates including additional structural features

[0270] The polymerization of HPMA was also carried out according to the [CTA]:[AIBN] ratio specified in Table 10. In Figure 10 there is a general procedure for synthesizing the PHPMA-lipid conjugate: In a 5mL Schlenk tube, HPMA (200 mg, 1.4 mmol) and AIBN (refer to Table 10) weredissolved in 1.0 mL of dry DMF under stirring. The respective alkylamide-based CTA (see Table 10) was then added in a form of solution including 1 mL of dry DMF. The polymerization mixture was purged with argon for 20 minutes. Afterwards, the Schlenk tube was placed into a heating block at 75 °C to initiate the polymerization, which was allowed to proceed for 18 hours. The reaction was then quenched by exposing the reaction mixture to air and liquid nitrogen (by opening the valve of the Schlenk tube and putting the Schlenk tube into the liquid nitrogen bath). To the polymerization solution, 3 mL of MeOH were added, and the reaction mixture was purified by flash chromatography using a Sephadex® LH-20 column, with MeOH as the mobile phase. The collected polymer solution in MeOH was concentrated to 2 mL under vacuum on a rotary vacuum evaporator and then dialyzed against water for 24 hours and lyophilized. The alkylamide-based lipid-polymer conjugate (Figure 10, listed in Table 10) was obtained as yellowish powder (yield, as indicated in Table 10) and characterized by size exclusion chromatography with multi-angle light scattering (SEC-MALS).bc x. f ^CH,)r'CH?" X p- >fX--....-x S Jl^ SX v- Q X.....<k V.-.--x |y- A, HN 'O A J 6 6 XXADA007012X OH. | HPMA AIBN, 75 X, 18 h, solvent i i..z-(CH2)nCH3L H. sSJ. Jk I. X...ox.......^ X....(CH^CH.^I [ AyY- O. - s HN:<O0°X... Polymer OHFigure 10. Synthetic pathway and structure of alkylamide-based lipid-polymer conjugate containing spacer.Table 10. Characteristics of lipid-polymer conjugate prepared from alkylamide-based CTA and containing spacer in 2 mL of DMF for 1.4 mmol (200 mg) of HPMA monomer.Polymer [CTA]: [I] n y D Yield Yield Mw,mmol (SEC)b(mg)SEC(g / mol)a(%)[ADA007012X]: [AIBN]ADA000263P 0.0450: 0.005 12 68 12500 1.18 106 44Example 46 - hydroxylation of polymers obtained from alkylamide-based CT As

[0271] The terminal tri thiocarbonate group of the lipid-poly mer conjugates was converted to hydroxyl groups as follows: In a 5mL Schlenk tube, 30 mg of starting polymer (see Table 11) were dissolved in 2 mL of water and the Schlenk tube was placed into a heating block at 75 °C for polymer complete solubilization (about 5 min). Hydrogen peroxide (H2O2; molar ratio of H₂O₂ to polymer = 10.0, as specified in Table 11) was added to the solution. H₂O₂ was used as a 30% w / w aqueous solution. The Schlenk tube was sealed with a rubber septum and left to stir for 16 hours at 70 °C, when exposed to air (with the stopcock valve open). The yellowish coloration of polymers completely disappeared after 16 hours as observed by visual inspection. Afterwards, 3 mL of MeOH was added to the polymer solution, and the polymer was purified by flash chromatography in a Sephadex® LH-20 column, with MeOH as the mobile phase. The collected polymer solution in MeOH was concentrated to 2 mL under vacuum on a rotary vacuum evaporator and then the polymerization solution was dialyzed against water for 24 h and lyophilized. The alkylamide-based hydroxyl-terminated lipid-polymer conjugate (Figure 11, see Table 11) was obtained as a white powder (yield, as indicated in Table 11) and characterized by size exclusion chromatography (UV-SEC-MALS) by detecting at a fixed wavelength of 280 nm, corresponding to the absorption assigned to the trithiocarbonate group of the CTA end-group. The complete disappearance of the trithiocarbonate group signal in the SEC chromatogram confirmed the successful modification of the polymer end-group.starting polymerOHH2O, 75 °CH2O2(30% v / v), 16 h(CH2)nCH3N^,(CH2)nCH3hydroxyl-terminated polymerOHFigure 11. Synthetic pathway and structure of hydroxyl-terminated alkylamide-based lipid-polymer conjugate. For a list of starting polymers and hydroxyl-terminated polymers, see Table 11.Table 11. Characteristics of alkylamide-based hydroxyl-terminated lipid-polymer conjugates.hydroxyl- Added Yield Starting Yieldterminated mmol of n y (%) polymer (mg)polymer H2O2C14-alkylamidesADA000005P ADA000002P 0.04 12 28 24 82ADA000007P ADA000004P 0.04 12 46 23 79 ADA000009P ADA000008P 0.10 12 17 25 87 ADA000040P ADA000039P 0.03 12 74 23 78 ADA000055P ADA000054P 0.02 12 125 22 74 ADA000102P ADA000060P 0.02 12 89 24 86ADA000205P ADA000097P 0.10 12 14 23 79ADA000206P ADA000098P 0.07 12 20 25 87ADA000212P ADA000207P 0.08 12 18 22 74C16- alkylamidesADA000049P ADA000037P 0.02 14 107 23 77C18-alkylamidesADA000048P ADA000047P 0.02 16 81 22 74 ADA000051P ADA000050P 0.02 16 100 23 77Example 47 - propargylation of polymers obtained from alkylamide-based CTAs

[0272] The terminal tri thio carbonate group of the lipid-polymer conjugate was modified to propargyl group as follows: In a 5mL Schlenk tube, 15 mg of starting polymer and ADA902085X (molar ratio of ADA902085X to polymer = 20.0, as specified in Table 12) were dissolved in 1 mL of dry DMSO. The solution was sealed with a rubber septum and purged with argon at RT for 20 min. The Schlenk tube was then placed into a heating block at 75 °C and the reaction mixture was allowed to react for 2 h. Afterwards, the solution was quenched by exposing the reaction mixture to air and liquid nitrogen. To the solution, 3 mL of MeOH were added and the mixture was then purified by flash chromatography in a Sephadex® LH-20 column using MeOH as mobile phase. The collected polymer solution in MeOH was concentrated to 2 mL under vacuum on a rotaryvacuum evaporator and then dialyzed against water for 24 h and then lyophilized. The alkylamide- based propargyl terminated lipid-polymer conjugate (Figure 12, Table 12) was obtained as a white powder (yield, as indicated in Table 12).ADA902085X2. DMSO, Ar 20 min, RT3. 75 °C, 2 h(CH2)nCH3(CH2)nCH3Propargyl-terminated polymerOHFigure 12. Synthetic pathway and structure of propargyl-terminated alkylamide-based lipid-polymer conjugate. For list of starting polymers and propargyl-terminated polymers, see Table 12.Table 12. Characteristics of alkylamide-based propargyl-terminated lipid-polymer conjugates.Propargyl-terminated Starting Added µmol of Yield Yield n ypolymer polymer ADA902085X (mg) (%) C14-alkylamidesADA000031P ADA000038P 24 12 72 11 73 C16-alkylamidesADA000036P ADA000037P 19 14 107 12 80 C18-alkylamidesADA000071P ADA000050P 21 16 100 12 80Example 48 - Poly(A / -(2-hydroxypropyl)methacrylamide)-alkylamide-based lipid conjugates

[0273] The polymerization of HPMA was carried out according to the [CTA]:[AIBN] ratio specified in Table 13. In Figure 13 there is a general procedure for synthesizing the PHPMA-lipid conjugate: In a Schlenk tube, HPMA (200 mg, 1.4 mmol) and AIBN (amount of substance: refers to Table 13) were dissolved in 1.0 mL of dry solvent (as listed in Table 13) under stirring. The respective alkylamide-based CTA (amount of substance refers to Table 13) was then added in 1 mL of dry solvent (refers to Table 13). The polymerization mixture was purged with argon for 20 minutes by using a needle which introduces argon into the tube through the septum. Afterwards, the Schlenk tube with the reaction mixture was placed into a heating block at 75 °C to initiate the polymerization, which was allowed to proceed for 18 hours. The reaction was then quenched by exposing the mixture to air and liquid nitrogen (by opening the stopcock valve of the Schlenk tube and putting the Schlenk tube into a liquid nitrogen bath). To the polymerization solution, 3 mL of MeOH was added, and the reaction mixture was purified by flash chromatography using a Sephadex® LH-20 column, with MeOH as the mobile phase. The collected polymer solution in MeOH was concentrated to 2 mL under vacuum on a rotary vacuum evaporator and then dialyzed against water for 24 hours and lyophilized. The alkylamide-based lipid-polymer conjugates (Figure 13, listed in Table 13) were obtained as yellowish powders (yield, as indicated in Table 13) and characterized by size exclusion chromatography with multi-angle light scattering (SEC- MALS).OH - HPMA AIBN, 75 °C, 18 h, solventFigure 13. Synthetic pathway and structure of alkylamide-based lipid-polymer conjugates containing spacer. For a list of CT As and polymers, see Table 13.Table 13. Characteristics of lipid-polymer conjugates prepared from alkylamide-based CT As in 2 mL of solvent for 1.4 mmol (200 mg) of HPMA monomer.Polymer [CTA]: [I] Solvent n y D Yield Yield Mw, SECmmol (SEC)b(mg) (%) (g / mol)aC14- [ADA007002X]:alkylamide [AIBN]ADA000208P 0.046: 0.003 DMF 12 16 3 600 1.14 152 6406- [ADA007004X]al kylamide: [AIBN]ADA000215P 0.068: 0.005 DMF 14 8 2200 1.14 144 5508- [ADA007005X]al kylamide: [AIBN]ADA000216P 0.068: 0.005 DMF 16 7 2200 1.16 140 53determined by SEC-MALS in DMF / 0.1 M LiBr;bDispersity as determined by SEC-MALS ( w / n).y= ( n of polymer measured by SEC - Mwof CTA) / A / w of HPMA monomer.Example 49 - hydroxylation of polymers obtained from alkylamide-based CT As

[0274] The terminal trithiocarbonate group of the lipid-polymer conjugates was converted to hydroxyl groups as follows: In a 5mL Schlenk tube, 30 mg of starting polymer (see Table 14) were dissolved in 2 mL of water and the Schlenk tube was placed into a heating block at 75 °C for polymer complete solubilization (about 5 min). Hydrogen peroxide (H2O2; molar ratio of H₂O₂ to polymer = 10.0, as specified in Table 14) was added to the solution. H₂O₂ was used as a 30% w / w aqueous solution. The Schlenk tube was sealed with a rubber septum and left to stir for 16 hours at 70 °C, when exposed to air (with the stopcock valve open). The yellowish coloration of polymers completely disappeared after 16 hours as observed by visual inspection. Afterwards, 3 mL of MeOH was added to the polymer solution, and the polymer was purified by flash chromatography in a Sephadex® LH-20 column, with MeOH as the mobile phase. The collected polymer solution in MeOH was concentrated to 2 mL under vacuum on a rotary vacuum evaporator and then the polymerization solution was dialyzed against water for 24 h and lyophilized. The alkylamide- based hydroxy 1-terminated lipid-polymer conjugate (Figure 14, see Table 14) was obtained as a white powder (yield, as indicated in Table 14) and characterized by size exclusion chromatography (UV-SEC-MALS) by detecting at a fixed wavelength of 280 nm, corresponding to the absorption assigned to the trithiocarbonate group of the RAFT end-group. The complete disappearance of the trithiocarbonate group signal in the SEC chromatogram confirmed the successful modification of the polymer end-group.(CH2)nCH3Figure 14. Synthetic pathway and structure of hydroxyl-terminated alkylamide-based lipid-polymer conjugate containing spacer. For a list of starting polymers and hydroxyl-terminated polymers, see Table 14.Table 14. Characteristics of alkylamide-based hydroxyl-terminated lipid-polymer conjugates containing spacer.hydroxyl- Starting Added n y Yield Yield terminated polymer mmol (mg) (%) polymer of H2O2C14- alkylamidesADA000213P ADA000208P 0.08 12 16 23 77C16- alkylamidesADA000234P ADA000215P 0.14 14 8 23 77C18- alkylamidesADA000235P ADA000216P 0.14 16 7 24 82Example 50 - Hydrogenation of polymers obtained from alkylamide-based CTAsThe terminal trithiocarbonate group of the lipid-polymer conjugate was modified to hydrogen group as follows: In a 5mL Schlenk tube, 15 mg of starting polymer and tri ethyl borane (TEB) (molar ratio of TEB to polymer = 5.0) were dissolved in 1 mL of dry Toluene at RT. The solution was kept in presence of oxygen (with the stopcock valve open) and left to stir for 5 min. The yellowish coloration of polymers gradually became lighter and completely disappeared after 1 min as observed by visual inspection. Afterwards, 3 mL of MeOH were added to the polymer solution, and the polymer waspurified by flash chromatography in a Sephadex® LH-20 column, with MeOH as the mobile phase. The collected polymer solution in MeOH was concentrated to 2 mL under vacuum on a rotary vacuum evaporator and then the polymer solution was dialyzed against water for 24h and lyophilized. The alkylamide-based hydrogen-terminated lipid-polymer conjugate (Figure 15, see Table 15) was obtained as a white powder (yield shown in Table 15) and characterized by size exclusion chromatography (UV-SEC-MALS) by detecting at a fixed wavelength of 280 nm, corresponding to the absorption assigned to the trithiocarbonate group of the CTA end-group. The complete disappearance of the tri thiocarbonate group signal in the SEC chromatogram along with the disappearance of the aromatic group of ADA007012X (CTA) at the 7-8 ppm region in 'H NMR confirmed the successful modification of the polymer end-group.„,(CHAnCH?starting polymerI 1. Triethyiborane (TEB) - 5.0 Eq. I 2. Toluene)RT 3. Oxygen, 5 min...(CHjOpCH;; 4.4,.„ J4jyA d HN OOH Hydrogemterminated polymerFigure 15. Synthetic pathway and structure of hydrogen-terminated alkylamide-based lipid-polymer conjugate.Table 15. Characteristics of alkylamide-based hydrogen-terminated lipid-polymer conjugate.Hydro gen- Starting Added n y Yield Yield terminated polymer pmol of (mg) (%) polymerTEBC14-alkylamideADA000266P ADA0002 6.0 12 68 11 7563PExample 51 -Thiolation of polymers obtained from alkylamide-based CTAsThe terminal tri thio carbonate group of the lipid-polymer conjugate was modified to thiol groups as follows: In a 5mL Schlenk tube, 15 mg of starting polymer and NaNs, (molar ratio of NaN? to polymer = 10.0) were dissolved in 1 mL of dry DMF at RT. The solution was kept in presence of oxygen (with the stopcock valve open) and left to stir for 5 min). The yellowish coloration of polymers gradually became lighter and completely disappeared after 5 min as observed by visual inspection. Afterwards, 3 mL of MeOH were added to the polymer solution, and the polymer was purified by flash chromatography in a Sephadex® LH-20 column, with MeOH as the mobile phase. The collected polymer solution in MeOH was concentrated to 2 mL under vacuum on a rotary vacuum evaporator and then the polymer solution was dialyzed against water for 24h and lyophilized. The alkylamide-based thiol-terminated lipid-polymer conjugate (Figure 16, see Table 16) was obtained as a white powder (yield shown in Table 16) and characterized by size exclusion chromatography (UV-SEC-MALS) by detecting at a fixed wavelength of 280 nm, corresponding to the absorption assigned to the trithiocarbonate group of the CTA end-group. The complete disappearance of the trithiocarbonate group signal in the SEC chromatogram along with the disappearance of the aromatic group of ADA007012X (CTA) at the 7-8 ppm region in1H NMR confirmed the successful modification of the polymer end-group.N KNThtaMeimmsted <4y mixFigure 16. Synthetic pathway and structure of thiol -terminated alkylamide-based lipid-poly mer conjugate.Table 16. Characteristics of alkylamide-based thiol-terminated lipid-polymer conjugate.Hydrogen- Starting Added pmol n y Yield Yield terminated polymer of NaN3(mg) (%) polymerC14-alkylamideADA000264P ADA000263P 12 12 68 11 75Example 52 - Pyridyl disulfide polymers obtained from alkylamide-based CTAsThe terminal trithiocarbonate group of the lipid-polymer conjugate was modified to pyridyl disulfide group as follows: In a 5mL Schlenk tube, 15 mg of starting polymer and ADA002021X (molar ratio of ADA002021X to polymer = 20.0, as specified in Table 17) were dissolved in 1 mL of dry DMSO.The solution was sealed with a rubber septum and purged with argon at RT for 20 min. The Schlenk tube was then placed into a heating block at 75 °C and the reaction mixture was allowed to react for 2 h. Afterwards, the solution was quenched by exposing the reaction mixture to air and liquid nitrogen. To the solution, 3 mL of MeOH were added and the mixture was then purified by flash chromatography in a Sephadex® LH-20 column using MeOH as mobile phase. The collected polymer solution in MeOH was concentrated to 2 mL under vacuum on a rotary vacuum evaporator and then dialyzed against water for 24 h and then lyophilized. The alkylamide-based pyridyl disulfide terminated lipid-polymer conjugate (Figure 17, Table 17) was obtained as a white powder (yield, as indicated in Table 17).2. DMSO, Ar 20 min, RT3. 75 °C, 2 hPyridyl disulfide-terminated polymerFigure 17. Synthetic pathway and structure of Pyridyl disulfide-terminated alkylamide-based lipid-polymer conjugate.Table 17. Characteristics of Pyridyl-disulfide terminated alkylamide-based lipid-polymer conjugates prepared from Pyridyl-disulfide modified imitator ADA002021X.PyridylStarting Added pmol n y Yield Yield disulfide - polymer of (mg) (%) terminatedADA002021XpolymerADA000175P ADA000 97 12 17 10 77008PLipid-poly mer conjugates prepared from the initiator-approach (lipid-i nitiator conjugated) Example 53 - Poly(A / -(2-hydroxypropyl)methacrylamide) homopolymer

[0275] Firstly, a PHPMA homopolymer with low molecular weight was prepared according to the [CTA]:[AIBN] ratio specified in Table 18 as follows: In a Schlenk tube, HPMA (200 mg, 1.4 mmol) and AIBN (refer to Table 18) were dissolved in 1 mL of dry z-PrOH under stirring. The CTA ADA900020X (see Table 18), was then added in a form of solution including 1 mL of dry z-PrOH. The polymerization mixture was purged with argon for 20 minutes. Afterwards, the Schlenk tube was placed into a heating block at 75 °C to initiate the polymerization, which was allowed to proceed for 18 hours. The reaction mixture was then quenched by exposing the mixture to air and liquid nitrogen. To the polymerization solution, 3 mL of MeOH was added, and the mixture was purified by flash chromatography using a Sephadex® LH-20 column, with MeOH as the mobile phase. The collected polymer solution in MeOH was concentrated to 2 mL under vacuum on a rotary vacuum evaporator and then dialyzed against water for 24 hours and lyophilized. The PHPMA-homopolymer (Figure 18, listed in Table 18) was obtained as yellowish powder (yield, as indicated in Table 18) and characterized by size exclusion chromatography with multi-angle light scattering (SEC-MALS).Figure 18. Synthetic pathway and structure of PHPMA homopolymer.Table 18. Characteristics of PHPMA homopolymer prepared in 2 mL of z-PrOH for 1.4 mmol (200 mg) of HPM A monomer.y Mw, SEC D Yield Yield Polymer [CTA]: [I] mmol(g / mol)a(SEC)b(mg) (%) [ADA900020X]: [AIBN]ADA000073P 0.0693: 0.0069 13 2700 1.25 165 75“Determined by SEC-MALS in DMF / 0.1 MLiBr;bDispersity as determined by SEC-MALSy = (Mnof polymer measured by SEC - Mwof CTA) / Mwof HPMA monomer.Example 54 - Poly(A / -(2-hydroxypropyl)methacrylamide) homopolymer-lipid modified

[0276] Following, the terminal tri thio carbonate group of the PHPMA homopolymer was modified to an alkylamide or glycerol-based lipid-end group (see Table 19) as follows: In a 5mL Schlenk tube, 15 mg of homopolymer (ADA000073P) and the respective lipid-initiator conjugate (Table 19) (molar ratio of lipid-initiator conjugate to polymer = 20.0, as specified in Table 19) were dissolved in 1 mL of dry DMSO. The solution was sealed with a rubber septum and purged with argon at RT for 20 min. The Schlenk tube was then placed into a heating block at 75 °C and the reaction mixture was allowed to react for 2 h. Afterwards, the solution was quenched by exposing the reaction mixture to air and liquid nitrogen. To the solution, 3 mL of a mixture of dioxane / MeOH was added and the mixture was then purified by flash chromatography in a Sephadex® LH-20 column using dioxane / MeOH mixture (1 / 1, v / v) as mobile phase. The collected polymer solution was concentrated to 2 mL under vacuum on a rotary vacuum evaporator and then dialyzed against water for 24 h and then lyophilized. The alkylamide-based lipid-polymer conjugate (Figure 19,Table 19) or glycerol-based lipid-polymer conjugates (Figure 20, Table 19) were obtained as white powders (yield, as indicated in Table 19).1. ADA002002X2. DMSO, Ar 20 min, RT3. 75 °C, 2 hH3C(H2C)12H3C(H2C)12^NFigure 19. Synthetic pathway and structure of alkylamide-based lipid-polymer conjugate obtained by the initiator approach. Value of y is defined in Table 19.1. ADA002003X2. DMSO, Ar 20 min, RT3. 75 “C, 2 hCH3(CH2)1VCH3(CH2)II y COOHOOHADA000078PFigure 20. Synthetic pathway and structure of glycerol-based lipid-polymer conjugate obtained by the initiator approach. Value of y is defined in Table 19.Table 19. Characteristics of lipid-polymer conjugates prepared from the lipid-initiator approach.Lipid-terminated Starting Added nmol of Mw, SEC D Yield Yield yPolymer polymer ADA002002X (g / mol)a(SEC)b(mg) (%) C14-alkylamideADA000075P ADA000073P 111 13 3 900 1.32 11 66 Lipid-terminated Starting Added nmol of Yield Yield Polymer polymer ADA002003X (mg) (%) C14-glycerolADA000078P ADA000073P 111 13 3 800 1.25 13 76“Determined by SEC- VIALS in DMF / 0.1 M LiBr;bDispersity as c etermined by SEC-MALS (MJh ^n).Polymer prepared by using the cleavable alkylamide-based CTAExample 55 - Poly(A / -(2-hydroxypropyl)methacrylamide)-cleavable-alkylamide-based lipid conjugatesThe polymerization of HPMA was carried out according to the [CTA]:[AIBN] ratio specified in Table 20. In Figure 21 there is a general procedure for synthesizing the cleavable PHPMA-lipid conjugate: In a Schlenk tube, HPMA (200 mg, 1.4 mmol) and AIBN (amount of substance: refers to Table 20) were dissolved in 1.0 mL of dry DMF under stirring. The respective cleavable alkylamide-based CTA (amount of substance: refers to Table 20) was then added in 1 mL of dry DMF. The polymerization mixture was purged with argon for 20 minutes by using a needle which introduces argon into the tube through the septum. Afterwards, the Schlenk tube with the reaction mixture was placed into a heating block at 75 °C to initiate the polymerization, which was allowed to proceed for 18 hours. The reaction was then quenched by exposing the mixture to air and liquid nitrogen (by opening the stopcock valve of the Schlenk tube and putting the Schlenk tube into the liquid nitrogen bath). To the polymerization solution, 3 mL of MeOH was added, and the mixture was purified by flash chromatography using a Sephadex® LH-20 column, with MeOH as the mobile phase. The collected polymer solution in MeOH was concentrated to 2 mL under vacuum on a rotary vacuum evaporator and then dialyzed against water for 24 hours and lyophilized. The cleavable alkylamide-based lipid-polymer conjugate (Figure 21, listed in Table 20) was obtained as yellowish powder (yield, as indicated in Table 20) and characterized by size exclusion chromatography with multi-angle light scattering (SEC-MALS).Table 20. Characteristics of cleavable lipid-polymer conjugate prepared from cleavable alkylamide-based CTA in 2 mL of DMF for 1.4 mmol (200 mg) of HPMA monomer.Polymer [CTA]: [I] y D Yield Yield Mw, SECmmol (SEC)b(mg) (%)(g / mol)a[ADA002013X]:[AIBN]ADA000147 0.043: 22 4 800 1.16 48 17P 0.006ADA000163 0.075: 7 2 300 1.15 32 14P 0.011determined by SEC-MALS in DMF / 0.1 M LiBr;bDispersity as determined by SEC-MALS (w / n). y = (Mnof polymer measured by SEC -wof CTA) / W\ of HPMA monomer.HPMA AIBN, 75 °C, 18 h, DMFf f \ A / HV S S4. vx" S” O’x-'- O' Y ’ | 6 HN " *'0 CH3(CH2)fi"" ••'■' N " A '''O Yx''OH polymerFigure 21. Synthetic pathway and structure of cleavable alkylamide-based lipid-polymer conjugate.Example 56 - isobutyronitrile termination of polymers obtained from cleavable alkylamide-based CTAsThe terminal trithiocarbonate group of the cleavable lipid-polymer conjugate was modified to isobutyronitrile group as follows: In a 5mL Schlenk tube, 15 mg of starting polymer and AIBN (molar ratio of AIBN to polymer = 20.0, as specified in Table 21) were dissolved in 1 mL of dry DMSO. The solution was sealed with a rubber septum and purged with argon at RT for 20 min. The Schlenk tube was then placed into a heating block at 75 °C and the reaction mixture was allowed to react for 2 h.Afterwards, the solution was quenched by exposing the reaction mixture to air and liquid nitrogen. To the solution, 3 mL of MeOH were added and the mixture was then purified by flash chromatography in a Sephadex® LH-20 column using MeOH as mobile phase. The collected polymer solution in MeOH was concentrated to 2 mL under vacuum on a rotary vacuum evaporator and then dialyzed against water for 24 h and then lyophilized. The cleavable alkylamide-based isobutyronitrile terminated lipid-polymer conjugate (Figure 22, listed in Table 21) was obtained as a white powder (yield, as indicated in Table 21).'s^s-4-f^HN ' k ' O5 yo CH3(CH2)n-.-xxhT X 'O ^Y""" CH3(CHY,starting polymer| 1. AIBN| 2. DMSO, Ar 20 min, RT3. 75 °C, 2 hCH3(CH2V'XX^''^CH3(CH2Ki'"'"Isobutyronitrile-terminated polymerFigure 22. Synthetic pathway and structure of cleavable isobutyronitrile-terminated alkylamide-based lipid-polymer conjugate.Table 21. Characteristics of isobutyronitrile terminated lipid-polymer conjugates prepared from cleavable alkylamide-based CTAsIsobutyronitrile- Starting Added n y Yield Yield terminated polymer pmol of (mg) (%) polymerAIBNCleavable C14- alkylamideADA000155P ADA0001 63 12 22 10 7747PADA000168P ADA0001 130 12 7 11 8563PPolymer prepared by using the cleavable glycerol-based CTAExample 57 - Poly(A / -(2-hydroxypropyl)methacrylamide)-cleavable-glycerol-based lipid conjugates

[0277] The polymerization of HPMA was carried out according to the [CTA]:[AIBN] ratio specified in Table 22. In the Figure 23 there is a general procedure for synthesizing the cleavable PHPMA- lipid conjugate: In a Schlenk tube, HPMA (200 mg, 1.4 mmol) and AIBN (amount of substance:refers to Table 22) were dissolved in 1.0 mL of dry DMF under stirring. The respective cleavable glycerol-based CTA (amount of substance: refers to Table 22) was then added in 1 mL of dry DMF. The polymerization mixture was purged with argon for 20 minutes by using a needle which introduces argon into the tube through the septum. Afterwards, the Schlenk tube with the reaction mixture was placed into a heating block at 75 °C to initiate the polymerization, which was allowed to proceed for 18 hours. The reaction was then quenched by exposing the mixture to air and liquid nitrogen (by opening the stopcock valve of the Schlenk tube and putting the Schlenk tube into the liquid nitrogen bath). To the polymerization solution, 3 mL of MeOH was added, and the mixture was purified by flash chromatography using a Sephadex® LH-20 column, with MeOH as the mobile phase. The collected polymer solution in MeOH was concentrated to 2 mL under vacuum on a rotary vacuum evaporator and then dialyzed against water for 24 hours and lyophilized. The cleavable glycerol-based lipid-polymer conjugate (Figure 23, listed in Table 22) was obtained as yellowish powder (yield, as indicated in Table 22) and characterized by size exclusion chromatography with multi-angle light scattering (SEC-MALS).HPMA AIBN.75 °C, 13 h, DMF(CH2)nCH3Figure 23. Synthetic pathway and structure of cleavable glycerol-based lipid-polymer conjugate. Value of y as defined in Table 22.Table 22. Characteristics of cleavable lipid-polymer conjugate prepared from cleavable glycerolbased CTA in 2 mL of DMF for 1.4 mmol (200 mg) of HPMA monomer.n y D Yield Yield Polymer [CTA]: [I] mmol SEC (SEC) (%) (mg) (g / mol)ab[ADA002013X]:[AIBN]ADA0000 0.022: 0.002 11 65 11 700 1.15 96 3994PADA00 0.044: 0.006 11 32 6 800 1.19 68 23 0151PADA00 0.080: 0.012 11 8 2 600 1.20 66 18 0164P“Determined by SEC-MALS in DMF / O.1 M LiBr;bDispersity as determined bySEC-MALS y = (Mnof polymer measured by SEC - Mwof CTA) / A7\v of HPMA monomer.Example 58 - isobutyronitrile termination of polymers obtained from cleavable glycerol-based CTAs

[0278] The terminal tri thio carbonate group of the cleavable lipid-polymer conjugate was modified to isobutyronitrile group as follows: In a 5mL Schlenk tube, 15 mg of starting polymer and AIBN (molar ratio of AIBN to polymer = 20.0, as specified in Table 23) were dissolved in 1 mL of dry DMSO. The solution was sealed with a rubber septum and purged with argon at RT for 20 min. The Schlenk tube was then placed into a heating block at 75 °C and the reaction mixture was allowed to react for 2 h. Afterwards, the solution was quenched by exposing the reaction mixture to air and liquid nitrogen. To the solution, 3 mL of MeOH were added and the mixture was then purified by flash chromatography in a Sephadex® LH-20 column using MeOH as mobile phase. The collected polymer solution in MeOH was concentrated to 2 mL under vacuum on a rotary vacuum evaporator and then dialyzed against water for 24 h and then lyophilized. The cleavable glycerol-based isobutyronitrile terminated lipid-polymer conjugate (Figure 24, Table 23) was obtained as a white powder (yield, as indicated in Table 23).(CH2)nCH31. AIBN2. DMSO, Ar 20 min, RT3. 75 °C, 2 hVr(CH2)nCH3Cleavable Isobutyronitrile-terminated polymer ADA000101PFigure 24. Synthetic pathway and structure of cleavable isobutyronitrile-terminated glycerol-based lipid-polymer conjugate.Table 23. Characteristics of isobutyronitrile terminated lipid-polymer conjugates prepared from cleavable glycerol-based CT AsAdded pmol Yield Isobutyronitrile- Starting Yieldof n y (%) terminated polymer polymer (mg)AIBNCleavable C14- glycerolADA000101P ADA000094P 51 11 65 22 85ADA000156P ADA000151P 44 11 32 10 77ADA000169P ADA000164P 115 11 8 11 85“Determined by SEC-MALS in DMF / O.1 M LiBr;bDispersity as determined by SEC-MALS (Afw / Afn).Polymers prepared by using 1,2-Distearoyl-sn-glycero-3-phosphoethanolamine (DSPE)-based CTAsExample 59 - Poly(A / -(2-hydroxypropyl)methacrylamide)-DSPE-based lipid conjugates

[0279] The polymerization of HPMA was carried out according to the [CTA]:[AIBN] ratio specified in Table 24. In Figure 25 there is a general procedure for synthesizing the PHPMA-lipid conjugate: In a Schlenk tube, HPMA (200 mg, 1.4 mmol) and AIBN (amount of substance: refers to Table 24) were dissolved in 1.0 mL of dry solvent (as listed in Table 24) under stirring. The respective DSPE-based CTA (amount of substance refers to Table 24) was then added in 1 mL of dry solvent (refers to Table 24). The polymerization mixture was purged with argon for 20 minutes by using a needle which introduces argon into the tube through the septum. Afterwards, the Schlenk tube with the reaction mixture was placed into a heating block at 75 °C to initiate the polymerization, which was allowed to proceed for 18 hours. The reaction was then quenched by exposing the mixture to air and liquid nitrogen (by opening the stopcock valve of the Schlenk tube and putting the Schlenk tube into a liquid nitrogen bath). To the polymerization solution, 3 mL of MeOH was added, and the mixture was purified by flash chromatography using a Sephadex® LH-20 column, with MeOH as the mobile phase. The collected polymer solution in MeOH was concentrated to 2 mL under vacuum on a rotary vacuum evaporator and then dialyzed against water for 24 hoursand lyophilized. The DSPE -based lipid-polymer conjugates (Figure 25 and Figure 26, listed in Table 24) were obtained as yellowish powders (yield, as indicated in Table 24) and characterized by size exclusion chromatography with multi-angle light scattering (SEC-MALS).AIBN, 75 °C, 18 h, solvent HPMAFigure 25. Synthetic pathway and structure of DSPE-based lipid-polymer conjugates. For list of CTAs and polymers, see Table 24.Figure 26. Synthetic pathway and structure of DSPE-based lipid-polymer conjugates containing spacer. For a list of CT As and polymers, see Table 24.Table 24. Characteristics of lipid-polymer conjugates prepared from DSPE-based CTAs in 2 mL of solvent for 1.4 mmol (200 mg) of HPMA monomer.Polymer [CTA]: [I] Solvent n y D Yield Yield Mw, SECmmol (SEC)b(mg) (%) (g / mol)aDSPE [ADA007015X]: [AIBN]ADA000255P 0.046: 0.009 Dioxane 15 74 12900 1.11 64 32DSPE-linker [ADA007014X]: [AIBN]ADA000256P 0.046: 0.009 Dioxane 15 26 5600 1.15 92 45determined by SEC-MALS in DMF / 0.1 M LiBr;bDispersity as determined by SEC-MALS (M- Mn).y= (Mnof polymer measured by SEC - Mwof CTA) / A w of HPMA monomer.Example 60 - hydroxylation of polymers obtained from DSPE-based CTAs

[0280] The terminal trithiocarbonate group of the lipid-polymer conjugates was converted to hydroxyl groups as follows: In a 5mL Schlenk tube, 30 mg of starting polymer (see Table 25) were dissolved in 2 mL of water and the Schlenk tube was placed into a heating block at 75 °C for polymer complete solubilization (about 5 min). Hydrogen peroxide (H2O2; molar ratio of H₂O₂ to polymer = 10.0, as specified in Table 25) was added to the solution. H₂O₂ was used as a 30% w / w aqueous solution. The Schlenk tube was sealed with a rubber septum and left to stir for 16 hours at 70 °C, when exposed to air (with the stopcock valve open). The yellowish coloration of polymers completely disappeared after 16 hours as observed by visual inspection. Afterwards, 3 mL of MeOH was added to the polymer solution, and the polymer was purified by flash chromatographyin a Sephadex® LH-20 column, with MeOH as the mobile phase. The collected polymer solution in MeOH was concentrated to 2 mL under vacuum on a rotary vacuum evaporator and then the polymerization solution was dialyzed against water for 24 h and lyophilized. The DSPE-based hydroxyl-terminated lipid-polymer conjugates (Figure 27 and Figure 28, see Table 25) was obtained as a white powder (yield, see Table 25) and characterized by size exclusion chromatography (UV-SEC-MALS) by detecting at a fixed wavelength of 280 nm, corresponding to the absorption assigned to the trithiocarbonate group of the RAFT end-group. The complete disappearance of the trithiocarbonate group signal in the SEC chromatogram confirmed the successful modification of the polymer end-group.starting polymerhydroxyl-terminated polymerFigure 27. Synthetic pathway and structure of hydroxyl-terminated DSPE-based lipid-polymer conjugate. For a list of starting polymers and hydroxyl-terminated polymers, see Table 25.0X^(CH2)nCH31. H2O, 75 °C 2. H2O2(30% w / w), 16 h vFigure 28. Synthetic pathway and structure of hydroxyl-terminated DSPE-containing spacer-based lipid-polymer conjugate. For a list of starting polymers and hydroxyl-terminated polymers, see Table 25.Table 25. Characteristics of DSPE-based hydroxyl-terminated lipid-polymer conjugates.hydroxyl- Starting Added mmol n y Yield Yield terminated polymer of H2O2 (mg) (%) polymerDSPEADA000257P ADA000255P 0.02 15 74 23 77DSPEcontainingspacerADA000258P ADA000256P 0.05 15 26 24 82Polymers prepared by using branched-based CTAsExample 61 - Poly(A / -(2-hydroxypropyl)methacrylamide)-branched-based lipid conjugates

[0281] The polymerization of HPMA was carried out according to the [CTA]:[AIBN] ratio specified in Table 26. In Figure 29, 30 and 31 there is a general procedure for synthesizing the PHPMA- lipid conjugate: In a Schlenk tube, HPMA (200 mg, 1.4 mmol) and AIBN (amount of substance: refers to Table 26) were dissolved in 1.0 mL of dry solvent (as listed in Table 26) under stirring. The respective branched-based CTA (amount of substance: see Table 26) was then added in 1 mL of dry solvent (see Table 26). The polymerization mixture was purged with argon for 20 minutes by introducing argon through a needle inserted through the septum. Afterwards, the Schlenk tube with the reaction mixture was placed into a heating block at 75 °C to initiate the polymerization, which was allowed to proceed for 18 hours. The reaction was then quenched by exposing the mixture to air and liquid nitrogen (by opening the stopcock valve of the Schlenk tube and putting the Schlenk tube into a liquid nitrogen bath). To the polymerization solution, 3 mL of MeOH was added, and the mixture was purified by flash chromatography using a Sephadex® LH-20 column,with MeOH as the mobile phase. The collected polymer solution in MeOH was concentrated to 2 mL under vacuum on a rotary vacuum evaporator and then dialyzed against water for 24 hours and lyophilized. The branched-based lipid-polymer conjugates (Figure 29, 30 and 31, listed in Table 26) were obtained as yellowish powders (yield, as indicated in Table 26) and characterized by size exclusion chromatography with multi-angle light scattering (SEC-MALS).Figure 29. Synthetic pathway and structure of symmetric branched-based lipid-polymer conjugates. For a list of CTAs and polymers, see Table 26.HPMA AIBN, 75 °C, 18h, DMFFigure 30. Synthetic pathway and structure of asymmetric branched-based lipid-polymer conjugates containing spacer. For a list of CTAs and polymers, see Table 26.Figure 31. Synthetic pathway and structure of asymmetric branched-based lipid-polymer conjugates containing spacer. For a list of CTAs and polymers, see Table 26.Table 26. Characteristics of lipid-polymer conjugates containing spacer prepared from branched-based CTAs in 2 mL of solvent for 1.4 mmol (200 mg) of HPMA monomer.Polymer [CTA]: [I] Solvent n y D Yield Yield Mw,mmol (SEC)b(mg) (%) SEC(g / mol)aSymmetric [ADA002049X]: [AIBN]ADA000243P 0.055: 0.008 DMF - 36 7000 1.14 170 66Symmetric [ADA002054X]: [AIBN]ADA000260P 0.055: 0.008 DMF - 49 9000 1.14 190 60Asymmetric [ADA002053X]: [AIBN]ADA000259P 0.055: 0.008 DMF - 40 7500 1.13 166 65determined by SEC-MALS in DMF / 0.1 M LiBr;bDispersity as determined by SEC-MALS (Afw / Afn).y= ( n of polymer measured by SEC - Mwof CTA) / A / w of HPMA monomer.Example 62 - hydroxylation of polymers obtained from branched-based CTAs

[0282] The terminal trithiocarbonate group of the lipid-polymer conjugates was converted to hydroxyl groups as follows: In a 5mL Schlenk tube, 30 mg of starting polymer (see Table 27) were dissolved in 2 mL of water and the Schlenk tube was placed into a heating block at 75 °C for polymer complete solubilization (about 5 min). Hydrogen peroxide (H2O2; molar ratio of H₂O₂ to polymer = 10.0, as specified in Table 27) was added to the solution. H₂O₂ was used as a 30% w / w aqueoussolution. The Schlenk tube was sealed with a rubber septum and left to stir for 16 hours at 70 °C, when exposed to air (with the stopcock valve open). The yellowish coloration of polymers completely disappeared after 16 hours as observed by visual inspection. Afterwards, 3 mL of MeOH was added to the polymer solution, and the polymer was purified by flash chromatography in a Sephadex® LH-20 column, with MeOH as the mobile phase. The collected polymer solution in MeOH was concentrated to 2 mL under vacuum on a rotary vacuum evaporator and then the polymerization solution was dialyzed against water for 24 h and lyophilized. The branched-based hydroxyl-terminated lipid-polymer conjugates (Figure 32, 33 and 34, see Table 27) was obtained as a white powder (yield, as indicated in Table 27) and characterized by size exclusion chromatography (UV-SEC-MALS) by detecting at a fixed wavelength of 280 nm, corresponding to the absorption assigned to the trithiocarbonate group of the RAFT end-group. The complete disappearance of the tri thio carbonate group signal in the SEC chromatogram confirmed the successful modification of the polymer end-group.Table 27. Characteristics of branched-based hydroxyl-terminated lipid-polymer conjugates.hydroxyl- Starting Added mmol n y Yield Yield terminated polymer of H2O2 (mg) (%) polymerSymmetricADA000245P ADA000243P 0.04 - 36 24 82SymmetricADA000262P ADA000260P 0.03 - 49 25 86AsymmetricADA000261P ADA000259P 0.04 - 40 24 82Figure 32. Synthetic pathway and structure of hydroxyl-terminated symmetric branched lipidpolymer conjugate. For list of starting polymers and hydroxyl-terminated polymers, see Table 27.1. H2O, 75 °C2. H2O2(30% w / w), 16 hhydroxyl-terminated polymerFigure 33. Synthetic pathway and structure of hydroxyl-terminated symmetric branched lipidpolymer conjugate. For list of starting polymers and hydroxyl-terminated polymers, see Table 27.Figure 34. Synthetic pathway and structure of hydroxyl -terminated asymmetric branched lipidpolymer conjugate. For a list of starting polymers and hydroxyl-terminated polymers, see Table 27.

[0283] Compounds of Formula I, Formula II and / or Formula V may be prepared from commercially available materials according to the procedures illustrated in Schemes 1 - 100

[0284] The following schemes may be employed in preparation of the compounds of Formula I, Formula II and / or Formula V.

[0285] The following descriptions of synthetic methods are designed to illustrate, but not to limit, general procedures for the preparation of some compounds of the present disclosure. Reactions leading to some compounds of the present disclosure may be summarized by general schemes 1 to 100 below. The variables in the schemes (e.g. R, Y etc.) may be as defined herein. A person skilled in the art will note that throughout the schemes the order of certain steps may be changed,such as the introduction or removal, or introduction and removal of a protecting group. Person skilled in the art will note that, during the reaction sequences and synthetic schemes described herein, the order of certain steps may be changed, such as the introduction or removal, or the introduction and removal of protecting groups. One of ordinary skills in the art will recognize that certain groups may require protection from the reaction conditions via the use of protecting groups. Protecting groups may also be used to differentiate similar functional groups in molecules. A list of protecting groups and how to introduce and remove these groups can be found in Greene, T. W., Wuts, P. G. M., Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999.

[0286] In the reaction schemes described herein, multiple stereoisomers may be produced. When no particular stereoisomer is indicated, it is understood to mean all possible stereoisomers that could be produced from the reaction. A person of ordinary skill in the art will recognize that the reactions can be optimized to give one isomer preferentially and new schemes may be devised to produce a single isomer. If mixtures are produced, techniques such as preparative thin layer chromatography, preparative HPLC, preparative chiral HPLC, preparative SFC, and combinations thereof, may be used to separate the isomers.

[0287] In the reaction schemes below, some roman numbers were intentionally omitted: LXVIII, LXIX and LXX.

[0285] In Scheme 1 above, in step 1, acid ADA900020X may react with amine I in presence of coupling reagent (e.g. PyBOP) and a base (e.g. EtsN) to afford presumably amide II. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0286] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 1 may take place in one flask without any purification or analysis.

[0287] In Scheme 2 above, in step 1, acid ADA900020X may react with 3 -azido- 1 -propanol (III) in presence of coupling reagent (e.g. PyBOP) and a base (e.g. EtsN) to afford presumably ester IV.Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0288] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 2 may take place in one flask without any purification or analysis.VI

[0289] In Scheme 3 above, in step 1, acid ADA900020X may react with 3-azido-l-propanamine (V) in presence of coupling reagent (e.g. PyBOP) and a base (e.g. EtsN) to afford presumably amide VI. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0290] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 3 may take place in one flask without any purification or analysis.step 1VII VIII

[0291] In Scheme 4 above, in step 1, acid ADA900020X may react with 3 -amino- 1 -propyne (VII) in presence of coupling reagent (e.g. PyBOP) and a base (e.g. EtsN) to afford presumably amide VIII. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0292] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 4 may take place in one flask without any purification or analysis.step 1IX X

[0293] In Scheme 5 above, in step 1, acid ADA900020X may react with 2-propyn- 1 -ol (IX) in presence of coupling reagent (e.g. PyBOP) and a base (e.g. EtsN) to afford presumably ester X.Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0294] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 5 may take place in one flask without any purification or analysis.

[0295] In Scheme 6 above, in step 1, 2-methyl-l -propanethiol (XI) may react with carbon disulfide (XII) in presence of a base (e.g. NaH) to afford sodium trithiocarbonate XIII. The step 1 may take place in an organic solvent (e.g. Et2O) at a temperature of 0 °C.

[0296] In step 2, the sodium trithiocarbonate XIII may react with oxidation reagent (e.g. iodine) to afford disulfide derivative XIV. The step 2 may take place in an organic solvent (e.g. Et2O) at room temperature.

[0297] In step 3, the disulfide derivative XIV may react with azobisisobutyronitrile (AIBN) to afford trithiocarbonate derivative XV. The step 3 may take place in an organic solvent (e.g. EtOAc) at a temperature of reflux.

[0298] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 6 may take place in one flask without any purification or analysis.HO step 1XVIXVII

[0299] In Scheme 7 above, in step 1, acid ADA900020X may react with 2-(2-(pyridin-2- yl)disulfanyl)ethanol (XVI) in presence of coupling reagent (e.g. PyBOP) and a base (e.g. EtsN) to afford presumably ester XVII. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0300] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 7 may take place in one flask without any purification or analysis.SCHEME 8

[0301] In Scheme 8 above, in step 1, acid ADA900020X may react with alcohol XVIII in presence of coupling reagent (e.g. PyBOP) and a base (e.g. EtsN) to afford presumably ester XIX. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0302] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 8 may take place in one flask without any purification or analysis.step 1

[0303] In Scheme 9 above, in step 1, acid ADA900020X may react with amine XX in presence of coupling reagent (e.g. PyBOP) and a base (e.g. EtsN) to afford presumably amide XXI. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0304] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 9 may take place in one flask without any purification or analysis.SCHEME 10step 1XXIIXXIII

[0305] In Scheme 10 above, in step 1, acid ADA900020X may react with dioleylamine (XXII) in presence of coupling reagent (e.g. PyBOP) and a base (e.g. EtsN) to afford presumably amide XXIII. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0306] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 10 may take place in one flask without any purification or analysis.SCHEME 11step 1XXIV XXV XXVIstep 2ADA900020XXXVII

[0307] In Scheme 11 above, in step 1, (Z)-9-octadecen-l -amine (XXIV) may react with 1 -iodohexadecane (XXV) in presence of a base (e.g. cesium hydroxide monohydrate) and molecular sieves (e.g. 4 A molecular sieves) to afford presumably secondary amine XXVI. Step 1 may take place in an organic solvent (e.g. DMF) at room temperature.

[0308] In step 2, acid ADA900020X may react with amine XXVI in presence of coupling reagent (e.g. PyBOP) and a base (e.g. Et₃N) to afford presumably amide XXVII. Step 2 may take place in an organic solvent (e.g. DCM) at room temperature.

[0309] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 11 may take place in one flask without any purification or analysis.SCHEME 12XXVIII

[0310] In Scheme 12 above, in step 1, dodec-5-yn-l -amine (XXVIII) may react with l-iodododec-5- yne (XXIX) in presence of a base (e.g. cesium hydroxide monohydrate) and molecular sieves (e.g.4 A molecular sieves) to afford presumably secondary amine XXX. Step 1 may take place in an organic solvent (e.g. DMF) at room temperature.

[0311] In step 2, acid ADA900020X may react with amine XXX in presence of coupling reagent (e.g.PyBOP) and a base (e.g. Et₃N) to afford presumably amide XXXI. Step 2 may take place in an organic solvent (e.g. DCM) at room temperature.

[0312] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 12 may take place in one flask without any purification or analysis.SCHEME 13XXVIIIXXXIII

[0313] In Scheme 13 above, in step 1, dodec-5-yn-l -amine (XXVIII) may react with 1 -iodododecane (XXIa) in presence of a base (e.g. cesium hydroxide monohydrate) and molecular sieves (e.g. 4 A molecular sieves) to afford presumably secondary amine XXXII. Step 1 may take place in an organic solvent (e.g. DMF) at room temperature.

[0314] In step 2, acid ADA900020X may react with amine XXXII in presence of coupling reagent (e.g. PyBOP (benzotriazole- 1-yl -oxy -tris-pyrrolidino-phosphonium hexafluorophosphate)) and a base (e.g. Et₃N) to afford presumably amide XXXIII. Step 2 may take place in an organic solvent (e.g. DCM) at room temperature.

[0315] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 13 may take place in one flask without any purification or analysis.SCHEME 14step 1XXVIII XXXVstep 2 ADA900020XXXXVI

[0316] In Scheme 14 above, in step 1, dodec-5-yn-l -amine (XXVIII) may react with (Z)-l-bromo-9- octadecene (XXXIV) in presence of a base (e.g. cesium hydroxide monohydrate) and molecular sieves (e.g. 4 A molecular sieves) to afford presumably secondary amine XXXV. Step 1 may take place in an organic solvent (e.g. DMF) at room temperature.

[0317] In step 2, acid ADA900020X may react with amine XXXV in presence of coupling reagent (e.g. PyBOP) and a base (e.g. Et₃N) to afford presumably amide XXXVI. Step 2 may take place in an organic solvent (e.g. DCM) at room temperature.

[0318] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 14 may take place in one flask without any purification or analysis.SCHEME 15

[0319] In Scheme 15 above, in step 1, acid ADA900020X may react with nonacosan- 15-ol (XXXVII) in presence of coupling reagent (e.g. PyBOP) and a base (e.g. Et₃N) to afford presumably amide XXXVIII. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0320] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 15 may take place in one flask without any purification or analysis.XLHN 7CH2)12CH3^(CH2)12CH3step 2XLI-W-12

[0321] In Scheme 16 above, in step 1, ester XVII may react with thiol XXXIX to afford presumably disulfide XL. Step 1 may take place in an organic solvent (e.g. MeOH) at 0 °C followed by an increase of the temperature to room temperature.

[0322] In step 2, disulfide XL may react with secondary amine XLI-W-12 in presence of coupling reagent (e.g. DIC) and a base (e.g. DMAP) to afford presumably amide XLII. Step 2 may take place in an organic solvent (e.g. DCM) at 0 °C followed by an increase of the temperature to room temperature.

[0323] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 16 may take place in one flask without any purification or analysis.

[0324] In Scheme 17 above, in step 1, acid XL may react with diacylglycerol XLIII-W-13 in presence of coupling reagent (e.g. PyBOP) and a base (e.g. Et₃N) to afford presumably ester XLIV. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0325] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 17 may take place in one flask without any purification or analysis.SCHEME 18XLVI

[0326] In Scheme 18 above, in step 1, acid ADA900020X may react with alcohol XLV in presence of coupling reagent (e.g. PyBOP) and a base (e.g. Et₃N) to afford presumably ester XLVI. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0327] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 18 may take place in one flask without any purification or analysis.SCHEME 19step 1ADA900020X XLVII XLVIIIstep 2 XLIX

[0328] In Scheme 19 above, in step 1, acid ADA900020X may react with ethane- 1,2-diol (XLVII) in presence of coupling reagent (e.g. DIC) and a base (e.g. DMAP) to afford presumably alcohol XLVIII. Step 1 may take place in an organic solvent (e.g. DCM) at 0 °C followed by an increase of the temperature to room temperature.

[0329] In step 2, alcohol XLVIII may react with oligoglycine XLIX in presence of coupling reagent (e.g. DIC) and a base (e.g. DMAP) to afford presumably ester L. Step 2 may take place in an organic solvent (e.g. DCM) at 0 °C followed by an increase of the temperature to room temperature.

[0330] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 19 may take place in one flask without any purification or analysis.SCHEME 20Lil

[0331] In Scheme 20 above, in step 1, acid ADA900020X may react with alcohol LI in presence of coupling reagent (e.g. DIC) and a base (e.g. DMAP) to afford presumably ester LII Step 1 may take place in an organic solvent (e.g. DCM) at 0 °C followed by an increase of the temperature to room temperature.

[0332] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 20 may take place in one flask without any purification or analysis.SCHEME 21V-501step 1

[0333] In Scheme 21 above, in step 1, acid V-501 may react with pentafluorophenol (LIII) in presence of coupling reagent (e.g. DIC (N,N'-diisopropylcarbodiimide)) to afford presumably ester LIVa.Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0334] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 21 may take place in one flask without any purification or analysis.SCHEME 22LIVb

[0335] In Scheme 22 above, in step 1, acid V-501 may react with 2-(2-(2-azidoethoxy)ethoxy)ethan- 1-amine (LV) in presence of coupling reagent (e.g. HBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3- tetramethyluronium hexafluorophosphate)) and a base (e.g. TEA (triethylamine)) to afford presumably amide LIVb. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0336] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 22 may take place in one flask without any purification or analysis.SCHEME 23V-501 IIIstep 1LIVc

[0337] In Scheme V-501-I above, in step 1, acid V-501 may react with 3 -azidopropan- l-ol (III) in presence of coupling reagent (e.g. DIC (N,N'-diisopropylcarbodiimide)) and a catalyst (e.g. DMAP (4-dimethylaminopyridine)) to afford presumably ester LIVc. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0338] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 23 may take place in one flask without any purification or analysis.SCHEME 24LlVd

[0339] In Scheme 24 above, in step 1, acid V-501 may react with 3-azidopropan-l -amine (V) in presence of coupling reagent (e.g. HBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate)) and a base (e.g. TEA (triethylamine)) to afford presumably amide LlVd.Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0340] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 24 may take place in one flask without any purification or analysis.SCHEME 25step 1

[0341] In Scheme 25 above, in step 1, acid V-501 may react with N-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)-5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamide (XLV) in presence of coupling reagent (e.g. DIC (N,N'-diisopropylcarbodiimide)) and a catalyst (e.g. DMAP (4-dimethylaminopyridine)) to afford presumably ester LIVe. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0342] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 25 may take place in one flask without any purification or analysis.SCHEME 26V-501 LVIstep 1LIVf

[0343] In Scheme 26 above, in step 1, acid V-501 may react with 2-(2-methoxyethoxy)ethan-l-ol (LVI) in presence of coupling reagent (e.g. DIC (N,N'-diisopropylcarbodiimide)) and a catalyst (e.g. DMAP (4-dimethylaminopyridine)) to afford presumably ester LIVf. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0344] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 26 may take place in one flask without any purification or analysis.SCHEME 27LIVg

[0345] In Scheme 27 above, in step 1, acid V-501 may react with N-(2-aminoethyl)maleimide trifluoroacetate salt (LVII) in presence of coupling reagent (e.g. HBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate)) and a base (e.g. 2,4,6-collidine) to afford presumably amide LIVg. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0346] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 27 may take place in one flask without any purification or analysis.SCHEME 28step 1LIVh

[0347] In Scheme 28 above, in step 1, acid V-501 may react with l-(2-(2-(2- hydroxyethoxy)ethoxy)ethyl)-1H-pyrrole-2,5-dione (LVIII) in presence of coupling reagent (e.g. DIC (N,N'-diisopropylcarbodiimide)) and a catalyst (e.g. DMAP (4-dimethylaminopyridine)) to afford presumably ester LIVh. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0348] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 28 may take place in one flask without any purification or analysis.SCHEME 29LIVi

[0349] In Scheme 29 above, in step 1, acid V-501 may react with N-hydroxysuccinimide (LIX) in presence of coupling reagent (e.g. DIC (N,N'-diisopropylcarbodiimide)) to afford presumably ester LIVi. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0350] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 29 may take place in one flask without any purification or analysis.SCHEME 30LIVj

[0351] In Scheme 30 above, in step 1, acid V-501 may react with 2-mercaptothiazoline (LX) in presence of coupling reagent (e.g. DIC (N,N'-diisopropylcarbodiimide)) and a catalyst (e.g. DMAP (4-dimethylaminopyridine)) to afford presumably amide LIVj. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0352] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 30 may take place in one flask without any purification or analysis.SCHEME 31step 1LIVk

[0353] In Scheme 31 above, in step 1, acid V-501 may react with 2-(3-hydroxypropyl)-3a,4,7,7a- tetrahydro-1H-4,7-epoxyisoindole-1,3(2H)-dion (LI) in presence of coupling reagent (e.g. DIC (N,N'-diisopropylcarbodiimide)) and a catalyst (e.g. DMAP (4-dimethylaminopyridine)) to afford presumably ester LIVk. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0354] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 31 may take place in one flask without any purification or analysis.SCHEME 32step 1LIVm

[0355] In Scheme 32 above, in step 1, acid V-501 may react with DBCO-C2-alcohol (LXI) in presence of coupling reagent (e.g. DIC (N,N'-diisopropylcarbodiimide)) and a catalyst (e.g. DMAP (4-dimethylaminopyridine)) to afford presumably ester LIVm. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0356] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 32 may take place in one flask without any purification or analysis.SCHEME 33LIVn

[0357] In Scheme 33 above, in step 1, acid V-501 may react with (E)-cyclooct-4-en-l-yl (2-((2- aminoethyl)disulfaneyl)ethyl)carbamate (LXII) in presence of coupling reagent (e.g. HBTU (2- (1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate)) and a base (e.g. TEA (triethylamine)) to afford presumably amide LIVn. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0358] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 33 may take place in one flask without any purification or analysis.SCHEME 34step 1MeOOCV-601LXIII

[0359] In Scheme 34 above, in step 1, methyl ester V-601 may react with NaOH to afford presumably carboxylic acid LXIII. Step 1 may take place in a mixture of water-miscible organic solvent (e.g. MeOH) and water at room temperature.

[0360] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 34 may take place in one flask without any purification or analysis.SCHEME 35

[0361] In Scheme 35 above, in step 1, acid LXIII may react with (4-(6-methyl- 1,2,4, 5-tetrazin-3- yl)phenyl)methanamine hydrochloride (LXIV) in presence of coupling reagent (e.g. HBTU (2- (1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate)) and a base (e.g. TEA(triethylamine)) to afford presumably amide LXVa. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0362] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 35 may take place in one flask without any purification or analysis.SCHEME 36

[0363] In Scheme 36 above, in step 1, acid LXIII may react with (4-( 1,2, 4, 5 -tetrazin-3 - yl)phenyl)methanamine hydrochloride (LXVI) in presence of coupling reagent (e.g. HBTU (2- (1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate)) and a base (e.g. TEA (triethylamine)) to afford presumably amide LXVb. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0364] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 36 may take place in one flask without any purification or analysis.SCHEME 37LXIII LXVIILXVc

[0365] In Scheme 37 above, in step 1, acid LXIII may react with (S)-2-pyridylthio cysteamine hydrochloride (LXVII) in presence of coupling reagent (e.g. HBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate)) and a base (e.g. TEA (triethylamine)) to afford presumably amide LXVc. Step 1 may take place in an organic solvent (e.g. DMF) at room temperature.

[0366] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 37 may take place in one flask without any purification or analysis.SCHEME 38LXIII XLIII-W-11step 1LXVd

[0367] In Scheme 38 above, in step 1, acid LXIII may react with 1,2-dimyristoylglycerol (XLIII-W- 11) in presence of coupling reagent (e.g. DIC (N,N'-diisopropylcarbodiimide)) and a catalyst (e.g. DMAP (4-dimethylaminopyridine)) to afford presumably ester LXVd. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0368] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 38 may take place in one flask without any purification or analysis.SCHEME 39

[0369] In Scheme 39 above, in step 1, acid LXIII may react with endo-BCN-PEG2-NH2(XX) in presence of coupling reagent (e.g. HBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate)) and a base (e.g. TEA (triethylamine)) to afford presumably amide LXVe.Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0370] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 39 may take place in one flask without any purification or analysis.SCHEME 40+ H3C(H2C)12^ N (CH2)12CH3H LXIII XLI-W-12step 1H3C(H2C)12^oH3C(H2C)12_^N„N Jt. ^(CH2)12CH3oxL^(CH2)12CH3LXVf

[0371] In Scheme 40 above, in step 1, acid LXIII may react with ditetradecylamine (XLI-W-12) in presence of coupling reagent (e.g. HATU (O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate)) and a base (e.g. TEA (triethylamine)) to afford presumably amide LXVf. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0372] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 40 may take place in one flask without any purification or analysis.SCHEME 41

[0373] In Scheme 41 above, in step 1, acid LXIII may react with pentafluorophenol (LIII) in presence of coupling reagent (e.g. DIC (N,N'-diisopropylcarbodiimide)) to afford presumably ester LXVg.Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0374] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 41 may take place in one flask without any purification or analysis.SCHEME 42step 1LXVh

[0375] In Scheme 42 above, in step 1, acid LXIII may react with 2-(2-(2-azidoethoxy)ethoxy)ethan- 1-amine (LV) in presence of coupling reagent (e.g. HBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3- tetramethyluronium hexafluorophosphate)) and a base (e.g. TEA (triethylamine)) to afford presumably amide LXVh. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0376] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 42 may take place in one flask without any purification or analysis.SCHEME 43step 1LXVi

[0377] In Scheme43 above, in step 1, acid LXIII may react with 3 -azidop ropan-l-ol (III) in presence of coupling reagent (e.g. DIC (N,N'-diisopropylcarbodiimide)) and a catalyst (e.g. DMAP (4- dimethylaminopyridine)) to afford presumably ester LXVi. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0378] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 43 may take place in one flask without any purification or analysis.SCHEME 44LXVj

[0379] In Scheme 44 above, in step 1, acid LXIII may react with 3 -azidopropan- 1 -amine (V) in presence of coupling reagent (e.g. HBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate)) and a base (e.g. TEA (triethylamine)) to afford presumably amide LXVj.Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0380] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 44 may take place in one flask without any purification or analysis.SCHEME 45LXIII XLVstep 1

[0381] In Scheme 45 above, in step 1, acid LXIII may react with N-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)-5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamide (XLV) in presence of coupling reagent (e.g. DIC (N,N'-diisopropylcarbodiimide)) and a catalyst (e.g. DMAP (4-dimethylaminopyridine)) to afford presumably ester LXVk. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0382] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 45 may take place in one flask without any purification or analysis.SCHEME 46step 1LXIII LVILXVm

[0383] In Scheme 46 above, in step 1, acid LXIII may react with 2-(2-methoxyethoxy)ethan-l-ol (LVI) in presence of coupling reagent (e.g. DIC (N,N'-diisopropylcarbodiimide)) and a catalyst (e.g. DMAP (4-dimethylaminopyridine)) to afford presumably ester LXVm. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0384] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 46 may take place in one flask without any purification or analysis.SCHEME 47

[0385] In Scheme 47 above, in step 1, acid LXIII may react with N-(2-aminoethyl)maleimide trifluoroacetate salt (LVII) in presence of coupling reagent (e.g. HBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate)) and a base (e.g. 2,4,6-collidine) to affordpresumably amide LXVn. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0386] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 47 may take place in one flask without any purification or analysis.SCHEME 48LXIII

[0387] In Scheme 48 above, in step 1, acid LXIII may react with l-(2-(2-(2- hydroxyethoxy)ethoxy)ethyl)-1H-pyrrole-2,5-dione (LVIII) in presence of coupling reagent (e.g. DIC (N,N'-diisopropylcarbodiimide)) and a catalyst (e.g. DMAP (4-dimethylaminopyridine)) to afford presumably ester LXVo. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0388] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 48 may take place in one flask without any purification or analysis.SCHEME 49LXIIILXVp

[0389] In Scheme 49 above, in step 1, acid LXIII may react with N-hydroxysuccinimide (LIX) in presence of coupling reagent (e.g. DIC (N,N'-diisopropylcarbodiimide)) to afford presumably ester LXVp. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0390] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 49 may take place in one flask without any purification or analysis.SCHEME 50LXVq

[0391] In Scheme 50 above, in step 1, acid LXIII may react with 2-mercaptothiazoline (LX) in presence of coupling reagent (e.g. DIC (N,N'-diisopropylcarbodiimide)) and a catalyst (e.g.DMAP (4-dimethylaminopyridine)) to afford presumably amide LXVq. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0392] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 50 may take place in one flask without any purification or analysis.SCHEME 50A

[0393] In Scheme 50A above, in step 1, acid LXIII may react with 2-(3-hydroxypropyl)-3a,4,7,7a- tetrahydro-l / f-4,7-epoxyisoindole-l,3(277)-dion (LI) in presence of coupling reagent (e.g. DIC ( N,N'-diisopropylcarbodiimide)) and a catalyst (e.g. DMAP (4-dimethylaminopyridine)) to afford presumably ester LXVr. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0394] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 50A may take place in one flask without any purification or analysis.SCHEME 51

[0395] In Scheme 51 above, in step 1, acid LXIII may react with DBCO-C2-alcohol (LXI) in presence of coupling reagent (e.g. DIC (N,N'-diisopropylcarbodiimide)) and a catalyst (e.g. DMAP (4-dimethylaminopyridine)) to afford presumably ester LXVs. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0396] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 51 may take place in one flask without any purification or analysis.SCHEME 52LXIII LXIIstep 1

[0397] In Scheme 52 above, in step 1, acid LXIII may react with (E)-cyclooct-4-en-l-yl (2-((2- aminoethyl)disulfaneyl)ethyl)carbamate (LXII) in presence of coupling reagent (e.g. HBTU (2- (1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate)) and a base (e.g. TEA (triethylamine)) to afford presumably amide LXVt. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0398] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 52 may take place in one flask without any purification or analysis.SCHEME 53LXXII

[0399] In Scheme 53 above, in step 1, amidine V-50 may react with mono methyl succinate (LXXI) in presence of coupling reagent (e.g. EDC (l-ethyl-3-(3-dimethylaminopropyl)carbodiimide)) and additive (e.g. NHS (N-hydroxysuccinimide)) to afford presumably carboxylic ester LXXII. Step 1 may take place in a mixture of water-miscible organic solvent (e.g. THF) and water at room temperature.

[0400] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 53 may take place in one flask without any purification or analysis.SCHEME 54LXXIII

[0401] In Scheme 54 above, in step 1, methyl ester LXXII may react with NaOH to afford presumably carboxylic acid LXXIII. Step 1 may take place in a mixture of water-miscible organic solvent (e.g. MeOH) and water at room temperature.

[0402] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 54 may take place in one flask without any purification or analysis.SCHEME 55LXXIIINHLXXIVa

[0403] In Scheme 55 above, in step 1, acid LXXIII may react with (4-(6-methyl- 1,2,4, 5-tetrazin-3- yl)phenyl)methanamine hydrochloride (LXIV) in presence of coupling reagent (e.g. HBTU (2- (l / / -benzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate)) and a base (e.g. TEA (tri ethylamine)) to afford presumably amide LXXIVa. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0404] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 55 may take place in one flask without any purification or analysis.SCHEME 56LXXIIINHLXXIVb

[0405] In Scheme 56 above, in step 1, acid LXXIII may react with (4-(l,2,4,5-tetrazin-3- yl)phenyl)methanamine hydrochloride (LXVI) in presence of coupling reagent (e.g. HBTU (2- (1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate)) and a base (e.g. TEA (triethylamine)) to afford presumably amide LXXIVb. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0406] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 56 may take place in one flask without any purification or analysis.SCHEME 57LXXIIILXXIVc

[0407] In Scheme 57 above, in step 1, acid LXXIII may react with (5)-2-pyridylthio cysteamine hydrochloride (LXVII) in presence of coupling reagent (e.g. HBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate)) and a base (e.g. TEA (triethylamine)) to afford presumably amide LXXIVc. Step 1 may take place in an organic solvent (e.g. DMF) at room temperature.

[0408] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 57 may take place in one flask without any purification or analysis.SCHEME 58LXXIII XLIII-W-11step 1H3C(H2C)11

[0409] In Scheme 58 above, in step 1, acid LXXIII may react with 1,2-dimyristoylglycerol (LXIII- W-ll) in presence of coupling reagent (e.g. DIC (N,N'-diisopropylcarbodiimide)) and a catalyst (e.g. DMAP (4-dimethylaminopyridine)) to afford presumably ester LXXIVd. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0410] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 58 may take place in one flask without any purification or analysis.SCHEME 59oLXXIII XXstep 1

[0411] In Scheme 59 above, in step 1, acid LXXIII may react with endo-BCN-PEG2-NH2(XX) in presence of coupling reagent (e.g. HBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate)) and a base (e.g. TEA (triethylamine)) to afford presumably amide LXXIVe. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0412] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 59 may take place in one flask without any purification or analysis.SCHEME 60LXXIII XLI-W-12step 1H3C(H2C)12^ H3C(H2C)12^NN (CH2)12CH3(CH2)12CH3LXXIVf

[0413] In Scheme 60 above, in step 1, acid LXXIII may react with ditetradecylamine (XLI-W-12) in presence of coupling reagent (e.g. HATU (O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate)) and a base (e.g. TEA (triethylamine)) to afford presumably amide LXXIVf. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0414] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 60 may take place in one flask without any purification or analysis.SCHEME 61LXXIII LIIIstep 1LXXIVg

[0415] In Scheme 61 above, in step 1, acid LXXIII may react with pentafluorophenol (LIII) in presence of coupling reagent (e.g. DIC (N,N'-diisopropylcarbodiimide)) to afford presumably ester LXXIVg. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0416] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 61 may take place in one flask without any purification or analysis.SCHEME 62LXXIII LVstep 1

[0417] In Scheme 62 above, in step 1, acid LXXIII may react with 2-(2-(2-azidoethoxy)ethoxy)ethan- 1-amine (LV) in presence of coupling reagent (e.g. HBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3- tetramethyluronium hexafluorophosphate)) and a base (e.g. TEA (triethylamine)) to afford presumably amide LXXIVh. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0418] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 62 may take place in one flask without any purification or analysis.SCHEME 63step 1LXXIVi

[0419] In Scheme 63 above, in step 1, acid LXXIII may react with 3 -azidopropan- l-ol (III) in presence of coupling reagent (e.g. DIC (N,N'-diisopropylcarbodiimide)) and a catalyst (e.g. DMAP (4-dimethylaminopyridine)) to afford presumably ester LXXIVi. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0420] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 63 may take place in one flask without any purification or analysis.SCHEME 64LXXIVj

[0421] In Scheme 64 above, in step 1, acid LXXIII may react with 3 -azidopropan- 1 -amine (V) in presence of coupling reagent (e.g. HBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate)) and a base (e.g. TEA (triethylamine)) to afford presumably amide LXXIVj. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0422] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 64 may take place in one flask without any purification or analysis.SCHEME 65

[0423] In Scheme 65 above, in step 1, acid LXXIII may react with N-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)-5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamide (XLV) in presence of coupling reagent (e.g. DIC (N,N'-diisopropylcarbodiimide)) and a catalyst (e.g. DMAP (4-dimethylaminopyridine)) to afford presumably ester LXXIVk. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0424] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 65 may take place in one flask without any purification or analysis.SCHEME 66LXXIVm

[0425] In Scheme 66 above, in step 1, acid LXXIII may react with 2-(2-methoxyethoxy)ethan-l-ol (LVI) in presence of coupling reagent (e.g. DIC (N,N'-diisopropylcarbodiimide)) and a catalyst (e.g. DMAP (4-dimethylaminopyridine)) to afford presumably ester LXXIVm. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0426] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 66 may take place in one flask without any purification or analysis.SCHEME 67LXXIII LVIIstep 1LXXIVn

[0427] In Scheme 67 above, in step 1, acid LXXIII may react with JN-(2-aminoethyl)maleimide trifluoroacetate salt (LVII) in presence of coupling reagent (e.g. HBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate)) and a base (e.g. 2,4,6-collidine) to afford presumably amide LXXIVn. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0428] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 67 may take place in one flask without any purification or analysis.SCHEME 68

[0429] In Scheme 68 above, in step 1, acid LXXIII may react with l-(2-(2-(2- hydroxyethoxy)ethoxy)ethyl)-1H-pyrrole-2,5-dione (LVIII) in presence of coupling reagent (e.g. DIC (N,N'-diisopropylcarbodiimide)) and a catalyst (e.g. DMAP (4-dimethylaminopyridine)) to afford presumably ester LXXIVo. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0430] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 68 may take place in one flask without any purification or analysis.SCHEME 69step 1LXXIVp

[0431] In Scheme 69 above, in step 1, acid LXXIII may react with JV-hydroxy succinimide (LIX) in presence of coupling reagent (e.g. DIC (N,N'-diisopropylcarbodiimide)) to afford presumably ester LXXIVp. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0432] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 69 may take place in one flask without any purification or analysis.SCHEME 70LXXIII LXstep 1LXXIVq

[0433] In Scheme 70 above, in step 1, acid LXXIII may react with 2-mercaptothiazoline (LX) in presence of coupling reagent (e.g. DIC (N,N'-diisopropylcarbodiimide)) and a catalyst (e.g. DMAP (4-dimethylaminopyridine)) to afford presumably amide LXXIVq. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0434] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 70 may take place in one flask without any purification or analysis.

[0435] SCHEME 71

[0436] In Scheme 71 above, in step 1, acid LXXIII may react with 2-(3-hydroxypropyl)-3a,4,7,7a-tetrahydro-1H-4,7-epoxyisoindole-1,3(2H)-dion (LI) in presence of coupling reagent (e.g. DIC (N,N'-diisopropylcarbodiimide)) and a catalyst (e.g. DMAP (4-dimethylaminopyridine)) to afford presumably ester LXXIVr. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0437] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 71 may take place in one flask without any purification or analysis.SCHEME 72LXXIII

[0438] In Scheme 72 above, in step 1, acid LXXIII may react with DBCO-C2-alcohol (LXI) in presence of coupling reagent (e.g. DIC (N,N'-diisopropylcarbodiimide)) and a catalyst (e.g. DMAP (4-dimethylaminopyridine)) to afford presumably ester LXXIVs. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0439] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 72 may take place in one flask without any purification or analysis.SCHEME 73

[0440] In Scheme 73 above, in step 1, acid LXXIII may react with (E)-cyclooct-4-en-l-yl (2-((2- aminoethyl)disulfaneyl)ethyl)carbamate (LXII) in presence of coupling reagent (e.g. HBTU (2- (1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate)) and a base (e.g. TEA (triethylamine)) to afford presumably amide LXXIVt. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0441] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 73 may take place in one flask without any purification or analysis.SCHEME 74V-50 LXXVstep 1LXXVIa

[0442] In Scheme 74 above, in step 1, amidine V-50 may react with 3-maleimidopropionic acid (LXXV) in presence of coupling reagent (e.g. EDC (l-ethyl-3-(3- dimethylaminopropyl)carbodiimide)) and additive (e.g. NHS (N-hydroxysuccinimide)) to afford presumably carboxylic amide LXXVIa. Step 1 may take place in a mixture of water-miscible organic solvent (e.g. THF) and water at room temperature.

[0443] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 74 may take place in one flask without any purification or analysis.SCHEME 75LXXVIb

[0444] In Scheme 75 above, in step 1, amidine V-50 may react with 2-(4-(l,2,4,5-tetrazin-3- yl)phenyl)acetic acid (LXXVII) in presence of coupling reagent (e.g. EDC (l-ethyl-3-(3- dimethylaminopropyl)carbodiimide)) and additive (e.g. NHS (N-hydroxysuccinimide)) to afford presumably carboxylic amide LXXVIb. Step 1 may take place in a mixture of water-miscible organic solvent (e.g. THF) and water at room temperature.

[0445] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 75 may take place in one flask without any purification or analysis.SCHEME 76LXIVstep 1V

[0446] In Scheme 76 above, in step 1, acid VA-057 may react with (4-(6-methyl- 1,2,4, 5-tetrazin-3- yl)phenyl)methanamine hydrochloride (LXIV) in presence of coupling reagent (e.g. HBTU (2- (1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate)) and a base (e.g. TEA (triethylamine)) to afford presumably amide LXXVIIIa. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0447] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 76 may take place in one flask without any purification or analysis.SCHEME 77VA-057 LXVIstep 1V

[0448] In Scheme 77 above, in step 1, acid VA-057 may react with (4-(l,2,4,5-tetrazin-3- yl)phenyl)methanamine hydrochloride (LXVI) in presence of coupling reagent (e.g. HBTU (2- (1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate)) and a base (e.g. TEA (triethylamine)) to afford presumably amide LXXVIIIb. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0449] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 77 may take place in one flask without any purification or analysis.SCHEME 78VA-057 LXVIIstep 1VLXXVIlIc

[0450] In Scheme 78 above, in step 1, acid VA-057 may react with (5)-2-pyridylthio cysteamine hydrochloride (LXVII) in presence of coupling reagent (e.g. HBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate)) and a base (e.g. TEA (triethylamine)) to afford presumably amide LXXVIlIc. Step 1 may take place in an organic solvent (e.g. DMF) at room temperature.

[0451] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 78 may take place in one flask without any purification or analysis.SCHEME 79VA-057 XLIII-W-11step 1LXXVIIId

[0452] In Scheme 79 above, in step 1, acid VA-057 may react with 1,2-dimyristoylglycerol (XLIII- W-ll) in presence of coupling reagent (e.g. DIC (N,N'-diisopropylcarbodiimide)) and a catalyst (e.g. DMAP (4-dimethylaminopyridine)) to afford presumably ester LXXVIIId. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0453] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 79 may take place in one flask without any purification or analysis.SCHEME 80VA-057 XXstep 1LXXVIlle

[0454] In Scheme 80 above, in step 1, acid VA-057 may react with endo-BCN-PEG2-NH2(XX) in presence of coupling reagent (e.g. HBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate)) and a base (e.g. TEA (triethylamine)) to afford presumably amide LXXVIlle. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0455] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 80 may take place in one flask without any purification or analysis.SCHEME 81+ H3C(H2C)12^N^(CH2)12CH3H VA-057 XLI-W-12step 1H3C(H2C)12H3C(H2C)12^NN 7CH2)12CH3(CH2)12CH3LXXVIIIf

[0456] In Scheme 81 above, in step 1, acid VA-057 may react with ditetradecylamine (XLI-W-12) in presence of coupling reagent (e.g. HATU (O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate)) and a base (e.g. TEA (triethylamine)) to afford presumably amide LXXVIIIf. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0457] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 81 may take place in one flask without any purification or analysis.SCHEME 82LXXVIIIg

[0458] In Scheme 82 above, in step 1, acid VA-057 may react with pentafluorophenol (LIII) in presence of coupling reagent (e.g. DIC (N,N'-diisopropylcarbodiimide)) to afford presumably ester LXXVIIIg. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0459] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 82 may take place in one flask without any purification or analysis.SCHEME 83VA-057 LVstep 1LXXVIlIh

[0460] In Scheme 83 above, in step 1, acid VA-057 may react with 2-(2-(2-azidoethoxy)ethoxy)ethan- 1-amine (LV) in presence of coupling reagent (e.g. HBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3- tetramethyluronium hexafluorophosphate)) and a base (e.g. TEA (triethylamine)) to afford presumably amide LXXVIlIh. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0461] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 83 may take place in one flask without any purification or analysis.SCHEME 84HO^^N3VA-057 IIIstep 1LXXVIIIi

[0462] In Scheme 84 above, in step 1, acid VA-057 may react with 3 -azidopropan- l-ol (III) in presence of coupling reagent (e.g. DIC (N,N'-diisopropylcarbodiimide)) and a catalyst (e.g. DMAP (4-dimethylaminopyridine)) to afford presumably ester LXXVIIIi. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0463] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 84 may take place in one flask without any purification or analysis.SCHEME 85VA-057 Vstep 1LXXVIIIj

[0464] In Scheme 85 above, in step 1, acid VA-057 may react with 3 -azidopropan- 1 -amine (V) in presence of coupling reagent (e.g. HBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate)) and a base (e.g. TEA (triethylamine)) to afford presumably amide LXXVIIIj. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0465] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 85 may take place in one flask without any purification or analysis.

[0466] SCHEME 86VA-057 XLVLXXVIIIk

[0467] In Scheme 86 above, in step 1, acid VA-057 may react with N-(2-(2-(2- hydroxyethoxy)ethoxy)ethyl)-5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4- yl)pentanamide (XLV) in presence of coupling reagent (e.g. DIC (N,N'-diisopropylcarbodiimide)) and a catalyst (e.g. DMAP (4-dimethylaminopyridine)) to afford presumably ester LXXVIIIk.Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0468] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 86 may take place in one flask without any purification or analysis.SCHEME 87VA-057 LVIstep 1LXXVIIIm

[0469] In Scheme 87 above, in step 1, acid VA-057 may react with 2-(2-methoxyethoxy)ethan-l-ol (LVI) in presence of coupling reagent (e.g. DIC (N,N'-diisopropylcarbodiimide)) and a catalyst (e.g. DMAP (4-dimethylaminopyridine)) to afford presumably ester LXXVIIIm. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0470] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 87 may take place in one flask without any purification or analysis.SCHEME 88VA-057 LVIIstep 1LXXVIIIn

[0471] In Scheme 88 above, in step 1, acid VA-057 may react with N-(2-aminoethyl)maleimide trifluoroacetate salt (LVII) in presence of coupling reagent (e.g. HBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate)) and a base (e.g. 2,4,6-collidine) to afford presumably amide LXXVIIIn. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0472] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 88 may take place in one flask without any purification or analysis.SCHEME 89VA-057 LVIIIstep 1LXXVIIIo

[0473] In Scheme 89 above, in step 1, acid VA-057 may react with l-(2-(2-(2- hydroxyethoxy)ethoxy)ethyl)-1H-pyrrole-2,5-dione (LVIII) in presence of coupling reagent (e.g. DIC (N,N'-diisopropylcarbodiimide)) and a catalyst (e.g. DMAP (4-dimethylaminopyridine)) to afford presumably ester LXXVIIIo. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0474] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 89 may take place in one flask without any purification or analysis.SCHEME 90step 1LXXVIIIp

[0475] In Scheme 90 above, in step 1, acid VA-057 may react with N-hydroxysuccinimide (LIX) in presence of coupling reagent (e.g. DIC (N,N'-diisopropylcarbodiimide)) to afford presumably ester LXXVIIIp. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0476] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 90 may take place in one flask without any purification or analysis.SCHEME 91LXXVIIIq

[0477] In Scheme 91 above, in step 1, acid VA-057 may react with 2-mercaptothiazoline (LX) in presence of coupling reagent (e.g. DIC (N,N'-diisopropylcarbodiimide)) and a catalyst (e.g. DMAP (4-dimethylaminopyridine)) to afford presumably amide LXXVIIIq. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0478] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 91 may take place in one flask without any purification or analysis.SCHEME 92LXXVIIIr

[0479] In Scheme 92 above, in step 1, acid VA-057 may react with 2-(3-hydroxypropyl)-3a,4,7,7a- tetrahydro-l / f-4,7-epoxyisoindole-l,3(277)-dion (LI) in presence of coupling reagent (e.g. DIC ( N,N'-diisopropylcarbodiimide)) and a catalyst (e.g. DMAP (4-dimethylaminopyridine)) to afford presumably ester LXXVIIIr. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0480] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 92 may take place in one flask without any purification or analysis.SCHEME 93VA-057step 1LXXVIIIs

[0481] In Scheme 93 above, in step 1, acid VA-057 may react with DBCO-C2-alcohol (LXI) in presence of coupling reagent (e.g. DIC (N,N'-diisopropylcarbodiimide)) and a catalyst (e.g. DMAP (4-dimethylaminopyridine)) to afford presumably ester LXXVIIIs. Step 1 may take place in an organic solvent (e.g. DCM) at room temperature.

[0482] Intermediates, which are not drawn in the scheme, may be present even though they were not analyzed. It may be difficult to separate and / or analyze the intermediates. The entirety of Scheme 93 may take place in one flask...

Claims

1. CLAIMS1. A compound of Formula I, or pharmaceutically acceptable salts or solvates thereof:JFormula Idesignates the bond to Y1;Q5I— NZ1Y¹ is selected from the group consisting of -O-, -NH- and Q;J1is selected from the group consisting of C1-C15 alkylene chains, C2-C15 alkenylene chains and C2-C15 alkynylene chains, wherein in said C1-C15 alkylene chains, C2-C15 alkenylene chains or C2-C15 alkynylene chains, one or more -CH2- groups may be replaced with -O- and / or -S-;T1is direct bond between J1and M1or is selected from the group consisting ofdesignates the bond to M1;M1is selected from the group consisting ofQ1is direct bond between M1and Q3or selected from the group consisting of0wherein δ3 designates the bond to M1;Q2is direct bond between M1and Q4or selected from the group consisting of0wherein δ3 designates the bond to M1;Q7HCQ3is selected from the group consisting of C8-C20 alkyl chains andQ8Q7| — HCQ4is selected from the group consisting of C8-C20 alkyl chains andu;Q5is selected from the group consisting of C8-C20 alkyl chains, C8-C20 alkenyl chains and C8-C20 alkynyl chains, wherein said C8-C20 alkyl chains, C8-C20 alkenyl chains and C8-C20 alkynyl chains may be linear or branched;Q6is selected from the group consisting of C8-C20 alkyl chains, C8-C20 alkenyl chains and C8-C20 alkynyl chains, wherein said C8-C20 alkyl chains, C8-C20 alkenyl chains and C8-C20 alkynyl chains may be linear or branched;Q7is selected from the group consisting of C8-C20 alkyl chains, C8-C20 alkenyl chains and C8-C20 alkynyl chains, wherein said C8-C20 alkyl chains, C8-C20 alkenyl chains and C8-C20 alkynyl chains may be linear or branched;Q8is selected from the group consisting of C8-C20 alkyl chains, C8-C20 alkenyl chains and C8-C20 alkynyl chains, wherein said C8-C20 alkyl chains, C8-C20 alkenyl chains and C8-C20 alkynyl chains may be linear or branched;X2is selected from the group consisting of -OH, -H, -SH, -N3,wherein δ5designates the bond to Y2;Y2is direct bond between X2and J2or selected from the group consisting of -CH3 and C1-C5 alkylene chains;, wherein 64 designates the bond to Y2;T2is direct bond between J2and M2or selected from the group consisting of C1-C8alkylene chains, wherein in said C1-C8alkylene chain, one or more -CH2- groups may be replaced with -O- or -S-;Q9is selected from the group consisting of C5-C20 alkyl chains;Q10is selected from the group consisting of C5-C20 alkyl chains;Q11is selected from the group consisting of C5-C20 alkyl chains;Q12is selected from the group consisting of C5-C20 alkyl chains;wherein y is an integer in the range of 2 to 200;OQ3and Q4are absent and X2is selected from the group consisting ofo, wherein δ5designates the bond to Y2, Y2is direct bond between X2and J2or selected from the groupconsisting of C1-C5 alkylene chains, J2is selected from the group consisting of, wherein 64 designates the bond to Y2, T2is direct bond between J2and M2or selected from the group consisting of C1-C8alkylene chains, wherein in said C1-C8alkylene chain, one or more -CH2- groups may be replaced with -O- orQ\ N-S-, M2is selected from the group consisting of Q10O0, wherein Q9is selected from the group consisting of C5-C20 alkyl chains, Q10is selected from the group consisting of C5-C20 alkyl chains, Q11is selected from the group consisting of C5-C20 alkyl chains and wherein Q12is selected from the group consisting of C5-C20 alkyl chains;wherein if Y1isQ6, then J1, T1, M1, Q1, Q2, Q3and Q4are absent;wherein if X2is -OH, -H, -SH,or N3, then Y2, J2, T2and M2are absent; wherein if Y2is -CH3, then J2, T2and M2are absent.

2. Compound according to claim 1,wherein X1is selected from the group consisting ofwherein 61 designates the bond to Y1;wherein if X1is, then Y1, J1, T1, M1, Q1, Q2, Q3and Q4are absent and X2is, Y2is selected from the group consisting of -CH3 and C1-C2 alkylene chains, J2is selectedfrom the group consisting of O and O, T2is direct bond between J2and M2or selected from the group consisting of C1-C4 alkylene chains, wherein in said C1-C4 alkylene chains one or more -CH2- groups may be replaced with -S-, M2is selected from the group O9Q11^SQ9consisting of Q and0, wherein Q9is C14 alkyl chain, Q10is C14 alkyl chain, Q11is C13 alkyl chain and Q12is C13 alkyl chain.

3. Compound according to claim 1 or 2,wherein Y1is selected from the group consisting of -O-, -NH- andwherein Q5is selected from the group consisting of C12-C18 alkyl chains, and wherein Q6is selected from the group consisting of C12-C18 alkyl chains;Q5| — Nwherein if Y1isQ6, then J1, T1, M1, Q1, Q2, Q3and Q4are absent.

4. Compound according to any preceding claim,wherein J1is selected from the group consisting of C1-C15 alkylene chains, wherein in said Ci- C15 alkylene chains, one or more -CH2- groups may be replaced with -O- and / or -S-.

5. Compound according to any preceding claim,wherein T1is direct bond between J1and M1or selected from the group consisting of6. Compound according to any preceding claim,Hc wherein M1is selected from the group consisting of and7. Compound according to any preceding claim,wherein Q1is direct bond between M1and Q3or selected from the group consisting ofand, wherein δ3 designates the bond to M1.

8. Compound according to any preceding claim,wherein Q2is direct bond between M1and Q4or selected from the group consisting of oo, wherein δ3 designates the bond to M1.

9. Compound according to any preceding claim,Q7| J _ 1 r4l f'z wherein Q3is selected from the group consisting of C11-C18alkyl chains anduwherein Q7is C8alkyl chain, and wherein Q8is C8alkyl chain.

10. Compound according to any preceding claim,Q7I — HC wherein Q4is selected from the group consisting of C11-C18alkyl chains andXQ8wherein Q7is C8alkyl chain, and wherein Q8is C8alkyl chain.

11. Compound according to any preceding claim,wherein X2is selected from the group consisting of -OH, -H, -SH, -N3,wherein if X2is -OH, -H, -SH,or -N3, then Y2, J2, T2and M2are absent.

12. Compound according to any preceding claim,wherein Y2is selected from the group consisting of -CH3 and C1-C2 alkylene chains;wherein if Y2is -CH3, then J2, T2and M2are absent.

13. Compound according to any preceding claim,wherein J2is selected from the group consisting of, wherein 64 designates the bond to Y2.

14. Compound according to any preceding claim,wherein T2is direct bond between J2and M2or selected from the group consisting of C1-C4 alkylene chains, wherein in said C1-C4 alkylene chains one or more -CH2- groups may be replaced with -S-.

15. An invention as described and / or shown within this application.

16. Compound according to any preceding claim,wherein M2is selected from the group consisting of Q10andwherein Q9is a C14 alkyl chain;wherein Q10is a C14 alkyl chain;wherein Q11is a C13 alkyl chain and wherein Q12is a C13 alkyl chain.

17. Compound according to any preceding claim, wherein y is an integer in the range of 5 to 100.

18. Compound according to any preceding claim, wherein y is an integer in the range of 5 to 50 or in the range of 17 to 50.

19. A compound according to any preceding claim, wherein the compound is selected from the group consisting of:y(CH2)13CH3OOH(CH2)12CH3H3C(H2C)12H3C(H2C)12^NoOH(CH2)12CH3N^X(CH2)12CH3wherein y is an integer in the range of 2 to 200.

20. A compound according to any preceding claim, wherein the compound is selected from the group consisting ofOOJI^X(CH2)11CH3IK) - 4‘> °X'X^°Y^X< CH2)«CH3HN O0OA^(CH2)„CH JL 50 HN^O0 IK) - - -..-4-'1 / ll\ Co oA^ICHalnCHjJ^'°Y^(CH2),]CH5Hooxlxx(CH2)13CH31^1I. 1 ‘> ^°Y^(CH2)13CH3HNX^Oo HO‘ t ' 'tr r ° ' ''°Y^'(CH2)„CH, HN^O0® OHO0JK^4CH2)i3CH3HO HN^OOOA^(CH8)15CH3H0" ‘ ’ J '" -i / I r0■ * '0rX<CH*CH30 r I 1 \ / O^'vx't^HihgCH^HO' H" N''^j © ’• '> ' O r " ■ ' '° V-> lCcH“2) >i5C r-HM3oOH(CH2)„CH3HO.(CH2)„CH3UN^(CH2)„CH3HO N-^(CH2)1Z, CH3^(CH2)WCH3HO^(CH2)12CH3HO W. X(CH2)„CH3|X'(CH2)i2CH3HO NX / (CH2)»CH3OH^(CH2)12CH3N^(CH2)12CH3OH.(CH2)12CH3HO” (CH2)12CH3HNOH(CH2)«CH3HO (CH2)12CH3HN^ AO14o °(CH2)12CH3HO (CH2)i2CH3HN'(CH2)12CH3HO (CH2)tCH3fX(CH2)14CH3HO N^X(CH2)14CH3^{CHJieCHa HO i l l\CK. NH Hooa I i i Z \ I ‘ - ■ 'ON f "a< OWHX“(32H)3£MH 001O. A^(CH2)„CH3HO 7 ' •• L; j0(CH2)„CH3O(CH2)12CH3HO (CH,)12CH3.(CH2|MCH3(CH2)t4CH3OH(CI-yieCHa (CHJWCH3H3C(H2C)t2^rAjO NC,bL > •CKXO^..x-x..: CH -r CH HN Opup HOSHO21FHO)^£HOB(2HOF21. A compound a compound of Formula I, or pharmaceutically acceptable salts or solvates thereof:M2Formula Io o OQ5Y1is selected from the group consisting of -O-, -NH- andJ1is selected from the group consisting of C1-C15 alkylene chains, C2-C15 alkenylene chains and C2-C15 alkynylene chains, wherein in said C1-C15 alkylene chains, C2-C15 alkenylene OH chains or C2-C15 alkynylene chains one or more -CH2- groups may be replaced withT1is a direct bond between J1and M1or selected from the group consistingofO OO OO O O and OHo^o^X52IIO5wherein δ2 designates the bond to M1;M1is selected from the group consisting ofQ1is direct bond between M1and Q3or selected from the group consisting of, wherein δ3 designates the bond to M1;Q2is direct bond between M1and Q4or selected from the group consisting ofO, wherein δ3 designates the bond to M1;Q3is selected from the group consisting of C5-C35 alkyl chains, C5-C35 alkenyl chains, C5-C35|-HC Q7alkynyl chains and Q, wherein said C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains may be linear or branched, wherein in said C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains one or more -CH2- groups may be replaced with groups selected from the group consisting of -CH(OH)-, -OC(=O)-, -C(=O)O-, -S-S-, -S-Se-, -Se-Se-, -Se-S-, -S-S-S-, -S-Se-S-, -C(=O)NH-, -NHC(=O)-, -O-, -O-C(=O)NH-, -NHC(=O)O-, -OC(=O)O-, -CF2-, -CHF- and -S-;Q4is selected from the group consisting of C5-C35 alkyl chains, C5-C35 alkenyl chains, C5-C35|-HC Q7alkynyl chains and Q8, wherein said C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains may be linear or branched, wherein in said C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains one or more -CH2- groups may be replaced with groups selected from the group consisting of -CH(OH)-, -OC(=O)-, -C(=O)O-, -S-S-, -S-Se-, -Se-Se-, -Se-S-, -S-S-S-, -S-Se-S-, -C(=O)NH-, -NHC(=O)-, -O-, -O-C(=O)NH-, -NHC(=O)O-, -OC(=O)O-, -CF2-, -CHF- and -S-;Q5is selected from the group consisting of C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains, wherein said C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains may be linear or branched, wherein in said C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains one or more -CH2- groups may be replaced with groups selected from the group consisting of -CH(OH)-, -OC(=O)-, -C(=O)O-, -S-S-, -S-Se-, -Se-Se-, -Se-S-, -S-S-S-, -S-Se-S-, -C(=O)NH-, -NHC(=O)-, -O-, -O-C(=O)NH-, -NHC(=O)O-, -OC(=O)O-, -CF2-, -CHF- and -S-;Q6is selected from the group consisting of C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains, wherein said C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains may be linear or branched, wherein in said C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains one or more -CH2- groups may be replaced with groups selected from the group consisting of -CH(OH)-, -OC(=O)-, -C(=O)O-, -S-S-, -S-Se-, -Se-Se-, -Se-S-, -S-S-S-, -S-Se-S-, -C(=O)NH-, -NHC(=O)-, -O-, -O-C(=O)NH-, -NHC(=O)O-, -OC(=O)O-, -CF2-, -CHF- and -S-;Q7is C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains, wherein said C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains may be linear or branched, wherein in said C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains one or more -CH₂- groups may be replaced with groups selected from the group consisting of -CH(OH)-, -OC(=O)-, -C(=O)O-, -S-S-, -S-Se-, -Se-Se-, -Se-S-, -S-S-S-, -S-Se-S-, -C(=O)NH-, -NHC(=O)-, -O-, -O-C(=O)NH-, -NHC(=O)O-, -OC(=O)O-, -CF₂-, -CHF- and -S-;Q⁸ is C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains, wherein said C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains may be linear or branched, wherein in said C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains one or more -CH₂- groups may be replaced with groups selected from the group consisting of -CH(OH)-, -OC(=O)-, -C(=O)O-, -S-S-, -S-Se-, -Se-Se-, -Se-S-, -S-S-S-, -S-Se-S-, -C(=O)NH-, -NHC(=O)-, -O-, -O-C(=O)NH-, -NHC(=O)O-, -OC(=O)O-, -CF₂-, -CHF- and -S-;Y2is direct bond between X2and J2or selected from the group consisting of -CH3, C1-C15 alkylene chains, C2-C15 alkenylene chains and C2-C15 alkynylene chains, wherein in said Ci-C15 alkylene chains, C2-C15 alkenylene chains or C2-C15 alkynylene chains one or more -CH₂-groups may be replaced with -O- and / or -S-;, wherein δ₄ designates the bond to Y²;T2is direct bond between J2and M2or selected from the group consisting of C1-C15 alkylene chains, C2-C15 alkenylene chains and C2-C15 alkynylene chains, wherein in said C1-C15 alkylene chains, C2-C15 alkenylene chains or C2-C15 alkynylene chains one or more -CH₂-groups may be replaced with -O- and / or -S-;Q9is selected from the group consisting of C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains, wherein said C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains may be linear or branched;Q10is selected from the group consisting of C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains, wherein said C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains may be linear or branched;Q11is selected from the group consisting of C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains, wherein said C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains may be linear or branched;Q12is selected from the group consisting of C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains, wherein said C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains may be linear or branched;wherein y is an integer in the range of 2 to 200, i is an integer in the range of 0 to 3, p is an integer in the range of 2 to 4, e is an integer in the range of 1 to 4 and t is an integer in the range of 1 to 2;and ’ ', wherein δ₅ designates the bond to Y², Y² is direct bond between X² and J² or selected from the group consisting of C1-C15 alkylene chains, C2-C15 alkenylene chains and C2-C15 alkynylene chains, wherein in said C1-C15 alkylene chains, C2-C15 alkenylene chains or C2-C15 alkynylene chains one or more -CH2- groups may be replaced with-O- and / or -S-, J2is selected from the group consisting ofO, wherein δ₄ designates the bond to Y2, T2is direct bond between J2and M2or selected from the group consisting of C1-C15 alkylene chains, C2-C15 alkenylene chains and C2-C15 alkynylene chains, wherein in said C1-C15 alkylene chains, C2-C15 alkenylene chains or C2-C15 alkynylene chains one or more -CH₂- groups may be replaced with-O- and / or -S- and M2is selected from the group consisting of Q10, wherein Q9is selected from the group consisting of C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains, wherein said C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains may be linear or branched, Q10is selected from the group consisting of C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains, wherein said C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains may be linear or branched, Q11is selected from the group consisting of C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains, wherein said C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains may be linear or branched and Q12is selected from the group consisting of C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains, wherein said C5-C35 alkyl chains, C5-C35 alkenyl chains and C5-C35 alkynyl chains may be linear or branched;wherein if Y1isQ6, then J1, T1, M1, Q1, Q2, Q3and Q4are absent;wherein if X2is -OH, -H, -Br, -Cl, -NH2, -SH,or N3, then Y2, J2, T2and M2are absent;wherein if Y2is -CH3, then J2, T2and M2are absent.

22. A lipid nanoparticle composition comprising at least one ionizable compound, at least one structural lipid, at least one sterol and at least one compound of Formula I.

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