ЛИПИДНЫЕ СОЕДИНЕНИЯ

Abstract

Настоящее изобретение относится к липидам, которые включают новые триазольные и алкил- и алкенозамещенные аминосоединения, промежуточные соединения в их синтезе и применение таких триазольных и алкил- и алкенозамещенных аминосоединений, например, в композициях липидных наночастиц для доставки лекарственного средства и лечения рака.

Description

LIPID COMPOUNDS CROSS REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims priority to U.S. Provisional Application No. 63 / 595,051 filed on November 01, 2023, the disclosure of which is incorporated herein by reference in its entirety. FIELD OF THE INVENTION

[0002] This application describes lipids that include novel triazole and alkyl-substituted amine compounds and intermediates used in the synthesis of the same. These triazole and alkyl- substituted amine compounds can be used, for example, in lipid nanoparticle compositions for drug delivery and cancer treatments. BACKGROUND OF THE INVENTION

[0003] It is of great interest for therapeutics, diagnostics, reagents and for biological assays to be able to deliver a nucleic acid into a cell, such as to cause intracellular translation of the nucleic acid and production of the encoded protein. Delivery of nucleic acids has been explored extensively as a potential therapeutic option for certain disease states. In particular, nucleic acid therapy has become an increasingly important option for treatment of various diseases, including cancer treatments. Intracellular delivery of nucleic acids can stimulate the innate immune response, which can be helpful for treatment of various diseases.

[0004] Thus, there is a need to develop lipid compounds that can be useful to facilitate the delivery of nucleic acids to targeted cells or subjects in need thereof. The present invention addresses this unmet need. BRIEF SUMMARY OF THE INVENTION

[0005] In an aspect, the present application relates to compounds represented generically by of formula (G1.1) and tautomers, stereoisomers, constitutional isomers, pharmaceutically acceptable salts and solvates thereof:

[0006] Compounds of general formula (G1.1)wherein moiety B in (G1.1) is C(O)O, OC(O), C(O)NH, HNC(O), or CH2CH2, p = 1-6; p’ = 0-4; p” = 0-4; m’ = 0, 1; moiety T is selected from CH((CH2)llCH3)-CH2)ll’CH3, ll = 2-6, ll’ = 2-6 CH3-(CH2)k-CH2, k = 2-14; (CH3-(CH2)k’)2-CH-(CH2)k”-CH2, k’ = 0-8, k” = 0-9; CH3-(CH2)kk-CH=CH-(CH2)kk’-CH2, kk = 5-8, kk’ = 5-8; CH3-(CH2)kp-CH=CH-(CH2)kp’-CH=CH-(CH2)kp”-CH2, kp = 5-7, kp” = 5-7, kp’ = 1-3; CH3-(CH2)l-O-C(O)-(CH2)kk”-CH2, l = 2-7, kk” = 0-4; and (CH3-(CH2)l-CH2)2-CH-MS-C(O)-(CH2)kk”-CH2, l = 2-7, kk” = 0-5, MS is O or NH;and when p > 1, then each one of the plurality of T tails is the same or different from the remaining T tails in the same molecule, and the amino moiety A in (G1.1) is selected depending on the p-value as follows, wherein the term * is used to refer to a N-binding site of an LT moiety, and *(*) (or (*)* indistinguishably) is used to refer to two separate N-binding sites of two LT moieties: p = 1, then A is *N((CH2)ir-N(NT1)(NT2))(X-(CH2)2-Y-OCO-CH(TA1)(TA2)), ir = 2-4, NT1 is H, or CH3, NT2is CH3, (CH2)r-OCO-(CH2)r’-CH3, (CH2)r-OH, or (CH2)r”-CH3, with r = 1-3, r’ = 1-3, and r” = 1-3, X is C(O)-O, C(O)-CH2, (CH2)nn-OCO with nn = 1-3, or CH2-(CH2)mm with mm = 0-3, Y is S-S-(CH2)n, n = 2,3, or (CH2)q, q = 3-6, OCO is O-C(O) or C(O)-O, TA1 is H or (CH2)m-CH3, and TA2is (CH2)m’-CH3, with m = 5-8 and m’ = 5-8; p = 2, then A is *(*)N-(CH2)t-Z, t = 2-6, Z is N-pyrrolidino, N-piperidino, OCH3, OH, N(CH2-CH3)2, or N(CH3)2, p = 4, then A is *(*)N-(CH2)w1-E-(CH2)w2-N(*)*, w1 = 2-6, w2 = 2-6, E is bond, substituted or unsubstituted amino, O-phenylene- O, O-(CH2)w3-(substituted or unsubstituted 1,4- piperazinediyl)-(CH2)w4-O, substituted or unsubstituted 1,4- piperazinediyl, S-S, XS-S-S-XS, XS-(substituted orunsubstituted 1,4-piperazinediyl)-XS, EE-(1,4- cyclohexanediyl)-EE, or EE-(1,3-cyclohexanediyl)-EE, wherein w3 = 0-4, w4 = 0-4, XS is C(O)-O-(CH2)2, and EE is O, C(O)-O or C(O)-NH, p = 5, then A is *(*)N-(CH2)p1-N*-(CH2)p2’-N(*)*, p1 = 2-5, p2 = 2-5, and p = 6, then A is *(*)N-(CH2)q1-N((CH2)q2-N(*)*)-(CH2)q3-N(*)*, wherein q1 = 2-4, q2 = 2-4, and q3 = 2-4.

[0007] When p > 1, then each one of the plurality of LT moieties may be the same or different from the remaining LT moieties in the same molecule.

[0008] In another aspect, the present application relates to compounds represented generically by by formula (G1.2) and tautomers, stereoisomers, constitutional isomers, pharmaceutically acceptable salts and solvates thereof:

[0009] The amino moiety A in (G1.2) is selected when q ≥ 1 as having its N* or N(*)* binding sites linked to at least one ST that differs from LT as indicated in general formula (G1.2).

[0010] R is OH, COOH, CHO, OR’, COOR’, C(O)NH2, or C(O)NHR’, with R’ being (CH2)q”CH3, with q’ = 1-4, q” = 1-4, B is as defined for formula (G1.1), p = 1-5 when q = 1-5, and p = 1-6 when q = 0-5, with (p + q) = 1-6 and p ≠ 0,q = 0 leads to the compounds of general formula (G1.1) with p = 1-6 as defined above. All the variables concerning the amino moiety A and the moiety(ies) LT not defined for (G1.2) are as defined for (G1.1), subject to the p and q restrictions set forth above. For example, A in (G1.2) is an amino moiety, and said amino moiety A is selected depending on the (p+q)-value as follows, wherein the term * is used to refer to a N-binding site of an LT moiety, and *(*) (or (*)* indistinguishably) is used to refer to two separate N-binding sites of two LT moieties: when p =1 and q = 0, then such compound would be a compound of formula (G1.1); when p = 1 and q = 1, then A is *(*)N-(CH2)t-Z, t = 2-6, Z is N-pyrrolidino, N-piperidino, OCH3, OH, N(CH2-CH3)2, or N(CH3)2, when p+q = 4, with p ≥ 1 and q ≥ 1, then A is *(*)N-(CH2)w1-E-(CH2)w2-N(*)*, w1 = 2-6, w2 = 2-6, E is bond, substituted or unsubstituted amino, O-phenylene- O, O-(CH2)w3-(substituted or unsubstituted 1,4- piperazinediyl)-(CH2)w4-O, substituted or unsubstituted 1,4- piperazinediyl, S-S, XS-S-S-XS, XS-(substituted or unsubstituted 1,4-piperazinediyl)-XS, EE-(1,4- cyclohexanediyl)-EE, or EE-(1,3-cyclohexanediyl)-EE, wherein w3 = 0-4, w4 = 0-4, XS is C(O)-O-(CH2)2, and EE is O, C(O)-O or C(O)-NH, when p+q = 5, with p ≥ 1 and q ≥ 1, then A is *(*)N-(CH2)p1-N*-(CH2)p2-N(*)*, p1 = 2-5, p2 = 2-5, and when p+q = 6, with p ≥ 1 and q ≥ 1, then A is *(*)N-(CH2)q1-N((CH2)q2-N(*)*)-(CH2)q3-N(*)*, q1 = 2-4, q2 = 2-4, and q3 = 2-4.

[0011] When p > 1, then each one of the plurality of LT moieties may be the same or different from the remaining LT moieties in the same molecule, and when q > 1, then each one of the plurality of ST moieties may be the same or different from the remaining ST moieties in the same molecule.

[0012] Formula (G1.2) envisages embodiments with the N* and N(*)* binding sites in the amino moiety A being linked to ST and / or LT according to any of the following binding embodiments for N*: N-ST and N-LT, and according to any of the following binding embodiments for N(*)*: N(LT)(LT) wherein the LT moieties are identical or different form each other, N(ST)(LT) and N(ST)(ST) wherein the ST moieties are identical or different form each other.

[0013] Each variable in (G1.1) and (G1.2) indicating the choice of a number of groups of substituents, or a choice of substituents, is elected independently from the choice of any other such variable, whether such variables have the same name (while referring to different groups) or not, unless explicitly indicated otherwise.

[0014] In another aspect, the present application relates to synthetic methods and intermediates used in the synthesis of triazoles (G1.1) and (G1.2) referred to above.

[0015] The present application relates in another aspect to compounds represented generically by formula (G2) and tautomers, stereoisomers, constitutional isomers, pharmaceutically acceptable salts and solvates thereof:, wherein each occurrence of LCHAIN1 - LCHAIN4 is linear or branched Ca-alkyl, with a = 9-15, or CH2(CH2)v’CH=CH(CH2)v”CH3, with v = 8-12, v’ = 1-4, v” = 2-5, and each occurrence of LCHAIN1 - LCHAIN4 is the same or different from each of any of the other three occurrences of LCHAIN1 - LCHAIN4, n = 0 - 4, n’ = 0 - 4, and each occurrence of n is the same or different from each occurrence of n’, Q is (CH2)rCH3with r = 0-2, or CH2(CH2)r’C(O)O(CH2)r”CH3with r’ = 0-3 and r” = 1-3.

[0016] The designations (MM1), (MM2), (MM3), MM4) and (MM5) refer to the various assignments for the moiety MM in Formula (G2).

[0017] Each variable in (G2) indicating the choice of a number of groups of substituents, or a choice of substituents, is elected independently from the choice of any other such variable,whether such variables have the same name (while referring to different groups) or not, unless explicitly indicated otherwise.

[0018] In another aspect, the present application relates to synthetic methods and intermediates used in the synthesis of compounds of any of formulae (G1.1), (G1.2) and (G2) referred to above.

[0019] In another aspect, the present application relates to a pharmaceutical composition comprising at least one compound, or combination thereof, as described herein or a stereoisomer, tautomer, constitutional isomer, pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0020] In another aspect, the present application relates to the use of at least one compound as described herein or a stereoisomer, tautomer, constitutional isomer, pharmaceutically acceptable salt or solvate thereof, or a combination thereof for the making of lipid nanoparticle compositions, for drug delivery or cancer treatment.

[0021] Other features and advantages of the present invention are apparent from additional descriptions provided herein, including different examples. The examples provided herein illustrate different components and methodology useful in practicing the present invention. Such examples do not limit the claimed invention. Based on the present disclosure, the skilled artisan can identify and employ other components and methodology useful for practicing the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] The foregoing summary, as well as the following detailed description of preferred embodiments of the present application, will be better understood when read in conjunction with the appended drawings. It should be understood, however, that the application is not limited to the precise embodiments shown in the drawings.

[0023] FIG.1. Tabular summary of in vitro screening results showing which LNPs resulted in expression of Gaussia luciferase from mRNA, pDNA, or both payloads.

[0024] FIG.2A. DNA-LNP data showing circulating levels of hFIX following in vivo delivery of hFIX transgene expression cassette DNA with LNPs comprising lipids according to this invention, such as lipids of Formula (G1.1).

[0025] FIG.2B. DNA-LNP data showing circulating levels of hFIX following in vivo delivery of hFIX transgene expression cassette DNA with LNPs comprising lipids according to this invention, such as lipids of Formula (G2).

[0026] FIG.2C. DNA-LNP data showing circulating levels of IL-6 (representative cytokine response) following in vivo delivery of hFIX transgene expression cassette DNA with LNPs comprising lipids according to this invention, such as lipids of Formula (G1.1).

[0027] FIG.2D. DNA-LNP data showing circulating levels of IL-6 (representative cytokine response) following in vivo delivery of hFIX transgene expression cassette DNA with LNPs comprising lipids according to this invention, such as lipids of Formula (G2).

[0028] FIG.3A. DNA-LNP data showing in vivo efficacy of multiple formulation compositions of the same ionizable lipid. Tabular summary of multiple LNP formulation compositions comprising the same ionizable lipid A4L1T14, a lipid of Formula (G1.1).

[0029] FIG.3B. DNA-LNP data showing in vivo efficacy of multiple LNP formulation compositions of the same ionizable lipid from FIG.3A. The graph shows circulating levels of hFIX after delivery of hFIX transgene expression cassette DNA-LNPs with different formulation compositions with the same ionizable lipid A4L1T14, a lipid of Formula (G1.1).

[0030] FIG.3C. DNA-LNP data showing in vivo efficacy of multiple LNP formulation compositions of the same ionizable lipid from FIG 3A. The graph shows circulating levels of IL-6 (representative cytokine response) after delivery of hFIX transgene expression cassette DNA- LNPs with different formulation compositions with the same ionizable lipid A4L1T14, a lipid of Formula (G1.1).

[0031] FIG.4A. mRNA-LNP in vivo data showing potency of mRNA-LNPs formulated with lipids A4L1T14 and A5L1T15. hEPO expression (circulating levels of hEPO) after single IV delivery of different doses of hEPO mRNA-LNPs. hEPO levels measured from plasma 6 h after dosing.

[0032] FIG.4B. mRNA-LNP in vivo data showing cytokine response following delivery of mRNA-LNPs formulated with lipids A4L1T14 and A5L1T15. Circulating MCP-1 (representative cytokine response) following single IV delivery of different doses of hEPO mRNA-LNPs. MCP-1 cytokine levels measured from plasma 6 h after dosing.

[0033] FIG.4C. mRNA-LNP in vivo data showing potency of mRNA-LNPs formulated with lipids A4L1T14 and A5L1T15. Time course of circulating levels of hEPO after IV delivery of each of two doses of hEPO mRNA-LNPs formulated with lipids A4L1T14 and A5L1T15.

[0034] FIG.5A. mRNA-LNP in vivo data showing that mRNA-LNPs formulated with lipids of the present invention, such as A4L1T14, can be re-dosed in vivo. Table of multiple LNP formulations of A4L1T14.

[0035] FIG.5B. mRNA-LNP in vivo data showing that mRNA-LNPs formulated with lipids of the present invention, such as A4L1T14, can be re-dosed in vivo. hEPO expression (circulating hEPO levels) after multiple IV dosings in mice of hEPO mRNA-LNPs from FIG.5A. hEPO levels measured from plasma 6 h after dosing.

[0036] FIG.6. mRNA-LNP in vivo data showing potency of lipids according to this invention for mRNA delivery. Expression of hEPO using mRNA delivery by LNPs containing various ionizable lipids, including lipids according to the present invention (Formulae (G1.1) and (G2)). hEPO mRNA-LNP administered via tail vein injection to wild-type mice; hEPO expression (circulating hEPO levels) measured 6 h post-injection.

[0037] FIG.7. mRNA-LNP in-vivo data showing potency of lipids according to this invention for delivery of firefly luciferase mRNA. Expression of firefly luciferase (Flux) in liver tissues after IV administration to mice of mRNA-LNPs formulated with various ionizable lipids, including lipids according to the present invention (Formula (G1.1)).

[0038] FIG.8A. mRNA-LNP in-vivo data showing responses to A4L1T14-based LNP formulations. Strength of anti-OVA IgG antibody response that was induced by A4LT14-based LNP formulations when OVA mRNA-LNP was delivered intramuscularly to mice.

[0039] FIG.8B. mRNA-LNP in-vivo data showing responses to A4L1T14-based LNP formulations. Strength of antigen-specific T cell (MHC-I tetramer+ CD8 cells) responses that were induced by A4L1T14-based LNP formulations following intramuscular injection of OVA mRNA-LNP.

[0040] FIG.8C. mRNA-LNP in-vivo data showing responses to A4L1T14-based formulations. Strength of antigen-specific T cell (IFN-γ+ CD8 cells) responses that were induced by A4L1T14-based LNP formulations following intramuscular injection of OVA mRNA-LNP. DETAILED DESCRIPTION OF THE INVENTION

[0041] Various publications, articles and patents are cited or described in the background and throughout the specification; each of these references is herein incorporated by reference in its entirety. Discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is for the purpose of providing context for the disclosure. Such discussion is not an admission that any or all of these matters form part of the prior art with respect to the disclosure.

[0042] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this invention pertains. Otherwise, certain terms used herein have the meanings as set forth in the specification. All patents, published patent applications, and publications cited herein are incorporated by reference as if set forth fully herein.

[0043] It must be noted that as used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural reference unless the context clearly dictates otherwise.

[0044] Unless otherwise indicated, the term “at least” preceding a series of elements is to be understood to refer to every element in the series. For example, the phrase “at least A, B, and C” means that each of A, B, and C is present. The term “at least one of” preceding a series of elements is to be understood to refer to a single element in the series or any combination of two or more elements in the series. For example, the phrase “at least one of A, B, and C” means that only A is present, only B is present, only C is present, both A and B are present, both A and C are present, both B and C are present, or each of A, B, and C is present. Depending on the context, “at least one of” preceding a series of elements can also encompass situations in which any one or more of the elements is present in greater than one instance, e.g., “at least one of A, B, and C” can also encompass situations in which A is present in duplicate alone or further in combination with any one or more of elements B and C.

[0045] As used herein, the term “and / or” between multiple recited elements is understood as encompassing both individual and combined options. For instance, where two elements are conjoined by “and / or,” a first option refers to the applicability of the first element without the second. A second option refers to the applicability of the second element without the first. A third option refers to the applicability of the first and second elements together. Any one of these options is understood to fall within the meaning, and therefore satisfy the requirement of the term “and / or” as used herein. Concurrent applicability of more than one of the options is also understood to fall within the meaning, and therefore satisfy the requirement of the term “and / or.”

[0046] Unless otherwise stated, any numerical value, such as a concentration or a concentration range described herein, is to be understood as being modified in all instances by the term “about” (whether written explicitly or not) and, in any case, “about” is to be construed when applied to the term that it modifies as understood by one of ordinary skill in the art, including the typical experimental uncertainties associated with the determination of the value of such term. As used herein, the use of a numerical range expressly includes all possible subranges, all individual numerical values within that range, including integers within such ranges and fractions of the values unless the context clearly indicates otherwise.

[0047] As used herein, “subject” means any animal, such as a mammal, to whom will be or has been treated by a method described herein. The term “mammal” as used herein, encompasses any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, and non-human primates (NHPs), such as monkeys or apes, humans, etc.

[0048] The phrase “pharmaceutically acceptable salt(s)” means those salts of a compound of interest that are safe and effective for topical use in mammals and that possess the desired biological activity. Pharmaceutically acceptable salts include salts of acidic or basic groups present in the specified compounds. Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, carbonate, bicarbonate, acetate, lactate, salicylate, citrate, tartrate, propionate, butyrate, pyruvate, oxalate, malonate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzensulfonate, p-toluenesulfonate andpamoate (i.e., 1,1 ′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Certain compounds used in the application can form pharmaceutically acceptable salts with various amino acids. Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, bismuth, and diethanolamine salts. For a review on pharmaceutically acceptable salts, see Berge, et al., 66 J. Pharm. Sci. 1-19 (1977), incorporated herein by reference.

[0049] As used herein, the term “alkyl” means a saturated, monovalent, unbranched or branched hydrocarbon chain. An alkyl group can be unsubstituted or substituted with one or more suitable substituents. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl, isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl), etc. An alkyl group can have a specified number of carbon atoms. When numbers appear in a subscript after the symbol “C”, the subscript defines with more specificity the number of carbon atoms which that particular alkyl can contain. For example, “C1 to C10alkyl” or “C1-10alkyl” is intended to include alkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 carbon atoms. Additionally, for example, “C1to C8alkyl” or “C1-8alkyl” denotes an alkyl having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms.

[0050] The term “cycloalkyl” refers to any stable monocyclic or polycyclic saturated hydrocarbon ring system. A cycloalkyl group can be unsubstituted or substituted with one or more suitable substituents. A cycloalkyl group can have a specified number of carbon atoms. For example, “C3 to C6 cycloalkyl” or “C3-6 cycloalkyl” includes cycloalkyl groups having 3, 4, 5, or 6 ring carbon atoms, i.e., cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Polycyclic cycloalkyls include bridged, fused, and spiro ring structures in which all ring atoms are carbon atoms. A “spiro ring” is a polycyclic ring system in which two rings share one carbon atom, referred to as the “spiro atom,” which is typically a quaternary carbon atom. A “fused ring” is a polycyclic ring system in which two rings share two adjacent atoms, referred to as “bridgehead atoms,” i.e., the two rings share one covalent bond such that the bridgehead atoms are directly connected. A “bridged ring” is a polycyclic ring system in which two rings share three or more atoms separating the bridgehead atoms by a bridge containing at least one atom. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.

[0051] As used herein, the term “alkenyl” means a linear or branched chain of hydrocarbons comprising at least one carbon to carbon double bond, optionally having the number of carbon atoms designated (i.e., C2-C4 alkenyl or C2-4alkenyl means an alkenyl having two to four carbon atoms).

[0052] As used herein, the term “alkynyl” means a linear or branched chain of hydrocarbons comprising at least one carbon to carbon triple bond, optionally having the number of carbon atoms designated (i.e., C2-C4 alkenyl or C2-4alkenyl means an alkenyl having two to four carbon atoms).

[0053] The term “aryl” as used herein is a group that contains any carbon-based aromatic group including, but not limited to, phenyl, naphthyl, anthracenyl, phenanthranyl, and the like. Aryl moieties are well known and described, for example, in Lewis, R. J., ed., Hawley’s Condensed Chemical Dictionary, 13th Edition, John Wiley & Sons, Inc., New York (1997). An aryl group can be substituted or unsubstituted with one or more suitable substituents. An aryl group can comprise a single ring structure (i.e., monocyclic) or multiple ring structures (i.e., polycyclic, e.g., bicyclic or tricyclic). For example, an aryl group can be a monocyclic aryl group, e.g., phenyl.

[0054] The term “heterocyclyl” includes stable monocyclic and polycyclic hydrocarbons that contain at least one heteroatom ring member, such as sulfur, oxygen, or nitrogen, wherein the ring structure is saturated or partially unsaturated, provided the ring system is not fully aromatic. A heterocyclyl group can be unsubstituted, or substituted with one or more suitable substituents at any one or more of the carbon atom(s) and / or nitrogen heteroatom(s) of the heterocyclyl. A heterocyclyl can comprise a single ring structure (i.e., monocyclic) or multiple ring structures (i.e., polycyclic, e.g., bicyclic). Polycyclic heterocyclyls include bridged, fused, and spiro ring structures in which at least one ring atom of at least one of the rings of the polycyclic ring system is a heteroatom, for instance oxygen, nitrogen, or sulfur, wherein bridged, fused, and spiro rings are as defined above. A heterocyclyl ring can be attached to the parent molecule at any suitable heteroatom (typically nitrogen) or carbon atom of the ring. The term “4- to 9-membered monocyclic or bicyclic heterocyclyl” includes any four, five, six, seven, eight, or nine membered monocyclic or bicyclic ring structure containing at least one heteroatom ring member selected from oxygen, nitrogen, and sulfur, or independently selected from oxygen and nitrogen, optionally containing one to three additional heteroatoms independently selected from oxygen,nitrogen, and sulfur, or independently selected from oxygen and nitrogen, wherein the ring structure is saturated or partially unsaturated, provided the ring structure is not fully aromatic.

[0055] As used herein, the term “heteroaryl" includes stable monocyclic and polycyclic aromatic hydrocarbons that contain at least one heteroatom ring member such as sulfur, oxygen, or nitrogen. A heteroaryl group can be unsubstituted or substituted with one or more suitable substituents. A heteroaryl can comprise a single ring structure (i.e., monocyclic) or multiple ring structures (i.e., polycyclic, e.g., bicyclic or tricyclic). Each ring of a heteroaryl group containing a heteroatom can contain one or two oxygen or sulfur atoms and / or from one to four nitrogen atoms provided that the total number of heteroatoms in each ring is four or less and each ring has at least one carbon atom. Heteroaryl groups which are polycyclic, e.g., bicyclic or tricyclic must include at least one fully aromatic ring, but the other fused ring or rings can be aromatic or non-aromatic. For example, for a bicyclic heteroaryl, the fused rings completing the bicyclic group can contain only carbon atoms and can be saturated, partially saturated, or unsaturated. A heteroaryl can be attached to the parent molecule at any available nitrogen or carbon atom of any ring of the heteroaryl group. In some embodiments, the term “heteroaryl” refers to 5- or 6-membered monocyclic groups and 9- or 10-membered bicyclic groups which have at least one heteroatom (O, S, or N) in at least one of the rings, wherein the heteroatom-containing ring typically has 1, 2, or 3 heteroatoms, such as 1 or 2 heteroatoms, selected from O, S, and / or N. A heteroaryl group can be unsubstituted, or substituted with one or more suitable substituents at any one or more of the carbon atom(s) and / or nitrogen heteroatom(s) of the heteroaryl. The nitrogen and sulfur heteroatom(s) of a heteroaryl can optionally be oxidized (i.e., N→O and S(O)r, wherein r is 0, 1 or 2).

[0056] The term “alkoxy” as used herein refers to an –O-alkyl group, wherein alkyl is as defined above. An alkoxy group is attached to the parent molecule through a bond to an oxygen atom. An alkoxy group can have a specified number of carbon atoms. For example, “C1 to C10 alkoxy” or “C1-10 alkoxy” is intended to include alkoxy groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 carbon atoms. Additionally, for example, “C1to C4alkoxy” or “C1-4alkoxy” denotes an alkoxy having 1, 2, 3, or 4 carbon atoms. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy, isopropoxy), butoxy (e.g., n-butoxy, isobutoxy, tert- butoxy), pentyloxy (e.g., n-pentyloxy, isopentyloxy, neopentyloxy), etc. An alkoxy group can beunsubstituted or substituted with one or more suitable substituents. Similarly, “alkylthio” or “thioalkoxy” represents an alkyl group as defined above attached to the parent molecule through a bond to a sulfur atom, for example, -S-methyl, -S-ethyl, etc. Representative examples of alkylthio include, but are not limited to, -SCH3, -SCH2CH3, etc.

[0057] As used herein, the term “halogen” means fluorine, chlorine, bromine, or iodine. Correspondingly, the term “halo” means fluoro, chloro, bromo, and iodo.

[0058] “Haloalkyl” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon radicals substituted with one or more halogen atoms. “Fluorinated alkyl” or “fluoroalkyl” in particular refers to any alkyl group as defined above substituted with at least one fluoro atom, e.g., one to three fluoro atoms, such as one, two, or three fluoroatoms. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2- trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Suitable examples of fluoroalkyl in particular include, but are not limited to, -CF3, -CHF2, -CH2F, -CH2CF3, -CF2CF3, and the like.

[0059] The terms “hydroxy” and “hydroxyl” can be used interchangeably, and refer to – OH.

[0060] The term “carboxy” refers to –COOH.

[0061] The term “ester” refers to -COOR, wherein R is alkyl as defined above.

[0062] The term “cyano” refers to –CN.

[0063] The term “oxo” refers to a double bonded oxygen group, i.e., a substituent group of the formula =O.

[0064] The term “keto” refers to -C(O)R, wherein R is alkyl as defined above.

[0065] The term “amino” refers to –NH2. One or more hydrogen atoms of an amino group can be replaced by a substituent such as an alkyl group, which is referred to as an “alkylamino.” Alkylamino groups have one or both hydrogen atoms of an amino group replaced with an alkyl group and is attached to the parent molecule through a bond to the nitrogen atom of the alkylamino group. For example, alkylamino includes methylamino (-NHCH3), dimethylamino (-N(CH3)2), -NHCH2CH3and the like.

[0066] The term “aminoalkyl” as used herein is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups substituted with one or more amino groups. For example, “C1-4aminoalkyl” is intended to include alkyl groups having 1, 2, 3, or 4 carbonatoms substituted with one or more amino groups. Aminoalkyl groups are attached to the parent molecule through a bond to a carbon atom of the alkyl moiety of the aminoalkyl group. Representative examples of aminoalkyl groups include, but are not limited to, -CH2NH2, - CH2CH2NH2, and –CH2CH(NH2)CH3.

[0067] As used herein, “amido” refers to –C(O)N(R)2, wherein each R is independently an alkyl group (including both branched and straight-chain alkyl groups) or a hydrogen atom. Examples of amido groups include, but are not limited to, -C(O)NH2, -C(O)NHCH3, and – C(O)N(CH3)2.

[0068] The terms “hydroxyl-substituted alkyl,” “hydroxylalkyl” and “hydroxyalkyl” are used interchangeably, and refer to a branched or straight-chain aliphatic hydrocarbon group substituted with one or more hydroxyl groups. Hydroxyalkyl groups are attached to the parent molecule through a bond to a carbon atom of the alkyl moiety of the hydroxyalkyl group. A hydroxyalkyl group can have a specified number of carbon atoms. For example, “C1 to C10 hydroxyalkyl” or “C1-10 hydroxyalkyl” is intended to include hydroxyalkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 carbon atoms. Additionally, for example, “C1to C4hydroxylalkyl” or “C1-4hydroxyalkyl” denotes a hydroxyalkyl group having 1, 2, 3, or 4 carbon atoms. Examples of hydroxyalkyl include, but are not limited to, hydroxylmethyl (-CH2OH), hydroxylethyl (- CH2CH2OH), etc.

[0069] For the avoidance of doubt, when a group is “bond”, then such group is not present while the connectivity of the rest of the molecular entity or moiety is unchanged and kept as such single molecular entity or moiety. For example, Eex being CH2 or bond in the molecular entity or moiety Aex-Eex-Bex, refers to the molecular entities or moieties Aex-CH2-Bexand Aex-Bex, the latter being the embodiment associated with the choice of Eex being bond.

[0070] The assignment “OCO is O-C(O) or C(O)-O”, or an analogous assignment, means that when OCO is O-C(O), then the illustrative moiety or molecular entity Yex-OCO-Vexhas an Yex-O bond as in Yex-O-C(O)-Vex, and when OCO is C(O)-O then the illustrative moiety or molecular entity Yex-OCO-Vex has a Vex-O bond as in Yex-C(O)-O-Vex.

[0071] In accordance with convention used in the art, notations such as:

[0072]

[0073] are used in structural formulas herein to depict a bond that is the point of attachment of a group, moiety or substituent to the core, backbone, or parent molecule structure. An asterisk or a plurality of asterisks are used to refer to a certain binding site, or plurality of binding sites; by way of illustration, the term *N refers to one N-binding site (the binding site for an LT or ST moiety), and *(*)N refers to two separate N-binding sites in the same N member (the binding sites in the same N member for two LT moieties (identical or different from each other), two ST moieties (identical or different from each other), or one ST and one LT moieties).

[0074] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent can be bonded to any atom on the ring.

[0075] The term “substituted” as used herein with respect to any organic radical (e.g., alkyl, cycloalkyl, heteroaryl, aryl, heterocyclyl, etc.) means that at least one hydrogen atom is replaced with a non-hydrogen group, provided that all normal valencies are maintained and that the substitution results in a stable compound. When a particular group is “substituted,” that group can have one or more substituents, such as from one to five substituents, one to three substituents, or one to two substituents, independently selected from the list of substituents. The term “independently” when used in reference to substituents, means that when more than one of such substituents is possible, such substituents can be the same or different from each other. Examples of suitable substituents include, but are not limited to, alkyl, halo, haloalkyl, alkoxy, amido, hydroxy, hydroxyalkyl, amino, carboxyl, ester, oxo, cyano, and the like.

[0076] When any variable occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-3 R groups, then said group can be optionally substituted with up to three R groups, and at each occurrence, R is selected independently from the definition of R.

[0077] The terms “optional” or “optionally” mean that the event or circumstance described subsequently can, but need not, occur, and such a description includes the situation in which the event or circumstance does or does not occur. For example, “optionally substituted heterocyclyl” means that a substituent group can be, but need not be, present, and such a description includes the situation of the heterocyclyl group being substituted by a suitable substituent and the heterocyclyl group not being substituted by any substituent.

[0078] One skilled in the art will recognize that in certain embodiments compounds described herein can have one or more asymmetric carbon atoms in their structure. As used herein, any chemical formulas with bonds shown only as solid lines and not as solid wedged or hashed wedged bonds, or otherwise indicated as having a particular configuration (e.g., R or S) around one or more atoms, contemplates each possible stereoisomer, or mixture of two or more stereoisomers. The term stereoisomers includes enantiomers and diastereomers. Enantiomers are stereoisomers that are non-super-imposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a racemate or racemic mixture. Diastereomers (or diastereoisomers) are stereoisomers that are not enantiomers, i.e., they are not related as mirror images, and occur when two or more stereoisomers of a compound have different configurations at one or more of the equivalent stereocenters and are not mirror images of each other. Substituent groups (e.g., alkyl, heterocyclyl, etc.) can contain stereocenters in either the R or S configuration.

[0079] Certain examples can contain chemical structures that comprise (R) or (S) terminology. When (R) or (S) is used in the name of a compound or in the chemical representation of the compound, it is intended to mean that the compound is a single isomer at that stereocenter, with established absolute configuration of either (R) or (S).

[0080] Stereochemically pure isomeric forms can be obtained by techniques known in the art in view of the present disclosure. For example, diastereoisomers can be separated by physical separation methods such as fractional crystallization and chromatographic techniques, and enantiomers can be separated from each other by the selective crystallization of the diastereomeric salts with optically active acids or bases or by chiral chromatography. Pure stereoisomers can also be prepared synthetically from appropriate stereochemically pure starting materials, or by using stereoselective reactions.

[0081] When compounds described herein can form tautomers, the term “tautomer” refers to compounds that are interchangeable forms of a particular compound structure and that vary in the displacement of hydrogen atoms and electrons. Tautomers are constitutional isomers of chemical compounds that readily interconvert, usually resulting in relocation of a proton (hydrogen). Thus, two structures can be in equilibrium through the movement of pi electrons and an atom (usually hydrogen). All tautomeric forms and mixtures of tautomers of the compounds described herein are included with the scope of the application.

[0082] Compounds described herein can exist in solvated and unsolvated forms. The term “solvate” means a physical association, e.g., by hydrogen bonding, of a compound of the application with one or more solvent molecules. The solvent molecules in the solvate can be present in a regular arrangement and / or a non-ordered arrangement. The solvate can comprise either a stoichiometric or nonstoichiometric amount of the solvent molecules. “Solvate” encompasses both solution-phase and isolable solvates. Compounds of the application can form solvates with water (i.e., hydrates) or common organic solvents. Illustrative solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Methods of solvation are generally known in the art.

[0083] Also included within the scope of the application are all isotopes of atoms occurring in the compounds described herein. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include13C and14C. Isotopically-labeled compounds can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.

[0084] As used herein, the name of a compound is intended to encompass all possible existing isomeric forms, including stereoisomers (e.g., enantiomers, diastereomers, racemate or racemic mixture, and any mixture thereof) and constitutional isomers, of the compound, unless indicated otherwise. Compounds

[0085] In one general aspect, the present application relates to a compound formula (G1.1) and tautomers, stereoisomers, constitutional isomers, pharmaceutically acceptable salts and solvates thereof:wherein moiety B in (G1.1) is C(O)O, OC(O), C(O)NH, HNC(O), or CH2CH2, p = 1-6; p’ = 0-4; p” = 0-4; m’ = 0, 1; moiety T is selected from CH((CH2)llCH3)-CH2)ll’CH3, ll = 2-6, ll’ = 2-6 CH3-(CH2)k-CH2, k = 2-14; (CH3-(CH2)k’)2-CH-(CH2)k”-CH2, k’ = 0-8, k” = 0-9; CH3-(CH2)kk-CH=CH-(CH2)kk’-CH2, kk = 5-8, kk’ = 5-8; CH3-(CH2)kp-CH=CH-(CH2)kp’-CH=CH-(CH2)kp”-CH2, kp = 5-7, kp” = 5-7, kp’ = 1-3; CH3-(CH2)l-O-C(O)-(CH2)kk”-CH2, l = 2-7, kk” = 0-4; and (CH3-(CH2)l-CH2)2-CH-MS-C(O)-(CH2)kk”-CH2, l = 2-7, kk” = 0-5, MS is O or NH; and when p > 1, then each one of the plurality of T tails may be the same or different from the remaining T tails in the same molecule,and the amino moiety A in (G1.1) is selected depending on the p-value as follows, wherein the term * is used to refer to a N-binding site of an LT moiety, and *(*) (or (*)* indistinguishably) is used to refer to two separate N-binding sites of two LT moieties: p = 1, then A is *N((CH2)ir-N(NT1)(NT2))(X-(CH2)2-Y-OCO-CH(TA1)(TA2)), ir = 2-4, NT1is H, or CH3, NT2is CH3, (CH2)r-OCO-(CH2)r’-CH3, (CH2)r-OH, or (CH2)r”-CH3, with r = 1-3, r’ = 1-3, and r” = 1-3, X is C(O)-O, C(O)-CH2, (CH2)nn-OCO with nn = 1-3, or CH2-(CH2)mmwith mm = 0-3, Y is S-S-(CH2)n, n = 2,3, or (CH2)q, q = 3-6, OCO is O-C(O) or C(O)-O, TA1is H or (CH2)m-CH3, and TA2 is (CH2)m’-CH3, with m = 5-8 and m’ = 5-8; p = 2, then A is *(*)N-(CH2)t-Z, t = 2-6, Z is N-pyrrolidino, N-piperidino, OCH3, OH, N(CH2-CH3)2, or N(CH3)2, p = 4, then A is *(*)N-(CH2)w1-E-(CH2)w2-N(*)*, w1 = 2-6, w2 = 2-6, E is bond, substituted or unsubstituted amino, O-phenylene- O, O-(CH2)w3-(substituted or unsubstituted 1,4- piperazinediyl)-(CH2)w4-O, substituted or unsubstituted 1,4- piperazinediyl, S-S, XS-S-S-XS, XS-(substituted or unsubstituted 1,4-piperazinediyl)-XS, EE-(1,4- cyclohexanediyl)-EE, or EE-(1,3-cyclohexanediyl)-EE,wherein w3 = 0-4, w4 = 0-4, XS is C(O)-O-(CH2)2, and EE is O, C(O)-O or C(O)-NH, p = 5, then A is *(*)N-(CH2)p1-N*-(CH2)p2’-N(*)*, p1 = 2-5, p2 = 2-5, and p = 6, then A is *(*)N-(CH2)q1-N((CH2)q2-N(*)*)-(CH2)q3-N(*)*, wherein q1 = 2-4, q2 = 2-4, and q3 = 2-4.

[0086] When p > 1, then each one of the plurality of LT moieties may be the same or different from the remaining LT moieties in the same molecule.

[0087] Each variable in (G1.1) indicating the choice of a number of groups of substituents, or a choice of substituents, is elected independently from the choice of any other such variable, whether such variables have the same name (while referring to different groups) or not, unless explicitly indicated otherwise.

[0088] In some embodiments, moiety A has one LT-substituted group indicated as *N in the assignment of A when p = 1 above.

[0089] In some embodiments, moiety A has one fully LT-substituted group indicated as *(*)N in the assignment of A when p = 2 above.

[0090] In some embodiments, moiety A has two fully LT-substituted groups, each indicated as *(*)N in the assignment of A when p = 4 above.

[0091] In some embodiments, moiety A has one LT-substituted group indicated as *N and two fully substituted groups, each indicated as *(*)N in the assignment of A when p = 5 above.

[0092] In some embodiments, moiety A has three fully LT-substituted groups, each indicated as *(*)N in the assignment of A when p = 6 above.

[0093] In some embodiments, p = 1, 2, 4-6.

[0094] When p > 1, all the LT moieties are identical in some embodiments of compounds of formula (G1.1), some of such LT moieties are the same whereas others are different in some other embodiments of compounds of formula (G1.1), and in still other embodiments of compounds of formula (G1.1), all the LT moieties are different.

[0095] T for each LT moiety is, in some embodiments, one of T1 – T23 in Table 2 without the azide moiety shown therein, and m’ = 0. T for each LT moiety is, in some embodiments, one of T1 – T23 in Table 2 without the azide moiety shown therein, and m’ = 1. The terms “moiety T” and “tail T” are used herein indistinguishably. Such T1-T23 without the corresponding azide moieties are as follows:Table T2 (part 1)Table T2 (part 2)

[0096] In some embodiments, p’ = 1.

[0097] In some embodiments, p” = 1.

[0098] In some embodiments, m’ = 1.

[0099] In some embodiments, p’ = p” = 1. In some embodiments in which p’ = p” = 1, B is CH2CH2.

[0100] In some embodiments, B is C(O)NH or HNC(O). In some of such embodiments where B is C(O)NH or HNC(O), p’ = p” = 1.

[0101] In some embodiments, B is C(O)O or OC(O). In some of such embodiments where B is C(O)O or OC(O), p’ = p” = 1.

[0102] In some embodiments, p’ = p” = m’ = 1.

[0103] In some embodiments, p is one of 1, 2, 3, 4, 5 and 6, and when p is one of 2, 3, 4, 5 and 6, then p’ = p” = 1 in each LT.

[0104] In some embodiments, p is one of 1, 2, 3, 4, 5 and 6, and when p is one of 2, 3, 4, 5 and 6, then p’ = p” = 1 in each LT and when p = 1 then m’ is 0 or 1.

[0105] In some embodiments, p is one of 1, 2, 3, 4, 5 and 6, and when p is one of 2, 3, 4, 5 and 6, then p’ = p” = 1 in each LT and when p is one of 2, 3, 4, 5 and 6, then m’ is 0 or 1 in each LT. In some of such embodiments, m’ is the same in each LT.

[0106] In some embodiments, p is one of 1, 2, 3, 4, 5 and 6, and when p is one of 2, 3, 4, 5 and 6, then p’ = p” = 1 in each LT, and tail T is selected from CH3-(CH2)k-CH2, k = 3 - 14, (CH3)2-CH-(CH2)4-CH2 or (CH3)2-CH-(CH2)5-CH2, CH3-(CH2)7-CH=CH-(CH2)6-CH2,CH3-(CH2)4-CH=CH-CH2-CH=CH-(CH2)6-CH2, and (CH3-(CH2)l-CH2)2-CH-O-C(O)-(CH2)3-CH2, l = 3 or 6; m’ is 0 or 1; and when p = 2, 3, 4, 5 or 6, then each one of the plurality of T tails is the same in each of said LT moieties, and each one of the plurality of m’ is the same in each of said LT moieties.

[0107] In some embodiments, tail T is selected from CH3-(CH2)k-CH2, k = 3 - 14, (CH3)2-CH-(CH2)4-CH2or (CH3)2-CH-(CH2)5-CH2, CH3-(CH2)7-CH=CH-(CH2)6-CH2, CH3-(CH2)4-CH=CH-CH2-CH=CH-(CH2)6-CH2, and (CH3-(CH2)l-CH2)2-CH-O-C(O)-(CH2)3-CH2, l = 3 or 6; and when p > 1, then each one of the plurality of T tails is the same as the remaining T tails in the same molecule.

[0108] In some embodiments, tail T is selected from CH3-(CH2)k-CH2, k = 3 - 14, (CH3)2-CH-(CH2)4-CH2 or (CH3)2-CH-(CH2)5-CH2, CH3-(CH2)7-CH=CH-(CH2)6-CH2, CH3-(CH2)4-CH=CH-CH2-CH=CH-(CH2)6-CH2, and (CH3-(CH2)l-CH2)2-CH-O-C(O)-(CH2)3-CH2, l = 3 or 6; and when p > 1, then each one of the plurality of T tails is different from the remaining T tails in the same molecule.

[0109] In some embodiments, m’ = 1, and tail T is selected from CH3-(CH2)k-CH2, k = 3 - 14, (CH3)2-CH-(CH2)4-CH2or (CH3)2-CH-(CH2)5-CH2, CH3-(CH2)7-CH=CH-(CH2)6-CH2, CH3-(CH2)4-CH=CH-CH2-CH=CH-(CH2)6-CH2, and (CH3-(CH2)l-CH2)2-CH-O-C(O)-(CH2)3-CH2, l = 3 or 6; and when p > 1, then each one of the plurality of T tails may be the same as or different from the remaining T tails in the same molecule.

[0110] In some embodiments, p = 1 and tail T is CH3-(CH2)k-CH2, k = 3 - 14.

[0111] In some embodiments, p = 1 and tail T is (CH3)2-CH-(CH2)4-CH2or (CH3)2-CH- (CH2)5-CH2.

[0112] In some embodiments, p = 1 and tail T is CH3-(CH2)7-CH=CH-(CH2)6-CH2.

[0113] In some embodiments, p = 1 and tail T is CH3-(CH2)4-CH=CH-CH2-CH=CH- (CH2)6-CH2, In some embodiments, p = 1 and tail T is (CH3-(CH2)l-CH2)2-CH- O-C(O)-(CH2)3-CH2, l = 3 or 6.

[0114] In some embodiments, p = 1 and A is *N((CH3)2N-(CH2)3)(X-(CH2)2-Y-OCO- (CH2)m- CH3), m = 6 - 8, X is C(O)-O, C(O)-CH2 or CH2-CH2, Y is S-S-(CH2)n, wherein n = 2, 3, or (CH2)q, wherein q = 3, 4, and OCO is O-C(O), or C(O)-O.

[0115] When p = 1 and the term -OCO- in A is -O-C(O)-, it entails a Y-O bond in reference to member Y in the assignment of A. When p = 1 and the term -OCO- in A and is -C(O)-O-, it entails a Y-C in reference to member Y in the assignment of A.

[0116] In some embodiments with p = 1, the moiety A-CH2-(CH2)p’-B-CH2(CH2)p” in (G1.1) is one of the following moieties in Table P1 (parts 1 and 2):Table P1 (part 1)Table P1 (part 2) wherein p’ = p” = 1, and B is C(O)O. The foregoing ten illustrative embodiments of moiety A- CH2-(CH2)p’-B-CH2(CH2)p”in (G1.1) when p = 1 (Table P1, parts 1 and 2) correspond, when in alkyne form, to the compounds Ai”L1, i” = 30—34 and 38-42 in Table 1. The N* member in each of such illustrative embodiments in the corresponding parent amine moiety A is the N member shown as a tertiary N that has the moiety CH2-CH2-C(O)O-CH2-CH2attached to it. For each of such illustrative embodiments, the parent amine A moiety would be each of the structures shown without the moiety CH2-CH2-C(O)O-CH2-CH2.

[0117] In light of the structural and IUPAC name complexities of compounds of formula (G1.1), specific compounds of formula (G1.1) are referred to below with the notation Ai”Lj”Tk”, where i”, j”, and k” are indices as defined below.

[0118] In some embodiments, p = 2 and A is *(*)N-(CH2)t-Z, t = 2 - 6, and Z is N-pyrrolidino, N-piperidino, OCH3, OH, N(CH2-CH3)2, or N(CH3)2.

[0119] In some embodiments with p = 2, A is one of the following in Table P2:

[0120] The foregoing illustrative amine moiety A embodiments for p = 2 in Table P2 correspond, when in amine forms, to the amines shown in Table 1 as A17-A29.

[0121] In some embodiments, p = 4 and A is *(*)N-(CH2)w1-E-(CH2)w2-N*(*), w1 = 2 - 6, w2 = 2 - 6, E is bond, substituted or unsubstituted amino, O-phenylene- O, O-(CH2)w3-(substituted or unsubstituted 1,4- piperazinediyl)-(CH2)w4-O, substituted or unsubstituted 1,4- piperazinediyl, S-S, XS-S-S-XS, XS-(substituted or unsubstituted 1,4-piperazinediyl)-XS, EE-(1,4- cyclohexanediyl)-EE, or EE-(1,3-cyclohexanediyl)-EE, wherein XS is C(O)-O-(CH2)2, and EE is O, C(O)-O or C(O)-NH, w3 = 0 - 4, and w4 = 0 - 4.

[0122] In some embodiments with p = 4, A is one of the following in Table P4:Table P4

[0123] The foregoing illustrative amine moiety A embodiments for p = 4 in Table P4 correspond, when in amine forms, to the amines shown in Table 1 as Ai”, with i” = 1-3, 5, 6, 8- 12, 14, 16, and 35-37.

[0124] In some embodiments, p = 5 and A is *(*)N-(CH2)p1-N*-(CH2)p2-N*(*), wherein p1 = 2 - 4, and p2 = 2 - 4.

[0125] In some embodiments with p = 5, A is given by the following Formula P5:Formula P5

[0126] The foregoing illustrative amine moiety A embodiment for p = 5, given by Formula P5, corresponds, when in amine form, to the amine shown in Table 1 as A4.

[0127] In some embodiments, p = 6 and A is *(*)N-(CH2)q1-N((CH2)q2-N*(*))-(CH2)3- N*(*), wherein q1 = 2 - 4 and q2 = 2 - 4.

[0128] In some embodiments with p = 6, A is given by the following Formula P6:Formula P6

[0129] The foregoing illustrative amine moiety A embodiment for p = 6 given by Formula P6 corresponds, when in amine form, to the amine shown in Table 1 as A7.

[0130] The term * refers to a N-binding site of an LT moiety, and *(*) refers to two separate binding sites at the same N-member of two LT moieties, as also indicated above.

[0131] In some embodiments, p = 4, E is bond, and w1 = w2 = 2.

[0132] In some embodiments, p = 4, E is unsubstituted O-phenylen-O, w1 = w2 = 3, and for each LT moiety each T is CH3-(CH2)k-CH2 with k = 4 and m’ = 1.

[0133] In some embodiments, p = 4, the substituted amino in E is , w1 = w2 = 3, and for each LT moiety each T is CH3-(CH2)k-CH2 with k = 5 and m’ = 1.

[0134] In some embodiments, p = 4, E is unsubstituted O-phenylen-O, w1 = w2 = 3, and for each LT moiety each T is CH3-(CH2)k-CH2with k = 9, and m’ = 1.

[0135] In some embodiments, p = 4, E is S-S, w1 = w2 = 2, and for each LT moiety each T is CH3-(CH2)k-CH2with k = 3, and m’ = 1.

[0136] In some embodiments, p = 5, p1 = 3, p2 = 4, and for each LT moiety each T is CH3-(CH2)k-CH2 with k = 6, and m’ = 1.

[0137] In some embodiments, p = 4, E is unsubstituted 1,4-piperazindiyl, w1 = w2 = 3, and for each LT moiety each T is CH3-(CH2)k-CH2 with k = 7, and m’ = 1.

[0138] In some embodiments, p = p’ = p” = 1, m’ = 1, T is CH3-(CH2)k-CH2 and k = 6.

[0139] In some embodiments, p = p’ = p” = 1, m’ = 1, T is CH3-(CH2)k-CH2and k = 6,

[0140] In some embodiments, p = 2, t = 3, Z is N-piperidino, p’ = 1, and for each LT moiety each T is CH3-(CH2)k-CH2 with k = 10, and m’ = 1.

[0141] In some embodiments, p = 4, E is substituted 1,4-piperazindiyl, w1 = w2 = 4, and for each LT moiety each T is CH3-(CH2)k-CH2with k = 4, and m’ = 1.

[0142] In some embodiments, p = 4, w1 = w2 = 3, E is unsubstituted C(O)-NH-(1,3- cyclohexanediyl)-NH-C(O), and for each LT moiety each T is CH3-(CH2)k-CH2 with k = 4, and m’ = 1.

[0143] In some embodiments, p = 4, E is O-(CH2)w3-(substituted or unsubstituted 1,4- piperazinediyl)-(CH2)w4-O, w1 = w2 = w3 = w4 = 2, and for each LT moiety each T is CH3- (CH2)k-CH2with k = 4, and m’ = 1.

[0144] In some embodiments, p = 2, t = 2, Z is N(CH2-CH3)2, and for each LT moiety each T is CH3-(CH2)7-CH=CH-(CH2)6-CH2, m’ = 1, and p’ = p” = 1.

[0145] In some embodiments, p = 2, t = 2, Z is N(CH2-CH3)2, and for each LT moiety m’ = 1, p’ = p” = 1, and each T is CH3-(CH2)k-CH2, with k = 11.

[0146] In some embodiments, p = 2, t = 2, Z is N-piperidino, and for each LT moiety m’ = 1, p’ = p” = 1, and each T is CH3-(CH2)k-CH2 , with k = 8.

[0147] In some embodiments, p = 2, t = 3, Z is N-pyrrolidino, and for each LT moiety m’ = 1, p’ = p” = 1, and each T is CH3-(CH2)k-CH2 , with k = 8.

[0148] In some embodiments, p = 1, m’ = 1, p’ = p” = 1, T is CH3-(CH2)4-CH=CH-CH2- CH=CH-(CH2)6-CH2, X is C(O)-O, Y is S-S-(CH2)nwith n = 2, OCO is O-C(O), and m = 7.

[0149] In some embodiments, p = 1, m’ = 1, p’ = p” = 1, T is (CH3-(CH2)l-CH2)2-CH-O- C(O)-(CH2)3-CH2, with l = 3, X is C(O)-CH2, Y is S-S-(CH2)n with n = 3, OCO is O-C(O), and m = 6.

[0150] In some embodiments, p = 1, m’ = 1, p’ = p” = 1, T is (CH3)2-CH-(CH2)4-CH2, X is CH2-CH2, Y is (CH2)qwith q = 4, OCO is O-C(O), and m = 7.

[0151] In some embodiments, p = 4, w1 = w2 = 4, E is XS-(substituted 1,4- piperazinediyl)-XS, XS is O-C(O)-(CH2)2, and for each LT moiety p’ = p” = 1, m’ = 1, T is CH3- (CH2)k-CH2with k = 4.

[0152] In some embodiments, p = 4, w1 = w2 = 2, E is S-S, and for each LT moiety p’ = p” = 1, m’ = 1, T is CH3-(CH2)k-CH2 with k = 3.

[0153] In some embodiments, p = 2, p’ = p” = 1, t = 2, Z is OH, and for each LT moiety m’ = 1, and T is CH3-(CH2)k-CH2with k = 5.

[0154] In some embodiments, p = 2, p’ = p” = 1, t = 4, Z is OH, and for each LT moiety m’ = 1, and T is CH3-(CH2)k-CH2with k = 6.

[0155] In some embodiments, p = 2, p’ = p” = 1, t = 6, Z is OH, and for each LT moiety m’ = 1, and T is CH3-(CH2)k-CH2 with k = 5.

[0156] In some embodiments, p = 2, p’ = p” = 1, t = 2, Z is N(CH3)2, and for each LT moiety m’ = 1, and T is CH3-(CH2)k-CH2with k = 9.

[0157] In some embodiments, p = 2, p’ = p” = 1, t = 4, Z is N(CH3)2, and for each LT moiety m’ = 1, and T is CH3-(CH2)k-CH2 with k = 6.

[0158] In some embodiments, p = 2, p’ = p” = 1, t = 5, Z is N(CH3)2, and for each LT moiety m’ = 1, and T is CH3-(CH2)k-CH2with k = 8.

[0159] In some embodiments, p = 4, w1 = w2 = 5, E is EE-(1,4-cyclohexanediyl)-EE, EE is C(O)-O, and for each LT moiety m’ = 1, p’ = p” = 1, T is CH3-(CH2)k-CH2 with k = 7.

[0160] In some embodiments, p = 4, w1 = w2 = 5, E is XS-S-S-XS, XS is C(O)-O-(CH2)2, and for each LT moiety m’ = 1, p’ = p” = 1, T is (CH3)2-CH-(CH2)5-CH2.

[0161] In some embodiments, p = 1, the amino moiety A is selected from the moieties given in Table P1, and the variables and group designators p’, p”, B, m’ and T are as set forth for general formula (G1.1).

[0162] In some embodiments, p = 1, the amino moiety A is selected from the moieties given in Table P1, and the variables and group designators p’, p”, B, m’ and T are as set forth for any one of the foregoing illustrative embodiments of compounds of formula (G1.1) for which such variables and group designators are specified.

[0163] In some embodiments, p = 1, moiety T is selected from the moieties given in Table T2, and the variables and group designators p’, p”, B, m’ and A are as set forth for general formula (G1.1).

[0164] In some embodiments, p = 1, moiety T is selected from the moieties given in Table T2, and the variables and group designators p’, p”, B, m’ and A are as set forth for any one of the foregoing illustrative embodiments of compounds of formula (G1.1) for which such variables and group designators are specified.

[0165] In some embodiments, p = 2, the amino moiety A is selected from the moieties given in Table P2, and the variables and group designators p’, p”, B, m’ and T are as set forth for general formula (G1.1).

[0166] In some embodiments, p = 2, the amino moiety A is selected from the moieties given in Table P2, and the variables and group designators p’, p”, B, m’ and T are as set forth for any one of the foregoing illustrative embodiments of compounds of formula (G1.1) for which such variables and group designators are specified.

[0167] In some embodiments, p = 2, moiety T is selected from the moieties given in Table T2, and the variables and group designators p’, p”, B, m’ and A are as set forth for general formula (G1.1).

[0168] In some embodiments, p = 2, moiety T is selected from the moieties given in Table T2, and the variables and group designators p’, p”, B, m’ and A are as set forth for any one of the foregoing illustrative embodiments of compounds of formula (G1.1) for which such variables and group designators are specified.

[0169] In some embodiments, p = 4, the amino moiety A is selected from the moieties given in Table P4, and the variables and group designators p’, p”, B, m’ and T are as set forth for general formula (G1.1).

[0170] In some embodiments, p = 4, the amino moiety A is selected from the moieties given in Table P4, and the variables and group designators p’, p”, B, m’ and T are as set forth for any one of the foregoing illustrative embodiments of compounds of formula (G1.1) for which such variables and group designators are specified.

[0171] In some embodiments, p = 4, moiety T is selected from the moieties given in Table T2, and the variables and group designators p’, p”, B, m’ and A are as set forth for general formula (G1.1).

[0172] In some embodiments, p = 4, moiety T is selected from the moieties given in Table T2, and the variables and group designators p’, p”, B, m’ and A are as set forth for any one of the foregoing illustrative embodiments of compounds of formula (G1.1) for which such variables and group designators are specified.

[0173] In some embodiments, p = 5, the amino moiety A is according to formula P5, and the variables and group designators p’, p”, B, m’ and T are as set forth for general formula (G1.1).

[0174] In some embodiments, p = 5, the amino moiety A is according to formula P5, and the variables and group designators p’, p”, B, m’ and T are as set forth for any one of the foregoing illustrative embodiments of compounds of formula (G1.1) for which such variables and group designators are specified.

[0175] In some embodiments, p = 5, moiety T is selected from the moieties given in Table T2, and the variables and group designators p’, p”, B, m’ and A are as set forth for general formula (G1.1).

[0176] In some embodiments, p = 5, moiety T is selected from the moieties given in Table T2, and the variables and group designators p’, p”, B, m’ and A are as set forth for any one of the foregoing illustrative embodiments of compounds of formula (G1.1) for which such variables and group designators are specified.

[0177] In some embodiments, p = 6, the amino moiety A is according to formula P6, and the variables and group designators p’, p”, B, m’ and T are as set forth for general formula (G1.1).

[0178] In some embodiments, p = 6, the amino moiety A is according to formula P6, and the variables and group designators p’, p”, B, m’ and T are as set forth for any one of the foregoing illustrative embodiments of compounds of formula (G1.1) for which such variables and group designators are specified.

[0179] In some embodiments, p = 6, moiety T is selected from the moieties given in Table T2, and the variables and group designators p’, p”, B, m’ and A are as set forth for general formula (G1.1).

[0180] In some embodiments, p = 6, moiety T is selected from the moieties given in Table T2, and the variables and group designators p’, p”, B, m’ and A are as set forth for any one of the foregoing illustrative embodiments of compounds of formula (G1.1) for which such variables and group designators are specified.

[0181] In another aspect, the present application relates to compounds represented generically by of formula (G1.2) and tautomers, stereoisomers, constitutional isomers, pharmaceutically acceptable salts and solvates thereof:

[0182] The amino moiety A in (G1.2) is selected when q ≥ 1 as having its N* or N(*)* binding sites linked to at least one ST that differs from LT as indicated in general formula (G1.2).

[0183] The illustrative embodiments of compounds of formula (G1.2) are such that, whether stated explicitly or not, p and q for the same satisfy the following characteristics (1) and (2): (1) p = 1-5 when q = 1-5, and p = 1-6 when q = 0-5, with (p + q) = 1-6 and p ≠ 0, and (2) q = 0 leads to the compounds of general formula (G1.1) with p = 1-6 as defined above.

[0184] R is OH, COOH, CHO, OR’, COOR’, C(O)NH2, or C(O)NHR’, with R’ being (CH2)q”CH3, with q’ = 1-4, q” = 1-4, q ≥ 1.

[0185] All the variables concerning the amino moiety A and the moiety(ies) LT not defined for (G1.2) are as defined for (G1.1), subject ot the p and q restrictions set forth above. For example, A in (G1.2) is an amino moiety, and said amino moiety A is selected depending on the (p+q)-value as follows, wherein the term * is used to refer to a N-binding site of an LTmoiety, and *(*) (or (*)* indistinguishably) is used to refer to two separate N-binding sites of two LT moieties: when p =1 and q = 0, then such compound would be a compound of formula (G1.1); when p = 1 and q = 1, then A is *(*)N-(CH2)t-Z, t = 2-6, Z is N-pyrrolidino, N-piperidino, OCH3, OH, N(CH2-CH3)2, or N(CH3)2, when p+q = 4, with p ≥ 1 and q ≥ 1, then A is *(*)N-(CH2)w1-E-(CH2)w2-N(*)*, w1 = 2-6, w2 = 2-6, E is bond, substituted or unsubstituted amino, O-phenylene- O, O-(CH2)w3-(substituted or unsubstituted 1,4- piperazinediyl)-(CH2)w4-O, substituted or unsubstituted 1,4- piperazinediyl, S-S, XS-S-S-XS, XS-(substituted or unsubstituted 1,4-piperazinediyl)-XS, EE-(1,4- cyclohexanediyl)-EE, or EE-(1,3-cyclohexanediyl)-EE, wherein w3 = 0-4, w4 = 0-4, XS is C(O)-O-(CH2)2, and EE is O, C(O)-O or C(O)-NH, when p+q = 5, with p ≥ 1 and q ≥ 1, then A is *(*)N-(CH2)p1-N*-(CH2)p2’-N(*)*, p1 = 2-5, p2 = 2-5, and when p+q = 6, with p ≥ 1 and q ≥ 1, then A is *(*)N-(CH2)q1-N((CH2)q2-N(*)* q1 = 2-4, q2 = 2-4, and q3 = 2-4

[0186] Illustrative embodiments of moiety T in formula (G1.2) are given in Table T2 (parts 1 and 2; herein referred to as “Table T2”) and the corresponding parent azido compounds are shown in Table 2.

[0187] To avoid repetitive recital, all the variables concerning the amino moiety A for p ≥ 2, the moiety(ies) LT, and illustrative embodiments of the same not defined explicitly for (G1.2) are as defined for (G1.1) subject to the p- and q-assignments for (G1.2) as set forth above.

[0188] When p > 1, then each one of the plurality of LT moieties may be the same or different from the remaining LT moieties in the same molecule, and when q > 1, then each one of the plurality of ST moieties may be the same or different from the remaining ST moieties in the same molecule.

[0189] In light of the structural and IUPAC name complexities of compounds of formula (G1.2), specific compounds of formula (G1.2) are referred to below with the notation Ai”(ST)q(LT)p, where i” being an index as defined below for compounds Ai”Lj”Tk” and p and q are as defined for p and q in reference to compounds of formula (G1.2)

[0190] Formula (G1.2) envisages embodiments with the N* and N(*)* binding sites in the amino moiety A being linked to ST and / or LT according to any of the following binding embodiments for binding site N*: N-ST (and q ≥ 1) and N-LT, and according to any of the following binding embodiments for binding site N(*)*: N(LT)(LT) wherein the LT moieties are identical or different form each other, N(ST)(LT) and N(ST)(ST) wherein the ST moieties are identical or different form each other.

[0191] Each variable in (G1.1) and (G1.2) indicating the choice of a number of groups of substituents, or a choice of substituents, is elected independently from the choice of any other such variable, whether such variables have the same name (while referring to different groups) or not, unless explicitly indicated otherwise.

[0192] As to illustrative embodiments of compounds of formula (G1.2), all the variable and group or moiety choices recited above for illustrative embodiments of (G1.1) are incorporated herein in reference to illustrative embodiments of (G1.2), subject to the p- and q-assignments for (G1.2) as set forth above. In addition, the following are further illustrative embodiments concerning (G1.2): In some embodiments R is OH, with q’ = 1-4. In other embodiments, R is OH, with q’ = 2. In some embodiments, p = 2 and q = 3. In other embodiments, p = 3, and q = 2. In some embodiments, p + q = 5, and A is *(*)N-(CH2)p1-N*-(CH2)p2’-N(*)*, p1 = 2-5, p2 = 2-5. In some embodiments with , p + q = 5, A is *(*)N-(CH2)4-N*-(CH2)3-N(*)*.In some embodiments, p + q = 5, p =3 and q = 2. In other embodiments, p + q = 5, p =2 and q = 3. In some embodiments with q ≥ 2, all the ST moieties are the same. In some embodiments with p ≥ 2, all the LT moieties are the same. In some embodiments with p ≥ 2 and q ≥ 2, all the ST moieties are the same and all the LT moieties are the same.

[0193] In some embodiments of compounds of formula (G1.2) with p + q = 2, p = 1 and q = 1, such compound embodiments have formulae Ai”(ST)1(LT)1, (or simply Ai”(ST)(LT)), i” = 17-29, wherein amine moiety A is one of amine moieties shown in Table P2, as described in illustrations for compounds of formula (G1.1) with p = 2. Embodiments of moiety T are given in Table T2. ST and LT moieties are illustratively embodied by any of the foregoing definitions given for the same.

[0194] In some embodiments of compounds of formula (G1.2) with p + q = 4, such compound embodiments have formulae Ai”(ST)1(LT)3, Ai”(ST)2(LT)2, or Ai”(ST)3(LT)1, i” = 1-3, 5, 6, 8-12, 14, 16, and 35-37, wherein amine moiety A is one of amine moieties shown in Table P4, as described in illustrations for compounds of formula (G1.1) with p = 4. ST and LT moieties are illustratively embodied by any of the foregoing definitions given for the same. Embodiments of moiety T are given in Table T2. When there is more than one ST moiety, all are identical in some embodiments, whereas there is at least one different in other embodiments. When there is more than one LT moiety, all are identical in some embodiments, whereas there is at least one different in other embodiments.

[0195] In some embodiments of compounds of formula (G1.2) with p + q = 5, such compound embodiments have formulae Ai”(ST)1(LT)4, Ai”(ST)2(LT)3, Ai”(ST)3(LT)2, or Ai”(ST)4(LT)1, i” = 4, wherein amine moiety A is the amine moiety shown in Formula P5, as described in illustrations for compounds of formula (G1.1) with p = 5. ST and LT moieties are illustratively embodied by any of the foregoing definitions given for the same. Embodiments of moiety T are given in Table T2. When there is more than one ST moiety, all are identical in some embodiments, whereas there is at least one different in other embodiments. When there is more than one LT moiety, all are identical in some embodiments, whereas there is at least one different in other embodiments.

[0196] In some embodiments of compounds of formula (G1.2) with p + q = 5, B is C(O)O. In some of such embodiments, all the LT moieties are the same, all the ST moieties are the same.

[0197] In some embodiments of compounds of formula (G1.2) with p + q = 5, with B being C(O)O, all the LT moieties being the same, and all the ST moieties are the same, each ST is

[0198] In some embodiments of compounds of formula (G1.2) with p + q = 6, such compound embodiments have formulae Ai”(ST)1(LT)5, Ai”(ST)2(LT)4, Ai”(ST)3(LT)3, Ai”(ST)4(LT)2, or Ai”(ST)5(LT)1, i” = 7, wherein amine moiety A is amine moiety shown as Formula P6, as described in illustrations for compounds of formula (G1.1) with p = 6. ST and LT moieties are illustratively embodied by any of the foregoing definitions given for the same. Embodiments of moiety T are given in Table T2. When there is more than one ST moiety, all are identical in some embodiments, whereas there is at least one different in other embodiments. When there is more than one LT moiety, all are identical in some embodiments, whereas there is at least one different in other embodiments.

[0199] Further illustrative embodiments of compounds of formula (G1.2) include, but are not limited to, the following compounds:

[0200] Compounds of formula Ai”(ST)1(LT)1, (or simply Ai”(ST)(LT)), i” = 17-29, wherein amine moiety A is one of amine moieties shown in Table P2, as described in illustrations for compounds of formula (G1.1) with p = 2. ST is (CH2)q’-R, with R selected from OH, COOH, CHO, OR’, COOR’, C(O)NH2, or C(O)NHR’, with R’ being (CH2)q”CH3, with q’ = 1-4, q” = 1- 4; and LT is one of Lj”Tk”, j” = 1-3, k” = 1-23. In some of such embodiments of compounds of formula Ai”(ST)1(LT)1, ST is CH2CH2CH2OH; compounds of formulae Ai”(ST)1(LT)3, Ai”(ST)2(LT)2, or Ai”(ST)3(LT)1, i” = 1-3, 5, 6, 8- 12, 14, 16, and 35-37, wherein amine moiety A is one of amine moieties shown in Table P4, as described in illustrations for compounds of formula (G1.1) with p = 4. ST is at least one of (CH2)q’-R, with R selected from OH, COOH, CHO, OR’, COOR’, C(O)NH2, or C(O)NHR’, with R’ being (CH2)q”CH3, with q’ = 1-4, q” = 1-4; and LT is at least one of Lj”Tk”, j” = 1-3, k” = 1-23. When there is more than one ST moiety, all are identical in some embodiments, whereas there is at least one different in other embodiments. When there is more than one LT moiety, all are identical in some embodiments, whereas there is at least one different in other embodiments. In some of such embodiments of compounds of formulae Ai”(ST)1(LT)3, Ai”(ST)2(LT)2, or Ai”(ST)3(LT)1, ST is CH2CH2CH2OH; compounds of formulae Ai”(ST)1(LT)4, Ai”(ST)2(LT)3, Ai”(ST)3(LT)2, or Ai”(ST)4(LT)1, i” = 4, wherein amine moiety A is the amine moiety shown in Formula P5, as described in illustrations for compounds of formula (G1.1) with p = 5. ST is at least one of (CH2)q’-R, with R selected from OH, COOH, CHO, OR’, COOR’, C(O)NH2, or C(O)NHR’, with R’ being (CH2)q”CH3, with q’ = 1-4, q” = 1-4; and LT is at least one of Lj”Tk”, j” = 1-3, k” = 1-23. When there is more than one ST moiety, all are identical in some embodiments, whereas there is at least one different in other embodiments. When there is more than one LT moiety, all are identical in some embodiments, whereas there is at least one different in other embodiments. In some of such embodiments of compounds of formulae Ai”(ST)1(LT)4, Ai”(ST)2(LT)3, Ai”(ST)3(LT)2, or Ai”(ST)4(LT)1, ST is CH2CH2CH2OH; compounds of formulae Ai”(ST)1(LT)5, Ai”(ST)2(LT)4, Ai”(ST)3(LT)3, Ai”(ST)4(LT)2, or Ai”(ST)5(LT)1, i” = 7, wherein amine moiety A is amine moiety shown as Formula P6, as described in illustrations for compounds of formula (G1.1) with p = 6. ST is at least one of (CH2)q’-R, with R selected from OH, COOH, CHO, OR’, COOR’, C(O)NH2, or C(O)NHR’, with R’ being (CH2)q”CH3, with q’ = 1-4, q” = 1-4; and LT is at least one of Lj”Tk”, j” = 1-3, k” = 1- 23. When there is more than one ST moiety, all are identical in some embodiments, whereas there is at least one different in other embodiments. When there is more than one LT moiety, all are identical in some embodiments, whereas there is at least one different in other embodiments. In some of such embodiments of compounds of formulae Ai”(ST)1(LT)5, Ai”(ST)2(LT)4, Ai”(ST)3(LT)3, Ai”(ST)4(LT)2, or Ai”(ST)5(LT)1, ST is CH2CH2CH2OH.

[0201] The foregoing illustratively formulae of type Ai”(ST)st(LT)lt, with indices i”, st and lt as defined above do not indicate the specific binding site of each of such ST and LT moieties to N* and N(*)* sites, so they are meant to represent embodiments in which each of the ST and each of the LT moieties may be bound to any N* or N(*)* binding site in amine moiety A. Notation to specify such binding sites for specific ST and LT moieties is set forth below.

[0202] In some embodiments, p+q = 2, the amino moiety A is selected from the moieties given in Table P2, and the variables and group designators R, q, q’, p’, p”, B, m’ and T are as set forth for general formula (G1.2).

[0203] In some embodiments, p+q = 2, the amino moiety A is selected from the moieties given in Table P2, and the variables and group designators R, q, q’, p’, p”, B, m’ and T are as set forth for any one of the foregoing illustrative embodiments of compounds of formula (G1.2) for which such variables and group designators are specified.

[0204] In some embodiments, p+q = 2, moiety T is selected from the moieties given in Table T2, and the variables and group designators R, q, q’, p’, p”, B, m’ and A are as set forth for general formula (G1.2).

[0205] In some embodiments, p+q = 2, moiety T is selected from the moieties given in Table T2, and the variables and group designators R, q, q’, p’, p”, B, m’ and A are as set forth for any one of the foregoing illustrative embodiments of compounds of formula (G1.2) for which such variables and group designators are specified.

[0206] In some embodiments, p+q = 4, the amino moiety A is selected from the moieties given in Table P4, and the variables and group designators R, q, q’, p’, p”, B, m’ and T are as set forth for general formula (G1.2).

[0207] In some embodiments, p+q = 4, the amino moiety A is selected from the moieties given in Table P4, and the variables and group designators R, q, q’, p’, p”, B, m’ and T are as set forth for any one of the foregoing illustrative embodiments of compounds of formula (G1.2) for which such variables and group designators are specified.

[0208] In some embodiments, p+q = 4, moiety T is selected from the moieties given in Table T2, and the variables and group designators R, q, q’, p’, p”, B, m’ and A are as set forth for general formula (G1.2).

[0209] In some embodiments, p+q = 4, moiety T is selected from the moieties given in Table T2, and the variables and group designators R, q, q’, p’, p”, B, m’ and A are as set forth for any one of the foregoing illustrative embodiments of compounds of formula (G1.2) for which such variables and group designators are specified.

[0210] In some embodiments, p+q = 5, the amino moiety A is according to formula P5, and the variables and group designators R, q, q’, p’, p”, B, m’ and T are as set forth for general formula (G1.2).

[0211] In some embodiments, p+q = 5, the amino moiety A is according to formula P5, and the variables and group designators R, q, q’, p’, p”, B, m’ and T are as set forth for any one of the foregoing illustrative embodiments of compounds of formula (G1.2) for which such variables and group designators are specified.

[0212] In some embodiments, p+q = 5, moiety T is selected from the moieties given in Table T2, and the variables and group designators R, q, q’, p’, p”, B, m’ and A are as set forth for general formula (G1.2).

[0213] In some embodiments, p+q = 5, moiety T is selected from the moieties given in Table T2, and the variables and group designators R, q, q’, p’, p”, B, m’ and A are as set forth for any one of the foregoing illustrative embodiments of compounds of formula (G1.2) for which such variables and group designators are specified.

[0214] In some embodiments, p+q = 6, the amino moiety A is according to formula P6, and the variables and group designators R, q, q’, p’, p”, B, m’ and T are as set forth for general formula (G1.2).

[0215] In some embodiments, p+q = 6, the amino moiety A is according to formula P6, and the variables and group designators R, q, q’, p’, p”, B, m’ and T are as set forth for any one of the foregoing illustrative embodiments of compounds of formula (G1.2) for which such variables and group designators are specified.

[0216] In some embodiments, p+q = 6, moiety T is selected from the moieties given in Table T2, and the variables and group designators R, q, q’, p’, p”, B, m’ and A are as set forth for general formula (G1.2).

[0217] In some embodiments, p+q = 6, moiety T is selected from the moieties given in Table T2, and the variables and group designators R, q, q’, p’, p”, B, m’ and A are as set forth for any one of the foregoing illustrative embodiments of compounds of formula (G1.2) for which such variables and group designators are specified.

[0218] In some of the foregoing illustrative embodiments of compounds of formula (G1.2), ST is selected from the moieties given in Table 2.1. In other of the foregoing embodiments of compounds of formula (G1.2), St is ST1, which is is -CH2CH2CH2OH.

[0219] Further illustrative embodiments of compounds of formula (G1.1), wherein p = 1, include, but are not limited to, the following compounds, and any tautomer, stereoisomer, constitutional isomer, pharmaceutically acceptable salt or solvate thereof:A30L1T1, A30L1T2, A30L1T3, A30L1T4, A30L1T5, A30L1T6, A30L1T7, A30L1T8, A30L1T9, A30L1T10, A30L1T11, A30L1T12, A30L1T13, A30L1T14, A30L1T15, A31L1T1, A31L1T2, A31L1T3, A31L1T4, A31L1T5, A31L1T6, A31L1T7, A31L1T8, A31L1T9, A31L1T10, A31L1T11, A31L1T12, A31L1T13, A31L1T14, A31L1T15, A32L1T1, A32L1T2, A32L1T3, A32L1T4, A32L1T5, A32L1T6, A32L1T7, A32L1T8, A32L1T9, A32L1T10, A32L1T11, A32L1T12, A32L1T13, A32L1T14, A32L1T15, A33L1T1, A33L1T2, A33L1T3, A33L1T4, A33L1T5, A33L1T6, A33L1T7, A33L1T8, A33L1T9, A33L1T10, A33L1T11, A33L1T12, A33L1T13, A33L1T14, A33L1T15, A34L1T1, A34L1T2, A34L1T3, A34L1T4, A34L1T5, A34L1T6, A34L1T7, A34L1T8, A34L1T9, A34L1T10, A34L1T11, A34L1T12, A34L1T13, A34L1T14, A34L1T15, A40L1T15, A41L1T15, A38L1T15, A39L1T15, and A42L1T20.

[0220] Further illustrative embodiments of compounds of formula (G1.1), wherein p = 2, include, but are not limited to, the following compounds, and any tautomer, stereoisomer, constitutional isomer, pharmaceutically acceptable salt or solvate thereof: A17L1T1, A17L1T2, A17L1T3, A17L1T4, A17L1T5, A17L1T6, A17L1T7, A17L1T8, A17L1T9, A17L1T10, A17L1T11, A17L1T12, A17L1T13, A17L1T14, A17L1T15, A18L1T1, A18L1T2, A18L1T3, A18L1T4, A18L1T5, A18L1T6, A18L1T7, A18L1T8, A18L1T9, A18L1T10, A18L1T11, A18L1T12, A18L1T13, A18L1T14, A18L1T15, A19L1, A19L1T1, A19L1T2, A19L1T3, A19L1T4, A19L1T5, A19L1T6, A19L1T7, A19L1T8, A19L1T9, A19L1T10, A19L1T11, A19L1T12, A19L1T13, A19L1T14, A19L1T15, A20L1T1, A20L1T2, A20L1T3, A20L1T4, A20L1T5, A20L1T6, A20L1T7, A20L1T8, A20L1T9, A20L1T10, A20L1T11, A20L1T12, A20L1T13, A20L1T14, A20L1T15, A21L1T1, A21L1T2, A21L1T3, A21L1T4, A21L1T5, A21L1T6, A21L1T7, A21L1T8, A21L1T9, A21L1T10, A21L1T11, A21L1T12, A21L1T13, A21L1T14, A21L1T15, A22L1T1, A22L1T2, A22L1T3, A22L1T4, A22L1T5, A22L1T6, A22L1T7, A22L1T8, A22L1T9, A22L1T10, A22L1T11, A22L1T12, A22L1T13, A22L1T14, A22L1T15, A23L1T1, A23L1T2, A23L1T3, A23L1T4, A23L1T5, A23L1T6, A23L1T7, A23L1T8, A23L1T9, A23L1T10, A23L1T11, A23L1T12, A23L1T13, A23L1T14, A23L1T15, A24L1T1, A24L1T2, A24L1T3, A24L1T4, A24L1T5, A24L1T6, A24L1T7, A24L1T8, A24L1T9, A24L1T10, A24L1T11, A24L1T12, A24L1T13, A24L1T14, A24L1T15,A25L1T1, A25L1T2, A25L1T3, A25L1T4, A25L1T5, A25L1T6, A25L1T7, A25L1T8, A25L1T9, A25L1T10, A25L1T11, A25L1T12, A25L1T13, A25L1T14, A25L1T15, A26L1T1, A26L1T2, A26L1T3, A26L1T4, A26L1T5, A26L1T6, A26L1T7, A26L1T8, A26L1T9, A26L1T10, A26L1T11, A26L1T12, A26L1T13, A26L1T14, A26L1T15, A27L1T1, A27L1T2, A27L1T3, A27L1T4, A27L1T5, A27L1T6, A27L1T7, A27L1T8, A27L1T9, A27L1T10, A27L1T11, A27L1T12, A27L1T13, A27L1T14, A27L1T15, A28L1T1, A28L1T2, A28L1T3, A28L1T4, A28L1T5, A28L1T6, A28L1T7, A28L1T8, A28L1T9, A28L1T10, A28L1T11, A28L1T12, A28L1T13, A28L1T14, A28L1T15, A29L1T1, A29L1T2, A29L1T3, A29L1T4, A29L1T5, A29L1T6, A29L1T7, A29L1T8, A29L1T9, A29L1T10, A29L1T11, A29L1T12, A29L1T13, A29L1T14, and A29L1T15.

[0221] Further illustrative embodiments of compounds of formula (G1.1), wherein p = 4, include, but are not limited to, the following compounds, and any tautomer, stereoisomer, constitutional isomer, pharmaceutically acceptable salt or solvate thereof: A1L1T1, A1L1T2, A1L1T3, A1L1T4, A1L1T5, A1L1T6, A1L1T7, A1L1T8, A1L1T9, A1L1T10, A1L1T11, A1L1T12, A1L1T13, A1L1T14, A1L1T15, A2L1T1, A2L1T2, A2L1T3, A2L1T4, A2L1T5, A2L1T6, A2L1T7, A2L1T8, A2L1T9, A2L1T10, A2L1T11, A2L1T12, A2L1T13, A2L1T14, A2L1T15, A3L1T1, A3L1T2, A3L1T3, A3L1T4, A3L1T5, A3L1T6, A3L1T7, A3L1T8, A3L1T9, A3L1T10, A3L1T11, A3L1T12, A3L1T13, A3L1T14, A3L1T15, A5L1T1, A5L1T2, A5L1T3, A5L1T4, A5L1T5, A5L1T6, A5L1T7, A5L1T8, A5L1T9, A5L1T10, A5L1T11, A5L1T12, A5L1T13, A5L1T14, A5L1T15, A6L1T1, A6L1T2, A6L1T3, A6L1T4, A6L1T5, A6L1T6, A6L1T7, A6L1T8, A6L1T9, A6L1T10, A6L1T11, A6L1T12, A6L1T13, A6L1T14, A6L1T15, A8L1T1, A8L1T2, A8L1T3, A8L1T4, A8L1T5, A8L1T6, A8L1T7, A8L1T8, A8L1T9, A8L1T10, A8L1T11, A8L1T12, A8L1T13, A8L1T14, A8L1T15, A9L1T1, A9L1T2, A9L1T3, A9L1T4, A9L1T5, A9L1T6, A9L1T7, A9L1T8, A9L1T9, A9L1T10, A9L1T11, A9L1T12, A9L1T13, A9L1T14, A9L1T15, A11L1T1, A11L1T2, A11L1T3, A11L1T4, A11L1T5, A11L1T6, A11L1T7, A11L1T8, A11L1T9, A11L1T10, A11L1T11, A11L1T12, A11L1T13, A11L1T14, A11L1T15, A12L1T1, A12L1T2, A12L1T3, A12L1T4, A12L1T5, A12L1T6, A12L1T7, A12L1T8, A12L1T9, A12L1T10, A12L1T11, A12L1T12, A12L1T13, A12L1T14, A12L1T15,A14L1T1, A14L1T2, A14L1T3, A14L1T4, A14L1T5, A14L1T6, A14L1T7, A14L1T8, A14L1T9, A14L1T10, A14L1T11, A14L1T12, A14L1T13, A14L1T14, A14L1T15, A16L1T1, A16L1T2, A16L1T3, A16L1T4, A16L1T5, A16L1T6, A16L1T7, A16L1T8, A16L1T9, A16L1T10, A16L1T11, A16L1T12, A16L1T13, A16L1T14, A16L1T15, A35L1T1, A35L1T2, A35L1T3, A35L1T4, A35L1T5, A35L1T6, A35L1T7, A35L1T8, A35L1T9, A35L1T10, A35L1T11, A35L1T12, A35L1T13, A35L1T14, A35L1T15, A36L1T1, A36L1T2, A36L1T3, A36L1T4, A36L1T5, A36L1T6, A36L1T7, A36L1T8, A36L1T9, A36L1T10, A36L1T11, A36L1T12, A36L1T13, A36L1T14, A36L1T15, A37L1T1, A37L1T2, A37L1T3, A37L1T4, A37L1T5, A37L1T6, A37L1T7, A37L1T8, A37L1T9, A37L1T10, A37L1T11, A37L1T12, A37L1T13, A37L1T14, A37L1T15, A5L2T21, A5L3T22, A6L2T18, A6L3T19, and A10L1T19.

[0222] Further illustrative embodiments of compounds of formula (G1.1), wherein p = 5, include, but are not limited to, the following compounds, and any tautomer, stereoisomer, constitutional isomer, pharmaceutically acceptable salt or solvate thereof: A4L1T1, A4L1T2, A4L1T3, A4L1T4, A4L1T5, A4L1T6, A4L1T7, A4L1T8, A4L1T9, A4L1T10, A4L1T11, A4L1T12, A4L1T13, A4L1T14, A4L1T15, A4L1T16, A4L1T17, A4L1T19, A4L2T18, A4L2T14, A4L3T19, and A4L3T14.

[0223] Further illustrative embodiments of compounds of formula (G1.1), wherein p = 6, include, but are not limited to, the following compounds, and any tautomer, stereoisomer, constitutional isomer, pharmaceutically acceptable salt or solvate thereof: A7L1T1, A7L1T2, A7L1T3, A7L1T4, A7L1T5, A7L1T6, A7L1T7, A7L1T8, A7L1T9, A7L1T10, A7L1T11, A7L1T12, A7L1T13, A7L1T14, and A7L1T15.

[0224] Illustrative embodiments of compounds of formula (G1.1) include, but are not limited to, the following compounds, and any tautomer, stereoisomer, constitutional isomer, pharmaceutically acceptable salt or solvate thereof: A1L1T1, A1L1T2, A1L1T3, A1L1T4, A1L1T5, A1L1T6, A1L1T7, A1L1T8, A1L1T9, A1L1T10, A1L1T11, A1L1T12, A1L1T13, A1L1T14, A1L1T15, A2L1T1, A2L1T2, A2L1T3, A2L1T4, A2L1T5, A2L1T6, A2L1T7, A2L1T8, A2L1T9, A2L1T10, A2L1T11, A2L1T12, A2L1T13, A2L1T14, A2L1T15, A3L1T1, A3L1T2, A3L1T3, A3L1T4, A3L1T5, A3L1T6, A3L1T7, A3L1T8, A3L1T9, A3L1T10, A3L1T11, A3L1T12, A3L1T13, A3L1T14, A3L1T15,A4L1T1, A4L1T2, A4L1T3, A4L1T4, A4L1T5, A4L1T6, A4L1T7, A4L1T8, A4L1T9, A4L1T10, A4L1T11, A4L1T12, A4L1T13, A4L1T14, A4L1T15, A4L1T16, A4L1T17 A4L1T19, A4L2T18, A4L2T14, A4L3T19, A4L3T14, A5L1T1, A5L1T2, A5L1T3, A5L1T4, A5L1T5, A5L1T6, A5L1T7, A5L1T8, A5L1T9, A5L1T10, A5L1T11, A5L1T12, A5L1T13, A5L1T14, A5L1T15, A5L2T21, A5L3T22, A6L1T1, A6L1T2, A6L1T3, A6L1T4, A6L1T5, A6L1T6, A6L1T7, A6L1T8, A6L1T9, A6L1T10, A6L1T11, A6L1T12, A6L1T13, A6L1T14, A6L1T15, A6L2T18, A6L3T19, A7L1T1, A7L1T2, A7L1T3, A7L1T4, A7L1T5, A7L1T6, A7L1T7, A7L1T8, A7L1T9, A7L1T10, A7L1T11, A7L1T12, A7L1T13, A7L1T14, A7L1T15, A8L1T1, A8L1T2, A8L1T3, A8L1T4, A8L1T5, A8L1T6, A8L1T7, A8L1T8, A8L1T9, A8L1T10, A8L1T11, A8L1T12, A8L1T13, A8L1T14, A8L1T15, A9L1T1, A9L1T2, A9L1T3, A9L1T4, A9L1T5, A9L1T6, A9L1T7, A9L1T8, A9L1T9, A9L1T10, A9L1T11, A9L1T12, A9L1T13, A9L1T14, A9L1T15, A10L1T19, A11L1T1, A11L1T2, A11L1T3, A11L1T4, A11L1T5, A11L1T6, A11L1T7, A11L1T8, A11L1T9, A11L1T10, A11L1T11, A11L1T12, A11L1T13, A11L1T14, A11L1T15, A12L1T1, A12L1T2, A12L1T3, A12L1T4, A12L1T5, A12L1T6, A12L1T7, A12L1T8, A12L1T9, A12L1T10, A12L1T11, A12L1T12, A12L1T13, A12L1T14, A12L1T15, A14L1T1, A14L1T2, A14L1T3, A14L1T4, A14L1T5, A14L1T6, A14L1T7, A14L1T8, A14L1T9, A14L1T10, A14L1T11, A14L1T12, A14L1T13, A14L1T14, A14L1T15, A16L1T1, A16L1T2, A16L1T3, A16L1T4, A16L1T5, A16L1T6, A16L1T7, A16L1T8, A16L1T9, A16L1T10, A16L1T11, A16L1T12, A16L1T13, A16L1T14, A16L1T15, A17L1T1, A17L1T2, A17L1T3, A17L1T4, A17L1T5, A17L1T6, A17L1T7, A17L1T8, A17L1T9, A17L1T10, A17L1T11, A17L1T12, A17L1T13, A17L1T14, A17L1T15, A18L1T1, A18L1T2, A18L1T3, A18L1T4, A18L1T5, A18L1T6, A18L1T7, A18L1T8, A18L1T9, A18L1T10, A18L1T11, A18L1T12, A18L1T13, A18L1T14, A18L1T15, A19L1, A19L1T1, A19L1T2, A19L1T3, A19L1T4, A19L1T5, A19L1T6, A19L1T7, A19L1T8, A19L1T9, A19L1T10, A19L1T11, A19L1T12, A19L1T13, A19L1T14, A19L1T15, A20L1T1, A20L1T2, A20L1T3, A20L1T4, A20L1T5, A20L1T6, A20L1T7, A20L1T8, A20L1T9, A20L1T10, A20L1T11, A20L1T12, A20L1T13, A20L1T14, A20L1T15,A21L1T1, A21L1T2, A21L1T3, A21L1T4, A21L1T5, A21L1T6, A21L1T7, A21L1T8, A21L1T9, A21L1T10, A21L1T11, A21L1T12, A21L1T13, A21L1T14, A21L1T15, A22L1T1, A22L1T2, A22L1T3, A22L1T4, A22L1T5, A22L1T6, A22L1T7, A22L1T8, A22L1T9, A22L1T10, A22L1T11, A22L1T12, A22L1T13, A22L1T14, A22L1T15, A23L1T1, A23L1T2, A23L1T3, A23L1T4, A23L1T5, A23L1T6, A23L1T7, A23L1T8, A23L1T9, A23L1T10, A23L1T11, A23L1T12, A23L1T13, A23L1T14, A23L1T15, A24L1T1, A24L1T2, A24L1T3, A24L1T4, A24L1T5, A24L1T6, A24L1T7, A24L1T8, A24L1T9, A24L1T10, A24L1T11, A24L1T12, A24L1T13, A24L1T14, A24L1T15, A25L1T1, A25L1T2, A25L1T3, A25L1T4, A25L1T5, A25L1T6, A25L1T7, A25L1T8, A25L1T9, A25L1T10, A25L1T11, A25L1T12, A25L1T13, A25L1T14, A25L1T15, A26L1T1, A26L1T2, A26L1T3, A26L1T4, A26L1T5, A26L1T6, A26L1T7, A26L1T8, A26L1T9, A26L1T10, A26L1T11, A26L1T12, A26L1T13, A26L1T14, A26L1T15, A27L1T1, A27L1T2, A27L1T3, A27L1T4, A27L1T5, A27L1T6, A27L1T7, A27L1T8, A27L1T9, A27L1T10, A27L1T11, A27L1T12, A27L1T13, A27L1T14, A27L1T15, A28L1T1, A28L1T2, A28L1T3, A28L1T4, A28L1T5, A28L1T6, A28L1T7, A28L1T8, A28L1T9, A28L1T10, A28L1T11, A28L1T12, A28L1T13, A28L1T14, A28L1T15, A29L1T1, A29L1T2, A29L1T3, A29L1T4, A29L1T5, A29L1T6, A29L1T7, A29L1T8, A29L1T9, A29L1T10, A29L1T11, A29L1T12, A29L1T13, A29L1T14, A29L1T15, A30L1T1, A30L1T2, A30L1T3, A30L1T4, A30L1T5, A30L1T6, A30L1T7, A30L1T8, A30L1T9, A30L1T10, A30L1T11, A30L1T12, A30L1T13, A30L1T14, A30L1T15, A31L1T1, A31L1T2, A31L1T3, A31L1T4, A31L1T5, A31L1T6, A31L1T7, A31L1T8, A31L1T9, A31L1T10, A31L1T11, A31L1T12, A31L1T13, A31L1T14, A31L1T15, A32L1T1, A32L1T2, A32L1T3, A32L1T4, A32L1T5, A32L1T6, A32L1T7, A32L1T8, A32L1T9, A32L1T10, A32L1T11, A32L1T12, A32L1T13, A32L1T14, A32L1T15, A33L1T1, A33L1T2, A33L1T3, A33L1T4, A33L1T5, A33L1T6, A33L1T7, A33L1T8, A33L1T9, A33L1T10, A33L1T11, A33L1T12, A33L1T13, A33L1T14, A33L1T15, A34L1T1, A34L1T2, A34L1T3, A34L1T4, A34L1T5, A34L1T6, A34L1T7, A34L1T8, A34L1T9, A34L1T10, A34L1T11, A34L1T12, A34L1T13, A34L1T14, A34L1T15, A35L1T1, A35L1T2, A35L1T3, A35L1T4, A35L1T5, A35L1T6, A35L1T7, A35L1T8, A35L1T9, A35L1T10, A35L1T11, A35L1T12, A35L1T13, A35L1T14, A35L1T15,A36L1T1, A36L1T2, A36L1T3, A36L1T4, A36L1T5, A36L1T6, A36L1T7, A36L1T8, A36L1T9, A36L1T10, A36L1T11, A36L1T12, A36L1T13, A36L1T14, A36L1T15, A37L1T1, A37L1T2, A37L1T3, A37L1T4, A37L1T5, A37L1T6, A37L1T7, A37L1T8, A37L1T9, A37L1T10, A37L1T11, A37L1T12, A37L1T13, A37L1T14, A37L1T15, A38L1T15, A39L1T15, A40L1T15, A41L1T15, and A42L1T20.

[0225] See also Table C1 (parts 1 and 2) regarding some of the compounds listed above.

[0226] Illustrative compounds of formula (G1.1) include, but are not limited to, the following compounds, and any tautomer, stereoisomer, constitutional isomer, pharmaceutically acceptable salt or solvate thereof: A2L1T2, A3L1T3, A8L1T8, A1L1T1, A4L1T4, A5L1T5, A5L1T15, A34L1T4, A11L1T11, A26L1T9, A6L1T2, A12L1T2, A14L1T2, A21L1T13, A24L1T12, A25L1T10, A22L1T7, A27L1T7, A30L1T13, A30L1T15, A31L1T14, A33L1T6, A37L1T2, A4L1T4, A18L1T3, A19L1T4, A20L1T3, A23L1T8, A28L1T4, A29L1T7, A35L1T5, A36L1T6, A4L1T16, A4L1T17, A4L1T19, A4L2T18, A4L2T14, A4L3T19, A4L3T14, A40L1T15, A41L1T15, A5L2T21, A5L3T22, A6L2T18, A6L3T19, A10L1T19, A38L1T15, A39L1T15, and A42L1T20.

[0227] Variables that are not specified for the foregoing illustrative embodiments are defined as the same variables are defined in formula (G1.1).

[0228] The foregoing illustrative lists of Ai”Lj”Tk” lipids, with j” = 1-3, k” = 1-23, and i” as given therein for each formula designation, are not limiting as to restricting their interpretation only to the collections of compounds whose formulae designations are expressly recited in such lists. Any subgroup of lipids recited in any of such lists, reciting any number of such lipids, represents a set of illustrative compounds of formula (G1.1) that include, but are not limited to, any such listed compound(s), and any tautomer, stereoisomer, constitutional isomer, pharmaceutically acceptable salt or solvate thereof.

[0229] Illustrative compounds of compounds of formula (G1.2) include, but are not limited to, the following compounds, and any tautomer, stereoisomer, constitutional isomer, pharmaceutically acceptable salt or solvate thereof: A4(L1T14)3(ST1)2, and A4(L1T14)2(ST1)3; A4(L1T14)1-1(L1T14)2-4(ST1)2-3(1), A4(L1T14)1-1(ST1)2-4(L1T14)2-3(1), A4(L1T14)2-4(ST1)1-1(L1T14)1-3(1)(ST1)1-3(1), A4(L1T14)1-4(ST1)1-4(ST1)1-1(L1T14)2-3(1), A4(L1T14)1-3(1)(ST1)1-3(1)(ST1)1-1(L1T14)2-4, and A4(L1T14)1-1(ST1)1-1(ST1)1-1(L1T14)2-3(1); A4(ST1)1-1(ST1)2-4(L1T14)2-3(1), A4(ST1)1-1(L1T14)2-4(ST1)2-3(1), A4(ST1)2-4(L1T14)1-1(ST1)1-3(1)(L1T14)1-3(1), A4(ST1)1-4(L1T14)1-4(L1T14)1-1(ST1)2-3(1), A4(ST1)1-3(1)(L1T14)1-3(1)(L1T14)1-1(ST1)2-4, and A4(ST1)1-1(L1T14)1-1(L1T14)1-1(ST1)2-3(1).

[0230] The present application relates in another aspect to a compound represented generically by formula (G2) and tautomers, stereoisomers, constitutional isomers, pharmaceutically acceptable salts and solvates thereof:, wherein each occurrence of LCHAIN1 - LCHAIN4 is linear or branched Ca-alkyl, with a = 9-15, or CH2(CH2)v’CH=CH(CH2)v”CH3, with v’ = 1-4, v” = 2-5, and each occurrence of LCHAIN1 - LCHAIN4 is the same or different from each of any of the other three occurrences of LCHAIN1 - LCHAIN4, n = 0 - 4, n’ = 0 - 4, and each occurrence of n is the same or different from each occurrence of n’, Q is (CH2)rCH3with r = 0-2, or CH2(CH2)r’C(O)O(CH2)r”CH3with r’ = 0-3 and r” = 1-3.

[0231] Each variable in (G2) indicating the choice of a number of groups of substituents, or a choice of substituents, is elected independently from the choice of any other such variable, whether such variables have the same name (while referring to different groups) or not, unless explicitly indicated otherwise.

[0232] The designations (MM1), (MM2), (MM3), and MM4) refer to the various assignments for the moiety MM in Formula (G2).

[0233] In some embodiments MM is MM1.

[0234] In some embodiments MM1 is

[0235] In some embodiments MM1 is

[0236] In some embodiments, each of LCHAIN1 – LCHAIN4 is a linear alkyl.

[0237] In some embodiments, at least one of LCHAIN1 – LCAHIN4 is a branched alkyl.

[0238] In some embodiments, LCHAIN1 = LCHAIN2 = LCHAIN3 = LCHAIN4 = linear alkyl.

[0239] In some embodiments, LCHAIN1 = LCHAIN2 = LCHAIN3 = LCHAIN4 = mono- unsaturated linear alkyl.

[0240] In some embodiments, LCHAIN1 = LCHAIN2 = LCHAIN3 = LCHAIN4 is CH3- (CH2)8-CH2, CH3-(CH2)10-CH2, or CH3-(CH2)12-CH2.

[0241] In some embodiments, LCHAIN1 = LCHAIN2 = LCHAIN3 = LCHAIN4 is CH2(CH2)v’CH=CH(CH2)v”CH3, with v’ = 2, v” = 4.

[0242] In some embodiments, n = n’.

[0243] In some embodiments, n = n’ = 1.

[0244] In some embodiments, n = 1 and n’ = 4.

[0245] In some embodiments, n = 4 and n’ = 1.

[0246] In some embodiments, n = 1 and n’ = 4, and LCHAIN1 = LCHAIN2 = LCHAIN3 = LCHAIN4 is CH3-(CH2)8-CH2, CH3-(CH2)10-CH2, or CH3-(CH2)12-CH2.

[0247] In some embodiments, MM1 is MM1.1, n = n’ = 1, and LCHAIN1 = LCHAIN2 = LCHAIN3 = LCHAIN4 is CH3-(CH2)8-CH2, CH3-(CH2)10-CH2, or CH3-(CH2)12-CH2.

[0248] In some embodiments, MM1 is MM1.2, n = n’ = 1, and LCHAIN1 = LCHAIN2 = LCHAIN3 = LCHAIN4 is CH3-(CH2)8-CH2, CH3-(CH2)10-CH2, or CH3-(CH2)12-CH2.

[0249] In some embodiments, MM is MM2.

[0250] In some embodiments, MM is MM3.

[0251] In some embodiments, MM is MM4.

[0252] In some embodiments, MM is MM4, and Q is (CH2)rCH3with r = 0-1, or CH2(CH2)r’C(O)O(CH2)r”CH3with r’ = 1-2 and r” = 1-3.

[0253] In some embodiments, MM is MM4, and Q is CH3, or CH2(CH2)r’C(O)O(CH2)r”CH3 with r’ = 1 and r” = 1.

[0254] In some embodiments, MM is MM4, and Q is CH3, or CH2(CH2)r’C(O)O(CH2)r”CH3 with r’ = r” = 1, and t = t’ = 1, 2.

[0255] In some embodiments, MM is MM4, t = 1, 2 and t’ = 1, 2.

[0256] In some embodiments, MM is MM4, t = t’ = 1, 2.

[0257] In some embodiments, MM is MM5, t1 = 1, 2, t2 = 1, 2, t3 = 1, 2, t4 = 1, 2.

[0258] In some embodiments, MM is MM5, t1 = t2 = t3 = t4 = 1, 2.

[0259] In some embodiments, MM is MM5, t1 = t2 = t3 = t4 = 1.

[0260] In some embodiments, MM is MM5, t1 = t2 = t3 = t4 = 1, Q is CH3.

[0261] In some embodiments, MM is MM2, n = n’ = 1, and LCHAIN1 = LCHAIN2 = LCHAIN3 = LCHAIN4 is CH3-(CH2)8-CH2, CH3-(CH2)10-CH2, or CH3-(CH2)12-CH2.

[0262] In some embodiments, MM is MM2, n = 1, n’ = 4, and LCHAIN1 = LCHAIN2 = LCHAIN3 = LCHAIN4 is CH3-(CH2)8-CH2, CH3-(CH2)10-CH2, or CH3-(CH2)12-CH2.

[0263] In some embodiments, MM is MM3, n = n’ = 1, and LCHAIN1 = LCHAIN2 = LCHAIN3 = LCHAIN4 is CH3-(CH2)8-CH2, CH3-(CH2)10-CH2, or CH3-(CH2)12-CH2.

[0264] In some embodiments, MM is MM3, n = 1, n’ = 4, and LCHAIN1 = LCHAIN2 = LCHAIN3 = LCHAIN4 is CH3-(CH2)8-CH2, CH3-(CH2)10-CH2, or CH3-(CH2)12-CH2.

[0265] In some embodiments, MM is MM4, n = n’ = 1, and LCHAIN1 = LCHAIN2 = LCHAIN3 = LCHAIN4 is CH3-(CH2)8-CH2, CH3-(CH2)10-CH2, or CH3-(CH2)12-CH2.

[0266] In some embodiments, MM is MM4, n = 1, n’ = 4, and LCHAIN1 = LCHAIN2 = LCHAIN3 = LCHAIN4 is CH3-(CH2)8-CH2, CH3-(CH2)10-CH2, or CH3-(CH2)12-CH2.

[0267] In some embodiments, MM is one of MM1, MM2 and MM3, and n, n’, LCHAIN1, LCHAIN2, LCHAIN3 and LCHAIN4 are defined as in any of the foregoing embodiments defining such indices and group designations.

[0268] In some embodiments, MM is MM4, and n, n’, LCHAIN1, LCHAIN2, LCHAIN3, LCHAIN4, Q, t, and t’ are defined as in any of the foregoing embodiments defining such indices and group designations. In some embodiments, MM is MM4, and n, n’, LCHAIN1, LCHAIN2,LCHAIN3, LCHAIN4, are defined as in any of the foregoing embodiments defining such indices and group designations, and Q, t, and t’ are defined as they are for formula (G2).

[0269] In some embodiments, MM is MM5, and n, n’, LCHAIN1, LCHAIN2, LCHAIN3, LCHAIN4, Q, t1, t2, t3, and t4 are defined as in any of the foregoing embodiments defining such indices and group designations. In some embodiments, MM is MM5, and n, n’, LCHAIN1, LCHAIN2, LCHAIN3, LCHAIN4, are defined as in any of the foregoing embodiments defining such indices and group designations, and Q, t1, t2, t3, and t4 are defined as they are for formula (G2).

[0270] Illustrative compounds of formula (G2) include, but are not limited to, compounds with the following formula, and any tautomer, stereoisomer, constitutional isomer, pharmaceutically acceptable salt or solvate thereof:

[0271] A101T101, A101T102, A101T103, A102T101, A102T102, A102T103, A103T101, A103T102, A103T103, A104T101, A104T102, A104T103, A105T101, A105T102, A105T103, A106T101, A106T102, A106T103, A107T101, A107T102, A107T103, A109T101, A107T104, A110T101, and A108T101.

[0272] The foregoing list of Aii”Tkk” lipids, with ii” = 101 - 110 and kk” = 101 - 104, is not limiting as to restricting its interpretation only to the collection of compounds whose formulae designations are expressly recited in such list. Any subgroup of lipids recited in any of such list, reciting any number of such lipids, represents a set of illustrative compounds of formula (G2) that include, but are not limited to, any such listed compound(s), and any tautomer, stereoisomer, constitutional isomer, pharmaceutically acceptable salt or solvate thereof. Methods of Preparation

[0273] Compounds described herein can be prepared by any number of processes as described generally below and more specifically illustrated by the illustrative compounds which follow in the Examples section herein.

[0274] By way of illustration, but not as a limitation, compounds of formulae (G1) and (G2) described herein can be prepared according to the following procedures shown in the following Examples as well as the examples shown in this application. One of ordinary skill in the art will recognize that, to obtain various compounds of formulae (G1) or (G2) as describedherein, starting materials can be suitably selected so that the ultimately desired substituent groups will be carried through (i.e., be stable over the course of the synthesis) the reaction scheme with or without protection as appropriate to yield the desired product. Alternatively, it may be necessary or desirable to employ, in place of the ultimately desired substituent, a suitable group that may be carried through (i.e., be stable over the course of the synthesis) the reaction scheme and replaced as appropriate with the desired substituent.

[0275] Unless otherwise specified, the variables in the following Examples and procedures are as defined above in reference to the various embodiments of compounds of formulae (G1) or (G2). If no temperature or temperature range is stated, it is to be understood that the reaction is to be conducted at room temperature. EXAMPLES

[0276] The following examples of the application are to further illustrate the nature of the application. It should be understood that the following examples do not limit the application and the scope of the application is to be determined by the appended claims.

[0277] Unless indicated otherwise, the abbreviations for chemical reagents and synthesis conditions have their ordinary meaning known in the art as follows: “ACN” refers to acetonitrile; “BnNH2” refers to benzylamine; “Boc” refers to tert-butoxycarbonyl; “BuBr” refers to 1-bromobutane (n-butyl bromide); “CAD” refers to charged aerosol detector; “DCC” refers to N,N’-dicyclohexylcarbodiimide; “DCM” refers to dichloromethane; “DEAD” refers to diethyl azodicarboxylate; “DHP” refers to dihydropyran; “DIEA” or “DIPEA” refers to N,N-diisopropylethylamine; “DLin-MC3-DMA” refers to 4-(dimethylamino)-butanoic acid, (10Z,13Z)-1-(9Z,12Z)- 9,12-octadecadien-1-yl-10,13-nonadecadien-1-yl ester (CAS # 1224606-06-7); “DMAP” refers to 4-dimethylaminopyridine; “DMF” refers to dimethylformamide;“DMSO” refers to dimethylsulfoxide; “DNA” refers to deoxyribonucleic acid; “DOPE” refers to 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine; “DPPF” refers to 1,1'-Bis(diphenylphosphino)ferrocene; “DSPC” refers to 1,2-distearoyl-sn-glycero-3-phosphocholine; “EA” refers to ethyl acetate; “EDCI” refers to 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; “EDTA” refers to ethylenediaminetetraacetic acid; “ELSD” refers to evaporative light-scattering detector; “EtOH” refers to ethanol; “FIX” refers to factor IX; “GalNAc” refers to N-acetylgalactosamine; “h”, “hr” or “hrs” refers to hours; “HATU” refers to hexafluorophosphate azabenzotriazole tetramethyl uronium (1- [Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate); “hEPO” refers to human erythropoietin; “Hex” refers to hexanes; “hFIX” refers to human factor IX; “HOBT” or “HOBt” refers to hydroxybenzotriazole (1H-1,2,3-Benzotriazol-1-ol); “IFN-γ” refers to interferon-gamma; “IgG” refers to immunoglobulin G; “IL-6” refers to interleukin-6; “i-PrOH” refers to isopropanol; “IV” refers to intravenous; “LAH” refers to lithium aluminum hydride; “LCMS” refers to liquid chromatography-mass spectrometry; “LDA” refers to lithium diisopropyl amide; “LLOQ” refers to the lower limit of quantification of an assay; “LNP” refers to lipid nanoparticles; “LP-01” refers to 9Z,12Z-octadecadienoic acid, 3-[4,4-bis(octyloxy)-1-oxobutoxy]-2-[[[[3-(diethylamino)propoxy]carbonyl]oxy]methyl]propyl ester (CAS # 1799316- 64-5); “MC3” see DLin-MC3-DMA; “MCP-1” refers to monocyte chemoattractant protein-1; “m-CPBA” refers to meta-chloroperoxybenzoic acid; “MHC-I tetramer” refers to class I major histocompatibility complex (MHC) tetramer; “MeOH” refers to methanol; “MTBE” refers to methyl tert-butyl ether; “min” refers to minutes; “mRNA” refers to messenger RNA; “NaHMDS” refers to sodium bis(trimethylsilyl)amide; “NaVC” refers to refers to L(+) sodium ascorbate, CAS # 134-03-2; “OTBDPS” refers to TBDPS ether; “OVA” refers to ovalbumin; “Pd / C” refers to palladium on carbon; “pDNA” refers to plasmid DNA; “PDI” refers to the polydispersity index, as a measure of the width of nanoparticle size distribution. “PE” refers to petroleum ether; “PEG” refers to polyethylene glycol; “PPh3” refers to triphenylphosphine; “Prep-HPLC” refers to preparative high performance liquid chromatography; “Prep-TLC” refers to preparatory thin layer chromatography; “Py” refers to pyridine; “RNA” refers to ribonucleic acid; “r.t.” and “rt” refer to room temperature; “RT” or “Rt” refers to retention time; “SM-102” refers to 8-[(2-hydroxyethyl)[6-oxo-6-(undecyloxy)hexyl]amino]-octanoic acid, 1-octylnonyl ester (CAS # 2089251-47-6); “TBAB” refers to tetrabutylammonium bromide; “TBAF” refers to tetrabutylammonium fluoride;“TBDPS” refers to tert-butyldiphenylsilyl; “TBDPSO” refers to TBDPS ether; “TBS” refers to tert-butyldimethylsilyl; “TBSO” refers to TBS ether” “t-BuOH” refers to tert-butyl alcohol; “TEA” refers to triethyl amine; “TFA” refers to trifluoroacetic acid; “THF” refers to tetrahydrofuran; “TLC” refers to thin layer chromatography; “TMSI” or “TMS-I” refers to trimethylsilyl iodide; “Tol” refers to toluene; “TsOH” refers to p-toluenesulfonic acid; “ULOQ” refers to the upper limit of quantification of an assay; and “VcNa”, “VCNa” or “VcONa” refers to L(+) sodium ascorbate, CAS # 134-03-2.

[0278] Compound designations, whether letters, numbers, or combinations of letters and numbers, may be typed in bold-face font or not, and this difference in font is not meant to confer any substantive difference to the compound designations. For the named compounds below, chemical names have been generated with the structure-to-name conversion tool of the software ChemDraw®(see furthermore note on chiral compound naming after Table 1).

[0279] Some embodiments of compounds of formulae (G1) are prepared by hydroamination of the alkene group(s) in one or more compound(s) of general formula (L), where GL is OCO (which is either C(O)-O or O-C(O)), OCNH (which is either C(O)NH or HN- C(O)), or CH2CH2, with the parent compound of a moiety A to yield a hydroaminated alkyne derivative whose alkyne moiety further undergoes cycloaddition with an azide (Tk”), wherein k” has the value determined by m’ and T, as more extensively described in the following Examples,to yield a triazole derivative within the scope of general formulae (G1). Other embodiments of compounds of formulae (G1) are prepared by cycloaddition with an azide (Tk”), wherein k” has the value determined by m’ and T, with an alkyne moiety AL as more extensively described in the following Examples. The values of pL’ in (L) and p’ in formulae (G1) are related in the form p’ = pL’ + 1, for p’ ≥ 1, so that when p’ = 1, 2, 3, 4, then pL’ = 0, 1, 2, 3, respectively. The values of pL” in (L) and p” in formulae (G1) are related in the form pL” - 1 = p”, so that when p” = 0, 1, 2, 3, 4, then pL” = 1, 2, 3, 4, 5, respectively. The natural number m’ is as defined for general formulae (G1).

[0280] Illustrative embodiments of compounds of general formula (G1.1) in the following examples are referred to with terms Ai”Lj”Tk", where i”, j”, and k” are labelling naturalnumbers. Sometimes reference is made to “compound Ai”Lj”Tk" ” and sometimes reference is made to “lipid Ai”Lj”Tk" ”, terms that are considered herein interchangeable and with the same meaning. In compound L, the variables p’ and p’’ (or pL’ and pL”) are judiciously chosen as to introduce the desired number of units between the alkene group and the moiety GL (in the case of p’ or pL’), and the desired number of units between the moiety GL and the alkyne group (in the case of p” or pL”). For example, when p’ = 1 and p” = 1 (or pL’ = 0 and pL” = 2), then compound L is selected from compounds L1, L2 and L3 in the following examples.

[0281] In some embodiments, the alkyne moiety is introduced by an alkene, such as L1 or L2, in which case the generated hydroaminated compounds are noted as Ai”L1Tk” or Ai”L2Tk”, respectively. In other embodiments, the alkyne moiety is introduced by an halide-derivative suchas L3.X. In other embodiments, the alkyne moiety is introduced by an aldehyde-derivative such as L3.A Whether such moiety is introduced by L3, L3.A or L3.X, the compounds where the moiety corresponding to GL is CH2CH2 are herein named with the term L3 appearing in them because the alkene (L3), aldehyde (L3.A) or halo (L3.X) intermediate does not change the structure of such final compounds Ai”L3Tk”, only the reaction performed in one of the synthetic steps to obtain them. As explained below, i” and k” are labelling natural numbers. Note that the appropriate choice of the length of the chain in embodiments such as L3.X and L3.A may lead to embodiments of formulae G1 where p’ = 0, such as by choosing a (CH2)5instead of a (CH2)6chain in alkyne L3.X or a (CH2)4CHO instead of a (CH2)5CHO chain in alkyne L3.A.

[0282] Embodiments that introduce moiety L with an aldehyde derivative such as L3.A rely on a reductive amination by reacting an aldehyde such as L3.A, with a starting amine to produce an alkylated amine that has a higher degree of substitution than the starting amine. Embodiments that introduce moiety L with a halide such as L3.X rely on an amine alkylation by reacting a halide, such as L3.X, with a starting amine to produce an alkylated amine that has a higher degree of substitution than the starting amine. As illustrated by the Examples of synthesis of compounds of formula (G1.2), this generation of alkyne derivatives is also applicable to the LT moiety(ies) in compounds of formula (G1.2).

[0283] Upon hydroamination / reductive amination / amine alkylation of L with a parent compound of an amino moiety A, the resulting aminated alkyne derivative is referred to as Ai”Lj” in the following examples, with i” and j” being labelling natural numbers. In compound Tk”, the variable m’ is judiciously chosen as to introduce the desired number of units between the azido group and the moiety T. Table 2 (parts 1 and 2) lists illustrative embodiments of such azides. Only “Table 2” is recited, with the same meaning, to refer to “Table 2, parts 1 and 2”).

[0284] The term Ai”Lj” is used herein to refer to such compound or moiety regardless of its preparation method. For example, as further described and illustrated in the Examples below, in some embodiments, Ai”Lj” is prepared through alkene hydroamination, aldehyde reductive amination or amine alkylation of an amine (comprising at least one primary and / or secondary amino group) with linkers that comprise each an alkene group, as indicated above, and in some other embodiments it is prepared as to generate directly compound Ai”Lj” without resorting to an alkene hydroamination, as shown for the preparation of compounds A30L1, A31L1, A32L1, A33L1, A34L1, A38L1, A39L1, A40L1, A41L1 and A42L1 whose structures are given in Table1, as described in the corresponding examples below. No matter how Ai”Lj” is generated, embodiments of compounds of formula (G1.1) are prepared through azide-alkyne cycloaddition of the alkyne group in moiety Ai”Lj” with an azide Tk” to yield compounds Ai”Lj”Tk". As illustrated by the Examples of synthesis of compounds of formula (G1.2), azide-alkyne cycloadditions analogous to the ones for compounds of formula (G1.1) are also applicable to the LT moiety(ies) in compounds of formula (G1.2).

[0285] By way of illustration, compounds A30L1, A31L1, A32L1, A33L1, A34L1, A38L1, A39L1, A40L1, A41L1, and A42L1 illustrate compounds Ai”Lj”, with i” = 30-34 and 38-42, and j” = 1, with only one alkyne group available for cycloaddition with an azide, as illustratively shown in Table 1. Although not synthesized through the alkene hydroamination of an isolated secondary amine, the fact that each of such compounds comprises only one L moiety with one alkyne group makes them subject to the terminology that they have one *N moiety each as far as nomenclature is concerned.

[0286] Each -NH2 group in amines Ai”, i” = 17-29, illustratively shown in Table 1, undergoes two hydroaminations with two linker compounds of formula (L), each one with the alkene group of each of such two compounds (L), for example, compound L1. Each of such -NH2 groups is an example of a *(*)N member. In this illustration, the final compound will thus comprise two linker-derived moieties, each with a moiety containing a triazole group and a tail attached to it (LT moiety). This is illustrated by compounds of formula Ai”L1Tk” with k” = 1-23 and i” = 17-29. Compounds of formula Ai”L2Tk” with k” = 14, 18, 21 and i” = 4-6, illustrate compounds obtained through hydroaminations with L2. Compounds of formula Ai”L3Tk” with k” = 14, 19, 22 and i” = 4-6, illustrate compounds obtained through reductive aminations with L3.O or through amine alkylations with L3.X.

[0287] In another illustration, compound of formula Ai”L1Tk” shown below, is an illustrative generic formula for compounds derived from a primary amine that could be, for example, any amine Ai”, i” = 17-29 shown in Table 1, and Tk”, k” = 1-23, could be any azide among those illustratively shown in Table 2. The group “RAi" ” is implicitly defined based on the formulae Ai”, i” = 17-29, given in Table 1, wherein RAi" is the moiety in each of such Ai”, i” = 17-29, that is attached to the terminus CH2-CH2-NH2in each of such Ai”, i” = 17-29. This compound is an illustration of an embodiment with p = 2 as defined for formula (G1.1), and the primary amino group is a *(*)N center.

[0288] In another illustration, compound of formula Ai”L1Tk”, with i" = 7 and k" = 7 shown below, is the formula for a compound derived from amine A7, shown in Table 1, that has three primary amino groups, each being a *(*)N member, and two linkers L1 attached to each of such primary amino groups, and in turn azide T7, shown in Table 2, attaches to each alkyno group of each of such L1 linkers, thus leading to compound A7L1T7, which was synthesized as described in the corresponding example given below. This compound is an illustration of an embodiment with p = 6 as defined for formula (G1.1):

[0289] In another illustration, compound of formula Ai”L1Tk” with i” = 16 and k” = 1 shown below, is the formula for a compound derived from amine A16, shown in Table 1, that has two terminal primary amino groups, each being a *(*)N member. Two linkers L1 attach to each of such primary amino groups and in turn azide T1, shown in Table 2, attaches to each alkyno group of each of such L1 linkers, thus leading to compound A16L1T1, which was synthesized as described in the corresponding example given below. This compound is an illustration of an embodiment with p = 4 as defined for formula (G1). Structural formula for A16L1T1:(A16L1T1)

[0290] Other illustrative embodiments of compounds with p = 4 as defined for formula (G1.1) are compounds A11L1T11, A12L1T2, A10L1T19 and A16L1T1.

[0291] A4L1T4 is an illustrative embodiment that has linkers L1 attached to all the *(*)N (here primary amino) and also *N (here secondary amino) members in amine A4 and where the notation *N refers here to the N member in the -NH- moiety in A4.

[0292] In another illustration, compound of formula Ai”L1Tk” with i” = 5 and k” = 15 shown below, is the formula for a compound derived from amine A5, shown in Table 1, that has two terminal primary amino groups. Each of such groups is a *(*)N member in this compound. Two linkers L1 attach to each of such primary amino groups and in turn azide T15, shown in Table 2, attaches to each alkyno group of each of such L1 linkers, thus leading to compound A5L1T15, which was synthesized according to Example A5L1T15 given below, and whose full structural formula is given below. This compound is an illustration of an embodiment with p = 4 as defined for formula (G1.1):

[0293] In another illustration, compound of formula Ai”L1Tk” with i” = 30 and k” = 15 shown below, is the formula for a compound derived from parent compound A30L1, shown in Table 1. One linker L1 is attached to the *N member in such compound A30L1 and in turn azide T15, shown in Table 2, attaches to the alkyno group of such L1 linker, thus leading to compound A30L1T15, which was synthesized according to Example A30L1T15 given below, and whose full structural formula is given below. This compound is an illustration of an embodiment with p = 1 as defined for formula (G1.1).

[0294] In light of the large space that would be taken by the full structural formulae for compounds Ai”Lj”Tk”, such as those referred to in Table C1 (parts 1 and 2), nomenclature is provided herein to refer to them concisely, and to ascertain the structural formula of any such lipid given as an Ai”Lj”Tk” formula or, vice versa, to name any of such structural formulae inthe Ai”Lj”Tk” notation. This is accomplished by relying on the formulae given in Tables 1-2 and the criteria provided throughout this application. The examples for the syntheses of the various moieties in Ai”Lj”Tk” lipids and the full Ai”Lj”Tk” compounds given below illustrate how to prepare such Ai”Lj”Tk” lipids. Ai”Lj”Tk” lipids for which no express synthesis narrative is provided are synthesized in reference to the synthetic examples given in this application. Such examples, together with those given explicitly for compounds of formula (G1.2), illustrate by analogy synthetic steps for moieties LT in compounds of formula (G1.2) whose syntheses are not explicitly given below. Known azide-alkyne chemistry may be used to supplement the synthetic methods illustratively described herein, to design alternative synthetic schemes, or to use in the synthesis of lipids for which no express synthesis is described herein, such as chemistry disclosed in references that include the following: N. Zuin Fantoni, et al., Chem. Rev.121, 7122-54 (2021) “A Hitchhiker’s Guide to Click-Chemistry with Nucleic Acids”; Y. Zhao, et al., Molecules 28(3), 1400 (2023) “Overview of 1,5-Selective Click Reaction of Azides with Alkynes or Their Synthetic Equivalents”; P.K. Avti, et al., Molecules 18(8), 9531-49 (2013) “Alkyne-Azide ‘Click’ Chemistry in Designing Nanocarriers for Applications in Biology”; and “Click Chemistry Azide-Alkyne Cycloaddition” in Organic Chemistry Portal, at <https: / / www.organic-chemistry.org / namedreactions / click-chemistry.shtm>.

[0295] According to the nomenclature for Ai”Lj”Tk” lipids used in Table C1 (parts 1 and 2), Tables 1-2 and in examples below, Lj” refers to the linker compound that comprises an alkene group and an alkyne group as shown for compound of formula (L). For some illustrative embodiments, such as those referred to in Table C1 (parts 1 and 2), j” = 1, so Lj” for such illustrative embodiments is L1. The following narrative description concerning L1 is analogously applicable to L2 and L3, for which it is not repeated. There are two L1-derived linker moieties that are attached to each *(*)N member of an Ai” moiety (i” = 1-12, 14, 16-29, 35-37), and there is one L1-derived linker moiety to each *N member of an Ai” moiety (i” = 4) or to the *N member of moieties Ai”L1 (i” = 30-34, 38-42) as indicated above. When amine Ai” has *N and *(*)N members (such as when i” = 4), such amine Ai” - linker L1 attachments take place at both the *N and *(*)N sites of the Ai” moiety. Because the alkyne group of each L1-derived linker moiety undergoes an azide-alkyne cycloaddition, generating a triazole with the rest (tail T as defined by general formula (Tk”)) of the azide reactant, the final compound will have as many triazole-T moieties derived from such azide-alkyne cycloaddition as linker moieties L1 areattached to the amine Ai”, i” = 1-12, 14, 16-29, 35-37, moiety or to the one L1 moiety of Ai”L1, i” = 30-34 and 38-42, moiety. Examples of such parent amines Ai” for such Ai”, i” = 1-12, 14, 16-29, 35-37, moieties, and examples of parent Ai”Lj”, i” = 30-34 and 38-42, compounds for such Ai”Lj”, i” = 30-34 and 38-42, moieties are shown in Table 1. Examples of azides comprising an azido group and a tail T are shown in Table 2. Examples of such tails T as incorporated in compounds of formulae (G1.1) and (G1.2), without the azido group, are shown in Table T2. Any one of Tables 2 and T2 may indistinguishably be referred to concerning any particular tail, or moiety, T in any compound of formulae (G1.1) and (G1.2), Examples of such amino moieties A as incorporated in compounds of formulae (G1.1) and (G1.2), are shown in Tables P1, P2, P4 and formulae P5 and P6. Any one of Tables 1 and Tables P1, P2, P4 and formulae P5 and P6 may indistinguishably be referred to concerning any particular amino moiety A in any compound of formulae (G1.1) and (G1.2), The examples below also provide illustrations of compounds designated according to such Ai”Lj”Tk" terminology. The structural formula of any Ai”Lj”Tk" referred to in these examples of compound of formula (G1.1) is determined by (a) identifying the amino moiety Ai”, i” = 1-12, 14, 16-29, 35-37, or intermediate Ai”L1, i” = 30-34 and 38-42, moiety as per the illustrations in Table 1; (b) when the relevant moiety is Ai”, i” = 1- 12, 14, 16-29, 35-37 (rather than Ai”L1, i” = 30-34 and 38-42), identifying the number of *N and *(*)N members in such amine Ai”, and attaching two L1 moieties by the alkene terminus of each of such L1 moiety as described above to each *(*)N member, and in some embodiments one L1 moiety to each *N member when present, to form moieties Ai”(L1)p, p = 1-6, and i” = 1-12, 14, 16-29, 35-37; and (c) attaching to each alkyne end of each moiety Ai”(L1)p, p = 1-6 and i” = 1- 12, 14, 16-37 the azido moiety of a tail Tk” as the result of an azide-alkyne cycloaddition with the formation of a triazole-tail moiety for each such L1 moiety. The number of *N and *(*)N members in each of the examples of Ai”, i” = 1-12, 14, 16-29, 35-37, and Ai”L1, i” = 30-34 and 38-42, is given below. The foregoing nomenclature criteria are provided for Ai”Lj”Tk” nomenclature purposes, and to convert (through the use of such nomenclature and the examples, express formulae, and moiety information provided herein) any compound designation in the form Ai”Lj”Tk”, with specified values for i", j”, and k”, to its corresponding cheructure, or vice versa. As noted above, the foregoing narrative description concerning L1 is analogously applicable to L2 and L3 regarding compounds Ai”Lj”Tk", j” = 1-3. Although only amines of type Ai”L1, i” = 30-34 and 38-42, are explicitly given in Table 1, the corresponding aminesAi”L2 and Ai”L3, i” = 30-34 and 38-42, are readily envisaged when the alkyne moiety in them as shown in Table 1 is changed to the corresponding alkyne moiety that formally corresponds with L2 and L3, respectively.

[0296] Various Tk” in some embodiments of lipids Ai”Lj”Tk” correspond to identical tails Tk” in Ai”Lj”Tk” derived from the same parent azide Tk”, whereas in other embodiments tails Tk” may be different. This feature equally applies to LT moieties in compounds of formula (G1.2). Unless indicated otherwise, the notation Ai”Lj”Tk” is to be interpreted herein as referring to a lipid embodiment in which the various Tk” are identical when more than one is present, as determined according to the criteria given above. Analogously, and unless indicated otherwise, the notation Ai”Lj”Tk” is to be interpreted herein as referring to a lipid embodiment in which the various Lj”, when a plurality of Lj” exist, are identical.

[0297] Table 1 (parts 1-4; herein referred to only as “Table 1”) shows illustrative embodiments of amines Ai”, i” = 1-12, 14, 16-29, and 35-37, that generate the corresponding Ai” moiety in compounds designated with the terminology Ai”Lj”Tk”, when i” = 1-12, 14, 16-29, and 35-37. The same Ai” designation is used for the parent amine and for the corresponding moiety in the Ai”Lj”Tk" compound. Table 1 also shows illustrative embodiments of compounds Ai”Lj”, i” = 30-34 and 38-42, and j” = 1, that generate the corresponding Ai”L1 moiety in compounds designated with the terminology Ai”L1Tk", when i” = 30-34 and 38-42. As with the amines and the corresponding amine moieties, the same Ai”L1 designation is used for the parent compound shown in Table 1 and for the corresponding moiety in the Ai”Lj”Tk" compound. The examples below provide further illustrations of such compounds and moieties. A first set of illustrative embodiments of Ai”Lj”, j” = 1, moieties include A1L1, A2L1, A3L1, A4L1, A5L1, A6L1, A7L1, A8L1, A9L1, A10L1, A11L1, A12L1, A14L1, A16L1, A17L1, A18L1, A19L1, A20L1, A21L1, A22L1, A23L1, A24L1, A25L1, A26L1, A27L1, A28L1, A29L1, A30L1, A31L1, A32L1, A33L1, A34L1, A35L1, A36L1, and A37L1. Analogous moieties to those given in the foregoing first set with the corresponding i” values, and with j” = 2, 3 instead of j” = 1, illustrate moieties Ai”L2 and Ai”L3, respectively. A second set of illustrative embodiments of Ai”Lj”, j” = 1, moieties include A30L1, A31L1, A32L1, A33L1, A34L1, A38L1, A39L1, A40L1, A41L1 and A42L1. Analogous moieties to those given in the foregoing second set with the corresponding i” values, and with j” = 2, 3 instead of j” = 1, illustrate moieties Ai”L2 andAi”L3, respectively, when the moiety L1 is replaced by an L2 or L3 moiety (such as L3.X, L3.A, or a moiety analogous to L3.X or L3.A that has a shorter chain, as indicated above).Table 1 (part 1)Table 1 (part 2)Table 1 (part 3)Table 1 (part 4)

[0298] The group that is displayed in Table 1 as “NH2” refers to the amino group “NH2”.

[0299] Chiral compounds that comprise one of the following amino moieties: A6, A8, A11, A12, A35, A37, A101 and A102, can present themselves in pure enantiomeric and racemate forms. The corresponding ChemDraw®-generated names have been edited to recite the terms trans / cis instead of the absolute stereocenter configurations R / S, even when the described synthesis procedures (see Example A12L1, as an illustration) and / or other disclosure provided inthe specification permit the identification of any such absolute stereocenter configuration. In addition to the compound forms explicitly, or by implication, identified in the specification, and no matter how they are named, the racemates thereof and the corresponding enantiomers are all envisaged within the scope of this invention.

[0300] The parent compounds Ai”L1, with i” = 30 - 34 and 38 - 42, illustrate embodiments in which p = 1 (one *N member) in formula (G1.1) when any of such Ai”L1, with i” = 30 - 34 and 38 - 42, is a moiety in a compound of formula (G1.1). The parent amines Ai”, with i” = 17 - 29, illustrate embodiments in which p = 2 (one *(*)N member (in these cases such *(*)N member being a primary amino group)) in formula (G1.1) when any of such Ai”, with i” = 17 - 29, is a moiety in a compound of formula (G1.1). The parent amines Ai”, with i” = 1-3, 5, 6, 8-10, 14, 35, 36 and 37, illustrate embodiments in which p = 4 (two *(*)N members (in these cases each of such *(*)N members being a primary amino group)) in formula (G1.1) when any of such Ai”, with i” = 1-3, 5, 6, 8-10, 14, 35, 36 and 37, is a moiety in a compound of formula (G1.1). The parent amines Ai”, with i” = 11, 12 and 16, illustrate further embodiments in which p = 4 (two *(*)N members (in these cases each of such *(*)N members being a primary amino group)) in formula (G1.1), when any of such Ai”, with i” = 11, 12, and 16, is a moiety in a compound of formula (G1.1). In reference to parent amines Ai” with i” = 11, 12 and 16, the NH group that is part of an amido moiety is not a *N member. The parent amine Ai”, with i” = 7, illustrates an embodiment in which p = 6 (three *(*)N members (in these cases each of such *(*)N members being a primary amino group)) in formula (G1.1) when such Ai”, with i” = 7, is a moiety in a compound of formula (G1.1). The parent amine Ai”, with i” = 4, illustrates an embodiment in which p = 5 (two *(*)N members and one *N member (in this case each of such *(*)N members being a primary amino group and such *N member being a secondary amino group)) in formula (G1.1) when such Ai”, with i” = 4, is a moiety in a compound of formula (G1.1). In reference to parent amine Ai” with i” = 4, the NH group is not part of an amido moiety, and it is in this case a *N member. As noted above, the foregoing narrative description concerning L1 in parent compounds Ai”L1 is analogously applicable to L2 and L3 regarding compounds Ai”Lj”Tk", j” = 1-3. Although only amines of type Ai”L1, i” = 30-34 and 38-42, are explicitly given in Table 1, the corresponding amines Ai”L2 and Ai”L3, i” = 30-34 and 38- 42, are readily envisaged when the alkyne moiety in them as shown in Table 1 is changed to thecorresponding alkyne moiety that formally corresponds with L2 and L3 (such as L3.X, L3.A, or a moiety analogous to L3.X or L3.A that has a shorter chain, as indicated above), respectively.Table 2 (part 1)Table 2 (part 2)

[0301] Table 2 shows illustrative embodiments of azides that generate the moiety that corresponds with the moiety in Formula (G1.1) and in moieties LT in compounds of formula (G1.2). By way of illustration of the use of the terminology in such moiety and also in the azide notation, T1 is generated by the choice m’ = 0 and T = (CH2)5CH3, or by the choice m’ = 1 and T = (CH2)4CH3; T15 is generated by the choice m’ = 0 and T = (CH2)5C(O)OCH((CH2)7CH3)(CH2)7CH3 or m’ = 1 and T = (CH2)4C(O)OCH((CH2)7CH3)(CH2)7CH3; T23 is generated only by the choice m’ = 0 and T = CH((CH2)4CH3)(CH2)4CH3.

[0302] The same Tk” designation is used for the parent azide in Table 2 and for the corresponding moiety in the Ai”Lj”Tk" compound for lipid embodiments in which the various Tk” in lipid Ai”Lj”Tk" are identical, which is as the notation Ai”Lj”Tk” is to be interpreted herein, unless indicated otherwise. The same Tk” designation is used for the parent azide in Table 2 and for the corresponding moiety in the LT moieties in compounds of formula (G1.2) for lipid embodiments in which the various Tk” in LT moieties in compounds of formula (G1.2)) are identical, which is as the corresponding notation in LT moieties in compounds of formula (G1.2) is to be interpreted herein, unless indicated otherwise.Table 2.1

[0303] Table 2.1 shows illustrative embodiments of moiety ST in Formula (G1.2). The notation in to moieties listed in Table 2.1 means -CH2. For example, ST1 is - CH2CH2CH2OH; ST3 when q’ = 0 is -CH2-CH2-COOH, and the same convention applies to ST1- ST8 in Table 2.1.

[0304] The tabular summary shown in Table C1 (parts 1 and 2) refers to compounds of formulae Ai”Lj”Tk" with k” = 1-15, j” = 1, and i” as indicated therein, as illustrative embodiments of compounds of formula (G1.1).Table C1

[0305] This table (parts 1 and 2) shows in a tabular arrangement 510 compound designations that correspond to compounds Ai”Lj”Tk" with k” = 1-15, j” = 1, and i” as indicated therein, made as illustrative embodiments of compounds of formula (G1.1). Table C1 (part 1) T1A1L1 A1L1A2L1 A2L1A3L1 A3L1A4L1 A4L1A5L1 A5L1A6L1 A6L1A7L1 A7L1A8L1 A8L1A9L1 A9L1A11L1 A11LA12L1 A12LA14L1 A14LA16L1 A16LA17L1 A17LA18L1 A18LA19L1 A19LA20L1 A20LA21L1 A21LA22L1 A22LA23L1 A23LA24L1 A24LA25L1 A25LA26L1 A26LA27L1 A27LA28L1 A28LA29L1 A29LA30L1 A30LA31L1 A31LA32L1 A32LA33L1 A33LA34L1 A34LA35L1 A35LA36L1 A36LA37L1 A37LTable C1 (part 2) A1L1A2L1A3L1A4L1A5L1A6L1A7L1A8L1A9L1A11L1A12L1A14L1A16L1A17L1A18L1A19L1A20L1A21L1A22L1A23L1A24L1A25L1A26L1A27L1A28L1A29L1A30L1A31L1A32L1A33L1A34L1A35L1A36L1A37L1

[0306] Compounds of formulae (G1) may present multiple constitutional isomers because of any one, or a combination of, a plurality of molecular features.

[0307] In one of such instances constitutional isomers of formula (G1.1) are generated, for example, when p > 1, not all of the LT moieties are identical and the amino moiety A presents a molecular asymmetry (such as A4, that has four methylene units linearly disposed on one side of the central group NH (an N* site) and three methylene units linearly disposed on the other side of such NH group). In another illustrative instance, constitutional isomers of formula (G1.1) are generated, for example, when p > 1, the amino moiety A does not present a molecular asymmetry,but different LT moieties may be bonded in different arrangements to the N(*)* and / or N* sites in the amino moiety A. For example, when two identical LT moieties (say, LT’ each) and other two identical moieties (say, LT” each), with LT’ being different from LT”, bind to all the available sites of, for example A5, then two constitutional isomers may be generated even though A5 does not present a molecular asymmetry (one constitutional isomers having both LT’ moieties bound to one terminal N(*)* center and both LT” moieties bound to the other terminal N(*)* center, and the other constitutional isomer having one LT’ and one LT” moieties bound to one terminal N(*)* center and one LT’ and one LT” moieties bound to the other terminal N(*)* center.

[0308] As indicated above, specific compounds of formula (G1.2) are referred to with the notation Ai”(ST)q(LT)p, where i” = 1-12, 14, 16-29, 35-37, and (p + q) being equal to the number of binding sites in Ai”(one for each N* member and two for each N(*)* member in Ai”), with p and q being subject to the restrictions given above for compounds of formula (G1.2).

[0309] In another instance, constitutional isomers of formula (G1.2) are generated when p ≥ q ≥ 1 in (G1.2) and the amino moiety A presents a molecular asymmetry (as illustratively indicated above in reference to A4) or not (as illustratively indicated above in reference to A5), with all the ST moieties (q > 1) being the same or different and / or all the LT moieties (p > 1) being the same or different. For example, a compound (G1.2) of formula A4(L1T14)3(ST1)2, with amino moiety A4, three L1T14 moieties, and two ST1 moieties, presents several constitutional isomers, such as A4(L1T14)1-1(L1T14)2-4(ST1)2-3(1)(whose full structure is shown below), A4(L1T14)1-1(ST1)2-4(L1T14)2-3(1)(whose full structure is shown below), A4(ST1)1-1(ST1)1-4(L1T14)1-4(L1T14)2-3(1), and A4(L1T14)1-1(ST1)1-4(L1T14)1-4(ST1)1-3(1)(L1T14)1-3(1).

[0310] In the foregoing A4(L1T14)3(ST1)2constitutional isomers, each ST and LT moiety within parenthesis has an index with two parts, each part being separated by a hyphen. The number on the left of the hyphen indicates the number of such ST or LT moieties at the binding site specified by the part of the index on the right-hand side of the hyphen. Such part of the index on the right-hand side of the hyphen refers to the number of the C-member in the amine moiety (A4 in this example) when it is named according to the IUPAC convention. A single digit on the right-hand side of the hyphen refers to the number of a C-member in the parent chain in theIUPAC nomenclature of A4 (and such number is assigned to the N(*)* or N* center bound to it), and a numerical term that has digit followed by another within parenthesis on the right-hand side of the hyphen refers to the number (digit preceding the parenthesis) of a C-member in a chain that is a substituent at the C-member in the parent chain indicated by the number within parenthesis (and such numerical term is assigned to the N(*)* or N* center bound to it). Accordingly, the name of A4 is N1-(3-aminopropyl)butane-1,4-diamine, and the N*(*) and N* centers in it are assigned the numbers according to the foregoing convention as shown in the illustrative structure below:

[0311] The 1-4 chain in the preceding figure is the parent chain according to IUPAC nomenclature, starting at methylene carbon 1 and ending at methylene carbon 4.

[0312] This nomenclature permits the listing of the LT and ST moieties in any order, while the named structure is definite. For example, the formulae A4(L1T14)1-1(L1T14)2-4(ST1)2-3(1), A4 (L1T14)2-4(L1T14)1-1(ST1)2-3(1), and A4(ST1)2-3(1)(L1T14)1-1(L1T14)2-4, all refer to the same structure that has two ST1 moieties at the N(*)* center 3(1), one L1T14 moiety at the N* center 1, and two L1T14 moieties at the N(*)* center 4.

[0313] The indices generated according to the foregoing convention are thus the ones used in illustrative compounds A4(L1T14)p(ST1)q, with p and q defined as in formula (G1.2). Because the IUPAC nomenclature is of general knowledge and acceptance, one of ordinary skill in the art would be able to name any other of the constitutional isomers within the scope of (G1.2). Theforegoing nomenclature convention presents the advantageous feature of being able to distinguish between identical terminal moieties in structurally symmetric amines. For example, even though A3 is symmetric with respect to the central tertiary amino moiety, the foregoing nomenclature permits distinguishing between the following (G1.2) constitutional isomers (each having (in this illustrative embodiment) two identical LTa moieties and two identical STb moieties, each chosen as indicated for LT and ST, respectively, in (G1.2)) A3(LTa)2-3(STb)2-3(1) and A3(LTa)1-3(STb)1-3(LTa)1-3(1)(STb)1-3(1), as shown in the illustrative structures below (where LTa represents an LT moiety and STb represents an ST moiety:Because the nomenclature defined above for (G1.2) constitutional isomers focuses on features of the amino moiety A, such nomenclature is analogously applicable to designate specific (G1.1) constitutional isomers and for compounds of formula (G1.1) that have a plurality of different LT moieties and each of such LT is to be specified the N* or N(*)* member to which it is bound.

[0314] As indicated above and as exemplified by the synthesis described below for illustrative embodiments of compounds of formula (G1.2), the synthesis part concerning the amino A and LT moieties in compounds of formula (G1.2) is analogous to that for compounds of formula (G1.1). As to the ST moieties in compounds of formula (G1.2), the synthesis proceeds through an initial amino moiety, or the preparation of the same. This initial amino moiety may correspond to the amino moiety Ai” of the final compound Ai”(ST)q(LT)p, or be part of it that is to be bound to ST moieties. In the latter case, once the ST moieties are substituting the desired positions, suitably protected when needed, the amino moiety that is substituted with such ST moieties (or ST precursors) that are suitably protected, is used to form the final amino moiety (through processes such as amine alkylation) while leaving N* and / or N(*)* members in it available for the desired reactions with linkers such as L1, L2, L3.A and L3.X, and subsequently with Tk”azides to form therein the LT moiety(ies) as in the synthesis of (G1.1) compounds, following with a deprotection of the ST moieties at the end of the process or at a convenient intermediate step.

[0315] Checked embodiments of compounds of formula (G1.1) in salt-free form exhibited purity above 85% by HPLC, and it was determined by ELSD, LCMS to be in the range of 86% to 100% with an average purity of 94% ± 5%. Illustrative embodiments of such purity determinations are provided in Table 3.Compound IDPurity(ELSD, LCMS)Net Weight Salt Type Physical PropertyA6L1T2 97% 200 mg free Yellow oilA12L1T2 100% 200 mg free yellow oilA14L1T2 87% 200 mg free Yellow oilA22L1T7 100% 200 mg free yellow solidA11L1T11 100% 200 mg Free Off-white solidA23L1T8 88% 200 mg free Yellow solidA24L1T12 95% 200 mg free Yellow solidA26L1T9 100% 200 mg free Yellow oilA28L1T4 87% 200 mg free Yellow solidA29L1T7 100% 200 mg free Yellow solidA35L1T5 98.36% 200 mg Free Brown solidA36L1T6 86.71% 200 mg Free Brown solidA2L1T2 100% 200 mg free Yellow oilA3L1T3 95.7% 200 mg free Yellow oilA8L1T8 92.2% 200 mg free Brown solidA7L1T7 96.9% 210 mg free Brown solidA16L1T1 94.3% 210 mg free Brown solidA18L1T3 96.69% 200 mg free Yellow oilA19L1T4 92.13% 200 mg free Yellow oilA20L1T3 86.01% 200 mg free Yellow oilA30L1T13 87.9% 200 mg free Yellow oilA31L1T14 91.9% 200 mg free Yellow oilA33L1T6 95.9% 200 mg free Yellow oil Table 3

[0316] By way of illustration, but not as limitation, examples below with preparation information illustrate the syntheses of the parent compounds and their derived moieties in a variety of Ai”Lj”Tk" and Ai”(ST)q(LT)p compounds that exemplify compounds of formulae (G1). Most of the lipids referred to in the tabular summary shown in Table C1 (parts 1 and 2) and elsewhere in the specification and drawings, with the designation described above and whose preparation is not described herein, were prepared according to synthesis methods analogous to those described below. Some of them have not yet actually been prepared, although synthesis schemes have been designed. Note that the full recitation of the synthesis of such compounds of formulae (G1) would be analogous to the synthesis recitations and schemes provided below for illustrative compounds of formulae (G1). Such cumulative information that may be generated with the teachings disclosed herein and the ordinary skill in the art is not provided here. Compounds that were synthesized, but whose syntheses are not presented herein explicitly, include compounds named in parts of this specification and drawings where physical, chemical and / or biochemical characteristics of such compounds are disclosed, either because they have been employed in standard experiments or tests referred to herein or because they have been used in tests or assays herein described (for example, compounds used to generate in vivo mRNA delivery test data presented below and in the drawings). See also general references on azide- alkyne click chemistry cited above, chemical reactions referred to above, and reactions explicitly set forth in the following Examples. Example AZ1

[0317] Azide Z1 is designated as azide T1 in Table 2. To a solution of compound 1 in this Example AZ1 (25 g, 117.89 mmol, 17.42 mL, 1 eq) in DMF (150 mL) was slowly added NaN3 (9.20 g, 141.46 mmol, 1.2 eq) in batches. The mixture was stirred at 60 °C for 2 h. TLC (Petroleum ether : Ethyl acetate=20:1, product Rf=0.58) showed reactant was used up. The reaction mixture was quenched by addition H2O 1000 mL at 20 °C and extracted with n-hexane 200 mL. The combined organic layers were washed with brine 300 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The aqueous phase was diluted 50 times, quenched with sodium hypochlorite, and left overnight, then discarded. Added 100 ml t- BuOH and concentrated in vacuum at 30 °C. Compound Z1 (46.4 g, 94.12 mmol, 79.84% yield, 25.8% purity) was obtained as colorless oil.12.0 g in a solution of t-BuOH (60 ml).1H NMR: (400 MHz, CDCl3) δ ppm 3.26 (t, J = 7.0 Hz, 2H), 1.60 (quin, J = 7.2 Hz, 2H), 1.34 - 1.28 (m, 6H), 0.93 - 0.86 (m, 3H). Example AZ2

[0318] Azide Z2 is designated as azide T2 in Table 2. To a solution of compound 1 in this Example AZ2 (20 g, 88.46 mmol, 1 eq) in DMF (120 mL) was added NaN3 (6.90 g, 106.15 mmol, 1.2 eq). The mixture was stirred at 60 °C for 2 h. TLC (Petroleum ether / Ethyl acetate = 1 / 0, product Rf = 0.55) showed compound 1 was used up. The reaction mixture was quenched by addition H2O 400 mL at 20 °C, and extracted with n-hexane 300 mL. The combined organic layers were washed with brine 200 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue and added t-BuOH (5V) to the residue. The extracted water was prepared into dilute aqueous solution with a ratio of more than 1:50 (aqueous phase: water). After cooling in ice bath, saturated sodium hypochlorite (NaClO) solution was slowlydropped into the solution under stirring. About 20 mL NaClO solution was needed to quench 1 g sodium azide, and the solution was left to stand overnight after stirring. The crude product was purified by silica gel chromatography eluted with PE / EtOAc = 1 / 0 to give product. Compound Z2 (45 g, 84.92 mmol, 83.48% yield, 26.65% purity) was obtained as colorless oil.12.0 g in a solution of t-BuOH (58 mL).1H NMR: (400 MHz CDCl3δ ppm 3.24 (t, J = 7.0 Hz, 2H), 1.64 - 1.55 (m, 2H), 1.52 (s, 7H), 1.26 (s, 47H), 0.93 - 0.83 (m, 3H). Example AZ3

[0319] Azide Z3 is designated as azide T3 in Table 2. To a solution of compound 1 in this Example AZ3 (21.6 g, 89.95 mmol, 1 eq) in DMF (130 mL) was added NaN3 (7.02 g, 107.94 mmol, 1.2 eq). The mixture was stirred at 60°C for 2 h. TLC(Petroleum ether : Ethyl acetate=20:1, Rf-sm=0.83, Rf-product= 0.5) showed reactant was used up. The reaction mixture was quenched by addition H2O 500 mL at 20 °C, and extracted with n-hexane 100*2 mL. The combined organic layers were washed with brine 300 mL, dried over Na2SO4, filtered under reduced pressure to give crude reaction mixture. The aqueous phase was diluted 50 times, quenched with sodium hypochlorite, and left overnight, then discarded. Compound Z3 (62.2 g, crude)（in t-BuOH） was obtained as colorless oil. The converted mass is about 11.3 g.1H NMR: (400 MHz CDCl3) δ ppm 3.21 (t, J = 6.9 Hz, 2H), 1.55 (quin, J = 7.1 Hz, 2H), 1.36 - 1.25 (m, 8H), 0.84 (t, J = 6.5 Hz, 5H). Example AZ4

[0320] Azide Z4 is designated as azide T4 in Table 2. To a solution of compound 1 in this Example AZ4 (20 g, 78.69 mmol, 1 eq) in DMF (120 mL) was added NaN3 (6.14 g, 94.43 mmol,1.2 eq). The mixture was stirred at 60°C for 2 h. TLC (Petroleum ether: Ethyl acetate=1:0, product Rf=0.45) indicated compound 1 was consumed completely. The reaction mixture was quenched by addition H2O 1000 mL at 20 °C and extracted with n-hexane 200 mL. The combined organic layers were washed with brine 300 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The aqueous phase was diluted 50 times, quenched with sodium hypochlorite, and left overnight, then discarded. The reaction mixture was extracted by adding t-BuOH (115 ml), reducing pressure and concentrating to get the product. Compound Z4 (50.1 g, 69.44 mmol, 76.73% yield, 23.46% purity).12.2 g in a solution of t-BuOH (64 ml) was obtained as a Brown oil.1H NMR: (400 MHz CDCl3)δ ppm 3.25 (br t, J = 6.5 Hz, 2H), 1.65 - 1.57 (m, 2H), 1.34 (br s, 6H), 0.97 - 0.78 (m, 3H). Example AZ5

[0321] Azide Z5 is designated as azide T5 in Table 2. To a solution of compound 1 in this Example AZ5 (20 g, 74.58 mmol, 1 eq) in DMF (120 mL) was slowly added NaN3 (5.82 g, 89.49 mmol, 1.2 eq) in batches. The mixture was stirred at 60 °C for 2 h. TLC (Petroleum ether : Ethyl acetate=20:1, product Rf=0.58) showed reactant was used up. The reaction mixture was quenched by addition H2O 300 mL at 20 °C and extracted with n-hexane 200 mL. The combined organic layers were washed with brine 300 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The aqueous phase was diluted 50 times, quenched with sodium hypochlorite, and left overnight, then discarded. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0). Compound Z5 (14.4 g, 78.56 mmol, 91.60% yield) was obtained as colorless oil.1H NMR: (400 MHz, CDCl3) δ ppm 3.26 (t, J = 7.0 Hz, 2H), 1.67 - 1.56 (m, 2H), 1.44 - 1.21 (m, 14H), 0.89 (t, J = 6.8 Hz, 3H). Example AZ6Example AZ6.1

[0322] To a solution of compound 1 in this Example AZ6 (54 g, 298.23 mmol, 39.02 mL, 1 eq) in THF (378 mL). The solution was then cooled to 0 °C, and NaH (14.31 g, 357.87 mmol, 60% purity, 1.2 eq) was added followed by BnBr (56.11 g, 328.05 mmol, 38.96 mL, 1.1 eq). The mixture was stirred at 20 °C for 12 h. TLC (Petroleum ether : Ethyl acetate=20:1, product Rf=0.5) showed reactant was used up. The reaction mixture was quenched by addition H2O 400 mL at 20 °C, and extracted with EtOAc 400 mL. The combined organic layers were washed with brine 50 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0~200 / 1). Compound 2 (54 g, 199.12 mmol, 66.77% yield) was obtained as colorless oil.1H NMR: (400 MHz, CDCl3) δ ppm 7.37 - 7.33 (m, 4H), 7.32 - 7.27 (m, 1H), 4.52 (s, 2H), 3.49 (t, J = 6.5 Hz, 2H), 3.42 (t, J = 6.8 Hz, 2H), 1.88 (quin, J = 6.9 Hz, 2H), 1.69 - 1.60 (m, 2H), 1.51 - 1.38 (m, 4H). Example AZ6.2

[0323] Compound 2 (66 g, 243.37 mmol, 1 eq) was dissolved in THF (462 mL). The solution was then cooled to 0 °C and a solution of [prepared from LiCl (1.24 g, 29.20 mmol, 598.69 μL, 0.12 eq) and CuCl2(1.96 g, 14.60 mmol, 0.06 eq) in THF (30 mL) was added followed by dropwise addition of bromo(isobutyl) magnesium (0.6 M, 608.42 mL, 1.5 eq). The solution was stirred at 0 °C for 1 h and then stirred at 20 °C for 11 h. TLC (Petroleum ether : Ethyl acetate=20:1, product Rf=0.41) showed reactant was used up. The reaction mixture was quenched by addition NH4Cl 600 mL at 20 °C, and extracted with EtOAc 600 mL. The combined organic layers were washed with brine 500 mL, dried over Na2SO4, filtered and concentratedunder reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0~100 / 1). Compound 3 (57 g, 229.47 mmol, 72.53% y 4 6

[0324] Compound 3 (57 g, 229.47 mmol, 1 eq) was dissolved in EtOH (500 mL). The solution was added Pd / C (5.70 g, 5.36 mmol, 10% purity, 2.33e-2 eq). The solution was stirred under 50 Psi at 25 °C for 12 h. TLC (Petroleum ether : Ethyl acetate=5:1, product Rf=0.25) showed reactant was used up. Reaction liquid filtration. The filter liquor was concentrated in vacuo. The filter cake is recycled to the corresponding recycling bucket The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0~200 / 1~50 / 1). Compound 4 (31 g, 195.86 mmol, 85.35% yield) was obtained as colorless oil.1H NMR: (400 MHz, CDCl3) δ ppm 3.70 - 3.60 (m, 2H), 1.63 - 1.47 (m, 3H), 1.40 - 1.22 (m, 9H), 1.20 - 1.11 (m, 2H), 0.87 (d, J = 6.7 Hz, 6H). Example AZ6.4

[0325] Compound 4 (30 g, 189.54 mmol, 1 eq) were dissolved in Tol. (300 mL) and imidazole (25.81 g, 379.07 mmol, 2 eq), molecular iodine (86.59 g, 341.17 mmol, 68.72 mL, 1.8 eq) and triphenylphosphane (99.43 g, 379.07 mmol, 2 eq) were slowly added to the solution. The reaction mixture was stirred for 12 h at 20 °C. TLC (Petroleum ether : Ethyl acetate=20:1, productRf=0.78) showed reactant was used up. The reaction mixture was quenched by addition Na2S2O3500 mL at 20 °C, and extracted with EtOAc 500 mL. The combined organic layers were washed with brine 500 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0). Compound 5 (31 g, 115.60 mmol, 60.99% yield) was obtained as colorless oil.1H NMR: (400 MHz, CDCl3) δ ppm 3.20 (t, J = 7.1 Hz, 2H), 1.83 (quin, J = 7.2 Hz, 2H), 1.59 - 1.46 (m, 1H), 1.44 - 1.35 (m, 2H), 1.34 - 1.23 (m, 6H), 1.16 (q, J = 6.7 Hz, 2H), 0.87 (d, J = 6.6 Hz, 6H). Example AZ6.5

[0326] Azide Z6 is designated as azide T6 in Table 2. To a solution of compound 5 (28 g, 104.41 mmol, 1 eq) in DMF (168 mL) was slowly added NaN3(8.15 g, 125.29 mmol, 1.2 eq) in batches. The mixture was stirred at 60 °C for 1 h. TLC (Petroleum ether : Ethyl acetate=20:1, product Rf=0.60) showed reactant was used up. The reaction mixture was quenched by addition H2O 1000 mL at 20 °C and extracted with n-hexane 200 mL. The combined organic layers were washed with brine 300 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The aqueous phase was diluted 50 times, quenched with sodium hypochlorite, and left overnight, then discarded. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0). Compound Z6 (16 g, 87.29 mmol, 76.01% yield) was obtained as colorless oil.1H NMR: (400 MHz, CDCl3) δ ppm 3.27 (t, J = 7.0 Hz, 2H), 1.67 - 1.46 (m, 3H), 1.42 - 1.24 (m, 8H), 1.16 (q, J = 6.7 Hz, 2H), 0.87 (d, J = 6.6 Hz, 6H). Example AZ7

[0327] Azide Z7 is designated as azide T7 in Table 2. To a solution of compound 1 in this Example AZ7 (20 g, 70.87 mmol, 1 eq) in DMF (120 mL) was added NaN3(5.53 g, 85.05 mmol, 1.2 eq).The mixture was stirred at 60 °C for 2 h. TLC (Petroleum ether / Ethyl acetate = 20 / 1, product Rf = 0.48) showed reactant was used up. The reaction mixture was quenched by addition H2O 400 mL at 20 °C, and extracted with n-hexane 300 mL. The combined organic layers were washed with brine 200 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The extracted water was prepared into dilute aqueous solution with a ratio of more than 1:50 (aqueous phase: water). After cooling in ice bath, saturated sodium hypochlorite (NaClO) solution was slowly dropped into the solution under stirring. About 200 mL NaClO solution was needed to quench 1 g sodium azide, and the solution was left to stand overnight after stirring. The crude product was purified by silica gel chromatography eluted with PE / EtOAc = 1 / 0. Compound Z7 (13.70 g, 69.43 mmol, 97.97% yield) was obtained as colorless oil.1H NMR: (400 MHz CDCl3)δ ppm 3.26 (t, J = 7.0 Hz, 2H), 1.42 - 1.20 (m, 18H), 0.89 (t, J = 6.8 Hz, 3H). Scheme AZ8

[0328] Azide Z8 is designated as azide T8 in Table 2. To a solution of compound 1 in this Example AZ8 (20 g, 67.52 mmol, 1 eq) in DMF (120 mL) was added NaN3 (5.27 g, 81.02 mmol, 1.2 eq). The mixture was stirred at 60 °C for 2 h. TLC (Petroleum ether / Ethyl acetate = 1 / 0, product Rf = 0.64) showed reactant was used up. The reaction mixture was quenched by addition H2O 400 mL at 20 °C, and extracted with n-hexane 300 mL. The combined organic layers were washed with brine 200 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The extracted water was prepared into dilute aqueous solution with a ratio of more than 1:50 (aqueous phase: water). After cooling in ice bath, saturated sodium hypochlorite (NaClO) solution was slowly dropped into the solution under stirring. About 200 mL NaClO solution was needed to quench 1 g sodium azide, and the solution was left to stand overnight after stirring. The crude product was purified by silica gel chromatography eluted with PE / EtOAc = 1 / 0 to give product. Compound Z8 (14.1 g, 66.72 mmol, 85.93% yield) was obtained as colorless oil.1H NMR: (400 MHz CDCl3)δ ppm 3.32 - 3.20 (m, 2H), 1.67 - 1.51 (m, 2H), 1.41 - 1.22 (m, 18H), 0.95 - 0.83 (m, 3H). Example AZ9 Example AZ9.1

[0329] To a solution of compound 1 in this Example AZ9.1 (23 g, 114.79 mmol, 1 eq) in toluene (230 mL), imidazole (8.61 g, 126.50 mmol, 1.10 eq), I2(52.44 g, 206.63 mmol, 41.62 mL, 1.8 eq), PPh3 (60.22 g, 229.59 mmol, 2 eq) were slowly added to the solution. The reaction mixture was stirred for 3 h at 20 °C. TLC (Petroleum ether / Ethyl acetate = 20 / 1, PMA, product Rf = 0.70) showed reactant was used up. The reaction mixture was diluted with saturated Na2S2O3solution (400 mL) and ethyl acetate (400 mL×3), the organic phases were extracted and washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (column height: 500 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether / Ethyl acetate=1 / 0 to 10 / 1). Compound 2 (37 g, 119.26 mmol, 95.57% yield) as colorless oil.1H NMR: (400 MHz, CDCl3) δ ppm 3.20 (t, J=7.09 Hz, 2 H) 1.83 (quin, J=7.15 Hz, 2 H) 1.36 - 1.45 (m, 2 H) 1.17 - 1.32 (m, 18 H) 0.89 (t, J=6.72 Hz, 3 H). Example AZ9.2

[0330] Azide Z9 is designated as azide T9 in Table 2. To a solution of compound 2 in this Example AZ9.2 (34 g, 109.59 mmol, 1 eq) in DMF (204 mL) was slowly added NaN3 (8.55 g, 131.50 mmol, 1.2 eq) in batches. The mixture was stirred at 60 °C for 2 h. TLC (Petroleum ether : Ethyl acetate=20:1, product Rf=0.50) showed reactant was used up. The reaction mixture was quenched by addition H2O 1000 mL at 20 °C and extracted with n-hexane 100*2 mL. The combined organic layers were washed with brine 300 mL, dried over Na2SO4, filtered andconcentrated under reduced pressure to give a residue. The aqueous phase was diluted 50 times, quenched with sodium hypochlorite, and left overnight, then discarded. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0). Compound Z9 (22 g, 97.62 mmol, 81.72% yield) was obtained as colorless oil.1H NMR: (400 MHz, CDCl3) δ ppm 3.26 (t, J = 7.0 Hz, 2H), 1.66 - 1.55 (m, 2H), 1.27 (s, 20H), 0.89 (t, J = 6.7 Hz, 3H). Example AZ10

[0331] Azide Z10 is designated as azide T10 in Table 2. To a solution of compound 1 in this Example AZ10 (20 g, 72.13 mmol, 21.51 mL, 1 eq) in DMF (120 mL) was added NaN3 (5.63 g, 86.55 mmol, 1.2 eq). The mixture was stirred at 60°C for 2 h. TLC (Petroleum ether: Ethyl acetate=1:0, product Rf=0.45) indicated compound 1 was consumed completely. The reaction mixture was quenched by addition H2O 1000 mL at 20 °C and extracted with n-hexane 200 mL. The combined organic layers were washed with brine 300 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The aqueous phase was diluted 50 times, quenched with sodium hypochlorite, and left overnight, then discarded. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0). Compound Z10 (13.74 g, 57.39 mmol, 79.57% yield) was obtained as a colorless oil.1H NMR: (400 MHz CDCl3)δ ppm 3.18 (t, J = 7.0 Hz, 2H), 1.53 (quin, J = 7.2 Hz, 2H), 1.31 - 1.17 (m, 22H), 0.87 - 0.74 (m, 3H). Example AZ11

[0332] Azide Z11 is designated as azide T11 in Table 2. To a solution of compound 1 in this Example AZ11 (20 g, 56.76 mmol, 1 eq) in DMF (120 mL) was added NaN3 (4.43 g, 68.12 mmol, 1.2 eq). The mixture was stirred at 60 °C for 2 h. TLC (Petroleum ether:Ethyl acetate=1:0, product Rf=0.45) indicated compound 1 was consumed completely. The reaction mixture was quenched by addition H2O 1000 mL at 20 °C and extracted with n-hexane 200 mL. The combined organic layers were washed with brine 300 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The aqueous phase was diluted 50 times, quenched with sodium hypochlorite, and left overnight, then discarded. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0). Compound Z11 (13.8 g, 51.64 mmol, 79.10% yield) was obtained as a colorless oil.1H NMR: (400 MHz CDCl3) δ ppm 3.33 - 3.21 (m, 2H), 1.72 - 1.53 (m, 2H), 1.29 (br s, 26H), 1.00 - 0.83 (m, 3H). Example AZ12 Example AZ12.1

[0333] Compound 1 in this Example AZ12.1 (20 g, 70.81 mmol, 20.00 mL, 1 eq) were dissolved in THF (140 mL) and added dropwise to a cooled suspension (0 °C) of LiAlH4(38.39 g, 106.21 mmol, 38.4 mL, 10.5% purity, 1.5 eq). The mixture was refluxed (60 °C) for 1 h and then stirred 16 h at 25 °C. TLC (Petroleum ether / Ethyl acetate = 5 / 1, product Rf = 0.51) showed reactant was used up. Dilute with appropriate amount of THF and cool to 0 °C, slowly add 4 mL water, add 4 mL sodium hydroxide solution of 15%, then add 12 mL water, heat up to room temperature and stir for 15 minutes, add some anhydrous MgSO4, stir for 15 minutes, filter and remove salt. The crude product was purified by silica gel chromatography eluted with PE: EtOAc=5:1 to give product as colorless oil. Compound 2 in this Example AZ12.1 (25 g, crude) was obtained as colorless oil.1H NMR: (400 MHz CDCl3)δ ppm 5.46 - 5.23 (m, 2H), 3.64 (t, J = 6.6 Hz, 2H), 2.12 - 1.95 (m, 4H), 1.64 - 1.49 (m, 2H), 1.46 - 1.07 (m, 22H), 0.98 - 0.79 (m, 3H). Example AZ12.2

[0334] Compound 2 in this Example AZ12.2 (25 g, 93.12 mmol, 1 eq) were dissolved in Tol. (175 mL) and imidazole (12.68 g, 186.24 mmol, 2 eq), I2 (42.54 g, 167.61 mmol, 33.76 mL,1.8 eq) and PPh3(48.85 g, 186.24 mmol, 2 eq) were slowly added to the solution. The reaction mixture was stirred for 2 hours at 20°C. TLC (Petroleum ether: Ethyl acetate = 5:1, product Rf = 0.9) showed reactant was used up. After addition of saturated Na2S2O3 solution (500 mL) and ethyl acetate (200 mL*3), the organic phases were extracted and washed with brine (300 mL). The organic phase was dried over MgSO4and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluted with PE: EtOAc = 1:0 to give product as colorless oil. Compound 3 in this Example AZ12.2 (17 g, 44.93 mmol, 44.27% yield) was obtained as colorless oil.1H NMR: (400 MHz CDCl3)δ ppm 5.36 (td, J = 2.9, 5.9 Hz, 2H), 3.20 (t, J = 7.0 Hz, 2H), 2.02 (br d, J = 6.0 Hz, 4H), 1.83 (s, 2H), 1.29 (br d, J = 11.3 Hz, 22H), 0.89 (s, 3H). Example AZ12.3

[0335] Azide Z12 is designated as azide T12 in Table 2. To a solution of compound 3 in this Example AZ12.3 (13 g, 34.36 mmol, 1 eq) in DMF (78 mL) was added NaN3(2.68 g, 41.23 mmol, 1.2 eq). The mixture was stirred at 60 °C for 2 h. TLC (Petroleum ether: Ethyl acetate = 1:0, product Rf = 0.24) showed a new signal point is generated and a small amount of reactant is left. The reaction mixture was quenched by addition H2O 400 mL at 20 °C, and extracted with n- hexane 300 mL. The combined organic layers were washed with brine 300 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The extracted water was prepared into dilute aqueous solution with a ratio of more than 1:50 (aqueous phase: water). After cooling in ice bath, saturated sodium hypochlorite (NaClO) solution was slowly dropped into the solution under stirring. About 20 mL NaClO solution was needed to quench 1 g sodium azide, and the solution was left to stand overnight after stirring. The crude product was purified by silica gel chromatography eluted with PE: EtOAc=1:0 to give product as colorless oil. Compound Z12 (10 g, 34.07 mmol, 99.17% yield) was obtained as colorless oil.1H NMR: (400 MHz CDCl3)δ ppm 5.36 (ddd, J = 2.6, 3.3, 5.8 Hz, 2H), 3.26 (t, J = 7.0 Hz, 2H), 2.12 - 1.94 (m, 4H), 1.67 - 1.54 (m, 2H), 1.30 (br d, J = 13.6 Hz, 22H), 0.93 - 0.85 (m, 3H).Example AZ13 Example AZ13.1

[0336] To a solution of compound 1 in this Example AZ13.1 (25 g, 93.82 mmol, 1 eq) were dissolved in toluene (250 mL) and imidazole (12.77 g, 187.65 mmol, 2 eq), I2(42.86 g, 168.88 mmol, 34.02 mL, 1.8 eq) and PPh3(49.22 g, 187.65 mmol, 2 eq) were slowly added to the solution. The reaction mixture was stirred for 3h at 20 °C. TLC (Petroleum ether / Ethyl acetate=1 / 0, phosphomolybdic acid, product Rf=0.55) showed product formation and reactant was used up. TLC showed that the reaction was over. After addition of saturated Na2S2O3solution, the aqueous phase was extracted with EA (250 mL*3). The combined organic phase was washed with brine (250 mL*2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (column height: 500 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether / Ethyl acetate=1 / 0 to 1 / 1). Compound 2 in this Example AZ13.1 (31 g, 82.37 mmol, 87.79% yield) was obtained as colorless oil.1H NMR: (400 MHz CDCl3) δ ppm 5.44 - 5.30 (m, 4H), 3.20 (t, J = 7.0 Hz, 2H), 2.78 (t, J = 6.4 Hz, 2H), 2.06 (q, J = 7.0 Hz, 4H), 1.88 - 1.79 (m, 2H), 1.39 - 1.26 (m, 16H), 0.90 (t, J = 6.8 Hz, 3H). Example AZ13.2

[0337] Azide Z13 is designated as azide T13 in Table 2. To a solution of compound 2 in this Example AZ13.2 (27 g, 71.74 mmol, 1 eq) in DMF (162 mL) was added NaN3(5.60 g, 86.09 mmol, 1.2 eq). The mixture was stirred at 60°C for 2 h. TLC (Petroleum ether: Ethyl acetate=1:0, product Rf=0.45) indicated compound 2 was consumed completely. The reaction mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0). Compound Z13 (15.77 g, 54.10 mmol, 67.94% yield), was obtained as a colorless oil1H NMR: (400 MHz CDCl3)δ ppm 5.42 - 5.19 (m, 4H), 3.19 (t, J = 6.9 Hz, 2H), 2.71 (t, J = 6.4 Hz, 2H), 1.98 (q, J = 6.7 Hz, 4H), 1.58 - 1.45 (m, 2H), 1.33 - 1.19 (m, 16H), 0.82 (t, J = 6.7 Hz, 3H).Example AZ14 Example AZ14.1

[0338] To a solution of compound 1 in this Example AZ14.1 (20 g, 116.07 mmol, 1 eq) in DCM (280 mL) was added EDCI (26.70 g, 139.29 mmol, 1.2 eq), DMAP (21.27 g, 174.11 mmol, 1.5 eq) and compound 2 (24.90 g, 127.68 mmol, 1.1 eq) were added in batches and stirred at 20 °C for 16 h. TLC (Petroleum ether / Ethyl acetate =20 / 1,DNP, product: Rf = 0.49) indicated compound 1 was consumed completely. The reaction mixture was diluted with water (275 mL), acidified with 2M hydrochloric acid (125 mL) and extracted with DCM (400 mL). The organic phase was extracted and washed with brine and dried over Na2SO4. The organic phase was concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography (column height: 250 mm, diameter: 60 mm, 100 - 200 mesh silica gel, Petroleum ether / Ethyl acetate= 200 / 1 to 50 / 1). Compound 3 in this AZ14.1 (33.7 g, 96.47 mmol, 66.49% yield) as colorless oil.1H NMR: (400 MHz CDCl3)δ ppm 0.87 - 0.98 (m, 6 H) 1.15 - 1.33 (m, 12 H) 1.44 - 1.54 (m, 6 H) 1.67 (quin, J=7.57 Hz, 2 H) 1.74 - 2.06 (m, 2 H) 2.32 (t, J=7.38 Hz, 2 H) 3.29 - 3.62 (m, 2 H) 4.88 (quin, J=6.25 Hz, 1 H). Example AZ14.2

[0339] Azide Z14 is designated as azide T14 in Table 2. To a solution of compound 3 in this Example AZ14.2 (28.5 g, 81.58 mmol, 1 eq) in DMF (170 mL) was added NaN3 (6.36 g, 97.90 mmol, 1.2 eq). The mixture was stirred at 60 °C for 16 h. TLC (Petroleum ether : Ethyl acetate=20:1, Rf-sm =0.5, Rf-product = 0.44) showed reactant was used up. The reaction mixture wasquenched by addition H2O 500 mL at 20 °C, and extracted with n-hexane 100*2 mL. The combined organic layers were washed with brine 200 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The aqueous phase was diluted 50 times, quenched with sodium hypochlorite, and left overnight, then discarded. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1:0-100:1). Compound Z14 (26.1 g, 83.80 mmol, 92.54% yield) was obtained as colorless oil.1H NMR: (400 MHz, CDCl3) δ ppm 4.87 (quin, J = 6.3 Hz, 1H), 3.27 (t, J = 6.9 Hz, 2H), 2.30 (t, J = 7.4 Hz, 2H), 1.71 - 1.58 (m, 4H), 1.56 - 1.47 (m, 4H), 1.46 - 1.37 (m, 2H), 1.34 - 1.23 (m, 12H), 0.90 - 0.86 (m, 6H). Example AZ15 Example AZ15.1

[0340] Compound 1 in this Example AZ15.1 (20 g, 77.98 mmol, 1 eq) was dissolved in DCM (280 mL) , stirred at 20 °C , and EDCI (17.94 g, 93.58 mmol, 1.2 eq), DMAP (14.29 g, 116.97 mmol, 1.5 eq) and Compound 2 in this Example AZ15.1 (16.73 g, 85.78 mmol, 1.1 eq) were added to the reaction system in batches and stirred at 20 °C for 12h. TLC (Petroleum ether / Ethyl acetate=20 / 1, phosphomolybdic acid, product Rf = 0.4) showed product formation and a small amount of reactants remaining. TLC showed that the reaction was over, acidified with 2M hydrochloric (75 mL 2M hydrochloric and 425 mL H2O) acid, The aqueous phase was extracted with DCM (280 mL*2).The combined organic phase was washed with brine (280 mL*2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (column height: 500 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether / Ethyl acetate=200 / 1 to 40 / 1). Compound 3 in this Example AZ15.1 (30 g, 69.20 mmol, 88.74% yield) was obtained as colorless oil.1HNMR: (400 MHz CDCl3) δ ppm 4.87 (t, J = 6.2 Hz, 1H), 3.41 (t, J = 6.8 Hz, 2H), 2.34 - 2.28 (m, 2H), 1.88 (s, 2H), 1.70 - 1.62 (m, 2H), 1.53 - 1.47 (m, 5H), 1.34 - 1.19 (m, 27H), 0.88 (s, 4H). Example AZ15.2

[0341] Azide Z15 is designated as azide T15 in Table 2. To a solution of compound 3 in this Example AZ15.2 (28 g, 64.59 mmol, 1 eq) in DMF (198 mL) was slowly added NaN3 (5.04 g, 77.51 mmol, 1.2 eq) in batches. The mixture was stirred at 60 °C for 2 h. TLC (Petroleum ether : Ethyl acetate=20:1, product Rf=0.49) showed reactant was used up. The reaction mixture was quenched by addition H2O 1000 mL at 20 °C and extracted with n-hexane 200 mL. The combined organic layers were washed with brine 300 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The aqueous phase was diluted 50 times, quenched with sodium hypochlorite, and left overnight, then discarded. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0). Compound Z15 (26.9 g, 67.99 mmol, 81.95% yield) was obtained as colorless oil.1H NMR: (400 MHz, CDCl3) δ ppm10.03 (s, 1 H), 8.58 (br d, J = 7.60 Hz, 1 H), 7.46 (br d, J = 8.40 Hz, 1 H), 7.23 - 7.35 (m, 4 H), 7.05 - 7.20 (m, 5 H), 6.85 (br d, J = 8.00 Hz, 1 H), 6.12 (dd, J = 10.0, 1.69 Hz, 1 H), 5.88 (s, 1 H), 5.37 (s, 1 H), 4.90 (br s, 1 H), 4.62 (br d, J = 3.20 Hz, 2 H), 4.29 - 4.40 (m, 1 H), 4.23 (br s, 1 H), 4.10 (s, 2 H), 3.84 (s, 2 H), 2.18 - 2.33 (m, 4 H), 1.77 - 2.16 (m, 5 H), 1.55 - 1.75 (m, 6 H), 1.39 (s, 3 H), 0.88 (s, 4 H). Example A30L1

[0342] This compound (A30L1: 9-(3-(dimethylamino)propyl)-8,12-dioxo-7,13-dioxa-3,4- dithia-9-azaheptadec-16-yn-1-yl nonanoate) was prepared according to the following scheme:Compound “Inter A” was also used in the synthesis of compounds A31L1, A32L1, A33L1 and A34L1. Example A30L1T15

[0343] To a solution of A30L1 (2.35 g, 4.30 mmol, 1.00 eq) in t-BuOH (20 mL) and H2O (20 mL) was added Cu(OAc)2(780 mg, 4.30 mmol, 1.0 eq) and L(+) sodium ascorbate (CAS: 134-03-2 mg, 852 mg, 4.30 mmol, 1.00 eq), T15 (2.55 g, 6.45 mmol, 1.50 eq) was added into the mixture and stirred at 25°C for 2 hrs. TLC (DCM : MeOH = 10 : 1, product: Rf = 0.4) showed the starting material was consumed completely. The suspension was filtered and the filtrate was diluted with H2O (100 mL) and extracted with ethyl acetate (100 mL*3). The combined organic layers were washed with brine (30 mL*2), dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate to DCM: MeOH = 3:1 to 10:1). Then crude product was purified by semi-preparative reverse phase HPLC (column: C1250×80mm, 10μm; mobile phase: [water (TFA)-ACN]; gradient: 65%-95% B over 25 min). The collected fraction was concentrated to remove acetonitrile, and extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with brine (20 mL*2), dried over Na2SO4, filtered and concentrated to give product. A30L1T15 (9-(3-(dimethylamino)propyl)-15-(1-(6-(heptadecan-9-yloxy)-6-oxohexyl)-1H-1,2,3- triazol-4-yl)-8,12-dioxo-7,13-dioxa-3,4-dithia-9-azapentadecyl nonanoate, 600 mg, 636.67 μmol, 14.81% yield) was obtained as a yellow oil.1H NMR (400 MHz CDCl3): δ 7.39 (br s, 1H), 4.86 (t, J = 6.4 Hz, 1H), 4.39 - 4.30 (m, 8H), 3.56 - 3.49 (m, 2H), 3.29 (br s, 2H), 3.07 (t, J = 6.4 Hz, 2H), 2.98 - 2.88 (m, 4H), 2.61 (m, 2H), 2.37 - 2.25 (m, 12H), 1.93 (m, 3H), 1.76 (m, 2H), 1.65 (dt, J = 7.2, 14.8 Hz, 4H), 1.50 (br d, J = 5.6 Hz, 4H), 1.44 - 1.35 (m, 3H), 1.26 (br s, 32H), 0.88 (t, J = 6.8 Hz, 9H). Example A31L1

[0344] This compound (A31L1: heptyl 4-((4-((3-(but-3-yn-1-yloxy)-3-oxopropyl)(3- (dimethylamino)propyl)amino)-4-oxobutyl)disulfaneyl)butanoate) was prepared according to the following scheme:Example A32L1

[0345] This compound (A32L1: nonyl 8-((3-(but-3-yn-1-yloxy)-3-oxopropyl)(3- (dimethylamino)propyl)amino)octanoate) was prepared according to the following scheme:Example A33L1

[0346] This compound (A33L1: 8-((3-(but-3-yn-1-yloxy)-3-oxopropyl)(3- (dimethylamino)propyl)amino)octyl nonanoate) was prepared according to the following scheme:Example A34L1A34L1: nonyl 8-((3-(but-3-yn-1-yloxy)-3-oxopropyl)(3- (dimethylamino)propyl)amino)-8-oxooctanoate Example A2L1T2

[0347] To a solution of compound T2 (220 mg, 1.56 mmol, 4.5 eq) in t-BuOH (2.0 mL), H2O (2.0 mL) was added VCNa (68.7 mg, 347 μmol, 1.0 eq) and Cu(OAc)2 (63.0 mg, 347 μmol, 1.0 eq), compound A2L1 (0.25 g, 347 μmol, 1.0 eq) .The mixture was stirred at 20 °C for 12h. TLC (Dichloromethane: Methanol = 10: 1, product Rf= 0.43) showed reactant was used up. The suspension was filtered through a pad of Celite and the filter cake was washed with DCM (50 mL), the organic phase was washed with (15, 5.0 mL) (0.1M EDTA, CH3COONa, pH = 5). The organic phase was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Without purification. Compound A2L1T2 (tetrakis(2-(1-heptyl-1H-1,2,3- triazol-4-yl)ethyl) 3,3',3'',3'''-(((1,4-phenylenebis(oxy))bis(propane-3,1- diyl))bis(azanetriyl))tetrapropionate, 0.2 g, 156 μmol, 44.9% yield) was obtained as yellow oil. Example A3L1T3tetrakis(2-(1-octyl-1H-1,2,3-triazol-4-yl)ethyl) 3,3',3'',3'''-(((methylazanediyl)bis(propane-3,1- diyl))bis(azanetriyl))tetrapropionate

[0348] To a solution of compound A3L1 (0.25 g, 390 μmol, 1.0 eq) in t-BuOH (2 mL), H2O (2 mL) was added VCNa (77.2 mg, 390 μmol, 1.0 eq) and Cu(OAc)2(70.8 mg, 390 μmol, 1.0 eq), compound T3 (302 mg, 1.95 mmol, 5.0 eq). The mixture was stirred at 20 °C for 12h. TLC (Dichloromethane: Methanol = 10: 1, product Rf = 0.43) showed reactant was used up. The suspension was filtered through a pad of Celite and the filter cake was washed with DCM (50 mL), the organic phase was washed with (15, 5 mL)(0.1M EDTA, CH3COONa, pH = 5) and then washed with saturated NaHCO3(10 mL). The organic phase was separated,dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Without purification. Compound A3L1T3 (0.2 g, 158 μmol, 40.7% yield) was obtained as yellow oil.Example A8L1T8

[0349] To a solution of compound A8L1 (0.2 g, 275 μmol, 1.0 eq) in t-BuOH (2.0 mL), H2O (2.0 mL) was added VCNa (54.5 mg, 275 μmol, 1.0 eq) and Cu(OAc)2 (50.0 mg, 275 μmol, 1.0 eq), compound T8 (291 mg, 1.38 mmol, 5.0 eq). The mixture was stirred at 20 °C for 12h. TLC (Dichloromethane: Methanol = 10: 1, product Rf= 0.43) showed reactant was used up. The suspension was filtered through a pad of Celite and the filter cake was washed with DCM (50 mL), the organic phase was washed with (15, 5.0 mL) (0.1M EDTA, CH3COONa, pH = 5) and then washed with saturated NaHCO3 (10 mL). The organic phase was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Without purification. Compound A8L1T8 (tetrakis(2-(1-dodecyl-1H-1,2,3-triazol-4-yl)ethyl) 3,3',3'',3'''-(((((trans)- cyclohexane-1,4-diyl)bis(oxy))bis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate, 0.2 g, 127μmol, 46.2% yield) was obtained as a brown solid. Example A1L1

[0350] To a solution of A1 (3 g, 19.70 mmol, 1 eq) in t-BuOH (18 mL) was added L1 (15.90 g, 128.05 mmol, 6.5 eq). The mixture was stirred at 90 °C for 24 h. TLC(Dichloromethane : Methanol=10:1, product Rf=0.64) showed the raw material response to complete. The mixture was evaporated to dryness. The residue was purified by column chromatography (product Rf = 0.61) (SiO2, Dichloromethane: Methanol=100 / 1 to 10 / 1). A1L1 (tetra(but-3-yn-1-yl) 3,3',3'',3'''-((disulfanediylbis(ethane-2,1-diyl))bis(azanetriyl))tetrapropionate, 4.5 g, 6.94 mmol, 35.21% yield) was obtained as yellow oil.1H NMR: 400 MHz CDCl3 δ 4.19 (t, J = 6.8 Hz, 8H), 2.71 - 2.88 (m, 16H), 2.44 - 2.59 (m, 16H), 2.03 (t, J = 2.6 Hz, 4H). Example A1L1T1

[0351] To a solution of A1L1 (300 mg, 462.37 μmol, 1 eq) in t-BuOH (2 mL), H2O (2 mL) was added VcONa (91.60 mg, 462.37 μmol, 1 eq), Cu(OAc)2 (83.98 mg, 462.37 μmol, 1 eq) and T1 (294.04 mg, 2.31 mmol, 5 eq). The mixture was stirred at 20 °C for 12 h. TLC (Dichloromethane: Methanol = 10:1, product Rf = 0.43) showed the raw material response to complete. The suspension was filtered through a pad of Celite and the filter cake was washed with DCM (15 mL). The organic phase was separated, washed with brine 5 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was dissolved in EtOAc (10 mL), then 20 mL (0.1M EDTA, CH3COONa, pH=5) was added, the mixture was stirred at 20 °C for 10 min. The organic phase was separated, washed with NaHCO320 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Without purification. A1L1T1 (tetrakis(2-(1-hexyl-1H-1,2,3-triazol-4-yl)ethyl) 3,3',3'',3'''- ((disulfanediylbis(ethane-2,1-diyl))bis(azanetriyl))tetrapropionate, 220 mg, 190.05 μmol, 41.10% yield, 100% purity) was obtained as yellow oil. Example A4L1

[0352] To a solution of A4 (3 g, 20.65 mmol, 1 eq) in t-BuOH (15 mL) was added L1 (16.67 g, 134.26 mmol, 6.5 eq). The mixture was stirred at 90 °C for 24 h. TLC (Dichloromethane: Methanol = 10:1, product Rf = 0.48) showed the raw material response to complete. The mixture was evaporated to dryness. The residue was purified by column chromatography (product Rf = 0.48) (SiO2, Dichloromethane: Methanol=100 / 1 to 10 / 1). A4L1 (di(but-3-yn-1-yl) 3,3'-((3-((4-(bis(3-(but-3-yn-1-yloxy)-3-oxopropyl)amino)butyl)(3-(but-3-yn-1- yloxy)-3-oxopropyl)amino)propyl)azanediyl)dipropionate, 4.5 g, 5.88 mmol, 28.44% yield) was obtained as yellow oil.1H NMR: 400 MHz CDCl3 δ 4.18 (t, J = 6.8 Hz, 10H), 2.77 (t, J = 7.2 Hz, 10H), 2.34 - 2.59 (m, 28H), 2.02 (t, J = 2.6 Hz, 5H), 1.55 (quin, J = 7.1 Hz, 2H), 1.33 - 1.44 (m, 4H). Example A4L1T4

[0353] To a solution of A4L1 (300 mg, 391.68 μmol, 1 eq) in t-BuOH (2 mL), H2O (2 mL) was added VcONa (77.59 mg, 391.68 μmol, 1 eq), Cu(OAc)2 (71.14 mg, 391.68 μmol, 1 eq) and T4 (397.79 mg, 2.35 mmol, 6 eq). The mixture was stirred at 20 °C for 12 h. TLC (Dichloromethane: Methanol = 10:1, product Rf = 0.43) showed the raw material response to complete. The suspension was filtered through a pad of Celite and the filter cake was washed with DCM (15 mL). The organic phase was separated, washed with brine 5 mL. The organic phase was separated then 20 mL (0.1M EDTA, CH3COONa, pH=5) was added, the mixture was stirred at 20 °C for 20 min. The organic phase was separated, washed with NaHCO320 mL, driedover Na2SO4, filtered and concentrated under reduced pressure to give a residue. Without purification. A4L1T4 (bis(2-(1-nonyl-1H-1,2,3-triazol-4-yl)ethyl) 3,3'-((3-((4-(bis(3-(2-(1-nonyl- 1H-1,2,3-triazol-4-yl)ethoxy)-3-oxopropyl)amino)butyl)(3-(2-(1-nonyl-1H-1,2,3-triazol-4- yl)ethoxy)-3-oxopropyl)amino)propyl)azanediyl)dipropionate, 0.22 g, 136.45 μmol, 34.84% yield, 100% purity) was obtained as a brown solid. Example A5L1

[0354] To a solution of compound A5 (3.00 g, 14.98 mmol, 1.00 eq) in t-BuOH (18 mL) was added compound L1 (11.1 g, 89.85 mmol, 6.00 eq). The mixture was stirred at 90 °C for 24 hours. LCMS showed the reactant A5 was consumed and one main peak was detected. The reaction mixture was concentrated under reduced pressure to give residue. The residue was purified by flash silica gel column chromatography (5 - 10% methanol in dichloromethane) to give the product. Compound A5L1 (tetra(but-3-yn-1-yl) 3,3',3'',3'''-((piperazine-1,4- diylbis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate, 7.5 g, 10.76 mmol, 71.87% yield) was obtained as a yellow oil. LCMS: Rt = 0.266, mas spectrum M + H = 349.5, 100%. Example A5L1T5

[0355] To a solution of A5L1 (300 mg, 430.50 μmol, 1 eq) in t-BuOH (3 mL), H2O (3 mL) was added VcONa (85.28 mg, 430.50 μmol, 1 eq), Cu(OAc)2 (78.19 mg, 430.50 μmol, 1 eq) and T5 (394.53 mg, 2.15 mmol, 5 eq). The mixture was stirred at 20 °C for 12 h. TLC (Dichloromethane: Methanol = 10:1, product Rf= 0.43) showed the raw material response to complete. The suspension was filtered through a pad of Celite and the filter cake was washed with DCM (15 mL). The organic phase was separated, washed with brine 5 mL. The organic phase was separated then 20 mL (0.1M EDTA, CH3COONa, pH=5) was added, the mixture was stirred at 20 °C for 20 min. The organic phase was separated, washed with NaHCO320 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Withoutpurification. A5L1T5 (tetrakis(2-(1-decyl-1H-1,2,3-triazol-4-yl)ethyl) 3,3',3'',3'''-((piperazine- 1,4-diylbis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate, 0.22 g, 126.15 μmol, 29.30% yield, 82% purity) was obtained as a yellow solid. Example A5L1T15

[0356] To a solution of A5L1 (3.00 g, 4.30 mmol, 1.00 eq), compound T15 (9.37 g, 23.6 mmol, 5.50 eq) in t-BuOH (30 mL), H2O (30 mL) was added L (+) sodium ascorbate (CAS: 134- 03-2, 852 mg, 4.30 mmol, 1.00 eq) and Cu(OAc)2 (781 mg, 4.30 mmol, 1.0 eq) at 25°C. The mixture was stirred at 25 °C for 12 hours. LCMS showed the reactant A5L1 was consumed and one main peak was detected. The reaction mixture was diluted with water (100 mL) and was extracted with ethyl acetate (100 mL× 3). The combined organic layers were washed by brine anddried over sodium sulfate. Then the mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel column chromatography (5 - 7% methanol in dichloromethane) to give the product (Dichloro methane: Methanol = 10:1, Rf = 0.4). Compound A5L1T15 (3.2 g, 1.30 mmol, 30.20% yield, 92.6% purity) was obtained as a yellow oil. LCMS: Rt= 0.585, 1 / 3(M + H) = 760.8, 92% purity.1H NMR: (400 MHz, CHLOROFORM-d) δ：7.39 (s, 4H), 4.96 - 4.80 (m, 4H), 4.42 - 4.27 (m, 16H), 3.06 (t, J = 6.6 Hz, 8H), 2.75 (t, J = 6.6 Hz, 8H), 2.44 (d, J = 5.6 Hz, 16H), 2.30 (t, J = 7.2 Hz, 12H), 1.93 ( t, J = 7.6 Hz, 8H), 1.73 - 1.63 (m, 12H), 1.51 (d, J = 4.8 Hz, 16H), 1.42 - 1.36 (m, 8H), 1.26 (s, 100H), 0.96 - 0.80 (m, 24H). Example A34_3

[0357] To a solution of A34_1 (5 g, 34.6 mmol, 1 eq) and A34_2 (18.1 g, 103 mmol, 3 eq) in DCM (30 mL) was added EDCI (9.97 g, 51.9 mmol, 1.5 eq) and DMAP (2.12 g, 17.3 mmol, 0.5 eq). The mixture was stirred at 20 °C for 12h. TLC (Petroleum ether: Ethyl acetate = 5:1, product Rf= 0.43) showed the raw material response to complete. The residue was diluted with H2O 100 mL and extracted with DCM 200 mL. Dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=100 / 1 to 20 / 1. A34_3 (8 g, 26.63 mmol, 76.82% yield) was obtained as a white solid. Example A34L1

[0358] To a solution of A34_3 (5.84 g, 19.44 mmol, 1.1 eq) in DCM (24 mL) was added EDCI (4.07 g, 21.21 mmol, 1.2 eq) and HOBt (2.87 g, 21.21 mmol, 1.2 eq) and DIEA (4.57 g, 35.35 mmol, 6.16 mL, 2 eq). The mixture was stirred for 10 min. B1 (4 g, 17.67 mmol, 1 eq) was added to the mixture and the mixture was stirred at 25 °C for 12 h. TLC (Dichloromethane: Methanol = 10:1, product Rf = 0.33) showed the raw material response to complete. The residue was diluted with H2O 100 mL and extracted with DCM 250 mL. The combined organic layers were washed with NaHCO3100 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol=100 / 1 to 20 / 1). A34L1 (nonyl 8-((3-(but-3- yn-1-yloxy)-3-oxopropyl)(3-(dimethylamino)propyl)amino)-8-oxooctanoate, 5.0 g, 8.89 mmol, 50.32% yield, 90.5% purity) was obtained as yellow oil. Example A34L1T4

[0359] A 40 mL glass bottle equipped with magnetic stirrer, to a solution of A34L1 (0.35 g, 619.19 μmol, 1 eq) in t-BuOH (1.7 mL) and H2O (1.7 mL) was added VcONa (122.66 mg,619.19 μmol, 1eq), Cu(OAc)2 (112.46 mg, 619.19 μmol, 1 eq) and T4 (480.37 mg, 681.11 μmol, 1.1 eq). The resulting mixture was stirred at 20 °C for 12 h. TLC (Dichloromethane: Methanol = 10:1, Rf=0.02) showed the starting material was consumed completely. The suspension was filtered through a pad of Celite and the filter cake was washed with DCM (15 mL). The organic phase was separated, washed with brine 10 mL , dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue.0.1 M EDTA : 2.92 g EDTA dissolved in 100 mL water and added about 3.25 g sodium acetate to adjust pH=5. The crude product was dissolved in EtOAc (5 mL), then 0.1M EDTA (10 mL) was added, the mixture was stirred at 20 °C for 5 min. The organic phase was separated, repeat the above steps three times, until the water phase becomes colorless, washed with NaHCO3 solution (10 mL×2). The organic phase dried over Na2SO4, filtered and concentrated under reduced pressure to give product. A34L1T4 (nonyl 8- ((3-(dimethylamino)propyl)(3-(2-(1-nonyl-1H-1,2,3-triazol-4-yl)ethoxy)-3-oxopropyl)amino)-8- oxooctanoate, 200 mg, 294.99 μmol, 47.64% yield) as brown oil. Example A11L1T11

[0360] To a solution of compound A11L1 (0.15 g, 192 mmol, 1.0 eq) in t-BuOH (1.00 mL) and H2O (1.00 mL) was added compound T11 (205 mg, 768 μmol, 4.0 eq) Sodium L-Ascorbate (38.0 mg, 192 μmol, 1.0 eq) and CuAc2(34.8 mg, 192 μmol, 1.0 eq) at 20 °C. The solution was stirred at 25 °C for 12 h. TLC (dichloromethane : methanol = 10 : 1, the starting material: Rf = 0.50, product: Rf = 0.48) showed the reaction was completed. The suspension was filtered through a pad of Celite and the filter cake was washed with DCM (15.0 mL). The organic phase was separated, washed with brine 5.00 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was dissolved in EtOAc (10.0 mL), THF (2.00 mL), then 20.0 mL (0.1M EDTA, AcONa, pH = 5) was added, the mixture was stirred at 25 °C for 30 min. The organic phase was separated, washed with brine 5.00 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give the A11L1T11 (tetrakis(2-(1- hexadecyl-1H-1,2,3-triazol-4-yl)ethyl) 3,3',3'',3'''-(((((trans)-cyclohexane-1,4- diyl)bis(azanediyl))bis(4-oxobutane-4,1-diyl))bis(azanetriyl))tetrapropionate, 108 μmol, 56.2% yield, 100% purity) as a off-white solid. Example A26L1T9

[0361] To a solution of A26L1 (0.15 g, 384 μmol, 1.0 eq) in t-BuOH (1.5 mL) H2O (1.5 mL) was added sodium ascorbate (76.0 mg, 384 μmol, 1.0 eq), diacetoxycopper (69.7 mg, 384 μmol, 1.0 eq) and T9 (176 mg, 960 μmol, 2.5 eq) at 25 °C. The mixture was stirred at 25 °C for 12 h. TLC (Dichloromethane / Methanol = 10 / 1, Product / Rf= 0.5, material / Rf= 0.3) showed thereaction was completely. The suspension was filtered through a pad of Celite and the filter cake was washed with DCM (15 mL), The organic phase was separated, washed with brine 5 mL, dried over Na2SO4, filtered and concentrated under vacuum to give a residue. The crude product was dissolved in EtOAc (10 mL) and THF (2 mL), then 20 mL(0.1M EDTA,CH3COONa, pH=5) was added to the mixture, the mixture was stirred at 25 °C for 30 min. The mixture was washed with NaHCO3 (5 ml). The organic phase was separated, washed with brine (5 mL), dried over Na2SO4, filtered and concentrated under vacuum to give A26L1T9 (bis(2-(1-tridecyl-1H-1,2,3-triazol-4- yl)ethyl) 3,3'-((3-(piperidin-1-yl)propyl)azanediyl)dipropionate, 0.2 g, 264 μmol, 68.8% yield) as yellow oil. Example A6L1T2

[0362] To a solution of compound A6L1 (0.2 g, 265 μmol, 1.0 eq) in H2O (1 ml), t-BuOH (1 ml) was added VcNa (52.62 mg, 265.61 μmol l, 1.0 eq), Cu(OAc)2(48.2 mg, 265.6 μmol, 1.0 eq) and compound T2 (225 mg, 1.59 mmol, 6.0 eq). The mixture was stirred at 25oC for 12 h. TLC (Dichloromethane / Methanol = 10 / 1, Rf = 0.31) showed reactant was used up. The suspension was filtered through a pad of Celite and the filter cake was washed with DCM (15 ml). The organic phase was separated, washed with brine 5 ml, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was dissolved in EtOAc (10 ml), THF (2 ml), then 20 ml (0.1 M EDTA,CH3COONa, pH=5) was added, the mixture was stirred at 25oC for 30 min. The organic phase was separated, washed withNaHCO3.aq 10 ml, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Compound A6L1T2 (tetrakis(2-(1-heptyl-1H-1,2,3-triazol-5-yl)ethyl) 3,3',3'',3'''- ((((trans)-2,5-dimethylpiperazine-1,4-diyl)bis(butane-4,1-diyl))bis(azanetriyl))tetrapropionate, 0.2 g, 151 μmol, 57.1% yield) was obtained as a yellow solid. Example A12L1T2

[0363] To a solution of A12L1 (0.3 g, 384 μmol, 1.0 eq) in t-BuOH (1.5 mL) H2O (1.5 mL) was added sodium ascorbate (76.0 mg, 384 μmol, 1.0 eq), diacetoxycopper (69.7 mg, 384 μmol, 1.0 eq) and T2 (244 mg, 1.7 mmol, 4.5 eq) at 25 °C. The mixture was stirred at 25 °C for 12 h. TLC (Dichloromethane / Methanol = 10 / 1, Product / Rf= 0.5, material / Rf= 0.3) showed thereaction was completely. The suspension was filtered through a pad of Celite and the filter cake was washed with DCM (15 mL), The organic phase was separated, washed with brine 5 mL, dried over Na2SO4, filtered and concentrated under vacuum to give a residue. The crude product was dissolved in EtOAc (10 mL) and THF (2 mL), then 20 mL (0.1M EDTA,CH3COONa, pH=5) was added to the mixture, the mixture was stirred at 25 °C for 30 min. The mixture was washed with NaHCO3 (5 ml). The organic phase was separated, washed with brine (5 mL), dried over Na2SO4, filtered and concentrated under vacuum to give A12L1T2 (tetrakis(2-(1-heptyl-1H-1,2,3-triazol-4- yl)ethyl) 3,3',3'',3'''-(((((cis)-cyclohexane-1,3-diyl)bis(azanediyl))bis(4-oxobutane-4,1- diyl))bis(azanetriyl))tetrapropionate, 0.2 g, 127 μmol, 33% yield) as yellow oil. Example A14L1T2

[0364] To a solution of compound A14L1 (0.2 g, 264 μmol, 1.0 eq) in H2O (1 ml), t- BuOH (1 ml) was added VcNa (52.3 mg, 264 μmol, 1.0 eq), Cu(OAc)2 (47.9 mg, 264 μmol, 1.0 eq) and compound T2 (223 mg, 1.59 mmol, 6.0 eq). The mixture was stirred at 25oC for 12 h. TLC (Dichloromethane / Methanol = 10 / 1, Rf= 0.31) showed reaction was used up. Thesuspension was filtered through a pad of Celite and the filter cakewas washed with DCM (15 ml). The organic phase was separated, washed with brine 5 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was dissolved in EtOAc (10 ml), THF (2 ml), then 20 ml(0.1 M EDTA, CH3COONa, pH=5) was added, the mixture was stirred at 25oC for 30 min. The organic phase was separated, washed with NaHCO3.aq 10 ml, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Compound A14L1T2 (tetrakis(2-(1-heptyl-1H-1,2,3-triazol-5-yl)ethyl) 3,3',3'',3'''- ((((piperazine-1,4-diylbis(ethane-2,1-diyl))bis(oxy))bis(ethane-2,1- diyl))bis(azanetriyl))tetrapropionate, 0.2 g, 151 μmol, 57.2% yield) was obtained as a yellow solid. Example A21L1T13

[0365] To a solution of compound A21L1 in t-BuOH (2 mL) and H2O (2 mL) was added VcONa (109 mg, 551 μmol, 1 eq) and CuOAc (100 mg, 551 μmol, 1 eq) and compound T13 (321 mg, 1.10 mmol, 2 eq). The mixture was stirred at 25 °C for 12h. LCMS (product: RT = 2.424 min; M + H / 2 = 473.5) showed the starting material was consumed completely. The suspension was filtered through a pad of Celite and the filter cake was washed with DCM (5 mL), filtered and concentrated under reduced pressure to give a residue. The crude product was dissolved inEtOAc (5 mL), then 15 mL (0.1M EDTA, CH3COONa, pH=5) was added the mixture was stirred at 25 °C for 10 min, and extracted with EtOAc (5 mL × 2). The combined organic layers were washed with NaHCO310mL. Then concentrated under reduced pressure to give a residue. Without purification. Compound A21L1T13 (2-(1-((8Z,11Z)-heptadeca-8,11-dien-1-yl)-1H- 1,2,3-triazol-4-yl)ethyl 3-((3-(2-(1-((9Z,12Z)-octadeca-9,12-dien-1-yl)-1H-1,2,3-triazol-4- yl)ethoxy)-3-oxopropyl)(2-(pyrrolidin-1-yl)ethyl)amino)propanoate, 0.2 g, 211 μmol, 38.3% yield) was obtained as a yellow oil. LCMS Rt = 2.855, M + H = 945.7, 91%. Example A24L1T12

[0366] To a solution of compound A24L1 (0.2 g, 548 μmol, 1 eq) in t-BuOH (2 mL) and H2O (2 mL) was added VcONa (108 mg, 548 μmol, 1 eq) and CuOAc (99.6 mg, 548 μmol, 1 eq) and compound T12 (322 mg, 1.10 mmol, 2 eq). The mixture was stirred at 25 °C for 12h. LCMS (product: RT = 2.558 min; M + H / 2 = 476) showed the starting material was consumed completely. The suspension was filtered through a pad of Celite and the filter cakewas washed with DCM (5 mL), filtered and concentrated under reduced pressure to give a residue. The crude product was dissolved in EtOAc (5 mL), then 15 mL(0.1M EDTA, CH3COONa, pH=5) was added,the mixture was stirred at 25 °C for 10 min, and extracted with EtOAc (5 ml × 2). The combined organic layers were washed with NaHCO310mL. Then concentrated under reduced pressure to give a residue. Without purification. Compound A24L1T12 (bis(2-(1-((Z)-octadec-9- en-1-yl)-1H-1,2,3-triazol-4-yl)ethyl) 3,3'-((2-(diethylamino)ethyl)azanediyl)dipropionate, 0.2 g, 210 μmol, 38.3% yield) was obtained as a yellow solid. LCMS: Rt= 2.140, M + H = 951.8, 95.6%.Example A25L1T10

[0367] To a solution of compound A25L1 (0.25 g, 660 μmol, 1 eq) in t-BuOH (2 mL) and H2O (2 mL) was added VcONa (130 mg, 660 μmol, 1 eq) and CuOAc (119 mg, 660 μmol, 1 eq) and compound T10 (316 mg, 1.32 mmol, 2 eq). The mixture was stirred at 25 °C for 12h. LCMS (product: RT = 2.040 min; M + H / 2 = 429) showed the starting material was consumed completely. The suspension was filtered through a pad of Celite and the filter cakewas washed with DCM (5 mL), filtered and concentrated under reduced pressure to give a residue.The crude product was dissolved in EtOAc (5 mL), then 15 mL(0.1M EDTA,CH3COONa, pH=5) was added, the mixture was stirred at 25 °C for 10 min, and extracted with EtOAc (5 ml × 2). The combined organic layers were washed with NaHCO310mL. Then concentrated under reduced pressure to give a residue. Without purification. Compound A25L1T10 (bis(2-(1-tetradecyl-1H- 1,2,3-triazol-4-yl)ethyl) 3,3'-((3-(diethylamino)propyl)azanediyl)dipropionate, 0.2 g, 233 μmol, 35.3% yield) was obtained as a yellow solid. LCMS: Rt = 2.065, M + H = 857.8, 95%. Example A22L1T7

[0368] To a solution of A22L1 (200 mg, 531 μmol, 1.0 eq) in 2-methylpropan-2-ol (1 mL) and H2O (1 mL) was added T7 (262 mg, 1.33 mmol, 2.5 eq) sodium; (2R)-2-[(1S)-1,2- dihydroxyethyl]-4-hydroxy-5-oxo-2H-furan-3-olate (105 mg, 531 μmol, 1.0 eq) and diacetoxycopper (96.5 mg, 531 μmol, 1.0 eq) at 20 °C. The mixture was stirred 12 h at 20 °C. TLC (Dichloromethane / Methanol = 10 / 1, Product / Rf = 0.4) showed the reaction was completely. The suspension was filtered through a pad of Celite and the filter cake was washed with DCM (15 mL). The organic phase was separated, washed with brine (5 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was dissolved in EtOAc (10 mL), THF (2 mL), then 20 mL (0.1M EDTA,CH3COONa, pH = 5) was added, the mixture was stirred at 25 °C for 30 min. The organic phase was separated, washed with sat. NaHCO3 (5 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Without purification. Obtained A22L1T7 (bis(2-(1-undecyl-1H-1,2,3-triazol-4-yl)ethyl) 3,3'-((2-(piperidin-1-yl)ethyl)azanediyl)dipropionate, 200 mg, 259 μmol, 48.8% yield) as yellow solid. LCMS: m / z = 386.3 (M / 2+H)+, Rt = 0.901 min. Example A27L1T7

[0369] To a solution of compound A27L1 (0.2 g, 531 μmol, 1.0 eq) in t-BuOH (2 ml)， H2O (2 ml) was added VcNa (105 mg, 531 μmol, 1.0 eq) and Cu(OAc)2(96.4 mg, 531 μmol, 1.0 eq) and compound T7 (262 mg, 1.33 mmol, 2.5 eq). The mixture was stirred at 25 °C for 12 h. TLC (Petroleum ether / Ethyl acetate = 10 / 1, product / Rf = 0.4; start material / Rf = 0.6) indicated compound A27L1 was consumed completely. The suspension was filtered through a pad of Celite and the filter cake was washed with DCM (10 ml). The organic phase was separated, washed with brine 5 ml, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was dissolved in EtOAc (10 ml), THF (2ml), then 5 ml (0.1M EDTA, CH3COONa, pH=5) was added, the mixture was stirred at 25 °C for 30 min. The organic phase was separated, washed with sat. NaHCO35 ml, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Compound A27L1T7 (bis(2-(1-undecyl-1H-1,2,3- triazol-5-yl)ethyl) 3,3'-((3-(pyrrolidin-1-yl)propyl)azanediyl)dipropionate, 0.2 g, 259 μmol, 48.8% yield) was obtained as yellow solid. Example A30L1T13

[0370] To a solution of compound A30L1 (300 mg, 549 μmol, 1.0 eq) in H2O (2 mL) and t-BuOH (2 mL) was added Cu(OAc)2(50 mg, 274 μmol, 0.5 eq) and sodium L-ascorbate (54 mg, 274 μmol, 0.5 eq) and compound T13 (184 mg, 631 μmol, 1.15 eq). The mixture was stirred at 15 °C for 15h. TLC (dichloromethane / methanol = 10 / 1, Rf = 0.3) indicated compound A30L1 was consumed completely and one new spot formed. The reaction was clean according to TLC. The mixture was diluted with EtOAc (20 mL) and filtered through a pad of Celite and the filter cake was washed with EtOAc (5 mL). The mixture was separated, washed with brine (5 mL). To the organic layer was added 20 mL (0.1M EDTA, AcONa, pH=5) and stirred at 25 °C for 30 min. The mixture was separated, washed with NaHCO3(15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was used into the next step without further purification. Compound A30L1T13 (9-(3-(dimethylamino)propyl)-15-(1- ((9Z,12Z)-octadeca-9,12-dien-1-yl)-1H-1,2,3-triazol-4-yl)-8,12-dioxo-7,13-dioxa-3,4-dithia-9- azapentadecyl nonanoate, 200 mg, 239 μmol, 43.5% yield) was obtained as a yellow oil. Example A31L1T14

[0371] To a solution of compound A31L1 (250 mg, 459 μmol, 1.0 eq) in H2O (2 mL) and t-BuOH (2 mL) was added Cu(OAc)2(42 mg, 229 μmol, 0.5 eq) and sodium L-ascorbate (45 mg, 229 μmol, 0.5 eq) and compound T14 (164 mg, 528 μmol, 1.15 eq). The mixture was stirred at 15 °C for 15h. TLC (dichloromethane / methanol = 10 / 1, Rf = 0.3) indicated compound A31L1 was consumed completely and one new spot formed. The reaction was clean according to TLC. The mixture was diluted with EtOAc (20 mL) and filtered through a pad of Celite and the filter cake was washed with EtOAc (5 mL). The mixture was separated, washed with brine (5 mL). To the organic layer was added 20 mL (0.1M EDTA, AcONa, pH=5) and stirred at 25 °C for 30 min. The mixture was separated, washed with NaHCO3(15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was used into the next step without further purification. Compound A31L1T14 (undecan-6-yl 6-(4-(7-(3- (dimethylamino)propyl)-4,8,17-trioxo-3,18-dioxa-12,13-dithia-7-azapentacosyl)-1H-1,2,3-triazol- 1-yl)hexanoate, 220 mg, 257 μmol, 56.0% yield) was obtained as a yellow oil.Example A33L1T6

[0372] To a solution of compound A33L1 (350 mg, 707 μmol, 1.0 eq) in H2O (2 mL) and t-BuOH (2 mL) was added Cu(OAc)2 (64 mg, 354 μmol, 0.5 eq) and sodium L-ascorbate (70 mg, 354μmol, 0.5 eq) and compound T6 (149 mg, 814 μmol, 1.15 eq). The mixture was stirred at 15 °C for 15h. TLC (dichloromethane / methanol = 10 / 1, Rf = 0.3) indicated compound A33L1 was consumed completely and one new spot formed. The reaction was clean according to TLC. The mixture was diluted with EtOAc (20 mL) and filtered through a pad of Celite and the filter cake was washed with EtOAc (5 mL). The mixture was separated, washed with brine (5 mL). To the organic layer was added 20 mL (0.1M EDTA, AcONa, pH=5) and stirred at 25 °C for 30 min. The mixture was separated, washed with NaHCO3 (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was used into the next step without further purification. Compound A33L1T6 (8-((3-(dimethylamino)propyl)(3-(2-(1- (8-methylnonyl)-1H-1,2,3-triazol-4-yl)ethoxy)-3-oxopropyl)amino)octyl nonanoate, 200 mg, 295 μmol, 41.7% yield) was obtained as a yellow oil. Example A37L1T2

[0373] To a solution of compound A37L1 (0.25 g, 278 μmol, 1.0 eq) in t-BuOH (2 ml), H2O (2 ml) was added VcNa (55.2 mg, 278 μmol, 1.0 eq) and Cu(OAc)2(50.6 mg, 278 μmol, 1.0 eq), compound T2 (157 mg, 1.11 mmol, 4.0 eq). The mixture was stirred at 25 °C for 12 h. TLC (Petroleum ether / Ethyl acetate = 10:1, product / Rf = 0.4; start material / Rf = 0.6) indicated compound A37L1 was consumed completely. The suspension was filtered through a pad of Celite and the filter cake was washed with DCM (10 ml). The organic phase was separated, washed with brine 5 ml, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was dissolved in EtOAc (10 ml), THF (2ml), then 5 ml (0.1 M EDTA, CH3COONa, pH=5) was added the mixture was stirred at 25 °C for 30 min. The organic phase was separated, washed with sat. NaHCO35 ml, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Compound A37L1T2 (tetrakis(2-(1-heptyl-1H-1,2,3- triazol-5-yl)ethyl) 3,3',3'',3'''-((((3,3'-((trans)-2,5-dimethylpiperazine-1,4- diyl)bis(propanoyl))bis(oxy))bis(butane-4,1-diyl))bis(azanetriyl))tetrapropionate, 0.2 g, 136 μmol, 49.0% yield) was obtained as brown oil. Example A2L1

[0374] To a solution of compound A2 (3.00 g, 13.4 mmol, 1.0 eq) in t-BuOH (30 mL) was added compound L1 (8.30 g, 66.9 mmol, 5.0 eq). The mixture was stirred at 90 °C for 12 h. TLC (Dichloromethane: Methanol = 10: 1, product Rf= 0.2) showed reactant was used up. The reaction mixture was concentrated under reduced pressure to remove t-BuOH (30 mL). The residue was diluted with H2O (10mL) and extracted with DCM (100mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 100 / 1 to Ethyl acetate / THF 20 / 1). Compound A2L1 (tetra(but-3-yn-1-yl) 3,3',3'',3'''-(((1,4- phenylenebis(oxy))bis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate, 4.00 g, 5.55 mmol, 41.5% yield) was obtained as yellow oil.1H NMR: 400 MHz CDCl3 δ ppm 6.82 (s, 4 H), 4.17 (t, J = 6.82 Hz, 8 H), 3.92 (t, J = 6.07 Hz, 4 H), 2.80 (t, J = 7.00 Hz, 8 H), 2.61 (t, J=6.82 Hz, 4 H), 2.44 - 2.56 (m, 16 H), 2.01 (t, J = 2.63 Hz, 3 H), 1.85-1.91 (m, 4 H), 1.56 (s, 2 H). Example A3L1

[0375] To a solution of compound A3 (2.00 g, 13.8 mmol, 1.0 eq) in t-BuOH (30 mL) was added compound L1 (8.55 g, 68.9 mmol, 5.0 eq). The mixture was stirred at 90 °C for 12 h. TLC (Dichloromethane: Methanol = 10: 1,product Rf= 0.2)showed reactant was used up. The reaction mixture was concentrated under reduced pressure to remove t-BuOH (30 mL). The residue was diluted with H2O (10 mL) and extracted with DCM (100 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 100 / 1 to Ethyl acetate / MeOH 20 / 1). Compound A3L1 (tetra(but-3-yn-1-yl) 3,3',3'',3'''- (((methylazanediyl)bis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate, 6.00 g, 9.35 mmol, 67.9% yield) was obtained as Light yellow oil.1H NMR: 400 MHz CDCl3δ ppm 4.19 (t, J = 6.82 Hz, 8 H), 2.78 (t, J = 7.13 Hz, 8 H), 2.54 (td, J = 6.82, 2.63 Hz, 8 H), 2.40 - 2.51 (m, 12 H), 2.31 (s, 4 H), 2.20 (s, 3 H), 2.02 (t, J = 2.63 Hz, 3 H), 1.60 (s, 4 H). Example A8L1

[0376] To a solution of compound A8 (3.00 g, 9.89 mmol, 1.0 eq, 2HCl) in t-BuOH (30 mL) was added K2CO3(4.10 g, 29.7 mmol, 3.0 eq) and compound L1 (6.14 g, 49.5 mmol, 5.0 eq). The mixture was stirred at 90°C for 12 h. TLC (Dichloromethane: Methanol = 10: 1, product Rf = 0.18) showed reactant was used up. The reaction mixture was concentrated under reduced pressure to remove t-BuOH (30 mL). The residue was diluted with H2O (10mL) and extracted with DCM (100mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 100 / 1 to Ethyl acetate / THF 20 / 1). Compound A8L1 (tetra(but-3-yn-1-yl) 3,3',3'',3'''-(((((trans)-cyclohexane-1,4- diyl)bis(oxy))bis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate, 3.00 g, 4.12 mmol, 41.7% yield, 99.9% purity) was obtained as yellow oil.1H NMR: 400 MHz CDCl3δ ppm 4.19 (t, J = 6.82 Hz, 8 H), 3.43 (t, J = 6.25 Hz, 4 H), 3.22 (s, 2 H), 2.77 (t, J = 7.13 Hz, 8 H), 2.41 - 2.61 (m, 20 H), 1.93 - 2.06 (m, 8 H), 1.63 - 1.72 (m, 4 H), 1.52 - 1.60 (m, 2 H), 1.22 - 1.33 (m, 4 H).Example A4L1

[0377] To a solution of A4 (3 g, 20.65 mmol, 1 eq) in t-BuOH (15 mL) was added L1 (16.67 g, 134.26 mmol, 6.5 eq). The mixture was stirred at 90 °C for 24 h. TLC (Dichloromethane: Methanol = 10:1, product Rf= 0.48) showed the raw material response to complete. The mixture was evaporated to dryness. The residue was purified by column chromatography (product Rf = 0.48) (SiO2, Dichloromethane: Methanol=100 / 1 to 10 / 1). A4L1 (di(but-3-yn-1-yl) 3,3'-((3-((4-(bis(3-(but-3-yn-1-yloxy)-3-oxopropyl)amino)butyl)(3-(but-3-yn-1- yloxy)-3-oxopropyl)amino)propyl)azanediyl)dipropionate, 4.5 g, 5.88 mmol, 28.44% yield) was obtained as yellow oil.1H NMR: 400 MHz CDCl3 δ 4.18 (t, J = 6.8 Hz, 10H), 2.77 (t, J = 7.2 Hz, 10H), 2.34 - 2.59 (m, 28H), 2.02 (t, J = 2.6 Hz, 5H), 1.55 (quin, J = 7.1 Hz, 2H), 1.33 - 1.44 (m, 4H). Example A34_3

[0378] To a solution of A34_1 (5 g, 34.6 mmol, 1 eq) and A34_2 (18.1 g, 103 mmol, 3 eq) in DCM (30 mL) was added EDCI (9.97 g, 51.9 mmol, 1.5 eq) and DMAP (2.12 g, 17.3 mmol, 0.5 eq). The mixture was stirred at 20 °C for 12h. TLC (Petroleum ether: Ethyl acetate = 5:1, product Rf = 0.43) showed the raw material response to complete. The residue was diluted with H2O 100 mL and extracted with DCM 200 mL. Dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=100 / 1 to 20 / 1. A34_3 (8 g, 26.63 mmol, 76.82% yield) was obtained as a white solid. Example L1

[0379] To a solution of compound L1-1 (200 g, 2.85 mol, 216 mL, 1 eq) in DCM (2 L) was added TEA (433 g, 4.28 mol, 596 mL, 1.5 eq) and compound L1-2 (310 g, 3.42 mol, 278 mL, 1.2 eq) at 0 °C. The mixture was stirred at 25 °C for 12 h. TLC (Petroleum ether : Ethyl acetate = 5:1, Rf= 0.45) showed reactant was used up. The reaction mixture was added H2O (1 L). The organic phase was separated, washed with brine 200 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Dichloromethane = 100 / 1 to 1 / 1). Compound L1 (but-3- yn-1-yl acrylate, 500 g, 4.03 mol, 70.6% yield) was obtained as a yellow oil.1H NMR: 400 MHz CDCl3 δ ppm 6.44 (dd, J = 17.2, 1.41 Hz, 1 H), 6.08 - 6.20 (m, 1 H), 5.86 (dd, J = 10.4, 1.34 Hz, 1 H), 4.27 (t, J = 6.8 Hz, 2 H), 2.58 (td, J = 6.8, 2.8 Hz, 2 H), 2.02 (t, J = 2.8 Hz, 1 H). In another illustrative embodiment, L1 was synthesized as follows:

[0380] To a solution of compound L1-1 (20 g, 285.3 mmol, 21.6 mL, 1.0 eq) in DCM (120 mL) was added TEA (43.3 g, 428.0 mmol, 59.5 mL, 1.5 eq) and compound L1-2 (30.99 g, 342.4 mmol, 27.8 mL, 1.2 eq) at 0 °C. The mixture was stirred at 25 °C for 12 h. TLC (Petroleum ether / Ethyl acetate = 2 / 1, Rf (compound L1-1) = 0.24, Rf (L1) = 0.77) indicated the reaction was complete. The reaction was pour into 50 mL H2O, and extracted with DCM (50 mL × 2), the combined organic phase was concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash®Silica Flash Column, Eluent of 0~20% Ethyl acetate / Petroleum ether gradient @ 100 mL / min). L1 (25 g, 201.3 mmol, 70.5% yield) was obtained as colorless oil. Example A6L1

[0381] To a solution of compound A6 (3 g, 11.7 mmol, 1 eq) in t-BuOH (100 mL) was added compound L1 (8.71 g, 70.2 mmol, 6 eq). The mixture was stirred at 90 °C for 12 h. TLC (Dichloromethane : Methanol = 10:1,Rf= 0.31) showed reactant was used up. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Dichloromethane / Methanol = 100 / 1 to 1 / 1). Compound A6L1 (tetra(but- 3-yn-1-yl) 3,3',3'',3'''-((((trans)-2,5-dimethylpiperazine-1,4-diyl)bis(butane-4,1- diyl))bis(azanetriyl))tetrapropionate, 4 g, 5.31 mmol, 45.4% yield) was obtained as a yellow oil.1H NMR: 400 MHz CDCl3 δ ppm 4.19 (t, J = 6.8 Hz, 8 H), 2.78 (t, J = 7.2 Hz, 12 H), 2.29 - 2.61 (m, 23 H), 2.13 - 2.27 (m, 3 H), 1.93 - 2.08 (m, 6 H), 1.30 - 1.52 (m, 8 H), 1.05 (br d, J = 6.0 Hz, 6 H).Example A7L1

[0382] To a solution of compound A7 (5.00 g, 22.2 mmol, 1.00 eq, HCl) in t-BuOH (30.0 mL) was added TEA (13.5 g, 133.5 mmol, 18.6 mL, 6.00 eq) and compound L1 (17.9 g, 144.6 mmol, 6.5 eq). The mixture was stirred at 90 °C for 12 h. LC-MS showed of compound A7consumed completely and 100% of desired compound was detected. TLC (Dichloromethane: Methanol = 10:1, Rf (product) = 0.43) indicated compound A7 was consumed completely and two new spots formed. The reaction mixture was concentrated under reduced pressure to remove t-BuOH (30.0 mL). The residue was purified by column chromatography (SiO2, DCM: MeOH = 100 / 1 to 10 / 1). Compound A7L1 (hexa(but-3-yn-1-yl) 3,3',3'',3''',3'''',3'''''-((nitrilotris(propane-3,1- diyl))tris(azanetriyl))hexapropionate, 4.00 g, 4.29 mmol, 19.3% yield) was obtained as yellow oil.1H NMR: 400 MHz CDCl3δ 4.17-4.20 (m, 12H), 3.05 (s, 1H), 2.70-2.87 (m, 12H), 2.31-2.63 ( m, 35H), 2.03 (s, 6H), 1.55-1.62 (m, 4H). Example A7L1T7

[0383] To a solution of A7L1 (200 mg, 214 μmol, 1.00 eq) in t-BuOH (2.0 mL) and H2O (2.0 mL) was added L(+) sodium ascorbate (CAS # 134-03-2, 42.5 mg, 214 μmol, 1.00 eq) and Cu(OAc)2(38.9 mg, 214 μmol, 1.00 eq) and compound T7 (274 mg, 1.39 mmol,6.50 eq). The mixture was stirred at 15 °C for 12 hrs. TLC (Dichloromethane: Methanol = 10:1, Rf(Product) = 0.43) indicated reactant 1 was consumed completely and two new spots formed. The suspension was filtered through a pad of Celite and the filter cake was washed with DCM (15 mL). The organic phase was separated and 20 mL (0.1M EDTA, CH3COONa, pH = 5) was added, the mixture was stirred at 25 °C for 30 min. The organic phase was separated, washed with sat. NaHCO3 (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Compound A7L1T7 (hexakis(2-(1-undecyl-1H-1,2,3-triazol-4-yl)ethyl) 3,3',3'',3''',3'''',3'''''-((nitrilotris(propane-3,1-diyl))tris(azanetriyl))hexapropionate, 200 mg, 91.5 μmol, 42.7% yield, 96.9% purity) was obtained as a brown solid. LC-MS RT (product) = 2.334 min) showed desired compound was detected. Example A9L1

[0384] To a solution of compound A9 (2.40 g, 10.4 mmol, 1.00 eq) in t-BuOH (15.0 mL) was added compound L1 (6.44 g, 51.9 mmol, 5.00 eq). The mixture was stirred at 95 °C for 12h. LC-MS showed of compound A9 consumed completely and 94% of desired compound was detected. The reaction mixture was allowed to cold to room temperature. The combined filtrates were concentrated to dryness. The residue was purified by column chromatography (SiO2, Petroleum ether / THF = 100 / 1 to 1 / 1). A9L1 (tetra(but-3-yn-1-yl) 3,3',3'',3'''-((((6- hydroxyhexyl)azanediyl)bis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate, 4.0 g, 5.50 mmol,26.49% yield) was obtained as yellow oil.1H NMR: 400 MHz CDCl3δ 4.17-4.26 (m, 8H), 3.60- 3.66 (m, 2H), 2.76-2.80 (m, 8H), 2.52-2.56 ( m, 8H), 2.35-2.46 (m, 18H), 2.01-2.05 (m, 4H), 1.52-1.61 (m, 6H), 1.26-1.46 (m, 7H). Example A11L1

[0385] To a solution of compound A11 (3.00 g, 10.5 mmol, 1.0 eq) in t-BuOH (45.0 mL) was added TEA (3.20 g, 31.6 mmol, 4.40 mL, 3.0 eq) and compound L1 (6.55 g, 52.7 mmol, 5.0 eq). The solution was stirred at 95 °C for 12 h. TLC (DCM : MeOH = 10 : 1, Rf = 0.60) and LCMS (product: RT = 0.934 min) showed the starting material was consumed completely. After filtration via filter paper, the mother liquid was concentrated under reduced pressure to dryness to provide a white solid. The crude product was purified by column chromatography on silica geleluted with petroleum EtOAc : THF : MeOH = 1 : 0 : 0 to 0 : 0 : 1. A11L1 (tetra(but-3-yn-1- yl) 3,3',3'',3'''-(((((trans)-cyclohexane-1,4-diyl)bis(azanediyl))bis(4-oxobutane-4,1- diyl))bis(azanetriyl))tetrapropionate, 3.60 g, 4.61 mmol, 43.7% yield) was obtained as a white solid.1H NMR: (400 MHz, CDCl3) δ: 6.27 - 6.25 (br d, J = 8.0 Hz, 2 H), 4.21 - 4.17 (t, J = 13.6 Hz, 8 H), 3.77 -3.76 (d, J = 6.4 Hz, 2 H), 2.73 - 2.72 (t, J = 6.4 Hz, 8 H), 2.56 - 2.53 (m, 8 H),2.46 (m, 8 H), 2.44 - 2.43 (m, 8 H), 2.13 (m, 4 H), 2.04 - 2.03 (t, J = 2.4 Hz, 4 H), 1.77 - 1.74 (t, J = 12.4 Hz, 4 H), 1.32 - 1.31 (m, 4 H), 1.28 (m, 4 H). Example A12L1

[0386] To a solution of A12 (5 g, 15.58 mmol, 1 eq, HCl) in t-BuOH (20 mL) was added TEA (4.73 g, 46.75 mmol, 6.51 mL, 3 eq) and L1 (11.61 g, 93.50 mmol, 6 eq). The mixture was stirred at 90 °C for 24h. LCMS showed the starting material was consumed completely. The mixture was evaporated to dryness. The residue was purified by column chromatography (product Rf=0.52) (SiO2, Petroleum ether / Ethyl acetate=100 / 1 to 10 / 1). A12L1 (tetra(but-3-yn-1-yl) 3,3',3'',3'''-(((((1R,3S)-cyclohexane-1,3-diyl)bis(azanediyl))bis(4-oxobutane- 4,1-diyl))bis(azanetriyl))tetrapropionate, 6 g, 7.68 mmol, 49.30% yield) was obtained as yellow oil.1H NMR: 400 MHz CDCl3 δ 6.17 (br d, J = 7.9 Hz, 2H), 4.19 (t, J = 6.8 Hz, 8H), 3.85 (dtd, J = 4.2, 7.8, 11.7 Hz, 2H), 2.65 - 2.83 (m, 8H), 2.55 (dt, J = 2.6, 6.8 Hz, 8H), 2.45 (t, J = 6.6 Hz, 8H), 2.38 (br t, J = 6.0 Hz, 4H), 2.19 - 2.27 (m, 1H), 2.12 (t, J = 7.0 Hz, 4H), 2.04 (t, J = 2.6 Hz, 4H), 2.02 - 1.94 (m, 2H), 1.68 - 1.86 (m, 5H), 1.62 (br s, 1H), 1.39 - 1.53 (m, 1H), 0.98 – 1.19 (m, 3H).Example A14L1

[0387] To a solution of compound A14 (3 g, 7.39 mmol, 1 eq, 4HCl) in t-BuOH (100 mL) was added K2CO3 (5.10 g, 36.9 mmol, 5 eq) and compound L1 (5.50 g, 44.3 mmol, 6 eq). The mixture was stirred at 90 °C for 12 h. TLC (Dichloromethane : Methanol = 10:1,Rf = 0.31) showed reactant was used up. The reaction mixture was concentrated under reduced pressure to yield a residue. The residue was purified by column chromatography (SiO2, Dichloromethane / Methanol = 100 / 1 to 1 / 1). Compound A14L1 (tetra(but-3-yn-1-yl) 3,3',3'',3'''-((((piperazine-1,4-diylbis(ethane-2,1-diyl))bis(oxy))bis(ethane-2,1- diyl))bis(azanetriyl))tetrapropionate, 3.9 g, 5.15 mmol, 69.8% yield) was obtained as a yellow oil.1H NMR: 400 MHz CDCl3 δ ppm 4.18 (t, J = 6.8 Hz, 8 H), 3.56 (t, J = 5.6 Hz, 4 H), 3.48 (t, J = 6.0 Hz, 4 H), 2.84 (t, J = 7.2 Hz, 8 H), 2.66 (t, J = 6.0 Hz, 5 H), 2.02 (t, J = 2.4 Hz, 4 H).Example A16L1

[0388] To a solution of compound A16 (4.30 g, 12.2 mmol, 1.00 eq, HCl) in t-BuOH (30.0 mL) was added K2CO3 (5.07 g, 36.7 mmol, 3.00 eq) and compound L1 (6.83 g, 55.0 mmol, 4.50 eq). The mixture was stirred at 90 °C for 12h. LC-MS (RT = 1.803) showed of compound A16 consumed completely and 100% of desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove t-BuOH (30 mL). The residue was purified by column chromatography (SiO2, DCM: MeOH = 100 / 1 to 10 / 1). Compound A16L1 (di(but-3- yn-1-yl) 4,22-bis(3-(but-3-yn-1-yloxy)-3-oxopropyl)-13-methyl-8,18-dioxo-4,9,13,17,22- pentaazapentacosanedioate, 4.00 g, 4.93 mmol, 40.3% yield) was obtained as yellow oil.1H NMR: 400 MHz CDCl3δ 8.84-8.87 (t, J = 8 Hz, 2H), 4.17-4.21 (t, J = 8 Hz, 8H), 3.29-3.33 (m, 4H), 2.74-2.78 (t, J = 8 Hz, 8H), 2.53-2.57 (m, 8H), 2.41-2.47 (m, 16H), 2.22 (s, 3H), 2.15-2.18 (t, J = 8 Hz, 4H), 2.03-2.04 (t, J = 4 Hz, 4H), 1.68-1.79 (m, 8H). Example Ai”L1, i” = 17 - 29

[0389] Compounds Ai”L1, i” = 17-29 can be prepared as schematically shown below, where the group “RAi” ” is implicitly defined based on the formulae Ai”, i” = 17 - 29, given in Table 1, as indicated above.

[0390] L1 is added to a solution of amine Ai”, i” = 17-29 in a solvent such as t-BuOH. The mixture is stirred, at for example 90 °C for a certain time, such as 12 h. The reaction is followed by, for example TLC (for example with dichloromethane / methanol = 10 / 1), where the respective Rf (Ai”) and Rf (Ai”L1) are used as indicators of reaction completion. The reaction medium is treated to obtain a final residue that eventually is purified, such as by column chromatography purification (for example SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1). Such reaction medium treatment may involve steps such as concentrated under vacuum yielding a first residue that is then subject to extraction, such as for example by diluting it with H2O and extracting with DCM, with the combined organic layer then dried over, for example, Na2SO4, filtered and concentrated under reduced pressure to give a final residue. Such preparation process yields compound Ai”L1, i” = 17-29 with yields that in embodiments of this invention ranged from 34% to over 90%. Example A16L1T1

[0391] To a solution of compound A16L1 (400 mg, 493 μmol, 1.00 eq) in t-BuOH (4.0 mL) and H2O (4.0 mL) was added L(+) sodium ascorbate (CAS # 134-03-2, 97.6 mg, 493 μmol, 1.00 eq) and Cu(OAc)2 (89.5 mg, 493 μmol, 1.00 eq) and compound T1 (313 mg, 2.46 mmol, 5.00 eq). The mixture was stirred at 15 °C for 12 h. TLC (Dichloromethane: Methanol = 10:1, Rf(product) = 0.43) indicated reactant 1 was consumed completely and two new spots formed. The suspension was filtered through a pad of Celite and the filter cake was washed with DCM (15 mL). The organic phase was separated and 20 mL (0.1M EDTA, CH3COONa, pH = 5) was added, the mixture was stirred at 25 °C for 30 min. The organic phase was separated, washed with sat. NaHCO3 (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Compound A16L1T1 (bis(2-(1-hexyl-1H-1,2,3-triazol-4-yl)ethyl) 4,22-bis(3-(2-(1-hexyl- 1H-1,2,3-triazol-4-yl)ethoxy)-3-oxopropyl)-13-methyl-8,18-dioxo-4,9,13,17,22- pentaazapentacosanedioate, 200 mg, 143 μmol, 29.0% yield, 94.3% purity) was obtained as yellow oil. LC-MS RT (product) = 1.402 min showed desired compound was detected. Example A17L1

[0392] To a solution of A17 (1 g, 13.3 mmol, 1.16 mL, 1.0 eq) in t-BuOH (10 mL) was added but-3-ynyl prop-2-enoate (4.13 g, 33.2 mmol, 2.5 eq). The mixture was stirred at 90 °C for 12 h. TLC (Dichloromethane / Methanol = 10 / 1, Rf (A17) = 0.06, Rf (A17L1) = 0.35) indicated the reaction was complete. The reaction was concentrated under vacuum, the residue was diluted with H2O (10 mL) and extracted with DCM (10 mL × 2). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 100 / 1 to 0 / 1). A17L1 (di(but-3-yn-1-yl) 3,3'-((2-methoxyethyl)azanediyl)dipropionate, 4.0 g, 12.3 mmol, 92.9% yield) was obtained as light yellow oil.1H NMR: 400 MHz CDCl3δ 4.19 (t, J = 6.80 Hz, 4 H), 3.44 (t, J = 6.00 Hz, 2 H), 3.34 (s, 3 H), 2.86 (t, J = 7.20 Hz, 4 H), 2.67 (t, J = 6.00 Hz, 2 H), 2.46 - 2.59 (m, 8 H), 2.01 (t, J = 2.40 Hz, 2 H). Example A18L1

[0393] To a solution of Compound A18L1-1 (1.00 g, 16.4 mmol, 988 μL, 1.00 eq) in t- BuOH (20 mL) was added but-3-ynyl prop-2-enoate (5.08 g, 40.9 mmol, 2.50 eq). The mixture was stirred at 90 °C for 12 h. LC-MS (Product Rt = 1.934, MS+1 = 310) showed Reactant 1 was consumed completely and one main peak with desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate to DCM: MeOH = 50:1 to 0:1) Compound A18L1 (di(but-3-yn-1-yl) 3,3'-((2-hydroxyethyl)azanediyl)dipropionate, 3.80 g, 12.3 mmol, 75.0% yield) as a yellow oil.1H NMR: 400 MHz CDCl3 δ 4.19 (t, J = 6.8 Hz, 4H), 3.58 (t, J = 4.8 Hz, 2H), 2.81 (t, J = 6.8 Hz, 4H), 2.47 - 2.61 (m, 10H), 2.01 (t, J = 2.8 Hz, 2H).Example A18L1T3

[0394] To a solution of Compound A18L1 (0.20 g, 647 μmol, 1.00 eq) in H2O (2 mL) and t-BuOH (2 mL) was added sodium;(2R)-2-[(1S)-1,2-dihydroxyethyl]-4-hydroxy-5-oxo- 2H-furan-3-olate (128 mg, 647 μmol, 1.00 eq), diacetoxycopper (117 mg, 647 μmol, 1 eq) and 1- azidooctane (1.12 g, 1.29 mmol, 2.00 eq). The mixture was stirred at 25 °C for 12 h. LC-MS (Product Rt = 1.065, MS+1 = 620.5) showed Reactant 1 was consumed completely and one main peak with desired mass was detected. The suspension was filtered through a pad of Celite and the filter cake was washed with DCM (10 mL), The organic phase was separated, washed with brine 5 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was dissolved in EtOAc (10 mL), then 20 mL(0.1M EDTA,CH3COONa, Ph = 5) was added, the mixture was stirred at 25 °C for 30 min. The organic phase was separated, washed with NaHCO315 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a A18L1T3 (bis(2-(1-octyl-1H-1,2,3-triazol-4-yl)ethyl) 3,3'-((2- hydroxyethyl)azanediyl)dipropionate, 0.20 g, 323 μmol, 49.9% yield) as a yellow oil. Example A19L1

[0395] To a solution of A19L1-1 (1.00 g, 11.2 mmol, 1.04 mL, 1.00 eq) in t-BuOH (20 mL) was added but-3-ynyl prop-2-enoate (3.48 g, 28.0 mmol, 2.50 eq). The mixture was stirred at 90 °C for 12 h. LC-MS (Product Rt=2.03, MS+1=338) showed Reactant 1 was consumed completely and one main peak with desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate to DCM: MeOH = 50:1 to 0:1) to give a compound A19L1 (di(but-3-yn-1-yl) 3,3'-((4-hydroxybutyl)azanediyl)dipropionate, 3.30 g, 9.78 mmol, 87.1% yield) as a yellow oil.1H NMR: 400 MHz CDCl3 δ 4.19 (t, J = 6.8 Hz, 4H), 3.83 (s, 1H), 3.57 (t, J = 5.6 Hz, 2H), 2.80 (t, J = 6.8 Hz, 4H), 2.45 - 2.55 (m, 10H), 2.01 (t, J = 2.8 Hz, 2H), 1.60 (t, J = 5.6 Hz, 4H). Example A19L1T4

[0396] To a solution of Compound A19L1 (0.20 g, 593 μmol, 1.00 eq) in H2O (2 mL) and t-BuOH (2 mL) was added sodium;(2R)-2-[(1S)-1,2-dihydroxyethyl]-4-hydroxy-5-oxo- 2H-furan-3-olate (117 mg, 593 μmol, 1.00 eq), diacetoxycopper (108 mg, 593 μmol, 1.00 eq) and 1-azidononane (826 mg, 1.19 mmol, 2.00 eq). The mixture was stirred at 25 °C for 12 h. LC-MS (Product Rt = 1.348, MS+1 = 676.5) showed Reactant 1 was consumed completely and one main peak with desired mass was detected. The suspension was filtered through a pad of Celite and the filter cake was washed with DCM (10 mL), the organic phase was separated, washed with brine 5 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was dissolved in EtOAc (10 mL), then 20 mL (0.1M EDTA, CH3COONa, pH = 5) was added, the mixture was stirred at 25 °C for 30 min. The organic phase was separated, washed with NaHCO315 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a Compound A19L1T4 (bis(2-(1-nonyl-1H-1,2,3-triazol-4-yl)ethyl) 3,3'- ((4-hydroxybutyl)azanediyl)dipropionate, 0.20 g, 296 μmol, 49.9% yield) as a yellow oil. Example A20L1

[0397] To a solution of Compound A20L1-1 (1.50 g, 12.8 mmol, 1.00 eq) in t-BuOH (20 mL) was added but-3-ynyl prop-2-enoate (3.97 g, 32.00 mmol, 2.5 eq). The mixture was stirred at 90 °C for 12 h. LC-MS (Product Rt = 2.21, MS+1 = 366) showed Reactant 1 was consumed completely and one main peak with desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate to DCM: MeOH = 50:1 to 0:1) to give a compound A20L1 (di(but-3-yn-1-yl) 3,3'-((6-hydroxyhexyl)azanediyl)dipropionate, 3.60 g, 9.85 mmol, 76.9% yield) as a yellow oil.1H NMR: 400 MHz CDCl3δ 4.18 (t, J = 6.8 Hz, 4H), 3.64 (t, J = 6.4 Hz, 2H), 2.77 (t, J = 7.2 Hz, 4H), 2.41 - 2.55 (m, 10H), 2.01 (t, J = 2.4 Hz, 2H), 1.46 - 1.60 (m, 2 H), 1.28 - 1.37 (m, 7H). Example A20L1T3

[0398] To a solution of A20L1 (0.25 g, 684.06 μmol, 1.00 eq) in H2O (2 mL) and t-BuOH (2 mL) was added sodium;(2R)-2-[(1S)-1,2-dihydroxyethyl]-4-hydroxy-5-oxo-2H-furan-3-olate (136 mg, 684 μmol, 1 eq), diacetoxycopper (124 mg, 684 μmol, 1.00 eq) and 1-azidooctane (1.18 g, 1.37 mmol, 2.00 eq). The mixture was stirred at 25 °C for 12 h. LC-MS (Product Rt = 1.152, MS+1 = 676.5) showed Reactant 1 was consumed completely and one main peak with desired mass was detected. The suspension was filtered through a pad of Celite and the filter cake was washed with DCM (10 mL), the organic phase was separated, washed with brine 5 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was dissolved in EtOAc (10 mL), then 20 mL (0.1M EDTA CH3COONa, pH = 5) was added, the mixture was stirred at 25 °C for 30 min. The organic phase was separated, washed with NaHCO315 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a Compound A20L1T3 (bis(2-(1-octyl-1H-1,2,3-triazol-4-yl)ethyl) 3,3'-((6- hydroxyhexyl)azanediyl)dipropionate, 0.20 g, 296 μmol, 43.2% yield) as a yellow oil. Example A21L1

[0399] To a solution of compound A21 (2.0 g, 17.5 mmol, 1 eq) in t-BuOH (20 mL) was added compound L1 (5.44 g, 43.7 mmol, 2.5 eq). The mixture was stirred at 90 °C for 12 h. TLC (Dichloromethane / Methanol = 10:1, compound A21 Rf = 0.02, compound L1 Rf = 0.55, compound A21L1 Rf= 0.20) indicated compound A21 was consumed completely. The reaction mixture was poured into H2O (30 mL), and extracted with DCM (20 mL × 3). Then the organic phase was concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~6% DCM / MeOH ethergradient @ 40 mL / min). Compound A21L1 (di(but-3-yn-1-yl) 3,3'-((2-(pyrrolidin-1- yl)ethyl)azanediyl)dipropionate, 4.4 g, 12.1 mmol, 69.3% yield) was obtained as a yellow oil.1H NMR: (400 MHz, CDCl3) δ ppm 4.18 (t, J = 6.80 Hz, 4 H), 2.81 (t, J = 6.80 Hz, 4 H), 2.58 - 2.61 (m, 2 H), 2.46 - 2.56 (m, 14 H), 2.01 (t, J = 2.40 Hz, 2 H), 1.77 (dt, J = 6.40, 3.20 Hz, 4 H) LCMS: Rt = 1.901, M + H = 363, 88%. Example A24L1

[0400] To a solution of compound A24 (3 g, 25.8 mmol, 3.63 mL, 1 eq) in t-BuOH (30 mL) was added compound L1 (8.01 g, 64.5 mmol, 2.5 eq). The mixture was stirred at 90 °C for12h. TLC (Dichloromethane / Methanol = 10 / 1, compound A24 Rf= 0.10, compound A24L1 Rf= 0.15) indicated compound A24 was consumed completely. The reaction mixture was poured into H2O (30 mL), and extracted with EtOAc (30 mL × 3). Then the organic phase was concentrated under vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 50 / 1 to 0 / 1). Compound A24L1 (di(but-3-yn-1-yl) 3,3'-((2- (diethylamino)ethyl)azanediyl)dipropionate, 7.0 g, 19.2 mmol, 74.3% yield) was obtained as a yellow oil.1H NMR: (400 MHz, CDCl3) δ ppm 4.19 (t, J = 6.80 Hz, 4 H), 2.81 (t, J = 7.20 Hz, 4 H), 2.48 - 2.56 (m, 16 H), 2.01 (t, J = 2.40 Hz, 2 H), 1.03 (t, J = 7.20 Hz, 6 H). LCMS: Rt= 1.936, M + H = 365, 89%. Example A25L1

[0401] To a solution of compound A25 (3 g, 23.0 mmol, 1 eq) in t-BuOH (30 mL) was added compound L1 (7.15 g, 57.5 mmol, 2.5 eq) .The mixture was stirred at 90 °C for 12h. TLC (Dichloromethane / Methanol = 10 / 1, compound A25 Rf = 0.05, compound A25L1 Rf = 0.12) indicated compound A25 was consumed completely. The reaction mixture was poured into H2O (30 mL), and extracted with EtOAc (30 mL × 3). Then the organic phase was concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash®Silica Flash Column, Eluent of 0~100% Ethyl acetate / Petroleum ether, gradient @ 40 mL / min). Compound A25L1 (di(but-3-yn-1-yl) 3,3'-((3-(diethylamino)propyl)azanediyl)dipropionate, 5.5 g, 14.3 mmol, 62.2% yield, 98.7% purity) was obtained as a yellow oil.1H NMR: (400 MHz, CDCl3) δ ppm 4.19 (t, J = 7.20 Hz, 4 H), 2.78 (t, J = 7.20 Hz, 4 H), 2.40 - 2.55 (m, 16 H), 2.01 (t, J = 2.40 Hz, 2 H), 1.58 (quin, J = 7.60 Hz, 2 H), 1.02 (t, J = 7.20 Hz, 6 H). LCMS: Rt= 1.572, M + H = 379, 98%.Example A22L1

[0402] To a solution of A22 (3.0 g, 23.4 mmol, 3.34 mL, 1.0 eq) in t-BuOH (50 mL) was added L1 (7.26 g, 58.5 mmol, 2.5 eq) at 25 °C. The mixture was stirred 12 h at 80 °C. TLC (Dichloromethane / Methanol = 10 / 1, Product / Rf = 0.5) showed the reaction was completely. The reaction mixture was quenched by addition H2O (100 mL) and then extracted with DCM (50 mL × 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 100 / 1 to Ethyl acetate / Methanol 40 / 1). Obtain A22L1 (di(but-3-yn-1-yl) 3,3'-((2-(piperidin-1-yl)ethyl)azanediyl)dipropionate, 3.0 g, 7.97 (

[0403] To a solution of compound A23 (3 g, 34.0 mmol, 3.72 mL, 1 eq) in t-BuOH (150 mL) was added compound L1 (10.6 g, 85.1 mmol, 2.5 eq). The mixture was stirred at90 °C for 12 h. TLC (Dichloromethane : Methanol = 10:1,Rf= 0.31) showed reactant was used up. The reaction mixture was concentrated under reduced pressure to yield a residue. The residue was purified by column chromatography (SiO2, Dichloromethane / Methanol = 100 / 1 to 1 / 1). Compound A23L1 (di(but-3-yn-1-yl) 3,3'-((2-(dimethylamino)ethyl)azanediyl)dipropionate, 4 g, 11.89 mmol, 34.9% yield) was obtained as a yellow oil.1H NMR: 400 MHz CDCl3δ ppm 4.19 (t, J = 6.8 Hz, 4 H), 2.82 (t, J = 7.2 Hz, 4 H), 2.44 - 2.62 (m, 10 H), 2.33 - 2.42 (m, 2 H), 2.25 (s, 6 H), 2.01 (t, J = 2.8 Hz, 2 H). Example A23L1T8

[0404] To a solution of compound A23L1 (0.2 g, 594 μmol, 1 eq) in t-BuOH (1 mL) H2O (1 mL) was added VCNa (117 mg, 594 μmol, 1 eq), Cu(OAc)2 (108 mg, 594 μmol, 1 eq) and compound T8 (314 mg, 1.49 mmol, 2.5 eq). The mixture was stirred at 25 °C for 12 h. TLC (Dichloromethane : Methanol = 10:1,Rf= 0.31) showed reactant was used up. The suspension was filtered through a pad of Celite and the filter cake was washed with DCM (15 mL), the organic phase was separated, washed with brine 5 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was dissolved in EtOAc (10 mL), THF (2mL), then 20 mL (0.1M EDTA, CH3COONa, pH = 5) was added, the mixture was stirred at 25 °C for 30 min. The organic phase was separated, washed with NaHCO3 (aq) 10 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue.Without purification. Compound A23L1T8 (bis(2-(1-dodecyl-1H-1,2,3-triazol-4-yl)ethyl) 3,3'- ((2-(dimethylamino)ethyl)azanediyl)dipropionate, 0.2 g, 263 μmol, 44.3% yield) was obtained as a yellow solid. Example A26L1

[0405] To a solution of A26 (3.0 g, 21.1 mmol, 1.0 eq) ) in t-BuOH (30 mL) was added L1 (6.55 g, 52.7 mmol, 2.5 eq) at 15 °C. The mixture was stirred at 90 °C for 12 h. TLC (Dichloromethane / Methanol=10 / 1, product / Rf= 0.55) showed reactant was completely. The reaction mixture was concentrated under reduced pressure to remove t-BuOH (15 mL). The residue was diluted with H2O (10 mL) and extracted with DCM 100 (mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether / Ethyl acetate=0 / 1 to give A26L1 (di(but-3-yn-1-yl) 3,3'-((3-(piperidin- 1-yl)propyl)azanediyl)dipropionate, 3.2 g, 8.19 mmol, 38.8% yield) as yellow oil.1H NMR: (400 MHz CDCl3) δ 4.18 (t, J = 6.0 Hz, 4H), 2.77 (t, J = 8.8 Hz, 4H), 2.53-2.54 (m, 4H), 2.52-2.53 (m, 7H), 2.48 (s, 3H), 2.45-2.46 (m, 2H), 2.01 (t, J = 2.8 Hz, 2H), 1.56-1.61 (m, 6H), 1.42 (s, 2H). LCMS: (M / 2 + H+) = 391.2. Example A27L1

[0406] To a solution of compound A27 (4.0 g, 31.2 mmol, 1.0 eq) in t-BuOH (80 ml) was added compound L1 (9.68 g, 77.9 mmol, 2.5 eq). The mixture was stirred at 90 °C for 12 h. TLC (Dichloromethane / Methanol = 10:1, product / Rf= 0.7; start material / Rf= 0.2) indicated compound A27 was consumed completely. The reaction mixture was concentrated under reduced pressure to remove t-BuOH (50 ml). The residue was diluted with H2O 50 ml and extracted with DCM 50 ml. The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=100 / 1 to 1 / 1). Compound A27L1 (di(but-3-yn-1-yl) 3,3'-((3-(pyrrolidin-1- yl)propyl)azanediyl)dipropionate, 6.0 g, 15.9 mmol, 51.0% yield) was obtained as yellow oil.1H NMR: 400 MHz CDCl3 δ 4.16-4.19 (t, J = 6.8 Hz, 4H), 2.76-2.79 (t, J = 7.2 Hz, 4H), 2.39-2.54 (m, 16H), 2.00-2.01 (t, J = 2.8 Hz, 2H), 1.77-1.81 (m, 4H), 1.72-1.77 (m, 2H). LCMS : (M+H+= 377). Example A28L1

[0407] To a solution of compound A28 (3 g, 25.8 mmol, 1 eq) in t-BuOH (100 mL) was added compound L1 (8.01 g, 64.5 mmol, 2.5 eq). The mixture was stirred at 90 °C for 12 h. TLC(Dichloromethane : Methanol = 10:1,Rf= 0.14) showed reactant was used up. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Dichloromethane / Methanol = 100 / 1 to 1 / 1). Compound A28L1 (di(but-3-yn-1-yl) 3,3'-((4-(dimethylamino)butyl)azanediyl)dipropionate, 4 g, 11.0 mmol, 42.5% yield) was obtained as a yellow oil.1H NMR: 400 MHz CDCl3δ ppm 4.18 (t, J = 6.8 Hz, 4 H), 2.77 (t, J = 7.2 Hz, 4 H), 2.53 (br d, J = 2.8 Hz, 4 H), 2.46 (br t, J = 7.2 Hz, 6 H), 2.22 (s, 8 H), 1.98 - 2.07 (m, 2 H), 1.43 (br t, J = 3.6 Hz, 4 H).

[0408] To a solution of compound A28L1 (0.2 g, 549 μmol, 1 eq) in H2O (1 mL), t-BuOH (1 mL) was added VCNa (109 mg, 549 μmol, 1 eq) , Cu(OAc)2 (100 mg, 549 μmol, 1 eq) and T4 (232 mg, 1.37 mmol, 2.5 eq). The mixture was stirred at 25 °C for 12 h. TLC (Dichloromethane : Methanol = 10:1,Rf = 0.31) showed reactant was used up. The suspension was filtered through a pad of Celite and the filter cake was washed with DCM (15 mL). The organic phase was separated, washed with brine 5 mL, dried over Na2SO4, filtered andconcentrated under reduced pressure to give a residue. The crude product was dissolved in EtOAc (10 mL), THF (2mL), then 20 mL (0.1M EDTA,CH3COONa, pH = 5) was added the mixture was stirred at 25 °C for 30 min. The organic phase was separated, washed with NaHCO3 (aq) 10 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Without purification. Compound A28L1T4 (bis(2-(1-nonyl-1H-1,2,3-triazol-4- yl)ethyl) 3,3'-((4-(dimethylamino)butyl)azanediyl)dipropionate, 0.2 g, 284 μmol, 51.8% yield) was obtained as a yellow solid. Example A29L1

[0409] To a solution of compound A29 (3 g, 23.0 mmol, 1 eq) in t-BuOH (100 mL) was added compound L1 (7.15 g, 57.6 mmol, 2.5 eq). The mixture was stirred at 90 °C for 12 h. TLC (Dichloromethane : Methanol = 10:1,Rf= 0.31) showed reactant was used up. The reaction mixture was concentrated under reduced pressure to yield a residue. The residue was purified by column chromatography (SiO2, Dichloromethane / Methanol = 100 / 1 to 1 / 1). Compound A29L1 (di(but-3-yn-1-yl) 3,3'-((5-(dimethylamino)pentyl)azanediyl)dipropionate, 4 g, 10.6 mmol, 45.9% yield) was obtained as a yellow oil.1H NMR: 400 MHz CDCl3 δ ppm 4.18 (t, J = 6.8 Hz, 4 H), 2.77 (t, J = 7.2 Hz, 4 H), 2.53 (td, J = 6.8, 2.8 Hz, 4 H), 2.36 – 2.50 (m, 6 H), 2.18 – 2.28 (m, 8 H), 2.01 (t, J = 2.4 Hz, 2 H), 1.37 – 1.52 (m, 4 H), 1.27 (br d, J = 7.2 Hz, 2 H). Example A29L1T7

[0410] To a solution of compound A29L1 (0.2 g, 528 μmol, 1 eq) in H2O (1.5 mL), t- BuOH (1.5 mL) was added VCNa (105 mg, 528 μmol, 1 eq) , Cu(Oac)2 (96.0 mg, 528 μmol, 1 eq) and T7 (261 mg, 1.32 mmol, 2.5 eq). The mixture was stirred at 25 °C for 12 h. TLC (Dichloromethane : Methanol = 10:1,Rf = 0.31) showed reactant was used up. The suspension was filtered through a pad of Celite and the filter cake was washed with DCM (15 mL). The organic phase was separated, washed with brine 5 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was dissolved in EtOAc (10 mL), THF (2mL), then 20 mL (0.1M EDTA, CH3COONa, pH= 5) was added, the mixture was stirred at 25 °C for 30 min. The organic phase was separated, washed with NaHCO3(aq) 10 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Without purification. Compound A29L1T7 (bis(2-(1-undecyl-1H-1,2,3-triazol-4- yl)ethyl) 3,3'-((5-(dimethylamino)pentyl)azanediyl)dipropionate, 0.2 g, 259 μmol, 48.9% yield) was obtained as a yellow solid. Example A32-2

[0411] To a solution of compound A32-1 (3.00 g, 19.2 mmol, 1.00 eq) in DCM (18.0 mL) was added EDCI (7.36 g, 38.4 mmol, 2.00 eq) and DMAP (469.2 mg, 3.84 mmol, 0.20 eq) and compound A32-1a (3.05 g, 21.1 mmol, 1.10 eq). The mixture was stirred at 15 °C for 12h. TLC (Petroleum ether: Ethyl acetate = 15:1, Rf (product) = 0.58) indicated compound A32-1 was consumed completely and two new spots formed. The reaction mixture was concentrated under reduced pressure to remove DCM (18.0 mL). The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=100 / 1 to 10 / 1). Compound A32-2 (3.80 g, 13.5 mmol, 70.1% yield) was obtained as white oil.1H NMR: 400 MHz CDCl3 δ 5.77-5.84 (m, 1H), 4.92-5.02 (m, 2H), 4.04-4.08 (m, 2H), 2.28-2.32 ( m, 2H), 2.02-2.05 (m, 2H), 1.58-1.62 (m, 4H), 1.28-1.39 (m, 18H), 0.87-0.90 (m, 3H). Example A32-3

[0412] Ozone was bubbled into a solution of compound A32-2 (3.80 g, 13.5 mmol, 1.00eq) in DCM (24.0 mL) at -78°C for 10 minutes. After excess O3 was purged by O2, PPh3 (5.29 g, 20.2 mmol, 1.50 eq) was added at -78°C, the mixture was stirred at 20°C for 12h. TLC (Petroleum ether: Ethyl acetate = 8:1, Rf (product) = 0.43) indicated compound A32-2 was consumed completely. The reaction mixture was concentrated under reduced pressure to remove DCM (30 mL). The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=100 / 1 to 10 / 1). Compound A32-3 (2.80 g, 9.84 mmol, 73.2% yield) was obtained as white oil.1H NMR: 400 MHz CDCl3 δ 9.76-9.77 (t, J = 4.0 Hz, 1H), 4.05-4.08 (t, J = 8.0 Hz, 2H), 2.41-2.45 (m, 2H), 2.28-2.32 (t, J = 8.0 Hz 2H), 1.62-1.64 (m, 6H), 1.28-1.39 (m, 16H), 0.87-0.90 (m, 3H). Example A32L1

[0413] To a solution of compound A32-3 (2.80 g, 9.84 mmol, 1.20 eq) in DCM(18.0 mL) was added compound A32-3a (1.86 g, 8.20 mmol, 1.00 eq) and HOAc (492.6 mg, 8.20 mmol, 469.6 μL, 1.00 eq) for 0.5 h and added NaBH(OAc)3 (1.74 g, 8.20 mmol, 1.00 eq). The mixture was stirred at 15 °C for 11.5 h. LC-MS showed of compound A32-3 consumed completely and 98% of desired compound was detected. The reaction mixture was concentrated to dryness. The residue was purified by column chromatography (SiO2, DCM: MeOH = 100 / 1 to 10 / 1). Compound A32L1 (nonyl 8-((3-(but-3-yn-1-yloxy)-3-oxopropyl)(3- (dimethylamino)propyl)amino)octanoate, 3.00 g, 6.06 mmol, 73.9% yield) was obtained as white oil.1H NMR: 400 MHz CDCl3 δ 4.17-4.20 (t, J = 4.0 Hz, 2H), 4.04-4.07 (t, J = 4.0 Hz, 2H), 2.68-2.81 (m, 4H), 2.52-2.56 (m, 8H), 2.45-2.49 (m, 4H), 2.37-2.41 (m, 2H), 2.27-2.31 (t, J = 8.0 Hz, 2H), 2.02-2.03 (m, 5H), 1.74-1.81 (m, 2H), 1.58-1.65 (m, 4H), 1.28-1.42 (m, 19H), 0.87-0.90 (m, 3H). Example cpd 2

[0414] To a solution of cpd 1 in DCM (40.0 mL) was added compound a (23.8 g, 103 mmol, 3.0 eq), HOBt (13.9 g, 103 mmol, 3.0 eq), TEA (12.2 g, 120 mmol, 16.7 mL, 3.5 eq) and EDCI (19.8 g, 103 mmol, 3.0 eq) at 0 °C. The reaction solution was stirred at 20 °C for 3 h. TLC (petroleum ether : ethyl acetate = 1 : 1, product: Rf= 0.6) showed the starting material was consumedcompletely. After filtration via filter paper or Celite pad, the organic layer was concentrated under reduced pressure to dryness to provide a white solid. The crude product was purified by column chromatography on silica gel eluted with petroleum ether : ethyl acetate = 1 : 0 to 0 : 1. Compound cpd 2 (11.5 g, 21.1 mmol, 61.5% yield) was obtained as a white solid.1HNMR: (400 MHz, CD3OD) δ: 4.80 (br s, 2 H), 3.04 - 3.01 (t, J = 14.0 Hz, 4 H), 2.33 - 2.29 (m, 4 H), 1.97 - 1.95 (d, J = 7.2 H, 4 H), 1.64 - 1.60 (m, 4 H), 1.56 - 1.54 (m, 4 H), 1.47 - 1.45 (m, 6 H), 1.43 (s, 18 H), 1.35 - 1.33 (m, 5 H). Example cpd 3

[0415] To a solution of cpd 2 in EtOAc (31.5 mL) and DCM (126 mL) was added 4 M HCl / EtOAc (4 M, 116 mL, 24.0 eq). The solution was stirred at 25 °C for 12 h. TLC (petroleum ether : ethyl acetate = 1 : 1, product: Rf = 0.60) showed the starting material was consumed completely. Filtered the white soild of cpd 3 (7.26 g, 17.4 mmol, 90.3% yield, 2 HCl) with suction and wash with 25.0 mL of DCM. Compound cpd 3 (7.26 g, 17.4 mmol, 90.3% yield, 2 HCl) was obtained as a white solid.1H NMR: (400 MHz, CD3OD) δ: 4.79 (s, 2 H), 2.94 - 2.90 (t, J = 15.2 Hz, 4 H), 2.37 - 2.33 (t, J = 14.8 Hz, 4 H), 1.97 - 1.96 (m, 4 H), 1.70 - 1.64 (m, 8 H), 1.55 (m, 4 H), 1.42 (m, 4 H). Example A35L1

[0416] To a solution of cpd 3 (4.00 g, 9.63 mmol, 1.0 eq, 2 HCl) in t-BuOH (120 mL) was added TEA (2.92 g, 28.8 mmol, 4.02 mL, 3.0 eq) and compound L1 (5.98 g, 48.1 mmol, 5.0 eq). The solution was stirred at 95 °C for 12 h. LCMS (product: RT = 0.509 min) and TLC (dichloromethane : methanol = 10 : 1, product: Rf = 0.6) showed the starting material was consumed completely. After filtration via filter paper or Celite pad, the organic layer was concentrated under reduced pressure to dryness. The crude product was purified by column chromatography on silica gel eluted with petroleum dichloromethane : ethyl acetate = 1 : 0 to 0 : 1. A35L1 (tetra(but-3-yn-1-yl) 3,3',3'',3'''-(((((trans)-cyclohexane-1,4-diyl)bis(oxy))bis(6- oxohexane-6,1-diyl))bis(azanetriyl))tetrapropionate, 5.50 g, 6.56 mmol, 68.0% yield) was obtained as a brown oil.1H NMR: (400 MHz, CDCl3) δ: 4.80 (s, 2 H), 4.20 - 4.17 (t, J = 13.6 Hz, 8 H), 2.79 - 2.75 (t, J = 14.8 Hz, 8 H), 2.55 - 2.52 (t, J = 16 Hz, 8 H), 2.47 - 2.46 (t, J = 14.0 Hz, 8 H), 2.42 - 2.38 (t, J = 14.4 Hz, 4 H), 2.28 (t, J = 15.2 Hz, 4 H), 2.02 - 2.01 (m, 4 H), 2.02 - 2.01 (m, 4 H), 1.99 - 1.93 (m, 4 H), 1.66 - 1.52 (m, 10 H), 1.47 - 1.40 (m, 4 H), 1.32 - 1.26 (m, 4 H).Example A35L1T5

[0417] To a solution of A35L1 (220 mg, 262 μmol, 1.0 eq) in t-BuOH (3.00 mL), H2O (3.00 mL) was added NaVC (51.9 mg, 262 μmol, 1.0 eq), Cu(OAc)2(47.6 mg, 262 μmol, 1.0 eq) and T5 (240 mg, 1.31 mmol, 5.0 eq). The solution was stirred at 25 °C for 12 h. TLC (DCM : MeOH = 10 : 1, product: Rf = 0.56) showed the starting material was consumed completely. The suspension was filtered through a pad of Celite and the filter cakewas washed with DCM (10 mL), The organic phase was separated, washed with brine 5.00 mL, dried over Na2SO4 and filtered. Then 15.0 mL of solution (0.1 M EDTA, CH3COONa, pH = 5) was added, the mixture was stirred at 25 °C for 30 min. The organic phase was separated, washed with brine 5.00 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. A35L1T5 (tetrakis(2-(1-decyl-1H-1,2,3-triazol-4-yl)ethyl) 3,3',3'',3'''-(((((trans)-cyclohexane-1,4- diyl)bis(oxy))bis(6-oxohexane-6,1-diyl))bis(azanetriyl))tetrapropionate, 200 mg, 139 μmol, 53.3% yield) was obtained as a brown solid.Example A36L1T6

[0418] To a solution of A36L1 (220 mg, 250 μmol, 1.0 eq) in t-BuOH (4.00 mL) and H2O (4.00 mL) was added NaVC (49.6 mg, 250 μmol, 1.0 eq), Cu(OAc)2(45.5 mg, 250 μmol, 1 eq) and L1 (229 mg, 1.25 mmol, 5.0 eq). The solution was stirred at 25 °C for 12 h. TLC (DCM : MeOH = 10 : 1, product: Rf = 0.56) showed the starting material was consumed completely. The suspension was filtered through a pad of Celite and the filter cake was washed with DCM (10.0 mL). The organic phase was separated, washed with brine 5.00 mL, dried over Na2SO4and filtered. Then 15.0 mL of solution (0.1 M EDTA, CH3COONa, pH = 5) was added, the mixture was stirred at 25 °C for 30 min. The organic phase was separated, washed with brine 5.00 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. A36L1T6 (tetrakis(2-(1-(8-methylnonyl)-1H-1,2,3-triazol-4-yl)ethyl) 3,3',3'',3'''-((((disulfanediylbis(ethane- 2,1-diyl))bis(oxy))bis(6-oxohexane-6,1-diyl))bis(azanetriyl))tetrapropionate, 200 mg, 136 μmol, 54.4% yield) was obtained as a brown solid.Example A37-3

[0419] To a solution of compound A37-1 (40.0 g, 211 mmol, 1.0 eq) in DCM (250 ml) was added EDCI (60.7 g, 317 mmol, 1.5 eq) and DMAP (5.16 g, 42.2 mmol, 0.2 eq) compound A37-2 (38.8 g, 253 mmol, 26.2 ml, 1.2 eq). The mixture was stirred at 25 °C for 12 h. TLC (Petroleum ether / Ethyl acetate = 2 / 1, product / Rf = 0.5; start material / Rf = 0.3) showed the raw material response to complete. The residue was diluted with H2O 15 ml and extracted with DCM 20 ml. The combined organic layers were washed with brine 15 ml, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=100 / 1 to 1 / 1). Compound A37-3 (10.0 g, 30.8 mmol, 14.5% yield) was obtained as yellow oil.1H NMR: 400 MHz CDCl3 δ 4.58 (s, 1H), 3.73-3.78 (m, 1H), 3.56-3.59 (d, J = 6.4, 2H), 3.14-3.16 (m, 2H), 2.81-2.85 (m, 2H) , 2.77-2.80 (m, 1H) , 1.64-1.71 (m, 2H), 1.52-1.61 (m, 2H), 1.44 (s, 9H). Example A37-5

[0420] To a solution of compound A37-4 (1.0 g, 8.76 mmol, 1.0 eq) in ACN (60 ml) was added K2CO3 (4.84 g, 35.0 mmol, 4.0 eq) and NaI (131 mg, 875 μmol, 0.1 eq) compound A37-3 (8.80 g, 27.1 mmol, 3.1 eq). The mixture was stirred at 80 °C for 12 h. TLC (Dichloromethane / Methanol = 10 / 1, product / Rf= 0.6; start material / Rf= 0.2) showed the raw material response to complete. The mixture was evaporated to dryness. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=100 / 1 to 1 / 1). Compound A37- 5 (5.0 g, 8.32 mmol, 95.0% yield) was obtained as a white solid.Example A37

[0421] To a solution of compound A37-5 (5.0 g, 8.32 mmol, 1.0 eq) in EtOAc (25 ml) was added HCl / EtOAc (4 M, 50 ml, 24.0 eq). The mixture was stirred at 15 °C for 12 h. TLC (Dichloromethane / Methanol = 10 / 1, product / Rf= 0; start material / Rf= 0.5) showed the raw material response to complete. Evaporate the solution on a water bath under reduced pressure using a rotary evaporator. Compound A37 (bis(4-aminobutyl) 3,3'-((2R,5S)-2,5- dimethylpiperazine-1,4-diyl)dipropionate, 3.5 g, 8.01 mmol, 96.2% yield, HCl) was obtained as a white solid.1H NMR: 400 MHz D2O δ 4.15-4.17 (m, 4H), 3.82-3.96 (m, 6H), 3.35-3.45 (m, 4H), 2.91-3.00 (m, 8H), 1.68-1.73 (m, 5H) , 1.48-1.50 (t, J = 6.0, 6H). Example A37L1

[0422] To a solution of compound A37 (3.0 g, 6.86 mmol, 1.0 eq, HCl) in t-BuOH (60 ml) was added NaOAc (1.69 g, 20.5 mmol, 3.0 eq) and compound L1 (4.26 g, 34.3 mmol, 5.0 eq). The mixture was stirred at 90 °C for 12 h. TLC (Dichloromethane / Methanol= 10 / 1, product / Rf= 0.6; start material / Rf = 0) indicated compound A37 was consumed completely. The reaction mixture was concentrated under reduced pressure to remove t-BuOH (50 ml). The residue was diluted with H2O 50 (ml) and extracted with DCM (50 ml). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give are residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=100 / 1 to 1 / 1). Compound A37L1 (tetra(but-3-yn-1-yl) 3,3',3'',3'''-((((3,3'-((trans)-2,5-dimethylpiperazine- 1,4-diyl)bis(propanoyl))bis(oxy))bis(butane-4,1-diyl))bis(azanetriyl))tetrapropionate, 4.0 g, 4.46 mmol, 64.9% yield) was obtained as yellow oil.1H NMR: 400 MHz CDCl3 δ 4.16-4.20 (m, 8H), 4.04-4.07 (d, J = 6.4 Hz, 4H), 3.04-3.13 (m, 2H), 2.73-2.80 (m, 10H), 2.53-2.70 (m, 2H), 2.50-2.52 (m, 8H), 2.32-2.47 (m, 18H), 1.99-2.06 (m, 6H), 1.56-1.63 (m, 4H), 1.43-1.50 (m, 4H),1.03-1.05 (t, J = 6.4 Hz, 6H). LCMS : (M / 2 + H+= 449). Example A4L1T161-pentylhexyl 4-[4-[2-[3-[4-[bis[3-oxo-3-[2-[1-[4-oxo-4-(1-pentylhexoxy)butyl]triazol-4- yl]ethoxy]propyl]amino]butyl-[3-[bis[3-oxo-3-[2-[1-[4-oxo-4-(1-pentylhexoxy)butyl]triazol-4- yl]ethoxy]propyl]amino]propyl]amino]propanoyloxy]ethyl]triazol-1-yl]butanoate

[0423] This compound has the chemical formula C117H204N18O20, with a molecular weight of 2183.03 g / mol, an exact mass of 2181.55 g / mol, and pKa values 8.168, 5,363 and 6.308. The compound preparation, and that of intermediates used in the same, were made as follows:

[0424] To a solution of compound 1 (500 mg, 2.90 mmol, 1.0 eq) in toluene (30 mL) was added TsOH.H2O (55.2 mg, 290 μmol, 0.1 eq) and compound 2 (1.45 g, 8.71 mmol, 3.0 eq). The reaction was stirred at 130 °C for 2 hrs. TLC (PE: EA = 10:1) showed the reactant (Rf = 0.40) was consumed completely and one new major spot (Rf = 0.50) was detected. The mixture was concentrated in vacuum to give residue. The crude product was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash®Silica Flash Column, Eluent of 0~1% Ethyl acetate / Petroleum ether gradient @ 30 mL / min). The product compound 3 (720 mg, 2.12 mmol, 73.2% yield, 94.8% purity) was obtained as a colorless oil which was confirmed by HNMR.1H NMR: NMR (400 MHz, CHLOROFORM-d): δ = 4.90 (q, J = 6.4 Hz, 1H), 3.48 (t, J = 6.4 Hz, 2H), 2.49 (t, J = 7.2 Hz, 2H), 2.18 (q, J = 6.8 Hz, 2H), 1.55 - 1.49 (m, 4H), 1.28 (br s, 12H), 0.91 - 0.87 (m, 6H).

[0425] To a solution of compound 3 (700 mg, 2.18 mmol, 1.0 eq) in DMF (5 mL) was added NaN3(250 mg, 3.85 mmol, 1.77 eq). The mixture was stirred at 60 °C for 2 hrs. TLC(PE: EA = 20: 1) showed the reactant (Rf= 0.50) was consumed completely and one new major spot (Rf= 0.53) was detected. The reaction was quenched by saturated NaHCO3(30 mL) to adjust to pH = 9 at 20 °C and extracted with PE (30 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The aqueous phase was diluted 50 times, quenched with sodium hypochlorite, and left overnight, then discarded. The product T16 (500 mg, 1.71 mmol, 78.7% yield, 97.2% purity) was obtained as yellow oil which was confirmed by HNMR and used for next step directly without purification.1H NMR: (400 MHz, CHLOROFORM-d): δ = 4.89 (q, J = 6.4 Hz, 1H), 3.36 (t, J = 6.8 Hz, 2H), 2.41 (t, J = 7.3 Hz, 2H), 1.92 (q, J = 7.2 Hz, 2H), 1.55 - 1.49 (m, 4H), 1.28 (br d, J = 2.8 Hz, 12H), 0.89 (br t, J = 6.4 Hz, 6H).

[0426] To a solution of compound T16 (300 mg, 392 μmol, 1.0 eq) in t-BuOH (3 mL) and H2O (3 mL) was added sodium;(2R)-2-[(1S)-1,2-dihydroxyethyl]-4-hydroxy-5-oxo-2H-furan-3- olate (77.6 mg, 392 μmol, 1.0 eq), Cu(OAc)2 (71.1 mg, 392 μmol, 1.0 eq) and compound A4L1 (666 mg, 2.35 mmol, 6.0 eq). The mixture was stirred at 20 °C for 1 h. LCMS showed the product (tp=0.471 min, [M+1]+=728.7) was the main peak. The mixture was diluted with water (30 mL) and extracted with dichloromethane (30 mL x 2). The combined organic phase was washed with brine (30 mL x 2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The crude product was purified by flash silica gel chromatography (ISCO®; 80.0 g SepaFlash®Silica Flash Column, Eluent of 5~8% Dichloromethane / Methanol ether gradient @ 70 mL / min). The residue was purified by prep-HPLC (column: CD12-ACCHROM phenyl- Hexyl 150 * 25 * 10 um; mobile phase: [water (TFA)-ACN]; gradient: 50%-80% B over 15 min). The product A4L1T16 (600 mg, 273 μmol, 69.6% yield, 99.2% purity) was obtained as a white solid which was confirmed by CAD: product: RT = 11.983 min., LCMS product: RT = 0.471 min.,1H NMR (400 MHz, CHLOROFORM-d): δ = 7.44 (s, 5H), 4.92 - 4.85 (m, 5H), 4.41 (t, J = 6.8 Hz, 10H), 4.34 (t, J = 6.9 Hz, 10H), 3.06 (t, J = 6.9 Hz, 10H), 2.75 (br t, J = 7.2 Hz, 10H), 2.45 - 2.32 (m, 28H), 2.25 - 2.18 (m, 10H), 1.67 (br s, 12H), 1.51 - 1.48 (m, 10H), 1.38 (br s, 4H), 1.27 (br s, 60H), 0.88 (br t, J = 6.4 Hz, 30H). Example A4L1T17

[0427] This compound has the chemical formula C147H264N18O20, with a molecular weight of 2603.84 g / mol, an exact mass of 2602.02 g / mol, and pKa values 8.168, 5,363 and 6.308. The compound preparation, and that of some intermediates used in the same, were made as follows:

[0428] A mixture of compound T14_7 (564 mg, 2.89 mmol, 1.1 eq), compound T14_11 (0.60 g, 2.63 mmol, 1.0 eq), EDCI (755 mg, 3.94 mmol, 1.5 eq) and DMAP (385 mg, 3.15 mmol, 1.2 eq) in DCM (30 mL) was stirred at 20 °C for 12 h. TLC (dichloromethane: methanol=10:1) showed the reactant (Rf = 0.46) was consumed completely and one new major spot (Rf = 0.88) was detected. The mixture was concentrated in vacuum to give residue. The crude product was by flash silica gel chromatography (petroleum ether: ethyl acetate = 0~2%). The product compound T14_12 (2.50 g, 6.17 mmol, 46.9% yield) was obtained as colourless oil.1H NMR(400 MHz, CDCl3): δ = 4.99 - 4.82 (m, 1H), 3.66 - 3.34 (m, 2H), 2.45 - 2.20 (m, 2H), 1.93 - 1.75 (m, 2H), 1.70 - 1.63 (m, 2H), 1.57 - 1.46 (m, 6H), 1.27 (br s, 20H), 1.01 - 0.83 (m, 6H).

[0429] A mixture of compound T14_12 (2.80 g, 6.91 mmol, 1.0 eq) in DMF (28 mL) wasadded NaN3(670 mg, 10.3 mmol, 1.49 eq) and purged with N2for 3 times, and then the mixture was stirred at 60 °C for 12 h under N2atmosphere. LCMS did not detected the desired MS. TLC (petroleum ether: ethyl acetate = 20:1) showed the reactant (Rf = 0.37) was consumed completely and one new major spot (Rf = 0.35) was detected. The reaction was quenched by saturated NaHCO3(28 mL) to adjust to pH = 9 at 20 °C and extracted with PE (30 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The aqueous phase was diluted 50 times, quenched with sodium hypochlorite, and left overnight, then discarded. The product compound T17 (2.40 g, 6.53 mmol, 94.55% yield) was obtained as colourless oil and used for next step directly without purification.1H NMR (400 MHz, CDCl3): δ = 4.93 - 4.83 (m, 1H), 3.31 - 3.25 (m, 2H), 2.31 (t, J = 7.4 Hz, 2H), 1.72 - 1.59 (m, 4H), 1.52 (br d, J = 5.6 Hz, 4H), 1.46 - 1.38 (m, 2H), 1.27 (br s, 20H), 0.89 (t, J = 6.8 Hz, 6H).

[0430] A mixture of compound L1 (1.54 g, 12.4 mmol, 6.0 eq) and compound A4 (0.30 g, 2.07 mmol, 1.0 eq) in t-BuOH (3 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 100 °C for 12 hrs under N2 atmosphere. LCMS showed the starting material was consumed completely. The mixture was concentrated in vacuum to give residue. The crude product was by flash silica gel chromatography (petroleum ether: ethyl acetate = 0~100%). The crude product was by flash silica gel chromatography (dichloromethane: methanol = 0-1%). The product A4L1 (4.80 g, 6.26 mmol, 60.6% yield, 99.8% purity) was obtained as yellow oil. LCMS product: RT = 0.295 min.1H NMR (400 MHz, CDCl3):

[0431] δ = 4.19 (t, J = 6.8 Hz, 10H), 2.83 - 2.71 (m, 10H), 2.54 (dt, J = 2.6, 6.8 Hz, 10H), 2.49 - 2.37 (m, 17H), 2.03 (t, J = 2.6 Hz, 4H), 1.68 (br s, 2H), 1.55 (q, J = 6.8 Hz, 2H), 1.39 (br s, 4H).

[0432] To a solution of compound A4L1 (500 mg, 653 μmol, 1.0 eq) in H2O (5 mL) and t- BuOH (5 mL) was added sodium;(2R)-2-[(1S)-1,2-dihydroxyethyl]-4-hydroxy-5-oxo-2H-furan-3- olate (129 mg, 653 μmol, 1.0 eq), Cu(OAc)2(118 mg, 653 μmol, 1.0 eq) and compound T17 (1.44 g, 3.92 mmol, 6.0 eq). The mixture was stirred at 20 °C for 2 h. LCMS showed the starting material was consumed completely. The mixture was diluted with water (30 mL) and extracted with dichloromethane (30 mL x 2). The combined organic phase was washed with brine (30 mL x 2), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum. The crude productwas by flash silica gel chromatography (dichloromethane: methanol = 0~10%). The residue was purified by prep-HPLC (column: CD12-ACCHROM phenyl-Hexyl 150 * 25 * 10 um; mobile phase: [water (TFA)-(ACN-THF2 / 1)]; gradient: 68%-98% B over 15 min) and lyophilized to give the product. The residue was purified by prep-HPLC (column: PHS-Phenyl-Hexyl 250 * 50 mm * 7 um; mobile phase: [water (HCl) - ACN]; gradient: 68%-98% B over 15 min) and lyophilized to give the product. The product A4L1T17 (400 mg, 140 μmol, 21.5% yield, 91.374% purity) was obtained as yellow oil. LCMS product: RT = 0.588 min. CAD product: RT = 9.556 min.

[0433] 1H NMR (400 MHz, CDCl3): δ = 7.41 (s, 5H), 4.89 (br s, 5H), 4.33 (br t, J = 6.8 Hz, 18H), 3.06 (t, J = 7.0 Hz, 10H), 2.78 - 2.72 (m, 8H), 2.47 - 2.35 (m, 16H), 2.30 (t, J = 7.4 Hz, 10H), 1.93 (q, J = 7.6 Hz, 10H), 1.72 - 1.59 (m, 26H), 1.51 (br d, J = 5.6 Hz, 20H), 1.41 - 1.36 (m, 12H), 1.26 (br s, 94H), 0.88 (t, J = 6.8 Hz, 30H). Example A4L2T18

[0434] This compound has the chemical formula C127H234N28O10, with a molecular weight of 2313.46 g / mol. The compound preparation, and that of some intermediates used in the same, were made as follows:

[0435] To a solution of compound 1 (1.00 g, 14.5 mmol, 1.0 eq) in DCM (40 mL) was added TEA (1.76 g, 17.4 mmol, 2.42 mL, 1.2 eq) and DMAP (88.4 mg, 724 μmol, 0.05 eq) and compound 1-1 (1.57 g, 17.4 mmol, 1.41 mL, 1.2 eq) in DCM (60 mL) at 0 °C. The mixture was stirred at 25 °C for 12 hrs. TLC (Petroleum ether: Ethyl acetate = 1:1, Rf= 0.51) indicated Reactant 1 was consumed completely and one new spot formed. The reaction was clean according to TLC. The residue was diluted with water (30 mL) and extracted withdichloromethane (50 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12.0 g SepaFlash®Silica Flash Column, Eluent of 0~30% Ethylacetate / Petroleum ethergradient @ 50 mL / min). Compound L2 (4.80 g, 38.9 mmol, 67.3% yield) was obtained as yellow oil.1H NMR (400 MHz, CDCl3): δ = 6.33 - 6.26 (m, 1H), 6.18 - 6.08 (m, 1H), 6.03 (br s, 1H), 5.66 (dd, J = 1.2, 10.3 Hz, 1H), 3.50 (q, J = 6.4 Hz, 2H), 2.45 (dt, J = 2.4, 6.4 Hz, 2H), 2.02 (t, J = 2.8 Hz, 1H).

[0436] To a solution of compound T14-11-1 (1.14 g, 5.84 mmol, 1.0 eq) in DCM (10 mL) was added DIEA (1.51 g, 11.7 mmol, 2.03 mL, 2.0 eq) and EDCI (1.34 g, 7.00 mmol, 1.2 eq) and DMAP (143 mg, 1.17 mmol, 0.2 eq). The mixture was stirred at 25 °C for 0.5 h. Then, compound T14-11-2 (1.00 g, 5.84 mmol, 1.0 eq) was added. The mixture was stirred at 25 °C for 11.5 h. TLC (Petroleum ether: Ethyl acetate=3:1, Rf = 0.52) indicated that the reactant was consumed completely and many new spots formed. The reaction was not optimal according to TLC. The residue was diluted with water (30 mL) and extracted with dichloromethane (30 mL x 3). The combined organic layers were washed with brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12.0 g SepaFlash®Silica Flash Column, Eluent of 0~20% Ethyl acetate / Petroleum ethergradient @ 60 mL / min). Compound T14-11 (700 mg, 2.01 mmol, 34.4% yield) was obtained as a light yellow solid.1H NMR (400 MHz, CDCl3):

[0437] δ = 5.09 (br d, J = 8.8 Hz, 1H), 3.98 - 3.84 (m, 1H), 3.56 - 3.36 (m, 2H), 2.18 (t, J = 7.2 Hz, 2H), 1.94 - 1.76 (m, 2H), 1.73 - 1.62 (m, 3H), 1.52 - 1.44 (m, 4H), 1.38 - 1.31 (m, 4H), 0.93 - 0.78 (m, 6H).

[0438] To a solution of compound T14-11 (2.56 g, 7.35 mmol, 1.0 eq) in DMF (15 mL) was added NaN3 (0.52 g, 8.00 mmol, 1.09 eq). The mixture was stirred at 60 °C for 2 h under N2 atmosphere. LC-MS showed the reactant was consumed completely and the desired mass was detected. The reaction mixture was adjusted to a pH of more than 9 with saturated sodium carbonate (50 mL) and was diluted with water (50 mL) was extracted with hexane (50 mL x 2). Then the combined organic layers were died over anhydrous sodium sulfate and were concentrated. The aqueous phase was diluted 50 times, quenched with sodium hypochlorite, and left overnight, then discarded. The crude product was used into the next step without furtherpurification. Compound T18 (2.18 g, 7.02 mmol, 95.5% yield) was obtained as yellow oil.

[0439] LCMS product: RT = 0.541 min.1H NMR (400 MHz, CDCl3): δ =5.07 (br d, J = 8.9 Hz, 1H), 4.00 - 3.84 (m, 1H), 3.28 (t, J = 6.8 Hz, 2H), 2.18 (t, J = 7.4 Hz, 2H), 1.68 - 1.60 (m, 4H), 1.52 - 1.39 (m, 4H), 1.30 (br d, J = 5.6 Hz, 14H), 0.88 (br t, J = 6.1 Hz, 6H).

[0440] To a solution of compound A4 (500 mg, 3.44 mmol, 1.0 eq) in t-BuOH (10 mL) was added L2 (2.54 g, 20.6 mmol, 6.0 eq). The mixture was stirred at 90 °C for 12 h. LC- MS showed the reactant was consumed completely and the desired mass was detected. The reaction mixture was concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 12.0 g SepaFlash®Silica Flash Column, Eluent of 0~15% Ethyl acetate / Petroleum ethergradient @ 40 mL / min). Compound A4L2 (1.20 g, 1.58 mmol, 45.8% yield) was obtained as yellow oil.

[0441] LCMS product: RT = 0.238 min.1H NMR (400 MHz, CDCl3): δ =3.45 - 3.35 (m, 10H), 2.92 - 2.69 (m, 10H), 2.65 - 2.52 (m, 4H), 2.50 - 2.35 (m, 24H), 2.05 (t, J = 2.4 Hz, 5H), 1.94 (br dd, J = 3.6, 5.6 Hz, 5H), 1.68 (br s, 2H), 1.48 (br d, J = 7.6 Hz, 4H).

[0442] To a solution of compound A4L2 (350 mg, 460 μmol, 1.0 eq) in t-BuOH (3.5 mL) and H2O (3.5 mL) was added sodium (2R)-2-[(1S)-1,2-dihydroxyethyl]-3-hydroxy-5-oxo- 2H-furan-4-olate (91.1 mg, 460 μmol, 1.0 eq) (CAS: 134-03-2) and Cu(OAc)2(83.5 mg, 460 μmol, 1.0 eq) and compound T18 (857 mg, 2.76 mmol, 6.0 eq). The mixture was stirred at 25 °C for 2 h. LC-MS showed the reactant was consumed completely and one main peak with desired m / z or desired mass was detected. The residue was diluted with water (30 mL) and extracted with dichloromethane (30 mL x 3). The combined organic layers were washed with brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: CD12-ACCHROM phenyl-Hexyl 150 * 25 * 10 um; mobile phase: [water (TFA)-(ACN-THF2 / 1)]; gradient: 42%- 72% B over 15 min). Compound A4L2T18 (190 mg, 81.3 μmol, 17.6% yield, 99.0% purity) was obtained as light yellow oil. LCMS product: RT = 0.571 min. CAD product: RT = 7.701 min.

[0443] 1H NMR: (400 MHz, CDCl3): δ = 7.93 - 7.82 (m, 4H), 7.59 - 7.45 (m, 5H), 5.71 (br s, 5H), 4.31 (br t, J = 7.2 Hz, 10H), 3.93 - 3.83 (m, 5H), 3.53 (br s, 10H), 2.92 (br t, J = 6.4 Hz, 10H), 2.64 (br d, J = 6.0 Hz, 8H), 2.33 (br d, J = 6.0 Hz, 12H), 2.16 (t, J = 7.2 Hz, 10H), 1.94 - 1.87 (m, 10H), 1.77 - 1.65 (m, 32H), 1.51 - 1.42 (m, 12H), 1.32 - 1.23 (m, 70H), 0.87 (br t, J =6.4 Hz, 30H).N1-(3-(bis(6-(1-(8-pentyltridecyl)-1H-1,2,3-triazol-4-yl)hexyl)amino)propyl)-N1,N4,N4-tris(6-(1- (8-pentyltridecyl)-1H-1,2,3-triazol-4-yl)hexyl)butane-1,4-diamine

[0444] This compound has the chemical formula C137H264N18, with a molecular weight of 2163.75 g / mol. The compound preparation, and that of some intermediates used in the same, were made as follows:

[0445] To a solution of A4L3 (250 mg, 364.35 μmol, 1 eq) in t-BuOH (3 mL) and H2O (3 mL) was added sodium;(2R)-2-[(1S)-1,2-dihydroxyethyl]-4-hydroxy-5-oxo-2H-furan-3-olate (72.18 mg, 364.35 μmol, 1 eq), diacetoxycopper (66.18 mg, 364.35 μmol, 1 eq) and T19 (646.01 mg, 2.19 mmol, 6 eq). The mixture was stirred at 20 °C for 1h. A new peak was detected by LCMS. The residue was diluted with water 30 mL and extracted with dichloromethane 10 mL (10 mL * 3). The combined organic layers were washed with brine (10 mL * 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residuewas purified by prep-HPLC (column: CD12-ACCHROM phenyl-Hexyl 150*25*10 um;mobile phase: [water(HCl)-ACN];gradient:68%-98% B over 15 min). Compound A4L3T19 (60 mg, 27.73 μmol, 7.61% yield) obtained as a light yellow oil. CAD: (M / 2 + H+) = 1082.7.

[0446] 1H NMR (400 MHz, CHLOROFORM-d): δ = 7.28 - 7.27 (m, 5H), 4.32 – 4.28 (m, 10H), 2.72 – 2.42 (m, 24H), 1.86 - 1.23 (m, , 195 H), 0.90 – 0.87 (m, 30H). Example A4L2T14

[0447] This compound has the chemical formula C127H229N23O15, with a molecular weight of 2318.38 g / mol. The compound preparation, and that of some intermediates used in the same, were made as follows:

[0448] To a solution of compound A4L2 (350 mg, 460 μmol, 1.0 eq) in t-BuOH (3.5 mL) and H2O (3.5 mL) was added sodium;(2R)-2-[(1S)-1,2-dihydroxyethyl]-4-hydroxy-5-oxo- 2H-furan-3-olate (91.1 mg, 460 μmol, 1.0 eq) and Cu(OAc)2(83.5 mg, 460 μmol, 1.0 eq) and compound T14 (859 mg, 2.76 mmol, 6.0 eq). The mixture was stirred at 20 °C for 2 h. LC-MS showed Reactant A4L2 was consumed completely and the desired mass was detected. The residue was diluted with water (30 mL) and extracted with dichloromethane (30 mL * 3). The combined organic layers were washed with brine (30 mL * 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: CD12-ACCHROM phenyl-Hexyl 150 * 25 * 10 um; mobile phase: [water (TFA) - (CAN – THF 2 / 1)]; gradient: 58%-88% B over 15 min). Compound A4L2T14 (200 mg, 85.1 μmol, 18.5% yield, 98.6% purity) was obtained as yellow oil. LCMS product: RT = 0.679 min. CAD product: RT = 12.391 min.1H NMR (400 MHz, CDCl3): δ = 7.79 (br d, J = 6.0 Hz, 4H), 7.58 - 7.43 (m, 5H), 4.86 - 4.86 (m, 1H), 4.86 (q, J = 6.4 Hz, 4H), 4.32 (br t, J = 7.2 Hz, 10H),59 - 3.48 (m, 10H), 2.93 (br t, J = 6.8 Hz, 10H), 2.65 (br d, J = 5.6 Hz, 8H), 2.29 (br t, J = 7.6 Hz, 16H), 1.96 - 1.88 (m, 12H), 1.78 (br d, J = 15.6 Hz, 14H), 1.67 (td, J = 7.6, 15.2 Hz, 12H), 1.55 - 1.45 (m, 22H), 1.37 - 1.20 (m, 70H), 0.93 - 0.84 (m, 30H). Example A4L1T19bis(2-(1-(8-pentyltridecyl)-1H-1,2,3-triazol-4-yl)ethyl) 3,3'-((3-((4-(bis(3-oxo-3-(2-(1-(8- pentyltridecyl)-1H-1,2,3-triazol-4-yl)ethoxy)propyl)amino)butyl)(3-oxo-3-(2-(1-(8- pentyltridecyl)-1H-1,2,3-triazol-4-yl)ethoxy)propyl)amino)propyl)azanediyl)dipropionate

[0449] This compound has the chemical formula C132H244N18O10, with a molecular weight of 2243.52 g / mol. The compound preparation, and that of some intermediates used in the same, were made as follows:

[0450] To a solution of A4L1 (280 mg, 366 μmol, 1.0 eq) in H2O (2 mL) and t-BuOH (2 mL) was added Cu(OAc)2 (66.4 mg, 366 μmol, 1.0 eq), sodium;(2R)-2-[(1S)-1,2- dihydroxyethyl]-4-hydroxy-5-oxo-2H-furan-3-olate (72.4 mg, 366 μmol, 1.0 eq) and compound T19 (648 mg, 2.19 mmol, 6.0 eq). The mixture was stirred at 20 °C for 2 h. LCMS showed the starting material was consumed completely. The mixture was diluted with water (30 mL) and extracted with dichloromethane (30 mL x 2). The combined organic phase was washed with brine (30 mL x 2), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: CD12-ACCHROM phenyl-Hexyl 150 * 25 * 10 um; mobile phase: [water (TFA) - (CAN – THF 2 / 1)]; gradient: 68%-98% B over 15 min) and lyophilized to give the product. The residue was purified by prep-HPLC (column: CD12- ACCHROM phenyl-Hexyl 150 * 25 * 10 um; mobile phase: [water (TFA) - (CAN – THF 2 / 1)]; gradient: 68%-98% B over 10 min) and lyophilized to give the product. The product A4L1T19 (170 mg, 73.3 μmol, 20.0% yield, 96.6% purity) was obtained as yellow oil. LCMS product: RT= 3.547 min. CAD product: RT = 11.557 min.1H NMR (400 MHz,CDCl3): δ = 7.60 - 7.35 (m, 5H), 4.33 (q, J = 6.8 Hz, 18H), 3.06 (br t, J = 6.9 Hz, 8H), 2.78 - 2.69 (m, 8H), 2.43 (br t, J = 7.0 Hz, 10H), 1.92 - 1.86 (m, 8H), 1.59 (br s, 22H), 1.36 - 1.28 (m, 39H), 1.23 (br s, 96H), 0.89 (t, J = 7.0 Hz, 30H). Example A4L3T14di(undecan-6-yl) 6,6'-((((3-((4-(bis(6-(1-(6-oxo-6-(undecan-6-yloxy)hexyl)-1H-1,2,3- triazol-4-yl)hexyl)amino)butyl)(6-(1-(6-oxo-6-(undecan-6-yloxy)hexyl)-1H-1,2,3-triazol-4- yl)hexyl)amino)propyl)azanediyl)bis(hexane-6,1-diyl))bis(1H-1,2,3-triazole-4,1- diyl))dihexanoate

[0451] This compound has the chemical formula C132H244N18O10, with a molecular weight of 2243.52 g / mol. The compound preparation, and that of some intermediates used in the same, were made as follows:

[0452] To a solution of A4L3 (350 mg, 510.09 μmol, 1 eq) in t-BuOH (3 mL) and H2O (3 mL) was added Cu(OAc)2 (92.65 mg, 510.09 μmol, 1 eq) , sodium;(2R)-2-[(1S)-1,2- dihydroxyethyl]-4-hydroxy-5-oxo-2H-furan-3-olate (101.05 mg, 510.09 μmol, 1 eq) and T14 (794.37 mg, 2.55 mmol, 5 eq). The mixture was stirred at 25 °C for 1h. LCMS showed the starting material was consumed completely. The mixture was diluted with water (10 mL) and extracted with dichloromethane (10 mL×2). The combined organic phase was washed with brine (10 mL ×2), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: CD12-ACCHROM phenyl-Hexyl 150*25*10 um; mobile phase: [water (TFA)-ACN]; gradient:55%-85% B over 15 min) and lyophilized to give the product. The residue was purified by prep-HPLC (column: CD12-ACCHROM phenyl-Hexyl 150*25*10 um; mobile phase: [water (HCl)-ACN]; gradient:60%-80% B over 10 min) and lyophilized to give the product. Compound of A4L3T14 (100 mg, 43.87 μmol, 8.60% yield, 98.421% purity) was obtained as a yellow oil. LCMS product: RT = 0.522 min. CAD product:RT = 13.559 min.

[0453] 1H NMR (400 MHz,CDCl3): δ = 7.29 - 7.27 (m, 5H), 4.92 - 4.82 (m, 5H), 4.31 (t, J = 7.2 Hz, 10H), 2.70 (t, J = 7.6 Hz, 10H), 2.47 - 2.35 (m, 12H), 2.30 (t, J = 7.2 Hz, 10H), 1.92 (, J = 7.2 Hz, 12H), 1.68 (d, J = 7.2, 15.1 Hz, 28H), 1.53 - 1.47 (m, 22H), 1.40 - 1.25 (m, 100H), 0.88 (t, J = 6.6 Hz, 30H). Example A10L1T19tetrakis(2-(1-(8-pentyltridecyl)-1H-1,2,3-triazol-4-yl)ethyl) 3,3',3'',3'''-(butane-1,4- diylbis(azanetriyl))tetrapropionate

[0454] The compound preparation, and that of some intermediates used in the same, were made as follows:

[0455] A mixture of T14_31-3B (0.57 g, 2.11 mmol, 1 eq), triphenylphosphane (1.38 g, 5.27 mmol, 2.5 eq), carbon tetrabromide (1.40 g, 4.21 mmol, 2 eq) and imidazole (573.83 mg, 8.43 mmol, 4 eq) in THF (10 mL) was stirred at 25 ℃ for 12 h under N2 atmosphere. TLC (Petroleum ether: Ethyl acetate = 1:0, Rf = 0.99) indicated that T14_31-3B was consumed completely and one new spot formed. The reaction mixture was quenched by adding water (10 mL), and then extracted with ethyl acetate 40 mL (20 mL * 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash®Silica Flash Column, Eluent of 0~10% Ethyl acetate / Petroleum ethergradient @ 60 mL / min). Compound T14_31-3A(1.3 g, 3.90 mmol, 92.52% yield) was obtained as a colourless oil.1H NMR (400MHz, CHLOROFORM-d): δ = 3.42 (t, J = 6.8 Hz, 2H), 1.87 (q, J = 7.2 Hz, 2H), 1.47 - 1.40 (m, 2H), 1.35 - 1.20 (m, 25H), 0.89 (t, J = 7.2 Hz, 6H).

[0456] To a solution of T14_31-3A(1.3 g, 3.90 mmol, 1 eq) in DMF (10 mL) was slowly added NaN3 (320 mg, 4.92 mmol, 1.26 eq). The mixture was stirred at 60 °C for 2 h. TLC (Petroleum ether : Ethyl acetate = 1:0, Rf = 0.9) indicated that T14_31-3A was consumed completely and one new spot formed. The reaction was quenched by saturated Na2CO3(10 mL) to adjust to pH = 9 at 20 °C and extracted with PE (20 mL). The combined organic layers werewashed with brine 20 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The aqueous phase was diluted 50 times, quenched with sodium hypochlorite, and left overnight, then discarded. The product was used into the next step without further purification. Compound T19 (0.8 g, 2.71 mmol, 69.43% yield) was obtained as a light yellow oil.1H NMR (400 MHz, CHLOROFORM-d): δ = 3.27 (t, J = 7.2 Hz, 2H), 1.64 - 1.59 (m, 2H), 1.40 - 1.21 (m, 27H), 0.89 (t, J = 7.2 Hz, 6H).

[0457] A mixture of A10 (0.3 g, 3.40 mmol, 342.08 μL, 1 eq), TEA (1.03 g, 10.21 mmol, 1.42 mL, 3 eq) and but-3-yn-1-yl acrylate (2.53 g, 20.42 mmol, 6 eq) was stirred at 100 °C for 12h. The desired mass was detected by LCMS. The reaction was quenched by adding water (10 mL), and then extracted with DCM 40 mL (20 mL * 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash®Silica Flash Column, Eluent of 0~10% MeOH / DCM ethergradient @ 50 mL / min). Compound A10L1 (1.6 g, 2.71 mmol, 79.60% yield, 99% purity) was obtained as a light yellow oil. LCMS: (M + H+) = 585.0.

[0458] 1H NMR (400 MHz, CHLOROFORM-d): δ = 4.19 (t, J = 6.8 Hz, 8H), 2.78 (t, J = 7.2 Hz, 8H), 2.56 – 2.52 (m, 8H), 2.47 (t, J = 7.2 Hz, 8H), 2.42 (s, 4H), 2.02 (t, J = 2.4 Hz, 4H), 1.40 (s, 4H).

[0459] To a solution of A10L1 (350 mg, 598.60 μmol, 1 eq) in t-BuOH (5 mL) and water (5 mL) was added sodium;(2R)-2-[(1S)-1,2-dihydroxyethyl]-4-hydroxy-5-oxo-2H-furan-3-olate (118.59 mg, 598.60 μmol, 1 eq), diacetoxycopper (108.73 mg, 598.60 μmol, 1 eq) and 1-azido-8- pentyltridecane (T19, 796.00 mg, 2.69 mmol, 4.5 eq). The mixture was stirred at 25 °C for 2 h. TLC (Dichloromethane : Methanol = 10:1, Rf = 0.9) indicated A10L1 was consumed completely and one new spot formed. The reaction mixture was quenched by adding water (10 mL), and then extracted with DCM 50 mL (25 mL * 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash®Silica Flash Column, Eluent of 0~10% MeOH / DCM ethergradient @ 30 mL / min). The residue was purified by prep-HPLC (column: CD12-WePure Biotech Phenyl-Hexyl 150*25mm*7um;mobile phase: [H2O(0.1%TFA)- ACN];gradient:65%-95% B over 15.0 min). Compound A10L1T19 (200 mg, 0.11 mmol, 18.47% yield, 97.69% purity) was obtained as a light yellow oil. CAD: (M / 2 + H+) = 884.0.

[0460] 1H NMR (400 MHz, CHLOROFORM-d): δ = 7.40 (s, 4H), 4.33 (q, J = 7.2 Hz,16H), 3.06 (t, J = 6.8 Hz, 8H), 2.74 (t, J = 6.8 Hz, 8H), 2.43 (t, J = 6.8 Hz, 12H), 1.89 (t, J = 6.8 Hz, 8H), 1.37 - 1.29 (m, 32H), 1.27 - 1.17 (m, 80H), 0.89 (t, J = 7.1 Hz, 24H). Examp6,6',6'',6'''-((((3,3',3'',3'''-((piperazine-1,4-diylbis(propane-3,1- diyl))bis(azanetriyl))tetrakis(propanoyl))tetrakis(azanediyl))tetrakis(ethane-2,1-diyl))tetrakis(1H- 1,2,3-triazole-4,1-diyl))tetrakis(N-(heptadecan-9-yl)hexanamide)

[0461] This compound has the chemical formula C130H244N24O8, with a molecular weight of 2271.54 g / mol. The compound preparation, and that of some intermediates used in the same, were made as follows:

[0462] To a solution of compound 2 (500 mg, 2.56 mmol, 1 eq) was dissolved in DCM (25 mL) , and EDCI (540 mg, 2.82 mmol, 1.1 eq) was added in portions at 0 °C , after stirring for 30 min, compound 3241-20-1 (720 mg, 2.82 mmol, 1.1 eq) ) was added dropwise to the reaction solution. After the dropwise addition, the mixture was stirred at 20 °C for 12 h. LCMS showed the product (RT = 0.680 min, [M+1]+=432.2) was the main peak. The mixture was concentrated in vacuum to give residue. The crude product was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash®Silica Flash Column, Eluent of 5~8% Ethylacetate / Petroleum ethergradient @ 40 mL / min). Compound T15_11-1 (800 mg, 1.85 mmol, 72.1% yield, 100% purity) was obtained as a white solid which was confirmed by HNMR. LCMS product: RT =0.680 min.

[0463] 1H NMR (400 MHz, CHLOROFORM-d): δ = 5.10 (br d, J = 8.8 Hz, 1H), 3.98 - 3.82 (m, 1H), 3.41 (t, J = 6.8 Hz, 2H), 2.18 (t, J = 7.6 Hz, 2H), 1.89 (quin, J = 7.2 Hz, 2H), 1.70 - 1.64 (m, 2H), 1.52 - 1.43 (m, 4H), 1.35 - 1.23 (m, 26H), 0.88 (t, J = 6.8 Hz, 6H).

[0464] To a solution of compound T15_11-1 (4.6 g, 10.6 mmol, 1.0 eq) in DMF (40 mL) was added NaN3 (650 mg, 10.0 mmol, 0.94 eq). The mixture was stirred at 60 °C for 2h. LCMS showed the product (RT = 0.690 min, [M+1]+=395.4) was the main peak. The reaction was quenched by saturated NaHCO3 (9 mL) to adjust to pH = 9 at 20 °C and extracted with PE 30 mL. The combined organic layers were washed with brine 40 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The aqueous phase was diluted 50 times, quenched with sodium hypochlorite, and left overnight, then discarded. The crude product was used for next step directly without purification. Compound T21 (4.1 g, 10.3 mmol, 97.5% yield, 99.9% purity) was obtained as a yellow solid which was confirmed by HNMR. LCMS product: RT = 0.690 min.1H NMR (400 MHz, CHLOROFORM-d): δ = 5.10 (br d, J = 9.2 Hz, 1H), 3.97 - 3.82 (m, 1H), 3.27 (t, J = 6.8 Hz, 2H), 2.17 (t, J = 7.6 Hz, 2H), 1.75 - 1.56 (m, 5H), 1.53 - 1.36 (m, 5H), 1.35 - 1.19 (m, 28H), 0.88 (t, J = 6.8 Hz, 6H).

[0465] To a solution of compound A5 (200 mg, 998 μmol, 1.0 eq) was added compound L2 (737 mg, 5.99 mmol, 6.0 eq). The mixture was stirred at 100 °C for 12h. LCMS showed the product (RT =0.336 min, [M+1]+= 693.4) was the main peak. The mixture was concentrated in vacuum to give residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 (250*70mm,10 um); mobile phase: [water(TFA)-ACN];gradient:0%-30% B over 25 min) and lyophilized to give the product. The compound A5L2 (600 mg, 865 μmol, 86.7% yield) was obtained as a yellow oil. LCMS product: RT = 0.336 min.

[0466] To a solution of compound A5L2 (300 mg, 432 μmol, 1.0 eq) in H2O (4 mL) and t- BuOH (4 mL) t-BuOH (4 mL) was added sodium;(2R)-2-[(1S)-1,2-dihydroxyethyl]-4-hydroxy-5- oxo-2H-furan-3-olate (85.7 mg, 432 μmol, 1.0 eq), Cu(OAc)2(78.6 mg, 432 μmol, 1.0 eq) and compound T21 (854 mg, 2.16 mmol, 5.0 eq). The mixture was stirred at 20 °C for 1 h. LCMS showed the product (tp=0.528 min, [M / 3]+= 758.2) was the main peak. The mixture was diluted with water (30 mL) and extracted with dichloromethane (30 mL×2). The combined organic phase was washed with brine (30 mL ×2), dried with anhydrous Na2SO4, filtered and concentrated invacuum. The residue was purified by prep-HPLC (column: CD27-PHS XP phenyl-Hexyl 150*25*7um;mobile phase: [water(TFA)-ACN];gradient:55%-85% B over 15 min). The compound A5L2T21 (120 mg, 47.81 μmol, 11.0% yield, 90.5% purity) was obtained as a white solid which was confirmed by HNMR. LCMS product: RT = 0.528 min. CAD product: RT = 13.727 min.1H NMR (400 MHz, CHLOROFORM-d): δ = 7.77 - 7.71 (m, 4H), 7.46 (s, 4H), 5.58 (br d, J = 9.2 Hz, 4H), 4.34 - 4.29 (m, 8H), 3.91 - 3.83 (m, 4H), 3.56 (q, J = 6.4 Hz, 8H), 2.92 (br t, J = 6.8 Hz, 8H), 2.65 (br t, J = 6.1 Hz, 8H), 2.43 (br t, J = 6.8 Hz, 10H), 2.34 - 2.27 (m, 12H), 2.16 (t, J = 7.2 Hz, 8H), 1.91 (td, J = 7.3, 14.8 Hz, 12H), 1.80 (br s, 22H), 1.67 (br s, 6H), 1.59 (br d, J = 6.4 Hz, 4H), 1.45 (br dd, J = 5.6, 10.7 Hz, 10H), 1.25 (br s, 88H), 0.88 (t, J = 6.8 Hz, 24H). Example A5L3T22N,N'-(piperazine-1,4-diylbis(propane-3,1-diyl))bis(6-(1-(8-octylhexadecyl)-1H-1,2,3- triazol-4-yl)-N-(6-(1-(8-octylhexadecyl)-1H-1,2,3-triazol-4-yl)hexyl)hexan-1-amine)

[0467] This compound has the chemical formula C138H268N16, with a molecular weight of 2151.77 g / mol. The compound preparation, and that of some intermediates used in the same, were made as follows:

[0468] To a solution of A5L3.X (100 mg, 157.97 μmol, 1 eq) in H2O (1 mL) and t-BuOH (1 mL) was added sodium;(2R)-2-[(1S)-1,2-dihydroxyethyl]-4-hydroxy-5-oxo-2H-furan-3-olate (31.29 mg, 157.97 μmol, 1 eq), diacetoxycopper (28.69 mg, 157.97 μmol, 1 eq) and T22 (299.87 mg, 789.83 μmol, 5 eq). The mixture was stirred at 25 °C for 1 h. LC-MS showed A5L3.X was consumed completely and one main peak with desired m / z. The reaction mixture was quenched by adding H2O (10 mL) at 25 °C, and extracted with DCM (10 mL *3). The combined organic layers were washed with brine (20 mL *2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: CD30- WePure Biotech Phenyl-Hexyl 250*50mm*7um;mobile phase: [H2O(0.1%TFA)- ACN:THF=2:1];gradient:70%-100% B over 15.0 min). Compound A5L3T22 (130 mg, 60.42 μmol, 38.25% yield) was obtained as a white solid. LCMS: (M / 3 + H+) = 718.1. CAD: (M / 3 + H+) = 718.3.1H NMR (400 MHz, CHLOROFORM-d): δ：7.28 (s, 4H), 4.31 (t, J = 7.4 Hz, 8H), 3.20 - 3.08 (m, 4H), 3.07 - 3.06 (m, 1H), 3.07 - 2.94 (m, 12H), 2.90 - 2.80 (m, 4H), 2.71 (t, J = 7.5 Hz, 7H), 2.17 - 2.05 (m, 4H), 1.93 - 1.86 (m, 11H), 1.70 (br d, J = 7.0 Hz, 18H), 1.43 - 1.37 (m, 14H), 1.32 (br d, J = 8.1 Hz, 22H), 1.27 (br s, 75H), 1.22 (br s, 60H), 0.92 - 0.85 (m, 24H). Example A6L2T18

[0469] This compound has the chemical formula C110H204N24O8, with a molecular weight of 1991.00 g / mol. The compound preparation, and that of some intermediates used in the same, were made as follows:

[0470] To a solution of compound A6L1T14_12-1 (1.00 g, 9.47 mmol, 1.0 eq, HCl) in DCM (10 mL) was added TEA (2.88 g, 28.4 mmol, 3.96 mL, 3.0 eq) and DMAP (57.8 mg, 473 μmol, 0.05 eq) and compound 2 (1.03 g, 11.3 mmol, 923 μL, 1.2 eq) in DCM (10 mL) at 0 °C. The mixture was stirred at 25 °C for 2 h. TLC (Petroleum ether: Ethyl acetate=1:1, Rf= 0.47) indicated compound A6L1T14_12-1 was consumed completely and one new spot formed. The reaction was clean according to TLC. The residue was diluted with water 30 mL and extracted with dichloromethane 50 mL (50 mL * 3). The combined organic layers were washed with brine 50 mL (50 mL * 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash®Silica Flash Column, Eluent of 0~30% Ethyl acetate / Petroleum ethergradient @ 60 mL / min). Compound L2 (4.15 g, 33.7 mmol, 71.1% yield) was obtained as a white solid.

[0471] 1H NMR (400 MHz, CDCl3): δ = 6.36 - 6.24 (m, 1H), 6.17 - 6.07 (m, 1H), 6.04 - 5.81 (m, 1H), 5.67 (dd, J = 1.4, 10.3 Hz, 1H), 3.51 (q, J = 6.3 Hz, 2H), 2.46 (dt, J = 2.6, 6.4 Hz, 2H), 2.03 (t, J = 2.7 Hz, 1H).

[0472] To a solution of compound A6 (500 mg, 1.71 mmol, 1.0 eq, HCl) in t-BuOH (10 mL) was added TEA (1.21 g, 11.9 mmol, 1.66 mL, 7.0 eq) and compound L2 (1.68 g, 13.6 mmol, 8.0 eq). The mixture was stirred at 100 °C for 12h. LC-MS showed that compound A6 was consumed completely and the desired mass was detected. The reaction mixture concentrated. The residue was purified by prep-HPLC (column: Phenomenex luna C18 (250*70mm,10 um);mobile phase: [water(TFA)-ACN];gradient:0%-30% B over 25 min). Compound A6L2 (300 mg, 400 μmol, 23.4% yield) was obtained as a light yellow oil. LCMS product: RT = 0.216 min.

[0473] 1H NMR (400 MHz, DEUTERIUM OXIDE): δ = 3.79 - 3.68 (m, 2H), 3.55 - 3.41 (m, 12H), 3.38 - 3.23 (m, 14H), 3.09 (br d, J = 10.4 Hz, 4H), 2.78 (br t, J = 6.1 Hz, 8H), 2.47 - 2.33 (m, 12H), 1.86 (br s, 6H), 1.79 - 1.68 (m, 2H), 1.40 (br d, J = 5.4 Hz, 6H).

[0474] To a solution of compound A6L2 (250 mg, 333 μmol, 1.0eq) in t-BuOH (3 mL) and H2O (3 mL) was added sodium;(2R)-2-[(1S)-1,2-dihydroxyethyl]-4-hydroxy-5-oxo-2H-furan- 3-olate (66.1 mg, 333 μmol, 1.0 eq), Cu(OAc)2(60.6 mg, 333 μmol, 1.0 eq) and compound T18 (518.13 mg, 1.67 mmol, 5 eq) .The mixture was stirred at 20 °C for 2h. LC-MS showed compound T18 was consumed completely and one main peak with the desired mass was detected. The residue was diluted with water 30 mL and extracted with dichloromethane 20 mL (20 mL * 3). The combined organic layers were washed with brine 20 mL (20 mL * 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: CD27-PHS XP phenyl-Hexyl 150*25*7um;mobile phase: [water(TFA)-ACN];gradient:35%-65% B over 10 min). Compound A6L2T18 (80 mg, 37.2 μmol, 11.1% yield, 92.6% purity) was obtained as a light yellow oil. LCMS product: RT = 0.508 min. CAD product: RT = 12.763 min.1H NMR (400 MHz, CDCl3): δ = 7.82 (br t, J = 5.6 Hz, 4H), 7.48 (s, 4H), 5.57 (br d, J = 9.2 Hz, 4H), 4.31 (t, J = 7.2 Hz, 8H), 3.94 - 3.83 (m, 4H), 3.55 (q, J = 6.8 Hz, 8H), 2.93 (t, J = 6.8 Hz, 8H), 2.81 - 2.58 (m, 12H), 2.40 (br s, 4H), 2.32 (br t, J = 6.4 Hz, 8H), 2.16 (t, J = 7.4 Hz, 8H), 1.94 - 1.87 (m, 8H), 1.70 - 1.64 (m, 10H), 1.50 - 1.43 (m, 8H), 1.39 - 1.21 (m, 76H), 0.97 (br s, 6H), 0.91 - 0.84 (m, 24H).ExamN,N'-(((trans)-2,5-dimethylpiperazine-1,4-diyl)bis(butane-4,1-diyl))bis(6-(1-(8- pentyltridecyl)-1H-1,2,3-triazol-4-yl)-N-(6-(1-(8-pentyltridecyl)-1H-1,2,3-triazol-4- yl)hexyl)hexan-1-amine)

[0475] This compound has the chemical formula C118H228N16, with a molecular weight of 1871.23 g / mol. The compound preparation, and that of some intermediates used in the same, were made as follows:

[0476] To a solution of compound 1 (5.00 g, 39.6 mmol, 1.0 eq) in THF (50 mL) was added CBr4(26.2 g, 79.2 mmol, 2.0eq) and PPh3(26.0 g, 99.0 mmol, 2.5 eq) and imidazole (2.70 g, 39.6 mmol, 1.0 eq). The mixture was stirred at 25 °C for 12h. TLC (Ethyl acetate: Petroleum ether=0:1, Rf = 0.42) indicated compound 1 was consumed completely and one new spot formed. The reaction was clean according to TLC. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash®Silica Flash Column, Eluent of 0%Ethylacetate / Petroleum ethergradient @ 50 mL / min). Compound L3.X (4.0 g, 21.15 mmol, 53.3% yield) was obtained as a colorless oil.

[0477] 1H NMR (400 MHz, CDCl3): δ = 3.42 (t, J = 6.8 Hz, 2H), 2.21 (br t, J = 6.8 Hz, 2H), 1.95 (br s, 1H), 1.93 - 1.83 (m, 2H), 1.56 (s, 2H), 1.46 (br s, 4H).

[0478] To a solution of compound A6 (1.00 g, 3.41 mmol, 1.0 eq, HCl) in MeCN (10 mL) and H2O (3 mL) was added K2CO3 (1.42 g, 10.24 mmol, 3.0 eq) and compound L3.X (2.91 g, 15.3 mmol, 4.5 eq). The mixture was stirred at 60 °C for 4h. LC-MS showed compound A6 was consumed completely and desired mass was detected. The residue was diluted with water 20 mLand extracted with ethyl acetate 20 mL (20 mL * 3). The combined organic layers were washed with brine 20 mL (20 mL * 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 (250*70mm,10 um); mobile phase: [water(TFA)-ACN];gradient:15%- 45% B over 25 min). Compound A6L3 was obtained as a white solid. LCMS product: RT = 0.351 min.1H NMR (400 MHz, METHANOL-d4): δ = 3.67 - 3.54 (m, 2H), 3.54 - 3.42 (m, 2H), 3.33 (br s, 2H), 3.27 - 3.10 (m, 12H), 3.10 - 2.91 (m, 4H), 2.24 - 2.16 (m, 11H), 1.89 - 1.67 (m, 16H), 1.60 - 1.47 (m, 16H), 1.46 - 1.34 (m, 14H).

[0479] To a solution of compound A6L3 (350 mg, 507 μmol, 1.0 eq) in H2O (3 mL) and t- BuOH (3 mL) was added sodium;(2R)-2-[(1S)-1,2-dihydroxyethyl]-4-hydroxy-5-oxo-2H-furan-3- olate (100 mg, 507 μmol, 1.0 eq, CAS: 134-03-2) and Cu (OAc)2(92.2 mg, 507 μmol, 1.0 eq) and compound T19 (750 mg, 2.54 mmol, 5.0 eq). The mixture was stirred at 20 °C for 2h. LC-MS showed compound A6L3 was consumed completely and the desired mass was detected. The residue was diluted with water 20 mL and extracted with dichloromethane 20 mL (20 mL * 3). The combined organic layers were washed with brine 30 mL (30 mL * 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: CD27-PHS XP phenyl-Hexyl 150*25*7um; mobile phase: [water(TFA)-ACN];gradient:60%-90% B over 15 min). Compound A6L3T19 (190 mg, 99.7 μmol, 19.6% yield, 98.2% purity) was obtained as a yellow oil. LCMS product: RT = 0.563 min. CAD product: RT = 16.097 min.1H NMR (400 MHz, CDCl3):

[0480] δ = 7.26 (s, 4H), 4.30 (t, J = 7.2 Hz, 8H), 2.79 (br s, 1H), 2.77 (br d, J = 1.6 Hz, 1H), 2.71 (t, J = 7.6 Hz, 10H), 2.51 - 2.32 (m, 12H), 2.23 (br dd, J = 2.4, 10.2 Hz, 2H), 2.06 - 1.97 (m, 2H), 1.92 - 1.85 (m, 8H), 1.67 (td, J = 7.6, 14.6 Hz, 32H), 1.51 - 1.36 (m, 24H), 1.30 (br s, 14H), 1.23 (br s, 80H), 1.04 (d, J = 6.0 Hz, 6H), 0.89 (t, J = 7.2 Hz, 24H). Example A39L1T15ethyl 9-(3-(2-(1-(6-(heptadecan-9-yloxy)-6-oxohexyl)-1H-1,2,3-triazol-4-yl)ethoxy)-3- oxopropyl)-1-((2-heptylnonanoyl)oxy)-8-oxo-7-oxa-3,4-dithia-9,13-diazapentadecan-15-oate

[0481] This compound has the chemical formula C58H107N5O10S2, with a molecular weight of 1098.64 g / mol, and a pKa = 6.366. The compound preparation, and that of some intermediates used in the same, were made as follows:

[0482] To a solution of compound A30-1A (1.00 g, 5.74 mmol, 1.00 mL, 1.0 eq) in compound L1 (570 mg, 4.59 mmol, 0.8 eq) was added to a 3-neck round bottom flask at 25oC. The mixture was stirred at 100 °C for 5 hrs. LCMS showed desired mass was detected. The mixture was concentrated in vacuum to give residue. The crude product was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash®Silica Flash Column, Eluent of 20~30% Ethylacetate / Petroleum ethergradient @ 50 mL / min). The compound A30-1C (800 mg, 2.58 mmol, 44% yield, 96.1% purity) was obtained as a yellow oil which was confirmed by HNMR. LCMS product: RT = 0.215 min.1H NMR (400 MHz, CDCl3):

[0483] δ = 5.04 (br s, 1H), 4.18 - 4.23 (m, 2H), 3.19 - 3.21 (m, 2H), 2.90 (t, J = 6.4 Hz, 2H), 2.69 (t, J = 6.8 Hz, 2H), 2.54 - 2.57 (m, 4H), 2.01 – 2.02 (m, 1H), 1.68 (s, 1H), 1.66 (quin, J = 6.4 Hz, 2H), 1.64 (s, 9H).

[0484] To a solution of compound A30L1-1A (1.00 g, 3.90 mmol, 1.0 eq) in DCM (8 mL) was added DMAP (571 mg, 4.68 mmol, 1.2 eq), DCC (885 mg, 4.29 mmol, 867 μL, 1.1 eq) and compound A30L1-1B (1.80 g, 11.7 mmol, 3.0 eq). The mixture was stirred at 20 °C for 12 h. TLC (PE: EA= 3:1) showed the reactant (Rf= 0.13) was consumed completely and one newmajor spot (Rf= 0.41) was detected. The mixture was filtered and the filtrate was concentrated to give crude product. The crude product was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash®Silica Flash Column, Eluent of 10~20% Ethylacetate / Petroleum ethergradient @ 50 mL / min). The compound A30L1-1C (3.70 g, 9.42 mmol, 80.5% yield) was obtained as a colorless oil which was confirmed by HNMR.

[0485] 1H NMR (400 MHz, CDCl3): δ = 4.31 - 4.41 (m, 2H), 3.83 - 3.96 (m, 2H), 2.83 – 3.00 (m, 4H), 2.28 - 2.40 (m, 1H), 2.03 - 2.20 (m, 1H), 1.55 - 1.65 (m, 2H), 1.44 (br dd, J = 6.0, 13.5 Hz, 2H), 1.26 - 1.29 (m, 20H), 0.99 - 0.78 (m, 6H).

[0486] To a solution of compound A30L1-1C (1.00 g, 2.55 mmol, 1.0 eq) in DCM (25 mL) was added Py (402 mg, 5.09 mmol, 411 μL, 2.0 eq) and compound 7 (770 mg, 3.82 mmol, 1.5 eq). The mixture was stirred at 0 °C for 30 min. TLC (PE : EA=3:1) showed the compound A30L1-1C (Rf= 0.40) was consumed completely and one new major spot (Rf= 0.62) was detected. Petroleum ether is poured into the reaction solution, filtered and concentrated in vacuum to afford the product. Compound A30L1-1D (1.40 g, 2.51 mmol, 98.5% yield) was obtained as a colorless oil which was confirmed by HNMR.1H NMR (400 MHz, CDCl3):

[0487] δ = 8.26 - 8.34 (m, 2H), 7.38 - 7.42 (m, 2H), 4.56 (t, J = 6.8 Hz, 2H), 4.37 (t, J = 6.8 Hz, 2H), 3.03 - 3.08 (m, 2H), 2.97 (t, J = 6.4 Hz, 2H), 2.30 - 2.40 (m, 1H), 1.57 - 1.64 (m, 2H), 1.41 - 1.49 (m, 2H), 1.26 - 1.31 (m, 20H), 0.86 - 0.91 (m, 6H).

[0488] To a solution of compound A30L1-1D (1.40 g, 2.51 mmol, 1.0 eq) in ACN (40 mL) was added Py (397 mg, 5.02 mmol, 405 μL, 2.0 eq) DMAP (153 mg, 1.26 mmol, 0.5 eq) and compound A30-1C (898 mg, 3.01 mmol, 1.2 eq). The mixture was stirred at 25 °C for 12 h. LCMS showed the product (Rt=0.635 min, [M+1]+=717.4) was the main peak. The mixture was concentrated in vacuum to give residue. The crude product was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash®Silica Flash Column, Eluent of 10~20% Ethylacetate / Petroleum ethergradient @ 50 mL / min). Compound A30-1H (1.74 g, 2.42 mmol, 96.4% yield, 99.7% purity) was obtained as a colorless oil which was confirmed by HNMR. LCMS product: RT = 0.635 min.1H NMR (400 MHz, CDCl3):

[0489] δ = 4.31 - 4.40 (m, 4H), 4.20 (t, J = 6.8 Hz, 2H), 3.47 - 3.59 (m, 2H), 3.27 - 3.40 (m, 2H), 3.12 (br d, J = 4.1 Hz, 2H), 2.94 (td, J = 6.5, 9.9 Hz, 4H), 2.64 (t, J = 7.1 Hz, 2H), 2.54 (dt, J = 2.4, 6.7 Hz, 2H), 2.34 (tt, J = 5.3, 8.8 Hz, 1H), 2.02 (br s, 1H), 1.53 - 1.79 (m, 5H), 1.46(s, 10H), 1.21 - 1.32 (m, 20H), 0.79 - 0.95 (m, 6H).

[0490] To a solution of compound A30-1H (850 mg, 1.19 mmol, 1.0 eq) in DCM (5 mL) was added HCl / dioxane (2 M, 11.85 mL, 20 eq). The mixture was stirred at 20 °C for 12h. LCMS showed the product (Rt = 0.491 min, [M+1]+= 617.5) was the main peak. The mixture was concentrated in vacuum to give residue. The product compound A30-1I (1.55 g, 2.35 mmol, 98.9% yield, 98.9% purity, HCl) was obtained as a colorless oil. LCMS product: RT = 0.491 min.

[0491] To a solution of compound A30-1I (800 mg, 1.22 mmol, 1.0 eq, HCl) in DCM (15 mL) was added TEA (185 mg, 1.84 mmol, 255 μL, 1.5 eq) then compound 11 (204 mg, 1.22 mmol, 135 μL, 1.0 eq) in DCM (5 mL) dropwise into the mixture. The mixture was stirred at 20 °C for 4 hrs. LCMS showed the product (RT = 3.626 min, [M+1]+= 703.5) was the main peak. The mixture was concentrated in vacuum to give residue. The crude product was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash®Silica Flash Column, Eluent of 4~5% Dichloromethane / Methanol ether gradient @ 20 mL / min). The product compound A39L1 (750 mg, 1.06 mmol, 43.4% yield, 99.8% purity) was obtained as a yellow oil which was confirmed by HNMR. LCMS product: RT = 3.626 min.1H NMR (400 MHz, CHLOROFORM-d):

[0492] δ = 4.34 (br t, J = 6.4 Hz, 4H), 4.16 - 4.24 (m, 4H), 3.48 - 3.59 (m, 2H), 3.29 - 3.44 (m, 4H), 2.89 - 2.98 (m, 4H), 2.60 - 2.69 (m, 4H), 2.54 (dt, J = 2.5, 6.7 Hz, 2H), 2.28 - 2.40 (m, 1H), 2.02 (br s, 1H), 1.76 (br d, J = 4.8 Hz, 2H), 1.53 - 1.67 (m, 2H), 1.44 (br dd, J = 5.6, 14.1 Hz, 2H), 1.18 - 1.33 (m, 23H), 0.88 (t, J = 6.8 Hz, 6H).

[0493] To a solution of compound A39L1 (750 mg, 1.07 mmol, 1.0 eq) in t-BuOH (8.0 mL) and H2O (8 mL) was added compound sodium;(2R)-2-[(1S)-1,2-dihydroxyethyl]-3-hydroxy- 5-oxo-2H-furan-4-olate (211 mg, 1.07 mmol, 1.0 eq) (CAS: 134-03-0), Cu(OAc)2 (193 mg, 1.07 mmol, 1.0 eq) and compound T15 (633 mg, 1.60 mmol, 1.5 eq). The mixture was stirred at 20 °C for 1 h. LCMS showed the product (RT = 0.662 min, [M / 2+1]+=550.2) was the main peak. The mixture was diluted with water (20 mL) and extracted with dichloromethane (20 mL x3). The combined organic layers were washed with brine (20 mL x 3), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum. The crude product was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash®Silica Flash Column, Eluent of 5~8% Dichloromethane / Methanol ethergradient @ 30 mL / min). The residue was further purified by semi-preparative reverse phase HPLC (column: CD12-ACCHROM phenyl-Hexyl 150*25*10um;mobile phase: [water (TFA)-ACN]; gradient: 62%-92% B over 10 min). Compound A39L1T15 (380 mg, 314 μmol, 29.47% yield, 90.9% purity) was obtained as a yellow oil which was confirmed by HNMR. LCMS product: RT = 0.662 min. CAD product: RT = 14.670 min.

[0494] 1H NMR (400 MHz, CHLOROFORM-d): δ = 7.38 (br d, J = 6.8 Hz, 1H), 4.86 (t, J = 6.2 Hz, 1H), 4.31 - 4.39 (m, 8H), 4.06 - 4.26 (m, 2H), 3.52 (br d, J = 3.4 Hz, 2H), 3.39 (s, 2H), 3.33 (br d, J = 5.3 Hz, 2H), 3.07 (t, J = 6.8 Hz, 2H), 2.90 - 2.97 (m, 4H), 2.53 - 2.69 (m, 4H), 2.32 - 2.38 (m, 1H), 2.30 (t, J = 7.2 Hz, 2H), 1.91 - 1.96 (m, 2H), 1.65 - 1.77 (m, 6H), 1.57 - 1.61 (m, 2H), 1.51 (br d, J = 6.0 Hz, 3H), 1.39 (br dd, J = 8.0, 15.5 Hz, 4H), 1.24 - 1.30 (m, 46H), 0.88 (t, J = 6.8 Hz, 12H). Example A40L1T1515-(1-(6-(heptadecan-9-yloxy)-6-oxohexyl)-1H-1,2,3-triazol-4-yl)-9-(3-((2- hydroxyethyl)amino)propyl)-8,12-dioxo-7,13-dioxa-3,4-dithia-9-azapentadecyl nonanoate

[0495] This compound preparation, and that of some intermediates used in the same, were made as follows:

[0496] To a solution of but-3-yn-1-ol (14 g, 199.74 mmol, 15.12 mL, 1 eq), DMAP (1.22 g, 9.99 mmol, 0.05 eq) and TEA (30.32 g, 299.62 mmol, 41.70 mL, 1.5 eq) in DCM (300 mL), was added compound 7 (21.69 g, 239.69 mmol, 19.47 mL, 1.2 eq) 0 °C. The mixture was then stirred at 25 °C for 12 h. TLC (PE: EA=5:1) indicated two new spots (Rf = 0.70). The reaction mixture was quenched by adding H2O 500 mL, and extracted with DCM 300 mL. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated underreduced pressure to give a residue. The crude product was distilled in vacuum (60 °C, 0.2 MPa pressure / oil pump). Compound L1 (75 g, 604.17 mmol, 60.49% yield) was obtained as a light yellow oil.1H NMR (400 MHz, CDCl3): δ = 6.45 (dd, J = 1.2, 17.2 Hz, 1H), 6.15 (dd, J = 10.4, 17.2 Hz, 1H), 5.86 (dd, J = 1.2, 10.4 Hz, 1H), 4.28 (t, J = 6.8 Hz, 2H), 2.58 (dt, J = 2.4, 6.8 Hz, 2H), 2.02 (t, J = 2.8 Hz, 1H).

[0497] A mixture of compound L1 (1.00 g, 5.74 mmol, 1.00 mL, 1.0 eq) and tert-butyl (3- aminopropyl)carbamate (570 mg, 4.59 mmol, 0.8 eq) was stirred at 100 °C for 5 h. LCMS showed that the desired mass was detected. The crude product was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash®Silica Flash Column, Eluent of 20~30% Ethylacetate / Petroleum ethergradient @ 50 mL / min). Compound 9 (800 mg, 2.58 mmol, 44% yield, 96.1% purity) was obtained as a yellow oil which was confirmed by HNMR. LCMS product: RT = 0.215 min.1H NMR (400 MHz, CDCl3): δ = 5.04 (s, 1H), 4.18 - 4.23 (m, 2H), 3.19 - 3.21 (m, 2H), 2.90 (t, J = 6.4 Hz, 2H), 2.69 (t, J = 6.8 Hz, 2H), 2.54 - 2.57 (m, 4H), 2.01 – 2.02 (m, 1H), 1.68 (s, 1H), 1.66 (quin, J = 6.4 Hz, 2H), 1.64 (s, 9H).

[0498] To a solution of 6-bromohexanoic acid (16.73 g, 85.78 mmol, 1.1 eq) and heptadecan-9-ol (20 g, 77.98 mmol, 1 eq) in DCM (2000 mL) was added DMAP (14.29 g, 116.97 mmol, 1.5 eq) and EDCI (17.94 g, 93.58 mmol, 1.2 eq). The mixture was stirred at 25 °C for 12 h. TLC (PE: EA=20:1) indicated two new spots (Rf = 0.77).1000 mL water were added to the reaction mixture, and the aqueous phase was extracted with DCM (500 mL × 3). The combined organic phase was washed with brine (200 mL × 3), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=30 / 1 to 20 / 1). Compound 11 (55 g, 126.87 mmol, 32.54% yield) was obtained as a yellow oil.1H NMR (400 MHz, CDCl3): δ = 4.87 (m, 1H), 3.54-3.39 (m, 1H), 2.33-2.29 (m, 2H), 1.9-1.26 (m, 34H), 0.90-0.86 (t, J = 6.4 Hz, 6H).

[0499] To a solution of 11 (55 g, 126.87 mmol, 1 eq) in DMF (550 mL) was added NaN3(9.95 g, 153.05 mmol, 1.21 eq). The mixture was stirred at 60 °C for 12hr. TLC(PE:EA=20:1) indicated one new spot was detected (Rf = 0.76). The reaction mixture was quenched by H2O 1000 mL at 20 °C and extracted with PE 1000 mL. The combined organic layers were washed with brine 500 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The aqueous phase was diluted 50 times, quenched with sodium hypochlorite, and left overnight, then discarded. The product was used into the next step without further purification. Compound T15 (45 g, 113.75 mmol, 89.65% yield) was obtained as a yellow oil.1H NMR (400 MHz, CDCl3):δ = 4.89-4.86 (m, 1H), 3.22 (m, 2H), 2.30 (m, 2H), 1.66-1.26 (m, 34H), 0.89-0.86 (t, J = 6.0 Hz, 6H).

[0500] To a solution of 1 (2.5 g, 16.21 mmol, 1 eq) in DCM (25 mL) was added TEA (2.46 g, 24.31 mmol, 3.38 mL, 1.5 eq) and nonanoyl chloride (1.43 g, 8.10 mmol, 1.52 mL, 0.5 eq) in DCM (15 mL). The mixture was stirred at 0°C for 0.5hr. LC-MS showed that compound 1 was consumed completely and the desired mass was detected. The reaction mixture was quenched with 50 mL water and the aqueous phase was extracted with DCM (50 mL × 3). The combined organic phases were washed with brine (20 mL × 3), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=20 / 1 to 10 / 1). Compound 2 (5.8 g, 19.70 mmol, 30.38% yield) was obtained as a colorless oil. LCMS: m / z = 317.1 (M+Na)+, Rt= 3.13 min.1H NMR (400 MHz, CDCl3): δ = 4.36 (t, J = 6.8 Hz, 2H), 3.90 (t, J = 5.6 Hz, 2H), 3.06 - 2.79 (m, 4H), 2.33 (t, J = 7.6 Hz, 2H), 1.67 - 1.60 (m, 2H), 1.35 - 1.24 (m, 11H), 0.97 - 0.77 (m, 3H).

[0501] To a solution of 2 (5 g, 16.98 mmol, 1 eq) in DCM (80 mL) was added Py (2.69 g, 33.96 mmol, 2.74 mL, 2 eq) and 4-nitrophenyl carbonochloridate (3.76 g, 18.68 mmol, 1.1 eq). The mixture was stirred at 0 °C for 30 min. The mixture was stirred at 25 °C for 8 h. TLC (PE:EA=10:1) indicated three new spots were detected (Rf = 0.51). The reaction mixture was quenched with 40 mL water. The aqueous phase was extracted with DCM (30.0 mL ×3). The reaction mixture was filtered and the filtrate was concentrated to remove the water under reduced pressure to give product. Crude compound 3 (4.5 g, 9.79 mmol, 57.67% yield) was obtained as a colorless oil.

[0502] To a solution of compound 3 (4.5 g, 9.79 mmol, 1 eq) in MeCN (70 mL) was added Py (1.55 g, 19.58 mmol, 1.58 mL, 2 eq), DMAP (598.11 mg, 4.90 mmol, 0.5 eq) and compound 9 (3.21 g, 10.77 mmol, 1.1 eq). The mixture was stirred at 25 °C for 12h. LC-MS showed that compound 3 was consumed completely and the desired mass was detected. The reaction mixture was quenched with 100 mL water, the aqueous phase was extracted with ethyl acetate (100 mL ×3). The combined organic phases were washed with brine (50 mL ×3), dried with anhydrous sodiumsulfate, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, DCM: MeOH=10:1). Compound 4 (2.3 g, 3.72 mmol, 37.96% yield) was obtained as a colorless oil. LCMS: m / z = 519.3 (M-100)+, Rt= 0.591 min.

[0503] 1H NMR (400 MHz, CDCl3): δ = 4.43 - 4.30 (m, 4H), 4.20 (t, J = 6.8 Hz, 2H), 3.52 (d, J = 6.4 Hz, 2H), 3.42 - 3.24 (m, 2H), 3.11 (d, J = 4.8 Hz, 2H), 2.94 (d, J = 6.4, 8.4 Hz, 4H), 2.64 (t, J = 7.2 Hz, 2H), 2.54 (t, J = 2.4, 6.8 Hz, 2H), 2.32 (t, J = 7.6 Hz, 2H), 2.08 - 2.01 (m, 2H), 1.70 (d, J = 6.0 Hz, 2H), 1.65 - 1.59 (m, 2H), 1.45 (s, 9H), 1.33 - 1.25 (m, 10H), 0.88 (t, J = 6.8 Hz, 3H).

[0504] A mixture of compound 4 (2 g, 3.23 mmol, 1 eq) and HCl / dioxane (2 M, 47.62 mL, 29.47eq) was stirred at 20 °C for 12hr. LC-MS showed that compound 4 was consumed completely and the desired mass was detected. The reaction mixture was concentrated under reduced pressure to give residue. Compound 5 (1.1 g, 2.12 mmol, 65.62% yield) was obtained as a colorless oil. LCMS: m / z = 519.3 (M+1)+, Rt = 0.44 min.

[0505] 1H NMR (400 MHz, CDCl3): δ = 4.41 - 4.30 (m, 4H), 4.20 (t, J = 6.8 Hz, 2H), 3.53 (t, J = 6.4 Hz, 2H), 3.48 (s, 2H), 3.06 (t, J = 6.4 Hz, 2H), 2.94 (q, J = 6.4 Hz, 4H), 2.65 (t, J = 6.8 Hz, 2H), 2.55 (t, J = 2.4, 6.8 Hz, 2H), 2.33 (t, J = 7.6 Hz, 2H), 2.12 - 2.02 (m, 3H), 1.62 (d, J = 7.2 Hz, 2H), 1.28 (d, J = 7.2 Hz, 10H), 0.93 - 0.82 (m, 3H).

[0506] To a solution of compound 5 (550 mg, 929.60 μmol, 1 eq, 2HCl) in DCM (8 mL) was added TEA (188.13 mg, 1.86 mmol, 258.78 μL, 2 eq) and 2-bromoethan-1-ol (116.17 mg, 929.60 μmol, 65.89 μL, 1 eq). The mixture was stirred at 50 °C for 6 h. LC-MS showed the desired mass was detected. The reaction mixture was quenched with 20 mL water and the aqueous phase was extracted with DCM (20 mL ×3). The combined organic phases were washed with brine (20 mL ×3), dried with anhydrous sodiumsulfate, filtered and concentrated in vacuum. Compound 6 (200 mg, 355.38 μmol, 38.23% yield) was obtained as a colorless oil. LCMS: m / z = 563.4 (M+1)+, Rt = 0.436 min.

[0507] To a solution of compou...

Claims

CLAIMS 1. A compound of formula (G1.1), wherein moiety B is C(O)O, OC(O), C(O)NH, HNC(O), or CH2CH2, p = 1-6; p’ = 0-4; p” = 0-4; m’ = 0, 1; moiety T is selected from CH((CH2)llCH3)-CH2)ll’CH3, ll = 2-6, ll’ = 2-6 CH3-(CH2)k-CH2, k = 2-14; (CH3-(CH2)k’)2-CH-(CH2)k”-CH2, k’ = 0-8, k” = 0-9; CH3-(CH2)kk-CH=CH-(CH2)kk’-CH2, kk = 5-8, kk’ = 5-8; CH3-(CH2)kp-CH=CH-(CH2)kp’-CH=CH-(CH2)kp”-CH2, kp = 5-7, kp” = 5-7, kp’ = 1-3; CH3-(CH2)l-O-C(O)-(CH2)kk”-CH2, l = 2-7, kk” = 0-4; and(CH3-(CH2)l-CH2)2-CH-MS-C(O)-(CH2)kk”-CH2, l = 2-7, kk” = 0-5, MS is O or NH; and when p > 1, then each one of the plurality of T moieties is the same or different from the remaining T moieties in the same molecule, and A is an amino moiety, and said amino moiety A is chosen depending on the p-value as follows, wherein the term * is used to refer to a N-binding site of an LT moiety, and *(*) (or (*)* indistinguishably) is used to refer to two separate N-binding sites of two LT moieties: when p = 1, then A is *N((CH2)ir-N(NT1)(NT2))(X-(CH2)2-Y-OCO-CH(TA1)(TA2)), ir = 2-4, NT1 is H, or CH3, NT2 is CH3, (CH2)r-OCO-(CH2)r’-CH3, (CH2)r-OH, or (CH2)r”-CH3, with r = 1-3, r’ = 1-3, and r” = 1-3, X is C(O)-O, C(O)-CH2, (CH2)nn-OCO with nn = 1-3, or CH2-(CH2)mm with mm = 0-3, Y is S-S-(CH2)n, n = 2,3, or (CH2)q, q = 3-6, OCO is O-C(O) or C(O)-O, TA1 is H or (CH2)m-CH3, and TA2 is (CH2)m’-CH3, with m = 5-8 and m’ = 5-8; when p = 2, then A is *(*)N-(CH2)t-Z, t = 2-6, Z is N-pyrrolidino, N-piperidino, OCH3, OH, N(CH2-CH3)2, or N(CH3)2, when p = 4, then A is *(*)N-(CH2)w1-E-(CH2)w2-N(*)*, w1 = 2-6, w2 = 2-6, E is bond, substituted or unsubstituted amino, O-phenylene- O, O-(CH2)w3-(substituted or unsubstituted 1,4-piperazinediyl)-(CH2)w4-O, substituted or unsubstituted 1,4- piperazinediyl, S-S, XS-S-S-XS, XS-(substituted or unsubstituted 1,4-piperazinediyl)-XS, EE-(1,4- cyclohexanediyl)-EE, or EE-(1,3-cyclohexanediyl)-EE, wherein w3 = 0-4, w4 = 0-4, XS is C(O)-O-(CH2)2, and EE is O, C(O)-O or C(O)-NH, when p = 5, then A is *(*)N-(CH2)p1-N*-(CH2)p2’-N(*)*, p1 = 2-5, p2 = 2-5, and when p = 6, then A is *(*)N-(CH2)q1-N((CH2)q2-N(*)*)-(CH2)q3-N(*)*, q1 = 2-4, q2 = 2-4, and q3 = 2-4. wherein, when p > 1, then each one of the plurality of LT moieties is the same or different from the remaining LT moieties in the same molecule, or a stereoisomer, tautomer, constitutional isomer, constitutional isomer, pharmaceutically acceptable salt or solvate thereof.

2. A compound of claim 1, wherein p = 2, 4, 5 or 6, and wherein all the LT moieties are identical.

3. A compound of claim 1, wherein p = 2, 4, 5 or 6, and wherein at least two LT moieties are the same and at least two LT moieties are diferent.

4. A compound of claim 1, wherein p = 2, 4, 5 or 6, and wherein all the LT moieties are different.

5. A compound of claim 1, wherein p’ = 1.

6. A compound of claim 1, wherein p” = 1.

7. A compound of claim 1, wherein m’ = 1.

8. A compound of claim 1, wherein p’ = 1 and p” = 1.

9. A compound of claim 8, wherein B is CH2CH2, C(O)NH, or C(O)O.

10. A compound of claim 8, wherein B is C(O)O.

11. A compound of claim 8, wherein B is CH2CH2.

12. A compound of claim 8, wherein B is C(O)NH.

13. A compound of claim 1, wherein p’ = p” = 1, and B is CH2CH2, C(O)NH, HNC(O), C(O)O or OC(O).

14. A compound of claim 1, wherein p is one of 1, 2, 3, 4, 5 and 6, and when p is one of 2, 3, 4, 5 and 6, then p’ = p” = 1 in each LT.

15. A compound of claim 1, wherein p is one of 1, 2, 3, 4, 5 and 6, and when p is 1, then p’ = p” = 1 in each LT.

16. A compound of claim 1, wherein, when p = 2-6, all the T moieties are identical.

17. A compound of any one of claims 1-16 wherein T for each LT moiety is selected from the following moieties:

18. A compound of claim 1, wherein moiety T is selected from CH((CH2)llCH3)-CH2)ll’CH3, ll = 2-6, ll’ = 2-6 CH3-(CH2)k-CH2, k = 2-14; (CH3-(CH2)k’)2-CH-(CH2)k”-CH2, k’ = 0-8, k” = 0-9;CH3-(CH2)kk-CH=CH-(CH2)kk’-CH2, kk = 5-8, kk’ = 5-8; CH3-(CH2)kp-CH=CH-(CH2)kp’-CH=CH-(CH2)kp”-CH2, kp = 5-7, kp” = 5-7, kp’ = 1-3; CH3-(CH2)l-O-C(O)-(CH2)kk”-CH2, l = 2-7, kk” = 0-4; and (CH3-(CH2)l-CH2)2-CH-MS-C(O)-(CH2)kk”-CH2, l = 2-7, kk” = 0-5, MS is O or NH; and when p = 2, 4, 5 or 6, then each one of the plurality of T moieties is the same in each of said LT moieties.

19. A compound of claim 1, wherein moiety T is selected from CH((CH2)llCH3)-CH2)ll’CH3, ll = 2-6, ll’ = 2-6 CH3-(CH2)k-CH2, k = 2-14; (CH3-(CH2)k’)2-CH-(CH2)k”-CH2, k’ = 0-8, k” = 0-9; CH3-(CH2)kk-CH=CH-(CH2)kk’-CH2, kk = 5-8, kk’ = 5-8; CH3-(CH2)kp-CH=CH-(CH2)kp’-CH=CH-(CH2)kp”-CH2, kp = 5-7, kp” = 5-7, kp’ = 1-3; CH3-(CH2)l-O-C(O)-(CH2)kk”-CH2, l = 2-7, kk” = 0-4; and (CH3-(CH2)l-CH2)2-CH-MS-C(O)-(CH2)kk”-CH2, l = 2-7, kk” = 0-5, MS is O or NH; p = 1, 2, 4, 5, or 6; and when p = 2, 4, 5 or 6, then each one of the plurality of T moieties is different from the remaining T moieties in each of said LT moieties.

20. A compound of claim 1, wherein moiety T is selected from CH((CH2)llCH3)-CH2)ll’CH3, ll = 2-6, ll’ = 2-6 CH3-(CH2)k-CH2, k = 2-14; (CH3-(CH2)k’)2-CH-(CH2)k”-CH2, k’ = 0-8, k” = 0-9; CH3-(CH2)kk-CH=CH-(CH2)kk’-CH2, kk = 5-8, kk’ = 5-8; CH3-(CH2)kp-CH=CH-(CH2)kp’-CH=CH-(CH2)kp”-CH2, kp = 5-7, kp” = 5-7, kp’ = 1-3; CH3-(CH2)l-O-C(O)-(CH2)kk”-CH2, l = 2-7, kk” = 0-4; and(CH3-(CH2)l-CH2)2-CH-MS-C(O)-(CH2)kk”-CH2, l = 2-7, kk” = 0-5, MS is O or NH; p = 1, 2, 4, 5, or 6, when p = 2, 4, 5 or 6, then each one of the plurality of T moieties is the same as or different from the remaining T moieties in each of said LT moieties; and m’ = 1 in each of said LT moieties.

21. A compound of claim 20, wherein, when p = 2, 4, 5 or 6, then each one of the plurality of T moieties is the same as the remaining T moieties in each of said LT moieties.

22. A compound of claim 20, wherein, when p = 2, 4, 5 or 6, then each one of the plurality of T moieties is different from the remaining T moieties in each of said LT moieties.

23. A compound of claim 1, wherein moiety T is selected from CH((CH2)llCH3)-CH2)ll’CH3, ll = 2-6, ll’ = 2-6 CH3-(CH2)k-CH2, k = 2-14; (CH3-(CH2)k’)2-CH-(CH2)k”-CH2, k’ = 0-8, k” = 0-9; CH3-(CH2)kk-CH=CH-(CH2)kk’-CH2, kk = 5-8, kk’ = 5-8; CH3-(CH2)kp-CH=CH-(CH2)kp’-CH=CH-(CH2)kp”-CH2, kp = 5-7, kp” = 5-7, kp’ = 1-3; CH3-(CH2)l-O-C(O)-(CH2)kk”-CH2, l = 2-7, kk” = 0-4; and (CH3-(CH2)l-CH2)2-CH-MS-C(O)-(CH2)kk”-CH2, l = 2-7, kk” = 0-5, MS is O or NH; p = 1, 2, 4, 5, or 6, when p = 2, 4, 5 or 6, then each one of the plurality of T moieties is the same as or different from the remaining T moieties in each of said LT moieties; and m’ = 0 in each of said LT moieties.

24. A compound of claim 23, wherein, when p = 2, 4, 5 or 6, then each one of the plurality of T moieties is the same as the remaining T moieties in each of said LT moieties.

25. A compound of claim 23, wherein, when p = 2, 4, 5 or 6, then each one of the plurality of T moieties is different from the remaining T moieties in each of said LT moieties.

26. A compound of claim 1, wherein p = 1, and the moiety A-CH2-(CH2)p’-B-CH2(CH2)p”-ʃ- in (G1.1), wherein p’ = p” = 1 and B is C(O)O, is selected from the following moieties:

27. A compound of claim 26, wherein moiety T is selected from the following moieties:

28. A compound of claim 1, wherein p = 2 and A is selected from the following moieties:

29. A compound of claim 28, wherein p’ = p” = 1, B is C(O)O, C(O)NH or CH2CH2, and moiety T is selected from the following moieties:

30. A compound of claim 1, wherein p = 4 and A is selected from the following moieties:

31. A compound of claim 30, wherein p’ = p” = 1, B is C(O)O, C(O)NH or CH2CH2, and moiety T is selected from the following moieties:

32. A compound of claim 1, wherein p = 5 and A is the following moiety:

33. A compound of claim 32, wherein p’ = p” = 1, B is C(O)O, C(O)NH or CH2CH2, and moiety T is selected from the following moieties:

34. A compound of claim 1, wherein p = 6 and A is the following moiety:

35. A compound of claim 34, wherein p’ = p” = 1, B is C(O)O, C(O)NH or CH2CH2, and moiety T is selected from the following moieties:.

36. A compound of claim 35, B is C(O)O.

37. A compound of claim 1, wherein p = 4, E is unsubstituted O-phenylen-O, w1 = w2 = 3, and for each LT moiety each T is CH3-(CH2)k-CH2 with k = 4 and m’ = 1.

38. A compound of claim 1, wherein p = 4, the substituted amino in E is , w1 = w2 = 3, and for each LT moiety each T is CH3-(CH2)k-CH2 with k = 5 and m’ = 1.

39. A compound of claim 1, wherein p = 4, E is unsubstituted O-phenylen-O, w1 = w2 = 3, and for each LT moiety each T is CH3-(CH2)k-CH2with k = 9, and m’ = 1.

40. A compound of claim 1, wherein p = 4, E is S-S, w1 = w2 = 2, and for each LT moiety each T is CH3-(CH2)k-CH2with k = 3, and m’ = 1.

41. A compound of claim 1, wherein p = 5, p1 = 3, p2 = 4, and for each LT moiety each T is CH3-(CH2)k-CH2with k = 6, and m’ = 1.

42. A compound of claim 1, wherein p = 4, E is unsubstituted 1,4-piperazindiyl, w1 = w2 = 3, and for each LT moiety each T is CH3-(CH2)k-CH2with k = 7, and m’ = 1.

43. A compound of claim 1, wherein p = p’ = p” = 1, m’ = 1, T is CH3-(CH2)k-CH2 and k = 6.

44. A compound of claim 1, wherein p = p’ = p” = 1, m’ = 0, T is CH3-(CH2)k-CH2and k = 6.

45. A compound of claim 1, wherein p = 2, t = 3, Z is N-piperidino, p’ = 1, and for each LT moiety each T is CH3-(CH2)k-CH2 with k = 10, and m’ = 1.

46. A compound of claim 1, wherein p = 4, E is substituted 1,4-piperazindiyl, w1 = w2 = 4, and for each LT moiety each T is CH3-(CH2)k-CH2 with k = 4, and m’ = 1.

47. A compound of claim 1, wherein p = 4, w1 = w2 = 3, E is unsubstituted C(O)-NH-(1,3- cyclohexanediyl)-NH-C(O), and for each LT moiety each T is CH3-(CH2)k-CH2with k = 4, and m’ = 1.

48. A compound of claim 1, wherein p = 4, E is O-(CH2)w3-(substituted or unsubstituted 1,4- piperazinediyl)-(CH2)w4-O, w1 = w2 = w3 = w4 = 2, and for each LT moiety each T is CH3- (CH2)k-CH2 with k = 4, and m’ = 1.

49. A compound of claim 1, wherein p = 2, t = 2, Z is N(CH2-CH3)2, and for each LT moiety each T is CH3-(CH2)7-CH=CH-(CH2)6-CH2, m’ = 1, and p’ = p” = 1.

50. A compound of claim 1, wherein p = 2, t = 2, Z is N(CH2-CH3)2, and for each LT moiety m’ = 1, p’ = p” = 1, and each T is CH3-(CH2)k-CH2 , with k = 11.

51. A compound of claim 1, wherein p = 2, t = 2, Z is N-piperidino, and for each LT moiety m’ = 1, p’ = p” = 1, and each T is CH3-(CH2)k-CH2 , with k = 8.

52. A compound of claim 1, wherein p = 2, t = 3, Z is N-pyrrolidino, and for each LT moiety m’ = 1, p’ = p” = 1, and each T is CH3-(CH2)k-CH2 , with k = 8.

53. A compound of claim 1, wherein p = 1, m’ = 1, p’ = p” = 1, T is CH3-(CH2)4-CH=CH-CH2- CH=CH-(CH2)6-CH2, X is C(O)-O, Y is S-S-(CH2)nwith n = 2, OCO is O-C(O), and m = 7.

54. A compound of claim 1, wherein p = 1, m’ = 1, p’ = p” = 1, T is (CH3-(CH2)l-CH2)2-CH-O- C(O)-(CH2)3-CH2, with l = 3, X is C(O)-CH2, Y is S-S-(CH2)nwith n = 3, OCO is O-C(O), and m = 6.

55. A compound of claim 1, wherein p = 1, m’ = 1, p’ = p” = 1, T is (CH3)2-CH-(CH2)4-CH2, X is CH2-CH2, Y is (CH2)q with q = 4, OCO is O-C(O), and m = 7.

56. A compound of claim 1, wherein p = 4, w1 = w2 = 4, E is XS-(substituted 1,4- piperazinediyl)-XS, XS is O-C(O)-(CH2)2, and for each LT moiety p’ = p” = 1, m’ = 1, T is CH3- (CH2)k-CH2 with k = 4.

57. A compound of claim 1, wherein p = 4, w1 = w2 = 2, E is S-S, and for each LT moiety p’ = p” = 1, m’ = 1, T is CH3-(CH2)k-CH2 with k = 3.

58. A compound of claim 1, wherein p = 2, p’ = p” = 1, t = 2, Z is OH, and for each LT moiety m’ = 1, and T is CH3-(CH2)k-CH2 with k = 5.

59. A compound of claim 1, wherein p = 2, p’ = p” = 1, t = 4, Z is OH, and for each LT moiety m’ = 1, and T is CH3-(CH2)k-CH2with k = 6.

60. A compound of claim 1, wherein p = 2, p’ = p” = 1, t = 6, Z is OH, and for each LT moiety m’ = 1, and T is CH3-(CH2)k-CH2with k = 5.

61. A compound of claim 1, wherein p = 2, p’ = p” = 1, t = 2, Z is N(CH3)2, and for each LT moiety m’ = 1, and T is CH3-(CH2)k-CH2with k = 9.

62. A compound of claim 1, wherein p = 2, p’ = p” = 1, t = 4, Z is N(CH3)2, and for each LT moiety m’ = 1, and T is CH3-(CH2)k-CH2with k = 6.

63. A compound of claim 1, wherein p = 2, p’ = p” = 1, t = 5, Z is N(CH3)2, and for each LT moiety m’ = 1, and T is CH3-(CH2)k-CH2with k = 8.

64. A compound of claim 1, wherein p = 4, w1 = w2 = 5, E is EE-(1,4-cyclohexanediyl)-EE, EE is C(O)-O, and for each LT moiety m’ = 1, p’ = p” = 1, T is CH3-(CH2)k-CH2 with k = 7.

65. A compound of claim 1, wherein p = 4, w1 = w2 = 5, E is XS-S-S-XS, XS is C(O)-O-(CH2)2, and for each LT moiety m’ = 1, p’ = p” = 1, T is (CH3)2-CH-(CH2)5-CH2.

66. A compound selected from the group: A1L1T1, A1L1T2, A1L1T3, A1L1T4, A1L1T5, A1L1T6, A1L1T7, A1L1T8, A1L1T9, A1L1T10, A1L1T11, A1L1T12, A1L1T13, A1L1T14, A1L1T15, A2L1T1, A2L1T2, A2L1T3, A2L1T4, A2L1T5, A2L1T6, A2L1T7, A2L1T8, A2L1T9, A2L1T10, A2L1T11, A2L1T12, A2L1T13, A2L1T14, A2L1T15, A3L1T1, A3L1T2, A3L1T3, A3L1T4, A3L1T5, A3L1T6, A3L1T7, A3L1T8, A3L1T9, A3L1T10, A3L1T11, A3L1T12, A3L1T13, A3L1T14, A3L1T15, A4L1T1, A4L1T2, A4L1T3, A4L1T4, A4L1T5, A4L1T6, A4L1T7, A4L1T8, A4L1T9, A4L1T10, A4L1T11, A4L1T12, A4L1T13, A4L1T14, A4L1T15, A4L1T16, A4L1T17 A4L1T19, A4L2T18, A4L2T14, A4L3T19, A4L3T14, A5L1T1, A5L1T2, A5L1T3, A5L1T4, A5L1T5, A5L1T6, A5L1T7, A5L1T8, A5L1T9, A5L1T10, A5L1T11, A5L1T12, A5L1T13, A5L1T14, A5L1T15, A5L2T21, A5L3T22, A6L1T1, A6L1T2, A6L1T3, A6L1T4, A6L1T5, A6L1T6, A6L1T7, A6L1T8, A6L1T9, A6L1T10, A6L1T11, A6L1T12, A6L1T13, A6L1T14, A6L1T15, A6L2T18, A6L3T19, A7L1T1, A7L1T2, A7L1T3, A7L1T4, A7L1T5, A7L1T6, A7L1T7, A7L1T8, A7L1T9, A7L1T10, A7L1T11, A7L1T12, A7L1T13, A7L1T14, A7L1T15, A8L1T1, A8L1T2, A8L1T3, A8L1T4, A8L1T5, A8L1T6, A8L1T7, A8L1T8, A8L1T9, A8L1T10, A8L1T11, A8L1T12, A8L1T13, A8L1T14, A8L1T15, A9L1T1, A9L1T2, A9L1T3, A9L1T4, A9L1T5, A9L1T6, A9L1T7, A9L1T8, A9L1T9, A9L1T10, A9L1T11, A9L1T12, A9L1T13, A9L1T14, A9L1T15, A10L1T19, A11L1T1, A11L1T2, A11L1T3, A11L1T4, A11L1T5, A11L1T6, A11L1T7, A11L1T8, A11L1T9, A11L1T10, A11L1T11, A11L1T12, A11L1T13, A11L1T14, A11L1T15, A12L1T1, A12L1T2, A12L1T3, A12L1T4, A12L1T5, A12L1T6, A12L1T7, A12L1T8, A12L1T9, A12L1T10, A12L1T11, A12L1T12, A12L1T13, A12L1T14, A12L1T15,A14L1T1, A14L1T2, A14L1T3, A14L1T4, A14L1T5, A14L1T6, A14L1T7, A14L1T8, A14L1T9, A14L1T10, A14L1T11, A14L1T12, A14L1T13, A14L1T14, A14L1T15, A16L1T1, A16L1T2, A16L1T3, A16L1T4, A16L1T5, A16L1T6, A16L1T7, A16L1T8, A16L1T9, A16L1T10, A16L1T11, A16L1T12, A16L1T13, A16L1T14, A16L1T15, A17L1T1, A17L1T2, A17L1T3, A17L1T4, A17L1T5, A17L1T6, A17L1T7, A17L1T8, A17L1T9, A17L1T10, A17L1T11, A17L1T12, A17L1T13, A17L1T14, A17L1T15, A18L1T1, A18L1T2, A18L1T3, A18L1T4, A18L1T5, A18L1T6, A18L1T7, A18L1T8, A18L1T9, A18L1T10, A18L1T11, A18L1T12, A18L1T13, A18L1T14, A18L1T15, A19L1, A19L1T1, A19L1T2, A19L1T3, A19L1T4, A19L1T5, A19L1T6, A19L1T7, A19L1T8, A19L1T9, A19L1T10, A19L1T11, A19L1T12, A19L1T13, A19L1T14, A19L1T15, A20L1T1, A20L1T2, A20L1T3, A20L1T4, A20L1T5, A20L1T6, A20L1T7, A20L1T8, A20L1T9, A20L1T10, A20L1T11, A20L1T12, A20L1T13, A20L1T14, A20L1T15, A21L1T1, A21L1T2, A21L1T3, A21L1T4, A21L1T5, A21L1T6, A21L1T7, A21L1T8, A21L1T9, A21L1T10, A21L1T11, A21L1T12, A21L1T13, A21L1T14, A21L1T15, A22L1T1, A22L1T2, A22L1T3, A22L1T4, A22L1T5, A22L1T6, A22L1T7, A22L1T8, A22L1T9, A22L1T10, A22L1T11, A22L1T12, A22L1T13, A22L1T14, A22L1T15, A23L1T1, A23L1T2, A23L1T3, A23L1T4, A23L1T5, A23L1T6, A23L1T7, A23L1T8, A23L1T9, A23L1T10, A23L1T11, A23L1T12, A23L1T13, A23L1T14, A23L1T15, A24L1T1, A24L1T2, A24L1T3, A24L1T4, A24L1T5, A24L1T6, A24L1T7, A24L1T8, A24L1T9, A24L1T10, A24L1T11, A24L1T12, A24L1T13, A24L1T14, A24L1T15, A25L1T1, A25L1T2, A25L1T3, A25L1T4, A25L1T5, A25L1T6, A25L1T7, A25L1T8, A25L1T9, A25L1T10, A25L1T11, A25L1T12, A25L1T13, A25L1T14, A25L1T15, A26L1T1, A26L1T2, A26L1T3, A26L1T4, A26L1T5, A26L1T6, A26L1T7, A26L1T8, A26L1T9, A26L1T10, A26L1T11, A26L1T12, A26L1T13, A26L1T14, A26L1T15, A27L1T1, A27L1T2, A27L1T3, A27L1T4, A27L1T5, A27L1T6, A27L1T7, A27L1T8, A27L1T9, A27L1T10, A27L1T11, A27L1T12, A27L1T13, A27L1T14, A27L1T15, A28L1T1, A28L1T2, A28L1T3, A28L1T4, A28L1T5, A28L1T6, A28L1T7, A28L1T8, A28L1T9, A28L1T10, A28L1T11, A28L1T12, A28L1T13, A28L1T14, A28L1T15, A29L1T1, A29L1T2, A29L1T3, A29L1T4, A29L1T5, A29L1T6, A29L1T7, A29L1T8, A29L1T9, A29L1T10, A29L1T11, A29L1T12, A29L1T13, A29L1T14, A29L1T15,A30L1T1, A30L1T2, A30L1T3, A30L1T4, A30L1T5, A30L1T6, A30L1T7, A30L1T8, A30L1T9, A30L1T10, A30L1T11, A30L1T12, A30L1T13, A30L1T14, A30L1T15, A31L1T1, A31L1T2, A31L1T3, A31L1T4, A31L1T5, A31L1T6, A31L1T7, A31L1T8, A31L1T9, A31L1T10, A31L1T11, A31L1T12, A31L1T13, A31L1T14, A31L1T15, A32L1T1, A32L1T2, A32L1T3, A32L1T4, A32L1T5, A32L1T6, A32L1T7, A32L1T8, A32L1T9, A32L1T10, A32L1T11, A32L1T12, A32L1T13, A32L1T14, A32L1T15, A33L1T1, A33L1T2, A33L1T3, A33L1T4, A33L1T5, A33L1T6, A33L1T7, A33L1T8, A33L1T9, A33L1T10, A33L1T11, A33L1T12, A33L1T13, A33L1T14, A33L1T15, A34L1T1, A34L1T2, A34L1T3, A34L1T4, A34L1T5, A34L1T6, A34L1T7, A34L1T8, A34L1T9, A34L1T10, A34L1T11, A34L1T12, A34L1T13, A34L1T14, A34L1T15, A35L1T1, A35L1T2, A35L1T3, A35L1T4, A35L1T5, A35L1T6, A35L1T7, A35L1T8, A35L1T9, A35L1T10, A35L1T11, A35L1T12, A35L1T13, A35L1T14, A35L1T15, A36L1T1, A36L1T2, A36L1T3, A36L1T4, A36L1T5, A36L1T6, A36L1T7, A36L1T8, A36L1T9, A36L1T10, A36L1T11, A36L1T12, A36L1T13, A36L1T14, A36L1T15, A37L1T1, A37L1T2, A37L1T3, A37L1T4, A37L1T5, A37L1T6, A37L1T7, A37L1T8, A37L1T9, A37L1T10, A37L1T11, A37L1T12, A37L1T13, A37L1T14, A37L1T15, A38L1T15, A39L1T15, A40L1T15 A41L1T15, and A42L1T20, and tautomers, stereoisomers, constitutional isomers, pharmaceutically acceptable salts and solvates thereof.

67. A compound of claim 66, selected from the group: A2L1T2, A3L1T3, A8L1T8, A1L1T1, A4L1T4, A5L1T5, A5L1T15, A34L1T4, A11L1T11, A26L1T9, A6L1T2, A12L1T2, A14L1T2, A21L1T13, A24L1T12, A25L1T10, A22L1T7, A27L1T7, A30L1T13, A30L1T15, A31L1T14, A33L1T6, A37L1T2, A4L1T4, A18L1T3, A19L1T4, A20L1T3, A23L1T8, A28L1T4, A29L1T7, A35L1T5, A36L1T6, A4L1T16, A4L1T17, A4L1T19, A4L2T18, A4L2T14, A4L3T19, A4L3T14, A40L1T15, A41L1T15, A5L2T21, A5L3T22, A6L2T18, A6L3T19, A10L1T19, A38L1T15, A39L1T15, and A42L1T20, and tautomers, stereoisomers, constitutional isomers, pharmaceutically acceptable salts and solvates thereof.

68. A compound selected from the group: A1L1, A2L1, A3L1, A4L1, A5L1, A6L1, A7L1, A8L1, A9L1, A11L1, A12L1, A14L1, A16L1, A17L1, A18L1, A19L1, A20L1, A21L1, A22L1, A23L1, A24L1, A25L1, A26L1, A27L1, A28L1, A29L1, A30L1, A31L1, A32L1, A33L1, A34L1, A35L1, A36L1, A37L1, A10L1, A38L1, A39L1, A40L1, A41L1, A42L1, A4L2, A5L2, A6L2, A4L3, A5L3, and A6L3.

69. A compound of formula (G1.2)wherein p = 1-5 when q = 1-5, and p = 1-6 when q = 0-5, with (p + q) = 1-6 and p ≠ 0; when p > 1, then each one of the plurality of LT moieties is the same or different from the remaining LT moieties in the same molecule, and when q > 1, then each one of the plurality of ST moieties is the same or different from the remaining ST moieties in the same molecule; R, in each ST moiety, is OH, COOH, CHO, OR’, COOR’, C(O)NH2, or C(O)NHR’, with R’ being H or (CH2)q”CH3, with q’ = 1-4, q” = 1-4, q ≥ 1; wherein moiety B is C(O)O, OC(O), C(O)NH, HNC(O), or CH2CH2, p’ = 0-4;p” = 0-4; m’ = 0, 1; moiety T is selected from CH((CH2)llCH3)-CH2)ll’CH3, ll = 2-6, ll’ = 2-6 CH3-(CH2)k-CH2, k = 2-14; (CH3-(CH2)k’)2-CH-(CH2)k”-CH2, k’ = 0-8, k” = 0-9; CH3-(CH2)kk-CH=CH-(CH2)kk’-CH2, kk = 5-8, kk’ = 5-8; CH3-(CH2)kp-CH=CH-(CH2)kp’-CH=CH-(CH2)kp”-CH2, kp = 5-7, kp” = 5-7, kp’ = 1-3; CH3-(CH2)l-O-C(O)-(CH2)kk”-CH2, l = 2-7, kk” = 0-4; and (CH3-(CH2)l-CH2)2-CH-MS-C(O)-(CH2)kk”-CH2, l = 2-7, kk” = 0-5, MS is O or NH; and when p > 1, then each one of the plurality of T moieties is the same or different from the remaining T moieties in the same molecule, and A is an amino moiety, and said amino moiety A is selected depending on the (p+q)-value as follows, wherein the term * is used to refer to a N-binding site of an LT moiety, and *(*) (or (*)* indistinguishably) is used to refer to two separate N-binding sites of two LT moieties: when p = 1 and q = 1, then A is *(*)N-(CH2)t-Z, t = 2-6, Z is N-pyrrolidino, N-piperidino, OCH3, OH, N(CH2-CH3)2, or N(CH3)2, when p+q = 4, with p ≥ 1 and q ≥ 1, then A is *(*)N-(CH2)w1-E-(CH2)w2-N(*)*, w1 = 2-6, w2 = 2-6, E is bond, substituted or unsubstituted amino, O-phenylene- O, O-(CH2)w3-(substituted or unsubstituted 1,4- piperazinediyl)-(CH2)w4-O, substituted or unsubstituted 1,4- piperazinediyl, S-S, XS-S-S-XS, XS-(substituted orunsubstituted 1,4-piperazinediyl)-XS, EE-(1,4- cyclohexanediyl)-EE, or EE-(1,3-cyclohexanediyl)-EE, wherein w3 = 0-4, w4 = 0-4, XS is C(O)-O-(CH2)2, and EE is O, C(O)-O or C(O)-NH, when p+q = 5, with p ≥ 1 and q ≥ 1, then A is *(*)N-(CH2)p1-N*-(CH2)p2’-N(*)*, p1 = 2-5, p2 = 2-5, and when p+q = 6, with p ≥ 1 and q ≥ 1, then A is *(*)N-(CH2)q1-N((CH2)q2-N(*)* q1 = 2-4, q2 = 2-4, and q3 = 2-4or a stereoisomer, tautomer, constitutional isomer, constitutional isomer, pharmaceutically acceptable salt or solvate thereof.

70. A compound of claim 69, wherein p = 2 and q = 3.

71. A compound of claim 69, wherein p = 3, and q = 2.

72. A compound of claim 69, wherein p + q = 5, and A is *(*)N-(CH2)p1-N*-(CH2)p2’-N(*)*, p1 = 2-5, p2 = 2-5.

73. A compound of claim 69, wherein p + q = 5, and A is *(*)N-(CH2)4-N*-(CH2)3-N(*)*.

74. A compound of claim 69, wherein q ≥ 2, and all the ST moieties are the same.

75. A compound of claim 69, wherein p ≥ 2, and all the LT moieties are the same.

76. A compound of claim 69, wherein p ≥ 2 and q ≥ 2, and all the ST moieties are the same and all the LT moieties are the same.

77. A compound of claim 69, wherein p + q = 2, p = 1 and q = 1, wherein said compound has formulae A(ST)(LT), wherein the amine moiety A is selected from the following moieties:

78. A compound of claim 77, wherein p’ = p” = 1, B is C(O)O, C(O)NH or CH2CH2, and moiety T is selected from the following moieties:

79. A compound of claim 69, wherein p + q = 4, p + q = 2, p ≥ 1 and q ≥ 1, and A is selected from the following moieties:

80. A compound of claim 79, wherein p’ = p” = 1, B is C(O)O, C(O)NH or CH2CH2, and moiety T is selected from the following moieties:

81. A compound of claim 80, wherein the [p, q] pair value is one of [p = 1, q = 3]; [p = 2, q = 2]; and [p = 3, q = 1].

82. A compound of claim 69, wherein p+q = 5, p ≥ 1 and q ≥ 1 and A is the following moiety:

83. A compound of claim 82, wherein p’ = p” = 1, B is C(O)O, C(O)NH or CH2CH2, and moiety T is selected from the following moieties:

84. A compound of claim 83, wherein the [p, q] pair value is one of [p = 1, q = 4]; [p = 2, q = 3]; [p = 3, q = 2], and [p = 4, q = 1].

85. A compound of claim 69, wherein p+q = 6, p ≥ 1 and q ≥ 1 and A is the following moiety:

86. A compound of claim 85, wherein p’ = p” = 1, B is C(O)O, C(O)NH or CH2CH2, and T is selected from the following moieties:

87. A compound of claim 86, wherein the [p, q] pair value is one of [p = 1, q = 5]; [p = 2, q = 4]; [p = 3, q = 3], [p = 4, q = 2], and [p = 5, q = 1].

88. A compound of claim 82, wherein B is C(O)O.

89. A compound of claim 88, wherein all the LT moieties are the same, all the ST moieties are the same.

90. A compound of claim 89, wherein each ST is CH2CH2CH2OH, and [p = 3 and q = 2] or [p = 2 and q = 3].

91. A compound of claim 90, wherein moiety T is .

92. A compound of claim 69, wherein (p + q) = 5, and the compound is selected from compounds: A4(L1T14)3(ST1)2, and A4(L1T14)2(ST1)3; wherein A4 isall the LT moieties are the same L1T14, wherein each of said L1T14 is defined by B being C(O)O; p’ =all ST moieties are the same ST1, wherein each of said ST1 moieties is CH2CH2CH2OH.

93. A compound of claim 92, wherein the compound is selected from the group: A4(L1T14)1-1(L1T14)2-4(ST1)2-3(1), A4(L1T14)1-1(ST1)2-4(L1T14)2-3(1), A4(L1T14)2-4(ST1)1-1(L1T14)1-3(1)(ST1)1-3(1), A4(L1T14)1-4(ST1)1-4(ST1)1-1(L1T14)2-3(1), A4(L1T14)1-3(1)(ST1)1-3(1)(ST1)1-1(L1T14)2-4, and A4(L1T14)1-1(ST1)1-1(ST1)1-1(L1T14)2-3(1).

94. A compound of claim 93, wherein the compound is selected from the group: A4(L1T14)1-1(L1T14)2-4(ST1)2-3(1), and A4(L1T14)1-1(ST1)2-4(L1T14)2-3(1).

95. A compound of claim 92, wherein the compound is selected from the group:A4(ST1)1-1(ST1)2-4(L1T14)2-3(1), A4(ST1)1-1(L1T14)2-4(ST1)2-3(1), A4(ST1)2-4(L1T14)1-1(ST1)1-3(1)(L1T14)1-3(1), A4(ST1)1-4(L1T14)1-4(L1T14)1-1(ST1)2-3(1), A4(ST1)1-3(1)(L1T14)1-3(1)(L1T14)1-1(ST1)2-4, and A4(ST1)1-1(L1T14)1-1(L1T14)1-1(ST1)2-3(1).

96. A compound of claim 95, wherein the compound is selected from the group: A4(L1T14)2- 4(ST1)1-1(ST1)2-3(1), and A4(ST1)2-4(ST1)1-1(L1T14)2-3(1).

97. A compound of formula (G2) or a tautomer, stereoisomer, constitutional isomer, pharmaceutically acceptable salt or solvates thereof,wherein each one of LCHAIN1, LCHIN2, LCHAIN3 and LCHAIN4 is a linear or branched Ca-alkyl, with a = 9-15, or CH2(CH2)v’CH=CH(CH2)v”CH3, with v’ = 1-4, v” = 2-5;and each occurrence of LCHAIN1 - LCHAIN4 is the same or different from each of any of the other three occurrences of LCHAIN1 - LCHAIN4; n = 0 – 4; n’ = 0 - 4, and each occurrence of n is the same or different from each occurrence of n’; Q is (CH2)rCH3 with r = 0-2, or CH2(CH2)r’C(O)O(CH2)r”CH3 with r’ = 0-3 and r” = 1-3.

98. A compound of claim 97, wherein each of LCHAIN1 - LCHAIN4 is a linear Ca-alkyl, with a = 9-15.

99. A compound of claim 97, at least one of LCHAIN1 - LCAHIN4 is a branched Ca-alkyl, with a = 9-15.

99. A compound of claim 98, wherein LCHAIN1 = LCHAIN2 = LCHAIN3 = LCHAIN4 = linear Ca-alkyl, with a = 9-15.

100. A compound of claim 99, wherein LCHAIN1 = LCHAIN2 = LCHAIN3 = LCHAIN4 is CH3-(CH2)8-CH2, CH3-(CH2)10-CH2, or CH3-(CH2)12-CH2.

101. A compound of claim 97, LCHAIN1 = LCHAIN2 = LCHAIN3 = LCHAIN4 is CH2(CH2)v’CH=CH(CH2)v”CH3, with v’ = 2, v” = 4.

102. A compound of claim 97, wherein n = n’.

103. A compound of claim 102, wherein n = n’ = 1.

104. A compound of claim 97, n = 1 and n’ = 4.

105. A compound of claim 97, wherein n = 4 and n’ = 1.

106. A compound of claim 97, wherein MM is MM1.

107. A compound of claim 106, wherein MM1 is .

108. A compound of claim 106, wherein MM1 is .

109. A compound of claim 107, wherein n = n’ = 1, and LCHAIN1 = LCHAIN2 = LCHAIN3 = LCHAIN4 is CH3-(CH2)8-CH2, CH3-(CH2)10-CH2, or CH3-(CH2)12-CH2.

110. A compound of claim 108, wherein n = n’ = 1, and LCHAIN1 = LCHAIN2 = LCHAIN3 = LCHAIN4 is CH3-(CH2)8-CH2, CH3-(CH2)10-CH2, or CH3-(CH2)12-CH2.

111. A compound of claim 97, wherein MM is MM2.

112. A compound of claim 97, wherein MM is MM3.

113. A compound of claim 97, wherein MM is MM4.

114. A compound of claim 113, wherein Q is (CH2)rCH3 with r = 0-1, or CH2(CH2)r’C(O)O(CH2)r”CH3with r’ = 1-2 and r” = 1-3.

115. A compound of claim 113, wherein Q is CH3, or CH2(CH2)r’C(O)O(CH2)r”CH3 with r’ = 1 and r” = 1.

116. A compound of claim 113, wherein Q is CH3, or CH2(CH2)r’C(O)O(CH2)r”CH3 with r’ = r” = 1, and t = t’ = 1, 2.

117. A compound of claim 113, wherein t = 1, 2 and t’ = 1, 2.

118. A compound of claim 113, wherein t = t’ = 1, 2.

119. A compound of claim 97, wherein MM is MM5.

120. A compound of claim 119, wherein t1 = 1, 2, t2 = 1, 2, t3 = 1, 2, t4 = 1, 2.

121. A compound of claim 119, wherein t1 = t2 = t3 = t4 = 1, 2.

122. A compound of claim 119, wherein t1 = t2 = t3 = t4 = 1.

123. A compound of claim 119, wherein t1 = t2 = t3 = t4 = 1, Q is CH3.

124. A compound of claim 111, wherein n = n’ = 1, and LCHAIN1 = LCHAIN2 = LCHAIN3 = LCHAIN4 is CH3- (CH2)8-CH2, CH3-(CH2)10-CH2, or CH3-(CH2)12-CH2.

125. A compound of claim 111, wherein n = 1, n’ = 4, and LCHAIN1 = LCHAIN2 = LCHAIN3 = LCHAIN4 is CH3-(CH2)8-CH2, CH3-(CH2)10-CH2, or CH3-(CH2)12-CH2.

126. A compound of claim 112, wherein n = n’ = 1, and LCHAIN1 = LCHAIN2 = LCHAIN3 = LCHAIN4 is CH3-(CH2)8-CH2, CH3-(CH2)10-CH2, or CH3-(CH2)12-CH2.

127. A compound of claim 112, wherein n = 1, n’ = 4, and LCHAIN1 = LCHAIN2 = LCHAIN3 = LCHAIN4 is CH3-(CH2)8-CH2, CH3-(CH2)10-CH2, or CH3-(CH2)12-CH2.

128. A compound of claim 113, wherein n = n’ = 1, and LCHAIN1 = LCHAIN2 = LCHAIN3 = LCHAIN4 is CH3-(CH2)8-CH2, CH3-(CH2)10-CH2, or CH3-(CH2)12-CH2.

129. A compound of claim 113, wherein n = 1, n’ = 4, and LCHAIN1 = LCHAIN2 = LCHAIN3 = LCHAIN4 is CH3-(CH2)8-CH2, CH3-(CH2)10-CH2, or CH3-(CH2)12-CH2.

130. A compound of any one of claims 98-101, 102-105, 109, 110, 125-129, wherein MM is selected from MM1, MM2 and MM3.

131. A compound of any one of claims 98-101, 102-105, 109, 110, 125-129, wherein MM is MM4, Q is (CH2)rCH3with r = 0-2, or CH2(CH2)r’C(O)O(CH2)r”CH3with r’ = 0-3 and r” = 1-3, t = 0-3, and t’ = 0-3.

132. A compound of any one of claims 98-101, 102-105, 109, 110, 125-129, wherein MM is MM5, Q is (CH2)rCH3 with r = 0-2, or CH2(CH2)r’C(O)O(CH2)r”CH3 with r’ = 0-3 and r” = 1-3, t1 = 1-3, t2 = 1-3, t3 = 1-3, and t4 = 1-3.

133. A compound selected from the group: A101T101, A101T102, A101T103, A102T101, A102T102, A102T103, A103T101, A103T102, A103T103, A104T101, A104T102, A104T103, A105T101, A105T102, A105T103, A106T101, A106T102, A106T103, A107T101, A107T102, A107T103, A109T101, A107T104, A110T101, A108T101, and tautomers, stereoisomers, constitutional isomers, constitutional isomers, pharmaceutically acceptable salts and solvates thereof.

134. A compound of any one of claims 1, 26-36, 66-69, 77-96, 97-133, wherein the compound is in the form of a pharmaceutically acceptable salt.

135. A lipid nanoparticle comprising one or more than one ionizable lipids, wherein at least one of said ionizable lipids is a compound of any one of claims 1, 26-36, 66-69, 77-96, 97-133.

136. A lipid nanoparticle of claim 135, wherein said at least one of said ionizable lipids is selected from compounds A4L1T14, A5L1T15, A7L1T14, A9L1T15, A3L1T14, A4L1T16, A4L1T17, A4L2T14, A4L2T18, A4L3T14, A6L1T16, A6L1T15, A5L1T15, A7L1T15, A9L1T2, A4L1T14, A12L1T3, A14L1T15, A16L1T13, A22L1T15, A24L1T15, A26L1T12, A27L1T12, A19L1T15, A32L1T15, A4L1T15, A106T101, and A107T101.

137. A lipid nanoparticle of claim 135, further comprising one or more than one helper lipid, one or more than one structural lipids, and one or more than one PEG-lipids.138, A lipid nanoparticle of claim 137, wherein said at least one ionizable lipid is selected from compounds A4L1T14, A5L1T15, A7L1T14, A9L1T15, A3L1T14, A4L1T16, A4L1T17, A4L2T14, A4L2T18, A4L3T14, A6L1T16, A6L1T15, A5L1T15, A7L1T15, A9L1T2, A4L1T14, A12L1T3, A14L1T15, A16L1T13, A22L1T15, A24L1T15, A26L1T12, A27L1T12, A19L1T15, A32L1T15, A4L1T15, A106T101, and A107T101.

139. A lipid nanoparticle of claim 137, wherein said one or more than one ionizable lipid is present in a total ionizable lipid mole percentage from about 15% to about 60%; said one or more than one helper lipid is present in a total helper lipid mole percentage from about 10% to about 30%; said structural lipid is present in a total structural lipid mole percentage from about 30% to about 65%; and said PEG lipid is present in a total PEG lipid mole percentage from about 0.01% to about 10%.

140. A lipid nanoparticle of claim 139, wherein said at least one ionizable lipid is selected from compounds A4L1T14, A5L1T15, A7L1T14, A9L1T15, A3L1T14, A4L1T16, A4L1T17, A4L2T14, A4L2T18, A4L3T14, A6L1T16, A6L1T15, A5L1T15, A7L1T15, A9L1T2, A4L1T14, A12L1T3, A14L1T15, A16L1T13, A22L1T15, A24L1T15, A26L1T12, A27L1T12, A19L1T15, A32L1T15, A4L1T15, A106T101, and A107T101. 141, A lipid nanoparticle of claim 140, wherein said at least one ionizable lipid is selected from compounds A4L1T14 and A5L1T15.

142. A lipid nanoparticle of claim 139, wherein said total ionizable lipid mole percentage is about 35%; said one total helper lipid mole percentage is about 16%; said total structural lipid mole percentage is about 46.5%; and said total PEG lipid mole percentage is about 2.5%; said total ionizable lipid mole percentage is about 50%; said one total helper lipid mole percentage is about 16%; said total structural lipid mole percentage is about 31.5%; and said total PEG lipid mole percentage is about 2.5%; said total ionizable lipid mole percentage is about 35%; said one total helper lipid mole percentage is about 16%; said total structural lipid mole percentage is about 45.5%; and said totalPEG lipid mole percentage is about 3.5%; said total ionizable lipid mole percentage is about 35%; said one total helper lipid mole percentage is about 16%; said total structural lipid mole percentage is about 46.5%; and said total PEG lipid mole percentage is about 2.5%; said total ionizable lipid mole percentage is about 35%; said one total helper lipid mole percentage is about 25%; said total structural lipid mole percentage is about 37.5%; and said total PEG lipid mole percentage is about 2.5%; said total ionizable lipid mole percentage is about 18.7%; said one total helper lipid mole percentage is about 20%; said total structural lipid mole percentage is about 58.1%; and said total PEG lipid mole percentage is about 3.1%; or said total ionizable lipid mole percentage is about 35%; said one total helper lipid mole percentage is about 16%; said total structural lipid mole percentage is about 46.5%; and said total PEG lipid mole percentage is about 2.5%.

143. A lipid nanoparticle of claim 142, wherein said one or more than one ionizable lipid is one compound and said compound is selected from compounds A4L1T14, A5L1T15, A7L1T14, A9L1T15, A3L1T14, A4L1T16, A4L1T17, A4L2T14, A4L2T18, A4L3T14, A6L1T16, A6L1T15, A5L1T15, A7L1T15, A9L1T2, A4L1T14, A12L1T3, A14L1T15, A16L1T13, A22L1T15, A24L1T15, A26L1T12, A27L1T12, A19L1T15, A32L1T15, A4L1T15, A106T101, and A107T101.

144. A lipid nanoparticle of claim 143, wherein said one or more than one ionizable lipid is one compound and said compound is selected from compounds A4L1T14 and A5L1T15.

145. A lipid nanoparticle of claim 142, wherein the lipid nanoparticle is an LNP and said LNP has a size in any of the following ranges: from about 10 nm to about 500 nm, from about 20 nm to about 400 nm, from about 40 nm to about 200 nm, from about 50 nm to about 180, from 55 nm to about 125 nm, and from 58 nm to about 100 nm.

146. A lipid nanoparticle of claim 145, wherein said one or more than one ionizable lipid is one compound and said compound is selected from compounds A4L1T14, A5L1T15, A7L1T14,A9L1T15, A3L1T14, A4L1T16, A4L1T17, A4L2T14, A4L2T18, A4L3T14, A6L1T16, A6L1T15, A5L1T15, A7L1T15, A9L1T2, A4L1T14, A12L1T3, A14L1T15, A16L1T13, A22L1T15, A24L1T15, A26L1T12, A27L1T12, A19L1T15, A32L1T15, A4L1T15, A106T101, and A107T101.

147. A lipid nanoparticle of claim 146, wherein said one or more than one ionizable lipid is one compound and said compound is selected from compounds A4L1T14 and A5L1T15.

148. A lipid nanoparticle of claim 135, further comprising a therapeutic agent.

149. A lipid nanoparticle of claim 148, wherein the therapeutic agent is a nucleic acid.

150. A lipid nanoparticle of claim 149, wherein the nucleic acid selected from an oligonucleotide, an RNA, and a DNA.

151. A lipid nanoparticle of claim 148, wherein the therapeutic agent is a nucleic acid selected from a plasmid, an immunostimulatory oligonucleotide, an siRNA, an antisense oligonucleotide, a microRNA, an antagomir, an aptamer, and a ribozyme.

152. A lipid nanoparticle of claim 148, wherein the therapeutic agent is a nucleic acid selected from a minigene, a plasmid, a minicircle, a small interfering RNA (siRNA), a microRNA (miRNA), an antisense oligonucleotides (ASO), a ribozyme, a closed ended double stranded DNA, a linear covalently closed DNA (ministring), a doggybone protelomere closed-ended DNA, a dumbbell linear DNA, a dicer-substrate dsRNA, a small hairpin RNA (shRNA), an asymmetrical interfering RNA (aiRNA), a microRNA (miRNA), an mRNA, a tRNA, an rRNA, a DNA viral vectors, a viral RNA vector, and any combination thereof.

153. A lipid nanoparticle of claim 146, further comprising a therapeutic agent that is a nucleic acid selected from a plasmid, an immunostimulatory oligonucleotide, an siRNA, an mRNA, an antisense oligonucleotide, a microRNA, an antagomir, an aptamer, and a ribozyme.

154. A lipid nanoparticle of claim 153, wherein the therapeutic agent is an mRNA and the lipid nanoparticle with said mRNA is a vaccine.

155. A pharmaceutical composition comprising a lipid nanoparticle of claim 148 and a pharmaceutically acceptable carrier.

156. A compound of any one of claims 1-67, 69-133, for use in LNP drug delivery, vaccine delivery or cancer immunotherapy.

157. A compound of claim 156 for use in vaccine delivery.

158. A compound of claim 156 for use in vaccine delivery, wherein the vaccine is an mRNA LNP.

159. A compound of claim 155, wherein the drug is dsDNA, DNA, mRNA, siRNA, or small molecule.

160. A method of treating a disease or disorder, comprising providing the subject a pharmaceutical composition of claim 155.

161. A method of inducing an immune response in a subject, comprising providing the subject a pharmaceutical composition of claim 15.

162. A method of claim 161, wherein said therapeutic agent within said pharmaceutical composition comprises an mRNA.

163. A method of claim 162, wherein the mRNA LNP is a vaccine.

164. A method of modulating the expression of a target gene in a cell, comprising providing the subject a pharmaceutical composition of claim 155.

165. A method for delivering a therapeutic level of active agent to a subject, comprising administering to the subject a pharmaceutical composition of claim 155.

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