Silicon-containing ionizable cationic lipids

Abstract

The invention relates to a novel silicon-containing ionizable cation lipid family, which belongs to a first-generation lipid with the trademark of LipexSilTM, and at least one of two side chains comprises a silyl acetal joint. So far, lipids comprising a silyl acetal linker are unprecedented in the art and are effective as ionizable cationic lipids in formulations of empty or loaded lipid nanoparticles (LNPs). The novel linker according to the invention is designed by means of a borane catalyst [WO2022 / 129966]. The present invention describes the synthesis of lipids of formula (I), the formation and characterization of nanoparticles and biological experiments that lipid nanoparticles prepared with these novel lipids are effective in delivering their articles (e.g., RNA, DNA, mRNA, siRNA, pDNA, circular DNA, biologically active small molecules) into cells.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine and drug delivery.

[0002] The present invention relates to a novel family of silicon-containing ionizable cationic lipids, which are marketed under the trademark LipexSil. TM The first generation of lipids, wherein at least one of the two side chains comprises a silyl acetal (silyl acetal) linker. So far, lipids comprising silyl acetal linkers are unprecedented in the art and are effective as ionizable cationic lipids in preparations of empty or loaded lipid nanoparticles (lipid nanoparticles, LNPs). The novel linker according to the present invention is designed by a borane catalyst [WO2022 / 129966]. The present invention describes the synthesis of lipids of formula (I), and the formation and characterization of nanoparticles and biological experiments show that lipid nanoparticles prepared with these novel lipids can effectively deliver their cargo (e.g., RNA, DNA, mRNA, siRNA, pDNA, circular DNA, biologically active small molecules) into cells. Background Art

[0003] In biological systems, there are many challenges associated with transfection of nucleic acid reagents (such as messenger RNA, antisense oligonucleotides, ribozymes, plasmids) and small molecules to induce the desired reaction. It is necessary to design and synthesize new second-generation lipids (biodegradable ionizable amine lipids) to improve the delivery of bioactive agents (such as DNA, RNA, mRNA and various small molecules) to cells. In the medical field, these treatments are the most effective and can selectively and directly target the affected cells or tissues with appropriate active agents. With this in mind, treatment efficiency should be improved and undesirable toxic side effects should be avoided or reduced. Loaded lipid nanoparticles (LNPs) comprising lipid components have been shown to be effective carrier systems that can be functionalized to protect payloads and deliver payloads to target sites. It should be emphasized that LNPs formed from ionizable cationic lipids have also been shown to be excellent lipid carriers in gene therapy.

[0004] LNPs also contain synthetic lipids that can be toxic to human cells, and the cytotoxicity of synthetic lipids depends on certain motifs in the lipids (e.g., type of headgroup, linker) that are related to their biodegradability and their metabolic pathways in the human body.

[0005] LNP has some key parameters that play an important role in successful drug delivery applications, such as particle size, polydispersity index (PDI), zeta potential and apparent pKa of LNP. According to literature data, the average particle size of LNP is generally between 100 and 400 nm, with a narrow particle size distribution, <0.2PDI (Advanced NanoBiomed Research, 2022, 2, 2100109). The apparent pKa of the optimal LNP is between 6 and 7 (Trends in Pharmacological Sciences, 2021, 42: 6, 448-460).

[0006] In the art, few examples have been found that show that silicon atoms containing lipids are also suitable components of LNPs [WO2011134675, WO 2021055835], and these LNPs are effective in delivering DNA, RNA, siRNA, and nucleotides. Silicon is an isostere of carbon in pharmaceutical research, and the introduction of silicon atoms can provide innovative solutions to medicinal chemistry problems. Silicon atoms contained in lipids can enhance lipophilicity, thereby improving membrane permeability. However, as gene therapy will become part of routine treatment in the next decade, the demand for efficient, biodegradable, and less toxic delivery platforms continues to grow. DETAILED DESCRIPTION

[0007] The present invention provides a series of novel silicon-containing lipids having the structure of formula (I), details of the synthesis method, details of the formation and characterization of LNPs, and toxicity and transfection experiments of loaded LNPs.

[0008] In one embodiment, the present invention provides an ionizable cationic lipid of formula (I) or a salt or stereoisomer thereof,

[0009]

[0010] in:

[0011] G 1 is an unsubstituted C2-C9 alkylene group,

[0012] -(CH2) x -CH=CH-(CH2) y -, wherein x is an integer selected from 1 to 6, y is an integer selected from 1 to 6, and the sum of x+y is an integer selected from 2 to 7, or

[0013] -(CH2) w -X-(CH2) z-, wherein w is an integer selected from 1 to 7, z is an integer selected from 2 to 7, and the sum of w+z is an integer selected from 3 to 8, wherein, -(CH2) z - is attached to N, and X is selected from O, S, SO and SO2;

[0014] T 1 for

[0015]

[0016] in

[0017] b 1 To G 1 The key,

[0018] X1 and X2 are the same or different and each independently represents O or S,

[0019] R1 is linear C1-C 17 Alkyl, nonlinear C3-C 17 Alkyl, in both cases optionally containing one S, SO, SO2, O or Si(R a )2, where R a C1-C6 alkyl at any position in the carbon chain, provided that the heteroatom is not in the α or Ω position of the carbon chain; C3-C 17 alkenyl, provided that there is at least one -CH2- group between the double bond and X2; or a polyunsaturated C8-C 20 alkenyl, provided that there is at least one -CH2- group between the first double bond and X2, or

[0020] R1 is

[0021]

[0022] Among them, R 17 、R 18 and R 19 are the same or different and can each independently be H, OH, -C1-C6 alkoxy or fluorine;

[0023] R2 is

[0024] Linear C1-C 17 Alkyl, nonlinear C3-C 17 Alkyl, in both cases optionally containing one S, SO, SO2, O or Si(R b )2, where R b C1-C6 alkyl at any position in the carbon chain, provided that the heteroatom is not in the α or Ω position of the carbon chain; C3-C 17alkenyl, provided that there is at least one -CH2- group between the double bond and the carbon connecting X1 and X2; or a polyunsaturated C8-C 20 alkenyl, provided that there is at least one -CH2- group between the first double bond and the carbon connecting X1 and X2, or

[0025] R2 is

[0026] Among them, R 20 、R 21 and R 22 are the same or different and can each independently be H, OH, -C1-C6 alkoxy or fluorine,

[0027] The condition is that R1 and R2 cannot exist at the same time;

[0028]

[0029] R1 is connected to R3 via an alkylene group or a monounsaturated alkenyl group to form a C5-C 30 -membered ring, or

[0030] R2 is connected to R3 via an alkylene group or a monounsaturated alkenyl group to form a C5-C 30 a membered ring, wherein the carbon atom at the first or second position of R2, numbered from the carbon atom to which X1 and X2 are attached, can be optionally substituted with an O or S heteroatom, or

[0031] R2 is connected to R1 via an alkylene group or a monounsaturated alkenyl group to form a C5-C 30 A ring wherein the carbon atom at the first or second position of R2 can be optionally substituted by an O or S heteroatom, the first or second position being separated from the carbon atom attached to X1 and X2.

[0032] Carbon atoms begin numbering;

[0033] R3 is

[0034]

[0035] R5-b 1 for

[0036]

[0037] in

[0038] b 2 is the link to X1,

[0039] Y1 is -O- or -CH2- or -O-CH2-CH2-, wherein -CH2- is attached to Si,

[0040] Each X3 is independently selected from the group consisting of C1-C4 alkyl or C1-C4 alkoxy,

[0041] R4 is a linear C2-C 17 Alkyl or nonlinear C3-C 17 Alkyl, in both cases optionally containing one S, SO, SO2, O or Si(R c )2, where R c C1-C6 alkyl at any position in the carbon chain, provided that the heteroatom is not in the α or Ω position of the carbon chain; C3-C 20 alkenyl, provided that there is at least one -CH2- group between the double bond and Y1; or a polyunsaturated C8-C 20 alkenyl, provided that there is at least one -CH2- group between the first double bond and Y1, or,

[0042] R4 is

[0043]

[0044] where b 3 is the bond to Y1,

[0045] R6, R7, R8 are the same or different and can each independently be H, OH, -C1-C6 alkoxy or fluorine;

[0046] D 1 Select from the group consisting of

[0047] as well as

[0048] in

[0049] b 4 is the bond to nitrogen,

[0050] R9 can be C1-C6 alkyl, cyclopentyl, cyclohexyl, hydroxyl, hydroxymethyl, hydroxyethyl, phenyl, benzyl, 4-hydroxybenzyl,

[0051]

[0052] R 10 and R 11 independently selected from H and C1-C6 alkyl,

[0053] m is an integer selected from 1 to 6,

[0054] n is an integer selected from 0 to 6,

[0055] o is an integer selected from 0 to 6,

[0056] p is an integer selected from 2 to 6,

[0057] q is an integer selected from 0 to 6,

[0058] j is an integer selected from 1 to 4,

[0059] Cy1 is a C3-C6 cycloalkyl group optionally substituted with one or more -OH groups, or

[0060] Cy1 is a pyranose or furanose ring, which can be attached via any of its OH groups, wherein the pyranose or furanose ring is optionally substituted by a -NH-CO-CH3 group, adenine, guanine, uracil, cytosine, thymine, a monosaccharide or oligosaccharide, or by a 4-, 5-, 6- or 7-membered heterocycle containing 1, 2, 3 or 4 heteroatoms selected from N, O or S; or

[0061] Cy1 is a 4-, 5-, 6- or 7-membered heterocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from O, N or S, wherein the heterocyclic ring is optionally replaced by R 12 replace,

[0062] in

[0063] R 12 represents a C1-C6 alkyl group, a peptide-containing arginine, a pyranose or furanose ring attached to a 4-, 5-, 6- or 7-membered heterocyclic ring via any of their ring carbon atoms, wherein the pyranose or furanose ring is optionally substituted with a -NH-CO-CH3 group, adenine, guanine, uracil, cytosine, thymine or a mono- or oligosaccharide,

[0064] R 12 can be a group selected from (d), (e) or (f), wherein b 4 is a bond to a heterocycle, m, n, o, p, R9, R 10 and R 11 as defined above, or

[0065] R 12 Can A group wherein r is an integer selected from 1 to 4, and Cy2 is a 4-, 5-, 6- or 7-membered heterocyclic ring comprising 1, 2, 3 or 4 heteroatoms selected from O, N and S, which is optionally substituted with a C1-C6 alkyl group;

[0066] P is selected from

[0067] (i)G 2 -T 2

[0068] in

[0069] G 2 As mentioned above G 1 Definition, where G 1 and G 2 Can be the same or different;

[0070] T 2 As mentioned above, T 1 Definition, b 1 To G 2 The key, and where T 1 and T 2 may be the same or different; or

[0071] (ii)G 2 -T 3

[0072] in

[0073] G 2 As defined above;

[0074] T 3 for

[0075] in

[0076] b 5 To G 2 The key,

[0077] X4 and X5 can be the same or different and are each independently O, S or NR d , where R d is H, C1-C6 alkyl, -OH or C1-C6 alkoxy,

[0078] R 13 is linear C2-C 17 Alkyl, nonlinear C3-C 17 alkyl, both optionally containing S, SO, SO2, O, Si(R e )2, where R e C1-C6 alkyl at any position in the carbon chain, provided that the heteroatom is not in the α or Ω position of the carbon chain; C3-C 20 alkenyl, provided that there is at least one -CH2- group between the double bond and X5; or polyunsaturated C8-C20 alkenyl, provided that there is at least one -CH2- group between the first double bond and X5, or

[0079] R 13 for

[0080] Among them, R 23 、R24 、R 25 are identical or different and can each independently be H, OH, -C1-C6 alkoxy or fluorine,

[0081] R 14 is linear C2-C 17 Alkyl, nonlinear C3-C 17 alkyl, both optionally containing S, SO, SO2, O, Si(R f )2, where R f C1-C6 alkyl at any position in the carbon chain, provided that the heteroatom is not at the α or Ω position of the carbon chain; C3-C 20 alkenyl, provided that there is at least one -CH2- group between the double bond and the carbon connecting X4 and X5; or a polyunsaturated C8-C 20 alkenyl, provided that there is at least one -CH2- between the first double bond and the carbon connecting X4 and X5, or

[0082] R 14 for

[0083] Among them, R 26 、R 27 、R 28 are the same or different and can each independently be H, OH, -C1-C6 alkoxy or fluorine, and (iii) T 4 ,in

[0084] T 4 for

[0085]

[0086] Among them, b 6 is the bond to the nitrogen atom, R 29 、R 30 、R 31 can be the same or different, and each independently can be H, OH, -C1-C6 alkoxy or fluorine;

[0087] Contains a double bond C4-C 20 alkenyl, provided that there is at least one -CH2- between the double bond and the N, or

[0088] Polyunsaturated C8-C 20 alkenyl, provided that there is at least one -CH2- between the first double bond and the nitrogen.

[0089] Unsubstituted C2-C9 alkylene means ethylene (-(CH2)2-), propylene (-(CH2)3-), butene (-(CH2)4-), pentene (-(CH2)5-), hexene (-(CH2)6-), heptene (-(CH2)7-), octene (-(CH2)8-) or nonene (-(CH2)9-).

[0090] Linear C1-C 17 The alkyl group means a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, a decyl group, an undecyl group, a dodecyl group, a tridecyl group, a tetradecyl group, a pentadecyl group, a hexadecyl group or a heptadecyl group.

[0091] Nonlinear C3-C 17 Alkyl means a saturated branched alkyl group containing 3 to 17 carbon atoms, for example isopropyl, isobutyl, 3-methylpentyl, 2-propylpentyl, 2-methylhexyl, 2-ethylhexyl, 2-ethyldecyl, 2-propyldecyl, 2-butyldecyl, 2-pentyldecyl, 2-hexyldecyl or 2-heptyldecyl.

[0092] C1-C6 alkyl groups are linear or non-linear alkyl groups containing 1 to 6 carbon atoms, for example methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, tert-butyl, neopentyl, isopentyl, neohexyl or isohexyl, preferably methyl or ethyl.

[0093] C1-C4 alkyl group means a linear or non-linear alkyl group containing 1 to 4 carbon atoms, preferably a methyl group.

[0094] Linear C1-C 17 Alkyl or nonlinear C3-C 17 Alkyl groups both contain one S, SO, SO2, O or Si(R)2, wherein R is a C1-C6 alkyl group as defined above at any position of the carbon chain, provided that the heteroatom is not at the α or Ω position of the carbon chain, and linear C1-C 17 Alkyl or nonlinear C3-C 17 Alkyl is as defined above, wherein one -CH2- of the alkyl chain, not at the terminal position on either side of the chain, is substituted by one of the following groups: -O-, -S-, -SO-, SO2-, -Si(R)2-.

[0095] Contains a double bond C3-C 17 Alkenyl or C3-C containing a double bond 20Alkenyl is intended to mean a linear or non-linear alkyl radical as defined above containing 3 to 17 or 3 to 20 carbon atoms, respectively, which contains one double bond in the chain, for example, hex-3-en-1-yl, oct-3-en-1-yl, dec-3-en-1-yl, dec-2-en-1-yl, undec-3-en-2-yl, preferably hex-3-en-1-yl, oct-3-en-1-yl.

[0096] C1-C6 alkoxy means an -O-C1-C6 alkyl group, wherein the C1-C6 alkyl group is as defined above.

[0097] C1-C4 alkoxy means an -O-C1-C4 alkyl group, wherein the C1-C4 alkyl group is as defined above, such as methoxy, ethoxy, propoxy, butoxy, isopropoxy, sec-butoxy or tert-butoxy.

[0098] Connected to R3 via alkylene or monounsaturated alkenyl to form C5-C 30 R1 of the membered ring means, for example:

[0099]

[0100] Connected to R3 via alkylene or monounsaturated alkenyl to form C5-C 30 R2 of a membered ring, wherein the carbon atom at the first or second position of R2 can be optionally substituted by an O or S heteroatom, the first or second position being numbered starting from the carbon atom to which X1 and X2 are attached, R2 means, for example:

[0101]

[0102] Connected to R1 via alkylene or monounsaturated alkenyl to form C5-C 30 R2 of a membered ring, wherein the carbon atom at the first or second position of R2 can be optionally substituted by an O or S heteroatom, the first or second position being numbered starting from the carbon atom to which X1 and X2 are attached, R2 means, for example:

[0103]

[0104] Polyunsaturated C8-C 20 Alkenyl means a linear alkyl chain containing from 8 to 20 carbon atoms, wherein more than one isolated double bond is present in the chain, preferably a group derived from omega-3 and omega-6 fatty acids, such as T 4 , R1 or R 13 One of the following groups:

[0105]

[0106] and R2 or R 14One of the following groups:

[0107]

[0108] Here, the groups are linked via b.

[0109] C3-C6 cycloalkyl means, for example, cyclopropyl, cyclopentyl or cyclohexyl.

[0110] A 4-, 5-, 6- or 7-membered heterocycle containing 1, 2, 3 or 4 heteroatoms selected from N, O or S is understood to mean an aromatic ring or an unsaturated, partially saturated or fully saturated heterocycle, for example azetidine, azetidine, pyrrolidine, oxazolidine, piperidine, piperazine, morpholine, pyrrole, imidazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,4,5-tetrazine, oxazole, isoxazole, thiazole, isothiazole, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, 1,2-thiazine, 1,3-thiazine, 1,4-thiazine, azepane or 1,4-thiazepine ring, preferably a pyrrolidine, imidazole, 1,2,3-triazole, piperidine, piperazine or morpholine ring.

[0111] Furanose refers to all stereoisomers of ribofuranose, deoxyribofuranose, xylofuranose, fructofuranose, glucosefuranose, galactofuranose, mannofuranose, allofuranose, arabinofuranose or altrofuranose, which can also be protected by, for example, acetyl, benzyl, benzoyl, isopropylidene or benzylidene groups. For example: 2,3,5,6-tetra-O-acetyl-galactofuranose.

[0112] Pyranose refers to all stereoisomers of glucopyranose, galactopyranose, mannopyranose, allopyranose, fructopyranose, arabinopyranose or altrose, which can also be protected, for example, by acetyl, benzyl, benzoyl, isopropylidene or benzylidene groups, for example: 2,3,4,6-tetra-O-acetyl-glucopyranose.

[0113] Monosaccharides, oligosaccharides mean monosaccharides as defined above and also mean oligosaccharides such as sucrose, lactose, maltose, isomaltose, cellobiose, trehalose.

[0114] Arginine containing peptides means peptides of 6 amino acids or less that include at least one arginine residue. The peptides are linked via their C-termini or N-termini.

[0115] Salts of compounds of formula (I) are salts of compounds of formula (I) with inorganic or organic acids. Preferred salts are salts of pharmaceutically acceptable acids. These salts are, for example, chlorides, sulfates, phosphates, formates, acetates, fumarates, maleates, oxalates, citrates or tartrates. Salts formed during purification or separation are also subject of the present invention.

[0116] Stereoisomers refer to optical and geometric isomers. The compounds of formula (I) may contain one or more asymmetric carbon atoms, so they can exist in the form of optical isomers, enantiomers or diastereomers. The compounds of formula (I) may contain double bonds, and the groups attached to the double bonds can have different (cis or trans) configurations, such as cis or trans fatty acid moieties.

[0117] A particular group of compounds of formula (I) are those wherein

[0118] G 1 is an unsubstituted C2-C9 alkylene group,

[0119] -(CH2) x -CH=CH-(CH2) y -, wherein x is an integer selected from 1 to 6, y is an integer selected from 1 to 6, and the sum of x+y is an integer selected from 2 to 7, or

[0120] -(CH2) w -X-(CH2) z -, wherein w is an integer selected from 1 to 7, z is an integer selected from 2 to 7, and the sum of w+z is an integer selected from 3 to 8, wherein, -(CH2) z - is attached to N, and X is selected from O, S, SO and SO2;

[0121] T 1 for in

[0122] b 1 To G 1 The key,

[0123] X1 and X2 are the same or different and each independently represents O or S,

[0124] R1 is linear C2-C 17 Alkyl, nonlinear C3-C17 Alkyl, in both cases optionally containing one S, SO, SO2, O or Si(R a )2, wherein Ra is a C1-C6 alkyl group at any position in the carbon chain, provided that the heteroatom is not at the α position or Ω position of the carbon chain; a C3-C6 alkyl group containing a double bond 17 alkenyl, provided that there is at least one -CH2- group between the double bond and X2; or a polyunsaturated C8-C 20 alkenyl, provided that there is at least one -CH2- group between the first double bond and X2,

[0125] R2 is linear C2-C 17 Alkyl, nonlinear C3-C 17 Alkyl, in both cases, optionally contains a S, SO, SO2, O or Si(R b )2, where R b is a C1-C6 alkyl group at any position in the carbon chain, provided that the heteroatom is not in the α or Ω position of the carbon chain; a C3-C6 alkyl group containing a double bond 17 alkenyl, provided that there is at least one -CH2- group between the double bond and the carbon connecting X1 and X2; or a polyunsaturated C8-C 20 alkenyl, provided that there is at least one -CH2- group between the first double bond and the carbon connecting X1 and X2,

[0126] R3 is

[0127] R5-b 1 for in

[0128] b 2 For the link to X1,

[0129] Y1 is -O- or -CH2- or -O-CH2-CH2-, wherein -CH2- is attached to Si,

[0130] Each X3 is independently selected from the group consisting of C1-C4 alkyl or C1-C4 alkoxy,

[0131] R4 is a linear C2-C 17 Alkyl, or nonlinear C3-C 17 Alkyl, in both cases optionally containing one S, SO, SO2, O or Si(R c )2, where R c C1-C6 alkyl at any position in the carbon chain, provided that the heteroatom is not in the α or Ω position of the carbon chain; C3-C 20 alkenyl, provided that there is at least one -CH2- group between the double bond and Y1; or a polyunsaturated C8-C20 alkenyl, provided that there is at least one -CH2- group between the first double bond and Y1, or,

[0132] R4 is

[0133] where b 3 is a bond to Y1, R6, R7, R8 can be the same or different, and each independently can be H, OH, -C1-C6 alkoxy or fluorine;

[0134] D 1 Select from the group consisting of

[0135] as well as in

[0136] b 4 is the bond to nitrogen,

[0137] R9 can be C1-C6 alkyl, hydroxyl, hydroxymethyl,

[0138] m is an integer selected from 1 to 6,

[0139] n is an integer selected from 0 to 6,

[0140] o is an integer selected from 0 to 6,

[0141] p is an integer selected from 2 to 6,

[0142] R 10 and R 11 independently selected from H and C1-C6 alkyl,

[0143] q is an integer selected from 0 to 6,

[0144] Cy1 is a C3-C6 cycloalkyl group optionally substituted with one or more -OH groups, or

[0145] Cy1 is a pyranose or furanose ring, which can be attached via any of its OH groups, wherein the pyranose or furanose ring is optionally substituted by a -NH-CO-CH3 group, adenine, guanine, uracil, cytosine, thymine, a monosaccharide or oligosaccharide, or by a 4-, 5-, 6- or 7-membered heterocycle containing 1, 2, 3 or 4 heteroatoms selected from N, O or S; or

[0146] Cy1 is a 4-, 5-, 6- or 7-membered heterocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from O, N or S, wherein the heterocyclic ring is optionally replaced by R 12 replace,

[0147] in

[0148] R 12represents a C1-C6 alkyl group, a peptide-containing arginine, a pyranose or furanose ring attached to a 4-, 5-, 6- or 7-membered heterocyclic ring via any of its ring carbon atoms, wherein the pyranose or furanose ring is optionally substituted by a -NH-CO-CH3 group, adenine, guanine, uracil, cytosine, thymine or a mono- or oligosaccharide,

[0149] R 12 can be a group selected from (d), (e) or (f), wherein b4 is a bond to a heterocycle, m, n, o, p, R9, R 10 and R 11 as defined above, or

[0150] R 12 Can A group wherein r is an integer selected from 1 to 4, and Cy2 is a 4-, 5-, 6- or 7-membered heterocyclic ring comprising 1, 2, 3 or 4 heteroatoms selected from O, N and S, which is optionally substituted with a C1-C6 alkyl group;

[0151] P is selected from

[0152] (i)G 2 -T 2 ,in

[0153] G 2 As mentioned above G 1 Defined as, where G 1 and G 2 can be the same or different;

[0154] T 2 As mentioned above, T 1 As defined, b 1 To G 2 The key, and where T 1 and T 2 may be the same or different; or

[0155] (ii)G 2 -T 3 ,in

[0156] G 2 As defined above;

[0157] T 3 for

[0158] in

[0159] b 5 To G 2 The key,

[0160] X4 and X5 can be the same or different and are each independently O, S or NR d , where R d is H, C1-C6 alkyl,

[0161] -OH or C1-C6 alkoxy,

[0162] R 13 is linear C2-C 17 Alkyl, nonlinear C3-C 17 alkyl, both optionally containing S, SO, SO2, O, Si(R e )2, where R e is a C1-C6 alkyl group at any position in the carbon chain, provided that the heteroatom is not in the α or Ω position of the carbon chain;

[0163] Contains a double bond C3-C 20 alkenyl, provided that there is at least one -CH2- group between the double bond and X5; or a polyunsaturated C8-C 20 alkenyl, provided that there is at least one -CH2- between the first double bond and X5;

[0164] R 14 is linear C2-C 17 Alkyl, nonlinear C3-C 17 alkyl, both optionally containing S, SO, SO2, O, Si(R f )2, where R f is a C1-C6 alkyl group at any position in the carbon chain, provided that the heteroatom is not in the α or Ω position of the carbon chain;

[0165] Contains a double bond C3-C 20 alkenyl, provided that there is at least one -CH2- group between the double bond and the carbon connecting X4 and X5;

[0166] or polyunsaturated C8-C 20 alkenyl, provided that there is at least one -CH2- between the first double bond and the carbon connecting X4 and X5; and

[0167] (iii)T 4 ,in

[0168] T 4 for

[0169]

[0170] Among them, b 6 is the bond to the nitrogen atom, R 29 、R 30 、R 31can be the same or different and each independently can be H, OH, -C1-C6 alkoxy or fluorine; or

[0171] Contains a double bond C4-C 20 Alkenyl, provided there is at least one -CH2- between the double bond and the N, or

[0172] Polyunsaturated C8-C 20 alkenyl, provided that there is at least one -CH2- between the first double bond and the nitrogen.

[0173] A narrower group of compounds of formula (I) are those wherein G 1 and G 2 (if present) are the same or different and are each independently a linear C4-C9 alkylene, preferably a C5-C9 alkylene, or alternatively, are each independently a linear C5, C6, C7 or C9 alkylene.

[0174] Another group of compounds of formula (I) is wherein R1 is a linear C1, C2, C4, C6, C7, C8, C9, C 10 or C 12 Alkyl, or R1 is a linear C9 alkenyl, and / or R2 is a linear C1, C3, C5, C6, C7, C8, C9 or C 11 Alkyl, preferably R1 is linear C2, C8, C 10 Alkyl, or R1 is a linear C9 alkenyl and / or R2 is a linear C1, C3, C7 or C9 alkyl.

[0175] The specific embodiment of this group is that T 1 (c) and R1 is linear C2, C4, C6, C7, C8, C9, C 10 or C 12 Alkyl, or R1 is a linear C9 alkenyl, and R2 is a linear C1, C3, C5, C6, C7, C8, C9 or C 11 Alkyl, preferably R1 is linear C2, C8, C 10 alkyl, or R1 is a linear C9 alkenyl, and R2 is a linear C1, C3, C7 or C9 alkyl.

[0176] Another group of compounds of formula (I) is wherein R4 is a linear C5, C7, C8 alkyl group, or R4 is a non-linear C 16 alkyl.

[0177] A specific embodiment of this group is wherein T 1 is (b).

[0178] Another group of compounds of formula (I) is wherein P is G 2 -T 2 .

[0179] In certain embodiments of this group, G 1 -T 1 and G 2 -T 2 are the same.

[0180] Another group of compounds of formula (I) is wherein P is G 2 -T 3 .

[0181] In certain embodiments of this group, T 1 -G 1 Has one of the following structures

[0182]

[0183] A narrower group of compounds of formula (I) is that wherein T 3 Has one of the following structures

[0184]

[0185] Among them, b 5 To G 2 key.

[0186] Another group of compounds of formula (I) is wherein P is T 4 .

[0187] In certain embodiments of this group, T 4 for

[0188]

[0189] Among them, b 6 is the bond to the nitrogen atom, R 29 、R 30 、R 31 can be the same or different and each independently can be H, OH, -C1-C6 alkoxy or fluorine;

[0190] or

[0191] Polyunsaturated C8-C 20 alkenyl, provided that there is at least one -CH2- between the first double bond and the nitrogen.

[0192] In other specific embodiments of this group, T 4 With the following structure

[0193]

[0194] Among them, b 6 is a bond to the nitrogen atom.

[0195] Another group of compounds of formula (I) is D 1 Has one of the following structures:

[0196]

[0197] Another group of compounds of formula (I) is that wherein D 1 Has one of the following structures:

[0198]

[0199] wherein q is an integer selected from 1 to 4, and b4 is a bond to nitrogen.

[0200] In some embodiments, D 1 Has one of the following structures:

[0201]

[0202] The present invention also provides lipid nanoparticles (LNPs) comprising a compound of formula (I) as defined above and a therapeutic agent (eg, RNA, DNA, mRNA, siRNA, pDNA, circular DNA or a small bioactive molecule).

[0203] In certain embodiments, the present invention provides lipid nanoparticles comprising a compound of formula (I) and mRNA (eg, luciferase or green fluorescence protein (GFP)).

[0204] The present invention also provides methods for delivering mRNA to cells.

[0205] The present invention opens up a new chemical space via silicon-containing joints, thereby producing novel biodegradable lipids of formula (I). The mentioned joints are difficult to synthesize using traditional chemical toolboxes, but the recently published borane catalysts [WO2022 / 129966] make their synthesis possible. The mixed acetal structural units of the present invention are prepared by a method similar to that described in WO2022 / 129966. These novel mixed acetals are structurally different from those disclosed in WO2022 / 129966, and are further distinguished in that the mixed acetal portion is retained and incorporated into the lipid according to the present invention.

[0206] Another important feature of the present invention is modularity. Due to the nature of the designed silicon-based linker, a large number of compounds and various lipid libraries can be designed and synthesized from simple and readily available starting materials.

[0207] Furthermore, the chemical stability of silicon-containing ionizable lipids (e.g., susceptibility to hydrolysis) can be fine-tuned by the chemical nature of the substituents and the number of O and Si atoms on the mixed silyl acetal group (linker), which is reflected in the biodegradability of the lipids.

[0208] Another aspect of the present invention is the preparation of compounds of formula (I) and the intermediates and building blocks used therein.

[0209] Compounds of formula (I) can be prepared according to the following reaction schemes.

[0210] General Reaction Scheme 1 - Synthesis of Symmetric Lipids

[0211]

[0212] General Reaction Scheme 1 shows a method for preparing the symmetrical lipids of the present invention having the structure of Formula (I), wherein T 1 -G 1 and P are the same, X6 is halogen or pseudohalogen, G 1 , X1, X2, R1, R2, R3, D 1 As described above, compounds of structures A-1, A-1', A-1", A-2, A-2', A-3, A-3', A-3", A-4, A-4' and A-6 can be purchased or prepared according to methods known in the art. The carboxylic acid derivative A-1 or A-1' or A-1" reacts with the alcohol derivative A-2 or A-2' under appropriate esterification conditions (e.g., oxalyl chloride, Et3N) to produce ester A-3 or A-3' or A-3", which can be converted into mixed silane acetal A-5 or A-5' or A-5". The mixed silane acetal A-5 or A-5' or A-5" corresponding to formula (II) containing halogen or pseudo-halogen atoms reacts with the amine derivative A-6 under appropriate alkylation conditions (e.g., KI, BrF(F3s)2 in CPME / MeCN) to produce compounds A-7 or A-7' or A-7", respectively.

[0213] General Reaction Scheme 2 - Synthesis of Asymmetric Lipids

[0214] Route A

[0215]

[0216] Route A of General Reaction Scheme 2 shows a method for preparing asymmetric lipids of the present invention having a structure of Formula (I), wherein T 1 -G 1 and P is different, and P is G 2 -T3 or T 4 , X6 is halogen or pseudohalogen, G 1 , X1, X2, R1, R2, R3, D 1 As defined above. Compounds of structures A-8, A-8' and A-6 can be purchased or prepared according to methods known in the art. The reaction of carboxylic acid derivatives A-8 or A-8' with methanol or ethanol (HO-X7) under appropriate esterification conditions (such as oxalyl chloride, Et3N) generates ester A-9 or A-9', which can be converted into mixed silyl acetals A-10 or A-10' using triethylsilane and an appropriate borane catalyst [borane catalyst is disclosed in WO2022 / 129966]. The resulting mixed silyl acetals A-10 or A-10' are converted into aldehydes (in advance or in situ), which are reacted with appropriate amine derivatives A-6 under reductive amination conditions (such as NaHB (OAc) 3, AcOH) to produce compounds A-11 or A-11' as intermediates. The reaction of intermediate A-11 or A-11' with mixed silyl acetal A-5 or A-5' or A-5" (compounds of formula II) under appropriate alkylation conditions (e.g., KI, BrF(F3s)2 in CPME / MeCN) produces compounds A-12 or A-12' or A-12".

[0217] Route B

[0218]

[0219] Scheme B of General Reaction Scheme 2 shows a method for preparing an asymmetric lipid of the present invention having the structure of Formula (I), wherein T 1 -G 1 and P is different, and P is G 2 -T 2 , G 2 -T 3 or T 4 , X6 is halogen or pseudohalogen, G 1 , X1, X2, R1, R2, R3, D 1As defined above. The silyl acetal A-5 or A-5' or A-5" corresponding to formula (II) containing a halogen or pseudohalogen is reacted with an amine derivative A-6 under appropriate alkylation conditions (e.g., KI, BrF(F3s)2 in CPME / MeCN) to produce A-13 or A-13' or A-13", as an intermediate having the structure of formula (Ia). The resulting intermediate A-13 or A-13' or A-13" is reacted with A-10 or A-10' (A-10 or A-10' is converted to an aldehyde (in advance or in situ)) under appropriate reductive amination conditions to produce A-14 or A-14' or A-14", or in other cases, A-13 or A-13' or A-13" is reacted with a silyl acetal containing a halogen or pseudohalogen to produce A-14 or A-14' or A-14".

[0220] General Reaction Scheme 3 - Synthesis of Headgroup-Modified Lipids via Click Chemistry

[0221]

[0222] General Reaction Scheme 3 shows a method for producing a headgroup-modified lipid having a structure of Formula (I) via click chemistry of the present invention, wherein T 1 -G 1 and P are the same or different, X6 is halogen or pseudohalogen, W is N3 or ethynyl, depending on the meaning of Z1, and G 1 , X1, X2, R1, R2, R3, D 1 , Z1 is as defined above. Only one case is shown in Scheme 3, but other cases can be similarly deduced based on general reaction schemes 1 and 2. Compounds of structures A-1, A-2, A-3, A-4, A-15 and A-19 can be purchased or prepared according to methods known in the art. The reaction of carboxylic acid derivative A-1 with alcohol derivative A-2 under appropriate esterification conditions (e.g., oxalyl chloride, Et3N) produces ester A-3, which can be converted into mixed silyl acetal A-5 under the action of appropriate silane derivative A-4 and borane catalyst [borane catalyst is disclosed in WO2022 / 129966]. The generated mixed silyl acetal A-5 containing halogen or pseudohalogen reacts with amine derivative A-15 under appropriate alkylation conditions (e.g., KI, BrF(F3s)2 in CPME / MeCN) to produce compound A-16 (compound of formula (Ib)).

[0223] From the obtained intermediate A-16, compound A-17 (Formula (Ic)) can be synthesized by further alkylation reaction as described above, or compound A-18 (Formula (Ic)) can be synthesized under appropriate reductive amination conditions (e.g., NaHB(OAc)3, AcOH). The reaction of A-17 or A-18 with A-19 under appropriate click chemistry conditions (e.g., azido sugar in DMF, CuBr, PMDT) produces compound A-7 or A-12, wherein D 1 is (g), and Cy1 is an optionally substituted 1,2,3-triazole ring. BRIEF DESCRIPTION OF THE DRAWINGS

[0224] Figure 1 Example 139 Transfection efficiency and toxicity at different doses of GFP mRNA (3.3-800 ng mRNA / well): (Experiment based on method B)

[0225] Figure 2 Example 153 Transfection efficiency and toxicity at different doses of GFP mRNA (3.3-800 ng mRNA / well): (Experiment based on method B)

[0226] Figure 3 Example 154: Transfection efficiency and toxicity at different doses of GFP mRNA (3.3-800 ng mRNA / well): (Experiment based on method B)

[0227] Figure 4 Example 155: Transfection efficiency and toxicity at different doses of GFP mRNA (3.3-800 ng mRNA / well): (Experiment based on method B)

[0228] Figure 5 Example 206 Transfection efficiency and toxicity at different doses of GFP mRNA (3.3-800 ng mRNA / well): (Experiment based on method B)

[0229] Figure 6 Example 209 Transfection efficiency and toxicity at different doses of GFP mRNA (3.3-800 ng mRNA / well): (Experiment based on method B)

[0230] Figure 7 Example 211 Transfection efficiency and toxicity at different doses of GFP mRNA (3.3-800 ng mRNA / well): (Experiment based on method B)

[0231] Example

[0232] The present invention is illustrated by the following examples. These examples illustrate the present invention but do not limit it. For all examples, standard processing and purification methods known to those skilled in the art can be used.

[0233] synthesis

[0234] Ester Synthesis (General Procedure AD)

[0235]

[0236] General Procedure A

[0237] A three-necked round-bottom flask was equipped with a dropping funnel, a drying tube (with CaCl ) and a thermometer and was charged with 1 equivalent of acid and diethyl ether (concentration: 1.0 mmol of acid in 0.8 mL of diethyl ether). The solution in the flask was cooled to 0° C. and 1.10 equivalents of oxalyl chloride were added dropwise. The reaction mixture was warmed to room temperature and stirred overnight. After this time, the mixture was concentrated under reduced pressure to give an oil which did not require further purification for the next use.

[0238] A three-necked round-bottom flask is equipped with a dropping funnel, a drying tube (with CaCl ) and a thermometer, and is equipped with 1.0 equivalents of alcohol, 1.0 equivalents of triethylamine and dichloromethane (concentration: 1.0mmol alcohol in 4.0ml dichloromethane). The mixture in the flask is cooled to 0° C. and a dichloromethane solution of 1.0 equivalents of acyl chlorides (concentration: 1.0mmol acyl chlorides in 1.0ml dichloromethane) is added dropwise. The reaction mixture is warming up to room temperature and stirred overnight. The reaction is monitored with TLC (hexane / ethyl acetate 4 / 1, PMA visualization). After spending the night, volatile matter is removed under reduced pressure, and triethylamine hydrochloride is filtered. The filtrate is evaporated under reduced pressure onto silica gel, and is purified by rapid column chromatography.

[0239] General Procedure B

[0240] A three-necked round-bottom flask was equipped with a dropping funnel, a drying tube (with CaCl ) and a thermometer and was charged with 1.0 equivalents of acid and diethyl ether (concentration: 1.0 mmol of acid in 0.8 mL of diethyl ether). The solution in the flask was cooled to 0° C. and 1.1 equivalents of oxalyl chloride were added dropwise. The reaction mixture was warmed to room temperature and stirred overnight. After this time, the mixture was concentrated under reduced pressure to give an oil which did not require further purification for the next use.

[0241] A three-necked round-bottom flask was equipped with a dropping funnel, a drying tube (with CaCl2) and a thermometer, and was charged with 1.0 equivalents of alcohol, 1.0 equivalents of triethylamine and dichloromethane (concentration: 1.0 mmol alcohol in 4 ml dichloromethane). The mixture in the flask was cooled to 0°C, and a dichloromethane solution of 1.0 equivalents of acyl chloride (concentration: 1.0 mmol acyl chloride in 1.0 ml dichloromethane) was added dropwise. The reaction mixture was warmed to room temperature and stirred overnight. The reaction was monitored by TLC (hexane / ethyl acetate 4 / 1, PMA visualization). After overnight, the mixture was concentrated to half, and the precipitated triethylamine hydrochloride was filtered off. The salt was washed with 20 ml dichloromethane and 50 ml hexane. The filtrate was evaporated. The residue was dissolved in 150 ml hexane, and 30 g of silica gel was added, stirred for 10 minutes and filtered. The silica gel was rinsed with 2 × 100 ml n-hexane. The filtrate was concentrated under reduced pressure to obtain the product as an oil.

[0242] General Procedure C

[0243] A three-necked round-bottom flask was equipped with a dropping funnel, a drying tube (with CaCl ) and a thermometer and charged with 1.25 equivalents of oxalyl chloride and anhydrous dichloromethane (concentration: 1.0 mmol of oxalyl chloride in 0.41 mL of anhydrous dichloromethane). The solution in the flask was cooled to 0° C. and 1.0 equivalents of acid were added dropwise. The reaction mixture was warmed to room temperature and stirred overnight. After this time, the mixture was concentrated under reduced pressure to give an oil which did not require further purification when used in the ester synthesis.

[0244] A three-necked round-bottom flask was equipped with a dropping funnel, a drying tube (with CaCl ) and a thermometer, and was charged with 1.0 equivalents of alcohol, 1.0 equivalents of triethylamine and dichloromethane (concentration: 1.0 mmol alcohol in 4 ml dichloromethane). The mixture in the flask was cooled to 0° C., and a dichloromethane solution of 1.0 equivalents of acyl chlorides (concentration: 1.0 mmol acyl chlorides in 1.0 ml dichloromethane) was added dropwise. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was monitored with TLC (hexane / ethyl acetate 9 / 1). After spending the night, volatile matter was removed under reduced pressure, and triethylamine hydrochloride was filtered. The filtrate was evaporated onto silica gel under reduced pressure, and purified by rapid column chromatography.

[0245] General Procedure D

[0246] A three-necked round-bottom flask was equipped with a dropping funnel, a drying tube (with CaCl ) and a thermometer, and was equipped with carboxylic acid (1.0 equivalent), alcohol (1.0 equivalent), DMAP (0.5 equivalent) and anhydrous dichloromethane (concentration: 1.0mmol carboxylic acid in 8.5mL anhydrous dichloromethane). The solution in the flask was cooled to 0° C. and a DCC solution (concentration: 1.0mmol DCC in 0.45mL anhydrous dichloromethane) was added dropwise. Afterwards, the reaction mixture was continued to stir for 1h at 0° C., then stirred at room temperature overnight. The reaction mixture was diluted with petroleum ether and filtered through a diatomaceous earth pad. The diatomaceous earth was washed with petroleum ether, and the filtrate was merged and concentrated under reduced pressure. The raw material was purified by rapid column chromatography (dichloromethane in 0-15% petroleum ether).

[0247] Ester Synthesis Example

[0248] Example 1

[0249] Synthesis of 6-Bromohexanoic Acid Octyl Ester

[0250] Octyl 6-bromohexanoate was prepared from 6-bromohexanoic acid and 1-octanol according to General Procedure A and purified using a 250 g silica gel column, eluent: hexane / ethyl acetate 4 / 1. The product was obtained as a light yellow oil: 27.7 g, 90.15 mmol, 87% yield.

[0251] 1H NMR (500MHz, CDCl3) δ4.08(t,2H), δ3.42(t,2H), δ2.33(t,2H), δ1.89(p,2H) ,δ1.70-1.60(m,4H),δ1.55-1.49(m,2H),δ1.45-1.21(m,10H),δ0.90(t,3H)

[0252] Example 2

[0253] Synthesis of 6-decylbromohexanoate

[0254] Decyl 6-bromohexanoate was prepared from 6-bromohexanoic acid and 1-decanol according to General Procedure A and purified using a 750 g silica gel column, eluent: 0-20% ethyl acetate in hexanes. The product was obtained as a light yellow oil: 35.0 g, 104.37 mmol, 89% yield.

[0255] 1H NMR (500MHz, benzene-d6) δ4.03(t,2H), δ2.86(t,2H), δ2.02(t,2H), δ1.48(p,2 H), δ1.41-1.34(m,4H), δ1.32-1.14(m,14H), δ1.09(m,2H), δ0.90(t,3H)

[0256] Example 3

[0257] Synthesis of 10-octyl bromodecanoate

[0258] Octyl 10-bromodecanoate was prepared from 10-bromodecanoic acid and 1-octanol according to General Procedure A and purified using a 250 g silica gel column, eluent: 0-20% ethyl acetate in hexanes. The product was obtained as a light yellow oil: 20.23 g, 55.67 mmol, 70% yield.

[0259] 1H NMR (500MHz, benzene-d6) δ4.06(t,2H), δ2.95(t,2H), δ2.19(t,2H), δ1.59(p,2H), δ1.53-1.43(m,4H), δ1.31-0.94(m,20H), δ0.88(t,3H)

[0260] Example 4

[0261] Synthesis of 6-bromooctanoic acid hexyl ester

[0262] 6-Bromooctyl hexanoic acid was prepared from octanoic acid and 6-bromo-1-hexanol according to General Procedure B. The product was obtained as a light yellow oil: 46.0 g, 149.70 mmol, 90% yield.

[0263] 1H NMR (500MHz, benzene-d6) δ3.95(t,2H), δ2.89(t,2H), δ2.17(t,2H), δ1.59(p,2H), δ1.40(p,2H), δ1.32(p,2H), δ1.27-1.10(m,8H), δ1.01(m,4H), δ0.85(t,3H)

[0264] Example 5

[0265] Synthesis of 6-bromodecanoic acid hexyl ester

[0266] Hexyl 6-bromodecanoate was prepared from decanoic acid and 6-bromo-1-hexanol according to General Procedure B as a light yellow oil: 26.4 g, 78.73 mmol, 75% yield.

[0267] 1H NMR (500MHz, benzene-d6) δ3.95(t,2H), δ2.89(t,2H), δ2.18(t,2H), δ1.61(p,2H), δ1.40(p,2H), δ1.32(p,2H), δ1.29-1.12(m,12H), δ1.01(m,4H), δ0.89(t,3H)

[0268] Example 6

[0269] Synthesis of 9-nonylbromooctanoate

[0270] Nonyl 9-bromooctanoate was prepared from octanoic acid and 9-bromo-1-nonanol according to General Procedure B. The product was obtained as a light yellow oil: 51.42 g, 147.18 mmol, 89% yield.

[0271] 1H NMR (500MHz, benzene-d6) δ4.05(t,2H), δ2.96(t,2H), δ2.18(t,2H), δ1.60(p,2H), δ1.48(m,4H), δ1.29-0.92(m,18H), δ0.85(t,3H)

[0272] Example 7

[0273] Synthesis of Octyl Caprylate

[0274] Octyl octanoate was prepared from octanoic acid and 1-octanol according to the general procedure B. The product was obtained as a light yellow oil: 37.40 g, 145.85 mmol, 89% yield.

[0275] 1H NMR (500MHz, benzene-d6) δ4.05(t,2H), δ2.17(t,2H), δ1.59(m,2H), δ1.48(m,2H), δ1.33-1.07(m,18H), δ0.86(m,6H)

[0276] Example 8

[0277] Synthesis of Heptyl Octanoate

[0278] Heptyl octanoate was prepared from octanoic acid and 1-heptanol according to the general procedure A. The product was obtained as a light yellow oil: 2.18 g, 8.99 mmol, 77% yield.

[0279] 1H NMR (500MHz, benzene-d6) δ3.99(t,2H), δ2.22(t,2H), δ1.57-1.49(m,4H), δ1.35-1.10(m,16H), δ0.83-0.79(m,6H)

[0280] Example 9

[0281] Synthesis of Nonyl Octanoate

[0282] Nonyl octanoate was prepared from octanoic acid and 1-nonanol according to General Procedure A. The product was obtained as a light yellow oil: 2.03 g, 7.05 mmol, 61% yield.

[0283] 1H NMR (500MHz, benzene-d6) δ3.99(t,2H), δ2.22(t,2H), δ1.57-1.50(m,4H), δ1.29-1.10(m,20H), δ0.83-0.79(m,6H)

[0284] Example 10

[0285] Synthesis of Octyl Heptanoate

[0286] Octyl heptanoate was prepared from heptanoic acid and 1-octanol according to the general procedure A. The product was obtained as a light yellow oil: 2.49 g, 10.27 mmol, 86% yield.

[0287] 1H NMR (500MHz, benzene-d6) δ3.99(t,2H), δ2.22(t,2H), δ1.57-1.50(m,4H), δ1.27-1.10(m,16H), δ0.83-0.79(m,6H)

[0288] Example 11

[0289] Synthesis of Octyl Nonanoate

[0290] Nonanoic acid octyl ester was prepared from nonanoic acid and 1-octanol according to the general procedure A. The product was obtained as a light yellow oil: 2.62 g, 9.69 mmol, 78% yield.

[0291] 1H NMR (500MHz, benzene-d6) δ3.99(t,2H), δ2.22(t,2H), δ1.57-1.50(m,4H), δ1.34-1.10(m,20H), δ0.83-0.79(m,6H)

[0292] Example 12

[0293] Synthesis of Hexyl Decanoate

[0294] Hexyl decanoate was prepared from decanoic acid and 1-hexanol according to the general procedure A. The product was obtained as a light yellow oil: 2.63 g, 10.26 mmol, 88% yield.

[0295] 1H NMR (500MHz, benzene-d6) δ3.99(t,2H), δ2.22(t,2H), δ1.57-1.48(m,4H), δ1.24-1.12(m,18H), δ0.84-0.79(m,6H)

[0296] Example 13

[0297] Synthesis of Decyl Hexanoate

[0298] Decyl hexanoate was prepared from hexanoic acid and 1-decanol according to the general procedure A. The product was obtained as a light yellow oil: 2.77 g, 10.8 mmol, 90% yield.

[0299] 1H NMR (500MHz, benzene-d6) δ3.99(t,2H), δ2.22(t,2H), δ1.60-1.49(m,4H), δ1.29-1.12(m,18H), δ0.85-0.79(m,6H)

[0300] Example 14

[0301] Synthesis of Octyl octanethioate

[0302] Octyl thiooctanoate was prepared from octanoic acid and 1-octanethiol according to General Procedure C. The product was obtained as a light yellow oil: 3.38 g, 13.08 mmol, 90% yield.

[0303] 1H NMR (500MHz, benzene-d6) δ2.79(t,2H), δ2.46(t,2H), δ1.63-1.53(m,2H), δ1.51-1.44(m,2H), δ1.35-1.10(m,18H), δ0.83-0.78(m,6H)

[0304] Example 15

[0305] Synthesis of Decyl Butyrate

[0306] Decyl butyrate was prepared from butyryl chloride and 1-decanol according to general procedure A. The product was obtained as a light yellow oil: 3.05 g, 13.36 mmol, 93% yield.

[0307] 1H NMR (500MHz, benzene-d6) δ4.05(t,2H), δ2.27(t,2H), δ1.72-1.57(m,4H), δ1.38-1.20(br.m,14H), δ0.94(t,3H), δ0.87(t,3H)

[0308] Example 16

[0309] Synthesis of (Z)-non-6-en-1-yl octanoate

[0310] (Z)-Non-6-en-1-yl octanoate was prepared from octanoic acid and (Z)-non-6-en-1-ol according to General Procedure C. The product was a light yellow oil: 2.10 g, 7.82 mmol, 85% yield.

[0311] 1H NMR (500MHz, benzene-d6) δ5.46-5.30(m,2H), δ4.03(t,2H), δ2.17(t,2H), δ2.03-1.91(m,4H), δ1.62-1.55(m,2H), δ1.50-1.42(m,2H) δ1.30-1.12(m,12H), δ0.93(t,3H), δ0.85(t,3H)

[0312] Example 17

[0313] Synthesis of (Z)-non-3-en-1-yl octanoate

[0314] (Z)-Non-3-en-1-yl octanoate was prepared from octanoic acid and (Z)-non-3-en-1-ol according to General Procedure C. The product was a light yellow oil: 2.17 g, 8.07 mmol, 88% yield.

[0315] 1H NMR (500MHz, benzene-d6) δ5.44-5.35(m,2H), δ5.27-5.18(m,2H), δ3.95(t,2H), δ2.31-2.13( m,4H),δ1.98-1.87(m,2H),δ1.58-1.44(m,2H)δ1.32-1.08(m,12H),δ0.82-0.73(m,6H)

[0316] Example 18

[0317] Synthesis of Heptadecan-9-yl 8-bromooctanoate

[0318] Heptadecan-9-yl 8-bromooctanoate was prepared from 8-bromooctanoic acid and heptadecan-9-ol according to General Procedure C. The product was obtained as a light yellow oil: 3.20 g, 6.93 mmol, 13% yield.

[0319] 1H NMR (500MHz, CDCl3) δ4.92-4.84(m,1H), δ3.41(t,2H), δ2.30(t,2H), δ1.90-1.84(m,2H), δ1.70-1.20(br.m,36H), δ0.89(m,6H)

[0320] Example 19

[0321] Synthesis of 6-ethoxy-6-oxohexyl-2-hexyldecanoate

[0322] Step a) is equipped with a 500ml 2-necked flask of stirring rod and reflux exchanger, under inert condition (nitrogen), 2-hexyldecanoic acid (44.6g, 51.0mL, 1 equivalent 174mmol) is dissolved in anhydrous toluene (150mL).Then, under agitation, add 5 drops of DMF and sulfuryl chloride (51.7g, 31.7mL, 2.5 equivalents 435mmol).The reaction mixture is at room temperature stirred, until gas evolution slows down (approximately 2 hours).Then the mixture is heated to 80-90 ℃, stirred for 2 hours, until gas evolution stops.By TLC, reaction is monitored.

[0323] Step b) next, removes solvent and residual sulfuryl chloride in vacuum, and the crude product obtained is used for next reaction step, and does not need to be further purified.Be equipped with 2 neck 500ml flasks of stirring rod, condenser and addition funnel, under inert condition (nitrogen), 6-hydroxyethyl hexanoate (26.4g, 26.8ml, 1 equivalent 165mmol) is dissolved in 100ml anhydrous toluene.Next, add triethylamine (25.0g, 34.5mL, 1.5 equivalents 248mmol), dropwise add the 2-hexyl decanoyl chloride (47.8g, 1.05 equivalents 174mmol) that is dissolved in 60ml anhydrous toluene subsequently.Immediately, start to form TEA-HCl and start precipitation.Monitor the reaction by TLC, and at room temperature (16h) continue to stir and spend the night.Next, reaction mixture is filtered through diatomite, and with extra toluene washing. The clear solution obtained is washed with 1M aqueous hydrochloric acid solution, and then washed with saturated NaHCO (aq) and saturated NaCl (aq). The organic phase of extraction is at MgSO Last drying, filter, and vacuum concentrate to obtain the crude product of 73.2g. Use silica gel column chromatography ester purification, with hexane and ethyl acetate as eluent, obtain 6-ethoxy-6-oxohexyl 2-hexyl decanoate (58.50g, 147mmol, the cumulative yield of two reaction steps is 89%).

[0324] 1H NMR(500MHz, CDCl3)δ4.16-4.12(q,2H),δ4.08(t,2H),δ2.33-2.30(m,2H),δ 1.71-1.54(m,6H),δ1.48-1.37(m,4H),δ1.34-1.20(br.m,24H),δ0.89(t,6H)

[0325] Example 20

[0326] Synthesis of 6-methoxy-6-oxohexyl 2-(decylthio)hexanoate

[0327]

[0328] Step a) purge a flame-dried 500ml three-necked round-bottom flask with an argon stream. The flask is equipped with a titration funnel, a thermometer, and an argon balloon and is equipped with 2-bromohexanoic acid (10.00g 51.27mmol) and 300ml anhydrous tetrahydrofuran. The reaction mixture is cooled to 0°C. KOtBu (16.51g, 69.21mmol) is added portionwise to maintain the internal temperature at 0°C. After stirring at 0°C for one hour, 1-decyl mercaptan (12.06g, 69.21mmol) is added dropwise to maintain the internal temperature at 0°C. The reaction mixture is stirred at room temperature overnight. The reaction is monitored by TLC (hexane / ethyl acetate 4:1, PMA visualization), and almost complete conversion is detected after stirring overnight. 250ml1N-HCl solution is added to the reaction mixture and extracted with 3×250ml hexane. The combined organic phase is washed with 3×100ml brine and dried on MgSO4, and filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography with gradient elution (0-20% EtOAc in n-hexane) to afford 2-(decylthio)hexanoic acid (12.46 g, 43.19 mmol, 84% yield) as a pale yellow oil.

[0329] 1H NMR (500MHz, DMSO-d6) δ3.15(t,1H), δ2.56(m,2H), δ1.78-1.67(m,1H), δ1.58-1.45(m,3H), δ1.39-1.17(m,18H), δ0.86(t,6H)

[0330] Step b) 6-Methoxy-6-oxohexyl 2-(decylthio)hexanoate was prepared from 2-(decylthio)hexanoic acid and methyl 6-hydroxyhexanoate according to General Procedure C and purified using a 250 g silica gel column, eluent: 0-10% ethyl acetate in hexane. The product was obtained as a brown oil: 10.77 g, 25.85 mmol, 79% yield.

[0331] 1H NMR (500MHz, benzene-d6) δ4.00(m,2H), δ3.33(s,3H), δ3.27(t,1H), δ2.74-2.65(m,1H), δ2.64-2.55( m,1H),δ2.02(t,3H),δ1.75(m,1H),δ1.58(m,2H),δ1.5-1.1(m,24H),δ0.90(t,3H),δ0.80(t,3H)

[0332] Example 21

[0333] Synthesis of 6-methoxy-6-oxohexyl 2-(pentylthio)decanoate

[0334]

[0335] Step a) purge the 250ml three-necked round-bottom flask of flame drying with argon stream.Flask is equipped with titration funnel, thermometer and argon balloon, and is equipped with 2-bromodecanoic acid (6.80g, 27.07mmol), 1-pentanethiol (3.81g, 36.55mmol) and 60ml anhydrous tetrahydrofuran (THF).Reaction mixture is cooled to 0 ℃.The KOtBu (8.72g, 77.7mmol) of 80ml anhydrous THF is added dropwise, while keeping internal temperature to 0 ℃.Reaction mixture is further stirred at room temperature and spends the night.By TLC (hexane / ethyl acetate 4: 1, PMA visualization) monitoring reaction, and detect almost complete conversion after spending the night.150ml 1N-HCl solution is added to reaction mixture, and with 3 × 150ml hexane extraction.The organic phase merging is washed with 2 × 150ml salt water, and MgSO4 upper drying, and filter and concentrating under reduced pressure. The crude product was purified by flash column chromatography with gradient elution (0-20% EtOAc in n-hexane) to afford 2-(pentylthio)decanoic acid (6.20 g, 22.59 mmol, 83% yield) as a pale yellow oil.

[0336] 1H NMR (500MHz, DMSO-d6) δ3.16(t,1H), δ2.56(m,2H), δ1.77-1.66(m,1H), δ1.58-1.44(m,3H), δ1.41-1.14(m,16H), δ0.85(t,6H)

[0337] Step b) 6-Methoxy-6-oxohexyl 2-(pentylthio)decanoate was prepared from 2-(pentylthio)decanoic acid and methyl 6-hydroxyhexanoate according to General Procedure C and purified using a 250 g silica gel column, eluent: 0-10% ethyl acetate in hexanes. The product was obtained as a brown oil: 9.37 g, 23.27 mmol, 75% yield.

[0338] 1H NMR (500MHz, benzene-d6) δ4.00(m,2H), δ3.33(s,3H), δ3.30(t,1H), δ2.71-2.64(m,1H), δ2.61-2.53(m,1H), δ2.0 2(t,3H),δ1.78(m,1H),δ1.55(m,2H),δ1.48-1.32(m,6H),δ1.32-1.07(m,16H),δ0.88(t,3H),δ0.81(t,3H)

[0339] Example 22

[0340] Synthesis of Methyl (4R)-4-((3R,10S,13R)-3-Methoxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoate

[0341] Under argon stream with lithocholic acid (5.00g, 13.30mmol), 240ml of anhydrous acetonitrile, cesium carbonate (9.53g, 29.26mmol) and methyl iodide (8.30g, 58.52mmol) are packed in the pressure bottle of 1000ml.The flask is sealed, and the reaction mixture is heated to 110 ℃ 24 hours.Then cool the reaction mixture, and add 20ml sodium sulfite (10w / w%) solution and 200ml water.The mixture is extracted with 3 × 200ml ethyl acetate.The organic phase merging is used 1 × 100ml salt water washing, and MgSO4 upper drying, filtration, and under reduced pressure concentrated. The residue was purified by flash column chromatography with gradient elution (5-20% ethyl acetate in hexanes) to afford methyl (4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanoate (1.30 g, 3.21 mmol, 24% yield) as a white solid.

[0342] 1H NMR (500MHz, benzene-d6) δ3.40(s,3H), δ3.38(t,3H), δ2.32-2.23(m,1H), δ2.20-2.10(m,1H), δ1.95-1.83(m,2 H), δ1.83-1.70(m,3H), δ1.67-1.54(m,3H), δ1.53-086(m,19H), δ0.84(d,3H), δ0.74(s,3H), δ0.52(s,3H)

[0343] Example 23

[0344] Synthesis of 6-bromohexanoic acid undecyl ester

[0345] Undecyl 6-bromohexanoate was prepared from 6-bromooctanoic acid and 1-undecanol according to General Procedure C. The product was obtained as a light yellow oil: 27.95 g, 80 mmol, 78% yield.

[0346] 1H NMR (500MHz, DMSO-d6) δ4.01(t,2H), δ3.52(t,2H), δ3.52(t,2H), δ2.30(t,2H), δ1.85-1. 78(m,2H),δ1.58-1.52(m,4H),δ1.42-1.38(m,2H),δ1.33-1.20(br.m,14H),δ0.87(t,3H)

[0347] Example 24

[0348] Synthesis of 4-chlorobutyl (9Z,12Z)-octadeca-9,12-dienoate

[0349] 4-Chlorobutyl (9Z,12Z)-octadeca-9,12-dienoate was prepared from (9Z,12Z)-octadeca-9,12-dienoic acid and 4-chlorobutan-1-ol according to General Procedure D. The product was obtained as a light yellow oil: 1.20 g, 3.23 mmol, 45% yield.

[0350] 1H NMR (500MHz, benzene-d6) δ5.41-5.27(m,4H), δ4.1(t,2H), δ3.58(t,2H), δ2.27(t,2H), δ2.29(t,2H), δ2.08-2.00(m,4H), δ1.86-1.78(m,4H), δ1.64-1.59(m,2H), δ1.37-1.25(m,14H), δ0.88(t,3H)

[0351] Example 25

[0352] Synthesis of 4-chlorobutyl (4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl) valerate

[0353] 4-Chlorobutyl (4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanoate was prepared from (4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanoic acid and 4-chlorobutan-1-ol according to General Procedure D. The product was obtained as a colorless oil: 2.75 g, 5.72 mmol, 81% yield.

[0354] 1H NMR(500MHz, CDCl3)δ4.12-4.07(m,2H),δ3.56(t,2H),δ3.34(s,3H)δ3.21-3.11(m,1H),δ2.40-2.29(m,1H ), δ2.26-2.14(m,1H), δ1.92-1.51(br.m,14H), δ1.49-0.99(br.m,16H), δ0.91-0.89(m,6H), δ0.63(s,3H)

[0355] Example of Silane Synthesis

[0356] Example 26

[0357] Synthesis of Dimethyl(Octyl)Silane

[0358]

[0359] The 250ml three-necked round-bottom flask of flame drying is purged with argon stream.Flask is equipped with septum, thermometer and argon balloon, and chloro(dimethyl)octylsilane (20.00g, 96.70mmol) and 100ml anhydrous diethyl ether are housed.Reaction mixture is cooled to 0 ℃, and lithium aluminum hydride (3.38g, 88.96mmol) is added in batches and exceeds 6 hours, and internal temperature maintains between 0-5 ℃.Reaction is stirred at room temperature and spends the night.Then reaction mixture is cooled to 0 ℃ again, and with the mixture cancellation of 30ml water and 50ml5w / w%NaOH solution, internal temperature is remained on and is lower than 5 ℃, adds another part water (30ml) subsequently, and is warming up to room temperature.Separate each phase, and with 25ml water washing organic phase, and use MgSO4 drying. After filtration of MgSO4, the volatiles were evaporated under reduced pressure to obtain the product as a colorless oil, dimethyl(octyl)silane (14.40 g, 83.53 mmol, 86% yield).

[0360] 1H NMR (500MHz, CDCl3) δ3.85 (m, 1H), δ1.25 (m, 12H), δ0.90 (t, 3H), δ0.59 (m, 2H), δ0.08 (d, 6H)

[0361] Example 27

[0362] Synthesis of Dimethyl(Hexyl)Silane

[0363]

[0364] The 250ml three-necked round-bottom flask of flame drying is purged with argon stream.Flask is equipped with thermometer, condenser, argon balloon, and chlorodimethylsilane (10.00g, 105.69mmol), 1-hexene (8.09g, 96.17mmol), Kasite (Karstedt) catalyst (0.111ml 2%Pt in the dimethylbenzene solution) and 100ml anhydrous tetrahydrofuran (THF) are housed.Reaction mixture refluxed 5 hours.By GC monitoring reaction, detect complete conversion after 5 hours reaction time.Reaction mixture is cooled to room temperature, concentrating under reduced pressure, obtains colorless oily chloro (hexyl) dimethylsilane (15.60g, 87.26mmol, productive rate 83%).

[0365] The 250ml three-necked round-bottom flask of flame drying is purged with argon stream.The flask is equipped with septum, thermometer and argon balloon, and is equipped with chloro(dimethyl)hexylsilane (15.60g, 87.26mmol) and 90ml anhydrous diethyl ether.The reaction mixture is cooled to 0 ℃, lithium aluminum hydride (3.05g, 80.28mmol) is added in batches over 5 hours, and keeps internal temperature between 0-5 ℃.The reaction is stirred at room temperature for an additional 1 hour.Then the reaction mixture is cooled to 0 ℃ again, and quenched with a mixture of 30ml water and 50ml 5w / w% NaOH solution, keeps internal temperature below 5 ℃, adds another part of water (30ml) subsequently, and is warming to room temperature.Separate each phase, and wash organic phase with 25ml water, and use MgSO4 drying.Through MgSO4 after filtration, volatile matter is evaporated under reduced pressure. The residue was purified by atmospheric distillation to give dimethyl(hexyl)silane (10.30 g, 71.36 mmol, 82% yield) as a colorless oil.

[0366] 1H NMR (500MHz, benzene-d6) δ4.12(m,1H), δ1.31(m,8H), δ0.89(t,3H), δ0.53(m,2H), δ0.04(d,6H)

[0367] Example 28

[0368] Synthesis of 1,1,3,3-Tetramethyl-1-octyldisiloxane

[0369]

[0370] A flame-dried 500 ml three-necked round-bottom flask was purged with an argon stream. The flask was equipped with a titration funnel, a thermometer, a condenser, an argon balloon, and charged with 1,1,3,3-tetramethyldisiloxane (119.70 g, 891 mmol), Wilkinson's catalyst (5 mg, 0.0054 mmol) and 48.50 ml of anhydrous toluene. The reaction mixture was heated to 40 ° C, and 1-octene (20.00 g, 178.22 mmol) was added dropwise to the reaction mixture. After the addition of 1-octene, the resulting mixture was stirred at 50 ° C for an additional 5 hours. After the reaction time, the mixture was stirred for 1 hour at 50 ° C. and the mixture was stirred for 1 hour at 50 ° C. After the reaction time, the mixture was stirred for 1 hour at 50 ° C. and the mixture was stirred for 1 hour at 50 ° C. After the reaction time, the mixture was stirred for 1 hour at 50 ° C. and the mixture was stirred for 1 hour at 50 ° C. 1 H NMR confirmed complete conversion. The reaction mixture was concentrated under reduced pressure to obtain 1,1,3,3-tetramethyl-1-octyldisiloxane (46.00 g, 186.58 mmol, 98% yield) as a colorless oil.

[0371] 1H NMR (500MHz, CDCl3) δ4.69 (m, 1H), δ1.28 (m, 12H), δ0.90 (t, 3H), δ0.55 (m, 2H), δ0.18 (d, 6H), δ0.07 (s, 6H)

[0372] Example 29

[0373] Synthesis of Dimethyl(Octyloxy)Silane

[0374]

[0375] A 250ml three-necked round-bottom flask was purged with a helium stream. The flask was equipped with a titration funnel, a thermometer, an argon balloon, and 1-octanol (5.20g, 40.00mmol), triethylamine (6.07g, 60.00mmol) and 40.0ml anhydrous toluene were housed. The reaction mixture was cooled to 0°C, and chlorodimethylsilane (4.54g, 48.00mmol) was added dropwise, with the internal temperature maintained between 0°C and 5°C. After adding the silane, the reaction was stirred at room temperature overnight. The reaction mixture was then filtered through a diatomaceous earth pad, and washed with 2 x 15ml pentane, and the precipitated triethylamine hydrochloride was filtered off. The filtrate was concentrated under reduced pressure. The crude product was purified by vacuum distillation at 0.02-0.05 mbar (46°C-51°C), and the resulting product was a colorless oil, dimethyl (octyloxy) silane (4.86g, 25.80mmol, 64% yield).

[0376] 1H NMR (500MHz, benzene-d6) δ4.88(m,1H), δ3.57(t,2H), δ1.54(p,2H), δ1.32(m,2H), δ1.23(m,8H), δ0.88(t,3H), δ0.15(d,6H)

[0377] Example 30

[0378] Synthesis of ((2-hexyldecyl)oxy)dimethylsilane

[0379]

[0380] A 250ml three-necked round-bottom flask was purged with a helium stream. The flask was equipped with a titration funnel, a thermometer, an argon balloon, and 2-hexyldecane-1-ol (6.23g, 22.87mmol), triethylamine (3.47g, 34.31mmol) and 44.2ml of anhydrous toluene were housed. The reaction mixture was cooled to 0°C, and chlorodimethylsilane (2.60g, 27.45mmol) was added dropwise, with the internal temperature maintained between 0°C and 5°C. After adding the silane, the reaction was stirred at room temperature overnight. The reaction mixture was then filtered through a diatomaceous earth pad, and washed with 2 × 15ml pentane, and the precipitated triethylamine hydrochloride was filtered off. The filtrate was concentrated under reduced pressure. The crude product was purified by vacuum distillation, and products obtained therefrom was a colorless oil ((2-hexyldecyl) oxygen base) dimethylsilane (2.61g, 8.68mmol, 34% yield).

[0381] 1H NMR (500MHz, benzene-d6) δ4.90(p,1H), δ3.57(d,2H), δ1.56(m,1H), δ1.47(m,2H), δ1.28(m,22H), δ0.90(m,6H), δ0.17(d,6H)

[0382] Example 31

[0383] Synthesis of 1,1,3,3-tetramethyl-1-(octyloxy)disiloxane

[0384]

[0385] The 500ml three-neck round-bottom flask of flame drying was purged with an argon stream. The flask was equipped with a titration funnel, a thermometer, an argon balloon, and was equipped with 1.41ml BrF (F 3s) 2-borane catalyst solution (202mg was dissolved in 4.00ml anhydrous toluene) [borane catalyst is disclosed in WO2022 / 129966] and 1,1,3,3-tetramethyldisiloxane (128.42g, 965mmol). The toluene solution of 1-octanol (4.15g, 31.87mmol, 16ml anhydrous toluene) was added dropwise to the reaction mixture, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then concentrated under reduced pressure. The crude product was purified by vacuum distillation using a Vigreux column at 0.02-0.05 mbar (52° C.-60° C.) to give 1,1,3,3-tetramethyl-1-(octyloxy)disiloxane (8.36 g, 21.86 mmol, 69% yield) as a colorless oil.

[0386] 1H NMR (500MHz, benzene-d6) δ5.04(m,1H), δ3.70(t,2H), δ1.60(p,2H), δ1.38(m,2H), δ1.27(m,8H), δ0.89(t,3H), δ0.21(d,6H), δ0.17(s,6H)

[0387] Example 32

[0388] Synthesis of (6-bromohexyl)dimethylsilane

[0389]

[0390] With argon gas stream purge flame-dried 250ml three-necked round-bottom flask.Be equipped with thermometer, condenser, argon balloon in the flask, and chlorodimethylsilane (6.38g, 67.40mmol), 6-bromo-1-hexene (10.00g, 61.33mmol), Karstedt catalyst (69.6 μ l 2% Pt in the dimethylbenzene solution) and 60ml anhydrous tetrahydrofuran (THF) are housed.Through GC, reaction is monitored, and detects and converts fully after spending the night.Reaction mixture is cooled to room temperature, and under reduced pressure concentrated to obtain yellow oil (6-bromohexyl) chlorodimethylsilane (16.65g, 64.61mmol, productive rate 96%).

[0391] A flame-dried 250ml three-necked round-bottom flask was purged with an argon stream. The flask was equipped with a titration funnel, a thermometer, an argon balloon, and was equipped with a grinding NaBH4 suspension (4.89g, 129.23mmol) and 11ml of anhydrous tetrahydrofuran. A mixture of (6-bromohexyl)chlorodimethylsilane (16.65g, 64.61mmol) and 50ml of anhydrous tetrahydrofuran was added dropwise to the suspension, and stirred at room temperature overnight. Volatiles were removed under reduced pressure, and 50ml of hexane was added to the residue. The suspension was passed through a small silica gel pad. The filtrate was concentrated under reduced pressure. The residue was further purified by vacuum distillation at 0.02-0.05 mbar (38-39°C) to obtain a colorless oil, (6-bromohexyl)dimethylsilane (9.70g, 43.45mmol, 67% yield).

[0392] 1H NMR (500MHz, benzene-d6)δ4.09(m,1H),δ2.95(t,2H),δ1.48(p,2H),δ1.20-1.04(m,6H),δ0.48-0.4(m,2H)δ0.02(d,6H)

[0393] Example 33

[0394] Synthesis of ((6-bromohexyl)oxy)dimethylsilane

[0395]

[0396] 250ml three-necked round-bottom flask is purged with helium stream.Flask is equipped with dropping funnel, thermometer, argon balloon, and 6-bromo-1-hexanol (8.00g, 44.20mmol), triethylamine (6.70g, 66.30mmol) and 44.2ml anhydrous toluene are housed.Reaction mixture is cooled to 0 ℃, and dropwise add chlorodimethylsilane (5.02g, 53.04mmol), temperature of reaction is remained between 0 ℃-5 ℃.After adding silane, reaction is at room temperature stirred and spent the night.Reaction mixture is filtered by diatomite pad, and with 2 × 15ml pentane washing, and filter out the triethylammonium hydrochloride of precipitation.Filtrate is under reduced pressure concentrated. The crude product was purified by vacuum distillation at 0.02-0.05 mbar (63-64° C.) to give ((6-bromohexyl)oxy)dimethylsilane (7.27 g, 30.39 mmol, 63% yield) as a colorless oil.

[0397] 1H NMR (500MHz, benzene-d6)δ4.85(m,1H),δ3.47(t,2H),δ2.90(t,2H),δ1.45(m,2H),δ1.37(m,2H),δ1.11(m,4H)δ0.14(d,6H)

[0398] Example 34

[0399] Synthesis of ((5-bromopentyl)oxy)dimethylsilane

[0400]

[0401] Under an Ar atmosphere, triethylamine (8.39 g, 82.94 mmol, 1.50 equivalents) was added to a stirred mixture of 5-bromopentane-1-ol (9.24 g, 55.29 mmol, 1.00 equivalents) and 50 ml of dry toluene. Chlorodimethylsilane (6.28 g, 66.35 mmol, 1.20 equivalents) was added, and the mixture became a white slurry. The mixture was shaken several times before stirring overnight. After 16 h, the mixture was filtered (glass frit) and the precipitate was rinsed with toluene. The filtrate was evaporated. The residue was diluted with petroleum ether (~20 ml) to obtain a white precipitate, which was separated by centrifugation. The clear solution was concentrated. The remaining oil was purified by vacuum distillation at 1 mbar to give a colorless oil ((5-bromopentyl)oxy)dimethylsilane (9.23 g, 40.99 mmol, 74% yield).

[0402] 1H NMR (500MHz, benzene-d6) δ4.84(m,1H), δ3.42(t,2H), δ2.92(t,2H), δ1.50-1.43(m,2H), δ1.35-1.18(m,4H), δ0.13(d,6H)

[0403] Example 35

[0404] Synthesis of ((4-bromobutyl)oxy)dimethylsilane

[0405]

[0406] Under an Ar atmosphere, triethylamine (7.93 g, 78.42 mmol, 1.50 equiv) was added to a stirred mixture of 4-bromobutane-1-ol (8.00 g, 52.28 mmol, 1.00 equiv) and 50 ml of dry toluene. Chlorodimethylsilane (5.93 g, 62.74 mmol, 1.20 equiv) was added, and the mixture became a white slurry. The mixture was shaken several times before stirring overnight. After 16 h, the mixture was filtered (glass frit) and the precipitate was rinsed with toluene. The filtrate was evaporated. The residue was diluted with petroleum ether (~20 ml) to give a white precipitate, which was separated by centrifugation. The clear solution was concentrated. The remaining oil was purified by vacuum distillation at 10 mbar (65-70° C.) to give a colorless oil ((4-bromobutyl)oxy)dimethylsilane (7.65 g, 36.22 mmol, 69% yield).

[0407] 1H NMR (500MHz, benzene-d6) δ4.78(m,1H), δ3.36(t,2H), δ2.96(t,2H), δ1.68-1.56(m,2H), δ1.46-1.34(m,2H), δ0.10(d,6H)

[0408] Example 36

[0409] Synthesis of 1-(4-bromobutoxy)-1,1,3,3-tetramethyldisiloxane

[0410]

[0411] A flame-dried 250ml three-necked round-bottom flask was purged with an argon stream. The flask was equipped with a titration funnel, a thermometer, an argon balloon and 100 μL of BrF (F 3 s) 2 borane catalyst [borane catalyst is disclosed in WO 2022 / 129966] solution (58.42 mg, dissolved in 100 μL) and 1,1,3,3-tetramethyldisiloxane (105.34 g, 784.22 mmol, 30 equivalents). A toluene solution of 4- bromo-1-butanol (4.00 g, 26.14 mmol, 16 ml of anhydrous toluene) was added dropwise to the reaction mixture, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then concentrated under reduced pressure. The crude product was purified by vacuum distillation using a Vigreux column at 5 mbar (65° C.-75° C.) to give 1-(4-bromobutoxy)-1,1,3,3-tetramethyldisiloxane (4.56 g, 15.98 mmol, 61% yield) as a colorless oil.

[0412] 1H NMR (500MHz, benzene-d6) δ4.99(m,1H), δ3.49(t,2H), δ3.00(t,2H), δ1.74.1.61(m,2H), δ1.54-1.40(m,2H), δ0.18(d,6H), δ0.10(s,6H)

[0413] Synthesis of Mixed Silane Acetals (General Procedure EF)

[0414] The BrF(F3s)2 and BrF(F4)2 borane catalysts disclosed in WO2022 / 129966 were used in the synthesis and are defined under the respective examples.

[0415] General Procedure E

[0416] The three-necked round-bottom flask of flame drying is purged with an argon stream. The flask is equipped with a diaphragm, a thermometer and an argon balloon, and is equipped with a mixture of anhydrous toluene (1.0ml toluene / 1.0mmol ester) and an ester. In the reaction mixture, a portion of catalyst solution is added, followed by dropwise addition of silane, with internal temperature maintained between 20-30°C. The reaction mixture is stirred at room temperature for several hours (described in detail in the examples). The reaction is monitored by TLC (hexane / ethyl acetate 9 / 1, PMA visualization, and if different, described in detail in the examples). After the reaction is complete, 1ml EtOAc, 0.6mlMeCN and silica gel are added to the reaction mixture, stirred for 10min, and silica gel is filtered off, and washed with 2 × 25ml n-pentanes. Volatiles are removed under reduced pressure to obtain crude product, by rapid column chromatography or by simple filtration via a short pad of silica gel to obtain product.

[0417] General Procedure F

[0418] A flame-dried three-necked round-bottom flask was purged with an argon stream. The flask was equipped with a septum, a thermometer, and an argon balloon and charged with the catalyst and anhydrous toluene (4.00 ml). The mixture of ester and silane was added dropwise to the catalyst solution, maintaining the internal temperature between 20-30°C. The reaction mixture was stirred for 12 hours. 1 The reaction was monitored by H NMR or TLC (described in detail in the examples). After the reaction was complete, 1 ml of EtOAc, 0.6 ml of MeCN, and silica gel were added to the reaction mixture, stirred for 10 min, and the silica gel was filtered off and washed with 2 x 15 ml of n-pentane. Volatiles were removed under reduced pressure to obtain a crude product, which was then filtered by flash column chromatography or by a short pad of silica gel to obtain the product.

[0419] Example of Synthesis of Mixed Silane Acetal

[0420] Example 37

[0421] Synthesis of ((6-bromo-1-(octyloxy)hexyl)oxy)dimethyl(octyl)silane

[0422]

[0423] ((6-Bromo-1-(octyloxy)hexyl)oxy)dimethyl(octyl)silane was prepared according to General Procedure E from 6-bromohexyl octanoate (4.00 g, 13.02 mmol) and dimethyl(octyl)silane (1.1 equiv., 2.47 g, 14.32 mmol) using 616 μl of BrF(F3s)2 borane as a catalyst (189 mg of catalyst dissolved in 4.00 ml of anhydrous toluene). The reaction was complete after 2 hours. The crude product was purified by flash column chromatography with a gradient elution (0-20% EtOAc in n-hexane) to give ((6-bromo-1-(octyloxy)hexyl)oxy)dimethyl(octyl)silane (4.72 g, 9.84 mmol, 76% yield) as a clear oil.

[0424] 1H NMR (500MHz, benzene-d6) δ4.79(dt,1H), δ3.73-3.69(dq,1H), δ3.35-3.31(dq,1H), δ2.95(t,2H) ,δ1.71-1.57(m,4H),δ1.47-1.19(m,28H),δ0.92-0.87(t,6H),δ0.71(dd,2H),δ0.2(d,6H)

[0425] Example 38

[0426] Synthesis of ((1-((6-bromohexyl)oxy)octyl)oxy)dimethyl(octyl)silane

[0427]

[0428] ((1-((6-bromohexyl)oxy)octyl)oxy)dimethyl(octyl)silane was prepared according to General Procedure E from octyl 6-bromohexanoate (5.00 g, 16.27 mmol) and dimethyl(octyl)silane (1.1 equiv., 3.09 g, 17.90 mmol) using 770 μl of BrF(Fs)2 borane catalyst solution (189 mg dissolved in 4.00 ml of anhydrous toluene). The reaction was complete after 2 hours. The crude product was purified by flash column chromatography (0-20% EtOAc in n-hexane) with a gradient elution to give ((1-((6-bromohexyl)oxy)octyl)oxy)dimethyl(octyl)silane (4.26 g, 8.88 mmol, 55% yield) as a clear oil.

[0429] 1H NMR (500MHz, benzene-d6) δ4.84(t,1H), δ3.68-3.64(dq,1H), δ3.30-3.27(dq,1H), δ2.94(t,2H), δ1.84-1.77(m,1H), δ1.75- 1.68(m,1H),δ1.54-1.44(m,8H),δ1.39(m,2H),δ1.36-1.17(m,20H),δ0.92-0.87(t,6H),δ0.71(dd,2H),δ0.22(d,6H)

[0430] Example 39

[0431] Synthesis of ((6-bromo-1-(decyloxy)hexyl)oxy)(hexyl)dimethylsilane

[0432]

[0433] ((6-Bromo-1-(decyloxy)hexyl)oxy)(hexyl)dimethylsilane was prepared according to General Procedure E from decyl 6-bromohexanoate (4.00 g, 11.93 mmol) and dimethyl(hexyl)silane (1.1 equiv., 1.89 g, 13.12 mmol) using 573 μl of BrF(Fs)2 borane catalyst solution (186 mg of catalyst dissolved in 4.00 ml of anhydrous toluene). The reaction was complete after 2 hours. The crude product was purified by flash column chromatography with a gradient elution (0-10% EtOAc in n-hexane) to give ((6-bromo-1-(decyloxy)hexyl)oxy)(hexyl)dimethylsilane (4.52 g, 9.42 mmol, 79% yield) as a clear oil.

[0434] 1H NMR (500MHz, benzene-d6) δ4.78(t,1H), δ3.73-3.69(dq,1H), δ3.36-3.31(dq,1H), δ2.94(t,2H), δ1.71-1.56(m,4H), δ1.54-1.47(m,2H), δ1.46-1.38(m,4H), δ1.37-1.17(m,22H), δ0.93-0.88(t,6H), δ0.69(dd,2H), δ0.21(d,6H)

[0435] Example 40

[0436] Synthesis of ((10-bromo-1-(octyloxy)decyl)oxy)(hexyl)dimethylsilane

[0437]

[0438] ((10-bromo-1-(octyloxy) decyl) oxygen base) (hexyl) dimethylsilane) was prepared according to General Procedure E from octyl 10-bromodecanoate (5.00 g, 11.69 mmol) and dimethyl(hexyl)silane (1.1 equivalents, 1.86 g, 12.86 mmol) using 517 μl BrF(Fs) borane catalyst (202 mg dissolved in 4.00 ml anhydrous toluene). The reaction was completed after spending the night. The crude product was purified by flash column chromatography (0-10% EtOAc in n-hexane) with a gradient elution to give ((10-bromo-1-(octyloxy) decyl) oxygen base) (hexyl) dimethylsilane) (3.60 g, 7.10 mmol, 61% yield) as a clear oil.

[0439] 1H NMR (500MHz, benzene-d6) δ4.87(t,1H), δ3.77-3.72(dq,1H), δ3.39-3.35(dq,1H), δ2.95(t,2H), δ1.86-1.78(m,1H), δ1.77-1.70(m,1H), δ1.67-1.61(p,2H), δ1.56-1.20(m,26H), δ1.17-1.11(p,4H), δ1.10-1.01(m,2H), δ0.94-0.86(m,6H), δ0.71(dd,2H), δ0.23(d,6H)

[0440] Example 41

[0441] Synthesis of ((1-((6-bromohexyl)oxy)decyl)oxy)(hexyl)dimethylsilane

[0442]

[0443] ((1-((6-bromohexyl)oxy)decyl)oxy)(hexyl)dimethylsilane was prepared from 6-bromohexyldecanoate (5.00 g, 14.91 mmol) and dimethyl(hexyl)silane (1.1 equiv., 2.37 g, 16.40 mmol) according to General Procedure E using 717 μl of BrF(Fs)2 borane catalyst solution (186 mg dissolved in 4.00 ml of anhydrous toluene). The reaction was complete after 3 hours. The crude product was purified by flash column chromatography with a gradient elution (0-10% EtOAc in n-hexane) to give ((1-((6-bromohexyl)oxy)decyl)oxy)(hexyl)dimethylsilane (5.04 g, 10.51 mmol, 71% yield) as a clear oil.

[0444] 1H NMR (500MHz, benzene-d6) δ4.84(t,1H), δ3.68-3.64(dq,1H), δ3.30-3.26(dq,1H), δ2.94(t,2H), δ1.85-1.77(m,1H), δ1.76-1.68(m,1H), δ1.61-1.41(m,8H), δ1.40-1.15(m,22H), δ0.92-0.88(m,6H), δ0.70(dd,2H), δ0.23(d,6H).

[0445] Example 42

[0446] Synthesis of ((1-((9-bromononyl)oxy)octyl)oxy)(hexyl)dimethylsilane

[0447]

[0448] ((1-((9-bromononyl)oxy)octyl)oxy)(hexyl)dimethylsilane was prepared from 9-bromononyl octanoate (5.00 g, 14.31 mmol) and dimethyl(hexyl)silane (1.1 equiv., 2.27 g, 15.74 mmol) according to General Procedure E using 633 μl of BrF(Fs)2 borane catalyst solution (202 mg dissolved in 4.00 ml of anhydrous toluene). The reaction was complete after stirring overnight. The crude product was purified by flash column chromatography with a gradient elution (0-10% EtOAc in n-hexane) to give ((1-((9-bromononyl)oxy)octyl)oxy)(hexyl)dimethylsilane (6.00 g, 12.15 mmol, 85% yield) as a clear oil.

[0449] 1H NMR (500MHz, benzene-d6) δ4.87(t,1H), δ3.77-3.72(dq,1H), δ3.39-3.35(dq,1H), δ2.95(t,2H), δ1.86-1.78(m,1H), δ1.77-1.68(m,1H) ,δ1.66-1.58(m,2H),δ1.57-1.18(m,24H),δ1.17-1.10(m,4H)δ1.09-1.01(m,2H),δ0.92-0.86(m,6H),δ0.71(dd,2H),δ0.23(d,6H)

[0450] Example 43

[0451] Synthesis of 12-(5-bromopentyl)-10,10-dimethyl-9,11,13-trioxa-10-silanheneicosane

[0452]

[0453] 12-(5-bromopentyl)-10,10-dimethyl-9,11,13-trioxa-10-silaheneicosane was prepared according to General Procedure E from octyl 6-bromohexanoate (5.00 g, 16.27 mmol) and dimethyl(octyloxy)silane (1.1 equivalents, 3.37 g, 17.90 mmol) using 503 μl of BrF(F3s)2 borane catalyst solution (253 mg dissolved in 3.50 ml of anhydrous toluene). The reaction was complete after stirring overnight. The crude product was purified by flash column chromatography with a gradient elution (0-10% EtOAc in n-hexane) to give 12-(5-bromopentyl)-10,10-dimethyl-9,11,13-trioxa-10-silaheneicosane (3.78 g, 7.63 mmol, 47% yield) as a clear oil.

[0454] 1H NMR(500MHz, benzene-d6)δ4.93(t,1H),δ3.85-3.83(dq,1H),δ3.76-3.73(t,2H),δ3.40-3.39(dq,1H),2.97(t,2H),δ1 .80-1.60(m,6H),δ1.60-1.50(m,2H),δ1.50-1.30(m,6H),δ1.57-1.18(m,18H),δ0.92-0.89(m,6H),δ0.23(d,6H)

[0455] Example 44

[0456] Synthesis of 1-bromo-8-heptyl-10,10-dimethyl-7,9,11-trioxa-10-silanonadecane

[0457]

[0458] According to General Procedure E, 1-bromo-8-heptyl-10,10-dimethyl-7,9,11-trioxa-10-silanonadecane was prepared from 6-bromohexyl octanoate (5.00 g, 16.27 mmol) and dimethyl(octyloxy)silane (1.1 equivalents, 3.37 g, 17.90 mmol) using 706 μl BrF(F3s)2 borane catalyst solution (206 mg dissolved in 4.00 ml anhydrous toluene). The reaction was complete after stirring overnight. The crude product was purified by flash column chromatography with a gradient elution (0-10% EtOAc in n-hexane) to give 1-bromo-8-heptyl-10,10-dimethyl-7,9,11-trioxa-10-silanonadecane (5.00 g, 10.08 mmol, 62% yield) as a clear oil.

[0459] 1H NMR (500MHz, benzene-d6) δ4.96(t,1H), δ3.79-3.71(dq,3H), δ3.34-3.30(dq,1H), δ2.94 (t,2H),δ1.92-1.75(m,2H),δ1.65-1.11(m,30H),δ0.90-0.87(m,6H),δ0.25(d,6H)

[0460] Example 45

[0461] Synthesis of 1-((6-bromo-1-(octyloxy)hexyl)oxy)-1,1,3,3-tetramethyl-3-octyldisiloxane

[0462]

[0463] 1-((6-Bromo-1-(octyloxy)hexyl)oxy)-1,1,3,3-tetramethyl-3-octyldisiloxane was prepared from octyl 6-bromohexanoate (5.0 g, 16.27 mmol) and 1,1,3,3-tetramethyl-1-octyldisiloxane (1.1 equiv., 4.41 g, 17.90 mmol) according to General Procedure E using 782 μl of BrF(F3s)2 borane catalyst solution (186 mg dissolved in 4.00 ml of anhydrous toluene). The reaction was complete after 3 hours. The crude product was purified by flash column chromatography with a gradient elution (0-10% EtOAc in n-hexane) to give 1-((6-Bromo-1-(octyloxy)hexyl)oxy)-1,1,3,3-tetramethyl-3-octyldisiloxane (7.80 g, 14.08 mmol, 87% yield) as a clear oil.

[0464] 1H NMR (500MHz, benzene-d6) δ4.92(dt,1H), δ3.85-3.80(dq,1H), δ3.40-3.36(dq,1H), δ2.96(t,2H), δ1.79-1.61(m,4 H), δ1.56-1.50(p,2H), δ1.48-1.20(p,26H), δ0.92-0.87(m,6H), δ0.66(m,2H), δ0.23(d,6H), δ0.19(s,6H).

[0465] Example 46

[0466] Synthesis of 1-((1-((6-bromohexyl)oxy)octyl)oxy)-1,1,3,3-tetramethyl-3-octyldisiloxane

[0467]

[0468] 1-((1-((6-bromohexyl)oxy)octyl)oxy)-1,1,3,3-tetramethyl-3-octyldisiloxane) was prepared from 6-bromohexyl octanoate (5.0 g, 16.27 mmol) and 1,1,3,3-tetramethyl-1-octyldisiloxane (1.1 eq, 4.41 g, 17.90 mmol) according to General Procedure E using 589 μl of BrF(Fs)2 borane catalyst solution (216 mg dissolved in 3.50 ml of anhydrous toluene). The reaction was complete after stirring overnight. The crude product was purified by flash column chromatography with a gradient elution (0-10% EtOAc in n-hexane) to give 1-((1-((6-bromohexyl)oxy)octyl)oxy)-1,1,3,3-tetramethyl-3-octyldisiloxane) (6.92 g, 12.49 mmol, 77% yield) as a clear oil.

[0469] 1H NMR (500MHz, benzene-d6) δ4.97(t,1H), δ3.79-3.75(dq,1H), δ3.35-3.30(dq,1H), δ2.94(t,2H), δ1.92 -1.75(m,2H),δ1.60-1.13(m,30H),δ0.92-0.87(m,6H),δ0.66(m,2H),δ0.22(d,6H),δ0.19(s,6H)

[0470] Example 47

[0471] Synthesis of 1-((6-bromo-1-(octyloxy)hexyl)oxy)-1,1,3,3-tetramethyl-3-(octyloxy)disiloxane

[0472]

[0473] 1-((6-Bromo-1-(octyloxy)hexyl)oxy)-1,1,3,3-tetramethyl-3-(octyloxy)disiloxane was prepared from octyl 6-bromohexanoate (5.0 g, 16.27 mmol) and 1,1,3,3-tetramethyl-1-(octyloxy)disiloxane (1.1 equiv, 4.70 g, 17.90 mmol) using 144 μl of BrF(Fs) borane catalyst solution (202 mg dissolved in 4.00 ml of anhydrous toluene) according to General Procedure E. The reaction was complete after stirring overnight. The crude product was purified by flash column chromatography with gradient elution (0-10% EtOAc in n-hexanes) to give 1-((6-bromo-1-(octyloxy)hexyl)oxy)-1,1,3,3-tetramethyl-3-(octyloxy)disiloxane (8.29 g, 14.55 mmol, 89% yield) as a clear oil.

[0474] 1H NMR (500MHz, benzene-d6) δ4.95(dt,1H), δ3.86-3.82(dq,1H), δ3.76-3.72(t,2H), δ3.41-3.37(dq,1H), δ2.96(t,2H), δ1.82-1. 59(m,6H), δ1.56-1.51(p,2H), δ1.46-1.35(m,6H), δ1.34-1.18(m,18H), δ0.90-0.87(m,6H), δ0.27(d,6H), δ0.21(s,6H).

[0475] Example 48

[0476] Synthesis of 1-((1-((6-bromohexyl)oxy)octyl)oxy)-1,1,3,3-tetramethyl-3-(octyloxy)disiloxane

[0477]

[0478] 1-((1-((6-Bromohexyl)oxy)octyl)oxy)-1,1,3,3-tetramethyl-3-(octyloxy)disiloxane was prepared from 6-bromohexyl octanoate (4.00 g, 13.01 mmol) and 1,1,3,3-tetramethyl-1-(octyloxy)disiloxane (1.1 equiv, 3.76 g, 14.32 mmol) using 565 μl of BrF(Fs) borane catalyst solution (206 mg dissolved in 4.00 ml of anhydrous toluene) according to General Procedure E. The reaction was complete after stirring overnight. The crude product was purified by flash column chromatography with gradient elution (0-10% EtOAc in n-hexanes) to afford 1-((1-((6-bromohexyl)oxy)octyl)oxy)-1,1,3,3-tetramethyl-3-(octyloxy)disiloxane (4.02 g, 7.05 mmol, 54% yield) as a clear oil.

[0479] 1H NMR (500MHz, benzene-d6) δ5.00(dt,1H), δ3.82-3.71(m,3H), δ3.36-3.31(dq 1H), δ2.94(t,2H), δ1.95-1.76(m,2H), δ1.68-1.45(m,8H), δ1.45-1.11(m,22H), δ0.90-0.87(m,6H), δ0.29(d,6H), δ0.22(s,6H)

[0480] Example 49

[0481] Synthesis of (6-bromohexyl)dimethyl((1-(octyloxy)octyl)oxy)silane

[0482]

[0483] (6-bromohexyl)dimethyl((1-(octyloxy)octyl)oxy)silane was prepared according to General Procedure E from octyl octanoate (5.00 g, 19.50 mmol) and (6-bromohexyl)dimethylsilane (1.1 equivalents, 4.79 g, 21.45 mmol) using 603 μl BrF(Fs)2 borane catalyst solution (248 mg dissolved in 3.43 ml anhydrous toluene). The reaction was stirred overnight to completion. The crude product was purified by flash column chromatography (0-5% EtOAc in n-hexane) with a gradient elution to give (6-bromohexyl)dimethyl((1-(octyloxy)octyl)oxy)silane (9.11 g, 18.99 mmol, 97% yield) as a clear oil. 1H NMR (500MHz, benzene-d6) δ4.87(dt,1H), δ3.77-3.72(dq,1H), δ3.40-3.35(dq 1H), δ2.99(t,2H), δ1.87-1.80(m,1H), δ1.77-1.70(m,1H), δ1.68-1.63(m,2H), δ1.57-1.49(p, 4H), δ1.48-1.40(p,2H), δ1.39-1.14(m,22H), δ0.92-0.88(m,6H), δ0.65(m,2H), δ0.23(d,6H).

[0484] Example 50

[0485] Synthesis of 1-Bromo-10-heptyl-8,8-dimethyl-7,9,11-trioxa-8-silanonadecane

[0486]

[0487] According to General Procedure E, 1-bromo-10-heptyl-8,8-dimethyl-7,9,11-trioxa-8-silanonadecane was prepared from octyl octanoate (5.00 g, 19.50 mmol) and ((6-bromohexyl)oxy)dimethylsilane (1.1 equivalents, 5.13 g, 21.45 mmol) using 603 μl BrF(Fs)2 borane catalyst solution (253 mg dissolved in 3.50 ml anhydrous toluene). The reaction was completed after stirring overnight. The crude product was purified by flash column chromatography with gradient elution (0-5% EtOAc in n-hexane) to give 1-bromo-10-heptyl-8,8-dimethyl-7,9,11-trioxa-8-silanonadecane (8.20 g, 10.08 mmol, 85% yield) as a clear oil.

[0488] 1H NMR (500MHz, benzene-d6) δ4.99(dt,1H), δ3.86-3.84(dq,1H), δ3.70-3.67(t,2H), δ3.42-3.41(dq 1H), δ2.96(t,2H), δ1.87-1.81(m,1H), δ1.79-1.70(m,1H), δ1.70-1.64(m,2H ), δ1.62-1.40(m,8H), δ1.40-1.13(m,20H), δ0.91-0.89(m,6H), δ0.27(d,6H)

[0489] Example 51

[0490] Synthesis of 10-(5-bromopentyl)-15-hexyl-12,12-dimethyl-9,11,13-trioxa-12-silatricosane

[0491]

[0492] 10-(5-Bromopentyl)-15-hexyl-12,12-dimethyl-9,11,13-trioxa-12-silatricosane was prepared from octyl-6-bromohexanoate (5.00 g, 16.27 mmol) and (2-hexyldecyl)oxy)dimethylsilane (1.1 eq, 5.38 g, 17.90 mmol) using 503 μl of BrF(F3s)2 borane catalyst (253 mg of catalyst dissolved in 3.50 ml of anhydrous toluene) according to General Procedure E. The reaction was complete after stirring overnight. The crude product was purified by flash column chromatography with gradient elution (0-2% EtOAc in n-hexane) to give 10-(5-bromopentyl)-15-hexyl-12,12-dimethyl-9,11,13-trioxa-12-silatricosane (6.66 g, 10.96 mmol, 67% yield) as a clear oil.

[0493] 1H NMR (500MHz, benzene-d6) δ4.93(dt,1H), δ3.86-3.82(dq,1H), δ3.72-3.71(d,2H), δ3.42-3.37(dq 1H), δ2.96(t,2H), δ1.81-1.47(m,9H), δ1.47-1.18(m,36H), δ0.91-0.88(m,9H), δ0.26(d,6H)

[0494] Example 52

[0495] Synthesis of 1-bromo-8-heptyl-13-hexyl-10,10-dimethyl-7,9,11-trioxa-10-silanheneicosane

[0496]

[0497] 1-Bromo-8-heptyl-13-hexyl-10,10-dimethyl-7,9,11-trioxa-10-silaheneicosane was prepared according to General Procedure E from 6-bromohexyl octanoate (4.00 g, 13.01 mmol) and (2-hexyldecyl)oxy)dimethylsilane (1.1 equiv., 4.30 g, 14.32 mmol) using 402 μl of BrF(Fs) borane catalyst solution (253 mg dissolved in 3.50 ml of anhydrous toluene). The reaction was complete after stirring overnight. The crude product was purified by flash column chromatography with a gradient elution (0-2% EtOAc in n-hexane) to give 1-bromo-8-heptyl-13-hexyl-10,10-dimethyl-7,9,11-trioxa-10-silaheneicosane (4.03 g, 6.63 mmol, 51% yield) as a clear oil.

[0498] 1H NMR (500MHz, benzene-d6) δ4.99(dt,1H), δ3.82-3.78(dq,1H),3.74-3.73(d,2H),3.37-3.33(dq 1H),2.96(t,2H),δ1.88-1.75(m,2H),δ1.75-1.45(m,9H),δ1.45-1.14(m,34H),δ0.92-0.89(m,9H),δ0.28(d,6H)

[0499] Example 53

[0500] Synthesis of triethyl(((9Z,12Z)-1-methoxyoctadec-9,12-dien-1-yl)oxy)silane

[0501]

[0502] Triethyl(((9Z,12Z)-1-methoxyoctadeca-9,12-dien-1-yl)oxy)silane was prepared from methyl (9Z,12Z)-octadeca-9,12-dienoate (12.68 g, 43.07 mmol) and triethylsilane (5.16 g, 44.36 mmol) according to General Procedure F using 208 mg (0.43 mmol) of BrF(F4)2 borane catalyst. 1 The reaction was monitored by H NMR. After purification, the product was obtained as a pale yellow oil, triethyl(((9Z,12Z)-1-methoxyoctadeca-9,12-dien-1-yl)oxy)silane (14.61 g, 35.56 mmol, 83% yield). 1 H NMR(500 MHz, benzene-d6) δ5.50-5.42(m,4H), δ4.74(t,1H), δ3.21(s,3H), δ2.86(t,2H), δ2.10-2.02(m,4H), δ1.77-1.68(m,1H), δ1.68-1.58( m,1H),δ1.58-1.50(m,1H),δ1.50-1.40(m,1H),δ1.40-1.20(m,14H),δ1.03-0.99(t,9H),δ0.90-0.80(m,3H),δ0.67-0.62(q,6H)

[0503] Example 54

[0504] Synthesis of Triethyl(((9Z,12Z,15Z)-1-Methoxyoctadeca-9,12,15-trien-1-yl)oxy)silane

[0505] Triethyl(((9Z,12Z,15Z)-1-methoxyoctadeca-9,12,15-trien-1-yl)oxy)silane was prepared from methyl (9Z,12Z,15Z)-octadeca-9,12,15-trienoate (11.55 g, 39.50 mmol) and triethylsilane (4.73 g, 40.68 mmol) using 191 mg (0.39 mmol) of BrF(F4)2 borane catalyst according to General Procedure F. The reaction mixture was stirred at 30°C overnight. The reaction was monitored by TLC (hexane / ethyl acetate 9:1). After purification, the product, triethyl(((9Z,12Z,15Z)-1-methoxyoctadeca-9,12,15-trien-1-yl)oxy)silane (15.81 g, 38.68 mmol, 98% yield), was obtained as a pale yellow oil.

[0506] 1H NMR(500 MHz, benzene-d6) δ5.32-5.17(m,6H), δ4.56(t,1H), δ3.02(s,3H), δ2.72-2.60(m,4H), δ1.93-1.75(m,4H), δ1. 64-1.39(m,2H),δ1.36-1.22(m,2H),δ1.16-1.01(m,8H),δ0.84(t,9H),δ0.72(m,3H),δ0.50-0.42(q,6H)

[0507] Example 55

[0508] Synthesis of (((5Z,8Z,11Z,14Z,17Z)-1-ethoxyeicosahedral-5,8,11,14,17-pentaen-1-yl)oxy)triethylsilane

[0509] (((5Z,8Z,11Z,14Z,17Z)-1-ethoxyeicosac-5,8,11,14,17-pentaen-1-yl)oxy)triethylsilane was prepared from (5Z,8Z,11Z,14Z,17Z)-eicosac-5,8,11,14,17-pentaenoic acid ethyl ester (13.28 g, 40.17 mmol) and triethylsilane (4.81 g, 41.37 mmol) using 194 mg (0.40 mmol) of BrF(F4)2 borane catalyst according to General Procedure F. 1 The reaction was monitored by H NMR. The product obtained was a light yellow oil (((5Z,8Z,11Z,14Z,17Z)-1-ethoxyeicosaccharide-5,8,11,14,17-pentaen-1-yl)oxy)triethylsilane (17.01 g, 38.08 mmol, 95% yield).

[0510] 1 H NMR(500 MHz, benzene-d6) δ5.52-5.39(m,10H), δ4.82(t,1H), δ3.70-3.64(dp,1H), δ3.37-3.31(dp,1H), δ2.91-2.80(m,8H), δ2.16-2.07(m,2H), δ2. 07-1.98(m,2H),δ1.83-1.74(m,1H),δ1.74-1.65(m,1H),δ1.65-1.54(m,2H),δ1.15(t,3H),δ1.04(t,9H),δ0.92(t,3H),δ0.67(q,6H)

[0511] Example 56

[0512] Synthesis of Triethyl(((4R)-1-methoxy-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentyl)oxy)silane

[0513]

[0514] Triethyl(((4R)-1-methoxy-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)pentyl)oxy)silane was prepared from methyl (4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)pentyl)oxy)silane according to General Procedure F using 21.72 mg (0.045 mmol) of BrF(F4)2 borane catalyst. The reaction was monitored by TLC (hexane / ethyl acetate 9:1, PMA visualization). The crude product was purified by flash column chromatography with gradient elution (0-10% EtOAc in n-hexane) to afford triethyl(((4R)-1-methoxy-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)pentyl)oxy)silane (0.84 g, 1.61 mmol, 36% yield) as a white solid.

[0515] 1 H NMR(500 MHz, benzene-d6) δ4.81-476(m,1H), δ4.76-4.68(m,1H), δ3.41(s,3H), δ3.25(d,3H), δ1.95-1.10( m,25H),δ1.10-1.02(t,12H),δ1.00(d,3H),δ0.75(s,3H),δ0.71-0.66(dq,6H),δ0.57(s,3H)

[0516] Example 57

[0517] Synthesis of 6-methoxy-6-(triethylsilyl)oxy)hexyl 2-(decylthio)hexanoate

[0518]

[0519] 6-Methoxy-6-(triethylsilyl)oxy)hexyl 2-(decylthio)hexanoate was prepared from 6-methoxy-6-oxohexyl 2-(decylthio)hexanoate (10.1 g, 24.24 mmol) and triethylsilane (3.10 g, 26.66 mmol) using 117 mg (0.24 mmol) of BrF(F4)2 borane catalyst according to General Procedure F. The reaction was monitored by TLC (hexane / ethyl acetate 9:1, PMA visualization). The crude product was purified by flash column chromatography with a gradient elution (0-10% EtOAc in n-hexane) to give 6-methoxy-6-(triethylsilyl)oxy)hexyl 2-(decylthio)hexanoate (4.35 g, 8.16 mmol, 34% yield) as a clear oil.

[0520] 1 H NMR (500MHz, benzene-d6) δ4.69(t,1H), δ4.12-4.03(m,2H), δ3.29(dt,1H), δ3.19 (s,3H)δ3.75-3.65(m,1H),δ3.65-3.57(m,1H),δ2.06-1.95(m,1H),δ1.79-1 .77(m,1H),δ1.77-1.63(m,1H),δ1.62-1.54(m,3H),δ1.53-1.46(m,2H),δ1 .43-1.14(m,22H),δ1.02(t,9H),δδ0.90(t,3H),δ0.80(t,3H),δ0.64(q,6H)

[0521] Example 58

[0522] Synthesis of 6-methoxy-6-((triethylsilyl)oxy)hexyl 2-(pentylthio)decanoate

[0523]

[0524] 6-Methoxy-6-((triethylsilyl)oxy)hexyl 2-(pentylthio)decanoate was prepared according to General Procedure F from 6-methoxy-6-oxohexyl 2-(pentylthio)decanoate (9.00 g, 22.35 mmol) and triethylsilane (2.86 g, 24.59 mmol) using 108 mg (0.22 mmol) of BrF(F4)2 borane catalyst. The reaction mixture was stirred at room temperature overnight. The reaction was monitored by TLC (hexane / ethyl acetate 9 / 1, PMA visualization). The crude product was purified by flash column chromatography with a gradient elution (0-10% EtOAc in n-hexane) to give 6-methoxy-6-((triethylsilyl)oxy)hexyl 2-(pentylthio)decanoate (5.79 g, 11.16 mmol, 50% yield) as a clear oil.

[0525] 1 H NMR (500MHz, benzene-d6) δ4.69(t,1H), δ4.14-4.03(m,2H), δ3.31(dt,1H), δ3.19 (s,3H)δ3.73-3.64(m,1H),δ3.62-3.53(m,1H),δ2.09-1.98(m,1H),δ1.84-1 .72(m,1H),δ1.70-1.62(m,1H),δ1.62-1.46(m,5H),δ1.46-1.33(m,4H),δ1 .31-1.12(m,16H),δ1.02(t,9H),δδ0.89(t,3H),δ0.81(t,3H),δ0.64(q,6H)

[0526] Example 59

[0527] Synthesis of 6-ethoxy-6-((triethylsilyl)oxy)hexyl 2-hexyldecanoate

[0528]

[0529] In the dry 100ml flask equipped with stirring rod, rubber septum, thermometer and nitrogen inlet, under inert condition (nitrogen), 6-ethoxy-6-oxohexyl 2-hexyl decanoate (23.9g, 60.0mmol, 1.0 equivalent) is dissolved in anhydrous toluene (30mL). Next, the toluene solution of catalyst, BrF (F4) 2 (14.49mg in 600 μ L anhydrous toluene) is added. Finally, triethylsilane (7.47g, 10.3ml, 64.2mmol, 1.07 equivalent) is added dropwise, and reaction temperature is maintained between 24 ℃ to 28 ℃. Sometimes, when the reaction starts, the release of hydrogen is observable, shows that there is a small amount of residual water in the system, but this does not affect the result of the reaction. Further stirring reaction is spent the night (about 20 hours) at room temperature. Reaction is monitored by TLC and NMR. After the reaction was complete, 1 ml of EtOAc, 0.6 ml of MeCN and silica gel were added to the reaction mixture and stirred for 10 min. The silica gel was filtered off and washed with 2 x 50 ml of n-pentane. Volatiles were removed under reduced pressure to give the product (29.00 g, 57.89 mmol, 97% yield) that could be used without further purification.

[0530] 1H NMR (500MHz, benzene-d6) δ4.79(t,1H), δ4.10(t,2H), δ3.66(m,1H), δ3.32(m,1H), δ2.50-2.39 (m,1H),δ1.86-1.20(br.m,32H),δ1.15(t,3H),δ1.04(t,9H),δ.91(q,6H),δ.67(q,6H),

[0531] Example 60

[0532] Synthesis of 1-Bromo-10-heptyl-8,8-dimethyl-7,9,11-trioxa-8-silaoctadecane

[0533]

[0534] 1-Bromo-10-heptyl-8,8-dimethyl-7,9,11-trioxa-8-silaoctadecane was prepared from heptyl octanoate (727.19 mg, 3.00 mmol, 1.0 equiv) and ((6-bromohexyl)oxy)dimethylsilane (789.44 mg, 3.30 mmol, 1.1 equiv) using 100 μl of BrF(F3s)2 borane catalyst solution (1.34 mg dissolved in 100 μl of anhydrous toluene) according to General Procedure E. The reaction was complete after stirring overnight. The crude product was purified by flash column chromatography with a gradient elution (20% to 66% DCM in petroleum ether) to give 1-bromo-10-heptyl-8,8-dimethyl-7,9,11-trioxa-8-silaoctadecane (1.34 g, 2.86 mmol, 95% yield) as a clear oil.

[0535] 1 H NMR(500 MHz, benzene-d6) δ4.96 (m, 1H), δ3.84-3.79 (m, 1H), δ3.66 (dt, 2H), δ3.43-3.35 (m, 1H), δ2.96 (t,2H),δ1.87-1.77(m,2H),δ1.70-1.10(br.m,28H),δ0.91-0.86(m,6H),δ0.27(m,6H)

[0536] Example 61

[0537] Synthesis of 1-Bromo-10-heptyl-8,8-dimethyl-7,9,11-trioxa-8-silicosane

[0538]

[0539] 1-Bromo-10-heptyl-8,8-dimethyl-7,9,11-trioxa-8-silaicosane was prepared from nonyl octanoate (811.35 mg, 3.00 mmol, 1.0 equiv) and ((6-bromohexyl)oxy)dimethylsilane (789.44 mg, 3.30 mmol, 1.1 equiv) using 100 μl of BrF(F4)2 borane catalyst solution (1.45 mg dissolved in 100 μl of anhydrous toluene) according to General Procedure E. The reaction was complete after stirring overnight (TLC petroleum ether:chloroform 1:1, ~0.4 Rf). The crude product was purified by flash column chromatography with gradient elution (20%-66% DCM in petroleum ether) to give 1-bromo-10-heptyl-8,8-dimethyl-7,9,11-trioxa-8-silaicosane (1.32 g, 2.59 mmol, 86% yield) as a clear oil.

[0540] 1 H NMR(500 MHz, benzene-d6)δ4.99(dt,1H),δ3.89-3.80(m,1H),δ3.68(t,2H),δ3.46-3.37(m,1H),δ2.96(t,2H),δ 1.98-1.75(m,2H),δ1.73-1.39(br.m,10H),δ1.38-1.11(br.m,22H),δ0.91(m,6H),δ0.27(d,6H)

[0541] Example 62

[0542] Synthesis of 1-bromo-10-hexyl-8,8-dimethyl-7,9,11-trioxa-8-silanonadecane

[0543]

[0544] 1-Bromo-10-hexyl-8,8-dimethyl-7,9,11-trioxa-8-silanonadecane was prepared from octyl heptanoate (727.19 mg, 3.0 mmol) and ((6-bromohexyl)oxy)dimethylsilane (789.44 mg, 3.30 mmol, 1.1 equiv) according to General Procedure E using 100 μl of BrF(F3s)2 borane catalyst solution (1.34 mg dissolved in 100 μl of anhydrous toluene). The reaction was complete after stirring overnight (TLC petroleum ether:chloroform 1:1, ~0.4 Rf). The crude product was purified by flash column chromatography with a gradient elution (20% to 66% DCM in petroleum ether) to afford 1-bromo-10-heptyl-8,8-dimethyl-7,9,11-trioxa-8-silanonadecane (1.26 g, 2.71 mmol, 90% yield) as a clear oil.

[0545] 1H NMR(500 MHz, benzene-d6) δ4.98 (dd, 1H), δ3.87-3.82 (m, 1H), δ3.68 (t, 2H), δ3.43-3.38 (m, 1H), δ2.96 (t,2H),δ1.93-1.76(m,2H),δ1.70-1.12(br.m,28H),δ0.92-0.87(m,6H),δ0.26(d,6H)

[0546] Example 63

[0547] Synthesis of 1-bromo-8,8-dimethyl-10-octyl-7,9,11-trioxa-8-silanonadecane

[0548]

[0549] 1-Bromo-8,8-dimethyl-10-octyl-7,9,11-trioxa-8-silanonadecane was prepared from octyl nonanoate (811.35 mg, 3.0 mmol) and ((6-bromohexyl)oxy)dimethylsilane (789.44 mg, 3.30 mmol, 1.1 eq) according to General Procedure E using 100 μl of BrF(F3s)2 borane catalyst solution (1.34 mg dissolved in 100 μl of anhydrous toluene). The reaction was complete after stirring overnight (TLC petroleum ether:chloroform 1:1, ~0.4 Rf). The crude product was purified by flash column chromatography with a gradient elution (20% to 66% DCM in petroleum ether) to afford 1-bromo-8,8-dimethyl-10-octyl-7,9,11-trioxa-8-silanonadecane (1.29 g, 2.62 mmol, 87% yield) as a clear oil.

[0550] 1 H NMR(500 MHz, benzene-d6) δ4.99 (m, 1H), δ3.88-3.83 (m, 1H), δ3.68 (t, 2H), δ3.44-3.39 (m, 1H), δ2.96 (t,2H),δ1.90-1.80(m,2H),δ1.71-1.14(br.m,32H),δ0.92-0.88(m,6H),δ0.27(d,6H)

[0551] Example 64

[0552] Synthesis of 1-Bromo-8,8-dimethyl-10-nonyl-7,9,11-trioxa-8-silaheptadecane

[0553]

[0554] 1-Bromo-8,8-dimethyl-10-nonyl-7,9,11-trioxa-8-silaheptadecane was prepared according to General Procedure E from hexyl decanoate (769.3 mg, 3.00 mmol, 1.0 equiv) and ((6-bromohexyl)oxy)dimethylsilane (789.44 g, 3.30 mmol, 1.1 equiv) using 100 μl of BrF(F4)2 borane catalyst solution (1.45 mg dissolved in 100 μl of anhydrous toluene). The reaction was complete after stirring overnight. The crude product was purified by flash column chromatography with a gradient elution (20–65% DCM in petroleum ether) to afford 1-bromo-8,8-dimethyl-10-nonyl-7,9,11-trioxa-8-silaheptadecane (1.20 g, 2.42 mmol, 81% yield) as a clear oil.

[0555] 1 H NMR (500MHz, benzene-d6) δ4.98(m,1H), δ3.86-3.79(m,1H), δ3.68(t,2H), δ3.43-3.36 (m,1H),δ2.96(t,2H),δ1.95-1.23(br.m,32H),δ0.93-0.86(m,6H),δ0.26(d,6H)

[0556] Example 65

[0557] Synthesis of 1-Bromo-8,8-dimethyl-10-pentyl-7,9,11-trioxa-8-silanheneicosane

[0558]

[0559] 1-Bromo-8,8-dimethyl-10-pentyl-7,9,11-trioxa-8-silaheneicosane was prepared according to General Procedure E from decyl hexanoate (769.27 mg, 3.00 mmol) and ((6-bromohexyl)oxy)dimethylsilane (789.44 mg, 3.30 mmol, 1.1 equiv) using 100 μl of BrF(F4)2 borane catalyst solution (1.45 mg dissolved in 100 μl of anhydrous toluene). The reaction was complete after stirring overnight. The crude product was purified by flash column chromatography with a gradient elution (20–65% DCM in petroleum ether) to afford 1-bromo-8,8-dimethyl-10-pentyl-7,9,11-trioxa-8-silaheneicosane (1.04 g, 2.11 mmol, 70% yield) as a clear oil.

[0560] 1H NMR (500MHz, benzene-d6) δ4.98(m,1H), δ3.88-3.81(m,1H), δ3.68(t,2H), δ3.45-3.37 (m,1H),δ2.96(t,2H),δ1.95-1.27(br.m,32H),δ0.95-0.84(m,6H),δ0.26(d,6H)

[0561] Example 66

[0562] Synthesis of ((6-bromohexyl)oxy)dimethyl((oxacyclohexadec-2-yl)oxy)silane

[0563]

[0564] ((6-bromohexyl)oxy)dimethyl((oxahexadecan-2-yl)oxy)silane was prepared according to General Procedure E from oxahexadecan-2-one (1.00 g, 3.827 mmol) and ((6-bromohexyl)oxy)dimethylsilane (1.00 g, 4.21 mmol, 1.1 equiv) using 100 μl BrF(Fs)2 borane catalyst solution (8.55 mg dissolved in 100 μl anhydrous toluene). The reaction was complete after stirring overnight. The solvent was evaporated, and ((6-bromohexyl)oxy)dimethyl((oxahexadecan-2-yl)oxy)silane (1.83 g, 3.83 mmol, 100% yield) was obtained as a clear oil.

[0565] 1 H NMR (500MHz, benzene-d6) δ4.80(dd,1H), δ3.85-3.78(m,1H), δ3.68(t,2H), δ3.40(t,2H ), δ3.31-3.22(m,1H), δ1.90-1.83(m,2H), δ1.75-1.18(br.m,32H), δ0.15(d,6H)

[0566] Example 67

[0567] Synthesis of 1-(4-bromobutoxy)-1,1,3,3-tetramethyl-3-((1-(octyloxy)octyl)oxy)disiloxane

[0568]

[0569] 1-(4-Bromobutoxy)-1,1,3,3-tetramethyl-3-((1-(octyloxy)octyl)oxy)disiloxane was prepared from octyl octanoate (750 mg, 2.925 mmol) and 1-(4-bromobutoxy)-1,1,3,3-tetramethyldisiloxane (0.75 equiv, 625.9 mg, 2.190 mmol) using 100 μl of BrF(F3s)2 borane catalyst solution (6.54 mg dissolved in 100 μl of anhydrous toluene) according to General Procedure E. The reaction was complete after stirring overnight. The crude product was purified by flash column chromatography with gradient elution (10-90% EtOAc in petroleum ether) to give 1-(4-bromobutoxy)-1,1,3,3-tetramethyl-3-((1-(octyloxy)octyl)oxy)disiloxane (1.27 g, 2.35 mmol, 80% yield) as a clear oil.

[0570] 1 H NMR (500MHz, benzene-d6) δ4.79 (dd, 1H), δ3.73-3.62 (m, 2H), δ3.44 (t, 1H), δ3.32-3 .26(m,1H),δ1.72-1.19(br.m,30H),δ0.89-0.86(m,6H),δ0.15-0.08(d,12H)

[0571] Example 68

[0572] Synthesis of 1-Bromo-8,8,10-trimethyl-7,9,11-trioxa-8-silanheneicosane

[0573]

[0574] 1-Bromo-8,8,10-trimethyl-7,9,11-trioxa-8-silaheneicosane was prepared according to General Procedure E from decyl acetate (400.03 mg, 1.997 mmol) and ((6-bromohexyl)oxy)dimethylsilane (477.73 mg, 1.997 mmol, 1.0 equiv) using 100 μl of BrF(F3s)2 borane catalyst solution (8.93 mg dissolved in 100 μl of anhydrous toluene). The reaction was complete after stirring overnight. The crude product was purified by flash column chromatography with a gradient elution (0-100% DCM and 1% TEA in petroleum ether) to give 1-bromo-8,8,10-trimethyl-7,9,11-trioxa-8-silaheneicosane (743 mg, 1.69 mmol, 85% yield) as a clear oil.

[0575] 1H NMR (500MHz, benzene-d6) δ5.05(m,1H), δ3.82-3.74(m,1H), δ3.66-3.55(m,2H), δ3.38-3. 31(m,1H),δ3.01-2.92(m,2H),δ1.66-1.10(br.m,27H),δ0.91(t,3H),δ0.20(t,6H)

[0576] Example 69

[0577] Synthesis of 1-Bromo-8,8-dimethyl-10-propyl-7,9,11-trioxa-8-silanheneicosane

[0578]

[0579] 1-Bromo-8,8-dimethyl-10-propyl-7,9,11-trioxa-8-silaheneicosane was prepared according to General Procedure E from decyl butyrate (1.00 g, 4.028 mmol, 1.0 equiv) and ((6-bromohexyl)oxy)dimethylsilane (1.060 g, 4.431 mmol, 1.1 equiv) using 100 μl of BrF(F3s)2 borane catalyst solution (9.0 mg dissolved in 100 μl of anhydrous toluene). The reaction was complete after stirring overnight. The crude product was purified by flash column chromatography with a gradient elution (20–65% DCM in petroleum ether) to afford 1-bromo-8,8-dimethyl-10-pentyl-7,9,11-trioxa-8-silaheneicosane (1.88 g, 4.0 mmol, 100% yield) as a clear oil.

[0580] 1 H NMR (500MHz, benzene-d6) δ4.81(dd,1H), δ3.70-3.63(m,3H), δ3.40(t,2H), δ3.34-3.29(m ,1H),δ1.90-1.83(m,2H),δ1.69-1.21(br.m,26H),δ0.93-0.86(m,6H),δ0.16(d,6H)

[0581] Example 70

[0582] Synthesis of 1-Bromo-8,8-dimethyl-10-propyl-7,9,11-trioxa-8-silatricosane

[0583]

[0584] 1-Bromo-8,8-dimethyl-10-propyl-7,9,11-trioxa-8-silatricosane was prepared according to General Procedure E from dodecyl butyrate (750 mg, 2.925 mmol, 1.0 equiv) and ((6-bromohexyl)oxy)dimethylsilane (699.70 mg, 2.925 mmol, 1.0 equiv) using 100 μl of BrF(F3s)2 borane catalyst solution (6.54 mg dissolved in 100 μl of anhydrous toluene). The reaction was complete after stirring overnight. The crude product was purified by flash column chromatography with a gradient elution (20–65% DCM in petroleum ether) to afford 1-bromo-8,8-dimethyl-10-pentyl-7,9,11-trioxa-8-silatricosane (1.38 g, 2.79 mmol, 96% yield) as a clear oil.

[0585] 1 H NMR (500MHz, benzene-d6) δ4.81(dd,1H), δ3.70-3.63(m,3H), δ3.40(t,2H), δ3.34-3.29(m ,1H),δ1.90-1.83(m,2H),δ1.68-1.21(br.m,30H),δ0.93-0.86(m,6H),δ0.16(d,6H)

[0586] Example 71

[0587] Synthesis of 13-bromo-6,6-dimethyl-4-nonyl-3,5,7-trioxa-6-silatridecane

[0588]

[0589] 13-Bromo-6,6-dimethyl-4-nonyl-3,5,7-trioxa-6-silatridecane was prepared from ethyl decanoate (400 mg, 1.997 mmol, 1.0 eq) and ((6-bromohexyl)oxy)dimethylsilane (525.46 mg, 2.196 mmol, 1.1 eq) using 100 μl BrF(F3s)2 borane catalyst solution (4.46 mg dissolved in 100 μl anhydrous toluene) according to General Procedure E. The reaction was completed after stirring overnight. The crude product was filtered through a short silica gel column to give 13-Bromo-6,6-dimethyl-4-nonyl-3,5,7-trioxa-6-silatridecane (883 mg, 1.51 mmol, 75% yield) as a clear oil. 1H NMR (500MHz, benzene-d6) δ5.04(dt,1H), δ3.89(m,1H), δ3.76(t,2H), δ3.48(m,1H), δ3.06(t,2H), δ2.01 -1.93(m,2H),δ1.70-1.52(m,6H),δ1.51-1.33(m,12H),δ1.28(m,7H),δ1.01(t,3H),δ0.33(d,6H)

[0590] Example 72

[0591] Synthesis of 13-bromo-6,6-dimethyl-4-undecyl-3,5,7-trioxa-6-silatridecane

[0592]

[0593] 13-Bromo-6,6-dimethyl-4-undecyl-3,5,7-trioxa-6-silatridecane was prepared according to General Procedure E from ethyl dodecanoate (1500 mg, 6.568 mmol, 1.0 equiv) and ((6-bromohexyl)oxy)dimethylsilane (1493 mg, 6.240 mmol, 0.95 equiv) using 100 μl of BrF(F3s)2 borane catalyst solution (29.36 mg dissolved in 100 μl of anhydrous toluene). The reaction was complete after stirring overnight. The crude product was filtered through a short column of silica gel to give 13-Bromo-6,6-dimethyl-4-undecyl-3,5,7-trioxa-6-silatridecane (3.04 g, 5.66 mmol, 86% yield) as a clear oil.

[0594] 1 H NMR(500 MHz,Toluene-d8)δ4.92(t,1H),δ3.81-3.73(m,1H),δ3.63(t,2H),δ3.39-3.32(m,1H), δ2.95(t,2H), δ1.88-1.74(m,2H), δ1.61-1.10(br.m,29H), δ0.90(t,3H), δ0.21(d,6H)

[0595] Example 73

[0596] Synthesis of 15-bromo-8,8-dimethyl-6-nonyl-5,7,9-trioxa-8-silapentadecane

[0597]

[0598] 15-Bromo-8,8-dimethyl-6-nonyl-5,7,9-trioxa-8-silapentadecane was prepared from butyl decanoate (400 mg, 1.75 mmol) and ((6-bromohexyl)oxy)dimethylsilane (460.91 g, 1.93 mmol, 1.1 equiv) using 100 μl of BrF(F3s)2 borane catalyst solution (7.83 mg dissolved in 100 μl of anhydrous toluene) according to General Procedure E. The reaction was complete after stirring overnight. The crude product was filtered through a short column of silica gel to give 1-15-bromo-8,8-dimethyl-6-nonyl-5,7,9-trioxa-8-silapentadecane (745 mg, 1.45 mmol, 83% yield) as a clear oil.

[0599] 1 H NMR(500 MHz, benzene-d6)δ4.97(dt,1H),δ3.86-3.77(m,1H),δ3.67(t,2H),δ3.43-3.32(m,1H),δ2 .96(t,2H),δ1.93-1.76(m,2H),δ1.66-1.10(br.m,26H),δ0.91(t,6H),δ0.25(d,6H)

[0600] Example 74

[0601] Synthesis of 15-bromo-8,8-dimethyl-6-undecyl-5,7,9-trioxa-8-silapentadecane

[0602]

[0603] 15-Bromo-8,8-dimethyl-6-undecyl-5,7,9-trioxa-8-silapentadecane was prepared from butyl dodecanoate (200 mg, 0.78 mmol) and ((6-bromohexyl)oxy)dimethylsilane (205.24 mg, 0.858 mmol, 1.1 equiv) using 100 μl of BrF(F3s)2 borane catalyst solution (0.70 mg dissolved in 100 μl of anhydrous toluene) according to General Procedure E. The reaction was complete after stirring overnight. The crude product was filtered through a short column of silica gel to give 15-Bromo-8,8-dimethyl-6-undecyl-5,7,9-trioxa-8-silatridecane (415 mg, 0.78 mmol, 100% yield) as a clear oil. 1H NMR(500 MHz, benzene-d6) δ5.01 (dt, 1H), δ3.90-3.82 (m, 1H), δ3.72 (t, 2H), δ3.46-3.39 (m, 1H), δ3.02 (t,2H),δ2.00-1.79(m,2H),δ1.70-1.15(br.m,30H),δ0.99-0.93(m,6H),δ0.29(d,6H)

[0604] Example 75

[0605] Synthesis of 13-bromo-4,6,6-trimethyl-3,5,7-trioxa-6-silatridecane

[0606]

[0607] 13-Bromo-4,6,6-trimethyl-3,5,7-trioxa-6-silatridecane was prepared from ethyl acetate (200 mg, 2.27 mmol) and ((6-bromohexyl)oxy)dimethylsilane (597.35 mg, 2.50 mmol, 1.1 equiv) using 100 μl of BrF(F3s)2 borane catalyst solution (5.07 mg dissolved in 100 μl of anhydrous toluene) according to General Procedure E. The reaction was complete after stirring overnight. The crude product was purified by flash column chromatography with a gradient elution (0-30% EtOAc and 1% TEA in petroleum ether) to give 13-bromo-4,6,6-trimethyl-3,5,7-trioxa-6-silatridecane (325 mg, 0.99 mmol, 44% yield) as a clear oil.

[0608] 1H NMR (500MHz, benzene-d6) δ5.01(q,1H), δ3.80-3.66(m,1H), δ3.61(t,2H), δ3.36-3. 26(m,1H),δ2.95(t,2H),δ1.56-1.36(m,7H),δ1.20-1.10(m,7H),δ0.18(s,6H)

[0609] Example 76

[0610] Synthesis of 1-bromo-9-heptyl-7,7-dimethyl-6,8,10-trioxa-7-silaoctadecane

[0611]

[0612] According to General Procedure E, 1-bromo-9-heptyl-7,7-dimethyl-6,8,10-trioxa-7-sila-heptadecane was prepared from octyl octanoate (1.54 mg, 6.0 mmol) and ((5-bromopentyl)oxy)dimethylsilane (1.486 mg, 6.6 mmol, 1.1 equivalents) using 100 μl BrF(F3s)2 borane catalyst solution (2.9 mg dissolved in 100 μl anhydrous toluene). The reaction was completed after stirring overnight. The crude product was purified by flash column chromatography with gradient elution (0-5% EtOAc in petroleum ether) to give 1-bromo-9-heptyl-7,7-dimethyl-6,8,10-trioxa-7-sila-heptadecane (2.63 g, 5.46 mmol, 91% yield) as a clear oil.

[0613] 1 H NMR (500MHz, benzene-d6) δ5.08(q,1H), δ3.97-3.90(m,1H), δ3.73(t,2H), δ3.54-3.47(m,1H), δ3 .07(t,2H),δ2.05-1.84(m,2H),δ1.81-1.27(br.m,28H),δ1.05-0.95(m,6H),δ0.35(d,6H)

[0614] Example 77

[0615] Synthesis of 1-bromo-10-heptyl-8,8-dimethyl-7,9-dioxa-11-thia-8-silaoctadecane

[0616]

[0617] 1-Bromo-10-heptyl-8,8-dimethyl-7,9-dioxa-11-thia-8-silaoctadecane was prepared from octyl octylthioate (817.47 mg, 3.00 mmol) and ((6-bromohexyl)oxy)dimethylsilane (789.44 mg, 3.30 mmol, 1.1 equiv) using 100 μl of BrF(F3s)2 borane catalyst solution (1.34 mg dissolved in 100 μl of anhydrous toluene) according to General Procedure E. The reaction was complete after stirring overnight. The crude product was purified by flash column chromatography with a gradient elution (20–65% DCM in petroleum ether) to give 1-bromo-10-heptyl-8,8-dimethyl-7,9-dioxa-11-thia-8-silaoctadecane (1.40 g, 2.74 mmol, 91% yield) as a clear oil.

[0618] 1 H NMR (500MHz, benzene-d6) δ5.09(t,1H), δ3.74-3.67(m,2H), δ3.00-2.92(m,2H), δ2.81-3.63( m,2H),δ2.09-1.85(m,2H),δ1.75-1.06(br.m,24H),δ0.92-0.81(m,10H),δ0.29(d,6H)

[0619] Example 78

[0620] Synthesis of (Z)-1-bromo-10-heptyl-8,8-dimethyl-7,9,11-trioxa-8-silaicos-17-ene

[0621]

[0622] (Z)-1-Bromo-10-heptyl-8,8-dimethyl-7,9,11-trioxa-8-silaicos-17-ene was prepared from (Z)-non-6-en-1-yl octanoate (1.0 g, 3.725 mmol) and ((6-bromohexyl)oxy)dimethylsilane (891.18 mg, 3.725 mmol, 1.0 equiv) using 100 μl BrF(F3s)2 borane catalyst solution (16.65 mg dissolved in 100 μl anhydrous toluene) according to General Procedure E. The reaction was complete after stirring overnight. The crude product was filtered through a short silica gel column to give (Z)-1-Bromo-10-heptyl-8,8-dimethyl-7,9,11-trioxa-8-silaicos-17-ene (1.66 g, 3.14 mmol, 84% yield) as a clear oil.

[0623] 1H NMR(500MHz, benzene-d6)δ5.49-5.36(m,2H),δ4.97(dd,1H),δ3.86-3.79(m,1H),δ3.67(t,2H),δ3.42-3.34(m,1H),δ 2.96(t,2H),δ2.08-1.97(m,4H),δ1.92-1.75(m,2H),δ1.69-1.08(br.m,24H),δ0.96-0.87(m,6H),δ0.25(d,6H)

[0624] Example 79

[0625] Synthesis of (Z)-1-Bromo-10-heptyl-8,8-dimethyl-7,9,11-trioxa-8-silaicos-14-ene

[0626]

[0627] (Z)-1-Bromo-10-heptyl-8,8-dimethyl-7,9,11-trioxa-8-silaicos-14-ene was prepared from (Z)-non-3-en-1-yl octanoate (xxx g, xxx mmol) and ((6-bromohexyl)oxy)dimethylsilane (891.18 mg, 3.725 mmol, 1.0 equiv) using 100 μl BrF(F3s)2 borane catalyst solution (16.65 mg dissolved in 100 μl anhydrous toluene). The reaction was complete after stirring overnight. The crude product was filtered through a short silica gel column to give (Z)-1-Bromo-10-heptyl-8,8-dimethyl-7,9,11-trioxa-8-silaicos-14-ene (1.81 g, 3.30 mmol, 89% yield) as a clear oil.

[0628] 1 H NMR (500MHz, benzene-d6) δ5.63-5.49(m,2H), δ4.98(dd,1H), δ3.90-3.82(m,1H), δ3.67(t,2H), δ3.48-3.40(m,1H), δ2.96(t,2H ), δ2.49-2.43(m,2H), δ2.11-2.03(m,2H), δ1.61-1.40(m,6H), δ1.38-1.10(br.m,20H), δ0.96-0.84(m,6H), δ0.25(d,6H)

[0629] Example 80

[0630] Synthesis of 10-bromo-3-((8Z,11Z)-heptadeca-8,11-dien-1-yl)-5,5-dimethyl-2,4,6-trioxa-5-siladecane

[0631]

[0632] 10-Bromo-3-((8Z,11Z)-heptadeca-8,11-dien-1-yl)-5,5-dimethyl-2,4,6-trioxa-5-siladecane was prepared from methyl (9Z,12Z)-octadeca-9,12-dienoate (395.00 mg, 1.341 mmol) and ((4-bromobutyl)oxy)dimethylsilane (311.59 mg, 1.476 mmol, 1.1 equiv) using 100 μl of BrF(F3s)2 borane catalyst solution (6.00 mg dissolved in 100 μl of anhydrous toluene) according to General Procedure E. The reaction was complete after stirring overnight. The crude product was purified by flash column chromatography with gradient elution (0-100% EtOAc in n-hexane) to give 10-bromo-3-((8Z,11Z)-heptadeca-8,11-dien-1-yl)-5,5-dimethyl-2,4,6-trioxa-5-siladecane (390 mg, 0.77 mmol, 58% yield) as a clear oil.

[0633] 1 H NMR (500MHz, benzene-d6) δ5.53-5.40(m,4H), δ4.77(t,1H), δ3.52(t,2H), δ3.24(s,3H), δ3.01(t,2H), δ2.87(t ,2H),δ2.12-2.01(m,4H),δ1.85-1.61(m,2H),δ1.53-1.07(br.m,20H),δ0.94-0.79(m,3H),δ0.15(s,6H)

[0634] Chromatographic methods for purification of lipids and intermediates

[0635] Purification Method A

[0636] Eluent A: DCM:MeOH:aq.NH3 80:20:1, Eluent B: DCM; Full gradient A:B 0:100 -> 100:0. Sample load ~200 mg; Column size: 25 g SiO2. Before loading the sample, condition the column with ~400 mL of A and then ~400 mL of B.

[0637] Purification Method B

[0638] Eluent A: EtOAc, Eluent B: Petroleum ether + 1% Et3N; Full gradient A:B 0:100 -> 100:0. Sample load ~200 mg; Column size: 25 g SiO2. Condition the column with ~400 mL of B before loading the sample.

[0639] Synthetic methods for the synthesis of intermediates and lipids (General Procedure GP)

[0640] General Procedure G

[0641] The MW reaction flask is equipped with 1.0 equivalents of ω-bromoalkylsilyl mixed acetal and 1.0 equivalents of amine, anhydrous acetonitrile (acetal / 1.54ml anhydrous acetonitrile of 1.0mmolω-bromoalkylsilyl mixed) and anhydrous cyclopentyl methyl ether (acetal / 0.51ml anhydrous cyclopentyl methyl ether of 1.0mmolω-bromoalkylsilyl mixed).To the reaction mixture that stirs, add K CO (2.0 equivalents) and KI (0.5 equivalent), and use argon purge and seal.The mixture that obtains was stirred 8 hours at 80 ℃.Then the reaction mixture is cooled to room temperature, and distributed between ethyl acetate and salt solution, then stirred violently 15 minutes.Organic phase separation and Na SO Upper drying, filtration and concentration.

[0642] General Procedure H

[0643] The MW reaction flask was charged with 2.5 equivalents of ω-bromoalkylsilyl mixed acetals and 1.0 equivalent of amine, 2.5 equivalents of diisopropylethylamine, and anhydrous ethanol (1.0 mmol of ω-bromoalkylsilyl mixed acetals / 2.4 ml of anhydrous ethanol) and purged with argon and sealed. The resulting mixture was stirred at 63°C for 18 hours. The reaction mixture was then cooled to room temperature and distributed between ethyl acetate and saline, and then stirred vigorously for 15 minutes. The organic phase was separated and dried over Na2SO4, filtered, and concentrated.

[0644] General Procedure I

[0645] The acetal of 2.5 equivalents of ω-bromoalkylsilyl mixing and 1.0 equivalents of amine, anhydrous acetonitrile (acetal of 1.0mmolω-bromoalkylsilyl mixing / 0.95ml anhydrous acetonitrile) and anhydrous cyclopentyl methyl ether (acetal of 1.0mmolω-bromoalkylsilyl mixing / 0.31ml anhydrous cyclopentyl methyl ether) are housed in the MW reaction flask. To the stirred reaction mixture, add K CO (3.0 equivalents) and KI (0.2 equivalents), and purge and seal with argon. The mixture obtained was stirred at 60 ℃ for 18 hours. The reaction mixture was then cooled to room temperature and distributed between ethyl acetate and salt solution, then stirred vigorously for 15 minutes. The organic phase was separated and at Na SO Upper drying, filtration and concentration.

[0646] General ProcedureJ

[0647] 1.0 equivalent of acetaldehyde, 1.0 equivalent of amine, 1.0 equivalent of acetic acid and anhydrous toluene (1.0mmol aldehyde / 6.5ml anhydrous toluene) are housed in the MW reaction flask. After stirring for 15 minutes, 3.0 equivalents of sodium triacetoxyborohydride are added, and the resulting mixture is stirred overnight. Then use ethyl acetate and NaHCO solution dilution reaction mixture, and vigorously stir 5 minutes, and carry out phase separation. Organic phase salt water washing is separated and Na SO upper drying, filter and concentrate.

[0648] General Procedure K

[0649] The acetal that ω-bromoalkylsilyl mixes, amine, anhydrous acetonitrile (acetal that 1.0mmol ω-bromoalkylsilyl mixes / 4.0ml anhydrous acetonitrile) and anhydrous cyclopentyl methyl ether (acetal that ω-bromoalkylsilyl mixes / 1.33ml anhydrous cyclopentyl methyl ether) are housed in the MW reaction flask.Add K to the reaction mixture that stirs CO (2.0 equivalents) and KI (0.2 equivalents), and purge and seal with argon.The mixture that obtains is stirred 18 hours at 62 ℃.Then the reaction mixture is cooled to room temperature, and distributed between ethyl acetate and salt solution, then stirred violently 15 minutes.Organic phase is separated and at Na SO Upper drying, filter and concentrate.

[0650] General Procedure

[0651] The acetal that 1.0 equivalents of ω-bromoalkylsilyl mixes, 2.0 equivalents of amine, 2.0 equivalents of K are housed in the MW reaction flask CO And absolute ethanol (acetal / 0.32ml absolute ethanol that 1.0mmol ω-bromoalkylsilyl mixes), and use argon purging and sealing.The mixture that obtains is at room temperature stirred overnight.Then reaction mixture is distributed between ethyl acetate and salt solution, and violently stirred 15 minutes.Organic phase separation and Na SO Upper drying, filtration and concentration.

[0652] General Procedures

[0653] The MW reaction flask was charged with 1.0 equivalents of a mixed silyl acetal, 3.0 equivalents of an amine, tetrahydrofuran (1.0 mmol of mixed silyl acetal / 4.5 ml of tetrahydrofuran) and water (1.0 mmol of mixed silyl acetal / 0.9 ml of water). 3.0 equivalents of trifluoroacetic acid were added to the reaction mixture and stirred for 6 hours. 2.3 equivalents of sodium triacetoxyborohydride were then added to the reaction mixture and stirred overnight at 60° C. The reaction mixture was cooled to room temperature, diluted with a saturated NaHCO solution, and extracted with ethyl acetate. The organic phase was washed with salt water, separated and dried over Na SO , filtered, and concentrated.

[0654] General Procedure N

[0655] A MW reaction flask was charged with 1.0 equivalent of an ω-bromoalkyl ester, an amine, 0.2 equivalent of KI, 2.2 equivalents of KCO, and anhydrous DMF (1.0 mmol of ω-bromoalkyl ester / 8.73 ml of anhydrous DMF), purged with argon, and sealed. The resulting mixture was stirred at 63°C for 18 hours. The reaction mixture was then cooled to room temperature, diluted with a saturated NaHCO solution, and extracted with ethyl acetate. The organic phase was washed with a saturated NaHCO solution, brine, separated, dried over NaSO, filtered, and concentrated.

[0656] General Procedure

[0657] A MW reaction flask was charged with 2.5 equivalents of ω-bromoalkylsilyl mixed acetal, 1.0 equivalent of amine, 3.0 equivalents of KCO, 0.2 equivalents of KI, and anhydrous DMF (1.0 mmol of ω-bromoalkylsilyl mixed acetal / 2.6 ml of anhydrous DMF), purged with argon, and sealed. The resulting mixture was stirred at 64°C for 24 h. The reaction mixture was then concentrated to dryness under vacuum, and the residue was purified by flash column chromatography.

[0658] General Procedures

[0659] A MW reaction flask was charged with 1.0 equivalent of a propargylamine derivative, 1.5 equivalents of an azide derivative, 0.33 equivalents of CuBr, 0.33 equivalents of 1,1,4,7,7-pentamethyldiethylenetriamine, and anhydrous DMF (0.1 mmol of propargylamine derivative / 3.0 ml of anhydrous DMF), purged with argon, and sealed. The resulting mixture was stirred at 50°C for 20 h. The reaction mixture was then concentrated to dryness under vacuum, and the residue was purified by flash column chromatography.

[0660] Examples of intermediate synthesis

[0661] Example 81

[0662] Synthesis of 4-((6-((dimethyl(octyl)silyl)oxy)-6-(octyloxy)hexyl)amino)butan-1-ol

[0663]

[0664] 4-((6-((dimethyl(octyl)silyl)oxy)-6-(octyloxy)hexyl)amino)butan-1-ol was prepared from ((6-bromo-1-(octyloxy)hexyl)oxy)dimethyl(octyl)silane (300.0 mg, 0.625 mmol, 1.0 equiv) and 4-amino-1-butanol (1115.01 mg, 12.51 mmol, 20.0 eq) according to General Procedure L. The crude product was purified by flash column chromatography according to Purification Method A to give the pure product as a colorless oil, 100.0 mg, 0.205 mmol, 33% yield.

[0665] 1 H NMR (500MHz, benzene-d6) δ4.89(t,1H), δ3.78-3.73(m,1H), δ3.65-3.62(m,2H), δ3.39-3.34(m,1H), δ2.31-2.27(m,4H), δ1.83-1.20(m,36H), δ0.94-0.88(m,6H), δ0.76-0.72(m,2H), δ0.26(d,6H)

[0666] Example 82

[0667] Synthesis of 13-heptyl-15,15-dimethyl-12,14-dioxa-5-aza-15-silatricosan-1-ol

[0668]

[0669] 13-Heptyl-15,15-dimethyl-12,14-dioxa-5-aza-15-silatricosan-1-ol was prepared from ((1-((6-bromohexyl)oxy)octyl)oxy)dimethyl(octyl)silane (300.0 mg, 0.625 mmol, 1.0 equiv) and 4-amino-1-butanol (1115.01 mg, 12.51 mmol, 20.0 equiv) according to General Procedure L. The crude product was purified by flash column chromatography according to Purification Method A to obtain the pure product as a colorless oil, 95.0 mg, 0.195 mmol, 31% yield.

[0670] 1 H NMR (500MHz, benzene-d6) δ4.89(t,1H), δ3.77-3.71(m,1H), δ3.64-3.61(m,2H), δ3.39-3.32(m,1H), δ2.30-2.29(m,4H), δ1.87-1.18(m,36H), δ0.92-0.88(m,6H), δ0.75-0.71(m,2H), δ0.25(d,6H)

[0671] Example 83

[0672] Synthesis of 4-((6-(octyloxy)-6-((1,1,3,3-tetramethyl-3-(octyloxy)disiloxanyl)oxy)hexyl)amino)butan-1-ol

[0673]

[0674] 4-((6-(octyloxy)-6-((1,1,3,3-tetramethyl-3-(octyloxy)disiloxanyl)oxy)hexyl)amino)butan-1-ol was prepared from 1-((6-bromo-1-(octyloxy)hexyl)oxy)-1,1,3,3-tetramethyl-3-(octyloxy)disiloxane (100.00 mg, 0.175 mmol, 1.0 equiv) and 4-amino-1-butanol (312.87 mg, 3.509 mmol, 20.0 equiv) according to General Procedure L. The crude product was purified by flash column chromatography according to Purification Method A to give the pure product as a colorless oil, 75.0 mg, 0.130 mmol, 74% yield.

[0675] 1 H NMR (500MHz, benzene-d6) δ5.03(t,1H), δ3.93-3.84(m,1H), δ3.78-3.75(t,2H), δ3.64-3.61(m,2H), δ3.49- 3.35(m,1H),δ2.36-2.25(m,4H),δ1.93-1.17(m,36H),δ0.92-0.88(m,6H),δ0.31(d,6H),δ0.25(s,6H)

[0676] Example 84

[0677] Synthesis of 15-heptyl-13,13-dimethyl-12,14,16-trioxa-5-aza-13-silanotetracosan-1-ol

[0678]

[0679] 15-Heptyl-13,13-dimethyl-12,14,16-trioxa-5-aza-13-silanetetaracon-1-ol was prepared from 1-bromo-10-heptyl-8,8-dimethyl-7,9,11-trioxa-8-silanonadecane (500.0 mg, 1.010 mmol, 1.0 equiv) and 4-amino-1-butanol (1.798 g, 20.175 mmol, 20.0 equiv) according to General Procedure L. The crude product was purified by flash column chromatography according to Purification Method A to obtain the pure product as a colorless oil, 200.0 mg, 0.397 mmol, 40% yield.

[0680] 1 H NMR (500MHz, benzene-d6) δ5.01(t,1H), δ3.93-3.79(m,1H), δ3.75(t,2H), δ3.61(t,1H), δ3.44 -3.40(m,2H),δ2.32-2.27(m,2H),δ1.96-1.14(m,38H),δ0.93-0.87(m,6H),δ0.28(d,6H)

[0681] Example 85

[0682] Synthesis of 4-(((5Z,8Z,11Z,14Z,17Z)-eicosyl-5,8,11,14,17-pentaen-1-yl)amino)butan-1-ol

[0683]

[0684] 4-(((5Z,8Z,11Z,14Z,17Z)-Eicosa-5,8,11,14,17-pentaen-1-yl)amino)butan-1-ol was prepared from (((5Z,8Z,11Z,14Z,17Z)-1-ethoxyeicosa-5,8,11,14,17-pentaen-1-yl)oxy)triethylsilane (1478.20 mg, 3.309 mmol, 1.0 equiv) and 4-amino-1-butanol (884.74 mg, 9.925 mmol, 3.0 equiv) according to General Procedure M. The crude product was purified by flash column chromatography according to Purification Method A to afford the pure product as a colorless oil, 983.0 mg, 2.734 mmol, 83% yield.

[0685] 1 H NMR (500MHz, CDCl3) δ5.43-5.27 (m, 10H), δ3.98 (broad s,2H),δ3.57(m,2H),δ2.88-2.76(m,8H),δ2.68-2.61(m,4H),δ2.12-2.03(m, 4H), δ1.71-1.60(m,4H), δ1.57-1.48(m,2H), δ1.43-1.35(m,2H), δ0.97(t,3H)

[0686] Example 86

[0687] Synthesis of 6-((4-hydroxybutyl)amino)hexyl 2-hexyldecanoate

[0688]

[0689] 6-((4-Hydroxybutyl)amino)hexyl 2-hexyldecanoate was prepared from 6-ethoxy-6-((triethylsilyl)oxy)hexyl 2-hexyldecanoate (1488.4 mg, 2.891 mmol, 1.0 equiv) and 4-amino-1-butanol (772.99 mg, 8.672 mmol, 3.0 equiv) according to General Procedure M. The crude product was purified by flash column chromatography according to Purification Method A to give the pure product as a colorless oil, 1056 mg, 2.469 mmol, 85% yield.

[0690] 1 H NMR (500MHz, CDCl3) δ4.05(t,2H), δ3.56(m,2H), δ2.65-2.58(m,4H), δ2.33-2.26(m,1H), δ1.70-1.19(m,36H), δ0.88-0.85(dt,6H)

[0691] Example 87

[0692] Synthesis of 6-((3-hydroxypropyl)amino)hexyl 2-hexyldecanoate

[0693]

[0694] 6-((3-Hydroxypropyl)amino)hexyl 2-hexyldecanoate was prepared from 6-ethoxy-6-((triethylsilyl)oxy)hexyl 2-hexyldecanoate and 3-aminopropanol (656.43 mg, 8.740 mmol, 3.0 equiv) according to General Procedure M. The crude product was purified by flash column chromatography according to Purification Method A to give the pure product as a colorless oil, 1265.0 mg, 1.651 mmol, 57% yield.

[0695] 1 H NMR (500MHz, CDCl3) δ4.03(t,2H), δ3.79(t,2H), δ2.92(t,2H), δ2.35-2.25(m,1H), δ1.95-1.90(t,2H), δ1.74-1.18(m,34H), δ0.86(t,6H)

[0696] Example 88

[0697] Synthesis of 6-((2-hydroxyethyl)amino)hexyl 2-hexyldecanoate

[0698]

[0699] 6-((2-Hydroxyethyl)amino)hexyl 2-hexyldecanoate was prepared from 6-ethoxy-6-((triethylsilyl)oxy)hexyl 2-hexyldecanoate (1000 mg, 1.942 mmol, 1.0 equiv) and 2-amino-1-ethanol (355.9 mg, 5.827 mmol, 3.0 equiv) according to General Procedure M. The crude product was purified by flash column chromatography according to Purification Method A to give the pure product as a colorless oil, 590.0 mg, 1.476 mmol, 76% yield.

[0700] 1 H NMR (500MHz, CDCl3) δ4.04(t,2H), δ3.86(t,2H), δ3.08-3.05(m,2H), δ2.95(t,2H), δ2.34-2.24(m,1H), δ1.77-1.12(m,32H), δ0.86(t,6H)

[0701] Example 89

[0702] Synthesis of 6-((2-(1-methylpyrrolidin-2-yl)ethyl)amino)hexyl 2-hexyldecanoate

[0703]

[0704] 6-((2-(1-Methylpyrrolidin-2-yl)ethyl)amino)hexyl 2-hexyldecanoate was prepared from 6-ethoxy-6-((triethylsilyl)oxy)2-hexyl 2-hexyldecanoate (850 mg, 1.651 mmol, 1.0 equiv) and 2-(1-methylpyrrolidin-2-yl)-ethan-1-amine (634.98 mg, 4.953 mmol, 3.0 equiv) according to General Procedure M. The crude product was purified by flash column chromatography according to Purification Method A to give the pure product as a colorless oil, 120.0 mg, 0.257 mmol, 16% yield.

[0705] 1 H NMR (500MHz, CDCl3) δ4.03(t,2H), δ3.27-3.22(m,1H), δ3.01-2.87(m,2H), δ2.82-2.75(m,1H), δ2.54(s ,3H),δ2.49-2.43(m,1H),δ2.33-2.25(m,2H),δ2.16-2.07(m,1H),δ2.04-1.17(br.m,38H),δ0.86(t,6H)

[0706] Example 90

[0707] Synthesis of 6-((4-hydroxybutyl)amino)hexyl 2-(pentylthio)decanoate

[0708]

[0709] 6-((4-Hydroxybutyl)amino)hexyl 2-(pentylthio)decanoate was prepared from 6-methoxy-6-(triethylsilyl)oxy)hexyl 2-(pentylthio)decanoate (1500.00 mg, 2.891 mmol, 1.0 equiv) and 4-amino-1-butanol (772.99 mg, 8.672 mmol, 3.0 equiv) according to General Procedure M. The crude product was purified by flash column chromatography according to Purification Method A to give the pure product as a colorless oil, 1123.0 mg, 2.519 mmol, 87% yield.

[0710] 1 H NMR (500MHz, CDCl3) δ4.11(t,2H), δ3.56(t,2H), δ3.22-3.19(m,1H), δ2.65 -2.42(m,6H),δ1.89-1.80(m,1H),δ1.70-1.16(m,31H),δ0.90-0.85(dt,6H)

[0711] Example 91

[0712] Synthesis of 6-((4-hydroxybutyl)amino)hexyl 2-(decylthio)hexanoate

[0713]

[0714] 6-((4-Hydroxybutyl)amino)hexyl 2-(decylthio)hexanoate was prepared from 6-methoxy-6-((triethylsilyl)oxy)hexyl 2-(decylthio)hexanoate (400.00 mg, 0.751 mmol, 1.0 equiv) and 4-amino-1-butanol (200.71 mg, 2.252 mmol, 3.0 equiv) according to General Procedure M. The crude product was purified by flash column chromatography according to Purification Method A to give the pure product as a colorless oil, 211.0 mg, 0.459 mmol, 61% yield.

[0715] 1 H NMR (500MHz, CDCl3) δ4.12(t,2H), δ3.56(m,2H), δ3.22-3.19(m,1H), δ2.66 -2.51(m,6H),δ1.90-1.81(m,1H),δ1.70-1.20(m,33H),δ0.91-0.86(dt,6H)

[0716] Example 92

[0717] Synthesis of 4-(((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)pentyl)amino)butan-1-ol

[0718]

[0719] 4-(((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)pentyl)amino)butan-1-ol was prepared from triethyl(((4R)-1-methoxy-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)pentyl)oxy)silane (237.00 mg, 0.455 mmol, 1.0 equiv) and 4-amino-1-butanol (121.67 mg, 1.365 mmol, 3.0 equiv) according to General Procedure M. The crude product was purified by flash column chromatography according to Purification Method A to afford the pure product as a colorless oil, 178.0 mg, 0.398 mmol, 87% yield.

[0720] 1 H NMR (500MHz, CDCl3) δ4.62(m,1H), δ3.76(s,3H), δ3.57(t,2H), δ2.66-2.63(m, 2H), δ2.61-2.49(m,2H), δ1.97-1.02(m,32H), δ0.92-0.89(m,6H), δ0.63(s,3H)

[0721] Example 93

[0722] Synthesis of 4-((4-hydroxybutyl)amino)butyl (4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)valerate

[0723]

[0724] 4-((4-Hydroxybutyl)amino)butyl (4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanoate was prepared from 4-chlorobutyl (4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanoate (237.00 mg, 0.455 mmol, 1.0 equiv) and 4-aminobutanol (121.67 mg, 1.365 mmol, 3.0 equiv) according to General Procedure K. The crude product was purified by flash column chromatography according to Purification Method A to afford the pure product as a colorless oil, 194.0 mg, 0.364 mmol, 80% yield.

[0725] 1 H NMR (500MHz, CDCl3) δ4.05(m,2H), δ3.60(t,2H), δ3.35(s,3H), δ3.18-3.11(m,1H), δ2.90-2.85(q,2H), δ2.80-2.71(q,3H), δ2.36-2.29(m,1H), δ2.22-2.14(m,1H), δ1.93-1.50(br.m,16H), δ1.44-0.88(br.m,18H), δ0.90-0.88(m,6H), δ0.62(s,3H)

[0726] Example 94

[0727] Synthesis of Undecyl 6-((2-Hydroxyethyl)amino) Hexanoate

[0728]

[0729] Undecyl 6-((2-hydroxyethyl)amino)hexanoate was prepared from undecyl 6-bromohexanoate (1000.00 mg, 2.862 mmol, 1.0 equiv) and 2-amino-1-ethanol (192.33 mg, 3.148 mmol, 1.1 equiv) according to General Procedure N. The crude product was purified by flash column chromatography according to Purification Method A to give the pure product as a colorless oil, 350.0 mg, 1.062 mmol, 37% yield.

[0730] 1H NMR (500MHz, CDCl3) δ4.04(t,2H), δ3.63(m,2H), δ2.76(m,2H), δ2.61(t,2H), δ2.29(t,2H), δ2.09(broad s,2H),δ1.67-1.57(m,4H),δ1.54-1.47(m,2H),δ1.39-1.22(m,18H),δ0.87(t,3H)

[0731] Example 95

[0732] Synthesis of Undecyl 6-((4-hydroxybutyl)amino)hexanoate

[0733]

[0734] Undecyl 6-((4-hydroxybutyl)amino)hexanoate was prepared from undecyl 6-bromohexanoate (1124.21 mg, 3.218 mmol, 1.0 equiv) and 4-amino-1-butanol (5737.05 mg, 64.36 mmol, 20 equiv) according to General Procedure N. The crude product was purified by flash column chromatography according to Purification Method A to give the pure product as a thick yellow oil, 969.0 mg, 2.607 mmol, 81% yield.

[0735] 1 H NMR (500MHz, CDCl3) δ4.03(t,2H), δ3.57(t,2H), δ2.71-2.63(m,4H), δ2.29(t,2H), δ1.69-1.52(m,10H), δ1.40-1.19(m,18H), δ0.86(t,3H)

[0736] Example 96

[0737] Synthesis of Heptadecan-9-yl 8-((2-hydroxyethyl)amino)octanoate

[0738]

[0739] Heptadecan-9-yl 8-((2-hydroxyethyl)amino)octanoate was prepared from heptadecan-9-yl 8-bromooctanoate (200.00 mg, 0.412 mmol, 1.0 equiv) and 2-amino-1-ethanol (27.66 mg, 0.453 mmol, 1.1 equiv) according to General Procedure N. The crude product was purified by flash column chromatography according to Purification Method A to give the pure product as a colorless oil, 100.0 mg, 0.226 mmol, 55% yield.

[0740] 1H NMR (500MHz, CDCl3) δ4.89-4.83(m,1H), δ3.62(s,2H), δ2.78-2.75(m,2H), δ2.60(t,2H), δ2.27(t,2H), δ1.65-1.56(m,2H), δ1.53-1.41(m,6H), δ1.36-1.16(m,30H), δ0.87(t,6H)

[0741] Example 97

[0742] Synthesis of Heptadecan-9-yl 8-((4-hydroxybutyl)amino)octanoate

[0743]

[0744] Heptadecan-9-yl 8-((4-hydroxybutyl)amino)octanoate was prepared from heptadecan-9-yl 8-bromooctanoate (950 mg, 1.841 mmol, 1.0 equiv) and 4-amino-1-butanol (3.28 g, 36.83 mmol, 20 equiv) according to General Procedure L. The crude product was purified by flash column chromatography according to Purification Method A to give the pure product as a colorless oil, 865.0 mg, 1.28 mmol, 69% yield.

[0745] 1 H NMR (500MHz, CDCl3) δ5.19(m,1H), δ3.80-3.76(m,2H), δ3.48-3.40(m,2H), δ2.61 (t,2H),δ2.51(t,2H),δ2.28(t,2H),δ1.83-1.10(br.m,40H),δ0.98-0.91(m,6H)

[0746] Example 98

[0747] Synthesis of 6-((Dimethyl(octyl)silyl)oxy)-6-(octyloxy)-N-(prop-2-yn-1-yl)hexane-1-amine

[0748]

[0749] The MW reaction flask was equipped with ((6-bromo-1-(octyloxy) hexyl) oxygen base) dimethyl (octyl) silane (400 mg, 0.834 mmol, 1.0 eq), propargylamine hydrochloride (381.69 mg, 0.834 mmol, 1.0 eq), K CO (806.79 mg, 5.838 mmol, 7.0 eq), KI (13.84 mg, 0.083 mmol, 0.1 equivalent), 1.5 ml of anhydrous acetonitrile and 1.0 ml of cyclopentyl methyl ether, and purged and sealed with argon. The resulting mixture was stirred at 62 ° C for 18 hours. The reaction mixture was then cooled to room temperature and distributed between ethyl acetate and salt solution, and then stirred vigorously for 15 minutes. The organic phase was separated and dried over Na SO, filtered and concentrated. According to purification method B, the crude product was purified by flash column chromatography to obtain the pure product as a colorless oil, 260 mg, 0.573 mmol, 69% yield.

[0750] 1H NMR (500MHz, benzene-d6) δ4.85(t,1H), δ3.77-3.72(q,1H), δ3.39-3.34(q,1H), δ3.16(d,2H), δ2.50( t,2H),δ1.93(t,1H),δ1.83-1.16(m,32H),δ0.94-0.88(m,6H),δ0.75-0.71(m,2H),δ0.24(d,6H)

[0751] Example 99

[0752] Synthesis of 6-((dimethyl(octyl)silyl)oxy)-N-(6-((dimethyl(octyl)silyl)oxy)-6-(octyloxy)hexyl)-6-(octyloxy)-N-(prop-2-yn-1-yl)hexane-1-amine

[0753]

[0754] A MW reaction flask was charged with ((6-bromo-1-(octyloxy)hexyl)oxy)dimethyl(octyl)silane (431.22 mg, 0.899 mmol, 1.2 eq), 6-((dimethyl(octyl)silyl)oxy)-6-(octyloxy)-N-(prop-2-yn-1-yl)hexane-1-amine (340.00 mg, 0.749 mmol, 1.0 eq), KCO (207.09 mg, 1.499 mmol, 2.0 eq), KI (12.44 mg, 0.075 mmol, 0.1 eq), 1.5 ml of anhydrous acetonitrile and 0.5 ml of cyclopentyl methyl ether, purged with argon and sealed. The resulting mixture was stirred at 62° C. for 24 hours. The reaction mixture was then cooled to room temperature and partitioned between ethyl acetate and brine, then stirred vigorously for 15 minutes. The organic phase was separated and dried over Na2SO4, filtered and concentrated.The crude product was purified by flash column chromatography according to purification method B to obtain the pure product as a colorless oil, 530 mg, 0.622 mmol, 83% yield.

[0755] 1 H NMR (500MHz, benzene-d6) δ4.87(t,2H), δ3.79-3.72(q,2H), δ3.42-3.34(q,2H), δ3.32(d,2H), δ2.51(t ,4H),δ1.92(t,1H),δ1.88-1.17(m,64H),δ0.95-0.89(m,12H),δ0.75-0.71(m,4H),δ0.25(d,12H)

[0756] Example 100

[0757] Synthesis of 6-(octyloxy)-N-(6-(octyloxy)-6-((1,1,3,3-tetramethyl-3-octyldisiloxanyl)oxy)hexyl)-N-(prop-2-yn-1-yl)-6-((1,1,3,3-tetramethyl-3-octyldisiloxanyl)oxy)hexane-1-amine

[0758]

[0759] A MW reaction flask was charged with 1-((6-bromo-1-(octyloxy)hexyl)oxy)-1,1,3,3-tetramethyl-3-octyldisiloxane (453.74 mg, 0.819 mmol, 2.5 eq), propargylamine hydrochloride (30.00 mg, 0.328 mmol, 1.0 eq), K2CO3 (181.18 mg, 1.311 mmol, 4.0 eq), KI (10.88 mg, 0.065 mmol, 0.2 eq), 1.2 ml of anhydrous acetonitrile, and 0.4 ml of cyclopentyl methyl ether, purged with argon, and sealed. The resulting mixture was stirred at 62°C for 18 hours. The reaction mixture was then cooled to room temperature and partitioned between ethyl acetate and brine, then stirred vigorously for 15 minutes. The organic phase was separated and dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash column chromatography according to purification method B to obtain the pure product as a colorless oil, 83 mg, 0.083 mmol, 25% yield.

[0760] 1 H NMR (500 MHz, benzene-d6) δ5.00 (t, 2H), δ3.90-3.83 (q, 2H), δ3.46-3.38 (q, 2H), δ3.33 (d, 2H), δ2.52 (t, 4H), δ1.92-1.17 (m, 65H), δ0.95-0.89 (m, 12H), δ0.71-0.66 (m, 4H), δ0.27 (d, 12H), δ0.22 (s, 12H), Example of lipid synthesis

[0761] Example 101

[0762] Synthesis of 4-(bis(6-((dimethyl(octyl)silyl)oxy)-6-(octyloxy)hexyl)amino)butan-1-ol

[0763]

[0764] ) 4-(Bis(6-((dimethyl(octyl)silyl)oxy)-6-(octyloxy)hexyl)amino)butan-1-ol was prepared from ((6-bromo-1(octyloxy)hexyl)oxy)dimethyl(octyl)silane (93.4 mg, 0.195 mmol, 1.0 equiv) and 4-((6-((dimethyl(octyl)silyl)oxy)-6-(octyloxy)hexyl)amino)butan-1-ol (95 mg, 0.195 mmol, 1.0 equiv) according to General Procedure G. The crude product was purified twice by flash column chromatography according to Purification Methods A and B to afford the pure product as a colorless oil, 70 mg, 0.079 mmol, 40% yield.

[0765] 1H NMR (500MHz, benzene-d6) δ4.88(t,2H), δ3.79-3.72(m,2H), δ3.62(t,2H), δ3.41-3.36(m,2H), δ2.33(t,4 H), δ2.24(t,2H), δ1.77-1.25(m,68H), δ0.94-0.89(m,12H), δ0.76-0.72(m,4H), δ0.26(d,12H); TOF MS ES+[M+H+]:886.8069m / z

[0766] Example 102

[0767] Synthesis of 5-(6-((1-((dimethyl(octyl)silyl)oxy)octyl)oxy)hexyl)-13-heptyl-15,15-dimethyl-12,14-dioxa-5-aza-15-silatricosan-1-ol

[0768]

[0769] 5-(6-((1-((dimethyl(octyl)silyl)oxy)octyl)oxy)hexyl)-13-heptyl-15,15-dimethyl-12,14-dioxa-5-aza-15-silatricosan-1-ol) was prepared from ((1-((6-bromohexyl)oxy)octyl)oxy)dimethyl(octyl)silane (147.47 mg, 0.307 mmol, 1.0 equiv) and 13-heptyl-15,15-dimethyl-12,14-dioxa-5-aza-15-silatricosan-1-ol (150.00 mg, 0.307 mmol, 1.0 equiv) according to General Procedure G. The crude product was purified twice by flash column chromatography according to Purification Methods A and B to afford the pure product as a colorless oil, 100 mg, 0.113 mmol, 37% yield.

[0770] 1 H NMR (500MHz, benzene-d6) δ4.89(t,2H), δ3.79-3.74(m,2H), δ3.63(t,2H), δ3.41-3.35(m,2H), δ2.32(m,4 H), δ2.25(t,2H), δ1.89-1.24(m,68H), δ0.95-0.89(m,12H), δ0.77-0.72(m,4H), δ0.26(d,12H); TOF MS ES+[M+H+]:886.8039m / z

[0771] Example 103

[0772] Synthesis of 4-(bis(6-(decyloxy)-6-((hexyldimethylsilyl)oxy)hexyl)amino)butan-1-ol

[0773]

[0774] 4-(Bis(6-(decyloxy)-6-((hexyldimethylsilyl)oxy)hexyl)amino)butan-1-ol was prepared from ((6-bromo-1-(decyloxy)hexyl)oxy)(hexyl)dimethylsilane (403.27 mg, 0.841 mmol, 2.5 equiv) and 4-amino-1-butanol (29.98 mg, 0.336 mmol, 1.0 equiv) according to General Procedure H. The crude product was purified twice by flash column chromatography according to Purification Methods A and B to afford the pure product as a colorless oil, 45 mg, 0.051 mmol, 15% yield.

[0775] 1 H NMR (500MHz, benzene-d6) δ4.89(t,2H), δ3.80-3.74(m,2H), δ3.63(t,2H), δ3.43-3.36(m,2H), δ2.35-2.31(m ,4H), δ2.25(t,2H), δ1.89-1.26(m,68H), δ0.96-0.91(m,12H), δ0.76-0.71(m,4H), δ0.25(d,12H); TOF MS ES+[M+H+]:886.8082m / z

[0776] Example 104

[0777] Synthesis of 5-(6-((1-((hexyldimethylsilyl)oxy)decyl)oxy)hexyl)-15,15-dimethyl-13-nonyl-12,14-dioxa-5-aza-15-silaheneicosan-1-ol

[0778]

[0779]

[0266] 5-(6-((1-((Hexyldimethylsilyl)oxy)decyl)oxy)hexyl)-15,15-dimethyl-13-nonyl-12,14-dioxa-5-aza-15-silannegocan-1-ol was prepared from ((1-((6-bromohexyl)oxy)decyl)oxy)(hexyl)dimethylsilane (403.27 mg, 0.841 mmol, 2.5 equiv) and 4-amino-1-butanol (30.00 mg, 0.336 mmol, 1.0 equiv) according to General Procedure H. The crude product was purified by flash column chromatography according to Purification Method A to afford the pure product as a colorless oil, 45 mg, 0.051 mmol, 15% yield, and 53 mg, 0.060 mmol, 18% yield.

[0780] 1 H NMR (500MHz, benzene-d6) δ4.89(t,2H), δ3.78-3.73(m,2H), δ3.63(t,2H), δ3.41-3.35(m,2H), δ2.34-2.30(m ,4H), δ2.25(t,2H), δ1.89-1.23(m,68H), δ0.96-0.90(m,12H), δ0.75-0.70(m,4H), δ0.25(d,12H); TOF MS ES+[M+H+]:886.8081m / z

[0781] Example 105

[0782] Synthesis of 5-(6-((dimethyl(octyloxy)silyl)oxy)-6-(octyloxy)hexyl)-13,13-dimethyl-11-(octyloxy)-12,14-dioxa-5-aza-13-siladocosan-1-ol

[0783]

[0784] 5-(6-((dimethyl(octyloxy)silyl)oxy)-6-(octyloxy)hexyl)-13,13-dimethyl-11-(octyloxy)-12,14-dioxa-5-aza-13-siladocosan-1-ol was prepared from 12-(5-bromopentyl)-10,10-dimethyl-9,11,13-trioxa-10-silaneconecan (416.72 mg, 0.841 mmol, 2.5 equiv) and 4-amino-1-butanol (29.98 mg, 0.336 mmol, 1.0 equiv) according to General Procedure I. The crude product was purified by flash column chromatography according to Purification Method B to afford the pure product as a colorless oil, 187 mg, 0.204 mmol, 61% yield. 1H NMR (500MHz, benzene-d6) δ5.01(dt,2H), δ3.89-3.84(m,2H), δ3.77(t,4H), δ3.62(t,2H), δ3.46-3.38(m,3H), δ2 TOF MS ES+[M+H+]:918.7984m / z

[0785] Example 106

[0786] Synthesis of 13-heptyl-5-(8-heptyl-10,10-dimethyl-7,9,11-trioxa-10-silanonadecyl)-15,15-dimethyl-12,14,16-trioxa-5-aza-15-silanetetaracon-1-ol

[0787]

[0788] 13-Heptyl-5-(8-heptyl-10,10-dimethyl-7,9,11-trioxa-10-silanonadecane)-15,15-dimethyl-12,14,16-trioxa-5-aza-15-silanetetracosan-1-ol was prepared from 1-bromo-8-heptyl-10,10-dimethyl-7,9,11-trioxa-10-silanonadecane (416.72 mg, 0.840 mmol, 2.5 equiv) and 4-amino-1-butanol (29.98 mg, 0.336 mmol, 1.0 equiv) according to General Procedure I. The crude product was purified by flash column chromatography according to Purification Method B to afford the pure product as a colorless oil, 146 mg, 0.159 mmol, 47% yield.

[0789] 1 H NMR (500MHz, benzene-d6) δ5.00(dt,2H), δ3.89-3.84(m,2H), δ3.79(t,4H), δ3.63(t,2H), δ3.45-3.38(m,2H), δ2.34 -2.30(t,4H),δ2.25(t,2H),δ1.96-1.79(m,4H),δ1.73-1.22(m,64H)δ0.94-0.89(m,12H),δ0.30(d,12H); TOF MS ES+[M+H+]:918.7991m / z

[0790] Example 107

[0791] Synthesis of 4-(bis(6-(octyloxy)-6-((1,1,3,3-tetramethyl-3-octyldisiloxanyl)oxy)hexyl)amino)butan-1-ol

[0792]

[0793] 4-(Bis(6-(octyloxy)-6-((1,1,3,3-tetramethyl-3-octyldisiloxanyl)oxy)hexyl)amino)butan-1-ol was prepared from 1-((6-bromo-1-(octyloxy)hexyl)oxy)-1,1,3,3-tetramethyl-3-octyldisiloxane (465.62 mg, 0.841 mmol, 2.5 equiv) and 4-amino-1-butanol (29.98 mg, 0.336 mmol, 1.0 equiv) according to General Procedure H. The crude product was purified by flash column chromatography according to Purification Method A to give the pure product as a colorless oil, 87 mg, 0.084 mmol, 25% yield.

[0794] 1 H NMR (500MHz, benzene-d6) δ5.01(dt,2H), δ3.91-3.84(m,2H), δ3.61(t,2H), δ3.45-3.41(m,2H), δ2.35-2.32(t,4H), δ2.25(t,2 TOF MSES + [M+H + ]:1034.8458m / z

[0795] Example 108

[0796] Synthesis of 13-heptyl-15,15,17,17-tetramethyl-5-(6-((1-((1,1,3,3-tetramethyl-3-octyldisiloxanyl)oxy)octyl)oxy)hexyl)-12,14,16-trioxa-5-aza-15,17-disilopentacosan-1-ol

[0797]

[0798] 13-Heptyl-15,15,17,17-tetramethyl-5-(6-((1-((1,1,3,3-tetramethyl-3-octyldisiloxanyl)oxy)octyl)oxy)hexyl)-12,14,16-trioxa-5-aza-15,17-disilapentacosan-1-ol was prepared from 1-((1-((6-bromohexyl)oxy)octyl)oxy)-1,1,3,3-tetramethyl-3-octyldisiloxane (465.62 mg, 0.841 mmol, 2.5 equiv) and 4-amino-1-butanol (29.98 mg, 0.336 mmol, 1.0 equiv) according to General Procedure I. The crude product was purified by flash column chromatography according to Purification Method A to afford the pure product as a colorless oil, 237 mg, 0.229 mmol, 66% yield.

[0799] 1 H NMR (500MHz, benzene-d6) δ5.01(dt,2H), δ3.88-3.83(m,2H), δ3.63(t,2H), δ3.45-3.38(m,2H), δ2.42-2.25(m ,6H), δ1.97-1.16(m,67H), δ0.97-0.84(m,13H), δ0.74-0.61(m,4H), δ0.28(d,12H), δ0.22(s,12H); TOF MSES + [M+H + ]:1034.8467m / z

[0800] Example 109

[0801] Synthesis of 4-(bis(6-(octyloxy)-6-((1,1,3,3-tetramethyl-3-(octyloxy)disiloxanyl)oxy)hexyl)amino)butan-1-ol

[0802]

[0803] 4-(Bis(6-(octyloxy)-6-((1,1,3,3-tetramethyl-3-(octyloxy)disiloxanyl)oxy)hexyl)amino)butan-1-ol was prepared from 1-((6-bromo-1-(octyloxy)hexyl)oxy)-1,1,3,3-tetramethyl-3-(octyloxy)disiloxane (319.90 mg, 0.561 mmol, 2.5 equiv) and 4-amino-1-butanol (20.02 mg, 0.225 mmol, 1.0 equiv) according to General Procedure I. The crude product was purified by flash column chromatography according to Purification Method A to give the pure product as a colorless oil, 60 mg, 0.056 mmol, 25% yield.

[0804] 1H NMR (500MHz, benzene-d6) δ5.03(dt,2H), δ3.91-3.85(m,2H), δ3.76(t,4H), δ3.61(t,2H), δ3.47-3.38(m,2H), δ2.35-2.31( TOF MSES + [M+H + ]:1066.8368m / z

[0805] Example 110

[0806] Synthesis of 13-heptyl-15,15,17,17-tetramethyl-5-(6-((1-((1,1,3,3-tetramethyl-3-(octyloxy)disiloxanyl)oxy)octyl)oxy)hexyl)-12,14,16,18-tetraoxa-5-aza-15,17-disilacosacan-1-ol

[0807]

[0808] 13-Heptyl-15,15,17,17-tetramethyl-5-(6-((1-((1,1,3,3-tetramethyl-3-(octyloxy)disiloxanyl)oxy)octyl)oxy)hexyl)-12,14,16,18-tetraoxa-5-aza-15,17-disilacosacon-1-ol) was prepared from 1-((1-((6-bromohexyl)oxy)octyl)oxy)-1,1,3,3-tetramethyl-3-(octyloxy)disiloxane (319.90 mg, 0.561 mmol, 2.5 equiv) and 4-amino-1-butanol (20.02 mg, 0.225 mmol, 1.0 equiv) according to General Procedure I. The crude product was purified by flash column chromatography according to Purification Method A to afford the pure product as a colorless oil, 97 mg, 0.091 mmol, 41% yield.

[0809] 1H NMR (500MHz, benzene-d6) δ5.04(dt,2H), δ3.90-3.84(m,2H), δ3.76(t,4H), δ3.62(t,2H), δ3.48-3.37(m,2H), δ2.34-2.30( m,4H), δ2.25(t,2H)δ1.95-1.80(m,4H), δ1.72-1.21(m,64H), δ0.94-0.87(m,12H), δ0.31(d,12H), δ0.24(s,12H); TOF MS ES+[M+H+]:1066.8358m / z

[0810] Example 111

[0811] Synthesis of 16-hexyl-5-(6-((((2-hexyldecyl)oxy)dimethylsilyl)oxy)-6-(octyloxy)hexyl)-13,13-dimethyl-11-(octyloxy)-12,14-dioxa-5-aza-13-silanotetracosan-1-ol

[0812]

[0813] 16-Hexyl-5-(6-((((2-hexyldecyl)oxy)dimethylsilyl)oxy)-6-(octyloxy)hexyl)-13,13-dimethyl-11-(octyloxy)-12,14-dioxa-5-aza-13-silanetetaracosan-1-ol was prepared from 10-(5-bromopentyl)-15-hexyl-12,12-dimethyl-9,11,13-trioxa-12-tricosane (511.07 mg, 0.841 mmol, 2.5 equiv) and 4-amino-1-butanol (29.98 mg, 0.336 mmol, 1.0 equiv) according to General Procedure I. The crude product was purified by flash column chromatography according to Purification Method B to afford the pure product as a colorless oil, 269 mg, 0.232 mmol, 69% yield.

[0814] 1 H NMR(500MHz, benzene-d6)δ5.02(dt,2H),δ3.91-3.84(m,2H),δ3.75-3.73(d,4H),δ3.61(t,2H),3.48-3.40(m,2H),δ 2.34(t,4H),δ2.26(t,2H),δ1.97-1.76(m,4H),δ1.73-1.18(m,92H),δ0.95-0.89(m,18H),δ0.29(d,12H); TOF MSES + [M 片段 +H +]:918.7993m / z

[0815] Example 112

[0816] Synthesis of 13-heptyl-5-(8-heptyl-13-hexyl-10,10-dimethyl-7,9,11-trioxa-10-silaheneicosyl)-18-hexyl-15,15-dimethyl-12,14,16-trioxa-5-aza-15-silaheneicosane-1-ol

[0817]

[0818] 13-Heptyl-5-(8-heptyl-13-hexyl-10,10-dimethyl-7,9,11-trioxa-10-silaheneicosane)-18-hexyl-15,15-dimethyl-12,14,16-trioxa-5-aza-15-silaheneicosane-1-ol was prepared from 1-bromo-8-heptyl-13-hexyl-10,10-dimethyl-7,9,11-trioxa-10-silaheneicosane (511.46 mg, 0.841 mmol, 2.5 equiv) and 4-amino-1-butanol (30.00 mg, 0.336 mmol, 1.0 equiv) according to General Procedure I. The crude product was purified by flash column chromatography according to Purification Method B to afford the pure product as a colorless oil, 328 mg, 0.283 mmol, 84% yield.

[0819] 1 H NMR(500MHz, benzene-d6)δ5.01(t,2H),δ3.90-3.83(m,2H),δ3.74-3.73(d,4H),δ3.62(t,2H),3.46-3.38(m,2H),δ 2.33(t,4H),δ2.25(t,2H),δ1.94-1.78(m,4H),δ1.72-1.19(m,92H),δ0.95-0.87(m,18H),δ0.29(d,12H); TOF MS ES+[M 片段 +H+]:918.7980m / z

[0820] Example 113

[0821] Synthesis of 5-(6-(dimethyl((1-(octyloxy)octyl)oxy)silyl)hexyl)-14-heptyl-12,12-dimethyl-13,15-dioxa-5-aza-12-silatricosan-1-ol

[0822]

[0823] 5-(6-(Dimethyl((1-(octyloxy)octyl)oxy)silyl)hexyl)-14-heptyl-12,12-dimethyl-13,15-dioxa-5-aza-12-silatricosan-1-ol was prepared from (6-bromohexyl)dimethyl((1-(octyloxy)octyl)oxy)silane (403.58 mg, 0.841 mmol, 2.5 equiv) and 4-amino-1-butanol (30.00 mg, 0.336 mmol, 1.0 equiv) according to General Procedure I. The crude product was purified twice by flash column chromatography according to Purification Methods A and B to afford the pure product as a colorless oil, 97 mg, 0.109 mmol, 32% yield.

[0824] 1 H NMR (500MHz, benzene-d6) δ4.88(m,2H), δ3.79-3.73(m,2H), δ3.64(t,2H), δ3.42-3.35(m,2H), δ2.40-2.36(m,4 H), δ2.31-2.28(m,2H), δ1.89-1.22(m,68H), δ0.93-087(m,12H), δ0.75-0.71(m,4H), δ0.25(d,12H); TOF MSES + [M+H + ]:886.8121m / z

[0825] Example 114

[0826] Synthesis of 15-heptyl-5-(10-heptyl-8,8-dimethyl-7,9,11-trioxa-8-silanonadecyl)-13,13-dimethyl-12,14,16-trioxa-5-aza-13-silanetetaracon-1-ol

[0827]

[0828] 15-Heptyl-5-(10-heptyl-8,8-dimethyl-7,9,11-trioxa-8-silanonadecane)-13,13-dimethyl-12,14,16-trioxa-5-aza-13-silanetetracosan-1-ol was prepared from 1-bromo-10-heptyl-8,8-dimethyl-7,9,11-trioxa-8-silanonadecane (416.72 mg, 0.841 mmol, 2.5 equiv) and 4-amino-1-butanol (29.98 mg, 0.336 mmol, 1.0 equiv) according to General Procedure I. The crude product was purified by flash column chromatography according to Purification Method B to obtain the pure product as a colorless oil, 169 mg, 0.184 mmol, 55% yield.

[0829] 1H NMR (500MHz, benzene-d6) δ5.00(m,2H), δ3.91-3.82(m,2H), δ3.76(t,4H), δ3.62(t,2H), δ3.46-3.38(m,2H), δ2. 33(t,4H),δ2.26(t,2H),δ1.96-1.76(m,4H),δ1.71-1.16(m,64H),δ0.95-0.85(m,12H),δ0.28(d,12H); TOF MSES + [M+H + ]:918.7974m / z

[0830] Example 115

[0831] Synthesis of 15-heptyl-5-(10-heptyl-8,8-dimethyl-7,9-dioxa-11-thia-8-silanonadecyl)-13,13-dimethyl-12,14-dioxa-16-thia-5-aza-13-silanotetracosan-1-ol

[0832]

[0833] 15-Heptyl-5-(10-heptyl-8,8-dimethyl-7,9-dioxa-11-thia-8-silanonadecane)-13,13-dimethyl-12,14-dioxa-16-thia-5-aza-13-silanetetracosan-1-ol was prepared from 1-bromo-10-heptyl-8,8-dimethyl-7,9-dioxa-11-thia-8-silanonadecane (555.14 mg, 1.085 mmol, 2.5 equiv) and 4-amino-1-butanol (38.68 mg, 0.4339 mmol, 1.0 equiv) according to General Procedure I. The crude product was purified by flash column chromatography according to Purification Method B to afford the pure product as a colorless oil, 170 mg, 0.179 mmol, 41% yield.

[0834] 1 H NMR (500MHz, benzene-d6) δ5.12(m,2H), δ3.83-3.75(m,4H), δ3.64-3.61(t,2H), δ2.81-2.66(m,4H), δ2.34(t ,4H), δ2.26(t,2H), δ2.08-1.90(m,4H), δ1.70-1.16(m,64H), δ0.93-0.89(m,12H), δ0.31(d,12H); TOF MSES + [M+H + ]:950.7537m / z

[0835] Example 116

[0836] Synthesis of 6-((dimethyl(octyl)silyl)oxy)-N-(6-((dimethyl(octyl)silyl)oxy)-6-(octyloxy)hexyl)-N-(2-(1-methylpyrrolidin-2-yl)ethyl)-6-(octyloxy)hexane-1-amine

[0837]

[0838] 6-((Dimethyl(octyl)silyl)oxy)-N-(6-((dimethyl(octyl)silyl)oxy)-6-(octyloxy)hexyl)-N-(2-(1-methylpyrrolidin-2-yl)ethyl)-6-(octyloxy)hexan-1-amine was prepared from ((6-bromo-1-(octyloxy)hexyl)oxy)dimethyl(octyl)silane (233.81 mg, 0.487 mmol, 2.5 equiv) and 2-(2-aminoethyl)-1-methylpyrrolidine (25.00 mg, 0.195 mmol, 1.0 equiv) according to General Procedure O. The crude product was purified by flash column chromatography according to Purification Method A to give the pure product as a colorless oil, 98 mg, 0.106 mmol, 54% yield.

[0839] 1 H NMR (500MHz, benzene-d6) δ4.89(t,2H), δ3.78-3.73(m,2H), δ3.41-3.35(m,2H), δ3.01(dt,1H), δ2.53-2.36 (m,6H),δ2.27(s,3H),δ2.12-1.19(m,72H),δ0.94-0.89(m,12H),δ0.76-0.72(4H),δ0.25(d,12H); TOF MSES + [M+H + ]:925.8552m / z

[0840] Example 117

[0841] Synthesis of 6-((dimethyl(octyloxy)silyl)oxy)-N-(6-((dimethyl(octyloxy)silyl)oxy)-6-(octyloxy)hexyl)-N-(2-(1-methylpyrrolidin-2-yl)ethyl)-6-(octyloxy)hexane-1-amine

[0842]

[0843] 6-((Dimethyl(octyloxy)silyl)oxy)-N-(6-((dimethyl(octyloxy)silyl)oxy)-6-(octyloxy)hexyl)-N-(2-(1-methylpyrrolidin-2-yl)ethyl)-6-(octyloxy)hexan-1-amine was prepared from 12-(5-bromopentyl)-10,10-dimethyl-9,11,13-trioxa-10-silaheneicosane (386.58 mg, 0.780 mmol, 2.5 equiv) and 2-(2-aminoethyl)-1-methylpyrrolidine (40.00 mg, 0.312 mmol, 1.0 equiv) according to General Procedure O. The crude product was purified by flash column chromatography according to Purification Method B to afford the pure product as a colorless oil, 33 mg, 0.034 mmol, 11% yield.

[0844] 1 H NMR (500MHz, benzene-d6) δ5.01(t,2H), δ3.90-3.83(m,2H), δ3.77(t,4H), δ3.46-3.36(m,2H), δ3.00(dt,1 H), δ2.53-2.36(m,6H), δ2.29(s,3H), δ2.10-1.17(m,72H), δ0.93-0.88(m,12H), δ0.28(d,12H); TOF MSES + [M 片段 +H + ]:845.7217m / z

[0845] Example 118

[0846] Synthesis of N-(2-(1-methylpyrrolidin-2-yl)ethyl)-6-(octyloxy)-N-(6-(octyloxy)-6-((1,1,3,3-tetramethyl-3-octyldisiloxanyl)oxy)hexyl)-6-((1,1,3,3-tetramethyl-3-octyldisiloxanyl)oxy)hexane-1-amine

[0847]

[0848] N-(2-(1-methylpyrrolidin-2-yl)ethyl)-6-(octyloxy)-N-(6-(octyloxy)-6-((1,1,3,3-tetramethyl-3-octyldisiloxanyl)oxy)hexyl)-6-((1,1,3,3-tetramethyl-3-octyldisiloxanyl)oxy)hexan-1-amine was prepared according to General Procedure O from 1-((6-bromo-1-(octyloxy)hexyl)oxy)-1,1,3,3-tetramethyl-3-octyldisiloxane (431.93 mg, 0.780 mmol, 2.5 equiv) and 2-(2-aminoethyl)-1-methylpyrrolidine (40.00 mg, 0.312 mmol, 1.0 equiv). The crude product was purified by flash column chromatography twice according to purification methods A and B to obtain the pure product as a colorless oil, 71 mg, 0.066 mmol, 21% yield.

[0849] 1 H NMR(500MHz, benzene-d6)δ5.02(t,2H),δ3.90-3.84(m,2H),δ3.46-3.30(m,2H),δ3.00(dt,1H),δ2.53-2.38(m,6H),δ 2.29(s,3H),δ2.14-1.20(m,72H),δ0.96-0.89(m,12H),δ0.74-0.66(m,4H),δ0.28(d,12H),δ0.21(s,12H); TOF MSES + [M 片段 +H + ]:518.4431m / z

[0850] Example 119

[0851] Synthesis of N-(2-(1-methylpyrrolidin-2-yl)ethyl)-6-(octyloxy)-N-(6-(octyloxy)-6-((1,1,3,3-tetramethyl-3-(octyloxy)disiloxyl)oxy)hexyl)-6-((1,1,3,3-tetramethyl-3-(octyloxy)disiloxyl)oxy)hexane-1-amine

[0852]

[0853] N-(2-(1-methylpyrrolidin-2-yl)ethyl)-6-(octyloxy)-N-(6-(octyloxy)-6-((1,1,3,3-tetramethyl-3-(octyloxy)disiloxanyl)oxy)hexyl)-6-((1,1,3,3-tetramethyl-3-(octyloxy)disiloxanyl)oxy)hexan-1-amine was prepared according to General Procedure O from 1-((6-bromo-1-(octyloxy)hexyl)oxy)-1,1,3,3-tetramethyl-3-(octyloxy)disiloxane (444.41 mg, 0.780 mmol, 2.5 equiv) and 2-(2-aminoethyl)-1-methylpyrrolidine (40.00 mg, 0.312 mmol, 1.0 equiv). The crude product was purified by flash column chromatography twice according to purification methods A and B to obtain the pure product as a colorless oil, 92 mg, 0.083 mmol, 27% yield.

[0854] 1 H NMR (500MHz, benzene-d6) δ5.04(t,2H), δ3.91-3.85(m,2H), δ3.76(t,4H), δ3.47-3.36(m,2H), δ3.00(dt,1H), δ2. 53-2.38(m,6H),δ2.29(s,3H),δ2.10-1.17(m,72H),δ0.93-0.89(m,12H),δ0.32(d,12H),δ0.25(s,12H); TOF MSES + [M 片段 +H + ]:603.4640m / z

[0855] Example 120

[0856] Synthesis of 6-((1-((dimethyl(octyl)silyl)oxy)octyl)oxy)-N-(6-((1-((dimethyl(octyl)silyl)oxy)octyl)oxy)hexyl)-N-(2-(1-methylpyrrolidin-2-yl)ethyl)hexane-1-amine

[0857]

[0858] 6-((1-((Dimethyl(octyl)silyl)oxy)octyl)oxy)-N-(6-((1-((dimethyl(octyl)silyl)oxy)octyl)oxy)hexyl)-N-(2-(1-methylpyrrolidin-2-yl)ethyl)hexan-1-amine was prepared from ((1-((6-bromohexyl)oxy)octyl)oxy)dimethyl(octyl)silane (374.1 mg, 0.780 mmol, 2.5 equiv) and 2-(2-aminoethyl)-1-methylpyrrolidine (40.00 mg, 0.312 mmol, 1.0 equiv) according to General Procedure O. The crude product was purified twice by flash column chromatography according to Purification Methods A and B to afford the pure product as a colorless oil, 109 mg, 0.118 mmol, 38% yield.

[0859] 1 H NMR (500MHz, benzene-d6) δ4.88(t,2H), δ3.79-3.73(m,2H), δ3.41-3.35(m,2H), δ3.00(dt,1H), δ2.53-2. 36(m,6H),δ2.29(s,3H),δ2.12-1.19(m,72H),δ0.95-0.89(m,12H),δ0.75-0.71(4H),δ0.25(d,12H)

[0860] Example 121

[0861] Synthesis of 8-heptyl-N-(8-heptyl-10,10-dimethyl-7,9,11-trioxa-10-silanonadecanyl)-10,10-dimethyl-N-(2-(1-methylpyrrolidin-2-yl)ethyl)-7,9,11-trioxa-10-silanonadecan-1-amine

[0862]

[0863] 8-Heptyl-N-(8-heptyl-10,10-dimethyl-7,9,11-trioxa-10-silanonadecan-1-amine)-10,10-dimethyl-N-(2-(1-methylpyrrolidin-2-yl)ethyl)-7,9,11-trioxa-10-silanonadecan-1-amine was prepared from 1-bromo-8-heptyl-10,10-dimethyl-7,9,11-trioxa-10-silanonadecan-1-amine (386.58 mg, 0.780 mmol, 2.5 equiv) and 2-(2-aminoethyl)-1-methylpyrrolidine (40.00 mg, 0.312 mmol, 1.0 equiv) according to General Procedure O. The crude product was purified by flash column chromatography according to Purification Method B to afford the pure product as a colorless oil, 60 mg, 0.063 mmol, 20% yield.

[0864] 1 H NMR (500MHz, benzene-d6) δ5.01(t,2H), δ3.90-3.84(m,2H), δ3.77(t,4H), δ3.46-3.40(m,2H), δ3.00(dt ,1H),δ2.53-2.37(m,6H),δ2.29(s,3H),δ2.10-1.17(m,72H),δ0.93-0.89(m,12H),δ0.29(d,12H)

[0865] Example 122

[0866] Synthesis of N-(2-(1-methylpyrrolidin-2-yl)ethyl)-6-((1-((1,1,3,3-tetramethyl-3-octyldisiloxanyl)oxy)octyl)oxy)-N-(6-((1-((1,1,3,3-tetramethyl-3-octyldisiloxanyl)oxy)octyl)oxy)hexyl)hexane-1-amine

[0867]

[0868] N-(2-(1-methylpyrrolidin-2-yl)ethyl)-6-((1-((1,1,3,3-tetramethyl-3-octyldisiloxanyl)oxy)octyl)oxy)-N-(6-((1-((1,1,3,3-tetramethyl-3-octyldisiloxanyl)oxy)octyl)oxy)hexyl)hexan-1-amine was prepared according to General Procedure O from 1-((1-((6-bromohexyl)oxy)octyl)oxy)-1,1,3,3-tetramethyl-3-octyldisiloxane (431.93 mg, 0.780 mmol, 2.5 equiv) and 2-(2-aminoethyl)-1-methylpyrrolidine (40.00 mg, 0.312 mmol, 1.0 equiv). The crude product was purified by flash column chromatography according to purification method B to obtain the pure product as a colorless oil, 200 mg, 0.186 mmol, 60% yield.

[0869] 1 H NMR (500MHz, benzene-d6) δ5.01(t,2H), δ3.91-3.83(m,2H), δ3.45-3.37(m,2H), δ2.99(dt,1H), δ2.52-2.36(m,6H) ,δ2.28(s,3H),δ2.10-1.20(m,72H),δ0.95-0.89(m,12H),δ0.69-0.65(m,4H),δ0.26(d,12H),δ0.20(s,12H)

[0870] Example 123

[0871] Synthesis of N-(2-(1-methylpyrrolidin-2-yl)ethyl)-6-((1-((1,1,3,3-tetramethyl-3-(octyloxy)disiloxanyl)oxy)octyl)oxy)-N-(6-((1-((1,1,3,3-tetramethyl-3-(octyloxy)disiloxanyl)oxy)octyl)oxy)hexyl)hexane-1-amine

[0872]

[0873] N-(2-(1-methylpyrrolidin-2-yl)ethyl)-6-((1-((1,1,3,3-tetramethyl-3-(octyloxy)disiloxanyl)oxy)octyl)oxy)-N-(6-((1-((1,1,3,3-tetramethyl-3-(octyloxy)disiloxanyl)oxy)octyl)oxy)hexyl)hexan-1-amine was prepared according to General Procedure O from 1-((1-((6-bromohexyl)oxy)octyl)oxy)-1,1,3,3-tetramethyl-3-(octyloxy)disiloxane (444.41 mg, 0.780 mmol, 2.5 equiv) and 2-(2-aminoethyl)-1-methylpyrrolidine (40.00 mg, 0.312 mmol, 1.0 equiv). The crude product was purified by flash column chromatography according to purification method B to obtain the pure product as a colorless oil, 100 mg, 0.090 mmol, 29% yield.

[0874] 1 H NMR(500MHz, benzene-d6)δ5.03(t,2H),δ3.93-3.83(m,2H),δ3.76(t,4H),δ3.46-3.35(m,2H),δ3.00(dt,1H),δ 2.54-2.35(m,6H),δ2.28(s,3H),δ2.10-1.17(m,72H),δ0.94-0.86(m,12H),δ0.32(d,12H),δ0.27(s,12H)

[0875] Example 124

[0876] Synthesis of 2-(4-((bis(6-((dimethyl(octyl)silyl)oxy)-6-(octyloxy)hexyl)amino)methyl)-1H-1,2,3-triazol-1-yl)ethan-1-ol

[0877]

[0878]

[0146] 2-(4-((bis(6-((dimethyl(octyl)silyl)oxy)-6-(octyloxy)hexyl)amino)methyl)-1H-1,2,3-triazol-1-yl)ethan-1-ol was prepared from 6-((dimethyl(octyl)silyl)oxy)-N-(6-((dimethyl(octyl)silyl)oxy)-6-(octyloxy)hexyl)-6-(octyloxy)-N-(prop-2-yn-1-yl)hexan-1-amine (130.00 mg, 0.152 mmol, 1.0 equiv) and 2-azidoethanol (39.84 mg (50%), 0.229 mmol, 1.5 equiv) according to General Procedure P. The crude product was purified twice by flash column chromatography according to Purification Methods A and B to afford the pure product as a colorless oil, 63 mg, 0.067 mmol, 44% yield.

[0879] 1 H NMR (500MHz, CDCl3) δ4.69(t,2H), δ4.48-4.45(m,2H), δ4.04-4.02(m,2H), δ3.78(s,2H), δ3.63-3.57(m,2H), δ3.31-3.25(m ,2H), δ4.45(t,4H), δ1.62-1.42(m,12H), δ1.41-1.18(m,53H), δ0.89-0.86(m,12H), δ0.62-0.58(m,4H), δ0.12(d,12H); TOF MSES + [M+H + ]:940.554m / z

[0880] Example 125

[0881] Synthesis of (3R,4R,5S,6R)-3-(4-((bis(6-((dimethyl(octyl)silyl)oxy)-6-(octyloxy)hexyl)amino)methyl)-1H-1,2,3-triazol-1-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-2,4,5-triol

[0882]

[0883]

[0146] (3R,4R,5S,6R)-3-(4-((bis(6-((dimethyl(octyl)silyl)oxy)-6-(octyloxy)hexyl)amino)methyl)-1H-1,2,3-triazol-1-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-2,4,5-triol was prepared from 6-((dimethyl(octyl)silyl)oxy)-N-(6-((dimethyl(octyl)silyl)oxy)-6-(octyloxy)hexyl)-6-(octyloxy)-N-(prop-2-yn-1-yl)hexan-1-amine (130.00 mg, 0.152 mmol, 1.0 equiv) and 2-azido-2-deoxy-D-glucose (46.93 mg, 0.229 mmol, 1.5 equiv). The crude product was purified by flash column chromatography according to purification method A to obtain the pure product as a colorless oil, 89 mg, 0.084 mmol, 55% yield. 1 H NMR (500MHz, CDCl3) δ7.83(s,1H), δ7.63(s,1H), δ5.35(s,1H), δ5.08(d,1 H),δ4.67(t,2H),δ4.34-4.13(m,2H),δ4.01(d,1H),δ3.95-3.75(m,2H),δ3 .74-3.46(br.m,6H),δ3.30-3.25(q,2H),δ2.42-2.39(br.m,4H),δ2.23(m ,1H), δ1.64-1.11(m,64H), δ0.87(m,12H), δ0.60(m,4H), δ0.11(d,12H); LC ESIMS[M+H + ]:1057.843m / z

[0884] Example 126

[0885] Synthesis of N-((2R,3R,4R,5S,6R)-2-(4-((bis(6-((dimethyl(octyl)silyl)oxy)-6-(octyloxy)hexyl)amino)methyl)-1H-1,2,3-triazol-1-yl)-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)acetamide

[0886]

[0887] The 1-amino-2-nitropropane-1-ylpyranose amine (100.00 mg, 0.117 mmol, 1.0 equiv) was prepared according to General Procedure P from 6-((dimethyl(octyl)silyl)oxy)-N-(6-((dimethyl(octyl)silyl)oxy)-6-(octyloxy)hexyl)-6-(octyloxy)-N-(prop-2-yn-1-yl)hexan-1-amine (100.00 mg, 0.117 mmol, 1.0 equiv) and 2-acetamido-2-deoxy-β-D-glucopyranosyl azide. N-((2R,3R,4R,5S,6R)-2-(4-((bis(6-((dimethyl(octyl)silyl)oxy)-6-(octyloxy)hexyl)amino)methyl)-1H-1,2,3-triazol-1-yl)-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)acetamide was prepared (43.32 mg, 0.176 mmol, 1.5 equiv). The crude product was purified by flash column chromatography according to purification method A to give the pure product as a colorless oil, 88 mg, 0.080 mmol, 68% yield.

[0888] 1 H NMR (500MHz, CDCl3) δ7.89(s,1H), δ6.95(s,1H), δ5.91(d,1H), δ5.30-4.87(s,2 H), δ4.71-4.68(m,2H), δ4.37-4.30(m,1H), δ3.95-3.87(m,4H), δ3.74-3.57(m,5 H), δ3.31-3.26(m,2H), δ2.47-2.40(m,4H), δ1.75(s,3H), δ1.63-1.41(m,12H), δ1.38-1.20(m,53H), δ0.89-0.86(m,12H), δ0.62-0.58(m,4H), δ0.12(d,12H); LC ESIMS[M+H + ]:1098.624m / z

[0889] Example 127

[0890] Synthesis of N-((2R,3R,4R,5S,6R)-2-(4-((bis(6-(octyloxy)-6-((1,1,3,3-tetramethyl-3-octyldisiloxanyl)oxy)hexyl)amino)methyl)-1H-1,2,3-triazol-1-yl)-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)acetamide

[0891]

[0892] Following General Procedure P, a 5-[4-nitro-2-nitro-1-yl]-4-nitro-2-nitropropane was prepared from 6-(octyloxy)-N-(6-(octyloxy)-6-((1,1,3,3-tetramethyl-3-octyldisiloxanyl)oxy)hexyl)-N-(prop-2-yn-1-yl)-6-((1,1,3,3-tetramethyl-3-octyldisiloxanyl)oxy)hexan-1-amine (83.00 mg, 0.083 mmol, 1.0 equiv) and 2-acetamido-2-deoxy-β-D-pyranose. Glycosyl azide (30.63 mg, 0.124 mmol, 1.5 equiv) was used to prepare N-((2R,3R,4R,5S,6R)-2-(4-((bis(6-(octyloxy)-6-((1,1,3,3-tetramethyl-3-octyldisiloxanyl)oxy)hexyl)amino)methyl)-1H-1,2,3-triazol-1-yl)-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)acetamide. The crude product was purified by flash column chromatography according to purification method A to give the pure product as a colorless oil, 30 mg, 0.024 mmol, 29% yield.

[0893] 1 H NMR (500MHz, CDCl3) δ8.04 (s, 1H), δ7.21 (s, 1H), δ5.89 (d, 1H), δ4.77 (t, 2H), δ4.39-4.36(m,1H), δ4.14-3.83(m,6H), δ3.69-3.65(m,3H), δ3.31-3.25(m,2H ), δ2.90-2.26(m,6H), δ1.75(s,3H), δ1.65-1.45(m,12H), δ1.43-1.13(m,53H) , δ0.89-0.85(m,12H), δ0.55-0.51(m,4H), δ0.11(d,12H), δ0.09(s,12H);); LC ESIMS[M+H + ]:1247.980m / z

[0894] Example 128

[0895] Synthesis of 6-((6-((dimethyl(octyl)silyl)oxy)-6-(octyloxy)hexyl)(4-hydroxybutyl)amino)hexyl 2-hexyldecanoate

[0896]

[0897] 6-((6-((dimethyl(octyl)silyl)oxy)-6-(octyloxy)hexyl)(4-hydroxybutyl)amino)hexyl 2-hexyldecanoate was prepared from 4-((6-((dimethyl(octyl)silyl)oxy)-6-(octyloxy)hexyl)amino)butan-1-ol (150 mg, 0.307 mmol, 1.0 equiv) and 6-oxohexyl 2-hexylhexanoate (109.01 mg, 0.307 mmol, 1.0 equiv) according to General Procedure J. The crude product was purified by flash column chromatography according to Purification Method A to give the pure product as a colorless oil, 90 mg, 0.109 mmol, 35% yield.

[0898] 1 H NMR (500MHz, benzene-d6) δ4.90(t,1H), δ4.12(t,2H), δ3.80-3.74(m,1H), δ3.62(t,2H), δ3.42-3.34(m,2H), δ2.48 (m,1H), δ2.35-2.23(m,5H), δ1.90-1.22(m,68H), δ0.95-0.88(m,12H), δ0.77-0.73(m,2H), δ0.26(d,6H); TOF MSES + [M+H + ]:826.7701m / z

[0899] Example 129

[0900] Synthesis of 15-heptyl-7-(4-hydroxybutyl)-17,17-dimethyl-14,16-dioxa-7-aza-17-silanopentacosyl 2-hexyldecanoate

[0901]

[0902] 15-Heptyl-7-(4-hydroxybutyl)-17,17-dimethyl-14,16-dioxa-7-aza-17-silapentacosanyl 2-hexyldecanoate was prepared from 13-heptyl-15,15-dimethyl-12,14-dioxa-5-aza-15-silatricosan-1-ol (150 mg, 0.307 mmol, 1.0 equiv) and 6-oxohexyl 2-hexyldecanoate (109.01 mg, 0.307 mmol, 1.0 equiv) according to General Procedure J. The crude product was purified by flash column chromatography according to Purification Method A to obtain the pure product as a colorless oil, 38 mg, 0.046 mmol, 15% yield.

[0903] 1H NMR (500MHz, benzene-d6) δ4.88(t,1H), δ4.11(t,2H), δ3.78-3.73(m,1H), δ3.62(t,2H), δ3.40-3.35(m,1H), δ2.47 (m,2H), δ2.35-2.22(m,5H), δ1.87-1.12(m,68H), δ0.93-0.88(m,12H), δ0.75-0.71(m,2H), δ0.25(d,6H); TOF MSES + [M+H + ]:826.7683m / z

[0904] Example 130

[0905] Synthesis of 7-(4-hydroxybutyl)-15,15-dimethyl-13-(octyloxy)-14,16-dioxa-7-aza-15-silanotetracosyl 2-hexyldecanoate

[0906]

[0907] 7-(4-Hydroxybutyl)-15,15-dimethyl-13-(octyloxy)-14,16-dioxa-7-aza-15-silanotetracosyl 2-hexyldecanoate was prepared from 12-(5-bromopentyl)-10,10-dimethyl-9,11,13-trioxa-10-silaheneconane (191.21 mg, 0.386 mmol, 1.1 equiv) and 6-((4-hydroxybutyl)amino)hexyl 2-hexyldecanoate (150 mg, 0.351 mmol, 1.0 equiv) according to General Procedure K. The crude product was purified by flash column chromatography according to Purification Method A to give the pure product as a colorless oil, 150 mg, 0.178 mmol, 51% yield. 1 H NMR (500MHz, benzene-d6) δ5.01(t,1H), δ4.12(t,2H), δ3.90-3.84(m,1H), δ3.77(t,2H), δ3.62(t,2H), δ3.46-3.34(m,2H), δ2 TOF MSES + [M+H + ]:842.7618m / z

[0908] Example 131

[0909] Synthesis of 15-heptyl-7-(4-hydroxybutyl)-17,17-dimethyl-14,16,18-trioxa-7-aza-17-silanol-hexacosyl 2-hexyldecanoate

[0910]

[0911] 15-Heptyl-7-(4-hydroxybutyl)-17,17-dimethyl-14,16,18-trioxa-7-aza-17-silacosanyl 2-hexyldecanoate was prepared from 1-bromo-8-heptyl-10,10-dimethyl-7,9,11-trioxa-10-silanonadecane (173.83 mg, 0.351 mmol, 1.0 equiv) and 6-((4-hydroxybutyl)amino)hexyl 2-hexyldecanoate (150.00 mg, 0.351 mmol, 1.0 equiv) according to General Procedure K. The crude product was purified by flash column chromatography according to Purification Method B to afford the pure product as a colorless oil, 153 mg, 0.182 mmol, 52% yield.

[0912] 1 H NMR (500MHz, benzene-d6) δ5.00(t,1H), δ4.11(t,2H), δ3.92-3.83(m,1H), δ3.76(t,2H), δ3.62(t,2H), δ3.44-3.40(m,2H) TOF MSES + [M+H + ]:842.7665m / z

[0913] Example 132

[0914] Synthesis of 6-((4-hydroxybutyl)(6-(octyloxy)-6-((1,1,3,3-tetramethyl-3-octyldisiloxanyl)oxy)hexyl)amino)hexyl 2-hexyldecanoate

[0915]

[0916] 6-((4-Hydroxybutyl)(6-(octyloxy)-6-((1,1,3,3-tetramethyl-3-octyldisiloxanyl)oxy)hexyl)amino)hexyl 2-hexyldecanoate was prepared from 1-((6-bromo-1-(octyloxy)hexyl)oxy)-1,1,3,3-tetramethyl-3-octyldisiloxane (168.33 mg, 0.304 mmol, 1.0 equiv) and 6-((4-hydroxybutyl)amino)hexyl 2-hexyldecanoate according to General Procedure K. The crude product was purified by flash column chromatography according to Purification Method B to give the pure product as a colorless oil, 142 mg, 0.158 mmol, 52% yield.

[0917] 1 H NMR (500MHz, benzene-d6) δ5.01(t,1H), δ4.12(t,2H), δ3.92-3.83(m,1H), δ3.62(t,2H), δ3.47-3.39(m,1H), δ2.47(m,1H) TOF MSES + [M+H + ]:900.7888m / z

[0918] Example 133

[0919] Synthesis of 15-heptyl-7-(4-hydroxybutyl)-17,17,19,19-tetramethyl-14,16,18-trioxa-7-aza-17,19-disilacosadecyl 2-hexyldecanoate

[0920]

[0921] 15-Heptyl-7-(4-hydroxybutyl)-17,17,19,19-tetramethyl-14,16,18-trioxa-7-aza-17,19-disilaheptacosyl 2-hexyldecanoate was prepared from 1-((1-((6-bromohexyl)oxy)octyl)oxy)-1,1,3,3-tetramethyl-3-octyldisiloxane (194.22 mg, 0.351 mmol, 1.0 equiv) and 6-((4-hydroxybutyl)amino)2-hexyl 2-hexyldecanoate (150 mg, 0.351 mmol, 1.0 equiv) according to General Procedure K. The crude product was purified by flash column chromatography according to Purification Method B to afford the pure product as a colorless oil, 169 mg, 0.188 mmol, 54% yield.

[0922] 1H NMR (500MHz, benzene-d6) δ5.01(t,1H), δ4.11(t,2H), δ3.93-3.85(m,1H), δ3.62(t,2H), δ3.45-3.38(m,1H), δ2.47(m,1H) TOF MSES + [M+H + ]:900.7840m / z

[0923] Example 134

[0924] Synthesis of 6-((4-hydroxybutyl)(6-(octyloxy)-6-((1,1,3,3-tetramethyl-3-(octyloxy)disiloxanyl)oxy)hexyl)amino)hexyl 2-hexyldecanoate

[0925]

[0926] 6-((4-Hydroxybutyl)(6-(octyloxy)-6-((1,1,3,3-tetramethyl-3-(octyloxy)disiloxanyl)oxy)hexyl)amino)hexyl 2-hexyldecanoate was prepared from 4-((6-(octyloxy)-6-((1,1,3,3-tetramethyl-3-(octyloxy)disiloxanyl)oxy)hexyl)amino)butan-1-ol (126 mg, 0.218 mmol, 1.0 equiv) and 6-oxohexyl 2-hexyldecanoate (77.29 mg, 0.218 mmol, 1.0 equiv) according to General Procedure J. The crude product was purified by flash column chromatography according to Purification Method A to give the pure product as a colorless oil, 53 mg, 0.058 mmol, 27% yield.

[0927] 1 H NMR (500MHz, benzene-d6) δ5.03(t,1H), δ4.11(t,2H), δ3.91-3.85(m,1H), δ3.76(t,2H), δ3.61(t,2H), δ3.46-3.41(m,1 H), δ2.46(m,1H), δ2.35-2.23(m,6H), δ1.96-1.11(m,68H), δ0.93-0.87(m,12H), δ0.30(d,6H), δ0.24(s,6H); TOF MSES + [M+H + ]:916.7822m / z

[0928] Example 135

[0929] Synthesis of 15-heptyl-7-(4-hydroxybutyl)-17,17,19,19-tetramethyl-14,16,18,20-tetraoxa-7-aza-17,19-disilicooctadecyl 2-hexyldecanoate

[0930]

[0931] 15-Heptyl-7-(4-hydroxybutyl)-17,17,19,19-tetramethyl-14,16,18,20-tetraoxa-7-aza-17,19-disiladioctadecyl 2-hexyldecanoate was prepared from 1-((1-((6-bromohexyl)oxy)octyl)oxy)-1,1,3,3-tetramethyl-3-(octyloxy)disiloxane (190.51 mg, 0.334 mmol, 1.1 equiv) and 6-((4-hydroxybutyl)amino)hexyl 2-hexyldecanoate (130 mg, 0.304 mmol, 1.0 equiv) according to General Procedure K. The crude product was purified by flash column chromatography according to Purification Method A to afford the pure product as a colorless oil, 51 mg, 0.056 mmol, 18% yield.

[0932] 1 H NMR (500MHz, benzene-d6) δ5.04(t,1H), δ4.12(t,2H), δ3.91-3.85(m,1H), δ3.76(t,2H), δ3.62(t,2H), δ3.47-3.36(m,1 H), δ2.47(m,1H), δ2.34-2.22(m,6H), δ1.96-1.09(m,68H), δ0.94-0.88(m,12H), δ0.31(d,6H), δ0.24(s,6H); TOF MSES + [M+H + ]:916.7834m / z

[0933] Example 136

[0934] Synthesis of 18-hexyl-7-(4-hydroxybutyl)-15,15-dimethyl-13-(octyloxy)-14,16-dioxa-7-aza-15-silanol-hexacosyl 2-hexyldecanoate

[0935]

[0936] 18-Hexyl-7-(4-hydroxybutyl)-15,15-dimethyl-13-(octyloxy)-14,16-dioxa-7-aza-15-silacosanyl 2-hexyldecanoate was prepared from 10-(5-bromopentyl)-15-hexyl-12,12-dimethyl-9,11,13-trioxa-12-silatricosane (234.50 mg, 0.386 mmol, 1.1 equiv) and 6-((4-hydroxybutyl)amino)hexyl 2-hexyldecanoate (150 mg, 0.351 mmol, 1.0 equiv) according to General Procedure K. The crude product was purified by flash column chromatography according to Purification Method A to give the pure product as a colorless oil, 179 mg, 0.188 mmol, 53% yield.

[0937] 1 H NMR (500MHz, benzene-d6) δ5.03(t,1H), δ4.12(t,2H), δ3.92-3.86(m,1H), δ3.75(d,2H), δ3.62(t,2H), δ3.48-3.42 (m,1H), δ2.51-2.44(m,1H), δ2.36-2.24(m,6H), δ1.97-1.13(m,81H), δ0.96-0.87(m,15H), δ0.30(d,6H); TOF MSES + [M+H + ]:954.8895m / z

[0938] Example 137

[0939] Synthesis of 15-heptyl-20-hexyl-7-(4-hydroxybutyl)-17,17-dimethyl-14,16,18-trioxa-7-aza-17-silanodioctadecyl 2-hexyldecanoate

[0940]

[0941] 15-Heptyl-20-hexyl-7-(4-hydroxybutyl)-17,17-dimethyl-14,16,18-trioxa-7-aza-17-siladocayl 2-hexyldecanoate was prepared from 1-bromo-8-heptyl-13-hexyl-10,10-dimethyl-7,9,11-trioxa-10-silaheneicosane (234.50 mg, 0.386 mmol, 1.1 equiv) and 6-((4-hydroxybutyl)amino)hexyl 2-hexyldecanoate (150 mg, 0.351 mmol, 1.0 equiv) according to General Procedure K. The crude product was purified by flash column chromatography according to Purification Method A to obtain the pure product as a colorless oil, 210 mg, 0.220 mmol, 63% yield.

[0942] 1 H NMR (500MHz, benzene-d6) δ5.03(t,1H), δ4.12(t,2H), δ3.91-3.85(m,1H), δ3.75(d,2H), δ3.62(t,2H), δ3.46-3.40 (m,1H), δ2.50-2.43(m,1H), δ2.34-2.24(m,6H), δ1.97-1.12(m,81H), δ0.96-0.87(m,12H), δ0.30(d,6H); TOF MSES + [M+H + ]:954.8887m / z

[0943] Example 138

[0944] Synthesis of 16-heptyl-7-(4-hydroxybutyl)-14,14-dimethyl-15,17-dioxa-7-aza-14-silanopentacosyl 2-hexyldecanoate

[0945]

[0946] 16-Heptyl-7-(4-hydroxybutyl)-14,14-dimethyl-15,17-dioxa-7-aza-14-silanopentacosyl 2-hexyldecanoate was prepared from (6-bromohexyl)dimethyl((1-(octyloxy)octyl)oxy)silane (185.04 mg, 0.386 mmol, 1.1 equiv) and 6-((4-hydroxybutyl)amino)hexyl 2-hexyldecanoate (150 mg, 0.351 mmol, 1.0 equiv) according to General Procedure K. The crude product was purified by flash column chromatography according to Purification Method A to give the pure product as a colorless oil, 197 mg, 0.238 mmol, 68% yield.

[0947] 1 H NMR (500MHz, benzene-d6) δ4.88(dt,1H), δ4.12(t,2H), δ3.79-3.73(m,1H), δ3.63(t,2H), δ3.41-3.35(m,1H), δ2.54-2 .42(m,1H), δ2.39-2.26(m,6H), δ1.88-1.13(m,68H), δ0.94-0.87(m,12H), δ0.76-0.72(m,2H), δ0.26(d,6H); TOF MSES + [M+H + ]:826.7684m / z

[0948] Example 139

[0949] Synthesis of 17-heptyl-7-(4-hydroxybutyl)-15,15-dimethyl-14,16,18-trioxa-7-aza-15-silanol-hexacosyl 2-hexyldecanoate

[0950]

[0951] 17-Heptyl-7-(4-hydroxybutyl)-15,15-dimethyl-14,16,18-trioxa-7-aza-15-silacosanyl 2-hexyldecanoate was prepared from 1-bromo-10-heptyl-8,8-dimethyl-7,9,11-trioxa-8-silanonadecane (191.21 mg, 0.351 mmol, 1.0 equiv) and 6-((4-hydroxybutyl)amino)hexyl 2-hexyldecanoate (150 mg, 0.351 mmol, 1.0 equiv) according to General Procedure K. The crude product was purified by flash column chromatography according to Purification Method A to give the pure product as a colorless oil, 94 mg, 0.112 mmol, 32% yield.

[0952] 1 H NMR (500MHz, benzene-d6) δ5.00(t,1H), δ4.12(t,2H), δ3.89-3.84(m,1H), δ3.77(t,2H), δ3.62(t,2H), δ3.45-3.37 (m,1H), δ2.50-2.43(m,1H), δ2.34-2.24(m,6H), δ1.95-1.12(m,68H), δ0.95-0.86(m,12H), δ0.28(d,6H); TOF MSES + [M+H + ]:842.7627m / z

[0953] Example 140

[0954] Synthesis of 17-heptyl-7-(4-hydroxybutyl)-15,15-dimethyl-14,16,18-trioxa-7-aza-15-silanopentacosyl 2-hexyldecanoate

[0955]

[0956] 17-Heptyl-7-(4-hydroxybutyl)-15,15-dimethyl-14,16,18-trioxa-7-aza-15-silapentacosanyl 2-hexyldecanoate was prepared from 1-bromo-10-heptyl-8,8-dimethyl-7,9,11-trioxa-8-silaoctadecane (522.56 mg, 1.122 mmol, 1.2 equiv) and 6-((4-hydroxybutyl)amino)hexyl 2-hexyldecanoate (400 mg, 0.935 mmol, 1.0 equiv) according to General Procedure K. The crude product was purified by flash column chromatography according to Purification Method A to give the pure product as a colorless oil, 355 mg, 0.428 mmol, 46% yield.

[0957] 1 H NMR (500MHz, benzene-d6) δ4.96(t,1H), δ4.09(t,2H), δ3.85-3.80(m,1H), δ3.74(t,2H), δ3.61(t,2H), δ3.41-3.36 (m,1H), δ2.47-2.40(m,1H), δ2.32-2.25(m,6H), δ1.91-1.15(m,66H), δ0.92-0.87(m,12H), δ0.25(d,6H); TOF MSES + [M+H + ]:828.7474m / z

[0958] Example 141

[0959] Synthesis of 17-heptyl-7-(4-hydroxybutyl)-15,15-dimethyl-14,16,18-trioxa-7-aza-15-silacosanyl 2-hexyldecanoate

[0960]

[0961] 17-Heptyl-7-(4-hydroxybutyl)-15,15-dimethyl-14,16,18-trioxa-7-aza-15-silacosanyl 2-hexyldecanoate was prepared from 1-bromo-10-heptyl-8,8-dimethyl-7,9,11-trioxa-8-silaicosane (326.04 mg, 0.640 mmol, 1.2 equiv) and 6-((4-hydroxybutyl)amino)hexyl 2-hexyldecanoate (228 mg, 0.533 mmol, 1.0 equiv) according to General Procedure K. The crude product was purified by flash column chromatography according to Purification Method A to give the pure product as a colorless oil, 144 mg, 0.168 mmol, 32% yield.

[0962] 1H NMR(500 MHz, benzene-d6) δ5.01(t,1H), δ4.12(t,2H), δ3.91-3.83(m,1H), δ3.77(t,2H), δ3.62(t,2H), δ3.47-3.36(m,1H ), δ2.52-2.42(m,1H), δ2.35-2.24(m,6H), δ1.98-1.10(br.m,68H), δ0.92-0.88(m,12H)δ0.29(d,6H); TOF MSES + [M+H + ]:856.7791 m / z

[0963] Example 142

[0964] Synthesis of 17-hexyl-7-(4-hydroxybutyl)-15,15-dimethyl-14,16,18-trioxa-7-aza-15-silanol-hexacosyl 2-hexyldecanoate

[0965] 17-Hexyl-7-(4-hydroxybutyl)-15,15-dimethyl-14,16,18-trioxa-7-aza-15-silacosanyl 2-hexyldecanoate was prepared from 1-bromo-10-hexyl-8,8-dimethyl-7,9,11-trioxa-8-silanonadecane (522.56 mg, 1.122 mmol, 1.2 equiv) and 6-((4-hydroxybutyl)amino)hexyl 2-hexyldecanoate (400.0 mg, 0.935 mmol, 1.0 equiv) according to General Procedure K. The crude product was purified by flash column chromatography according to Purification Method A to give the pure product as a colorless oil, 385 mg, 0.465 mmol, 50% yield.

[0966] 1 H NMR(500 MHz, benzene-d6) δ5.00(t,1H), δ4.12(t,2H), δ3.93-3.82(m,1H), δ3.77(t,2H), δ3.62(t,2H), δ3.45-3.37(m,1H ), δ2.51-2.41(m,1H), δ2.35-2.24(m,6H), δ1.98-1.07(br.m,66H), δ0.95-0.86(m,12H)δ0.28(d,6H); TOF MSES + [M+H + ]:828.7489 m / z

[0967] Example 143

[0968] Synthesis of 7-(4-hydroxybutyl)-15,15-dimethyl-17-octyl-14,16,18-trioxa-7-aza-15-silanol-hexacosyl 2-hexyldecanoate

[0969] 7-(4-Hydroxybutyl)-15,15-dimethyl-17-octyl-14,16,18-trioxa-7-aza-15-silacosanyl 2-hexyldecanoate was prepared from 1-bromo-8,8-dimethyl-10-octyl-7,9,11-trioxa-8-silanonadecane (554.04 mg, 1.122 mmol, 1.2 equiv) and 6-((4-hydroxybutyl)amino)hexyl 2-hexyldecanoate (400 mg, 0.935 mmol, 1.0 equiv) according to General Procedure K. The crude product was purified by flash column chromatography according to Purification Method A to give the pure product as a colorless oil, 398 mg, 0.465 mmol, 50% yield.

[0970] 1 H NMR(500 MHz, CDCl3) δ5.11(t,1H), δ4.22(t,2H), δ4.00-3.93(m,1H), δ3.88(t,2H), δ3.72(t,2H), δ3.56-3.45(m,1 H), δ2.60-2.51(m,1H), δ2.45-2.34(m,6H), δ2.05-1.21(br.m,70H), δ1.04-0.98(m,12H)δ0.39(d,6H); TOF MSES + [M+H + ]:856.7808 m / z

[0971] Example 144

[0972] Synthesis of 18-(4-hydroxybutyl)-10,10-dimethyl-8-nonyl-7,9,11-trioxa-18-aza-10-silanotetracosane-24-yl 2-hexyldecanoate

[0973]

[0974] 18-(4-Hydroxybutyl)-10,10-dimethyl-8-nonyl-7,9,11-trioxa-18-aza-10-silacosan-24-yl 2-hexyldecanoate was prepared from 1-bromo-8,8-dimethyl-10-nonyl-7,9,11-trioxa-8-silaheptadecane (556.25 mg, 1.122 mmol, 1.2 equiv) and 6-((4-hydroxybutyl)amino)hexyl 2-hexyldecanoate (400 mg, 0.9352 mmol, 1.0 equiv) according to General Procedure K. The crude product was purified by flash column chromatography according to Purification Method A to give the pure product as a colorless oil, 344 mg, 0.408 mmol, 44% yield. H NMR(500 MHz, benzene-d6) δ5.00(t,1H), δ4.12(t,2H), δ3.88-3.82(m,1H), δ3.77(t,2H), δ3.62(t,2H), δ3.44-3.38(m,1H ), δ2.51-2.43(m,1H), δ2.34-2.24(m,6H), δ1.95-1.15(br.m,68H), δ0.93-0.88(m,12H)δ0.28(d,6H); TOF MSES + [M+H + ]:842.7653 m / z

[0975] Example 145

[0976] Synthesis of 7-(4-hydroxybutyl)-15,15-dimethyl-17-pentyl-14,16,18-trioxa-7-aza-15-siladioctadecyl 2-hexyldecanoate

[0977] 7-(4-Hydroxybutyl)-15,15-dimethyl-17-pentyl-14,16,18-trioxa-7-aza-15-siladioctadecyl 2-hexyldecanoate was prepared from 1-bromo-8,8-dimethyl-10-pentyl-7,9,11-trioxa-8-silaheneicosane (556.25 mg, 1.122 mmol, 1.2 equiv) and 6-((4-hydroxybutyl)amino)hexyl 2-hexyldecanoate (400 mg, 0.935 mmol, 1.0 equiv) according to General Procedure K. The crude product was purified by flash column chromatography according to Purification Method B to afford the pure product as a colorless oil, 375 mg, 0.445 mmol, 48% yield. H NMR(500 MHz, benzene-d6) δ4.97(t,1H), δ4.10(t,2H), δ3.87-3.82(m,1H), δ3.75(t,2H), δ3.61(t,2H), δ3.42-3.38(m,1H ), δ2.47-2.41(m,1H), δ2.33-2.23(m,6H), δ1.91-1.10(br.m,68H), δ0.93-0.88(m,12H)δ0.26(d,6H); TOF MSES + [M+H + ]:842.7642 m / z

[0978] Example 146

[0979] Synthesis of 16-heptyl-7-(4-hydroxybutyl)-14,14-dimethyl-13,15,17-trioxa-7-aza-14-silanopentacosyl 2-hexyldecanoate

[0980] 16-Heptyl-7-(4-hydroxybutyl)-14,14-dimethyl-13,15,17-trioxa-7-aza-14-silanopentacosyl 2-hexyldecanoate was prepared from 1-bromo-9-heptyl-7,7-dimethyl-6,8,10-trioxa-7-silaoctadecane (270.26 mg, 0.561 mmol, 1.2 equiv) and 6-((4-hydroxybutyl)amino)hexyl 2-hexyldecanoate (200 mg, 0.468 mmol, 1.0 equiv) according to General Procedure K. The crude product was purified by flash column chromatography according to Purification Method A to give the pure product as a colorless oil, 150 mg, 0.181 mmol, 39% yield. H NMR(500 MHz, benzene-d6) δ5.01(t,1H), δ4.12(t,2H), δ3.90-3.83(m,1H), δ3.78(t,2H), δ3.62(t,2H), δ3.47-3.39(m ,1H),δ3.36(t,2H),δ2.34-2.24(m,6H),δ1.96-1.08(br.m,66H),δ0.94-0.88(m,12H)δ0.29(d,6H); LC ESI MS[M+H + ]:828.860 m / z

[0981] Example 147

[0982] Synthesis of 17-heptyl-7-(4-hydroxybutyl)-15,15-dimethyl-14,16-dioxa-18-thia-7-aza-15-silacosanyl 2-hexyldecanoate

[0983]

[0984] 17-Heptyl-7-(4-hydroxybutyl)-15,15-dimethyl-14,16-dioxa-18-thia-7-aza-15-silacosanyl 2-hexyldecanoate was prepared from 1-bromo-10-heptyl-8,8-dimethyl-7,9-dioxa-11-thia-8-silanonadecane (574.28 mg, 1.122 mmol, 1.2 equiv) and 6-((4-hydroxybutyl)amino)hexyl 2-hexyldecanoate (400 mg, 0.935 mmol, 1.0 equiv) according to General Procedure K. The crude product was purified by flash column chromatography according to Purification Method A to give the pure product as a colorless oil, 288 mg, 0.330 mmol, 35% yield. H NMR(500 MHz, benzene-d6) δ5.11(t,1H), δ4.12(t,2H), δ3.83-3.74(m,2H), δ3.62(t,2H), δ2.80-2.65(m,2H), δ2.5 0-2.41(m,1H),δ2.34-2.23(m,6H),δ2.07-1.15(br.m,68H),δ0.93-0.89(m,12H)δ0.31(d,6H); TOF MS ES+[M+H + ]:858.7407 m / z

[0985] Example 148

[0986] Synthesis of 17-heptyl-7-(2-hydroxyethyl)-15,15-dimethyl-14,16,18-trioxa-7-aza-15-silanol-hexacosyl 2-hexyldecanoate

[0987]

[0988] 17-Heptyl-7-(2-hydroxyethyl)-15,15-dimethyl-14,16,18-trioxa-7-aza-15-silacosanyl 2-hexyldecanoate was prepared from 1-bromo-10-heptyl-8,8-dimethyl-7,9,11-trioxa-8-silanonadecane (654.83 mg, 1.321 mmol, 1.1 equiv) and 6-((2-hydroxyethyl)amino)hexyl 2-hexyldecanoate (480 mg, 1.201 mmol, 1.0 equiv) according to General Procedure K. The crude product was purified by flash column chromatography according to Purification Method B to afford the pure product as a colorless oil, 190 mg, 0.233 mmol, 19% yield.

[0989] 1H NMR (500MHz, benzene-d6) δ5.00(dt,1H), δ4.12(t,2H), δ3.91-3.82(m,1H), δ3.77(t,2H), δ3.52(t,2H), δ3.46-3.38( m,1H), δ2.52-2.43(m,1H), δ2.38-2.24(m,6H), δ1.97-1.07(br.m,64H), δ0.95-0.88(m,12H), δ0.28(d,6H); TOF MSES + [M+H + ]:814.7322m / z

[0990] Example 149

[0991] Synthesis of 9-heptyl-20-(4-hydroxybutyl)-7,7-dimethyl-8,10-dioxa-20-aza-7-silanol-26-yl 2-hexyldecanoate

[0992]

[0993] 9-Heptyl-20-(4-hydroxybutyl)-7,7-dimethyl-8,10-dioxa-20-aza-7-silacosan-26-yl 2-hexyldecanoate was prepared from ((1-((9-bromononyl)oxy)octyl)oxy)(hexyl)dimethylsilane (634.84 mg, 1.286 mmol, 1.1 equiv) and 6-((4-hydroxybutyl)amino)hexyl 2-hexyldecanoate (500 mg, 1.169 mmol, 1.0 equiv) according to General Procedure K. The crude product was purified by flash column chromatography according to Purification Method B to afford the pure product as a colorless oil, 439 mg, 0.522 mmol, 45% yield.

[0994] 1 H NMR (500MHz, benzene-d6) δ4.89(dt,1H), δ4.12(t,2H), δ3.80-3.74(m,1H), δ3.63(t,2H), δ3.42-3.36(m,1H), δ2.49-2.4 4(m,1H),δ2.36-2.25(m,6H),δ1.87-1.11(br.m,70H),δ0.95-0.88(m,12H),δ0.74-0.70(m,2H),δ0.25(d,6H); TOF MSES + [M+H + ]:840.7838m / z

[0995] Example 150

[0996] Synthesis of 17-heptyl-7-(4-hydroxybutyl)-13,13,15,15-tetramethyl-12,14,16,18-tetraoxa-7-aza-13,15-disilacosadecyl 2-hexyldecanoate

[0997]

[0998] 17-Heptyl-7-(4-hydroxybutyl)-13,13,15,15-tetramethyl-12,14,16,18-tetraoxa-7-aza-13,15-disilacosanyl 2-hexyldecanoate was prepared from 1-(4-bromobutoxy)-1,1,3,3-tetramethyl-3-((1-(octyloxy)octyl)oxy)disiloxane (501.6 mg, 0.926 mmol, 1.1 equiv) and 6-((4-hydroxybutyl)amino)hexyl 2-hexyldecanoate (360 mg, 0.842 mmol, 1.0 equiv) according to General Procedure K. The crude product was purified by flash column chromatography according to Purification Method B to afford the pure product as a colorless oil, 194 mg, 0.218 mmol, 26% yield.

[0999] 1 H NMR(500MHz, benzene-d6)δ4.69(t,1H),δ3.95(t,2H),δ3.61-3.51(m,3H),δ3.48-3.41(m,2H),δ3.21-3.16(m,1H),δ 2.41-2.30(m,6H), δ2.23-2.16(m,1H), δ1.64-1.06(br.m,64H), δ0.77(t,12H), δ0.05(d,6H), δ0.00(s,6H); LC ESIMS[M+H + ]:888.640m / z

[1000] Example 151

[1001] Synthesis of 6-((6-((dimethyl((oxacyclohexadec-2-yl)oxy)silyl)oxy)hexyl)(4-hydroxybutyl)amino)hexyl 2-hexyldecanoate

[1002]

[1003] 6-((6-((Dimethyl((oxacyclohexadec-2-yl)oxy)silyl)oxy)hexyl)(4-hydroxybutyl)amino)hexyl 2-hexyldecanoate was prepared from ((6-bromohexyl)oxy)dimethyl((oxacyclohexadec-2-yl)oxy)silane (911.1 mg, 1.900 mmol, 1.25 equiv) and 6-((4-hydroxybutyl)amino)hexyl 2-hexyldecanoate (650 mg, 1.520 mmol, 1.0 equiv) according to General Procedure K. The crude product was purified by flash column chromatography according to Purification Method B to give the pure product as a colorless oil, 366 mg, 0.443 mmol, 29% yield.

[1004] 1 H NMR (500MHz, benzene-d6) δ4.96-4.93(dd,1H), δ4.12(t,2H), δ3.98-3.90(m,1H), δ3.74(t,2H), δ3.62(t,2H), δ2.35-2. 27(m,1H), δ2.50-2.40(m,1H), δ2.34-2.24(m,6H), δ1.97-1.10(br.m,70H), δ0.93-0.88(m,6H), δ0.25(d,6H); LC ESIMS[M+H + ]:826.680m / z

[1005] Example 152

[1006] Synthesis of (Z)-17-heptyl-7-(4-hydroxybutyl)-15,15-dimethyl-14,16,18-trioxa-7-aza-15-silacosadeca-24-en-1-yl 2-hexyldecanoate

[1007]

[1008] (Z)-17-Heptyl-7-(4-hydroxybutyl)-15,15-dimethyl-14,16,18-trioxa-7-aza-15-silaheptacosan-24-en-1-yl 2-hexyldecanoate was prepared from (Z)-1-bromo-10-heptyl-8,8-dimethyl-7,9,11-trioxa-8-silaicosane-17-ene (1.073 g, 2.057 mmol, 1.1 equiv) and 6-((4-hydroxybutyl)amino)hexyl 2-hexyldecanoate (800 mg, 1.870 mmol, 1.0 equiv) according to General Procedure K. The crude product was purified by flash column chromatography according to Purification Method B to obtain the pure product as a colorless oil, 200 mg, 0.234 mmol, 12% yield.

[1009] 1H NMR (500MHz, benzene-d6) δ5.48-5.38(m,2H), δ4.98(dt,1H), δ4.12(t,2H), δ3.92-3.81(m,1H), δ3.76(t,2H), δ3.62(t,2H), δ3.42-3.36( LC ESIMS[M+H + ]:854.778m / z

[1010] Example 153

[1011] Synthesis of (Z)-17-heptyl-7-(4-hydroxybutyl)-15,15-dimethyl-14,16,18-trioxa-7-aza-15-silacosano-21-en-1-yl 2-hexyldecanoate

[1012]

[1013] (Z)-17-Heptyl-7-(4-hydroxybutyl)-15,15-dimethyl-14,16,18-trioxa-7-aza-15-silaheptacosan-21-en-1-yl 2-hexyldecanoate was prepared from (Z)-1-bromo-10-heptyl-8,8-dimethyl-7,9,11-trioxa-8-silaicosane-14-ene (1.073 g, 2.057 mmol, 1.1 equiv) and 6-((4-hydroxybutyl)amino)hexyl 2-hexyldecanoate (800 mg, 1.870 mmol, 1.0 equiv) according to General Procedure K. The crude product was purified by flash column chromatography according to Purification Method B to afford the pure product as a colorless oil, 350 mg, 0.410 mmol, 22% yield.

[1014] 1 H NMR (500MHz, benzene-d6) δ5.63-5.49(m,2H), δ5.00(dt,1H), δ4.12(t,2H), δ3.91-3.84(m,1H), δ3.76(t,2H), δ3.62(t,2H), δ3.49-3.39(m,1H), δ2 .50-2.41(m,3H),δ2.35-2.23(m,5H),δ2.10-2.03(m,2H),δ1.93-1.75 (m,4H)δ1.68-1.12(br.m,60H),δ0.95-0.85(m,12H),δ0.27(d,6H); LC ESIMS[M+H+ ]:854.778m / z

[1015] Example 154

[1016] Synthesis of 7-(4-hydroxybutyl)-15,15,17-trimethyl-14,16,18-trioxa-7-aza-15-siladioctadecyl 2-hexyldecanoate

[1017]

[1018] 7-(4-Hydroxybutyl)-15,15,17-trimethyl-14,16,18-trioxa-7-aza-15-siladocayl 2-hexyldecanoate was prepared from 1-bromo-8,8,10-trimethyl-7,9,11-trioxa-8-silaheneicosane (700.88 mg, 1.595 mmol, 1.1 equiv) and 6-((4-hydroxybutyl)amino)hexyl 2-hexyldecanoate (620 mg, 1.445 mmol, 1.0 equiv) according to General Procedure K. The crude product was purified by flash column chromatography according to Purification Method B to afford the pure product as a colorless oil, 146 mg, 0.186 mmol, 13% yield.

[1019] 1 H NMR (500MHz, benzene-d6) δ5.09(q,1H), δ4.12(t,2H), δ3.85-3.79(m,1H), δ3.73(t,2H), δ3.62(t,2H), δ3.40-3.35(m,1H), δ2 .51-2.45(m,1H), δ2.34-2.23(m,6H), δ1.85-1.76(m,2H), δ1.70-1.14(br.m,62H), δ0.93-0.87(m,9H), δ0.24(d,6H); LC ESIMS[M+H + ]:786.693m / z

[1020] Example 155

[1021] Synthesis of 7-(4-hydroxybutyl)-15,15-dimethyl-17-propyl-14,16,18-trioxa-7-aza-15-siladioctadecyl 2-hexyldecanoate

[1022]

[1023] 7-(4-Hydroxybutyl)-15,15-dimethyl-17-propyl-14,16,18-trioxa-7-aza-15-siladocayl 2-hexyldecanoate was prepared from 1-bromo-8,8-dimethyl-10-propyl-7,9,11-trioxa-8-silaheneicosane (721.56 mg, 1.543 mmol, 1.1 equiv) and 6-((4-hydroxybutyl)amino)hexyl 2-hexyldecanoate (600 mg, 1.403 mmol, 1.0 equiv) according to General Procedure K. The crude product was purified by flash column chromatography according to Purification Method B to afford the pure product as a colorless oil, 248 mg, 0.305 mmol, 22% yield.

[1024] 1 H NMR (500MHz, benzene-d6) δ4.97(t,1H), δ4.11(t,2H), δ3.87-3.81(m,1H), δ3.75(t,2H), δ3.61(t,2H), δ3.42-3.37( m,1H),δ2.50-2.43(m,1H),δ2.33-2.23(m,6H),δ1.89-1.15(br.m,64H),δ0.96-0.87(m,12H)δ0.26(d,6H); TOF MSES + [M+H + ]:814.7308m / z

[1025] Example 156

[1026] Synthesis of 7-(4-hydroxybutyl)-15,15-dimethyl-17-propyl-14,16,18-trioxa-7-aza-15-silatriacontyl 2-hexyldecanoate

[1027]

[1028] 7-(4-Hydroxybutyl)-15,15-dimethyl-17-propyl-14,16,18-trioxa-7-aza-15-silatriacontyl 2-hexyldecanoate was prepared from 1-bromo-8,8-dimethyl-10-propyl-7,9,11-trioxa-8-silatricosane (903.91 mg, 1.824 mmol, 1.2 equiv) and 6-((4-hydroxybutyl)amino)hexyl 2-hexyldecanoate (650 mg, 1.520 mmol, 1.0 equiv) according to General Procedure K. The crude product was purified by flash column chromatography according to Purification Method B to afford the pure product as a colorless oil, 285 mg, 0.338 mmol, 22% yield.

[1029] H NMR (500MHz, benzene-d6) δ4.97(t,1H), δ4.11(t,2H), δ3.89-3.81(m,1H), δ3.75(t,2H), δ3.62(t,2H), δ3.44-3.37( LC ESIMS[M+H + ]:842.890m / z

[1030] Example 157

[1031] Synthesis of 14-(4-hydroxybutyl)-6,6-dimethyl-4-nonyl-3,5,7-trioxa-14-aza-6-silaneicosane-20-yl 2-hexyldecanoate

[1032]

[1033] 14-(4-Hydroxybutyl)-6,6-dimethyl-4-nonyl-3,5,7-trioxa-14-aza-6-silaicostan-20-yl 2-hexyldecanoate was prepared from 13-bromo-6,6-dimethyl-4-nonyl-3,5,7-trioxa-6-silatridecane (644.36 mg, 1.466 mmol, 1.1 equiv) and 6-((4-hydroxybutyl)amino)hexyl 2-hexyldecanoate (570 mg, 1.33 mmol, 1.0 equiv) according to General Procedure K. The crude product was purified by flash column chromatography according to Purification Method B to obtain the pure product as a colorless oil, 100 mg, 0.127 mmol, 10% yield.

[1034] 1 H NMR(500 MHz, benzene-d6)δ4.97(dt,1H),δ4.12(t,2H),δ3.87-3.80(m,1H),δ3.75(t,2H),δ3.62(t,2H),δ3.45-3.35(m,1H),δ2.50- TOF MSES + [M+H + ]:786.7024 m / z

[1035] Example 158

[1036] Synthesis of 14-(4-hydroxybutyl)-6,6-dimethyl-4-undecyl-3,5,7-trioxa-14-aza-6-silaneicosane-20-yl 2-hexyldecanoate

[1037] 14-(4-Hydroxybutyl)-6,6-dimethyl-4-undecyl-3,5,7-trioxa-14-aza-6-silaicostan-20-yl-2-hexyldecanoate was prepared from 13-bromo-6,6-dimethyl-4-undecyl-3,5,7-trioxa-6-silatridecane (829.38 mg, 1.543 mmol, 1.1 equiv) and 6-((4-hydroxybutyl)amino)hexyl 2-hexyldecanoate (600 mg, 1.403 mmol, 1.0 equiv) according to General Procedure K. The crude product was purified by flash column chromatography according to Purification Method B to give the pure product as a colorless oil, 190 mg, 0.233 mmol, 17% yield. 1 H NMR(500 MHz, benzene-d6) δ4.97(t,1H), δ4.11(t,2H), δ3.83-3.80(m,1H), δ3.74(t,2H), δ3.62(t,2H), δ3.43-3.34(m,1H), δ2.49- 2.42(m,1H), δ2.33-2.25(m,6H), δ1.92-1.76(m,4H), δ1.65-1.14(br.m,63H), δ0.98-0.85(m,9H), δ0.25(d,6H); LC ESI MS[M+H + ]:814.747 m / z

[1038] Example 159

[1039] Synthesis of 17-heptyl-15,15-dimethyl-7-(2-(1-methylpyrrolidin-2-yl)ethyl)-14,16,18-trioxa-7-aza-15-silacosanyl 2-hexyldecanoate

[1040]

[1041] 17-Heptyl-15,15-dimethyl-7-(2-(1-methylpyrrolidin-2-yl)ethyl)-14,16,18-trioxa-7-aza-15-silacosanyl 2-hexyldecanoate was prepared from 1-bromo-10-heptyl-8,8-dimethyl-7,9,11-trioxa-8-silanonadecane (233.6 mg, 0.471 mmol, 1.0 equiv) and 6-((2-(1-methylpyrrolidin-2-yl)ethyl)amino)hexyl 2-hexyldecanoate (220 mg, 0.471 mmol, 1.0 equiv) according to General Procedure K. The crude product was purified by flash column chromatography according to Purification Method B to afford the pure product as a colorless oil, 72 mg, 0.082 mmol, 17% yield.

[1042] 1 H NMR(500 MHz, benzene-d6)δ5.01(dt,1H),δ4.13(t,2H),δ3.91-3.84(m,1H),δ3.78(t,2H),δ3.45-3.40(m,1H),δ3.00(t,1H)δ2.5 TOF MSES + [M+H + ]:881.8089 m / z

[1043] Example 160

[1044] Synthesis of 16-heptyl-14,14-dimethyl-7-(2-(1-methylpyrrolidin-2-yl)ethyl)-15,17-dioxa-7-aza-14-silanopentacosyl 2-hexyldecanoate

[1045]

[1046] 16-Heptyl-14,14-dimethyl-7-(2-(1-methylpyrrolidin-2-yl)ethyl)-15,17-dioxa-7-aza-14-silanopentacosyl 2-hexyldecanoate was prepared from (6-bromohexyl)dimethyl((1-(octyloxy)octyl)oxy)silane (81.76 mg, 0.170 mmol, 1.14 equiv) and 6-((2-(1-methylpyrrolidin-2-yl)ethyl)amino)hexyl 2-hexyldecanoate (70.00 mg, 0.15 mmol, 1.0 equiv) according to General Procedure K. The crude product was purified by flash column chromatography according to Purification Method B to give the pure product as a colorless oil, 40 mg, 0.046 mmol, 31% yield.

[1047] 1 H NMR(500 MHz, benzene-d6)δ4.89(t,1H),δ4.13(t,2H),δ3.78-3.74(m,1H),δ3.41-3.36(m,1H),δ3.00(td,1H)δ2.54-2.38(m,6H) ,δ2.29(s,3H),δ2.12-1.93(m,3H)δ1.89-1.20(br.m,70H),δ0.94-0.88(m,12H),δ0.78-0.73(m,2H)δ0.29(d,6H)

[1048] Example 161

[1049] Synthesis of 16-(4-hydroxybutyl)-8,8-dimethyl-6-nonyl-5,7,9-trioxa-16-aza-8-silandocosan-22-yl 2-hexyldecanoate

[1050] 16-(4-Hydroxybutyl)-8,8-dimethyl-6-nonyl-5,7,9-trioxa-16-aza-8-siladocosan-22-yl 2-hexyldecanoate was prepared from 15-bromo-8,8-dimethyl-6-nonyl-5,7,9-trioxa-8-silapentadecane (661.41 mg, 1.414 mmol, 1.1 equiv) and 6-((4-hydroxybutyl)amino)hexyl 2-hexyldecanoate (550 mg, 1.286 mmol, 1.0 equiv) according to General Procedure K. The crude product was purified by flash column chromatography according to Purification Method A to give the pure product as a colorless oil, 112 mg, 0.137 mmol, 11% yield.

[1051] 1 H NMR(500 MHz, benzene-d6) δ4.99 (dt, 1H), δ4.12 (t, 2H), δ3.88-3.80 (m, 1H), δ3.77 (t, 2H), δ3.62 (t, 2H), δ3.43-3.36 (m, 1H), δ2.51- 2.44(m,1H), δ2.35-2.23(m,6H), δ1.97-1.76(m,4H), δ1.68-1.13(br.m,60H), δ0.94-0.89(m,12H), δ0.29(d,6H); LC ESI MS[M+H + ]:814.702 m / z

[1052] Example 162

[1053] Synthesis of 16-(4-hydroxybutyl)-8,8-dimethyl-6-undecyl-5,7,9-trioxa-16-aza-8-silandocosan-22-yl 2-hexyldecanoate

[1054]

[1055] 16-(4-Hydroxybutyl)-8,8-dimethyl-6-undecyl-5,7,9-trioxa-16-aza-8-siladocosan-22-yl 2-hexyldecanoate was prepared from 15-bromo-8,8-dimethyl-6-undecyl-5,7,9-trioxa-8-silapentadecane (411.21 mg, 0.772 mmol, 1.1 equiv) and 6-((4-hydroxybutyl)amino)hexyl 2-hexyldecanoate (300 mg, 0.702 mmol, 1.0 equiv) according to General Procedure K. The crude product was purified by flash column chromatography according to Purification Method A to give the pure product as a colorless oil, 186 mg, 0.221 mmol, 32% yield. 1 H NMR(500 MHz, benzene-d6) δ4.99 (dt, 1H), δ4.12 (t, 2H), δ3.94-3.80 (m, 1H), δ3.76 (t, 2H), δ3.62 (t, 2H), δ3.43-3.36 (m, 1H), δ2.52- TOF MSES + [M+H + ]:842.7631 m / z

[1056] Example 163

[1057] Synthesis of 14-(4-hydroxybutyl)-4,6,6-trimethyl-3,5,7-trioxa-14-aza-6-silaneicosane-20-yl 2-hexyldecanoate

[1058]

[1059] 14-(4-Hydroxybutyl)-4,6,6-trimethyl-3,5,7-trioxa-14-aza-6-silaicostan-20-yl 2-hexyldecanoate was prepared from 13-bromo-4,6,6-trimethyl-3,5,7-trioxa-6-silatridecane (311.48 mg, 0.952 mmol, 1.1 equiv) and 6-((4-hydroxybutyl)amino)hexyl 2-hexyldecanoate (370 mg, 0.865 mmol, 1.0 equiv) according to General Procedure K. The crude product was purified by flash column chromatography according to Purification Method B to give the pure product as a colorless oil, 170 mg, 0.252 mmol, 29% yield.

[1060] 1 H NMR(500 MHz, benzene-d6)δ5.04(q,1H),δ4.11(t,2H),δ3.82-3.72(m,1H),δ3.70(t,2H),δ3.62(t,2H),δ3.37-3.27(m,1H),δ2.52- TOF MSES + [M+H + ]:674.5767 m / z

[1061] Example 164

[1062] Synthesis of 17-heptyl-7-(3-hydroxypropyl)-15,15-dimethyl-14,16,18-trioxa-7-aza-15-silanol-hexacosyl 2-hexyldecanoate

[1063]

[1064] 17-Heptyl-7-(3-hydroxypropyl)-15,15-dimethyl-14,16,18-trioxa-7-aza-15-silacosanyl 2-hexyldecanoate was prepared from 1-bromo-10-heptyl-8,8-dimethyl-7,9,11-trioxa-8-silanonadecane (498.19 mg, 1.00 mmol, 1.1 equiv) and 6-((3-hydroxypropyl)amino)hexyl 2-hexyldecanoate (378.02 mg, 0.914 mmol, 1.0 equiv) according to General Procedure K. The crude product was purified by flash column chromatography according to Purification Method B to afford the pure product as a colorless oil, 50 mg, 0.060 mmol, 6% yield.

[1065] 1H NMR (500MHz, benzene-d6) δ5.01(dt,1H), δ4.12(t,2H), δ3.91-3.82(m,1H), δ3.75(t,2H), δ3.46-3.38(m,1H), δ2.52-2.4 3(m,1H),δ2.41-2.21(m,6H),δ1.95-1.76(m,4H),δ1.69-1.10(br.m,64H),δ0.97-0.81(m,12H),δ0.29(d,6H); TOF MSES + [M+H + ]:828.7505m / z

[1066] Example 165

[1067] Synthesis of 16-heptyl-7-(2-hydroxyethyl)-14,14-dimethyl-15,17-dioxa-7-aza-14-silanopentacosyl 2-hexyldecanoate

[1068]

[1069] 16-Heptyl-7-(2-hydroxyethyl)-14,14-dimethyl-15,17-dioxa-7-aza-14-silanopentacosyl 2-hexyldecanoate was prepared from (6-bromohexyl)dimethyl((1-(octyloxy)octyl)oxy)silane (263.80 mg, 0.550 mmol, 1.1 equiv) and 6-((2-hydroxyethyl)amino)hexyl 2-hexyldecanoate (200 mg, 0.500 mmol, 1.0 equiv) according to General Procedure K. The crude product was purified by flash column chromatography according to Purification Method B to give the pure product as a colorless oil, 180 mg, 0.225 mmol, 45% yield.

[1070] 1 H NMR (500MHz, benzene-d6) δ4.90-4.87(m,1H), δ4.12(t,2H), δ3.79-3.74(m,1H), δ3.51(t,2H), δ3.46-3.36(m,2H), δ2.51-2 .46(m,1H), δ2.39-2.26(m,6H), δ1.88-1.73(m,4H), δ1.69-1.18(br.m,62H), δ0.94-0.87(m,12H), δ0.26(d,6H); TOF MSES + [M+H + ]:798.7377m / z

[1071] Example 166

[1072] Synthesis of 6-((6-((dimethyl(octyl)silyl)oxy)-6-(octyloxy)hexyl)(4-hydroxybutyl)amino)hexyl 2-(decylthio)hexanoate

[1073]

[1074] 6-((6-((dimethyl(octyl)silyl)oxy)-6-(octyloxy)hexyl)(4-hydroxybutyl)amino)hexyl 2-(decylthio)hexanoate was prepared from 4-((6-((dimethyl(octyl)silyl)oxy)-6-(octyloxy)hexyl)amino)butan-1-ol (150.00 mg, 0.307 mmol, 1.0 equiv) and 6-oxohexyl 2-(decylthio)hexanoate (118.87 mg, 0.307 mmol, 1.0 equiv) according to General Procedure J. The crude product was purified twice by flash column chromatography according to purification methods A and B to afford the pure product as a colorless oil, 130 mg, 0.151 mmol, 49% yield. 1 H NMR (500MHz, benzene-d6) δ4.89(dt,1H), δ4.17-4.06(m,2H), δ3.79-3.73(m,1H), δ3.62(t,2H), δ3.42-3.30(m,2H), δ2.78-2.71(m,1H), δ2.67-2.60 (m,1H),δ2.35-2.23(m,6H),δ2.09-1.99(m,1H),δ1.89-1.11(m,65H),δ 0.94-0.89(m,9H), δ0.83(t,3H), δ0.77-0.72(m,2H), δ0.26(d,6H); TOF MSES + [M+H + ]:858.7409m / z

[1075] Example 167

[1076] Synthesis of 15-heptyl-7-(4-hydroxybutyl)-17,17-dimethyl-14,16-dioxa-7-aza-17-silanopentacosyl 2-(decylthio)hexanoate

[1077] 15-Heptyl-7-(4-hydroxybutyl)-17,17-dimethyl-14,16-dioxa-7-aza-17-silapentacosanyl 2-(decylthio)hexanoate was prepared from 13-heptyl-15,15-dimethyl-12,14-dioxa-5-aza-15-silatricosan-1-ol (150.00 mg, 0.307 mmol, 1.0 equiv) and 6-oxohexyl 2-(decylthio)hexanoate (118.87 mg, 0.307 mmol, 1.0 equiv) according to General Procedure J. The crude product was purified twice by flash column chromatography according to Purification Methods A and B to afford the pure product as a colorless oil, 142 mg, 0.165 mmol, 54% yield.

[1078] 1 H NMR (500MHz, benzene-d6) δ4.88(dt,1H), δ4.16-4.07(m,2H), δ3.79-3.73(m,1H), δ3.62(t,2H), δ3.41-3.30(m,2H), δ2.77-2.70(m,1H), δ2.67-2.60 (m,1H),δ2.34-2.23(m,6H),δ2.08-1.99(m,1H),δ1.88-1.12(m,65H),δ 0.94-0.88(m,9H), δ0.83(t,3H), δ0.76-0.72(m,2H), δ0.25(d,6H); TOF MSES + [M+H + ]:858.7404m / z

[1079] Example 168

[1080] Synthesis of 7-(4-hydroxybutyl)-15,15-dimethyl-13-(octyloxy)-14,16-dioxa-7-aza-15-silanotetracosyl 2-(decylthio)hexanoate

[1081]

[1082] 7-(4-Hydroxybutyl)-15,15-dimethyl-13-(octyloxy)-14,16-dioxa-7-aza-15-silanotetracosyl 2-(decylthio)hexanoate was prepared from 12-(5-bromopentyl)-10,10-dimethyl-9,11,13-trioxa-10-silanneonicosane (177.88 mg, 0.359 mmol, 1.1 equiv) and 6-((4-hydroxybutyl)amino)hexyl 2-(decylthio)hexanoate (150.00 mg, 0.326 mmol, 1.0 equiv) according to General Procedure K. The crude product was purified by flash column chromatography according to Purification Method A to give the pure product as a colorless oil, 140 mg, 0.160 mmol, 49% yield.

[1083] 1 H NMR (500MHz, benzene-d6) δ5.01(dt,1H), δ4.16-4.06(m,2H), δ3.89-3.84(m,1H), δ3.77(t,2H), δ3.62(t,2H), δ3.45-3.30(m,2H), δ2.77-2.70(m, 1H), δ2.67-2.60(m,1H), δ2.37-2.19(m,6H), δ2.08-1.99(m,1H), δ1. 95-1.09(m,65H), δ0.95-0.87(m,9H), δ0.83(t,3H), δ0.28(d,6H); TOF MSES + [M+H + ]:874.7339m / z

[1084] Example 169

[1085] Synthesis of 15-heptyl-7-(4-hydroxybutyl)-17,17-dimethyl-14,16,18-trioxa-7-aza-17-silanol-hexacosyl 2-(decylthio)hexanoate

[1086]

[1087] 15-Heptyl-7-(4-hydroxybutyl)-17,17-dimethyl-14,16,18-trioxa-7-aza-17-silacosanyl 2-(decylthio)hexanoate was prepared from 1-bromo-8-heptyl-10,10-dimethyl-7,9,11-trioxa-10-silanonadecane (161.71 mg, 0.326 mmol, 1.0 equiv) and 6-((4-hydroxybutyl)amino)hexyl 2-(decylthio)hexanoate (150.00 mg, 0.326 mmol, 1.0 equiv) according to General Procedure K. The crude product was purified by flash column chromatography according to Purification Method A to give the pure product as a colorless oil, 123 mg, 0.141 mmol, 43% yield. 1 H NMR (500MHz, benzene-d6) δ5.01(dt,1H), δ4.16-4.07(m,2H), δ3.93-3.84(m,1H), δ3.77(t,2H), δ3.62(t,2H), δ3.45-3.30(m,2H), δ3.78-3.71(m, 1H), δ2.67-2.60(m,1H), δ2.34-2.23(m,6H), δ2.09-2.00(m,1H), δ1. 95-1.11(m,65H), δ0.94-0.89(m,9H), δ0.83(t,3H), δ0.28(d,6H); TOF MSES + [M+H + ]:874.7355m / z

[1088] Example 170

[1089] Synthesis of 6-((4-hydroxybutyl)(6-(octyloxy)-6-((1,1,3,3-tetramethyl-3-octyldisiloxanyl)oxy)hexyl)amino)hexyl 2-(decylthio)hexanoate

[1090]

[1091] 6-((4-Hydroxybutyl)(6-(octyloxy)-6-((1,1,3,3-tetramethyl-3-octyldisiloxanyl)oxy)hexyl)amino)hexyl 2-(decylthio)hexanoate was prepared from 1-((6-bromo-1-(octyloxy)hexyl)oxy)-1,1,3,3-tetramethyl-3-octyldisiloxane (156.59 mg, 0.2828 mmol, 1.0 equiv) and 6-((4-hydroxybutyl)amino)hexyl 2-(decylthio)hexanoate (130.00 mg, 0.2828 mmol, 1.0 equiv) according to General Procedure K. The crude product was purified by flash column chromatography according to Purification Method B to give the pure product as a colorless oil, 152 mg, 0.163 mmol, 58% yield.

[1092] 1 H NMR (500MHz, benzene-d6) δ5.00(dt,1H), δ4.17-4.05(m,2H), δ3.90-3.82(m,1H), δ3.61(t,2H), δ3.46-3.28(m,2H), δ3.78-3.58(m,2H), δ2.36-2. 23(m,6H),δ2.09-1.97(m,1H),δ1.93-1.09(m,65H),δ0.94-0.88(m,9 H), δ0.83(t,3H), δ0.70-0.65(m,2H), δ0.27(d,6H), δ0.21(d,6H); TOF MSES + [M+H + ]:932.7584m / z

[1093] Example 171

[1094] Synthesis of 15-heptyl-7-(4-hydroxybutyl)-17,17,19,19-tetramethyl-14,16,18-trioxa-7-aza-17,19-disilacosadecyl 2-(decylthio)hexanoate

[1095]

[1096] 15-Heptyl-7-(4-hydroxybutyl)-17,17,19,19-tetramethyl-14,16,18-trioxa-7-aza-17,19-disilaheptacosanoyl 2-(decylthio)hexanoate was prepared from 1-((1-((6-bromohexyl)oxy)octyl)oxy)-1,1,3,3-tetramethyl-3-octyldisiloxane (177.88 mg, 0.321 mmol, 0.98 equiv) and 6-((4-hydroxybutyl)amino)hexyl 2-(decylthio)hexanoate (150.00 mg, 0.326 mmol, 1.0 equiv) according to General Procedure K. The crude product was purified by flash column chromatography according to Purification Method A to give the pure product as a colorless oil, 184 mg, 0.197 mmol, 60% yield.

[1097] 1H NMR (500MHz, benzene-d6) δ5.00(t,1H), δ4.16-4.05(m,2H), δ3.89-3.84(m,1H), δ3.6 2(t,2H), δ3.45-3.39(m,1H), δ3.34-3.30(m,1H), δ3.77-3.70(m,1H), δ2.67-2. 60(m,1H),δ2.34-2.23(m,6H),δ2.08-1.99(m,1H),δ1.95-1.12(m,65H),δ0.95- 0.89(m,9H), δ0.83(t,3H), δ0.71-0.65(m,2H), δ0.27(d,6H), δ0.21(d,6H); TOF MSES + [M+H + ]:932.7599m / z

[1098] Example 172

[1099] Synthesis of 6-((4-hydroxybutyl)(6-(octyloxy)-6-((1,1,3,3-tetramethyl-3-(octyloxy)disiloxanyl)oxy)hexyl)amino)hexyl 2-(decylthio)hexanoate

[1100]

[1101] 6-((4-Hydroxybutyl)(6-(octyloxy)-6-((1,1,3,3-tetramethyl-3-(octyloxy)disiloxanyl)oxy)hexyl)amino)hexyl 2-(decylthio)hexanoate was prepared from 4-((6-(octyloxy)-6-((1,1,3,3-tetramethyl-3-(octyloxy)disiloxanyl)oxy)hexyl)amino)butan-1-ol (90 mg, 0.159 mmol, 1.0 equiv) and 6-oxohexyl 2-(decylthio)hexanoate (61.54 mg, 0.159 mmol, 1.0 equiv) according to General Procedure J. The crude product was purified twice by flash column chromatography according to Purification Methods A and B to afford the pure product as a colorless oil, 40 mg, 0.042 mmol, 26% yield.

[1102] 1H NMR (500MHz, benzene-d6) δ5.04(dt,1H), δ4.16-4.06(m,2H), δ3.91-3.86(m,1H), δ3 .76(t,2H),δ3.62(t,2H),δ3.47-3.40(m,1H),δ3.34-3.30(m,1H),δ2.77-2.71 (m,1H), δ2.67-2.60(m,1H), δ2.37-2.21(m,6H), δ2.11-1.98(m,1H), δ1.95-1. 11(m,65H),δ0.94-0.89(m,9H),δ0.83(t,3H),δ0.31(d,6H),δ0.25(s,6H); TOF MS ES + [M+H + ]:948.7556m / z

[1103] Example 173

[1104] Synthesis of 15-heptyl-7-(4-hydroxybutyl)-17,17,19,19-tetramethyl-14,16,18,20-tetraoxa-7-aza-17,19-disilicooctadecyl 2-(decylthio)hexanoate

[1105]

[1106] 15-Heptyl-7-(4-hydroxybutyl)-17,17,19,19-tetramethyl-14,16,18,20-tetraoxa-7-aza-17,19-disiladioctadecyl 2-(decylthio)hexanoate was prepared from 1-((1-((6-bromohexyl)oxy)octyl)oxy)-1,1,3,3-tetramethyl-3-(octyloxy)disiloxane (204.49 mg, 0.359 mmol, 1.1 equiv) and 6-((4-hydroxybutyl)amino)hexyl 2-(decylthio)hexanoate (150.00 mg, 0.326 mmol, 1.0 equiv) according to General Procedure K. The crude product was purified by flash column chromatography according to Purification Method A to give the pure product as a colorless oil, 192 mg, 0.202 mmol, 62% yield.

[1107] 1H NMR (500MHz, benzene-d6) δ5.04(dt,1H), δ4.16-4.06(m,2H), δ3.90-3.85(m,1H), δ3. 76(t,2H),δ3.62(t,2H),δ3.46-3.40(m,1H),δ3.33-3.30(m,1H),δ2.77-2.70( m,1H),δ2.67-2.60(m,1H),δ2.34-2.23(m,6H),δ2.08-1.99(m,1H),δ1.96-1.1 2(m,65H),δ0.95-0.88(m,9H),δ0.83(t,3H),δ0.31(d,6H),δ0.24(s,6H);;TOF MS ES + [M+H + ]:948.7554m / z

[1108] Example 174

[1109] Synthesis of 18-hexyl-7-(4-hydroxybutyl)-15,15-dimethyl-13-(octyloxy)-14,16-dioxa-7-aza-15-silanol-hexacosyl 2-(decylthio)hexanoate

[1110]

[1111] 18-Hexyl-7-(4-hydroxybutyl)-15,15-dimethyl-13-(octyloxy)-14,16-dioxa-7-aza-15-silacosanyl 2-(decylthio)hexanoate was prepared from 10-(5-bromopentyl)-15-hexyl-12,12-dimethyl-9,11,13-trioxa-12-silatricosane (218.15 mg, 0.359 mmol, 1.1 equiv) and 6-((4-hydroxybutyl)amino)hexyl 2-(decylthio)hexanoate (150.00 mg, 0.326 mmol, 1.0 equiv) according to General Procedure K. The crude product was purified by flash column chromatography according to Purification Method A to give the pure product as a colorless oil, 158 mg, 0.160 mmol, 49% yield.

[1112] 1H NMR (500MHz, benzene-d6) δ5.03(dt,1H), δ4.16-4.07(m,2H), δ3.92-3.86(m,1H), δ3.76(d,2H), δ3.62(t,2H), δ3.48-3.42(m,1H), δ3.34-3.30(m,1H), δ2.77 -2.70(m,1H),δ2.67-2.60(m,1H),δ2.36-2.24(m,6H),δ2.08-1.99(m,1H), δ1.97-1.12(m,78H), δ0.95-0.89(m,12H), δ0.83(t,3H), δ0.30(d,6H); TOF MSES + [M+H + ]:986.8613m / z

[1113] Example 175

[1114] Synthesis of 15-heptyl-20-hexyl-7-(4-hydroxybutyl)-17,17-dimethyl-14,16,18-trioxa-7-aza-17-silanodioctadecyl 2-(decylthio)hexanoate

[1115]

[1116] 15-Heptyl-20-hexyl-7-(4-hydroxybutyl)-17,17-dimethyl-14,16,18-trioxa-7-aza-17-siladocadecyl 2-(decylthio)hexanoate was prepared from 1-bromo-8-heptyl-13-hexyl-10,10-dimethyl-7,9,11-trioxa-10-silaheneicosane (218.15 mg, 0.359 mmol, 1.1 equiv) and 6-((4-hydroxybutyl)amino)hexyl 2-(decylthio)hexanoate (150.00 mg, 0.326 mmol, 1.0 equiv) according to General Procedure K. The crude product was purified by flash column chromatography according to Purification Method A to give the pure product as a colorless oil, 190 mg, 0.193 mmol, 59% yield.

[1117] 1H NMR (500MHz, benzene-d6) δ5.02(dt,1H), δ4.16-4.07(m,2H), δ3.92-3.85(m,1H) ,δ3.75(d,2H),δ3.62(t,2H),δ3.46-3.40(m,1H),δ3.34-3.30(m,1H),δ2.7 7-2.70(m,1H),δ2.67-2.60(m,1H),δ2.34-2.24(m,6H),δ2.08-1.99(m,1H) , δ1.96-1.12(m,78H), δ0.96-0.89(m,12H), δ0.83(t,3H), δ0.30(d,6H); LC ESI MS[M+H + ]:986.763m / z

[1118] Example 176

[1119] Synthesis of 17-heptyl-7-(4-hydroxybutyl)-15,15-dimethyl-14,16,18-trioxa-7-aza-15-silacosanyl 2-(decylthio)hexanoate

[1120]

[1121] 17-Heptyl-7-(4-hydroxybutyl)-15,15-dimethyl-14,16,18-trioxa-7-aza-15-silacosanyl 2-(decylthio)hexanoate was prepared from 1-bromo-10-heptyl-8,8-dimethyl-7,9,11-trioxa-8-silanonadecane (177.88 mg, 0.359 mmol, 1.0 equiv) and 6-((4-hydroxybutyl)amino)hexyl 2-(decylthio)hexanoate (150.00 mg, 0.326 mmol, 1.0 equiv) according to General Procedure K. The crude product was purified by flash column chromatography according to Purification Method A to give the pure product as a colorless oil, 94 mg, 0.107 mmol, 33% yield. 1 H NMR (500MHz, benzene-d6) δ5.00(dt,1H), δ4.16-4.07(m,2H), δ3.89-3.84(m,1H) ,δ3.77(t,2H),δ3.62(t,2H),δ3.45-3.37(m,1H),δ3.34-3.30(m,1H),δ2.7 7-2.70(m,1H),δ2.67-2.60(m,1H),δ2.34-2.24(m,6H),δ2.08-1.99(m,1H) , δ1.95-1.12(m,65H), δ0.95-0.87(m,9H), δ0.83(t,3H), δ0.28(d,6H); TOF MSES+ [M+H + ]:874.7365m / z

[1122] Example 177

[1123] Synthesis of 6-((6-((dimethyl(octyl)silyl)oxy)-6-(octyloxy)hexyl)(4-hydroxybutyl)amino)hexyl 2-(pentylthio)decanoate

[1124]

[1125]

[0146] 6-((6-((dimethyl(octyl)silyl)oxy)-6-(octyloxy)hexyl)(4-hydroxybutyl)amino)hexyl 2-(pentylthio)decanoate was prepared from 4-((6-((dimethyl(octyl)silyl)oxy)-6-(octyloxy)hexyl)amino)butan-1-ol (150.00 mg, 0.307 mmol, 1.0 equiv) and 6-oxohexyl 2-(pentylthio)decanoate (114.56 mg, 0.307 mmol, 1.0 equiv) according to General Procedure J. The crude product was purified twice by flash column chromatography according to Purification Methods A and B to afford the pure product as a colorless oil, 120 mg, 0.142 mmol, 46% yield. 1 H NMR (500MHz, benzene-d6) δ4.89(t,1H), δ4.17-4.07(m,2H), δ3.82-3.74(m,1H), δ3.62(t,2H), δ3.42-3.33(m,2H), δ2.75-2.69(m,1H), δ2.65-2.58( m,1H),δ2.35-2.23(m,6H),δ2.12-2.03(m,1H),δ1.89-1.11(m,63H),δ 0.95-0.89(m,9H), δ0.84(t,3H), δ0.77-0.73(m,2H), δ0.26(d,6H); TOF MSES + [M+H + ]:844.7249m / z

[1126] Example 178

[1127] Synthesis of 15-heptyl-7-(4-hydroxybutyl)-17,17-dimethyl-14,16-dioxa-7-aza-17-silanopentacosyl 2-(pentylthio)decanoate

[1128]

[1129] 15-Heptyl-7-(4-hydroxybutyl)-17,17-dimethyl-14,16-dioxa-7-aza-17-silapentacosanyl 2-(pentylthio)decanoate was prepared from 13-heptyl-15,15-dimethyl-12,14-dioxa-5-aza-15-silatricosan-1-ol (150.00 mg, 0.307 mmol, 1.0 equiv) and 6-oxohexyl 2-(pentylthio)decanoate (114.56 mg, 0.307 mmol, 1.0 equiv) according to General Procedure J. The crude product was purified twice by flash column chromatography according to Purification Methods A and B to afford the pure product as a colorless oil, 142 mg, 0.168 mmol, 55% yield.

[1130] 1 H NMR (500MHz, benzene-d6) δ4.88(t,1H), δ4.17-4.07(m,2H), δ3.79-3.73(m,1H), δ3.62(t,2H), δ3.40-3.31(m,2H), δ2.75-2.68(m,1H), δ2.64-2.57( m,1H),δ2.37-2.23(m,6H),δ2.11-2.00(m,1H),δ1.86-1.11(m,63H),δ 0.94-0.91(m,9H), δ0.84(t,3H), δ0.75-0.71(m,2H), δ0.25(d,6H); TOF MSES + [M+H + ]:844.7228m / z

[1131] Example 179

[1132] Synthesis of 7-(4-hydroxybutyl)-15,15-dimethyl-13-(octyloxy)-14,16-dioxa-7-aza-15-silanotetracosyl 2-(pentylthio)decanoate

[1133]

[1134] 7-(4-Hydroxybutyl)-15,15-dimethyl-13-(octyloxy)-14,16-dioxa-7-aza-15-silanotetracosyl 2-(pentylthio)decanoate was prepared from 12-(5-bromopentyl)-10,10-dimethyl-9,11,13-trioxa-10-silaheneconane (183.47 mg, 0.370 mmol, 1.1 equiv) and 6-((4-hydroxybutyl)amino)hexyl 2-(pentylthio)decanoate (150 mg, 0.337 mmol, 1.0 equiv) according to General Procedure K. The crude product was purified by flash column chromatography according to Purification Method A to give the pure product as a colorless oil, 132 mg, 0.153 mmol, 46% yield. 1 H NMR (500MHz, benzene-d6) δ5.01(t,1H), δ4.17-4.07(m,2H), δ3.89-3.82(m,1H), δ3.77(t,2H), δ3.62(t,2H), δ3.46-3.28(m,2H), δ2.75-2.68(m,1H), δ2.64 -2.58(m,1H),δ2.35-2.22(m,6H),δ2.11-2.02(m,1H),δ1.95-1.76(m,3H) , δ1.71-1.12(m,60H), δ0.94-0.87(m,9H), δ0.84(t,3H), δ0.28(d,6H); TOF MSES + [M+H + ]:860.7214m / z

[1135] Example 180

[1136] Synthesis of 15-heptyl-7-(4-hydroxybutyl)-17,17-dimethyl-14,16,18-trioxa-7-aza-17-silanolhexacosyl 2-(pentylthio)decanoate

[1137]

[1138] 15-Heptyl-7-(4-hydroxybutyl)-17,17-dimethyl-14,16,18-trioxa-7-aza-17-silacosanyl 2-(pentylthio)decanoate was prepared from 1-bromo-8-heptyl-10,10-dimethyl-7,9,11-trioxa-10-silanonadecane (166.79 mg, 0.336 mmol, 1.0 equiv) and 6-((4-hydroxybutyl)amino)hexyl 2-(pentylthio)decanoate (150 mg, 0.336 mmol, 1.0 equiv) according to General Procedure K. The crude product was purified by flash column chromatography according to Purification Method A to give the pure product as a colorless oil, 100 mg, 0.116 mmol, 35% yield.1 H NMR (500MHz, benzene-d6) δ5.00(t,1H), δ4.17-4.07(m,2H), δ3.89-3.83(m,1H), δ3.76(t,2H), δ3.62(t,2H), δ3.44-3.32(m,2H), δ2.75-2.68(m,1H), δ2.64 -2.57(m,1H),δ2.33-2.23(m,6H),δ2.11-2.01(m,1H),δ1.95-1.76(m,3H) , δ1.71-1.13(m,60H), δ0.94-0.87(m,9H), δ0.84(t,3H), δ0.28(d,6H); TOF MSES + [M+H + ]:860.7202m / z

[1139] Example 181

[1140] Synthesis of 6-((4-hydroxybutyl)(6-(octyloxy)-6-((1,1,3,3-tetramethyl-3-octyldisiloxanyl)oxy)hexyl)amino)hexyl 2-(pentylthio)decanoate

[1141]

[1142] 6-((4-Hydroxybutyl)(6-(octyloxy)-6-((1,1,3,3-tetramethyl-3-octyldisiloxanyl)oxy)hexyl)amino)hexyl 2-(pentylthio)decanoate was prepared from 1-((6-bromo-1-(octyloxy)hexyl)oxy)-1,1,3,3-tetramethyl-3-octyldisiloxane (186.36 mg, 0.337 mmol, 1.0 equiv) and 6-((4-hydroxybutyl)amino)hexyl 2-(pentylthio)decanoate (150 mg, 0.337 mmol, 1.0 equiv) according to General Procedure K. The crude product was purified by flash column chromatography according to Purification Method B to give the pure product as a colorless oil, 120 mg, 0.131 mmol, 39% yield.

[1143] 1H NMR (500MHz, benzene-d6) δ5.00(t,1H), δ4.18-4.05(m,2H), δ3.90-3.82(m,1H), δ3.61(t,2H), δ3.46-3.30(m,2H), δ2.75-2.55(m,2H), δ2.36-2.23(m,6H) ,δ2.12-1.99(m,1H),δ1.94-1.73(m,3H)δ1.70-1.12(m,60H),δ0.95-0.88 (m,9H),δ0.84(t,3H),δ0.70-0.65(m,2H),δ0.27(d,6H),δ0.21(s,6H); TOF MSES + [M+H + ]:918.7435m / z

[1144] Example 182

[1145] Synthesis of 15-heptyl-7-(4-hydroxybutyl)-17,17,19,19-tetramethyl-14,16,18-trioxa-7-aza-17,19-disilacosadecyl 2-(pentylthio)decanoate

[1146]

[1147] 15-Heptyl-7-(4-hydroxybutyl)-17,17,19,19-tetramethyl-14,16,18-trioxa-7-aza-17,19-disilaheptacosanoyl 2-(pentylthio)decanoate was prepared from 1-((1-((6-bromohexyl)oxy)octyl)oxy)-1,1,3,3-tetramethyl-3-octyldisiloxane (161.52 mg, 0.292 mmol, 1.0 equiv) and 6-((4-hydroxybutyl)amino)hexyl 2-(pentylthio)decanoate (130 mg, 0.292 mmol, 1.0 equiv) according to General Procedure K. The crude product was purified by flash column chromatography according to Purification Method B to give the pure product as a colorless oil, 122 mg, 0.133 mmol, 45% yield.

[1148] 1H NMR (500MHz, benzene-d6) δ5.01(t,1H), δ4.18-4.05(m,2H), δ3.89-3.82(m,1H), δ3.62(t,2H), δ3.45-3.31(m,2H), δ2.76-2.56(m,2H), δ2.34-2. 23(m,6H),δ2.12-2.00(m,1H),δ1.96-1.12(m,63H),δ0.94-0.88(m,9 H), δ0.84(t,3H), δ0.70-0.65(m,2H), δ0.27(d,6H), δ0.21(s,6H); TOF MSES + [M+H + ]:918.7426m / z

[1149] Example 183

[1150] Synthesis of 6-((4-hydroxybutyl)(6-(octyloxy)-6-((1,1,3,3-tetramethyl-3-(octyloxy)disiloxanyl)oxy)hexyl)amino)hexyl 2-(pentylthio)decanoate

[1151]

[1152] 6-((4-Hydroxybutyl)(6-(octyloxy)-6-((1,1,3,3-tetramethyl-3-(octyloxy)disiloxanyl)oxy)hexyl)amino)hexyl 2-(pentylthio)decanoate was prepared from 4-((6-(octyloxy)-6-((1,1,3,3-tetramethyl-3-(octyloxy)disiloxanyl)oxy)hexyl)amino)butan-1-ol (121.00 mg, 0.209 mmol, 1.0 equiv) and 6-oxohexyl 2-(pentylthio)decanoate (78.0 mg, 0.209 mmol, 1.0 equiv) according to General Procedure J. The crude product was purified twice by flash column chromatography according to Purification Methods A and B to afford the pure product as a colorless oil, 53 mg, 0.057 mmol, 27% yield.

[1153] 1H NMR (500MHz, benzene-d6) δ5.04(t,1H), δ4.17-4.07(m,2H), δ3.91-3.86(m,1H) ,δ3.76(t,2H),δ3.62(t,2H),δ3.47-3.33(m,2H),δ2.75-2.68(m,1H),δ2 .65-2.58(m,1H),δ2.36-2.23(m,6H),δ2.12-2.02(m,1H),δ1.97-1.11(m ,63H), δ0.93-0.89(m,9H), δ0.84(t,3H), δ0.32(d,6H), δ0.25(s,6H); TOF MSES + [M+H + ]:934.7384m / z

[1154] Example 184

[1155] Synthesis of 15-heptyl-7-(4-hydroxybutyl)-17,17,19,19-tetramethyl-14,16,18,20-tetraoxa-7-aza-17,19-disilicooctadecyl 2-(pentylthio)decanoate

[1156]

[1157] 15-Heptyl-7-(4-hydroxybutyl)-17,17,19,19-tetramethyl-14,16,18,20-tetraoxa-7-aza-17,19-disiladioctadecyl 2-(pentylthio)decanoate was prepared from 1-((1-((6-bromohexyl)oxy)octyl)oxy)-1,1,3,3-tetramethyl-3-(octyloxy)disiloxane (182.80 mg, 0.321 mmol, 1.1 equiv) and 6-((4-hydroxybutyl)amino)hexyl 2-(pentylthio)decanoate (130.00 mg, 0.292 mmol, 1.0 equiv) according to General Procedure K. The crude product was purified twice by flash column chromatography according to Purification Methods A and B to afford the pure product as a colorless oil, 101 mg, 0.109 mmol, 37% yield.

[1158] 1H NMR (500MHz, benzene-d6) δ5.04(t,1H), δ4.17-4.07(m,2H), δ3.90-3.85(m,1H) ,δ3.76(t,2H),δ3.62(t,2H),δ3.46-3.32(m,2H),δ2.75-2.68(m,1H),δ2 .64-2.57(m,1H),δ2.34-2.23(m,6H),δ2.11-2.02(m,1H),δ1.96-1.10(m ,63H), δ0.92-0.89(m,9H), δ0.84(t,3H), δ0.31(d,6H), δ0.24(s,6H); TOF MSES + [M+H + ]:934.7424m / z

[1159] Example 185

[1160] Synthesis of 18-hexyl-7-(4-hydroxybutyl)-15,15-dimethyl-13-(octyloxy)-14,16-dioxa-7-aza-15-silanolhexacosyl 2-(pentylthio)decanoate

[1161]

[1162] 18-Hexyl-7-(4-hydroxybutyl)-15,15-dimethyl-13-(octyloxy)-14,16-dioxa-7-aza-15-silacosanyl 2-(pentylthio)decanoate was prepared from 10-(5-bromopentyl)-15-hexyl-12,12-dimethyl-9,11,13-trioxa-12-tricosane (225.01 mg, 0.370 mmol, 1.1 equiv) and 6-((4-hydroxybutyl)amino)hexyl 2-(pentylthio)decanoate (150.00 mg, 0.336 mmol, 1.0 equiv) according to General Procedure K. The crude product was purified twice by flash column chromatography according to Purification Methods A and B to afford the pure product as a colorless oil, 130 mg, 0.134 mmol, 40% yield.

[1163] 1H NMR (500MHz, benzene-d6) δ5.03(t,1H), δ4.17-4.07(m,2H), δ3.92-3.86(m,1H), δ3.76(d,2H), δ3.62(t,2H), δ3.48-3.32(m,2H), δ2.75-2.68(m,1 TOF MSES + [M+H + ]:972.8441m / z

[1164] Example 186

[1165] Synthesis of 15-heptyl-20-hexyl-7-(4-hydroxybutyl)-17,17-dimethyl-14,16,18-trioxa-7-aza-17-siladioctadecyl-2-(pentylthio)decanoate

[1166]

[1167] 15-Heptyl-20-hexyl-7-(4-hydroxybutyl)-17,17-dimethyl-14,16,18-trioxa-7-aza-17-siladocadecyl-2-(pentylthio)decanoate was prepared from 1-bromo-8-heptyl-13-hexyl-10,10-dimethyl-7,9,11-trioxa-10-silaheneicosane (204.56 mg, 0.336 mmol, 1.0 equiv) and 6-((4-hydroxybutyl)amino)hexyl 2-(pentylthio)decanoate (150.00 mg, 0.336 mmol, 1.0 equiv) according to General Procedure K. The crude product was purified by flash column chromatography according to Purification Method B to afford the pure product as a colorless oil, 161 mg, 0.165 mmol, 49% yield.

[1168] 1H NMR (500MHz, benzene-d6) δ5.03(t,1H), δ4.19-4.07(m,2H), δ3.94-3.85(m,1H), δ3.76(d,2H), δ3.62(t,2H), δ3.48-3.32(m,2H), δ2.77 TOF MSES + [M+H + ]:972.8463m / z

[1169] Example 187

[1170] Synthesis of 16-heptyl-7-(4-hydroxybutyl)-14,14-dimethyl-15,17-dioxa-7-aza-14-silanopentacosyl 2-(pentylthio)decanoate

[1171]

[1172] 16-Heptyl-7-(4-hydroxybutyl)-14,14-dimethyl-15,17-dioxa-7-aza-14-silanopentacosyl 2-(pentylthio)decanoate was prepared from (6-bromohexyl)dimethyl((1-(octyloxy)octyl)oxy)silane (177.55 mg, 0.370 mmol, 1.1 equiv) and 6-((4-hydroxybutyl)amino)hexyl 2-(pentylthio)decanoate (150.00 mg, 0.336 mmol, 1.0 equiv) according to General Procedure K. The crude product was purified by flash column chromatography according to Purification Method A to give the pure product as a colorless oil, 178 mg, 0.211 mmol, 63% yield.

[1173] 1 H NMR (500MHz, benzene-d6) δ4.88(t,1H), δ4.17-4.07(m,2H), δ3.79-3.73(m,1H), δ3.63(t,2H), δ3.41-3.31(m,2H), δ2.75-2.68(m,1H), δ2.64-2.57( m,1H),δ2.37-2.24(m,6H),δ2.11-2.01(m,1H),δ1.88-1.13(m,63H),δ 0.92-0.89(m,9H), δ0.84(t,3H), δ0.76-0.72(m,2H), δ0.24(d,6H); TOF MSES + [M+H+ ]:844.7252m / z

[1174] Example 188

[1175] Synthesis of 17-heptyl-7-(4-hydroxybutyl)-15,15-dimethyl-14,16,18-trioxa-7-aza-15-silacosanyl 2-(pentylthio)decanoate

[1176]

[1177] 17-Heptyl-7-(4-hydroxybutyl)-15,15-dimethyl-14,16,18-trioxa-7-aza-15-silacosanyl 2-(pentylthio)decanoate was prepared from 1-bromo-10-heptyl-8,8-dimethyl-7,9,11-trioxa-8-silanonadecane (183.47 mg, 0.370 mmol, 1.1 equiv) and 6-((4-hydroxybutyl)amino)hexyl 2-(pentylthio)decanoate (150.00 mg, 0.336 mmol, 1.0 equiv) according to General Procedure K. The crude product was purified by flash column chromatography according to Purification Method A to give the pure product as a colorless oil, 79 mg, 0.092 mmol, 27% yield. 1 H NMR (500MHz, benzene-d6) δ5.00(t,1H), δ4.17-4.07(m,2H), δ3.89-3.83(m,1H), δ3.77(t,2H), δ3.62(t,2H), δ3.45-3.32(m,2H), δ2.75-2.68(m, 1H), δ2.64-2.57(m,1H), δ2.34-2.24(m,6H), δ2.11-2.02(m,1H), δ1. 95-1.13(m,63H), δ0.92-0.89(m,9H), δ0.84(t,3H), δ0.28(d,6H); TOF MSES + [M+H + ]:860.7207m / z

[1178] Example 189

[1179] Synthesis of Heptadec-9-yl 8-((6-((dimethyl(octyl)silyl)oxy)-6-(octyloxy)hexyl)(2-hydroxyethyl)amino)octanoate

[1180]

[1181] Heptadecan-9-yl 8-((6-((dimethyl(octyl)silyl)oxy)-6-(octyloxy)hexyl)(2-hydroxyethyl)amino)octanoate was prepared from ((6-bromo-1-(octyloxy)hexyl)oxy)dimethyl(octyl)silane (155.28 mg, 0.324 mmol, 1.1 equiv) and heptadecan-9-yl 8-((2-hydroxyethyl)amino)octanoate (130.00 mg, 0.294 mmol, 1.0 equiv) according to General Procedure K. The crude product was purified by flash column chromatography according to Purification Method A to give the pure product as a colorless oil, 180 mg, 0.214 mmol, 73% yield.

[1182] 1 H NMR (500MHz, benzene-d6) δ5.16(m,1H), δ4.88(t,1H), δ3.79-3.72(m,1H), δ3.50(t,2H), δ3.41-3.35(m,1H) , δ2.37-2.23(m,8H), δ1.87-1.12(m,70H), δ0.93-0.89(m,12H), δ0.76-0.71(m,2H), δ0.25(d,6H); TOF MSES + [M+H + ]:840.7825m / z

[1183] Example 190

[1184] Synthesis of Heptadecan-9-yl 18-(2-hydroxyethyl)-10,10-dimethyl-12-(octyloxy)-9,11-dioxa-18-aza-10-silahexacano-26-oate

[1185]

[1186] Heptadecan-9-yl 18-(2-hydroxyethyl)-10,10-dimethyl-12-(octyloxy)-9,11-dioxa-18-aza-10-silahexacosanoate was prepared from 12-(5-bromopentyl)-10,10-dimethyl-9,11,13-trioxa-10-silaheneicosane (160.45 mg, 0.324 mmol, 1.1 equiv) and 8-((2-hydroxyethyl)amino)octanoate (130.00 mg, 0.294 mmol, 1.0 equiv) according to General Procedure K. The crude product was purified by flash column chromatography according to Purification Method A to afford the pure product as a colorless oil, 152 mg, 0.177 mmol, 60% yield.

[1187] 1H NMR (500MHz, benzene-d6) δ5.20-5.14(m,1H), δ5.01(t,1H), δ3.90-3.84(m,1H), δ3.77(t,2H), δ3.50(t,2H) , δ3.44-3.36(m,1H), δ2.37-2.23(m,8H), δ1.94-1.13(m,70H), δ0.96-0.87(m,12H), δ0.28(d,6H); TOF MSES + [M+H + ]:856.7795m / z

[1188] Example 191

[1189] Synthesis of Heptadec-9-yl 8-((2-hydroxyethyl)(6-(octyloxy)-6-((1,1,3,3-tetramethyl-3-octyldisiloxanyl)oxy)hexyl)amino)octanoate

[1190]

[1191] Heptadecan-9-yl 8-((2-hydroxyethyl)(6-(octyloxy)-6-((1,1,3,3-tetramethyl-3-octyldisiloxanyl)oxy)hexyl)amino)octanoate was prepared from 1-((6-bromo-1-(octyloxy)hexyl)oxy)-1,1,3,3-tetramethyl-3-octyldisiloxane (179.28 mg, 0.324 mmol, 1.1 equiv) and heptadecan-9-yl 8-((2-hydroxyethyl)amino)octanoate (130.00 mg, 0.294 mmol, 1.0 equiv) according to General Procedure K. The crude product was purified by flash column chromatography according to Purification Method A to give the pure product as a colorless oil, 203 mg, 0.222 mmol, 75% yield.

[1192] 1 H NMR (500MHz, benzene-d6) δ5.19-5.12(m,1H), δ5.01(t,1H), δ3.89-3.83(m,1H), δ3.50(t,2H), δ3.45-3.38(m,1H), δ2. 37-2.24(m,8H),δ1.93-1.12(m,70H),δ0.93-0.89(m,12H),δ0.69-0.65(m,2H),δ0.27(d,6H),δ0.21(s,6H); TOF MSES + [M+H + ]:914.7997m / z

[1193] Example 192

[1194] Synthesis of Heptadec-9-yl 8-((2-hydroxyethyl)(6-(octyloxy)-6-((1,1,3,3-tetramethyl-3-(octyloxy)disiloxanyl)oxy)hexyl)amino)octanoate

[1195]

[1196] Heptadecan-9-yl 8-((2-hydroxyethyl)(6-(octyloxy)-6-((1,1,3,3-tetramethyl-3-(octyloxy)disiloxanyl)oxy)hexyl)amino)octanoate was prepared from 1-((6-bromo-1-(octyloxy)hexyl)oxy)-1,1,3,3-tetramethyl-3-(octyloxy)disiloxane (184.46 mg, 0.324 mmol, 1.1 equiv) and heptadecan-9-yl 8-((2-hydroxyethyl)amino)octanoate (130.00 mg, 0.294 mmol, 1.0 equiv) according to General Procedure K. The crude product was purified by flash column chromatography according to Purification Method A to give the pure product as a colorless oil, 186 mg, 0.200 mmol, 68% yield.

[1197] 1 H NMR (500MHz, benzene-d6) δ5.19-5.13(m,1H), δ5.04(t,1H), δ3.91-3.85(m,1H), δ3.75(t,2H), δ3.50(t,2H), δ3. 46-3.37(m,1H),δ2.37-2.23(m,8H),δ1.95-1.12(m,70H),δ0.95-0.87(m,12H),δ0.31(d,6H),δ0.24(s,6H)

[1198] Example 193

[1199] Synthesis of Heptadec-9-yl-10-heptyl-20-(4-hydroxybutyl)-12,12-dimethyl-9,11,13-trioxa-20-aza-12-siladioctadecyl-28-oate

[1200]

[1201] Heptadecan-9-yl 10-heptyl-20-(4-hydroxybutyl)-12,12-dimethyl-9,11,13-trioxa-20-aza-12-siladocadecyl-28-oate was prepared from 1-bromo-10-heptyl-8,8-dimethyl-7,9,11-trioxa-8-silanonadecane (649.92 mg, 1.311 mmol, 1.1 equiv) and heptadecan-9-yl 8-((4-hydroxybutyl)amino)octanoate (560 mg, 0.1.192 mmol, 1.0 equiv) according to General Procedure K. The crude product was purified by flash column chromatography according to Purification Method B to give the pure product as a colorless oil, 213 mg, 0.241 mmol, 20% yield. 1 H NMR (500MHz, benzene-d6) δ5.16(m,1H), δ5.00(t,1H), δ3.91-3.82(m,1H), δ3.76(t,2H), δ3.62(t,2H), δ3.46-3.38 (m,2H),δ2.36-2.24(m,7H),δ1.96-1.77(m,2H)δ1.71-1.12(m,73H),δ0.94-0.87(m,12H),δ0.28(d,6H); TOF MSES + [M+H + ]:884.8111m / z

[1202] Example 194

[1203] Synthesis of 4-((6-((dimethyl(octyl)silyl)oxy)-6-(octyloxy)hexyl)((5Z,8Z,11Z,14Z,17Z)-eicosyl-5,8,11,14,17-pentaen-1-yl)amino)butan-1-ol

[1204]

[1205] 4-(Bis(6-((dimethyl(octyl)silyl)oxy)-6-(octyloxy)hexyl)amino)butan-1-ol was prepared from ((6-bromo-1-(octyloxy)hexyl)oxy)dimethyl(octyl)silane (148.06 mg, 0.309 mmol, 1 eq) and 4-(((5Z,8Z,11Z,14Z,17Z)-eicosaf-5,8,11,14,17-pentaen-1-yl)amino)butan-1-ol (150 mg (74% purity), 0.309 mmol, 1.0 eq) according to General Procedure G. The crude product was purified by flash column chromatography according to Purification Method A to give the pure product as a colorless oil, 100 mg, 0.132 mmol, 43% yield. 1H NMR(500MHz, benzene-d6)δ5.53-5.38(m,10H),δ4.88(dt,1H),δ3.78-3.73(m,1H),δ3.61(t,2H),δ3.41-3.35(m,1H),δ2.92-2.83(m,8H),δ TOF MSES + [M+H + ]:758.6862m / z

[1206] Example 195

[1207] Synthesis of 13-heptyl-5-((5Z,8Z,11Z,14Z,17Z)-eicosyl-5,8,11,14,17-pentaen-1-yl)-15,15-dimethyl-12,14-dioxa-5-aza-15-silatricosan-1-ol

[1208]

[1209] 13-Heptyl-5-((5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentaen-1-yl)-15,15-dimethyl-12,14-dioxa-5-aza-15-silatricosan-1-ol was prepared according to General Procedure G from ((1-((6-bromohexyl)oxy)octyl)oxy)dimethyl(octyl)silane (148.06 mg, 0.309 mmol, 1.0 equiv) and 4-(((5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentaen-1-yl)amino)butan-1-ol (150 mg (74% purity), 0.309 mmol, 1.0 equiv). The crude product was purified by flash column chromatography according to purification method A to obtain the pure product as a colorless oil, 234 mg, 0.207 mmol, 67% yield.

[1210] 1H NMR (500MHz, benzene-d6) δ5.60-5.39(m,10H), δ4.89-4.85(m,1H), δ3.78-3.73(m,1H), δ3.61(t,2H), δ3.40-3.31(m,1H), δ2.91-2.81(m,8 H), δ2.32(m,4H), δ2.26(t,2H), δ2.10-2.01(m,4H), δ1.88-1.19(m,40H), δ0.96-0.89(m,9H), δ0.78-0.71(m,2H), δ0.24(t,6H); TOF MSES + [M+H + ]:758.6857m / z

[1211] Example 196

[1212] Synthesis of 5-((5Z,8Z,11Z,14Z,17Z)-eicosyl-5,8,11,14,17-pentaen-1-yl)-13,13-dimethyl-11-(octyloxy)-12,14-dioxa-5-aza-13-silandocosan-1-ol

[1213]

[1214] 5-((5Z,8Z,11Z,14Z,17Z)-Eicosa-5,8,11,14,17-pentaen-1-yl)-13,13-dimethyl-11-(octyloxy)-12,14-dioxa-5-aza-13-siladocosan-1-ol was prepared according to General Procedure K from 12-(5-bromopentyl)-10,10-dimethyl-9,11,13-trioxa-10-silaneconecan (227.43 mg, 0.459 mmol, 1.1 equiv) and 4-(((5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentaen-1-yl)amino)butan-1-ol (150 mg, 0.417 mmol, 1 equiv). The crude product was purified by flash column chromatography according to purification method A to obtain the pure product as a colorless oil, 145 mg, 0.187 mmol, 45% yield.

[1215] 1H NMR (500MHz, benzene-d6) δ5.53-5.39(m,10H), δ5.00(m,1H), δ3.89-3.87(m,1H), δ3.77(t,2H), δ3.61(t,2H), δ3.45-3.35(m,1H), δ2.92- TOF MSES + [M+H + ]:774.6801m / z

[1216] Example 197

[1217] Synthesis of 13-heptyl-5-((5Z,8Z,11Z,14Z,17Z)-eicosahedral-5,8,11,14,17-pentaen-1-yl)-15,15-dimethyl-12,14,16-trioxa-5-aza-15-siladoca-1-ol

[1218]

[1219] 13-Heptyl-5-((5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentaen-1-yl)-15,15-dimethyl-12,14,16-trioxa-5-aza-15-silanonadecan-1-ol was prepared from 1-bromo-8-heptyl-10,10-dimethyl-7,9,11-trioxa-10-silanonadecane (206.76 mg, 0.417 mmol, 1.0 equiv) and 4-(((5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentaen-1-yl)amino)butan-1-ol (150 mg, 0.417 mmol, 1.0 equiv). The crude product was purified by flash column chromatography according to purification method B to obtain the pure product as a colorless oil, 155 mg, 0.200 mmol, 48% yield.

[1220] 1H NMR (500MHz, benzene-d6) δ5.50-5.39(m,10H), δ5.00(t,1H), δ3.89-3.83(m,1H), δ3.76(t,2H), δ3.61(t,2H), δ3.44-3.37(m,1H), δ2.92-2.83(m, 8H), δ2.34-2.31(m,4H), δ2.25(t,2H), δ2.10-1.99(m,4H), δ1.94-1. 78(m,2H), δ1.72-1.17(m,38H), δ0.95-0.87(m,9H), δ0.27(d,6H); TOF MSES + [M+H + ]:774.6811m / z

[1221] Example 198

[1222] Synthesis of 4-(((5Z,8Z,11Z,14Z,17Z)-eicosahedral-5,8,11,14,17-pentaen-1-yl)(6-(octyloxy)-6-((1,1,3,3-tetramethyl-3-octyldisiloxanyl)oxy)hexyl)amino)butan-1-ol

[1223]

[1224] 4-(((5Z,8Z,11Z,14Z,17Z)-Eicosa-5,8,11,14,17-pentaen-1-yl)(6-(octyloxy)-6-((1,1,3,3-tetramethyl-3-octyldisiloxanyl)oxy)hexyl)amino)butan-1-ol was prepared according to General Procedure K from 1-((6-bromo-1-(octyloxy)hexyl)oxy)-1,1,3,3-tetramethyl-3-octyldisiloxane (231.02 mg, 0.417 mmol, 1.0 equiv) and 4-(((5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentaen-1-yl)amino)butan-1-ol (150 mg, 0.417 mmol, 1 equiv). The crude product was purified by flash column chromatography according to purification method B to obtain the pure product as a colorless oil, 187 mg, 0.225 mmol, 54% yield.

[1225] 1H NMR (500MHz, benzene-d6) δ5.52-5.38(m,10H), δ5.00(t,1H), δ3.89-3.83(m,1H) ,δ3.61(t,2H),δ3.44-3.37(m,1H),δ2.92-2.80(m,8H),δ2.36-2.29(m,4H) ,δ2.25(t,2H),δ2.09-1.99(m,4H),δ1.94-1.77(m,2H),δ1.72-1.19(m,38H ), δ0.95-0.88(m,9H), δ0.69-0.65(m,2H), δ0.26(d,6H), δ0.21(s,6H); TOF MSES + [M+H + ]:832.7034m / z

[1226] Example 199

[1227] Synthesis of 13-heptyl-5-((5Z,8Z,11Z,14Z,17Z)-eicosyl-5,8,11,14,17-pentaen-1-yl)-15,15,17,17-tetramethyl-12,14,16-trioxa-5-aza-15,17-disilopentacosan-1-ol

[1228]

[1229] A 5-[[(6-bromohexyl)oxy)octyl]oxy)-1,1,3,3-tetramethyl-3-octyldisiloxane (231.02 mg, 0.417 mmol, 1.0 equiv) and 4-[[(5Z,8Z,11Z,14Z,17Z)-eicosahedral-5,8,11,14,17-pentaen-1-yl)amino]butyl]-thiazolinone (50 mg, 0.417 mmol, 1.0 equiv) were prepared according to General Procedure K. 13-Heptyl-5-((5Z,8Z,11Z,14Z,17Z)-eicosahedral-5,8,11,14,17-pentaen-1-yl)-15,15,17,17-tetramethyl-12,14,16-trioxa-5-aza-15,17-disilapentacosan-1-ol was prepared from 1-heptyl-5-((5Z,8Z,11Z,14Z,17Z)-eicosahedral-5,8,11,14,17-pentaen-1-yl)-15,15,17,17-tetramethyl-12,14,16-trioxa-5-aza-15,17-disilapentacosan-1-ol (150 mg, 0.417 mmol, 1 equiv). The crude product was purified by flash column chromatography according to purification method B to obtain the pure product as a colorless oil, 180 mg, 0.216 mmol, 52% yield.

[1230] 1H NMR (500MHz, benzene-d6) δ5.55-5.40(m,10H), δ5.01(t,1H), δ3.93-3.81(m,1H), δ3.61(t,2H), δ3.45-3.37(m,1H), δ2.92-2.83(m,8H), δ2.37-2.17 (m,6H),δ2.11-1.98(m,4H),δ1.95-1.75(m,2H),δ1.73-1.18(m,38H),δ 0.96-0.88(m,9H), δ0.70-0.65(m,2H), δ0.29(d,6H), δ0.22(s,6H); TOF MSES + [M+H + ]:832.7026m / z

[1231] Example 200

[1232] Synthesis of 4-(((5Z,8Z,11Z,14Z,17Z)-eicosahedral-5,8,11,14,17-pentaen-1-yl)(6-(octyloxy)-6-((1,1,3,3-tetramethyl-3-(octyloxy)disiloxanyl)oxy)hexyl)amino)butan-1-ol

[1233]

[1234]

[0266] 4-(((5Z,8Z,11Z,14Z,17Z)-Eicosa-5,8,11,14,17-pentaen-1-yl)(6-(octyloxy)-6-((1,1,3,3-tetramethyl-3-(octyloxy)disiloxanyl)oxy)hexyl)amino)butan-1-ol was prepared according to General Procedure J from 4-((6-(octyloxy)-6-((1,1,3,3-tetramethyl-3-(octyloxy)disiloxanyl)oxy)hexyl)amino)butan-1-ol (12.6 mg, 0.218 mmol, 1.0 equiv) and (5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentaenol (62.44 mg. 0.218 mmol 1.0 equiv). The crude product was purified by flash column chromatography according to purification method A to obtain the pure product as a colorless oil, 50 mg, 0.059 mmol, 27% yield.

[1235] 1H NMR (500MHz, benzene-d6) δ5.53-5.41(m,10H), δ5.01(t,1H), δ3.93-3.85(m,1H ),δ3.76(t,2H)δ3.62(t,2H),δ3.47-3.37(m,1H),δ2.92-2.82(m,8H),δ2 .36-2.32(m,4H),δ2.26(t,2H)δ2.10-1.99(m,4H),δ1.95-1.79(m,2H),δ 1.72-1.20(m,38H), δ0.95-0.89(m,9H), δ0.31(d,6H), δ0.25(s,6H); TOF MSES + [M+H + ]:848.6975m / z

[1236] Example 201

[1237] Synthesis of 13-heptyl-5-((5Z,8Z,11Z,14Z,17Z)-eicosyl-5,8,11,14,17-pentaen-1-yl)-15,15,17,17-tetramethyl-12,14,16,18-tetraoxa-5-aza-15,17-disilacosan-1-ol

[1238]

[1239] According to General Procedure K, a mixture of 1-((1-((6-bromohexyl)oxy)octyl)oxy)-1,1,3,3-tetramethyl-3-(octyloxy)disiloxane (209.17 mg, 0.367 mmol, 1.1 equiv) and 4-(((5Z,8Z,11Z,14Z,17Z)-eicosaf-5,8,11,14,17-pentaen-1-yl)amino)butyl- 13-Heptyl-5-((5Z,8Z,11Z,14Z,17Z)-eicosahedral-5,8,11,14,17-pentaen-1-yl)-15,15,17,17-tetramethyl-12,14,16,18-tetraoxa-5-aza-15,17-disilacosan-1-ol was prepared from 1-ol (120 mg, 0.334 mmol, 1.0 equiv). The crude product was purified by flash column chromatography according to purification method A to obtain the pure product as a colorless oil, 125 mg, 0.147 mmol, 44% yield.

[1240] 1H NMR (500MHz, benzene-d6) δ5.53-5.39(m,10H), δ5.04(dt,1H), δ3.90-3.84(m,1 H),δ3.76(t,2H)δ3.61(t,2H),δ3.46-3.34(m,1H),δ2.93-2.81(m,8H),δ 2.43-2.30(m,4H),δ2.25(t,2H)δ2.11-2.00(m,4H),δ1.96-1.80(m,2H), δ1.72-1.19(m,38H), δ0.95-0.87(m,9H), δ0.31(d,6H), δ0.24(s,6H); TOF MSES + [M+H + ]:848.6992m / z

[1241] Example 202

[1242] Synthesis of 16-hexyl-5-((5Z,8Z,11Z,14Z,17Z)-eicosyl-5,8,11,14,17-pentaen-1-yl)-13,13-dimethyl-11-(octyloxy)-12,14-dioxa-5-aza-13-siladoca-1-ol

[1243]

[1244] The 1,2-dimethyl-2-oxo-1,2-dimethyl ... 16-Hexyl-5-((5Z,8Z,11Z,14Z,17Z)-eicosah-5,8,11,14,17-pentaen-1-yl)-13,13-dimethyl-11-(octyloxy)-12,14-dioxa-5-aza-13-siladoca-1-ol was prepared from 16-hexyl-5-((5Z,8Z,11Z,14Z,17Z)-eicosah-5,8,11,14,17-pentaen-1-yl)-13,13-dimethyl-11-(octyloxy)-12,14-dioxa-5-aza-13-siladoca-1-ol with 16-hexyl)butan-1-ol (135 mg, 0.375 mmol, 1.0 equiv). The crude product was purified by flash column chromatography according to purification method A to give the pure product as a colorless oil, 185 mg, 0.209 mmol, 56% yield.

[1245] 1H NMR (500MHz, benzene-d6) δ5.53-5.39(m,10H), δ5.02(t,1H), δ3.92-3.86(m,1H), δ3.76(d,2H), δ3.61(t,2H), δ3.48-3.38(m,1H), δ2.93-2.82(m, 8H), δ2.37-2.30(m,4H), δ2.26(t,2H), δ2.10-1.99(m,4H), δ1.96-1.7 9(m,2H), δ1.73-1.23(m,51H), δ0.96-0.89(m,12H), δ0.30(d,6H); TOF MSES + [M+H + ]:886.8077m / z

[1246] Example 203

[1247] Synthesis of 13-heptyl-18-hexyl-5-((5Z,8Z,11Z,14Z,17Z)-eicosyl-5,8,11,14,17-pentaen-1-yl)-15,15-dimethyl-12,14,16-trioxa-5-aza-15-silacosan-1-ol

[1248]

[1249] The product was prepared according to General Procedure K from 1-bromo-8-heptyl-13-hexyl-10,10-dimethyl-7,9,11-trioxa-10-silaheneicosane (241.73 mg, 0.398 mmol, 1.1 equiv) and 4-(((5Z,8Z,11Z,14Z,17Z)-eicosaf-5,8,11,14,17-pentaen-1-yl)amino)butane 13-heptyl-18-hexyl-5-((5Z,8Z,11Z,14Z,17Z)-eicosah-5,8,11,14,17-pentaen-1-yl)-15,15-dimethyl-12,14,16-trioxa-5-aza-15-silacosane-1-ol was prepared from 1-heptyl-18-hexyl-5-((5Z,8Z,11Z,14Z,17Z)-eicosah-5,8,11,14,17-pentaen-1-yl)-15,15-dimethyl-12,14,16-trioxa-5-aza-15-silacosane-1-ol (130.00 mg, 0.361 mmol, 1.0 equiv). The crude product was purified by flash column chromatography according to purification method A to obtain the pure product as a colorless oil, 197 mg, 0.222 mmol, 61% yield.

[1250] 1H NMR (500MHz, benzene-d6) δ5.53-5.39(m,10H), δ5.02(t,1H), δ3.90-3.85(m,1H), δ3.75(d,2H), δ3.61(t,2H), δ3.46-3.37(m,1H), δ2.93-2.82(m, 8H), δ2.35-2.30(m,4H), δ2.25(t,2H), δ2.10-1.99(m,4H), δ1.97-1.8 0(m,2H), δ1.71-1.24(m,51H), δ0.95-0.89(m,12H), δ0.30(d,6H); TOF MSES + [M+H + ]:886.8049m / z

[1251] Example 204

[1252] Synthesis of 14-heptyl-5-((5Z,8Z,11Z,14Z,17Z)-eicosyl-5,8,11,14,17-pentaen-1-yl)-12,12-dimethyl-13,15-dioxa-5-aza-12-silatricosan-1-ol

[1253]

[1254] 14-Heptyl-5-((5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentaen-1-yl)-12,12-dimethyl-13,15-dioxa-5-aza-12-silatricosan-1-ol was prepared according to General Procedure K from (6-bromohexyl)dimethyl((1-(octyloxy)octyl)oxy)silane (198.08 mg, 0.413 mmol, 1.1 equiv) and 4-(((5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentaen-1-yl)amino)butan-1-ol (135.00 mg, 0.375 mmol, 1.0 equiv). The crude product was purified by flash column chromatography according to purification method A to obtain the pure product as a colorless oil, 159 mg, 0.210 mmol, 56% yield.

[1255] 1H NMR (500MHz, benzene-d6) δ5.53-5.39(m,10H), δ4.88(t,1H), δ3.79-3.73(m,1H), δ3.62(t,2H), δ3.41-3.35(m,1H), δ2.93-2.81(m,8H), δ2 TOF MSES + [M+H + ]:758.6862m / z

[1256] Example 205

[1257] Synthesis of 15-heptyl-5-((5Z,8Z,11Z,14Z,17Z)-eicosyl-5,8,11,14,17-pentaen-1-yl)-13,13-dimethyl-12,14,16-trioxa-5-aza-13-siladoca-1-ol

[1258]

[1259] 15-Heptyl-5-((5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentaen-1-yl)-13,13-dimethyl-12,14,16-trioxa-5-aza-13-silanonadecan-1-ol was prepared from 1-bromo-10-heptyl-8,8-dimethyl-7,9,11-trioxa-8-silanonadecane (227.43 mg, 0.417 mmol, 1.0 equiv) and 4-(((5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentaen-1-yl)amino)butan-1-ol (150 mg, 0.417 mmol, 1.0 equiv). The crude product was purified by flash column chromatography according to purification method A to obtain the pure product as a colorless oil, 155 mg, 0.200 mmol, 48% yield.

[1260] 1H NMR (500MHz, benzene-d6) δ5.53-5.39(m,10H), δ5.00(t,1H), δ3.89-3.84(m,1H), δ3.75(t,2H), δ3.61(t,2H), δ3.45-3.35(m,1H), δ2.93-2.81(m, 8H), δ2.34-2.30(m,4H), δ2.25(t,2H), δ2.11-1.99(m,4H), δ1.95-1. 78(m,2H), δ1.71-1.20(m,38H), δ0.95-0.87(m,9H), δ0.28(d,6H); TOF MSES + [M+H + ]:774.6809m / z

[1261] Example 206

[1262] Synthesis of 15-heptyl-5-(4-hydroxybutyl)-13,13-dimethyl-12,14,16-trioxa-5-aza-13-silacosyl (9Z,12Z)-octadeca-9,12-dienoate

[1263]

[1264] 15-Heptyl-5-(4-hydroxybutyl)-13,13-dimethyl-12,14,16-trioxa-5-aza-13-silacosyl(9Z,12Z)-octadeca-9,12-dienoate was prepared from 1-bromo-10-heptyl-8,8-dimethyl-7,9,11-trioxa-8-silanonadecane (501.9 mg, 1.013 mmol, 1.1 equiv) and 4-((4-hydroxybutyl)amino)butyl(9Z,12Z)-octadeca-9,12-dienoate (390.0 mg, 0.921 mmol, 1.0 equiv) according to General Procedure K. The crude product was purified by flash column chromatography according to Purification Method B to afford the pure product as a colorless oil, 72 mg, 0.086 mmol, 9% yield.

[1265] 1H NMR (500MHz, benzene-d6) δ5.54-5.43(m,4H), δ4.99(dd,1H), δ4.06(t,2H), δ3.88-3.83(m,1H), δ3.76(t,2H), δ3.58(t,2H), δ3.44-3.39(m,1H ), δ2.88(t,2H), δ2.29-2.16(m,7H), δ2.10-2.04(m,4H), δ1.94-1.77(m,2H), δ1.68-1.14(m,56H), δ0.91-0.87(m,9H), δ0.28(d,6H); TOF MSES + [M+H + ]:838.7358m / z

[1266] Example 207

[1267] Synthesis of 5-(3-((8Z,11Z)-heptadeca-8,11-dien-1-yl)-5,5-dimethyl-2,4,6-trioxa-5-siladecane-10-yl)-15-heptyl-13,13-dimethyl-12,14,16-trioxa-5-aza-13-silacosan-1-ol

[1268]

[1269] According to General Procedure K, 10-bromo-3-((8Z,11Z)-heptadeca-8,11-dien-1-yl)-5,5-dimethyl-2,4,6-trioxa-5-siladecane (176.6 mg, 0.349 mmol, 1.1 equiv) and 15-heptyl-13,13-dimethyl-12,14,16-trioxa-5-aza-13-silacosan- 5-(3-((8Z,11Z)-heptadeca-8,11-dien-1-yl)-5,5-dimethyl-2,4,6-trioxa-5-siladecane-10-yl)-15-heptyl-13,13-dimethyl-12,14,16-trioxa-5-aza-13-silacosan-1-ol was prepared from 1-ol (160 mg, 0.317 mmol, 1.0 equiv). The crude product was purified by flash column chromatography according to purification method B to obtain the pure product as a colorless oil, 42 mg, 0.045 mmol, 14% yield.

[1270] 1H NMR (500MHz, benzene-d6) δ5.55-5.44(m,4H), δ5.01(dd,1H), δ4.81(dd,1H), δ3.93 -3-84(m,1H),δ3.79-3.72(m,4H),δ3.61(t,2H),δ3.45-3.38(m,1H),δ3.32(s ,3H),δ2.90(t,2H),δ2.45-2.24(m,6H),δ2.12-2.06(m,4H),δ1.96-1.75(m,4 H), δ1.71-1.20(m,58H), δ0.93-0.88(m,9H), δ0.30(d,6H), δ0.25(d,6H); TOF MSES + [M+H + ]:928.7825m / z

[1271] Example 208

[1272] Synthesis of 5-(4-hydroxybutyl)-13,13,15-trimethyl-12,14,16-trioxa-5-aza-13-silacosyl(9Z,12Z)-octadeca-9,12-dienoate

[1273]

[1274] 5-(4-Hydroxybutyl)-13,13,15-trimethyl-12,14,16-trioxa-5-aza-13-silacosanyl(9Z,12Z)-octadeca-9,12-dienoate was prepared from 1-bromo-8,8,10-trimethyl-7,9,11-trioxa-8-silaheneicosane (836.9 mg, 1.713 mmol, 1.1 equiv) and 4-((4-hydroxybutyl)amino)butyl(9Z,12Z)-octadeca-9,12-dienoate (660.0 mg, 1.558 mmol, 1.0 equiv) according to General Procedure K. The crude product was purified by flash column chromatography according to Purification Method B to afford the pure product as a colorless oil, 50 mg, 0.064 mmol, 4% yield.

[1275] 1H NMR (500MHz, benzene-d6) δ5.55-5.45(m,4H), δ5.09(q,1H), δ4.07(t,2H), δ3.85-3.79(m,1H), δ3.73(t,2H), δ3.58(t,2H), δ3.40-3 .34(m,1H), δ2.89(t,2H), δ2.29-2.17(m,8H), δ2.11-2.05(m,4H), δ1.70-1.15(m,51H), δ0.94-0.80(m,6H), δ0.24(d,6H); LC ESIMS[M+H + ]:782.670m / z

[1276] Example 209

[1277] Synthesis of Undecyl 9-heptyl-20-(2-hydroxyethyl)-7,7-dimethyl-8,10-dioxa-20-aza-7-silacosan-26-oate

[1278]

[1279] Undecyl 9-heptyl-20-(2-hydroxyethyl)-7,7-dimethyl-8,10-dioxa-20-aza-7-silacosa-26-oate was prepared from ((1-((9-bromononyl)oxy)octyl)oxy)(hexyl)dimethylsilane (206.00 mg, 0.417 mmol, 1.1 equiv) and undecyl 6-((2-hydroxyethyl)amino)hexanoate (125.00 mg, 0.379 mmol, 1.0 equiv) according to General Procedure K. The crude product was purified by flash column chromatography according to Purification Method A to afford the pure product as a colorless oil, 201 mg, 0.2708 mmol, 71% yield.

[1280] 1 H NMR (500MHz, benzene-d6) δ4.89(dt,1H), δ4.08(t,2H), δ3.80-3.74(m,1H), δ3.49(t,2H), δ3.42-3.37(m,1H), δ2.3 4(t,2H),δ2.30-2.17(m,6H),δ1.88-1.15(m,58H),δ0.95-0.87(m,9H),δ0.74-0.70(m,2H),δ0.25(d,6H); TOF MSES + [M+H + ]:742.6735m / z

[1281] Example 210

[1282] Synthesis of Undecyl 6-((10-((Hexyldimethylsilyl)oxy)-10-(octyloxy)decyl)(2-hydroxyethyl)amino)hexanoate

[1283]

[1284] Undecyl 6-((10-((hexyldimethylsilyl)oxy)-10-(octyloxy)decyl)(2-hydroxyethyl)amino)hexanoate was prepared from ((10-bromo-1-(octyloxy)decyl)oxy)(hexyl)dimethylsilane (211.85 mg, 0.417 mmol, 1.1 equiv) and undecyl 6-((2-hydroxyethyl)amino)hexanoate (125.00 mg, 0.379 mmol, 1.0 equiv) according to General Procedure K. The crude product was purified by flash column chromatography according to Purification Method A to give the pure product as a colorless oil, 200 mg, 0.264 mmol, 70% yield.

[1285] 1 H NMR (500MHz, benzene-d6) δ4.89(dt,1H), δ4.08(t,2H), δ3.77-3.73(m,1H), δ3.49(t,2H), δ3.39-3.36(m,1H), δ2.3 4(t,2H), δ2.29-2.17(m,6H), δ1.90-1.15(m,60H), δ0.94-0.88(m,9H), δ0.74-0.70(m,2H), δ0.25(d,6H); TOF MSES + [M+H + ]:756.6902m / z

[1286] Example 211

[1287] Synthesis of Undecyl 17-heptyl-7-(4-hydroxybutyl)-15,15-dimethyl-14,16,18-trioxa-7-aza-15-silanol hexacosanoate

[1288]

[1289] Undecyl 17-heptyl-7-(4-hydroxybutyl)-15,15-dimethyl-14,16,18-trioxa-7-aza-15-silacosanate was prepared from 1-bromo-10-heptyl-8,8-dimethyl-7,9,11-trioxa-8-silanonadecane (485.15 mg, 0.979 mmol, 1.0 equiv) and undecyl 6-((4-hydroxybutyl)amino)hexanoate (350.0 mg, 0.979 mmol, 1.0 equiv) according to General Procedure K. The crude product was purified by flash column chromatography according to Purification Method B to afford the pure product as a colorless oil, 179 mg, 0.231 mmol, 24% yield.

[1290] 1 H NMR(500MHz, benzene-d6)δ5.11(dd,1H),δ4.18(t,2H),δ3.87(t,2H),δ3.71(t,2H),δ3.55-3.46(m,1H),δ 2.41-2.29(m,7H), δ2.06-1.88(m,2H), δ1.80-1.28(m,59H), δ1.04-0.99(m,9H), δ0.39(d,6H); TOF MSES + [M+H + ]:772.6857m / z

[1291] Example 212

[1292] Synthesis of Undecyl 6-((6-((Dimethyl((oxacyclohexadec-2-yl)oxy)silyl)oxy)hexyl)(4-hydroxybutyl)amino)hexanoate

[1293]

[1294] Undecyl 6-((6-((dimethyl((oxacyclohexadec-2-yl)oxy)silyl)oxy)hexyl)(4-hydroxybutyl)amino)hexanoate was prepared from ((6-bromohexyl)oxy)dimethyl((oxacyclohexadec-2-yl)oxy)silane (1.032 g, 2.153 mmol, 1.1 equiv) and undecyl 6-((4-hydroxybutyl)amino)hexanoate (700.0 mg, 1.958 mmol, 1.0 equiv) according to General Procedure K. The crude product was purified by flash column chromatography according to Purification Method B to give the pure product as a colorless oil, 250 mg, 0.331 mmol, 21% yield. 1H NMR (500MHz, benzene-d6) δ4.95-4.92(dd,1H), δ4.06(t,2H), δ3.95-3.90(m,1H), δ3.73(t,2H), δ3.60(t,2H), δ3.40(t,1H), δ3.29(t ,1H), δ2.30-2.17(m,7H), δ1.94-1.87(m,1H), δ1.84-1.80(m,1H), δ1.74-1.15(m,60H), δ0.93-0.90(m,3H), δ0.24(d,6H); TOF MSES + [M+H + ]:756.6555m / z

[1295] Example 213

[1296] Synthesis of Undecyl 7-(4-hydroxybutyl)-15,15,17-trimethyl-14,16,18-trioxa-7-aza-15-siladioctadecanoate

[1297]

[1298] Undecyl 7-(4-hydroxybutyl)-15,15,17-trimethyl-14,16,18-trioxa-7-aza-15-siladioctadecanoate was prepared from 1-bromo-8,8,10-trimethyl-7,9,11-trioxa-8-silaheneicosane (1250.0 mg, 2.842 mmol, 1.1 equiv) and undecyl 6-((4-hydroxybutyl)amino)hexanoate (960.0 mg, 2.583 mmol, 1.0 equiv) according to General Procedure K. The crude product was purified by flash column chromatography according to Purification Method B to afford the pure product as a colorless oil, 435 mg, 0.607 mmol, 23% yield.

[1299] 1 H NMR(500MHz, benzene-d6)δ5.09(q,1H),δ4.07(t,2H),δ3.85-3.76(m,1H),δ3.72(t,2H),δ3.61(t,2H),δ 3.40-3.33(m,1H), δ2.31-2.17(m,8H), δ1.70-1.15(m,55H), δ0.93-0.89(m,6H), δ0.25(d,6H); TOF MSES + [M+H + ]:716.6218m / z

[1300] Example 214

[1301] Synthesis of 4-((6-((dimethyl(octyl)silyl)oxy)-6-(octyloxy)hexyl)((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)pentyl)amino)butan-1-ol

[1302]

[1303]

[0266] 4-((6-((Dimethyl(octyl)silyl)oxy)-6-(octyloxy)hexyl)((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)pentyl)amino)butan-1-ol was prepared according to General Procedure J from 4-((6-((dimethyl(octyl)silyl)oxy)-6-(octyloxy)hexyl)amino)butan-1-ol (150.00 mg, 0.307 mmol, 1.0 equiv) and (4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanal (115.17 mg, 0.307 mmol, 1.0 equiv). The crude product was purified by flash column chromatography twice according to purification methods A and B to obtain the pure product as a colorless oil, 120 mg, 0.142 mmol, 46% yield.

[1304] 1 H NMR (500MHz, benzene-d6) δ4.88(dt,1H), δ4.78-4.70(m,1H), δ3.79-3.73(m,1H), δ3.64(t,2H), δ3.43(s,3H), δ3 .43-3.36(m,1H), δ2.42-2.38(m,4H), δ2.31(t,2H), δ1.97-0.70(m,78H), δ0.61(s,3H), δ0.26(d,6H); TOF MSES + [M+H + ]:846.7743m / z

[1305] Example 215

[1306] Synthesis of 13-heptyl-5-((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)pentyl)-15,15-dimethyl-12,14-dioxa-5-aza-15-silatricosan-1-ol

[1307]

[1308] A 5-nitro-1-nitro-2-nitro-1-ol (500 mg, 0.307 mmol, 1.0 equiv) and (4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)pentane were prepared according to General Procedure J from 13-heptyl-15,15-dimethyl-12,14-dioxa-5-aza-15-silatricosan-1-ol (150.00 mg, 0.307 mmol, 1.0 equiv). 13-heptyl-5-((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)pentyl)-15,15-dimethyl-12,14-dioxa-5-aza-15-silatricosan-1-ol was prepared from 1,4-dioxa-5-aza-15-silatricosan-1-ol and 1,15-dimethyl-12,14-dioxa-5-aza-15-silatricosan-1-ol using 1,15-dimethyl-3-hydroxy-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)pentyl)-15,15-dimethyl-12,14-dioxa-5-aza-15-silatricosan-1-ol. The crude product was purified twice by flash column chromatography according to purification methods A and B to give the pure product as a colorless oil, 163 mg, 0.193 mmol, 63% yield. 1 HNMR (500MHz, benzene-d6) δ4.87(dt,1H), δ4.77-4.69(m,1H), δ3.77-3.72(m,1H), δ3.64(t,2H), δ3.43(s ,3H), δ3.39-3.35(m,1H), δ2.43-2.30(m,6H), δ1.96-0.70(m,78H), δ0.61(s,3H), δ0.25(d,6H); TOF MSES + [M+H + ]:846.7725m / z

[1309] Example 216

[1310] Synthesis of 5-((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)pentyl)-13,13-dimethyl-11-(octyloxy)-12,14-dioxa-5-aza-13-silandocosan-1-ol

[1311]

[1312] Following General Procedure K, a 5-[[(4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl]pentyl]amino]-12-(5-bromopentyl)-10,10-dimethyl-9,11,13-trioxa-10-silaheneicosane)-113.25 mg, 0.228 mmol, 1.1 equiv) was added. 5-((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)pentyl)-13,13-dimethyl-11-(octyloxy)-12,14-dioxa-5-aza-13-siladocosan-1-ol was prepared from 5-((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)pentyl)-13,13-dimethyl-11-(octyloxy)-12,14-dioxa-5-aza-13-siladocosan-1-ol from 1-( ...

[1313] 1 H NMR (500MHz, benzene-d6) δ5.00(dt,1H), δ4.78-4.70(m,1H), δ3.89-3.84(m,1H), δ3.77(t,2H), δ3.64(t, 2H), δ3.45-3.43(m,4H), δ2.32-2.29(m,6H), δ1.97-0.75(m,76H), δ0.61(s,3H), δ0.28(d,6H); TOF MSES + [M+H + ]:862.7687m / z

[1314] Example 217

[1315] Synthesis of 13-heptyl-5-((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)pentyl)-15,15-dimethyl-12,14,16-trioxa-5-aza-15-siladoca-1-ol

[1316]

[1317] A 5-nitro-1- hydroxy-2-nitro-1- ... 13-heptyl-5-((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentyl)-15,15-dimethyl-12,14,16-trioxa-5-aza-15-silacosan-1-ol was prepared from 1-heptyl-1-ol (93.00 mg, 0.208 mmol, 1.0 equiv). The crude product was purified by flash column chromatography according to purification method A to obtain the pure product as a colorless oil, 39 mg, 0.045 mmol, 22% yield. 1 HNMR (500MHz, benzene-d6) δ5.00(dt,1H), δ4.78-4.68(m,1H), δ3.88-3.83(m,1H), δ3.77(t,2H), δ3.66-3.61 (m,2H), δ3.46-3.39(m,4H), δ2.45-2.25(m,6H), δ1.97-0.75(m,76H), δ0.61(s,3H), δ0.28(d,6H); TOF MSES + [M+H + ]:862.7692m / z

[1318] Example 218

[1319] Synthesis of 4-(((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)pentyl)(6-(octyloxy)-6-((1,1,3,3-tetramethyl-3-octyldisiloxanyl)oxy)hexyl)amino)butan-1-ol

[1320]

[1321] Following General Procedure K, a 5-[[(6-bromo-1-(octyloxy)hexyl)oxy)-1,1,3,3-tetramethyl-3-octyldisiloxane (126.53 mg, 0.228 mmol, 1.1 equiv) and 4-[[(4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)pentyl]amino]-1-[ ... 4-(((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)pentyl)(6-(octyloxy)-6-((1,1,3,3-tetramethyl-3-octyldisiloxanyl)oxy)hexyl)amino)butan-1-ol was prepared from butan-1-ol (93.00 mg, 0.208 mmol, 1.0 equiv). The crude product was purified by flash column chromatography according to purification method A to give the pure product as a colorless oil, 107 mg, 0.116 mmol, 56% yield.

[1322] 1 H NMR (500MHz, benzene-d6) δ5.01(dt,1H), δ4.78-4.70(m,1H), δ3.89-3.82(m,1H), δ3.64(t,2H), δ3.48-3. 39(m,4H), δ2.45-2.29(m,6H), δ1.97-0.70(m,78H), δ0.61(s,3H), δ0.27(d,6H), δ0.22(s,6H); TOF MSES + [M+H + ]:920.7921m / z

[1323] Example 219

[1324] Synthesis of 13-heptyl-5-((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)pentyl)-15,15,17,17-tetramethyl-12,14,16-trioxa-5-aza-15,17-disilopentacosan-1-ol

[1325]

[1326] A precipitate was prepared according to General Procedure K from 1-((1-((6-bromohexyl)oxy)octyl)oxy)-1,1,3,3-tetramethyl-3-octyldisiloxane (126.53 mg, 0.228 mmol, 1.1 equiv) and 4-(((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)pentyl)amino)butan-1 13-heptyl-5-((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentyl)-15,15,17,17-tetramethyl-12,14,16-trioxa-5-aza-15,17-disilapentacosane-1-ol (93.00 mg, 0.208 mmol, 1.0 equiv) was prepared from 13-heptyl-5-((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentyl)-15,15,17,17-tetramethyl-12,14,16-trioxa-5-aza-15,17-disilapentacosane-1-ol. The crude product was purified by flash column chromatography according to purification method A to obtain the pure product as a colorless oil, 65 mg, 0.071 mmol, 34% yield.

[1327] 1 H NMR (500MHz, benzene-d6) δ5.01(dt,1H), δ4.78-4.70(m,1H), δ3.88-3.83(m,1H), δ3.64(t,2H), δ3.43-3. 38(m,4H), δ2.41-2.29(m,6H), δ1.97-0.70(m,78H), δ0.61(s,3H), δ0.26(d,6H), δ0.21(s,6H); TOF MSES + [M+H + ]:920.7930m / z

[1328] Example 220

[1329] Synthesis of 4-(((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)pentyl)(6-(octyloxy)-6-((1,1,3,3-tetramethyl-3-(octyloxy)disiloxanyl)oxy)hexyl)amino)butan-1-ol

[1330]

[1331] A 5-nitropropane-17-ol suspension was prepared according to General Procedure J from 4-((6-(octyloxy)-6-((1,1,3,3-tetramethyl-3-(octyloxy)disiloxanyl)oxy)hexyl)amino)butan-1-ol (121.00 mg, 0.209 mmol, 1.0 equiv) and (4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)amino)butan-1-ol (121.00 mg, 0.209 mmol, 1.0 equiv). )valeraldehyde (87.42 mg. 0.209 mmol, 1.0 equiv) was used to prepare 4-(((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)pentyl)(6-(octyloxy)-6-((1,1,3,3-tetramethyl-3-(octyloxy)disiloxanyl)oxy)hexyl)amino)butan-1-ol. The crude product was purified by flash column chromatography according to purification method A to obtain the pure product as a colorless oil, 50 mg, 0.053 mmol, 25% yield.

[1332] 1 H NMR (500MHz, benzene-d6) δ5.03(t,1H), δ4.77-4.70(m,1H), δ3.92-3.85(m,1H), δ3.76(t,2H), δ3.63(t,2H), δ3 .46-3.37(m,4H), δ2.48-2.29(m,6H), δ1.97-0.75(m,76H), δ0.61(s,3H), δ0.31(d,6H), δ0.25(s,6H); TOF MSES + [M+H + ]:936.7874m / z

[1333] Example 221

[1334] Synthesis of 13-heptyl-5-((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)pentyl)-15,15,17,17-tetramethyl-12,14,16,18-tetraoxa-5-aza-15,17-disilacosan-1-ol

[1335]

[1336] A precipitate was prepared according to General Procedure K from 1-((1-((6-bromohexyl)oxy)octyl)oxy)-1,1,3,3-tetramethyl-3-octyldisiloxane (130.19 mg, 0.228 mmol, 1.1 equiv) and 4-(((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)pentyl)amino)butan-1-yl)-1-[[(4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)pentyl)amino)butan-1-yl]-1-[ ... 13-heptyl-5-((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentyl)-15,15,17,17-tetramethyl-12,14,16,18-tetraoxa-5-aza-15,17-disilacosan-1-ol) was prepared from 1,2-dimethyl-5-((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentyl)-15,15,17,17-tetramethyl-12,14,16,18-tetraoxa-5-aza-15,17-disilacosan-1-ol) using 4-[ ...[

[1337] 1 H NMR (500MHz, benzene-d6) δ5.03(t,1H), δ4.78-4.70(m,1H), δ3.90-3.84(m,1H), δ3.76(t,2H), δ3.64(t,2H), δ3 .47-3.37(m,4H), δ2.43-2.29(m,6H), δ1.97-0.75(m,76H), δ0.61(s,3H), δ0.31(d,6H), δ0.24(s,6H); TOF MSES + [M+H + ]:936.7881m / z

[1338] Example 222

[1339] Synthesis of 16-hexyl-5-((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)pentyl)-13,13-dimethyl-11-(octyloxy)-12,14-dioxa-5-aza-13-silanotetracosan-1-ol

[1340]

[1341] Following General Procedure K, a mixture of 10-(5-bromopentyl)-15-hexyl-12,12-dimethyl-9,11,13-trioxa-12-silatricosane (194.14 mg, 0.319 mmol, 1.19 equiv) and 4-(((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)pentyl)amino 16-Hexyl-5-((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)pentyl)-13,13-dimethyl-11-(octyloxy)-12,14-dioxa-5-aza-13-silacosan-1-ol was prepared from 1,2-dimethyl-5-((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)pentyl)-13,13-dimethyl-11-(octyloxy)-12,14-dioxa-5-aza-13-silacosan-1-ol .... The crude product was purified twice by flash column chromatography according to purification methods A and B to obtain the pure product as a colorless oil, 100 mg, 0.103 mmol, 38% yield.

[1342] 1 H NMR (500MHz, benzene-d6) δ5.02(t,1H), δ4.78-4.70(m,1H), δ3.91-3.86(m,1H), δ3.76(d,2H), δ3.64(t, 2H), δ3.47-3.37(m,4H), δ2.47-2.26(m,6H), δ1.97-0.74(m,92H), δ0.61(s,3H), δ0.29(d,6H); TOF MSES + [M+H + ]:974.8928m / z

[1343] Example 223

[1344] Synthesis of 13-heptyl-18-hexyl-5-((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentyl)-15,15-dimethyl-12,14,16-trioxa-5-aza-15-silahexacosan-1-ol

[1345]

[1346] A 5-nitro-1- hydroxy-2-nitro-1- ...2- 1- 1- 2- 1- 1- 2- 1- 1- 2- 1- 1- 1- 2- 1- 1- 2- 1- 1- 1- 2- 1- 1- 1- 2- 1- 1- 1- 2- 1- 1- 1- 2- 1- 1- 1- 2- 1- 1- 1- 2- 1- 1- 1- 2- 1- 1- 1- 2- 1- 1- 1- 2- 1- 1- 2- 1- 1- 2- 1- 1- 2- 1- 1- 2- 1- 1- 2- 1- 1- 2- 1- 1- 2- 1- 1- 2- 13-heptyl-18-hexyl-5-((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentyl)-15,15-dimethyl-12,14,16-trioxa-5-aza-15-silacosan-1-ol was prepared from 1-heptyl-18-hexyl-5-((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentyl)-15,15-dimethyl-12,14,16-trioxa-5-aza-15-silacosan-1-ol. The crude product was purified by flash column chromatography according to purification method A to obtain the pure product as a colorless oil, 109 mg, 0.112 mmol, 42% yield.

[1347] 1 H NMR (500MHz, benzene-d6) δ5.02(t,1H), δ4.78-4.70(m,1H), δ3.90-3.84(m,1H), δ3.75(d,2H), δ3.64(t, 2H), δ3.46-3.38(m,4H), δ2.41-2.30(m,6H), δ1.97-0.75(m,92H), δ0.61(s,3H), δ0.30(d,6H); TOF MSES + [M+H + ]:974.8949m / z

[1348] Example 224

[1349] Synthesis of 14-heptyl-5-((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)pentyl)-12,12-dimethyl-13,15-dioxa-5-aza-12-silatricosan-1-ol

[1350]

[1351] A precipitate was prepared according to General Procedure K from (6-bromohexyl)dimethyl((1-(octyloxy)octyl)oxy)silane (176.76 mg, 0.368 mmol, 1.10 equiv) and 4-(((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)pentyl)amino)butan-1-ol. (150.00 mg, 0.335 mmol, 1.0 equiv) Preparation of 14-heptyl-5-((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentyl)-12,12-dimethyl-13,15-dioxa-5-aza-12-silatricosan-1-ol. The crude product was purified by flash column chromatography according to Purification Method A to give the pure product as a colorless oil, 106 mg, 0.125 mmol, 37% yield.

[1352] 1 H NMR(500MHz, benzene-d6)δ4.88(dt,1H),δ4.78-4.70(m,1H),δ3.79-3.73(m,1H),δ3.65(t,2H),δ3.43(s,3H),δ3 .41-3.36(m,1H), δ2.44-2.40(m,4H), δ2.33(t,2H), δ1.97-0.71(m,78H), δ0.61(s,3H), δ0.25(d,6H); TOF MSES + [M+H + ]:846.7731m / z

[1353] Example 225

[1354] Synthesis of 15-heptyl-5-((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)pentyl)-13,13-dimethyl-12,14,16-trioxa-5-aza-13-silanetetaracon-1-ol

[1355]

[1356] Following General Procedure K, a mixture of 1-bromo-10-heptyl-8,8-dimethyl-7,9,11-trioxa-8-silanonadecane (152.21 mg, 0.307 mmol, 1.10 equiv) and 4-(((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)pentyl)amino)butyl- 15-heptyl-5-((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentyl)-13,13-dimethyl-12,14,16-trioxa-5-aza-13-silanetetaracosan-1-ol was prepared from 1-heptyl-5-((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentyl)-13,13-dimethyl-12,14,16-trioxa-5-aza-13-silanetetaracosan-1-ol (125.00 mg, 0.279 mmol, 1.0 equiv). The crude product was purified twice by flash column chromatography according to purification methods A and B to obtain the pure product as a colorless oil, 43 mg, 0.050 mmol, 18% yield.

[1357] 1 H NMR (500MHz, benzene-d6) δ5.00(td,1H), δ4.78-4.70(m,1H), δ3.89-3.84(m,1H), δ3.77(t,2H), δ3.64(t, 2H), δ3.46-3.38(m,4H), δ2.41-2.30(m,6H), δ1.97-0.75(m,76H), δ0.61(s,3H), δ0.28(d,6H); TOF MSES + [M+H + ]:862.7667m / z

[1358] Example 226

[1359] Synthesis of 15-heptyl-5-(4-hydroxybutyl)-13,13-dimethyl-12,14,16-trioxa-5-aza-13-silacosyl (4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl) valerate

[1360]

[1361] Following General Procedure K, a 1-bromo-10-heptyl-8,8-dimethyl-7,9,11-trioxa-8-silanonadecane (582.14 mg, 1.174 mmol, 1.1 equiv) and 4-((4-hydroxybutyl)amino)butyl (4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-1-bromo-10-heptyl-8,8-dimethyl-7,9,11-trioxa-8-silanonadecane (582.14 mg, 1.174 mmol, 1.1 equiv) were added. 15-Heptyl-5-(4-hydroxybutyl)-13,13-dimethyl-12,14,16-trioxa-5-aza-13-silacosanyl (4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)valerate (555.0 mg, 1.068 mmol, 1.0 equiv) was prepared. The crude product was purified by flash column chromatography according to purification method B to give the pure product as a colorless oil, 84 mg, 0.089 mmol, 83% yield.

[1362] 1 H NMR (500MHz, benzene-d6) δ5.01(td,1H), δ4.10(t,2H), δ3.90-3.84(m,1H), δ3.77(t,2H), δ3.59(t,2H), δ3.45-3.40(m,1H), δ3.25 TOF MSES + [M+H + ]:948.8075m / z

[1363] Example 227

[1364] Synthesis of 14-heptyl-5-(4-hydroxybutyl)-12,12-dimethyl-13,15-dioxa-5-aza-12-silatricosyl (4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanoate

[1365]

[1366] A 1-Hydroxy-2-nitropropane-1H-yl)-1,2-dimethyl-3-nitropropane-1H-yl)-1,2-dimethyl-3-nitropropane-1H-yl)-1,2-dimethyl-3-nitropropane-1H-yl)-1,2-dimethyl-3-nitropropane-1H-yl)-1,2-dimethyl-3-nitropropane-1H-yl)-1,2-dimethyl-3-nitropropane-1H-yl)-1,2-dimethyl-3-nitropropane-1H-yl)-1,2-dimethyl-3-nitropropane-1H-yl)-1,2-dimethyl-3-nitropropane-1H-yl)-1,2-dimethyl-3-nitropropane-1H-yl)-1,2-dimethyl-3-nitropropane-1 (550.0 mg, 1.058 mmol, 1.0 equiv) Preparation of 14-heptyl-5-(4-hydroxybutyl)-12,12-dimethyl-13,15-dioxa-5-aza-12-silatricosyl (4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoate. The crude product was purified by flash column chromatography according to purification method B to obtain the pure product as a colorless oil, 250 mg, 0.268 mmol, 25% yield.

[1367] 1H NMR (500MHz, benzene-d6) δ4.89(td,1H), δ4.10(t,2H), δ3.79-3.74(m,1H), δ3.60(t,2H), δ3.41-3.36(m,1H), δ3.25(s,3H), δ3.08-3.02(m,1H) TOF MS ES+[M+H+]:932.8140m / z

[1368] Preparation, characterization, transfection and viability study of lipid nanoparticles

[1369] According to in vitro transfection efficiency and the toxicity test to HeLa cells, synthetic lipids were tested. In order to perform the above-mentioned biological test, suitable LNP must be prepared from synthetic lipids. The preparation techniques of method A and method B are different. Particle size, PDI and the zeta potential of gained LNP were measured by dynamic light scattering technique (Dynamic Light Scattering technique, DLS). Before biological test, the encapsulation efficiency (EE) of load LNP was determined by using RiboGreen RNA. In the case of method A, luciferase-mRNA was transfected into the cell, and in the case of method B, GFP mRNA was transfected into the cell. Carry out simultaneously with the transfection experiment, in the case of method A, use resazurin (resazurin) test to determine the toxicity of the LNP studied and in the case of method B, use MTT to determine the toxicity of the LNP studied. In the case of certain lipids, the apparent pKA in LNPs was determined by titration with TNS according to the method described in Angew Chem Int Ed Engl. 2012, 51(34), 8529-8533, doi: 10.1002 / anie.201203263).

[1370] Method A

[1371] LNP preparation and dialysis (method A)

[1372] preparation:

[1373] 1. If necessary, prepare a stock solution by dissolving a known amount of lipid powder in an appropriate solvent. The recommended solvent is ethanol, and the recommended concentration is generally in the range of 10-50 mM. Higher concentrations are preferred to allow flexibility in mRNA-LNP concentration.

[1374] 2. Remove the lipid stock solution from the -20°C freezer. For long-term storage, use -80°C.

[1375] 3. Check the vials for precipitates. DOPE (CAS#474922-05-1) (20 mM) and DSPE-PEG (CAS#474922-26-4) (5 mM) may require a 5-30 minute incubation step at 37°C with intermittent vortexing to resuspend the contents. Vials with large amounts of precipitate (from freeze-thaw cycles) may not be recyclable. As a final result, the lipids can be heated to 50°C for resuspending, but the time should be as short as possible to prevent oxidation or other modification or degradation processes.

[1376] 4. Mix the lipids by vortexing for 2 minutes.

[1377] 5. Cool the lipid stock solution to room temperature by incubating on the bench, optionally protected from light. Cooling the solution prevents excessive evaporation of ethanol or similar solvents upon opening.

[1378] 6. Meanwhile, thaw RNA samples, including the latest SecNLuc control, by inserting the frozen tubes into a room temperature aluminum block.

[1379] 7. For each LNP formulation with the same mRNA composition, prepare an RNA master mix in a clean tube according to Table 1 below. Using a master mix allows for more accurate comparison of lipid formulations in relation to each other. Aliquot the master mix into a number of new tubes equal to the number of samples + controls. Each tube contains 375 μl of mRNA in 10 mM citric acid, pH 4.0.

[1380] 8. Prepare a lipid master mix for each LNP formulation with the same lipid composition, excluding the lipid of interest, in a new tube according to Table 1 below. Use of the master mix allows for more accurate comparison of the novel ionizable lipids in relation to one another. Aliquot the master mix into multiple new tubes equal in number to the sample + control. Each tube contains 65.5 μl of the lipid master mix.

[1381] 9. Add the desired ionizable lipid to the equally divided lipid master mix. Mix thoroughly by pipetting up and down. Label the tubes according to the ionizable lipid being used.

[1382] 10. Turn on the power to the 'L1 Preparation Machine' (L1 FM) and allow it to calibrate the motor position.

[1383] Table 1 Lipid preparation solution

[1384]

[1385] *The proprietary core lipid belongs to RiboPro BV and is described as compound 101 in patent application GB2302736.0

[1386] Rinse and pre-wet:

[1387] 11. Place a new microfluidics cartridge (COC plastic) into the loading slot of the L1 FM.

[1388] 12. Load a 2 ml Eppendorf tube onto the "receiving station" of the L1 FM.

[1389] 13. Fill one "Flush Syringe" (A) with 1 ml of RNase-free H2O and the other "Flush Syringe" (B) with 1 ml of 99% EtOH, a designated "Wash" stock solution.

[1390] 14. Hold the syringes in the correct orientation, with the H2O-filled syringe on the left and the EtOH-filled syringe on the right.

[1391] 15. Flush the chip by pressing "Button 2" (100 μg), holding the chip in place and checking the movement of the syringe with the machine working

[1392] 16. Restart the machine for the next configuration.

[1393] 17. Discard the flow-through tubing.

[1394] Preparation:

[1395] 18. Fill a new syringe (C) with the RNA mixture prepared previously in step 6 through a blunt 18G stainless steel needle. The volume should be approximately 85% of the total volume of the formulation + 25 μl (dead volume). Make sure to remove all bubbles by tapping gently.

[1396] 19. Fill a new syringe (D) with the lipid master mix through a blunt 18G stainless steel needle. The volume should be approximately 35% of the total volume of the formulation + 25 μl (dead volume). Again, make sure to remove all air bubbles.

[1397] 20. Hold the syringes in the correct orientation, with syringe A on the left and syringe B on the right

[1398] 21. Load the "Receiving Station" with an appropriately sized collection container (2 ml Eppendorf tube).

[1399] 22. Press the microfluidic chip against the back of the machine with your thumb and hold it there. Press "Button 1" (40 μg). L1 FM pushes the total volume of the syringe through the microfluidic mixer chip at a total flow rate (TFR) of 12 ml / ml, with a perfect 3:1 ratio (mRNA in water: lipid in EtOH).

[1400] 23. Remove the sample tubes from the "Receiving Station" and label the tubes accordingly.

[1401] 24. Reset the machine to prepare for the next preparation.

[1402] Dialysis:

[1403] 25. Transfer the individual preparations to 100 kDa MWCO, SpectraPor Biotech dialysis tubing and close with the designated clamps.

[1404] 26. Immerse the dialysis bag in a beaker filled with 1x PBS buffer pH 7.4 and stir at 230 RPM at room temperature.

[1405] 27. After incubation at room temperature for 2 hours, regenerate 1x PBS buffer (pH 7.4) with stirring.

[1406] 28. Regenerate the buffer and incubate at room temperature for 2 hours with stirring.

[1407] 29. Remove the dialysis bag from the dialysis apparatus and extract the LNP sample using a sterile pipette tip.

[1408] 30. Dilute the sample to 1 ml with sterile 1x PBS and measure the zeta potential, size, and PDI using a DLS machine.

[1409] Size and size distribution measurement using dynamic light scattering (Method A)

[1410] Turn on the DLS (Dynamic Light Scattering) machine 30 minutes before use. This allows the laser to warm up and the sample station to equilibrate to the set operating temperature (usually room temperature).

[1411] 1. Optionally, if manufacturing in discrete batches (ie, processed in multiple dialysis cassettes), separate preparations of each unique construct are pooled.

[1412] 2. Disassemble folded capillary cells (DTS1070), using one sample per construct.

[1413] 3. Rinse the cuvette by turning it upside down (injection port down) and inject 1 ml of H2O into one port. This will distribute the fluid through the cell and out the other port.

[1414] 4. Repeat this step with a syringe filled with 1 ml of air. This will dry out any excess water that may remain within the cells after flushing.

[1415] 5. Turn the cuvette over so that the injection port is at the top.

[1416] 6. Dilute 10 μl of dialyzed LNP preparation into 690 μl of 1x PBS buffer, pH 7.4.

[1417] 7. Add the sample to the cell by using a clean syringe, not exceeding the "max fill" line on the cuvette.

[1418] 8. Select the "Size & Zeta" option in the "Method Builder" of the "ZS Explorer" software and measure the sample to determine size, PDI, and zeta potential.

[1419] Encapsulation efficiency (method A)

[1420] Required solution:

[1421] 1. Preparation of sample stock solutions: In the top row of a 96-well plate (row A in the plate), use a multichannel pipette to add 297 μL of TE buffer, pH 7.4, to a single well for each sample and a single well for a PBS blank.

[1422] 2. Add 3 μL of sample (0.5 mg / mL) to each well, bringing the final volume to 300 μL. Add 3 μL of PBS to a blank well. Mix using a pipette. This is the stock solution for each sample. The final RNA concentration in these stock solutions should be approximately 4-7 μg / mL.

[1423] 3. mRNA-LNP sample setup:

[1424] a. Add 50 μL of TE buffer, pH 7.5, to the two wells directly below each sample (rows B and C in the plate).

[1425] b. Add 50 μL of sample stock from row A to the wells in rows B and C (perform this assay twice. All liquid handling should be done using a multichannel pipette).

[1426] c. Add 50 μL of Triton buffer to the wells in rows D and E (in the plate) below each sample.

[1427] d. Add 50 μL of sample stock solution from row A to the wells in rows D and E.

[1428] 4. RiboGreen RNA Standard Curve Setup: Dilute the RNA standard to yield a final concentration of 20 μg / mL RNA stock solution in TE buffer, pH 7.4. The final volume should be 150 μL. According to Table 2 below, create a standard curve (twice) using the RNA stock solution (20 μg / mL siRNA), TE buffer, pH 7.5, and Triton buffer.

[1429] Table 2 Preparation of RiboGreen RNA standard curve

[1430] Final mRNA concentration RNA stock solution (μl) TE buffer (μl) Triton buffer (μl) Total volume (μl) 2.5 25 25 50 100 1 10 40 50 100 0.5 5 45 50 100 0.25 2.5 47.5 50 100 0.1 1 49 50 100

[1431] 5. Once the samples and standard curve are prepared, incubate the plate at 37°C for 10 minutes to lyse the mRNA-LNPs in the presence of Triton X-100.

[1432] 6. Meanwhile, prepare the RiboGreen solution: Add the total number of sample wells and standard curve wells. Add 3 to this number, then multiply the total by 100. This is the total volume of RiboGreen solution required for the assay, in μL. In a 15 mL RNase-free Falcon tube, dilute the RiboGreen reagent 1:100 in TE buffer, pH 7.5, to the calculated total volume.

[1433] 7. Add RiboGreen Solution and Read Samples: Remove the 96-well plate from the 37°C incubator and allow it to cool to room temperature, as RiboGreen binding is somewhat temperature-dependent. Add 100 μL of RiboGreen solution to each well. Prick any bubbles with a needle. Read using a fluorescence plate reader (excitation = 480, emission = 525).

[1434] 8. Sample Analysis: Calculate the mRNA concentration using the data generated from the RiboGreen standard curve.

[1435] Luciferase-mRNA transfection efficiency (Method A)

[1436] Control transfection preparation:

[1437] 1. Prepare mRNA solution by adding 100 ng mRNA (SecNLuc, #P009024, RiboPro) to 5 μl Opti-MEM

[1438] a. Multiply by the number of wells including different concentrations and add 10% extra

[1439] b. We used a standard setup of 100ng-50ng-10ng mRNA / well in triplicate, which would require 528ng mRNA (including a 10% excess).

[1440] Transfection:

[1441] 2. (If applicable) Prepare different concentrations (e.g. 100 / 50 / 10 ng) in Opti-MEM.

[1442] 3. Add 10 μl to each well and mix carefully with a pipette.

[1443] 4. Stir the plate by rotating it horizontally at a moderate speed. Rotate in the opposite direction 3 times.

[1444] 5. Incubate for 24 hours (incubator).

[1445] Nano-Glo assay

[1446] background:

[1447] This protocol is used to measure the luciferase activity of secreted NanoLuc and is based on the Promega (Nano- Luciferase Assay System (#N1110-1150). This protocol is designed for 384-well plates, but for other plates, the volumes can be changed accordingly.

[1448] program:

[1449] 1. Cells (HeLa) were plated in 96-well plates, grown to 80% confluency, transfected with SecNanoLuc mRNA, and incubated for the desired time (24 h).

[1450] 2. After incubation, the translated protein accumulates in the culture medium. Transfer the medium to a new plate or tube.

[1451] 3. Transfer 12 μl of each sample to a 384-well plate with black walls and a clear bottom.

[1452] a. Black siding is important to prevent light from other wells from penetrating; alternatively, multiple wells can be left blank between samples.

[1453] 4. Set up the plate reader

[1454] 5. Place 1 volume of Nano- Luciferase assay substrate and 50 volumes of Nano- Prepare the required amount of Nano- Luciferase assay reagent

[1455] a. Composition: 100 mM MES pH 6; 1 mM EDTA; 0.5% NP-50; 150 mM KCl; 1 mM DTT; 35 mM thiourea

[1456] b. Briefly spin the tube containing the substrate in a microcentrifuge before use

[1457] 6. Add and mix (by pipetting) 12 μl Nano- Luciferase assay reagent

[1458] a. Wait about 3 minutes before measuring luminescence. The luminescence intensity will gradually decay, and the signal half-life is about 120 minutes at room temperature.

[1459] 7. Measure luminescence in a plate reader using a standard luciferase assay (this involves mixing the samples in the plate reader)

[1460] Remark

[1461] Nano- Thaw the luciferase assay buffer to room temperature, but do not exceed 25°C at any time during the procedure.

[1462] Assessment of cell viability using the resazurin assay (Method A)

[1463] background:

[1464] This protocol is used to determine cellular metabolic activity as a measure of cell viability after exposure to potentially toxic substances. Resazurin is converted to resorufin in the mitochondria via reduction, which has a higher fluorescence at ~600 nm compared to unconverted resazurin. Lower amounts / percentages of conversion correlate with reduced cellular metabolism and, indirectly, cell death and toxicity. Interpretation of the readings must be cautious, as a 50% reduction in resazurin conversion can mean a 50% reduction in cellular metabolism or 50% cell death in 100% viable cells, as well as any combination in between.

[1465] program:

[1466] 1. Prepare a 0.25 mg / ml resazurin stock solution in fresh cell culture medium. Resazurin concentrations in solution will naturally decrease over time, especially in culture medium, and a fresh stock solution should be prepared every 2-3 days. The stock solution should be stored at 4°C and protected from light. For HeLa cells, use DMEM / F12 with 10% FCS.

[1467] 2. Dilute the stock solution 10x to 0.025 mg / ml in fresh cell culture medium -> ready to apply to cells. For HeLa cells, use DMEM / F12 with 10% FCS.

[1468] 3. Collect the 96-well plate and replace the spent cell culture medium with 100 μl of Resazurin solution per well. Add some Resazurin solution to wells without cells for background measurement.

[1469] 4. Incubate in an incubator at 37°C, 5% CO2, and 95% RH for 50 minutes.

[1470] 5. Transfer the resazurin solution to a new 96-well or 384-well plate.

[1471] 6. Measure in a plate reader using 540 / 25 nm (excitation) and 610 / 40 nm (emission) using standard settings (PTM low / OD-1.0).

[1472] 7. Subtract the average background measurement from all samples. Set the average of the negative control (which received only OptiMEM during transfection) to 100%, and express all values ​​as a percentage of the control activity. Generally, at lower treatment levels, an increase in metabolic activity is shown, while for toxic substances, a sigmoidal curve can be obtained at toxic concentrations, with lower activity indicating higher toxicity.

[1473] Method B

[1474] LNP preparation (method B)

[1475] Required solution:

[1476] 0.33ug / uL mRNA (RiboPro, ready-made mRNA; eGFP with Cap1) in DEPC-treated water

[1477] 0.04ug / uL mRNA (RiboPro, ready-made mRNA; eGFP with Cap1) in DEPC-treated water

[1478] Table 3 Lipid preparation solutions in anhydrous ethanol

[1479] Reagents mol / L Tested lipids 7.36E-03 ALC-0159 (CAS#1849616-42-7) 2.54E-04 DSPC (CAS#4539-70-2) 1.49E-03 Chol(CAS#57-88-5) 7.36E-03 DOTAP (CAS#132172-61-3) 7.36E-03

[1480] MEM (Sigma, cat#M5650-500mL)

[1481] Diluent: 10 mL MEM + 0.036 mL ethanol

[1482] Liposome solution (ThermoFish / Invitgen, cat# 11668-019, 1 mg / mL solution)

[1483] program:

[1484] 1. Negative control:

[1485] a.) Place 360 ​​μL of diluent into the Eppendorf tube.

[1486] 2. Lipid formulations tested:

[1487] In a 1.5 mL Eppendorf tube:

[1488] a) Place 2.9 μL of 0.33 μg / μL mRNA solution into the Eppendorf tube

[1489] b) Add 1.94 μL of the supplied test lipid in ethanol and immediately mix by pipetting up and down several times (pipette the solution up and down several times before transferring to a pipette tip saturated with ethanol vapor)

[1490] c) Incubate for 15 minutes.

[1491] d) Add 536 μL of MEM and mix the solution by vortexing.

[1492] e) Incubate for 30 minutes.

[1493] 3. Lipofectamine-50 control formulation (according to the manufacturer's instructions)

[1494] a) Place 13.5 μL of the 0.04 μg / μL mRNA solution into a 1.5 mL sterile Eppendorf tube.

[1495] b) Add 527 μL MEM

[1496] c) Add 2.16 μL of liposome stock solution and vortex.

[1497] d) Incubate for 15 minutes

[1498] 4. Lipofectamine-6 ​​control formulation:

[1499] a) Place 45 μL of Lipofectamine-50 solution into a 1.5 mL sterile Eppendorf tube.

[1500] b) Add 315 μL of MEM and vortex.

[1501] c) Incubate for 15 minutes

[1502] Size and size distribution measurement using dynamic light scattering (Method B)

[1503] 1. Transfer 100 μL of freshly prepared LNP formulation into a DLS microvial container.

[1504] 2. Place the preparation into a Zetasizer preheated to 37°C.

[1505] 3. Allow the sample to equilibrate for 5 minutes.

[1506] 4. Perform three dimensional measurements (settings: position and automatic gain).

[1507] 5. For QC, check the correlation curve for interference. Report the Z-average and PDI based on the cumulant fit.

[1508] Encapsulation efficiency (method B)

[1509] Required solution:

[1510] Ribogreen (Invitgen / Thermo Fisher Scientific, CAT#10207502)

[1511] Table 4 Lipid preparation ethanol solution

[1512] Reagents mol / L Tested lipids 7.36E-03 ALC-0159 (CAS#1849616-42-7) 2.54E-04 DSPC (CAS#4539-70-2) 1.49E-03 Chol(CAS#57-88-5) 7.36E-03 DOTAP (CAS#132172-61-3) 7.36E-03

[1513] 0.33ug / uL mRNA solution in DEPC-treated water (RiboPro, finished mRNA; eGFP with Cap1)

[1514] 1X TE (Tris-EDTA) buffer (10 mM Tris-HCl, 1 mM EDTA, pH 7.5)

[1515] 0.1% TritonX-100 in 1X TE (Tris-EDTA) buffer

[1516] program:

[1517] 1. Prepare RiboGreen working solution:

[1518] a) Dilute RiboGreen reagent in 1X TE buffer according to the manufacturer's instructions (1:200 dilution).

[1519] 2. Preparation of RNA standards:

[1520] a) Dilute RNA standards of known concentration in 1X TE buffer to create a series of standards with varying RNA concentrations, ranging from 0.1 to 1.000 ng / mL.

[1521] b) Aliquot 100 μL of each standard into different wells of a black 96-well plate.

[1522] 3. Preparation of liposome samples:

[1523] a) Place 2.9 μL of 0.33 μg / μL mRNA solution into the Eppendorf tube

[1524] b) Add 1.94 uL of the lipid formulation ethanol solution and immediately mix by pipetting up and down several times (CAUTION! Pipette the solution up and down several times before transferring to a pipette tip saturated with ethanol vapor)

[1525] c) Incubate for 15 minutes.

[1526] d) Add 268 μL of 1x TE buffer and mix the solution by vortexing.

[1527] e) Incubate for 30 minutes.

[1528] Transfer 100uL of the obtained sample to a separate Eppendorf tube and dilute with an additional 100uL of 1x TE buffer. Vortex briefly = control sample

[1529] g) Transfer 100 μL of the obtained sample to a separate Eppendorf tube and dilute with 100 μL of 0.1% Triton X-100 solution. Vortex briefly and incubate at 37° C. for 15 minutes to lyse the sample.

[1530] h) Aliquot 100 μL of the control sample and lysate sample into different wells of a black 96-well plate.

[1531] 4. Perform RiboGreen Assay:

[1532] a) Add 100 μL of RiboGreen working solution to each well containing RNA standards and liposome samples.

[1533] b) Gently mix the contents of the wells by pipetting up and down or by shaking the plate on an orbital shaker.

[1534] c) Incubate the plate at room temperature in the dark for 5-10 minutes.

[1535] d) Using a fluorescence microplate reader, measure the fluorescence intensity of each well with an excitation wavelength of 480 nm and an emission wavelength of 525 nm.

[1536] e) Record the fluorescence values ​​of RNA standards and liposome samples.

[1537] 5. Calculate mRNA encapsulation efficiency:

[1538] a) Create an RNA standard curve by plotting RNA concentration (ng / mL) on the x-axis and the corresponding fluorescence intensity on the y-axis. Fit the data with a linear regression model.

[1539] b) The mRNA concentration in the liposome sample was determined by interpolating its fluorescence value on the standard curve.

[1540] c) mRNA encapsulation efficiency was calculated as the percentage of mRNA content in the liposome control sample relative to the liposome lysate sample. Transfection efficiency of GFP-mRNA (Method B)

[1541] Required solution:

[1542] MEM (Sigma, cat#M5650-500mL)

[1543] Fetal bovine serum, FBS (Sigma, CAT#F7524-500 ml)

[1544] Solution of preparation (see above)

[1545] Diluent: 10 mL MEM + 0.036 mL ethanol

[1546] Phosphate-buffered saline, PBS

[1547] program:

[1548] 1. Fill the edge wells of a 96-well plate with 100 μL of medium.

[1549] 2. Plate 10,000 HeLa cells in each well of a 96-well plate. Do not use the edge wells. A total of 60 wells should be plated. Incubate in MEM + 10% FBS at 37°C in a humidified atmosphere with 5% CO2 for 24 hours.

[1550] 3. Check under a microscope. The degree of confluence must be equal to or close to 80%.

[1551] 4. Gently remove the medium (aspiration). Add 50 μL of the following preparations:

[1552] a) 6 wells, diluent-negative control

[1553] b) 6 wells, Lipofectamine-50-positive control

[1554] c) 6 wells, Lipofectamine-6-secondary positive control

[1555] d) 6 wells per formulation - test samples.

[1556] 5. Incubate the plate at 37°C for 1 hour.

[1557] 6. Add 50 μL of MEM + 20% FBS (to 10% after dilution).

[1558] 7. Place the plate in an incubator at 37°C in a humidified atmosphere containing 5% CO2 for 23 h (total incubation 24 h).

[1559] After 24 hours, aspirate the medium without disturbing the cells. Gently wash the cells with 100 μL of warm PBS. Aspirate the PBS.

[1560] 9. Add 100 μL of fresh PBS to the washed cells and read GFP fluorescence on a plate reader.

[1561] 10. This can then be followed by viability assessment using the MTT assay.

[1562] Assessment of cell viability using MTT assay (Method B)

[1563] Required solution:

[1564] MEM (Sigma, cat#M5650-500mL)

[1565] Fetal bovine serum, FBS (Sigma, CAT#F7524-500 ml)

[1566] Thiazolyl blue tetrazolium bromide, MTT (TCI Chemicals, cat# D0801-5G)

[1567] Solution for preparation (see "Preparation of GFP mRNA-loaded LNPs" protocol)

[1568] Diluent: 10 mL MEM + 0.036 mL ethanol

[1569] Phosphate-buffered saline, PBS

[1570] program:

[1571] 1. Plate 10,000 HeLa cells in each well of a 96-well plate. Do not use the edge wells. A total of 60 wells should be plated. Incubate in MEM + 10% FBS at 37°C in a humidified atmosphere with 5% CO2 for 24 hours.

[1572] 2. Check under a microscope. The degree of confluence must be equal to or close to 80%.

[1573] 3. Gently remove the medium (aspiration). Add 50 μL of the following preparations:

[1574] a) 6 wells, diluent-negative control

[1575] b) 6 wells, Lipofectamine-50-positive control

[1576] c) 6 wells, Lipofectamine-6-secondary positive control

[1577] d) 6 wells per formulation - test samples.

[1578] 4. Incubate the plate at 37°C for 1 hour.

[1579] 5. Add 50uL MEM + 20% FBS (to 10% after dilution).

[1580] 6. Place the plate in an incubator at 37°C for 23 hours (total incubation 24 hours).

[1581] 7. Prepare a 1 mg / mL MTT solution in sterile PBS. Filter-sterilize the solution using a 0.22 μm filter and protect from light. This solution should be prepared fresh before the assay.

[1582] 8. After the treatment time, carefully remove the treatment medium from each well.

[1583] a. Add 100 μL of MTT solution to each well.

[1584] b. Incubate the plate at 37°C in a humidified atmosphere containing 5% CO2 for 2-4 hours.

[1585] 9. After incubation, carefully remove the MTT solution from each well without disturbing the formazan crystals. Add 100-150 μL of solubilization solution (0.04 M HCl in isopropanol) to each well to dissolve the formazan crystals. Gently pipette up and down or shake the plate on an orbital shaker for 5-10 minutes to ensure complete dissolution.

[1586] 10. Measure the absorbance of each well at 570 nm using a microplate reader. Measure the absorbance at a reference wavelength of 650 nm to subtract background absorbance.

[1587] 11. Calculate relative cell viability (%) by comparison with blank control (untreated culture).

[1588] The above experimental results using the lipids according to the present invention and reference compounds are summarized in Table 5 below.

[1589] Table 5

[1590]

[1591]

[1592]

[1593]

[1594] in conclusion

[1595] Thanks to the novel modular approach of the novel ionizable cationic lipid library described in the present invention, the vast prospects of chemical space become accessible. By utilizing commercially available starting materials and implementing proprietary borane catalysts (as described in WO2022 / 129966), compounds of formula (I) can be synthesized.

[1596] The results from LNP preparation and transfection studies provide evidence that the novel silicon-containing lipids described in the present invention produce nanoparticles of suitable size, polydispersity index (PDI) and zeta potential. In addition, apparent pKa values ​​were determined in some cases that were consistent with the optimal range.

[1597] Furthermore, lipid nanoparticles formed from lipids of formula (I) demonstrated their potential to deliver GFP and luciferase mRNA into cells while exhibiting low to moderate cytotoxicity. Notably, a number of lipids of formula (I) from this study exhibited comparable or even better transfection efficiencies than the reference compound ALC-0315.

Claims

1. A compound having a structure of formula (I) or a salt or stereoisomer thereof, in: G 1 is an unsubstituted C2-C9 alkylene group, -(CH2) x -CH=CH-(CH2) y -, wherein x is an integer selected from 1 to 6, y is an integer selected from 1 to 6, and the sum of x+y is an integer selected from 2 to 7, or -(CH2) w -X-(CH2) z -, wherein w is an integer selected from 1 to 7, z is an integer selected from 2 to 7, and the sum of w+z is an integer selected from 3 to 8, wherein -(CH2) z - is attached to N, and X is selected from O, S, SO and SO2; T 1 for in b 1 To G 1 The key, X1 and X2 are the same or different and each independently represents O or S, R1 is linear C1-C 17 Alkyl, nonlinear C3-C 17 Alkyl, in both cases optionally containing one S, SO, SO2, O or Si(R a )2, where R a is a C1-C6 alkyl group at any position in the carbon chain, provided that the heteroatom is not in the α or Ω position of the carbon chain; a C3-C 17 alkenyl, provided that there is at least one -CH2- group between the double bond and X2; or a polyunsaturated C8-C 20 alkenyl, provided that there is at least one -CH2- group between the first double bond and X2, or R1 is Among them, R 17 , R 18 and R 19 are the same or different and can each independently be H, OH, -C1-C6 alkoxy or fluorine; R2 is Linear C1-C 17 Alkyl, nonlinear C3-C 17 Alkyl, in both cases optionally containing one S, SO, SO2, O or Si (R b )2, where R b is a C1-C6 alkyl group at any position in the carbon chain, provided that the heteroatom is not in the α or Ω position of the carbon chain; a C3-C 17 alkenyl, provided that there is at least one -CH2- group between the double bond and the carbon connecting X1 and X2; or a polyunsaturated C8-C 20 alkenyl, provided that there is at least one -CH2- group between the first double bond and the carbon connecting X1 and X2, or R2 is Among them, R 20 , R 21 and R 22 are the same or different and can each independently be H, OH, -C1-C6 alkoxy or fluorine, The condition is that R1 and R2 cannot exist at the same time; and or R1 is connected to R3 via an alkylene group or a monounsaturated alkenyl group to form a C5-C 30 -membered ring, or R2 is connected to R3 via an alkylene group or a monounsaturated olefin group to form a C5-C 30 wherein the carbon atom at the first or second position of R2 can be optionally substituted by an O or S heteroatom, the first or second position being numbered from the carbon atom to which X1 and X2 are attached, or R2 is connected to R1 via an alkylene group or a monounsaturated olefin group to form a C5-C 30 a membered ring, wherein the carbon atom at the first or second position of R2 can be optionally substituted by an O or S heteroatom, the first or second position being numbered starting from the carbon atom to which the carbon atom to which X1 and X2 are attached is attached; R3 is R5-b 1 for in b 2 For linking with X1, Y1 is -O- or -CH2- or -O-CH2-CH2-, wherein -CH2- is attached to Si, Each X3 is independently selected from the group consisting of C1-C4 alkyl or C1-C4 alkoxy, R4 is a linear C2-C 17 Alkyl or nonlinear C3-C 17 Alkyl, in both cases optionally containing one S, SO, SO2, O or Si(R c )2, where R c is a C1-C6 alkyl group at any position in the carbon chain, provided that the heteroatom is not in the α or Ω position of the carbon chain; a C3-C 20 alkenyl, provided that there is at least one -CH2- group between the double bond and Y1; or a polyunsaturated C8-C 20 alkenyl, provided that there is at least one CH2-group between the first double bond and Y1, or, R4 is where b 3 is the bond to Y1, R6, R7, R8 are the same or different and can each independently be H, OH, -C1-C6 alkoxy or fluorine; D 1 Select from the group consisting of as well as in b 4 is the bond to nitrogen, R9 can be C1-C6 alkyl, cyclopentyl, cyclohexyl, hydroxyl, hydroxymethyl, hydroxyethyl, phenyl, benzyl, 4-hydroxybenzyl, R 10 and R 11 independently selected from H and C1-C6 alkyl, m is an integer selected from 1 to 6, n is an integer selected from 0 to 6, o is an integer selected from 0 to 6, p is an integer selected from 2 to 6, q is an integer selected from 0 to 6, j is an integer selected from 1 to 4, Cy1 is a C3-C6 cycloalkyl group optionally substituted with one or more -OH groups, or Cy1 is a pyranose or furanose ring, which can be linked via any of its OH groups, wherein the pyranose or furanose ring is optionally substituted by a -NH-CO-CH3 group, adenine, guanine, uracil, cytosine, thymine, a monosaccharide or an oligosaccharide, or by a 4-, 5-, 6- or 7-membered heterocycle containing 1, 2, 3 or 4 heteroatoms selected from N, O or S; or Cy1 is a 4-, 5-, 6- or 7-membered heterocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from O, N or S, wherein the heterocyclic ring is optionally replaced by R 12 replace, in R 12 represents a C1-C6 alkyl group, a peptide-containing arginine, a pyranose or furanose ring attached to a 4-, 5-, 6- or 7-membered heterocyclic ring via any of their ring carbon atoms, wherein the pyranose or furanose ring is optionally substituted by a -NH-CO-CH3 group, adenine, guanine, uracil, cytosine, thymine or a mono- or oligosaccharide, R 12 can be a group selected from (d), (e) or (f), wherein b4 is a bond to a heterocycle, m, n, o, p, R9, R 10 and R 11 As defined above, or R 12 Can A group wherein r is an integer selected from 1 to 4, and Cy2 is a 4-, 5-, 6- or 7-membered heterocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from O, N and S, which is optionally substituted with a C1-C6 alkyl group; P is selected from (i)G 2 -T 2 in G 2 As mentioned above G 1 Defined as, where G 1 and G 2 can be the same or different; T 2 As mentioned above T 1 As defined, b 1 Yes to G 2 The key, and where T 1 and T 2 can be the same or different; or (ii) G 2 -T 3 in G 2 As defined above; T 3 for in b 5 To G 2 The key, X4 and X5 can be the same or different and are each independently O, S or NR d , where R d is H, C1-C6 alkyl, -OH or C1-C6 alkoxy, R 13 For linear C2-C 17 Alkyl, nonlinear C3-C 17 alkyl, both optionally containing S, SO, SO2, O, Si(R e )2, where R e is a C1-C6 alkyl group at any position in the carbon chain, provided that the heteroatom is not in the α or Ω position of the carbon chain; a C3-C 20 alkenyl, provided that there is at least one -CH2- group between the double bond and X5; or a polyunsaturated C8-C 20 alkenyl, provided that there is at least one -CH2- between the first double bond and X5, or R 13 for Among them, R 23 , R 24 , R 25 are the same or different and can each independently be H, OH, -C1-C6 alkoxy or fluorine, R 14 For linear C2-C 17 Alkyl, nonlinear C3-C 17 alkyl, both optionally containing S, SO, SO2, O, Si(R f )2, where R f is a C1-C6 alkyl group at any position in the carbon chain, provided that the heteroatom is not in the α or Ω position of the carbon chain; a C3-C 20 alkenyl, provided that there is at least one -CH2- group between the double bond and the carbon connecting X4 and X5; or a polyunsaturated C8-C 20 alkenyl, provided that there is at least one -CH2- between the first double bond and the carbon connecting X4 and X5, or R 14 for Among them, R 26 , R 27 , R 28 are the same or different and can each independently be H, OH, -C1-C6 alkoxy or fluorine; and (iii) T 4 ,in T 4 for Among them, b 6 is the bond to the nitrogen atom, R 29 , R 30 , R 31 can be the same or different, and each independently can be H, OH, -C1-C6 alkoxy or fluorine; Contains a double bond C4-C 20 alkenyl, provided that there is at least one -CH2- between the double bond and the N, or Polyunsaturated C8-C 20 Alkenyl, provided that there is at least one -CH2- between the first double bond and the N.

2. The compound according to claim 1, wherein G 1 and if there is G 2 are the same or different and are each independently a linear C4-C9 alkylene group, preferably a C5-C9 alkylene group, or optionally, are each independently a linear C5, C6, C7 or C9 alkylene group.

3. The compound according to claim 1 or 2, wherein R1 is linear C1, C2, C4, C6, C7, C8, C9, C 10 or C 12 alkyl, or R1 is a linear C9 alkenyl, and / or R2 is a linear C1, C3, C5, C6, C7, C8, C9 or C 11 Alkyl, preferably R1 is linear C2, C8, C 10 Alkyl, or R1 is a linear C9 alkenyl and / or R2 is a linear C1, C3, C7 or C9 alkyl.

4. The compound according to claim 3, wherein T 1 is (c) and R1 is linear C2, C4, C6, C7, C8, C9, C 10 or C 12 alkyl, or R1 is a linear C9 alkenyl, and R2 is a linear C1, C3, C5, C6, C7, C8, C9 or C 11 Alkyl, preferably R1 is linear C2, C8, C 10 alkyl, or R1 is a linear C9 alkenyl, and R2 is a linear C1, C3, C7 or C9 alkyl.

5. The compound according to any one of claims 1 to 3, wherein P is G 2 -T 2 .

6. The compound according to claim 5, wherein G 1 -T 1 and G 2 -T 2 for the same.

7. The compound according to any one of claims 1 to 3, wherein P is G 2 -T 3 .

8. The compound according to claim 7, wherein T 1 -G 1 Has one of the following structures 9. The compound according to claim 7 or 8, wherein T 3 With the following structure Among them, b 5 To G 2 key.

10. The compound according to claim 7 or 8, wherein T 3 Has one of the following structures Among them, b 5 To G 2 key.

11. The compound according to claim 7 or 8, wherein T 3 Has one of the following structures Among them, b 5 To G 2 key.

12. The compound according to claim 7 or 8, wherein T 3 With the following structure Among them, b 5 To G 2 key.

13. The compound according to any one of claims 1 to 3, wherein P is T 4 .

14. The compound according to claim 13, wherein T 4 for Among them, b 6 is the bond to the nitrogen atom, R 29 , R 30 , R 31 can be the same or different, and each independently can be H, OH, -C1-C6 alkoxy or fluorine; or Polyunsaturated C8-C 20 alkenyl, provided that there is at least one -CH2- between the first double bond and the N.

15. The compound according to claim 14, wherein T 1 -G 2 Has one of the following structures 16. The compound according to claim 14 or 15, wherein T 4 With the following structure Among them, b 6 is a bond to the nitrogen atom.

17. A compound according to any one of claims 1 to 16, wherein D 1 Has one of the following structures:

18. A compound according to any one of claims 1 to 16, wherein D 1 Has one of the following structures: wherein q is an integer selected from 1 to 4, and b 4 is a bond to nitrogen.

19. The compound according to claims 1-16, wherein D 1 Has one of the following structures:

20. The compound according to claim 1, which has one of the following structures:

21. A compound having any one of the following structures (Ia), (Ib), (Ic), in, D 1 , G 1 、T 1 and P is as claimed in claim 1, and Z1 is Where b4 is the bond to N s is an integer from 1 to 6 t is an integer from 2 to 6.

22. A compound having the following structure (II) in, G 1 According to claim 1; T 1 for Among them, b 1 , X1 and X2, R1, R2, R3 and R5 are as described in claim 1; and X6 is selected from Cl, Br, I, OM, OT, OTf.

23. The compound according to claim 22, which has any one of the following structures:

24. A lipid nanoparticle comprising a therapeutic agent and a compound according to any one of claims 1 to 20, in particular a compound according to claim 8, 9, 10, 11, 12 or 20.

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