Lipid prodrugs of pregnane neurosteroids and uses thereof

Abstract

To provide novel lipid drug conjugates which facilitate stable transport of a pharmaceutical agent to the intestinal lymph and readily revert to a parent drug so as to be active.SOLUTION: Provided is a compound of the following Formula I, wherein A is a therapeutic agent selected from a naturally occurring or non-naturally occurring pregnane neurosteroid, or an analog or prodrug thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to compounds in prodrug form, particularly compounds that enhance the transport of pharmaceutical agents into the lymphatic system and the subsequent release of the parent drug. The present invention also relates to compositions and methods of using such prodrugs.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. US62 / 713,972, filed August 2, 2018, and U.S. Provisional Patent Application No. US62 / 789,352, filed January 7, 2019, the entire contents of each of which are incorporated herein by reference. [Background technology]

[0003] The lymphatic system consists of a specialized network of vessels, nodes, and lymphatic tissues distributed throughout the body in close proximity to the vascular system. The lymphatic system plays many important roles in immune response, fluid balance, nutrient absorption, lipid homeostasis, and tumor metastasis. Due to the unique anatomical and physiological characteristics of the lymphatic system, targeted drug delivery to and through the lymphatic system has been suggested as a means to improve both pharmacokinetic and pharmacodynamic profiles.

[0004] Lymphatic transport of drugs has the potential to promote oral bioavailability through bypassing first-pass metabolism, altering systemic drug disposition, and promoting efficacy against lymphatic or lymphocyte-mediated pathologies (such as lymphoma, leukemia, lymphoid tumor metastasis, autoimmune diseases, lymphatic-resident infections, and transplant rejection). For drugs to access the intestinal lymph, they must first associate with intestinal lymph lipoproteins, which are assembled in intestinal absorptive cells (enterocytes) in response to lipid absorption. Association with these lipoproteins subsequently enhances drug transport into the lymph, because the size of lipoproteins prevents immediate diffusion across the vascular endothelium lining the capillaries draining the small intestine. Instead, these large colloidal structures enter small lymphatic vessels because the lymphatic endothelium is significantly more permeable than the vascular endothelium.

[0005] Historically, drugs with high lymphatic transport have been highly lipophilic (usually, but not exclusively, logD > 5 and solubility in long-chain triglycerides > 50 mg / g) to enhance physical association with lipoproteins. Thus, highly lipophilic analogs of drugs have been envisioned as one means of enhancing lymphatic drug transport. However, chemical modification of the parent drug can result in reduced efficacy, and in many cases, a significant increase in lipophilicity correlates with increased toxicity.

[0006] Lipid-soluble prodrug forms of compounds provide a means to temporarily increase the lipophilicity and lipoprotein affinity of pharmaceutical compounds, thereby increasing lymphatic targeting. Upon transport via the lymphatic system, the prodrug is cleaved, thereby releasing the parent drug for activity at its target site.

[0007] Lipophilic esters of drugs have been explored as more bioavailable versions of existing drugs. For example, testosterone undecanoate is a commercially available drug for hypogonadism and other conditions. Oral administration of testosterone itself is problematic due to extensive first-pass metabolism in the liver and the resulting very low bioavailability. The undecanoate ester of testosterone redirects a small percentage of the absorbed dose into the lymphatic system, thereby avoiding first-pass metabolism in the liver and improving the oral bioavailability of testosterone. However, this process is still highly inefficient, and testosterone bioavailability is thought to be <5% after oral administration of the undecanoate ester. Summary of the Invention [Problem to be solved by the invention]

[0008] Therefore, there is a need to develop novel lipid drug conjugates that facilitate stable transport of drug agents to the intestinal lymph and readily revert to the parent drug to be active. [Means for solving the problem]

[0009] In one aspect, the present invention provides a compound of formula I

[0010] [ka]

[0011] or a pharmaceutically acceptable salt thereof, wherein each variable is as defined herein. to provide.

[0012] In another aspect, the present invention provides a method of treating a disease, disorder, or condition (such as one of those disclosed herein, e.g., postpartum depression), comprising administering to a patient in need thereof an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. [Brief explanation of the drawings]

[0013] [Figure 1]

[0023] Figure 1 shows plasma concentrations of allopregnanolone over 24 hours following oral administration of ALLO-FSI(5)-C5βMe-TG(I-3). The figure shows data from individual rats. [Figure 2] 1 shows plasma concentrations of allopregnanolone over 24 hours following oral administration of ALLO-C10-TG (I-1). The figure shows data from individual rats. [Figure 3A] 1 shows plasma concentrations of ALLO after administration of an ALLO prodrug. Data in panel A are presented as mean ± standard deviation (if n≧3) or mean ± range (if n=2). [Figure 3B] Data from individual rats following administration of ALLO-CMSI-C5βMe-TG are shown (due to significant differences in the rat 2 profile compared to rats 1 and 3, data from rat 2 were excluded for panel A and for the mean plots in Table 2). [Figure 4] Figure 1 shows the plasma concentrations of allopregnanolone in rats after oral administration of the prodrugs ALLO-FSI-C5βMe-TG (I-3), ALLO-CMSI-C5βMe-TG (I-2), or ALLO-C10-TG (I-1) (top graph), and after intravenous administration of allopregnanolone (control experiment, n=1, bottom graph). The calculated area under the curve (AUC) for each test compound is also shown as a fraction of the intravenously administered allopregnanolone control (bottom graph). The calculated bioavailability ("BA") of the test compounds was 18% for I-3, 42% for I-2, and 35% for I-1. BA = calculated bioavailability in plasma after oral administration of the prodrug. [Figure 5] 1 shows the lymphatic uptake of compound I-1 in rats. [Figure 6] FIG. 1 shows dose-normalized blood concentrations of free allopregnanolone over time in beagle dogs following oral administration of the lipid prodrug compound ALL-CMSI-C5βMe-TG(I-2) compared to orally administered allopregnanolone. [Figure 7] FIG. 1 shows dose-normalized plasma concentrations of free allopregnanolone over time in cynomolgus monkeys following oral administration of lipid prodrug compound ALL-CMSI-C5βMe-TG (I-2) compared to orally administered allopregnanolone. [Figure 8] 1 shows the hydrolysis profile of lipid prodrug compound ALL-C10-TG (I-1) over time to the monoglyceride form, acid intermediate, and free ALLO via incubation with porcine pancreatic lipase. [Figure 9] 1 shows the hydrolysis profile of lipid prodrug compound ALL-CMSI-C5βMe-TG (I-2) to the monoglyceride form and free ALLO over time via incubation with porcine pancreatic lipase. [Figure 10] FIG. 1 shows the hydrolysis profile of the lipid prodrug compound ALL-C10-TG (I-1) into the monoglyceride form, acid intermediate, and free ALLO over time in rat plasma supplemented with lipoprotein lipase (LPL). [Figure 11] FIG. 1 shows the hydrolysis profile of the lipid prodrug compound ALL-C10-TG (I-1) into the monoglyceride form, acid intermediate, and free ALLO over time in lipoprotein lipase (LPL)-supplemented dog plasma. [Figure 12] 1 shows the hydrolysis profile of the lipid prodrug compound ALL-CMSI-C5βMe-TG (I-2) to the monoglyceride form and free ALLO over time in rat plasma supplemented with lipoprotein lipase (LPL). [Figure 13] 1 shows the hydrolysis profile of the lipid prodrug compound ALL-CMSI-C5βMe-TG (I-2) to the monoglyceride form and free ALLO over time in lipoprotein lipase (LPL)-supplemented dog plasma. [Figure 14] FIG. 1 shows the hydrolysis profile of the lipid prodrug compound ALL-CMSI-C5βMe-TG (I-2) to the monoglyceride form and free ALLO over time in human plasma supplemented with lipoprotein lipase (LPL). DETAILED DESCRIPTION OF THE INVENTION

[0014] 1. General Description of Certain Embodiments of the Invention Lymphatic-directed prodrugs The compounds of the present invention and compositions thereof are useful in enhancing the transport of therapeutic agents into the lymphatic system and subsequently facilitating the release of the parent drug (ie, the therapeutic agent).

[0015] In one aspect, the present invention provides a compound of formula I

[0016] [ka]

[0017] or a pharmaceutically acceptable salt thereof, R 1 and R 2 are each independently hydrogen, an acid labile group, a lipid, or —C(O)R 3 and; Each R 3 are independently saturated or unsaturated, linear or branched, and optionally substituted C 1-37 It is a hydrocarbon chain; X is -O-, -NR-, -S-, -O(C 1-6 aliphatic)-O-, -O(C 1-6 aliphatic)-S-, -O(C 1-6 aliphatic)-NR-, -S(C 1-6 aliphatic)-O-, -S(C 1-6 aliphatic)-S-, -S(C 1-6 aliphatic)-NR-, -NR(C 1-6 aliphatic)-O-, -NR(C 1-6 Aliphatic)-S-, or -NR(C 1-6 aliphatic)-NR-, C 1-6 0 to 2 methylene units of the aliphatic group are independently optionally replaced by -O-, -NR-, or -S-; C 1-6 aliphatic groups are optionally substituted independently with 1, 2, or 3 deuterium or halogen atoms; Each R is independently hydrogen or C 1-6 an optionally substituted group selected from an aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocycle, a phenyl, an 8-10 membered bicyclic aromatic carbocycle, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Y is absent or is -C(O)-, -C(NR)-, or -C(S)-; L is a covalent bond or a saturated or unsaturated, linear or branched, optionally substituted divalent C 1-30 is a hydrocarbon chain, wherein 0 to 8 methylene units of L are independently replaced by -Cy-, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -C(S)-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O-, or an amino acid; wherein one methylene unit of L is optionally replaced by -M-; or L is

[0018] [ka]

[0019] where either the right or left side of L is attached to A; each -Cy- is independently an optionally substituted 3- to 6-membered divalent saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Each R 4 and R 5are independently hydrogen, deuterium, halogen, -CN, -OR, -NR2, -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8-10 membered bicyclic aromatic carbocycle, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or C optionally substituted with a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having one to four heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having one to four heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having one to five heteroatoms independently selected from nitrogen, oxygen, or sulfur; 1-6 an aliphatic group or C 1-6 aliphatic is optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; or Two Rs attached to the same carbon atom 4 or R 5 together with the carbon atoms to which they are attached form a 3- to 6-membered spirocyclic saturated monocyclic carbocyclic ring or a 3- to 6-membered spirocyclic saturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; -M- is a self-immolative group; n is 0 to 18; each m is independently 0 to 6; A is a therapeutic agent selected from naturally occurring or non-naturally occurring pregnane neurosteroids, or analogs or prodrugs thereof. to provide.

[0020] In one aspect, the present invention provides a method of treating a disease, disorder, or condition in a patient in need thereof, comprising administering to the patient an effective amount of a disclosed lipid prodrug (such as a compound of Formula I or a pharmaceutically acceptable salt thereof).

[0021] It is understood that the disclosed lipid prodrugs can exist in the form of a pharmaceutically acceptable salt. Thus, a reference to a "lipid prodrug" is also a disclosure of a "lipid prodrug or a pharmaceutically acceptable salt thereof." It follows that such lipid prodrugs or pharmaceutically acceptable salts thereof can be used in pharmaceutical compositions and methods of use, such as those disclosed herein.

[0022] One approach to targeting drugs to the lymphatic transport system is to use prodrugs that participate in endogenous pathways that control the absorption, transport (including passive transport), and metabolism of dietary lipids. In one aspect, the present invention provides lipid prodrugs comprising a therapeutic agent conjugated to a glycerol-based moiety containing two fatty acids or other lipids. Without wishing to be bound by theory, it is believed that such prodrugs mimic dietary triglycerides so as to participate in the processing and metabolism of triglycerides in the gastrointestinal tract. Where appropriate, certain lipid prodrug scaffolds can be modified from the literature for use in accordance with the present disclosure. For example, certain drug-lipid conjugates and lipid prodrug scaffolds are disclosed in WO2017 / 041139 and WO2016 / 023082 (each of which is incorporated herein by reference in its entirety). Further examples of drug-lipid conjugates where the parent drug contains an available carboxylic acid group and is directly conjugated to the glyceride backbone are described in Paris, G. et al., J. Med. Chem. 1979, 22, (6), 683-687; Garzon Aburbeh, A. et al., J. Med. Chem. 1983, 26, (8), 1200-1203; Deverre, JR; et al., J. Pharm. Pharmacol. 1989, 41, (3), 191-193; Mergen, F. et al., J. Pharm. Pharmacol. 1991, 43, (11), 815-816; Garzon Aburbeh, A. et al., J. Med. Chem. 1986, 29, (5), 687-69; and Han, S. et al. al., J. Control. Release 2014, 177, 1-10.

[0023] In a further example, if the drug does not contain an available carboxylic acid, a short linker (Scriba, G.K.E., Arch. Pharm. (Weinheim) 1995, 328, (3), 271-276; and Scriba, G.K.E. et al., J. Pharm. Pharmacol. 1995, 47, (11), 945-948). In other examples, ester linkages to drugs and ether linkages to glycerides have been used (Sugihara, J. et al., J. Pharmacobiodyn. 1988, 11, (5), 369-376; and Sugihara, J. et al., J. Pharmacobiodyn. 1988, 11, (8), 555-562).

[0024] The typical use of prodrug strategies to improve the pharmacokinetic properties of therapeutic agents (active pharmaceutical agents) relies on in vivo cleavage to the parent drug via nonspecific degradation or enzymatic cleavage, thereby allowing the drug to exert its biological activity. In one aspect, the present invention provides modified glyceride-based compounds (lipid prodrugs) that direct lymphatic transport of therapeutic agents and improve cleavage of lipid prodrugs to therapeutic agents.

[0025] Dietary lipids (including triglycerides) follow a specific metabolic pathway to gain access to the lymph (and ultimately the systemic circulation) that is completely distinct from that of other nutrients (such as proteins and carbohydrates). After ingestion, dietary triglycerides are hydrolyzed by lipases in the lumen to release one monoglyceride and two fatty acids for each molecule of triglyceride. The monoglyceride and two fatty acids are subsequently absorbed into enterocytes and re-esterified to triglycerides.

[0026] Re-synthesized triglycerides are assembled into intestinal lipoproteins (primarily chylomicrons). After formation, chylomicrons are exocytosed from enterocytes and subsequently gain selective access to the intestinal lymphatics. Once within the lymphatic system, chylomicrons containing packaged triglycerides flow through a series of capillaries, nodes, and ducts to enter the systemic circulation at the junction of the left subclavian and internal jugular veins. After entering the circulation, triglycerides in chylomicrons are preferentially and efficiently absorbed by tissues with high expression levels of lipoprotein lipase, such as adipose tissue, liver, and possibly certain types of tumor tissue.

[0027] Lipid prodrugs behave similarly to natural triglycerides and are expected to be transported into and through the lymphatic system, reaching the systemic circulation without interacting with the liver. In some embodiments, the lipid prodrug is cleaved to release the therapeutic agent after the prodrug reaches the systemic circulation or after reaching the target tissue. In some embodiments, the lipid prodrug releases the therapeutic agent by destruction of a self-immolative linker connecting the therapeutic agent to the glycerol-derived group or by enzymatic cleavage of the linker. In this manner, the pharmacokinetic and pharmacodynamic profiles of the parent therapeutic agent are engineered to facilitate access to lymph and lymphatic tissues, thereby enhancing oral bioavailability by avoiding first-pass metabolism (and potentially intestinal excretion). Thus, in some embodiments, the disclosed lipid prodrugs have improved oral bioavailability, reduced first-pass metabolism, reduced liver toxicity, or other improved pharmacokinetic properties compared to the parent therapeutic agent. In some embodiments, the disclosed lipid prodrugs have increased drug targeting (compared to the parent therapeutic agent) to sites within lymph, lymph nodes, and lymphatic tissues, as well as to sites of high lipid utilization and lipoprotein lipase expression (such as adipose tissue, liver, and some tumors). In some embodiments, the disclosed lipid prodrugs are delivered to the central nervous system (CNS) or cross the blood-brain barrier (BBB) ​​via the lymphatic system.

[0028] In certain embodiments, the present invention provides a method for modulating the delivery, distribution, or other properties of a therapeutic agent. In one aspect, the present invention provides a method for delivering a therapeutic agent to the systemic circulation of a patient in need thereof, wherein the therapeutic agent partially, substantially, or completely bypasses first-pass hepatic metabolism in the patient, comprising administering to the patient a lipid prodrug of the disclosed therapeutic agent. In another aspect, the present invention provides a method for modifying a therapeutic agent to partially, substantially, or completely bypass first-pass hepatic metabolism in the patient after administration of the therapeutic agent, comprising preparing a lipid prodrug of the disclosed therapeutic agent. In some embodiments, the lipid prodrug is administered orally. In some embodiments, preparing the lipid prodrug comprises conjugating the therapeutic agent to a glycerol-based scaffold comprising two fatty acids or other lipids, thereby providing the lipid prodrug.

[0029] In another aspect, the present invention provides a method for improving the oral bioavailability of a therapeutic agent, enhancing intestinal absorption of a therapeutic agent, or reducing intestinal metabolism, degradation, or excretion of a therapeutic agent, comprising preparing a lipid prodrug of the disclosed therapeutic agent.

[0030] In another aspect, the present invention provides a method for modifying (e.g., improving) delivery of a therapeutic agent to a target tissue, comprising preparing a lipid prodrug of the disclosed therapeutic agent. In some embodiments, the target tissue is lymph, a lymph node (such as a mesenteric lymph node), adipose tissue, liver, or a tumor (such as a lymph node site of metastasis). In some embodiments, the target tissue is the brain or CNS.

[0031] Lipid prodrugs that readily convert to the parent therapeutic agent after transport via the systemic circulation reduce free drug concentrations in the gastrointestinal (GI) tract, which may provide benefits such as reduced gastrointestinal irritation or toxicity and / or increased drug solubility in intestinal bile salt micelles (due to similarity to endogenous monoglycerides). The disclosed lipid prodrugs may also have increased passive membrane permeability in certain embodiments (due to their greater lipophilicity compared to the parent therapeutic agent). In some embodiments, lipid prodrugs have higher solubility in lipid formulations or vehicles, including either lipids alone or mixtures of lipids with surfactants and / or cosolvents, enabling the use of lipophilic formulations for otherwise highly hydrophilic therapeutic agents.

[0032] Lipid prodrugs of allopregnanolone and other pregnane neurosteroids In one aspect, the present invention provides a compound of formula I

[0033] [ka]

[0034] or a pharmaceutically acceptable salt thereof, R 1 and R 2 are each independently hydrogen, an acid labile group, a lipid, or —C(O)R 3 and; Each R 3 are independently saturated or unsaturated, linear or branched, and optionally substituted Converted C 1-37 It is a hydrocarbon chain; X is -O-, -NR-, -S-, -O(C 1-6 aliphatic)-O-, -O(C 1-6 aliphatic)-S-, -O(C 1-6 aliphatic)-NR-, -S(C 1-6 aliphatic)-O-, -S(C 1-6 aliphatic)-S-, -S(C 1-6 aliphatic)-NR-, -NR(C 1-6 aliphatic)-O-, -NR(C 1-6Aliphatic)-S-, or -NR(C 1-6 aliphatic)-NR-, C 1-6 0 to 2 methylene units of the aliphatic group are independently optionally replaced by -O-, -NR-, or -S-; C 1-6 aliphatic groups are optionally substituted independently with 1, 2, or 3 deuterium or halogen atoms; Each R is independently hydrogen or C 1-6 an optionally substituted group selected from an aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocycle, a phenyl, an 8-10 membered bicyclic aromatic carbocycle, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Y is absent or is -C(O)-, -C(NR)-, or -C(S)-; L is a covalent bond or a saturated or unsaturated, linear or branched, optionally substituted divalent C 1-30 is a hydrocarbon chain, wherein 0 to 8 methylene units of L are independently replaced by -Cy-, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -C(S)-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O-, or an amino acid; wherein one methylene unit of L is optionally replaced by -M-; or L is

[0035] [ka]

[0036] where either the right or left side of L is attached to A; each -Cy- is independently an optionally substituted 3- to 6-membered divalent saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Each R 4 and R 5 are independently hydrogen, deuterium, halogen, -CN, -OR, -NR2, -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8-10 membered bicyclic aromatic carbocycle, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. or optionally substituted by -CN, -OR, -NR2, -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8-10 membered bicyclic aromatic carbocycle, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 1-6 fat or C 1-6 aliphatic is optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; or Two Rs attached to the same carbon atom 4 or R 5 together with the carbon atoms to which they are attached form a 3- to 6-membered spirocyclic saturated monocyclic carbocyclic ring or a 3- to 6-membered spirocyclic saturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; -M- is a self-immolative group; n is 0 to 18; each m is independently 0 to 6; A is a therapeutic agent selected from naturally occurring or non-naturally occurring pregnane neurosteroids, or analogs or prodrugs thereof. to provide.

[0037] R as defined above and described herein 1 and R 2 are each independently hydrogen, an acid labile group, a lipid (such as a fatty acid), or -C(O)R 3 is.

[0038] In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is an acid labile group. In some embodiments, R 1 is a lipid. In some embodiments, R 1 is a fatty acid. In some embodiments, R 1 is -C(O)R 3 In some embodiments, R 1 is selected from those shown in Table 1 below.

[0039] In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is an acid labile group. In some embodiments, R 2 is a lipid. In some embodiments, R 2 is a fatty acid. In some embodiments, R 2 is -C(O)R 3 In some embodiments, R 2 is selected from those shown in Table 1 below.

[0040] In some embodiments, each R 1 and R 2are independently a fatty acid, a phosphatide, a phospholipid, or an analog thereof (such as those described in detail below). In some embodiments, each fatty acid is independently a saturated or unsaturated medium or long chain fatty acid. In some embodiments, each fatty acid is independently a C2-C 40 In some embodiments, each fatty acid independently has a C6-C 20 , C8-C 20 , C 10 -C 20 , C 10 -C 18 , C 12 -C 18 , C 14 -C 18 , C 16 -C 18 , or C 10 -C 16 In some embodiments, each fatty acid is independently selected from oleic acid, palmitic acid, EPA, or DHA.

[0041] In some embodiments, R 1 and R 2 are each independently selected from an acid labile group (such as tert-butoxycarbonyl (Boc)), an amino acid, a PEG group, —C(O)OR, —C(O)NR, —CHOR, —C(NR)R, or —P(O)OR.

[0042] For clarity, R 1 or R 2 is defined as a fatty acid, R 1 or R 2 is understood to be the acyl residue of a fatty acid. Thus, for example, R 1 is defined as palmitic acid, then R 1 is the acyl moiety of palmitic acid (i.e., -C(O)C 15 H 31 )

[0043] Each R is as defined above and described herein. 3are independently saturated or unsaturated, linear or branched, and optionally substituted C 1-37 It is a hydrocarbon chain.

[0044] In some embodiments, R 3 is optionally replaced by saturated linear C 1-37 In some embodiments, R 3 is an unsaturated linear optionally substituted C 1-37 In some embodiments, R 3 is a saturated branched optionally substituted C 1-37 In some embodiments, R 3 is an unsaturated branched optionally substituted C 1-37 In some embodiments, R 3 is selected from those shown in Table 1 below.

[0045] As defined above and described herein, X is —O—, —NR—, —S—, —O(C 1-6 aliphatic)-O-, -O(C 1-6 aliphatic)-S-, -O(C 1-6 aliphatic)-NR-, -S(C 1-6 aliphatic)-O-, -S(C 1-6 aliphatic)-S-, -S(C 1-6 aliphatic)-NR-, -NR(C 1-6 aliphatic)-O-, -NR(C 1-6 Aliphatic)-S-, or -NR(C 1-6 aliphatic)-NR-, C 1-6 0 to 2 methylene units of the aliphatic group are independently optionally replaced by -O-, -NR-, or -S-; C 1-6 Aliphatic groups are optionally substituted independently with 1, 2, or 3 deuterium or halogen atoms.

[0046] In some embodiments, X is -O-. In some embodiments, X is -NR-. In some embodiments, X is -S-. In some embodiments, X is -O(C 1-6 In some embodiments, X is —O(C 1-6 In some embodiments, X is —O(C 1-6 In some embodiments, X is -S(C 1-6 In some embodiments, X is -S(C 1-6 In some embodiments, X is -S(C 1-6 In some embodiments, X is —NR(C 1-6 In some embodiments, X is —NR(C 1-6 In some embodiments, X is —NR(C 1-6 In any of the above embodiments, the divalent C is -NR-. 1-6 0 to 2 methylene units of the aliphatic group are independently optionally replaced by -O-, -NR-, or -S-, forming a divalent C 1-6 Aliphatic groups are optionally substituted independently with 1, 2, or 3 deuterium or halogen atoms. In some embodiments, X is selected from those shown in Table 1 below.

[0047] As defined above and described herein, Y is absent, -C(O)-, -C(NR)-, or -C(S)-.

[0048] In some embodiments, Y is absent. In some embodiments, Y is -C(O)-. In some embodiments, Y is -C(NR)-. In some embodiments, Y is -C(S)-. In some embodiments, Y is selected from those shown in Table 1 below.

[0049] As defined above and described herein, L is a covalent bond or a saturated or unsaturated, linear or branched, optionally substituted divalent C 1-30 is a hydrocarbon chain, wherein 0 to 8 methylene units of L are independently replaced by -Cy-, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -C(S)-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O-, or an amino acid; wherein one methylene unit of L is optionally replaced by -M-; or L is

[0050] [ka]

[0051] and either the right or left side of L is attached to A. In some embodiments, L is a covalent bond. In some embodiments, L is a saturated or unsaturated, linear or branched, optionally substituted divalent C 1-30 (For example, C 3-30 , C 5-30 , C 7-30 , C 3-25 , C 5-25 , C 7-25 , C 3-20 , C 5-20 , or C 7-20 and the like) hydrocarbon chain, wherein 0 to 8 (i.e., 0, 1, 2, 3, 4, 5, 6, 7, or 8) methylene units of L are independently replaced by -Cy-, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -C(S)-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O-, or an amino acid; and one methylene unit of L is optionally replaced by -M-. In some embodiments, L is

[0052] [ka]

[0053] and either the right or left side of L is attached to A. In some embodiments, L is a covalent bond or a saturated or unsaturated, linear or branched, optionally substituted divalent C 1-30 (For example, C 3-30 , C 5-30 , C 7-30 , C 3-25 , C 5-25 , C 7-25 , C 3-20 , C 5-20 , or C 7-20 etc.) hydrocarbon chain, and 0 to 8 (i.e., 0, 1, 2, 3, 4, 5, 6, 7, or 8) methylene units of L are -Cy-, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -C(S)-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O-, or

[0054] [ka]

[0055] one methylene unit of L is optionally replaced by -M-; or L is

[0056] [ka]

[0057] and either the right or left side of L is attached to A. In some embodiments, L is a saturated or unsaturated, linear or branched, optionally substituted divalent C 1-20 (For example, C 3-20 , C 5-20, or C 7-20 etc.) hydrocarbon chain, and 0 to 8 (i.e., 0, 1, 2, 3, 4, 5, 6, 7, or 8) methylene units of L are -Cy-, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -C(S)-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O-, or

[0058] [ka]

[0059] and one methylene unit of L is optionally replaced by -M-. In some embodiments, L is a covalent bond or a bivalent saturated or unsaturated, linear or branched C 1-16 , C 1-12 , C 1-10 , or C 6-16 It is a hydrocarbon chain, and 0 to 6, 0 to 4, 0 to 3, or 0 to 1 methylene units of L are -Cy-, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -C(S)-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O-,

[0060] [ka]

[0061] and one methylene unit of L is optionally replaced by -M-. In some embodiments, L is a divalent saturated linear C 1-20 , C 1-16 , C 1-12 , C 1-10 , or C 1-6a hydrocarbon chain, wherein 0 to 6, 0 to 4, 0 to 3, or 0 to 1 methylene units of L are independently replaced by -Cy-, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, or -NRC(O)O-; and one methylene unit of L is optionally replaced by -M-. In some embodiments, L is a divalent saturated linear C 1-20 , C 1-16 , C 1-12 , C 1-10 , or C 1-6 is a hydrocarbon chain, and L has 0 to 6, 0 to 4, 0 to 3, or 0 to 1 methylene units. independently replaced by -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, or -C(S)-; one methylene unit of L is optionally replaced by -M-.

[0062] In some embodiments, L is 1, 2, 3, or 4 R 4 Divalent saturated C optionally substituted with a group 1-30 , C 1-25 , C 1-20 , C 3-20 , C 5-20 , or C 7-20 A hydrocarbon chain in which 0 to 4 methylene units of L are independently replaced by -O-, -OC(O)-, -C(O)O-, or -C(O)-; one methylene unit of L is optionally replaced by -M-.

[0063] In some embodiments, L is selected from deuterium, halogen, —CN, a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 4-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from phenyl, nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or C optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms. 1-6 a divalent saturated C optionally substituted with 1, 2, 3 or 4 groups selected from aliphatic groups 1-25 , C 5-25 , C 7-25 , or C 1-20 is a hydrocarbon chain; 0 to 4 methylene units of L are independently replaced by -O-, -OC(O)-, -C(O)O-, or -C(O)-; and one methylene unit of L is optionally replaced by -M-.

[0064] In some embodiments, L is (—OCH2CH2—) 1-8 (i.e., 1 to 8 polyethylene glycol (PEG) units). In some embodiments, L comprises 1, 2, 3, 4, 5, 6, 7, or 8 PEG units.

[0065] In some embodiments, 0 to 6 units of L are independently replaced by -O-, -S-, -OC(O)-, -C(O)O-, -C(O)-, or -C(S)-; one methylene unit of L is optionally replaced by -M-.

[0066] In some embodiments, L is

[0067] [ka]

[0068] In some embodiments, L includes:

[0069] [ka]

[0070] In some embodiments, L includes:

[0071] [ka]

[0072] In some embodiments, L includes:

[0073] [ka]

[0074] Includes: In some embodiments, L is

[0075] [ka]

[0076] In some embodiments, L includes:

[0077] [ka]

[0078] In some embodiments, L includes:

[0079] [ka]

[0080] In some embodiments, L includes:

[0081] [ka]

[0082] In some embodiments, one methylene unit of L is replaced by -M-.

[0083] In some embodiments, 1, 2, 3, or 4 available hydrogen atoms of L are R 4 groups (i.e., L is 1, 2, 3, or 4 R 4 groups).

[0084] In some embodiments, a methylene unit of L is replaced by an amino acid. The amino acid may be naturally occurring or non-naturally occurring. In some embodiments, the amino acid is selected from a non-polar amino acid or a branched chain amino acid (BCAA). In some embodiments, the amino acid is selected from valine, isoleucine, leucine, methionine, alanine, proline, glycine, phenylalanine, tyrosine, tryptophan, histidine, asparagine, glutamine, serine threonine, lysine, arginine, histidine, aspartic acid, glutamic acid, cysteine, selenocysteine, or tyrosine. In some embodiments, the amino acid is an L-amino acid. In some embodiments, the amino acid is a D-amino acid.

[0085] In some embodiments, L is selected from those shown in Table 1 below. As defined above and described herein, each -Cy- is independently an optionally substituted 3- to 6-membered divalent saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0086] In some embodiments, -Cy- is an optionally substituted 3-6 membered divalent saturated ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, -Cy- is an optionally substituted 5 membered divalent saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, -Cy- is an optionally substituted 6 membered divalent saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, -Cy- is selected from those shown in Table 1 below.

[0087] Each R is as defined above and described herein. 4 and R 5 are independently hydrogen, deuterium, halogen, -CN, -OR, -NR2, -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8-10 membered bicyclic aromatic carbocycle, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. or optionally substituted by -CN, -OR, -NR2, -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8-10 membered bicyclic aromatic carbocycle, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 1-6 an aliphatic group or C 1-6Aliphatic is optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; or two R 4 or R 5 together with the carbon atoms to which they are attached form a 3- to 6-membered spirocyclic saturated monocyclic carbocyclic ring or a 3- to 6-membered spirocyclic saturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0088] In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is deuterium. In some embodiments, R 4 is halogen. In some embodiments, R 4 In some embodiments, R 4 is -OR. In some embodiments, R 4 is -NR2. In some embodiments, R 4 is -SR. In some embodiments, R 4 is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 4 is phenyl. In some embodiments, R 4 is an 8-10 membered bicyclic aromatic carbocycle. In some embodiments, R 4 is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 4 is a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 4 is an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 4is optionally substituted by -CN, -OR, -NR2, -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8-10 membered bicyclic aromatic carbocycle, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; C 1-6 In some embodiments, R 4 is C optionally substituted by 1, 2, 3, 4, 5 or 6 deuterium or halogen atoms 1-6 In some embodiments, two R are bonded to the same carbon atom. 4 together with the carbon atoms to which they are attached form a 3- to 6-membered spirocyclic saturated monocyclic carbocyclic ring or a 3- to 6-membered spirocyclic saturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0089] In some embodiments, each R 4 are independently hydrogen, deuterium, halogen, —CN, or C optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms. 1-4 aliphatic; or two R attached to the same carbon atom 4 together with the carbon atoms to which they are attached form a 3- to 6-membered spirocyclic saturated monocyclic carbocyclic ring or a 3- to 6-membered spirocyclic saturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0090] In some embodiments, R 4 At least one of the is not hydrogen. In some embodiments, R 4 is C optionally substituted by 1, 2, 3, 4, 5 or 6 deuterium or halogen atoms 1-4In some embodiments, R 4 is C optionally substituted by 1, 2 or 3 deuterium or halogen atoms 1-4 In some embodiments, R 4 is methyl optionally substituted with 1, 2, or 3 deuterium or halogen atoms. In some embodiments, R 4 is ethyl. In some embodiments, R 4 is n-propyl. In some embodiments, R 4 is isopropyl. In some embodiments, R 4 is n-butyl. In some embodiments, R 4 is isobutyl. In some embodiments, R 4 is tert-butyl. In some embodiments, R 4 is selected from those shown in Table 1 below.

[0091] In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is deuterium. In some embodiments, R 5 is halogen. In some embodiments, R 5 In some embodiments, R 5 is -OR. In some embodiments, R 5 is -NR2. In some embodiments, R 5 is -SR. In some embodiments, R 5 is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 5 is phenyl. In some embodiments, R 5 is an 8-10 membered bicyclic aromatic carbocycle. In some embodiments, R 5is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 5 is a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 5 is an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 5 -CN, -OR, -NR2, -SR, 3-8 membered saturated or partially saturated C optionally substituted by an unsaturated monocyclic carbocycle, phenyl, an 8-10 membered bicyclic aromatic carbocycle, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 1-6 In some embodiments, R 5 is C optionally substituted by 1, 2, 3, 4, 5 or 6 deuterium or halogen atoms 1-6 In some embodiments, two R are bonded to the same carbon atom. 5 together with the carbon atoms to which they are attached form a 3- to 6-membered spirocyclic saturated monocyclic carbocyclic ring or a 3- to 6-membered spirocyclic saturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0092] In some embodiments, each R 5 are independently hydrogen, deuterium, halogen, —CN, or C optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms. 1-4 aliphatic; or two R attached to the same carbon atom 5together with the carbon atoms to which they are attached form a 3- to 6-membered spirocyclic saturated monocyclic carbocyclic ring or a 3- to 6-membered spirocyclic saturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0093] In some embodiments, R 5 At least one of the is not hydrogen. In some embodiments, R 5 is C optionally substituted by 1, 2, 3, 4, 5 or 6 deuterium or halogen atoms 1-4 In some embodiments, R 5 is methyl optionally substituted with 1, 2, or 3 deuterium or halogen atoms. In some embodiments, R 5 is ethyl. In some embodiments, R 5 is n-propyl. In some embodiments, R 5 is isopropyl. In some embodiments, R 5 is n-butyl. In some embodiments, R 5 is isobutyl. In some embodiments, R 5 is tert-butyl. In some embodiments, R 5 is selected from those shown in Table 1 below.

[0094] As defined above and described herein, -M- is a self-immolative group. In some embodiments, -M- is an acetal, o-benzyl alcohol, p-benzyl alcohol, a styryl group, a coumarin, or a group that self-immolates via a cyclization reaction. In some embodiments, -M- is selected from a disulfide, a hydrazone, an acetal self-immolative group, a carboxyacetal self-immolative group, a carboxy(methyl acetal) self-immolative group, a para-hydroxybenzylcarbonyl self-immolative group, a flipped ester self-immolative group, a trimethyl lock, or a 2-hydroxyphenylcarbamate (2-HPC) self-immolative group.

[0095] In some embodiments, -M- is

[0096] [ka]

[0097] where each R 6 are hydrogen, deuterium, and C 1-10 independently selected from an aliphatic, a halogen, or -CN; Each R 7 are independently selected from hydrogen, deuterium, halogen, -CN, -OR, -NR2, -NO2, -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8-10 membered bicyclic aromatic carbocycle, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or optionally substituted by -CN, -OR, -NR2, -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8-10 membered bicyclic aromatic carbocycle, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 1-6 an aliphatic group or C 1-6 aliphatic is optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; Each Z 1 is independently selected from -O-, -NR-, or -S-; Each Z 2are independently selected from -O-, -NR-, -S-, -OC(O)-, -NRC(O)O-, or -OC(O)NR-; Each Z 3 is =N- or =C(R 7 )-independently selected from; Each Z 4 -O-, -NR-, -S-, -C(R 6 )2-, or a covalent bond.

[0098] In some embodiments, -M- is one of the following:

[0099] [ka]

[0100] is selected from one of In the formula, each R 6 are hydrogen, deuterium, and C 1-5 independently selected from an aliphatic, a halogen, or -CN; Each R 7are independently selected from hydrogen, deuterium, halogen, -CN, -OR, -NR2, -NO2, -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8-10 membered bicyclic aromatic carbocycle, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or optionally substituted by -CN, -OR, -NR2, -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8-10 membered bicyclic aromatic carbocycle, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 1-6 an aliphatic group or C 1-6 aliphatic is optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; Each Z 1 is independently selected from -O-, -NR-, or -S-; Each Z 2 are independently selected from -O-, -NR-, -S-, -OC(O)-, -NRC(O)O-, or -OC(O)NR-; Each Z 3 is =N- or =C(R 7 )-independently selected from; Each Z 4 -O-, -NR-, -S-, -C(R 6 )2-, or a covalent bond.

[0101] As generally defined above and described herein, each R 6 are hydrogen, deuterium, and C 1-5In some embodiments, R is independently selected from aliphatic, halogen, or —CN. 6 is hydrogen. In some embodiments, R 6 is deuterium In some embodiments, R 6 is C 1-5 In some embodiments, R 6 is halogen. In some embodiments, R 6 is -CN.

[0102] In some embodiments, R 6 is hydrogen, C 1-5 In some embodiments, R is alkyl, halogen, or —CN. 6 is hydrogen or C 1-3 In some embodiments, R 6 is hydrogen or methyl.

[0103] In some embodiments, R in the above formula 6 Each instance of R is the same. 6 In some embodiments, one R 6 is hydrogen. In some embodiments, one R 6 is C 1-5 In some embodiments, each R 6 is hydrogen. In some embodiments, each R 6 is C 1-5 In some embodiments, R 6 is selected from those shown in Table 1 below.

[0104] As generally defined above and described herein, each R 7are independently selected from hydrogen, deuterium, halogen, -CN, -OR, -NR2, -NO2, -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8-10 membered bicyclic aromatic carbocycle, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or optionally substituted by -CN, -OR, -NR2, -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8-10 membered bicyclic aromatic carbocycle, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 1-6 an aliphatic group or C 1-6 An aliphatic group is optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms.

[0105] In some embodiments, R 7 is hydrogen. In some embodiments, R 7 is deuterium. In some embodiments, R 7 is halogen. In some embodiments, R 7 In some embodiments, R 7 is -OR. In some embodiments, R 7 is -NR2. In some embodiments, R 7 is —NO. In some embodiments, R 7 is -SR. In some embodiments, R 7is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 7 is phenyl. In some embodiments, R 7 is an 8-10 membered bicyclic aromatic carbocycle. In some embodiments, R 7 is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 7 is a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 7 is an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 7 is -CN, -OR, -NR2, -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8-10 membered bicyclic aromatic carbocycle, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, C optionally substituted by a 10-membered monocyclic heteroaromatic ring or an 8-10-membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 1-6 In some embodiments, R 7 is C optionally substituted by 1, 2, 3, 4, 5 or 6 deuterium or halogen atoms 1-6 It is an aliphatic group.

[0106] In some embodiments, R 7is optionally substituted by hydrogen, deuterium, halogen, -CN, -OR, -NR2, -NO2, -SR, a 3- to 6-membered saturated or partially unsaturated monocyclic carbocycle, phenyl, a 4- to 6-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or -CN, -OR, -NR2, -SR, a 3- to 6-membered saturated or partially unsaturated monocyclic carbocycle, phenyl, or a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 1-6 an aliphatic group or C 1-6 The aliphatic group is optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms. 7 is optionally substituted by hydrogen, deuterium, halogen, —CN, a 3- to 6-membered saturated or partially unsaturated monocyclic carbocycle, phenyl, a 5- to 6-membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or —CN, a 3- to 6-membered saturated or partially unsaturated monocyclic carbocycle, phenyl, or a 5- to 6-membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 1-4 alkyl group or C 1-4 The alkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms. 7 is hydrogen, halogen, -CN, -OR, or C 1-4 It is alkyl.

[0107] In some embodiments, R is hydrogen or C 1-4 It is alkyl. In some embodiments, R 7 is selected from those shown in Table 1 below.

[0108] As generally defined above and described herein, each Z1 is independently selected from -O-, -NR-, or -S-. 1 is —O—. In some embodiments, Z 1 is -NR-. In some embodiments, Z 1 is -S. In some embodiments, Z 1 is -NH- or -NMe-.

[0109] In some embodiments, Z 1 is selected from those shown in Table 1 below. As generally defined above and described herein, each Z 2 are independently selected from —O—, —NR—, —S—, —OC(O)—, —NRC(O)O—, or —OC(O)NR—.

[0110] In some embodiments, Z 2 is —O—. In some embodiments, Z 2 is -NR-. In some embodiments, Z 2 is -S-. In some embodiments, Z 2 is -OC(O)-. In some embodiments, Z 2 is -NRC(O)O-. In some embodiments, Z 2 is -OC(O)NR-.

[0111] In some embodiments, each Z 2 are independently selected from —O—, —NH—, —NMe—, —S—, —OC(O)—, —NHC(O)O—, —NMeC(O)O—, —OC(O)NH—, or —OC(O)NMe—.

[0112] In some embodiments, Z 2 is covalently attached to A. In some embodiments, Hey, Z 2 is -O- or -OC(O)O-.

[0113] In some embodiments, Z 2 is selected from those shown in Table 1 below. In some embodiments, Z 1 is -O- and Z 2 is -O- or -OC(O)O-.

[0114] As generally defined above and described herein, each Z 3 is =N- or =C(R 7 In some embodiments, Z 3 is ═N—. In some embodiments, Z 3 is =C(R 7 )-.

[0115] In some embodiments, Z 3 is selected from those shown in Table 1 below. As generally defined above and described herein, each Z 4 -O-, -NR-, -S-, -C(R 6 )2-, or a covalent bond. 4 is —O—. In some embodiments, Z 4 is -NR-. In some embodiments, Z 4 is -S-. In some embodiments, Z 4 is -C(R 6 )2-. In some embodiments, Z 4 is a covalent bond.

[0116] In some embodiments, Z 4 is selected from those shown in Table 1 below. In some embodiments, -M- is one of the following:

[0117] [ka]

[0118] is selected from one of the following: In some embodiments, -M- is

[0119] [ka]

[0120] is. In some embodiments, -M- is

[0121] [ka]

[0122] is. In some embodiments, -M- is

[0123] [ka]

[0124] is selected from. In some embodiments, -M- is

[0125] [ka]

[0126] is selected from. In some embodiments, -M- is

[0127] [ka]

[0128] is selected from. In some embodiments, -M- is

[0129] [ka]

[0130] is selected from. In some embodiments, -M- is

[0131] [ka]

[0132] is selected from. In some embodiments, -M- is selected from those shown in Table 1 below.

[0133] As defined above and described herein, n is 0-18. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 7. In some embodiments, n is 8. In some embodiments, n is 9. In some embodiments, n is 10. In some embodiments, n is 11. In some embodiments, n is 12. In some embodiments, n is 13. In some embodiments, n is 14. In some embodiments, n is 15. In some embodiments, n is 16. In some embodiments, n is 17. In some embodiments, n is 18. In some embodiments, n is 1 to 16, 1 to 14, 1 to 12, 1 to 10, 1 to 8, 1 to 6, 1 to 3, 2 to 16, 2 to 14, 2 to 12, 2 to 10, 2 to 8, 2 to 6, 3 to 12, 3 to 10, 3 to 8, 3 to 6, 4 to 10, 4 to 8, 4 to 6, 5 to 10, 5 to 8, 5 to 6, 6 to 10, 6 to 8, or 8 to 12.

[0134] As defined above and described herein, each m is independently 0 to 6. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6. In some embodiments, each m is independently 0, 1, or 2. In some embodiments, each m is independently 1, 2, 3, or 4.

[0135] As defined above and described herein, A is a therapeutic agent selected from naturally occurring or non-naturally occurring pregnane neurosteroids, or analogs or prodrugs thereof. Exemplary naturally occurring or non-naturally occurring pregnane neurosteroids include those described herein. In some embodiments, A is allopregnanolone, or an analog or prodrug thereof. In some embodiments, A is allopregnanolone.

[0136] In some embodiments, A is a naturally occurring or non-naturally occurring (e.g., synthetic) pregnane neurosteroid, or an analog or prodrug thereof. In some embodiments, A is selected from allopregnanolone (5α-pregnan-3α-ol-20-one), 3,5-tetrahydroprogesterone, pregnanolone (5β-pregnan-3α-ol-20-one), isopregnanolone (5α-pregnan-3β-ol-20-one), epipregnanolone (5β-pregnan-3β-ol-20-one), 21-hydroallopregnanolone, or an analog or prodrug thereof.

[0137] In some embodiments, A is alphadolone (3α,21-dihydroxy-5α-pregnane-11,20-dione), alfaxolone (3α-hydroxy-5α-pregnane-11,20-dione), ganaxolone (3α-hydroxy-3β-methyl-5α-pregnan-20-one), hydroxydione (21-hydroxy-5β-pregnane-3,20-dione), minaxolone (11α-(dimethylamino)-2β-ethoxy-3α-hydroxy-5α-pregnan-20-one), Org 20599 (21-chloro-3α-hydroxy-2β-morpholin-4-yl-5β-pregnan-20-one), Org 21465 (2β-(2,2-dimethyl-4-morpholinyl)-3α-hydroxy-11,20-dioxo-5α-pregnan-21-yl methanesulfonate), Lenanolone (3α-hydroxy-5β-pregnane-11,20-dione), or SAGE-217 (1-(2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydride 1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile).

[0138] In some embodiments, A is selected from allopregnanolone, pregnanolone, pregnenolone, ganaxolone, alphaxalone, 3β-dihydropregesterone, isopregnanolone, epipregnanolone, or 21-hydroxyallopregnanolone.

[0139] In some embodiments, A is allopregnanolone, isopregnanolone, or an analog or prodrug thereof. In some embodiments, A is isopregnanolone, or an analog or prodrug thereof. In some embodiments, A is allopregnanolone or isopregnanolone. In some embodiments, A is isopregnanolone.

[0140] In some embodiments, the pregnane neurosteroid is ganaxolone or allopregnanolone.

[0141] Those skilled in the art will recognize that the specific lipid prodrugs shown in Table 1 are in the form of prodrugs. For example, progesterone is a prodrug of allopregnanolone. Accordingly, it will be appreciated that the lipid prodrug moieties of the present invention are attached to a therapeutic agent or its active form. For purposes of clarity, and by way of example, it will be understood that the lipid prodrug moieties provided are attached at any modifiable oxygen, sulfur, or nitrogen atom of the pregnane neurosteroid. For example, allopregnanolone has the following structure:

[0142] [ka]

[0143] and can be attached to the lipid prodrug moiety, for example, via its hydroxyl (OH) group or at another chemically modifiable position.

[0144] As used herein, the parentheses around Therapeutic Agent A indicate

[0145] [ka]

[0146] teeth,

[0147] [ka]

[0148] means that the moiety is covalently attached to A at any available, modifiable nitrogen, oxygen, or sulfur atom. For purposes of clarity, and as a non-limiting example, the available, modifiable nitrogen, oxygen, or sulfur atoms in the compound structures of the following therapeutic agents are shown below, with each wavy bond corresponding to Formula I, or another formula shown herein:

[0149] [ka]

[0150] Define the connection points of In some embodiments, A is

[0151] [ka]

[0152] is. In some embodiments, A is

[0153] [ka]

[0154] is. In some embodiments, A is

[0155] [ka]

[0156] is. In some embodiments, the present invention provides a compound of formula Ia:

[0157] [ka]

[0158] or a pharmaceutically acceptable salt thereof (wherein L, R 1, R 2 and X are each defined above and are provided herein both alone and in combination in the embodiments.

[0159] In some embodiments, the present invention provides a compound of formula Ib:

[0160] [ka]

[0161] or a pharmaceutically acceptable salt thereof, wherein each of L and A is defined above and described both alone and in combination in the embodiments herein.

[0162] In some embodiments, the present invention provides a compound of formula Ic:

[0163] [ka]

[0164] or a pharmaceutically acceptable salt thereof (wherein L, R 1 , R 2 and X are each defined above and are provided herein both alone and in combination in the embodiments.

[0165] In some embodiments, the present invention provides a compound of formula II:

[0166] [ka]

[0167] or a pharmaceutically acceptable salt thereof (wherein R 1 , R 2 , R 4 , X, M, and A are each defined above and are provided herein both alone and in combination in the embodiments.

[0168] In some embodiments, the present invention provides a compound of formula III:

[0169] [ka]

[0170] or a pharmaceutically acceptable salt thereof (wherein R 1 , R 2 , R 4 , R 5 , X, M, and A are each defined above and are provided herein both alone and in combination in the embodiments.

[0171] In some embodiments, the present invention provides a compound of formula IV:

[0172] [ka]

[0173] or a pharmaceutically acceptable salt thereof (wherein R 1 , R 2 , R 4 , R 5 , X, n, and A are each defined above and are provided herein both alone and in combination in the embodiments.

[0174] In some embodiments, the present invention provides a compound of formula V:

[0175] [ka]

[0176] or a pharmaceutically acceptable salt thereof (wherein R 1 , R 2 , X, and M are each defined above and are provided herein both alone and in combination in the embodiments.

[0177] In some embodiments, the present invention provides a compound of formula VI:

[0178] [ka]

[0179] or a pharmaceutically acceptable salt thereof (wherein R 1 , R 2 , R 4 and M are each defined above and are provided herein both alone and in combination in the embodiments.

[0180] In some embodiments, the present invention provides a compound of formula VII-a, VII-b, VII-c, VII-d, VII-e, VII-f, or VII-g:

[0181] [ka]

[0182] [ka]

[0183] or a pharmaceutically acceptable salt thereof (wherein R 1 , R 2 , R 4 , R 5 and M are each defined above and are provided herein both alone and in combination in the embodiments.

[0184] In some embodiments, the present invention provides a compound of formula VIII-a or VIII-b:

[0185] [ka]

[0186] or a pharmaceutically acceptable salt thereof (wherein R 1 , R2 , R 4 , R 5 , X, n, M, and A are each defined above and are provided herein both alone and in combination in the embodiments.

[0187] In some embodiments, the present invention provides a compound of formula VIII-c or VIII-d:

[0188] [ka]

[0189] or a pharmaceutically acceptable salt thereof (wherein R 1 , R 2 , R 4 , R 5 Each of M, A, and M is defined above and is provided herein both alone and in combination in the embodiments.

[0190] In some embodiments, the present invention provides a compound of formula IX-a or IX-b:

[0191] [ka]

[0192] or a pharmaceutically acceptable salt thereof (wherein R 1 , R 2 , R 4 , R 5 and M are each defined above and are provided herein both alone and in combination in the embodiments.

[0193] In some embodiments, the present invention provides a compound of formula IX-c or IX-d:

[0194] [ka]

[0195] or a pharmaceutically acceptable salt thereof (wherein R 1 , R 2 , R 4 , R 5 and M are each defined above and are provided herein both alone and in combination in the embodiments.

[0196] In some embodiments, the present invention provides a compound of formula X:

[0197] [ka]

[0198] or a pharmaceutically acceptable salt thereof (wherein R 1 , R 2 , X, and M are each defined above and are provided herein both alone and in combination in the embodiments.

[0199] In some embodiments, the present invention provides a compound of formula XI:

[0200] [ka]

[0201] or a pharmaceutically acceptable salt thereof (wherein R 1 , R 2 , R 4 and M are each defined above and are provided herein both alone and in combination in the embodiments.

[0202] In some embodiments, the present invention provides a compound of formula XII-a, XII-b, XIIc, XII-d, XII-e, XII-f, or XII-g:

[0203] [ka]

[0204] [ka]

[0205] or a pharmaceutically acceptable salt thereof (wherein R 1 , R 2 , R 4 , R 5 and M are each defined above and are provided herein both alone and in combination in the embodiments.

[0206] In some embodiments, the present invention provides a compound of formula XIII-a or XIII-b:

[0207] [ka]

[0208] or a pharmaceutically acceptable salt thereof (wherein R 1 , R 2 , R 4 , R 5 and M are each defined above and are provided herein both alone and in combination in the embodiments.

[0209] In some embodiments, the present invention provides a compound of formula XIII-c or XIII-d:

[0210] [ka]

[0211] or a pharmaceutically acceptable salt thereof (wherein R 1 , R 2 , R 4 , R 5 and M are each defined above and are provided herein both alone and in combination in the embodiments.

[0212] In the formula above, when a range of numbers (such as 0 to 4 or 1 to 18) is disclosed, each individual integer within the range is also specifically disclosed. Thus, the above range of 0 to 4 includes 0, 1, 2, 3, and 4. The range 1 to 18 includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, and 18. The range 0 to 1 includes 0 and 1 (i.e., the group is optionally present). When more than one range is disclosed in a formula, each range is optionally selected independently of the disclosed ranges. For example, in the above formula VII-c, each range of 0 to 4 and 1 to 18 varies independently of the others.

[0213] In one embodiment, the present invention provides a lipid prodrug compound shown in Table 1, or a pharmaceutically acceptable salt thereof.

[0214] [Table 1-1]

[0215] [Table 1-2]

[0216] [Table 1-3]

[0217] [Table 1-4]

[0218] [Table 1-5]

[0219] [Table 1-6]

[0220] [Table 1-7]

[0221] [Table 1-8]

[0222] [Table 1-9]

[0223] In some embodiments, the present invention provides a compound shown in Table 1 above, or a pharmaceutically acceptable salt thereof.

[0224] Lipids, including fatty acids, phospholipids, lipid processing mimetics, and mixtures thereof, for use in the disclosed lipid prodrugs. The lipid prodrugs described in this disclosure mimic the lipid processing that occurs in the human body.

[0225] A variety of lipids are suitable for use in the lipid prodrugs of the present disclosure. In some embodiments, the lipid prodrug comprises a fatty acid, a phosphatide, a phospholipid or analog thereof (e.g., phophatidylcholine, lecithin, phosphatidylethanolamine, cephalin, or phosphatidylserine, or an analog or portion thereof (such as a partially hydrolyzed portion thereof)), or other lipid processing mimic (e.g., a group cleaved by lipase, other digestive enzymes, or other mechanisms in the gastrointestinal tract that allow the lipid prodrug to mimic dietary lipid processing). In some embodiments, the fatty acid is a short-chain fatty acid, a medium-chain fatty acid, or a long-chain fatty acid. In some embodiments, the fatty acid is a saturated fatty acid. In some embodiments, the fatty acid is an unsaturated fatty acid. In some embodiments, the fatty acid is a monounsaturated fatty acid. In some embodiments, the fatty acid is a polyunsaturated fatty acid (such as an omega-3 fatty acid or an omega-6 fatty acid). In some embodiments, the lipid (e.g., fatty acid) comprises a C2-C60 In some embodiments, the lipid (e.g., fatty acid) has a C2-C 28 In some embodiments, the lipid (e.g., fatty acid) has a C2-C 40 In some embodiments, the lipid (e.g., fatty acid) has a C2-C 12 Chain or C4-C 12 In some embodiments, the lipid (e.g., fatty acid) has a C4-C 40 In some embodiments, the lipid (e.g., fatty acid) has a C4-C 40 , C2-C 38 , C2-C 36 , C2-C 34 , C2-C 32 , C2-C 30 , C4-C 30 , C2-C 28 , C4-C 28 , C2-C 26 , C4-C 26 , C2-C 24 , C4-C 24 , C6-C 24 , C8-C 24 , C 10 -C 24 , C2-C 22 , C4-C 22 , C6-C 22 , C8-C 22 , C 10 -C 22 , C2-C 20 , C4-C 20 , C6-C 20 , C8-C 20 , C 10 -C 20 , C2-C 18 , C4-C 18 , C6-C 18 , C8-C 18 , C 10 -C 18 , C 12 -C 18 , C 14 -C 18 , C 16 -C 18 , C2-C 16 , C4-C 16 , C6-C16 、C8-C 16 、C 10 -C 16 、C 12 -C 16 、C 14 -C 16 、C2-C 15 、C4-C 15 、C6-C 15 、C8-C 15 、C9-C 15 、C 10 -C 15 、C 11 -C 15 、C 12 -C 15 、C 13 -C 15 、C2-C 14 、C4-C 14 、C6-C 14 、C8-C 14 、C9-C 14 、C 10 -C 14 、C 11 -C 14 、C 12 -C 14 、C2-C 13 、C4-C 13 、C6-C 13 、C7-C 13 、C8-C 13 、C9-C 13 、C 10 -C 13 、C 10 -C 13 、C 11 -C 13 、C2-C 12 、C4-C 12 、C6-C 12 、C7-C 12 、C8-C 12 、C9-C 12 、C 10 -C 12 、C2-C 11 、C4-C 11 、C6-C 11 、C7-C 11 、C8-C 11 、C9-C 11 、C2-C 10 、C4-C 10, C2-C9, C4-C9, C2-C8, C4-C8, C2-C7, C4-C7, C2-C6, or C4-C6 chains. In some embodiments, the lipids (e.g., fatty acids) have a C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 , C 22 , C 23 , C 24 , C 25 , C 26 , C 27 , C 28 , C 29 , C 30 , C 31 , C 32 , C 33 , C 34 , C 35 , C 36 , C 37 , C 38 , C 39 , C 40 , C 41 , C 42 , C 43 , C 44 , C 45 , C 46 , C 47 , C 48 , C 49 , C 50 , C 51 , C 52 , C 53 , C 54 , C 55 , C 56 , C 57 , C 58 , C 59 , or C 60 In some embodiments, the lipid prodrug comprises two fatty acids, each independently selected from fatty acids having a chain with any one of the above ranges or numbers of carbon atoms. In some embodiments, one of the fatty acids is independently selected from a C6-C21 A fatty acid with a chain structure, one of which is independently C 12 -C 36 In some embodiments, each fatty acid independently has a chain of 11, 12, 13, 14, 15, 16, or 17 carbon atoms.

[0226] In some embodiments, the lipid prodrug comprises two lipids, in some embodiments, the two lipids (e.g., fatty acids) together have 6 to 80 carbon atoms (6 to 80 equivalent carbon number (ECN)).In some embodiments, the lipids (e.g., fatty acids) are selected from the group consisting of 6 to 80, 8 to 80, 10 to 80, 12 to 80, 14 to 80, 16 to 80, 18 to 80, 20 to 80, 22 to 80, 24 to 80, 26 to 80, 28 to 80, 30 to 80, 4 to 76, 6 to 76, 8 to 76, 10 to 76, 12 to 76, 14 to 76, 16 to 76, 18 to 76, 20 to 76, 22 to 76, 24 to 76, 26 to 76, 28 to 76, 30 to 76, 6 to 72, 8 to 72, 10 to 72, 12 to 72, 14 to 72, 16 to 72, 18 to 72, 20 to 72, 22 to 72 ... 72, 26-72, 28-72, 30-72, 6-68, 8-68, 10-68, 12-68, 14-68, 16-68, 18-68, 20-68, 22-68, 24-68, 26-68, 28-68, 30-68, 6-64, 8-64, 10-64, 12-64, 14-64, 16-64, 18-64, 20-64, 22-64, 24-64, 26-64, 28-64, 30-64, 6-60, 8-60, 10-60, 12-56, 14-56, 16-56, 18-56, 20-56, 22-56, 24-56, 26-56, 28 ~56, 30~56, 6~52, 8~52, 10~52, 12~52, 14~52, 16~52, 18~52, 20~52, 22~52, 24~52, 26~52, 28~52, 30~52, 6~48, 8~48, 10~48, 12~48, 14~48, 16~48, 18~48, 20~48, 22~48, 24~48, 26~48, 28~48, 30~48, 6~44, 8~44, 10~44, 12~44, 14~44, 16~44, 18~44, 20~44, 22~44, 24~44, 26~44, 28~44, 30~44, and having an ECN of 6-40, 8-40, 10-40, 12-40, 14-40, 16-40, 18-40, 20-40, 22-40, 24-40, 26-40, 28-40, 30-40, 6-36, 8-36, 10-36, 12-36, 14-36, 16-36, 18-36, 20-36, 22-36, 24-36, 26-36, 28-36, 30-36, 6-32, 8-32, 10-32, 12-32, 14-32, 16-32, 18-32, 20-32, 22-32, 24-32, 26-32, 28-32, or 30-32.

[0227] Suitable fatty acids include saturated straight-chain fatty acids, saturated branched fatty acids, unsaturated fatty acids, hydroxy fatty acids, and polycarboxylic acids. In some embodiments, such fatty acids have up to 32 carbon atoms.

[0228] Examples of useful saturated straight-chain fatty acids include those with an even number of carbon atoms (such as butyric acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, cerotic acid, octacosanoic acid, triacontanoic acid, and n-dotriacontanoic acid) and those with an odd number of carbon atoms (such as propionic acid, n-valeric acid, enanthic acid, pelargonic acid, hendecanoic acid, tridecanoic acid, pentadecanoic acid, heptadecanoic acid, nonadecanoic acid, heneicosanoic acid, tricosanoic acid, pentacosanoic acid, and heptacosanoic acid).

[0229] Examples of suitable saturated branched fatty acids include isobutyric acid, isocaproic acid, isocaprylic acid, isocapric acid, isolauric acid, 11-methyldodecanoic acid, isomyristic acid, 13-methyltetradecanoic acid, isopalmitic acid, 15-methylhexadecanoic acid, isostearic acid, 17-methyloctadecanoic acid, isoarachidic acid, 19-methyleicosanoic acid, α-ethylhexanoic acid, α-hexyldecanoic acid, α-heptylundecanoic acid, 2-decyltetradecanoic acid, 2-undecyltetradecanoic acid, 2-decylpentadecanoic acid, 2-undecylpentadecanoic acid, and Fine Oxocol 1800 acid (a product of Nissan Chemical Industries, Ltd.). Suitable saturated odd-carbon branched fatty acids include anteiso fatty acids terminated with an isobutyl group (6-methyl-octanoic acid, 8-methyl-decanoic acid, 10-methyl-dodecanoic acid, 12-methyl-tetradecanoic acid, etc.). 14-methyl-hexadecanoic acid, 16-methyl-octadecanoic acid, 18-methyl-eicosanoic acid, 20-methyl-docosanoic acid, 22-methyl-tetracosanoic acid, 24-methyl-cerotic acid, and 26-methyloctacosanoic acid, etc.

[0230] Examples of suitable unsaturated fatty acids include 4-decenoic acid, caproleic acid, 4-dodecenoic acid, 5-dodecenoic acid, lauroleic acid, 4-tetradecenoic acid, 5-tetradecenoic acid, 9-tetradecenoic acid, palmitoleic acid, 6-octadecenoic acid, oleic acid, 9-octadecenoic acid, 11-octadecenoic acid, 9-eicosenoic acid, cis-11-eicosenoic acid, cetoleic acid, 13-docosenoic acid, 15-tetracosenoic acid, 17-hexacosenoic acid, 6,9, These include 12,15-hexadecatetraenoic acid, linoleic acid, linolenic acid, α-eleostearic acid, β-eleostearic acid, punicic acid, 6,9,12,15-octadecatetraenoic acid, parinaric acid, 5,8,11,14-eicosatetraenoic acid, 5,8,11,14,17-eicosapentaenoic acid, 7,10,13,16,19-docosapentaenoic acid, 4,7,10,13,16,19-docosahexaenoic acid, and the like.

[0231] Examples of suitable hydroxy fatty acids include α-hydroxylauric acid, α-hydroxymyristic acid, α-hydroxypalmitic acid, α-hydroxystearic acid, ω-hydroxylauric acid, α-hydroxyarachidic acid, 9-hydroxy-12-octadecenoic acid, ricinoleic acid, α-hydroxybehenic acid, 9-hydroxy-trans-10,12-octadecadienoic acid, kamolenic acid, iprolic acid, 9,10-dihydroxystearic acid, 12-hydroxystearic acid, and the like.

[0232] Examples of suitable polycarboxylic acids include oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, D,L-malic acid, and the like.

[0233] In some embodiments, each fatty acid is independently selected from propionic acid, butyric acid, valeric acid, caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, undecylic acid, lauric acid, tridecylic acid, myristic acid, pentadecanoic acid, palmitic acid, margaric acid, stearic acid, nonadecylic acid, arachidic acid, heneicosylic acid, behenic acid, tricosylic acid, lignoceric acid, pentacosylic acid, cerotic acid, heptacosylic acid, montanic acid, nonacosylic acid, melissic acid, henatriacontylic acid, lacceroic acid, psyllic acid, gedaic acid, ceroplastic acid, hexatriacontylic acid, heptatriacontanoic acid, or octatriacontanoic acid.

[0234] In some embodiments, each fatty acid is independently selected from α-linolenic acid, stearidonic acid, eicosapentaenoic acid, docosahexaenoic acid, linoleic acid, γ-linoleic acid, dihomo-γ-linoleic acid, arachidonic acid, docosatetraenoic acid, palmitoleic acid, vaccenic acid, paulic acid, oleic acid, elaidic acid, gondoic acid, erucic acid, nervonic acid, mead acid, adrenic acid, bosseopentaenoic acid, ozubondo acid, sardine acid, herring acid, docosahexaenoic acid, or tetracosanolpentaenoic acid, or another monounsaturated or polyunsaturated fatty acid.

[0235] In some embodiments, one or both of the fatty acids are essential fatty acids. Given the beneficial health effects of certain essential fatty acids, the therapeutic benefit of the disclosed lipid prodrugs can be increased by including such fatty acids in the lipid prodrug. In some embodiments, the essential fatty acid is linolenic acid, γ-linolenic acid, dihomo-γ-linolenic acid, or α-linolenic acid. The essential fatty acid is an n-6 or n-3 fatty acid selected from the group consisting of arachidonic acid, adrenic acid, docosapentaenoic n-6 acid, alpha-linolenic acid, stearidonic acid, 20:4 n-3 acid, eicosapentaenoic acid, docosapentaenoic n-3 acid, or docosahexaenoic acid.

[0236] In some embodiments, each fatty acid is independently selected from all-cis-7,10,13-hexadecatrienoic acid, α-linolenic acid, stearidonic acid, eicosatrienoic acid, eicosatetraenoic acid, eicosapentaenoic acid (EPA), docosapentaenoic acid, docosahexaenoic acid (DHA), tetracosapentaenoic acid, tetracosahexaenoic acid, or lipoic acid. In other embodiments, the fatty acid is selected from eicosapentaenoic acid, docosahexaenoic acid, or lipoic acid. Other examples of fatty acids include all-cis-7,10,13-hexadecatrienoic acid, alpha-linolenic acid (ALA or all-cis-9,12,15-octadecatrienoic acid), stearidonic acid (STD or all-cis-6,9,12,15-octadecatetraenoic acid), eicosatrienoic acid (ETE or all-cis-11,14,17-eicosatrienoic acid), and eicosatetraenoic acid (ETA or all-cis-8,11,14,17-eicosatrienoic acid). Examples of fatty acids include eicosatetraenoic acid, eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA, clupanodonic acid, or all-cis-7,10,13,16,19-docosapentaenoic acid), docosahexaenoic acid (DHA or all-cis-4,7,10,13,16,19-docosahexaenoic acid), tetracosapentaenoic acid (all-cis-9,12,15,18,21-docosahexaenoic acid), or tetracosahexaenoic acid (nisinic acid or all-cis-6,9,12,15,18,21-tetracosenoic acid). In some embodiments, the fatty acid is a medium-chain fatty acid, such as lipoic acid.

[0237] Fatty acid chains vary greatly in chain length and can be classified according to chain length (eg, as short chain to very long chain).

[0238] Short chain fatty acids (SCFAs) are fatty acids with a chain of about 5 carbons or less (e.g., butyric acid). In some embodiments, each of the fatty acids is independently an SCFA. In some embodiments, one of the fatty acids is independently an SCFA.

[0239] Medium-chain fatty acids (MCFAs) include fatty acids with chains of about 6 to 12 carbons that can form medium-chain triglycerides. In some embodiments, each of the fatty acids is independently an MCFA. In some embodiments, one of the fatty acids is independently an MCFA.

[0240] Long-chain fatty acids (LCFAs) include fatty acids with chains of 13 to 21 carbons. In some embodiments, each of the fatty acids is independently an LCFA. In some embodiments, one of the fatty acids is independently an LCFA.

[0241] Very long chain fatty acids (VLCFAs) include fatty acids with a chain of 22 or more carbons (22-60, 22-50, or 22-40 carbons). In some embodiments, each of the fatty acids is independently a VLCFA. In some embodiments, one of the fatty acids is independently a VLCFA.

[0242] In some embodiments, one of the fatty acids is independently an MCFA and one is independently an LCFA.

[0243] Therapeutic Agents and Exemplary Associated Disorders In accordance with the present invention, various therapeutic agents may be administered in the form of lymphotropic lipids (e.g., cyclosporine ... For example, the therapeutic agent may be covalently conjugated to a triglyceride scaffold. In some embodiments, by conjugating a therapeutic agent to a lymphatic-directed lipid, the present invention provides enhanced desirable properties of the therapeutic agent, such as improved oral bioavailability, minimizing drug breakdown in the intestine, avoiding the hepatic first-pass effect, improving delivery of the therapeutic agent to a target tissue, or increasing the solubility and stability of the therapeutic agent (including in vivo drug solubility and stability).

[0244] As described herein, the present invention provides compounds of Formula I, wherein the therapeutic agent is a pregnane neurosteroid, or an analog or prodrug thereof.

[0245] In general, neurotransmitters regulate the conductance of ions across neuronal membranes. Gamma-aminobutyric acid (GABA) exerts a wide range of effects on overall neuronal excitability by modulating chloride ion conductance via the GABA receptor-chloride ionophore complex (GR). As intracellular chloride levels increase, neurons become hyperpolarized and less susceptible to excitatory inputs. It is well known that the GR complex mediates anxiety, seizure behavior, and sedation through this mechanism.

[0246] Certain endogenous steroids (such as the A-ring reduced metabolites of progesterone) act as selective allosteric modulators of the GR complex without classical steroid hormone activity. In particular, pregnane neurosteroids, such as allopregnanolone (3α-hydroxy-5α-pregnan-20-one) and allotetrahydrodeoxycorticosterone (5α,3α-THDOC), act as potent positive allosteric modulators of GR, producing neuroprotective effects as well as anxiolytic (Bitran, D. et al. J. Neuroendocrinol 7(3):171-7(1995)), anticonflict (Perche, F. et al. Aggress Behav 27(2):130-8(2001)), anticonvulsant (Frye, CA Brain Res. 643(1-2):194-203(1995)), and antinociceptive (Wiebe, J.P. & Kavaliers, M. Brain Res. 461(1):150-7(1988)). Furthermore, the antidepressant effects of allopregnanones are well established in animal models (e.g., Frye, CA & Walf, AA Horm Behav 41(3):306-15 (2002)), and low levels of allopregnanolone are associated with various depressive mood disorders (e.g., Anreen, L. et al. Psychoneuroendocrinology 34(8):1121-32 (2009)). Additionally, pregnane neurosteroid treatment has been shown to have positive effects in various neurological conditions, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, Niemann-Pick type C, fragile X-associated tremor / ataxia syndrome (FXTAS), diabetic neuropathy, status epilepticus (including benzodiazepine resistance), and traumatic brain injury (Irwin, RW et al. Front. Cell. Neurosci. 8:203. doi:10.3389 / fncel.2014.00203).

[0247] Nevertheless, neurosteroids are susceptible to metabolism and have low bioavailability (Rupprecht, R. Psychoneuroendocrinology, 28(2):139-68(2003)). Therefore, there is a need for neurosteroid (e.g., allopreganolone) prodrugs that have improved bioavailability and avoid first-pass metabolism by the liver.

[0248] In some embodiments, the disclosed lipid prodrugs comprise a therapeutic agent selected from neuroactive steroids (such as allopregnanolone, pregnanolone, pregnenolone, 3β-dihydropregesterone, isopregnanolone, epipregnanolone, and 21-hydroxyallopregnanolone), or others disclosed herein. The amide is selected from allopregnanolone or 21-hydroxyallopregnanolone.

[0249] In some embodiments, the present invention provides a method for treating various disorders, including postpartum depression (Osborne, L. M. et al. Psychoneuroendocrinology 79:116-21 (2017)), depression, anxiety (Schule, C. et al. Prog. Neurobiol. 113: 79-87 (2014)), Niemann-Pick disease or related neurological and physical symptoms (Griffin, L. D. et al. Nat. Med. 10(7):704-11 (2004)), status epilepticus (Rogawski, M. A. et al. Epilepsy 54(s6):93-8 (2013)); Alzheimer's disease, Parkinson's disease, multiple sclerosis, Niemann-Pick type C, paraneoplastic tremor / ataxia syndrome, diabetic neuropathy, or traumatic brain injury (Irwin, R. Et al. al. Front. Cell. Neurosci. 8:203. doi:10.3389 / fncel.2014.00203; Irwin, RW & Brinton, RD Prog. Neurobiol 113:40-55(2014) etc.).

[0250] In other embodiments, the present invention provides methods for treating or preventing a disease, disorder, or condition in which increased levels of a pregnane neurosteroid (such as allopregnanolone) are beneficial, or a disease, disorder, or condition caused by a deficiency of a pregnane neurosteroid (such as allopregnanolone deficiency), comprising administering an effective amount of the disclosed lipid prodrug to a subject in need thereof.

[0251] In some embodiments, the present invention provides a method for treating GABAergic disorders, comprising administering an effective amount of the disclosed lipid prodrugs to a subject in need thereof. A Methods for treating associated diseases, disorders, or conditions are provided.

[0252] In some embodiments, the present invention provides a method for treating GABAergic disorders, comprising administering an effective amount of the disclosed lipid prodrugs to a subject in need thereof. A The present invention provides a method for treating a disease, disorder, or condition caused by a defect in the activation of

[0253] In some embodiments, the disease, disorder, or condition is selected from postpartum depression, depression, major depressive disorder, bipolar disorder, mood disorder, anxiety, post-traumatic stress disorder (PTSD), premenstrual dysphoric disorder (PMDD), premenstrual syndrome, generalized anxiety disorder, seasonal affective disorder (SAD), social anxiety, memory loss, low stress tolerance, Niemann-Pick disease type C or related neurological or physical symptoms, epilepsy, essential tremor, epileptiform disorder, NMDA dysfunction, migraine, status epilepticus, sleep disorders (e.g., insomnia), fragile X syndrome, depression induced by another medication (e.g., finasteride or another 5-alpha reductase inhibitor), PCDH19 female epilepsy, sexual dysfunction, Parkinson's disease, or Alzheimer's disease. In some embodiments, the status epilepticus is highly refractory status epilepticus (SRSE) (a severe form of uncontrolled convulsions).

[0254] In some embodiments, the disease, disorder, or condition is selected from postpartum depression, depression, major depressive disorder, bipolar disorder, Niemann-Pick disease type C, epilepsy, essential tremor, epileptiform disorder, NMDA dysfunction, status epilepticus, Parkinson's disease, or Alzheimer's disease. In some embodiments, the status epilepticus is highly refractory status epilepticus (SRSE), a severe form of uncontrolled seizures.

[0255] In some embodiments, the present invention provides a method for treating depressive mood disorders (e.g., major depressive disorder, bipolar disorder, seasonal affective disorder (SAD), cyclothymic disorder, premenstrual dysphoric disorder, persistent depressive disorder, severe mood dysregulation disorder, depression associated with a medical illness, postpartum depression), and / or anxiety disorders (e.g., panic disorder and The present invention provides a method for treating post-traumatic stress disorder.

[0256] Allopregnanolone (ALLO; brexanolone; SAGE-547) is currently being investigated as a treatment for postpartum depression (NCT2614547; Kanes, S. et al. Lancet 390(10093):480-9(2017)).

[0257] In some embodiments, the therapeutic agent is ganaxolone or allopregnanolone.

[0258] 2. definition Although the terms used herein are believed to be well understood by those of ordinary skill in the art, definitions are set forth herein to facilitate description of the subject matter disclosed herein.

[0259] As used herein, the term "about," when referring to a numerical value or range of a parameter (such as mass, weight, volume, time, concentration, biological activity, clogP, or percentage), is meant to encompass a variation of, for example, ±20%, in some embodiments ±10%, in some embodiments ±5%, in some embodiments ±1%, in some embodiments ±0.5%, and in some embodiments ±0.1% from the stated value or range.

[0260] As used herein, the terms "treatment," "treat," and "treating" refer to ameliorating, alleviating, delaying the onset of, or inhibiting the progression of a disease or disorder described herein, or one or more symptoms thereof. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., taking into account the history of symptoms and / or taking into account genetic or other susceptibility factors). Treatment may be continued after symptoms have been cured to, for example, prevent or delay their recurrence.

[0261] The term "lipid," as used herein, refers to natural and unnatural hydrophobic and / or lipophilic fats, oils, polymers, hydrocarbons, and other such materials. In some embodiments, suitable lipids, when incorporated into lipid prodrugs, are processed or metabolized similarly to, or mimic the processing or metabolism of, triglycerides in the gastrointestinal tract. The term "glyceride" refers to esters of glycerol (1,2,3-propanetriol) with the acyl groups of fatty acids or other lipids, known as acylglycerols. If only one position on the glycerol molecule is esterified with a fatty acid, a "monoglyceride" is produced; if two positions are esterified, a "diglyceride" is produced; and if all three positions on the glycerol are esterified with fatty acids, a "triglyceride" or "triacylglycerol" is produced. If all esterified positions contain the same fatty acid, the glyceride is called "simple"; or if different fatty acids are involved, "mixed." The carbons of the glycerol backbone are designated sn-1, sn-2, and sn-3, with sn-2 being the middle and sn-1 and sn-3 being the ends of the glycerol.

[0262] Naturally occurring fats and oils are mostly composed of triglycerides, in which the three fatty acyl residues may be identical or non-identical. The term "long-chain triglyceride" (or "LCT") refers to both simple and mixed triglycerides containing fatty acids with more than 12 carbon atoms (long-chain fatty acids, "LCFA"), while the term "medium-chain triglyceride" (or "MCT") refers to simple triglycerides containing fatty acids with 4-12 carbon atoms. This refers to both triglycerides and mixed triglycerides.

[0263] The term "ECN" or "equivalent carbon number" refers to the total number of carbon atoms in the acyl chains of a glyceride molecule. For example, tripalmitin (tripalmitic glycerol), a simple triglyceride containing three 16-carbon atom acyl groups, has an ECN of 3 x 16 = 48. Conversely, a triglyceride with an ECN of 40 may have "mixed" acyl chain lengths such as 8, 16, and 16; 10, 14, and 16; or 8, 14, and 18. Naturally occurring oils are often "mixed" with respect to specific fatty acids, but tend not to contain LCFAs and MCFAs on the same glycerol backbone. Thus, triacylglycerols with an ECN of 24-30 typically contain predominantly medium-chain fatty acids, while triacylglycerols with an ECN greater than 43 typically contain predominantly long-chain fatty acids. Triacylglycerols with an ECN of 32 to 42 typically contain one or two MCFAs in combination with one or two LCFAs to "fill out" the triglyceride. Triacylglycerols with an ECN in the range greater than 30 and less than 48 represent mixed triacylglycerol species that are typically absent or present at significantly lower concentrations in physical mixtures. Fatty acids present in foods usually contain an even number of carbon atoms in unbranched chains (e.g., lauric acid or dodecanoic acid).

[0264] The term "self-immolative group," as used herein, refers to a divalent chemical moiety that includes a covalent scissile bond as one of its divalent bonds and a stable covalent bond to a therapeutic agent as the other divalent bond, where the bond to the therapeutic agent is unstable upon cleavage of the scissile bond. Examples of self-immolative groups include, but are not limited to, disulfide groups, hydrazones, acetal self-immolative groups, carboxyacetal self-immolative groups, carboxy(methyl acetal) self-immolative groups, para-hydroxybenzylcarbonyl self-immolative groups, inverted ester self-immolative groups, and trimethyl lock, or 2-hydroxyphenylcarbamate (2-HPC) self-immolative groups. Numerous other suitable self-immolative groups are known in the art, as described, for example, in CA Blencowe et al., Polym. Chem. 2011, 2, 773-790 and F. Kratz et al., ChemMedChem. 2008, 3(1), 20-53; Huvelle, S. et al., Org. Biomol. Chem. 2017, 15(16), 3435-3443; and Alouane, A. et al., Angewandte Chemie International Edition 2015, 54(26), 7492-7509; and Levine, M. et al., Chem. Sci. VL-IS-3(8), 2412-2420 (each of which is incorporated herein by reference in its entirety).

[0265] As used herein, the terms "therapeutic agent," "active pharmaceutical agent," "active drug," or "pharmaceutical agent" include any therapeutic or imaging (imaging) agent that benefits from transport via the intestinal lymphatic system, e.g., to enable oral administration (e.g., of a therapeutic agent administered intravenously), to avoid first-pass metabolism, to avoid liver or other toxicity, or for targeted delivery within the lymphatic system.

[0266] The lipid prodrug compounds of the present invention include those generally described herein and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, chemical elements are defined in accordance with the Periodic Table of the Elements,Handbook of Chemistry and Physics,98 th Additionally, general principles of organic chemistry are identified in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," 5th Ed. ,Ed.:Smith,MBand March,J.,John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0267] The terms "aliphatic" or "aliphatic group," as used herein, refer to a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more units of unsaturation, or a monocyclic or bicyclic hydrocarbon (also referred to herein as "carbocyclic," "alicyclic," or "cycloalkyl") that is fully saturated or contains one or more units of unsaturation, but is not aromatic, having a single point of attachment to the rest of the molecule. Unless otherwise specified, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In still other embodiments, an aliphatic group contains 1-3 aliphatic carbon atoms, and in yet other embodiments, an aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, "alicyclic" (or "carbocycle," or "cycloalkyl") refers to a monocyclic C3-C6 hydrocarbon having a single point of attachment to the rest of the molecule and that is fully saturated or contains one or more units of unsaturation, but is not aromatic. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups, and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0268] As used herein, the term "bicyclic ring" or "bicyclic ring system" refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or containing one or more units of unsaturation, having one or more atoms in common between the two rings of the ring system. Thus, the term encompasses any permissible ring fusion (such as ortho-fused or spirocyclic rings). As used herein, the term "heterobicyclic" is a subset of "bicyclic," requiring that one or more heteroatoms be present in one or both rings of the bicyclic ring. Such heteroatoms are present at the ring junction, are optionally substituted, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphonates and phosphates), boron, and the like. In some embodiments, bicyclic groups have 7 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. As used herein, the term "bridged bicyclic" refers to any bicyclic ring system (i.e., having at least one bridge and being carbocyclic or heterocyclic, saturated or partially unsaturated). As defined by IUPAC, a "bridge" is an unbranched chain of atoms or a single atom or valence bond connecting two bridgeheads, and a "bridgehead" is any skeletal atom of the ring system that is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include the groups described below, in which each group is attached to the remainder of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, bridged bicyclic groups are optionally substituted with one or more substituents, such as those described for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bicyclic rings include:

[0269] [ka]

[0270] Examples include: Exemplary bridged bicyclic compounds include:

[0271] [ka]

[0272] Examples include: The term "lower alkyl" refers to C 1-4 Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0273] The term "lower haloalkyl" refers to a C substituted with one or more halogen atoms. 1-4 refers to a linear or branched alkyl group.

[0274] The term "heteroatom" means one or more of boron, oxygen, sulfur, nitrogen, phosphorus, or silicon (including any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen; or a substitutable nitrogen of a heterocyclic ring, such as N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (including as in N-substituted pyrrolidinyl).

[0275] The term "unsaturated," as used herein, means that a moiety has one or more units of unsaturation.

[0276] As used herein, "divalent C 1-8 (or C 1-6 The term "saturated or unsaturated, straight or branched hydrocarbon chain of the formula (I)" refers to straight or branched divalent alkylene, alkenylene, and alkynylene chains as defined herein.

[0277] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group (i.e., -(CH2) n -), where n is preferably a positive integer of 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms have been replaced by a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0278] The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced by a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0279] The term "halogen" means F, Cl, Br, or I. The term "aryl," used alone or as part of a larger moiety, such as in "aralkyl," "aralkoxy," or "aryloxyalkyl," refers to a monocyclic or bicyclic ring system having a total of 5 to 14 ring members, in which at least one ring in the system is aromatic and each ring in the system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring." In certain embodiments of the present invention, "aryl" refers to an aromatic ring system, including, but not limited to, phenyl, biphenyl, naphthyl, anthracyl, and the like, which may bear one or more substituents. As used herein, groups in which an aromatic ring is fused to one or more non-aromatic rings (such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like) are also encompassed within the scope of the term "aryl."

[0280] The terms "heteroaryl" and "heteroar-," used alone or as part of a larger moiety (e.g., "heteroaralkyl" or "heteroaralkoxy"), refer to groups having 5 to 10 ring atoms (preferably 5, 6, or 9 ring atoms); sharing 6, 10, or 14 pi-electrons in a cyclic arrangement; and having 1 to 5 heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms "heteroaryl" and "heteroar-," as used herein, also encompass groups in which a heteroaromatic ring is fused to one or more aryl, alicyclic, or heterocyclyl rings, and the radical or point of attachment is on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Heteroaryl groups can be monocyclic or bicyclic. The use of "heteroaryl" The term may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," and any of these terms encompass rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl, where the alkyl and heteroaryl portions independently are optionally substituted.

[0281] As used herein, the terms "heterocycle," "heterocyclyl," "heterocyclic radical," and "heterocyclic ring" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety, as defined above, that is either saturated or partially unsaturated and has one or more (preferably 1-4) heteroatoms in addition to carbon atoms. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur, or nitrogen, the nitrogen can be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or + It can be NR (as in N-substituted pyrrolidinyl).

[0282] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure, and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms "heterocycle," "heterocyclyl," "heterocyclyl ring," "heterocyclic group," "heterocyclic moiety," and "heterocyclic radical" are used interchangeably herein and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or alicyclic rings (e.g., indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl). Heterocyclyl groups can be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.

[0283] As used herein, the term "partially unsaturated" refers to a ring moiety that includes at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings with multiple sites of unsaturation, but is not intended to encompass aryl or heteroaryl moieties as defined herein.

[0284] As described herein, the compounds of the present invention may contain "optionally substituted" moieties. Generally, the term "substituted," whether preceded by the term "optionally," means that one or more hydrogen atoms in the specified moiety are replaced with a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in a given structure can be substituted with more than one substituent selected from a specified group, the substituents may be either the same or different at all positions. Combinations of substituents envisioned by the present invention are preferably those that result in the formation of stable or chemically feasible compounds. The term "stable," as used herein, refers to compounds that are substantially unaltered when subjected to conditions that allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0285] Each optional substituent on a substitutable carbon is a halogen; -(CH) 0-4 R 〇 ;-(CH2) 0-4 OR 〇 ;-O(CH2) 0-4 R 〇 , -O-(CH2) 0-4 C(O ) OR 〇 ;-(CH2) 0-4 CH(OR 〇 )2;-(CH2) 0-4 SR 〇 ;-(CH2) 0-4 Ph(R〇 -(CH2) 0-4 O(CH2) 0-1 Ph(R 〇 -CH=CHPh(R 〇 -(CH2) 0-4 O(CH2) 0-1 -pyridyl (R 〇 -NO2; -CN; -N3; ​​-(CH2) 0-4 N(R 〇 )2;-(CH2) 0-4 N(R 〇 )C(O)R 〇 ;-N(R 〇 )C(S)R 〇 ;-(CH2) 0-4 N(R 〇 )C(O)NR 〇 2;-N(R 〇 )C(S)NR 〇 2;-(CH2) 0-4 N(R 〇 )C(O)OR 〇 ;-N(R 〇 )N(R 〇 )C(O)R 〇 ;-N(R 〇 )N(R 〇 )C(O)NR 〇 2;-N(R 〇 )N(R 〇 )C(O)OR 〇 ;-(CH2) 0-4 C(O)R 〇 ;-C(S)R 〇 ;-(CH2) 0-4 C(O)OR 〇 ;-(CH2) 0-4 C(O)SR 〇 ;-(CH2) 0-4 C(O)OSiR 〇 3;-(CH2) 0-4 OC(O)R 〇 ;-OC(O)(CH2) 0-4 SR-, SC(S)SR 〇 ;-(CH2) 0-4 SC(O)R 〇 ;-(CH2) 0-4 C(O)NR 〇2;-C(S)NR 〇 2;-C(S)SR 〇 ;-SC(S)SR 〇 , -(CH2) 0-4 OC(O)NR 〇 2;-C(O)N(OR 〇 )R 〇 ;-C(O)C(O)R 〇 ;-C(O)CH2C(O)R 〇 ;-C(NOR 〇 )R 〇 ;-(CH2) 0-4 SSR 〇 ;-(CH2) 0-4 S(O)2R 〇 ;-(CH2) 0-4 S(O)2OR 〇 ;-(CH2) 0-4 OS(O)2R 〇 ;-S(O)2NR 〇 2;-S(O)(NR 〇 )R 〇 ;-S(O)2N=C(NR 〇 2)2;-(CH2) 0-4 S(O)R 〇 ;-N(R 〇 )S(O)NR 〇 2;-N(R 〇 )S(O)2R 〇 ;-N(OR 〇 )R 〇 ;-C(NH)NR 〇 2;-P(O)2R 〇 ;-P(O)R 〇 2;-OP(O)R 〇 2;-OP(O)(OR 〇 )2;SiR 〇 3;-(C 1-4 linear or branched alkylene)ON(R 〇 )2; or -(C 1-4 linear or branched alkylene)C(O)ON(R 〇 is a monovalent substituent independently selected from

[0286] Each R 〇 are independently hydrogen, C 1-6 Aliphatic, -CH2Ph, -O(CH2) 0-1Ph, -CH2- (a 5-6 membered heteroaryl ring), or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the above definition, two independently occurring R 〇 together with their intervening atom(s) form a 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which R is selected from =O and =S 〇 or each R 〇 is a halogen, -(CH2) 0-2 R ● ,-(Halo R ● ), -(CH2) 0-2 OH, -(CH2) 0-2 OR ● , -(CH2) 0-2 CH(OR ● )2;-O(HaloR ● ), -CN, -N 3 , -(CH2) 0-2 C(O)R ● , -(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR ● , -(CH2) 0-2 SR ● , -(CH2) 0-2 SH, -(CH2) 0-2 NH2, -(CH2) 0-2 NHR ● , -(CH2) 0-2 NR ● 2, -NO2, -SiR ● 3,-OSiR ● 3. -C(O)SR ● , -(C 1-4 linear or branched alkylene)C(O)OR ● , or -SSR ● is optionally substituted by monovalent substituents independently selected from

[0287] Each R ● is C1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; ● is unsubstituted or, if preceded by halo, substituted only with one or more halogens; or the optional substituents on the saturated carbon are ═O, ═S, ═NNR * 2, =NNHC(O)R * , =NNHC(O)OR * , =NNHS(O)2R * , =NR * , =NOR * , -O(C(R * 2)) 2-3 O-, or -S(C(R * 2)) 2-3 A divalent substituent independently selected from -S- or attached to a substitutable carbon adjacent to an "optionally substituted" group is -O(CR * 2) 2-3 O- and non Each R that appeared dependently * is hydrogen, C 1-6 It is selected from aliphatic or unsubstituted 5-6 membered saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0288] R * C 1-6 When it is aliphatic, R * is halogen, -R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, and each R ● is C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; ● is unsubstituted or, if preceded by halo, substituted with only one or more halogens.

[0289] The optional substituents on the substitutable nitrogen are independently -R † , -NR † 2. -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CHC(O)R † , -S(O)2R † , -S(O)NR † 2. -C(S)NR † 2. -C(NH)NR † 2, or -N(R † )S(O)2R † and each R † are independently hydrogen, C 1-6 an aliphatic, unsubstituted -OPh, or an unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two independently occurring R † together with their intervening atom(s) form an unsubstituted 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R † C 1-6 When it is aliphatic, R † is halogen, -R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, and each R ● is C 1-4Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; ● is unsubstituted or, if preceded by halo, substituted with only one or more halogens.

[0290] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reactions, and the like, commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19 (incorporated herein by reference). Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts include salts of amino groups (or other basic groups) formed with inorganic acids (such as hydrochloric, hydrobromic, phosphoric, sulfuric, and perchloric acids), or with organic acids (such as acetic, oxalic, maleic, tartaric, citric, succinic, or malonic acids), or by using other methods (such as ion exchange) used in the art. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, besylate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, and nitrate. , oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like.

[0291] Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N + (C 1-4 Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0292] Unless otherwise stated, structures depicted herein are intended to encompass all isomeric (e.g., anantiomers, diastereomers, and geometric (or conformational)) forms of the structure; for example, R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Thus, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomers of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant to encompass compounds that differ only in the presence of one or more isotopically enriched atoms. For example, the replacement of hydrogen by deuterium or tritium, or 13 C or 14 Compounds having this structure including the replacement of a carbon with a C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools, probes in biological assays, or as therapeutic agents according to the invention.

[0293] 3. Uses, Formulation and Administration Use of lymphotropic lipid prodrugs The disclosed lymphotropic lipid prodrugs, as well as pharmaceutically acceptable compositions comprising the disclosed lipid prodrugs and a pharmaceutically acceptable excipient, diluent, or carrier, are useful in the treatment of a variety of diseases, disorders, or conditions, including those described herein.

[0294] Those skilled in the art will recognize and appreciate that each of the therapeutic agents described herein is known to be associated with the treatment of one or more diseases, disorders, or conditions. Accordingly, it will be appreciated that in certain embodiments, the present invention provides a method of treating a disease, disorder, or condition in a patient in need thereof, comprising administering to said patient a disclosed lipid prodrug.

[0295] The lipid prodrugs disclosed herein are useful for stable transport of pharmaceutical agents to intestinal lymph and release of pharmaceutical agents in lymph, lymphocytes, lymphoid tissues, tissues with high lipase activity (e.g., adipose tissue, certain cancers, liver), or systemic circulation. The disclosed lipid prodrugs are particularly useful for transport and release of pharmaceutical agents that benefit from avoiding first-pass metabolism (e.g., therapeutic agents that exhibit greater than about 50% first-pass metabolism when administered orally). In some embodiments, the therapeutic agent exhibits greater than about 60% first-pass metabolism when administered orally. In some embodiments, the therapeutic agent exhibits greater than about 70%, 80%, or 90% first-pass metabolism when administered orally.

[0296] Stable transport to intestinal lymph, and lymph, lymphocytes, lymphoid tissue, high lipase activity Therapeutic agents that may benefit from release in certain tissues (such as adipose tissue, certain cancers, the liver) or in the systemic circulation include, but are not limited to, those listed herein, such as allopregnanolone, pregnanolone, pregnenolone, 3β-dihydropregesterone, isopregnanolone, epipregnanolone, ganaxolone, or 21-hydroxyallopregnanolone.

[0297] The lipid prodrugs disclosed herein are useful for targeted release of therapeutic agents not only within the lymphatic system (e.g., in lymph, lymphocytes, and lymphoid tissues), but also in tissues with high lipase activity (such as adipose tissue, certain cancers, or the liver). In some embodiments, a therapeutic agent exhibits low lymphatic transport when administered orally. In some embodiments, a therapeutic agent exhibits less than 70%, 60%, 50%, 40%, 30%, 20%, 15%, 10%, 8%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.25%, 0.2%, 0.15%, or 0.1% lipase activity when administered orally. In contrast, the present invention provides improved lymphatic transport of such therapeutic agents. In some embodiments, the disclosed lipid prodrugs, when administered orally, exhibit lymphatic transport of at least 1%, 5%, 7.5%, 10%, 12.5%, 15%, 20%, 25%, 30%, 35%, 40%, or 50%. In some embodiments, the disclosed lipid prodrugs, when administered orally, exhibit lymphatic transport of about 1-50%, 5-40%, 10-30%, 15-25%, or about 50%, 40%, 30%, 25%, 20%, 15%, 12.5%, 10%, 7.5%, 5%, 2.5%, or 1%, as measured by either the w / w% of lipid prodrug or the w / w% of therapeutic agent administered in lipid prodrug form versus unmodified therapeutic agent.

[0298] In some embodiments, the disclosed lipid prodrugs are delivered to the central nervous system (CNS) or cross the blood-brain barrier (BBB) ​​via the lymphatic system.

[0299] In some embodiments, the present invention provides methods for treating or preventing a disease, disorder, or condition, comprising administering to a subject in need thereof an effective amount of the disclosed lipid prodrugs comprising a pregnane neurosteroid therapeutic agent.

[0300] Pharmaceutically acceptable compositions According to another embodiment, the present invention provides a composition comprising a lipid prodrug of the present disclosure and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of lipid prodrug in the composition is an amount effective to treat the relevant disease, disorder, or condition in a patient in need thereof ("effective amount"). In some embodiments, the composition of the present disclosure is formulated for oral administration to a patient.

[0301] The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the agent with which it is formulated. Pharmaceutically acceptable carriers, adjuvants, or vehicles that can be used in the disclosed compositions include, but are not limited to, ion exchangers, alumina, stearates (such as aluminum stearate), lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts, or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat. In some embodiments, the composition comprises a lipophilic mixture (such as a lipophilic mixture). They are formulated as a gel-based composition, etc.

[0302] The compositions of the present invention may be administered orally, parenterally, enterally, intracisternally, intraperitoneally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. In some embodiments, the compositions are administered orally, intraperitoneally, or intravenously. In some embodiments, the compositions are transmucosal formulations. In some embodiments, the compositions are injected directly into the lymphatic system. Sterile injectable forms of the compositions of the present invention may be aqueous or oily suspensions. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent (e.g., as a solution in 1,3-butanediol). Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[0303] Any bland, odorless, fixed oil can be used to aid in the delivery of the composition, including synthetic monoglycerides or diglycerides. Fatty acids (such as oleic acid and its glyceride derivatives) are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils (such as olive oil or castor oil, especially their polyoxyethylated versions). These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersants (such as carboxymethylcellulose or similar dispersants) commonly used in the preparation of pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants (such as Tween, Span, and other emulsifiers or bioavailability enhancers) commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms can also be used for formulation purposes.

[0304] Pharmaceutically acceptable compositions can be orally administered in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions, or solutions.In the case of tablets for oral use, commonly used carriers include lactose and corn starch.Lubricants (such as magnesium stearate) can also be added.For oral administration in capsule form, useful diluents include lactose and dried corn starch.When aqueous suspensions are required for oral use, active ingredients are combined with emulsifiers and suspending agents.If desired, certain sweeteners, flavorings, or colorings can also be added.

[0305] Alternatively, the pharmaceutically acceptable composition can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the drug with a suitable non-irritating excipient (solid at room temperature but liquid at rectal temperature, which will melt in the rectum and release the drug). Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0306] In some embodiments, the pharmaceutically acceptable composition is formulated for oral administration. Such formulations can be administered with or without food. In some embodiments, the pharmaceutically acceptable composition is administered without food. In other embodiments, the pharmaceutically acceptable composition is administered with food.

[0307] The specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, body weight, general health, sex, diet, time of administration, excretion rate, and the like. It will also be understood that the results will depend on a variety of factors, including the severity of the condition, drug combination, and the judgment of the treating physician and the severity of the particular condition being treated.

[0308] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs.In addition to the active compound, liquid dosage forms may contain inert diluents commonly used in the art (such as water or other solvents), solubilizers and emulsifiers (such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof).In addition to inert diluents, oral compositions may also contain adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavorings, and fragrances.

[0309] Injectable preparations (e.g., sterile injectable aqueous or oleaginous suspensions) can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions, suspensions, or emulsions (e.g., as solutions in 1,3-butanediol) in non-toxic parenterally acceptable diluents or solvents. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution (USP), and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any bland, odorless fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0310] The injectable preparations can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which are dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0311] In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This can be accomplished by using a liquid suspension of crystalline or amorphous material with low water solubility. The rate of absorption of the compound then depends on its dissolution rate, which may depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form can be achieved by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsulated matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending on the compound-to-polymer ratio and the nature of the particular polymer employed, the compound release rate can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations can also be prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0312] Compositions for rectal or vaginal administration are preferably suppositories, which can be prepared by mixing a compound of the present invention with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol, or a suppository wax that is solid at ambient temperature but liquid at body temperature and therefore will melt in the rectum or vaginal cavity and release the active compound.

[0313] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is present in at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or mixed with a) filler or extender substances (such as starches, lactose, sucrose, glucose, mannitol, and silicic acid), b) binders (such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia gum), c) moisturizing substances (such as glycerol), d) disintegrating agents (such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate), e) solution retarders (such as paraffin), f) absorption accelerators (such as quaternary ammonium compounds), g) wetting agents (such as cetyl alcohol and glycerol monostearate), h) adsorbent materials (such as kaolin and bentonite clay), and i) lubricating substances (such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof). In the case of capsules, tablets, and pills, the dosage form may also contain buffering agents.

[0314] Solid compositions of a similar type may also be used as fillers in soft and hard-filled gelatin capsules using not only lactose or milk sugar but also excipients such as high molecular weight polyethylene glycols and the like. Solid dosage forms such as tablets, dragees, capsules, pills, and granules may be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may also optionally contain opacifying agents and may be of a composition that releases the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be used as fillers in soft and hard-filled gelatin capsules using not only lactose or milk sugar but also excipients such as high molecular weight polyethylene glycols and the like.

[0315] The therapeutic agent may also be in microencapsulated form with one or more excipients as described above. Solid dosage forms such as tablets, dragees, capsules, pills, and granules may be prepared with coatings and shells, such as enteric coatings, release-controlling coatings, and other coatings well known in the pharmaceutical formulation art. In such solid dosage forms, the active compound may be mixed with at least one inert diluent (such as sucrose, lactose, or starch). Such dosage forms may also contain, as is customary, additional substances other than inert diluents, such as tableting lubricants and other tableting aids (such as magnesium stearate and microcrystalline cellulose). In the case of capsules, tablets, and pills, the dosage forms may also contain buffering agents. They may also optionally contain opacifying agents and be of a composition that releases the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0316] Dosage forms for topical or transdermal administration of the compounds of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers, as needed. Ophthalmic formulations, ear drops, and eye drops are also contemplated within the scope of the present invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of the compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate-controlling membrane or dispersing the compound in a polymer matrix or gel.

[0317] In some embodiments, the lipid prodrug is formulated as an orally administrable lipid-based formulation. Lipid-based formulations for oral delivery are known in the art. Lipid vehicles and the resulting lipid formulations can be usefully classified according to their shared common characteristics according to the Lipid Formulation Classification System (LFCS) (Pouton, CW, Eur.J.Pharm.Sci.11(Supp 2), S93-S98, 2000; Pouton, CW, Eur.J.Pharm.Sci.29 278-287, 2006), as described below.

[0318] The lipid vehicle and resulting lipid formulation may contain oils / lipids and / or surfactants, optionally with cosolvents. In the LFCS nomenclature, Type I formulations contain oils or lipids (such as monoglycerides, diglycerides, and triglycerides, and combinations thereof) that require digestion. Type II formulations are water-insoluble self-emulsifying drug delivery systems (SEDDS) that contain the lipids and oils used in Type I formulations along with additional water-insoluble surfactants. Type III formulations are SEDDSs or self-microemulsifying drug delivery systems (SMEDDS) that contain the lipids and oils used in Type I formulations along with additional water-soluble surfactants and / or cosolvents (Type IIIa) or a higher proportion of water-soluble components (Type IIIb). Type IV formulations contain predominantly hydrophilic surfactants and cosolvents (e.g., PEG, propylene glycol, and diethylene glycol monoethyl ether) and are useful for drugs that are poorly water-soluble but not lipophilic. Any such lipid formulations (Types I-IV) are contemplated herein for use with the disclosed lipid prodrugs or pharmaceutical compositions thereof.

[0319] In some embodiments, the lipid vehicle contains one or more oils or lipids without additional surfactants, co-surfactants, or co-emulsifiers, or co-solvents, i.e., it consists essentially of one or more oils or lipids. In some further embodiments, the lipid vehicle contains one or more oils or lipids together with one or more water-insoluble surfactants and, optionally, one or more co-solvents. In some embodiments, the lipid vehicle contains one or more oils or lipids together with one or more water-soluble surfactants and, optionally, one or more co-solvents. In some embodiments, the lipid vehicle contains a mixture of oils / lipids, surfactants, and co-solvents. In some embodiments, the lipid vehicle consists essentially of one or more surfactants / co-surfactants / co-emulsifiers and / or solvents / co-solvents.

[0320] Examples of oils or lipids that may be used in the present invention include almond oil, babassu oil, blackcurrant seed oil, borage oil, canola oil, castor oil, coconut oil, cod liver oil, corn oil, cottonseed oil, evening primrose oil, fish oil, grapeseed oil, mustard oil, olive oil, palm kernel oil, palm oil, peanut oil, rapeseed oil, safflower oil, sesame oil, shark liver oil, soybean oil, sunflower oil, walnut oil, wheat germ oil, avocado oil, bran oil, hydrogenated castor oil, hydrogenated coconut oil, hydrogenated cottonseed oil, hydrogenated palm oil, hydrogenated soybean oil, partially hydrogenated soybean oil, hydrogenated vegetable oil, caprylic / capric glycerides, fractionated triglycerides, glyceryl tricaprate, glyceryl tricaproate, glyceryl tricaprylate Glyceryl tricaprylate / glyceryl caprate, glyceryl tricaprylate / glyceryl caprate, glyceryl tricaprylate / glyceryl caprate / glyceryl laurate, glyceryl tricaprylate / glyceryl caprate / glyceryl linoleate, glyceryl tricaprylate / glyceryl caprate / glyceryl stearate, glyceryl trilaurate, glyceryl monolaurate, glyceryl behenate, glyceryl monolinoleate, glyceryl trilinolenate, glyceryl trioleate, glyceryl triundecanoate, glyceryl tristearate, linoleic glycerides, saturated polyglycolized glycerides, primarily C 8-12 Synthetic medium-chain triglycerides containing fatty acid chains, primarily C 8-12 Medium chain triglycerides containing fatty acid chains, mainly >C 12 Long chain fatty acid containing These include triglycerides, modified triglycerides, fractionated triglycerides, and mixtures thereof.

[0321] Examples of monoglycerides and diglycerides that can be used in such formulations include glycerol monoesters and glycerol diesters having fatty acid chains of 8 to 40 carbon atoms, such as hydrolyzed coconut oil (e.g., Capmul® MCM) and hydrolyzed corn oil (e.g., Maisine™ 35-1). In some embodiments, the monoglycerides and diglycerides are mono- or di-saturated fatty acid esters of glycerol having fatty acid chains of 8 to 18 carbon atoms (e.g., glyceryl monostearate, glyceryl distearate, glyceryl monocaprylate, glyceryl dicaprylate, glyceryl monocaprate, and glyceryl dicaprate). Mixtures of fatty acids adapted for the promotion of absorption and transport of lipid-soluble compounds ("structured glycerides") are disclosed, for example, in U.S. Pat. No. 6,013,665 (incorporated herein by reference).

[0322] Suitable surfactants for use in lipid formulations include C 8-22 Propylene glycol mono- and diesters of fatty acids (such as, but not limited to, propylene glycol monocaprylate, propylene glycol dicaprylate, and propylene glycol monolaurate, sold under trade names such as Capryol® 90, Labrafac® PG, and Lauroglycol® FCC), sugar fatty acid esters (such as, but not limited to, sucrose palmitate, sucrose laurate, and sucrose stearate); sorbitan fatty acid esters (such as, but not limited to, sorbitan laurate, sorbitan palmitate, and sorbitan oleate); polyoxyethylene sorbitan fatty acid esters (such as, but not limited to, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, and polysorbate 85); mono- and di-fatty acid esters of polyoxyethylene (including, but not limited to, polyoxyl 40 stearate and polyoxyl 40 oleate); C 8-22 Polyoxyethylene monoesters and diesters of fatty acids, and C 8-22Mixtures of glyceryl monoesters, diesters, and triesters of fatty acids (such as those sold under trade names such as Labrasol®, Gelucire® 44 / 14, Gelucire® 50 / 13, and Labrafil®); polyoxyethylene castor oil compounds (such as, but not limited to, Polyoxyl 35 castor oil, Polyoxyl 40 hydrogenated castor oil, and Polyoxyl 60 hydrogenated castor oil, such as those sold under trade names such as Cremophor® / Kolliphor EL, Cremophor® / Kolliphor® RH40, and Cremophor® / Kolliphor® RH60); polyoxyethylene alkyl ethers (including, but not limited to, Polyoxyl 20 cetostearyl ether and Polyoxyl 10 oleyl ether); DL-α-tocopheryl polyethylene glycol succinate; glyceryl monoesters, diesters, and triesters; C 8-22 Glyceryl monoesters, diesters, and triesters of fatty acids; sucrose monoesters, diesters, and triesters; sodium dioctyl sulfosuccinate; polyoxyethylene-polyoxypropylene copolymers (such as, but not limited to, poloxamer 124, poloxamer 188, and poloxamer 407); C 8-22 Polyoxyethylene ethers of fatty alcohols (including, but not limited to, polyoxyethylene lauryl alcohol, polyoxyethylene cetyl alcohol, polyoxyethylene stearyl alcohol, polyoxyethylene oleyl alcohol, such as those sold under the trade names Brij® 35, Brij® 58, Brij® 78, Brij® 98, etc.), or mixtures of any two or more thereof.

[0323] Co-emulsifiers or co-surfactants may be used in the formulation. Suitable co-emulsifiers or co-surfactants may be phosphoglycerides; phospholipids (e.g., lecithin), or free fatty acids that are liquid at room temperature (e.g., iso-stearic acid, oleic acid, linoelic acid, linolenic acid, palmitic acid, stearic acid, lauric acid, capric acid, caprylic acid, and caproic acid).

[0324] Suitable solvents / co-solvents include ethanol, propylene glycol, polyethylene glycol, diethylene glycol monoethyl ether, and glycerol.

[0325] Polymers can also be used in formulations to inhibit drug precipitation or modify the rate of drug release. A range of polymers have been shown to impart these properties and are well known to those skilled in the art. Suitable polymers include hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetylsuccinate, other cellulose-derived polymers (such as methylcellulose); poly(meth)acrylates (such as the Eudragit series of polymers, including Eudragit E100), polyvinylpyrrolidone, or others, such as those described in Warren et al., Mol.Pharmaceutics 2013, 10, 2823-2848.

[0326] Formulations can be specifically chosen to provide sustained release of the active agent in the gastrointestinal (GI) tract to control the rate of absorption. Many different approaches can be used to achieve these results, including the use of high melting point lipids that disperse / erode slowly in the GI tract, or polymers that form a slowly eroding matrix. These formulations can take the form of large unitary dosage forms or can be present as a matrix of microparticles or nanoparticles, for example, as described in Mishra, Handbook of Encapsulation and Controlled Release, CRC Press, Boca Raton, (2016) ISBN 978-1-4822-3234-9, Wilson and Crowley Controlled Release in Oral Drug Delivery, Springer, NY, ISBN 978-1-4614-1004-1 (2011), or Wise, Handbook of Pharmaceutical Controlled Release Technology, Marcel Dekker, NY, ISBN 0-82467-0369-3 (2000).

[0327] The formulation may also contain ingredients commonly known to those skilled in the art to be included in lipid-based formulations, including antioxidants (e.g., butylhydroxyanisole (BHA) or butylhydroxytoluene (BHT)), and coagulants (microporous silica, such as magnesium aluminometasilicate (Neusilin)).

[0328] In some embodiments, lipid prodrugs may be orally co-administered with enzyme inhibitors to increase the stability of the prodrug in the gastrointestinal tract or intestinal cells. In certain embodiments, the enzyme inhibitor inhibits pancreatic lipase, an example of which includes, but is not limited to, Alli® (orlistat). In other embodiments, it is contemplated that the enzyme inhibitor will inhibit cellular lipase enzymes, such as monoacylglycerol lipase, an example of which includes, but is not limited to, JZL184 (4-nitrophenyl-4-[bis(1,3-benzodioxol-5-yl)(hydroxy)methyl]piperidine-1-carboxylate).

[0329] Combination therapy The provided lipid prodrugs, or pharmaceutically acceptable compositions thereof, can be administered to a patient in need thereof in combination with one or more additional therapeutic agents and / or therapeutic processes. It is possible.

[0330] Lipid prodrugs or pharmaceutically acceptable compositions thereof can be administered alone or in combination with one or more other therapeutic compounds, and possible combination therapy takes the form of a fixed combination, or the administration of lipid prodrugs or compositions and one or more other therapeutic compounds, which are administered staggered or independently, or the combined administration of a fixed combination and one or more other therapeutic compounds.The disclosed lipid prodrugs or compositions can be administered for tumor therapy, in addition to or in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination thereof.Long-term therapy is equally possible as adjuvant therapy in the context of other treatment strategies such as those described above.Other possible treatments are therapy to maintain the patient's condition after tumor regression, or in some cases, chemopreventive therapy, for example, in patients at risk.

[0331] Such additional agents can be administered separately from the lipid prodrug or composition provided as part of a multiple dosage regimen. Alternatively, these agents can be part of a single dosage form that is mixed together with the disclosed lipid prodrug in a single composition.If administered as part of a multiple dosage regimen, the two active agents can be provided simultaneously, consecutively, or within a period.

[0332] As used herein, the terms "combination," "combined," and related terms refer to simultaneous or sequential administration of therapeutic agents according to the present disclosure. For example, the disclosed lipid prodrugs can be administered simultaneously or sequentially with another therapeutic agent, either in separate unit dosage forms or together in a single unit dosage form. Thus, the present disclosure provides single unit dosage forms comprising the disclosed lipid prodrugs, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. In some embodiments, the additional agent is formulated in a composition separate from the lipid prodrug.

[0333] The amounts of both the disclosed lipid prodrugs and additional therapeutic agent (in compositions containing such additional therapeutic agents) that can be combined with carrier materials to produce a single dosage form will vary depending on the patient being treated and the particular mode of administration. In certain embodiments, the compositions of the present invention should be formulated so that a dosage of between about 0.01 and 500 mg / kg body weight / day of the disclosed lipid prodrugs can be administered.

[0334] In compositions containing an additional therapeutic agent, the additional therapeutic agent and the disclosed lipid prodrug may act synergistically. Thus, the amount of the additional therapeutic agent in such compositions will be less than that required in a monotherapy utilizing only that therapeutic agent. In such compositions, a dosage of between about 0.01 μg / kg and 100 mg / kg body weight / day of the additional therapeutic agent may be administered.

[0335] The amount of additional therapeutic agent present in the compositions of the invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably, the amount of additional therapeutic agent in the compositions disclosed herein will be in the range of about 50% to 100% of the amount that would normally be present in a composition comprising that agent as the only therapeutically active agent.

[0336] Examples of drugs with which the lipid prodrugs of the present invention can be used in combination include treatments for Alzheimer's disease (such as Aricept® and Excelon®); treatments for HIV (such as ritonavir); treatments for Parkinson's disease (such as L-DOPA / carbidopa, entacapone, ropinirole, pramipexole, bromocriptine, pergolide, trihexyphendyl, and amantadine); drugs for the treatment of multiple sclerosis (MS) (beta interferon (e.g., Avonex®)); and Rebif®), Copaxone®, and mitoxantrone; treatments for asthma (such as albuterol and Singulair®); drugs for the treatment of schizophrenia (such as Zyprexa, Risperdal, Seroquel, and haloperidol); anti-inflammatory drugs (such as corticosteroids, TNF blockers, IL-1 RAs, azathioprine, cyclophosphamide, and sulfasalazine); immunomodulators and immunosuppressants (such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophophamide, azathioprine, and sulfasalazine); neurotrophic factors (such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anticonvulsants, ion channel blockers, riluzole, and anti-Parkinson's agents); drugs for the treatment of cardiovascular disease (such as beta blockers, ACE inhibitors, drugs for the treatment of liver disease (such as corticosteroids, cholestyramine, interferons, and antivirals); drugs for the treatment of blood disorders (such as corticosteroids, anti-leukemia agents, and growth factors); drugs that prolong or improve pharmacokinetics (such as cytochrome P450 inhibitors (i.e., inhibitors of metabolic degradation) and CYP3A4 inhibitors (e.g., ketokenozole and ritonavir)), and drugs for the treatment of immunodeficiency diseases (such as gamma globulin).

[0337] In certain embodiments, the combination therapy of the invention includes a monoclonal antibody or an siRNA therapeutic.

[0338] In another embodiment, the present invention provides a method of treating an inflammatory disease, disorder, or condition (such as a neuroinflammatory disease or Alzheimer's disease) by administering to a patient in need thereof a disclosed lipid prodrug and one or more additional therapeutic agents. Such additional therapeutic agents may be small molecules or biologics, such as acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS) (such as aspirin, ibuprofen, naproxen, etodolac (Lodine®), and celecoxib), colchicine (Colcrys®), corticosteroids (such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and the like), probenecid, allopurinol, febuxostat (Ulo), fluticasone, fluoxetine ... ric®), sulfasalazine (Azulfidine®), antimalarials [such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®)], methotrexate (Rheumatrex®), gold salts [such as gold thioglucose (Solganal®), gold thiomalate (Myochrysine®), and auranofin (Ridaura®)], D-penicillamine (D epen® or Cuprimine®), azathioprine (Imuran®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®) as well as "anti-TNF" agents [etanercept (Enbrel®), infliximab (Remicade®), golimumab (Simp oni (registered trademark), certolizumab pegol (Cimzia (registered trademark), and adalimumab (Humira (registered trademark)), etc.), "anti-IL-1" agents [anakinra (Kineret (registered trademark) and rilonacept (Arcalyst (registered trademark), canakinumab (Ilaris (registered trademark)), etc.], anti-Jak inhibitors [tofacitinib, etc.], antibodies [rituximab (Rituxan (registered trademark)), etc.], "anti-T cell" agents [abatacept (Orencia (registered trademark)), etc.],"Anti-IL-6" agents [such as tocilizumab (Actemra®)], diclofenac, cortisone, hyaluronic acid [Synvisc® or Hyalgan®], monoclonal antibodies (such as tanezumab), anticoagulants [such as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®)], , antidiarrheal medications (such as diphenoxylate (Lomotil®) and loperamide (Imodium®)), bile acid binders (such as cholestyramine), alosetron (Lotronex®), lubiprostone (Amitiza®), laxatives (such as milk of magnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol®, Senokot®), anticholinergics or anticonvulsants (such as dicyclomine (Bentyl®), Sing ulair®, etc.)], beta-2 agonists [albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®), and formoterol (Foradil®), etc.], anticholinergics [ipratropium bromide (Atro vent® and tiotropium (Spiriva®), inhaled corticosteroids [beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), and flunisolide (Aerobid®)], Afviar®, Symbicort®, Duler®, a (registered trademark), cromolyn sodium (Intal (registered trademark)), methylxanthines [theophylline (Theo-Dur (registered trademark), Theolair (registered trademark), Slo-bid (registered trademark), Uniphyl (registered trademark), Theo-24 (registered trademark), and aminophylline, etc.], IgE antibodies [omalizumab (Xolair (registered trademark)), etc.], nucleoside reverse transcriptase inhibitors [zidovudine (Retrovir (registered trademark), abacavir (Ziagen (registered trademark), abacavir / lamivudine (Epzicom (registered trademark),abacavir / lamivudine / zidovudine (Trizivir®), didanosine (Videx®), emtricitabine (Emtriva®), lamivudine (Epivir®), lamivudine / zidovudine (Combivir®), stavudine (Zerit®), and zalcitabine (Hivid®), etc.], non-nucleoside reverse transcriptase inhibitors [delavirdine (Rescriptor®), efavirenz (Sustiva®), nevirapine (Viramune®), and etravirine (Intelence®), etc.); nucleotide reverse transcriptase inhibitors (tenofovir (Viread®), etc.); protease inhibitors (amprenavir (Agenerase®), atazanavir (Reyataz®), darunavir (Prezista®), fosamprenavir (Lexiva®), etc.); [such as lorcaserin (Fuzeon®) and maraviroc (Selzentry®)], entry inhibitors [such as raltegravir (Isentress®)], doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), bortezomib (Velcade®), and dexamethasone (Decadron®) in combination with lenalidomide (Revlimid®), or any combination(s) thereof. ,

[0339] In another embodiment, the present invention provides a method for the treatment of rheumatoid arthritis by administering the disclosed lipid prodrugs, as well as other anti-rheumatic drugs such as citalopram (Celexa®), escitalopram (Lexapro®), fluoxetine (Prozac®), fluvoxamine (Luvox®), and steroids such as steroids like ... ) / Luvox CR®), paroxetine (Paxil® / Paxil CR®), sertraline (Zoloft®), desvenlafaxine (Pristiq®), duloxetine (Cymbalta®), venlafaxine (Effexor® / Effexor XR®), milnacipran (Savella®), levomilnacipran (Fetzima®), amitriptyline (Elavil®), desipramine (Norpramin®), doxepin (Sinequan®), imipramine (Tofranil®), nortriptyline (Pamelor®), amoxapine, clomipramine (Anafranil®), maprotiline (Ludiomil®), trimipramine (Surmontil®), protriptyline (Vivactil®), phenelzine (Nardil®), selegiline (Emsam®), tranylcypromine (Parna and / or anxiety disorders (e.g., panic disorder and post-traumatic stress disorder), comprising administering to a patient in need thereof one or more additional therapeutic agents selected from benzodiazepine (Benibari®), bupropion (Wellbutrin®), mirtazapine (Remeron®), nefazodone (Serzone®), tradzone (Desyrel®, Oleptro®), vilazodone (Viibryd®), and vortioxetine (Brintellix®).

[0340] In some embodiments, the present invention provides methods of treating Alzheimer's disease comprising administering to a patient in need thereof a disclosed lipid prodrug and one or more additional therapeutic agents selected from donepezil (Aricept®), rivastigmine (Excelon®), galantamine (Razadyne®), tacrine (Cognex®), and memantine (Namenda®).

[0341] The disclosed lipid prodrugs and compositions, as well as any co-administered additional therapeutic agents according to the methods of the present invention, can be administered in any amount and using any route of administration effective for treating or reducing the severity of a disease, disorder, or condition (such as an inflammatory disorder, a neurodegenerative or neurological disorder, or schizophrenia). The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular drug, its mode of administration, and the like. The disclosed lipid prodrugs are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The term "dosage unit form," as used herein, refers to a physically discrete unit of drug appropriate for the patient being treated. However, it will be understood that the total daily usage of the disclosed lipid prodrugs or compositions thereof, and any co-administered additional therapeutic agents, will be determined by the attending physician within the scope of sound medical judgment. The specific effective dosage level for any particular patient or organism will depend on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific lipid prodrug used; the specific composition used; the patient's age, weight, general health, sex, and diet; the time of administration, route of administration, and excretion rate of the specific lipid prodrug or composition; the duration of treatment; drugs used in combination or concomitantly with the specific lipid prodrug or composition used, and similar factors well known in the medical arts. The term "subject" or "patient," as used herein, means an animal, preferably a mammal, and most preferably a human.

[0342] In some embodiments, the dose is selected to account for lymphatic uptake, metabolism, and release of the parent drug allopregnanolone (allo). For example, If a given dose is absorbed more efficiently than an equivalent oral or intravenous dose of allopregnanolone, the dose of the lipid prodrug can be reduced by an appropriate amount to produce the desired plasma or lymphatic concentration of allopregnanolone. In some embodiments, the dose is selected so that the orally administered dose of the lipid prodrug, upon lymphatic uptake, metabolism, and release of the parent drug allopregnanolone in the patient, provides the desired effective concentration (e.g., plasma or lymphatic concentration) of allopregnanolone to treat a disease, disorder, or condition (such as those disclosed herein).

[0343] In some embodiments, the dosage of the lipid prodrug or pharmaceutically acceptable salt thereof is about 0.01 mg / kg to about 100 mg / kg. In some embodiments, the dosage of the lipid prodrug or pharmaceutically acceptable salt thereof is about 0.1 mg / kg to about 25 mg / kg. In some embodiments, the dosage of the lipid prodrug or pharmaceutically acceptable salt thereof is about 0.5 mg / kg to about 15 mg / kg. In some embodiments, the dosage of the lipid prodrug or pharmaceutically acceptable salt thereof is about 1 mg / kg to about 10 mg / kg. In some embodiments, the dosage of the lipid prodrug or pharmaceutically acceptable salt thereof is about 2 mg / kg to about 7.5 mg / kg. In some embodiments, the dosage of the lipid prodrug or pharmaceutically acceptable salt thereof is about 3.0 mg / kg to about 7.0 mg / kg. In some embodiments, the dose of the lipid prodrug or pharmaceutically acceptable salt thereof is about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.3, 1.5, 1.7, 2.0, 2.5, 3.0, 3.5, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, or 10.0 mg / kg.

[0344] In some embodiments, the dose is about 1 mg to about 5 g of lipid prodrug or a pharmaceutically acceptable salt thereof. In some embodiments, the dose is about 10 mg to about 2.5 g of lipid prodrug or a pharmaceutically acceptable salt thereof. In some embodiments, the dose is about 100 mg to about 2.0 g of lipid prodrug or a pharmaceutically acceptable salt thereof. In some embodiments, the dose is about 250 mg to about 1.0 g of lipid prodrug or a pharmaceutically acceptable salt thereof. In some embodiments, the dose is about 500 mg to about 1.0 g of lipid prodrug or a pharmaceutically acceptable salt thereof.

[0345] In some embodiments, the dosage of the lipid prodrug or pharmaceutically acceptable salt thereof is calculated to provide a particular dose of allopregnanolone when the prodrug is administered orally. In some embodiments, the dosage of the lipid prodrug or pharmaceutically acceptable salt thereof is calculated to provide about 0.01 mg / kg to about 100 mg / kg of allopregnanolone, 0.1 mg / kg to about 25 mg / kg, about 0.5 mg / kg to about 15 mg / kg, about 1 mg / kg to about 10 mg / kg, about 2 mg / kg to about 7.5 mg / kg, or about 3.0 mg / kg to about 7.0 mg / kg of allopregnanolone. In some embodiments, the dose of the lipid prodrug or pharmaceutically acceptable salt thereof is calculated to provide about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.3, 1.5, 1.7, 2.0, 2.5, 3.0, 3.5, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, or 10.0 mg / kg of allopregnanolone when the prodrug is administered orally.

[0346] In some embodiments, the dose of the lipid prodrug or pharmaceutically acceptable salt thereof is calculated to provide about 5 mg to about 3 g of allopregnanolone when the prodrug is administered orally. In some embodiments, the dose is calculated to provide about 50 mg to about 2.5 g of allopregnanolone, or about 100 mg to about 1.5 g, or about 250 mg to about 1.0 g of allopregnanolone.

[0347] 4. Methods for making lipid prodrugs General Method for Making Lipid Prodrugs The lipid prodrug compounds of the present invention may generally be prepared or isolated by synthetic and / or semi-synthetic methods known to those skilled in the art for similar compounds, as well as by methods detailed in the Examples herein.

[0348] The therapeutic agents contained in the disclosed lipid prodrugs (e.g., conjugated to glyceride-based prodrugs) can be purchased commercially or prepared by organic synthesis, semi-synthesis, fermentation (e.g., via viral vectors), and similar methods known in the art.

[0349] In some embodiments, protecting groups (as defined below) can be used to manipulate the therapeutic agent in preparation for conjugation to the remainder of the lipid prodrug structure, e.g., to prevent undesired side reactions from occurring.

[0350] In synthetic methods described herein where a particular protecting group ("PG"), leaving group ("LG"), or transformation condition is indicated, one of skill in the art will recognize that other protecting groups, leaving groups, and transformation conditions are suitable and contemplated. Such groups and transformations are described in detail in March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, M.B. Smith and J. March, 2007, Vol. 7, No. 1, pp. 111-114, 1997. thEdition, John Wiley & Sons, 2013, Comprehensive Organic Transformations, RC Larock, 3 rd Edition, John Wiley & Sons, 2018, and Protective Groups in Organic Synthesis, PGMWuts, 5 th edition, John Wiley & Sons, 2014, each of which is incorporated herein by reference in its entirety.

[0351] As used herein, the phrase "leaving group" (LG) includes, but is not limited to, halogen (e.g., fluoride, chloride, bromide, iodide), sulfonate (e.g., mesylate, tosylate, benzenesulfonate, brosylate, nosylate, triflate), diazonium, and the like.

[0352] As used herein, the phrase "oxygen protecting group" includes, for example, carbonyl protecting groups and hydroxyl protecting groups. Hydroxyl protecting groups are well known in the art and are described in Protective Groups in Organic Synthesis, PGMWuts, 5 thedition, John Wiley & Sons, 2014, and Philip Kocienski, in Protecting Groups, Georg Thieme Verlag Stuttgart, New York, 1994 (the entire contents of which are incorporated herein by reference). Examples of suitable hydroxyl protecting groups include, but are not limited to, esters, allyl ethers, ethers, silyl ethers, alkyl ethers, arylalkyl ethers, and alkoxyalkyl ethers. Examples of such esters include formates, acetates, carbonates, and sulfonates. Specific examples include formate, benzoyl formate, chloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate, 4,4-(ethylenedithio)pentanoate, pivaloate (trimethylacetyl), crotonate, 4-methoxy-crotonate, benzoate, p-benzylbenzoate, Examples of silyl ethers include 2,4,6-trimethylbenzoate, carbonate (methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, vinyl, allyl, and p-nitrobenzyl). Examples of such silyl ethers include trimethylsilyl ether, triethylsilyl ether, t-butyldimethylsilyl ether, t-butyldiphenylsilyl ether, triisopropylsilyl ether, and other trialkylsilyl ethers. Alkyl ethers include methyl ether, benzyl ether, p-methoxybenzyl ether, 3,4-dimethoxybenzyl ether, trityl ether, t-butyl ether, allyl ether, and allyloxycarbonyl ether or derivatives. Alkoxyalkyl ethers include acetals such as methoxymethyl ether, methylthiomethyl ether, (2-methoxyethoxy)methyl ether, benzyloxymethyl ether, β-(trimethylsilyl)ethoxymethyl ether, and tetrahydropyranyl ether. Examples of arylalkyl ethers include benzyl, p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, O-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, and 2-picolyl and 4-picolyl.

[0353] Amino protecting groups are well known in the art and are in Organic Synthesis,PGMWuts,5 th edition, John Wiley & Sons, 2014, and Philip Kocienski, in Protecting Groups, Georg Thieme Verlag Stuttgart, New York, 1994, the entire contents of which are incorporated herein by reference. Suitable amino-protecting groups include, but are not limited to, aralkylamines, carbamates, cyclic imides, allylamines, amides, and the like. Examples of such groups include t-butyloxycarbonyl (Boc), ethyloxycarbonyl, methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyloxocarbonyl (Cbz), allyl, phthalimide, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, phenylacetyl, trifluoroacetyl, benzoyl, and the like.

[0354] Those skilled in the art will recognize that functional groups present in the various compounds of the present invention (such as aliphatic groups, alcohols, carboxylic acids, esters, amides, aldehydes, halogens, and nitriles) can be interconverted by techniques well known in the art, including, but not limited to, reduction, oxidation, esterification, hydrolysis, partial oxidation, partial reduction, halogenation, dehydration, partial hydration, and hydration. See, e.g., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure,MBSmith and J.March,7 th Edition, John Wiley & Sons, 2013, which is incorporated herein by reference in its entirety. Such interconversions require one or more of the techniques described above, and certain methods for synthesizing compounds of the invention are described below.

[0355] As a general strategy, the compounds of the present invention can be synthesized via one of the following routes.

[0356] [ka]

[0357] Diacid chloride i (readily available from the corresponding malonic acid) can be reacted with diglycerides (such as ii) in the presence of pyridine or another suitable base to give acid-triglycerides (acid-TG) iii (see Scheme 1). 15 H 31 Although shown with a fatty acid side chain of: , other fatty acids (such as those described above) can be substituted in this and other formulas described below.

[0358] [ka]

[0359] In cases where acid anhydride ia is available, acid-TG iii can be generated by ring opening with diglyceride ii in the presence of pyridine or another suitable base (Scheme 2). 4 and R 5 This method works best when are identical (e.g., both Me), but R 4 and R 5 are different from each other, will result in a regioisomeric mixture of the acid-TG product iv. Therefore, other methods (such as those outlined in Scheme 3) can be advantageously used in this situation.

[0360] [ka]

[0361] R 4 =Me or other alkyl or substituted, and R 5In certain embodiments, where =H, the known carboxylic acid v (Lienard, BMR et al., Org. Biomol. Chem. 2008, 6, (13), 2282-2292) can be used as a starting point to obtain acid-TG iv as a single regioisomer (see Scheme 3). Coupling of 1,3-DG ii with acid v under standard conditions produces TBDPS-protected triglyceride vi, which can be treated with appropriate conditions (such as TBAF and AcOH) to afford alcohol vii. A two-step oxidation process (e.g., PCC followed by KMnO) can then be used to transform alcohol vii into the desired acid-TG iv via the intermediate aldehyde viii.

[0362] [ka]

[0363] For the synthesis of compounds containing an acetal self-immolative (ASI) group between the pharmaceutical agent and the alkyl spacer, the alcohol-bearing parent molecule must be functionalized and activated prior to conjugation with the acid-triglyceride iii, as outlined above in Scheme 4. Treatment of the alcohol with DMSO in a mixture of acetic anhydride and acetic acid results in the formation of the (methylthio)methyl (MTM) ether ix. Activation of the MTM ether ix using sulfuryl chloride is presumed to form a sulfoxide species, which can react with the carboxylate of the acid-triglyceride iv to afford the target compound x.

[0364] [ka]

[0365] In cases where the pharmaceutical agent contains an alcohol, phenol, or amine (primary or secondary) functionality, modified versions of the acetal self-immolative group containing an additional carboxy group can be used. Reaction of the parent drug with a chloroalkyl chloroformate gives the chloroalkyl carbonate (shown) or carbamate xi (see Scheme 5). Displacement of the halide leaving group is then achieved by treatment with the carboxylate derived from acid-TG iv in a suitable solvent (such as refluxing toluene) to give the target compound xii.

[0366] [ka]

[0367] To synthesize prodrugs containing a trimethyl lock (TML) self-immolative group (Levine, MN; Raines, RTChem. Sci. 2012, 3, 2412-2420, incorporated herein by reference) between the pharmaceutical agent and the alkyl spacer to facilitate systemic release of the parent molecule, the acid-triglyceride iv must be functionalized with a TML moiety prior to conjugation with the pharmaceutical agent, as outlined in Scheme 6. The reaction of TML phenol xiii with acid-TG iv under standard conditions is shown in Scheme 6. Coupling affords triglyceride xiv, which can be deprotected under acidic conditions (10-camphorsulfonic acid) to afford alcohol xv. Alcohol xv can be sequentially oxidized first to aldehyde xvi and then to acid xvii, followed by coupling under standard conditions to pharmaceutical agents containing either an alcohol (as shown), an amine, or a sulfonamide to afford target compound xviii.

[0368] [ka]

[0369] To synthesize compounds containing a p-hydroxybenzyl (PHB) carbonyl self-immolative group, the primary hydroxyl group of p-hydroxybenzyl alcohol (xix) is first protected as a silyl ether and the free phenolic hydroxyl group is coupled with acid-TG iv to give PHB triglyceride xxi (see Scheme 7). After removal of the silicon protecting group, primary alcohol xxii can be activated by treatment with p-nitrophenyl (PNP) chloroformate to give PNP carbonate xxiii. Displacement of the PNP group is then achieved by reaction with a pharmaceutical agent (denoted A-OH) under basic conditions to give the desired compound xxiv.

[0370] [ka]

[0371] Without wishing to be bound by theory, it is believed that the inverted ester self-immolative (FSI) group can release the free pharmaceutical agent via a cyclization mechanism (resulting in the loss of either a four-carbon (FSI-4) or five-carbon (FSI-5) lactone). Alternatively, drug liberation can occur via in vivo chemical or enzymatic mechanisms. FSI prodrugs can be synthesized by coupling a pharmaceutical agent (denoted A-OH) with either 4-bromobutyric acid (m=1) or 5-bromovaleric acid (m=2) (xxv) to give bromide xxvi (see Scheme 8). Displacement of bromide xxvi with the carboxylate derived from acid-TG iv generates the desired ester bond in the target compound xxvii. [Example]

[0372] Example 1: Synthesis of intermediates List of abbreviations equiv or eq: molar equivalent rt: room temperature UV: Ultraviolet light HPLC: High-pressure liquid chromatography Rt: retention time LCMS or LC-MS: Liquid Chromatography Mass Spectrometry NMR: nuclear magnetic resonance TLC: Thin Layer Chromatography sat: saturation aq: water-based Ac: Acetyl BINAP: (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene Bn: Benzyl DCC: N,N'-dicyclohexylcarbodiimide DCM: dichloromethane DCE: dichloroethane DEA: Diethylamine DIPA: Diisopropylamine DMF: N,N-dimethylformamide DMSO: dimethyl sulfoxide ACN or MeCN: acetonitrile DIPEA: Diisopropylethylamine EA or EtOAc: Ethyl acetate EDCI, EDC, or EDAC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide TEA: Triethylamine THF: tetrahydrofuran TBS: tert-butyldimethylsilyl KHMDS: potassium hexamethyldisilylazide Tf: Trifluoromethanesulfonate Ms: methanesulfonyl NBS: N-bromosuccinimide PCC: Pyridinium chlorochromate PE: Petroleum ether TFA: Trifluoroacetic acid MMPP: Magnesium monoperoxyphthalate HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate Cy: Cyclohexyl Tol: Toluene DMP: Dess-Martin periodinane IBX: 2-iodoxybenzoic acid PMB: p-methoxybenzyl SEM: [2-(trimethylsilyl)ethoxy]methyl 1,3-DG (Intermediate-2) :

[0373] [ka]

[0374] DMF (1 mL, 13.7 mmol) and thionyl chloride (500 mL, 6.3 mol) The resulting mixture was heated under reflux for 3 hours. It was concentrated to dryness to give palmitoyl chloride (453 g, 1.64 mol, 97% yield) as a slightly yellow oil, which was used in the next step without further purification.

[0375] To a mixture of 1,3-dihydroxypropan-2-one (77 g, 0.855 mol) and anhydrous pyridine (140 g, 1.76 mol) in anhydrous dichloromethane (2500 mL) was added palmitoyl chloride (453 g, 1.64 mol) at room temperature under nitrogen. The mixture was stirred at room temperature for 16 hours. It was diluted with MeOH (1000 mL) and water (2000 mL) and stirred for 30 minutes. The precipitate was collected by filtration and dried to give Intermediate-1 (462 g, 0.815 mmol, 95% yield) as a white solid.

[0376] Intermediate-1 (220 g, 388 mmol) was dissolved in a solution of THF (3000 mL) and water (200 mL) at 0° C. Sodium borohydride (22 g, 579 mmol) was added in small portions. After the addition, the mixture was filtered to obtain a cake, which was dried to give compound Intermediate-2 (1,3-DG) (177 g, 311 mmol, 80% yield) as a white solid. LC-MS: MS m / z = 591 (M+ Na+), RT = 4.39 minutes; 1 H NMR (400 MHz, chloroform-d) δ 4.20-4.05 (m, 5H), 2.35 (t, J = 7.6 Hz, 4H), 1.62 (t , J = 7.6 Hz, 4H), 1.25 (s, 48H), 0.88 (t, J = 6.6 Hz, 6H). C5βMe-acid-2-TG (intermediate-4):

[0377] [ka]

[0378] A mixture of 3-methylglutaric acid (500 mg, 3.42 mmol) and DMF (2 drops) in thionyl chloride (2.48 mL, 34.2 mmol) was heated to reflux for 2 h. The reaction was cooled to room temperature, diluted with toluene (5 mL), and concentrated under reduced pressure to give the diacid chloride intermediate-3 (584 mg, 83%) as a yellow oil, which was used without purification. 1 H NMR (400 MHz, CDCl3) δ 3.02 (dd, J = 17.3, 6 .1 Hz, 2H), 2.89 (dd, J = 17.3, 7.2 Hz, 2H), 2.61 (m, 1H), 1.13 (d, J = 6.8 Hz, 2H). A solution of Intermediate-2 (1,3-DG) (50.0 mg, 0.0879 mmol) and pyridine (71.1 μL, 0.879 mmol) in dichloromethane (2 mL) was added to the acid chloride Intermediate-3 (80.4 mg, 0.439) in dichloromethane (1.5 mL), and the mixture was heated to reflux for 2 h. The reaction was cooled to room temperature, diluted with ethyl acetate (15 mL) and 1 M HCl (5 mL), and the organic phase was separated. The aqueous layer was further extracted with ethyl acetate (2 × 20 mL), and the combined organic extracts were washed with 1 M HCl (20 mL) and brine (2 × 30 mL), dried (MgSO), and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (20% to 45% ethyl acetate / hexanes) afforded Intermediate-4 (54.0 mg, 88%) as a colorless solid. 1 H NMR (400 MHz, CDCl3) δ 5.27 (m, 1H), 4.311 (dd, J = 11.9, 4.2 Hz, 1H), 4.305 (dd, J = 11.9, 4 .2 Hz, 1H), 4.14 (dd, J = 11.9, 5.6 Hz, 2H), 2.52 - 2.39 (m, 3H), 2.36 - 2.24 (m, 6H), 1.66 - 1.55 (m, 4H), 1.37 - 1.17 (m, 48H), 1.06 (d, J = 6.3 Hz, 3H), 0.88 (t, J = 6.8 Hz, 6H); 13 C NMR (101 MHz, CDCl3) δ 178.1 (C), 173.5 (2C;C), 171.4 (C), 69.3 (CH), 62.2 (2C;CH2), 40.7 (CH2), 40.4 (CH2), 34.1 (2C;CH2), 32 .1 (2C;CH2), 29.82 (6C;CH2), 29.78 (4C;CH2 ), 29.74 (2C;CH2), 29.6 (2C;CH2), 29.5 (2C;CH2), 29.4 (2C;CH2), 29.2 (2C;CH2), 27.3 (CH), 25.0 (2C;CH2), 22.8 (2C;CH2), 19.8 (CH3), 14.2 (2C;CH3);ESI-HRMS: C 41 H 76 NaO8[M + Na + ] calculated value 719.5432; observed value 719.5451. Alternative procedure (large scale):

[0379] [ka]

[0380] A mixture of 3-methylglutaric acid (100 g, 685 mmol) and acetyl chloride (250 mL, 3.53 mol) was heated under reflux for 16 hours, then concentrated to dryness and added to a solution of pyridine (270 g, 3.4 mol) and benzyl alcohol (100 g, 926 mmol) in dichloromethane (1500 mL) at room temperature. The mixture was stirred for 72 hours. The reaction was concentrated, and the residue was purified by silica column chromatography eluting with 0-50% ethyl acetate in petroleum ether to give Intermediate-6 (70 g, 297 mmol, 43% yield) as a slightly yellow oil. 1 H NMR (400 MHz , chloroform-d) δ 7.39-7.30 (m, 5H), 5.12 (s, 2H ), 2.52-2.25 (m, 5H), 1.04 (d, J = 6.6 Hz, 3H). To a mixture of Intermediate-6 (70 g, 297 mmol) and Intermediate-2 (1,3-DG) (80 g, 140 mmol) in dichloromethane (1500 mL) was added EDCI (115 g, 600 mmol) and DMAP (3.66 g, 30 mmol). Triethylamine (100 mL, 719 mmol) was added dropwise at 0 °C. The mixture was stirred at room temperature for 72 h. The reaction was concentrated to dryness, and the residue was purified by silica column chromatography eluting with 0 to 50% ethyl acetate in petroleum ether to give Intermediate-7 (68 g, 86.5 mmol, 29% yield) as a white solid. 1 H NMR (400 MH z, chloroform-d) δ 7.40-7.32 (m, 5H), 5.30-5.24 (m, 1H), 5.12 (s, 2H), 4.31-4.27 (m, 2H), 4.17-4.10 (m, 2H), 2.50-2.38 (m, 3H), 2.34-2.28 (m, 6H), 1.61-1.55 (m, 4H), 1.35-1.20 (m , 48H), 1.02 (d, J = 6.4 Hz, 3H), 0.88 (t, J = 6.6 Hz, 6H). Intermediate-7 (68 g, 86.5 mmol) and palladium on carbon (3 g) were suspended in THF (400 mL). The mixture was hydrogenated under a hydrogen atmosphere at 30° C. for 16 hours, then filtered and concentrated to dryness. The residue was further purified by trituration with hexane to give Intermediate-4 (C5βMe-acid-2-TG) (51 g, 73.2 mmol, 84% yield) as a white solid. LC-MS: MS m / z = 719 (M+ Na+), RT = 3.83 minutes. 1 H NMR (400 MHz, chloroform-d) δ 5.31-5.25 (m, 1H), 4.34-4.29 (m, 2H), 4.16-4.12 (m, 2H), 2.49-2.40 (m, 3H), 2.33-2.28 (m, 6H). 1.62-1.57 (m, 4H), 1.35-1.20 (m, 48H), 1.06 (d, J = 6.4 Hz, 3H), 0.88 (t, J = 6.6 Hz, 6H) . C10-acid-2-TG (intermediate-9):

[0381] [ka]

[0382] A mixture of sebacic acid (88.0 mg, 0.435 mmol) and DMF (1 drop) in thionyl chloride (316 μL, 4.35 mmol) was heated to reflux for 1.5 h. The reaction was cooled to room temperature, diluted with toluene (5 mL), and concentrated under reduced pressure to give the diacid chloride Intermediate-8 (104 mg, quantitative) as a yellow oil, which was used without purification. 1 HN MR (400 MHz, chloroform-d) δ 2.88 (t, J = 7.3 Hz, 4H), 1.76–1.66 (m, 4H), 1.42–1.26 (m, 8H). A solution of Intermediate-2 (1,3-DG) (45.0 mg, 0.0791 mmol) and pyridine (64.0 μL, 0.791 mmol) in dichloromethane (1.5 mL) was added to the diacid chloride Intermediate-8 (104 mg, 0.435 mmol) in dichloromethane (1.5 mL), and the mixture was stirred at room temperature for 1.5 hours. The reaction was diluted with ethyl acetate (5 mL), water (10 mL), and 1 M HCl (3 mL), and the aqueous layer was extracted with ethyl acetate (3×15 mL). The combined organic extracts were washed with 1 M HCl (30 mL) and brine (30 mL), dried (MgSO), and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (20% to 50% ethyl acetate / hexane) afforded Intermediate-9 (C10-acid-2-TG) (24.3 mg, 41%) as a pale yellow solid. 1 H NMR (400 MHz, CDCl3) δ 5.26 (m, 1H), 4.29 (dd, J = 11.9, 4.4 Hz, 2H), 4.14 (dd, J = 11.9, 5.9 Hz, 2H), 2.37 - 2.27 (m, 8H), 1.70 - 1.53 (m, 8H), 1.39 - 1.19 (m, 56H), 0.87 (t, J = 6.9 Hz, 6H); 13 C NMR (101 MHz, CDCl3) δ 178.6 (C), 173.5 (2C;C), 173.0 (C), 69.0 (CH), 62.2 (CH2), 34.3 (CH2), 34.2 (2C;CH2), 33.9 (CH2), 32.01 (2C;CH2), 29.85 (6C;CH2), 29.81 (4C;CH2), 29.77 (2C;CH2), 29.6 (2C;CH2), 29.5 (2C;CH2), 29.4 (2C;CH2), 29.3 (2C;CH2), 29.2 (2C;CH2), 29.11 (CH2), 29.10 (CH2), 25.00 (2C;CH2), 24.95 (CH2), 24.8 (CH2), 22.8 (2C;CH2), 14.3 (2C;CH3). Alternative procedure (large scale):

[0383] [ka]

[0384] A mixture of sebacic acid (100 g, 495 mmol) and acetyl chloride (250 mL, 3.53 mol) was heated to reflux for 16 hours, then cooled and concentrated to dryness. It was added to a solution of pyridine (270 g, 3.4 mol) and benzyl alcohol (100 g, 926 mmol) in dichloromethane (1500 mL) at room temperature, and the mixture was stirred for 72 hours. The reaction was concentrated, and the residue was purified by column chromatography eluting with 0-50% ethyl acetate in petroleum ether to give Intermediate-11 (82 g, 281 mmol, 57% yield) as a slightly yellow oil. LC-MS: MS m / z = 293 ( M+ H+), RT = 1.45 minutes. To a mixture of Intermediate-11 (82 g, 281 mmol) and Intermediate-2 (1,3-DG) (80 g, 140 mmol) in dichloromethane (1500 mL) was added EDCI (115 g, 600 mmol) and DMAP (3.66 g, 30 mmol). Triethylamine (100 mL, 719 mmol) was then added dropwise at 0 °C. The mixture was stirred at room temperature for 72 h. The reaction was concentrated to dryness, and the residue was purified by column chromatography eluting with 0-50% ethyl acetate in petroleum ether to give Intermediate-12 (65 g, 77 mmol, 27% yield) as a white solid. 1 H NMR (400 MHz , chloroform-d) δ 7.38-7.29 (m, 5H), 5.27-5.25 (m, 1H), 5.11 (s, 2H), 4.31-4.27 (m, 2H), 4.17-4.12 (m, 2H), 2.37-2.29 (m, 8H), 1.65-1.57 (m, 8H), 1.35-1.20 (m, 56H), 0.88 (t, J = 6.6 Hz, 6H). Intermediate-12 (65 g, 77 mmol) and palladium on carbon (3 g) were suspended in THF (400 mL). The mixture was hydrogenated under a hydrogen atmosphere at 30° C. for 16 hours, then filtered, and the filtrate was concentrated to dryness and further purified by trituration with hexane to give Intermediate-9 (C10-acid-2-TG) (50 g, 66.4 mmol, 86% yield) as a white solid. LC-MS: MS m / z = 775 (M+ Na+), RT = 5.95 min; 1 H NMR (400 MHz, chloroform-d) δ 5.29-5.24 (m, 1H), 4.31-4.27 (m, 2H), 4.19-4.12 (m, 2H) , 2.37-2.39 (m, 8H), 1.65-1.58 (m, 8H), 1.3 5-1.20 (m, 56H), 0.88 (t, J = 6.6 Hz, 6H). Intermediate-120 was prepared using an analogous method.

[0385]

change

[0386] 1 H NMR (401 MHz, CDCl3) δ 5.25 (m, 1H), 4.2 8 (dd, J = 11.9, 4.3 Hz, 2H), 4.13 (dd, J = 11.9, 5.9 Hz, 2H), 2.35 - 2.26 (m, 8H), 1.65 - 1.54 (m, 8H), 1.35 - 1.18 (m, 58H), 0.86 (t, J = 6.9 Hz, 6H); 13 C NMR (101 MHz, CDCl3) δ 179.9 (C), 173.4 (2C;C), 173.0 (C), 69.0 (CH) , 62.2 (2C;CH2), 34.3 (CH2), 34.2 (2C;CH2), 34.1 (CH2), 32.0 (2C;CH2), 29.81 (6C;CH2), 29.77 (4C;CH2), 29.74 (2C;CH2), 29.59 (2C;CH2), 29.48 (2C;CH2), 29.38 (2C;CH2), 29.3 6 (CH2), 29.31 (2C;CH2), 29.22 (2C;CH2), 29.15 (CH2), 29.13 (CH2), 25.0 (3C;CH2), 24.8 (CH2), 22.8 (2C;CH2), 14.2 (2C;CH3). ESI-HRMS: C 46 H 86 NaO8[M + Na + ]についての calculated value 789.6215; measured value 789.6218. Cα'βMe-acid-2-TG (Intermediate-23 and Intermediate-27):

[0387]

change

[0388] [ka]

[0389] Intermediate-13: Prepared according to Young, IS; Kerr, MAJ Am. Chem. Soc. 2007, 129, 1465-1469.

[0390] Intermediate-14: Prepared according to Chowdhury, R.; Ghosh, S.K. Org. Lett. 2009, 11, 3270-3273.

[0391] n-Butyllithium (n-BuLi, 1.6 M in hexanes, 765 μL, 1.23 mmol) was slowly added to a solution of TMS-acetylene (198 μL, 1.40 mmol) in THF (1.5 mL) at −78° C., and the mixture was stirred at −78° C. for 5 minutes, then warmed to room temperature and stirred for an additional 15 minutes. The reaction was recooled to −50° C., and a solution of bromide Intermediate-14 (90.0 mg, 0.350 mmol) in THF (1 mL) was added dropwise, and the mixture was stirred at −50° C. for 15 minutes and then at room temperature for 17 hours. The reaction was diluted with brine (15 mL), and the aqueous phase was extracted with ethyl acetate (3×15 mL). The combined organic extracts were washed with brine (30 mL), dried (MgSO), and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (4%-5% ethyl acetate / hexane) afforded TMS alkyne intermediate-15 (45.9 mg, 48%) and desilylated alkyne intermediate-16 (9.7 mg, 1 14% by 1 H NMR integration and also contained a small amount of PPh3. 1 H NMR (400 MHz, CDCl3) δ 7.37 - 7.26 (m, 5H), 4.50 (s, 2H), 3.48 (t, J = 6.5 Hz, 2H), 2.23 (t, J = 7.0 Hz, 2H), 1.68 - 1.60 (m, 2H), 1.58 - 1.42 (m, 4H), 0.14 (s , J = 3.4 Hz, 7H). Tetrabutylammonium fluoride (TBAF, 1.0 M in THF, 201 μL, 0.201 mmol) was added dropwise to a 7:2 mixture of silylalkyne intermediate-15 and alkyne intermediate-16 (total 55.6 mg, 0.215 mmol) in THF (1 mL) at 0 °C, and the mixture was stirred at room temperature for 1 h. The reaction was diluted with water (5 mL) and saturated aqueous NH4Cl (3 mL), and the aqueous phase was extracted with ethyl acetate (3 × 10 mL). The combined organic extracts were washed with brine (20 mL), dried (MgSO4), and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (4% ethyl acetate / hexanes) afforded alkyne intermediate-16 (37.5 mg, 53% over two steps) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 7.39 - 7.27 (m, 5H), 4.51 (s, 2H), 3.49 (t, J = 6.5 Hz, 2H), 2.21 (td, J = 6.9, 2.6 Hz, 2H), 1.95 (t, J = 2.7 Hz, 1H), 1.70 - 1.61 (m, 2H), 1.60 - 1.48 (m, 4H); 13 C NMR (101 MHz, CDCl3) δ 138.7 (C), 128.5 (2C;CH), 127.7 (2C;CH), 127.6 (CH), 84.6 (C), 73.0 (CH2), 70.3 (CH2), 68.4 (CH), 29.4 (CH2), 28.4 (CH2), 25.5 (CH2 ), 18.5 (CH2). Intermediate-17: Prepared according to Kim, H.-O. et al. Synlett 1998, 1059-1060.

[0392] A suspension of PdCl(PPh) (16.8 mg, 0.0240 mmol) in DMF (1.5 mL) was degassed using N gas for 5 min, then a degassed solution of CuI (9.1 mg, 0.0480 mmol), EtN (66.8 μL, 0.480 mmol), and alkyne intermediate-16 (48.5 mg, 0.240 mmol) and enol triflate intermediate-17 (94.3 mg, 0.360 mmol) in DMF (2 mL) was added. The mixture was degassed for an additional 5 min using a stream of N and then heated at 0 °C for 1 h. The reaction was cooled to room temperature, diluted with ethyl acetate (30 mL), washed with 1 M HCl, saturated aqueous NaHCO, water, and brine (20 mL each), dried (MgSO), and concentrated under reduced pressure to give the crude product. Silica gel chromatography (4% to 5% ethyl acetate / hexanes) afforded enyne intermediate-18 (46.6 mg, 62%) as a pale yellow oil. 1 H NMR (400 MHz, CDCl3) δ 7.37 - 7.24 (m, 5H), 5.92 (m, 1H), 4.50 (s, 2H), 4.17 (q, J = 7.1 Hz, 2H), 3.48 (t, J = 6.5 Hz, 2H), 2 .45 (t, J = 7.0 Hz, 2H), 2.01 (d, J = 1.4 Hz, 3H), 1.69 - 1.59 (m, 4H), 1.56 - 1.49 (m, 2H), 1.27 (t, J = 7.1 Hz, 3H); 13 C NMR (101 MHz, CDCl3) δ 165.4 (C), 138.8 (C), 135.9 (C), 128.5 (2C;CH), 127.7 (2C;CH), 127.6 (CH), 123.4 (CH), 102.9 (C), 80.0 (C), 73.0 (CH2), 70.4 (CH2), 60.0 (CH2), 29.4 (CH2), 28.4 (CH2 ), 26.0 (CH3), 25.7 (CH2), 20.1 (CH2), 14.4 (CH3). A solution of benzyl ether Intermediate-18 (31.4 mg, 0.100 mmol) in ethyl acetate (8 mL) in a three-necked round-bottom flask was evacuated and flushed twice with N gas, then palladium on carbon (10% w / w, 26.6 mg, 0.0250 mmol) was added, and the resulting suspension was evacuated and flushed three times with N. The flask was fitted with a H balloon and evacuated and flushed three times with H, and the reaction mixture was stirred under 1 atm of H at room temperature for 1 h. The flask was then evacuated and flushed with N, and the reaction mixture was filtered through a pad of Celite, washing with ethyl acetate (30 mL). The filtrate was concentrated under reduced pressure to afford saturated alcohol Intermediate-19 (23.0 mg, quantitative) as a colorless oil, which was used without purification. 1 H NMR (400 MHz, CDCl3) δ 4.12 (q, J = 7.1 Hz, 2H), 3 .63 (t, J = 6.6 Hz, 2H), 2.28 (dd, J = 14.6, 6.1 Hz, 1H), 2.09 (dd, J = 14.6, 8.1 Hz, 1H), 1.94 (m, 1H), 1.60 - 1.50 (m, 2H), 1.25 (t, J = 6.6 Hz, 3H), 1.40 - 1.13 (m, 10H), 0.92 (d , J = 6.6 Hz, 3H); 13 C NMR (101 MHz, CDCl3) δ 173.6 (C), 63.2 (CH2), 60.2 (CH2), 42.1 (CH 2), 36.8 (CH2), 32.9 (CH2), 30.5 (CH), 29.8 (CH2), 29.5 (CH2), 26.9 (CH2), 25.8 (CH2), 19.9 (CH3), 14.4 (CH3). Imidazole (9.6 mg, 0.141 mmol) and tert-butyl(chloro)diphenylsilane (TBDPSCl, 50.8 μL, 0.195 mmol) were added to a solution of alcohol Intermediate-19 (18.0 mg, 0.0781 mmol) in DMF (3 mL), and the mixture was stirred at room temperature for 16 h. The reaction was diluted with ethyl acetate (20 mL), washed with brine (2 × 20 mL), dried (MgSO), and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (4% ethyl acetate / hexanes with 0.5% EtN) gave TBDPS ether Intermediate-20 (33.7 mg, 92%) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 7.70 - 7.64 (m, 4H), 7.45 - 7.33 (m, 6H), 4.13 (q, J = 7.1 Hz, 2H), 3.65 (t, J = 6.5 Hz, 2H ), 2.28 (dd, J = 14.6, 6.0 Hz, 1H), 2.09 (dd, J = 14.6, 8.2 Hz, 1H), 1.94 (m, 1H), 1.60 - 1.50 (m, 2H), 1.38 - 1.21 (m, 3H), 1.05 (s, J = 2.9 Hz, 2H), 1.05 (s, 9H), 0.93 (d, J = 6.6 Hz, 3H); 13 C NMR (101 MHz, CDCl3) δ 173.6 (C), 135.7 (4C;CH), 134.3 (2C;C), 129.6 (2C;CH), 127.7 (4C;CH), 64.1 (CH2), 60.2 (CH2), 4 2.1 (CH2), 36.9 (CH2), 32.7 (CH2), 30.5 (CH ), 29.9 (CH2), 29.5 (CH2), 27.01 (3C;CH3), 26.99 (CH2), 25.9 (CH2), 19.9 (CH3), 19.4 ( C), 14.4 (CH3). A solution of potassium hydroxide (2.0 M, 427 μL, 0.853 mmol) was dissolved in ethanol. To the ester Intermediate-20 (40.0 mg, 0.0853 mmol) in HCl (2 mL) was added and the mixture was heated at 80° C. for 2 h. The reaction was cooled to room temperature, acidified to pH 1 by the addition of 1 M HCl, and the organic solvent was removed under reduced pressure. The residue was diluted with water (5 mL), and the aqueous phase was extracted with ethyl acetate (3×15 mL). The combined organic extracts were washed with brine (30 mL), dried (MgSO), and concentrated under reduced pressure to give crude acid Intermediate-21 (37.6 mg, quantitative) as a colorless oil, which was used without purification. 1 H NMR (400 MHz, CDCl3) δ 7.74 - 7.63 (m, 4H), 7.45 - 7.34 (m, 6H), 3.65 (t, J = 6.5 Hz, 2H) , 2.35 (dd, J = 15.0, 5.9 Hz, 1H), 2.14 (dd, J = 15.0, 8.2 Hz, 1H), 1.95 (m, 1H), 1.61 - 1 .50 (m, 2H), 1.38 - 1.18 (m, 10H), 1.04 (s, 9H), 0.96 (d, J = 6.6 Hz, 3H); 13 C NMR (101 MHz, CDCl3) δ 179.5 (C), 135.7 (4C;CH), 134.3 (2C;C), 129.6 (2C;CH), 127.7 (4C;CH), 64.1 (CH2), 41.7 (CH2), 36.8 (CH2), 32.7 (CH2), 3 0.3 (CH), 29.8 (CH2), 29.5 (CH2), 27.01 (3C ;CH3), 26.97 (CH2), 25.9 (CH2), 19.8 (CH3), 19.4 (C).Note: The two sets of signals are 1 H and 13Although doubling was observed in both C NMR spectra, only the major set of signals is reported above. It was not clear whether the doubling was due to the presence of two highly related compounds or the presence of both monomeric and dimeric species due to the high concentration of the NMR sample.

[0393] DMAP (10.1 mg, 0.0831 mmol), EDC·HCl (39.8 mg, 0.208 mmol), and intermediate-2 (1,3-DG) (70.9 mg, 0.125 mmol) were added to a solution of acid intermediate-21 (36.6 mg, 0.0831 mmol) in dichloromethane (2.5 mL), and the mixture was stirred at room temperature for 21 h. The reaction was diluted with dichloromethane (5 mL), silica gel was added, and the mixture was concentrated under reduced pressure. Purification by silica gel chromatography (4% to 5% ethyl acetate / hexane) afforded triglyceride intermediate-22 (39.9 mg, 48% over two steps) as a colorless solid. 1 H NMR (400 MHz, CDCl3) δ 7.69 - 7.64 (m , 4H), 7.44 - 7.34 (m, 6H), 5.28 (m, 1H), 4.289 / 4.287 (each dd, J = 11.8, 4.2 Hz, 2H), 4. 14 (dd, J = 12.0, 5.9 Hz, 2H), 3.65 (t, J = 6.5 Hz, 2H), 2.37 - 2.27 (m, 5H), 2.11 (dd, J = 14.7, 8.4 Hz, 1H), 1.92 (m, 1H), 1.67 - 1.50 (m, 8H), 1.39 - 1.14 (m, 56H), 1.04 (s, 9H), 0.93 (d, J = 6.6 Hz, 3H), 0.88 (t, J = 6.9 Hz, 6H); 13 C NMR (101 MHz, CDCl3) δ 173.5 (2C;C), 172.5 (C), 135.7 (4C;CH), 134.3 (2C;C), 1 29.6 (2C;CH), 127.7 (4C;CH), 68.9 (CH), 64.1 (CH2), 62.3 (2C;CH2), 41.8 (CH2), 36.8 (C H2), 34.2 (2C;CH2), 32.7 (CH2), 32.1 (2C;CH2), 30.5 (CH), 29.9 (CH2), 29.84 (6C;CH2), 29.80 (4C;CH2), 29.76 (2C;CH2), 29.6 (2C;C H2), 29.54 (CH2), 29.51 (2C;CH2), 29.4 (2C;CH2), 29.3 (2C;CH2), 27.02 (CH2), 27.00 (3C;CH3), 25.9 (CH2), 25.0 (2C;CH2), 22.8 (2C;CH2), 19.7 (CH3), 19.4 (C), 14.3 (2C;CH3). Tetrabutylammonium fluoride (TBAF, 1.0 M in THF, 98.3 μL, 98.3 μmol) was added to the TBDPS ether intermediate-22 (39 To a solution of 1.0 mg (39.3 μmol) of 1H NMR (δ 1.04-1.06, 1.06-1.08 ... 1 H NMR (400 MHz, CDCl3) δ 5.28 (m, 1H), 4.29 (dd, J = 11.9, 4.3 Hz, 2H), 4.14 (dd, J = 11.9, 5.9 Hz, 2H), 3.64 (t, J = 6.6 Hz, 2 H), 2.36 - 2.27 (m, 5H), 2.12 (dd, J = 14.7, 8.2 Hz, 1H), 1.93 (m, 1H), 1.65 - 1.52 (m, 6H), 1.39 - 1.16 (m, 58H), 0.93 (d, J = 6.6 Hz, 3H), 0.88 (t, J = 6.9 Hz, 6H); 13 C NMR (101 MHz, CDCl3) δ 173.5 (2C;C), 172.5 (C), 68.9 (CH), 63.2 (CH2), 62.3 (2C;CH2), 41.8 (CH2), 36.7 (CH2), 34.2 (2C;CH2), 32.9 (CH2), 32.1 (2C;CH2), 30.5 (CH), 29.84 (4C;CH2), 29.83 (2C;CH2), 29.80 (4C;CH2), 29.77 (2C;CH2), 29.6 (2C;CH2), 29.5 (3C;CH2), 29.4 (2C;CH2 ), 29.3 (3C;CH2), 26.9 (CH2), 25.8 (CH2), 2 5.0 (2C;CH2), 22.8 (2C;CH2), 19.7 (CH3), 14.3 (2C;CH3). Pyridinium chlorochromate (PCC, 12.0 mg, 55.8 μmol) was added to a suspension of alcohol Intermediate-23 (21.0 mg, 27.9 μmol) and Celite (15 mg) in dichloromethane (1.5 mL) at 0° C., and the mixture was stirred at room temperature for 1.75 h. The reaction was filtered through a short pad of silica gel eluted with ethyl acetate, and the filtrate was concentrated under reduced pressure to give crude aldehyde Intermediate-24 (20.9 mg, quantitative) as a yellow oil, which was used without purification. 1 H NMR (400 MHz, CDCl3) δ 9.76 (s, 1H), 5.28 (m, 1H), 4.29 (dd, J = 11.6, 3.5 Hz, 2H), 4.14 (dd, J = 11.6, 5.7 Hz, 2H), 2.42 (t, J = 7.1 Hz, 2H), 2.36 - 2.25 (m, 5H), 2.12 (dd, J = 14.5, 8.3 Hz, 1H), 1.93 (m, 1H), 1.72 - 1.53 (m, 6H), 1.42 - 1.05 (m, 56H), 0.93 (d, J = 6.5 Hz, 3H), 0.88 (t, J = 6.6 Hz, 6H). Intermediate-25: Prepared according to Gossauer, A.; Kuhne, G. Liebigs. Ann. Chem. 1977, 664-686.

[0394] A solution of ylide intermediate-25 (8.1 mg, 19.0 μmol) in toluene (0.4 mL) was added to aldehyde intermediate-24 (11.0 mg, 14.6 μmol) in toluene (0.6 mL), and the mixture was heated to reflux for 4 h. The reaction was cooled to room temperature and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (5% to 10% ethyl acetate / hexanes) gave α,β-unsaturated benzyl ester intermediate-26 (7.1 mg, 54%) as a yellow oil. 1 H NMR (401 MHz, CDCl3) δ 7.41 - 7.27 (m, 5H), 6.81 (td, J = 7.5, 1.4 Hz , 1H), 5.27 (m, 1H), 5.18 (s, 2H), 4.29 (dd, J = 11.9, 4.3 Hz, 2H), 4.14 (dd, J = 11.9, 6. 0 Hz, 2H), 2.36 - 2.27 (m, 5H), 2.20 - 2.08 ( m, 3H), 1.93 (m, 1H), 1.85 (d, J = 1.2 Hz, 3H ), 1.67 - 1.54 (m, 6H), 1.47 - 1.38 (m, 2H), 1.37 - 1.19 (m, 54H), 0.93 (d, J = 6.6 Hz, 3H ), 0.88 (t, J = 6.9 Hz, 6H); 13 C NMR (101 MHz, CDCl3) δ 173.4 (2C;C), 172.4 (C), 168.2 (C), 143.2 (CH), 136.6 (C), 128.7 (2C;CH), 128 .2 (CH), 128.1 (2C;CH), 127.6 (C), 69.0 (CH ), 66.3 (CH2), 62.3 (2C;CH2), 41.8 (CH2), 3 6.8 (CH2), 34.2 (2C;CH2), 32.1 (2C;CH2), 30.5 (CH), 29.85 (6C;CH2), 29.81 (4C;CH2), 29.77 (2C;CH2), 29.74 (CH2), 29.63 (2C;CH2), 29.56 (CH2), 29.51 (2C;CH2), 29.4 (2C;CH2) , 29.3 (2C;CH2), 28.9 (CH2), 28.7 (CH2), 27 .0 (CH2), 25.0 (2C;CH2), 22.8 (2C;CH2), 19.7 (CH2), 14.3 (2C;CH2), 12.6 (CH2). A solution of benzyl ether intermediate-26 (48.5 mg, 54.0 μmol) in ethyl acetate (2.5 mL) in a two-neck flask was evacuated and flushed with N gas (three times each). Palladium on carbon (10% w / w, 11.5 mg, 10.8 μmol) was then added, and the resulting suspension was evacuated and flushed with N gas (three times each). The flask was fitted with a H balloon, evacuated and flushed with H (three times each), and the reaction mixture was stirred under 1 atm of H at room temperature for 3 h. The reaction was filtered through a pad of Celite, washed with ethyl acetate, and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (10%–20% ethyl acetate / hexanes) afforded the saturated acid intermediate-27 (Cα′βMe-acid-2-TG) (28.1 mg, 64%) as a colorless oil. 11H NMR (401 MHz, CDCl3) δ 5.27 (m, 1H), 4.29 (dd, J = 11.9, 4.3 Hz, 2H), 4.14 (dd, J = 11.9, 6.1 Hz, 2H), 2.46 (m, 1H), 2.37 - 2.26 (m, 5H), 2.12 (dd, J = 14.7, 8.2 Hz, 1 H), 1.94 (m, 1H), 1.73 - 1.55 (m, 5H), 1.41 (m, 1H), 1.37 - 1.20 (m, 60H), 1.18 (d, J = 7. 0 Hz, 3H), 0.93 (d, J = 6.6 Hz, 3H), 0.88 (t, J = 6.9 Hz, 6H); 13 13C NMR (101 MHz, CDCl3) δ 182.3 (C), 173.5 (2C;C), 172.5 (C), 69.0 (CH) , 62.3 (2C;CH2), 41.8 (CH2), 39.4 (CH), 36. 8 (CH2), 34.2 (2C;CH2), 33.7 (CH2), 32.1 (2 C;CH2), 30.5 (CH), 29.84 (6C;CH2), 29.80 (4C;CH2), 29.77 (2C;CH2), 29.62 (2C;CH2), 29 .60 (CH2), 29.57 (CH2), 29.5 (2C;CH2), 29.4 (2C;CH2), 29.3 (2C;CH2), 27.3 (CH2), 27.0 (CH2), 25.0 (2C;CH2), 22.8 (2C;CH2), 19.7 (CH3), 17.0 (CH3), 14.3 (2C;CH3). C4-Acid-2-TG (Intermediate-28):

[0395]

Chemistry

[0396] 4-(Dimethylamino)pyridine (DMAP, 15.5 mg, 0.127 mmol) was added to a solution of 1,3-diglyceride intermediate-2 (72.2 mg, 0.127 mmol) and succinic anhydride (25.4 mg, 0.254 mmol) in pyridine / THF / CHCl (0.5 mL each), and the mixture was stirred at room temperature for 17 hours. Excess succinic anhydride (25.4 mg, 0.254 mmol) and DMAP (15.5 mg, 0.127 mmol) were added, and the solution was heated at 40° C. for an additional 22 hours. The reaction was diluted with ethyl acetate (25 mL), washed with 1 M HCl (20 mL) and brine (2×30 mL), dried (MgSO), and concentrated under reduced pressure to give the crude product. Silica gel chromatography (15% to 25% ethyl acetate / hexanes) afforded the acid-TG Intermediate-28 (77.0 mg, 91%) as a colorless solid. 1 H NMR (400 MHz, CDCl3) δ 5.27 (m, 1H), 4.30 (dd, J = 12.0, 4.3 H z, 2H), 4.15 (dd, J = 12.0, 5.8 Hz, 2H), 2.72 - 2.61 (m, 4H), 2.31 (t, J = 7.6 Hz, 4H), 1.67 - 1.54 (m, 4H), 1.36 - 1.19 (m, 48H), 0.88 (t, J = 6.9 Hz, 6H); 13 C NMR (101 MHz, CDCl3) δ 176.9 (C), 173.5 (2C;C), 171.4 (C), 69.8 (CH), 62.0 (2C;CH2), 34.2 (2C;CH2), 32.1 (2C;CH2), 29.84 (6C;CH2), 29.81 (4C;CH2), 29. 77 (2C;CH2), 29.6 (2C;CH2), 29.5 (2C;CH2), 29.4 (2C;CH2), 29.3 (2C;CH2), 29.0 (CH2), 28.8 (CH2), 25.0 (2C;CH2), 22.8 (2C;CH2), 14.3 (2C;CH3). C6-acid-2-TG (intermediate-29):

[0397] [ka]

[0398] A solution of 1,3-diglyceride intermediate-2 (75.0 mg, 0.132 mmol) and pyridine (107 μL, 1.32 mmol) in CHCl (2.5 mL) was added to diacid chloride 1 (96.1 mL, 0.659 mmol) in CHCl (2.5 mL), and the mixture was heated to reflux for 3.5 h. The reaction was cooled to room temperature and dissolved in ethyl acetate (30 mL). The diluted organic extract was washed with 1 M HCl (20 mL) and brine (2 × 20 mL), dried (MgSO), and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (15% to 25% ethyl acetate / hexanes) afforded Acid-TG Intermediate-29 (52.7 mg, 57%) as a colorless solid. 1 H NMR (400 MHz, CDCl3) δ 5.26 (m, 1H), 4.30 (dd, J = 11 .9, 4.3 Hz, 2H), 4.14 (dd, J = 11.9, 5.9 Hz, 2H), 2.41 - 2.34 (m, 4H), 2.31 (t, J = 7.6 Hz , 4H), 1.72 - 1.65 (m, 4H), 1.65 - 1.56 (m, 4 H), 1.35 - 1.20 (m, 48H), 0.88 (t, J = 6.8 Hz , 6H); 13 C NMR (101 MHz, CDCl3) δ 178.3 (C), 173.5 (2C;C), 172.4 (C), 69.3 (CH), 62.2 (2 C;CH2), 34.2 (2C;CH2), 33.8 (CH2), 33.5 (CH2), 32.1 (2C;CH2), 29.84 (6C;CH2), 29.81 (4C;CH2), 29.77 (2C;CH2), 29.6 (2C;CH2), 29. 5 (2C;CH2), 29.4 (2C;CH2), 29.3 (2C;CH2), 25.0 (2C;CH2), 24.3 (CH2), 24.1 (CH2), 22.8 (2C;CH2), 14.3 (2C;CH2). C10βMe-acid-2-TG (Intermediate-30):

[0399] [ka]

[0400] A solution of sodium chlorite (22.7 mg, 0.251 mmol) and sodium phosphate monobasic (NaHPO, 23.4 mg, 0.195 mmol) in water (1 mL) was added dropwise to aldehyde Intermediate-24 (20.9 mg, 0.0279 mmol) in t-BuOH (1.5 mL) and 2,3-dimethyl-2-butene (0.3 mL), and the reaction was stirred at room temperature for 2.25 h. The reaction was diluted with water (10 mL), and the aqueous layer was extracted with ethyl acetate (3 × 15 mL). The combined organic extracts were washed with brine (30 mL), dried (MgSO), and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (10% to 20% ethyl acetate / hexanes with 0.5% acetic acid) afforded acid Intermediate-30 (16.1 mg, 75%) as a colorless solid. 1 H NMR (400 MHz, CDCl3) δ 5.27 (m, 1H), 4.29 (dd, J = 11.9, 4.3 Hz, 2H), 4.14 (dd, J = 12.0, 6.0 Hz, 2H), 2.37 - 2.27 (m, 7H), 2.12 (dd, J = 1 4.7, 8.2 Hz, 1H), 1.93 (m, 1H), 1.67 - 1.55 (m, 6H), 1.40 - 1.14 (m, 56H), 0.93 (d, J = 6. 6 Hz, 3H), 0.88 (t, J = 6.9 Hz, 6H); 13 C NMR ( 101 MHz, CDCl3) δ 179.7 (C), 173.5 (2C;C), 172.4 (C), 69.0 (CH), 62.3 (2C;CH2), 41.8 (C H2), 36.7 (CH2), 34.2 (2C;CH2), 34.1 (CH2), 32.1 (2C;CH2), 30.4 (CH), 29.82 (6C;CH2), 29.79 (4C;CH2), 29.75 (2C;CH2), 29.6 (2C;C H2), 29.5 (3C;CH2), 29.4 (2C;CH2), 29.24 (2 C;CH2), 29.16 (CH2), 26.8 (CH2), 25.0 (2C;CH2), 24.8 (CH2), 22.8 (2C;CH2), 19.7 (CH3), 14.2 (2C;CH3). C12βMe-OH-2-TG (intermediate-121): Intermediate-121 was prepared using a method similar to that described above for the synthesis of Intermediate-24.

[0401] [ka]

[0402] 1 H NMR (401 MHz, CDCl3) δ 5.28 (m, 1H), 4.2 9 (dd, J = 11.9, 4.3 Hz, 2H), 4.14 (dd, J = 11.8, 6.0 Hz, 2H), 3.64 (t, J = 6.6 Hz, 2H), 2. 32 (dd, J = 14.6, 5.8 Hz, 1H), 2.30 (t, J = 7.5 Hz, 4H), 2.12 (dd, J = 14.6, 8.2 Hz, 1H), 1 .94 (m, 1H), 1.64 - 1.49 (m, 6H), 1.40 - 1.13 (m, 62H), 0.93 (d, J = 6.6 Hz, 3H), 0.88 (t, J = 6.9 Hz, 6H); 13 C NMR (101 MHz, CDCl3) δ 173.3 (2C;C), 172.4 (C), 68.9 (CH), 62.9 (CH2 ), 62.2 (2C;CH2), 41.7 (CH2), 36.7 (CH2), 3 4.1 (2C;CH2), 32.9 (CH2), 32.0 (2C;CH2), 30.4 (CH), 29.80 (CH2), 29.76 (6C;CH2), 29.72 (4C;CH2), 29.68 (2C;CH2), 29.65 (CH2), 29.62 (CH2), 29.53 (2C;CH2), 29.50 (CH2), 29.4 (2C;CH2), 29.3 (2C;CH2), 29.2 (2C;CH2), 27.0 (CH2), 25.8 (CH2), 24.9 (2C;CH2), 22.7 ( 2C;CH2), 19.6 (CH3), 14.2 (2C;CH3). C12α'βMe-OH-2-TG (intermediate-143):

[0403]

Chemistry

[0404] Pyridinium chlorochromate (16.5 mg, 0.0765 mmol) and Celite (16.5 mg) were added to a solution of alcohol Intermediate-121 (40.0 mg, 0.0512 mmol) in CHCl (2.5 mL) at 0° C., and the resulting suspension was stirred at 0° C. for 15 min and then at room temperature for 3 h. The reaction mixture was filtered through a plug of silica gel and acetic acid was added. Elution with ethyl acetate (50 mL) and concentration of the filtrate under reduced pressure gave the corresponding aldehyde as a pale yellow oil, which was used without purification.

[0405] The crude aldehyde was redissolved in diethyl ether (2.5 mL) and cooled to −10°C (ice / brine bath). Methylmagnesium bromide (3.0 M in diethyl ether, 18.8 μL, 0.0563 mmol) was added, and the reaction vessel was transferred to a freezer (−20°C) and allowed to stand for 19 h. The mixture was warmed to −10°C and quenched by the slow addition of saturated aqueous NH₄Cl (4 mL) and then warmed to room temperature. The aqueous layer was extracted with ethyl acetate (3 × 20 mL), and the combined organic extracts were washed with water (25 mL) and brine (25 mL), dried (MgSO₄), and concentrated under reduced pressure to give the crude product. Silica gel chromatography (0% to 15% ethyl acetate / hexanes) afforded alcohol Intermediate-143 (21.6 mg, 53%) as a white solid. 1 H NMR (401 MHz, CDCl3) δ 5.27 (m, 1H), 4.29 (dd, J = 11.9, 3.8 Hz, 2H), 4.14 (dd, J = 11.9, 6.0 Hz, 2 H), 3.78 (m, 1H), 2.32 (dd, J = 14.6, 5.8 Hz, 1H), 2.30 (t, J = 7.5 Hz, 4H), 2.12 (dd, J = 14.7, 8.2 Hz, 1H), 1.93 (m, 1H), 1.66 - 1.56 (m, 6H), 1.52 - 1.21 (m, 62H), 1.18 (d, J = 6 .2 Hz, 3H), 0.93 (d, J = 6.6 Hz, 3H), 0.88 (t , J = 6.9 Hz, 6H). 13 C NMR (101 MHz, CDCl3) δ 173.5 (2C;C), 172.5 (C), 69.0 (CH), 68.3 (C H), 62.3 (2C;CH2), 41.9 (CH2), 39.5 (CH2), 36.8 (CH2), 34.2 (2C;CH2), 32.1 (2C;CH2), 30.5 (CH), 29.90 (CH2), 29.85 (6C;CH2), 29.81 (4C;CH2), 29.78 (3C;CH2), 29.75 (CH2), 29.72 (CH2), 29.6 (2C;CH2), 29.5 (2C;CH2), 29.4 (2C;CH2), 29.3 (2C;CH2), 27.1 (CH2), 25.9 (CH2), 25.0 (2C;CH2), 23.7 (CH3), 22.8 (2 C;CH2), 19.7 (CH3), 14.3 (2C;CH3). C12β'βMe-OH-2-TG (intermediate-148):

[0406] [ka]

[0407] Borane-dimethylsulfide complex (1.05 M in THF, 94.0 μL, 98.9 μmol) was added to a solution of carboxylic acid intermediate-27 (40.0 mg, 49.4 μmol) in THF (1.5 mL) at −5° C., and the mixture was stirred at −5° C. for 40 min and then placed in a refrigerator for 19 h. The reaction was slowly diluted with cold water (20 mL), and the aqueous phase was extracted with ethyl acetate (3 × 20 mL). The combined organic extracts were washed with brine (30 mL), dried (MgSO), and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (5% to 15% ethyl acetate / hexanes) afforded alcohol intermediate-148 (35.8 mg, 91%) as a colorless oil.1 H NMR (401 MHz, CDCl3) δ 5.27 (m, 1H), 4.29 (dd, J = 11.8, 4.2 Hz, 2H), 4.14 (dd, J = 11.9, 5.9 Hz, 2H), 3.51 (dd, J = 10.5, 5.8 Hz, 1H), 3.42 (dd, J = 10.5, 6.5 Hz, 1H), 2.33 (dd, J = 14. 8, 6.0 Hz, 1H), 2.30 (t, J = 7.6 Hz, 4H), 2.1 2 (dd, J = 14.8, 8.2 Hz, 1H), 1.93 (m, 1H), 1 .65 - 1.50 (m, 5H), 1.44 - 1.05 (m, 62H), 0.93 (d, J = 6.7 Hz, 3H), 0.92 (d, J = 6.7 Hz, 3H ), 0.88 (t, J = 6.9 Hz, 6H). C12-acid-2-TG (intermediate-37):

[0408] [ka]

[0409] A mixture of dodecanedioic acid (700 mg, 3.04 mmol) and DMF (2 drops) in thionyl chloride (2.20 mL, 30.4 mmol) was heated to reflux for 2 h. The reaction was cooled to room temperature, diluted with toluene (5 mL), and concentrated under reduced pressure to give the diacid chloride Intermediate-36 (812 mg, quantitative) as a yellow oil, which was used without purification. 1 HNM R (400 MHz, CDCl3): δ 2.88 (t, J = 7.3 Hz, 4H ), 1.76 - 1.65 (m, 4H), 1.42 - 1.23 (m, 12H). A solution of 1,3-diglyceride Intermediate-2 (40.0 mg, 0.0703 mmol) and pyridine (56.9 μL, 0.703 mmol) in CHCl (1.5 mL) was added to diacid chloride Intermediate-36 (93.9 mg, 0.352 mmol) in CHCl (1.5 mL), and the mixture was stirred at room temperature for 16 h. The reaction was diluted with ethyl acetate (3 mL), water (10 mL), and 1 M HCl (2 mL), and the aqueous layer was extracted with ethyl acetate (3 × 15 mL). The combined organic extracts were washed with 1 M HCl (30 mL) and brine (2 × 30 mL), dried (MgSO), and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (20% to 45% ethyl acetate / hexanes) afforded acid-TG Intermediate-37 (30.7 mg, 56%) as a colorless solid. 1 H NMR (400 MHz, CDCl3): δ 5.26 (m, 1H), 4.2 9 (dd, J = 11.9, 4.3 Hz, 2H), 4.14 (dd, J = 11.9, 5.9 Hz, 2H), 2.38 - 2.26 (m, 8H), 1.69 - 1.54 (m, 8H), 1.38 - 1.19 (m, 60H), 0.87 (t, J = 6.9 Hz, 6H). C15βMe-acid-2-TG (Intermediate-49):

[0410] [ka]

[0411] A solution of 1,10-decanediol (1.05 g, 6.00 mmol) in DMF (7 mL) was added dropwise to a suspension of sodium hydride (60% w / w in mineral oil), washed twice with anhydrous gasoline (240 mg, 6.00 mmol) in DMF (8 mL) at 0 °C, and the mixture was stirred at room temperature for 1 h. Benzyl bromide (784 μL, 3.50 mmol) was added dropwise, and the mixture was stirred at room temperature for 1.5 h. The reaction was diluted with ethyl acetate (30 mL), quenched with water (20 mL), and the aqueous phase was extracted with ethyl acetate (3 × 30 mL). The combined organic extracts were washed with water and brine (60 mL each), dried (MgSO), and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (20% to 30% ethyl acetate / hexanes) afforded benzyl ether intermediate-38 (657 mg, 41%) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 7.39 - 7.24 (m, 5H), 4.50 (s, 2H), 3.64 (t, J = 6.6 Hz, 2H), 3.46 (t, J = 6.7 Hz, 2H), 1. 65 - 1.52 (m, 4H), 1.40 - 1.25 (m, 12H). Carbon tetrabromide (1.05 g, 3.17 mmol) and triphenylphosphine (1.07 g, 4.08 mmol) were added to a solution of alcohol Intermediate-38 (600 mg, 1.11 mmol) in CHCl (20 mL) at 0 °C, and the mixture was stirred at room temperature for 2.5 h. The reaction was diluted with CHCl (20 mL), silica gel was added, and the solvent was evaporated under reduced pressure. Purification by silica gel chromatography (3% to 4% ethyl acetate / hexane) afforded bromide Intermediate-39 (658 mg, 89%) as a colorless oil. . 1 H NMR (400 MHz, CDCl3) δ 7.41 - 7.26 (m, 5H), 4.50 (s, 2H), 3.46 (t, J = 6.6 Hz, 2H), 3. 40 (t, J = 6.9 Hz, 2H), 1.91 - 1.79 (m, 2H), 1.68 - 1.56 (m, 2H), 1.47 - 1.23 (m, 12H). n-Butyllithium (n-BuLi, 1.6 M in hexanes, 4.01 mL, 6.42 mmol) was slowly added to a solution of TMS-acetylene (1.02 mL, 7.22 mmol) in THF (9 mL) at −78° C., and the mixture was stirred at −78° C. for 5 minutes, then warmed to room temperature and further stirred for 15 minutes. The reaction was recooled to −50° C., and a solution of bromide Intermediate-39 (525 mg, 1.60 mmol) and DMPU (1.06 mL, 8.82 mmol) in THF (6 mL) was added dropwise, and the mixture was stirred at −50° C. for 30 minutes and then at room temperature for 22 hours. The reaction was diluted with brine (15 mL), and the organic solvent was evaporated under reduced pressure. The aqueous residue was extracted with ethyl acetate (3×25 mL), and the combined organic extracts were washed with brine (50 mL), dried (MgSO), and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (3.5% to 4.5% ethyl acetate / hexanes) afforded TMS alkyne intermediate-40 (489 mg, 88%) as a colorless oil containing a small amount (<10%) of desilylated alkyne intermediate-41. 1 HNM R (400 MHz, CDCl3) δ 7.37 - 7.25 (m, 5H), 4.50 (s, 2H), 3.46 (t, J = 6.7 Hz, 2H), 2.21 (t, J = 7.2 Hz, 2H), 1.65 - 1.58 (m, 2H), 1.54 - 1.46 (m, 2H), 1.41 - 1.24 (m, 12H), 0.14 (s, 9H). Tetrabutylammonium fluoride (TBAF, 1.0 M in THF, 1.61 mL, 1.61 mmol) was added dropwise to silylalkyne Intermediate-40 (463 mg, 1.34 mmol) in THF (12 mL) at 0 °C, and the mixture was stirred at room temperature for 40 min. The reaction was diluted with water (10 mL), and the aqueous phase was extracted with ethyl acetate (3 × 20 mL). The combined organic extracts were washed with brine (40 mL), dried (MgSO), and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (4% to 5% ethyl acetate / hexanes) afforded alkyne Intermediate-41 (361 mg, 98%) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 7.38 - 7.25 (m, 5H), 4.50 (s, 2H), 3.46 (t, J = 6.7 Hz, 2H), 2.18 (td, J = 7.1, 2.6 Hz, 2H), 1.94 (t, J = 2.7 Hz, 1H), 1.65 - 1.57 (m, 2H), 1.55 - 1.48 (m, 2H), 1.43 - 1.24 (m, 12H). 13 C NMR (101 MHz, CDCl3) δ 138.86 (C), 128.49 (2C;CH), 12 7.77 (2C;CH), 127.61 (CH), 84.97 (C), 73.00 (CH2), 70.67 (CH2), 68.18 (CH), 29.91 (CH2 ), 29.67 (CH2), 29.59 (CH2), 29.57 (CH2), 2 9.23 (CH2), 28.89 (CH2), 28.63 (CH2), 26.33 (CH2), 18.54 (CH2). A suspension of PdCl(PPh) (32.2 mg, 0.0459 mmol) in DMF (4 mL) was degassed using a stream of N gas for 5 min, then a degassed solution of CuI (35.0 mg, 0.184 mmol), EtN (256 μL, 1.84 mmol), and alkyne Intermediate-41 (250 mg, 0.918 mmol) and enol triflate Intermediate-17 (313 mg, 1.19 mmol) in DMF (6 mL) was added. The mixture was degassed for an additional 5 min using a stream of N and then heated at 70 °C for 1 h. The reaction was cooled to room temperature, diluted with ethyl acetate (40 mL), washed with 1 M HCl, saturated aqueous NaHCO, water, and brine (30 mL each), dried (MgSO), and concentrated under reduced pressure to give the crude product. Silica gel chromatography (4% to 5% ethyl acetate / hexanes) afforded enyne intermediate-42 (269 mg, 76%) as a pale yellow oil. 1 H NMR (400 MHz, CDCl3) δ 7.38 - 7.24 (m , 5H), 5.92 (m, 1H), 4.50 (s, 2H), 4,18 (t, J = 7.1 Hz, 2H), 3.46 (t, J = 6.7 Hz, 2H), 2.43 (t, J = 7.2 Hz, 2H), 2.01 (d, J = 1.4 Hz, 3H) , 1.65 - 1.55 (m, 4H), 1.46 - 1.24 (m, 12H); 13 C NMR (101 MHz, CDCl3) δ 165.4 (C), 138.8 ( C), 135.9 (C), 128.5 (2C;CH), 127.7 (2C;CH), 127.6 (CH), 123.3 (CH), 103.3 (C), 79.9 (C), 73.0 (CH2), 70.6 (CH2), 60.0 (CH2), 29.9 (CH2), 29.65 (CH2), 29.59 (CH2), 29.56 (CH2), 29.2 (CH2), 29.1 (CH2), 28.6 (CH2), 26.3 (CH2), 26.0 (CH3), 20.1 (CH2), 14.4 (CH3). A solution of benzyl ether Intermediate-42 (246 mg, 0.640 mmol) in ethyl acetate (25 mL) in a three-necked round-bottom flask was evacuated and flushed twice with N gas, then palladium on carbon (10% w / w, 102 mg, 0.0960 mmol) was added, and the resulting suspension was evacuated and flushed three times again with N. The flask was fitted with a H balloon, evacuated and flushed three times with H, and the reaction mixture was stirred under 1 atm of H at room temperature for 1 h. The reaction mixture was then filtered through a pad of Celite, and the pad was washed with ethyl acetate (40 mL). The filtrate was concentrated under reduced pressure to afford saturated alcohol Intermediate-43 (192 mg, quantitative) as a colorless oil, which was used without purification. 1 H NMR (400 MHz, CDCl3) δ 4.12 ( q, J = 7.1 Hz, 2H), 3.63 (t, J = 6.6 Hz, 2H), 2.28 (dd, J = 14.6, 6.0 Hz, 1H), 2.08 (dd, J = 14.6, 8.1 Hz, 1H), 1.93 (m, 1H), 1.60 - 1.51 (m, 2H), 1.43 - 1.12 (m, 23H), 0.92 (d, J = 6.6 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 173. 6 (C), 63.2 (CH2), 60.2 (CH2), 42.1 (CH2), 36.9 (CH2), 32.9 (CH2), 30.5 (CH), 29.9 (CH2 ), 29.74 (4C;CH2), 29.70 (CH2), 29.6 (CH2), 27.0 (CH2), 25.9 (CH2), 19.9 (CH3), 14.4 (CH3). Imidazole (32.0 mg, 0.0469 mmol) and tert-butyl(chloro)diphenylsilane (TBDPSCl, 183 μL, 0.704 mmol) were added to a solution of alcohol Intermediate-43 (70.5 mg, 0.235 mmol) in DMF (7 mL), and the mixture was stirred at room temperature for 17 h. The reaction was diluted with ethyl acetate (20 mL), washed with water (20 mL) and brine (2 × 20 mL), dried (MgSO), and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (3%–4% ethyl acetate / hexanes with 0.5% EtN) afforded TBDPS ether Intermediate-44 (117 mg, 93%) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 7.70 - 7.63 (m, 4H), 7.44 - 7.34 (m, 6H), 4.12 (q, J = 7.1 Hz, 2H), 3.65 (t, J = 6.5 Hz, 2H), 2.29 (dd, J = 14.6, 6.0 Hz, 1H), 2.09 (dd, J = 14.6, 8.2 Hz, 1H), 1.95 (m, 1H), 1.60 - 1.50 (m, 2H), 1.38 - 1.14 (m, 23 H), 1.04 (s, J = 2.8 Hz, 9H), 0.92 (d, J = 6.6 Hz, 3H); 13 C NMR (101 MHz, CDCl3) δ 173.5 (C ), 135.7 (4C;CH), 134.3 (2C;C), 129.6 (2C;CH), 127.7 (4C;CH), 64.1 (CH2), 60.2 (CH2), 42.1 (CH2), 36.9 (CH2), 32.7 (CH2), 30.5 (C H), 29.9 (CH2), 29.79 (3C;CH2), 29.77 (2C;CH2), 29.5 (CH2), 27.1 (CH2), 27.0 (3C;CH3), 25.9 (CH2), 19.9 (CH3), 19.4 (C), 14.4 (CH3). A solution of potassium hydroxide (2.0 M, 390 μL, 0.781 mmol) was added to ester Intermediate-44 (42.1 mg, 0.0781 mmol) in ethanol (2 mL), and the mixture was heated at 60° C. for 1.5 h. The reaction was acidified to pH 1 by the addition of 1 M HCl, diluted with water (10 mL), and the aqueous phase was extracted with ethyl acetate (3×15 mL). The combined organic extracts were washed with brine (30 mL), dried (MgSO), and concentrated under reduced pressure to afford crude acid Intermediate-45 (39.9 mg, quantitative) as a colorless oil, which was used without purification. 1 H NMR (400 MHz, CDCl3) δ 7.75 - 7.66 (m, 4H), 7.46 - 7.35 (m, 6H), 3.67 (t, J = 6.5 Hz, 2H), 2.36 (dd, J = 15.0, 5.9 Hz, 1H), 2.15 (dd, J = 14.9, 8.2 Hz, 1H), 1.97 (m, 1H), 1.61 - 1.52 (m, 2H), 1.41 - 1.17 ( m, 20H), 1.06 (s, 9H), 0.98 (d, J = 6.6 Hz, 3 H); 13C NMR (101 MHz, CDCl3) δ 179.7 (C), 135.7 (4C;CH), 134.3 (2C;C), 129.6 (2C;CH), 127.7 (4C;CH), 64.2 (CH2), 41.7 (CH2), 36.8 ( CH2), 32.7 (CH2), 30.3 (CH), 29.9 (CH2), 29 .80 (2C;CH2), 29.78 (2C;CH2), 29.75 (CH2), 29.5 (CH2), 27.1 (CH2), 27.0 (3C;CH3), 25.9 (CH2), 19.8 (CH3), 19.4 (C). 4-(Dimethylamino)pyridine (DMAP, 9.5 mg, 0.0781 mmol), EDC·HCl (29.9 mg, 0.156 mmol), and 1,3-diglyceride intermediate-2 (53.3 mg, 0.0937 mmol) were added to a solution of acid intermediate-45 (39.9 mg, 0.0781 mmol) in CHCl (2.5 mL), and the mixture was stirred at room temperature for 19 h. The reaction was diluted with CHCl (5 mL), silica gel was added, and the mixture was concentrated under reduced pressure. Purification by silica gel chromatography (4%–5% ethyl acetate / hexane) afforded triglyceride intermediate-46 (72.8 mg, 88% over two steps) as a colorless solid. 1 H NMR (400 MHz, CDCl3) δ 7.73 - 7.63 (m, 4H), 7.49 - 7.31 (m, 6H), 5.29 (m, 1H), 4.30 (dd, J = 11.9, 4.2 Hz, 2H), 4.15 (dd, J = 11.9, 6.1 Hz, 2H), 3.66 (t, J = 6.5 Hz, 2H), 2.34 (dd, J = 14.6, 6.0 Hz, 1H ), 2.31 (t, J = 7.5 Hz, 4H), 2.13 (dd, J = 14.6, 8.3 Hz, 1H), 1.94 (m, 1H), 1.68 - 1.52 (m, 6H), 1.44 - 1.16 (m, 68H), 1.05 (s, 9H), 0.94 (d, J = 6.6 Hz, 3H), 0.88 (t, J = 6.8 Hz, 6H ); 13 C NMR (101 MHz, CDCl3) δ 173.4 (2C;C), 172.5 (C), 135.7 (4C;CH), 134.3 (2C;C), 129.6 (2C;CH), 127.7 (4C;CH), 68.9 (CH), 64.1 ( CH2), 62.3 (2C;CH2), 41.8 (CH2), 36.8 (CH2), 34.2 (2C;CH2), 32.7 (CH2), 32.1 (2C;CH2), 30.5 (CH), 30.0 (CH2), 29.84 (8C;CH2), 29. 80 (6C;CH2), 29.76 (2C;CH2), 29.61 (2C;CH2 ), 29.54 (CH2), 29.50 (3C;CH2), 29.4 (2C;CH2), 29.3 (2C;CH2), 27.2 (CH2), 27.0 (3C;CH3), 25.9 (CH2), 25.0 (2C;CH2), 22.8 (2C;CH2), 19.7 (CH3), 19.3 (C), 14.3 (2C;CH3). Tetrabutylammonium fluoride (TBAF, 1.0 M in THF, 186 μL, 0.186 mmol) and acetic acid (10.6 μL, 0.186 mmol) were dissolved in THF (3 mL). To the TBDPS ether Intermediate-46 (65.7 mg, 0.0619 mmol) in HCl was added dropwise at 0 °C, and the mixture was stirred at room temperature for 19 h. The reaction was diluted with water (10 mL), and the aqueous phase was extracted with ethyl acetate (3 × 15 mL). The combined organic extracts were washed with saturated aqueous NaHCO and brine (30 mL each), dried (MgSO), and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (10% to 15% ethyl acetate / hexanes) gave the alcohol Intermediate-47 (34.2 mg, 67%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 5.27 (m , 1H), 4.28 (dd, J = 11.9, 4.3 Hz, 2H), 4.14 (dd, J = 11.8, 6.0 Hz, 2H), 3.63 (t, J = 6.6 Hz, 2H), 2.32 (dd, J = 14.6, 5.9 Hz, 1H), 2.30 (t, J = 7.6 Hz, 4H), 2.11 (dd, J = 14.6, 8.3 Hz, 1H), 1.92 (m, 1H), 1.66 - 1.52 (m, 6H), 1.40 - 1.13 (m, 68H), 0.92 (d, J = 6.6 Hz, 3H) , 0.87 (t, J = 6.9 Hz, 6H); 13 C NMR (101 MHz, CDCl3) δ 173.5 (2C;C), 172.5 (C), 68.9 (CH) , 63.2 (CH2), 62.3 (2C;CH2), 41.8 (CH2), 36 .8 (CH2), 34.2 (2C;CH2), 32.9 (CH2), 32.1 ( 2C;CH2), 30.5 (CH), 29.9 (CH2), 29.84 (8C;CH2), 29.80 (6C;CH2), 29.76 (2C;CH2), 29.73 (CH2), 29.62 (2C;CH2), 29.57 (CH2), 29.5 (2C;CH2), 29.4 (2C;CH2), 29.3 (2C;CH2), 27.1 (CH2), 25.9 (CH2), 25.0 (2C;CH2), 22.8 (2C;CH2), 19.7 (CH3), 14.3 (2C;CH3). Pyridinium chlorochromate (PCC, 14.7 mg, 68.0 μmol) was added to a suspension of alcohol Intermediate-47 (28.0 mg, 34.0 μmol) and Celite (15 mg) in CHCl (1.5 mL) at 0° C., and the mixture was stirred at room temperature for 1 h. The reaction was filtered through a short pad of silica gel eluted with ethyl acetate, and the filtrate was concentrated under reduced pressure to give crude aldehyde Intermediate-48 (27.9 mg, quantitative) as a yellow oil, which was used without purification. 1 H NMR (400 MHz, CDCl3) δ 9.76 (s, 1H), 5.28 (m, 1H), 4.29 (dd, J = 11.6, 3.5 Hz, 2H), 4.14 (dd, J = 11.9, 5.8 Hz, 2H) , 2.42 (t, J = 6.8 Hz, 2H), 2.36 - 2.25 (m, 5H), 2.12 (dd, J = 14.4, 8.5 Hz, 1H), 1.94 (m, 1H), 1.69 - 1.51 (m, 6H), 1.42 - 1.09 (m, 66H), 0.93 (d, J = 6.4 Hz, 3H), 0.88 (t, J = 6.3 Hz, 6H). A solution of sodium chlorite (27.6 mg, 0.306 mmol) and sodium phosphate monobasic (NaHPO, 28.8 mg, 0.238 mmol) in water (1.2 mL) was added dropwise to aldehyde Intermediate-48 (27.9 mg, 0.0340 mmol) in t-BuOH (1.8 mL) and 2,3-dimethyl-2-butene (0.4 mL), and the reaction was stirred at room temperature for 16 hours. The reaction was acidified to pH 2 using 1 M HCl, diluted with water (10 mL), and the aqueous layer was extracted with ethyl acetate (3 × 15 mL). The combined organic extracts were washed with brine (30 mL), dried (MgSO), and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (10%-15% ethyl acetate / hexanes with 0.5% acetic acid) afforded acid intermediate-49 (24.3 mg, 85%) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 5.29 (m, 1H), 4.29 (dd, J = 11.9, 3.8 Hz, 2H), 4 .14 ​​(dd, J = 11.9, 6.1 Hz, 2H), 2.37 - 2.27 ( m, 7H), 2.11 (dd, J = 14.7, 8.3 Hz, 1H), 1.92 (m, 1H), 1.68 - 1.54 (m, 6H), 1.40 - 1.13 (m , 66H), 0.93 (d, J = 6.6 Hz, 3H), 0.87 (t, J = 6.8 Hz, 6H); 13 C NMR (101 MHz, CDCl3) δ 179. 5 (C), 173.5 (2C;C), 172.5 (C), 68.9 (CH), 62.3 (2C;CH2), 41.9 (CH2), 36.8 (CH2), 34.2 (2C;CH2), 34.1 (CH2), 32.1 (2C;CH2), 30.5 (CH), 29.93 (CH2), 29.85 (8C;CH2), 29.81 (4C;CH2), 29.77 (2C;CH2), 29.73 (CH2), 29.62 (2C;CH2), 29.58 (CH2), 29.51 (2C;CH2), 29.4 2 (2C;CH2), 29.39 (CH2), 29.26 (2C;CH2), 29.2 (CH2), 27.1 (CH2), 25.0 (2C;CH2), 24.8 ( CH2), 22.8 (2C;CH2), 19.7 (CH2), 14.3 (2C;CH2). Using a similar method, Intermediate-118 was prepared from 1,8-octanediol.

[0412] [ka]

[0413] 1 1H NMR (400 MHz, CDCl3) δ 5.31 (s, 1H), 4.3 3 (dd, J = 8.4, 4.4 Hz, 2H), 4.19 (dd, J = 11.8, 5.9 Hz, 2H), 2.47 (m, 1H), 2.37 (dt, J = 1 5.6, 7.4 Hz, 6H), 1.65 (s, 7H), 1.31 (d, J = 13.3 Hz, 58H), 1.18 (d, J = 6.9 Hz, 3H), 0.92 (t, J = 6.6 Hz, 6H); 13 13C NMR (101MHz, CDCl3) δ 179.73 (1C), 175.87 (1C), 173.31 (2C), 68 .70 (1C), 62.13 (1C), 39.50 (1C), 34.04 (3C ), 33.57(1C), 31.93 (4C), 29.71-29.01 (18C ), 27.07 (1C), 24.85 (3C), 24.62 (1C), 22.7 0 (4C), 17.03 (1C), 14.14 (3C). MASS (ESI, -ve) m / z: 766.0 (M-1). (ESI, +ve) m / z: 785.0 (M+18). C15α'βMe-acid-2-TG (intermediate-62):

[0414]

Chem.

[0415] Intermediate-50: Prepared according to Subba Reddy, B.V. et al. Helv. Chim. Acta. 2013, 96, 1983-1990.

[0416] Intermediate-51: A known compound that can be prepared as disclosed in Takagi, Y. et al. Tetrahedron: Asymm. 2004, 15, 2591-2594. 1 H NMR (401 MHz, CDCl3) δ 7.39 - 7.23 (m , 5H), 4.50 (s, 2H), 3.47 (t, J = 6.6 Hz, 2H) , 3.40 (t, J = 6.9 Hz, 2H), 1.90 - 1.80 (m, 2H), 1.66 - 1.57 (m, 2H), 1.48 - 1.26 (m, 8H). n-Butyllithium (n-BuLi, 2.0 M in cyclohexane, 18.1 mL, 36.3 mmol) was slowly added to a solution of TMS-acetylene (5.7 mL, 41.5 mmol) in THF (45 mL) at −78°C, and the mixture was stirred at −78°C for 5 min, then warmed to room temperature and stirred for an additional 15 min. The reaction was recooled to −78°C, and a solution of bromide Intermediate-51 (3.10 g, 10.4 mmol) and DMPU (6.3 mL, 51.8 mmol) in THF (30 mL) was slowly added, and the mixture was stirred at −78°C for 30 min and then at room temperature for 18 h. The reaction was diluted with water (60 mL), and most of the organic solvent was removed under reduced pressure. The residue was diluted with brine (120 mL), and the aqueous phase was washed with ethyl acetate. The resulting mixture was extracted with hexane (3 × 100 mL). The combined organic extracts were washed with brine (3 × 100 mL), dried (MgSO), and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (Reveleris 80 g column, 60 mL / min, 4% to 40% ethyl acetate / hexane) gave TMS alkyne intermediate-52 (3.05 g, 93%) as a colorless oil. 1 H NMR (401 MHz, CDCl3) δ 7.36 - 7.25 (m, 5H), 4.50 (s, 2H), 3.46 (t, J = 6.6 Hz, 2H), 2.21 (t, J = 7.2 Hz, 2H), 1. 65 - 1.57 (m, 2H), 1.55 - 1.46 (m, 2H), 1.41 - 1.27 (m, 8H), 0.15 (s, 9H). Tetrabutylammonium fluoride (TBAF, 1.0 M in THF, 9.7 mL, 9.70 mmol) was added dropwise to silylalkyne Intermediate-52 (3.05 g, 9.62 mmol) in THF (40 mL) at 0 °C, and the mixture was stirred at room temperature for 1 h. The reaction was diluted with water (25 mL), and the organic solvent was removed under reduced pressure. The resulting solution was diluted with brine (100 mL), and the aqueous phase was extracted with ethyl acetate (3 × 50 mL). The combined organic extracts were washed with brine (3 × 50 mL), dried (MgSO), and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (Reveleris 80 g column, 60 mL / min, 3% to 10% ethyl acetate / hexanes) gave alkyne Intermediate-53 (2.17 g, 92%). 1 H NMR (401 MHz, CDCl3) δ 7.38 - 7.25 (m, 5H), 4.50 (s, 2H), 3.46 (t, J = 6.6 Hz, 2H), 2.18 (td, J = 7.1, 2.6 Hz, 2H), 1.94 (t, J = 2.7 Hz, 1H), 1.66 - 1.56 (m, 2H), 1.57 - 1.48 (m, 2H), 1.43 - 1.27 (m, 8H); 13 C NMR (101 MHz, CDCl3) δ 138.8 (C), 128.4 (2C;CH), 127.7 (2C;CH), 127.6 (CH), 84.8 (C), 73.0 (CH), 70.6 (CH2), 68.2 (CH), 29.8 (CH2), 29.4 (CH2), 29.1 (CH2), 28.8 (CH2) , 28.6 (CH2), 26.2 (CH2), 18.5 (CH2). Intermediate-17 was prepared as described above.

[0417] A suspension of PdCl(PPh) (605 mg, 0.862 mmol) in DMF (40 mL) was degassed using N gas for 5 min, then a degassed solution of CuI (335 mg, 1.76 mmol), EtN (2.40 μL, 17.2 mmol), and alkyne 4 (2.11 g, 8.62 mmol), and enol triflate intermediate-17 (3.40 g, 13.00 mmol) in DMF (50 mL) was added. The mixture was degassed for an additional 5 min using a stream of N and then heated at 70 °C for 1 h. The reaction was cooled to room temperature and concentrated under reduced pressure to approximately one-quarter of its original volume. The resulting solution was diluted with ethyl acetate (80 mL), washed with 1 M HCl, saturated aqueous NaHCO, water, and brine (30 mL each), dried (MgSO), and concentrated under reduced pressure to give the crude product. Silica gel chromatography (Reveleris 80 g column, 60 mL / min, 5% to 20% ethyl acetate / hexanes) afforded enyne intermediate-54 (2.35 g, 76%) as a pale yellow oil. 1 H NMR (401 MHz, CDCl3) δ 7.37 - 7.24 (m, 5H), 5.92 (d, J = 1.4 Hz, 1H), 4.50 (s , 2H), 4.18 (q, J = 7.1 Hz, 2H), 3.46 (t, J = 6.6 Hz, 2H), 2.43 (t, J = 7.2 Hz, 2H), 2.01 ( d, J = 1.4 Hz, 3H), 1.65 - 1.55 (m, 4H), 1.46 - 1.30 (m, 8H), 1.28 (t, J = 7.1 Hz, 3H); 13 C NMR (101 MHz, CDCl3) δ 165.4 (C), 138.8 (C), 135.9 (C), 128.5 (2C;CH), 127.7 (2C;CH), 1 27.6 (CH), 123.4 (CH), 103.2 (C), 79.9 (C), 73.0 (CH2), 70.6 (CH2), 60.0 (CH2), 29.9 (C H2), 29.4 (CH2), 29.2 (CH2), 29.0 (CH2), 28 .6 (CH2), 26.3 (CH2), 26.0 (CH3), 20.1 (CH2 ), 14.4 (CH3). A solution of benzyl ether Intermediate-54 (707 mg, 1.98 mmol) in ethyl acetate (80 mL) in a three-necked round-bottom flask was evacuated and flushed twice with N gas, then palladium on carbon (10% w / w, 525 mg, 0.494 mmol) was added, and the resulting suspension was evacuated and flushed three times again with N. The flask was fitted with a H balloon and evacuated and flushed three times with H, and the reaction mixture was stirred under 1 atm of H at room temperature for 2 h. The flask was then evacuated and flushed with N, and the reaction mixture was filtered through a pad of Celite, washing with ethyl acetate (80 mL). The filtrate was concentrated under reduced pressure to afford saturated alcohol Intermediate-55 (540 mg, quantitative) as a colorless oil, which was used without purification. 1 H NMR (401 MHz, CDCl3) δ 4.13 (q, J = 7.1 Hz, 2H), 3.64 (t, J = 6.6 Hz, 2H), 2.28 (dd, J = 14.6, 6.0 Hz, 1H), 2.09 (dd, J = 14.6, 8.1 Hz, 1H), 1.94 (m, 1H), 1.62 - 1.51 (m, 2H), 1.39 - 1.21 (m , 16H), 1.25 (t, J = 7.1 Hz, 3H), 0.93 (d, J = 6.6 Hz, 3H). Imidazole (670 mg, 9.85 mmol) and tert-butyl(chloro)diphenylsilane (TBDPSCl, 3.5 mL, 13.6 mmol) were added to a solution of alcohol Intermediate-55 (1.48 g, 5.42 mmol) in CHCl (80 mL) at 0 °C, and the mixture was stirred at room temperature for 2.5 h. The reaction was concentrated to half its volume under reduced pressure, washed with water (2 × 20 mL) and brine (30 mL), dried (MgSO), and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (Reveleris 80 g column, 60 mL / min, 1% to 16% ethyl acetate / hexanes) gave TBDPS ether Intermediate-56 (2.46 g, 89%) as a colorless oil. 1 H NMR (401 MHz, CDCl3) δ 7.75 - 7.64 (m, 4H), 7.46 - 7.35 (m, 6H), 4.13 (q, J = 7.1 Hz, 2H), 3.65 (t, J = 6.5 Hz, 2H), 2.29 (dd, J = 14.6, 6.0 Hz, 1H), 2.09 (dd, J = 14.6, 8.2 Hz, 1H), 1.95 (m, 1H), 1.61 - 1.50 (m, 2H), 1.38 - 1.20 (m, 19H), 1.05 (s, 9H), 0.93 (d, J = 6.6 Hz, 3H). A solution of potassium hydroxide (2.0 M, 11.3 mL, 22.6 mmol) was added to ester Intermediate-56 (1.15 g, 2.26 mmol) in ethanol (40 mL), and the mixture was stirred at room temperature for 19 h. The reaction was adjusted to pH 2 by the addition of 1 M HCl, and the organic solvent was removed under reduced pressure. The residue was diluted with water (15 mL), and the aqueous phase was extracted with ethyl acetate (3 × 20 mL). The combined organic extracts were washed with brine (30 mL), dried (MgSO), and concentrated under reduced pressure to give the crude product. Silica gel chromatography (5% to 25% ethyl acetate / hexanes) afforded a pure sample of acid Intermediate-57 (321 mg, 29%) as a pale yellow oil, which was used for analytical purposes. An additional 750 mg of 9 was obtained containing a slight contamination of an unknown TBDPS species; this material was carried forward to a later stage in the reaction sequence for purification. 1 H NMR (401 MHz, CDCl3) δ 7.70 - 7.64 (m, 4H), 7.44 - 7 .34 (m, 6H), 3.65 (t, J = 6.5 Hz, 2H), 2.35 ( dd, J = 15.0, 5.9 Hz, 1H), 2.14 (dd, J = 15.0 , 8.2 Hz, 1H), 1.95 (m, 1H), 1.60 - 1.51 (m, 2H), 1.39 - 1.16 (m, 16H), 1.04 (s, 9H), 0.9 6 (d, J = 6.6 Hz, 3H); 13 C NMR (101 MHz, CDCl3) δ 179.3 (C), 135.7 (4C;CH), 134.4 (2C;C), 129.6 (2C;CH), 127.7 (4C;CH), 64.2 (CH2), 41.7 (CH2), 36.8 (CH2), 32.7 (CH2), 30.3 (CH ), 29.9 (CH2), 29.76 (2C;CH2), 29.72 (CH2), 29.5 (CH2), 27.1 (CH2), 27.0 (3C;CH3), 25. 9 (CH2), 19.8 (CH3), 19.4 (C). DMAP (80.8 mg, 0.661 mmol), EDC·HCl (230 mg, 1.20 mmol), and 1,3-diglyceride intermediate-2 (374 mg, 0.658 mmol) were added to a solution of acid intermediate-57 (288 mg, 0.597 mmol) in CHCl (20 mL), and the mixture was stirred at room temperature for 20 h. The reaction was diluted with CHCl (20 mL), silica gel was added, and the mixture was concentrated under reduced pressure. Purification by silica gel chromatography (5% to 8% ethyl acetate / hexane) afforded triglyceride intermediate-58 (416 mg, 67%) as a colorless solid. 1 H NMR (401 M H z, CDCl3) δ 7.69 - 7.64 (m, 4H), 7.44 - 7.34 (m, 6H), 5.28 (m, 1H), 4.289 / 4.288 (each dd , J = 11.9, 4.3 Hz, 2H), 4.14 (dd, J = 12.0, 6.0 Hz, 2H), 3.65 (t, J = 6.5 Hz, 2H), 2.34 (d d, J = 15.0, 5.9 Hz, 1H), 2.30 (t, J = 7.5 Hz, 4H), 2.12 (dd, J = 14.6, 8.3 Hz, 1H), 1.93 ( m, 1H), 1.66 - 1.50 (m, 6H), 1.45 - 1.14 (m, 64H), 1.04 (s, 9H), 0.93 (d, J = 6.6 Hz, 3H), 0.88 (t, J = 6.6 Hz, 6H). Tetrabutylammonium fluoride (TBAF, 1.0 M in THF, 574 μL, 0.574 mmol) and acetic acid (32.8 μL, 0.574 mmol) were added to a solution of TBDPS ether Intermediate-58 (395 mg, 0.383 mmol) in THF (15 mL) at 0 °C, and the mixture was stirred at room temperature for 17 h. The reaction was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (30 mL), washed with water (2 × 20 mL) and brine (30 mL), dried (MgSO), and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (5% to 25% ethyl acetate / hexanes) afforded alcohol Intermediate-59 (282 mg, 93%) as a colorless solid. 1 H NMR (401 M Hz, CDCl3) δ 5.28 (m, 1H), 4.286 / 4.285 (eac h dd, J = 11.8, 4.2 Hz, 2H), 4.14 (dd, J = 11.9, 5.7 Hz, 2H), 3.63 (t, J = 6.6 Hz, 2H), 2.3 3 (dd, J = 15.0, 5.9 Hz, 1H), 2.30 (t, J = 7.5 Hz, 4H), 2.12 (dd, J = 14.7, 8.3 Hz, 1H), 1. 93 (m, 1H), 1.68 - 1.52 (m, 6H), 1.49 - 1.15 (m, 64H), 0.93 (d, J = 6.6 Hz, 3H), 0.88 (t, J = 6.6 Hz, 6H); 13 C NMR (101 MHz, CDCl3) δ 173.5 (2C;C), 172.5 (C), 69.0 (CH), 63.2 (CH2 ), 62.3 (2C;CH2), 41.9 (CH2), 36.8 (CH2), 3 4.2 (2C;CH2), 33.0 (CH2), 32.1 (2C;CH2), 30.5 (CH), 29.9 (CH2), 29.84 (6C;CH2), 29.81 (4C;CH2), 29.77 (2C;CH2), 29.74 (CH2), 29. 71 (CH2), 29.62 (2C;CH2), 29.57 (CH2), 29.5 (2C;CH2), 29.4 (2C;CH2), 29.3 (3C;CH2), 27.1 (CH2), 25.9 (CH2), 25.0 (2C;CH2), 22.8 ( 2C;CH2), 19.7 (CH3), 14.3 (2C;CH3). Pyridinium chlorochromate (PCC, 143 mg, 0.664 mmol) was added to a suspension of alcohol Intermediate-59 (263 mg, 0.331 mmol) and Celite (150 mg) in CHCl (18 mL) at 0° C., and the mixture was stirred at room temperature for 4 h. The reaction was filtered through a short pad of silica gel, eluting with ethyl acetate, and the filtrate was evaporated under reduced pressure. Concentration at rt gave crude aldehyde Intermediate-60 (262 mg, quantitative) as a yellow oil which was used without purification. 1 H NMR (401 MHz, CDCl3) δ 9.76 (t, J = 1.8 Hz, 1H), 5.27 (m, 1H), 4.29 (dd , J = 11.8, 4.1 Hz, 2H), 4.14 (dd, J = 11.8, 6.0 Hz, 2H), 2.42 (td, J = 7.4, 1.8 Hz, 2H), 2 .33 (dd, J = 15.0, 5.9 Hz, 1H), 2.30 (t, J = 7.5 Hz, 4H), 2.12 (dd, J = 14.7, 8.3 Hz, 1H), 1.93 (m, 1H), 1.69 - 1.53 (m, 6H), 1.45 - 1.16 (m, 62H), 0.93 (d, J = 6.6 Hz, 3H), 0.88 (t , J = 6.8 Hz, 6H). Intermediate-25 was prepared as described above.

[0418] A solution of ylide intermediate-25 (270 mg, 0.637 mmol) in toluene (10 mL) was added to aldehyde intermediate-60 (262 mg, 0.331 mmol) in toluene (8 mL), and the mixture was heated to reflux for 20 h. The reaction was cooled to room temperature and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (5% to 15% ethyl acetate / hexanes) gave α,β-unsaturated benzyl ester intermediate-61 (273 mg, 88%) as a yellow oil. 1 H NMR (401 MHz, CDCl3) δ 7.40 - 7.27 (m, 5H), 6.82 (td, J = 7.5, 1.4 Hz, 1H), 5.28 (m, 1H), 5.18 (s, 2H), 4.29 (dd, J = 11.9, 4.3 Hz, 2H), 4.14 (dd, J = 11.9, 6.0 Hz, 2H), 2.33 (dd, J = 15.0, 5.9 Hz, 1H), 2.30 (t, J = 7.5 Hz, 4H), 2.20 - 2.07 (m, 3H), 1.92 (m, 1H), 1.85 (d, J = 1.2 Hz, 3H), 1.65 - 1.53 (m, 4H), 1.47 - 1.37 (m, 2H), 1.36 - 1.14 (m, 62H), 0.93 (d, J = 6.6 Hz, 3H), 0.88 (t, J = 6.9 Hz, 6H); 13 C NMR (101 MHz, CDCl3) δ 173.4 (2C;C), 172.5 (C), 168.2 (C), 143.3 (CH ), 136.6 (C), 128.6 (2C;CH), 128.13 (CH), 1 28.11 (2C;CH), 127.5 (C), 68.9 (CH), 66.3 ( CH2), 62.3 (2C;CH2), 41.8 (CH2), 36.8 (CH2), 34.2 (2C;CH2), 32.1 (2C;CH2), 30.5 (CH), 29.9 (CH2), 29.84 (6C;CH2), 29.80 (4C;CH2) , 29.76 (2C;CH2), 29.70 (CH2), 29.61 (3C;CH2), 29.57 (CH2), 29.5 (2C;CH2), 29.4 (2C;CH2), 29.3 (3C;CH2), 28.9 (CH2), 28.7 (CH2), 27.1 (CH2), 25.0 (2C;CH2), 22.8 (2C;CH2), 19.7 (CH3), 14.3 (2C;CH3), 12.5 (CH3). A solution of benzyl ester Intermediate-61 (246 mg, 0.262 mmol) in ethyl acetate (10 mL) in a two-neck flask was evacuated and flushed with N gas (three times each). Palladium on carbon (10% w / w, 55.7 mg, 0.0524 mmol) was then added, and the resulting suspension was evacuated and flushed with N again (three times each). The flask was fitted with a H balloon, evacuated and flushed with H (three times each), and the reaction mixture was stirred under 1 atm of H at room temperature for 1.5 h. The reaction was filtered through a pad of Celite, washed with ethyl acetate, and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (5% to 20% ethyl acetate / hexanes) afforded the saturated acid Intermediate-62 (193 mg, 87%) as a colorless solid. 1 H NMR (401 MHz, CDCl3) δ 5.28 (m, 1H), 4.291 / 4.28 9 (each dd, J = 11.8, 4.2 Hz, 2H), 4.147 / 4.1 44 (each dd, J = 11.9, 6.0 Hz, 2H), 2.46 (m, 1H), 2.33 (dd, J = 15.0, 5.9 Hz, 1H), 2.31 (t, J = 7.5 Hz, 4H), 2.12 (dd, J = 14.7, 8.2 Hz, 1H), 1.94 (m, 1H), 1.73 - 1.55 (m, 5H), 1.50 - 1.21 (m, 67H), 1.18 (d, J = 7.0 Hz, 3H), 0.93 (d, J = 6.6 Hz, 3H), 0.88 (t, J = 6.9 Hz, 6 H). Ph-C3-phenol-2-TG (Intermediate-67):

[0419] [ka]

[0420] DBU (108 μL, 1.08 mmol) and t-butyldiphenylsilyl chloride (TBDPSCl, 338 μL, 1.30 mmol) were added to a solution of (4-hydroxyphenyl)propionic acid (Intermediate-63; commercially available) (120 mg, 0.722 mmol) in DMF (4 mL), and the mixture was stirred at room temperature for 1 h. The reaction was diluted with ethyl acetate (15 mL), and the organic phase was washed with water and brine (15 mL each), dried (MgSO), and concentrated under reduced pressure to give the crude product. Silica gel chromatography (4.5% ethyl acetate / hexane) afforded the silyl ester Intermediate-64 (165 mg, 36%) as a colorless oil. 1 H NMR (400 MHz, CDCl): δ 7.75 - 7.70 (m, 4H), 7.63 - 7.58 (m, 4H), 7 .46 - 7.31 (m, 12H), 6.97 - 6.91 (m, 2H), 6.71 - 6.67 (m, 2H), 2.87 (t, J = 7.6 Hz, 2H), 2.72 (t, J = 7.6 Hz, 2H), 1.11 (s, 9H), 1.07 (s , 9H); 13 C NMR (101 MHz, CDCl3): δ 172.3 (C), 154.1 (C), 135.7 (4C;CH), 135.4 (4C;CH), 1 33.2 (2C;C), 133.0 (C), 132.0 (2C;C), 130.1 (2C;CH), 130.0 (2C;CH), 129.2 (2C;CH), 127.9 (4C;CH), 127.8 (4C;CH), 119.7 (2C;CH), 37.9 (CH2), 30.4 (CH2), 27.0 (3C;CH3), 26.7 (3C;CH3), 19.6 (C), 19.2 (C). Potassium carbonate (157 mg, 1.14 mmol) was dissolved in THF (3 mL), methanol ( To a solution of TBDPS ester Intermediate-64 (147 mg, 0.228 mmol) in water (1.5 mL) and water (1.5 mmol) was added, and the mixture was stirred at room temperature for 2.5 h. The reaction was acidified to pH 2 by the addition of 1 M HCl, and the aqueous layer was extracted with ethyl acetate (3 × 15 mL). The combined organic extracts were washed with water (30 mL), saturated aqueous NaHCO (30 mL), and brine (30 mL), dried (MgSO), and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (20% to 35% to 50% ethyl acetate / hexanes) gave acid Intermediate-65 (82.4 mg, 89%) as a colorless solid. 1 H NMR (400 MHz, CDCl3) δ 7.74 - 7.67 (m, 4H), 7.45 - 7.32 (m, 6H), 6.95 - 6.88 ( m, 2H), 6.71 - 6.65 (m, 2H), 2.82 (t, J = 7.8 Hz, 2H), 2.58 (t, J = 7.8 Hz, 2H), 1.09 (s, 9 H); 13 C NMR (101 MHz, CDCl3): δ 179.2 (C), 154.3 (C), 135.7 (4C;CH), 133.1 (2C;C), 132.7 (C), 130.0 (2C;CH), 129.1 (2C;CH), 127.9 ( 4C;CH), 119.8 (2C;CH), 35.9 (CH2), 29.9 (CH2), 26.7 (3C;CH3), 19.6 (C). DMAP (8.2 mg, 0.0667 mmol), EDC·HCl (25.6 mg, 0.133 mmol), and 1,3-diglyceride intermediate-2 (41.7 mg, 0.0734 mmol) were added to a solution of acid intermediate-65 (27.0 mg, 0.0666 mmol) in CHCl (2 mL), and the mixture was stirred at room temperature for 19 h. The reaction was diluted with CHCl (3 mL), silica gel was added, and the mixture was concentrated under reduced pressure. Purification by silica gel chromatography (5% to 7.5% ethyl acetate / hexane) afforded triglyceride intermediate-66 (54.4 mg, 85%) as a colorless solid. 1 H NMR (400 MHz, CDCl3) δ 7.74 - 7.66 (m, 4H), 7.45 - 7.33 (m, 6H), 6.94 - 6.87 (m, 2H), 6.71 - 6 .64 (m, 2H), 5.24 (m, 1H), 4.25 (dd, J = 11.9, 4.3 Hz, 2H), 4.11 (dd, J = 11.9, 5.9 Hz, 2H ), 2.81 (t, J = 7.8 Hz, 2H), 2.60 - 2.51 (m, 2H), 2.28 (t, J = 7.5 Hz, 4H), 1.64 - 1.56 (m, 4H), 1.35 - 1.20 (m, 48H), 1.09 (s, 9H), 0.8 8 (t, J = 6.8 Hz, 6H); 13 C NMR (101 MHz, CDCl3) δ 173.4 (2C;C), 172.2 (C), 154.2 (C), 135.7 (4C;CH), 133.1 (2C;C), 132.7 (C), 130.0 ( 2C;CH), 129.1 (2C;CH), 127.9 (4C;CH), 119. 8 (2C;CH), 69.2 (CH), 62.1 (2C;CH2), 36.0 ( CH2), 34.2 (2C;CH2), 32.1 (2C;CH2), 30.1 (CH2), 29.85 (2C;CH2), 29.81 (2C;CH2), 29.76 (2C;CH2), 29.6 (2C;CH2), 29.5 (2C;CH2), 29 .4 (2C;CH2), 29.3 (2C;CH2), 26.7 (3C;CH3), 25.0 (2C;CH2), 22.8 (2C;CH2), 19.6 (C), 14.3 (2C;CH3). Acetic acid (6.5 μL, 0.114 mmol) and tetrabutylammonium fluoride (TBAF, 1.0 M in THF, 114 μL, 0.114 mmol) were added to a solution of TBDPS ether Intermediate-66 (54.5 mg, 0.0570 mmol) in THF (1.2 mL) at 0 °C, and the mixture was stirred at room temperature for 30 min. The reaction was diluted with water (10 mL), and the aqueous layer was extracted with ethyl acetate (3 × 10 mL). The combined organic extracts were washed with saturated aqueous NaHCO (20 mL) and brine (20 mL), dried (MgSO), and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (10% to 15% ethyl acetate / hexanes) afforded phenol Intermediate-67 (37.0 mg, 90%) as a colorless solid. 1 H NMR (400 MHz, CDCl3) δ 7.09 - 7.03 (m, 2H), 6.78 - 6.72 (m, 2H), 5.25 (m, 1H), 4.62 (s, 1H), 4.25 (dd, J = 11.9, 4.4 Hz, 2H), 4.11 (dd, J = 11.9, 5.8 Hz, 2H), 2.88 (t, J = 7.7 Hz, 2H), 2.61 (t, J = 7.7 Hz , 2H), 2.29 (t, J = 7.6 Hz, 4H), 1.64 - 1.56 (m, 4H), 1.34 - 1.18 (m, 48H), 0.88 (t, J = 6. 9 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 173.6 ( 2C;C), 172.3 (C), 154.4 (C), 132.3 (C), 129 .5 (2C;CH), 115.5 (2C;CH), 69.2 (CH), 62.2 (2C;CH2), 36.2 (CH2), 34.2 (2C;CH2), 32.1 (2C;CH2), 30.2 (CH2), 29.83 (6C;CH2), 29.79 (4C;CH2), 29.76 (2C;CH2), 29.6 (2C;CH2), 2 9.5 (2C;CH2), 29.4 (2C;CH2), 29.2 (2C;CH2) , 25.0 (2C;CH2), 22.8 (2C;CH2), 14.3 (2C;CH3). C6-ET-alcohol-2-TG (Intermediate-73):

[0421] [ka]

[0422] Intermediate-69 is a known compound that can be prepared, for example, as described in Sang-sup, J. et al. Tetrahedron: Asymmetry 1997, 8, 1187-1192.

[0423] Alcohol Intermediate-68 (commercially available; 90.0 mg, 0.499 mmol) was added in a single portion to a suspension of t-BuOK (84.1 mg, 0.749 mmol) in THF (2 mL), and the mixture was stirred at room temperature for 1 h. A solution of bromide Intermediate-69 (190 mg, 0.699 mmol) in THF (1 mL) and TBAI (36.9 mg, 0.100 mmol) was then added, and the resulting mixture was heated to reflux for 20 h. The reaction was cooled to room temperature, diluted with ethyl acetate (10 mL), quenched with water (15 mL), and the aqueous phase was extracted with ethyl acetate (3 × 20 mL). The combined organic extracts were washed with water and brine (50 mL each), dried (MgSO), and concentrated under reduced pressure to give the crude product. Silica gel chromatography (5-15%-25% ethyl acetate / hexane) gave a sample of the semi-pure product, which was resubjected to column chromatography (5%-12.5% ​​ethyl acetate / toluene) to isolate the ether-linked glycerol intermediate. -70 (48.0 mg, 26%) was obtained as a colorless oil. 1 H NMR (400 MHz , CDCl3): δ 7.54 - 7.49 (m, 2H), 7.39 - 7.26 (m, 8H), 5.55 (s, 1H), 4.50 (s, 2H), 4.33 (d d, J = 12.5, 1.4 Hz, 2H), 4.07 - 4.01 (m, 2H) , 3.55 (t, J = 6.7 Hz, 2H), 3.47 (t, J = 6.6 H z, 2H), 3.25 (m, 1H), 1.71 - 1.59 (m, 4H), 1.45 - 1.39 (m, 4H). A mixture of benzylidene acetal Intermediate-70 (46.0 mg, 0.124 mmol), concentrated HCl (2 drops), and MeOH (1.5 mL) was heated to reflux for 2 h and then cooled to room temperature. The reaction was diluted with ethyl acetate (30 mL) and water (10 mL), and the organic phase was washed with saturated aqueous NaHCO, water, and brine (30 mL each), dried (MgSO), and concentrated under reduced pressure to give the crude product. Silica gel chromatography (40% to 80% ethyl acetate / hexanes) afforded diol Intermediate-71 (23.5 mg, 67%) as a colorless oil. 1 H NMR (400 MHz, CDCl3): δ 7.36 - 7.27 (m, 5H), 4.50 (s, 2H), 3.76 (dd, J = 11.6, 4.4 Hz, 2H), 3.67 (dd, J = 11.6, 5.1 Hz, 2H), 3.57 (t, J = 6.6 Hz, 2H), 3.50 - 3.42 (m, 3H), 1.67 - 1.56 (m, 4H), 1.43 - 1.36 (m, 4 H). A solution of freshly prepared palmitoyl chloride (91.6 mg, 0.333 mmol) in CHCl (1.5 mL) and pyridine (30.3 μL, 0.375 mmol) was added to diol Intermediate-71 (23.5 mg, 0.0833 mmol), and the reaction was stirred at room temperature for 16 h. The reaction mixture was diluted with CHCl (30 mL) and quenched with water (10 mL). The organic phase was washed with water, saturated aqueous NaHCO, and brine (30 mL each), dried (MgSO), and concentrated under reduced pressure to give the crude product. Silica gel chromatography (5% to 10% ethyl acetate / hexanes) afforded glyceride Intermediate-72 (44.8 mg, 71%) as a colorless solid. 1 H NMR (400 M Hz, CDCl3): δ 7.36 - 7.26 (m, 5H), 4.50 (s, 2H), 4.18 (dd, J = 11.6, 4.9 Hz, 2H), 4.11 (dd, J = 11.6, 5.5 Hz, 2H), 3.68 (dd, J = 10.4, 5.3 Hz, 1H), 3.55 (t, J = 6.6 Hz, 2H), 3.46 (t , J = 6.6 Hz, 2H), 2.32 (t, J = 7.6 Hz, 4H), 1 .67 - 1.54 (m, 8H), 1.34 - 1.21 (m, 52H), 0.88 (t, J = 6.9 Hz, 6H); 13 C NMR (100 MHz, CDCl3): δ 173.7 (2C;C), 138.8 (C), 128.5 (2C;CH) , 127.7 (2C;CH), 127.6 (CH), 75.3 (CH), 73. 0 (CH2), 70.7 (CH2), 70.5 (CH2), 63.2 (2C;C H2), 34.3 (2C;CH2), 32.1 (2C;CH2), 30.0 (CH2), 29.87 (CH2), 29.84 (2C;CH2), 29.80 (2C;CH2), 29.76 (2C;CH2), 29.6 (2C;CH2), 29.5 (2C;CH2), 29.4 (2C;CH2), 29.3 (2C;CH2), 26. 2 (CH2), 26.0 (CH2), 25.1 (2C;CH2), 22.8 (2 C;CH2), 14.3 (2C;CH3). A solution of benzyl ether intermediate-72 (43.5 mg, 57.3 μmol) in ethyl acetate / hexane (10 mL each) was subjected to hydrogenolysis using an HCube hydrogenator under recycling conditions (10% Pd / C cartridge, 6 bar, full H mode at flow rate = 1 mL / min) with the column temperature set at 25 °C for 1.5 h and then at 35 °C for an additional 1 h. Concentration of the reaction mixture under reduced pressure afforded alcohol intermediate-73 (38.2 mg, quantitative) as a colorless solid, which was used without purification. 1 H NMR (400 MHz, CDCl3): δ 4.19 (dd, J = 11.6, 4.9 Hz, 2 H), 4.11 (dd, J = 11.6, 5.5 Hz, 2H), 3.67 (m, 1H), 3.64 (t, J = 6.5 Hz, 2H), 3.55 (t, J = 6 .5 Hz, 2H), 2.32 (t, J = 7.6 Hz, 4H), 1.66 - 1.56 (m, 8H), 1.41 - 1.34 (m, 4H), 1.33 - 1.18 (m, 48H), 0.88 (t, J = 6.8 Hz, 6H). C4-ET-alcohol-2-TG (Intermediate-78):

[0424] [ka]

[0425] Intermediate-74 is a known compound that can be prepared as described in Charette, AB et al. J. Am. Chem. Soc. 2001, 123, 11829-11830.

[0426] Alcohol Intermediate-68 (commercially available; 135 mg, 0.749 mmol) was added in a single portion to a suspension of t-BuOK (118 mg, 1.05 mmol) in THF (2.5 mL), and the mixture was stirred at room temperature for 1 h. A solution of bromide Intermediate-74 (273 mg, 1.12 mmol) in THF (2 mL) was then added, and the resulting mixture was heated to reflux for 26 h. The reaction was cooled to room temperature, diluted with ethyl acetate (10 mL), quenched with water (20 mL), and the aqueous phase was extracted with ethyl acetate (3 × 25 mL). The combined organic extracts were washed with water and brine (60 mL each), dried (MgSO), and concentrated under reduced pressure to give the crude product. Silica gel chromatography (10%–20% ethyl acetate / hexanes) afforded the ether-linked glycerol Intermediate-75 (103 mg, 40%) as a colorless oil. 1 H NMR (400 MHz, CDCl): δ 7.53 - 7.48 (m, 2H), 7.38 - 7.27 (m, 8H), 5 .55 (s, 1H), 4.50 (s, 2H), 4.37 - 4.27 (m, 2H), 4.08 - 3.98 (m, 2H), 3.61 - 3.55 (m, 2H), 3.54 - 3.50 (m, 2H), 3.25 (m, 1H), 1.82 - 1.65 (m, 4H); 13 C NMR (100 MHz, CDCl3): δ 138.8 (C), 138.3 (C), 128.9 (CH), 128.4 (2C;CH), 128.3 (2C;CH), 127.7 (2C;CH), 127.6 (CH), 126.3 (2C;CH), 101.4 (C), 73.0 (CH2), 70.7 ( CH), 70.3 (CH2), 69.1 (2C;CH2), 68.7 (CH2), 26.7 (CH2), 26.6 (CH2). Benzylidene acetal intermediate-75 (102 mg, 0.298 mmol), concentrated HCl A mixture of (2 drops) and MeOH (4 mL) was heated to reflux for 2 hours and then cooled to room temperature. The reaction was diluted with ethyl acetate (40 mL) and water (15 mL), and the organic phase was washed with saturated aqueous NaHCO, water, and brine (40 mL each), dried (MgSO), and concentrated under reduced pressure to give the crude product. Silica gel chromatography (25% to 65% to 90% ethyl acetate / hexanes) gave diol Intermediate-76 (58.8 mg, 78%) as a colorless oil. 1 H NMR (400 MHz, CDCl3): δ 7.38 - 7.24 (m, 5H), 4.50 (s, 2H), 3.71 (dd, J = 11.6, 4.6 Hz, 2H), 3.64 (dd, J = 11.6, 4.9 Hz, 2H), 3.60 - 3.55 (m, 2H), 3.52 - 3.46 (m, 2 H), 3.41 (m, 1H), 2.59 (br s, 2H), 1.75 - 1.61 (m, 4H); 13 C NMR (100 MHz, CDCl3): δ 138.5 (C), 128.5 (2C;CH), 127.8 (2C;CH), 127.7 (CH), 78.8 (CH), 73.0 (CH2), 70.2 (CH2), 69.8 (CH2), 62.2 (2C;CH2), 27.1 (CH2), 26.4 (CH2). A solution of palmitoyl chloride (131 mg, 0.475 mmol) in CHCl (2 mL) and pyridine (48.0 μL, 0.594 mmol) was added to diol Intermediate-76 (30.2 mg, 0.119 mmol), and the reaction was stirred at room temperature for 19 h. The reaction mixture was diluted with CHCl (40 mL) and quenched with water (20 mL). The organic phase was washed with water, saturated aqueous NaHCO, and brine (40 mL each), dried (MgSO), and concentrated under reduced pressure to give the crude product. Silica gel chromatography (6% ethyl acetate / hexane) afforded triglyceride Intermediate-77 (72.4 mg, 83%) as a colorless solid. 1H NMR (400 MHz, CDCl3): δ 7.38 - 7.26 (m, 5H), 4.50 (s, 2H), 4.18 (dd, J = 11.6, 4.9 Hz, 2H), 4.11 (dd, J = 11.6, 5.5 Hz, 2H), 3.67 (m, 1H), 3.58 (t, J = 6.1 Hz, 2 H), 3.48 (t, J = 6.1 Hz, 2H), 2.31 (t, J = 7.6 Hz, 4H), 1.73 - 1.55 (m, 8H), 1.37 - 1.19 (m , 48H), 0.88 (t, J = 6.9 Hz, 6H); 13 C NMR (100 MHz, CDCl3): δ 173.7 (2C;C), 138.7 (C), 128.5 (2C;CH), 127.7 (2C;CH), 127.6 (CH), 75.4 (CH), 73.0 (CH2), 70.4 (CH2), 70.2 (CH2), 63.1 (2C;CH2), 34.3 (2C;CH2), 32.1 (2C;CH2) , 29.82 (6C;CH2), 29.79 (4C;CH2), 29.74 (2C;CH2), 29.6 (2C;CH2), 29.5 (2C;CH2), 29.4 (2C;H2), 29.3 (2C;CH2), 26.8 (CH2), 26.5 (CH2), 25.0 (2C;CH2), 22.8 (2C;CH2), 14.2 (2C;CH3). A solution of benzyl ether intermediate-77 (70.0 mg, 95.8 μmol) in ethyl acetate / hexane (25 mL each) was subjected to hydrogenolysis using an HCube hydrogenator under recycling conditions (10% Pd / C cartridge, 6 bar, full H mode at flow rate = 1 mL / min) with the column temperature set at 50 °C for 2.5 h. Concentration of the reaction mixture under reduced pressure gave the crude product, which was purified by silica gel chromatography (10% to 30% ethyl acetate / hexane) to give alcohol intermediate-78 (55.0 mg, 90%) as a colorless solid. 1 H NMR (400 MHz, CDCl): δ 4.20 (dd, J = 11.7, 4.8 Hz, 2H), 4.11 (dd, J = 11.7, 5.5 Hz, 2H), 3.69 (m, 1H), 3.64 (t, J = 5.9 Hz, 2H), 3.60 (t, J = 5.8 Hz, 2H), 2. 32 (t, J = 7.5 Hz, 4H), 1.70 - 1.55 (m, 8H), 1.33 - 1.19 (m, 48H), 0.87 (t, J = 6.8 Hz, 6H) ; 13 C NMR (100 MHz, CDCl3): δ 173.7 (2C;C), 75.5 (CH), 70.5 (CH2), 63.0 (2C;CH2), 62.6 ( CH2), 34.3 (2C;CH2), 32.0 (2C;CH2), 29.9 (CH2), 29.82 (2C;CH2), 29.78 (2C;CH2), 29.7 (2C;CH2), 29.6 (2C;CH2), 29.5 (2C;CH2), 29. 4 (2C;CH2), 29.3 (2C;CH2), 26.7 (CH2), 25.0 (2C;CH2), 22.8 (2C;CH2), 14.2 (2C;CH3). C5ββDiMe-acid-2-TG (Intermediate-79):

[0427] [ka]

[0428] To a solution of compound Intermediate-2 (5.0 g, 8.78 mmol) in chloroform (150 ml), DCC (3.62 g, 17.57 mmol) and DMAP (0.53 g, 4.39 mmol) were added, followed by the addition of 3,3-dimethylglutaric acid (2.81 g, 17.57 mmol) at room temperature, and then stirred for 48 hours. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a Celite bed, washed with dichloromethane (100 ml), and the filtrate was evaporated to obtain the crude desired compound, which was purified by combi-flash purification. The compound was eluted using 6% ethyl acetate in hexane and concentrated to obtain Intermediate-79 (C5ββDiMe-acid-2-TG) (2.0 g, 32%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 5.33 (m, 1H), 4.33 (m, 2H), 4.18 (m, 2H), 2.5 1 (s, 4H), 2.35 (t, 4H), 1.64 (t, 4H), 1.29 (m, 49H), 1.19 (s, 6H), 0.92 (t, 6H); 13 C NMR (101 MHz, CDCl3) δ 176.4 (1C), 173.3 (2C), 171.0 (1C),69.1 (1C), 62.1 (2C), 45.0 (1C) 4 4.7 (1C), 34.0 (3C), 32.6 (1C), 31.9 (3H), 29.7-29.1 (14C), 27.7 (3C), 24.8 (3C), 22.7 (3C), 14.1 (3C); HPLC (ELSD): 10.07 min, purity 97.74 %; MASS (ESI, -ve) m / z: 710 (M-1). C12a'aMe-acid-2-TG (Intermediate-81):

[0429] [ka]

[0430] To a solution of diisopropylamine (DIPA) (3.18 g, 81.08 mmol) in anhydrous THF (45 mL) was added n-BuLi (2.5 M in hexane) (32 mL, 81.08 mmol) at −78° C. The reaction mixture was stirred at −78° C. for 30 minutes, then propionic acid (1.5 g, 20.27 mmol) was added and the reaction mixture was stirred at −78° C. for an additional 30 minutes. 1,8-Dibromooctane (2.75 g, 10.13 mmol) was added and the reaction mixture was stirred and allowed to warm from −78° C. to room temperature over 3 hours. The reaction was monitored for completion by TLC. An additional identical batch starting with 1.5 g of propionic acid was prepared and the two batches were combined before workup. The combined reaction mixture was diluted with water (100 mL), acidified with 1N HCl (25 ml), extracted with ethyl acetate (3 x 100 ml), and the combined organic layer was dried over NaSO and evaporated to give crude compound. The title compound was purified by Combiflash purification, eluting with 10% ethyl acetate / hexane as the mobile phase. After evaporation, intermediate-80 (0.99 g, 9.5%) was obtained as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 2.57 - 2.39 (m, 2H), 1.71 (m, 2H), 1.50- 1.43 (m, 2H), 1.40-1.25 (m, 14H), 1.22 (d, J = 7.2 Hz 6H). To a solution of compound Intermediate-2 (2.7 g, 4.74 mmol) in chloroform (50 ml), DCC (1.95 g, 9.49 mmol) and DMAP (0.28 g, 2.30 mmol) were added, and the reaction was stirred at room temperature for 30 minutes. Intermediate-80 (2.44 g, 9.49 mmol) was added at room temperature and stirred for 2 hours. The reaction was monitored by TLC until completion, after which the reaction mixture was filtered through Celite, washed with DCM (45 ml), and then evaporated to give the crude product, which was purified by CombiFlash purification eluting with 7% ethyl acetate / hexane. After evaporation, Intermediate-81 (C12a'aMe acid-2-TG) (1.7 g, 44.3%) was obtained as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 5.32 (m, 1H), 4.33 (m, 2H), 4.19 (m, 2H), 2.49 (m, 2H), 2.34 (m , 4H), 1.72-1.62 (m, 4H), 1.49-1.40 (m, 4H) . 1.38 - 1.29 (m, 59H), 1.24 -1.17(m, 8H), 0 .92 (m, 6H); 13 C NMR (101 MHz, CDCl3) δ 181.7 (1C), 176.0 (1C), 173.4 (2C), 68.7 (2C), 62.2 (3C), 39.6 (2C), 39.2 (1C), 34.1 (3C), 33.7 (1C), 32.0 (3C), 29.7-29.2 (17C), 27.2 ( 1C), 24.9 (3C), 22.7 (3C), 17.1 (2C), 16.9 (1C), 14.2 (3C).

[0431] [ka]

[0432] Bromotriglyceride intermediate-91: DMAP (10.7 mg, 0.0979 mmol) and EDC·HCl (41.8 mg, 0.220 mmol) were added to a solution of bromoacetic acid (24.4 mg, 0.176 mmol) and Intermediate-2 (50.0 mg, 0.0879 mmol) in CHCl (2 mL), and the mixture was stirred at room temperature for 22 h. The reaction was diluted with CHCl (5 mL), silica gel was added, and the solvent was removed under reduced pressure. Silica gel chromatography (4% ethyl acetate / hexane) afforded bromotriglyceride Intermediate-91 (50.3 mg, 83%) as a colorless solid. 1 H NMR (400 MHz, CDCl3) δ 5.31 (m, 1H), 4.34 (dd, J = 12.1, 4.0 Hz, 2H), 4.17 (dd, J = 12.1, 6.1 Hz, 2H), 3.84 (s, 2H), 2.32 (t, J = 7.6 Hz, 4H), 1.66 - 1.56 (m, 4H), 1.35 - 1.20 (m, 48H), 0.88 (t, J = 6.9 Hz, 6H); 13 C NMR (101 MHz, CDCl3) δ 173.4 (2C;C) , 166.7 (C), 71.3 (CH), 61.9 (2C;CH2), 34.1 (2C;CH2), 32.1 (2C;CH2), 29.84 (2C;CH2), 2 9.80 (2C;CH2), 29.75 (2C;CH2), 29.6 (2C;CH2) 2), 29.5 (2C;CH2), 29.4 (2C;CH2), 29.3 (2C;CH2), 25.5 (CH2), 25.0 (2C;CH2), 22.8 (2C;CH2), 14.3 (2C;CH2). Iodotriglyceride intermediate-95:

[0433] [ka]

[0434] Intermediate-93 is a known compound prepared from cycloheptanone as shown above (see Kai, K. et al. Tetrahedron 2008, 64, 6760-6769). To prepare Intermediate-94, chlorotrimethylsilane (TMSC1, 208 μL, 1.64 mmol) was added to a suspension of lactone Intermediate-93 (70.0 mg, 0.546 mmol) and sodium iodide (246 mg, 1.64 mmol) in acetonitrile (1.5 mL), and the mixture was heated to reflux for 16 hours. The reaction was cooled to room temperature, diluted with ethyl acetate and water (10 mL each), and extracted with ethyl acetate (3 × 15 mL). The combined organic extracts were washed with 1 M NaSO and brine (40 mL each), dried (MgSO), and concentrated under reduced pressure to give the crude product. Silica gel chromatography (100% CHCl to 50% ethyl acetate / hexane) afforded semi-pure acid intermediate-94 (59.8 mg, 43%) as a yellow oil. However, due to the presence of m-CPBA impurity, accurate yield and clean NMR spectrum could not be obtained, and it was carried forward to the next step. 1 H NMR (400 MHz, CDCl3) δ 3.19 (t, J = 7.0 Hz, 2H), 2.37 (t, J = 7.4 Hz, 2H), 1.88 - 1.80 (m, 2H), 1.7 1 - 1.61 (m, 2H), 1.46 - 1.33 (m, 4H). DMAP (15.2 mg, 0.124 mmol) and DCC (51.3 mg, 0.248 mmol) were added sequentially to a solution of acid intermediate-94 (35.0 mg, 0.137 mmol) and 1,3-diglyceride intermediate-2 (70.7 mg, 0.124 mmol) in CHCl (4 mL), and the mixture was stirred at room temperature for 17 h. The resulting suspension was diluted with CHCl, cooled to 0 °C, filtered through Celite, and washed with additional CHCl. ​​The organic phase was washed with 1 M HCl, saturated aqueous NaHCO, and brine, dried (MgSO), and concentrated under reduced pressure to give the crude product. Silica gel chromatography (3.5% to 4.5% ethyl acetate / hexanes) afforded semi-pure iodotriglyceride intermediate-95 (83.6 mg, 84%) as a colorless solid. However, due to the presence of m-CPBA impurity, accurate yield and clean NMR spectrum could not be obtained and it was carried forward to the next step. 1 H NMR (400 MHz, CDCl3) δ 5.26 (m, 1H), 4.30 (dd, J = 11.9, 4.4 Hz, 2H), 4.14 (dd, J = 11.9, 5.9 Hz, 2H), 3. 18 (t, J = 7.0 Hz, 2H), 2.36 - 2.27 (m, 6H), 1.86 - 1.77 (m, 2H), 1.68 - 1.52 (m, 6H), 1.45 - 1.18 (m, 52H), 0.88 (t, J = 6.9 Hz, 6H).

[0435] [ka]

[0436] DMAP (17.2 mg, 0.141 mmol) and EDC·HCl (67.4 mg, 0.352 mmol) were added to a solution of 1,3-diglyceride intermediate-2 (80.0 mg, 0.141 mmol) and 12-bromododecanoic acid (51.0 mg, 0.183 mmol) in CHCl (2.5 mL), and the mixture was stirred at room temperature for 18 h. The reaction was diluted with CHCl (10 mL), silica gel was added, and the mixture was concentrated under reduced pressure. Purification by silica gel chromatography (5%–10% ethyl acetate / hexane) afforded bromotriglyceride intermediate-97 (105 mg, 90%) as a colorless solid. 1 H NMR (401 MHz, CDCl3) δ 5.25 (m, 1H), 4.2 8 (dd, J = 11.9, 4.3 Hz, 2H), 4.13 (dd, J = 11.9, 5.9 Hz, 2H), 3.38 (t, J = 6.9 Hz, 2H), 2. 30 (t, J = 7.5 Hz, 2H), 2.29 (t, J = 7.5 Hz, 4 H), 1.88 - 1.79 (m, 2H), 1.65 - 1.55 (m, 6H), 1.45 - 1.36 (m, 2H), 1.34 - 1.18 (m, 60H), 0 .86 (t, J = 6.8 Hz, 6H); 13 C NMR (101 MHz, CDCl3) δ 173.4 (2C;C), 172.9 (C), 69.0 (CH), 62.2 (2C;CH2), 34.3 (CH2), 34.2 (2C;CH2), 34.0 (CH2), 33.0 (CH2), 32.1 (2C;CH2), 29.82 ( 6C;CH2), 29.78 (4C;CH2), 29.74 (2C;CH2), 2 9.60 (3C;CH2), 29.54 (2C;CH2), 29.48 (2C;C H2), 29.39 (2C;CH2), 29.38 (CH2), 29.23 (2C;CH2), 29.17 (CH2), 28.9 (CH2), 28.3 (CH2), 25.0 (2C;CH2), 22.8 (2C;CH2), 14.2 (2C;CH3). Intermediate-105:

[0437] [ka]

[0438] Intermediate-99: A suspension of 1,16-hexanediol (200 mg, 0.774 mmol) in DMF (2 mL) was added to a suspension of NaH (34.1 mg, 60% w / w dispersion in mineral oil, washed twice with anhydrous gasoline, 8.51 mmol) in DMF (1 mL) at 0 °C, and the mixture was stirred at 0 °C for 10 min and then at room temperature for 30 min. TBDPSCl (221 μL, 0.851 mmol) was added, and the mixture was stirred at room temperature for 17 h. The reaction was diluted with ethyl acetate (50 mL), washed with water and brine (2 × 40 mL each), dried (MgSO), and concentrated under reduced pressure to give the crude product. Silica gel chromatography (15% ethyl acetate / hexane) afforded TBDPS ether intermediate-99 (124 mg, 32%) as a colorless solid. 1 H NMR (401 MHz, CDCl3) δ 7.70 - 7.63 (m, 4H), 7.45 - 7.34 (m, 6H), 3.64 (td, J = 6.5, 3.6 Hz, 4H), 1.61 - 1.46 (m, 4H), 1.39 - 1.19 (m, 24H), 1.04 (s, 9H). Intermediate-100: Pyridinium chlorochromate (PCC, 106 mg, 0.491 mmol) and Celite (100 mg) were added to alcohol Intermediate-99 (122 mg, 0.246 mmol) in CHCl (6 mL) at 0° C., and the mixture was stirred at 0° C. for 10 min and then at room temperature for 1.5 h. The reaction was filtered through a short pad of silica gel, eluting with 50% ethyl acetate / hexane (80 mL), and the filtrate was concentrated under reduced pressure to give crude aldehyde Intermediate-100 (121 mg, quantitative) as a yellow oil, which was used immediately without purification.

[0439] Intermediate-101: Ylidmethyl 2-(triphenyl-λ 5 (-phosphanylidene) acetate (205 mg, 0.614 mmol) was added to the crude aldehyde Intermediate-100 (121 mg, 0.246 mmol) in toluene (6 mL), and the mixture was heated to reflux for 1 h. The reaction was cooled to room temperature and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (4% ethyl acetate / hexanes) gave α,β-unsaturated methyl ester Intermediate-101 (100 mg, 74%, 6:1 mixture of E / Z isomers) as a yellow oil. NMR data for the major isomer is provided. 1 H NMR (401 MHz, CDCl3) δ 7.74 - 7.66 (m, 4H), 7.48 - 7.36 (m, 6H) , 7.01 (dt, J = 15.6, 7.0 Hz, 1H), 5.85 (dt, J = 15.6, 1.5 Hz, 1H), 3.74 (s, 3H), 3.69 (t, J = 6.5 Hz, 2H), 2.22 (qd, J = 7.3, 1.5 Hz, 2 H), 1.64 - 1.55 (m, 2H), 1.47 (dd, J = 13.9, 6.9 Hz, 2H), 1.42 - 1.25 (m, 22H), 1.09 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 167.3 (C), 149.9 (CH), 135.7 (4C;CH), 134.3 (2C;C), 129.6 (2C;CH), 127.7 (4C;CH), 120.9 (CH), 64.1 ( CH2), 51.4 (CH3), 32.7 (CH2), 32.3 (CH2), 2 9.79 (2C;CH2), 29.75 (2C;CH2), 29.74 (CH2) , 29.66 (CH2), 29.52 (CH2), 29.50 (CH2), 29 .3 (CH2), 28.1 (CH2), 27.0 (3C;CH2), 25.9 ( CH2), 19.3 (C). Intermediate-102: A solution of alkene Intermediate-101 (99.0 mg, 0.180 mmol) in ethyl acetate (5 mL) in a two-neck flask was evacuated and flushed with N gas three times each, then palladium on carbon (10% w / w, 28.7 mg, 0.0270 mmol) was added, and the resulting suspension was evacuated and flushed with N three times again. The flask was fitted with a H balloon, evacuated and flushed with H three times, and the reaction mixture was stirred under 1 atm of H at room temperature for 1 h. The reaction was filtered through a pad of Celite, washed with ethyl acetate (80 mL), and concentrated under reduced pressure to afford the saturated methyl ester Intermediate-102 (99.4 mg, quantitative) as a colorless oil, which was used without purification. 1 H NMR (401 MHz, CDCl3) δ 7.75 - 7.67 (m, 4H), 7.47 - 7.36 (m, 6H), 3.69 (t, J = 6.5 Hz, 2H), 3.68 (s, 3H), 2.33 (t, J = 7.5 Hz, 2H), 1.7 0 - 1.54 (m, 4H), 1.43 - 1.23 (m, 26H), 1.09 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 174.4 (C), 135.7 (4C;CH), 134.3 (2C;C), 129.6 (2C;CH), 127.7 (4C;CH), 64.1 (CH2), 51.5 (CH3), 3 4.2 (CH2), 32.7 (CH2), 29.82 (2C;CH2), 29.81 (2C;CH2), 29.78 (CH2), 29.76 (CH2), 29.75 (CH2), 29.73 (CH2), 29.6 (CH2), 29.5 (CH2) , 29.4 (CH2), 29.3 (CH2), 27.0 (3C;CH3), 25 .9 (CH2), 25.1 (CH2), 19.3 (C). Intermediate-103: A solution of potassium hydroxide (2.0 M, 530 μL, 1.06 mmol) was added to ester Intermediate-102 (26.0 mg, 0.0854 mmol) in ethanol (3 mL), and the mixture was heated at 70° C. for 50 minutes. The reaction was acidified to pH 3 by the addition of 1 M HCl and diluted with ethyl acetate (40 mL). The organic phase was washed with water (2×30 mL) and brine (30 mL), dried (MgSO), and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (15% ethyl acetate / hexanes) gave acid Intermediate-103 (76.8 mg, 80%) as a colorless oil. 1 H NMR (401 MHz, CDCl3) δ 7.73 - 7.67 (m, 4H), 7.44 - 7.37 (m, 6H), 3.68 (t, J = 6.5 Hz, 2H), 2.37 (t, J = 7.5 Hz, 2H), 1.70 - 1.53 (m, 4H), 1.4 1 - 1.23 (m, 26H), 1.07 (s, 9H); 13 C NMR (101 MHz, CDCl3) δ 180.4 (C), 135.7 (4C;CH), 134 .3 (2C;C), 129.6 (2C;CH), 127.7 (4C;CH), 64.2 (CH2), 34.2 (CH2), 32.7 (CH2), 29.83 (4C ;CH2), 29.81 (CH2), 29.78 (2C;CH2), 29.76 (CH2), 29.6 (CH2), 29.5 (CH2), 29.4 (CH2), 2 9.2 (CH2), 27.0 (3C;CH3), 25.9 (CH2), 24.8 (CH2), 19.4 (C). Intermediate-104: DMAP (10.2 mg, 0.0839 mmol), EDC·HCl (40.2 mg, 0.210 mmol), and 1,3-diglyceride intermediate-2 (52.5 mg, 0.0923 mmol) were added to a solution of acid intermediate-103 (45.2 mg, 0.0839 mmol) in CHCl (4 mL), and the mixture was stirred at room temperature for 22 h. The reaction was diluted with CHCl (10 mL), silica gel was added, and the mixture was concentrated under reduced pressure. Purification by silica gel chromatography (4% to 6% ethyl acetate / hexane) afforded triglyceride intermediate-104 (84.9 mg, 93%) as a colorless solid. 1 HN MR (401 MHz, CDCl3) δ 7.71 - 7.65 (m, 4H), 7.45 - 7.34 (m, 6H), 5.28 (m, 1H), 4.31 (dd, J = 11.9, 4.3 Hz, 2H), 4.16 (dd, J = 11.9, 6.0 Hz, 2H), 3.66 (t, J = 6.5 Hz, 2H), 2.325 (t, J = 7.5 Hz, 2H), 2.319 (t, J = 7.5 Hz, 4H), 1.69 - 1.52 (m, 8H), 1.42 - 1.20 (m, 74H), 1.06 (s, 9H), 0.89 (t, J = 6.8 Hz, 6H); 13 C NMR (1 01 MHz, CDCl3) δ 173.4 (2C;C), 173.0 (C), 135.7 (4C;CH), 134.3 (2C;C), 129.6 (2C;CH), 127.7 (4C;CH), 69.0 (CH), 64.1 (CH2), 62.2 ( 2C;CH2), 34.3 (CH2), 34.2 (2C;CH2), 32.7 (CH2), 32.1 (2C;CH2), 29.86 (2C;CH2), 29.84 (9C;CH2), 29.80 (5C;CH2), 29.77 (2C;CH2), 2 9.76 (2C;CH2), 29.65 (CH2), 29.61 (2C;CH2) , 29.53 (CH2), 29.50 (2C;CH2), 29.44 (CH2), 29.41 (2C;CH2), 29.25 (2C;CH2), 29.22 (CH2), 27.0 (3C;CH3), 25.9 (CH2), 25.04 (CH2), 24.99 (2C;CH2), 22.8 (2C;CH2), 19.3 (C), 14.2 (2C;CH3). Intermediate-105: Tetrabutylammonium fluoride (TBAF, 1.0 M in THF, 154 μL, 0.154 mmol) and acetic acid (8.8 μL, 0.154 mmol) were added to a solution of TBDPS ether Intermediate-104 (84.0 mg, 0.0771 mmol) in THF (3 mL) at 0 °C, and the mixture was stirred at 0 °C for 15 min and then at room temperature for 7 h. The reaction was diluted with ethyl acetate (40 mL), washed with water (30 mL) and brine (2 × 30 mL), dried (MgSO), and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (7.5% to 20% ethyl acetate / hexanes) afforded alcohol Intermediate-105 (40.5 mg, 62%) as a colorless solid. 1 H NMR (401 MHz, CDCl3) δ 5.26 (m, 1H), 4.29 (dd, J = 11.9, 4.3 Hz, 2H), 4.14 (dd, J = 11.9, 6.0 Hz, 2H), 3.64 (t, J = 6.6 Hz, 2H), 2.31 (t, J = 7.5 Hz, 2H), 2.30 (t, J = 7.5 Hz, 4H), 1.67 - 1.51 (m, 8H), 1.44 - 1.17 (m, 74H), 0.88 (t, J = 6.8 Hz, 6H); 13 C NMR (101 MHz, CDCl3) δ 173.5 (2C;C), 173.1 (C), 69.0 (CH), 63.3 (CH2 ), 62.3 (2C;CH2), 34.4 (CH2), 34.2 (2C;CH2), 33.0 (CH2), 32.1 (2C;CH2), 29.82 (10C;CH2), 29.80 (6C;CH2), 29.76 (3C;CH2), 29.75 (CH2), 29.65 (CH2), 29.63 (2C;CH2), 29.59 (CH2), 29.51 (2C;CH2), 29.45 (CH2), 29.42 (2C; CH2), 29.27 (2C;CH2), 29.23 (CH2), 25.9 (CH2), 25.1 (CH2), 25.0 (2C;CH2), 22.8 (2C;CH2), 14.3 (2C;CH3). Intermediate-110(TML(CO 2 H)-C4-2-TG):

[0440]

change

[0441] Intermediate 106: Amsberry, K Let al. Pharm Res. 1991, 8, 455-461.

[0442] DMAP (18.3 mg, 0.149 mmol) and EDC·HCl (71.6 mg, 0.374 mmol) were added to a solution of Intermediate-28 (100 mg, 0.149 mmol) and phenol Intermediate-106 (53.0 mg, 0.164 mmol) in CHCl (4 mL), and the mixture was stirred at room temperature for 19 h. The reaction was diluted with CHCl (5 mL), silica gel was added, and the mixture was concentrated under reduced pressure. Purification by silica gel chromatography (3% to 7.5% ethyl acetate / hexane) afforded TML-TG Intermediate-107 (84.6 mg, 58%) as a colorless oil. 1 H NMR (400 MHz , CDCl3) δ 6.80 (d, J = 2.0 Hz, 1H), 6.55 (d, J = 1.9 Hz, 1H), 5.29 (m, 1H), 4.31 (dd, J = 11.9, 4.4 Hz, 2H), 4.16 (dd, J = 12.0, 5.8 Hz, 2H), 3.51 - 3.44 (m, 2H), 2.85 (t, J = 6.9 Hz, 2H), 2.75 (t, J = 6.9 Hz, 2H), 2.51 (s, 3H) , 2.30 (t, J = 7.6 Hz, 4H), 2.22 (s, 3H), 2.0 6 - 1.99 (m, 2H), 1.65 - 1.56 (m, 4H), 1.46 ( s, 6H), 1.37 - 1.20 (m, 48H), 0.88 (t, J = 6. 9 Hz, 6H), 0.84 (s, 9H), -0.03 (s, 6H); 13 CN MR (101 MHz, CDCl3) δ 173.4 (2C;C), 171.5 (C), 171.3 (C), 149.7 (C), 138.5 (C), 136.1 (C), 134.1 (C), 132.5 (CH), 123.1 (CH), 69.8 (CH), 62.0 (2C;CH2), 60.9 (CH2), 46.1 (CH2), 39.2 (C), 34.1 (2C;CH2), 32.1 (2C;CH2), 31 .9 (2C;CH3), 29.9 (CH2), 29.83 (6C;CH2), 29.79 (4C;CH2), 29.75 (2C;CH2), 29.6 (2C;CH2 ), 29.5 (2C;CH2), 29.4 (2C;CH2), 29.2 (2C;CH2), 29.0 (CH2), 26.1 (3C;CH3), 25.4 (CH3), 25.0 (2C;CH2), 22.8 (2C;CH2), 20.3 (CH3), 18.3 (C), 14.3 (2C;CH3), -5.21 (2C;CH3).ES I-HRMS: C 58 H 105 O9Si [M + H + ] calculated value 973.7522; observed value 973.7515. 10-Camphorsulfonic acid (3.0 mg, 12.9 μmol) was added to TBS ether Intermediate-107 (83.7 mg, 86.0 μmol) in CHCl (1 mL) and MeOH (1 mL), and the mixture was stirred at room temperature for 1 h. The reaction was diluted with CHCl (20 mL), and the organic phase was washed with saturated aqueous NaHCO and brine (20 mL each), dried (MgSO), and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (15% to 25% ethyl acetate / hexanes) afforded alcohol Intermediate-108 (59.9 mg, 81%) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 6.81 (d, J = 2.0 Hz, 1H), 6.5 6 (d, J = 1.4 Hz, 1H), 5.28 (m, 1H), 4.30 (dd , J = 12.0, 4.4 Hz, 2H), 4.17 (dd, J = 12.0, 5.8 Hz, 2H), 3.51 (t, J = 6.8 Hz, 2H), 2.88 (t , J = 6.6 Hz, 2H), 2.75 (t, J = 6.6 Hz, 2H), 2 .52 (s, 3H), 2.29 (t, J = 7.6 Hz, 4H), 2.22 ( s, 3H), 2.05 (t, J = 7.4 Hz, 2H), 1.65 - 1.57 (m, 4H), 1.50 (s, 6H), 1.37 - 1.20 (m, 48H), 0.88 (t, J = 6.9 Hz, 6H); 13 C NMR (101 MHz, CDCl3) δ 173.5 (2C;C), 171.71 (C), 171.70 (C) , 149.8 (C), 138.5 (C), 136.3 (C), 133.9 (C), 132.6 (CH), 123.2 (CH), 69.8 (CH), 62.0 (2C;CH2), 60.5 (CH2), 45.9 (CH2), 39.2 (C), 3 4.1 (2C;CH2), 32.1 (2C;CH3), 32.0 (2C;CH2) , 29.84 (CH2), 29.80 (6C;CH2), 29.77 (4C;CH2), 29.72 (2C;CH2), 29.6 (2C;CH2), 29.5 (2C;CH2), 29.4 (2C;CH2), 29.2 (2C;CH2), 28.9 (CH2), 25.5 (CH3), 24.9 (2C;CH2), 22.8 (2C;CH2), 20.3 (CH3), 14.2 (2C;CH3).ESI-HRMS: C 52 H 90 NaO9[M + Na + ]についての calculated value 881.6477; measured value 88 1.6489. Pyridinium chlorochromate (PCC, 30.1 mg, 0.139 mmol) was added to a suspension of alcohol Intermediate-108 (59.9 mg, 0.0697 mmol) and Celite (30 mg) in CHCl (3 mL) at 0° C., and the mixture was stirred at room temperature for 2 h. The reaction was filtered through a short pad of silica gel, eluting with 50% ethyl acetate / hexane (50 mL), and the filtrate was concentrated under reduced pressure to give crude aldehyde Intermediate-109 (59.8 mg, quantitative) as a yellow oil, which was used without purification. 1 H NMR (400 MHz, CDCl3) δ 9.54 (t, J = 2.6 Hz, 1H), 6. 84 (d, J = 2.0 Hz, 1H), 6.60 (d, J = 1.4 Hz, 1 H), 5.28 (m, 1H), 4.30 (dd, J = 12.0, 4.3 Hz, 2H), 4.16 (dd, J = 12.0, 5.8 Hz, 2H), 2.86 ( t, J = 6.7 Hz, 2H), 2.83 (d, J = 2.6 Hz, 2H), 2.75 (t, J = 6.3 Hz, 2H), 2.53 (s, 3H), 2.30 (t, J = 7.6 Hz, 4H), 2.23 (s, 3H), 1.64 - 1.5 8 (m, 4H), 1.56 (s, 3H), 1.55 (s, 3H), 1.32 - 1.22 (m, 48H), 0.88 (t, J = 6.9 Hz, 6H). Potassium permanganate (12.2 mg, A solution of aldehyde Intermediate-109 (59.8 mg, 69.7 μmol) in acetone (1.6 mL) was added to aldehyde Intermediate-109 (59.8 mg, 69.7 μmol) and the mixture was stirred at room temperature for 17 hours. The reaction was diluted with water (10 mL), acidified to pH 2 using 1 M HCl, and the aqueous layer was extracted with CHCl (3 × 15 mL). The combined organic extracts were washed with brine (40 mL), dried (MgSO), and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (10% to 25% ethyl acetate / hexanes) gave acid Intermediate-110 (30.4 mg, 50%) as a colorless solid. 1 H NMR (400 MH z, CDCl3) δ 6.81 (d, J = 1.6 Hz, 1H), 6.58 (d , J = 1.4 Hz, 1H), 5.28 (m, 1H), 4.30 (dd, J = 11.9, 4.4 Hz, 2H), 4.16 (dd, J = 12.0, 5.8H z, 2H), 2.88 (t, J = 6.6 Hz, 2H), 2.84 (s, 2H ), 2.75 (t, J = 6.6 Hz, 2H), 2.53 (s, 3H), 2. 29 (t, J = 7.6 Hz, 4H), 2.22 (s, 3H), 1.64 - 1.58 (m, J = 9.3 Hz, 4H), 1.57 (s, 6H), 1.34 - 1.20 (m, 48H), 0.88 (t, J = 6.8 Hz, 6H); 13 C NMR (101 MHz, CDCl3) δ 176.1 (C), 173.6 (2C;C), 171.6 (C), 171.4 (C), 149.5 (C), 138.2 (C), 136.5 (C), 133.4 (C), 132.7 (CH), 123.0 (CH), 69.8 (CH), 62.0 (2C;CH2), 47.6 (CH2), 38.8 (C), 34.1 (2C;CH2), 32.1 (2C;CH2), 31.5 (2C;CH3), 29.9 (CH2), 29.84 (6C;CH2), 29.80 (4C;CH2), 29.76 (2C;CH2), 29.6 (2C;CH2) , 29.5 (2C;CH2), 29.4 (2C;CH2), 29.2 (2C;CH2), 29.0 (CH2), 25.4 (CH3), 25.0 (2C;CH2), 22.8 (2C;CH2), 20.4 (CH3), 14.3 (2C;CH3).E SI-HRMS: C 52 H 88 NaO 10 [M + Na + ] calculated value 895.6270; observed value 895.6266. Using a similar method, Intermediate-119 was prepared by EDC coupling with Intermediate-37 in 84% yield.

[0443] [ka]

[0444] 1 H NMR (401 MHz, CDCl3) δ 6.80 (d, J = 1.9 H z, 1H), 6.55 (d, J = 1.7 Hz, 1H), 5.26 (m, 1H ), 4.29 (dd, J = 11.9, 4.4 Hz, 2H), 4.14 (dd, J = 11.9, 5.9 Hz, 2H), 2.83 (s, 2H), 2.55 (t , J = 7.5 Hz, 2H), 2.53 (s, 3H), 2.32 (t, J = 7.5 Hz, 2H), 2.31 (t, J = 7.5 Hz, 4H), 2.22 ( s, 3H), 1.78 - 1.69 (m, 2H), 1.67 - 1.54 (m, 6H), 1.57 (s, 6H), 1.45 - 1.20 (m, 60H), 0.8 8 (t, J = 6.8 Hz, 6H); 13 C NMR (101 MHz, CDCl ) δ 176.3 (C), 173.5 (2C;C), 173.1 (C), 173.0 (C), 149.7 (C), 138.2 (C), 136.4 (C), 133.5 (C), 132.5 (CH), 123.2 (CH), 69.0 (CH), 62.2 (2C;CH2), 47.4 (CH2), 38.9 (C), 35.2 (CH 2), 34.3 (CH2), 34.2 (2C;CH2), 32.1 (2C;CH2), 31.4 (2C;CH3), 29.84 (6C;CH2), 29.80 (4C;CH2), 29.76 (2C;CH2), 29.62 (2C;CH2), 29. 53 (2C;CH2), 29.50 (2C;CH2), 29.41 (2C;CH2 ), 29.38 (2C;CH2), 29.30 (CH2), 29.26 (2C;CH2), 29.19 (CH2), 25.4 (CH3), 25.0 (3C;CH2), 24.8 (CH2), 22.8 (2C;CH2), 20.4 (CH3), 14 .3 (2C;CH3). Intermediate-122 was also prepared using a similar method.

[0445] [ka]

[0446] 1 H NMR (401 MHz, CDCl3) δ 6.79 (d, J = 1.9 H z, 1H), 6.51 (d, J = 1.8 Hz, 1H), 5.26 (m, 1H ), 4.292 / 4.284 (each dd, J = 11.8, 4.2 Hz, 2 H), 4.14 (dd, J = 11.9, 6.1 Hz, 2H), 2.84 (s, 2H), 2.67 (m, 1H), 2.53 (s, 3H), 2.44 (m, 1H), 2.30 (t, J = 7.6 Hz, 4H), 2.22 (s, 3H), 1. 84 (m, 1H), 1.69 - 1.45 (m, 7H), 1.573 (s, 3H), 1.567 (s, 3H), 1.45 - 1.19 (m, 63H), 1.14 (d, J = 7.0 Hz, 3H), 0.88 (t, J = 6.9 Hz, 6H); 13 C NMR (101 MHz, CDCl3) δ 176.1 (2C;C), 175.9 (C), 173.5 (2C;C), 150.1 (C), 138.2 (C), 136.4 (C), 133.6 (C), 132.5 (CH), 123.0 (CH) ), 68.9 (CH), 62.30 / 62.27 (2C;CH2), 47.3 (CH2), 40.2 (CH), 39.7 (CH), 39.0 (C), 34.2 (2C;CH2), 33.8 (CH2), 33.6 (CH2), 32.1 (2C;CH2), 31.5 (CH3), 29.84 (2C;CH2), 29.80 (2C;CH2), 29.76 (2C;CH2), 29.65 (2C;CH2), 29.61 (2C;CH2), 29.59 (2C;CH2), 29.5 (2C;CH2), 2 9.4 (2C;CH2), 29.28 / 29.27 (2C;CH2), 27.34 (CH2), 27.28 (CH2), 25.5 (CH3), 25.0 (2C;CH2), 22.8 (2C;CH2), 20.4 (CH3), 17.2 (CH3), 16.9 (CH3), 14.3 (2C;CH3). Intermediate-154 is similar to the する method and uses して to modulate した.

[0447] [Chemical]

[0448] 1 H NMR (400 MHz, CDCl3) δ 6.84 (s, 1H), 6.5 8 (s, 1H), 5.30 (m, 1H), 4.34 (dd, J = 11.9, 3.4 Hz, 2H), 4.18 (dd, J = 11.9, 6.0 Hz, 2H), 2.84 (s, 2H), 2.75 - 2.47 (m, 5H), 2.44 - 2. 31 (m, 4H), 2.25 (s, 3H), 1.59 (d, J = 14.7 H z, 4H), 1.27 (m, 58H), 1.15 (d, J = 6.2 Hz, 3 H), 0.90 (t, J = 6.6 Hz, 6H); 13 C NMR (101 MHz, CDCl3) δ 176.09 (1C), 173.42 (2C), 171.36 (1C), 171.23 (1C), 149.25 (1C), 138.10 (1C), 136.27 (1C), 133.31 (1C), 132.49 (1C), 12 2.95 (2C), 69.20 (1C), 62.06 (2C), 47.38 (1 C), 41.11 (1C), 40.52 (1C), 38.63 (1C), 34. 02 (2C), 31.94 (3C), 31.34 (1C), 31.30 (1C) , 29.71 - 29.13 (16C), 27.20 (1C), 25.31 (1C), 24.84 (2C), 22.71 (3C), 20.28 (1C), 19.81 (1C), 14.15 (3C). HPLC (ELSD): 9.17 minutes, purity 99. 22%;MASS (ESI, +ve) m / z: 919.31 (M+18). LCMS (m / z): 919.0 (M+18), 08.14 min, 100% purity. Intermediate-112 1,3-dioleoylglycerol (1,3-DG-oleate):

[0449] [ka]

[0450] To a solution of 2,5-bis(hydroxymethyl)-1,4-dioxane-2,5-diol (5 g, 27.7 mol) in chloroform (20 vol), pyridine (5.5 mL, 69 0.4 mol), followed by oleoyl chloride (11 mL, 54.9 mol), were added and the mixture was stirred at room temperature for 1 h. The solvent was evaporated and the reaction mixture was dissolved in ethyl acetate (30 vol) and washed with 1 N HCl (10 vol). The organic layer was dried and the solvent was evaporated under vacuum. The crude material was recrystallized from cold methanol (20 vol). The resulting solid was further washed with cold methanol and dried to give ketone Intermediate-111 (11 g, 62%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 5.36 (t , J = 11.6 Hz, 4H), 4.78 (s, 4H), 2.47 (m, 4H ), 2.38 (m, 8H), 1.71 (m, 2H), 1.34-1.30 (m, 42H), 0.93 (m, 6H). Sodium borohydride (NaBH, 307 mg, 8.09 mmol) was added to a solution of Intermediate-111 (5 g, 8.09 mmol) in THF (20 vol) at 0 °C, and then the reaction mixture was stirred at room temperature for 15 min. The reaction was monitored by TLC, and upon completion, the reaction mixture was filtered through a Celite bed to remove excess sodium borohydride, the Celite bed was washed with ethyl acetate (30 vol), and the organic layer was washed with a 1 N solution of acetic acid (10 vol). The solvent was dried over NaSO, and the solvent was removed under vacuum. The crude material was column purified. The product was eluted with 5% to 10% ethyl acetate / hexane to give 1,3-DG-oleate (Intermediate-112) (2 g, 39%) as a viscous liquid. 1 H NMR (400 MHz, CDCl3) δ 5.39 (m, 4H), 4.20 (m, 5H), 2.44 (d, 1H), 2.36 (m, 4H), 2. 01 (m, 8H), 2.47 - 2.25 (m, 12H), 2.17 (m, 1H), 2.02 (ddd, J = 13.4, 4.9, 3.3 Hz, 1H), 1.85 (m, 1H), 1.77 (m, 1H), 1.64 (m, 2H), 1.57- 1.26 (m, 42H), 0.9 (t, 6H); 13 C NMR (101 MHz, CDCl3) δ 173.9 (2C,C=O), 130.1 (2C), 129.7 (2C), 68.4 (C,CH), 65.1 (2C), 34.1 (2C), 31 .9 (2C), 29.8-29.1 (18C), 27.3 (2C), 24.9 ( 2C), 22.7 (2C), 14.1 (2C). HPLC (ELSD): 9.6 2 minutes, purity 99.27%. MS (ESI, +ve) m / z: 639.2 (MH + +H2O). Intermediate-113 (C10-Acid-TG-Oleate):

[0451] [ka]

[0452] Pyridine (0.19 mL, 2.41 mmol) was added to a suspension of DG-oleate Intermediate-112 (150 mg, 0.241 mmol) in DCM (20 vol). After 5 min, sebacoyl chloride (289 mg, 1.2 mmol) was added dropwise with stirring at room temperature. The reaction mixture was stirred at 40 °C for 2 h. The reaction was monitored by TLC, and upon completion, it was diluted with DCM (20 vol) and washed with water (20 vol), aqueous sodium bicarbonate (10 vol), and brine (10 vol). The resulting organic layer was dried over NaSO, filtered, and the solvent was removed under reduced pressure. The crude material was column purified. The product was eluted with 5-10% ethyl acetate / hexane to give C10-acid-TG-oleate Intermediate-113 (60 mg, 30%) as a viscous liquid. 1 H NMR (400 MHz, CDCl3) δ 5.43 (m, 4H), 5.29 (m, 1H), 4.35 (d , 2H), 4.20 (m, 2H), 2.40 (m, 8H), 2.05 (m, 8H), 1.65 (m, 10H), 1.33-1.18 (m 46 H), 0.93 (t, 6H); 13 C NMR (101 MHz, CDCl3) δ 1.78 (1C, C=O, 173.3 (2C, C=O), 172.8 (1C, C=O), 130.1 (2C), 129.8 (2C), 68.9 (C, CH), 62.1 (2C), 60.5 (2C), 34.2 (4C), 31.9 (2C), 29.8-29.0 (18C), 27.3 (4C), 24.9 (4C), 22.7 (2C),14.2 (2C). HPLC (ELSD): 10.90 min, purity 99%. MS (ESI, +ve) m / z: 823.8 (MH + +H2O). Alternative procedure (large scale): To a stirred solution of Intermediate-112 (3.00 g, 4.80 mmol) and sebacic acid (1.94 g, 9.60 mmol) in DCM (45 ml) was added 4-(dimethylamino)pyridine (DMAP, 0.58 g, 4.80 mmol), followed by EDC·HCl (1.82 g, 9.60 mmol). The resulting reaction mixture was stirred at room temperature for 6 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give a crude sticky material, which was purified by column chromatography using silica gel (100-200 mesh). The pure compound was eluted with 15% ethyl acetate and hexane as the mobile phase. The pure fractions were concentrated under reduced pressure to give pure Intermediate-113 (2.95 g). , 75.8%) was obtained as a viscous liquid.

[0453] Intermediate-115 (1,3-DG-Butyrate):

[0454] [ka]

[0455] To a solution of 2,5-bis-(hydroxymethyl)-1,4-dioxane-2,5-diol (2.0 g, 1.11 mmol) in chloroform (40 ml), pyridine (2.2 mL, 2.77 mmol) was added, followed by butyryl chloride (2.3 mL, 2.22 mol), and then stirred at room temperature for 16 hours. After completion, the solvent was evaporated, redissolved in ethyl acetate (60 ml), and washed with 1N HCl (20 ml). The combined organic layers were dried and evaporated under vacuum. The crude material was purified by column chromatography. The product was eluted with 5-10% ethyl acetate / hexane to give Intermediate-114 (1.4 g, 54%) as a viscous liquid. 1 H NMR (400 MHz, CDCl3) δ 4.8 (s, 4H), 2. 45 (t, 4H), 1.79-1.69 (m, 4H), 1.04-0.98 (t , 6H); 13C NMR (101 MHz, CDCl3) δ 198.2 (1C=O), 172.2 (2C=O), 66.1 (2C), 35.9 (2C), 18.3 (2C), 14.1 (2C). HPLC (ELSD): 1.73 min, purity 99.8 %. Sodium borohydride (NaBH4, 230 mg, 6.10 mmol) was added to a solution of Intermediate-114 (1.3 g, 6.1 mmol) in THF (26 ml) at 0 °C, and then the reaction mixture was stirred at room temperature for 15 minutes. The reaction was monitored by TLC, and upon completion, the reaction mixture was filtered through a Celite bed to remove excess sodium borohydride, the Celite bed was washed with ethyl acetate (40 ml), and the combined organic layer was washed with a 1N solution of acetic acid (13 ml). The organic layer was dried over Na2SO4, and the solvent was removed under vacuum. The crude material was purified by column chromatography. The product was eluted with 5-10% ethyl acetate / hexane to give Intermediate-115 (1.0 g, 70.6%) as a viscous liquid. 1 H NMR (400 MHz, CDCl3) δ 4.25-4.13 (m, 5H), 2.4 (s, 1H), 2.38 (t, 4H), 1.75-1.66 (m, 4H), 1.01-0.98 (t, 6H); 13 C NMR (101 MHz, CD Cl3) δ 173.8 (2C=O), 68.3 (1C), 65.0 (2C), 35.9 (2C), 18.4 (2C), 13.6 (2C). HPLC (ELSD) : 1.8 min, 100% purity. MS (ESI, +ve) m / z: 255.37 (M + + 23). Intermediate-125:

[0456] [ka]

[0457] Intermediate-45 was prepared as described above and coupled with Intermediate-115 using EDC and DMAP in a manner similar to that described above to give Intermediate-124. Intermediate-124: 1 H NMR (401 MHz, CDCl3) δ 7.70 - 7.64 (m, 4H), 7.42 - 7.35 (m, 6H), 5.29 (m, 1H), 4.307 / 4.305 (each dd, J = 11.9, 4.2 Hz, 2H), 4.159 / 4.157 (each dd, J = 11.9, 6.0 Hz, 2H), 3.66 (t, J = 6.5 Hz, 2H), 2.34 (dd, J = 14.7, 5.9 Hz, 1H), 2.30 (t, J = 7.4 Hz, 4H), 2.13 (dd, J = 14.7, 8.3 Hz, 1H), 1.95 (m, 1H), 1.70 - 1.50 (m, 6H), 1.37 - 1.17 (m, 20H), 1.05 ( s, 9H), 0.95 (t, J = 7.5 Hz, 6H). 0.94 (d, J = 6.4 Hz, 3H); 13 C NMR (101 MHz, CDCl3) δ 173. 2 (2C;C), 172.5 (C), 135.7 (4C;CH), 134.3 ( 2C;C), 129.6 (2C;CH), 127.7 (4C;CH), 68.9 (CH), 64.1 (CH2), 62.3 (2C;CH2), 41.8 (CH2), 36.8 (CH2), 36.0 (2C;CH2), 32.7 (CH2), 30. 5 (CH), 29.9 (CH2), 29.80 (3C;CH2), 29.76 ( CH2), 29.75 (CH2), 29.5 (CH2), 27.1 (CH2), 27.0 (3C;CH3), 25.9 (CH2), 19.7 (CH3), 19.3 (C) 18.5 (2C;CH2), 13.7 (2C;CH3). Intermediate-125: Tetrabutylammonium fluoride (TBAF, 1.0 M in THF, 243 μL, 0.243 mmol) and AcOH (13.9 μL, 0.243 mmol) were added dropwise to TBDPS ether 3 (58.7 mg, 0.0809 mmol) in THF (4 mL) at 0 °C, and the mixture was stirred at room temperature for 19 h. The reaction was diluted with water (10 mL), and the aqueous phase was extracted with ethyl acetate (3 × 15 mL). The combined organic extracts were washed with saturated aqueous NaHCO and brine (30 mL each), dried (MgSO), and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (6% to 20% ethyl acetate / hexanes) afforded alcohol intermediate-125 (26.7 mg, 68%) as a colorless oil. 1 H NMR (401 MHz, CDCl3) δ 5.28 (m, 1H), 4.298 / 4.295 (each dd, J = 11.9, 4.3 Hz, 2H) , 4.153 / 4.151 (each dd, J = 11.9, 6.0 Hz, 2H ), 3.64 (t, J = 6.6 Hz, 2H), 2.33 (dd, J = 14.7, 5.9 Hz, 1H), 2.30 (t, J = 8.4, 6.5 Hz, 4H) , 2.12 (dd, J = 14.7, 8.3 Hz, 1H), 1.93 (m, 1 H), 1.70 - 1.46 (m, 8H), 1.38 - 1.16 (m, 18H) , 0.95 (t, J = 7.4 Hz, 6H), 0.93 (d, J = 6.7 H z, 3H); 13C NMR (101 MHz, CDCl3) δ 173.3 (2C;C), 172.5 (C), 69.0 (CH), 63.2 (CH2), 62.3 (2C;CH2), 41.9 (CH2), 36.8 (CH2), 36.1 (2C;CH2), 33.0 (CH2), 30.5 (CH), 29.9 (CH2), 29. 78 (CH2), 29.76 (2C;CH2), 29.74 (CH2), 29.71 (CH2), 29.6 (CH2), 27.1 (CH2), 25.9 (CH2) , 19.7 (CH3), 18.5 (2C;CH2), 13.8 (2C;CH3). Intermediate-126:

[0458] [ka]

[0459] Prepared using a method similar to that shown above. 1 H NMR (401 MHz , CDCl3) δ 5.23 (m, 1H), 4.26 (dd, J = 11.9, 4.3 Hz, 2H), 4.11 (dd, J = 11.9, 6.0 Hz, 2H), 3.36 (t, J = 6.9 Hz, 2H), 2.28 (t, J = 7.4 Hz , 2H), 2.26 (t, J = 7.4 Hz, 4H), 1.84 - 1.75 (m, 2H), 1.66 - 1.52 (m, 6H), 1.42 - 1.33 (m, 2H), 1.31 - 1.19 (m, 12H), 0.90 (t, J = 7.4H z, 6H); 13 C NMR (101 MHz, CDCl3) δ 173.1 (2C;C), 172.9 (C), 68.9 (CH), 62.1 (2C;CH2), 35 .9 (2C;CH2), 34.2 (CH2), 34.0 (CH2), 32.9 ( CH2), 29.5 (CH2), 29.43 (CH2), 29.42 (CH2), 29.3 (CH2), 29.1 (CH2), 28.8 (CH2), 28.2 (CH2), 24.9 (CH2), 18.4 (2C;CH2), 13.7 (2C;CH3);ESI-HRMS: C 23 H 41 79 BrNaO6[M + Na + ] calculated value 515.1979; measured value 515.1995. Intermediate-117 1,3-bis-decanoylglycerol (1,3-DG-decanoate):

[0460] [ka]

[0461] To a solution of 2,5-bis-(hydroxymethyl)-1,4-dioxane-2,5-diol (0.2 g, 1.11 mmol) in chloroform (4.0 ml) was added pyridine (0.2 The mixture was stirred at room temperature for 16 hours. The solvent was evaporated, redissolved in ethyl acetate (6 ml) and washed with 1N HCl (2 ml). The organic layer was dried and the solvent was evaporated under vacuum. The crude material was purified by column chromatography. The product was eluted with 5-10% ethyl acetate / hexane to give Intermediate-116 (0.09 g, 20.36%) as a viscous liquid. 1 H NMR (400 MHz, CDCl3) δ 4.8 (m, 4H), 2.46 (m, 4H), 1.73-1.66 (m, 4H), 1.30 (m, 24H), 0.91 (t, 6H); 13 C NMR (101 MHz, CDCl3) δ 198.2 (1C=O), 172.0 (2C=O), 66.1 (2C), 33.7 (2C) , 31.8 (2C), 29.3 (2C), 29.2 (2C), 29.0 (2C), 24.8 (2C), 22.6 (2C), 14.12 (2C). HPLC (ELSD): 2.88 min, 100% purity. Sodium borohydride (NaBH4) (7 mg, 0.2 mmol) was added to a solution of Intermediate-116 (80 mg, 0.2 mmol) in THF (2 ml) at 0 °C, and then the reaction mixture was stirred at room temperature for 15 minutes. The reaction was monitored by TLC, and after completion, the reaction mixture was filtered through a celite bed to remove excess sodium borohydride, and the celite bed was washed with ethyl acetate (3 ml). The organic layer was washed with 1 M acetic acid (1 ml). The solvent was dried over Na2SO4, and the solvent was removed under vacuum. The crude material was purified by column chromatography. The product was eluted with 5-10% ethyl acetate / hexane to give Intermediate-117 (70 mg, 100%) as a viscous liquid. 1 H NMR (400 MHz, CDCl3) δ 4.2-4.1 (m, 5H), 2.51 (s, 1H) , 2.38 (t, 4H), 1.68-1.64 (m, 4H), 1.32-1.2 9 (m, 22H), 0.91 (t, 6H); 13 C NMR (101 MHz, C DCl3) δ 173.0 (2C=O), 68.3 (1C), 65.0 (2C), 34.1 (2C), 31.8 (2C), 29.7 (2C), 29.4 (2C), 29.3 (2C), 29.1 (2C), 24.9 (2C), 22.7 (2C), 14.1 (2C). HPLC (ELSD): 10.70 min, purity 97.6%. Intermediate-123:

[0462] [ka]

[0463] Tetra-n-butylammonium hydrogen sulfate (0.034 g, 0.098 mmol) and potassium bicarbonate (0.198 g, 1.977 mmol) in distilled water (10 ml) were added to a stirred solution of Intermediate-81 (0.4 g, 0.494 mmol) and tetra-n-butylammonium hydrogen sulfate (0.034 g, 0.098 mmol) in dichloromethane (10 ml) at room temperature and stirred for 0.5 hours. Then chloromethyl chlorosulfate (0.06 A solution of 123 ml (2 ml, 0.618 mmol) was added dropwise at room temperature and stirred vigorously for 18 hours at room temperature. The reaction was monitored by TLC, and after completion of the reaction, the reaction mixture was diluted with DCM (25 ml). The organic phase was separated, and the aqueous phase was extracted with DCM (2 x 50 ml). The combined organic layers were washed with water (50 ml), brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude material. The crude material was purified by silica 100-200 mesh column chromatography, and the compound was eluted with 20% ethyl acetate / hexane as the mobile phase and visualized with KMnO4 solution. Intermediate-123 (0.250 g, 59%) was obtained as a viscous liquid. 1 H NMR (400 MHz, CDCl3) δ 5.75 (m, 2H), 5.32-5.30 (m, 1H), 4.33 (dd, J = 11.9, 4.3 Hz, 2H), 4.18 (dd, J = 11.9, 6.0 Hz, 2H), 2.56-2.45 (m, 2H), 2.36-2.32 (t, J =7.2 Hz, 4H), 1.66-1.62 (m,4H), 1.48-1.40 (m,8H), 1.29 (m, 56H), 1.19 (dd, J = 11.2, 7. 0 Hz, 6H), 0.92 (t, J = 6.7 Hz, 6H). Using a similar method, Intermediate-155 was prepared.

[0464] [ka]

[0465] Tetra-n-butylammonium hydrogen sulfate (24 mg, 0.072 mmol) and potassium bicarbonate (286 mg, 2.86 mmol) in distilled water (10 ml) were added to a stirred solution of acid linker intermediate-4 (0.5 g, 0.72 mmol) and tetra-n-butylammonium hydrogen sulfate (24 mg, 0.072 mmol) in dichloromethane (10 ml) at room temperature and stirred for 0.5 hours. Chloromethyl chlorosulfate (0.092 ml, 0.89 mmol) was then added dropwise at room temperature and vigorously stirred at room temperature for 18 hours. The reaction was monitored by TLC, and after completion of the reaction, the reaction mixture was diluted with DCM (5 ml). The organic phase was separated, and the aqueous phase was extracted with DCM (2 × 5 ml). The combined organic layers were washed with water (10 ml), brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude material. The crude material was purified by silica column chromatography, and the compound was eluted with 15% ethyl acetate / hexane as the mobile phase. Pure fractions were concentrated in a rotavap to give intermediate-155 C5bMe chloromethyl ester (0.250 g, 47%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 5.76 (s, 2H), 5.33 (m, 1H), 4.34 (dd, 2H), 4.18 (dd, 2H), 2.5-2.3 (m, 8H), 1.66-1.6 4 (m, 2H), 1.60 (s, 3H), 1.29 (m, 48H), 1.09 (d, 3H), 0.91 (t, 6H).MS (ESI, +ve) m / z: 763 (MH + +18). C15-acid-2-TG (intermediate-129):

[0466] [ka]

[0467] 4-(Dimethylamino)pyridine (22.5 mg, 0.184 mmol) and N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide (EDC·HCl, 88.3 mg, 0.461 mmol) were added to a solution of pentadecanedioic acid (100 mg, 0.369 mmol) and compound Intermediate-2 (105 mg, 0.184 mmol) in CHCl (5 mL), and the mixture was stirred at room temperature for 17 h. The reaction was diluted with CHCl (10 mL), silica gel was added, and the mixture was concentrated under reduced pressure. Purification by silica gel chromatography (15% to 25% ethyl acetate / hexane) afforded Intermediate-129 (C15-acid-2-TG) (113 mg, 75%) as a colorless solid. 1 HN MR (401 MHz, CDCl3) δ 5.26 (m, 1H), 4.29 (dd , J = 11.9, 4.3 Hz, 2H), 4.14 (dd, J = 11.9, 6.0 Hz, 2H), 2.34 (t, J = 7.5 Hz, 2H), 2.31 (t , J = 7.5 Hz, 2H), 2.30 (t, J = 7.5 Hz, 4H), 1 .67 - 1.56 (m, 8H), 1.38 - 1.17 (m, 66H), 0.87 (t, J = 6.8 Hz, 6H); 13 C NMR (101 MHz, CDCl3) δ 179.6 (C), 173.5 (2C;C), 173.0 (C), 69.0 (CH), 62.2 (2C;CH2), 34.4 (CH2), 34.2 (2C; CH2), 34.1 (CH2), 32.1 (2C;CH2), 29.84 (6C;CH2), 29.80 (4C;CH2), 29.76 (2C;CH2), 29.7 5 (2C;CH2), 29.72 (CH2), 29.62 (2C;CH2), 29.58 (CH2), 29.50 (2C;CH2), 29.43 (CH2), 29.41 (2C;CH2), 29.38 (CH2), 29.25 (2C;CH2), 29.21 (2C;CH2), 25.03 (CH2), 25.00 (2C;CH2) , 24.8 (CH2), 22.8 (2C;CH2), 14.3 (2C;CH3). MASI-C12α'αMe-chloride-2-TG (Intermediate-136):

[0468] [ka]

[0469] A solution of Intermediate-81 (0.5 g, 0.618 mmol) in DCM (5 ml), DMF (2 drops) and oxalyl chloride (1.1 ml, 12.36 mmol) was added at 0° C., followed by The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, then coevaporated three times with DCM (5 mL each) and dried under reduced pressure. The resulting acid chloride was dissolved in DCM (20 mL), and then ZrCl4 (0.33 g, 1.45 mmol) in DCM (10 mL) was added dropwise to the reaction mixture at 0 °C and stirred at 0 °C for 10 minutes. Paraldehyde (0.383 g, 2.90 mmol) was then added, and the reaction mixture was stirred at 0 °C for 0.5 hours and at room temperature for 1 hour. The reaction mixture was diluted with DCM (50 mL) and water (50 mL). The organic layer was washed with water (25 mL) and brine (25 mL), dried over Na2SO4, and concentrated under reduced pressure to give the crude product. Purification by column chromatography on silica gel eluting with 5% to 15% ethyl acetate / hexane gave Intermediate-136 (0.135 g, 21%) as a viscous oil. 1H NMR (400 MHz, CDCl3) δ 6.61-6.57 (q, 1H), 5.32 (m, 1H), 4.33 (dd, J = 11.6, 3.7 Hz, 2H), 4.19 (dd, J = 11.9, 6.1 Hz, 2H), 2.49 (m, 2H), 2.34 (t, J = 7.6 Hz, 4H), 1.83 (d, J = 5.6 Hz, 2H), 1.72-1.62 (m, 4H), 1.49-1.40 (m, 5H). 1.38 -1.29 (m, 60H), 1.24 - 1.17(m, 6H), 0.92 (t, 6H). MASI-C12α'βMe-chloride-2-TG (Intermediate-142):

[0470] [ka]

[0471] A solution of Intermediate-27 (0.5 g, 0.618 mmol) in DCM (5 mL), DMF (2 drops), and oxalyl chloride (1.1 mL, 12.36 mmol) were added at 0° C., and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, then coevaporated three times with DCM (5 mL each), and dried under reduced pressure. The resulting acid chloride was dissolved in DCM (20 mL), and ZrCl4 (0.33 g, 1.45 mmol) in DCM (10 mL) was added dropwise to the reaction mixture at 0° C. and stirred at 0° C. for 10 minutes. Paraldehyde (0.383 g, 2.90 mmol) was then added, and the reaction mixture was stirred at 0° C. for 0.5 hours and at room temperature for 1 hour. The reaction mixture was diluted with DCM (50 mL) and water (50 mL). The organic layer was washed with water (25 mL) and brine (25 mL), dried over NaSO, and concentrated under reduced pressure to give the crude product. Purification by column chromatography on silica gel eluting with 5% to 15% ethyl acetate / hexane gave Intermediate-142 (0.170 g, 32%) as a viscous oil. 1 H NMR (400 MHz, CDCl3) δ 6.61 - 6.57 (q, J = 5.6 Hz, 1H), 5.3 2 (m, 1H), 4.33 (dd, J = 11.6, 3.7 Hz, 2H), 4 .19 (dd, J = 11.9, 6.1 Hz, 2H), 2.49 (m, 2H), 2.39 - 2.32 (t, J = 7.6 Hz, 6H), 2.18 - 2.12 (m, 2H), 2.08 - 1.97(m,2H), 1.83 (d, J = 5.6 Hz, 3H), 1.64-1.56 (m, 8H), 1.38 - 1.29 (m, 54H), 1.21 - 1.19 (m, 6H), 0.92 (t, J = 6.0H z, 6H). MASI-C10-chloride-2-TG (Intermediate-165):

[0472] [ka]

[0473] A solution of intermediate-9 (1.0 g, 1.32 mmol) in DMF (2 drops) and SOCl (0.98 mL, 13.29 mmol) was heated to reflux for 1.25 h. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, coevaporated three times with toluene (5 mL each), and dried under reduced pressure. The resulting acid chloride was dissolved in DCM (20 mL) and cooled to 0 °C. A solution of ZrCl (309 mg, 1.32 mmol) in DCM (10 mL) was added dropwise, and the mixture was stirred at 0 °C for 10 min. Paraldehyde (351 mg, 2.65 mmol) was added, and the reaction mixture was stirred at 0 °C for 0.5 h and at room temperature for 1 h. The reaction mixture was diluted with DCM (10 mL) and water (10 mL). The organic phase was washed with water and brine (10 mL each), dried over Na SO , and concentrated under reduced pressure. The resulting material was purified by silica gel column chromatography by eluting the compound with 5%-15% ethyl acetate / hexane and concentrated under reduced pressure to give Intermediate-165 (300 mg, 30%) as a brown oil. 1H NMR (400 MHz, CDCl3) δ 6.59 ( d, J = 5.8 Hz, 1H), 5.30 (t, J = 5.5 Hz, 1H), 4.26 (dd, J = 11.9, 5.1 Hz, 2H), 4.18 (dd, J = 11.6, 5.9 Hz, 2H), 2.40 - 2.33 (m, 8H), 1.83 (d, J = 5.9 Hz, 3H), 1.67 (m, 12H), 1.32 (s , 52H), 0.92 (t, J = 6.6 Hz, 6H). MASI-C5βMe-chloride-2-TG (Intermediate-166):

[0474]

change

[0475] The synthesis method of Intermediate-165 is described and the method is used, and the compound of Intermediate-4 and Intermediate-166 is prepared. 1 H NMR (400 MHz, CDCl3) δ 6.59 ( d, J = 5.8 Hz, 1H), 5.46 - 5.22 (m, 1H), 4.35 (dd, J = 12.0, 4.2 Hz, 2H), 4.18 (dd, J = 11. 9, 6.0 Hz, 2H), 2.56 - 2.41 (m, 3H), 2.40 - 2 .27 (m, 6H), 1.83 (d, J = 5.8 Hz, 3H), 1.64 ( m, 4H), 1.31 (d, J = 9.6 Hz, 48H), 1.09 (dd, J = 6.6, 2.6 Hz, 3H), 0.92 (t, J = 6.7 Hz, 6H). C10α'αMe-acid-2-TG (Intermediate-150):

[0476]

change

[0477] Intermediate C10α'αMe-acid-2-TG (Intermediate-150) was prepared from hexane-1,6-diol as shown in Scheme 38 using the method described above. 1 H NMR (400 MHz, CDCl3) δ 5.35 - 5.24 (m, ...

Claims

1. Compounds of Formula I 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, R １ and R ２ are each independently hydrogen, an acid labile group, a lipid, or —C(O)R ３ and Each R ３ is independently saturated or unsaturated, linear or branched, and optionally substituted C １－３７ is a hydrocarbon chain; X is —O—, —NR—, —S—, —O(C １－６ aliphatic) -O-, -O(C １－６ aliphatic) -S-, -O(C １－６ aliphatic) -NR-, -S(C １－６ aliphatic) -O-, -S(C １－６ aliphatic) -S-, -S(C １－６ aliphatic) -NR-, -NR(C １－６ aliphatic) -O-, -NR(C １－６ aliphatic)-S-, or -NR(C １－６ aliphatic)-NR-, １－６ 0 to 2 methylene units of the aliphatic group are optionally replaced independently by —O—, —NR—, or —S—; １－６ aliphatic groups are optionally substituted independently with 1, 2, or 3 deuterium or halogen atoms; Each R is independently hydrogen or C １－６ an optionally substituted group selected from an aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocycle, a phenyl, an 8-10 membered bicyclic aromatic carbocycle, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Y is absent or is —C(O)—, —C(NR)—, or —C(S)—; L is a covalent bond or a saturated or unsaturated, linear or branched, optionally substituted divalent C １－３０ It is a hydrocarbon chain, and 0 to 8 methylene units of L are -Cy-, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O) ２ -, -C(S)-, -NRS(O) ２ -, -S(O) ２ independently replaced by NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, —NRC(O)O—, or an amino acid; one methylene unit of L is optionally replaced by -M—; or L is, 【Chemistry 2】 wherein either the right or left side of L is attached to A; Each -Cy- is independently 0 to 4 hetero atoms independently selected from nitrogen, oxygen, or sulfur. an optionally substituted 3- to 6-membered bivalent saturated, partially unsaturated, or aromatic ring having a heteroatom; Each R ４ and R ５ are independently hydrogen, deuterium, halogen, —CN, —OR, —NR ２ , -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8-10 membered bicyclic aromatic carbocycle, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or ２ , -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8-10 membered bicyclic aromatic carbocycle, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, C １－６ an aliphatic group, or １－６ aliphatic is optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; or Two R bonded to the same carbon atom ４ or R ５ together with the carbon atoms to which they are attached form a 3- to 6-membered spirocyclic saturated monocyclic carbocyclic ring or a 3- to 6-membered spirocyclic saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; -M- is a self-immolative group; n is 0 to 18; each m is independently 0 to 6; A is a therapeutic agent selected from naturally occurring or non-naturally occurring pregnane neurosteroids, or analogs or prodrugs thereof.

2. R １ and R ２ -C(O)R ３ 2. The compound of claim 1, wherein:

3. Each R ３ are independently saturated or unsaturated unbranched C ２－３７ 3. The compound of claim 1 or 2, which is a hydrocarbon chain.

4. The compound according to any one of claims 1 to 3, wherein X is -O-.

5. The compound according to any one of claims 1 to 4, wherein Y is -C(O)-.

6. L is a saturated or unsaturated, linear or branched, optionally substituted divalent C ７－２０ It is a hydrocarbon chain, and 0 to 8 methylene units of L are -Cy-, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O) ２ -, -C(S)-, -NRS(O) ２ -, -S(O) ２ 6. The compound of any one of claims 1 to 5, wherein each of L is independently replaced by NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O-, or an amino acid; and one methylene unit of L is optionally replaced by -M-.

7. L is a covalent bond or a saturated or unsaturated, linear or branched, optionally substituted divalent C １－３０ It is a hydrocarbon chain, and 0 to 8 methylene units of L are -Cy-, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O) ２ -, -C(S)-, -NRS(O) ２ -, -S(O) ２ NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, —NRC(O)O—, or 【Transformation 3】 one methylene unit of L is optionally replaced by -M-; or L, 【Chemistry 4】 and either the right or left side of L is bonded to A.

8. L is selected from the group consisting of deuterium, halogen, -CN, a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 4-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from phenyl, nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or C optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms. １－６ optionally selected from 1, 2, 3, or 4 groups selected from aliphatic groups; saturated divalent C substituted with １－２５ 6. The compound of any one of claims 1 to 5, wherein L is a hydrocarbon chain; 0 to 4 methylene units of L are independently replaced by -O-, -OC(O)-, -C(O)O-, or -C(O)-; and one methylene unit of L is optionally replaced by -M-.

9. -M- is one of the following: 【Transformation 5】 is selected from one of In the formula, each R ６ However, hydrogen, deuterium, C １－５ independently selected from aliphatic, halogen, or —CN; Each R ７ is hydrogen, deuterium, halogen, -CN, -OR, -NR ２ , -NO ２ , -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8-10 membered bicyclic aromatic carbocycle, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or ２ , -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8-10 membered bicyclic aromatic carbocycle, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, C １－６ an aliphatic group, or １－６ aliphatic is optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; Each Z １ is independently selected from —O—, —NR—, or —S—; Each Z ２ are independently selected from —O—, —NR—, —S—, —OC(O)—, —NRC(O)O—, or —OC(O)NR—; Each Z ３ is independently selected from =N- or =C(R7)-; Each Z ４ is -O-, -NR-, -S-, -C(R ６ ) ２ 9. The compound of any one of claims 1 to 8, wherein each of the groups is independently selected from: -; or a covalent bond.

10. -M-, 【Transformation 6】 10. The compound of claim 9 selected from:

11. -M-, 【Transformation 7】 11. The compound according to claim 9 or 10, selected from:

12. Each R ４ are independently hydrogen, deuterium, halogen, —CN, or C optionally substituted by 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; １－４ aliphatic; or two R ４ together with the carbon atoms to which they are attached form a 3- to 6-membered spirocyclic saturated monocyclic carbocyclic ring or a 3- to 6-membered spirocyclic saturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

13. Each R ５ are independently hydrogen, deuterium, halogen, —CN, or C optionally substituted by 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; １－４ aliphatic; or two R ５ together with the carbon atoms to which they are attached form a 3- to 6-membered spirocyclic saturated monocyclic carbocyclic ring or a 3- to 6-membered spirocyclic saturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

14. Each R ４ and R ５ are optionally substituted by hydrogen, or 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; １－４ The compound of any one of claims 1 to 13, which is alkyl.

15. 14. The compound of any one of claims 1 to 13, wherein A is selected from allopregnanolone, pregnanolone, pregnenolone, ganaxolone, alphaxalone, 3β-dihydropregesterone, isopregnanolone, epipregnanolone, or 21-hydroxyallopregnanolone.

16. The compound of any one of claims 1 to 14, wherein A is allopregnanolone.

17. The compound has the formula VIII-a or VIII-b: 【Transformation 8】 12. The compound of any one of claims 1 to 11, which is: or a pharmaceutically acceptable salt thereof.

18. 2. The compound of claim 1, wherein the compound is selected from one of those in Table 1, or a pharmaceutically acceptable salt thereof.

19. A pharmaceutically acceptable composition comprising a compound according to any one of claims 1 to 18 and a pharmaceutically acceptable excipient, carrier, adjuvant, or vehicle.

20. 20. The pharmaceutically acceptable composition of claim 19, further comprising an additional therapeutic agent.

21. 21. The pharmaceutically acceptable composition of claim 19 or 20, wherein the composition is formulated for oral administration.

22. 20. A method for treating or preventing a disease, disorder, or condition in which increased levels of a pregnane neurosteroid are beneficial, or a disease, disorder, or condition caused by a deficiency of a pregnane neurosteroid, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1 to 18.

23. A method for treating GABAergic disorders, comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 18. Ａ A method for treating a disease, disorder, or condition caused by a deficiency in the activation of

24. 24. The method of claim 22 or 23, wherein the disease, disorder, or condition is selected from postpartum depression, depression, major depressive disorder, bipolar disorder, mood disorder, anxiety, post-traumatic stress disorder (PTSD), premenstrual dysphoric disorder (PMDD), premenstrual syndrome, generalized anxiety disorder, seasonal affective disorder (SAD), social anxiety, memory loss, low stress tolerance, Niemann-Pick disease type C or related neurological or physical symptoms, epilepsy, essential tremor, epileptiform disorder, NMDA dysfunction, migraine, status epilepticus, sleep disorder, fragile X syndrome, 5-alpha reductase inhibitor-induced depression, PCDH19 female epilepsy, sexual dysfunction, Parkinson's disease, or Alzheimer's disease.

25. 25. The method of claim 24, wherein the disease, disorder, or condition is selected from postpartum depression, depression, major depressive disorder, bipolar disorder, Niemann-Pick type C, epilepsy, essential tremor, epileptiform disorder, NMDA dysfunction, status epilepticus, highly refractory status epilepticus (SRSE), Parkinson's disease, or Alzheimer's disease.

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