Lipid prodrugs of neurosteroids

Abstract

The present invention provides lymphatic-directed lipid prodrugs, pharmaceutical compositions thereof, methods for producing such prodrugs and compositions, and methods for improving the bioavailability or other properties of therapeutic agents that comprise a lipid prodrug moiety. The present invention also provides methods for treating a disease, disorder, or condition (such as those disclosed herein), comprising administering to a patient in need thereof a disclosed lipid prodrug or pharmaceutical composition thereof.

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 followed by enhanced release of the parent drug. The invention also relates to compositions of such prodrugs and methods of use thereof.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. US62 / 970,607, filed February 5, 2020, U.S. Provisional Patent Application No. US63 / 009,533, filed April 14, 2020, and U.S. Provisional Patent Application No. US63 / 070,064, filed August 25, 2020, each of which is incorporated by reference in its entirety. [Background technology]

[0003] Neurosteroids are steroids synthesized in the brain and regulate neuronal excitability through rapid, non-genomic actions. Originally coined by French physiologist Etienne Baulieu, the term "neurosteroid" is now widely used to refer to steroids synthesized in the brain. Circulating steroid hormones serve as precursors for the synthesis of neurosteroids produced locally in the hippocampus and other brain structures. Imbalances in neurosteroid levels are associated with numerous diseases, disorders, and pathologies. They are classified as pregnane neurosteroids (e.g., allopregnanolone and allotetrahydrodeoxycorticosterone) and androstane neurosteroids (e.g., androstanediol and etiocholanone). Neurosteroids, such as allopregnanolone, are positive allosteric modulators of GABA-A receptors with potent antiseizure activity in various animal models. Neurosteroids increase both synaptic and tonic inhibition. They are endogenous regulators of seizure susceptibility, anxiety, and stress. Sulfated neurosteroids, such as pregnenolone sulfate, which are negative GABA-A receptor modulators, are memory enhancers. Sex differences in susceptibility to brain disorders may be due to neurosteroid and sexual dimorphism in specific structures of the human brain. Synthetic neurosteroids that exhibit better bioavailability and efficacy, as well as drugs that improve neurosteroid synthesis, have therapeutic potential for anxiety, epilepsy, and other brain disorders.

[0004] However, the therapeutic use of neurosteroids has been hampered by challenges with selective delivery to specific tissues of the body, such as the brain, as well as unwanted metabolism of neurosteroids when delivered orally.

[0005] 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 several 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.

[0006] Lymphatic drug transport has the potential to improve oral bioavailability by avoiding first-pass metabolism, alter systemic pharmacokinetics, and enhance efficacy against lymphatic or lymphocyte-mediated pathologies such as lymphoma, leukemia, lymphatic 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 by intestinal absorptive cells (enterocytes) in response to lipid absorption. Association with these lipoproteins then facilitates drug transport into the lymph, as their size precludes facile diffusion across the vascular endothelium lining the capillaries draining the small intestine. Instead, these large colloidal structures enter lymphatic capillaries because the lymphatic endothelium is significantly more permeable than the vascular endothelium.

[0007] 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 facilitate physical association with lipoproteins. Therefore, highly lipophilic analogs of drugs have been envisioned as one means to enhance lymphatic transport of drugs. However, chemical modification of the parent drug can result in reduced efficacy, and in many cases, significant increases in lipophilicity have been correlated with increased toxicity.

[0008] Compounds in the form of lipophilic prodrugs provide a means to temporarily increase the lipophilicity and lipoprotein affinity of pharmaceutical compounds, thereby increasing lymphatic targeting. Upon transport through the lymphatic system, the prodrug is cleaved, thereby releasing the parent drug for activity at its target site. Summary of the Invention [Problem to be solved by the invention]

[0009] Therefore, there is a need to develop novel lipid-drug conjugates that facilitate stable transport of drugs to the intestinal lymph and that readily revert to the active parent drug. The present invention addresses this need and also provides other related advantages. [Means for solving the problem]

[0010] In one aspect, the present invention provides a compound of formula I:

[0011] [ka]

[0012] or a pharmaceutically acceptable salt thereof, wherein each variable is as defined herein.

[0013] In another aspect, the present invention provides a method of treating a disease, disorder, or condition (such as one of those disclosed herein), the method comprising administering to a patient in need thereof an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof. DETAILED DESCRIPTION OF THE INVENTION

[0014] 1. Overview of Certain Embodiments of the Invention Lymphatic-directed prodrugs The compounds of the present invention, and compositions thereof, are useful in facilitating the transport of therapeutic agents into the lymphatic system, followed by enhanced 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, wherein R 1 and R 2 each independently represents hydrogen, an acid labile group, a lipid, or —C(O)R 3 and Each R 3 are independently saturated or unsaturated, straight chain or branched, 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-, and the C 1-6 0 to 2 methylene units of the aliphatic group are independently and optionally replaced with -O-, -NR-, or -S-, and the C 1-6 aliphatic groups are independently and optionally substituted with 1, 2, or 3 deuterium or halogen atoms; Each R is independently hydrogen or C 1-6an 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 heterocycle 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 a hydrocarbon chain in which 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, and one methylene unit of L is optionally replaced by -M-; or L,

[0018] [ka]

[0019] and either the right or left side of L is

[0020] [ka]

[0021] is bound to 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 R4 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 heterocycle 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. ring or is optionally substituted with -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 heterocycle 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 Aliphatic group (or the C 1-6 aliphatic optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; or R attached to the same carbon atom 4 or R 5 two occurrences of 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;

[0022] [ka]

[0023] is a therapeutic agent selected from naturally occurring or non-naturally occurring neurosteroids or analogs or prodrugs thereof.

[0024] In one aspect, the invention provides a method of treating a disease, disorder, or condition in a patient in need thereof, the method 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.

[0025] It is understood that the disclosed lipid prodrugs may exist in the form of a pharmaceutically acceptable salt. Thus, 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 may be used in pharmaceutical compositions and methods of use, such as those disclosed herein.

[0026] One strategy for 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 that include neurosteroids, such as pregnane neurosteroids, conjugated to glycerol-based moieties 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.

[0027] Dietary lipids, including triglycerides, gain access to the lymphatic (and ultimately the systemic circulation) through specific metabolic pathways that are distinct from other nutrients such as proteins and carbohydrates. After ingestion, dietary triglycerides are hydrolyzed in the lumen by lipases to release one monoglyceride and two fatty acids per triglyceride molecule. The monoglyceride and two fatty acids are then absorbed into enterocytes and re-esterified to triglycerides.

[0028] Re-synthesized triglycerides are assembled into intestinal lipoproteins (primarily chylomicrons). After formation, chylomicrons are released from enterocytes by exocytosis and then gain preferential 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 taken up by tissues with high expression levels of lipoprotein lipase, such as adipose tissue, liver, and potentially certain types of tumor tissue.

[0029] 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 a neurosteroid, such as a pregnane neurosteroid, after the prodrug reaches the systemic circulation or a target tissue. In some embodiments, the lipid prodrug releases a neurosteroid, such as a pregnane neurosteroid, by destruction of a self-immolative linker connecting the neurosteroid to the glycerol-derived group or by enzymatic cleavage of the linker. In this way, the pharmacokinetic and pharmacodynamic profiles of the parent neurosteroid may be manipulated to improve access to lymph and lymphatic tissues, thereby promoting 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 hepatotoxicity, or other improved pharmacokinetic properties compared to the parent neurosteroid. In some embodiments, the disclosed lipid prodrugs have increased drug targeting (compared to the parent therapeutic agent) to sites within lymph, lymph nodes, and lymphoid tissues, as well as to sites of high lipid availability 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) via the lymphatic system or cross the blood-brain barrier (BBB).

[0030] In certain aspects, the present invention provides methods for modulating the delivery, distribution, or other properties of neurosteroids, such as pregnane neurosteroids. In one aspect, the present invention provides a method for delivering a neurosteroid to the systemic circulation of a patient in need thereof, comprising administering to the patient a lipid prodrug of the disclosed neurosteroid, wherein the neurosteroid partially, substantially, or completely bypasses first-pass hepatic metabolism in the patient. In another aspect, the present invention provides a method for modifying a neurosteroid to partially, substantially, or completely bypass first-pass hepatic metabolism in a patient after administration of the neurosteroid, comprising preparing a lipid prodrug of the disclosed neurosteroid. In some embodiments, the lipid prodrug is administered orally. In some embodiments, preparing the lipid prodrug comprises covalently conjugating the neurosteroid to a glycerol-based scaffold comprising two fatty acids or other lipids, thereby providing the lipid prodrug.

[0031] In another aspect, the present invention provides a method for improving the oral bioavailability of a neurosteroid, enhancing intestinal absorption of a neurosteroid, or reducing metabolism, degradation, or excretion of a neurosteroid in the intestine, comprising preparing a lipid prodrug of the disclosed neurosteroid.

[0032] In another aspect, the present invention provides a method for modifying, e.g., improving, delivery of a neurosteroid to a target tissue, comprising preparing a lipid prodrug of the disclosed neurosteroid. 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 metastasis site. In some embodiments, the target tissue is the brain or CNS.

[0033] Lipid prodrugs that readily convert to the parent therapeutic agent after transport via the systemic circulation have reduced free drug concentrations in the gastrointestinal (GI) tract, which may provide benefits in 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, in certain embodiments, have increased passive membrane permeability (due to greater lipophilicity compared to the parent therapeutic agent). In some embodiments, lipid prodrugs have higher solubility in lipid formulations or vehicles containing either lipid alone or a mixture of lipid with a surfactant and / or cosolvent, allowing the use of lipophilic formulations for otherwise highly hydrophilic therapeutic agents.

[0034] Lipid prodrugs of neurosteroids In one aspect, the present invention provides a compound of formula I:

[0035] [ka]

[0036] or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 each independently represents hydrogen, an acid labile group, a lipid, or —C(O)R 3 and Each R 3 are independently saturated or unsaturated, straight chain or branched, 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 1-6aliphatic)-NR-, and the C 1-6 0 to 2 methylene units of the aliphatic group are independently and optionally replaced with -O-, -NR-, or -S-, and the C 1-6 aliphatic groups are independently and optionally substituted 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 heterocycle 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 a hydrocarbon chain in which 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, and one methylene unit of L is optionally replaced by -M-; or L,

[0037] [ka]

[0038] and either the right or left side of L is

[0039] [ka]

[0040] is bound to 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 heterocycle 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. ring or is optionally substituted with -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 heterocycle 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 Aliphatic group (or the C 1-6 aliphatic optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; or R attached to the same carbon atom 4 or R 5 two occurrences of 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;

[0041] [ka]

[0042] is a therapeutic agent selected from naturally occurring or non-naturally occurring neurosteroids or analogs or prodrugs thereof.

[0043] 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.

[0044] 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 are selected from those illustrated in Figure 1 below.

[0045] 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 are selected from those illustrated in Figure 1 below.

[0046] In some embodiments, R 1 and R2 are independently a fatty acid, a phosphatide, a phospholipid, or an analog thereof, such as those detailed 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 independently has an even number of carbon atoms. In some embodiments, each fatty acid independently has an odd number of carbon atoms. In some embodiments, each fatty acid independently has a C2-C6 40 In some embodiments, each fatty acid independently has a C6 to C6 20 , C8~C 20 , C 10 ~C 20 , C 10 ~C 18 , C 12 ~C 18 , C 14 ~C 18 , C 16 ~C 18 , C 10 ~C 16 , C4~C 10 , or C6~C 10 In some embodiments, each fatty acid independently has a linear C6-C 20 In some embodiments, each fatty acid is independently a linear C 12 ~C 18 In some embodiments, each fatty acid is independently a straight chain saturated C-C 10 In some embodiments, each fatty acid is independently selected from oleic acid, palmitic acid, octanoic acid, heptanoic acid, nonanoic acid, EPA, or DHA. In some embodiments, each fatty acid is oleic acid. In some embodiments, each fatty acid is heptanoic acid. In some embodiments, each fatty acid is octanoic acid. In some embodiments, each fatty acid is nonanoic acid.

[0047] 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.

[0048] To be clear, R 1 or R 2 If is defined as a fatty acid, then R 1 or R 2 is understood to be the acyl residue of a fatty acid. 1 If is defined as palmitic acid, then R 1 is the acyl moiety of palmitic acid, i.e., -C(O)C 15 H 31 is.

[0049] As defined above and described herein, each R 3 are independently saturated or unsaturated, straight-chain or branched, optionally substituted C 1-37 It is a hydrocarbon chain.

[0050] In some embodiments, R 3 is a saturated, linear, optionally substituted 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 a saturated, linear, optionally substituted C 1-20 In some embodiments, R 3 is an unsaturated, linear, optionally substituted C 1-20 In some embodiments, R 3 is a saturated, branched, optionally substituted C 1-20 In some embodiments, R 3 is an unsaturated, branched, optionally substituted C 1-20 In some embodiments, R 3are selected from those illustrated in Figure 1 below.

[0051] 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-, and the C 1-6 0 to 2 methylene units of the aliphatic group are independently and optionally replaced with -O-, -NR-, or -S-, and the C 1-6 Aliphatic groups are independently and optionally substituted with 1, 2, or 3 deuterium or halogen atoms.

[0052] 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 1-60 to 2 methylene units of the aliphatic group are independently and optionally replaced with -O-, -NR-, or -S- to form a divalent C 1-6 The aliphatic groups are independently and optionally substituted with 1, 2, or 3 deuterium or halogen atoms. In some embodiments, X is selected from those depicted in Figure 1 below.

[0053] As defined above and described herein, Y is absent, -C(O)-, -C(NR)-, or -C(S)-.

[0054] 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 depicted in Figure 1 below.

[0055] As defined above and described herein, L is a covalent bond or a saturated or unsaturated, linear or branched, optionally substituted bivalent C 1-30 a hydrocarbon chain in which 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, and 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

[0058] [ka]

[0059] is bonded to. In some embodiments, L is a covalent bond. In some embodiments, L is a saturated or unsaturated, straight 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), wherein 0 to 8 (i.e., 0, 1, 2, 3, 4, 5, 6, 7, or 8) methylene units of L are independently replaced with -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 wherein one methylene unit of L is optionally replaced with -M-. In some embodiments, L is

[0060] [ka]

[0061] and either the right or left side of L is

[0062] [ka]

[0063] In some embodiments, L is attached to

[0064] [ka]

[0065] and either the right or left side of L is

[0066] [ka]

[0067] In some embodiments, L is attached to

[0068] [ka]

[0069] and either the right or left side of L is

[0070] [ka]

[0071] In some embodiments, L is attached to

[0072] [ka]

[0073] and either the right or left side of L is

[0074] [ka]

[0075] In some embodiments, L is attached to

[0076] [ka]

[0077] and either the right or left side of L is

[0078] [ka]

[0079] In some embodiments, L is attached to

[0080] [ka]

[0081] and either the right or left side of L is

[0082] [ka]

[0083] is bonded to. In some embodiments, L is a covalent bond or a saturated or unsaturated, straight-chain 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 wherein 0 to 8 (i.e., 0, 1, 2, 3, 4, 5, 6, 7, or 8) methylene units of L are independently -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

[0084] [ka]

[0085] wherein one methylene unit of L is optionally replaced with -M-; or L,

[0086] [ka]

[0087] and either the right or left side of L is

[0088] [ka]

[0089] is bonded to. In some embodiments, L is a saturated or unsaturated, straight-chain or branched, optionally substituted divalent C 1-20 (For example, C 3-20 , C 5-20 , or C 7-20 and wherein 0 to 8 (i.e., 0, 1, 2, 3, 4, 5, 6, 7, or 8) methylene units of L are independently -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

[0090] [ka]

[0091] In some embodiments, L is a covalent bond or a divalent saturated or unsaturated, straight or branched C 1-16 , C 1-12 , C 1-10 or C 6-16a hydrocarbon chain, wherein 0 to 6, 0 to 4, 0 to 3, or 0 to 1 methylene units of L are independently -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-,

[0092] [ka]

[0093] and one methylene unit of L is optionally replaced with -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 In some embodiments, L is a hydrocarbon chain, wherein 0 to 6, 0 to 4, 0 to 3, or 0 to 1 methylene units of L are independently replaced with -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 with -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 A hydrocarbon chain in which 0 to 6, 0 to 4, 0 to 3, or 0 to 1 methylene units of L are independently replaced with -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, or -C(S)-; and one methylene unit of L is optionally replaced with -M-.

[0094] 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 , C1-20 , 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 with -O-, -OC(O)-, -C(O)O-, or -C(O)-, and one methylene unit of L is optionally replaced with -M-.

[0095] In some embodiments, L is 1, 2, 3, or 4 R 4 Divalent saturated C optionally substituted with a group 3-30 , C 3-25 , C 3-20 , C 3-15 , C 5-10 , C 5-15 , or C 7-15 A hydrocarbon chain in which 0 to 4 methylene units of L are independently replaced with -O-, -OC(O)-, -C(O)O-, or -C(O)-, and one methylene unit of L is optionally replaced with -M-.

[0096] In some embodiments, L is 1, 2, 3, or 4 R 4 Divalent saturated C optionally substituted with a group 3-30 , C 3-25 , C 3-20 , C 3-15 , C 5-10 , C 5-15 , or C 7-15 A hydrocarbon chain in which one to two methylene units of L are independently replaced with -O-, -OC(O)-, -C(O)O-, or -C(O)-, and one methylene unit of L is optionally replaced with -M-.

[0097] In some embodiments, L is deuterium, halogen, —CN, or C optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms. 1-6 Divalent saturated C optionally substituted with 1, 2, 3, or 4 groups selected from aliphatic groups 3-30 , C 3-25 , C 3-20 , C 3-15 , C 5-10 , C5-15 , or C 7-15 A hydrocarbon chain in which 0 to 4 methylene units of L are independently replaced with -O-, -OC(O)-, -C(O)O-, or -C(O)-, and one methylene unit of L is optionally replaced with -M-.

[0098] In some embodiments, L is deuterium, halogen, —CN, or C optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms. 1-6 Divalent saturated C optionally substituted with 1, 2, 3, or 4 groups selected from aliphatic groups 3-30 , C 3-25 , C 3-20 , C 3-15 , C 5-10 , C 5-15 , or C 7-15 A hydrocarbon chain in which one to two methylene units of L are independently replaced with -O-, -OC(O)-, -C(O)O-, or -C(O)-, and one methylene unit of L is optionally replaced with -M-.

[0099] In some embodiments, L is selected from deuterium, halogen, -CN, a 3-6 membered saturated or partially unsaturated monocyclic carbocycle, a 4-6 membered saturated or partially unsaturated monocyclic heterocycle 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 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 A hydrocarbon chain in which 0 to 4 methylene units of L are independently replaced with -O-, -OC(O)-, -C(O)O-, or -C(O)-, and one methylene unit of L is optionally replaced with -M-.

[0100] 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.

[0101] In some embodiments, 0 to 6 units of L are independently replaced with -O-, -S-, -OC(O)-, -C(O)O-, -C(O)-, or -C(S)-, and one methylene unit of L is optionally replaced with -M-.

[0102] In some embodiments, L is

[0103] [ka]

[0104] In some embodiments, L includes:

[0105] [ka]

[0106] In some embodiments, L includes:

[0107] [ka]

[0108] In some embodiments, L includes:

[0109] [ka]

[0110] Includes. In some embodiments, L is

[0111] [ka]

[0112] In some embodiments, L includes:

[0113] [ka]

[0114] In some embodiments, L includes:

[0115] [ka]

[0116] In some embodiments, L includes:

[0117] [ka]

[0118] In some embodiments, one methylene unit of L is replaced with -M-. In some embodiments, 1, 2, 3, or 4 available hydrogen atoms of L are R 4 group, i.e., L is optionally replaced with 1, 2, 3, or 4 R 4 The group is substituted.

[0119] In some embodiments, the methylene unit of L is replaced with an amino acid. The amino acid may be natural or non-natural. In some embodiments, the amino acid is selected from non-polar or branched-chain amino acids (BCAAs). 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.

[0120] In some embodiments, L is selected from those depicted in Figure 1 below. As defined above and described herein, each -Cy- is independently an optionally substituted 3- to 6-membered bivalent saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0121] 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 depicted in Figure 1 below.

[0122] As defined above and described herein, 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 heterocycle 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. ring or is optionally substituted with -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 heterocycle 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 Aliphatic group (or the C 1-6 aliphatic optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms) or R bonded to the same carbon atom 4 or R 5 two occurrences of, taken 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.

[0123] In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is deuterium. In some embodiments, R 4 is a halogen. In some embodiments, R 4 is -CN. In some embodiments, R 4 is -OR. In some embodiments, R 4is -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. 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 heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 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. 4 is optionally substituted with -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 heterocycle 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 4 is C optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; 1-6 In some embodiments, R 1 and R 2 are attached to the same carbon atom. 4 two occurrences of, taken 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.

[0124] 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 R bonded to the same carbon atom 4 two occurrences of, taken 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.

[0125] In some embodiments, R 4 At least one occurrence of is not hydrogen. In some embodiments, R 4 is C optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; 1-4 In some embodiments, R 4 is C optionally substituted with 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. 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 are selected from those illustrated in Figure 1 below.

[0126] In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is deuterium. In some embodiments, R 5is a halogen. In some embodiments, R 5 is -CN. 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. 5 is phenyl. In some embodiments, R 5 is an 8-10 membered bicyclic aromatic carbocycle. In some embodiments, R 5 is a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 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. 5 is optionally substituted with -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 heterocycle 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 with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; 1-6 In some embodiments, R 1 and R 2 are attached to the same carbon atom. 5two occurrences of, taken 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.

[0127] 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 R bonded to the same carbon atom 5 two occurrences of, taken 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.

[0128] In some embodiments, R 5 At least one occurrence of is not hydrogen. In some embodiments, R 5 is C optionally substituted with 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. 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 are selected from those illustrated in Figure 1 below.

[0129] 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, an inverted ester self-immolative group, a trimethyl lock, or a 2-hydroxyphenylcarbamate (2-HPC) self-immolative group. In some embodiments, -M- is an acetal. In some embodiments, -M- is a carboxyacetal. In some embodiments, -M- is a carboxy(methyl acetal). In some embodiments, -M- is an acetal self-immolative group. In some embodiments, -M- is a carboxyacetal self-immolative group. In some embodiments, -M- is a carboxy(methyl acetal) self-immolative group.

[0130] In some embodiments, -M- is

[0131] [ka]

[0132] and In the formula, each R 6 are independently hydrogen, deuterium, C 1-10 selected from aliphatic, halogen, or -CN; Each R 7are independently 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 heterocycle 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 ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. a heteroaromatic ring, or optionally substituted with -CN, -OR, -NR2, -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8-10 membered bicyclic carbocycle, a 4-8 membered saturated or partially unsaturated monocyclic heterocycle 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 Aliphatic group (or the C 1-6 aliphatic optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; each Z 1 are 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 are independently =N- or =C(R 7 )-selected from each Z 4 are independently -O-, -NR-, -S-, -C(R 6 )2-, or a covalent bond.

[0133] In some embodiments, -M- is selected from one of the following:

[0134] [ka]

[0135] In the formula, each R 6 are independently hydrogen, deuterium, C 1-5 selected from aliphatic, halogen, or -CN; Each R 7 are independently 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 heterocycle 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 ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. a heteroaromatic ring, or optionally substituted with -CN, -OR, -NR2, -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8-10 membered bicyclic carbocycle, a 4-8 membered saturated or partially unsaturated monocyclic heterocycle 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 Aliphatic group (or the C 1-6 aliphatic optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; each Z 1 are 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 are independently =N- or =C(R 7 )-selected from each Z 4 are independently -O-, -NR-, -S-, -C(R 6 )2-, or a covalent bond.

[0136] As generally defined above and described herein, each R 6 are independently hydrogen, deuterium, C 1-5 In some embodiments, R is 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 a halogen. In some embodiments, R 6 is -CN.

[0137] In some embodiments, R 6 is hydrogen, C 1-5 In some embodiments, R is an alkyl, halogen, or —CN. 6 is hydrogen or C 1-3 In some embodiments, R 6 is hydrogen or methyl.

[0138] In some embodiments, the example R in the above formula 6 Each occurrence 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 are selected from those illustrated in Figure 1 below.

[0139] As generally defined above and described herein, each R 7are independently 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 heterocycle 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 aromatic carbocycle having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. a bicyclic heteroaromatic ring, or optionally substituted with -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 heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, C 1-6 Aliphatic group (or the C 1-6 Aliphatic groups are selected from optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms.

[0140] In some embodiments, R 7 is hydrogen. In some embodiments, R 7 is deuterium. In some embodiments, R 7 is a halogen. In some embodiments, R 7 is -CN. 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 7 is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. 7is 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 heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 7 is a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 7 is an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 7 is optionally substituted with -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 heterocycle 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 7 is C optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; 1-6 It is an aliphatic group.

[0141] In some embodiments, R 7is 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 heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or is optionally substituted with -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 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 1-6 Aliphatic group (or the C 1-6 The aliphatic group is optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms. In some embodiments, R 7 is a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from hydrogen, deuterium, halogen, -CN, a 3-6 membered saturated or partially unsaturated monocyclic carbocycle, phenyl, nitrogen, oxygen, or sulfur, or is optionally substituted with -CN, a 3-6 membered saturated or partially unsaturated monocyclic carbocycle, phenyl, or a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 1-4 Alkyl group (or the C 1-4 The alkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms. In some embodiments, R 7 is hydrogen, halogen, -CN, -OR, or C 1-4 It is alkyl.

[0142] In some embodiments, R is hydrogen or C 1-4 It is alkyl. In some embodiments, R 7 are selected from those illustrated in Figure 1 below.

[0143] 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-.

[0144] In some embodiments, Z 1 are selected from those illustrated in Figure 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—.

[0145] 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-.

[0146] 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—.

[0147] In some embodiments, Z 2 teeth,

[0148] [ka]

[0149] In some embodiments, Z2 is -O- or -OC(O)O-.

[0150] In some embodiments, Z 2 are selected from those illustrated in Figure 1 below. In some embodiments, Z 1 is -O- and Z 2 is -O- or -OC(O)O-.

[0151] As generally defined above and described herein, each Z 3 are independently =N- or =C(R 7 In some embodiments, Z 3 is ═N—. In some embodiments, Z 3 is =C(R 7 )-.

[0152] In some embodiments, Z 3 are selected from those illustrated in Figure 1 below. As generally defined above and described herein, each Z 4 are independently -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.

[0153] In some embodiments, Z 4 are selected from those illustrated in Figure 1 below. In some embodiments, -M- is selected from one of the following:

[0154] [ka]

[0155] In some embodiments, -M- is

[0156] [ka]

[0157] is. In some embodiments, -M- is

[0158] [ka]

[0159] is. In some embodiments, -M- is

[0160] [ka]

[0161] is selected from. In some embodiments, -M- is

[0162] [ka]

[0163] is selected from. In some embodiments, -M- is

[0164] [ka]

[0165] is selected from. In some embodiments, -M- is

[0166] [ka]

[0167] is selected from. In some embodiments, -M- is

[0168] [ka]

[0169] is selected from. In some embodiments, -M- is

[0170] [ka]

[0171] is selected from. In some embodiments, -M- is

[0172] [ka]

[0173] is selected from. In some embodiments, -M- is

[0174] [ka]

[0175] is. In some embodiments, -M- is

[0176] [ka]

[0177] In some embodiments, -M- is

[0178] [ka]

[0179] In some embodiments, -M- is

[0180] [ka]

[0181] is. In some embodiments, -M- is selected from those depicted in Figure 1 below.

[0182] 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.

[0183] 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.

[0184] As defined above and described herein,

[0185] [ka]

[0186] is a therapeutic agent selected from naturally occurring or non-naturally occurring neurosteroids, or analogs or prodrugs thereof. Exemplary neurosteroids include those described herein.

[0187] Neurosteroid analogs include deuterated and isotopically enriched forms of neurosteroids, such as pregnane neurosteroids. In some embodiments, the analogs are fatty acid ester derivatives of neurosteroids. For example, a neurosteroid with two hydroxyl groups may be esterified at one hydroxyl and prepared as a lipid prodrug of Formula I, where the lipid prodrug moiety is attached to the other hydroxyl. In some embodiments, the fatty acid ester comprises a carbon chain of 8 to 20 carbons. In some embodiments, the fatty acid is one of those described herein.

[0188] In some embodiments,

[0189] [ka]

[0190] is allopregnanolone or an analog or prodrug thereof.

[0191] [ka]

[0192] is allopregnanolone. In some embodiments,

[0193] [ka]

[0194] is isopregnanolone or an analog or prodrug thereof. In some embodiments,

[0195] [ka]

[0196] is isopregnanolone. In some embodiments,

[0197] [ka]

[0198] is a pregnane neurosteroid. In some embodiments,

[0199] [ka]

[0200] is selected from allopregnanolone (also known as brexanolone, SAGE-547, 5α-pregnan-3α-ol-20-one, 3α-hydroxy-5α-pregnan-20-one, or 3α,5α-tetrahydroprogesterone), 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.

[0201] In some embodiments,

[0202] [ka]

[0203] These include alphadolone (3α,21-dihydroxy-5α-pregnane-11,20-dione), alphaxolone (3α-hydroxy-5α-pregnane-11,20-dione), ganaxolone (3α-hydroxy-3β-methyl-5α-pregnane-20-one), hydroxydione (21-hydroxy-5β-pregnane-3,20-dione), minaxolone (11α-(dimethylamino)-2β-ethoxy-3α-hydroxy-5α-pregnane-20-one), Org 20599 (21-chloro-3α-hydroxy-2β-morpholin-4-yl-5β-pregnane-20-one), and 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-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile).

[0204] In some embodiments,

[0205] [ka]

[0206] are allopregnanolone, pregnanolone, pregnenolone, ganaxolone, alphaxalone, 3β-dihydroprogesterone, isopregnanolone, epipregnanolone, or 21-hydroxyallopregnanolone.

[0207] In some embodiments, the present invention provides a compound of Formula I, wherein:

[0208] [ka]

[0209] teeth,

[0210] [ka]

[0211] which gives a compound of formula II:

[0212] [ka]

[0213] or a pharmaceutically acceptable salt thereof, wherein: Ring B is selected from phenyl, a 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic, carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-10 membered monocyclic or bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and Ring B is further optionally substituted with 1-2 oxo groups; R 6is optionally replaced by C 1-6 is an aliphatic group, R 7a is optionally replaced by C 1-6 is an aliphatic group, R 7b is hydrogen or optionally substituted C 1-6 an aliphatic group, or R 7a and R 7b optionally, together with their intervening carbon atoms, form a 4- to 7-membered saturated or partially unsaturated spirocyclic carbocyclic or heterocyclic ring having, in addition to carbon, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R 7a and R 7b optionally taken together to form an oxo group; R 8 is absent or is hydrogen,

[0214] [ka]

[0215] represents a single or double bond, where:

[0216] [ka]

[0217] If one of the is a double bond, the other

[0218] [ka]

[0219] is a single bond,

[0220] [ka]

[0221] If one of the groups is a double bond, R 8 is absent, R 1 , R 2 , X, Y, and L, both singly and in combination, are as defined above and in the embodiments herein.

[0222] In some embodiments, the present invention provides a compound of Formula I, wherein:

[0223] [ka]

[0224] but,

[0225] [ka]

[0226] which results in formula III:

[0227] [ka]

[0228] or a pharmaceutically acceptable salt thereof, wherein R 9 is hydrogen or methyl, R 10 is -OC(O)R, R 11 is hydrogen or methyl, R 12 is alpha or beta hydrogen or methyl; R 13 is -C(O)R, R, R 1 , R 2 , X, Y, and L, both singly and in combination, are as defined above and in the embodiments herein.

[0229] In some embodiments, the present invention provides a compound of Formula I, wherein:

[0230] [ka]

[0231] but,

[0232] [ka]

[0233] which results in formula IV:

[0234] [ka]

[0235] or a pharmaceutically acceptable salt thereof, wherein Z is =O, =S, =NR, =NOR, R 14 is hydrogen, hydroxyl, -CHO, -CHS, -CHNR, -CHOR, -CHSR, -CHN(R)2, -CHN(R)(OR), 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 heterocycle 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; R 17 is hydrogen, -OH, oxo, or C 1-6an optionally substituted group selected from aliphatic or 4-8 membered saturated or partially unsaturated monocyclic heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R 15 , R 16 , R 18 , R 19 , and R 20 is independently absent, hydrogen, halogen, -OR, or an optionally substituted group selected from 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; R 21 and R 22 are each independently hydrogen or optionally substituted C 1-6 Aliphatic group or -OC 1-6 selected from aliphatic groups, or R 21 and R 22 optionally taken together to form an oxo group; R, R 1 , R 2 , X, Y, and L, both singly and in combination, are as defined above and in the embodiments herein.

[0236] In some embodiments, the present invention provides a compound of Formula I, wherein:

[0237] [ka]

[0238] but,

[0239] [ka]

[0240] which gives Equation V:

[0241] [ka]

[0242] or a pharmaceutically acceptable salt thereof, wherein

[0243] [ka]

[0244] is a double bond or a single bond, Z is =O, =S, =NR, or =NOR; R 23 is hydrogen, -OH, 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 heterocycle 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; R 26 is 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 heterocycle 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; R 26a is hydrogen, or R 26 and R26a optionally taken together to form an oxo group; R 24 , R 25 , R 27 , and R 28 are each independently hydrogen, —OH, halogen, 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 heterocycle 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, with the proviso that

[0245] [ka]

[0246] is a double bond, R 28 is absent, R 29 is hydrogen, halogen, -OR, or C 1-6 an optionally substituted group selected from an aliphatic or 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle; R 30 is hydrogen or C 1-6 an optionally substituted group selected from an aliphatic or 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle; R 31 is -OH, or R 30 and R 31 optionally taken together to form an oxo group; R 32 is hydrogen, halogen, -OH, or C 1-6an optionally substituted group selected from an aliphatic or 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle; R 32a is hydrogen, halogen, or optionally substituted C 1-6 an aliphatic group, provided that:

[0247] [ka]

[0248] is a double bond, R 32a is absent, R, R 1 , R 2 , X, Y, and L, both singly and in combination, are as defined above and in the embodiments herein.

[0249] In certain embodiments, the present invention provides compounds of formula I, wherein:

[0250] [ka]

[0251] but,

[0252] [ka]

[0253] [ka]

[0254] [ka]

[0255] whereby formula VI-a:

[0256] [ka]

[0257] [ka]

[0258] [ka]

[0259] [ka]

[0260] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , X, Y, and L are as defined above and as described in embodiments herein, and the variable R of the A group 1 , R 2a , R 2b , R A , A (or ring A), and n are each as described and defined in US2020 / 0024301, the entirety of which is incorporated herein by reference.

[0261] In certain embodiments, the present invention provides compounds of formula I, wherein:

[0262] [ka]

[0263] but,

[0264] [ka]

[0265] whereby Formula VII:

[0266] [ka]

[0267] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , X, Y, and L are as defined above and as described in embodiments herein;

[0268] [ka]

[0269] Base variable R 1 , R 2 , R 3 , R 4 , and R 5 each as described and defined in US2019 / 0337975, which is incorporated herein by reference in its entirety.

[0270] In some embodiments,

[0271] [ka]

[0272] is not allopregnanolone or an analog or prodrug thereof.

[0273] [ka]

[0274] is not allopregnanolone. In some embodiments,

[0275] [ka]

[0276] is not a naturally occurring pregnane neurosteroid. In some embodiments,

[0277] [ka]

[0278] is not 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.

[0279] In some embodiments,

[0280] [ka]

[0281] These include alphadolone (3α,21-dihydroxy-5α-pregnane-11,20-dione), alphaxolone (3α-hydroxy-5α-pregnane-11,20-dione), ganaxolone (3α-hydroxy-3β-methyl-5α-pregnane-20-one), hydroxydione (21-hydroxy-5β-pregnane-3,20-dione), minaxolone (11α-(dimethylamino)-2β-ethoxy-3α-hydroxy-5α-pregnane-20-one), Org 20599 (21-chloro-3α-hydroxy-2β-morpholin-4-yl-5β-pregnane-20-one), and Org is not selected from 21465 (2β-(2,2-dimethyl-4-morpholinyl)-3α-hydroxy-11,20-dioxo-5α-pregnan-21-yl methanesulfonate), lennanolone (3α-hydroxy-5β-pregnane-11,20-dione), or SAGE-217 (1-(2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile).

[0282] In some embodiments,

[0283] [ka]

[0284] is not selected from pregnanolone, pregnenolone, 3β-dihydroprogesterone, isopregnanolone, epipregnanolone, or 21-hydroxyallopregnanolone.

[0285] In some embodiments, a neurosteroid

[0286] [ka]

[0287] is a naturally occurring or non-naturally occurring (e.g., synthetic) inhibitory neurosteroid. In some embodiments, the neurosteroid is a naturally occurring inhibitory neurosteroid selected from: 3α-Dihydroprogesterone (3α-DHP): pregn-4-en-3α-ol-20-one, 5α-dihydroprogesterone (5α-DHP; allopregnanedione): 5α-pregnane-3,20-dione, 5β-Dihydroprogesterone (5β-DHP; pregnanedione): 5β-pregnane-3,20-dione, Allopregnanediol: 5α-pregnane-3α,20α-diol, Allopregnanolone (brexanolone, SAGE-547): 5α-pregnan-3α-ol-20-one; Dihydrodeoxycorticosterone (DHDOC): 21-hydroxy-5α-pregnan-20-one, Pregnanediol: 5β-pregnane-3α,20α-diol, Pregnanolone (eltanolone): 5β-pregnan-3α-ol-20-one, Tetrahydrodeoxycorticosterone (THDOC): 3α,21-dihydroxy-5α-pregnan-20-one, Deoxycorticosterone (desoxycortone): 21-hydroxypregn-4-ene-3,20-dione, Pregnenolone (P5): (pregn-5-en-3β-ol-20-one), and Progesterone (P4) (pregn-4-ene-3,20-dione).

[0288] In some embodiments,

[0289] [ka]

[0290] is a non-naturally occurring (e.g., synthetic) inhibitory neurosteroid selected from: Alphadolone: ​​3α,21-dihydroxy-5α-pregnane-11,20-dione, Alphadolone acetate: 3α,21-dihydroxy-5α-pregnane-11,20-dione 21-acetate, Alphaxalone: ​​3α-hydroxy-5α-pregnane-11,20-dione, EIDD-036(P4-20-O): 20-(hydroxyimino)pregn-4-en-3-one, Ganaxolone: ​​3β-methyl-5α-pregnan-3α-ol-20-one, Hydroxydione: 21-hydroxy-5β-pregnane-3,20-dione, Minaxolone: ​​11α-(dimethylamino)-2β-ethoxy-5α-pregnan-3α-ol-20-one, ORG-20599: 21-chloro-2β-morpholin-4-yl-5β-pregnan-3α-ol-20-one, ORG-21465: 2β-(2,2-dimethyl-4-morpholinyl)-3α-hydroxy-11,20-dioxo-5α-pregnan-21-yl methanesulfonate, Lenanolone: ​​5β-pregnan-3α-ol-11,20-dione, SGE-516, SGE-872, SAGE-217 (zuranolone): 3α-hydroxy-3β-methyl-21-(4-cyano-1H-pyrazol-1′-yl)-19-nor-5β-pregnan-20-one, or a proneurosteroid, such as EIDD-1723, P1-185, and Progesterone carboxymethyl oxime (P4-3-CMO).

[0291] In some embodiments,

[0292] [ka]

[0293] is a naturally occurring or non-naturally occurring (e.g., synthetic) excitatory neurosteroid. In some embodiments,

[0294] [ka]

[0295] is a naturally occurring excitatory neurosteroid selected from: 3β-Dihydroprogesterone (3β-DHP): pregn-4-en-3β-ol-20-one, Epipregnanolone: ​​5β-pregnan-3β-ol-20-one, Isopregnanolone (sepranolon): 5α-pregnan-3β-ol-20-one, Pregnenolone sulfate (PS): pregn-5-en-3β-ol-20-one 3β-sulfate, or Pregnenolone (P5): pregn-5-en-3β-ol-20-one.

[0296] In some embodiments,

[0297] [ka]

[0298] is epipregnanolone sulfate (5β-pregnan-3β-ol-20-one 3β-sulfate).

[0299] In some embodiments,

[0300] [ka]

[0301] is a naturally occurring or non-naturally occurring (e.g., synthetic) neurotrophic neurosteroid. In some embodiments,

[0302] [ka]

[0303] teeth, BNN-27: 17α,20R-epoxypregn-5-ene-3β,21-diol.

[0304] In some embodiments,

[0305] [ka]

[0306] is a naturally occurring or non-naturally occurring (e.g., synthetic) anti-neurotrophic neurosteroid. In some embodiments,

[0307] [ka]

[0308] teeth, Dexamethasone: 9α-fluoro-11β,17α,21-trihydroxy-16α-methylpregna-1,4-diene-3,20-dione or an analog thereof.

[0309] In some embodiments,

[0310] [ka]

[0311] is selected from natural or non-natural (e.g., synthetic) pheromones and pherins. In some embodiments,

[0312] [ka]

[0313] teeth, Pregnadienedione (PDD): pregna-4,20-diene-3,6-dione, Selected from PH10, PH15, PH30, PH56, PH78, PH84, and Salubrin (PH80).

[0314] In some embodiments,

[0315] [ka]

[0316] teeth, Pregnenolone (P5): pregn-5-en-3β-ol-20-one, Progesterone (P4): pregn-4-ene-3,20-dione, 3β-Methoxypregnenolone (MAP-4343): 3β-Methoxypregn-5-en-20-one, Cyclopregnol (neurosterone): 6β-hydroxy-3:5-cyclopregnan-20-one.

[0317] In some embodiments,

[0318] [ka]

[0319] is a compound selected from those described in WO2019094724, the contents of each of which are incorporated herein by reference in their entirety.

[0320] [ka]

[0321] is a compound of formula IA, IB, II, or III, as described in WO2019094724:

[0322] [ka]

[0323] In some embodiments,

[0324] [ka]

[0325] is selected from Co26749 / WAY-141839, Co134444, and Co177843:

[0326] [ka]

[0327] In some embodiments,

[0328] [ka]

[0329] is a compound selected from those described in US2016 / 0229887, the contents of which are incorporated herein by reference in their entirety.

[0330] In some embodiments,

[0331] [ka]

[0332] is a compound selected from those described in Martinez Botella G. et al., J. Med. Chem. 2015, 58, 8, 3500-3511, the contents of which are incorporated herein by reference in their entirety.

[0333] In some embodiments,

[0334] [ka]

[0335] is a compound selected from those described in Paul SM et al., J Neurosci. 2013, 33(44):17290-300, the contents of which are incorporated herein by reference in their entirety.

[0336] In some embodiments,

[0337] [ka]

[0338] is a compound selected from the table below.

[0339] [Table 1]

[0340] [Table 2]

[0341] Those skilled in the art will understand that certain lipid prodrugs shown in the table are in the form of prodrugs. Thus, it will be understood that the lipid prodrug moieties of the present invention are attached to a therapeutic agent or its active form. For 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 a pregnane neurosteroid. For example, allopregnanolone has the following structure:

[0342] [ka]

[0343] and may be attached to the lipid prodrug moiety, for example, via its hydroxyl (OH) group or at another chemically modifiable position such as a ketone.

[0344] As used herein, a therapeutic agent

[0345] [ka]

[0346] The illustration of the brackets around

[0347] [ka]

[0348] The moiety is at any available modifiable nitrogen, oxygen, or sulfur atom.

[0349] [ka]

[0350] For purposes of clarity, and by way of non-limiting example, the available modifiable nitrogen, oxygen, or sulfur atoms in the structures of the following therapeutic compounds are depicted below, where each wavy bond defines a point of attachment to Formula I or another formula depicted herein.

[0351] [ka]

[0352] [ka]

[0353] In some embodiments,

[0354] [ka]

[0355] teeth,

[0356] [ka]

[0357] is. In some embodiments,

[0358] [ka]

[0359] teeth,

[0360] [ka]

[0361] is. In some embodiments,

[0362] [ka]

[0363] teeth,

[0364] [ka]

[0365] is. In some embodiments, the present invention provides a compound of formula Ia:

[0366] [ka]

[0367] or a pharmaceutically acceptable salt thereof, wherein L, R 1, R 2 Each of X, and X, both singly and in combination, is as defined above and as described in embodiments herein.

[0368] In some embodiments, the present invention provides a compound of formula Ib:

[0369] [ka]

[0370] or a pharmaceutically acceptable salt thereof, wherein L and

[0371] [ka]

[0372] Each of the following, both singly and in combination, is as defined above and as described in embodiments herein.

[0373] In some embodiments, the present invention provides a compound of formula Ic:

[0374] [ka]

[0375] or a pharmaceutically acceptable salt thereof, wherein L, R 1 , R 2 Each of X, and X, both singly and in combination, is as defined above and as described in embodiments herein.

[0376] In some embodiments, the present invention provides a compound of formula Id:

[0377] [ka]

[0378] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 4 , X, M, and

[0379] [ka]

[0380] Each of the following, both singly and in combination, is as defined above and as described in embodiments herein.

[0381] In some embodiments, the present invention provides a compound of formula Ie:

[0382] [ka]

[0383] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 4 , R 5 , X, M, and

[0384] [ka]

[0385] Each of the following, both singly and in combination, is as defined above and as described in embodiments herein.

[0386] In some embodiments, the present invention provides a compound of formula If:

[0387] [ka]

[0388] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R4 , R 5 ,X,n,and

[0389] [ka]

[0390] Each of the following, both singly and in combination, is as defined above and as described in embodiments herein.

[0391] In some embodiments, the present invention provides a compound of formula Ig:

[0392] [ka]

[0393] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , X, M, and

[0394] [ka]

[0395] Each of the following, both singly and in combination, is as defined above and as described in embodiments herein.

[0396] In some embodiments, the present invention provides a compound of formula Ih:

[0397] [ka]

[0398] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 4 , M, and

[0399] [ka]

[0400] Each of the following, both singly and in combination, is as defined above and as described in embodiments herein.

[0401] In some embodiments, the present invention provides a compound of formula VIII-a, VIII-b, VIII-c, VIII-d, VIII-e, VIII-f, or VIII-g:

[0402] [ka]

[0403] [ka]

[0404] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 4 , R 5 , M, and

[0405] [ka]

[0406] Each of the following, both singly and in combination, is as defined above and as described in embodiments herein.

[0407] In some embodiments, the present invention provides a compound of formula IX-a or IX-b

[0408] [ka]

[0409] or a pharmaceutically acceptable salt thereof, wherein R 1 , R2 , R 4 , R 5 Each of and M, both singly and in combination, is as defined above and as described in embodiments herein.

[0410] In some embodiments, the present invention provides a compound of formula IX-c or IX-d:

[0411] [ka]

[0412] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 4 , R 5 Each of and M, both singly and in combination, is as defined above and as described in embodiments herein.

[0413] In some embodiments, the present invention provides a compound of formula X:

[0414] [ka]

[0415] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , X, and M, both singly and in combination, are as defined above and in the embodiments herein.

[0416] In some embodiments, the present invention provides a compound of formula XI:

[0417] [ka]

[0418] or a pharmaceutically acceptable salt thereof, wherein R 1 , R2 , R 4 Each of and M, both singly and in combination, is as defined above and as described in embodiments herein.

[0419] In some embodiments, the present invention provides a compound of formula XII-a, XII-b, XII-c, XII-d, XII-e, XII-f, or XII-g:

[0420] [ka]

[0421] [ka]

[0422] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 4 , R 5 Each of and M, both singly and in combination, is as defined above and as described in embodiments herein.

[0423] In some embodiments, the present invention provides a compound of formula XIII-a or XIII-b:

[0424] [ka]

[0425] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 4 , R 5 Each of -M-, both singly and in combination, is as defined above and as described in embodiments herein.

[0426] In some embodiments, the present invention provides a compound of formula XIII-c or XIII-d:

[0427] [ka]

[0428] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 4 , R 5 Each of and M, both singly and in combination, is as defined above and as described in embodiments herein.

[0429] In the above formula, when a numerical range, such as 0 to 4 or 1 to 18, is disclosed, each individual integer within that 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 independently and optionally selected from the disclosed ranges. For example, in the above formula VIII-c, each range of 0 to 4 and 1 to 18 varies independently of the other ranges.

[0430] In another aspect, the present invention provides a compound of formula XIV:

[0431] [ka]

[0432] or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 each independently represents hydrogen or —C(O)R 3 and Each R 3 are independently saturated or unsaturated, straight chain or branched, optionally substituted C 1-37 is a hydrocarbon chain, X is -O-, Y is —C(O)—; L is a saturated or unsaturated, linear or branched, optionally substituted divalent C 3-20 a hydrocarbon chain in which 0 to 2 methylene units of L are independently replaced by -Cy-, -O-, -N(R)-, -S-, -OC(O)-, -C(O)O-, or -C(O)-, and 1 methylene unit of L is optionally replaced by -M-; or L,

[0433] [ka]

[0434] and the right side of L is

[0435] [ka]

[0436] is bound to 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 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 heterocycle 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; Each R 4 and R 5are independently hydrogen, deuterium, halogen, -CN, -OR, -NR2, -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocycle, a 4-8 membered saturated or partially unsaturated monocyclic heterocycle 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 optionally substituted with -CN, -OR, -NR2, -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocycle, a 4-8 membered saturated or partially unsaturated monocyclic heterocycle 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; 1-6 Aliphatic group (or the C 1-6 aliphatic optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; or R attached to the same carbon atom 4 or R 5 two occurrences of 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;

[0437] [ka]

[0438] is a therapeutic agent selected from naturally occurring or non-naturally occurring pregnane neurosteroids or analogs or prodrugs thereof.

[0439] In some embodiments, L is

[0440] [ka]

[0441] In some embodiments, L is

[0442] [ka]

[0443] In some embodiments, L is

[0444] [ka]

[0445] In some embodiments, L is

[0446] [ka]

[0447] In some embodiments, L is

[0448] [ka]

[0449] In some embodiments, L is

[0450] [ka]

[0451] In some embodiments, n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, or 0 to 12, 0 to 10, 0 to 8, or 0 to 6, or 1 to 12, 1 to 10, 1 to 8, or 1 to 6, or 2 to 12, 2 to 10, 2 to 8, or 2 to 6, or 0 to 4. In some embodiments, each m is independently 0, 1, 2, or 3, or each m is independently 0 or 1. In some embodiments, each m is 0. In some embodiments, each m is 1. In some embodiments, each m is 0 or 1 and n is 2 to 12.

[0452] In some embodiments, -M- is

[0453] [ka]

[0454] In some embodiments, -M- is

[0455] [ka]

[0456] is. In some embodiments, -M- is

[0457] [ka]

[0458] is. In some embodiments, -M- is

[0459] [ka]

[0460] In some embodiments, -M- is

[0461] [ka]

[0462] In some embodiments, -M- is

[0463] [ka]

[0464] In some embodiments, the right hand side of the above embodiment of -M- is, for example,

[0465] [ka]

[0466] With available O atoms,

[0467] [ka]

[0468] is bonded to. In some embodiments, -M- is

[0469] [ka]

[0470] In some embodiments, -M- is

[0471] [ka]

[0472] In some embodiments, -M- is

[0473] [ka]

[0474] In some embodiments, the right hand side of the above embodiment of -M- is, for example,

[0475] [ka]

[0476] With available O atoms,

[0477] [ka]

[0478] is bonded to. In some embodiments, R 4 One occurrence of is hydrogen, and R 5 An example of one occurrence of is hydrogen. 4 and R 5 are independently hydrogen, deuterium, halogen, —CN, or optionally substituted with —OR or 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; C 1-6 It is aliphatic.

[0479] In some embodiments, R 4 or R 5 One occurrence of is C 1-3 C such as alkyl 1-6 alkyl, e.g., methyl. In some embodiments, R 4 and R 5 The two occurrences of each independently represent C 1-3 C such as alkyl 1-6 Alkyl, for example, methyl.

[0480] In some embodiments, -M- is present. In some embodiments, -M- is present and R 4 or R 5 In some embodiments, at least one of -M- is present and R 4 or R5 At least one of the 1-3 C such as alkyl 1-6 In some embodiments, -M- is present and R 4 and R 5 At least two occurrences of C 1-3 C such as alkyl 1-6 Alkyl, for example, methyl.

[0481] In some embodiments, -M- is absent. In some embodiments, -M- is absent and R 4 or R 5 In some embodiments, at least one of -M- is not hydrogen. 4 or R 5 At least one of the 1-3 C such as alkyl 1-6 In some embodiments, -M- is absent and R 4 and R 5 At least two occurrences of C 1-3 C such as alkyl 1-6 alkyl, e.g., methyl. In some embodiments, R 4 Two occurrences of R 5 Two occurrences of, or R 4 One occurrence of and R 5 There is one occurrence of each R 4 and R 5 is independently optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; 1-3 C such as alkyl 1-6 alkyl (eg, methyl).

[0482] In some embodiments,

[0483] [ka]

[0484] is allopregnanolone. In some embodiments,

[0485] [ka]

[0486] is isoallopregnanolone. In some embodiments, L is

[0487] [ka]

[0488] and either the right or left side of L is

[0489] [ka]

[0490] and -M- is

[0491] [ka]

[0492] and In the formula, each R 6 are independently hydrogen, deuterium, C 1-10 selected from aliphatic, halogen, or -CN; Each R 7are independently 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 heterocycle 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 ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. a heteroaromatic ring, or optionally substituted with -CN, -OR, -NR2, -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8-10 membered bicyclic carbocycle, a 4-8 membered saturated or partially unsaturated monocyclic heterocycle 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 Aliphatic group (or the C 1-6 aliphatic optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; each Z 1 are 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 are independently =N- or =C(R 7 )-selected from each Z 4 are independently -O-, -NR-, -S-, -C(R 6 )2-, or a covalent bond.

[0493] In some embodiments, -M- is

[0494] [ka]

[0495] is. In another embodiment, the compound of formula XV:

[0496] [ka]

[0497] Provided herein is a compound of the formula: R 1 and R 2 are each independently a fatty acid; Each R 4 are independently hydrogen, deuterium, halogen, —CN, or optionally substituted with halogen, —CN, —OR, —NR2, or —SR; 1-6 is an aliphatic group, -M-,

[0498] [ka]

[0499] is. In some embodiments of Formula XV, R 1 and R 2 is heptanoic acid. In some embodiments of Formula XV, R 1 and R 2 is octanoic acid. In some embodiments of Formula XV, R 1 and R 2 Each of these is nonanoic acid.

[0500] In some embodiments of Formula XV, each R 4 is hydrogen. In some embodiments of Formula XV, each R 4 is methyl.

[0501] In some embodiments of Formula XV, -M- is

[0502] [ka]

[0503] In some embodiments of Formula XV, -M- is

[0504] [ka]

[0505] In some embodiments of Formula XV, -M- is

[0506] [ka]

[0507] is. In one aspect, the present invention provides lipid prodrug compounds shown in Table 1.

[0508] [Table 3]

[0509] [Table 4]

[0510] [Table 5]

[0511] [Table 6]

[0512] [Table 7]

[0513] [Table 8]

[0514] Table 9

[0515] Table 10

[0516] Table 11

[0517] Table 12

[0518] Table 13

[0519] Table 14

[0520] Table 15

[0521] Table 16

[0522] Table 17

[0523] Table 18

[0524] In some embodiments, the present invention provides compounds as depicted in Table 1 above, wherein one or both of the fatty acids depicted above (R 1 and R 2 positions) are independently replaced with another fatty acid.

[0525] Lipids, including fatty acids, phospholipids, lipid processing mimetics, and mixtures thereof, for use in the disclosed lipid prodrugs The lipid prodrugs according to the present disclosure mimic the lipid processing that occurs in the human body.

[0526] 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 an analog thereof (e.g., phophatidylcholine, lecithin, phosphatidylethanolamine, cephalin, or phosphatidylserine, or an analog or portion thereof, e.g., a partially hydrolyzed portion thereof), or other lipid processing mimic (e.g., a group that is cleaved by lipase, other digestive enzymes, or other mechanisms in the GI tract, thereby enabling the lipid prodrug to mimic lipid processing in food). In some embodiments, the fatty acid is a short-chain, medium-chain, or 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 (omega-3) or omega-6 (omega-6) fatty acid. In some embodiments, the lipid, e.g., the fatty acid, is a C2-C 60 In some embodiments, the lipid, e.g., fatty acid, has a C2 to C6 chain. 28 In some embodiments, the lipid, e.g., fatty acid, has a C2 to C6 chain. 40 In some embodiments, the lipid, e.g., fatty acid, has a C2 to C6 chain. 12 or C4~C 12In some embodiments, the lipid, e.g., fatty acid, has a C4 to C6 40 In some embodiments, the lipid, e.g., fatty acid, has a C4 to C6 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~C 16 , 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~C15 , 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 lipid, e.g., fatty acid, is 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 containing any one of the above ranges or numbers of carbon atoms. In some embodiments, one of the fatty acids is independently selected from fatty acids having a chain containing any one of the above ranges or numbers of carbon atoms. 21 fatty acids with chains, 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.

[0527] In some embodiments, the lipid prodrug comprises two lipids, e.g., fatty acids, that 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, 24 to 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, 6 Having an ECN of ~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.

[0528] 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.

[0529] Examples of useful saturated straight-chain fatty acids include those having 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, hexacosanoic acid, octacosanoic acid, triacontanoic acid, and n-dotriacontanoic acid, and those having 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.

[0530] 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 terminating in an isobutyl group, such as 6-methyl-octanoic acid, 8-methyl-decanoic acid, 10-methyl-dodecanoic acid, 12-methyl-tetradecanoic acid, 14-methyl-hexadecanoic acid, 16-methyl-octadecanoic acid, 18-methyl-eicosanoic acid, 20-methyl-docosanoic acid, 22-methyl-tetracosanoic acid, 24-methyl-hexacosanoic acid, and 26-methyloctacosanoic acid.

[0531] 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-octadecenoic acid, 18-octadecenoic acid, 19-octadecenoic acid, 20-octadecenoic acid, 21-octadecenoic acid, 22-octadecenoic acid, 23-octadecenoic acid, 24-octadecenoic acid, 25-octadecenoic acid, 26-octadecenoic acid, 27-octadecenoic acid, 28-octadecenoic acid, 29-octadecenoic acid, 30-octadecenoic acid, 31-octadecenoic acid, 32-octadecenoic acid, 33-octadecenoic acid, 34-octadecenoic acid, 35-octadecenoic acid, 36-octadecenoic acid, 37-octadecenoic acid, 38-octadecenoic acid, 39-octadecenoic acid, 40-octadecenoic acid, 41-octadecenoic acid, 42-octadecenoic acid, 43-octadecenoic acid, 44-octadecenoic acid, 45-octadecenoic acid, 46-octadecenoic acid, 47- ,9,12,15-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, etc.

[0532] 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.

[0533] 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.

[0534] 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, pentadecylic 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, lacceric acid, psyllic acid, geddic acid, ceroplastic acid, hexatriacontylic acid, heptatriacontanoic acid, or octatriacontanoic acid.

[0535] In some embodiments, each fatty acid is independently selected from α-linolenic acid, stearidonic acid, eicosapentaenoic acid, docosahexaenoic acid, linoleic acid, gamma-linoleic acid, dihomo-gamma-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.

[0536] In some embodiments, one or both of the fatty acids are essential fatty acids. Considering the beneficial health effects of certain essential fatty acids, including such fatty acids in the lipid prodrug may increase the therapeutic benefit of the disclosed lipid prodrug. In some embodiments, the essential fatty acid is an n-6 or n-3 essential fatty acid selected from the group consisting of linolenic acid, gamma-linolenic acid, dihomo-gamma-linolenic acid, arachidonic acid, adrenic acid, docosapentaenoic n-6 acid, alpha-linolenic acid, stearidonic acid, 20:4n-3 acid, eicosapentaenoic acid, docosapentaenoic n-3 acid, or docosahexaenoic acid.

[0537] 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), eicosatetraenoic acid (ETA or all-cis-8,11,14,17-eicosatetraenoic acid), and eicosapentaenoic acid (E PA), 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.

[0538] Fatty acid chains vary widely in their chain length and can be categorized according to chain length, for example, as short chain to very long chain.

[0539] Short-chain fatty acids (SCFAs) are fatty acids having 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.

[0540] Medium-chain fatty acids (MCFAs) are fatty acids having 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.

[0541] Long-chain fatty acids (LCFAs) include fatty acids having about 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.

[0542] Very long chain fatty acids (VLCFAs) include fatty acids having about 22 or more carbons, e.g., 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.

[0543] In some embodiments, one of the fatty acids is independently an MCFA and one is independently an LCFA.

[0544] Therapeutic Agents and Exemplary Associated Disorders According to the present invention, various therapeutic agents can be covalently conjugated to lymphatic-targeting lipids, e.g., triglyceride backbones, described herein. In some embodiments, by conjugating a therapeutic agent to a lymphatic-targeting lipid, the present invention provides for the enhancement of 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 target tissues, or increasing the solubility and stability of the therapeutic agent (including the in vivo solubility and stability of the drug).

[0545] 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.

[0546] In general, neurotransmitters regulate the conductance of ions across neuronal membranes. Gamma-aminobutyric acid (GABA) exerts a profound influence on overall neuronal excitability by modulating chloride ion conductance through 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, via this mechanism, the GR complex mediates anxiety, seizure activity, and sedation.

[0547] Certain endogenous steroids, such as the A-ring reduced metabolites of progesterone, act as selective allosteric modulators of the GR complex without the activity of classical steroid hormones. 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 anxiolytic (Bitran, D. et al. J. Neuroendocrinol 7(3):171-7(1995)), anticonflict (Perche, F. et al. Aggress Behav 27(2):130-8(2001)), antiseizure (Frye, CA Brain Res. 643(1-2):194-203(1995)), and antinociceptive (Wiebe, J.P. & Kavaliers, M. Brain Res. 461(1):150-7(1988)), as well as neuroprotective effects. Furthermore, the antidepressant effects of allopregnanes 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)). Furthermore, pregnane neurosteroid treatment has been shown to have positive effects in various neurological conditions (e.g., 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).

[0548] Nevertheless, neurosteroids are susceptible to metabolism and have low bioavailability (Rupprecht, R. Psychoneuroendocrinology, 28(2):139-68(2003)). As a result, there is a need for neurosteroid (e.g., allopregnanolone) prodrugs that have improved bioavailability and bypass first-pass metabolism by the liver.

[0549] In some embodiments, the disclosed lipid prodrugs comprise a therapeutic agent selected from a neuroactive steroid such as allopregnanolone, pregnanolone, pregnenolone, 3β-dihydroprogesterone, isopregnanolone, epipregnanolone, and 21-hydroxyallopregnanolone, or others disclosed herein, hi some embodiments, the neuroactive steroid is selected from allopregnanolone or 21-hydroxyallopregnanolone.

[0550] The compounds disclosed herein can be used to treat, for example, postpartum depression (Osborne, L. M. et al. Psychoneuroendocrinology 79:116-21 (2017)), depression (Almeida, F. B. et al. Neurobiology of Stress 12 (2020) 100-218; Melon, L. et al. Front. Endocrinol. 9:703. (2018); Almeida, F. B. et al. Physiology & Behavior 194 (2018) 246-251), anxiety (Schuele, 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. al. Epilepsia 54(s6):93-8(2013)), Alzheimer's disease, Parkinson's disease, multiple sclerosis, Niemann-Pick type C, paraneoplastic tremor / ataxia syndrome, diabetic neuropathy, stroke (Kaminski, RM et al. Epilepsia, 45(7):864-867, (2004)), or traumatic brain injury (Irwin, RW et al. Front. Cell. Neurosci. 8:203. doi:10.3389 / fncel.2014.00203; Irwin, RW & Brinton, RD Prog. Neurobiol 113:40-55(2014)). In some embodiments, provided herein are methods for treating a neurological disease or condition, e.g., postpartum depression, depression, anxiety, Niemann-Pick disease, status epilepticus, Alzheimer's disease, Parkinson's disease, multiple sclerosis, Niemann-Pick type C, paraneoplastic tremor / ataxia syndrome, diabetic neuropathy, stroke, or traumatic brain injury, comprising administering to a subject in need thereof a compound of the present invention.

[0551] In other embodiments, the present invention provides a method for treating or preventing a disease, disorder, or condition in which increased levels of a pregnane neurosteroid, such as allopregnanolone, is beneficial, or a disease, disorder, or condition caused by a deficiency of a pregnane neurosteroid, such as an allopregnanolone deficiency, comprising administering to a subject in need thereof an effective amount of the disclosed lipid prodrug.

[0552] In some embodiments, the present invention provides a method for treating GABA A Methods for treating associated diseases, disorders, or conditions are provided, comprising administering to a subject in need thereof an effective amount of the disclosed lipid prodrugs.

[0553] In some embodiments, the present invention provides a method for treating GABA A The present invention provides a method for treating a disease, disorder, or condition caused by underactivation of a lipid prodrug, the method comprising administering to a subject in need thereof an effective amount of the disclosed lipid prodrug.

[0554] 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 hypofunction, migraine, status epilepticus, sleep disorders such as insomnia, fragile X syndrome, depression induced by another medication (such as 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 super-refractory status epilepticus (SRSE), a severe form of uncontrolled seizures. In some embodiments, the disease, disorder, or condition is depression induced by another drug (such as finasteride or another 5-alpha reductase inhibitor). In some embodiments, the depression induced by another drug is post-finasteride syndrome.

[0555] 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 hypofunction, status epilepticus, Parkinson's disease, or Alzheimer's disease. In some embodiments, the status epilepticus is very refractory status epilepticus (SRSE), a severe form of uncontrolled seizures.

[0556] In some embodiments, the present invention provides methods of 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 post-traumatic stress disorder), the methods comprising administering to a subject in need thereof a disclosed lipid prodrug.

[0557] In some embodiments, the present invention provides a method for treating non-REM sleep disorders associated with multiple sclerosis, traumatic brain injury, ischemia, stroke, peripheral neuropathy, neuropathic pain, spinal cord trauma, or Alzheimer's disease (AD) or Parkinson's disease (PD), comprising administering the disclosed lipid prodrug to a subject in need thereof.See, for example, Biol Psychiatry.2010 Nov 15;68(10):956-963, which is incorporated herein by reference in its entirety.

[0558] In some embodiments, the present invention provides a method for reducing neuroinflammation in a subject, the method comprising administering to a subject in need thereof a disclosed lipid prodrug. In some embodiments, the subject has AD or PD. See, e.g., Canelif Yilmaz, et al., Frontiers in Neuroendocrinology, https: / / doi.org / 10.1016 / j.yfrne.2019.100788, which is incorporated herein by reference in its entirety.

[0559] Allopregnanolone (ALLO, brexanolone, SAGE-547) is currently under investigation as a treatment for postpartum depression (NCT2614547, Kanes, S. et al. Lancet 390(10093):480-9(2017)).

[0560] In some embodiments, the present invention provides a method of treating fragile X syndrome or fragile X-associated syndrome in a subject, the method comprising administering a disclosed lipid prodrug to a subject in need thereof. In some embodiments, the present invention provides a method of treating fragile X syndrome in a subject, the method comprising administering a disclosed lipid prodrug to a subject in need thereof. In some embodiments, the present invention provides a method of treating fragile X-associated syndrome in a subject, the method comprising administering a disclosed lipid prodrug to a subject in need thereof. In some embodiments, the present invention provides a method of treating fragile X-associated tremor / ataxia syndrome in a subject, the method comprising administering a disclosed lipid prodrug to a subject in need thereof.

[0561] In some embodiments, the present invention provides methods of treating epilepsy and related epileptic disorders in a subject, the methods comprising administering a disclosed lipid prodrug to a subject in need thereof. In some embodiments, the epileptic disorder is acute repetitive seizures. In some embodiments, the epileptic disorder is treatment-resistant seizures. In some embodiments, the epileptic disorder is status epilepticus. In some embodiments, the epileptic disorder is a convulsive condition, including but not limited to, status epilepticus, epileptic seizures, or convulsions. Specific types of epileptic seizures include, but are not limited to, tonic-clonic (grand mal), partial (focal) seizures, catamenial seizures, acute repetitive seizures, psychomotor (complex partial) seizures, absence seizures (petit mal), and myoclonic seizures.

[0562] In some embodiments, the present invention provides a method of treating a demyelinating disease in a subject, the method comprising administering a disclosed lipid prodrug to a subject in need thereof. In some embodiments, the demyelinating disease is selected from multiple sclerosis, neuromyelitis optica, optic neuritis, transverse myelitis, acute disseminated encephalomyelitis, adrenoleukodystrophy and adrenomyeloneuropathy, Guillain-Barré syndrome, antimyelin-associated glycoprotein peripheral neuropathy, Charcot-Marie-Tooth disease, progressive inflammatory neuropathy, chronic inflammatory demyelinating polyneuropathy, and amyotrophic lateral sclerosis (ALS). In some embodiments, the demyelinating disease is multiple sclerosis. In some embodiments, the multiple sclerosis is relapsing-remitting multiple sclerosis (RRMS) or primary progressive multiple sclerosis.

[0563] In some embodiments, the present invention provides methods of treating a lysosomal storage disorder in a subject, the method comprising administering to a subject in need thereof a disclosed lipid prodrug. In some embodiments, the lysosomal storage disorder is selected from the group consisting of Farber disease, Krabbe disease, Fabry disease, Schindler disease, GM1 gangliosidosis, GM2 gangliosidosis, Tay-Sachs disease, Zandhoff disease, Gaucher disease, lysosomal acid lipase deficiency, Niemann-Pick disease, sulfatidosis, metachromatic leukodystrophy, Hurler syndrome, Scheie syndrome, Hurler-Scheie syndrome, Hunter syndrome, Sanfilippo syndrome, Morquio syndrome, and Marsh syndrome. Selected from Tow-Lamy syndrome, Sly syndrome, hyaluronidase deficiency, sialidosis, Eisel's disease, phosphotransferase deficiency, mucolipidin 1 deficiency, neuronal ceroid lipofuscinosis, Wolman disease, alpha-mannosidosis, beta-mannosidosis, aspartylglucosaminuria, fucosidosis, cystinosis, pyknodysostosis, Salla disease, childhood free sialic acid storage disease, Pompe disease, Danon disease, cholesteryl ester storage disease, and lysosomal diseases.

[0564] In some embodiments, the present invention provides a method of treating a nervous system disorder in a subject, the method comprising administering to a subject in need thereof a disclosed lipid prodrug. In some embodiments, the nervous system disorder is Angelman syndrome, Rett syndrome, Dravet syndrome, Lennox-Gastaut syndrome, or catamenial epilepsy. In some embodiments, the nervous system disorder is Angelman syndrome, Rett syndrome, or Dravet syndrome. In some embodiments, the nervous system disorder is Lennox-Gastaut syndrome or catamenial epilepsy.

[0565] In some embodiments, the present invention provides a method for treating a sleep disorder in a subject, the method comprising administering to a subject in need thereof a disclosed lipid prodrug. In some embodiments, the sleep disorder is secondary to rheumatoid arthritis. In some embodiments, the sleep disorder is obstructive sleep apnea, insomnia, or restless legs syndrome.

[0566] In some embodiments, the present invention provides a method of treating hepatic encephalopathy in a subject, the method comprising administering to a subject in need thereof a disclosed lipid prodrug.

[0567] In some embodiments, the present invention provides a method of treating chronic pain in a subject, the method comprising administering to a subject in need thereof a disclosed lipid prodrug.

[0568] In some embodiments, the therapeutic agent is ganaxolone or allopregnanolone. 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 explanation of the subject matter of the present disclosure.

[0569] 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 intended to encompass variations from the stated value or range, 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%.

[0570] As used herein, the terms "treatment," "treat," and "treating" refer to ameliorating, alleviating, delaying the onset of, or arresting the progression of a disease or disorder as 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., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, e.g., to prevent or delay their recurrence.

[0571] 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, when incorporated into a lipid prodrug, suitable lipids are processed or metabolized similarly to, or mimic the processing or metabolism of, triglycerides in the GI tract. The term "glyceride" refers to an ester of glycerol (1,2,3-propanetriol) with the acyl radical of a fatty acid or other lipid, also known as an acylglycerol. When only one position of the glycerol molecule is esterified with a fatty acid, a "monoglyceride" is produced; when two positions are esterified, a "diglyceride" is produced; and when all three positions of the glycerol are esterified with fatty acids, a "triglyceride" or "triacylglycerol" is produced. Glycerides are referred to as "simple" when all esterified positions contain the same fatty acid, or as "mixed" when different fatty acids are involved. The carbons of the glycerol backbone are designated sn-1, sn-2, and sn-3, with sn-2 being in the middle of the glycerol and sn-1 and sn-3 being at the ends.

[0572] Naturally occurring oils and fats consist primarily of triglycerides, in which the three fatty acyl residues may or may not be 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 both simple and mixed triglycerides containing fatty acids with 4 to 12 carbon atoms.

[0573] The term "ECN" or "carbon number equivalent" 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 acyl radicals, 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. Natural 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 of 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 in the ECN range above 30 and below 48 typically represent mixed triacylglycerol species that are 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).

[0574] The term "self-immolative group," as used herein, refers to a divalent chemical moiety that contains a scissile covalent bond as one of its divalent bonds and a stable covalent bond to a therapeutic agent as its other divalent bond, such that cleavage of the scissile bond destabilizes the bond to the therapeutic agent. 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. Several other suitable self-immolative groups are known in the art, such as those described 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.

[0575] As used herein, the terms "therapeutic agent," "active pharmaceutical agent," "active drug," or "pharmaceutical agent" include any therapeutic agent or imaging agent for which transport via the intestinal lymphatic system would be beneficial, e.g., to enable oral administration (e.g., of an intravenously administered therapeutic agent), to avoid first-pass metabolism, to avoid liver or other toxicity, or for targeted delivery within the lymphatic system.

[0576] 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 specified. For purposes of this invention, chemical elements are defined as defined in the Periodic Table of the Elements, CAS version (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," 5 th Ed., Ed.: Smith, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0577] As used herein, the term "aliphatic" or "aliphatic group" means 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, having a single point of attachment to the rest of the molecule; or a monocyclic or bicyclic hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic (also referred to herein as "carbocyclic," "cycloaliphatic," or "cycloalkyl"). 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, "cycloaliphatic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C3-C6 hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic, with a single point of attachment to the rest of the molecule. 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.

[0578] 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, and having one or more atoms in common between the two rings of the ring system. Thus, the term includes any permissible ring fusion, such as ortho-fused or spirocyclic. As used herein, the term "heterobicyclic" is a subset of "bicyclic," requiring one or more heteroatoms to be present in one or both rings of the bicycle. Such heteroatoms may be present at ring junctions, 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., carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a "bridge" is an unbranched chain or valence bond of atoms (or atoms) connecting two bridgeheads, where 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, where 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:

[0579] [ka]

[0580] Exemplary bridged bicyclic compounds include:

[0581] [ka]

[0582] The term "lower alkyl" refers to C 1-4 It refers to a straight-chain or branched alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0583] The term "lower haloalkyl" refers to a C alkyl group substituted with one or more halogen atoms. 1-4 It refers to a straight-chain or branched alkyl group.

[0584] The term "heteroatom" refers to boron, oxygen, sulfur, nitrogen, phosphorus, or silicon (any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen; or a substitutable nitrogen of a heterocycle, e.g., N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (including as in N-substituted pyrrolidinyl)).

[0585] As used herein, the term "unsaturated" means that a moiety has one or more units of unsaturation.

[0586] As used herein, "divalent C 1-8 (or C 1-6 The term "saturated or unsaturated, straight or branched hydrocarbon chain" refers to divalent alkylene, alkenylene, and alkynylene chains, which are straight or branched, as defined herein.

[0587] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2) n -, where n is a positive integer, preferably 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 with a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0588] 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 with a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0589] The term "halogen" means F, Cl, Br, or I. The term "aryl," used alone or as part of a larger moiety, 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. Also included within the scope of the term "aryl" as used herein are groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthoimidyl, phenanthridinyl, or tetrahydronaphthyl.

[0590] The terms "heteroaryl" and "heteroar-," used alone or as part of a larger moiety, such as "heteroaralkyl" or "heteroaralkoxy," refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; groups having 6, 10, or 14 pi electrons shared in a cyclic arrangement; and groups 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. As used herein, the terms "heteroaryl" and "heteroar-" also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, 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 term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," any of which terms include rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.

[0591] As used herein, the terms "heterocycle," "heterocyclyl," "heterocyclic radical," and "heterocycle" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated and has, in addition to carbon atoms, one or more, preferably 1 to 4, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes substituted nitrogen. By way of example, in a saturated or partially unsaturated ring having 0 to 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 may also be NR (as in N-substituted pyrrolidinyl).

[0592] A heterocycle 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 cycloaliphatic rings, such as 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, where the alkyl and heterocyclyl portions independently are optionally substituted.

[0593] 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 include aryl or heteroaryl moieties, as defined herein.

[0594] As described herein, compounds of the invention may contain "optionally substituted" moieties. In general, the term "substituted," whether preceded by the term "optionally," means that one or more hydrogens of the specified moiety may be replaced with a suitable substituent. Unless otherwise specified, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents may be the same or different at each and every position. Combinations of substituents envisioned by the present invention are preferably those that result in the formation of stable or chemically feasible compounds. As used herein, the term "stable" refers to compounds that are substantially unchanged when subjected to conditions that permit their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0595] Each optional substituent on a substitutable carbon is selected from the group consisting of halogen, -(CH2), 0-4 R°, -(CH2) 0-4 OR°, -O(CH2) 0-4 R°, -O-(CH2) 0-4 C(O)OR°, -(CH2) 0-4 CH(OR°)2, -(CH2) 0-4 SR°, -(CH2) 0-4 Ph (which may be replaced by R°), —(CH2) 0-4 O(CH2) 0-1Ph (which may be substituted with R°), -CH=CHPh (which may be substituted with R°), -(CH2) 0-4 O(CH2) 0-1 -pyridyl (which may be substituted with R°), -NO2, -CN, -N3, -(CH2) 0-4 N(R°)2, -(CH2) 0-4 N(R°)C(O)R°, -N(R°)C(S)R°, -(CH2) 0-4 N(R°)C(O)NR°2, -N(R°)C(S)NR°2, -(CH2) 0-4 N(R°)C(O)OR°, -N(R°)N(R°)C(O)R°, -N(R°)N(R°)C(O)NR°2, -N(R°)N(R°)C(O)OR°, -(CH2) 0-4 C(O)R°, -C(S)R°, -(CH2) 0-4 C(O)OR°, -(CH2) 0-4 C(O)SR°, -(CH2) 0-4 C(O)OSiR°3, -(CH2) 0-4 OC(O)R°, -OC(O)(CH2) 0-4 SR-, SC(S)SR°, -(CH2) 0-4 SC(O)R°, -(CH2) 0-4 C(O)NR°2, -C(S)NR°2, -C(S)SR°, -SC(S)SR°, -(CH2) 0-4 OC(O)NR°2, -C(O)N(OR°)R°, -C(O)C(O)R°, -C(O)CH2C(O)R°, -C(NOR°)R°, -(CH2) 0-4 SSR°, -(CH2) 0-4 S(O)2R°, -(CH2) 0-4 S(O)2OR°, -(CH2) 0-4 OS(O)2R°, -S(O)2NR°2, -S(O)(NR°)R°, -S(O)2N=C(NR°2)2, -(CH2) 0-4 S(O)R°, -N(R°)S(O)2NR°2, -N(R°)S(O)2R°, -N(OR°)R°, -C(NH)NR°2, -P(O)2R°, -P(O)R°2, -OP(O)R°2, -OP(O)(OR°)2, SiR°3, -(C 1-4 Linear or branched alkylene)ON(R°)2, or -(C 1-4are monovalent substituents independently selected from linear or branched alkylene)C(O)ON(R°)2.

[0596] Each R° is independently hydrogen, C 1-6 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, -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 instances of R° taken 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 may be substituted on a saturated carbon atom of R° with a divalent substituent selected from =O and =S; or each R° is selected from halogen, -(CH2) 0-2 R ● ,-(Halo R ● ), -(CH2) 0-2 OH, -(CH2) 0-2 OR ● , -(CH2) 0-2 CH(OR ● )2, -O(HaloR ● ), -CN, -N3, -(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 with a monovalent substituent independently selected from

[0597] Each R ● independently, C 1-4 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, wherein each R ● is unsubstituted or, if preceded by halo, is substituted with only 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 or the divalent substituent attached to a vicinal substitutable carbon of an "optionally substituted" group is -O(CR * 2) 2-3 O-, wherein R * Examples of each of these independently occurring groups are 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.

[0598] R * C 1-6 If aliphatic, R * is optionally a halogen, -R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ●2, or -NO2, wherein each R ● independently, C 1-4 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, when preceded by halo, substituted with only one or more halogens.

[0599] 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 † where 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 R † two independently occurring instances of, taken 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 If aliphatic, R † is optionally a halogen, -R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR● , -NR ● 2, or -NO2, wherein each R ● independently, C 1-4 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, when preceded by halo, substituted with only one or more halogens.

[0600] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is suitable, within the scope of sound medical judgment, for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and that is 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 acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or formed by using other methods used in the art, such as ion exchange. 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-hydroxy-ethanesulfonate, lactobionate. Salts include, but are not limited to, sodium nitrate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like.

[0601] Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N + (C 1-4 Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations, formed where appropriate using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0602] Unless otherwise specified, structures depicted herein are also intended to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure, e.g., R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Accordingly, 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 specified, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise specified, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, including the replacement of hydrogen with deuterium or tritium, or replacing a carbon with a methyl group. 13 C enrichment or 14 Compounds having the present structure, including replacements with C-enriched carbons, are within the scope of this invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents according to the present invention.

[0603] 3. Use, Formulation, and Administration Use of lymphatic-directed lipid prodrugs The disclosed lymphatic vessel-targeting lipid prodrugs, as well as pharmaceutically acceptable compositions comprising the disclosed lipid prodrugs and a pharmaceutically acceptable excipient, diluent, or carrier, are useful for treating a variety of diseases, disorders, or conditions, including those described herein.

[0604] 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 the patient a disclosed lipid prodrug.

[0605] The disclosed lipid prodrugs are useful for stable transport of pharmaceuticals to intestinal lymph and release of pharmaceuticals in lymph, lymphocytes, lymphoid tissues, tissues with high lipase activity (e.g., adipose tissue, certain cancers, liver), or in the systemic circulation. The disclosed lipid prodrugs are particularly useful for transport and release of pharmaceuticals for which avoidance of first-pass metabolism is beneficial, such as 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.

[0606] Therapeutic agents that may benefit from stable transport to the intestinal lymph and release into lymph, lymphocytes, lymphoid tissues, tissues with high lipase activity (such as adipose tissue, certain cancers, the liver), or into the systemic circulation include, but are not limited to, the therapeutic agents listed herein, such as allopregnanolone, pregnanolone, pregnenolone, 3β-dihydroprogesterone, isopregnanolone, epipregnanolone, ganaxolone, or 21-hydroxyallopregnanolone.

[0607] The lipid prodrugs of the present disclosure are also useful for targeted release of therapeutic agents within the lymphatic system, for example, in lymph, lymphocytes, and lymphoid tissues, as well as 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% lymphatic transport when administered orally. In contrast, the present invention allows for improved lymphatic transport of such therapeutic agents. In some embodiments, the disclosed lipid prodrugs exhibit lymphatic transport of at least 1%, 5%, 7.5%, 10%, 12.5%, 15%, 20%, 25%, 30%, 35%, 40%, or 50% when administered orally. In some embodiments, the disclosed lipid prodrugs 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% when administered orally, as measured by comparing either the w / w% of administered lipid prodrug or the w / w% of the therapeutic agent in its lipid prodrug form to the unmodified therapeutic agent.

[0608] In some embodiments, the disclosed lipid prodrugs are delivered to the central nervous system (CNS) via the lymphatic system or cross the blood-brain barrier (BBB).

[0609] In some embodiments, the present invention provides a method for treating or preventing a disease, disorder, or condition, the method comprising administering to a subject in need thereof an effective amount of a lipid prodrug comprising the disclosed pregnane neurosteroid therapeutic.

[0610] In some embodiments, the present invention provides a pharmaceutical composition comprising a disclosed lipid prodrug formulated substantially as described in one of the Examples below, or another exemplary formulation herein. In some embodiments, such a pharmaceutical composition, when administered to a subject, provides a pharmacokinetic result as described in Tables B, C, D, or E below.

[0611] 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 a relevant disease, disorder, or condition in a patient in need of such treatment ("effective amount"). In some embodiments, the composition of the present disclosure is formulated for oral administration to a patient.

[0612] 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, protamine sulfate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium chloride, salts or electrolytes such as 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 is formulated as a lipophilic mixture, such as a lipid-based composition.

[0613] 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, for example, 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.

[0614] Any non-irritating fixed oil, including synthetic mono- or diglycerides, may be used to aid in the delivery of the composition. Fatty acids such as oleic acid and its glyceride derivatives are useful for the preparation of injectables, as well as natural pharmaceutically acceptable oils such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as carboxymethylcellulose or similar dispersants, which are commonly used to formulate pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants, such as Tween, Spans, and other emulsifiers or bioavailability enhancers, which are commonly used to prepare pharmaceutically acceptable solid, liquid, or other dosage forms, may also be used for formulation purposes.

[0615] Pharmaceutically acceptable compositions can be orally administered in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or aqueous solutions.For tablets intended 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 coloring agents can also be added.

[0616] Alternatively, the pharmaceutically acceptable composition may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, thereby melting in the rectum and releasing the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0617] In some embodiments, the pharmaceutically acceptable composition is formulated for oral administration. Such formulations may 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.

[0618] It should also be understood that 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, the patient's age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, as well as the judgment of the treating physician and the severity of the particular disease being treated.

[0619] 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, flavoring agents, and aromatics. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may 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 non-irritating fixed oil, including synthetic mono- or diglycerides, may be used. In addition, fatty acids such as oleic acid may be used in the preparation of injectables. Injectable preparations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium before use.

[0620] 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 may be accomplished by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends on its dissolution rate, which may in turn depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form can be accomplished 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 used, the release rate of the compound 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.

[0621] Compositions for rectal or vaginal administration are preferably suppositories, which can be prepared by mixing a compound of the invention with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or a suppository wax, which is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum or vaginal cavity to release the active compound.

[0622] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; c) humectants 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) humectants such as, for example, cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay; and i) lubricants 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 comprise buffering agents.

[0623] Solid compositions of a similar type may also be used as fillers in soft- and hard-filled gelatin capsules using excipients such as lactose or milk sugar, and high molecular weight polyethylene glycols, and the like. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release 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 excipients such as lactose or milk sugar, and high molecular weight polyethylene glycols, and the like.

[0624] The therapeutic agent may also be in microencapsulated form with one or more of the excipients described above. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings, release-controlling coatings, and other coatings well known in the pharmaceutical formulation arts. In such solid dosage forms, the active compound may be admixed with at least one inert diluent, such as sucrose, lactose, or starch. Such dosage forms may also contain, as is common practice, 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 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.

[0625] 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 admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers, if required. Ophthalmic formulations, ear drops, and eye drops are also contemplated within the scope of the present invention. Furthermore, 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 active compound in the proper 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 by dispersing the compound in a polymer matrix or gel.

[0626] In some embodiments, lipid prodrugs are formulated as orally administrable lipid-based formulations.Lipid-based formulations for oral delivery are known in the art and may, for example, comprise a substantially non-aqueous vehicle that typically contains one or more lipid components.Lipid vehicles and 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.

[0627] The lipid vehicle and the resulting lipid formulation may contain oils / lipids and / or surfactants, optionally with cosolvents. In LFCS terminology, Type I formulations contain oils or lipids that require digestion, such as monoglycerides, diglycerides, and triglycerides, and combinations thereof. Type II formulations are water-insoluble self-emulsifying drug delivery systems (SEDDS) that contain the lipids and oils used in Type I formulations 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 with additional water-soluble surfactants and / or cosolvents (Type IIIa) or a higher proportion of water-soluble components (Type IIIb). Type IV formulations contain primarily 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.

[0628] In some embodiments, the lipid vehicle contains one or more oils or lipids without additional surfactants, co-surfactants, co-emulsifiers, or co-solvents, i.e., it essentially consists 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, optionally together with 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, optionally together with 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 essentially consists of one or more surfactants / co-surfactants / co-emulsifiers, and / or solvents / co-solvents.

[0629] 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 seed 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, rice 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, and the like. Glycerides, glyceryl tricaprate, glyceryl tricaproate, glyceryl tricaprylate, glyceryl tricaprylate / caprate, glyceryl tricaprylate / caprate, glyceryl tricaprylate / caprate / laurate, glyceryl tricaprylate / caprate / linoleate, glyceryl tricaprylate / caprate / stearate, glyceryl trilaurate, glyceryl monolaurate, glyceryl behenate, glyceryl monolinoleate, glyceryl trilinolenate, glyceryl trioleate, glyceryl triundecanoate, glyceryl tristearate, linoleic glyceride, 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 Examples of suitable triglycerides include long chain triglycerides containing fatty acid chains longer than 10 ...

[0630] Examples of mono- and diglycerides that can be used in such formulations include glycerol monoesters and diesters with fatty acid chains having 8 to 40 carbon atoms, including hydrolyzed coconut oil (e.g., Capmul® MCM) and hydrolyzed corn oil (e.g., Maisine™ 35-1). In some embodiments, the mono- and diglycerides are mono- or di-saturated fatty acid esters of glycerol with fatty acid chains of 8 to 18 carbon atoms in length (e.g., glyceryl monostearate, glyceryl distearate, glyceryl monocaprylate, glyceryl dicaprylate, glyceryl monocaprate, and glyceryl dicaprate). Mixtures of fatty acids adapted to improve absorption and transport of lipid-soluble compounds ("structured glycerides") are disclosed, for example, in U.S. Pat. No. 6,013,665, which is incorporated herein by reference.

[0631] Suitable surfactants for use in the lipid formulation include, but are not limited to, C surfactants such as propylene glycol monocaprylate, propylene glycol dicaprylate, propylene glycol monolaurate, sold under trade names such as Capryol® 90, Labrafac® PG, Lauroglycol® FCC, etc. 8-22 Propylene glycol mono- and diesters of fatty acids, including, but not limited to, sugar fatty acid esters such as 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; polyoxyethylene mono- and di-fatty acid esters, including, but not limited to, polyoxyl 40 stearate and polyoxyl 40 oleate; C glycerides of glycerol, such as those sold under trade names such as Labrasol®, Gelucire® 44 / 14, Gelucire® 50 / 13, and Labrafil®. 8-22Polyoxyethylene monoesters and diesters of fatty acids and C 8-22 mixtures of glyceryl monoesters, diesters, and triesters of fatty acids; 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, as 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; dioctyl sodium sulfosuccinate; polyoxyethylene-polyoxypropylene copolymers, such as, but not limited to, Poloxamer 124, Poloxamer 188, and Poloxamer 407; 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, and the like; 8-22 Polyoxyethylene ethers of fatty alcohols, or mixtures of any two or more thereof.

[0632] Co-emulsifiers or co-surfactants may be used in the formulation.Suitable co-emulsifiers or co-surfactants may be phosphoglycerides; phospholipids such as lecithin, or free fatty acids that are liquid at room temperature, such as iso-stearic acid, oleic acid, linoleic acid, linolenic acid, palmitic acid, stearic acid, lauric acid, capric acid, caprylic acid, and caproic acid.

[0633] Suitable solvents / co-solvents include ethanol, propylene glycol, polyethylene glycol, diethylene glycol monoethyl ether, and glycerol.

[0634] Polymers may also be used in formulations to prevent drug precipitation or change drug release.Various polymers have been shown to provide 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 Eudragit series polymers, including Eudragit E100, polyvinylpyrrolidone, or others, such as those described in Warren et al., Mol.Pharmaceutics 2013,10,2823-2848.

[0635] Formulations may be specifically selected to allow sustained release of the active agent in the gastrointestinal (GI) tract to control the rate of absorption. Many different strategies may be used to achieve these goals, including high melting point lipids that disperse / erode slowly in the GI tract, or polymers that form a slowly eroding matrix. These formulations may take the form of a large monolithic dosage form or may be present as a matrix of microparticles or nanoparticles, such as those 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).

[0636] 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., butylated hydroxyanisole (BHA) or butylated hydroxytoluene (BHT), and solidifying agents such as microporous silica, e.g., magnesium aluminometasilicate (Neusilin).

[0637] 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 is Alli® (orlistat). In other embodiments, the enzyme inhibitor is contemplated to inhibit cellular lipase enzymes, such as monoacylglycerol lipase, an example of which is JZL184 (4-nitrophenyl-4-[bis(1,3-benzodioxol-5-yl)(hydroxy)methyl]piperidine-1-carboxylate).

[0638] Combination therapy The provided lipid prodrugs, or pharmaceutically acceptable compositions thereof, may be administered to a patient in need thereof in combination with one or more additional therapeutic agents and / or therapeutic processes.

[0639] 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 can be in the form of a fixed combination of lipid prodrugs or compositions and one or more other therapeutic compounds, or administration that is time-delayed or administered independently, or a fixed combination and the combined administration of one or more other therapeutic compounds.Otherwise or in addition, the disclosed lipid prodrugs or compositions can be administered in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination thereof, especially for tumor treatment.In the context of other therapeutic strategies such as those mentioned above, long-term therapy is equally possible, as is adjuvant therapy.Other possible treatments include therapy to maintain patient status after tumor regression, or even, for example, chemoprevention therapy in patients at risk.

[0640] These additional drugs can be administered separately from the lipid prodrug or composition provided as part of a multiple-dose regimen.Alternatively, these drugs can be part of a single dosage form, and be mixed together with the disclosed lipid prodrug in a single composition.When administered as part of a multiple-dose regimen, these two active drugs can be presented simultaneously, sequentially, or within a certain period of each other.

[0641] 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 may be administered together with another therapeutic agent in separate unit dosage forms or in a single unit dosage form, simultaneously or sequentially. Thus, the present disclosure provides a single unit dosage form comprising the disclosed lipid prodrug, 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.

[0642] The amounts of both the disclosed lipid prodrugs and additional therapeutic agent (in compositions containing additional therapeutic agents as described above) 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 about 0.01 to 500 mg / kg body weight / day of the disclosed lipid prodrugs can be administered.

[0643] In compositions containing an additional therapeutic agent, the additional therapeutic agent and the disclosed lipid prodrug may act synergistically. Thus, the amount of additional therapeutic agent in such compositions will be less than the amount required in a monotherapy utilizing only that therapeutic agent. In such compositions, a dosage of about 0.01 μg / kg to 100 mg / kg body weight / day of the additional therapeutic agent may be administered.

[0644] The amount of additional therapeutic agent present in the compositions of the invention will not exceed 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 of the present disclosure will range from about 50% to 100% of the amount that would normally be present in a composition comprising that agent as the only therapeutically active agent.

[0645] Examples of drugs that may be combined with the lipid prodrugs of the present invention include, but are not limited to, drugs for treating Alzheimer's disease such as Aricept® and Exelon®, drugs for treating HIV such as ritonavir; drugs for treating Parkinson's disease such as L-DOPA / carbidopa, entacapone, ropinirole, pramipexole, bromocriptine, pergolide, trihexyphendyl, and amantadine; drugs for treating multiple sclerosis (MS) such as beta interferons (e.g., Avonex® and Rebif®), Copaxone®, and mitoxantrone; drugs for treating asthma such as albuterol and Singulair®, drugs for treating schizophrenia such as Zyprexa, Risperdal, Seroquel, and haloperidol; corticosteroids, TNF blockers, IL-1 Anti-inflammatory agents such as RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulators and immunosuppressants such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferon, corticosteroids, cyclophosphamide, azathioprine, and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferon, anticonvulsants, ion channel blockers, riluzole, and antiparkinsonian drugs; beta-blockers, ACE inhibitors, diuretics, nitrates, calcium agents for treating cardiovascular disease, such as muon channel blockers, and statins; agents for treating liver disease, such as corticosteroids, cholestyramine, interferons, and antivirals; agents for treating blood disorders, such as corticosteroids, anti-leukemia agents, and growth factors; agents that prolong or improve pharmacokinetics, such as cytochrome P450 inhibitors (i.e., inhibitors of metabolic degradation) and CYP3A4 inhibitors (e.g., ketoconazole and ritonavir), and agents for treating immune deficiency disorders, such as gamma globulins.

[0646] In certain embodiments, the combination therapy of the invention comprises a monoclonal antibody or an siRNA therapeutic.

[0647] 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 can be small molecules or biologics, for example, nonsteroidal anti-inflammatory drugs (NSAIDS) such as acetaminophen, aspirin, ibuprofen, naproxen, etodolac (Lodine®), and celecoxib; corticosteroids such as colchicine (Colcrys®), prednisone, prednisolone, methylprednisolone, hydrocortisone, and the like; probenecid; allopurinol; febuxostat; antimalarials such as methotrexate (Rheumatrex®), gold salts such as gold thioglucose (Solganal®), gold thiomalate (Myochrysine®), and auranofin (Ridaura®); Ciramine (Depen® or Cuprimine®), azathioprine (Imuran®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®), as well as etanercept (Enbrel®), infliximab (Remicade®), golimumab (Simpson®), and other anti-inflammatory drugs. i®), cetolizumab pegol (Cimzia®), and adalimumab (Humira®), "anti-IL-1" agents such as anakinra (Kineret®) and rilonacept (Arcalyst®), anti-Jak inhibitors such as canakinumab (Ilaris®), tofacitinib, antibodies such as rituximab (Rituxan®), "anti-T cell" agents such as abatacept (Orencia®),"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®), antidiarrheals such as diphenoxylate (Lomotil®) and loperamide (Imodium®), cholestyramine, alosetron (Lotronex®), laxatives such as milk of magnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol®, and Senokot®; anticholinergics or antispasmodics such as dicyclomine (Bentyl®), Singulair®; albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaprotease inhibitors (Proventil® HFA), levalbuterol (Xopenex®), methadone (Proventil® HFA ... beta-2 agonists such as Lenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®), and formoterol (Foradil®); anticholinergics such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®); beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®); Inhaled corticosteroids such as flunisolide (Aerobid®), Afviar®, Symbicort®, Dulera®, cromolyn sodium (Intal®), theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®,Methylxanthines such as Theo-24® and aminophylline, IgE antibodies such as omalizumab (Xolair®), zidovudine (Retrovir®), abacavir (Ziagen®), abacavir / lamivudine (Epzicom®), abacavir / lamivudine / zidovudine (Trizivir®), didanosine (Videx®), emtricitabine (Emtriva®), lamivudine (Epivir®), lamivudine / zidovudine (Com nucleoside reverse transcriptase inhibitors such as delavirdine (Rescriptor®), efavirenz (Sustiva®), nevirapine (Viramune®), and etravirine (Intelence®); nucleotide reverse transcriptase inhibitors such as tenofovir (Viread®); amprenavir (Agenerase®); ), atazanavir (Reyataz®), darunavir (Prezista®), fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir (Kaletra®), nelfinavir (Viracept®), ritonavir (Norvir®), saquinavir (Fortovase® or Invirase®), and protease inhibitors such as tipranavir (Aptivus®), These may include entry inhibitors such as fuvirtide (Fuzeon®) and maraviroc (Selzentry®), integrase inhibitors such as dexamethasone (Decadron®) in combination with raltegravir (Isentress®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), bortezomib (Velcade®), and lenalidomide (Revlimid®), or any combination(s) thereof.

[0648] In another embodiment, the present invention provides a method of 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 post-traumatic stress disorder) by administering to a patient in need thereof the disclosed lipid prodrugs, as well as other anti-inflammatory drugs such as citalopram (Celexa®), escitalopram (Lexapro®), fluoxetine (Prozac®), fluvoxamine (Luvox® / Luvox CR®), paroxetine (Paxil® / Paxil®), and / or anti-inflammatory drugs (e.g., steroids, anti-inflammatory drugs ... 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 (Vivact®), il®), phenelzine (Nardil®), selegiline (Emsam®), tranylcypromine (Parnate®), bupropion (Wellbutrin®), mirtazapine (Remeron®), nefazodone (Serzone®), toradosone (Desyrel®, Oleptro®), vilazodone (Viibryd®), and vortioxetine (Brintellix®).

[0649] 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 (Exelon®), galantamine (Razadyne®), tacrine (Cognex®), and memantine (Namenda®).

[0650] The disclosed lipid prodrugs and compositions, and any co-administered additional therapeutic agents, according to the methods of the present invention may 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 between subjects depending on the subject's species, age, and general condition, the severity of the infection, the specific drug, its mode of administration, and the like. The disclosed lipid prodrugs are preferably formulated in unit dosage forms for ease of administration and uniformity of dosage. As used herein, the term "unit dosage form" 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 rate of excretion of the specific lipid prodrug or composition; the duration of treatment; drugs used in combination with or concomitantly with the specific lipid prodrug or composition used, and similar factors well known in the medical field. As used herein, the term "subject" or "patient" refers to an animal, preferably a mammal, and most preferably a human.

[0651] In some embodiments, the dose is selected to take into account lymphatic uptake, metabolism, and release of the parent drug allopregnanolone (allo). For example, if a given dose of lipid prodrug is absorbed more efficiently than an equivalent oral or intravenous dose of allopregnanolone, the dose of the lipid prodrug is reduced by an appropriate amount to produce a desired plasma or lymphatic concentration of allopregnanolone. In some embodiments, the dose is selected so that an orally administered dose of lipid prodrug, upon lymphatic uptake, metabolism, and release of the parent drug allopregnanolone in a patient, provides an effective concentration, e.g., plasma or lymphatic concentration, of allopregnanolone desired to treat a disease, disorder, or condition (such as those disclosed herein).

[0652] 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 a 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.

[0653] 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.

[0654] 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.

[0655] 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, hi 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.

[0656] 4. Methods for preparing 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.

[0657] 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., with viral vectors), and similar methods known in the art.

[0658] In some embodiments, for example, to prevent unwanted side effects, 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.

[0659] In the synthetic methods described herein, where a particular protecting group ("PG"), leaving group ("LG"), or transformation condition is illustrated, one of skill in the art will understand that other protecting groups, leaving groups, and transformation conditions are also 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. th Edition, 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 hereby incorporated by reference in its entirety.

[0660] 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.

[0661] As used herein, the phrase "oxygen protecting group" includes, for example, carbonyl protecting groups, hydroxyl protecting groups, etc. Hydroxyl protecting groups are well known in the art and include those detailed in Protective Groups in Organic Synthesis, PGM Wuts, 5th edition, John Wiley & Sons, 2014, and Philip Kocienski, in Protecting Groups, Georg Thieme Verlag Stuttgart, New York, 1994, which are incorporated herein by reference in their entirety. 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 formates such as methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, vinyl, allyl, and p-nitrobenzyl formates, benzoyl formates, chloroacetates, trifluoroacetates, methoxyacetates, triphenylmethoxyacetates, p-chlorophenoxyacetates, 3-phenylpropionates, 4-oxopentanoates, 4,4-(ethylenedithio)pentanoates, pivalic (trimethylacetyl) acid esters, crotonates, 4-methoxycrotonates, benzoates, p-benzylbenzoates, 2,4,6-trimethylbenzoates, and carbonates. Examples of such silyl ethers include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, and other trialkylsilyl ethers. Alkyl ethers include methyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, trityl, t-butyl, allyl, and allyloxycarbonyl ethers or derivatives.Alkoxyalkyl ethers include acetals such as methoxymethyl, methylthiomethyl, (2-methoxy)methyl, benzyloxymethyl, beta-(trimethylsilyl)ethoxymethyl, and tetrahydropyranyl ethers. 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- and 4-picolyl.

[0662] Amino protecting groups are well known in the art and are described in Protective Groups in Organic Synthesis, PGMWuts, 5 th edition, John Wiley & Sons, 2014, and Philip Kocienski, in Protecting Groups, Georg Thieme Verlag Stuttgart, New York, 1994, which are incorporated herein by reference in their entireties. 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.

[0663] Those skilled in the art will appreciate that various functional groups present in the 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, for example, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, M.B. Smith and J. March, 2007, Vol. 7, No. 1, pp. 111-114, 2007. th Edition, John Wiley & Sons, 2013, which is incorporated herein by reference in its entirety. Such interconversions may require one or more of the techniques described above, and certain methods for synthesizing compounds of the invention are described below.

[0664] As a general strategy, the compounds of the present invention can be synthesized via one of the following routes.

[0665] [ka]

[0666] Scheme 1. Synthesis of compounds of formula iii-a. Diacid chloride i, which is readily available from the corresponding malonic acid, can be reacted with a diglyceride such as ii in the presence of pyridine or another suitable base to give the acid-triglyceride (acid-TG) iii-a (see Scheme 1). Formula iii-a can be represented by the formula C 15 H 31 Although shown as having a fatty acid side chain, other fatty acids (such as those listed above) can be substituted in this and other formulas described below.

[0667] [ka]

[0668] Scheme 2. Synthesis of compounds of formula iii-b. If anhydride ia is available, it can be ring-opened with diglyceride ii in the presence of pyridine or another suitable base to generate acid-TG iii-b (Scheme 2). This method involves the R 4 and R 5 It works best when R 4 and R 5 will result in a mixture of regioisomers of the acid-TG product iv. Consequently, in this situation, other methods such as that outlined in Scheme 3 can be advantageously employed.

[0669] [ka]

[0670] Scheme 3. Synthesis of compounds of formula iv (wherein R 4 = Me, alkyl, etc., and R 5 =H).

[0671] R 4 =Me or other alkyl or substituted, and R 5 In a specific example 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-a as a single regioisomer (see Scheme 3). Coupling of acid v with 1,3-DG ii under standard conditions produces TBDPS-protected triglyceride vi, which can be treated with appropriate conditions, such as TBAF and AcOH, to afford alcohol vii. Alcohol vii can then be converted to the desired acid-TG iv via the intermediate aldehyde viii using a two-step oxidation process (e.g., PCC followed by KMnO).

[0672] [ka]

[0673] Scheme 4. Synthesis of compounds of formula x where -M- is an acetal self-immolative (ASI) group.

[0674] For the synthesis of compounds containing an acetal self-immolative (ASI) group between the drug and alkyl spacer, the parent molecule must be functionalized and activated with an alcohol prior to conjugation with acid-triglyceride iii, as outlined above in Scheme 4. Treatment of the alcohol with DMSO in a mixture of acetic anhydride and acetic acid leads to the formation of the (methylthio)methyl (MTM) ether ix. Activation of the MTM ether ix with sulfuryl chloride forms a putative sulfoxide species, which can react with the carboxylate of acid-triglyceride iv-b to afford the target compound x.

[0675] [ka]

[0676] Scheme 5. Synthesis of compounds of formula xii, where -M- is a carboxyacetal (CASI) or carboxy(methylacetal) (CMSI) self-immolative group.

[0677] If the drug contains an alcohol, phenol, or amine (primary or secondary) functional group, 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 leaving group on the halide is then accomplished by treatment with the carboxylate derived from acid-TG iv-c in a suitable solvent such as refluxing toluene to give the target compound xii.

[0678] [ka]

[0679] Scheme 6. Synthesis of compounds of formula xviii where -M- is a trimethyl-lock (TML) self-immolative group.

[0680] For the synthesis of prodrugs containing a trimethyl lock (TML) self-immolative group (Levine, MN; Raines, RTChem. Sci. 2012, 3, 2412-2420, incorporated herein by reference) between the drug and the alkyl spacer to facilitate systemic release of the parent molecule, acid-triglyceride iv is typically functionalized with a TML moiety prior to conjugation with the drug, as outlined in Scheme 6. Coupling of acid-TG iv with TML phenol xiii under standard conditions provides triglyceride xiv, which can be deprotected under acidic conditions (10-camphorsulfonic acid) to provide alcohol xv. Sequential oxidation of alcohol xv first to aldehyde xvi and then to acid xvii, followed by coupling to a drug containing either an alcohol (as shown), an amine, or a sulfonamide under standard conditions, provides target compound xviii.

[0681] [ka]

[0682] Scheme 7. Synthesis of compounds of formula xxiv where -M- is a p-hydroxybenzylcarbonyl (PHB) self-immolative group.

[0683] 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 the 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 chloroformate (PNP) to give PNP carbonate xxiii. Displacement of the PNP group is then accomplished by reaction with a pharmaceutical agent (A-OH as shown) under basic conditions to give the desired compound xxiv.

[0684] [ka]

[0685] Scheme 8. Synthesis of compounds of formula III, where -M- is an inverted ester self-immolative (FSI) group.

[0686] Without wishing to be bound by theory, it is believed that the inverted ester self-immolative (FSI) group can liberate the free drug 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 in vivo via chemical or enzymatic mechanisms. FSI prodrugs can be synthesized by coupling the drug (shown as 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 target compound xxvii. [Example]

[0687] 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 DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene DCC: N,N'-dicyclohexylcarbodiimide DCM: dichloromethane DCE: dichloroethane DEA: Diethylamine DIPA: Diisopropylamine DM water: demineralized water DMF: N,N-dimethylformamide DMSO: dimethyl sulfoxide DMPU: N,N'-dimethylpropylene urea 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(Int-2):

[0688] [ka]

[0689] Scheme 9. Synthesis of Int-2. DMF (1 mL, 13.7 mmol) was added to a mixture of palmitic acid (433 g, 1.69 mol) in thionyl chloride (500 mL, 6.3 mol) at room temperature. The resulting reaction mixture was heated at reflux for 3 h. It was concentrated to dryness to give palmitoyl chloride (453 g, 1.64 mol, 97% yield) as a yellowish oil, which was used in the next step without further purification.

[0690] 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) at room temperature under nitrogen, palmitic acid chloride (453 g, 1.64 mol) was added. The mixture was stirred at room temperature for 16 h. It was diluted with MeOH (1000 mL) and water (2000 mL) and stirred for 30 min. The precipitate was collected by filtration and dried to give Int-1 (462 g, 0.815 mmol, 95% yield) as a white solid.

[0691] Int-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 portionwise. After the addition, the mixture was filtered to obtain a cake, which was dried to obtain compound Int-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 min; 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 (Int-4):

[0692] [ka]

[0693] Scheme 10. Synthesis of Int-4. 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 afford the diacid chloride Int-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 Int-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 Int-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 Int-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 H76 NaO8[M + Na + ] calculated value 719.5432; measured value 719.5451. Alternative procedure (larger scale):

[0694] [ka]

[0695] Scheme 11. Alternative synthesis of Int-4. A mixture of 3-methylglutaric acid (100 g, 685 mmol) and acetyl chloride (250 mL, 3.53 mol) was heated at reflux for 16 h, 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 h. The reaction was concentrated, and the residue was purified by silica column chromatography eluting with 0–50% ethyl acetate in petroleum ether to give Int-6 (70 g, 297 mmol, 43% yield) as a yellowish 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 Int-6 (70 g, 297 mmol) and Int-2(1,3-DG) (80 g, 140 mmol) in dichloromethane (1500 mL) were 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 Int-7 (68 g, 86.5 mmol, 29% yield) as a white solid. 1H NMR (400 MHz, 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). Int-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 h, then filtered and concentrated to dryness. The residue was further purified by trituration with hexane to give Int-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 min. 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). C5βMe-acid-2-TG-oleate (Int-210): Compound Int-210 was prepared from Int-112 using the procedure illustrated in Scheme 10 for the synthesis of Int-4.

[0696] [ka]

[0697] 1H NMR (400 MHz, CDCl3) δ 5.41 (m, 4H), 5.30 (m,1H), 4.35 (m, 2H), 4.20 (m,2H), 2.54 (d, 2H), 2.39 (m, 4H), 2.36 (m,2H), 2.05 (m, 8H),1.74 (m,1H), 1.73 (m, 4H), 1.1-1.3 (m, 40H), 1.05 (d, 3H), 0.9 (t, 6H); 13 C NMR (101 MHz, CDCl3) δ 176.7 (1C, C=O), 173.3 (2C, C=O), 171.8 (1C, C=O), 130.01 (2C), 129.74 (2C), 68.86 (C, CH), 62.13 (2C), 42.26 2C), 40.9 (2C), 37.09 (1C), 33.99 (2C), 31.91 (2C), 29.78-29.10 (14C), 27.7 (3C), 24.82 (2C), 22.71 (2C), 19.7 (1C), 16.32 (1C) 14.14 (2C);MS (ESI, -ve) m / z: 784.4 (M-1). C10-acid-2-TG:

[0698] [ka]

[0699] Scheme 12. Synthesis of Int-9. 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 afford the diacid chloride Int-8 (104 mg, quantitative) as a yellow oil, which was used without purification. 1 H NMR (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 Int-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 Int-8 (104 mg, 0.435 mmol) in dichloromethane (1.5 mL), and the mixture was stirred at room temperature for 1.5 h. 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 / hexanes) afforded Int-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 (larger scale):

[0700] [ka]

[0701] Scheme 13. Synthesis of Int-9. A mixture of sebacic acid (100 g, 495 mmol) and acetyl chloride (250 mL, 3.53 mol) was heated at reflux for 16 h, 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 h. The reaction was concentrated, and the residue was purified by column chromatography eluting with 0–50% ethyl acetate in petroleum ether to give Int-11 (82 g, 281 mmol, 57% yield) as a yellowish oil. LC-MS: MS m / z = 293 (M+ H+), RT = 1.45 min.

[0702] To a mixture of Int-11 (82 g, 281 mmol) and Int-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 to 50% ethyl acetate in petroleum ether to give Int-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). Int-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 Int-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), 1.35-1.20 (m, 56H), 0.88 (t, J = 6.6 Hz, 6H). Int-120 was prepared using a similar method.

[0703] [ka]

[0704] 1 H NMR (401 MHz, CDCl3) δ 5.25 (m, 1H), 4.28 (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); 13C 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), 29.36 (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 + ] Calculated value: 789.6215; measured value: 789.6218. Cα'βMe-acid-2-TG (Int-23 and Int-27):

[0705] [ka]

[0706] Scheme 14. Synthesis of Int-23 and Int-27. Int-13: Prepared according to Young, IS, Kerr, MAJ Am. Chem. Soc. 2007, 129, 1465-1469.

[0707] Prepared according to Int-14: Chowdhury, R., Ghosh, S.K. Org. Lett. 2009, 11, 3270-3273.

[0708] 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 min, then warmed to room temperature and stirred for an additional 15 min. The reaction was recooled to −50 °C, and a solution of bromide Int-14 (90.0 mg, 0.350 mmol) in THF (1 mL) was added dropwise, and the mixture was stirred at −50 °C for 15 min and then at room temperature for 17 h. 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% to 5% ethyl acetate / hexane) afforded the TMS alkyne Int-15 (45.9 mg, 48%) and the desilylated alkyne Int-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 Int-15 and alkyne Int-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 Int-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). Int-17: Prepared according to Kim, H.-O. et al. Synlett 1998, 1059-1060.

[0709] 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 CuI (9.1 mg, 0.0480 mmol), EtN (66.8 μL, 0.480 mmol), and a degassed solution of alkyne Int-16 (48.5 mg, 0.240 mmol) and enol triflate Int-17 (94.3 mg, 0.360 mmol) in DMF (2 mL) were added. The mixture was degassed for an additional 5 min using a stream of N and then heated at 50 °C for 1 h. The reaction mixture 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 the enyne Int-18 (46.6 mg, 62%) as a pale yellow oil. 1H 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). In a three-neck round-bottom flask, a solution of benzyl ether Int-18 (31.4 mg, 0.100 mmol) in ethyl acetate (8 mL) was evacuated and flushed with N gas twice, then palladium on carbon (10% (w / w), 26.6 mg, 0.0250 mmol) was added, and the resulting suspension was again evacuated and flushed with N (3 times). The flask was fitted with a H balloon, evacuated, and flushed with H (3 times), and the reaction mixture was stirred under 1 atmosphere 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 Celite pad, washing with ethyl acetate (30 mL). The filtrate was concentrated under reduced pressure to afford the saturated alcohol Int-19 (23.0 mg, quantitative) as a colorless oil, which was used without purification. 1H 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 (CH2), 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 Int-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) afforded the TBDPS ether Int-20 (33.7 mg, 92%) as a colorless oil. 1H 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), 42.1 (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 added to the ester Int-20 (40.0 mg, 0.0853 mmol) in ethanol (2 mL), 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 solvents were 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 afford the crude acid Int-21 (37.6 mg, quantitative) as a colorless oil, which was used without purification. 1H 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), 30.3 (CH), 29.8 (CH2), 29.5 (CH2), 27.01 (3C;CH3), 26.97 (CH2), 25.9 (CH2), 19.8 (CH3), 19.4 (C).Note: 1 H and 13 Two sets of signals were observed in both C NMR spectra, but only the major set of signals is reported above. It was unclear whether the doubling was due to the presence of two closely related compounds or to the presence of both monomeric and dimeric species resulting from the high concentration of the NMR sample.

[0710] DMAP (10.1 mg, 0.0831 mmol), EDC·HCl (39.8 mg, 0.208 mmol), and Int-2(1,3-DG) (70.9 mg, 0.125 mmol) were added to a solution of acid Int-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 Int-22 (39.9 mg, 48% over two steps) as a colorless solid.1 1H 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 13C NMR (101 MHz, CDCl3) δ 173.5 (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), 29.9 (CH2), 29.84 (6C;CH2), 29.80 (4C;CH2), 29.76 (2C;CH2), 29.6 (2C;CH2), 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 a solution of TBDPS ether Int-22 (39.0 mg, 39.3 μmol) in THF (2.5 mL) at 0 °C, and the mixture was stirred at room temperature for 3 h. The reaction was diluted with water (10 mL) and extracted with ethyl acetate (3 × 15 mL). The organic extract was 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) afforded the alcohol Int-23 (21.8 mg, 74%) as a colorless solid. 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, 2H), 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), 25.0 (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 Int-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 eluting with ethyl acetate, and the filtrate was concentrated under reduced pressure to give crude aldehyde Int-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). Prepared according to Int-25: Gossauer, A.; Kuhne, G. Liebigs. Ann. Chem. 1977, 664-686.

[0711] A solution of the ylide Int-25 (8.1 mg, 19.0 μmol) in toluene (0.4 mL) was added to the aldehyde Int-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) afforded the α,β-unsaturated benzyl ester Int-26 (7.1 mg, 54%) as a yellow oil. 1H 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), 36.8 (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). In a two-neck flask, a solution of benzyl ether Int-26 (48.5 mg, 54.0 μmol) in ethyl acetate (2.5 mL) was evacuated and flushed with N gas (three times each), then palladium on carbon (10% (w / w), 11.5 mg, 10.8 μmol) was added, and the resulting suspension was again evacuated and flushed with N (three times each). The flask was equipped with a H balloon, evacuated, and flushed with H (three times each), and the reaction mixture was stirred under 1 atmosphere of H at room temperature for 3 hours. The reaction was filtered through a pad of Celite, washing with ethyl acetate, and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (10% to 20% ethyl acetate / hexanes) afforded the saturated acid Int-27 (Cα'βMe-acid-2-TG) (28.1 mg, 64%) as a colorless oil. 1 H 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, 1H), 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); 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 (2C;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(Int-28):

[0712] [ka]

[0713] Scheme 15. Synthesis of Int-28. 4-(Dimethylamino)pyridine (DMAP, 15.5 mg, 0.127 mmol) was added to a solution of 1,3-diglyceride Int-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 h. An additional portion of succinic anhydride (25.4 mg, 0.254 mmol) and DMAP (15.5 mg, 0.127 mmol) was added, and the solution was heated at 40 °C for an additional 22 h. 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-TGInt-28 (77.0 mg, 91%) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 5.27 (m, 1H), 4.30 (dd, J = 12.0, 4.3 Hz, 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(Int-29):

[0714]

change

[0715] Synthesis of スキーム16.Int-29. A solution of 1,3-diglyceride Int-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 diluted with ethyl acetate (30 mL). The 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 the acid-TGint-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, 4H), 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 (2C;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 (Int-30):

[0716] [ka]

[0717] Scheme 17. Synthesis of Int-30. A solution of sodium chlorite (22.7 mg, 0.251 mmol) and monobasic sodium phosphate (NaHPO, 23.4 mg, 0.195 mmol) in water (1 mL) was added dropwise to aldehyde Int-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 the acid Int-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 = 14.7, 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); 13C NMR (101 MHz, CDCl3) δ 179.7 (C), 173.5 (2C;C), 172.4 (C), 69.0 (CH), 62.3 (2C;CH2), 41.8 (CH2), 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;CH2), 29.5 (3C;CH2), 29.4 (2C;CH2), 29.24 (2C;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(Int-121): Int-121 was prepared using a method similar to that described above for the synthesis of Int-23.

[0718] [ka]

[0719] 1 H NMR (401 MHz, CDCl3) δ 5.28 (m, 1H), 4.29 (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); 13C 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), 34.1 (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(Int-143):

[0720] [ka]

[0721] Pyridinium chlorochromate (16.5 mg, 0.0765 mmol) and Celite (16.5 mg) were added to a solution of alcohol Int-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 silica gel plug eluting with ethyl acetate (50 mL), and the filtrate was concentrated under reduced pressure to give the corresponding aldehyde as a pale yellow oil, which was used without purification.

[0722] 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 slowly by the 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 the alcohol Int-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, 2H), 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). 13C NMR (101 MHz, CDCl3) δ 173.5 (2C;C), 172.5 (C), 69.0 (CH), 68.3 (CH), 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 (2C;CH2), 19.7 (CH3), 14.3 (2C;CH3). C12α'βMe-OH-2-TG-oleate (Int-270): Int-269 and Int-270 were prepared from Int-235 using methods similar to those described above for the synthesis of Int-143.

[0723] [ka]

[0724] C12βMe-aldehyde-2-TG-oleate (Int-269). 11H NMR (401 MHz, CDCl3) δ 9.76 (t, J = 1.8 Hz, 1H), 5.39 - 5.24 (m, 5H), 4.29 (dd, J = 11.9, 4.2 Hz, 2H), 4.14 (dd, J = 11.8, 6.1 Hz, 2H), 2.42 (td, J = 7.3, 1.8 Hz, 2H), 2.32 (dd, J = 14.7, 5.9 Hz, 1H), 2.30 (t, J = 7.6 Hz, 4H), 2.12 (dd, J = 14.7, 8.3 Hz, 1H), 2.05 - 1.87 (m, 9H), 1.69 - 1.50 (m, 6H), 1.38 - 1.14 (m, 52H), 0.93 (d, J = 6.6 Hz, 3H), 0.88 (t, J = 6.8 Hz, 6H).

[0725]

Chem.

[0726] C12α’βMe-OH-2-TG-oleate (Int-270). 1 1H NMR (401 MHz, CDCl3) δ 5.39 - 5.24 (m, 5H), 4.28 (dd, J = 12.0, 4.0 Hz, 2H), 4.14 (dd, J = 11.9, 6.1 Hz, 2H), 3.78 (m, 1H), 2.36 - 2.27 (m, 5H), 2.11 (dd, J = 14.7, 8.2 Hz, 1H), 2.06 - 1.88 (m, 9H), 1.66 - 1.56 (m, 4H), 1.49 - 1.20 (m, 56H), 1.18 (d, J = 6.2 Hz, 3H), 0.92 (d, J = 6.6 Hz, 3H), 0.87 (t, J = 6.9 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 173.4 (2C;C), 172.5 (C), 130.1 (2C;CH), 129.8 (2C;CH), 68.9 (CH), 68.3 (CH), 62.3 (2C;CH2), 41.8 (CH2), 39.5 (CH2), 36.8 (CH2), 34.2 (2C;CH2), 32.0 (2C;CH2), 30.5 (CH), 29.89 (2C;CH2), 29.88 (CH2), 29.83 (2C;CH2), 29.77 (CH2), 29.72 (CH2), 29.70 (CH2), 29.65 (2C;CH2), 29.45 (4C;CH2), 29.30 (2C;CH2), 29.24 (2C;CH2), 29.22 (2C;CH2), 27.4 (2C;CH2), 27.3 (2C;CH2), 27.0 (CH2), 25.9 (CH2), 25.0 (2C;CH2), 23.6 (CH3), 22.8 (2C;CH2), 19.7 (CH3), 14.2 (2C;CH3);ESI-HRMS:C 53 H 98 NaO7[M + Na + ] Calculated value: 869.7205; measured value: 869.7206. C12β'βMe-OH-2-TG(Int-148):

[0727] [ka]

[0728] Borane-dimethyl sulfide complex (1.05 M in THF, 94.0 μL, 98.9 μmol) was added to a solution of carboxylic acid Int-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 the alcohol Int-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), 2.12 (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(Int-37):

[0729] [ka]

[0730] Scheme 18. Synthesis of Int-37. 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 afford the diacid chloride Int-36 (812 mg, quantitative) as a yellow oil, which was used without purification. 1 H NMR (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 Int-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 Int-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 the acid-TGint-37 (30.7 mg, 56%) as a colorless solid. 1 H NMR (400 MHz, CDCl3): δ 5.26 (m, 1H), 4.29 (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(Int-49):

[0731] [ka]

[0732] Scheme 19. Synthesis of Int-49. 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 petrol (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 the benzyl ether Int-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 Int-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 Int-39 (658 mg, 89%) as a colorless oil. 1H 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 stirred for an additional 15 minutes. The reaction was recooled to −50 °C, and a solution of bromide Int-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 the TMS alkyne Int-40 (489 mg, 88%) as a colorless oil containing a small amount of desilylated alkyne Int-41 (<10%). 1 H NMR (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 silyl alkyne Int-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 Int-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), 127.77 (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), 29.23 (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 for 5 min, then CuI (35.0 mg, 0.184 mmol), EtN (256 μL, 1.84 mmol), and a degassed solution of alkyne Int-41 (250 mg, 0.918 mmol) and enol triflate Int-17 (313 mg, 1.19 mmol) in DMF (6 mL) were 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 Int-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). In a three-neck round-bottom flask, a solution of benzyl ether Int-42 (246 mg, 0.640 mmol) in ethyl acetate (25 mL) was evacuated and flushed with N gas twice, then palladium on carbon (10% (w / w), 102 mg, 0.0960 mmol) was added, and the resulting suspension was again evacuated and flushed with N (three times). The flask was equipped with a H balloon, evacuated, and flushed with H (three times), and the reaction mixture was stirred under 1 atmosphere of H at room temperature for 1 h. The reaction mixture was then filtered through a Celite pad, and the pad was washed with ethyl acetate (40 mL). The filtrate was concentrated under reduced pressure to afford the saturated alcohol Int-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 Int-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% to 4% ethyl acetate / hexanes with 0.5% EtN) afforded the TBDPS ether Int-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, 23H), 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 (CH), 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 the ester Int-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 the crude acid Int-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, 3H); 13 C 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 Int-2 (53.3 mg, 0.0937 mmol) were added to a solution of acid Int-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% to 5% ethyl acetate / hexane) afforded triglyceride Int-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); 13C 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 added dropwise to TBDPS ether Int-46 (65.7 mg, 0.0619 mmol) in THF (3 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 (10% to 15% ethyl acetate / hexanes) afforded the alcohol Int-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 Int-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 eluting with ethyl acetate, and the filtrate was concentrated under reduced pressure to give crude aldehyde Int-48 (27.9 mg, quantitative) as a yellow oil, which was used without purification. 1H 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 monobasic sodium phosphate (NaHPO, 28.8 mg, 0.238 mmol) in water (1.2 mL) was added dropwise to aldehyde Int-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 h. 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% to 15% ethyl acetate / hexanes with 0.5% acetic acid) afforded the acid Int-49 (24.3 mg, 85%) as a colorless solid. 1 H 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); 13C 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), 29.42 (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). C8βMe-acid-2-TG-oleate (Int-178):

[0733] [ka]

[0734] Compound Int-177 (CβMe-OH-2-TG-oleate) was prepared from 1-(tert-butyldiphenylsilyloxy)-pent-4-yne, benzyl (Z)-3-(((trifluoromethyl)sulfonyl)oxy)but-2-enoate (Int-198; prepared similarly to Int-17), and Int-112 using the Pd-coupling, hydrogenation, EDC-coupling, and TBAF deprotection procedures described for the synthesis of Int-49. 1H NMR (400 MHz, CDCl3) δ 5.36 (m, 5H), 4.33 (dd, J = 11.9, 4.2 Hz, 2H), 4.18 (dd, J = 11.9, 6.1 Hz, 2H), 3.68 (t, J = 6.6 Hz, 2H), 2.33 (dt, J = 11.2, 5.6 Hz, 5H), 2.15 (m, 2H), 2.05 (q, J = 6.3 Hz, 8H), 1.63 (dt, J = 15.3, 7.5 Hz, 6H), 1.34 (p, J = 6.9, 5.0 Hz, 46H), 0.95 (d, J = 6.4 Hz, 3H), 0.90 (d, J = 6.8 Hz, 6H); 13 C NMR (101 MHz, CDCl3) δ 173.30 (2C), 172.27 (1C), 130.04 (2C), 129.73 (2C), 68.87 (1C), 62.92 (1C), 62.16 (2C), 41.67 (1C), 36.56 (1C), 34.05 (2C), 32.72 (1C), 31.93 (2C), 30.27 (1C), 29.79 - 29.12 (16C), 27.24 (2C), 27.20 (2C), 26.67 (1C), 25.84 (1C), 24.86 (2C), 22.70 (2C), 19.60 (1C), 14.12 (2C);MS (ESI, +ve) m / z: 778.0 (M+1), 794.96 (M+18). To a solution of Int-177 (4.0 g, 5.14 mmol) in acetone (40 mL) was added freshly prepared Jones reagent (6.4 mL, 2.1 equiv.) dropwise at 0 °C, and the resulting reaction mixture was stirred at 0 °C for 4 h. The reaction mixture was quenched with water (40 mL) and extracted with ethyl acetate (3 × 40 mL). The combined organic layers were dried over NaSO and evaporated under reduced pressure. The residue was purified by column chromatography using silica gel (100-200 mesh), eluting the product with 8-10% ethyl acetate / hexane to give Int-178 (1.5 g, 37%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 5.35 (m, 5H), 4.32 (dd, J = 11.9, 4.3 Hz, 2H), 4.31 (dd, J = 12.4, 6.1 Hz, 2H), 2.38 (t, J = 7.5 Hz, 5H), 2.20 (m, 2H), 2.02 - 2.01 (m, 8H), 1.63 (m, 6H), 1.24 (m, 46H), 0.95 (d, J = 7.2 Hz, 3H), 0.89 (t, J = 7.2 Hz, 6H); 13 C NMR (101 MHz, CDCl3) δ 178.66 (1C), 173.26 (2C), 172.13 (1C), 130.01 (2C), 129.71 (2C), 68.95 (1C), 65.32 (1C), 62.15 (2C), 36.21 (1C), 34.02 (2C), 33.89 (1C), 31.90 (2C), 30.15 (1C), 29.76- 29.09 (14C), 27.22 (2C), 27.18 (2C), 26.36 (1C), 24.83 (2C), 23.39(1C), 23.07(2C), 22.67(2C), 19.49 (1C),14.07 (2C);MS (ESI, -ve) m / z: 790.15 (M-1). C10βMe-acid-2-TG-oleate (Int-187):

[0735] [ka]

[0736] Compounds Int-185 and Int-186 were prepared from 1-benzyloxy-pentan-5-ol and Int-112 according to the procedure described for the synthesis of Int-43 and Int-47. Oxidation of Int-186 to Int-187 was carried out using Jones reagent according to the procedure described for the preparation of Int-178.

[0737] Int-185. 1H NMR (400 MHz, CDCl3) δ 4.12 (q, J = 7.1 Hz, 2H), 3.63 (t, J = 6.5 Hz, 2H), 2.27 (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, 15H), 0.92 (d, J = 6.6 Hz, 3H). C10βMe-OH-2-TG-オレエート(Int-186). 1 H NMR (400 MHz, CDCl3) δ 5.495 (m, 4H), 5.376 (m, 1H), 4.367 (m, 2H), 4.176 (m, 2H), 3.657 (t, 2H), 2.345 (m, 6H), 2.178 (m, 2H), 2.108-1.980 (m, 8H), 1.335-1.303 (m, 56H), 0.975-0.898 (m, 9H); 13 C NMR (101 MHz, CDCl3) δ 173.31 (2C), 172.35 (1C), 130.02 (2C), 129.72 (2C), 68.79 (1C), 63.01 (1C), 62.16 (2C), 41.68 (2C), 36.61 (2C), 34.03 (2C), 32.77 (2C), 31.91 (2C), 30.33 (1C), 29.71 (4C), 29.53 (4C), 29.33 (4C), 29.12 (4C), 27.21 (2C), 26.81 (2C), 25.70 (2C), 24.84 (2C), 22.69 (2C), 19.58 (1C), 14.13 (1C); MS (ESI, +ve) m / z: 823.03 (M+18). C10βMe-acid-2-TG-オレエート (Int-187). 1H NMR (400 MHz, CDCl3) δ 5.383 (m, 4H), 5.329 (m, 1H), 4.339 (m, 2H), 4.191 (m, 2H), 2.387 (m, 8H), 2.190-2.04 (m, 10H), 1.651 (m, 8H), 1.435-1.253 (m, 46H), 0.977-0.903 (m, 9H); 13 C NMR (101 MHz, CDCl3) δ 178.96 (1C), 173.29 (2C), 172.29 (1C), 130.01 (2C), 129.71 (2C), 68.82 (1C), 62.15 (1C) , 41.66 (2C), 36.55 (2C), 34.03 (2C), 33.85 (2C), 31.90 (2C), 30.30 (1C), 29.77 (4C), 29.70 (4C), 29.52 (2C), 29.32 (2C), 29.17 (2C), 29.10 (2C), 29.02 (2C), 27.22 (1C), 27.17(2C), 26.69 (2C), 24.83 (1C), 24.63 (2C), 22.68 (1C), 19.53 (1C), 14.11 (1C);MS (ESI, -ve) m / z: 818.01 (M-1). C15βMe-acid-2-TG-oleate (Int-233):

[0738] [ka]

[0739] Compound Int-232 was prepared from Int-45 and Int-112 according to the procedure described for the conversion of Int-45 to Int-47. Oxidation of Int-232 to Int-233 was carried out using Jones reagent according to the procedure described for the preparation of Int-178.

[0740] C15βMe-OH-2-TG-oleate (Int-232). MS (ESI, +ve) m / z: 893.17 (M+18). C15βMe-acid-2-TG-oleate (Int-233). MS (ESI, -ve) m / z: 888.23 (M-1). C12βMe-acid-2-TG-oleate (Int-236):

[0741] [ka]

[0742] Compounds Int-234 and Int-235 were prepared from 1-benzyloxy-heptan-7-ol and Int-112 according to the procedure described for the synthesis of Int-43 and Int-47. Oxidation of Int-235 to Int-236 was carried out using Jones reagent according to the procedure described for the preparation of Int-178.

[0743] Int-234. MS (ESI, +ve) m / z: 259.29 (M+1). C12βMe-OH-2-TG-oleate (Int-235). 1 H NMR (400 MHz, CDCl3) 5.38-5.32 (m, 5H), 4.35 (dd, J = 12.0, 4.0 Hz, 2H), 4.14 (dd, J = 11.6, 5.3 Hz, 2H), 3.68 (t, J = 6.4 Hz, 2H), 2.39 - 1.11 (m, 86H), 0.98 (d, J = 6.6 Hz, 3H), 0.93 (t, J = 6.4 Hz, 6H); 13 C NMR (101 MHz, CDCl3) 173.3, 172.4, 130.0, 129.75, 68.8, 63.1, 62.2, 41.7, 36.6, 34.0, 32.8, 31.9, 30.3, 29.7, 29.1, 27.2, 26.9, 25.7, 24.8, 22.7, 19.6, 14.1;MS (ESI, +ve) m / z: 851.13 (M+18). C12βMe-acid-2-TG-oleate (Int-236). 1H NMR (400 MHz, CDCl3) 5.38-5.32 (m, 5H), 4.35 (dd, J = 16.0, 4.4 Hz, 2H), 4.17 (dd, J = 12.0, 6.0 Hz, 2H), 2.39 - 1.11 (m, 88H), 0.98 (d, J = 6.6 Hz, 3H), 0.93 (t, J = 6.4 Hz, 6H); 13 C NMR (101 MHz, CDCl3) 179.4, 173.3, 172.4, 130.0, 129.74, 68.8, 62.2, 41.7, 36.6, 34.0, 33.9, 31.9, 30.3, 29.7, 29.5, 29.4, 29.3, 26.9, 24.8, 24.6, 22.7, 19.5, 14.1;MS (ESI, +ve) m / z: 845.93 (M+18). C12βMe-acid-2-TG (Int-247):

[0744] [ka]

[0745] Compound Int-247 was prepared by oxidation of Int-121 using PCC and KMnO4 following the procedure described for the preparation of Int-110 from Int-108.

[0746] C12βMe-acid-2-TG(Int-247). 1 H NMR (400 MHz, CDCl3) 5.32 (p, J = 5.2 Hz, 1H), 4.33 (dd, J = 11.9, 4.4 Hz, 2H), 4.18 (dd, J = 11.9, 6.0 Hz, 2H), 2.36 (h, J = 9.0, 8.1 Hz, 8H), 2.16 (dd, J = 14.8, 8.1 Hz, 1H),1.97 (s, 2H) 1.64 (s, 6H), 1.33 (s, 58H), 0.97 (d, J = 6.4 Hz, 3H), 0.91 (t, J = 6.0 Hz, 6H); 13C NMR (101 MHz, CDCl3) 173.35 (2C), 172.37 (1C), 68.79 (1C), 63.033 (1C), 62.16 (1C), 41.70 (1C), 36.66 (1C), 34.05 (2C), 32.79 (1C), 31.94 (2C), 30.35 (1C), 29.71-29.06 (25C), 26.89 (1C), 25.73 (1C), 24.86 (2C), 22.71 (2C), 19.55 (1C), 14.15 (2C);MS (ESI, -ve) m / z: 793 (M-1);(ESI, +ve) m / z: 813 (M+18). C15α'βMe-acid-2-TG (Int-62):

[0747] [ka]

[0748] Scheme 20. Synthesis of Int-62. Int-50: Prepared according to Subba Reddy, BV et al. Helv. Chim. Acta. 2013, 96, 1983-1990.

[0749] Int-51: 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. 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 Int-51 (3.10 g, 10.4 mmol) and DMPU (6.3 mL, 51.8 mmol) in THF (30 mL) was slowly added. 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 extracted with ethyl acetate (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 / hexanes) gave TMS alkyne Int-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 silyl alkyne Int-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 Int-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). Int-17 was prepared as described above.

[0750] A suspension of PdCl(PPh) (605 mg, 0.862 mmol) in DMF (40 mL) was degassed using N gas for 5 min, then CuI (335 mg, 1.76 mmol), EtN (2.40 mL, 17.2 mmol), and a degassed solution of alkyne Int-53 (2.11 g, 8.62 mmol) and enol triflate Int-17 (3.40 g, 13.00 mmol) in DMF (50 mL) were 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 Int-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); 13C 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), 103.2 (C), 79.9 (C), 73.0 (CH2), 70.6 (CH2), 60.0 (CH2), 29.9 (CH2), 29.4 (CH2), 29.2 (CH2), 29.0 (CH2), 28.6 (CH2), 26.3 (CH2), 26.0 (CH3), 20.1 (CH2), 14.4 (CH3). In a three-neck round-bottom flask, a solution of benzyl ether Int-54 (707 mg, 1.98 mmol) in ethyl acetate (80 mL) was evacuated and flushed with N gas twice, then palladium on carbon (10% (w / w), 525 mg, 0.494 mmol) was added, and the resulting suspension was again evacuated and flushed with N (three times). The flask was fitted with a H balloon, evacuated, and flushed with H (three times), and the reaction mixture was stirred under 1 atmosphere 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 Celite pad, washing with ethyl acetate (80 mL). The filtrate was concentrated under reduced pressure to afford the saturated alcohol Int-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 Int-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 the TBDPS ether Int-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 = 6.6Hz, 3H). A solution of potassium hydroxide (2.0 M, 11.3 mL, 22.6 mmol) was added to the ester Int-56 (1.15 g, 2.26 mmol) in ethanol (40 mL), and the mixture was stirred at room temperature for 19 hours. 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 Int-57 (321 mg, 29%) as a pale yellow oil, which was used for analytical purposes. An additional 750 mg of 9 was obtained, containing slight contamination by an unknown TBDPS species; this material was carried forward for purification at a later stage in the reaction sequence. 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), 0.96 (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 Int-2 (374 mg, 0.658 mmol) were added to a solution of acid Int-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 Int-58 (416 mg, 67%) as a colorless solid. 1 H NMR (401 MHz, CDCl3) δ 7.69 - 7.64 (m, 4H), 7.44 - 7.34 (m, 6H), 5.28 (m, 1H), 4.289 / 4.288 (dd, J = 11.9, 4.3 Hz, 2H, respectively), 4.14 (dd, J = 12.0, 6.0 Hz, 2H), 3.65 (t, J = 6.5 Hz, 2H), 2.34 (dd, 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 Int-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 the alcohol Int-59 (282 mg, 93%) as a colorless solid.1 H NMR (401 MHz, CDCl3) δ 5.28 (m, 1H), 4.286 / 4.285 (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), 2.33 (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), 1.68 - 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), 34.2 (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 Int-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 concentrated under reduced pressure to give crude aldehyde Int-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). Int-25 was prepared as described above.

[0751] A solution of ylide Int-25 (270 mg, 0.637 mmol) in toluene (10 mL) was added to aldehyde Int-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 the α,β-unsaturated benzyl ester Int-61 (273 mg, 88%) as a yellow oil. 1H 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), 128.11 (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). In a two-neck flask, a solution of the benzyl ester Int-61 (246 mg, 0.262 mmol) in ethyl acetate (10 mL) was evacuated and flushed with N gas (three times each), then palladium on carbon (10% (w / w), 55.7 mg, 0.0524 mmol) was added, and the resulting suspension was again evacuated and flushed with N (three times each). The flask was equipped with a H balloon, evacuated, and flushed with H (three times each), and the reaction mixture was stirred under 1 atmosphere of H at room temperature for 1.5 h. The reaction was filtered through a Celite pad, washing 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 Int-62 (193 mg, 87%) as a colorless solid. 1 H NMR (401 MHz, CDCl3) δ 5.28 (m, 1H), 4.291 / 4.289 (each dd, J = 11.8, 4.2 Hz, 2H), 4.147 / 4.144 (each 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, 6H). C15α'βMe-acid-2-TG-butyrate (Int-219):

[0752] [ka]

[0753] Scheme 20-A. Synthesis of Int-219. Using the procedure for the preparation of Int-56 described above, Int-211 was prepared from dec-9-yn-1-ol and TBDPSCl. 1 H NMR (400 MHz, CDCl3) δ 7.72 (dd, J = 6.4, 1.8 Hz, 4H), 7.48 - 7.40 (m, 6H), 3.71 (t, J = 6.4 Hz, 2H), 2.24 (td, J = 6.8, 2.4 Hz, 2H), 1.98 (s, 1H), 1.63 (dq, J = 6.4 Hz, 2H), 1.47 (m, 4H), 1.40 (m, 6H), 1.09 (s, 9H). A suspension of PdCl(PPh) (6.44 g, 9.18 mmol) in CHCN (180 mL) was degassed using N gas for 5 min, then CuI (1.74 g, 9.18 mmol), EtN (18.54 g, 183.7 mmol), and a degassed solution of alkyne Int-211 (36.0 g, 91.8 mmol) and Int-198 (29.75 g, 91.83 mmol) in CHCN (180 mL) were added. The mixture was degassed for an additional 5 min using a stream of N and then heated at 60 °C for 2 h. The reaction was cooled to room temperature, diluted with water (360 mL), and extracted with EtOAc (3 × 360 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The resulting oil was purified by column chromatography using silica gel (100-200 mesh) eluting the product with 4-7% EtOAc in hexane to give Int-212 (33.0 g, 63.5%). 1 H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 6.0 Hz, 4H), 7.43 (dd, J = 18.4, 10.7, 8.0 Hz, 11H), 6.02 (s, 1H), 5.22 (s, 2H), 3.69 (t, 2H), 2.44 (t, 2H), 2.06 (s, 3H), 1.59 (dq, 2H), 1.38 (ddd, J = 15.2, 10.9, 6.1 Hz, 4H), 1.31 (dd, J = 7.3, 3.8 Hz, 6H), 1.08 (s, 9H). Int-213 was prepared from Int-212 similar to the procedure for the preparation of Int-59 described above. 1 H NMR (400 MHz, CDCl3) δ 7.41 (dd, J = 12.7, 4.8 Hz, 5H), 6.09 (s, 1H), 5.21 (d, J = 11.2 Hz, 2H), 3.69 (t, J = 6.4 Hz, 2H), 2.44 (t, J = 7.2 Hz, 2H), 2.08 (s, 3H), 1.58 (p, J = 7.1 Hz, 2H), 1.48 - 1.43 (m, 10H). Int-214 was prepared from Int-213 similar to the procedure for the preparation of Int-60 described above.

[0754] To a solution of Int-214 (19 g, 58.2 mmol) in toluene (190 mL) at room temperature under a nitrogen atmosphere was added Int-215 (68.19 g, 174.8 mmol; prepared from triphenylphosphine and tert-butyl 2-bromopropanoate). The resulting reaction mixture was heated at 90 °C for 2 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting oil was purified by column chromatography using silica gel (100-200 mesh), eluting the product with 2-4% EtOAc in hexane to give Int-216 (15.0 g, 58.9%). 1 H NMR (400 MHz, CDCl3) δ 7.43 - 7.35 (m, 5H), 6.69 (t, J = 7.2 Hz, 1H), 6.09 (s, 1H), 5.19 (s, 2H), 2.39 (t, J = 12.8 Hz, 2H), 2.18 (q, J = 7.4 Hz, 2H), 2.03 (s, 3H), 1.82 (s, 3H), 1.61 - 1.55 (m, 12H), 1.45 (s, 9H). Palladium on carbon (10% (w / w), 19 g) was added to a solution of Int-216 (19 g, 43.37 mmol) in ethyl acetate (190 mL) in an autoclave, and the autoclave was evacuated and refilled with N (3 times). 2 The mixture was pressurized with H pressure, and the reaction mixture was stirred at room temperature for 72 hours. The reaction mixture was filtered through a Celite pad, which was washed with additional ethyl acetate (380 mL). The filtrate was concentrated under reduced pressure to give Int-217 (13 g, 84.2%) as a colorless oil, which was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3) δ 2.39-2.29 (m, 3H), 2.19 - 2.12 (m, 1H), 1.96 (s, 2H), 1.46 (s, 9H), 1.27 (s, 18H), 1.10 (d, J = 6.8 Hz, 3H), 0.97 (d, J = 6.6 Hz, 3H). To a stirred solution of Int-217 (6.0 g, 16.4 mmol) and Int-115 (3.81 g, 16.4 mmol) in DCM (120.0 mL) at room temperature, EDC.HCl (7.8 g, 41.1 mmol) and DMAP (2.0 g, 16.4 mmol) were added. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo. The resulting residue was purified by column chromatography using silica gel eluting with 4-5% EtOAc in n-hexane to give Int-218 (6.0 g, 62.5%) as a brownish viscous liquid. 1H NMR (400 MHz, CDCl3) δ 5.34 - 5.23 (m, 1H), 4.33 (dd, J = 12.1, 4.2 Hz, 2H), 4.17 (dd, J = 11.9, 6.0 Hz, 2H), 2.30 (dd, J = 8.7, 6.2 Hz, 5H), 2.12 (dd, J = 14.7, 8.3 Hz, 2H), 1.93 (s, 1H), 1.66 (p, J = 7.4 Hz, 6H), 1.44 (s, 9H), 1.35 - 1.15 (m, 18H), 1.08 (d, J = 7.0 Hz, 3H), 0.99 - 0.88 (m, 9H). To a stirred solution of Int-218 (6.0 g, 10.5 mmol) in DCM (120 mL) at room temperature, TFA (12.0 mL, 2.0 vol) was added, and the solution was stirred at room temperature for 3.0 h. The reaction mixture was concentrated in vacuo. The residue was diluted with water (500 mL) and extracted with ethyl acetate (2 x 500 mL). The combined organic layers were washed with sodium bicarbonate solution and brine, then dried over sodium sulfate, filtered, and concentrated in vacuo to give Int-219 (5.1 g, 94%) as a yellowish viscous liquid. 1 H NMR (400 MHz, CDCl3) δ 5.33 (ddd, J = 10.3, 6.0, 4.2 Hz, 1H), 4.30 (dd, J = 11.9, 4.3 Hz, 2H), 4.16 (dd, J = 11.9, 6.0 Hz, 2H), 2.47 (h, J = 6.9 Hz, 2H), 2.31 (q, J = 8.2, 7.6 Hz, 6H), 2.12 (dd, J = 14.6, 8.3 Hz, 1H), 1.64 (dt, J = 14.8, 7.4 Hz, 6H), 1.27 (m, 15H), 1.18 (d, J = 6.9 Hz, 6H), 1.01 - 0.84 (m, 9H); 13C NMR (101 MHz, CDCl3) δ 183.51 (1C), 173.61 (2C), 172.85 (1C), 68.92 (1C), 62.26 (2C), 41.72 (1C), 39.38 (1C), 36.66 (1C), 35.93 MS (ESI, +ve) m / z: 532.70 (M+18). C15α'βMe-acid-2-TG-octanoate (Int-220): Compound Int-220 was prepared from Int-217 and Int-192 using the procedure described for the synthesis of Int-219.

[0755] [ka]

[0756] 1 H NMR (400 MHz, CDCl3) δ 5.32 (t, J = 12.4 Hz, 2H), 4.33 (dd, J = 11.6, 4.0 Hz, 2H), 4.19 (dd, J = 12.0, 6.0 Hz, 2H), 2.51 (m,1H), 2.37 (m, 6H), 2.17 (m, 1H), 1.71 (m, 6H), 1.30 (d, J = 10.4 Hz, 34H), 1.21 (d, J = 6.8 Hz, 3H), 0.96 - 0.88 (m, 9H); 13C NMR (101 MHz, CDCl3) δ 182.71 (1C), 173.44 (2C), 172.49 (1C), 69.84 (1C), 62.21 (2C), 41.74 (1C), 39.30 (1C), 36.70 (1C), 34.07 MS (ESI, +ve) m / z: 644.89 (M+18). C15α'βMe-acid-2-TG-oleate (Int-221): Compound Int-221 was prepared from Int-217 and Int-112 using the procedure described for the synthesis of Int-219.

[0757] [ka]

[0758] 1 H NMR (400 MHz, CDCl3) δ 5.38-5.32 (m, 5H), 4.35-4.32 (dd, J = 4.4 Hz, 12.0 Hz, 2H), 4.20-4.15 (dd, J = 6.0 Hz, 11.6 Hz, 2H), 2.49 (m, 1H), 2.34 (t, J = 7.2 Hz, 2H), 2.09-2.04 (m, 5H), 1.71 - 1.64 (m, 6H), 1.34-1.30 (m, 66H), 1.13 (d, J = 6.9 Hz, 3H), 0.96 (d, J = 6.9 Hz, 3H), 0.91 (t, J = 6.0 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 182.72 (1C), 173.33 (2C), 172.42 (1C), 130.03 (2C), 129.73 (2C), 68.83 (1C), 62.19 (2C), 41.71 (1C), 39.31 (1C), 36.69 (1C), 34.05 (2C), 33.53 (1C), 31.94 (2C), 30.36 (1C), 29.79 - 29.12 (23C), 27.21 (4C), 26.97 (1C), 24.85 (2C), 22.71 (2C), 19.57 (1C), 16.85 (1C), 14.14 (2C);MS (ESI, -ve) m / z: 902 (M-1). (ESI, +ve) m / z: 921 (M+18). C18α'βMe-acid-2-TG-oleate (Int-224): Using the procedure described for the synthesis of Int-219, compounds Int-222, Int-223, and Int-224 were prepared from Int-112 and tert-butyldimethyl(tridec-12-yn-1-yloxy)silane (prepared from dodecane-1,12-diol by mono-TBS protection (with TBSCl, imidazole, and DMAP in a mixture of DCM and DMF)), followed by PCC oxidation and Ohira reagent homologation (similar to the procedure for the synthesis of Int-197 from Int-195).

[0759] [ka]

[0760] Int-222. 1 H NMR (400 MHz, CDCl3) 2.42-2.31 (m, 2H), 2.21 - 2.14 (m, 1H), 2.00 (m, 1H), 1.49 (s, 9H), 1.29 (m, 26H), 1.13 (d, J = 7.2 Hz, 3H), 0.99 (d, J = 6.4 Hz, 3H). C18α’βMe-CO2tBu-2-TG-oleate (Int-223). 1 H NMR (400 MHz, CDCl3) δ 5.40-5.32 (m, 5H), 4.35-4.31 (dd, J = 4.4 Hz, 12.0 Hz, 2H), 4.20-4.16 (dd, J = 6.0 Hz, 11.6 Hz, 2H), 2.39-2.31 (m, 6H), 2.16 (m, 1H), 2.05 (m, 9H), 1.64 (m, 6H), 1.49 (s, 9H), 1.41 - 1.27 (m, 64H), 1.13 (d, J = 6.9 Hz, 3H), 0.96 (d, J = 6.9 Hz, 3H), 0.90 (m, 6H). C18α’βMe-acid-2-TG-oleate (Int-224). 1 H NMR (400 MHz, CDCl3) δ 5.41-5.31 (m, 5H), 4.35-4.31 (dd, J = 4.4 Hz, 12.0 Hz, 2H), 4.20-4.15 (dd, J = 6.0 Hz, 11.6 Hz, 2H), 2.54 (m, 1H), 2.39-2.33 (m, 4H), 2.19-2.13 (m, 1H), 2.09-2.02 (m, 6H), 1.75 - 1.63 (m, 6H), 1.34-1.30 (m, 68H), 1.23-1.21 (d, J = 6.8 Hz, 3H), 0.98-0.87 (m, 9H); 13C NMR (101 MHz, CDCl3) δ 182.21 (1C), 173.32 (2C), 172.40 (1C), 130.03 (2C), 129.74 (2C), 68.83 (1C), 62.21 (2C), 41.73 (1C), 39.24 (1C), 36.73 (1C), 34.06 (2C), 33.57 (1C), 31.93 (2C), 30.40 (1C), 29.79-29.12 (26C), 27.25 (2C), 27.20 (2C), 26.97 (1C), 24.86 (2C), 22.71 (2C), 19.59 (1C), 16.85 (1C), 14.14 (2C); MS (ESI, +ve) m / z: 963.09 (M+18). C12α'βMe-acid-2-TG-oleate (Int-231): Compounds Int-229, Int-230, and Int-231 were prepared from Int-112 and hept-6-yn-1-ol using the procedure described for the synthesis of Int-219.

[0761] [ka]

[0762] Int-229. 1 H NMR (400 MHz, CDCl3) 2.38-2.28 (m, 3H), 2.18 - 2.12 (m, 2H), 1.96 (s, 2H), 1.45 (s, 9H), 1.28 (s, 12H), 1.10 (d, J = 6.9 Hz, 3H), 0.97 (d, J = 6.6 Hz, 3H). C12α'βMe-CO2tBu-2-TG-oleate (Int-230). 11H NMR (400 MHz, CDCl3) δ 5.38 - 5.32 (m, 5H), 4.33 (dd, J = 11.6 Hz, 4.0 Hz, 2H), 4.18 (dd, J = 11.6 Hz, 6.0 Hz, 2H), 2.39 - 2.33 (m, 6H), 2.18 - 1.97 (m, 10H), 1.64 - 1.61 (m, 6H), 1.48 (s, 9H), 1.33 - 1.30 (m, 52H), 1.13 (d, J = 13.0 Hz, 3H), 0.97 (d, J = 7.2 Hz, 3H), 0.92 (t, J = 6.0 Hz, 6H). C12α’βMe-acid-2-TG-oleate (Int-231). 1 1H NMR (400 MHz, CDCl3) δ 5.42 - 5.29 (m, 5H), 4.33 (dd, J = 4.4 Hz, 12.0 Hz, 2H), 4.18 (dd, J = 6.0 Hz, 11.6 Hz, 2H), 2.55 - 2.46 (m, 1H), 2.39 - 2.33 (t, J = 7.2 Hz, 5H), 2.16 (q, J = 6.4 Hz, 1H), 2.05 - 1.97 (m, 8H), 1.74 - 1.63 (m, 5H), 1.49 - 1.44 (m, 2H), 1.34 - 1.30 (m, 52H), 1.13 (d, J = 13.0 Hz, 3H), 0.97 (d, J = 7.2 Hz, 3H), 0.92 (t, J = 6.0 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 182.75 (1C), 173.32 (2C), 172.38 (1C), 130.03 (2C), 129.73 (2C), 68.83 (1C), 62.19 (2C), 41.71 (1C), 39.31 (1C), 36.69 (1C), 34.05 (2C), 33.53 (1C), 31.94 (2C), 30.36 (1C), 29.79 - 29.12 (19C), 27.25 (2C), 27.20 (2C), 27.15 (2C), 24.85 (2C), 22.71 (2C), 19.57 (1C), 16.85 (1C), 14.14 (2C);MS (ESI, -ve) m / z: 859.93 (M-1);(ESI, +ve) m / z: 878.94 (M+18). Ph-C3-phenol-2-TG(Int-67):

[0763] [ka]

[0764] Scheme 21. Synthesis of Int-67. 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 (Int-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 / hexanes) afforded the silyl ester Int-64 (165 mg, 36%) as a colorless oil. 1H NMR (400 MHz, CDCl3): 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), 133.2 (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 added to a solution of TBDPS ester Int-64 (147 mg, 0.228 mmol) in THF (3 mL), methanol (1.5 mL), and water (1.5 mmol), 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%, 50% ethyl acetate / hexanes) afforded the acid Int-65 (82.4 mg, 89%) as a colorless solid. 1H 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, 9H); 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 Int-2 (41.7 mg, 0.0734 mmol) were added to a solution of acid Int-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 Int-66 (54.4 mg, 85%) as a colorless solid. 1H 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), 0.88 (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 Int-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 the phenol Int-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); 13 C 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), 29.5 (2C;CH2), 29.4 (2C;CH2), 29.2 (2C;CH2), 25.0 (2C;CH2), 22.8 (2C;CH2), 14.3 (2C;CH3). DMPh-C10βMe-phenol-2-TG-oleate (Int-202):

[0765] [ka]

[0766] Scheme 21-A. Synthesis of Int-202. To a stirred solution of Int-193 (40.0 g, 199 mmol) in DCM (400 mL) at room temperature, DMAP (24.27 g, 199.0 mmol) and TEA (40.19 g, 398.0 mmol) were added. TBDMSCl (44.9 g, 298.4 mmol) was added in small portions, and the resulting reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water (400 mL) and extracted with DCM (3 × 400 mL). The combined organic layers were dried over sodium sulfate and evaporated under vacuum. The resulting material was purified by column chromatography using silica gel (100-200 mesh). The desired product was eluted with 100% hexane as the mobile phase. Pure fractions were concentrated under vacuum to give Int-194 (60.0 g, 95.7%). 1 H NMR (400 MHz, CDCl3): δ 7.11 (s, 2H), 2.19 (s, 6H), 1.04(s, 9H), 0.66 (s, 6H). A suspension of PdCl2(PPh3)2 (5.11 g, 7.29 mmol) in DMF (230 mL) was degassed using N2 gas for 5 min, then CuI (1.38 g, 7.29 mmol), Et3N (29.46 g, 291 mmol), and a degassed solution of Int-194 (23 g, 87.5 mmol) and hex-5-yn-1-ol (8.59 g, 87.5 mmol) were added. The mixture was degassed for an additional 5 min using a stream of N2 and then heated at 60 °C for 2 h. The reaction mixture was cooled to room temperature, diluted with cold water (300 mL), and extracted with ethyl acetate (3 × 250 mL). The combined organic layers were dried over sodium sulfate and evaporated under reduced pressure. The resulting material was purified by column chromatography using silica gel (100–200 mesh). The desired product was eluted with 10% ethyl acetate / hexane as the mobile phase. The pure fractions were concentrated in vacuo to give Int-195 (21.0 g, 43.3%). 1 H NMR (400 MHz, CDCl3) δ 7.03 (s, 2H), 2.57 (s, 6H), 2.48 (t, 2H), 2.47 (t, 2H), 1.80 (m, 4H), 1.32 (s, 9H), 0.95 (s, 6H). To a stirred solution of Int-195 (5.0 g, 15.0 mmol) in DCM (50 mL) at 0 °C, PCC (6.49 g, 30.1 mmol) was added slowly. The reaction mixture was allowed to reach room temperature and stirred for 2 h. The reaction mixture was filtered through a bed of Celite. The filtrate was evaporated in vacuo to give Int-196 (4.16 g, 83.3%), which was used directly in the next step without further purification. 1 H NMR (400 MHz, CDCl3): δ 9.88 (s, 1H), 7.07 (s, 2H), 2.71 (t, J = 14.4 Hz, 2H), 2.53 (t, J = 13.6 Hz, 2H), 2.09 (s, 6H), 1.23 (m, 2H), 0.98 (s, 9H), 0.20 (s, 6H). To a stirred solution of Int-196 (6.0 g, 18 mmol) in MeOH (60 mL) at 0 °C, K2CO3 (10.3 g, 72.7 mmol) was added, followed by dropwise addition of Ohira's reagent (6.98 g, 36.4 mmol). The reaction mixture was allowed to warm slowly to room temperature and then stirred at room temperature for 3.5 h. The reaction mixture was evaporated in vacuo. The residue was diluted with water (60 mL) and extracted with ethyl acetate (5 × 60 mL). The combined organic layers were dried over sodium sulfate and evaporated under reduced pressure. The resulting material was purified by column chromatography using silica gel (100-200 mesh). The desired product was eluted with 2% ethyl acetate / hexane as the mobile phase. Pure fractions were concentrated in vacuo to give Int-197 (21.0 g, 64.8%). 1 H NMR (400 MHz, CDCl3): δ 7.41 (s, 2H), 2.59-2.51 (m, 6H), 2.24 (s, 6H), 1.8...

Claims

1. Compound of formula I-47. 【Chemistry 1】

2. 10. A pharmaceutically acceptable composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

3. 3. The pharmaceutically acceptable composition of claim 2, wherein the composition is formulated for oral administration.

4. 10. A formulation for oral administration comprising a compound of claim 1 or a pharmaceutically acceptable composition of claim 2 or 3.

5. 5. The oral formulation of claim 4, further comprising a lipid-based vehicle.

6. 6. The oral dosage form of claim 5, wherein the lipid-based vehicle comprises sesame oil.

7. 7. The oral formulation of claim 5, wherein the lipid-based vehicle is a substantially non-aqueous vehicle.

8. 6. The oral dosage form of claim 5, wherein the lipid-based vehicle comprises a self-emulsifying drug delivery system (SEDDS).

9. 9. The oral formulation of claim 8, wherein the SEDDS comprises sesame oil and a water-soluble surfactant.

10. 10. The oral administration formulation according to claim 9, wherein the water-soluble surfactant comprises polyoxyethylene castor oil.

11. 11. The oral formulation of claim 10, wherein the polyoxyethylene castor oil comprises polyoxyl 40 hydrogenated castor oil.

12. The oral formulation according to any one of claims 8 to 11, wherein the SEDDS further comprises glycerol monoesters and diesters having fatty acid chains with 8 to 40 carbon atoms.

13. The oral dosage form according to any one of claims 8 to 12, wherein the SEDDS is substantially non-aqueous.

14. The formulation for oral administration according to any one of claims 4 to 13, which is a capsule.

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