Lipid prodrugs of neurosteroids

Abstract

We provide lipid prodrugs of neurosteroids. [Solution] The present invention provides lymphoid-directed lipid prodrugs, their pharmaceutically acceptable compositions, methods for producing such prodrugs and compositions, and methods for improving the bioavailability or other properties of therapeutic agents comprising a portion of a lipid prodrug. The present invention also provides methods for treating diseases, disorders, or pathological conditions, the methods comprising administering the disclosed lipid prodrug or its pharmaceutically acceptable composition to a patient in need thereof.

Description

[Technical Field]

[0001] The present invention relates to compounds in the form of prodrugs, particularly compounds that promote the transport of pharmaceuticals into the lymphatic system and subsequently enhance the release of the parent drug. The present invention also relates to compositions of such prodrugs and methods of use thereof.

[0002] Cross-reference of related applications This application claims the interests of U.S. Provisional Patent Application No. US62 / 970,607 filed on 5 February 2020, U.S. Provisional Patent Application No. US63 / 009,533 filed on 14 April 2020, and U.S. Provisional Patent Application No. US63 / 070,064 filed on 25 August 2020, each of which is incorporated herein by reference in its entirety. [Background technology]

[0003] Neurosteroids are steroids synthesized in the brain that regulate neuronal excitability through rapid non-genomic effects. Originally coined by the French physiologist Etienne Baulieu, the term "neurosteroid" is now widely used to refer to steroids synthesized in the brain. Circulating steroid hormones act as precursors for the synthesis of neurosteroids, which are locally produced in the hippocampus and other brain structures. Imbalances in neurosteroid levels are associated with numerous diseases, disorders, and pathologies. These are classified as pregnane neurosteroids (e.g., allopregnanolone and allotetrahydrodeoxycorticosterone) and androstaner neurosteroids (e.g., androstanediol and ethiocholanone). Neurosteroids such as allopregnanolone are positive allosteric modulators of the GABA-A receptor, exhibiting potent anti-seizure activity in various animal models. Neurosteroids increase both synaptic and sustained 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 damage may be due to neurosteroids and sex dimorphism in specific structures of the human brain. Synthetic neurosteroids that exhibit better bioavailability and efficacy, as well as drugs that enhance neurosteroid synthesis, have therapeutic potential in anxiety, epilepsy, and other brain disorders.

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

[0005] The lymphatic system consists of a specialized network of tubes, nodes, and lymphoid tissues distributed throughout the body in close proximity to the vascular system. The lymphatic system plays several important roles in immune responses, 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 via the lymphatic system has been suggested as a means of improving both pharmacokinetic and pharmacodynamic profiles.

[0006] Lymphatic transport of drugs has the potential to improve oral bioavailability by avoiding first-pass metabolism, alter systemic pharmacokinetics, and enhance efficacy against lymphoid or lymphocyte-mediated pathologies such as lymphoma, leukemia, lymphoid tumor metastasis, autoimmune diseases, lymphoid commensal infections, and graft rejection. For drugs to access the intestinal lymphoid, they must first associate with intestinal lymphoid lipoproteins assembled in intestinal absorptive cells (intestinal cells) in response to lipid absorption. This association with lipoproteins is then carried out according to their size. Therefore, easy diffusion across the vascular endothelium lining the capillaries flowing from the small intestine is eliminated beforehand, thus facilitating drug transport into the lymph. Instead, these large colloidal structures enter the lymphatic capillaries because the lymphatic endothelium is considerably more permeable than the vascular endothelium.

[0007] Historically, drugs with high lymphatic transport have been highly lipophilic to facilitate physical association with lipoproteins (though not exclusively, typically logD > 5 and solubility in long-chain triglycerides greater than 50 mg / g). Therefore, highly lipophilic analogues of drugs have been considered a means of promoting drug lymphatic transport. However, chemical modifications of parent drugs can lead to reduced potency, and in many cases, a significant increase in lipophilicity is correlated with increased toxicity.

[0008] Compounds in the form of lipophilic prodrugs provide a means to temporarily increase the lipophilicity and lipoprotein affinity of a pharmaceutical compound, thereby increasing its targeting to the lymphatic system. Upon transport through the lymphatic system, the prodrug is cleaved, thereby releasing the parent drug to become active at its target site. [Overview of the Initiative] [Problems that the invention aims to solve]

[0009] Therefore, there is a need to develop novel lipid-pharmaceutical conjugates that facilitate the stable transport of pharmaceuticals into the intestinal lymphoid and that readily revert to the parent drug to become active. This invention addresses this need and also provides other relevant advantages. [Means for solving the problem]

[0010] In one embodiment, the present invention relates to formula I:

[0011] [ka]

[0012] We provide compounds of or pharmaceutically acceptable salts thereof, where each variable element is as defined herein.

[0013] In another embodiment, the present invention provides a method for treating a disease, disorder, or condition (such as one of those disclosed herein) comprising administering an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, to a patient in need thereof. [Modes for carrying out the invention]

[0014] 1. Overview of a specific embodiment of the present invention Lymphatic system-directed prodrugs The compounds and compositions of the present invention are useful in promoting the transport of therapeutic agents into the lymphatic system, and subsequently improving the release of the parent drug, i.e., the therapeutic agent.

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

[0016]

Chemical formula

[0017] or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are each independently hydrogen, an acid-labile group, a lipid, or -C(O)R 3 and each R 3 is independently a saturated or unsaturated, straight-chain or branched, optionally substituted C 1-37 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 0 to 2 methylene units of the C 1-6 aliphatic group are independently and optionally replaced by -O-, -NR-, or -S-, and the C 1-6 aliphatic group is independently and optionally substituted with 1, 2, or 3 deuterium or halogen atoms each R is independently hydrogen or C 1-6A optionally substituted group selected from aliphatic, 3-8 member saturated or partially unsaturated monocyclic carbocycles, phenyl, 8-10 member bicyclic aromatic carbocycles, 4-8 member saturated or partially unsaturated monocyclic heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 5-6 member monocyclic heteroaromatic rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 8-10 member bicyclic heteroaromatic rings having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Y is either absent, or -C(O)-, -C(NR)-, or -C(S)-. L is either covalently bonded, or optionally substituted with divalent C, which is saturated or unsaturated, linear or branched. 1-30 It is 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 amino acids, 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] It is connected, Each -Cy- independently has 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and is an optionally substituted 3 to 6-membered divalent saturated, partially unsaturated, or aromatic ring. Each R4 and R 5 The atoms are independently hydrogen, deuterium, halogens, -CN, -OR, -NR2, -SR, 3-8 member saturated or partially unsaturated monocyclic carbon rings, phenyl, 8-10 member bicyclic aromatic carbon rings, 4-8 member saturated or partially unsaturated monocyclic heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 5-6 member monocyclic heteroaromatic rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 8-10 member bicyclic heteroaromatic rings having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. A ring, or optionally substituted with -CN, -OR, -NR2, -SR, a 3- to 8-membered saturated or partially unsaturated monocyclic carbon ring, phenyl, an 8- to 10-membered bicyclic aromatic carbon ring, a 4- to 8-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 an 8- to 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 The aliphatic atom is optionally substituted with 1, 2, 3, 4, 5, or 6 deutherium or halogen atoms, or R bonded to the same carbon atom 4 or R 5 These two occurrences, together with the carbon atoms bonded to them, form a 3-6 member spirocyclic saturated monocyclic carbocyclic ring, or a 3-6 member spirocyclic saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. -M- is a self-destructing group, n is between 0 and 18. Each m is independent and ranges from 0 to 6.

[0022] [ka]

[0023] However, whether it is a natural or unnatural neurosteroid or its analogue or prodrug It is a treatment agent that is selected from among others.

[0024] In one embodiment, the present invention provides a method for treating a disease, disorder, or condition in a patient requiring treatment for such a disease, disorder, or condition, the method comprising administering to the patient an effective amount of the 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 pharmaceutically acceptable salts. Therefore, a reference to “lipid prodrugs” also constitutes a disclosure of “lipid prodrugs or pharmaceutically acceptable salts thereof.” 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 approach to directing drugs to the lymphatic transport system is to use prodrugs that are involved in endogenous pathways that control the absorption, transport (including passive transport), and metabolism of lipids in food. In one embodiment, the present invention provides a lipid prodrug comprising a neurosteroid, such as a pregnane neurosteroid, conjugated to a glycerol-based portion containing two fatty acids or other lipids. While not wishing to be bound by theory, such prodrugs are thought to mimic triglycerides in food so as to be involved in the processing and metabolism of triglycerides in the gastrointestinal tract.

[0027] Dietary lipids, including triglycerides, follow a specific metabolic pathway distinct from that of other nutrients such as proteins and carbohydrates to gain access to the lymphatic system (and ultimately to the systemic circulation). After ingestion, triglycerides in food are hydrolyzed in the lumen by lipase, releasing one monoglyceride and two fatty acids for each triglyceride molecule. The monoglyceride and two fatty acids are then absorbed into intestinal cells and re-esterified into triglycerides.

[0028] The resynthesized triglycerides are assembled into intestinal lipoproteins (primarily chylomicrons). After formation, chylomicrons are released from intestinal cells by exocytosis and subsequently gain preferential access to the intestinal lymphatic vessels. Once in the lymphatic system, the chylomicrons containing packaged triglycerides flow out through a series of capillaries, nodes, and tubules, joining the systemic circulation at the junction of the left subclavian vein and internal jugular vein. After entering the bloodstream, the triglycerides in the chylomicrons are preferentially and efficiently taken up by tissues with high levels of lipoprotein lipase expression, such as adipose tissue, the liver, and potentially certain types of tumor tissue.

[0029] Lipid prodrugs are expected to behave similarly to natural triglycerides, be transported into and via the lymphatic system, and reach systemic circulation without interacting with the liver. In some embodiments, the lipid prodrug is cleaved after the prodrug has reached systemic circulation or target tissue, releasing a neurosteroid such as a pregnane neurosteroid. In some embodiments, the lipid prodrug releases a neurosteroid such as a pregnane neurosteroid by disrupting a self-destructing linker that binds the neurosteroid to a 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 the lymph and lymphoid tissues, thereby promoting oral bioavailability by avoiding first-pass metabolism (and potentially intestinal emptying). Accordingly, in some embodiments, the disclosed lipid prodrug has 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 prodrug is used to access the lymph, lymph nodes, and lymphoid tissues. It has increased drug targeting (compared to the parent agent) to sites within tissues, as well as to sites with high lipid utilization and lipoprotein lipase expression, such as adipose tissue, the liver, and certain 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 embodiments, the present invention provides methods for modulating the delivery, distribution, or other properties of neurosteroids, such as pregnane neurosteroids. In one embodiment, the present invention provides a method for delivering a neurosteroid into the systemic circulation of a patient in need, comprising the step of administering a disclosed lipid prodrug of a neurosteroid to the patient, such that the neurosteroid partially, substantially, or completely bypasses first-pass hepatic metabolism in the patient. In another embodiment, 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 the step of preparing a disclosed lipid prodrug of a neurosteroid. In some embodiments, the lipid prodrug is administered orally. In some embodiments, preparing the lipid prodrug involves covalently conjugating a neurosteroid to a glycerol-based backbone 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 the intestinal absorption of a neurosteroid, or reducing the metabolism, degradation, or excretion of a neurosteroid in the intestines, comprising the step of preparing a lipid prodrug of a disclosed neurosteroid.

[0032] In another embodiment, the present invention provides a method for modifying, for example improving, the delivery of a neurosteroid to a target tissue, comprising the step of preparing a lipid prodrug of a disclosed neurosteroid. In some embodiments, the target tissue is a tumor such as lymph, lymph nodes (e.g., mesenteric lymph nodes), adipose tissue, liver, or lymph node metastasis sites. 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 systemic circulation have reduced free drug concentrations in the gastrointestinal (GI) tract, which may offer benefits in terms of reduced gastrointestinal irritation or toxicity and / or increased drug solubility in enteric bile salt micelles (due to similarity with endogenous monoglycerides). The disclosed lipid prodrugs may also, in certain embodiments, have increased passive membrane permeability (due to higher lipophilicity compared to the parent therapeutic agent). In some embodiments, the lipid prodrugs have higher solubility in lipid formulations or vehicles containing either lipids alone or mixtures of lipids with surfactants and / or cosolvents, thereby enabling the use of lipophilic formulations for otherwise highly hydrophilic therapeutic agents.

[0034] Lipid prodrugs of neurosteroids In one embodiment, the present invention relates to formula I:

[0035] [ka]

[0036] We provide a compound of or a pharmaceutically acceptable salt thereof, in which, R 1 and R 2 However, each independently comprises hydrogen, an acid-unstable group, a lipid, or -C(O)R 3 And, Each R 3 Independently, saturated or unsaturated, linear or branched, C is optionally substituted. 1-37 It is a hydrocarbon chain, X is -O-, -NR-, -S-, -O(C1-6 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 It is 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 The aliphatic group is independently and optionally substituted with one, two, or three deuterium or halogen atoms. Each R is independently either hydrogen or C 1-6 A optionally substituted group selected from aliphatic, 3-8 member saturated or partially unsaturated monocyclic carbocycles, phenyl, 8-10 member bicyclic aromatic carbocycles, 4-8 member saturated or partially unsaturated monocyclic heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 5-6 member monocyclic heteroaromatic rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 8-10 member bicyclic heteroaromatic rings having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Y is either absent, or -C(O)-, -C(NR)-, or -C(S)-. L is either covalently bonded, or optionally substituted with divalent C, which is saturated or unsaturated, linear or branched. 1-30 It is 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 amino acids, 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] It is connected, Each -Cy- independently has 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and is an optionally substituted 3 to 6-membered divalent saturated, partially unsaturated, or aromatic ring. Each R 4 and R 5 The atoms are independently hydrogen, deuterium, halogens, -CN, -OR, -NR2, -SR, 3-8 member saturated or partially unsaturated monocyclic carbon rings, phenyl, 8-10 member bicyclic aromatic carbon rings, 4-8 member saturated or partially unsaturated monocyclic heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 5-6 member monocyclic heteroaromatic rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 8-10 member bicyclic heteroaromatic rings having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. A ring, or optionally substituted with -CN, -OR, -NR2, -SR, a 3- to 8-membered saturated or partially unsaturated monocyclic carbon ring, phenyl, an 8- to 10-membered bicyclic aromatic carbon ring, a 4- to 8-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 an 8- to 10-membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, C 1-6 Aliphatic group (or the C 1-6The aliphatic atom is optionally substituted with 1, 2, 3, 4, 5, or 6 deutherium or halogen atoms, or R bonded to the same carbon atom 4 or R 5 These two occurrences, together with the carbon atoms bonded to them, form a 3-6 member spirocyclic saturated monocyclic carbocyclic ring, or a 3-6 member spirocyclic saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. -M- is a self-destructing group, n is between 0 and 18. Each m is independent and ranges from 0 to 6.

[0041] [ka]

[0042] However, the therapeutic agent is selected from natural or unnatural neurosteroids, their analogues, or prodrugs.

[0043] As defined above and as described herein, R 1 and R 2 Each of these independently comprises hydrogen, an acid-unstable group, lipids such as fatty acids, or -C(O)R 3 That is the case.

[0044] In some embodiments, R 1 is hydrogen. In some embodiments, R 1 R is an acid-unstable group. In some embodiments, 1 It 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 The option is selected from those shown in Figure 1 below.

[0045] In some embodiments, R 2 is hydrogen. In some embodiments, R2 R is an acid-unstable group. In some embodiments, 2 It 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 The option is selected from those shown in Figure 1 below.

[0046] In some embodiments, R 1 and R 2 Each of these is independently a fatty acid, phosphatide, phospholipid, or analogue thereof, for example, as detailed below. In some embodiments, each fatty acid is independently a saturated or unsaturated medium-chain 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 C2-C 40 It has a chain. In some embodiments, each fatty acid is independently C6-C 20 , C8~C 20 , C 10 ~C 20 , C 10 ~C 18 , C 12 ~C 18 , C 14 ~C 18 , C 16 ~C 18 , C 10 ~C 16 , C4~C 10 , or C6~C 10 It has a chain. In some embodiments, each fatty acid is independently a linear C6-C 20 These are fatty acids. In some embodiments, each fatty acid is independently a linear C 12 ~C 18 These are fatty acids. In some embodiments, each fatty acid is independently a linear saturated C6-C6 fatty acid. 10It is a fatty acid. 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 acid-labile groups such as tert-butoxycarbonyl (Boc), amino acids, PEG groups, -C(O)OR, -C(O)NR2, -CH2OR, -C(NR)R, or -P(O)2OR.

[0048] For the sake of clarity, when R 1 or R 2 is defined as a fatty acid, it is understood that R 1 or R 2 is the acyl residue of the fatty acid. Thus, for example, when R 1 is defined as palmitic acid, R 1 is the acyl portion of palmitic acid, i.e., -C(O)C 15 H 31 is.

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

[0050] In some embodiments, R 3 is a saturated, straight-chain, optionally substituted C 1-37 hydrocarbon chain. In some embodiments, R 3 is an unsaturated, straight-chain, optionally substituted C 1-37 hydrocarbon chain. In some embodiments, R 3 is a saturated, branched, optionally substituted C 1-37 hydrocarbon chain. In some embodiments, R3 C is an unsaturated, branched, and optionally substituted C. 1-37 It is a hydrocarbon chain. In some embodiments, R 3 C is saturated, linear, and can be substituted at will. 1-20 It is a hydrocarbon chain. In some embodiments, R 3 C is an unsaturated, linear, and optionally substituted C. 1-20 It is a hydrocarbon chain. In some embodiments, R 3 C is a saturated, branched, and arbitrarily substituted C 1-20 It is a hydrocarbon chain. In some embodiments, R 3 C is an unsaturated, branched, and optionally substituted C. 1-20 It is a hydrocarbon chain. In some embodiments, R 3 The option is selected from those shown 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(C1 -6 aliphatic)-NR-, -NR(C 1-6 aliphatic)-O-, -NR(C 1-6 Aliphatic)-S-, or -NR(C 1-6 It is 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 The aliphatic group is independently and optionally substituted with one, two, or three 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 It is aliphatic (-O-). In some embodiments, X is -O(C 1-6It is aliphatic)-S-. In some embodiments, X is -O(C 1-6 It is aliphatic)-NR-. In some embodiments, X is -S(C 1-6 It is aliphatic)-O-. In some embodiments, X is -S(C 1-6 It is aliphatic)-S-. In some embodiments, X is -S(C 1-6 It is aliphatic)-NR-. In some embodiments, X is -NR(C 1-6 It is aliphatic)-O-. In some embodiments, X is -NR(C 1-6 It is aliphatic)-S-. In some embodiments, X is -NR(C 1-6 It is aliphatic)-NR-. In any of the embodiments described above, divalent C 1-6 The 0 to 2 methylene units of the aliphatic group can be independently and optionally replaced with -O-, -NR-, or -S-, resulting in a divalent C 1-6 The aliphatic group is independently and optionally substituted with one, two, or three deutherium or halogen atoms. In some embodiments, X is selected from those illustrated in Figure 1 below.

[0053] As defined above and as described herein, Y is either absent or -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 illustrated in Figure 1 below.

[0055] As defined above and described herein, L is a covalent or optionally substituted divalent C, which is saturated or unsaturated, linear or branched. 1-30It is 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 amino acids, 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] It is connected. In some embodiments, L is a covalent bond. In some embodiments, L is a divalent carbon atom that is saturated or unsaturated, linear or branched, and optionally substituted. 1-30 (For example, C 3-30 , C 5-30 , C 7-30 , C 3-25 , C 5-25 , C 7-25 , C 3-20 , C 5-20 , or C 7-20 (etc.) A hydrocarbon chain in which 0 to 8 methylene units of L (i.e., 0, 1, 2, 3, 4, 5, 6, 7, or 8) 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 amino acids, and one methylene unit of L is optionally replaced by -M-. In some embodiments, L is

[0060] [ka]

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

[0062] [ka]

[0063] It is coupled to. In some embodiments, L is

[0064] [ka]

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

[0066] [ka]

[0067] It is coupled to. In some embodiments, L is

[0068] [ka]

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

[0070] [ka]

[0071] It is coupled to. In some embodiments, L is

[0072] [ka]

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

[0074] [ka]

[0075] It is coupled to. In some embodiments, L is

[0076] [ka]

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

[0078] [ka]

[0079] It is coupled to. In some embodiments, L is

[0080] [ka]

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

[0082] [ka]

[0083] It is connected. In some embodiments, L is covalently bonded or optionally substituted with divalent C, which is saturated or unsaturated, linear or branched. 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 , C5-20 , or C 7-20 (etc.) A hydrocarbon chain in which 0 to 8 methylene units (i.e., 0, 1, 2, 3, 4, 5, 6, 7, or 8) 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] It is replaced by an amino acid selected from, and 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] It is connected. In some embodiments, L is a divalent C that is saturated or unsaturated, linear or branched, and optionally substituted. 1-20 (For example, C 3-20 , C 5-20 , or C 7-20(etc.) A hydrocarbon chain in which 0 to 8 methylene units (i.e., 0, 1, 2, 3, 4, 5, 6, 7, or 8) 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] It is replaced with natural amino acids such as, and one methylene unit of L is optionally replaced with -M-. In some embodiments, L is covalent or divalent saturated or unsaturated, linear or branched C 1-16 , C 1-12 , C 1-10 or C 6-16 A hydrocarbon chain in which 0-6, 0-4, 0-3, or 0-1 methylene units of L can independently be -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] It is replaced by -M-, and one methylene unit of L is optionally replaced with -M-. In some embodiments, L is divalent saturated, linear C 1-20 , C 1-16 , C 1-12 , C 1-10 , or C 1-6A hydrocarbon chain in which 0-6, 0-4, 0-3, or 0-1 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 It is a hydrocarbon chain in which 0-6, 0-4, 0-3, or 0-1 methylene units of L are independently replaced by -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 by -M-.

[0094] In some embodiments, L is 1, 2, 3, or 4 R 4 Divalent saturated C, which can be optionally substituted with the base. 1-30 , C 1-25 , C 1-20 , C 3-20 , C 5-20 , or C 7-20 It is a hydrocarbon chain in which 0 to 4 methylene units of L are independently replaced by -O-, -OC(O)-, -C(O)O-, or -C(O)-, and 1 methylene unit of L is optionally replaced by -M-.

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

[0096] In some embodiments, L is 1, 2, 3, or 4 R 4 Divalent saturated C, which can be optionally substituted with the base. 3-30 , C 3-25 , C 3-20 , C 3-15 , C 5-10 , C 5-15 , or C 7-15 It is a hydrocarbon chain in which one or 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, which is optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms. 1-6 Divalent saturated carbon, optionally substituted with 1, 2, 3, or 4 aliphatic groups. 3-30 , C 3-25 , C 3-20 , C 3-15 , C 5-10 , C 5-15 , or C 7-15 It is a hydrocarbon chain in which 0 to 4 methylene units of L are independently replaced by -O-, -OC(O)-, -C(O)O-, or -C(O)-, and 1 methylene unit of L is optionally replaced by -M-.

[0098] In some embodiments, L is deuterium, halogen, -CN, or C, which is optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms. 1-6 Divalent saturated carbon, optionally substituted with 1, 2, 3, or 4 aliphatic groups. 3-30 , C 3-25 , C 3-20 , C 3-15, C 5-10 , C 5-15 , or C 7-15 It is a hydrocarbon chain in which one or 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 a deuterium, halogen, -CN, a 3-6 member saturated or partially unsaturated monocyclic carbon ring, a 4-6 member saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from phenyl, nitrogen, oxygen, or sulfur, a 5-6 member 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 carbon, optionally substituted with 1, 2, 3, or 4 aliphatic groups. 1-25 , C 5-25 , C 7-25 , or C 1-20 It is a hydrocarbon chain in which 0 to 4 methylene units of L are independently replaced by -O-, -OC(O)-, -C(O)O-, or -C(O)-, and 1 methylene unit of L is optionally replaced by -M-.

[0100] In some embodiments, L is (-OCH2CH2-) 1-8 (i.e., containing 1 to 8 polyethylene glycol (PEG) units). In some embodiments, L contains 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] Includes. In some embodiments, L is

[0105] [ka]

[0106] Includes. In some embodiments, L is

[0107] [ka]

[0108] Includes. In some embodiments, L is

[0109] [ka]

[0110] Includes. In some embodiments, L is

[0111] [ka]

[0112] Includes. In some embodiments, L is

[0113] [ka]

[0114] Includes. In some embodiments, L is

[0115] [ka]

[0116] Includes. In some embodiments, L is

[0117] [ka]

[0118] This includes. In some embodiments, one methylene unit of L is replaced with -M-. In some embodiments, one, two, three, or four available hydrogen atoms of L are R 4 The base is replaced, i.e., L is of any choice, 1, 2, 3, or 4 R 4 It is substituted with the base.

[0119] In some embodiments, the methylene unit L is replaced with an amino acid. The amino acid may be in its natural or unnatural form. In some embodiments, the amino acid is selected from nonpolar 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 shown in Figure 1 below. As defined above and described herein, each -Cy- is an optionally substituted 3- to 6-membered divalent saturated, partially unsaturated, or aromatic ring having 0 to 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 illustrated in Figure 1 below.

[0122] As defined above and described herein, each R 4 and R 5 It is independently hydrogen, deuterium, halogen, -CN, -OR, -NR2, -SR, 3-8 member saturated or partially unsaturated monocyclic carbon ring, phenyl, 8-10 member bicyclic aromatic carbon ring, nitrogen, oxygen, or sulfur, having 1-2 heteroatoms independently selected from these, a 4-8 member saturated or partially unsaturated monocyclic heterocycle, a 5-6 member monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 member bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or -CN, -OR, -NR2, -SR, 3-8 member saturated or A 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, which are optionally substituted with C 1-6 Aliphatic group (or the C 1-6The aliphatic atom is either optionally substituted with 1, 2, 3, 4, 5, or 6 deutherium or halogen atoms, or bonded to the same carbon atom. 4 or R 5 These two occurrences, together with the carbon atoms bonded to them, form a 3- to 6-membered spirocyclic saturated monocyclic carbocyclic, or a 3- to 6-membered spirocyclic saturated heterocyclic having 1-2 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 4 is -NR2. In some embodiments, R 4 is -SR. In some embodiments, R 4 R is a 3- to 8-membered saturated or partially unsaturated monocyclic carbon ring. In some embodiments, R 4 is phenyl. In some embodiments, R 4 It is an 8-10 membered bicyclic aromatic carbon ring. In some embodiments, R 4 R is a 4-8 member saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 4 R is a 5-6 member monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 4 R is an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 4C is optionally substituted with -CN, -OR, -NR2, -SR, a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 4- to 8-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 an 8- to 10-membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 1-6 It is an aliphatic group. In some embodiments, R 4 C is optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms. 1-6 It is an aliphatic group. In some embodiments, R is bonded to the same carbon atom. 4 These two occurrences, together with the carbon atoms bonded to them, form a 3- to 6-membered spirocyclic saturated monocyclic carbocyclic, or a 3- to 6-membered spirocyclic saturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0124] Some implementation methods, each R 4 C is independently hydrogen, deuterium, halogen, -CN, or 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 These two occurrences, together with the carbon atoms bonded to them, form a 3- to 6-membered spirocyclic saturated monocyclic carbocyclic, or a 3- to 6-membered spirocyclic saturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0125] In some embodiments, R 4 At least one instance of its occurrence is not hydrogen. In some embodiments, R 4 C is optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms. 1-4It is aliphatic. In some embodiments, R 4 C is optionally substituted with 1, 2, or 3 deuterium or halogen atoms. 1-4 It is alkyl. In some embodiments, R 4 is a methyl atom optionally substituted with one, two, or three deutherium or halogen atoms. In some embodiments, R 4 is ethyl. In some embodiments, R 4 is n-propyl. In some embodiments, R 4 is isopropyl. In some embodiments, R 4 is n-butyl. In some embodiments, R 4 isobutyl. In some embodiments, R 4 is tert-butyl. In some embodiments, R 4 The option is selected from those shown in Figure 1 below.

[0126] In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is deuterium. In some embodiments, R 5 is 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 R is a 3- to 8-membered saturated or partially unsaturated monocyclic carbon ring. In some embodiments, R 5 is phenyl. In some embodiments, R 5 It is an 8-10 membered bicyclic aromatic carbon ring. In some embodiments, R 5 R is a 4-8 member saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 5R is a 5-6 member monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 5 R is an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 5 C is optionally substituted with -CN, -OR, -NR2, -SR, a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 4- to 8-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 an 8- to 10-membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 1-6 It is an aliphatic group. In some embodiments, R 5 C is optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms. 1-6 It is an aliphatic group. In some embodiments, R is bonded to the same carbon atom. 5 These two occurrences, together with the carbon atoms bonded to them, form a 3- to 6-membered spirocyclic saturated monocyclic carbocyclic, or a 3- to 6-membered spirocyclic saturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0127] Some implementation methods, each R 5 C is independently hydrogen, deuterium, halogen, -CN, or 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 These two occurrences, together with the carbon atoms bonded to them, form a 3- to 6-membered spirocyclic saturated monocyclic carbocyclic, or a 3- to 6-membered spirocyclic saturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0128] In some embodiments, R 5 At least one instance of its occurrence is not hydrogen. In some embodiments, R 5 C is optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms. 1-4 It is aliphatic. In some embodiments, R 5 R is a methyl atom optionally substituted with one, two, or three deuterium or halogen atoms. In some embodiments, R 5 is ethyl. In some embodiments, R 5 is n-propyl. In some embodiments, R 5 is isopropyl. In some embodiments, R 5 is n-butyl. In some embodiments, R 5 isobutyl. In some embodiments, R 5 is tert-butyl. In some embodiments, R 5 The option is selected from those shown in Figure 1 below.

[0129] As defined above and described herein, -M- is a self-destructing group. In some embodiments, -M- represents acetal, o-benzyl alcohol, or p-benzyl It is an alcohol, a styryl group, a coumarin, or a group that self-destructs via a cyclization reaction. In some embodiments, -M- is selected from a disulfide, a hydrazone, an acetal self-destructing group, a carboxyacetal self-destructing group, a carboxy(methylacetal) self-destructing group, a para-hydroxybenzylcarbonyl self-destructing group, an inverted ester self-destructing group, a trimethyl lock, or a 2-hydroxyphenylcarbamate (2-HPC) self-destructing group. In some embodiments, -M- is an acetal. In some embodiments, -M- is a carboxyacetal. In some embodiments, -M- is a carboxy(methylacetal). In some embodiments, -M- is an acetal self-destructing group. In some embodiments, -M- is a carboxyacetal self-destructing group. In some embodiments, -M- is a carboxy(methylacetal) self-destructing group.

[0130] In some embodiments, -M- is

[0131] [ka]

[0132] And, In the formula, each R 6 These independently become hydrogen, deutherium, and C 1-10 Selected from aliphatic, halogen, or -CN, Each R 7 These independently include hydrogen, deuterium, halogens, -CN, -OR, -NR2, -NO2, -SR, 3-8 member saturated or partially unsaturated monocyclic carbon rings, phenyl, 8-10 member bicyclic aromatic carbon rings, 4-8 member saturated or partially unsaturated monocyclic heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 5-6 member monocyclic heteroaromatic rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 8-10 member bicyclic heteroaromatic rings having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or -CN, -OR, -NR2, -SR, optionally substituted with a 3-8 member saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8-10 member bicyclic aromatic carbocycle, a 4-8 member saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 member monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 member bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, C 1-6 Aliphatic group (or the C 1-6 The aliphatic atom is optionally substituted with 1, 2, 3, 4, 5, or 6 deutherium or halogen atoms. each Z 1 These are independently selected from -O-, -NR-, or -S-, each Z 2 These are independently selected from -O-, -NR-, -S-, -OC(O)-, -NRC(O)O-, or -OC(O)NR-, each Z 3 These are independent of =N- or =C(R 7 )- Selected from, each Z 4 These are independent of -O-, -NR-, -S-, and -C(R 6 )2-, or selected from covalent bonds.

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

[0134] [ka]

[0135] In the formula, each R 6 These independently become hydrogen, deutherium, and C 1-5 Selected from aliphatic, halogen, or -CN, Each R 7Independently, hydrogen, deuterium, halogen, -CN, -OR, -NR2, -NO2, -SR, 3-8 member saturated or partially unsaturated monocyclic carbon ring, phenyl, 8-10 member bicyclic aromatic carbon ring, nitrogen, oxygen, or sulfur, with 1-2 heteroatoms independently selected from these, a 4-8 member saturated or partially unsaturated monocyclic heterocycle, a 5-6 member monocyclic heteroaromatic ring, with 1-4 heteroatoms independently selected from these, a 8-10 member bicyclic heteroaromatic ring, with 1-5 heteroatoms independently selected from these, a 3-8 member saturated or partially unsaturated monocyclic carbon ring, phenyl, 8-10 member bicyclic aromatic carbon ring, nitrogen, oxygen, or sulfur, with 1-2 heteroatoms independently selected from these, a 4-8 member saturated or partially unsaturated monocyclic heterocycle, nitrogen, oxygen, or sulfur C is optionally substituted with a 5-6 member monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from or from sulfur, or an 8-10 member bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 1-6 Aliphatic group (or the C 1-6 The aliphatic atom is optionally substituted with 1, 2, 3, 4, 5, or 6 deutherium or halogen atoms. each Z 1 These are independently selected from -O-, -NR-, or -S-, each Z 2 These are independently selected from -O-, -NR-, -S-, -OC(O)-, -NRC(O)O-, or -OC(O)NR-, each Z 3 These are independent of =N- or =C(R 7 )- Selected from, each Z 4 These are independent of -O-, -NR-, -S-, and -C(R 6 )2-, or selected from covalent bonds.

[0136] As generally defined above and as described herein, each R 6These are independently hydrogen, deutherium, and C 1-5 Selected from aliphatic, halogen, or -CN. In some embodiments, R 6 is hydrogen. In some embodiments, R 6 is deuterium. In some embodiments, R 6 C 1-5 It is aliphatic. In some embodiments, R 6 is a halogen. In some embodiments, R 6 It is -CN.

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

[0138] In some embodiments, the example R in the above formula 6 Each occurrence is the same. In some embodiments, each R 6 They are different. In some embodiments, one R 6 is hydrogen. In some embodiments, one R 6 C 1-5 It is aliphatic. In some embodiments, each R 6 is hydrogen. In some embodiments, each R 6 C 1-5 It is aliphatic. In some embodiments, R 6 The option is selected from those shown in Figure 1 below.

[0139] As generally defined above and as described herein, each R 7These are independently hydrogen, deuterium, halogens, -CN, -OR, -NR2, -NO2, -SR, 3-8 member saturated or partially unsaturated monocyclic carbon rings, phenyl, 8-10 member bicyclic aromatic carbon rings, 4-8 member saturated or partially unsaturated monocyclic heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 5-6 member monocyclic heteroaromatic rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 8-10 member atoms 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- to 8-membered saturated or partially unsaturated monocyclic heterocycle, phenyl, an 8- to 10-membered bicyclic aromatic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 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 The aliphatic group is optionally selected from (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 -NO2. In some embodiments, R 7 is -SR. In some embodiments, R 7 This is a saturated or It is a partially unsaturated monocyclic carbon ring. In some embodiments, R 7is phenyl. In some embodiments, R 7 It is an 8-10 membered bicyclic aromatic carbon ring. In some embodiments, R 7 R is a 4-8 member saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 7 R is a 5-6 member monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 7 R is an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 7 C is optionally substituted with -CN, -OR, -NR2, -SR, a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 4- to 8-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 an 8- to 10-membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 1-6 It is an aliphatic group. In some embodiments, R 7 C is 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 7C is optionally substituted with a 5-6 member monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from hydrogen, deuterium, halogen, -CN, -OR, -NR2, -NO2, -SR, a 3-6 member saturated or partially unsaturated monocyclic carbocycle, a 4-6 member saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from phenyl, nitrogen, oxygen, or sulfur, or a 5-6 member monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from -CN, -OR, -NR2, -SR, a 3-6 member saturated or partially unsaturated monocyclic carbocycle, phenyl, or a 5-6 member 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 C is a 5-6 member monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from hydrogen, deuterium, halogens, -CN, a 3-6 member saturated or partially unsaturated monocyclic carbocycle, phenyl, nitrogen, oxygen, or sulfur, or is optionally substituted with a 5-6 member monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from -CN, a 3-6 member saturated or partially unsaturated monocyclic carbocycle, phenyl, or 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 deutherium 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 The option is selected from those shown in Figure 1 below.

[0143] As generally defined above and as described herein, each Z1 In some embodiments, Z 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 It is -NH- or -NMe-.

[0144] In some embodiments, Z 1 The option is selected from those shown in Figure 1 below. As generally defined above and as described herein, each Z 2 The following 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 It is -OC(O)NR-.

[0146] In some embodiments, each Z 2 The following 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] It is covalently bonded to Z. In some embodiments, Z2 It is -O- or -OC(O)O-.

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

[0151] As generally defined above and as described herein, each Z 3 These are independent of =N- or =C(R 7 )- Selected from. In some embodiments, Z 3 In some embodiments, Z 3 is =C(R 7 )-is.

[0152] In some embodiments, Z 3 The option is selected from those shown in Figure 1 below. As generally defined above and as described herein, each Z 4 These are independently -O-, -NR-, -S-, and -C(R 6 )2-, or selected from covalent bonding. In some embodiments, Z 4 is -O-. In some embodiments, Z 4 is -NR-. In some embodiments, Z 4 is -S-. In some embodiments, Z 4 -C(R 6 )2-. In some embodiments, Z 4 This is a covalent bond.

[0153] In some embodiments, Z 4 The option is selected from those shown 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] That is the case. In some embodiments, -M- is

[0158] [ka]

[0159] That is the case. In some embodiments, -M- is

[0160] [ka]

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

[0162] [ka]

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

[0164] [ka]

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

[0166] [ka]

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

[0168] [ka]

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

[0170] [ka]

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

[0172] [ka]

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

[0174] [ka]

[0175] That is the case. In some embodiments, -M- is

[0176] [ka]

[0177] In some embodiments, -M- is

[0178] [ka]

[0179] In some embodiments, -M- is

[0180] [ka]

[0181] That is the case. In some embodiments, -M- is selected from those shown in Figure 1 below.

[0182] As defined above and as described herein, n is between 0 and 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 1-16, 1-14, 1-12, 1-10, 1-8, 1-6, 1-3, 2-16, 2-14, 2-12, 2-10, 2-8, 2-6, 3-12, 3-10, 3-8, 3-6, 4-10, 4-8, 4-6, 5-10, 5-8, 5-6, 6-10, 6-8, or 8-12.

[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 as described herein,

[0185] [ka]

[0186] Therapeutic agents are selected from natural or unnatural neurosteroids, their analogs, or prodrugs. 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 having two hydroxyl groups may be esterified at one hydroxyl to prepare a lipid prodrug of formula I, where the lipid prodrug moiety is bonded to the other hydroxyl. In some embodiments, the fatty acid ester contains a carbon chain of 8 to 20 carbon atoms. In some embodiments, the fatty acid is one of those described herein.

[0188] In some embodiments,

[0189] [ka]

[0190] is allopregnanolone or its analogues or prodrugs. In some embodiments,

[0191] [ka]

[0192] This is allopregnanolone. In some embodiments,

[0193] [ka]

[0194] isopregnanolone or its analogues or prodrugs. In some embodiments,

[0195] [ka]

[0196] It is isopregnanolone. In some embodiments,

[0197] [ka]

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

[0199] [ka]

[0200] The drug is selected from allopregnanolone (also known as brexanolone, SAGE-547, 5α-pregnane-3α-ol-20-one, 3α-hydroxy-5α-pregnane-20-one, or 3α,5α-tetrahydroprogesterone), 3,5-tetrahydroprogesterone, pregnanolonone (5β-pregnane-3α-ol-20-one), isopregnanolone (5α-pregnane-3β-ol-20-one), epipregnanolonone (5β-pregnane-3β-ol-20-one), 21-hydroalopregnanolone, or their analogues or prodrugs.

[0201] In some embodiments,

[0202] [ka]

[0203] This includes alfadron (3α,21-dihydroxy-5α-pregnane-11,20-dione), alfaxolone (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-morpholine-4-yl-5β-pregnane-20-one), Org Selected from 21465 (2β-(2,2-dimethyl-4-morpholinyl)-3α-hydroxy-11,20-dioxo-5α-pregnane-21-ylmethanesulfonate), Renanolon (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-carbonitride).

[0204] In some embodiments,

[0205] [ka]

[0206] These are allopregnanolone, pregnanolon, pregnenolone, ganaxolone, alfaxalone, 3β-dihydroprogesterone, isopregnanolone, epipregnanolon, or 21-hydroxyalopregnanolone.

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

[0208] [ka]

[0209] teeth,

[0210] [ka]

[0211] Therefore, the compound of formula II,

[0212] [ka]

[0213] or provide a pharmaceutically acceptable salt thereof, in the formula, Ring B is selected from phenyl, a 4-11 member saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic heterocyclic, having 1-3 heteroatoms independently selected from a carbon ring or nitrogen, oxygen, and sulfur, or a 5-10 member 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 6However, C is replaced by choice. 1-6 It is an aliphatic group, R 7a However, C is replaced by choice. 1-6 It is an aliphatic group, R 7b However, C is substituted with hydrogen or of any choice. 1-6 It is an aliphatic group, or R 7a and R 7b However, optionally, together with these intervening carbon atoms, they form a 4-7 member saturated or partially unsaturated spirocyclic carbocyclic or heterocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur in addition to carbon, or R 7a and R 7b However, they can optionally come together to form an oxo group, R 8 However, it is either absent or hydrogen.

[0214] [ka]

[0215] However, this represents a single bond or a double bond, and here,

[0216] [ka]

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

[0218] [ka]

[0219] It is a single bond,

[0220] [ka]

[0221] If one of them is a double bond, R 8 He is absent, R 1 , R 2 Each of X, Y, and L, both individually and in combination, is as defined above and as described 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] Therefore, equation III:

[0227] [ka]

[0228] We provide a compound of or a pharmaceutically acceptable salt thereof, in which, R 9 However, it is hydrogen or methyl, R 10 However, it is -OC(O)R, R 11 However, it is hydrogen or methyl, R 12 However, it is an alpha or beta hydrogen or a methyl group. R 13 However, it is -C(O)R, R, R 1 , R 2 Each of X, Y, and L, both individually and in combination, is as defined above and as described 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] Therefore, equation IV:

[0234] [ka]

[0235] We provide a compound of or a pharmaceutically acceptable salt thereof, in which, Z is O, S, NR, and NOR. R 14 However, it is hydrogen, hydroxyl, -CHO, -CHS, -CHNR, -CH2OR, -CH2SR, -CH2N(R)2, -CH2N(R)(OR), or C 1-6 A optionally substituted group selected from aliphatic, 3-8 member saturated or partially unsaturated monocyclic carbocycles, phenyl, 8-10 member bicyclic aromatic carbocycles, 4-8 member saturated or partially unsaturated monocyclic heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 5-6 member monocyclic heteroaromatic rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 8-10 member bicyclic heteroaromatic rings having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. R 17 However, is it hydrogen, -OH, oxo, or C? 1-6An optionally substituted group selected from aliphatic or 4-8 member saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, R 15 , R 16 , R 18 , R 19 , and R 20 The group is an optionally substituted group, which is independently selected from a 5-6 member monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from hydrogen, halogen, -OR, nitrogen, oxygen, or sulfur, or an 8-10 member bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. R 21 and R 22 However, each can be independently substituted with hydrogen or C of any choice. 1-6 Aliphatic group or -OC 1-6 Selected from aliphatic groups, or R 21 and R 22 However, they can optionally come together to form an oxo group, R, R 1 , R 2 Each of X, Y, and L, both individually and in combination, is as defined above and as described 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] Therefore, equation V:

[0241] [ka]

[0242] We provide a compound of or a pharmaceutically acceptable salt thereof, in which,

[0243] [ka]

[0244] However, it is either a double bond or a single bond, Z is O, S, NR, or NOR. R 23 However, it is either hydrogen, -OH, or C 1-6 A optionally substituted group selected from aliphatic, 3-8 member saturated or partially unsaturated monocyclic carbocycles, phenyl, 8-10 member bicyclic aromatic carbocycles, 4-8 member saturated or partially unsaturated monocyclic heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 5-6 member monocyclic heteroaromatic rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 8-10 member bicyclic heteroaromatic rings having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. R 26 However, is it hydrogen, or C 1-6 A optionally substituted group selected from aliphatic, 3-8 member saturated or partially unsaturated monocyclic carbocycles, phenyl, 8-10 member bicyclic aromatic carbocycles, 4-8 member saturated or partially unsaturated monocyclic heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 5-6 member monocyclic heteroaromatic rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 8-10 member bicyclic heteroaromatic rings having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. R 26a However, is it hydrogen, or R 26 and R26a However, they can optionally come together to form an oxo group, R 24 , R 25 , R 27 , and R 28 However, each is independently hydrogen, -OH, halogen, or C 1-6 A group that can be optionally substituted, selected from aliphatic, 3-8 member saturated or partially unsaturated monocyclic carbocycles, phenyl, 8-10 member bicyclic aromatic carbocycles, 4-8 member saturated or partially unsaturated monocyclic heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 5-6 member monocyclic heteroaromatic rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 8-10 member bicyclic heteroaromatic rings having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, however,

[0245] [ka]

[0246] If R is a double bond, 28 Provided that they are absent, R 29 However, it is hydrogen, halogen, -OR, or C 1-6 An optionally substituted group, selected from aliphatic or 3-8 membered saturated or partially unsaturated monocyclic carbon rings. R 30 However, is it hydrogen, or C 1-6 An optionally substituted group, selected from aliphatic or 3-8 membered saturated or partially unsaturated monocyclic carbon rings. R 31 However, is it -OH or R 30 and R 31 However, they can optionally come together to form an oxo group, R 32 However, it is hydrogen, halogen, -OH, or C 1-6An optionally substituted group, selected from aliphatic or 3-8 membered saturated or partially unsaturated monocyclic carbon rings. R 32a However, C is substituted with hydrogen, halogen, or of any choice. 1-6 It is an aliphatic group, however,

[0247] [ka]

[0248] If R is a double bond, 32a Provided that they are absent, R, R 1 , R 2 Each of X, Y, and L, both individually and in combination, is as defined above and as described in the embodiments herein.

[0249] In certain embodiments, the present invention provides a compound of formula I, wherein,

[0250] [ka]

[0251] but,

[0252] [ka]

[0253] [ka]

[0254] [ka]

[0255] And so, equation VI-a:

[0256] [ka]

[0257] [ka]

[0258] [ka]

[0259] [ka]

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

[0261] In certain embodiments, the present invention provides a compound of formula I, wherein,

[0262] [ka]

[0263] but,

[0264] [ka]

[0265] And so, equation VII:

[0266] [ka]

[0267] It forms a compound of or a pharmaceutically acceptable salt thereof, in which R 1 , R 2 X, Y, and L are as defined above and as described in the embodiments herein,

[0268] [ka]

[0269] The base variable R 1 , R 2 , R 3 , R 4 , and R 5 Each of these is as described and defined in US2019 / 0337975, the entirety of which is incorporated herein by reference.

[0270] In some embodiments,

[0271] [ka]

[0272] It is neither allopregnanolone nor its analogues or prodrugs. In some embodiments,

[0273] [ka]

[0274] It is not Allopregnanolone. In some embodiments,

[0275] [ka]

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

[0277] [ka]

[0278] This is not selected from allopregnanolone (5α-pregnane-3α-ol-20-one), 3,5-tetrahydroprogesterone, pregnanolonone (5β-pregnane-3α-ol-20-one), isopregnanolone (5α-pregnane-3β-ol-20-one), epipregnanolonone (5β-pregnane-3β-ol-20-one), 21-hydroalopregnanolone, or their analogs or prodrugs.

[0279] In some embodiments,

[0280] [ka]

[0281] This includes alfadron (3α,21-dihydroxy-5α-pregnane-11,20-dione), alfaxolone (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-morpholine-4-yl-5β-pregnane-20-one), Org Not selected from 21465 (2β-(2,2-dimethyl-4-morpholinyl)-3α-hydroxy-11,20-dioxo-5α-pregnane-21-ylmethanesulfonate), Renanolon (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] This is not selected from pregnanolon, pregnenolone, 3β-dihydroprogesterone, isopregnanolone, epipregnanolon, or 21-hydroxyalopregnanolone.

[0285] In some embodiments, neurosteroids

[0286] [ka]

[0287] This is a native or non-native (e.g., synthetic) inhibitory neurosteroid. In some embodiments, the neurosteroid is a native inhibitory neurosteroid selected from the following: 3α-dihydroprogesterone (3α-DHP):pregna-4-en-3α-ol-20-one, 5α-dihydroprogesterone (5α-DHP; allopregnandione): 5α-pregnane-3,20-dione, 5β-dihydroprogesterone (5β-DHP; pregnanedione): 5β-pregnane-3,20-dione, Allopregnandiol: 5α-pregnane-3α,20α-diol, Allopregnanolone (brexanolone, SAGE-547): 5α-pregnane-3α-all-20-one, Dihydrodeoxycorticosterone (DHDOC):21-hydroxy-5α-pregnane-20-one, Pregnanediol: 5β-pregnane-3α,20α-diol, Pregnanolon (Ertanolone): 5β-pregnane-3α-all-20-one, Tetrahydrodeoxycorticosterone (THDOC):3α,21-dihydroxy-5α-pregnane-20-one, Deoxycorticosterone (desoxycorton): 21-hydroxypregna-4-ene-3,20-dione Pregnenolone (P5): (pregna-5-en-3β-ol-20-one), and Progesterone (P4) (pregna-4-ene-3,20-dione).

[0288] In some embodiments,

[0289] [ka]

[0290] This is a non-natural (e.g., synthetic) inhibitory neurosteroid selected from the following: Alphadron: 3α,21-dihydroxy-5α-pregnane-11,20-dione, Alphadron 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)pregna-4-en-3-one, Ganaxolone: ​​3β-methyl-5α-pregnane-3α-ol-20-one, Hydroxydione: 21-hydroxy-5β-pregnane-3,20-dione Minaxolone: ​​11α-(dimethylamino)-2β-ethoxy-5α-pregnane-3α-ol-20-one, ORG-20599:21-Chloro-2β-Morpholin-4-yl-5β-pregnane-3α-ol-20-one, ORG-21465: 2β-(2,2-dimethyl-4-morpholinyl)-3α-hydroxy-11,20-dioxo-5α-pregnane-21-ylmethanesulfonate, Renanolon: 5β-pregnane-3α-ol-11,20-dione, SGE-516, SGE-872, SAGE-217 (Zulanolone): 3α-hydroxy-3β-methyl-21-(4-cyano-1H-pyrazole-1'-yl)-19-nor-5β-pregnane-20-one, or proneurosteroid, for example, EIDD-1723, P1-185, and Progesterone carboxymethyl oxime (P4-3-CMO).

[0291] In some embodiments,

[0292] [ka]

[0293] These are excitatory neurosteroids of the natural or unnatural (e.g., synthetic) type. In some embodiments,

[0294] [ka]

[0295] It is a naturally occurring excitatory neurosteroid selected from the following: 3β-dihydroprogesterone (3β-DHP):pregna-4-en-3β-ol-20-one, Epipregnanolone: ​​5β-pregnane-3β-all-20-one, Isopregnanolon (sepranolon): 5α-pregnane-3β-ol-20-one, Pregnenolone sulfate (PS): Pregnane-5-en-3β-ol-20-one 3β-sulfate, or Pregnenolone (P5): Pregna-5-en-3β-all-20-one.

[0296] In some embodiments,

[0297] [ka]

[0298] This is epipregnanolon sulfate (5β-pregnane-3β-ol-20-one 3β-sulfate).

[0299] In some embodiments,

[0300] [ka]

[0301] These are natural or unnatural (e.g., synthetic) neurotrophic neurosteroids. In some embodiments,

[0302] [ka]

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

[0304] In some embodiments,

[0305] [ka]

[0306] These are natural or unnatural (e.g., synthetic) antineurotrophic neurosteroids. In some embodiments,

[0307] [ka]

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

[0309] In some embodiments,

[0310] [ka]

[0311] These are selected from natural or unnatural (e.g., synthetic) pheromones and ferrin. In some embodiments,

[0312] [ka]

[0313] teeth, Pregnadiene (PDD): Pregna-4,20-diene-3,6-dione The following are selected: PH10, PH15, PH30, PH56, PH78, PH84, and Salubrin (PH80).

[0314] In some embodiments,

[0315] [ka]

[0316] teeth, Pregnenolone (P5): Pregna-5-en-3β-all-20-one, Progesterone (P4): Pregna-4-en-3,20-dione, 3β-Methoxypregnenolone (MAP-4343): 3β-Methoxypregnane-5-en-20-one, Selected from cyclopregnol (neurosterone):6β-hydroxy-3:5-cyclopregnan-20-one.

[0317] In some embodiments,

[0318] [ka]

[0319] This is a compound selected from those described in WO2019094724, and the same document Each of the contents is incorporated herein by reference in its entirety. In some embodiments,

[0320] [ka]

[0321] This refers to compounds of formula IA, IB, II, or III, as described in WO2019094724:

[0322] [ka]

[0323] In some embodiments,

[0324] [ka]

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

[0326] [ka]

[0327] In some embodiments,

[0328] [ka]

[0329] This 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] The compound is 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] The compound is 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] The compound is 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 prodrug form. Therefore, it will be understood that the lipid prodrug portion of the present invention can be conjugated to a therapeutic agent or its active form. For clarity and as an example, it will be understood that the provided lipid prodrug portion can be conjugated with any modifiable oxygen, sulfur, or nitrogen atom of a pregnane neurosteroid. For example, allopregnanolone has the following structure:

[0342] [ka]

[0343] It may have a hydroxyl (OH) group and 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] When used herein, therapeutic agent

[0345] [ka]

[0346] The diagram of the parentheses around it is,

[0347] [ka]

[0348] The portion is made of any available modifiable nitrogen, oxygen, or sulfur atoms.

[0349] [ka]

[0350] This means that they are covalently bonded. For clarity and as a non-limiting example, the available modifiable nitrogen, oxygen, or sulfur atoms in the structures of the following therapeutic compounds are illustrated below, where each wavy bond defines a bond point to Formula I or another formula illustrated herein.

[0351] [ka]

[0352] [ka]

[0353] In some embodiments,

[0354] [ka]

[0355] teeth,

[0356] [ka]

[0357] That is the case. In some embodiments,

[0358] [ka]

[0359] teeth,

[0360] [ka]

[0361] That is the case. In some embodiments,

[0362] [ka]

[0363] teeth,

[0364] [ka]

[0365] That is the case. In some embodiments, the present invention relates to formula Ia:

[0366] [ka]

[0367] We provide compounds of or pharmaceutically acceptable salts thereof, where L, R 1 , R 2Each of , and X, both individually and in combination, is as defined above and as described in the embodiments herein.

[0368] In some embodiments, the present invention relates to formula Ib:

[0369] [ka]

[0370] We provide compounds of or pharmaceutically acceptable salts thereof, in which L and

[0371] [ka]

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

[0373] In some embodiments, the present invention relates to formula Ic:

[0374] [ka]

[0375] We provide compounds of or pharmaceutically acceptable salts thereof, where L, R 1 , R 2 Each of , and X, both individually and in combination, is as defined above and as described in the embodiments herein.

[0376] In some embodiments, the present invention relates to formula Id:

[0377] [ka]

[0378] We provide compounds of or pharmaceutically acceptable salts thereof, in which R 1 , R 2 , R 4 , X, M, and

[0379] [ka]

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

[0381] In some embodiments, the present invention relates to formula Ie:

[0382] [ka]

[0383] We provide compounds of or pharmaceutically acceptable salts thereof, in which R 1 , R 2 , R 4 , R 5 , X, M, and

[0384] [ka]

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

[0386] In some embodiments, the present invention is expressed by formula If:

[0387] [ka]

[0388] We provide compounds of or pharmaceutically acceptable salts thereof, in which R 1 , R 2 , R4 , R 5 , X, n, and

[0389] [ka]

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

[0391] In some embodiments, the present invention relates to formula Ig:

[0392] [ka]

[0393] We provide compounds of or pharmaceutically acceptable salts thereof, in which R 1 , R 2 , X, M, and

[0394] [ka]

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

[0396] In some embodiments, the present invention relates to formula I h:

[0397] [ka]

[0398] We provide compounds of or pharmaceutically acceptable salts thereof, in which R 1 , R 2 , R 4 , M, and

[0399] [ka]

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

[0401] In some embodiments, the present invention relates to formulas VIII-a, VIII-b, VIII-c, VIII-d, VIII-e, VIII-f, or VIII-g:

[0402] [ka]

[0403] [ka]

[0404] We provide compounds of or pharmaceutically acceptable salts thereof, in which R 1 , R 2 , R 4 , R 5 , M, and

[0405] [ka]

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

[0407] In some embodiments, the present invention relates to formula IX-a or IX-b

[0408] [ka]

[0409] We provide compounds of or pharmaceutically acceptable salts thereof, in which R 1 , R2 , R 4 , R 5 , Each of and M, both individually and in combination, is as defined above and as described in the embodiments herein.

[0410] In some embodiments, the present invention relates to formula IX-c or IX-d:

[0411] [ka]

[0412] We provide compounds of or pharmaceutically acceptable salts thereof, in which R 1 , R 2 , R 4 , R 5 Each of , and M, both individually and in combination, is as defined above and as described in the embodiments herein.

[0413] In some embodiments, the present invention relates to formula X:

[0414] [ka]

[0415] We provide compounds of or pharmaceutically acceptable salts thereof, in which R 1 , R 2 Each of X and M, individually and in combination, is as defined above and as described in the embodiments herein.

[0416] In some embodiments, the present invention relates to formula XI:

[0417] [ka]

[0418] We provide compounds of or pharmaceutically acceptable salts thereof, in which R1 , R 2 , R 4 Each of , and M, both individually and in combination, is as defined above and as described in the embodiments herein.

[0419] In some embodiments, the present invention relates to formulas XII-a, XII-b, XII-c, XII-d, XII-e, XII-f, or XII-g:

[0420] [ka]

[0421] [ka]

[0422] We provide compounds of or pharmaceutically acceptable salts thereof, in which R 1 , R 2 , R 4 , R 5 Each of , and M, both individually and in combination, is as defined above and as described in the embodiments herein.

[0423] In some embodiments, the present invention relates to formula XIII-a or XIII-b:

[0424] [ka]

[0425] We provide compounds of or pharmaceutically acceptable salts thereof, in which R 1 , R 2 , R 4 , R 5 Each of -M-, both individually and in combination, is as defined above and as described in the embodiments herein.

[0426] In some embodiments, the present invention relates to formula XIII-c or XIII-d:

[0427] [ka]

[0428] We provide compounds of or pharmaceutically acceptable salts thereof, in which R 1 , R 2 , R 4 , R 5 Each of , and M, both individually and in combination, is as defined above and as described in the embodiments herein.

[0429] In the above formulas, when a range of numbers such as 0-4 or 1-18 is disclosed, the individual integers within that range are also specifically disclosed. Thus, the range 0-4 above includes 0, 1, 2, 3, and 4. The range 1-18 includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, and 18. The range 0-1 includes 0 and 1, i.e., its base exists of arbitrary choice. If more than one range is disclosed in a formula, each range is independently and of arbitrary choice selected from the disclosed ranges. For example, in formula VIII-c above, the ranges 0-4 and 1-18 vary independently of the other ranges.

[0430] In another embodiment, the present invention relates to formula XIV:

[0431] [ka]

[0432] We provide a compound of or a pharmaceutically acceptable salt thereof, in which, R 1 and R 2 However, each independently, hydrogen or -C(O)R 3 And, Each R 3 Independently, saturated or unsaturated, linear or branched, C is optionally substituted.1-37 It is a hydrocarbon chain, X is -O-, Y is -C(O)-, L is a divalent C which is saturated or unsaturated, linear or branched, and optionally substituted. 3-20 It is 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] It is connected, Each -Cy- independently has 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and is an optionally substituted 3 to 6-membered divalent saturated, partially unsaturated, or aromatic ring. Each R is independently either hydrogen or C 1-6 Aliphatic, 3-8 member saturated or partially unsaturated monocyclic carbocycles, phenyl, 8-10 member bicyclic aromatic carbocycles, 4-8 member saturated or partially unsaturated monocyclic heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 5-6 member monocyclic heteroaromatic rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 8-10 member bicyclic heterocycles having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. A group that is selected from the aromatic ring and can be optionally substituted. Each R 4 and R 5C is independently a 5-6 member monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from hydrogen, deuterium, halogens, -CN, -OR, -NR2, -SR, 3-8 member saturated or partially unsaturated monocyclic carbocarriates, 4-8 member saturated or partially unsaturated monocyclic heterocycles having 1-2 heteroatoms independently selected from phenyl, nitrogen, oxygen, or sulfur, or optionally substituted with a 5-6 member monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from -CN, -OR, -NR2, -SR, 3-8 member saturated or partially unsaturated monocyclic carbocarriates, 4-8 member saturated or partially unsaturated monocyclic heterocycles having 1-2 heteroatoms independently selected from phenyl, nitrogen, oxygen, or sulfur, 1-6 Aliphatic group (or the C 1-6 The aliphatic atom is optionally substituted with 1, 2, 3, 4, 5, or 6 deutherium or halogen atoms, or R bonded to the same carbon atom 4 or R 5 These two occurrences, together with the carbon atoms bonded to them, form a 3-6 member spirocyclic saturated monocyclic carbocyclic ring, or a 3-6 member spirocyclic saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. -M- is a self-destructing group, n is between 0 and 18. Each m is independent and ranges from 0 to 6.

[0437] [ka]

[0438] However, the therapeutic agent is selected from natural or unnatural pregnane neurosteroids, their analogues, or prodrugs.

[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 0-12, 0-10, 0-8, or 0-6, or 1-12, 1-10, 1-8, or 1-6, or 2-12, 2-10, 2-8, or 2-6, or 0-4. 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 2-12.

[0452] In some embodiments, -M- is

[0453] [ka]

[0454] In some embodiments, -M- is

[0455] [ka]

[0456] That is the case. In some embodiments, -M- is

[0457] [ka]

[0458] That is the case. 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 side of the above embodiment of -M- is, for example,

[0465] [ka]

[0466] Of the available oxygen atoms,

[0467] [ka]

[0468] It is connected. 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 side of the above embodiment of -M- is, for example,

[0475] [ka]

[0476] Of the available oxygen atoms,

[0477] [ka]

[0478] It is connected. In some embodiments, R 4 One example of its appearance is hydrogen, and R 5 One example of its appearance is hydrogen. In some embodiments, each R 4 and R 5 C is independently hydrogen, deuterium, halogen, -CN, or -OR, or optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms. 1-6 It is an aliphatic.

[0479] In some embodiments, R 4 or R 5 One example of its appearance is C 1-3 C such as alkyl 1-6 Alkyl, for example, methyl. In some embodiments, R 4 and R 5 The two occurrences of C are, independently of each other, 1-3 C such as alkyl 1-6 Alkyl compounds, for example, methyl compounds.

[0480] In some embodiments, -M- is present. In some embodiments, -M- is present, and R 4 or R 5 At least one of them is not hydrogen. In some embodiments, -M- is present, and R 4 or R5 At least one of them is C 1-3 C such as alkyl 1-6 Alkyl, for example, methyl. In some embodiments, -M- is present, and R 4 and R 5 At least two occurrences of C are independent of each other. 1-3 C such as alkyl 1-6 Alkyl compounds, for example, methyl compounds.

[0481] In some embodiments, -M- is absent. In some embodiments, -M- is absent, and R 4 or R 5 At least one of them is not hydrogen. In some embodiments, -M- is absent, and R 4 or R 5 At least one of them is C 1-3 C such as alkyl 1-6 Alkyl, for example, methyl. In some embodiments, -M- is absent, and R 4 and R 5 At least two occurrences of C are independent of each other. 1-3 C such as alkyl 1-6 Alkyl, for example, methyl. In some embodiments, R 4 Two examples of its appearance, R 5 Two examples of its appearance, or R 4 One example of its appearance and R 5 There is one instance of this occurring, and each R 4 and R 5 C is independently and optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms. 1-3 C such as alkyl 1-6 Selected from alkyl groups (e.g., methyl).

[0482] In some embodiments,

[0483] [ka]

[0484] This is allopregnanolone. In some embodiments,

[0485] [ka]

[0486] It is isoalopregnanolone. In some embodiments, L is

[0487] [ka]

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

[0489] [ka]

[0490] It is coupled with -M-,

[0491] [ka]

[0492] And, In the formula, each R 6 These independently become hydrogen, deutherium, and C 1-10 Selected from aliphatic, halogen, or -CN, Each R 7Independently, hydrogen, deuterium, halogens, -CN, -OR, -NR2, -NO2, -SR, 3-8 member saturated or partially unsaturated monocyclic carbon rings, phenyl, 8-10 member bicyclic aromatic carbon rings, 4-8 member saturated or partially unsaturated monocyclic heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 5-6 member monocyclic heteroaromatic rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 8-10 member bicyclic rings having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. A heteroaromatic ring, or a 3- to 8-membered saturated or partially unsaturated monocyclic heterocycle, phenyl, an 8- to 10-membered bicyclic aromatic heterocycle, a 4- to 8-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 an 8- to 10-membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which can be optionally substituted with C 1-6 Aliphatic group (or the C 1-6 The aliphatic atom is optionally substituted with 1, 2, 3, 4, 5, or 6 deutherium or halogen atoms. each Z 1 These are independently selected from -O-, -NR-, or -S-, each Z 2 These are independently selected from -O-, -NR-, -S-, -OC(O)-, -NRC(O)O-, or -OC(O)NR-, each Z 3 These are independent of =N- or =C(R 7 )- Selected from, each Z 4 These are independent of -O-, -NR-, -S-, and -C(R 6 )2-, or covalent bond They are selected.

[0493] In some embodiments, -M- is

[0494] [ka]

[0495] That is the case. In another aspect, equation XV:

[0496] [ka]

[0497] Compounds of or pharmaceutically acceptable salts thereof are provided herein, in which, R 1 and R 2 Each of these is independently a fatty acid. Each R 4 C is independently hydrogen, deuterium, halogen, -CN, or optionally substituted with halogen, -CN, -OR, -NR2, or -SR. 1-6 It is an aliphatic group, -M- is,

[0498] [ka]

[0499] That is the case. In some embodiments of formula XV, R 1 and R 2 Each of them is a heptanoic acid. In some embodiments of formula XV, R 1 and R 2 Each of them is octanoic acid. In some embodiments of formula XV, R 1 and R 2 Each of these is a nonanoic acid.

[0500] In some embodiments of formula XV, each R 4 is hydrogen. In some embodiments of formula XV, each R 4 It 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] That is the case. In one embodiment, the present invention provides lipid prodrug compounds as 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 illustrated in Table 1 above, wherein one or both of the fatty acids illustrated above (R of the formula illustrated herein) 1 and R 2 At this position, it is independently replaced by another fatty acid.

[0525] Lipids, including fatty acids, phospholipids, lipid processing mimetic, and mixtures thereof, for use in the disclosed lipid prodrugs. The lipid prodrugs disclosed herein mimic lipid processing that occurs in the human body.

[0526] Various lipids are suitable for use in the lipid prodrugs of this disclosure. In some embodiments, the lipid prodrug comprises a fatty acid, phosphatide, phospholipid, or analogue thereof (e.g., phophatidylcholine, lecithin, phosphatidylethanolamine, kephalin, or phosphatidylserine, or analogues or portions thereof, e.g., partially hydrolyzed portions thereof), or other lipid processing mimics (e.g., groups that are cleaved in a GI tube by lipase, other digestive enzymes, or other mechanisms, 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 ω These are polyunsaturated fatty acids such as omega-3 or omega-6 fatty acids. In some embodiments, the lipids, for example, fatty acids are C2-C 60 It has a chain. In some embodiments, the lipid, for example, a fatty acid, is C2-C 28 It has a chain. In some embodiments, the lipid, for example, a fatty acid, is C2-C 40 It has a chain. In some embodiments, the lipid, for example, a fatty acid, is C2-C 12Or C4~C 12 It has a chain. In some embodiments, the lipid, for example, fatty acid, is C4-C 40 It has a chain. In some embodiments, the lipid, for example, fatty acid, is C4-C 40 , C2~C 38 , C2~C 36 , C2~C 34 , C2~C 32 , C2~C 30 , C4~C 30 , C2~C 28 , C4~C 28 , C2~C 26 , C4~C 26 , C2~C 24 , C4~C 24 , C6~C 24 , C8~C 24 , C 10 ~C 24 , C2~C 22 , C4~C 22 , C6~C 22 , C8~C 22 , C 10 ~C 22 , C2~C 20 , C4~C 20 , C6~C 20 , C8~C 20 , C 10 ~C 20 , C2~C 18 , C4~C 18 , C6~C 18 , C8~C 18 , C 10 ~C 18 , C 12 ~C 18 , C 14 ~C 18 , C 16 ~C 18 , C2~C 16 , C4~C 16 , C6~C 16 , C8~C 16 , C 10 ~C 16 , C 12 ~C 16 , C 14 ~C 16 , C2~C 15 , C4~C 15 , C6~C15 , C8 - C 15 , C9 - C 15 , C 10 - C 15 , C 11 - C 15 , C 12 - C 15 , C 13 - C 15 , C2 - C 14 , C4 - C 14 , C6 - C 14 , C8 - C 14 , C9 - C 14 , C 10 - C 14 , C 11 - C 14 , C 12 - C 14 , C2 - C 13 , C4 - C 13 , C6 - C 13 , C7 - C 13 , C8 - C 13 , C9 - C 13 , C 10 - C 13 , C 10 - C 13 , C 11 - C 13 , C2 - C 12 , C4 - C 12 , C6 - C 12 , C7 - C 12 , C8 - C 12 , C9 - C 12 , C 10 - C 12 , C2 - C 11 , C4 - C 11 , C6 - C 11 , C7 - C 11 , C8 - C 11 , C9 - C 11 , C2 - C 10 , C4 - C 10 , C2 - C9, C4 - C9, C2 - C8, C4 - C8, C2 - C7, C4 - C7, C2 - C6, or has a C4 - C6 chain. 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 , C14 , 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 It has a chain. 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-mentioned ranges or numbers of carbon atoms. In some embodiments, one of the fatty acids is independently C6-C 21 It is a fatty acid with a chain, one of which is independently C 12 ~C 36 These are fatty acids having a chain. 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. In some embodiments, the two lipids, for example, fatty acids, together have 6 to 80 carbon atoms (6 to 80 equivalent carbon numbers (ECN)). In some embodiments, the lipids, for example, fatty acids, are 6-80, 8-80, 10-80, 12-80, 14-80, 16-80, 18-80, 20-80, 22-80, 24-80, 26-80, 28-80, 30-80, 4-76, 6-76, 8-76, 10-76, 12-76, 14-76, 16-76, 18-76, 20-76, 22-76, 24-76, 26-76, 28-76, 30-76, 6-72, 8-72, 10-72, 12-72, 14-72, 16-72, 18-72, 20-72, 22-72, 24-72, 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, 8-4 8, 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, 6~40, 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, 1 It has ECNs of 8-36, 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-chain 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 with an even number of carbon atoms, such as butyric acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, hexacosanic acid, octacosanic acid, triacontanoic acid, and n-dotriacontanoic acid, as well as those with an odd number of carbon atoms, such as propionic acid, n-valeric acid, enanthic acid, pelargonic acid, hendecanoic acid, tridecanoic acid, pentadecanoic acid, heptadecanoic acid, nonadecanoic acid, heneicosanic acid, tricosanic acid, pentacosanoic acid, and heptacosanoic acid.

[0530] Suitable examples of saturated branched fatty acids include isobutyric acid, isocaproic acid, isocaprylic acid, isocapric acid, isolauric acid, 11-methyldodecanoic acid, isomyristateic acid, 13-methyltetradecanoic acid, isopalmitic acid, 15-methylhexadecanoic acid, isostearic acid, 17-methyloctadecanoic acid, isoarachinic 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 fineoxocol 1800 acid (a product of Nissan Chemical Industries, Ltd.). Suitable saturated odd-carbon branched fatty acids include anteiso fatty acids terminated with an isobutyl group, 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, and 6 Examples include 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, and 4,7,10,13,16,19-docosahexaenoic acid.

[0532] Suitable examples of hydroxy fatty acids include α-hydroxylauric acid, α-hydroxymyristic acid, α-hydroxypalmitic acid, α-hydroxystearic acid, ω-hydroxylauric acid, α-hydroxyarachinic acid, 9-hydroxy-12-octadecenoic acid, ricinoleic acid, α-hydroxybehenic acid, 9-hydroxy-trans-10,12-octadecadienoic acid, kamolenic acid, iprophosphate, 9,10-dihydroxystearic acid, and 12-hydroxystearic acid.

[0533] Suitable examples of polycarboxylic acids include oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, and D,L-malic acid.

[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, henicosyl acid, behenic acid, tricosylic acid, lignoceric acid, pentacosylic acid, cerotic acid, heptacosyl acid, montanic acid, nonacosyl acid, melissic acid, henatriconcylic acid, lacceroic acid, psyllic acid, geddic acid, ceroplastic acid, hexatriaconcylic acid, heptatriacontanoic acid, or octatricontanoic acid.

[0535] In some embodiments, each fatty acid is independently selected from alpha-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, pauric acid, oleic acid, elaidic acid, gondouic acid, erucic acid, nervonic acid, meadic acid, adrenaline, boseopentaenoic acid, ozubondoic acid, sardine acid, herringic 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. The therapeutic benefits of the disclosed lipid prodrug may be increased by including such fatty acids in the lipid prodrug, taking into account the beneficial health effects of certain essential fatty acids. In some embodiments, the essential fatty acids are n-6 or n-3 essential fatty acids selected from the group consisting of linolenic acid, gamma-linolenic acid, dihomo-gamma-linolenic acid, arachidonic acid, adrenaline, docosapentaenoic acid, alpha-linolenic acid, stearidonic acid, 20:4n-3 acid, eicosapentaenoic acid, docosapentaenoic acid, or docosahexaenoic acid.

[0537] In some embodiments, each fatty acid is independently selected from whole-cis-7,10,13-hexadecatrienoic acid, alpha-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 7,10,13-hexadecatrienoic acid, alpha-linolenic acid (ALA or 9,12,15-octadecatrienoic acid), stearidonic acid (STD or 6,9,12,15-octadecatetetraenoic acid), eicosatrienoic acid (ETE or 11,14,17-eicosatrienoic acid), eicosatetraenoic acid (ETA or 8,11,14,17-eicosatetraenoic acid), eicosapentaenoic acid (EPA), and docosapentaenoic acid (DPA, clupanodonic acid or 7,10,13,16,19-docosapentaenoic acid). Examples include tetracosapentaenoic acid (DHA or fully cis-4,7,10,13,16,19-docosahexaenoic acid), tetracosapentaenoic acid (fully cis-9,12,15,18,21-docosahexaenoic acid), or tetracosahexaenoic acid (nisinic acid or fully 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 greatly in length and can be classified according to their length, for example, from short chains to very long chains.

[0539] Short-chain fatty acids (SCFAs) are fatty acids having approximately five or fewer carbon atoms (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 approximately 6 to 12 carbon atoms 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 approximately 13 to 21 carbon atoms. 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 approximately 22 or more carbon atoms, for example, 22-60, 22-50, or 22-40 carbon atoms. 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 the other is independently an LCFA.

[0544] Therapeutic agents and exemplary related diseases The present invention allows various therapeutic agents to be covalently conjugated to lymphoid-directed lipids, such as triglyceride backbones, as described herein. In some embodiments, by conjugating a therapeutic agent to a lymphoid-directed lipid, the present invention provides improvements to desirable properties of the therapeutic agent, such as improved oral bioavailability, minimization of drug degradation in the intestines, avoidance of the first-pass effect in the liver, improved delivery of the therapeutic agent to target tissues, or increased solubility and stability of the therapeutic agent (including 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] Generally, neurotransmitters regulate ion conductance across the entire neuronal membrane. Gamma-aminobutyric acid (GABA) significantly influences overall neuronal excitability by regulating chloride ion conductance via the GABA receptor-chloride ionophore complex (GR). As intracellular chloride levels increase, neurons become hyperpolarized and less susceptible to excitatory input. It is well known that the GR complex mediates anxiety, seizure activity, and sedative effects through this mechanism.

[0547] Certain endogenous steroids, such as metabolites of progesterone with reduced A ring, act as selective allosteric modulators of the GR complex without the activity of classical steroid hormones. In particular, allopregnanolone (3α-hydroxy-5α-pregnane- Pregnane neurosteroids such as 20-one and allotetrahydrodeoxycorticosterone (5α,3α-THDOC) act as potent positive allosteric modulators of GR, providing anxiolytic (Bitran, D. et al. J. Neuroendocrinol 7(3):171-7(1995)) and anti-conflict (Perche, F. et al.) effects. Al. Aggress Behav 27(2):130-8 (2001)), antiseizure (Frye, CABrain Res. 643(1-2):194-203 (1995)), antinociceptive (Wiebe, JP & Kavaliers, M. Brain Res. 461(1):150-7 (1988)), and neuroprotective effects. Furthermore, the antidepressant effects of allopregnans are well-established in animal models (e.g., Frye, CA & Walf, AAHorm 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 therapy 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,R et al. Front.Cell.Neurosci.8:203.doi:10.3389 / fncel.2014.00203).

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

[0549] In some embodiments, the disclosed lipid prodrugs include neurotropic steroids such as allopregnanolone, pregnanolone, pregnenolone, 3β-dihydroprogesterone, isopregnanolone, epipregnanolonone, and 21-hydroxyalopregnanolone, or therapeutic agents selected from others disclosed herein. In some embodiments, the neurotropic steroid is selected from allopregnanolone or 21-hydroxyalopregnanolone.

[0550] The compounds disclosed herein can be used, for example, to treat postpartum depression (Osborne, L. et al. Psychoneuroendocrinology 79:116-21 (2017)), depression (Almeida, F. et al. Neurobiology of Stress 12 (2020) 100218, Melon, L. et al.). al. Front. Endocrinol. 9:703. (2018), Almeida, FB 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, LD et al. Nat. Med. 10(7):704-11 (2004)), status epilepticus (Rogawski, MA et al. Epilepsy 54(s6):93-8 (2013)), Alzheimer's disease, Parkinson's disease, multiple sclerosis, Niemann-Pick type C, fragile X-associated tremor / ataxia syndrome, diabetic neuropathy, seizures (Kaminski, RMet al.Epilepsia,45(7):864-867,(2004)) or traumatic brain injury (Irwin,RWet al.Front.Cell.Neurosci.8:203.doi:10.3389 / fncel.2014.00203, Irwin,RW& Brinton,RDProg.Neuobiol 113:40-55(2014 It can treat a variety of diseases, including )), or one or more symptoms thereof. In some embodiments, methods for treating neurological disorders or conditions, such as postpartum depression, depression, anxiety, Niemann-Pick disease, status epilepticus, Alzheimer's disease, Parkinson's disease, multiple sclerosis, Niemann-Pick type C, fragile X-associated tremor / ataxia syndrome, diabetic neuropathy, seizures, or traumatic brain injury are provided herein, the methods comprising administering the compounds of the present invention to a subject in need thereof.

[0551] In other embodiments, the present invention provides a method for treating or preventing a disease, disorder, or condition in which an increase in the level 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 allopregnanolone deficiency, the method comprising administering an effective amount of the disclosed lipid prodrug to a subject in need thereof.

[0552] In some embodiments, the present invention is GABA A The present invention provides a method for treating a related disease, disorder, or condition, the method comprising administering an effective amount of the disclosed lipid prodrug to a subject in need thereof.

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

[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, amnesia, low stress tolerance, Niemann-Pick disease type C or associated neurological or somatic symptoms, epilepsy, essential tremor, epileptic-like disorder, NMDA dysfunction, migraine, status epilepticus, sleep disorders such as insomnia, fragile X syndrome, depression induced by another drug (such as finasteride or another 5-alpha reductase inhibitor), PCDH19 girl epilepsy, sexual dysfunction, Parkinson's disease, or Alzheimer's disease. In some embodiments, status epilepticus is extremely refractory status epilepticus (SRSE), which is 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, epileptic-like disorder, NMDA dysfunction, status epilepticus, Parkinson's disease, or Alzheimer's disease. In some embodiments, status epilepticus is extremely refractory status epilepticus (SRSE), which is a severe form of uncontrolled seizures.

[0556] In some embodiments, the present invention provides a method for treating depressive mood disorders (e.g., major depressive disorder, bipolar disorder, seasonal affective disorder (SAD), cyclothymic disorder, premenstrual dysphoric disorder, persistent depressive disorder, severe mood dysregulation, depression associated with a medical condition, postpartum depression) and / or anxiety disorders (e.g., panic disorder and post-traumatic stress disorder), the method comprising administering a disclosed lipid prodrug to a subject in need thereof.

[0557] In some embodiments, the present invention provides a method for treating multiple sclerosis, traumatic brain injury, ischemia, stroke, peripheral neuropathy, neuropathic pain, spinal cord injury, or non-REM sleep disorders associated with Alzheimer's disease (AD) or Parkinson's disease (PD), the method comprising administering a disclosed lipid prodrug to a subject in need thereof. For example, B Please refer to iol 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 a disclosed lipid prodrug to a subject in need thereof. In some embodiments, the subject has AD or PD. See, for example, 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, prexanolone, SAGE-547) is currently under investigation as a treatment for postpartum depression (NCT2614547, Kanes, S. et al.). al.Lancet 390(10093):480-9(2017)).

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

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

[0562] In some embodiments, the present invention provides a method for 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 adrenospinal neuropathy, 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 a method for treating lysosomal storage disorders in subjects, the method comprising administering a disclosed lipid prodrug to a subject in need thereof. In some embodiments, lysosomal storage disorders include Faber disease, Krabbe disease, Fabry disease, Schindler disease, GM1 gangliosidosis, GM2 gangliosidosis, Tay-Sachs disease, Sandhoff disease, Gaucher disease, lysosomal acid lipase deficiency, Niemann-Pick disease, sulfatidosis, metachromatic leukodystrophy, Hurler syndrome, and Sharton The following conditions are selected: Ye syndrome, Haller-Schey syndrome, Hunter syndrome, Sanfilippo syndrome, Morquio syndrome, Maloto-Lamy syndrome, Sly syndrome, hyaluronidase deficiency, sialidosis, Icel disease, phosphotransferase deficiency, mucolipidine 1 deficiency, neuronal ceroid lipofuscinosis, Wolmann disease, alpha-mannose disease, beta-mannose disease, aspartylglucosamiuria, fucoside disease, cystinosis, concentrated dysostosis, Salah disease, childhood free sialic acid storage, Pompe disease, Danon disease, cholesteryl ester storage, and lysosomal storage diseases.

[0564] In some embodiments, the present invention provides a method for treating a neurological disorder in a subject, the method comprising administering a disclosed lipid prodrug to a subject in need thereof. In some embodiments, the neurological disorder is Angelman syndrome, Rett syndrome, Dravet syndrome, Lennox-Gastaut syndrome, or catamenial epilepsy. In some embodiments, the neurological disorder is Angelman syndrome, Rett syndrome, or Dravet syndrome. In some embodiments, the neurological 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 a disclosed lipid prodrug to a subject in need thereof. In some embodiments, the sleep disorder is secondary to rheumatoid arthritis. In some embodiments, the sleep disorder is obstructive sleep apnea, insomnia, or restless leg syndrome.

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

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

[0568] In some embodiments, the therapeutic agent is ganaxolone or allopregnanolone. 2.Definition The terms used herein will be readily understood by those skilled in the art, but their definitions are provided herein for the convenience of explaining the subject matter of this disclosure.

[0569] When used herein, the term “approximately” 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 include variations from the specified value or range, for example, ±20%, ±10% in some embodiments, ±5% in some embodiments, ±1% in some embodiments, ±0.5% in some embodiments, and ±0.1% in some embodiments.

[0570] As used herein, the terms “treatment,” “to treat,” and “to treat” mean restoring, alleviating, delaying the onset of, or halting the progression of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment may be administered after the onset of one or more symptoms. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to an susceptible individual before the onset of symptoms (e.g., in light of a medical history of the symptoms and / or in light of genetic factors or other susceptibility factors). Treatment may also be continued after the symptoms have disappeared, for example, to prevent or delay their recurrence.

[0571] As used herein, the term “lipid” refers to natural and non-natural hydrophobic and / or lipophilic fats, oils, polymers, hydrocarbons, and other such materials. In some embodiments, when incorporated into a lipid prodrug, suitable lipids are triglycerides in the GI tube. They are processed or metabolized in a similar manner, or they mimic such processing or metabolism. The term "glyceride" refers to an ester of glycerol (1,2,3-propanetriol) with an acyl radical of a fatty acid or other lipid, also known as an acylglycerol. If only one position of the glycerol molecule is esterified with a fatty acid, a "monoglyceride" is produced; if two positions are esterified, a "diglyceride" is produced; and if all three positions of glycerol are esterified with fatty acids, a "triglyceride" or "triacylglycerol" is produced. Glycerides are called "simple" if all esterification positions involve the same fatty acid, or "mixed" if different fatty acids are involved. The carbon atoms of the glycerol skeleton are denoted as sn-1, sn-2, and sn-3, with sn-2 being in the center of glycerol and sn-1 and sn-3 at the ends.

[0572] Natural oils and fats consist primarily of triglycerides, where three fatty acyl residues may or may not be identical. The term "long-chain triglycerides" (or "LCTs") refers to both simple and mixed triglycerides containing fatty acids with more than 12 carbon atoms (long-chain fatty acids, "LCFAs"), while the term "medium-chain triglycerides" (or "MCTs") refers to both simple and mixed triglycerides containing fatty acids with 4 to 12 carbon atoms.

[0573] The term "ECN" or "carbon equivalent" refers to the total number of carbon atoms in the acyl chain of a glyceride molecule. For example, tripalmitine (tripalmitineglycerol), a simple triglyceride containing three acyl radicals with 16 carbon atoms each, has an ECN of 3 × 16 = 48. Conversely, triglycerides with an ECN of 40 may have "mixed" acyl chain lengths such as 8, 16, and 16; 10, 14, and 16; 8, 14, and 18. Natural oils are often "mixed" with respect to certain fatty acids, but tend not to contain LCFAs and MCFAs on the same glycerol backbone. Therefore, triacylglycerols with an ECN of 24-30 typically contain predominantly medium-chain fatty acids, while triacylglycerols with an ECN greater than 43 typically contain predominantly long-chain fatty acids. Triacylglycerols with an ECN of 32–42 typically contain one or two MCFAs in combination with one or two LCFAs to "fill" the triglycerides. Triacylglycerols in the ECN range of over 30 and under 48 typically represent mixed triacylglycerol species that are absent in physical mixtures or present at significantly lower concentrations. Fatty acids present in food usually contain an even number of carbon atoms in their unbranched chains (e.g., lauric acid or dodecanoic acid).

[0574] As used herein, the term "self-destructing group" refers to a divalent chemical moiety that includes a readily cleavable covalent bond as one of its divalent bonds and a stable covalent bond with the therapeutic agent as the other divalent bond, where the bond with the therapeutic agent becomes unstable when the readily cleavable bond is broken. Examples of self-destructing groups include, but are not limited to, disulfide groups, hydrazones, acetal self-destructing groups, carboxyacetal self-destructing groups, carboxy(methylacetal) self-destructing groups, para-hydroxybenzylcarbonyl self-destructing groups, inverted ester self-destructing groups, and trimethyllock or 2-hydroxyphenylcarbamate (2-HPC) self-destructing groups. Several other suitable self-destructing groups are known in the art, for example, CABlencowe 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, MNet al. Such as those described in 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 drug,” “active agent,” or “drug” include any therapeutic agent or imaging (contrast) agent for which transport via the enterolymphatic system would be beneficial, for example, to enable oral administration (e.g., a therapeutic agent administered intravenously), to avoid first-pass metabolism, to avoid hepatotoxicity or other toxicity, or for targeted delivery within the lymphatic system.

[0576] The lipid prodrug compounds of the present invention include those described herein in general terms and are further illustrated by the classes, subclasses, and types disclosed herein. When used herein, unless otherwise specified, the following definitions apply. For the purposes of the present invention, chemical elements refer to the periodic table, CAS edition (Handbook of Chemistry and Physics, 98 th The general principles of organic chemistry are identified according to the Ed. 5. Additionally, the general principles of organic chemistry are found in “Organic Chemistry,” Thomas Sorrell, University Science Books, Sausalito: 1999, and “March's Advanced Organic Chemistry,” 5. th This work is described in Ed., Ed.: Smith, MB and March, J., John Wiley & Sons, New York: 2001, and the entire contents of that document are incorporated herein by reference.

[0577] As used herein, the terms “aliphatic” or “aliphatic group” mean a linear (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain having a single bond site to the rest of the molecule and containing one or more fully saturated or unsaturated units, or a monocyclic or bicyclic hydrocarbon that is fully saturated or contains one or more unsaturated units but is not aromatic (also referred herein as “carbocyclic compound,” “cyclic aliphatic,” or “cycloalkyl”). Unless otherwise specified, an aliphatic group contains 1 to 6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1 to 5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1 to 4 aliphatic carbon atoms. Still in other embodiments, an aliphatic group contains 1 to 3 aliphatic carbon atoms, and still in other embodiments, an aliphatic group contains 1 to 2 aliphatic carbon atoms. In some embodiments, “cyclic aliphatic” (or “carbocyclic compound” or “cycloalkyl”) refers to a monocyclic C3-C6 hydrocarbon that is not aromatic, is fully saturated or contains one or more unsaturated units, and has a single bond site to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl groups, alkenyl groups, 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., a carbocyclic or heterocyclic ring that is saturated or has one or more unsaturated units and has one or more atoms common between the two rings of the ring system. Thus, the term includes any acceptable ring condensation, such as ortho condensation or spirocyclic rings. As used herein, the term “hetero-bicyclic” is a subset of “bicyclic” that requires the presence of one or more heteroatoms in one or both of the rings. Such heteroatoms may be present at the ring junction, are optionally substituted, and can be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidation forms such as sulfones and sulfonates), phosphorus (including oxidation forms such as phosphonates and phosphates), boron, etc. In some embodiments, the bicyclic group has 7 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In this context, 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(s) connecting two bridgeheads, where “bridgehead” is any skeletal atom of a ring system 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 bonded to the rest of the molecule by any substituteable carbon or nitrogen atom. Unless otherwise specified, bridged bicyclic groups are optionally substituted with one or more substituents, as described for aliphatic groups. Additionally or alternatively, any substituteable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary biringual rings include the following:

[0579] [ka]

[0580] Exemplary cross-linked bicyclic compounds include the following:

[0581] [ka]

[0582] The term "lower alkyl" is C 1-4 This refers to linear or branched alkyl groups. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, and isobutyl alkyl groups. And tert-butyl.

[0583] The term "lower haloalkyl" refers to a carbon atom substituted with one or more halogen atoms. 1-4 This refers to linear or branched alkyl groups.

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

[0585] As used herein, the term “unsaturated” means that a part has one or more unsaturated units.

[0586] When used herein, "divalent C" 1-8 (or C 1-6 The term “saturated or unsaturated, linear or branched hydrocarbon chain” refers to a linear or branched divalent alkylene, alkenylene, and alkylene chain 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 1-6, 1-4, 1-3, 1-2, or 2-3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced by substituents. Preferred substituents include those listed 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 by substituents. Preferred substituents include the substituted aliphatic groups listed below.

[0589] The term "halogen" refers to F, Cl, Br, or I. The term "aryl," used alone or as part of a larger phrase such as "aralkyl," "aralkoxy," or "aryloxyalkyl," refers to a monocyclic or bicyclic ring system having a total of 5 to 14 ring members, wherein 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, etc., which may have one or more substituents. Groups in which an aromatic ring is condensed with one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthoimidyl, phenantridinyl, or tetrahydronaphthyl, are also included within the scope of the term "aryl" as used herein.

[0590] The terms "heteroaryl" and "heteroar-" used alone or as part of a larger phrase, 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 π 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, including any oxidized form of nitrogen or sulfur, and any quaternized form of basic nitrogen. Heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, and thiazolyl. This includes diazolyl, pyridyl, pyridadinyl, pyrimidinyl, pyrazinyl, indolidinyl, prinyl, naphthilidinyl, and pteridinyl. As used herein, the terms “heteroaryl” and “hetero-” also include groups in which a heteroaromatic ring is condensed to one or more aryl, cyclic aliphatic, or heterocyclyl rings, and the radical or bond site is located on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolidinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazine-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 may include optionally substituted rings. The term "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl group, where the alkyl and heteroaryl portions are substituted independently and at will.

[0591] As used herein, the terms “heterocyclic compound,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic” are interchangeable and refer to a stable 5- to 7-membered monocyclic heterocyclic moiety or a 7- to 10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated and has one or more, preferably 1 to 4, heteroatoms as defined above, in addition to the carbon atom. As used with respect to the ring atoms of a heterocyclic compound, the term “nitrogen” includes substituted nitrogen. For example, in a saturated or partially unsaturated ring having 0 to 3 heteroatoms selected from oxygen, sulfur, or nitrogen, nitrogen may be N (such as in 3,4-dihydro-2H-pyrrolyl), NH (such as in pyrrolidinyl), or + It may also be an NR (similar to those found in N-substituted pyrrolidinyls).

[0592] Heterocyclic radicals can be bonded to their pendant group by any heteroatom or carbon atom, thereby resulting 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, trahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms “heterocyclic compound,” “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 rings, heteroaryl rings, or cyclic aliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenantridinyl, or tetrahydroquinolinyl. The heterocyclyl group may be monocyclic or bicyclic. The term “heterocyclylalkyl” refers to an alkyl group substituted with a heterocyclyl, where the alkyl moiety and the heterocyclyl moiety are optionally substituted independently.

[0593] As used herein, the term “partially unsaturated” refers to a ring moiety containing at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple unsaturated moies, but not to include aryl or heteroaryl moies as defined herein.

[0594] When described herein, the compounds of the present invention may contain a “optionally substituted” portion. Generally, the term “substituted” is preceded by the term “optionally.” Whether or not, it means that one or more hydrogens of the specified portion are replaced with suitable substituents. Unless otherwise specified, a “optionally substituted” group may have suitable substituents at each of its substituted positions, and if more than one position in any given structure can be replaced by more than one substituent selected from the specified group, the substituents may be the same or different at all positions. The substituent combinations envisioned by the present invention preferably result in the formation of stable or chemically feasible compounds. As used herein, “stable” means a compound that remains substantially unchanged when subjected to conditions that enable their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0595] Each optionally substituted substituent on the carbon is a 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 (this may be substituted with R°), -(CH2) 0-4 O(CH2) 0-1Ph (this may be substituted with R°), -CH=CHPh (this 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 alkylenes) ON(R°)2, or -(C 1-4It is a monovalent substituent independently selected from linear or branched alkylene (C(O)ON(R°)2).

[0596] Each R° independently corresponds to hydrogen, C 1-6 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, -CH2- (a 5-6 member heteroaryl ring), or a 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the above definition, two independent examples of R° together with their intervening atoms(s) to form a 3-12 member saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur (this may be substituted on the saturated carbon atom of R° with a divalent substituent selected from =O and =S), or each R° is a halogen, -(CH2) 0-2 R ● ,-(HaroR ● ), -(CH2) 0-2 OH, -(CH2) 0-2 Ure ● ,-(CH2) 0-2 CH(OR ● )2, -O(HaroR ● ), -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 ● It is optionally substituted with a monovalent substituent that is independently selected from it.

[0597] Each R ● C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 A 5-6 member saturated ring, partially unsaturated ring, or aryl ring having 0-4 heteroatoms independently selected from Ph, nitrogen, oxygen, or sulfur, where each R ● However, if unsubstituted, or if preceded by a halo, it may be substituted with only one or more halogens, or the optional substituent on the saturated carbon may be =O, =S, =NNR * 2. =NNHC(O)R * ,=NNHC(O)OR * ,=NNHS(O)2R * ,=NR * 、=NOR * , -O(C(R * 2)) 2-3 O-, or -S(C(R * 2)) 2-3 A divalent substituent that is independently selected from S-, or a divalent substituent bonded to a vicinalally substituted carbon of the "optionally substituted" group, is -O(CR * 2) 2-3 O-, and in the formula, R * Each of these is an independent example of existence: hydrogen, C 1-6 The rings are selected from aliphatic, or unsubstituted 5-6 member saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0598] R * C 1-6 If it is aliphatic, R * This is optional, halogen, -R ● ,-(HaroR ● ), -OH, -OR ● ,-O(HaroR ● ), -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● , -NR● 2. or substituted with -NO2, wherein each R ● is independently C 1-4 aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and each R ● is unsubstituted or, when preceded by halo, is substituted with only one or more halogens.

[0599] Optional substituents on replaceable nitrogen are independently -R † , -NR † 2, -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CH2C(O)R † , -S(O)2R † , -S(O)2NR † 2, -C(S)NR † 2, -C(NH)NR † 2, or -N(R † )S(O)2R † , wherein each R † is independently hydrogen, C 1-6 aliphatic, unsubstituted -OPh, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, in the case where two independent occurrences of R † together with their intervening atom(s) form an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and when R † is C 1-6 aliphatic, R † is optionally halogen, -R ● , -(haloR ● ), -OH, -OR ● , -O(haloR ● ), -CN, -C(O)OH, -C(O)OR ●, -NH2, -NHR ● , -NR ● 2, or substituted with -NO2, wherein each R ● is independently C 1-4 aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or selected from a 5- to 6-membered saturated ring, partially unsaturated ring, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and each R ● 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 salts that are suitable for use in contact with the tissues of humans and lower animals within the scope of sound medical judgment, without undue toxicity, irritation, allergic response, etc., and that have 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 suitable inorganic and organic acids and This includes those derived from 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 by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipine, alginate, ascorbate, aspartate, benzenesulfonic acid, benzoate, besilate, bisulfate, borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, and lactobion. This includes salts, lactates, laurates, lauryl sulfates, malates, maleates, malons, methanesulfons, 2-naphthalenesulfons, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectinates, persulfates, 3-phenylpropionates, phosphates, pivalates, propions, stearates, succinates, sulfates, tartrates, thiocyans, p-toluenesulfons, undecanoates, valersates, etc.

[0601] Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N + (C 1-4Alkyl) tetrasalts are included. Typical alkali salts 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, which are formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates, where appropriate.

[0602] Unless otherwise specified, the structures illustrated herein are also intended to include all isomers (e.g., enantiomers, diastereomers, and geometric (or conformational) forms) of that structure, such as the R and S configurations, Z and E double bond isomers, and Z and E conformational isomers for each chiral center. Thus, single stereochemical isomers of the compound, as well as mixtures of enantiomers, diastereomers, and geometric (or conformational) forms, are within the scope of the invention. Unless otherwise specified, all tautomer forms of the compounds of the invention are within the scope of the invention. In addition, unless otherwise specified, the structures illustrated herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms, such as, for example, the substitution of hydrogen with deuterium or tritium, or carbon 13 C concentration or 14 Compounds having the current structure, including those with carbon-enriched carbon substitution, fall within the scope of the present 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 vessel-targeting lipid prodrugs The disclosed lymphatic vessel-directed lipid prodrugs, and pharmaceutically acceptable compositions comprising the disclosed lipid prodrugs with pharmaceutically acceptable excipients, diluents, or carriers, are useful for treating a variety of diseases, disorders, or conditions. Such diseases, disorders, or conditions include those described herein.

[0604] Those skilled in the art will recognize and understand that each of the therapeutic agents described herein is known to be related to the treatment of one or more diseases, disorders, or conditions. Therefore, in certain embodiments, the present invention provides a therapeutic agent to a patient who requires treatment for a disease, disorder, or condition. It will be understood that the present invention provides a method for treating a disease, disorder, or condition, comprising administering a disclosed lipid prodrug to the patient.

[0605] The lipid prodrugs disclosed herein are useful for the stable transport of pharmaceuticals to the intestinal lymphoid and for the release of pharmaceuticals into the lymph, lymphocytes, lymphoid tissues, tissues with high lipase activity (adipose tissue, certain cancers, liver, etc.), or into systemic circulation. The disclosed lipid prodrugs are particularly useful for the transport and release of pharmaceuticals for which avoiding first-pass metabolism is beneficial, such as therapeutic agents that exhibit more than about 50% first-pass metabolism when administered orally. In some embodiments, the therapeutic agent exhibits more than about 60% first-pass metabolism when administered orally. In some embodiments, the therapeutic agent exhibits more than about 70%, 80%, or 90% first-pass metabolism when administered orally.

[0606] Therapeutic agents that may be beneficial to be reliably transported to the intestinal lymphoid and released into the lymph, lymphocytes, lymphoid tissue, tissues with high lipase activity (adipose tissue, certain cancers, liver, etc.), or into systemic circulation include, but are not limited to, therapeutic agents listed herein, such as allopregnanolone, pregnanolone, pregnenolone, 3β-dihydroprogesterone, isopregnanolone, epipregnanolonone, ganaxolone, or 21-hydroxyalopregnanolone.

[0607] The lipid prodrugs of this 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, the therapeutic agents exhibit low lymphatic transport when administered orally. In some embodiments, the therapeutic agents exhibit 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% when administered orally. In contrast, the present invention enables improved lymphatic transport of such therapeutic agents. In some embodiments, the disclosed lipid prodrugs exhibit at least 1%, 5%, 7.5%, 10%, 12.5%, 15%, 20%, 25%, 30%, 35%, 40%, or 50% lymphatic transport when administered orally. In some embodiments, the disclosed lipid prodrugs exhibit approximately 1–50%, 5–40%, 10–30%, 15–25%, or approximately 50%, 40%, 30%, 25%, 20%, 15%, 12.5%, 10%, 7.5%, 5%, 2.5%, or 1% lymphatic transport when administered orally, as measured by comparing the w / w% of the administered lipid prodrug or the w / w% of the therapeutic agent in the lipid prodrug form with 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 pathological condition, the method comprising administering to a subject in need a lipid prodrug comprising an effective amount of a disclosed pregnane neurosteroid therapeutic agent.

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

[0611] Pharmacologically 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 LAG is an effective amount ("effective dose") to treat a patient who requires treatment for the relevant disease, disorder, or condition. In some embodiments, the compositions of this disclosure are 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 impair the pharmacological activity of the drug formulated with it. pharmaceutically acceptable carriers, adjuvants, or vehicles that may be used in the disclosed compositions include, but are not limited to, ion exchangers, stearates such as alumina and aluminum stearate, buffering substances such as lecithin, serum proteins such as human serum albumin and phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium chloride, and zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat. In some embodiments, the compositions are formulated as lipophilic mixtures such as lipid-based compositions.

[0613] The compositions of the present invention may be administered orally, parenterally, enterally, intracisionally, intraperitoneally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implantable reservoir. As used herein, the term “parenteral” includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intrafocal, 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. The sterile injectable formulations 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 dispersants or wetting and suspending agents. The sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic, parenterally acceptable diluents or solvents, for example, as a solution in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterilized fixative oil is conventionally used as a solvent or suspension 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 in the preparation of injectable formulations, as are naturally pharmaceutically acceptable oils such as olive oil or castor oil, particularly 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 in the formulation of 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 in the manufacture of pharmaceutically acceptable solids, liquids, or other dosage forms, may also be used for formulation purposes.

[0615] Pharmacopoeia-acceptable compositions may be administered orally 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 may 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, the active ingredient is combined with emulsifiers and suspending agents. Certain sweeteners, flavorings, or colorants may also be added, if desired. It may be added.

[0616] Alternatively, pharmaceutically acceptable compositions 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, and therefore dissolves in the rectum to release 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 formulation 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 compounds used, age, weight, overall health, sex, diet, administration time, excretion rate, drug combinations, as well as the judgment of the treating physician and the severity of the specific disease being treated.

[0619] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, particulate emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, the liquid dosage form may contain, for example, 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 fragrances. Injectable preparations, such as sterile aqueous or oily suspensions for injection, may be formulated according to known techniques using suitable dispersants or wetting and suspending agents. Sterile injectable preparations may also be sterile injection solutions, suspensions, or emulsions in non-toxic, parenterally acceptable diluents or solvents, such as a solution in 1,3-butanediol. Acceptable vehicles and solvents that may be used include water, Ringer's solution (USP), and isotonic sodium chloride solution. In addition, sterile fixatives are conventionally used as solvents or suspensions. For this purpose, any non-irritating fixative, including synthetic mono or diglycerides, may be used. In addition, fatty acids such as oleic acid are used in the preparation of injectable preparations. Injectable preparations may be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable media before use.

[0620] To extend the effects of the compounds of the present invention, it is often desirable to slow down the absorption of the compounds from subcutaneous or intramuscular injection. This may be accomplished by using a liquid suspension of a crystalline or amorphous material that is poorly soluble in water. Then, the absorption rate of the compound may depend on its dissolution rate, which in turn may depend on the crystal size and crystalline form. Alternatively, the absorption delay of parenterally administered compound forms is accomplished by dissolving or suspending the compound in an oily vehicle. Depot formulations for injection are prepared by forming a microencapsulation matrix of the compound in a biodegradable polymer such as polylactide-polyglycolide. Depending on the compound-to-polymer ratio and the properties of the specific polymer used, the release rate of the compound can be controlled. Other examples of biodegradable polymers include poly(orthoester) and poly(anhydrous). Depot injection formulations are also compatible with body tissues. It can also be prepared by encapsulating the compound in liposomes or microparticle emulsions.

[0621] Compositions for rectal or vaginal administration are preferably suppositories, which can be prepared by mixing the compound of the present invention with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol, or 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 bulking agents such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and acacia; c) humectants such as glycerol; d) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) dissolution retarders such as paraffin; f) absorption enhancers such as quaternary ammonium compounds; g) wetting agents such as 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 glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also include a buffering agent.

[0623] Similar solid compositions may also be used as fillers in flexible and rigid gelatin capsules, using excipients such as lactose, and high molecular weight polyethylene glycol. Solid dosage forms of tablets, sugar-coated tablets, capsules, pills, and granules can be prepared by coatings and outer shells, such as enteric coatings and other coatings well known in the field of pharmaceutical formulation. They may optionally contain opacifiers, and they may be compositions that optionally release the active ingredient(s) only in, or preferentially in, a delayed manner in a specific part of the intestinal tract. Examples of embedding compositions that can be used include polymers and waxes. Similar solid compositions may also be used as fillers in flexible and rigid gelatin capsules, using excipients such as lactose, and high molecular weight polyethylene glycol.

[0624] Therapeutic agents may also be in microencapsulated form with one or more of the excipients described above. Solid dosage forms of tablets, sugar-coated tablets, capsules, pills, and granules may be prepared by coatings and shells such as enteric coatings, controlled-release coatings, and other coatings well known in the field of pharmaceutical formulation. In such solid dosage forms, the active compound may be miscible with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may also contain additional substances other than inert diluents, such as tableting lubricants and other tableting aids, as is common practice, e.g., magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage forms may also contain buffers. These may optionally contain opacifiers and may be compositions that optionally delay the release of the active ingredient(s) only in or preferentially in a particular part of the intestinal tract. Examples of embedding compositions that may 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 mixed under sterile conditions with a pharmaceutically acceptable carrier and, if necessary, any required preservatives or buffers. Ophthalmic formulations, ear drops, and eye drops are also within the scope of the present invention. It is intended to be contained within. Furthermore, the present invention intends to use transdermal patches, which have the additional advantage of providing controlled delivery of the compound to the body. Such dosage forms can be made by dissolving or distributing the active compound in a suitable medium. Absorption enhancers can also be used to increase the flow of the compound across the skin. Its rate can be controlled either by providing a rate control membrane or by dispersing the compound in a polymer matrix or gel.

[0626] In some embodiments, lipid prodrugs are formulated as orally administered lipid-based formulations. Lipid-based formulations for oral delivery are known in the art and may include, for example, substantially non-aqueous vehicles typically containing one or more lipid components. Lipid vehicles and the resulting lipid formulations can be usefully classified according to their shared common characteristics, as described below, 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).

[0627] Lipid vehicles and the resulting lipid formulations may optionally contain oils / lipids and / or surfactants, along with a co-solvent. 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) containing the lipids and oils used in Type I formulations, along with an additional water-insoluble surfactant. Type III formulations are SEDDSs or self-microemulsifying drug delivery systems (SMEDDS) containing the lipids and oils used in Type I formulations, along with an additional water-soluble surfactant and / or co-solvent (Type IIIa) or a higher proportion of water-soluble components (Type IIIb). Type IV formulations primarily contain hydrophilic surfactants and co-solvents (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 formulation (types I-IV) is intended herein for use with the disclosed lipid prodrug or its pharmaceutically acceptable composition.

[0628] In some embodiments, the lipid vehicle contains one or more oils or lipids without additional surfactants, co-surfactants or co-emulsifiers, or co-solvents; that is, 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, and 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, and 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, grape seed 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, and wheat germ oil. Bud 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 glyceride, fractionated triglycerides, glyceryl tricaprate, glyceryl tricaproate, glyceryl tricaprylate, glyceryl tricaprylate, glyceryl tricaprylate / caprate, glyceryl tricaprate / 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, mainly C 8-12 Synthetic medium-chain triglycerides containing fatty acid chains, mainly C 8-12 Medium-chain triglycerides containing fatty acid chains, mainly C 12 Examples include long-chain triglycerides containing extra fatty acid chains, modified triglycerides, fractionated triglycerides, and mixtures thereof.

[0630] Examples of monoglycerides and diglycerides that may 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-l). In some embodiments, the monoglycerides and diglycerides are monosaturated or disaturated fatty acid esters of glycerol having fatty acid chains with a carbon chain length of 8 to 18 carbon atoms (e.g., glyceryl monostearate, glyceryl distearate, glyceryl monocaprylate, glyceryl dicaprylate, glyceryl monocaprate, and glyceryl dicaprate). Mixtures of fatty acids adapted to improve the absorption and transport of lipid-soluble compounds ("structured glycerides") are disclosed, for example, in U.S. Patent No. 6,013,665, which is incorporated herein by reference.

[0631] Suitable surfactants for use in lipid preparations include, but are not limited to, propylene glycol monocaprylic acid, propylene glycol dicaprylic acid, propylene glycol monolauric acid, etc., sold under trademark names such as Capryol® 90, Labrafac® PG, and Lauroglycol® FCC. 8-22 Sugar fatty acid esters, including but not limited to propylene glycol monoesters and diesters of fatty acids, such as sucrose palmitate, sucrose laurate, and sucrose stearate; sorbitan fatty acid esters, including but not limited to sorbitan laurate, sorbitan palmitate, and sorbitan oleate; polyoxyethylene sorbitan fatty acid esters, including but not limited to polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, and polysorbate 85; polyoxyethylene mono-fatty acids and di-fatty acid esters, including but not limited to polyoxyl stearate 40 and polyoxyl oleate 40; C 8-22 Polyoxyethylene monoesters and diesters of fatty acids, and C 8-22 Mixtures of fatty acids with glyceryl monoesters, diesters, and triesters; polyoxyethylene castor oil compounds such as polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, and polyoxyl 60 hydrogenated castor oil, which are marketed under trademark 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 8-22Glyceryl monoesters, diesters, and triesters of fatty acids; sucrose monoesters, diesters, and triesters; sodium dioctyl sulfosuccinate; polyoxyethylene-polyoxypropylene copolymers, such as poloxamer 124, poloxamer 188, and poloxamer 407, but not limited to these; polyoxyethylene, such as those marketed under trademark names such as Brij® 35, Brij® 58, Brij® 78, and Brij® 98. C includes, but is not limited to, lauryl alcohol, polyoxyethylene cetyl alcohol, polyoxyethylene stearyl alcohol, and polyoxyethylene oleyl alcohol. 8-22 It contains polyoxyethylene ethers of fatty alcohols, or any two or more mixtures thereof.

[0632] Coemulsifiers or co-surfactants may be used in the formulation. Suitable coemulsifiers 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 to alter drug release. Various polymers have been shown to impart these properties and are well known to those skilled in the art. Suitable polymers include hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetylsuccinate, other cellulose-derived polymers, e.g., methylcellulose; poly(meth)acrylates, e.g., the Eudragit series of polymers including Eudragit E100, polyvinylpyrrolidone, or others, e.g., as described in Warren et al., Mol. Pharmaceutics 2013, 10, 2823-2848.

[0635] The formulation may be specifically selected to allow for sustained release of the active substance in the gastrointestinal (GI) tract in order to control the absorption rate. These objectives may be achieved using a number of different strategies, including high-melting-point lipids that slowly disperse / erode in the GI tract, or polymers that form a slowly eroding matrix. These formulations may take the form of a large, integrated dosage form, or they may exist as a matrix of microparticles or nanoparticles, as described, for example, 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 materials commonly known to those skilled in the art, including antioxidants such as butylated hydroxyanisole (BHA) or butylated hydroxytoluene (BHT), and solidifying agents such as microporous silica, such as magnesium aluminometasilicate (Neusilin).

[0637] In some embodiments, the lipid prodrug may be orally co-administered with an enzyme inhibitor 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 expected 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 Examples include, but are not limited to, (t).

[0638] Combination therapy The provided lipid prodrug, or any pharmaceutically acceptable composition thereof, may be administered to patients in need in combination with one or more additional therapeutic agents and / or therapeutic processes.

[0639] Lipid prodrugs or pharmaceutically acceptable compositions thereof may be administered alone or in combination with one or more other therapeutic compounds, and possible combination therapies may take the form of a fixed combination of the lipid prodrug or composition with one or more other therapeutic compounds, or administrations given at different times or independently of each other, or combination administration of the fixed combination with one or more other therapeutic compounds. Disclosed lipid prodrugs or compositions may otherwise or in addition to, in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination thereof, particularly for the treatment of tumors. In connection with the other therapeutic strategies described above, long-term therapy is equally possible, as is adjuvant therapy. Other possible therapies include therapies to maintain the patient's condition after tumor regression, or even chemoprevention therapy in patients at risk, for example.

[0640] Such additional agents may be administered separately from the provided lipid prodrug or composition as part of a multidose regimen. Alternatively, they may be part of a single dosage form mixed with the lipid prodrug disclosed in a single composition. When administered as part of a multidose regimen, the two active agents may be presented simultaneously, sequentially, or from each other within a certain period of time.

[0641] As used herein, the terms “combined,” “combined,” and related terms refer to the simultaneous or sequential administration of therapeutic agents according to the Disclosure. For example, the disclosed lipid prodrug may be administered together with another therapeutic agent in separate unit dosage forms or in a single unit dosage form, simultaneously or sequentially. Accordingly, the 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 prodrug and the additional therapeutic agent (in the composition containing the additional therapeutic agent as described above), which can be combined with a carrier material to produce a single dosage form, will vary depending on the patient being treated and the specific mode of administration. In certain embodiments, the composition of the present invention should be formulated so that the disclosed lipid prodrug can be administered in doses of about 0.01 to 500 mg / kg body weight / day.

[0643] In compositions containing additional therapeutic agents, the additional therapeutic agent and the disclosed lipid prodrug may act synergistically. Therefore, the amount of additional therapeutic agent in such compositions will be less than the amount required in monotherapy using only that therapeutic agent. In such compositions, the additional therapeutic agent may be administered at a dose of approximately 0.01 μg / kg to 100 mg / kg body weight / day.

[0644] The amount of additional therapeutic agent present in the composition of the present invention does not exceed the amount typically administered in a composition containing that therapeutic agent as the sole active agent. Preferably, the amount of additional therapeutic agent in the composition of the present disclosure will be in the range of about 50% to 100% of the amount typically present in a composition containing that agent as the sole therapeutic active agent.

[0645] Examples of drugs that can be combined with the lipid prodrug of the present invention include, but are not limited to, A Drugs for treating Alzheimer's disease such as ricept(registered trademark) and Exelon(registered trademark), drugs for treating HIV such as ritonavir; drugs for treating Parkinson's disease such as L-DOPA / carbidopa, entacapone, ropinirole, pramipexole, bromocriptine, pergolide, trihexyphenidyl, and amantadine; drugs for treating multiple sclerosis (MS) such as beta-interferons (e.g., Avonex(registered trademark) and Rebif(registered trademark)), Copaxone(registered trademark), and mitoxantrone; drugs for treating asthma such as albuterol and Singulair(registered trademark), 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; immunomodulatory and immunosuppressant agents 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 antiparkinson's disease drugs; beta-blockers, ACE inhibitors, diuretics, nitrates, calcium Examples include drugs for treating cardiovascular diseases such as mucochannel blockers and statins; drugs for treating liver diseases such as corticosteroids, cholestyramine, interferon, and antiviral agents; drugs for treating hematological disorders such as corticosteroids, antileukemia agents, and growth factors; drugs that prolong or improve pharmacokinetics such as cytochrome P450 inhibitors (i.e., inhibitors of metabolic degradation) and CYP3A4 inhibitors (e.g., ketoconazole and ritonavir); and drugs for treating immunodeficiency disorders such as gamma globulin.

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

[0647] In another embodiment, the present invention provides a method for treating inflammatory diseases, disorders, or conditions such as neuroinflammatory diseases or Alzheimer's disease by administering the disclosed lipid prodrug and one or more additional therapeutic agents to patients requiring treatment for such inflammatory diseases, disorders, or conditions. Such additional therapeutic agents may be small molecules or biological preparations, and include, 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 their equivalents; probenecid, allopurinol, febuxostat (U Antimalarial drugs such as loric(registered trademark), sulfasalazine (Azulfidine(registered trademark)), hydroxychloroquine (Plaquenil(registered trademark)), and chloroquine (Aralen(registered trademark)), gold salts such as methotrexate (Rheumatrex(registered trademark)), gold thioglucose (Solganal(registered trademark)), gold thiomalate (Myochrysine(registered trademark)), and auranofin (Ridaura(registered trademark)), and D-penicillamine (D epen(registered trademark) or Cuprimine(registered trademark), azathioprine (Imuran(registered trademark)), cyclophosphamide (Cytoxan(registered trademark)), chlorambucil (Leukeran(registered trademark)), cyclosporine (Sandimmune(registered trademark)), leflunomide (Arava(registered trademark)), as well as etanercept (Enbrel(registered trademark)), infliximab (Remicade(registered trademark)), golimumab (Simponi(registered trademark)), Anti-TNF agents such as cetrizumab pegol (Cimzia®) and adalimumab (Humira®), anti-IL-1 agents such as anakinra (Kineret®) and lilonacept (Arcalyst®), anti-Jak inhibitors such as canakinumab (Ilaris®) and tofacitinib, antibodies such as rituximab (Rituxan®), anti-T cell agents such as abatacept (Orencia®), and tocilizumab (Actemra(registered trademark)), anti-IL-6 agents such as diclofenac, cortisone, hyaluronic acid (Synvisc(registered trademark) or Hyalgan(registered trademark)), monoclonal antibodies such as tanezumab, anticoagulants such as heparin (Calcinparine(registered trademark) or Liquaemin(registered trademark)) and warfarin (Coumadin(registered trademark)), antidiarrheal agents such as diphenoxylate (Lomotil(registered trademark)) and loperamide (Imodium(registered trademark)), cholestyramine, alosetron (Lotronex(registered trademark)), ruby Bile acid binders such as Prostone (Amitiza®), laxatives such as magnesium milk, polyethylene glycol (MiraLax®), Dulcolax®, Correctol®, and Senokot®, anticholinergics or antispasmodics such as dicyclomine (Bentyl®) and Singulair®, albuterol (Ventolin® HFA, Proventil® HFA), revalbuterol (Xopenex®), metaproterenol (A Beta-2 agonists such as lupent®, pyrbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®), and formoterol (Foradil®); anticholinergic agents such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®); beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®) )), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), and inhaled corticosteroids such as flunisolide (Aerobid®), Afviar®, Symbicort®, Dulera®, and cromolyn sodium (Intal®), theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®),Methylxanthines such as Theo-24 (registered trademark) and aminophylline, IgE antibodies such as omalizumab (Xolair (registered trademark)), zidovudine (Retrovir (registered trademark)), abacavir (Ziagen (registered trademark)), abacavir / lamivudine (Epzicom (registered trademark)), abacavir / lamivudine / zidovudine (Trizivir (registered trademark)), didanosine (Videx (registered trademark)), emtricitabine (Emtriva (registered trademark)), lamivudine (Epivir (registered trademark)), lamivudine / zidovudine (Com Nucleoside reverse transcriptase inhibitors such as bivir(registered trademark), stabuzin (Zerit(registered trademark)), and zalcitabine (Hivid(registered trademark)); non-nucleoside reverse transcriptase inhibitors such as delaviridine (Rescriptor(registered trademark)), efavirenz (Sustiva(registered trademark)), nevirapine (Viramune(registered trademark)), and etravirine (Intelence(registered trademark)); nucleotide reverse transcriptase inhibitors such as tenofovir (Viread(registered trademark)); amprenavir (Agenerase(registered trademark)) ), 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®), etc. This may include entry inhibitors such as Fuvirtide (Fuzeon®) and Maraviroc (Selzentry®), integrase inhibitors such as raltegravir (Isentress®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), bortezomib (Velcade®), and dexamethasone (Decadron®) in combination with lenalidomide (Revlimid®), or any combination(s) of these.

[0648] In another embodiment, the present invention relates to a method for treating depressive mood disorders (e.g., major depressive disorder, bipolar disorder, seasonal affective disorder (SAD), cyclothymic disorder, premenstrual dysphoric disorder, persistent depressive disorder, severe mood dysregulation, depression associated with a medical condition, postpartum depression) and / or anxiety disorders (e.g., panic disorder and post-traumatic stress disorder), wherein the patient in need is provided with the disclosed lipid prodrugs, as well as citalopram (Celexa®), escitalopram (Lexapro®), fluoxetine (Prozac®), fluvoxamine (Luvox® / Luvox CR®), paroxetine (Paxil® / Paxil CR (registered trademark), sertraline (Zoloft (registered trademark)), desvenlafaxine (Pristiq (registered trademark)), duloxetine (Cymbalta (registered trademark)), venlafaxine (Effexor (registered trademark) / Effexor XR (registered trademark)), milnacipran (Savella (registered trademark)), levomirnacipran (Fetzima (registered trademark)), amitriptyline (Elavil (registered trademark)), desipramine (Norpramin (registered trademark)), doxepin (Sinequan (registered trademark)), imipramine (Tofranil (registered trademark)), nortriptyline (Pamelor (registered trademark)), amoxapine, clomipramine (Anafranil (registered trademark)), maprotiline (Ludiomil (registered trademark)), trimipramine (Surmontil (registered trademark)), protriptyline (Vivact The present invention provides a method comprising administering one or more additional therapeutic agents selected from il (registered trademark), phenelzine (Nardil (registered trademark)), selegiline (Emsam (registered trademark)), tranylcypromine (Parnate (registered trademark)), bupropion (Wellbutrin (registered trademark)), mirtazapine (Remeron (registered trademark)), nefazodone (Serzone (registered trademark)), tradzone (Desyrel (registered trademark), Oleptro (registered trademark)), vilazodone (Viibryd (registered trademark)), and vortioxetine (Brintellix (registered trademark)).

[0649] In some embodiments, the present invention provides a method for treating Alzheimer's disease, comprising administering to a patient in need a disclosed lipid prodrug, as well as 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, as well as any additional co-administered therapeutic agents, according to the methods of the present invention, may be administered in any amount and via any route of administration that is effective in treating or alleviating the severity of diseases, disorders, or conditions such as inflammatory disorders, neurodegenerative disorders, neurological disorders, or schizophrenia. The exact amount required will vary among subjects depending on the species, age, and general condition of the subject, the severity of the infection, the specific drug, and its mode of administration. 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 individualized unit of the drug appropriate for the patient being treated. However, it will be understood that the total daily dose of the disclosed lipid prodrugs or compositions and any additional co-administered therapeutic agents will be determined by the attending physician within the bounds of sound medical judgment. The specific effective dose level for any particular patient or organism will depend on a variety of factors, including the disorder being treated and its severity; the activity of the specific lipid prodrug used; the specific composition used; the patient's age, weight, overall health, sex, and diet; the timing, route of administration, and excretion rate of the specific lipid prodrug or composition; the duration of treatment; drugs used in combination with or concurrently with the specific lipid prodrug or composition used; and similar factors well known in the medical field. The terms “subject” or “patient” used here refer to animals, preferably mammals, most preferably humans.

[0651] In some embodiments, the dose is selected to take into account the uptake, metabolism, and release of the parent drug allopregnanolone (allo) into the lymphatic system. For example, if a given dose of the 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 yield a desired plasma or lymphatic system concentration of allopregnanolone. In some embodiments, the dose is selected so that the orally administered dose of the lipid prodrug provides a desired effective concentration of allopregnanolone, e.g., a plasma or lymphatic system concentration, upon uptake, metabolism, and release of the parent drug allopregnanolone into the patient's lymphatic system, to treat a disease, disorder, or condition (such as those disclosed herein).

[0652] In some embodiments, the dose of the lipid prodrug or its pharmaceutically acceptable salt is about 0.01 mg / kg to about 100 mg / kg. In some embodiments, the dose of the lipid prodrug or its pharmaceutically acceptable salt is about 0.1 mg / kg to about 25 mg / kg. In some embodiments, the dose of the lipid prodrug or its pharmaceutically acceptable salt is about 0.5 mg / kg to about 15 mg / kg. In some embodiments, the dose of the lipid prodrug or its pharmaceutically acceptable salt is about 1 mg / kg to about 10 mg / kg. In some embodiments, the dose of the lipid prodrug or its pharmaceutically acceptable salt is about 2 mg / kg to about 7.5 mg / kg. In some embodiments, the dose of the lipid prodrug or its pharmaceutically acceptable salt 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 approximately 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 a lipid prodrug or a pharmaceutically acceptable salt thereof. In some embodiments, the dose is about 10 mg to about 2.5 g of a lipid prodrug or a pharmaceutically acceptable salt thereof. In some embodiments, the dose is about 100 mg to about 2.0 g of a lipid prodrug or a pharmaceutically acceptable salt thereof. In some embodiments, the dose is about 250 mg to about 1.0 g of a lipid prodrug or a pharmaceutically acceptable salt thereof. In some embodiments, the dose is about 500 mg to about 1.0 g of a lipid prodrug or a pharmaceutically acceptable salt thereof.

[0654] In some embodiments, the dose of the lipid prodrug or a pharmaceutically acceptable salt thereof is calculated to provide a specific dose of allopregnanolone when the prodrug is administered orally. In some embodiments, the dose of the lipid prodrug or a pharmaceutically acceptable salt thereof is calculated to provide allopregnanolone in doses of approximately 0.01 mg / kg to approximately 100 mg / kg, 0.1 mg / kg to approximately 25 mg / kg, approximately 0.5 mg / kg to approximately 15 mg / kg, approximately 1 mg / kg to approximately 10 mg / kg, approximately 2 mg / kg to approximately 7.5 mg / kg, and approximately 3.0 mg / kg to approximately 7.0 mg / kg. In some embodiments, the dose of the lipid prodrug or a pharmaceutically acceptable salt thereof is calculated to provide approximately 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 its pharmaceutically acceptable salt provides approximately 5 mg to approximately 3 g of allopregnanolone when the prodrug is administered orally. The dosage is calculated as follows. In some embodiments, the dosage is calculated to provide approximately 50 mg to approximately 2.5 g of allopregnanolone, or approximately 100 mg to approximately 1.5 g, or approximately 250 mg to approximately 1.0 g of allopregnanolone.

[0656] 4. Method for preparing lipid prodrugs General methods for preparing 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 with respect to similar compounds, as well as by the methods detailed in the examples herein.

[0657] The therapeutic agents contained in the disclosed lipid prodrugs (e.g., conjugated to a glyceride-based prodrug) may be commercially purchased or prepared by organic synthesis, semi-synthesis, fermentation (e.g., with a viral vector), and similar methods known in the art.

[0658] In some embodiments, for example, protecting groups (such as those defined below) can be used to prepare the therapeutic agent for conjugation to the remainder of the lipid prodrug structure, in order to prevent undesirable side effects.

[0659] Where a specific protecting group ("PG"), leaving group ("LG"), or conversion condition is illustrated in the synthesis method described herein, those skilled in the art will understand that other protecting groups, leaving groups, and conversion conditions are also suitable and intended. Such groups and conversions are described in March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, MBSmith and J. March, 7 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 thThis is detailed in edition, John Wiley & Sons, 2014, and each part of that work is thereby incorporated herein by reference.

[0660] As used herein, the term “leaving group” (LG) includes, but is not limited to, halogens (e.g., fluorides, chlorides, bromides, iodides), sulfonates (e.g., mesylates, tosylates, benzenesulfonates, brosylates, nosylates, triflates), diazoniums, etc.

[0661] As used herein, the term “oxygen protecting group” includes, for example, carbonyl protecting groups, hydroxyl protecting groups, etc. Hydroxyl protecting groups are well known in the art and are detailed in Protective Groups in Organic Synthesis, PGMWuts, 5th edition, John Wiley & Sons, 2014, and Philip Kocienski, in Protecting Groups, Georg Thieme Verlag Stuttgart, New York, 1994, the entire literature of which is incorporated herein by reference. Suitable examples of 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 formic acid esters, acetate esters, carbonate esters, and sulfonic acid esters. Specific examples include methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, vinyl, and Examples of silyl ethers include lyl, and formic acid esters such as p-nitrobenzyl, benzoylformate, chloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionic acid, 4-oxopentanoate, 4,4-(ethylenedithio)pentanoate, pivalate (trimethylacetyl) ester, crotonic acid ester, 4-methoxy-crotonic acid ester, benzoic acid ester, p-benzylbenzoate, 2,4,6-trimethylbenzoate, and carbonate esters. 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 ether. Examples of arylalkyl ethers include benzyl, p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, O-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, and 2- and 4-picolyl.

[0662] Amino protecting groups are well known in the art, as seen in Protective Groups in Organic Synthesis, PGMWuts, 5 thThis includes details provided in edition, John Wiley & Sons, 2014, and Philip Kocienski, in Protecting Groups, Georg Thieme Verlag Stuttgart, New York, 1994, the entire literature of which is incorporated herein by reference. Suitable amino protecting groups include, but are not limited to, aralkylamines, carbamates, cyclic imides, allylamines, and amides. Examples of such groups include t-butyloxycarbonyl (Boc), ethyloxycarbonyl, methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyl oxocarbonyl (Cbz), allyl, phthalimide, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, phenylacetyl, trifluoroacetyl, and benzoyl.

[0663] Those skilled in the art will understand 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. For example, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, MBSmith and J. March, 7 th See Edition, John Wiley & Sons, 2013, the entire document of which is incorporated herein by reference. Such interconversions may require one or more of the techniques described above, and certain methods for synthesizing the compounds of the present 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 the compound of formula iii-a. Acid triglycerides (acid-TG) iii-a can be obtained by reacting diglycerides such as ii with acid dichloride i (which is readily available from the corresponding malonic acid) in the presence of pyridine or another suitable base (see Scheme 1). Formula iii-a is C 15 H 31 Although it is shown to have a fatty acid side chain, other fatty acids (such as those mentioned above) can be substituted in this formula and the other formulas described below.

[0667] [ka]

[0668] Scheme 2. Synthesis of the compound of formula iii-b. If acid anhydride ia is available, acid-TG iii-b can be produced by ring-opening with diglyceride ii in the presence of pyridine or another suitable base (Scheme 2). This method is used for acid anhydride ia. 4 and R 5 It works best when they are identical (for example, both are Me), but R 4 and R 5 If these are different from each other, it will result in a mixture of positional isomers of the acid-TG product iv. Consequently, in this situation, other methods, such as those outlined in Scheme 3, can be advantageously used.

[0669] [ka]

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

[0671] R 4 =Me or other alkyl or substitution, R 5 In a specific example where =H, a known carboxylic acid v (Lienard, BMRet 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 positional isomer (see Scheme 3). Coupling of acid v with 1,3-DG ii under standard conditions yields TBDPS-protected triglyceride vi, which can be treated with TBAF and AcOH under appropriate conditions to obtain alcohol vii. Alcohol vii can then be converted to the desired acid-TG iv via an intermediate aldehyde vii using a two-step oxidation process (e.g., PCC followed by KMnO4).

[0672] [ka]

[0673] Scheme 4. Synthesis of the compound of formula x (wherein -M- is an acetal self-destructing (ASI) group).

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

[0675] [ka]

[0676] Scheme 5. Synthesis of the compound of formula xii (wherein -M- is a carboxyacetal (CASI) or carboxy(methylacetal) (CMSI) self-destructing group).

[0677] If the pharmaceutical product contains an alcohol, phenol, or amine (primary or secondary) functional group, a modified version of the acetal self-destructing group containing an additional carboxyl group can be used. Reaction of the parent drug with chloroalkyl chloroformate yields chloroalkyl carbonate (illustrated) or carbamate xi (see Scheme 5). Substitution of the leaving group of the halide is then carried out by treatment with a carboxylate derived from acid-TG iv-c in a suitable solvent such as refluxed toluene to obtain the target compound xii.

[0678] [ka]

[0679] Scheme 6. Synthesis of the compound of formula xviii (wherein -M- is a trimethyl-lock (TML) self-destructing group).

[0680] To facilitate the systemic release of the parent molecule, trimethyl is placed between the drug and the alkyl spacer. For the synthesis of prodrugs containing the loc (TML) self-destructing group (Levine, MN; Raines, RTChem.Sci. 2012, 3, 2412-2420 (as incorporated herein by reference)), typically, as outlined in Scheme 6, acid-triglyceride iv is functionalized with the TML moiety before conjugation with a pharmaceutical. Coupling of acid-TG iv with TML phenol xiii under standard conditions yields triglyceride xiv, which can be deprotected under acidic conditions (10-camphor sulfonic acid) to obtain alcohol xv. Sequential oxidation of alcohol xv first to aldehyde xvi, then to acid xvii, followed by coupling to a pharmaceutical containing any of the alcohols (illustrated), amines, or sulfonamides under standard conditions can yield the target compound xviii.

[0681] [ka]

[0682] Scheme 7. Synthesis of the compound of formula xxiv (wherein -M- is the p-hydroxybenzylcarbonyl (PHB) self-destructing group).

[0683] To synthesize compounds containing the p-hydroxybenzyl (PHB) carbonyl self-destructing group, the primary hydroxyl group of p-hydroxybenzyl alcohol (xix) is first protected as a silyl ether, and the free phenolic hydroxyl group is coupled with acid-TG iv to obtain PHB triglyceride xxi (see Scheme 7). After removal of the silicon protecting group, the primary alcohol xxii is activated by treatment with p-nitrophenyl chloroformate (PNP) to obtain PNP carbonate xxiii. Subsequently, under basic conditions, the PNP group is substituted by reaction with a pharmaceutical agent (A-OH shown in the figure). This process yields the desired compound xxiv.

[0684] [ka]

[0685] Scheme 8. Synthesis of the compound of formula III (wherein -M- is an inverted ester self-destructing (FSI) group).

[0686] While we do not wish to be constrained by theory, it is conceivable that the inverted ester self-destructing (FSI) group can release the drug via a cyclization mechanism resulting in the loss of either a 4-carbon (FSI-4) lactone or a 5-carbon (FSI-5) lactone. Alternatively, drug release may occur in vivo via a chemical or enzymatic mechanism. FSI prodrugs can be synthesized by coupling the drug (A-OH shown in the diagram) with either 4-bromobutyric acid (m=1) or 5-bromovaleric acid (m=2) (xxv) to obtain bromide xxvi (see Scheme 8). Substitution of bromide xxvi with a carboxylate derived from acid-TG iv generates the desired ester bond in the target compound xxvii. [Examples]

[0687] Example 1: Synthesis of the intermediate List of abbreviations equiv or eq: molar equivalent rt: room temperature UV: Ultraviolet light HPLC: High-Pressure Liquid Chromatography Rt: retention time LC-MS 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(diphenylphosphin)-1,1'-binaphthalene Bn: Benzyl DBU:1,8-Diazabicyclo[5.4.0]Undeca-7-En DCC:N,N'-Dicyclohexylcarbodiimide DCM: Dichloromethane DCE: Dichloroethane DEA: Diethylamine DIPA: Diisopropylamine DM water: Desalinated water DMF: N,N-dimethylformamide DMSO: Dimethyl sulfoxide DMPU: N,N'-dimethylpropylene urea ACN or MeCN: Acetonitrile DIPEA: Diisopropylethylamine EA or methoxy: ethyl acetate EDCI, EDC, or EDAC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide TEA: Triethylamine THF: Tetrahydrofuran TBS: tert-butyldimethylsilyl KHMDS: Potassium hexamethyldisilyl azide 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: Des Martin Periodine 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 at room temperature to a mixture of palmitic acid (433 g, 1.69 mol) in thionyl chloride (500 mL, 6.3 mol). The resulting reaction mixture was heated under reflux for 3 hours. It was concentrated to dryness to obtain palmitoyl chloride (453 g, 1.64 mol, 97% yield) as a yellowish oil, which was used in the next step without further purification.

[0690] Under nitrogen, 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 was mixed with palmitate chloride (453 g, 1.64 mol). The mixture was stirred at room temperature for 16 hours. It was diluted with MeOH (1000 mL) and water (2000 mL) and stirred for 30 minutes. The precipitate was collected by filtration and dried to obtain Int-1 (462 g, 0.815 mmol, yield 95%) 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 in small amounts. 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 ¹H 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 under reflux for 2 hours. The reaction mixture was cooled to room temperature, diluted with toluene (5 mL), and concentrated under reduced pressure to obtain the acid dioxide 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 mmol) in dichloromethane (1.5 mL), and the mixture was heated under reflux for 2 hours. The reaction product was cooled to room temperature and diluted with ethyl acetate (15 mL) and 1 M HCl (5 mL) to separate the organic phase. The aqueous layer was further extracted with ethyl acetate (2 × 20 mL), and the combined organic extract was washed with 1 M HCl (20 mL) and brine (2 × 30 mL), dried, and concentrated under reduced pressure to obtain the crude product. Purification by silica gel chromatography (20% to 45% ethyl acetate / hexane) yielded Int-4 (54.0 mg, 88%) as a colorless solid. 11H 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 13C NMR (101 MHz, CDCl3) δ 178.1 (C), 173.5 (2 C;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;CH 2), 29.4 (2C;CH2), 29.2 (2C;CH2), 27.3 (CH), 25.0 (2C;CH2), 22.8 (2C;CH2), 19.8 (CH3), 14.2 (2C;CH3); ESI-HRMS: C 41 H 76 NaO8 [M + Na + calculated value for 719.5432; measured value 719.5451. Alternative procedure (larger scale):

[0694]

Chemical Structure

[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 under reflux for 16 hours, then concentrated to dryness, and added at room temperature to a solution of pyridine (270 g, 3.4 mol) and benzyl alcohol (100 g, 926 mmol) in dichloromethane (1500 mL). The mixture was stirred for 72 hours. The reaction product was concentrated, and the residue was purified by silica column chromatography while eluting with 0-50% ethyl acetate in petroleum ether to obtain Int-6 (70 g, 297 mmol, yield 43%) as a yellowish oil. 1 ¹H 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). A mixture of Int-6 (70 g, 297 mmol) and Int-2 (1,3-DG) (80 g, 140 mmol) in dichloromethane (1500 mL) was mixed with 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 hours. The reaction product was concentrated to dryness, and the residue was purified by silica column chromatography while eluting with 0-50% ethyl acetate in petroleum ether to obtain Int-7 (68 g, 86.5 mmol, yield 29%) as a white solid. 1 ¹H NMR (400 MHz, chloroform-d) δ 7.40-7.32 (m, 5H), 5.30-5.24 (m, 1 H), 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, 48 H), 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 carbon (3 g) were suspended in THF (400 mL). The mixture was hydrogenated under a hydrogen atmosphere at 30°C for 16 hours, then filtered and concentrated to dryness. The residue was further purified by trituration with hexane to obtain Int-4 (C5βMe-acid-2-TG) (51 g, 73.2 mmol, yield 84%) as a white solid. LC-MS: MS m / z = 719 (M+ Na+), R T = 3.83 minutes. 1 ¹H 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, 6 H), 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] 1 H 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);13 ¹¹¹ M NMR (10¹¹ M) Hz, 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 under reflux for 1.5 hours. The reaction mixture was cooled to room temperature, diluted with toluene (5 mL), and concentrated under reduced pressure to obtain the acid dioxide Int-8 (104 mg, quantified) as a yellow oil, which was used without purification. 1 HN MR (400 MHz, chloroform-d) δ 2.88 (t, J = 7.3 Hz, 4H), 1.76 - 1.66 (m, 4H), 1.42 - 1.26 (m, 8H) ). A solution of Int-2 (1,3-DG) (45.0 mg, 0.0791 mmol) and pyridine (64.0 μL, 0.791 mmol) in dichloromethane (1.5 mL) is mixed with dichloromethane (1.5 mL) containing the dichloride Int-8 (104 mg, 0.435 mmol) The mixture was added to the ethanol solution and stirred at room temperature for 1.5 hours. The reaction product 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 extract was washed with 1 M HCl (30 mL) and brine (30 mL), dried, and concentrated under reduced pressure to obtain the crude product. Purification by silica gel chromatography (20% to 50% ethyl acetate / hexane) yielded 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 under reflux for 16 hours, then cooled and concentrated to dryness. This was added at room temperature to a solution of pyridine (270 g, 3.4 mol) and benzyl alcohol (100 g, 926 mmol) in dichloromethane (1500 mL), and the mixture was stirred for 72 hours. The reaction product was concentrated, and the residue was purified by column chromatography while eluting with 0-50% ethyl acetate in petroleum ether to obtain Int-11 (82 g, 281 mmol, yield 57%) as a yellowish oil. LC-MS: MS m / z = 293 (M + H+), RT = 1.45 minutes.

[0702] A mixture of Int-11 (82 g, 281 mmol) and Int-2 (1,3-DG) (80 g, 140 mmol) in dichloromethane (1500 mL) was mixed with EDCI (115 g, 600 mmol) and DMAP (3.66 g, 30 mmol). Then, triethylamine (100 mL, 719 mmol) was added dropwise at 0°C. The mixture was stirred at room temperature for 72 hours. The reaction product was concentrated to dryness, and the residue was purified by column chromatography while eluting with 0 to 50% ethyl acetate in petroleum ether to obtain Int-12 (65 g, 77 mmol, yield 27%) as a white solid. 1 ¹H 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 (6 H). Int-12 (65 g, 77 mmol) and palladium 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, the filtrate was concentrated to dryness, and further purified by trituration with hexane to obtain Int-9 (C10-acid-2-TG) (50 g, 66.4 mmol, yield 86%) as a white solid. LC-MS: MS m / z = 775 (M+ Na+), RT = 5.95 min; 1 ¹H 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); 13 C NMR (101 MHz, CDCl3) δ 179.9 (C), 173.4 (2C;C), 173.0 (C), 69.0 (CH), 62.2 (2C;CH2), 34.3 (CH2), 34.2 (2C;CH2), 3 4.1 (CH2), 32.0 (2C;CH2), 29.81 (6C;CH2), 29.77 (4C;CH2), 29.74 (2C;CH2), 29.59 (2C;C H2), 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-H RMS:C 46 H 86 NaO8[M + Na + Calculated value for ] 789.6215; actual Measured value: 789.6218. C12α'βMe-acid-2-TG(Int-23 and Int-27):

[0705] [ka]

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

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

[0708] n-butyllithium (n-BuLi, 1.6 M in hexane, 765 μL, 1.23 mmol) was slowly added at -78°C to a solution of TMS-acetylene (198 μL, 1.40 mmol) in THF (1.5 mL). The mixture was stirred at -78°C for 5 minutes, then warmed to room temperature and stirred for another 15 minutes. The reaction mixture 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. The mixture was stirred at -50°C for 15 minutes, then at room temperature for 17 hours. The reaction mixture 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, and concentrated under reduced pressure to obtain the crude product. Purification by silica gel chromatography (4% to 5% ethyl acetate / hexane) yielded TMS alkyne Int-15 (45.9 mg, 48%) and desilylated alkyne Int-16 (9.7 mg, 1 14% and a small amount of PPH3 were also detected by 14% NMR integration. It was obtained as a colorless oil contained within. 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 at 0°C to a 7:2 mixture of silyl alkyne Int-15 and alkyne Int-16 (55.6 mg combined, 0.215 mmol) in THF (1 mL), and the mixture was stirred at room temperature for 1 hour. The reaction product was diluted with water (5 mL) and saturated NH4Cl aqueous solution (3 mL), and the aqueous phase was extracted with ethyl acetate (3 × 10 mL). The combined organic extract was washed with brine (20 mL), dried, and concentrated under reduced pressure to obtain the crude product. Alkyne Int-16 (37.5 mg, 53% over two steps) was obtained as a colorless oil by silica gel chromatography (4% ethyl acetate / hexane). 1 H NMR (400 MHz, CDCl3) δ 7.39 - 7.27 (m, 5H), 4.51 (s, 2H), 3.49 (t, J = 6.5 Hz, 2 H), 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), 1 8.5 (CH2). Prepared according to Int-17: Kim, H.-O. et al. Synlett 1998, 1059-1060.

[0709] A suspension of PdCl2(PPh3)2 (16.8 mg, 0.0240 mmol) in DMF (1.5 mL) was degassed using N2 gas for 5 minutes, and then CuI (9.1 mg, 0.0480 mmol), Et3N (66.8 μL, 0.480 mmol), and degassed solutions 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 further degassed using N2 stream for 5 minutes and then heated at 50°C for 1 hour. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (30 mL), washed with 1 M HCl, saturated NaHCO3 aqueous solution, water, and brine (20 mL each), dried, and concentrated under reduced pressure to obtain the crude product. Silica gel chromatography (4% Enine Int-18 (46.6 mg, 62%) was obtained as a pale yellow oil by 5% ethyl acetate / hexane. 1 H NMR (400 MHz, CDCl3) δ 7.37 - 7.24 (m, 5H), 5.92 (m, 1H), 4.50 (s, 2H), 4.17 (q, J = 7.1 Hz, 2H), 3.48 (t, J = 6.5 Hz, 2H), 2.45 (t, J = 7.0 Hz, 2H), 2.01 (d, J = 1.4 Hz, 3H), 1.69 - 1.59 (m, 4H), 1.56 - 1.49 ( m, 2H), 1.27 (t, J = 7.1 Hz, 3H); 13 1C 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-necked round-bottom flask, a solution of benzyl ether Int-18 (31.4 mg, 0.100 mmol) in ethyl acetate (8 mL) was evacuated twice, flushed with N2 gas, and then palladium carbon (10% (w / w), 26.6 mg, 0.0250 mmol) was added. The resulting suspension was evacuated again and flushed with N2 (three times). An H2 balloon was attached to the flask, evacuated, and flushed with H2 (three times). The reaction mixture was stirred at room temperature for 1 hour under 1 atm of H2. The flask was then evacuated and flushed with N2. The reaction mixture was filtered by washing with ethyl acetate (30 mL) and passing through a Celite pad. The filtrate was concentrated under reduced pressure to obtain saturated alcohol Int-19 (23.0 mg, quantified) as a colorless oil, which was used without purification. 1 H NMR (400 MHz, CDCl3) δ 4.12 (q, J = 7.1 Hz, 2H), 3.63 (t, J = 6.6 Hz, 2H), 2.28 (dd, J = 14.6, 6.1 Hz, 1H), 2.09 (dd, J = 14.6, 8.1 Hz, 1H), 1.94 (m, 1H), 1 .60 - 1.50 (m, 2H), 1.25 (t, J = 6.6 Hz, 3H), 1.40 - 1.13 (m, 10H), 0.92 (d, J = 6.6 Hz, 3H) ); 13 C NMR (101 MHz, CDCl3) δ 173.6 (C), 63.2 (CH2), 60.2 (CH2), 42.1 (CH2), 36.8 (CH2), 32.9 (CH2), 30.5 (CH), 29.8 (CH2), 29.5 (CH 2), 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 hours. The reaction product was diluted with ethyl acetate (20 mL), washed with brine (2 × 20 mL), dried, and concentrated under reduced pressure to obtain the crude product. Purification by silica gel chromatography (4% ethyl acetate / hexane with 0.5% Et3N) yielded TBDPS ether Int-20 (33.7 mg, 92%) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 7.70 - 7.64 (m, 4H), 7.45 - 7.33 (m, 6H), 4.13 ( q, J = 7.1 Hz, 2H), 3.65 (t, J = 6.5 Hz, 2H), 2.28 (dd, J = 14.6, 6.0 Hz, 1H), 2.09 (dd, J = 14.6, 8.2 Hz, 1H), 1.94 (m, 1H), 1.60 - 1.50 (m, 2H), 1.38 - 1.21 (m, 3H), 1.05 (s, J = 2.9 Hz, 2H), 1.05 (s, 9H), 0.93 (d, J = 6.6Hz , 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), 2 6.99 (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 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 solvent was removed under reduced pressure. The residue was diluted with water (5 mL), and the aqueous phase was extracted with ethyl acetate (3 × 15 mL). The combined organic extracts were washed with brine (30 mL), dried (MgSO4), and concentrated under reduced pressure to give crude acid Int-21 (37.6 mg, quantitative) as a colorless oil, which was used without purification. 1 H NMR (400 MHz, CDCl3) δ 7.74 - 7.63 (m, 4H), 7.45 - 7.34 (m, 6H), 3.65 (t, J = 6.5 Hz, 2H), 2.35 (dd, J = 15.0, 5.9 Hz, 1H), 2.14 (dd, J = 15. 0, 8.2 Hz, 1H), 1.95 (m, 1H), 1.61 - 1.50 (m, 2H), 1.38 - 1.18 (m, 10H), 1.04 (s, 9H), 0.96 (d, J = 6.6 Hz, 3H); 13 C NMR (101 MHz, CDCl3) δ 179.5 (C), 135.7 (4C;CH), 134.3 (2C;C), 129.6 (2C;CH), 127.7 (4C;CH), 64.1 (CH2), 41.7 (CH2), 36.8 (CH2), 32.7 (CH2), 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 13Two sets of signals were observed in both NMR spectra of 1C, but only the primary signal set is reported above. It was unclear whether the duplication 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 hours. The reaction product 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) yielded triglyceride Int-22 (39.9 mg, 48% over two steps) as a colorless solid. 1 H NMR (400 MHz, CDCl3) δ 7.69 - 7.64 ( m, 4H), 7.44 - 7.34 (m, 6H), 5.28 (m, 1H), 4.289 / 4.287 (dd, J = 11.8, 4.2 Hz, 2H), 4.14 respectively (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 = 1 4.7, 8.4 Hz, 1H), 1.92 (m, 1H), 1.67 - 1.50 (m, 8H), 1.39 - 1.14 (m, 56H), 1.04 (s, 9H), 0.93 (d, J = 6.6 Hz, 3H), 0.88 (t, J = 6.9 Hz, 6H); 13 C NMR (101 MHz, CDCl3) δ 173.5 (2C;C) , 172.5 (C), 135.7 (4C;CH), 134.3 (2C;C), 1 29.6 (2C;CH), 127.7 (4C;CH), 68.9 (CH), 64.1 (CH2), 62.3 (2C;CH2), 41.8 (CH2), 36.8 (C H2), 34.2 (2C;CH2), 32.7 (CH2), 32.1 (2C;CH2), 30.5 (CH), 29.9 (CH2), 29.84 (6C;CH2), 29.80 (4C;CH2), 29.76 (2C;CH2), 29.6 (2C;C H2), 29.54 (CH2), 29.51 (2C;CH2), 29.4 (2C;CH2), 29.3 (2C;CH2), 27.02 (CH2), 27.00 (3C ;CH3), 25.9 (CH2), 25.0 (2C;CH2), 22.8 (2C;CH2), 19.7 (CH3), 19.4 (C), 14.3 (2C;CH3). Tetrabutylammonium fluoride (TBAF, 1.0 M, 98.3 μL, 98.3 μmol) was added at 0°C to a solution of TBDPS ether Int-22 (39.0 mg, 39.3 μmol) in THF (2.5 mL), and the mixture was stirred at room temperature for 3 hours. The reaction product was diluted with water (10 mL), extracted with ethyl acetate (3 × 15 mL), washed with brine (30 mL), dried, and concentrated under reduced pressure to obtain the crude product. Purification by silica gel chromatography (10% to 20% ethyl acetate / hexane) yielded 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); 13 ¹¹¹ MHz, ¹¹¹ 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), 2 9.6 (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 at 0°C to a suspension of alcohol Int-23 (21.0 mg, 27.9 μmol) and Celite (15 mg) in dichloromethane (1.5 mL), and the mixture was stirred at room temperature for 1.75 hours. The reaction product was filtered through a silica gel short pad while eluting with ethyl acetate, and the filtrate was concentrated under reduced pressure to obtain crude aldehyde Int-24 (20.9 mg, quantified) 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, 6 H). Prepared according to Int-25:Gossauer, A.; Kuhne, G. Liebigs. Ann. Chem. 1977, 664-686.

[0711] A solution of ylide Int-25 (8.1 mg, 19.0 μmol) in toluene (0.4 mL) was added to aldehyde Int-24 (11.0 mg, 14.6 μmol) in toluene (0.6 mL), and the mixture was heated under reflux for 4 hours. The reaction product was cooled to room temperature and concentrated under reduced pressure to obtain the crude product. Purification by silica gel chromatography (5% to 10% ethyl acetate / hexane) yielded α,β-unsaturated benzyl ester Int-26 (7.1 mg, 54%) as a yellow oil. 1 H NMR (401 MHz, CDCl3) δ 7.41 - 7.27 (m, 5H), 6.81 (td, J = 7.5, 1.4 Hz, 1H), 5.27 (m, 1H), 5.18 (s, 2H), 4.29 (dd, J = 11.9, 4.3 Hz, 2H), 4.14 (dd, J = 11.9 , 6.0 Hz, 2H), 2.36 - 2.27 (m, 5H), 2.20 - 2. 08 (m, 3H), 1.93 (m, 1H), 1.85 (d, J = 1.2 Hz , 3H), 1.67 - 1.54 (m, 6H), 1.47 - 1.38 (m, 2 H), 1.37 - 1.19 (m, 54H), 0.93 (d, J = 6.6 Hz , 3H), 0.88 (t, J = 6.9 Hz, 6H); 13 1C 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 (CH 2), 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-necked flask, benzyl ether Int-26(4) in ethyl acetate (2.5 mL) The solution of 8.5 mg (54.0 μmol) was evacuated and flushed with N2 gas (3 times each), then palladium carbon (10% (w / w), 11.5 mg, 10.8 μmol) was added, the resulting suspension was evacuated again and flushed with N2 (3 times each). An H2 balloon was attached to the flask, it was evacuated and flushed with H2 (3 times each), and the reaction mixture was stirred at room temperature for 3 hours under 1 atm of H2. The reaction mixture was filtered through a Celite pad while washing with ethyl acetate, and concentrated under reduced pressure to obtain the crude product. Purification by silica gel chromatography (10% to 20% ethyl acetate / hexane) yielded saturated acid Int-27 (C12α'βMe-acid-2-TG) (28.1 mg, 64%) as a colorless oil. 11H NMR (401 MHz, CDCl3) δ 5.27 (m, 1H), 4.29 (dd, J = 11.9, 4.3 Hz, 2H), 4.14 (dd, J = 11. 9, 6.1 Hz, 2H), 2.46 (m, 1H), 2.37 - 2.26 (m, 5H), 2.12 (dd, J = 14.7, 8.2 Hz, 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); 13 13C NMR (101 MHz, CDCl3) δ 182.3 (C), 1 73.5 (2C;C), 172.5 (C), 69.0 (CH), 62.3 (2C ;CH2), 41.8 (CH2), 39.4 (CH), 36.8 (CH2), 3 4.2 (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]

Chem.

[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 / CH2Cl2 (0.5 mL each), and the mixture was stirred at room temperature for 17 hours. Additional amounts of succinic anhydride (25.4 mg, 0.254 mmol) and DMAP (15.5 mg, 0.127 mmol) were added, and the solution was heated at 40°C for a further 22 hours. The reaction product was diluted with ethyl acetate (25 mL), washed with 1 M HCl (20 mL) and brine (2 × 30 mL), dried, and concentrated under reduced pressure to obtain the crude product. Acid-TGInt-28 (77.0 mg, 91%) was obtained as a colorless solid by silica gel chromatography (15% to 25% ethyl acetate / hexane). 1 H 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 ¹³C NMR (10¹ MHz, CDCl₃) δ 176.9 (C), 173.5 (2C;C), 171.4 (C), 69.8 (C H), 62.0 (2C;CH2), 34.2 (2C;CH2), 32.1 (2C;CH2), 29.84 (6C;CH2), 29.81 (4C;CH2), 29.7 7 (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] [ka]

[0715] Scheme 16. Synthesis of Int-29. CH2Cl2 (2.5 mL) contains 1,3-diglyceride Int-2 (75.0 mg, 0 A solution of 0.132 mmol) and pyridine (107 μL, 1.32 mmol) is added to dichloride 1 (96.1 mL, 0.659 mmol) in CH2Cl2 (2.5 mL), The mixture was heated under reflux for 3.5 hours. The reaction product was cooled to room temperature, diluted with ethyl acetate (30 mL), and the organic extract was washed with 1 M HCl (20 mL) and brine (2 × 20 mL). It was dried and concentrated under reduced pressure to obtain the crude product. Purification by silica gel chromatography (15% to 25% ethyl acetate / hexane) yielded acid-TGInt-29 (52.7 mg, 57%) as a colorless solid. 1 1H 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, 2 H), 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); 13C NMR (101 MHz, CDCl3) δ 178.3 (C), 173.5 (2C;C), 172.4 (C), 69.3 (CH), 62.2 (2C;C H2), 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 (NaH2PO4, 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 mixture was stirred at room temperature for 2.25 hours. The reaction mixture was diluted with water (10 mL), and the aqueous layer was extracted with ethyl acetate (3 × 15 mL). The combined organic extract was washed with brine (30 mL), dried, and concentrated under reduced pressure to obtain the crude product. Purification by silica gel chromatography (10% to 20% ethyl acetate / hexane with 0.5% acetic acid) yielded acid Int-30 (16.1 mg, 75%) as a colorless solid. 1 1H 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, 6 H), 1.40 - 1.14 (m, 56H), 0.93 (d, J = 6.6 Hz , 3H), 0.88 (t, J = 6.9 Hz, 6H); 13 1C 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 the one described above for the synthesis of Int-23.

[0718] [ka]

[0719] 11H NMR (401 MHz, CDCl3) δ 5.28 (m, 1H), 4.2 9 (dd, J = 11.9, 4.3 Hz, 2H), 4.14 (dd, J = 11.8, 6.0 Hz, 2H), 3.64 (t, J = 6.6 Hz, 2H), 2. 32 (dd, J = 14.6, 5.8 Hz, 1H), 2.30 (t, J = 7.5 Hz, 4H), 2.12 (dd, J = 14.6, 8.2 Hz, 1H), 1 .94 (m, 1H), 1.64 - 1.49 (m, 6H), 1.40 - 1.13 (m, 62H), 0.93 (d, J = 6.6 Hz, 3H), 0.88 (t, J = 6.9 Hz, 6H); 13 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), 3 4.1 (2C;CH2), 32.9 (CH2), 32.0 (2C;CH2), 30.4 (CH), 29.80 (CH2), 29.76 (6C;CH2), 29.72 (4C;CH2), 29.68 (2C;CH2), 29.65 (CH2), 29.62 (CH2), 29.53 (2C;CH2), 29.50 (CH2), 29.4 (2C;CH2), 29.3 (2C;CH2), 29.2 (2C;CH2), 27.0 (CH2), 25.8 (CH2), 24.9 (2C;CH2), 22.7 ( 2C;CH2), 19.6 (CH3), 14.2 (2C;CH3). C12α’βMe-OH-2-TG (Int-143):

[0720]

Chem.

[0721] Pyridinium chlorochromate (16.5 mg, 0.0765 mmol) and Celite (16.5 mg) are mixed with alcohol Int-121 (40 mg) in CH2Cl2 (2.5 mL). The aldehyde was added to a solution of 0 mg (0.0512 mmol) at 0°C, and the resulting suspension was stirred at 0°C for 15 minutes, then at room temperature for 3 hours. The reaction mixture was filtered through a silica gel plug while eluting with ethyl acetate (50 mL), and the filtrate was concentrated under reduced pressure to obtain the corresponding aldehyde as a pale yellow oil, which was used without purification.

[0722] Crude aldehyde was redissolved in diethyl ether (2.5 mL) and cooled to -10°C (ice / brine bath). Methyl magnesium bromide (3.0 M, 18.8 μL, 0.0563 mmol in diethyl ether) was added, and the reaction vessel was moved to a freezer (-20°C) and allowed to stand for 19 hours. The mixture was warmed to -10°C, the reaction was slowly stopped by adding saturated NH4Cl aqueous solution (4 mL), and then warmed to room temperature. The aqueous layer was extracted with ethyl acetate (3 × 20 mL), the combined organic extract was washed with water (25 mL) and brine (25 mL), dried (MgSO4), and concentrated under reduced pressure to obtain the crude product. Alcohol Int-143 (21.6 mg, 53%) was obtained as a white solid by silica gel chromatography (0% to 15% ethyl acetate / hexane). 1 1H 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). 13 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): Similar to the method described above for the synthesis of Int-143, Int-269 and Int-270 were prepared from Int-235.

[0723] [ka]

[0724] C12βMe-aldehyde-2-TG-oleate (Int-269). 1 H 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), 2.1 2 (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); 13 13C NMR (101 MHz, CDCl3) δ 173.4 (2C;C), 172.5 (C), 130.1 (2C;CH), 129.8 (2C;CH), 68.9 (C H), 68.3 (CH), 62.3 (2C;CH2), 41.8 (CH2), 3 9.5 (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, 94.0 μL, 98.9 μmol in THF) was mixed with carboxylic acid Int-27 (40.0 mg, 49.9 μmol) in THF (1.5 mL). The mixture was added to a 4 μmol solution at -5°C, stirred at -5°C for 40 minutes, and then allowed to stand in a refrigerator for 19 hours. The reaction product was slowly diluted with cold water (20 mL), and the aqueous phase was extracted with ethyl acetate (3 × 20 mL). The combined organic extract was washed with brine (30 mL), dried, and concentrated under reduced pressure to obtain the crude product. Purification by silica gel chromatography (5% to 15% ethyl acetate / hexane) yielded the alcohol Int-148 (35.8 mg, 91%) as a colorless oil. 1 1H NMR (401 MH) z, 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 under reflux for 2 hours. The reaction mixture was cooled to room temperature, diluted with toluene (5 mL), and concentrated under reduced pressure to obtain the dichloride Int-36 (812 mg, quantified) as a yellow oil, which was used without purification. 1 H NM R (400 MHz, CDCl3): δ 2.88 (t, J = 7.3 Hz, 4H ), 1.76 - 1.65 (m, 4H), 1.42 - 1.23 (m, 12H). A solution of 1,3-diglyceride Int-2 (40.0 mg, 0.0703 mmol) and pyridine (56.9 μL, 0.703 mmol) in CH2Cl2 (1.5 mL) was added to dichloride Int-36 (93.9 mg, 0.352 mmol) in CH2Cl2 (1.5 mL), and the mixture was stirred at room temperature for 16 hours. The reaction product 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 extract was washed with 1 M HCl (30 mL) and brine (2 × 30 mL), dried, and concentrated under reduced pressure to obtain the crude product. Purification by silica gel chromatography (20% to 45% ethyl acetate / hexane) yielded acid-TGInt-37 (30.7 mg, 56%) as a colorless solid. 1 H NM R (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 0.9 Hz, 6H). C15βMe-acid-2-TG(Int-49):

[0731] [ka]

[0732] Synthesis of scheme 19.Int-49. A solution of 1,10-decanediol (1.05 g, 6.00 mmol) in DMF (7 mL) was added dropwise at 0°C to a suspension of sodium hydride (60% w / w in mineral oil, washed twice with dehydrated petrol (240 mg, 6.00 mmol)) in DMF (8 mL), and the mixture was stirred at room temperature for 1 hour. Benzyl bromide (784 μL, 3.50 mmol) was added dropwise, and the mixture was stirred at room temperature for 1.5 hours. The reaction product was diluted with ethyl acetate (30 mL), the reaction was stopped 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, and concentrated under reduced pressure to obtain the crude product. Benzyl ether Int-38 (657 mg, 41%) was obtained as a colorless oil by silica gel chromatography (20% to 30% ethyl acetate / hexane). 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 at 0°C to a solution of alcohol Int-38 (600 mg, 1.11 mmol) in CH2Cl2 (20 mL), and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was diluted with CH2Cl2 (20 mL), silica gel was added, and the solvent was evaporated under reduced pressure. By purification using silica gel chromatography (3%-4% ethyl acetate / hexane), bromide Int-39 (658 mg, 89%) was obtained as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 7.41 - 7.26 (m, 5H), 4.50 (s, 2H), 3.46 (t, J = 6.6 Hz, 2H), 3.40 (t, J = 6.9 Hz, 2H), 1.91 - 1.79 (m, 2H), 1.6 8 - 1.56 (m, 2H), 1.47 - 1.23 (m, 12H). n-butyllithium (n-BuLi, 1.6 M in hexane, 4.01 mL, 6.42 mmol) was slowly added at -78°C to a solution of TMS-acetylene (1.02 mL, 7.22 mmol) in THF (9 mL). The mixture was stirred at -78°C for 5 minutes, then warmed to room temperature and stirred for another 15 minutes. The reaction mixture was cooled 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. The mixture was stirred at -50°C for 30 minutes, then at room temperature for 22 hours. The reaction mixture 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). The combined organic extract was washed with brine (50 mL), dried, and concentrated under reduced pressure to obtain the crude product. Purification by silica gel chromatography (3.5% to 4.5% ethyl acetate / hexane) yielded TMS alkyne Int-40 (489 mg, 88%) as a colorless oil containing a small amount of desilylated alkyne Int-41 (<10%). 1 1H 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 minutes. The reaction product was diluted with water (10 mL), and the aqueous phase was extracted with ethyl acetate (3 × 20 mL). The combined organic extract was washed with brine (40 mL), dried, and concentrated under reduced pressure to obtain the crude product. Alkyne Int-41 (361 mg, 98%) was obtained as a colorless oil by silica gel chromatography (4% to 5% ethyl acetate / hexane). 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), 2.1 8 (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 1C 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 PdCl2(PPh3)2 (32.2 mg, 0.0459 mmol) in DMF (4 mL) was degassed using an N2 gas stream for 5 minutes, and then CuI (35.0 mg, 0.184 mmol), Et3N (256 μL, 1.84 mmol), and degassed solutions 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 further using an N2 stream for 5 minutes, and then heated at 70°C for 1 hour. The reaction product was cooled to room temperature, diluted with ethyl acetate (40 mL), washed with 1 M HCl, saturated NaHCO3 aqueous solution, water, and brine (30 mL each), dried, and concentrated under reduced pressure to obtain the crude product. Silica gel chromatography (4% to 5% ethyl acetate) Enin Int-42 (269 mg, 76%) was obtained as a pale yellow oil using hexane. 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-necked round-bottom flask, a solution of benzyl ether Int-42 (246 mg, 0.640 mmol) in ethyl acetate (25 mL) was evacuated twice, flushed with N2 gas, and then palladium carbon (10% (w / w), 102 mg, 0.0960 mmol) was added. The resulting suspension was evacuated again and flushed with N2 (three times). An H2 balloon was attached to the flask, evacuated, and flushed with H2 (three times). The reaction mixture was stirred at room temperature for 1 hour under 1 atm of H2. 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 obtain saturated alcohol Int-43 (192 mg, quantified) 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). 1 3 C NMR (101 MHz, CDCl3) δ 173.6 (C), 63.2 (C H2), 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 hours. The reaction product was diluted with ethyl acetate (20 mL), washed with water (20 mL) and brine (2 × 20 mL), dried, and concentrated under reduced pressure to obtain the crude product. Purification by silica gel chromatography (3% to 4% ethyl acetate / hexane with 0.5% Et3N) yielded TBDPS ether Int-44 (117 mg, 93%) as a colorless oil. 1 1H NMR (400 MH) z, 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), 4 2.1 (CH2), 36.9 (CH2), 32.7 (CH2), 30.5 (CH ), 29.9 (CH2), 29.79 (3C;CH2), 29.77 (2C;CH 2), 29.5 (CH2), 27.1 (CH2), 27.0 (3C;CH3), 25.9 (CH2), 19.9 (CH3), 19.4 (C), 14.4 (CH3 ). A solution of potassium hydroxide (2.0 M, 390 μL, 0.781 mmol) was added to ester Int-44 (42.1 mg, 0.0781 mmol) in ethanol (2 mL), and the mixture was heated at 60 °C for 1.5 hours. The reaction product was acidified to pH 1 by adding 1 M HCl, diluted with water (10 mL), and the aqueous phase was extracted with ethyl acetate (3 × 15 mL). The combined organic extract was washed with brine (30 mL), dried, and concentrated under reduced pressure to obtain crude acid Int-45 (39.9 mg, quantified) 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 (2 C;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 CH2Cl2 (2.5 mL), and the mixture was stirred at room temperature for 19 hours. The reaction product was diluted with CH2Cl2 (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) yielded 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, 2 H), 4.15 (dd, J = 11.9, 6.1 Hz, 2H), 3.66 (t, J = 6.5 Hz, 2H), 2.34 (dd, J = 14.6, 6.0 Hz, 1H), 2.31 (t, J = 7.5 Hz, 4H), 2.13 (dd, J = 14.6, 8.3 Hz, 1H), 1.94 (m, 1H), 1.68 - 1.52 (m, 6H), 1.44 - 1.16 (m, 68H), 1.05 (s, 9H), 0.94 (d, J = 6.6 Hz, 3H), 0.88 (t, J = 6.8 Hz, 6H); 13 C NMR (101 MHz, CDCl3) δ 173.4 (2C;C) , 172.5 (C), 135.7 (4C;CH), 134.3 (2C;C), 1 29.6 (2C;CH), 127.7 (4C;CH), 68.9 (CH), 64.1 (CH2), 62.3 (2C;CH2), 41.8 (CH2), 36.8 (C H2), 34.2 (2C;CH2), 32.7 (CH2), 32.1 (2C;CH2), 30.5 (CH), 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 hours. The reaction product 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 NaHCO3 solution and brine (30 mL each), dried, and concentrated under reduced pressure to obtain the crude product. Purification by silica gel chromatography (10% to 15% ethyl acetate / hexane) yielded alcohol Int-47 (34.2 mg, 67%) as a colorless oil. 1 H 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 ¹³C 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 at 0°C to a suspension of alcohol Int-47 (28.0 mg, 34.0 μmol) and Celite (15 mg) in CH2Cl2 (1.5 mL), and the mixture was stirred at room temperature for 1 hour. The reaction product was filtered through a silica gel short pad while eluting with ethyl acetate, and the filtrate was concentrated under reduced pressure to obtain crude aldehyde Int-48 (27.9 mg, quantified) as a yellow oil, which was used without purification. 1 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 (NaH2PO4, 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 mixture was stirred at room temperature for 16 hours. The reaction mixture 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 extract was washed with brine (30 mL), dried, and concentrated under reduced pressure in ((MgSO4)) to obtain the crude product. Purification by silica gel chromatography (10% to 15% ethyl acetate / hexane with 0.5% acetic acid) yielded 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, 6 6H), 0.93 (d, J = 6.6 Hz, 3H), 0.87 (t, J = 6.8 Hz, 6H); 13 C NMR (101 MHz, CDCl3) δ 179.5 ( C), 173.5 (2C;C), 172.5 (C), 68.9 (CH), 62. 3 (2C;CH2), 41.9 (CH2), 36.8 (CH2), 34.2 (2 C;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 (C8βMe-OH-2-TG-oleate) was prepared from 1-(tert-butyldiphenylsilyloxy)-penta-4-yne, benzyl(Z)-3-(((trifluoromethyl)sulfonyl)oxy)buta-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. 1 H 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), (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, J = 390). 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), 4 1.67 (1C), 36.56 (1C), 34.05 (2C), 32.72 (1 C), 31.93 (2C), 30.27 (1C), 29.79 - 29.12 (16C), 27.24 (2C), 27.20 (2C), 26.67 (1C), .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). Int-177 (4.0 g, 5.14 mmol) A freshly prepared Jones reagent (6.4 mL, 2.1 equivalents) was added dropwise at 0°C, and the resulting reaction mixture was stirred at 0°C for 4 hours. The reaction mixture was stopped with water (40 mL) and extracted with ethyl acetate (3 × 40 mL). The combined organic layer was dried over Na₂SO₄ and evaporated under reduced pressure. The residue was purified by column chromatography using silica gel (100-200 mesh) while eluting the product with 8-10% ethyl acetate / hexane to obtain Int-178 (1.5 g, 37%) as a colorless oil. 1 H 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 (2 C), 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 (14 C), 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-benzyloxypentan-5-ol and Int-112, respectively, following 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, following the procedure described for the preparation of Int-178.

[0737] Int-185. 1 H 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-oleate (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), 2.108-1.98 0 (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), 3 1.91 (2C), 30.33 (1C), 29.71 (4C), 29.53 (4 C), 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). 1 H 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), 30.3 0 (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-benzyloxyheptan-7-ol and Int-112, respectively, following 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, following 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 - 1.1 1 (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, 1 4.1; MS (ESI, +ve) m / z: 851.13 (M+18). C12βMe-acid-2-TG-oleate (Int-236). 1 H 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 (d d, 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); 13 ¹¹¹ MHz, ¹¹¹ 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) 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 was prepared according to Subba Reddy, BVet al. Helv. Chim. Acta. 2013, 96, 1983-1990.

[0749] A known compound that can be prepared as disclosed in 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 at -78°C to a solution of TMS-acetylene (5.7 mL, 41.5 mmol) in THF (45 mL), and the mixture was stirred at -78°C for 5 minutes. The mixture was heated to room temperature and stirred for a further 15 minutes. The reaction mixture was cooled again to -78°C, and solutions of bromide Int-51 (3.10 g, 10.4 mmol) and DMPU (6.3 mL, 51.8 mmol) in THF (30 mL) were slowly added. The mixture was stirred at -78°C for 30 minutes, then at room temperature for 18 hours. The reaction mixture 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, and concentrated under reduced pressure to obtain the crude product. Purification by silica gel chromatography (Reveleris 80 g column, 60 mL / min, 4% to 40% ethyl acetate / hexane) yielded 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 - 1.5 7 (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 hour. The reaction product 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, and concentrated under reduced pressure to obtain the crude product. Purification by silica gel chromatography (Reveleris 80 g column, 60 mL / min, 3% to 10% ethyl acetate / hexane) yielded alkyne Int-53 (2.17 g, 92%). 1H 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 (2 C;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 PdCl2(PPh3)2 (605 mg, 0.862 mmol) in DMF (40 mL) was degassed for 5 minutes using N2 gas, and then CuI (335 mg, 1.76 mmol), Et3N (2.40 mL, 17.2 mmol), and degassed solutions 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 further degassed for 5 minutes using N2 stream, and then heated at 70°C for 1 hour. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to about one-quarter of its original volume. The resulting solution was diluted with ethyl acetate (80 mL), washed with 1 M HCl, saturated NaHCO3 aqueous solution, water, and brine (30 mL each), dried, and concentrated under reduced pressure to obtain the crude product. Enine Int-54 (2.35 g, 76%) was obtained as a pale yellow oil by silica gel chromatography (Reveleris 80 g column, 60 mL / min, 5% to 20% ethyl acetate / hexane).1 H NMR (401 MHz, CDCl3) δ 7.37 - 7.24 (m, 5H), 5.92 (d, J = 1.4 Hz, 1H), 4.50 (s, 2H), 4.18 (q, J = 7.1 Hz, 2H), 3.46 (t, J = 6.6 Hz, 2H), 2.43 (t, J = 7.2 Hz, 2H), 2.01 (d, J = 1.4 Hz, 3H), 1.65 - 1.55 (m, 4H) , 1.46 - 1.30 (m, 8H), 1.28 (t, J = 7.1 Hz, 3H); 13 C NMR (101 MHz, CDCl3) δ 165.4 (C), 138.8 (C), 135.9 (C), 128.5 (2C;CH), 127.7 (2C; CH), 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 (CH 2), 28.6 (CH2), 26.3 (CH2), 26.0 (CH3), 20. 1 (CH2), 14.4 (CH3). In a three-necked round-bottom flask, a solution of benzyl ether Int-54 (707 mg, 1.98 mmol) in ethyl acetate (80 mL) was evacuated twice and flushed with N2 gas. Then, palladium carbon (10% (w / w), 525 mg, 0.494 mmol) was added, and the resulting suspension was evacuated again and flushed with N2 (three times). An H2 balloon was attached to the flask, evacuated, and flushed with H2 (three times). The reaction mixture was stirred at room temperature for 2 hours under 1 atm of H2. Then, the flask was evacuated and flushed with N2. The reaction mixture was filtered by washing with ethyl acetate (80 mL) and passing through a Celite pad. The filtrate was concentrated under reduced pressure to obtain saturated alcohol Int-55 (540 mg, quantified) 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 at 0°C to a solution of alcohol Int-55 (1.48 g, 5.42 mmol) in CH2Cl2 (80 mL), and the mixture was stirred at room temperature for 2.5 hours. The reaction product was concentrated under reduced pressure to half its volume, washed with water (2 × 20 mL) and brine (30 mL), dried in (MgSO4), and concentrated under reduced pressure to obtain the crude product. Purification by silica gel chromatography (Reveleris 80 g column, 60 mL / min, 1% to 16% ethyl acetate / hexane) yielded 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 0.6 Hz, 3H). A solution of potassium hydroxide (2.0 M, 11.3 mL, 22.6 mmol) was added to 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 mixture was adjusted to pH 2 by adding 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, and concentrated under reduced pressure to obtain the crude product. A pure sample of acid Int-57 (321 mg, 29%) was obtained as a pale yellow oil by silica gel chromatography (5% to 25% ethyl acetate / hexane), which was used for analysis. An additional 750 mg+ of 9 was obtained, containing slight contamination by an unknown TBDPS species; this material was carried over and purified 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 = 6.6H z, 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 CH2Cl2 (20 mL), and the mixture was stirred at room temperature for 20 hours. The reaction product was diluted with CH2Cl2 (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) yielded triglyceride Int-58 (416 mg, 67%) as a colorless solid. 1 1H NMR (401 M) Hz, CDCl3) δ 7.69 - 7.64 (m, 4H), 7.44 - 7.34 (m, 6H), 5.28 (m, 1H), 4.289 / 4.288 (dd, J respectively) = 11.9, 4.3 Hz, 2H), 4.14 (dd, J = 12.0, 6.0 Hz, 2H), 3.65 (t, J = 6.5 Hz, 2H), 2.34 (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 at 0°C to a solution of TBDPS ether Int-58 (395 mg, 0.383 mmol) in THF (15 mL), and the mixture was stirred at room temperature for 17 hours. The reaction product was concentrated under reduced pressure, the residue was diluted with ethyl acetate (30 mL), washed with water (2 × 20 mL) and brine (30 mL), dried, and concentrated under reduced pressure to obtain the crude product. Purification by silica gel chromatography (5% to 25% ethyl acetate / hexane) yielded 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, respectively), 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 at 0°C to a suspension of alcohol Int-59 (263 mg, 0.331 mmol) and Celite (150 mg) in CH2Cl2 (18 mL), and the mixture was stirred at room temperature for 4 hours. The reaction product was filtered through a silica gel short pad while eluting with ethyl acetate, and the filtrate was concentrated under reduced pressure to obtain crude aldehyde Int-60 (262 mg, quantified) as a yellow oil, which was used without purification. 1 1H NMR (401 MHz, CDCl3) δ 9.76 (t, J = 1.8 Hz, 1H), 5.27 (m, 1H), 4.2 9 (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, 2 H), 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 under reflux for 20 hours. The reaction product was cooled to room temperature and concentrated under reduced pressure to obtain the crude product. Purification by silica gel chromatography (5% to 15% ethyl acetate / hexane) yielded α,β-unsaturated benzyl ester Int-61 (273 mg, 88%) as a yellow oil. 1 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), 1.6 5 - 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 ¹³C 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-necked flask, a solution of benzyl ester Int-61 (246 mg, 0.262 mmol) in ethyl acetate (10 mL) was evacuated and flushed with N2 gas (3 times each), then palladium carbon (10% (w / w), 55.7 mg, 0.0524 mmol) was added, the resulting suspension was evacuated again and flushed with N2 (3 times each). An H2 balloon was attached to the flask, it was evacuated and flushed with H2 (3 times each), and the reaction mixture was stirred at room temperature under 1 atm of H2 for 1.5 hours. The reaction mixture was filtered through a Celite pad while washing with ethyl acetate, and concentrated under reduced pressure to obtain the crude product. Purification by silica gel chromatography (5% to 20% ethyl acetate / hexane) revealed saturated acid Int- 62 (193 mg, 87%) was obtained 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 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, 1 H), 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 H z, 3H), 0.88 (t, J = 6.9 Hz, 6H). C15α'βMe-acid-2-TG-butyrate (Int-219):

[0752] [ka]

[0753] Synthesis of scheme 20-A.Int-219. Using the procedure for preparing Int-56 described above, Int-211 was prepared from deca-9-in-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 PdCl2(PPh3)2 (6.44 g, 9.18 mmol) in CH3CN (180 mL) was degassed using N2 gas for 5 minutes, and then CuI (1.74 g, 9.18 mmol), Et3N (18.54 g, 183.7 mmol), and degassed solutions of alkynes Int-211 (36.0 g, 91.8 mmol) and Int-198 (29.75 g, 91.83 mmol) in CH3CN (180 mL) were added. The mixture was further degassed using a stream of N2 for 5 minutes, and then heated at 60°C for 2 hours. The reaction mixture was cooled to room temperature, diluted with water (360 mL), and extracted with SiO2 (3 × 360 mL). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained oil was purified by column chromatography using silica gel (100 to 200 mesh) while eluting the product with 4-7% phenylethylamine in hexane to obtain 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), 1.5 9 (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 using a procedure similar to that for preparing 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 using a procedure similar to that for preparing Int-60 described above.

[0754] Int-215 (68.19 g, 174.8 mmol; prepared from triphenylphosphine and t-butyl 2-bromopropanoate) was added to a solution of Int-214 (190 mL) in toluene (190 mL) at room temperature under a nitrogen atmosphere. The resulting reaction mixture was heated at 90 °C for 2 hours. 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) while eluting the product with 2-4% phenylethylamine in hexane to obtain 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-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. The autoclave was evacuated and N2 was refilled (3 times). The autoclave was evacuated and N2 was refilled to 10 kg / cm³. 2 The reaction mixture was pressurized with H2 pressure and stirred at room temperature for 72 hours. The reaction mixture was filtered through a Celite pad and washed with additional ethyl acetate (380 mL). The filtrate was concentrated under reduced pressure to obtain Int-217 (13 g, 84.2%) as a colorless oil, which was used in the next step without further purification. 1H 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 H z, 3H). Int-217 (6.0 g, 16.4 mmol) in DCM (120.0 mL) at room temperature. EDC.HCl (7.8g, 41.1mmol) and DMAP (2.0g, 16.4mmol) were added to a stirred solution of Int-115 (3.81g, 16.4mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under vacuum. The resulting residue was purified by column chromatography using silica gel while eluting with 4-5% phenylethylamine in n-hexane to obtain Int-218 (6.0g, 62.5%) as a brownish, viscous liquid. 1 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 hours. The reaction mixture was concentrated under vacuum. The residue was diluted with water (500 mL) and extracted with ethyl acetate (2 × 500 mL). The combined organic layers were washed with sodium bicarbonate solution and brine, then dried over sodium sulfate, filtered, and concentrated under vacuum to obtain Int-219 (5.1 g, 94%) as a yellowish, viscous liquid. 1 1H 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); 13 C 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 (2C), 33.5 2 (1C), 30.39 (1C), 29.76-29.45 (6C), 27.12 (1C), 26.91 (1C), 19.53 (1C), 18.33 (2C), 16.80 (1C), 13.60 (2C);MS (ESI, +ve) m / z: 53 2.70 (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); 13 13C NMR (10¹ MHz, CDC) l3) 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 (2C), 33.55 (2C), 3 1.69 (1C), 30.39 (1C), 29.80-28.93 (14C), 27.16 (1C), 26.95 (1C), 19.58 (1C), 16.85 (1 C), 14.09 (2C);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); 13 C 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), 31.9 4 (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 (ES I, -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(trideca-12-in-1-yloxy)silane (which was 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), 2.39-2.3 1 (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); 13 C 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): Using the procedure described for the synthesis of Int-219, compounds Int-229, Int-230, and Int-231 were prepared from Int-112 and hepta-6-in-1-ol.

[0761]

Chem.

[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). 1 H 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), 1.4 8 (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 H NMR (400 MHz, CDCl3) δ 5.4...

Claims

1. Compound of formula I, 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, in the formula, R １ and R ２ However, each independently comprises hydrogen, an acid-unstable group, a lipid, or -C(O)R. ３ And, Each R ３ The C molecules are independently saturated or unsaturated, linear or branched, and optionally substituted. １－３７ It is a hydrocarbon chain, X is —O—, —NR—, —S—, —O(C １－６ aliphatic)-O—, —O(C １－６ aliphatic)-S—, —O(C １－６ aliphatic)-NR—, —S(C １－６ aliphatic)-O—, —S(C １－６ aliphatic)-S—, —S(C １－６ aliphatic)-NR—, —NR(C １－６ aliphatic)-O—, —NR(C １－６ aliphatic)-S—, or —NR(C １－６ aliphatic)-NR—, and 0 to 2 methylene units of the C １－６ aliphatic group are independently and optionally replaced by —O—, —NR—, or —S—, and the C １－６ aliphatic group is independently and optionally substituted by 1, 2, or 3 deuterium or halogen atoms, Each R is independently either hydrogen or C １－６ A optionally substituted group selected from aliphatic, 3-8 member saturated or partially unsaturated monocyclic carbocycles, phenyl, 8-10 member bicyclic aromatic carbocycles, 4-8 member saturated or partially unsaturated monocyclic heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-6 member monocyclic heteroaromatic rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 8-10 member bicyclic heteroaromatic rings having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Y is either absent, or -C(O)-, -C(NR)-, or -C(S)- L is either covalently bonded, or optionally substituted with divalent C, which is saturated or unsaturated, linear or branched. １－３０ It is a hydrocarbon chain, and the 0 to 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) ２ It is replaced by NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O-, or an amino acid, and one methylene unit of L is optionally replaced with -M-, or L, 【Chemistry 2】 And either the right or left side of L is 【Transformation 3】 It is connected, Each -Cy- independently has 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and is an optionally substituted 3 to 6-membered divalent saturated ring, partially unsaturated ring, or aromatic ring. Each R ４ and R ５ These independently consist of hydrogen, deuterium, halogen, -CN, -OR, and -NR. ２ -SR, a 3-8 member saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8-10 member bicyclic aromatic carbocycle, a 4-8 member saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 member monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 member bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or -CN, -OR, -NR ２ , -SR, a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, phenyl, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted with C １－６ Aliphatic group (or the C) １－６ The aliphatic atom is optionally substituted with 1, 2, 3, 4, 5, or 6 deutherium or halogen atoms, or R bonded to the same carbon atom ４ or R ５ These two occurrences, together with the carbon atoms bonded to them, form a 3-6 member spirocyclic saturated monocyclic carbocyclic ring, or a 3-6 member spirocyclic saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. -M- is a self-destructing group, n is between 0 and 18. Each m is independent and ranges from 0 to 6. 【Chemistry 4】 However, natural or unnatural neurosteroids or their analogues or prodrugs There is a certain therapeutic agent, The aforementioned compound, or a pharmaceutically acceptable salt thereof.

2. R １ and R ２ However, -C(O)R ３ The compound according to claim 1.

3. Each R ３ These independently form saturated or unsaturated unbranched C ２－３７ The compound according to claim 1 or 2, which is a hydrocarbon chain.

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

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

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

7. L is either covalently bonded, or optionally substituted with divalent C, which is saturated or unsaturated, linear or branched. １－３０ It is a hydrocarbon chain, and the 0 to 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) ２ NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O-, or 【Transformation 5】 It is replaced by an amino acid selected from, and one methylene unit of L is optionally replaced with -M-, or L, 【Transformation 6】 And either the right or left side of L is 【Transformation 7】 It is connected, The compound according to any one of claims 1 to 5.

8. L is a combination of deuterium, halogens, -CN, a 3-6 member saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from phenyl, nitrogen, oxygen, and sulfur, a 5-6 member monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and C which is optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms. １－６ A saturated divalent carbon atom optionally substituted with one, two, three, or four aliphatic groups. １－２５ The compound according to any one of claims 1 to 5, wherein 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 1 methylene unit of L is optionally replaced with -M-.

9. -M- is selected from one of the following: 【Transformation 8】 In the formula, each R ６ These independently become hydrogen, deutherium, and C １－５ It is aliphatic, halogen, or -CN, Each R ７ These independently consist of hydrogen, deuterium, halogen, -CN, -OR, and -NR. ２ , -NO ２ -SR, a 3-8 member saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 member bicyclic aromatic carbocyclic ring, a 4-8 member saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 member monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur It is a bicyclic heteroaromatic ring with 8 to 10 members, or -CN, -OR, -NR ２ , -SR, a 3-8 member saturated or partially unsaturated monocyclic carbocycle, phenyl, a 4-8 member saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 member monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 member bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, optionally substituted with C １－６ Aliphatic group (or the C) １－６ (The aliphatic atom is optionally substituted with 1, 2, 3, 4, 5, or 6 deutherium or halogen atoms.) Each Z １ These are independently -O-, -NR-, or -S-, Each Z ２ These are independently -O-, -NR-, -S-, -OC(O)-, -NRC(O)O-, or -OC(O)NR-, Each Z ３ Independently, =N- or =C(R ７ ) - and Each Z ４ These are independent of -O-, -NR-, -S-, and -C(R ６ ) ２ - or covalent bond, The compound according to any one of claims 1 to 8.

10. -M- 【Chemistry 9】 A compound according to claim 9, selected from the above.

11. -M- is, 【Chemistry 10】 A compound according to claim 9 or 10, selected from the above.

12. Each R ４ C is independently hydrogen, deuterium, halogen, -CN, or 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 The compound according to any one of claims 1 to 11, wherein the two occurrences of the carbon atoms bonded to them together form a 3-6 member spirocyclic saturated monocyclic carbocyclic ring, or a 3-6 member spirocyclic saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

13. Each R ５ C is independently hydrogen, deuterium, halogen, -CN, or 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 The compound according to any one of claims 1 to 12, wherein the two occurrences of the carbon atoms bonded to them together form a 3-6 member spirocyclic saturated monocyclic carbocyclic ring, or a 3-6 member spirocyclic saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

14. Each R ４ and R ５ C independently is either hydrogen or optionally substituted with 1, 2, 3, 4, 5, or 6 deutherium or halogen atoms. １－４ A compound according to any one of claims 1 to 13, wherein it is alkyl. 【Request Item 15】 【Chemistry 11】 The compound according to any one of claims 1 to 13, wherein the compound is allopregnanolone, pregnanolon, pregnenolone, ganaxolone, alfaxalone, 3β-dihydroprogesterone, isopregnanolone, epipregnanolon, or 21-hydroxyalopregnanolone. 【Request Item 16】 【Chemistry 12】 The compound according to any one of claims 1 to 14, wherein the compound is allopregnanolone. 【Request Item 17】 【Chemistry 13】 The compound according to any one of claims 1 to 11, wherein the compound is a non-natural (synthetic) excitatory neurosteroid.

18. The compound according to claim 1, wherein the compound is one of the compounds listed in Table 1.

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

20. A pharmaceutically acceptable composition according to claim 19, further comprising an additional therapeutic agent.

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

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

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

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

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

26. The method according to claim 22 or 23, wherein the disease, disorder, or pathological condition is Fragile X syndrome or Fragile X-associated syndrome.

27. The method according to claim 22 or 23, wherein the disease, disorder, or condition is Fragility X-associated tremor / ataxia syndrome (FXTAS).

28. The method according to claim 22 or 23, wherein the disease, disorder, or condition is epilepsy or an epileptic disorder.

29. The method according to claim 28, wherein the epileptic disorder is acute recurrent seizures, treatment-resistant seizures, status epilepticus, or epileptic seizures or convulsions.

30. The method according to claim 28, wherein the epileptic disorder is an epileptic seizure selected from tonic-clonic seizures (grand mal seizures), partial (focal) seizures, catamenial seizures, acute recurrent seizures, psychomotor (complex partial) seizures, absence seizures (petit mal seizures), and myoclonic seizures.

31. The method according to claim 22 or 23, wherein the disease, disorder, or pathological condition is a demyelinating disease.

32. The method according to claim 31, wherein the demyelinating disease is multiple sclerosis, neuromyelitis optica, optic neuritis, transverse myelitis, acute disseminated encephalomyelitis, adrenoleukodystrophy and adrenal spinal neuropathy, Guillain-Barré syndrome, antimyelin-associated glycoprotein peripheral neuropathy, Charcot-Marie-Tooth disease, progressive inflammatory neuropathy, chronic inflammatory demyelinating polyneuropathy, or amyotrophic lateral sclerosis (ALS).

33. The method according to claim 31, wherein the demyelinating disease is multiple sclerosis.

34. The method according to claim 33, wherein the multiple sclerosis is relapsing-remitting multiple sclerosis or primary progressive multiple sclerosis.

35. The method according to claim 22 or 23, wherein the disease, disorder, or pathological condition is a lysosome storage disorder.

36. The aforementioned lysosome storage disorders include Faber disease, Krabbe disease, Fabry disease, Schindler disease, GM1 gangliosidosis, GM2 gangliosidosis, Tay-Sachs disease, Sandhoff disease, Gaucher disease, lysosomal acid lipase deficiency, Niemann-Pick disease, sulfatidosis, metachromatic leukodystrophy, Harler syndrome, Schiet syndrome, Harler-Schey syndrome, Hunter syndrome, Sanfilippo syndrome, Morquio syndrome, and Maloto-Lamy syndrome. The method according to claim 35, wherein the disease is one of the following: Sly syndrome, hyaluronidase deficiency, sialidosis, Icel disease, phosphotransferase deficiency, mucolipidine 1 deficiency, neuronal ceroid lipofuscinosis, Wolmann disease, alpha-mannosis, beta-mannosis, aspartylglucosamiuria, fucoside disease, cystinosis, concentrated dysostosis, Salah disease, childhood free sialic acid storage disease, Pompe disease, Danon disease, cholesteryl ester storage disease, or lysosomal storage disease.

37. The method according to claim 22 or 23, wherein the disease, disorder, or pathological condition is a sleep disorder.

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