WO2022235587A1 - Lipid prodrugs of tryptamine and phenethylamine psychedelics and uses thereof - Google Patents

Lipid prodrugs of tryptamine and phenethylamine psychedelics and uses thereof Download PDF

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WO2022235587A1
WO2022235587A1 PCT/US2022/027336 US2022027336W WO2022235587A1 WO 2022235587 A1 WO2022235587 A1 WO 2022235587A1 US 2022027336 W US2022027336 W US 2022027336W WO 2022235587 A1 WO2022235587 A1 WO 2022235587A1
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acid
independently selected
membered
nitrogen
sulfur
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PCT/US2022/027336
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French (fr)
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Sam CLARK
Matthew Alexander James Duncton
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Terran Biosciences Inc.
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Publication of WO2022235587A1 publication Critical patent/WO2022235587A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/543—Lipids, e.g. triglycerides; Polyamines, e.g. spermine or spermidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C07D209/16—Tryptamines

Definitions

  • R 1 and R 2 are each independently hydrogen, an acid-labile group, a lipid, or -C(0)R 3 ; each R 3 is independently a saturated or unsaturated, straight or branched, optionally substituted Ci- 37 hydrocarbon chain;
  • X is -0-, -NR-, -S-, -0(Ci- 6 aliphatic)-0-, -0(Ci- 6 aliphatic)-S-, -0(Ci- 6 aliphatic)-NR-, -S(Ci- 6 aliphatic)-0-, -S(Ci- 6 aliphatic)-S-, -S(Ci- 6 aliphatic)-NR-, -NR(C I-6 aliphatic)-0-, -NR(Ci- 6 aliphatic)-S-, or -NR(C I-6 aliphatic)-NR-, wherein 0 to 2 methylene units of the Ci- 6 aliphatic group are independently and optionally replaced with -0-, -NR-, or -S- and the Ci- 6 aliphatic group is independently and optionally substituted with 1, 2, or 3 deuterium or halogen atoms; each R is independently hydrogen or an optionally substituted group selected from
  • Y is absent or is -C(O)-, -C(NR)-, or -C(S)-;
  • L is a covalent bond or a saturated or unsaturated, straight or branched, optionally substituted bivalent C 1-30 hydrocarbon chain, wherein 0-8 methylene units of L are independently replaced by -Cy-, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -SO 2 -, -C(S)-, - NRSO2-, -SO2NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O-, or an amino acid; and wherein 1 methylene unit of L is optionally replaced with -M-; or wherein either the right-hand side or left-hand side of L is attached to A; each -Cy
  • R 1 and R 2 are -C(O)R 3 .
  • each R 3 is independently a saturated or unsaturated, unbranched C 2-37 hydrocarbon chain.
  • each R 3 is C15H31.
  • X is -O-.
  • Y is -C(O)-.
  • L is a saturated or unsaturated, straight or branched, optionally substituted bivalent C 7-20 hydrocarbon chain, wherein 0-8 methylene units of L are independently replaced by -Cy-, -O-, -NR-, -S-, -OC(O)-, - C(O)0-, -C(O)-, -S(O)-, -S(O)2-, - C(S)-, -NRSO2-, -SO2NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O-, or an amino acid; and wherein 1 methylene unit of L is optionally replaced with -M-.
  • L is a covalent bond or a saturated or unsaturated, straight or branched, optionally substituted bivalent C1-30 hydrocarbon chain, wherein 0-8 methylene units of L are independently replaced by -Cy-, -O-, -NR-, -S-, - OC(O)-, -C(O)0-, -C(O)-, -S(O)-, -SO 2 -, -C(S)-, -NRSO 2 -, -S, -OC(O)NR-, -NRC(O)O-, or an amino acid selected from wherein 1 methylene unit of L is optionally replaced with -M-; or wherein either the right-hand side or left-hand side of L is attached to A.
  • L is a saturated bivalent C1-25 hydrocarbon chain optionally substituted with 1, 2, 3, or 4 groups selected from deuterium, halogen, -CN, a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 4-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a C 1-6 aliphatic group optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; wherein 0-4 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 with -M-.
  • -M- is selected from one
  • each R 6 is independently selected from hydrogen, deuterium, C1-5 aliphatic, halogen, or - CN; each R 7 is independently selected from hydrogen, deuterium, halogen, -CN, -OR, -NR2, -NO2, -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a Ci- 6 aliphatic group optionally substituted with -CN, -OR, -NR2, -SR, a 3-8 membered
  • -M- is selected from
  • each R 4 is independently hydrogen, deuterium, halogen, - CN, or Ci- 4 aliphatic optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; or two instances of R 4 attached to the same carbon atom, taken together with the carbon atom to which they are attached, form a 3-6 membered spirocyclic saturated monocyclic carbocyclic ring or 3-6 membered spirocyclic saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • each R 5 is independently hydrogen, deuterium, halogen, -CN, or C1-4 aliphatic optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; or two instances of R 5 attached to the same carbon atom, taken together with the carbon atom to which they are attached, form a 3-6 membered spirocyclic saturated monocyclic carbocyclic ring or 3-6 membered spirocyclic saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • each R 4 and R 5 is independently hydrogen or Ci- 4 alkyl optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms.
  • each R 4 and R 5 is independently hydrogen or methyl.
  • L is a bond, , , [00010]
  • p is 1, 2, 3, 4, 5, 6, 7, or 8.
  • p is an integer of 1 to 7.
  • p is 1.
  • p is 2.
  • p is 3.
  • p is 4.
  • p is 5.
  • p is 6.
  • p is 7.
  • L is a bond
  • A is selected from N,N-Dimethyltryptaminec (DMT), 5- MeO-DMT (5-methoxy-N,N-dimethyltryptamine), and O-methyl-bufotenin.
  • DMT N,N-Dimethyltryptaminec
  • 5- MeO-DMT 5-methoxy-N,N-dimethyltryptamine
  • O-methyl-bufotenin O-methyl-bufotenin.
  • A is DMT or 5-MeO-DMT.
  • the compound is of Formula VIII-a or Formula VIII-b:
  • the compound is selected from one of those in Table 1, or a pharmaceutically acceptable salt thereof.
  • compositions comprising a compound according to those described herein , and a pharmaceutically acceptable excipient, carrier, adjuvant, or vehicle.
  • the pharmaceutically acceptable compositions further comprise an additional therapeutic agent.
  • the composition is formulated for oral administration.
  • a disease, disorder, or condition in which an increased level of a tryptamine or phenethyl amine psychedelic such as DMT or 5-MeO-DMT is beneficial or a disease, disorder, or condition caused by a deficiency in a tryptamine or phenethylamine psychedelic such as DMT or 5- MeO-DMT, comprising administering to a subject in need thereof an effective amount of a compound described herein.
  • kits for treating a disease, disorder, or condition caused by deficient activation of serotonin 5HT receptors comprising administering to a subject in need thereof an effective amount of a compound described herein.
  • FIG. 1 shows some exemplary lipid prodrugs of 5-MeO-DMT and DMT.
  • FIGs. 2A-2B show plasma concentration-time profiles of DMT prodrug
  • R 1 and R 2 are each independently hydrogen, an acid-labile group, a lipid, or -C(O)R 3 ; each R 3 is independently a saturated or unsaturated, straight or branched, optionally substituted C 1-37 hydrocarbon chain;
  • X is -O-, -NR-, -S-, -O(C1-6 aliphatic)-O-, -O(C1-6 aliphatic)-S-, -O(C1-6 aliphatic)-NR-, -S(C1-6 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-, wherein: R 1 and R 2 are each independently hydrogen, an acid-labile group, a lipid, or -C(
  • -M- is a self-immolative group
  • n is 0-18
  • each m is independently 0-6;
  • A is a therapeutic agent selected from a naturally-occurring or non naturally-occurring tryptamine or phenethylamine psychedelic such as DMT or 5-MeO-DMT or an analogue or prodrug thereof.
  • the present invention provides a method of treating a disease, disorder, or condition in a patient in need thereof, comprising administering to the patient an effective amount of a disclosed lipid prodrug, such as a compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • a disclosed lipid prodrug such as a compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • lipid prodrug may exist in the form of a pharmaceutically acceptable salt.
  • a reference to a “lipid prodrug” is also a disclosure of “lipid prodrug or a pharmaceutically acceptable salt thereof.” It follows that such a lipid prodrug or pharmaceutically acceptable salt thereof may be used in a pharmaceutical composition and a method of use, such as those disclosed herein.
  • lipid prodrug comprising a therapeutic agent conjugated to a glycerol- based moiety comprising two fatty acids or other lipids.
  • a prodrug mimics a dietary triglyceride, such that it participates in triglyceride processing and metabolism in the GI tract.
  • certain lipid prodrug scaffolds may be modified from the literature for use in accordance with the present disclosure.
  • lipid prodrug scaffolds are disclosed in WO 2017/041 139 and WO 2016/023082, each of which is hereby incorporated by reference in its entirety.
  • Further examples of drug-lipid conjugates where the parent drug contains an available carboxylic acid group and has been directly conjugated to a glyceride backbone are described in Paris, G . Y. et ak, J . Med. Chem. 1979, 22, (6), 683-687; Garzon Aburbeh, A . et ak, J . Med. Chem. 1983, 26, (8), 1200-1203; Deverre, J . R.; et al, J . Pharm. Pharmacol.
  • Typical use of prodrug strategies to improve a therapeutic agent’s (active pharmaceutical agent’s) pharmacokinetic properties relies on cleavage in vivo to the parent agent via non-specific degradation or enzymatic cleavage, thus allowing the agent to exert its biological activity.
  • the present invention in one aspect, provides modified glyceride-based compounds (lipid prodrugs) that direct lymphatic transport of a therapeutic agent and improve cleavage of the lipid prodrug to the therapeutic agent.
  • Dietary lipids including triglycerides, follow a particular metabolic pathway to gain access to the lymph (and ultimately the systemic circulation) that is entirely distinct from that of other nutrients such as proteins and carbohydrates.
  • dietary triglycerides are hydrolyzed by lipases in the lumen to release one monoglyceride and two fatty acids for each molecule of triglyceride. The monoglyceride and two fatty acids are subsequently absorbed into enterocytes and re-esterified to triglycerides.
  • triglycerides are assembled into intestinal lipoproteins, primarily chylomicrons. After formation, chylomicrons are exocytosed from enterocytes and subsequently gain preferential access to the intestinal lymphatics. Once within the lymphatic system, chylomicrons containing packaged triglycerides drain through a series of capillaries, nodes and ducts to join the systemic circulation at the junction of the left subclavian vein and internal jugular vein. Following entry into blood circulation, triglycerides in chylomicrons are preferentially and efficiently taken up by tissues with high expression levels of lipoprotein lipases, such as adipose tissue, the liver, and potentially certain types of tumor tissues.
  • lipoprotein lipases such as adipose tissue, the liver, and potentially certain types of tumor tissues.
  • Lipid prodrugs are expected to behave similarly to natural triglycerides and to be transported to and through the lymphatic system to reach the systemic circulation without interacting with the liver.
  • the lipid prodrugs are cleaved, releasing the therapeutic agent, after the prodrugs have reached the systemic circulation, or after reaching a target tissue.
  • the lipid prodrugs release the therapeutic agent by destruction of a self-immolative linker that attaches the therapeutic agent to the glycerol- derived group, or by enzymatic cleavage of a linker.
  • the disclosed lipid prodrug has improved oral bioavailability, reduced first pass metabolism, reduced liver toxicity, or improved other pharmacokinetic properties as compared with the parent therapeutic agent.
  • the disclosed lipid prodrug has increased drug targeting (as compared with the parent therapeutic agent) to sites within the lymph, lymph nodes and lymphoid tissues, and to sites of high lipid utilization and lipoprotein lipase expression such as adipose tissue, liver and some tumors.
  • a disclosed lipid prodrug is delivered to the central nervous system (CNS) or crosses the blood- brain barrier (BBB) via the lymphatic system.
  • the present invention provides methods of modulating the delivery, distribution, or other properties of a therapeutic agent.
  • the present invention provides a method of delivering a therapeutic agent to the systemic circulation of a patient in need thereof, wherein the therapeutic agent partially, substantially, or completely bypasses first pass liver metabolism in the patient, comprising the step of administering to the patient a disclosed lipid prodrug of the therapeutic agent.
  • the present invention provides a method of modifying a therapeutic agent to partially, substantially, or completely bypass first pass liver metabolism in a patient after administration of the therapeutic agent, comprising the step of preparing a disclosed lipid prodrug of the therapeutic agent.
  • the lipid prodrug is administered orally.
  • preparing the lipid prodrug comprises the step of conjugating a therapeutic agent to a glycerol- based scaffold comprising two fatty acids or other lipids, thereby providing the lipid prodrug.
  • the present invention provides a method of improving oral bioavailability of a therapeutic agent, enhancing gut absorption of a therapeutic agent, or decreasing metabolism, decomposition, or efflux in the gut of a therapeutic agent, comprising the step of preparing a disclosed lipid prodrug of the therapeutic agent.
  • the present invention provides a method of modifying, e.g., improving, delivery of a therapeutic agent to a target tissue, comprising the step of preparing a disclosed lipid prodrug of the therapeutic agent.
  • the target tissue is the lymph, a lymph node (such as a mesenteric lymph node), adipose tissue, liver, or a tumor, such as a lymph node site of metastasis.
  • the target tissue is the brain or CNS.
  • Lipid prodrugs that readily convert to parent therapeutic agent after transport via the systemic circulation have reduced free drug concentrations in the gastrointestinal (GI) tract, which may provide benefits in reducing gastrointestinal irritation or toxicity, and/or in increased drug solubility in intestinal bile salt micelles (due to similarities to endogenous monoglycerides).
  • Disclosed lipid prodrugs may also in certain embodiments have increased passive membrane permeability (due to greater lipophilicity compared with the parent therapeutic agent).
  • the lipid prodrug has greater solubility in lipid formulations or vehicles comprising either lipids alone or mixtures of lipids with surfactants and/or cosolvents, allowing for the use of lipophilic formulations for otherwise highly hydrophilic therapeutic agents.
  • R 1 and R 2 are each independently hydrogen, an acid-labile group, a lipid, or -C(O)R 3 ; each R 3 is independently a saturated or unsaturated, straight or branched, optionally substituted C 1-37 hydrocarbon chain;
  • X is -O-, -NR-, -S-, -O(C1-6 aliphatic)-O-, -O(C1-6 aliphatic)-S-, -O(C1-6 aliphatic)-NR-, -S(C1-6 aliphatic)-O-, -S(C1-6 aliphatic)-S-, -S(C1-6 aliphatic)-NR-, -NR(C1-6 aliphatic)
  • A is a therapeutic agent selected from a naturally-occurring or non naturally-occurring tryptamine or phenethylamine psychedelic such as DMT or 5-MeO-DMT or an analogue or prodrug thereof.
  • R 1 and R 2 are each independently hydrogen, an acid-labile group, a lipid such as a fatty acid, or -C(0)R 3 .
  • R 1 is hydrogen. In some embodiments, R 1 is an acid-labile group. In some embodiments, R 1 is a lipid. In some embodiments, R 1 is a fatty acid. In some embodiments, R 1 is -C(0)R 3 . In some embodiments, R 1 is selected from those depicted in Table 1, below.
  • R 2 is hydrogen. In some embodiments, R 2 is an acid-labile group. In some embodiments, R 2 is a lipid. In some embodiments, R 2 is a fatty acid. In some embodiments, R 2 is -C(0)R 3 . In some embodiments, R 2 is selected from those depicted in Table 1, below.
  • each of R 1 and R 2 is independently a fatty acid, phosphatide, phospholipid, or analogue thereof, such as those described in detail below.
  • each fatty acid is independently a saturated or unsaturated medium-chain or long-chain fatty acid.
  • each fatty acid independently has a C2-C40 chain.
  • each fatty acid independently has a C6-C20, C8-C20, C10-C20, C10-C15, C12-C18, C14-C18, C16-C18, or C10-C16 chain.
  • each fatty acid is independently selected from oleic acid, palmitic acid, EPA, or DHA.
  • R 1 and R 2 are each independently selected from an acid labile group such as tert-butoxycarbonyl (Boc), an amino acid, PEG group, -C(0)OR, - C(0)NR 2 , -CH2OR, -C(NR)R, or -P(0) 2 OR.
  • an acid labile group such as tert-butoxycarbonyl (Boc)
  • an amino acid PEG group, -C(0)OR, - C(0)NR 2 , -CH2OR, -C(NR)R, or -P(0) 2 OR.
  • R 1 or R 2 is defined as a fatty acid
  • R 1 or R 2 is the acyl residue of the fatty acid.
  • R 1 is the acyl portion of palmitic acid, i.e. -C(0)Ci 5 H 3i.
  • each R3 is independently a saturated or unsaturated, straight or branched, optionally substituted C 1.37 hydrocarbon chain.
  • R 3 is a saturated, straight, optionally substituted Ci- 37 hydrocarbon chain. In some embodiments, R 3 is an unsaturated, straight, optionally substituted Ci- 37 hydrocarbon chain. In some embodiments, R 3 is a saturated, branched, optionally substituted Ci- 37 hydrocarbon chain. In some embodiments, R 3 is an unsaturated, branched, optionally substituted C1-37 hydrocarbon chain. In some embodiments, R3 is selected from those depicted in Table 1, below. [00049] In some embodiments, each R 3 is independently a saturated or unsaturated, straight or branched, optionally substituted C1-27 hydrocarbon chain.
  • each R3 is independently a saturated or unsaturated, straight or branched, optionally substituted C 1-21 hydrocarbon chain. In some embodiments, each R 3 is independently a saturated or unsaturated, straight or branched, optionally substituted C1-20 hydrocarbon chain. In some embodiments, each R3 is independently a saturated or unsaturated, straight or branched, optionally substituted C 1-19 hydrocarbon chain. In some embodiments, each R 3 is independently a saturated or unsaturated, straight or branched, optionally substituted C 1-18 hydrocarbon chain. In some embodiments, each R3 is independently a saturated or unsaturated, straight or branched, optionally substituted C 1-17 hydrocarbon chain.
  • each R 3 is independently a saturated or unsaturated, straight or branched, optionally substituted C3-17 hydrocarbon chain. In some embodiments, each R3 is independently a saturated or unsaturated, straight or branched, optionally substituted C5-17 hydrocarbon chain. In some embodiments, each R 3 is independently a saturated or unsaturated, straight or branched, optionally substituted C7-17 hydrocarbon chain. In some embodiments, each R3 is independently a saturated or unsaturated, straight or branched, optionally substituted C 9-17 hydrocarbon chain.
  • each R 3 is optionally substituted C 7 H 15, C 8 H 17, C 9 H 19, C10H21, C11H23 , C12H25 , C13H27 , C14H29 , C15H31 , C16H33 , C17H35, or C18H37.
  • each R 3 is optionally substituted C 15 H 31 .
  • each R 3 is unsubstituted C 15 H 31 .
  • X is -O-, -NR-, -S-, -O(C1-6 aliphatic)-O-, - (C1-6 aliphatic)-S-, -O(C1-6 aliphatic)-NR-, -S(C1-6 aliphatic)-O-, -S(C1-6 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-, wherein 0-2 methylene units of the C 1-6 aliphatic group are independently and optionally replaced with -O-, -NR-, or -S- and the C1-6 aliphatic group is independently and optionally substituted with 1, 2, or 3 deuterium or halogen atoms.
  • X is -O-. In some embodiments, X is -NR-. In some embodiments, X is -S-. In some embodiments, X is -O(C1-6 aliphatic)-O-. In some embodiments, X is -O(C1-6 aliphatic)-S-. In some embodiments, X is -O(C1-6 aliphatic)-NR-. In some embodiments, X is -S(C 1-6 aliphatic)-O-. In some embodiments, X is -S(C1-6 aliphatic)-S-. In some embodiments, X is -S(C1-6 aliphatic)-NR-.
  • X is -NR(C1-6 aliphatic)-O-. In some embodiments, X is -NR(C1-6 aliphatic)- S-. In some embodiments, X is - NR(C1-6 aliphatic)-NR-. In any of the foregoing embodiments, 0-2 methylene units of the bivalent C 1-6 aliphatic group are independently and optionally replaced with -O-, -NR-, or -S- and the bivalent C1-6 aliphatic group is independently and optionally substituted with 1, 2, or 3deuterium or halogen atoms. In some embodiments, X is selected from those depicted in Table 1, below.
  • Y is absent or is -C(O)-, -C(NR)-, or - C(S)-. In some embodiments, Y is absent. In some embodiments, Y is -C(O)-. In some embodiments, Y is -C(NR)-. In some embodiments, Y is -C(S)-. In some embodiments, Y is selected from those depicted in Table 1, below.
  • L is a covalent bond or a saturated or unsaturated, straight or branched, optionally substituted bivalent C1-30 hydrocarbon chain, wherein 0-8 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) 2 NR-, -NRC(O)-, - C(O)NR-, -OC(O)NR-, -NRC(O)O-, or an amino acid; and wherein 1 methylene unit of L is optionally replaced with -M-; or L is wherein either the right-hand side or left-hand side of L is attached to A .
  • L is a covalent bond.
  • L is a saturated or unsaturated, straight or branched, optionally substituted bivalent C1-30 (e.g., C3- 30, C5-30, C7-30, C325, C5-25, C7-25, C3-20, C5-20, or C7-2o, etc.) hydrocarbon chain, wherein 0-8 (i.e., 0, 1, 2, 3, 4, 5, 6, 7, or 8) methylene units of L are independently replaced by -Cy-, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O) 2 -, -C(S)-, -NRS(O) 2 -, - S(O) 2 NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, -NRC(O)-, -NRC(O)NR
  • L is , wherein either the right-hand side or left-hand side of L is attached to A .
  • L is a covalent bond or a saturated or unsaturated, straight or branched, optionally substituted bivalent C1-30 (e.g., C3-30, C5-30, C7 -30, C5-25, C5-25, C3-25, C3-20, C5-20, or C7-20, etc.) hydrocarbon chain, wherein 0-8 (i.e., 0, 1, 2, 3, 4, 5, 6, 7, or 8) methylene units of L are independently replaced by -Cy-, -O-, -NR-, -S-, -OC(O)-, - C(O)O-, -C(O)-, -S(O)-, -S(O) 2 -, -C(S)-, -NRS(O) 2 , -S(O) 2 NR, -NRC(O)-,
  • L is a saturated or unsaturated, straight or branched, optionally substituted bivalent C1-20 (e.g., C3-20, C5-20, or C7-20, etc.) hydrocarbon chain, wherein 0-8 (i.e., 0, 1, 2, 3, 4, 5, 6, 7, or 8) methylene units of L are independently replaced by -Cy-, -O-, -NR-, -S-, -OC(O)-, -C(O)0-, -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 a naturally -occurring amino and wherein 1 methylene unit of L is optionally replaced with -M-.
  • 0-8 i.e., 0,
  • L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C1-16, C1-12 ,C1-10 or C 6 -12 hydrocarbon chain, wherein 0-6, 0-4, 0-3, or 0-1 methylene units of L are independently replaced by -Cy-, - O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O) 2 -, -C(S)-, -NRS(O) 2 -, -S(O) 2 NR- , -NRC(O)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O, and 1 methylene unit of L is optionally replaced with -M-.
  • L is a bivalent, saturated, straight C1-20, C1-16, C1- 12 ,C1-10 or C1-6 hydrocarbon chain, wherein 0-6, 0-4, 0-3, or 0-1 methylene units of L are independently replaced by -Cy-, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, - S(O)2-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(0)NR-, -OC(O)NR-, or -NRC(O)O-; and 1 methylene unit of L is optionally replaced with -M-.
  • L is a bivalent, saturated, straight C1-20, C1-16, C1-12, C1-10 or C1-6 hydrocarbon chain, wherein 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 1 methylene unit of L is optionally replaced with -M-.
  • L is a bivalent, saturated Cl-30, Cl-25, Cl-20, C3-20, C5-20, or C7-20 hydrocarbon chain optionally substituted with 1, 2 , 3, or 4 R 4 groups, wherein 0-4 methylene units of L are independently replaced by -0-, -OC(O)-, -C(0)0-, or - C(O)-; and 1 methylene unit of L is optionally replaced with -M-.
  • L is a bivalent, saturated Cl-25 C5-25, C7-25, or Cl-20 hydrocarbon chain optionally substituted with 1, 2 , 3, or 4 groups selected from deuterium, halogen, -CN, a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 4-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a Ci- 6 aliphatic group optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; wherein 0-4 methylene units of L are independently replaced by -0-, -0C(0)-, -C(0)0-, or -C(0)-; and 1 methylene unit of L is optionally replaced with -M-.
  • L comprises (-OCH2CH2-) I -8 (i.e., 1-8 polyethylene glycol (PEG) units). In some embodiments, L comprises 1, 2, 3, 4 , 5, 6 , 7, or 8 PEG units.
  • 0-6 units of L are independently replaced by -0-, -S-, - OC(O)-, -C(0)0-, -C(O)-, or -C(S)-; and 1 methylene unit of L is optionally replaced with - M-
  • L comprises
  • L comprises
  • L comprises
  • L comprise
  • L comprises
  • L comprises
  • L comprises
  • L comprises
  • 1 methylene unit of L is replaced with -M-.
  • 1, 2, 3, or 4 available hydrogen atoms of L are replaced with an R 4 group, i.e., L is optionally substituted with 1, 2, 3, or 4 R 4 groups.
  • a methylene unit of L is replaced with an amino acid.
  • the amino acid may be naturally-occurring or non-naturally occurring.
  • the amino acid is selected from a non-polar or branched chain amino acid (BCAA).
  • 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.
  • the amino acid is an L- amino acid.
  • the amino acid is a D-amino acid.
  • L is a bond, wherein p is an integer of 1 to 8.
  • p is 1, 2, 3, 4, 5, 6, 7, or 8. In certain embodiments, p is an integer of 1 to 7. In certain embodiments, p is 1. In certain embodiments p is 2. In certain embodiments p is 3. In certain embodiments p is 4. In certain embodiments p is 5. In certain embodiments p is 6. In certain embodiments p is 7.
  • L is a bond
  • L is selected from those depicted in Table 1, below.
  • each -Cy- is independently an optionally substituted 3-6 membered bivalent saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • -Cy- is an optionally substituted 3-6 membered bivalent saturated ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • -Cy- is an optionally substituted 5-membered bivalent saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • -Cy- is an optionally substituted 6- membered bivalent saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • -Cy- is selected from those depicted in Table 1, below.
  • each R4 and R5 is independently hydrogen, deuterium, halogen, -CN, -OR, -NR2, -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4- 8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1- 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a Ci-6 aliphatic group optionally substituted with -CN, -OR, -NR2, -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 member
  • R 4 is hydrogen. In some embodiments, R 4 is deuterium.
  • R4 is 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 is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R4 is phenyl. In some embodiments, R 4 is an 8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments, R 4 is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R 4 is a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 4 is an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R 4 is a Cl -6 aliphatic group optionally substituted with -CN, -OR, -NR2, -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R 4 is a Cl -6 aliphatic group optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms.
  • each R 4 is independently hydrogen, deuterium, halogen, - CN, or Cl-4 aliphatic optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; or two instances of R4 attached to the same carbon atom, taken together with the carbon atom to which they are attached, form a 3-6 membered spirocyclic saturated monocyclic carbocyclic ring or 3-6 membered spirocyclic saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • At least one instance of R 4 is not hydrogen.
  • R 4 is Cl-4 aliphatic optionally substituted with 1, 2, 3, 4,
  • R 4 is Cl-4 alkyl optionally substituted with 1, 2, or 3 deuterium or halogen atoms. In some embodiments, R 4 is methyl optionally substituted with 1, 2, or 3 deuterium or halogen atoms. In some embodiments, R 4 is ethyl. In some embodiments, R 4 is n-propyl. In some embodiments, R 4 is isopropyl. In some embodiments, R 4 is n-butyl. In some embodiments, R 4 is isobutyl. In some embodiments, R 4 is tert-butyl. In some embodiments, R 4 is selected from those depicted in Table 1, below.
  • R 5 is hydrogen. In some embodiments, R 5 is deuterium. In some embodiments, R 5 is halogen. In some embodiments, R 5 is -CN. In some embodiments,
  • R 5 is -OR. In some embodiments, R 5 is -NR2. In some embodiments, R 5 is -SR. In some embodiments, R 5 is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 5 is phenyl. In some embodiments, R 5 is an 8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments, R 5 is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 5 is a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R5 is an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R 5 is a Cl-6 aliphatic group optionally substituted with -CN, -OR, -NR2, -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R 5 is a Cl-6 aliphatic group optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms.
  • each R 5 is independently hydrogen, deuterium, halogen, - CN, or Cl-4 aliphatic optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; or two instances of R 5 attached to the same carbon atom, taken together with the carbon atom to which they are attached, form a 3-6 membered spirocyclic saturated monocyclic carbocyclic ring or 3-6 membered spirocyclic saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • At least one instance of R 5 is not hydrogen.
  • each R 4 and R 5 is independently hydrogen or methyl. In some embodiments, each R 4 is hydrogen and/or each R 5 is methyl. In some embodiments, each R 4 is methyl and/or each R 5 is hydrogen.
  • R 5 is Cl-4 aliphatic optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms. In some embodiments, R 5 is methyl optionally substituted with 1, 2, or 3 deuterium or halogen atoms. In some embodiments, R 5 is ethyl. In some embodiments, R 5 is n-propyl. In some embodiments, R 5 is isopropyl. In some embodiments,
  • R 5 is n-butyl. In some embodiments, R 5 is isobutyl. In some embodiments, R 5 is tert-butyl. In some embodiments, R 5 is selected from those depicted in Table 1, below.
  • -M- is a self-immolative group.
  • -M- is an acetal, an O-benzylalcohol, an i-benzyl alcohol, a styryl group, a coumarin, or a group that self-immolates via a cyclization reaction.
  • -M- is selected from a disulfide, hydrazone, acetal self-immolative group, carboxyacetal self-immolative group, carboxy(methylacetal) self-immolative group, para- hydroxybenzyl carbonyl self-immolative groups, flipped ester self-immolative group, trimethyl lock, or 2-hydroxyphenyl carbamate (2-HPC) self-immolative group.
  • -M- is selected from one of the following: wherein each R 6 is independently selected from hydrogen, deuterium, C1-5 aliphatic, halogen, or - CN; each R 7 is independently selected from hydrogen, deuterium, halogen, -CN, -OR, -NR2, -NO2, -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a Ci- 6 aliphatic group optionally substituted with -
  • -M- is selected from one of the following: wherein each R6 is independently selected from hydrogen, deuterium, Cl -5 aliphatic, halogen, or -CN; each R7 is independently selected from hydrogen, deuterium, halogen, -CN, -OR, -NR2, - N02, -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a C 1-6 aliphatic group optionally substituted with -
  • each R 6 is independently selected from hydrogen, deuterium, Cl -5 aliphatic, halogen, or -CN. In some embodiments,
  • R 6 is hydrogen. In some embodiments, R 6 is deuterium. In some embodiments, R 6 is Cl -5 aliphatic.
  • R 6 is halogen. In some embodiments, R 6 is -CN.
  • R 6 is hydrogen, Cl -5 alkyl, halogen, or -CN. In some embodiments, R 6 is hydrogen or Cl-3 alkyl. In some embodiments, R 6 is hydrogen or methyl. [000102] In some embodiments, each instance of R 6 in the above formulae is the same. In some embodiments, each R 6 is different. In some embodiments, one R 6 is hydrogen. In some embodiments, one R 6 is Cl -5 aliphatic. In some embodiments, each R 6 is hydrogen. In some embodiments, each R 6 is Cl -5 aliphatic. In some embodiments, R 6 is selected from those depicted in Table 1, below.
  • each R7 is independently selected from hydrogen, deuterium, halogen, -CN, -OR, -NR2, -NO2, -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a Ci- 6 aliphatic group optionally substituted with -CN, -OR, -NR2, -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl
  • R 7 is hydrogen. In some embodiments, R 7 is deuterium. In some embodiments, R 7 is 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 is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 7 is phenyl. In some embodiments, R 7 is an 8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments, R 7 is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 7 is a 5-6 membered monocyclic heteroaromatic ring having 1-
  • R 7 is or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R 7 is or a Cl-6 aliphatic group optionally substituted with -CN, -OR, -NR2, -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4- 8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-
  • R 7 is a Cl-6 aliphatic group optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms.
  • R 7 is hydrogen, deuterium, halogen, -CN, -OR, -NR2, - NO 2, - SR, a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 4-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a Ci-6 aliphatic group optionally substituted with -CN, - OR, -NR2, -SR, a 3- 6 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, or a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or the Cl-6 aliphatic group is optionally substituted with 1, 2, 3, 4, 5, or 6 de
  • R 7 is hydrogen, deuterium, halogen, - CN, a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 5- 6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a Cl-4 alkyl group optionally substituted with -CN, a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, or a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or the Cl-4 alkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms.
  • R 7 is hydrogen, halogen, -CN, -OR, or Cl-4 alkyl. [000106] In some embodiments, R is hydrogen or Cl-4 alkyl.
  • R 7 is selected from those depicted in Table 1, below.
  • each Z 1 is independently selected from -0-, -NR-, or -S-. In some embodiments, Z 1 is -0-. In some embodiments, Z 1 is -NR-. In some embodiments, Z 1 is -S. In some embodiments, Z 1 is -NH- or -NMe-.
  • Z 1 is selected from those depicted in Table 1, below.
  • each Z 2 is independently selected from -0-, -NR-, -S-, -OC(O)-, -NRC(0)0-, or -OC(0)NR-.
  • Z 2 is -0-. In some embodiments, Z 2 is -NR-. In some embodiments, Z 2 is -S-. In some embodiments, Z2 is -OC(O)-. In some embodiments, Z2 is - NRC(0)0-. In some embodiments, Z 2 is -OC(0)NR-.
  • each Z 2 is independently selected from -0-, -NH-, -NMe-, -S-, -OC(O)-, -NHC(0)0-, -NMeC(0)0-, -OC(0)NH-, or -OC(0)NMe-.
  • Z 2 is covalently bound to A .
  • Z 2 is -O- or -0C(0)0-.
  • Z 2 is selected from those depicted in Table 1, below.
  • Z 1 is -O- and Z 2 is -O- or -0C(0)0-.
  • Z 3 is selected from those depicted in Table 1, below.
  • each Z 4 is independently selected from -O-, -NR-, -S-, -C(R 6 )2-, or a covalent bond.
  • Z 4 is -O-.
  • Z 4 is -NR-.
  • Z 4 is -S-.
  • Z 4 is - C(R 6 )2-.
  • Z 4 is a covalent bond.
  • Z 4 is selected from those depicted in Table 1, below.
  • -M- is selected from one of the following:
  • -M- is [000122] In some embodiments, -M- is
  • -M- is
  • -M- is
  • -M- is selected from those depicted in Table 1, below.
  • n is 0-18.
  • 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.
  • 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
  • each m is independently 0-6. 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 .
  • A is a therapeutic agent selected from a naturally-occurring or non naturally-occurring tryptamine or phenethyl amine psychedelic such as DMT or 5-MeO-DMT or an analogue or prodrug thereof.
  • a naturally-occurring or non naturally-occurring tryptamine or phenethylamine psychedelic such as DMT or 5- MeO-DMT include those described herein.
  • A is DMT or an analogue or prodrug thereof.
  • A is 5-MeO-DMT .
  • A is a naturally-occurring or non naturally-occurring (e.g., synthetic) tryptamine or phenethylamine psychedelic such as DMT or 5-MeOo-DMT or an analogue or prodrug thereof. In some embodiments, A is selected from DMT or 5- MeO-DMT
  • A is selected from psilocybin, psilocin, baeocystin, norbaeocystin, lisurgide, LSD, dimethyltryptamine, carboxamindotryptamine, ibogaine, tabernanthalog, 3,4-methylenedioxy-methamphetamine (MDMA), 1-acetyl LSD, O-acetyl psilocin, mescaline (3,4,5-trimethoxy phenethylamine), proscaline (2-(3,5-dimethoxy-4- propoxyphenyl)ethanamine), metaescaline (2-(3-ethoxy-4,5-dimethoxyphenyl)ethanamine), allylescaline (4-Allyloxy-3,5-dimethyloxy phenylethylamine), methallylescaline (4- Methallyloxy-3,5 dimethoxyphenethylamine), asym
  • the psychedelic comprises LSD or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof.
  • the LSD derivative is 1P-LSD, 1B-LSD, ETH-LAD, lP-ETH-LAD, AL-LAD, LSZ, LSM-775, l-(4-Bromofuro[2,3-f] [l]benzofuran-8-yl)propan-
  • the psychedelic comprises mescaline or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof.
  • the mescaline derivative is mescaline-NBOMe, proscaline (2-(3,5-dimethoxy-4- propoxyphenyl)ethanamine), or metaescaline (2-(3-ethoxy-4,5-dimethoxyphenyl)ethanamine).
  • the psychedelic comprises a phenethylamine, a tryptamine, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof.
  • the phenethylamine, the tryptamine, or the pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof comprises 25I-NBOH, N-(2- Methoxybenzyl)-2-(3,4,5-trimethoxyphenyl)ethanamine, N-(2-hydroxybenzyl)-2,5- dimethoxy-4-iodo-phenethylamine, N-(2-hydroxybenzyl)-2,5-dimethoxy-4-chloro- phenethylamine, N-(2-hydroxybenzyl)-2,5-dimethoxy-4-bromo-phenethylamine, 4-Allyloxy- 3,5-dimethyloxyphenylethylamine, N-(2-fluorobenzyl)-2,5-dimethoxy-4-iodo- phenethylamine, 2,5-dimethoxy-4-tert-butylthio-phenethylamine, 2,5-dimethoxy-4-
  • the psychedelic is psilocybin or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof. In some embodiments, the psychedelic is 1 -acetyl LSD or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof. In some embodiments, the psychedelic is O-acetyl psilocin, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof.
  • A is MDL-11,939, ketanserin, ritanserin, altanserin, acepromazine, mianserin, mirtazapine, quetiapine, SB204741, SB206553, SB242084, LY272015, SB243213, Blonanserin, SB200646, RS102221, nefazodone, MDL-100,907, pimavanserin, nelotanserin, lorcaserin, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, prodrug, or combinations thereof.
  • the tryptamine or phenethylamine psychedelic is DMT or 5-MeO-DMT.
  • lipid prodrugs shown in Table 1 are in the form of prodrugs.
  • a lipid prodrug moiety of the presentinvention is attached to the therapeutic agent or the active form thereof.
  • a provided lipid prodrug moiety is attached at any modifiable oxygen, sulfur, or nitrogen atom of a tryptamine or phenethylamine psychedelic such as DMT or 5-MeO-DMT.
  • DMT has the following structure: may be attached to the lipid prodrug moiety e.g., via its indole nitrogen (NH) group or at another chemically modifiable position.
  • brackets around a therapeutic agent A means that the moiety is covalently attached to A at any availablemodifiable nitrogen, oxygen, or sulfur atom.
  • available modifiable nitrogen, oxygen, or sulfur atoms in the following therapeutic agent compound structures are depicted below, wherein each wavy bond defines the point of attachment to formula I or another of the formulae depicted herein attached at any m o d i f i ab 1 e oxygen, sulfur, or nitrogen atom of a tryptamine or phenethylamine psychedelic such as DMT or 5-MeO-DMT.
  • DMT tryptamine or phenethylamine psychedelic
  • DMT has the following structure: and may be attached to the lipid prodrug moiety e.g., via its indole nitrogen (NH) group or at another chemically modifiable position
  • brackets around a therapeutic agent [000139] means that the moiety is covalently attached to A at any availablemodifiable nitrogen, oxygen, or sulfur atom.
  • available modifiable nitrogen, oxygen, or sulfur atoms in the following therapeutic agent compound structures are depicted below, wherein each wavy bond defines the point of attachment to formula I or another of the formulae depicted herein:
  • the present invention provides a compound of Formula I-b: or a pharmaceutically acceptable salt thereof, wherein each of L and A is as defined above and described in embodiments herein, both singly and in combination.
  • the present invention provides a compound of Formula I-c: pharmaceutically acceptable salt thereof, wherein each of L, R 1 , R 2 , and X is as defined above and described in embodiments herein, both singly and in combination.
  • the present invention provides a compound of Formula II: or a pharmaceutically acceptable salt thereof, wherein each of R 1 , R 2 , X, M, and A is as defined above and described in embodiments herein, both singly and in combination.
  • the present invention provides a compound of Formula III: or a pharmaceutically acceptable salt thereof, wherein each of R 1 , R 2 , R 4 , R 5 , M, and A is as defined above and described in embodiments herein, both singly and in combination.
  • the present invention provides a compound of Formula IV: or a pharmaceutically acceptable salt thereof, wherein each of R 1 , R 2 , R 4 , R 5 , X, n, and A is as defined above and described in embodiments herein, both singly and in combination.
  • the present invention provides a compound of Formula pharmaceutically acceptable salt thereof, wherein each of R 1 , R 2 , X, and M is as defined above and described in embodiments herein, both singly and in combination.
  • the present invention provides a compound of pharmaceutically acceptable salt thereof, wherein each of R 1 , and M is as defined above and described in embodiments herein, both singly and in combination.
  • the present invention provides a compound of Formula VII: pharmaceutically acceptable salt thereof, wherein each of R 1 , R 2 , R 4 , R 5 , and M is as defined above and described in embodiments herein, both singly and in combination.
  • the present invention provides a compound of Formula VIII-a or Vlll-b: or a pharmaceutically acceptable salt thereof, wherein each of R 1 , R 2 , R 4 , R 5 , n, M, and A is as defined above and described in embodiments herein, both singly and in combination [000147] In some embodiments, the present invention provides a compound of Formula VIII-c or Vlll-d:
  • each of R1, R ⁇ , R ⁇ , M, and A is as defined above and described in embodiments herein, both singly and in combination.
  • each of R1, R ⁇ , R ⁇ , M, and A is as defined above and described in embodiments herein, both singly and in combination.
  • R is an alkyl, e.g., a Ci-26 alkyl, preferably, a long-chain alkyl such as C 15 H 31 or C 17 H 35 .
  • the present invention provides a lipid prodrug compound, or pharmaceutically acceptable salt thereof, shown in Table 1 : Lipids, Including Fatty Acids, Phospholipids, Lipid-Processing Mimetics, and Mixtures Thereof, for Use in Disclosed Lipid Prodrugs
  • Lipid prodrugs according to the present disclosure mimic the lipid-processing that takes place in the human body.
  • the lipid prodrug comprises a fatty acid, phosphatide, phospholipid, or analogue thereof (e.g., phophatidyl choline, lecithin, phosphatidyl ethanolamine, cephalin, or phosphatidyl serine or analogue or portion thereof, such as a partially hydrolyzed portion thereof), or other lipid-processing mimetic (e.g., a group cleaved by lipases, other digestive enzymes, or other mechanisms in the GI tract that enables the lipid prodrug to mimic dietary lipid processing).
  • a fatty acid phosphatide, phospholipid, or analogue thereof
  • lipid-processing mimetic e.g., a group cleaved by lipases, other digestive enzymes, or other mechanisms in the GI tract that enables the lipid prodrug to mimic dietary lipid processing.
  • the fatty acid is a short-chain, medium-chain, or long- chain fatty acid. In some embodiments, the fatty acid is a saturated fatty acid. In some embodiments, the fatty acid is an unsaturated fatty acid. In some embodiments, the fatty acid is a monounsaturated fatty acid. In some embodiments, the fatty acid is a polyunsaturated fatty acid, such as an o-3 (omega- 3) or 0-6 (omega-6) fatty acid. In some embodiments, the lipid, e.g, fatty acid, has a C2- C60 chain. In some embodiments, the lipid, e.g., fatty acid, has a C2-C28 chain.
  • the lipid, e.g, fatty acid has a C2-C40 chain. In some embodiments, the lipid, e.g, fatty acid, has a C2-C 12 or C4-C 12 chain. In some embodiments, the lipid, e.g, fatty acid, has a C4-C40 chain.
  • the lipid e.g, fatty acid
  • the lipid has a C4- C40, C2-C38, C2-C36, C2-C34, C2-C32, C2-C30, C4-C30, C2-C28, C4-C28, C2-C26, C4- C22, C2-C20, C4-C20, C6-C20, C8-C20, C10-C20, C2-C18, C4-C18, C6-C18, C8-C18, C10-C18, C12-C18, C14-C18, C16-C18, C2-C16, C4- C16, C6-C16, C8-C16, C10-C16, C12-C16, C14-C16, C2-C15, C4-C15, C6-C15, C8-C15, C9-C15, C10-C15, C11-C15, C12- C15, C13-C15, C2-C14,
  • the lipid e.g., fatty acid
  • the lipid has a C2, C3, C4, C5, C6, C7, C8, C9, CIO, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, C47, C48, C49, C50, C51, C52, C53, C54, C55, C56, C57, C58, C59, or C60 chain.
  • the lipid prodrug comprises two fatty acids, each of which s independently selected from a fatty acid having a chain with any one of the foregoing ranges or numbers of carbon atoms.
  • one of the fatty acids is independently a fatty acid with a Cg-C 21 chain and one is independently a fatty acid with a C 12 -C 36 chain.
  • each fatty acid independently has a chain of 11, 12, 13, 14, 15, 16, or 17 carbon atoms.
  • the lipid prodrug comprises two lipids.
  • the two lipids e.g., fatty acids, taken together have 6-80 carbon atoms (an equivalent carbon number (ECN) of 6-80).
  • the lipids e.g., fatty acids
  • the lipids have an ECN of 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
  • Suitable fatty acids include saturated straight-chain fatty acids, saturated branched fatty acids, unsaturated fatty acids, hydroxy fatty acids, and polycarboxylic acids. In some embodiments, such fatty acids have up to 32 carbon atoms.
  • Examples of useful saturated straight-chain fatty acids include those having an even number of carbon atoms, such as butyric acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachic acid, behenic acid, lignoceric acid, hexacosanoic acid, octacosanoic acid, triacontanoic acid and n-dotriacontanoic acid, and those having an odd number of carbon atoms, such as propionic acid, n-valeric acid, enanthic acid, pelargonic acid, hendecanoic acid, tridecanoic acid, pentadecanoic acid, heptadecanoic acid, nonadecanoic acid, heneicosanoic acid, tricosanoic acid, pentacosanoic acid, and heptacosanoic acid.
  • saturated branched fatty acids include isobutyric acid, isocaproic acid, isocaprylic acid, isocapric acid, isolauric acid, 11 -m ethyl dodecanoic acid, isomyristic acid, 13 -methyl -tetradecanoic acid, isopalmitic acid, 15-methyl -hexadecanoic acid, isostearic acid, 17-methyloctadecanoic acid, isoarachic acid, 19-methyl-eicosanoic acid, a-ethyl- hexanoic acid, a-hexyldecanoic acid, a-heptylundecanoic acid, 2- decyltetradecanoic acid, 2-undecyltetradecanoic acid, 2-decylpentadecanoic acid, 2- undecylpentadecanoic acid, and Fineoxocol 1800 acid.
  • Suitable saturated odd-carbon branched fatty acids include anteiso fatty acids terminating 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.
  • 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
  • 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, cN-1 1-eicosenoic acid, cetoleic acid, 13-docosenoic acid, 15-tetracosenoic acid, 17-hexacosenoic acid, 6,9,12,15- hexadecatetraenoic acid, linoleic acid, linolenic acid, a-eleostearic acid, b-eleostearic acid, punicic acid, 6,
  • Suitable hydroxy fatty acids include a-hydroxylauric acid, a- hydroxymyristic acid, a-hydroxypalmitic acid, a-hydroxystearic acid, co-hydroxylauric acid, a- hydroxyarachic acid, 9-hydroxy- 12-octadecenoic acid, ricinoleic acid, a -hydroxybehenic acid, 9- hydroxy -trans-10,12-octadecadienic acid, kamolenic acid, ipurolic acid, 9,10- dihydroxystearic acid, 12-hydroxystearic acid and the like.
  • polycarboxylic acids examples include oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, D,L-malic acid, and the like.
  • each fatty acid is independently selected from Propionic acid, Butyric acid, Valeric acid, Caproic acid, Enanthic acid, Caprylic acid, Pelargonic acid, Capric acid, ETndecylic acid, Why acid, Tridecylic acid, Myristic acid,
  • Pentadecylic acid Palmitic acid, Margaric acid, Stearic acid, Nonadecylic acid, arachidic acid, Heneicosylic acid, Behenic acid, Tricosylic acid, Lignoceric acid, Pentacosylic acid, Cerotic acid, Heptacosylic acid, Montanic acid, Nonacosylic acid, Melissic acid, Henatriacontylic acid, Lacceroic acid, Psyllic acid, geddic acid, ceroplastic acid, hexatriacontylic acid, heptatriacontanoic acid, or octatriacontanoic acid.
  • each fatty acid is independently selected from a- 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, paullinic acid, oleic acid, elaidic acid, gondoic acid, erucic acid, nervonic acid, mead acid, adrenic acid, bosseopentaenoic acid, ozubondo acid, sardine acid, herring acid, docosahexaenoic acid, or tetracosanolpentaenoic acid, or another monounsaturated or polyunsaturated fatty acid.
  • one or both of the fatty acids is an essential fatty acid.
  • the therapeutic benefits of disclosed lipid prodrugs may be increased by including such fatty acids in the lipid prodrug.
  • the essential fatty acid is an n-6 or n-3 essential fatty acid selected from the group consisting of linolenic acid, gamma-linolenic acid, dihomo- gamma-linolenic acid, arachidonic acid, adrenic acid, docosapentaenoic n-6 acid, alpha- linolenic acid, stearidonic acid, the 20:4n-3 acid, eicosapentaenoic acid, docosapentaenoic n-3 acid, or docosahexaenoic acid.
  • each fatty acid is independently selected from all-cv.s- 7, 0, 3-hexadecatrienoic acid, a -linolenic acid, stearidonic acid, eicosatrienoic acid, eicosatetraenoic acid, eicosapentaenoic acid (EPA), docosapentaenoic acid, docosahexaenoic acid (DHA),tetracosapentaenoic acid, tetracosahexaenoic acid, or lipoic acid.
  • the fattyacid is selected from eicosapentaenoic acid, docosahexaenoic acid, or lipoic acid.
  • fatty acids include al l-c/.v-7, 10, 13-hexadecatri enoic acid, a- linolenic acid (ALA orall-67.s-9, 12, 15-octadecatri enoic acid), stearidonic acid (STD or all- cv.v-6,9, 2, 5-octadecatetraenoic acid), eicosatrienoic acid (ETE or all-c/.s- 1 1, 14, 17- eicosatri enoic acid), eicosatetraenoic acid (ETA or all-cv.s-8, 11, 14, 17-eicosatetraenoic acid), eicosapentaenoic acid(EPA), docosapentaenoic acid (DP A, clupan
  • the fatty acid is a medium-chain fatty acid such as lipoic acid.
  • Fatty acid chains differ greatly in the length of their chains and may be categorizedaccording to chain length, e.g., as short to very long.
  • Short-chain fatty acids are fatty acids with chains of about five or less carbons (e.g, butyric acid).
  • each of the fatty acids is independently a SCFA.
  • one of the fatty acids is independently a SCFA.
  • Medium-chain fatty acids include fatty acids with chains of about 6-12 carbons, which can form medium-chain triglycerides.
  • each of the fatty acids is independently a MCFA.
  • one of the fatty acids is independently a MCFA.
  • Long-chain fatty acids include fatty acids with chains of 13-21 carbons.
  • each of the fatty acids is independently a LCFA.
  • one of the fatty acids is independently a LCFA.
  • VLCFA Very long chain fatty acids
  • fatty acids with chains of 22 or more carbons such as 22-60, 22-50, or 22-40 carbons.
  • each of the fatty acids is independently a VLCFA.
  • one of the fatty acids is independently a VLCFA.
  • one of the fatty acids is independently a MCFA and one is independently a LCFA.
  • compositions comprising a lipid prodrug described herein (e.g., prodrugs of DMT or 5-MeO-DMT of Formula I) and a serotonin receptor modulator.
  • a lipid prodrug described herein e.g., prodrugs of DMT or 5-MeO-DMT of Formula I
  • the lipid prodrugs described herein have activity as a 5-HT2A modulator.
  • the serotonin receptor modulator is a serotonin receptor antagonist.
  • compositions comprising a lipid prodrug described herein (e.g., prodrugs of DMT or 5- MeO-DMT of Formula I) and a serotonin receptor modulator, wherein the serotonin receptor modulator is a serotonin receptor inverse agonist.
  • compositions comprising a lipid prodrug described herein (e.g., prodrugs of DMT or 5-MeO-DMT of Formula I) and a serotonin receptor modulator, wherein the serotonin receptor modulator is a serotonin receptor allosteric modulator.
  • the serotonin receptor is serotonin receptor 1, serotonin receptor 2, serotonin receptor 4, serotonin receptor 5, serotonin receptor 6, or serotonin receptor 7.
  • the serotonin receptor is serotonin receptor 1 A, serotonin receptor IB, serotonin receptor ID, serotonin receptor IE, serotonin receptor IF, serotonin receptor 2A, serotonin receptor 2B, serotonin receptor 2C, serotonin receptor 4, serotonin receptor 5A, serotonin receptor 5B, serotonin receptor 6, or serotonin receptor 7.
  • the serotonin receptor is serotonin receptor 2 A.
  • the serotonin receptor modulator is a serotonin receptor antagonist selected from the group consisting of ketanserin, volinanserin (MDL- 100907), eplivanserin (SR-46349), pimavanserin (ACP-103), glemanserin (MDL-11939), ritanserin, flibanserin, nelotanserin, blonanserin, mianserin, mirtazapine, roluperiodone (CYR-101, MIN- 101), quetiapine, olanzapine, altanserin, acepromazine, nefazodone, risperidone, pruvanserin, AC-90179, AC -279, adatanserin, fananserin, HY10275, benanserin, butanserin, manserin, iferanserin, lidanserin, pelanserin, seganserin, tropanserin, lorcaserin,
  • the serotonin receptor antagonist co-administered with the lipid prodrug described herein is an additional serotonin receptor modulator.
  • the additional serotonin receptor modulator is ketanserin or a pharmaceutically acceptable salt, solvate, metabolite, deuterated analogue, derivative, or prodrug thereof.
  • the additional serotonin receptor modulator is pimavanserin or a pharmaceutically acceptable salt, solvate, metabolite, deuterated analogue, derivative, or prodrug thereof.
  • the additional serotonin receptor modulator is eplivanserin or a pharmaceutically acceptable salt, solvate, metabolite, deuterated analogue, derivative, or prodrug thereof. In some embodiments, the additional serotonin receptor modulator is flibanserin or a pharmaceutically acceptable salt, solvate, metabolite, deuterated analogue, derivative, or prodrug thereof. In some embodiments, the additional serotonin receptor modulator is roluperiodone or a pharmaceutically acceptable salt, solvate, metabolite, deuterated analogue, derivative, or prodrug thereof.
  • the additional serotonin receptor modulator is volinanserin or a pharmaceutically acceptable salt, solvate, metabolite, deuterated analogue, derivative, or prodrug thereof. In some embodiments, the additional serotonin receptor modulator is ritanserin or a pharmaceutically acceptable salt, solvate, metabolite, deuterated analogue, derivative, or prodrug thereof. In some embodiments, the additional serotonin receptor modulator is nelotanserin or a pharmaceutically acceptable salt, solvate, metabolite, deuterated analogue, derivative, or prodrug thereof. In some embodiments, the additional serotonin receptor modulator is pruvanserin or a pharmaceutically acceptable salt, solvate, metabolite, deuterated analogue, derivative, or prodrug thereof.
  • compositions comprising a lipid prodrug compound described herein (e.g., prodrug of DMT or 5-MeO-DMT of Formula I) having activity as a 5- HT2A modulator co-administered with an additional serotonin receptor modulator in a defined dosage range.
  • the additional serotonin receptor modulator for use with the compounds disclosed herein is eplivanserin, wherein the eplivanserin is administered in about 1 mg to about 40 mg, or about 5 mg to about 10 mg.
  • the additional serotonin receptor modulator for use with the compounds disclosed herein is volinanserin, wherein the volinanserin is administered in about 1 mg to about 60 mg, or about 5 mg to about 20 mg.
  • the additional serotonin receptor modulator for use with compounds disclosed herein is ketanserin, wherein the ketanserin is administered in about 10 mg to about 80 mg, about 30 mg to about 50 mg, or about 40 mg.
  • the additional serotonin receptor modulator for use with the compounds disclosed herein is ritanserin, wherein the ritanserin is administered in about 1 mg to about 40 mg, or about 2.5 mg to about 10 mg.
  • the additional serotonin receptor modulator for use with the compounds disclosed herein is pimavanserin, wherein the pimavanserin is administered in about 1 mg to about 60 mg, or about 17 mg to about 34 mg.
  • the additional serotonin receptor modulator for use with the is nelotanserin, wherein the nelotanserin is administered in about 1 mg to about 80 mg, or about 40 mg to about 80 mg.
  • the additional serotonin receptor modulator for use with the compounds disclosed herein is pruvanserin, wherein the pruvanserin is administered in about 1 mg to about 40 mg, or about 3 mg to about 10 mg.
  • the additional serotonin receptor modulator for use with the compounds disclosed herein is flibanserin, wherein the flibanserin is administered in about 10 mg to about 200 mg, or about 80 mg to about 120 mg, or about 100 mg.
  • a variety of therapeutic agents may be covalently conjugated to the lymphatic system-directing lipids, e.g., triglyceride scaffolds, described herein.
  • the present disclosure provides enhanced desirable properties of the therapeutic agent such as improving oral bioavailability, minimizing destruction of the agent in the gut, avoiding liver first-pass effect, improving therapeutic agent delivery to a target tissue, or increasing the solubility and stability of the therapeutic agents, including the solubility and stability of the agents in vivo.
  • the present disclosure provides a compound of formula I, wherein the therapeutic agent is a tryptamine or phenethyl amine psychedelic such as DMT or 5-MeO-DMT or an analogue or prodrug thereof.
  • the therapeutic agent is a tryptamine or phenethyl amine psychedelic such as DMT or 5-MeO-DMT or an analogue or prodrug thereof.
  • a disclosed lipid prodrug comprises a therapeutic agent selected from neuroactive steroids, such as tryptamine or phenethylamine psychedelic such as (N,N-dimethyltryptamine) DMT, or 5-methoxy-N,N-dimethyltryptamine (5-MeO- DMT) , pregnanolone, pregnenolone, 3b- dihydropregesterone, isopregnanolone, epipregnanolone, and 21-hydroxytryptamine or phenethylamine psychedelic such as (N,N- dimethyltryptamine) DMT, or 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), or others disclosed herein.
  • neuroactive steroids such as tryptamine or phenethylamine psychedelic such as (N,N-dimethyltryptamine) DMT, or 5-methoxy-N,N-dimethyltryptamine (5-
  • the neuroactive steroid is selected from tryptamine or phenethylamine psychedelic such as (N,N-dimethyltryptamine) DMT, or 5 -m ethoxy -N,N- dimethyltryptamine (5-MeO-DMT) or 21-hydroxytryptamine or phenethylamine psychedelic such as (N,N-dimethyltryptamine) DMT, or 5-methoxy-N,N-dimethyltryptamine (5-MeO- DMT).
  • the present disclosure provides a method of treating or preventing a disease, disorder, or condition in which an increased level of a tryptamine or phenethylamine psychedelic such as DMT or 5-MeO-DMT , such as tryptamine or phenethylamine psychedelic such as (N,N-dimethyltryptamine) DMT, or 5 -m ethoxy -N,N- dimethyltryptamine (5-MeO-DMT) , is beneficial, or a disease, disorder, or condition caused by a deficiency in a tryptamine or phenethylamine psychedelic such as DMT or 5- MeO-DMT , such as an tryptamine or phenethylamine psychedelic such as (N,N- dimethyltryptamine) DMT, or 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) deficiency, comprising a tryptamine or
  • the present disclosure provides a method of treating a 5HT serotonin receptor related disease, disorder, or condition, comprising administering to a subject in need thereof an effective amount of a disclosed lipid prodrug.
  • the present disclosure provides a method of treating a disease, disorder, or condition caused by deficient activation of serotonin, comprising administering to a subject in need thereof an effective amount of a disclosed lipid prodrug.
  • the therapeutic agent is DMT or 5-MeO-DMT.
  • lipid prodrug described herein e.g., a compound of Formula I
  • a pharmaceutically acceptable salt thereof such as sodium EDTA
  • the pharmaceutical composition thereof as described herein in the preparation of a medicament for treating or preventing a disease, disorder, or condition in which an increased level of a tryptamine or phenethylamine psychedelic such as DMT or 5-MeO-DMT , such as tryptamine or phenethylamine psychedelic such as (N,N-dimethyltryptamine) DMT, or 5- methoxy-N,N-dimethyltryptamine (5-MeO-DMT) , is beneficial, or a disease, disorder, or condition caused by a deficiency in a tryptamine or phenethylamine psychedelic such as DMT or 5-MeO-DMT , such as an tryptamine or phenethylamine psychedelic such as (N,
  • a lipid prodrug described herein is for use in a method of treating or preventing a disease, disorder, or condition in which an increased level of a tryptamine or phenethylamine psychedelic such as DMT or 5-MeO-DMT , such as tryptamine or phenethylamine psychedelic such as (N,N-dimethyltryptamine) DMT, or 5- methoxy-N,N-dimethyltryptamine (5-MeO-DMT) , is beneficial, or a disease, disorder, or condition caused by a deficiency in a tryptamine or phenethylamine psychedelic such as DMT or 5-MeO-DMT , such as an tryptamine or phenethylamine psychedelic such as (N,N- dimethyltryptamine) DMT, or 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT)
  • compositions comprising a lipid prodrug described herein (e.g., a compound of Formula I) or a pharmaceutically acceptable salt thereof, for use in treating or preventing a disease, disorder, or condition in which an increased level of a tryptamine or phenethylamine psychedelic such as DMT or 5-MeO-DMT , such as tryptamine or phenethylamine psychedelic such as (N,N- dimethyltryptamine) DMT, or 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), is beneficial, or a disease, disorder, or condition caused by a deficiency in a tryptamine or phenethylamine psychedelic such as DMT or 5-MeO-DMT , such as an tryptamine or phenethylamine psychedelic such as (N,N-dimethyltryptamine) DMT, or
  • lipid prodrug described herein e.g., a compound of Formula I
  • a pharmaceutically acceptable salt thereof or the pharmaceutical composition thereof as described herein, in the preparation of a medicament for treating a 5HT serotonin receptor related disease, disorder, or condition in a subject in need thereof.
  • a lipid prodrug described herein is for use in a method of treating a 5HT serotonin receptor related disease, disorder, or condition in a subject in need thereof.
  • a compound is, for example, a compound of Formula (I) as disclosed herein, or a pharmaceutical composition comprising the compound disclosed herein, and a pharmaceutically acceptable excipient, as disclosed herein.
  • compositions comprising a lipid prodrug described herein (e.g., a compound of Formula I) or a pharmaceutically acceptable salt thereof, for use in treating a 5HT serotonin receptor related disease, disorder, or condition in a subject in need thereof.
  • a lipid prodrug described herein e.g., a compound of Formula I
  • a pharmaceutically acceptable salt thereof for use in treating a 5HT serotonin receptor related disease, disorder, or condition in a subject in need thereof.
  • the terms “individual(s)”, “subject(s)” and “patient(s)” mean any mammal.
  • the mammal is a human.
  • the mammal is a non-human. None of the terms require or are limited to situations characterized by the supervision (e.g. constant or intermittent) of a health care worker (e.g. a doctor, a registered nurse, a nurse practitioner, a physician’s assistant, an orderly or a hospice worker). While the terms used herein are believed to be well understood by one of ordinary skill in the art, definitions are set forth herein to facilitate explanation of the presently-disclosed subject matter.
  • treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein.
  • treatment may be administered after one or more symptoms have developed.
  • treatment may be administered in the absence of symptoms.
  • treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g, in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.
  • lipid refers to natural and non-natural hydrophobic and/or lipophilic fats, oils, polymers, hydrocarbons, and other such materials.
  • suitable lipids when incorporated into a lipid prodrug, are processed or metabolized similarly to triglyercides in the GI tract or mimic such processing or metabolism.
  • glycolide refers to an ester of glycerol (1,2,3-propanetriol) with acyl radicals of fatty acids or other lipids and is also known as an acylglycerol.
  • a “monoglyceride” is produced; if two positions are esterified, a “diglyceride” is produced; and if all three positions of the glycerol are esterified with fatty acid a “triglyceride” or “triacylglycerol” is produced.
  • a glyceride is called “simple” if all esterified positions contain the same fatty acid; or “mixed” if different fatty acids are involved.
  • the carbons of the glycerol backbone are designated sn-1, sn-2 and sn-3, with sn-2 being in the middle and sn-1 and sn-3 being the ends of the glycerol.
  • Naturally occurring oils and fats consist largely of triglycerides wherein the 3 fatty acyl residues may or may not be identical.
  • long chain triglycerides or “LCT” means both a simple and mixed triglyceride containing fatty acids with more than 12 carbon atoms (long chain fatty acids, “LCFA”)
  • MCT medium chain triglycerides
  • ECN equivalent carbon number
  • tripalmitin tripalmitic glycerol
  • ECN acyl chain lengths of 8, 16 and 16; 10, 14 and 16; 8, 14 and 18, etc.
  • Naturally occurring oils are frequently “mixed” with respect to specific fatty acids, but tend not to contain LCFAs and MCFAs on the same glycerol backbone.
  • triacylglycerols with ECNs of 24-30 typically contain predominately medium chain fatty acids, while triacylglycerols with ECNs of greater than 43 typically contain predominantly long chain fatty acids.
  • Triacylglycerols having an ECNs of 32- 42 typically contain one or two MCFA in combination with one or two LCFAs to “fill” the triglyceride.
  • Triacylglycerols with ECNs in the range of greater than 30 to less than 48 typically represent mixed triacylglycerol species that are absent from or are present in significantly lower concentrations in physical mixtures.
  • the fatty acids that occur in foods usually contain an even number of carbon atoms in an unbranched chain, e.g., lauric or dodecanoic acid.
  • self-immolative group refers to a bivalent chemical moiety that comprises a covalent, scissile bond as one of its bivalent bonds and a stable, covalent bond with a therapeutic agent as its other bivalent bond, wherein the bond with the therapeutic agent becomes labile upon cleavage of the scissile bond.
  • self-immolative groups include, but are not limited to, disulfide groups, hydrazones, acetal self-immolative groups, carboxyacetal self-immolative groups, carboxy(methylacetal) self- immolative groups, para- hydroxybenzyl carbonyl self-immolative groups, flipped ester self- immolative groups, and trimethyl lock, or 2-hydroxyphenyl carbamate (2-HPC) self- immolative groups.
  • the term “therapeutic agent,” “active pharmaceutical agent,” “active agent,” or “pharmaceutical agent” includes any therapeutic agent or imaging (contrasting) agent which would benefit from transport via the intestinal lymphatic system, for example, to enable oral administration (e.g., of an intravenously administered therapeutic agent), to avoid first pass metabolism, avoid liver toxicity or other toxicity, or for targeted delivery within the lymphatic system.
  • Pharmaceutical agent includes any therapeutic agent or imaging (contrasting) agent which would benefit from transport via the intestinal lymphatic system, for example, to enable oral administration (e.g., of an intravenously administered therapeutic agent), to avoid first pass metabolism, avoid liver toxicity or other toxicity, or for targeted delivery within the lymphatic system.
  • Lipid prodrug compounds of the present disclosure include those described generally herein, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated.
  • aliphatic or “aliphatic group,” as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocycle,” “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule.
  • aliphatic groups contain 1-6 aliphatic carbon atoms.
  • aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms.
  • “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refers to a monocyclic C 3 -C 6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule.
  • Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
  • the term “bicyclic ring” or “bicyclic ring system” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or having one or more units of unsaturation, having one or more atoms in common between the two rings of the ring system.
  • the term includes any permissible ring fusion, such as ortho-fused or spirocyclic.
  • heterocyclic is a subset of “bicyclic” that requires that one or more heteroatoms are present in one or both rings of the bicycle. Such heteroatoms may be present at ring junctions and are optionally substituted, and may be selected from nitrogen (including N- oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphonates and phosphates), boron, etc.
  • a bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • bridged bicyclic refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge.
  • a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen).
  • a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted.
  • Exemplary bicyclic rings include:
  • Exemplary bridged bicyclics include:
  • lower alkyl refers to a Ci- 4 straight or branched alkyl group.
  • exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and r - butyl.
  • lower haloalkyl refers to a C1- 4 straight or branched alkyl group that is substituted with one or more halogen atoms.
  • heteroatom means one or more of boron, oxygen, sulfur, nitrogen, phosphorus, or silicon (including any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), H (as in pyrrolidinyl) or R + (as in N-substituted pyrrolidinyl)).
  • unsaturated as used herein, means that a moiety has one or more units of unsaturation.
  • bivalent C1 (or C1 -6 ) saturated or unsaturated, straight or branched, hydrocarbon chain refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.
  • alkylene refers to a bivalent alkyl group.
  • An “alkylene chain” is a polymethylene group, i.e., -(CH 2 ) n- , wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3.
  • a substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
  • alkenylene refers to a bivalent alkenyl group.
  • a substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
  • halogen means F, Cl, Br, or I.
  • aryl used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members.
  • aryl may be used interchangeably with the term “aryl ring.”
  • aryl refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents.
  • aryl is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.
  • heteroaryl and “heteroar-,” used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 ⁇ electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms.
  • heteroatom refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quatemized form of a basic nitrogen.
  • Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl.
  • heteroaryl and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring.
  • Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, AH quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-£]-l,4-oxazin- 3(4H)-one.
  • heteroaryl group may be mono- or bicyclic.
  • heteroaryl may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any ofwhich terms include rings that are optionally substituted.
  • heteroarylkyl refers to analkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independentlyare optionally substituted.
  • heterocycle As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7-lO-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above.
  • nitrogen includes a substituted nitrogen.
  • the nitrogen may be N (as in 3,4- dihydro-27T pyrrolyl, NH (as in pyrrolidinyl), or + NR (as in N substituted pyrrolidinyl).
  • a heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted.
  • saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl.
  • heterocycle refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.
  • partially unsaturated refers to a ring moiety that includes at least one double or triple bond.
  • partially unsaturated is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.
  • compounds of the disclosure may contain “optionally substituted” moieties.
  • substituted whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent.
  • an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • Combinations of substituents envisioned by this disclosure are preferably those that result in the formation of stable or chemically feasible compounds.
  • R* is C 1-6 aliphatic
  • R* is optionally substituted with halogen, -R*, - (haloR*), -OH, -OR*, -O(haloR*), -CN, -C(O)OH, -C(O)OR*, -NH 2 , -NHR*, -NR* 2 , or - NO2, wherein each R* is independently selected from C1-4 aliphatic, -CH2Ph, -O(CH2)o-Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R* is unsubstituted or where preceded by halo is substituted only with one or more halogens.
  • An optional substituent on a substitutable nitrogen is independently -R, -NR, - C(O)R, -C(O)OR*, -C(O)C(O)R*, -C(O)CH 2 C(O)R*, -S(O) 2 R*, -S(O) 2 NR*, -C(S)NR*, -2 C(NH)NR* or -N(R*)S(O) 2 R*; wherein each R' is independently hydrogen, C1-6 aliphatic, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, two independent occurrences of R ⁇ , taken together with their intervening atom(s) form an unsubstituted 3-l2-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected
  • the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts include salts of an amino group (or other basic group) 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.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid
  • 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.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, besylate, bisulfate, borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy- ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamo
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (Ci-4alkyl)4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the disclosure. Unless otherwise stated, all tautomeric forms of the compounds of the disclosure are within the scope of the disclosure.
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this disclosure.
  • Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present disclosure.
  • Disclosed lymphatic-directing lipid prodrugs as well as pharmaceutically acceptable compositions comprising a disclosed lipid prodrug, and a pharmaceutically acceptable excipient, diluent, or carrier, are useful for treating a variety of diseases, disorders or conditions. Such diseases, disorders, or conditions include those described herein.
  • diseases, disorders, or conditions include those described herein.
  • each of the therapeutic agents described herein are known to be associated with treatment of one or more diseases, disorders, or conditions. Accordingly, it will be appreciated that, in certain embodiments, the present disclosure provides a method of treating a disease, disorder, or condition in a patient in need thereof comprising administering to said patient a disclosed lipid prodrug.
  • lipid prodrugs are useful for the stable transport of pharmaceutical agents to the intestinal lymph and release of the pharmaceutical agents in the lymph, lymphocytes, lymphoid tissues, tissues with high lipase activity such as adipose tissue, certain cancers, the liver, or in the systemic circulation.
  • Disclosed lipid prodrugs are particularity useful for the transport and release of pharmaceutical agents that benefit from avoidance of first pass metabolism, for example, therapeutic agents that exhibit greater than about 50% first pass metabolism when administered orally. In some embodiments, the therapeutic agent exhibits greater than about 60% first pass metabolism when administered orally. In some embodiments, the therapeutic agent exhibits greater than about 70%, 80%, or 90% first pass metabolism when administered orally.
  • Therapeutic agents that may benefit from the stable transport to the intestinal lymph and release in the lymph, lymphocytes, lymphoid tissues, tissues with high lipase activity such as adipose tissue, certain cancers, the liver or in the systemic circulation include, but are not limited to, therapeutic agents listed herein such DMT, 5-MeO-DMT, or derivatives and prodrugs of such.
  • the presently disclosed lipid prodrugs are also useful for the targeted release of the therapeutic agent within the lymphatic system, for example, in the lymph, lymphocytes and lymphoid tissues, as well as in tissues with high lipase activity such as adipose tissue, certain cancers, or the liver.
  • the therapeutic agent exhibits poor lymphatic transport when administered orally.
  • the therapeutic exhibits less than 70%, 60%, 50%, 40%, 30%, 20%, 15%, 10%, 8%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.25%, 0.2%, 0.15%, or 0.1% when administered orally.
  • the present disclosure provides for improved lymphatic transport of such therapeutic agents.
  • a disclosed lipid prodrug exhibits 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, a disclosed lipid prodrug exhibits about 1-50%, 5-40%, 10-30%, 15-25%, or about 50%, 40%, 30%, 25%, 20%, 15%, 12.5%, 10%, 7.5%, 5%, 2.5%, or 1% lymphatic transport when administered orally, as measured by either w/w% of the lipid prodrug administered or w/w% of the therapeutic agent in its lipid prodrug form vs. the unmodified therapeutic agent.
  • a disclosed lipid prodrug is delivered to the central nervous system (CNS) or crosses the blood-brain barrier (BBB) via the lymphatic system.
  • the present disclosure provides a method of treating or preventing a disease, disorder, or condition, comprising administering to a subject in need thereof an effective amount of a disclosed lipid prodrug that comprises a tryptamine or phenethylamine psychedelic such as DMT or 5-MeO-DMT therapeutic.
  • the presently disclosed lipid prodrugs can be used for increasing neuronal plasticity.
  • the compounds described herein can also be used to treat any brain disease.
  • the compounds described herein can also be used to treat any neurological condition.
  • the compounds described herein can also be used for increasing at least one of translation, transcription or secretion of neurotrophic factors.
  • “treatment” or “treating " or “palliating” or “ameliorating” are used interchangeably herein. These terms refer to an approach for obtaining beneficial or desired results including, but not limited to, therapeutic benefit and/or a prophylactic benefit.
  • compositions are administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.
  • lipid prodrug described herein e.g., a compound of Formula I
  • the compounds have, for example, anti- addictive properties, antidepressant properties, anxiolytic properties, or a combination thereof.
  • the neurological disease is a neuropsychiatric disease.
  • the neuropsychiatric disease is a mood or anxiety disorder.
  • the neurological disease is a migraine, headaches (e.g., cluster headache), post- traumatic stress disorder (PTSD), anxiety, depression, neurodegenerative disorder,
  • Alzheimer’s disease, Parkinson’s disease psychological disorder, treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, frontotemporal dementia, Parkinson’s dementia, dementia, lewy body dementia, multiple system atrophy, and addiction (e.g., substance use disorder).
  • the neurological disease is a migraine or cluster headache.
  • the neurological disease is a neurodegenerative disorder, Alzheimer’s disease, or Parkinson’s disease.
  • the neurological disease is a psychological disorder, treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, post-traumatic stress disorder (PTSD), addiction (e.g., substance use disorder), depression, or anxiety.
  • the neuropsychiatric disease is a psychological disorder, treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, post-traumatic stress disorder (PTSD), addiction (e.g., substance use disorder), depression, or anxiety.
  • the neuropsychiatric disease or neurological disease is post-traumatic stress disorder (PTSD), addiction (e.g., substance use disorder), schizophrenia, depression, or anxiety.
  • the neuropsychiatric disease or neurological disease is addiction (e.g., substance use disorder).
  • the neuropsychiatric disease or neurological disease is depression.
  • the neuropsychiatric disease or neurological disease is anxiety.
  • the neuropsychiatric disease or neurological disease is post- traumatic stress disorder (PTSD).
  • the neurological disease is stroke or traumatic brain injury.
  • the neuropsychiatric disease or neurological disease is schizophrenia.
  • lipid prodrug described herein e.g., a compound of Formula I.
  • a therapeutically effective amount of the compound of Formula I is administered.
  • the disease or disorder is a musculoskeletal pain disorder including fibromyalgia, muscle pain, joint stiffness, osteoarthritis, rheumatoid arthritis, muscle cramps.
  • provided herein are method of treating a disease of women’s reproductive health, for example, premenstrual dysphoric disorder (PMDD), premenstrual syndrome (PMS), post-partum depression, and menopause.
  • a lipid prodrug described herein e.g., a compound of Formula I
  • the compounds described herein elicit a biological response by activating the 5-HT2A receptor (e.g., allosteric modulation or modulation of a biological target that activates the 5-HT2A receptor).
  • 5-HT2A agonism has been correlated with the promotion of neural plasticity (Ly et al., 2018).
  • the compounds described herein are 5-HT2A modulators and promote neural plasticity (e.g., cortical structural plasticity).
  • the compounds described herein are selective 5-HT2A modulators and promote neural plasticity (e.g., cortical structural plasticity).
  • promotion of neural plasticity includes, for example, increased dendritic spine growth, increased synthesis of synaptic proteins, strengthened synaptic responses, increased dendritic arbor complexity, increased dendritic branch content, increased spinogenesis, increased neuritogenesis, or any combination thereof.
  • increased neural plasticity includes, for example, increased cortical structural plasticity in the anterior parts of the brain.
  • the 5-HT2A modulators are non- hallucinogenic.
  • non-hallucinogenic 5-HT2A modulators e.g., 5-HT2A agonists
  • the hallucinogenic potential of the compounds described herein is assessed in vitro.
  • the hallucinogenic potential assessed in vitro of the compounds described herein is compared to the hallucinogenic potential assessed in vitro of hallucinogenic homologs.
  • the compounds described herein elicit less hallucinogenic potential in vitro than the hallucinogenic homologs.
  • lipid prodrug described herein e.g., a compound of Formula I
  • a pharmaceutically acceptable salt thereof or the pharmaceutical composition thereof as described herein, in the preparation of a medicament for treating neurological diseases in a subject in need thereof.
  • a lipid prodrug described herein is for use in a method of treating neurological diseases in a subject in need thereof.
  • a compound is, for example, a compound of Formula (I) as disclosed herein, or a pharmaceutical composition comprising the compound disclosed herein, and a pharmaceutically acceptable excipient, as disclosed herein.
  • a pharmaceutical composition comprising a lipid prodrug described herein (e.g., a compound of Formula I) or a pharmaceutically acceptable salt thereof, for use in treating neurological diseases in a subject in need thereof.
  • compositions comprising a lipid prodrug described herein e.g., prodrugs of DMT or 5-MeO-DMT of Formula I
  • methods of use e.g., methods of treating a disease, disorder, or condition caused by deficient activation of serotonin 5HT receptors
  • methods of use are described herein of compositions comprising a lipid prodrug described herein (e.g., prodrugs of DMT or 5-MeO-DMT of Formula I) having activity as a 5- HT2A modulator co-administered with an additional serotonin receptor modulator.
  • the additional serotonin receptor modulator is a serotonin receptor antagonist.
  • compositions comprising a lipid prodrug described herein (e.g., prodrugs of DMT or 5-MeO-DMT of Formula I) and a serotonin receptor modulator, wherein the serotonin receptor modulator is a serotonin receptor inverse agonist.
  • compositions comprising a lipid prodrug described herein (e.g., prodrug of DMT or 5-MeO-DMT of Formula I) and a serotonin receptor modulator, wherein the serotonin receptor modulator is a serotonin receptor allosteric modulator.
  • the serotonin receptor is serotonin receptor 1, serotonin receptor 2, serotonin receptor 4, serotonin receptor 5, serotonin receptor 6, or serotonin receptor 7.
  • the serotonin receptor is serotonin receptor 1 A, serotonin receptor IB, serotonin receptor ID, serotonin receptor IE, serotonin receptor IF, serotonin receptor 2 A, serotonin receptor 2B, serotonin receptor 2C, serotonin receptor 4, serotonin receptor 5A, serotonin receptor 5B, serotonin receptor 6, or serotonin receptor 7.
  • the serotonin receptor is serotonin receptor 2 A.
  • the additional serotonin receptor modulator described herein is selected from the group consisting of ketanserin, volinanserin (MDL- 100907), eplivanserin (SR-46349), pimavanserin (ACP-103), glemanserin (MDL-11939), ritanserin, flibanserin, nelotanserin, blonanserin, mianserin, mirtazapine, roluperiodone (CYR-101, MIN- 101), quetiapine, olanzapine, altanserin, acepromazine, nefazodone, risperidone, pruvanserin, AC-90179, AC -279, adatanserin, fananserin, HY10275, benanserin, butanserin, manserin, iferanserin, lidanserin, pelanserin, seganserin, tropanserin, lorcaserin, ICI-1693
  • the additional serotonin receptor modulator is ketanserin or a pharmaceutically acceptable salt, solvate, metabolite, deuterated analogue, derivative, or prodrug thereof.
  • the additional serotonin receptor modulator is pimavanserin or a pharmaceutically acceptable salt, solvate, metabolite, deuterated analogue, derivative, or prodrug thereof.
  • the additional serotonin receptor modulator is eplivanserin or a pharmaceutically acceptable salt, solvate, metabolite, deuterated analogue, derivative, or prodrug thereof.
  • the additional serotonin receptor modulator is flibanserin or a pharmaceutically acceptable salt, solvate, metabolite, deuterated analogue, derivative, or prodrug thereof. In some embodiments, the additional serotonin receptor modulator is roluperiodone or a pharmaceutically acceptable salt, solvate, metabolite, deuterated analogue, derivative, or prodrug thereof. In some embodiments, the additional serotonin receptor modulator is volinanserin or a pharmaceutically acceptable salt, solvate, metabolite, deuterated analogue, derivative, or prodrug thereof.
  • the additional serotonin receptor modulator is ritanserin or a pharmaceutically acceptable salt, solvate, metabolite, deuterated analogue, derivative, or prodrug thereof. In some embodiments, the additional serotonin receptor modulator is nelotanserin or a pharmaceutically acceptable salt, solvate, metabolite, deuterated analogue, derivative, or prodrug thereof. In some embodiments, the additional serotonin receptor modulator is pruvanserin or a pharmaceutically acceptable salt, solvate, metabolite, deuterated analogue, derivative, or prodrug thereof.
  • compositions comprising a lipid prodrug described herein (e.g., prodrug of DMT or 5-MeO-DMT of Formula I) having activity as a 5-HT2A modulator co-administered with an additional serotonin receptor modulator in a defined dosage range.
  • the additional serotonin receptor modulator for use with the compounds disclosed herein is eplivanserin, wherein the eplivanserin is administered in about 1 mg to about 40 mg, or about 5 mg to about 10 mg.
  • the additional serotonin receptor modulator for use with the compounds disclosed herein is volinanserin, wherein the volinanserin is administered in about 1 mg to about 60 mg, or about 5 mg to about 20 mg.
  • the additional serotonin receptor modulator for use with compounds disclosed herein is ketanserin, wherein the ketanserin is administered in about 10 mg to about 80 mg, about 30 mg to about 50 mg, or about 40 mg.
  • the additional serotonin receptor modulator for use with the compounds disclosed herein is ritanserin, wherein the ritanserin is administered in about 1 mg to about 40 mg, or about 2.5 mg to about 10 mg.
  • the additional serotonin receptor modulator for use with the compounds disclosed herein is pimavanserin, wherein the pimavanserin is administered in about 1 mg to about 60 mg, or about 17 mg to about 34 mg.
  • the additional serotonin receptor modulator for use with the is nelotanserin, wherein the nelotanserin is administered in about 1 mg to about 80 mg, or about 40 mg to about 80 mg.
  • the additional serotonin receptor modulator for use with the compounds disclosed herein is pruvanserin, wherein the pruvanserin is administered in about 1 mg to about 40 mg, or about 3 mg to about 10 mg.
  • the additional serotonin receptor modulator for use with the compounds disclosed herein is flibanserin, wherein the flibanserin is administered in about 10 mg to about 200 mg, or about 80 mg to about 120 mg, or about 100 mg.
  • compositions comprising a lipid prodrug described herein (e.g., prodrugs of DMT or 5-MeO-DMT of Formula I) having activity as a 5-HT2A modulator co-administered with an additional serotonin receptor modulator.
  • a lipid prodrug described herein e.g., prodrugs of DMT or 5-MeO-DMT of Formula I
  • a disclosed compound is co-administered with an additional serotonin receptor modulator in the same or in separate compositions.
  • the compound is administered in a modified release formulation such that the subject is effectively pretreated with an additional serotonin receptor modulator prior to release of an effective amount of the psychedelic.
  • the additional serotonin receptor modulator is administered or released from a composition provided herein prior to the administration and/or release of the psychedelic. This allows pretreatment to attenuate activation of the serotonin receptor by the psychedelic.
  • compositions comprising a lipid prodrug described herein (e.g., prodrugs of DMT or 5-MeO-DMT of Formula I) having activity as a 5-HT2A modulator co-administered with an additional serotonin receptor modulator.
  • a lipid prodrug described herein e.g., prodrugs of DMT or 5-MeO-DMT of Formula I
  • the additional serotonin receptor modulator is used to pretreat a subject.
  • the additional serotonin receptor modulator is administered or released from the composition provided herein to pretreat a subject by at least about at about 5 minutes, 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.25 hours, 1.5 hours, 2 hours, or 3 hours prior to the release of the psychedelic compound disclosed herein.
  • the additional serotonin receptor modulator attenuates the activation of the serotonin receptor when the serotonin receptor modulator is used to pretreat at most about 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, or more than 9 hours prior to the release of the psychedelic.
  • the additional serotonin receptor modulator attenuates the activation of the serotonin receptor when the additional serotonin receptor modulator is used to pretreat in a range of about 5 minutes to about 3 hours, about 10 minutes to about 3 hours, about 20 minutes to about 3 hours, about 30 minutes to about 3 hours, about 40 minutes to about 3 hours, about 50 minutes to about 3 hours, about 1 hour to about 3 hours, about 5 minutes to about 2 hours, about 10 minutes to about 2 hours, about 20 minutes to about 2 hours, about 30 minutes to about 2 hours, about 40 minutes to about 2 hours, about 50 minutes to about 2 hours, about 1 hour to about 2 hours, about 5 minutes to about 1 hour, about 10 minutes to about 1 hour, about 20 minutes to about 1 hour, about 30 minutes to about 1 hour, about 40 minutes to about 1 hour, or about 50 minutes to about 1 hour prior to the release of the psychedelic.
  • the additional serotonin receptor modulator is administered at about 1 hour to about 3 hours prior to the administration of the psychedelic
  • the additional serotonin receptor modulator is eplivanserin, wherein the eplivanserin is administered to pretreat at least 15 minutes prior to the administration of the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is eplivanserin, wherein the eplivanserin is administered to pretreat between at least 30 minutes prior and 360 minutes prior to the release or administration of the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is eplivanserin, wherein the eplivanserin is administered to pretreat between at least 60 minutes prior and 360 minutes prior to the release or administration the compound disclosed herein.
  • the additional serotonin receptor modulator is eplivanserin, wherein the eplivanserin is administered to pretreat at between least 90 minutes and 240 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is eplivanserin, wherein the eplivanserin is administered to pretreat at least 120 minutes prior to the compound disclosed herein.
  • the additional serotonin receptor modulator is eplivanserin, wherein the eplivanserin is administered to pretreat at least 150 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is eplivanserin, wherein the eplivanserin is administered to pretreat at least 180 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is eplivanserin, wherein the eplivanserin is administered to pretreat at least 210 minutes prior to the compound disclosed herein.
  • the additional serotonin receptor modulator is eplivanserin, wherein the eplivanserin is administered to pretreat at least 240 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is eplivanserin, wherein the eplivanserin is administered to pretreat at least 270 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is eplivanserin, wherein the eplivanserin is administered to pretreat at least 300 minutes prior to the compound disclosed herein.
  • the additional serotonin receptor modulator is eplivanserin, wherein the eplivanserin is administered to pretreat at least 330 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is eplivanserin, wherein the eplivanserin is administered to pretreat at least 360 minutes prior to administration or release of the compound disclosed herein. In some preferred embodiments, the additional serotonin receptor modulator is eplivanserin, wherein eplivanserin is administered to pretreat between about 60 minutes and about 180 minutes prior to the administration or release of the compound disclosed herein.
  • the additional serotonin receptor modulator is volinanserin, wherein the volinanserin is administered to pretreat a subject between at least 15 minutes and 360 minutes prior to the administration or release of the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is volinanserin, wherein the volinanserin is administered to pretreat between at least 30 minutes and 360 minutes prior to the administration or release of the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is volinanserin, wherein the volinanserin is administered to pretreat between at least 60 minutes and 240 minutes prior to the administration or release of the compound disclosed herein.
  • the additional serotonin receptor modulator is volinanserin, wherein the volinanserin is administered to pretreat at least 90 minutes prior to compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is volinanserin, wherein the volinanserin is administered to pretreat at least 120 minutes prior to the compound disclosed herein.
  • the additional serotonin receptor modulator is volinanserin, wherein the volinanserin is administered to pretreat at least 150 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is volinanserin, wherein the volinanserin is administered to pretreat between about 15 minutes and about 150 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is volinanserin, wherein the volinanserin is administered to pretreat at least 180 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is volinanserin, wherein the volinanserin is administered to pretreat at least 210 minutes prior to the compound disclosed herein.
  • the additional serotonin receptor modulator is volinanserin, wherein the volinanserin is administered to pretreat at least 240 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is volinanserin, wherein the volinanserin is administered to pretreat at least 270 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is volinanserin, wherein the volinanserin is administered to pretreat at least 300 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is volinanserin, wherein the volinanserin is administered to pretreat at least 330 minutes prior to compound disclosed herein.
  • the additional serotonin receptor modulator is volinanserin, wherein the volinanserin is administered to pretreat at least 360 minutes prior to the compound disclosed herein. In some preferred embodiments, the additional serotonin receptor modulator is volinanserin, wherein volinanserin is administered to pretreat between about 60 minutes and about 180 minutes prior to the administration of the compound disclosed herein.
  • the additional serotonin receptor modulator is ketanserin, wherein the ketanserin is administered to pretreat at least 15 minutes prior to the administration of the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is ketanserin, wherein the ketanserin is administered to pretreat between at least 30 minutes and 360 minutes prior to the administration or release of the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is ketanserin, wherein the ketanserin is administered to pretreat between at least 60 minutes and 240 minutes prior to the administration or release of the compound disclosed herein.
  • the additional serotonin receptor modulator is ketanserin, wherein the ketanserin is administered to pretreat at least 90 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is ketanserin, wherein the ketanserin is administered to pretreat at least 120 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is ketanserin, wherein the ketanserin is administered to pretreat at least 150 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is ketanserin, wherein the ketanserin is administered to pretreat between about 15 minutes and about 150 minutes prior to the compound disclosed herein.
  • the additional serotonin receptor modulator is ketanserin, wherein the ketanserin is administered to pretreat at least 180 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is ketanserin, wherein the ketanserin is administered to pretreat at least 210 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is ketanserin, wherein the ketanserin is administered to pretreat at least 240 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is ketanserin, wherein the ketanserin is administered to pretreat at least 270 minutes prior to the compound disclosed herein.
  • the additional serotonin receptor modulator is ketanserin, wherein the ketanserin is administered to pretreat at least 300 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is ketanserin, wherein the ketanserin is administered to pretreat at least 330 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is ketanserin, wherein the ketanserin is administered to pretreat at least 360 minutes prior to the compound disclosed herein. In some preferred embodiments, the additional serotonin receptor modulator is ketanserin, wherein ketanserin is administered to pretreat between about 60 minutes and about 180 minutes prior to the administration of the compound disclosed herein.
  • the additional serotonin receptor modulator is ritanserin, wherein the ritanserin is administered to pretreat at least 15 minutes prior to the administration of the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is ritanserin, wherein the ritanserin is administered to pretreat at least 30 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is ritanserin wherein the ritanserin is administered to pretreat between at least 60 minutes and 240 minutes prior to the administration or release of the compound disclosed herein.
  • the additional serotonin receptor modulator is ritanserin, wherein the ritanserin is administered to pretreat at least 90 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is ritanserin, wherein the ritanserin is administered to pretreat at least 120 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is ritanserin, wherein the ritanserin is administered to pretreat at least 150 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is ritanserin, wherein the ritanserin is administered to pretreat between about 15 minutes and about 150 minutes prior to the compound disclosed herein.
  • the additional serotonin receptor modulator is ritanserin, wherein the ritanserin is administered to pretreat at least 180 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is ritanserin, wherein the ritanserin is administered to pretreat at least 210 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is ritanserin, wherein the ritanserin is administered to pretreat at least 240 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is ritanserin, wherein the ritanserin is administered to pretreat at least 270 minutes prior to the compound disclosed herein.
  • the additional serotonin receptor modulator is ritanserin, wherein the ritanserin is administered to pretreat at least 300 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is ritanserin, wherein the ritanserin is administered to pretreat at least 330 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is ritanserin, wherein the ritanserin is administered to pretreat at least 360 minutes prior to the compound disclosed herein. In some preferred embodiments, the additional serotonin receptor modulator is ritanserin, wherein ritanserin is administered to pretreat between about 60 minutes and about 180 minutes prior to the administration of the compound disclosed herein.
  • the additional serotonin receptor modulator is pimavanserin, wherein the pimavanserin is administered to pretreat at least 15 minutes prior to the administration of the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is pimavanserin, wherein the pimavanserin is administered to pretreat at least 30 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is pimavanserin, wherein the pimavanserin is administered to pretreat between at least 60 minutes and 240 minutes prior to the administration or release of the compound disclosed herein.
  • the additional serotonin receptor modulator is pimavanserin, wherein the pimavanserin is administered to pretreat at least 90 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is pimavanserin, wherein the pimavanserin is administered to pretreat at least 120 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is pimavanserin, wherein the pimavanserin is administered to pretreat at least 150 minutes prior to the compound disclosed herein.
  • the additional serotonin receptor modulator is pimavanserin, wherein the pimavanserin is administered to pretreat between about 15 minutes and about 150 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is pimavanserin, wherein the pimavanserin is administered to pretreat at least 180 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is pimavanserin, wherein the pimavanserin is administered to pretreat at least 210 minutes prior to the compound disclosed herein.
  • the additional serotonin receptor modulator is pimavanserin, wherein the pimavanserin is administered to pretreat at least 240 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is pimavanserin, wherein the pimavanserin is administered to pretreat at least 270 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is pimavanserin, wherein the pimavanserin is administered to pretreat at least 300 minutes prior to the compound disclosed herein.
  • the additional serotonin receptor modulator is pimavanserin, wherein the pimavanserin is administered to pretreat at least 330 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is pimavanserin, wherein the pimavanserin is administered to pretreat at least 360 minutes prior to the compound disclosed herein. In some preferred embodiments, the additional serotonin receptor modulator is pimavanserin, wherein pimavanserin is administered to pretreat between about 60 minutes and about 180 minutes prior to the administration of the compound disclosed herein.
  • the additional serotonin receptor modulator is nelotanserin, wherein the nelotanserin is administered to pretreat at least 15 minutes prior to the administration of the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is nelotanserin, wherein the nelotanserin is administered to pretreat at least 30 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is nelotanserin, wherein the nelotanserin is administered to pretreat between at least 60 minutes and 240 minutes prior to the administration or release of the compound disclosed herein.
  • the additional serotonin receptor modulator is nelotanserin, wherein the nelotanserin is administered to pretreat at least 90 minutes prior to the compound disclosed herein. In some embodiments, the serotonin receptor modulator is nelotanserin, wherein the nelotanserin is administered to pretreat at least 120 minutes prior to the compound disclosed herein.
  • the additional serotonin receptor modulator is nelotanserin, wherein the nelotanserin is administered to pretreat at least 150 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is nelotanserin, wherein the nelotanserin is administered to pretreat between about 15 minutes and about 150 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is nelotanserin, wherein the nelotanserin is administered to pretreat at least 180 minutes prior to the compound disclosed herein.
  • the additional serotonin receptor modulator is nelotanserin, wherein the nelotanserin is administered to pretreat at least 210 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is nelotanserin, wherein the nelotanserin is administered to pretreat at least 240 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is nelotanserin, wherein the nelotanserin is administered to pretreat at least 270 minutes prior to the compound disclosed herein.
  • the additional serotonin receptor modulator is nelotanserin, wherein the nelotanserin is administered to pretreat at least 300 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is nelotanserin, wherein the nelotanserin is administered to pretreat at least 330 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is nelotanserin, wherein the nelotanserin is administered to pretreat at least 360 minutes prior to the compound disclosed herein. In some preferred embodiments, the additional serotonin receptor modulator is nelotanserin, wherein nelotanserin is administered to pretreat between about 60 minutes and about 180 minutes prior to the administration of the compound disclosed herein.
  • the additional serotonin receptor modulator is pruvanserin, wherein the pruvanserin is administered to pretreat at least 15 minutes prior to the administration of the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is pruvanserin, wherein the pruvanserin is administered to pretreat at least 30 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is pruvanserin, wherein the pruvanserin is administered to pretreat between at least 60 minutes and 240 minutes prior to the administration or release of the compound disclosed herein.
  • the additional serotonin receptor modulator is pruvanserin, wherein the pruvanserin is administered to pretreat at least 90 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is pruvanserin, wherein the pruvanserin is administered to pretreat at least 120 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is pruvanserin, wherein the pruvanserin is administered to pretreat at least 150 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is pruvanserin, wherein the pruvanserin is administered to pretreat between about 15 minutes and about 150 minutes prior to the compound disclosed herein.
  • the additional serotonin receptor modulator is pruvanserin, wherein the pruvanserin is administered to pretreat at least 180 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is pruvanserin, wherein the pruvanserin is administered to pretreat at least 210 minutes prior to the compound disclosed herein.
  • the additional serotonin receptor modulator is pruvanserin, wherein the pruvanserin is administered to pretreat at least 240 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is pruvanserin, wherein the pruvanserin is administered to pretreat at least 270 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is pruvanserin, wherein the pruvanserin is administered to pretreat at least 300 minutes prior to the compound disclosed herein.
  • the additional serotonin receptor modulator is pruvanserin, wherein the pruvanserin is administered to pretreat at least 330 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is pruvanserin, wherein the pruvanserin is administered to pretreat at least 360 minutes prior to the compound disclosed herein. In some preferred embodiments, the additional serotonin receptor modulator is pruvanserin, wherein pruvanserin is administered to pretreat between about 60 minutes and about 180 minutes prior to the administration of the compound disclosed herein.
  • compositions comprising a lipid prodrug described herein (e.g., prodrug of DMT or 5-MeO-DMT of Formula I) having activity as a 5-HT2A modulator co-administered with an additional serotonin receptor modulator.
  • methods for co administering compounds described herein co-administered with an additional serotonin receptor modulator are described herein.
  • the co-administration comprises a pretreatment with an additional serotonin receptor modulator.
  • co-administration is used in a method of treating a brain disorder.
  • co-administration is used in a method of increasing neuronal plasticity.
  • co-administration is used in a method of increasing translation of neurotrophic factors. In some embodiments, co administration is used in a method of increasing transcription of neurotrophic factors. In some embodiments, co-administration is used in a method of increasing secretion of neurotrophic factors.
  • lipid prodrugs e.g., a compound of Formula I
  • the compounds described herein can function as 5-HT2A agonists alone, or in combination with a second therapeutic agent that also is a 5-HT2A modulator.
  • the second therapeutic agent can be an agonist or an antagonist.
  • administering a 5-HT2A antagonist in combination with a compound of the present invention to mitigate undesirable effects of 5-HT2A agonism, such as potential hallucinogenic effects.
  • Serotonin receptor modulators useful as second therapeutic agents for combination therapy as described herein are known to those of skill in the art and include, without limitation, MDL-11,939, eplivanserin (SR-46,349), ketanserin, ritanserin, altanserin, acepromazine, mianserin, mirtazapine, quetiapine, SB204741, SB206553, SB242084, LY272015, SB243213, blonanserin, SB200646, RSI 02221, nefazodone, MDL-100,907, pimavanserin, flibanserin, nelotanserin and lorcaserin.
  • the serotonin receptor modulator used as a second therapeutic is pimavanserin or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof.
  • the serotonin receptor modulator is administered prior to a compound disclosed herein, such as about three or about hours prior administration the compounds described herein (e.g., a compound of Formula I).
  • the serotonin receptor modulator is administered at most about one hour prior to the compounds described herein (e.g., a compound of Formula I).
  • the second therapeutic agent is a serotonin receptor modulator.
  • the second therapeutic agent serotonin receptor modulator is provided at a dose of from about 10 mg to about 350 mg. In some embodiments, the serotonin receptor modulator is provided at a dose of from about 20 mg to about 200 mg. In some embodiments, the serotonin receptor modulator is provided at a dose of from about 10 mg to about 100 mg.
  • the compound described herein e.g., a compound of Formula I
  • the compound described herein is provided at a dose of from about 10 mg to about 100 mg, or from about 20 to about 200 mg, or from about 15 to about 300 mg
  • the serotonin receptor modulator is provided at a dose of about 10 mg to about 100 mg.
  • the compounds described herein are non-hallucinogenic 5-HT2A modulators (e.g., 5-HT2A agonists) and are used to treat neurological diseases.
  • the neurological diseases comprise decreased neural plasticity, decreased cortical structural plasticity, decreased 5-HT2A receptor content, decreased dendritic arbor complexity, loss of dendritic spines, decreased dendritic branch content, decreased spinogenesis, decreased neuritogenesis, retraction of neurites, or any combination thereof.
  • the compounds described herein are non-hallucinogenic 5-HT2A modulators (e.g., 5-HT2A agonists) and are used for increasing neuronal plasticity.
  • non-hallucinogenic 5-HT2A modulators e.g., 5-HT2A agonists
  • non-hallucinogenic 5-HT2A modulators e.g., 5-HT2A agonists
  • the compounds described herein are administered at a low dose that is lower than a dose that would produce noticeable psychedelic effects but high enough to provide a therapeutic benefit.
  • This dose range is predicted to be between 200 pm and 2mg.
  • Neuronal plasticity refers to the ability of the brain to change structure and/or function throughout a subject’s life. New neurons can be produced and integrated into the central nervous system throughout the subject’s life. Increasing neuronal plasticity includes, but is not limited to, promoting neuronal growth, promoting neuritogenesis, promoting synaptogenesis, promoting dendritogenesis, increasing dendritic arbor complexity, increasing dendritic spine density, and increasing excitatory synapsis in the brain. In some embodiments, increasing neuronal plasticity comprises promoting neuronal growth, promoting neuritogenesis, promoting synaptogenesis, promoting dendritogenesis, increasing dendritic arbor complexity, and increasing dendritic spine density.
  • kits for increasing neuronal plasticity comprising contacting a neuronal cell with a compound described herein (e.g., a compound of Formula I). In some embodiments, increasing neuronal plasticity improves a brain disorder described herein.
  • methods of treating a disease or disorder in a subject in need thereof comprising administering the presently disclosed lipid prodrugs (e.g., a compound of Formula I) in the subject, wherein the compound described herein increases neuronal plasticity in the subject.
  • the disease or disorder is neurodegenerative disorder, Alzheimer’s, Parkinson’s disease, psychological disorder, depression, addiction, anxiety, post- traumatic stress disorder, treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, or substance use disorder.
  • the increased neuronal plasticity improves anti-addictive properties, antidepressant properties, anxiolytic properties, or a combination thereof.
  • the disease or disorder is a neuropsychiatric disease.
  • the neuropsychiatric disease is a mood or anxiety disorder.
  • the neuropsychiatric disease includes, for example, migraine, cluster headache, post-traumatic stress disorder (PTSD), schizophrenia, anxiety, depression, and addiction (e.g., substance abuse disorder).
  • brain disorders include, for example, migraines, addiction (e.g., substance use disorder), depression, and anxiety.
  • the experiment or assay to determine increased neuronal plasticity of the compounds described herein is a phenotypic assay, a dendritogenesis assay, a spinogenesis assay, a synaptogenesis assay, a Sholl analysis, a concentration-response experiment, a 5-HT2A agonist assay, a 5-HT2A antagonist assay, a 5-HT2A binding assay, or a 5-HT2A blocking experiment (e.g., ketanserin blocking experiments).
  • the experiment or assay to determine the hallucinogenic potential of any compound of the present invention is a mouse head-twitch response (HTR) assay.
  • HTR mouse head-twitch response
  • Neurotrophic factors refer to a family of soluble peptides or proteins which support the survival, growth, and differentiation of developing and mature neurons.
  • Increasing at least one of translation, transcription, or secretion of neurotrophic factors can be useful for, but not limited to, increasing neuronal plasticity, promoting neuronal growth, promoting neuritogenesis, promoting synaptogenesis, promoting dendritogenesis, increasing dendritic arbor complexity, increasing dendritic spine density, and increasing excitatory synapsis in the brain.
  • increasing at least one of translation, transcription, or secretion of neurotrophic factors can increasing neuronal plasticity.
  • increasing at least one of translation, transcription, or secretion of neurotrophic factors can promoting neuronal growth, promoting neuritogenesis, promoting synaptogenesis, promoting dendritogenesis, increasing dendritic arbor complexity, and/or increasing dendritic spine density.
  • lipid prodrugs e.g., a compound of Formula I
  • methods for increasing at least one of translation, transcription, or secretion of neurotrophic factors comprising contacting a neuronal cell with the presently disclosed lipid prodrugs (e.g., a compound of Formula I).
  • methods for increase at least one of translation, transcription, or secretion of neurotrophic factors in a subject in need thereof comprising administering to the subject a compound described herein (e.g., a compound of Formula I).
  • increasing at least one of translation, transcription or secretion of neurotrophic factors treats a disease or disorder such as a migraine, headaches (e.g., cluster headache), post-traumatic stress disorder (PTSD), anxiety, depression, neurodegenerative disorder, Alzheimer’s disease, Parkinson’s disease, psychological disorder, treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, and addiction (e.g., substance use disorder).
  • a disease or disorder such as a migraine, headaches (e.g., cluster headache), post-traumatic stress disorder (PTSD), anxiety, depression, neurodegenerative disorder, Alzheimer’s disease, Parkinson’s disease, psychological disorder, treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, and addiction (e.g., substance use disorder).
  • the experiment or assay used to determine increase translation of neurotrophic factors includes ELISA, western blot, immunofluorescence assays, proteomic experiments, and mass spectrometry.
  • the experiment or assay used to determine increase transcription of neurotrophic factors includes gene expression assays, RT-PCR, in situ mRNA hybridization, and microarrays.
  • the experiment or assay used to determine increase secretion of neurotrophic factors includes ELISA, western blot, immunofluorescence assays, proteomic experiments, and mass spectrometry.
  • a provided lipid prodrug, or pharmaceutically acceptable composition thereof may be administered to a patient in need thereof in combination with one or more additional therapeutic agents and/or therapeutic processes.
  • the disclosed lipid prodrugs and compositions, and any co-administered additional therapeutic agents, according to the method of the present disclosure, may be administered using any amount and any route of administration effective for treating or lessening the severity of a disease, disorder, or condition such as an inflammatory disorder, a neurodegenerative or neurological disorder, or schizophrenia.
  • a disease, disorder, or condition such as an inflammatory disorder, a neurodegenerative or neurological disorder, or schizophrenia.
  • the exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like.
  • Disclosed lipid prodrugs are preferably formulated in dosage unit form for ease of administration and uniformity of dosage.
  • the expression “dosage unit form” as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated.
  • lipid prodrug or composition thereof any co-administered additional therapeutic agents will be decided by the attending physician within the scope of sound medical judgment.
  • the specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific lipid prodrug employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific lipid prodrug or composition; the duration of the treatment; drugs used in combination or coincidental with the specific lipid prodrug or composition employed, and like factors well known in the medical arts.
  • subject or “patient,” as used herein, means an animal, preferably a mammal, and most preferably a human.
  • the methods described herein further comprise administering one or more second therapeutic agent therapeutic agent that is lithium, olanzapine (Zyprexa), quetiapine (Seroquel), risperidone (Risperdal), ariprazole (Abilify), ziprasidone (Geodon), clozapine (Clozaril), divalproex sodium (Depakote), lamotrigine (Lamictal), valproic acid (Depakene), carbamazepine (Equetro), topiramate (Topamax), levomilnacipran (Fetzima), duloxetine (Cymbalta, Yentreve), venlafaxine (Effexor), citalopram (Celexa), fluvoxamine (Luvox), escitalopram (Lexapro), fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), c
  • the second therapeutic agent is an empathogenic agent.
  • suitable empathogenic agents for use in combination with a compound described herein are selected from the phenethylamines, such as 3,4- methylene- dioxymethamphetamine (MDMA) and analogs thereof.
  • MDMA 3,4- methylene- dioxymethamphetamine
  • suitable empathogenic agents for use in combination with the presently disclosed compounds include, without limitation,
  • MDAL N-Allyl-3,4-methylenedioxy-amphetamine
  • MDBU N-Butyl-3,4-methylenedioxyamphetamine
  • MDBZ N-Benzyl-3,4-methylenedioxyamphetamine
  • MDCPM N-Cyclopropylmethyl-3,4-methylenedioxyamphetamine
  • MDDM N-Ethyl-3,4-methylenedioxyamphetamine
  • MDDE N-Ethyl-3,4-methylenedioxyamphetamine
  • MDHOET N-Isopropyl-3,4-methylenedioxyamphetamine
  • MDMC N-Methyl-3, 4-ethyl enedioxyamphetamine
  • MDMEO N-Methoxy-3,4-methylenedioxyamphetamine
  • MDMEOET N-(2-Methoxyethyl)-3,4-methylenedioxyamphetamine alpha, alpha, N-Trimethyl-3,4-methylenedioxyphenethylamine (MDMP;
  • MDPEA 3.4-Methyl enedioxyphenethylamine alpha, alpha-Dimethyl-3,4-methylenedioxyphenethylamine (MDPH; 3,4- methylenedioxyphentermine)
  • Methylone also known as "3,4-methylenedioxy-N-methylcathinone
  • Ethylone also known as 3,4-methylenedioxy-N-ethylcathinone GHB or Gamma Hydroxybutyrate or sodium oxybate N-Propyl-3,4-methylenedioxyamphetamine (MDPR).
  • GHB 3,4-methylenedioxy-N-ethylcathinone
  • MDPR sodium oxybate N-Propyl-3,4-methylenedioxyamphetamine
  • the compounds of the present invention are used in combination with the standard of care therapy for a neurological disease described herein.
  • the standard of care therapies may include, for example, lithium, olanzapine, quetiapine, risperidone, ariprazole, ziprasidone, clozapine, divalproex sodium, lamotrigine, valproic acid, carbamazepine, topiramate, levomilnacipran, duloxetine, venlafaxine, citalopram, fluvoxamine, escitalopram, fluoxetine, paroxetine, sertraline, clomipramine, amitriptyline, desipramine, imipramine, nortriptyline, phenelzine, tranylcypromine, diazepam, alprazolam, clonazepam, or any combination thereof.
  • Nonlimiting examples of standard of care therapy for depression are sertraline, fluoxetine, escitalopram, venlafaxine, or aripiprazole.
  • Non-limiting examples of standard of care therapy for depression are citralopram, escitalopram, fluoxetine, paroxetine, diazepam, or sertraline. Additional examples of standard of care therapeutics are known to those of ordinary skill in the art.
  • the present disclosure provides a composition comprising a lipid prodrug of the present disclosure and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • the amount of lipid prodrug in the composition is an amount effective to treat the relevant disease, disorder, or condition in a patient in need thereof (an “effective amount”).
  • a composition of the present disclosure is formulated for oral administration to a patient.
  • compositions include, but are not limited to, ion exchangers, alumina, stearates such as aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose- based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene
  • compositions of the present disclosure may be administered orally, parenterally, enterally, intracistemally, intraperitoneally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrastemal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • the composition is administered orally, intraperitoneally, or intravenously.
  • the composition is a transmucosal formulation.
  • the composition is injected directly into the lymphatic system.
  • Sterile injectable forms of the compositions of this disclosure may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • a non-toxic parenterally acceptable diluent or solvent for example as a solution in 1,3-butanediol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer’s solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or di-glycerides.
  • Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically- acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
  • Other commonly used surfactants such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
  • compositions may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
  • carriers commonly used include lactose and com starch.
  • Lubricating agents such as magnesium stearate, may also be added.
  • useful diluents include lactose and dried corn starch.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
  • compositions may be administered in the form of suppositories for rectal administration.
  • suppositories for rectal administration.
  • suppositories can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter, beeswax and polyethylene glycols.
  • the pharmaceutically acceptable composition is formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, the pharmaceutically acceptable composition is administered without food. In other embodiments, the pharmaceutically acceptable composition is administered with food. It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated.
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3 -butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • the oral compositions can contain inert diluents commonly used in the art such as, for
  • Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer’s solution, U.S.P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • the rate of compound release can be controlled.
  • biodegradable polymers include poly(orthoesters) and poly(anhydrides).
  • Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this disclosure with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f ) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetylene glycol, g,
  • Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • embedding compositions that can be used include polymeric substances and waxes.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
  • Therapeutic agents can also be in micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g ., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • additional substances other than inert diluents e.g ., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.
  • Dosage forms for topical or transdermal administration of a compound of this disclosure include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this disclosure.
  • the present disclosure contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body.
  • Such dosage forms can be made by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • the lipid prodrug is formulated as an orally administrable, lipid-based formulation.
  • Lipid-based formulations for oral delivery are known in the art and may include, for example, substantially non-aqueous vehicles which typically contain one or more lipid components.
  • the lipid vehicles and resulting lipid formulations may be usefully classified as described below according to their shared common features according to the lipid formulation classification system (LFCS).
  • LFCS lipid formulation classification system
  • Lipid vehicles, and the resulting lipid formulations may contain oil/lipids and/or surfactants, optionally with co-solvents.
  • Type I formulations include oils or lipids which require digestion, such as mono, di and tri-glycerides and combinations thereof.
  • Type II formulations are water-insoluble self-emulsifying drug delivery systems (SEDDS) which contain lipids and oils used in Type I formulations, with additional water insoluble surfactants.
  • SEDDS water-insoluble self-emulsifying drug delivery systems
  • Type III formulations are SEDDS or self-microemulsifying drug delivery systems (SMEDDS) which contain lipids and oils used in Type I formulations, with additional water-soluble surfactants and/or co-solvents (Type Ilia) or a greater proportion of water-soluble components (Type Illb).
  • Type IV formulations contain predominantly hydrophilic surfactants and co-solvents (e.g PEG, propylene glycol and diethylene glycol monoethyl ether) and are useful for drugs which are poorly water soluble but not lipophilic. Any such lipid formulation (Type I- IV) is contemplated herein for use with a disclosed lipid prodrug or pharmaceutical composition thereof.
  • the lipid vehicle contains one or more oils or lipids, without additional surfactants, co-surfactants or co-emulsifiers, or co-solvents, i.e. it consists essentially of one or more oils or lipids. In some further embodiments, the lipid vehicle contains one or more oils or lipids together with one or more water-insoluble surfactants, optionally together with one or more co-solvents. In some embodiments, the lipid vehicle contains one or more oils or lipids together with one or more water-soluble surfactants, optionally together with one or more co-solvents. In some embodiments, the lipid vehicle contains a mixture of oil/lipid, surfactant and co-solvent. In some embodiments, the lipid vehicle consists essentially of one or more surfactants/co-surfactants/co-emulsifiers, and/or solvents/co- sol vents .
  • Examples of mono and diglycerides which may be used in such formulations include glycerol mono- and diesters having fatty acid chains from 8 to 40 carbon atoms, including hydrolysed coconut oils (e.g., Capmul® MCM), hydrolysed corn oil (e.g, MaisineTM35-1).
  • the monoglycerides and diglycerides are mono-or di- saturated fatty acid esters of glycerol having fatty acid chains of 8 to 18 carbon chain length (e.g, glyceryl monostearate, glyceryl distearate, glyceryl monocaprylate, glyceryl dicaprylate, glyceryl monocaprate and glyceryl dicaprate).
  • Mixtures of fatty acids (“structured glycerides”) adapted for enhancing the absorption and transport of lipid soluble compounds are disclosed in, e.g ., U.S. Patent No. 6,013,665, which is hereby incorporated by reference.
  • Suitable surfactants for use in the lipid formulations include propylene glycol mono- and di-esters of Cx-22 fatty acids, such as, but not limited to, propylene glycol monocaprylate, propylene glycol dicaprylate, propylene glycol monolaurate, sold under trade names such as Capryol® 90, Labrafac® PG, Lauroglycol® FCC, sugar fatty acid esters, such as, but not limited to, sucrose palmitate, sucrose laurate, and sucrose stearate; sorbitan fatty acid esters such as, but not limited to, sorbitan laurate, sorbitan palmitate, and sorbitan oleate; polyoxyethylene sorbitan fatty acid esters such as, but not limited to, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, and polysorbate 85; polyoxyethylene mono- and di-fatty acid esters including, but not limited to, polyoxyl 40 stearate
  • a co-emulsifier, or co-surfactant may be used in the formulation.
  • a suitable co emulsifier or co-surfactant may be a phosphoglyceride; a phospholipid, for example lecithin, or a free fatty acid that is liquid at room temperature, for example, iso-stearic acid, oleic acid, linoelic acid, linolenic acid, palmitic acid, stearic acid, lauric acid, capric acid, caprylic acid, and caproic acid.
  • Suitable solvents/co-solvents include ethanol, propylene glycol, polyethylene glycol, di ethylene glycol monoethyl ether, and glycerol.
  • a polymer may also be used in the formulation to inhibit drug precipitation or to alter the rate of drug release.
  • a range of polymers have been shown to impart these properties and are well known to those skilled in the art.
  • Suitable polymers include hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetyl succinate, other cellulose-derived polymers such as methylcellulose; poly(meth)acrylates, such as the Eudragit series of polymers, including Eudragit El 00, polyvinylpyrrolidone.
  • Formulations may be chosen specifically to provide for sustained release of the active in the gastrointestinal (GI) tract in order to control the rate of absorption. Many different approaches may be used to achieve these ends including the use of high melting point lipids that disperse/erode slowly in the GI tract, or polymers that form a matrix that slowly erodes. These formulations may take the form of large monolithic dose forms or may be present as micro or nano-particulate matrices.
  • Formulations may also contain materials commonly known to those skilled in the art to be included in lipid based formulations, including antioxidants, for example, butylated hydroxyanisole (BHA) or butylated hydroxytoluene (BHT) and solidifying agents such as microporous silica, for example magnesium alumino-metasilicate (Neusilin).
  • antioxidants for example, butylated hydroxyanisole (BHA) or butylated hydroxytoluene (BHT)
  • solidifying agents such as microporous silica, for example magnesium alumino-metasilicate (Neusilin).
  • the lipid prodrug may be co-administered orally with an enzyme inhibitor to increase stability of the prodrug in the gastrointestinal tract or enterocyte.
  • the enzyme inhibitor inhibits pancreatic lipases, examples of which include, but are not limited to, Alii® (orlistat).
  • the enzyme inhibitor will inhibit cellular lipase enzymes such as monoacylglycerol lipase, an example of which includes, but is not limited to, JZL184 (4-nitrophenyl-4-[bis(l,3- benzodioxol- 5-yl)(hydroxy)methyl]piperidine-l-carboxylate).
  • a dose is selected to account for lymphatic uptake, metabolism, and release of the parent drug tryptamine or phenethylamine psychedelic such as (N,N-dimethyltryptamine) DMT, or 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) (alio).
  • tryptamine or phenethylamine psychedelic such as (N,N-dimethyltryptamine) DMT, or 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) (alio).
  • lipid prodrug is absorbed more efficiently than an equivalent oral or intravenous dose of tryptamine or phenethylamine psychedelic such as (N,N-dimethyltryptamine) DMT, or 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT)
  • the dose of lipid prodrug is decreased by an appropriate amount to result in the desired plasma or lymphatic system concentration of tryptamine or phenethylamine psychedelic such as (N,N- dimethyltryptamine) DMT, or 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) .
  • the dose is selected such that an orally-administered dose of lipid prodrug provides, upon lymphatic uptake in the patient, metabolism, and release of the parent drug tryptamine or phenethylamine psychedelic such as (N,N-dimethyltryptamine) DMT, or 5- methoxy-N,N-dimethyltryptamine (5-MeO-DMT) , a desired, effective concentration, e.g., a plasma or lymphatic system concentration, of tryptamine or phenethylamine psychedelic such as (N,N-dimethyltryptamine) DMT, or 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) to treat a disease, disorder, or condition, such as those disclosed herein.
  • tryptamine or phenethylamine psychedelic such as (N,N-dimethyltryptamine) DMT, or 5- methoxy-N,N-dimethyltry
  • the dose of lipid prodrug or a pharmaceutically acceptable salt thereof is about 0.01 mg/kg to about 100 mg/kg. In some embodiments, the dose of lipid prodrug or a pharmaceutically acceptable salt thereof is about 0.1 mg/kg to about 25 mg/kg. In some embodiments, the dose of lipid prodrug or a pharmaceutically acceptable salt thereof is about 0.5 mg/kg to about 15 mg/kg. In some embodiments, the dose of lipid prodrug or a pharmaceutically acceptable salt thereof is about 1 mg/kg to about 10 mg/kg. In some embodiments, the dose of lipid prodrug or a pharmaceutically acceptable salt thereof is about 2 mg/kg to about 7.5 mg/kg.
  • the dose of lipid prodrug or a pharmaceutically acceptable salt thereof is about 3.0 mg/kg to about 7.0 mg/kg. In some embodiments, the dose of lipid prodrug or a pharmaceutically acceptable salt thereof is about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.3, 1.5, 1.7, 2.0, 2.5, 3.0, 3.5, 4.0, 5.0, 6.0, 7.0,
  • the dose is about 1 mg to about 5 g of lipid prodrug or a pharmaceutically acceptable salt thereof. In some embodiments, the dose is about 10 mg to about 2.5 g of lipid prodrug or a pharmaceutically acceptable salt thereof. In some embodiments, the dose is about 100 mg to about 2.0 g of lipid prodrug or a pharmaceutically acceptable salt thereof. In some embodiments, the dose is about 250 mg to about 1.0 g of lipid prodrug or a pharmaceutically acceptable salt thereof. In some embodiments, the dose is about 500 mg to about 1.0 g of lipid prodrug or a pharmaceutically acceptable salt thereof.
  • the dose of lipid prodrug or a pharmaceutically acceptable salt thereof is calculated to provide a particular dose of tryptamine or phenethylamine psychedelic such as (N,N-dimethyltryptamine) DMT, or 5 -m ethoxy -N,N-dimethyltryptamine (5-MeO-DMT) when the prodrug is administered orally.
  • tryptamine or phenethylamine psychedelic such as (N,N-dimethyltryptamine) DMT, or 5 -m ethoxy -N,N-dimethyltryptamine (5-MeO-DMT)
  • the dose of lipid prodrug or a pharmaceutically acceptable salt thereof is calculated to provide about 0.01 mg/kg to about 100 mg/kg of tryptamine or phenethylamine psychedelic such as (N,N- dimethyltryptamine) DMT, or 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) , 0.1 mg/kg to about 25 mg/kg, about 0.5 mg/kg to about 15 mg/kg, about 1 mg/kg to about 10 mg/kg, about 2 mg/kg to about 7.5 mg/kg, about 3.0 mg/kg to about 7.0 mg/kg of tryptamine or phenethylamine psychedelic such as (N,N-dimethyltryptamine) DMT, or 5 -m ethoxy -N,N- dimethyltryptamine (5-MeO-DMT) .
  • tryptamine or phenethylamine psychedelic such as (N,N- dimethyltrypt
  • the dose of lipid prodrug or a pharmaceutically acceptable salt thereof is calculated to provide about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.3, 1.5, 1.7, 2.0, 2.5, 3.0, 3.5, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, or 10.0 mg/kg of tryptamine or phenethylamine psychedelic such as (N,N-dimethyltryptamine) DMT, or 5- methoxy-N,N-dimethyltryptamine (5-MeO-DMT) when the prodrug is administered orally.
  • tryptamine or phenethylamine psychedelic such as (N,N-dimethyltryptamine) DMT, or 5- methoxy-N,N-dimethyltryptamine (5-MeO-DMT) when the prodrug is administered orally.
  • the dose of lipid prodrug or a pharmaceutically acceptable salt thereof is calculated to provide about 5 mg to about 3 g of tryptamine or phenethylamine psychedelic such as (N,N-dimethyltryptamine) DMT, or 5 -m ethoxy -N,N-dimethyltryptamine (5-MeO-DMT) when the prodrug is administered orally.
  • tryptamine or phenethylamine psychedelic such as (N,N-dimethyltryptamine) DMT, or 5 -m ethoxy -N,N-dimethyltryptamine (5-MeO-DMT)
  • the dose is calculated to provide about 50 mg to about 2.5 g of tryptamine or phenethylamine psychedelic such as (N,N-dimethyltryptamine) DMT, or 5-methoxy-N,N-dimethyltryptamine (5-MeO- DMT) , or about 100 mg to about 1.5 g, or about 250 mg to about 1.0 g of tryptamine or phenethylamine psychedelic such as (N,N-dimethyltryptamine) DMT, or 5 -m ethoxy -N,N- dimethyltryptamine (5-MeO-DMT) .
  • lipid prodrug compounds of this disclosure may be prepared or isolated in general by synthetic and/or semi synthetic methods known to those skilled in the art for analogous compounds and by methods described in herein.
  • the therapeutic agents comprised in disclosed lipid prodrugs may be purchased commercially or prepared by organic synthesis, semi -synthesis, fermentation (e.g, with viral vectors), and like methods known in the art.
  • protecting groups as defined below can be used to manipulate therapeutic agents in preparation for conjugation to the remainder of the lipid prodrug structure, for example, to prevent undesired side reactions from taking place.
  • LG protecting group
  • PG protecting group
  • LG leaving group
  • the phrase “leaving group” includes, but is not limited to, halogens (e.g ., fluoride, chloride, bromide, iodide), sulfonates (e.g, mesylate, tosylate, benzenesulfonate, brosylate, nosylate, triflate), diazonium, and the like.
  • oxygen protecting group includes, for example, carbonylprotecting groups, hydroxyl protecting groups, etc.
  • suitable hydroxyl protecting groups include, but are not limited to, esters, allyl ethers, ethers, silyl ethers, alkyl ethers, arylalkyl ethers, and alkoxyalkyl ethers.
  • esters include formates, acetates, carbonates, and sulfonates.
  • Examples include formate, benzoyl formate, chloroacetate, trifluoroacetate, methoxyacetate,triphenylmethoxyacetate, p- chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate, 4,4-(ethylenedithio)pentanoate, pivaloate (trimethylacetyl), crotonate, 4-methoxy-crotonate, benzoate, p-benzylbenzoate, 2,4,6-trimethylbenzoate, carbonates such as methyl, 9-fluorenylmethyl, ethyl, 2,2,2- trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, vinyl, allyl, and p-nitrobenzyl.
  • silyl ethers examples include trimethylsilyl, triethylsilyl,t-butyldimethylsilyl, t- butyldiphenylsilyl, triisopropylsilyl, and other trialkylsilyl ethers.
  • Alkylethers 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-methoxyethoxy)methyl, benzyloxymethyl, beta- (trimethylsilyl)ethoxymethyl, and tetrahydropyranyl ethers.
  • arylalkyl ethers includebenzyl, p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, O-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, and 2- and 4-picolyl.
  • Suitable amino protecting groups include, but are not limited to, aralkyl amines, carbamates, cyclic imides, allyl amines, amides, and the like.
  • Examples of such groups include t-butyloxy carbonyl (Boc), ethyloxycarbonyl, methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyl oxocarbonyl (Cbz), allyl, phthalimide, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), formyl, acetyl, chloroacetyl, dichloroacetyl, tri chloroacetyl, phenylacetyl, trifluoroacetyl, benzoyl, and the like.
  • Compounds I-1 through I-30 can be synthesized by reacting an acid (carboxylic acid RCOO 2 H) with 2-(1H-indol-3-yl)-N,N-dimethylethanamine or 2-(5-methoxy-1H-indol-3- yl)-N,N-dimethylethanamine under standard amide coupling conditions, employing well- known coupling (activating) reagents such as DCC, EDCI, HATU, COMU, T3P, BOP, BOP- Cl, etc.
  • the solvent for such reactions can be DMF, DCM, 1,2-DCE, ACN, THF, etc. .
  • acid-TG iv can be generated by ring-opening reaction with diglyceride ii in the presence of pyridine or another appropriate base (see Scheme 3 above).
  • This method works best when R 4 and R 5 of acid anhydride i-a are identical, e.g. , both R 4 and R 5 are Me.
  • this method will result in a regioisomeric mixture of acid-TG products iv when R 4 and R 5 differ from each other. Consequently, other methods, such as that outlined in Scheme 4 below, can be advantageously employed in this circumstance.
  • a modified version of the acetal self- immolative group can be used where an additional carboxy group is included.
  • Reaction of the parent drug with a chloroalkyl chloroformate gives chloroalkyl carbonates (shown) or carbamates xi (see Scheme 6 above).
  • Displacement of the halide leaving group is then accomplished by treatment with the carboxylate derived from acid-TG iv in an appropriate solvent such as refluxing toluene to afford the target compound xii.
  • the acid- triglyceride iv must be functionalized with the TML moiety priorto conjugation with a pharmaceutical agent as outlined in Scheme 7 above. Coupling of acid-TG iv with TML phenol xiii under standard conditions gives triglyceride xiv, which can be deprotected under acidic conditions (10-camphorsulfonic acid) to give alcohol xv.
  • TML trimethyl lock
  • UPLC-MS analysis was carried out on a WatersTM Acquity UPLC system consisting of an Acquity I-Class Sample Manager-FL, Acquity I-Class Binary Solvent Manager and an Acquity UPLC Column Manager.
  • UV detection was afforded using an Acquity UPLC PDA detector (scanning from 210 to 400 nm), whilst mass detection was achieved using an Acquity QDa detector (mass scanning from 100-1250 Da; positive and negative modes simultaneously), and ELS detection was achieved using an Acquity UPLC ELS Detector.
  • a WatersTM Acquity UPLC BEH C18 column (2.1 x 50 mm, 1.7 mm) was used to separate the analytes.
  • Samples were prepared by dissolution (with or without sonication) into 1 mL of 50% (v/v) MeCN in water. The resulting solutions were then filtered through a 0.2 mm syringe filter before submitting for analysis. All of the solvents, including formic acid and 36% ammonia solution, were purchased as the HPLC grade.
  • Step 2 Decane-2,9-dione [000331] To a stirred solution of N,N'-dimethoxy-N,N'-dimethyl-octanediamide (4.30 g, 16.5 mmol) in Et2O (40 mL) cooled to -78 °C under an atmosphere of N2 was added a solution of MeLi (1.6M in Et2O; 26 mL, 41.3 mmol) dropwise. The reaction mixture was allowed to warm to room temperature and stirring was continued for 21 hrs. A saturated solution of NH 4 Cl (20 mL) was added carefully and the mixture was extracted with EtOAc (3 x 80 mL).
  • Step 3 Diethyl (2E,10E)-3,10-dimethyldodeca-2,10-dienedioate [000332] To a stirred mixture of NaH, 60% in mineral oil (1.51 g, 37.7 mmol) in THF (40 mL) at 0 °C under an Ar atmosphere was added triethyl phosphonoacetate (7.5 mL, 37.7 mmol) in THF (15 mL) dropwise. The mixture was stirred at 0 °C for 30 min, then decane- 2,9-dione (2.14 g, 12.6 mmol) in THF (15 mL). The mixture was allowed to warm to room temperature and was stirred at room temperature for 2 days.
  • Step 4 Diethyl 3,10-dimethyldodecanedioate [000333] A mixture of diethyl (2E,10E)-3,10-dimethyldodeca-2,10-dienedioate (3.52 g, 11.3 mmol) and Palladium on activated carbon (Johnson Matthey-type 424; 0.49 g, 4.59 mmol) in EtOAc (50 mL) was stirred under an atmosphere of H2 (balloon) at room temperature for 20 hrs, then filtered through a pad of Celite, and the filter cake washed with EtOAc.
  • H2 balloon
  • Step 5 3,10-Dimethyldodecanedioic acid [000334] To a solution of diethyl 3,10-dimethyldodecanedioate (3.50 g, 11.1 mmol) in THF (25 mL), EtOH (25 mL) and H2O (25 mL) was added NaOH (1.87 g, 46.7 mmol). The reaction mixture was stirred at room temperature for 21 h. The volatile solvents were evaporated and the mixture was then acidified by addition of 1N HCl (until pH acidic) and extracted with EtOAc (3 x 100 mL).
  • 1N HCl until pH acidic
  • Step 6 12-[2-Hexadecanoyloxy-1-(hexadecanoyloxymethyl)ethoxy]-3,10-dimethyl-12-oxo- dodecanoic acid [000335] To a stirred solution of 1,3-dihexadecanoylglycerol (250 mg, 0.44 mmol) and 3,10-dimethyldodecanedioic acid (193 mg, 0.75 mmol) in DCM (3.5 mL) was added 4- dimethylaminopyridine (91 mg, 0.75 mmol) followed by N-[3-(dimethylamino)propyl]-N'- ethyl-formamidine hydrochloride (286 mg, 1.49 mmol).
  • Step 7 [2-(12-Chloro-3,10-dimethyl-12-oxo-dodecanoyl)oxy-3-hexadecanoyloxy-propyl] hexadecanoate
  • Oxalyl chloride (0.32 mL, 3.7 mmol) was added dropwise to a solution of 12-[2- hexadecanoyloxy-1-(hexadecanoyloxymethyl)ethoxy]-3,10-dimethyl-12-oxo-dodecanoic acid (1.0 g, 1.24 mmol) in DCM (10 mL) under an atmosphere of N2 at rt followed by DMF (1 drop).
  • Step 8 [2-[12-[3-[2-(dimethylamino)ethyl]indol-1-yl]-3,10-dimethyl-12-oxo-dodecanoyl]oxy-3- [000337]
  • 2-(1H-indol-3-yl)-N,N-dimethylethanamine 300 mg, 1.59 mmol
  • NaHMDS 2M solution in THF, 0.88 mL, 0.2 mmol
  • the crude residue was purified by column chromatography on silica gel (eluent: MeOH in DCM, from 0:1 to 1:19) to afford a mixture of the desired product and 12-[2-hexadecanoyloxy-1-(hexadecanoyloxymethyl)ethoxy]-3,10- dimethyl-12-oxo-dodecanoic acid.
  • the mixture was purified further by SCX-2 column.
  • the crude product was loaded onto the SCX-2 column as a solution with 20% MeOH in DCM + 1% AcOH and the acid was eluted by washing the column with 20% MeOH in DCM (10 mL).
  • Step 1 [2-(12-chloro-3,11-dimethyl-12-oxo-dodecanoyl)oxy-3-hexadecanoyloxy-propyl] hexadecanoate
  • Oxalyl chloride 0.061 mL, 0.73 mmol
  • 12- [2-hexadecanoyloxy-1-(hexadecanoyloxymethyl)ethoxy]-2,10-dimethyl-12-oxo-dodecanoic acid (196 mg, 0.24 mmol) and DMF (1 drop) in DCM (2 mL) at room temperature under an atmosphere of N2.
  • Step 2 2-((3-(2-(dimethylamino)ethyl)-5-methoxy-1H-indole-1-carbonyl)oxy)propane-1,3-diyl dipalmitate [000343] To 5-MeO-DMT (48 mg, 0.22 mmol) in DCM (2 mL) at -78 °C under an atmosphere of N 2 was added NaHMDS, 1M in THF (440 ⁇ L, 0.44 mmol).
  • Step 1 4-((1,3-bis(palmitoyloxy)propan-2-yl)oxy)-4-oxobutanoic acid
  • 1,3-dipalmitin (288 mg, 0.51 mmol) and succinic anhydride (151 mg, 1.52 mmol) in THF (2 mL) pyridine (2 mL) and DCM (2 mL)
  • DMAP 62 mg, 0.51 mmol
  • Step 2 2-((4-chloro-4-oxobutanoyl)oxy)propane-1,3-diyl dipalmitate [000346] To a mixture of 4-((1,3-bis(palmitoyloxy)propan-2-yl)oxy)-4-oxobutanoic acid (50 mg, 0.07 mmol) in anhydrous THF (5 mL) and anhydrous DMF (10 mL) was added oxalyl chloride (0.5 mL, 6.0 mmol) and the mixture was stirred at room temperature overnight.
  • Step 1 6-((1,3-bis(palmitoyloxy)propan-2-yl)oxy)-6-oxohexanoic acid
  • 1,3-dipalmitin (1.00 g, 1.76 mmol) in pyridine (1.4 mL) and DCM (30 mL) was added adipoyl chloride (1.60 g, 1.30 mL, 1.52 mmol) and the mixture was stirred at 55 °C for 3.5 h.
  • Step 2 2-((6-chloro-6-oxohexanoyl)oxy)propane-1,3-diyl dipalmitate
  • oxalyl chloride 8.2 g, 5.45 mL, 64.6 mmol
  • Step 3 2- 3-(2-(dimethylamino)ethyl)-5-methoxy-1H-indol-1-yl)-6- oxohexanoyl)oxy)propane-1,3-diyl dipalmitate [000351] To a mixture of 5-MeO-DMT (314 mg, 1.44 mmol) in anhydrous THF (10 mL) at -78 °C under an atmosphere of N2 was added NaHMDS, 1M in THF (1.73 mL, 1.73 mmol) and the mixture was stirred at -78 °C for 30 min.2-((6-Chloro-6-oxohexanoyl)oxy)propane- 1,3-diyl dipalmitate (1.44 mmol) in anhydrous THF (5 mL) was added and the mixture was stirred at -78 °C for 10 min.
  • Step 1 1-(1,3-Bis(palmitoyloxy)propan-2-yl) 5-(1-(((ethylthio)carbonyl)oxy)ethyl) 3- methylpentanedioate
  • O-(1-chloroethyl) S-ethyl carbonothioate (128 mg, 0.76 mmol) was dissolved in DMF (1.3 mL) and K2CO3 (0.53 g, 3.82 mmol) was added.
  • This material was purified by column chromatography on silica gel (EtOAc / PE, 0:1 to 1:0) to give 1-(1,3-bis(palmitoyloxy)propan-2-yl) 5-(1- (((ethylthio)carbonyl)oxy)ethyl) 3-methylpentanedioate (329 mg, 88%) as an oil.
  • Step 2 1-(1,3-bis(palmitoyloxy)propan-2-yl) 5-(1-((chlorocarbonyl)oxy)ethyl) 3- methylpentanedioate
  • 1-(1,3-bis(palmitoyloxy)propan-2-yl) 5-(1- (((ethylthio)carbonyl)oxy)ethyl) 3-methylpentanedioate 165 mg, 0.20 mmol
  • DCM 3 mL
  • sulfuryl chloride 68 mg, 40 ⁇ L, 0.50 mmol
  • Step 3 1-(1,3-bis(palmitoyloxy)propan-2-yl) 5-(1-((3-(2-(dimethylamino)ethyl)-1H-indole-1- carbonyl)oxy)ethyl) 3-methylpentanedioate [000355] To a mixture of DMT (75 mg, 0.40 mmol) in anhydrous THF (3 mL) at 0 °C under an atmosphere of N2 was added NaHMDS, 1M in THF (0.48 mL, 0.48 mmol) and the mixture was stirred at 0 °C for 30 min.1-(1,3-bis(palmitoyloxy)propan-2-yl) 5-(1- ((chlorocarbonyl)oxy)ethyl) 3-methylpentanedioate (160 mg, 0.20 mmol) in anhydrous THF (1 mL) was added the mixture was warmed to room temperature and stirred for 24 h, then concentrated
  • Example 14 Pharmacokinetics of selected compounds following a single intravenous or oral administration in rats.
  • PK pharmacokinetic
  • SD Sprague-Dawley rats following intravenous (IV) or oral (PO) administration of dimethyltryptamine (DMT), 5-methoxy dimethyltryptamine (5-MeO-DMT), Compound 1-31 at 1 mg/kg (IV) or 10 mg/kg (PO).
  • DMT dimethyltryptamine
  • 5-MeO-DMT 5-methoxy dimethyltryptamine
  • Compound 1-31 at 1 mg/kg (IV) or 10 mg/kg (PO).
  • Sprague-Dawley rats were supplied by Charles River (Margate UK) and were specific pathogen free. Male rats weighed between 175 - 225 g on receipt and were allowed to acclimate for 5-7 days.
  • Rats were group housed in sterilised individual ventilated cages that exposed the animals at all times to HEPA filtered sterile air. Animals had free access to food and water (sterile) and sterile aspen chip bedding (changed at least once weekly). The room temperature was maintained at 22°C +/- 1°C, with a relative humidity of 60% and maximum background noise of 56 dB. Rats were exposed to 12-hour light/dark cycles.
  • test compound and control were diluted with 10% v/v DMSO, 40% v/v PEG-400, 50% v/v water.
  • the test compound or the control were administered in a dose volume of 2 mL/kg for intravenous administration (IV) and 5 mL/kg for oral administration (PO).
  • Each test compound was administered as a single IV bolus (via a lateral tail-vein) or a single oral gavage in cohorts of 3 rats per administration route.
  • a 100 pL whole blood sample (EDTA) was collected via the tail-vein at time- points described in TABLE 8.
  • the blood sample was centrifuged to separate plasma. Approximately 40 pL of the separated plasma was dispensed per time-point, per rat, in a 96 well plate and frozen until analysis. Bioanalysis was carried out on the separated plasma samples.
  • TABLE 8 Sample collection points for single IV and oral dose pharmacokinetics study.
  • MeO-DMT MeO-DMT.
  • the contents were mixed by vortex to provide a -1000 pg/mL standard solution in DMSO).
  • control matrix was rat plasma (male Sprague Dawley, EDTA).
  • Calibration and quality control (QC) standards were prepared by spiking control matrix with working solutions containing DMT or 5MeO-DMT.
  • the DMT prodrug Compound 1-31 was synthesized according to methods described herein in Example 2 and pharmacokinetic properties were assessed after IV or oral administration in a rat model.
  • the measured concentrations are summarized in Tables 11 and 12 and are also shown in FIG. 2A (IV administration) and FIG. 2B (PO administration).
  • Dose formulations were made at equivalent concentrations of active compound adjusted for molecular weight of the prodrug.
  • the 5.28 mg/kg IV and 52.8 mg/kg PO dose formulations were 115% and 114% of their nominal concentrations respectively.
  • the IV dose formulation was a clear solution and the PO dose formulation was a white homogeneous suspension. Nominal doses are used in PK parameter determinations.
  • the 5-MeO-DMT prodrug Compound 1-31 was synthesized according to methods described herein in Example 3 and pharmacokinetic properties were assessed after IV or oral administration in a rat model.
  • the measured concentrations are summarized in Tables 15 and 16 and are also shown in FIG. 4A (IV administration) and FIG. 4B (PO administration).
  • the 5-MeO-DMT prodrug Compound 1-35 was synthesized according to methods described herein in Example 6 and pharmacokinetic properties of the 5-MeO-DMT metabolite were assessed after oral administration in a rat model.
  • Mean plasma concentration was measured at 0.25, 0.50, 0.75, 1.00, 2.00, 4.00, 7.00, and 24.0 hours post administration. At all measured timepoints, the mean plasma concentration in each animal tested was BLQ (below lower limit of quantitation of 0.5 ng/mL).
  • the DMT prodrug Compound 1-35 was synthesized according to methods described herein in Example 7 and pharmacokinetic properties of the DMT metabolite were assessed after oral administration in a rat model.
  • the measured concentrations are summarized in Table 19 and are also shown in FIG. 6.

Abstract

The present disclosure provides lipid prodrugs of psychedelic tryptamines and phenethylamines including N,N-Dimethyltryptamine (DMT or N,N-DMT) 5-MeO-DMT (5-methoxy-N,N-dimethyltryptamine) or O-methyl-bufotenin, pharmaceutical compositions thereof, methods of producing such prodrugs and compositions, as well as methods of improving the bioavailability or other properties of a therapeutic agent that comprises part of the lipid prodrug. The present disclosure also provides methods of treating a disease, disorder, or condition such as those disclosed herein, comprising administering to a patient in need thereof a disclosed lipid prodrug or a pharmaceutical composition thereof.

Description

LIPID PRODRUGS OF TRYPT AMINE AND PHENETHYL AMINE PSYCHEDELICS AND USES THEREOF
CROSS-REFERENCE
[0001] This patent application claims the benefit of U.S. Provisional Patent Application No. 63/183,577 filed May 3, 2021; and U.S. Provisional Patent Application No. 63/278,911 filed November 12, 2021; each of which is incorporated herein by reference in their entirety.
BRIEF SUMMARY
[0002] Provided herein, in certain embodiments, are compounds of Formula I :
Figure imgf000003_0001
Formula I or a pharmaceutically acceptable salt thereof, wherein:
R1 and R2 are each independently hydrogen, an acid-labile group, a lipid, or -C(0)R3; each R3 is independently a saturated or unsaturated, straight or branched, optionally substituted Ci-37 hydrocarbon chain;
X is -0-, -NR-, -S-, -0(Ci-6 aliphatic)-0-, -0(Ci-6 aliphatic)-S-, -0(Ci-6 aliphatic)-NR-, -S(Ci-6 aliphatic)-0-, -S(Ci-6 aliphatic)-S-, -S(Ci-6 aliphatic)-NR-, -NR(CI-6 aliphatic)-0-, -NR(Ci- 6 aliphatic)-S-, or -NR(CI-6 aliphatic)-NR-, wherein 0 to 2 methylene units of the Ci-6 aliphatic group are independently and optionally replaced with -0-, -NR-, or -S- and the Ci-6 aliphatic group is independently and optionally substituted with 1, 2, or 3 deuterium or halogen atoms; each R is independently hydrogen or an optionally substituted group selected from Ci-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
Y is absent or is -C(O)-, -C(NR)-, or -C(S)-; L is a covalent bond or a saturated or unsaturated, straight or branched, optionally substituted bivalent C1-30 hydrocarbon chain, wherein 0-8 methylene units of L are independently replaced by -Cy-, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -SO2-, -C(S)-, - NRSO2-, -SO2NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O-, or an amino acid; and wherein 1 methylene unit of L is optionally replaced with -M-; or wherein either the right-hand side or left-hand side of L is attached to A; each -Cy- is independently an optionally substituted 3-6 membered bivalent saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each R4 and R5 is independently hydrogen, deuterium, halogen, -CN, -OR, -NR2, -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a C1-6 aliphatic group optionally substituted with -CN, -OR, -NR2, -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or the C1-6 aliphatic is optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; or two instances of R4 or R5 attached to the same carbon atom, taken together with the carbon atom to which they are attached, form a 3-6 membered spirocyclic saturated monocyclic carbocyclic ring or 3-6 membered spirocyclic saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; -M- is a self-immolative group; n is 0-18; each m is independently 0-6; and A is a therapeutic agent selected from a naturally-occurring or non naturally-occurring tryptamine or phenethylamine psychedelic such as DMT or 5-MeO-DMT or an analogue or prodrug thereof. [0003] In some embodiments, R1 and R2 are -C(O)R3. In some embodiments, each R3 is independently a saturated or unsaturated, unbranched C2-37 hydrocarbon chain. In some embodiments, each R3 is C15H31. In some embodiments, X is -O-. In some embodiments, Y is -C(O)-. In some embodiments, L is a saturated or unsaturated, straight or branched, optionally substituted bivalent C7-20 hydrocarbon chain, wherein 0-8 methylene units of L are independently replaced by -Cy-, -O-, -NR-, -S-, -OC(O)-, - C(O)0-, -C(O)-, -S(O)-, -S(O)2-, - C(S)-, -NRSO2-, -SO2NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O-, or an amino acid; and wherein 1 methylene unit of L is optionally replaced with -M-. In some embodiments, L is a covalent bond or a saturated or unsaturated, straight or branched, optionally substituted bivalent C1-30 hydrocarbon chain, wherein 0-8 methylene units of L are independently replaced by -Cy-, -O-, -NR-, -S-, - OC(O)-, -C(O)0-, -C(O)-, -S(O)-, -SO2-, -C(S)-, -NRSO2-, -S, -OC(O)NR-, -NRC(O)O-, or an amino acid selected from
Figure imgf000005_0001
Figure imgf000006_0001
wherein 1 methylene unit of L is optionally replaced with -M-; or
Figure imgf000006_0002
wherein either the right-hand side or left-hand side of L is attached to A. In some embodiments, L is a saturated bivalent C1-25 hydrocarbon chain optionally substituted with 1, 2, 3, or 4 groups selected from deuterium, halogen, -CN, a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 4-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a C1-6 aliphatic group optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; wherein 0-4 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 with -M-. [0004] In some embodiments, -M- is selected from one of the following:
Figure imgf000007_0001
wherein each R6 is independently selected from hydrogen, deuterium, C1-5 aliphatic, halogen, or - CN; each R7 is independently selected from hydrogen, deuterium, halogen, -CN, -OR, -NR2, -NO2, -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a Ci-6 aliphatic group optionally substituted with -CN, -OR, -NR2, -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or the Ci-6 aliphatic is optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; each 7} is independently selected from -0-, -NR-, or -S-; each Z2 is independently selected from -0-, -NR-, -S-, -OC(O)-, -NRC(0)0-, or -0C(0)NR-; each Z3 is independently selected from =N- or =C(R7)-; and each Z4 is independently selected from -0-, -NR-, -S-, -C(R6)2-, or a covalent bond. [0005] In some embodiments, -M- is selected from:
Figure imgf000008_0001
[0006] In some embodiments, -M- is selected from
Ary
Figure imgf000008_0002
[0007] In some embodiments, each R4 is independently hydrogen, deuterium, halogen, - CN, or Ci-4 aliphatic optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; or two instances of R4 attached to the same carbon atom, taken together with the carbon atom to which they are attached, form a 3-6 membered spirocyclic saturated monocyclic carbocyclic ring or 3-6 membered spirocyclic saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, each R5 is independently hydrogen, deuterium, halogen, -CN, or C1-4 aliphatic optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; or two instances of R5 attached to the same carbon atom, taken together with the carbon atom to which they are attached, form a 3-6 membered spirocyclic saturated monocyclic carbocyclic ring or 3-6 membered spirocyclic saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, each R4 and R5 is independently hydrogen or Ci-4 alkyl optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms. In some embodiments, each R4 and R5 is independently hydrogen or methyl.
Figure imgf000009_0001
[0009] In some embodiments, L is a bond,
Figure imgf000010_0001
, ,
Figure imgf000010_0002
[00010] In certain embodiments, p is 1, 2, 3, 4, 5, 6, 7, or 8. In certain embodiments, p is an integer of 1 to 7. In certain embodiments, p is 1. In certain embodiments p is 2. In certain embodiments p is 3. In certain embodiments p is 4. In certain embodiments p is 5. In certain embodiments p is 6. In certain embodiments p is 7. [00011] In some embodiments, L is a bond,
Figure imgf000010_0003
, ,
Figure imgf000010_0004
[00012] In some embodiments, A is selected from N,N-Dimethyltryptaminec (DMT), 5- MeO-DMT (5-methoxy-N,N-dimethyltryptamine), and O-methyl-bufotenin. [00013] In some embodiments, A is DMT or 5-MeO-DMT. [00014] In some embodiments,
Figure imgf000010_0005
. [00015] In some embodiments, the compound is of Formula VIII-a or Formula VIII-b:
Figure imgf000011_0001
or a pharmaceutically acceptable salt thereof.
[00016] In some embodiments, the compound is selected from one of those in Table 1, or a pharmaceutically acceptable salt thereof.
[00017] Provided herein, in certain embodiments, are pharmaceutically acceptable compositions comprising a compound according to those described herein , and a pharmaceutically acceptable excipient, carrier, adjuvant, or vehicle. In some embodiments, the pharmaceutically acceptable compositions further comprise an additional therapeutic agent.
In some embodiments, the composition is formulated for oral administration.
[00018] Provided herein, in certain embodiments, are methods of treating or preventing a disease, disorder, or condition in which an increased level of a tryptamine or phenethyl amine psychedelic such as DMT or 5-MeO-DMT is beneficial, or a disease, disorder, or condition caused by a deficiency in a tryptamine or phenethylamine psychedelic such as DMT or 5- MeO-DMT, comprising administering to a subject in need thereof an effective amount of a compound described herein.
[00019] Provided herein, in certain embodiments, are methods of treating a disease, disorder, or condition caused by deficient activation of serotonin 5HT receptors comprising administering to a subject in need thereof an effective amount of a compound described herein.
BRIEF DESCRIPTION OF THE DRAWINGS [00020] FIG. 1 shows some exemplary lipid prodrugs of 5-MeO-DMT and DMT. [00021] FIGs. 2A-2B show plasma concentration-time profiles of DMT prodrug
Compound 1-31 (R=H) in different male Sprague Dawley rats following IV dosing or PO administration of DMT prodrug Compound 1-31 (R=H). [00022] FIGs.3A-3B show plasma concentration-time profiles of DMT in different male Sprague Dawley rats following IV dosing or PO administration of DMT prodrug Compound I-31 (R=H). [00023] FIGs.4A-4B show plasma concentration-time profiles of DMT prodrug Compound I-31 (R=MeO) in different male Sprague Dawley rats following IV dosing or PO administration of DMT prodrug Compound I-31 (R=MeO). [00024] FIG.5 shows plasma concentration-time profiles of 5-MeO-DMT in different male Sprague Dawley rats following IV dosing of DMT prodrug Compound I-31 (R=MeO). [00025] FIG.6 shows mean concentration-time profiles of DMT in male Sprague Dawley rats following PO dosing of DMT Prodrug Compound I-35 (R=H) at 52.8 mg/kg (Equivalent to 10 mg/kg of DMT). DETAILED DESCRIPTION General Description of Certain Aspects of the Disclosure Lymphatic System-Directing Prodrugs of psychedelic tryptamine and phenethylamines including DMT and 5-MeO-DMT [00026] Compounds of the present invention, and compositions thereof, are useful in promoting transport of a therapeutic agent to the lymphatic system and in subsequently enhancing release of the parent drug, i.e. the therapeutic agent. [00027] In one aspect, provided herein are compounds of Formula I :
Figure imgf000012_0001
Formula I or a pharmaceutically acceptable salt thereof, wherein: R1 and R2 are each independently hydrogen, an acid-labile group, a lipid, or -C(O)R3; each R3 is independently a saturated or unsaturated, straight or branched, optionally substituted C1-37 hydrocarbon chain; X is -O-, -NR-, -S-, -O(C1-6 aliphatic)-O-, -O(C1-6 aliphatic)-S-, -O(C1-6 aliphatic)-NR-, -S(C1-6 aliphatic)-O-, -S(C1-6 aliphatic)-S-, -S(C1-6 aliphatic)-NR-, -NR(C1-6 aliphatic)-O-, -NR(C1- 6 aliphatic)-S-, or -NR(C1-6 aliphatic)-NR-, wherein 0 to 2 methylene units of the C1-6 aliphatic group are independently and optionally replaced with -O-, -NR-, or -S- and the C1-6 aliphatic group is independently and optionally substituted with 1, 2, or 3 deuterium or halogen atoms; each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Y is absent or is -C(O)-, -C(NR)-, or -C(S)-; L is a covalent bond or a saturated or unsaturated, straight or branched, optionally substituted bivalent C1-30 hydrocarbon chain, wherein 0-8 methylene units of L are independently replaced by -Cy-, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -SO2-, -C(S)-, - NRSO2-, -SO2NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O-, or an amino acid; and wherein 1 methylene unit of L is optionally replaced with -M-; or wherein either the right-hand side or left-hand side of L is attached to A; each -Cy- is independently an optionally substituted 3-6 membered bivalent saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each R4 and R5 is independently hydrogen, deuterium, halogen, -CN, -OR, -NR2, -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a C1-6 aliphatic group optionally substituted with -CN, -OR, -NR2, -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or the C1-6 aliphatic is optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; or two instances of R4 or R5 attached to the same carbon atom, taken together with the carbon atom to which they are attached, form a 3-6 membered spirocyclic saturated monocyclic carbocyclic ring or 3-6 membered spirocyclic saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
-M- is a self-immolative group; n is 0-18; each m is independently 0-6; and
A is a therapeutic agent selected from a naturally-occurring or non naturally-occurring tryptamine or phenethylamine psychedelic such as DMT or 5-MeO-DMT or an analogue or prodrug thereof.
[00028] In one aspect, the present invention provides a method of treating a disease, disorder, or condition in a patient in need thereof, comprising administering to the patient an effective amount of a disclosed lipid prodrug, such as a compound of Formula I, or a pharmaceutically acceptable salt thereof.
[00029] It is understood that a disclosed lipid prodrug may exist in the form of a pharmaceutically acceptable salt. Thus, a reference to a “lipid prodrug” is also a disclosure of “lipid prodrug or a pharmaceutically acceptable salt thereof.” It follows that such a lipid prodrug or pharmaceutically acceptable salt thereof may be used in a pharmaceutical composition and a method of use, such as those disclosed herein.
[00030] One approach to directing drugs into the lymphatic transport system is to employ prodrugs that participate in endogenous pathways that control the absorption, transport (including passive transport), and metabolism of dietary lipids. In one aspect, the present invention provides a lipid prodrug comprising a therapeutic agent conjugated to a glycerol- based moiety comprising two fatty acids or other lipids. Without wishing to be bound by theory, it is believed that such a prodrug mimics a dietary triglyceride, such that it participates in triglyceride processing and metabolism in the GI tract. Where appropriate, certain lipid prodrug scaffolds may be modified from the literature for use in accordance with the present disclosure. For example, certain drug-lipid conjugates and lipid prodrug scaffolds are disclosed in WO 2017/041 139 and WO 2016/023082, each of which is hereby incorporated by reference in its entirety. Further examples of drug-lipid conjugates where the parent drug contains an available carboxylic acid group and has been directly conjugated to a glyceride backbone are described in Paris, G . Y. et ak, J . Med. Chem. 1979, 22, (6), 683-687; Garzon Aburbeh, A . et ak, J . Med. Chem. 1983, 26, (8), 1200-1203; Deverre, J . R.; et al, J . Pharm. Pharmacol. 1989, 41, (3), 191-193; Mergen, F. et al., J . Pharm. Pharmacol. 1991, 43, ( 11), 815-816; Garzon Aburbeh, A . et al., J . Med. Chem. 1986, 29, (5), 687-69; and Han, S . et al., J . Control. Release 2014, 177, 1-10.
[00031] Further examples have used a short linker where the drug does not contain an available carboxylic acid (Scriba, G . K . E., Arch. Pharm. (Weinheim) 1995, 328, (3), 271- 276; and Scriba, G . K . E . et al., J . Pharm. Pharmacol. 1995, 47, ( 11), 945-948). Other examples have utilized an ester linkage to the drug and an ether linkage to the glyceride (Sugihara, J . et al., J . Pharmacobiodyn. 1988, 11, (5), 369-376; and Sugihara, J . et al., J . Pharmacobiodyn. 1988, 11, (8), 555-562).
[00032] Typical use of prodrug strategies to improve a therapeutic agent’s (active pharmaceutical agent’s) pharmacokinetic properties relies on cleavage in vivo to the parent agent via non-specific degradation or enzymatic cleavage, thus allowing the agent to exert its biological activity. The present invention, in one aspect, provides modified glyceride-based compounds (lipid prodrugs) that direct lymphatic transport of a therapeutic agent and improve cleavage of the lipid prodrug to the therapeutic agent.
[00033] Dietary lipids, including triglycerides, follow a particular metabolic pathway to gain access to the lymph (and ultimately the systemic circulation) that is entirely distinct from that of other nutrients such as proteins and carbohydrates. After ingestion, dietary triglycerides are hydrolyzed by lipases in the lumen to release one monoglyceride and two fatty acids for each molecule of triglyceride. The monoglyceride and two fatty acids are subsequently absorbed into enterocytes and re-esterified to triglycerides.
[00034] Resynthesized triglycerides are assembled into intestinal lipoproteins, primarily chylomicrons. After formation, chylomicrons are exocytosed from enterocytes and subsequently gain preferential access to the intestinal lymphatics. Once within the lymphatic system, chylomicrons containing packaged triglycerides drain through a series of capillaries, nodes and ducts to join the systemic circulation at the junction of the left subclavian vein and internal jugular vein. Following entry into blood circulation, triglycerides in chylomicrons are preferentially and efficiently taken up by tissues with high expression levels of lipoprotein lipases, such as adipose tissue, the liver, and potentially certain types of tumor tissues.
[00035] Lipid prodrugs are expected to behave similarly to natural triglycerides and to be transported to and through the lymphatic system to reach the systemic circulation without interacting with the liver. In some embodiments, the lipid prodrugs are cleaved, releasing the therapeutic agent, after the prodrugs have reached the systemic circulation, or after reaching a target tissue. In some embodiments, the lipid prodrugs release the therapeutic agent by destruction of a self-immolative linker that attaches the therapeutic agent to the glycerol- derived group, or by enzymatic cleavage of a linker. In this way, the pharmacokinetic and pharmacodynamic profiles of the parent therapeutic agent may be manipulated to enhance access to the lymph and lymphoid tissues, thereby promoting oral bioavailability via avoidance of first pass metabolism (and potentially intestinal efflux). Accordingly, in some embodiments, the disclosed lipid prodrug has improved oral bioavailability, reduced first pass metabolism, reduced liver toxicity, or improved other pharmacokinetic properties as compared with the parent therapeutic agent. In some embodiments, the disclosed lipid prodrug has increased drug targeting (as compared with the parent therapeutic agent) to sites within the lymph, lymph nodes and lymphoid tissues, and to sites of high lipid utilization and lipoprotein lipase expression such as adipose tissue, liver and some tumors. In some embodiments, a disclosed lipid prodrug is delivered to the central nervous system (CNS) or crosses the blood- brain barrier (BBB) via the lymphatic system.
[00036] In certain aspects, the present invention provides methods of modulating the delivery, distribution, or other properties of a therapeutic agent. In one aspect, the present invention provides a method of delivering a therapeutic agent to the systemic circulation of a patient in need thereof, wherein the therapeutic agent partially, substantially, or completely bypasses first pass liver metabolism in the patient, comprising the step of administering to the patient a disclosed lipid prodrug of the therapeutic agent. In another aspect, the present invention provides a method of modifying a therapeutic agent to partially, substantially, or completely bypass first pass liver metabolism in a patient after administration of the therapeutic agent, comprising the step of preparing a disclosed lipid prodrug of the therapeutic agent. In some embodiments, the lipid prodrug is administered orally. In some embodiments, preparing the lipid prodrug comprises the step of conjugating a therapeutic agent to a glycerol- based scaffold comprising two fatty acids or other lipids, thereby providing the lipid prodrug. [00037] In another aspect, the present invention provides a method of improving oral bioavailability of a therapeutic agent, enhancing gut absorption of a therapeutic agent, or decreasing metabolism, decomposition, or efflux in the gut of a therapeutic agent, comprising the step of preparing a disclosed lipid prodrug of the therapeutic agent.
[00038] In another aspect, the present invention provides a method of modifying, e.g., improving, delivery of a therapeutic agent to a target tissue, comprising the step of preparing a disclosed lipid prodrug of the therapeutic agent. In some embodiments, the target tissue is the lymph, a lymph node (such as a mesenteric lymph node), adipose tissue, liver, or a tumor, such as a lymph node site of metastasis. In some embodiments, the target tissue is the brain or CNS. [00039] Lipid prodrugs that readily convert to parent therapeutic agent after transport via the systemic circulation have reduced free drug concentrations in the gastrointestinal (GI) tract, which may provide benefits in reducing gastrointestinal irritation or toxicity, and/or in increased drug solubility in intestinal bile salt micelles (due to similarities to endogenous monoglycerides). Disclosed lipid prodrugs may also in certain embodiments have increased passive membrane permeability (due to greater lipophilicity compared with the parent therapeutic agent). In some embodiments, the lipid prodrug has greater solubility in lipid formulations or vehicles comprising either lipids alone or mixtures of lipids with surfactants and/or cosolvents, allowing for the use of lipophilic formulations for otherwise highly hydrophilic therapeutic agents. Lipid Prodrugs of DMT, 5-MeO-DMT and Other tryptamine and phenethylamine psychedelics [00040] In one aspect, provided herein, in certain embodiments, are compounds of Formula I :
Figure imgf000017_0001
Formula I or a pharmaceutically acceptable salt thereof, wherein: R1 and R2 are each independently hydrogen, an acid-labile group, a lipid, or -C(O)R3; each R3 is independently a saturated or unsaturated, straight or branched, optionally substituted C1-37 hydrocarbon chain; X is -O-, -NR-, -S-, -O(C1-6 aliphatic)-O-, -O(C1-6 aliphatic)-S-, -O(C1-6 aliphatic)-NR-, -S(C1-6 aliphatic)-O-, -S(C1-6 aliphatic)-S-, -S(C1-6 aliphatic)-NR-, -NR(C1-6 aliphatic)-O-, -NR(C1- 6 aliphatic)-S-, or -NR(C1-6 aliphatic)-NR-, wherein 0 to 2 methylene units of the C1-6 aliphatic group are independently and optionally replaced with -O-, -NR-, or -S- and the C1-6 aliphatic group is independently and optionally substituted with 1, 2, or 3 deuterium or halogen atoms; each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Y is absent or is -C(O)-, -C(NR)-, or -C(S)-; L is a covalent bond or a saturated or unsaturated, straight or branched, optionally substituted bivalent C1-30 hydrocarbon chain, wherein 0-8 methylene units of L are independently replaced by -Cy-, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -SO2-, -C(S)-, - NRSO2-, -SO2NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O-, or an amino acid; and wherein 1 methylene unit of L is optionally replaced with -M-; or wherein either the right-hand side or left-hand side of L is attached to A; each -Cy- is independently an optionally substituted 3-6 membered bivalent saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each R4 and R5 is independently hydrogen, deuterium, halogen, -CN, -OR, -NR2, -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a C1-6 aliphatic group optionally substituted with -CN, -OR, -NR2, -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or the C1-6 aliphatic is optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; or two instances of R4 or R5 attached to the same carbon atom, taken together with the carbon atom to which they are attached, form a 3-6 membered spirocyclic saturated monocyclic carbocyclic ring or 3-6 membered spirocyclic saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; -M- is a self-immolative group; n is 0-18; each m is independently 0-6; and
A is a therapeutic agent selected from a naturally-occurring or non naturally-occurring tryptamine or phenethylamine psychedelic such as DMT or 5-MeO-DMT or an analogue or prodrug thereof.
[00041] As defined above and described herein, R1 and R2 are each independently hydrogen, an acid-labile group, a lipid such as a fatty acid, or -C(0)R3.
[00042] In some embodiments, R1 is hydrogen. In some embodiments, R1 is an acid-labile group. In some embodiments, R1 is a lipid. In some embodiments, R1 is a fatty acid. In some embodiments, R1 is -C(0)R3. In some embodiments, R1 is selected from those depicted in Table 1, below.
[00043] In some embodiments, R2 is hydrogen. In some embodiments, R2 is an acid-labile group. In some embodiments, R2 is a lipid. In some embodiments, R2 is a fatty acid. In some embodiments, R2 is -C(0)R3. In some embodiments, R2 is selected from those depicted in Table 1, below.
[00044] In some embodiments, each of R1 and R2 is independently a fatty acid, phosphatide, phospholipid, or analogue thereof, such as those described in detail 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 a C2-C40 chain. In some embodiments, each fatty acid independently has a C6-C20, C8-C20, C10-C20, C10-C15, C12-C18, C14-C18, C16-C18, or C10-C16 chain. In some embodiments, each fatty acid is independently selected from oleic acid, palmitic acid, EPA, or DHA.
[00045] In some embodiments, R1 and R2 are each independently selected from an acid labile group such as tert-butoxycarbonyl (Boc), an amino acid, PEG group, -C(0)OR, - C(0)NR2, -CH2OR, -C(NR)R, or -P(0)2OR.
[00046] For clarity, it is understood that, when R1 or R2 is defined as a fatty acid, R1 or R2 is the acyl residue of the fatty acid. Thus, for example, when R1 is defined as palmitic acid, R1 is the acyl portion of palmitic acid, i.e. -C(0)Ci5H3i.
[00047] As defined above and described herein, each R3 is independently a saturated or unsaturated, straight or branched, optionally substituted C 1.37 hydrocarbon chain.
[00048] In some embodiments, R3 is a saturated, straight, optionally substituted Ci-37 hydrocarbon chain. In some embodiments, R3 is an unsaturated, straight, optionally substituted Ci-37 hydrocarbon chain. In some embodiments, R3 is a saturated, branched, optionally substituted Ci-37 hydrocarbon chain. In some embodiments, R3 is an unsaturated, branched, optionally substituted C1-37 hydrocarbon chain. In some embodiments, R3 is selected from those depicted in Table 1, below. [00049] In some embodiments, each R3 is independently a saturated or unsaturated, straight or branched, optionally substituted C1-27 hydrocarbon chain. In some embodiments, each R3 is independently a saturated or unsaturated, straight or branched, optionally substituted C1-21 hydrocarbon chain. In some embodiments, each R3 is independently a saturated or unsaturated, straight or branched, optionally substituted C1-20 hydrocarbon chain. In some embodiments, each R3 is independently a saturated or unsaturated, straight or branched, optionally substituted C1-19 hydrocarbon chain. In some embodiments, each R3 is independently a saturated or unsaturated, straight or branched, optionally substituted C1-18 hydrocarbon chain. In some embodiments, each R3 is independently a saturated or unsaturated, straight or branched, optionally substituted C1-17 hydrocarbon chain. In some embodiments, each R3 is independently a saturated or unsaturated, straight or branched, optionally substituted C3-17 hydrocarbon chain. In some embodiments, each R3 is independently a saturated or unsaturated, straight or branched, optionally substituted C5-17 hydrocarbon chain. In some embodiments, each R3 is independently a saturated or unsaturated, straight or branched, optionally substituted C7-17 hydrocarbon chain. In some embodiments, each R3 is independently a saturated or unsaturated, straight or branched, optionally substituted C9-17 hydrocarbon chain. [00050] In some embodiments, each R3 is optionally substituted C7H15, C8H17, C9H19, C10H21, C11H23 , C12H25 , C13H27 , C14H29 , C15H31 , C16H33 , C17H35, or C18H37. In some embodiments, each R3 is optionally substituted C15H31. In some embodiments, each R3 is unsubstituted C15H31. [00051] As defined above and described herein, X is -O-, -NR-, -S-, -O(C1-6 aliphatic)-O-, - (C1-6 aliphatic)-S-, -O(C1-6 aliphatic)-NR-, -S(C1-6 aliphatic)-O-, -S(C1-6 aliphatic)-S-, -S(C1-6 aliphatic)-NR-, -NR(C1-6 aliphatic)-O-, -NR(C1-6 aliphatic)-S-, or - NR(C1-6 aliphatic)-NR-, wherein 0-2 methylene units of the C1-6 aliphatic group are independently and optionally replaced with -O-, -NR-, or -S- and the C1-6 aliphatic group is independently and optionally substituted with 1, 2, or 3 deuterium or halogen atoms. [00052] In some embodiments, X is -O-. In some embodiments, X is -NR-. In some embodiments, X is -S-. In some embodiments, X is -O(C1-6 aliphatic)-O-. In some embodiments, X is -O(C1-6 aliphatic)-S-. In some embodiments, X is -O(C1-6 aliphatic)-NR-. In some embodiments, X is -S(C1-6 aliphatic)-O-. In some embodiments, X is -S(C1-6 aliphatic)-S-. In some embodiments, X is -S(C1-6 aliphatic)-NR-. In some embodiments, X is -NR(C1-6 aliphatic)-O-. In some embodiments, X is -NR(C1-6 aliphatic)- S-. In some embodiments, X is - NR(C1-6 aliphatic)-NR-. In any of the foregoing embodiments, 0-2 methylene units of the bivalent C1-6 aliphatic group are independently and optionally replaced with -O-, -NR-, or -S- and the bivalent C1-6 aliphatic group is independently and optionally substituted with 1, 2, or 3deuterium or halogen atoms. In some embodiments, X is selected from those depicted in Table 1, below. [00053] As defined above and described herein, Y is absent or is -C(O)-, -C(NR)-, or - C(S)-. In some embodiments, Y is absent. In some embodiments, Y is -C(O)-. In some embodiments, Y is -C(NR)-. In some embodiments, Y is -C(S)-. In some embodiments, Y is selected from those depicted in Table 1, below. [00054] As defined above and described herein, L is a covalent bond or a saturated or unsaturated, straight or branched, optionally substituted bivalent C1-30 hydrocarbon chain, wherein 0-8 methylene units of L are independently replaced by -Cy-, -O-, -NR-, -S-, - OC(O)-, - C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -C(S)-, -NRS(O)2-, -S(O) 2NR-, -NRC(O)-, - C(O)NR-, -OC(O)NR-, -NRC(O)O-, or an amino acid; and wherein 1 methylene unit of L is optionally replaced with -M-; or L is
Figure imgf000021_0001
wherein either the right-hand side or left-hand side of L is attached to A . [00055] In some embodiments, L is a covalent bond. In some embodiments, L is a saturated or unsaturated, straight or branched, optionally substituted bivalent C1-30 (e.g., C3- 30, C5-30, C7-30, C325, C5-25, C7-25, C3-20, C5-20, or C7-2o, etc.) hydrocarbon chain, wherein 0-8 (i.e., 0, 1, 2, 3, 4, 5, 6, 7, or 8) methylene units of L are independently replaced by -Cy-, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -C(S)-, -NRS(O)2-, - S(O)2NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O-, or an amino acid; and wherein 1 methylene unit of L is optionally replaced with -M-. [00056] In some embodiments, L is
Figure imgf000021_0002
, wherein either the right-hand side or left-hand side of L is attached to A . [00057] In some embodiments, L is a covalent bond or a saturated or unsaturated, straight or branched, optionally substituted bivalent C1-30 (e.g., C3-30, C5-30, C7 -30, C5-25, C5-25, C3-25, C3-20, C5-20, or C7-20, etc.) hydrocarbon chain, wherein 0-8 (i.e., 0, 1, 2, 3, 4, 5, 6, 7, or 8) methylene units of L are independently replaced by -Cy-, -O-, -NR-, -S-, -OC(O)-, - C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -C(S)-, -NRS(O)2, -S(O)2NR, -NRC(O)-, -C(O)NR-, - OC(O)NR-, NRC(O)O-, or an amino acid selected from
Figure imgf000022_0001
and wherein 1 methylene unit of L is optionally replaced with -M-; or L is
Figure imgf000022_0002
wherein either the right-hand side or left-hand side of L is attached to A . [00058] In some embodiments, L is a saturated or unsaturated, straight or branched, optionally substituted bivalent C1-20 (e.g., C3-20, C5-20, or C7-20, etc.) hydrocarbon chain, wherein 0-8 (i.e., 0, 1, 2, 3, 4, 5, 6, 7, or 8) methylene units of L are independently replaced by -Cy-, -O-, -NR-, -S-, -OC(O)-, -C(O)0-, -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 a naturally -occurring amino
Figure imgf000023_0003
Figure imgf000023_0001
and wherein 1 methylene unit of L is optionally replaced with -M-. In some embodiments, L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C1-16, C1-12 ,C1-10 or C6-12 hydrocarbon chain, wherein 0-6, 0-4, 0-3, or 0-1 methylene units of L are independently replaced by -Cy-, - O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -C(S)-, -NRS(O)2-, -S(O)2NR- , -NRC(O)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O,
Figure imgf000023_0002
and 1 methylene unit of L is optionally replaced with -M-. [00059] In some embodiments, L is a bivalent, saturated, straight C1-20, C1-16, C1- 12 ,C1-10 or C1-6 hydrocarbon chain, wherein 0-6, 0-4, 0-3, or 0-1 methylene units of L are independently replaced by -Cy-, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, - S(O)2-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(0)NR-, -OC(O)NR-, or -NRC(O)O-; and 1 methylene unit of L is optionally replaced with -M-. [00060] In some embodiments, L is a bivalent, saturated, straight C1-20, C1-16, C1-12, C1-10 or C1-6 hydrocarbon chain, wherein 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 1 methylene unit of L is optionally replaced with -M-. [00061] In some embodiments, L is a bivalent, saturated Cl-30, Cl-25, Cl-20, C3-20, C5-20, or C7-20 hydrocarbon chain optionally substituted with 1, 2 , 3, or 4 R4 groups, wherein 0-4 methylene units of L are independently replaced by -0-, -OC(O)-, -C(0)0-, or - C(O)-; and 1 methylene unit of L is optionally replaced with -M-.
[00062] In some embodiments, L is a bivalent, saturated Cl-25 C5-25, C7-25, or Cl-20 hydrocarbon chain optionally substituted with 1, 2 , 3, or 4 groups selected from deuterium, halogen, -CN, a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 4-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a Ci-6 aliphatic group optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; wherein 0-4 methylene units of L are independently replaced by -0-, -0C(0)-, -C(0)0-, or -C(0)-; and 1 methylene unit of L is optionally replaced with -M-.
[00063] In some embodiments, L comprises (-OCH2CH2-)I-8 (i.e., 1-8 polyethylene glycol (PEG) units). In some embodiments, L comprises 1, 2, 3, 4 , 5, 6 , 7, or 8 PEG units.
[00064] In some embodiments, 0-6 units of L are independently replaced by -0-, -S-, - OC(O)-, -C(0)0-, -C(O)-, or -C(S)-; and 1 methylene unit of L is optionally replaced with - M-
Figure imgf000024_0001
[00065] In some embodiments, L comprises
Figure imgf000024_0002
[00066] In some embodiments, L comprises
Figure imgf000025_0001
[00067] In some embodiments, L comprises
Figure imgf000025_0002
[00068] In some embodiments, L comprise
Figure imgf000025_0003
[00069] In some embodiments, L comprises
Figure imgf000025_0004
[00070] In some embodiments, L comprises
Figure imgf000025_0005
[00071] In some embodiments, L comprises
Figure imgf000026_0001
[00072] In some embodiments, L comprises
[00073] In some embodiments, 1 methylene unit of L is replaced with -M-.
[00074] In some embodiments, 1, 2, 3, or 4 available hydrogen atoms of L are replaced with an R4 group, i.e., L is optionally substituted with 1, 2, 3, or 4 R4 groups.
[00075] In some embodiments, a methylene unit of L is replaced with an amino acid. The amino acid may be naturally-occurring or non-naturally occurring. In some embodiments, the amino acid is selected from a non-polar or branched chain amino acid (BCAA). In some embodiments, the amino acid is selected from valine, isoleucine, leucine, methionine, alanine, proline, glycine, phenylalanine, tyrosine, tryptophan, histidine, asparagine, glutamine, serine threonine, lysine, arginine, histidine, aspartic acid, glutamic acid, cysteine, selenocysteine, or tyrosine. In some embodiments, the amino acid is an L- amino acid. In some embodiments, the amino acid is a D-amino acid.
Figure imgf000026_0002
Figure imgf000027_0001
[00077] In some embodiments, L is a bond,
Figure imgf000027_0002
Figure imgf000027_0003
Figure imgf000027_0004
wherein p is an integer of 1 to 8.
[00078] In certain embodiments, p is 1, 2, 3, 4, 5, 6, 7, or 8. In certain embodiments, p is an integer of 1 to 7. In certain embodiments, p is 1. In certain embodiments p is 2. In certain embodiments p is 3. In certain embodiments p is 4. In certain embodiments p is 5. In certain embodiments p is 6. In certain embodiments p is 7.
[00079] In some embodiments, L is a bond,
Figure imgf000027_0005
Figure imgf000027_0006
[00080]
[00081] In some embodiments, L is selected from those depicted in Table 1, below.
[00082] As defined above and described herein, each -Cy- is independently an optionally substituted 3-6 membered bivalent saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[00083] In some embodiments, -Cy- is an optionally substituted 3-6 membered bivalent saturated ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, -Cy- is an optionally substituted 5-membered bivalent 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 bivalent saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, -Cy- is selected from those depicted in Table 1, below.
[00084] As defined above and described herein, each R4 and R5 is independently hydrogen, deuterium, halogen, -CN, -OR, -NR2, -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4- 8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1- 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a Ci-6 aliphatic group optionally substituted with -CN, -OR, -NR2, -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4- 8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1- 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or the Cl -6 aliphatic is optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; or two instances of R4 or R5 attached to the same carbon atom, taken together with the carbon atom to which they are attached, form a 3-6 membered spirocyclic saturated monocyclic carbocyclic ring or 3-6 membered spirocyclic saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[00085] In some embodiments, R4 is hydrogen. In some embodiments, R4 is deuterium.
[00086] In some embodiments, R4 is halogen. In some embodiments, R4 is -CN. In some embodiments, R4 is -OR. In some embodiments, R4 is -NR2 . In some embodiments, R4 is - SR. In some embodiments, R4 is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R4 is phenyl. In some embodiments, R4 is an 8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments, R4 is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R4 is a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R4 is an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R4 is a Cl -6 aliphatic group optionally substituted with -CN, -OR, -NR2, -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R4 is a Cl -6 aliphatic group optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms. In some embodiments, two instances of R4 attached to the same carbon atom, taken together with the carbon atom to which they are attached, form a 3-6 membered spirocyclic saturated monocyclic carbocyclic ring or 3-6 membered spirocyclic saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[00087] In some embodiments, each R4 is independently hydrogen, deuterium, halogen, - CN, or Cl-4 aliphatic optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; or two instances of R4 attached to the same carbon atom, taken together with the carbon atom to which they are attached, form a 3-6 membered spirocyclic saturated monocyclic carbocyclic ring or 3-6 membered spirocyclic saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[00088] In some embodiments, at least one instance of R4 is not hydrogen.
[00089] In some embodiments, R4 is Cl-4 aliphatic optionally substituted with 1, 2, 3, 4,
5, or 6 deuterium or halogen atoms. In some embodiments, R4 is Cl-4 alkyl optionally substituted with 1, 2, or 3 deuterium or halogen atoms. In some embodiments, R4 is methyl optionally substituted with 1, 2, or 3 deuterium or halogen atoms. In some embodiments, R4 is ethyl. In some embodiments, R4 is n-propyl. In some embodiments, R4 is isopropyl. In some embodiments, R4 is n-butyl. In some embodiments, R4 is isobutyl. In some embodiments, R4 is tert-butyl. In some embodiments, R4 is selected from those depicted in Table 1, below.
[00090] In some embodiments, R5 is hydrogen. In some embodiments, R5 is deuterium. In some embodiments, R5 is halogen. In some embodiments, R5 is -CN. In some embodiments,
R5 is -OR. In some embodiments, R5 is -NR2. In some embodiments, R5 is -SR. In some embodiments, R5 is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R5 is phenyl. In some embodiments, R5 is an 8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments, R5 is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R5 is a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R5 is an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R5 is a Cl-6 aliphatic group optionally substituted with -CN, -OR, -NR2, -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R5 is a Cl-6 aliphatic group optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms. In some embodiments, two instances of R5 attached to the same carbon atom, taken together with the carbon atom to which they are attached, form a 3-6 membered spirocyclic saturated monocyclic carbocyclic ring or 3-6 membered spirocyclic saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[00091] In some embodiments, each R5 is independently hydrogen, deuterium, halogen, - CN, or Cl-4 aliphatic optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; or two instances of R5 attached to the same carbon atom, taken together with the carbon atom to which they are attached, form a 3-6 membered spirocyclic saturated monocyclic carbocyclic ring or 3-6 membered spirocyclic saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[00092] In some embodiments, at least one instance of R5 is not hydrogen.
[00093] In some embodiments, each R4 and R5 is independently hydrogen or methyl. In some embodiments, each R4 is hydrogen and/or each R5 is methyl. In some embodiments, each R4 is methyl and/or each R5 is hydrogen.
[00094] In some embodiments, R5 is Cl-4 aliphatic optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms. In some embodiments, R5is methyl optionally substituted with 1, 2, or 3 deuterium or halogen atoms. In some embodiments, R5 is ethyl. In some embodiments, R5 is n-propyl. In some embodiments, R5 is isopropyl. In some embodiments,
R5 is n-butyl. In some embodiments, R5 is isobutyl. In some embodiments, R5 is tert-butyl. In some embodiments, R5 is selected from those depicted in Table 1, below.
[00095] As defined above and described herein, -M- is a self-immolative group. [00096] In some embodiments, -M- is an acetal, an O-benzylalcohol, an i-benzyl alcohol, a styryl group, a coumarin, or a group that self-immolates via a cyclization reaction. In some embodiments, -M- is selected from a disulfide, hydrazone, acetal self-immolative group, carboxyacetal self-immolative group, carboxy(methylacetal) self-immolative group, para- hydroxybenzyl carbonyl self-immolative groups, flipped ester self-immolative group, trimethyl lock, or 2-hydroxyphenyl carbamate (2-HPC) self-immolative group.
[00097] In some embodiments, -M- is selected from one of the following:
Figure imgf000031_0001
wherein each R6 is independently selected from hydrogen, deuterium, C1-5 aliphatic, halogen, or - CN; each R7 is independently selected from hydrogen, deuterium, halogen, -CN, -OR, -NR2, -NO2, -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a Ci-6 aliphatic group optionally substituted with -CN, -OR, -NR2, -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or the Ci-6 aliphatic is optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; each Z1 is independently selected from -0-, -NR-, or -S-; each Z2 is independently selected from -0-, -NR-, -S-, -OC(O)-, -NRC(0)0-, or -0C(0)NR-; each Z3 is independently selected from =N- or =C(R7)-; and each Z4 is independently selected from -0-, -NR-, -S-, -C(R6)2-, or a covalent bond.
[00098] In some embodiments, -M- is selected from one of the following:
Figure imgf000032_0001
wherein each R6 is independently selected from hydrogen, deuterium, Cl -5 aliphatic, halogen, or -CN; each R7 is independently selected from hydrogen, deuterium, halogen, -CN, -OR, -NR2, - N02, -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a C 1-6 aliphatic group optionally substituted with -CN, -OR, -NR2, -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or the Cl-6 aliphatic is optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; each Z1 is independently selected from -0-, -NR-, or -S-; each Z2 is independently selected from -0-, -NR-, -S-, -OC(O)-, -NRC(0)0-, or -0C(0)NR-; each Z3 is independently selected from =N- or =C(R7)-; and each Z4 is independently selected from -0-, -NR-, -S-, -C(R6)2-, or a covalent bond.
[00099] As defined generally above and described herein, each R6 is independently selected from hydrogen, deuterium, Cl -5 aliphatic, halogen, or -CN. In some embodiments,
R6 is hydrogen. In some embodiments, R6 is deuterium. In some embodiments, R6 is Cl -5 aliphatic.
[000100] In some embodiments, R6 is halogen. In some embodiments, R6 is -CN.
[000101] In some embodiments, R6 is hydrogen, Cl -5 alkyl, halogen, or -CN. In some embodiments, R6 is hydrogen or Cl-3 alkyl. In some embodiments, R6 is hydrogen or methyl. [000102] In some embodiments, each instance of R6 in the above formulae is the same. In some embodiments, each R6 is different. In some embodiments, one R6 is hydrogen. In some embodiments, one R6 is Cl -5 aliphatic. In some embodiments, each R6 is hydrogen. In some embodiments, each R6 is Cl -5 aliphatic. In some embodiments, R6 is selected from those depicted in Table 1, below.
[000103] As defined generally above and described herein, each R7 is independently selected from hydrogen, deuterium, halogen, -CN, -OR, -NR2, -NO2, -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a Ci-6 aliphatic group optionally substituted with -CN, -OR, -NR2, -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or the Cl-6 aliphatic group is optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms.
[000104] In some embodiments, R7 is hydrogen. In some embodiments, R7 is deuterium. In some embodiments, R7 is halogen. In some embodiments, R7 is -CN. In some embodiments,
R7 is -OR. In some embodiments, R7 is -NR2 . In some embodiments, R7 is -NO2 . In some embodiments, R7 is -SR. In some embodiments, R7 is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R7 is phenyl. In some embodiments, R7 is an 8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments, R7 is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R7 is a 5-6 membered monocyclic heteroaromatic ring having 1-
4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R7 is or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R7 is or a Cl-6 aliphatic group optionally substituted with -CN, -OR, -NR2, -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4- 8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-
5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R7 is a Cl-6 aliphatic group optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms.
[000105] In some embodiments, R7 is hydrogen, deuterium, halogen, -CN, -OR, -NR2, - NO 2, - SR, a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 4-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a Ci-6 aliphatic group optionally substituted with -CN, - OR, -NR2, -SR, a 3- 6 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, or a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or the Cl-6 aliphatic group is optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms. In some embodiments, R7 is hydrogen, deuterium, halogen, - CN, a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 5- 6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a Cl-4 alkyl group optionally substituted with -CN, a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, or a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or the Cl-4 alkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms. In some embodiments, R7 is hydrogen, halogen, -CN, -OR, or Cl-4 alkyl. [000106] In some embodiments, R is hydrogen or Cl-4 alkyl.
[000107] In some embodiments, R7 is selected from those depicted in Table 1, below.
[000108] As defined generally above and described herein, each Z1 is independently selected from -0-, -NR-, or -S-. In some embodiments, Z1 is -0-. In some embodiments, Z1 is -NR-. In some embodiments, Z1 is -S. In some embodiments, Z1 is -NH- or -NMe-.
[000109] In some embodiments, Z1 is selected from those depicted in Table 1, below.
[000110] As defined generally above and described herein, each Z2 is independently selected from -0-, -NR-, -S-, -OC(O)-, -NRC(0)0-, or -OC(0)NR-.
[000111] In some embodiments, Z2 is -0-. In some embodiments, Z2 is -NR-. In some embodiments, Z2 is -S-. In some embodiments, Z2 is -OC(O)-. In some embodiments, Z2 is - NRC(0)0-. In some embodiments, Z2 is -OC(0)NR-.
[000112] In some embodiments, each Z2 is independently selected from -0-, -NH-, -NMe-, -S-, -OC(O)-, -NHC(0)0-, -NMeC(0)0-, -OC(0)NH-, or -OC(0)NMe-.
[000113] In some embodiments, Z2 is covalently bound to A . In some embodiments, Z2 is -O- or -0C(0)0-.
[000114] In some embodiments, Z2 is selected from those depicted in Table 1, below.
[000115] In some embodiments, Z1 is -O- and Z2 is -O- or -0C(0)0-.
[000116] As defined generally above and described herein, each Z3 is independently selected from =N- or =C(R7)-. In some embodiments, Z3 is =N-. In some embodiments, Z3 is =C(R7)-.
[000117] In some embodiments, Z3 is selected from those depicted in Table 1, below.
[000118] As defined generally above and described herein, each Z4 is independently selected from -O-, -NR-, -S-, -C(R6)2-, or a covalent bond. In some embodiments, Z4 is -O-. In some embodiments, Z4 is -NR-. In some embodiments, Z4 is -S-. In some embodiments, Z4 is - C(R6)2-. In some embodiments, Z4 is a covalent bond.
[000119] In some embodiments, Z4 is selected from those depicted in Table 1, below. [000120] In some embodiments, -M- is selected from one of the following:
Figure imgf000036_0002
[000121] In some embodiments, -M- is
Figure imgf000036_0001
[000122] In some embodiments, -M- is
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000038_0002
Figure imgf000038_0003
Figure imgf000038_0004
Figure imgf000039_0001
[000126] In some embodiments, -M- is
Figure imgf000039_0002
[000127] In some embodiments, -M- is
Figure imgf000039_0003
In some embodiments, -M- is selected from those depicted in Table 1, below.
[000128] As defined above and described herein, n is 0-18.
[000129] 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
[000130] As defined above and described herein, each m is independently 0-6. 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 .
[000131] As defined above and described herein, A is a therapeutic agent selected from a naturally-occurring or non naturally-occurring tryptamine or phenethyl amine psychedelic such as DMT or 5-MeO-DMT or an analogue or prodrug thereof. Exemplary naturally-occurring or non naturally-occurring tryptamine or phenethylamine psychedelics such as DMT or 5- MeO-DMT include those described herein. In some embodiments, A is DMT or an analogue or prodrug thereof. In some embodiments, A is 5-MeO-DMT .
[000132] In some embodiments, A is a naturally-occurring or non naturally-occurring (e.g., synthetic) tryptamine or phenethylamine psychedelic such as DMT or 5-MeOo-DMT or an analogue or prodrug thereof. In some embodiments, A is selected from DMT or 5- MeO-DMT
[000133] In some embodiments, A is selected from psilocybin, psilocin, baeocystin, norbaeocystin, lisurgide, LSD, dimethyltryptamine, carboxamindotryptamine, ibogaine, tabernanthalog, 3,4-methylenedioxy-methamphetamine (MDMA), 1-acetyl LSD, O-acetyl psilocin, mescaline (3,4,5-trimethoxy phenethylamine), proscaline (2-(3,5-dimethoxy-4- propoxyphenyl)ethanamine), metaescaline (2-(3-ethoxy-4,5-dimethoxyphenyl)ethanamine), allylescaline (4-Allyloxy-3,5-dimethyloxy phenylethylamine), methallylescaline (4- Methallyloxy-3,5 dimethoxyphenethylamine), asymbescaline (3,4-Diethoxy-5- methoxyphenethylamine), or a pharmaceutically acceptable salt, solvate, metabolite, derivative, prodrug, or combinations thereof. In some embodiments, the psychedelic comprises LSD or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof. In some embodiments, the LSD derivative is 1P-LSD, 1B-LSD, ETH-LAD, lP-ETH-LAD, AL-LAD, LSZ, LSM-775, l-(4-Bromofuro[2,3-f] [l]benzofuran-8-yl)propan-
2-amine. In some embodiments, the psychedelic comprises mescaline or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof. In some embodiments, the mescaline derivative is mescaline-NBOMe, proscaline (2-(3,5-dimethoxy-4- propoxyphenyl)ethanamine), or metaescaline (2-(3-ethoxy-4,5-dimethoxyphenyl)ethanamine). In some embodiments, the psychedelic comprises a phenethylamine, a tryptamine, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof. In some embodiments, the phenethylamine, the tryptamine, or the pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof comprises 25I-NBOH, N-(2- Methoxybenzyl)-2-(3,4,5-trimethoxyphenyl)ethanamine, N-(2-hydroxybenzyl)-2,5- dimethoxy-4-iodo-phenethylamine, N-(2-hydroxybenzyl)-2,5-dimethoxy-4-chloro- phenethylamine, N-(2-hydroxybenzyl)-2,5-dimethoxy-4-bromo-phenethylamine, 4-Allyloxy- 3,5-dimethyloxyphenylethylamine, N-(2-fluorobenzyl)-2,5-dimethoxy-4-iodo- phenethylamine, 2,5-dimethoxy-4-tert-butylthio-phenethylamine, 2,5-dimethoxy-4-propylthio- phenethylamine, 2,5-dimethoxy-4-propylphenethylamine, 2,5-dimethoxy-4- nitrophenethylamine, 2, 5 -dimethoxy-4-nitroamphetamine, 2, 5 -dimethoxy-4- methylphenethylamine, 2,5-dimethoxy-4-methylamphetamine, 2,5-dimethoxy-4- isopropylthio-phenethylamine, 2,5-dimethoxy-4-iodophenethylamine, 2,5-dimethoxy-4- iodoamphetamine, 2,5-dimethoxy-4-fluorophenethylamine, 2,5-dimethoxy-4-ethylthio- phenethylamine, 2,5-dimethoxy-4-ethylphenethylamine, 2,5-dimethoxy-4- cyclopropylmethylthio-phenethylamine, 2,5-dimethoxy-4-chlorophenethylamine, 2,5- dimethoxy-4-chloroamphetamine, 2,5-dimethoxy-4-bromophenethylamine, 2,5-dimethoxy-4- bromoamphetamine, 2,5-dimethoxy-4-bromo-P-ketophenethylamine, 2,5-dimethoxy-4-(2- fluoroethylthio)-phenethylamine, 2-(4-propyl-2,5-dimethoxyphenyl)-N-[(2- methoxyphenyl)methyl]ethanamine, 2-(4-m ethyl-2, 5-dimethoxyphenyl)-N-[(2- methoxyphenyl)methyl]ethanamine, 2-(4-iodo-2,5-dimethoxyphenyl)-N-[(2- methoxyphenyl)methyl]ethanamine, 2-(4-fluoro-2,5-dimethoxyphenyl)-N-[(2- methoxyphenyl)methyl]ethanamine, 2-(4-ethyl-2,5-dimethoxyphenyl)-N-[(2- methoxyphenyl)methyl]ethanamine, 2-(4-chloro-2,5-dimethoxyphenyl)-N-[(2- methoxyphenyl)methyl]ethanamine, 2-(4-bromo-2,5-dimethoxyphenyl)-N-[(2- methoxyphenyl)methyl]ethanamine, 4-AcO-MET, 4-AcO-MALT and 4-AcO-DALT, Aeruginascin or N,N,N-trimethyl-4-phosphoryloxytryptamine, 4-Hydroxy -N,N,N- trimethyltryptamine, 5-MeO-DMT, Ibogaine,, [3-(2-Dimethylaminoethyl)-lH-indol-4-yl] dihydrogen phosphate, 4-hydroxytryptamine, 4-hydroxy -N,N-dimethyl tryptamine, [3-(2- methylaminoethyl)-lH-indol-4-yl] dihydrogen phosphate, 4-hydroxy -N-methyltryptamine, [3- (aminoethyl)-lH-indol-4-yl] dihydrogen phosphate, [3-(2- trimethylaminoethyl )-lH-indol-4- yl] dihydrogen phosphate, and 4-hydroxy-N,N,N-trimethyltryptamine, 6-Allyl-N,N-diethyl- NL, N,N-Dibu tyl-T, N,N-Diethyl-T, N,N-Diisopropyl-T, 5-Methyoxy-alpha-methyl-T, N,N- Dimethyl-T, 2,alpha-Dimethyl-T, alpha, N-Dimethyl-T, N,N-Dipropyl-T, N-Ethyl-N- isopropyl-T, alpha-Ethyl-T, 6,N,N-Triethyl-NL, 3,4-Dihydro-7-methoxy 1-methyl-C, 7- Methyoxy-l-methyl-C, N,N-Dibutyl-4-hydroxy-T, N,N-Di ethyl -4-hydroxy-T, N,N- Diisopropyl-4-hydroxy-T, N,N-Dimethyl-4-hydroxy-T, N,N-Dimethyl-5- hydroxy-T, N, N-Dipropyl-4-hydroxy-T, N-Ethyl-4- hydroxy-N-methyl-T, 4-Hydroxy-N-isopropyl-N- methyl-T, 4-Hydroxy -N-methyl-N-propyl-T, 4-Hydroxy -N,N-tetram ethylene-T Ibogaine, N,N-Diethyl-L, N-Butyl-N-methyl-T, N,N-Diisopropyl-4,5-methylenedioxy-T, N,N- Diisopropyl- 5,6-methylenedioxy-T, N,N-Dimethyl-4,5-methylenedioxy T, N,N- Dimethyl-5,6-methylenedioxy-T, N-Isopropyl-N methyl-5, 6-methylenedioxy-T, N,N- Diethyl-2-methyl-T, 2,N,N-Trimethyl-T, N-Acetyl-5-methoxy-T, N,N-Diethyl-5- methoxy-T, N,N-Diisopropyl-5-methoxy-T, 5-Methoxy-N, N-dimethyl-T, N-Isopropyl-4- methoxy-N-methyl-T, N-Iso propyl-5-methoxy-N-methyl-T,5,6-Dimethoxy-Nisopropyl- N-methyl-T, 5-Methoxy-N-methyl-T, 5-MethoxyN,N-tetramethylene-T, 6-Methoxy-l- methyl-l,2,3,4-tetrahydro-C, 5-Methoxy-2,N,N-trimethyl-T, N,N Dimethyl-5- methylthio-T, N-Isopropyl-N-methyl-T, alpha Methyl-T, N-Ethyl-T, N-Methyl-T, 6- Propyl-N L, N,N Tetram ethylene-T, Tryptamine, 7-Methoxy-l-methyl-l, 2,3,4- tetrahydro-C, alpha, N-Dimethyl-5-methoxy-T, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, prodrug, or combinations thereof. In some embodiments, the psychedelic is psilocybin or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof. In some embodiments, the psychedelic is 1 -acetyl LSD or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof. In some embodiments, the psychedelic is O-acetyl psilocin, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof.
[000134] In some embodiments, A is MDL-11,939, ketanserin, ritanserin, altanserin, acepromazine, mianserin, mirtazapine, quetiapine, SB204741, SB206553, SB242084, LY272015, SB243213, Blonanserin, SB200646, RS102221, nefazodone, MDL-100,907, pimavanserin, nelotanserin, lorcaserin, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, prodrug, or combinations thereof.
[000135] In some embodiments, the tryptamine or phenethylamine psychedelic is DMT or 5-MeO-DMT.
[000136] One of ordinary skill in the art will appreciate that certain lipid prodrugs shown in Table 1 are in the form of prodrugs. Thus, it will be appreciated that a lipid prodrug moiety of the presentinvention is attached to the therapeutic agent or the active form thereof. For the purpose of clarity, and by way of example, it will be understood that a provided lipid prodrug moiety is attached at any modifiable oxygen, sulfur, or nitrogen atom of a tryptamine or phenethylamine psychedelic such as DMT or 5-MeO-DMT. For example, DMT has the following structure:
Figure imgf000043_0001
may be attached to the lipid prodrug moiety e.g., via its indole nitrogen (NH) group or at another chemically modifiable position. [000137] As used herein, depiction of brackets around a therapeutic agent, A
Figure imgf000043_0002
means that the moiety is covalently attached to A at any availablemodifiable nitrogen, oxygen, or sulfur atom. For purposes of clarity and by way of non-limiting examples, available modifiable nitrogen, oxygen, or sulfur atoms in the following therapeutic agent compound structures are depicted below, wherein each wavy bond defines the point of attachment to formula I or another of the formulae depicted herein attached at any m o d i f i ab 1 e oxygen, sulfur, or nitrogen atom of a tryptamine or phenethylamine psychedelic such as DMT or 5-MeO-DMT. For example,
DMT has the following structure:
Figure imgf000043_0003
and may be attached to the lipid prodrug moiety e.g., via its indole nitrogen (NH) group or at another chemically modifiable position
[000138] As used herein, depiction of brackets around a therapeutic agent,
Figure imgf000043_0004
[000139] means that the
Figure imgf000044_0001
moiety is covalently attached to A at any availablemodifiable nitrogen, oxygen, or sulfur atom. For purposes of clarity and by way of non-limiting examples, available modifiable nitrogen, oxygen, or sulfur atoms in the following therapeutic agent compound structures are depicted below, wherein each wavy bond defines the point of attachment to formula I or another of the formulae depicted herein:
Figure imgf000044_0002
[000140] In some emb odim ents , Ais
Figure imgf000044_0003
[000141] In some emb odi ments, the present invention provides a compound of Formula I-b:
Figure imgf000044_0004
or a pharmaceutically acceptable salt thereof, wherein each of L and A is as defined above and described in embodiments herein, both singly and in combination.
In some embodiments, the present invention provides a compound of Formula I-c:
Figure imgf000045_0001
pharmaceutically acceptable salt thereof, wherein each of L, R 1, R2, and X is as defined above and described in embodiments herein, both singly and in combination.In some embodiments, the present invention provides a compound of
Figure imgf000045_0002
Formula II: or a pharmaceutically acceptable salt thereof, wherein each of R 1, R2,
Figure imgf000045_0003
X, M, and A is as defined above and described in embodiments herein, both singly and in combination. [000142] In some embodiments, the present invention provides a compound of Formula III:
Figure imgf000045_0004
or a pharmaceutically acceptable salt thereof, wherein each of R 1, R2, R4, R5,
Figure imgf000045_0005
M, and A is as defined above and described in embodiments herein, both singly and in combination. [000143] In some embodiments, the present invention provides a compound of Formula IV:
Figure imgf000046_0001
or a pharmaceutically acceptable salt thereof, wherein each of R 1, R2, R4, R5, X, n, and A is as defined above and described in embodiments herein, both singly and in combination. [000144] In some embodiments, the present invention provides a compound of Formula
Figure imgf000046_0002
pharmaceutically acceptable salt thereof, wherein each of R 1, R2, X, and M is as defined above and described in embodiments herein, both singly and in combination. [000145] In some embodiments, the present invention provides a compound of
Figure imgf000046_0003
pharmaceutically acceptable salt thereof, wherein each of R 1,
Figure imgf000046_0004
and M is as defined above and described in embodiments herein, both singly and in combination.In some embodiments, the present invention provides a compound of Formula VII:
Figure imgf000046_0005
pharmaceutically acceptable salt thereof, wherein each of R 1, R2, R4, R5, and M is as defined above and described in embodiments herein, both singly and in combination. [000146] In some embodiments, the present invention provides a compound of Formula VIII-a or Vlll-b:
Figure imgf000047_0001
or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R4, R5,
Figure imgf000047_0002
n, M, and A is as defined above and described in embodiments herein, both singly and in combination [000147] In some embodiments, the present invention provides a compound of Formula VIII-c or Vlll-d:
Figure imgf000048_0001
or a pharmaceutically acceptable salt thereof, wherein each of R1, R^,
Figure imgf000048_0002
R^, M, and A is as defined above and described in embodiments herein, both singly and in combination. [000148] In the above formulae, when a range of numbers, such as 0-4 or 1-18, is disclosed, individual integers within the range are also specifically disclosed. Thus, the above range of 0-4 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. the group is optionally present. Where more than one range is disclosed in a formula, each range is independently and optionally selected from the disclosed range. For example, in Formula VII-c above, each 0-4 and 1-18 range is varied independently of the others.
[000149] In certain embodiments, provided herein are compound having the following formula:
Figure imgf000049_0001
, wherein R is an alkyl, e.g., a Ci-26 alkyl, preferably, a long-chain alkyl such as C15H31 or C17H35.
[000150] In one aspect, the present invention provides a lipid prodrug compound, or pharmaceutically acceptable salt thereof, shown in Table 1 :
Figure imgf000049_0002
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Lipids, Including Fatty Acids, Phospholipids, Lipid-Processing Mimetics, and Mixtures Thereof, for Use in Disclosed Lipid Prodrugs
[000151] Lipid prodrugs according to the present disclosure mimic the lipid-processing that takes place in the human body.
[000152] A variety of lipids are suitable for use in lipid prodrugs of the present disclosure. In some embodiments, the lipid prodrug comprises a fatty acid, phosphatide, phospholipid, or analogue thereof (e.g., phophatidyl choline, lecithin, phosphatidyl ethanolamine, cephalin, or phosphatidyl serine or analogue or portion thereof, such as a partially hydrolyzed portion thereof), or other lipid-processing mimetic (e.g., a group cleaved by lipases, other digestive enzymes, or other mechanisms in the GI tract that enables the lipid prodrug to mimic dietary lipid processing). In some embodiments, the fatty acid is a short-chain, medium-chain, or long- chain fatty acid. In some embodiments, the fatty acid is a saturated fatty acid. In some embodiments, the fatty acid is an unsaturated fatty acid. In some embodiments, the fatty acid is a monounsaturated fatty acid. In some embodiments, the fatty acid is a polyunsaturated fatty acid, such as an o-3 (omega- 3) or 0-6 (omega-6) fatty acid. In some embodiments, the lipid, e.g, fatty acid, has a C2- C60 chain. In some embodiments, the lipid, e.g., fatty acid, has a C2-C28 chain. In some embodiments, the lipid, e.g, fatty acid, has a C2-C40 chain. In some embodiments, the lipid, e.g, fatty acid, has a C2-C 12 or C4-C 12 chain. In some embodiments, the lipid, e.g, fatty acid, has a C4-C40 chain. In some embodiments, the lipid, e.g, fatty acid, has a C4- C40, C2-C38, C2-C36, C2-C34, C2-C32, C2-C30, C4-C30, C2-C28, C4-C28, C2-C26, C4-
Figure imgf000055_0001
C22, C2-C20, C4-C20, C6-C20, C8-C20, C10-C20, C2-C18, C4-C18, C6-C18, C8-C18, C10-C18, C12-C18, C14-C18, C16-C18, C2-C16, C4- C16, C6-C16, C8-C16, C10-C16, C12-C16, C14-C16, C2-C15, C4-C15, C6-C15, C8-C15, C9-C15, C10-C15, C11-C15, C12- C15, C13-C15, C2-C14, C4-C14, C6-C14, C8-C14, C9-C14, C10-C14, C11-C14, C12-C14, C2- C13, C4-C13, C6-C13, C7-C13, C8-C13, C9-C13, C10-C13, C10-C13, C11-C13, C2- C12, C4-C12, C6-C12, C7-C12, C8-C12, C9-C12, C10-C12, C2-C11, C4-C11, Ce-Cn, C7-C11, C8-C11, C9-C11, C2-C10, C4-C10, C2-C9, C4-C9, C2-C8, C4-C8, C2-C7, C4-C7, C2-C6, or C4-C6 chain. In some embodiments, the lipid, e.g., fatty acid, has a C2, C3, C4, C5, C6, C7, C8, C9, CIO, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, C47, C48, C49, C50, C51, C52, C53, C54, C55, C56, C57, C58, C59, or C60 chain. In some embodiments, the lipid prodrug comprises two fatty acids, each of which s independently selected from a fatty acid having a chain with any one of the foregoing ranges or numbers of carbon atoms. In some embodiments, one of the fatty acids is independently a fatty acid with a Cg-C 21 chain and one is independently a fatty acid with a C 12 -C 36 chain. In some embodiments, each fatty acid independently has a chain of 11, 12, 13, 14, 15, 16, or 17 carbon atoms.
[000153] In some embodiments, the lipid prodrug comprises two lipids. In some embodiments, the two lipids, e.g., fatty acids, taken together have 6-80 carbon atoms (an equivalent carbon number (ECN) of 6-80). In some embodiments, the lipids, e.g., fatty acids, have an ECN of 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, 8-48, 10-48, 12-48, 14-48, 16-48, 18-48, 20-48, 22-48, 24-48, 26-48, 28-48, 30-48, 6-44, 8-44, 10-44, 12-44, 14-44, 16-44, 18-44, 20-44, 22-44, 24-44, 26-44, 28-44, 30-44, 6-40, 8-40, 10-40, 12-40, 14-40, 16-40, 18-40, 20-40, 22-40, 24-40, 26-40, 28-40, 30-40, 6-36, 8-36, 10-36, 12-36, 14-36, 16-36, 18-36, 20-36, 22-36, 24-36, 26-36, 28-36, 30-36, 6-32, 8-32, 10- 32, 12-32, 14-32, 16-32, 18-32, 20-32, 22-32, 24-32, 26-32, 28-32, or 30-32.
[000154] Suitable fatty acids include saturated straight-chain fatty acids, saturated branched fatty acids, unsaturated fatty acids, hydroxy fatty acids, and polycarboxylic acids. In some embodiments, such fatty acids have up to 32 carbon atoms.
[000155] Examples of useful saturated straight-chain fatty acids include those having an even number of carbon atoms, such as butyric acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachic acid, behenic acid, lignoceric acid, hexacosanoic acid, octacosanoic acid, triacontanoic acid and n-dotriacontanoic acid, and those having an odd number of carbon atoms, such as propionic acid, n-valeric acid, enanthic acid, pelargonic acid, hendecanoic acid, tridecanoic acid, pentadecanoic acid, heptadecanoic acid, nonadecanoic acid, heneicosanoic acid, tricosanoic acid, pentacosanoic acid, and heptacosanoic acid.
[000156] Examples of suitable saturated branched fatty acids include isobutyric acid, isocaproic acid, isocaprylic acid, isocapric acid, isolauric acid, 11 -m ethyl dodecanoic acid, isomyristic acid, 13 -methyl -tetradecanoic acid, isopalmitic acid, 15-methyl -hexadecanoic acid, isostearic acid, 17-methyloctadecanoic acid, isoarachic acid, 19-methyl-eicosanoic acid, a-ethyl- hexanoic acid, a-hexyldecanoic acid, a-heptylundecanoic acid, 2- decyltetradecanoic acid, 2-undecyltetradecanoic acid, 2-decylpentadecanoic acid, 2- undecylpentadecanoic acid, and Fineoxocol 1800 acid. Suitable saturated odd-carbon branched fatty acids include anteiso fatty acids terminating 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.
[000157] 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, cN-1 1-eicosenoic acid, cetoleic acid, 13-docosenoic acid, 15-tetracosenoic acid, 17-hexacosenoic acid, 6,9,12,15- hexadecatetraenoic acid, linoleic acid, linolenic acid, a-eleostearic acid, b-eleostearic acid, punicic acid, 6,9,12,15-octadecatetraenoic acid, parinaric acid, 5,8, 11,14-eicosatetraenoicacid, 5,8,1 1,14,17-eicosapentaenoic acid, 7,10,13,16,19-docosapentaenoic acid, 4,7, 10, 13, 16, 19- docosahexaenoic acid, and the like.
[000158] Examples of suitable hydroxy fatty acids include a-hydroxylauric acid, a- hydroxymyristic acid, a-hydroxypalmitic acid, a-hydroxystearic acid, co-hydroxylauric acid, a- hydroxyarachic acid, 9-hydroxy- 12-octadecenoic acid, ricinoleic acid, a -hydroxybehenic acid, 9- hydroxy -trans-10,12-octadecadienic acid, kamolenic acid, ipurolic acid, 9,10- dihydroxystearic acid, 12-hydroxystearic acid and the like.
[000159] Examples of suitable polycarboxylic acids include oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, D,L-malic acid, and the like.
[000160] 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, ETndecylic acid, Laurie acid, Tridecylic acid, Myristic acid,
Pentadecylic acid, Palmitic acid, Margaric acid, Stearic acid, Nonadecylic acid, arachidic acid, Heneicosylic acid, Behenic acid, Tricosylic acid, Lignoceric acid, Pentacosylic acid, Cerotic acid, Heptacosylic acid, Montanic acid, Nonacosylic acid, Melissic acid, Henatriacontylic acid, Lacceroic acid, Psyllic acid, geddic acid, ceroplastic acid, hexatriacontylic acid, heptatriacontanoic acid, or octatriacontanoic acid.
[000161] In some embodiments, each fatty acid is independently selected from a- 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, paullinic acid, oleic acid, elaidic acid, gondoic acid, erucic acid, nervonic acid, mead acid, adrenic acid, bosseopentaenoic acid, ozubondo acid, sardine acid, herring acid, docosahexaenoic acid, or tetracosanolpentaenoic acid, or another monounsaturated or polyunsaturated fatty acid.
[000162] In some embodiments, one or both of the fatty acids is an essential fatty acid.
In view of the beneficial health effects of certain essential fatty acids, the therapeutic benefits of disclosed lipid prodrugs may be increased by including such fatty acids in the lipid prodrug. In some embodiments, the essential fatty acid is an n-6 or n-3 essential fatty acid selected from the group consisting of linolenic acid, gamma-linolenic acid, dihomo- gamma-linolenic acid, arachidonic acid, adrenic acid, docosapentaenoic n-6 acid, alpha- linolenic acid, stearidonic acid, the 20:4n-3 acid, eicosapentaenoic acid, docosapentaenoic n-3 acid, or docosahexaenoic acid.
[000163] In some embodiments, each fatty acid is independently selected from all-cv.s- 7, 0, 3-hexadecatrienoic acid, a -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 fattyacid is selected from eicosapentaenoic acid, docosahexaenoic acid, or lipoic acid. Otherexamples of fatty acids include al l-c/.v-7, 10, 13-hexadecatri enoic acid, a- linolenic acid (ALA orall-67.s-9, 12, 15-octadecatri enoic acid), stearidonic acid (STD or all- cv.v-6,9, 2, 5-octadecatetraenoic acid), eicosatrienoic acid (ETE or all-c/.s- 1 1, 14, 17- eicosatri enoic acid), eicosatetraenoic acid (ETA or all-cv.s-8, 11, 14, 17-eicosatetraenoic acid), eicosapentaenoic acid(EPA), docosapentaenoic acid (DP A, clupanodonic acid or all - cv.s-7, 0, 3 , 6, 9-docosapentaenoic acid), docosahexaenoic acid (DHA or all-cv.s-4,7, 10, 13, 16, 19-docosahexaenoic acid), tetracosapentaenoic acid (al 1- .s-9, 12, 15, 18,2 1- docosahexaenoic acid), ortetracosahexaenoic acid (nisinic acid or all-c/.v-6,9, 12, 15, 18,2 1- tetracosenoic acid). In someembodiments, the fatty acid is a medium-chain fatty acid such as lipoic acid. [000164] Fatty acid chains differ greatly in the length of their chains and may be categorizedaccording to chain length, e.g., as short to very long.
[000165] Short-chain fatty acids (SCFA) are fatty acids with chains of about five or less carbons (e.g, butyric acid). In some embodiments, each of the fatty acids is independently a SCFA. In some embodiments, one of the fatty acids is independently a SCFA.
[000166] Medium-chain fatty acids (MCFA) include fatty acids with chains of about 6-12 carbons, which can form medium-chain triglycerides. In some embodiments, each of the fatty acids is independently a MCFA. In some embodiments, one of the fatty acids is independently a MCFA.
[000167] Long-chain fatty acids (LCFA) include fatty acids with chains of 13-21 carbons. In some embodiments, each of the fatty acids is independently a LCFA. In some embodiments, one of the fatty acids is independently a LCFA.
[000168] Very long chain fatty acids (VLCFA) include fatty acids with chains of 22 or more carbons, such as 22-60, 22-50, or 22-40 carbons. In some embodiments, each of the fatty acids is independently a VLCFA. In some embodiments, one of the fatty acids is independently a VLCFA.
[000169] In some embodiments, one of the fatty acids is independently a MCFA and one is independently a LCFA.
Lipid prodrug compositions in combination with serotonin receptor modulators [000170] In another aspect, provided herein are compositions comprising a lipid prodrug described herein (e.g., prodrugs of DMT or 5-MeO-DMT of Formula I) and a serotonin receptor modulator. In some embodiments, the lipid prodrugs described herein have activity as a 5-HT2A modulator. In some embodiments, the serotonin receptor modulator is a serotonin receptor antagonist. Further described herein, in some embodiments, provided herein are compositions comprising a lipid prodrug described herein (e.g., prodrugs of DMT or 5- MeO-DMT of Formula I) and a serotonin receptor modulator, wherein the serotonin receptor modulator is a serotonin receptor inverse agonist. Further described herein, in some embodiments, are compositions comprising a lipid prodrug described herein (e.g., prodrugs of DMT or 5-MeO-DMT of Formula I) and a serotonin receptor modulator, wherein the serotonin receptor modulator is a serotonin receptor allosteric modulator. In some embodiments, the serotonin receptor is serotonin receptor 1, serotonin receptor 2, serotonin receptor 4, serotonin receptor 5, serotonin receptor 6, or serotonin receptor 7. In some embodiments, the serotonin receptor is serotonin receptor 1 A, serotonin receptor IB, serotonin receptor ID, serotonin receptor IE, serotonin receptor IF, serotonin receptor 2A, serotonin receptor 2B, serotonin receptor 2C, serotonin receptor 4, serotonin receptor 5A, serotonin receptor 5B, serotonin receptor 6, or serotonin receptor 7. In some embodiments the serotonin receptor is serotonin receptor 2 A.
[000171] In some embodiments, the serotonin receptor modulator is a serotonin receptor antagonist selected from the group consisting of ketanserin, volinanserin (MDL- 100907), eplivanserin (SR-46349), pimavanserin (ACP-103), glemanserin (MDL-11939), ritanserin, flibanserin, nelotanserin, blonanserin, mianserin, mirtazapine, roluperiodone (CYR-101, MIN- 101), quetiapine, olanzapine, altanserin, acepromazine, nefazodone, risperidone, pruvanserin, AC-90179, AC -279, adatanserin, fananserin, HY10275, benanserin, butanserin, manserin, iferanserin, lidanserin, pelanserin, seganserin, tropanserin, lorcaserin, ICI-169369, methiothepin, methysergide, trazodone, cinitapride, cyproheptadine, brexpiprazole, cariprazine, agomelatine, setoperone, 1-(1-Naphthyl)piperazine, LY-367265, pirenperone, metergoline, deramciclane, amperozide, AMD A, cinanserin, LY-86057, GSK-215083, cyamemazine, mesulergine, BF-1, LY-215840, sergolexole, spiramide, LY-53857, amesergide, LY-108742, pipamperone, LY-314228, 5-I-R91150, 5-MeO-NBpBrT, 9- Aminomethyl-9,10-dihydroanthracene, niaprazine, SB-215505, SB-204741 , SB-206553, SB- 242084, LY-272015, SB-243213, SB-200646, and RS-102221, or a pharmaceutically acceptable salt, solvate, metabolite, deuterated analog, derivative, prodrug, or combinations thereof. In some embodiments, the serotonin receptor antagonist co-administered with the lipid prodrug described herein (e.g., prodrugs of DMT or 5-MeO-DMT of Formula I) is an additional serotonin receptor modulator. In some embodiments, the additional serotonin receptor modulator is ketanserin or a pharmaceutically acceptable salt, solvate, metabolite, deuterated analogue, derivative, or prodrug thereof. In some embodiments, the additional serotonin receptor modulator is pimavanserin or a pharmaceutically acceptable salt, solvate, metabolite, deuterated analogue, derivative, or prodrug thereof. In some embodiments, the additional serotonin receptor modulator is eplivanserin or a pharmaceutically acceptable salt, solvate, metabolite, deuterated analogue, derivative, or prodrug thereof. In some embodiments, the additional serotonin receptor modulator is flibanserin or a pharmaceutically acceptable salt, solvate, metabolite, deuterated analogue, derivative, or prodrug thereof. In some embodiments, the additional serotonin receptor modulator is roluperiodone or a pharmaceutically acceptable salt, solvate, metabolite, deuterated analogue, derivative, or prodrug thereof. In some embodiments, the additional serotonin receptor modulator is volinanserin or a pharmaceutically acceptable salt, solvate, metabolite, deuterated analogue, derivative, or prodrug thereof. In some embodiments, the additional serotonin receptor modulator is ritanserin or a pharmaceutically acceptable salt, solvate, metabolite, deuterated analogue, derivative, or prodrug thereof. In some embodiments, the additional serotonin receptor modulator is nelotanserin or a pharmaceutically acceptable salt, solvate, metabolite, deuterated analogue, derivative, or prodrug thereof. In some embodiments, the additional serotonin receptor modulator is pruvanserin or a pharmaceutically acceptable salt, solvate, metabolite, deuterated analogue, derivative, or prodrug thereof.
[000172] In some embodiments, are compositions comprising a lipid prodrug compound described herein (e.g., prodrug of DMT or 5-MeO-DMT of Formula I) having activity as a 5- HT2A modulator co-administered with an additional serotonin receptor modulator in a defined dosage range. In some embodiments, the additional serotonin receptor modulator for use with the compounds disclosed herein is eplivanserin, wherein the eplivanserin is administered in about 1 mg to about 40 mg, or about 5 mg to about 10 mg. In some embodiments, the additional serotonin receptor modulator for use with the compounds disclosed herein is volinanserin, wherein the volinanserin is administered in about 1 mg to about 60 mg, or about 5 mg to about 20 mg. In some embodiments, the additional serotonin receptor modulator for use with compounds disclosed herein is ketanserin, wherein the ketanserin is administered in about 10 mg to about 80 mg, about 30 mg to about 50 mg, or about 40 mg. In some embodiments, the additional serotonin receptor modulator for use with the compounds disclosed herein is ritanserin, wherein the ritanserin is administered in about 1 mg to about 40 mg, or about 2.5 mg to about 10 mg. In some embodiments, the additional serotonin receptor modulator for use with the compounds disclosed herein is pimavanserin, wherein the pimavanserin is administered in about 1 mg to about 60 mg, or about 17 mg to about 34 mg. In some embodiments, the additional serotonin receptor modulator for use with the is nelotanserin, wherein the nelotanserin is administered in about 1 mg to about 80 mg, or about 40 mg to about 80 mg. In some embodiments, the additional serotonin receptor modulator for use with the compounds disclosed herein is pruvanserin, wherein the pruvanserin is administered in about 1 mg to about 40 mg, or about 3 mg to about 10 mg. In some embodiments, the additional serotonin receptor modulator for use with the compounds disclosed herein is flibanserin, wherein the flibanserin is administered in about 10 mg to about 200 mg, or about 80 mg to about 120 mg, or about 100 mg.
Therapeutic Agents and Exemplary Associated Diseases
[000173] In accordance with the present disclosure, a variety of therapeutic agents may be covalently conjugated to the lymphatic system-directing lipids, e.g., triglyceride scaffolds, described herein. In some embodiments, by conjugating a therapeutic agent to a lymphatic system-directing lipid, the present disclosure provides enhanced desirable properties of the therapeutic agent such as improving oral bioavailability, minimizing destruction of the agent in the gut, avoiding liver first-pass effect, improving therapeutic agent delivery to a target tissue, or increasing the solubility and stability of the therapeutic agents, including the solubility and stability of the agents in vivo.
[000174] As described herein, the present disclosure provides a compound of formula I, wherein the therapeutic agent is a tryptamine or phenethyl amine psychedelic such as DMT or 5-MeO-DMT or an analogue or prodrug thereof.
[000175] In some embodiments, a disclosed lipid prodrug comprises a therapeutic agent selected from neuroactive steroids, such as tryptamine or phenethylamine psychedelic such as (N,N-dimethyltryptamine) DMT, or 5-methoxy-N,N-dimethyltryptamine (5-MeO- DMT) , pregnanolone, pregnenolone, 3b- dihydropregesterone, isopregnanolone, epipregnanolone, and 21-hydroxytryptamine or phenethylamine psychedelic such as (N,N- dimethyltryptamine) DMT, or 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), or others disclosed herein. In some embodiments, the neuroactive steroid is selected from tryptamine or phenethylamine psychedelic such as (N,N-dimethyltryptamine) DMT, or 5 -m ethoxy -N,N- dimethyltryptamine (5-MeO-DMT) or 21-hydroxytryptamine or phenethylamine psychedelic such as (N,N-dimethyltryptamine) DMT, or 5-methoxy-N,N-dimethyltryptamine (5-MeO- DMT).
[000176] In other embodiments, the present disclosure provides a method of treating or preventing a disease, disorder, or condition in which an increased level of a tryptamine or phenethylamine psychedelic such as DMT or 5-MeO-DMT , such as tryptamine or phenethylamine psychedelic such as (N,N-dimethyltryptamine) DMT, or 5 -m ethoxy -N,N- dimethyltryptamine (5-MeO-DMT) , is beneficial, or a disease, disorder, or condition caused by a deficiency in a tryptamine or phenethylamine psychedelic such as DMT or 5- MeO-DMT , such as an tryptamine or phenethylamine psychedelic such as (N,N- dimethyltryptamine) DMT, or 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) deficiency, comprising administering to a subject in need thereof an effective amount of a disclosed lipid prodrug.
[000177] In some embodiments, the present disclosure provides a method of treating a 5HT serotonin receptor related disease, disorder, or condition, comprising administering to a subject in need thereof an effective amount of a disclosed lipid prodrug.
[000178] In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition caused by deficient activation of serotonin, comprising administering to a subject in need thereof an effective amount of a disclosed lipid prodrug. In some embodiments, the therapeutic agent is DMT or 5-MeO-DMT.
[000179] In another aspect, provided herein are uses of a lipid prodrug described herein (e.g., a compound of Formula I) or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof as described herein, in the preparation of a medicament for treating or preventing a disease, disorder, or condition in which an increased level of a tryptamine or phenethylamine psychedelic such as DMT or 5-MeO-DMT , such as tryptamine or phenethylamine psychedelic such as (N,N-dimethyltryptamine) DMT, or 5- methoxy-N,N-dimethyltryptamine (5-MeO-DMT) , is beneficial, or a disease, disorder, or condition caused by a deficiency in a tryptamine or phenethylamine psychedelic such as DMT or 5-MeO-DMT , such as an tryptamine or phenethylamine psychedelic such as (N,N- dimethyltryptamine) DMT, or 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) deficiency. [000180] In another aspect, a lipid prodrug described herein is for use in a method of treating or preventing a disease, disorder, or condition in which an increased level of a tryptamine or phenethylamine psychedelic such as DMT or 5-MeO-DMT , such as tryptamine or phenethylamine psychedelic such as (N,N-dimethyltryptamine) DMT, or 5- methoxy-N,N-dimethyltryptamine (5-MeO-DMT) , is beneficial, or a disease, disorder, or condition caused by a deficiency in a tryptamine or phenethylamine psychedelic such as DMT or 5-MeO-DMT , such as an tryptamine or phenethylamine psychedelic such as (N,N- dimethyltryptamine) DMT, or 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) deficiency. Such a compound is, for example, a compound of Formula (I) as disclosed herein, or a pharmaceutical composition comprising the compound disclosed herein, and a pharmaceutically acceptable excipient, as disclosed herein.
[000181] In another aspect, provided herein are pharmaceutical compositions comprising a lipid prodrug described herein (e.g., a compound of Formula I) or a pharmaceutically acceptable salt thereof, for use in treating or preventing a disease, disorder, or condition in which an increased level of a tryptamine or phenethylamine psychedelic such as DMT or 5-MeO-DMT , such as tryptamine or phenethylamine psychedelic such as (N,N- dimethyltryptamine) DMT, or 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), is beneficial, or a disease, disorder, or condition caused by a deficiency in a tryptamine or phenethylamine psychedelic such as DMT or 5-MeO-DMT , such as an tryptamine or phenethylamine psychedelic such as (N,N-dimethyltryptamine) DMT, or 5 -m ethoxy -N,N- dimethyltryptamine (5-MeO-DMT) deficiency.
[000182] In another aspect, provided herein are uses of a lipid prodrug described herein (e.g., a compound of Formula I) or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof as described herein, in the preparation of a medicament for treating a 5HT serotonin receptor related disease, disorder, or condition in a subject in need thereof.
[000183] In another aspect, a lipid prodrug described herein is for use in a method of treating a 5HT serotonin receptor related disease, disorder, or condition in a subject in need thereof. Such a compound is, for example, a compound of Formula (I) as disclosed herein, or a pharmaceutical composition comprising the compound disclosed herein, and a pharmaceutically acceptable excipient, as disclosed herein.
[000184] In another aspect, provided herein are pharmaceutical compositions comprising a lipid prodrug described herein (e.g., a compound of Formula I) or a pharmaceutically acceptable salt thereof, for use in treating a 5HT serotonin receptor related disease, disorder, or condition in a subject in need thereof.
Definitions
[000185] Throughout this disclosure, various embodiments are presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of any embodiments. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range to the tenth of the unit of the lower limit unless the context clearly dictates otherwise. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual values within that range, for example, 1.1, 2, 2.3, 5, and 5.9. This applies regardless of the breadth of the range. The upper and lower limits of these intervening ranges may independently be included in the smaller ranges, and are also encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure, unless the context clearly dictates otherwise.
[000186] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of any embodiment. As used herein, the singular forms “a,” “an”, and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will be further understood that the terms “comprises” and/or “comprising,” when used in this specification, specify the presence of stated features, integers, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof. As used herein, the term “and/or” includes any and all combinations of one or more of the associated listed items.
[000187] Unless specifically stated or obvious from context, as used herein, the term “about” in reference to a number or range of numbers is understood to mean the stated number and numbers +/- 10% thereof, or 10% below the lower listed limit and 10% above the higher listed limit for the values listed for a range.
[000188] As used herein, the terms “individual(s)”, “subject(s)” and “patient(s)” mean any mammal. In some embodiments, the mammal is a human. In some embodiments, the mammal is a non-human. None of the terms require or are limited to situations characterized by the supervision (e.g. constant or intermittent) of a health care worker (e.g. a doctor, a registered nurse, a nurse practitioner, a physician’s assistant, an orderly or a hospice worker). While the terms used herein are believed to be well understood by one of ordinary skill in the art, definitions are set forth herein to facilitate explanation of the presently-disclosed subject matter.
[000189] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g, in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.
[000190] The term “lipid,” as used herein, refers to natural and non-natural hydrophobic and/or lipophilic fats, oils, polymers, hydrocarbons, and other such materials. In some embodiments, suitable lipids, when incorporated into a lipid prodrug, are processed or metabolized similarly to triglyercides in the GI tract or mimic such processing or metabolism. The term “glyceride” refers to an ester of glycerol (1,2,3-propanetriol) with acyl radicals of fatty acids or other lipids and is 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 the glycerol are esterified with fatty acid a “triglyceride” or “triacylglycerol” is produced. A glyceride is called “simple” if all esterified positions contain the same fatty acid; or “mixed” if different fatty acids are involved. The carbons of the glycerol backbone are designated sn-1, sn-2 and sn-3, with sn-2 being in the middle and sn-1 and sn-3 being the ends of the glycerol.
[000191] Naturally occurring oils and fats consist largely of triglycerides wherein the 3 fatty acyl residues may or may not be identical. The term “long chain triglycerides” (or “LCT”) means both a simple and mixed triglyceride containing fatty acids with more than 12 carbon atoms (long chain fatty acids, “LCFA”), whereas the term “medium chain triglycerides” (or “MCT”) means both a simple and mixed triglyceride containing fatty acids with 4 to 12 carbon atoms.
[000192] The term “ECN” or “equivalent carbon number” means the sum of the number of carbon atoms in the acyl chains of a glyceride molecule. For example, tripalmitin (tripalmitic glycerol), which is a simple triglyceride containing 3 acyl radicals of 16 carbon atoms, has an ECN of 3x16=48. Conversely, a triglyceride with an ECN=40 may have “mixed” acyl chain lengths of 8, 16 and 16; 10, 14 and 16; 8, 14 and 18, etc. Naturally occurring oils are frequently “mixed” with respect to specific fatty acids, but tend not to contain LCFAs and MCFAs on the same glycerol backbone. Thus, triacylglycerols with ECNs of 24-30 typically contain predominately medium chain fatty acids, while triacylglycerols with ECNs of greater than 43 typically contain predominantly long chain fatty acids. Triacylglycerols having an ECNs of 32- 42 typically contain one or two MCFA in combination with one or two LCFAs to “fill” the triglyceride. Triacylglycerols with ECNs in the range of greater than 30 to less than 48 typically represent mixed triacylglycerol species that are absent from or are present in significantly lower concentrations in physical mixtures. The fatty acids that occur in foods usually contain an even number of carbon atoms in an unbranched chain, e.g., lauric or dodecanoic acid.
[000193] The term “self-immolative group,” as used herein, refers to a bivalent chemical moiety that comprises a covalent, scissile bond as one of its bivalent bonds and a stable, covalent bond with a therapeutic agent as its other bivalent bond, wherein the bond with the therapeutic agent becomes labile upon cleavage of the scissile bond. Examples of self-immolative groups include, but are not limited to, disulfide groups, hydrazones, acetal self-immolative groups, carboxyacetal self-immolative groups, carboxy(methylacetal) self- immolative groups, para- hydroxybenzyl carbonyl self-immolative groups, flipped ester self- immolative groups, and trimethyl lock, or 2-hydroxyphenyl carbamate (2-HPC) self- immolative groups.
[000194] As used herein, the term “therapeutic agent,” “active pharmaceutical agent,” “active agent,” or “pharmaceutical agent” includes any therapeutic agent or imaging (contrasting) agent which would benefit from transport via the intestinal lymphatic system, for example, to enable oral administration (e.g., of an intravenously administered therapeutic agent), to avoid first pass metabolism, avoid liver toxicity or other toxicity, or for targeted delivery within the lymphatic system. [000195] Lipid prodrug compounds of the present disclosure include those described generally herein, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. [000196] The term “aliphatic” or “aliphatic group,” as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocycle,” “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refers to a monocyclic C3-C6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl. [000197] As used herein, the term “bicyclic ring” or “bicyclic ring system” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or having one or more units of unsaturation, having one or more atoms in common between the two rings of the ring system. Thus, the term includes any permissible ring fusion, such as ortho-fused or spirocyclic. As used herein, the term “heterobicyclic” is a subset of “bicyclic” that requires that one or more heteroatoms are present in one or both rings of the bicycle. Such heteroatoms may be present at ring junctions and are optionally substituted, and may be selected from nitrogen (including N- oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphonates and phosphates), boron, etc. In some embodiments, a bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. As used herein, the term “bridged bicyclic” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bicyclic rings include:
Figure imgf000068_0001
[000198] Exemplary bridged bicyclics include:
Figure imgf000069_0001
[000199] The term “lower alkyl” refers to a Ci-4 straight or branched alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and r - butyl. [000200] The term “lower haloalkyl” refers to a C1-4 straight or branched alkyl group that is substituted with one or more halogen atoms. [000201] The term “heteroatom” means one or more of boron, oxygen, sulfur, nitrogen, phosphorus, or silicon (including any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), H (as in pyrrolidinyl) or R+ (as in N-substituted pyrrolidinyl)). [000202] The term “unsaturated,” as used herein, means that a moiety has one or more units of unsaturation. [000203] As used herein, the term “bivalent C1 (or C1-6) saturated or unsaturated, straight or branched, hydrocarbon chain” refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein. [000204] The term “alkylene” refers to a bivalent alkyl group. An “alkylene chain” is a polymethylene group, i.e., -(CH2)n- , wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group. [000205] The term “alkenylene” refers to a bivalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group. [000206] The term “halogen” means F, Cl, Br, or I. [000207] The term “aryl” used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein 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 disclosure, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term “aryl,” as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like. [000208] The terms “heteroaryl” and “heteroar-,” used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 π electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quatemized form of a basic nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, AH quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-£]-l,4-oxazin- 3(4H)-one. A heteroaryl group may be mono- or bicyclic. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any ofwhich terms include rings that are optionally substituted. The term “heteroaralkyl” refers to analkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independentlyare optionally substituted.
[000209] As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7-lO-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4- dihydro-27T pyrrolyl, NH (as in pyrrolidinyl), or +NR (as in N substituted pyrrolidinyl).
[000210] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3/ / indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. A heterocyclyl group may be mono- or bicyclic. The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.
[000211] As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.
[000212] As described herein, compounds of the disclosure may contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this disclosure are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein. [000213] Each optional substituent on a substitutable carbon is a monovalent substituent independently selected from halogen; -(CH2)o-R; -(CH2)o-OR°; -O(CH2)o-4R, -O-(CH2)o- C(O)OR; -(CH2)O-CH(OR)2 ; -(CH2)O-SR°; -(CH2)o-Ph, which may be substituted with R; - (CH2)o-O(CH 2)o-Ph which may be substituted with R; -CH=CHPh, which may be substituted with R; -(CH2)o-40(CH 2)o-i-pyridyl which may be substituted with R; -NO2; -CN; -N3; - (CH2)ON(R)2 ; -(CH2)O-N(R)C(O)R; -N(R)C(S)R; -(CH2)O-N(R)C(O)NR2; -N(R)C(S)NR2 ; -(CH2)O-N(R)C(O)OR; -N(R)N(R)C(O)R; -N(R)N(R)C(O)NR2; -N(R)N(R)C(O)OR; - (CH2)o-C(O)R; -C(S)R; -(CH2)o-C(O)OR; -(CH2)o-4C(O)SR; -(CH2)o-C(O)OSiR; -(CH2)O- C(O)R; -OC(O)CH2SR-SC(S)SR°; -(CH2)O-SC(O)R°; -(CH2)O-C(O)NR2; -C(S)NR2; - C(S)SR; -SC(S)SR, -(CH2)O-C(O)NR2; -C(O)N(OR)R; -C(O)C(O)R; -C(O)CH2C(O)R; - C(NOR)R; -CH2-SSR; -(CH2)O-S(O)2R; -(CH2)O S(O)2OR; -(CH2)o-OS(O)2R; -S(O)2NR2 ; - S(O)(NR)R; -S(O)2N=C(NR2)2 ; -(CH2)O-S(O)R; -N(R)S(O)2NR2; -N(R)S(O)2R; -N(OR)R; - C(NH)NR2; -P(O)2R; -P(O)R2; -OP(O)R2; -OP(O)(OR)2; -SiR3° ; -(C1-4 straight or branched alkylene)O-NR2; or -(C1-4 straight or branched alkylene)C(O)O-NR2. [000214] Each R° is independently hydrogen, C1-6 aliphatic, -CH2Ph, -O(CH2)o-Ph, -CH2- (5- 6 membered heteroaryl ring), or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted by a divalent substituent on a saturated carbon atom of R° selected from =0 and =S; or each R° is optionally substituted with a monovalent substituent independently selected from halogen, -(CH2)o-R*, -(haloR*), -(CH2)o-OH, -(CH2)o-OR*, - (CH2)O-CH(OR*)2 ; -O(haloR*), -CN, - N3, -(CH2)o-C(O)R*, -(CH2)o-C(O)OH, -(CH2)o- C(O)OR·, -(CH2)o-SR·, -(CH2)o-SH, -(CH2)o-NH2, -(CH2)o-NHR·, -(CH2)o-NR*2 , -NO2, - SiR*3, -OSiR*3, -C(O)SR*-(C1- 4 straight or branched alkylene)C(0)OR*, or -SSR*. [000215] Each R * is independently selected from Ci-4 aliphatic, -CH 2Ph, -0(CH 2)o-iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R is unsubstituted or where preceded by halo is substituted only with one or more halogens; or wherein an optional substituent on a saturated carbon is a divalent substituent independently selected from =O, =S, =NNR*, =NNHC(O)R =NNHC(O)OR *, =NNHS(O)2R*, =NR*, =NOR*, - O(C(R*))2-, or -S(C(R*))2-S-, or a divalent substituent bound to vicinal substitutable carbons of an “optionally substituted” group is -O(CR*)O-, wherein each independent occurrence of R* is selected from hydrogen, C1-6 aliphatic or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [000216] When R* is C1-6 aliphatic, R* is optionally substituted with halogen, -R*, - (haloR*), -OH, -OR*, -O(haloR*), -CN, -C(O)OH, -C(O)OR*, -NH2, -NHR*, -NR*2, or - NO2, wherein each R* is independently selected from C1-4 aliphatic, -CH2Ph, -O(CH2)o-Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R* is unsubstituted or where preceded by halo is substituted only with one or more halogens. [000217] An optional substituent on a substitutable nitrogen is independently -R, -NR, - C(O)R, -C(O)OR*, -C(O)C(O)R*, -C(O)CH2C(O)R*, -S(O)2R*, -S(O)2NR*, -C(S)NR*, -2 C(NH)NR* or -N(R*)S(O)2R*; wherein each R' is independently hydrogen, C1-6 aliphatic, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, two independent occurrences of R÷, taken together with their intervening atom(s) form an unsubstituted 3-l2-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein when R' is C1-6 aliphatic, R' is optionally substituted with halogen, -R*, -(haloR*), -OH, -OR*, - O(haloR*), -CN, -C(O)OH, -C(O)OR*, - NH2, -NHR*, -NR*2, or -NO2 wherein each R * is independently selected from C1-4 aliphatic, -CH2Ph, -O(CH2)o-Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R* is unsubstituted or where preceded by halo is substituted only with one or more halogens. [000218] As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts include salts of an amino group (or other basic group) 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 adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, besylate, bisulfate, borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy- ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.
[000219] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(Ci-4alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate. [000220] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the disclosure. Unless otherwise stated, all tautomeric forms of the compounds of the disclosure are within the scope of the disclosure. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13C- or 14C-enriched carbon are within the scope of this disclosure. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present disclosure.
Uses, Formulation and Administration
Uses of Lymphatic-Directing Lipid Prodrugs
[000221] Disclosed lymphatic-directing lipid prodrugs, as well as pharmaceutically acceptable compositions comprising a disclosed lipid prodrug, and a pharmaceutically acceptable excipient, diluent, or carrier, are useful for treating a variety of diseases, disorders or conditions. Such diseases, disorders, or conditions include those described herein. [000222] One of ordinary skill in the art will recognize and appreciate that each of the therapeutic agents described herein are known to be associated with treatment of one or more diseases, disorders, or conditions. Accordingly, it will be appreciated that, in certain embodiments, the present disclosure provides a method of treating a disease, disorder, or condition in a patient in need thereof comprising administering to said patient a disclosed lipid prodrug.
[000223] The presently disclosed lipid prodrugs are useful for the stable transport of pharmaceutical agents to the intestinal lymph and release of the pharmaceutical agents in the lymph, lymphocytes, lymphoid tissues, tissues with high lipase activity such as adipose tissue, certain cancers, the liver, or in the systemic circulation. Disclosed lipid prodrugs are particularity useful for the transport and release of pharmaceutical agents that benefit from avoidance of first pass metabolism, for example, therapeutic agents that exhibit greater than about 50% first pass metabolism when administered orally. In some embodiments, the therapeutic agent exhibits greater than about 60% first pass metabolism when administered orally. In some embodiments, the therapeutic agent exhibits greater than about 70%, 80%, or 90% first pass metabolism when administered orally.
[000224] Therapeutic agents that may benefit from the stable transport to the intestinal lymph and release in the lymph, lymphocytes, lymphoid tissues, tissues with high lipase activity such as adipose tissue, certain cancers, the liver or in the systemic circulation include, but are not limited to, therapeutic agents listed herein such DMT, 5-MeO-DMT, or derivatives and prodrugs of such.
[000225] The presently disclosed lipid prodrugs are also useful for the targeted release of the therapeutic agent within the lymphatic system, for example, in the 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 agent exhibits poor lymphatic transport when administered orally. In some embodiments, the therapeutic exhibits less than 70%, 60%, 50%, 40%, 30%, 20%, 15%, 10%, 8%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.25%, 0.2%, 0.15%, or 0.1% when administered orally. In contrast, the present disclosure provides for improved lymphatic transport of such therapeutic agents. In some embodiments, a disclosed lipid prodrug exhibits 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, a disclosed lipid prodrug exhibits about 1-50%, 5-40%, 10-30%, 15-25%, or about 50%, 40%, 30%, 25%, 20%, 15%, 12.5%, 10%, 7.5%, 5%, 2.5%, or 1% lymphatic transport when administered orally, as measured by either w/w% of the lipid prodrug administered or w/w% of the therapeutic agent in its lipid prodrug form vs. the unmodified therapeutic agent.
[000226] In some embodiments, a disclosed lipid prodrug is delivered to the central nervous system (CNS) or crosses the blood-brain barrier (BBB) via the lymphatic system. [000227] In some embodiments, the present disclosure provides a method of treating or preventing a disease, disorder, or condition, comprising administering to a subject in need thereof an effective amount of a disclosed lipid prodrug that comprises a tryptamine or phenethylamine psychedelic such as DMT or 5-MeO-DMT therapeutic.
Methods of Use
[000228] In some embodiments, the presently disclosed lipid prodrugs, such as a compound of Formula I, can be used for increasing neuronal plasticity. In some embodiments, the compounds described herein can also be used to treat any brain disease. In some embodiments, the compounds described herein can also be used to treat any neurological condition. In some embodiments, the compounds described herein can also be used for increasing at least one of translation, transcription or secretion of neurotrophic factors. [000229] As used herein, "treatment" or "treating " or "palliating" or "ameliorating" are used interchangeably herein. These terms refer to an approach for obtaining beneficial or desired results including, but not limited to, therapeutic benefit and/or a prophylactic benefit. By "therapeutic benefit" is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is afflicted with the underlying disorder in some embodiments. For prophylactic benefit, in some embodiments, the compositions are administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made. [000230] Provided herein are methods of treating neurological diseases in a subject need thereof comprising administering a lipid prodrug described herein (e.g., a compound of Formula I) to the subject. In some embodiments, the compounds have, for example, anti- addictive properties, antidepressant properties, anxiolytic properties, or a combination thereof. In some embodiments, the neurological disease is a neuropsychiatric disease. In some embodiments, the neuropsychiatric disease is a mood or anxiety disorder. In some embodiments, the neurological disease is a migraine, headaches (e.g., cluster headache), post- traumatic stress disorder (PTSD), anxiety, depression, neurodegenerative disorder,
Alzheimer’s disease, Parkinson’s disease, psychological disorder, treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, frontotemporal dementia, Parkinson’s dementia, dementia, lewy body dementia, multiple system atrophy, and addiction (e.g., substance use disorder). In some embodiments, the neurological disease is a migraine or cluster headache. In some embodiments, the neurological disease is a neurodegenerative disorder, Alzheimer’s disease, or Parkinson’s disease. In some embodiments, the neurological disease is a psychological disorder, treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, post-traumatic stress disorder (PTSD), addiction (e.g., substance use disorder), depression, or anxiety. In some embodiments, the neuropsychiatric disease is a psychological disorder, treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, post-traumatic stress disorder (PTSD), addiction (e.g., substance use disorder), depression, or anxiety. In some embodiments, the neuropsychiatric disease or neurological disease is post-traumatic stress disorder (PTSD), addiction (e.g., substance use disorder), schizophrenia, depression, or anxiety. In some embodiments, the neuropsychiatric disease or neurological disease is addiction (e.g., substance use disorder). In some embodiments, the neuropsychiatric disease or neurological disease is depression. In some embodiments, the neuropsychiatric disease or neurological disease is anxiety. In some embodiments, the neuropsychiatric disease or neurological disease is post- traumatic stress disorder (PTSD). In some embodiments, the neurological disease is stroke or traumatic brain injury. In some embodiments, the neuropsychiatric disease or neurological disease is schizophrenia.
[000231] In another aspect, provided herein are methods of treating a disease or disorder, comprising administering to a subject in need thereof a lipid prodrug described herein (e.g., a compound of Formula I. In some embodiments, a therapeutically effective amount of the compound of Formula I is administered. In some embodiments, the disease or disorder is a musculoskeletal pain disorder including fibromyalgia, muscle pain, joint stiffness, osteoarthritis, rheumatoid arthritis, muscle cramps. In some embodiments, provided herein are method of treating a disease of women’s reproductive health, for example, premenstrual dysphoric disorder (PMDD), premenstrual syndrome (PMS), post-partum depression, and menopause.
[000232] In some embodiments, a lipid prodrug described herein (e.g., a compound of Formula I) have activity as 5-HT2A modulators. In some embodiments, the compounds described herein (e.g., a compound of Formula I) elicit a biological response by activating the 5-HT2A receptor (e.g., allosteric modulation or modulation of a biological target that activates the 5-HT2A receptor). 5-HT2A agonism has been correlated with the promotion of neural plasticity (Ly et al., 2018). 5-HT2A antagonists abrogate the neuritogenesis and spinogenesis effects of hallucinogenic compounds with 5-HT2A agonist activity, for example., DMT, LSD, and DOF In some embodiments, the compounds described herein (e.g., a compound of Formula I) are 5-HT2A modulators and promote neural plasticity (e.g., cortical structural plasticity). In some embodiments, the compounds described herein (e.g., a compound of Formula I) are selective 5-HT2A modulators and promote neural plasticity (e.g., cortical structural plasticity). In some embodiments, promotion of neural plasticity includes, for example, increased dendritic spine growth, increased synthesis of synaptic proteins, strengthened synaptic responses, increased dendritic arbor complexity, increased dendritic branch content, increased spinogenesis, increased neuritogenesis, or any combination thereof. In some embodiments, increased neural plasticity includes, for example, increased cortical structural plasticity in the anterior parts of the brain.
[000233] In some embodiments, the 5-HT2A modulators (e.g., 5-HT2A agonists) are non- hallucinogenic. In some embodiments, non-hallucinogenic 5-HT2A modulators (e.g., 5-HT2A agonists) are used to treat neurological diseases, which modulators do not elicit dissociative side-effects. In some embodiments, the hallucinogenic potential of the compounds described herein is assessed in vitro. In some embodiments, the hallucinogenic potential assessed in vitro of the compounds described herein is compared to the hallucinogenic potential assessed in vitro of hallucinogenic homologs. In some embodiments, the compounds described herein elicit less hallucinogenic potential in vitro than the hallucinogenic homologs.
[000234] In another aspect, provided herein are uses of a lipid prodrug described herein (e.g., a compound of Formula I) or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof as described herein, in the preparation of a medicament for treating neurological diseases in a subject in need thereof.
[000235] In another aspect, a lipid prodrug described herein is for use in a method of treating neurological diseases in a subject in need thereof. Such a compound is, for example, a compound of Formula (I) as disclosed herein, or a pharmaceutical composition comprising the compound disclosed herein, and a pharmaceutically acceptable excipient, as disclosed herein. [000236] In another aspect, provided herein are pharmaceutical compositions comprising a lipid prodrug described herein (e.g., a compound of Formula I) or a pharmaceutically acceptable salt thereof, for use in treating neurological diseases in a subject in need thereof.
Co-Administration of Lipid prodrug Compound and an additional serotonin receptor modulator
[000237] In some embodiments described herein are methods of using a compositions comprising a lipid prodrug described herein (e.g., prodrugs of DMT or 5-MeO-DMT of Formula I) having activity as a 5-HT2A modulator. In some embodiments, methods of use (e.g., methods of treating a disease, disorder, or condition caused by deficient activation of serotonin 5HT receptors) are described herein of compositions comprising a lipid prodrug described herein (e.g., prodrugs of DMT or 5-MeO-DMT of Formula I) having activity as a 5- HT2A modulator co-administered with an additional serotonin receptor modulator. In some embodiments, the additional serotonin receptor modulator is a serotonin receptor antagonist. Further described herein, in some embodiments, are methods of use of compositions comprising a lipid prodrug described herein (e.g., prodrugs of DMT or 5-MeO-DMT of Formula I) and a serotonin receptor modulator, wherein the serotonin receptor modulator is a serotonin receptor inverse agonist. Further described herein, in some embodiments, are methods of use of compositions comprising a lipid prodrug described herein (e.g., prodrug of DMT or 5-MeO-DMT of Formula I) and a serotonin receptor modulator, wherein the serotonin receptor modulator is a serotonin receptor allosteric modulator. In some embodiments, the serotonin receptor is serotonin receptor 1, serotonin receptor 2, serotonin receptor 4, serotonin receptor 5, serotonin receptor 6, or serotonin receptor 7. In some embodiments, the serotonin receptor is serotonin receptor 1 A, serotonin receptor IB, serotonin receptor ID, serotonin receptor IE, serotonin receptor IF, serotonin receptor 2 A, serotonin receptor 2B, serotonin receptor 2C, serotonin receptor 4, serotonin receptor 5A, serotonin receptor 5B, serotonin receptor 6, or serotonin receptor 7. In some embodiments the serotonin receptor is serotonin receptor 2 A.
[000238] In some embodiments, the additional serotonin receptor modulator described herein is selected from the group consisting of ketanserin, volinanserin (MDL- 100907), eplivanserin (SR-46349), pimavanserin (ACP-103), glemanserin (MDL-11939), ritanserin, flibanserin, nelotanserin, blonanserin, mianserin, mirtazapine, roluperiodone (CYR-101, MIN- 101), quetiapine, olanzapine, altanserin, acepromazine, nefazodone, risperidone, pruvanserin, AC-90179, AC -279, adatanserin, fananserin, HY10275, benanserin, butanserin, manserin, iferanserin, lidanserin, pelanserin, seganserin, tropanserin, lorcaserin, ICI-169369, methiothepin, methysergide, trazodone, cinitapride, cyproheptadine, brexpiprazole, cariprazine, agomelatine, setoperone, 1-(1-Naphthyl)piperazine, LY-367265, pirenperone, metergoline, deramciclane, amperozide, AMD A, cinanserin, LY-86057, GSK-215083, cyamemazine, mesulergine, BF-1, LY-215840, sergolexole, spiramide, LY-53857, amesergide, LY-108742, pipamperone, LY-314228, 5-I-R91150, 5-MeO-NBpBrT, 9- Aminomethyl-9,10-dihydroanthracene, niaprazine, SB-215505, SB-204741 , SB-206553, SB- 242084, LY-272015, SB-243213, SB-200646, and RS-102221, or a pharmaceutically acceptable salt, solvate, metabolite, deuterated analog, derivative, prodrug, or combinations thereof. In some embodiments, the additional serotonin receptor modulator is ketanserin or a pharmaceutically acceptable salt, solvate, metabolite, deuterated analogue, derivative, or prodrug thereof. In some embodiments, the additional serotonin receptor modulator is pimavanserin or a pharmaceutically acceptable salt, solvate, metabolite, deuterated analogue, derivative, or prodrug thereof. In some embodiments, the additional serotonin receptor modulator is eplivanserin or a pharmaceutically acceptable salt, solvate, metabolite, deuterated analogue, derivative, or prodrug thereof. In some embodiments, the additional serotonin receptor modulator is flibanserin or a pharmaceutically acceptable salt, solvate, metabolite, deuterated analogue, derivative, or prodrug thereof. In some embodiments, the additional serotonin receptor modulator is roluperiodone or a pharmaceutically acceptable salt, solvate, metabolite, deuterated analogue, derivative, or prodrug thereof. In some embodiments, the additional serotonin receptor modulator is volinanserin or a pharmaceutically acceptable salt, solvate, metabolite, deuterated analogue, derivative, or prodrug thereof. In some embodiments, the additional serotonin receptor modulator is ritanserin or a pharmaceutically acceptable salt, solvate, metabolite, deuterated analogue, derivative, or prodrug thereof. In some embodiments, the additional serotonin receptor modulator is nelotanserin or a pharmaceutically acceptable salt, solvate, metabolite, deuterated analogue, derivative, or prodrug thereof. In some embodiments, the additional serotonin receptor modulator is pruvanserin or a pharmaceutically acceptable salt, solvate, metabolite, deuterated analogue, derivative, or prodrug thereof.
[000239] In some embodiments, methods of use are described herein of compositions comprising a lipid prodrug described herein (e.g., prodrug of DMT or 5-MeO-DMT of Formula I) having activity as a 5-HT2A modulator co-administered with an additional serotonin receptor modulator in a defined dosage range. In some embodiments, the additional serotonin receptor modulator for use with the compounds disclosed herein is eplivanserin, wherein the eplivanserin is administered in about 1 mg to about 40 mg, or about 5 mg to about 10 mg. In some embodiments, the additional serotonin receptor modulator for use with the compounds disclosed herein is volinanserin, wherein the volinanserin is administered in about 1 mg to about 60 mg, or about 5 mg to about 20 mg. In some embodiments, the additional serotonin receptor modulator for use with compounds disclosed herein is ketanserin, wherein the ketanserin is administered in about 10 mg to about 80 mg, about 30 mg to about 50 mg, or about 40 mg. In some embodiments, the additional serotonin receptor modulator for use with the compounds disclosed herein is ritanserin, wherein the ritanserin is administered in about 1 mg to about 40 mg, or about 2.5 mg to about 10 mg. In some embodiments, the additional serotonin receptor modulator for use with the compounds disclosed herein is pimavanserin, wherein the pimavanserin is administered in about 1 mg to about 60 mg, or about 17 mg to about 34 mg. In some embodiments, the additional serotonin receptor modulator for use with the is nelotanserin, wherein the nelotanserin is administered in about 1 mg to about 80 mg, or about 40 mg to about 80 mg. In some embodiments, the additional serotonin receptor modulator for use with the compounds disclosed herein is pruvanserin, wherein the pruvanserin is administered in about 1 mg to about 40 mg, or about 3 mg to about 10 mg. In some embodiments, the additional serotonin receptor modulator for use with the compounds disclosed herein is flibanserin, wherein the flibanserin is administered in about 10 mg to about 200 mg, or about 80 mg to about 120 mg, or about 100 mg.
[000240] In some embodiments, methods of use are described herein of compositions comprising a lipid prodrug described herein (e.g., prodrugs of DMT or 5-MeO-DMT of Formula I) having activity as a 5-HT2A modulator co-administered with an additional serotonin receptor modulator. In some embodiments, a lipid prodrug described herein (e.g., prodrugs of DMT or 5-MeO-DMT of Formula I) functions in vivo as a psychedelic. In certain embodiments, such as those described above, a disclosed compound is co-administered with an additional serotonin receptor modulator in the same or in separate compositions. In one embodiment, the compound is administered in a modified release formulation such that the subject is effectively pretreated with an additional serotonin receptor modulator prior to release of an effective amount of the psychedelic. Thus, in some embodiments, the additional serotonin receptor modulator is administered or released from a composition provided herein prior to the administration and/or release of the psychedelic. This allows pretreatment to attenuate activation of the serotonin receptor by the psychedelic.
[000241] In some embodiments, methods of use are described herein of compositions comprising a lipid prodrug described herein (e.g., prodrugs of DMT or 5-MeO-DMT of Formula I) having activity as a 5-HT2A modulator co-administered with an additional serotonin receptor modulator. In some embodiments, a lipid prodrug described herein (e.g., prodrugs of DMT or 5-MeO-DMT of Formula I) functions in vivo as a psychedelic. In some embodiments, the additional serotonin receptor modulator is used to pretreat a subject. In some embodiments, the additional serotonin receptor modulator is administered or released from the composition provided herein to pretreat a subject by at least about at about 5 minutes, 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.25 hours, 1.5 hours, 2 hours, or 3 hours prior to the release of the psychedelic compound disclosed herein. In some embodiments, the additional serotonin receptor modulator attenuates the activation of the serotonin receptor when the serotonin receptor modulator is used to pretreat at most about 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, or more than 9 hours prior to the release of the psychedelic. In some embodiments, the additional serotonin receptor modulator attenuates the activation of the serotonin receptor when the additional serotonin receptor modulator is used to pretreat in a range of about 5 minutes to about 3 hours, about 10 minutes to about 3 hours, about 20 minutes to about 3 hours, about 30 minutes to about 3 hours, about 40 minutes to about 3 hours, about 50 minutes to about 3 hours, about 1 hour to about 3 hours, about 5 minutes to about 2 hours, about 10 minutes to about 2 hours, about 20 minutes to about 2 hours, about 30 minutes to about 2 hours, about 40 minutes to about 2 hours, about 50 minutes to about 2 hours, about 1 hour to about 2 hours, about 5 minutes to about 1 hour, about 10 minutes to about 1 hour, about 20 minutes to about 1 hour, about 30 minutes to about 1 hour, about 40 minutes to about 1 hour, or about 50 minutes to about 1 hour prior to the release of the psychedelic. In a preferred embodiment, the additional serotonin receptor modulator is administered at about 1 hour to about 3 hours prior to the administration of the psychedelic.
[000242] In some embodiments, the additional serotonin receptor modulator is eplivanserin, wherein the eplivanserin is administered to pretreat at least 15 minutes prior to the administration of the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is eplivanserin, wherein the eplivanserin is administered to pretreat between at least 30 minutes prior and 360 minutes prior to the release or administration of the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is eplivanserin, wherein the eplivanserin is administered to pretreat between at least 60 minutes prior and 360 minutes prior to the release or administration the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is eplivanserin, wherein the eplivanserin is administered to pretreat at between least 90 minutes and 240 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is eplivanserin, wherein the eplivanserin is administered to pretreat at least 120 minutes prior to the compound disclosed herein.
[000243] In some embodiments, the additional serotonin receptor modulator is eplivanserin, wherein the eplivanserin is administered to pretreat at least 150 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is eplivanserin, wherein the eplivanserin is administered to pretreat at least 180 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is eplivanserin, wherein the eplivanserin is administered to pretreat at least 210 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is eplivanserin, wherein the eplivanserin is administered to pretreat at least 240 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is eplivanserin, wherein the eplivanserin is administered to pretreat at least 270 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is eplivanserin, wherein the eplivanserin is administered to pretreat at least 300 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is eplivanserin, wherein the eplivanserin is administered to pretreat at least 330 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is eplivanserin, wherein the eplivanserin is administered to pretreat at least 360 minutes prior to administration or release of the compound disclosed herein. In some preferred embodiments, the additional serotonin receptor modulator is eplivanserin, wherein eplivanserin is administered to pretreat between about 60 minutes and about 180 minutes prior to the administration or release of the compound disclosed herein.
[000244] In some embodiments, the additional serotonin receptor modulator is volinanserin, wherein the volinanserin is administered to pretreat a subject between at least 15 minutes and 360 minutes prior to the administration or release of the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is volinanserin, wherein the volinanserin is administered to pretreat between at least 30 minutes and 360 minutes prior to the administration or release of the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is volinanserin, wherein the volinanserin is administered to pretreat between at least 60 minutes and 240 minutes prior to the administration or release of the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is volinanserin, wherein the volinanserin is administered to pretreat at least 90 minutes prior to compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is volinanserin, wherein the volinanserin is administered to pretreat at least 120 minutes prior to the compound disclosed herein.
[000245] In some embodiments, the additional serotonin receptor modulator is volinanserin, wherein the volinanserin is administered to pretreat at least 150 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is volinanserin, wherein the volinanserin is administered to pretreat between about 15 minutes and about 150 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is volinanserin, wherein the volinanserin is administered to pretreat at least 180 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is volinanserin, wherein the volinanserin is administered to pretreat at least 210 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is volinanserin, wherein the volinanserin is administered to pretreat at least 240 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is volinanserin, wherein the volinanserin is administered to pretreat at least 270 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is volinanserin, wherein the volinanserin is administered to pretreat at least 300 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is volinanserin, wherein the volinanserin is administered to pretreat at least 330 minutes prior to compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is volinanserin, wherein the volinanserin is administered to pretreat at least 360 minutes prior to the compound disclosed herein. In some preferred embodiments, the additional serotonin receptor modulator is volinanserin, wherein volinanserin is administered to pretreat between about 60 minutes and about 180 minutes prior to the administration of the compound disclosed herein.
[000246] In some embodiments, the additional serotonin receptor modulator is ketanserin, wherein the ketanserin is administered to pretreat at least 15 minutes prior to the administration of the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is ketanserin, wherein the ketanserin is administered to pretreat between at least 30 minutes and 360 minutes prior to the administration or release of the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is ketanserin, wherein the ketanserin is administered to pretreat between at least 60 minutes and 240 minutes prior to the administration or release of the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is ketanserin, wherein the ketanserin is administered to pretreat at least 90 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is ketanserin, wherein the ketanserin is administered to pretreat at least 120 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is ketanserin, wherein the ketanserin is administered to pretreat at least 150 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is ketanserin, wherein the ketanserin is administered to pretreat between about 15 minutes and about 150 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is ketanserin, wherein the ketanserin is administered to pretreat at least 180 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is ketanserin, wherein the ketanserin is administered to pretreat at least 210 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is ketanserin, wherein the ketanserin is administered to pretreat at least 240 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is ketanserin, wherein the ketanserin is administered to pretreat at least 270 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is ketanserin, wherein the ketanserin is administered to pretreat at least 300 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is ketanserin, wherein the ketanserin is administered to pretreat at least 330 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is ketanserin, wherein the ketanserin is administered to pretreat at least 360 minutes prior to the compound disclosed herein. In some preferred embodiments, the additional serotonin receptor modulator is ketanserin, wherein ketanserin is administered to pretreat between about 60 minutes and about 180 minutes prior to the administration of the compound disclosed herein.
[000247] In some embodiments, the additional serotonin receptor modulator is ritanserin, wherein the ritanserin is administered to pretreat at least 15 minutes prior to the administration of the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is ritanserin, wherein the ritanserin is administered to pretreat at least 30 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is ritanserin wherein the ritanserin is administered to pretreat between at least 60 minutes and 240 minutes prior to the administration or release of the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is ritanserin, wherein the ritanserin is administered to pretreat at least 90 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is ritanserin, wherein the ritanserin is administered to pretreat at least 120 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is ritanserin, wherein the ritanserin is administered to pretreat at least 150 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is ritanserin, wherein the ritanserin is administered to pretreat between about 15 minutes and about 150 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is ritanserin, wherein the ritanserin is administered to pretreat at least 180 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is ritanserin, wherein the ritanserin is administered to pretreat at least 210 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is ritanserin, wherein the ritanserin is administered to pretreat at least 240 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is ritanserin, wherein the ritanserin is administered to pretreat at least 270 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is ritanserin, wherein the ritanserin is administered to pretreat at least 300 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is ritanserin, wherein the ritanserin is administered to pretreat at least 330 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is ritanserin, wherein the ritanserin is administered to pretreat at least 360 minutes prior to the compound disclosed herein. In some preferred embodiments, the additional serotonin receptor modulator is ritanserin, wherein ritanserin is administered to pretreat between about 60 minutes and about 180 minutes prior to the administration of the compound disclosed herein.
[000248] In some embodiments, the additional serotonin receptor modulator is pimavanserin, wherein the pimavanserin is administered to pretreat at least 15 minutes prior to the administration of the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is pimavanserin, wherein the pimavanserin is administered to pretreat at least 30 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is pimavanserin, wherein the pimavanserin is administered to pretreat between at least 60 minutes and 240 minutes prior to the administration or release of the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is pimavanserin, wherein the pimavanserin is administered to pretreat at least 90 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is pimavanserin, wherein the pimavanserin is administered to pretreat at least 120 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is pimavanserin, wherein the pimavanserin is administered to pretreat at least 150 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is pimavanserin, wherein the pimavanserin is administered to pretreat between about 15 minutes and about 150 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is pimavanserin, wherein the pimavanserin is administered to pretreat at least 180 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is pimavanserin, wherein the pimavanserin is administered to pretreat at least 210 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is pimavanserin, wherein the pimavanserin is administered to pretreat at least 240 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is pimavanserin, wherein the pimavanserin is administered to pretreat at least 270 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is pimavanserin, wherein the pimavanserin is administered to pretreat at least 300 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is pimavanserin, wherein the pimavanserin is administered to pretreat at least 330 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is pimavanserin, wherein the pimavanserin is administered to pretreat at least 360 minutes prior to the compound disclosed herein. In some preferred embodiments, the additional serotonin receptor modulator is pimavanserin, wherein pimavanserin is administered to pretreat between about 60 minutes and about 180 minutes prior to the administration of the compound disclosed herein.
[000249] In some embodiments, the additional serotonin receptor modulator is nelotanserin, wherein the nelotanserin is administered to pretreat at least 15 minutes prior to the administration of the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is nelotanserin, wherein the nelotanserin is administered to pretreat at least 30 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is nelotanserin, wherein the nelotanserin is administered to pretreat between at least 60 minutes and 240 minutes prior to the administration or release of the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is nelotanserin, wherein the nelotanserin is administered to pretreat at least 90 minutes prior to the compound disclosed herein. In some embodiments, the serotonin receptor modulator is nelotanserin, wherein the nelotanserin is administered to pretreat at least 120 minutes prior to the compound disclosed herein.
[000250] In some embodiments, the additional serotonin receptor modulator is nelotanserin, wherein the nelotanserin is administered to pretreat at least 150 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is nelotanserin, wherein the nelotanserin is administered to pretreat between about 15 minutes and about 150 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is nelotanserin, wherein the nelotanserin is administered to pretreat at least 180 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is nelotanserin, wherein the nelotanserin is administered to pretreat at least 210 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is nelotanserin, wherein the nelotanserin is administered to pretreat at least 240 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is nelotanserin, wherein the nelotanserin is administered to pretreat at least 270 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is nelotanserin, wherein the nelotanserin is administered to pretreat at least 300 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is nelotanserin, wherein the nelotanserin is administered to pretreat at least 330 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is nelotanserin, wherein the nelotanserin is administered to pretreat at least 360 minutes prior to the compound disclosed herein. In some preferred embodiments, the additional serotonin receptor modulator is nelotanserin, wherein nelotanserin is administered to pretreat between about 60 minutes and about 180 minutes prior to the administration of the compound disclosed herein.
[000251] In some embodiments, the additional serotonin receptor modulator is pruvanserin, wherein the pruvanserin is administered to pretreat at least 15 minutes prior to the administration of the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is pruvanserin, wherein the pruvanserin is administered to pretreat at least 30 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is pruvanserin, wherein the pruvanserin is administered to pretreat between at least 60 minutes and 240 minutes prior to the administration or release of the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is pruvanserin, wherein the pruvanserin is administered to pretreat at least 90 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is pruvanserin, wherein the pruvanserin is administered to pretreat at least 120 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is pruvanserin, wherein the pruvanserin is administered to pretreat at least 150 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is pruvanserin, wherein the pruvanserin is administered to pretreat between about 15 minutes and about 150 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is pruvanserin, wherein the pruvanserin is administered to pretreat at least 180 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is pruvanserin, wherein the pruvanserin is administered to pretreat at least 210 minutes prior to the compound disclosed herein.
[000252] In some embodiments, the additional serotonin receptor modulator is pruvanserin, wherein the pruvanserin is administered to pretreat at least 240 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is pruvanserin, wherein the pruvanserin is administered to pretreat at least 270 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is pruvanserin, wherein the pruvanserin is administered to pretreat at least 300 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is pruvanserin, wherein the pruvanserin is administered to pretreat at least 330 minutes prior to the compound disclosed herein. In some embodiments, the additional serotonin receptor modulator is pruvanserin, wherein the pruvanserin is administered to pretreat at least 360 minutes prior to the compound disclosed herein. In some preferred embodiments, the additional serotonin receptor modulator is pruvanserin, wherein pruvanserin is administered to pretreat between about 60 minutes and about 180 minutes prior to the administration of the compound disclosed herein.
[000253] In some embodiments, methods of use are described herein of compositions comprising a lipid prodrug described herein (e.g., prodrug of DMT or 5-MeO-DMT of Formula I) having activity as a 5-HT2A modulator co-administered with an additional serotonin receptor modulator. In some embodiments described herein are methods for co administering compounds described herein co-administered with an additional serotonin receptor modulator. In some embodiments, the co-administration comprises a pretreatment with an additional serotonin receptor modulator. In some embodiments, co-administration is used in a method of treating a brain disorder. In some embodiments, co-administration is used in a method of increasing neuronal plasticity. In some embodiments, co-administration is used in a method of increasing translation of neurotrophic factors. In some embodiments, co administration is used in a method of increasing transcription of neurotrophic factors. In some embodiments, co-administration is used in a method of increasing secretion of neurotrophic factors.
Methods of Treating a Brain Disorder
[000254] In yet another aspect, provided herein are method for treating a brain disorder in a subject in need thereof, comprising administering the presently disclosed lipid prodrugs (e.g., a compound of Formula I) to the subject. The compounds described herein (e.g., a compound of Formula I) can function as 5-HT2A agonists alone, or in combination with a second therapeutic agent that also is a 5-HT2A modulator. In such cases the second therapeutic agent can be an agonist or an antagonist. In some embodiments, administering a 5-HT2A antagonist in combination with a compound of the present invention to mitigate undesirable effects of 5-HT2A agonism, such as potential hallucinogenic effects. Serotonin receptor modulators useful as second therapeutic agents for combination therapy as described herein are known to those of skill in the art and include, without limitation, MDL-11,939, eplivanserin (SR-46,349), ketanserin, ritanserin, altanserin, acepromazine, mianserin, mirtazapine, quetiapine, SB204741, SB206553, SB242084, LY272015, SB243213, blonanserin, SB200646, RSI 02221, nefazodone, MDL-100,907, pimavanserin, flibanserin, nelotanserin and lorcaserin. In some embodiments, the serotonin receptor modulator used as a second therapeutic is pimavanserin or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof. In some embodiments, the serotonin receptor modulator is administered prior to a compound disclosed herein, such as about three or about hours prior administration the compounds described herein (e.g., a compound of Formula I). In some embodiments, the serotonin receptor modulator is administered at most about one hour prior to the compounds described herein (e.g., a compound of Formula I). Thus, in some embodiments of combination therapy with the compounds described herein (e.g., a compound of Formula I), the second therapeutic agent is a serotonin receptor modulator. In some embodiments the second therapeutic agent serotonin receptor modulator is provided at a dose of from about 10 mg to about 350 mg. In some embodiments, the serotonin receptor modulator is provided at a dose of from about 20 mg to about 200 mg. In some embodiments, the serotonin receptor modulator is provided at a dose of from about 10 mg to about 100 mg.
In certain embodiments, the compound described herein (e.g., a compound of Formula I) is provided at a dose of from about 10 mg to about 100 mg, or from about 20 to about 200 mg, or from about 15 to about 300 mg, and the serotonin receptor modulator is provided at a dose of about 10 mg to about 100 mg.
[000255] In some embodiments, the compounds described herein (e.g., a compound of Formula I) are non-hallucinogenic 5-HT2A modulators (e.g., 5-HT2A agonists) and are used to treat neurological diseases. In some embodiments, the neurological diseases comprise decreased neural plasticity, decreased cortical structural plasticity, decreased 5-HT2A receptor content, decreased dendritic arbor complexity, loss of dendritic spines, decreased dendritic branch content, decreased spinogenesis, decreased neuritogenesis, retraction of neurites, or any combination thereof.
[000256] In some embodiments, the compounds described herein (e.g., a compound of Formula I are non-hallucinogenic 5-HT2A modulators (e.g., 5-HT2A agonists) and are used for increasing neuronal plasticity. In some embodiments, non-hallucinogenic 5-HT2A modulators (e.g., 5-HT2A agonists) are used for treating a brain disorder. In some embodiments, non-hallucinogenic 5-HT2A modulators (e.g., 5-HT2A agonists) are used for increasing at least one of translation, transcription, or secretion of neurotrophic factors. [000257] In some embodiments the compounds described herein (e.g., a compound of Formula I) are administered at a low dose that is lower than a dose that would produce noticeable psychedelic effects but high enough to provide a therapeutic benefit. This dose range is predicted to be between 200 pm and 2mg.
Methods for Increasing Neuronal Plasticity
[000258] Neuronal plasticity refers to the ability of the brain to change structure and/or function throughout a subject’s life. New neurons can be produced and integrated into the central nervous system throughout the subject’s life. Increasing neuronal plasticity includes, but is not limited to, promoting neuronal growth, promoting neuritogenesis, promoting synaptogenesis, promoting dendritogenesis, increasing dendritic arbor complexity, increasing dendritic spine density, and increasing excitatory synapsis in the brain. In some embodiments, increasing neuronal plasticity comprises promoting neuronal growth, promoting neuritogenesis, promoting synaptogenesis, promoting dendritogenesis, increasing dendritic arbor complexity, and increasing dendritic spine density.
[000259] In another aspect, provided herein are methods for increasing neuronal plasticity, comprising contacting a neuronal cell with a compound described herein (e.g., a compound of Formula I). In some embodiments, increasing neuronal plasticity improves a brain disorder described herein. [000260] Also provided are methods of treating a disease or disorder in a subject in need thereof comprising administering the presently disclosed lipid prodrugs (e.g., a compound of Formula I) in the subject, wherein the compound described herein increases neuronal plasticity in the subject. In some embodiment, the disease or disorder is neurodegenerative disorder, Alzheimer’s, Parkinson’s disease, psychological disorder, depression, addiction, anxiety, post- traumatic stress disorder, treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, or substance use disorder.
[000261] In some embodiments, the increased neuronal plasticity improves anti-addictive properties, antidepressant properties, anxiolytic properties, or a combination thereof. In some embodiments, the disease or disorder is a neuropsychiatric disease. In some embodiments, the neuropsychiatric disease is a mood or anxiety disorder. In some embodiments, the neuropsychiatric disease includes, for example, migraine, cluster headache, post-traumatic stress disorder (PTSD), schizophrenia, anxiety, depression, and addiction (e.g., substance abuse disorder). In some embodiments, brain disorders include, for example, migraines, addiction (e.g., substance use disorder), depression, and anxiety.
[000262] In some embodiments, the experiment or assay to determine increased neuronal plasticity of the compounds described herein (e.g., a compound of Formula I) is a phenotypic assay, a dendritogenesis assay, a spinogenesis assay, a synaptogenesis assay, a Sholl analysis, a concentration-response experiment, a 5-HT2A agonist assay, a 5-HT2A antagonist assay, a 5-HT2A binding assay, or a 5-HT2A blocking experiment (e.g., ketanserin blocking experiments). In some embodiments, the experiment or assay to determine the hallucinogenic potential of any compound of the present invention is a mouse head-twitch response (HTR) assay.
Methods of Increasing Translation, Transcription, or Secretion of Neurotrophic Factors [000263] Neurotrophic factors refer to a family of soluble peptides or proteins which support the survival, growth, and differentiation of developing and mature neurons.
Increasing at least one of translation, transcription, or secretion of neurotrophic factors can be useful for, but not limited to, increasing neuronal plasticity, promoting neuronal growth, promoting neuritogenesis, promoting synaptogenesis, promoting dendritogenesis, increasing dendritic arbor complexity, increasing dendritic spine density, and increasing excitatory synapsis in the brain. In some embodiments, increasing at least one of translation, transcription, or secretion of neurotrophic factors can increasing neuronal plasticity. In some embodiments, increasing at least one of translation, transcription, or secretion of neurotrophic factors can promoting neuronal growth, promoting neuritogenesis, promoting synaptogenesis, promoting dendritogenesis, increasing dendritic arbor complexity, and/or increasing dendritic spine density.
[000264] In another aspect, provided herein are methods for increasing at least one of translation, transcription or secretion of neurotrophic factors, comprising contacting a neuronal cell with the presently disclosed lipid prodrugs (e.g., a compound of Formula I). [000265] Also provided herein are methods for increase at least one of translation, transcription, or secretion of neurotrophic factors in a subject in need thereof, comprising administering to the subject a compound described herein (e.g., a compound of Formula I). In some embodiments, increasing at least one of translation, transcription or secretion of neurotrophic factors treats a disease or disorder such as a migraine, headaches (e.g., cluster headache), post-traumatic stress disorder (PTSD), anxiety, depression, neurodegenerative disorder, Alzheimer’s disease, Parkinson’s disease, psychological disorder, treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, and addiction (e.g., substance use disorder).
[000266] In some embodiments, the experiment or assay used to determine increase translation of neurotrophic factors includes ELISA, western blot, immunofluorescence assays, proteomic experiments, and mass spectrometry. In some embodiments, the experiment or assay used to determine increase transcription of neurotrophic factors includes gene expression assays, RT-PCR, in situ mRNA hybridization, and microarrays. In some embodiments, the experiment or assay used to determine increase secretion of neurotrophic factors includes ELISA, western blot, immunofluorescence assays, proteomic experiments, and mass spectrometry.
Combination Therapies
[000267] A provided lipid prodrug, or pharmaceutically acceptable composition thereof, may be administered to a patient in need thereof in combination with one or more additional therapeutic agents and/or therapeutic processes.
[000268] The disclosed lipid prodrugs and compositions, and any co-administered additional therapeutic agents, according to the method of the present disclosure, may be administered using any amount and any route of administration effective for treating or lessening the severity of a disease, disorder, or condition such as an inflammatory disorder, a neurodegenerative or neurological disorder, or schizophrenia. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. Disclosed lipid prodrugs are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression “dosage unit form” as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of a disclosed lipid prodrug or composition thereof and any co-administered additional therapeutic agents will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific lipid prodrug employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific lipid prodrug or composition; the duration of the treatment; drugs used in combination or coincidental with the specific lipid prodrug or composition employed, and like factors well known in the medical arts. The term “subject” or “patient,” as used herein, means an animal, preferably a mammal, and most preferably a human.
[000269] In some embodiments, the methods described herein further comprise administering one or more second therapeutic agent therapeutic agent that is lithium, olanzapine (Zyprexa), quetiapine (Seroquel), risperidone (Risperdal), ariprazole (Abilify), ziprasidone (Geodon), clozapine (Clozaril), divalproex sodium (Depakote), lamotrigine (Lamictal), valproic acid (Depakene), carbamazepine (Equetro), topiramate (Topamax), levomilnacipran (Fetzima), duloxetine (Cymbalta, Yentreve), venlafaxine (Effexor), citalopram (Celexa), fluvoxamine (Luvox), escitalopram (Lexapro), fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), clomipramine (Anafranil), amitriptyline (Elavil), desipramine (Norpramin), imipramine (Tofranil), nortriptyline (Pamelor), phenelzine (Nardil), tranylcypromine (Parnate), diazepam (Valium), alprazolam (Xanax), or clonazepam (Klonopin).
[000270] In certain embodiments, the second therapeutic agent is an empathogenic agent. Examples of suitable empathogenic agents for use in combination with a compound described herein (e.g., a compound of Formula I) are selected from the phenethylamines, such as 3,4- methylene- dioxymethamphetamine (MDMA) and analogs thereof. Other suitable empathogenic agents for use in combination with the presently disclosed compounds include, without limitation,
N-Allyl-3,4-methylenedioxy-amphetamine (MDAL) N-Butyl-3,4-methylenedioxyamphetamine (MDBU) N-Benzyl-3,4-methylenedioxyamphetamine (MDBZ) N-Cyclopropylmethyl-3,4-methylenedioxyamphetamine (MDCPM) N,N-Dimethyl-3,4-methylenedioxyamphetamine (MDDM) N-Ethyl-3,4-methylenedioxyamphetamine (MDE; MDEA) N-(2-Hydroxyethyl)-3,4-methylenedioxy amphetamine (MDHOET) N-Isopropyl-3,4-methylenedioxyamphetamine (MDIP)
N-Methyl-3, 4-ethyl enedioxyamphetamine (MDMC) N-Methoxy-3,4-methylenedioxyamphetamine (MDMEO) N-(2-Methoxyethyl)-3,4-methylenedioxyamphetamine (MDMEOET) alpha, alpha, N-Trimethyl-3,4-methylenedioxyphenethylamine (MDMP;
3.4-Methyl enedioxy-N-methylphentermine)
N-Hydroxy-3,4-methylenedioxyamphetamine (MDOH)
3.4-Methyl enedioxyphenethylamine (MDPEA) alpha, alpha-Dimethyl-3,4-methylenedioxyphenethylamine (MDPH; 3,4- methylenedioxyphentermine)
N-Propargyl-3,4-methylenedioxyamphetamine (MDPL)
Methyl enedioxy-2-aminoindane (MDAI)
1 , 3 -B enzodioxolyl -N-methylbutanamine MBDB N-methyl-l,3-benzodioxolylbutanamine, MBDB,
3.4-methylenedioxy-N-methyl-a-ethylphenylethylamine
3.4-Methylenedioxyamphetamine MDA
Methylone (also known as "3,4-methylenedioxy-N-methylcathinone)
Ethylone, also known as 3,4-methylenedioxy-N-ethylcathinone GHB or Gamma Hydroxybutyrate or sodium oxybate N-Propyl-3,4-methylenedioxyamphetamine (MDPR).
[000271] In some embodiments, the compounds of the present invention are used in combination with the standard of care therapy for a neurological disease described herein. Non-limiting examples of the standard of care therapies, may include, for example, lithium, olanzapine, quetiapine, risperidone, ariprazole, ziprasidone, clozapine, divalproex sodium, lamotrigine, valproic acid, carbamazepine, topiramate, levomilnacipran, duloxetine, venlafaxine, citalopram, fluvoxamine, escitalopram, fluoxetine, paroxetine, sertraline, clomipramine, amitriptyline, desipramine, imipramine, nortriptyline, phenelzine, tranylcypromine, diazepam, alprazolam, clonazepam, or any combination thereof. Nonlimiting examples of standard of care therapy for depression are sertraline, fluoxetine, escitalopram, venlafaxine, or aripiprazole. Non-limiting examples of standard of care therapy for depression are citralopram, escitalopram, fluoxetine, paroxetine, diazepam, or sertraline. Additional examples of standard of care therapeutics are known to those of ordinary skill in the art.
Pharmaceutical Compositions
[000272] According to another embodiment, the present disclosure provides a composition comprising a lipid prodrug of the present disclosure and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of lipid prodrug in the composition is an amount effective to treat the relevant disease, disorder, or condition in a patient in need thereof (an “effective amount”). In some embodiments, a composition of the present disclosure is formulated for oral administration to a patient.
[000273] The term “pharmaceutically acceptable carrier, adjuvant, or vehicle” refers to a nontoxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the agent with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the disclosed compositions include, but are not limited to, ion exchangers, alumina, stearates such as aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose- based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, polyethylene glycol and wool fat. In some embodiments, the composition is formulated as a lipophilic mixture, such as a lipid-based composition.
[000274] Compositions of the present disclosure may be administered orally, parenterally, enterally, intracistemally, intraperitoneally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term “parenteral” as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrastemal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. In some embodiments, the composition is administered orally, intraperitoneally, or intravenously. In some embodiments, the composition is a transmucosal formulation. In some embodiments, the composition is injected directly into the lymphatic system. Sterile injectable forms of the compositions of this disclosure may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer’s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.
[000275] To aid in delivery of the composition, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically- acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
[000276] Pharmaceutically acceptable compositions may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and com starch. Lubricating agents, such as magnesium stearate, may also be added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
[000277] Alternatively, pharmaceutically acceptable compositions may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.
[000278] In some embodiments, the pharmaceutically acceptable composition is formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, the pharmaceutically acceptable composition is administered without food. In other embodiments, the pharmaceutically acceptable composition is administered with food. It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated.
[000279] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3 -butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
[000280] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer’s solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.
[000281] Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
[000282] In order to prolong the effect of a compound of the present disclosure, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide- polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
[000283] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this disclosure with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
[000284] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f ) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
[000285] Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like. [000286] Therapeutic agents can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g ., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.
[000287] Dosage forms for topical or transdermal administration of a compound of this disclosure include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this disclosure. Additionally, the present disclosure contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
[000288] In some embodiments, the lipid prodrug is formulated as an orally administrable, lipid-based formulation. Lipid-based formulations for oral delivery are known in the art and may include, for example, substantially non-aqueous vehicles which typically contain one or more lipid components. The lipid vehicles and resulting lipid formulations may be usefully classified as described below according to their shared common features according to the lipid formulation classification system (LFCS).
[000289] Lipid vehicles, and the resulting lipid formulations, may contain oil/lipids and/or surfactants, optionally with co-solvents. In the LFCS terminology, Type I formulations include oils or lipids which require digestion, such as mono, di and tri-glycerides and combinations thereof. Type II formulations are water-insoluble self-emulsifying drug delivery systems (SEDDS) which contain lipids and oils used in Type I formulations, with additional water insoluble surfactants. Type III formulations are SEDDS or self-microemulsifying drug delivery systems (SMEDDS) which contain lipids and oils used in Type I formulations, with additional water-soluble surfactants and/or co-solvents (Type Ilia) or a greater proportion of water-soluble components (Type Illb). Type IV formulations contain predominantly hydrophilic surfactants and co-solvents (e.g PEG, propylene glycol and diethylene glycol monoethyl ether) and are useful for drugs which are poorly water soluble but not lipophilic. Any such lipid formulation (Type I- IV) is contemplated herein for use with a disclosed lipid prodrug or pharmaceutical composition thereof.
[000290] In some embodiments, the lipid vehicle contains one or more oils or lipids, without additional surfactants, co-surfactants or co-emulsifiers, or co-solvents, i.e. it consists essentially of one or more oils or lipids. In some further embodiments, the lipid vehicle contains one or more oils or lipids together with one or more water-insoluble surfactants, optionally together with one or more co-solvents. In some embodiments, the lipid vehicle contains one or more oils or lipids together with one or more water-soluble surfactants, optionally together with one or more co-solvents. In some embodiments, the lipid vehicle contains a mixture of oil/lipid, surfactant and co-solvent. In some embodiments, the lipid vehicle consists essentially of one or more surfactants/co-surfactants/co-emulsifiers, and/or solvents/co- sol vents .
[000291] Examples of oils or lipids which may be used in the present disclosure include almond oil, babassu oil, blackcurrant seed oil, borage oil, canola oil, castor oil, coconut oil, cod liver oil, com 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, wheat germ oil, avocado oil, bran oil, hydrogenated castor oil, hydrogenated coconut oil, hydrogenated cottonseed oil, hydrogenated palm oil, hydrogenated soybean oil, partially hydrogenated soybean oil, hydrogenated vegetable oil, caprylic/capric glycerides, fractionated triglycerides, glyceryl tricaprate, glyceryl tricaproate, glyceryl tricaprylate, glyceryl tricaprylate/caprate, glyceryl tricaprylate/caprate, glyceryl tricaprylate/caprate/laurate, glyceryl tricaprylate/caprate/linoleate, glyceryl tricaprylate/caprate/stearate, glyceryl trilaurate, glyceryl monolaurate, glyceryl behenate, glyceryl monolinoleate, glyceryl trilinolenate, glyceryl trioleate, glyceryl triundecanoate, glyceryl tristearate linoleic glycerides, saturated polyglycolized glycerides, synthetic medium chain triglycerides containing primarily C -i2 fatty acid chains, medium chain triglycerides containing primarily C -i2 fatty acid chains, long chain triglycerides containing primarily >C fatty acid chains, modified triglycerides, fractionated triglycerides, and mixtures thereof. [000292] Examples of mono and diglycerides which may be used in such formulations include glycerol mono- and diesters having fatty acid chains from 8 to 40 carbon atoms, including hydrolysed coconut oils (e.g., Capmul® MCM), hydrolysed corn oil (e.g, Maisine™35-1). In some embodiments, the monoglycerides and diglycerides are mono-or di- saturated fatty acid esters of glycerol having fatty acid chains of 8 to 18 carbon chain length (e.g, glyceryl monostearate, glyceryl distearate, glyceryl monocaprylate, glyceryl dicaprylate, glyceryl monocaprate and glyceryl dicaprate). Mixtures of fatty acids (“structured glycerides”) adapted for enhancing the absorption and transport of lipid soluble compounds are disclosed in, e.g ., U.S. Patent No. 6,013,665, which is hereby incorporated by reference.
[000293] Suitable surfactants for use in the lipid formulations include propylene glycol mono- and di-esters of Cx-22 fatty acids, such as, but not limited to, propylene glycol monocaprylate, propylene glycol dicaprylate, propylene glycol monolaurate, sold under trade names such as Capryol® 90, Labrafac® PG, Lauroglycol® FCC, sugar fatty acid esters, such as, but not limited to, sucrose palmitate, sucrose laurate, and sucrose stearate; sorbitan fatty acid esters such as, but not limited to, sorbitan laurate, sorbitan palmitate, and sorbitan oleate; polyoxyethylene sorbitan fatty acid esters such as, but not limited to, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, and polysorbate 85; polyoxyethylene mono- and di-fatty acid esters including, but not limited to, polyoxyl 40 stearate and polyoxyl 40 oleate; a mixture of polyoxyethylene mono- and di-esters of Cx-22 fatty acids and glyceryl mono-, di-, and tri-esters of Cx-22 fatty acids as sold under tradenames such as Labrasol®, Gelucire® 44/14, Gelucire® 50/13, and Labrafil®; polyoxyethylene castor oils compound such as, but not limited to, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, and polyoxyl 60 hydrogenated castor oil, as are sold under tradenames such as Cremophor®/Kolliphor EL, Cremophor®/Kolliphor® REMO, and Cremophor®/Kolliphor® RH60; polyoxyethylene alkyl ethers including, but not limited to, polyoxyl 20 cetostearyl ether and polyoxyl 10 oleyl ether; DL-a-tocopheryl polyethylene glycol succinate; glyceryl mono-, di-, and tri-esters; glyceryl mono-, di-, and tri-esters of Cx-22 fatty acids; sucrose mono-, di-, and tri-esters; sodium dioctylsulfosuccinate; polyoxyethylene- polyoxypropylene copolymers such as, but not limited to poloxamer 124, poloxamer 188, and poloxamer 407; polyoxyethylene ethers of Cx-22 fatty alcohols including, but not limited to, polyoxyethylenelauryl alcohol, polyoxyethylenecetyl alcohol, polyoxyethylene stearyl alcohol, polyoxyethyleneoleyl alcohol, as sold under tradenames such as Brij® 35, Brij® 58, Brij® 78, Brij® 98, or a mixture of any two or more thereof.
[000294] A co-emulsifier, or co-surfactant, may be used in the formulation. A suitable co emulsifier or co-surfactant may be a phosphoglyceride; a phospholipid, for example lecithin, or a free fatty acid that is liquid at room temperature, for example, iso-stearic acid, oleic acid, linoelic acid, linolenic acid, palmitic acid, stearic acid, lauric acid, capric acid, caprylic acid, and caproic acid.
[000295] Suitable solvents/co-solvents include ethanol, propylene glycol, polyethylene glycol, di ethylene glycol monoethyl ether, and glycerol.
[000296] A polymer may also be used in the formulation to inhibit drug precipitation or to alter the rate of drug release. A range of polymers have been shown to impart these properties and are well known to those skilled in the art. Suitable polymers include hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetyl succinate, other cellulose-derived polymers such as methylcellulose; poly(meth)acrylates, such as the Eudragit series of polymers, including Eudragit El 00, polyvinylpyrrolidone.
[000297] Formulations may be chosen specifically to provide for sustained release of the active in the gastrointestinal (GI) tract in order to control the rate of absorption. Many different approaches may be used to achieve these ends including the use of high melting point lipids that disperse/erode slowly in the GI tract, or polymers that form a matrix that slowly erodes. These formulations may take the form of large monolithic dose forms or may be present as micro or nano-particulate matrices.
[000298] Formulations may also contain materials commonly known to those skilled in the art to be included in lipid based formulations, including antioxidants, for example, butylated hydroxyanisole (BHA) or butylated hydroxytoluene (BHT) and solidifying agents such as microporous silica, for example magnesium alumino-metasilicate (Neusilin).
[000299] In some embodiments, the lipid prodrug may be co-administered orally with an enzyme inhibitor to increase stability of the prodrug in the gastrointestinal tract or enterocyte. In certain embodiments, the enzyme inhibitor inhibits pancreatic lipases, examples of which include, but are not limited to, Alii® (orlistat). In other embodiments it is envisaged that the enzyme inhibitor will inhibit cellular lipase enzymes such as monoacylglycerol lipase, an example of which includes, but is not limited to, JZL184 (4-nitrophenyl-4-[bis(l,3- benzodioxol- 5-yl)(hydroxy)methyl]piperidine-l-carboxylate).
[000300] In some embodiments, a dose is selected to account for lymphatic uptake, metabolism, and release of the parent drug tryptamine or phenethylamine psychedelic such as (N,N-dimethyltryptamine) DMT, or 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) (alio). For example, if a given dose of lipid prodrug is absorbed more efficiently than an equivalent oral or intravenous dose of tryptamine or phenethylamine psychedelic such as (N,N-dimethyltryptamine) DMT, or 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) , the dose of lipid prodrug is decreased by an appropriate amount to result in the desired plasma or lymphatic system concentration of tryptamine or phenethylamine psychedelic such as (N,N- dimethyltryptamine) DMT, or 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) . In some embodiments, the dose is selected such that an orally-administered dose of lipid prodrug provides, upon lymphatic uptake in the patient, metabolism, and release of the parent drug tryptamine or phenethylamine psychedelic such as (N,N-dimethyltryptamine) DMT, or 5- methoxy-N,N-dimethyltryptamine (5-MeO-DMT) , a desired, effective concentration, e.g., a plasma or lymphatic system concentration, of tryptamine or phenethylamine psychedelic such as (N,N-dimethyltryptamine) DMT, or 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) to treat a disease, disorder, or condition, such as those disclosed herein.
[000301] In some embodiments, the dose of lipid prodrug or a pharmaceutically acceptable salt thereof is about 0.01 mg/kg to about 100 mg/kg. In some embodiments, the dose of lipid prodrug or a pharmaceutically acceptable salt thereof is about 0.1 mg/kg to about 25 mg/kg. In some embodiments, the dose of lipid prodrug or a pharmaceutically acceptable salt thereof is about 0.5 mg/kg to about 15 mg/kg. In some embodiments, the dose of lipid prodrug or a pharmaceutically acceptable salt thereof is about 1 mg/kg to about 10 mg/kg. In some embodiments, the dose of lipid prodrug or a pharmaceutically acceptable salt thereof is about 2 mg/kg to about 7.5 mg/kg. In some embodiments, the dose of lipid prodrug or a pharmaceutically acceptable salt thereof is about 3.0 mg/kg to about 7.0 mg/kg. In some embodiments, the dose of lipid prodrug or a pharmaceutically acceptable salt thereof is about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.3, 1.5, 1.7, 2.0, 2.5, 3.0, 3.5, 4.0, 5.0, 6.0, 7.0,
8.0, 9.0, or 10.0 mg/kg.
[000302] In some embodiments, the dose is about 1 mg to about 5 g of lipid prodrug or a pharmaceutically acceptable salt thereof. In some embodiments, the dose is about 10 mg to about 2.5 g of lipid prodrug or a pharmaceutically acceptable salt thereof. In some embodiments, the dose is about 100 mg to about 2.0 g of lipid prodrug or a pharmaceutically acceptable salt thereof. In some embodiments, the dose is about 250 mg to about 1.0 g of lipid prodrug or a pharmaceutically acceptable salt thereof. In some embodiments, the dose is about 500 mg to about 1.0 g of lipid prodrug or a pharmaceutically acceptable salt thereof.
[000303] In some embodiments, the dose of lipid prodrug or a pharmaceutically acceptable salt thereof is calculated to provide a particular dose of tryptamine or phenethylamine psychedelic such as (N,N-dimethyltryptamine) DMT, or 5 -m ethoxy -N,N-dimethyltryptamine (5-MeO-DMT) when the prodrug is administered orally. In some embodiments, the dose of lipid prodrug or a pharmaceutically acceptable salt thereof is calculated to provide about 0.01 mg/kg to about 100 mg/kg of tryptamine or phenethylamine psychedelic such as (N,N- dimethyltryptamine) DMT, or 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) , 0.1 mg/kg to about 25 mg/kg, about 0.5 mg/kg to about 15 mg/kg, about 1 mg/kg to about 10 mg/kg, about 2 mg/kg to about 7.5 mg/kg, about 3.0 mg/kg to about 7.0 mg/kg of tryptamine or phenethylamine psychedelic such as (N,N-dimethyltryptamine) DMT, or 5 -m ethoxy -N,N- dimethyltryptamine (5-MeO-DMT) . In some embodiments, the dose of lipid prodrug or a pharmaceutically acceptable salt thereof is calculated to provide about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.3, 1.5, 1.7, 2.0, 2.5, 3.0, 3.5, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, or 10.0 mg/kg of tryptamine or phenethylamine psychedelic such as (N,N-dimethyltryptamine) DMT, or 5- methoxy-N,N-dimethyltryptamine (5-MeO-DMT) when the prodrug is administered orally. [000304] In some embodiments, the dose of lipid prodrug or a pharmaceutically acceptable salt thereof is calculated to provide about 5 mg to about 3 g of tryptamine or phenethylamine psychedelic such as (N,N-dimethyltryptamine) DMT, or 5 -m ethoxy -N,N-dimethyltryptamine (5-MeO-DMT) when the prodrug is administered orally. In some embodiments, the dose is calculated to provide about 50 mg to about 2.5 g of tryptamine or phenethylamine psychedelic such as (N,N-dimethyltryptamine) DMT, or 5-methoxy-N,N-dimethyltryptamine (5-MeO- DMT) , or about 100 mg to about 1.5 g, or about 250 mg to about 1.0 g of tryptamine or phenethylamine psychedelic such as (N,N-dimethyltryptamine) DMT, or 5 -m ethoxy -N,N- dimethyltryptamine (5-MeO-DMT) .
Methods of Making Lipid Prodrugs GeneralMethods for Making Lipid Prodrugs
[000305] The lipid prodrug compounds of this disclosure (e.g., prodrugs of DMT or 5- MeO-DMT of Formula I) may be prepared or isolated in general by synthetic and/or semi synthetic methods known to those skilled in the art for analogous compounds and by methods described in herein.
[000306] The therapeutic agents comprised in disclosed lipid prodrugs (e.g., conjugated to a glyceride-based prodrug) may be purchased commercially or prepared by organic synthesis, semi -synthesis, fermentation (e.g, with viral vectors), and like methods known in the art. [000307] In some embodiments, protecting groups (as defined below) can be used to manipulate therapeutic agents in preparation for conjugation to the remainder of the lipid prodrug structure, for example, to prevent undesired side reactions from taking place. [000308] In the synthesis methods described herein, where a particular protecting group (“PG”), leaving group (“LG”), or transformation condition is depicted, one of ordinary skill in the art will appreciate that other protecting groups, leaving groups, and transformation conditions are also suitable and are contemplated. [000309] As used herein, the phrase “leaving group” (LG) includes, but is not limited to, halogens ( e.g ., fluoride, chloride, bromide, iodide), sulfonates (e.g, mesylate, tosylate, benzenesulfonate, brosylate, nosylate, triflate), diazonium, and the like.
[000310] As used herein, the phrase “oxygen protecting group” includes, for example, carbonylprotecting groups, hydroxyl protecting groups, etc. Examples of suitable hydroxyl protecting groups include, but are not limited to, esters, allyl ethers, ethers, silyl ethers, alkyl ethers, arylalkyl ethers, and alkoxyalkyl ethers. Examples of such esters include formates, acetates, carbonates, and sulfonates. Specificexamples include formate, benzoyl formate, chloroacetate, trifluoroacetate, methoxyacetate,triphenylmethoxyacetate, p- chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate, 4,4-(ethylenedithio)pentanoate, pivaloate (trimethylacetyl), crotonate, 4-methoxy-crotonate, benzoate, p-benzylbenzoate, 2,4,6-trimethylbenzoate, carbonates such as methyl, 9-fluorenylmethyl, ethyl, 2,2,2- trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, vinyl, allyl, and p-nitrobenzyl. Examples of such silyl ethers include trimethylsilyl, triethylsilyl,t-butyldimethylsilyl, t- butyldiphenylsilyl, triisopropylsilyl, and other trialkylsilyl ethers. Alkylethers 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-methoxyethoxy)methyl, benzyloxymethyl, beta- (trimethylsilyl)ethoxymethyl, and tetrahydropyranyl ethers. Examples of arylalkyl ethers includebenzyl, p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, O-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, and 2- and 4-picolyl.
[000311] Suitable amino protecting groups include, but are not limited to, aralkyl amines, carbamates, cyclic imides, allyl amines, amides, and the like. Examples of such groups include t-butyloxy carbonyl (Boc), ethyloxycarbonyl, methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyl oxocarbonyl (Cbz), allyl, phthalimide, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), formyl, acetyl, chloroacetyl, dichloroacetyl, tri chloroacetyl, phenylacetyl, trifluoroacetyl, benzoyl, and the like.
[000312] One of skill in the art will appreciate that various functional groups present in compounds of the disclosure 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. Such interconversions may require one or more of the aforementioned techniques, and certain methods for synthesizing compounds of the disclosure are described below. EXAMPLES
[000313] These examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein.
Abbreviations app apparent Boc tert-butyl carbamate br broad d doublet dd doublet of doublets
DCM dichloromethane DIPEA diisopropylethylamine DMA dimethylacetamide DMAP 4-dimethylaminopyridine DMF N,N-dimethylformamide DMSO dimethyl sulfoxide
EtOAc or AcOEt ethyl acetate
HC1 hydrochloric acid h hextet; sextet
HPLC high pressure liquid chromatography LC-MS liquid chromatography and mass spectrometry MeOH methanol MeCN acetonitrile MS mass spectrometry m multiplet min(s) minute(s) mL milliliter(s) pL microliter(s) m/z mass to charge ratio P pentet q quartet
NaHCCb sodium hydrogen carbonate Na2S04 sodium sulfate NMP N-methyl-2-pyrrolidone NMR nuclear magnetic resonance Rt retention time s singlet t triplet THF tetrahydrofuran Example 1: General Synthesis and Analyzing Methods [000314] Exemplary Compounds I-1 through I-30 can be synthesized by acylating 2-(1H- indol-3-yl)-N,N-dimethylethanamine or 2-(5-methoxy-1H-indol-3-yl)-N,N- dimethylethanamine with an appropriate acid chloride under basic conditions (Scheme 1). Alternatively, Compounds I-1 through I-30 can be synthesized by reacting an acid (carboxylic acid RCOO2H) with 2-(1H-indol-3-yl)-N,N-dimethylethanamine or 2-(5-methoxy-1H-indol-3- yl)-N,N-dimethylethanamine under standard amide coupling conditions, employing well- known coupling (activating) reagents such as DCC, EDCI, HATU, COMU, T3P, BOP, BOP- Cl, etc. The solvent for such reactions can be DMF, DCM, 1,2-DCE, ACN, THF, etc.
Figure imgf000108_0001
. [000315] As another general strategy, compounds of the present disclosure may also be synthesized via one of the following routes described in Schemes 2 to 9:
Figure imgf000108_0002
Scheme 2. Synthesis of compounds of Formula iii. [000316] Diacid chlorides i, which are readily available from the corresponding malonic acids, can be reacted with a diglyceride such as compound ii in the presence of pyridine or another appropriate base to give acid-triglyceride (acid-TG) iii (see Scheme 2 above). Compounds of Formula iii is shown with C15H31 fatty acid side chains, but other fatty acids (such as those described above) can be substituted in this and other Formulas described below.
Figure imgf000109_0001
Scheme 3. Synthesis of compounds of Formula iv.
[000317] In cases where acid anhydride i-a is available, acid-TG iv can be generated by ring-opening reaction with diglyceride ii in the presence of pyridine or another appropriate base (see Scheme 3 above). This method works best when R4 and R5 of acid anhydride i-a are identical, e.g. , both R4 and R5 are Me. However, this method will result in a regioisomeric mixture of acid-TG products iv when R4 and R5 differ from each other. Consequently, other methods, such as that outlined in Scheme 4 below, can be advantageously employed in this circumstance.
Figure imgf000109_0003
Scheme 4. Synthesis of compounds of Formula iv where
Figure imgf000109_0002
, =
H.
[000318] To obtain acid-TG iv as a single regioisomer in the specific example where R4 = Me or other alkyl or substitution and R5 = H, the known carboxylic acid v (Lienard, B . M . R . et ak, Org. Biomol. Chem. 2008, 6, (13), 2282-2292) can be used as a starting point (see Scheme 4 above). Coupling of acid v with 1,3 -DG ii under standard conditions produces TBDPS -protected triglyceride vi, which can be treated with appropriate conditions such as TBAF and AcOH to afford alcohol vii. A two-step oxidation process (for example, PCC, then KMn04) can then be used to transform alcohol vii into the desired acid-TG iv via the intermediate aldehyde viii.
Figure imgf000110_0001
X
Scheme 5. Synthesis of compounds of Formula x wherein -M- is an acetal self- immolative (ASI) group.
[000319] For the synthesis of compounds containing an acetal self-immolative (ASI) group between the pharmaceutical agent and the alkyl spacer, the alcohol-bearing parent molecule must be functionalized and activated prior to conjugation with acid-triglyceride iii as outlined above in Scheme 5. Treatment of an 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 using sulfuryl chloride forms a presumed sulfoxide species that can react with the carboxylate of acid-triglyceride iv to give the target compound x.
Figure imgf000111_0001
Scheme 6. Synthesis of compounds of Formula xii wherein -M- is a carboxyacetal (CASI) or carboxy(methylacetal) (CMSI) self-immolative group.
[000320] In cases where the pharmaceutical agent contains an alcohol, phenol or amine (primary or secondary) functional group, a modified version of the acetal self- immolative group can be used where an additional carboxy group is included. Reaction of the parent drug with a chloroalkyl chloroformate gives chloroalkyl carbonates (shown) or carbamates xi (see Scheme 6 above). Displacement of the halide leaving group is then accomplished by treatment with the carboxylate derived from acid-TG iv in an appropriate solvent such as refluxing toluene to afford the target compound xii.
Figure imgf000112_0001
Scheme 7. Synthesis of compounds of Formula xviii wherein -M- is a trimethyl-lock (TML) self-immolative group.
[000321] For the synthesis of prodrugs containing a trimethyl lock (TML) self- immolative group between the pharmaceutical agent and the alkyl spacer to facilitate systemic release of the parent molecule, the acid- triglyceride iv must be functionalized with the TML moiety priorto conjugation with a pharmaceutical agent as outlined in Scheme 7 above. Coupling of acid-TG iv with TML phenol xiii under standard conditions gives triglyceride xiv, which can be deprotected under acidic conditions (10-camphorsulfonic acid) to give alcohol xv. Sequential oxidation of alcohol xv firstly to aldehyde xvi and then acid xvii, followed by coupling to either an alcohol (shown), amine or sulfonamide-containing pharmaceutical agent under standard conditions can give the target compound xviii.
Figure imgf000113_0002
Figure imgf000113_0001
Scheme 8. Synthesis of compounds of Formula xxiv wherein -M- is a p-hydroxybenzyl carbonyl (PHB) self-immolative group. [000322] For the synthesis of compounds containing a p-hydroxybenzyl (PHB) carbonyl self- immolative group, the primary hydroxyl group of p-hydroxybenzyl alcohol xix is first protected as a silyl ether and the free phenolic hydroxyl group coupled with acid-TG iv to give PHB triglyceride xxi (see Scheme 8 above). After removal of the silicon protecting group, primary alcohol xxii can be activated by treatment with p-nitrophenyl (PNP) chloroformate to give PNP carbonate xxiii. Displacement of the PNP group is then achieved by reaction with a pharmaceutical agent (A-OH shown) under basic conditions to give the desired compound xxiv.
Figure imgf000114_0001
Scheme 9. Synthesis of compounds of Formula xxvii wherein -M- is a flipped-ester self- immolative (FSI) group.
[000323] Without wishing to be bound by theory, it is believed that the flipped-ester self- immolative (FSI) group can liberate the free pharmaceutical agent by a cyclization mechanism, resulting in loss of either a four-carbon (FSI-4) or five-carbon (FSI-5) lactone. Alternatively, liberation of the agent may occur by a chemical or enzymatic mechanism in vivo. FSI prodrugs can be synthesized by coupling the pharmaceutical agent (A-OH shown) with either 4-bromobutyric acid (m = 1) or 5-bromovaleric acid (m = 2) (xxv) to give bromide xxvi (see Scheme 9 above). Displacement of bromide xxvi using the carboxylate derived from acid-TG iv generates the desired ester bond in target compound xxvii.
NMR analysis.
[000324] ¾, 13C, 19F and 31P NMR analyses were conducted on a Bruker™ Avance 400
MHz NMR spectrometer using deuterated chloroform or deuterated dimethyl sulfoxide as solvent. The shift (d) of each signal was measured in parts per million (ppm) relative the residual solvent peak, and the multiplicity reported together with the associated coupling constant (./), where applicable.
UPLC-MS Analysis Methodology.
[000325] UPLC-MS analysis was carried out on a Waters™ Acquity UPLC system consisting of an Acquity I-Class Sample Manager-FL, Acquity I-Class Binary Solvent Manager and an Acquity UPLC Column Manager. UV detection was afforded using an Acquity UPLC PDA detector (scanning from 210 to 400 nm), whilst mass detection was achieved using an Acquity QDa detector (mass scanning from 100-1250 Da; positive and negative modes simultaneously), and ELS detection was achieved using an Acquity UPLC ELS Detector. A Waters™ Acquity UPLC BEH C18 column (2.1 x 50 mm, 1.7 mm) was used to separate the analytes.
Samples were prepared by dissolution (with or without sonication) into 1 mL of 50% (v/v) MeCN in water. The resulting solutions were then filtered through a 0.2 mm syringe filter before submitting for analysis. All of the solvents, including formic acid and 36% ammonia solution, were purchased as the HPLC grade.
Conditions (Acidic 2 min).
[000326] 0.1% v/v Formic acid in water [Eluent A]; 0.1% v/v Formic acid in MeCN
[Eluent B]; flow rate 0.8mL/min; column oven 50 °C; sample manager 20 °C; injection volume 2 mL and 1.5 minutes equilibration time between samples. Gradient parameters are provided in TABLE 2.
TABLE 2
Figure imgf000115_0001
Conditions (Acidic 4 min).
[000327] 0.1% v/v formic acid in water [Eluent A]; 0.1% v/v formic acid in MeCN [Eluent
B]; flow rate 0.8 mL/min; column oven 50 °C; sample manager 20 °C; injection volume 2 mL and 1.5 minutes equilibration time between samples. Gradient parameters are provided in
TABLE 3
TABLE 3
Figure imgf000115_0002
Conditions (Acidic 6 min). [000328] 0.1% v/v formic acid in water [Eluent A]; 0.1% v/v formic acid in MeCN [Eluent
B]; flow rate 0.8 mL/min; column oven 50 °C; sample manager 20 °C; injection volume 2 mL and 1.5 minutes equilibration time between samples. Gradient parameters are provided in
TABLE 4
TABLE 4
Figure imgf000116_0001
Conditions (Basic 2 min).
[000329] 0.1% ammonia in water [Eluent A]; 0.1% ammonia in MeCN [Eluent B]; flow rate 0.8 mL/min; column oven 50 °C; sample manager 20 °C; injection volume 2 mL and 1.5 minutes equilibration time between samples. Gradient parameters are provided in TABLE 5.
TABLE 5
Figure imgf000116_0002
Conditions (Basic 4 min).
0.1% ammonia in water [Eluent A]; 0.1% ammonia in MeCN [Eluent B]; flow rate 0.8 mL/min; column oven 50 °C; sample manager 20 °C; injection volume 2 mL and 1.5 minutes equilibration time between samples. Gradient parameters are provided in TABLE 6.
TABLE 6
Figure imgf000116_0003
Figure imgf000117_0002
Conditions (Basic 6 min).
0.1% ammonia in water [Eluent A]; 0.1% ammonia in MeCN [Eluent B]; flow rate 0.8 mL/min; column oven 50 °C; sample manager 20 °C; injection volume 2 mL and 1.5 minutes equilibration time between samples. Gradient parameters are provided in TABLE 7.
TABLE 7
Figure imgf000117_0003
Example 2: Synthesis of [2-[12-[3-[2-(dimethylamino)ethyl]indol-l-yl]-3,10-dimethyl-12-oxo- dodecanoyl]oxy-3-hexadecanoyloxy-propyl] hexadecanoate (Compound 1-31 (R = H))
Figure imgf000117_0001
Step 1: Step 1: N,N'-Dimethoxy-N,N'-dimethyl-octanediamide
Figure imgf000118_0001
[000330] To a stirred solution of octanedioic acid (5.0 g, 28.7 mmol) in THF (125 mL) at room temperature was added N-O-dimethyl hydroxylamine HCl (10.0 g, 103 mmol), 1,3- dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (19.7 g, 103 mmol), 4- dimethylaminopyridine (4.15 g, 34.0 mmol) and Et3N (23 mL, 161 mmol). The resulting slurry was stirred at room temperature for 20 h, then poured into 1N HCl solution (280mL) (sufficient to achieve pH< 7), and was extracted with EtOAc (3 x 80mL). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel (80g cartridge, Eluent: EtOAc / iso-hexane 0 to 100%) to give N,N'-dimethoxy-N,N'-dimethyl- octanediamide (4.3 g, 58% yield) as an oil. UPLC-MS (Acidic method, 2min): rt 0.87 min, m/z = 261.2 [M+H+]+; 1H NMR (CDCl3) δ 3.67 (d, J = 2.5 Hz, 6H), 3.17 (d, J = 2.5 Hz, 6H), 2.41 (t, J = 7.6 Hz, 4H), 1.64 (q, J = 3.4 Hz, 4H), 1.36 (h, J = 3.2 Hz, 4H). Note: Signal at 1.64ppm overlapping with a water peak. Step 2: Decane-2,9-dione
Figure imgf000118_0002
[000331] To a stirred solution of N,N'-dimethoxy-N,N'-dimethyl-octanediamide (4.30 g, 16.5 mmol) in Et2O (40 mL) cooled to -78 °C under an atmosphere of N2 was added a solution of MeLi (1.6M in Et2O; 26 mL, 41.3 mmol) dropwise. The reaction mixture was allowed to warm to room temperature and stirring was continued for 21 hrs. A saturated solution of NH4Cl (20 mL) was added carefully and the mixture was extracted with EtOAc (3 x 80 mL). The combined organic layers were washed with H2O (80 mL), and brine (80 mL), then dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel (80 g cartridge, Eluent: EtOAc / iso- hexane 0% to 30%) to give decane-2,9-dione (2.14 g, 76% yield) as a solid.1H NMR (CDCl3) δ 2.41 (t, J = 7.4 Hz, 4H), 2.12 (s, 6H), 1.56 (t, J = 7.2 Hz, 4H), 1.37 – 1.17 (m, 4H). Step 3: Diethyl (2E,10E)-3,10-dimethyldodeca-2,10-dienedioate
Figure imgf000119_0001
[000332] To a stirred mixture of NaH, 60% in mineral oil (1.51 g, 37.7 mmol) in THF (40 mL) at 0 °C under an Ar atmosphere was added triethyl phosphonoacetate (7.5 mL, 37.7 mmol) in THF (15 mL) dropwise. The mixture was stirred at 0 °C for 30 min, then decane- 2,9-dione (2.14 g, 12.6 mmol) in THF (15 mL). The mixture was allowed to warm to room temperature and was stirred at room temperature for 2 days. H2O (50 mL) was added, and the mixture was extracted with EtOAc (3 x 70 mL). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel (80 g cartridge, eluent: EtOAc / iso- hexane, 0% to 20%) to give diethyl (2E,10E)-3,10-dimethyldodeca-2,10-dienedioate (3.52 g, 90% yield) as an oil. UPLC-MS (2min, acidic) 1.42-1.43min, m/z = 311 [M+H]+; 1H NMR (CDCl3) δ 5.65 (s, 2H), 4.14 (q, J = 7.2 Hz, 4H), 2.69 – 2.51 (m, 1H), 2.13 (d, J = 8.9 Hz, 8H), 1.87 (s, 1H), 1.46 (q, J = 6.9 Hz, 4H), 1.28 (q, J = 7.4 Hz, 10H). Step 4: Diethyl 3,10-dimethyldodecanedioate
Figure imgf000119_0002
[000333] A mixture of diethyl (2E,10E)-3,10-dimethyldodeca-2,10-dienedioate (3.52 g, 11.3 mmol) and Palladium on activated carbon (Johnson Matthey-type 424; 0.49 g, 4.59 mmol) in EtOAc (50 mL) was stirred under an atmosphere of H2 (balloon) at room temperature for 20 hrs, then filtered through a pad of Celite, and the filter cake washed with EtOAc. The filtrate was concentrated under reduced pressure to give diethyl 3,10- dimethyldodecanedioate (3.50 g, 98% yield) as a solid. UPLC-MS (2 min, acidic): 2.58min, m/z = 315.3 [M+H]+; 1H NMR (CDCl3) δ 4.11 (q, J = 7.1 Hz, 4H), 2.27 (dd, J = 14.6, 6.0 Hz, 2H), 2.07 (dd, J = 14.6, 8.1 Hz, 2H), 1.92 (h, J = 6.7 Hz, 2H), 1.25 (q, J = 7.3, 6.2 Hz, 16H), 0.91 (d, J = 6.6 Hz, 6H). Step 5: 3,10-Dimethyldodecanedioic acid
Figure imgf000119_0003
[000334] To a solution of diethyl 3,10-dimethyldodecanedioate (3.50 g, 11.1 mmol) in THF (25 mL), EtOH (25 mL) and H2O (25 mL) was added NaOH (1.87 g, 46.7 mmol). The reaction mixture was stirred at room temperature for 21 h. The volatile solvents were evaporated and the mixture was then acidified by addition of 1N HCl (until pH acidic) and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give 3,10- dimethyldodecanedioic acid (3.0 g, 100% yield) as a solid.1H NMR (CDCl3) δ 2.34 (dd, J = 15.0, 6.1 Hz, 2H), 2.15 (dd, J = 15.0, 7.9 Hz, 2H), 1.96 (p, J = 6.4 Hz, 2H), 1.41 – 1.13 (m, 12H), 0.96 (d, J = 6.6 Hz, 6H). Step 6: 12-[2-Hexadecanoyloxy-1-(hexadecanoyloxymethyl)ethoxy]-3,10-dimethyl-12-oxo- dodecanoic acid
Figure imgf000120_0001
[000335] To a stirred solution of 1,3-dihexadecanoylglycerol (250 mg, 0.44 mmol) and 3,10-dimethyldodecanedioic acid (193 mg, 0.75 mmol) in DCM (3.5 mL) was added 4- dimethylaminopyridine (91 mg, 0.75 mmol) followed by N-[3-(dimethylamino)propyl]-N'- ethyl-formamidine hydrochloride (286 mg, 1.49 mmol). The mixture was stirred at room temperature for 22 hrs, then the mixture was concentrated under reduced pressure and the crude residue was purified by column chromatography on silica gel (12 g cartridge, eluent: MeOH in DCM 0% to 5%) to give 12-[2-hexadecanoyloxy-1- (hexadecanoyloxymethyl)ethoxy]-3,10-dimethyl-12-oxo-dodecanoic acid (258 mg, 73% yield) as a solid.1H NMR (CDCl3) δ 5.33 – 5.20 (m, 1H), 4.29 (dd, J = 11.9, 4.3 Hz, 2H), 4.14 (dd, J = 12.0, 6.0 Hz, 2H), 2.41 – 2.25 (m, 6H), 2.21 – 2.04 (m, 2H), 2.03 – 1.87 (m, 2H), 1.61 (q, J = 7.1 Hz, 4H), 1.26 (d, J = 7.0 Hz, 57H), 0.95 (dd, J = 13.8, 6.7 Hz, 6H), 0.88 (t, J = 6.7 Hz, 5H). Step 7: [2-(12-Chloro-3,10-dimethyl-12-oxo-dodecanoyl)oxy-3-hexadecanoyloxy-propyl] hexadecanoate
Figure imgf000120_0002
[000336] Oxalyl chloride (0.32 mL, 3.7 mmol) was added dropwise to a solution of 12-[2- hexadecanoyloxy-1-(hexadecanoyloxymethyl)ethoxy]-3,10-dimethyl-12-oxo-dodecanoic acid (1.0 g, 1.24 mmol) in DCM (10 mL) under an atmosphere of N2 at rt followed by DMF (1 drop). The mixture was stirred at room temperature for 18 hrs, then concentrated under reduced pressure and the crude product was used directly in the next step without further purification. Step 8: [2-[12-[3-[2-(dimethylamino)ethyl]indol-1-yl]-3,10-dimethyl-12-oxo-dodecanoyl]oxy-3-
Figure imgf000121_0001
[000337] To a stirred solution of 2-(1H-indol-3-yl)-N,N-dimethylethanamine (300 mg, 1.59 mmol) in THF (10 mL) at -78 °C under at atmosphere of N2 was added NaHMDS (2M solution in THF, 0.88 mL, 0.2 mmol). After stirring at -78 °C for 30 min, crude [2-(12-chloro- 3,10-dimethyl-12-oxo-dodecanoyl)oxy-3-hexadecanoyloxy-propyl] hexadecanoate (1.19 g, 1.43 mmol) dissolved in THF (10 mL). The reaction mixture was allowed to warm to room temperature and stirred for 19 hrs. H2O was added and the mixture was extracted with DCM (x 2). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel (eluent: MeOH in DCM, from 0:1 to 1:19) to afford a mixture of the desired product and 12-[2-hexadecanoyloxy-1-(hexadecanoyloxymethyl)ethoxy]-3,10- dimethyl-12-oxo-dodecanoic acid. The mixture was purified further by SCX-2 column. The crude product was loaded onto the SCX-2 column as a solution with 20% MeOH in DCM + 1% AcOH and the acid was eluted by washing the column with 20% MeOH in DCM (10 mL). The desired product was eluted with 20% MeOH in DCM + 1% Et3N to give [2-[12-[3-[2- (dimethylamino)ethyl]indol-1-yl]-3,10-dimethyl-12-oxo-dodecanoyl]oxy-3-hexadecanoyloxy- propyl] hexadecanoate (190 mg, 12% yield). UPLC (5 min, acidic, LIPO_DSM method): rt = 3.28 min, m/z = 979.8 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 8.47 (d, J = 8.1 Hz, 1H), 7.53 (d, J = 7.7 Hz, 1H), 7.39 – 7.32 (m, 1H), 7.29 (d, J = 5.7 Hz, 2H), 5.27 (s, 1H), 4.29 (dd, J = 11.9, 4.2 Hz, 2H), 4.14 (dd, J = 12.0, 6.0 Hz, 2H), 2.86 (dt, J = 11.4, 6.6 Hz, 3H), 2.66 (dt, J = 11.8, 7.7 Hz, 3H), 2.55 (d, J = 7.2 Hz, 1H), 2.34 (s, 6H), 2.30 (t, J = 7.4 Hz, 5H), 2.26 – 2.16 (m, 1H), 2.13 (d, J = 8.3 Hz, 1H), 1.93 (s, 1H), 1.59 (q, J = 7.6 Hz, 8H), 1.26 (d, J = 8.6 Hz, 59H), 1.04 (t, J = 6.2 Hz, 5H), 0.97 – 0.83 (m, 10H). Example 3: Synthesis of [2-[12-[3-[2-(dimethylamino)ethyl]-5-methoxy-indol-l-yl]-3,10-dimethyl- 12-oxo-dodecanoyl]oxy-3-hexadecanoyloxy-propyl] hexadecanoate (Compound 1-31 (R = MeO))
Figure imgf000122_0001
[000338] To a stirred solution of 2-(5-methoxy- l//-indol-3-yl)-Af,Af-dimethyl-ethanamine (348 mg, 1.59 mmol) in THF (10 mL) cooled at -78 °C under an atmosphere of N2 was added NaHMDS (1M solution in THF, 1.75 mL, 1.75 mmol). After stirring for ~30min, crude [2- ( 12-chloro-3 , 10-dimethyl- 12-oxo-dodecanoyl)oxy-3 -hexadecanoyloxy -propyl] hexadecanoate (1.19 g, 1.43 mmol) dissolved in THF (10 mL) was added and the mixture allowed to warm to room temperature and stirred for 19 hrs. The crude material was first purified by automated column chromatography on silica gel (eluent: MeOH in DCM, from 0: 1 to 1 : 19). Further purification by ion exchange chromatography was performed using an SCX-2 column loading the cartridge with the mixture of product in 20% MeOH in DCM + 1% AcOH. Acidic impurities were removed by flushing with 20% MeOH in DCM then eluting the desired product with 20% MeOH in DCM + 1% Et3N to give [2-[12-[3-[2-(dimethylamino)ethyl]-5- methoxy-indol-l-yl]-3,10-dimethyl-12-oxo-dodecanoyl]oxy-3-hexadecanoyloxy-propyl] hexadecanoate (103 mg, 6% yield) as a solid. UPLC (5 min, acidic, LIPO DSM method): rt = 3.02 min, m/z = 1009.8 [M+H]+; ¾NMR (400 MHz, CDCh) d 8.30 (d, J= 8.9 Hz, 1H), 7.26 (1H is under CDCh peak), 6.91 (d, J= 2.5 Hz, 1H), 6.88 (dd, J= 8.9, 2.6 Hz, 1H), 5.25 - 5.16 (m, 1H), 4.22 (dd, J= 12.0, 4.5 Hz, 2H), 4.07 (dd, J= 12.0, 6.0 Hz, 2H), 3.80 (s, 3H), 2.82 - 2.71 (m, 3H), 2.56 (ddd, J= 10.2, 7.9, 3.9 Hz, 3H), 2.27 (s, 6H), 2.23 (t, J= 7.5 Hz, 5H), 2.12 (d, J= 7.4 Hz, 1H), 2.05 (dd, J= 14.7, 8.4 Hz, 1H), 1.86 (s, 1H), 1.53 (t, J= 7.3 Hz, 5H), 1.18 (s, 61H), 0.96 (d, J= 6.6 Hz, 4H), 0.86 (d, J= 6.6 Hz, 3H), 0.83 - 0.79 (m, 6H).
Example 4: Synthesis of [2-[12-[3-[2-(dimethylamino)ethyl]indol-l-yl]-3,ll-dimethyl-12-oxo- dodecanoyl]oxy-3-hexadecanoyloxy-propyl] hexadecanoate (Compound 1-32 (R = H))
Figure imgf000123_0001
Step 1: [2-(12-chloro-3,11-dimethyl-12-oxo-dodecanoyl)oxy-3-hexadecanoyloxy-propyl] hexadecanoate
Figure imgf000123_0002
[000339] Oxalyl chloride (0.061 mL, 0.73 mmol) was added dropwise to a solution of 12- [2-hexadecanoyloxy-1-(hexadecanoyloxymethyl)ethoxy]-2,10-dimethyl-12-oxo-dodecanoic acid (196 mg, 0.24 mmol) and DMF (1 drop) in DCM (2 mL) at room temperature under an atmosphere of N2. The mixture was stirred at room temperature for 2 hrs, and then concentrated under reduced pressure and the crude product was used directly in the next step without further purification.1H NMR (400 MHz, CDCl3) δ 5.29 – 5.23 (m, 1H), 4.29 (ddd, J = 11.9, 4.3, 0.8 Hz, 2H), 4.14 (ddd, J = 11.8, 6.0, 0.8 Hz, 2H), 2.92 – 2.80 (m, 1H), 2.37 – 2.26 (m, 5H), 2.12 (dd, J = 14.7, 8.2 Hz, 1H), 2.00 – 1.88 (m, 1H), 1.86 – 1.74 (m, 1H), 1.65 – 1.57 (m, 5H), 1.39 – 1.15 (m, 63H), 0.93 (d, J = 6.6 Hz, 3H), 0.92 – 0.76 (m, 6H).
Figure imgf000123_0003
[000340] To a stirred solution of 2-(1H-indol-3-yl)-N,N-dimethylethanamine (50 mg, 0.266 mmol) in THF (1 mL) at -78 °C under an atmosphere of N2 was added NaHMDS (1M in THF, 0.30 mL, 0.3 mmol). After stirring at -78 °C for ~30min, a solution of crude [2-(12- chloro-3, 11 -dimethyl- 12-oxo-dodecanoyl)oxy-3-hexadecanoyloxy-propyl] hexadecanoate (200 mg, 0.24 mmol) dissolved in THF (1 mL) was added and the mixture allowed to warm to room temperature and stirred for 19 hrs, then concentrated under reduced pressure. The crude residue was purified by SCX column (2g), loading with 20% MeOH v/v in DCM (+2% AcOH) and eluting with 20% MeOH v/v in DCM (+2% AcOH) and finally 20% MeOH v/v in DCM (+1% Et3N). The elutions of both the acidic and basic were purified separately by automated column chromatography on silica gel (20 g cartridge) [Eluent: MeOH (0% to 5%; v/v) in DCM] with each column giving fractions containing the desired product. The two portions were combined in CDCh and concentrated to dryness to afford the desired product [2-[12-[3-[2-(dimethylamino)ethyl]indol-l-yl]-3,l l-dimethyl-12-oxo- dodecanoyl]oxy-3-hexadecanoyloxy-propyl] hexadecanoate (175 mg, 71% yield) as an oil. UPLC-MS analysis (4 min, acidic LIPO DSM): rt = 2.89 min, m/z = 979.8 [M+H]+; 1HNMR (400 MHz, CDCh) d 8.51 (d, J= 8.2 Hz, 1H), 7.55 (d, J= 7.7 Hz, 1H), 7.45 (s, 1H), 7.38 (t, J = 7.8 Hz, 1H), 7.31 (t, 7= 7.4 Hz, 1H), 5.30 - 5.23 (m, 1H), 4.28 (dd, 7= 11.9, 4.3 Hz, 2H), 4.14 (dd, J = 12.0, 6.0 Hz, 2H), 3.30 - 3.03 (m, 5H), 2.72 (s, 6H), 2.36 - 2.26 (m, 5H), 2.16 - 2.07 (m, 1H), 1.95 - 1.84 (m, 1H), 1.66 - 1.56 (m, 5H), 1.44 - 1.09 (m, 63H), 0.91 (d, J = 6.5 Hz, 3H), 0.88 (t, J = 6.7 Hz, 6H).
Example 5: Synthesis of [2-[12-[3-[2-(dimethylamino)ethyl]-5-methoxy-indol-l-yl]-3,ll- dimethyl-12-oxo-dodecanoyl] oxy-3-hexadecanoyloxy-propyl] hexadecanoate (Compound 1-32 (R = MeO))
Figure imgf000124_0001
[000341] [2-[12-[3-[2-(dimethylamino)ethyl]-5-methoxy-indol-l-yl]-3,l 1 -dimethyl- 12- oxo-dodecanoyl]oxy-3-hexadecanoyloxy-propyl] hexadecanoate was synthesized by analogous methods to those de-scribed for [2-[12-[3-[2-(dimethylamino)ethyl]indol-l-yl]- 3,l l-dimethyl-12-oxo-dodecanoyl]oxy-3-hexadecanoyloxy-propyl] hexadecanoate to afford the title compound (126 mg, 48% yield) as a solid. UPLC-MS analysis (4 min, acidic lipo method): m/z = 1009.9 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 8.39 (d, J = 9.1 Hz, 1H), 7.41 (s, 1H), 7.06 (d, J = 2.5 Hz, 1H), 6.98 (dd, J = 9.0, 2.5 Hz, 1H), 5.29 – 5.22 (m, 1H), 4.33 – 4.24 (m, 2H), 4.18 – 4.09 (m, 2H), 3.90 (s, 3H), 3.24 – 3.13 (m, 2H), 3.16 – 3.08 (m, 3H), 2.74 (s, 6H), 2.36 – 2.24 (m, 5H), 2.16 – 2.09 (m, 1H), 1.97 – 1.79 (m, 3H), 1.64 – 1.50 (m, 6H), 1.43 – 1.05 (m, 61H), 0.95 – 0.84 (m, 9H). Example 6: Synthesis of 2-((3-(2-(dimethylamino)ethyl)-5-methoxy-1H-indole-1- carbonyl)oxy)propane-1,3-diyl dipalmitate (Compound I-35 (R = MeO))
Figure imgf000125_0001
Step 1: 2-((chlorocarbonyl)oxy)propane-1,3-diyl dipalmitate
Figure imgf000125_0002
[000342] To 1,3-dipalmitin (250 mg, 0.44 mmol) in anhydrous CH2Cl2 (5 mL) under an atmosphere of N2 was added DMAP (172 mg, 1.41 mmol) followed by triphosgene (48 mg, 0.16 mmol). The mixture was stirred at room temperature for 1 h to give a solution of the chloroformate used directly in the next step. Step 2: 2-((3-(2-(dimethylamino)ethyl)-5-methoxy-1H-indole-1-carbonyl)oxy)propane-1,3-diyl dipalmitate
Figure imgf000125_0003
[000343] To 5-MeO-DMT (48 mg, 0.22 mmol) in DCM (2 mL) at -78 °C under an atmosphere of N2 was added NaHMDS, 1M in THF (440 µL, 0.44 mmol). The mixture was stirred for 30 min at -78 °C, then the above solution of 2-((chlorocarbonyl)oxy)propane-1,3- diyl dipalmitate (0.44 mmol) was added, and the mixture was stirred at -78 °C for 10 min, then warmed to room temperature and stirred overnight. The mixture was quenched with H2O (5 mL), the layers were separated, and the aqueous layer was extracted with DCM (2 x 5 mL). The combined organic layers were washed with H2O (3 x 5 mL) and saturated brine (5 mL), dried (MgSO4), filtered and the filtrate was concentrated to give crude product. This material was purified twice by normal phase column chromatography on silica gel (EtOAc / PE 0:1 to 1:0) to give 2-((3-(2-(dimethylamino)ethyl)-5-methoxy-1H-indole-1-carbonyl)oxy)propane- 1,3-diyl dipalmitate (85 mg, 48%) as an oil. HPLC: 98.3 % purity at 300 nM; m/z = 813.55 [M+H]+ (note: direct injection into the mass spectrometer); 1H NMR (300 MHz, CDCl3) δ 7.92 (br. s, 1H, ArH), 7.29 (br. S, 1H, ArH), 6.94 (d, J = 2.5 Hz, 1H, ArH), 6.86 (dd, J = 9.0, 2.6 Hz, 1H, ArH), 5.41 (m, 1H, CH), 4.33 (m, 4H, 2 × CH2), 3.80 (s, 3H, OMe), 2.80 (m, 2H, CH2), 2.60 (m, 2H, CH2), 2.28 (m, 10H, 2 x NMe and 2 x CH2), 1.52 (m, 4H, 2 x CH2), 1.18 (m, 48H, CH2), 0.80 (m, 6H, 2 x CH3); 13C NMR: (75.5 MHz, CDCl3) δ 173.3, 158.2, 156.3, 116.1, 102.1, 77.2, 62.0, 58.8, 55.8, 45.3, 37.9, 34.1, 31.9, 29.7, 29.7, 29.6, 29.4, 29.4, 29.3, 29.1, 24.9, 22.7, 14.1. Example 7: Synthesis of 2-((3-(2-(dimethylamino)ethyl)-1H-indole-1- carbonyl)oxy)propane-1,3-diyl dipalmitate (Compound I-35 (R = H))
Figure imgf000126_0001
[000344] To DMT (41 mg, 0.22 mmol) in DCM (2 mL) at -78 °C under an atmosphere of N2 was added NaHMDS, 1M in THF (440 µL, 0.44 mmol). The mixture was stirred for 30 min at -78 °C, then a solution of 2-((chlorocarbonyl)oxy)propane-1,3-diyl dipalmitate (0.44 mmol) was added, and the mixture was stirred at -78 °C for 10 min, then warmed to room temperature and stirred overnight. The mixture was quenched with H2O (5 mL), the layers were separated, and the aqueous layer was extracted with DCM (2 x 5 mL). The combined organic layers were washed with H2O (3 x 5 mL) and saturated brine (5 mL), dried (MgSO4), filtered and the filtrate was concentrated under reduced pressure. The crude residue was purified by normal phase column chromatography on silica gel (EtOAc / PE, 0:1 to 1:0) to give 2-((3-(2-(dimethylamino)ethyl)-1H-indole-1-carbonyl)oxy)propane-1,3-diyl dipalmitate (91 mg, 54%) as an oil. HPLC: 97.1 % purity at 257 nM; m/z = 783.65 [M+H]+ (note: direct injection into the mass spectrometer); 1H NMR (300 MHz, CDCl3) δ 8.04 (br. s, 1H, ArH), 7.48 (br. m, 1H, ArH), 7.26 (m, 3H, 3 x ArH), 5.44 (m, 1H, CH), 4.33 (m, 4H, 2 x CH2), 2.83 (m, 2H, CH2), 2.61 (m, 2H, CH2), 2.26 (m, 10H, 2 x NMe and 2 x CH2), 1.51 (m, 4H, 2 x CH2), 1.18 (m, 48H, CH2), 0.80 (m, 6H, 2 x CH3); 13C NMR: (75.5 MHz, CDCl3) δ 173.3, 124.8, 123.0, 119.1, 115.3, 108.6, 77.2, 62.0, 59.1, 49.9, 45.5, 34.1, 31.9, 29.7, 29.7, 29.7, 29.6, 29.4, 29.4, 29.2, 29.1, 24.8, 23.5, 22.7, 14.1. Example 8: Synthesis of 2-((4-(3-(2-(dimethylamino)ethyl)-5-methoxy-1H-indol-1-yl)-4- oxobutanoyl)oxy)propane-1,3-diyl dipalmitate (Compound I-15 (R = MeO))
Figure imgf000127_0001
Step 1: 4-((1,3-bis(palmitoyloxy)propan-2-yl)oxy)-4-oxobutanoic acid
Figure imgf000127_0002
[000345] To a mixture of 1,3-dipalmitin (288 mg, 0.51 mmol) and succinic anhydride (151 mg, 1.52 mmol) in THF (2 mL) pyridine (2 mL) and DCM (2 mL), was added DMAP (62 mg, 0.51 mmol). The mixture was heated to 40 °C and stirred for 22 h. The mixture was diluted with EtOAc (25 mL) and the organic phase was washed with 1M HCl (25 mL), H2O (25 mL), saturated brine (25 mL), dried (MgSO4), filtered and the filtrate was concentrated. to give 4- ((1,3-bis(palmitoyloxy)propan-2-yl)oxy)-4-oxobutanoic acid (326 mg, 94%) as a solid. m/z = 667.50 [M-H]+ (note: direct injection into the mass spectrometer); 1H NMR (300 MHz, CDCl3) δ 5.21 (m, 1H, CH), 4.24 (dd, J = 12.0, 4.2 Hz, 2H, CH2), 4.08 (dd, J = 12.0, 5.7 Hz, 2H, CH2), 2.61 (m, 4H, 2 x CH2), 2.24 (t, J = 7.5 Hz, 4H, 2 x CH2), 1.54 (m, 4H, 2 ×CH2), 1.18 (m, 48H, CH2), 0.80 (m, 6H, 2 x CH3). Step 2: 2-((4-chloro-4-oxobutanoyl)oxy)propane-1,3-diyl dipalmitate
Figure imgf000128_0001
[000346] To a mixture of 4-((1,3-bis(palmitoyloxy)propan-2-yl)oxy)-4-oxobutanoic acid (50 mg, 0.07 mmol) in anhydrous THF (5 mL) and anhydrous DMF (10 mL) was added oxalyl chloride (0.5 mL, 6.0 mmol) and the mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo to give 2-((4-chloro-4-oxobutanoyl)oxy)propane-1,3-diyl dipalmitate, which was used without purification. Step 3: 2- 3-(2-(dimethylamino)ethyl)-5-methoxy-1H-indol-1-yl)-4- oxobutanoyl)oxy)propane-1,3-diyl dipalmitate
Figure imgf000128_0002
[000347] To 5-MeO-DMT (176 mg, 0.80 mmol) in anhydrous THF (5 mL) under an atmosphere of N2 at °C added NaHMDS, 1M in THF (800 ^L, 0.80 mmol) and the mixture was stirred at -78 °C for 30 min.2-((4-Chloro-4-oxobutanoyl)oxy)propane-1,3-diyl dipalmitate (0.40 mmol) in anhydrous THF (5 mL) was added and the mixture was stirred at - 78 °C for 10 min. NaI (50 mg, 0.3 mmol) was added and the mixture was warmed to room temperature and stirred for an additional 24 h, then quenched with H2O (1 mL) and concentrated to give an oil. The residue was dissolved in DCM (25 mL) and the resulting mixture was washed with H2O (3 x 25 mL), saturated brine (25 mL), dried (MgSO4), filtered and the filtrate was concentrated under reduced pressure. The residue was purified twice by column chromatography on silica gel (MeOH / EtOAc 0:1 to 1:1) to give the product in approximately 90 % purity by 1H NMR. This material was combined with other batches and purified by chromatography on a Biotage Sfär KP-NH column (MeOH / EtOAc 0:1 to 1:1) to give the product (38 mg) as a solid. m/z = 869.60 [M+H]+ (note: direct injection into the mass spectrometer); 1H NMR (300 MHz, CDCl3) δ 8.30 (d, J = 7.8 Hz, 1H, ArH), 7.30 (br. s, 1H, ArH), 6.95 (m, 2H, ArH), 5.32 (m, 1H, CH), 4.34 (dd, J = 12.0, 4.2 Hz, 2H, CH2), 4.19 (dd, J = 12.0, 5.7 Hz, 2H, CH2), 3.87 (s, 3H, OCH3), 3.23 (t, J = 6.6 Hz, 2H, CH2), 2.85 (m, 4H, CH2), 2.64 (m, 2H, CH2), 2.33 (m, 8H, NMe2 and CH2), 1.60 (m, 12H, 6 x CH2), 1.18 (m, 42H, 21 x CH2), 0.89 (m, 6H, 2 x CH3). Example 9: Synthesis of 2-((4-(3-(2-(dimethylamino)ethyl)-1H-indol-1-yl)-4- oxobutanoyl)oxy)propane-1,3-diyl dipalmitate (Compound I-15 (R = H))
Figure imgf000129_0001
[000348] To DMT (275 mg, 1.46 mmol) in anhydrous THF (5 mL) at room temperature under an atmosphere of N2 was added NaHMDS, 1M in THF (1.1 mL, 1.60 mmol) and the mixture was stirred 30 min.2-((4-Chloro-4-oxobutanoyl)oxy)propane-1,3-diyl dipalmitate (1.00 g, 1.46 mmol) in anhydrous THF (10 mL) was added and the mixture was stirred at room temperature overnight, then concentrated under reduced pressure, dissolved in DCM (60 mL) and the resulting mixture was washed with saturated aqueous sodium bicarbonate (70 mL), saturated brine (25 mL), dried (MgSO4), filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc / PE, 0:1 to 1:0), followed by purification by column chromatography on silica gel (MeOH / EtOAc, 0:1 to 1:1) to give the product (100 mg) as a solid. TLC: Rf = 0.07 (EtOAc - MeOH, 4 : 1 v/v); m/z = 839.60 [M+H]+ (note: direct injection into the mass spectrometer). Example 10: Synthesis of 2-((6-(3-(2-(dimethylamino)ethyl)-5-methoxy-1H-indol-1-yl)-6- oxohexanoyl)oxy)propane-1,3-diyl dipalmitate (Compound I-1 (R = MeO))
Figure imgf000129_0002
Step 1: 6-((1,3-bis(palmitoyloxy)propan-2-yl)oxy)-6-oxohexanoic acid
Figure imgf000130_0001
[000349] To a mixture of 1,3-dipalmitin (1.00 g, 1.76 mmol) in pyridine (1.4 mL) and DCM (30 mL) was added adipoyl chloride (1.60 g, 1.30 mL, 1.52 mmol) and the mixture was stirred at 55 °C for 3.5 h. The mixture was diluted with EtOAc (200 mL) and the organic phase was washed with 1M HCl (200 mL), saturated brine (2 x 200 mL), dried (MgSO4), filtered and the filtrate was concentrated under reduced pressure. The residue was entrained into petrol (3 x 20 mL) at 55 °C and the combined extracts were concentrated to give 6-((1,3- bis(palmitoyloxy)propan-2-yl)oxy)-6-oxohexanoic acid (1.51 g, 100 %) as a solid. m/z = 695.50 [M-H]+ (note: direct injection into the mass spectrometer); 1H NMR (300 MHz, CDCl3) δ 5.18 (m, 1H, CH), 4.16 (m, 4H, 2 x CH2), 2.38 (m, 8H, 4 x CH2), 1.59 (m, 12H, 6 x CH2), 1.19 (obscured m, 44H, 22 x CH2), 0.81 (m, 6H, 2 x CH3). Step 2: 2-((6-chloro-6-oxohexanoyl)oxy)propane-1,3-diyl dipalmitate
Figure imgf000130_0002
[000350] To a mixture of 6-((1,3-bis(palmitoyloxy)propan-2-yl)oxy)-6-oxohexanoic acid (0.5 g, 0.72 mmol) in anhydrous THF (10 mL) was added oxalyl chloride (8.2 g, 5.45 mL, 64.6 mmol) and the mixture was stirred at room temperature overnight, then concentrated in vacuo to give 2-((6-chloro-6-oxohexanoyl)oxy)propane-1,3-diyl dipalmitate as a residue, which was used without purification. Step 3: 2- 3-(2-(dimethylamino)ethyl)-5-methoxy-1H-indol-1-yl)-6- oxohexanoyl)oxy)propane-1,3-diyl dipalmitate
Figure imgf000130_0003
[000351] To a mixture of 5-MeO-DMT (314 mg, 1.44 mmol) in anhydrous THF (10 mL) at -78 °C under an atmosphere of N2 was added NaHMDS, 1M in THF (1.73 mL, 1.73 mmol) and the mixture was stirred at -78 °C for 30 min.2-((6-Chloro-6-oxohexanoyl)oxy)propane- 1,3-diyl dipalmitate (1.44 mmol) in anhydrous THF (5 mL) was added and the mixture was stirred at -78 °C for 10 min. NaI (32 mg, 0.22 mmol) was added and the mixture was warmed to room temperature and stirred for 24 h. The mixture was concentrated to give a residue, which was taken up in DCM (150 mL) and washed with saturated aqueous sodium carbonate (150 mL), H2O (2 x 150 mL), saturated brine (150 mL), dried (MgSO4), filtered and the filtrate was concentrated under reduced pressure to give a semi-solid. This material was purified by column chromatography on silica gel (EtOAc / PE, 0:1 to 1:0), followed by purification by column chromatography on silica gel (MeOH / EtOAc, 0:1 to 1:1) to give the product (55 mg) as an oil. TLC: Rf = 0.07 (EtOAc - MeOH, 4 : 1 v/v); m/z = 897.60 [M+H]+ (note: direct injection into the mass spectrometer). Example 11: Synthesis of 2-((6-(3-(2-(dimethylamino)ethyl)-1H-indol-1-yl)-6- oxohexanoyl)oxy)propane-1,3-diyl dipalmitate (Compound I-1 (R = H))
Figure imgf000131_0001
[000352] To a mixture of DMT (271 mg, 1.44 mmol) in anhydrous THF (10 mL) at -78 °C under an atmosphere of N2 was added NaHMDS, 1M in THF (1.73 mL, 1.73 mmol) and the mixture was stirred at -78 °C for 30 min.2-((6-Chloro-6-oxohexanoyl)oxy)propane-1,3-diyl dipalmitate (0.72 mmol) in anhydrous THF (5 mL) was added and the mixture was stirred at - 78 °C for 10 min. NaI (32 mg, 0.22 mmol) was added and the mixture was warmed to room temperature and stirred for 24 h, then concentrated to give a residue, which was taken up in DCM (150 mL) and washed with saturated aqueous sodium carbonate (150 mL), H2O (2 x 150 mL), saturated brine (150 mL), dried (MgSO4), filtered and the filtrate was concentrated under reduced pressure. This material was purified by column chromatography on silica gel (EtOAc / PE, 0:1 to 1:0), followed by purification by column chromatography on silica gel (MeOH / EtOAc, 0:1 to 1:1) to give the product (27 mg) as an oil. TLC: Rf = 0.15 (EtOAc - MeOH, 4 : 1 v/v); m/z = 867.60 [M+H]+ (note: direct injection into the mass spectrometer). Example 12: Synthesis of 1-(1,3-bis(palmitoyloxy)propan-2-yl) 5-(1-((3-(2- (dimethylamino)ethyl)-1H-indole-1-carbonyl)oxy)ethyl) 3-methylpentanedioate (Compound I-16 (R = H))
Figure imgf000132_0001
Step 1: 1-(1,3-Bis(palmitoyloxy)propan-2-yl) 5-(1-(((ethylthio)carbonyl)oxy)ethyl) 3- methylpentanedioate
Figure imgf000132_0002
[000353] O-(1-chloroethyl) S-ethyl carbonothioate (128 mg, 0.76 mmol) was dissolved in DMF (1.3 mL) and K2CO3 (0.53 g, 3.82 mmol) was added. The mixture was stirred for 30 min before 5-((1,3-bis(palmitoyloxy)propan-2-yl)oxy)-3-methyl-5-oxopentanoic acid (326 mg, 0.45 mmol) in DMF (1.5 mL) was added and the resulting mixture was heated to 100 °C and stirred for 2 h. The mixture was diluted with H2O (5 mL) and extracted with EtOAc (3 x 5 mL). The combined organic layers were dried (MgSO4), filtered and the filtrate was concentrated under reduced pressure. This material was purified by column chromatography on silica gel (EtOAc / PE, 0:1 to 1:0) to give 1-(1,3-bis(palmitoyloxy)propan-2-yl) 5-(1- (((ethylthio)carbonyl)oxy)ethyl) 3-methylpentanedioate (329 mg, 88%) as an oil.1H NMR (300 MHz, CDCl3) δ 6.97 (q, J = 5.5 Hz, 1H, CH), 5.29 (m, 1H, CH), 4.33 (dd, J = 12.0, 4.2 Hz, 2H, CH2), 4.16 (dd, J = 11.9, 6.1 Hz, 2H, CH2), 2.88 (m, 2H, CH2), 2.38 (m, 8H, 4 x CH2), 1.56 (m, 12H, 6 x CH2), 1.19 (obscured m, 47H, CH and 23 x CH2), 1.06 (d, J = 6.0 Hz, 3H, CH3), 0.90 (m, 6H, 2 x CH3). Step 2: 1-(1,3-bis(palmitoyloxy)propan-2-yl) 5-(1-((chlorocarbonyl)oxy)ethyl) 3- methylpentanedioate
Figure imgf000132_0003
[000354] To a mixture of 1-(1,3-bis(palmitoyloxy)propan-2-yl) 5-(1- (((ethylthio)carbonyl)oxy)ethyl) 3-methylpentanedioate (165 mg, 0.20 mmol) in DCM (3 mL) at 0 °C was added sulfuryl chloride (68 mg, 40 ^L, 0.50 mmol). The mixture was warmed to room temperature and stirred for 3 h, then the solvent was removed under reduced pressure to give 1-(1,3-bis(palmitoyloxy)propan-2-yl) 5-(1-((chlorocarbonyl)oxy)ethyl) 3- methylpentanedioate (208 mg) which was used without purification. (Note: an aliquot was quenched with methanol and analysed by MS; m/z = 821.50, consistent for protonated parent ion of methanol adduct [M+Na]+, direct injection into the mass spectrometer). Step 3: 1-(1,3-bis(palmitoyloxy)propan-2-yl) 5-(1-((3-(2-(dimethylamino)ethyl)-1H-indole-1- carbonyl)oxy)ethyl) 3-methylpentanedioate
Figure imgf000133_0001
[000355] To a mixture of DMT (75 mg, 0.40 mmol) in anhydrous THF (3 mL) at 0 °C under an atmosphere of N2 was added NaHMDS, 1M in THF (0.48 mL, 0.48 mmol) and the mixture was stirred at 0 °C for 30 min.1-(1,3-bis(palmitoyloxy)propan-2-yl) 5-(1- ((chlorocarbonyl)oxy)ethyl) 3-methylpentanedioate (160 mg, 0.20 mmol) in anhydrous THF (1 mL) was added the mixture was warmed to room temperature and stirred for 24 h, then concentrated under reduced pressure to give a residue containing the title compound (300 mg). LC-MS: Rt = 0.45 min; m/z = 955.60 [M+H]+. Example 13: Synthesis of 1-(1,3-bis(palmitoyloxy)propan-2-yl) 5-(1-((3-(2- (dimethylamino)ethyl)-5-methoxy-1H-indole-1-carbonyl)oxy)ethyl) 3-methylpentanedioate (Compound I-16 (R = MeO))
Figure imgf000133_0002
[000356] To a mixture of 5-MeO-DMT (87 mg, 0.40 mmol) in anhydrous THF (3 mL) at 0 °C under an atmosphere of N2 was added NaHMDS, 1M in THF (0.48 mL, 0.48 mmol) and the mixture was stirred at 0 °C for 30 min.1-(1,3-bis(palmitoyloxy)propan-2-yl) 5-(1- ((chlorocarbonyl)oxy)ethyl) 3-methylpentanedioate (160 mg, 0.20 mmol) in anhydrous THF (1 mL) was added and the mixture was warmed to room temperature and stirred for 24 h, then concentrated under reduced pressure to give a residue containing the title compound (594 mg). LC-MS: Rt = 0.45 min; m/z = 985.60 [M+H]+.
Example 14: Pharmacokinetics of selected compounds following a single intravenous or oral administration in rats.
[000357] A pharmacokinetic (PK) study was performed in three male Sprague-Dawley (SD) rats following intravenous (IV) or oral (PO) administration of dimethyltryptamine (DMT), 5-methoxy dimethyltryptamine (5-MeO-DMT), Compound 1-31 at 1 mg/kg (IV) or 10 mg/kg (PO).
IN VIVO METHODS.
Rat Strain.
[000358] Sprague-Dawley rats were supplied by Charles River (Margate UK) and were specific pathogen free. Male rats weighed between 175 - 225 g on receipt and were allowed to acclimate for 5-7 days.
Animal Housing.
[000359] Rats were group housed in sterilised individual ventilated cages that exposed the animals at all times to HEPA filtered sterile air. Animals had free access to food and water (sterile) and sterile aspen chip bedding (changed at least once weekly). The room temperature was maintained at 22°C +/- 1°C, with a relative humidity of 60% and maximum background noise of 56 dB. Rats were exposed to 12-hour light/dark cycles.
Treatment.
[000360] Each test compound and control (DMT or 5-MeO-DMT) were diluted with 10% v/v DMSO, 40% v/v PEG-400, 50% v/v water. The test compound or the control (DMT or 5- MeO-DMT) were administered in a dose volume of 2 mL/kg for intravenous administration (IV) and 5 mL/kg for oral administration (PO).
Single IV/PO dose pharmacokinetics study in rats.
[000361] Each test compound was administered as a single IV bolus (via a lateral tail-vein) or a single oral gavage in cohorts of 3 rats per administration route. Following dose administrations, a 100 pL whole blood sample (EDTA) was collected via the tail-vein at time- points described in TABLE 8. The blood sample was centrifuged to separate plasma. Approximately 40 pL of the separated plasma was dispensed per time-point, per rat, in a 96 well plate and frozen until analysis. Bioanalysis was carried out on the separated plasma samples. TABLE 8: Sample collection points for single IV and oral dose pharmacokinetics study.
Figure imgf000135_0001
BIO ANAL YSIS METHODS.
DMT Stock Preparation.
[000362] 2.4 mL of DMSO was pipetted into an amber vial containing 2.4 mg salt-free
DMT. The contents were mixed by vortex to provide a -1000 pg/mL standard solution in DMSO.
5-MeO-DMT Stock Preparation.
[000363] 2.5 mL of DMSO was pipetted into amber vial containing 2.5 mg salt-free 5-
MeO-DMT. The contents were mixed by vortex to provide a -1000 pg/mL standard solution in DMSO).
Preparation of calibration and quality control standards.
[000364] Separate calibration curve and QC standards were prepared from individual standard to minimise the chance of MRM crosstalk during analysis. The dilutions were performed as detailed in TABLE 9.
TABLE 9: Preparation of 1 to 5000 ng/mL Cal and QC working solution.
Figure imgf000136_0001
[000365] All samples were diluted to volume with 50:50 methanol/water (v/v) in individual 1.5 mL Eppendorf tubes and mixed by vortexing.
[000366] The control matrix was rat plasma (male Sprague Dawley, EDTA). Calibration and quality control (QC) standards were prepared by spiking control matrix with working solutions containing DMT or 5MeO-DMT.
Dose formulation samples.
[000367] Dose formulation samples were diluted in two steps with 50:50 (v/v) methanol/water to an appropriate concentration, then diluted 10:90 (v/v) with control matrix to match to the calibration standard in plasma.
Sample Extraction procedure.
[000368] Calibration and QC standards, incurred samples, blank matrix and dose formulation samples were extracted by protein precipitation, via the addition of a bespoke acetonitrile (CEECN) -based Internal Standard (IS) solution, containing compounds including Metoprolol and Rosuvastatin, both of which were monitored for during analysis. Following centrifugation, a 40 pL aliquot of supernatant was diluted by the addition of 80 pL water. The prepared sample extracts were analysed by LC-MS/MS. Example Bioanalytical Method and Assay Procedure.
1 According to the plate layout, aliquot to wells in 0.8 mL 96-well plate (Abgene). 30 pL for Calibration, QC standards, blanks and dose formulation check.
2 Prepare Calibration and QC standards according to the assay information. Dilute dose formulation according to the assay information. Aliquot incurred samples according to the plate layout & assay information.
3 Add 90 pL of CH3CN internal standard and vortex mix for 5 minutes at 850 rpm.
4 Centrifuge at nominally 4000 rpm for 10 minutes.
6 Transfer 40 pL of supernatant into a new 0.8 mL Abgene plate.
6 Add 80 pL of water to all transferred supernatant.
7 Vortex mix for 30 seconds at 1400 rpm.
8 Analyse immediately by LC-MS/MS or store at +4 °C until analysis.
[000369] The analysis was performed using the following solvent system and gradient described in TABLE 10.
TABLE 10
Figure imgf000137_0001
Measurement of Concentration of DMT and Compound 1-31 ( ) after IV or oral
Figure imgf000138_0001
administration of Compound 1-31 (R = H)
[000370] The DMT prodrug Compound 1-31 was synthesized according to methods described herein in Example 2 and pharmacokinetic properties were assessed after IV or oral administration in a rat model. The concentration of DMT prodrug Compound 1-31 (R=H) was measured in each rat at various sampling timepoints after IV or oral administration of Compound 1-31 (R =H) to rats. The measured concentrations are summarized in Tables 11 and 12 and are also shown in FIG. 2A (IV administration) and FIG. 2B (PO administration). [000371] Dose formulations were made at equivalent concentrations of active compound adjusted for molecular weight of the prodrug. The 5.28 mg/kg IV and 52.8 mg/kg PO dose formulations were 115% and 114% of their nominal concentrations respectively. The IV dose formulation was a clear solution and the PO dose formulation was a white homogeneous suspension. Nominal doses are used in PK parameter determinations.
Table 11. Summary of DMT Prodrug Compound 1-31 (R=H) cone determined following IV dosing to male Sprague Dawley rat at 5.28 mg/kg
Figure imgf000138_0002
Table 12. Summary of DMT Prodrug Compound 1-31 (R=H) cone determined following PO dosing to male Sprague Dawley rat at 52.8 mg/kg
Figure imgf000138_0003
[000372] Effective half-life has been calculated for animal 2 due to a two compartmental profile. Half-life and related parameters could not be calculated for animal 3 due to poor r2 fitting. [000373] Following IV administration at 5.28 mg/kg a C0 of 459 ± 52.2 ng/mL was measured, Clast of 5.66 ± 1.80 ng/mL, AUC0-2h of 77.7 ± 31.8 ng.hr/mL, half-life of 0.407 h and CL = 1050 mL/min/kg. Half-life and related parameters could not be calculated for all animals due to too few data points after the Cmax. [000374] Following PO administration at 52.8 mg/kg a Cmax of 92.7 ± 52.9 ng/mL was measured at tmax 2.00 h, Clast of 65.4 ± 49.0 ng/mL and AUC0-2h of 101 ± 47.0 ng.hr/mL. [000375] AUC0-t was recalculated for Tlast=2h in order to determine bioavailability. Bioavailability determined using AUC0-2h was 13.0 ± 6.05%. [000376] The concentration of DMT was also measured in each rat at various sampling timepoints after IV or oral administration of Compound I-31 (R =H) to rats. The measured concentrations are summarized in Tables 13 and 14 and are also shown in FIG.3A (IV administration) and FIG.3B (PO administration). Table 13. Summary of DMT conc. determined following IV administration of DMT Prodrug Compound I-31 (R=H) to male Sprague Dawley rat at 5.28 mg/kg (Equivalent to 1 mg/kg of DMT)
Figure imgf000139_0001
BLQ: below lower limit of quantification (0.5 ng/mL) Table 14. Summary of DMT conc. determined following PO administration of DMT Prodrug Compound I-31 (R=H) to male Sprague Dawley rat at 52.8 mg/kg (Equivalent to 10 mg/kg of DMT)
Figure imgf000139_0002
Figure imgf000140_0001
BLQ: below lower limit of quantification (0.5 ng/mL)
[000377] IV leg animals dosed with 5.28 mg/kg of DMT Prodrug Compound 1-31 (R=H) which, when adjusted for molecular weight, is equivalent to 1 mg/kg of DMT. Following IV administration at equivalent to 1 mg/kg a DMT Cmax of 8.94 ± 1.73 ng/mL was measured at tmax 0.0833 h, Clast of 1.91 ± 0.315 ng/mL and AUCO-t of 8.66 ± 3.71 ng.hr/mL. IV administration PK profiles for the DMT Prodrug Compound 1-31 demonstrated a substantial improvement in the length of systemic bioavailability of the DMT metabolite and reduced first pass metabolism of the prodrug.
[000378] PO leg animals dosed with 52.8 mg/kg of DMT Prodrug Compound 1-31 (R=H) which, when adjusted for molecular weight, is equivalent to 10 mg/kg of DMT. Following PO administration at equivalent to 10 mg/kg a DMT Cmax of 15.6 ± 6.08 ng/mL was measured at tmax 4.00 h, Ciast of 7.86 ± 2.55 ng/mL and AUCo-t of 68.0 ± 17.9 ng.hr/mL. PO administration PK profiles for the DMT Prodrug Compound 1-31 demonstrated a substantial improvement in the length of systemic bioavailability of the DMT metabolite and reduced first pass metabolism of the prodrug.
Measurement of Concentration of 5-MeO-DMT and Compound 1-31 (R=MeO) after IV or oral administration of Compound 1-31 (R=MeO)
[000379] The 5-MeO-DMT prodrug Compound 1-31 was synthesized according to methods described herein in Example 3 and pharmacokinetic properties were assessed after IV or oral administration in a rat model. The concentration of 5-MeO-DMT prodrug Compound 1-31 (R=MeO) was measured in each rat at various sampling timepoints after IV or oral administration of Compound 1-31 (R =MeO) to rats. The measured concentrations are summarized in Tables 15 and 16 and are also shown in FIG. 4A (IV administration) and FIG. 4B (PO administration).
[000380] Dose formulations were made at equivalent concentrations of active adjusted for molecular weight of the pro-drug. The 4.69 mg/kg IV and 46.9 mg/kg PO dose formulations were 119% and 140% of their nominal concentrations respectively. Both dose formulations were clear solutions. Nominal doses are used in PK parameter determinations. Table 15. Summary of DMT Prodrug Compound 1-31 (R=MeO) cone determined following IV dosing to male Sprague Dawley rat at 4.69 mg/kg
Figure imgf000141_0001
BLQ: below lower limit of quantification (0.5 ng/mL)
Table 16. Summary of DMT Prodrug Compound 1-31 (R=MeO) cone determined following PO dosing to male Sprague Dawley rat at 46.9 mg/kg
Figure imgf000141_0002
[000381] The concentration of 5-MeO-DMT was also measured in each rat at various sampling timepoints after IV or oral administration of Compound 1-31 (R =MeO) to rats. The measured concentrations are summarized in Tables 17 and 18 and results of IV administration are also shown in FIG. 5.
Table 17. Summary of 5-MeO-DMT cone determined following IV administration of DMT Prodrug Compound 1-31 (R=MeO) to male Sprague Dawley rat at 4.69 mg/kg (Equivalent to 1 mg/kg of 5-MeO-DMT)
Figure imgf000141_0003
Figure imgf000142_0001
Table 18. Summary of 5-MeO-DMT cone determined following PO administration of DMT Prodrug Compound 1-31 (R=MeO) to male Sprague Dawley rat at 46.9 mg/kg (Equivalent to 10 mg/kg of 5-MeO-DMT)
Figure imgf000142_0002
Measurement of Concentration of 5-MeO-DMT after oral administration of DMT
Prodrug Compound 1-35 tR = MeO)
[000382] The 5-MeO-DMT prodrug Compound 1-35 was synthesized according to methods described herein in Example 6 and pharmacokinetic properties of the 5-MeO-DMT metabolite were assessed after oral administration in a rat model. The concentration of 5- MeO-DMT was measured in each rat at various sampling timepoint after oral administration of Compound 1-35 (R =MeO) at lOmg/kg to male Sprague-Dawley rats. Mean plasma concentration was measured at 0.25, 0.50, 0.75, 1.00, 2.00, 4.00, 7.00, and 24.0 hours post administration. At all measured timepoints, the mean plasma concentration in each animal tested was BLQ (below lower limit of quantitation of 0.5 ng/mL).
Measurement of Concentration of DMT after oral administration of DMT Prodrug Compound 1-35 tR = H)
[000383] The DMT prodrug Compound 1-35 was synthesized according to methods described herein in Example 7 and pharmacokinetic properties of the DMT metabolite were assessed after oral administration in a rat model. The concentration of DMT was measured in each rat at various sampling timepoints after oral administration of Compound 1-35 (R =H) to rats. The measured concentrations are summarized in Table 19 and are also shown in FIG. 6. Table 19. Summary of DMT cone determined following PO administration of DMT Prodrug Compound 1-35 (R=H) to male Sprague Dawley rat at 52.8 mg/kg (Equivalent to 10 mg/kg of DMT)
Figure imgf000143_0002
000384] The calculated mean pharmacokinetics (PK) parameters are summarized in Table
20
Table 20. Mean Pharmacokinetics parameters of DMT following PO dosing to male Sprague Dawley rat at 52.8 mg/kg (Equivalent to 10 mg/kg of DMT)
Figure imgf000143_0001

Claims

CLAIMS We claim: 1. A compound of Formula I :
Figure imgf000144_0001
I or a pharmaceutically acceptable salt thereof, wherein: R1 and R2 are each independently hydrogen, an acid-labile group, a lipid, or -C(O)R3; each R3 is independently a saturated or unsaturated, straight or branched, optionally substituted C1-37 hydrocarbon chain; X is -O-, -NR-, -S-, -O(C1-6 aliphatic)-O-, -O(C1-6 aliphatic)-S-, -O(C1-6 aliphatic)-NR-, -S(C1-6 aliphatic)-O-, -S(C1-6 aliphatic)-S-, -S(C1-6 aliphatic)-NR-, -NR(C1-6 aliphatic)-O-, -NR(C1- 6 aliphatic)-S-, or -NR(C1-6 aliphatic)-NR-, wherein 0 to 2 methylene units of the C1-6 aliphatic group are independently and optionally replaced with -O-, -NR-, or -S- and the C1-6 aliphatic group is independently and optionally substituted with 1, 2, or 3 deuterium or halogen atoms; each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Y is absent or is -C(O)-, -C(NR)-, or -C(S)-; L is a covalent bond or a saturated or unsaturated, straight or branched, optionally substituted bivalent C1-30 hydrocarbon chain, wherein 0-8 methylene units of L are independently replaced by -Cy-, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -SO2-, -C(S)-, - NRSO2-, -SO2NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O-, or an amino acid; and wherein 1 methylene unit of L is optionally replaced with -M-; or wherein either the right-hand side or left-hand side of L is attached to A; each -Cy- is independently an optionally substituted 3-6 membered bivalent saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each R4 and R5 is independently hydrogen, deuterium, halogen, -CN, -OR, -NR2, -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a Ci-6 aliphatic group optionally substituted with -CN, -OR, -NR2, -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or the Ci-6 aliphatic is optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; or two instances of R4 or R5 attached to the same carbon atom, taken together with the carbon atom to which they are attached, form a 3-6 membered spirocyclic saturated monocyclic carbocyclic ring or 3-6 membered spirocyclic saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
-M- is a self-immolative group; n is 0-18; each m is independently 0-6; and
A is a therapeutic agent selected from a naturally-occurring or non naturally-occurring tryptamine or phenethylamine psychedelic such as DMT or 5-MeO-DMT or an analogue or prodrug thereof.
2. The compound according to claim 1, wherein R1 and R2 are -C(0)R3.
3. The compound according to claim 1 or 2, wherein each R3 is independently a saturated or unsaturated, unbranched C2-37 hydrocarbon chain.
4. The compound according to claim 3, wherein each R3 is C15H31.
5. The compound according to any one of claims 1-4, wherein X is -O-.
6. The compound according to any one of claims 1-5, wherein Y is -C(O)-.
7. The compound according to any one of claims 1-6, wherein L is a saturated or unsaturated, straight or branched, optionally substituted bivalent C7-20 hydrocarbon chain, wherein 0-8 methylene units of L are independently replaced by -Cy-, -O-, -NR-, -S-, -OC(O)- , - C(O)0-, -C(O)-, -S(O)-, -S(O)2-, -C(S)-, -NRSO2-, -SO2NR-, -NRC(O)-, -C(O)NR-, - OC(O)NR-, -NRC(O)O-, or an amino acid; and wherein 1 methylene unit of L is optionally replaced with -M-.
8. The compound according to any one of claims 1-6, wherein L is a covalent bond or a saturated or unsaturated, straight or branched, optionally substituted bivalent C1-30 hydrocarbon chain, wherein 0-8 methylene units of L are independently replaced by -Cy-, -O-, -NR-, -S-, - OC(O)-, -C(O)0-, -C(O)-, -S(O)-, -SO2-, -C(S)-, -NRSO2-, -S, - OC(O)NR-, -NRC(O)O-, or an amino acid selected from
Figure imgf000146_0001
Figure imgf000147_0001
or wherein 1 methylene unit of L is optionally replaced with -M-; or
Figure imgf000147_0002
wherein either the right-hand side or left-hand side of L is attached to A.
9. The compound according to any one of claims 1-6, wherein L is a saturated bivalent Ci-25 hydrocarbon chain optionally substituted with 1, 2, 3, or 4 groups selected from deuterium, halogen, -CN, a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 4-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a Ci-6 aliphatic group optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; wherein 0-4 methylene units of L are independently replaced by -0-, -0C(0)-, -C(0)0-, or -C(0)-; and 1 methylene unit of L is optionally replaced with -M-.
10. The compound according to any one of claims 1-9, wherein -M- is selected from one of the following:
Figure imgf000148_0001
wherein each R6 is independently selected from hydrogen, deuterium, C1-5 aliphatic, halogen, or - CN; each R7 is independently selected from hydrogen, deuterium, halogen, -CN, -OR, -NR2, -NO2, -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a Ci-6 aliphatic group optionally substituted with -CN, -OR, -NR2, -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or the Ci-6 aliphatic is optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; each Z1 is independently selected from -O-, -NR-, or -S-; each Z2 is independently selected from -O-, -NR-, -S-, -OC(O)-, -NRC(O)O-, or -OC(O)NR-; each Z3 is independently selected from =N- or =C(R7)-; and each Z4 is independently selected from -O-, -NR-, -S-, -C(R6)2-, or a covalent bond.
11. The compound according to claim 10, wherein -M- is selected from
Figure imgf000149_0001
12. The compound according to claim 10 or 11, wherein -M- is selected from
Figure imgf000149_0002
Figure imgf000150_0001
13. The compound according to any one of claims 1-12, wherein each R4 is independently hydrogen, deuterium, halogen, -CN, or C1-4 aliphatic optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; or two instances of R4 attached to the same carbon atom, taken together with the carbon atom to which they are attached, form a 3-6 membered spirocyclic saturated monocyclic carbocyclic ring or 3-6 membered spirocyclic saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
14. The compound according to any one of claims 1-13, wherein each R5 is independently hydrogen, deuterium, halogen, -CN, or Ci-4 aliphatic optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; or two instances of R5 attached to the same carbon atom, taken together with the carbon atom to which they are attached, form a 3-6 membered spirocyclic saturated monocyclic carbocyclic ring or 3-6 membered spirocyclic saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
15. The compound according to any one of claims 1-14, wherein each R4 and R5 is independently hydrogen or Ci-4 alkyl optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms.
16. The compound according to any one of claims 1-14, wherein each R4 and R5 is independently hydrogen or methyl.
17. The compound according to claim 1, wherein L i
Figure imgf000150_0002
Figure imgf000150_0003
Figure imgf000151_0004
18 The compound according to claim 1, wherein L is a bond,
Figure imgf000151_0001
Figure imgf000151_0002
an integer of 1 to 8.
19 The compound according to claim 1, wherein L is a bond,
Figure imgf000151_0003
Figure imgf000152_0001
20. The compound according to any one of claims 1-19, wherein A is selected from N,N-Dimethyltryptamine (DMT), 5-MeO-DMT (5-methoxy-N,N-dimethyltryptamine) or O- methyl-bufotenin.
21. The compound according to any of claims 1-20, wherein A is DMT or 5-MeO- DMT.
22. The compound according to any one of claims 1-19, wherein
Figure imgf000152_0002
Figure imgf000152_0003
23. The compound according to claim 1, wherein the compound is of Formula VUI-a or Formula VIII-b:
Figure imgf000152_0004
VIII-b or a pharmaceutically acceptable salt thereof.
24. The compound according to claim 1, wherein the compound is selected from one of the compounds listed in Table 1, or a pharmaceutically acceptable salt thereof.
25. A pharmaceutically acceptable composition comprising a compound according to any of claims 1-24, and a pharmaceutically acceptable excipient, carrier, adjuvant, or vehicle.
26. The pharmaceutically acceptable composition according to claim 25, further comprising an additional therapeutic agent.
27. The pharmaceutically acceptable composition according to claim 25 or 26, wherein the composition is formulated for oral administration.
28. A method of treating or preventing a disease, disorder, or condition in which an increased level of a tryptamine or phenethylamine psychedelic such as N,N- Dimethyltryptamine (DMT), 5-MeO-DMT (5-methoxy-N,N-dimethyltryptamine) is beneficial, or a disease, disorder, or condition caused by a deficiency in a tryptamine or phenethylamine psychedelic such as DMT or 5-MeO-DMT, comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1-
24, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim
25.
29. A method of treating a disease, disorder, or condition caused by deficient activation of serotonin 5HT receptors comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1-24, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 25.
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