Hallucinogenic and non-hallucinogenic serotonin receptor agonists and methods of making and using same - Patents.com

Abstract

Hallucinogenic and non-hallucinogenic serotonin receptor agonists are disclosed herein along with methods of making and using the same.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. Provisional Application No. 63 / 325,515 filed March 30, 2022, U.S. Provisional Application No. 63 / 319,200 filed March 11, 2022, U.S. Provisional Application No. 63 / 314,379 filed February 26, 2022, U.S. Provisional Application No. 63 / 314,378 filed February 26, 2022, U.S. Provisional Application No. 6 3 / 314,377, U.S. Provisional Application No. 63 / 285,688 filed December 3, 2021, U.S. Provisional Application No. 63 / 285,679 filed December 3, 2021, U.S. Provisional Application No. 63 / 285,656 filed December 3, 2021, U.S. Provisional Application No. 63 / 239,965 filed September 2, 2021, U.S. Provisional Application No. No. 63 / 239,964, U.S. Provisional Application No. 63 / 239,963 filed September 2, 2021, U.S. Provisional Application No. 63 / 238,135 filed August 28, 2021, U.S. Provisional Application No. 63 / 238,134 filed August 28, 2021, U.S. Provisional Application No. 63 / 238,133 filed August 28, 2021, U.S. This application claims priority to U.S. Provisional Application No. 63 / 238,132, filed August 12, 2021, U.S. Provisional Application No. 63 / 232,614, filed August 12, 2021, U.S. Provisional Application No. 63 / 232,548, filed August 12, 2021, and U.S. Provisional Application No. 63 / 232,539, filed August 12, 2021, the entire contents of each of which are incorporated herein by reference for all purposes.

[0002] The present disclosure relates to hallucinogenic and non-hallucinogenic serotonin receptor agonist compounds, combinations thereof, and methods of using them to treat and prevent a variety of human conditions. [Background technology]

[0003] Many people around the world suffer from mental or mood disorders, such as depression, anxiety, compulsive behavior, and post-traumatic stress disorder (PTSD). Altered synaptic connections have been observed in brains affected by these types of illnesses and disorders. Certain "psychedelic" drugs, such as psilocybin and LSD, have been found to alleviate symptoms of depression and PTSD in clinical trials. This is thought to be due to 5-HT2A receptor signaling, which stimulates what is called neuroplasticity. Neuroplasticity helps the brain form new neural connections, which is thought to produce rapid and lasting positive mood effects. Studies have demonstrated that psilocybin-based psychotherapy can almost immediately reduce depressive symptoms in patients after a single high dose.

[0004] However, hallucinogen-based medications have several limitations that hinder their widespread adoption. Most notably, tryptamine drugs such as psilocybin and LSD are hallucinogenic and must be administered in a clinical setting in the presence of a medical professional. Second, well-known 5-HT2A receptor agonists, such as psilocin (the active compound of the prodrug psilocybin), are known to be cardiotoxic due to their potent agonistic effects at the 5-HT2B receptor.

[0005] To date, little (if any) research has been conducted to develop tryptamine-like analogs or tryptamine mimetics that are non-hallucinogenic and non-cardiotoxic while maintaining their ability to modulate 5-HT2A receptors. Thus, there remains a need to develop novel active compounds that exhibit these properties to provide patients with a therapeutic option that can be administered daily / weekly alone in their own homes without the oversight of a medical professional. Summary of the Invention

[0006] Provided herein are hallucinogenic and non-hallucinogenic compounds of Formula I: [ka] (In the formula, X and Y are each independently selected from hydrogen, deuterium, optionally substituted C1-C8 alkyl, and optionally substituted C2-C8 alkenyl, or Y, together with X and the nitrogen atom therebetween, form a 3-7 membered heterocyclic ring optionally containing 1-2 additional ring hetero moieties selected from O, S, S(O), SO2, and NR9; W1 is NR1, O, Se, Se(O), SeO 2、 selected from S, S(O), and SO; W2 is selected from -CD2-, -CHD-, -(CD2)2-, -CH2-, and -(CH2)2-; Z4 is selected from N and CR4; Z5 is selected from N and CR5; Z6 is selected from N and CR6; Z7 is selected from N and CR7; R1 is selected from hydrogen, deuterium, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, -C(O)R8, -C(O)OR8, -P(O)O2(R9)2, -C(O)N(R9)2, -SOR8, and -S02R8; R2, R3, R 3’ R6 and R7 are each independently selected from hydrogen, deuterium, -N(R9)2, -SR9, halo, optionally substituted C1-C8 alkyl, -C1-C8 alkoxy, and optionally substituted C2-C8 alkenyl, or Y is absent, and R3, together with the carbon atom to which it is attached and the nitrogen atom to which X is attached, form a 3-7 membered heterocyclic ring optionally containing 1-2 additional ring hetero moieties selected from O, S, S(O), SO2, and NR9; R4 and R5 are each independently selected from hydrogen, deuterium, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, halo, hydroxyl, -N(R9)2, -SR9, -C1-C8 alkoxy, -OC(O)R8, -OC(O)OR8, -OP(O)O2(R9)2, and -OSO2R8; R8 is selected from optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, and optionally substituted aryl; R9 is independently selected from hydrogen, deuterium, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, and optionally substituted aryl; and Salts, solvates, hydrates, and prodrugs thereof are disclosed.

[0007] The present disclosure also relates to compositions comprising, consisting of, or consisting essentially of a compound of Formula I and an excipient. The present disclosure further relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound of Formula I, wherein the excipient is a pharmaceutically acceptable carrier.

[0008] The present disclosure further relates to a method for preventing or treating a psychiatric disorder, comprising administering a therapeutically effective amount of a compound of formula I or a pharmaceutical composition containing same to a subject in need thereof.

[0009] Embodiments of the present disclosure also relate to compositions comprising, consisting of, or consisting essentially of a first compound selected from the compounds of Formula I; and a second active compound. In certain embodiments, the second active compound comprises a serotonergic compound.

[0010] Also described herein are methods for preventing or treating inflammation and / or pain, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a composition (e.g., a pharmaceutically acceptable composition) containing the compound of Formula I.

[0011] Unless the context indicates otherwise, a reference to a compound of Formula I includes all subgenuses of Formula I (eg, Formulas Ia, Ib, II, etc.). DETAILED DESCRIPTION OF THE INVENTION

[0012] compound Provided herein are compounds of formula I: [ka] (X and Y are each independently selected from hydrogen, deuterium, optionally substituted C1-C8 alkyl, and optionally substituted C2-C8 alkenyl, or Y, together with X and the nitrogen atom therebetween, forms a 3-7 membered heterocyclic ring optionally containing 1-2 additional ring hetero moieties selected from O, S, S(O), SO2, and NR9; W1 is NR1, O, Se, Se(O), SeO 2、 selected from S, S(O), and SO; W2 is selected from -CD2-, -CHD-, -(CD2)2-, -CH2-, and -(CH2)2-; Z4 is selected from N and CR4; Z5 is selected from N and CR5; Z6 is selected from N and CR6; Z7 is selected from N and CR7; R1 is selected from hydrogen, deuterium, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, -C(O)R8, -C(O)OR8, -P(O)O2(R9)2, -C(O)N(R9)2, -SOR8, and -S02R8; R2, R3, R 3’ R6 and R7 are each independently selected from hydrogen, deuterium, -N(R9)2, -SR9, halo, optionally substituted C1-C8 alkyl, -C1-C8 alkoxy, and optionally substituted C2-C8 alkenyl, or Y is absent, and R3, together with the carbon atom to which it is attached and the nitrogen atom to which X is attached, form a 3-7 membered heterocyclic ring optionally containing 1-2 additional ring hetero moieties selected from O, S, S(O), SO2, and NR9; R4 and R5 are each independently selected from hydrogen, deuterium, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, halo, hydroxyl, -N(R9)2, -SR9, -C1-C8 alkoxy, -OC(O)R8, -OC(O)OR8, -OP(O)O2(R9)2, and -OSO2R8; R8 is selected from optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, and optionally substituted aryl; R9 is independently selected from hydrogen, deuterium, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, and optionally substituted aryl; and Salts, solvates, hydrates, and prodrugs thereof are disclosed.

[0013] As used herein, the term "alkyl" refers to a linear, branched, or cyclic saturated hydrocarbon group. As used herein, alkyl has 1 to 20 carbon atoms, 1 to 10 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 3 carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl. When an alkyl residue having a specific number of carbon atoms is named by chemical name or specified by molecular formula, all positional isomers having that number of carbon atoms are included; thus, for example, "butyl" includes n-butyl, isobutyl, sec-butyl, and tert-butyl; and "propyl" includes n-propyl and isopropyl. In some embodiments, a deuterium atom may be substituted for a hydrogen atom. When alkyls described herein are referred to as "substituted," they can be substituted with any substituent(s) such as those found in the exemplary compounds and embodiments disclosed herein, as well as deuterium, aryl, heteroaryl, hydroxy, alkoxy, alkylsulfonamido, arylsulfonamido, and halo.

[0014] As used herein, the term "alkenyl" refers to an alkyl group containing one or more carbon-carbon double bonds. An "alkynyl" group is an alkyl group containing one or more carbon-carbon triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, allyl, CH=CH(CH), -CH=C(CH), -C(CH)=CH, -C(CH)=CH(CH), -C(CHCH)=CH, -C≡CH, -C≡C(CH), -C≡C(CHCH), -CHC≡CH, CHC≡C(CH), and CHC≡C(CHCH), among others. When alkenyls and alkynyls described herein are referred to as "substituted," they can be substituted with any substituent(s) found in the exemplary compounds and embodiments disclosed herein, as well as deuterium, aryl, heteroaryl, hydroxy, alkoxy, alkylsulfonamido, arylsulfonamido, and halo.

[0015] As used herein, the term "alkoxy" refers to --O-(alkyl), where alkyl is as defined above.

[0016] As used herein, the term "aryl" refers to an aromatic carbocyclic group of 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl). In some embodiments, heteroaryl groups contain 6 to 14 carbons, and in other cases 6 to 12 or even 6 to 10 carbon atoms, in the ring portion of the group. Particular aryls include phenyl, biphenyl, naphthyl, and the like. The phrase "aryl group" also includes groups containing condensed rings, such as condensed aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and the like). When aryls described herein are referred to as "substituted," they can be substituted with any substituent(s) such as those found in the exemplary compounds and embodiments disclosed herein, as well as deuterium, aryl, alkyl, heteroaryl, hydroxyl, and halo.

[0017] As used herein, the term "heteroaryl" refers to an aromatic ring system having 1 to 4 heteroatoms as ring atoms in the heteroaromatic ring system, with the remainder of the atoms being carbon atoms. In some embodiments, heteroaryl groups contain 3 to 6 ring atoms, and in other cases 6 to 9 or even 6 to 10 atoms in the ring portion of the group. Suitable heteroatoms include oxygen, sulfur, and nitrogen. In certain embodiments, the heteroaryl ring system is monocyclic or bicyclic.

[0018] As used herein, the term "heterocyclic ring" or "heterocyclyl" or "heterocycloalkyl" refers to a non-aromatic cycloalkyl in which 1 to 4 of the ring carbon atoms are replaced with heteroatoms independently selected from O, S, and N. In some embodiments, heterocyclyl groups contain 3 to 10 ring members, while other such groups have 3 to 5, 3 to 6, or 3 to 8 ring members. A heterocyclyl can also be attached to another group at any ring atom (i.e., at any carbon atom or heteroatom of the heterocyclic ring). Heterocycloalkyl groups can be substituted or unsubstituted. Heterocyclyl groups encompass saturated and partially saturated ring systems. Furthermore, the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, which ring may be fused to an aryl or heteroaryl ring, regardless of attachment to the rest of the molecule. The phrase also includes bridged polycyclic ring systems containing heteroatoms.

[0019] As used herein, the term "hetero moiety" refers to any group containing a heteroatom, such as amino, O, Se, Se(O), SeO. 2、 Refers to S, S(O), and SO2.

[0020] As used herein, the terms "halo" or "halogen" refer to a fluorine, chlorine, bromine, or iodine atom.

[0021] As used herein, the term "hydroxyl" refers to an --OH group.

[0022] As used herein, the term "alkylsulfonamide" refers to a moiety containing -S(=O)2-NR2, where each R group is selected from alkyl or H.

[0023] As used herein, the term "arylsulfonamide" refers to a moiety containing -S(=O)2-NR2, where each R group is selected from aryl or H.

[0024] In some embodiments, the compound of Formula I contains one or more chiral centers. In some circumstances, the compound of Formula I comprises a racemic mixture. In some embodiments, the compound of Formula I comprises an (S) enantiomer. In some embodiments, the compound of Formula I comprises an (R) enantiomer. In some embodiments, the (S) and (R) designations refer to the absolute stereochemistry of compounds with multiple stereocenters. In such cases, the conformation of one of those chiral centers may be referred to in terms of its relative (D) or (L) configuration.

[0025] In some embodiments, X and Y are independently selected from hydrogen, deuterium, and optionally substituted C1-C8 alkyl, wherein the alkyl group contains a cycloalkyl moiety (e.g., cyclopropyl, cyclobutyl, etc.).

[0026] In some embodiments, R, R, R 3’ , R6, and R7 are each independently selected from hydrogen, deuterium, halo, -N(R9)2, -SR9, optionally substituted C1-C8 alkyl, -C1-C8 alkoxy, and optionally substituted C2-C8 alkenyl, or Y is absent and R3, together with the carbon to which it is attached and the nitrogen atom to which X is attached, form a 3-7 membered heterocyclic ring optionally containing 1-2 additional ring hetero moieties selected from O, S, S(O), SO2, and NR9. In some embodiments, R2, R3, R6, and R7 are each independently selected from hydrogen, deuterium, halo, optionally substituted C1-C8 alkyl, and optionally substituted C2-C8 alkenyl.

[0027] In some embodiments, R4 and R5 are each independently selected from hydrogen, deuterium, -N(R9), -SR9, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, halo, hydroxyl, -C1-C8 alkoxy, -OC(O)R8, -OC(O)OR8, -OP(O)O2(R9), and -OSOR8. In some embodiments, R4 and R5 are each independently selected from hydrogen, deuterium, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, halo, hydroxyl, -C1-C8 alkoxy, -OC(O)R8, -OC(O)OR8, -OP(O)O2(R9), and -OSOR8.

[0028] In certain embodiments, at least one of R4 and R5 is selected from a C1-C5 alkoxy group, or in some embodiments, a C2-C4 alkoxy group, which may be a straight-chain or branched C1-C5 alkoxy group or a C2-C4 alkoxy group, e.g., straight-chain, and may be methoxy or ethoxy. In some embodiments, R5 is C1-C5 alkoxy. In some embodiments, R4 is selected from hydrogen and fluorine, and R5 is C1-C5 alkoxy. In some embodiments, at least one of R4 and R5 is selected from C1-C5 alkyl or C1-C4 alkyl, e.g., straight-chain C1-C4 alkyl. In some embodiments, R5 is selected from methyl, ethyl, n-propyl, or n-butyl, e.g., methyl or ethyl. In some embodiments, at least one of R4 and R5 is halo. In some embodiments, R4 is fluoro. In some embodiments, R4 is fluoro, and R5 is selected from hydrogen and C1-C5 alkoxy. In some embodiments, at least one of R4 and R5 is -OC(O)R8. In some embodiments, R4 is selected from -OC(O)R8, and R5 is hydrogen or fluoro.

[0029] In some embodiments, R8 is selected from optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, and optionally substituted aryl. In some embodiments, R9 is selected from hydrogen, deuterium, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, and optionally substituted aryl. In some embodiments, R8 is selected from methyl, ethyl, propyl, and isopropyl. In some embodiments, R9 is selected from methyl, ethyl, propyl, and isopropyl.

[0030] Exemplary halo moieties for compounds of formula I include chloro, bromo, fluoro, and iodo. In certain embodiments, compounds of formula I include at least one fluoro moiety.

[0031] In some embodiments, W1 is selected from NR1, O, Se, Se(O), SeO2S, S(O), and SO2. In some embodiments, W1 is NR1. In some embodiments, W1 is O. In some embodiments, W1 is S. In some embodiments, W1 is Se. In some embodiments, Z4 is selected from N and CR4; Z5 is selected from N and CR5; Z6 is selected from N and CR6; and Z7 is selected from N and CR7. In some embodiments, Z4 is N. In some embodiments, Z5 is N. In some embodiments, Z6 is N. In some embodiments, Z7 is N.

[0032] In some embodiments, R1 is selected from hydrogen, deuterium, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, —C(O)R8, —C(O)OR8, —P(O)O2(R9)2, —C(O)N(R9)2, —SOR8, and —S2R8. In some embodiments, R1 is hydrogen. In some embodiments, R1 is optionally substituted C1-C8 alkyl. In some embodiments, R1 is optionally substituted C2-C4 alkyl. In some embodiments, R1 is methyl. In some embodiments, R1 is ethyl. In some embodiments, R1 is isopropyl.

[0033] In some embodiments, W2 is selected from -CD2-, -CDH-, -(CD2)2-, -CH2-, and -(CH2)2-. In some embodiments, W2 is selected from -CH2-. In some embodiments, W2 is selected from -(CH2)2-. In some embodiments, W2 is selected from -CD2-. In some embodiments, W2 is selected from -(CD2)2-. In some embodiments, W2 is -CDH-. In some embodiments, when W2 is -CDH-, W2 represents a stereocenter in the (R) or (S) conformation.

[0034] In certain embodiments, the alkyl groups of Formula I are selected from C1-C8 alkyl, C2-C8 alkyl, C3-C8 alkyl, and C4-C8 alkyl, or methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butylpentyl, isopentyl, hexyl, heptyl, octyl, etc. In certain embodiments, the alkenyl groups of Formula I are selected from C2-C8 alkenyl, C3-C8 alkenyl, and C4-C8 alkenyl, or ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, etc. In certain embodiments, the alkyl and alkenyl groups of Formula I can be unsubstituted or substituted with one or more groups selected from aryl, heteroaryl, hydroxy, alkoxy, alkylsulfonamido, arylsulfonamido, and halo. In certain embodiments, the aryl groups of formula I can be unsubstituted or substituted with one or more groups selected from aryl, alkyl, heteroaryl, hydroxyl, and halo. In certain embodiments, the alkoxy groups of formula I can be unsubstituted or substituted with one or more groups selected from aryl, alkyl, heteroaryl, hydroxyl, and halo.

[0035] In some embodiments, X and / or Y can be a straight-chain C1-C4 alkyl or a C2-C4 alkenyl. In some embodiments, X and Y are each methyl, X and Y are each ethyl, or X is methyl and Y is ethyl. In certain embodiments, X and / or Y is a C1-C8 alkyl or C2-C8 alkenyl optionally substituted with at least one halo group, e.g., fluorine. In certain embodiments, at least one of X or Y comprises a group selected from -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, and -CH2CH2F. In certain embodiments, at least one of X or Y comprises a group selected from -CD3, -CH2CD3, -CD2CH3, and -CD2CD3.

[0036] In some embodiments, X is unsubstituted C1-C8 alkyl. In some embodiments, X is methyl. In some embodiments, X is ethyl. In some embodiments, X is n-propyl. In some embodiments, X is isopropyl. In some embodiments, X is cyclopropyl. In some embodiments, Y is hydrogen. In some embodiments, Y is unsubstituted C1-C8 alkyl. In some embodiments, Y is methyl. In some embodiments, Y is ethyl. In some embodiments, Y is n-propyl. In some embodiments, Y is isopropyl. In some embodiments, Y is cyclopropyl.

[0037] In some embodiments, R, R, R 3’ , R6, and R7 are each independently selected from hydrogen, deuterium, halo, or C1-C4 alkyl, e.g., straight-chain C1-C4 alkyl. In some embodiments, R2, R3, R6, and R7 are each independently selected from hydrogen, deuterium, halo, methyl, ethyl, n-propyl, isopropyl, n-butyl, and isobutyl. In other embodiments, R2, R3, R6, and R7 are each independently selected from hydrogen, deuterium, methyl, and ethyl.

[0038] In some embodiments, R2 is hydrogen. In some embodiments, R3 and R 3’ are each independently selected from hydrogen, methyl, and ethyl. In some embodiments, R is hydrogen. In some embodiments, R is methyl and R 3’ is hydrogen. In some embodiments, R and R 3’ are both hydrogen. In some embodiments, R and R 3’ are both deuterium. In some embodiments, R is hydrogen and R 3’ is deuterium. In some embodiments, R and R 3’When R and R are not the same, it represents a stereocenter, in which case the compound of formula I comprises a racemic mixture. 3’ are not the same, it represents a stereocenter, in which case the compound of Formula I comprises the (S) enantiomer. In some embodiments, when R is not hydrogen, it represents a stereocenter, in which case the compound of Formula I comprises the (R) enantiomer. In some embodiments, the racemic mixture can be resolved to provide pure enantiomers or mixtures enriched in either the (R) or (S) enantiomers.

[0039] In some embodiments, R6 and R7 are each independently selected from hydrogen, halo, methyl, ethyl, n-propyl, isopropyl, n-butyl, and isobutyl. In some embodiments, R6 is selected from hydrogen and halo. In some embodiments, R6 is selected from hydrogen and fluorine. In some embodiments, R6 is fluorine. In some embodiments, R7 is selected from hydrogen and optionally substituted C1-C4 alkyl. In some embodiments, R7 is selected from hydrogen, methyl, and ethyl. In some embodiments, R7 is optionally substituted C1-C4 alkyl. In some embodiments, when R6 is fluoro, then R7 is selected from hydrogen and optionally substituted C1-C4 alkyl.

[0040] In some embodiments, R4 is hydrogen and R5 is selected from optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, halo, hydroxyl, —C1-C8 alkoxy, —OC(O)R8, —OC(O)OR8, —OP(O)O2(R9)2, and —OSO2R8. In some embodiments, R5 is selected from unsubstituted C1-C8 alkyl, hydroxyl, —C1-C8 alkoxy, —OC(O)R8, —OC(O)OR8, —OP(O)O2(R9)2, and —OSO2R8. In some embodiments, R5 is selected from unsubstituted C2-C8 alkyl, hydroxyl, —C1-C8 alkoxy, —OC(O)R8, —OC(O)OR8, —OP(O)O2(R9)2, and —OSO2R8. In some embodiments, R5 is selected from unsubstituted C2-C8 alkyl, hydroxyl, —C1-C8 alkoxy, —OC(O)R8, —OC(O)OR8, —OP(O)O2(R9)2, and —OSO2R8. In some embodiments, R5 is hydroxy. In some embodiments, R5 is -OC(O)R8. In some embodiments, R8 is unsubstituted C1-C4 alkyl. In some embodiments, R8 is methyl.

[0041] In some embodiments, R5 is hydrogen and R4 is selected from optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, halo, hydroxyl, —C1-C8 alkoxy, —OC(O)R8, —OC(O)OR8, —OP(O)O2(R9)2, and —OSO2R8. In some embodiments, R4 is selected from unsubstituted C1-C8 alkyl, hydroxyl, —C1-C8 alkoxy, —OC(O)R8, —OC(O)OR8, —OP(O)O2(R9)2, and —OSO2R8. In some embodiments, R5 is selected from unsubstituted C1-C8 alkyl, —C2-C8 alkoxy, —OC(O)R8, —OC(O)OR8, —OP(O)O2(R9)2, and —OSO2R8. In some embodiments, R5 is selected from unsubstituted C1-C8 alkyl, —C2-C8 alkoxy, —OC(O)R8, —OC(O)OR8, —OP(O)O2(R9)2, and —OSO2R8. In some embodiments, R5 is —OC(O)R8. In some embodiments, R8 is unsubstituted C1-C4 alkyl. In some embodiments, R8 is methyl.

[0042] In certain embodiments, one or more hydrogen atoms on a compound of Formula I can be replaced with one or more deuterium atoms. For example, in certain embodiments, R6 can include a deuterium atom as a replacement for hydrogen, or when R7 is -CH3, each hydrogen atom can be replaced to form a -CD3 residue. Similarly, another non-limiting example includes when X and / or Y are -CH3, each hydrogen atom can be replaced to form a -CD3 residue.

[0043] In some embodiments, R4 is not halo. In some embodiments, R5 is not halo. In some embodiments, one of R4 and R5 is hydrogen and the other of R4 and R5 is selected from hydroxyl, —OC(O)R8, —OC(O)OR8, and —C1-C8 alkoxy; R6 is selected from hydrogen and fluorine; and R7 is selected from hydrogen, methyl, and ethyl.

[0044] In some embodiments of compounds of formula I, when X and Y are both methyl, W1 is S, W2 is -CH2-, Z4 is CR4, Z5 is CR5, Z6 is CR6, Z7 is CR7, and R2, R3, R5, R6, and R7 are all hydrogen, then R4 is not hydroxyl or methoxy.

[0045] In some embodiments of compounds of formula I, when X and Y are both methyl, W1 is S, W2 is -CH2-, Z4 is CR4, Z5 is CR5, Z6 is CR6, Z7 is CR7, and R2, R3, R4, R6, and R7 are all hydrogen, then R5 is not hydroxy or methoxy.

[0046] In some embodiments of compounds of formula I, when X and Y are both ethyl, W1 is S, W2 is -CH2-, Z4 is CR4, Z5 is CR5, Z6 is CR6, Z7 is CR7, and R2, R3, R4, R6, and R7 are all hydrogen, then R5 is not methoxy.

[0047] In some embodiments of compounds of formula I, when X and Y are both methyl, W1 is S, W2 is -CH2-, Z4 is CR4, Z5 is CR5, Z6 is CR6, and Z7 is CR7, then at least one of R2, R3, R4, R5, R6, or R7 is not hydrogen.

[0048] In some embodiments of compounds of formula I, when X and Y are both propyl, W1 is S, W2 is -CH2-, Z4 is CR4, Z5 is CR5, Z6 is CR6, and Z7 is CR7, then at least one of R2, R3, R4, R5, R6, or R7 is not hydrogen.

[0049] In some embodiments of compounds of formula I, when X is methyl, Y is hydrogen, W1 is S, W2 is -CH2-, Z4 is CR4, Z5 is CR5, Z6 is CR6, and Z7 is CR7, then at least one of R2, R3, R4, R5, R6, or R7 is not hydrogen.

[0050] In some embodiments of compounds of formula I, when X is ethyl, Y is hydrogen, W1 is S, W2 is -CH2-, Z4 is CR4, Z5 is CR5, Z6 is CR6, and Z7 is CR7, then at least one of R2, R3, R4, R5, R6, or R7 is not hydrogen.

[0051] In some embodiments of compounds of formula I, when X and Y are both methyl, W1 is Se, W2 is -CH2-, Z4 is CR4, Z5 is CR5, Z6 is CR6, Z7 is CR7, and R2, R3, R5, R6, and R7 are all hydrogen, then R4 is not hydroxyl or methoxy.

[0052] In some embodiments of compounds of formula I, when X and Y are both methyl, W1 is O, W2 is -CH2-, Z4 is CR4, Z5 is CR5, Z6 is CR6, Z7 is CR7, and R2, R3, R4, R6, and R7 are all hydrogen, then R5 is not hydroxy, methoxy, or bromo.

[0053] In some embodiments of compounds of formula I, when X and Y are both methyl, W1 is O, W2 is -CH2-, Z4 is CR4, Z5 is CR5, Z6 is CR6, Z7 is CR7, and R2, R3, R4, R5, and R6 are all hydrogen, then R7 is not methoxy.

[0054] In some embodiments of compounds of formula I, when X is methyl or ethyl, Y is hydrogen, W1 is O, W2 is -CH2-, Z4 is CR4, Z5 is CR5, Z6 is CR6, Z7 is CR7, and R2, R3, R4, R6, and R7 are all hydrogen, then R5 is not methoxy.

[0055] In some embodiments of compounds of formula I, when X is methyl, Y is hydrogen, W1 is O, W2 is CH2-, Z4 is CR4, Z5 is CR5, Z6 is CR6, and Z7 is CR7, then at least one of R2, R3, R4, R5, R6, or R7 is not hydrogen.

[0056] In some embodiments of compounds of formula I, when X is methyl, Y is hydrogen, W is O, W is -CH-, Z is CR, Z is CR, Z is CR, Z is CR, and R, R, R, R, and R are all hydrogen, then R is not methoxy.

[0057] In some embodiments of compounds of formula I, when X is methyl, Y is hydrogen, W1 is O, W2 is -CH2-, Z4 is CR4, Z5 is CR5, Z6 is CR6, Z7 is CR7, and R2, R3, R4, R5, and R6 are all hydrogen, then R7 is not methoxy.

[0058] In some embodiments of compounds of formula I, when X and Y are both methyl, W1 is NH, W2 is -CH2-, Z4 is N, Z5 is CR5, Z6 is CR6, and Z7 is CR7, then at least one of R2, R3, R5, R6, or R7 is not hydrogen.

[0059] In some embodiments of compounds of formula I, when X and Y are both methyl, W1 is NH, W2 is -CH2-, Z4 is N, Z5 is CR5, Z6 is CR6, Z7 is CR7, and R2, R3, R6, and R7 are all hydrogen, then R5 is not methyl or methoxy.

[0060] In some embodiments of compounds of formula I, when X and Y are both methyl, W1 is NH, W2 is -CH2-, Z4 is CR4, Z5 is N, Z6 is CR6, and Z7 is CR7, then at least one of R2, R3, R4, R6, or R7 is not hydrogen.

[0061] In some embodiments of compounds of formula I, when X and Y are both methyl, W1 is NH, W2 is -CH2-, Z4 is CR4, Z5 is N, Z6 is CR6, Z7 is CR7, and R3, R4, R6, and R7 are all hydrogen, then R2 is not ethyl or iodo.

[0062] In some embodiments of compounds of formula I, when X and Y are both ethyl, W1 is NH, W2 is -CH2-, Z4 is CR4, Z5 is CR5, Z6 is N, and Z7 is CR7, then at least one of R2, R3, R4, R5, or R7 is not hydrogen.

[0063] In some embodiments of compounds of formula I, when X and Y are both methyl, W1 is NH, W2 is -CH2-, Z4 is CR4, Z5 is CR5, Z6 is CR6, Z7 is N, and R2, R3, R4, and R5 are all hydrogen, then R6 is not chloro.

[0064] In some embodiments of compounds of formula I, when X is hydrogen, Y is methyl, W1 is NH, W2 is -CH2-, Z4 is CR4, Z5 is CR5, Z6 is CR6, Z7 is N, and R2, R3, R4, and R5 are all hydrogen, then R6 is not chloro.

[0065] In some embodiments of compounds of formula I, when X and Y are both methyl, W1 is NH, W2 is -CH2-, Z4 is CR4, Z5 is CR5, Z6 is CR6, and Z7 is N, then at least one of R2, R3, R4, R5, or R6 is not hydrogen.

[0066] In some embodiments, when X and Y are both methyl, W1 is NH, W2 is -CH2-, Z4 is CR4, Z5 is CR5, Z6 is CR6, Z7 is N, and R3, R4, R5 and R6 are all hydrogen, then R2 is not ethyl or iodo.

[0067] In some embodiments, the compound of formula I is a compound of formula II: [ka] (In the formula, X is selected from hydrogen and deuterium; W3 is absent or -(CZ'2) n wherein n is an integer selected from 1 and 2, and each Z' is independently selected from hydrogen, deuterium, and fluorine; a, b, and c are each independently selected from hydrogen, deuterium, and fluorine; All other variables are as defined above).

[0068] In certain embodiments of compounds of Formula II, W3 is absent. In certain embodiments, n=1. In certain embodiments, Z4 is CR4 and R4 is fluorine. In certain embodiments, Z6 is CR6 and R6 is fluorine. In certain embodiments, Z4 is N. In certain embodiments, Z5 is N. In certain embodiments, Z6 is N. In certain embodiments, Z7 is N. In certain embodiments, W3 is selected from -CH2-, -CHF-, -CF2-, and -CD2-. In certain embodiments, a is fluorine and b and c are each hydrogen. In certain embodiments, a is hydrogen and b and c are each fluorine. In certain embodiments, a, b, and c are all fluorine. In certain embodiments, a, b, and c are all hydrogen. In certain embodiments, a, b, and c are all deuterium.

[0069] In certain embodiments, W2 is selected from -CH2-, -CD2-, and -CHD-. In certain embodiments, R3 and R 3’ are both hydrogen. In certain embodiments, R and R 3’ are both deuterium. In certain embodiments, R is hydrogen and R 3’ In certain embodiments, W2 is -CHD-, R3 is hydrogen, and R 3’ is deuterium. In certain embodiments, W3 is -CH2-. In certain embodiments, W3 is -CD2-. In some embodiments, W2 is -CH2-, R3 is hydrogen, and R 3’is deuterium, Z is CR, Z is CR, Z is CR, Z is CR, and R, R, R, R, and R are all hydrogen. In some embodiments, W is -CH-, R is deuterium, and R 3’ is hydrogen, Z4 is CR4, Z5 is CR5, Z6 is CR6, Z7 is CR7, and R2, R4, R5, R6 and R7 are all hydrogen.

[0070] Exemplary compounds of Formula I include: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] and salts, solvates, hydrates, and prodrugs of any of the foregoing compounds.

[0071] In some embodiments, the compound of Formula I comprises a salt. In some embodiments, the compound of Formula I comprises a pharmaceutically acceptable salt. Exemplary salts include, but are not limited to, HCl, HI, HBr, HF, ascorbate, hydrofumarate, fumarate, oxalate, maleate, and the like. In certain embodiments, the compound of Formula I is in its free base form. In some embodiments, the compound of Formula I comprises a salt, such as a [1:1] salt (e.g., HCl, hydrofumarate) or a [2:1] salt (e.g., oxalate, fumarate). In a [1:1] salt, one ammonium cation of one compound of Formula I is balanced by a single anion (e.g., Cl-, I-). In a [2:1] salt, two ammonium cations of two molecules of Formula I are balanced by a dianionic species, such as the dianion derived from a diacid, e.g., oxalic acid and fumaric acid. Other exemplary salts include zwitterionic forms of compounds of Formula I, such as when R4 is -OP(O)O2(R9)2 and each R9 is hydrogen (deprotonation of the -OH on R4 results in -O - and quaternary ethylammonium residues (e.g., -(CH2)2N + H(CH3)2).

[0072] Other exemplary compounds of Formula I include those in Table 1 below, which are also represented by Formula Ia: [ka] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12]

[0073] Other exemplary compounds of Formula I include those in Table 2 below, which are also represented by Formula Ib: [ka] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9] [Table 2-10] [Table 2-11]

[0074] Other exemplary compounds of Formula I include those in Table 3 below, which are also represented by Formula Ic: [ka] [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] [Table 3-9] [Table 3-10] [Table 3-11]

[0075] Other exemplary compounds of Formula I include those in Table 4 below, which are also represented by Formula Id: [ka] [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] [Table 4-6] [Table 4-7] [Table 4-8]

[0076] Other exemplary compounds of Formula I include those in Table 5 below, which are also represented by Formula Ie: [ka] [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5] [Table 5-6] [Table 5-7] [Table 5-8]

[0077] Other exemplary compounds of Formula I include those in Table 6 below, which are also represented by the formula If: [ka] [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] [Table 6-5] [Table 6-6] [Table 6-7] [Table 6-8] [Table 6-9] [Table 6-10]

[0078] Other exemplary compounds of Formula I include those in Table 7 below, which are also represented by Formula Ig: [ka] [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4] [Table 7-5] [Table 7-6] [Table 7-7] [Table 7-8] [Table 7-9] [Table 7-10] [Table 7-11]

[0079] Other exemplary compounds of Formula I include those in Table 8 below, which are also represented by Formula Ih: [ka] [Table 8-1] [Table 8-2] [Table 8-3] [Table 8-4] [Table 8-5] [Table 8-6] [Table 8-7] [Table 8-8] [Table 8-9] [Table 8-10] [Table 8-11]

[0080] Compositions and Methods As used herein, the term "5-HT1A" refers to the 5-HT1A receptor. As used herein, the term "5-HT2A" refers to the 5-HT2A receptor.

[0081] As used herein, the term "effective amount" in reference to a compound disclosed herein means an amount capable of treating or preventing a disorder, disease or condition disclosed herein, or a symptom thereof.

[0082] As used herein, the term "hallucination" (and related terms, e.g., "hallucinogenic" and "hallucinogen") refers to perceptions in the absence of external stimuli that have the properties of real perception. In some embodiments, hallucinations can be vivid, substantial, and perceived as located in external, objective space. As used herein, hallucinations can occur in any sensory modality, including, but not limited to, vision, hearing, smell, taste, touch, proprioception, equilibrium, nociception, thermoception, and chronoception. In some embodiments, the hallucination is selected from visual hallucinations, auditory hallucinations, olfactory hallucinations, gustatory hallucinations, tactile hallucinations, proprioceptive hallucinations, equilibrium hallucinations, nociception, thermoceptive hallucinations, chronoceptive hallucinations, and any combination thereof. In some embodiments, the hallucination is a visual hallucination.

[0083] As used herein, the term "prevent" or "preventing" refers to a method of delaying and / or eliminating, in whole or in part, the onset, recurrence, or spread of a disorder, disease, or condition; inhibiting a subject from acquiring a disorder, disease, or condition; or reducing a subject's risk of acquiring a disorder, disease, or condition.

[0084] As used herein, the term "treat" or "treating" refers to the total or partial alleviation of a disorder, disease or condition, or one or more symptoms associated with a disorder, disease or condition, or the slowing or halting of further progression or worsening of those symptoms, or the alleviation or eradication of the cause(s) of the disorder, disease or condition itself.

[0085] Further embodiments of the present disclosure describe novel compounds and compositions, as well as methods for administering them. In some embodiments, the compounds provided herein are for use in the methods provided herein. In some embodiments, the present disclosure provides the use of the compounds provided herein in the preparation of a medicament for treating one or more of the diseases or disorders provided herein.

[0086] In certain embodiments, the method includes administering a serotonin 5-HT1A agonist and a serotonin 5-HT2A agonist. Without being bound by any particular theory, it has surprisingly been discovered that in certain embodiments, administering a serotonin 5-HT1A agonist and a serotonin 5-HT2A agonist can be effective in preventing or treating one or more of the conditions described herein. It has also surprisingly been discovered that in certain embodiments, administering a serotonin 5-HT1A agonist and a hallucinogenic 5-HT2A agonist can effectively treat a patient without the patient experiencing the hallucinogenic effects of the 5-HT2A agonist. While not intending to be bound by any particular theory, it is believed that patients may experience therapeutic benefits without experiencing the hallucinogenic symptoms typically associated with administration of a 5-HT2A agonist because the 5-HT1A agonist can "turn off" the hallucinogenic effects of the 5-HT2A agonist without significantly altering its agonism at the 5-HT2A receptor. In some embodiments, the 5-HT1A agonist is a partial agonist. In some embodiments, the 5-HT1A agonist is a full agonist. In some embodiments, the 5-HT2A agonist is a partial agonist. In some embodiments, the 5-HT2A agonist is a full agonist. In some embodiments, the 5-HT1A and / or 5-HT2A agonist may be selected from compounds of Formula I herein. In some embodiments, the 5-HT1A and 5-HT2A agonists are the same compound (e.g., a compound of Formula I).

[0087] As defined herein, a "full agonist" shall mean an agonist having an Emax% of at least 90% for a relevant serotonin receptor agonist assay (e.g., BRET2, calcium mobilization, beta-arrestin) when compared to an industry-accepted control compound for that particular receptor assay (e.g., serotonin (5-OH-tryptamine)). In some embodiments, a "full agonist" will exhibit an Emax% of at least 90, at least 91, at least 92, at least 93, at least 94, at least 95, at least 96, at least 97, at least 98, or at least 99%. Also, as defined herein, a "partial agonist" shall mean an agonist having an Emax% of less than 90% for a relevant serotonin receptor when compared to an industry-accepted control compound for that particular receptor assay (e.g., serotonin (5-OH-tryptamine)). In some embodiments, a "partial agonist" will exhibit an Emax% of less than 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10%, or even less than 5%. In some embodiments, a partial agonist will exhibit an Emax% of about 0.1 to about 89.9%, e.g., about 1 to about 89, about 5 to about 85, about 50 to about 88, about 40 to about 85, about 35 to about 75, about 25 to about 65, or about 20 to about 55%.

[0088] In some embodiments, a 5-HT1A agonist, as used herein, is selected from the group consisting of buspirone (8-[4-(4-pyrimidin-2-ylpiperazin-1-yl)butyl]-8-azaspiro[4.5]decane-7,9-dione), 5-OH-buspirone, 6-OH-buspirone, tandospirone ((1R,2R,6S,7S)-4-{4-[4-(pyrimidin-2-yl)piperazin-1-yl]butyl}-4-azatricyclo[5.2.1.02,6]decane-3,5-dione), gepirone (4,4-dimethyl-1 ...4-(4-(4-pyrimidin-2-ylpiperazin lazin-1-yl)butyl]piperidine-2,6-dione), alnespirone ((+)-4-dihydro-2H-chromen-3-yl]-propylamino]butyl]-8-azaspiro[4.5]decane-7,9-dione), binospirone (8-[2-(2,3-dihydro-1,4-benzodioxin-2-ylmethylamino)ethyl]-8-azaspiro[4.5]decane-7,9-dione), ipsapirone (9,9-dioxo-8-[4-(4-pyrimidin-2-ylpiperazin-1-yl)butyl]-9,6-thia-8-azabicyclo[4.3]-lambda-6).0]nona-1,3,5-trien-7-one), perospirone (3aR,7aS)-2-{4-[4-(1,2-benzisothiazol-3-yl)piperazin-1-yl]butyl}hexahydro-1H-isoindole-1,3(2H)-dione, befiladol (F-13,640) (3-chloro-4-fluorophenyl-[4-fluoro-4-([(5-methylpyridin-2-yl)methylamino]methyl]piperidine-1 -yl]methanone, repinotan ((R)-(-)-2-[4-[(chroman-2-ylmethyl)-amino]-butyl]-1,1-dioxo-benzo[d]isothiazolone), piclozotan (3-chloro-4-[4-[4-(2-pyridinyl)-1,2,3,6-tetrahydropyridin-1-yl]butyl]-1,4-benzoxazepin-5(4H)-one), osemozotan (5-(3-[((2S)-1,4-benzodioxane -2-ylmethyl)amino]propoxy)-1,3-benzodioxole), flesinoxan (4-fluoro-N-[2-[4-[(3S)-3-(hydroxymethyl)-2,3-dihydro-1,4-benzodioxin-8-yl]piperazin-1-yl]ethyl]benzamide), flibanserin (1-(2-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}ethyl)-1,3-dihydro-2H-benzamide), The compound of formula I is selected from the group consisting of 1-[(2R)-3,4-dihydro-2H-chromen-2-yl]-N-([5-(4-fluorophenyl)pyridin-3-yl]methyl)methanamine, ...], and a compound of formula I, or a prodrug, salt, or derivative thereof.

[0089] In some embodiments, the serotonin 5-HT1A agonist and the 5-HT2A agonist are administered simultaneously. In some embodiments, the serotonin 5-HT1A agonist and the 5-HT2A agonist are administered at different times. In some embodiments, the serotonin 5-HT1A agonist and the 5-HT2A agonist are administered sequentially. In some embodiments, the serotonin 5-HT1A agonist is administered first and the 5-HT2A agonist is administered second. In some embodiments, the serotonin 5-HT2A agonist is administered about 30 minutes to about 12 hours, e.g., about 1 hour to about 6 hours, after administration of the 5-HT1A agonist. In some embodiments, the serotonin 5-HT1A agonist and the 5-HT2A agonist are administered simultaneously in the same composition. In some embodiments, the 5-HT1A agonist is selected from buspirone, 5-OH-buspirone, 6-OH-buspirone, and 8-OH-DPAT. In some embodiments, the 5-HT1A agonist is buspirone. In some embodiments, the 5-HT1A agonist is selected from a compound of Formula I, such as a compound of Formula II. In some embodiments, the 5-HT2A agonist is hallucinogenic. In some embodiments, the 5-HT2A agonist is non-hallucinogenic. In some embodiments, the 5-HT2A agonist is selected from a compound of Formula I, such as a compound of Formula II.

[0090] In some embodiments, the 5-HT2A agonist and the 5-HT1A agonist can comprise the same compound. In some embodiments, the compounds of Formula I described herein (e.g., compounds of Formula II) can act as both 5-HT1A and 5-HT2A receptor agonists. In some embodiments, the compounds described herein are full agonists for both 5-HT1A and 5-HT2A.

[0091] In some embodiments, the 5-HT1A agonist and the 5-HT2A agonist are full agonists at the 5-HT1A receptor and the 5-HT2A receptor, respectively. In some embodiments, the 5-HT1A agonist exhibits a higher level of molar potency (i.e., a lower EC2) for activating the 5-HT1A receptor than the 5-HT2A agonist exhibits when activating the 5-HT2A receptor. 50 ) Without being bound by any particular scientific theory, it has been surprisingly discovered that, in certain embodiments, compounds that are agonists for 5-HT1A and 5-HT2A (but that exhibit higher molar potency for 5-HT1A) may be useful for patients needing / desiring non-hallucinogenic 5-HT2A modulation. In other embodiments, the 5-HT1A agonist is a partial agonist (e.g., buspirone) and the 5-HT2A agonist is a full agonist for the 5-HT1A and 5-HT2A receptors, respectively. In other embodiments, the 5-HT1A agonist is a partial agonist (e.g., buspirone) and the 5-HT2A agonist is a partial agonist for the 5-HT1A and 5-HT2A receptors, respectively.

[0092] In certain embodiments, methods are described for treating, preventing, ameliorating, or curing a disease or disorder through a non-hallucinogenic therapeutic treatment regimen involving modulation of the 5-HT1A receptor. In certain embodiments, the method includes identifying a subject in need of treatment for a disease or condition associated with modulation of the 5-HT1A receptor; selecting a compound of Formula I (e.g., comprising Formula II); and administering the compound to the subject in need of treatment, wherein the compound modulates activity at both the 5-HT1A and 5-HT2A receptors. In certain embodiments, the compound of Formula I is a full agonist at the 5-HT1A receptor. In certain embodiments, the compound of Formula I is a full agonist at both the 5-HT1A and 5-HT2A receptors. In certain embodiments, the compound of Formula I is a partial agonist at the 5-HT1A receptor and a full agonist at the 5-HT2A receptor. In certain embodiments, the compound of Formula I is a partial agonist at the 5-HT1A receptor and a partial agonist at the 5-HT2A receptor. In certain embodiments, compounds of Formula I have a higher molar potency (lower EC 50 ) is shown.

[0093] In certain embodiments, the 5-HT1A agonist has an EC50 for activating the 5-HT1A receptor of less than about 100 nM, e.g., less than about 75 nM, less than about 50 nM, less than about 25 nM, less than about 15 nM, less than about 10 nM, or less than about 5 nM. 50 In certain embodiments, the 5-HT2A agonist has an EC for activating the 5-HT2A receptor of less than about 100 nM, e.g., less than about 75 nM, less than about 50 nM, less than about 25 nM, less than about 15 nM, less than about 10 nM, or less than about 5 nM. 50 In certain embodiments, the 5-HT1A agonist has an EC2 for activating the 5-HT1A receptor of about 0.01 nM to about 100 nM, e.g., about 0.05 to about 50 nM, about 0.1 to about 25 nM, or about 0.5 to about 10 nM. 50In certain embodiments, the 5-HT2A agonist has an EC50 for activating the 5-HT2A receptor of about 0.01 nM to about 100 nM, e.g., about 0.05 to about 50 nM, about 0.1 to about 25 nM, or about 0.5 to about 10 nM. 50 In certain embodiments, the 5-HT2A agonist has an EC50 for activating the 5-HT2A receptor of about 5 nM to about 75 nM, e.g., about 10 to about 60 nM, about 15 to about 50 nM, or about 20 to about 40 nM. 50 In some embodiments, the 5-HT1A agonist / 5-HT2A agonist has a 5-HT1A receptor:5-HT2A receptor EC ratio ranging from about 1:2 to about 1:100, e.g., from about 1:5 to about 1:50 or from about 1:10 to about 1:40. 50 In some embodiments, one or more compounds of Formula I independently exhibit a 5-HT1A receptor:5-HT2A receptor EC ratio in the range of about 1:2 to about 1:100, e.g., about 1:5 to about 1:50, or about 1:10 to about 1:40. 50 Ratios are shown. Full vs. partial agonism (Emax%) and molar potency (EC 50 Relevant test parameters for determining 5-HT include those known to those skilled in the art, such as the 5-HT functional assay described further below.

[0094] In some embodiments, novel compounds and compositions, as well as methods for administering the same, are also described. In certain embodiments, the methods include administering a serotonin 5-HT2A agonist and a serotonin 5-HT2B antagonist. Without being bound by any particular theory, in certain embodiments, it has surprisingly been discovered that administering a serotonin 5-HT2A agonist and a serotonin 5-HT2B antagonist can be effective in preventing or treating one or more of the conditions described herein. In some embodiments, it has surprisingly been discovered that administering a serotonin 5-HT2A agonist and a serotonin 5-HT2B antagonist can effectively treat patients while also reducing serotonin 5-HT2B-induced cardiac toxicity (e.g., cardiac valve fibrosis and hypertrophy). It has also been surprisingly discovered that, in certain embodiments, administering a serotonin 5-HT2B antagonist and a 5-HT2A agonist can be safely and effectively used to treat patients described herein without the patient experiencing the hallucinogenic effects that can be associated with hallucinogenic 5-HT2A agonists. In some embodiments, the 5-HT2A agonist is a full agonist. In some embodiments, the 5-HT2A agonist is a partial agonist. In some embodiments, the 5-HT2B antagonist is a full antagonist. In some embodiments, the 5-HT2B antagonist is a partial antagonist.

[0095] Exemplary serotonin 5-HT2B receptor antagonists include, but are not limited to, agomelatine, amisulpride, aliprazole, carprazine, clozapine, cyproheptadine, mCCP, sarpogrelate, lisuride, tegasulod, metadoxine, and promethazine. In certain embodiments, the 5-HT2B antagonist is not an antagonist at any of the other serotonin 5-HT type receptor subtypes, such as 5-HT1A and 5-HT2A. In certain embodiments, the 5-HT2B receptor antagonist is also a full or partial agonist at the 5-HT1A and / or 5-HT2A receptors.

[0096] In some embodiments, the serotonin 5-HT2A agonist and the 5-HT2B antagonist are administered simultaneously. In some embodiments, the serotonin 5-HT2A agonist and the 5-HT2B antagonist are administered at different times. In some embodiments, the serotonin 5-HT2A agonist and the 5-HT2B antagonist are administered simultaneously in the same composition. In some embodiments, the serotonin 5-HT1A agonist and the 5-HT2B antagonist are administered sequentially. In some embodiments, the serotonin 5-HT2B antagonist is administered first and the 5-HT2A agonist is administered second. In some embodiments, the serotonin 5-HT2A agonist is administered about 30 minutes to about 12 hours, e.g., about 1 hour to about 6 hours, after administration of the 5-HT2B antagonist. In some embodiments, the 5-HT2A agonist is hallucinogenic. In some embodiments, the 5-HT2A agonist is non-hallucinogenic. In some embodiments, the 5-HT2A agonist is selected from a compound of Formula I, such as a compound of Formula II.

[0097] In certain embodiments of compounds of Formula I, Applicants have discovered that the size and nature of the alkyl groups for X and / or Y can dramatically affect the metabolism of such compounds. For example, compounds such as 5-MeO-dimethyltryptamine (5-MeO-DMT) and dimethyltryptamine (DMT) are theorized to be inactive upon oral administration due to rapid metabolism of the methylamino residue by monoamine oxidase (MAO) enzymes. On the other hand, the oral stability of psilocin (4-OH-dimethyltryptamine) is largely due to the intramolecular coordination (hydrogen bonding) between the 4-OH group and the dimethylamino residue, which is also theorized to effectively block / inhibit rapid MAO degradation.

[0098] Without being bound by any particular scientific theory, applicants have surprisingly found that substituting alkyl groups X and / or Y with substituents, such as deuterium and fluorine, can aid in the inhibition of MAO degradation of those groups even in the absence of a hydrogen bond donor (e.g., -OH) at the 4-position (e.g., R4 in Formula I). ​​Also, or alternatively, applicants have found that using non-methyl alkyl groups, such as ethyl or n-propyl, for X and / or Y (or when W3 in Formula II is -(CH2)) n -, where a, b, and c are each hydrogen, and n is 1 or 2) can also slow down or inhibit rapid MAO metabolism upon oral administration. This, in turn, allows for the preparation of orally available compounds of Formula I that are highly active serotonergic agents without the need for special formulation procedures (e.g., dosages containing MAO inhibitors) or the presence of hydrogen bond donors at the 4-position, which in some cases can negatively affect the properties of the base compound (e.g., reduced 5-HT1A and / or 5-HT2A agonism).

[0099] In some embodiments, Applicant also provides alpha-deuterated (R and / or R 3’ are deuterium) can dramatically improve the pharmacokinetics of those compounds. Without being bound by any particular scientific theory, it is believed that heavier deuterium isotopes interfere with the enzymatic metabolism of those compounds. However, in some embodiments, it may not be desirable to "over-deuterate" a compound, for example, by including deuterated species for residues X and Y or deuteration at the beta position (i.e., W2), which may further alter the pharmacokinetic profile of the compound in an undesirable manner (e.g., significantly extended half-life). Thus, in some embodiments, Applicant has discovered that minimal deuteration can be used to achieve a desired pharmacokinetic outcome. For example, in some embodiments, heavier deuterium isotopes can be used to "over-deuterate" a compound, for example, by including deuterated species for residues X and Y or deuteration at the beta position (i.e., W2), which may further alter the pharmacokinetic profile of the compound in an undesirable manner (e.g., significantly extended half-life). Accordingly, in some embodiments, Applicant has discovered that minimal deuteration can be used to achieve a desired pharmacokinetic outcome. For example, in some embodiments, 3’A single deuterium atom at the alpha position can significantly enhance the desired pharmacokinetic profile. It is theorized that this may be due, in part, to the creation of a stereocenter at the alpha position upon deuteration, which affects the ability of enzymes to metabolize the compound (e.g., preventing MAO degradation and / or the ability of enzymes to oxidize the alpha position during metabolic processing).

[0100] In one embodiment, the compounds of Formula I, methods, and pharmaceutical compositions described herein are used to modulate neurotransmitter receptor activity by administering a therapeutically effective amount of a compound of Formula I. The methods include administering a therapeutically effective amount of a compound of Formula I to prevent or treat psychiatric disorders, such as those discussed herein. The compound of Formula I can be administered neat or as a pharmaceutical composition comprising a compound of Formula I, as discussed below.

[0101] In some embodiments, compounds of Formula I can be used to prevent and / or treat psychiatric disorders. The present disclosure provides methods for preventing and / or treating psychiatric disorders by administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, including the exemplary embodiments discussed above. The mental disorder may be selected from depression; psychotic disorder; schizophrenia; schizophreniform disorder (acute schizophrenic episode); schizoaffective disorder; bipolar I disorder (mania, manic disorder, manic depression); bipolar II disorder; major depressive disorder; major depressive disorder with psychotic features (psychotic depression); delusional disorder (paranoia); shared psychotic disorder (shared paranoid disorder); brief psychotic disorder (other and unspecified reaction psychosis); psychotic disorder not otherwise specified (unspecified psychosis); paranoid personality disorder; schizotypal personality disorder; schizotypal personality disorder; anxiety disorder; social anxiety disorder; substance-induced anxiety disorder; selective mutism; panic disorder; panic attacks; agoraphobia; attention deficit syndrome, post-traumatic stress disorder (PTSD), premenstrual dysphoric disorder (PMDD), and premenstrual syndrome (PMS).

[0102] In some embodiments, the compounds of Formula I can be used to prevent and / or treat brain disorders. The present disclosure provides methods for preventing and / or treating brain disorders by administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, including the exemplary embodiments discussed above. The brain disorder can be selected from Huntington's disease, Alzheimer's disease, dementia, and Parkinson's disease.

[0103] In some embodiments, compounds of Formula I can be used to prevent and / or treat developmental disorders, delirium, dementia, amnestic disorders and other cognitive disorders, mental disorders due to somatic pathology, substance-related disorders, schizophrenia and other psychotic disorders, mood disorders, anxiety disorders, somatic type disorders, factitious disorders, dissociative disorders, eating disorders, sleep disorders, impulse control disorders, adjustment disorders, or personality disorders. The present disclosure provides methods for preventing and / or treating these disorders by administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, including the exemplary embodiments discussed above.

[0104] In some embodiments, compounds of Formula I can be used to prevent and / or treat inflammation and / or pain, such as inflammation and / or pain associated with inflammatory skeletal or muscular diseases or conditions. Accordingly, the present disclosure relates to methods for preventing and / or treating inflammation and / or pain by administering a therapeutically effective amount of a compound of Formula I to a subject in need thereof, including the exemplary embodiments discussed above. Generally speaking, treatable "pain" includes nociceptive, neuropathic, and mixed types. The methods of the present disclosure may reduce or alleviate symptoms associated with inflammation, including, but not limited to, treating localized signs of inflammation characterized in some cases by acute or chronic swelling, pain, redness, elevated temperature, or loss of function. The methods of the present disclosure may reduce or alleviate symptoms of pain regardless of its cause, including, but not limited to, reducing pain of various severity levels, i.e., mild, moderate, and severe pain, acute pain, and chronic pain. The methods of the present disclosure are effective in treating inflammation, such as joint pain, muscle pain, tendon pain, burn pain, and pain caused by rheumatoid arthritis. Skeletal or muscular diseases or conditions that may be treated include, but are not limited to, musculoskeletal sprains, musculoskeletal strains, tendinopathy, peripheral radiculopathy, osteoarthritis, degenerative joint disease, polymyalgia rheumatica, juvenile arthritis, gout, ankylosing spondylitis, psoriatic arthritis, systemic lupus erythematosus, costochondritis, tendinitis, bursitis, such as common lateral epicondylitis (tennis elbow), medial epicondylitis (baseball elbow) and trochanteric bursitis, temporomandibular joint syndrome, and fibromyalgia.

[0105] In other embodiments, the methods and compositions disclosed herein involve regulating neurotransmitter receptor activity with a formulation comprising a compound of Formula I. In one embodiment, the methods and compositions disclosed herein involve administering a first dosage formulation comprising at least one compound of Formula I and a second active compound. In one embodiment, the methods disclosed herein involve administering a first dosage formulation comprising a compound of Formula I and a neurotransmitter activity modulator (e.g., a second serotonergic agent). In one embodiment, the methods disclosed herein involve administering a first dosage formulation comprising at least a compound of Formula I and a second dosage form comprising at least one cannabinoid, at least one terpene, or a second serotonergic agent.

[0106] The present disclosure relates to compositions comprising, consisting essentially of, or consisting of an effective amount of a compound of Formula I and an excipient. The terms "composition" and "formulation" are used interchangeably herein. Other embodiments relate to pharmaceutical compositions comprising, consisting essentially of, or consisting of a therapeutically effective amount of a compound of Formula I (including those discussed above) and a pharmaceutically acceptable excipient (also known as a pharmaceutically acceptable carrier). As discussed above, compounds of Formula I can be therapeutically useful for preventing and / or treating, for example, psychiatric disorders, brain disorders, pain and inflammation, and other disorders, such as those discussed above.

[0107] In some embodiments, the compositions described herein may comprise at least one compound of Formula I and a second compound selected from at least one of a second serotonergic agent, a cannabinoid, a terpene, or an MAO inhibitor. In certain embodiments, the second compound may be derived from a natural source, such as fungi (e.g., shiitake mushroom; Yamabushitake mushroom (containing terpenes, e.g., erinacine and hericenones)) and plants (e.g., cannabis). Thus, in certain embodiments, the second compound may be derived from or extracted from fungal or plant material, meaning that the second compound may or may not be "purified" depending on the extraction method used to obtain it.

[0108] Within the context of the present disclosure, the term "purified" means separated from other compounds or substances, e.g., plant or fungal material, e.g., protein, chitin, cellulose, or water. In one embodiment, the term "purified" refers to a compound that is substantially free of other substances. In one embodiment, the term "purified" refers to a compound that is substantially free of a second compound (e.g., an enantiomeric compound of Formula I that exhibits 99% enantiomeric excess after resolution). In one embodiment, the term "purified" refers to a compound that is substantially free of biological material, e.g., mold, fungus, plant material, or bacteria.

[0109] In one embodiment, the term "purified" refers to a compound or composition that has been crystallized. In one embodiment, the term "purified" refers to a compound or composition that has been chromatographed, for example, by gas chromatography, liquid chromatography (e.g., LC, HPLC, etc.), etc. In one embodiment, the term "purified" refers to a compound or composition that has been distilled. In one embodiment, the term "purified" refers to a compound or composition that has been sublimated. In one embodiment, the term "purified" refers to a compound or composition that has been subjected to two or more processes selected from crystallization, chromatography, distillation, or sublimation.

[0110] In one embodiment, the term "purified" refers to a compound having a purity ranging from about 80% to about 100%, meaning that the compound comprises about 80% to about 100% of the total mass of the composition. In one embodiment, the term "purified" refers to a compound having a purity ranging from about 90% to about 100%, meaning that the compound comprises about 90% to about 100% of the total mass of the composition. In one embodiment, the term "purified" refers to a compound having a purity ranging from about 95% to about 100%, meaning that the compound comprises about 95% to about 100% of the total mass of the composition. In one embodiment, the term "purified" refers to a compound having a purity ranging from about 99% to about 100% pure, meaning that the compound comprises about 99% to about 100% of the total mass of the composition. In one embodiment, the term "purified" refers to a compound having a purity ranging from about 99.9% to about 100%, meaning that the compound comprises about 99.9% to about 100% of the total mass of the composition.

[0111] As used herein, the term "specific ratio" refers to the amount of one compound relative to the amount of another compound(s). In one embodiment, there is about a 1:1 ratio of 4-acetoxy-3-[2-(dimethylamino)ethyl]-benzo[b]thiophene) to 4-hydroxy-N,N-dimethyltryptamine. In one embodiment, the specific ratio of the compounds is measured in the same units, e.g., grams, kilograms, pounds, ounces, etc. In one embodiment, the specific ratio of the compounds is measured in moles, i.e., molar concentration ratio or molar ratio.

[0112] As used herein, the term "specific amount" refers to a compound or the amount of a compound. In one embodiment, the specific amount is the combined amount of two compounds in a sample. In one embodiment, the specific amount is measured by dry weight. In one embodiment, the specific amount has 1, 2, 3, or 4 significant digits.

[0113] Disclosed herein are compositions comprising a compound of Formula I and a second compound. In one embodiment, the compositions disclosed herein comprise a molar ratio of the compound of Formula I (e.g., comprising a 5-HT2A receptor agonist) to the second compound (e.g., comprising a 5-HT1A receptor agonist) ranging from about 10:1 to about 1:10. In one embodiment, the compositions disclosed herein comprise a molar ratio of the compound of Formula I to the second compound ranging from about 100:1 to about 1:100. In one embodiment, the compositions disclosed herein comprise a molar ratio of the compound of Formula I to the second compound ranging from about 1,000:1 to about 1:1,000. In one embodiment, the compositions disclosed herein comprise a molar ratio of the compound of Formula I to the second compound ranging from about 10,000:1 to about 1:10,000.

[0114] Within the context of the present disclosure, unless otherwise specified, the serotonergic compounds (e.g., tryptamine compounds) described herein may exist in their protonated or deprotonated (salt or free base) forms or mixtures thereof, depending on the context, e.g., the pH of the solution or composition. However, in certain embodiments, the serotonergic compounds described herein will be lipid-soluble, meaning that they tend to combine with lipids and fats and can easily cross biological membranes in the animal or human body (e.g., the blood-brain barrier). In certain embodiments, the free base form of the serotonergic compounds will be lipid-soluble.

[0115] As used herein, the term "salt" refers to a neutralized ionic compound. In one embodiment, a salt is formed from the neutralization of an acid and a base. In one embodiment, a salt is electrically neutral.

[0116] In one embodiment, the compositions and methods disclosed herein comprise administering a first cannabinoid, hi one embodiment, the first cannabinoid is a first purified cannabinoid.

[0117] As used herein, the term "cannabinoid" refers to compounds and their derivatives from a class of molecules commonly found in plants of the Cannabis genus. In one embodiment, the cannabinoid is endogenous to animals, i.e., an endogenous cannabinoid. In one embodiment, the cannabinoid is derived from a plant, e.g., a Cannabis plant, e.g., a phytocannabinoid. In one embodiment, the cannabinoid is artificially created in a laboratory, i.e., a synthetic cannabinoid. Many cannabinoids can be identified by the letter "cannabi" in their chemical name. There are at least 113 different cannabinoids isolated from Cannabis, which exhibit a variety of effects (similar and different).

[0118] Examples of cannabinoids within the context of the present disclosure include the following molecules: cannabichromene (CBC), cannabichromenic acid (CBCA), cannabichromevarin (CBCV), cannabichromevaric acid (CBCVA), cannabicyclol (CBL), cannabicyclolic acid (CBLA), cannabicyclovaline (CBLV), cannabidiol (CBD), cannabidiol monomethyl ether (CBDM), cannabidiolic acid (CBDA), cannabidiolcol (CBD-C1), cannabidivarin (CBDV), cannabidivaric acid (CBDVA), cannabielsoic acid B (CBEA-B), cannabielsoin (CBE), cannabielsoic acid A (CBEA-A), cannabigerol (CBG), cannabigerol monomethyl ether (CBGM), cannabigerolic acid (CBGA), cannabigerolic acid monomethyl ether (CBGA M), cannabigerovarin (CBGV), cannabigerovaric acid (CBGVA), cannabinodiol (CBND), cannabinodivarine (CBDV), cannabinol (CBN), cannabinol methyl ether (CBNM), cannabinol-C2 (CBN-C2), cannabinol-C4 (CBN-C4), cannabinolic acid (CBNA), cannabiocur (CBN-C1), cannabivarin (CBV), cannabidiol (CBT), cannabidiolvaline (CBTV), 10-ethoxy-9-hydroxy-delta-6a-tetrahydrocannabinol, cannabiditran (CBT), cannabilipsol (CBR), 8,9-dihydroxy-delta-6a-tetrahydrocannabinol, delta-8-tetrahydrocannabinol (delta-8-THC), delta-8-tetrahydrocannabinolic acid (delta-8-THC).8-THCA), delta-9-tetrahydrocannabinol (THC), delta-9-tetrahydrocannabinol-C4 (THC-C4), delta-9-tetrahydrocannabinolic acid A (THCA-A), delta-9-tetrahydrocannabinolic acid B (THCA-B), delta-9-tetrahydrocannabinolic acid-C4 (THCA-C4), delta-9-tetrahydrocannabiolchol (THC-C1), delta-9-tetrahydrocannabiolcholic acid (THCA-C1), delta-9-tetrahydrocannabivarin (THCV), delta-9-tetrahydrocannabi These include valine, 10-oxo-delta-6a-tetrahydrocannabinol (OTHC), cannabichromanone (CBCF), cannabifuran (CBF), cannabiglendol, delta-9-cis-tetrahydrocannabinol (cis-THC), trihydroxy-delta-9-tetrahydrocannabinol (triOH-THC), dehydrocannabifuran (DCBF), and 3,4,5,6-tetrahydro-7-hydroxy-alpha-alpha-2-trimethyl-9-n-propyl-2,6-methano-2H-1-benzoxocin-5-methanol.

[0119] In one embodiment, the term "cannabinoid" refers to a compound selected from THC, THCA, THCV, THCVA, CBC, CBCA, CBCV, CBCVA, CBD, CBDA, CBDV, CBDVA, CBG, CBGA, CBGV, or CBGVA.

[0120] Within the context of this disclosure, the term "THC" includes any derivative of delta-9-tetrahydrocannabinol and / or its salts. In one embodiment, the compositions disclosed herein include THC and a compound of Formula I. In one embodiment, the THC is purified THC. In one embodiment, the methods disclosed herein include administering a composition comprising THC and a compound of Formula I. In one embodiment, the THC is purified THC.

[0121] Within the context of the present disclosure, the term "THCA" includes any derivative of tetrahydrocannabinolic acid and / or its salts. In one embodiment, the compositions disclosed herein include THCA and a compound of Formula I. In one embodiment, the THCA is purified THCA. In one embodiment, the methods disclosed herein include administering a composition comprising THCA and a compound of Formula I. In one embodiment, the THCA is purified THCA.

[0122] Within the context of the present disclosure, the term "THCV" includes any derivative of delta-9-tetrahydrocannabivarin and / or its salts. In one embodiment, the compositions disclosed herein comprise THCV and a compound of Formula I. In one embodiment, the THCV is purified THCV. In one embodiment, the methods disclosed herein comprise administering a composition comprising THCV and a compound of Formula I. In one embodiment, the THCV is purified THCV.

[0123] Within the context of the present disclosure, the term "THCVA" includes any derivative of delta-9-tetrahydrocannabivarinic acid and / or its salt. In one embodiment, the compositions disclosed herein include THCVA and a compound of Formula I. In one embodiment, the THCVA is purified THCVA. In one embodiment, the methods disclosed herein include administering a composition comprising THCVA and a compound of Formula I. In one embodiment, the THCVA is purified THCVA.

[0124] Within the context of the present disclosure, the term "CBC" includes any derivative of cannabichromene and / or its salts. In one embodiment, the composition disclosed herein comprises CBC and a compound of Formula I. In one embodiment, the CBC is purified CBC. In one embodiment, the method disclosed herein comprises administering a composition comprising CBC and a compound of Formula I. In one embodiment, the CBC is purified CBC.

[0125] Within the context of the present disclosure, the term "CBCA" includes any derivative of cannabichromene acid and / or its salts. In one embodiment, a composition disclosed herein comprises a CBCA and a compound of Formula I. In one embodiment, the CBCA is purified CBCA. In one embodiment, a method disclosed herein comprises administering a composition comprising a CBCA and a compound of Formula I. In one embodiment, the CBCA is purified CBCA.

[0126] Within the context of the present disclosure, the term "CBCV" includes any derivative of cannabichromevalin and / or its salts. In one embodiment, a composition disclosed herein comprises a CBCV and a compound of Formula I. In one embodiment, the CBCV is purified CBCV. In one embodiment, a method disclosed herein comprises administering a composition comprising a CBCV and a compound of Formula I. In one embodiment, the CBCV is purified CBCV.

[0127] Within the context of the present disclosure, the term "CBCVA" includes any derivative of cannabichromevaric acid and / or its salts. In one embodiment, a composition disclosed herein comprises a CBCVA and a compound of Formula I. In one embodiment, the CBCVA is purified CBCVA. In one embodiment, a method disclosed herein comprises administering a composition comprising a CBCVA and a compound of Formula I. In one embodiment, the CBCVA is purified CBCVA.

[0128] Within the context of the present disclosure, the term "CBD" includes any derivative of cannabidiol and / or its salts. In one embodiment, a composition disclosed herein comprises CBD and a compound of Formula I. In one embodiment, the CBD is purified CBD. In one embodiment, a method disclosed herein comprises administering a composition comprising CBD and a compound of Formula I. In one embodiment, the CBD is purified CBD.

[0129] Within the context of the present disclosure, the term "CBDA" includes any derivative of cannabidiolic acid and / or its salts. In one embodiment, a composition disclosed herein comprises CBDA and a compound of Formula I. In one embodiment, the CBDA is purified CBDA. In one embodiment, a method disclosed herein comprises administering a composition comprising CBDA and a compound of Formula I. In one embodiment, the CBDA is purified CBDA.

[0130] Within the context of the present disclosure, the term "CBDV" includes any derivative of cannabidivarin and / or its salts. In one embodiment, the compositions disclosed herein comprise CBDV and a compound of Formula I. In one embodiment, the CBDV is purified CBDV. In one embodiment, the methods disclosed herein comprise administering a composition comprising CBDV and a compound of Formula I. In one embodiment, the CBDV is purified CBDV.

[0131] Within the context of the present disclosure, the term "CBDVA" includes any derivative of cannabidivarinic acid and / or its salts. In one embodiment, a composition disclosed herein comprises CBDVA and a compound of formula I. In one embodiment, the CBDVA is purified CBDVA. In one embodiment, a method disclosed herein comprises administering a composition comprising CBDVA and a compound of formula I. In one embodiment, the CBDVA is purified CBDVA.

[0132] Within the context of the present disclosure, the term "CBG" includes any derivative of cannabigerol and / or its salts. In one embodiment, a composition disclosed herein comprises CBG and a compound of Formula I. In one embodiment, the CBG is purified CBG. In one embodiment, a method disclosed herein comprises administering a composition comprising CBG and a compound of Formula I. In one embodiment, the CBG is purified CBG.

[0133] Within the context of the present disclosure, the term "CBGA" includes any derivative of cannabigerolic acid and / or its salts. In one embodiment, a composition disclosed herein comprises CBGA and a compound of Formula I. In one embodiment, the CBGA is purified CBGA. In one embodiment, a method disclosed herein comprises administering a composition comprising CBGA and a compound of Formula I. In one embodiment, the CBGA is purified CBGA.

[0134] Within the context of the present disclosure, the term "CBGV" includes any derivative of cannabigerovarin and / or its salts. In one embodiment, a composition disclosed herein comprises CBGV and a compound of Formula I. In one embodiment, the CBGV is purified CBGV. In one embodiment, a method disclosed herein comprises administering a composition comprising CBGV and a compound of Formula I. In one embodiment, the CBGV is purified CBGV.

[0135] Within the context of the present disclosure, the term "CBGVA" includes any derivative of cannabigerovarinic acid and / or its salts. In one embodiment, a composition disclosed herein comprises CBGVA and a compound of Formula I. In one embodiment, the CBGVA is purified CBGVA. In one embodiment, a method disclosed herein comprises administering a composition comprising CBGVA and a compound of Formula I. In one embodiment, the CBGVA is purified CBGVA.

[0136] In one embodiment, a composition disclosed herein comprises a compound of Formula I and a purified cannabinoid in a specific ratio (e.g., molar ratio) ranging from about 100:1 to about 1:100. In one embodiment, a composition disclosed herein comprises a compound of Formula I and a purified cannabinoid in a specific ratio (e.g., molar ratio) ranging from about 75:1 to about 1:75. In one embodiment, a composition disclosed herein comprises a compound of Formula I and a purified cannabinoid in a specific ratio (e.g., molar ratio) ranging from about 50:1 to about 1:50. In one embodiment, a composition disclosed herein comprises a compound of Formula I and a purified cannabinoid in a specific ratio (e.g., molar ratio) ranging from about 25:1 to about 1:25. In one embodiment, a composition disclosed herein comprises a compound of Formula I and a purified cannabinoid in a specific ratio (e.g., molar ratio) ranging from about 10:1 to about 1:10. In one embodiment, the compositions disclosed herein comprise a compound of formula I and a purified cannabinoid in a specific ratio (e.g., molar ratio) ranging from about 5:1 to about 1:5.

[0137] In one embodiment, the compositions and methods disclosed herein include a compound of Formula I, a first purified cannabinoid, and a second purified cannabinoid. In one embodiment, the second purified cannabinoid is selected from THC, THCA, THCV, THCVA, CBC, CBCA, CBCV, CBCVA, CBD, CBDA, CBDV, CBDVA, CBG, CBGA, CBGV, or CBGVA.

[0138] In one embodiment, a composition disclosed herein comprises a compound of Formula I and a first purified cannabinoid and a second purified cannabinoid in a specific ratio (e.g., molar ratio) ranging from about 100:1 to about 1:100. In one embodiment, a composition disclosed herein comprises a compound of Formula I and a first purified cannabinoid and a second purified cannabinoid in a specific ratio (e.g., molar ratio) ranging from about 75:1 to about 1:75. In one embodiment, a composition disclosed herein comprises a compound of Formula I and a first purified cannabinoid and a second purified cannabinoid in a specific ratio (e.g., molar ratio) ranging from about 50:1 to about 1:50.

[0139] In one embodiment, a composition disclosed herein comprises a compound of Formula I and a first purified cannabinoid and a second purified cannabinoid in a specific ratio (e.g., molar ratio) ranging from about 25:1 to about 1:25. In one embodiment, a composition disclosed herein comprises a compound of Formula I and a first purified cannabinoid and a second purified cannabinoid in a specific ratio (e.g., molar ratio) ranging from about 10:1 to about 1:10. In one embodiment, a composition disclosed herein comprises a compound of Formula I and a first purified cannabinoid and a second purified cannabinoid in a specific ratio (e.g., molar ratio) ranging from about 5:1 to about 1:5.

[0140] In one embodiment, the compositions and methods disclosed herein comprise administering a compound of formula I and a terpene. In one embodiment, the terpene is a purified terpene.

[0141] As used herein, the term "terpene" refers to a compound that belongs to a large class of compounds that are often biosynthesized from five-carbon isoprene units. In one embodiment, terpenes are isolated from plants, such as conifers, hemp, basil, etc. In one embodiment, terpenes are produced by insects, such as termites or swallowtail butterflies. In one embodiment, terpenes are volatile compounds. In one embodiment, terpenes produce odors. In one embodiment, terpenes are the major components of natural resins, such as turpentine produced from resins. In one embodiment, terpenes are biosynthetically derived from isoprene units, which have the molecular formula CH. In one embodiment, the molecular formula of a terpene is (CH) n (wherein n is a multiple of the number of linked isoprene units, for example, 1 to 5).

[0142] Within the context of the present disclosure, when a terpene is chemically modified, for example, by oxidation or rearrangement of the carbon skeleton, the resulting compound is referred to as a "terpenoid." In the relevant art, terpenoids are sometimes referred to as isoprenoids.

[0143] In one embodiment, terpenes are the major component(s) of essential oils from plants and / or flowers. Essential oils are widely used as fragrances in perfumery, medicine, and alternative medicine, e.g., aromatherapy.

[0144] In one embodiment, terpenes are classified according to the number of isoprene (C5H8) units in the compound (e.g., monoterpenes (C 10 H 16 ), sesquiterpenes (C 15 H 24 ), diterpenes (C 20 H 32 ), triterpenes (C 30 H 48 ), or tetraterpenes (C 40 H 64 )).

[0145] Examples of terpenes within the context of the present disclosure include acetanisole, acetylcedrene, anethole, anisole, benzaldehyde, bornyl acetate, borneol, cadinene, cafestol, caffeic acid, camphene, camphor, capsaicin, carene, carotene, carvacrol, carvone, alpha-caryophyllene, beta-caryophyllene, caryophyllene oxide, cedrene, cedrene epoxide, secanal, cedrol, cembrene, cinnamaldehyde, cinnamic acid, citronellal, and citronellol. , cymene, eicosane, elemene, estragole, ethyl acetate, ethyl cinnamate, ethyl maltol, eucalyptol / 1,8-cineole, eudesmol, eugenol, euphor, farnesene, farnesol, fenchone, geraniol, geranyl acetate, guaia-1(10),11-diene, guaiacol, guaiol, guaien, gurjunene, hernialin, hexanoic acid, humulene, ionone, ipsdienol, isoamyl acetate, isoamido Alcohol, Isoamylformate, Isoborneol, Isomyrcenol, Isoprene, Isopulegol, Isovaleric Acid, Lavandulol, Limonene, Gamma-Linolenic Acid, Linalool, Longifolene, Lycopene, Menthol, Methyl Butyrate, 3-Mercapto-2-Methylpentanal, Beta-Mercaptoethanol, Mercaptoacetic Acid, Methyl Salicylate, Methylbutenol, Methyl-2-Methylvalerate, Methylthiobutyrate, Beta-Myrcene, Gamma-Murolene, Nepetalactone, Nerol , nerolidol, neryl acetate, nonanaldehyde, nonanoic acid, ocimene, octanal, octanoic acid, pentyl butyrate, phellandrene, phenylacetaldehyde, phenylacetic acid, phenylethanethiol, phytol, pinene, propanethiol, pristimerin, pulegone, retinol, rutin, sabinene, squalene, taxadiene, terpineol, terpin-4-ol, terpinolenene, thujone, thymol, umbelliferone, undecanal, verdoxane, and vanillin.

[0146] In one embodiment, the terpene to be purified is selected from bornyl acetate, alpha-bisabolol, borneol, camphene, camphor, carene, beta-caryophyllene, cedrene, cymene, elemene, eucalyptol, eudesmol, farnesene, fenchol, geraniol, guaiacol, humulene, isoborneol, limonene, linalool, menthol, beta-myrcene, nerolidol, ocimene, phellandrene, phytol, pinene, pulegone, sabinene, terpineol, terpinolenene, or valencene.

[0147] Within the context of the present disclosure, the term "bornyl acetate" includes any derivatives and / or salts thereof, including any isomeric, structural, and / or enantiomeric variations thereof. In one embodiment, a composition disclosed herein comprises bornyl acetate and a compound of Formula I. In one embodiment, the bornyl acetate comprises purified bornyl acetate. In one embodiment, a method disclosed herein comprises administering a composition comprising bornyl acetate and a compound of Formula I. In one embodiment, the bornyl acetate comprises purified bornyl acetate.

[0148] Within the context of the present disclosure, the term "alpha-bisabolol" includes any derivatives and / or salts thereof, including any isomeric, structural, and / or enantiomeric variations thereof. In one embodiment, a composition disclosed herein comprises alpha-bisabolol and a compound of Formula I. In one embodiment, the alpha-bisabolol comprises purified alpha-bisabolol. In one embodiment, a method disclosed herein comprises administering a composition comprising alpha-bisabolol and a compound of Formula I. In one embodiment, the alpha-bisabolol comprises purified alpha-bisabolol.

[0149] Within the context of the present disclosure, the term "borneol" includes any derivatives and / or salts thereof, including any isomeric, structural, and / or enantiomeric variations thereof. In one embodiment, the composition disclosed herein comprises borneol and a compound of Formula I. In one embodiment, the borneol comprises purified borneol. In one embodiment, the method disclosed herein comprises administering a composition comprising borneol and a compound of Formula I. In one embodiment, the borneol is purified borneol.

[0150] Within the context of the present disclosure, the term "camphene" includes any derivatives and / or salts thereof, including any isomeric, structural, and / or enantiomeric variations thereof. In one embodiment, the composition disclosed herein comprises camphene and a compound of Formula I. In one embodiment, the camphene comprises purified camphene. In one embodiment, the method disclosed herein comprises administering a composition comprising camphene and a compound of Formula I. In one embodiment, the camphene is purified camphene.

[0151] Within the context of the present disclosure, the term "camphor" includes any derivatives and / or salts thereof, including any isomeric, structural and / or enantiomeric variations thereof. In one embodiment, the composition disclosed herein comprises camphor and a compound of Formula I. In one embodiment, the camphor comprises purified camphor. In one embodiment, the method disclosed herein comprises administering a composition comprising camphor and a compound of Formula I. In one embodiment, the camphor is purified camphor.

[0152] Within the context of the present disclosure, the term "carene" includes any derivatives and / or salts thereof, including any isomeric, structural, and / or enantiomeric variations thereof. In one embodiment, the composition disclosed herein comprises carene and a compound of Formula I. In one embodiment, the carene comprises purified carene. In one embodiment, the method disclosed herein comprises administering a composition comprising carene and a compound of Formula I. In one embodiment, the carene is purified carene.

[0153] Within the context of the present disclosure, the term "beta-caryophyllene" includes any derivatives and / or salts thereof, including any isomeric, structural, and / or enantiomeric variations thereof. In one embodiment, a composition disclosed herein comprises beta-caryophyllene and a compound of Formula I. In one embodiment, the beta-caryophyllene comprises purified beta-caryophyllene. In one embodiment, a method disclosed herein comprises administering a composition comprising beta-caryophyllene and a compound of Formula I. In one embodiment, the beta-caryophyllene comprises purified beta-caryophyllene.

[0154] Within the context of the present disclosure, the term "cedrene" includes any derivatives and / or salts thereof, including any isomeric, structural, and / or enantiomeric variations thereof. In one embodiment, the compositions disclosed herein comprise cedrene and a compound of Formula I. In one embodiment, the cedrene comprises purified cedrene. In one embodiment, the methods disclosed herein comprise administering a composition comprising cedrene and a compound of Formula I. In one embodiment, the cedrene is purified cedrene.

[0155] Within the context of the present disclosure, the term "cymene" includes any derivatives and / or salts thereof, including any isomeric, structural, and / or enantiomeric variations thereof. In one embodiment, the composition disclosed herein comprises cymene and a compound of Formula I. In one embodiment, the cymene comprises purified cymene. In one embodiment, the method disclosed herein comprises administering a composition comprising cymene and a compound of Formula I. In one embodiment, the cymene is purified cymene.

[0156] Within the context of the present disclosure, the term "elemene" includes any derivatives and / or salts thereof, including any isomeric, structural, and / or enantiomeric variations thereof. In one embodiment, the composition disclosed herein comprises elemene and a compound of Formula I. In one embodiment, the elemene comprises purified elemene. In one embodiment, the method disclosed herein comprises administering a composition comprising elemene and a compound of Formula I. In one embodiment, the elemene is purified elemene.

[0157] Within the context of the present disclosure, the term "eucalyptol" includes any derivatives and / or salts thereof, including any isomeric, structural, and / or enantiomeric variations thereof. In one embodiment, the compositions disclosed herein comprise eucalyptol and a compound of Formula I. In one embodiment, the eucalyptol comprises purified eucalyptol. In one embodiment, the methods disclosed herein comprise administering a composition comprising eucalyptol and a compound of Formula I. In one embodiment, the eucalyptol is purified eucalyptol.

[0158] Within the context of the present disclosure, the term "eudesmol" includes any derivatives and / or salts thereof, including any isomeric, structural, and / or enantiomeric variations thereof. In one embodiment, the compositions disclosed herein comprise eudesmol and a compound of Formula I. In one embodiment, the eudesmol comprises purified eudesmol. In one embodiment, the methods disclosed herein comprise administering a composition comprising eudesmol and a compound of Formula I. In one embodiment, the eudesmol is purified eudesmol.

[0159] Within the context of the present disclosure, the term "farnesene" includes any derivatives and / or salts thereof, including any isomeric, structural, and / or enantiomeric variations thereof. In one embodiment, the compositions disclosed herein comprise farnesene and a compound of Formula I. In one embodiment, the farnesene comprises purified farnesene. In one embodiment, the methods disclosed herein comprise administering a composition comprising farnesene and a compound of Formula I. In one embodiment, the farnesene is purified farnesene.

[0160] Within the context of the present disclosure, the term "fenchol" includes any derivatives and / or salts thereof, including any isomeric, structural, and / or enantiomeric variations thereof. In one embodiment, the composition disclosed herein comprises fenchol and a compound of Formula I. In one embodiment, the fenchol comprises purified fenchol. In one embodiment, the method disclosed herein comprises administering a composition comprising fenchol and a compound of Formula I. In one embodiment, the fenchol is purified fenchol.

[0161] Within the context of the present disclosure, the term "geraniol" includes any derivatives and / or salts thereof, including any isomeric, structural, and / or enantiomeric variations thereof. In one embodiment, the composition disclosed herein comprises geraniol and a compound of Formula I. In one embodiment, the geraniol comprises purified geraniol. In one embodiment, the method disclosed herein comprises administering a composition comprising geraniol and a compound of Formula I. In one embodiment, the geraniol is purified geraniol.

[0162] Within the context of the present disclosure, the term "guaiacol" includes any derivatives and / or salts thereof, including any isomeric, structural, and / or enantiomeric variations thereof. In one embodiment, the composition disclosed herein comprises guaiacol and a compound of Formula I. In one embodiment, the guaiacol comprises purified guaiacol. In one embodiment, the method disclosed herein comprises administering a composition comprising guaiacol and a compound of Formula I. In one embodiment, the guaiacol is purified guaiacol.

[0163] Within the context of the present disclosure, the term "humulene" includes any derivatives and / or salts thereof, including any isomeric, structural, and / or enantiomeric variations thereof. In one embodiment, the composition disclosed herein comprises humulene and a compound of Formula I. In one embodiment, the humulene comprises purified humulene. In one embodiment, the method disclosed herein comprises administering a composition comprising humulene and a compound of Formula I. In one embodiment, the humulene is purified humulene.

[0164] Within the context of the present disclosure, the term "isoborneol" includes any derivatives and / or salts thereof, including any isomeric, structural, and / or enantiomeric variations thereof. In one embodiment, the compositions disclosed herein comprise isoborneol and a compound of Formula I. In one embodiment, the isoborneol comprises purified isoborneol. In one embodiment, the methods disclosed herein comprise administering a composition comprising isoborneol and a compound of Formula I. In one embodiment, the isoborneol is purified isoborneol.

[0165] Within the context of the present disclosure, the term "limonene" includes any derivatives and / or salts thereof, including any isomeric, structural, and / or enantiomeric variations thereof. In one embodiment, a composition disclosed herein comprises limonene and a compound of Formula I. In one embodiment, the limonene comprises purified limonene. In one embodiment, a method disclosed herein comprises administering a composition comprising limonene and a compound of Formula I. In one embodiment, the limonene is purified limonene.

[0166] In the context of the present disclosure, the term "linalool" includes any derivative and / or its salt, including any isomeric, structural and / or enantiomeric variations thereof.In one embodiment, the composition disclosed herein comprises linalool and a compound of formula I.In one embodiment, the linalool comprises purified linalool.In one embodiment, the method disclosed herein comprises administering a composition comprising linalool and a compound of formula I.In one embodiment, the linalool is purified linalool.

[0167] Within the context of the present disclosure, the term "menthol" includes any derivatives and / or salts thereof, including any isomeric, structural, and / or enantiomeric variations thereof. In one embodiment, the composition disclosed herein comprises menthol and a compound of Formula I. In one embodiment, the menthol comprises purified menthol. In one embodiment, the method disclosed herein comprises administering a composition comprising menthol and a compound of Formula I. In one embodiment, the menthol is purified menthol.

[0168] Within the context of the present disclosure, the term "beta-myrcene" includes any derivatives and / or salts thereof, including any isomeric, structural, and / or enantiomeric variations thereof. In one embodiment, a composition disclosed herein comprises beta-myrcene and a compound of Formula I. In one embodiment, the beta-myrcene comprises purified beta-myrcene. In one embodiment, a method disclosed herein comprises administering a composition comprising beta-myrcene and a compound of Formula I. In one embodiment, the beta-myrcene comprises purified beta-myrcene.

[0169] Within the context of the present disclosure, the term "nerolidol" includes any derivatives and / or salts thereof, including any isomeric, structural, and / or enantiomeric variations thereof. In one embodiment, a composition disclosed herein comprises nerolidol and a compound of Formula I. In one embodiment, the nerolidol comprises purified nerolidol. In one embodiment, a method disclosed herein comprises administering a composition comprising nerolidol and a compound of Formula I. In one embodiment, the nerolidol is purified nerolidol.

[0170] Within the context of the present disclosure, the term "ocimene" includes any derivatives and / or salts thereof, including any isomeric, structural, and / or enantiomeric variations thereof. In one embodiment, the composition disclosed herein comprises ocimene and a compound of Formula I. In one embodiment, the ocimene comprises purified ocimene. In one embodiment, the method disclosed herein comprises administering a composition comprising ocimene and a compound of Formula I. In one embodiment, the ocimene is purified ocimene.

[0171] Within the context of the present disclosure, the term "phellandrene" includes any derivatives and / or salts thereof, including any isomeric, structural, and / or enantiomeric variations thereof. In one embodiment, a composition disclosed herein comprises phellandrene and a compound of Formula I. In one embodiment, the phellandrene comprises purified phellandrene. In one embodiment, a method disclosed herein comprises administering a composition comprising phellandrene and a compound of Formula I. In one embodiment, the phellandrene is purified phellandrene.

[0172] Within the context of the present disclosure, the term "phytol" includes any derivatives and / or salts thereof, including any isomeric, structural, and / or enantiomeric variations thereof. In one embodiment, the composition disclosed herein comprises phytol and a compound of Formula I. In one embodiment, the phytol comprises purified phytol. In one embodiment, the method disclosed herein comprises administering a composition comprising phytol and a compound of Formula I. In one embodiment, the phytol is purified phytol.

[0173] Within the context of the present disclosure, the term "pinene" includes any derivatives and / or salts thereof, including any isomeric, structural, and / or enantiomeric variations thereof. In one embodiment, a composition disclosed herein comprises pinene and a compound of Formula I. In one embodiment, the pinene comprises purified pinene. In one embodiment, a method disclosed herein comprises administering a composition comprising pinene and a compound of Formula I. In one embodiment, the pinene is purified pinene.

[0174] Within the context of the present disclosure, the term "pulegone" includes any derivatives and / or salts thereof, including any isomeric, structural, and / or enantiomeric variations thereof. In one embodiment, the compositions disclosed herein comprise pulegone and a compound of Formula I. In one embodiment, the pulegone comprises purified pulegone. In one embodiment, the methods disclosed herein comprise administering a composition comprising pulegone and a compound of Formula I. In one embodiment, the pulegone is purified pulegone.

[0175] Within the context of the present disclosure, the term "sabinene" includes any derivatives and / or salts thereof, including any isomeric, structural, and / or enantiomeric variations thereof. In one embodiment, a composition disclosed herein comprises sabinene and a compound of Formula I. In one embodiment, the sabinene comprises purified sabinene. In one embodiment, a method disclosed herein comprises administering a composition comprising sabinene and a compound of Formula I. In one embodiment, the sabinene is purified sabinene.

[0176] Within the context of the present disclosure, the term "terpineol" includes any derivatives and / or salts thereof, including any isomeric, structural, and / or enantiomeric variations thereof. In one embodiment, a composition disclosed herein comprises terpineol and a compound of Formula I. In one embodiment, the terpineol comprises purified terpineol. In one embodiment, a method disclosed herein comprises administering a composition comprising terpineol and a compound of Formula I. In one embodiment, the terpineol is purified terpineol.

[0177] Within the context of the present disclosure, the term "terpinolenene" includes any derivatives and / or salts thereof, including any isomeric, structural, and / or enantiomeric variations thereof. In one embodiment, a composition disclosed herein comprises terpinolenene and a compound of Formula I. In one embodiment, the terpinolenene comprises purified terpinolenene. In one embodiment, a method disclosed herein comprises administering a composition comprising terpinolenene and a compound of Formula I. In one embodiment, the terpinolenene is purified terpinolenene.

[0178] Within the context of the present disclosure, the term "valencene" includes any derivatives and / or salts thereof, including any isomeric, structural, and / or enantiomeric variations thereof. In one embodiment, the composition disclosed herein comprises valencene and a compound of Formula I. In one embodiment, the valencene comprises purified valencene. In one embodiment, the method disclosed herein comprises administering a composition comprising valencene and a compound of Formula I. In one embodiment, the valencene is purified valencene.

[0179] In one embodiment, the compositions and methods disclosed herein include one or more optionally purified erinacin molecules. In one embodiment, the compositions and methods disclosed herein include erinacin A. In one embodiment, the compositions and methods disclosed herein include erinacin B. In one embodiment, the compositions and methods disclosed herein include erinacin C. In one embodiment, the compositions and methods disclosed herein include erinacin D. In one embodiment, the compositions and methods disclosed herein include erinacin E. In one embodiment, the compositions and methods disclosed herein include erinacin F. In one embodiment, the compositions and methods disclosed herein include erinacin G. In one embodiment, the compositions and methods disclosed herein include erinacin H. In one embodiment, the compositions and methods disclosed herein include erinacin I. In one embodiment, the compositions and methods disclosed herein include erinacin J. In one embodiment, the compositions and methods disclosed herein include erinacin K. In one embodiment, the compositions and methods disclosed herein include erinacin P. In one embodiment, the compositions and methods disclosed herein include erinacin Q. In one embodiment, the compositions and methods disclosed herein include erinacine R. In one embodiment, the compositions and methods disclosed herein include erinacine S. In one embodiment, the erinacine molecule is a purified erinacine molecule. In one embodiment, the compositions and methods disclosed herein include one or more purified erinacine molecules and purified pyridine-3-carboxylic acid. In one embodiment, the compositions and methods disclosed herein include one or more purified erinacine molecules and a purified cannabinoid, such as CBD.

[0180] Within the context of the present disclosure, the term "erinacine A" includes any derivatives and / or salts thereof, including any isomeric, structural, and / or enantiomeric variations thereof. In one embodiment, the compositions and methods disclosed herein comprise administering a formulation comprising erinacine A and a compound of Formula I. In one embodiment, the compositions and methods disclosed herein comprise administering a formulation of purified erinacine A and a compound of Formula I.

[0181] Within the context of the present disclosure, the term "erinacin B" includes any derivatives and / or salts thereof, including any isomeric, structural, and / or enantiomeric variations thereof. In one embodiment, the compositions and methods disclosed herein comprise administering a formulation comprising erinacin B and a compound of Formula I. In one embodiment, the compositions and methods disclosed herein comprise administering a formulation of purified erinacin B and a compound of Formula I.

[0182] Within the context of the present disclosure, the term "erinacine C" includes any derivatives and / or salts thereof, including any isomeric, structural, and / or enantiomeric variations thereof. In one embodiment, the compositions and methods disclosed herein comprise administering a formulation comprising erinacine C and a compound of Formula I. In one embodiment, the compositions and methods disclosed herein comprise administering a formulation of purified erinacine C and a compound of Formula I.

[0183] Within the context of the present disclosure, the term "erinacin D" includes any derivatives and / or salts thereof, including any isomeric, structural, and / or enantiomeric variations thereof. In one embodiment, the compositions and methods disclosed herein comprise administering a formulation comprising erinacin D and a compound of Formula I. In one embodiment, the compositions and methods disclosed herein comprise administering a formulation of purified erinacin D and a compound of Formula I.

[0184] Within the context of the present disclosure, the term "erinacine E" includes any derivatives and / or salts thereof, including any isomeric, structural, and / or enantiomeric variations thereof. In one embodiment, the compositions and methods disclosed herein comprise administering a formulation comprising erinacine E and a compound of Formula I. In one embodiment, the compositions and methods disclosed herein comprise administering a formulation of purified erinacine E and a compound of Formula I.

[0185] Within the context of the present disclosure, the term "erinacin F" includes any derivatives and / or salts thereof, including any isomeric, structural, and / or enantiomeric variations thereof. In one embodiment, the compositions and methods disclosed herein comprise administering a formulation comprising erinacin F and a compound of Formula I. In one embodiment, the compositions and methods disclosed herein comprise administering a formulation of purified erinacin F and a compound of Formula I.

[0186] Within the context of the present disclosure, the term "erinacin G" includes any derivatives and / or salts thereof, including any isomeric, structural, and / or enantiomeric variations thereof. In one embodiment, the compositions and methods disclosed herein comprise administering a formulation comprising erinacin G and a compound of Formula I. In one embodiment, the compositions and methods disclosed herein comprise administering a formulation of purified erinacin G and a compound of Formula I.

[0187] Within the context of the present disclosure, the term "erinacine H" includes any derivatives and / or salts thereof, including any isomeric, structural, and / or enantiomeric variations thereof. In one embodiment, the compositions and methods disclosed herein comprise administering a formulation comprising erinacine H and a compound of Formula I. In one embodiment, the compositions and methods disclosed herein comprise administering a formulation of purified erinacine H and a compound of Formula I.

[0188] Within the context of the present disclosure, the term "erinacine I" includes any derivatives and / or salts thereof, including any isomeric, structural, and / or enantiomeric variations thereof. In one embodiment, the compositions and methods disclosed herein comprise administering a formulation comprising erinacine I and a compound of Formula I. In one embodiment, the compositions and methods disclosed herein comprise administering a formulation of purified erinacine I and a compound of Formula I.

[0189] Within the context of the present disclosure, the term "erinacine J" includes any derivatives and / or salts thereof, including any isomeric, structural, and / or enantiomeric variations thereof. In one embodiment, the compositions and methods disclosed herein comprise administering a formulation comprising erinacine J and a compound of Formula I. In one embodiment, the compositions and methods disclosed herein comprise administering a formulation of purified erinacine J and a compound of Formula I.

[0190] Within the context of the present disclosure, the term "erinacin K" includes any derivatives and / or salts thereof, including any isomeric, structural, and / or enantiomeric variations thereof. In one embodiment, the compositions and methods disclosed herein comprise administering a formulation comprising erinacin K and a compound of Formula I. In one embodiment, the compositions and methods disclosed herein comprise administering a formulation of purified erinacin K and a compound of Formula I.

[0191] Within the context of the present disclosure, the term "erinacin P" includes any derivatives and / or salts thereof, including any isomeric, structural, and / or enantiomeric variations thereof. In one embodiment, the compositions and methods disclosed herein comprise administering a formulation comprising erinacin P and a compound of Formula I. In one embodiment, the compositions and methods disclosed herein comprise administering a formulation of purified erinacin P and a compound of Formula I.

[0192] Within the context of the present disclosure, the term "erinacine Q" includes any derivatives and / or salts thereof, including any isomeric, structural, and / or enantiomeric variations thereof. In one embodiment, the compositions and methods disclosed herein comprise administering a formulation comprising erinacine Q and a compound of Formula I. In one embodiment, the compositions and methods disclosed herein comprise administering a formulation of purified erinacine Q and a compound of Formula I.

[0193] Within the context of the present disclosure, the term "Erinacin R" includes any derivatives and / or salts thereof, including any isomeric, structural, and / or enantiomeric variations thereof. In one embodiment, the compositions and methods disclosed herein comprise administering a formulation comprising Erinacin R and a compound of Formula I. In one embodiment, the compositions and methods disclosed herein comprise administering a formulation of purified Erinacin R and a compound of Formula I.

[0194] Within the context of the present disclosure, the term "erinacine S" includes any derivatives and / or salts thereof, including any isomeric, structural, and / or enantiomeric variations thereof. In one embodiment, the compositions and methods disclosed herein comprise administering a formulation comprising erinacine S and the compound of Formula I. In one embodiment, the compositions and methods disclosed herein comprise administering a formulation of purified erinacine S and the compound of Formula I.

[0195] The erinacine chemical structure is taken from Li IC, Lee LY, Tzeng TW, et al. Neurohealth properties of Hericium erinaceus mycelia enriched with erinacines. In: Behavioural Neurology. 2018. doi:10.1155 / 2018 / 5802634.

[0196] In one embodiment, the compositions and methods disclosed herein include one or more optionally purified hericenone molecules. In one embodiment, the compositions and methods disclosed herein include hericenone A. In one embodiment, the compositions and methods disclosed herein include hericenone B. In one embodiment, the compositions and methods disclosed herein include hericenone C. In one embodiment, the compositions and methods disclosed herein include hericenone D. In one embodiment, the compositions and methods disclosed herein include hericenone E. In one embodiment, the compositions and methods disclosed herein include hericenone F. In one embodiment, the compositions and methods disclosed herein include hericenone G. In one embodiment, the compositions and methods disclosed herein include purified hericenone H.

[0197] Within the context of the present disclosure, the term "hericenone A" includes any derivatives and / or salts thereof, including any isomeric, structural, and / or enantiomeric variations thereof. In one embodiment, the compositions and methods disclosed herein include administering a formulation comprising hericenone A and a compound of Formula I. In one embodiment, the compositions and methods disclosed herein include administering a formulation of purified hericenone A and a compound of Formula I.

[0198] Within the context of the present disclosure, the term "hericenone B" includes any derivatives and / or salts thereof, including any isomeric, structural, and / or enantiomeric variations thereof. In one embodiment, the compositions and methods disclosed herein comprise administering a formulation comprising hericenone B and a compound of Formula I. In one embodiment, the compositions and methods disclosed herein comprise administering a formulation of purified hericenone B and a compound of Formula I.

[0199] Within the context of the present disclosure, the term "hericenone C" includes any derivatives and / or salts thereof, including any isomeric, structural, and / or enantiomeric variations thereof. In one embodiment, the compositions and methods disclosed herein include administering a formulation comprising hericenone C and a compound of Formula I. In one embodiment, the compositions and methods disclosed herein include administering a formulation of purified hericenone C and a compound of Formula I.

[0200] Within the context of the present disclosure, the term "hericenone D" includes any derivatives and / or salts thereof, including any isomeric, structural, and / or enantiomeric variations thereof. In one embodiment, the compositions and methods disclosed herein include administering a formulation comprising hericenone D and a compound of Formula I. In one embodiment, the compositions and methods disclosed herein include administering a formulation of purified hericenone D and a compound of Formula I.

[0201] Within the context of the present disclosure, the term "hericenone E" includes any derivatives and / or salts thereof, including any isomeric, structural, and / or enantiomeric variations thereof. In one embodiment, the compositions and methods disclosed herein include administering a formulation comprising hericenone E and a compound of Formula I. In one embodiment, the compositions and methods disclosed herein include administering a formulation of purified hericenone E and a compound of Formula I.

[0202] Within the context of the present disclosure, the term "Helicenone F" includes any derivatives and / or salts thereof, including any isomeric, structural, and / or enantiomeric variations thereof. In one embodiment, the compositions and methods disclosed herein comprise administering a formulation comprising Hericenone F and a compound of Formula I. In one embodiment, the compositions and methods disclosed herein comprise administering a formulation of purified Hericenone F and a compound of Formula I.

[0203] Within the context of the present disclosure, the term "hericenone G" includes any derivatives and / or salts thereof, including any isomeric, structural, and / or enantiomeric variations thereof. In one embodiment, the compositions and methods disclosed herein include administering a formulation comprising hericenone G and a compound of Formula I. In one embodiment, the compositions and methods disclosed herein include administering a formulation of purified hericenone G and a compound of Formula I.

[0204] Within the context of the present disclosure, the term "hericenone H" includes any derivatives and / or salts thereof, including any isomeric, structural, and / or enantiomeric variations thereof. In one embodiment, the compositions and methods disclosed herein comprise administering a formulation comprising hericenone H and a compound of Formula I. In one embodiment, the compositions and methods disclosed herein comprise administering a formulation of purified hericenone H and a compound of Formula I.

[0205] In one embodiment, the compositions and methods disclosed herein include one or more purified hericenone molecules and purified pyridine-3-carboxylic acid. In one embodiment, the compositions and methods disclosed herein include one or more purified hericenone molecules and a purified cannabinoid, such as CBD.

[0206] Within the context of the present disclosure, the term "pyridine-3-carboxylic acid" includes any derivatives and / or salts thereof, including any isomeric, structural, and / or enantiomeric variations thereof. In one embodiment, the compositions and methods disclosed herein comprise administering a formulation comprising pyridine-3-carboxylic acid and a compound of Formula I. In one embodiment, the compositions and methods disclosed herein comprise administering a formulation of purified pyridine-3-carboxylic acid and a compound of Formula I.

[0207] In one embodiment, the compositions and methods disclosed herein include one or more purified hericenone molecules and one or more purified erinacine molecules.

[0208] In one embodiment, the compositions and methods disclosed herein include one or more purified serotonergic derivatives, one or more purified hericenone molecules, and one or more purified erinacine molecules.

[0209] In one embodiment, the compositions and methods disclosed herein include one or more purified serotonergic derivatives, one or more purified hericenone molecules, one or more purified erinacine molecules, and one or more purified cannabinoids.

[0210] In one embodiment, the compositions and methods disclosed herein include one or more purified serotonergic derivatives, one or more purified hericenone molecules, one or more purified erinacine molecules, and purified pyridine-3-carboxylic acid.

[0211] In one embodiment, the compositions and methods disclosed herein include one or more compounds of Formula I and a compound selected from the group consisting of Bacopa monnieri (e.g., the purified molecule bacoside A3), Centella asiatica (e.g., the purified molecule asiaticoside), Gingko biloba (e.g., the purified molecule myricetin), Zingiber officinale (e.g., the purified molecule zingerone), Ocimum sanctum (e.g., the purified molecule linalool), Polygonum cuspidatum (e.g., the purified molecule resveratrol), Origanum vulgare (e.g., the purified molecule carvacrol), Origanum onites (e.g., the purified molecule thymol), Rosmarinus officinalis (e.g., the purified molecule rosmarinic acid), Rosmarinus eriocalyx (e.g., the purified molecule camphor), Curcuma longa (e.g., the purified molecule curcumin), Camellia sinensis (e.g., purified molecule theobromine), Lavandula spica (e.g., purified molecule caryophyllene), Scutellaria lateriflora (e.g., purified molecule baicalin), Avena sativa (e.g., purified molecule avenalin), Avena byzantina (e.g., purified molecule beta-glucan), Salvia divinorum (e.g., purified molecule salvinorin A), Banisteriopsis caapi (e.g., purified molecule harmine), Psychotria species (e.g., purified molecule dimethyltryptamine), Tabernanthe iboga (e.g., purified molecule ibogaine), Voacanga africana (e.g., purified molecule voacangin), Tabernaemontana undulata (e.g., purified molecule ibogamine), Lophophora williamsii (e.g., purified molecule mescaline), Ipomoea tricolor (e.g., the purified molecule ergonovine), and / or Argyreianervosa (e.g., purified molecule Ergin) (e.g., one or more purified molecules obtained by extracting and then purifying one or more compounds from an organism selected from Ergin).

[0212] In one embodiment, the compositions disclosed herein comprise a compound derivative of formula I and a purified terpene in a specific ratio (eg, molar ratio) ranging from about 100:1 to about 1:100.

[0213] In one embodiment, the compositions disclosed herein include a compound of formula I and a purified terpene in a specific ratio (eg, molar ratio) ranging from about 75:1 to about 1:75.

[0214] In one embodiment, the compositions disclosed herein include a compound of formula I and a purified terpene in a specific ratio (eg, molar ratio) ranging from about 50:1 to about 1:50.

[0215] In one embodiment, the compositions disclosed herein include a compound of formula I and a purified terpene in a specific ratio (eg, molar ratio) ranging from about 25:1 to about 1:25.

[0216] In one embodiment, the compositions disclosed herein include a compound of formula I and a purified terpene in a specific ratio (e.g., molar ratio) ranging from about 10:1 to about 1:10.

[0217] In one embodiment, the compositions disclosed herein include a compound of formula I and a purified terpene in a specific ratio (e.g., molar ratio) ranging from about 5:1 to about 1:5.

[0218] In one embodiment, the compositions and methods disclosed herein include a compound of formula I, a purified cannabinoid, and a purified terpene.

[0219] In one embodiment, the compositions disclosed herein include a compound of formula I and a purified cannabinoid in a specific ratio (e.g., molar ratio) ranging from about 100:1 to about 1:100, and a compound of formula I and a purified terpene in a specific ratio (e.g., molar ratio) ranging from about 100:1 to about 1:100.

[0220] In one embodiment, the compositions disclosed herein include a compound of formula I and a purified cannabinoid in a specific ratio (e.g., molar ratio) ranging from about 75:1 to about 1:75, and a compound of formula I and a purified terpene in a specific ratio (e.g., molar ratio) ranging from about 75:1 to about 1:75.

[0221] In one embodiment, the compositions disclosed herein include a compound of formula I and a purified cannabinoid in a specific ratio (e.g., molar ratio) ranging from about 50:1 to about 1:50, and a compound of formula I and a purified terpene in a specific ratio (e.g., molar ratio) ranging from about 50:1 to about 1:50.

[0222] In one embodiment, the compositions disclosed herein include a compound of formula I and a purified cannabinoid in a specific ratio (e.g., molar ratio) ranging from about 25:1 to about 1:25, and a compound of formula I and a purified terpene in a specific ratio (e.g., molar ratio) ranging from about 25:1 to about 1:25.

[0223] In one embodiment, the compositions disclosed herein include a compound of formula I and a purified cannabinoid in a specific ratio (e.g., molar ratio) ranging from about 10:1 to about 1:10, and a compound of formula I and a purified terpene in a specific ratio (e.g., molar ratio) ranging from about 10:1 to about 1:10.

[0224] In one embodiment, the compositions disclosed herein include a compound of formula I and a purified cannabinoid in a specific ratio (e.g., molar ratio) ranging from about 5:1 to about 1:5, and a compound of formula I and a purified terpene in a specific ratio (e.g., molar ratio) ranging from about 5:1 to about 1:5.

[0225] In one embodiment, the purified terpene modulates the activity of a neurotransmitter activity modulator, such as a compound of Formula I, a serotonergic agent, an adrenergic agent, a dopaminergic agent, a psilocybin derivative, or the like.

[0226] As used herein, the term "serotonergic agent" refers to a compound that binds to, blocks, or otherwise affects (via an allosteric response) the activity of a serotonin receptor. In one embodiment, a serotonergic agent binds to a serotonin receptor. In one embodiment, a serotonergic agent indirectly affects a serotonin receptor, e.g., through interactions that affect the reactivity of other molecules at the serotonin receptor. In one embodiment, a serotonergic agent is an agonist, e.g., a compound that activates a serotonin receptor. In one embodiment, a serotonergic agent is an antagonist, e.g., a compound that binds to but does not activate a serotonin receptor, e.g., blocks the receptor. In one embodiment, a serotonergic agent is a compound that binds to an effector molecule, e.g., an enzyme for allosteric regulation. In one embodiment, a serotonergic agent acts (either directly or indirectly) at multiple types of receptors (e.g., SHT, dopamine, adrenergic, acetylcholine, etc.).

[0227] In one embodiment, the serotonergic agent is an antidepressant.

[0228] In one embodiment, the serotonergic agent is an anxiolytic agent.

[0229] In one embodiment, the serotonergic agent is a selective serotonin reuptake inhibitor.

[0230] In one embodiment, the serotonergic agent is a selective serotonin norepinephrine reuptake inhibitor.

[0231] In some embodiments, the compound of Formula I is a serotonergic agent. In some embodiments, at least one compound of Formula I is administered with a second serotonergic agent, such as one of the serotonergic agents identified below.

[0232] Some exemplary serotonergic agents include the following molecules: 4-hydroxy-N-methyltryptamine (also known as 3[2-(methylamino)ethyl]-1H-indol-4-ol), aeruginacin (also known as [3-[2-(trimethylazaniumyl)ethyl]-1H-indol-4-yl]hydrogen phosphate), baeocystin (also known as [3-[2-(methylamino)ethyl]-1H-indol-4-yl]dihydrogen phosphate), bufotenidine (also known as 3-[2-(trimethylazaniumyl)ethyl]-1H-indol-5-ol), , bufotenin (also known as 3-[2-(dimethylamino)ethyl]-1H-indol-5-ol), ethosybin (also known as [3-[2-(diethylamino)ethyl]-1H-indol-4-yl] dihydrogen phosphate), norbaeocystin (also known as [3-(2-aminoethyl)-1H-indol-4-yl] dihydrogen phosphate), norpsilocin, psilocin (also known as 3-[2-(dimethylamino)ethyl]-1H-indol-4-ol), psilocybin (also known as [3-[2-(dimethylamino)ethyl]-1H-indol -4-yl]dihydrogen phosphate), serotonin (also known as 3-(2-aminoethyl)-1H-indol-5-ol), 1P-LSD (also known as (6aR,9R)-N,N-diethyl-7-methyl-4-propanoyl-6,6a,8,9-tetrahydroindolo[4,3-fg]quinoline-9-carboxamide), ALD-52 (also known as (6aR,9R)-4-acetyl-N,N-diethyl-7-methyl-6,6a,8,9-tetrahydroindolo[4,3-fg]quinoline-9-carboxamide), AL-LAD (also known as (6aR,9 R)-N,N-diethyl-7-prop-2-enyl-6,6a,8,9-tetrahydro-4H-indolo[4,3-fg]quinoline-9-carboxamide), BU-LAD (also known as (6aR,9R)-7-butyl-N,N-diethyl-6,6a,8,9-tetrahydro-4H-indolo[4,3-fg]quinoline-9-carboxamide), DAL (also known as (6aR,9R)-7-methyl-N,N-bis(prop-2-enyl)-6,6a,8,9-tetrahydro-4H-indolo[4,3-fg]quinoline-9-carboxamide),DAM-57 (also known as (6aR,9R)-N,N,7-trimethyl-6,6a,8,9-tetrahydro-4H-indolo[4,3-fg]quinoline-9-carboxamide), EIPLA (also known as (6aR,9R)-N-ethyl-7-methyl-N-propan-2-yl-6,6a,8,9-tetrahydro-4H-indolo[4,3-fg]quinoline-9-carboxamide), ETH-LAD (also known as (6aR,9R)-N,N,7-triethyl-6,6a,8,9-tetrahydro-4H-indolo[4,3-fg]quinoline-9-carboxamide) ), LAE-32 (also known as (6aR,9R)-N-ethyl-7-methyl-6,6a,8,9-tetrahydro-4H-indolo[4,3-fg]quinoline-9-carboxamide), LPD-824 (also known as [(6aR,9R)-7-methyl-6,6a,8,9-tetrahydro-4H-indolo[4,3-fg]quinolin-9-yl]-pyrrolidin-1-ylmethanone), LSB (also known as (6aR,9R)-N-butan-2-yl-7-methyl-6,6a,8,9-tetrahydro-4H-indolo[4,3-fg]quinoline-9-carboxamide), L SA (also known as (6aR,9R)-7-methyl-6,6a,8,9-tetrahydro-4H-indolo[4,3-fg]quinoline-9-carboxy-amide), LSD-25 (also known as (6aR,9R)-N,N-diethyl-7-methyl-6,6a,8,9-tetrahydro-4H-indolo[4,3-fg]quinoline-9-carboxamide), LSD-PiP (also known as (7-methyl-6,6a,8,9-tetrahydro-4H-indolo[4,3-fg]quinolin-9-yl)-piperidin-1-ylmethanone), LSM-775 (also known as (6aR,9R) -7-methyl-6,6a,8,9-tetrahydro-4H-indolo[4,3-fg]quinolin-9-yl]-morpholin-4-ylmethanone), LSP (also known as (6aR,9R)-7-methyl-N-pentan-3-yl-6,6a,8,9-tetrahydro-4H-indolo[4,3-fg]quinoline-9-carboxamide), LSZ (also known as [(6aR,9R)-7-methyl-6,6a,8,9-tetrahydro-4H-indolo[4,3-fg]quinolin-9-yl]-[-(2S,4S)-2,4-dimethylazetidin-1-yl]methanone),Methergine (also known as (6aR,9R)-N-(1-hydroxybutan-2-yl)-7-methyl-6,6a,8,9-tetrahydro-4H-indolo[4,3-fg]quinoline-9-carboxamide), MiPLA (also known as (6aR,9R)-N,7-dimethyl-N-propan-2-yl-6,6a,8,9-tetrahydro-4H-indolo[4,3-fg]quinoline-9-carboxamide), NDTDI, PARGY-LAD, PRO-LAD (also known as (6aR,9R)-N,N-diethyl-7-propyl-6,6a,8,9-tetrahydro-4 H-indolo[4,3-fg]quinoline-9-carboxamide), 2-Me-DET (also known as N,N-diethyl-2-(2-methyl-1H-indol-3-yl)ethanamine), 2-Me-DMT (also known as N,N-dimethyl-2-(2-methyl-1H-indol-3-yl)ethanamine), 2,alpha-DMT (also known as 1-(2-methyl-1H-indol-3-yl)propan-2-amine), 4-AcO-DALT (also known as [3-[2-[bis(prop-2-enyl)amino]ethyl]-1H-indol-4-yl]acetate), 4-A cO-DET (also known as [3-[2-(diethylamino)ethyl]-1H-indol-4-yl]acetate), 4-AcO-DIPT (also known as 3-[2-(diisopropylamino)ethyl]-1H-indol-4-yl acetate), 4-AcO-DMT (also known as [3-[2-(dimethylamino)ethyl]-1H-indol-4-yl]acetate), 4-AcO-DPT (also known as [3-[2-(dipropylamino)ethyl]-1H-indol-4-yl]acetate), 4-AcO-EPT (also known as 3-{2-[ethyl(propyl)amino]ethyl {3-(2-(methylamino)ethyl)-1H-indol-4-yl]acetate), 4-AcO-MET (also known as [3-[2-[ethyl(methyl)amino]ethyl]-1H-indol-4-yl]acetate), 4-AcO-MIPT (also known as [3-[2-[methyl(propan-2-yl)amino]ethyl]-1H-indol-4-yl]acetate), 4-AcO-MPT, 4-HO-DBT (also known as 3-[2-(dibutylamino)ethyl]-1H-indol-4-ol), 4-HO-DET (also known as 3-[2-(diethylamino)ethyl]-1H-indol-4-ol),4-HO-DIPT (also known as 3-[2-[di(propan-2-yl)amino]ethyl]-1H-indol-4-ol), 4-HO-DPT (also known as 3-[2-(dipropylamino)ethyl]-1H-indol-4-ol), 4-HO-EPT, 4-HO-MCPT, 4-HO-MET (also known as 3-[2-[ethyl(methyl)amino]ethyl]-1H-indol-4-ol), 4-HO-MIPT (also known as 3-[2-[methyl(propan-2-yl)amino]ethyl]-1H-indol-4-ol), 4-HO-MPMI (also known as 3-[(1-methylpyrrolidin-2-yl)methyl]-1H-indol-4-ol), 4-HO-MPT (also known as 3-[2-[methyl(propyl)amino]ethyl]-1H-indol-4-ol), 4-HO-Pyr-T (also known as 3-(2-pyrrolidin-1-ylethyl)-1H-indol-4-ol), 4-MeO-MIPT (also known as N-[2-(4-methoxy-1H-indol-3-yl)ethyl]-N-methylpropan-2-amine), 4,5-MDO-DIPT (also known as N-[2-(6H-[1,3]dioxolo[4,5- e]indol-8-yl)ethyl]-N-propan-2-ylpropan-2-amine-), 4,5-MDO-DMT (also known as 2-(6H-[1,3]dioxolo[4,5-e]indol-8-yl)-N,N-dimethylethanamine), 5-BROMO-DMT (also known as 2-(5-bromo-1H-indol-3-yl)-N,N-dimethylethanamine), 5-chloro-alpha-MT (also known as 1-(5-chloro-1H-indol-3-yl)propan-2-amine), 5-fluoro-AMT (also known as 1-(5-fluoro-1H-indol-3-yl)propan-2-amine), 5-chloro-alpha-MT (also known as 1-(5-fluoro-1H-indol-3-yl)propan-2-amine), 5-fluoro ... 5-MeO-AET (also known as 1-(5-methoxy-1H-indol-3-yl)butan-2-amine), 5-MeO-AMT (also known as 1-(5-methoxy-1H-indol-3-yl)propan-2-amine), 5-MeO-DALT (also known as N-[2-(5-methoxy-1H-indol-3-yl)ethyl]-N-prop-2-enylprop-2-en-1-amine), 5-MeO-DET (also known as N,N-diethyl-2-(5-methoxy-1H-indol-3-yl)ethanamine),5-MeO-DiPT (also known as N-[2-(5-methoxy-1H-indol-3-yl)ethyl]-N-propan-2-ylpropan-2-amine), 5-MeO-DMT (also known as 2-(5-methoxy-1H-indol-3-yl)-N,N-dimethylethanamine), 5-MeO-DPT (also known as N-[2-(5-methoxy-1H-indol-3-yl)ethyl]-N-propylpropan-1-amine), 5-MeO-EiPT (also known as N-ethyl-N-[2-(5-methoxy-1H-indol-3-yl)ethyl]propan-2-amine), 5-Me O-MALT (also known as N-[2-(5-methoxy-1H-indol-3-yl)ethyl]-N-methylprop-2-en-1-amine), 5-MeO-MiPT (also known as N-[2-(5-methoxy-1H-indol-3-yl)ethyl]-N-methylpropan-2-amine), 5-MeO-NMT (also known as 2-(5-methoxy-1H-indol-3-yl)-N-methylethanamine; hydrochloride), 5-MeO-Pyr-T (also known as 4-fluoro-5-methoxy-3-(2-pyrrolidin-1-ylethyl)-1H-indole), 5-MeO-TMT (also known as 2- (5-methoxy-2-methyl-1H-indol-3-yl)-N,N-dimethylethanamine), 5-MeS-DMT (also known as N,N-dimethyl-2-(5-methylsulfanyl-1H-indol-3-yl)ethanamine), 5,6-MDO-DIPT (also known as N-[2-(5H-[1,3]dioxolo[4,5-f]indol-7-yl)ethyl]-N-propan-2-ylpropan-2-amine-), 5,6-MDO-DMT (also known as 2-(5H-[1,3]dioxolo[4,5-f]indol-7-yl)-N,N-dimethylethanamine), 5,6-MDO-MIPT (also known as N-[2-(5H-[1,3]dioxolo[4,5-f]indol-7-yl)ethyl]-N-ethylpropan-2-amine), 5,6-MeO-MIPT (also known as N-[2-(5,6-dimethoxy-1H-indol-3-yl)ethyl]-N-methylpropan-2-amine), 5,N,N-TMT (also known as N,N-dimethyl-2-(5-methyl-1H-indole-3-ethanamine), 6-MeO-THH (also known as 6-methoxy-1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole),Alpha-ET (also known as 1-(1H-indol-3-yl)butan-2-amine), Alpha-MT (also known as 1-(1H-indol-3-yl)propan-2-amine), Alpha-TMT (also known as 1-(1H-indol-3-yl)-N,N-dimethylpropan-2-amine), Alpha,N-DMT (also known as 2-(1H-indol-3-yl)-N,N-dimethylethanamine), Alpha,N,O-TMS (also known as 1-(5-methoxy-1H-indol-3-yl)-N-methylpropan-2-amine), Alpha,O-DMS (also known as 1-(5-methoxy-, 1H-indol-3-yl)propan-2-amine), DALT (also known as N-[2-(1H-indol-3-yl)ethyl]-N-prop-2-enylprop-2-en-1-amine), DBT (also known as N-butyl-N-[2-(1H-indol-3-yl)ethyl]butan-1-amine), DET (also known as N,N-diethyl-2-(1H-indol-3-yl)ethanamine), DiPT (also known as N-[2-(5-methoxy-1H-indol-3-yl)ethyl]-N-propan-2-ylpropan-2-amine), DMT (also known as 2 -(1H-indol-3-yl)-N,N-dimethylethanamine), DPT (also known as N-[2-(1H-indol-3-yl)ethyl]-N-propylpropan-1-amine), EiPT (also known as N-ethyl-N-[2-(1H-indol-3-yl)ethyl]propan-2-amine), harmaline (also known as 7-methoxy-1-methyl-3,4-dihydro-2H-pyrido[3,4-b]indole), harmine (also known as 7-methoxy-1-methyl-9H-pyrido[3,4-b]indole), MALT, MBT (also known as 3H-1,3-benzophenone-4-one), zothiazole-2-thione), melatonin (also known as N-[2-(5-methoxy-1H-indol-3-yl)ethyl]acetamide), MET (also known as N-ethyl-2-(1H-indol-3-yl)-N-methylethanamine), MiPT (also known as N-[2-(1H-indol-3-yl)ethyl]-N-methylpropan-2-amine), MPT (also known as 3-[2-[methyl(propyl)amino]ethyl]-1H-indol-4-ol), NET (also known as N-ethyl-2-(1H-indol-3-yl)ethanamine), NMT( (alias 2-(1H-indol-3-yl)-N-methylethanamine), PiPT (alias N-[2-(1H-indol-3-yl)ethyl]-N-propan-2-ylpropan-1-amine), Pi-T (alias 3-(2-pyrrolidin-1-ylethyl)-1H-indole), T (alias 2-(1H-indol-3-yl)ethanamine), tetrahydroharmine (alias 7-methoxy-1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole), 2-Br-4,5-MDA (alias 1-(6-bromo-1,3-benzodioxol-5-yl)propan-2-amine), 2-TIM (also known as 2-(3,4-dimethoxy-2-methylsulfanylphenyl)ethanamine), 2-TOET (also known as 1-(4-ethyl-5-methoxy-2-methylsulfanylphenyl)propan-2-amine), 2-TOM (also known as 1-(5-methoxy-4-methyl-2-methylsulfanylphenyl)propan-2-amine), 2,4-DMA (also known as 1-(2,4-dimethoxyphenyl)propan-2-amine), 2,5-DMA (also known as 1-(2,5-dimethoxyphenyl)propan-2-amine), 2C-B (also known as 2-(4-bromo-2,5-dimethoxyphenyl)ethanamine), 2C-C (also known as 2-(4-chloro-2,5-dimethoxyphenyl)ethanamine), 2C-D (also known as 2-(2,5-dimethoxy-4-methoxyphenyl)ethanamine), 2C-E (also known as 2-(4-ethyl-2,5-dimethoxyphenyl)ethanamine), 2C-F (also known as 2-(4-fluoro-2,5-dimethoxyphenyl)ethanamine), 2C-G (also known as 2-(2,5-dimethoxy-3,4-dimethylphenyl)ethanamine), 2C-G-3 (also known as 2-(4,7-dimethoxy-2,3-dihydro-1H-inden-5-yl)ethanamine), 2C-G-4 (also known as 2-(1,4-dimethoxy-5,6,7,8-tetrahydronaphthalen-2-yl)ethanamine), 2C-G-5 (also known as CAS 207740-20-3), 2C-GN (also known as 2-(1,4-dimethoxynaphthalen-2-yl)ethanamine), 2C-H (also known as 2-(2,5-dimethoxyphenyl)ethanamine), 2C-I (also known as 2-(4-iodo-2,5-dimethoxyphenyl)ethanamine), phenyl)ethanamine), 2C-N (also known as 2-(2,5-dimethoxy-4-nitrophenyl)ethanamine), 2C-O-4 (also known as 2-(2,5-dimethoxy-4-propan-2-yloxyphenyl)ethanamine), 2C-P (also known as 2-(2,5-dimethoxy-4-propylphenyl)ethanamine), 2C-SE (also known as 2-(2,5-dimethoxy-4-methylselanylphenyl)ethanamine), 2C-T (also known as 2-(2,5-dimethoxy-4-methylsulfanylphenyl)ethanamine), 2C-T-13 (also known as 2-[2,5-dimethoxy-4-(2-methoxyethylsulfanyl)phenyl]ethanamine), 2C-T-15 (also known as 2-(4-cyclopropylsulfanyl-2,5-dimethoxyphenyl)ethanamine), 2C-T-17 (also known as 2-(4-butan-2-ylsulfanyl-2,5-dimethoxyphenyl)ethanamine), 2C-T-2 (also known as 2-(4-ethylsulfanyl-2,5-dimethoxyphenyl)ethanamine), 2C-T-2 (also known as 2-[4-(2-fluoroethylsulfanyl)-2,5-dimethoxyphenyl]ethanamine), 2C- T-4 (also known as 2-(2,5-dimethoxy-4-propan-2-ylsulfanylphenyl)ethanamine), 2C-T-7 (also known as 2-(2,5-dimethoxy-4-propylsulfanylphenyl)ethanamine), 2C-T-8 (also known as 2-[4-(cyclopropylmethylsulfanyl)-2,5-dimethoxyphenyl]ethanamine), 2C-T-9 (also known as 2-(4-butylsulfanyl-2,5-dimethoxyphenyl)ethanamine), 2C-TFM (also known as 2-[2,5-dimethoxy-4-(trifluoromethyl)phenyl]ethanamine), 2T -MMDA-3a (also known as 1-(4-methylsulfanyl-1,3-benzodioxol-5-yl)propan-2-amine), 3-T-tris (also known as 2-(3,4-diethoxy-5-ethylsulfanylphenyl)ethanamine), 3-TASB (also known as 2-(3-ethoxy-4-ethylsulfanyl-5-methoxyphenyl)ethanamine), 3-TE (also known as 2-(4-ethoxy-3-methoxy-5-methylsulfanylphenyl)ethanamine), 3-TFM (also known as 2-(2,4-dimethoxy-3-methylsulfanylphenyl)ethanamine) ), 3-TM (also known as 2-(3,4-dimethoxy-5-methylsulfanylphenyl)ethanamine), 3-TME (also known as 2-(3-ethylsulfanyl-4,5-dimethoxyphenyl)ethanamine), 3-TSB (also known as 2-(3-ethoxy-5-ethylsulfanyl-4-methoxyphenyl)ethanamine), 3,4-DMA (also known as 1-(3,4-dimethoxyphenyl)propan-2-amine), 3C-BZ (also known as 1-(3,5-dimethoxy-4-phenylmethoxyphenyl)propan-2-amine), 3C-E (also known as 1-(4-ethoxy-3,5-dimethoxyphenyl)propan-2-amine), 4-Br-3,5-DMA (also known as 1-(4-bromo-3,5-dimethoxyphenyl)propan-2-amine), 4-D (also known as CAS 1020518-87-9), 4-MA (also known as 1-(4-methoxyphenyl)propan-2-amine), 4-T-TRIS (also known as 2-(3,5-diethoxy-4-ethylsulfanylphenyl)ethanamine), 4-TASB (also known as 2-(3-ethoxy-4-ethylsulfanyl-5-methoxyphenyl)ethanamine), 4-TE (also known as 2-(4-ethylsulfanylphenyl)ethanamine), 4-TIM (also known as 2-(2,3-dimethoxy-4-methylsulfanylphenyl)ethanamine), 4-TM (also known as 2-(3,5-dimethoxy-4-methylsulfanylphenyl)ethanamine), 4-TME (also known as 2-(3-ethoxy-5-methoxy-4-methylsulfanylphenyl)ethanamine), 4-TSB (also known as 2-(3,5-diethoxy-4-methylsulfanylphenyl)ethanamine), 4T-MMDA-2 (also known as 1-(5-methoxy-1,3-benzoxathiol) 5-TASB (also known as 2-(3,4-diethoxy-5-methylsulfanylphenyl)ethanamine), 5-TME (also known as 2-(3-ethoxy-4-methoxy-5-methylsulfanylphenyl)ethanamine), 5-TOET (also known as 1-(4-ethyl-2-methoxy-5-methylsulfanylphenyl)propan-2-amine), 5-TOM (also known as 1-(2-methoxy-4-methyl-5-methylsulfanylphenyl)propan-2-amine), 25B-NBF (also known as 2-(4-bromo-2,5-diphenyl)propan-2-amine), 25B-NBOH (also known as 2-[[2-(4-bromo-2,5-dimethoxyphenyl)ethylaminomethyl]phenol), 25B-NBOMe (also known as 2-(4-bromo-2,5-dimethoxyphenyl)-N[(2-methoxyphenyl)methyl]ethanamine), 25C-NB3OMe (also known as 2-(4-chloro-2,5-dimethoxyphenyl)-N-[((3-methoxyphenyl)methyl]ethanamine), 25C-NB4OMe (also known as 2-(4-chloro-2,25C-NBF (also known as 2-(4-chloro-2,5-dimethoxyphenyl)-N-[(2-fluorophenyl)methyl]ethanamine), 25C-NBOH (also known as 2-(4-chloro-2,5-dimethoxyphenyl)ethylaminomethyl]phenol), 25C-NBOMe (also known as 2-(4-chloro-2,5-dimethoxyphenyl)-N[(2-methoxyphenyl)methyl]ethanamine), 25CN-NBOH (also known as 4-[2-[(2-hydroxyphenyl) 2-(2,5-dimethoxyphenyl)methylamino-1-ethyl]-2,5-dimethoxybenzonitrile), 25CN-NBOMe (also known as CAS 1354632-16-8), 25D-NBOMe (also known as 2-(2,5-dimethoxy-4-methoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine), 25E-NBOMe (also known as 2-(4-ethyl-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine), 25G-NBOMe (also known as 2-(2,5-dimethoxy-3,4-dimethylphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine), 25H-NB3OMe (also known as 2-(4-iodo-2,5-dimethoxyphenyl)-N-[(3-methoxyphenyl)methyl]ethanamine), 25H-NBOMe (also known as 2-(2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine), 25H-NB34MD (also known as N-(1,3-benzodioxol-5-ylmethyl)-2-(4-iodo-2,5-dimethoxyphenyl)ethanamine), 25I-NB3OMe (also known as 2-(4-iodo-2,5-dimethoxyphenyl)-N-[(3-methoxyphenyl)methyl]ethanamine), 25I-NB4OMe (also known as 2-(4-iodo-2,5-dimethoxyphenyl)-N-[(3-methoxyphenyl)methyl]ethanamine). phenyl)-N-[(4-methoxyphenyl)methyl]ethanamine), 25I-NBF (also known as N-[(2-fluorophenyl)methyl]-2-(4-iodo-2,5-dimethoxyphenyl)ethanamine), 25I-NBMD (also known as N-(1,3-benzodioxol-4-ylmethyl)-2-(4-iodo-2,5-dimethoxyphenyl)ethanamine), 25I-NBOH (also known as 2-[[2-(4-iodo-2,5-dimethoxyphenyl)ethylamino]methyl]phenol), 25I-NBOMe (also known as 2-(4-iodo-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine), 25iP-NBOMe (also known as 2-(2,5-dimethoxy-4-propan-2-ylphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine), 25N-NBOMe (also known as 2-(2,5-dimethoxy-4-nitrophenyl)-N-[(2-methoxyphenyl)methyl]ethanamine), 25P-NBOMe (also known as 2-(2,5-dimethoxy-4-propylphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine), 25TFM-NBOMe (also known as 2-[2,5-dimethoxy-4-(trifluoromethyl)phenyl]-N-[(2, -methoxyphenyl)methyl]ethanamine), 2CBCB-NBOMe (also known as 1-[(7R)-3-bromo-2,5-dimethoxy-7-bicyclo[4.2.0]octa-1(6),2,4-trienyl]-N-[(-2-methoxyphenyl)methyl]methanamine), 2CBFly-NBOMe (also known as 2-(4-bromo-2,3,6,7-tetrahydrofuro[2,3-f][1]benzofuran-8-yl)-N-[(2-methoxyphenyl)methyl]tanamine), AEM (also known as 1-(3,4,5-trimethoxyphenyl)butan-2-amine), amine), AL (also known as 2-(3,5-dimethoxy-4-prop-2-enoxyphenyl)ethanamine), ALEPH (also known as 1-(2,5-dimethoxy-4-methylsulfanylphenyl)propan-2-amine; hydrochloride), ALEPH-2 (also known as 1-(4-ethylsulfanyl-2,5-dimethoxyphenyl)propan-2-amine), ALEPH-4 (also known as 1-(2,5-dimethoxy-4-propan-2-ylsulfanylphenyl)propan-2-amine), ALEPH-6 (also known as 1-(2,5-dimethoxy-4-phenylsulfanylphenyl)propan-2-amine) (2R)-1-(2,5-dimethoxy-4-methoxyphenyl)butan-2-amine), ALEPH-7 (also known as 1-(2,5-dimethoxy-4-propylsulfanylphenyl)propan-2-amine), ARIADNE (also known as (2R)-1-(2,5-dimethoxy-4-methoxyphenyl)butan-2-amine), ASB (also known as 2-(3,4-diethoxy-5-methoxyphenyl)ethanamine), B (also known as 2-(4-butoxy-3,5-dimethoxyphenyl)ethanamine), BEATRICE (also known as 1-(2,5-dimethoxy-4-methoxyphenyl)-N-methylpropan-2-amine), Beta-D (also known as 2,2-dideuterio-2-(3,4,5-trimethoxyphenyl)ethanamine), BIS-TOM (also known as 1-[4-methyl-2,5-bis(methylsulfanyl)phenyl]propan-2-amine), bk-2C-B (also known as 2-amino-1-(4-bromo-2,5-dimethoxyphenyl)ethanone), BOB (also known as 2-(4-bromo-2,5-dimethoxyphenyl)-2-methoxyethanamine), BOD (also known as 2-(2,5-dimethoxy-4-methoxyphenyl)-2-methoxyethanamine), BOH (also known as 2-(1,3-benzodioxol-5-yl)-2-methoxyethanamine), BOHD (also known as 2-amino-1-(2,5-dimethoxy-4-methylphenyl)ethanol), BOM (also known as 2-methoxy-2-(3,4,5-trimethoxyphenyl)ethanamine), Bromo-DragonFLY (also known as 1-(4-bromofuro[2,3-f][1]benzofuran-8-yl)propan-2-amine), Butyrone (also known as 1-(1,3-benzodioxyl-5-yl)-2-(methylamino)butan-1-one), CPM (also known as 2-[4-(cyclopropyl 2-(2,5-dimethoxy-4-methoxyphenyl)ethanamine), DESOXY (also known as 2-(3,5-dimethoxy-4-methylphenyl)ethanamine), DMCPA (also known as 2-(2,5-dimethoxy-4-methoxyphenyl)cyclopropan-1-amine), DME (also known as 2-amino-1-(3,4-dimethoxyphenyl)ethanol), DMMDA (also known as 1-(4,7-dimethoxy-1,3-benzodioxol-5-yl)propan-2-amine), DMMDA-2 (also known as 1-(6,7-dimethoxy-1,3-benzodioxol-5-yl)propan-2-amine), DMPEA (also known as 2-(3,4-dimethoxyphenyl)ethanamine), DOAM (also known as 1-(2,5-dimethoxy-4-pentylphenyl)propan-2-amine), DOB (also known as 1-(4-bromo-2,5-dimethoxyphenyl)propan-2-amine), DOBU (also known as 1-(4-butyl-2,5-dimethoxyphenyl)propan-2-amine), DOC (also known as 1-(4-chloro-2,5-dimethoxyphenyl)propan-2-amine), DOEF (also known as 1-[4-(2-fluoroethyl)-2,5- dimethoxyphenyl]propan-2-amine), DOET (also known as 1-(4-ethyl-2,5-dimethoxyphenyl)propan-2-amine), DOF (also known as 1-(4-fluoro-2,5-dimethoxyphenyl)propan-2-amine), DOI (also known as 1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine), DOM (also known as 1-(2,5-dimethoxy-4-methoxyphenyl)propan-2-amine), DON (also known as 1-(2,5-dimethoxy-4-nitrophenyl)propan-2-amine), DOPR (also known as 1-(2,5-Dimethoxy-4-propylphenyl)propan-2-amine), DOTFM (also known as 1-[2,5-dimethoxy-4-(trifluoromethyl)phenyl]propan-2-amine), E (also known as 2-(4-ethoxy-3,5-dimethoxyphenyl)ethanamine), EBDP (also known as 1-(1,3-benzodioxol-5-yl)-N-ethylpentan-2-amine), EEE (also known as 1-(2,4,5-triethoxyphenyl)propan-2-amine), EEM (also known as 1-(2,4-diethoxy-5-methoxyphenyl)propan-2-amine) amine), EME (also known as 1-(2,5-diethoxy-4-methoxyphenyl)propan-2-amine), EMM (also known as 1-(2-ethoxy-4,5-dimethoxyphenyl)propan-2-amine), ETHYL-J (also known as 1-(1,3-benzodioxol-5-yl)-N-ethylbutan-2-amine), ETHYL-K (also known as 1-(1,3-benzodioxol-5-yl)-N-ethylpentan-2-amine), F-2 (also known as 1-(5-methoxy-2-methyl-2,3-dihydro-1-benzofuran-6-yl)propan-2-amine) ), F-22 (also known as 1-(5-methoxy-2,2-dimethyl-3H-1-benzofuran-6-yl)propan-2-amine), FLEA (also known as N-[1-(1,3-benzodioxol-5-yl)propan-2-yl]-N-methylhydroxylamine), G-3 (also known as 1-(4,7-dimethoxy-2,3-dihydro-1H-inden-5-yl)propan-2-amine), G-4 (also known as 1-(1,4-dimethoxy-5,6,7,8-tetrahydronaphthalen-2-yl)propan-2-amine), G-5 (also known as 3,6-dimethoxy- 4-(2-aminopropyl)benzonorbornane), GN (also known as 1-(1,4-dimethoxynaphthalen-2-yl)propan-2-amine), GANESHA (also known as 1-(2,5-dimethoxy-3,4-dimethylphenyl)propan-2-amine), HOT-17 (also known as N-[2-(4-butan-2-ylsulfanyl-2,5-dimethoxyphenyl)ethyl]hydroxylamine), HOT-2 (also known as N-[2-(4-ethylsulfanyl-2,5-dimethoxyphenyl)ethyl]hydroxylamine), HOT-7 (also known as N-[2-(2,5-Dimethoxy-4-propylsulfanylphenyl)ethyl]hydroxylamine), IDNNA (also known as 1-(4-iodo-2,5-dimethoxyphenyl)-N,N-dimethylpropan-2-amine), IM (also known as 2-(2,3,4-trimethoxyphenyl)ethanamine), IP (also known as 2-(3,5-dimethoxy-4-propan-2-yloxyphenyl)ethanamine), IRIS (also known as 1-(5-ethoxy-2-methoxy-4-methoxyphenyl)propan-2-amine), J (also known as 1-(1,3-benzodioxol-5-yl)butanol), phen-2-amine), dismsculine (also known as [(1R)-4,5,6-trimethoxy-2,3-dihydro-1H-inden-1-yl]methanamine), LOPHOPHINE (also known as 2-(7-methoxy-1,3-benzodioxol-5-yl)ethanamine), M (also known as 2-(3,4,5-trimethoxypheny)ethanamine), MADAM-6 (also known as N-methyl-1-(6-methyl-1,3-benzodioxol-5-yl)propan-2-amine), MAL (also known as 2-[3,5-dimethoxy-4-(2-methylprop-2-enoxy)phenamine] N-[1-(1,3-benzodioxol-5-yl)propan-2-yl]ethanamine), MDA (also known as 1-(1,3-benzodioxol-5-yl)propan-2-amine), MDAL (also known as 1-(1,3-benzodioxol-5-yl)-N-prop-2-enylpropan-2-amine), MDBU (also known as N-[1-(1,3-benzodioxol-5-yl)propan-2-yl]butan-1-amine), MDBZ (also known as 1-(1,3-benzodioxol-5-yl)-N-benzylpropan-2-amine), MDCPM (also known as 1-(3a,7a-dihydro-1,3-benzodioxol-5-yl)propan-2-amine), 1-(1,3-benzodioxol-5-yl)-N-(cyclopropylmethyl)propan-2-amine), MDDM (also known as 1-(1,3-benzodioxol-5-yl)-N,N-dimethylpropan-2-amine), MDE (also known as 1-(1,3-benzodioxol-5-yl)-N-ethylpropan-2-amine), MDHOET (also known as 2-[1-(1,3-benzodioxol-5-yl)propan-2-ylamino]ethanol), MDIP (also known as 1-(1,3-benzodioxol-5-yl)-N-propan-2-ylpropan-2-amine), MDMA (also known as 1-(1,3-benzodioxol-5-yl)-N-methylpropan-2-amine), MDMC (also known as 1-(2,3-dihydro-1,4-benzodioxin-6-yl)-N-methylpropan-2-amine), MDMEO (also known as 1-(1,3-benzodioxol-5-yl)-N-methoxypropan-2-amine), MDMEOET (also known as 1-(1,3-benzodioxol-5-yl)-N-(2-methoxyethyl)propan-2-amine), MDMP (also known as 1-(1,3-benzodioxol-5-yl)-N,2-dimethylpropan-2-amine), -amine), MDOH (also known as N-[1-(1,3-benzodioxol-5-yl)propan-2-yl]hydroxylamine), MDPEA (also known as 2-(1,3-benzodioxol-5-yl)ethanamine), MDPH (also known as 1-(1,3-benzodioxol-5-yl)-2-methylpropan-2-amine), MDPL (also known as 1-(1,3-benzodioxol-5-yl)-N-prop-2-ynylpropan-2-amine), MDPR (also known as 1-(1,3-benzodioxol-5-yl)-N-propylpropan-2-amine), ME (also known as 2-(3-ethoxy-4,5-dimethoxyphenyl)ethanamine), MEDA (also known as 1-(5-methoxy-2,3-dihydro-1,4-benzodioxin-7-yl)propan-2-amine), MEE (also known as 1-(4,5-diethoxy-2-methoxyphenyl)propan-2-amine), MEM (also known as 1-(4-ethoxy-2,5-dimethoxyphenyl)propan-2-amine), MEPEA (also known as 2-(4-ethoxy-3-methoxyphenyl)ethanamine), META-DOB (also known as 1-(5-bromo-2,4- dimethoxyphenyl)propan-2-amine), META-DOT (also known as 1-(2,4-dimethoxy-5-methylsulfanylphenyl)propan-2-amine), METHYL-DMA (also known as 1-(2,5-dimethoxyphenyl)-N-methylpropan-2-amine), METHYL-DOB (also known as 1-(4-bromo-2,5-dimethoxyphenyl)-N-methylpropan-2-amine), METHYL-J (also known as 1-(1,3-benzodioxol-5-yl)-N-methylbutan-2-amine), METHYL-K (also known as 1-(1,3-benzodioxol-5-yl)-N-methylpentan-2-amine), METHYL-MA (also known as 1-(4-methoxyphenyl)-N-methylpropan-2-amine), METHYL-MMDA-2 (also known as 1-(6-methoxy-1,3-benzodioxol-5-yl)-N-methylpropan-2-amine), MMDA (also known as 1-(7-methoxy-1,3-benzodioxol-5-yl)propan-2-amine), MMDA-2 (also known as 1-(6-methoxy-1,3-benzodioxol-5-yl)propan-2-amine), MMDA-3a (also known as 1-(4-methoxy-1,3-benzodi, oxol-5-yl)propan-2-amine), MMDA-3b (also known as 1-(7-methoxy-1,3-benzodioxol-4-yl)propan-2-amine), MME (also known as 1-(5-ethoxy-2,4-dimethoxyphenyl)propan-2-amine), MP (also known as 2-(3,4-dimethoxy-5-propoxyphenyl)ethanamine), MPM (also known as 1-(2,4-dimethoxy-5-propoxyphenyl)propan-2-amine), NBOMe-mescaline (also known as N-[(2-methoxyphenyl)methyl]-2-(3,4,5-trimethoxypheny)ethanamine), ORTHO-DOT (also known as 1-(4,5-dimethoxy-2-methylsulfanylphenyl)propan-2-amine), P (also known as 2-(3,5-dimethoxy-4-propoxyphenyl)propan-2-amine), phenyl)ethanamine), PE (also known as 2-[3,5-dimethoxy-4-(2-phenylethoxy)phenyl]ethanamine), PEA (also known as 2-phenylethanamine), Propynyl (also known as 2-(3,5-dimethoxy-4-prop-2-ynoxyphenyl)ethanamine), Psi-2C-T-4, Psi-DOM (also known as 1-(2,6-dimethoxy-4-methoxyphenyl)propan-2-amine), SB (also known as 2-(3,5-diethoxy-4-methoxyphenyl)ethanamine), TA (also known as 1-(2,3,4,5-tetramethoxyphenyl)propan-2-amine), TB (also known as 2-(4-butylsulfanyl-3,5-dimethoxyphenyl)ethanamine), TCB-2 (also known as (3-bromo-2,5-dimethoxy-7-bicyclo[4.2.0]octa-1(6),2,4-trienyl)methanamine; hydrobromide), TMA (also known as 1-(3,4,5-trimethoxyphenyl)propan-2-amine), TMA-2 (also known as 1-(2,4,5-trimethoxyphenyl)propan-2-amine), TMA-3 (also known as 1-(2,3,4-trimethoxyphenyl)propan-2-amine), TMA-4 (also known as 1-(2,3,5-trimethoxyphenyl)propan-2-amine), TMA-5 (also known as 1-(2,3,6-trimethoxyphenyl)propan-2-amine), These include TMA-6 (also known as 1-(2,4,6-trimethoxyphenyl)propan-2-amine), TMPEA (also known as 2-(2,4,5-trimethoxyphenyl)ethanamine), TOMSO (also known as 1-(2-methoxy-4-methyl-5-methylsulfinylphenyl)propan-2-amine), TP (also known as 2-(3,5-dimethoxy-4-propylsulfanylphenyl)ethanamine), and Tris (also known as 2-(3,4,5-triethoxyphenyl)ethanamine).

[0233] In one embodiment, the serotonergic agent is alprazolam, amphetamine, aripiprazole, azapirone, barbiturates, bromazepam, bupropion, buspirone, cannabinoids, chlordiazepoxide, citalopram, clonazepam, clorazepate, dextromethorphan, diazepam, duloxetine, escitalopram, fluoxetine, flurazepam, fluvoxamine, lorazepam, lysergic acid, benzodiazepine, benzocaine ... acid diethylamide, lysergamide, 3,4-methylenedioxymethamphetamine, milnacipran, mirtazapine, naratriptan, paroxetine, pethidine, phenethylamine, psicaine, oxazepam, reboxetine, selenic, serotonin, sertraline, temazepam, tramadol, triazolam, tryptamine, venlafaxine, vortioxetine, and / or derivatives thereof.

[0234] In one embodiment, serotonin acts by acting as a ligand at a serotonin receptor, for example, at a 5-HT receptor. In one embodiment, serotonin is produced by an organism for use as a neurotransmitter within that organism. In one embodiment, the compositions and methods disclosed herein increase activity at a serotonin receptor. In one embodiment, the compositions and methods disclosed herein decrease activity at a serotonin receptor.

[0235] As used herein, the term "serotonin receptor" refers to a collection of extracellular proteins capable of receiving a signal and activating an internal signaling pathway that causes a cellular response. In one embodiment, serotonin receptors are found on cells within the central nervous system of an organism. In one embodiment, serotonin receptors are found on cells within the peripheral nervous system of an organism. In one embodiment, serotonin is the natural ligand for serotonin receptors. In one embodiment, serotonin receptors regulate the release of neurotransmitters such as glutamate, gamma-aminobutyric acid, dopamine, epinephrine (also known as norepinephrine), acetylcholine, etc. In one embodiment, serotonin receptors regulate the release of hormones such as oxytocin, prolactin, vasopressin, cortisol, corticotropin, substance P, etc.

[0236] Examples of serotonin receptors include 5-HT 1A , 5-HT 1B , 5-HT 1D , 5-HT 1E , 5-HT 2A , 5-HT 2B , 5-HT 2C , 5-HT3, 5-HT4, 5-HT 5A , 5-HT 5B , 5-HT6, and 5-HT7.

[0237] As used herein, the term "adrenergic agonist" refers to a compound that binds to, blocks, or otherwise affects (via an allosteric response) the activity of an adrenergic receptor. In one embodiment, an adrenergic agonist binds to an adrenergic receptor. In one embodiment, an adrenergic agonist indirectly affects an adrenergic receptor, e.g., through an interaction that affects the responsiveness of other molecules at the adrenergic receptor. In one embodiment, an adrenergic agonist is an agonist, e.g., a compound that activates an adrenergic receptor. In one embodiment, an adrenergic agonist is an antagonist, e.g., a compound that binds to but does not activate an adrenergic receptor, e.g., blocks the receptor. In one embodiment, an adrenergic agonist is a compound that binds to an effector molecule, e.g., an enzyme for allosteric regulation. In one embodiment, the adrenergic agent acts (either directly or indirectly) at multiple types of receptors (eg, 5HT, dopamine, adrenergic, acetylcholine, etc.).

[0238] In one embodiment, the adrenergic agent is an antidepressant.

[0239] In one embodiment, the adrenergic agent is a norepinephrine transporter inhibitor.

[0240] In one embodiment, the adrenergic agent is a vesicular monoamine transporter inhibitor.

[0241] In one embodiment, the adrenergic agent is selected from adrenaline, agmatine, amoxapine, aptazapine, atomoxetine, bupropion, clonidine, doxepin, duloxetine, esmirtazpine, mianserin, mirtazapine, norepinephrine, phentolamine, phenylephrine, piperoxane, reserpine, ritodrine, setiptiline, tesofensine, timolol, trazodone, trimipramine, or xylazine.

[0242] In one embodiment, the adrenergic agent acts at an adrenergic receptor, for example, by acting as a ligand at an adrenergic receptor. In one embodiment, adrenaline is produced by an organism for use as a neurotransmitter within the organism. In one embodiment, norepinephrine is produced by an organism for use as a neurotransmitter within the organism. In one embodiment, the compositions and methods disclosed herein increase activity at an adrenergic receptor. In one embodiment, the compositions and methods disclosed herein decrease activity at an adrenergic receptor.

[0243] As used herein, the term "adrenergic receptor" refers to a collection of extracellular proteins that can receive a signal and activate an internal signaling pathway that causes a cellular response. In one embodiment, adrenergic receptors are found on cells within the central nervous system of an organism. In one embodiment, adrenergic receptors are found on cells within the sympathetic nervous system of an organism.

[0244] As used herein, the term "dopamine agonist" refers to a compound that binds to, blocks, or otherwise affects (via an allosteric response) the activity of a dopamine receptor. In one embodiment, a dopamine agonist binds to a dopamine receptor. In one embodiment, a dopamine agonist indirectly affects a dopamine receptor, e.g., through an interaction that affects the responsiveness of other molecules at the dopamine receptor. In one embodiment, a dopamine agonist is an agonist, e.g., a compound that activates a dopamine receptor. In one embodiment, a dopamine agonist is an antagonist, e.g., a compound that binds to but does not activate a dopamine receptor, e.g., blocks the receptor. In one embodiment, a dopamine agonist is a compound that binds to an effector molecule, e.g., an enzyme for allosteric regulation. In one embodiment, a dopamine agonist acts (either directly or indirectly) at multiple types of receptors (e.g., 5HT, dopamine, adrenergic, acetylcholine, etc.).

[0245] In one embodiment, the dopamine agonist is a dopamine transporter inhibitor.

[0246] In one embodiment, the dopamine agonist is a vesicular monoamine transporter inhibitor.

[0247] In one embodiment, the dopamine agonist is selected from amineptine, apomorphine, benzylpiperazine, bromocriptine, cabergoline, chlorpromazine, clozapine, dihydrexidine, domperidone, dopamine, fluphenazine, haloperidol, ketamine, loxapine, methamphetamine, olanzapine, pemoline, perphenazine, pergolide, phencyclidine, phenethylamine, phenmetrazine, pimozide, piribedil, psychostimulants, reserpine, risperidone, ropinirole, tetrabenazine, or thioridazine.

[0248] In one embodiment, a dopamine agonist acts at a dopamine receptor, for example, by acting as a ligand at a dopamine receptor. In one embodiment, dopamine is produced by an organism for use as a neurotransmitter within that organism. In one embodiment, the compositions and methods disclosed herein increase activity at a dopamine receptor. In one embodiment, the compositions and methods disclosed herein decrease activity at a dopamine receptor.

[0249] As used herein, the term "dopamine receptor" refers to a collection of extracellular proteins that can receive a signal and activate an internal signaling pathway that causes a cellular response. In one embodiment, dopamine receptors are found on cells within the central nervous system of an organism.

[0250] In one embodiment, the purified terpene modulates the activity of neurotransmitters at their native receptors, such as serotonin at serotonin receptors, dopamine at dopaminergic receptors, and norephedrine at adrenergic receptors.

[0251] In one embodiment, the purified terpene is active at one or more receptors, for example, a serotonin receptor, an adrenergic receptor, a dopamine receptor, a GABAergic receptor, a glutaminergic receptor, a histaminergic receptor, a cholinergic receptor, an opioid receptor, or a glycinergic receptor.

[0252] In one embodiment, the compositions disclosed herein comprise a monoamine oxidase inhibitor.

[0253] As used herein, the term "monoamine oxidase inhibitor" refers to a molecule that binds to a monoamine oxidase enzyme, thereby reducing the activity of the monoamine oxidase enzyme. Within the context of the present disclosure, examples of monoamine oxidase inhibitors include aurorix, deprenyl, eldepryl, emsam, humoril, hydracarbazine, isocarboxazid, linezolid, manerix, nidrazide, phenelzine, pyrazidol, procarbazine, rasagiline, and tranylcypromine. In one embodiment, monoamine oxidase catalyzes the oxidation of monoamines, such as serotonin, dopamine, norepinephrine, amphetamine, adrenaline, etc.

[0254] In one embodiment, the compositions disclosed herein include a stabilizer. As used herein, the term "stabilizer" refers to a compound useful for preventing the decomposition of an active ingredient, such as a compound of Formula I, a psilocybin derivative, a cannabinoid, a terpene, or the like. In one embodiment, the stabilizer prevents the active ingredient from decomposing. In one embodiment, the stabilizer prevents the serotonergic agent from reacting with other compounds in the composition, such as cannabinoids, terpenes, bases, acids, or the like. In one embodiment, the stabilizer prevents the serotonergic agent from reacting with the ambient atmosphere, such as heat, light, water, and / or oxygen. In one embodiment, the stabilizer includes an antioxidant. In one embodiment, the stabilizer includes a pH buffer.

[0255] In one embodiment, the methods and compositions disclosed herein include an antioxidant. As used herein, the term "antioxidant" refers to a compound and / or composition useful for preventing oxidation. In one embodiment, the antioxidant protects the active ingredient from "free radicals." Within the context of this disclosure, a "free radical" is an atom, molecule, or ion with an unpaired valence electron. In one embodiment, the antioxidant is an electron donor.

[0256] In one embodiment, the antioxidant is selected from ascorbic acid, lycopene, tocopherol, melatonin, retinol, astaxanthin, lutein, apigenin, carnosine, selenium, zinc, curcumin, and / or salts or derivatives thereof.

[0257] In one embodiment, the antioxidant is ascorbic acid and / or its salts or derivatives. Within the context of the present disclosure, the term "ascorbic acid" includes vitamin C and / or its salts or derivatives.

[0258] In one embodiment, the antioxidant prevents oxidation of a composition comprising one or more compounds disclosed herein, e.g., a compound of Formula I, a psilocybin derivative, a cannabinoid, a terpene, and / or mixtures thereof, e.g., by preventing oxidation of a phenolic group attached to a psilocybin derivative.

[0259] As used herein, the term "oxidation" refers to the formal loss of electrons and / or an increase in formal oxidation state and / or the addition of oxygen atom(s). As used herein, "reduction" refers to the formal gain of electrons and / or a decrease in formal oxidation state. Zumdahl, Steven S., et al. Chemistry, 7th Edition. Cengage Learning, 2018.

[0260] In one embodiment, the methods and compositions disclosed herein comprise a pH buffer.

[0261] As used herein, the term "pH buffer" refers to a compound or composition useful for maintaining the pH of a composition. In one embodiment, the pH buffer comprises a weak acid and a corresponding conjugate base. In one embodiment, the pH buffer comprises a weak base and a corresponding conjugate acid. In one embodiment, the pH buffer does not change the pH of the composition upon addition of a strong acid and / or base.

[0262] In one embodiment, the pH buffer maintains the pH of the composition at about 7. In one embodiment, the pH buffer maintains the pH of the composition below about 7. In one embodiment, the pH buffer maintains the pH of the composition above about 7. In one embodiment, the pH buffer maintains the pH of the composition in the range of about 2 to about 6. In one embodiment, the pH buffer maintains the pH of the composition in the range of about 5 to about 7. In one embodiment, the pH buffer maintains the pH of the composition in the range of about 6 to about 8. In one embodiment, the pH buffer maintains the pH of the composition in the range of about 7 to about 10.

[0263] In one embodiment, the pH buffer comprises citric acid, acetic acid, monosodium phosphate, N-cyclohexyl-2-aminoethanesulfonic acid, borate, hydrochloric acid, and / or sodium hydroxide.

[0264] In one embodiment, the methods disclosed herein include administering a composition comprising an acid.

[0265] As used herein, the term "acid" refers to an acid that contains a proton, i.e., H + "Acid" refers to a molecule or ion capable of donating and / or accepting electrons. In one embodiment, "acid" refers to a Lewis acid. In one embodiment, "acid" refers to a Bronsted acid. In one embodiment, the acid is determined by the pH of the composition. In one embodiment, a pH of less than 7 indicates the presence of an acid.

[0266] In one embodiment, the compositions and methods disclosed herein involve administering a formulation that includes a base.

[0267] As used herein, the term "base" refers to a base that contains a proton, i.e., H + In one embodiment, "base" refers to a molecule or ion capable of accepting an electron pair, i.e., a Lewis base. In one embodiment, the presence of a base is determined by the pH of the compound. In one embodiment, a pH greater than 7 indicates the presence of a base.

[0268] In one embodiment, the compositions and methods disclosed herein involve administering a water-insoluble composition.

[0269] In some embodiments, the compositions described herein are non-aqueous.

[0270] As used herein, the term "water-soluble" refers to a compound or composition that can be dissolved in water at standard temperature and pressure. In one example, 1 g of a compound dissolves in 1 L of water. In one example, 2 g of a compound dissolves in 1 L of water. In one example, 5 g of a compound dissolves in 1 L of water. In one example, 10 g of a compound dissolves in 1 L of water. In one embodiment, the solubility of a compound in water is an inherent property of the compound. In one embodiment, the solubility of a compound in water can be enhanced by another compound, for example, an excipient.

[0271] In one embodiment, the compositions and methods disclosed herein involve administering a compound of formula I present as and / or present in a homogenous mixture within a dosage formulation.

[0272] In one embodiment, the compositions and methods disclosed herein include administering a compound of Formula I and at least one second compound (e.g., a serotonergic agent, a cannabinoid, a terpene, an excipient, a stabilizer, an antioxidant, etc.) present as a homogenous mixture within a dosage formulation and / or present within a homogenous mixture.

[0273] As used herein, the term "homogeneous mixture" refers to a solid, liquid, or gaseous composition having two or more compounds present in one state or substance, e.g., a clear, colorless solution. In one embodiment, a homogeneous mixture disclosed herein has the same proportions, concentrations, and / or ratios of its components across different samples. In one embodiment, the components in a homogeneous mixture are in the same state of matter. In one embodiment, a homogeneous mixture includes one or more compounds in solution, e.g., a compound of Formula I and a cannabinoid in a clear solution. In one embodiment, a composition disclosed herein exists as a homogeneous mixture, e.g., a solution without particulate matter, a solution with comparable concentrations between samples, a powder with similar particle size, etc.

[0274] Provided herein is a method for modulating activity at a neurotransmitter receptor, comprising: administering a neurotransmitter activity modulator; and administering to a person in need of treatment a dosage formulation comprising a compound of Formula I, wherein the dosage formulation modulates activity at a neurotransmitter receptor. A method is disclosed, comprising:

[0275] As used herein, the term "modulating the activity of a neurotransmitter activity-modulating agent" refers to altering, manipulating, and / or regulating the ability of a compound or composition to affect a neurotransmitter receptor. In one embodiment, modulating the activity of a neurotransmitter activity-modulating agent comprises administering an agonist at the neurotransmitter receptor. In one embodiment, modulating the activity of a neurotransmitter activity-modulating agent comprises administering an antagonist at the neurotransmitter receptor.

[0276] As used herein, the term "administering" (e.g., administering a drug) refers to medicating, treating, giving, and / or providing. In one embodiment, administering a neurotransmitter activity-modulating agent includes providing the neurotransmitter activity-modulating agent to an organism (e.g., a human) having a neurotransmitter receptor. In one embodiment, administering a neurotransmitter activity-modulating agent includes providing the neurotransmitter activity-modulating agent together with a compound of Formula I, e.g., providing a formulation having each of the neurotransmitter activity-modulating agent and the compound of Formula I in a single dosage. In one embodiment, administering a neurotransmitter activity-modulating agent includes applying a transdermal composition, e.g., applying a topical composition having each of the neurotransmitter activity-modulating agent and the compound of Formula I to the skin. In one embodiment, administering a neurotransmitter activity-modulating agent includes providing a transmucosal preparation, e.g., providing a fast-dissolving tablet having an absorption enhancer having each of the neurotransmitter activity-modulating agent and the compound of Formula I.

[0277] In one embodiment, the methods disclosed herein include administering the composition by inhalation to cross the blood-brain barrier.

[0278] As used herein, the term "neurotransmitter activity modulating agent" refers to a compound or composition that reacts with or affects activity at a neurotransmitter receptor, such as a compound of Formula I, a serotonergic agent, an adrenergic receptor, a dopamine receptor, a GABAergic receptor, a glutaminergic receptor, a histaminergic receptor, a cholinergic receptor, an opioid receptor, or a glycinergic receptor. In one embodiment, an anxiolytic agent binds to a neurotransmitter receptor. In one embodiment, a neurotransmitter activity modulating agent binds to a neurotransmitter receptor. In one embodiment, a neurotransmitter activity modulating agent indirectly affects a neurotransmitter receptor, for example, through an interaction that affects the responsiveness of other molecules at the neurotransmitter receptor. In one embodiment, a neurotransmitter activity modulating agent is an agonist. In one embodiment, a neurotransmitter activity modulating agent is an antagonist. In one embodiment, a neurotransmitter activity modulating agent acts (either directly or indirectly) at multiple types of neurotransmitter receptors.

[0279] In one embodiment, the neurotransmitter activity modulator is selected from aripiprazole, bupropion, citalopram, clomipramine, dextroamphetamine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, mirtazapine, paroxetine, quetiapine, reboxetine, risperidone, sertraline, and venlafaxine.

[0280] As used herein, the term "first dosage formulation" refers to a compound(s) selected to produce a reaction, effect, and / or result in an organism, for example, to produce activity at a neurotransmitter receptor, react with another compound, enhance the effect of another active ingredient, inhibit the biosynthesis of a compound, etc. In one embodiment, the first dosage formulation comprises a compound of Formula I. In one embodiment, the first dosage formulation comprises a first purified cannabinoid. In one embodiment, the first dosage formulation comprises a first purified terpene. In one embodiment, the first dosage formulation comprises a compound of Formula I and a purified serotonergic derivative. In one embodiment, the first dosage formulation comprises a compound of Formula I and a first purified cannabinoid. In one embodiment, the first dosage formulation comprises a compound of Formula I and a first purified terpene. In one embodiment, the first dosage formulation comprises a compound of Formula I, a first purified cannabinoid, and a first purified terpene. In one embodiment, the first dosage formulation comprises a compound of Formula I and a neurotransmitter activity modulator.

[0281] In one embodiment, the second dosage formulation comprises a compound of Formula I. In one embodiment, the second dosage formulation comprises a second compound of Formula I. In one embodiment, the second dosage formulation comprises a second serotonergic agent.

[0282] In one embodiment, the method disclosed herein comprises administering a second dosage formulation. In one embodiment, the method disclosed herein comprises administering a third dosage formulation. In one embodiment, the method disclosed herein comprises administering a fourth dosage formulation. In one embodiment, the method disclosed herein comprises administering more than four dosage formulations.

[0283] In certain embodiments, the dosage formulation contains a desired amount of at least one compound of Formula I. In certain embodiments, the dosage formulation contains about 0.01 to about 1,000 mg of the compound, e.g., about 0.1 to about 500 mg, about 0.5 to about 100 mg, or about 1 to about 50 mg. In certain embodiments, the dosage formulation is calculated to contain the amount of the compound of Formula I based on mg of compound per kg of subject (mg / kg). In certain embodiments, the mg / kg range can be about 0.001 to about 10 mg / kg, e.g., about 0.01 to about 5, about 0.05 to about 4, about 0.05 to about 3, about 0.05 to about 3, about 0.05 to about 2, or about 0.05 to about 1 mg / kg. In some embodiments, the compound is administered in an amount of less than about 1 mg / kg, e.g., about 0.001 to about 0.99, about 0.01 to about 0.85, about 0.05 to about 0.75, about 0.01 to about 0.50, about 0.01 to about 0.25, or about 0.01 to about 0.10 mg / kg.

[0284] In one embodiment, the methods disclosed herein include administering one or more active ingredients, e.g., a compound(s) of Formula I, a cannabinoid, a terpene, a neurotransmitter activity modulator, etc., in more than two doses.

[0285] Provided herein is a method for treating a psychiatric problem, comprising: Identifying people in need of treatment; and administering a compound of formula I to a person in need of treatment, wherein the compound of formula I modulates activity at a neurotransmitter receptor; A method is disclosed, comprising:

[0286] As used herein, the term "identifying a person in need of treatment" refers to analyzing, diagnosing, and / or determining whether a person needs treatment for a disease or condition. In one embodiment, identifying a person in need of treatment includes diagnosing a person with a medical condition, such as a neurological disorder, a chemical imbalance, a genetic condition, etc. In one embodiment, identifying a person in need of treatment includes conducting a psychiatric evaluation. In one embodiment, identifying a person in need of treatment includes conducting a blood test. In one embodiment, identifying a person in need of treatment includes determining whether a person has obsessive-compulsive disorder. In one embodiment, identifying a person in need of treatment includes self-identifying as having obsessive-compulsive disorder.

[0287] As used herein, the term "mental disorder" refers to a condition in which a person exhibits a pattern of behavioral and / or psychological symptoms that affect multiple areas of life and cause distress to the person experiencing these symptoms. In one embodiment, the mental disorder is caused by a genetic disorder. In one embodiment, the mental disorder is caused by a biological condition, such as excess hormone production, lack of activity at a neurotransmitter receptor, lack of neurotransmitter production, etc. In one embodiment, the neurotransmitter receptor is a serotonin receptor.

[0288] In one embodiment, the mental problem is an anxiety disorder. In one embodiment, the mental problem is a depressive disorder. In one embodiment, the mental problem is an obsessive-compulsive disorder. In one embodiment, the mental problem is characterized by neurodegeneration.

[0289] As used herein, the term "anxiety disorder" refers to a state of worry, uncertainty, and / or fear resulting from anticipation of an event and / or situation. Anxiety disorders can disrupt a person's physical and mental functioning. These disruptions can cause minor to debilitating handicaps in a person's daily life. Anxiety disorders can cause physiological symptoms, such as muscle tension, heart palpitations, sweating, dizziness, shortness of breath, etc. Anxiety disorders can also cause psychological symptoms, such as fear of dying, fear of distress or humiliation, fear of the event occurring, etc.

[0290] In one embodiment, the anxiety disorder comprises acute stress disorder, anxiety due to a medical condition, generalized anxiety disorder, panic disorder, panic attacks, phobias, post-traumatic stress disorder, separation anxiety disorder, social anxiety disorder, substance-induced anxiety disorder, or selective mutism.

[0291] As used herein, the term "acute stress disorder" refers to a condition that develops after exposure to one or more traumatic events. Examples of traumatic events include, but are not limited to, war, rape or sexual assault, physical assault, robbery, childhood physical or sexual assault, kidnapping or hostage-taking, terrorist attack, torture, natural disaster, and / or critical self-harm. In one embodiment, acute stress disorder occurs within one day of experiencing the traumatic event. In one embodiment, acute stress disorder occurs within three days of experiencing the traumatic event. In some examples, acute stress disorder occurs within one week of experiencing the traumatic event. In some examples, acute stress disorder occurs within one month of experiencing the traumatic event.

[0292] As used herein, the term "anxiety caused by another medical condition" refers to a condition in which anxiety symptoms develop as a result of the physiological and psychological consequences of an unrelated illness, injury, and / or disease, such as an endocrine disorder, cardiovascular disorder, respiratory disorder, metabolic disorder, neurological disease, etc.

[0293] As used herein, the term "generalized anxiety disorder" refers to persistent and excessive anxiety and worry about a variety of areas, such as work, school, social settings, etc., that an individual perceives as difficult to control. The individual also experiences physical symptoms including restlessness, vigilance, and / or nervousness; easily tiring, difficulty concentrating or clearing the mind, irritability, muscle tension, and sleep disturbances.

[0294] As used herein, the term "panic disorder" refers to a condition in which an individual experiences recurrent and unexpected panic attacks. The individual persistently worries about having more panic attacks, and these panic attacks cause him or her to change his or her behavior in maladaptive ways (e.g., avoiding exercise, unfamiliar places, new people, etc.).

[0295] As used herein, the term "panic attack" refers to a sudden surge of intense fear or intense discomfort that peaks within a short period of time, e.g., within seconds, minutes, hours, etc. In some instances, a panic attack refers to physical and / or cognitive symptoms. Panic attacks can be predictable, for example, in response to a typically feared object or situation. In some instances, a panic attack occurs for no apparent reason.

[0296] As used herein, the term "phobia" refers to a condition of fear, anxiety, or avoidance of a specific object and / or situation. In some instances, a phobia involves persistent, situation-induced fear, anxiety, or avoidance to an extent disproportionate to the actual risk. Examples of phobias include, but are not limited to, fear or anxiety of animals, natural environments, injection injuries, etc.

[0297] As used herein, the term "post-traumatic stress disorder" refers to a condition that develops after experiencing and / or witnessing a traumatic event, or after learning that a traumatic event has occurred to a loved one. In some instances, a person exhibits symptoms of post-traumatic stress disorder within one week of experiencing the traumatic event. In some instances, a person exhibits symptoms of post-traumatic stress disorder within one month of experiencing the traumatic event. In some instances, a person exhibits symptoms of post-traumatic stress disorder within one year of experiencing the traumatic event. In some instances, a person exhibits symptoms of post-traumatic stress disorder more than one year after experiencing the traumatic event. In some instances, post-traumatic stress disorder involves a person reliving the traumatic event through intrusive and distressing recollections of the event, flashbacks, and / or nightmares. In some instances, symptoms of post-traumatic stress disorder include emotional numbness and avoidance of places, people, and activities that remind one of the trauma. In some instances, symptoms of post-traumatic stress disorder include increased arousal, such as difficulty sleeping and concentrating, anxiety, and irritability and anger.

[0298] As used herein, the term "neurodegeneration" refers to the progressive loss of neuronal structure or function, including, but not limited to, neuronal death. Many neurodegenerative diseases (including amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, and Huntington's disease) result from neurodegenerative processes. Such diseases are incurable and result in the progressive degeneration and / or death of neuronal cells. Several attempts have been made to treat such diseases and conditions using fungal and plant extracts. However, all of these methods suffer from a common drawback: they cannot provide consistent or reliable amounts of therapeutic compounds because the fungal and / or plant extracts rely on the highly variable chemical composition of specific naturally occurring organisms.

[0299] As used herein, the term "separation anxiety disorder" refers to a condition in which an individual experiences fear and / or anxiety about separation from an attachment figure to a degree that is developmentally inappropriate. In some instances, separation anxiety disorder involves fear or anxiety about harm coming to the attachment figure. In some instances, separation anxiety disorder involves fear of an event that will result in loss or separation from the attachment figure and a reluctance to be separated from the attachment figure. In some instances, separation anxiety disorder involves distressing nightmares and / or psychotic symptoms.

[0300] As used herein, the term "social anxiety disorder" refers to a condition in which an individual fears, is anxious about, or avoids social interactions and situations that involve the possibility of being observed. These social interactions and situations include meeting unfamiliar people, situations in which an individual may be observed eating or drinking, situations in which an individual performs in front of others, etc. In some instances, social anxiety disorder is caused by fear of being negatively evaluated by others, being embarrassed, humiliated, rejected, and / or making others uncomfortable.

[0301] As used herein, the term "substance-induced anxiety disorder" refers to a condition in which anxiety is caused by substance addiction and / or withdrawal or by medical treatment. In some instances, withdrawal from the substance increases anxiety.

[0302] As used herein, the term "selective mutism" refers to a condition characterized by an individual's consistent inability to speak in social situations where speech is expected, e.g., school, lectures, meetings, etc., even though the individual may speak in other situations. The inability to speak has significant consequences for achievement in academic and occupational settings and / or otherwise interferes with normal social communication.

[0303] In some instances, anxiety disorders include medical diagnoses based on criteria and classifications from the Diagnostic and Statistical Manual of Medical Disorders, 5th Ed. In some instances, anxiety disorders include medical diagnoses based on an independent medical evaluation. In some instances, anxiety disorders include medical diagnoses based on self-assessment.

[0304] In one embodiment, the methods and compositions disclosed herein comprise administering an anti-anxiety medication.

[0305] As used herein, the term "anxiolytic" refers to a compound or composition that reacts with or affects activity at a neurotransmitter receptor, such as a compound of Formula I, a serotonergic agent, an adrenergic receptor, a dopamine receptor, a GABAergic receptor, a glutaminergic receptor, a histaminergic receptor, a cholinergic receptor, an opioid receptor, or a glycinergic receptor. In one embodiment, the anxiolytic binds to a neurotransmitter receptor. In one embodiment, the anxiolytic indirectly affects a neurotransmitter receptor, for example, through an interaction that affects the responsiveness of other molecules at the neurotransmitter receptor. In one embodiment, the anxiolytic is an agonist. In one embodiment, the anxiolytic is an antagonist. In one embodiment, the anxiolytic acts (either directly or indirectly) at multiple types of neurotransmitter receptors.

[0306] In one embodiment, the anti-anxiety agent is selected from alprazolam, an alpha blocker, an antihistamine, a barbiturate, a beta blocker, bromazepam, a carbamate, chlordiazepoxide, clonazepam, clorazepate, diazepam, flurazepam, lorazepam, an opioid, oxazepam, temazepam, or triazolam.

[0307] As used herein, the term "depressive disorder" refers to a condition of low mood and aversion to activities that persists for a period of time and can affect a person's thoughts, behaviors, emotions, and sense of well-being. In one embodiment, a depressive disorder disrupts a person's physical and mental functioning. In one embodiment, a depressive disorder causes physiological symptoms, such as weight loss, aches or pains, headaches, cramps, digestive problems, etc. In one embodiment, a depressive disorder causes psychological symptoms, such as persistent sadness; anxiety; feelings of hopelessness and irritability; feelings of guilt, worthlessness, or helplessness; loss of interest or enjoyment in hobbies and activities; difficulty concentrating, remembering, or making decisions, etc.

[0308] In one embodiment, the depressive disorder is selected from atypical depression, bipolar disorder, catatonic depression, depression due to a medical condition, major depressive disorder, postpartum depression, premenstrual dysphoric disorder, or seasonal affective disorder.

[0309] As used herein, the term "atypical depression" refers to a condition in which an individual shows signs of mood reactivity (i.e., mood brightens in response to actual or potential positive events), significant weight gain, increased appetite, excessive sleepiness, a heavy, lead-like feeling in the arms or legs, and / or a long-standing pattern of interpersonal rejection sensitivity (leading to significant social or occupational impairment).Exemplary symptoms of atypical depression include, but are not limited to, daily sadness or depressed mood; loss of enjoyment in things that were once enjoyable; major weight changes (gain or loss) or appetite changes; nearly daily insomnia or excessive sleepiness; physical restlessness or fatigue that can be noticed by others; daily fatigue or loss of energy; nearly daily feelings of despair, worthlessness, or excessive guilt; nearly daily concentration or decision-making problems; recurrent thoughts of death or suicide, suicide plans, or suicide attempts.

[0310] As used herein, the term "bipolar disorder" refers to a condition that causes an individual to experience abnormal changes in mood, energy, activity level, and ability to perform daily tasks. Individuals with bipolar disorder experience periods of abnormally intense emotions, changes in sleep patterns and activity levels, and abnormal behavior. These distinct periods are called "mood episodes." Mood episodes are dramatically different from the person's typical mood and behavior. Exemplary symptoms of manic excessive behavior include, but are not limited to, abnormally cheerful, nervous, or irritable behavior; increased activity, energy, or agitation; exaggerated feelings of happiness and self-confidence; decreased need for sleep; abnormal talkativeness; racing thoughts; distractibility; and inappropriate decision-making, such as spending too much, taking sexual risks, or making poor investments. Exemplary symptoms of a depressive episode, low mood, include, but are not limited to, depressed mood, e.g., feelings of sadness, emptiness, hopelessness, or crying; marked loss of interest or pleasure in all or nearly all activities; significant weight loss, weight gain, or decreased or increased appetite; insomnia or hypersomnia; restlessness or slowed behavior; fatigue or loss of energy; feelings of worthlessness or excessive or inappropriate guilt; decreased ability to think or concentrate, or indecisiveness; and suicidal thoughts, plans, or attempts.

[0311] As used herein, the term "catatonic depression" refers to a condition that causes an individual to remain silent and immobile for long periods of time. Exemplary symptoms of catatonic depression include, but are not limited to, feelings of sadness that may occur daily, loss of interest in most activities, sudden weight gain or loss, changes in appetite, difficulty falling asleep or waking up, feelings of restlessness, irritability, feelings of worthlessness, feelings of guilt, fatigue, difficulty concentrating, difficulty thinking, difficulty making decisions, thoughts of suicide or death, and / or suicide attempts.

[0312] As used herein, the term "depressive disorder due to a medical condition" refers to a condition in which an individual experiences depressive symptoms caused by another illness. Examples of medical conditions known to cause depressive disorders include, but are not limited to, HIV / AIDS, diabetes, arthritis, stroke, brain disorders such as Parkinson's disease, Huntington's disease, multiple sclerosis, and Alzheimer's disease, metabolic conditions (e.g., vitamin B12 deficiency), autoimmune conditions (e.g., lupus and rheumatoid arthritis), viral or other infectious diseases (hepatitis, mononucleosis, herpes), back pain, and certain cancers (e.g., pancreatic).

[0313] As used herein, the term "major depressive disorder" refers to a condition characterized by periods of depressed mood that are present across most circumstances. Major depressive disorder is often accompanied by low self-esteem, loss of interest in normally enjoyable activities, little energy, and pain without apparent cause. In some instances, major depressive disorder is characterized by periods of depression that last for two weeks. In some instances, individuals experience periods of depression that are separated by years. In some instances, individuals experience nearly constant depressive symptoms. Major depressive disorder can adversely affect a person's personal, work, or school life, as well as sleep, eating habits, and overall health. Two to seven percent of adults with major depressive disorder attempt suicide, and up to 60% of people who attempt suicide also have major depressive disorder or another related mood disorder. Dysthymia is a subtype of major depressive disorder that consists of the same cognitive and physical problems as major depressive disorder, with less severe but longer-lasting symptoms. Exemplary symptoms of major depressive disorder include, but are not limited to, sadness, crying, feelings of emptiness or hopelessness; angry outbursts, irritability or frustration, even over small things; loss of interest or pleasure in most or all normal activities; sleep disturbances, including insomnia or hypersomnia; fatigue and lack of energy; loss of appetite, weight loss or gain; anxiety, agitation or restlessness; slowed thinking, speech, or body movements; feelings of worthlessness or guilt, preoccupation with past failures or self-blame; problems thinking, concentrating, making decisions, and remembering; frequent thoughts of death, suicidal thoughts, suicide attempts, or suicide; and unexplained physical problems, such as back pain or headaches.

[0314] As used herein, the term "postpartum depression" refers to a condition resulting from childbirth and hormonal changes, psychological adjustment to parenthood, and / or fatigue. Although postpartum depression is often associated with women, men can suffer from postpartum depression as well. Exemplary symptoms of postpartum depression include, but are not limited to, feelings of sadness, despair, emptiness, or overwhelm; crying more often than usual or for no apparent reason; worrying or feeling excessive anxiety; feeling moody, irritable, or restless; excessive sleeping or being unable to sleep even when the baby is sleeping; having problems concentrating, remembering details, and making decisions; experiencing anger or rage; losing interest in normally enjoyable activities; suffering from physical aches and pains, including frequent headaches, stomach problems, and muscle aches; eating too little or too much; withdrawing or avoiding friends and family; having problems bonding or forming an emotional attachment with the baby; persistently doubting one's ability to care for the baby; and thoughts of harming oneself or the baby.

[0315] As used herein, the term "premenstrual dysphoric disorder" refers to a condition in which an individual experiences mood lability, irritability, restlessness, and anxiety symptoms that recur during the premenstrual phase of the cycle and remit around the time of the onset of menstruation or shortly thereafter. Exemplary symptoms of premenstrual dysphoric disorder include, but are not limited to, lability (e.g., mood swings), irritability or anger, depressed mood, anxiety, and tension, decreased interest in usual activities, difficulty concentrating, lethargy and lack of energy, changes in appetite (e.g., overeating or craving certain foods), excessive or insomnia, feeling overwhelmed or out of control, physical symptoms (e.g., breast tenderness or swelling, joint or muscle pain, a feeling of "fullness," and weight gain), self-deprecating thoughts, feelings of agitation or irritability, decreased interest in usual activities (e.g., work, school, friends, hobbies), subjective difficulty concentrating, and easy fatigue.

[0316] As used herein, the term "seasonal affective disorder" refers to a condition in which an individual experiences mood changes based on the time of year. In some instances, an individual experiences low mood, low energy, or other depressive symptoms during the fall and / or winter seasons. In some instances, an individual experiences low mood, low energy, or other depressive symptoms during the spring and / or summer seasons. Exemplary symptoms of seasonal affective disorder include, but are not limited to, feeling depressed most or almost every day; losing interest in previously enjoyed activities; having low energy; having sleep problems; experiencing changes in appetite or weight; feeling sluggish or agitated; having difficulty concentrating; feeling hopeless, worthless, or guilty; and having frequent thoughts of death or suicide.

[0317] In one embodiment, a depressive disorder comprises a medical diagnosis based on criteria and classification from the Diagnostic and Statistical Manual of Medical Disorders, 5th Ed. In one embodiment, a depressive disorder comprises a medical diagnosis based on an independent medical evaluation.

[0318] In one embodiment, the methods and compositions disclosed herein comprise administering an antidepressant.

[0319] As used herein, the term "antidepressant" refers to a compound or compounds that respond to or affect activity at neurotransmitter receptors, such as compounds of Formula I, serotonergic agents, adrenergic receptors, dopamine receptors, GABAergic receptors, glutaminergic receptors, histaminergic receptors, cholinergic receptors, opioid receptors, or glycinergic receptors. In one embodiment, an antidepressant binds to a neurotransmitter receptor. In one embodiment, an antidepressant indirectly affects a neurotransmitter receptor, e.g., through interactions that affect the responsiveness of other molecules at the neurotransmitter receptor. In one embodiment, an antidepressant is an agonist. In one embodiment, an antidepressant is an antagonist. In one embodiment, an antidepressant acts (either directly or indirectly) at multiple types of neurotransmitter receptors.

[0320] In one embodiment, the antidepressant is selected from bupropion, citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, mirtazapine, paroxetine, reboxetine, sertraline, and venlafaxine.

[0321] Disclosed herein are methods of treating headache and / or migraine, comprising identifying a person in need of treatment and administering a composition disclosed herein to the person in need of treatment.

[0322] Disclosed herein are methods of treating nicotine addiction, comprising identifying a person in need of treatment and administering to the person in need thereof a composition disclosed herein.

[0323] Disclosed herein are methods of treating drug addiction, comprising identifying a person in need of treatment and administering to the person in need a composition disclosed herein.

[0324] Disclosed herein is a method of treating alcoholism, comprising identifying a person in need of treatment and administering to the person in need thereof a composition disclosed herein.

[0325] The compositions disclosed herein are useful for the treatment of obsessive-compulsive disorder, various intractable psychiatric disorders, chronic depression, post-traumatic stress disorder, and drug or alcohol addiction in humans. The compositions disclosed herein are also useful in the context of meditative, spiritual, and religious practices within a variety of settings.

[0326] As used herein, the term "obsessive-compulsive disorder" refers to a condition in which an individual has obsessions that cause feelings of anxiety, fear, anxiety, etc., and a compulsion to perform tasks to alleviate the feelings of anxiety. Obsessions are thoughts that recur and persist despite an individual's efforts to ignore or confront them. In some instances, obsessions are relatively vague, accompanied by a general sense of confusion or tension accompanied by the belief that life cannot proceed as usual while the uncertainty persists. In other instances, obsessions may be more intense, preoccupying with thoughts or images of someone close to them dying, or intrusive thoughts related to the integrity of relationships. Other obsessions concern the possibility that someone or something other than themselves (e.g., God, the devil, or disease) will harm them or the people or things they care about. In some instances, individuals perform compulsive rituals because they feel an inexplicable need to do so. In some instances, individuals perform compulsive rituals to relieve anxiety resulting from specific obsessions. The person feels that these actions somewhat prevent the frightening event from happening or keep the event from their thoughts.

[0327] In one embodiment, the obsessive-compulsive disorder is selected from addiction, body dysmorphic disorder, skin picking disorder, hoarding disorder, obsessive-compulsive disorder, and trichotillomania.

[0328] As used herein, the term "addiction" refers to a physical and / or psychological dependence on a substance, activity, and / or any other habit. In one embodiment, addiction is caused by an individual's altered brain chemistry in response to stimulants, e.g., substances that release large amounts of serotonin, activities that release large amounts of adrenaline, etc. In one embodiment, addiction is a dependence on a substance, e.g., drugs, alcohol, nicotine, food, etc. In one embodiment, addiction is a dependence on an activity, e.g., gambling, eating, shopping, etc.

[0329] As used herein, the term "body dysmorphic disorder" refers to a condition characterized by an obsessive belief that some aspect of an individual's appearance is severely flawed and requires extraordinary measures to conceal or correct it. Exemplary symptoms of body dysmorphic disorder include, but are not limited to, being extremely preoccupied with perceived flaws in appearance that others may not see or may seem minor; the belief that the flaws in appearance disfigure or deform the individual; the belief that others negatively single out or ridicule the individual's appearance; engaging in behaviors aimed at correcting or hiding the perceived flaws that are difficult to resist or control, such as frequently checking in the mirror, grooming, or picking at skin; attempting to hide the perceived flaws with styling, makeup, or clothing; constantly comparing one's appearance with others; constantly seeking reassurance from others about one's appearance; having perfectionist tendencies; frequently seeking unsatisfying cosmetic procedures; avoiding social situations; and being so preoccupied with one's appearance that it causes great distress or problems in one's social life, work, school, or other areas of functioning.

[0330] As used herein, the term "skin picking disorder" refers to a condition in which a person has a recurring urge to pick at their own skin. In some instances, skin picking disorder causes people to pick at their skin, often to the point where damage is caused.

[0331] As used herein, the term " hoarding disorder " refers to the condition of persistent difficulty in discarding or letting go of possessions, regardless of their value.The exemplary symptoms of hoarding disorder include but are not limited to: being unable to throw away possessions; severe anxiety when trying to discard items; having great difficulty in sorting or arranging possessions; indecisiveness about what to keep or where to put things; distress such as feeling overwhelmed or embarrassed by possessions; suspicion of other people touching the items; obsessive thoughts and behaviors; fear of missing or needing the items in the future; checking the trash for the items that have been discarded by mistake; and functional impairment, such as loss of living space, social isolation, family or marital discord, financial difficulties, health crisis, etc.

[0332] As used herein, the term "obsessive-compulsive disorder" refers to a condition in which an individual has uncontrollable, recurrent thoughts and behaviors that they feel an urge to repeat over and over again. In some instances, obsessive-compulsive disorder manifests itself as an individual needing to clean to reduce fears that germs, dirt, or chemicals will contaminate the individual, and the individual spends a lot of time washing themselves or cleaning their surroundings. In some instances, obsessive-compulsive disorder manifests itself as an individual needing relief from anxiety. An individual may utter a name, phrase, or repeat an action several times. The individual believes that these repetitions will not actually prevent harm, but fears of harm will arise if the repetition is not performed. In some instances, obsessive-compulsive disorder manifests itself as an individual creating checking rituals, for example, to reduce fears of harming themselves or others by forgetting to lock a door or turn off an appliance. In some instances, OCD manifests as an individual needing to organize and arrange their surroundings to reduce discomfort, for example, placing things in a specific order, arranging household items in a particular way or symmetrically, etc. In some instances, OCD manifests as an individual needing to respond to intrusive obsessions, for example, praying or saying phrases to reduce anxiety or prevent future frightening events. In some instances, OCD is caused by another medical condition. In some instances, OCD is caused by a substance.

[0333] As used herein, the term "trichotillomania" refers to a condition in which the individual self-induced and recurrent loss of hair, such as pulling out one's own hair. In some instances, trichotillomania involves an individual who pulls out their hair in one location. In some instances, trichotillomania involves an individual who pulls out their hair in multiple locations. Exemplary symptoms of trichotillomania include, but are not limited to, recurrent pulling out of one's own hair, resulting in noticeable hair loss; increased tension just before or when resisting the act of pulling out hair; feelings of enjoyment, satisfaction, or relief when pulling out hair; the disorder is not explained by another mental disorder and is not due to a general medical condition (i.e., skin lesions); repeated attempts to reduce or stop pulling out hair; the disorder causes significant distress or dysfunction in social, occupational, or other important areas of functioning; distress, including feelings of loss of control, financial difficulties, and embarrassment; and dysfunction due to avoidance of work, school, or other public situations.

[0334] In one embodiment, obsessive-compulsive disorder comprises a medical diagnosis based on criteria and classification from the Diagnostic and Statistical Manual of Medical Disorders, 5th Ed. In one embodiment, obsessive-compulsive disorder comprises a medical diagnosis based on an independent medical evaluation.

[0335] In some embodiments, the compositions described herein further comprise at least one compound that does not act on serotonin receptors.

[0336] In some embodiments, the compositions described herein comprise a serotonergic agent, wherein the serotonergic agent is selected from Formula I. In some embodiments, the composition comprises a single serotonergic agent. In some embodiments, the serotonergic agent consists essentially of a compound of Formula I.

[0337] While the disclosed disclosure has been described with reference to various exemplary embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present disclosure. Those skilled in the art will recognize that various modifications can be made to the exemplary embodiments without departing from the scope of the present disclosure.

[0338] It should be understood that when a specific compound is referred to, the present disclosure also contemplates salts and derivatives of that compound, as well as degradation products, such as oxidized versions of the explicitly disclosed molecule.

[0339] Moreover, it should be understood that various features and / or characteristics of different embodiments herein may be combined with one another. Thus, it is to be understood that numerous modifications may be made to the exemplary embodiments and other arrangements may be devised without departing from the scope of the present disclosure.

[0340] Moreover, other embodiments of the present disclosure will be apparent to those skilled in the art from consideration of the specification and practice of the present disclosure disclosed herein. It is intended that the specification and examples be considered as exemplary only, with the scope and spirit being indicated by the claims.

[0341] As used herein, any concentration range, percentage range, ratio range, or integer range should be understood to include any integer value within the stated range, and fractions thereof (such as tenths and hundredths of integers), where appropriate, unless otherwise indicated. As used herein, the terms "about" and "approximately" mean ±20%, ±10%, ±5%, or ±1% of the indicated range, value, or structure, unless otherwise indicated. [Example]

[0342] Synthetic Scheme A: Benzothiophene and Thienopyridine Analogues The benzothiophene and thienopyridine compounds of Formula I can be synthesized by the following exemplary procedure: Scheme 1A [ka]

[0343] The thiophenol starting compound, compound A, is alkylated with chloroacetone, and the resulting thioether (compound B) is cyclized under dehydrative acidic conditions to produce the 3-methylbenzothiophene intermediate, compound C. Compound C is then monobrominated with N-bromosuccinimide (NBS) to provide compound D, 3-bromomethylbenzothiophene.

[0344] Scheme 2A [ka]

[0345] The nitrile intermediate, compound E, is prepared by nucleophilic displacement of the bromine of compound D with cyanide. The nitrile group is then reduced with lithium aluminum hydride in EtO to provide the 3-aminoethylbenzothiophene intermediate, compound F. From there, a single reductive alkylation can be performed using the corresponding aldehyde X-CHO in a suitable solvent (e.g., THF, DCM, etc.) to form a secondary amine residue and compounds such as references 319 and 320 listed in Table 1. Dialkylated variants of compound G can then be prepared using reductive alkylation with aldehyde Y-CHO.

[0346] Scheme 3A Numerous variations of the benzothiophene and thienopyridine compounds of the present disclosure, including compounds generally represented by Compound H, can be synthesized from commercially purchased starting materials from companies such as Sigma-Aldrich® (e.g., benzothiophene, 2-methylthiaphthene, benzothiophene-2-methanol), Fisher Scientific® (e.g., 5-methylbenzothiophene), and SpiroChem (e.g., 7-methoxy-5-methylbenzothiophene) and then used according to the method set forth in Zhang et al., J. Org. Chem. 2000, 65, 4732-4735, which is incorporated herein by reference in its entirety. An exemplary scheme is shown below, where X is an alkyl group (e.g., C-C alkyl, e.g., methyl or ethyl) derived from the corresponding alkyl glyoxylate: [ka]

[0347] In some embodiments, compounds of formula I (wherein W is S(O) or SO), such compounds can be prepared by starting with their thio precursors (i.e., W = S) and subjecting the thio precursor to oxidation conditions, such as those set forth in Thiemann et al., "The chemistry of thiophene S-oxides and related compounds," Issue 5 Eurasian Conference on Heterocyclic Chemistry, ARKIVOC 2009(ix)96-113 (incorporated herein by reference for all purposes).

[0348] Example 1A. Preparation of 4-methoxy-3-N,N-dimethylaminoethylbenzothiophene (also known as 4-methoxy Thiopsil™) [ka]

[0349] 3-Methylthiophenol is used as Compound A and Scheme 1A is pursued to provide 4-methoxy-3-bromomethylbenzothiophene (designated as Compound D). Via Scheme 2A, Compound D is reacted with a cyanide salt to provide 4-methoxy-3-cyanomethylbenzothiophene (used as Compound E). Compound E is then reduced with LiAlH to provide 4-methoxy-3-aminoethylbenzothiophene (Compound F), which is then reductively alkylated using the corresponding aldehydes X-CHO and Y-CHO in two separate steps using a suitable solvent (e.g., THF, DCM, etc.), followed by aqueous workup of the crude reaction mixture and purification via silica gel column chromatography to provide 4-methoxy-3-N,N-dimethylaminoethylbenzothiophene.

[0350] Example 2A. Preparation of 4-hydroxy-3-N,N-dimethylaminoethylbenzothiophene (also known as Thiopsil™) [ka]

[0351] To a suspension of NaH (0.024 mol) in 25 ml of dry DMF, ethanethiol (0.024 mol) is added at 0° C. under nitrogen and vigorous stirring. After 1 h, a solution of the product of Example 1 (0.01 mol) in 20 ml of dry DMF is added all at once, and the reaction mixture is refluxed for 1 h. The solvent is removed under vacuum, and the residue is purified via silica gel column chromatography (EtOAC / hexane) to provide 4-hydroxy-3-N,N-dimethylaminoethylbenzothiophene (also known as Thiopsil).

[0352] Example 3A. Preparation of 4-acetoxy-3-N,N-dimethylaminoethylbenzothiophene (also known as Thiopsilacetin™) [ka]

[0353] To a solution of the product of Example 2A (0.01 mol) in pyridine stirred at 25°C under a nitrogen blanket, catalytic amounts of DMAP and AcO (0.011 mol) in pyridine (0.012 mol) are added. Stirring is continued for 1 hour. After quenching with aqueous workup, the solvent is removed under vacuum and the residue is purified via silica gel column chromatography to provide Thiopsilacetin.

[0354] Example 4A. Preparation of 5-methoxy-3-N,N-dimethylaminoethylbenzothiophene (also known as Bufothiophene™) [ka]

[0355] The synthetic procedure of Example 1A is repeated using 4-methylthiophenolic acid as the starting material to produce 5-methoxy-3-N,N-dimethylaminoethylbenzothiophene.

[0356] Example 5. Preparation of N-isopropyl-N-methylaminoethylbenzothiophene [ka]

[0357] The synthetic procedure of Example 11A was repeated using isopropylmethylamine as the secondary amine to provide N-isopropyl-N-methylaminoethylbenzothiophene.

[0358] Example 6A. Preparation of N-ethyl-N-methylaminoethylbenzothiophene [ka]

[0359] The synthetic procedure of Example 1A is repeated using 2-mercaptopyridine as the starting material and CH3-CHO and CH3CH2-CHO as alkylating agents to produce the N-ethyl-N-methylaminoethylthiopheno[2,3-b]pyridine target compound.

[0360] Example 7A. Preparation of N-ethyl-N-propylaminoethylbenzothiophene [ka]

[0361] The synthetic procedure of Example 1A is repeated using 2-amino-3-pyridinecarboxylic acid as the starting material and CH3CH2-CHO and CH3(CH2)2-CHO as alkylating agents to produce the N-ethyl-N-propylaminoethylthiopheno[2,3-b]pyridine target compound.

[0362] Example 8A. Preparation of 3-(N,N-dimethylaminoethyl)benzo[b]thiophen-4-yl phosphate (also known as Thiocybin™) [ka]

[0363] A 2000 mL four-neck round-bottom flask was equipped with an overhead stirrer, a J-Kem temperature controller, a 100 mL addition funnel, and a rubber septum through which positive pressure dry N2 was inserted. The septum was removed, and the flask was sequentially charged with Thiopsil (60.2 mmol) prepared according to the method in Example 2A and anhydrous THF (500 mL). The mixture was stirred for 15 minutes, and the flask was immersed in a solid CO2 / acetone cooling bath at -78 °C. When the internal temperature of the reaction reached -67 °C, a 2.5 M solution of BuLi in hexane (28.9 mL, 72.3 mmol) was added dropwise over several minutes, maintaining a reading of less than -60 °C. After stirring the reaction mixture for 10 minutes, tetrabenzyl pyrophosphate (35.7 g, 66.2 mmol) was added in one portion, and the mixture was stirred vigorously. After 1.5 hours, the solid CO2 / acetone cooling bath is removed and the temperature is allowed to rise gradually to -25°C over 2 hours.

[0364] Amino-bonded silica gel (30 g) is added in one portion, and the reaction is diluted with EtOAc (600 mL). The mixture is filtered through a pad of Celite and washed with EtOAc (400 mL). The filter cake is reslurried in EtOAc (400 mL) for 10 min and filtered again. The combined filtrates are concentrated and transferred to a 500 mL single-neck round-bottom flask. Optionally, redissolve the resulting oil in DCM (100 mL) and heat to boiling with a heat gun for 5 min. Allow the flask to come to room temperature and then keep at 4 °C overnight. The crude reaction product (zwitterion precipitate) is filtered through a Buchner funnel and then triturated with DCM (4 °C ~ 100 mL). The zwitterion precipitate is then transferred to a 250 mL single-neck round-bottom flask and thoroughly dried in a vacuum oven at 40 °C overnight to provide benzyl {3-[2-(benzyldimethylammonio)ethyl]-benzo[b]thiophen-4-yl}phosphate.

[0365] To a 2000 mL round-bottom flask, add the benzyl phosphate product (35.6 mmol) produced according to the method in the preceding paragraph, followed by CH3OH (1200 mL). The mixture is degassed and refilled with N2. 10% Pd / C (1.1 g) is added, and the mixture is degassed and refilled with a H2 balloon at 1 atmosphere. The reaction mixture is stirred overnight at room temperature. The flask is degassed and refilled with N2, and the suspension is filtered through a pad of Celite via a Buchner funnel. The filter pad is washed with CH3OH (500 mL), and the filtrate is concentrated and dried under vacuum overnight to give a crude solid. The crude solid is suspended in i-PrOH (200 mL), boiled for 30 minutes, and then filtered at high temperature (50-60 °C). The collected solid is washed with acetone to give a colored solid. The solid is then suspended in 25% CH3OH / i-PrOH, boiled for 30 minutes, filtered hot, and washed with 25% CH3OH / i-PrOH to give a colored solid which is the Thiocybin product.

[0366] Example 9A. Preparation of N-ethyl-N-methylaminoethylbenzothiophene [ka]

[0367] The synthetic procedure of Example 16A was repeated using ethylmethylamine as the secondary amine to provide the desired product in good yield.

[0368] Example 10A. Preparation of N-ethyl-N-propylaminoethylbenzothiophene [ka]

[0369] The synthetic procedure of Example 11A was repeated using ethyl-n-propylamine as the secondary amine to provide N-ethyl-N-propylaminoethylbenzothiophene.

[0370] Example 11A. Preparation of N-methyl-Nn-propylaminoethylbenzothiophene [ka]

[0371] Benzo[b]thiophene (1 eq.) was placed under nitrogen in a dry reaction flask equipped with a glass stir bar and containing 5 mol% ytterbium triflate. Excess ethyl glyoxylate was distilled (according to the method shown below*) and collected directly into the reaction flask. The reaction was stirred under nitrogen at room temperature for 24 hours. The resulting crude ester intermediate was concentrated under vacuum and purified via flash chromatography using 5:1 EtOAc:hexanes.

[0372] The purified ester intermediate was placed in a dry reaction flask under nitrogen, followed by anhydrous methanol and 1.2 eq of the secondary amine methyl n-propylamine. The reaction was stirred at room temperature for 24 h or until the ester was consumed as judged by TLC (9:1 DCM:MeOH).

[0373] The crude dried hydroxyamide intermediate was placed in a reaction flask containing a stir bar under nitrogen. To this was added 2Me-THF followed by 3 eq of LiAlH4 as a 2.0 M solution of LiAlH4 in 2Me-THF over 1 min. The reaction was slightly exothermic and then heated to 65 °C for 4 h. The reaction mixture was then cooled to 0-20 °C and slowly quenched with THF / HO (4:1) under stirring for approximately 30 min. The reaction mixture was then carefully diluted with DCM / MeOH (9:1) and then filtered through a pad of Celite. The filtered solution was then concentrated under reduced pressure and purified via flash chromatography using 5:1 EtOAc:hexane to provide the desired product as a colorless oil.

[0374] *50% ethyl glyoxylate oligomer in toluene (Fluka) was distilled at atmospheric pressure using a short (2 in) Vigreaux column and an oil bath temperature of 130-185°C (gradually increased over a 30 minute period) until only a small residue remained. The first few mL were discarded, then the entire volume was collected. The resulting yellowish distillate, containing the toluene-ethyl glyoxylate mixture, was immediately redistilled at 30 Torr. After the toluene reaction, pure ethyl glyoxylate was distilled at 48-50°C / 30 Torr.

[0375] Example 12A. Preparation of N-ethylaminoethylbenzothiophene [ka]

[0376] To a vigorously stirred solution of carbaldehyde (1 mmol) prepared according to the method of Example 15A in MeCN (10 mL) at 0 °C was added EtNH3Cl (5 mmol) and NaOAc (5 mmol). The reaction mixture was stirred at 0 °C for 15 min, and then excess NaHB(OAc)3 was added. The reaction mixture was stirred at 0 °C for 5 h and then allowed to gradually warm to room temperature overnight. The reaction mixture was quenched by the addition of 1 M HCl and diluted with diethyl ether. The phases were separated, and the organic phase was washed with 1 M HCl (x2). The combined acidic aqueous phase was basified by the addition of solid NaOH. The aqueous phase was extracted with DCM (x3-x5) and dried over anhydrous sodium sulfate. After filtration, the solvent was removed in vacuo to give a crude oil. The target compound was purified as a tanish solid by silica gel column chromatography (load with DCM and elute with 1% MeOH / DCM, then 5% MeOH / DCM doped with 1% NEt3).

[0377] Example 13A. Preparation of N-isopropylaminoethylbenzothiophene [ka]

[0378] The synthesis of Example 16A was repeated using isopropylamine as the amine to give the target compound as a tan-colored semi-solid in 65% yield.

[0379] Example 14A. Preparation of N-cyclopropylaminoethylbenzothiophene [ka]

[0380] The synthetic procedure of Example 16A is repeated except replacing the secondary amine with cyclopropylamine to yield the desired product.

[0381] Example 15A. Formation of a benzothiophene-extended carbaldehyde intermediate [ka]

[0382] To a stirred suspension of Wittig salt (3.60 g, 10.5 mmol, 1.7 eq) in THF at 0 °C, n-BuLi solution (4.2 mL, 10.5 mmol, 1.7 eq, 2.5 M in hexane) was added dropwise. The resulting reaction mixture became homogeneous and red. Carbaldehyde (1.0 g, 6.2 mmol, 1.0 eq) was added as a solid in one portion to the reaction mixture. After 15 min, the reaction mixture was diluted with diethyl ether and quenched with 1 M HCl (aq). The phases were separated, and the aqueous phase was extracted with diethyl ether (x2). The combined organic extracts were washed with water and brine and dried over anhydrous sodium sulfate. After filtration, the solvent was removed in vacuo. The enol ether could be isolated from the crude product as a pale yellow oil (862 mg, 73%) by column chromatography (loaded with PhMe and eluted with 0–5% ethyl acetate in hexane).

[0383] To a solution of the enol ether (607 mg, 3.19 mmol, 1.0 eq) in THF (12.8 mL) was added 1 M HCl (aq. 19.2 mL). The reaction mixture was refluxed for 4 h, then cooled to room temperature and diluted with water and diethyl ether. The phases were separated and the aqueous phase was extracted with diethyl ether (x2). The combined organic extracts were washed with water and brine and dried over anhydrous sodium sulfate. After filtration, the solvent was removed in vacuo to give the desired extended carbaldehyde as a crude oil (553 mg).

[0384] Example 16A. Preparation of N,N-dimethylaminoethylbenzothiophene [ka]

[0385] To a solution of target-extended carbaldehyde (1.0 eq) prepared according to the method of Example 15A in acetonitrile (0.1 M) was added dimethylamine (2–5 eq) and several beads of activated Hole 3A MS. After stirring for 10 min at room temperature, NaHB(OAc)3 (>5 eq) was added in one portion. The reaction mixture was stirred at room temperature for 18–24 h, then quenched by the addition of 1 M HCl and diluted with diethyl ether. The phases were separated, and the organic phase was washed with 1 M HCl (x2). The combined aqueous phase was made basic by the addition of solid NaOH. The aqueous phase was extracted with DCM (x3), and the combined DCM washes were dried over anhydrous sodium sulfate. Analytical purity was achieved by purification by column chromatography (removal of the major impurity from DCM with 1% MeOH / DCM, followed by elution with 5% MeOH / DCM doped with approximately 1% NEt3) to afford the product as a colorless oil.

[0386] Example 17A. Preparation of N-isopropyl-N-methylaminoethylbenzothiophene [ka]

[0387] The synthetic procedure of Example 16A was repeated using isopropylmethylamine as the secondary amine to provide the desired product as a colorless oil in 68% yield.

[0388] Example 18A. Preparation of N-methylaminoethylbenzothiophene [ka]

[0389] The method of Example 12A was repeated using methylamine hydrochloride as the primary amine to give the target compound in 61% yield as an off-white solid.

[0390] Example 19A. Preparation of Hydrofumarates (aka [1:1] Fumarate) The [1:1] hydrofumarate salt of each one of the compounds is prepared separately from the compounds of Examples 1-7A, 9-14A, and 16-18A using the following procedure: One equivalent of the free base product is dissolved in acetone and added dropwise to a solution of fumaric acid (1 equivalent) in acetone. A precipitate forms immediately, and the precipitate / acetone is stored at -20°C overnight. The solid is then filtered and washed with ice-cold acetone to produce the desired crystalline hydrofumarate salt.

[0391] Example 20A. Preparation of Fumarate Salt (also known as [2:1] Fumarate) The [2:1] fumarate salt of each one of the compounds is prepared separately from the compounds of Examples 1-7A, 9-14A, and 16-18A using the following procedure: One equivalent of the free base product is dissolved in acetone and added dropwise to a solution of fumaric acid (0.5 equivalents) in acetone. A precipitate forms immediately, and the precipitate / acetone is stored at -20°C overnight. The solid is then filtered and washed with ice-cold acetone to produce the desired crystalline fumarate salt.

[0392] Synthetic Scheme B: Benzoselenophene and selenophenopyridine analogs As shown below, the Compound A starting material can be converted to the benzoselenophene and selenophenopyridine compounds of Formula I: Scheme 1B [ka]

[0393] The starting compound A, 2-aminobenzoic acid (also known as anthranilic acid analog) is treated with HNO2 (from HCl and NaNO2) to form the diazonium salt. From there, the diazonium salt is treated with Na2Se2 (prepared from NaOH, water, Se, and rongalite). After 1 hour, activated charcoal is added and the basic solution is filtered. After acidification with concentrated HCl, the crude product is filtered, washed with water, and oven-dried to yield a cream-powder (which may turn red upon standing). This diselenide is then dissolved in NaOH and anhydrous Na2CO3 is added. The solution is warmed to 70°C and Na2SO4 is introduced. The mixture is refluxed for 1 hour, cooled to 60°C, and a neutral aqueous solution of chloroacetic acid is added and refluxed for 2 hours. After cooling, concentrated HCl is added until the pH is 1, and the precipitate is collected and washed with water. Recrystallization yields the diacid intermediate compound B.

[0394] Compound B is then mixed with acetic anhydride and dry sodium acetate under reflux for 2 hours. After removal of the reagents and standard workup, the solid residue is purified by liquid chromatography and recrystallized to provide the acetate intermediate compound C. From there, compound C is treated with HCl under reflux for 3 hours. After removal of the reagents and standard workup, selenoindoxyl compound D is purified by silica gel column chromatography.

[0395] Scheme 2B [ka]

[0396] Dialkylcarbamoylmethylenetriphenylphosphorane Preparation: A solution of triphenylphosphine and the desired dialkylchloroacetamide is refluxed for 2 hours. After cooling, the solid is filtered and air-dried. White crystals of the phosphonium salt intermediate are obtained. The phosphonium salt is suspended in water and CHCl3. After dropwise addition of NaOH, the mixture is vigorously stirred for 2 hours. After decantation and removal of the solvent, the solid is recrystallized to provide the phosphorane intermediate.

[0397] The selenoindoxyl intermediate, Compound D, is combined with phosphorane and refluxed in dry toluene under nitrogen for 24 hours. After removal of the solvent, the residue is recrystallized to provide the amide, Compound E, which can be further purified by chromatography.

[0398] To a suspension of LiAlH in dry THF (50 ml) is added dropwise a solution of amide compound E in dry THF. The mixture is refluxed for 1 hour, cooled (0°C) and hydrolyzed successively with water and NaOH. After filtration of the salts, the cake is washed with THF and the organic phase is dried and evaporated under vacuum to yield compound F.

[0399] In certain embodiments, compound F may contain an alkoxy group (e.g., methoxy) at R4 or R5. To convert the alkoxy residue to a hydroxyl group, compound F may be treated with NaH in dry DMF, and ethanethiol is added at 0°C under nitrogen and vigorous stirring. After 1 hour, a solution of compound F in dry DMF is added all at once, and the reaction mixture is refluxed for 1 hour. The solvent is removed under vacuum, and the residue is diluted with water. Extraction and column chromatography may provide the purified compound.

[0400] Scheme 3B Numerous variations of the benzoselenophene and selenophenopyridine compounds of the present disclosure, including compounds generally represented by Compound H, can be synthesized from starting materials, such as benzoselenophene, commercially purchased from companies such as Accela®, and then used according to the method set forth in Zhang et al., J. Org. Chem. 2000, 65, 4732-4735 (incorporated herein by reference in its entirety). An exemplary scheme is shown below, where X is an alkyl group (e.g., C-C alkyl, e.g., methyl or ethyl) derived from the corresponding alkyl glyoxylate: [ka]

[0401] Scheme 4B Numerous variations of the benzoselenophene and selenophenopyridine compounds of the present disclosure, including compounds generally represented by Compound O, can be synthesized from starting materials, such as bromobenzene, commercially purchased from companies such as Accela®, and then used according to the methods set forth in E. Paegle, et al., Chem Asian J 2016 Vol. 11 Issue 13 Pages 1929-38 (incorporated herein by reference in its entirety). An exemplary scheme is shown below. [ka]

[0402] In some embodiments, compounds of formula I (wherein W is Se(O) or SeO) can be prepared by starting with a seleno precursor of those compounds (i.e., W = Se) and subjecting the seleno precursor to oxidation conditions, such as those set forth in Nakayama et al., "Oxidation of Tetraarylselenophenes and Benzo[b]selenophene with m-Chloroperbenzoic Acid," Chemistry Letters, 495 (1995) (incorporated herein by reference for all purposes).

[0403] Example 1B. Preparation of 4-Methoxy-3-N,N-dimethylaminoethylbenzoselenophene (also known as 4-Methoxy Selenopsil™) [ka]

[0404] Using 6-methoxyanthranilic acid as Compound A, Scheme 1B is carried out to provide 4-methoxybenzo[b]selenophen-3(2h)-one (used as Compound D). Via Scheme 2B, Compound D is reacted with the desired phosphorane prepared from triphenylphosphine and dimethylchloroacetamide to provide 4-methoxy-N,N-dimethylbenzo[b]selenophene-3-acetamide (used as Compound E). Compound E is then reduced with LiAlH to complete Scheme 2, providing a crude reaction mixture of 4-methoxyselenopsil, which is quenched, extracted via aqueous workup, and purified via silica gel column chromatography (EtOAC / hexane) to provide 4-methoxy-3-N,N-dimethylaminoethylbenzoselenophene.

[0405] Example 2B. Preparation of 4-hydroxy-3-N,N-dimethylaminoethylbenzoselenophene (also known as Selenopsil™) [ka]

[0406] To a suspension of NaH (0.024 mol) in 25 ml of dry DMF, ethanethiol (0.024 mol) is added at 0° C. under nitrogen and vigorous stirring. After 1 h, a solution of the product of Example 1 (0.01 mol) in 20 ml of dry DMF is added all at once, and the reaction mixture is refluxed for 1 h. The solvent is removed under vacuum, and the residue is purified via silica gel column chromatography (EtOAC / hexane) to provide 4-hydroxy-3-N,N-dimethylaminoethylbenzoselenophene (also known as Selenopsil).

[0407] Example 3B. Preparation of 4-acetoxy-3-N,N-dimethylaminoethylbenzoselenophene (also known as Selenopsilacetin™) [ka]

[0408] To a solution of the product of Example 2B (0.01 mol) in pyridine stirred at 25°C under a nitrogen blanket, catalytic amounts of DMAP and AcO (0.011 mol) in pyridine (0.012 mol) are added. Stirring is continued for 1 hour. After quenching with aqueous workup, the solvent is removed under vacuum, and the residue is purified via silica gel column chromatography to provide Selenopsilacetin.

[0409] Example 4B. Preparation of 5-Methoxy-3-N,N-dimethylaminoethylbenzoselenophene (also known as Bufoselenophene™) [ka]

[0410] The synthetic procedure of Example 1B is repeated using 5-methoxyanthranilic acid as the starting material to produce 5-methoxy-3-N,N-dimethylaminoethylbenzoselenophene.

[0411] Example 5B. Preparation of N-isopropyl-N-methylaminoethylbenzoselenophene [ka]

[0412] The synthetic procedure of Example 11B was repeated using isopropylmethylamine as the secondary amine to provide the N-isopropyl-N-methylaminoethylbenzoselenophene target compound.

[0413] Example 6B. Preparation of N-ethyl-N-methylaminoethylbenzoselenophene[2,3-b]pyridine [ka]

[0414] The synthetic procedure of Example 1B is repeated using 2-amino-3-pyridinecarboxylic acid and 2-chloro-N-ethyl-N-methylacetamide as starting materials to form the desired phosphorane, ultimately yielding the N-ethyl-N-methylaminoethylselenopheno[2,3-b]pyridine target compound.

[0415] Example 7B. Preparation of N-ethyl-N-propylaminoethylbenzoselenopheno[2,3-b]pyridine [ka]

[0416] The synthetic procedure of Example 1B is repeated using 2-amino-3-pyridinecarboxylic acid and 2-chloro-N-propylacetamide as starting materials to form the desired phosphorane, ultimately yielding the N-ethyl-N-propylaminoethylselenopheno[2,3-b]pyridine target compound.

[0417] Example 8B. Preparation of 3-(N,N-dimethylaminoethyl)benzo[b]selenophen-4-yl phosphate (also known as Selenocybin™) [ka]

[0418] A 2000 mL four-neck round-bottom flask was equipped with an overhead stirrer, a J-Kem temperature controller, a 100 mL addition funnel, and a rubber septum through which positive pressure dry N2 was inserted. The septum was removed, and the flask was sequentially charged with Selenopsil (60.2 mmol) prepared according to the method in Example 2 and anhydrous THF (500 mL). The mixture was stirred for 15 minutes, and the flask was immersed in a solid CO2 / acetone cooling bath at -78 °C. When the internal temperature of the reaction reached -67 °C, a 2.5 M solution of BuLi in hexane (28.9 mL, 72.3 mmol) was added dropwise over several minutes, maintaining a reading of less than -60 °C. After stirring the reaction mixture for 10 minutes, tetrabenzyl pyrophosphate (35.7 g, 66.2 mmol) was added in one portion, and the mixture was stirred vigorously. After 1.5 hours, the solid CO2 / acetone cooling bath is removed and the temperature is allowed to rise gradually to -25°C over 2 hours.

[0419] Amino-bonded silica gel (30 g) is added in one portion, and the reaction is diluted with EtOAc (600 mL). The mixture is filtered through a pad of Celite and washed with EtOAc (400 mL). The filter cake is reslurried in EtOAc (400 mL) for 10 min and filtered again. The combined filtrates are concentrated and transferred to a 500 mL single-neck round-bottom flask. Optionally, redissolve the resulting oil in DCM (100 mL) and heat to boiling with a heat gun for 5 min. Allow the flask to come to room temperature and then keep at 4 °C overnight. The crude reaction product (zwitterion precipitate) is filtered through a Buchner funnel and then triturated with DCM (4 °C ~ 100 mL). The zwitterion precipitate is then transferred to a 250 mL single-neck round-bottom flask and thoroughly dried in a vacuum oven at 40 °C overnight to provide benzyl{3-[2-(benzyldimethylammonio)ethyl]-benzo[b]selenophen-4-yl}phosphate.

[0420] To a 2000 mL round-bottom flask, add the benzyl phosphate product (35.6 mmol) produced according to the method in the preceding paragraph, followed by CH3OH (1200 mL). The mixture is degassed and refilled with N2. 10% Pd / C (1.1 g) is added, and the mixture is degassed and refilled with a H2 balloon at 1 atmosphere. The reaction mixture is stirred overnight at room temperature. The flask is degassed and refilled with N2, and the suspension is filtered through a pad of Celite via a Buchner funnel. The filter pad is washed with CH3OH (500 mL), and the filtrate is concentrated and dried under vacuum overnight to give a crude solid. The crude solid is suspended in i-PrOH (200 mL), boiled for 30 minutes, and then filtered at high temperature (50-60 °C). The collected solid is washed with acetone to give a colored solid. The solid is then suspended in 25% CH3OH / i-PrOH, boiled for 30 minutes, filtered hot, and washed with 25% CH3OH / i-PrOH to give a colored solid which is the selenocybin product.

[0421] Example 9B. Preparation of N-ethyl-N-methylaminoethylbenzoselenophene [ka]

[0422] The synthesis of Example 16A was repeated using the extended carbaldehyde of Example 16B as the starting material, except that ethylmethylamine was used as the secondary amine, to give the target compound as a brownish oil in 62% yield.

[0423] Example 10B. Preparation of N-ethyl-N-propylaminoethylbenzoselenophene [ka]

[0424] The synthetic procedure of Example 11B was repeated using ethyl-n-propylamine as the secondary amine to provide the N-ethyl-N-propylaminoethylbenzoselenophene target compound.

[0425] Example 11B. Preparation of N-methyl-Nn-propylaminoethylbenzoselenophene [ka]

[0426] Benzo[b]selenophene (1 eq.) was placed under nitrogen in a dry reaction flask equipped with a glass stir bar and containing 5 mol% ytterbium triflate. Excess ethyl glyoxylate was distilled (according to the method described below*) and collected directly in the reaction flask. The reaction was stirred under nitrogen at room temperature for 24 hours. The resulting crude ester intermediate was concentrated under vacuum and purified via flash chromatography using 5:1 EtOAc:hexanes.

[0427] The purified ester intermediate was placed in a dry reaction flask under nitrogen, followed by anhydrous methanol and 1.2 eq of the secondary amine methyl n-propylamine. The reaction was stirred at room temperature for 24 h or until the ester was consumed as judged by TLC (9:1 DCM:MeOH).

[0428] The crude dried hydroxyamide intermediate was placed in a reaction flask containing a stir bar under nitrogen. To this was added 2Me-THF followed by 3 eq of LiAlH4 as a 2.0 M solution of LiAlH4 in 2Me-THF over 1 min. The reaction was slightly exothermic and then heated to 65 °C for 4 h. The reaction mixture was then cooled to 0-20 °C and slowly quenched with THF / HO (4:1) under stirring for approximately 30 min. The reaction mixture was then carefully diluted with DCM / MeOH (9:1) and then filtered through a pad of Celite. The filtered solution was then concentrated under reduced pressure and purified via flash chromatography using 5:1 EtOAc:hexane to provide the desired product.

[0429] *50% ethyl glyoxylate oligomer in toluene (Fluka) was distilled at atmospheric pressure using a short (2 in) Vigreaux column and an oil bath temperature of 130-185°C (gradually increased over 30 min 187 hr) until only a small residue remained. The first few mL were discarded, then the entire volume was collected. The resulting yellowish distillate, containing the toluene-ethyl glyoxylate mixture, was immediately redistilled at 30 Torr. After the toluene reaction, pure ethyl glyoxylate was distilled at 48-50°C / 30 Torr.

[0430] Example 12B. Preparation of N-ethylaminoethylbenzoselenophene [ka]

[0431] The synthesis of Example 12A was repeated using the extended carbaldehyde of Example 16B as the starting material, except that ethylamine hydrochloride was used as the primary amine, to afford the target compound as a tan-colored semi-solid in 59% yield.

[0432] Example 13B. Preparation of N-isopropylaminoethyl benzoselenophene [ka]

[0433] 11.9 mg of 3-(aminoethyl)benzoselenophene was suspended in 7 mL of THF under nitrogen, followed by acetone as a standard solution in THF. Acetic acid (also as a standard solution in THF) and sodium triacetoxyborohydride were then added, and the reaction mixture was stirred for 24 hours. The reaction was quenched with NaHCO3, extracted with Et2O, and then concentrated under reduced pressure. The crude product was purified using SiO2 chromatography with 10% MeOH in DCM as the eluent to yield the desired product.

[0434] Example 14B. Preparation of N-cyclopropylaminoethylbenzoselenophene [ka]

[0435] The synthesis of Example 16A was repeated using the extended carbaldehyde of Example 16B as the starting material, except that cyclopropylamine was used as the amine, to give the target compound as a tan solid in 45% yield.

[0436] Example 15B. Preparation of selenophene carbaldehyde intermediate [ka]

[0437] To a solution of 3-bromoselenophene (3.6 mmol) in THF (15 mL) at -78 °C, n-BuLi (4.7 mmol) was added dropwise. The reaction mixture was stirred at this temperature for 15 minutes, and then DMF (10.8 mmol) was added dropwise. The reaction mixture was warmed to room temperature and then quenched by the addition of water. The phases were separated, and the aqueous phase was extracted with diethyl ether (x3). The combined organic extracts were washed with water and brine and dried over anhydrous sodium sulfate. After filtration, the solvent was removed in vacuo to give a crude oil. The carbaldehyde was isolated from the crude mixture by silica gel chromatography (eluent: 0, 2, 5, 7% ethyl acetate in hexane) as a pale orange solid (39% yield).

[0438] Example 16B. Formation of an extended carbaldehyde intermediate [ka]

[0439] The target-extended selenophene carbaldehyde intermediate was produced using the method of Example 15A, except that the carbaldehyde intermediate produced in Example 15B was used as the starting material to provide the target-extended carbaldehyde as a brownish oil in 64% yield.

[0440] Example 17B. Preparation of N,N-dimethylaminoethylbenzoselenophene [ka]

[0441] The synthesis of Example 16A was repeated except that the elongated carbaldehyde of Example 16B was used as the starting material to give the target compound as a colorless oil in 66% yield.

[0442] Example 18B. Preparation of N-methylbenzoselenophene [ka]

[0443] The synthesis of Example 12A was repeated using the extended carbaldehyde of Example 16B as the starting material, except that methylamine hydrochloride was used as the primary amine, to give the target compound as a whitish oil in 54% yield.

[0444] Example 19B. Formation of Hydrofumarates (aka [1:1] Fumarate) The [1:1] hydrofumarate salt of each one of the compounds is prepared separately from the compounds of Examples 1-7B, 9-14B and 17-18B using the following procedure: One equivalent of the free base product is dissolved in acetone and added dropwise to a solution of fumaric acid (1 equivalent) in acetone. A precipitate forms immediately, and the precipitate / acetone is stored at -20°C overnight. The solid is then filtered and washed with ice-cold acetone to produce the desired crystalline hydrofumarate salt.

[0445] Example 20B. Preparation of Fumarate Salt (also known as [2:1] Fumarate) The [2:1] fumarate salt of each one of the compounds is prepared separately from the compounds of Examples 1-7B, 9-14B and 17-18B using the following procedure: One equivalent of the free base product is dissolved in acetone and added dropwise to a solution of fumaric acid (0.5 equivalents) in acetone. A precipitate forms immediately, and the precipitate / acetone is stored at -20°C overnight. The solid is then filtered and washed with ice-cold acetone to produce the desired crystalline fumarate salt.

[0446] Synthetic Scheme C: Benzofuran and furopyridine analogues As shown below, the Compound A starting material can be converted to the benzofuran and furopyridine compounds of Formula I: Scheme 1C [ka]

[0447] Scheme 2C Numerous variations of benzofuran and furopyridine starting materials, including compounds generally represented by compound H, can be purchased commercially from companies such as Sigma Aldrich® (e.g., benzofuran, 2-methylbenzofuran, 5-bromobenzofuran, 2-phenylbenzofuran), and then used according to the exemplary scheme shown below to produce compound K, which can then be alkylated using an appropriate alkyl halide in the presence of a base using known methods to form the desired mono- or di-alkylaminoethyl analog of formula I: [ka]

[0448] Scheme 3C Numerous variations of the benzofuran and furanopyridine compounds of the present disclosure, including compounds generally represented by Compound H, can be synthesized from starting materials purchased commercially from companies such as Sigma® (e.g., benzofuran) and Santa Cruz® (e.g., 5-methoxybenzofuran) and then used according to the methods set forth in Zhang et al., J. Org. Chem. 2000, 65, 4732-4735, which is incorporated herein by reference in its entirety. An exemplary scheme is shown below, where X is an alkyl group (e.g., C-C alkyl, e.g., methyl or ethyl) derived from the corresponding alkyl glyoxylate: [ka]

[0449] Example 1C. Preparation of 4-Methoxy-3-N,N-dimethylaminoethylbenzofuran (also known as 4-Methoxy Furanopsil™) [ka]

[0450] Scheme 1 is carried out using 2,6-dimethoxybenzoyl chloride as Compound A to provide 4-methoxybenzo[b]furan-3(2h)-one (Compound B). Compound B is reacted with methyl(triphenylphosphoranylidene)acetate to provide 4-methoxy-N,N-dimethylbenzo[b]furan-3-acetamide (Compound C), which is then reduced to the primary alcohol with LiAlH and tosylated to form Compound D. The tosylate is then displaced with dimethylamine under acidic conditions, and the reaction mixture is quenched, extracted via aqueous workup, and purified via silica gel column chromatography (EtOAC / hexane) to provide 4-methoxy-3-N,N-dimethylaminoethylbenzofuran.

[0451] Example 2C. Preparation of 4-hydroxy-3-N,N-dimethylaminoethylbenzofuran (also known as furanopsil™) [ka]

[0452] To a suspension of NaH (0.024 mol) in 25 ml of dry DMF, ethanethiol (0.024 mol) is added at 0° C. under nitrogen and vigorous stirring. After 1 h, a solution of the product of Example 1 (0.01 mol) in 20 ml of dry DMF is added all at once, and the reaction mixture is refluxed for 1 h. The solvent is removed under vacuum, and the residue is purified via silica gel column chromatography (EtOAC / hexane) to provide 4-hydroxy-3-N,N-dimethylaminoethylbenzofuran (also known as Furanopsil).

[0453] Example 3C. Preparation of 4-acetoxy-3-N,N-dimethylaminoethylbenzofuran (also known as Furanopsilacetin™) [ka]

[0454] To a solution of the product of Example 2C (0.01 mol) in pyridine stirred at 25°C under a nitrogen blanket, catalytic amounts of DMAP and AcO (0.011 mol) in pyridine (0.012 mol) are added. Stirring is continued for 1 hour. After quenching with aqueous workup, the solvent is removed under vacuum and the residue is purified via silica gel column chromatography to provide Furanopsilacetin.

[0455] Example 4C. Preparation of 5-methoxy-3-N,N-dimethylaminoethylbenzofuran (also known as Bufofuranopsil™) [ka]

[0456] The synthetic procedure of Example 1C is repeated using 2,5-dimethoxybenzyl chloride as the starting material to produce 5-methoxy-3-N,N-dimethylaminoethylbenzofuran.

[0457] Example 5C. Preparation of N-isopropyl-N-methylaminoethylbenzofuran [ka]

[0458] The synthetic procedure of Example 11C was followed using isopropylmethylamine as the secondary amine to provide the N-isopropyl-N-methylaminoethylbenzofuran target compound.

[0459] Example 6C. Preparation of N-ethyl-N-methylaminoethylfuro[2,3-b]pyridine [ka]

[0460] The synthetic procedure of Example 4C is repeated using 2-methoxy-3-pyridinecarbonyl chloride and methylethylamine to finally produce the N-ethyl-N-methylaminoethylfuro[2,3-b]pyridine target compound.

[0461] Example 7C. Preparation of N-ethyl-N-propylaminoethylfuro[2,3-b]pyridine [ka]

[0462] The synthetic procedure of Example 5C is repeated using ethyl n-propylamine instead of methylethylamine to ultimately yield the N-ethyl-N-propylaminoethylfuro[2,3-b]pyridine target compound.

[0463] Example 8C. Preparation of 3-(N,N-dimethylaminoethyl)benzo[b]furan-4-yl phosphate (also known as Furocybin™) [ka]

[0464] A 2000 mL four-neck round-bottom flask was equipped with an overhead stirrer, a J-Kem temperature controller, a 100 mL addition funnel, and a rubber septum through which positive pressure dry N2 was inserted. The septum was removed, and the flask was sequentially charged with Furanopsil (60.2 mmol) prepared according to the method in Example 2 and anhydrous THF (500 mL). The mixture was stirred for 15 minutes, and the flask was immersed in a solid CO2 / acetone cooling bath at -78 °C. When the internal temperature of the reaction reached -67 °C, a 2.5 M solution of BuLi in hexane (28.9 mL, 72.3 mmol) was added dropwise over several minutes, maintaining a reading of less than -60 °C. After stirring the reaction mixture for 10 minutes, tetrabenzyl pyrophosphate (35.7 g, 66.2 mmol) was added in one portion, and the mixture was stirred vigorously. After 1.5 hours, the solid CO2 / acetone cooling bath is removed and the temperature is allowed to rise gradually to -25°C over 2 hours.

[0465] Amino-bonded silica gel (30 g) is added in one portion and the reaction is diluted with EtOAc (600 mL). The mixture is filtered through a pad of Celite and washed with EtOAc (400 mL). The filter cake is reslurried in EtOAc (400 mL) for 10 min and filtered again. The combined filtrates are concentrated and transferred to a 500 mL single-neck round-bottom flask. Optionally, redissolve the resulting oil in DCM (100 mL) and heat to boiling with a heat gun for 5 min. Allow the flask to come to room temperature and then keep at 4 °C overnight. The crude reaction product (zwitterion precipitate) is filtered through a Buchner funnel and then triturated with DCM (4 °C ~ 100 mL). The zwitterion precipitate is then transferred to a 250 mL single-neck round-bottom flask and thoroughly dried in a vacuum oven at 40 °C overnight to provide benzyl {3-[2-(benzyldimethylammonio)ethyl]-benzo[b]furan-4-yl}phosphate.

[0466] To a 2000 mL round-bottom flask, add the benzyl phosphate product (35.6 mmol) produced according to the method in the preceding paragraph, followed by CH3OH (1200 mL). The mixture is degassed and refilled with N2. 10% Pd / C (1.1 g) is added, and the mixture is degassed and refilled with a H2 balloon at 1 atmosphere. The reaction mixture is stirred overnight at room temperature. The flask is degassed and refilled with N2, and the suspension is filtered through a pad of Celite via a Buchner funnel. The filter pad is washed with CH3OH (500 mL), and the filtrate is concentrated and dried under vacuum overnight to give a crude solid. The crude solid is suspended in i-PrOH (200 mL), boiled for 30 minutes, and then filtered at high temperature (50-60 °C). The collected solid is washed with acetone to give a colored solid. The solid is then suspended in 25% CH3OH / i-PrOH, boiled for 30 minutes, filtered hot, and washed with 25% CH3OH / i-PrOH to give a colored solid which is the furanosybin product.

[0467] Example 9C. Preparation of N-ethyl-N-methylaminoethylbenzofuran [ka]

[0468] The synthetic procedure of Example 11C was repeated using ethylmethylamine as the secondary amine to provide the N-ethyl-N-methylaminoethylbenzofuran target compound.

[0469] Example 10C. Preparation of N-ethyl-N-propylaminoethylbenzofuran [ka]

[0470] The synthetic procedure of Example 11C was repeated using ethyl-n-propylamine as the secondary amine to provide the N-ethyl-N-propylaminoethylbenzofuran target compound.

[0471] Example 11C. Preparation of N-methyl-Nn-propylaminoethylbenzofuran [ka]

[0472] Benzo[b]furan (1 eq.) was placed under nitrogen in a dry reaction flask equipped with a glass stir bar and containing 5 mol% ytterbium triflate. Excess ethyl glyoxylate was distilled (according to the method shown below*) and collected directly in the reaction flask. The reaction was stirred under nitrogen at room temperature for 24 hours. The resulting crude ester intermediate was concentrated under vacuum and purified via flash chromatography using 5:1 EtOAc:hexanes.

[0473] The purified ester intermediate was placed in a dry reaction flask under nitrogen, followed by anhydrous methanol and 1.2 eq of the secondary amine methyl n-propylamine. The reaction was stirred at room temperature for 24 h or until the ester was consumed as judged by TLC (9:1 DCM:MeOH).

[0474] The crude dried hydroxyamide intermediate was placed in a reaction flask containing a stir bar under nitrogen. To this was added 2Me-THF followed by 3 eq of LiAlH4 as a 2.0 M solution of LiAlH4 in 2Me-THF over 1 min. The reaction was slightly exothermic and then heated to 65 °C for 4 h. The reaction mixture was then cooled to 0-20 °C and slowly quenched with THF / HO (4:1) under stirring for approximately 30 min. The reaction mixture was then carefully diluted with DCM / MeOH (9:1) and then filtered through a pad of Celite. The filtered solution was then concentrated under reduced pressure and purified via flash chromatography using 5:1 EtOAc:hexane to provide the desired product.

[0475] *50% ethyl glyoxylate oligomer in toluene (Fluka) was distilled at atmospheric pressure using a short (2 in) Vigreaux column and an oil bath temperature of 130-185°C (gradually increased over a 30 minute period) until only a small residue remained. The first few mL were discarded, then the entire volume was collected. The resulting yellowish distillate, containing the toluene-ethyl glyoxylate mixture, was immediately redistilled at 30 Torr. After the toluene reaction, pure ethyl glyoxylate was distilled at 48-50°C / 30 Torr.

[0476] Example 12C. Preparation of N-ethylaminoethyl benzofuran [ka]

[0477] The synthesis of Example 12A was repeated using the extended carbaldehyde of Example 16C as the starting material, except that ethylamine hydrochloride was used as the primary amine, to give the target compound as a whitish solid in 15% yield.

[0478] Example 13C. Preparation of N-isopropylaminoethyl benzofuran [ka]

[0479] The synthesis of Example 16A was repeated using the extended carbaldehyde of Example 16C as the starting material, except that isopropylamine was used as the amine to give the target compound as a whitish solid in 27% yield.

[0480] Example 14C. Preparation of N-cyclopropylaminoethyl benzofuran [ka]

[0481] The synthesis of Example 16A was repeated using the extended carbaldehyde of Example 16C as the starting material, except that cyclopropylamine was used as the amine, to give the target compound as a whitish solid in 22% overall yield.

[0482] Example 15C. Preparation of (2R)- and (2S)-1-(benzofuran-3-yl)-N-methylpropan-2-amine Racemic 1-(benzofuran-3-yl)-N-methylpropan-2-amine hydrochloride (Cayman Chemical) was converted to the free base and subjected to HPLC separation to provide two separate compositions enriched in the (S) and (R) enantiomers, respectively: [ka]

[0483] Example 16C. Formation of an extended benzocarbaldehyde intermediate [ka]

[0484] The target-extended benzofuranocarbaldehyde intermediate was produced using the method of Example 15A, except that benzofurano-3-carbaldehyde was used as the starting material to produce the target-extended carbaldehyde as a pale orange oil in 54% crude yield.

[0485] Example 17C. Preparation of N,N-dimethylaminoethylbenzofuran [ka]

[0486] The synthesis of Example 16A was repeated except that the elongated carbaldehyde of Example 16C was used as the starting material to give the target compound as a yellow oil in 20% yield.

[0487] Example 18C. Preparation of N-methylaminoethylbenzofuran [ka]

[0488] The synthesis of Example 16A was repeated using the extended carbaldehyde of Example 16C as the starting material, except that methylamine hydrochloride was used as the primary amine, to give the target compound as a whitish solid in 35% yield.

[0489] Example 19C. Preparation of 6-methoxy-N,N-dimethylaminoethylbenzofuran [ka]

[0490] To a solution of carboxylic acid (1 eq) in dichloromethane at 0 °C under a N atmosphere were added PyBOP (1.5 eq), i-PrNEt (1.5-3.0 eq), and dimethylamine (1.5 eq) sequentially. The reaction mixture was warmed to room temperature and stirred for 2 h. After completion of the reaction, the mixture was concentrated in vacuo, and the crude oil was purified by silica gel chromatography (50% ethyl acetate in hexanes) to give the dimethylamide as an off-white solid in 90% yield.

[0491] The dimethylamide intermediate (1 eq) was dissolved in THF under an inert atmosphere and cooled to 0 °C. A solution of LiAlH in 2-Me-THF (2.3 M, 2.5 eq) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 16 h. The mixture was quenched by the addition of EtO and water at 0 °C and filtered through a pad of Celite. The aqueous layer was extracted with EtOAc (3x), and the combined organic layers were washed with brine (3x), dried over NaSO, and concentrated in vacuo. The crude oil was purified by silica gel chromatography (5% MeOH in CHCl) to give the target amine as a yellow solid in 43% yield.

[0492] Example 20C. Preparation of 6-methoxy-N-ethylaminoethylbenzofuran [ka]

[0493] The procedure of Example 19C was repeated except that ethylmethylamine was used as the secondary amine to give the target compound as a yellowish oil in 38% yield.

[0494] Example 21C. Preparation of 6-methoxy-N-ethyl-N-methylaminoethylbenzofuran [ka]

[0495] The procedure of Example 19C was repeated except that ethylamine hydrochloride was used as the primary amine to give the target compound as a whitish solid in 41% yield.

[0496] Example 22C. Preparation of 6-methoxy-N-methylaminoethylbenzofuran [ka]

[0497] The procedure of Example 19C was repeated except that methylamine hydrochloride was used as the primary amine to give the target compound as a tanish solid in 32% yield.

[0498] *Another modification to the procedure of Example 19C: 3.5 eq of LAH was used and refluxed for 36 hours.

[0499] Example 23C. Preparation of Hydrofumarates (aka [1:1] Fumarate) The [1:1] hydrofumarate salt of each one of the compounds is prepared separately from the compounds of Examples 1-7C, 9-15C and 17-22C using the following procedure: One equivalent of the free base product is dissolved in acetone and added dropwise to a solution of fumaric acid (1 equivalent) in acetone. A precipitate forms immediately, and the precipitate / acetone is stored at -20°C overnight. The solid is then filtered and washed with ice-cold acetone to produce the desired crystalline hydrofumarate salt.

[0500] Example 24C. Preparation of Fumarate Salt (also known as [2:1] Fumarate) The [2:1] fumarate salt of each one of the compounds is prepared separately from the compounds of Examples 1-7C, 9-15C and 17-22C using the following procedure: One equivalent of the free base product is dissolved in acetone and added dropwise to a solution of fumaric acid (0.5 equivalents) in acetone. A precipitate forms immediately, and the precipitate / acetone is stored at -20°C overnight. The solid is then filtered and washed with ice-cold acetone to produce the desired crystalline fumarate salt.

[0501] Synthetic Scheme D: Indole and azaindole analogs As illustrated below, the indole and azaindole compounds of Formula I can be synthesized by the following exemplary procedures: Scheme 1D [ka]

[0502] Indole, 4-azaindole, 5-azaindole, 6-azaindole, and 7-azaindole can be prepared starting from the relevant indole starting material using the general synthetic scheme shown above. Exemplary indole starting materials include 4-benzyloxy-7-methylindole (VulcanChem), 6-fluoroindole (Sigma), 5-methoxy-6-fluoroindole (Biosynth Carbosynth), 1-ethylindole, and the like. Exemplary azaindole starting materials can be purchased commercially, including 4-azaindole, 5-azaindole, 6-azaindole, and 7-azaindole (Sigma); 6-fluoro-4-azaindole (Synthonix); 5-methoxy-7-methyl-4-azaindole (Sigma); 6-fluoro-7-azaindole (Shanghai Jizhi); 5-methoxy-7-azaindole and 6-fluoro-5-methoxy-7-azaindole (Achemblock), and the like.

[0503] Example 1D. Preparation of 5-methoxyketoamide intermediate [ka]

[0504] A three-necked round-bottom flask equipped with an addition funnel was charged with oxalyl chloride (0.185 mL, 2.18 mmol, 1.5 eq) in 5 mL of anhydrous EtO under an inert atmosphere. The flask was cooled to 0 °C, and a solution of 5-methoxyindole (240 mg, 1.45 mmol, 1 eq) in 5 mL of ether was added dropwise via the addition funnel. After complete addition, the reaction was stirred at 0 °C for 1 h. The reaction mixture was diluted with anhydrous hexane. The resulting bright orange solid was filtered through a Hirsch funnel and washed several times with a (3 / 1) hexane / EtO mixture. The solid was used in the next step without further purification.

[0505] In a two-neck round-bottom flask, the acid chloride intermediate (336 mg, 1.31 mmol, 1 eq) was dissolved in THF (10 mL) under an inert atmosphere. Benzylethylamine (0.33 mL, 2.2 mmol, 1.7 eq) and triethylamine (0.26 mL, 1.9 mmol, 1.5 eq) were added via syringe. The reaction mixture was stirred at room temperature for 3 h. Anhydrous hexane (10 mL) was added and stirred at 40 °C for 30 min. The resulting hydrochloride salt was filtered through a Hirsch funnel, and the ketoamide precipitated from the mother liquor as an off-white solid. The solid was collected and used for the next step without further purification.

[0506] Example 2D. Preparation of 3-(ethylaminoethyl)-5-methoxyindole [ka]

[0507] In a two-necked round-bottom flask equipped with a condenser, the ketoamide (100 mg, 0.28 mmol, 1 eq) prepared according to the method of Example 1D was dissolved in THF (5 mL) under an inert atmosphere. The flask was cooled to 0 °C, LAH (53 mg, 1.4 mmol, 5 eq) was added, and the mixture was heated to reflux for 4 h. The reaction mixture was quenched by the addition of DI HO (10 mL), and the aqueous layer was extracted with EtO (3 × 5 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over sodium sulfate, and concentrated in vacuo. The crude solid was purified via SiO column chromatography to give the benzylethylamine intermediate product as a yellow oil.

[0508] To the purified benzylmethylamine intermediate (1 mmol) in MeOH (10 mL) was added 10 wt / wt% Pd / C (10-15%). The reaction mixture was degassed to remove oxygen and stirred under a hydrogen atmosphere (1 atm) for 18-24 h. Upon completion, the reaction mixture was filtered through a pad of Celite, and the solvent was removed in vacuo to yield a crude oil. The target ethylamine product was isolated from the crude by silica gel chromatography (loading with DCM and eluting with 1% MeOH / DCM, then 5% MeOH / DCM doped with 1% NEt3) as a whitish solid.

[0509] Example 3D. Preparation of 3-(ethylaminoethyl)-6-fluoro-5-methoxy-7-azaindole [ka]

[0510] The synthetic procedures of Examples 1D and 2D were repeated except that 6-fluoro-5-methoxyindole was used as the starting material to provide the desired product as a yellowish solid in 75% yield.

[0511] Example 4D. Preparation of 3-(ethylaminoethyl)-5-methoxy-7-azaindole [ka]

[0512] The synthetic procedures of Examples 1D and 2D are repeated except using 5-methoxy-7-azaindole as the starting material to provide the desired product in good yield.

[0513] Example 5D. Preparation of 3-(ethylaminoethyl)-4-hydroxy-7-methylindole [ka]

[0514] The synthetic procedures of Examples 1D and 2D are repeated except using 6-fluoro-4-azaindole as the starting material to provide the desired product in good yield.

[0515] Example 6D. Preparation of indole carbaldehyde intermediate. [ka]

[0516] To a stirred suspension of Wittig salt (10.5 mmol, 1.7 eq) in THF at 0 °C, n-BuLi solution (10.5 mmol, 1.7 eq, 2.5 M in hexane) was added dropwise. The resulting reaction mixture became homogeneous and red. The carbaldehyde starting material (6.2 mmol, 1.0 eq) was added as a solid in one portion to the reaction mixture. After 15 min, the reaction mixture was diluted with diethyl ether and quenched with 1 M HCl (aq). The phases were separated, and the aqueous phase was extracted with diethyl ether (x2). The combined organic extracts were washed with water and brine and dried over anhydrous sodium sulfate. After filtration, the solvent was removed in vacuo. The enol ether could be isolated from the crude product as an oil by column chromatography (loaded with PhMe and eluted with 0–5% ethyl acetate in hexane).

[0517] To a solution of the enol ether (1 mmol, 1.0 eq) in THF (4.8 mL) was added 1 M HCl (7.2 mL aq). The reaction mixture was refluxed for 4 h, then cooled to room temperature and diluted with water and diethyl ether. The phases were separated and the aqueous phase was extracted with diethyl ether (x2). The combined organic extracts were washed with water and brine and dried over anhydrous sodium sulfate. After filtration, the solvent was removed in vacuo to give a crude oil, which was used in the next step without further purification.

[0518] Example 7D. Preparation of 3-(ethylaminoethyl)-indole [ka]

[0519] To a solution of the carbaldehyde intermediate (1.0 eq) prepared according to the method of Example 6D in acetonitrile (0.1 M) was added benzylethylamine (2-5 eq) and several beads of activated hol 3A MS. After stirring for 10 min at room temperature, NaHB(OAc)3 (>5 eq) was added in one portion. The reaction mixture was stirred at room temperature for 18-24 h, then quenched by the addition of 1 M HCl and diluted with diethyl ether. The phases were separated, and the organic phase was washed with 1 M HCl (x2). The combined aqueous phase was basified by the addition of solid NaOH. The aqueous phase was extracted with DCM (x3), and the combined DCM washes were dried over anhydrous sodium sulfate. After filtration, the solvent was removed in vacuo to afford the benzylethylamine intermediate compound in good yield and purity. Analytical purity was achieved by purification by column chromatography (DCM to 1% MeOH / DCM to remove major impurities, then eluting with 5% MeOH / DCM doped with approximately 1% NEt3).

[0520] To a solution of the benzylethylamine intermediate (1 mmol) in MeOH (10 mL) was added 10 wt / wt% Pd / C (10-15%). The reaction mixture was degassed to remove oxygen and stirred under a hydrogen atmosphere (1 atm) for 18-24 h. Upon completion, the reaction mixture was filtered through a pad of Celite, and the solvent was removed in vacuo to yield a crude oil. The target ethylamine was isolated from the crude product as an off-white solid in 56% yield by purification via silica gel chromatography (loading with DCM and eluting with 1% MeOH / DCM, then 5% MeOH / DCM doped with 1% NEt3).

[0521] Example 8D. Preparation of 1-ethyl-3-(ethylaminoethyl)-indole [ka]

[0522] The procedures of Examples 6D and 7D were repeated using 1-ethylindole-3-carbaldehyde as the starting material to provide the desired product in good yield as a whitish semi-solid.

[0523] Example 8D. Preparation of 7-methyl-3-(ethylaminoethyl)-indole [ka]

[0524] The procedures of Examples 6D and 7D were repeated using 7-methylindole-3-carbaldehyde as the starting material to provide the desired product as a whitish semi-solid in 65% yield.

[0525] Example 9D. Preparation of 1-ethyl-5-methoxy-3-(ethylaminoethyl)-indole [ka]

[0526] The procedures of Examples 6D and 7D were repeated using 5-methoxy-1-ethiendole-3-carbaldehyde as the starting material to provide the desired product in good yield.

[0527] Example 10D. Preparation of 3-(N,N-dimethylaminoethyl)-pyrrolo[3,2-b]pyridine [ka]

[0528] The procedures of Examples 6D and 7D were repeated except using 1H-pyrrolo[3,2-b]pyridine-3-carbaldehyde as the starting material and dimethylamine as the secondary amine (no Pd / C debenzylation required) to provide the desired product as a whitish oil in approximately 10% overall yield.

[0529] Example 11D. Preparation of 3-(N-ethyl-N-methylaminoethyl)-pyrrolo[3,2-b]pyridine [ka]

[0530] The procedure of Example 10D was repeated except that ethylmethylamine was used as the secondary amine to provide the desired product as a whitish oil in about 32% overall yield.

[0531] Example 12D. Preparation of 3-(N-methylaminoethyl)-pyrrolo[3,2-b]pyridine [ka]

[0532] The procedure of Example 10D was repeated except that methylamine hydrochloride was used as the secondary amine to provide the desired product as a whitish oil in about 14% overall yield.

[0533] Example 13D. Preparation of 3-(N-ethylaminoethyl)-pyrrolo[3,2-b]pyridine [ka]

[0534] The procedure of Example 10D was repeated except that ethylamine hydrochloride was used as the secondary amine to provide the desired product as a whitish oil in about 31% overall yield.

[0535] Example 14D. Preparation of 3-(N,N-dimethylaminoethyl)-pyrrolo[3,2-c]pyridine [ka]

[0536] The procedure of Example 10D was repeated except that 1H-pyrrolo[3,2-b]pyridine-3-carbaldehyde was used as the starting material to provide the desired product as a whitish oil in about 30% overall yield.

[0537] Example 15D. Preparation of 3-(N-ethyl-N-methylaminoethyl)-pyrrolo[3,2-c]pyridine [ka]

[0538] The procedure of Example 11D was repeated except that 1H-pyrrolo[3,2-b]pyridine-3-carbaldehyde was used as the starting material to provide the desired product as a whitish oil in about 29% overall yield.

[0539] Example 16D. Preparation of 3-(N-methylaminoethyl)-pyrrolo[3,2-c]pyridine [ka]

[0540] The procedure of Example 12D was repeated except that 1H-pyrrolo[3,2-b]pyridine-3-carbaldehyde was used as the starting material to provide the desired product as a whitish solid in about 26% overall yield.

[0541] Example 17D. Preparation of 3-(N-ethylaminoethyl)-pyrrolo[3,2-c]pyridine [ka]

[0542] The procedure of Example 13D was repeated except that 1H-pyrrolo[3,2-b]pyridine-3-carbaldehyde was used as the starting material to provide the desired product as a whitish solid in about 29% overall yield.

[0543] Example 18D. Preparation of 3-(N,N-dimethylaminoethyl)-pyrrolo[2,3-c]pyridine [ka]

[0544] The procedure of Example 10D was repeated except that 1H-pyrrolo[2,3-c]pyridine-3-carbaldehyde was used as the starting material to provide the desired product as a whitish solid in about 22% overall yield.

[0545] Example 19D. Preparation of 3-(N-ethyl-N-methylaminoethyl)-pyrrolo[2,3-c]pyridine [ka]

[0546] The procedure of Example 11D was repeated except that 1H-pyrrolo[2,3-c]pyridine-3-carbaldehyde was used as the starting material to provide the desired product as a whitish oil in about 25% overall yield.

[0547] Example 20D. Preparation of 3-(N-methylaminoethyl)-pyrrolo[2,3-c]pyridine [ka]

[0548] The procedure of Example 12D was repeated except that 1H-pyrrolo[2,3-c]pyridine-3-carbaldehyde was used as the starting material to provide the desired product as a whitish solid in about 27% overall yield.

[0549] Example 21D. Preparation of 3-(N-ethylaminoethyl)-pyrrolo[2,3-c]pyridine [ka]

[0550] The procedure of Example 13D was repeated except that 1H-pyrrolo[2,3-c]pyridine-3-carbaldehyde was used as the starting material to provide the desired product as a whitish oil in approximately 20% overall yield.

[0551] Example 22D. Preparation of 3-(N,N-dimethylaminoethyl)-pyrrolo[2,3-b]pyridine [ka]

[0552] The procedure of Example 10D was repeated except that 1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde was used as the starting material to provide the desired product as a whitish solid in about 31% overall yield.

[0553] Example 23D. Preparation of 3-(N-ethyl-N-methylaminoethyl)-pyrrolo[2,3-b]pyridine [ka]

[0554] The procedure of Example 11D was repeated except that 1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde was used as the starting material to provide the desired product as a whitish oil in about 40% overall yield.

[0555] Example 24D. Preparation of 3-(N-methylaminoethyl)-pyrrolo[2,3-b]pyridine [ka]

[0556] The procedure of Example 12D was repeated except that 1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde was used as the starting material to provide the desired product as a whitish solid in about 34% overall yield.

[0557] Example 25D. Preparation of 3-(N-ethylaminoethyl)-pyrrolo[2,3-b]pyridine [ka]

[0558] The procedure of Example 13D was repeated except that 1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde was used as the starting material to provide the desired product as a whitish solid in about 35% overall yield.

[0559] Example 26D. Preparation of 4-benzyloxy-3-(N-benzyl-N-ethylaminoethyl)indole [ka]

[0560] The procedures of Examples 1D and 2D were repeated except that 4-benzyloxyindole was used as the starting indole and benzylethylamine was used as the secondary amine (the Pd / C debenzylation step of Example 2D was not performed) to provide the desired product as a whitish solid.

[0561] Example 27D. Preparation of 4-acetoxy-3-(N-ethylaminoethyl)indole [ka]

[0562] To a solution of the benzylethylamine intermediate (1 mmol) prepared according to the procedure in Example 26D in MeOH (10 mL) was added 10 wt / wt% Pd / C (10-15%). The reaction mixture was degassed to remove oxygen and stirred under a hydrogen atmosphere (1 atm) for 18-24 h. Upon completion, the reaction mixture was filtered through a pad of Celite and the solvent was removed in vacuo to yield a crude oil, which represented the debenzylated phenolic indole.

[0563] The debenzylated phenolic intermediate was dissolved in anhydrous DCM (10 mL) under nitrogen and cooled to 0 °C. EtN (1.2 eq) was added to the solution, followed by Boc-anhydride (1.1 eq) in a dropwise manner, and the reaction mixture was stirred at room temperature until the disappearance of the starting material, as monitored by TLC. The reaction mixture was then diluted with DCM (20 mL) and washed successively with water and brine. The organic layer was then dried over sodium sulfate and concentrated to yield the N-BOC-protected intermediate.

[0564] The N-BOC-protected intermediate was then taken up in DCM (15 mL) and the solution was cooled to 0 °C. EtN (2.1 eq) was added to the solution, followed by dropwise addition of acetyl chloride (1.3 eq), and the contents were then stirred at room temperature until disappearance of the starting material (according to TLC). Upon completion, the reaction mixture was diluted with DCM and washed with water and brine washes. The organic layer was removed, dried under sodium sulfate, and reduced under pressure to give an oily residue.

[0565] The residue was then taken up in anhydrous DCM, to which HCl in ether (2N; 10 equivalents) was added dropwise to the stirred solution at 0° C. Stirring was continued until the starting material was consumed by TLC monitoring. The resulting precipitate after completion of the reaction was filtered, washed with cold DCM, diethyl ether, and dried under vacuum to produce the desired compound as a yellowish solid in 33% overall yield.

[0566] Example 28D. Preparation of 3-(N-methylaminoethyl)indole [ka]

[0567] The procedure according to Example 7D was repeated except that benzylmethylamine was used as the secondary amine to give the desired product as a whitish solid in 52% yield.

[0568] Example 29D. Preparation of 7-methyl-3-(methylaminoethyl)-indole [ka]

[0569] The procedures of Examples 6D and 7D were repeated using 7-methylindole-3-carbaldehyde as the starting material and methylbenzylamine as the secondary amine to provide the desired product as a whitish semi-solid in 62% yield.

[0570] Example 30D. Preparation of 6-fluoro-5-methoxy-3-(N-methylaminoethyl)indole [ka]

[0571] The procedures of Examples 1D and 2D were repeated except that 6-fluoro-5-methoxyindole was used as the starting indole and benzylmethylamine was used as the secondary amine to provide the desired product as a whitish solid in approximately 34% overall yield.

[0572] Example 31D. Preparation of 6-fluoro-5-methoxy-3-(N,N-dimethylaminoethyl)indole [ka]

[0573] The procedures of Examples 1D and 2D were repeated except that 6-fluoro-5-methoxyindole was used as the starting indole and dimethylamine was used as the secondary amine (the Pd / C debenzylation step of Example 2D was not performed) to provide the desired product as a whitish solid in approximately 40% overall yield.

[0574] Example 32D. Preparation of 6-fluoro-5-methoxy-3-(N-ethyl-N-methylaminoethyl)indole [ka]

[0575] The procedures of Examples 1D and 2D were repeated, except that 6-fluoro-5-methoxyindole was used as the starting indole and ethylmethylamine was used as the secondary amine (the Pd / C debenzylation step of Example 2D was not performed), to provide the desired product as a yellowish solid in approximately 48% overall yield.

[0576] Example 33D. Preparation of 5-methoxy-7-methyl-3-(N-methylaminoethyl)indole [ka]

[0577] The procedures of Examples 1D and 2D were repeated except that 5-methoxy-7-methylindole was used as the starting indole and benzylmethylamine was used as the secondary amine to provide the desired product as a whitish solid in approximately 32% overall yield.

[0578] Example 34D. Preparation of 5-methoxy-7-methyl-3-(N-ethylaminoethyl)indole [ka]

[0579] The procedures of Examples 1D and 2D were repeated except that 5-methoxy-7-methylindole was used as the starting indole and benzylethylamine was used as the secondary amine to provide the desired product as a whitish solid in approximately 36% overall yield.

[0580] Example 35D. Preparation of 5-methoxy-7-methyl-3-(N,N-dimethylaminoethyl)indole [ka]

[0581] The procedures of Examples 1D and 2D were repeated, except that 5-methoxy-7-methylindole was used as the starting indole and dimethylamine was used as the secondary amine (the Pd / C debenzylation step of Example 2D was not performed), to provide the desired product as a whitish solid in approximately 48% overall yield.

[0582] Example 36D. Preparation of 5-methoxy-7-methyl-3-(N-ethyl-N-methylaminoethyl)indole [ka]

[0583] The procedures of Examples 1D and 2D were repeated, except that 5-methoxy-7-methylindole was used as the starting indole and ethylmethylamine was used as the secondary amine (the Pd / C debenzylation step of Example 2D was not performed), to provide the desired product as a yellowish solid in approximately 52% overall yield.

[0584] Example 37D. Preparation of 4-acetoxy-7-methyl-3-(N-methylaminoethyl)indole [ka]

[0585] The procedures of Examples 26D and 27D were repeated except that 4-benzyloxy-7-methylindole was used as the starting indole and benzylmethylamine was used as the secondary amine to provide the desired product as a whitish solid in approximately 27% overall yield.

[0586] Example 38D. Preparation of 4-acetoxy-7-methyl-3-(N-ethylaminoethyl)indole [ka]

[0587] The procedures of Examples 26D and 27D were repeated except that 4-benzyloxy-7-methylindole was used as the starting indole and benzylethylamine was used as the secondary amine to provide the desired product as a whitish solid in approximately 45% overall yield.

[0588] Example 39D. Preparation of 4-acetoxy-7-methyl-3-(N,N-dimethylaminoethyl)indole [ka]

[0589] The procedures of Examples 26D and 27D were repeated except that 4-benzyloxy-7-methylindole was used as the starting indole and dimethylamine was used as the secondary amine to provide the desired product as a thin oil in approximately 39% overall yield.

[0590] Example 40D. Preparation of 4-acetoxy-7-methyl-3-(N-ethyl-N-methylaminoethyl)indole [ka]

[0591] The procedures of Examples 26D and 27D were repeated except that 4-benzyloxy-7-methylindole was used as the starting indole and ethylmethylamine was used as the secondary amine to provide the desired product as a thin oil in approximately 37% overall yield.

[0592] Example 41D. Preparation of 4-hydroxy-7-methyl-3-(N-methylaminoethyl)indole [ka]

[0593] To a solution of acetoxyamine (1.0 mmol) prepared according to the procedure in Example 37D in aqueous methanol (4:1, 0.1 M) was added ammonium acetate (617 mg, 8 mmol) under an inert atmosphere and stirred at room temperature for 4 hours. The methanol was removed in vacuo, and the residue was extracted with ethyl acetate (3x), washed with brine, and then dried over anhydrous sodium sulfate. Concentration of the dried organic phase afforded the crude phenol, which was purified via silica gel chromatography (5% MeOH in CHCl) to give the target phenol as a white solid in 86% yield.

[0594] Example 42D. Preparation of 4-hydroxy-7-methyl-3-(N-ethylaminoethyl)indole [ka]

[0595] The procedure of Example 41D was repeated except that the acetoxyindole of Example 38D served as the starting material to provide the desired product as a white solid in 90% yield.

[0596] Example 43D. Preparation of 4-hydroxy-7-methyl-3-(N,N-dimethylaminoethyl)indole [ka]

[0597] The procedure of Example 41D was repeated except that the acetoxyindole of Example 39D served as the starting material to provide the desired product as a white solid in 96% yield.

[0598] Example 44D. Preparation of 4-hydroxy-7-methyl-3-(N-ethyl-N-methylaminoethyl)indole [ka]

[0599] The procedure of Example 41D was repeated except that the acetoxyindole of Example 40D served as the starting material to provide the desired product as a white solid in 92% yield.

[0600] Example 45D. Preparation of 4-acetoxy-6-fluoro-3-(N-methylaminoethyl)indole [ka]

[0601] The procedures of Examples 26D and 27D were repeated except that 4-benzyloxy-6-fluoroindole was used as the starting indole and benzylmethylamine was used as the secondary amine to provide the desired product as a whitish solid in approximately 22% overall yield.

[0602] Example 46D. Preparation of 4-acetoxy-6-fluoro-3-(N-ethylaminoethyl)indole [ka]

[0603] The procedures of Examples 26D and 27D were repeated except that 4-benzyloxy-6-fluoroindole was used as the starting indole and benzylethylamine was used as the secondary amine to provide the desired product as a whitish solid in approximately 45% overall yield.

[0604] Example 47D. Preparation of 4-acetoxy-7-methyl-3-(N,N-dimethylaminoethyl)indole [ka]

[0605] The procedures of Examples 26D and 27D were repeated except that 4-benzyloxy-7-methylindole was used as the starting indole and dimethylamine was used as the secondary amine to provide the desired product as a thin oil in approximately 39% overall yield.

[0606] Example 48D. Preparation of 4-acetoxy-7-methyl-3-(N-ethyl-N-methylaminoethyl)indole [ka]

[0607] The procedures of Examples 26D and 27D were repeated except that 4-benzyloxy-7-methylindole was used as the starting indole and ethylmethylamine was used as the secondary amine to provide the desired product as a thin oil in approximately 37% overall yield.

[0608] Example 49D. Preparation of 4-hydroxy-6-fluoro-7-methyl-3-(N-ethylaminoethyl)indole [ka]

[0609] The procedure of Example 1D is repeated except that 6-fluoro-7-methyl-1-(triisopropylsilyl)indole is used as the starting indole to provide the desired silyl-protected ketoamide intermediate without further purification.

[0610] TIPS-protected ketoamide (1 eq), Pd(OAc)2 (0.1 eq), and glycine (4 eq) are placed in a flame-dried reaction flask, followed by the addition of 1 mL of HFIP / AcOH (3 / 2) via syringe under air. The reaction mixture is stirred at room temperature for 10 min and then placed in a preheated oil bath at 80 °C for 17 h before being diluted with ethyl acetate and quenched with NaHCO3. The reaction mixture is extracted three times with ethyl acetate and dried using anhydrous sodium sulfate, which is then filtered and concentrated in vacuo to provide the 4-acetylated ketoamide intermediate.

[0611] To a solution of 4-acetylated ketoamide (1 eq) in THF at 0 °C under an inert atmosphere, LiAlH (53 mg, 1.4 mmol, 5 eq) is added in one portion and the mixture is heated under reflux for 4 h. The reaction is quenched by the addition of water, and the aqueous layer is extracted with EtO. The combined organic layers are washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to provide the crude benzylethylamine intermediate.

[0612] The benzylethylamine intermediate (1 eq) bearing the TIPs protecting group is suspended in THF at room temperature under an inert atmosphere, followed by the addition of a 1 M solution of tetrabutylammonium fluoride (TBAF) in tetrahydrofuran. The solution is stirred for 10 min at room temperature, then poured into a saturated solution of sodium carbonate and extracted with dichloromethane (3 x 10 mL). The combined organic layers are washed with water, dried over sodium sulfate, and evaporated under reduced pressure. The residue is purified via silica gel chromatography (5-9% MeOH in DCM) to yield the deprotected benzethylamine intermediate.

[0613] To a solution of the deprotected benzylethylamine intermediate (1 equivalent) in MeOH, add 10 wt / wt% Pd / C (10-15%). The reaction mixture is degassed to remove oxygen and stirred under a hydrogen atmosphere (1 atm) for 18-24 hours. Upon completion, the reaction mixture is filtered through a pad of Celite and the solvent is removed in vacuo. The target debenzylated ethylamine target compound can be isolated from the crude product by purification via silica gel chromatography (load with DCM, elution with 1% MeOH / DCM, then 5% MeOH / DCM doped with 1% NEt3).

[0614] Example 50D. Preparation of 4-hydroxy-6-fluoro-7-methyl-3-(N-methylaminoethyl)indole [ka]

[0615] The procedure of Example 49D is repeated except that benzylmethylamine is used as the secondary amine to provide the desired product.

[0616] Example 51D. Preparation of 4-hydroxy-6-fluoro-7-methyl-3-(N,N-dimethylaminoethyl)indole [ka]

[0617] The procedure of Example 50D is repeated except using dimethylamine as the secondary amine (and not performing the final Pd / C debenzylation step) to provide the desired product.

[0618] Example 52D. Preparation of 4-hydroxy-6-fluoro-7-methyl-3-(N-ethyl-N-methylaminoethyl)indole [ka]

[0619] The procedure of Example 50D is repeated except that ethylmethylamine is used as the secondary amine (and the final Pd / C debenzylation step is omitted) to provide the desired product.

[0620] Example 53D. Preparation of 4-acetoxy-6-fluoro-7-methyl-3-(N-ethylaminoethyl)indole [ka]

[0621] The 4-hydroxyl product (1 eq) prepared according to the method of Example 49D is dissolved in anhydrous DCM under nitrogen and cooled to 0 ° C. EtN (1.2 eq) is added to the solution, followed by Boc-anhydride (1.1 eq) in a dropwise manner, and the reaction mixture is stirred at room temperature until the disappearance of the starting material, as monitored by TLC. The reaction mixture is then diluted with DCM and washed successively with water and brine. The organic layer is then dried over sodium sulfate and concentrated to yield the N-BOC-protected intermediate.

[0622] The N-BOC-protected intermediate is then taken up in DCM and the solution is cooled to 0 °C. EtN (2.1 eq) is added to the solution, followed by dropwise addition of acetyl chloride (1.3 eq), and the reaction is then stirred at room temperature until disappearance of the starting material (according to TLC). Upon completion, the reaction mixture is diluted with DCM and washed with water and brine washes. The organic layer is removed, dried under sodium sulfate, and reduced under pressure to give an oily residue.

[0623] The residue was then taken up in anhydrous DCM, to which HCl in ether (2 M; 12 equivalents) was added dropwise to the stirred solution at 0° C. Stirring was continued until the starting material was consumed by TLC monitoring. After completion of the reaction, the resulting precipitate was filtered, washed with cold DCM, diethyl ether, and dried under vacuum to yield the desired compound.

[0624] Example 54D. Preparation of 4-acetoxy-6-fluoro-7-methyl-3-(N-methylaminoethyl)indole [ka]

[0625] The procedure of Example 53D is repeated using as the starting material the product prepared according to the method of Example 50D to provide the desired product.

[0626] Example 55D. Preparation of 4-acetoxy-6-fluoro-7-methyl-3-(N,N-dimethylaminoethyl)indole [ka]

[0627] The procedure of Example 53D is repeated except using as the starting material the product prepared according to the method of Example 51D to provide the desired product.

[0628] Example 56D. Preparation of 4-acetoxy-6-fluoro-7-methyl-3-(N-ethyl-N-methylaminoethyl)indole [ka]

[0629] The procedure of Example 55D is repeated, except for the product prepared by Example 52D, to provide the desired product.

[0630] Example 57D. Preparation of 4-fluoro-3-(N-ethylaminoethyl)indole [ka]

[0631] The procedures of Examples 1D and 2D are repeated except using 4-fluoroindole as the starting material to provide the desired product.

[0632] Example 58D. Preparation of 3-(Nn-propylaminoethyl)indole [ka]

[0633] The procedures of Examples 1D and 2D are repeated except using indole as the starting material and benzyl-n-propylamine as the secondary amine to provide the desired product.

[0634] Example 59D. Preparation of 4-hydroxy-3-(N-ethylaminoethyl)indole [ka]

[0635] The procedures of Examples 38D and 42D were followed except that 4-benzyloxyindole was used as the starting indole to provide the desired product in good yield.

[0636] Example 60D. Preparation of 3-(N-2-fluoroethylaminoethyl)indole [ka]

[0637] To a solution of the approved aldehyde (1.0 eq) in acetonitrile (0.1 M) is added 2-fluoroethylamine (2-5 eq) and a few beads of activated hol 3A MS. After stirring at room temperature for 10 min, NaHB(OAc)3 (>5 eq) is added in one portion. The reaction mixture is stirred at room temperature for 18-24 h, then quenched by the addition of 1 M HCl and diluted with diethyl ether. The phases are separated, and the organic phase is washed with 1 M HCl (x2). The combined aqueous phase is basified by the addition of solid NaOH. The aqueous phase is extracted with DCM (x3), and the combined DCM washes are dried over anhydrous sodium sulfate. After filtration, the solvent is removed in vacuo and purified via SiO2 chromatography eluting with 1-5% MeOH in DCM to obtain the desired product.

[0638] Example 61D. Preparation of 3-(N-ethyl-d2-aminoethyl)indole [ka]

[0639] A solution of C-3 carbaldehyde (2.5 mmol) and ammonium acetate (1.94 mmol, 0.8 eq) in nitromethane (8 mL) is heated under reflux under an inert atmosphere for 3 h or until the reaction is complete by TLC. The resulting reaction mixture is cooled to room temperature and the precipitated solid is collected via filtration on a Buchner funnel to give the alpha-beta unsaturated nitro adduct.

[0640] To a solution of lithium aluminum hydride (18.4 mmol, 5.3 equiv.) in anhydrous THF (15 mL) is added the alpha-beta unsaturated nitro compound (3.48 mmol) in portions. The resulting solution is stirred at room temperature under an inert atmosphere for 24 hours. Ethyl acetate (15 mL) is then added slowly to the reaction mixture, followed by water (1 mL) and sodium sulfate hexahydrate. The resulting mixture is stirred for an additional hour, then filtered through Celite and concentrated under reduced pressure. The residual oil is purified via SiO2 chromatography eluting with MeOH:TEA:EA (3:2:15) to give the primary amine.

[0641] A primary amine (0.68 mmol) and triethylamine (1.02 mmol) are dissolved in methanol and then cooled to 0 °C, followed by dropwise addition of acetyl chloride (0.68 mmol, 1.0 eq). The resulting mixture is warmed to room temperature and stirred for 4 hours. When the starting material is consumed according to TLC, it is concentrated in vacuo, and the residue is taken up in dichloromethane and then washed with 10% citric acid, saturated sodium bicarbonate, and brine. The organic layers are combined, dried using sodium sulfate, filtered, and concentrated to give the desired amide intermediate.

[0642] To a solution of the amide intermediate (1.0 mmol) in THF (15 mL) under an inert atmosphere at 0 °C, LiAlD powder (3.5 eq) is added portionwise and then heated under reflux for 24 h. The reaction is quenched at 0 °C using EtO (20 mL) and water (2 mL) followed by filtration through a pad of Celite. The aqueous phase is extracted three times with ethyl acetate, and the combined organic layers are washed three times with brine before being dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product is purified via SiO chromatography using 5% MeOH in DCM to give the desired product.

[0643] Example 62D. Preparation of 3-(N-ethyl-d2-aminoethyl-d2)indole [ka]

[0644] The alpha-beta unsaturated nitro starting material is prepared according to the method of Example 61D. To a solution of lithium aluminum deuteride (18.4 mmol, 5.3 equiv.) in anhydrous THF (15 mL) is added the alpha-beta unsaturated nitro compound (3.48 mmol) in portions. The resulting solution is stirred at room temperature under an inert atmosphere for 24 hours. Ethyl acetate (15 mL) is then added slowly to the reaction mixture, followed by water (1 mL) and sodium sulfate hexahydrate. The resulting mixture is stirred for an additional hour before being filtered through Celite and concentrated under reduced pressure. The residue is purified via SiO2 chromatography eluting with MeOH:TEA:EA (3:2:15) to give the d4 primary amine. Acetylation and deuterium reduction of the d4 primary amine proceed according to the procedure of Example 61D to give the desired d5 indole product.

[0645] Example 63D. Preparation of 3-(N-ethylaminoethyl-d2)indole [ka]

[0646] The procedure of Example 62D is repeated except that the reduction of the amide is carried out with lithium aluminum hydride instead of lithium aluminum deuteride to give the desired deuterated indole.

[0647] Example 64D. Preparation of 3-(N-2-fluoroethylaminoethyl-d1)indole [ka]

[0648] The procedure of Example 60D is repeated except that sodium cyanoborodeuteride is used in place of sodium triacetoxyborohydride and the reaction is carried out in a MeOH and THF solvent system to afford the desired deuterated indole.

[0649] Example 65D. Preparation of 3-(N-ethylaminoethyl-d1)indole [ka]

[0650] The procedure of Example 64D is repeated except that benzylethylamine is used instead of 2-F-ethylamine, which is then debenzylated according to 27D to give the desired deuterated indole.

[0651] Example 66D. Production of tryptamine d1 [ka]

[0652] To a vial equipped with a stir bar was added the selected aldehyde (1 eq), followed by triethylamine (1.5 eq), hydroxylamine hydrochloride (1.2 eq), and DMSO. The vial was capped and heated at 90°C for 1 hour. The reaction mixture was cooled to room temperature, and water and ether were added to the vial. The aqueous layer was removed and extracted with ether. The combined ethereal layers were washed with water, then brine, dried over MgSO4, and concentrated under reduced pressure. The resulting pale residue was used crude without further purification.

[0653] To a solution of lithium aluminum deuteride (5.3 eq) in anhydrous ether was slowly added the oxime (3.48 mmol) in ether. The resulting solution was refluxed under an inert atmosphere for 8 hours. After cooling, the excess hydride was decomposed by the dropwise addition of water. The complex was hydrolyzed by the addition of 30% sodium hydroxide solution. The mixture was stirred at room temperature for 30 minutes. An additional aliquot of water was then added. The ether layer was then decanted from the granular residue of metal hydroxide. The residue was washed several times with ether, and all washes were combined with the original ether fraction and filtered through Celite. The combined ether fractions were then purified via SiO2 chromatography eluting with MeOH:TEA:EA (3:2:15), after which the solvent was concentrated under reduced pressure, to give the desired primary amine.

[0654] Example 67D. Preparation of 3-(N-ethylaminoethyl-d1)indole [ka]

[0655] The procedures of Examples 62D and 63D are repeated except that the alpha-deuterated tryptamine of Example 66D is utilized to form the amide and LAH is used as the reducing agent to produce the desired deuterated indole.

[0656] Example 68D. Resolution of 3-(N-ethylaminoethyl-d1)indole The product produced according to Example 67D is resolved using known enantiomer resolution methods, such as HPLC or the cyclic crystallization method of bitartrate diastereomers described in Foreman et al., J. Pharm. Sci., 58(2):189-192 (1969), incorporated herein by reference in its entirety for all purposes, to provide two separate compositions enriched in the (S) and (R) enantiomers, respectively: [ka]

[0657] Example 69D. Preparation of Hydrofumarates (aka [1:1] Fumarate) The [1:1] hydrofumarate salt of each one of the compounds is prepared separately from the compounds of Examples 2-5D, 7-25D and 27-68D using the following procedure: One equivalent of the free base product is dissolved in acetone and added dropwise to a solution of fumaric acid (1 equivalent) in acetone. A precipitate forms immediately, and the precipitate / acetone is stored at -20°C overnight. The solid...

Claims

1. Compounds of Formula I: 【Chemical 1】 (In the formula, X is unsubstituted C １ -C ８ Alkyl, unsubstituted C ２ -C ８ Alkenyl, C substituted with at least one deuterium １ -C ８ Alkyl and C substituted with at least one deuterium ２ -C ８ alkenyl; Y is an unsubstituted C １ -C ８ Alkyl, unsubstituted C ２ -C ８ Alkenyl, C substituted with at least one deuterium １ -C ８ Alkyl and C substituted with at least one deuterium ２ -C ８ alkenyl, or Y, together with X and the nitrogen atom therebetween, is selected from O, S, S(O), SO ２ , and N.R. ９ forming a 3- to 7-membered heterocyclic ring optionally containing 1-2 additional ring hetero moieties selected from W １ is Se, Se(O), SeO ２、 selected from S, S(O), and O; W ２ Ha, -CD ２ -, - (CD ２ ) ２ -, -CHD-, -CH ２ - and - (CH ２ ) ２ - selected from; Z ４ is N and CR ４ Selected from: Z ５ is N and CR ５ Selected from: Z ６ is CR ６ and Z ７ is N and CR ７ Selected from: R ２ , R ３ , R ３’ and R ７ are each independently hydrogen, deuterium, or —N(R ９ ) ２ , -SR ９ , halo, optionally substituted C １ -C ８ Alkyl, —C １ -C ８ Alkoxy, and optionally substituted C ２ -C ８ alkenyl, or Y is absent and R ３ together with the carbon atom to which it is bonded and the nitrogen atom to which X is bonded, form O, S, S(O), SO ２ , and N.R. ９ forming a 3- to 7-membered heterocyclic ring optionally containing 1-2 additional ring hetero moieties selected from R ４ is hydrogen, deuterium, optionally substituted C １ -C ８ Alkyl, optionally substituted C ２ -C ８ Alkenyl, halo, hydroxyl, -N(R ９ ) ２ , -SR ９ , -C １ -C ８ Alkoxy, —OC(O)R ８ , -OC(O)OR ８ , -OP(O)O ２ (R ９ ) ２ , and -OSO ２ R ８ Selected from: R ５ is hydrogen, deuterium, optionally substituted C １ -C ８ Alkyl, optionally substituted C ２ -C ８ Alkenyl, halo, hydroxyl, -N(R ９ ) ２ , -SR ９ , -C １ -C ８ Alkoxy, —OC(O)R ８ , -OC(O)OR ８ , -OP(O)O ２ (R ９ ) ２ , and -OSO ２ R ８ Selected from: R ６ is a C substituted with fluoro and at least one halo １ -C ８ alkyl; R ８ is an optionally substituted C １ -C ８ Alkyl, optionally substituted C ２ -C ８ selected from alkenyl, and optionally substituted aryl; R ９ are independently hydrogen, deuterium, optionally substituted C １ -C ８ Alkyl, optionally substituted C ２ -C ８ alkenyl, and optionally substituted aryl; and Salts, solvates, hydrates, and prodrugs thereof.

2. Z ４ is CR ４ 2. The compound of claim 1, wherein:

3. R ４ is hydrogen, deuterium, hydroxyl, optionally substituted C １ -C ８ Alkyl, —C １ -C ８ Alkoxy, and —OC(O)R ８ 2. The compound of claim 1 selected from:

4. R ４ The compound of claim 3 , wherein is hydrogen.

5. R ２ is hydrogen or deuterium.

6. R ３ and R ３’ are each independently selected from hydrogen and deuterium.

7. Y is absent and R ３ together with the carbon atom to which it is bonded and the nitrogen atom to which X is bonded, form O, S, S(O), SO ２ , and N.R. ９ 10. The compound of claim 1, wherein the compound forms a 3- to 7-membered heterocyclic ring optionally containing 1-2 additional ring hetero moieties selected from:

8. W １ is selected from S and Se.

9. W ２ Ha, -CD ２ -, -CHD-, and -CH ２ The compound of claim 1, wherein the compound is selected from:

10. Z ４ is CR ４ and Z ５ is CR ５ and Z ７ is CR ７ 2. The compound of claim 1, wherein:

11. R ２ , R ３ , R ３’ and R ７ are each independently hydrogen, deuterium, or —N(R ９ ) ２ , -SR ９ , halo, optionally substituted C １ -C ８ Alkyl, —C １ -C ８ Alkoxy, and optionally substituted C ２ -C ８ The compound of claim 1 , wherein the alkyl is selected from the group consisting of: alkenyl;

12. X and Y are each independently an unsubstituted C １ -C ８ Alkyl and C substituted with at least one deuterium １ -C ８ 2. The compound of claim 1, wherein X and Y are each independently selected from methyl, ethyl, n-propyl, and isopropyl.

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

14. 14. A composition according to claim 13 for use in the treatment of the human or animal body.

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