Substituted N-propylamine-fused heterocyclic mescaline derivatives

Abstract

Novel fused mescaline derivative compounds, particularly substituted N-propylamine-fused heterocyclic mescaline derivatives, such as substituted N-propylamine-fused dioxolane mescaline derivatives, and pharmaceutical and recreational drug formulations containing same are disclosed. Methods of making and using these compounds are also disclosed.

Description

[Technical Field]

[0001] Related Applications This application claims the benefit of U.S. Provisional Application No. 63 / 426,553, filed November 18, 2022; the entire contents of U.S. Patent Application No. 63 / 426,553 are hereby incorporated by reference.

[0002] Field of Disclosure The compositions and methods disclosed herein relate to the chemical compound known as mescaline. Additionally, the compositions and methods disclosed herein relate particularly to fused heterocyclic mescaline derivatives, more particularly to fused heterocyclic mescaline derivatives having a substituted N-propylamine chain. [Background technology]

[0003] The following paragraphs are provided by way of background to the present disclosure, but they are not an admission that everything discussed therein is prior art or part of the knowledge of those skilled in the art.

[0004] Biochemical pathways in living cells can be classified as part of primary metabolism or part of secondary metabolism. Pathways that are part of a cell's primary metabolism involve catabolism to generate energy or anabolism to produce building blocks for the cell. Secondary metabolites, on the other hand, are produced by cells and have no apparent anabolic or catabolic effect. It has long been recognized that secondary metabolites can be useful in many respects, for example, as therapeutic compounds.

[0005] For example, mescaline (chemical name 3,4,5-trimethoxyphenethylamine) is a secondary metabolite naturally produced by certain cactus species belonging to various genera within the Cactaceae plant family. Cactus species capable of producing mescaline include, for example, cactus species belonging to the genus Lophophora, such as Ubatama (Peyote) and Lophophora diffusa, and cactus species belonging to the genus Echinopsis / Trichocereus, such as Echinopsis pachanoi / Trichocereus pachanoi (also known as San Pedro), Echinopsis peruviana / Trichocereus peruvianus (also known as Peruvian Torch), Echinopsis lageniformis / Trichocereus brijesii (also known as Bolivian Torch), and Echinopsis scopulicola / Trichocereus scopulicola.

[0006] Technological interest in mescaline is well established. Thus, for example, mescaline is a psychoactive compound and is therefore used as a recreational drug. Mescaline is also used in Native American religious ceremonies and for spiritual purposes by indigenous Andean cultures. Furthermore, mescaline is being evaluated for its potential in the treatment of addiction, particularly alcohol addiction (Bogenschutz, MP and Johnson MW (2016), Prog. in Neuro-Psychopharmacol. & Biol. Psychiatry 64; 250-258; Romeu, A Get al. (2017), Exp. Clin. Psychopharmacol. 2016 Aug; 24(4): 229-268).

[0007] Although mescaline has low toxicity, adverse side effects, including panic attacks, paranoia, and psychotic states (sometimes together or individually referred to as "bad trips"), are not uncommonly experienced by mescaline users. Additionally, mescaline can induce nausea and vomiting.

[0008] Therefore, there is a need in the art for improved mescaline compounds. Summary of the Invention

[0009] The following paragraphs are intended to introduce the reader to a more detailed description and are not intended to define or limit the claimed subject matter of the present disclosure.

[0010] In one aspect, the present disclosure relates to mescaline and derivative compounds.

[0011] In another aspect, the disclosure relates to fused heterocyclic mescaline derivatives and methods of making and using these compounds.

[0012] In another aspect, the disclosure relates to fused heterocyclic mescaline derivatives having a substituted N-propylamine chain, and methods of making and using these compounds.

[0013] Thus, in one aspect, the present disclosure provides, in at least one embodiment, in accordance with the teachings herein, a compound having formula (I) or (II): [ka] In formula (I) or (II): [ka] is a single or double bond; X1, X2, and X3 are independently selected from a hydrogen atom, O-alkyl, acyl, N-alkyl, OH, halogen, or NH2; X4 is an alkylene group or a substituted alkylene group; R1 is hydrogen, an alkyl group, or an oxo group; R1 is R 1b , the carbon atom to which R1 is bonded, and R 1b together with the nitrogen atom to which it is attached form an optionally substituted saturated or unsaturated 3- to 10-membered heterocyclic ring, and when the heterocyclic ring is unsaturated, R1a is optional and non-existent; R 1a and R 1b are each independently selected from an alkyl group, a hydroxylalkyl group, an optionally substituted alkyl-aryl group, or a hydrogen atom; or R 1a and R 1b taken together with the nitrogen atom to which they are attached form a 3- to 10-membered optionally substituted heterocycle; and R2 and R3 are each independently selected from an alkyl group, an O-alkyl group, a hydrogen atom, or R2 and R3 taken together with the oxygen atom and the carbon atom to which they are attached form an oxirane ring.

[0014] In at least one embodiment, in one aspect, the chemical compound having formula (I) is a ) or (I b The compound having formula (II) can be a compound having formula (II a ) or (II b ) can be a compound having: [ka] In formula (Ia), (Ib), (IIa), or (IIb): X1, X2, and X3 are independently selected from a hydrogen atom, O-alkyl, acyl, N-alkyl, OH, halogen, or NH2; X4 is an alkylene group or a substituted alkylene group; R1 is hydrogen, an alkyl group, or an oxo group; R1 is R 1b , the carbon atom to which R1 is attached and R 1b together with the nitrogen atom to which it is attached form an optionally substituted saturated or unsaturated 3- to 10-membered heterocyclic ring, and when the heterocyclic ring is unsaturated, R 1a is optional and non-existent; R 1a and R 1bare each independently selected from an alkyl group, a hydroxylalkyl group, an optionally substituted alkyl-aryl group, or a hydrogen atom; or R 1a and R 1b taken together with the nitrogen atom to which they are attached form a 3- to 10-membered optionally substituted heterocycle; and R2 and R3 are each independently selected from an alkyl group, an O-alkyl group, a hydrogen atom, or R2 and R3 taken together with the oxygen atom and the carbon atom to which they are attached form an oxirane ring.

[0015] In at least one embodiment, in one aspect, X4 can be a (C1-C3)-alkylene group or a substituted (C1-C3)-alkylene group.

[0016] In at least one embodiment, in one aspect, X4 can be a methylene group (-CH2-) or a substituted methylene group.

[0017] In at least one embodiment, in one aspect, the methylene group can be substituted with at least one halogen.

[0018] In at least one embodiment, in one aspect, the substituted methylene group can be substituted with two halogen substituents.

[0019] In at least one embodiment, in one aspect, the substituted methylene group can be substituted with two identical halogen substituents and can optionally be (—CF 2 —).

[0020] In at least one embodiment, in one aspect, a ), (I b ), (II a ), and (II b ) are compounds having the chemical formula (I c ), (I d ), (II c ), or (II d ) can have: [ka]

[0021] In at least one embodiment, in one aspect, an amino group (—NR 1a R 1b ) is protonated, and (-N + HR 1a R 1b ) and can form chemical formula (I), (II), (I a ), (I b ), (II a ), (II b ), (I c ), (I d ), (II c ), or (II d ) further contains a negatively charged anion that balances the positively charged nitrogen atom.

[0022] In at least one embodiment, in one aspect, X1, X2, and X3 can each be a hydrogen atom (H).

[0023] In at least one embodiment, in one aspect, at least one of X1, X2, and X3 can each be an O-alkyl group or a halogen.

[0024] In at least one embodiment, in one aspect, each X3 can be an O-alkyl group, optionally a methoxy group, or a halogen, optionally a bromine.

[0025] In at least one embodiment, in one aspect, R2 and R3 can independently or simultaneously be a (C1-C6)-alkyl group.

[0026] In at least one embodiment, in one aspect, R2 and R3 can independently or simultaneously be a (C1-C3)-alkyl group.

[0027] In at least one embodiment, in one aspect, R2 and R3 can be methyl groups.

[0028] In at least one embodiment, in one aspect, R2 can be a (C1-C6)-alkyl group and R3 can be a hydrogen atom.

[0029] In at least one embodiment, in one aspect, R2 can be a (C1-C3)-alkyl group and R3 can be a hydrogen atom.

[0030] In at least one embodiment, in one aspect, R2 can be a methyl group or an ethyl group, and R3 can be a hydrogen atom.

[0031] In at least one embodiment, in one aspect, R3 can be a (C1-C6)-alkyl group and R2 can be a hydrogen atom.

[0032] In at least one embodiment, in one aspect, R3 can be a (C1-C3)-alkyl group and R2 can be a hydrogen atom.

[0033] In at least one embodiment, in one aspect, R3 can be a methyl group and R2 can be a hydrogen atom.

[0034] In at least one embodiment, in one aspect, R2 and R3 can each be a methoxy group.

[0035] In at least one embodiment, in one aspect, R2 can independently or simultaneously be a (C1-C6)-O-alkyl group and R3 can be a hydrogen atom.

[0036] In at least one embodiment, in one aspect, R2 can independently or simultaneously be a (C1-C3)-O-alkyl group and R3 can be a hydrogen atom.

[0037] In at least one embodiment, in one aspect, R2 can be a methoxy group and R3 can be a hydrogen atom.

[0038] In at least one embodiment, in one aspect, R3 can be a (C1-C6)-O-alkyl group and R2 can be a hydrogen atom.

[0039] In at least one embodiment, in one aspect, R3 can be a (C1-C3)-O-alkyl group and R2 can be a hydrogen atom.

[0040] In at least one embodiment, in one aspect, R3 can be a methoxy group and R2 can be a hydrogen atom.

[0041] In at least one embodiment, in one aspect, R2 and R3 can each be a hydrogen atom.

[0042] In at least one embodiment, in one aspect, a ), (II a ), (I c ), or (II c ), R2 and R3 together with the oxygen atom can form an oxirane ring.

[0043] In at least one embodiment, in one aspect, R 1a can be a hydrogen atom, and R 1b can be a (C1-C6)-alkyl group.

[0044] In at least one embodiment, in one aspect, R 1a and R 1b may independently or simultaneously be a (C1-C6)-alkyl group.

[0045] In at least one embodiment, in one aspect, R 1a and R1b may independently or simultaneously be a (C1-C3)-alkyl group.

[0046] In at least one embodiment, in one aspect, R 1a can be a hydrogen atom, and R 1b can be a (C1-C6)-hydroxylalkyl group.

[0047] In at least one embodiment, in one aspect, R 1a can be a hydrogen atom, and R 1b can be a methanol group (-CH2OH), an ethanol group (-C2H4OH), a propanol group (-C3H6OH), or a butanol group (-C4H8OH).

[0048] In at least one embodiment, in one aspect, R 1a can be a hydrogen atom, and R 1b can be a hydroxyl alkyl group having the formula (HA): [ka] wherein Y1 and Y2 are each simultaneously or independently a hydrogen atom or a (C1-C6)-alkyl group.

[0049] In at least one embodiment, in one aspect, R 1a can be a hydrogen atom, and R 1b can be an alkyl-aryl group.

[0050] In at least one embodiment, in one aspect, the alkyl-aryl group can be a (C1-C6)-alkyl-aryl group.

[0051] In at least one embodiment, in one aspect, the alkyl-aryl group can be a (C1-C6)-alkyl-phenyl group.

[0052] In at least one embodiment, in one aspect, the alkyl-aryl group can be a (CH2)-phenyl group.

[0053] In at least one embodiment, in one aspect, R 1a and R 1b can be taken together with the nitrogen atom to which they are attached to form a 3-10 membered optionally substituted heterocycle, which heterocycle further contains an oxygen atom.

[0054] In at least one embodiment, in one aspect, R 1a and R 1b can be taken together with the nitrogen atom to which they are attached to form a 3-10 membered optionally substituted heterocycle, which further comprises an oxygen atom, and which heterocycle is further substituted with at least one (C1-C6)-alkyl group.

[0055] In at least one embodiment, in one aspect, the heterocycle can be further substituted with two (C1-C6)-alkyl groups, independently or simultaneously, from the same heterocycle carbon atom.

[0056] In at least one embodiment, in one aspect, the heterocycle can be further substituted with two methyl groups on one single heterocycle carbon atom.

[0057] In at least one embodiment, in one aspect, the heterocycle can be further substituted with two methyl groups on two separate heterocycle carbon atoms.

[0058] In at least one embodiment, in one aspect, the heterocycle can be a 5- or 6-membered heterocycle.

[0059] In at least one embodiment, in one aspect, R is R 1b , R 1btogether with the nitrogen atom to which R is attached and the carbon atom to which R is attached can form an optionally substituted saturated or unsaturated 3- to 10-membered heterocyclic ring, which heterocyclic ring contains, in addition to the nitrogen atom, an oxygen atom.

[0060] In at least one embodiment, in one aspect, R is R 1b , R 1b together with the nitrogen atom to which R is attached and the carbon atom to which R is attached can form an optionally substituted saturated or unsaturated 3-10 membered heterocyclic ring, which, in addition to the nitrogen atom, contains an oxygen atom and is substituted with at least one (C-C) alkyl group.

[0061] In at least one embodiment, in one aspect, R is R 1b , R 1b and the carbon atom to which R is attached can together form an optionally substituted saturated or unsaturated 3- to 10-membered heterocyclic ring, which, in addition to the nitrogen atom, contains an oxygen atom and is substituted, independently or simultaneously, with at least two (C-C) alkyl groups, the alkyl groups being substituents on the same heterocyclic carbon atom.

[0062] In at least one embodiment, in one aspect, the alkyl group can be a methyl group.

[0063] In at least one embodiment, in one aspect, the heterocycle can be partially saturated.

[0064] In at least one embodiment, in one aspect, the heterocycle can be a 5- or 6-membered heterocycle.

[0065] In at least one embodiment, in one aspect, when the heterocycle is unsaturated, R 1a can not exist.

[0066] In at least one embodiment, in one aspect, when the heterocycle is unsaturated and the nitrogen participates in the formation of an unsaturated bond, R1a can not exist.

[0067] In at least one embodiment, in one aspect, the chemical compound having formula (I) or (II) can be selected from the group of compounds having chemical formulas (A); (B); (C); (D); (E); (F); and (G): [ka] In formula (B), X 4a and X 4b are independently or simultaneously a halogen or a hydrogen atom, and R in formulas (A), (B), (C), (D), (E), and (F) 1a and R 1b are independently selected from an alkyl group, an optionally substituted alkyl-aryl group, or a hydrogen atom, or R in formulas (A), (B), (C), (D), (E), and (F). 1a and R 1b taken together with the nitrogen atom to which they are attached form a 3- to 10-membered optionally substituted heterocycle; R2 in formulas (C), (F), and (G), Y1 and Y2 in (G) are alkyl groups or hydrogen atoms; and X3 in formulas (C), (F), and (G) is a halogen, an O-alkyl group, or a hydrogen atom.

[0068] In at least one embodiment, in one aspect, the chemical compound having formula (I) can be selected from the group of compounds having the following chemical formulas: A(I)-A(III); B(I)-B(V); C(I)-C(XIII); D(I)-D(III); E(I)-(V); F(I)-(VI); and G(I)-G(V): (A):A(I);A(II);and A(III): [ka] (B): B(I); B(II); B(III); B(IV); and B(V): [ka] (C):C(I);C(II);C(III);C(IV);C(V);C(VI);C(VII);C(VIII);C(IX);C(X);C(XI);C(XII); and C(XIII): [ka] (D): D(I); D(II); and D(III): [ka] (E):E(I);E(II);E(III);E(IV); and E(V): [ka] (F): F(I); F(II); F(III); F(IV); F(V); and F(VI): [ka] and (G): G(I); G(II); G(III); G(IV); and G(V): [ka] In each of compounds A(I)-G(V), the nitrogen atom of the N-propylamine moiety may optionally be protonated and contains a negatively charged anion that balances the positively charged nitrogen atom.

[0069] In at least one embodiment, in one aspect, the compound can be a stereoisomeric compound selected from stereoisomeric compounds consistent with A(I), A(II), A(III), C(VII), C(IX), C(XI), F(II), G(II), and G(IV) that contain an N-propylamine moiety, wherein the C2 atom of the N-propylamine moiety is a chiral carbon atom.

[0070] In at least one embodiment, in one aspect, the compound can be a first stereoisomeric compound present in a mixture, the mixture comprising a second stereoisomeric compound, the second stereoisomeric compound being the stereoisomeric counterpart of the first stereoisomeric compound, and optionally, the mixture being a racemic mixture.

[0071] In at least one embodiment, in one aspect, a stereoisomeric compound can be substantially free of its corresponding counterpart stereoisomeric compound.

[0072] In at least one embodiment, in one aspect, the compound having formula A(II) is a ) or A(II b ) can be selected from stereoisomeric compounds having: [ka]

[0073] In at least one embodiment, in one aspect, the selected compound can be in a mixture that further includes other stereoisomeric compounds, and optionally, the mixture is a racemic mixture.

[0074] In another aspect, the present disclosure relates to pharmaceutical and recreational drug formulations comprising fused heterocyclic mescaline derivatives. Accordingly, in one aspect, the present disclosure provides, in at least one embodiment, a pharmaceutical or recreational drug formulation comprising an effective amount of a chemical compound selected from compounds having the chemical formula (I) or (II), together with a pharmaceutically acceptable excipient, diluent, or carrier: [ka] In formula (I) or (II): [ka] is a single or double bond; X1, X2, and X3 are independently selected from a hydrogen atom, O-alkyl, acyl, N-alkyl, OH, halogen, or NH2; X4 is an alkylene group or a substituted alkylene group; R1 is hydrogen, an alkyl group, or an oxo group; R1 is R 1b , the carbon atom to which R1 is attached and R 1b together with the nitrogen atom to which it is attached form an optionally substituted saturated or unsaturated 3- to 10-membered heterocyclic ring, and when the heterocyclic ring is unsaturated, R 1a is optional and non-existent; R 1a and R 1b are each independently selected from an alkyl group, a hydroxylalkyl group, an optionally substituted alkyl-aryl group, or a hydrogen atom; or R 1a and R 1b taken together with the nitrogen atom to which they are attached form a 3- to 10-membered optionally substituted heterocycle; and R2 and R3 are each independently selected from an alkyl group, an O-alkyl group, a hydrogen atom, or R2 and R3 taken together with the oxygen atom and the carbon atom to which they are attached form an oxirane ring.

[0075] In another aspect, the present disclosure relates to a method for treating a psychiatric disorder. Accordingly, in one embodiment, the present disclosure further provides a method for treating a cranial nerve disorder, the method comprising administering to a subject in need thereof a pharmaceutical formulation comprising a compound having formula (I) or (II): [ka] In formula (I) or (II): [ka] is a single or double bond; X1, X2, and X3 are independently selected from a hydrogen atom, O-alkyl, acyl, N-alkyl, OH, halogen, or NH2; X4 is an alkylene group or a substituted alkylene group; R1 is hydrogen, an alkyl group, or an oxo group; R1 is R 1b , the carbon atom to which R is attached, and R 1b together with the nitrogen atom to which it is attached form an optionally substituted saturated or unsaturated 3- to 10-membered heterocyclic ring, and when the heterocyclic ring is unsaturated, R 1a is optional and non-existent; R 1a and R 1b are each independently selected from an alkyl group, a hydroxylalkyl group, an optionally substituted alkyl-aryl group, or a hydrogen atom; or R 1a and R 1b taken together with the nitrogen atom to which they are attached form a 3- to 10-membered optionally substituted heterocycle; and R2 and R3 are each independently selected from an alkyl group, an O-alkyl group, or a hydrogen atom, or R2 and R3 together with an oxygen atom and the carbon atom to which they are attached form an oxirane ring; The pharmaceutical formulation is administered in an amount effective to treat a cranial nerve disorder in a subject.

[0076] In at least one embodiment, in one aspect, upon administration, a compound having formula (I) or (II) can interact with a receptor in a subject, thereby modulating the receptor and exerting a pharmacological effect.

[0077] In at least one embodiment, in one aspect, the receptor can be a G protein-coupled receptor (GPCR).

[0078] In at least one embodiment, in one aspect, the receptor can be a 5-HT receptor.

[0079] In at least one embodiment, in one aspect, the receptor is 5-HT 1A Receptor, 5-HT 2A Receptor, 5-HT 2B Receptor, 5-HT2C Receptor, 5-HT7 receptor, α 2A The receptor may be a D3 receptor, a D4 receptor, or a MT1 receptor.

[0080] In at least one embodiment, in one aspect, upon administration, a compound having formula (I) or (II) can interact with a transmembrane transport protein in a subject, thereby modulating the transmembrane transport protein and exerting a pharmacological effect.

[0081] In at least one embodiment, in one aspect, the transmembrane transport protein can be a dopamine active transporter (DAT), a norephedrine transporter (NET), or a serotonin transporter (SERT) transmembrane transport protein.

[0082] In at least one embodiment, in one aspect, the disorder can be a G protein-coupled receptor (GPCR)-mediated disorder.

[0083] In at least one embodiment, in one aspect, the disorder can be a 5-HT receptor mediated disorder.

[0084] In at least one embodiment, the disorder is 5-HT 1A Receptor-mediated disorders, 5-HT 2A Receptor-mediated disorders, 5-HT 2B Receptor-mediated disorders, 5-HT 2C Receptor-mediated disorders, 5-HT 1D Receptor-mediated disorders, 5-HT7 receptor-mediated disorders, α 2A It can be a receptor-mediated disorder, a D3 receptor-mediated disorder, or an MT1 receptor-mediated disorder.

[0085] In at least one embodiment, a dose of about 0.001 mg to about 5,000 mg may be administered.

[0086] In another aspect, the disclosure provides, in at least one embodiment, a method for modulating: (i) 5-HT 1A Receptor, 5-HT 2A Receptor, 5-HT 2B Receptor, 5-HT 2C Receptor, 5-HT7 receptor, α 2A receptor, D3 receptor, or MT1 receptor; or (ii) a transmembrane transport protein selected from a dopamine active transporter (DAT), a norephedrine transporter (NET), or a serotonin transporter (SERT) transmembrane transport protein, the method comprising: (i) a 5-HT 1A Receptor, 5-HT 2A Receptor, 5-HT 2B Receptor, 5-HT 2C Receptor, 5-HT7 receptor, α 2A receptor, D3 receptor, or MT1 receptor; and (ii) dopamine active transporter (DAT), norephedrine transporter (NET), or serotonin transporter (SERT) transmembrane transport proteins, under reaction conditions sufficient to modulate (i) 5-HT 1A Receptor, 5-HT 2A Receptor, 5-HT 2B Receptor, 5-HT 2C Receptor, 5-HT7 receptor, α 2A receptor, D3 receptor, or MT1 receptor; or (ii) a dopamine active transporter (DAT), a norephedrine transporter (NET), or a serotonin transporter (SERT) transmembrane transport protein with a compound selected from a first chemical compound having the chemical formula (I) and a second chemical compound having the chemical formula (II): [ka] In formula (I) or (II): [ka] is a single or double bond; X1, X2, and X3 are independently selected from a hydrogen atom, O-alkyl, acyl, N-alkyl, OH, halogen, or NH2; X4 is an alkylene group or a substituted alkylene group; R1 is hydrogen, an alkyl group, or an oxo group; R1 is R 1b , the carbon atom to which R is attached, and R 1b together with the nitrogen atom to which it is attached form an optionally substituted saturated or unsaturated 3- to 10-membered heterocyclic ring, and when the heterocyclic ring is unsaturated, R 1a is optional and non-existent; R 1a and R 1b are each independently selected from an alkyl group, a hydroxylalkyl group, an optionally substituted alkyl-aryl group, or a hydrogen atom; or R 1a and R 1b taken together with the nitrogen atom to which they are attached form a 3- to 10-membered optionally substituted heterocycle; and R2 and R3 are each independently selected from an alkyl group, an O-alkyl group, a hydrogen atom, or R2 and R3 taken together with the oxygen atom and the carbon atom to which they are attached form an oxirane ring.

[0087] In at least one embodiment, in one aspect, the reaction conditions can be in vitro reaction conditions.

[0088] In at least one embodiment, in one aspect, the reaction conditions can be in vivo reaction conditions.

[0089] In another aspect, the present disclosure relates to methods of making mescaline derivatives. Accordingly, in one aspect, in at least one embodiment, provided herein is a method of making a first chemical compound having the chemical formula (I) or (II): [ka] In formula (I) or (II): [ka] is a single or double bond; X1, X2, and X3 are independently selected from a hydrogen atom, O-alkyl, acyl, N-alkyl, OH, halogen, or NH2; X4 is an alkylene group or a substituted alkylene group; R1 is hydrogen, an alkyl group, or an oxo group; R1 is R 1b , the carbon atom to which R1 is attached and R 1b together with the nitrogen atom to which it is attached form an optionally substituted saturated or unsaturated 3- to 10-membered heterocyclic ring, and when the heterocyclic ring is unsaturated, R 1a is optional and non-existent; R 1a and R 1b are each independently selected from an alkyl group, a hydroxylalkyl group, an optionally substituted alkyl-aryl group, or a hydrogen atom; or R 1a and R 1b taken together with the nitrogen atom to which they are attached form a 3- to 10-membered optionally substituted heterocycle; and R2 and R3 are each independently selected from an alkyl group, an O-alkyl group, or a hydrogen atom, or R2 and R3 together with an oxygen atom and the carbon atom to which they are attached form an oxirane ring; The method includes performing at least one chemical synthesis reaction selected from the reactions shown in Figures 3A(i), 3A(ii), 3B(i), 3B(ii), 3B(iii), and 3C.

[0090] In at least one embodiment, in one aspect, the compound having formula (I) can be a compound having formula (A): [ka] In the formula, R 1a and R 1b are each independently selected from an alkyl group, an optionally substituted alkyl-aryl group, or a hydrogen atom; or R 1aand R 1b taken together with the nitrogen atom to which they are attached form a 3- to 10-membered optionally substituted heterocycle; The at least one chemical synthesis reaction is a reaction selected from (g); (f) and (g); (e), (f), and (g); and (d), (e), (f), and (g) shown in Figures 3A(i) and 3A(ii).

[0091] In at least one embodiment, in one aspect, the compound having formula (I) can be a compound having formula (B): [ka] In formula (B), X 4a and X 4b are independently or simultaneously a halogen atom or a hydrogen atom, and R 1a and R 1b are each independently selected from an alkyl group, an optionally substituted alkyl-aryl group, or a hydrogen atom; or R 1a and R 1b taken together with the nitrogen atom to which they are attached form a 3- to 10-membered optionally substituted heterocycle; The at least one chemical synthesis reaction is a reaction selected from (i); (f); (f) and (i); (e) and (f); (e), (f), and (i); (d), (e), and (f); and (d), (e), (f), and (i) shown in Figure 3A(i).

[0092] In at least one embodiment, in one aspect, the compound having formula (I) can be a compound having formula (C): [ka] In the formula, R 1a and R 1b are each independently selected from an alkyl group, a hydroxyl alkyl group, or a hydrogen atom, or R 1a and R 1btaken together with the nitrogen atom to which they are attached form a 3-10 membered optionally substituted heterocycle, R2 is selected from an alkyl group or a hydrogen atom, and X3 is an O-alkyl group, a halogen, or a hydrogen atom; and wherein the at least one chemical synthesis reaction is a reaction selected from the following: (i) {(h) in Figure 3A(i) and 3A(ii); (c) and (h); (b), (c), and (h); and (a), (b), (c), and (h)}; (ii) {(f) in Figure 3B(i) and 3B(ii); (d) and (f); (c2), (d), and (f); (c1), (d), and (f); (b), (c2), (d), and (f); (a), (b), (c2), (d), and (f); and (a), (c1), (d), and (f)}; (iii) {(e) in Figure 3B(i) and 3B(ii); (d) and (e); (c2), (d), and (e); (c1), (d), and (e); (b), (c2), (d), and (e); (a), (b), (c2), (d), and (e); and (a), (c1), (d), and (e)}; (iv) {(d) in Figures 3B(i) and 3B(ii); (c1) and (d); (c2) and (d); (b), (c2), and (d); and (a), (c1), and (d); and (a), (b), (c2) and (d)}; or (v) {(i); (c1) and (i); (c2) and (i); (b), (c2), and (i); and (a), (c1), and (i); and (a), (b), (c2) and (i) in Figures 3B(i) and 3B(ii)}; or (vi) {(g) in Figures 3B(i) and 3B(ii); (d) and (g); (c2), (d), and (g); (c1), (d), and (g); (b), (c2), (d), and (g); (a), (b), (c2), (d), and (g); and (a), (c1), (d), and (g)}.

[0093] In at least one embodiment, in one aspect, the compound having formula (I) can be a compound having formula (D): [ka] In the formula, R 1a and R 1b are each independently selected from an alkyl group or a hydrogen atom, or R 1a and R 1b taken together with the nitrogen atom to which they are attached form a 3- to 10-membered optionally substituted heterocycle; The at least one chemical synthesis reaction is a reaction selected from (c); (b) and (c); and (a), (b), and (c) shown in Figures 3A(i) and 3A(ii).

[0094] In at least one embodiment, in one aspect, the compound having formula (I) can be a compound having formula (E): [ka] In the formula, R 1a and R 1b are each independently selected from an alkyl group, an optionally substituted alkyl-aryl group, or a hydrogen atom; or R 1a and R 1b taken together with the nitrogen atom to which they are attached form a 3- to 10-membered optionally substituted heterocycle; The at least one chemical synthesis reaction is shown in Figure 3C (b); and a reaction selected from (a) and (b).

[0095] In at least one embodiment, in one aspect, the compound having formula (I) can be a compound having formula (F): [ka] In the formula, R 1a and R 1bare each independently selected from a hydroxyl alkyl group or a hydrogen atom, or R 1a and R 1b taken together with the nitrogen atom to which they are attached form a 3- to 10-membered optionally substituted heterocycle; R2 is an alkyl group or a hydrogen atom, and X3 is an O-alkyl group, a halogen, or a hydrogen atom; and at least one chemical synthesis reaction is a reaction selected from the following: (c1); (c2); (b) and (c2); (a) and (c1); (a), (b), and (c2) shown in Figures 3B(i) and 3B(ii).

[0096] In at least one embodiment, in one aspect, the compound having formula (I) can be a compound having formula (G): [ka] In the formula, X3 is a hydrogen atom, a halogen atom, or an O-alkyl group; R2, Y1, and Y2 are each independently an alkyl group or a hydrogen atom; and the at least one chemical synthesis reaction is a reaction selected from (h); (c1) and (h); (c2) and (h); (b), (c2), and (h); and (a), (c1), and (h); and (a), (b), (c2) and (h) in Figures 3B(i), 3B(ii), and 3B(iii).

[0097] In another aspect, the present disclosure provides, in at least one embodiment, the use of a chemical compound having chemical formula (I) or (II) in the manufacture of a pharmaceutical or recreational drug formulation: [ka] In formula (I) or (II): [ka] is a single or double bond; X1, X2, and X3 are independently selected from a hydrogen atom, O-alkyl, acyl, N-alkyl, OH, halogen, or NH2; X4 is an alkylene group or a substituted alkylene group; R1 is hydrogen, an alkyl group, or an oxo group; R1 is R 1b , the carbon atom to which R1 is attached and R 1b together with the nitrogen atom to which it is attached form an optionally substituted saturated or unsaturated 3- to 10-membered heterocyclic ring, and when the heterocyclic ring is unsaturated, R 1a is optional and non-existent; R 1a and R 1b are each independently selected from an alkyl group, a hydroxylalkyl group, an optionally substituted alkyl-aryl group, or a hydrogen atom; or R 1a and R 1b taken together with the nitrogen atom to which they are attached form a 3- to 10-membered optionally substituted heterocycle; and R2 and R3 are each independently selected from an alkyl group, an O-alkyl group, a hydrogen atom, or R2 and R3 taken together with the oxygen atom and the carbon atom to which they are attached form an oxirane ring.

[0098] In at least one embodiment, in one aspect, manufacturing can include formulating a chemical compound with an excipient, diluent, or carrier.

[0099] In another aspect, the present disclosure provides, in at least one embodiment, the use of a chemical compound having the chemical formula (I) or (II) as a pharmaceutical or recreational drug formulation, together with a diluent, carrier, or excipient: [ka] In formula (I) or (II): [ka] is a single or double bond; X1, X2, and X3 are independently selected from a hydrogen atom, O-alkyl, acyl, N-alkyl, OH, halogen, or NH2; X4 is an alkylene group or a substituted alkylene group; R1 is hydrogen, an alkyl group, or an oxo group; R1 is R 1b , the carbon atom to which R1 is attached and R 1b together with the nitrogen atom to which it is attached form an optionally substituted saturated or unsaturated 3- to 10-membered heterocyclic ring, and when the heterocyclic ring is unsaturated, R 1a is optional and non-existent; R 1a and R 1b are each independently selected from an alkyl group, a hydroxylalkyl group, an optionally substituted alkyl-aryl group, or a hydrogen atom; or R 1a and R 1b taken together with the nitrogen atom to which they are attached form a 3- to 10-membered optionally substituted heterocycle; and R2 and R3 are each independently selected from an alkyl group, an O-alkyl group, a hydrogen atom, or R2 and R3 taken together with the oxygen atom and the carbon atom to which they are attached form an oxirane ring.

[0100] Other features and advantages will become apparent from the following detailed description. It should be understood, however, that the detailed description, while indicating preferred implementations of the disclosure, is given by way of example only, since various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from the detailed description.

[0101] The present disclosure will now be described, by way of example, in the paragraphs provided below and with reference to the accompanying figures. The figures provided herein are provided for a better understanding of example embodiments and to more clearly show how various embodiments may be implemented. The figures are not intended to limit the disclosure. [Brief explanation of the drawings]

[0102] [Figure 1] The chemical structure of mescaline is shown, identifying the phenyl portion (including substituted phenyl groups) and the ethylamine portion of the compound. [Figure 2] Certain prototypical structures of mescaline derivative compounds are shown. The prototypical structures include a phenyl moiety (including substituted phenyl groups) and an N-propylamine moiety, as shown. The carbon atoms are numbered C1, C2, C3, etc. to indicate their position within the phenyl or N-propylamine moiety, respectively. Thus, for example, from Figure 2, it will be apparent that an N-propylamine chain extends from the C1 carbon of the phenyl group. Furthermore, it should be noted that certain compounds can be named similarly. Thus, for example, the C1 carbon atom of the N-propylamine chain is aminated, and the chain is called N-propylamine. As another example, in 2,3(1,3)dioxolanephenyl-N-propylamine, the phenyl moiety carbon atoms C2 and C3 each participate in the formation of a (1,3)dioxolane group (i.e., a pentane in which the 1st and 3rd carbons are replaced with oxygen atoms). Similarly, in 3,4,5-trimethoxyphenethylamine (mescaline), the phenyl moiety carbon atoms C3, C4, and C5 are each bonded to a methoxy group. [Figure 3A] (i) [Figure 3A] (ii) [Figure 3B] (i) [Figure 3B] (ii) [Figure 3B] (iii) and [Figure 3C]Exemplary synthetic pathways and the chemical reactions comprising such pathways are shown for certain exemplary mescaline compounds of the present disclosure, particularly exemplary mescaline derivative compounds (A), (B), (C), and (D) (Figures 3A(i) and 3A(ii)); compounds (C) and (F) (Figures 3B(i) and 3B(ii)); compound (E) (Figure 3C); and compound (G) (Figures 3B(i), 3B(ii), and 3B(iii)). The individual chemical reactions are designated as (a), (b), (c), (d), (e), (f), (g), (h), and (i) in Figures 3A(i) and 3A(ii); (a), (b), (c), (d), (e), (f), (g), (h), and (i) in Figures 3B(i), 3B(ii), and 3B(iii); and (a) and (b) in Figure 3C. [Figure 4A] , [Figure 4B] , [Figure 4C] , and [Figure 4D] 1A-1D provide exemplary reactions in exemplary chemical synthetic routes for the synthesis of certain exemplary compounds according to the present disclosure. [Figure 5A] , [Figure 5B] , [Figure 5C] , and [Figure 5D] 10 provides further exemplary reactions in another exemplary chemical synthetic route for the synthesis of another exemplary compound according to the present disclosure. [Figure 6A] and [Figure 6B] 10 provides further exemplary reactions in another exemplary chemical synthetic route for the synthesis of another exemplary compound according to the present disclosure. [Figure 7A] and [Figure 7B] 10 provides further exemplary reactions in another exemplary chemical synthetic route for the synthesis of another exemplary compound according to the present disclosure. [Figure 8] 1 shows exemplary chemical reactions for the synthesis of additional exemplary compounds according to the present disclosure. [Figure 9] 10 shows another example chemical reaction for the synthesis of another example compound according to the present disclosure. [Figure 10]10 shows another example chemical reaction for the synthesis of another example compound according to the present disclosure. [Figure 11] 10 shows another example chemical reaction for the synthesis of another example compound according to the present disclosure. [Figure 12A] and [Figure 12B] 10 provides further exemplary reactions in another exemplary chemical synthetic route for the synthesis of another exemplary compound according to the present disclosure. [Figure 13] 10 shows another example chemical reaction for the synthesis of another example compound according to the present disclosure. [Figure 14A] , [Figure 14B] , [Figure 14C] , [Figure 14D] , [Figure 14E] , [Figure 14F] , [Figure 14G] , [Figure 14H] , [Figure 14I] , [Figure 14J] , [Figure 14K] , and [Figure 14L]14A-14D show various graphs representing certain experimental results, particularly those obtained in conducting experimental assays to evaluate the pharmaceutical efficacy of exemplary compounds having formula B(II), including, in particular: a radioligand 5-HT1A receptor saturation binding assay (binding curve) using radiolabeled 8-hydroxy-DPAT[propyl-2,3-ring-1,2,3-3H]; a 5-HT1A receptor competition assay using DMSO (negative control) (FIG. 14B); a 5-HT1A receptor competition assay using tryptophan (negative control) (FIG. 14C); a 5-HT1A receptor competition assay using serotonin (positive control) (FIG. 14D); a 5-HT1A receptor competition assay using mescaline (positive control) (FIG. 14D). 5-HT1A receptor competition assay using 2C-B (positive control) (Figure 14E); 5-HT1A receptor competition assay using 2C-B (positive control) (Figure 14F); 5-HT1A receptor competition assay using MDMA (positive control) (Figure 14G); 5-HT1A receptor competition assay using escalin (Figure 14H); 5-HT1A receptor competition assay using proscalin (Figure 14I); 5-HT1A receptor competition assay using fluoxetine (positive control) (Figure 14J); 5-HT1A receptor competition assay using vortioxetine (positive control) (Figure 14K); 5-HT1A receptor competition assay using a compound having formula B(II) (Figure 14L). [Figure 15A] , [Figure 15B] , [Figure 15C] , [Figure 15D] , [Figure 15E] , [Figure 15F] , [Figure 15G] , and [Figure 15H]15A-15C show various graphs depicting certain experimental results, particularly graphs obtained in conducting experimental assays to evaluate the pharmaceutical efficacy of exemplary compounds having formula B(II), including, in particular: a radioligand 5-HT2A receptor saturation binding assay (binding curve) using radiolabeled [H-ketanserin] (FIG. 15A); a 5-HT2A receptor competition assay using psilocin (positive control) (FIG. 15B); a 5-HT2A receptor competition assay using tryptophan (negative control) (FIG. 15C); a 5-HT2A receptor competition assay using escalin (FIG. 15D); a 5-HT2A receptor competition assay using proscalin (FIG. 15E); a 5-HT2A receptor competition assay using 2C-B (positive control) (FIG. 15F); and a 5-HT2A receptor competition assay using MDMA (positive control) (FIG. 15G), and a 5-HT2A receptor competition assay using a compound having formula B(II) (FIG. 15H). [Figure 16A] , [Figure 16B] , [Figure 16C] , [Figure 16D] , [Figure 16E] , [Figure 16F] , [Figure 16G] , and [Figure 16H]16A-16C show various graphs depicting certain experimental results, particularly graphs obtained in conducting experimental assays evaluating the pharmaceutical efficacy of exemplary compounds having formula B(II), including, in particular: a 5-HT1A cAMP receptor assay for detecting relative levels of cAMP in cells with (+5-HT1A) and without (-5-HT1A) 5-HT1A receptors stimulated with varying amounts of forskolin (FIG. 16A); a 5-HT1A cAMP receptor assay for detecting relative levels of cAMP in cells with (+5-HT1A) and without (-5-HT1A) 5-HT1A receptors stimulated with 4 μM forskolin and varying amounts of 8-OH-DPAT (FIG. 16B); and a 5-HT1A cAMP receptor assay for detecting relative levels of cAMP in cells with (+5-HT1A) and without (-5-HT1A) 5-HT1A receptors stimulated with 4 μM forskolin and varying amounts of serotonin (FIG. 16B). cAMP receptor assay (Figure 16C); 5-HT1A cAMP receptor assay to detect relative levels of cAMP in cells with (+5-HT1A) and without (-5-HT1A) 5-HT1A receptors stimulated with 4 μM forskolin and various amounts of psilocin (Figure 16D); 5-HT1A cAMP receptor assay to detect relative levels of cAMP in cells with (+5-HT1A) and without (-5-HT1A) 5-HT1A receptors stimulated with 4 μM forskolin and various amounts of mescaline (Figure 16E); 5-HT1A cAMP receptor assay to detect relative levels of cAMP in cells with (+5-HT1A) and without (-5-HT1A) 5-HT1A receptors stimulated with 4 μM forskolin and various amounts of MDMA (Figure 16F). cAMP receptor assay (Figure 16F); 5-HT1A cAMP receptor assay to detect relative levels of cAMP in cells with (+5-HT1A) and without (-5-HT1A) 5-HT1A receptors stimulated with 4 μM forskolin and various amounts of 2C-B (Figure 16G); and 5-HT1A cAMP receptor assay to detect relative levels of cAMP in cells with (+5-HT1A) and without (-5-HT1A) 5-HT1A receptors stimulated with 4 μM forskolin and various amounts of Compound B(II) (Figure 16H). [Figure 17] 10 shows another example chemical reaction for the synthesis of another example compound according to the present disclosure. [Figure 18] 10 shows another example chemical reaction for the synthesis of another example compound according to the present disclosure. [Figure 19A] , [Figure 19B] , and [Figure 19C] 10 provides further exemplary reactions in another exemplary chemical synthetic route for the synthesis of another exemplary compound according to the present disclosure. [Figure 20] 10 shows another example chemical reaction for the synthesis of another example compound according to the present disclosure. [Figure 21] 10 shows another example chemical reaction for the synthesis of another example compound according to the present disclosure. [Figure 22A] and [Figure 22B] 10 provides further exemplary reactions in another exemplary chemical synthetic route for the synthesis of another exemplary compound according to the present disclosure. [Figure 23] 10 shows another example chemical reaction for the synthesis of another example compound according to the present disclosure. [Figure 24] 10 shows another example chemical reaction for the synthesis of another example compound according to the present disclosure. [Figure 25A] and [Figure 25B] 10 provides further exemplary reactions in another exemplary chemical synthetic route for the synthesis of another exemplary compound according to the present disclosure. [Figure 26] 10 shows another example chemical reaction for the synthesis of another example compound according to the present disclosure. [Figure 27] 10 shows another example chemical reaction for the synthesis of another example compound according to the present disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0103] The figures, together with the following detailed description, will make apparent to those skilled in the art how the disclosure may be practiced in practice.

[0104] Various compositions, systems, or processes are described below to provide an example of one embodiment of each claimed subject matter. The embodiments described below do not limit any claimed subject matter, and any claimed subject matter may encompass processes, compositions, or systems different from those described below. The claimed subject matter is not limited to compositions, processes, or systems having all the features of any one composition, system, or process described below, or to features common to some or all of the compositions, systems, or processes described below. It is possible that a composition, system, or process described below is not an embodiment of any claimed subject matter. Any subject matter disclosed in the compositions, systems, or processes described below that is not claimed in this document may be the subject of other means of protection, for example, a continuing patent application, and the applicant(s), inventor(s), or owner(s) do not intend to abandon, disclaim, or dedicate to the public any such subject matter by its disclosure in this document.

[0105] In this specification and claims, singular forms such as "a," "an," and "the" include plural references and vice versa unless the context clearly dictates otherwise. Throughout this specification, unless otherwise indicated, "comprise," "comprises," and "comprising" are used inclusively rather than exclusively, so that a stated integer or group of integers may include one or more other unstated integers or groups of integers.

[0106] When ranges are used herein for physical properties, e.g., molecular weight, or chemical properties, e.g., chemical formulas, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. Except in the working examples, or where otherwise indicated, all numerical values ​​expressing quantities of material ingredients or reaction conditions used herein should be understood to be modified in all instances by the term "about." The term "about," when used to refer to a numerical value or numerical range, means that the stated numerical value or numerical range is approximate within experimental variability (or within statistical experimental error); thus, the numerical value or numerical range may vary by 1% to 15% of the stated numerical value or numerical range, as will be readily recognized by the context. Furthermore, any range of values ​​described herein is intended to specifically include the limits of the range and any intermediate values ​​or subranges within the given range, and all such intermediate values ​​and subranges are individually and specifically disclosed (e.g., a range of 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.90, 4, and 5). Similarly, other terms of degree, such as "substantially" and "approximately," are used herein to mean a reasonable amount of deviation from the modified term so that the end result is not materially altered. These terms of degree should be construed to include deviations from the modified term if such deviations do not negate the meaning of the term they modify.

[0107] Unless otherwise specified, scientific and technical terms used in connection with the formulations described herein have the meanings commonly understood by those skilled in the art. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present invention, which is defined solely by the claims.

[0108] All publications, patents, and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference in its entirety.

[0109] Terms and Definitions The term "mescaline" refers to a chemical compound having the structure set forth in Figure 1. Mescaline is also known in the art as 3,4,5 trimethoxyphenethylamine. Mescaline is further shown to contain a phenyl moiety, including a substituted phenyl group, and an ethylamine moiety, as shown in Figure 1.

[0110] The term "mescaline derivative prototype structure" refers to the chemical structure shown in Figure 2. The mescaline derivatives disclosed herein include the mescaline derivative prototype structure shown in Figure 2, where various atoms may be substituted as described herein. The prototype structure is shown to include a phenyl moiety and an N-propylamine (rather than an ethylamine moiety as in mescaline, see Figure 1). Additionally, certain carbon atoms in the mescaline derivative prototype structure are shown as numbered. In this regard, certain carbon atoms in the phenyl moiety of the prototype structure are shown as numbered separately from the carbon atoms in the N-propylamine moiety. These numbered carbons may be referenced herein, for example, as C1 of the phenyl moiety, C2 of the phenyl moiety, or C3 of the N-propylamine moiety. The N-propylamine chain is shown to extend from the C1 carbon atom of the phenyl moiety of the prototype structure. In general terms, disclosed herein are further shown to be mescaline derivatives that: (i) are adjacent carbon atoms C2 and C3 of the phenyl moiety of the prototype structure (as represented by formula (I) a ) and formula (I b )) or C3 and C4 (formula (II a ) and formula (II b)) is a heterocycle, particularly, in some embodiments, a 5-membered heterocycle, particularly, in some embodiments, involved in fusion to a (1,3) dioxolane ring; and (ii) the N-propylamine chain extending from the C1 atom of the phenyl moiety of the prototype structure is, in example embodiments, a substituted N-propylamine chain, particularly, an N-propylamine chain that may have a substituted C2 and / or C3 carbon atom (-CHR2-CHR3-) or (-CR2=CR3-), where R2 and / or R3 are substituents. Thus, the mescaline derivatives disclosed herein can be said to be N-propylamine-fused heterocycle mescaline derivatives.

[0111] A straight bond or a wavy or tortuous bond drawn specifically toward a chiral atom, e.g., a chiral carbon atom, in a structural chemical formula indicates that the stereochemistry of the chiral atom is undefined. Examples of such chemical structural formulas are structural formulas (a), (b), and (c): [ka] Thus, for example, a straight bond or a wavy or tortuous bond drawn towards a chiral atom is intended to represent either the S- or R-configuration, as well as mixtures thereof, in a single drawing. When a straight bond or a wavy or tortuous bond is attached to a double bond moiety (e.g., -C=C-), either cis- or trans- (or (E)- or (Z)-) geometric isomers, or mixtures thereof, are included.

[0112] The term "chiral carbon atom" is used herein to denote a carbon atom that is bonded to four different substituents.

[0113] The terms "stereoisomer" and "stereoisomeric compound" are intended herein to refer to one chemical compound with respect to another chemical compound, both compounds having the same chemical formula when the structural formulas are drawn with straight bonds. However, when the structural formulas of the two compounds are drawn with one or more wedge bonds ( [ka] ), thus defining the three-dimensional configuration of the compound, the compound is configured differently in three dimensions. In this regard, a wedge bond can represent the existence of stereoisomers of a compound. A pair of stereoisomers can include two compounds that are configured three-dimensionally such that they are mirror images of each other. Thus, for example, compounds (a(i)) and (a(ii)) are stereoisomers that are mirror images of each other when R2 = R1 = H, or when R2 = H and R1 is an oxo group. [ka] It is noted that stereoisomers can occur in mixtures containing various relative amounts of the stereoisomers, for example, mixtures containing equimolar or approximately equimolar amounts of two stereoisomers (which may also be called "racemic mixtures").

[0114] As used herein to denote a chemical structure or formula, " [ka] " designates a chemical bond which may be either saturated or unsaturated.

[0115] The terms "hydroxy group" and "hydroxy," as used herein, refer to a molecule containing an oxygen atom bonded to a hydrogen atom and having the chemical formula -OH. The hydroxy group can be chemically bonded to another moiety through its oxygen atom.

[0116] The terms "amino" and "amino group" are used herein to refer to a molecule containing one nitrogen atom bonded to a hydrogen atom and having the formula -NH2. An amino group may also be protonated and have the formula -NH3 + In its protonated form, the amino group may form an ammonium salt, such as an ammonium chloride or sulfate salt, or an organic ammonium salt, all of which are referred to herein as NH3 + Z -The amino group can be chemically bonded to another moiety through its nitrogen atom. It is further noted that a moiety bonded to an amino group can be referred to herein as an "aminated" moiety; for example, an aminated mescaline derivative is a mescaline derivative bearing an amino group.

[0117] The term "oxo group," as used herein, refers to a =0 group, which can be formed, for example, by replacing two hydrogens bonded to the same carbon atom with =0.

[0118] The term "carbonyl group" as used herein refers to a C=O group, which can be formed by replacing two hydrogens bonded to the same carbon atom with =O.

[0119] The term "oxirane" as used herein refers to a three-membered oxygen containing heterocycle having the following chemical formula: [ka]

[0120] The terms "halogen," "halogen group," "halo-," and "halogenated," as used herein, refer to a class of chemical elements consisting of fluorine (F), chlorine (Cl), bromine (Br), and iodine (I). Thus, a halogenated compound can refer to a "fluorinated," "chlorinated," "brominated," or "iodinated" compound.

[0121] The term "alkyl group" as used herein means a group of the formula -C n H 2n+1 The alkyl group (including O-alkyl, and alkyl groups present in acyl and O-acyl) in any of the embodiments of the present disclosure may be C1-C 20 In another embodiment, the alkyl group is C-C 10In another embodiment, the alkyl group is C1-C6-alkyl. In another embodiment, the alkyl group is methyl, ethyl, propyl, butyl or pentyl.

[0122] The terms "O-alkyl group" and "alkoxy group" are used interchangeably herein and have the formula -OC n H 2n+1 represents a hydrocarbon group arranged in a chain having the formula: O-alkyl groups include, but are not limited to, O-methyl groups (-O-CH) (i.e., methoxy), O-ethyl groups (-O-C) (i.e., ethoxy), O-propyl groups (-O-C) (i.e., propoxy), and O-butyl groups (-O-C) (i.e., butoxy).

[0123] The term "N-alkyl group" as used herein refers to a group of the formula -NC n H 2n+1 N-alkyl groups include, but are not limited to, N-methyl (-N-CH), N-ethyl (-N-C2H5), N-propyl (-N-C3H7), and N-butyl (-N-C4H9) groups.

[0124] The term "hydroxylalkyl" as used herein refers to a hydrocarbon radical arranged in a linear chain, substituted with at least one hydroxy group (chemical formula -C n H 2n The term "hydroxyl alkyl" refers to a hydrocarbon group arranged in a branched chain (including a straight chain having OH) or branched chain substituted with at least one hydroxy group. In the chemical formula shown, depending on the carbon chain, the length-specific hydroxyl alkyl group may be referred to as a methanol group (n=1) or hydroxymethyl, an ethanol group (n=2) or hydroxyethyl, a propanol group (n=3) or hydroxypropyl, a butanol group (n=4) or hydroxybutyl, etc. Further examples of hydroxyl alkyl include hydrocarbon groups having the formula: [ka] In the formula, Y1 and Y2 are each simultaneously or independently a hydrogen atom or an alkyl group (e.g., -CH3, -CH2-CH3).

[0125] The term "acyl group," as used herein, refers to a carbon atom double-bonded to oxygen and single-bonded to an alkyl group. The carbon atom can be further bonded to another moiety. An acyl group has the chemical formula: -C(=O)-C n H 2n+1 , for example, (C1-C6)-acyl, (C1-C3)-acyl, etc. Furthermore, depending on the carbon chain, length-specific acyl groups may be referred to as formyl (n=0), acetyl (n=1), propionyl (n=2), butyryl (n=3), pentanoyl (n=4), etc.

[0126] The term "O-acyl group," as used herein, refers to an acyl group in which a carbon atom is single-bonded to an additional oxygen atom. The additional oxygen atom can be bonded to another moiety. An O-acyl group has the chemical formula: -OC(=O)-C n H 2n+1 , for example, -O-(C1-C6)-acyl, -O-(C1-C3)-acyl, etc. Furthermore, depending on the carbon chain, length-specific O-acyl groups may be referred to as O-formyl groups (n=0), O-acetyl groups (n=1), O-propionyl groups (n=2), O-butyryl groups (n=3), O-pentanoyl groups (n=4), etc.

[0127] The term "alkylene" is used herein to refer to a divalent alkyl group.

[0128] The term "hetero" as used herein (e.g., "heterocycle," "heterocyclic," "heterocyclic group") refers to a saturated or partially saturated or aromatic cyclic group in which one or two ring atoms are heteroatoms selected from N, O, or S, and the remaining ring atoms are C. For example, a ring containing one or two heteroatoms selected from O, S, or N (C-C 20 ), (C3-C 10 ), and (C3-C6) cyclic groups.

[0129] The term "aryl group" as used herein refers to an aromatic ring compound in which at least one hydrogen atom has been removed from the aromatic ring, allowing for bonding to another moiety of a carbon atom within the aromatic ring. An aryl group is an optionally substituted C-C 14 -aryl. The aryl group may further be optionally substituted C-C 10 -aryl, or phenyl. Further aryl groups include phenyl, naphthyl, tetrahydronaphthyl, phenanthrenyl, biphenylenyl, indanyl, or indenyl.

[0130] The term "alkyl-aryl," as used herein, refers to an alkylene group substituted with an aryl group.

[0131] The term "receptor" as used herein refers to a protein that resides on the surface of a cell or within a cell without being bound to the cell surface (e.g., a soluble receptor) and that can mediate signal transduction to and / or from or within the cell, thereby affecting cellular physiology. Receptors are divided into classes, e.g., G protein-coupled receptors ("GPCRs"), families, e.g., 5-HT receptors, and subfamilies, e.g., 5-HT 1A Receptor, 5-HT 2A receptors, and 5-HT 2BIn this regard, "signal transduction" refers to a response in the form of a series of chemical reactions that can occur when a molecule, including, for example, the fused heterocyclic mescaline derivatives disclosed herein, interacts with a receptor. Signal transduction generally proceeds across the cell membrane and / or within the cell to reach a target molecule or chemical reaction, resulting in a modulation in cellular physiology. Thus, signal transduction can be considered a transduction process, whereby molecules that interact with receptors can modulate cellular physiology, and further, signal transduction can be a process by which molecules inside the cell can be regulated by molecules outside the cell. Signal transduction and the interaction between molecules and receptors, for example, affinity, binding efficiency, and kinetics, can be measured using various assays, for example, receptor binding assays (e.g., radioligand binding assays), for example, [ 3 [H]ketanserin assay is a method for detecting 5-HT receptor 2A These assays can be used to assess receptor activity, such as competitive assays, and saturation binding assays.

[0132] The term "G protein-coupled receptor" or "GPCR" refers herein to a class of evolutionarily related transmembrane receptors that can interact with a class of proteins known as G-proteins (guanine nucleotide-binding proteins). GPCRs can mediate cellular responses to external stimuli (Weis and Kobilka, 2018, Annual Review of Biochemistry 87:897-919) and can be activated by interacting with a ligand, e.g., a neurotransmitter such as serotonin or dopamine, which can then initiate receptor interaction with a G-protein and induce dissociation of the G-protein into α and βγ subunits. These α and βγ subunits can then further mediate downstream signal transduction. GPCRs can also activate other signaling pathways, e.g., via arrestin proteins and kinases. Certain ligands can preferentially activate a subset of all GPCR signaling pathways. Signaling pathways downstream of GPCRs can mediate therapeutic effects or cause adverse drug effects (Bock and Bermudez, 2021, FEBS Journal 288:2513-2528).

[0133] The term "5-HT receptor" as used herein refers to a family of GPCR receptors found in the central and peripheral nervous system, and includes subfamilies, e.g., 5-HT 1A Receptor, 5-HT 2A receptors, and 5-HT 2B The 5-HT receptor binds to specific G-proteins, such as Gα i , Gα q / 11 , and Gα s5-HT receptors can mediate signal transduction through 5-HT receptors, and can be involved in the control of multiple physiological processes, including, for example, cognition, mood, and sleep-wake cycle regulation (McCorvy and Roth, 2015, Pharmacology and Therapeutics 150:129-142). 5-HT receptors can also mediate signal transduction through arrestin and G-protein-independent signal pathways. 5-HT receptors are involved in multiple cranial nerve disorders, including migraine and neuropsychiatric disorders, such as schizophrenia and depression.

[0134] "5-HT 1A The term "receptor" is used herein to refer to a subfamily of the family of receptors for the neurotransmitter and peripheral signal mediator serotonin. 1A The 5-HT receptor can mediate multiple central and peripheral physiological functions of serotonin. 1A Although ligand activity at 5-HT is not generally associated with hallucinations, many hallucinogenic compounds have been shown to activate 5-HT receptors. 1A It is known to modulate 5-HT receptors and induce physiological responses (Inserra et al., 2020, Pharmacol. Rev 73:202). 1A The receptor is involved in a variety of neurological disorders, including depression and anxiety, schizophrenia, and Parkinson's disease (Behav. Pharm. 2015, 26:45-58).

[0135] "5-HT 2A The term "receptor" is used herein to refer to a subfamily of the family of receptors for the neurotransmitter and peripheral signal mediator serotonin. 2A The 5-HT receptor can mediate multiple central and peripheral physiological functions of serotonin. Central nervous system actions can include mediating the hallucinogenic effects of hallucinogenic compounds. 2A The receptor is involved in various cranial nerve disorders (Nat.Rev.DrugDisov.2022,21:463-473;Science 2022,375:403-411).

[0136] "5-HT 2B The term "5-HT receptor" (also referred to herein as "HT2B" and "HTR2B"), as used herein, refers to a subfamily of the family of receptors for the neurotransmitter and peripheral signal mediator serotonin. 2B The 5-HT receptor can mediate multiple central and peripheral physiological functions of serotonin. Central nervous system actions can include mediating the hallucinogenic effects of hallucinogenic compounds. 2B The receptor is involved in various cranial nerve disorders, such as schizophrenia (Pharmacol. Ther. 2018, 181:143-155) and migraine (Cephalalgia 2017, 37:365-371).

[0137] "5-HT 2C The term "5-HT2C receptor" (also referred to herein as "HT2C" and "HTR2C"), as used herein, refers to a subfamily of the family of receptors for the neurotransmitter and peripheral signal mediator serotonin. 2C Antagonism of 5-HT receptors can increase the availability of norepinephrine and dopamine in the prefrontal cortex, leading to antidepressant and nootropic effects (Savino et al., 2023, Brain Science 13:734). 2C The receptor may play a role in food intake and weight control (Przegalinski et al., 2023, Nutrients 15:1449).

[0138] The term "5-HT7 receptor" (also referred to herein as "HT7" and "HTR7"), as used herein, refers to a subfamily of the family of receptors for the neurotransmitter and peripheral signal mediator serotonin. 1DThe receptor is involved in various neurological disorders, including Alzheimer's disease, dementia, and related depressive disorders (Quintero-Villegas and Valdes-Ferrer, 2022, Molecular Medicine 28:70).

[0139] "α 2A The term "α-2A receptor" (also referred to herein as "α-2A" and "alpha 2A") refers to a subfamily of the family of receptors for catecholamine neurotransmitters and signal mediators, such as norepinephrine (noradrenaline) and epinephrine (adrenaline). α-2A receptors are involved in various neurological disorders, including schizophrenia, bipolar disorder, and post-traumatic stress disorder (PTSD) (Saggu et al., 2023, Molecular Psychiatry 28:588-600).

[0140] The term "MT1 receptor" (also referred to herein as "MT1") refers to a subfamily of receptors for the neurotransmitter and signal mediator melatonin. MT1 receptors are involved in various neurological disorders, including sleep disorders and depression (Boiko et al., 2022, Neurochemical Research 47:2909-2924).

[0141] The term "D3 receptor" (also referred to herein as "D3") refers to a subfamily of receptors for the neurotransmitter and signal mediator dopamine. D3 receptors are involved in various neurological disorders, including schizophrenia, drug addiction, and Parkinson's disease (Kim, 2023, International Journal of Molecular Sciences 24:6742).

[0142] The term "DAT" as used herein refers to a transmembrane transport protein, also known as the "dopamine active transporter," which is involved in the transport of dopamine into the cytosol. DAT is involved in various cranial nerve disorders, particularly dopamine-related disorders, such as attention deficit hyperactivity disorder (ADHD), bipolar disorder, and clinical depression and anxiety (Am. J. Med. Genet. B Neuropsychiatr. Genet. 2018, 177: 211-231).

[0143] The term "NET" as used herein refers to a transmembrane transport protein, also known as the "norepinephrine transporter" or "noradrenaline transporter" or "NAT," which transports extracellular norepinephrine or noradrenaline to Na + / Cl - NETs are involved in dependent reuptake and are involved in various neurological disorders, including attention deficit hyperactivity disorder (ADHD) and clinical depression (Neurosci. Biobehav. Rev, 2013, 37:1786-800).

[0144] The term "SERT" as used herein refers to a transmembrane transport protein, also known as the "serotonin transporter," which is involved in neuronal serotonin transport, particularly from the synaptic cleft back to the presynaptic neuron, thereby terminating the action of serotonin. SERT is involved in various cranial neurological disorders, including anxiety and depression (Pharmacol. Rep. 2018, 70:37-46).

[0145] The term "modulate a receptor," as used herein, refers to the ability of a compound disclosed herein to alter receptor function. A receptor modulator can activate or inhibit receptor activity, depending on the concentration of compound exposed to the receptor. Such activation or inhibition may be conditional on the occurrence of a specific event, e.g., activation of a signal transduction pathway, and / or may only occur in specific cell types. The term "modulate a receptor" also refers to altering receptor function by increasing or decreasing the likelihood of complex formation and multimerization between the receptor and a natural binding partner. A receptor modulator can increase the likelihood of such a complex forming between the receptor and a natural binding partner, and can increase or decrease the likelihood of complex formation between the receptor and a natural binding partner, depending on the concentration of compound exposed to the receptor, and / or can decrease the likelihood of complex formation between the receptor and a natural binding partner. It has further been shown that the disclosed fused heterocyclic mescaline derivatives can alter receptor function by acting as agonists or antagonists of the receptor, and that the disclosed fused heterocyclic mescaline derivatives can alter receptor function by directly interacting with or binding to the receptor, or indirectly interacting with the receptor through one or more other molecular moieties. Generally, the receptor can be any receptor, including any of the receptors specified herein, for example, 5-HT 1A , 5-HT 2A , 5-HT 2B , 5-HT 2C , 5-HT7, α 2A Thus, to refer to modulating a particular receptor, for example, "5-HT 1A receptors," "5-HT 2A receptors," "5-HT 2B It will be clear that terms such as "modulate a receptor" and "modulate a receptor" may be used herein.

[0146] The term "receptor-mediated disorder" as used herein refers to a disorder characterized by abnormal receptor activity. Receptor-mediated disorders can be mediated completely or partially by modulating the receptor. In particular, receptor-mediated disorders are those in which modulation of the receptor results in some effect on the underlying disease, e.g., administration of a receptor modulator results in some improvement in at least some of the treated subjects. Generally, the receptor can be any receptor, including any of the receptors specified herein, e.g., 5-HT 1A , 5-HT 2A , 5-HT 2B , 5-HT 2C , 5-HT7, α 2A , D3, or MT1 receptors. Thus, to refer to a particular receptor-mediated disorder, one might use, for example, "5-HT 1A receptor-mediated disorders," "5-HT 2A receptor-mediated disorders," "5-HT 2B It will be clear that terms such as "receptor-mediated disorder" may be used.

[0147] The term "pharmaceutical formulation" as used herein refers to a preparation in a form that enables the active ingredients, including psychoactive ingredients, contained therein to provide effective therapy and that does not contain other ingredients that cause excessive toxicity, allergic response, irritation, or other adverse reactions that are commensurate with a reasonable risk / benefit ratio. Pharmaceutical formulations may also contain other pharmaceutical ingredients, such as excipients, carriers, diluents, or adjuvants.

[0148] The term "recreational drug formulation" as used herein refers to a preparation in a form that renders the psychoactive ingredients contained therein effective for recreational administration and that does not contain other ingredients that cause excessive toxicity, allergic response, irritation, or other adverse reactions that are commensurate with a reasonable risk / benefit ratio. Recreational drug formulations may also contain other ingredients, such as excipients, carriers, diluents, or adjuvants.

[0149] The term "effective for administration as a recreational drug" as used herein refers to a preparation in a form that, when administered, generally in the form of self-administration, enables a subject to spontaneously induce psychoactive effects for non-medical purposes. Effects may include altered states of consciousness, gratification, pleasure, euphoria, altered perceptions, or hallucinations.

[0150] The term "effective amount," as used herein, refers to an amount of an active agent, pharmaceutical preparation, or recreational drug preparation sufficient to induce a desired biological or therapeutic effect, including a prophylactic effect and further including a psychoactive effect. Such effects may include effects on the signs, symptoms, or causes of a disorder or disease, or any other desired alteration of a biological system. An effective amount may vary depending, for example, on the health status, stage of injury, disorder, or disease, weight, or sex of the subject being treated, timing of administration, mode of administration, age of the subject, etc., all of which can be determined by one of ordinary skill in the art.

[0151] The terms "treating" and "treatment," etc., as used herein, are intended to mean obtaining a desired physiological, pharmacological, or biological effect, and include prophylactic and therapeutic treatments. The effect may result in the inhibition, attenuation, amelioration, or reversal of the signs, symptoms, or causes of a disorder or disease, including psychological and psychiatric disorders and disorders. Clinical evidence of prevention or treatment may vary with the disorder or disease, the subject, and the treatment selected.

[0152] The term "pharmaceutically acceptable" as used herein refers to a material, including an excipient, carrier, diluent, or adjuvant, that is compatible with other materials in a pharmaceutical or recreational drug formulation, is suitable for use in contact with a subject, within the bounds of reasonable medical judgment, and is free of excessive toxicity, allergic response, irritation, or other adverse reactions commensurate with a reasonable risk / benefit ratio.

[0153] The term "substantially free," as used herein to describe a composition, indicates that a composition comprising a first compound is substantially free of a second compound. Preferably, a composition comprising a first compound comprises less than 5%, less than 2.5%, less than 1%, less than 0.5%, less than 0.1%, or less than 0.01% by mole of the second compound.

[0154] The terms "substantially pure" and "isolated" are used interchangeably herein to describe a compound, e.g., a mescaline derivative, that has been separated from components that naturally accompany it. Typically, a compound is substantially pure when at least 60%, more preferably at least 75%, more preferably at least 90%, 95%, 96%, 97%, or 98%, and most preferably at least 99% (by volume, wet or dry weight, or by mole percent or mole fraction) of the total material in a sample is the compound of interest. Purity can be measured by any appropriate method, e.g., in the case of polypeptides, by chromatography, gel electrophoresis, or HPLC analysis.

[0155] General Practice As mentioned above, the present disclosure relates to mescaline derivatives. In particular, the present disclosure provides novel heterocyclic mescaline derivatives, in which a phenyl moiety participates in forming a heterocyclic structure, and in example embodiments, a dioxolane ring fused to the phenyl moiety is included. Thus, the compounds of the present disclosure can be referred to as fused heterocyclic mescaline derivatives. Furthermore, the mescaline derivatives contain an N-propylamine chain (rather than an ethylamine chain as in mescaline). The N-propylamine chain can contain various substituents, particularly C2 and / or C3 substituents. In addition, the amine group in the N-propylamine chain can be substituted. Thus, the mescaline derivatives disclosed herein can be referred to as N-propylamine-fused heterocyclic mescaline derivatives. In general, the novel compounds provided herein exhibit functional properties that deviate from those of mescaline. Thus, for example, the mescaline derivatives of the present disclosure can exhibit pharmacological properties that deviate from those of mescaline. Furthermore, the mescaline derivatives can exhibit physicochemical properties that differ from those of mescaline. Thus, for example, fused heterocyclic mescaline derivatives can exhibit excellent solubility in solvents, such as aqueous solvents. In this regard, fused heterocyclic mescaline derivatives are useful in formulating pharmaceutical and recreational drug formulations. In one embodiment, the fused heterocyclic mescaline derivatives of the present disclosure can be conveniently chemically synthesized. This method avoids the need to extract mescaline from cactus plants and perform subsequent chemical reactions to obtain the fused heterocyclic mescaline derivatives. Furthermore, the propagation of cactus plants can be avoided, thereby limiting dependence on climate and weather, as well as potential legal and social issues associated with the cultivation of cactus plants containing psychoactive compounds. The method can efficiently obtain substantial amounts of fused heterocyclic mescaline derivatives.

[0156] In the following, selected embodiments are described with reference to the drawings.

[0157] First, exemplary fused heterocycle mescaline derivatives are described, followed by exemplary methods of using and preparing the fused heterocycle mescaline derivatives.

[0158] Thus, in one aspect, the present disclosure provides derivatives of the compound known as mescaline, the chemical structure of which is shown in Figure 1. The derivatives provided herein are, in particular, fused heterocycle derivatives of mescaline. In this regard, the term "fused heterocycle" is intended to refer to derivatives in which a heterocycle is bonded to two adjacent carbon atoms in the phenyl ring of mescaline. Similarly, the term "fused dioxolane" refers to derivatives in which a dioxolane is bonded to two adjacent carbon atoms in the phenyl ring of mescaline. Additionally, the derivatives are N-propylamine mescaline derivatives. In this regard, with reference to Figure 2, "N-propylamine" refers to mescaline derivatives comprising an N-propylamine chain, and in particular, in example embodiments, the C2 and / or C3 atoms of the N-propylamine chain are specifically substituted with one or more substituents.

[0159] Thus, in one aspect, the present disclosure provides, in accordance with the teachings herein, in at least one embodiment, a chemical compound having the chemical formula (I) or (II): [ka] In formula (I) or (II): [ka] is a single or double bond; X1, X2, and X3 are independently selected from a hydrogen atom, O-alkyl, acyl, N-alkyl, OH, halogen, or NH2; X4 is an alkylene group or a substituted alkylene group; R1 is hydrogen, an alkyl group, or an oxo group; R1 is R 1b , the carbon atom to which R1 is attached and R 1b together with the nitrogen atom to which it is attached form an optionally substituted saturated or unsaturated 3- to 10-membered heterocyclic ring, and when the heterocyclic ring is unsaturated, R 1a is optional and non-existent; R1a and R 1b are each independently selected from an alkyl group, a hydroxylalkyl group, an optionally substituted alkyl-aryl group, or a hydrogen atom; or R 1a and R 1b taken together with the nitrogen atom to which they are attached form a 3- to 10-membered optionally substituted heterocycle; and R2 and R3 are each independently selected from an alkyl group, an O-alkyl group, a hydrogen atom, or R2 and R3 taken together with the oxygen atom and the carbon atom to which they are attached form an oxirane ring.

[0160] In one embodiment, the chemical compound having formula (I) is a ) or (I b The compound having formula (II) can be a compound having formula (II a ) or (II b ) can be a compound having: [ka] In formula (Ia), (Ib), (IIa), or (IIb): X1, X2, and X3 are independently selected from a hydrogen atom, O-alkyl, acyl, N-alkyl, OH, halogen, or NH2; X4 is an alkylene group or a substituted alkylene group; R1 is hydrogen, an alkyl group, or an oxo group; R1 is R 1b , the carbon atom to which R1 is attached and R 1b together with the nitrogen atom to which it is attached form an optionally substituted saturated or unsaturated 3- to 10-membered heterocyclic ring, and when the heterocyclic ring is unsaturated, R 1a is optional and non-existent; R 1a and R 1b are each independently selected from an alkyl group, a hydroxylalkyl group, an optionally substituted alkyl-aryl group, or a hydrogen atom; or R 1a and R 1btaken together with the nitrogen atom to which they are attached form a 3- to 10-membered optionally substituted heterocycle; and R2 and R3 are each independently selected from an alkyl group, an O-alkyl group, a hydrogen atom, or R2 and R3 taken together with the oxygen atom and the carbon atom to which they are attached form an oxirane ring.

[0161] Therefore, the formula (I a ), (I b ), (II a ), and (II b ), X1, X2, and X3 can be independently selected from a hydrogen atom, an O-alkyl, an N-alkyl, an acyl, OH, a halogen, or NH2. In an example embodiment, X1, X2, and X3 can each independently be selected from a hydrogen atom, an O-alkyl (e.g., O—(C1-C 10 )-alkyl, O-(C1-C6)-alkyl, or O-(C1-C3)-alkyl (methoxy, ethoxy, propoxy)), acyl (e.g., -(C=O)(C1-C6)-acyl, -(C=O)(C1-C3)-acyl) N-alkyl (e.g., N-(C1-C 10)-alkyl, N-(C1-C6)-alkyl, or N-(C1-C3)-alkyl), OH, halogen (C, F, Cl, I), or NH2. In further example embodiments, all three of X1, X2, and X3 can be the same substituent. In further example embodiments, all three of X1, X2, and X3 can be the same O-alkyl group (e.g., methoxy, ethoxy), non-identical O-alkyl groups, or partially identical O-alkyl groups (i.e., two identical O-alkyl groups, one non-identical O-alkyl group); identical N-alkyl groups, non-identical N-alkyl groups, or partially identical N-alkyl groups (i.e., two identical N-alkyl groups, one non-identical N-alkyl group); identical; or identical, non-identical, or partially identical halogens (i.e., two identical halogens, one non-identical halogen). In further example embodiments, two of X1, X2, and X3 can be the same substituent. In yet additional example embodiments, all three of X1, X2, and X3 can be non-identical substituents.

[0162] Turning to X4, we further consider the formula (I a ), (I b ), (II a ), and (II b ), X4 can be an alkylene group or a substituted alkylene group. In one example embodiment, X4 can be an unsubstituted alkylene, such as (C1-C 10 )-alkylene, (C1-C6)-alkylene, or (C1-C3)-alkylene (methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-)).

[0163] In one example embodiment, X4 can be a substituted alkylene, for example, (C1-C 10) substituted alkylene, (C1-C6) substituted alkylene or (C1-C3) substituted alkylene (substituted methylene (e.g., -CHR-, where R is a substituent), substituted ethylene (e.g., -CHRCH2-, where R is a substituent), substituted propylene (e.g., -CH2CHRCH2-, where R is a substituent). Substituents include, for example, oxo groups (forming carbonyl), hydroxy, halogens (F, Cl, Br, I), O-alkyl (e.g., O-(C1-C 10 )-alkyl, O—(C1-C6)-alkyl, or —O—(C1-C3)-alkyl), N-alkyl (e.g., N—(C1-C 10 )-alkyl, N-(C1-C6)-alkyl, or N-(C1-C3)-alkyl), acyl (e.g., (C1-C 10 )-acyl, (C1-C6)-acyl, or (C1-C3)-acyl), O-acyl (e.g., O-(C1-C 10 )-acyl, O-(C1-C6)-acyl, or O-(C1-C3)-acyl)aryl (e.g., C6-C 10 Aryl, e.g., phenyl, naphthyl), and alkyl-aryl groups (e.g., (C-C 10 (C-C)-alkyl-aryl, (C-C)-alkyl-aryl, or (C-C)-alkyl-aryl). Further included are mono- and poly-substituted alkylenes. Poly-substituted alkylenes include substitution of the same alkylene carbon atom (thus a halogen substituent may be, for example, -CHCF- or -CF-) or of different carbon atoms (e.g., -CHF-CHF-).

[0164] In one example embodiment, X4 can be unsubstituted alkylene, particularly (methylene (-CH2-)), and has the formula (I a ), (I b ), (II a ), and (II b ) are compounds having the chemical formula (I c ), (I d ), (II c ), and (II d ) can have: [ka]

[0165] As previously set forth herein, the present disclosure, in one aspect, provides, among other things, substituted N-propylamine chains, particularly in example embodiments, substituted C2 and / or C3 carbon atoms (—CHR2—CHR3—) (formula (I) a ), (II a ), (I c ), and (II c ) or (-CR2=CR3-) (formula (I b ), (II b ), (I d ) and (II d )) and R2 and / or R3 are substituents.

[0166] Further exemplary embodiments of mescaline derivatives containing N-propylamine chains are now described with reference to selected examples of R2 and R3 substituents contained in the N-propylamine chain. a ), (I b ), (II a ), and (II b Referring to formula (I), R2 and R3 can each independently be selected from an alkyl group, an O-alkyl group, or a hydrogen atom. a ), (I b ), (II a ), and (II b ), and formula (I c ), (I d ), (II c ) and (II d ), in certain example embodiments, X, X, and X can each be selected to be H, as shown herein by example compounds A(I)-C(III); C(VI)-C(XII); D(I)-F(III), and G(I)-G(IV). These example embodiments are intended to be included with, but not limited to, the example embodiments described hereinafter with respect to R and R.

[0167] Thus, for example, the compound of formula (I a ), (I b ), (II a ), (II b ), (I c ), (I d ), (II c ), and (II d ), in one example embodiment, R2 and R3 can each independently be selected from an alkyl group, an O-alkyl group, or a hydrogen atom.

[0168] Subsequently, the formula (I a ), (I b ), (II a ), (II b ), (I c ), (I d ), (II c ), and (II d ), in one example embodiment, R2 and R3 can each be a (C1-C6)-alkyl group, a (C1-C3)-alkyl group, or a methyl group.

[0169] Subsequently, the formula (I a ), (I b ), (II a ), (II b ), (I c ), (I d ), (II c ), and (II d ), in one example embodiment, R2 can be a (C1-C6)-alkyl group, a (C1-C3)-alkyl group, or a methyl group, and R3 can be a hydrogen atom.

[0170] Subsequently, the formula (I a ), (I b ), (II a ), (II b ), (I c ), (I d ), (II c ), and (II d), in one example embodiment, R3 can be a (C1-C6)-alkyl group, a (C1-C3)-alkyl group, or a methyl group, and R2 can be a hydrogen atom.

[0171] Subsequently, the formula (I a ), (I b ), (II a ), (II b ), (I c ), (I d ), (II c ), and (II d ), in one example embodiment, R2 and R3 can each be a hydrogen atom.

[0172] Subsequently, the formula (I a ), (I b ), (II a ), (II b ), (I c ), (I d ), (II c ), and (II d ), in one example embodiment, R2 can be a (C1-C6)-O-alkyl group, a (C1-C3)-O-alkyl group, or a methoxy group, and R3 can be a hydrogen atom.

[0173] Subsequently, the formula (I a ), (I b ), (II a ), (II b ), (I c ), (I d ), (II c ), and (II d ), in one example embodiment, R3 can be a (C1-C6)-O-alkyl group, a (C1-C3)-O-alkyl group, or a methoxy group, and R2 can be a hydrogen atom.

[0174] Subsequently, the formula (I a ), (I b ), (II a ), (II b ), (I c ), (I d), (II c ), and (II d ), in one example embodiment, R2 and R3 can be methoxy groups.

[0175] Formula (I a ), (II a ), (I c ), and (II c ), in one example embodiment, R2 and R3 can be taken together with an oxygen atom to form an oxirane.

[0176] Again, formula (I a ), (I b ), (II a ), (II b ), (I c ), (I d ), (II c ), and (II d ), in one example embodiment, R1 can be hydrogen, an alkyl group, for example, a (C1-C6) alkyl group, a (C1-C3) alkyl group, or a methyl group, or R1 can be an oxo group, or, continuing with formula (I a ), (I b ), (II a ), (II b ), (I c ), (I d ), (II c ), and (II d ), in another example embodiment, R1 is R 1b , the carbon atom to which R1 is attached and R 1b can be taken together with the nitrogen atom to which it is attached to form a 3- to 10-membered heterocyclic ring, for example, a 5- or 6-membered ring. Furthermore, the heterocyclic ring can be optionally substituted or saturated or unsaturated, and when the heterocyclic ring is unsaturated, R 1a can optionally be absent.

[0177] Again, formula (I a ), (I b ), (II a ), (II b ), (Ic ), (I d ), (II c ), and (II d ), in one example embodiment, R 1a can be a hydrogen atom, and R 1b can be a (C1-C6)-alkyl group.

[0178] Subsequently, the formula (I a ), (I b ), (II a ), (II b ), (I c ), (I d ), (II c ), and (II d ), in one example embodiment, R 1a and R 1b can each be a (C1-C6)-alkyl group or a (C1-C3)-alkyl group.

[0179] Subsequently, the formula (I a ), (I b ), (II a ), (II b ), (I c ), (I d ), (II c ), and (II d ), in one example embodiment, R 1a can be a hydrogen atom, and R 1b can be a hydroxyl alkyl group, such as a hydroxyl-(C1-C6)-alkyl group, or a hydroxyl-(C1-C3)-alkyl group, or -CH2-CH2-CH2OH, -CH2-CH2OH, or -CH2OH, or in other embodiments, a hydroxyl alkyl group having the formula: [ka] In the formula, Y1 and Y2 are each simultaneously or independently a hydrogen atom or an alkyl group (e.g., -CH3, -CH2-CH3, or -CH2-CH2-CH3).

[0180] Subsequently, the formula (I a ), (I b ), (II a ), (II b ), (I c ), (I d ), (II c ), and (II d ), in one example embodiment, R 1a can be a hydrogen atom, and R 1b may be an alkyl-aryl group, for example a (C1-C6)-alkyl-aryl group, such as a (C1-C6)-alkyl-phenyl group (e.g., (CH2)-phenyl), or a (C1-C3)-alkyl-aryl group, for example a (C1-C3)-alkyl-phenyl group.

[0181] Subsequently, the formula (I a ), (I b ), (II a ), (II b ), (I c ), (I d ), (II c ), and (II d ), in one example embodiment, R 1a and R 1b can each independently be selected from an alkyl group, a hydroxylalkyl group, an optionally substituted alkyl-aryl group, or a hydrogen atom, such as compounds having the formula (A); (B); (C); (D); (E); (F); or (G) (described further below), where R 1a and R 1b is selected in this way.

[0182] Subsequently, the formula (I a ), (I b ), (II a ), (II b ), (I c ), (I d ), (II c ), and (II d ), in one example embodiment, R 1a and R 1bcan be taken together with the nitrogen atom to which they are attached to form a 3-10 membered optionally substituted heterocycle, which heterocycle further contains an oxygen atom.

[0183] Subsequently, the formula (I a ), (I b ), (II a ), (II b ), (I c ), (I d ), (II c ), and (II d ), in one example embodiment, R 1a and R 1b can be taken together with the nitrogen atom to which they are attached to form a 3-10 membered, e.g., 5- or 6-membered, optionally substituted heterocycle, wherein the heterocycle further comprises an oxygen atom, and the heterocycle is further substituted with at least one (C-C)-alkyl group, e.g., at least one methyl group, or at least two methyl groups, and the (C-C)-alkyl group may be two substituents on a single (i.e., the same) heterocycle carbon atom, or two or more substituents on two or more different heterocycle carbon atoms.

[0184] Subsequently, the formula (I a ), (I b ), (II a ), (II b ), (I c ), (I d ), (II c ), and (II d ), in one example embodiment, R1 is R 1b and R can be taken together to form an optionally substituted saturated or unsaturated 3- to 10-membered ring, e.g., a 5- or 6-membered heterocycle, which contains an oxygen atom along with the nitrogen atom and can be optionally substituted with at least two alkyl groups, e.g., methyl groups, where the alkyl groups are substituents on the same heterocycle carbon atom. The 3- to 10-membered heterocycle can be saturated or partially saturated, and when the heterocycle is unsaturated, R 1a can optionally be absent.

[0185] In some embodiments, R is R 1b and together with R form an optionally substituted saturated or unsaturated 3- to 10-membered ring, and when the heterocycle is unsaturated, R 1a may be absent, especially when the heterocycle is unsaturated and the nitrogen participates in the formation of an unsaturated bond, R 1a can not exist.

[0186] In a further embodiment, the compound of formula (I), (II), (I a ), (I b ), (II a ), (II b ), (I c ), (I d ), (II c ), and (II d The amino group (-NR 1a R 1b ) is protonated, and (-N + HR 1a R 1b ) and can form chemical formula (I), (II), (I a ), (I b ), (II a ), (II b ), (I c ), (I d ), (II c ), and (II d ) has a negatively charged anion, such as sulfate (SO4 2- ), nitrate ions (NO3 - ), or chloride ions (Cl - ) further includes.

[0187] Next, to further illustrate the mescaline derivative compounds provided by the present disclosure, exemplary compounds according to Formulas (I) and (II) are provided. These include compounds having the following formulae: (A); (B); (C); (D); (E); (F); and (G), as well as compounds having the following formulae: A(I)-A(III); B(I)-(V); C(I)-C(XIII); D(I)-D(III); E(I)-E(V); F(I)-F(VI); and G(I)-G(V).

[0188] Thus, the present disclosure, in one aspect, provides exemplary compounds having the formulas (A); (B); (C); (D); (E); (F); and (G): [ka] In formula (B), X 4a and X 4b are independently or simultaneously a halogen or a hydrogen atom, and R in formulas (A), (B), (C), (D), (E), and (F) 1a and R 1b are independently selected from an alkyl group, an optionally substituted alkyl-aryl group, or a hydrogen atom, or R in formulas (A), (B), (C), (D), (E), and (F). 1a and R 1b taken together with the nitrogen atom to which they are attached form a 3- to 10-membered optionally substituted heterocycle; R2 in formulas (C), (F) and (G), and Y1 and Y2 in (G) are alkyl groups or hydrogen atoms; and X3 in formulae (C), (F) and (G) is a halogen, an O-alkyl group or a hydrogen atom.

[0189] The disclosure further provides, in one aspect, example compounds A(I)-A(III): [ka] In each of compounds A(I)-A(III), optionally, the nitrogen atom of the N-propylamine moiety is protonated, and A(I)-A(III) contain a negatively charged anion that balances the positively charged nitrogen atom.

[0190] In another aspect, the present disclosure provides example compounds B(I)-B(V): [ka] In each of compounds B(I)-B(V), optionally, the nitrogen atom of the N-propylamine moiety is protonated, and B(I)-B(V) contain a negatively charged anion that balances the positively charged nitrogen atom.

[0191] In another aspect, the present disclosure provides example compounds C(I)-C(XIII): [ka] In each of compounds C(I)-C(XIII), optionally, the nitrogen atom of the N-propylamine moiety is protonated, and C(I)-C(XIII) contain a negatively charged anion that balances the positively charged nitrogen atom.

[0192] In another aspect, the disclosure provides example compounds D(I)-D(III): [ka] In each of compounds D(I)-D(III), optionally, the nitrogen atom of the N-propylamine moiety is protonated, and D(I)-D(III) contain a negatively charged anion that balances the positively charged nitrogen atom.

[0193] In another aspect, the disclosure provides example compounds E(I)-E(V): [ka] In each of compounds E(I)-E(V), optionally, the nitrogen atom of the N-propylamine moiety is protonated, and E(I)-E(V) contain a negatively charged anion that balances the positively charged nitrogen atom.

[0194] In another aspect, the present disclosure provides exemplary compounds F(I)-F(VI): [ka] In each of compounds F(I)-F(VI), optionally, the nitrogen atom of the N-propylamine moiety is protonated, and F(I)-F(VI) contain a negatively charged anion that balances the positively charged nitrogen atom.

[0195] In another aspect, the disclosure provides example compounds G(I)-G(V): [ka] In each of compounds G(I)-G(V), optionally, the nitrogen atom of the N-propylamine moiety is protonated, and G(I)-G(V) contain a negatively charged anion that balances the positively charged nitrogen atom.

[0196] Examples of the negatively charged anion in each of the above include chloride, nitrate, and sulfate ions.

[0197] In one embodiment, the compound can be a stereoisomeric compound corresponding to a chemical compound having formula A(I), A(II), A(III), C(VII), C(IX), C(XI), F(II), G(II) or G(IV), wherein the C2 atom of the N-propylamine moiety of the chemical compound is a chiral carbon atom. Thus, for example, in one embodiment, the stereoisomeric compound can be a chemical compound having formula A(II a ) or A(II b ) can be selected from compounds having: [ka] Similarly, it will be understood that stereoisomeric compounds consistent with chemical compounds having formula A(I), A(III), C(VII), C(XI), F(II), G(II) or G(IV) (wherein the C2 atom of the N-propylamine portion of the chemical compound is a chiral carbon atom) may be selected and are included herein.

[0198] In one embodiment, the compound can be included in a mixture of a pair of stereoisomeric compounds, the mixture comprising a pair of stereoisomeric compounds. The mixture can contain various relative molar amounts of a first and corresponding second counterpart stereoisomeric compound (e.g., A(II)). a ) and A(II b )), for example, at least 10% (mol / mol) of a first stereoisomeric compound and 90% (mol / mol) of a second corresponding counterpart stereoisomeric compound, or 20% (mol / mol) of a first stereoisomeric compound and 80% (mol / mol) of a second corresponding counterpart stereoisomeric compound, or 30% (mol / mol) of a first stereoisomeric compound and 70% (mol / mol) of a second corresponding counterpart stereoisomeric compound, or 40% (mol / mol) of a first stereoisomeric compound and 60% (mol / mol) of a second corresponding counterpart stereoisomeric compound, or equimolar or approximately equimolar amounts of the first and second corresponding counterpart stereoisomeric compounds.

[0199] Thus, briefly summarized, in one aspect, the present disclosure provides novel chemical compounds, which are derivatives of mescaline, fused mescaline derivatives, and in one example embodiment, include fused dioxolane mescaline derivatives. The novel chemical compounds have the chemical formula (I) or (II): [ka] In formula (I) or (II): [ka] is a single or double bond; X1, X2, and X3 are independently selected from a hydrogen atom, O-alkyl, acyl, N-alkyl, OH, halogen, or NH2; X4 is an alkylene group or a substituted alkylene group; R1 is hydrogen, an alkyl group, or an oxo group; R1 is R 1b , the carbon atom to which R1 is attached and R 1btogether with the nitrogen atom to which it is attached form an optionally substituted saturated or unsaturated 3- to 10-membered heterocyclic ring, and when the heterocyclic ring is unsaturated, R 1a is optional and non-existent; R 1a and R 1b are each independently selected from an alkyl group, a hydroxylalkyl group, an optionally substituted alkyl-aryl group, or a hydrogen atom; or R 1a and R 1b taken together with the nitrogen atom to which they are attached form a 3- to 10-membered optionally substituted heterocycle; and R2 and R3 are each independently selected from an alkyl group, an O-alkyl group, a hydrogen atom, or R2 and R3 taken together with the oxygen atom and the carbon atom to which they are attached form an oxirane ring.

[0200] The condensed mescaline derivatives of the present disclosure can be used to prepare pharmaceutical or recreational drug formulations. Thus, in one embodiment, the present disclosure further provides, in another aspect, pharmaceutical and recreational drug formulations comprising the condensed mescaline derivatives. Thus, in one aspect, the present disclosure further provides, in a further embodiment, pharmaceutical or recreational drug formulations comprising a chemical compound selected from a first chemical compound having the chemical formula (I) and (II), together with a diluent, carrier, or excipient: [ka] In formula (I) or (II): [ka] is a single or double bond; X1, X2, and X3 are independently selected from a hydrogen atom, O-alkyl, acyl, N-alkyl, OH, halogen, or NH2; X4 is an alkylene group or a substituted alkylene group; R1 is hydrogen, an alkyl group, or an oxo group; R1 is R1b , the carbon atom to which R1 is attached and R 1b together with the nitrogen atom to which it is attached form an optionally substituted saturated or unsaturated 3- to 10-membered heterocyclic ring, and when the heterocyclic ring is unsaturated, R 1a is optional and non-existent; R 1a and R 1b are each independently selected from an alkyl group, a hydroxylalkyl group, an optionally substituted alkyl-aryl group, or a hydrogen atom; or R 1a and R 1b taken together with the nitrogen atom to which they are attached form a 3- to 10-membered optionally substituted heterocycle; and R2 and R3 are each independently selected from an alkyl group, an O-alkyl group, a hydrogen atom, or R2 and R3 taken together with the oxygen atom and the carbon atom to which they are attached form an oxirane ring.

[0201] Pharmaceutical or recreational drug formulations can be prepared as liquids, tablets, capsules, microcapsules, nanocapsules, transdermal patches, gels, foams, oils, aerosols, nanoparticles, powders, creams, emulsions, micelles, films, sprays, suppositories, infusions, teas, decoctions, suppositories, and the like, and may contain a pharmaceutically acceptable salt or solvate of a condensed mescaline derivative compound together with an excipient. The term "excipient," as used herein, refers to any material component other than the disclosed chemical compound. As those skilled in the art will readily recognize, the choice of excipient may depend on factors such as the particular method of administration, and the effect of the excipient on the solubility of the disclosed chemical compounds and their preparation methods will be readily apparent to those skilled in the art. Such compositions and methods for their preparation can be found, for example, in "Remington's Pharmaceutical Sciences," 22nd Edition (Pharmaceutical Press and Philadelphia College of Pharmacy at the University of the Sciences, 2012).

[0202] Pharmaceutical and drug formulations containing the disclosed condensed mescaline derivatives can be administered orally. Oral administration can involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration can be employed, so that the compound enters the bloodstream directly from the mouth. Formulations suitable for oral administration include both solid and liquid formulations.

[0203] Solid formulations include tablets, capsules (including particulates, liquids, microcapsules, or powders), lozenges (including liquid-filled lozenges), chews, multi- and nanoparticulates, gels, solid solutions, liposomal preparations, microencapsulated preparations, creams, films, pessaries, suppositories, and sprays.

[0204] Liquid preparations include suspension, solution, syrup and elixir.Such preparations can be used as filler in soft or hard capsule, and can typically comprise carrier such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or suitable oil, and one or more emulsifiers and / or suspending agents.Liquid preparations can also be prepared by reconstituting solid from, for example, a sachet.

[0205] Binders are commonly used to impart cohesion to tablet formulations. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose, and hydroxypropyl methylcellulose.

[0206] Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous, etc.), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, and dicalcium phosphate dihydrate.

[0207] Tablets may also optionally contain surfactants, such as sodium lauryl sulfate and polysorbate 80. When present, surfactants may comprise from 0.2% (w / w) to 5% (w / w) of the tablet.

[0208] Tablets may further comprise lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulfate. Lubricants generally comprise 0.25% (w / w) to 10% (w / w) or 0.5% (w / w) to 3% (w / w) of the tablet.

[0209] In addition to the fused heterocyclic mescaline derivative, the tablet may contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinized starch, and sodium alginate. Generally, the disintegrant will comprise 1% (w / w) to 25% (w / w) or 5% (w / w) to 20% (w / w) of the dosage form.

[0210] Other possible adjunct ingredients include antioxidants, colorants, flavorants, preservatives, and taste-masking agents.

[0211] For tablet dosage forms, depending on the desired effective amount of the chemical compound, the chemical compounds of the present disclosure may comprise from 1% (w / w) to 80% (w / w) of the dosage form, more typically from 5% (w / w) to 60% (w / w) of the dosage form.

[0212] An exemplary tablet comprises up to about 80% (w / w) of the chemical compound, about 10% (w / w) to about 90% (w / w) of a binder, about 0% (w / w) to about 85% (w / w) of a diluent, about 2% (w / w) to about 10% (w / w) of a disintegrant, and about 0.25% (w / w) to about 10% (w / w) of a lubricant.

[0213] Tablet formulations are described in "Pharmaceutical Dosage Forms: Tablets", Vol. 1-Vol. 3, CRC Press (2008).

[0214] Pharmaceutical and recreational drug formulations containing the disclosed fused heterocyclic mescaline derivatives can also be administered directly into the bloodstream, muscle, or internal organs. Thus, pharmaceutical and recreational drug formulations can be administered parenterally (e.g., by subcutaneous, intravenous, intraarterial, intrathecal, intraventricular, intracranial, intramuscular, or intraperitoneal injection). Parenteral formulations are typically aqueous solutions, which may contain excipients such as salts, carbohydrates, and buffers (in one embodiment, to a pH of 3 to 9), although in some applications they may more suitably be formulated as sterile non-aqueous solutions or in a dry form for use in combination with a suitable vehicle, such as sterile water.

[0215] Formulations containing the disclosed fused heterocyclic mescaline derivatives for parenteral administration can be formulated for immediate and / or modified release. Modified release formulations include delayed-release, sustained-release, pulsed-release, controlled-release, targeted-release, and programmed-release. Thus, the disclosed chemical compounds can be formulated as solids, semisolids, or thixotropic liquids for administration as implanted depots that provide modified release of the active compound. Examples of such formulations include drug-coated stents and poly(dl-lactic-coglycolic acid) (PGLA) microspheres.

[0216] The pharmaceutical or recreational drug formulations of the present disclosure can also be administered topically to the skin or mucosa, i.e., dermally or transdermally. Examples of pharmaceutical and recreational drug formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, powders, cosmetics, oils, eye drops, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages, and microemulsions. Liposomes can also be used. Examples of carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. Penetration enhancers may be incorporated (see, for example, Finnin, B. and Morgan, TM, 1999 J.Pharm.Sci, 88(10), 955-958).

[0217] Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (eg Powderject™, Bioject™, etc.) injection.

[0218] Pharmaceutical and recreational drug formulations for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous, or organic solvents, or mixtures thereof, as well as powders. Liquid or solid pharmaceutical compositions can contain suitable pharmaceutically acceptable excipients. In some embodiments, pharmaceutical compositions are administered by oral or nasal respiratory routes for local or systemic effect. Pharmaceutical compositions in pharmaceutically acceptable solvents can be nebulized using an inert gas. Nebulized solutions can be inhaled directly from the nebulizing device, or the nebulizing device can be attached to a face mask tent or intermittent positive pressure breathing machine. Solution, suspension, or powder pharmaceutical compositions can be administered, for example, orally or nasally, from a device that delivers the formulation in an appropriate manner.

[0219] In further embodiments, the fused heterocyclic mescaline compounds of the present disclosure are used as recreational drugs, and the compounds can be included in compositions such as foods or food products, beverages, food seasonings, personal care products such as cosmetics, fragrances or bath oils, or oils (both for topical administration as massage oils, and for combustion or aerosolization). The chemical compounds of the present disclosure can also be included in "vape" products, which can also contain other drugs, such as nicotine, and flavorings.

[0220] The pharmaceutical preparations comprising the chemical compounds of the present disclosure can be used to treat a subject, in particular to treat a psychiatric disorder in a subject.Thus, in a further embodiment, the present disclosure includes a method for treating a psychiatric disorder, the method comprising administering to a subject in need thereof a pharmaceutical preparation comprising a chemical compound selected from a first chemical compound having chemical formula (I) and (II): [ka] In formula (I) or (II): [ka] is a single or double bond; X1, X2, and X3 are independently selected from a hydrogen atom, O-alkyl, acyl, N-alkyl, OH, halogen, or NH2; X4 is an alkylene group or a substituted alkylene group; R1 is hydrogen, an alkyl group, or an oxo group; R1 is R 1b , the carbon atom to which R1 is attached and R 1b together with the nitrogen atom to which it is attached form an optionally substituted saturated or unsaturated 3- to 10-membered heterocyclic ring, and when the heterocyclic ring is unsaturated, R 1a is optional and non-existent; R 1a and R 1bare each independently selected from an alkyl group, a hydroxylalkyl group, an optionally substituted alkyl-aryl group, or a hydrogen atom; or R 1a and R 1b taken together with the nitrogen atom to which they are attached form a 3- to 10-membered optionally substituted heterocycle; and R2 and R3 are each independently selected from an alkyl group, an O-alkyl group, a hydrogen atom, or R2 and R3 taken together with the oxygen atom and the carbon atom to which they are attached form an oxirane ring.

[0221] Neurological disorders, e.g., psychiatric disorders, that can be treated include, for example, neurodevelopmental disorders, such as intellectual disability, global developmental delay, communication disorders, autism spectrum disorders, and attention deficit hyperactivity disorder (ADHD); bipolar and related disorders, such as manic and depressive episodes; anxiety disorders, such as generalized anxiety disorder (GAD), agoraphobia, social anxiety disorder, specific phobias (e.g., natural events, medical, animal, situational), panic disorder, and separation anxiety disorder; stress disorders, such as acute stress disorder, adjustment disorder, post-traumatic stress disorder (PTSD), and reactive attachment disorder; dissociative disorders, such as dissociative amnesia, dissociative identity disorder, and depersonalization / derealization disorder; somatoform disorders, e.g., eating disorders, such as anorexia nervosa, bulimia nervosa, rumination disorder, pica, and binge eating disorder; sleep disorders, such as narcolepsy, insomnia disorder, hypersomnia, breathing-related sleep disorder, parasomnia, and restless legs syndrome; disruptive disorders, such as kleptomania, pyromania, intermittent explosive disorder, conduct disorder, and oppositional defiant disorder; depressive disorders, such as severe mood dysregulation disorder, major depressive disorder (MDD), persistent depressive disorder (dysthymia), premenstrual dysphoric disorder, substance / medication-induced depressive disorder, postpartum depression, and depressive disorders caused by another medical condition, such as psychological and existential distress in the setting of life-threatening cancer (ACS). Pharmacol. Transl. Sci. 4:553-562; J. Psychiatr. Res. 137:273-282); substance-related disorders, such as alcohol-related disorders, cannabis-related disorders, inhalant use-related disorders, stimulant use disorders, and tobacco use disorders; neurocognitive disorders, such as delirium; schizophrenia; obsessive-compulsive disorders, such as obsessive-compulsive disorder (OCD), body dysmorphic disorder, hoarding disorder, trichotillomania disorder, skin picking disorder, substance / medication-induced obsessive-compulsive disorder, and obsessive-compulsive disorder associated with another medical condition; and personality disorders, such as antisocial personality disorder, avoidant personality disorder, emotionally unstable personality disorder, dependent personality disorder, histrionic personality disorder, narcissistic personality disorder, obsessive-compulsive personality disorder, paranoid personality disorder, schizoid personality disorder, and schizotypal personality disorder.Cranial nerve disorders that can be treated further include headache disorders, such as migraine, including, for example, auricular migraine, non-auricular migraine, menstrual migraine, chronic migraine, vestibular migraine, abdominal migraine, hemiplegic migraine, and other headache disorders.

[0222] In one embodiment, the compounds of the present disclosure can be used to contact a receptor, thereby modulating the receptor. Such contacting includes placing the compound of the present disclosure and the receptor together under in vitro conditions, for example, by introducing the compound into a sample containing the receptor, for example, a sample containing a purified receptor, or a sample containing cells containing the receptor. In vitro conditions further include the conditions described in Example 2. Contacting also includes placing the compound of the present disclosure and the receptor together under in vivo conditions. Such in vivo conditions include, for example, administering a pharmaceutically effective amount of the compound of the present disclosure to an animal or human subject, when the compound is formulated with a pharmaceutically active carrier, diluent, or excipient as previously described, thereby treating the subject. Upon contact with the receptor, the compound can activate or inhibit the receptor.

[0223] In one aspect, receptors that can be contacted with compounds of the present disclosure include, for example, 5-HT 1A Receptor, 5-HT 2A Receptor, 5-HT 2B Receptor, 5-HT 2C Receptor, 5-HT7 receptor, α 2A receptor, D3 receptor, or MT1 receptor.

[0224] Thus, in a further aspect, the condition treatable thereby can be any receptor-mediated disorder, for example, 5-HT 1A Receptor-mediated disorders, 5-HT 2A Receptor-mediated disorders, 5-HT 2B Receptor-mediated disorders, 5-HT 2C Receptor-mediated disorders, 5-HT7 receptor-mediated disorders, α 2AThe disorders include, but are not limited to, schizophrenia, psychotic disorders, attention deficit hyperactivity disorder, autism, and bipolar disorder.

[0225] In some embodiments, upon contact with the receptor, the compound can modulate the receptor. However, at the same time, other receptors cannot be modulated, for example, the compound can modulate a first receptor, e.g., 5-HT 1A The compound may activate or inhibit a second receptor, e.g., 5-HT 2A receptors or the first 5-HT 2A receptors and secondary 5-HT 1A Upon contact with the receptor, the compound binds to the first 5-HT 2A Modulates receptors, e.g., 5-HT 2A The compound can activate or inhibit the 5-HT receptor; however, it also inhibits the second 5-HT receptor. 1A The receptors cannot be regulated.

[0226] In one embodiment, in one aspect, when administered, the compound of the present disclosure can interact with transmembrane transport protein in a subject, thereby regulating the transmembrane transport protein and exerting a pharmacological effect. Such contacting includes, for example, introducing the compound into a sample containing the transmembrane transport protein, for example, a sample containing purified transmembrane transport protein, or a sample containing cells containing the transmembrane transport protein, thereby placing the compound of the present disclosure and the transmembrane transport protein together under in vitro conditions. Contacting further includes placing the compound of the present disclosure and the transmembrane transport protein together under in vivo conditions. Such in vivo conditions include, for example, administering a pharmaceutically effective amount of the compound of the present disclosure to an animal or human subject, when the compound is formulated with the pharmaceutically active carrier, diluent, or excipient described above, thereby treating the subject.

[0227] In one embodiment, in one aspect, the transmembrane transport protein can be a dopamine active transporter (DAT), a norephedrine transporter (NET), or a serotonin transporter (SERT) transmembrane transport protein.

[0228] Turning now to methods of making the disclosed fused heterocyclic mescaline derivatives, a general comment will first indicate that the disclosed fused heterocyclic mescaline derivatives can be prepared in any suitable manner, for example, by any organic chemical synthetic method, biosynthetic method, or combination thereof.

[0229] Examples of suitable chemical reactions that can be performed thereby are shown in Figures 3A(i), 3A(ii), 3B(i), 3B(ii), 3B(iii), and 3C, and are further detailed in the Examples section below.

[0230] Generally, as known to those skilled in the art, to conduct a chemical synthesis reaction, selected reactants are reacted under reaction conditions that allow the reactants to chemically react with one another and form the product, i.e., the heterocyclic mescaline derivative of the present disclosure. Such reaction conditions can be selected, adjusted, and optimized as known to those skilled in the art. The reaction can be carried out in any suitable reaction vessel (e.g., tube, bottle). Suitable solvents that can be used are polar solvents, such as, for example, dichloromethane, dichloroethane, toluene, and so-called participating solvents, such as acetonitrile and diethyl ether. Suitable temperatures can range, for example, from about -78°C to about 60°C. Additionally, catalysts, also known as promoters, such as iodonium dicollidine perchlorate (IDCP), any silver or mercury salt, trimethylsilyl trifluoromethanesulfonate (TMS-triflate, TMSOTf), or trifluoromethanesulfonic acid (triflic acid, TfOH), N-iodosuccinimide, or methyl triflate may be included in the reaction. Furthermore, reaction times may be varied. As will be readily recognized by those skilled in the art, the reaction conditions may be optimized, for example, by preparing multiple reactant preparations and reacting them in separate reaction vessels under different reaction conditions, such as at different temperatures or using different solvents, evaluating the resulting fused heterocyclic mescaline derivative reaction products, adjusting the reaction conditions, and selecting the desired reaction conditions. Further general guidance regarding suitable reaction conditions for carrying out the reaction can be found, for example, in: Y. Zou et al., Eur. J. Med. Chem., 138, 199-211 (2017); KN Campbell et al., J. Org. Chem., 16, 1736-1740 (1951); D. Ghosh, et al., Tetrahedr. Lett., 58, 2014-2018 (2017); M. G. Cabiddu et al., Tetrahedron 59, 4383-4387 (2003).

[0231] In accordance with the foregoing, in one aspect, included herein, in accordance with at least one embodiment, is a method of making a first chemical compound having chemical formula (I) or (II): [ka] In formula (I) or (II): [ka] is a single or double bond; X1, X2, and X3 are independently selected from a hydrogen atom, O-alkyl, acyl, N-alkyl, OH, halogen, or NH2; X4 is an alkylene group or a substituted alkylene group; R1 is hydrogen, an alkyl group, or an oxo group; R1 is R 1b , the carbon atom to which R1 is attached and R 1b together with the nitrogen atom to which it is attached form an optionally substituted saturated or unsaturated 3- to 10-membered heterocyclic ring, and when the heterocyclic ring is unsaturated, R 1a is optional and non-existent; R 1a and R 1b are each independently selected from an alkyl group, a hydroxylalkyl group, an optionally substituted alkyl-aryl group, or a hydrogen atom; or R 1a and R 1b taken together with the nitrogen atom to which they are attached form a 3- to 10-membered optionally substituted heterocycle; and R2 and R3 are each independently selected from an alkyl group, an O-alkyl group, or a hydrogen atom, or R2 and R3 together with an oxygen atom and the carbon atom to which they are attached form an oxirane ring; The method includes performing at least one chemical synthesis reaction selected from the reactions shown in Figures 3A(i), 3A(ii), and 3B(i), 3B(ii), 3B(iii), and 3C.

[0232] Referring to Figures 3A(i) and 3A(ii), in one embodiment, the compound having formula (I) can be a compound having formula (A): [ka] In the formula, R 1a and R 1b are each independently selected from an alkyl group, an optionally substituted alkyl-aryl group, or a hydrogen atom; or R 1a and R 1b taken together with the nitrogen atom to which they are attached form a 3- to 10-membered optionally substituted heterocycle; The at least one chemical synthesis reaction is a reaction selected from (g); (f) and (g); (e), (f), and (g); and (d), (e), (f), and (g) shown in Figures 3A(i) and 3A(ii).

[0233] Referring to FIG. 3A(i), in one embodiment, the compound having formula (I) can be a compound having formula (B): [ka] In formula (B), X 4a and X 4b are independently or simultaneously a halogen atom or a hydrogen atom, and R 1a and R 1b are each independently selected from an alkyl group, an optionally substituted alkyl-aryl group, or a hydrogen atom; or R 1a and R 1b taken together with the nitrogen atom to which they are attached form a 3- to 10-membered optionally substituted heterocycle; The at least one chemical synthesis reaction is a reaction selected from (i); (f); (f) and (i); (e) and (f); (e), (f), and (i); (d), (e), and (f); and (d), (e), (f), and (i) shown in Figure 3A(i).

[0234] With continued reference to Figures 3A(i) and 3A(ii), and further reference to Figures 3B(i) and 3B(ii), in one embodiment, a compound of formula (I a ) or (I c ) can be a compound having the formula (C): [ka] In the formula, R 1a and R 1b are each independently selected from an alkyl group, a hydroxyl alkyl group, or a hydrogen atom, or R 1a and R 1b taken together with the nitrogen atom to which they are attached form a 3-10 membered optionally substituted heterocycle, R2 is selected from an alkyl group or a hydrogen atom, and X3 is an O-alkyl group, a halogen, or a hydrogen atom; The at least one chemical synthesis reaction is a reaction selected from the following: (i) {(h); (c) and (h); (b), (c), and (h) in Figure 3A(i) and 3A(ii); and (a), (b), (c), and (h) (for compounds C(I), C(II), and C(III))}; or (ii) {(f); (d) and (f); (c2), (d), and (f); (c1), (d), and (f); (b), (c2), (d), and (f); (a), (b), (c2), (d), and (f); and (a), (c1), (d), and (f) (for compounds C(VIII) and C(IX)) in Figures 3B(i) and 3B(ii)}; or (iii) {(e); (d) and (e); (c2), (d), and (e); (c1), (d), and (e); (b), (c2), (d), and (e); (a), (b), (c2), (d), and (e); and (a), (c1), (d), and (e) (for compounds C(VI) and C(VII)) in Figures 3B(i) and 3B(ii)}; or (iv) {(d); (c1) and (d); (c2) and (d); (b), (c2), and (d); and (a), (c1), and (d); and (a), (b), (c2) and (d) in Figures 3B(i) and 3B(ii) (for compounds C(I), C(II), C(III), C(V), C(X), C(XI), and C(XII)}; or (v) {(i); (c1) and (i); (c2) and (i); (b), (c2), and (i); and (a), (c1), and (i); and (a), (b), (c2) and (i) in Figures 3B(i) and 3B(ii) (for compound C(XIII))}; or (vi) {(g); (d) and (g); (c2), (d), and (g); (c1), (d), and (g); (b), (c2), (d), and (g); (a), (b), (c2), (d), and (g); and (a), (c1), (d), and (g) (for compound C(IV)) in Figures 3B(i) and 3B(ii)}.

[0235] With continued reference to Figures 3A(i) and 3A(ii), in one embodiment, a compound of formula (I b ) or (I d ) can be a compound having the formula (D): [ka] In the formula, R 1a and R 1b are each independently selected from an alkyl group or a hydrogen atom, or R 1a and R 1b taken together with the nitrogen atom to which they are attached form a 3- to 10-membered optionally substituted heterocycle; The at least one chemical synthesis reaction is a reaction selected from (c); (b) and (c); and (a), (b), and (c) shown in Figures 3A(i) and 3A(ii).

[0236] Referring to FIG. 3C, in one embodiment, the compound having formula (I) can be a compound having formula (E): [ka] In the formula, R 1a and R 1b are each independently selected from an alkyl group, an optionally substituted alkyl-aryl group, or a hydrogen atom; or R 1a and R 1b taken together with the nitrogen atom to which they are attached form a 3- to 10-membered optionally substituted heterocycle; At least one chemical synthesis reaction is a reaction selected from (b); (a) and (b) shown in Figure 3C.

[0237] Referring to Figures 3B(i) and 3B(ii), in one embodiment, the compound having formula (I) can be a compound having formula (F): [ka] In the formula, R 1a and R 1b are each independently selected from a hydroxyl alkyl group and a hydrogen atom, or R 1a and R 1b taken together with the nitrogen atom to which they are attached form a 3-10 membered optionally substituted heterocycle, R2 is an alkyl group or a hydrogen atom, and X3 is an O-alkyl group, a halogen, or a hydrogen atom; The at least one chemical synthesis reaction is a reaction selected from (c1); (c2); (b) and (c2); (a) and (c1); (a), (b), and (c2) in Figures 3B(i) and 3B(ii).

[0238] Referring to Figures 3B(i), 3B(ii), and 3B(iii), in one embodiment, the compound having formula (I) can be a compound having formula (G): [ka] wherein R2, Y1, and Y2 are each independently an alkyl group or a hydrogen atom, and X3 is hydrogen or a halogen atom; The at least one chemical synthesis reaction is a reaction selected from {(h); (c1) and (h); (c2) and (h); (b), (c2), and (h); and (a), (c1), and (h); and (a), (b), (c2) and (h)} in Figures 3B(i), 3B(ii), and 3B(iii).

[0239] It will now be apparent from the foregoing that novel heterocyclic mescaline derivatives are disclosed herein. The heterocyclic mescaline derivatives may be formulated for use as pharmaceuticals or recreational drugs. Embodiments and implementations of the present disclosure are further illustrated by the following examples.

[0240] Example Example 1 - Preparation of the first N-propylamine-fused heterocyclic mescaline derivative Referring to FIG. 4A, to a suspension of sodium hydride (330 mg, 8.24 mmol) in dry THF (5 mL) was added a solution of triethyl phosphonoacetate (1.67 mL, 8.24 mmol) in dry THF (10 mL) under an inert atmosphere at 0° C. After stirring for 30 minutes, a solution of piperonal (1.00 g, 6.59 mmol) in dry THF (5 mL) was added dropwise over 10 minutes. The reaction mixture was allowed to warm gradually to room temperature overnight. Water (5 mL) was added to the stirred mixture, and the solvent was removed under reduced pressure. The remaining aqueous residue was extracted with ethyl acetate (3×25 mL). The organic extracts were combined, dried over anhydrous MgSO4, filtered, and concentrated to give 13 (1.35 g, 93%). 1H NMR (400 MHz, CDCl) δ 7.57 (d, J = 16.0 Hz, 1H), 7.00 (d, J = 1.8 Hz, 1H), 6.97 (ddd, J = 7.9, 1.7, 0.6 Hz, 1H), 6.78 (d, J = 8.0 Hz, 1H), 6.24 (d, J = 15.9 Hz, 1H), 5.97 (s, 2H), 4.23 (q, J = 7.1 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H) (Figure 4A, chemical reaction (a); see also chemical reaction (a), Figure 3A(i)).

[0241] Referring now to Figure 4B, to a solution of 13 (826 mg, 3.75 mmol) in dry THF (18.8 mL) under a nitrogen atmosphere at -78 °C, DIBAL (1 M in THF, 15.0 mL, 15.0 mmol) was added over 10 min. The reaction mixture was stirred at -78 °C for 3 h until completion, as monitored by TLC (20% EtOAc / Hexane). The reaction was quenched at 0 °C by the dropwise addition of water (4 mL), followed by 15% aqueous NaOH (4 mL), and water (10 mL) and stirred at room temperature for 15 min. Anhydrous MgSO4 was added, and the slurry was stirred for 3 days and then filtered. The filtrate was concentrated under reduced pressure to give a pale yellow oily solid. Purification by flash column chromatography on silica gel (12 g, 0–20% EtOAc / Hex) afforded 14 as an off-white solid (422 mg, 63%). 1 H NMR (400 MHz, CDCl) δ 6.92 (d, J = 1.7 Hz, 1H), 6.81 (dd, J = 7.9, 1.7 Hz, 1H), 6.75 (d, J = 8.0 Hz, 1H), 6.51 (dt, J = 15.7, 1.5 Hz, 1H), 6.19 (dt, J = 15.8, 5.9 Hz, 1H), 5.95 (s, 2H), 4.28 (dd, J = 5.9, 1.5 Hz, 2H) (Figure 4B, chemical reaction (b1); see also chemical reaction (b), Figure 3A(i)).

[0242] Referring now to Figure 4C, to a solution of 14 (307 mg, 1.72 mmol) in DCM (17.2 mL) was added manganese(IV) oxide (908 mg, 10.3 mmol). The reaction mixture was stirred under ambient conditions for 18 h. Additional manganese(IV) oxide (359 mg, 4.08 mmol) was added, and the solution was stirred for another 3 h, at which point the reaction was complete as determined by TLC (40% EtOAc / Hex). The reaction mixture was diluted with DCM (20 mL), filtered through Celite, and washed with DCM (20 mL). The filtrate was concentrated under reduced pressure to give a crude white solid. Purification by column chromatography on silica (4 g, 0–12% EtOAc / Hex) afforded the product, Intermediate J, as a white solid (282 mg, 93%). 1 H NMR (400 MHz, CDCl) δ 9.67 (d, J = 7.7 Hz, 1H), 7.40 (d, J = 15.8 Hz, 1H), 7.12-7.07 (m, 2H), 6.92-6.85 (m, 1H), 6.58 (dd, J = 15.8, 7.7 Hz, 1H), 6.07 (s, 2H) (Figure 4A, chemical reaction (b2); see also chemical reaction (b), Figure 3A(i)).

[0243] Referring now to Figure 4D, to a solution of J (136 mg, 772 μmol) in dry MeOH (5.15 mL) under a nitrogen atmosphere was added diethylamine (80.3 μL, 772 μmol). The reaction mixture was refluxed for 3 h. Upon cooling to room temperature, sodium cyanoborohydride (255 mg, 3.86 mmol) was added, and the reaction mixture was stirred at room temperature under a nitrogen atmosphere for 18 h. Methanol was removed by rotary evaporation, and the residue was dissolved in ethyl acetate (15 mL) and washed with brine (3 × 10 mL). The organic phase was dried over anhydrous MgSO4, filtered, and concentrated. The crude residue was purified by FC on silica gel (4 g, 0–6% MeOH / DCM) to give MM709 as a yellow, oily solid (45 mg, 25%). LRMS-HESI: [M+H] + m / z calculated 234.15, observed 234.15. 1H NMR (400 MHz, CDCl) δ 6.95 (d, J = 1.7 Hz, 1H), 6.82 (dd, J = 8.1, 1.7 Hz, 1H), 6.77 (d, J = 8.0 Hz, 1H), 6.49-6.42 (m, 1H), 6.15 (dt, J = 15.7, 6.8 Hz, 1H), 5.97 (s, 2H), 3.28 (d, J = 6.8 Hz, 2H), 2.62 (q, J = 7.2 Hz, 4H), 1.10 (t, J = 7.2 Hz, 6H) (Figure 4A, chemical reaction (c); see also chemical reaction (c), Figure 3A(ii)).

[0244] MM709 has been shown to correspond to chemical compound D(I): [ka]

[0245] 5-HT Receptor Radioligand Competition Assay. 5-HT 1A and 5-HT 2A Activity at the receptor was evaluated as described for Example 2, except that compounds having formula D(I) were evaluated instead of compounds having formula B(II). Table 1 shows the K i The radioligand competition assay results for the positive control, negative control, and compound having formula D(I) are shown in the form of K values. Considering the results for both the positive and negative controls (the negative control has a reliable K value), i Insufficient data are available for calculations (i.e., K i >1000μM), 5-HT 1A The K obtained for the compound having formula D(I) at the receptor i The value (11.0 μM, Table 1) indicates ligand-receptor binding. 2A The K obtained for the compound having formula D(I) at the receptor i The value (21 μM, Table 1) represents the ligand-receptor binding.

[0246] 5-HT 1A Receptor Functional Cellular Response Assay: 5-HT in Engineered Cellular Systems 1AFunctional engagement of the receptor was assessed as described in Example 2, except that a compound having formula D(I) was evaluated instead of a compound having formula B(II). Table 2 shows the functional assay results for the positive control, calibrator, and compound having formula D(I) as measured by EC 50 Considering the results for the control and calibrator compounds, negative cell responses are shown in the form of EC 50 EC for compounds having formula D(I) in this assay, corresponding to a value >1000 μM 50 Values ​​(>1000 μM, Table 2) suggested little or no ligand-receptor binding.

[0247] In vitro investigation of pharmacological interaction profiles at receptors and transporters associated with target health conditions Compounds having formula D(I) were evaluated for binding and / or interaction at 11 different receptors and transporters with known or suspected associations with mental health conditions and / or neuropathologies. This study was performed by the contract research organization (CRO) Eurofins Cerep (Cell L'Evescault, France) using standard assay procedures (https: / / www.eurofinsdiscovery.com / solution / target-based-assays). Data were analyzed using derivative molecules at the following eight GPCR receptors: HTR1A (5-HTR1B); 1A ), HTR2A(5-HTR 2A ), HTR2B(5-HT 2B ), HTR2C(5-HT 2C ), HTR7 (5-HT7), alpha 2A (α 2A), MT1 (MT1), D3 (D3), and three transporters (SERT, DAT, NET). Assays were performed using the same materials and procedures outlined in Example 2, except that a compound having formula D(I) was used instead of a compound having formula B(II). Overall assay conditions are summarized in Tables 3 and 4 for GPCRs and transporters, respectively. Results for all calibrator compounds, control compounds, and test compounds, such as the compound having formula D(I), are summarized in Table 5.

[0248] Example 2 - Preparation of a second N-propylamine-fused heterocyclic mescaline derivative Referring to FIG. 5A, to a suspension of sodium hydride (330 mg, 8.24 mmol) in dry THF (5.00 mL) was added a solution of triethyl-2-phosphonopropionate (1.82 mL, 8.24 mmol) in dry THF (10.0 mL) under an inert atmosphere at 0° C. After stirring for 30 minutes, a solution of piperonal (1.00 g, 6.59 mmol) in dry THF (5.00 mL) was added dropwise over 10 minutes. The reaction mixture was gradually warmed to room temperature and stirred for 18 hours. Water (5 mL) was added to the stirred mixture, and the solvent was removed under reduced pressure. The remaining aqueous residue was extracted with ethyl acetate (3×25 mL). The organic extracts were combined, dried over anhydrous MgSO4, filtered, and concentrated to give 15 (1.55 g, 100%). 1 H NMR (400 MHz, CDCl) δ 7.60 (dd, J = 2.0, 1.1 Hz, 1H), 6.96-6.90 (m, 2H), 6.84 (d, J = 8.0 Hz, 1H), 5.99 (s, 2H), 4.27 (q, J = 7.1 Hz, 2H), 2.12 (d, J = 1.5 Hz, 3H), 1.35 (t, J = 7.1 Hz, 3H) (Figure 5A, chemical reaction (d), see also chemical reaction (d), Figure 3A(i)).

[0249] Referring to Figure 5B, to a solution of 15 (1.55 g, 6.62 mmol) in dry THF (33.1 mL) under a nitrogen atmosphere at -78 °C, diisobutylaluminum hydride (DIBAL) (1 M THF solution, 19.9 mL, 19.9 mmol) was added over 10 min. The reaction mixture was stirred at -78 °C for an additional 2 h. The reaction was quenched at 0 °C by the dropwise addition of water (0.4 mL), followed by 15% aqueous NaOH (0.4 mL), and water (1 mL) and stirred at room temperature for 15 min. Anhydrous MgSO4 was added, and the slurry was stirred for 15 min and then filtered. The filtrate was concentrated under reduced pressure to give a colorless oil. Purification by flash chromatography on silica gel (25 g, 0–20% EtOAc / Hex) gave 16 (1.21 g, 95%). 1 H NMR (400 MHz, CDCl) δ 6.80-6.76 (m, 2H), 6.73 (dd, J = 8.1, 1.6 Hz, 1H), 6.41 (q, J = 1.6 Hz, 1H), 5.94 (s, 2H), 4.14 (d, J = 1.4 Hz, 2H), 1.87 (d, J = 1.4 Hz, 3H) (Figure 5B, chemical reaction (e1); see also chemical reaction (e), Figure 3A(i)).

[0250] Referring to Figure 5C, manganese(IV) oxide (1.44 g, 16.4 mmol) was added to a solution of 16 (524 mg, 2.73 mmol) in DCM (27.3 mL). The dark reaction mixture was allowed to stir for 18 h. Additional manganese(IV) oxide (565 mg, 6.43 mmol) was added to the reaction mixture, which was then stirred for 3 h, at which point the reaction was complete as determined by TLC (40% EtOAc / Hex). The reaction mixture was diluted with DCM (20 mL), filtered through Celite, and washed with DCM (20 mL). The filtrate was concentrated under reduced pressure to give a crude white solid. Purification by flash column chromatography on silica gel (4 g, 0–12% EtOAc / Hex) afforded the product, Intermediate K, as a white solid (474 ​​mg, 91%). 1H NMR (400 MHz, CDCl) δ 9.55 (s, 1H), 7.17 (q, J = 1.4 Hz, 1H), 7.12-7.07 (m, 2H), 6.92 (d, J = 8.0 Hz, 1H), 6.06 (s, 2H), 2.09 (d, J = 1.4 Hz, 3H) (Figure 5C, chemical reaction (e2); see also chemical reaction (e), Figure 3A(i)).

[0251] Referring to Figure 5D, to a solution of K (130 mg, 684 μmol) in dry methanol (4.56 mL) under a nitrogen atmosphere, pyrrolidine (56.4 μL, 684 μmol) was added. The reaction mixture was refluxed for 4 h, then cooled to room temperature, and sodium cyanoborohydride (226 mg, 3.42 mmol) was added. After stirring overnight at room temperature, the methanol was removed under reduced pressure, and the residue was dissolved in ethyl acetate (25 mL) and washed with brine (2 × 20 mL). The organic phase was dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. Purification by FC on silica gel (4 g, 0-6% MeOH / DCM) gave MM710 as a yellow oil (64 mg, 38%). LRMS-HESI: [M+H] + Calculated m / z 246.15, observed 246.17. 1 H NMR (400 MHz, CDCl) δ 6.85-6.73 (m, 3H), 6.39-6.34 (m, 1H), 5.96 (s, 2H), 3.15 (d, J = 1.4 Hz, 2H), 2.56 (ddt, J = 6.8, 4.8, 2.1 Hz, 4H), 1.94 (d, J = 1.4 Hz, 3H), 1.85-1.80 (m, 4H) (Figure 5D, chemical reaction (f), see also chemical reaction (f), Figure 3A(i)).

[0252] MM710 has been shown to correspond to chemical compound B(II): [ka]

[0253] 5-HT receptor radioligand competition assay 5-HT 1AReceptor. Competition assays were performed as follows: SPA beads (RPNQ0011), radiolabeled 8-hydroxy-DPAT [propyl-2,3-ring-1,2,3- 3 H] (labeled 7-(dipropylamino)-5,6,7,8-tetrahydronaphthalen-1-ol; NET929250UC), 5-HT 1A Membranes containing HT (6110501400UA) and isoplate-96 microplates (6005040) were from Perkin Elmer (perkinelmer.com). Radioactive binding assays were performed using a scintillation proximity assay (SPA; Maguire et al., 2012, Methods in Molecular Biology 897:31-77). For saturation binding assays, 10 μg of HT was used. 1A The receptor-containing membrane mixture was pre-coupled to 1 mg of SPA beads in binding buffer [50 mM Tris-HCl pH 7.4, 10 mM magnesium sulfate, 0.5 mM EDTA, 3.7% (v / v) glycerol, 1 mM ascorbic acid, 10 μM pargyline HCl] for 1 h at room temperature on a tube rotator. After pre-coupling, the beads and membranes were mixed with increasing amounts of 8-hydroxy-DPAT [propyl-2,3-ring-1,2,3- 3 The samples were aliquoted into an Isoplate-96 microplate containing [H] (0.1525 nM to 5 nM) and incubated for 2 h at room temperature in the dark with shaking. After incubation, the samples were read on a MicroBeta2 microplate counter (perkinelmer.com). Nonspecific binding was performed in the presence of 100 μM metergoline (M3668-500MG, Sigma-Aldrich). 8-hydroxy-DPAT (K DThe equilibrium binding constants for 8-hydroxy-DPAT (K) were determined from saturation binding curves using one-site saturation binding analysis in GraphPad PRISM software (Version 9.2.0). Test compounds were dissolved in 100 mM dimethyl sulfoxide (DMSO) and dilutions were performed in assay buffer. Competitive binding assays were performed similarly to the saturation binding assays using 0.5 nM hot 8-hydroxy-DPAT and different concentrations of DMSO (up to 1%), tryptophan (3 nM to 1 mM), or unlabeled test compound (3 nM to 1 mM). i Values ​​were calculated from competitive displacement data using competitive binding analysis from GraphPad PRISM software. Serotonin was used as a positive control because it is the natural endogenous ligand for all serotonergic receptors. 2C-B, MDMA, and mescaline were used as positive controls because they exert relatively strong (2C-B; Rickli et al., 2015, Neuropharmacology 99:546) or more moderate (MDMA, Simmler et al., 2013, British J. Pharmacol. 168:458; mescaline, Rickli et al., 2016, Eur. Neuropharm. 26:1327) 5-HT receptor activity, respectively. 1A Escarin and proscarin were included in this study for comparison purposes because they are phenylalkylamine-type molecules with 5-HT receptor binding activity. 1A Although the receptor binding mode(s) is / are under investigation, they are established mescaline-type hallucinogens with therapeutic potential (Shulgin and Shulgin, 1990. PIHKAL: A Chemical Love Story. 1st ed., Transform Press). Fluoxetine and vortioxetine were included as positive controls because they bind to 5-HT 1A8-hydroxy-DPAT is a widely prescribed drug with established receptor binding (Owens et al., 1997, Journal of Pharmacology and Experimental Therapeutics 283:1305-1322; Celada et al., 2013, CNS Drugs 27:703-716). Figure 14A shows the K D Figures 14B and 14C show the binding curves used to determine K. Figures 14B and 14C show the binding curves for the negative controls DMSO and tryptophan, respectively. As can be seen in Figures 14B and 14C, the data showed no binding for these negative controls. i Decision (i.e., K i The binding curves shown in Figures 14D, 14E, 14F, and 14G were compared to the positive control (K i The data reveals the ability to determine: serotonin, mescaline, 2C-B, and MDMA, respectively. The S-curves and K in Figures 14D, 14E, 14F, and 14G i value (i.e., K i <1000 μM) indicates 5-HT at the indicated ligand concentrations. 1A The data in Figures 14H and 14I demonstrate the 5-HT receptor binding of escalin and proscalin, respectively, at the concentrations shown. 1A The data in Figures 14J and 14K suggest that fluoxetine and vortioxetine bind to the 5-HT receptor. 1A The data in Figure 14L show that compounds having formula B(II) bind to the 5-HT receptor above the levels observed for the negative control. 1A Binding to the 5-HT receptor is shown (Figures 14A and 14B). 1A K obtained for control and test compounds in receptor binding assays i The data are summarized in Table 1.

[0254] 5-HT 2A Receptor. Competition assay for 5-HT 1AThe assay was performed in the same manner as above, with the following differences: SPA beads (RPNQ0010), [ 3 H]ketanserin (NET1233025UC), and 5-HT 2A The membranes containing [ES-313-M400UA] were from PerkinElmer. After prebinding, the beads and membranes were washed with increasing amounts of [ 3 The antibody was aliquoted into an Isoplate-96 microplate along with [H]ketanserin (0.1525 nM to 5 nM). Nonspecific binding was determined in the presence of 20 mM spiperone (S7395-250MG, Sigma-Aldrich). The equilibrium binding constant (K d ) was determined from the saturation binding curves using the "one-site saturation binding analysis" method in the inGraphPad PRISM software (Version 9.2.0). Competitive binding assays were performed using fixed (1 nM) [ 3 Similar saturation binding assays were performed using [H]ketanserin and different concentrations of unlabeled test compound (3 nM to 1 mM). Tryptophan was included as a negative control because it inhibits 5-HT 2A In contrast, 2C-B and MDMA were used as positive controls because they have no activity at the 5-HT receptor, respectively, as they have relatively strong (Marcher-Roersted et al., 2020, ACS Chem. Neurosci. 11:1238) or more moderate (Simmler et al., 2013, British J. Pharmacol. 168:458) 5-HT receptor activity. 2A Escarin and proscarin were included in this study for comparison purposes because they are phenylalkylamine-type molecules with 5-HT receptor binding activity. 2A The receptor binding mode is under investigation, as they are well-established mescaline-type hallucinogens known to induce head-twitch responses in mice (Halberstadt et al., 2019, J. Psychopharm. 33:406-414). Mouse head-twitch responses are related to 5-HT 2A(Halberstadt, 2015, Behav. Brain Res. 277:99). Psilocin is included as an additional positive control because it acts as a partial agonist against 5-HT 2A Figure 15A shows the K resulting from specific binding. D In addition to (Panel 2), K D Data supporting the overall decision are shown (Panel 1). Figure 15B shows the data obtained for psilocin and the 5-HT4040 relative to this positive control. 2A Figure 15C shows the data obtained for tryptophan and the 5-HT binding relative to this negative control. 2A Figures 15D and 15E show the binding data for escarin and proscarin, respectively, and the resulting K i Values ​​(i.e., <1000 μM) represent the 5-HT at the indicated concentrations. 2A Figure 15F shows the binding data for 2C-B and the resulting K i values ​​(i.e., <1000 μM) were 5-HT 2A Figure 15G shows the binding data for MDMA and the resulting K i Values ​​(i.e., <1000 μM) indicate the concentration of 5-HT at the indicated concentration. 2A The data in Figure 15H demonstrate that compounds having formula B(II) exhibit 5-HT binding at the receptor above the levels observed for the negative control. 2A Binding to the 5-HT receptor is shown (Figure 15C). 2A K obtained for control and test compounds in receptor binding assays i The data are summarized in Table 1. [Table 1]

[0255] Functional receptor potency assay 5-HT 1AReceptor: 5-HT 1A A Chinese hamster ovary (CHO)-derived cell line, CHO-K1 / 5-HT, stably transformed to express serotonin receptors 1A / Gα15 (GenScript M00330) was used to detect 5-HT 1A Specific agonist-mediated stimulation of 5-HT signaling was assessed in these non-neuronal cells. 1A The stimulation of Gα i / o Activates the protein, leading to inhibition of adenylyl cyclase (AC) type I (Rojas and Felder, 2016, Frontiers in Cellular Neuroscience 10:272; Polter and Li, 2010, Cell Signaling 22:1406-1412). In cells stimulated with 4 μM forskolin (which directly stimulates AC and increases intracellular cAMP levels), 5-HT 1A Activation was quantitatively assessed by measuring reduced intracellular cAMP levels. All cells were grown and maintained as monolayers in Ham's F12 nutrient mixture supplemented with 10% fetal bovine serum (FBS), 200 μg / mL Zeocin, or 100 μg / mL Hygromycin. All were obtained from ThermoFisher Scientific and used according to the manufacturer's instructions. Cells were cultured and incubated at 37°C in a humidified oxygen atmosphere with 5% CO2. 5-HT 1ATo assess signal transduction activation, cells were first seeded at a density of 30,000 cells / well in 100 mL of complete growth medium into tissue-culture-treated, white-walled, clear-bottom 96-well plates (Corning, corning.com). Cells were cultured for 24 hours in a humidified incubator at 37°C and 5% CO2. Cells were then stimulated for 20 minutes with test compounds prepared in titrations starting at 1 mM and dissolved in induction medium (serum-free medium containing 4 μM forskolin (Sigma-Aldrich), 500 μM isobutyl-1-methylxanthine (IBMX, Sigma-Aldrich), and 100 μM RO20-1724 (Sigma-Aldrich)). Changes in intracellular cAMP levels were measured using a commercially available cAMP-Glo ​​assay kit (Promega, promega.ca) according to the manufacturer's protocol. Luminescence levels from cells stimulated with induction medium alone were used to establish the maximum level of intracellular cAMP (100%) for each assay run. 1A Figure 16B shows that the level of cAMP increases in cultured cells incubated with increasing concentrations of forskolin (FSK), regardless of expression. As the level of 8-OH-DPAT increases, the level of 5-HT stimulated with 4 μM forskolin increases. 1A Cells expressing the receptor (+5-HT 1A ) and showed a reduction in cAMP levels in these cells, suggesting that 8-OH-DPAT-induced 5-HT 1A Conversely, this trend of decreasing %cAMP levels with increasing 8-OH-DPAT is consistent with the 5-HT 1A It is not observed in cells lacking expression of the receptor. 8-OH-DPAT (7-(dipropylamino)-5,6,7,8-tetrahydronaphthalen-1-ol) inhibits 5-HT 1A It is an established full agonist of the receptor (Larsson et al., 1990, Neuropharmacology 29:85-91) and was included as a positive control to ensure functionality of the cellular response system. Figure 16C shows the effect of 4 μM forskolin-stimulated 5-HT on increasing levels of serotonin. 1AReceptor-expressing cells (+5-HT 1A ) and showed a reduction in cAMP levels in these cells, suggesting that serotonin-induced 5-HT 1A Conversely, this tendency for a decrease in %cAMP levels with an increase in serotonin is due to the 5-HT receptor binding. 1A It is not observed in cells lacking expression of the 5-HT receptor. 1A Psilocin, MDMA, and 2C-B were included as calibrator compounds because they are natural ligands for the 5-HT receptor and therefore were included as positive controls. 1A Although they are known to bind to receptors to varying degrees (Marcher-Roersted et al., 2020, ACS Chem. Neurosci. 11:1238; Simmler et al., 2013, British J. Pharmacol. 168:458), their ability to elicit cellular responses in this particular functional assay is unknown. 1A Although the binding mode of mescaline to the receptor remains unclear, it was included for comparative purposes due to the structural similarity of its phenylethylamine backbone to other derivatives in this application. Figure 16D shows the effect of increasing levels of psilocin on 4 mM forskolin-stimulated 5-HT 1A Receptor-expressing cells (+5-HT 1A ) and showed a reduction in cAMP levels in these cells, suggesting that psilocin-induced 5-HT 1A Conversely, this trend of decreasing %cAMP levels with increasing psilocin is due to 5-HT receptor binding. 1A Figures 16E and 16F show the 4 μM forskolin-stimulated 5-HT4 receptor activity with increasing levels of mescaline and MDMA, respectively. 1A Receptor-expressing cells (+5-HT 1A These results demonstrate mild or no changes in cAMP levels in this cell system due to mescaline or MDMA-induced mild 5-HT 1A Receptor binding or 5-HT 1AFigure 16G shows the effect of 4 mM forskolin-stimulated 5-HT2+ on increasing levels of 2C-B. 1A Receptor-expressing cells (+5-HT 1A ) and showed a reduction in cAMP levels in these cells, suggesting that 2C-B-induced 5-HT 1A Conversely, this trend of decreasing %cAMP levels with increasing 2C-B is consistent with the 5-HT receptor binding. 1A It is not observed in cells lacking expression of the receptor. 1A Receptor binding assessment is shown in Figure 16H. 1A Comparison of the data obtained in cultures with those obtained in -5-HT1A cultures indicates receptor modulation at elevated ligand concentrations (EC 50 = 40.1 μM). Table 2 shows the functional 5-HT 1A EC2 values ​​for all control, calibrator, and test compounds obtained using the receptor assay 50 The data is summarized below. [Table 2]

[0256] In vitro investigation of pharmacological interaction profiles at receptors and transporters associated with target health conditions To extend the pharmacological profiling to include a broader range of targets known to be involved in or relevant to neurological disorders, compounds having formula B(II) were evaluated for binding and / or interaction at nine different receptors and transporters. This study was performed by the contract research organization (CRO) Eurofins Cerep (Cell L'Evescault, France) using standard assay procedures (https: / / www.eurofinsdiscovery.com / solution / target-based-assays). Data were analyzed using derivative molecules at the following eight GPCR receptors: HTR1A (5-HTR1B), HTR2 (5-HTR3B), HTR4 (5-HTR5B), HTR6 (5-HTR6C), HTR7 (5-HTR8), HTR9 (5-HTR9C), HTR10 (5-HTR10C), HTR11 (5-HTR11C), HTR12 (5-HTR12C), HTR13 (5-HTR14C), HTR15 (5-HTR15C), HTR16 (5-HTR16C), HTR17 (5-HTR18C), HTR18C, HTR19 (5-HTR19C), HTR18C, HTR19C, HTR18D, HTR19E, HTR19F, HTR19F, HTR20F, HTR21F, HTR22F, HTR23F, HTR24F, HTR25F, HTR26F, HTR27F, HTR28F, HTR29F, HTR30F, HTR31F, HTR32F, HTR33F, HTR34F, HTR35F, HTR36F, HTR37F, HTR38F, HTR39F, HTR40F, HTR41F, HTR42F, HTR43F, HTR44F, HTR45F, HTR46F, HTR47F, HTR481A ), HTR2A(5-HTR 2A ), HTR2B(5-HT 2B ), HTR2C(5-HT 2C ), HTR7 (5-HT7), alpha 2A (α 2A Assay conditions were developed for interactions with MT1 (MT1), D3 (D3), and three transporters (SERT, DAT, and NET). Assay conditions are summarized in Tables 3 and 4 for GPCRs and transporters, respectively. On-site positive controls are routinely applied as part of standard industry practice at Eurofins Cerep (https: / / www.eurofins.com / contact-us / worldwide-interactive-map / france / eurofins-cerep-france / ) to ensure the functionality of each assay. Additionally, to specifically calibrate each assay for compounds with a phenylalkylamine (PAA) structural scaffold, a series of six PAA-type calibrator compounds were added to the assay: MDMA, mescaline, 2C-B, escaline, proscaline, and DOB. Additional tryptamine-type calibrators employed in these assays included serotonin and melatonin. Tryptophan served as a negative control for all assays. Tryptophan is not known to interact with either the target receptor or transporter. Seven widely marketed pharmaceuticals used in the treatment of mental health disorders with long-established pharmacological profiles were also subjected to assay calibration purposes: vortioxetine, trazodone, duloxetine, imipramine, agomelatine, bupropion, and vilazodone. Results for all calibrator compounds, control compounds, and test compounds, including the compound having formula B(II), are summarized in Table 5. [Table 3] [Table 4]

[0257] i. Competition assay to measure binding affinity at the alpha2A receptor The assay was performed according to the method described by Langin et al. [Eur. J. Pharmacol. 167:95-104, 1989] using the conditions outlined in Table 3. The purpose of this experiment was to determine the K i Because the goal was to measure the general binding ability of the test ligand, rather than to obtain detailed binding information, only a single concentration of test ligand was used (10 μM). Briefly, recombinant receptors were expressed using CHO cells, and membrane preparations were performed at 4°C. Binding experiments were performed in a 400 μL final volume of Tris-Mg 2+ The incubation was carried out using 100 μL membrane suspension incubated with radioligand, cold ligand to ensure specific binding by the test ligand, and test molecule (10 μM) in buffer. The incubation was quenched by adding 4 mL ice-cold washing buffer (10 mM Tris-HCl, 0.5 mM MgCl2). Bound and free radioligand were separated by filtration under vacuum through GF / C Whatman filters. The filters were then washed and subjected to scintillation counting. Results were expressed as a percentage of control-specific binding ([measured specific binding / control-specific binding]). * 100) The results for the compound having formula B(II) are shown in Table 5.

[0258] ii. Competitive assay to measure binding affinity at the D3 receptor The assay was performed according to the method described by Mackenzie et al. [Eur. J. Pharmacol. 266:79-85, 1994] using the conditions outlined in Table 3. The purpose of this experiment was to determine the K iSince the goal was to measure the general binding ability of the test ligand, rather than to obtain detailed binding information, only a single concentration of test ligand was used (10 μM). Briefly, recombinant receptors were expressed using CHO cells, and membrane preparations were performed at 4°C. Binding experiments were performed using 100 μL membrane suspension, radioligand, cold ligand to ensure specific binding by the test ligand, and test molecule (10 μM) in a final volume of 400 μL. Bound and free radioligand were separated by filtration under vacuum through GF / C Whatman filters. The filters were then washed and subjected to scintillation counting. Results were expressed as a percentage of control-specific binding ([measured specific binding / control-specific binding]). * 100) The results for the compound having formula B(II) are shown in Table 5.

[0259] iii. Competitive assay to measure binding affinity at the MT1 receptor The assay was performed according to the method described by Witt-Endersby and Dubocovich [Mol. Pharmacol. 50:166-174, 1996] using the conditions outlined in Table 3. The purpose of this experiment was to determine the K i Since the goal was to measure the general binding ability of the test ligand, rather than to obtain detailed binding information, only a single concentration of test ligand was used (10 μM). Briefly, recombinant receptors were expressed using CHO cells, and membrane preparations were performed at 4°C. Binding experiments were performed using 100 μL membrane suspension, radioligand, cold ligand to ensure specific binding by the test ligand, and test molecule (10 μM) in a final volume of 500 μL. Bound and free radioligand were separated by filtration under vacuum through GF / C Whatman filters. The filters were then washed and subjected to scintillation counting. Results were expressed as a percentage of control-specific binding ([measured specific binding / control-specific binding]). * 100) The results for the compound having formula B(II) are shown in Table 5.

[0260] iv.5-HT 1A Competitive assays for measuring binding affinity at receptors The assay was performed according to the method described by Mulheron et al. [J. Biol. Chem. 269:12954-12962, 1994] using the conditions outlined in Table 3. The purpose of this experiment was to determine the K i Since the goal was to measure the general binding ability of the test ligand, rather than to obtain detailed binding information, only a single concentration of test ligand was used (10 μM). Briefly, HEK-293 cells were used to express the recombinant receptor, and membrane preparations were performed at 4°C. Binding experiments were performed using radioligand, 30 μg protein (membrane suspension), cold ligand to ensure specific binding by the test ligand, and test molecule (10 μM) to a final volume of 200 μL. Bound and free radioligand were separated by filtration under vacuum through glass fiber Whatman filters. The filters were then washed and subjected to scintillation counting. Results were expressed as a percentage of control-specific binding ([measured specific binding / control-specific binding]). * 100) The results for the compound having formula B(II) are shown in Table 5.

[0261] v.5-HT 2A Competitive assays for measuring binding affinity at receptors The assay was performed according to the method described by Bryant et al. [Life Sci. 15:1259-1268, 1996] using the conditions outlined in Table 3. Briefly, HEK-293 cells were used to express the recombinant receptor, and membrane preparations were performed at 4°C. Binding experiments were performed using radioligand, 30 μg protein (membrane suspension), cold ligand to ensure specific binding by the test ligand, and test molecule (10 μM) to a final volume of 300 μL. Bound and free radioligand were separated by filtration under vacuum through glass fiber Whatman filters. The filters were then washed and subjected to scintillation counting. Results were expressed as a percentage of control-specific binding ([measured specific binding / control-specific binding]). * 100) The results for the compound having formula B(II) are shown in Table 5.

[0262] vi.5-HT 2B Competitive assays for measuring binding affinity at receptors The assay was performed according to the method described by Kursar et al. [Mol. Pharmacol. 46:227-234, 1994] using the conditions outlined in Table 3. The purpose of this experiment was to determine the K i Since the goal was to measure the general binding ability of the test ligand, rather than to obtain detailed binding information to obtain values, only a single concentration of test ligand was used (10 μM). Briefly, recombinant receptors were expressed using CHO cells, and membrane preparations were performed at 4°C. Binding experiments were performed using radioligand, 0.2 mL (approximately 100 μg protein) membrane suspension, cold ligand to ensure specific binding by the test ligand, and test molecule (10 μM) in 50 mM Tris pH 7.4. Bound and free radioligand were separated by filtration under vacuum through glass fiber Whatman filters. The filters were then washed and subjected to scintillation counting. Results were expressed as a percentage of control-specific binding ([measured specific binding / control-specific binding]). * 100) The results for the compound having formula B(II) are shown in Table 5.

[0263] vii.5-HT 2C Competitive assays for measuring binding affinity at receptors The assay was performed according to the method described by Bryant et al. [Life Sci. 15:1259-1268, 1996] using the conditions outlined in Table 3. The purpose of this experiment was to determine the K i Because our goal was to measure the general binding capacity of the test ligand, rather than to obtain detailed binding information, only a single concentration of test ligand was used (10 μM). Briefly, HEK-293 cells were used to express the recombinant receptor, and membrane preparations were performed at 4°C. Binding experiments were performed using radioligand, 0.2 mL (approximately 100 μg protein) membrane suspension, cold ligand to ensure specific binding by the test ligand, and test molecule (10 μM) to a final volume of 800 μL with 3 mM CaCl, 0.1% sodium ascorbate, and 50 mM Tris pH 7.4. Bound and free radioligand were separated by filtration under vacuum through glass fiber Whatman filters. The filters were then washed and subjected to scintillation counting. Results were expressed as a percentage of control-specific binding ([measured specific binding / control-specific binding]). * 100) The results for the compound having formula B(II) are shown in Table 5.

[0264] viii. Competitive assay to measure binding affinity at the 5-HT7 receptor The assay was performed according to the method described by Shen et al. [J. Biol. Chem. 268:18200-18204, 1993] using the conditions outlined in Table 3. The purpose of this experiment was to determine the K iSince the goal was to measure the general binding ability of the test ligand, rather than to obtain detailed binding information, only a single concentration of test ligand was used (10 μM). Briefly, HEK-293 cells were used to express the recombinant receptor, and membrane preparations were performed at 4°C. Binding experiments were performed using radioligand, 30 μg protein (membrane suspension), cold ligand to ensure specific binding by the test ligand, and test molecule (10 μM) to a final volume of 200 μL. Bound and free radioligand were separated by filtration under vacuum through glass fiber Whatman filters. The filters were then washed and subjected to scintillation counting. Results were expressed as a percentage of control-specific binding ([measured specific binding / control-specific binding]). * 100) The results for the compound having formula B(II) are shown in Table 5.

[0265] ix. Competitive Assay for Measuring Binding Affinity at the Serotonin Transporter (SERT) The assay was performed according to the method described by Tatsumi et al. [Eur J Pharmacol 368:277-283, 1999] using the conditions outlined in Table 4. The purpose of this experiment was to determine the K i Since the goal was to measure the general binding capacity of the test ligand, rather than to obtain detailed binding information, only a single concentration of test ligand was used (10 μM). Briefly, recombinant transporters were expressed using CHO cells, and membrane preparations were performed at 4°C. Binding experiments were performed using radioligand, 30 μg protein (membrane suspension), cold ligand to ensure specific binding by the test ligand, and test molecule (10 μM) to a final volume of 200 μL. Bound and free radioligand were separated by filtration under vacuum through Whatman glass fiber filters. The filters were then washed and subjected to scintillation counting. Results were expressed as a percentage of control-specific binding ([measured specific binding / control-specific binding]). * 100) The results for the compound having formula B(II) are shown in Table 5.

[0266] x. Competitive assay to measure binding affinity at the norepinephrine transporter (NET) The assay was performed according to the method described by Pacholczyk et al. [Nature 350: 350-354, 1991] using the conditions outlined in Table 4. The purpose of this experiment was to determine the K i Since the goal was to measure the general binding capacity of the test ligand, rather than to obtain detailed binding information, only a single concentration of test ligand was used (10 μM). Briefly, recombinant transporters were expressed using CHO cells, and membrane preparations were performed at 4°C. Binding experiments were performed using radioligand, 30 μg protein (membrane suspension), cold ligand to ensure specific binding by the test ligand, and test molecule (10 μM) to a final volume of 200 μL. Bound and free radioligand were separated by filtration under vacuum through Whatman glass fiber filters. The filters were then washed and subjected to scintillation counting. Results were expressed as a percentage of control-specific binding ([measured specific binding / control-specific binding]). * 100) The results for the compound having formula B(II) are shown in Table 5.

[0267] xi. Competitive assays for measuring binding affinity at the dopamine transporter (DAT) The assay was performed according to the method described by Pristupa et al. [Mol. Pharmacol. 45:125-135, 1994] using the conditions outlined in Table 4. The purpose of this experiment was to determine the K iSince the goal was to measure the general binding capacity of the test ligand, rather than to obtain detailed binding information, only a single concentration of test ligand was used (10 μM). Briefly, recombinant transporters were expressed using CHO cells, and membrane preparations were performed at 4°C. Binding experiments were performed using radioligand, 50 μg protein (membrane suspension), cold ligand to ensure specific binding by the test ligand, and test molecule (10 μM) to a final volume of 200 μL. Bound and free radioligand were separated by filtration under vacuum through Whatman glass filters. The filters were then washed and subjected to scintillation counting. Results were expressed as a percentage of control-specific binding ([measured specific binding / control-specific binding]). * 100) The results for the compound having formula B(II) are shown in Table 5. [Table 5]

[0268] Example 3 - Preparation of a third N-propylamine-fused heterocyclic mescaline derivative Referring to Figure 6A, triethylamine (924 µL, 6.59 mmol) was added dropwise to formic acid (622 µL, 16.5 mmol) at 0 °C. After this, piperonal (1) (500 mg, 3.30 mmol) and 2,2-dimethyl-1,3-dioxane-4,6-dione (2) (533 mg, 3.63 mmol) were added, and the entire mixture was dissolved in DMF (20 mL). The flask was heated to 105 °C, and CO2 gradually evolved from the reaction mixture. After 3 h, the mixture was cooled to room temperature and 40 mL of cold water was added. The pH was adjusted to approximately 2 with 1 M aqueous HCl, and the aqueous phase was extracted with EtOAc (4 x 30 mL). All organic layers were combined, washed with dilute aqueous HCl (0.1 M), water, brine, and dried (MgSO4). The mixture was filtered, concentrated and purified by FC on silica gel (12 g, DCM / MeOH, 100:0 to 90:10) to give phenylpropionic acid N (542 mg, 85%) as a pale yellow solid. 1H NMR (400 MHz, CDCl) δ 6.73 (d, J = 7.8 Hz, 1H), 6.70 (d, J = 1.7 Hz, 1H), 6.66 (dd, J = 7.9 Hz, 1.8 Hz, 1H), 5.93 (s, 2H), 2.88 (t, 7.6 Hz, 2H), 2.63 (t, 7.7 Hz, 2H) (Figure 6A, chemical reaction (a); see also chemical reaction (a) in Figure 3B(i)).

[0269] Referring to Figure 6B, N-phenylpropionic acid (200 mg, 1.03 mmol), EDC.HCl (416 mg, 2.06 mmol), and N-hydroxysuccinimide (242 mg, 2.06 mmol) were added to a vial, followed by anhydrous THF (2.06 mL) and DMF (515 μL). The resulting mixture was stirred for 1 hour (the material gradually dissolved), after which pyrrolidine (173 μL, 2.06 mmol) was added. The reaction was stirred overnight at room temperature. The mixture was poured into a separatory funnel containing 50 mL of water and 50 mL of EtOAc. The aqueous phase was extracted with ethyl acetate (3 × 30 mL), and the combined organic layers were washed with 0.1 M HCl, water, brine, and dried over MgSO4. After filtration and evaporation of the solvent, the crude residue was purified by FC on silica gel (12 g, DCM / MeOH 100:0 to 90:10) to give the pure product, MM716 (205 mg, 80%) as a colorless oil. LRMS-HESI: [M+H] + Calculated m / z 248.13, observed 248.16. 1 H NMR (400 MHz, CDCl) δ 6.73-6.66 (m, 3H), 5.91 (s, 2H), 3.47-3.44 (m, 2H), 3.32-3.29 (m, 2H), 2.90 (t, J = 7.8 Hz, 2H), 2.51 (t, J = 7.8 Hz, 2H), 1.89-1.81 (m, 4H) (Figure 6B, chemical reaction (c); see also chemical reaction (c1) in Figure 3B(i) and Figure 3B(ii)).

[0270] MM716 has been shown to correspond to chemical compound F(III): [ka]

[0271] 5-HT Receptor Radioligand Competition Assay. 5-HT 1A and 5-HT 2A Activity at the receptor was evaluated as described for Example 2, except that a compound having formula F(III) was evaluated instead of a compound having formula B(II). Table 1 shows the radioligand competition assay results for the positive control, negative control, and compound having formula F(III) as a function of K i Considering the results for both the positive and negative controls, the negative control shows a reliable K i Insufficient data were available for the calculation (i.e., K i >1000μM), 5-HT 1A The K obtained for the compound having formula D(I) at the receptor i Values ​​(>1000 μM, Table 1) indicate little or no ligand-receptor binding. 2A The K obtained for compounds with formula F(III) at the receptor i The value (152 μM, Table 1) represents the ligand-receptor binding.

[0272] In vitro investigation of pharmacological interaction profiles at receptors and transporters associated with target health conditions Compounds having formula F(III) were evaluated for binding and / or interaction at 11 different receptors and transporters with known or suspected associations with mental health conditions and / or neuropathologies. This study was performed by the contract research organization (CRO) Eurofins Cerep (Cell L'Evescault, France) using standard assay procedures (https: / / www.eurofinsdiscovery.com / solution / target-based-assays). Data were analyzed by comparing derivative molecules with the following eight GPCR receptors: HTR1A (5-HTR1B), HTR2A (5-HTR3A), HTR4A (5-HTR5A), HTR6A (5-HTR6B), HTR7A (5-HTR8A), HTR9A (5-HTR9A), HTR10A (5-HTR11A), HTR12A (5-HTR13A), HTR14A (5-HTR15A), HTR16A (5-HTR16A), HTR17A (5-HTR18A), HTR18B (5-HTR19A), HTR19B (5-HTR19B), HTR18C (5-HTR19B), HTR19C (5-HTR19C), HTR18D (5-HTR19C), HTR19D (5-HTR19D), HTR19E (5-HTR19E), HTR20A (5-HTR20A), HTR21A (5-HTR21A), HTR22A (5-HTR22A), HTR23A (5-HTR23A), HTR30A (5-HTR19C), HTR31A (5-HTR19C), HTR41A (5-HTR19C), HTR42A (5-HTR19C), HTR43A (5-HTR19C), HTR54A (5-HTR19C), HTR55A (5-HTR19C 1A ), HTR2A(5-HTR 2A ), HTR2B(5-HT 2B ), HTR2C(5-HT2C ), HTR7 (5-HT7), alpha 2A (α 2A ), MT1 (MT1), D3 (D3), and three transporters (SERT, DAT, NET). Assays were performed using the same materials and procedures outlined in Example 2, except that a compound having formula F(III) was used instead of a compound having formula B(II). Overall assay conditions are summarized in Tables 3 and 4 for GPCRs and transporters, respectively. Results for all calibrator compounds, control compounds, and test compounds, such as the compound having formula F(III), are summarized in Table 5.

[0273] Example 4 - Preparation of a fourth N-propylamine-fused heterocyclic mescaline derivative Referring to Figure 7A, triethylamine (917 µL, 6.55 mmol) was added dropwise to formic acid (618 µL, 16.4 mmol) at 0 °C. After this, 6-bromo-1,3-benzodioxole-5-carboxaldehyde (1) (750 mg, 3.27 mmol) and 2,2-dimethyl-1,3-dioxane-4,6-dione (2) (530 mg, 3.60 mmol) were added, and the entire mixture was dissolved in DMF (19.8 mL). The flask was heated to 105 °C, and CO2 was gradually released from the reaction mixture. After 3 h, the mixture was cooled to room temperature and 40 mL of cold water was added. The pH was adjusted to approximately 2 with 1 M aqueous HCl, and the aqueous phase was extracted with EtOAc (4 x 30 mL). All organic layers were combined, washed with dilute aqueous HCl (0.1 M), water, brine, and dried (MgSO4). The mixture was filtered, concentrated and purified by FC on silica gel (12 g, DCM / MeOH, 100:0 to 90:10) to give pure compound O (611 mg, 68%) as a light brown solid. 1 H NMR (400 MHz, CDCl) δ 6.99 (s, 1H), 6.76 (s, 1H), 5.95 (s, 2H), 2.98 (t, J = 7.7 Hz, 2H), 2.66 (t, J = 7.6 Hz, 2H) (Figure 7A, chemical reaction (a), see also chemical reaction (a) in Figure 3B(i)).

[0274] Referring to Figure 7B, phenylpropionic acid 0 (200 mg, 732 μmol), EDC.HCl (296 mg, 1.46 mmol), and N-hydroxysuccinimide (172 mg, 1.46 mmol) were added to a vial, followed by anhydrous THF (1.46 mL) and DMF (366 μL). The resulting mixture was stirred for 1 hour (the material gradually dissolved), after which pyrrolidine (123 μL, 1.46 mmol) was added. The reaction was stirred overnight at room temperature. The mixture was poured into a separatory funnel containing 50 mL of water and 50 mL of EtOAc. The aqueous phase was extracted with ethyl acetate (3 × 30 mL), and the combined organic layers were washed with 0.1 M HCl, water, brine, and dried over MgSO4. After filtration and evaporation of the solvent, the crude material was subjected to purification by FC on silica gel (12 g, DCM / MeOH 100:0 to 90:10) to give the pure product, MM717 (180 mg, 75%) as a white solid. LRMS-HESI: [M+H] + Calculated m / z 328.04, observed 327.98. 1 H NMR (400 MHz, CDCl) δ 6.97 (s, 1H), 6.81 (s, 1H), 5.93 (s, 2H), 3.46 (brt, J = 6.9 Hz, 2H), 3.35 (brt, J = 6.7 Hz, 2H), 3.00 (t, J = 7.8 Hz, 2H), 2.53 (t, J = 7.8 Hz, 2H), 1.93-1.82 (m, 4H) (Figure 7B, reaction (c), see also reaction (c1) in Figure 3B(i) and Figure 3B(ii)).

[0275] MM717 has been shown to correspond to the chemical compound F(IV): [ka]

[0276] 5-HT Receptor Radioligand Competition Assay. 5-HT 1AActivity at the receptor was evaluated as described in Example 2, except that a compound having formula F(IV) was evaluated instead of a compound having formula B(II). Table 1 shows the radioligand competition assay results for the positive control, negative control, and compound having formula F(IV), as measured by K i Considering the results for both the positive and negative controls, the negative control shows a reliable K i Insufficient data were available for the calculation (i.e., K i >1000μM), 5-HT 1A The K obtained for the compound having formula F(IV) at the receptor i The value (84.5 μM, Table 1) represents the ligand-receptor binding.

[0277] In vitro investigation of pharmacological interaction profiles at receptors and transporters associated with target health conditions Compounds having formula F(IV) were evaluated for binding and / or interaction at 11 different receptors and transporters with known or suspected associations with mental health conditions and / or neuropathologies. This study was performed by the contract research organization (CRO) Eurofins Cerep (Cell L'Evescault, France) using standard assay procedures (https: / / www.eurofinsdiscovery.com / solution / target-based-assays). Data were analyzed by comparing derivative molecules with the following eight GPCR receptors: HTR1A (5-HTR1B), HTR2A (5-HTR3A), HTR4A (5-HTR5A), HTR6A (5-HTR6B), HTR7A (5-HTR8A), HTR9A (5-HTR9A), HTR10A (5-HTR11A), HTR12A (5-HTR13A), HTR14A (5-HTR15A), HTR16A (5-HTR16A), HTR17A (5-HTR18A), HTR18B (5-HTR19A), HTR19B (5-HTR19B), HTR18C (5-HTR19B), HTR19C (5-HTR19C), HTR18D (5-HTR19C), HTR19D (5-HTR19C), HTR19E (5-HTR19E), HTR20A (5-HTR20A), HTR21A (5-HTR21A), HTR22A (5-HTR22A), HTR23A (5-HTR23A), HTR30A (5-HTR19C), HTR31A (5-HTR19C), HTR41A (5-HTR19C), HTR42A (5-HTR19C), HTR43A (5-HTR19C), HTR54A (5-HTR19C), HTR55A (5-HTR19C 1A ), HTR2A(5-HTR 2A ), HTR2B(5-HT 2B ), HTR2C(5-HT 2C ), HTR7 (5-HT7), alpha 2A (α 2A), MT1 (MT1), D3 (D3), and three transporters (SERT, DAT, NET). Assays were performed using the same materials and procedures outlined in Example 2, except that a compound having formula F(IV) was used instead of a compound having formula B(II). Overall assay conditions are summarized in Tables 3 and 4 for GPCRs and transporters, respectively. Results for all calibrator compounds, control compounds, and test compounds, such as the compound having formula F(IV), are summarized in Table 5.

[0278] Example 5 - Preparation of a fifth N-propylamine-fused heterocyclic mescaline derivative Referring to Figure 8, MM716 (150 mg, 607 μmol) (prepared as described in Example 3) was added to a round-bottom flask, followed by dry THF (5.50 mL). The solution was cooled to 0 °C. Lithium aluminum hydride (2 M in THF, 910 μL, 1.82 mmol) was carefully added, and the mixture was allowed to warm to room temperature and react overnight. The mixture was cooled to 0 °C, and excess LiAlH was quenched with cold water (5 mL). The resulting solution was poured into a separatory funnel containing 30 mL of water, and the aqueous phase was extracted with EtOAc (4 × 30 mL). The organic layers were combined, washed with brine, dried (MgSO), filtered, and concentrated to leave a colorless oil. The crude product was purified by FC on silica gel (4 g, DCM / MeOH 100:0 to 90:10) to give the desired product, MM719 (91.0 mg, 64%), as a colorless oil. LRMS-HESI:[M+H] + Calculated m / z 234.15, observed 234.12. 1 H NMR (400 MHz, CDCl) δ 6.71 (d, J = 7.9 Hz, 1H), 6.68 (d, J = 1.7 Hz, 1H), 6.62 (dd, J = 7.9 Hz, 1.7 Hz, 1H), 5.91 (s, 2H), 2.59-2.45 (m, 8H), 1.86-1.75 (m, 6H) (Figure 8, chemical reaction (d); see also chemical reaction (d) in Figure 3B(ii)).

[0279] MM719 has been shown to correspond to chemical compound C(III): [ka]

[0280] 5-HT Receptor Radioligand Competition Assay. 5-HT 1A Activity at the receptor was evaluated as described in Example 2, except that a compound having formula C(III) was evaluated instead of a compound having formula B(II). Table 1 shows the radioligand competition assay results for the positive control, negative control, and compound having formula C(III) as a function of K i Considering the results for both the positive and negative controls, the negative control shows a reliable K i Insufficient data were available for the calculation (i.e., K i >1000μM), 5-HT 1A The K obtained for compounds with formula C(III) at the receptor i The value (2.33 μM, Table 1) represents the ligand-receptor binding.

[0281] In vitro investigation of pharmacological interaction profiles at receptors and transporters associated with target health conditions Compounds having formula C(III) were evaluated for binding and / or interaction at 11 different receptors and transporters with known or suspected associations with mental health conditions and / or neuropathologies. This study was performed by the contract research organization (CRO) Eurofins Cerep (Cell L'Evescault, France) using standard assay procedures (https: / / www.eurofinsdiscovery.com / solution / target-based-assays). Data were analyzed by comparing derivative molecules with the following eight GPCR receptors: HTR1A (5-HTR1B), HTR2A (5-HTR3A), HTR4A (5-HTR5A), HTR6A (5-HTR6B), HTR7A (5-HTR8A), HTR9A (5-HTR9A), HTR10A (5-HTR11A), HTR12A (5-HTR13A), HTR14A (5-HTR15A), HTR16A (5-HTR16A), HTR17A (5-HTR18A), HTR18B (5-HTR19A), HTR19B (5-HTR19B), HTR18C (5-HTR19B), HTR19C (5-HTR19C), HTR18D (5-HTR19C), HTR19D (5-HTR19C), HTR19E (5-HTR19C), HTR19F (5-HTR19C), HTR19F (5-HTR19C), HTR20A ...30A (5-HTR19C), HTR30A (5-HTR19C), HTR40A (5-HTR19C), HTR40A (5-HTR19C 1A ), HTR2A(5-HTR 2A ), HTR2B(5-HT 2B ), HTR2C(5-HT 2C), HTR7 (5-HT7), alpha 2A (α 2A ), MT1 (MT1), D3 (D3), and three transporters (SERT, DAT, NET). Assays were performed using the same materials and procedures outlined in Example 2, except that a compound having formula C(III) was used instead of a compound having formula B(II). Overall assay conditions are summarized in Tables 3 and 4 for GPCRs and transporters, respectively. Results for all calibrator compounds, control compounds, and test compounds, such as the compound having formula C(III), are summarized in Table 5.

[0282] Example 6 - Preparation of a sixth N-propylamine-fused heterocyclic mescaline derivative Referring to Figure 9, compound MM719 (70.0 mg, 300 μmol) (prepared as described in Example 5) was dissolved in acetic acid (1.58 mL). To this was added a solution of bromine (25.0 μL, 486 μmol) in acetic acid (250 μL). The reaction mixture was allowed to react at room temperature for 3 hours, at which point starting material was no longer present (TLC, DCM / MeOH 9:1). The mixture was poured into water (15 mL), and the pH was increased to approximately 10 using 1 M aqueous NaOH. The aqueous layer was extracted with DCM (3 × 25 mL). The combined organic layers were washed with water, brine, dried over MgSO4, filtered, and concentrated to leave a colorless oil. The crude material was purified by FC on silica gel (4 g, DCM / MeOH 100:0 to 90:10) to give MM720 (65.1 mg, 69%) as a colorless oil. LRMS-HESI:[M+H] + Calculated m / z 312.06, observed 312.05. 1 H NMR (400 MHz, CDCl) δ 6.97 (s, 1H), 6.71 (s, 1H), 5.94 (s, 2H), 2.70-2.66 (m, 2H), 2.57-2.50 (m, 6H), 1.85-1.77 (m, 6H). (Figure 9, chemical reaction (g1); see also chemical reaction (g) in Figure 3B(ii)).

[0283] MM720 has been shown to correspond to the chemical compound C(IV): [ka]

[0284] 5-HT Receptor Radioligand Competition Assay. 5-HT 1A Activity at the receptor was evaluated as described in Example 2, except that a compound having formula C(IV) was evaluated instead of a compound having formula B(II). Table 1 shows the radioligand competition assay results for the positive control, negative control, and compound having formula C(IV), as measured by K i Considering the results for both the positive and negative controls, the negative control shows a reliable K i Insufficient data were available for the calculation (i.e., K i >1000μM), 5-HT 1A The K obtained for the compound having formula C(IV) at the receptor i The value (0.596 μM, Table 1) represents the ligand-receptor binding.

[0285] In vitro investigation of pharmacological interaction profiles at receptors and transporters associated with target health conditions Compounds having formula C(IV) were evaluated for binding and / or interaction at 11 different receptors and transporters with known or suspected associations with mental health conditions and / or neuropathologies. This study was performed by the contract research organization (CRO) Eurofins Cerep (Cell L'Evescault, France) using standard assay procedures (https: / / www.eurofinsdiscovery.com / solution / target-based-assays). Data were analyzed by comparing derivative molecules with the following eight GPCR receptors: HTR1A (5-HTR1B), HTR2A (5-HTR3A), HTR4A (5-HTR5A), HTR6A (5-HTR6B), HTR7A (5-HTR8A), HTR9A (5-HTR9A), HTR10A (5-HTR11A), HTR12A (5-HTR13A), HTR14A (5-HTR15A), HTR16A (5-HTR16A), HTR17A (5-HTR18A), HTR18B (5-HTR19A), HTR19B (5-HTR19B), HTR18C (5-HTR19B), HTR19C (5-HTR19C), HTR18D (5-HTR19C), HTR19D (5-HTR19D), HTR19E (5-HTR19E), HTR20A (5-HTR20A), HTR21A (5-HTR21A), HTR22A (5-HTR22A), HTR23A (5-HTR23A), HTR30A (5-HTR19C), HTR31A (5-HTR19C), HTR41A (5-HTR19C), HTR42A (5-HTR19C), HTR43A (5-HTR19C), HTR54A (5-HTR19C), HTR55A (5-HTR19C 1A ), HTR2A(5-HTR 2A ), HTR2B(5-HT 2B ), HTR2C(5-HT 2C ), HTR7 (5-HT7), alpha 2A (α2A ), MT1 (MT1), D3 (D3), and three transporters (SERT, DAT, NET). Assays were performed using the same materials and procedures outlined in Example 2, except that a compound having formula C(IV) was used instead of a compound having formula B(II). Overall assay conditions are summarized in Tables 3 and 4 for GPCRs and transporters, respectively. Results for all calibrator compounds, control compounds, and test compounds, such as the compound having formula C(IV), are summarized in Table 5.

[0286] Example 7 - Preparation of the seventh N-propylamine-fused heterocyclic mescaline derivative Referring to Figure 10, to a solution of MM710 (47.0 mg, 192 μmol) (prepared as described in Example 2) in ethanol (1.92 mL) under a nitrogen atmosphere was added palladium on carbon 10 wt% (20.4 mg, 192 μmol). H2 gas (balloon) was bubbled through the mixture for 15 minutes until a hydrogen atmosphere was established, then the mixture was left under hydrogen for 36 hours. The catalyst was removed through a 0.45 μm syringe filter, which was then washed with methanol (3 mL). The filtrate was concentrated under reduced pressure. Purification by FC on silica gel (4 g, 0-10% MeOH / DCM) afforded MM730 (racemic) as a white powder (16.8 mg, 34%). LRMS-HESI: [M+H] + Calculated m / z 248.16, observed 248.20. 1 H NMR (400 MHz, CDCl) δ 6.75 (d, J = 7.9 Hz, 1H), 6.67 (d, J = 1.7 Hz, 1H), 6.62 (dd, J = 7.8, 1.7 Hz, 1H), 5.95 (s, 2H), 3.47-2.97 (m, 4H), 2.85 (d, J = 6.8 Hz, 2H), 2.70 (dd, J = 13.8, 7.1 Hz, 1H), 2.54 (dd, J = 13.8, 7.3 Hz, 1H), 2.22-2.06 (m, 5H), 1.22 (d, J = 6.6 Hz, 3H) (Figure 10, chemical reaction (g2); see also chemical reaction (g) in Figure 3A(ii)).

[0287] MM730 has been shown to correspond to chemical compound A(II): [ka]

[0288] 5-HT Receptor Radioligand Competition Assay. 5-HT 1A Activity at the receptor was evaluated as described in Example 2, except that a compound having Formula A(II) was evaluated instead of a compound having Formula B(II). Table 1 shows the radioligand competition assay results for the positive control, negative control, and compound having Formula A(II). i Considering the results for both the positive and negative controls, the negative control shows a reliable K i Insufficient data were available for the calculation (i.e., K i >1000μM), 5-HT 1A The K obtained for the compound having formula A(II) at the receptor i The value (8.0 μM, Table 1) indicates the ligand-receptor binding.

[0289] In vitro investigation of pharmacological interaction profiles at receptors and transporters associated with target health conditions Compounds having formula A (II) were evaluated for binding and / or interaction at 11 different receptors and transporters with known or suspected associations with mental health conditions and / or neuropathologies. This study was performed by the contract research organization (CRO) Eurofins Cerep (Cell L'Evescault, France) using standard assay procedures (https: / / www.eurofinsdiscovery.com / solution / target-based-assays). Data were analyzed by comparing derivative molecules with the following eight GPCR receptors: HTR1A (5-HTR1B), HTR2A (5-HTR3A), HTR4A (5-HTR5A), HTR6A (5-HTR6B), HTR7A (5-HTR8A), HTR9A (5-HTR9A), HTR10A (5-HTR11A), HTR12A (5-HTR13A), HTR14A (5-HTR15A), HTR16A (5-HTR16A), HTR17A (5-HTR18A), HTR18B (5-HTR19A), HTR19B (5-HTR19B), HTR18C (5-HTR19B), HTR19C (5-HTR19C), HTR18D (5-HTR19C), HTR19D (5-HTR19C), HTR19E (5-HTR19E), HTR20A (5-HTR20A), HTR21A (5-HTR21A), HTR22A (5-HTR22A), HTR23A (5-HTR23A), HTR30A (5-HTR19C), HTR31A (5-HTR19C), HTR41A (5-HTR19C), HTR42A (5-HTR19C), HTR43A (5-HTR19C), HTR44A (5-HTR19C), HTR51A (5-HTR19C 1A ), HTR2A(5-HTR 2A ), HTR2B(5-HT 2B ), HTR2C(5-HT 2C), HTR7 (5-HT7), alpha 2A (α 2A ), MT1 (MT1), D3 (D3), and three transporters (SERT, DAT, NET). Assays were performed using the same materials and procedures outlined in Example 2, except that a compound having Formula A(II) was used instead of a compound having Formula B(II). Overall assay conditions are summarized in Tables 3 and 4 for GPCRs and transporters, respectively. Results for all calibrator compounds, control compounds, and test compounds, such as compounds having Formula A(II), are summarized in Table 5.

[0290] Example 8 - Preparation of the eighth N-propylamine-fused heterocyclic mescaline derivative Referring to Figure 11, to a solution of MM709 (45.0 mg, 193 μmol) (prepared as described in Example 1) in ethanol (1.93 mL) under a nitrogen atmosphere was added palladium on carbon 10% wt (20.5 mg, 0.0193 μmol). H2 gas (balloon) was bubbled through the mixture for 15 minutes until a hydrogen atmosphere was established, then the mixture was left under hydrogen for 36 hours with vigorous stirring. The catalyst was removed through a 0.45 μm syringe filter, which was then washed with methanol (3 mL). The filtrate was concentrated under reduced pressure. Purification by FC on silica gel (4 g, 0-10% MeOH / DCM) gave MM731 as a white powder (12.6 mg, 28%). LRMS-HESI: [M+H] + Calculated m / z 236.16, observed 236.17. 1 H NMR (400 MHz, CDCl) δ 6.74 (d, J = 7.9 Hz, 1H), 6.69-6.61 (m, 2H), 5.94 (s, 2H), 3.09 (q, J = 7.4 Hz, 4H), 2.98-2.90 (m, 2H), 2.65 (t, J = 7.2 Hz, 2H), 2.17-2.06 (m, 2H), 1.36 (t, J = 7.3 Hz, 6H) (Figure 11, chemical reaction (h); see also chemical reaction (h) in Figure 3A(ii)).

[0291] MM731 has been shown to correspond to chemical compound C(I): [ka]

[0292] 5-HT Receptor Radioligand Competition Assay. 5-HT 1A Activity at the receptor was evaluated as described in Example 2, except that a compound having formula C(I) was evaluated instead of a compound having formula B(II). Table 1 shows the radioligand competition assay results for the positive control, negative control, and compound having formula C(I), as measured by K i Considering the results for both the positive and negative controls, the negative control shows a reliable K i Insufficient data were available for the calculation (i.e., K i >1000μM), 5-HT 1A The K obtained for the compound having formula C(I) at the receptor i The value (2.9 μM, Table 1) represents the ligand-receptor binding.

[0293] In vitro investigation of pharmacological interaction profiles at receptors and transporters associated with target health conditions Compounds having formula C(I) were evaluated for binding and / or interaction at 11 different receptors and transporters with known or suspected associations with mental health conditions and / or neuropathologies. This study was performed by the contract research organization (CRO) Eurofins Cerep (Cell L'Evescault, France) using standard assay procedures (https: / / www.eurofinsdiscovery.com / solution / target-based-assays). Data were analyzed using derivative molecules at the following eight GPCR receptors: HTR1A (5-HTR1B), HTR2A (5-HTR3A), HTR4A (5-HTR5A), HTR6A (5-HTR6B), HTR7A (5-HTR8A), HTR9A (5-HTR9A), HTR10A (5-HTR11A), HTR12A (5-HTR13A), HTR14A (5-HTR15A), HTR16A (5-HTR16A), HTR17A (5-HTR18A), HTR18B (5-HTR19A), HTR19B (5-HTR19B), HTR18C (5-HTR19B), HTR19C (5-HTR19C), HTR18D (5-HTR19C), HTR19D (5-HTR19D), HTR19E (5-HTR19E), HTR20A (5-HTR20A), HTR21A (5-HTR21A), HTR22A (5-HTR22A), HTR23A (5-HTR23A), HTR30A (5-HTR19C), HTR31A (5-HTR19C), HTR41A (5-HTR19C), HTR42A (5-HTR19C), HTR43A (5-HTR19C), HTR54A (5-HTR19C), HTR55A (5-HTR19C), 1A ), HTR2A(5-HTR 2A ), HTR2B(5-HT 2B ), HTR2C(5-HT 2C), HTR7 (5-HT7), alpha 2A (α 2A ), MT1 (MT1), D3 (D3), and three transporters (SERT, DAT, NET). Assays were performed using the same materials and procedures outlined in Example 2, except that a compound having formula C(I) was used instead of a compound having formula B(II). Overall assay conditions are summarized in Tables 3 and 4 for GPCRs and transporters, respectively. Results for all calibrator compounds, control compounds, and test compounds, such as compounds having formula C(I), are summarized in Table 5.

[0294] Example 9 - Preparation of the ninth N-propylamine-fused heterocyclic mescaline derivative Referring to Figure 12A, triethylamine (933 µL, 6.66 mmol) was added dropwise to formic acid (628 µL, 16.7 mmol) at 0 °C. After this, 6-methoxy-1,3-benzodioxole-5-carbaldehyde (1) (600 mg, 3.33 mmol) and 2,2-dimethyl-1,3-dioxane-4,6-dione (2) (539 mg, 3.66 mmol) were added, and the entire mixture was dissolved in DMF (20.2 mL). The flask was heated to 105 °C, and CO2 gradually evolved from the reaction mixture. After 3 h, the mixture was cooled to room temperature and 40 mL of cold water was added. The pH was adjusted to approximately 2 with 1 M aqueous HCl, and the aqueous phase was extracted with EtOAc (4 x 30 mL). All organic layers were combined, washed with dilute aqueous HCl (0.1 M), water, brine, and dried (MgSO4). The mixture was filtered, concentrated and purified by FC on silica gel (12 g, DCM / MeOH, 100:0 to 90:10) to give intermediate Q (490 mg, 66%). 1 H NMR (400 MHz, CDCl) δ 6.67 (s, 1H), 6.50 (s, 1H), 5.89 (s, 2H), 3.76 (s, 3H), 2.85 (t, J = 7.6 Hz, 2H), 2.60 (t, J = 7.7 Hz, 2H) (Figure 12A, chemical reaction (a), see also chemical reaction (a) in Figure 3B(i)).

[0295] Referring to FIG. 12B, phenyl proprionic acid Q (160 mg, 714 μmol), EDC.HCl (288 mg, 1.43 mmol), and N-hydroxysuccinimide (168 mg, 1.43 mmol) were added to a vial, followed by anhydrous THF (1.43 mL) and DMF (357 μL). The resulting mixture was stirred for 1 hour (the material gradually dissolved), after which pyrrolidine (120 μL, 1.43 mmol) was added. The reaction was stirred overnight at room temperature. The mixture was poured into a separatory funnel containing 50 mL of water and 50 mL of EtOAc. The aqueous phase was extracted with ethyl acetate (3×30 mL), and the combined organic layers were washed with 0.1 M HCl, water, brine, and dried over MgSO4. After filtration and evaporation of the solvent, the remaining crude material was purified by FC on silica gel (4 g, DCM / MeOH 100:0 to 90:10) to give the pure product, MM735 (153 mg, 77%), as a pale orange solid. LRMS-HESI: [M+H] + Calculated m / z 278.14, observed 278.13. 1 H NMR (400 MHz, CDCl) δ 6.70 (s, 1H), 6.50 (s, 1H), 5.88 (s, 2H), 3.76 (s, 3H), 3.48-3.34 (brm, 4H), 2.90-2.86 (m, 2H), 2.52-2.48 (m, 2H), 1.86 (brm, 4H) (Figure 12B, chemical reaction (c), see also chemical reaction (c1) in Figure 3B(i) and Figure 3B(ii)).

[0296] MM735 has been shown to correspond to the chemical compound F(V): [ka]

[0297] 5-HT Receptor Radioligand Competition Assay. 5-HT 1AActivity at the receptor was evaluated as described in Example 2, except that a compound having formula F(V) was evaluated instead of a compound having formula B(II). Table 1 shows the radioligand competition assay results for the positive control, negative control, and compound having formula F(V), as measured by K i Considering the results for both the positive and negative controls, the negative control shows a reliable K i Insufficient data were available for the calculation (i.e., K i >1000μM), 5-HT 1A The K obtained for compounds with formula F(V) at the receptor i The value (363.5 μM, Table 1) represents the ligand-receptor binding.

[0298] 5-HT 1A Receptor Functional Cellular Response Assay: 5-HT in Engineered Cellular Systems 1A Functional engagement of the receptor was assessed as described in Example 2, except that a compound having formula F(V) was evaluated instead of a compound having formula B(II). Table 2 shows the functional assay results for the positive control, calibrator, and compound having formula F(V) as measured by EC 50 Considering the results for the control and calibrator compounds, negative cell responses are shown in the form of EC 50 EC for compounds having the formula F(V) in this assay, corresponding to a value >1000 μM 50 The value (10.0 μM, Table 2) suggested ligand-receptor binding.

[0299] In vitro investigation of pharmacological interaction profiles at receptors and transporters associated with target health conditions Compounds having formula F(V) were evaluated for binding and / or interaction at 11 different receptors and transporters with known or suspected associations with mental health conditions and / or neuropathologies. This study was performed by the contract research organization (CRO) Eurofins Cerep (Cell L'Evescault, France) using standard assay procedures (https: / / www.eurofinsdiscovery.com / solution / target-based-assays). Data were analyzed by comparing derivative molecules with the following eight GPCR receptors: HTR1A (5-HTR1B), HTR2A (5-HTR3A), HTR4A (5-HTR5A), HTR6A (5-HTR6B), HTR7A (5-HTR8A), HTR9A (5-HTR9A), HTR10A (5-HTR11A), HTR12A (5-HTR13A), HTR14A (5-HTR15A), HTR16A (5-HTR16A), HTR17A (5-HTR18A), HTR18B (5-HTR19A), HTR19B (5-HTR19B), HTR18C (5-HTR19B), HTR19C (5-HTR19C), HTR18D (5-HTR19C), HTR19D (5-HTR19D), HTR19E (5-HTR19E), HTR20A (5-HTR20A), HTR21A (5-HTR21A), HTR22A (5-HTR22A), HTR23A (5-HTR23A), HTR30A (5-HTR19C), HTR31A (5-HTR19C), HTR41A (5-HTR19C), HTR42A (5-HTR19C), HTR43A (5-HTR19C), HTR54A (5-HTR19C), HTR55A (5-HTR19C 1A ), HTR2A(5-HTR 2A ), HTR2B(5-HT 2B ), HTR2C(5-HT 2C ), HTR7 (5-HT7), alpha 2A (α 2A ), MT1 (MT1), D3 (D3), and three transporters (SERT, DAT, NET). Assays were performed using the same materials and procedures outlined in Example 2, except that a compound having formula F(V) was used instead of a compound having formula B(II). Overall assay conditions are summarized in Tables 3 and 4 for GPCRs and transporters, respectively. Results for all calibrator compounds, control compounds, and test compounds, such as the compound having formula F(V), are summarized in Table 5.

[0300] Example 10 - Preparation of the tenth N-propylamine-fused heterocyclic mescaline derivative Referring to Figure 13, MM735 (120 mg, 433 μmol) (prepared as described in Example 9) was added to a round-bottom flask, followed by dry THF (3.92 mL). The reaction mixture was cooled to 0 °C. Lithium aluminum hydride (2 M in THF, 649 μL, 1.30 mmol) was carefully added, and the mixture was allowed to warm to room temperature and react overnight. The mixture was cooled to 0 °C, and excess LiAlH was quenched with cold water (4 mL). The resulting solution was poured into a separatory funnel containing 30 mL of water, and the aqueous phase was extracted with EtOAc (4 × 30 mL). The organic layers were combined, washed with brine, dried (MgSO), filtered, and concentrated to leave a colorless oil. The crude residue was purified by FC on silica gel (4 g, DCM / MeOH 100:0 to 90:10) to give the desired product, MM736 (70.0 mg, 61%), as a colorless oil. LRMS-HESI:[M+H] + Calculated m / z 264.16, observed 264.15. 1 H NMR (400 MHz, CDCl) δ 6.64 (s, 1H), 6.50 (s, 1H), 5.88 (s, 2H), 3.75 (s, 3H), 2.58-2.54 (m, 8H), 1.81 (brs, 6H) (Figure 13, chemical reaction (d), see also chemical reaction (d) in Figure 3B(ii)).

[0301] MM736 has been shown to be a chemical compound consistent with C(V): [ka]

[0302] 5-HT Receptor Radioligand Competition Assay. 5-HT 1A Activity at the receptor was evaluated as described in Example 2, except that a compound having formula C(V) was evaluated instead of a compound having formula B(II). Table 1 shows the radioligand competition assay results for the positive control, negative control, and compound having formula C(V), as measured by K i Considering the results for both the positive and negative controls, the negative control shows a reliable K iInsufficient data were available for the calculation (i.e., K i >1000μM), 5-HT 1A The K obtained for the compound with formula C(V) at the receptor i The value (5.0 μM, Table 1) indicates the ligand-receptor binding.

[0303] 5-HT 1A Receptor Functional Cellular Response Assay: 5-HT in Engineered Cellular Systems 1A Functional engagement of the receptor was assessed as described in Example 2, except that a compound having formula C(V) was evaluated instead of a compound having formula B(II). Table 2 shows the functional assay results for the positive control, calibrator, and compound having formula C(V) as measured by EC 50 Considering the results for the control and calibrator compounds, negative cell responses are shown in the form of EC 50 EC for compounds having formula C(V) in this assay, corresponding to a value >1000 μM 50 The value (116.3 μM, Table 2) suggested ligand-receptor binding.

[0304] In vitro investigation of pharmacological interaction profiles at receptors and transporters associated with target health conditions Compounds having formula C(V) were evaluated for binding and / or interaction at 11 different receptors and transporters with known or suspected associations with mental health conditions and / or neuropathologies. This study was performed by the contract research organization (CRO) Eurofins Cerep (Cell L'Evescault, France) using standard assay procedures (https: / / www.eurofinsdiscovery.com / solution / target-based-assays). Data were analyzed using derivative molecules at the following eight GPCR receptors: HTR1A (5-HTR1B), HTR2A (5-HTR3A), HTR4A (5-HTR5A), HTR6A (5-HTR6B), HTR7A (5-HTR8A), HTR9A (5-HTR9A), HTR10A (5-HTR11A), HTR12A (5-HTR13A), HTR14A (5-HTR15A), HTR16A (5-HTR16A), HTR17A (5-HTR18A), HTR18B (5-HTR19A), HTR19B (5-HTR19B), HTR18C (5-HTR19B), HTR19C (5-HTR19C), HTR18D (5-HTR19C), HTR19D (5-HTR19C), HTR19E (5-HTR19E), HTR20A (5-HTR20A), HTR21A (5-HTR21A), HTR22A (5-HTR22A), HTR23A (5-HTR23A), HTR30A (5-HTR19C), HTR31A (5-HTR19C), HTR41A (5-HTR19C), HTR42A (5-HTR19C), HTR43A (5-HTR19C), HTR54A (5-HTR19C), HTR55A (5-HTR19C), 1A ), HTR2A(5-HTR 2A ), HTR2B(5-HT 2B ), HTR2C(5-HT 2C), HTR7 (5-HT7), alpha 2A (α 2A ), MT1 (MT1), D3 (D3), and three transporters (SERT, DAT, NET). Assays were performed using the same materials and procedures outlined in Example 2, except that a compound having formula C(V) was used instead of a compound having formula B(II). Overall assay conditions are summarized in Tables 3 and 4 for GPCRs and transporters, respectively. Results for all calibrator compounds, control compounds, and test compounds, such as the compound having formula C(V), are summarized in Table 5.

[0305] Example 11 - Preparation of the eleventh N-propylamine-fused heterocyclic mescaline derivative Referring to FIG. 17, to a solution of K (216 mg, 1.14 mmol) (prepared as described in Example 2) in MeOH (7.57 mL) under a nitrogen atmosphere was added benzylamine (248 μL, 2.27 mmol). The reaction mixture was heated to 61° C. for 3 hours. After cooling to room temperature, sodium cyanoborohydride (300 mg, 4.54 mmol) was added, and the reaction was allowed to stir at the same temperature under a nitrogen atmosphere for 18 hours. The reaction mixture was diluted with DCM (80 mL) and washed with water (50 mL) and brine (2×50 mL). The organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a crude pale yellow oil. Purification by column chromatography on 12 g normal phase silica using a 0-8 then 70% ethyl acetate-hexane gradient gave the product, MM754 (130 mg, 41%), as a colorless oil. LRMS-HESI: [M+H] + Calculated m / z 282.15, observed m / z 282.23. 1H NMR (400 MHz, CDCl) δ 7.39-7.29 (m, 5H), 6.84-6.78 (m, 2H), 6.78-6.71 (m, 1H), 6.39 (q, J = 1.6 Hz, 1H), 5.97 (s, 2H), 3.83 (s, 2H), 3.35 (d, J = 1.4 Hz, 2H), 1.93 (d, J = 1.4 Hz, 3H). (Figure 17, chemical reaction (f), see also chemical reaction (f) in Figure 3A(i)).

[0306] MM754 has been shown to correspond to chemical compound B(IV): [ka]

[0307] Example 12 - Preparation of the twelfth N-propylamine-fused heterocyclic mescaline derivative Referring to Figure 18, in a capped, pressure-rated vial, MM754 (106 mg, 377 μmol) (prepared as described in Example 11) was dissolved in formic acid (213 μL, 5.65 mmol) and formaldehyde (37% aqueous solution, 252 μL, 3.39 mmol) was added. The reaction mixture was heated at 90 °C with a vent needle for 18 hours. MS indicated the reaction was complete. The reaction mixture was diluted with water (20 mL), basified with 15% NaOH to pH 12, and extracted with DCM (3 x 20 mL). The organic extracts were combined, washed with brine (20 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the crude product. Purification by column chromatography on 4 g normal phase silica using a 0-10% methanol-dichloromethane eluent gradient gave MM755 as a colorless oil (48.3 mg, 43%). LRMS-HESI: [M+H] + Calculated m / z 296.16, observed m / z 296.22. 1H NMR (400 MHz, CDCl) δ 7.42-7.33 (m, 4H), 7.31-7.26 (m, 1H), 6.87-6.75 (m, 3H), 6.43-6.39 (m, 1H), 5.98 (s, 2H), 3.54 (s, 2H), 3.05 (d, J = 1.2 Hz, 2H), 2.22 (s, 3H), 1.97 (d, J = 1.4 Hz, 3H). (Figure 18, chemical reaction (i), see also chemical reaction (i) in Figure 3A(i)).

[0308] MM755 has been shown to correspond to chemical compound B(III): [ka]

[0309] Example 13 - Preparation of the thirteenth N-propylamine-fused heterocyclic mescaline derivative Referring to Figure 19A, to a suspension of sodium hydride (261 mg, 6.51 mmol) in dry THF (3.95 mL) at 0 °C under an inert atmosphere was added a solution of triethyl-2-phosphonopropionate (1.44 mL, 6.51 mmol) in dry THF (7.90 mL). After stirring for 30 minutes, a solution of 2,2-difluoro-5-formylbenzodioxole (703 μL, 5.21 mmol) in dry THF (3.95 mL) was added dropwise over 10 minutes. The reaction mixture was gradually warmed to room temperature, and stirring was continued for 18 hours. Water (5 mL) was added to the stirred mixture, and the organic solvent was removed under reduced pressure. The aqueous residue was extracted with ethyl acetate (3 × 25 mL), and the organic extracts were combined, dried over magnesium sulfate, and the solvent was removed under reduced pressure. Purification by dry-loading column chromatography on 25 g normal phase silica using a 0-7% ethyl acetate-hexane eluent gradient gave Intermediate 20 as a colorless oil (1.19 g, 85%). LRMS-HESI: [M+H] + Calculated m / z 271.08, observed m / z 271.10. 1H NMR (400 MHz, CDCl) δ 7.63 (tq, J = 1.5, 0.8 Hz, 1H), 7.18-7.07 (m, 3H), 4.30 (q, J = 7.1 Hz, 2H), 2.12 (d, J = 1.6 Hz, 3H), 1.37 (t, J = 7.1 Hz, 3H). (Figure 19A, chemical reaction (d), see also chemical reaction (d) in Figure 3A(i)).

[0310] Referring to FIG. 19B, lithium aluminum hydride (352 mg, 8.81 mmol) was suspended in anhydrous THF (22.0 mL) in a flame-dried flask at −78° C. under a nitrogen atmosphere. To this suspension was added a solution of Intermediate 20 (1.19 g, 4.40 mmol) in anhydrous THF (22.0 mL), and the reaction mixture was stirred at the same temperature for 5 hours. LCMS indicated that the reaction was incomplete; therefore, more dry ice was added, and the insulated bowl was further insulated with tin foil overnight. The reaction mixture was warmed to 0° C. and quenched by the sequential addition of water (0.4 mL), 15% NaOH (0.4 mL), and water (1.2 mL). The reaction mixture was warmed to room temperature and stirred for 15 minutes. Anhydrous magnesium sulfate was added, and the suspension was mixed for an additional 15 minutes. The suspension was filtered, and the filter cake was washed with THF (50 mL) and diethyl ether (50 mL). The filtrate was concentrated under reduced pressure to give a crude colorless oil. Purification by column chromatography on 24 g normal phase silica using a 0-15% ethyl acetate-hexane gradient afforded, after fraction collection, a colorless oil (890 mg). This material was used immediately in the next step. To a solution of this colorless oil (575 mg) in DCM (16.6 mL) was added manganese(IV) oxide (1.17 g, 13.3 mmol), and the reaction mixture was stirred for 18 h. After MS confirmation of product formation, the reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. Purification by column chromatography using a 0-7-15% ethyl acetate-hexane eluent gradient afforded intermediate R as a white solid (376 mg, 54% over two steps). LRMS-HESI: [M+H] + Calculated m / z 227.05, observed m / z 227.03. 1H NMR (400 MHz, CDCl) δ 9.60 (s, 1H), 7.34-7.26 (m, 2H), 7.23 (q, J = 1.5 Hz, 1H), 7.17 (dd, J = 8.2, 0.5 Hz, 1H), 2.09 (d, J = 1.4 Hz, 3H). (Figure 19B, chemical reaction (e), see also chemical reaction (e) in Figure 3A(i)).

[0311] Referring to FIG. 19C, to a solution of intermediate R (308 mg, 1.36 mmol) in MeOH (13.6 mL) under a nitrogen atmosphere was added pyrrolidine (228 μL, 2.72 mmol). The reaction mixture was heated to 60° C. for 4 hours and then cooled to room temperature, after which sodium cyanoborohydride (360 mg, 5.45 mmol) was added. The reaction mixture was allowed to stir at the same temperature for 18 hours and then concentrated under reduced pressure. After dilution with DCM (100 mL), the solution was washed with water (2×25 mL) and brine (25 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Purification by column chromatography on 12 g normal phase silica using a gentle 0-4% methanol-dichloromethane eluent gradient afforded MM775 as a yellow oil (42 mg, 11%). LRMS-HESI: [M+H] + Calculated m / z 282.13, observed m / z 282.12. 1 H NMR (400 MHz, CDCl) δ 7.03-6.93 (m, 3H), 6.44-6.39 (m, 1H), 3.15 (d, J = 1.3 Hz, 2H), 2.55 (ddt, J = 7.5, 6.1, 2.4 Hz, 4H), 1.92 (d, J = 1.4 Hz, 3H), 1.86-1.80 (m, 4H). (Figure 19C, chemical reaction (f), see also chemical reaction (f) in Figure 3A(i)).

[0312] MM775 has been shown to correspond to chemical compound B(V): [ka]

[0313] Example 14 - Preparation of the fourteenth N-propylamine-fused heterocyclic mescaline derivative Referring to Figure 20, J (242 mg, 1.37 mmol) (prepared as described in Example 1) was dissolved in MeOH (13.7 mL) under a nitrogen atmosphere. Acetic acid (197 μL, 3.43 mmol) was added and the solution was allowed to stir for 5 minutes, after which butylamine (363 mg, 2.75 mmol) was added. The reaction was heated to 60°C for 4 hours, then cooled to room temperature, and sodium cyanoborohydride (336 mg, 5.49 mmol) was added. The reaction mixture was allowed to stir under a nitrogen atmosphere for 4 days. The reaction mixture was diluted with DCM (60 mL) and added to a separatory funnel with water (50 mL). The aqueous phase was adjusted to pH 7-8 with saturated NaHCO3 and extracted with DCM (3 x 10 mL). The organic phases were combined, washed with water (20 mL) and brine (20 mL), then dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a crude yellow gummy solid. Purification by column chromatography on 4 g normal phase silica using a 0-10% methanol-dichloromethane eluent gradient gave impure product. A second purification by column chromatography on 4 g normal phase silica using a 5% methanol-dichloromethane eluent system gave MM756 as an off-white solid (98.7 mg, 31%). LRMS-HESI: [M+H] + Calculated m / z 234.14, observed m / z 234.07. 1 H NMR (400MHz, CDCl3) δ6.92(d, J=1.7Hz, 1H), 6.80(ddd, J=8.0, 1.7, 0.5Hz, 1H), 6.73(d, J=7.9Hz, 1H), 6.52-6.44(m, 1H), 6.15(dt, J=15.8, 6. 7Hz, 1H), 5.92(s, 2H), 3.46(dd, J=6.7, 1.4Hz, 2H), 2.75-2.68(m, 2H), 1.66-1.54(m, 2H), 1.36(dq, J=14.6, 7.4Hz, 2H), 0.91(t, J=7.4Hz, 3H). (See Figure 20, chemical reaction (c), also see chemical reaction (c) in Figure 3A(ii)).

[0314] MM756 has been shown to correspond to chemical compound D(II): [ka]

[0315] Example 15 - Preparation of the 15th N-propylamine-fused heterocyclic mescaline derivative Referring to Figure 21, to a solution of MM756 (57.2 mg, 245 μmol) (prepared as described in Example 14) in denatured ethanol (4.90 mL) under a nitrogen atmosphere was added palladium on carbon 10 wt% (26.1 mg, 0.0245 μmol). Hydrogen gas was bubbled through the solution for 10 minutes and then allowed to establish as an atmosphere. The reaction mixture was allowed to stir for 50 minutes, at which point LCMS indicated the reaction was complete. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give MM761 as a pale yellow solid (52.4 mg, 91%). LRMS-HESI: [M+H] + Calculated m / z 236.16, observed m / z 236.17. 1 H NMR (400 MHz, CDCl) δ 6.72 (d, J = 7.9 Hz, 1H), 6.68 (d, J = 1.7 Hz, 1H), 6.65-6.61 (m, 1H), 5.91 (s, 2H), 2.78-2.68 (m, 4H), 2.59 (t, J = 7.6 Hz, 2H), 1.95 (p, J = 7.6 Hz, 2H), 1.68-1.58 (m, 2H), 1.35 (h, J = 7.4 Hz, 2H), 0.91 (t, J = 7.4 Hz, 3H). (Figure 21, chemical reaction (h); see also chemical reaction (h) in Figure 3A(ii)).

[0316] MM761 has been shown to correspond to chemical compound C(II): [ka]

[0317] Example 16 - Preparation of the 16th N-propylamine-fused heterocyclic mescaline derivative Referring to FIG. 22A, phenylpropionic acid N (250 mg, 1.29 mmol) (prepared as described in Example 3), N-hydroxysuccinimide (302 mg, 2.57 mmol), and EDC.HCl (520 mg, 2.57 mmol) were added to a vial, followed by anhydrous THF (2.57 mL) and DMF (644 μL). The resulting mixture was stirred for 1 hour (the material gradually dissolved), after which ethanolamine (157 μL, 2.57 mmol) was added. The reaction was stirred overnight at room temperature. In the morning, a major spot was observed by TLC (UV, DCM:MeOH 9:1), and the mixture was poured into a separatory funnel containing 50 mL of water and 50 mL of EtOAc. The aqueous phase was extracted with ethyl acetate (3×30 mL), and all organic layers were combined, washed with 0.1 M HCl, water, brine, and dried over MgSO. After evaporation of the solvent, the crude material was subjected to purification on a CombiFlash system (12 g silica, DCM:MeOH 100:0 to 90:10) to give MM715 (120 mg, 39%) as a colorless solid. LRMS-HESI: [M+Na] + Calculated m / z 260.09, observed m / z 260.08, [M+H] + Calculated m / z 238.11, observed 238.09. 1 H NMR (400 MHz, CDCl) δ 6.72 (d, J = 7.9 Hz, 1H), 6.68 (d, J = 1.8 Hz, 1H), 6.64 (dd, J = 7.9 Hz, 1.8 Hz, 1H), 5.91 (s, 2H), 5.89 (brs, 1H), 3.66 (t, J = 5.0 Hz, 2H), 3.39-3.35 (m, 2H), 2.88 (t, J = 7.6 Hz, 2H), 2.45 (t, J = 7.6 Hz, 2H). (Figure 22A, chemical reaction (c1); see also chemical reaction (c1) in Figure 3B(ii)).

[0318] Referring to FIG. 22B, a round-bottom flask was charged with MM715 (500 mg, 2.11 mmol), which was dissolved in dry THF (19.2 mL) and cooled to 0 °C. Once cooled, lithium aluminum hydride (2.0 M in THF, 4.21 mL, 8.43 mmol) was carefully added, and the mixture was allowed to warm to room temperature and react overnight. TLC monitoring (UV-vis, DCM:MeOH 9:1) indicated the disappearance of the starting material. The reaction was cooled to 0 °C and diluted with diethyl ether (20 mL). To this was added 320 μL of water, and after the vigorous bubbling subsided, 320 μL of 15% aqueous NaOH and finally an additional 960 μL of water were added. After stirring for 10 minutes, the mixture was dried over MgSO, filtered, and concentrated to leave a colorless oil. This material was subjected to FC (12 g silica, DCM:MeOH 100:0 to 85:15) to give MM781 (281 mg, 60%) as a colorless solid. LRMS-HESI: [M+H] + Calculated m / z 224.13, observed m / z 224.10. 1 H NMR (400 MHz, CDCl δ 6.72 (d, J = 7.8 Hz, 1H), 6.68-6.67 (m, 1H), 6.63-6.61 (m, 1H), 5.92 (s, 2H), 3.64-3.61 (m, 2H), 2.78-2.76 (m, 2H), 2.66-2.62 (m, 2H), 2.61-2.57 (m, 2H), 1.81-1.74 (m, 2H). (Figure 22B, chemical reaction (d); see also chemical reaction (d) in Figure 3B(ii)).

[0319] MM781 has been shown to correspond to chemical compound C(X): [ka]

[0320] Example 17 - Preparation of the 17th N-propylamine-fused heterocyclic mescaline derivative Referring to Figure 23, intermediate Q (300 mg, 1.34 mmol) (prepared as described in Example 9), N-hydroxysuccinimide (314 mg, 2.68 mmol), and EDC.HCl (540 mg, 2.68 mmol) were added to a vial, followed by anhydrous THF (2.68 mL) and DMF (669 μL). The resulting mixture was stirred for 1 hour (the material gradually dissolved), after which ethanolamine (245 μL, 4.01 mmol) was added. The reaction was stirred overnight at room temperature. In the morning, a major spot was observed on TLC (UV, DCM:MeOH 9:1), and the mixture was poured into a separatory funnel containing 50 mL of water and 50 mL of EtOAc. The aqueous phase was extracted with ethyl acetate (3 × 30 mL), and all organic layers were combined, washed with 0.1 M HCl, water, brine, and dried over MgSO4. After evaporation of the solvent, the crude material was subjected to purification by flash chromatography (12 g silica, DCM:MeOH 100:0 to 90:10) to give the pure product, MM776 (156 mg, 44%) as a colorless solid. LRMS-HESI: [M+Na] + Calculated m / z 290.10, observed m / z 290.07, [M+H] + Calculated m / z 268.12, observed m / z 268.13. 1 H NMR (400 MHz, CDCl) δ 6.65 (s, 1H), 6.50 (s, 1H), 5.97 (brs, 1H), 5.88 (s, 2H), 3.76 (s, 3H), 3.67-3.65 (m, 2H), 3.39-3.35 (m, 2H), 2.85 (t, J = 7.5 Hz, 2H), 2.73 (brs, 1H), 2.44 (t, J = 7.6 Hz, 2H). (Figure 23, chemical reaction (c1); see also chemical reaction (c1) in Figure 3B(ii)).

[0321] MM776 has been shown to correspond to the chemical compound F(VI): [ka]

[0322] Example 18 - Preparation of the 18th N-propylamine-fused heterocyclic mescaline derivative Referring to FIG. 24, a round-bottom flask was charged with MM776 (75.0 mg, 281 μmol) (prepared as described in Example 17), which was dissolved in dry THF (2.55 mL) and cooled to 0° C. Once cooled, lithium aluminum hydride (2.0 M in THF, 499 μL, 999 μmol) was carefully added, and the mixture was allowed to warm to room temperature and react overnight. TLC monitoring (UV-vis, DCM:MeOH 9:1) indicated the disappearance of the starting material. The reaction was cooled to 0° C. and diluted with diethyl ether (4 mL). To this was added 40 μL of water, and after vigorous bubbling subsided, 40 μL of 15% aqueous NaOH was added, followed by an additional 120 μL of water. After stirring for 10 minutes, the mixture was dried over MgSO4, filtered, and concentrated to leave MM780 (28.4 mg, 40%) as a white solid. LRMS-HESI:[M+H] + Calculated m / z 254.14, observed m / z 254.14. 1 H NMR (400 MHz, CDCl) δ 6.63 (s, 1H), 6.51 (s, 1H), 5.89 (s, 2H), 3.76 (s, 3H), 3.71-3.69 (m, 2H), 2.85-2.82 (m, 2H), 2.71 (t, J = 7.1 Hz, 2H), 2.59 (t, J = 7.4 Hz, 2H), 1.81 (p, J = 7.3 Hz, 2H). (Figure 24, chemical reaction (d); see also chemical reaction (d) in Figure 3B(ii)).

[0323] MM780 has been shown to correspond to chemical compound C(XII): [ka]

[0324] Example 19 - Preparation of the 19th N-propylamine-fused heterocyclic mescaline derivative Referring to FIG. 25A, intermediate O (380 mg, 1.39 mmol) (prepared as described in Example 4), N-hydroxysuccinimide (327 mg, 2.78 mmol), and EDC.HCl (562 mg, 2.78 mmol) were added to a vial, followed by anhydrous THF (2.78 mL) and DMF (696 μL). The resulting mixture was stirred for 1 hour (the material gradually dissolved), after which ethanolamine (255 μL, 4.17 mmol) was added. The reaction was stirred overnight at room temperature. In the morning, a major spot was observed on TLC (UV, DCM:MeOH 9:1), and the mixture was poured into a separatory funnel containing 50 mL of water and 50 mL of EtOAc. The aqueous phase was extracted with ethyl acetate (3×30 mL), and all organic layers were combined, washed with 0.1 M HCl, water, brine, and dried over MgSO. After evaporation of the solvent, the crude material was subjected to purification by FC (12 g silica, DCM:MeOH 100:0 to 90:10) to give the pure product, intermediate T (246 mg, 56%) as a colorless solid. LRMS-HESI: [M+Na] + Calculated m / z 338.00, observed m / z 397.97, [M+H] + Calculated m / z 316.02, observed m / z 316.02. 1 H NMR (400 MHz, CDCl) δ 6.97 (s, 1H), 6.74 (s, 1H), 6.02 (brs, 1H), 5.93 (s, 2H), 3.69-3.67 (m, 2H), 3.41-3.37 (m, 2H), 2.97 (t, J = 7.6 Hz, 2H), 2.46 (t, J = 7.7 Hz, 2H) (Figure 25A, chemical reaction (c1); see also chemical reaction (c1) in Figure 3B(ii)).

[0325] Referring to Figure 25B, intermediate T (90.0 mg, 285 μmol) was added to a round-bottom flask, which was dissolved in dry THF (2.59 mL) and cooled to 0 °C. Once cooled, borane-THF complex 1 M in THF (1.71 mL, 1.71 mmol) was carefully added, and the mixture was heated to reflux for 4 hours. At this point, substantial conversion had occurred as determined by LCMS, and the mixture was cooled to 0 °C. Excess borane was carefully quenched with saturated sodium bicarbonate solution, and the resulting mixture was poured into a separatory funnel containing 5 mL of DCM and 5 mL of water. The aqueous layer was extracted with DCM (3 × 5 mL), and the organic layers were combined, washed with brine, dried (MgSO), filtered, and concentrated to give the crude material. Purification was carried out by FC (4 g silica, DCM:MeOH 100:0 to 85:15) to give the pure material, MM782 (28.4 mg, 33%) as a colorless gummy solid. LRMS-HESI: [M+H] + Calculated m / z 302.04, observed m / z 302.01. 1 H NMR (400 MHz, CDCl) δ 6.98 (s, 1H), 6.71 (s, 1H), 5.94 (s, 2H), 3.70-3.67 (m, 2H), 2.85-2.83 (m, 2H), 2.74-2.69 (m, 4H), 1.85-1.78 (m, 2H). (Figure 25B, chemical reaction (i), see also chemical reaction (i) in Figure 3B(ii)).

[0326] MM782 has been shown to correspond to chemical compound C(XIII): [ka]

[0327] 5-HT 1A Receptor Functional Cellular Response Assay: 5-HT in Engineered Cellular Systems 1A Functional engagement of the receptor was assessed as described in Example 2, except that a compound having formula C(XIII) was evaluated instead of a compound having formula B(II). Table 2 shows the functional assay results for the positive control, calibrator, and compound having formula C(XIII) in EC50 Considering the results for the control and calibrator compounds, negative cell responses are shown in the form of EC 50 EC for compounds having formula C(XIII) in this assay, corresponding to an EC value >1000 μM 50 The value (22.95 μM, Table 2) suggested ligand-receptor binding.

[0328] Example 20 - Preparation of the 20th N-propylamine-fused heterocyclic mescaline derivative Referring to Figure 26, MM715 (95.0 mg, 400 μmol) (prepared as described in Example 16) was suspended in CHCl3 (3.09 mL). To this was added thionyl chloride (88.5 μL, 1.20 mmol), and the mixture was allowed to stir at room temperature overnight. In the morning, the reaction was monitored by TLC (UV, 9:1 DCM:MeOH). It was determined that no starting material remained and a new, less polar compound had formed. Excess thionyl chloride was quenched with water, and the reaction mixture was poured into a separatory funnel containing 15 mL of water. The aqueous layer was extracted with DCM (3 x 10 mL). All organic layers were combined, washed with water, brine, dried (MgSO4), filtered, and concentrated to give the intermediate amidoethyl chloride (61.0 mg, 60%) as a yellow powder. LRMS-HESI: [M+H] + Calculated m / z 256.07, observed m / z 256.08. 1H NMR (400 MHz, CDCl3) δ 6.74-6.64 (m, 3H), 5.92 (s, 2H), 5.74 (brs, 1H), 3.58-3.56 (m, 4H), 2.89 (t, J = 7.5 Hz, 2H), 2.46 (t, J = 7.6 Hz, 2H). This was used in the next step without further purification. To the vial was added amidoethyl chloride (47.0 mg, 184 μmol) and potassium carbonate (50.8 mg, 368 μmol), followed by DMF (888 μL). The temperature was increased to 75 °C, and the mixture was allowed to react overnight. In the morning, the reaction was monitored by TLC (DCM:MeOH 9:1), and the mixture was observed to contain no starting material. The mixture was poured into a separatory funnel containing 10 mL of water and 10 mL of DCM. The aqueous layer was extracted with DCM (2 x 10 mL), and all organic layers were combined, washed with water, brine, dried (MgSO4), and filtered. The resulting tan oil was subjected to FC (4 g silica, DCM:MeOH 100:0 to 90:10) to give the desired product MM779 (9.6 mg, 24%) as a colorless oil. LRMS-HESI: [M+H] + Calculated m / z 220.10, observed m / z 220.07. 1 H NMR (400 MHz, CDCl) δ 6.72 (d, J = 7.9 Hz, 1H), 6.70 (dd, J = 1.7 Hz, 0.5 Hz, 1H), 6.67-6.64 (m, 1H), 5.92 (s, 2H), 4.25-4.20 (m, 2H), 3.85-3.79 (m, 2H), 2.89-2.85 (m, 2H), 2.55-2.51 (m, 2H). (Figure 26, chemical reaction (h); see also chemical reaction (h) in Figure 3B(iii)).

[0329] MM779 has been shown to correspond to chemical compound G(I): [ka]

[0330] Example 21 - Preparation of the 21st N-propylamine-fused heterocyclic mescaline derivative Referring to Figure 27, intermediate T (121 mg, 383 µmol) (prepared as described in Example 19) was suspended in CHCl3 (2.95 mL). To this was added thionyl chloride (84.6 µL, 1.15 mmol), and the mixture was allowed to stir at room temperature overnight. In the morning, the reaction was monitored by TLC (DCM:MeOH 9:1), and the mixture was observed to be free of starting material. Excess thionyl chloride was quenched by the addition of water, and the resulting mixture was poured into a separatory funnel containing 10 mL of water and 10 mL of DCM. The aqueous layer was extracted with DCM (2 x 10 mL), and the organic layers were combined, washed with water, brine, dried (MgSO4), and filtered. Concentration of this solution afforded the intermediate amidoethyl chloride product (86.3 mg, 67%), isolated as a yellow solid. LRMS-HESI: [M+H] + Calculated m / z 333.98, observed m / z 333.96. 1 H NMR (400 MHz, CDCl3) δ 6.99 (s, 1H), 6.75 (s, 1H), 5.95 (s, 2H), 5.76 (brs, 1H), 3.58-3.57 (m, 2H), 3.00 (t, J = 7.6 Hz, 2H), 2.47 (t, J = 7.6 Hz, 2H). This was used in the next step without further purification. To the vial was added amidoethyl chloride (59.0 mg, 176 μmol) and potassium carbonate (48.7 mg, 353 μmol), followed by DMF (852 μL). The temperature was increased to 75 °C, and the mixture was allowed to react overnight. In the morning, the reaction was monitored by TLC (DCM:MeOH 9:1), and the mixture was observed to contain no starting material. The mixture was poured into a separatory funnel containing 10 mL of water and 10 mL of DCM. The aqueous layer was extracted with DCM (2 x 10 mL), and all organic layers were combined, washed with water, brine, dried (MgSO4), and filtered. After concentration, the crude material was subjected to FC (4 g silica, DCM:MeOH 100:0 to 95:5) to give the pure product, MM778 (35.0 mg, 67%), as a pale yellow solid. LRMS-HESI: [M+H] + Calculated m / z 298.01, observed m / z 298.00. 1H NMR (400 MHz, CDCl) δ 6.98 (s, 1H), 6.74 (s, 1H), 5.94 (s, 2H), 4.24 (t, J = 9.5 Hz, 2H), 3.83 (t, J = 9.5 Hz, 2H), 2.98 (t, J = 7.9 Hz, 2H), 2.53 (t, J = 8.0 Hz, 2H). (Figure 27, chemical reaction (h), see also chemical reaction (h) in Figure 3B(iii)).

[0331] MM778 has been shown to correspond to chemical compound G(I): [ka]

[0332] 5-HT 1A Receptor Functional Cellular Response Assay: 5-HT in Engineered Cellular Systems 1A Functional engagement of the receptor was assessed as described in Example 2, except that a compound having formula G(V) was evaluated instead of a compound having formula B(II). Table 2 shows the functional assay results for the positive control, calibrator, and compound having formula G(V) in EC 50 Considering the results for the control and calibrator compounds, negative cell responses are shown in the form of EC 50 EC for compounds having the formula G(V) in this assay, corresponding to a value >1000 μM 50 The value (129.5 μM, Table 2) suggested ligand-receptor binding.

Claims

1. A compound having the chemical formula (I) or (II): 【Chemistry 1】 In formula (I) or (II): 【Chemistry 2】 is a single or double bond; X １ , X ２ , and X ３ are independently a hydrogen atom, O-alkyl, acyl, N-alkyl, OH, halogen, or NH ２ Selected from: X ４ is an alkylene group or a substituted alkylene group; R １ is hydrogen, an alkyl group, or an oxo group; R １ is R １ｂ , R １ and the carbon atom to which R １ｂ together with the nitrogen atom to which it is attached to form an optionally substituted saturated or unsaturated 3- to 10-membered heterocyclic ring, and when the heterocyclic ring is unsaturated, R １ａ is optional and not present; R １ａ and R １ｂ are each independently selected from an alkyl group, a hydroxylalkyl group, an optionally substituted alkyl-aryl group, or a hydrogen atom; or R １ａ and R １ｂ taken together with the nitrogen atom to which they are attached form a 3- to 10-membered optionally substituted heterocycle; and R ２ and R ３ are each independently selected from an alkyl group, an O-alkyl group, or a hydrogen atom; or R ２ and R ３ together with the oxygen atom and the carbon atom to which they are attached form an oxirane ring.

2. The compound having formula (I) is ａ ) or (I ｂ ) and said compound having formula (II) is a compound having formula (II ａ ) or (II ｂ ) is a compound having: 【Transformation 3】 Chemical formula (I ａ ), (I ｂ ), (II ａ ), or (II ｂ ) in: X １ , X ２ , and X ３ are independently a hydrogen atom, O-alkyl, acyl, N-alkyl, OH, halogen, or NH ２ Selected from: X ４ is an alkylene group or a substituted alkylene group; R １ is hydrogen, an alkyl group, or an oxo group; R １ is R １ｂ , R １ and the carbon atom to which R １ｂ together with the nitrogen atom to which it is attached to form an optionally substituted saturated or unsaturated 3- to 10-membered heterocyclic ring, and when the heterocyclic ring is unsaturated, R １ａ is optional and not present; R １ａ and R １ｂ are each independently selected from an alkyl group, a hydroxylalkyl group, an optionally substituted alkyl-aryl group, or a hydrogen atom; or R １ａ and R １ｂ taken together with the nitrogen atom to which they are attached form a 3- to 10-membered optionally substituted heterocycle; and R ２ and R ３ are each independently selected from an alkyl group, an O-alkyl group, or a hydrogen atom; or R ２ and R ３ The compound of claim 1 , wherein, together with the oxygen atom and the carbon atom to which they are attached, form an oxirane ring.

3. X ４ (C １ -C ３ )-alkylene group or substituted (C １ -C ３ 3. The compound according to claim 2, wherein the aryl group is a aryl group.

4. X ４ is a methylene group (-CH ２ 3. The compound of claim 2, wherein the aryl group is a substituted methylene group.

5. The compound of claim 4 , wherein the methylene group is substituted with at least one halogen.

6. The compound of claim 4 , wherein the substituted methylene group is substituted with two halogen substituents.

7. The substituted methylene group is substituted with two identical halogen substituents, and optionally (—CF ２ The compound according to claim 4, wherein:

8. Formula (I ａ ), (I ｂ ), (II ａ ), and (II ｂ ) are each represented by the chemical formula (I ｃ ), (I ｄ ) 、 (II ｃ ), or (II ｄ ) the compound of claim 1 ： 【Chemistry 4】

9. The amino group (—NR １ａ R １ｂ ) is protonated, and (-N ＋ HR １ａ R １ｂ ) and forming a compound of formula (I), (II), (I ａ ), (I ｂ ), (II ａ ), (II ｂ ), (I ｃ ), (I ｄ ), (II ｃ ), or (II ｄ 9. The compound of claim 1, wherein the nitrogen atom is a nitrogen atom having a positive charge and the nitrogen atom is a nitrogen atom having a negative charge.

10. X １ , X ２ , X ３ The compound of claim 1 or 8, wherein each is a hydrogen atom (H).

11. X １ , X ２ , X ３ The compound according to claim 1 or 8, wherein at least one of is an O-alkyl group or a halogen.

12. X ３ is an O-alkyl group, optionally a methoxy group, or a halogen, optionally bromine.

13. R ２ and R ３ independently or simultaneously (C １ -C ６ 9. The compound according to claim 1 or 8, wherein the aryl group is a 2-alkyl group.

14. R ２ and R ３ independently or simultaneously (C １ -C ３ 9. The compound according to claim 1 or 8, wherein the aryl group is a 2-alkyl group.

15. R ２ and R ３ The compound according to claim 1 or 8, wherein is a methyl group.

16. R ２ (C １ -C ６ )-alkyl group, and R ３ The compound according to claim 1 or 8, wherein is a hydrogen atom.

17. R ２ (C １ -C ３ )-alkyl group, and R ３ The compound according to claim 1 or 8, wherein is a hydrogen atom.

18. R ２ is a methyl group or an ethyl group, and R ３ The compound according to claim 1 or 8, wherein is a hydrogen atom.

19. R ３ (C １ -C ６ )-alkyl group, and R ２ The compound according to claim 1 or 8, wherein is a hydrogen atom.

20. R ３ (C １ -C ３ )-alkyl group, and R ２ The compound according to claim 1 or 8, wherein is a hydrogen atom.

21. R ３ is a methyl group, and R ２ The compound according to claim 1 or 8, wherein is a hydrogen atom.

22. R ２ and R ３ The compound of claim 1 or 8, wherein each is a methoxy group.

23. R ２ independently or simultaneously (C １ -C ６ )-O-alkyl group, and R ３ The compound according to claim 1 or 8, wherein is a hydrogen atom.

24. R ２ independently or simultaneously (C １ -C ３ )-O-alkyl group, and R ３ The compound according to claim 1 or 8, wherein is a hydrogen atom.

25. R ２ is a methoxy group, and R ３ The compound according to claim 1 or 8, wherein is a hydrogen atom.

26. R ３ (C １ -C ６ )-O-alkyl group, and R ２ The compound according to claim 1 or 8, wherein is a hydrogen atom.

27. R ３ (C １ -C ３ )-O-alkyl group, and R ２ The compound according to claim 1 or 8, wherein is a hydrogen atom.

28. R ３ is a methoxy group, and R ２ The compound according to claim 1 or 8, wherein is a hydrogen atom.

29. R ２ and R ３ The compound of claim 1 or 8, wherein each is a hydrogen atom.

30. Formula (I ａ ), (II ａ ), (I ｃ ), or (II ｃ ) in which R ２ and R ３ The compound according to claim 8 , wherein, together with the oxygen atom, forms an oxirane ring.

31. R １ａ is a hydrogen atom, and R １ｂ (C １ -C ６ 9. The compound according to claim 1 or 8, wherein the aryl group is a 2-alkyl group.

32. R １ａ and R １ｂ independently or simultaneously (C １ -C ６ 9. The compound according to claim 1 or 8, wherein the aryl group is a 2-alkyl group.

33. R １ａ and R １ｂ independently or simultaneously (C １ -C ３ 9. The compound according to claim 1 or 8, wherein the aryl group is a 2-alkyl group.

34. R １ａ is a hydrogen atom, and R １ｂ (C １ -C ６ 9. The compound according to claim 1, wherein the hydroxyl group is a hydroxyl group.

35. R １ａ is a hydrogen atom, and R １ｂ is a methanol group (-CH ２ OH), ethanol group (-C ２ H ４ OH), propanol group (-C ３ H ６ OH), or butanol group (-C ４ H ８ 10. The compound of claim 1 or 8, wherein:

36. R １ａ is a hydrogen atom, and R １ｂ is a hydroxyl alkyl group having the formula (HA): 【Transformation 5】 In the formula, Y １ and Y ２ are each simultaneously or independently a hydrogen atom or (C １ -C ６ 9. The compound according to claim 1 or 8, wherein the aryl group is a 2-alkyl group.

37. R １ａ is a hydrogen atom, and R １ｂ The compound of claim 1 or 8, wherein is an alkyl-aryl group.

38. The alkyl-aryl group is (C １ -C ６ 38. The compound of claim 37, wherein the aryl group is a )-alkyl-aryl group.

39. The alkyl-aryl group is (C １ -C ６ 38. The compound of claim 37, wherein the aryl group is a phenyl group.

40. The alkyl-aryl group is (CH ２ 38. The compound of claim 37, wherein the aryl group is a phenyl group.

41. R １ａ and R １ｂ The compound of claim 1 or 8, wherein: taken together with the nitrogen atom to which they are attached, form a 3-10 membered optionally substituted heterocycle, said heterocycle further comprising an oxygen atom.

42. R １ａ and R １ｂ taken together with the nitrogen atom to which they are attached form a 3-10 membered optionally substituted heterocycle, said heterocycle further comprising an oxygen atom, said heterocycle containing at least one (C １ -C ６ 9. The compound of claim 1 or 8, further substituted with a )-alkyl group.

43. The heterocycle may be independently or simultaneously formed from two (C １ -C ６ 43. The compound of claim 42, further substituted with a )-alkyl group.

44. 43. The compound of claim 42, wherein said heterocycle is further substituted on one single heterocycle carbon atom with two methyl groups.

45. 43. The compound of claim 42, wherein the heterocycle is further substituted with two methyl groups on two separate heterocycle carbon atoms.

46. 43. The compound of claim 42, wherein the heterocycle is a 5- or 6-membered heterocycle.

47. R １ is R １ｂ , R １ｂ a nitrogen atom to which R is bonded, and １ taken together with the carbon atom to which it is attached to form an optionally substituted saturated or unsaturated 3-10 membered heterocycle, said heterocycle containing an oxygen atom in addition to said nitrogen atom.

48. R １ is R １ｂ , R １ｂ a nitrogen atom to which R is bonded, and １ together with the carbon atom to which it is attached to form an optionally substituted saturated or unsaturated 3-10 membered heterocyclic ring, said heterocyclic ring containing, in addition to said nitrogen atom, an oxygen atom and at least one (C １ -C ６ 10. The compound of claim 1 or 8, wherein the compound is substituted with an alkyl group.

49. R １ is R １ｂ , R １ｂ a nitrogen atom to which R is bonded, and １ together with the carbon atom to which it is attached to form an optionally substituted saturated or unsaturated 3- to 10-membered heterocyclic ring, said heterocyclic ring containing, in addition to said nitrogen atom, an oxygen atom, and independently or simultaneously containing at least two (C １ -C ６ 10. The compound of claim 1 or 8, wherein said alkyl groups are substituents on the same heterocyclic carbon atom.

50. 50. The compound of claim 48 or 49, wherein the alkyl group is a methyl group.

51. 51. The compound of any one of claims 47 to 50, wherein the heterocycle is partially saturated.

52. 52. The compound of any one of claims 47 to 51, wherein the heterocycle is a 5- or 6-membered heterocycle.

53. When the heterocycle is unsaturated, R １ａ 53. The compound of any one of claims 47 to 52, wherein is absent.

54. When the heterocycle is unsaturated and the nitrogen atom is involved in the formation of an unsaturated bond, R １ａ 53. The compound of any one of claims 47 to 52, wherein is absent.

55. The chemical compound having formula (I) or (II) is selected from the group of compounds having chemical formulas (A); (B); (C); (D); (E); (F); and (G): 【Transformation 6】 In formula (B), X ４ａ and X ４ｂ are independently or simultaneously a halogen or a hydrogen atom, and R in formulas (A), (B), (C), (D), (E), and (F) １ａ and R １ｂ are independently selected from an alkyl group, an optionally substituted alkyl-aryl group, or a hydrogen atom, or R １ａ and R １ｂ taken together with the nitrogen atom to which they are attached form a 3- to 10-membered optionally substituted heterocycle; R in formulas (C), (F), and (G) ２ , and Y in (G) １ and Y ２ is an alkyl group or a hydrogen atom; and X in formulas (C), (F), and (G) ３ The compound according to claim 1, wherein is a halogen, an O-alkyl group, or a hydrogen atom.

56. Said chemical compound having formula (I) is selected from the group of compounds having chemical formulae A(I)-A(III); B(I)-B(V); C(I)-C(XIII); D(I)-D(III); E(I)-(V); F(I)-(VI); and G(I)-G(V): (A): A(I); A(II); and A(III): 【Transformation 7】 (B): B(I); B(II); B(III); B(IV); and B(V): 【Transformation 8】 (C): C(I); C(II); C(III); C(IV); C(V); C(VI); C(VII); C(VIII); C(IX); C(X); C(XI); C(XII); and C(XIII): 【Chemistry 9】 (D): D(I); D(II); and D(III): 【Chemistry 10】 (E): E(I); E(II); E(III); E(IV); and E(V): 【Chemistry 11】 (F): F(I); F(II); F(III); F(IV); F(V); and F(VI): 【Chemistry 12】 G(I); G(II); G(III); G(IV); and G(V): 【Chemistry 13】 2. The compound of claim 1, wherein in each of compounds A(I) to G(V), the nitrogen atom of the N-propylamine moiety is optionally protonated and comprises a negatively charged anion that balances the positively charged nitrogen atom.

57. The compound is a stereoisomeric compound selected from the group consisting of stereoisomeric compounds corresponding to A(I), A(II), A(III), C(VII), C(IX), C(XI), F(II), G(II), and G(IV) containing an N-propylamine moiety, wherein the C ２ 57. The compound of claim 56, wherein the atom is a chiral carbon atom.

58. 58. The compound of claim 57, wherein the compound is a first stereoisomeric compound present in a mixture, the mixture comprising a second stereoisomeric compound, the second stereoisomeric compound being the stereoisomeric counterpart of the first stereoisomeric compound, and optionally, the mixture being a racemic mixture.

59. 58. The compound of claim 57, wherein said stereoisomeric compound is substantially free of its corresponding counterpart stereoisomeric compound.

60. The compound having the formula A(II) is ａ ) or A (II ｂ 58. The compound of claim 57, selected from stereoisomeric compounds having: 【Chemistry 14】

61. 61. The compound of claim 60, wherein the selected compound is present in a mixture further comprising other stereoisomeric compounds, and optionally, the mixture is a racemic mixture.

62. 1. A pharmaceutical or recreational drug formulation comprising an effective amount of a chemical compound selected from compounds having formula (I) or (II), together with a pharmaceutically acceptable excipient, diluent, or carrier: 【Chemistry 15】 In formula (I) or (II): 【Chemistry 16】 is a single or double bond; X １ , X ２ , and X ３ are independently a hydrogen atom, O-alkyl, acyl, N-alkyl, OH, halogen, or NH ２ Selected from: X ４ is an alkylene group or a substituted alkylene group; R １ is hydrogen, an alkyl group, or an oxo group; R １ is R １ｂ , R １ and the carbon atom to which R １ｂ together with the nitrogen atom to which it is attached to form an optionally substituted saturated or unsaturated 3- to 10-membered heterocyclic ring, and when the heterocyclic ring is unsaturated, R １ａ is optional and not present; R １ａ and R １ｂ are each independently selected from an alkyl group, a hydroxylalkyl group, an optionally substituted alkyl-aryl group, or a hydrogen atom; or R １ａ and R １ｂ taken together with the nitrogen atom to which they are attached form a 3- to 10-membered optionally substituted heterocycle; and R ２ and R ３ are each independently selected from an alkyl group, an O-alkyl group, or a hydrogen atom; or R ２ and R ３ are pharmaceutical or recreational drug preparations which, together with the oxygen atoms and the carbon atoms to which they are attached, form an oxirane ring.

63. 1. A method for treating a cranial nerve disorder, the method comprising administering to a subject in need thereof a pharmaceutical formulation comprising a compound having formula (I) or (II): 【Chemistry 17】 In formula (I) or (II): [Chemistry 18] is a single or double bond; X １ , X ２ , and X ３ are independently a hydrogen atom, O-alkyl, acyl, N-alkyl, OH, halogen, or NH ２ Selected from: X ４ is an alkylene group or a substituted alkylene group; R １ is hydrogen, an alkyl group, or an oxo group; R １ is R １ｂ , R １ and a carbon atom to which R １ｂ together with the nitrogen atom to which it is attached to form an optionally substituted saturated or unsaturated 3- to 10-membered heterocyclic ring, and when the heterocyclic ring is unsaturated, R １ａ is optional and not present; R １ａ and R １ｂ are each independently selected from an alkyl group, a hydroxylalkyl group, an optionally substituted alkyl-aryl group, or a hydrogen atom; or R １ａ and R １ｂ taken together with the nitrogen atom to which they are attached form a 3- to 10-membered optionally substituted heterocycle; and R ２ and R ３ are each independently selected from an alkyl group, an O-alkyl group, or a hydrogen atom; or R ２ and R ３ together with the oxygen atom and the carbon atom to which they are attached to form an oxirane ring, The method wherein the pharmaceutical preparation is administered in an amount effective to treat the cranial nerve disorder in the subject.

64. 64. The method of claim 63, wherein, upon administration, the compound having formula (I) or (II) interacts with a receptor in the subject, thereby modulating the receptor and exerting a pharmacological effect.

65. 65. The method of claim 64, wherein the receptor is a G protein-coupled receptor (GPCR).

66. 65. The method of claim 64, wherein the receptor is a 5-HT receptor.

67. The receptor is 5-HT １Ａ Receptor, 5-HT ２Ａ Receptor, 5-HT ２Ｂ Receptor, 5-HT ２Ｃ Receptor, 5-HT ７ receptor, α ２Ａ Receptor, D ３ receptor, or MT １ 65. The method of claim 64, wherein the receptor is a receptor.

68. 64. The method of claim 63, wherein, upon administration, the compound having formula (I) or (II) interacts with a transmembrane transport protein in the subject, thereby modulating the transmembrane transport protein and exerting a pharmacological effect.

69. 69. The method of claim 68, wherein the transmembrane transport protein is a dopamine active transporter (DAT), a norephedrine transporter (NET), or a serotonin transporter (SERT) transmembrane transport protein.

70. 64. The method of claim 63, wherein the disorder is a G protein-coupled receptor (GPCR)-mediated disorder.

71. 64. The method of claim 63, wherein the disorder is a 5-HT receptor-mediated disorder.

72. The disorder is 5-HT １Ａ Receptor-mediated disorders, 5-HT ２Ａ Receptor-mediated disorders, 5-HT ２Ｂ Receptor-mediated disorders, 5-HT ２Ｃ Receptor-mediated disorders, 5-HT １Ｄ Receptor-mediated disorders, 5-HT ７ Receptor-mediated disorders, α ２Ａ Receptor-mediated disorders, D ３ receptor-mediated disorders, or MT １ 64. The method of claim 63, which is a receptor-mediated disorder.

73. 64. The method of claim 63, wherein a dose of about 0.001 mg to about 5,000 mg is administered.

74. (i) 5-HT １Ａ Receptor, 5-HT ２Ａ Receptor, 5-HT ２Ｂ Receptor, 5-HT ２Ｃ Receptor, 5-HT ７ receptor, α ２Ａ Receptor, D ３ receptor, or MT １ or (ii) a transmembrane transport protein selected from a dopamine active transporter (DAT), a norephedrine transporter (NET), or a serotonin transporter (SERT) transmembrane transport protein, said method comprising: (i) modulating said 5-HT receptor; １Ａ receptor, the 5-HT ２Ａ receptor, the 5-HT ２Ｂ receptor, the 5-HT ２Ｃ receptor, the 5-HT ７ receptor, the α ２Ａ Receptor, the D ３ receptor, or the MT １ or (ii) the dopamine active transporter (DAT), the norephedrine transporter (NET), or the serotonin transporter (SERT) transmembrane transport protein with a compound selected from a first chemical compound having a chemical formula (I) and a second chemical compound having a chemical formula (II), １Ａ receptor, the 5-HT ２Ａ receptor, the 5-HT ２Ｂ receptor, the 5-HT ２Ｃ receptor, the 5-HT ７ receptor, the α ２Ａ Receptor, the D ３ receptor, or the MT １ (ii) contacting under reaction conditions sufficient to modulate the dopamine active transporter (DAT), the norephedrine transporter (NET), or the serotonin transporter (SERT) transmembrane transport protein; 【Chemistry 19】 In formula (I) or (II): 【Chemistry 20】 is a single or double bond; X １ , X ２ , and X ３ are independently a hydrogen atom, O-alkyl, acyl, N-alkyl, OH, halogen, or NH ２ Selected from: X ４ is an alkylene group or a substituted alkylene group; R １ is hydrogen, an alkyl group, or an oxo group; R １ is R １ｂ , R １ and a carbon atom to which R １ｂ together with the nitrogen atom to which it is attached to form an optionally substituted saturated or unsaturated 3- to 10-membered heterocyclic ring, and when the heterocyclic ring is unsaturated, R １ａ is optional and not present; R １ａ and R １ｂ are each independently selected from an alkyl group, a hydroxylalkyl group, an optionally substituted alkyl-aryl group, or a hydrogen atom; or R １ａ and R １ｂ taken together with the nitrogen atom to which they are attached form a 3- to 10-membered optionally substituted heterocycle; and R ２ and R ３ are each independently selected from an alkyl group, an O-alkyl group, or a hydrogen atom; or R ２ and R ３ together with the oxygen atom and the carbon atom to which they are attached form an oxirane ring.

75. 75. The method of claim 74, wherein the reaction conditions are in vitro reaction conditions.

76. 75. The method of claim 74, wherein the reaction conditions are in vivo reaction conditions.

77. 1. A method of making a first chemical compound having chemical formula (I) or (II): 【Chemistry 21】 In formula (I) or (II): 【Chemistry 22】 is a single or double bond; X １ , X ２ , and X ３ are independently a hydrogen atom, O-alkyl, acyl, N-alkyl, OH, halogen, or NH ２ Selected from: X ４ is an alkylene group or a substituted alkylene group; R １ is hydrogen, an alkyl group, or an oxo group; R １ is R １ｂ , R １ and the carbon atom to which R １ｂ together with the nitrogen atom to which it is attached to form an optionally substituted saturated or unsaturated 3- to 10-membered heterocyclic ring, and when the heterocyclic ring is unsaturated, R １ａ is optional and not present; R １ａ and R １ｂ are each independently selected from an alkyl group, a hydroxylalkyl group, an optionally substituted alkyl-aryl group, or a hydrogen atom; or R １ａ and R １ｂ taken together with the nitrogen atom to which they are attached form a 3- to 10-membered optionally substituted heterocycle; and R ２ and R ３ are each independently selected from an alkyl group, an O-alkyl group, or a hydrogen atom; or R ２ and R ３ together with the oxygen atom and the carbon atom to which they are attached to form an oxirane ring, The method comprises performing at least one chemical synthesis reaction selected from the reactions depicted in Figures 3A(i), 3A(ii), 3B(i), 3B(ii), 3B(iii), and 3C.

78. The compound having formula (I) is a compound having formula (A): 【Chemistry 23】 In the formula, R １ａ and R １ｂ are each independently selected from an alkyl group, an optionally substituted alkyl-aryl group, or a hydrogen atom; or R １ａ and R １ｂ taken together with the nitrogen atom to which they are attached form a 3- to 10-membered optionally substituted heterocycle; 78. The method of claim 77, wherein the at least one chemical synthesis reaction is selected from (g); (f) and (g); (e), (f), and (g); and (d), (e), (f), and (g), as shown in Figures 3A(i) and 3A(ii).

79. The compound having formula (I) is a compound having formula (B): 【Chemistry 24】 In formula (B), X ４ａ and X ４ｂ are independently or simultaneously a halogen atom or a hydrogen atom, and R １ａ and R １ｂ are each independently selected from an alkyl group, an optionally substituted alkyl-aryl group, or a hydrogen atom; or R １ａ and R １ｂ taken together with the nitrogen atom to which they are attached form a 3- to 10-membered optionally substituted heterocycle; 78. The method of claim 77, wherein the at least one chemical synthesis reaction is a reaction selected from (i); (f); (f) and (i); (e) and (f); (e), (f), and (i); (d), (e), and (f); and (d), (e), (f), and (i) shown in FIG. 3A(i).

80. The compound having formula (I) is a compound having formula (C): 【Chemistry 25】 In the formula, R １ａ and R １ｂ are each independently selected from an alkyl group, a hydroxyl alkyl group, or a hydrogen atom, or R １ａ and R １ｂ taken together with the nitrogen atom to which they are attached form a 3- to 10-membered optionally substituted heterocycle, R ２ is selected from an alkyl group or a hydrogen atom, and X ３ is an O-alkyl group, a halogen, or a hydrogen atom, 78. The method of claim 77, wherein the at least one chemical synthesis reaction is a reaction selected from the following: (i) {(h) in Figures 3A(i) and 3A(ii); (c) and (h); (b), (c), and (h); and (a), (b), (c), and (h)}; (ii) {(f) in Figures 3B(i) and 3B(ii); (d) and (f); (c2), (d), and (f); (c1), (d), and (f); (b), (c2), (d), and (f); (a), (b), (c2), (d), and (f); and (a), (c1), (d), and (f)}; (iii) {(e); (d) and (e); (c2), (d), and (e); (c1), (d), and (e); (b), (c2), (d), and (e); (a), (b), (c2), (d), and (e); and (a), (c1), (d), and (e) in Figures 3B(i) and 3B(ii)}; (iv) {(d) in Figures 3B(i) and 3B(ii); (c1) and (d); (c2) and (d); (b), (c2), and (d); and (a), (c1), and (d); and (a), (b), (c2) and (d)}; or (v) {(i) in Figures 3B(i) and 3B(ii); (c1) and (i); (c2) and (i); (b), (c2), and (i); and (a), (c1), and (i); and (a), (b), (c2) and (i)}; or (vi) {(g); (d) and (g); (c2), (d), and (g); (c1), (d), and (g); (b), (c2), (d), and (g); (a), (b), (c2), (d), and (g); and (a), (c1), (d), and (g) in Figures 3B(i) and 3B(ii)}.

81. The compound having formula (I) is a compound having formula (D): 【Chemistry 26】 In the formula, R １ａ and R １ｂ are each independently selected from an alkyl group or a hydrogen atom, or R １ａ and R １ｂ taken together with the nitrogen atom to which they are attached form a 3- to 10-membered optionally substituted heterocycle; 78. The method of claim 77, wherein the at least one chemical synthesis reaction is a reaction selected from (c); (b) and (c); and (a), (b), and (c) shown in Figures 3A(i) and 3A(ii).

82. The compound having formula (I) is a compound having formula (E): 【Chemistry 27】 In the formula, R １ａ and R １ｂ are each independently selected from an alkyl group, an optionally substituted alkyl-aryl group, or a hydrogen atom; or R １ａ and R １ｂ taken together with the nitrogen atom to which they are attached form a 3- to 10-membered optionally substituted heterocycle; 78. The method of claim 77, wherein the at least one chemical synthesis reaction is a reaction selected from (b) shown in Figure 3C; and (a) and (b).

83. The compound having formula (I) is a compound having formula (F): 【Chemistry 28】 In the formula, R １ａ and R １ｂ are each independently selected from a hydroxyl alkyl group or a hydrogen atom, or R １ａ and R １ｂ taken together with the nitrogen atom to which they are attached form a 3-10 membered optionally substituted heterocycle, and R ２ is an alkyl group or a hydrogen atom, and X ３ is an O-alkyl group, a halogen, or a hydrogen atom, 78. The method of claim 77, wherein the at least one chemical synthesis reaction is a reaction selected from (c1); (c2); (b) and (c2); (a) and (c1); (a), (b), and (c2) shown in Figures 3B(i) and 3B(ii).

84. The compound having formula (I) is a compound having formula (G): 【Chemistry 29】 In the formula, X ３ is a hydrogen atom, a halogen atom, or an O-alkyl group, and R ２ , Y １ and Y ２ are each independently an alkyl group or a hydrogen atom, 78. The method of claim 77, wherein the at least one chemical synthesis reaction is a reaction selected from {(h); (c1) and (h); (c2) and (h); (b), (c2), and (h); and (a), (c1), and (h); and (a), (b), (c2) and (h) in Figures 3B(i), 3B(ii), and 3B(iii).

85. 1. Use of a chemical compound having formula (I) or (II) in the manufacture of a pharmaceutical or recreational drug formulation: 【Transformation 30】 In formula (I) or (II): 【Chemistry 31】 is a single or double bond; X １ , X ２ , and X ３ are independently a hydrogen atom, O-alkyl, acyl, N-alkyl, OH, halogen, or NH ２ Selected from: X ４ is an alkylene group or a substituted alkylene group; R １ is hydrogen, an alkyl group, or an oxo group; R １ is R １ｂ , R １ and the carbon atom to which R １ｂ together with the nitrogen atom to which it is attached to form an optionally substituted saturated or unsaturated 3- to 10-membered heterocyclic ring, and when the heterocyclic ring is unsaturated, R １ａ is optional and not present; R １ａ and R １ｂ are each independently selected from an alkyl group, a hydroxylalkyl group, an optionally substituted alkyl-aryl group, or a hydrogen atom; or R １ａ and R １ｂ taken together with the nitrogen atom to which they are attached form a 3- to 10-membered optionally substituted heterocycle; and R ２ and R ３ are each independently selected from an alkyl group, an O-alkyl group, or a hydrogen atom; or R ２ and R ３ When used, the oxygen atom and the carbon atom to which they are attached form an oxirane ring.

86. 86. The use of claim 85, wherein said manufacturing comprises formulating said chemical compound with an excipient, diluent, or carrier.

87. 1. Use of a compound having the formula (I) or (II) together with a diluent, carrier, or excipient as a pharmaceutical or recreational drug formulation comprising: 【Chemistry 32】 In formula (I) or (II): 【Transformation 33】 is a single or double bond; X １ , X ２ , and X ３ are independently a hydrogen atom, O-alkyl, acyl, N-alkyl, OH, halogen, or NH ２ Selected from: X ４ is an alkylene group or a substituted alkylene group; R １ is hydrogen, an alkyl group, or an oxo group; R １ is R １ｂ , R １ and the carbon atom to which R １ｂ together with the nitrogen atom to which it is attached to form an optionally substituted saturated or unsaturated 3- to 10-membered heterocyclic ring, and when the heterocyclic ring is unsaturated, R １ａ is optional and not present; R １ａ and R １ｂ are each independently selected from an alkyl group, a hydroxylalkyl group, an optionally substituted alkyl-aryl group, or a hydrogen atom; or R １ａ and R １ｂ taken together with the nitrogen atom to which they are attached form a 3- to 10-membered optionally substituted heterocycle; and R ２ and R ３ are each independently selected from an alkyl group, an O-alkyl group, or a hydrogen atom; or R ２ and R ３ When used, the oxygen atom and the carbon atom to which they are attached form an oxirane ring.

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