Substituted N-propylamine fused heterocyclic myocarine derivatives

Abstract

Disclosed are novel fused myocarine derivative compounds, in particular, substituted N-propylamine fused heterocyclic myocarine derivatives, including substituted N-propylamine fused dioxolane myocarine derivatives, and pharmaceutical and entertaining pharmaceutical formulations containing the same. Methods of making and using these compounds are also disclosed.

Description

[0001] Related Applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 426,553, filed on Nov. 18, 2022; the entire content of U.S. Patent Application No. 63 / 426,553 is hereby incorporated by reference. Technical Field

[0003] The compositions and methods disclosed herein relate to a compound known as mescaline. In addition, the compositions and methods disclosed herein particularly relate to fused heterocyclic mescaline derivatives, and more particularly to fused heterocyclic mescaline derivatives having a substituted N-propylamine chain. Background Art

[0004] The following paragraphs are provided as background art for the present disclosure. However, they do not admit that any of the content discussed therein is prior art or part of the knowledge of those skilled in the art.

[0005] Biochemical pathways in the cells of living organisms can be classified as part of primary metabolism or part of secondary metabolism. Pathways that are part of the primary metabolism of a cell are involved in catabolism for energy production or in anabolism for the production of building blocks of the cell. On the other hand, secondary metabolites are produced by cells without an apparent anabolic or catabolic function. It has long been recognized that secondary metabolites are useful in many ways, including as therapeutic compounds.

[0006] For example, mescaline (chemically known as 3,4,5-trimethoxyphenethylamine) is a secondary metabolite that is naturally produced by certain cactus species in multiple genera within the cactus family, which belongs to the Cactaceae. Cactus species that can produce mescaline include, for example, cactus species belonging to the genus Lophophora, including Lophophora williamsii (peyote) and Lophophora diffusa; and cactus species belonging to the genus Echinopsis / Trichocereus, including Echinopsis pachanoi / Trichocereus pachanoi (also known as San Pedro cactus), Echinopsis peruviana / Trichocereus peruvianus (also known as Peruvian torch), (Echinopsis lageniformis / Trichocereus bridgesii) / (also known as Bolivian torch) and Echinopsis scopulicola / Trichocereus scopulicola.

[0007] Interest in mescaline in the art 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 in Andean indigenous cultures. In addition, the potential of mescaline in the treatment of addiction, particularly alcohol addiction, has been evaluated (Bogenschutz, M.P. and Johnson M.W. (2016), Prog. in Neuro-Psychopharmacol. & Biol. Psychiatry 64; 250-258; Romeu, A.G. et al. (2017), Exp. Clin. Psychopharmacol. August 2016; 24(4):229–268).

[0008] Although mescaline has low toxicity, mescaline users do not infrequently experience adverse side effects, including, for example, panic attacks, paranoia, and psychotic states, sometimes collectively or individually referred to as a "bad trip." In addition, mescaline can cause nausea and vomiting.

[0009] Accordingly, there is a need in the art for improved mescaline compounds. SUMMARY OF THE INVENTION

[0010] The following paragraphs are intended to introduce the reader to a more detailed description and are not intended to limit or restrict the claimed subject matter of the present disclosure.

[0011] In one aspect, the present disclosure relates to mescaline and derivatives thereof.

[0012] In another aspect, the present disclosure relates to fused heterocyclic mescaline derivatives, and methods of making and using these compounds.

[0013] In another aspect, the present disclosure relates to fused heterocyclic mescaline derivatives having a substituted N-propylamine chain and methods of making and using these compounds.

[0014] Thus, in one aspect, in accordance with the teachings herein, the present disclosure provides, in at least one embodiment, a compound having Formula (I) or (II):

[0015]

[0016] Wherein, in Formula (I) or (II):

[0017] is a single bond or a double bond;

[0018] X1, X2, and X3 are independently selected from a hydrogen atom, O-alkyl, acyl, N-alkyl, OH, halogen, or NH2;

[0019] X4 is an alkylene group or a substituted alkylene group;

[0020] R1 is hydrogen, an alkyl group, or an oxo group, or

[0021] R1 is joined to R 1b and the carbon atom to which R1 is attached and the nitrogen atom to which R 1b is attached to form an optionally substituted saturated or unsaturated 3- to 10-membered heterocycle, and when the heterocycle is unsaturated, R 1a is optionally absent;

[0022] R 1a and R 1beach independently selected from an alkyl group, a hydroxyalkyl group, an optionally substituted alkyl-aryl group or a hydrogen atom, or R 1a and R 1b together with the nitrogen atom to which they are attached are joined to form an optionally substituted 3- to 10-membered heterocycle; and

[0023] R2 and R3 are each independently selected from an alkyl group, an O-alkyl group, a hydrogen atom, or R2 and R3 together with the oxygen atom and the carbon atom to which they are attached form an ethylene oxide ring.

[0024] In at least one embodiment, on the one hand, the compound having formula (I) can be a compound having formula (I a ) or (I b ), and the compound having formula (II) can be a compound having formula (II a ) or (II b ):

[0025]

[0026] wherein, in chemical formulas (I a ), (I b ), (II a ) or (II b ):

[0027] X1, X2 and X3 are independently selected from a hydrogen atom, O-alkyl, acyl, N-alkyl, OH, halogen or NH2;

[0028] X4 is an alkylene group or a substituted alkylene group;

[0029] R1 is hydrogen, an alkyl group or an oxo group, or

[0030] R1 is joined to R 1b and the carbon atom to which R1 is attached and R 1b the nitrogen atom to which it is attached to form an optionally substituted saturated or unsaturated 3- to 10-membered heterocycle, and when the heterocycle is unsaturated, R 1a is optionally absent;

[0031] R 1a and R 1b are each independently selected from an alkyl group, a hydroxyalkyl group, an optionally substituted alkyl-aryl group or a hydrogen atom, or R 1a and R 1b together with the nitrogen atom to which they are attached are joined to form an optionally substituted 3- to 10-membered heterocycle; and

[0032] R2 and R3 are each independently selected from an alkyl group, an O-alkyl group, a hydrogen atom, or R2 and R3 are joined together with an oxygen atom and the carbon atom to which they are attached to form an ethylene oxide ring.

[0033] In at least one embodiment, in one aspect, X4 can be a (C1-C3)-alkylene group or a substituted (C1-C3)-alkylene group.

[0034] In at least one embodiment, in one aspect, X4 can be a methylene group (-CH2-) or a substituted methylene group.

[0035] In at least one embodiment, in one aspect, the methylene group can be substituted by at least one halogen.

[0036] In at least one embodiment, in one aspect, the substituted methylene group can be substituted by two halogen substituents.

[0037] In at least one embodiment, in one aspect, the substituted methylene group can be substituted by two identical halogen substituents and can optionally be (-CF2-).

[0038] In at least one embodiment, in one aspect, the compound having the formula (I a ), (I b ), (II a ) and (II b ) can respectively have the chemical formula (I c ), (I d ), (II c ) or (II d ) as follows:

[0039]

[0040] In at least one embodiment, in one aspect, the amino group (-NR 1a R 1b ) can be protonated to form (-N + HR 1a R 1b ), and the chemical formulas (I), (II), (I a ), (I b ), (II a ), (II b ), (I c ), (I d ), (II c ) or (II d ) further include a negatively charged anion that balances the positively charged nitrogen atom.

[0041] In at least one embodiment, in one aspect, X1, X2, X3 can each be a hydrogen atom (H).

[0042] In at least one embodiment, in one aspect, at least one of X1, X2, X3 can each be an O-alkyl group or a halogen.

[0043] In at least one embodiment, in one aspect, X3 can each be an O-alkyl group, optionally a methoxy group, or a halogen, optionally bromine.

[0044] In at least one embodiment, in one aspect, R2 and R3 can independently or simultaneously be (C1-C6)-alkyl groups.

[0045] In at least one embodiment, in one aspect, R2 and R3 can independently or simultaneously be (C1-C3)-alkyl groups.

[0046] In at least one embodiment, in one aspect, R2 and R3 can be methyl groups.

[0047] In at least one embodiment, in one aspect, R2 can be a (C1-C6)-alkyl group and R3 can be a hydrogen atom.

[0048] In at least one embodiment, in one aspect, R2 can be a (C1-C3)-alkyl group and R3 can be a hydrogen atom.

[0049] 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.

[0050] In at least one embodiment, in one aspect, R3 can be a (C1-C6)-alkyl group and R2 can be a hydrogen atom.

[0051] In at least one embodiment, in one aspect, R3 can be a (C1-C3)-alkyl group and R2 can be a hydrogen atom.

[0052] In at least one embodiment, in one aspect, R3 can be a methyl group and R2 can be a hydrogen atom.

[0053] In at least one embodiment, in one aspect, R2 and R3 can each be a methoxy group.

[0054] 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.

[0055] In at least one embodiment, on the one hand, R2 can be, independently or simultaneously, a (C1-C3)-O-alkyl group, and R3 can be a hydrogen atom.

[0056] In at least one embodiment, on the one hand, R2 can be a methoxy group, and R3 can be a hydrogen atom.

[0057] In at least one embodiment, on the one hand, R3 can be a (C1-C6)-O-alkyl group, and R2 can be a hydrogen atom.

[0058] In at least one embodiment, on the one hand, R3 can be a (C1-C3)-O-alkyl group, and R2 can be a hydrogen atom.

[0059] In at least one embodiment, on the one hand, R3 can be a methoxy group, and R2 can be a hydrogen atom.

[0060] In at least one embodiment, on the one hand, R2 and R3 can each be a hydrogen atom.

[0061] In at least one embodiment, on the one hand, in formula (I a ), (II a ), (I c ) or (II c ), R2 and R3 can be linked together with the oxygen atom to form an ethylene oxide ring.

[0062] In at least one embodiment, on the one hand, R 1a can be a hydrogen atom, and R 1b can be a (C1-C6)-alkyl group.

[0063] In at least one embodiment, on the one hand, R 1a and R 1b can be, independently or simultaneously, (C1-C6)-alkyl groups.

[0064] In at least one embodiment, on the one hand, R 1a and R 1b can be, independently or simultaneously, (C1-C3)-alkyl groups.

[0065] In at least one embodiment, on the one hand, R 1a can be a hydrogen atom, and R 1b can be a (C1-C6)-hydroxyalkyl group.

[0066] In at least one embodiment, on the one hand, R 1a can be a hydrogen atom, and R 1bIt can be a methanol group (-CH2OH), an ethanol group (-C2H4OH), a propanol group (-C3H6OH), or a butanol group (-C4H8OH).

[0067] In at least one embodiment, on the one hand, R 1a can be a hydrogen atom, and R 1b can be a hydroxyalkyl group having the formula (HA):

[0068]

[0069] wherein Y1 and Y2 are each simultaneously or independently a hydrogen atom or a (C1-C6)-alkyl group.

[0070] In at least one embodiment, on the one hand, R 1a can be a hydrogen atom, and R 1b can be an alkyl-aryl group.

[0071] In at least one embodiment, on the one hand, the alkyl-aryl group can be a (C1-C6)-alkyl-aryl group.

[0072] In at least one embodiment, on the one hand, the alkyl-aryl group can be a (C1-C6)-alkyl-phenyl group.

[0073] In at least one embodiment, on the one hand, the alkyl-aryl group can be a (CH2)-phenyl group.

[0074] In at least one embodiment, on the one hand, R 1a and R 1b can be joined together with the nitrogen atom to which they are attached to form a 3- to 10-membered optionally substituted heterocycle, wherein the heterocycle further includes an oxygen atom.

[0075] In at least one embodiment, on the one hand, R 1a and R 1b can be joined together with the nitrogen atom to which they are attached to form a 3- to 10-membered optionally substituted heterocycle, wherein the heterocycle further includes an oxygen atom, and wherein the heterocycle is further substituted by at least one (C1-C6)-alkyl group.

[0076] In at least one embodiment, on the one hand, the heterocycle can be further independently or simultaneously substituted by two (C1-C6)-alkyl groups from the same heterocyclic carbon atom.

[0077] In at least one embodiment, on the one hand, the heterocycle can be further substituted by two methyl groups on a single heterocyclic carbon atom.

[0078] In at least one embodiment, on the one hand, the heterocycle can be further substituted by two methyl groups on two separate heterocyclic carbon atoms.

[0079] In at least one embodiment, on the one hand, the heterocycle can be a 5 - or 6 - membered heterocycle.

[0080] In at least one embodiment, on the one hand, R1 can be connected to the nitrogen atom to which R 1b and R 1b are attached, and the carbon atom to which R1 is attached are joined together to form an optionally substituted saturated or unsaturated 3 - 10 - membered heterocycle, wherein the heterocycle includes an oxygen atom in addition to the nitrogen atom.

[0081] In at least one embodiment, on the one hand, R1 can be connected to the nitrogen atom to which R 1b and R 1b are attached, and the carbon atom to which R1 is attached are joined together to form an optionally substituted saturated or unsaturated 3 - 10 - membered heterocycle, wherein the heterocycle includes an oxygen atom in addition to the nitrogen atom and is substituted by at least one (C1 - C6) alkyl group.

[0082] In at least one embodiment, on the one hand, R1 can be connected to the nitrogen atom to which R 1b and R 1b are attached, and the carbon atom to which R1 is attached are joined together to form an optionally substituted saturated or unsaturated 3 - 10 - membered heterocycle, wherein the heterocycle includes an oxygen atom in addition to the nitrogen atom and is independently or simultaneously substituted by at least two (C1 - C6) alkyl groups, and the alkyl groups are substituents on the same heterocyclic carbon atom.

[0083] In at least one embodiment, on the one hand, the alkyl group can be a methyl group.

[0084] In at least one embodiment, on the one hand, the heterocycle can be partially saturated.

[0085] In at least one embodiment, on the one hand, the heterocycle can be a 5 - or 6 - membered heterocycle.

[0086] In at least one embodiment, on the one hand, when the heterocycle is unsaturated, R 1a can be absent.

[0087] In at least one embodiment, on the one hand, when the heterocycle is unsaturated and nitrogen participates in the formation of an unsaturated bond, R 1a can be absent.

[0088] In at least one embodiment, on the one hand, a 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):

[0089]

[0090] wherein in formula (B), X 4a and X 4b are independently or simultaneously a halogen or hydrogen atom, wherein R 1a and R 1b in formulas (A), (B), (C), (D), (E) and (F) are independently selected from alkyl groups, optionally substituted alkyl-aryl groups or hydrogen atoms, or wherein R 1a and R 1b together with the nitrogen atom to which they are attached are joined together to form a 3- to 10-membered optionally substituted heterocycle;

[0091] wherein R2 in formulas (C), (F) and (G) and Y1 and Y2 in (G) are alkyl groups or hydrogen atoms; and

[0092] wherein X3 in formulas (C), (F) and (G) is a halogen, O-alkyl group or hydrogen atom.

[0093] In at least one embodiment, on the one hand, a compound having formula (I) can be selected from the group of compounds having 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):

[0094] (A): A(I); A(II); and A(III):

[0095]

[0096] (B): B(I); B(II); B(III); B(IV); and B(V):

[0097]

[0098] (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):

[0099]

[0100]

[0101] (D): D(I); D(II); and D(III):

[0102]

[0103] (E): E(I); E(II); E(III); E(IV); and E(V):

[0104]

[0105] (F): F(I); F(II); F(III); F(IV); F(V); and F(VI):

[0106]

[0107] (G): G(I); G(II); G(III); G(IV); and G(V):

[0108]

[0109] Wherein in each of compounds A(I) to G(V), optionally, the nitrogen atom of the N-propylamine moiety may be protonated and includes a negatively charged anion that balances the positively charged nitrogen atom.

[0110] In at least one embodiment, on the one hand, the compound may be a stereoisomeric compound selected from the stereoisomeric compounds corresponding to A(I), A(II), A(III), C(VII), C(IX), C(XI), F(II), G(II), and G(IV), which contains an N-propylamine moiety, wherein the C2 atom of its N-propylamine moiety is a chiral carbon atom.

[0111] In at least one embodiment, on the one hand, the compound may be a first stereoisomeric compound present in a mixture that contains a second stereoisomeric compound, which is a stereoisomeric counterpart of the first stereoisomeric compound, wherein, optionally, the mixture is a racemic mixture.

[0112] In at least one embodiment, on the one hand, the stereoisomeric compound may be substantially free of its corresponding counterpart stereoisomeric compound.

[0113] In at least one embodiment, on the one hand, the compound having the formula A(II) may be selected from the stereoisomeric compounds having the formula A(II a ) or A(II b ):

[0114]

[0115] In at least one embodiment, on the one hand, the selected compound can be in a mixture further comprising other stereoisomeric compounds, where optionally, the mixture is a racemic mixture.

[0116] On the other hand, the present disclosure relates to pharmaceutical and recreational drug formulations comprising fused heterocyclic mescaline derivatives. Thus, in one aspect, in at least one embodiment, the present disclosure provides a pharmaceutical or recreational drug formulation comprising an effective amount of a compound selected from compounds having the formula (I) or (II) and a pharmaceutically acceptable excipient, diluent, or carrier:

[0117]

[0118] Wherein, in formula (I) or (II):

[0119] is a single bond or a double bond;

[0120] X1, X2, and X3 are independently selected from a hydrogen atom, O-alkyl, acyl, N-alkyl, OH, halogen, or NH2;

[0121] X4 is an alkylene group or a substituted alkylene group;

[0122] R1 is hydrogen, an alkyl group, or an oxo group, or

[0123] R1 is connected to R 1b and the carbon atom to which R1 is attached and the nitrogen atom to which R 1b is attached together to form an optionally substituted saturated or unsaturated 3- to 10-membered heterocycle, and when the heterocycle is unsaturated, R 1a is optionally absent;

[0124] R 1a and R 1b are each independently selected from an alkyl group, a hydroxyalkyl group, an optionally substituted alkyl-aryl group, or a hydrogen atom, or R 1a and R 1b together with the nitrogen atom to which they are attached form an optionally substituted 3- to 10-membered heterocycle; and

[0125] R2 and R3 are each independently selected from an alkyl group, an O-alkyl group, a hydrogen atom, or R2 and R3 are connected to the oxygen atom and the carbon atom to which they are attached to form an ethylene oxide ring.

[0126] On the other hand, the present disclosure relates to methods for treating mental disorders. Thus, 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 preparation comprising a compound having formula (I) or (II):

[0127]

[0128] wherein, in formula (I) or (II):

[0129] is a single bond or a double bond;

[0130] X1, X2 and X3 are independently selected from a hydrogen atom, O-alkyl, acyl, N-alkyl, OH, halogen or NH2;

[0131] X4 is an alkylene group or a substituted alkylene group;

[0132] R1 is hydrogen, an alkyl group or an oxo group, or R1 is linked to the carbon atom to which R 1b and the nitrogen atom to which R1 is linked and R 1b are linked together to form an optionally substituted saturated or unsaturated 3- to 10-membered heterocycle, and when the heterocycle is unsaturated, R 1a is optionally absent;

[0133] R 1a and R 1b are each independently selected from an alkyl group, a hydroxyalkyl group, an optionally substituted alkyl-aryl group or a hydrogen atom, or R 1a and R 1b together with the nitrogen atom to which they are linked are linked together to form a 3- to 10-membered optionally substituted heterocycle; and

[0134] R2 and R3 are each independently selected from an alkyl group, an O-alkyl group, a hydrogen atom, or R2 and R3 are linked to the oxygen atom and the carbon atom to which they are linked to form an ethylene oxide ring,

[0135] wherein the pharmaceutical preparation is administered in an effective amount to treat the cranial nerve disorder of the subject.

[0136] In at least one embodiment, on the one hand, after administration, the compound having formula (I) or (II) can interact with a receptor in the subject, thereby modulating the receptor and exerting a pharmacological effect.

[0137] In at least one embodiment, on the one hand, the receptor can be a G protein-coupled receptor (GPCR).

[0138] In at least one embodiment, on the one hand, the receptor can be a 5-HT receptor.

[0139] In at least one embodiment, on the one hand, the receptor can be 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.

[0140] In at least one embodiment, on the one hand, after administration, a compound having formula (I) or (II) can interact with a transmembrane transporter in a subject, thereby modulating the transmembrane transporter and exerting a pharmacological effect.

[0141] In at least one embodiment, on the one hand, the transmembrane transporter can be a dopamine active transporter (DAT), a norepinephrine transporter (NET) or a serotonin transporter (SERT) transmembrane transporter.

[0142] In at least one embodiment, on the one hand, the disorder can be a G protein-coupled receptor (GPCR)-mediated disorder.

[0143] In at least one embodiment, on the one hand, the disorder can be a 5-HT receptor-mediated disorder.

[0144] In at least one embodiment, on one aspect, the disorder can be 5-HT 1A receptor-mediated disorder, 5-HT 2A receptor-mediated disorder, 5-HT 2B receptor-mediated disorder, 5-HT 2C receptor-mediated disorder, 5-HT 1D receptor-mediated disorder, 5-HT7 receptor-mediated disorder, α 2A receptor-mediated disorder, D3 receptor-mediated disorder or MT1 receptor-mediated disorder.

[0145] In at least one embodiment, on the one hand, a dose of about 0.001 mg to about 5,000 mg can be administered.

[0146] On the other hand, in at least one embodiment, the present disclosure provides a method for modulating (i) a receptor selected from 5-HT 1A receptor, 5-HT 2A receptor, 5-HT 2B receptor, 5-HT 2C receptor, 5-HT7 receptor, α 2Aa receptor of the 5-HT receptor, D3 receptor or MT1 receptor; or (ii) a method of a transmembrane transporter selected from the dopamine active transporter (DAT), norepinephrine transporter (NET) or serotonin transporter (SERT), the method comprising, under reaction conditions sufficient to modulate (i) the 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; (ii) a dopamine active transporter (DAT), norepinephrine transporter (NET) or serotonin transporter (SERT) transmembrane transporter is contacted with a first compound selected from a compound of formula (I) and a second compound of formula (II): 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), norepinephrine transporter (NET) or serotonin transporter (SERT) transmembrane transporter, wherein, in formula (I) or (II):

[0147]

[0148] is a single bond or a double bond;

[0149] is a single bond or a double bond;

[0150] X1, X2 and X3 are independently selected from a hydrogen atom, O-alkyl, acyl, N-alkyl, OH, halogen or NH2;

[0151] X4 is an alkylene group or a substituted alkylene group;

[0152] R1 is hydrogen, an alkyl group or an oxo group, or

[0153] R1 is linked to R 1b and the carbon atom to which R1 is attached and the nitrogen atom to which R 1b is attached together to form an optionally substituted saturated or unsaturated 3- to 10-membered heterocycle, and when the heterocycle is unsaturated, R 1a is optionally absent;

[0154] R 1a and R 1b are each independently selected from an alkyl group, a hydroxyalkyl group, an optionally substituted alkyl-aryl group or a hydrogen atom, or R1a and R 1b are linked together with the nitrogen atom to which they are attached to form an optionally substituted 3- to 10-membered heterocycle; and

[0155] R2 and R3 are each independently selected from an alkyl group, an O-alkyl group, a hydrogen atom, or R2 and R3 are linked together with an oxygen atom and the carbon atom to which they are attached to form an ethylene oxide ring.

[0156] In at least one embodiment, on the one hand, the reaction conditions can be in vitro reaction conditions.

[0157] In at least one embodiment, on the one hand, the reaction conditions can be in vivo reaction conditions.

[0158] On the other hand, the present disclosure relates to a method for preparing mescaline derivatives. Thus, on the one hand, in at least one embodiment, a method for preparing a first compound having the formula (I) or (II) is provided herein:

[0159]

[0160] wherein, in formula (I) or (II):

[0161] is a single bond or a double bond;

[0162] X1, X2 and X3 are independently selected from a hydrogen atom, O-alkyl, acyl, N-alkyl, OH, halogen or NH2;

[0163] X4 is an alkylene group or a substituted alkylene group;

[0164] R1 is hydrogen, an alkyl group or an oxo group, or

[0165] R1 is linked together with R 1b and the carbon atom to which R1 is attached and R 1b to form an optionally substituted saturated or unsaturated 3- to 10-membered heterocycle, and when the heterocycle is unsaturated, R 1a is optionally absent;

[0166] R 1a and R 1b are each independently selected from an alkyl group, a hydroxyalkyl group, an optionally substituted alkyl-aryl group or a hydrogen atom, or R 1a and R 1b are linked together with the nitrogen atom to which they are attached to form an optionally substituted 3- to 10-membered heterocycle; and

[0167] R2 and R3 are each independently selected from an alkyl group, an O-alkyl group, a hydrogen atom, or R2 and R3 are joined together with the oxygen atom and the carbon atom to which they are attached to form an ethylene oxide ring, and

[0168] wherein the method involves performing at least one chemical synthesis reaction selected from those depicted in Figure 3A(i), Figure 3A(ii), Figure 3B(i), Figure 3B(ii), Figure 3B(iii), and Figure 3C the reactions depicted therein.

[0169] In at least one embodiment, on the one hand, the compound having the formula (I) can be a compound having the formula (A):

[0170]

[0171] wherein 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 are joined together with the nitrogen atom to which they are attached to form a 3- to 10-membered optionally substituted heterocycle,

[0172] and 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) depicted in Figure 3A(i) and Figure 3A(ii).

[0173] In at least one embodiment, on the one hand, the compound having the formula (I) can be a compound having the formula (B):

[0174]

[0175] wherein in formula (B), X 4a and X 4b are independently or simultaneously a halogen atom or a hydrogen atom, wherein 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 are joined together with the nitrogen atom to which they are attached to form a 3- to 10-membered optionally substituted heterocycle,

[0176] and 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) depicted in Figure 3A(i).

[0177] In at least one embodiment, on the one hand, a compound having the chemical formula (I) can be a compound having the formula (C):

[0178]

[0179] wherein R 1a and R 1b are each independently selected from an alkyl group, a hydroxyalkyl group or a hydrogen atom, or R 1a and R 1b together with the nitrogen atom to which they are attached are joined to form a 3- to 10-membered optionally substituted heterocycle, wherein R2 is selected from an alkyl group or a hydrogen atom, and wherein X3 is an O-alkyl group, a halogen or a hydrogen atom,

[0180] and at least one chemical synthesis reaction is a reaction selected from the following:

[0181] (i) { (h) in FIGS. 3A(i) and 3A(ii); (c) and (h); (b), (c) and (h); and (a), (b), (c) and (h)};

[0182] (ii) { (f) in FIGS. 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)};

[0183] (iii) { (e) in FIGS. 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)};

[0184] (iv) { (d) in FIGS. 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

[0185] (v) { (i) in FIGS. 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

[0186] (vi) (g) in FIGS. 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).

[0187] In at least one embodiment, on the one hand, a compound having the chemical formula (I) can be a compound having the formula (D):

[0188]

[0189] wherein R 1a and R 1b are each independently selected from an alkyl group, a hydrogen atom, or R 1a and R 1b together with the nitrogen atom to which they are attached are joined to form a 3- to 10-membered optionally substituted heterocycle,

[0190] and at least one chemical synthesis reaction is a reaction selected from (c) depicted in FIGS. 3A(i) and 3A(ii); (b) and (c); and (a), (b) and (c).

[0191] In at least one embodiment, on the one hand, a compound having the chemical formula (I) can be a compound having the formula (E):

[0192]

[0193] wherein 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 together with the nitrogen atom to which they are attached are joined to form a 3- to 10-membered optionally substituted heterocycle,

[0194] and at least one chemical synthesis reaction is a reaction selected from Figure 3C (b) depicted therein; and (a) and (b).

[0195] In at least one embodiment, on the one hand, a compound having the chemical formula (I) can be a compound having the formula (F):

[0196]

[0197] wherein R 1a and R 1b are each independently selected from a hydroxyalkyl group or a hydrogen atom, or R 1a and R 1blinked together with the nitrogen atom to which they are attached to form an optionally substituted 3- to 10-membered heterocycle, and

[0198] wherein R2 is an alkyl group or a hydrogen atom, and X3 is an O-alkyl group, a halogen, or a hydrogen atom,

[0199] and at least one chemical synthesis reaction is selected from (c1); (c2); (b) and (c2); (a) and (c1); (a), (b) and (c2) depicted in Figure 3B(i) and Figure 3B(ii).

[0200] In at least one embodiment, on the one hand, the compound having the chemical formula (I) can be a compound having the formula (G):

[0201]

[0202] wherein X3 is a hydrogen atom, a halogen atom, or an O-alkyl group, and wherein R2, Y1, and Y2 are each independently an alkyl group or a hydrogen atom,

[0203] and at least one chemical synthesis reaction is 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 Figure 3B(i), Figure 3B(ii), and Figure 3B(iii).

[0204] On the other hand, the present disclosure provides, in at least one embodiment, the use of a compound having the chemical formula (I) or (II) in the manufacture of a pharmaceutical or recreational drug formulation:

[0205]

[0206] wherein, in the chemical formula (I) or (II):

[0207] is a single bond or a double bond;

[0208] X1, X2, and X3 are independently selected from a hydrogen atom, O-alkyl, acyl, N-alkyl, OH, halogen, or NH2;

[0209] X4 is an alkylene group or a substituted alkylene group;

[0210] R1 is hydrogen, an alkyl group, or an oxo group, or

[0211] R1 is linked together with R 1b and the carbon atom to which R1 is attached and R 1b the nitrogen atom to which it is attached to form an optionally substituted saturated or unsaturated 3- to 10-membered heterocycle, and when the heterocycle is unsaturated, R1a Optionally absent;

[0212] R 1a and R 1b are each independently selected from an alkyl group, a hydroxyalkyl group, an optionally substituted alkyl-aryl group, or a hydrogen atom, or R 1a and R 1b together with the nitrogen atom to which they are attached are joined to form a 3- to 10-membered optionally substituted heterocycle; and

[0213] R2 and R3 are each independently selected from an alkyl group, an O-alkyl group, a hydrogen atom, or R2 and R3 together with the oxygen atom and the carbon atom to which they are attached form an oxirane ring.

[0214] In at least one embodiment, on the one hand, manufacturing may include formulating a compound with an excipient, diluent, or carrier.

[0215] On the other hand, the present disclosure provides in at least one embodiment the use of a compound of formula (I) or (II) together with a diluent, carrier, or excipient as a pharmaceutical or recreational drug formulation:

[0216]

[0217] wherein, in formula (I) or (II):

[0218] is a single bond or a double bond;

[0219] X1, X2, and X3 are independently selected from a hydrogen atom, O-alkyl, acyl, N-alkyl, OH, halogen, or NH2;

[0220] X4 is an alkylene group or a substituted alkylene group;

[0221] R1 is hydrogen, an alkyl group, or an oxo group, or

[0222] R1 together with R 1b and the carbon atom to which R1 is attached and R 1b the nitrogen atom to which it is attached are joined to form an optionally substituted saturated or unsaturated 3- to 10-membered heterocycle, and when the heterocycle is unsaturated, R 1a is optionally absent;

[0223] R 1a and R 1b are each independently selected from an alkyl group, a hydroxyalkyl group, an optionally substituted alkyl-aryl group, or a hydrogen atom, or R 1a and R 1b together with the nitrogen atom to which they are attached are joined to form a 3- to 10-membered optionally substituted heterocycle; and

[0224] R2 and R3 are each independently selected from an alkyl group, an O-alkyl group, a hydrogen atom, or R2 and R3 are joined together with an oxygen atom and the carbon atom to which they are attached to form an ethylene oxide ring.

[0225] Other features and advantages will become apparent from the following detailed description. However, it should be understood that the detailed description, although indicating preferred embodiments of the present disclosure, is given by way of illustration only, since various changes and modifications within the spirit and scope of the present disclosure will become apparent to those skilled in the art from the detailed description. BRIEF DESCRIPTION OF THE DRAWINGS

[0226] The present disclosure is described by way of example in the paragraphs provided below in conjunction with the accompanying drawings. The drawings provided herein are provided for a better understanding of the exemplary embodiments and more clearly show how the various embodiments can be implemented. These drawings are not intended to limit the present disclosure.

[0227] Figure 1 The chemical structure of mescaline is depicted, and the phenyl moiety and the ethylamine moiety of the compound containing a substituted phenyl group are identified.

[0228] Figure 2 Depicts a certain prototype structure of a mescaline-derived compound. The prototype structure contains a phenyl moiety containing a substituted phenyl group and an N-propylamine moiety, as indicated. The carbon atoms have been numbered C1, C2, C3, etc. to indicate their positions in the phenyl moiety or the N-propylamine moiety, respectively. Thus, for example, from Figure 2 it will be clear that the N-propylamine chain extends from the C1 carbon of the phenyl group. In addition, it should be noted that certain compounds can be named according to this. 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)dioxolane phenyl N-propylamine, the phenyl moiety carbon atoms C2 and C3 each participate in the formation of the (1,3)dioxolane group (i.e., a pentane in which the carbons at positions 1 and 3 have been replaced by 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.

[0229] FIG. 3A(i), FIG. 3A(ii), FIG. 3B(i), FIG. 3B(ii), FIG. 3B(iii) and Figure 3CIllustrates exemplary synthetic routes of certain exemplary mescaline compounds of the present disclosure and chemical reactions comprising such routes, particularly exemplary mescaline-derived compounds (A), (B), (C), and (D) (FIGS. 3A(i) and 3A(ii)); compounds (C) and (F) (FIGS. 3B(i) and 3B(ii)); compound (E)( Figure 3C ); and compound (G) (FIGS. 3B(i), 3B(ii), and 3B(iii)). Individual chemical reactions are represented as (a), (b), (c), (d), (e), (f), (g), (h), and (i) in FIGS. 3A(i) and 3A(ii); (a), (b), (c), (d), (e), (f), (g), (h)(i) in FIGS. 3B(i), 3B(ii), and 3B(iii); and Figure 3C (a) and (b) in

[0230] Figure 4A , Figure 4B , Figure 4C and Figure 4D depict exemplary reactions in exemplary chemical synthesis routes for synthesizing specific exemplary compounds according to the present disclosure.

[0231] Figure 5A , Figure 5B , Figure 5C and Figure 5D depict additional exemplary reactions in another exemplary chemical synthesis route for synthesizing another exemplary compound according to the present disclosure.

[0232] Figure 6A and Figure 6B depict additional exemplary reactions in another exemplary chemical synthesis route for synthesizing another exemplary compound according to the present disclosure.

[0233] Figure 7A and Figure 7B depict additional exemplary reactions in another exemplary chemical synthesis route for synthesizing another exemplary compound according to the present disclosure.

[0234] Figure 8 depicts an exemplary chemical reaction for synthesizing another exemplary compound according to the present disclosure.

[0235] Figure 9 depicts another exemplary chemical reaction for synthesizing another exemplary compound according to the present disclosure.

[0236] Figure 10 depicts another exemplary chemical reaction for synthesizing another exemplary compound according to the present disclosure.

[0237] Figure 11 Depicts another exemplary chemical reaction for synthesizing another exemplary compound according to the present disclosure.

[0238] Figure 12A and Figure 12B Depicts additional exemplary reactions in another exemplary chemical synthesis pathway for synthesizing another exemplary compound according to the present disclosure.

[0239] Figure 13 Depicts another exemplary chemical reaction for synthesizing another exemplary compound according to the present disclosure.

[0240] 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 Depicts various graphs representing certain experimental results, particularly graphs obtained when performing experimental assays to evaluate the drug efficacy of an exemplary compound having the chemical formula B(II), particularly using a radiolabeled 8-hydroxy-DPAT[propyl-2,3-cyclo-1,2,3- 3 H](binding curve) radioligand for the 5-HT 1A receptor saturation binding assay( Figure 14A ); 5-HT 1A receptor competition assay using DMSO (negative control)( Figure 14B ); 5-HT 1A receptor competition assay using tryptophan (negative control)( Figure 14C ); 5-HT 1A receptor competition assay using serotonin (positive control)( Figure 14D ); 5-HT 1A receptor competition assay using mescaline (positive control)( Figure 14E ); 5-HT 1A receptor competition assay using 2C-B (positive control)( Figure 14F ); 5-HT 1A receptor competition assay using MDMA (positive control)( Figure 14G ); 5-HT 1A receptor competition assay using escaline( Figure 14H ); 5-HT 1A receptor competition assay using proscaline( Figure 14I); 5-HT receptor competition assay using fluoxetine (positive control) 1A ); Figure 14J ); 5-HT receptor competition assay using vortioxetine (positive control) 1A ); Figure 14K ); 5-HT receptor competition assay using a compound of formula B(II) 1A ); Figure 14L ).

[0241] Figure 15A , Figure 15B , Figure 15C , Figure 15D , Figure 15E , Figure 15F , Figure 15G and Figure 15H depict various graphs representing certain experimental results, especially graphs obtained when performing experimental assays to evaluate the pharmaceutical efficacy of exemplary compounds of formula B(II), especially using radiolabeled 3 3H-ketanserin] radioligand 5-HT 2A receptor saturation binding assay (binding curve)( Figure 15A ); 5-HT receptor competition assay using psilocin (positive control) 2A ); Figure 15B ); 5-HT receptor competition assay using tryptophan (negative control) 2A ); Figure 15C ); 5-HT receptor competition assay using lysergic acid amide 2A ); Figure 15D ); 5-HT receptor competition assay using prosucaline 2A ); Figure 15E ); 5-HT receptor competition assay using 2C-B (positive control) 2A ); Figure 15F ); and 5-HT receptor competition assay using MDMA (positive control) 2A ); Figure 15G ); and 5-HT receptor competition assay using a compound of formula B(II) 2A ); Figure 15H ).

[0242] Figure 16A , Figure 16B , Figure 16C , Figure 16D , Figure 16E , Figure 16F , Figure 16G and Figure 16HDepicts various graphs representing certain experimental results, especially those obtained when conducting experimental assays to evaluate the pharmaceutical efficacy of an exemplary compound having the chemical formula B(II), in particular, detecting the relative levels of cAMP in cells with (+5-HT 1A ) and without (-5-HT 1A ) 5-HT 1A receptors stimulated with different amounts of forskolin in a 5-HT 1A cAMP receptor assay ( Figure 16A );detecting the relative levels of cAMP in cells with (+5-HT 1A ) and without (-5-HT 1A ) 5-HT 1A receptors stimulated with 4 μM forskolin and different amounts of 8-OH-DPAT in a 5-HT 1A cAMP receptor assay ( Figure 16B );detecting the relative levels of cAMP in cells with (+5-HT 1A ) and without (-5-HT 1A ) 5-HT 1A receptors stimulated with 4 μM forskolin and different amounts of serotonin in a 5-HT 1A cAMP receptor assay ( Figure 16C );detecting the relative levels of cAMP in cells with (+5-HT 1A ) and without (-5-HT 1A ) 5-HT 1A receptors stimulated with 4 μM forskolin and different amounts of psilocybin in a 5-HT 1A cAMP receptor assay ( Figure 16D );detecting the relative levels of cAMP in cells with (+5-HT 1A ) and without (-5-HT 1A ) 5-HT 1A receptors stimulated with 4 μM forskolin and different amounts of mescaline in a 5-HT 1A cAMP receptor assay ( Figure 16E );detecting the relative levels of cAMP in cells with (+5-HT 1A ) and without (-5-HT 1A ) 5-HT 1A receptors stimulated with 4 μM forskolin and different amounts of MDMA in a 5-HT 1A cAMP receptor assay ( Figure 16F );detecting the relative levels of cAMP in cells with (+5-HT 1A ) and without (-5-HT 1A ) 5-HT1A The relative level of cAMP in cells of the receptor for 5-HT 1A cAMP receptor assay ( Figure 16G ); and detecting the relative level of cAMP in cells with (+5-HT 1A ) and without (-5-HT 1A ) 5-HT 1A receptors stimulated with 4 μM forskolin and different amounts of Compound B (II). 1A cAMP receptor assay ( Figure 16H ).

[0243] Figure 17 Depicts another exemplary chemical reaction for synthesizing another exemplary compound according to the present disclosure.

[0244] Figure 18 Depicts another exemplary chemical reaction for synthesizing another exemplary compound according to the present disclosure.

[0245] Figure 19A 、 Figure 19B and Figure 19C Depict additional exemplary reactions in another exemplary chemical synthesis pathway for synthesizing another exemplary compound according to the present disclosure.

[0246] Figure 20 Depicts another exemplary chemical reaction for synthesizing another exemplary compound according to the present disclosure.

[0247] Figure 21 Depicts another exemplary chemical reaction for synthesizing another exemplary compound according to the present disclosure.

[0248] Figure 22A and Figure 22B Depict additional exemplary reactions in another exemplary chemical synthesis pathway for synthesizing another exemplary compound according to the present disclosure.

[0249] Figure 23 Depicts another exemplary chemical reaction for synthesizing another exemplary compound according to the present disclosure.

[0250] Figure 24 Depicts another exemplary chemical reaction for synthesizing another exemplary compound according to the present disclosure.

[0251] Figure 25A and Figure 25B Depict additional exemplary reactions in another exemplary chemical synthesis pathway for synthesizing another exemplary compound according to the present disclosure.

[0252] Figure 26Depicts another exemplary chemical reaction for synthesizing another exemplary compound according to the present disclosure.

[0253] Figure 27 Depicts another exemplary chemical reaction for synthesizing another exemplary compound according to the present disclosure.

[0254] The accompanying drawings and the following detailed description enable those skilled in the art to understand how to implement the present disclosure in practice. Detailed Description

[0255] Various compositions, systems, or processes will be described below to provide examples of embodiments of each claimed subject matter. The embodiments described below do not limit any claimed subject matter, and any claimed subject matter may cover processes, compositions, or systems different from those described below. The claimed subject matter is not limited to a composition, process, or system having all the features of any one of the compositions, systems, or processes described below, or to the features common to many or all of the compositions, systems, or processes described below. The compositions, systems, or processes described below may not be embodiments 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 matter of another protective document, e.g., a continuing patent application, and the applicant, inventor, or owner does not intend to disclaim, disavow, or dedicate to the public any such subject matter by its disclosure in this document.

[0256] As used herein and in the claims, singular forms such as "a," "an," and "the" include plural referents, and vice versa, unless the context clearly dictates otherwise. Throughout this specification, unless otherwise stated, "comprise," "comprises," and "comprising" are used inclusively rather than exclusively, so the stated integer or group of integers may include one or more other unstated integers or groups of integers.

[0257] When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. Except in the operating examples, or where otherwise indicated, all numbers expressing quantities of ingredients or reaction conditions used herein should be understood to be modified in all instances by the term “about.” When referring to a number or numerical range, the term “about” means that the recited number or numerical range is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range may vary between 1% and 15% of the recited number or numerical range, as will be readily appreciated by one of ordinary skill in the art. In addition, any numerical range recited herein is intended to specifically include the limiting values of the range, as well as any intermediate values or subranges within the given range, and all such intermediate values and subranges are specifically and individually disclosed (e.g., a range of 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.90, 4, and 5). Similarly, other degree terms, such as “substantially” and “approximately” as used herein, mean a reasonable deviation amount of the modified term, such that the ultimate result is not significantly changed. These degree terms should be construed to include the deviation of the modified term, if such deviation does not negate the meaning of the term it modifies.

[0258] Unless otherwise defined, scientific and technical terms used in connection with the formulations described herein shall have the meanings commonly understood by one of ordinary skill in the art. The terms used herein are for the purpose of describing particular embodiments only and are not intended to limit the scope of the invention, which is defined solely by the claims.

[0259] All publications, patents, and patent applications are hereby 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.

[0260] Terms and Definitions

[0261] The term “mescaline” refers to a compound having the Figure 1 structure shown in. It should be noted that mescaline is also known in the art as 3,4,5-trimethoxyphenethylamine. It should also be noted that, as Figure 1 shown in, mescaline includes a phenyl moiety and an ethylamine moiety containing a substituted phenyl group.

[0262] The term “mescaline derivative prototype structure” refers to the Figure 2 chemical structure shown in. The mescaline derivatives disclosed herein include Figure 2The prototypical structure of the mescaline derivative shown therein, in which various atoms can be substituted as described herein. It should be noted that the prototypical structure contains a phenyl moiety and N-propylamine (instead of the ethylamine moiety as in the case of mescaline, see: Figure 1 ). In addition, it should be noted that specific carbon atoms in the prototypical structure of the mescaline derivative are numbered. In this regard, it should be noted that the specific carbon atoms in the phenyl moiety of the prototypical structure are numbered separately from the carbon atoms in the N-propylamine moiety. These numbered carbons may be referred to herein, for example, C1 of the phenyl moiety, C2 of the phenyl moiety, or C3 of the N-propylamine moiety, etc. It should be noted that the N-propylamine chain extends from the C1 carbon atom of the phenyl moiety of the prototypical structure. It should also be noted that, generally speaking, what is disclosed herein are mescaline derivatives in which: (i) adjacent carbon atoms C2 and C3 (formula (I a ) and formula (I b )) or C3 and C4 (formula (II a ) and formula (II b )) of the phenyl moiety of the prototypical structure participate in the formation of a fused heterocycle, in some embodiments, especially a 5-membered heterocycle, and in some embodiments, especially (1,3)dioxolane; and (ii) in exemplary embodiments, the N-propylamine chain extending from the C1 atom of the phenyl moiety of the prototypical structure is a substituted N-propylamine chain, especially an N-propylamine chain that can have substituted C2 and / or substituted C3 carbon atoms (-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 heterocyclic mescaline derivatives.

[0263] In structural chemical formulas, a straight bond or a wavy bond or a bent bond drawn to a chiral atom (including especially a chiral carbon atom) indicates that the stereochemistry of the chiral atom is not defined. Examples of such chemical structural formulas are structural formulas (a), (b), and (c):

[0264]

[0265] Thus, for example, a straight bond or a wavy bond or a bent bond drawn to a chiral atom is intended to represent the S-configuration or the R-configuration, and mixtures thereof, in a single drawing. When a straight bond or a wavy bond or a bent bond is attached to a double bond moiety (such as -C=C-), it includes cis- or trans- (or (E)- or (Z)-) geometric isomers, or mixtures thereof.

[0266] As used herein, the term "chiral carbon atom" refers to a carbon atom bonded to four different substituents.

[0267] As used herein, the terms "stereoisomer" and "stereoisomeric compound" are intended to refer to a compound relative to another compound, where when the structural formula is represented by straight bonds, the two compounds have the same chemical formula. However, when the structural formulas of the two compounds are represented by one or more wedge bonds drawn to an atom, thereby defining the three-dimensional configuration of the compound, the compounds are configured differently in three dimensions. In this regard, the wedge bond can indicate the presence of a stereoisomer of the compound. A pair of stereoisomers can include two compounds configured in three dimensions such that they are mirror images of each other. Thus, for example, when R2 = R1 = H or when R2 = H and R1 is an oxo group, compounds (a(i)) and (a(ii)) are stereoisomers that are mirror images of each other,

[0268]

[0269] It should be noted that stereoisomers can exist in mixtures containing different relative amounts of stereoisomers, including mixtures containing equimolar or approximately equimolar amounts of two stereoisomers, which can also be referred to as "racemic mixtures".

[0270] As used herein, the expressions used to depict chemical structures or chemical formulas refer to chemical bonds that can be saturated or unsaturated.

[0271] As used herein, the terms "hydroxy group" and "hydroxy" 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 entity through its oxygen atom.

[0272] As used herein, the terms "amino" and "amino group" refer to a molecule containing a nitrogen atom bonded to a hydrogen atom and having the formula -NH2. The amino group can also be protonated and have the formula -NH3 + . In its protonated form, the amino group can form ammonium salts, such as chloride or sulfate ammonium salts, or organic ammonium salts, all of which can be represented herein as NH3 + Z - . The amino group can be chemically bonded to another entity through its nitrogen atom. In addition, it should be noted that the entity attached to the amino group can be referred to herein as an "aminated" entity. For example, an aminated mescaline derivative is a mescaline derivative having an amino group.

[0273] As used herein, the term "oxo group" refers to the group =O and can be formed, for example, by replacing two hydrogens bonded to the same carbon atom with =O.

[0274] As used herein, the term "carbonyl group" refers to the group C=O and can be formed by replacing two hydrogens bonded to the same carbon atom with =O.

[0275] As used herein, the term "ethylene oxide" refers to a three-membered oxygen-containing heterocycle having the chemical formula .

[0276] As used herein, the terms "halogen", "halogen group", "halo", and "halogenated" refer to the 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.

[0277] As used herein, the term "alkyl group" refers to a hydrocarbon group arranged in a chain having the chemical formula -C n H 2n+1 . Alkyl groups include, but are not limited to, methyl group (-CH3), ethyl group (-C2H5), propyl group (-C3H7), and butyl group (-C4H9). The alkyl groups in any of the embodiments of the present disclosure (including O-alkyl, and the alkyl groups present in acyl and O-acyl) are C1-C 20 -alkyl. In another embodiment, the alkyl group is C1-C 10 alkyl. In another embodiment, the alkyl group is C1-C6-alkyl. In another embodiment, the alkyl group is methyl, ethyl, propyl, butyl, or pentyl.

[0278] As used herein, the terms "O-alkyl group" and "alkoxy group" are used interchangeably and refer to a hydrocarbon group arranged in a chain having the chemical formula -O-C n H 2n+1 . O-alkyl groups include, but are not limited to, O-methyl group (-O-CH3) (i.e., methoxy), O-ethyl group (-O-C2H5) (i.e., ethoxy), O-propyl group (-O-C3H7) (i.e., propoxy), and O-butyl group (-O-C4H9) (i.e., butoxy).

[0279] As used herein, the term "N-alkyl group" refers to a hydrocarbon group arranged in a chain having the chemical formula -N-C n H 2n+1 . N-alkyl groups include, but are not limited to, N-methyl group (-N-CH3), N-ethyl group (-N-C2H5), N-propyl group (-N-C3H7), and N-butyl group (-N-C4H9).

[0280] As used herein, the term "hydroxyalkyl" refers to a straight-chain group (including having the chemical formula -C nH 2n a hydrocarbon group arranged in a straight chain of OH; or a hydrocarbon group arranged in a branched chain and substituted with at least one hydroxyl group. In the described chemical formula, depending on the carbon chain, a hydroxyalkyl group of a specific length can 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. Other exemplary hydroxyalkyls include hydrocarbon groups having the following formula: wherein Y1 and Y2 are each simultaneously or independently a hydrogen atom or an alkyl group (e.g., -CH3, -CH2-CH3).

[0281] As used herein, the term "acyl group" refers to a carbon atom that is double-bonded to an oxygen and single-bonded to an alkyl group. The carbon atom can be further bonded to another entity. The acyl group can be represented by the chemical formula -C(=O)-C n H 2n+1 or described, for example, as (C1-C6)-acyl, (C1-C3)-acyl, etc. In addition, depending on the carbon chain, an acyl group of a specific length can be referred to as a formyl group (n = 0), an acetyl group (n = 1), a propionyl group (n = 2), a butyryl group (n = 3), a valeryl group (n = 4), etc.

[0282] As used herein, the term "O-acyl group" refers to an acyl group in which the carbon atom is single-bonded to an additional oxygen atom. The additional oxygen atom can be bonded to another entity. The O-acyl group can be represented by the chemical formula -O-C(=O)-C n H 2n+1 or described, for example, as -O-(C1-C6)-acyl, -O-(C1-C3)-acyl, etc. In addition, depending on the carbon chain, an O-acyl group of a specific length can be referred to as an O-formyl group (n = 0), an O-acetyl group (n = 1), an O-propionyl group (n = 2), an O-butyryl group (n = 3), an O-valeryl group (n = 4), etc.

[0283] As used herein, the term "alkylene" refers to a divalent alkyl group.

[0284] As used herein, the term "hetero" (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. Examples include (C3-C 20 ) containing one or two heteroatoms selected from O, S, or N, (C3-C 10 ) and (C3-C6) cyclic groups.

[0285] As used herein, the term "aryl group" refers to an aromatic ring compound in which at least one hydrogen atom has been removed from the aromatic ring to allow a carbon atom in the aromatic ring to bond to another entity. The aryl group may optionally be a substituted C6-C 14 -aryl. The aryl group may further optionally be a substituted C6-C 10 aryl or phenyl. Additional aryl groups include phenyl, naphthyl, tetrahydronaphthyl, phenanthryl, biphenyl, indanyl, or indenyl, etc.

[0286] As used herein, the term "alkyl-aryl" refers to an alkylene group substituted with an aryl group.

[0287] As used herein, the term "receptor" refers to a protein (e.g., a soluble receptor) present on the surface of a cell or in a cell not associated with the cell surface that is capable of mediating signal transduction to and / or from the cell or intracellularly and thereby affecting cell physiology. Receptors can be classified into such categories as the G protein-coupled receptor ("GPCR") family (such as the 5-HT receptor) and subfamilies (such as the 5-HT 1A receptor, 5-HT 2A receptor, and 5-HT 2B receptor), etc. In 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 occurs across the cell membrane and / or intracellularly to reach a target molecule or chemical reaction and results in the regulation of cell physiology. Thus, signal transduction can be considered a transduction process by which a molecule interacting with a receptor can regulate cell physiology, and in addition, signal transduction can be a process by which a molecule intracellularly can be regulated by a molecule extracellularly. The signal transduction and interaction between a molecule and a receptor, including, for example, affinity, binding efficiency, and kinetics, can be evaluated by a variety of assays, including, for example, an assay known as a receptor binding assay (e.g., a radioligand binding assay, such as, for example, 3 The [H] ketanserin assay can be used to evaluate the receptor activity of the receptor 5-HT 2A ), competition assays, and saturation binding assays, etc.

[0288] As used herein, the term "G protein-coupled receptor" or "GPCR" refers to a class of evolutionarily related transmembrane receptors that are capable of interacting with a class of proteins called 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 interaction with ligands, including neurotransmitters such as serotonin or dopamine, which can then, for example, initiate the interaction of the receptor with the G protein and can trigger the dissociation of the G protein into α and βγ subunits. In turn, these α and βγ subunits can mediate additional downstream signaling. GPCRs can also activate other signaling pathways, for example, through arrestin proteins and kinases. Certain ligands can preferentially activate subsets of all GPCR signaling pathways. The signaling pathways downstream of GPCRs can mediate therapeutic efficacy or can cause drug side effects (Bock and Bermudez, 2021, FEBS Journal 288:2513-2528).

[0289] As used herein, the term "5-HT receptor" refers to a family of GPCR receptors found in the central and peripheral nervous systems and includes subfamilies such as 5-HT 1A receptors, 5-HT 2A receptors, and 5-HT 2B receptors. 5-HT receptors can mediate signaling through specific G proteins (especially including Gα i , Gα q / 11 , and Gα s ) and can be involved in the control of a variety of physiological processes, including the regulation of cognition, mood, and the sleep-wake cycle, for example (McCorvy and Roth, 2015, Pharmacology and Therapeutics 150:129-142). 5-HT receptors can further mediate signaling through arrestin proteins as well as G protein-independent signaling pathways. 5-HT receptors are associated with various brain nerve disorders, including migraine and neuropsychiatric disorders such as schizophrenia and depression.

[0290] As used herein, the term "5-HT 1A receptor" refers to a subfamily of the receptor family for the neurotransmitter and peripheral signaling mediator serotonin. 5-HT 1A receptors can mediate a variety of central and peripheral physiological functions of serotonin. In 5-HT 1AThe ligand activity at [the relevant site] is generally not related to hallucinations, although many hallucinogenic compounds are known to modulate 5-HT 1A receptors to produce physiological responses (Inserra et al., 2020, Pharmacol. Rev. 73:202). 5-HT 1A receptors are associated with various brain nerve disorders, including depression and anxiety, schizophrenia, and Parkinson's disease (Behav. Pharm. 2015, 26:45–58).

[0291] As used herein, the term "5-HT 2A receptor" refers to a subfamily of the receptor family of the neurotransmitter and peripheral signaling mediator serotonin. 5-HT 2A receptors can mediate various central and peripheral physiological functions of serotonin. Central nervous system effects can include modulating the hallucinogenic effects of hallucinogenic compounds. 5-HT 2A receptors are associated with various brain nerve disorders (Nat. Rev. Drug Discov. 2022, 21:463-473; Science 2022, 375:403-411).

[0292] As used herein, the term "5-HT 2B receptor" (also referred to herein as "HT2B" and "HTR2B") refers to a subfamily of the receptor family of the neurotransmitter and peripheral signaling mediator serotonin. 5-HT 2B receptors can mediate various central and peripheral physiological functions of serotonin. Central nervous system effects can include modulating the hallucinogenic effects of hallucinogenic compounds. 5-HT 2B receptors are associated with various brain nerve disorders, including schizophrenia (Pharmacol. Ther. 2018, 181:143-155) and migraine (Cephalalgia 2017, 37:365-371).

[0293] As used herein, the term "5-HT 2C receptor" (also referred to herein as "HT2C" and "HTR2C") refers to a subfamily of the receptor family of the neurotransmitter and peripheral signaling mediator serotonin. Drugs such as agomelatine's antagonism of 5-HT 2C receptors can increase the availability of norepinephrine and dopamine in the prefrontal cortex and can result in antidepressant and nootropic effects (Savino et al., 2023, Brain Science 13:734). Additionally, 5-HT 2CReceptors can play a role in food intake and weight control (Przegaliński et al., 2023, Nutrients 15:1449).

[0294] As used herein, the term "5-HT7 receptor" (also referred to herein as "HT7" and "HTR7") refers to a subfamily of the receptor family for the neurotransmitter and peripheral signaling mediator serotonin. 5-HT 1D Receptors are associated with various brain nerve disorders, including Alzheimer's disease, dementia, and related depressive disorders (Quintero-Villegas and Valdés-Ferrer, 2022, Molecular Medicine 28:70).

[0295] As used herein, the term "α 2A Receptor" (also referred to herein as "α-2A" and "α2A") refers to a subfamily of the receptor family for catecholamine neurotransmitters and signaling mediators such as norepinephrine (noradrenaline) and epinephrine (adrenaline). The α-2A receptor is associated with various brain nerve disorders, including schizophrenia, bipolar disorder, and post-traumatic stress disorder (PTSD) (Saggu et al., 2023, Molecular Psychiatry 28:588-600).

[0296] The term "MT1 receptor" (also referred to herein as "MT1") as used herein refers to a subfamily of the receptor family for the neurotransmitter and signaling mediator melatonin. The MT1 receptor is associated with various brain nerve disorders, including sleep disorders and depression (Boiko et al., 2022, Neurochemical Research 47:2909-2924).

[0297] The term "D3 receptor" (also referred to herein as "D3") as used herein refers to a subfamily of the receptor family for the neurotransmitter and signaling mediator dopamine. The D3 receptor is associated with various brain nerve disorders, including schizophrenia, drug addiction, and Parkinson's disease (Kim, 2023, International Journal of Molecular Sciences 24:6742).

[0298] As used herein, the term "DAT" refers to a transmembrane transporter protein, also known as "dopamine active transporter", which is involved in the transport of dopamine into the cytosol. DAT is associated with various brain nerve disorders, especially dopamine-related disorders such as attention deficit hyperactivity disorder (ADHD), bipolar disorder, and clinical depression, anxiety (Am. J. Med. Genet. B Neuropsychiatr. Genet. 2018, 177: 211-231).

[0299] As used herein, the term "NET" refers to a transmembrane transporter protein, also known as "norepinephrine transporter" or "noradrenaline transporter" or "NAT", which is involved in the Na + / Cl - -dependent reuptake of extracellular norepinephrine or noradrenaline. NET is associated with various brain nerve disorders, including attention deficit hyperactivity disorder (ADHD) and clinical depression (Neurosci. Biobehav. Rev 2013, 37: 1786-800).

[0300] As used herein, the term "SERT" refers to a transmembrane transporter protein, also known as "serotonin transporter", which is involved in neuronal serotonin transport, especially from the synaptic cleft back to the presynaptic neuron, thereby terminating the action of serotonin. SERT is associated with various brain nerve disorders, including anxiety and depression (Pharmacol. Rep. 2018, 70: 37-46).

[0301] As used herein, the term "modulating receptor" refers to the ability of the compounds disclosed herein to alter receptor function. A receptor modulator can activate the activity of a receptor or inhibit the activity of a receptor, depending on the concentration of the compound to which the receptor is exposed. Such activation or inhibition may depend on the occurrence of a particular event, such as the activation of a signal transduction pathway, and / or may manifest only in certain cell types. The term "modulating receptor" also refers to altering the function of a receptor by increasing or decreasing the probability of forming a complex between the receptor and a native binding partner to form a multimer. A receptor modulator can increase the probability of forming such a complex between the receptor and a native binding partner, can increase or decrease the probability of forming a complex between the receptor and a native binding partner depending on the concentration of the compound to which the receptor is exposed, and / or can decrease the probability of forming a complex between the receptor and a native binding partner. It should also be noted that the fused heterocyclic mescaline derivatives of the present disclosure can alter the function of a receptor by acting as an agonist or antagonist of the receptor, and depending on the fused heterocyclic mescaline derivatives of the present disclosure can alter the function of a receptor by directly interacting with it or binding to it, or by indirectly interacting with it via one or more other molecular entities. Generally, the receptor can be any receptor, including any of the receptors set forth herein, such as, for example, 5-HT 1A 、5-HT 2A 、5-HT 2B 、5-HT 2C 、5-HT7、α 2A 、MT1 receptor. Thus, it will be apparent that, in order to refer to modulating a particular receptor, terms such as "modulating the 5-HT 1A receptor", "modulating the 5-HT 2A receptor", "modulating the 5-HT 2B receptor", etc. can be used herein.

[0302] As used herein, the term "receptor-mediated disorder" refers to a disorder characterized by abnormal receptor activity. A receptor-mediated disorder can be mediated, in whole or in part, by modulating a receptor. In particular, a receptor-mediated disorder is a disorder in which modulation of the receptor results in some effect on the underlying disorder, 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 set forth herein, such as, for example, 5-HT 1A 、5-HT 2A 、5-HT 2B 、5-HT 2C 、5-HT7、α 2A 、D3 or MT1 receptor. Thus, it will be apparent that, in order to refer to a particular receptor-mediated disorder, terms such as "5-HT 1A receptor-mediated disorder", "5-HT2A "receptor-mediated disorders", "5-HT" 2B terms such as "receptor-mediated disorders".

[0303] As used herein, the term "pharmaceutical preparation" refers to a preparation in a form that allows the active ingredient (including psychoactive ingredients) contained therein to provide effective treatment and does not contain any other ingredients that cause excessive toxicity, allergic reactions, irritation, or other adverse responses commensurate with a reasonable risk / benefit ratio. A pharmaceutical preparation may contain other pharmaceutical ingredients, such as excipients, carriers, diluents, or adjuvants.

[0304] As used herein, the term "recreational drug preparation" refers to a preparation in a form that allows the psychoactive ingredient contained therein to be effectively administered as a recreational drug and does not contain any other ingredients that cause excessive toxicity, allergic reactions, irritation, or other adverse responses commensurate with a reasonable risk / benefit ratio. A recreational drug preparation may contain other ingredients, such as excipients, carriers, diluents, or adjuvants.

[0305] As used herein, the term "effectively administered as a recreational drug" refers to a preparation in a form that allows a subject to voluntarily induce a psychoactive effect for non-medical purposes after administration, typically in the form of self-administration. Such an effect may include a change in the state of consciousness, a sense of satisfaction, pleasure, euphoria, perceptual distortion, or hallucination.

[0306] As used herein, the term "effective amount" refers to the amount of an active agent, pharmaceutical or recreational drug preparation that is sufficient to induce a desired biological effect or therapeutic effect (including a prophylactic effect and further including a psychoactive effect). Such an effect may include an effect on the signs, symptoms, or etiology of a disorder or disease, or an effect on any other desired change in a biological system. The effective amount may vary depending on, for example, the health status of the subject being treated, the stage of injury, the stage of the disorder or disease, body weight or gender, the time of administration, the mode of administration, the age of the subject, etc., all of which can be determined by those skilled in the art.

[0307] As used herein, terms such as "treating" and "treatment" are intended to mean obtaining a desired physiological, pharmacological, or biological effect and include prophylactic treatment and therapeutic treatment. Such an effect may result in the inhibition, attenuation, improvement, or reversal of the signs, symptoms, or etiology of the disorder or disease attributable to the disorder or disease, which includes mental and psychiatric disorders and conditions. The clinical evidence of prevention or treatment may vary depending on the disorder or disease, the subject, and the treatment selected.

[0308] As used herein, the term "pharmaceutically acceptable" refers to materials that are compatible with the other materials in a pharmaceutical or recreational drug formulation and, within the scope of sound medical judgment, are suitable for contact with a subject without excessive toxicity, allergic response, irritation, or other adverse reactions commensurate with a reasonable risk / benefit ratio, including excipients, carriers, diluents, or adjuvants.

[0309] As used herein, the term "substantially free of" when used to describe a composition means that a second compound is substantially absent from a composition that comprises a first compound. Preferably, a composition that comprises 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 percentage of the second compound.

[0310] As used interchangeably herein, the terms "substantially pure" and "isolated" describe a compound, such as a mescaline derivative, that has been separated from the components that naturally accompany it. Generally, 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, by wet weight or dry weight, or by mole percentage or mole fraction) of the total material in the sample is the compound of interest. Purity can be measured by any suitable method, for example, in the case of a polypeptide, by chromatography, gel electrophoresis, or HPLC analysis.

[0311] General embodiments

[0312] As mentioned above, the present disclosure relates to mescaline derivatives. In particular, the present disclosure provides novel heterocyclic mescaline derivatives in which the phenyl moiety participates in the formation of the heterocyclic structure, which, in an exemplary embodiment, includes a dioxolane fused to the phenyl moiety. Thus, the compounds of the present disclosure may be said to be fused heterocyclic mescaline derivatives. Further, the mescaline derivatives include an N-propylamine chain (instead of an ethylamine chain, as is the case for mescaline). The N-propylamine chain may contain various substituent groups, especially including C2 and / or C3 substituent groups. Further, the amine group in the N-propylamine chain may be substituted. Thus, the mescaline derivatives disclosed herein may be said to be N-propylamine fused heterocyclic mescaline derivatives. Generally, the novel compounds provided herein exhibit functional properties that deviate from those of mescaline. Thus, for example, the mescaline derivatives of the present disclosure may exhibit pharmacological properties that deviate from those of mescaline. Further, the mescaline derivatives may exhibit physicochemical properties that are different from those of mescaline. Thus, for example, the fused heterocyclic mescaline derivatives may exhibit excellent solubility in solvents such as aqueous solvents. In this regard, the fused heterocyclic mescaline derivatives may be used in the formulation of pharmaceutical and recreational drug preparations. In one embodiment, the fused heterocyclic mescaline derivatives of the present disclosure may be conveniently chemically synthesized. The practice of this method avoids the extraction of mescaline from cactus plants and the subsequent chemical reactions to obtain the fused heterocyclic mescaline derivatives. Further, the growth of cactus plants may be avoided, thereby limiting the dependence on climate and weather, as well as the potential legal and social challenges associated with growing cactus plants containing psychoactive compounds. The method may effectively produce large quantities of the fused heterocyclic mescaline derivatives.

[0313] Hereinafter, selected embodiments will be described with reference to the accompanying drawings.

[0314] Exemplary fused heterocyclic mescaline derivatives will first be described. Thereafter, exemplary methods of using and preparing the fused heterocyclic mescaline derivatives will be described.

[0315] 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 Herein. The derivatives provided herein are in particular fused heterocyclic derivatives of mescaline. It should be noted that, in this regard, the term "fused heterocycle" refers to such derivatives in which the heterocycle is bonded to two adjacent carbon atoms present in the benzene ring of mescaline. Similarly, the term "fused dioxolane" refers to such derivatives in which the dioxolane is bonded to two adjacent carbon atoms present in the benzene ring of mescaline. Further, the derivatives are N-propylamine mescaline derivatives. In this regard, reference is made to Figure 2"N-propylamine" refers to a mescaline derivative containing an N-propylamine chain, where, in particular, in an exemplary embodiment, specifically, the C2 and / or C3 atoms of the N-propylamine chain are substituted with one or more substituents.

[0316] Thus, in one aspect, in accordance with the teachings herein, in at least one embodiment, the present disclosure provides compounds having the chemical formula (I) or (II):

[0317]

[0318] wherein, in chemical formula (I) or (II):

[0319] is a single bond or a double bond;

[0320] X1, X2, and X3 are independently selected from a hydrogen atom, O-alkyl, acyl, N-alkyl, OH, halogen, or NH2;

[0321] X4 is an alkylene group or a substituted alkylene group;

[0322] R1 is hydrogen, an alkyl group, or an oxo group, or

[0323] R1 is connected to R 1b and the carbon atom to which R1 is attached and the nitrogen atom to which R 1b is attached are connected together to form an optionally substituted saturated or unsaturated 3- to 10-membered heterocycle, and when the heterocycle is unsaturated, R 1a is optionally absent;

[0324] R 1a and R 1b are each independently selected from an alkyl group, a hydroxyalkyl group, an optionally substituted alkyl-aryl group, or a hydrogen atom, or R 1a and R 1b together with the nitrogen atom to which they are attached are connected together to form a 3- to 10-membered optionally substituted heterocycle; and

[0325] R2 and R3 are each independently selected from an alkyl group, an O-alkyl group, a hydrogen atom, or R2 and R3 are connected to an oxygen atom and the carbon atom to which they are attached to form an ethylene oxide ring.

[0326] In one embodiment, the compound having formula (I) can be a compound having formula (I a ) or (I b ), and the compound having formula (II) can be a compound having formula (II a ) or (II b ):

[0327]

[0328] Wherein, in chemical formula (I a ), (I b ), (II a ), or (II b ):

[0329] X1, X2 and X3 are independently selected from a hydrogen atom, O-alkyl, acyl, N-alkyl, OH, halogen or NH2;

[0330] X4 is an alkylene group or a substituted alkylene group;

[0331] R1 is hydrogen, an alkyl group or an oxo group, or

[0332] R1 is linked to R 1b and the carbon atom to which R1 is attached and the nitrogen atom to which R 1b is attached to form an optionally substituted saturated or unsaturated 3- to 10-membered heterocycle, and when the heterocycle is unsaturated, R 1a is optionally absent;

[0333] R 1a and R 1b are each independently selected from an alkyl group, a hydroxyalkyl group, an optionally substituted alkyl-aryl group or a hydrogen atom, or R 1a and R 1b are linked together with the nitrogen atom to which they are attached to form an optionally substituted 3- to 10-membered heterocycle; and

[0334] R2 and R3 are each independently selected from an alkyl group, an O-alkyl group, a hydrogen atom, or R2 and R3 are linked together with an oxygen atom and the carbon atom to which they are attached to form an ethylene oxide ring.

[0335] Thus, with reference to formula (I a ), (I b ), (II a ), and (II b ), X1, X2 and X3 can be independently selected from a hydrogen atom, O-alkyl, N-alkyl, acyl, OH, halogen or NH2. In an exemplary embodiment, X1, X2 and X3 can each independently be selected from a hydrogen atom, 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 another exemplary embodiment, all three of X1, X2 and X3 can be the same substituent. In another exemplary embodiment, all three of X1, X2 and X3 can be the same O-alkyl group (e.g., methoxy group, ethoxy group), different O-alkyl groups or partially the same O-alkyl groups (i.e., 2 identical O-alkyl groups, 1 different O-alkyl group); the same N-alkyl group, different N-alkyl groups or partially the same N-alkyl groups (i.e., 2 identical N-alkyl groups, 1 different N-alkyl group); the same acyl group, different acyl groups or partially the same acyl groups (i.e., 2 identical acyl groups, 1 different acyl group); the same; or the same, different or partially the same halogen (i.e., 2 identical halogens, 1 different halogen). In another exemplary embodiment, two of X1, X2 and X3 can be the same substituent. In yet another exemplary embodiment, all three of X1, X2 and X3 can be different substituents.

[0336] Turning to X4 and further referring to formula (I a ), (I b ), (II a ), and (II b ), X4 can be an alkylene group or a substituted alkylene group. In an exemplary embodiment, X4 can be an unsubstituted alkylene, including, for example, (C1-C 10 )-alkylene, (C1-C6)-alkylene or (C1-C3)-alkylene (methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-).

[0337] In an exemplary embodiment, X4 can be a substituted alkylene, including, 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). The substituent can be selected, for example, from an oxo group (forming a carbonyl), a hydroxyl group, a halogen (F, Cl, Br, I), an O-alkyl (e.g., O-(C1-C 10 )-alkyl, O-(C1-C6)-alkyl or -O-(C1-C3)-alkyl), an 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, such as phenyl, naphthyl) and alkyl-aryl groups (e.g., (C1-C 10 )-alkylaryl, (C1-C6)-alkylaryl or (C1-C3)-alkylaryl). Further includes monosubstituted alkylene and polysubstituted alkylene. Polysubstituted alkylene includes substituents on the same alkylene carbon atom (thus halogen substituents can be, for example, -CH2CF2- or -CF2-) or substituents on different carbon atoms (e.g., -CHF-CHF-).

[0338] In an exemplary embodiment, X4 can be an unsubstituted alkylene, especially (methylene (-CH2-)), and compounds having the chemical formula (I a ), (I b ), (II a ) and (II b ) can have the chemical formula (I c ), (I d ), (II c ) and (II d ) respectively:

[0339]

[0340] As described previously herein, in one aspect, the present disclosure particularly includes mescaline derivatives containing a substituted N-propylamine chain, especially in an exemplary embodiment, having a substituted C2 and / or substituted C3 carbon atom (-CHR2-CHR3-) (formulas (I a ), (II a ), (I c ) and (II c ) or (-CR2=CR3-) (formulas (I b ), (II b ), (I d ) and (II d )) of the N-propylamine chain, where R2 and / or R3 are substituents.

[0341] Next, additional exemplary embodiments of mescaline derivatives including the chain will be described with respect to exemplary selections of the R2 and R3 substituents included in the N-propylamine chain. Referring to formula (I a ), (Ib ), (II a ) and (II b ), R2 and R3 can each independently be selected from an alkyl group, an O-alkyl group or a hydrogen atom. Further, referring to formula (I a ), (I b ), (II a ), and (II b ), and formula (I c ), (I d ), (II c ), and (II d ), it should be noted that in certain exemplary embodiments, X1, X2, X3 can each be selected as H, as shown herein by the exemplary compounds A(I)–C(III); C(VI)-C(XII); D(I)–F(III) and G(I)–G(IV). These exemplary embodiments are particularly but not exclusively intended to be included in combination with the exemplary embodiments described below with respect to R2 and R3.

[0342] Thus, for example, referring to formula (I a ), (I b ), (II a ), (II b ), (I c ), (I d ), (II c ), and (II d ), in an exemplary embodiment, R2 and R3 can each independently be selected from an alkyl group, an O-alkyl group or a hydrogen atom.

[0343] Continuing to refer to formula (I a ), (I b ), (II a ), (II b ), (I c ), (I d ), (II c ), and (II d ), in an exemplary embodiment, R2 and R3 can each be a (C1-C6)-alkyl group, a (C1-C3)-alkyl group or a methyl group.

[0344] Continuing to refer to formula (I a ), (I b ), (II a ), (II b ), (I c ), (I d ), (II c ), and (II d), in an exemplary embodiment, R2 may be a (C1-C6)-alkyl group, a (C1-C3)-alkyl group or a methyl group, and R3 may be a hydrogen atom.

[0345] Continuing to refer to formula (I a ), (I b ), (II a ), (II b ), (I c ), (I d ), (II c ), and (II d ), in an exemplary embodiment, R3 may be a (C1-C6)-alkyl group, a (C1-C3)-alkyl group or a methyl group, and R2 may be a hydrogen atom.

[0346] Continuing to refer to formula (I a ), (I b ), (II a ), (II b ), (I c ), (I d ), (II c ), and (II d ), in an exemplary embodiment, R2 and R3 may each be a hydrogen atom.

[0347] Continuing to refer to formula (I a ), (I b ), (II a ), (II b ), (I c ), (I d ), (II c ), and (II d ), in an exemplary embodiment, R2 may be a (C1-C6)-O-alkyl group, a (C1-C3)-O-alkyl group or a methoxy group, and R3 may be a hydrogen atom.

[0348] Continuing to refer to formula (I a ), (I b ), (II a ), (II b ), (I c ), (I d ), (II c ), and (II d ), in an exemplary embodiment, R3 may be a (C1-C6)-O-alkyl group, a (C1-C3)-O-alkyl group or a methoxy group, and R2 may be a hydrogen atom.

[0349] Continuing to refer to formula (I a), (I b ), (II a ), (II b ), (I c ), (I d ), (II c ), and (II d ), in an exemplary embodiment, R2 and R3 may be methoxy groups.

[0350] Referring again to formula (I a ), (II a ), (I c ), and (II c ), in an exemplary embodiment, R2 and R3 may be joined together with an oxygen atom to form ethylene oxide.

[0351] Referring again to formula (I a ), (I b ), (II a ), (II b ), (I c ), (I d ), (II c ), and (II d ), in an exemplary embodiment, R1 may be hydrogen, an alkyl group, including a (C1-C6) alkyl group, a (C1-C3) alkyl group, or a methyl group, or R1 may be an oxo group, or continuing to refer to formula (I a ), (I b ), (II a ), (II b ), (I c ), (I d ), (II c ), and (II d ), in another exemplary embodiment, R1 is joined to R 1b and the carbon atom to which R1 is attached and the nitrogen atom to which R 1b is attached to form a 3- to 10-membered heterocycle, such as a 5-membered or 6-membered ring. Further, the heterocycle may be optionally substituted or saturated or unsaturated, and further, when the heterocycle is unsaturated, R 1a may optionally be absent.

[0352] Referring again to formula (I a ), (I b ), (II a ), (II b ), (I c ), (I d ), (II c ), and (II d ), in an exemplary embodiment, R1a can be a hydrogen atom, and R 1b can be a (C1-C6)-alkyl group.

[0353] Continuing to refer to formula (I a ), (I b ), (II a ), (II b ), (I c ), (I d ), (II c ), and (II d ), in an exemplary embodiment, R 1a and R 1b can each be a (C1-C6)-alkyl group or a (C1-C3)-alkyl group.

[0354] Continuing to refer to formula (I a ), (I b ), (II a ), (II b ), (I c ), (I d ), (II c ), and (II d ), in an exemplary embodiment, R 1a can be a hydrogen atom, and R 1b can be a hydroxyalkyl group, such as a hydroxy-(C1-C6)-alkyl group, or a hydroxy-(C1-C3)-alkyl group, or -CH2-CH2-CH2OH, -CH2-CH2OH, or -CH2OH, or in other embodiments, a hydroxyalkyl group having the formula:

[0355]

[0356] wherein Y1 and Y2 are each simultaneously or independently a hydrogen atom or an alkyl group (e.g., -CH3, -CH2-CH3, or -CH2-CH2-CH3).

[0357] Continuing to refer to formula (I a ), (I b ), (II a ), (II b ), (I c ), (I d ), (II c ), and (II d ), in an exemplary embodiment, R 1a can be a hydrogen atom, and R 1bIt may be an alkyl-aryl group, including (C1-C6)-alkyl-aryl groups such as (C1-C6)-alkyl-phenyl groups (e.g., (CH2)-phenyl), or (C1-C3)-alkyl-aryl groups such as (C1-C3)-alkyl-phenyl groups.

[0358] Continuing to refer to formula (I a ), (I b ), (II a ), (II b ), (I c ), (I d ), (II c ), and (II d ), in an exemplary embodiment, R 1a and R 1b may each independently be selected from an alkyl group, a hydroxyalkyl group, an optionally substituted alkyl-aryl group, or a hydrogen atom, including, for example, compounds having the chemical formula (A); (B); (C); (D); (E); (F); or (G) (described further below), where R 1a and R 1b are so selected.

[0359] Continuing to refer to formula (I a ), (I b ), (II a ), (II b ), (I c ), (I d ), (II c ), and (II d ), in an exemplary embodiment, R 1a and R 1b may be joined together with the nitrogen atom to which they are attached to form a 3- to 10-membered optionally substituted heterocycle, where the heterocycle further includes an oxygen atom.

[0360] Continuing to refer to formula (I a ), (I b ), (II a ), (II b ), (I c ), (I d ), (II c ), and (II d ), in an exemplary embodiment, R 1a and R 1bThe heterocyclic ring may be linked together with the nitrogen atom to which they are attached to form a 3-10 membered, for example 5-membered or 6-membered optionally substituted heterocyclic ring, wherein the heterocyclic ring further comprises an oxygen atom, and wherein the heterocyclic ring is further substituted by at least one (C1-C6)-alkyl group, for example at least one methyl group or at least two methyl groups, wherein the (C1-C6)-alkyl group may be two substituents on a single (i.e. the same) heterocyclic carbon atom, or two or more substituents on two or more different heterocyclic carbon atoms.

[0361] Continue to refer to formula (I a )、(I b )、(II a )、(II b )、(I c )、(I d )、(II c ) and (II d ), in an exemplary embodiment, R1 may be 1b are connected together to form an optionally substituted saturated or unsaturated 3-10 membered ring, such as a 5-membered or 6-membered heterocyclic ring, wherein the heterocyclic ring together with the nitrogen atom includes an oxygen atom, and may be optionally substituted by at least two alkyl groups (e.g., methyl groups), which are substituents on the same heterocyclic carbon atom. The 3-10 membered heterocyclic ring may be saturated or partially saturated, and when the heterocyclic ring is unsaturated, R 1a May optionally be absent.

[0362] In some embodiments, wherein R1 and R 1b are connected together to form an optionally substituted saturated or unsaturated 3-10 membered ring. When the heterocyclic ring is unsaturated, R 1a may be absent, and in particular, when the heterocycle is unsaturated and the nitrogen participates in the formation of an unsaturated bond, R 1a It may not exist.

[0363] In another embodiment, formula (I), (II), (I a )、(I b )、(II a )、(II b )、(I c )、(I d )、(II c ) and (II d ) in the compound with an amino group (-NR 1a R 1b ) can be protonated to form (-N + HR 1a R 1b ), and chemical formula (I), (II), (I a )、(Ib ), (II a ), (II b ), (I c ), (I d ), (II c ), and (II d ), and (II) further include anions that balance the positively charged nitrogen atoms, such as sulfate ions (SO4 2- ), nitrate ions (NO3 - ), or chloride ions (Cl - ).

[0364] Next, to further illustrate the mescaline-derived compounds provided according to the present disclosure, exemplary compounds according to formulas (I) and (II) are provided. These include compounds having chemical formulas (A); (B); (C); (D); (E); (F); and (G), and further include compounds having chemical formulas 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).

[0365] Thus, in one aspect, the present disclosure provides exemplary compounds having chemical formulas (A); (B); (C); (D); (E); (F); and (G):

[0366]

[0367] wherein in formula (B), X 4a and X 4b are independently or simultaneously a halogen or a hydrogen atom, wherein R 1a and R 1b in formulas (A), (B), (C), (D), (E), and (F) are independently selected from an alkyl group, an optionally substituted alkyl-aryl group, or a hydrogen atom, or wherein R 1a and R 1b together with the nitrogen atom to which they are attached are joined together to form a 3- to 10-membered optionally substituted heterocycle;

[0368] wherein R2 in formulas (C), (F), and (G), and Y1 and Y2 in (G) are an alkyl group or a hydrogen atom; and

[0369] wherein X3 in formulas (C), (F), and (G) is a halogen, an O-alkyl group, or a hydrogen atom.

[0370] In one aspect, the present disclosure further provides exemplary compounds A(I)-A(III):

[0371]

[0372] In each of compounds A(I) to A(III), optionally, the nitrogen atom of the N-propylamine moiety is protonated, and A(I) to A(III) include a negatively charged anion that balances the positively charged nitrogen atom.

[0373] On the other hand, the present disclosure provides exemplary compounds B(I)-B(V):

[0374]

[0375]

[0376] In each of compounds B(I) to B(V), optionally, the nitrogen atom of the N-propylamine moiety is protonated, and B(I) to B(V) include a negatively charged anion that balances the positively charged nitrogen atom.

[0377] On the other hand, the present disclosure provides exemplary compounds C(I)-C(XIII):

[0378]

[0379] In each of compounds C(I) to C(XIII), optionally, the nitrogen atom of the N-propylamine moiety is protonated, and C(I) to C(XIII) include a negatively charged anion that balances the positively charged nitrogen atom.

[0380] On the other hand, the present disclosure provides exemplary compounds D(I)-D(III):

[0381]

[0382] In each of compounds D(I) to D(III), optionally, the nitrogen atom of the N-propylamine moiety is protonated, and D(I) to D(III) include a negatively charged anion that balances the positively charged nitrogen atom.

[0383] On the other hand, the present disclosure provides exemplary compounds E(I)–E(V):

[0384]

[0385] In each of compounds E(I) to E(V), optionally, the nitrogen atom of the N-propylamine moiety is protonated, and E(I) to E(V) include a negatively charged anion that balances the positively charged nitrogen atom.

[0386] In another aspect, the present disclosure provides exemplary compounds F(I)–F(VI):

[0387]

[0388] Wherein in each of compounds F(I) to F(VI), optionally, the nitrogen atom of the N-propylamine moiety is protonated, and F(I) to F(VI) include a negatively charged anion that balances the positively charged nitrogen atom.

[0389] In another aspect, the present disclosure provides exemplary compounds G(I)–G(V):

[0390]

[0391]

[0392] Wherein in each of compounds G(I) to G(V), optionally, the nitrogen atom of the N-propylamine moiety is protonated, and G(I) to G(V) include a negatively charged anion that balances the positively charged nitrogen atom.

[0393] The negatively charged anion in each of the foregoing includes, for example, a chloride ion, a nitrate ion, or a sulfate ion.

[0394] In one embodiment, the compound can be a stereoisomeric compound corresponding to a 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 compound is a chiral carbon atom. Thus, for example, in one embodiment, the stereoisomeric compound can be selected from compounds having formula A(II a ) or A(II b ):

[0395]

[0396] It should be understood that similarly, stereoisomeric compounds corresponding to compounds having formula A(I), A(III), C(VII), C(XI), F(II), G(II), or G(IV) can be selected and included herein, wherein the C2 atom of the N-propylamine moiety of the compound is a chiral carbon atom.

[0397] 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 have different relative molar amounts of a first stereoisomeric compound and the corresponding second counterpart stereoisomeric compound (e.g., A(II a ) and A(II b), e.g., at least 10% (mol / mol) of the first stereoisomeric compound and 90% (mol / mol) of the second corresponding stereoisomeric compound, or 20% (mol / mol) of the first stereoisomeric compound and 80% (mol / mol) of the second corresponding stereoisomeric compound, or 30% (mol / mol) of the first stereoisomeric compound and 70% (mol / mol) of the second corresponding stereoisomeric compound, or 40% (mol / mol) of the first stereoisomeric compound and 60% (mol / mol) of the second corresponding stereoisomeric compound, or equimolar or approximately equimolar amounts of the first stereoisomeric compound and the second corresponding stereoisomeric compound.

[0398] Thus, in short, on the one hand, the present disclosure provides new compounds which are derivatives of mescaline, fused mescaline derivatives, including in exemplary embodiments fused dioxolane mescaline derivatives. The new compounds have the chemical formula (I) or (II):

[0399]

[0400] wherein, in the chemical formula (I) or (II):

[0401] is a single bond or a double bond;

[0402] X1, X2 and X3 are independently selected from a hydrogen atom, O-alkyl, acyl, N-alkyl, OH, halogen or NH2;

[0403] X4 is an alkylene group or a substituted alkylene group;

[0404] R1 is hydrogen, an alkyl group or an oxo group, or

[0405] R1 is linked to R 1b and the carbon atom to which R1 is attached and the nitrogen atom to which R 1b is attached are linked together to form an optionally substituted saturated or unsaturated 3- to 10-membered heterocycle, and when the heterocycle is unsaturated, R 1a is optionally absent;

[0406] R 1a and R 1b are each independently selected from an alkyl group, a hydroxyalkyl group, an optionally substituted alkyl-aryl group or a hydrogen atom, or R 1a and R 1b together with the nitrogen atom to which they are attached are linked together to form a 3- to 10-membered optionally substituted heterocycle; and

[0407] R2 and R3 are each independently selected from an alkyl group, an O-alkyl group, a hydrogen atom, or R2 and R3 are joined together with the oxygen atom and the carbon atom to which they are attached to form an ethylene oxide ring.

[0408] The fused 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 a fused mescaline derivative. Thus, in one aspect, the present disclosure provides, in additional embodiments, a pharmaceutical or recreational drug formulation comprising a compound selected from a first compound having formula (I) and (II), and a diluent, a carrier, or an excipient:

[0409]

[0410] wherein, in formula (I) or (II):

[0411] is a single bond or a double bond;

[0412] X1, X2, and X3 are independently selected from a hydrogen atom, O-alkyl, acyl, N-alkyl, OH, halogen, or NH2;

[0413] X4 is an alkylene group or a substituted alkylene group;

[0414] R1 is hydrogen, an alkyl group, or an oxo group, or

[0415] R1 is joined together with R 1b and the carbon atom to which R1 is attached and the nitrogen atom to which R 1b is attached to form an optionally substituted saturated or unsaturated 3- to 10-membered heterocycle, and when the heterocycle is unsaturated, R 1a is optionally absent;

[0416] R 1a and R 1b are each independently selected from an alkyl group, a hydroxyalkyl group, an optionally substituted alkyl-aryl group, or a hydrogen atom, or R 1a and R 1b are joined together with the nitrogen atom to which they are attached to form a 3- to 10-membered optionally substituted heterocycle; and

[0417] R2 and R3 are each independently selected from an alkyl group, an O-alkyl group, a hydrogen atom, or R2 and R3 are joined together with the oxygen atom and the carbon atom to which they are attached to form an ethylene oxide ring.

[0418] Pharmaceutical or recreational drug preparations can be formulated as liquids, tablets, capsules, microcapsules, nanocapsules, transdermal patches, gels, foams, oils, aerosols, nanoparticles, powders, creams, emulsions, micellar systems, films, sprays, ovules, infusions, teas, decoctions, suppositories, etc., and include pharmaceutically acceptable salts or solvates of fused mescaline-derived compounds and excipients. As used herein, the term "excipient" means any ingredient other than the compounds of the present disclosure. As will be readily understood by those skilled in the art, the choice of excipient can depend on factors such as the particular mode of administration and the effect of the excipient on the solubility of the compounds of the present disclosure, and their methods of preparation will be readily understood by those skilled in the art. Such compositions and their methods of 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).

[0419] Pharmaceutical and drug preparations containing the fused mescaline derivatives of the present disclosure can be administered orally. Oral administration can involve swallowing such that the compound enters the gastrointestinal tract, or can employ buccal or sublingual administration, by which the compound enters the bloodstream directly from the mouth. Preparations suitable for oral administration include both solid and liquid formulations.

[0420] Solid formulations include tablets, capsules (containing granules, liquids, microcapsules or powders), lozenges (including liquid-filled lozenges), chewables, multiparticulates and nanoparticles, gels, solid solutions, liposomal products, microencapsulated products, creams, films, ovules, suppositories and sprays.

[0421] Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations can be used as fillers in soft or hard capsules and generally contain a carrier such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or a suitable oil, and one or more emulsifying and / or suspending agents. Liquid formulations can also be prepared, for example, by reconstituting a solid from a sachet.

[0422] Binders are commonly used to impart cohesiveness to tablet formulations. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose.

[0423] The tablets may also contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous, etc.), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, and dibasic calcium phosphate dihydrate.

[0424] The tablets may also optionally contain surface active agents such as sodium lauryl sulfate and polysorbate 80. When present, the surface active agent may comprise from 0.2% (w / w) to 5% (w / w) of the tablets.

[0425] The tablets may further contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate and sodium lauryl sulfate. The lubricant generally comprises from 0.25% (w / w) to 10% (w / w) or from 0.5% (w / w) to 3% (w / w) of the tablets.

[0426] In addition to the fused heterocyclic mescaline derivatives, the tablets may contain disintegrants. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinized starch, and sodium alginate. Typically, the disintegrant will comprise from 1% (w / w) to 25% (w / w) or from 5% (w / w) to 20% (w / w) of the dosage form.

[0427] Other possible adjuvants include antioxidants, colorants, flavorants, preservatives, and taste-masking agents.

[0428] For tablet dosage forms, depending on the desired effective amount of the compound, the 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.

[0429] Exemplary tablets contain up to about 80% (w / w) of the 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.

[0430] The formulation of tablets is discussed in "Pharmaceutical Dosage Forms: Tablets", Volumes 1 to 3, CRC Press (2008).

[0431] Pharmaceutical and recreational drug formulations containing the fused heterocyclic mescaline derivatives of the present disclosure 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, intra-arterial, intrathecal, intraventricular, intracranial, intramuscular, or intraperitoneal injection). Parenteral formulations are generally aqueous solutions that can contain excipients such as salts, carbohydrates, and buffers (in one embodiment, pH 3-9), however, for 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.

[0432] Formulations containing the fused heterocyclic mescaline derivatives of the present disclosure for parenteral administration can be formulated for immediate release and / or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release. Thus, the compounds of the present disclosure can be formulated as solids, semi-solids, or thixotropic liquids for administration as implanted reservoirs, providing modified release of the active compound. Examples of such formulations include drug-coated stents and poly(dl-lactic-co-glycolic) acid (PGLA) microspheres.

[0433] 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. Exemplary 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. Exemplary carriers include alcohols, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. Penetration enhancers can be incorporated (see, e.g., Finnin, B. and Morgan, T.M., 1999 Journal of Pharmaceutical Sciences 88(10), 955-958).

[0434] Other topical administration means include delivery by electroporation, iontophoresis, sonophoresis, sonoporation, and micro-needle or needleless (e.g., Powderject TM 、Bioject TM etc.) injection.

[0435] Medicinal and recreational drug preparations for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous solvents or organic solvents or mixtures thereof, as well as powders. The liquid or solid drug compositions may contain suitable pharmaceutically acceptable excipients. In some embodiments, the drug compositions are administered via the oral or nasal breathing route to obtain local or systemic effects. The drug compositions in pharmaceutically acceptable solvents may be atomized by using an inert gas. The atomized solution may be inhaled directly from the atomizing device, or the atomizing device may be connected to a face mask tent or an intermittent positive pressure ventilator. The solution, suspension or powder drug compositions may be administered, for example, orally or nasally, from a device that delivers the preparation in a suitable manner.

[0436] In further embodiments, where the fused heterocyclic mescaline compounds of the present disclosure are used as recreational drugs, the compounds may be included in compositions such as foods or food products, beverages, food flavorings, personal care products such as cosmetics, perfumes or bath oils, or oils (both for topical application as massage oils, or for burning or atomizing). The compounds of the present disclosure may also be included in "vape" products, which may also include other drugs such as nicotine and flavorings.

[0437] Drug preparations containing the compounds of the present disclosure may be used to treat a subject, and in particular to treat a subject's mental disorders. Thus, in further embodiments, the present disclosure includes a method for treating mental disorders, the method comprising administering to a subject in need thereof a drug preparation comprising a compound selected from a first compound having formula (I) and (II):

[0438]

[0439] wherein, in formula (I) or (II):

[0440] is a single bond or a double bond;

[0441] X1, X2 and X3 are independently selected from a hydrogen atom, O-alkyl, acyl, N-alkyl, OH, halogen or NH2;

[0442] X4 is an alkylene group or a substituted alkylene group;

[0443] R1 is hydrogen, an alkyl group or an oxo group, or

[0444] R1 is linked to R 1b and the carbon atom to which R1 is attached and the nitrogen atom to which R 1b is attached are linked together to form an optionally substituted saturated or unsaturated 3- to 10-membered heterocycle, and when the heterocycle is unsaturated, R 1a is optionally absent;

[0445] R 1a and R 1b are each independently selected from an alkyl group, a hydroxyalkyl group, an optionally substituted alkyl-aryl group or a hydrogen atom, or R 1a and R 1b together with the nitrogen atom to which they are attached are joined to form a 3- to 10-membered optionally substituted heterocycle; and

[0446] R2 and R3 are each independently selected from an alkyl group, an O-alkyl group, a hydrogen atom, or R2 and R3 together with the oxygen atom and the carbon atom to which they are attached form an ethylene oxide ring.

[0447] Brain nerve disorders that can be treated, including mental disorders, including, for example, neurodevelopmental disorders such as intellectual disability, global developmental delay, communication disorders, autism spectrum disorder, and attention deficit hyperactivity disorder (ADHD); bipolar disorder 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, animals, situations), 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; somatic symptom disorders such as somatic symptom disorder, illness anxiety disorder, conversion disorder, and factitious disorder; eating disorders such as anorexia nervosa, bulimia nervosa, rumination disorder, pica, and binge eating disorder; sleep disorders such as narcolepsy, insomnia disorder, hypersomnolence, sleep-related breathing disorders, parasomnias, and restless legs syndrome; disruptive disorders such as kleptomania, pyromania, intermittent explosive disorder, conduct disorder, and oppositional defiant disorder; depressive disorders such as disruptive mood dysregulation disorder, major depressive disorder (MDD), persistent depressive disorder (dysthymia), premenstrual dysphoric disorder, substance / medication-induced depressive disorder, postpartum depression, and depression caused by another medical condition (e.g., psychological and existential distress in the case 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, excoriation disorder, substance / medication-induced obsessive-compulsive disorder, and obsessive-compulsive disorder related to another medical condition; and personality disorders such as antisocial personality disorder, avoidant personality disorder, borderline 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. Brain nerve disorders that can be further treated include headache disorders, including migraine, including, for example, auditory migraine, non-auditory migraine, menstrual migraine, chronic migraine, vestibular migraine, abdominal migraine, hemiplegic migraine, and other headache disorders.

[0448] In one aspect, the compounds of the present disclosure can be used to contact a receptor so as to modulate the receptor. Such contact includes bringing 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, such as a sample containing a purified receptor, or a sample containing cells comprising the receptor. The in vitro conditions further include the conditions described in Example 2 herein. The contact further includes bringing the compound of the present disclosure and the receptor together under in vivo conditions. Such in vivo conditions include administering, for example, 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 described above for treating a subject. After contacting the receptor, the compound can activate the receptor or inhibit the receptor.

[0449] In one aspect, the receptors that can be contacted with the compounds of the present disclosure include, for example, 5-HT 1A receptors, 5-HT 2A receptors, 5-HT 2B receptors, 5-HT 2C receptors, 5-HT7 receptors, α 2A receptors, D3 receptors, or MT1 receptors.

[0450] Thus, in a further aspect, the medical conditions that can be treated according to the present disclosure can be any receptor-mediated disorder, including, 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 2A receptor-mediated disorders, D3 receptor-mediated disorders, or MT1 receptor-mediated disorders. Such disorders include but are not limited to schizophrenia, psychotic disorders, attention deficit hyperactivity disorder, autism, and bipolar disorder.

[0451] In some embodiments, after contacting the receptor and the receptor, the compound can modulate the receptor. However, at the same time, other receptors may not be modulated. For example, the compound can activate or inhibit a first receptor, such as a 5-HT 1A receptor. However, at the same time, the compound may not modulate a second receptor, such as a 5-HT 2A receptor, or after contacting a first 5-HT 2A receptor and a second 5-HT 1A receptor, the compound can modulate the first 5-HT 2A receptor, for example, activate or inhibit a 5-HT 2A receptor. However, at the same time, the compound may not modulate the second 5-HT 1A receptor.

[0452] In one embodiment, on the one hand, after administration, the compounds of the present disclosure can interact with transmembrane transporters in a subject, thereby modulating the transmembrane transporters and exerting a pharmacological effect. Such contact includes bringing the compounds of the present disclosure and transmembrane transporters together under in vitro conditions, for example, by introducing the compound into a sample containing transmembrane transporters, such as a sample containing purified transmembrane transporters, or a sample containing cells comprising transmembrane transporters. The contact further includes bringing the compounds of the present disclosure and transmembrane transporters together under in vivo conditions. Such in vivo conditions include administering, for example, a pharmaceutically effective amount of the compounds of the present disclosure to an animal or human subject when the compound is formulated with a pharmaceutically active carrier, diluent, or excipient as described above to treat the subject.

[0453] In one embodiment, on the one hand, the transmembrane transporter can be a dopamine active transporter (DAT), a norepinephrine transporter (NET), or a serotonin transporter (SERT) transmembrane transporter.

[0454] Turning now to the method for preparing the fused heterocyclic mescaline derivatives of the present disclosure, first, it is noted by way of general comment that the fused heterocyclic mescaline derivatives of the present disclosure can be prepared in any suitable manner, including by any organic chemical synthesis method, biosynthetic method, or a combination thereof.

[0455] Examples of suitable chemical reactions that can be carried out according to the present disclosure are depicted in FIGS. 3A(i), 3A(ii), 3B(i), 3B(ii), 3B(iii), and Figure 3C are further described in detail elsewhere in the Examples section below.

[0456] Typically, as is known to those skilled in the art, for performing a chemical synthesis reaction, the selected reactants are reacted under reaction conditions that permit the reactants to chemically react with each other and form a product (i.e., the heterocyclic mescaline derivatives of the present disclosure). Such reaction conditions can be selected, adjusted, and optimized as is known to those skilled in the art. The reaction can be carried out in any suitable reaction vessel (e.g., tube, flask). 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 be, for example, in the range of, for example, about -78 °C to about 60 °C. In addition, a catalyst, also referred to as a promoter, such as iodonium dicollidine perchlorate (IDCP), any silver or mercury salt, trimethylsilyl trifluoromethanesulfonate (TMS-trifluoromethanesulfonate, TMSOTf) or trifluoromethanesulfonic acid (trifluoromethanesulfonic acid, TfOH), N-iodosuccinimide, methyl trifluoromethanesulfonate can be included in the reaction. In addition, the reaction time can vary. As will be readily understood by those skilled in the art, the reaction conditions can be optimized, for example, by preparing several reactant preparations and carrying out the reaction in separate reaction vessels under different reaction conditions, such as different temperatures, using different solvents, etc., evaluating the resulting fused heterocyclic mescaline derivative reaction products, adjusting the reaction conditions, and selecting the desired reaction conditions. Additional 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), K. N. 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).

[0457] According to the foregoing, in one aspect, according to at least one embodiment, provided herein is a method for preparing a first compound having the chemical formula (I) or (II):

[0458]

[0459] wherein, in the chemical formula (I) or (II):

[0460] is a single bond or a double bond;

[0461] X1, X2, and X3 are independently selected from a hydrogen atom, O-alkyl, acyl, N-alkyl, OH, halogen, or NH2;

[0462] X4 is an alkylene group or a substituted alkylene group;

[0463] R1 is hydrogen, an alkyl group, or an oxo group, or

[0464] R1, together with the carbon atom to which R 1b is attached and the nitrogen atom to which R 1b is attached, is joined together to form an optionally substituted saturated or unsaturated 3- to 10-membered heterocycle, and when the heterocycle is unsaturated, R 1a is optionally absent;

[0465] R 1a and R 1b are each independently selected from an alkyl group, a hydroxyalkyl group, an optionally substituted alkyl-aryl group, or a hydrogen atom, or R 1a and R 1b together with the nitrogen atom to which they are attached are joined together to form an optionally substituted 3- to 10-membered heterocycle; and

[0466] R2 and R3 are each independently selected from an alkyl group, an O-alkyl group, a hydrogen atom, or R2 and R3, together with an oxygen atom and the carbon atom to which they are attached, are joined together to form an ethylene oxide ring,

[0467] wherein the method involves performing at least one chemical synthesis reaction selected from those depicted in Figure 3A(i), Figure 3A(ii), and Figure 3B(i), Figure 3B(ii), Figure 3B(iii), and Figure 3C the reactions depicted therein.

[0468] Referring to Figure 3A(i) and Figure 3A(ii), in one embodiment, the compound having the chemical formula (I) can be a compound having the formula (A):

[0469]

[0470] wherein 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 together with the nitrogen atom to which they are attached are joined together to form an optionally substituted 3- to 10-membered heterocycle,

[0471] and 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) depicted in Figure 3A(i) and Figure 3A(ii).

[0472] Referring to FIG. 3A(i), in one embodiment, the compound having the chemical formula (I) can be a compound having the formula (B):

[0473]

[0474] wherein in formula (B), X 4a and X 4b are independently or simultaneously a halogen atom or a hydrogen atom, R 1a and R 1b each independently selected from an alkyl group, an optionally substituted alkyl-aryl group or a hydrogen atom, or R 1a and R 1b together with the nitrogen atom to which they are attached are joined together to form a 3- to 10-membered optionally substituted heterocycle,

[0475] and 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) depicted in FIG. 3A(i).

[0476] Continuing to refer to FIG. 3A(i) and FIG. 3A(ii) and further referring to FIG. 3B(i) and FIG. 3B(ii), in one embodiment, the compound having the chemical formula (I a ) or (I c ) can be a compound having the formula (C):

[0477]

[0478] wherein R 1a and R 1b each independently selected from an alkyl group, a hydroxyalkyl group or a hydrogen atom, or R 1a and R 1b together with the nitrogen atom to which they are attached are joined together to form a 3- to 10-membered optionally substituted heterocycle, wherein R2 is selected from an alkyl group or a hydrogen atom, and wherein X3 is an O-alkyl group, a halogen or a hydrogen atom,

[0479] and at least one chemical synthesis reaction is a reaction selected from the following:

[0480] (i) { (h) in FIGS. 3A(i) and 3A(ii); (c) and (h); (b), (c) and (h); and (a), (b), (c) and (h) (for compounds C(I), C(II) and C(III))}; or

[0481] (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) (for compounds C(VIII) and C(IX)); or

[0482] (iii) (e) in Figures 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) (for compounds C(VI) and C(VII)); or

[0483] (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) (for compounds C(I), C(II), C(III), C(V), C(X), C(XI) and C(XII)); or

[0484] (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) (for compound C(XIII)); or

[0485] (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) (for compound C(IV)).

[0486] Continuing to refer to Figures 3A(i) and 3A(ii), in one embodiment, a compound having the chemical formula (I b ) or (I d ) can be a compound having the formula (D):

[0487]

[0488] wherein R 1a and R 1b are each independently selected from an alkyl group, a hydrogen atom, or R 1a and R 1bLinked together with the nitrogen atoms to which they are attached to form a 3- to 10-membered optionally substituted heterocycle,

[0489] and at least one chemical synthesis reaction is a reaction selected from (c); (b) and (c); and (a), (b) and (c) depicted in FIGS. 3A(i) and 3A(ii).

[0490] Reference Figure 3C , in one embodiment, a compound having the chemical formula (I) can be a compound having the formula (E):

[0491]

[0492] wherein 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 are linked together with the nitrogen atoms to which they are attached to form a 3- to 10-membered optionally substituted heterocycle,

[0493] and at least one chemical synthesis reaction is selected from Figure 3C the reactions (b); (a) and (b) depicted therein.

[0494] Referring to FIGS. 3B(i) and 3B(ii), in one embodiment, a compound having the chemical formula (I) can be a compound having the formula (F):

[0495]

[0496] wherein R 1a and R 1b are each independently selected from a hydroxyalkyl group and a hydrogen atom, or R 1a and R 1b are linked together with the nitrogen atoms to which they are attached to form a 3- to 10-membered optionally substituted heterocycle, and wherein R2 is an alkyl group or a hydrogen atom, X3 is an O-alkyl group, a halogen or a hydrogen atom,

[0497] and at least one chemical synthesis reaction is a reaction selected from (c1); (c2); (b) and (c2); (a) and (c1); (a), (b) and (c2) in FIGS. 3B(i) and 3B(ii).

[0498] Referring to FIGS. 3B(i), 3B(ii) and 3B(iii), in one embodiment, a compound having the chemical formula (I) can be a compound having the formula (G):

[0499]

[0500] wherein R2, Y1, and Y2 are each independently an alkyl group or a hydrogen atom, and X3 is hydrogen or a halogen,

[0501] and at least one chemical synthesis reaction is a reaction selected from those in Figure 3B(i), Figure 3B(ii), and Figure 3B(iii): {(h); (c1) and (h); (c2) and (h); (b), (c2) and (h); and (a), (c1) and (h); and (a), (b), (c2) and (h)}.

[0502] It will now be apparent from the foregoing that novel heterocyclic mescaline derivatives are disclosed herein. The heterocyclic mescaline derivatives can be formulated for use as medicinal or recreational drugs. Exemplary embodiments and implementations of the present disclosure are further illustrated by the following examples.

[0503] Examples

[0504] Example 1 - Preparation of the First N - propylamine - fused Heterocyclic Mescaline Derivative

[0505] Reference Figure 4A , at 0 °C under an inert atmosphere, a solution of triethyl phosphonoacetate (1.67 mL, 8.24 mmol) in dry THF (10 mL) was added to a suspension of sodium hydride (330 mg, 8.24 mmol) in dry THF (5 mL). 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 slowly 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 combined organic extracts were dried over anhydrous MgSO4, filtered, and concentrated to give 13 (1.35 g, 93%). 1 H NMR (400 MHz, CDCl3) 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) in Figure 3A(i)).

[0506] Next, reference Figure 4B, at -78 °C, under a nitrogen atmosphere, DIBAL (1 M in THF, 15.0 mL, 15.0 mmol) was added to a solution of 13 (826 mg, 3.75 mmol) in dry THF (18.8 mL) over 10 minutes. The reaction mixture was stirred at -78 °C for 3 hours until the reaction was complete, 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 solution (4 mL) and water (10 mL), and stirred at room temperature for 15 minutes. Anhydrous MgSO4 was added and the slurry was stirred for 3 days before filtration. 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 to 20% EtOAc / Hex) gave 14 (422 mg, 63%) as an off-white solid. 1 1H NMR (400 MHz, CDCl3) 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) in further Figure 3A(i)).

[0507] Next, referring to Figure 4C , manganese(IV) oxide (908 mg, 10.3 mmol) was added to a solution of 14 (307 mg, 1.72 mmol) in DCM (17.2 mL). The reaction mixture was stirred at ambient conditions for 18 h. More manganese(IV) oxide (359 mg, 4.08 mmol) was added and the solution was stirred for a further 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 white crude solid. Purification by column chromatography on silica gel (4 g, 0 to 12% EtOAc / Hex) gave the product, intermediate J (282 mg, 93%), as a white solid. 1 1H NMR (400 MHz, CDCl3) 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 For the chemical reaction (b2), see also the chemical reaction (b) in Figure 3A(i).

[0508] Next, with reference to Figure 4D , under a nitrogen atmosphere, diethylamine (80.3 μL, 772 μmol) was added to a solution of J (136 mg, 772 μmol) in dry MeOH (5.15 mL). The reaction mixture was refluxed for 3 h. After 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 to 6% MeOH / DCM) to give MM709 (45 mg, 25%) as a yellow oily solid. LRMS-HESI: Calculated for [M+H] + was 234.15 m / z, found 234.15. 1 H NMR (400 MHz, CDCl3) 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 For the chemical reaction (c), see also the chemical reaction (c) in Figure 3A(ii).

[0509] It should be noted that MM709 corresponds to compound D(I):

[0510]

[0511] 5-HT receptor radioligand competition assay. The activity of 5-HT 1A and 5-HT 2A receptors was evaluated as described for Example 2, except that a compound of formula D(I) was evaluated instead of a compound of formula B(II). Table 1 shows the results of the radioligand competition assay for the positive control, negative control and the compound of formula D(I) in the form of K i values. Given the results of both the positive control and negative control, the data from the negative control were insufficient for reliable K i calculation (i.e., K i> 1000 μM), for the compound of formula D(I) at 5-HT 1A The K i value obtained at the receptor (11.0 μM, Table 1) indicates ligand-receptor binding. Similarly, for the compound of formula D(I) at 5-HT 2A The K i value at the receptor (21 μM, Table 1) indicates ligand-receptor binding.

[0512] 5-HT 1A Receptor functional cell response assay. The functional engagement of the 5-HT 1A receptor within the engineered cell system was evaluated as described for Example 2, except that compounds of formula D(I) were evaluated instead of compounds of formula B(II). Table 2 shows the results of the functional assays for the positive control, calibrator, and compounds of formula D(I) in the form of EC 50 values. Given the results of the control and calibrator compounds, where a negative cell response corresponds to an EC 50 value > 1000 μM, in this assay, the EC 50 values of the compounds of formula D(I) (> 1000 μM, Table 2) indicate little or no ligand-receptor engagement.

[0513] In vitro investigation of the pharmacological interaction profiles of receptors and transporters relevant to the target health condition.

[0514] Evaluate the binding and / or interaction of compounds of formula D(I) at 11 different receptors and transporters that have known or suspected links to mental health conditions and / or neuropathologies. This study was conducted by the contract research organization (CRO) Eurofins Cerep (Cell L’Evescault, France) using standard detection procedures (https: / / www.eurofinsdiscovery.com / solution / target-based-assays). Profiles were generated for the derivative molecule with respect to the following 8 G protein-coupled receptors (GPCRs): HTR1A (5-HTR 1A ), HTR2A (5-HTR 2A ), HTR2B (5-HT 2B ), HTR2C (5-HT 2C ), HTR7 (5-HT7), α2A (α 2A) Data on the interaction of MT1 (MT1), D3 (D3)), and three transporters (SERT, DAT, NET). The assays were conducted using the same materials and procedures as outlined in Example 2, except that the compound of formula D(I) was used instead of the compound of formula B(II). The general assay conditions for GPCR and transporters are summarized in Tables 3 and 4, respectively. The results for all calibrator compounds, control compounds, and test compounds (including the compound of formula D(I)) are summarized in Table 5.

[0515] Example 2 - Preparation of the Second N - propylamine - fused Heterocyclic Mescaline Derivative

[0516] Reference Figure 5A , at 0 °C under an inert atmosphere, a solution of triethyl 2-phosphonopropionate (1.82 mL, 8.24 mmol) in dry THF (10.0 mL) was added dropwise over 10 minutes to a suspension of sodium hydride (330 mg, 8.24 mmol) in dry THF (5.00 mL). 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 allowed to warm slowly to room temperature and stirred for 18 h. 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 combined organic extracts were dried over anhydrous MgSO4, filtered, and concentrated to give 15 (1.55 g, 100%). 1 H NMR (400 MHz, CDCl3) 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 For the chemical reaction (d) of, see also: the chemical reaction (d) of Figure 3A(i)).

[0517] Reference Figure 5B, at -78 °C under a nitrogen atmosphere, within 10 minutes, diisobutylaluminum hydride (DIBAL) (1 M in THF, 19.9 mL, 19.9 mmol) was added to a solution of 15 (1.55 g, 6.62 mmol) in dry THF (33.1 mL). The reaction mixture was stirred at -78 °C for an additional 2 hours. The reaction was quenched at 0 °C by the dropwise addition of water (0.4 mL), followed by 15% aqueous NaOH solution (0.4 mL) and water (1 mL), and stirred at room temperature for 15 minutes. Anhydrous MgSO4 was added, and the slurry was stirred for 15 minutes before filtration. The filtrate was concentrated under reduced pressure to give a colorless oil. Purification by flash chromatography on silica gel (25 g, 0 to 20% EtOAc / Hex) gave 16 (1.21 g, 95%).

[0518] 1 1H NMR (400 MHz, CDCl3) 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 For the chemical reaction (e1), see also the chemical reaction (e) in Figure 3A(i).

[0519] Reference 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 hours. More manganese(IV) oxide (565 mg, 6.43 mmol) was added to the reaction mixture and stirred for an additional 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 white crude solid. Purification by flash column chromatography on silica gel (4 g, 0 to 12% EtOAc / Hex) gave the product as a white solid, intermediate K (474 mg, 91%). 1 1H NMR (400 MHz, CDCl3) 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 For the chemical reaction (e2), see also the chemical reaction (e) in Figure 3A(i).

[0520] Reference Figure 5D , under a nitrogen atmosphere, pyrrolidine (56.4 μL, 684 μmol) was added to a solution of K (130 mg, 684 μmol) in dry methanol (4.56 mL). 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, methanol was removed under reduced pressure, 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 (4 g, 0 to 6% MeOH / DCM) on silica gel gave MM710 (64 mg, 38%) as a yellow oil. LRMS-HESI: For [M+H] + Calculated value is 246.15 m / z, measured value is 246.17. 1 H NMR (400 MHz, CDCl3) 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 For the chemical reaction (f), see: also further the chemical reaction (f) of Figure 3A(i).

[0521] It should be noted that MM710 corresponds to compound B(II):

[0522]

[0523] 5-HT receptor radioligand competition assay.

[0524] 5-HT 1A receptor. The competition assay was carried out as follows: SPA beads (RPNQ0011), radiolabeled 8-hydroxy-DPAT [propyl-2,3-cyclo-1,2,3- 3 H] (labeled 7-(dipropylamino)-5,6,7,8-tetrahydronaphthalen-1-ol; NET929250UC), containing 5-HT 1AThe membranes (6110501400UA) and isoplate-96 microplates (6005040) were from Perkin Elmer (perkinelmer.com). Radioligand binding assays were performed using scintillation proximity assay (SPA; Maguire et al., 2012, Methods in Molecular Biology 897:31-77). For saturation binding assays, at room temperature, in a tube rotator, 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], a mixture of 10 μg of membranes containing the HT 1A receptor was pre-coupled with 1 mg of SPA beads for 1 h. After pre-coupling, the beads and membranes were aliquoted into isoplate-96 microplates with increasing amounts of 8-hydroxy-DPAT [propyl-2,3-cyclo-1,2,3- 3 H] (0.1525 nM to 5 nM) and incubated for 2 h at room temperature in the dark with shaking. After incubation, samples were read on a MicroBeta 2 microplate counter (perkinelmer.com). Nonspecific binding was performed in the presence of 100 μM methysergide (M3668-500MG, Sigma-Aldrich). The equilibrium binding constant (K D ) of 8-hydroxy-DPAT was determined from the saturation binding curve using a one-site saturation binding analysis from GraphPad PRISM software (version 9.2.0). Test compounds were dissolved in dimethyl sulfoxide (DMSO) to 100 mM and diluted in assay buffer. Competition binding assays were performed similar to 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 compounds (3 nM to 1 mM). The K iValues. 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 are phenylalkylamine-type molecules with relatively strong (2C-B; Rickli et al., 2015, Neuropharmacology 99:546) or more modest (MDMA, Simmler et al., 2013, British J. Pharmacol. 168:458; mescaline, Rickli et al., 2016, Eur. Neuropharm. 26:1327) 5-HT 1A receptor binding activity. Iscarine and proscaline were included in this study for comparison purposes because although their 5-HT 1A receptor binding patterns have not been fully studied, they were identified as 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 are widely prescribed drugs that establish binding to 5-HT 1A receptors (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 binding curve used to determine the K D of 8-hydroxy-DPAT. Figure 14B and Figure 14C show the binding curves of the negative controls DMSO and tryptophan, respectively. As seen in Figure 14B and Figure 14C , the data excluded K i determination (i.e., K i > 1000 μM), indicating that these negative controls did not bind. Figure 14D , Figure 14E , Figure 14F and Figure 14G The binding curves shown in reveal data that allow for the determination of K i for the positive controls: serotonin, mescaline, 2C-B, and MDMA, respectively. Figure 14D , Figure 14E , Figure 14F andFigure 14G The s-curve and K in i value (i.e., K i <1000 μM) revealed the binding of 5-HT at the indicated ligand concentrations 1A receptor. Figure 14H and Figure 14I The data in 1A showed that at the indicated concentrations, lysergic acid amide and proscaline bind to the 5-HT Figure 14J and Figure 14K The data in 1A showed the binding of fluoxetine and vortioxetine to the 5-HT Figure 14L The data in 1A showed that the compound having formula B(II) binds to the 5-HT Figure 14A and Figure 14B ) at a level higher than that observed for the negative control ( 1A The resulting K i data for the control and test compounds in the 5-HT

[0525] 5-HT 2A receptor. The competition assay was performed as in the 5-HT 1A assay, but with the following differences. SPA beads (RPNQ0010), 3 2A H] ketanserin (NET1233025UC) and membranes containing 5-HT 3 were from PerkinElmer. After pre-coupling, the beads and membranes were aliquoted into an isoplate-96 microplate with increasing amounts of d 3 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 2A receptor) of ketanserin was determined from the saturation binding curve using the "One-site saturation binding analysis" method in GraphPad PRISM software (version 9.2.0). The competition binding assay was performed using a fixed (1 nM) ​​et al., 2020, ACS Chem. Neurosci. 11:1238) or more modestly (Simmler et al., 2013, British Journal of Pharmacology 168:458) 5-HT 2A receptor binding activity. Iscarine and proscaline were included in this study for comparison purposes because, although their 5-HT 2A receptor binding patterns have not been fully studied, they are recognized mescaline-type hallucinogens known to induce head twitch responses in mice (Halberstadt et al., 2019, Journal of Psychopharmacology 33:406-414). The head twitch response in mice is associated with 5-HT 2A receptor engagement (Halberstadt, 2015, Behavioural Brain Research 277:99). Psilocybin was included as an additional positive control because it exhibits well-established binding to the 5-HT 2A receptor as a partial agonist. Figure 15A Shows data supporting the overall K D determination for ketanserin ( Figure 1 ), and the K D attributed to specific binding ( Figure 2 ). Figure 15B Shows data obtained for psilocybin and supports the binding of this positive control at the 5-HT 2A receptor. Figure 15C Shows data obtained for tryptophan and supports the lack of binding of this negative control at the 5-HT 2A receptor. Figure 15D And Figure 15E respectively reveal the binding data for iscarine and proscaline, and the resulting K i values (i.e., <1000 μM) reveal binding at the 5-HT 2A receptor at the indicated concentrations. Figure 15F Reveals the binding data for 2C-B, and the resulting K i value (i.e., <1000 μM) reveals binding at the 5-HT 2A receptor. Figure 15G Reveals the binding data for MDMA, and the resulting K i value (i.e., <1000 μM) reveals binding at the 5-HT 2A receptor at the indicated concentrations. Figure 15H The data in 2A show that the compounds having formula B(II) bind to the 5-HT Figure 15C ) at levels higher than those observed for the negative control. At 5-HT 2AThe resulting K of the control and assay compounds in the receptor binding assay i The data are summarized in Table 1.

[0526] Table 1. 5-HT 1A and 5-HT 2A Summary of data from radioligand competition assays for the receptor.

[0527] Molecule <![CDATA[5-HT 1A ,K i (μM)]]> <![CDATA[5-HT 2A ,K i (μM)]]> DMSO >1000 >1000 Tryptophan >1000 >1000 Serotonin 0.0025 N.D. Psilocybin N.D. 0.0257 Mescaline 8.5 N.D. 2C - B 0.200 0.414 MDMA 11 39.9 Iscarine 12.4 61 Proscaline 9.4 82 Fluoxetine 0.306 N.D. Vortioxetine 0.0043 N.D. D(I) 11 21 B(II) 824 7 F(III) >1000 152 F(IV) 84.5 N.D. C(III) 2.33 N.D. C(IV) 0.596 N.D. A(II) 8.0 N.D. C(I) 2.9 N.D. F(V) 363.5 N.D. C(V) 50 ND

[0528] N.D. = Not determined

[0529] Functional receptor potency assay.

[0530] 5-HT 1A receptor. Chinese hamster ovary (CHO)-derived cell line CHO-K1 / 5-HT 1A stably transfected to express the serotonin receptor / Gα15 (GenScript M00330) was used to evaluate the stimulation of specific agonist-mediated 5-HT 1A signal transduction. In these non-neuronal cells, stimulation of 5-HT 1A activates the Gα 1A protein, resulting in the inhibition of type I adenylyl cyclase (AC) (Rojas and Felder, 2016, Frontiers in Cellular Neuroscience 10:272; Polter and Li, 2010, Cell Signalling 22:1406 - 1412). In cells stimulated with 4 μM forskolin that directly stimulates AC to increase intracellular cAMP levels, the activation of 5-HT i / o was quantitatively evaluated by measuring the decreased intracellular cAMP levels. All cells were grown and maintained as a monolayer in Ham's F12 nutrient mixture supplemented with 10% fetal bovine serum (FBS), 200 μg / mL blasticidin, or 100 μg / mL hygromycin, and all reagents were obtained from ThermoFisher Scientific and used according to the manufacturer's instructions. The cells were cultured and incubated at 37 °C in a humidified oxygen atmosphere containing 5% CO2. To evaluate 5-HT 1A activation. 1AFor activation of signal transduction, cells were first seeded at a density of 30,000 cells / well in 100 μL of complete growth medium in tissue culture-treated, white-walled, clear-bottom 96-well plates (Corning, corning.com). The cells were cultured in a humidified incubator at 37 °C and 5% CO2 for 24 h. The cells were then stimulated with the test compound for 20 minutes. The test compound was prepared as a dilution series starting from 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 RO 20-1724 (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 derived from cells stimulated with induction medium alone were used to establish the maximal level of intracellular cAMP (100%) for each assay run. Figure 16A Shows increased levels of cAMP in cultured cells incubated with increasing concentrations of forskolin (FSK), independent of 5-HT 1A expression. Figure 16B Shows that as the level of 8-OH-DPAT increases, in cells expressing the 5-HT 1A receptor stimulated with 4 μM forskolin (+5-HT 1A ), the cAMP level decreases, indicating that in these cells the 5-HT 1A receptor is bound by 8-OH-DPAT. In contrast, no such trend of decreasing %cAMP level with increasing 8-OH-DPAT was observed in cells lacking expression of the 5-HT 1A receptor. 8-OH-DPAT (7-(dipropylamino)-5,6,7,8-tetrahydronaphthalen-1-ol) is a well-established full agonist of the 5-HT 1A receptor (Larsson et al., 1990, Neuropharmacology 29:85-91) and was included as a positive control to ensure the functionality of the cell response system. Figure 16C Shows that as the level of serotonin increases, in cells expressing the 5-HT 1A receptor stimulated with 4 μM forskolin (+5-HT 1A ), the cAMP level decreases, indicating that in these cells the 5-HT 1A receptor is bound by serotonin. In contrast, no such trend of decreasing %cAMP level with increasing serotonin was observed in cells lacking expression of the 5-HT 1A receptor. Serotonin is 5-HT1A The native ligand of the receptor and is thus included as a positive control. Psilocybin, MDMA, and 2C-B are included as calibrator compounds because although these compounds are all known to bind to the 5-HT 1A receptor to varying degrees (Marcher- et al., 2020, ACS Chem. Neurosci. 11:1238; Simmler et al., 2013, British Journal of Pharmacology 168:458), their ability to elicit a cellular response in this particular functional assay is unknown. The binding mode of mescaline to the 5-HT 1A receptor has not been fully studied, but it is included for comparison purposes because of the similarity in its phenethylamine backbone structure to other derivatives in this application. Figure 16D Shows a decrease in cAMP levels in cells expressing the 5-HT 1A receptor (+5-HT 1A ) stimulated with 4 mM forskolin as the level of psilocybin increases, indicating binding of psilocybin to the 5-HT 1A receptor in these cells. In contrast, no such trend of decreasing %cAMP levels with increasing psilocybin was observed in cells lacking expression of the 5-HT 1A receptor. Figure 16E And Figure 16F Show a slight change or no change in cAMP levels in cells expressing the 5-HT 1A receptor (+5-HT 1A ) stimulated with 4 μM forskolin as the levels of mescaline and MDMA increase, respectively. These results indicate that in this cell system, there is a mild or no 5-HT 1A receptor engagement by mescaline or MDMA, respectively. Figure 16G Shows a decrease in cAMP levels in cells expressing the 5-HT 1A receptor (+5-HT 1A ) stimulated with 4 mM forskolin as the level of 2C-B increases, indicating 5-HT 1A receptor engagement by 2C-B in these cells. In contrast, no such trend of decreasing %cAMP levels with increasing 2C-B was observed in cells lacking expression of the 5-HT 1A receptor. The 5-HT 1A receptor engagement assessment of the compound named B(II) is shown in Figure 16H . Comparison of the data obtained in +5-HT 1A cultures with the data obtained in -5-HT1A cultures indicates that at elevated ligand concentrations (EC 50Receptor regulation at [compound concentration] = 40.1 μM). Table 2 summarizes the EC data for all controls, calibrators, and test compounds obtained using the functional 5-HT 1A receptor assay. 50 Data.

[0531] Table 2. Summary of data from the functional 5-HT 1A receptor assay.

[0532] Molecule <![CDATA[5-HT 1A ,EC 50 (μM)]]> 5 - OH - DPAT 0.0007118 Serotonin 0.001142 Psilocybin 0.9567 Mescaline >1000 2C - B 5.945 MDMA >1000 D(I) >1000 B(II) 40.1 F(V) 10.0 C(V) 116.3 G(V) 129.5 C(XIII) 22.95

[0533] In vitro investigation of the pharmacological interaction profiles of receptors and transporters relevant to the target health condition.

[0534] To expand the pharmacological profiling to include a broader range of targets known to be associated or linked to brain disorders, the binding and / or interaction of compounds of formula B(II) were evaluated on 9 different receptors and transporters. This study was conducted 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 generated on the interaction of the derived molecules with the following 8 G protein-coupled receptors (GPCRs): HTR1A (5-HTR 1A ), HTR2A (5-HTR 2A ), HTR2B (5-HT 2B ), HTR2C (5-HT 2C ), HTR7 (5-HT7), α2A (α 2A ), MT1 (MT1), D3 (D3)), and 3 transporters (SERT, DAT, NET). The assay conditions for the GPCRs and transporters are summarized in Tables 3 and 4, respectively. In-house positive controls were used as in Eurofins Cerep

[0535] Part of the standard industry practice of (https: / / www.eurofins.com / contact-us / worldwide-interactive-map / france / eurofins-cerep-franc e / ) is routinely applied to ensure the functionality of each assay. To further calibrate each assay, especially for compounds with a phenylalkylamine (PAA) structural scaffold, an additional set of six PAA-type calibration compounds was submitted for the assays: MDMA, mescaline, 2C-B, isocarline, proscaline, and DOB. The additional tryptamine-type calibration standards used in these assays include serotonin and melatonin. Tryptophan was submitted as a negative control for all assays because tryptophan is known not to interact with any target receptor or transporter. In addition, seven widely marketed drugs used to treat mental health disorders and with a long-established pharmacological profile were submitted for assay calibration purposes: vortioxetine, trazodone, duloxetine, imipramine, agomelatine, bupropion, and vilazodone. The results of all calibration compounds, control compounds, and test compounds (including compounds having formula B(II)) are summarized in Table 5.

[0536] Table 3. Summary of the conditions for the GPCR (receptor) binding assay. Cold ligand was included in the assay to ensure that only specific binding was evaluated.

[0537]

[0538] Table 4. Summary of the conditions for the transporter binding assay. Cold ligand was included in the assay to ensure that only specific binding was evaluated.

[0539]

[0540] i. Competitive assay for measuring the binding affinity at the α2a receptor.

[0541] The assay was performed using the conditions summarized in Table 3 according to the method described by Langin et al. [Eur. J. Pharmacol. 167:95 - 104, 1989]. Since the purpose of this experiment was to measure the general binding potential of the test ligand rather than to obtain detailed binding information for generating K i values, only a single concentration of the test ligand (10 μM) was used. Briefly, CHO cells were used to express the recombinant receptor and membrane preparation was carried out at 4 °C. In a final volume of 400 μL of Tris-Mg 2+In buffer, binding experiments were performed using 100 μL of membrane suspension incubated with a radioligand, a cold ligand to ensure specific binding of the test ligand, and a test molecule (10 μM). Incubation was quenched by adding 4 mL of ice-cold wash buffer (10 mM Tris-HCl, 0.5 mM MgCl2). Bound and free radioligands were separated by filtration through a GF / C Whatman filter under vacuum. The filter was then washed and subjected to scintillation counting. Results were expressed as a percentage of control specific binding ([measured specific binding / control specific binding] * 100). Results for compounds of formula B(II) are shown in Table 5.

[0542] ii. Competition assay to measure binding affinity at the D3 receptor.

[0543] The assay was performed using the conditions summarized in Table 3 according to the method described by Mackenzie et al. [European Journal of Pharmacology 266:79 - 85, 1994]. Since the purpose of this experiment was to measure the general binding potential of the test ligand rather than to obtain detailed binding information to generate K i values, only a single concentration of the test ligand (10 μM) was used. Briefly, CHO cells were used to express the recombinant receptor and membrane preparation was carried out at 4 °C. Binding experiments were performed using 100 μL of membrane suspension, a radioligand, a cold ligand to ensure specific binding of the test ligand, and a test molecule (10 μM) in a final volume of 400 μL. Bound and free radioligands were separated by filtration through a GF / C Whatman filter under vacuum. The filter was then washed and subjected to scintillation counting. Results were expressed as a percentage of control specific binding ([measured specific binding / control specific binding] * 100). Results for compounds of formula B(II) are shown in Table 5.

[0544] iii. Competition assay to measure binding affinity at the MT1 receptor.

[0545] The assay was performed using the conditions summarized in Table 3 according to the method described by Witt-Endersby and Dubocovich [Molecular Pharmacology (Mol. Pharmacol.) 50:166 - 174, 1996]. Since the purpose of this experiment was to measure the general binding potential of the test ligand rather than to obtain detailed binding information to generate K iDetailed binding information of the values, so only a single concentration of the test ligand (10 μM) was used. Briefly, CHO cells were used to express the recombinant receptor, and membrane preparation was carried out at 4 °C. A binding experiment was performed using 100 μL of membrane suspension, radioactive ligand, cold ligand to ensure specific binding by the test ligand, and test molecule (10 μM) with a final volume of 500 μL. The bound radioactive ligand and free radioactive ligand were separated by filtration through a GF / C Whatman filter under vacuum. Then the filter was washed and subjected to scintillation counting. The results were expressed as a percentage of the control specific binding ([Measured specific binding / Control specific binding] * 100). The results of the compounds having formula B(II) are shown in Table 5.

[0546] iv. Competitive assay for measuring the binding affinity at the 5-HT 1A receptor.

[0547] The assay was carried out using the conditions summarized in Table 3 according to the method described by Mulheron et al. [Journal of Biological Chemistry (J. Biol. Chem.) 269:12954 - 12962, 1994]. Since the purpose of this experiment was to measure the general binding potential of the test ligand rather than obtaining detailed binding information for generating K i values, only a single concentration of the test ligand (10 μM) was used. Briefly, HEK-293 cells were used to express the recombinant receptor, and membrane preparation was carried out at 4 °C. A binding experiment was performed using radioactive ligand, 30 μg of 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. The bound radioactive ligand and free radioactive ligand were separated by filtration through a glass fiber Whatman filter under vacuum. Then the filter was washed and subjected to scintillation counting. The results were expressed as a percentage of the control specific binding ([Measured specific binding / Control specific binding] * 100). The results of the compounds having formula B(II) are shown in Table 5.

[0548] v. Competitive assay for measuring the binding affinity at the 5-HT 2A receptor.

[0549] Assays were performed using the conditions summarized in Table 3 according to the method described by Bryant et al. [Life Sci. 15: 1259 - 1268, 1996]. Briefly, HEK - 293 cells were used to express the recombinant receptor, and membrane preparation was carried out at 4 °C. Binding experiments were performed using a radioactive ligand, 30 μg of protein (membrane suspension), a cold ligand to ensure specific binding of the test ligand, and the test molecule (10 μM) to a final volume of 300 μL. The bound and free radioactive ligands were separated by filtration through a glass fiber Whatman filter under vacuum. The filter was then washed and subjected to scintillation counting. Results were expressed as a percentage of control specific binding ([measured specific binding / control specific binding] * 100). Results for compounds having formula B(II) are shown in Table 5.

[0550] vi. Competitive assay to measure binding affinity at the 5 - HT 2B receptor.

[0551] Assays were performed using the conditions summarized in Table 3 according to the method described by Kursar et al. [Mol. Pharmacol. 46: 227 - 234, 1994]. Since the purpose of this experiment was to measure the general binding potential of the test ligand rather than to obtain detailed binding information for generating K i values, only a single concentration of the test ligand (10 μM) was used. Briefly, CHO cells were used to express the recombinant receptor, and membrane preparation was carried out at 4 °C. Binding experiments were performed using a radioactive ligand in 50 mM Tris pH 7.4, 0.2 mL (approx. 100 μg of protein) of membrane suspension, a cold ligand to ensure specific binding of the test ligand, and the test molecule (10 μM). The bound and free radioactive ligands were separated by filtration through a glass fiber Whatman filter under vacuum. The filter was then washed and subjected to scintillation counting. Results were expressed as a percentage of control specific binding ([measured specific binding / control specific binding] * 100). Results for compounds having formula B(II) are shown in Table 5.

[0552] vii. Competitive assay to measure binding affinity at the 5 - HT 2C receptor.

[0553] Assays were performed using the conditions summarized in Table 3 according to the method described by Bryant et al. [Life Sci. 15: 1259 - 1268, 1996]. Since the purpose of this experiment was to measure the general binding potential of the test ligand rather than to obtain detailed binding information for generating K iDetailed binding information of the values, so only a single concentration of the test ligand (10 μM) was used. Briefly, HEK-293 cells were used to express the recombinant receptor and membrane preparation was carried out at 4 °C. Binding experiments were performed using the radioligand, 0.2 mL (approx. 100 μg protein) of membrane suspension, cold ligand to ensure specific binding by the test ligand, and the test molecule (10 μM) in 3 mM CaCl2, 0.1% sodium ascorbate and 50 mM Tris pH 7.4, with a final volume of 800 μL. The bound radioligand and free radioligand were separated by filtration through a glass fiber Whatman filter under vacuum. The filter was then washed and subjected to scintillation counting. The results were expressed as a percentage of the control specific binding ([measured specific binding / control specific binding] * 100). The results for the compounds of formula B(II) are shown in Table 5.

[0554] viii. Competition assay for measuring the binding affinity at the 5-HT7 receptor.

[0555] The assay was carried out using the conditions summarized in Table 3 according to the method described by Shen et al. [Journal of Biological Chemistry 268:18200 - 18204, 1993]. Since the aim of this experiment was to measure the general binding potential of the test ligand rather than to obtain detailed binding information for generating K i values, only a single concentration of the test ligand (10 μM) was used. Briefly, HEK-293 cells were used to express the recombinant receptor and membrane preparation was carried out at 4 °C. Binding experiments were performed using the radioligand, 30 μg protein (membrane suspension), cold ligand to ensure specific binding by the test ligand, and the test molecule (10 μM) to a final volume of 200 μL. The bound radioligand and free radioligand were separated by filtration through a glass fiber Whatman filter under vacuum. The filter was then washed and subjected to scintillation counting. The results were expressed as a percentage of the control specific binding ([measured specific binding / control specific binding] * 100). The results for the compounds of formula B(II) are shown in Table 5.

[0556] ix. Competition assay for measuring the binding affinity at the serotonin transporter (SERT).

[0557] The assay was carried out using the conditions summarized in Table 4 according to the method described by Tatsumi et al. [European Journal of Physiology (Eur J Pharmacol) 368:277 - 283, 1999]. Since the aim of this experiment was to measure the general binding potential of the test ligand rather than to obtain detailed binding information for generating K iDetailed binding information of the values, so only a single concentration of the test ligand (10 μM) was used. Briefly, CHO cells were used to express the recombinant transporter, and membrane preparation was carried out at 4 °C. Binding experiments were performed using a radioligand, 30 μg of protein (membrane suspension), a cold ligand to ensure specific binding by the test ligand, and the test molecule (10 μM) to a final volume of 200 μL. The bound radioligand and free radioligand were separated by filtration through a Whatman glass fiber filter under vacuum. The filter was then washed and subjected to scintillation counting. The results were expressed as a percentage of the control specific binding ([measured specific binding / control specific binding] * 100). The results for the compounds having formula B(II) are shown in Table 5.

[0558] x. Competitive assay for measuring binding affinity at the norepinephrine transporter (NET).

[0559] The assay was carried out using the conditions summarized in Table 4 according to the method described by Pacholczyk et al. [Nature 350: 350 - 354, 1991]. Since the purpose of this experiment was to measure the general binding potential of the test ligand rather than to obtain detailed binding information yielding K i Detailed binding information of the values, so only a single concentration of the test ligand (10 μM) was used. Briefly, CHO cells were used to express the recombinant transporter, and membrane preparation was carried out at 4 °C. Binding experiments were performed using a radioligand, 30 μg of protein (membrane suspension), a cold ligand to ensure specific binding by the test ligand, and the test molecule (10 μM) to a final volume of 200 μL. The bound radioligand and free radioligand were separated by filtration through a Whatman glass fiber filter under vacuum. The filter was then washed and subjected to scintillation counting. The results were expressed as a percentage of the control specific binding ([measured specific binding / control specific binding] * 100). The results for the compounds having formula B(II) are shown in Table 5.

[0560] xi. Competitive assay for measuring binding affinity at the dopamine transporter (DAT).

[0561] The assay was carried out using the conditions summarized in Table 4 according to the method described by Pristupa et al. [Molecular Pharmacology 45: 125 - 135, 1994]. Since the purpose of this experiment was to measure the general binding potential of the test ligand rather than to obtain detailed binding information yielding K iDetailed binding information of the values, so only a single concentration of the test ligand (10 μM) was used. Briefly, CHO cells were used to express the recombinant transporter, and membrane preparation was carried out at 4 °C. Binding experiments were performed using a radioactive ligand, 50 μg of protein (membrane suspension), a cold ligand to ensure specific binding of the test ligand, and a test molecule (10 μM) to a final volume of 200 μL. The bound radioactive ligand and the free radioactive ligand were separated by filtration through a Whatman glass fiber filter under vacuum. The filter was then washed and subjected to scintillation counting. The results were expressed as a percentage of the control specific binding ([Measured specific binding / Control specific binding] * 100). The results for the compounds of formula B(II) are shown in Table 5.

[0562] Table 5. Results of binding assays based on GPCR and transporter competition. Data are shown as a percentage of the control specific binding.

[0563]

[0564]

[0565] Example 3 - Preparation of the Third N - propylamine - fused Heterocyclic Mescaline Derivative

[0566] Reference Figure 6A , triethylamine (924 μL, 6.59 mmol) was added dropwise to formic acid (622 μL, 16.5 mmol) at 0 °C. Subsequently, 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 whole mixture was dissolved in DMF (20 mL). The flask was heated to 105 °C, and CO2 was slowly released from the reaction mixture. After 3 h, the mixture was cooled back 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 afford phenylpropanoic acid N as a pale yellow solid (542 mg, 85%). 1 1H NMR (400 MHz, CDCl3) 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 6AChemical reaction (a); see also: Chemical reaction (a) in Figure 3B(i) further below).

[0567] Reference Figure 6B , phenylpropionic acid N (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 one hour (the materials dissolved slowly) before adding pyrrolidine (173 μL, 2.06 mmol). 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 EtOA. The aqueous phase was extracted with ethyl acetate (3 × 30 mL), all the organic layers were combined, 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 afford the pure product MM716 (205 mg, 80%) as a colorless oil. LRMS-HESI: For [M+H] + Calculated value is 248.13 m / z, found value is 248.16. 1 1H NMR (400 MHz, CDCl3) 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) further below).

[0568] It should be noted that MM716 corresponds to compound F(III):

[0569]

[0570] 5-HT receptor radioligand competition assay. In addition to evaluating compounds of formula F(III) in place of compounds of formula B(II), the activity at the 5-HT 1A and 5-HT 2A receptors was evaluated as described for Example 2. Table 1 shows the results of the radioligand competition assay for the positive control, negative control, and compounds of formula F(III) in the form of K i values. Considering the results of both the positive control and negative control, where the data from the negative control were insufficient for reliable K i calculation (i.e., Ki > 1000 μM), for the compounds of formula D(I) at the 5-HT 1A receptor, the obtained K i value (> 1000 μM, Table 1) indicates little or no ligand-receptor binding. In contrast, for the compounds of formula F(III) at the 5-HT 2A receptor, the obtained K i value (152 μM, Table 1) indicates ligand-receptor binding.

[0571] In vitro investigation of the pharmacological interaction profiles of receptors and transporters relevant to the target health condition.

[0572] Evaluate the binding and / or interaction of compounds of formula F(III) at 11 different receptors and transporters that have known or suspected links to mental health conditions and / or neuropathologies. This study was conducted 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 on the interaction of the derived molecules with the following 8 G protein-coupled receptors (GPCRs): HTR1A (5-HTR 1A ), HTR2A (5-HTR 2A ), HTR2B (5-HT 2B ), HTR2C (5-HT 2C ), HTR7 (5-HT7), α2A (α 2A ), MT1 (MT1), D3 (D3)) and 3 transporters (SERT, DAT, NET) were generated. The assays were performed using the same materials and procedures outlined in Example 2, except that the compounds of formula F(III) were used instead of the compounds of formula B(II). The overall assay conditions for the GPCRs and transporters are summarized in Tables 3 and 4, respectively. The results of all calibrator compounds, control compounds, and test compounds (including the compounds of formula F(III)) are summarized in Table 5.

[0573] Example 4 - Preparation of the Fourth N - propylamine - fused Heterocyclic Mescaline Derivative

[0574] Reference Figure 7A, triethylamine (917 μL, 6.55 mmol) was added dropwise to formic acid (618 μL, 16.4 mmol) at 0 °C. Subsequently, 6-bromo-1,3-benzodioxole-5-carbaldehyde (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 whole mixture was dissolved in DMF (19.8 mL). The flask was heated to 105 °C and CO2 was slowly released from the reaction mixture. After 3 hours, the mixture was cooled back to room temperature and 40 mL of cold water was added. The pH was adjusted to about 2 with 1 M aqueous HCl, and the aqueous phase was extracted with EtOAc (4 × 30 mL). All the 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 afford pure compound O (611 mg, 68%) as a light brown solid. 1 H NMR (400 MHz, CDCl3) 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 further Figure 3B(i)).

[0575] Reference Figure 7B , phenylpropanoic acid O (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 one hour (the materials slowly dissolved) before adding pyrrolidine (123 μL, 1.46 mmol). 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), all the organic layers were combined, washed with 0.1 M HCl, water, brine, and dried over MgSO4. After filtration and evaporation of the solvent, the crude material was purified by FC on silica gel (12 g, DCM / MeOH 100∶0 to 90∶10) to afford pure product MM717 (180 mg, 75%) as a white solid. LRMS-HESI: For [M+H] + Calculated value is 328.04 m / z, found value is 327.98. 11H NMR (400 MHz, CDCl3) δ 6.97 (s, 1H), 6.81 (s, 1H), 5.93 (s, 2H), 3.46 (br t, J = 6.9 Hz, 2H), 3.35 (br t, 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 Chemical reaction (c); see also: further chemical reactions (c1) in Figures 3B(i) and 3B(ii).

[0576] It should be noted that MM717 corresponds to compound F(IV):

[0577]

[0578] 5-HT receptor radioligand competition assay. In addition to evaluating compounds of formula F(IV) in place of compounds of formula B(II), the activity at the 5-HT 1A receptor was evaluated as described for Example 2. Table 1 shows the results of the radioligand competition assay for the positive control, negative control, and compounds of formula F(IV) in the form of K i values. Given the results of both the positive control and negative control, where the data from the negative control were insufficient for reliable K i calculation (i.e., K i > 1000 μM), the K 1A value (84.5 μM, Table 1) obtained for the compounds of formula F(IV) at the 5-HT i receptor indicates ligand-receptor binding.

[0579] In vitro investigation of the pharmacological interaction profiles of receptors and transporters related to target health conditions.

[0580] The binding and / or interaction of compounds of formula F(IV) at 11 different receptors and transporters, which have known or suspected links to mental health conditions and / or neuropathologies, was evaluated. This study was conducted by the contract research organization (CRO) Eurofins Cerep (Cell L’Evescault, France) using standard assay procedures (https: / / www.eurofinsdiscovery.com / solution / target-based-assays). Profiles were generated for the following 8 G protein-coupled receptor (GPCR) receptors: HTR1A (5-HTR 1A ), HTR2A (5-HTR 2A ), HTR2B (5-HT2B )、HTR2C (5-HT 2C )、HTR7 (5-HT7), α2A (α 2A )、MT1 (MT1), D3 (D3)) and data on the interaction of three transporters (SERT, DAT, NET). The assays were performed using the same materials and procedures outlined in Example 2, except that the compound of formula F(IV) was used in place of the compound of formula B(II). The overall assay conditions for the GPCRs and transporters are summarized in Tables 3 and 4, respectively. The results for all calibrator compounds, control compounds, and test compounds (including the compound of formula F(IV)) are summarized in Table 5.

[0581] Example 5 - Preparation of the Fifth N - propylamine - fused Heterocyclic Mescaline Derivative

[0582] Reference 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 added carefully, and the mixture was warmed to room temperature and allowed to react overnight. The mixture was cooled to 0 °C, and the excess LiAlH4 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). All organic layers were combined, washed with brine, dried (MgSO4), 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 afford the desired product MM719 (91.0 mg, 64%) as a colorless oil. LRMS-HESI: For [M+H] + Calculated value is 234.15 m / z, found value is 234.12. 1 1H NMR (400 MHz, CDCl3) 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 further Figure 3B(ii)).

[0583] It should be noted that MM719 corresponds to compound C(III):

[0584]

[0585] 5-HT receptor radioligand competition assay. In addition to evaluating a compound of formula C(III) in place of a compound of formula B(II), activity at the 5-HT 1A receptor was evaluated as described for Example 2. Table 1 shows the results of the radioligand competition assay for the positive control, negative control, and compounds of formula C(III) in the form of K i values. Given the results for both the positive control and negative control, where the data generated for the negative control were insufficient for reliable K i calculation (i.e., K i > 1000 μM), the K 1A value (2.33 μM, Table 1) obtained for the compounds of formula C(III) at the 5-HT i receptor indicates ligand-receptor binding.

[0586] In vitro investigation of the pharmacological interaction profiles of receptors and transporters relevant to target health conditions.

[0587] The binding and / or interaction of compounds of formula C(III) was evaluated at 11 different receptors and transporters that have known or suspected links to mental health conditions and / or neuropathologies. This study was conducted 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 generated on the interaction of the derived molecules with the following 8 G protein-coupled receptors (GPCRs): HTR1A (5-HTR 1A ), HTR2A (5-HTR 2A ), HTR2B (5-HT 2B ), HTR2C (5-HT 2C ), HTR7 (5-HT7), α2A (α 2A ), MT1 (MT1), D3 (D3)), and 3 transporters (SERT, DAT, NET). The assays were performed using the same materials and procedures outlined in Example 2, except that a compound of formula C(III) was used in place of a compound of formula B(II). The overall assay conditions for the GPCRs and transporters are summarized in Tables 3 and 4, respectively. The results for all calibrator compounds, control compounds, and test compounds (including compounds of formula C(III)) are summarized in Table 5.

[0588] Example 6 - Preparation of the Sixth N - propylamine - fused Heterocyclic Mescaline Derivative

[0589] ReferenceFigure 9 , Compound MM719 (70.0 mg, 300 μmol) (prepared as described in Example 5) was dissolved in acetic acid (1.58 mL). A solution of bromine (25.0 μL, 486 μmol) in acetic acid (250 μL) was added thereto. The reaction mixture was allowed to react at room temperature for 3 hours, at which time no starting material remained (TLC, DCM / MeOH 9:1). The mixture was poured into water (15 mL), and the pH was increased to approximately 10 with 1 M aqueous NaOH. The aqueous layer was extracted with DCM (3 × 25 mL), all organic layers were combined, washed with water and 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 afford MM720 (65.1 mg, 69%) as a colorless oil. LRMS-HESI: For [M+H] + , calculated value is 312.06 m / z, found value is 312.05. 1 1H NMR (400 MHz, CDCl3) 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) further below).

[0590] It should be noted that MM720 corresponds to compound C(IV):

[0591]

[0592] 5-HT receptor radioligand competition assay. In addition to evaluating compounds of formula C(IV) instead of compounds of formula B(II), the activity at the 5-HT 1A receptor was evaluated as described for Example 2. Table 1 shows the results of the radioligand competition assay for the positive control, negative control, and compounds of formula C(IV) in terms of K i values. Given the results for both the positive control and negative control, where the data from the negative control were insufficient for reliable K i calculation (i.e., K i > 1000 μM), the K 1A value (0.596 μM, Table 1) obtained for the compounds of formula C(IV) at the 5-HT i receptor indicates ligand-receptor binding.

[0593] In vitro investigation of the pharmacological interaction profiles of receptors and transporters relevant to the target health condition.

[0594] Assess the binding and / or interaction of compounds of formula C(IV) at 11 different receptors and transporters that have a known or suspected link to mental health conditions and / or neuropathologies. This study was conducted 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 generated on the interaction of the derived molecule with the following 8 G protein-coupled receptor (GPCR) receptors: HTR1A (5-HTR 1A ), HTR2A (5-HTR 2A ), HTR2B (5-HT 2B ), HTR2C (5-HT 2C ), HTR7 (5-HT7), α2A (α 2A ), MT1 (MT1), D3 (D3)), and 3 transporters (SERT, DAT, NET). The assays were conducted using the same materials and procedures outlined in Example 2, except that compounds of formula C(IV) were used in place of compounds of formula B(II). The overall assay conditions for the GPCRs and transporters are summarized in Tables 3 and 4, respectively. The results for all calibrator compounds, control compounds, and test compounds (including compounds of formula C(IV)) are summarized in Table 5.

[0595] Example 7 - Preparation of the Seventh N - propylamine - fused Heterocyclic Mescaline Derivative

[0596] Reference Figure 10 , under a nitrogen atmosphere, 10 wt% palladium on carbon (20.4 mg, 192 mmol) was added to a solution of MM710 (47.0 mg, 192 mmol) (prepared as described in Example 2) in ethanol (1.92 mL). H2 gas (balloon) was bubbled through the mixture for 15 minutes until a hydrogen atmosphere was established, and then the mixture was placed under hydrogen for 36 h. The catalyst was removed via a 0.45 mm syringe filter, and the filter was then washed with methanol (3 mL). The filtrate was concentrated under reduced pressure. Purification by FC on silica gel (4 g, 0 to 10% MeOH / DCM) yielded MM730 (racemate) as a white powder (16.8 mg, 34%). LRMS-HESI: Calculated for [M+H] + 248.16 m / z, found 248.20. 11H NMR (400 MHz, CDCl3) 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 The chemical reaction (g2); see also: the chemical reaction (g) in Figure 3A(ii) further below).

[0597] It should be noted that MM730 corresponds to compound A(II):

[0598]

[0599] 5-HT receptor radioligand competition assay. In addition to evaluating compounds of formula A(II) in place of compounds of formula B(II), the activity at the 5-HT 1A receptor was evaluated as described for Example 2. Table 1 shows the results of the radioligand competition assay for the positive control, negative control, and compounds of formula A(II) in the form of K i values. Given the results for both the positive control and negative control, where the data from the negative control were insufficient for reliable K i calculation (i.e., K i > 1000 μM), the K 1A values obtained for compounds of formula A(II) at the 5-HT i receptor (8.0 μM, Table 1) indicate ligand-receptor binding.

[0600] In vitro investigation of the pharmacological interaction profiles of receptors and transporters relevant to the target health condition.

[0601] The binding and / or interaction of compounds of formula A(II) at 11 different receptors and transporters known or suspected to be linked to mental health conditions and / or neuropathologies was evaluated. This study was conducted by the contract research organization (CRO) Eurofins Cerep (Cell L’Evescault, France) using standard assay procedures (https: / / www.eurofinsdiscovery.com / solution / target-based-assays). Profiles were generated for the following 8 G protein-coupled receptors (GPCRs): HTR1A (5-HTR1A ), HTR2A (5-HTR 2A ), HTR2B (5-HT 2B ), HTR2C (5-HT 2C ), HTR7 (5-HT7), α2A (α 2A ), MT1 (MT1), D3 (D3)) and data on the interaction of three transporters (SERT, DAT, NET). The assays were conducted using the same materials and procedures outlined in Example 2, except that the compound of formula A(II) was used in place of the compound of formula B(II). The overall assay conditions for the GPCRs and transporters are summarized in Tables 3 and 4, respectively. The results for all calibrator compounds, control compounds, and test compounds (including the compound of formula A(II)) are summarized in Table 5.

[0602] Example 8 - Preparation of the Eighth N - propylamine - fused Heterocyclic Mescaline Derivative

[0603] Reference Figure 11 , under a nitrogen atmosphere, 10 wt% palladium on carbon (20.5 mg, 0.0193 mmol) was added to a solution of MM709 (45.0 mg, 193 mmol) (prepared as described in Example 1) in ethanol (1.93 mL). H2 gas (balloon) was bubbled through the mixture for 15 minutes until a hydrogen atmosphere was established, and then the mixture was left under hydrogen with vigorous stirring for 36 h. The catalyst was removed via a 0.45 mm syringe filter, and then the filter was washed with methanol (3 mL). The filtrate was concentrated under reduced pressure. Purification by FC on silica gel (4 g, 0 to 10% MeOH / DCM) gave MM731 (12.6 mg, 28%) as a white powder. LRMS-HESI: For [M+H] + calculated value is 236.16 m / z, found value is 236.17. 1 H NMR (400 MHz, CDCl3) 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 of the chemical reaction (h); see also: the chemical reaction (h) in further Figure 3A(ii)).

[0604] It should be noted that MM731 corresponds to compound C(I):

[0605]

[0606] 5-HT receptor radioligand competition assay. In addition to evaluating the replacement of the compound of formula C(I) with the compound of formula B(II), the activity at the 5-HT 1A receptor was evaluated as described for Example 2. Table 1 shows the results of the radioligand competition assay of the positive control, negative control, and the compound of formula C(I) in the form of K i values. Given the results of both the positive control and the negative control, where the data generated by the negative control were insufficient for reliable K i calculation (i.e., K i > 1000 μM), the K 1A value (2.9 μM, Table 1) obtained for the compound of formula C(I) at the 5-HT i receptor indicates ligand-receptor binding.

[0607] In vitro investigation of the pharmacological interaction profiles of receptors and transporters related to the target health condition.

[0608] The binding and / or interaction of the compound of formula C(I) at 11 different receptors and transporters, which have known or suspected associations with mental health conditions and / or neuropathologies, were evaluated. This study was conducted 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 on the interaction of the derived molecule with the following 8 G protein-coupled receptors (GPCRs): HTR1A (5-HTR 1A ), HTR2A (5-HTR 2A ), HTR2B (5-HT 2B ), HTR2C (5-HT 2C ), HTR7 (5-HT7), α2A (α 2A ), MT1 (MT1), D3 (D3)) and 3 transporters (SERT, DAT, NET) were generated. The assays were performed using the same materials and procedures outlined in Example 2, except that the compound of formula C(I) was used in place of the compound of formula B(II). The overall assay conditions for GPCRs and transporters are summarized in Tables 3 and 4, respectively. The results of all calibrator compounds, control compounds, and test compounds (including the compound of formula C(I)) are summarized in Table 5.

[0609] Example 9 - Preparation of the Ninth N - propylamine - fused Heterocyclic Mescaline Derivative

[0610] Reference Figure 12A, triethylamine (933 μL, 6.66 mmol) was added dropwise to formic acid (628 μL, 16.7 mmol) at 0 °C. Subsequently, 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 whole mixture was dissolved in DMF (20.2 mL). The flask was heated to 105 °C, and CO2 was slowly released from the reaction mixture. After 3 hours, the mixture was cooled back to room temperature, and 40 mL of cold water was added. The pH was adjusted to about 2 with 1 M aqueous HCl, and the aqueous phase was extracted with EtOAc (4 × 30 mL). All the 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, CDCl3) 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 The chemical reaction (a); see also: the chemical reaction (a) in Figure 3B(i) further below).

[0611] See Figure 12B , phenylpropionic 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 one hour (the materials slowly dissolved) before adding pyrrolidine (120 μL, 1.43 mmol). 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), all the organic layers were combined, washed with 0.1 M HCl, water, brine, and dried over MgSO4. After filtering and evaporating 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 light orange solid. LRMS-HESI: For [M + H] + Calculated value is 278.14 m / z, found value is 278.13. 1HNMR (400 MHz, CDCl3) δ 6.70 (s, 1H), 6.50 (s, 1H), 5.88 (s, 2H), 3.76 (s, 3H), 3.48 - 3.34 (br m, 4H), 2.90 - 2.86 (m, 2H), 2.52 - 2.48 (m, 2H), 1.86 (br m, 4H) ( Figure 12B Chemical reaction (c); see also: further chemical reactions (c1) in Figures 3B(i) and 3B(ii).

[0612] It should be noted that MM735 corresponds to compound F(V):

[0613]

[0614] 5-HT receptor radioligand competition assay. In addition to evaluating compounds of formula F(V) in place of compounds of formula B(II), the activity at the 5-HT 1A receptor was evaluated as described for Example 2. Table 1 shows the results of the radioligand competition assay for the positive control, negative control, and compounds of formula F(V) in the form of K i values. Given the results of both the positive control and negative control, where the data from the negative control were insufficient for reliable K i calculation (i.e., K i > 1000 μM), the K 1A values obtained for compounds of formula F(V) at the 5-HT i receptor (363.5 μM, Table 1) indicate ligand-receptor binding.

[0615] 5-HT 1A receptor functional cell response assay. In addition to evaluating compounds of formula F(V) in place of compounds of formula B(II), the functional engagement of the 5-HT 1A receptor within an engineered cell system was evaluated as described for Example 2. Table 2 shows the results of the functional assays for the positive control, calibrator, and compounds of formula F(V) in the form of EC 50 values. Given the results of the control and calibrator compounds, where the negative cell response corresponded to an EC 50 value > 1000 μM, in this assay, the EC 50 value of the compound of formula F(V) (10.0 μM, Table 2) indicates ligand-receptor engagement.

[0616] In vitro investigation of the pharmacological interaction profiles of receptors and transporters relevant to target health conditions.

[0617] Evaluate the binding and / or interaction of compounds of formula F(V) at 11 different receptors and transporters that have a known or suspected link to mental health conditions and / or neuropathologies. This study was conducted 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 generated on the interaction of the derived molecules with the following 8 G protein-coupled receptor (GPCR) receptors: HTR1A (5-HTR 1A ), HTR2A (5-HTR 2A ), HTR2B (5-HT 2B ), HTR2C (5-HT 2C ), HTR7 (5-HT7), α2A (α 2A ), MT1 (MT1), D3 (D3)), and 3 transporters (SERT, DAT, NET). The assays were performed using the same materials and procedures outlined in Example 2, except that compounds of formula F(V) were used instead of compounds of formula B(II). The overall assay conditions for the GPCRs and transporters are summarized in Tables 3 and 4, respectively. The results for all calibrator compounds, control compounds, and test compounds (including compounds of formula F(V)) are summarized in Table 5.

[0618] Example 10 - Preparation of the Tenth N - propylamine - fused Heterocyclic Mescaline Derivative

[0619] Reference 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 added carefully, and the mixture was warmed to room temperature and allowed to react overnight. The mixture was cooled to 0 °C, and the excess LiAlH4 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). All the organic layers were combined, washed with brine, dried (MgSO4), 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 afford the desired product MM736 (70.0 mg, 61%) as a colorless oil. LRMS-HESI: Calculated for [M+H] + 264.16 m / z, found 264.15.1 1H NMR (400 MHz, CDCl3) 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 (br s, 6H) ( Figure 13 Chemical reaction (d); see also chemical reaction (d) in further Figure 3B(ii).

[0620] It should be noted that MM736 corresponds to compound C(V):

[0621]

[0622] 5-HT receptor radioligand competition assay. In addition to evaluating compounds of formula C(V) in place of compounds of formula B(II), the activity at the 5-HT 1A receptor was evaluated as described for Example 2. Table 1 shows the results of the radioligand competition assay for the positive control, negative control, and compounds of formula C(V) in the form of K i values. Given the results of both the positive control and negative control, where the data from the negative control were insufficient for reliable K i calculation (i.e., K i > 1000 μM), the K 1A values obtained for compounds of formula C(V) at the 5-HT i receptor (5.0 μM, Table 1) indicate ligand-receptor binding.

[0623] 5-HT 1A receptor functional cell response assay. In addition to evaluating compounds of formula C(V) in place of compounds of formula B(II), the functional engagement of the 5-HT 1A receptor within an engineered cell system was evaluated as described for Example 2. Table 2 shows the results of the functional assay for the positive control, calibrator, and compounds of formula C(V) in the form of EC 50 values. Given the results of the control and calibrator compounds, where the negative cell response corresponded to an EC 50 value > 1000 μM, in this assay, the EC 50 value of the compound of formula C(V) (116.3 μM, Table 2) indicates ligand-receptor engagement.

[0624] In vitro investigation of the pharmacological interaction profiles of receptors and transporters relevant to the target health condition.

[0625] Evaluate the binding and / or interaction of compounds of formula C(V) at 11 different receptors and transporters that have a known or suspected link to mental health conditions and / or neuropathologies. This study was conducted 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 was generated on the interaction of the derived molecule with the following 8 G protein-coupled receptor (GPCR) receptors: HTR1A (5-HTR 1A ), HTR2A (5-HTR 2A ), HTR2B (5-HT 2B ), HTR2C (5-HT 2C ), HTR7 (5-HT7), α2A (α 2A ), MT1 (MT1), D3 (D3)), and 3 transporters (SERT, DAT, NET). The assays were performed using the same materials and procedures outlined in Example 2, except that compounds of formula C(V) were used instead of compounds of formula B(II). The overall assay conditions for the GPCRs and transporters are summarized in Tables 3 and 4, respectively. The results for all calibrator compounds, control compounds, and test compounds (including compounds of formula C(V)) are summarized in Table 5.

[0626] Example 11 - Preparation of the Eleventh N - propylamine - fused Heterocyclic Mescaline Derivative

[0627] Reference Figure 17 , under a nitrogen atmosphere, benzylamine (248 μL, 2.27 mmol) was added to a solution of K (216 mg, 1.14 mmol) (prepared as described in Example 2) in MeOH (7.57 mL). 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 of 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: calculated for [M+H] + 282.15 m / z, found 282.23 m / z. 11H NMR (400 MHz, CDCl3) 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 For the chemical reaction (f), see also the chemical reaction (f) in Figure 3A(i).

[0628] It should be noted that MM754 corresponds to compound B(IV):

[0629]

[0630] Example 12 - Preparation of the Twelfth N - propylamine - fused Heterocyclic Mescaline Derivative

[0631] Reference Figure 18 , in a capped vial of rated pressure, 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 for 18 h with an exhaust needle. MS indicated completion of the reaction. The reaction mixture was diluted with water (20 mL), basified with 15% NaOH until the pH was about 12, and extracted with DCM (3 × 20 mL). The combined organic extracts were 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 of normal-phase silica gel using a 0 to 10% methanol-dichloromethane eluent gradient gave MM755 (48.3 mg, 43%) as a colorless oil. LRMS-HESI: For [M+H] + Calculated value is 296.16 m / z, measured value is 296.22 m / z. 1 1H NMR (400 MHz, CDCl3) 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 For the chemical reaction (i), see also the chemical reaction (i) in Figure 3A(i).

[0632] It should be noted that MM755 corresponds to compound B(III):

[0633]

[0634] Example 13 - Preparation of the Thirteenth N - propylamine - fused Heterocyclic Mescaline Derivative

[0635] Reference Figure 19A , at 0 °C under an inert atmosphere, a solution of triethyl 2-phosphonopropionate (1.44 mL, 6.51 mmol) in dry THF (7.90 mL) was added to a suspension of sodium hydride (261 mg, 6.51 mmol) in dry THF (3.95 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 allowed to warm slowly to room temperature and stirring was continued for 18 h. Water (5 mL) was added to the stirred mixture and the organic solvents were removed under reduced pressure. The aqueous residue was extracted with ethyl acetate (3 × 25 mL) and the combined organic extracts were dried over magnesium sulfate and the solvent was removed under reduced pressure. Purification by dry load column chromatography on 25 g of normal phase silica using a 0 to 7% ethyl acetate - hexane eluent gradient provided the intermediate 20 (1.19 g, 85%) as a colorless oil. LRMS-HESI: For [M+H] + Calculated 271.08 m / z, found 271.10 m / z. 1 H NMR (400 MHz, CDCl3) 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 For the chemical reaction (d), see also: the chemical reaction (d) in further Figure 3A(i)).

[0636] Reference Figure 19B, under a nitrogen atmosphere, in a flame-dried flask at -78 °C, lithium aluminum hydride (352 mg, 8.81 mmol) was suspended in anhydrous THF (22.0 mL). A solution of intermediate 20 (1.19 g, 4.40 mmol) in anhydrous THF (22.0 mL) was added to the suspension, and the reaction mixture was allowed to stir at the same temperature for 5 h. By LCMS, the reaction was incomplete, so more dry ice was added and the warming 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 allowed to stir for 15 minutes. Anhydrous magnesium sulfate was added, and the suspension was mixed for an additional 15 minutes. The suspension was filtered, and the 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 of normal-phase silica using a 0 to 15% ethyl acetate - hexane gradient gave a colorless oil (890 mg) after collecting fractions. This material was quickly used in the next step. Manganese(IV) oxide (1.17 g, 13.3 mmol) was added to a solution of the colorless oil (575 mg) in DCM (16.6 mL), and the reaction mixture was stirred for 18 h. After MS confirmed the formation of the product, 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 gave intermediate R as a white solid (376 mg, 54% over 2 steps). LRMS-HESI: For [M+H] + Calculated 227.05 m / z, found 227.03 m / z. 1 H NMR (400 MHz, CDCl3) 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 For the chemical reaction (e), see also: the chemical reaction (e) in Figure 3A(i) further below).

[0637] Refer to Figure 19C, under a nitrogen atmosphere, pyrrolidine (228 μL, 2.72 mmol) was added to a solution of intermediate R (308 mg, 1.36 mmol) in MeOH (13.6 mL). The reaction mixture was heated to 60 °C for 4 h, then cooled to room temperature, and then sodium cyanoborohydride (360 mg, 5.45 mmol) was added. The reaction mixture was allowed to stir at the same temperature for 18 h 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 of normal-phase silica using a slow 0 - 4% methanol - dichloromethane eluent gradient gave MM775 (42 mg, 11%) as a yellow oil. LRMS - HESI: For [M + H] + Calculated 282.13 m / z, found 282.12 m / z. 1 H NMR (400 MHz, CDCl3) 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 For the chemical reaction (f), see also the chemical reaction (f) in Figure 3A(i)).

[0638] It should be noted that MM775 corresponds to compound B(V):

[0639]

[0640] Example 14 - Preparation of the Fourteenth N - propylamine - fused Heterocyclic Mescaline Derivative

[0641] Reference Figure 20, under a nitrogen atmosphere, J (242 mg, 1.37 mmol) (prepared as described in Example 1) was dissolved in MeOH (13.7 mL). Acetic acid (197 μL, 3.43 mmol) was added, and the solution was allowed to stir for 5 minutes, then butylamine (363 mg, 2.75 mmol) was added. The reaction was heated to 60 °C for 4 h, 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 × 10 mL). The combined organic phases were 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 viscous solid. Purification by column chromatography on 4 g of normal-phase silica using a 0 to 10% methanol - dichloromethane eluent gradient gave an impure product. Second purification by column chromatography on 4 g of normal-phase silica using a 5% methanol - dichloromethane eluent system gave MM756 (98.7 mg, 31%) as an off-white solid. LRMS - HESI: For [M + H] + Calculated 234.14 m / z, found 234.07 m / z. 1 H NMR (400 MHz, CDCl3) δ 6.92 (d, J = 1.7 Hz, 1H), 6.80 (ddd, J = 8.0, 1.7, 0.5 Hz, 1H), 6.73 (d, J = 7.9 Hz, 1H), 6.52–6.44 (m, 1H), 6.15 (dt, J = 15.8, 6.7 Hz, 1H), 5.92 (s, 2H), 3.46 (dd, J = 6.7, 1.4 Hz, 2H), 2.75–2.68 (m, 2H), 1.66–1.54 (m, 2H), 1.36 (dq, J = 14.6, 7.4 Hz, 2H), 0.91 (t, J = 7.4 Hz, 3H). ( Figure 20 For the chemical reaction (c), see also: the chemical reaction (c) in Figure 3A(ii)).

[0642] It should be noted that MM756 corresponds to compound D(II):

[0643]

[0644] Example 15 - Preparation of the Fifteenth N - propylamine - fused Heterocyclic Mescaline Derivative

[0645] Refer to Figure 21, under a nitrogen atmosphere, 10 wt% palladium on carbon (26.1 mg, 0.0245 μmol) was added to a solution of MM756 (57.2 mg, 245 μmol) (prepared as described in Example 14) in denatured ethanol (4.90 mL). Hydrogen was bubbled through the solution for 10 minutes, and then the atmosphere was established. The reaction mixture was allowed to stir for 50 minutes, at which point LCMS indicated completion of the reaction. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to afford MM761 (52.4 mg, 91%) as a pale yellow solid. LRMS-HESI: For [M+H] + Calculated 236.16 m / z, found 236.17 m / z. 1 H NMR (400 MHz, CDCl3) 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 For the chemical reaction (h), see also the chemical reaction (h) in Figure 3A(ii)).

[0646] It should be noted that MM761 corresponds to compound C(II):

[0647]

[0648] Example 16 - Preparation of the Sixteenth N - propylamine - fused Heterocyclic Mescaline Derivative

[0649] Refer to Figure 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 one hour (the materials slowly dissolved) before adding ethanolamine (157 μL, 2.57 mmol). The reaction was stirred overnight at room temperature. In the morning, the main 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 the 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 purified on a CombiFlash system (12 g of silica, DCM∶MeOH 100∶0 to 90∶10) to afford MM715 (120 mg, 39%) as a colorless solid. LRMS-HESI: For [M+Na] + Calculated value is 260.09 m / z, measured value is 260.08 m / z, for [M+H] + Calculated value is 238.11 m / z, measured value is 238.09. 1 H NMR (400 MHz, CDCl3) 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 (br s, 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 For the chemical reaction (c1), see also: the chemical reaction (c1) in Figure 3B(ii) further below).

[0650] Reference Figure 22B, MM715 (500 mg, 2.11 mmol) was added to a round-bottom flask, 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 warmed to room temperature and allowed to react overnight. Monitoring by TLC (UV-vis, DCM∶MeOH 9∶1) showed that the starting material had disappeared. The reaction was cooled to 0 °C and diluted with ether (20 mL). 320 μL of water was added thereto, and after the vigorous bubbling had ceased, 320 μL of 15% aqueous NaOH was added, and finally an additional 960 μL of water was added. After stirring for 10 minutes, the mixture was dried over MgSO4, filtered, and concentrated to leave a colorless oil. The material was subjected to FC (12 g silica, DCM∶MeOH 100∶0 to 85∶15) to afford MM781 (281 mg, 60%) as a colorless solid. LRMS-HESI: for [M+H] + Calculated 224.13 m / z, found 224.10 m / z. 1 H NMR (400 MHz, CDCl3 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 For the chemical reaction (d), see also the chemical reaction (d) in further Figure 3B(ii).

[0651] It should be noted that MM781 corresponds to compound C(X):

[0652]

[0653] Example 17 - Preparation of the Seventeenth N - propylamine - fused Heterocyclic Mescaline Derivative

[0654] Refer 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 the addition of anhydrous THF (2.68 mL) and DMF (669 μL). The resulting mixture was stirred for one hour (the materials dissolved slowly) before the addition of ethanolamine (245 μL, 4.01 mmol). The reaction was stirred overnight at room temperature. In the morning, the 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 the 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 purified by flash chromatography (12 g of silica, DCM∶MeOH 100∶0 to 90∶10) to afford the pure product MM776 (156 mg, 44%) as a colorless solid. LRMS-HESI: For [M+Na] + Calculated for 290.10 m / z, found 290.07 m / z, for [M+H] + Calculated for 268.12 m / z, found 268.13 m / z. 1 H NMR (400 MHz, CDCl3) δ 6.65 (s, 1H), 6.50 (s, 1H), 5.97 (br s, 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 (br s, 1H), 2.44 (t, J = 7.6 Hz, 2H). ( Figure 23 For the chemical reaction (c1), see also: the chemical reaction (c1) in further Figure 3B(ii)).

[0655] It should be noted that MM776 corresponds to compound F(VI):

[0656]

[0657] Example 18 - Preparation of the Eighteenth N - propylamine - fused Heterocyclic Mescaline Derivative

[0658] Refer to Figure 24, MM776 (75.0 mg, 281 μmol) (prepared as described in Example 17) was added to a round-bottom flask, 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 warmed to room temperature and allowed to react overnight. Monitoring by TLC (UV-vis, DCM∶MeOH 9∶1) showed that the starting material had disappeared. The reaction was cooled to 0 °C and diluted with ether (4 mL). 40 μL of water was added thereto, and after the vigorous bubbling had ceased, 40 μL of 15% aqueous NaOH was added, and finally 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: For [M+H] + Calculated 254.14 m / z, found 254.14 m / z. 1 H NMR (400 MHz, CDCl3) 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 For the chemical reaction (d), see also the chemical reaction (d) in Figure 3B(ii)).

[0659] It should be noted that MM780 corresponds to compound C (XII):

[0660]

[0661] Example 19 - Preparation of the Nineteenth N - propylamine - fused Heterocyclic Mescaline Derivative

[0662] Refer to Figure 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 one hour (the materials dissolved slowly) before adding ethanolamine (255 μL, 4.17 mmol). The reaction was stirred overnight at room temperature. In the morning, the main 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 the 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 purified via FC (12 g of silica, DCM∶MeOH 100∶0 to 90∶10) to afford the pure product as a colorless solid, Intermediate T (246 mg, 56%). LRMS-HESI: Calculated for [M+Na] + is 338.00 m / z, found 397.97 m / z, for [M+H] + Calculated is 316.02 m / z, found 316.02 m / z. 1 H NMR (400 MHz, CDCl3) δ 6.97 (s, 1H), 6.74 (s, 1H), 6.02 (br s, 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 For the chemical reaction (c1) of (

[0663] See also further the chemical reaction (c1) in Figure 3B(ii)). Figure 25B, Intermediate T (90.0 mg, 285 μmol) was added to a round-bottom flask, dissolved in dry THF (2.59 mL), and cooled to 0 °C. Once cooled, 1 M borane-THF complex in THF (1.71 mL, 1.71 mmol) was carefully added, and the mixture was heated to reflux for 4 h. At this point, LCMS determined that significant conversion had occurred, and the mixture was cooled to 0 °C. The excess borane was carefully quenched with saturated sodium bicarbonate solution, and the resulting mixture was poured into a separatory funnel containing 5 mL DCM and 5 mL water. The aqueous layer was extracted with DCM (3 × 5 mL), all the organic layers were combined, washed with brine, dried (MgSO4), filtered, and concentrated to give the crude material. Purification by FC (4 g silica, DCM∶MeOH 100∶0 to 85∶15) provided the pure material MM782 (28.4 mg, 33%) as a colorless gummy solid. LRMS-HESI: For [M+H] + Calculated 302.04 m / z, found 302.01 m / z. 1 1H NMR (400 MHz, CDCl3) 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 For the chemical reaction (i), see: also further the chemical reaction (i) in Figure 3B (ii)).

[0664] It should be noted that MM782 corresponds to compound C (XIII):

[0665]

[0666] 5-HT 1A receptor functional cell response assay. In addition to evaluating the engineered cell system for 5-HT within the engineered cell system by evaluating a compound having formula C (XIII) instead of a compound having formula B (II), 1A receptor functional engagement. Table 2 shows the results of the functional assays for the positive control, calibrator, and compound having formula C (XIII) in the form of EC 50 values. Given the results of the control and calibrator compounds, where the negative cell response corresponds to an EC 50 value > 1000 μM, in this assay, the EC 50 value (22.95 μM, Table 2) of the compound having formula C (XIII) indicates ligand-receptor engagement.

[0667] Example 20 - Preparation of the Twentieth N - propylamine - fused Heterocyclic Mescaline Derivative

[0668] Reference Figure 26 , MM715 (95.0 mg, 400 μmol) (prepared as described in Example 16) was suspended in CHCl3 (3.09 mL). Thionyl chloride (88.5 μL, 1.20 mmol) was added thereto, and the mixture was stirred overnight at room temperature. The reaction was monitored in the morning by TLC (UV, 9:1 DCM:MeOH). It was determined that no starting material remained and a new, less polar compound had formed. The 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 × 10 mL). All the organic layers were combined, washed with water and brine, dried (MgSO4), filtered and concentrated to afford the intermediate aminoethyl chloride as a yellow powder (61.0 mg, 60%). LRMS-HESI: for [M+H] + Calculated value is 256.07 m / z, found value is 256.08 m / z. 1 1H NMR (400 MHz, CDCl3) δ 6.74 - 6.64 (m, 3H), 5.92 (s, 2H), 5.74 (br s, 1H), 3.58 - 3.56 (m, 4H), 2.89 (t, J = 7.5 Hz, 2H), 2.46 (t, J = 7.6 Hz, 2H). It was used in the next step without further purification. Aminoethyl chloride (47.0 mg, 184 μmol) and potassium carbonate (50.8 mg, 368 μmol) were added to a vial, followed by DMF (888 μL). The temperature was raised to 75 °C and the mixture was allowed to react overnight. The reaction was monitored in the morning by TLC (DCM:MeOH 9:1), and it was observed that the mixture did not contain 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 × 10 mL), all the organic layers were combined, washed with water and brine, dried (MgSO4) and filtered. The resulting brown oil was subjected to FC (4 g silica, DCM:MeOH 100:0 to 90:10) to afford the desired product MM779 as a colorless oil (9.6 mg, 24%). LRMS-HESI: for [M+H] + Calculated value is 220.10 m / z, found value is 220.07 m / z. 11H NMR (400 MHz, CDCl3) 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 For the chemical reaction (h), see also the chemical reaction (h) in Figure 3B(ii).

[0669] It should be noted that MM779 corresponds to compound G(I):

[0670]

[0671] Example 21 - Preparation of the Twenty - first N - propylamine - fused Heterocyclic Mescaline Derivative

[0672] Reference Figure 27 , the intermediate T (121 mg, 383 μmol) (prepared as described in Example 19) was suspended in CHCl3 (2.95 mL). Thionyl chloride (84.6 μL, 1.15 mmol) was added thereto, and the mixture was stirred overnight at room temperature. The reaction was monitored by TLC (DCM∶MeOH 9∶1) in the morning, and it was observed that the mixture did not contain the starting material. The excess thionyl chloride was quenched by adding 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 × 10 mL), and all the organic layers were combined, washed with water and brine, dried (MgSO4) and filtered. Concentration of the solution afforded the intermediate aminoethyl chloride product (86.3 mg, 67%) as a yellow solid. LRMS-HESI: For [M+H] + Calculated value is 333.98 m / z, found value is 333.96 m / z. 11H NMR (400 MHz, CDCl3) δ 6.99 (s, 1H), 6.75 (s, 1H), 5.95 (s, 2H), 5.76 (br s, 1H), 3.58 - 3.57 (m, 2H), 3.00 (t, J = 7.6 Hz, 2H), 2.47 (t, J = 7.6 Hz, 2H). It was used in the next step without further purification. Acetamidoethyl chloride (59.0 mg, 176 μmol) and potassium carbonate (48.7 mg, 353 μmol) were added to a vial, followed by DMF (852 μL). The temperature was raised to 75 °C and the mixture was allowed to react overnight. The reaction was monitored by TLC (DCM∶MeOH 9∶1) in the morning and it was observed that the mixture did not contain 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 × 10 mL), all the 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 afford the pure product MM778 (35.0 mg, 67%) as a pale yellow solid. LRMS - HESI: For [M + H] + Calculated 298.01 m / z, found 298.00 m / z. 1 1H NMR (400 MHz, CDCl3) 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 For the chemical reaction (h), see also: the chemical reaction (h) in further Figure 3B(iii)).

[0673] It should be noted that MM778 corresponds to compound G(I):

[0674]

[0675] 5 - HT 1A Receptor functional cell response assay. The functional engagement of the 5 - HT receptor within the engineered cell system was evaluated as described for Example 2, except that compounds having formula G(V) were evaluated in place of compounds having formula B(II). Table 2 shows the results of the functional assays for the positive control, calibrators and compounds having formula G(V) in terms of EC 1A values. Given the results of the control and calibrator compounds, where the negative cell response corresponds to EC 50 values 50Values > 1000 μM, in this assay, the EC 50 value (129.5 μM, Table 2) indicates ligand-receptor binding.

Claims

1. A compound having the formula (I) or (II): Among them, In formula (I) or (II): is a single bond or a 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, or R1 and R 1b and the carbon atom to which R1 is attached and R 1b which is attached to the nitrogen atom are joined together to form an optionally substituted saturated or unsaturated 3- to 10-membered heterocyclic ring, and when the heterocyclic ring is unsaturated, R 1a is optionally absent; R 1a and R 1b are each independently selected from an alkyl group, a hydroxyalkyl group, an optionally substituted alkyl-aryl group or a hydrogen atom, or R 1a and R 1b together with the nitrogen atom to which they are attached are joined to form an optionally substituted 3- to 10-membered heterocycle; and R2 and R3 are each independently selected from an alkyl group, an O-alkyl group, a hydrogen atom, or R2 and R3 are joined together with the oxygen atom and the carbon atom to which they are attached to form an ethylene oxide ring.

2. The compound according to claim 1, wherein the compound having formula (I) is a compound having formula (I a ) or (I b ), and the compound having formula (II) is a compound having formula (II a ) or (II b ): Among them, In chemical formula (I a ), (I b ), (II a ), or (II b ): 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, or R1 and R 1b and the carbon atom to which R1 is attached and R 1b are joined together to form an optionally substituted saturated or unsaturated 3- to 10-membered heterocycle, and when the heterocycle is unsaturated, R 1a is optionally absent; R 1a and R 1b are each independently selected from an alkyl group, a hydroxyalkyl group, an optionally substituted alkyl-aryl group or a hydrogen atom, or R 1a and R 1b are joined together with the nitrogen atom to which they are attached to form an optionally substituted 3- to 10-membered heterocycle; and R2 and R3 are each independently selected from an alkyl group, an O-alkyl group, a hydrogen atom, or R2 and R3 are joined together with the oxygen atom and the carbon atom to which they are attached to form an ethylene oxide ring.

3. The compound according to claim 2, wherein X4 is a (C1-C3)-alkylene group or a substituted (C1-C3)-alkylene group.

4. The compound according to claim 2, wherein X4 is a methylene group (-CH2-) or a substituted methylene group.

5. The compound according to claim 4, wherein the methylene group is substituted by at least one halogen.

6. The compound according to claim 4, wherein the substituted methylene group is substituted by two halogen substituents.

7. The compound according to claim 4, wherein the substituted methylene group is substituted by two identical halogen substituents and is optionally (-CF2-).

8. The compound according to claim 1, wherein the compounds having the formula (I a ), (I b ), (II a ) and (II b ) have the chemical formulas (I c ), (I d ), (II c ) or (II d ) respectively:

9. A compound according to any one of claims 1 to 8, wherein the amino group (-NR 1a R 1b ) is protonated to form (-N + HR 1a R 1b ), and the chemical formula (I), (II), (I a ), (I b ), (II a ), (II b ), (I c ), (I d ), (II c ) or (II d ) further comprises a negatively charged anion that balances the positively charged nitrogen atom.

10. The compound according to claim 1 or 8, wherein X1, X2, X3 are each a hydrogen atom (H).

11. The compound according to claim 1 or 8, wherein at least one of X1, X2, X3 is an O-alkyl group or a halogen.

12. The compound according to claim 1 or 8, wherein X3 is an O-alkyl group, optionally a methoxy group, or a halogen, optionally bromine.

13. The compound according to claim 1 or 8, wherein R2 and R3 are independently or simultaneously (C1-C6)-alkyl groups.

14. The compound according to claim 1 or 8, wherein R2 and R3 are independently or simultaneously (C1-C3)-alkyl groups.

15. The compound according to claim 1 or 8, wherein R2 and R3 are methyl groups.

16. The compound according to claim 1 or 8, wherein R2 is a (C1-C6)-alkyl group and R3 is a hydrogen atom.

17. The compound according to claim 1 or 8, wherein R2 is a (C1-C3)-alkyl group and R3 is a hydrogen atom.

18. The compound according to claim 1 or 8, wherein R2 is a methyl group or an ethyl group and R3 is a hydrogen atom.

19. The compound according to claim 1 or 8, wherein R3 is a (C1-C6)-alkyl group and R2 is a hydrogen atom.

20. The compound according to claim 1 or 8, wherein R3 is a (C1-C3)-alkyl group and R2 is a hydrogen atom.

21. The compound according to claim 1 or 8, wherein R3 is a methyl group and R2 is a hydrogen atom.

22. The compound according to claim 1 or 8, wherein R2 and R3 are each a methoxy group.

23. The compound according to claim 1 or 8, wherein R2 is independently or simultaneously a (C1-C6)-O-alkyl group and R3 is a hydrogen atom.

24. The compound according to claim 1 or 8, wherein R2 is independently or simultaneously a (C1-C3)-O-alkyl group and R3 is a hydrogen atom.

25. The compound according to claim 1 or 8, wherein R2 is a methoxy group and R3 is a hydrogen atom.

26. The compound according to claim 1 or 8, wherein R3 is a (C1-C6)-O-alkyl group and R2 is a hydrogen atom.

27. The compound according to claim 1 or 8, wherein R3 is a (C1-C3)-O-alkyl group and R2 is a hydrogen atom.

28. The compound according to claim 1 or 8, wherein R3 is a methoxy group and R2 is a hydrogen atom.

29. The compound according to claim 1 or 8, wherein R2 and R3 are each a hydrogen atom.

30. The compound according to claim 8, wherein in formula (I a ), (II a ), (I c ) or (II c ), R2 and R3 together with the oxygen atom are linked to form an ethylene oxide ring.

31. The compound according to claim 1 or 8, wherein R 1a is a hydrogen atom and R 1b is a (C1-C6)-alkyl group.

32. The compound according to claim 1 or 8, wherein R 1a and R 1b are independently or simultaneously (C1-C6)-alkyl groups.

33. The compound according to claim 1 or 8, wherein R 1a and R 1b are independently or simultaneously (C1-C3)-alkyl groups.

34. The compound according to claim 1 or 8, wherein R 1a is a hydrogen atom and R 1b is a (C1-C6)-hydroxyalkyl group.

35. The compound according to claim 1 or 8, wherein R 1a is a hydrogen atom, and R 1b is a methanol group (-CH2OH), an ethanol group (-C2H4OH), a propanol group (-C3H6OH) or a butanol group (-C4H8OH).

36. The compound according to claim 1 or 8, wherein R 1a is a hydrogen atom and R 1b is a hydroxyalkyl group having the formula (HA): wherein Y1 and Y2 are each simultaneously or independently a hydrogen atom or a (C1-C6)-alkyl group.

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

38. The compound according to claim 37, wherein the alkyl-aryl group is a (C1-C6)-alkyl-aryl group.

39. The compound according to claim 37, wherein the alkyl-aryl group is a (C1-C6)-alkyl-phenyl group.

40. The compound according to claim 37, wherein the alkyl-aryl group is a (CH2)-phenyl group.

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

42. The compound according to claim 1 or 8, wherein R 1a and R 1b are linked together with the nitrogen atom to which they are attached to form an optionally substituted 3- to 10-membered heterocycle, wherein the heterocycle further comprises an oxygen atom and wherein the heterocycle is further substituted by at least one (C1-C6)-alkyl group.

43. The compound according to claim 42, wherein the heterocycle is further independently or simultaneously substituted by two (C1-C6)-alkyl groups from the same heterocyclic carbon atom.

44. The compound according to claim 42, wherein the heterocycle is further substituted by two methyl groups on a single heterocyclic carbon atom.

45. The compound according to claim 42, wherein the heterocycle is further substituted by two methyl groups on two independent heterocyclic carbon atoms.

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

47. The compound according to claim 1 or 8, wherein the nitrogen atom to which R1 and R 1b and R 1b are attached is joined to the carbon atom to which R1 is attached to form an optionally substituted saturated or unsaturated 3- to 10-membered heterocycle, which heterocycle includes an oxygen atom in addition to the nitrogen atom.

48. The compound according to claim 1 or 8, wherein the nitrogen atom to which R1 and R 1b and R 1b are attached is linked to the carbon atom to which R1 is attached to form an optionally substituted saturated or unsaturated 3- to 10-membered heterocycle, which heterocycle further comprises an oxygen atom in addition to the nitrogen atom and is substituted by at least one (C1-C6) alkyl group.

49. The compound according to claim 1 or 8, wherein the nitrogen atom to which R1 and R 1b and R 1b are attached and the carbon atom to which R1 is attached are joined together to form an optionally substituted saturated or unsaturated 3- to 10-membered heterocycle, wherein the heterocycle further comprises an oxygen atom in addition to the nitrogen atom and is independently or simultaneously substituted by at least two (C1-C6) alkyl groups, and the alkyl groups are substituents on the same heterocyclic carbon atom.

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

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

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

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

54. A compound according to any one of claims 47 to 52, wherein when the heterocycle is unsaturated and nitrogen is involved in the formation of the unsaturated bond, R 1a is absent.

55. The compound according to claim 1, wherein the compound having formula (I) or (II) is selected from the group consisting of compounds having chemical formulas (A); (B); (C); (D); (E); (F); and (G): wherein in formula (B), X 4a and X 4b are independently or simultaneously a halogen or hydrogen atom, wherein R 1a and R 1b in formulas (A), (B), (C), (D), (E) and (F) are independently selected from an alkyl group, an optionally substituted alkyl-aryl group or a hydrogen atom, or wherein R 1a and R 1b are joined together with the nitrogen atom to which they are attached to form a 3- to 10-membered optionally substituted heterocycle; wherein R2 in formulas (C), (F) and (G), and Y1 and Y2 in (G) are alkyl groups or hydrogen atoms; and wherein X3 in formulas (C), (F) and (G) is a halogen, an O-alkyl group or a hydrogen atom.

56. The compound according to claim 1, wherein the compound having formula (I) is selected from the group of compounds having 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): (B): B(I); B(II); B(III); B(IV); and B(V): (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): (D): D(I); D(II); and D(III): (E): E(I); E(II); E(III); E(IV); and E(V): (F): F(I); F(II); F(III); F(IV); F(V); and F(VI): and (G): G(I); G(II); G(III); G(IV); and G(V): wherein in each of the compounds A(I) to G(V), optionally, the nitrogen atom of the N-propylamine moiety can be protonated and includes a negatively charged anion that balances the positively charged nitrogen atom.

57. The compound according to claim 56, wherein the compound is a stereoisomeric compound selected from the stereoisomeric compounds corresponding to A(I), A(II), A(III), C(VII), C(IX), C(XI), F(II), G(II) and G(IV), which comprises an N-propylamine moiety, wherein the C2 atom of its N-propylamine moiety is a chiral carbon atom.

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

59. The compound according to claim 57, wherein the stereoisomeric compound is substantially free of its corresponding counterpart stereoisomeric compound.

60. The compound according to claim 57, wherein the compound having the formula A(II) is selected from the stereoisomeric compounds having the formula A(II a ) or A(II b ):

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

62. A pharmaceutical or recreational drug preparation comprising an effective amount of a compound selected from the compounds having chemical formula (I) or (II) and a pharmaceutically acceptable excipient, diluent or carrier: Among them, In chemical formula (I) or (II): is a single bond or a 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, or R1 and R 1b and the carbon atom to which R1 is attached and the nitrogen atom to which R 1b is attached are joined together to form an optionally substituted saturated or unsaturated 3- to 10-membered heterocycle, and when the heterocycle is unsaturated, R 1a is optionally absent; R 1a and R 1b are each independently selected from an alkyl group, a hydroxyalkyl group, an optionally substituted alkyl-aryl group, or a hydrogen atom, or R 1a and R 1b are joined together with the nitrogen atom to which they are attached to form an optionally substituted 3- to 10-membered heterocycle; and R2 and R3 are each independently selected from an alkyl group, an O-alkyl group, a hydrogen atom, or R2 and R3 are joined together with an oxygen atom and the carbon atom to which they are attached to form an ethylene oxide ring.

63. A method for treating a cranial nerve disorder, the method comprising administering to a subject in need thereof a pharmaceutical preparation comprising a compound having formula (I) or (II): Among them, In formula (I) or (II): is a single bond or a 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, or R1 and R 1b and the carbon atom to which R1 is attached and the nitrogen atom to which R 1b is attached are joined together to form an optionally substituted saturated or unsaturated 3- to 10-membered heterocycle, and when the heterocycle is unsaturated, R 1a is optionally absent; R 1a and R 1b are each independently selected from an alkyl group, a hydroxyalkyl group, an optionally substituted alkyl-aryl group or a hydrogen atom, or R 1a and R 1b are joined together with the nitrogen atom to which they are attached to form an optionally substituted 3- to 10-membered heterocycle; and R2 and R3 are each independently selected from an alkyl group, an O-alkyl group, a hydrogen atom, or R2 and R3 are joined together with an oxygen atom and the carbon atom to which they are attached to form an ethylene oxide ring, wherein the pharmaceutical preparation is administered in an effective amount to treat the cranial nerve disorder of the subject.

64. The method according to claim 63, wherein after 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. The method according to claim 64, wherein the receptor is a G protein-coupled receptor (GPCR).

66. The method according to claim 64, wherein the receptor is a 5-HT receptor.

67. The method according to claim 64, wherein the receptor is 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.

68. The method according to claim 63, wherein after administration, the compound having formula (I) or (II) interacts with a transmembrane transporter in the subject, thereby modulating the transmembrane transporter and exerting a pharmacological effect.

69. The method according to claim 68, wherein the transmembrane transporter is a dopamine active transporter (DAT), a norepinephrine transporter (NET) or a serotonin transporter (SERT) transmembrane transporter.

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

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

72. The method according to claim 63, wherein the disorder is a 5-HT 1A receptor-mediated disorder, a 5-HT 2A receptor-mediated disorder, a 5-HT 2B receptor-mediated disorder, a 5-HT 2C receptor-mediated disorder, a 5-HT 1D receptor-mediated disorder, a 5-HT7 receptor-mediated disorder, an α 2A receptor-mediated disorder, a D3 receptor-mediated disorder or an MT1 receptor-mediated disorder.

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

74. A method for modulating (i) a receptor selected from a 5-HT 1A receptor, a 5-HT 2A receptor, a 5-HT 2B receptor, a 5-HT 2C receptor, a 5-HT7 receptor, an α 2A receptor, a D3 receptor or an MT1 receptor; or (ii) a transmembrane transporter selected from a dopamine active transporter (DAT), a norepinephrine transporter (NET) or a serotonin transporter (SERT), the method comprising, under reaction conditions sufficient to modulate (i) the 5-HT 1A receptor, the 5-HT 2A receptor, the 5-HT 2B receptor, the 5-HT 2C receptor, the 5-HT7 receptor, the α 2A receptor, the D3 receptor or the MT1 receptor; (ii) the dopamine active transporter (DAT), the norepinephrine transporter (NET) or the serotonin transporter (SERT) transmembrane transporter, contacting (i) the 5-HT 1A receptor, the 5-HT 2A receptor, the 5-HT 2B receptor, the 5-HT 2C receptor, the 5-HT7 receptor, the α 2A receptor, the D3 receptor or the MT1 receptor; or (ii) the dopamine active transporter (DAT), the norepinephrine transporter (NET) or the serotonin transporter (SERT) transmembrane transporter with a first compound having the formula (I) and a second compound having the formula (II): Among them, In formula (I) or (II): is a single bond or a 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, or R1 and R 1b and the carbon atom to which R1 is attached and R 1b and the nitrogen atom to which it is attached are joined together to form an optionally substituted saturated or unsaturated 3- to 10-membered heterocyclic ring, and when the heterocyclic ring is unsaturated, R 1a is optionally absent; R 1a and R 1b are each independently selected from an alkyl group, a hydroxyalkyl group, an optionally substituted alkyl-aryl group or a hydrogen atom, or R 1a and R 1b together with the nitrogen atom to which they are attached form an optionally substituted 3- to 10-membered heterocycle; and R2 and R3 are each independently selected from an alkyl group, an O-alkyl group, a hydrogen atom, or R2 and R3 are joined together with an oxygen atom and the carbon atom to which they are attached to form an ethylene oxide ring.

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

76. The method according to claim 74, wherein the reaction conditions are in vivo reaction conditions.

77. A method for preparing a first compound having the chemical formula (I) or (II): Among them, In the chemical formula (I) or (II): is a single bond or a 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, or R1 and R 1b together with the carbon atom to which R1 is attached and the nitrogen atom to which R 1b is attached form an optionally substituted saturated or unsaturated 3- to 10-membered heterocycle, and when the heterocycle is unsaturated, R 1a is optionally absent; R 1a and R 1b are each independently selected from an alkyl group, a hydroxyalkyl group, an optionally substituted alkyl-aryl group or a hydrogen atom, or R 1a and R 1b together with the nitrogen atom to which they are attached are joined to form an optionally substituted 3- to 10-membered heterocycle; and R2 and R3 are each independently selected from an alkyl group, an O-alkyl group, a hydrogen atom, or R2 and R3 are joined together with an oxygen atom and the carbon atom to which they are attached to form an ethylene oxide ring, and wherein the method involves performing at least one chemical synthesis reaction selected from the reactions depicted in Figure 3A(i), Figure 3A(ii), Figure 3B(i), Figure 3B(ii), Figure 3B(iii), and Figure 3C.

78. The method according to claim 77, wherein the compound having the chemical formula (I) is a compound having the chemical formula (A): wherein 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 are joined together with the nitrogen atom to which they are attached to form an optionally substituted 3- to 10-membered heterocycle, and 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) depicted in Figure 3A(i) and Figure 3A(ii).

79. The method according to claim 77, wherein the compound having the chemical formula (I) is a compound having the formula (B): wherein in formula (B), X 4a and X 4b are independently or simultaneously a halogen atom or a hydrogen atom, wherein 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 are joined together with the nitrogen atom to which they are attached to form an optionally substituted 3- to 10-membered heterocycle, and 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) depicted in Figure 3A(i).

80. The method according to claim 77, wherein the compound having the chemical formula (I) is a compound having the formula (C): wherein R 1a and R 1b are each independently selected from an alkyl group, a hydroxyalkyl group or a hydrogen atom, or R 1a and R 1b together with the nitrogen atom to which they are attached are joined to form a 3- to 10-membered optionally substituted heterocycle, wherein R2 is selected from an alkyl group or a hydrogen atom, and wherein X3 is an O-alkyl group, a halogen or a hydrogen atom, and the at least one chemical synthesis reaction is a reaction selected from the following: (i) {(h) in Figure 3A(i) and Figure 3A(ii); (c) and (h); (b), (c), and (h); and (a), (b), (c), and (h)}; (ii) {(f) in Figure 3B(i) and Figure 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 Figure 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 Figure 3B(i) and Figure 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 FIGS. 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) in FIGS. 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)}.

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

82. The method according to claim 77, wherein the compound having the chemical formula (I) is a compound having the formula (E): wherein 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 together with the nitrogen atom to which they are attached form an optionally substituted 3- to 10-membered heterocycle, And the at least one chemical synthesis reaction is a reaction selected from (b) depicted in FIG. 3C; and (a) and (b).

83. The method according to claim 77, wherein the compound having the chemical formula (I) is a compound having the formula (F): wherein R 1a and R 1b are each independently selected from a hydroxyalkyl group or a hydrogen atom, or R 1a and R 1b together with the nitrogen atom to which they are attached form an optionally substituted 3- to 10-membered heterocycle, and Wherein R2 is an alkyl group or a hydrogen atom, and X3 is an O-alkyl group, a halogen or a hydrogen atom, And the at least one chemical synthesis reaction is a reaction selected from (c1) depicted in FIGS. 3B(i) and 3B(ii); (c2); (b) and (c2); (a) and (c1); (a), (b) and (c2).

84. The method according to claim 77, wherein the compound having the chemical formula (I) is a compound having the formula (G): Wherein X3 is a hydrogen atom, a halogen atom or an O-alkyl group, Wherein 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) in FIGS. 3B(i), 3B(ii) and 3B(iii); (c1) and (h); (c2) and (h); (b), (c2) and (h); and (a), (c1) and (h); and (a), (b), (c2) and (h)}.

85. Use of a compound having the chemical formula (I) or (II) in the manufacture of a pharmaceutical or recreational drug preparation: Among them, In the chemical formula (I) or (II): is a single bond or a 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, or R1 and R 1b together with the carbon atom to which R1 is attached and the nitrogen atom to which R 1b is attached form an optionally substituted saturated or unsaturated 3- to 10-membered heterocycle, and when the heterocycle is unsaturated, R 1a is optionally absent; R 1a and R 1b are each independently selected from an alkyl group, a hydroxyalkyl group, an optionally substituted alkyl-aryl group or a hydrogen atom, or R 1a and R 1b together with the nitrogen atom to which they are attached are joined to form an optionally substituted 3- to 10-membered heterocycle; and R2 and R3 are each independently selected from an alkyl group, an O-alkyl group, a hydrogen atom, or R2 and R3 are joined together with an oxygen atom and the carbon atom to which they are attached to form an ethylene oxide ring.

86. Use according to claim 85, wherein said manufacturing comprises formulating said compound together with an excipient, diluent or carrier.

87. Use of a compound of formula (I) or (II) together with a diluent, carrier or excipient as a pharmaceutical or recreational drug preparation: Among them, In formula (I) or (II): is a single bond or a 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, or R1 and R 1b and the carbon atom to which R1 is attached and the nitrogen atom to which R 1b are attached are joined together to form an optionally substituted saturated or unsaturated 3- to 10-membered heterocycle, and when the heterocycle is unsaturated, R 1a is optionally absent; R 1a and R 1b are each independently selected from an alkyl group, a hydroxyalkyl group, an optionally substituted alkyl-aryl group or a hydrogen atom, or R 1a and R 1b together with the nitrogen atom to which they are attached are joined to form an optionally substituted 3- to 10-membered heterocycle; and R2 and R3 are each independently selected from an alkyl group, an O-alkyl group, a hydrogen atom, or R2 and R3 are joined together with an oxygen atom and the carbon atom to which they are attached to form an ethylene oxide ring.

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