Tetracyclic compounds for treating brain damage

Abstract

Provided herein are tetracyclic heterocyclic compounds that may be useful in methods of treating disease or enhancing neuroplasticity. The compounds may also be useful for increasing dendritic spine density.

Description

[Technical Field]

[0001] Cross-reference of related applications This application asserts the right to end the war in relation to U.S. Provisional Patent Application No. 63 / 174,266, filed on 13 April 2021, which is incorporated herein by reference in whole for all purposes.

[0002] Description of the rights to inventions made with research and development support from the U.S. government. The present invention was made with government support under grant number R01GM128997, granted by the National Institutes of Health in the United States. The government has certain rights with respect to the present invention. [Background technology]

[0003] background Alterations in synaptic connectivity and plasticity have been observed in the brains of individuals with neuropsychiatric and neurological disorders. Psychoplastogens promote neuronal growth and improve neuronal structure through mechanisms that may involve activation of serotonin 5-HT2 receptors. Modulators of these biological targets, such as N,N-dimethyltryptamine (DMT), ibogaine, and lysergic acid diethylamide (LSD), have demonstrated psychoplastogen properties. For example, LSD and other analogues of ergoline scaffolds can correct detrimental structural changes associated with neuropsychiatric and neurological disorders. Such structural changes include, for example, loss of dendritic spines and synapses in the prefrontal cortex (PFC), as well as a decrease in the complexity of dendritic branching. Furthermore, pyramidal neurons in the PFC perform top-down control across brain regions that regulate motivation, fear, reward, and cognition. Hallucinogenic psychoplastogens have demonstrated antidepressant, anxiolytic, and antitoxic effects in clinical settings. However, their subjective effects were limited to their clinical utility. Furthermore, hallucinogenic compounds are contraindicated for psychotic disorders such as schizophrenia, and it is well known that they cause loss of dendritic spines in the proximal foci (PFC). Therefore, non-hallucinogenic psychoplastogens may offer clear advantages over their hallucinogenic counterparts.

[0004] Compounds having improved physiological and chemical properties and reduced hallucinogenic (e.g., non-hallucinogenic) characteristics compared to their hallucinogenic (e.g., ergoline) counterparts, and possessing clinically relevant therapeutic efficacy, are provided herein. [Overview of the project]

[0005] Brief Overview of the Invention In one embodiment, the following formula (K): [ka] {In the formula, Each R 1a , R 1b , R 1c , and R1d is independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkoxyalkyl, halogen, C 1-6 haloalkyl, C 1-6 haloalkoxy, -NO2, or -CN; or two R groups on adjacent ring atoms are combined to form C 1a cycloalkyl or a 4- to 8-member heterocycloalkyl having 1 to 2 heteroatoms each independently being N, O, or S; 4-8 R 2a and R 2b are each independently H, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 alkoxyalkyl, C 1-6 haloalkyl, or C 1-6 haloalkoxy; or R 2a and R 2b are combined to form a 4- to 8-member heterocycloalkyl having 1 to 2 heteroatoms each independently being N, O, or S; R 3 is H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyalkyl, C 1-6 haloalkyl, or C 1-6 haloalkoxy; R 3a is absent or C 1-6 alkyl; or R 3 and R 3a are combined to form a 3- to 8-member heterocycloalkyl having 1 to 2 heteroatoms each independently being N, O, or S; Subscripts m and p are each independently 0 to 2, and subscripts n and r are each independently 0 to 3}, a compound having such a structure or a pharmaceutically acceptable salt thereof is provided herein.

[0006] ​ In another embodiment, the following formula (J): [ka] {In the formula, Each R 1a , R 1b , R 1c , and R 1d H and C are independent of each other. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyls, halogens, C 1-6 Haloalkyl, C 1-6 It is a haloalkoxy, -NO2, or -CN; or two R atoms on adjacent ring atoms. 1a The base is combined to form C 4-8 Forming cycloalkyls or 4-8 membered heterocycloalkyls having 1-2 heteroatoms that are independently N, O, or S; R 2a and R 2b These are H and C, which are independent of each other. 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, C 1-6 Haloalkyl, or C 1-6 Is it a haloalkoxy; or R 2a and R 2b These are combined to form a 4-8 membered heterocycloalkyl group, each independently having 1-2 heteroatoms that are N, O, or S; R 3 H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, C 1-6 Haloalkyl, or C 1-6 It is a haloalkoxy; The subscripts m and p are independently 0 to 2, and Compounds having the structure {where the subscripts n and r are independently 0 to 3} or pharmaceutically acceptable salts thereof are provided herein.

[0007] In another embodiment, the present invention features the following structure characterized by unit cell dimensions a=7.0716(6)Å, α=90°, b=14.4326(12)Å, β=90°, c=23.0876(19)Å, and γ=90°: [ka] The present invention provides a crystalline compound of (7aS,10R)-10-(diethylcarbamoyl)-8,8-dimethyl-7a,8,9,10-tetrahydro-7H-indro[7,1-fg][1,7]naphthyridine-8-ium iodide having the following properties:

[0008] In another embodiment, a pharmaceutical composition comprising a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof is provided herein.

[0009] In another embodiment, a method for treating a disease is provided herein, comprising administering a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof to a subject in need thereof, thereby treating the disease.

[0010] In another embodiment, a method for enhancing neuronal plasticity is provided herein, comprising contacting a neuron with a compound of the present invention or a pharmaceutically acceptable salt thereof in an amount sufficient to enhance the neuronal plasticity of the neuron, wherein the compound causes a maximum number of dendritic intersections that increases by more than 1.0 times according to Scholl analysis.

[0011] In another embodiment, a method for enhancing neuronal plasticity and increasing dendritic spine density is provided herein, comprising contacting a neuron with a compound of the present invention or a pharmaceutically acceptable salt thereof in an amount sufficient to enhance the neuronal plasticity and increase the dendritic spine density of the neuron. [Brief explanation of the drawing]

[0012] [Figure 1] Figure 1 shows the structural rationale for the rational design of JRT, including a structural comparison of N,N-dimethylisotryptamine and LSD using JRT.

[0013] [Figure 2] Figure 2 shows that the total synthesis of (±)-JRT was completed in 12 steps and achieved an overall yield of 11%.

[0014] [Figure 3A-3E] Figures 3A to 3E demonstrate that (+)-JRT is highly selective for serotonin receptors. Figure 3A shows the binding profiles of (+)-JRT and (-)-JRT compared to (+)-LSD. Orange and white cells indicate Ki values ​​less than 10 μM and greater than 10 μM, respectively. Figure 3B shows that conventional GPCR binding and function assays indicate that (+)-JRT is a potent agonist of the 5-HT2 receptor. Figures 3C to 3E show that PsychLight assays indicate that (+)-JRT and (-)-JRT have potential low hallucinogenicity. Figure 3C shows a representative image of PSYLI2 cells after treatment in agonist mode. Figure 3D shows the concentration-response psychLight assay performed in agonist mode. Figure 3E shows the single-concentration psychLight assay (1 μM) performed in antagonist mode.

[0015] [Figure 4] Figure 4 shows that (+)-JRT promotes structural plasticity in vivo. Using electron microscopy, we demonstrated that a single dose of (+)-JRT (1 mg / kg) increased dendritic spine density in the PFC 24 hours after administration. The data represent spines counted in 5-8 dendritic segments per animal, using 3 animals per group.

[0016] [Figures 5A-5D]Figures 5A to 5D show that (+)-JRT exhibits antipsychotic, antidepressant, and cognitive-enhancing effects in vivo. Figure 5A shows that a mouse head spasm response (HTR) assay in male and female animals demonstrates that (+)-JRT has potential low hallucinogenicity when the assay is performed in agonist mode. Furthermore, (+)-JRT (1 mg / kg) demonstrates antipsychotic properties by antagonizing HTR induced by LSD (0.2 mg / kg). Figure 5B shows that pretreatment with (+)-JRT (1 mg / kg) can block AMPH-induced hyperspontaneous movement in female mice but not in male mice. Figure 5C shows that a rat FST performed 24 hours after compound administration demonstrates that (+)-JRT produces an antidepressant effect comparable to ketamine at substantially low doses. Doses (mg / mL) are shown within or above the bars representing various treatment groups. Figure 5D shows that the 4-odor discrimination and reversal assay demonstrates that (+)-JRT does not affect stimulus discrimination but rescues cognitive impairment caused by unpredictable mild stress. AMPH = D-amphetamine.

[0017] [Figure 6] Figure 6 shows the selectivity profiles of (+)-JRT and (-)-JRT across 55 central nervous system targets. The effects of (+)-JRT (10 μM) and (-)-JRT (10 μM) on various targets were evaluated by Eurofins Discovery. Assays were performed in double series, and the results were averaged. Targets with ≥50% inhibition are highlighted in blue.

[0018] [Figure 7] Figure 7 shows the NMR spectrum of compounds 14 and 15 in their thermodynamic equilibrium states.

[0019] [Figure 8] Figure 8 shows the chiral HPLC graph for (±)-JRT.

[0020] [Figure 9] Figure 9 shows the chiral HPLC graph for (-)-JRT.

[0021] [Figure 10] Figure 10 shows the chiral HPLC graph for (+)-JRT.

[0022] [Figure 11] Figure 11 shows the X-ray crystal structure for 16. One molecule of 16 and one solvent molecule of DCM are present. The atomic numbering corresponds to the provided atomic coordinates. [Modes for carrying out the invention]

[0023] Detailed description of the present invention I. General Rules Tetracyclic ergoline analogs of heterocyclic compounds are provided herein. The compounds of the present invention are useful in the treatment of diseases such as brain disorders, neuropsychiatric disorders, and other neurological disorders. The compounds of the present invention are also useful for enhancing neuroplasticity, increasing dendritic spine density, or both. II. Definition

[0024] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which the present invention belongs. In addition, any method or material similar to or equivalent to those described herein may be used in carrying out the present invention. For the purposes of the present invention, the following terms are defined:

[0025] "A," "an," or "the" include not only aspects involving one component but also aspects involving multiple components. For example, the singular forms "a," "an," and "the" include multiple referents unless the context clearly indicates otherwise. Thus, for example, a reference to "a cell" includes multiple such cells, and a reference to "the agent" includes one or more agents known to those skilled in the art, and so on.

[0026] "Alkyl" means a linear or branched, saturated, aliphatic group having the number of carbon atoms indicated. Unless otherwise specified, the disclosures provided herein regarding "alkyl" are intended to encompass a separate description of saturated alkyl. Alkyl groups as described herein are generally monovalent, but may also be divalent, as may be described herein as "alkylene" or "alkylenyl" groups. Alkyl is C 1-2 , C 1-3 , C 1-4 , C 1-5 , C 1-6 , C 1-7 , C 1-8 , C 1-9 , C 1-10 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 and C 5-6 It can contain any number of carbon atoms, such as C. 1-6 Alkyls include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, and hexyl. Alkyls also include, but are not limited to, heptyl, octyl, nonyl, and decyl, and can also refer to alkyl groups having up to 20 carbon atoms. Alkyls may be substituted or unsubstituted.

[0027] "Alkenyl" means a straight-chain or branched hydrocarbon having at least two carbon atoms and at least one double bond. Alkenyl may contain any number of carbons, such as C2, C 2-3 、C 2-4 、C 2-5 、C 2-6 、C 2-7 、C 2-8 、C 2-9 、C 2-10 、C3、C 3-4 、C 3-5 、C 3-6 、C4、C 4-5 、C 4-6 、C5、C 5-6 、and C6, etc. The alkenyl group may have any suitable number of double bonds, including, but not limited to, 1, 2, 3, 4, 5 or more. Examples of alkenyl groups include, but are not limited to, vinyl (ethenyl), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl, 2-pentenyl, isopentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl, 2,4-hexadienyl, or 1,3,5-hexatriene. The alkenyl group may be substituted or unsubstituted.

[0028] "Alkynyl" means either a straight-chain or branched hydrocarbon having at least two carbon atoms and at least one triple bond. Alkynyl may contain any number of carbons, such as C2, C 2-3 、C 2-4 、C 2-5 、C 2-6 、C 2-7 、C 2-8 、C 2-9 、C 2-10 、C3、C 3-4 、C 3-5 、C 3-6 、C4、C 4-5 、C 4-6 、C5、C 5-6, and C6, and may contain any number of carbon atoms. Examples of alkynyl groups include, but are not limited to, acetylenyl, propynyl, 1-butynyl, 2-butynyl, butadiinyl, 1-pentynyl, 2-pentynyl, isopentinyl, 1,3-pentadinyl, 1,4-pentadinyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,3-hexadinyl, 1,4-hexadinyl, 1,5-hexadinyl, 2,4-hexadinyl, or 1,3,5-hexatriinyl. The alkynyl group may be substituted or unsubstituted.

[0029] "Alkoxy" refers to an alkyl group having an oxygen atom linked to the alkyl group at the bonding site: alkyl-O-. Similar to alkyl groups, alkoxy groups may have any preferred number of carbon atoms, such as C1-6. Examples of alkoxy groups include methoxy, ethoxy, propoxy, iso-propoxy, butoxy, 2-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy, and hexoxy. Alkoxy groups may be further substituted with various substituents described herein. Alkoxy groups may be substituted or unsubstituted.

[0030] "Alkoxyalkyl" refers to a group having an alkyl component and an alkoxy component, where the alkyl component links to the heterocycloalkyl component at its bonding site. The alkyl component is as defined above, except that it is at least divalent, i.e., alkylene, in order to link to the heterocycloalkyl component and the bonding site. The alkyl component is C 0-6 , C 1-2 , C 1-3 , C 1-4 , C 1-5 , C 1-6 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 and C 5-6It may contain any number of carbon atoms, such as those mentioned above. In some cases, it may lack an alkyl component. The alkoxy component is as defined above. Examples of alkoxyalkyl groups, though not limited to these, include 2-ethoxyethyl and methoxymethyl.

[0031] "Halogens" refer to fluorine, chlorine, bromine, and iodine.

[0032] A "haloalkyl" refers to an alkyl group, as previously defined, in which some or all of the hydrogen atoms are replaced by halogen atoms. Like alkyl groups, haloalkyl groups can have any preferred number of carbon atoms, such as C1-6. Examples of haloalkyl groups include trifluoromethyl and fluoromethyl. In some cases, the term "perfluoro" may be used to define a compound or radical in which all hydrogen atoms are replaced by fluorine. For example, perfluoromethyl refers to 1,1,1-trifluoromethyl.

[0033] A "haloalkoxy" refers to an alkoxy group in which some or all of the hydrogen atoms are replaced by halogen atoms. Similar to alkyl groups, haloalkoxy groups are C 1-6 It may have any suitable number of carbon atoms. The alkoxy group may be substituted with one, two, three or more halogens. When all hydrogens are replaced with halogens, such as fluorine, the compound is totally substituted, for example, totally fluorine-substituted. Examples of haloalkoxys include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and perfluoroethoxy.

[0034] "Cycloalkyl" refers to a saturated or partially unsaturated, monocyclic, fused bicyclic, or bridging polycyclic ring assembly containing 3 to 12 ring atoms, or the number of atoms indicated. Cycloalkyl is C 3-6 , C 4-6 , C 5-6 , C 3-8 , C 4-8 , C 5-8 , C6-8 , C 3-9 , C 3-10 , C 3-11 , and C 3-12 These may contain any number of carbon atoms. In some embodiments, the cycloalkyl is a spiroring or a crosslinked compound. In some embodiments, the cycloalkyl is optionally fused to an aromatic ring, and the attachment point is at a carbon atom other than the aromatic ring carbon atom. Saturated monocyclic cycloalkyl rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. Saturated bicyclic and polycyclic cycloalkyl rings include, for example, norbornane, [2.2.2]bicyclooctane, decahydronaphthalene, and adamantane. Cycloalkyl groups may also be partially unsaturated, having one or more double or triple bonds within the ring. Representative partially unsaturated cycloalkyl groups include, but are not limited to, cyclobutene, cyclopentene, cyclohexene, cyclohexadiene (1,3- and 1,4-isomers), cycloheptene, cycloheptadiene, cyclooctene, cyclooctadiene (1,3-, 1,4- and 1,5-isomers), norbornene, and norbornadiene. When the cycloalkyl group is a saturated monocyclic C3-8 cycloalkyl group, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. 3-6 When referring to cycloalkyl groups, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyl groups may be substituted or unsubstituted.

[0035] A "heterocycloalkyl" refers to a cycloalkyl as defined above, having 3 to 12 ring members and 1 to 4 N, O, and S heteroatoms. The heteroatoms may be oxidized, for example, -S(O)- and -S(O)2-, but are not limited to these. A heterocycloalkyl can contain any number of ring members, such as 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12. Any suitable number of heteroatoms, such as 1, 2, 3, or 4, or 1 to 2, 1 to 3, 1 to 4, 2 to 3, 2 to 4, or 3 to 4, may be included in a heterocycloalkyl. In some embodiments, the heterocycloalkyl is a spiroring or a crosslinked compound. In some embodiments, the heterocycloalkyl is optionally fused to an aromatic ring, and the attachment point is at a carbon or heteroatom other than the aromatic ring carbon atom (e.g., a nitrogen atom). Heterocycloalkyl groups may include groups such as aziridine, azetidine, pyrrolidine, piperidine, azepane, azocane, quinuclidine, pyrazolidine, imidazolidine, piperazine (1,2-, 1,3-, and 1,4-isomers), oxirane, oxetane, tetrahydrofuran, oxane (tetrahydropyran), oxepane, thiran, thiethane, thiolane (tetrahydrothiophene), thian (tetrahydrothiopyran), oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, morpholine, thiomorpholine, dioxane, or dithiane. Heterocycloalkyl groups may condense to aromatic or non-aromatic ring systems to form members containing, but not limited to, indoline. Heterocycloalkyl groups may be unsubstituted or substituted. For example, a heterocycloalkyl group may contain C 1-6 It may be substituted with alkyl or oxo (=O), etc.

[0036] Heterocycloalkyl groups can be bonded via any position on the ring. For example, aziridine can be 1- or 2-azeridine, azetidine can be 1- or 2-azetidine, pyrrolidine can be 1-, 2-, or 3-pyrrolidine, piperidine can be 1-, 2-, 3-, or 4-piperidine, pyrazolidine can be 1-, 2-, 3-, or 4-pyrazolidine, imidazolidine can be 1-, 2-, 3-, or 4-imidazolidine, and piperazine can be 1-, 2-, 3-, or 4-piperazine. Tetrahydrofuran can be 1- or 2-tetrahydrofuran, oxazolidine can be 2-, 3-, 4-, or 5-oxazolidine, isoxazolidine can be 2-, 3-, 4-, or 5-isoxazolidine, thiazolidine can be 2-, 3-, 4-, or 5-thiazolidine, isothiazolidine can be 2-, 3-, 4-, or 5-isothiazolidine, and morpholine can be 2-, 3-, or 4-morpholine.

[0037] When a heterocycloalkyl group contains 3 to 8 ring components and 1 to 3 heteroatoms, typical ring components include, but are not limited to, pyrrolidine, piperidine, tetrahydrofuran, oxane, tetrahydrothiophene, thiane, pyrazolidine, imidazolidine, piperazine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, morpholine, thiomorpholine, dioxane, and dithiane. Heterocycloalkyl groups can also form rings having 5 to 6 ring components and 1 to 2 heteroatoms, and typical ring components include, but are not limited to, pyrrolidine, piperidine, tetrahydrofuran, tetrahydrothiophene, pyrazolidine, imidazolidine, piperazine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, and morpholine.

[0038] The terms “heterocyclic” or “heterocyclic” refer to aromatic heterocyclic rings (also known as heteroaryls) and heterocycloalkyl rings (also known as heteroalicyclic groups) containing 1 to 4 heteroatoms in the ring, where each heteroatom in the ring is selected from O, S, and N, and each heterocyclic group in the ring has 3 to 10 atoms in its ring system, provided that no ring contains two adjacent O or S atoms. Unless otherwise specified herein, heterocyclyl radicals are monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which optionally include fused or bridged ring systems. Heteroatoms in heterocyclyl radicals are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. Heterocyclyl radicals are partially or completely saturated. Heterocyclyls are bonded to the rest of the molecule by any atom in the ring. Non-aromatic heterocyclic groups (also known as heterocycloalkyls) contain a ring with 3 to 10 atoms in its ring system, while aromatic heterocyclic groups contain a ring with 5 to 10 atoms in its ring system. Heterocyclic groups include benzo-fused ring systems.Examples of non-aromatic heterocyclic groups include pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinol, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, azilidinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithi These are oranil, dihydropyranil, dihydrothienyl, dihydrofuranil, pyrazolidinil, imidazolinil, imidazolidinil, 3-azabicyclo[3.1.0]hexanil, 3-azabicyclo[4.1.0]heptanil, 3H-indolyl, indoline-2-onyl, isoindoline-1-onyl, isoindoline-1,3-dionyl, 3,4-dihydroisoquinoline-1(2H)-onyl, 3,4-dihydroquinoline-2(1H)-onyl, isoindoline-1,3-dithionyl, benzo[d]oxazole-2(3H)-onyl, 1H-benzo[d]imidazole-2(3H)-onyl, benzo[d]thiazole-2(3H)-onyl, and quinolidinil. Examples of aromatic heterocyclic groups include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, sinnolinyl, indazolyl, indolidinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, flazanyl, benzoflazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthylidinyl, and phlopyridinyl. The aforementioned groups are, if possible, carbon-bonded (or carbon-linked) or nitrogen-bonded. For example, groups derived from pyrrole include pyrrole-1-yl (N-bonded) or pyrrole-3-yl (C-bonded).Furthermore, imidazole-derived groups include imidazole-1-yl or imidazole-3-yl (both N-bonded), or imidazole-2-yl, imidazole-4-yl, or imidazole-5-yl (all C-bonded). Heterocyclic groups include benzo-condensed ring systems. Non-aromatic heterocycles are optionally substituted with one or two oxo (=O) moieties, such as pyrrolidine-2-one. In some embodiments, at least one of the two rings of a bicyclic heterocycle is aromatic. In some embodiments, both rings of a bicyclic heterocycle are aromatic. Unless otherwise specified herein, the term “heterocyclyl” means a heterocyclyl radical as defined above, which is optionally substituted with one or more substituents selected from the following: alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralquinyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R. y -OR x , -R y -OC(O)-R x , -R y -OC(O)-OR x , -R y -OC(O)-N(R x )2, -R y -N(R x )2, -R y -C(O)R x , -R y -C(O)OR x , -R y -C(O)N(R x )2, -R y -O-Rz-C(O)N(R x )2, -R y -N(R x )C(O)OR x , -R y -N(Rx )C(O)R x , -R y -N(R x )S(O) t R x (t is 1 or 2), -R y -S(O) t R x (t is 1 or 2), -R y -S(O) t Ure x (t is 1 or 2), and -R y -S(O) t N(R x )2(t is 1 or 2)(where R x Each of these is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), and R y Each of the substituents is independently a directly bonded, or a linear or branched alkylene or alkenylene chain, and Rz is a linear or branched alkylene or alkenylene chain, where each of the substituents is unsubstituted unless otherwise specified.

[0039] "Salt" refers to the acid acid or base salt of the compound used in the method of the present invention. Examples of pharmaceutically acceptable salts include mineral acid salts (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid), organic acid salts (e.g., acetic acid, propionic acid, glutamic acid, citrate), and quaternary ammonium salts (e.g., methyl iodide, ethyl iodide). It is understood that pharmaceutically acceptable salts are nontoxic. Further information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference.

[0040] The pharmaceutically acceptable salts of the acidic compounds of the present invention are salts formed with a base, i.e., cationic salts such as alkali metal salts and alkaline earth metal salts, for example sodium salts, lithium salts, potassium salts, calcium salts, magnesium salts, and ammonium salts, for example ammonium salts, trimethylammonium salts, diethylammonium salts, and tris-(hydroxymethyl)-methylammonium salts.

[0041] Similarly, acid addition salts of mineral acids, organic carboxylic acids, and organic sulfonic acids, such as hydrochloric acid, methanesulfonic acid, and maleic acid, are also possible if a basic group such as pyridyl constitutes part of the structure.

[0042] The neutral form of the compound can be regenerated by contacting the salt with a base or acid and isolating the parent compound by conventional methods. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salt is equivalent to the parent form of the compound for the purposes of this invention.

[0043] "Therapeutic effective dose or dosage," "therapeutic sufficient dose or dosage," or "effective dose or sufficient dose or dosage" refers to the dose that produces a therapeutic effect when administered. The appropriate dose depends on the purpose of the treatment and can be determined by those skilled in the art using known techniques (see, for example, Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins). In sensitized cells, the therapeutic effective dose is often lower than the conventional therapeutic effective dose for unsensitized cells.

[0044] "To treat," "to treat," and "treatment" refer to any sign of success in treating or improving an injury, pathology, condition, or symptom (e.g., pain), including objective or subjective parameters such as remission, relief, reduction of symptoms, or making the symptom, injury, pathology, or condition more tolerable to the patient, a reduction in the frequency or duration of the symptom or condition, or, in some cases, prevention of the onset of symptoms. Treatment or improvement of symptoms may also be based on any objective or subjective parameters, including, for example, the results of a physical examination.

[0045] "Disease" refers to an abnormal cellular function within an organism that is not the direct result of physical or external injury. A disease can be any condition that causes distress, dysfunction, helplessness, impairment, infection, pain, or even death. Diseases include, but are not limited to, genetic diseases such as hereditary and non-hereditary disorders, infectious diseases, non-infectious diseases such as cancer, deficiencies, neurological disorders, and physiological disorders.

[0046] "Administration" refers to oral administration, suppository administration, topical contact, parenteral administration, intravenous, intraperitoneal, intramuscular, intrafocal, intranasal or subcutaneous administration, subarachnoid administration, or implantation of a continuous release device, such as a mini-osmosis pump.

[0047] The term "subject" is not limited to this, but refers to animals such as primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, and other mammals. In certain embodiments, the subject is a human.

[0048] "Neuroplasticity" refers to the brain's ability to continuously change its structure and / or function throughout its lifespan. Examples of brain changes, though not limited to these, include the ability to adapt to or respond to internal and / or external stimuli such as injury, as well as the ability to generate new nerve processes, dendritic spines, and synapses.

[0049] A "dendritic intersection" refers to a dendritic branch that overlaps with another branch or forms a cluster. Dendritic intersections are measured using Scholl analysis.

[0050] Dendrite spines are small membranes that protrude from dendrites and can receive electrical signals from the axon of a synapse. Dendrite spines are useful in transmitting electrical signals to the cell body of a neuron. A single neuron's dendrite can contain hundreds to thousands of spines. Dendrite spine density refers to the number of spines per unit length of dendritic tissue. For example, 5 μm -1 The dendritic spine density refers to the presence of 5 spines per 1 μm area of ​​the dendritic.

[0051] "To regulate" or "to regulate" or "regulation" refers to an increase or decrease in the amount, characteristics, or effect of a particular activity, function, or molecule. Not as an illustrative means or limitation, but as an example of a G protein-binding receptor (e.g., 5HT). 2A or 5HT 2CAgonists, partial agonists, antagonists, and allosteric modulators (e.g., positive allosteric modulators) of the receptor are modulators of the receptor.

[0052] "Agonism" refers to the activation of a receptor or enzyme by a modulator or agonist, which produces a biological response.

[0053] An "agonist" refers to a modulator that binds to a receptor or enzyme and activates the receptor, thereby producing a biological response. For example, "5HT" is used. 2A The "agonist" is 5HT with a concentration of approximately 100 μM or less. 2A Regarding activity EC 50 It can be used to refer to compounds exhibiting the following characteristics. In some embodiments, the term “agonist” includes full agonists or partial agonists. A “full agonist” refers to a modulator that binds to and activates a receptor in the maximal response induced by the agonist at the receptor. A “partial agonist” refers to a modulator that binds to and activates a given receptor, but has a partial efficacy at the receptor that is weaker than the maximal response induced by a full agonist. A “functionally selective agonist” refers to a modulator that produces one or part of a biological response that is possible by the activation of a receptor. For example, 5HT 2A Receptor activation is known to cause many downstream effects, including enhanced neuroplasticity, increased intracellular calcium concentration, and hallucinations, among many other biological responses. Functionally selective agonists are 5HT 2A Receptor activation will likely produce only a portion of the possible biological responses.

[0054] A "positive allosteric modulator" refers to a modulator that binds to a site different from the orthosteric binding site, thereby enhancing or amplifying the effect of an agonist.

[0055] "Antagonism" refers to the inactivation of a receptor or enzyme by a modulator or antagonist. Receptor antagonism occurs, for example, when a molecule is unable to bind to a receptor and produce activity. "Functionally selective antagonists" block one signaling pathway but do not affect others.

[0056] An "antagonist" or "neutralizing antagonist" refers to a modulator that binds to a receptor or enzyme and inhibits the biological response. An antagonist is completely inactive in the absence of an agonist or inverse agonist, but can inhibit the activity of either, thereby preventing an alteration of the biological response. III. Compound

[0057] This invention provides tetracyclic and heterocyclic compounds useful for treating various neurological diseases and disorders, as well as for enhancing neuroplasticity.

[0058] In some embodiments, the compounds provided herein improved physiological and chemical properties as a result of hydrogen bond donor loss, reduced total polar surface area, and improved central nervous system multi-parameter optimization (MPO) score. (e.g., hallucinogenic 5-HT modulators) 2A and / or 5HT 2C Non-hallucinogenic compounds that have demonstrated similar therapeutic efficacy to hallucinogenic 5-HT modulators (e.g., 5HT) are described herein in several embodiments. In some embodiments, the non-hallucinogenic compounds described herein are used for neurological disorders, similar to hallucinogenic 5-HT modulators (e.g., 5HT) 2A and / or 5HT 2C It provides better therapeutic efficacy than a modulator.

[0059] Heterocyclic compounds useful for treating various diseases, including brain disorders and other conditions, are provided herein. In some embodiments, the heterocyclic compounds provided herein are 5-HT2 modulators that promote neural plasticity (e.g., cortical plasticity).

[0060] In some embodiments, the following formula (K): [ka] {In the formula, Each R 1a , R 1b , R 1c , and R 1d H and C are independent of each other. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyls, halogens, C 1-6 Haloalkyl, C 1-6 It is a haloalkoxy, -NO2, or -CN; or two R atoms on adjacent ring atoms. 1a The base is combined to form C 4-8 Forming cycloalkyls or 4-8 membered heterocycloalkyls having 1-2 heteroatoms that are independently N, O, or S; R 2a and R 2b These are H and C, which are independent of each other. 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, C 1-6 Haloalkyl, or C 1-6 Is it a haloalkoxy; or R 2a and R 2b These are combined to form a 4-8 membered heterocycloalkyl group, each independently having 1-2 heteroatoms that are N, O, or S; R 3 H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, C 1-6 Haloalkyl, or C 1-6 It is a haloalkoxy; R 3a is absent or C 1-6 Is it alkyl; or, R 3 and R 3aThese are combined to form a 3-8 membered heterocycloalkyl group, each independently having 1-2 heteroatoms that are N, O, or S; The subscripts m and p are independently 0 to 2, and Compounds having the structure {where the subscripts n and r are independently 0 to 3} or pharmaceutically acceptable salts thereof are provided herein.

[0061] In some embodiments, the following formula (J): [ka] {In the formula, Each R 1a , R 1b , R 1c , and R 1d H and C are independent of each other. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyls, halogens, C 1-6 Haloalkyl, C 1-6 It is a haloalkoxy, -NO2, or -CN; or two R atoms on adjacent ring atoms. 1a The base is combined to form C 4-8 Forming cycloalkyls or 4-8 membered heterocycloalkyls having 1-2 heteroatoms that are independently N, O, or S; R 2a and R 2b These are H and C, which are independent of each other. 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, C 1-6 Haloalkyl, or C 1-6 Is it a haloalkoxy; or R 2a and R 2b These are combined to form a 4-8 membered heterocycloalkyl group, each independently having 1-2 heteroatoms that are N, O, or S; R 3 H, C 1-6alkyl, C 1-6 alkoxy, C 1-6 alkoxyalkyl, C 1-6 haloalkyl, or C 1-6 haloalkoxy; subscripts m and p are each independently 0 to 2, and subscripts n and r are each independently 0 to 3}, a compound having the structure or a salt thereof acceptable as a medicament is provided herein.

[0062] In some embodiments, the following formula (I):

Chemical formula

[0063] In some embodiments, the following formula (Ia), formula (Ib), formula (Ic), or formula (Id):

Chemical formula

[0064] In some embodiments, the following formula (Ia):

Chemical formula

[0065] In some embodiments, the following formula (Ib):

Chemical formula

[0066] In some embodiments, the following formula (Ic):

Chemical formula

[0067] In some embodiments, the following formula (Id): [ka] Compounds having the structure are provided herein.

[0068] R 1a R1 can be any suitable functional group. In some embodiments, R1 1a H, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyls, halogens, C 1-6 Haloalkyl, C 1-6 It is a haloalkoxy, -NO2, or -CN. In some embodiments, R 1a H, C 1-6 Alkyl, C 1-6 It is an alkoxy or halogen. In some embodiments, R 1a H, C 1-6 It is an alkoxy or halogen. In some embodiments, R 1a H is H.

[0069] R 2a and R 2b R can be any suitable functional group. In some embodiments, R 2a and R 2b These are H and C, respectively, independently. 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, C 1-6 Haloalkyl, or C 1-6 Is it a haloalkoxy; or R 2a and R 2bThese are combined to form a 4-8 membered heterocycloalkyl group, each having 1-2 heteroatoms that are independently N, O, or S. In some embodiments, R 2a and R 2b These are H and C, respectively, independently. 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxyalkyl, or C 1-6 In some embodiments, R 2a and R 2b These are, independently, H or C 1-6 It is alkyl. In some embodiments, R 2a and R 2b Each of them is independent of C 1-6 It is alkyl. In some embodiments, R 2a and R 2b Each of them is independently ethyl.

[0070] R 3 R can be any suitable functional group. In some embodiments, R 3 H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, C 1-6 Haloalkyl, or C 1-6 It is a haloalkoxy. In some embodiments, R 3 H or C 1-6 It is alkyl. In some embodiments, R 3 is C 1-6 It is alkyl. In some embodiments, R 3 It is methyl.

[0071] In some embodiments, R 3a is either absent or C 1-6 It may be alkyl. In some embodiments, R 3a It does not exist. In some embodiments, R 3a is C 1-6 It is alkyl. In some embodiments, R 3ais methyl.

[0072] The subscripts m, n, p, and r can be any suitable integers. In some embodiments, the subscripts m and p are each independently 0 to 2; and the subscripts n and r are each independently 0 to 3. In some embodiments, n is 0.

[0073] In some embodiments, the following structure:

Chemical formula

[0074] In some embodiments, the following structure:

Chemical formula

[0075] In some embodiments, the following structure:

Chemical formula

[0076] In some embodiments, the following structure:

Chemical formula

[0077] In some embodiments, the following structure:

Chemical formula

[0078] In some embodiments, the following structure: [ka] Compounds having or pharmaceutically acceptable salts thereof are provided herein.

[0079] In some embodiments, the following structure: [ka] Compounds having the above are provided herein.

[0080] In some embodiments, the following structure: [ka] Compounds having or pharmaceutically acceptable salts thereof are provided herein.

[0081] In some embodiments, the following structure: [ka] Compounds having or pharmaceutically acceptable salts thereof are provided herein.

[0082] In some embodiments, the following structure: [ka] Compounds having the above are provided herein.

[0083] In some embodiments, the present invention features the following structure characterized by unit cell dimensions a=7.0716(6)Å, α=90°, b=14.4326(12)Å, β=90°, c=23.0876(19)Å, and γ=90°: [ka] The present invention provides a crystalline compound of (7aS,10R)-10-(diethylcarbamoyl)-8,8-dimethyl-7a,8,9,10-tetrahydro-7H-indro[7,1-fg][1,7]naphthyridine-8-ium iodide having the following properties:

[0084] The compounds of the present invention may also exist in the form of salts, such as acidic or basic salts. Exemplary examples of pharmaceutically acceptable salts are salts of mineral acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid), salts of organic acids (e.g., fumaric acid, acetic acid, propionic acid, glutamic acid, citric acid), and salts of quaternary ammonium compounds (e.g., methyl iodide, ethyl iodide). Pharmaceutically acceptable salts are understood to be non-toxic. Further information regarding preferred pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference.

[0085] The present invention also includes isotope-labeled compounds of the present invention, in which one or more atoms are replaced by one or more atoms having a specific atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the present invention include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, sulfur, and chlorine (e.g., 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 18 F, 35 S and 36 Examples include Cl. The isotope-labeled compounds of the present invention are useful for assays of the tissue distribution of the compounds, as well as their prodrugs and metabolites; preferred isotopes for such assays include 3 H 14 C is one example. In addition, under certain circumstances, heavier isotopes, such as deuterium ( 2Substitution with H, etc., can provide high metabolic stability, which can lead to therapeutic benefits such as an extension of the half-life in vivo or a reduction in the required dose. Generally, the isotope-labeled compounds of the present invention can be prepared according to methods known to those skilled in the art by using an isotope-labeling reagent instead of a non-isotopically labeled reagent. The compounds of the present invention can be isotope-labeled at positions adjacent to the basic amine of the aromatic ring and the methyl group of the methoxy substituent.

[0086] The present invention comprises all tautomers and stereoisomers of the compounds of the present invention in mixtures or in pure or substantially pure form. The compounds of the present invention have a chiral center on a carbon atom, and therefore the compounds of the present invention may exist as diastereomers, enantiomers, or mixtures thereof. All conformational isomers (e.g., cis and trans isomers) and all optical isomers (e.g., enantiomers and diastereomers), racemates, diastereomers, and other mixtures of such isomers, as well as solvates, hydrates, isomorphs, polymorphs, and tautomers are within the scope of the present invention. The compounds of the present invention can be prepared using diastereomers, enantiomers, or racemic mixtures as starting materials. Furthermore, diastereomer and enantiomer products can be separated by chromatography, fractional crystallization, or other methods known to those skilled in the art. 5-HT

[0087] 5-HT2 agonism correlates with the promotion of neuroplasticity (Ly et al., 2018). 5-HT2 antagonists neutralize the neurite and spine formation effects of hallucinogenic compounds with 5-HT2 agonist activity, such as DMT, LSD, and DOI. Furthermore, DMT and other psychedelic compounds promote increased dendritic branching complexity, dendritic spine density, and synapse formation via 5-HT2-dependent processes. Importantly, the psychoplastogenic effects of the compounds provided herein are also blocked under these conditions, indicating the involvement of the 5-HT2 receptor in their mechanism of action. In addition, modulation of the 5-HT2 receptor appears to be important for neuroplasticity, as well as in various psychological states such as anxiety, depression, post-traumatic stress disorder (PTSD), and schizophrenia.

[0088] Furthermore, non-hallucinogenic compounds (e.g., lithulide and 6-MeO-DMT) are 5HT 2A When the sensor assay is run in antagonist mode, 5-HT is bound and removed (compete off). In addition, compounds that are non-hallucinogenic in animals (e.g., humans), such as 6-F-DET and ketanserine, are not affected by 5HT in the antagonist mode sensor assay. 2A It competes with the binding of 5HT to 5HT. In some embodiments, the compounds provided herein are 5HT of 5HT 2A To prevent bonding to 5HT. In some embodiments, 2A The sensor assay is in antagonist mode. In some embodiments, the compounds provided herein are 5-HT of 5HT 2A It prevents binding to and has non-hallucinogenic potential. In some embodiments, the compounds provided herein are 5HT of 5HT 2A It prevents binding to and is non-hallucinogenic. In some embodiments, the compounds provided herein are antagonists of 5-HT. 2AIt prevents binding to and has non-hallucinogenic potential. In some embodiments, the compounds provided herein prevent binding to 5-HT in antagonist mode and are non-hallucinogenic compounds. In some embodiments, the compounds provided herein inhibit the response of the sensor assay in antagonist mode and have non-hallucinogenic potential. In some embodiments, the compounds provided herein inhibit the response of the sensor assay in antagonist mode and are non-hallucinogenic compounds.

[0089] In some embodiments, the effect of the compounds provided herein on agonist mode sensor assays is that the compounds are 5-HT 2A Receptors and / or 5-HT 2C This suggests that the compounds are non-hallucinogenic ligands for the receptor. In some embodiments, the effect of the compounds provided herein on an antagonist-mode sensor assay is that the compounds are 5-HT 2A Receptors and / or 5-HT 2C This suggests that the compounds are non-hallucinogenic ligands for the receptor. In some embodiments, the effects of the compounds provided herein on agonist and antagonist mode sensor assays both indicate that the compounds are 5-HT 2A Receptors and / or 5-HT 2C This suggests that it is a non-hallucinogenic ligand for the receptor.

[0090] In some embodiments, non-hallucinogenic compounds exhibiting similar therapeutic potential to hallucinogenic 5-HT2 agonists are described herein. In some embodiments, the non-hallucinogenic compounds described herein offer superior therapeutic potential to hallucinogenic 5-HT2 agonists for neurological disorders. In some embodiments, the compounds of the present invention are 5-HT 2A Receptors and / or 5-HT 2C It acts as a receptor modulator and promotes neural plasticity (e.g., cortical plasticity).

[0091] In some embodiments, the compounds provided herein are 5-HT 2A Receptors and / or 5-HT 2C It has activity at the receptor. In some embodiments, the compounds provided herein are 5-HT 2A Receptors and / or 5-HT 2C By activating receptors, biological responses are elicited (e.g., allosteric regulation or 5-HT). 2A Receptors and / or 5-HT 2C (Modification of biological targets that activate receptors). In some embodiments, the compounds provided herein selectively target 5-HT 2A It acts as a modulator and promotes neural plasticity (e.g., cortical structure plasticity). In some embodiments, the compounds provided in the present invention are selective 5-HT 2C It acts as a modulator and promotes neural plasticity (e.g., cortical structure plasticity). In some embodiments, promotion of neural plasticity includes, for example, increased dendritic spine growth, increased synaptic protein synthesis, enhanced synaptic response, increased complexity of dendritic branching, increased dendritic branch content, increased spine formation, increased neurite formation, or any combination thereof. In some embodiments, enhancement of neural plasticity includes, for example, enhanced cortical structure plasticity in the anterior part of the brain.

[0092] In some embodiments, the compounds provided herein (e.g., 5-HT) 2A Modulator and / or 5-HT 2C The modulator is non-hallucinogenic. In some embodiments, the compounds provided herein (e.g., 5-HT) 2A Modulator and / or 5-HT 2CThe modulator is used to treat neurological disorders, and this modulator does not induce dissociative side effects. In some embodiments, the hallucinogenic potential of the compounds described herein is evaluated in vitro. In some embodiments, the hallucinogenic potential of the compounds described herein, as evaluated in vitro, is compared to the hallucinogenic potential of the hallucinogenic homolog. In some embodiments, the compounds provided herein do not exhibit as much non-hallucinogenic potential in vitro as the hallucinogenic homolog.

[0093] In some embodiments, the compounds provided herein (e.g., 5-HT) 2A Modulator and / or 5-HT 2C Modulators are used to treat neurological disorders. In some embodiments, neurological disorders include decreased neuroplasticity, decreased cortical structure plasticity, and 5-HT 2A Decreased receptor content, 5-HT 2C This includes increased receptor content, decreased complexity of dendritic branching, loss of dendritic spines, decreased dendritic branch content, decreased spine formation, decreased neurite formation, neurite regression, or any combination thereof.

[0094] In some embodiments, the compounds provided herein (e.g., 5-HT) 2A Modulator and / or 5-HT 2C Modulators are used to increase neural plasticity. In some embodiments, compounds provided herein (e.g., 5-HT) are used. 2A Modulator and / or 5-HT 2C Modulators are used to treat brain disorders. In some embodiments, the compounds provided herein (e.g., 5-HT) 2A Modulator and / or 5-HT 2C Modulators are used to increase at least one of the following: translation, transcription, or secretion of neurotrophic factors.

[0095] In some embodiments, the compounds provided herein, including pharmaceutically acceptable salts and solvates thereof, are non-hallucinogenic psychoplastogens. In some embodiments, non-hallucinogenic psychoplastogens promote neuronal growth, improve the structure of neurons, or improve their combination. IV. Pharmaceutical Compositions and Formulations

[0096] In some embodiments, pharmaceutical compositions comprising a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof are provided herein.

[0097] The compositions of the present invention can be prepared in a wide variety of oral, parenteral, and topical dosage forms. Oral preparations include tablets, pills, powders, capsules, liquids, licks, cachets, gels, syrups, slurries, and suspensions suitable for oral administration by patients. The compositions of the present invention can also be administered by injection, i.e., intravenously, intramuscularly, intradermally, subcutaneously, duodenally, or intraperitoneally. Furthermore, the compositions described herein can be administered by inhalation, for example, intranasally. In addition, the compositions of the present invention can be administered percutaneously. The compositions of the present invention can also be administered by intraocular, intravaginal, and intrarectal routes (including suppositories), gas infusion, powders, and aerosol formulations (for examples of inhaled steroids, see Rohatagi, J. Clin. Pharmacol. 35:1187-1193, 1995; Tjwa, Ann. Allergy Asthma Immunol. 75:107-111, 1995). Therefore, the present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier or excipient and the compound of the present invention.

[0098] For preparing pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers may be solid or liquid. Preparations in solid form include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. Solid carriers may be one or more substances that can act as diluents, flavorings, binders, preservatives, tablet disintegrants, or encapsulating materials. Detailed information regarding formulation and administration procedures is readily available in scientific literature and patent documents; see, for example, the latest edition of Remington's Pharmaceutical Sciences, Maack Publishing Co, Easton PA ("Remington's").

[0099] In the powder, the carrier is a finely pulverized solid, which is present in the mixture together with the finely pulverized active ingredient. In the tablet, the active ingredient is mixed in a suitable ratio with a carrier having the required binding properties and compressed into the desired shape and size. The powder and tablet preferably contain 5% or 10% to 70% of the compound of the present invention.

[0100] Suitable solid excipients include, but are not limited to, magnesium carbonate; magnesium stearate; talc; pectin; dextrin; starch; tragacanth; low-melting-point wax; cocoa butter; carbohydrates; sugars (including, but not limited to, lactose, sucrose, mannitol or sorbitol, and starches derived from corn, wheat, rice, potato or other plants); cellulose (e.g., methylcellulose, hydroxypropylmethylcellulose or sodium carboxymethylcellulose); and gum (including arabic and tragacanth); and proteins (including, but not limited to, gelatin and collagen). If desired, disintegrants or solubilizers (e.g., cross-linked polyvinylpyrrolidone, agar, alginic acid or its salts (e.g., sodium alginate)) may be added.

[0101] The core of the sugar formulation is coated with a suitable coating, such as a concentrated sugar solution, which may also contain gum arabic, talc, polyvinylpyrrolidone, Carbopol gel, polyethylene glycol, and / or titanium dioxide, a lacquer solution, and a suitable organic solvent or solvent mixture. Dyes or pigments may be added to the tablet or sugar formulation coating for product identification or to indicate the amount of the active compound (i.e., dosage). The pharmaceutical formulations of the present invention can also be used orally, for example, in push-in capsules made of gelatin, and in soft-seal capsules made of gelatin and a coating such as glycerol or sorbitol. Push-in capsules may contain the compound of the present invention in a mixture of a filler or binder such as lactose or starch, a lubricant such as talc or magnesium stearate, and a stabilizer as needed. In soft capsules, the compound of the present invention may be dissolved or suspended in a suitable liquid such as fatty oil, liquid paraffin, or liquid polyethylene glycol, with or without a stabilizer.

[0102] To prepare the suppositories, a mixture of fatty acid glycerides or a low-melting-point wax such as cocoa butter is first melted, and the compound of the present invention is uniformly dispersed therein by stirring. Then, the melted homogeneous mixture is poured into a mold of a suitable size and cooled to solidify.

[0103] Preparations in liquid form include solutions, suspensions, and emulsions, such as water or water / propylene glycol solutions. For parenteral injection, liquid preparations may be formulated as solutions in aqueous polyethylene glycol solutions.

[0104] Aqueous solutions suitable for oral use can be prepared by dissolving the compounds of the present invention in water and adding suitable colorants, fragrances, stabilizers, and thickeners as desired. Aqueous suspensions suitable for oral use may contain the finely ground active components in a viscous material (e.g., natural or synthetic rubber, resin, methylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and gum arabic) and a dispersant or wetting agent (e.g., naturally occurring phosphatides (e.g., lecithin), alkylene oxides and fatty acid condensates (e.g., polyoxyethylene stearate), ethylene oxides and long-chain aliphatic alcohol condensates (e.g., heptadecaethyleneoxycetanol), ethylene oxides and fatty acids and It can be produced by dispersing in water with a condensate of a partial ester derived from xitol (e.g., polyoxyethylene sorbitol mono-oleate) or a condensate of ethylene oxide with a partial ester derived from fatty acids and hexitol anhydride (e.g., polyoxyethylene sorbitan mono-oleate). The aqueous suspension may also contain one or more preservatives (e.g., ethyl p-hydroxybenzoate or n-propyl p-hydroxybenzoate), one or more colorants, one or more flavorings, and one or more sweeteners (e.g., sucrose, aspartame, or saccharin). The formulation can be adjusted in terms of osmolality.

[0105] This also includes preparations in solid form that are intended to be converted into liquid preparations for oral administration immediately before use. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active ingredient, colorants, flavorings, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, and the like.

[0106] An oily suspension may be formulated by suspending the compound of the present invention in a vegetable oil (e.g., peanut oil, olive oil, sesame oil, or coconut oil) or mineral oil (e.g., liquid paraffin); or a mixture thereof. The oily suspension may contain a thickener (e.g., beeswax, solid paraffin, or cetyl alcohol). A sweetener (e.g., glycerol, sorbitol, or sucrose) may be added to provide a palatable oral preparation. These formulations can be preserved by adding an antioxidant such as ascorbic acid. For an example of an injectable oily vehicle, see Minto, J. Pharmacol. Exp. Ther. 281:93-102, 1997. The pharmaceutical formulation of the present invention may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil or mineral oil, or a mixture thereof, as described above. Suitable emulsifiers include naturally occurring gums (e.g., gum arabic and gum tragacanth), naturally occurring phosphatides (e.g., soy lecithin), esters or partial esters derived from fatty acids and hexitol anhydrides (e.g., sorbitan monooleate), and condensates of these partial esters with ethylene oxide (e.g., polyoxyethylene sorbitan monooleate). The emulsion may also contain sweeteners and flavorings, as in the formulations of syrups and elixirs. Such formulations may also contain lubricants, preservatives, or colorants.

[0107] The compositions of the present invention can also be delivered as microspheres for slow release within the body. For example, microspheres can be formulated for administration via intradermal injection of drug-containing microspheres that slowly release under the skin (see Rao, J. Biomater Sci. Polym. Ed. 7:623-645, 1995; as a biodegradable, injectable gel formulation (see, for example, Gao Pharm. Res. 12:857-863, 1995); or as microspheres for oral administration (see, for example, Eyles, J. Pharm. Pharmacol. 49:669-674, 1997). Both transdermal and intradermal routes provide consistent delivery over several weeks or months.

[0108] In another embodiment, the compositions of the present invention may be formulated for parenteral administration (e.g., intravenous (IV) administration or administration into the lumen of a body cavity or organ). The formulation for administration typically comprises a solution of the composition of the present invention dissolved in a pharmaceutically acceptable carrier. Acceptable vehicles and solvents that can be used are water and Ringer's solution and isotonic sodium chloride. Furthermore, sterilized fixative oils may conventionally be used as solvents or suspension media. For this purpose, any non-irritating fixative oil containing synthetic mono- or diglycerides may be used. Furthermore, fatty acids such as oleic acid may similarly be used in the preparation of injectables. These solutions are sterilized and typically do not contain undesirable substances. These formulations may be sterilized by conventional, well-known sterilization procedures. These formulations may contain pharmaceutically acceptable auxiliary substances (e.g., pH adjusters and buffers, toxicity modifiers, e.g., sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate, etc.) as needed to approximate physiological conditions. The concentration of the composition of the present invention in these formulations can vary considerably and may be selected mainly based on the volume, viscosity, body weight, etc., according to the specific dosage mode selected and the patient's needs. For IV administration, the formulation may be a sterile injectable preparation (e.g., a sterile injectable aqueous or oily suspension). This suspension may be formulated according to known techniques using suitable dispersants or wetting agents and suspending agents. The sterile injectable formulation may also be a sterile injectable solution or suspension in a non-toxic, parenterally acceptable diluent or solvent (e.g., a solution of 1,3-butanediol).

[0109] In other embodiments, and in some embodiments, formulations of the compositions of the present invention may be delivered by using liposomes, which may fuse with the cell membrane or be endocytotic, i.e., delivered by using ligands attached to the liposomes or ligands directly attached to oligonucleotides that bind to cell surface membrane protein receptors, thereby endocytosis. In particular, the use of liposomes can be focused on delivering the compositions of the present invention to target cells in vivo, especially when the liposome surface has ligands specific to target cells or, separately, is preferentially oriented to specific organs (see, for example, Al-Muhammed, J. Microencapsul. 13:293-306, 1996; Chonn, Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro, Am. J. Hosp. Pharm. 46:1576-1587, 1989).

[0110] The compositions of the present invention can be delivered by any suitable means, including oral, parenteral, and topical methods. Transdermal administration methods via topical routes can be formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.

[0111] Pharmaceuticals are preferably available in unit dosage forms. In such forms, the preparation is subdivided into unit doses containing an appropriate amount of the compound of the present invention. A unit dosage form may be a packaged preparation, the packaging containing separate amounts of the preparation (e.g., packaged tablets, capsules, and powders in vials or ampoules). Alternatively, a unit dosage form may be the capsule, tablet, cachet or lollipop itself, or an appropriate number of these in packaged forms.

[0112] The compound of the present invention may be present in any suitable amount and may depend on various factors, including but not limited to the subject's body weight and age, and disease state. Suitable dosage ranges for the compound of the present invention include about 0.1 mg to about 10,000 mg, or about 1 mg to about 1,000 mg, or about 10 mg to about 750 mg, or about 25 mg to about 500 mg, or about 50 mg to about 250 mg. Suitable dosages for the compound of the present invention include about 1 mg, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1,000 mg.

[0113] The compounds of the present invention can be administered at any preferred frequency, interval, and duration. For example, the compounds of the present invention may be administered once per hour, twice per hour, three times per hour or more, once per day, twice per day, three times per day or more, or once every two, three, four, five, six, or seven days to provide a preferred dose level. When the compounds of the present invention are administered multiple times a day, typical intervals include 5, 10, 15, 20, 30, 45, and 60 minutes, and 1, 2, 4, 6, 8, 10, 12, 16, 20, and 24 hours. The compounds of the present invention may be administered once, twice, three times, or more over periods of one hour, one to six hours, one to twelve hours, one to twenty-four hours, six to twelve hours, twelve to twenty-four hours, one day, one to seven days, one week, one to four weeks, one month, one to twelve months, one year or more, or indefinitely.

[0114] The composition may also include other suitable therapeutic agents. The compounds described herein may be used in combination with other active agents known to be useful in modulating glucocorticoid receptors, or with adjuvants that may not be effective on their own but may contribute to the effectiveness of active agents.

[0115] The compounds of the present invention may be administered co-administered with other active substances. Co-administration includes administering the compounds of the present invention and the active substances within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of each other. Co-administration also includes administering the compounds of the present invention and the active substances simultaneously, nearly simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other) or sequentially in any order. Furthermore, each compound and active substance of the present invention may be administered once a day, or two, three, or more times per day, to provide a preferred daily dose level.

[0116] In some embodiments, simultaneous administration can be achieved by simultaneous formulation, i.e., by preparing a single pharmaceutical composition containing both the compound of the present invention and the active substance. In other embodiments, the compound of the present invention and the active substance are formulated separately.

[0117] The compounds and active substances of the present invention may be provided in compositions of the present invention in any preferred weight ratio, such as about 1:100 to about 100:1 (w / w), or about 1:50 to about 50:1, about 1:25 to about 25:1, about 1:10 to about 10:1, or about 1:5 to 5:1 (w / w). The compounds and other active substances of the present invention may be provided in any preferred weight ratio, such as about 1:100 (w / w), 1:50, 1:25, 1:10, 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 10:1, 25:1, 50:1, or 100:1 (w / w). Other dosages and dose ratios of the compounds and active substances of the present invention are preferred in the compositions and methods of the present invention. V. Treatment Methods

[0118] In some embodiments, for example, but not limited thereto, a method for treating a disease or disorder, such as a neurological disorder, comprising administering a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof to a subject in need thereof, thereby treating the disease or disorder, is provided herein.

[0119] In some embodiments, methods for enhancing neuronal plasticity are provided herein, comprising contacting nerve cells with a compound of the present invention or a pharmaceutically acceptable salt thereof in an amount sufficient to enhance the neuronal plasticity of the nerve cells, wherein the compound causes a maximum number of dendritic intersections that increases by more than 1.0 times according to Scholl analysis. Neurological disorders

[0120] Neuronal plasticity and its changes are responsible for many neurological diseases and disorders. For example, changes in the number and morphology (e.g., length, crossing, density) of dendritic spines during development and adulthood are associated with synapse formation, maintenance, and decomposition, and these changes are thought to establish and reconstruct connectivity within neural circuits. Furthermore, the structural plasticity of dendritic spines is coordinated with synaptic function and plasticity. For instance, spine enlargement is associated with long-term potentiation in neural circuits, while long-term depression is associated with spine reduction.

[0121] Furthermore, dendritic spines undergo experience-dependent morphological changes in living animals, and even subtle changes in dendritic spines can affect synaptic function, synaptic plasticity, and connectivity patterns in neural circuits. For example, neurological disorders and conditions such as neurodegenerative diseases and disorders (e.g., Alzheimer's disease and Parkinson's disease) and neuropsychiatric disorders and conditions (e.g., depression and schizophrenia) are associated with disease-specific disturbances in the shape, size, and / or number of dendritic spines, suggesting that dendritic spines function as a common underlying factor in diseases, including those involving information processing disorders.

[0122] Unless otherwise indicated, neurological disorders or conditions usually refer to disorders or conditions of the central nervous system (CNS) of an individual (e.g., the brain, spine, and / or nerves).

[0123] In some embodiments, methods for treating neurological disorders or disorders using compounds provided herein (e.g., compounds of formula (K), formula (J), formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id), or pharmaceutically acceptable salts or solvates thereof) are provided herein.

[0124] In some cases, compounds useful for treating various brain disorders and other conditions are provided herein. In some embodiments, the compounds provided herein are 5-HT 2A It is a modulator and promotes neural plasticity (e.g., cortical plasticity). In some embodiments, 5-HT 2A Modulator (e.g., 5-HT) 2A Agonists are used to treat brain disorders. In some embodiments, the compounds provided herein are 5-HT 2C It is a modulator and promotes neural plasticity (e.g., cortical plasticity). In some embodiments, 5-HT 2C Modulators are used to treat brain disorders. In some embodiments, brain disorders include decreased neuroplasticity, decreased cortical structure plasticity, and 5-HT 2A Decreased receptor content, 5-HT 2C This includes increased receptor content, decreased complexity of dendritic branching, loss of dendritic spines, decreased dendritic branch content, decreased spine formation, decreased neurite formation, neurite regression, or any combination thereof.

[0125] In one embodiment, the compounds provided herein (e.g., compounds of formula (K), formula (J), formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id), or pharmaceutically acceptable salts or solvates thereof) improve the number and morphology of dendritic spines lost in neurological disorders or disorders.

[0126] In some embodiments, the compounds of the present invention are used to treat neurological disorders. In some embodiments, the compounds have, for example, antitoxic, antidepressant, anxiolytic properties, or a combination thereof. In some embodiments, the neurological disorder is a neuropsychiatric disorder. In some embodiments, the neuropsychiatric disorder is a mood or anxiety disorder. In some embodiments, the neurological disorder is a migraine, headache (e.g., cluster headache), post-traumatic stress disorder (PTSD), anxiety, depression, neurodegenerative disorders, Alzheimer's disease, Parkinson's disease, mental disorders, treatment-resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, and intoxication (e.g., substance use disorder). In some embodiments, the disorder is a headache disorder. In some embodiments, the neurological disorder is a migraine or cluster headache. In some embodiments, the disorder is a migraine. In some embodiments, the disorder is a cluster headache. In some embodiments, the disorder is intoxication. In some embodiments, the disorder is a substance use disorder. In some embodiments, the disorder is alcohol use disorder. In some embodiments, the disorder is alcohol use disorder.

[0127] In some embodiments, the neurological disorder is a neurodegenerative disorder, Alzheimer's disease, or Parkinson's disease. In some embodiments, the neurological disorder is a psychiatric disorder, treatment-resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, post-traumatic stress disorder (PTSD), addiction (e.g., substance use disorder), depression, or anxiety. In some embodiments, the neuropsychiatric disorder is a psychiatric disorder, treatment-resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, post-traumatic stress disorder (PTSD), addiction (e.g., substance use disorder), depression, or anxiety. In some embodiments, the neuropsychiatric disorder or neurological disorder is post-traumatic stress disorder (PTSD), addiction (e.g., substance use disorder), schizophrenia, depression, or anxiety. In some embodiments, the neuropsychiatric disorder or neurological disorder is addiction (e.g., substance use disorder). In some embodiments, the neuropsychiatric disorder or neurological disorder is depression. In some embodiments, the neuropsychiatric disorder or neurological disorder is anxiety. In some embodiments, the neuropsychiatric disorder or neurological disorder is post-traumatic stress disorder (PTSD). In some embodiments, the neurological disorder is a stroke or traumatic brain injury. In some embodiments, the neuropsychiatric disorder or neurological disorder is schizophrenia.

[0128] In some embodiments, the disease is a neuropsychiatric disorder. In some embodiments, the disease is a neurodegenerative disorder.

[0129] In some embodiments, the compounds of the present invention are used to treat brain disorders. In some embodiments, the compounds have, for example, antitoxic, antidepressant, anxiolytic properties, or a combination thereof. In some embodiments, the brain disorder is a neuropsychiatric disorder. In some embodiments, the neuropsychiatric disorder is a mood or anxiety disorder. In some embodiments, examples of brain disorders include migraines, cluster headaches, post-traumatic stress disorder (PTSD), anxiety, depression, schizophrenia, and intoxication (e.g., substance use disorder). In some embodiments, examples of brain disorders include migraines, intoxication (e.g., substance use disorder), depression, and anxiety.

[0130] In some embodiments, methods for enhancing neuronal plasticity are provided herein, comprising contacting nerve cells with a compound of the present invention or a pharmaceutically acceptable salt thereof in an amount sufficient to enhance the neuronal plasticity of the nerve cells, wherein the compound causes a maximum number of dendritic intersections that increases by more than 1.0 times according to Scholl analysis.

[0131] Neuroplasticity refers to the brain's ability to change structure and / or function throughout an individual's life. Throughout an individual's life, new neurons are generated and integrated into the central nervous system. Enhancements of neuroplasticity include, but are not limited to, accelerated neuronal growth, accelerated neurite formation, accelerated synapse formation, accelerated dendritic formation, increased complexity of dendritic branching, increased density of dendritic spines, and increased excitatory synapses in the brain. In some embodiments, enhancements of neuroplasticity include accelerated neuronal growth, accelerated neurite formation, accelerated synapse formation, accelerated dendritic formation, increased complexity of dendritic branching, and increased density of dendritic spines.

[0132] In some embodiments, enhancing neuroplasticity can treat neurodegenerative disorders, Alzheimer's disease, Parkinson's disease, psychiatric disorders, depression, addiction, anxiety, post-traumatic stress disorder, treatment-resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, or substance use disorders. In some embodiments, the neuropsychiatric disorder is bipolar disorder. In some embodiments, the disease is depression. In some embodiments, the disease is a neurodegenerative disease. In some embodiments, the disease is Alzheimer's disease or Parkinson's disease. In some embodiments, the disease is Alzheimer's disease. In some embodiments, the disease is Parkinson's disease.

[0133] In some embodiments, the compounds of the present invention are used to enhance neuroplasticity. In some embodiments, the compounds used to enhance neuroplasticity have, for example, antitoxic, antidepressant, anxiolytic properties, or a combination thereof. In some embodiments, a decrease in neuroplasticity is associated with neuropsychiatry. In some embodiments, neuropsychiatry is a mood or anxiety disorder. In some embodiments, neuropsychiatry includes, for example, migraine, cluster headache, post-traumatic stress disorder (PTSD), schizophrenia, anxiety, depression, and addiction (e.g., substance use disorder). In some embodiments, brain disorders include, for example, migraine, addiction (e.g., substance use disorder), depression, and anxiety. In some embodiments, the disease is neuropsychiatry.

[0134] In some embodiments, experiments or assays to determine the increase in neuronal plasticity of any compound of the present invention include phenotypic assays, dendritic formation assays, neurite formation assays, synapse formation assays, Scholl analysis, concentration-response experiments, and 5-HT assays. 2A Agonist assay, 5-HT 2A Antagonist assay, 5-HT 2A Binding assay, or 5-HT 2A This is a blockade experiment (e.g., a ketanserine blockade experiment). In some embodiments, the experiment or assay used to determine the hallucinogenic potential of the compounds provided herein is a mouse head spasm response (HTR) assay.

[0135] The compound of the present invention is 5-HT 2A It has modulator activity. In some embodiments, the compounds of the present invention are 5-HT 2A It has activity as a modulator. In some embodiments, the compounds of the present invention are 5-HT 2A Activates receptors (e.g., allosteric regulation or 5-HT) 2A It induces a biological response by modulating the biological targets that activate receptors. 5-HT 2AThe activity was associated with promoting neuroplasticity. In some embodiments, 5HT 2A The sensor assay is either agonist mode or antagonist mode. In some embodiments, 5HT 2A The sensor assay is in agonist mode.

[0136] In some embodiments, the compounds described herein are selective 5-HT 2A It is a modulator. In some embodiments, the compounds described herein are 5-HT 2A It acts as a modulator and promotes neural plasticity (e.g., cortical plasticity). In some embodiments, the compounds described herein selectively promote 5-HT 2A It acts as a modulator and promotes neural plasticity (e.g., cortical structure plasticity). In some embodiments, the promotion of neural plasticity includes, for example, enhanced dendritic spine growth, increased synaptic protein synthesis, enhanced synaptic response, enhanced dendritic branch complexity, enhanced dendritic branch content, enhanced spine formation, enhanced neurite formation, or any combination thereof. In some embodiments, enhanced neural plasticity includes, for example, enhanced cortical structure plasticity in the anterior part of the brain.

[0137] In some embodiments, non-hallucinogenic 5-HT 2A Modulator (e.g., 5-HT) 2A Agonists are used to treat diseases. In some embodiments, non-hallucinogenic 5-HT 2A Modulator (e.g., 5-HT) 2A Agonists are used to enhance neuroplasticity. In some embodiments, non-hallucinogenic 5-HT 2A Modulator (e.g., 5-HT) 2A Agonists are used to enhance neuronal plasticity and dendritic spine density.

[0138] In some embodiments, experiments or assays to determine the increase in neuronal plasticity of any compound of the present invention include phenotypic assays, dendritic formation assays, neurite formation assays, synapse formation assays, Scholl analysis, concentration-response experiments, and 5-HT assays. 2C Agonist assay, 5-HT 2C Antagonist assay, 5-HT 2C Binding assay, or 5-HT 2C This is a blockade experiment (e.g., a ketanserine blockade experiment). In some embodiments, the experiment or assay used to determine the hallucinogenic potential of the compounds provided herein is a mouse head spasm response (HTR) assay.

[0139] The compound of the present invention is 5-HT 2C It has modulator activity. In some embodiments, the compounds of the present invention are 5-HT 2C It has activity as a modulator. In some embodiments, the compounds of the present invention are 5-HT 2C Activates receptors (e.g., allosteric regulation or 5-HT) 2C It induces a biological response by modulating the biological targets that activate receptors. 5-HT 2C The activity was associated with promoting neuroplasticity. In some embodiments, 5HT 2C The sensor assay is either agonist mode or antagonist mode. In some embodiments, 5HT 2C The sensor assay is in agonist mode.

[0140] In some embodiments, the compounds described herein are selective 5-HT 2C It is a modulator. In some embodiments, the compounds described herein are 5-HT 2C It acts as a modulator and promotes neural plasticity (e.g., cortical plasticity). In some embodiments, the compounds described herein selectively promote 5-HT 2CIt acts as a modulator and promotes neural plasticity (e.g., cortical structure plasticity). In some embodiments, the promotion of neural plasticity includes, for example, enhanced dendritic spine growth, increased synaptic protein synthesis, enhanced synaptic response, enhanced dendritic branch complexity, enhanced dendritic branch content, enhanced spine formation, enhanced neurite formation, or any combination thereof. In some embodiments, enhanced neural plasticity includes, for example, enhanced cortical structure plasticity in the anterior part of the brain.

[0141] In some embodiments, non-hallucinogenic 5-HT 2C Modulator (e.g., 5-HT) 2C Agonists are used to treat diseases. In some embodiments, non-hallucinogenic 5-HT 2C Modulator (e.g., 5-HT) 2C Agonists are used to enhance neuroplasticity. In some embodiments, non-hallucinogenic 5-HT 2C Modulator (e.g., 5-HT) 2C Agonists are used to enhance neuronal plasticity and dendritic spine density.

[0142] In some embodiments, methods for enhancing neuronal plasticity and increasing dendritic spine density are provided herein, comprising contacting nerve cells with a compound of the present invention or a pharmaceutically acceptable salt thereof in an amount sufficient to enhance the neuronal plasticity and increase the dendritic spine density of the nerve cells.

[0143] Dendrite spines are dynamic and can change significantly over time in terms of density, shape, and volume. The growth or loss of dendritic spines, which can contribute to dendritic spine density, may be important for reinforced neural pathways for learning, memory, and general cognitive functions. Increasing dendritic spine density may be useful in the treatment of neurological disorders such as neurodegenerative diseases and neuropsychiatric disorders, though this is not limited to these.

[0144] Increased dendritic spine density can be measured by staining and immunocytochemical methods known to those skilled in the art. Examples of staining methods, though not limited to these, include electron microscopy, Golgi staining, crystal violet staining, DAPI staining, and eosin staining. For example, Golgi staining can be used to measure dendritic spine density.

[0145] In some embodiments, the compounds or pharmaceutically acceptable salts thereof provided herein are useful for promoting neuronal growth and / or improving neuronal structure.

[0146] In some embodiments, the compounds or pharmaceutically acceptable salts thereof provided herein are non-hallucinogenic psychoplastogens useful for treating one or more diseases or disorders associated with loss of synaptic connectivity and / or plasticity.

[0147] In some embodiments, individuals administered with the compounds provided herein do not experience hallucinogenic events (at any point after the administration of the compounds to the individuals).

[0148] In some embodiments, methods for treating diseases or disorders in individuals requiring such treatment are provided herein, wherein the diseases or disorders are neurological diseases and disorders.

[0149] In some embodiments, compounds useful for modulating 5-hydroxytriptan (5-HT) receptors (e.g., pharmaceutically acceptable salts or solvates thereof) are provided herein. In some embodiments, the 5-HT receptor modulated by the compounds provided herein is the 5-hydroxytryptamine receptor 2A (5-HT 2A ) In some embodiments, the 5-HT receptor modulated by the compounds provided herein is the 5-hydroxytryptamine receptor 2C (5-HT 2C )

[0150] In some embodiments, 5-HT 2A 5-hydroxytryptamine receptor 2A (5-HT) is useful for treating one or more diseases or disorders related to activity. 2A Modulators of ) are provided herein. In some embodiments, 5-HT 2C 5-hydroxytryptamine receptor 2C(5-HT) is useful for treating one or more diseases or disorders related to activity. 2C A modulator of ) is provided herein.

[0151] In some embodiments, compounds or pharmaceutically acceptable salts thereof provided herein are used to prepare agents for the treatment of diseases or illnesses in mammals, where the benefit is to be derived from the inhibition or reduction of 5-HT2A activity.

[0152] In some embodiments, compounds or pharmaceutically acceptable salts thereof provided herein are used to prepare agents for the treatment of diseases or illnesses in mammals, which are to be beneficial from promoting nerve cell growth and / or improving nerve cell structure.

[0153] A method for treating any of the diseases or illnesses described herein in a mammal requiring such treatment comprises the step of administering to the mammal at least one of the compounds described herein or a pharmaceutically acceptable salt thereof, an active metabolite, a prodrug, or a pharmaceutically acceptable solvate thereof in a therapeutically effective amount.

[0154] In certain embodiments, compositions containing the compounds described herein are administered for prophylactic and / or therapeutic purposes. In certain therapeutic uses, the compositions are administered to mammals already suffering from a disease or illness in an amount sufficient to cure or at least partially block at least one symptom of the disease or illness. The effective dose for this use depends on the severity and course of the disease or illness, previous treatments, the mammal's health status, body weight, and response to the drug, as well as the judgment of the healthcare professional. The therapeutically effective dose is determined at will, but is not limited, by methods including dose escalation and / or dose determination clinical trials.

[0155] For preventative use, compositions containing the compounds described herein are administered to mammals susceptible to or at risk of developing a particular disease, disorder, or illness. Such amounts are defined as “a preventatively effective amount or dose.” In this use, the exact amount also depends on the condition and weight of the mammal. When used in mammals, the effective amount for this use depends on the severity and course of the disease, disorder, or illness, previous treatments, the mammal’s health status and response to the drug, and the judgment of the healthcare professional. In some embodiments, the preventative treatment includes administering the compounds described herein or a pharmaceutically acceptable salt thereof to a mammal that has previously experienced at least one symptom of the disease being treated and is currently in remission, in order to prevent recurrence of the disease or symptoms of illness.

[0156] In some embodiments where the mammalian condition does not improve, the compound may be administered chronically, i.e., over a long period including the mammal's lifetime, at the discretion of the healthcare professional, to alleviate, suppress, or limit the symptoms of the mammalian disease or illness.

[0157] In some embodiments in which the condition of the mammal is improved, the dose of the administered drug is temporarily reduced or temporarily stopped for a certain period (i.e., a “drug-free period”). In some embodiments, the length of the drug-free period is between 2 days and 1 year, with the exception of 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or more than 28 days. The dose reduction during the drug-free period is between 10% and 100%, with the exception of 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.

[0158] As the patient's condition improves, a maintenance dose is administered as needed. Subsequently, in certain embodiments, the dose and / or frequency of administration is reduced, depending on the symptoms, to a level at which the improved disease, impairment, or illness is maintained. However, in some embodiments, mammals require intermittent treatment over a long period if symptoms recur.

[0159] The amount of a given drug corresponding to such a quantity varies depending on factors such as the specific compound, the state and severity of the disease, and the unique characteristics of the subject or host requiring treatment (e.g., weight, sex). Nevertheless, it is determined according to the specific circumstances surrounding the case, including, for example, the specific drug being administered, the route of administration, the disease being treated, and the subject or host being treated.

[0160] However, generally, doses used for the treatment of adult humans are typically in the range of 0.01 mg to 5000 mg per day. In some embodiments, doses used for the treatment of adults are approximately 1 mg to 1000 mg per day. In some embodiments, the desired dose is preferably presented as a single dose or as divided doses administered simultaneously or at appropriate intervals, for example, as two, three, four or more subdoses per day.

[0161] In some embodiments, the appropriate daily dose of the compounds described herein or their pharmaceutically acceptable salts is about 0.01 to about 50 mg per kg of body weight. In some embodiments, the daily dose or the amount of the active ingredient in the dosage form may be less or more than the range shown herein, based on many variables relating to the individual treatment regimen. In some embodiments, the daily dose and unit dose may be modified, but are not limited, depending on many variables, including the activity of the compound used, the disease or illness being treated, the mode of administration, the requirements of the individual subject, the severity of the disease or illness being treated, and the physician's judgment.

[0162] The toxicity and therapeutic efficacy of these treatment regimens are determined by standard pharmaceutical procedures in cell culture or experimental animals, including, but not limited to, the determination of LD50 and ED50. The dose-to-toxicity ratio is the therapeutic index, which is expressed as the ratio between LD50 and ED50. In some embodiments, data obtained from cell culture assays and animal studies are used in formulating therapeutically effective daily dose ranges and / or therapeutically effective unit doses for use in mammals, including humans. In some embodiments, the daily doses of the compounds described herein are within a range of blood concentrations containing the ED50 of minimal toxicity. In some embodiments, the daily dose ranges and / or unit doses vary within this range depending on the dosage form used and the route of administration utilized.

[0163] In any of the embodiments described herein, in further embodiments, an effective amount of the compound described herein, or a pharmaceutically acceptable salt thereof, is administered (a) systemically to a mammal and / or (b) orally to a mammal and / or (c) intravenously to a mammal and / or (d) by infusion to a mammal and / or (e) topically to a mammal and / or (f) non-systemically or topically to a mammal.

[0164] Further embodiments include a single dose of an effective amount of the compound, which may include any of the above embodiments in which (i) the compound is administered once a day, or (ii) the compound is administered to a mammal multiple times over a day.

[0165] Further embodiments include multiple administrations of an effective amount of the compound, including, in any of the embodiments described above, (i) the compound is administered continuously or intermittently, as in a single dose, (ii) the interval between multiple doses is every 6 hours, (iii) the compound is administered to a mammal every 8 hours, (iv) the compound is administered to a mammal every 12 hours, or (v) the compound is administered to a mammal every 24 hours. In further or alternative embodiments, the method includes a drug-free period, where the administration of the compound is temporarily interrupted or the amount of the compound being administered is temporarily reduced, and at the end of the drug-free period, the administration of the compound is resumed. In one embodiment, the length of the drug-free period varies from 2 days to 1 year.

[0166] In some embodiments, the therapeutic efficacy of one of the compounds described herein is enhanced by the administration of an adjuvant (i.e., the adjuvant itself has minimal therapeutic benefit, but when combined with another therapeutic agent, it enhances the overall therapeutic benefit to the patient). Alternatively, in some embodiments, the effect received by the patient is increased by administering one of the compounds described herein together with another similarly therapeutic agent (including a therapeutic regimen).

[0167] In some embodiments, various therapeutically effective doses of the compounds disclosed herein are utilized in formulating pharmaceutical compositions and / or in treatment regimens in which the compounds disclosed herein are administered in combination with one or more additional agents, such as additional therapeutically effective drugs or adjuvants. The therapeutically effective doses of the drugs and other agents used in combination therapy regimens are determined by means similar to those specified above for the active ingredients themselves, at the discretion of the parties. Furthermore, the preventive / treatment methods described herein include the use of metronomic dosing, i.e., providing more frequent and lower doses to minimize toxic side effects. In some embodiments, the combination therapy regimens include treatment regimens in which the administration of the compounds described herein, or pharmaceutically acceptable salts thereof, is initiated before, during, or after treatment with a second agent described herein and continues during or after treatment with the second agent. Combination therapy regimens include treatments in which the compounds described herein, or pharmaceutically acceptable salts thereof, and a second agent used in combination are administered simultaneously or at different times and / or at intervals that increase or decrease the duration of treatment. Combination therapy also includes periodic treatments that are initiated and stopped at various points in time to support the clinical management of the patient.

[0168] It should be understood that dosing regimens for treating, preventing, or improving diseases in which relief is needed will be modified to suit various factors (e.g., the disease or disorder the subject is suffering from, the subject's age, weight, sex, diet, and medical condition). Therefore, in some cases, the dosing regimen actually used will vary, and in some embodiments, it will deviate from the dosing regimens specified herein. [Examples]

[0169] VI. Examples Detailed method Data Analysis and Statistics. The treatment was randomized, and data were analyzed by experimenters blinded to the treatment condition. Unless otherwise noted, statistical analysis was performed using GraphPad Prism (version 9.1.2). All comparisons were planned before each experiment. Data are expressed as mean ± SEM, with asterisks indicating *p<0.05, **p<0.01, ***p<0.001, and ****p<0.0001, unless otherwise noted.

[0170] Molecular docking. Docking of (+)-JRT to 5-HT2AR was performed using Autodock Vina (version 1.1.2), and the previously published structure of 5-HT2AR was bound to LSD (PDB: 7wc6). First, the existing ligand (i.e., LSD) of the published structure was removed from the protein. Next, (+)-JRT was bound at the known active site according to specific parameters. The binding pocket search region was defined as a 40x40x40 grid with a spacing of 0.375 Å at coordinates x=-28, y=-11, z=142, as shown in MGL AutoDockTools (version 1.5.7) with exhaustiveness setting 20. The created three-dimensional structure was analyzed and exported using MGL AutoDockTools (version 1.5.7). The (+)-JRT PDB structure was created by converting the ChemDraw structure using UCSF Chimera. 3D images of the binding sites were generated using UCSF Chimera (version 1.16) from Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco (with support from NIH P41 RR-01081).

[0171] Drugs. Many of the drugs used in these tests, including D-amphetamine sulfate (Sigma Aldrich, 1180004), ketamine hydrochloride (Spectrum, K1068), and ketanserine (APExBIO, B2248), were purchased from commercial suppliers. Lysergic acid diethylamide (LSD) hemitaltrate was generously provided by the NIH Drug Supply Program. Both (+)-JRT and (-)-JRT were synthesized in-house and determined to be analytically pure based on NMR and LC-MS data. For cell culture experiments, molecular biology grade dimethyl sulfoxide (Sigma-Aldrich) with VEH = 0.1% (agonist test) or 0.2% (antagonist test). For in vivo experiments, unless otherwise noted, compounds were administered at 5 mL / kg ip using 0.9% physiological saline as the vehicle. VEH = USP grade physiological saline (0.9%). For all cell experiments, free bases were used, while for in vivo studies, fumarates of (+)-JRT and (-)-JRT were used. Stock solutions for behavioral analysis were freshly prepared before use.

[0172] Animals. All experimental procedures involving animals were approved by the Institutional Animal Care and Use Committee (IACUC) at the University of California, Davis, the Salk Institute, Weill Cornell Medicine, or the Contract Research Organization (CRO) where the study was conducted. All procedures involving animals followed the principles described in the National Institutes of Health Guide for the Care and Use of Laboratory Animals. Unless otherwise noted, animals were obtained from Jackson Laboratory (Sacramento, CA) or bred in-house. Power analysis was performed to ensure appropriate sample sizes for all experiments involving animals. Animals were housed in cages with 2-5 animals of the same sex, and unless otherwise noted, feed and water were ad libitum. The lights in the ecological zoo were turned on at 7:00 AM and turned off at 7:00 PM. The University of California, Davis, the Salk Institute, and Weill Cornell Medicine are accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC).

[0173] Radioligand binding selectivity panel. Competitive radioligand binding for (+)-JRT(10 μM) and (-)-JRT(10 μM) was performed across a panel of receptors using Eurofins Discovery. LSDK i The values ​​were obtained from forecasts and, whenever possible, matched with the receptor's radioactive ligand and origin.

[0174] Radioligand Binding Test (5-HT2AR and 5-HT2CR). Competitive radioligand binding assays for 5-HT2AR and 5-HT2CR were performed using conventional methods with Epics Therapeutics SA (Belgium, FAST-0505B). Simply put, competitive binding was tested using binding buffer, membrane extract, and radiotrace [ 3 The assay was performed in parallel in the wells of a 96-well plate (Master Block, Greiner, 786201) containing the [H]-DOI and the test compound. Nonspecific binding was measured by co-incubation with a 200-fold excess of non-radioactive competing DOI. Samples were incubated at a final volume of 0.1 mL for a temperature and duration optimized for either 5-HT2AR or 5-HT2CR, and then filtered through a filtration plate. The filters were washed six times with 0.5 ml of ice-cold wash buffer (optimized for 5-HT2AR), and 50 μl of Microscint20 (Packard) was added to each well. The plate was incubated on an orbital shaker for 15 minutes, and then counted using TopCount™ for 1 minute per well.

[0175] Radioligand binding test (5-HT2BR). A competitive radioligand binding test for 5-HT2BR was performed using the conventional method (catalog #1333) at Eurofins Cerep SA (Celle l'Evescault, France).

[0176] IP1 assay (5-HT2AR and 5-HT2CR). The IPOne HTRF assay for 5-HT2AR and 5-HT2CR was performed using conventional methods at Epics Therapeutics SA (Belgium, FAST-0505I). Briefly, CHO-K1 cells expressing human recombinant 5-HT2AR, cultured to the intermediate logarithmic phase in antibiotic-free medium, were detached using PBS-EDTA, centrifuged, and resuspended in antibiotic-free medium. Next, 20,000 cells were dispersed in a 96-well plate and incubated overnight at 5% CO2 and 37°C. For the agonist test, the medium was removed, and 20 μl of assay buffer + 20 μl of the test compound or reference agonist (α-Me-5-HT) was added to each well. The plate was incubated at 5% CO2 and 37°C for 60 minutes. After adding a lysis buffer containing IP1-d2 and anti-IP1 cryptotate detection reagents, the plates were incubated at room temperature for 1 hour, and the fluorescence ratio was measured using an HTRF kit according to the manufacturer's specifications.

[0177] IP1 assay (5-HT2BR). The 5-HT2BR IP1 assay was performed using the conventional method (catalog #3344) with Eurofins Cerep SA (Celle l'Evescault, France).

[0178] β-Arrestin Activation (PathHunter®). The 5-HT2AR PathHunter® β-arrestin agonist assay was performed using Eurofins DiscoverX (Frement, CA, Catalog # 86-0001P-2090AG). The PathHunter® β-arrestin assay uses β-galactosidase (βGal) as a functional reporter and observes GPCR activation in a homogeneous, non-imaging assay format using a technique developed by DiscoverX called Enzyme Fragment Complementation (EFC). The enzyme is split into two inactive complementary parts: a small peptide called ProLink® (PK) and a large protein called Enzyme Acceptor (EA). Next, PK and EA are expressed as fusion proteins in U2OS cells, with PK fused to the GPCR of interest and EA fused to β-arrestin. When the target GPCR is activated and β-arrestin is recruited to the receptor, PK and EA scavenging occur, restoring β-Gal activity as measured using chemiluminescent PathHunter® Detection Reagents.

[0179] PsychLight assay. The Psychlight assay was performed using a previously published method. Briefly, a glass-bottomed 96-well plate was coated overnight with 50 μg / mL poly-D-lysine at room temperature and then washed with Dulbecco's PBS. PSYLI2 cells were suspended in DMEM containing 10% FBS with 5% penicillin-streptomycin, cultured on plates at a density of 40,000 cells / well, and incubated for 24 hours before each experiment (37°C, 5% CO2). Immediately before the experiment, the stock drug solution in DMSO was diluted 1:100 in imaging medium spread throughout an empty 96-well plate (treated plate), and then the plate map was randomized. The imaging medium consisted of 1x HBSS containing 0.5 M MgCl2 and 5 M CaCl2. Cells cultured in separate 96-well plates were gently washed three times with imaging medium, and the wells were then filled with imaging medium. All imaging and incubation (both agonist and antagonist modes) were performed at ambient atmosphere and temperature. Data were taken from two plates, each containing 2-3 wells analyzed. VEH treatment conditions were normalized to 0%ΔF / F.

[0180] In the agonist mode experiment, 180 μL of imaging medium was added to each well containing PSYLI2 cells. The wells were then imaged using a Thermofisher CellInsight CX7HCS Platform at 40× (NA=0.6). The region of interest (ROI) followed the default ROI pattern of each well, ensuring no positional bias and no overlap of ROIs (exposure = 400 ms, LED power = 100%). Next, 20 μL from the treatment plate was transferred to a plate containing PSYLI2 cells to obtain a final dilution of 1:1000. 5-HT (10 μM), ketanserine (10 μM), and DMSO (0.1%) were used as positive, negative, and vehicle controls, respectively. After a 5-minute incubation, the same ROI was re-imaged using the same settings.

[0181] Once imaging was complete, the images were exported and analyzed using a custom Python script. In short, segmentation was performed on individual images, and a mask was created to highlight the membranes of HEK293T cells. This mask was created by calculating the average fluorescence intensity of the overall image and using that value as a threshold. Pixels with intensity exceeding this threshold were incorporated into the mask. Pixel intensities were obtained from the mask-enhanced regions, then used to calculate %ΔF / F, and exported to Excel. The %ΔF / F value for each well was calculated using the following equation:

number

[0182] In the antagonist mode experiment, 160 μL of imaging medium was added to each well of the assay plate. The wells were then imaged using the CellInsight CX7HCS Platform at 40 × (NA=0.6). The ROI followed the default ROI pattern of each well, which was unbiased in terms of location and did not overlap (exposure = 400 ms, LED power = 100%). A 100 μM stock solution of 5-HT in DMSO was diluted 1:100 with imaging buffer. Next, 20 μL of this solution was added to a PSYLI2 cell-containing plate for a final concentration of 111 nM 5-HT (0.1% DMSO). The same ROI was imaged after a 5-minute incubation. Next, 20 μL from the treated plate was transferred to a PSYLI2 cell-containing plate for a final dilution of 1:1000 (0.2% DMSO). After a 5-minute incubation, the same ROI was re-imaged using the same settings.

[0183] Once imaging was complete, the images were exported and analyzed using a custom Python script. In short, segmentation was performed on individual images, and a mask was created to highlight the membranes of HEK293T cells. This mask was created by calculating the average fluorescence intensity of the overall image and using that value as a threshold. Pixels with intensity exceeding this threshold were incorporated into the mask. Pixel intensities were obtained from the mask-enhanced regions, then used to calculate %ΔF / F, and exported to Excel. The %ΔF / F values ​​for each well were then calculated using the following equation:

number

[0184] Dendritic formation in vivo. Female C57BL / 6J mice (Jackson Laboratory, Sacramento, CA) were treated with VEH (saline vein thromboembolization) or (+)-JRT (n=3 / group). After 24 hours, the animals were sacrificed by transcardiac perfusion of oxygenated Ringer's solution, followed by perfusion with fixative (2% paraformaldehyde, 2.5% glutaraldehyde, and 3 mM calcium chloride in 0.1 M cacodylate buffer). The brain was carefully excised from the skull and post-fixed overnight in the same fixative. The brain was then rinsed with PBS, and 100 μm coronal sections reaching the prefrontal cortex were collected using a vibrating microtome (Leica). The inferior limbic cortex region was microdissected according to Allen's atlas and further processed for electron microscopy. In short, the samples were stained with 1.5% reduced osmium tetroxide for 45 minutes, thoroughly rinsed, further stained overnight with 1% aqueous uranyl acetate at 4°C, dehydrated, and embedded in Eponate 12 epoxy resin. The block surface from the medial cortical surface to the corpus callosum was prepared, and 150–250 serial ultrathin sections (55 nm) were collected on a silicon chip using a diamond knife (Diatome) with an ultramicrotome (Leica). The serial sections on the silicon chip were mounted on a scanning electron microscope (SEM; Zeiss Sigma VP) for imaging. The apical pilosa region was identified, and a series of images were collected from the region of interest identified on the serial sections. Following image alignment (achieved using SWiFT-IR via 3dem.org), each animal dataset comprised a volume of at least 20 × 20 × 10 μm with voxel dimensions of 8 × 8 × 55 nm. Cross-sections of eight random dendrites were sampled from the central portion of each volume. The dendritic midline and dendritic spine skeleton were traced by two experts using VAST Lite software. Dendritic spine density (spines / μm) was calculated for each volume.

[0185] Head spasm response assay. The HTR assay was performed using an equal number of male and female C57BL / 6J mice. Mice were obtained from Jackson Laboratory (Sacramento, CA) and were approximately 8–12 weeks old at the time of the experiment. After compound administration, animals were placed in an empty arena (40 cm × 40 cm) and photographed for 20 minutes. During the examination, the arena was cleaned with 70% ethanol. Animals were given a 1-week washout period before retesting. Animals were tested up to 4 times. All drug treatments were randomized, and no animals received the same drug and dose twice. For blocking experiments, animals were administered (+)-JRT (1 mg / kg) or vehicle (physiological saline) by IP injection and placed in an empty cage for 15 minutes. Next, animals were administered LSD (0.2 mg / kg, IP), placed in the test arena, and photographed for 20 minutes. The videos were then scored by two blinded observers, and the results were averaged (Pearson correlation coefficient > 0.9).

[0186] Amphetamine-induced movement. An amphetamine-induced hyperactive movement assay was performed using male and female C57BL / 6J mice approximately 8 weeks old at the time of the experiment. First, the animals were placed in a test arena (40 cm × 40 cm) for 15 minutes to obtain baseline measurements of locomotion and to acclimate the animals to the test arena. Next, the animals were administered (+)-JRT (1 mg / kg) or VEH (2.5 mL / kg, ip) and returned to the test arena. After 15 minutes, the animals were administered D-amphetamine (3 mg / kg) or VEH (2.5 mL / kg) and returned to the test arena for 60 minutes. Locomotion throughout the experiment was quantified using the ANYmaze Video Tracking System, version 7.07 (Stoelting Co.).

[0187] Forced swimming (FST) rat study. This study was conducted by Psychogenics (Paramus, NJ). Male Sprague Dolly rats were purchased from Envigo (Indianapolis, IN), assigned unique identification numbers (marked on the tail) upon receipt, and housed in groups of three rats per cage in ventilated cages. All animals were kept in groups of three for the remainder of the study. All rats were acclimatized to the colony room for up to one week prior to medication administration. During the acclimatization period, rats were experimented with and treated daily and weighed to ensure proper health and fitness. Room temperature was maintained at 20°C to 23°C with a relative humidity of 30% to 70%. Lab Rodent Diet 5001 (WF Fisher, Cat # 11015) and water were provided ad libitum. Animals were randomly assigned to treatment groups. All studies were conducted during the light phase of the light / dark cycle. The operational tests were conducted according to the established protocols approved by the IACUC Committee and PGI Standard Operation Procedures (SOPs). Each forced swimming chamber was constructed of clear acrylic (height = 40 cm; diameter = 20.3 cm). Only one rat was placed in the swimming chamber at a time for each swimming test. After each animal, the water was changed and the chamber was cleaned. The water depth was 16 cm in the first swimming session (preliminary test) and 30 cm in the second swimming session (test). The water was maintained at 23°C ± 1°C throughout all swimming sessions. At the end of each swimming test, the rats were dried with paper towels and returned to their home cages. To ensure the safety of the animals during the swimming tests, all animals were carefully observed, and any animals that could not maintain a posture with their noses above the water were immediately removed from the water and not used further in that test. First, the animals were subjected to a 15-minute preliminary test. Immediately after the preliminary test, they were administered the compound or VEH by ip injection (1 ml / kg). Racemiketamine hydrochloride (10 mg / kg) was used as a positive control. A salt correction factor of 1.36 was used when preparing the (+)-JRT formulation to ensure a dose corresponding to that of the free base.A second FST was performed 24 hours after compound administration. This test lasted 5 minutes and was videotaped. A blinded experimenter manually scored the videotapes for swimming, climbing, and immobility behaviors. Scoring of the forced swimming test was performed by trained technicians using a time-sampling technique, observing the videotaped test animals every 5 seconds and recording the observed behaviors (e.g., immobility, swimming, or climbing). A total of 60 behaviors were recorded per subject per session.

[0188] 4-Odor discrimination and reversal. The 4-odor discrimination and reversal behavioral analysis was performed as previously described with minor modifications. Dietary restriction was initiated 5 days before the discrimination and reversal tests to reduce the animals' body weight to ~80% of their starting weight. A total of 31 2-3 month old C57BL / 6J mice were used in this assay. Eleven mice (5 males, 6 females) were treated as VEH / non-stress controls, 10 animals (4 males, 6 females) as the VEH / stress group, and 10 animals (4 males, 6 females) as the treatment / stress group. Both the VEH / stress and VEH / treatment groups were subjected to a 7-day unpredictable mild stress protocol using previously validated stressors. Two stressors were added during the day, and an additional nocturnal stressor was added on 4 of those days. In short, the following stressors were used: Day 1: AM = predator odor (order) 30 minutes, PM = instability (damp bedding + incline 30 minutes), night = inclined cage; Day 2: AM = overcrowding / social interaction (30 minutes), PM = restraint stress (30 minutes), night = none; Day 3: AM = restraint stress (30 minutes), PM = predator odor (30 minutes), night = none; Day 4: AM = exposure to a new room (30 minutes) Day 5: AM = Tail suspension (6 mins), PM = Restraint stress (30 mins), Night = Inclined cage; Day 6: AM = Instability (damp bedding + incline for 30 mins), PM = Overcrowding / Social interaction (30 mins), Night = None; Day 7: AM = Restraint stress (30 mins), PM = Overcrowding / Social interaction (30 mins), Night = Exposure to light.

[0189] Following unpredictable mild stress, the animals underwent habituation / forming / training on days 7 and 8 prior to identification, and then a reversal test on day 9. The behavioral apparatus was a 12-inch x 12-inch x 9-inch (length x width x height) opaque acrylic box with a 3-inch long transparent acrylic inner wall in the center of each outer wall, creating four detachable, 6-inch diameter transparent cylinders that mounted in the center of the box. On the first training day (day 7), mice were habituated to the apparatus and four 4-ounce white ceramic pots (Yachi, www.amazon.com) (each placed in one corner of the quarter of the box with a piece (~0.015g) of Honey Nut Cheerio (General Mills, Golden Valley, MN) as a food reward inside). For this first day of habituation, the mice were placed in a central cylinder, and then the cylinder was removed to begin each round of habituation; the mice were allowed to explore freely until all of the food rewards in the four pots were consumed or 10 minutes had elapsed. The mice were then returned to the cylinder, and the pots were re-fed as needed for a total of six rounds of habituation throughout the first day.

[0190] On the second training day (day 8), VEH (saline solution) or (+)-JRT (1 mg / kg) was administered by IP injection. After a short recovery period, the formation was carried out using one pot. Food rewards were supplied with increased amounts of pine shavings (Living World, www.amazon.com) covering the food so that the mice had to dig it up to obtain the reward. The pot was moved between four quadrants of the apparatus to ensure that each position received an equal reward; after finding and consuming the food reward, the mice were returned to the central cylinder between trials. Trials were started by placing the food reward in an empty dish (4 trials), then dusting off the added pine bedding (4 trials), followed by trials where the dish was filled to a quarter (4 trials), half (4 trials), and full (12 trials) with pine shavings.

[0191] On the day of the experiment (day 9), four pots were filled with pine shavings and fitted with a piece of filter paper scented with one drop of essential oil (LorAnn Oils, Lansing, MI) attached to the inner rim. Rosemary, thyme, clove, and nutmeg were used in the initial discrimination phase, with rosemary acting as a reward scent to indicate pots containing food rewards. Mice were placed in a central cylinder and then allowed to explore the arena after the cylinder was removed at the start of each trial. The trial was ended after 3 minutes had elapsed, either when the mouse found and ate the food reward, when it began digging in an unrewarded pot, or when no digging occurred. The mouse was then returned to the central cylinder, re-fed in the rewarding pot if necessary, and the pots were rearranged so that no two pots remained in the same quarter during consecutive trials. Trials in which no digging was observed were recorded as misses; after two consecutive misses, pine shavings and pots containing food rewards in wells within the shavings were placed in the central cylinder to reinforce digging. In 8 out of 10 consecutive trials, the mice passed this discrimination phase when they successfully located and ate the food reward. Immediately after discrimination, the pine shavings were replaced in all pots, and the thyme scenting agent was replaced with a new cinnamon scenting agent. The reward scenting agent was changed from rosemary to clove. In 8 out of 10 consecutive trials, the mice were again considered to have passed this inversion phase after successfully located and ate the food reward. Materials and methods

[0192] All reagents were obtained from commercial suppliers, and unless otherwise noted, reactions were carried out using oven-dried glassware (120°C) under an inert N2 atmosphere. Air and moisture-sensitive liquids and solutions were transferred via syringe or stainless steel cannula. Organic solutions were concentrated under reduced pressure (~5 Torr) by rotary evaporation. Solvents were purified by passing them through an activated alumina column under 12 psi N2. Chromatography was performed using Fisher Chemical™ silica gel adsorbent (230-400 mesh, grade 60). Compounds purified by chromatography were typically applied to the adsorbent bed using the presented solvent conditions with minimal additional dichloromethane as needed for solubility. Thin-layer chromatography (TLC) was performed on a Merck silica gel 60 F254 plate (250 μm). Visualization of the developed chromatogram was achieved by fluorescent quenching or staining with aqueous potassium permanganate or Ehrlich's reagent.

[0193] Nuclear magnetic resonance (NMR) spectra, 1 H and 13 The C values ​​were acquired using a Bruker400 operating at 400 and 100 MHz and internally standardized against the residual solvent signal. 1 ¹H NMR data were recorded as follows: chemical shift (δ, ppm), multiplicity (s, singlet; d, doublet; t, triplet; q, quadruplet; quint, quintlet; m, multiplet), coupling constant (Hz), and integral value. 13 We report the 13C NMR data in terms of chemical shift (δ, ppm). Infrared spectra were recorded using a Thermo Nicolet iS10 Fourier transform infrared (FTIR) spectrometer with Smart iTX Accessory [Diamond Attenuated Total Reflectance (ATR)] and reported in terms of absorption frequency (ν, cm). -1 Liquid chromatography-mass spectrometry (LC-MS) was performed using a Waters LC-MS equipped with an ACQUITY Arc QDa detector. Example 1: Preparation of N,N-diethyl-8-methyl-7a,8,9,10-tetrahydro-7H-indro[7,1-fg][1,7]naphthyridine-10-carboxamide (14, major diastereomer, (±)-JRT) [ka] 3-Bromo-5-(diethylcarbamoyl)pyridine 1-oxide(3) [ka]

[0194] To a mixture of 5-bromonicotinic acid (10,000 g, 49,503 mmol, 1.0 equiv) in DCM (250 mL), cooled to 0°C, oxalyl chloride (6.37 mL, 74.2 mmol, 1.5 equiv) was slowly added. DMF (0.5 mL) was added dropwise to the suspension, and the mixture was warmed to ambient temperature and stirred for 1 hour. The mixture was cooled to 0°C, and a solution of diethylamine (25.61 mL, 247.5 mmol, 5.0 equiv) in DCM (250 mL) was slowly added via cannula. The mixture was warmed to ambient temperature and stirred for 30 minutes. H2O (500 mL) was added, followed by 2 M HCl (40 mL) to a pH of 1-2. The layers were separated, and the aqueous layer was further extracted with DCM (3 × 200 mL). The organic extracts were combined and washed sequentially with saturated aqueous solution NaHCO3 (1 × 250 mL) and saline solution (1 × 250 mL). The organic extracts were dried with Na2SO4 and concentrated under reduced pressure.

[0195] To a solution of the brown oil obtained in DCM (200 mL), cooled to 0°C, MCPBA (70-75% equilibrium) (22.781 g, 99.006 mmol, 2.0 equiv) was added. The mixture was heated to ambient temperature and stirred for 18 hours. Saturated aqueous solution NaHCO3 (500 mL) was added to the solution, followed by 1 M NaOH (500 mL). The layers were separated, and the aqueous layer was further extracted with 10% IPA in DCM (3 × 200 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (siRNA, then 12% MeOH in siRNA) and concentrated under reduced pressure. The resulting pale yellow oil was dissolved in DCM (50 mL), and hexane (500 mL) was slowly added to the solution with vigorous stirring. The suspension was cooled to 0°C, filtered, and washed with 100 mL of cold hexane to obtain 3 (11.041 g, 82%) as a white solid.

[0196] 1 H NMR (400 MHz, CDCl3) δ = 8.32 (t, J = 1.5 Hz, 1H), 8.09 (t, J = 1.3 Hz, 1H), 7.35 (t, J = 1.3 Hz, 1H), 3.54 - 3.46 (m, 2H), 3.29 - 3.21 (m, 2H), 1.24 - 1.12 (m, 6H) ppm. 13 C NMR (100 MHz, CDCl3) δ = 164.3, 141.0, 136.3, 135.9, 126.4, 120.7, 43.5, 39.9, 14.4, 12.8 ppm. LRMS (ES + ) m / z [M + H] + C 10 H 14 BrN2O2 + Calculated value: 273.02; Measured value: 273.12. IR (Diamond, ATR) ν 3445, 3068, 2973, 2934, 1633 cm -1 . 5-Bromo-6-chloro-N,N-diethylnicotinamide (4) [ka]

[0197] To a solution of 3 (9.900 g, 36.395 mmol, 1.0 equiv) and Et3N (10.15 mL, 72.79 mmol, 2.0 equiv) cooled to -61°C (CHCl3 / dry ice) in DCM (180 mL), oxalyl chloride (6.24 mL, 72.8 mmol, 2.0 equiv) was slowly added dropwise. The mixture was stirred for 30 minutes, then MeOH (5 mL) was slowly added, followed by heating to ambient temperature, and then saturated aqueous solution NaHCO3 (25 mL) was added. The solution was poured into 1 M NaOH (600 mL), and the layers were separated. The aqueous layer was further extracted with DCM (3 × 150 mL). The organic extracts were combined, washed with brine (250 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by chromatography using silica gel (25% toluene in hexane) to obtain 4 (9.442 g, 89%) as a crystalline white solid.

[0198] 1 H NMR (400 MHz, CDCl3) δ = 8.34 (s, 1H), 7.96 (s, 1H), 3.59 - 3.42 (m, 2H), 3.36 - 3.18 (m, 2H), 1.28 - 1.10 (m, 6H) ppm. 13 C NMR (100 MHz, CDCl3) δ = 166.0, 151.5, 145.3, 140.7, 133.0, 120.5, 43.6, 39.9, 14.4, 12.9 ppm. LRMS (ES + ) m / z [M + H] + C 10 H 13 BrClN2O + Calculated value: 290.99; Measured value: 291.00. IR (Diamond, ATR) ν 2974, 2935, 1627, 1574 cm -1 . Diethyl 2-(3-bromo-5-(diethylcarbamoyl)pyridine-2-yl)malonic acid (6) [ka]

[0199] To a vigorously stirred mixture of 4 (5.000 g, 17.243 mmol, 1.0 equiv) and NaI (20.676 g, 137.94 mmol, 8.0 equiv) in acetonitrile (40 mL), TMSCl (3.28 mL, 25.86 mmol, 1.5 equiv) was slowly added. The mixture was stirred at ambient temperature for 30 minutes, then 1 / 4 of the reaction volume was removed and heated at reflux temperature for 1 hour, with the contents being collected in a Dean-Stark receiver during this period. The resulting yellow suspension was cooled to ambient temperature, diluted with DCM (150 mL), and added to saturated aqueous NaHCO3 solution (250 mL). Saturated aqueous Na2S2O3 solution (100 mL) was added with vigorous stirring, followed by 1 M NaOH (80 mL). The resulting clear solution was transferred to a separatory funnel, and the layers were separated. The aqueous layer was further extracted using DCM (3 × 100 mL). The organic extracts were combined, washed with brine (200 mL), dried over Na₂SO₄, and concentrated under reduced pressure.

[0200] The resulting pale orange solid was added to a sealable screw-cap flask along with copper(I) iodide (0.861 mmol, 0.164 g, 0.05 equiv), picolinic acid (0.212 g, 1.72 mmol, 0.1 equiv), and Cs2CO3 (16.854 g, 51.729 mmol, 3.0 equiv). 1,4-dioxane (43 mL) and diethyl malonate (5.26 mL, 34.5 mmol, 2.0 equiv) were added, and the flask was sealed. The mixture was stirred and heated at 90°C for 16 hours. The mixture was allowed to cool to ambient temperature, filtered through Celite, and the filter cake was washed with SiO2 (200 mL). The filtrate was added to H2O (500 mL), then 1 M HCl (10 mL) was added, and the layers were separated. The aqueous layer was further extracted with ethyl acetate (2 × 200 mL). The organic extracts were combined, washed with brine (250 mL), dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (20% ethyl acetate in hexane to 50% ethyl acetate in hexane) to obtain 6 (5.461 g, 76%) as a pale yellow oil.

[0201] 1 H NMR (400 MHz, CDCl3) δ = 8.52 (d, J = 1.8 Hz, 1H), 7.92 (d, J = 1.8 Hz, 1H), 5.22 (s, 1H), 4.34 - 4.23 (m, 4H), 3.62 - 3.44 (m, 2H), 3.38 - 3.19 (m, 2H), 1.32 - 1.10 (m, 12H) ppm. 13 LRMS (ES + ) m / z [M + H] + C 17 H 24 BrN2O5 +Calculated value for 415.09; measured value for 415.19. IR (Diamond, ATR) ν 2980, 2937, 1735, 1631 cm -1 . 3-Bromo-5-(diethylcarbamoyl)-2-methylpyridine 1-oxide(8) [ka]

[0202] To a solution of 6 (5.350 g, 12.92 mmol, 1.0 equiv) in MeOH (130 mL), 32 mL of 2 M NaOH aqueous solution was added, and the solution was stirred and heated at 50°C for 16 hours. To the resulting suspension, 45 mL of 1 M citric acid aqueous solution was added to adjust the pH to 4, and the solution was stirred and heated at 60°C for 24 hours. The solution was cooled to ambient temperature, and the MeOH was removed by concentration under reduced pressure. The solution was added to H2O (250 mL) and extracted with DCM (3 × 200 mL). The organic layers were combined, washed with brine (250 mL), dried over Na2SO4, and concentrated under reduced pressure.

[0203] To a solution of the obtained residue in DCM (50 mL) cooled to 0°C, MCPBA (70-75% equilibrium) (5.946 g, 25.84 mmol, 2.0 equiv) was slowly added. The solution was heated to ambient temperature and stirred for 22 hours. The solution was added to 150 mL of 1 M NaOH, and the layers were separated. The aqueous layer was further extracted with 10% isopropyl alcohol in DCM (3 × 100 mL). The organic extracts were combined, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (siRNA, then 10% MeOH in siRNA) to obtain 8 (3.469 g, 94%) as a white solid.

[0204] 1H NMR (400 MHz, CDCl3) δ = 8.19 (d, J = 0.9 Hz, 1H), 7.4 (d, J = 0.9 Hz, 1H), 3.58 - 3.39 (m, 2H), 3.36 - 3.18 (m, 2H), 2.66 (s, 3H), 1.24 - 1.10 (m, 6H) ppm. 13 C NMR (100 MHz, CDCl3) δ = 164.6, 150.2, 136.2, 133.0, 127.0, 122.1, 43.5, 39.9, 17.4, 14.4, 12.8 ppm. LRMS (ES + ) m / z [M + H] + C 11 H 16 BrN2O2 + Calculated value: 287.04; Measured value: 287.12. IR (Diamond, ATR) ν 3455, 2972, 2935, 1632 cm -1 . 5-Bromo-N,N-diethyl-6-(hydroxymethyl)nicotinamide(9) [ka]

[0205] To a solution of 8 (1.301 g, 4.531 mmol, 1.0 equiv) cooled to 0°C in DCM (22.6 mL), anhydrous trifluoroacetic acid (1.57 mL, 11.3 mmol, 2.5 equiv) was added dropwise. The solution was warmed to ambient temperature, stirred for 4 hours, and then concentrated under reduced pressure. The residue was redissolved in DCM (22.6 mL), and then 45.2 mL of 2 M aqueous Na2CO3 solution was added. The two-phase solution was vigorously stirred at ambient temperature for 18 hours, and then poured into H2O (100 mL). The layers were separated, and the aqueous layer was further extracted with DCM (3 × 50 mL). The organic extracts were combined, washed with brine (100 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dimethyl) to obtain 9 (1.119 g, 86%) as a yellow oil.

[0206] 1 H NMR (400 MHz, CDCl3) δ = 8.53 (d, J = 1.7 Hz, 1H), 7.90 (d, J = 1.7 Hz, 1H), 4.77 (d, J = 4.7 Hz, 2H), 4.23 (t, J = 4.7 Hz, 1H), 3.64 - 3.46 (m, 2H), 3.38 - 3.18 (m, 2H), 1.32 - 1.08 (m, 6H) ppm. 13 C NMR (100 MHz, CDCl3) δ = 166.8, 157.6, 144.1, 138.6, 133.2, 118.7, 63.4, 43.6, 39.9, 14.5, 12.9 ppm. LRMS (ES + ) m / z [M + H] + C 11 H 16 Calculated value for BrN2O2: 287.04; Measured value: 287.12. IR (Diamond, ATR) ν: 3412, 2972, 2934, 1624, 1588 cm⁻¹ -1 . 5-Bromo-N,N-diethyl-6-(hydroxymethyl)-1-methyl-1,2,3,6-tetrahydropyridine-3-carboxamide (10, major diastereomer) 5-Bromo-N,N-diethyl-6-(hydroxymethyl)-1-methyl-1,2,3,6-tetrahydropyridine-3-carboxamide (11, a few diastereomers) [ka]

[0207] To a solution of 9 (0.980 g, 3.413 mmol, 1.0 equiv) in MeCN (4.25 mL) in a vial, MeI (1.28 mL, 20.5 mmol, 6.0 equiv) was added. The vial was sealed, and the solution was heated at 70°C for 24 hours with stirring, and then cooled to ambient temperature. To the mixture, toluene (8.5 mL) was added with vigorous stirring, followed by hexane (8.5 mL). The suspension was cooled to 0°C, filtered, and washed with hexane (2 × 5 mL). The resulting yellow solid was dried under reduced pressure and used directly in the next step.

[0208] To a solution of the obtained methylpyridinium salt (1.285 g, 2.995 mmol, 1.0 equiv) in MeOH (30 mL), cooled to 0°C, AcOH (0.51 mL, 8.9 mmol, 3.0 equiv) was added, followed by the dropwise addition of NaCNBH3 (0.565 g, 8.98 mmol, 3.0 equiv) in MeOH (6 mL). The solution was heated to ambient temperature, stirred for 16 hours, and then concentrated under reduced pressure. The residue was dissolved in HCl (100 mL) and added to 1 M NaOH (200 mL). The layers were separated, and the aqueous layer was further extracted with HCl (3 × 100 mL). The organic extracts were combined, washed with brine (150 mL), dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (3% MeOH in DCM) to obtain an inseparable mixture of diastereomers 10 (major diastereomer) and 11 (minor diastereomer) (0.726 g, 70%) (5:2 dr) as a pale yellow oil.

[0209] 1 H NMR (400 MHz, CDCl3) δ = 6.21 † (s, 1H), 6.11 * (d, J = 2.8 Hz, 0.4H), 3.94 † (dd, J = 2.0 Hz, 1H), 3.88 - 3.78 (m, 1.4H), 3.70 - 3.64 * (m, 0.4H), 3.59* (dd, J = 8.8, 11.6 Hz, 0.4H), 3.54 - 3.47 † (m, 1H), 3.34 (quint, J = 7.3 Hz, 5.6H), 3.21 * (dd, J = 9.4, 13.6 Hz, 0.4H), 3.14 - 3.08 * (m, 0.4H), 3.02 - 2.92 † (m, 2H), 2.88 - 2.80 † (m, 1H), 2.76 * (dd, J = 5.1, 14 Hz, 0.4H), 2.55 * (s, 1.2H), 2.45 † (s, 3H), 2.24 - 2.14 (m, 4.2H), 1.09 (t, J = 7.1 Hz, 4.2H) ppm. 13 C NMR (100 MHz, CDCl3) δ = 170.22, 170.15, 130.4, 127.6, 123.3, 122.9, 68.6, 67.6, 60.9, 59.6, 53.6, 47.0, 43.5, 42.9, 42.2, 42.1, 41.3, 40.7, 40.4, 36.7, 15.1, 14.9, 13.2, 13.1 ppm. LRMS (ES + ) m / z [M + H] + C 12 H 22 BrN2O2 + Calculated value: 305.09; Measured value: 305.14. IR (Diamond, ATR) ν 3418, 2970, 2934, 2799, 1629 cm -1 .

[0210] † These arise exclusively from the major diastereomers. 1 This indicates a 1H NMR signal. * indicates a signal exclusively arising from a small number of diastereomers. 1 This refers to the 1H NMR signal; unspecified signals result from a mixture of both. N,N-diethyl-6-(hydroxymethyl)-5-(1H-indole-7-yl)-1-methyl-1,2,3,6-tetrahydropyridine-3-carboxamide (12, major diastereomer, 16 stereochemistry assigned based on crystal structure) N,N-diethyl-6-(hydroxymethyl)-5-(1H-indole-7-yl)-1-methyl-1,2,3,6-tetrahydropyridine-3-carboxamide (13, a small number of diastereomers, with the stereochemistry of syn assigned based on the assignment of 12) [ka]

[0211] A mixture of diastereomers 10 and 11 (5:2 dr) (0.698 g, 2.29 mmol, 1.0 equiv), 1,4-dioxane (22.9 mL), indole-7-boronic acid pinacol ester (0.834 g, 3.43 mmol, 1.5 equiv), and 2 M aqueous solution of Na2CO3 (2.29 mL) was added to a vial. The solution was spurged with N2 for 10 minutes, and then Pd(PPh3)4 (0.132 g, 0.114 mmol, 0.05 equiv) was added. The vial was sealed, and the mixture was heated in a preheated oil bath at 100°C for 4 hours with stirring. The mixture was cooled to ambient temperature, added to H2O (400 mL), and extracted with SiO2 (3 × 150 mL). The organic extracts were combined, washed with brine (200 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (from 2% MeOH in DCM to 10% MeOH in DCM) to obtain off-white semi-solids of 12 (major diastereomer) (0.398 g, 51%) and 13 (minor diastereomer) (0.148 g, 19%).

[0212] Major diastereomers, 12. 1H NMR (400 MHz, CDCl3) δ = 9.46 (s, 1H), 7.56 (d, J = 7.8 Hz, 1H), 7.22 (t, J = 2.8 Hz, 1H), 7.06 (t, J = 7.3 Hz, 1H), 7.00 (dd, J = 0.9, 8.4 Hz, 1H), 6.53 (dd, J = 2.1, 3.2 Hz, 1H), 5.92 (s, 1H), 3.79 (dd, J = 3.0, 11.2 Hz, 1H), 3.74 - 3.66 (m, 1H), 3.50 - 3.28 (m, 5H), 3.26 - 3.08 (m, 3H), 3.07 - 2.96 (m, 1H), 2.52 (s, 2H), 1.23 (t, J = 7.1 Hz, 3H), 1.10 (t, J = 7.1 Hz, 3H) ppm. 13 C NMR (100 MHz, CDCl3) δ = 171.7, 137.3, 135.4, 128.11, 128.05, 124,9, 124.1, 121.4, 119.9, 119.4, 102.4, 66.8, 59.1, 54.0, 43.2, 42.0, 40.3, 39.3, 14.9, 13.1 ppm. LRMS (ES + ) m / z [M + H] + C 20 H 28 N3O2 + Calculated value: 342.22; Measured value: 342.32. IR (Diamond, ATR) ν 3267, 2970, 2932, 1615 cm -1 .

[0213] A small number of diastereomers, 13. 1H NMR (400 MHz, CDCl3) δ = 9.86 (s, 1H), 7.55 (d, J = 7.8 Hz, 1H), 7.29 - 7.24 (m, 1H), 7.07 (t, J = 7.4 Hz, 1H), 6.98 (dd, J = 0.6, 7.6 Hz, 1H), 6.51 (dd, J = 2.1 Hz, 3.2 Hz, 1H), 6.08 - 6.04 (m, 1H0, 3.76 - 3.68 (m, 1H), 3.64 - 3.28 (m, 8H), 3.15 - 3.06 (m 1H), 2.99 (dd, J = 5.7, 13.2 Hz, 1H), 2.66 (s, 3H), 1.26 (t, J = 7.2 Hz, 3H), 1.17 (t, J = 7.1 Hz, 3H) ppm. 13 C NMR (100 MHz, CDCl3) δ = 173.0, 135.7, 135.0, 128.4, 125.6, 125.4, 123.8, 120.0, 119.4, 119.0, 102.1, 64.8, 60.9, 48.6, 42.7, 42.3, 40.6, 34.8, 15.1, 13.3 ppm. LRMS (ES + ) m / z [M + H] + C 20 H 28 N3O2 + Calculated value: 342.22; Measured value: 342.32. IR (Diamond, ATR) ν 3270, 2973, 2934, 1613 cm -1 . N,N-diethyl-8-methyl-7a,8,9,10-tetrahydro-7H-indro[7,1-fg][1,7]naphthyridine-10-carboxamide(14,(±)-JRT) [ka]

[0214] To a solution of 12 (0.250 g, 0.732 mmol, 1.0 equiv) in 7.3 mL of CHCl3 cooled to 0°C, freshly ground NaOH (0.234 g, 5.86 mmol, 8.0 equiv) was added. A solution of TsCl (0.167 g, 0.878 mmol, 1.2 equiv) in 1.5 mL of CHCl3 was added dropwise over 10 minutes. The mixture was heated to ambient temperature and stirred for 1.5 hours. The mixture was cooled to 0°C, and DMSO (3.7 mL) was slowly added. Then, the mixture was heated to ambient temperature and stirred for 1 hour. The mixture was partitioned with H2O (250 mL) and HCl (200 mL), and the layers were separated. The aqueous layer was further extracted with HCl (3 × 100 mL). The organic extracts were combined, washed with brine (250 mL), dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (from 8% MeOH in HCl to 12% MeOH in HCl) to obtain 14 (0.168 g, 71%) as an off-white semi-solid.

[0215] 1 H NMR (400 MHz, CDCl3) δ = 7.5 (d, J = 7.9 Hz, 1H), 7.31 (d, J = 7.3 Hz, 1H), 7.08 - 7.04 (m, 2H), 6.46 (d, J = 3.0 Hz, 1H), 6.31 (s, 1H), 4.66 (dd, J = 5.4, 11.2 Hz, 1H), 3.90 - 3.82 (m, 1H), 3.80 (t, J = 11.1 Hz, 1H), 3.54 - 3.40 (m, 5H), 3.05 (dd, J = 5.0, 11.2 Hz, 1H), 2.95 (t, J = 10.7 Hz, 1H), 2.59 (s, 3H), 1.26 (t, J = 7.1Hz, 3H), 1.18 (t, J = 7.1Hz, 3H) ppm. 13C NMR (100 MHz, CDCl) δ = 171.2, 133.2, 132.5, 126.3, 126.2, 120.3, 120.0, 118.91, 118.88, 114.9, 101.3, 60.5, 55.8, 48.0, 44.0, 42.1, 40.3, 39.9, 15.0, 13.2 ppm. LRMS (ES + ) m / z [M + H] + C 20 H 26 N3O + Calculated value: 324.21; Measured value: 324.29. IR (Diamond, ATR) ν 2972, 2869, 2798, 1636 cm -1 . Example 2: Preparation of N,N-diethyl-8-methyl-7a,8,9,10-tetrahydro-7H-indro[7,1-fg][1,7]naphthyridine-10-carboxamide (15, a small number of diastereomers) [ka]

[0216] To a solution of 13 (0.130 g, 0.381 mmol, 1.0 equiv) in CHCl3 (3.8 mL), cooled to 0°C, freshly ground NaOH (0.122 g, 3.05 mmol, 8.0 equiv) was added. A solution of TsCl (0.087 g, 0.46 mmol, 1.2 equiv) in CHCl3 (0.76 mL) was added dropwise over 10 minutes. The mixture was heated to ambient temperature and stirred for 1.5 hours. The mixture was cooled to 0°C, and DMSO (1.9 mL) was slowly added. Then, the mixture was heated to ambient temperature and stirred for 3 hours. The mixture was partitioned with H2O (200 mL) and HCl (150 mL), and the layers were separated. The aqueous layer was further extracted with HCl (3 × 50 mL). The organic extracts were combined, washed with brine (100 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (from 8% MeOH in HCl to 12% MeOH in HCl) to obtain 15 (0.044 g, 36%) as a brown semi-solid.

[0217] 1 H NMR (400 MHz, CDCl3) δ = 7.48 (d, J = 7.9 Hz, 1H), 7.22 (d, J = 7.2 Hz, 1H), 7.08 - 7.02 (m, 2H), 6.45 (d, J = 3.0 Hz, 1H), 6.37 (dd, J = 2.0, 3.6 Hz, 1H), 4.50 (dd, J = 5.5, 11.2 Hz, 1H), 4.02 (t, J = 11.2 Hz, 1H), 3.66 - 3.60 (m, 1H), 3.56 - 3.30 (m, 5H), 3.15 (dd, J = 5.7, 12.2 Hz, 1H), 2.83 (dd, J = 4.8, 12.2 Hz, 1H), 2.62 (s, 3H), 1.27 (t, J = 7.0 Hz, 3H), 1.13 (t, J = 7.0 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl) δ = 171.5, 133.4, 133.4, 126.5, 126.2, 120.4, 120.1, 119.9, 118.9, 114.2, 101.2, 58.6, 52.5, 47.9, 43.6, 42.0, 40.3, 37.4, 15.0, 13.2 ppm. LRMS (ES + ) m / z [M + H] + C 20 H 26 N3O + Calculated value: 324.21; Measured value: 324.29. IR (Diamond, ATR) ν 2969, 2932, 2871, 2791, 1634 cm -1 . Example 3: Thermodynamic Equilibrium [ka]

[0218] Diastereomers 14 and 15 in MeOH (1 mL) (in a 1:2 ratio) 1 To a solution of (0.014 g, 0.043 mmol, 1.0 equiv) (measured by 1H NMR analysis), 0.5 mL of 2 M NaOH aqueous solution was added. The solution was heated at 60°C for 1 hour and then concentrated under reduced pressure. The mixture was partitioned with H2O (20 mL) and DCM (10 mL), and the layers were separated. The aqueous layer was further extracted with DCM (2 × 10 mL). The organic extracts were combined, washed with brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure. Diastereomers 14 and 15 were mixed in a 5:1 ratio (with 14 as the major diastereomer and 15 as a minor diastereomer). 1 The product was obtained by 1H NMR analysis, and 14 is shown as the thermodynamically preferred product. See Figure 7. Example 4: Fumarate [ka]

[0219] While stirring at 50°C, 14 (0.135 g, 0.417 mmol, 1.0 equiv) in acetone (2 mL) was slowly added to a solution of fumaric acid (0.051 g, 0.438 mmol, 1.05 equiv) in acetone (6 mL). The solution was slowly cooled to room temperature while stirring, and then hexane (15 mL) was slowly added. The suspension was cooled to 0°C over 1 hour, and then refrigerated overnight in a -20°C freezer. The resulting mixture was filtered, washed with ice-cold 1:1 acetone / hexane (2 mL), and dried in a vacuum oven at 50°C to obtain (±)-JRT·fumarate (1:1 salt, 0.126 g, 69%) as a beige solid. 1 H NMR (400 MHz, MeOD4) δ = 7.45 (d, J = 7.8 Hz, 1H), 7.30 (d, J = 7.3 Hz, 1H), 7.21 (d, J = 3.1 Hz, 1H), 7.03 (t, J = 7.6 Hz, 1H), 6.74 (s, 2H), 6.44 (d, J = 3.04 Hz, 1H), 6.36 (s, 1H), 4.94 - 4.86 (m, 1H), 4.08 - 4.00 (m, 1H), 3.80 (t, J = 11.1 Hz, 1H), 3.72 - 3.65 (m, 1H), 3.56 (q, J = 7.2 Hz, 2H), 3.45 (septet, J = 7.6 Hz, 2H), 3.29 - 3.23 (m, 1H), 2.99 (t, J = 11.1 Hz, 1H), 2.74 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H), 1.18 (t, J = 7.1 Hz, 3H) ppm. 13 C NMR (100 MHz, MeOD4) δ = 173.0, 168.8, 135.4, 134.4, 133.1, 128.0, 127.8, 121.32, 121.26, 119.2, 119.1, 115.8, 102.4, 61.6, 56.4, 47.7, 43.8, 43.6, 42.0, 40.2, 15.1, 13.3 ppm. LRMS (ES +) m / z [M + H] + C 20 H 26 N3O + Calculated value: 324.21; Measured value: 324.35. IR (Diamond, ATR) ν 2971, 2869, 2799, 1630 cm -1 . Example 5: Chiral separation of (+)-JRT and (-)-JRT [ka]

[0220] Racemic (±)-JRT(14) was separated into its enantiomers by preparation chiral HPLC using an Agilent 1260 Infinity II (Chiralpak-IC 250×30 mm, 5 μm; eluent: 50:50 mixture of 0.1% diethylamine (v / v) in n-hexane and 50% MeOH (v / v) in CH2Cl2; 35.0 mL / min).

[0221] First elution peak, (-)-JRT. See Figure 9. Analytical chiral HPLC R t = 7.81 min (Chiralpak-IC 250 × 4.6 mm, 5 μm; Eluent: 50:50 mixture of 0.1% DEA and isopropanol in n-hexane, 1.0 mL / min). 250 mg, light brown semi-solid; LC-MS: m / z = 324.1 [M + H] + .

[0222] (-)-JRT·Fumarate. In a sealed tube, fumaric acid (81 mg, 0.69 mmol, 1.0 equiv) in acetone (0.81 mL) was heated to 40°C and stirred for 1 hour. To the resulting clear solution, (-)-JRT (226 mg, 0.69 mmol, 1.0 equiv) dissolved in acetone (1.13 mL) was added, and the mixture was stirred at 40°C for 2 hours. After cooling to room temperature, volatiles were removed to obtain a residue, which was then ground with diethyl ether and subsequently with n-pentane to obtain a light brown semi-solid. This was then freeze-dried to obtain 270 mg of (-)-JRT as a 1:1 fumarate (light brown solid). NMR data were consistent with those reported for (±)-JRT. Specific rotation [α] D 20 -9.9 (c = 0.0011 in ethanol).

[0223] Second elution peak. See Figure 10. Analytical chiral HPLC R t = 10.14 mins (Chiralpak-IC 250 × 4.6 mm, 5 μm; Eluent: 50:50 mixture of 0.1% DEA and isopropanol in n-hexane, 1.0 mL / min). 290 mg, light brown semi-solid; LC-MS: m / z = 324.1 [M + H] + .

[0224] (+)-JRT·Fumarate. In a sealed tube, fumaric acid (95 mg, 0.82 mmol, 1.0 equiv) was added to acetone (0.95 mL), heated to 40°C, and stirred for 1 hour. The resulting clear solution was treated with (+)-JRT (266 mg, 0.82 mmol, 1.0 equiv) dissolved in acetone (1.33 mL), and stirred at 40°C for 2 hours. After cooling to room temperature, volatile matter was removed to obtain a residue, which was then ground with diethyl ether and subsequently with n-pentane to obtain a light brown solid. This solid was then freeze-dried to obtain 250 mg of (+)-JRT as a 1:1 fumarate (light brown solid). NMR data were consistent with those reported for (±)-JRT. Specific rotation [α] D 20+8.7 (c=0.0011 in ethanol). Example 6: (7aS,10R)-10-(diethylcarbamoyl)-8,8dimethyl 7a,8,9,10-tetrahydro-7H-indro[7,1-fg][1,7]naphthyridine 8-ium iodide (16) [ka]

[0225] A mixture of (+)-JRT·Humarate (0.030 g), saturated aqueous NaHCO3 (30 mL), and DCM (30 mL) was vigorously stirred for 20 minutes. The layers were separated, and the aqueous layer was further extracted with DCM (2 × 30 mL). The combined organic extract was washed with brine (1 × 50 mL), dried over Na2SO4, and concentrated under reduced pressure. The resulting free base was dissolved in DCM (4 mL), then methyl iodide (0.4 mL) was added, and the solution was stirred in a drum vial at ambient temperature for 14 hours. Upon completion of the reaction, the stirring bar was removed, and the drum vial was placed in a 20 mL scintillation vial containing a solution of hexane (5 mL) and Et2O (5 mL) as reverse solvents for vapor diffusion. The two-chamber system was sealed only by capping an outer 20 mL scintillation vial, and the system was left in the dark at ambient temperature for one month, during which time crystals suitable for X-ray diffraction analysis were precipitated. The single crystals were used for X-ray analysis, and the remainder was filtered, washed with ice-cold Et2O (1 mL), and dried in vacuum to obtain 16 (0.019 g, 60%) as a light brown crystalline solid. 1H NMR (400 MHz, CDCl3) δ = 7.55 (d, J = 7.0 Hz, 1H), 7.48 (d, J = 7.5 Hz, 1H), 7.32 (d, J = 2.9 Hz, 1H), 7.12 (t, J = 7.7 Hz, 1H), 6.63 (s, 1H), 6.54 (d, J = 3.0 Hz, 1H), 5.18 - 5.10 (m, 1H), 5.06 - 4.99 (m, 1H), 4.34 - 4.26 (m, 1H), 4.21 (t, J = 11.3 Hz, 1H), 4.06 (t, J = 11.4 Hz, 1H), 3.99 - 3.92 (m, 1H), 3.76 - 3.62 (m, 2H), 3.59 (s, 3H), 3.56 - 3.40 (m, 2H), 3.35 (s, 3H), 1.38 (t, J = 3.1 Hz, 3H), 1.20 (t, J = 3.1 Hz, 3H) ppm. LRMS (ES + ) m / z [M] + C 21 H 28 N3O + Calculated value: 338.22; Measured value: 338.45. IR (Diamond, ATR) ν 3456, 2971, 2932, 1633 cm -1 . Example 7: X-ray crystallography

[0226] Approximate orthogonal dimensions: 0.248 × 0.448 × 0.594 mm 3 An orange block having the characteristic was placed and optically centered using a Bruker Duo APEXII CCD system at -183°C (90K). Unit cell indexing was performed using a random set of reflections collected from three series of 0.5° wide ω-scans, 10 sec / frame, and 30 frames / series, which were well dispersed in reciprocal space. Five ω-scan data frame series were collected using 606 frames collected series-wise at 0.3° wide scans, 15 sec / frame, and variable φ angles (φ=0°, 72°, 144°, 216°, 288°) [MoK αThe distance from the crystal to the detection device is 5.15 cm, which means that 2θ max This provided a complete sphere of data for =61.40°. [Table 1] [Table 2] [Table 3]

[0227] Structural determination and refinement. All crystallographic calculations were performed on a Surface Pro 7 with a 1.30GHz Intel i7-1065G7 processor (4 cores, 8 processors) and 16GB of expanded memory. The collected data were corrected for Lorentz and polarization effects using Saint and for absorption using Blessing's method, and then merged for incorporation with the Sadabs program. The SHELXTL program package was implemented to determine possible space groups and set up the initial files. System symmetry, extinction rules, and intensity statistics indicated a non-centrosymmetric orthorhombic space group P212121 (No. 19). The structure was determined by a direct method using the placed molecules with the XT program. The structure was refined using XL. The collected 48,297 data points were merged into 28,854 based on the same factor, and then merged down to 7,321 eigendata for least-squares refinement [R(int)=0.0163]. All non-hydrogen atoms were refined anisotropically. The hydrogen atom was idealized through the final refinement stage. The final structure was set to R(F)=1.89% and wR(F) for all 7321 intrinsic reflections. 2 For those 7222 data points with )=4.96% and GOF=1.081[Fo>4σ(Fo), R(F)=1.84, wR(F 2The model was refined to convergence with [)=4.93]. The final difference-Fourier map lacked features indicating that the structure was correct and complete. An empirical correction for vanishing was also attempted and found to be negative, and therefore not applied. The absolute structure parameters of the structure were determined as Flack(x), -0.014(3); Hooft(y), -0.013(2); and Parsons(z), -0.013(3), and it was shown that the absolute configuration of the structure was precisely determined; these values ​​would approach approximately 1.0 if the structure were inverted. Example 8: Serotonin assay

[0228] Serotonin 5-HT2A in vitro radioligand binding competition assay. The 5-HT2A radioligand binding competition assay was performed using conventional methods at Epics Therapeutics SA (Belgium, FAST-0505B). Briefly, competitive binding is performed in two wells of a 96-well plate (Master Block, Greiner, 786201) containing binding buffer (optimized for each receptor), membrane extract (protein / well amount optimized for each receptor), radioactive tracer [3H]-DOI (final concentration optimized for each receptor), and the test compound. Nonspecific binding is determined by co-incubation with a 200-fold excess of cold competitor. Samples are incubated at the optimal temperature and duration for each receptor in a final volume of 0.1 ml, and then filtered on a filter plate. The filters are washed six times with 0.5 ml of ice-cold wash buffer (optimized for each receptor), and 50 μl of Microscint 20 (Packard) is added to each well. The plates are incubated in an orbital shaker for 15 minutes, followed by counting at 1 minute per well using TopCount™.

[0229] Serotonin 5-HT2A in vitro cell IPOne activating assay. The 5-HT2A IPOne HTRF assay was performed using conventional methods at Epics Therapeutics SA (Belgium, FAST-0505I). Briefly, human recombinant 5-HT2A receptor-expressing CHO-K1 cells, grown to the mid-log phase in antibiotic-free culture medium, were detached with PBS-EDTA, centrifuged, and resuspended in antibiotic-free medium. 20,000 cells were dispensed into 96-well plates and incubated overnight at 37°C in 5% CO2.

[0230] For agonist testing, remove the culture medium and add 20 μl of assay buffer and 20 μl of the test compound or reference agonist to each well. Incubate the plate in 5% CO2 at 37°C for 60 minutes.

[0231] After adding the lysis buffer containing IP1-d2 and anti-IP1 cryptotate detection reagents, incubate the plate at room temperature for 1 hour, and measure the fluorescence ratio using the HTRF kit according to the manufacturer's specifications.

[0232] Serotonin 5-HT2C in vitro radioligand binding competition assay. The 5-HT2C edit (accession number AAF35842.1) radioligand binding competition assay was performed using conventional methods at Epics Therapeutics SA (Belgium, FAST-0507B). Briefly, competitive binding is performed in two wells of a 96-well plate (Master Block, Greiner, 786201) containing binding buffer (optimized for each receptor), membrane extract (protein / well amount optimized for each receptor), radiotelescopic tracer [3H]-DOI (final concentration optimized for each receptor), and the test compound. Non-specific binding is determined by co-incubation with a 200-fold excess of cold competitor. Samples are incubated at the optimal temperature and duration for each receptor in a final volume of 0.1 ml, and then filtered on a filter plate. The filters are washed six times with 0.5 ml of ice-cold wash buffer (optimized for each receptor), and 50 μl of Microscint 20 (Packard) is added to each well. The plates are incubated in an orbital shaker for 15 minutes, followed by counting at 1 minute per well using TopCount™.

[0233] Serotonin 5-HT2C in vitro cell IPOne activating assay. The 5-HT2C IPOne HTRF assay was performed using conventional methods at Epics Therapeutics SA (Belgium, FAST-0507I). Briefly, CHO-K1 cells expressing human recombinant 5-HT2C editing receptor (accession number AAF35842.1), grown to the mid-log phase in antibiotic-free culture medium, were detached with PBS-EDTA, centrifuged, and resuspended in antibiotic-free medium. 20,000 cells were dispensed into 96-well plates and incubated overnight at 37°C in 5% CO2.

[0234] For agonist testing, remove the culture medium and add 20 μl of assay buffer and 20 μl of the test compound or reference agonist to each well. Incubate the plate in 5% CO2 at 37°C for 60 minutes.

[0235] After adding the lysis buffer containing IP1-d2 and anti-IP1 cryptotate detection reagents, incubate the plate at room temperature for 1 hour, and measure the fluorescence ratio using the HTRF kit according to the manufacturer's specifications. Example 9: Neurite Assay

[0236] Neurite growth in primary neuronal cell culture assays. Alterations in neurite growth patterns are associated with trauma as well as psychiatric and neurodegenerative disorders. The discovery of novel compounds that can positively influence neurite formation is crucial for developing new therapies for neurological diseases. Measurement of neurite growth in rat cortical neurons using an automated image-based assay is used to determine the neuroplastic effects of the compounds of this invention. The neurite growth assay was performed using Neurofit SAS (France), as described below.

[0237] Pregnant Wistar rats (Janvier, France) were used in the study. The Wistar rats were delivered six days prior to use. Upon arrival at Neurofit's animal facility, the Wistar rats were housed individually in cages and kept in rooms with controlled temperature (21-22°C) and an inverted light-dark cycle (12 hours / 12 hours, lights on: 17:30-05:30, lights off: 05:30-17:30), with free access to food and water.

[0238] Female Wistar rats at 17 days of gestation were sacrificed by cervical dislocation, and the fetuses were removed from the uterus. Their brains were placed in Leibovitz ice medium (L15, Gibco, Fisher bioblock, France). The cerebral cortex was dissected, and the meninges were carefully removed. Cortical neurons were dissociated by trypsinization (trypsin-EDTA, Gibco) at 37°C for 30 minutes in the presence of 0.1 mg / ml DNAse I (Roche, France). The reaction was stopped by adding Dulbecco's modified Eagle medium (DMEM, Gibco) containing 10% fetal bovine serum (FBS, Gibco). This suspension was triturated using a 10 ml pipette and a 21 G needle syringe, and centrifuged at 350 × g for 10 minutes at room temperature. The dissociated cell pellet was resuspended in a medium consisting of 2% B27 supplement (Gibco), 0.5 mM L-glutamine (Gibco), and Neurobasal (Gibco) supplemented with an antibiotic-antimicrobial mixture. Viable cells were counted using a Neubauer cytometer with a trypan blue exclusion test (Sigma). Cells were seeded at a density of 10,000 cells per well in poly-L-lysine pre-coated 96-well plates (Costar). Different concentrations of the test compound were added to the culture. Donepezil (positive control) was tested at 250 nM.

[0239] After 72 hours (3 days) of plating, the cultures were fixed in paraformaldehyde (4%, Sigma) in PBS at 4°C for 30 minutes. Next, the cells were permeabilized with 0.1% Triton X100 for 30 minutes, saturated with PBS containing 3% BSA, and incubated with 1 / 10,000 anti-βIII tubulin antibody (Sigma) in PBS containing 0.5% BSA for 1 hour. The cells were washed three times with PBS containing 0.5% BSA and incubated with goat anti-mouse antibody conjugated to AF488 (Invitrogen A11001) diluted to 1 / 1000 in PBS containing 0.5% BSA for 1 hour. Finally, the nuclei were stained with 1 mg / ml DAPI at 1 / 1000 in PBS containing 0.5% BSA. After washing with PBS, the plates were photographed, the neurite network was examined, and analysis was performed using High-Content Screening (CellInsight, Thermo Scientific). The main parameters analyzed were the mean number of neurites per neuron and the mean total length of neurites per neuron. Data analysis was performed using analysis of variance (ANOVA). Fisher's Protected Least Significant Difference test was used for multiple comparisons. A p-value of ≤0.05 was considered statistically significant. The software used was StatView 5.0 from the SAS Institute.

[0240] In some embodiments, the compounds of the present invention increase the pattern of neurite growth. In some embodiments, the compounds of the present invention increase the average length of neurites compared to a control. In some embodiments, the compounds of the present invention increase the branching points of neurites compared to a control. In some embodiments, the compounds of the present invention significantly increase the number of new neurites and / or the average neurite length and / or the total length of dendritic branching compared to a control.

[0241] While the present invention has been described in some detail by illustrations and examples for the purpose of clarifying understanding, those skilled in the art will recognize that certain changes and modifications may be implemented within the scope of the appended claims. Furthermore, each reference provided herein is referred to by reference to the same extent as each individual reference is referred to by reference. In the event of any conflict between the present application and the references provided herein, the present application shall prevail. Some aspects of the present invention are described below. 1. The following equation (K): [ka] {In the formula, Each R 1a , R 1b , R 1c , and R 1d H and C are independent of each other. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyls, halogens, C 1-6 Haloalkyl, C 1-6 It is a haloalkoxy, -NO2, or -CN; Alternatively, two R atoms on adjacent ring atoms 1a The base is combined to form C 4-8 Forming cycloalkyls or 4-8 membered heterocycloalkyls having 1-2 heteroatoms that are independently N, O, or S; R 2a and R 2b These are H and C, which are independent of each other. 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, C 1-6 Haloalkyl, or C 1-6 Is it a haloalkoxy? Alternatively, R 2a and R 2bThese are combined to form a 4-8 membered heterocycloalkyl group, each independently having 1-2 heteroatoms that are N, O, or S; R 3 H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, C 1-6 Haloalkyl, or C 1-6 It is a haloalkoxy; R 3a is absent or C 1-6 Is it alkyl? Alternatively, R 3 and R 3a These are combined to form a 3-8 membered heterocycloalkyl group, each independently having 1-2 heteroatoms that are N, O, or S; The subscripts m and p are independently 0 to 2, and A compound having the structure {where the subscripts n and r are independently 0 to 3}, or a pharmaceutically acceptable salt thereof. 2. The following equation (J): [ka] {In the formula, Each R 1a , R 1b , R 1c , and R 1d H and C are independent of each other. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyls, halogens, C 1-6 Haloalkyl, C 1-6 It is a haloalkoxy, -NO2, or -CN; Alternatively, two R atoms on adjacent ring atoms 1a The base is combined to form C 4-8 Forming cycloalkyls or 4-8 membered heterocycloalkyls having 1-2 heteroatoms that are independently N, O, or S; R 2a and R 2b These are H and C, which are independent of each other. 1-6Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, C 1-6 Haloalkyl, or C 1-6 Is it a haloalkoxy? Alternatively, R 2a and R 2b These are combined to form a 4-8 membered heterocycloalkyl group, each independently having 1-2 heteroatoms that are N, O, or S; R 3 H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, C 1-6 Haloalkyl, or C 1-6 It is a haloalkoxy; The subscripts m and p are independently 0 to 2, and A compound or pharmaceutically acceptable salt thereof as described in item 1, having the structure {where the subscripts n and r are independently 0 to 3}. 3. The following equation (I): [ka] A compound or pharmaceutically acceptable salt thereof having the structure described in item 1 or 2. 4. The following equations (Ia), (Ib), (Ic), or (Id): [ka] A compound having the structure described in any of items 1 to 3, or a pharmaceutically acceptable salt thereof. 5. The following equation (Ia): [ka] A compound having the structure described in any of items 1 to 4, or a pharmaceutically acceptable salt thereof. 6. The following equation (Ib): [ka] A compound having the structure described in any of items 1 to 4, or a pharmaceutically acceptable salt thereof. 7. The following equation (Ic): [ka] A compound having the structure described in any of items 1 to 4, or a pharmaceutically acceptable salt thereof. 8. The following formula (Id): [ka] A compound having the structure described in any of items 1 to 4, or a pharmaceutically acceptable salt thereof. 9. The above R 1a However, H, C 1-6 Alkyl, C 1-6 A compound or pharmaceutically acceptable salt thereof, as described in any of items 1-8, which is an alkoxy or halogen. 10. The above R 1a However, a compound or pharmaceutically acceptable salt thereof, as described in any of items 1 to 9, which is H. 11. The above R 2a and R 2b However, H and C are independent of each other. 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxyalkyl, or C 1-6 A compound or pharmaceutically acceptable salt thereof, which is a haloalkyl compound, as described in any of items 1-10. 12. The above R 2a and R 2b However, each is independent of H or C 1-6 A compound or pharmaceutically acceptable salt thereof, which is alkyl, as described in any of items 1 to 11. 13. The above R 2a and R 2b However, each is independent of C 1-6 A compound or pharmaceutically acceptable salt thereof, which is alkyl, as described in any of items 1 to 12. 14. The above R 2a and R 2bHowever, each is independently ethyl, and is a compound or pharmaceutically acceptable salt thereof as described in any of items 1 to 13. 15. The above R 3 However, H or C 1-6 A compound or pharmaceutically acceptable salt thereof, which is alkyl, as described in any of items 1-14. 16. The above R 3 C 1-6 A compound or pharmaceutically acceptable salt thereof, which is alkyl, as described in any of items 1-15. 17. The above R 3 A compound or pharmaceutically acceptable salt thereof, as described in any of items 1 to 16, wherein the compound is methyl. 18. A compound or pharmaceutically acceptable salt thereof described in any of items 1 to 17, wherein n is 0. 19. The following structure: [ka] A compound or pharmaceutically acceptable salt thereof, as described in any of items 1 to 18, having the properties of any of the compounds described in items 1 to 18. 20. The following structure: [ka] A compound having any of the characteristics described in items 1 to 19. 21. The following structure: [ka] A compound or pharmaceutically acceptable salt thereof, as described in any of items 1 to 19, having the properties of any of the compounds described in items 1 to 19. 22. The following structure: [ka] A compound or pharmaceutically acceptable salt thereof, as described in any of items 1 to 19, having the properties of any of the compounds described in items 1 to 19. 23. The following structure: [ka] A compound having any of the characteristics described in items 1 to 19. 24. The following structure: [ka] A compound or pharmaceutically acceptable salt thereof, as described in any of items 1 to 19, having the properties of any of the compounds described in items 1 to 19. 25. The following structure: [ka] A compound or pharmaceutically acceptable salt thereof, as described in any of items 1 to 19, having the properties of any of the compounds described in items 1 to 19. 26. The following structure: [ka] A compound or pharmaceutically acceptable salt thereof, as described in any of items 1 to 19, having the properties of any of the compounds described in items 1 to 19. 27. The following structure: [ka] A compound as described in item 1, having the properties of: 28. The following structure is characterized by unit cell dimensions of a=7.0716(6)Å, α=90°, b=14.4326(12)Å, β=90°, c=23.0876(19)Å, and γ=90°: [ka] A crystalline compound of (7aS,10R)-10-(diethylcarbamoyl)-8,8-dimethyl-7a,8,9,10-tetrahydro-7H-indro[7,1-fg][1,7]naphthyridine-8-ium iodide having the following properties. 29. A pharmaceutical composition comprising a therapeutically effective amount of any of the compounds described in items 1 to 28 or a pharmaceutically acceptable salt thereof. 30. A method for treating a disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof described in any of items 1 to 28, thereby treating the disease. 31. The method according to item 30, wherein the disease is a neuropsychiatric disorder. 32. The method according to item 31, wherein the neuropsychiatric disorder is schizophrenia. 33. The method according to item 31, wherein the neuropsychiatric disorder is bipolar disorder. 34. The method according to item 30, wherein the disease is depression. 35. The method according to item 30, wherein the disease is a neurodegenerative disease. 36. The method according to item 30, wherein the disease is Alzheimer's disease or Parkinson's disease. 37. The method according to item 30, wherein the disease is Alzheimer's disease. 38. The method according to item 30, wherein the disease is Parkinson's disease. 39. The method according to item 30, wherein the disease is headache disorder. 40. The method according to item 30, wherein the disease is a migraine. 41. The method according to item 30, wherein the disease is cluster headache. 42. The method according to item 30, wherein the disease is poisoning. 43. The method according to item 30, wherein the disease is a substance use disorder. 44. The method according to item 30, wherein the disease is alcohol use disorder. 45. A method for enhancing neuronal plasticity, comprising contacting a neuron with a compound or pharmaceutically acceptable salt thereof described in any of items 1 to 28 in an amount sufficient to enhance the neuronal plasticity of the neuron (the compound causing a maximum number of dendritic intersections to increase by more than 1.0 times according to Scholl analysis). 46. ​​A method for enhancing neuronal plasticity and increasing dendritic spine density, comprising contacting a neuron with a compound or pharmaceutically acceptable salt thereof described in any of items 1 to 28 in an amount sufficient to enhance the neuronal plasticity and increase the dendritic spine density of the neuron.

Claims

1. The following equation (K): 【Chemistry 1】 {During the ceremony, Each R 1a 、R 1b 、R 1c 、and R 1d are independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkoxyalkyl, halogen, C 1-6 haloalkyl, C 1-6 haloalkoxy, -NO 2 , or -CN; Alternatively, two R atoms on adjacent ring atoms 1a The base is combined to form C 4-8 Forming cycloalkyls or 4-8 membered heterocycloalkyls having 1-2 heteroatoms that are independently N, O, or S; R 2a and R 2b These are H and C, which are independent of each other. 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, C 1-6 Haloalkyl, or C 1-6 Is it a haloalkoxy? Alternatively, R 2a and R 2b These are combined to form 4-8 membered heterocycloalkyls, each independently having 1-2 heteroatoms that are N, O, or S; R 3 H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, C 1-6 Haloalkyl, or C 1-6 It is a haloalkoxy; R 3a is absent or C 1-6 Is it alkyl? Alternatively, R 3 and R 3a These are combined to form 3- to 8-membered heterocycloalkyls, each independently having 1-2 heteroatoms that are N, O, or S; The subscripts m and p are independently 0 to 2, and A compound having the structure {where the subscripts n and r are independently 0 to 3} or a pharmaceutically acceptable salt thereof.

2. The following equation (I): 【Chemistry 2】 A compound or pharmaceutically acceptable salt thereof having the structure described in claim 1.

3. The following equations (Ia), (Ib), (Ic), or (Id): 【Transformation 3】 A compound or pharmaceutically acceptable salt thereof having the structure described in claim 1.

4. The aforementioned R 1a However, H, C 1-6 Alkyl, C 1-6 A compound or pharmaceutically acceptable salt thereof according to claim 1, which is an alkoxy or halogen.

5. The aforementioned R 1a The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein H is present.

6. The aforementioned R 2a and R 2b However, H and C are independent of each other. 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxyalkyl, or C 1-6 A compound or pharmaceutically acceptable salt thereof, which is a haloalkyl compound, as described in claim 1.

7. The aforementioned R 2a and R 2b However, each is independent of C 1-6 A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is alkyl.

8. The aforementioned R 2a and R 2b The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein each is independently ethyl.

9. The aforementioned R 3 However, H or C 1-6 A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is alkyl.

10. The aforementioned R 3 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is methyl.

11. The following structure: 【Chemistry 4】 A compound or pharmaceutically acceptable salt thereof according to claim 1, having the properties of the compound described in claim 1.

12. The following structure: 【Transformation 5】 The compound according to claim 1, having the following characteristics.

13. The following structure: 【Transformation 6】 A compound or pharmaceutically acceptable salt thereof according to claim 1, having the properties of the compound described in claim 1.

14. The following structure: 【Transformation 7】 A compound or pharmaceutically acceptable salt thereof according to claim 1, having the properties of the compound described in claim 1.

15. The following structure: 【Transformation 8】 The compound according to claim 1, having the following characteristics.

16. The following structure: 【Chemistry 9】 The compound according to claim 1, having the following characteristics.

17. The following structure is characterized by unit cell dimensions a = 7.0716 (6) Å, α = 90°, b = 14.4326 (12) Å, β = 90°, c = 23.0876 (19) Å, and γ = 90°: 【Chemistry 10】 A crystalline compound of (7aS,10R)-10-(diethylcarbamoyl)-8,8-dimethyl-7a,8,9,10-tetrahydro-7H-indro[7,1-fg][1,7]naphthyridine-8-ium iodide having the following properties.

18. A pharmaceutical composition comprising a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17.

19. A pharmaceutical composition for treating a disease, comprising a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17.

20. The pharmaceutical composition according to claim 19, wherein the disease is a neuropsychiatric disorder.

21. The pharmaceutical composition according to claim 20, wherein the neuropsychiatric disorder is schizophrenia.

22. The pharmaceutical composition according to claim 20, wherein the neuropsychiatric disorder is bipolar disorder.

23. The pharmaceutical composition according to claim 19, wherein the disease is depression.

24. The pharmaceutical composition according to claim 19, wherein the disease is a neurodegenerative disease.

25. The pharmaceutical composition according to claim 19, wherein the disease is Alzheimer's disease.

26. The pharmaceutical composition according to claim 19, wherein the disease is Parkinson's disease.

27. The pharmaceutical composition according to claim 19, wherein the disease is headache disorder.

28. The pharmaceutical composition according to claim 190, wherein the disease is migraine.

29. The pharmaceutical composition according to claim 19, wherein the disease is cluster headache.

30. The pharmaceutical composition according to claim 19, wherein the disease is poisoning.

31. The pharmaceutical composition according to claim 19, wherein the disease is a substance use disorder.

32. The pharmaceutical composition according to claim 19, wherein the disease is alcohol use disorder.

33. A pharmaceutical composition for enhancing neuronal plasticity, comprising a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17 in an amount sufficient to enhance the neuronal plasticity of nerve cells, wherein the compound causes a maximum number of dendritic intersections to increase by more than 1.0 times according to Scholl analysis.

34. A pharmaceutical composition for enhancing neuronal plasticity and increasing dendritic spine density, comprising a compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 17 in an amount sufficient to enhance neuronal plasticity and increase dendritic spine density in nerve cells.

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