Deamidoed ergot tetralines for the treatment of brain disorders

Abstract

Provided herein are tetracyclic heterocyclic compounds useful in methods of treating a disease or for increasing neural plasticity. These compounds can also be used to increase dendritic spine density.

Description

Cross-references to related applications

[0001] This application claims priority to U.S. Provisional Application No. 63 / 588,936, filed on October 9, 2023, which is incorporated herein by reference in its entirety.

[0002] Declaration of rights regarding inventions made under federally funded research and development. This invention was made with government support from the National Institutes of Health (NIH), grant number R01GM128997. The government holds certain rights to this invention.

[0003] background Alterations in synaptic connectivity and plasticity have been observed in the brains of individuals with neuropsychiatric disorders and neurological diseases / 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 diacetamide (LSD), have all exhibited neuroplasticity-promoting properties. For example, LSD and other ergoline skeletal analogs have been able to correct detrimental changes in neuronal structure associated with neuropsychiatric disorders and neurological diseases / disorders. Such structural changes include, for example, loss of dendritic spines and synapses in the prefrontal cortex (PFC) and reduced dendritic branching complexity. Furthermore, pyramidal neurons in the PFC show top-down modulation of brain regions controlling motivation, fear, reward, and cognition. Psychoplastogens have shown antidepressant, anti-anxiety, and anti-addiction effects in clinical practice. However, their subjective effects limit their clinical applicability. Furthermore, hallucinogenic compounds are contraindicated for psychotic disorders such as schizophrenia, which are known to involve the loss of dendritic spines in the PFC. Therefore, non-hallucinogenic psychoplasticogens may have unique advantages over their hallucinogenic counterparts.

[0004] This article provides compounds with clinically relevant therapeutic efficacy, improved physicochemical properties, and reduced hallucinogenic (e.g., non-hallucinogenic) properties compared to their hallucinogenic counterparts (e.g., ergoline).

[0005] Brief Overview of the Invention In one embodiment, this document provides a compound or a pharmaceutically acceptable salt thereof having the structure of formula (J): (J) in: R1a R 1b R 1c and R 1d Each independently is C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, halogen, C 1-6 Haloalkyl, C 1-6 Haloalkoxy groups, -NO2, or -CN; Alternatively, two R atoms on adjacent ring atoms 1a Groups combine to form C 4-8 Cycloalkyl or 4- to 8-membered heterocycloalkyl having one or two heteroatoms that are each independently N, O or S; R 2 For H, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl or C 1-6 Halogenated alkoxy groups; R 3 It does not exist, or it is H or C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, C 1-6 Halogenated alkyl or C 1-6 Halogenated alkoxy groups; R 3a It does not exist, or it is C. 1-6 alkyl; Or, R 3 and R 3a Combining to form 3- to 8-membered heterocyclic alkyl groups having 1 to 2 heteroatoms that are each independently N, O, or S; The dashed keys a, b, and c are either nonexistent or independent keys; The subscripts m and p are each independently 0, 1, or 2; and The subscripts n and r are each 0, 1, 2 or 3 independently.

[0006] In one embodiment, this document provides a compound or a pharmaceutically acceptable salt thereof having the structure of formula (J): (J) in: R 1a R 1b R 1c and R 1dEach independently is C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, halogen, C 1-6 Haloalkyl, C 1-6 Haloalkoxy groups, -NO2, or -CN; Alternatively, two R atoms on adjacent ring atoms 1a Groups combine to form C 4-8 Cycloalkyl or 4- to 8-membered heterocycloalkyl having one or two heteroatoms that are each independently N, O or S; R 2 For H, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl or C 1-6 Halogenated alkoxy groups; R 3 It does not exist, or it is H or C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, C 1-6 Halogenated alkyl or C 1-6 Halogenated alkoxy groups; R 3a It does not exist, or it is C. 1-6 alkyl; Or, R 3 and R 3a Combining to form 3- to 8-membered heterocyclic alkyl groups having 1 to 2 heteroatoms that are each independently N, O, or S; The dashed keys a, b, and c are either nonexistent or independent keys; When the dashed key b is a key, R 3a It does not exist; The subscripts m and p are each independently 0, 1, or 2; and The subscripts n and r are each 0, 1, 2 or 3 independently.

[0007] In another embodiment, this document provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof.

[0008] In another embodiment, this document provides a method for treating a disease, the method comprising administering a therapeutically effective amount of the compound of the invention or a pharmaceutically acceptable salt thereof to a subject in need, thereby treating the disease.

[0009] In another embodiment, this document provides a method for increasing neural plasticity, the method comprising contacting a neuronal cell with an amount sufficient to increase the neural plasticity of the neuronal cell by a compound of the present invention or a pharmaceutically acceptable salt thereof, wherein the compound produces a greater than 1.0-fold increase in the maximum number of dendritic crossings as determined by Shore analysis.

[0010] In another embodiment, this document provides a method for increasing neural plasticity and increasing dendritic spine density, the method comprising contacting a neuronal cell with an amount sufficient to increase the neural plasticity of the neuronal cell and increase its dendritic spine density of a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0011] Brief description of the attached figures Figure 1A The synthesis of isotryptoline (13, Example 1) is shown, which is an isosteric isotope of didehydro-N-methyl-ergoline.

[0012] Figure 1B The synthesis of isotryptine (20, Example 2) is shown, which is an isotryptine electron isostere of lysergine.

[0013] Figure 2 The synthesis of compounds 31 and 32 (Example 3) is shown.

[0014] Figure 3 The synthesis of haloindole derivatives of isotryptoline is shown.

[0015] Detailed Description of the Invention I. Overview This document provides tetracyclic ergoline analogs of heterocyclic compounds of formulas (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or pharmaceutically acceptable salts thereof. The compounds of this invention can be used to treat diseases such as brain disorders, neuropsychiatric disorders, and other neurological disorders. The compounds of this invention can also be used to increase neural plasticity, increase dendritic spine density, or both.

[0016] II. Definition Unless otherwise expressly stated, all technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which this invention pertains. Furthermore, any methods or materials similar to or equivalent to those described herein may be used in the implementation of this invention. For the purposes of this invention, the following terms are defined as follows.

[0017] The terms “a,” “an,” or “the” include not only aspects with only one member but also aspects with multiple members. For example, unless the context clearly specifies otherwise, the singular forms “a,” “an,” and “the” include plural references. Thus, for example, a reference to “a cell” includes multiple such cells, while a reference to “the agent” includes one or more agents known to those skilled in the art, and so on.

[0018] “Alkyl” refers to a straight-chain or branched saturated aliphatic group having a specified number of carbon atoms. Unless otherwise stated, “alkyl” as disclosed herein is intended to include a separate description of saturated alkyl groups. Alkyl groups described herein are typically monovalent, but may also be divalent, and may also be described herein as “alkylene” or “alkylenyl” groups. Alkyl groups may include any number of carbon atoms, for example, C1... 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 For example, C 1-6 Alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, and hexyl. Alkyl groups can also refer to alkyl groups containing up to 20 carbon atoms, such as, but not limited to, heptyl, octyl, nonyl, and decyl. Alkyl groups can be substituted or unsubstituted.

[0019] "Alkenyl" refers to a straight-chain or branched hydrocarbon containing at least two carbon atoms and at least one double bond. Alkenyl groups can include any number of carbon atoms, such as C2, C3, C4, etc. 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 C4-6 C5, C 5-6 And C6. The alkenyl group can have any 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, 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-hextrienyl. The alkenyl group can be substituted or unsubstituted.

[0020] "Alynyl group" refers to a straight-chain or branched hydrocarbon containing at least two carbon atoms and at least one triple bond. Alynyl groups can include any number of carbon atoms, such as C2, C3, C4, etc. 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. Examples of alkynyl groups include, but are not limited to: acetyl, propynyl, 1-butynyl, 2-butynyl, butyrynyl, 1-pentynyl, 2-pentynyl, isopentenynyl, 1,3-pentyrynyl, 1,4-pentyrynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,3-hexadiynyl, 1,4-hexadiynyl, 1,5-hexadiynyl, 2,4-hexadiynyl, or 1,3,5-hextriynyl. The alkynyl group can be substituted or unsubstituted.

[0021] "Alkoxy group" refers to an alkyl group containing one oxygen atom, which connects the alkyl group to the bonding point: alkyl-O-. As for the alkyl group, the alkoxy group can have any suitable number of carbon atoms, for example, C10 ... 1-6 Alkoxy groups include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, hexoxy, etc. Alkoxy groups can be further substituted by various substituents described herein. Alkoxy groups can be substituted or unsubstituted.

[0022] "Alkoxyalkyl" refers to a group having an alkyl moiety and an alkoxy moiety, wherein the alkyl moiety connects the alkoxy moiety to a junction. The alkyl moiety is as described above, except that the alkyl moiety is at least divalent, is alkylene, and can connect to both the alkoxy moiety and the junction. The alkyl moiety can include any number of carbon atoms, for example, C1. 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 5-6 In some cases, the alkyl moiety may be absent. The alkoxy moiety is as defined above. Examples of alkoxyalkyl groups include, but are not limited to, 2-ethoxyethyl and methoxymethyl.

[0023] "Halogens" refers to fluorine, chlorine, bromine, and iodine.

[0024] "Halogenated alkyl" refers to an alkyl group as defined above, in which some or all of its hydrogen atoms are replaced by halogen atoms. As for the alkyl group, the halogenated alkyl group can have any suitable number of carbon atoms, such as C2. 1-6 For example, alkyl halides include trifluoromethyl, fluoromethyl, etc. In some cases, the term "perfluorinated" can be used to define compounds or groups in which all hydrogen atoms are replaced by fluorine. For example, perfluoromethyl refers to 1,1,1-trifluoromethyl.

[0025] "Haloalkoxy group" refers to an alkoxy group in which some or all of the hydrogen atoms are replaced by halogen atoms. As for alkyl groups, haloalkoxy groups can have any suitable number of carbon atoms, such as C0. 1-6 Alkoxy groups can be substituted with one, two, three, or more halogens. When all hydrogens are substituted with a halogen (e.g., fluorine), these compounds are fully substituted, for example, perfluorinated. Haloalkoxy groups include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, perfluoroethoxy, etc.

[0026] "Cycloalkyl" refers to a monocyclic, fused bicyclic, or bridged polycyclic ring containing 3 to 12 ring atoms or a specified number of ring atoms, forming a saturated or partially unsaturated ring. Cycloalkyl groups can include any number of carbon atoms, such as C64. 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 In some embodiments, the cycloalkyl group is a spirocyclic or bridged ring compound. In some embodiments, the cycloalkyl group is optionally fused with an aromatic ring, and the bonding point is located on a carbon atom of a non-aromatic ring. 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. The cycloalkyl group may also be partially unsaturated, containing one or more double or triple bonds in 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), norbornne, and norbornadiene. When the cycloalkyl group is a saturated monocyclic C 3-8 When cycloalkyl is used, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. When the cycloalkyl group is a saturated monocyclic C14, it is considered to be cycloalkyl. 3-6 When cycloalkyl is used, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyl groups can be substituted or unsubstituted. The ring of a cycloalkyl group may contain one or more double bonds.

[0027] "Heterocyclic alkyl" refers to a saturated ring system having 3 to 12 ring members and 1 to 4 N, O, and S heteroatoms. Heteroatoms may also be oxidized, such as, but not limited to, -S(O)- and -S(O)2-. Heterocyclic alkyl groups may include any number of ring atoms, 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 ring members. Heterocyclic alkyl groups may include any suitable number of heteroatoms, such as 1, 2, 3, or 4 heteroatoms, or 1 to 2 heteroatoms, 1 to 3 heteroatoms, 1 to 4 heteroatoms, 2 to 3 heteroatoms, 2 to 4 heteroatoms, or 3 to 4 heteroatoms. In some embodiments, the heterocyclic alkyl group is a spirocyclic compound or a bridging compound. In some embodiments, the heterocyclic alkyl group is optionally fused with an aromatic ring, and the connection point is located on a carbon atom or heteroatom (e.g., a nitrogen atom) of a non-aromatic ring carbon atom. Heterocyclic alkyl groups may include, for example, aziridine, aziridine, pyrrolidine, piperidine, aziridine-heptane, aziridine-octane, quinine ring, pyrazolidine, imidazolidine, piperazine (1,2-, 1,3- and 1,4- isomers), ethylene oxide, oxacyclobutane, tetrahydrofuran, oxane (tetrahydropyran), oxacycloheptane, thiocyclopropane, thiocyclobutane, thiolane (tetrahydrothiophene), thiane (tetrahydrothiaran), oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxopentane, dithiopentane, morpholine, thiomorpholine, dioxane, or dithiane. Heterocyclic alkyl groups can also fused with aromatic or non-aromatic ring systems to form compounds including, but not limited to, indoline. Heterocyclic alkyl groups can be unsubstituted or substituted. For example, heterocyclic alkyl groups can be C10-C2 ... 1-6 Alkyl or oxo (=O) substitution, etc.

[0028] Heterocyclic alkyl groups can be attached at any position on the ring. For example, aziridine can be 1- or 2-aziridine, aziridine can be 1- or 2-aziridine, 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, and imidazoline can be 1-, 2-, 3-, or 4-imidazoline. Piperazine can be 1-, 2-, 3-, or 4-piperazine, and tetrahydrofuran can be 1- or 2-tetrahydrofuran. Oxazolidine can be 2-, 3-, 4- or 5-oxazolidine, isoxazolidine can be 2-, 3-, 4- or 5-isooxazolidine, thiazoline can be 2-, 3-, 4- or 5-thiazoline, isothiazolidine can be 2-, 3-, 4- or 5-isothiazoline, and morpholine can be 2-, 3- or 4-morpholine.

[0029] When a heterocyclic alkyl group comprises 3 to 8 ring members and 1 to 3 heteroatoms, representative members include, but are not limited to, pyrrolidine, piperidine, tetrahydrofuran, oxahexane, tetrahydrothiophene, thiohexane, pyrazolidine, imidazoline, piperazine, oxazolidine, isoxazolidine, thiazoline, isothiazolidine, morpholine, thiomorpholine, dioxahexane, or dithiazoline. Heterocyclic alkyl groups can also form rings having 5 to 6 ring members and 1 to 2 heteroatoms, with representative members including, but not limited to, pyrrolidine, piperidine, tetrahydrofuran, tetrahydrothiophene, pyrazolidine, imidazoline, piperazine, oxazolidine, isoxazolidine, thiazoline, isothiazolidine, and morpholine.

[0030] "Aryl" refers to an aromatic ring system having any suitable number of ring atoms and any suitable number of rings. An aryl group can include any suitable number of ring atoms, such as 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 ring atoms, and 6 to 10, 6 to 12, or 6 to 14 ring members. Aryl groups can be monocyclic, fused to form bicyclic or tricyclic groups, or linked by bonds to form biaryl groups. Representative aryl groups include phenyl, naphthyl, and biphenyl. Other aryl groups include benzyl, which has a methylene linker. Some aryl groups have 6 to 12 ring members, such as phenyl, naphthyl, or biphenyl. Other aryl groups have 6 to 10 ring members, such as phenyl or naphthyl. Still other aryl groups have 6 ring members, such as phenyl. Aryl groups can be substituted or unsubstituted.

[0031] "Heteroaryl" refers to a monocyclic or fused bicyclic or tricyclic aromatic ring system consisting of 5 to 16 ring atoms, wherein 1 to 5 ring atoms are heteroatoms, such as N, O, or S. Other heteroatoms may also be used, including but not limited to B, Al, Si, and P. Heteroatoms may also be oxidized, such as, but not limited to, -S(O)- and -S(O)2-. A heteroaryl group may include any number of ring atoms, such as 5 to 6, 5 to 8, 6 to 8, 5 to 9, 5 to 10, 5 to 11, or 5 to 12 ring members. A heteroaryl group may include any suitable number of heteroatoms, such as 1, 2, 3, 4, or 5, or 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, 2 to 5, 3 to 4, or 3 to 5. The heteroaryl group may have 5 to 8 ring members and 1 to 4 heteroatoms, or 5 to 8 ring members and 1 to 3 heteroatoms, or 5 to 6 ring members and 1 to 4 heteroatoms, or 5 to 6 ring members and 1 to 3 heteroatoms. The heteroaryl group may include groups such as pyrrole, pyridine, imidazole, pyrazole, triazole, tetraazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5- isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. The heteroaryl group may also fuse with an aromatic ring system (such as a benzene ring) to form members including, but not limited to: benzopyrroles such as indole and isoindole, benzopyridines such as quinoline and isoquinoline, benzopyrazine (quinoxaline), benzopyrimidine (quinazoline), benzopyridazines such as phthalazine and zoline, benzothiophene, and benzofuran. Other heteroaryl groups include heteroaryl rings linked by bonds, such as bipyridine. Heteroaryl groups can be substituted or unsubstituted.

[0032] Heteroaryl groups can be attached at any position on the ring. For example, pyrrole includes 1-, 2-, and 3-pyrrole; pyridine includes 2-, 3-, and 4-pyridine; imidazole includes 1-, 2-, 4-, and 5-imidazolium; pyrazole includes 1-, 3-, 4-, and 5-pyrazole; triazole includes 1-, 4-, and 5-triazole; tetraazole includes 1-, and 5-tetraazole; pyrimidine includes 2-, 4-, 5-, and 6-pyrimidine; pyridazine includes 3- and 4-pyridazine; 1,2,3-triazine includes 4- and 5-triazine; 1,2,4-triazine includes 3-, 5-, and 6-triazine; 1,3,5-triazine includes 2-triazine; thiophene includes 2- and 3-thiophene; furan includes... 2- and 3-furans, thiazoles including 2-, 4- and 5-thiazoles, isothiazoles including 3-, 4- and 5-isothiazoles, oxazoles including 2-, 4- and 5-oxazoles, isoxazoles including 3-, 4- and 5-isooxazoles, indole including 1-, 2- and 3-indole, isoindole including 1- and 2-isoindole, quinoline including 2-, 3- and 4-quinoline, isoquinoline including 1-, 3- and 4-isoquinoline, quinazoline including 2- and 4-quinazoline, cenline including 3- and 4-cenline, benzothiophene including 2-benzothiophene and 3-benzothiophene, and benzofurans including 2- and 3-benzofurans.

[0033] Some heteroaryl groups include groups having 5 to 10 ring members and 1 to 3 ring atoms (including N, O, or S), such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4-, and 1,3,5- isomers), thiophene, furan, thiazole, isothiazole, oxazole, isoxazole, indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, zoline, benzothiophene, and benzofuran. Other heteroaryl groups include compounds having 5 to 8 ring members and 1 to 3 heteroatoms, such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4-, and 1,3,5- isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. Other heteroaryl groups include those with 9 to 12 ring members and 1 to 3 heteroatoms, such as indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, zoline, benzothiophene, benzofuran, and bipyridine. Still others include those with 5 to 6 ring members and 1 to 2 ring atoms (including N, O, or S), such as pyrrole, pyridine, imidazole, pyrazole, pyrazine, pyrimidine, pyridazine, thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole.

[0034] Some heteroaryl compounds include 5 to 10 ring members and only contain nitrogen heteroatoms, such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5- isomers), indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, and zoline. Other heteroaryl groups include 5 to 10 ring members and only contain oxygen heteroatoms, such as furan and benzofuran. Some other heteroaryl groups include 5 to 10 ring members and only contain sulfur heteroatoms, such as thiophene and benzothiophene. Other heteroaryl groups include 5 to 10 ring members and at least two heteroatoms, such as imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5- isomers), thiazole, isothiazole, oxazole, isoxazole, quinoxaline, quinazoline, phthalazine, and zoline.

[0035] The term “optionally substituted” or “substituted” means that the referred group is optionally substituted by one or more other groups, which may be selected individually and independently from halogens, -CN, -NH2, -NH(alkyl), -N(alkyl)2, -OH, -CO2H, -CO2alkyl, -C(=O)NH2, -C(=O)NH(alkyl), -C(=O)N(alkyl)2, -S(=O)2NH2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, alkyl, cycloalkyl, fluoroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, alkylthio, arylthio, alkyl sulfoxide, aryl sulfoxide, alkyl sulfone, and aryl sulfone. In some other embodiments, optional substituents may be independently selected from halogens, -CN, -NH2, -NH(CH3), -N(CH3)2, -OH, -CO2H, -CO2(C1-C4 alkyl), -C(=O)NH2, -C(=O)NH(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)2, -S(=O)2NH2, -S(=O)2NH(C1-C4 alkyl), -S(=O)2N(C1-C4 alkyl)2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 fluoroalkyl, C1-C4 heteroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, -SC1-C4 alkyl, -S(=O)C1-C4 alkyl and -S(=O)2C1-C4 alkyl. In some embodiments, the optional substituents are independently selected from halogens, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CF3, -OCH3, and -OCF3. In some embodiments, the substituted group is replaced by one or two of the above groups. In some embodiments, the optional substituents on the aliphatic carbon atom (acyclic or cyclic) include oxo (=O).

[0036] “Salt” refers to the acidic or basic salt of the compound used in the methods of this invention. Typical examples of pharmaceutically acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, etc.) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid, etc.) salts, and quaternary ammonium (iodomethane, iodoethane, etc.) salts. It is understood that pharmaceutically acceptable salts are non-toxic. More 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.

[0037] The pharmaceutically acceptable salts of the acidic compounds of the present invention are salts that form with bases, i.e., cationic salts, such as alkali metal salts and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium, and ammonium salts (such as ammonium salts, trimethylammonium salts, diethylammonium salts and tri(hydroxymethyl)methylammonium salts).

[0038] Similarly, acid addition salts of mineral acids, organic carboxylic acids, and organic sulfonic acids (e.g., hydrochloric acid, methanesulfonic acid, maleic acid) are also possible, as long as the basic groups such as pyridyl groups form the structural sites.

[0039] The neutral form of the compound can be regenerated by contacting the salt with a base or acid and separating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms in some physical properties (such as solubility in polar solvents), but otherwise, for the purposes of this invention, these salts are equivalent to the parent form of the compound.

[0040] "Therapeutic effective dose" or "therapeutic adequate dose" or "effective or adequate dose" refers to a dose administered to produce a therapeutic effect. The exact dose depends on the therapeutic purpose 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). For sensitized cells, the effective therapeutic dose can usually be lower than the effective dose of conventional treatment for non-sensitized cells.

[0041] "Treatment," "being treated," and "therapeutic methods" refer to any successful indicator of treatment or improvement of an injury, pathology, condition, or symptom (such as pain), including any objective or subjective parameters such as relief; remission; reduction of symptoms or making the symptoms, injury, pathology, or condition more tolerable to the patient; reduction of the frequency or duration of symptoms or condition; or, in some cases, prevention of the occurrence of symptoms. Treatment or remission of symptoms can be based on any objective or subjective parameters, including, for example, the results of a physical examination.

[0042] "Disease" refers to an abnormal cellular function within an organism that is not a direct result of physical or external damage. Disease can refer to any condition that causes pain, dysfunction, disability, disorder, infection, or even death. Diseases include, but are not limited to, hereditary diseases (such as genetic and non-hereditary diseases), infectious diseases, non-infectious diseases (such as cancer), nutritional deficiencies, neurological disorders, and physiological diseases.

[0043] "Administration" refers to oral administration, suppository administration, local contact administration, parenteral, intravenous, intraperitoneal, intramuscular, intralesional, intranasal, or subcutaneous administration, intrathecal administration, or implantation of a sustained-release device (such as a micro-osmotic pump) into the subject.

[0044] "Subject" refers to an animal (such as a mammal), including but not limited to primates (such as humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, etc. In some implementations, the subject is a human.

[0045] "Neuroplasticity" refers to the brain's ability to continuously change its structure and / or function throughout a subject's life. Examples of brain changes include, but are not limited to, the ability to adapt to or respond to internal and / or external stimuli (such as due to injury), and the ability to generate new neurites, dendritic spines, and synapses.

[0046] "Dendrical crossing" refers to dendritic branches that overlap or form clusters. Dendritic crossing can be measured using Sholl analysis.

[0047] Dendritic spines are tiny, membranous structures that extend from dendrites and receive electrical signals from axons at synapses. They are crucial for transmitting electrical signals to the cell body of neurons. A single neuron's dendrites can contain hundreds to thousands of spines. Dendritic spine density refers to the number of spines along the length of a dendrite. For example, a dendritic spine density of 5µm... -1 This indicates that there are 5 spines per 1 µm dendrite length.

[0048] "Modulate," "modulate," or "adjust" refers to an increase or decrease in the quantity, quality, or effect of a particular activity, function, or molecule. For example (but not limited to), G protein-coupled receptors (5HT)... 2A Or 5HT 2C Agonists, partial agonists, antagonists, and allosteric modulators (e.g., orthoallosteric modulators) are regulators of receptors.

[0049] "Agonism" refers to the biological response produced by activating receptors or enzymes through regulators (or agonists).

[0050] An "agonist" is a regulator that binds to a receptor or enzyme and activates that receptor to produce a biological response. For example, "5HT..." 2A "Agonist" can be used to refer to the effect of 5HT 2A Activity exhibits EC 50 Compounds not exceeding approximately 100 μM. In some embodiments, the term "agonist" includes full agonists or partial agonists. A "full agonist" is a regulator that binds to and activates the receptor, thereby eliciting the maximal response of the agonist on the receptor. A "partial agonist" is a regulator that binds to and activates a specific receptor, but has partial potency (i.e., less than the maximal response) on that receptor relative to a full agonist. A "functionally selective agonist" is a regulator that, upon receptor activation, may produce one or a portion of a biological response. For example, 5HT is known to... 2A Activation of the receptor triggers numerous downstream effects, including increased neural plasticity, elevated intracellular calcium concentration, hallucinations, and many other biological responses. Functionally selective agonists produce only 5-HT. 2A Part of the possible biological responses following receptor activation.

[0051] "Positive allosteric modulators" are modulators that bind to sites different from the orosteric binding site and enhance or amplify the agonist effect.

[0052] "Antagonism" refers to the inactivation of receptors or enzymes through modulators or antagonists. For example, receptor antagonism means that a molecule binds to the receptor and prevents its activity. "Functionally selective antagonists" block one signaling pathway while keeping other signaling pathways intact.

[0053] "Antagonists" or "neutral antagonists" are regulators that bind to receptors or enzymes and block biological responses. Antagonists are inactive in the absence of an agonist or inverse agonist, but they can block the activity of an agonist or inverse agonist without altering the biological response.

[0054] In the chemical structures described in this application, bold, non-wedge-shaped bonds are used to represent stereocenters of unknown stereochemistry. Chemical structures with bold, non-wedge-shaped bonds can represent mixtures of various stereoisomers.

[0055] III. Compounds The present invention provides tetracyclic heterocyclic compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II) or (III), which can be used to treat various neurological diseases and disorders and increase neuronal plasticity.

[0056] In some embodiments, due to the loss of hydrogen bond donors, the total polar surface area decreases, and the central nervous system multi-parameter optimization (MPO) score improves. Compared to ergoline compounds, compounds of formulas (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III) exhibit improved physicochemical properties. Non-psychotropic compounds are described in some embodiments herein, which unexpectedly exhibit similar properties to psychoactive 5-HT modulators (e.g., 5HT). 2A and / or 5HT 2C Similar therapeutic potential to hallucinogenic 5-HT modulators. In some embodiments, the non-hallucinogenic compounds described herein offer greater therapeutic potential than hallucinogenic 5-HT modulators (e.g., 5HT). 2A and / or 5HT 2C (Regulatory agents) have better therapeutic potential for treating nervous system diseases.

[0057] This document provides heterocyclic compounds of formulas (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III) for the treatment of a variety of diseases, such as brain disorders and other conditions. In some embodiments, the heterocyclic compounds provided herein are 5-HT2 modulators and can enhance neural plasticity (e.g., cortical structural plasticity).

[0058] In some embodiments, this document provides a compound or a pharmaceutically acceptable salt thereof having the structure of formula (J): (J) in: R 1a R 1b R 1c and R1d Each independently is C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, halogen, C 1-6 Haloalkyl, C 1-6 Haloalkoxy groups, -NO2, or -CN; Alternatively, two R atoms on adjacent ring atoms 1a Groups combine to form C 4-8 Cycloalkyl or 4- to 8-membered heterocycloalkyl having one or two heteroatoms that are each independently N, O or S; R 2 For H, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl or C 1-6 Halogenated alkoxy groups; R 3 It does not exist, or it is H or C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, C 1-6 Halogenated alkyl or C 1-6 Halogenated alkoxy groups; R 3a It does not exist, or it is C. 1-6 alkyl; Or, R 3 and R 3a Combining to form 3- to 8-membered heterocyclic alkyl groups having 1 to 2 heteroatoms that are each independently N, O, or S; The dashed keys a, b, and c are either nonexistent or independent keys; The subscripts m and p are each independently 0, 1, or 2; and The subscripts n and r are each 0, 1, 2 or 3 independently.

[0059] In some embodiments, this document provides a compound or a pharmaceutically acceptable salt thereof having the structure of formula (J): (J) in: R 1a R 1b R 1c and R 1d Each independently is C 1-6 Alkyl, C 2-6 alkenyl, C2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, halogen, C 1-6 Haloalkyl, C 1-6 Haloalkoxy groups, -NO2, or -CN; Alternatively, two R atoms on adjacent ring atoms 1a Groups combine to form C 4-8 Cycloalkyl or 4- to 8-membered heterocycloalkyl having one or two heteroatoms that are each independently N, O or S; R 2 For H, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl or C 1-6 Halogenated alkoxy groups; R 3 It does not exist, or it is H or C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, C 1-6 Halogenated alkyl or C 1-6 Halogenated alkoxy groups; R 3a It does not exist, or it is C. 1-6 alkyl; Or, R 3 and R 3a Combining to form 3- to 8-membered heterocyclic alkyl groups having 1 to 2 heteroatoms that are each independently N, O, or S; The dashed keys a, b, and c are either nonexistent or independent keys; When the dashed key b is a key, R 3a It does not exist; The subscripts m and p are each independently 0, 1, or 2; and The subscripts n and r are each 0, 1, 2 or 3 independently.

[0060] In some embodiments, this document provides compounds of formula (J) or pharmaceutically acceptable salts thereof having the structure of formula (Ja): (Ja).

[0061] In some embodiments, this document provides compounds of formula (J) or (Ja) or pharmaceutically acceptable salts thereof having the structure of formula (Ja-1): (Ja-1).

[0062] In some embodiments, compounds of formula (J), (Ja), (Ja-1) or pharmaceutically acceptable salts thereof are provided herein, having the structure of formula (Jb): (Jb).

[0063] In some embodiments, this document provides compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II) or (III), or pharmaceutically acceptable salts thereof, wherein R 2 For H, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl or C 1-6 Haloalkoxy. In some embodiments, compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II) or (III), or pharmaceutically acceptable salts thereof, wherein R 2 For H, C 1-6 Alkyl, C 1-6 Alkoxyalkyl or C 1-6 Hydroxyalkyl. In some embodiments, compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II) or (III), or pharmaceutically acceptable salts thereof, wherein R 2 It is H, methyl, ethyl, n-propyl, isopropyl, -CH2OCH3, CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2OH, or -CH2CH2OH. In some embodiments, this document provides compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or pharmaceutically acceptable salts thereof, wherein R 2It is H, Me, or CH2OH. In some embodiments, this document provides compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or pharmaceutically acceptable salts thereof, wherein R 2 For Me or CH2OH. In some embodiments, this document provides compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II) or (III), or pharmaceutically acceptable salts thereof, wherein R 2 For H. In some embodiments, this document provides compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II) or (III), or pharmaceutically acceptable salts thereof, wherein R 2 For Me. In some embodiments, this document provides compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II) or (III), or pharmaceutically acceptable salts thereof, wherein R 2 It is CH2OH.

[0064] In some embodiments, this document provides compounds of formula (J), (Ja) or (Ja-1), or pharmaceutically acceptable salts thereof, having a structure of formula (Ja-1a), (Ja-1b), (Ja-1c) or (Ja-1d): (Ja-1a), (Ja-1b), (Ja-1c), or (Ja-1d).

[0065] In some embodiments, this document provides compounds of formula (J), (Ja) or (Ja-1), or pharmaceutically acceptable salts thereof, having a structure of formula (Jb-1), (Jb-2), (Jb-3) or (Jb-4): (Jb-1), (Jb-1), (Jb-3), or (Jb-4).

[0066] In some embodiments, this document provides compounds of formula (J), (Ja) or (Ja-1), or pharmaceutically acceptable salts thereof, having the structure of formula (Ja-1a): (Ja-1a).

[0067] In some embodiments, this document provides compounds of formula (J), (Ja) or (Ja-1), or pharmaceutically acceptable salts thereof, having the structure of formula (Ja-lb): (Ja-1b).

[0068] In some embodiments, this document provides compounds of formula (J), (Ja) or (Ja-1), or pharmaceutically acceptable salts thereof, having the structure of formula (Ja-lc): (Ja-1c).

[0069] In some embodiments, this document provides compounds of formula (J), (Ja) or (Ja-1), or pharmaceutically acceptable salts thereof, having the structure of formula (Ja-ld): (Ja-1d).

[0070] In some embodiments, this document provides compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3) or (Jb-4), or pharmaceutically acceptable salts thereof, having the structure of formula (Jb-1): (Jb-1).

[0071] In some embodiments, this document provides compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Jb-2), (Jb-3) or (Jb-4), or pharmaceutically acceptable salts thereof, having the structure of formula (Jb-2): (Jb-2).

[0072] In some embodiments, this document provides compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Jb-2), (Jb-3) or (Jb-4), or pharmaceutically acceptable salts thereof, having the structure of formula (Jb-3): (Jb-3).

[0073] In some embodiments, this document provides compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Jb-2), (Jb-3) or (Jb-4), or pharmaceutically acceptable salts thereof, having the structure of formula (Jb-4): (Jb-4).

[0074] In some embodiments, this document provides compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II) or (III), or pharmaceutically acceptable salts thereof, wherein each R 1a Independently for C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, halogen, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -NO2, or –CN. In some embodiments, this document provides compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or pharmaceutically acceptable salts thereof, wherein each R 1a Independently for C 1-6 Alkyl, C 1-6 Alkoxy, halogen, C 1-6 Haloalkoxy or -CN. In some embodiments, this document provides compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II) or (III), or pharmaceutically acceptable salts thereof, wherein each R 1aIndependently for C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl or halogen. In some embodiments, compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II) or (III), or pharmaceutically acceptable salts thereof, wherein each R 1a Independently for C 1-3 Alkyl, C 1-3 Alkyl or halogen. In some embodiments, compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II) or (III), or pharmaceutically acceptable salts thereof, wherein each R 1a Independently, it is Me, MeO, fluorine, or chlorine. In some embodiments, this document provides compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or pharmaceutically acceptable salts thereof, wherein each R 1a Independently for C 1-6 Alkyl groups. In some embodiments, compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II) or (III), or pharmaceutically acceptable salts thereof, wherein each R 1a Independently for C 1-6 Alkyl or halogen. In some embodiments, compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II) or (III), or pharmaceutically acceptable salts thereof, wherein each R 1a Independently methoxy, fluorine, or chlorine. In some embodiments, compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or pharmaceutically acceptable salts thereof, wherein each R1a Independently halogenated. In some implementations, each R... 1a It can be either fluorine or chlorine.

[0075] In some embodiments, compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or pharmaceutically acceptable salts thereof, wherein the subscript n is 0, 1, 2, or 3. In some embodiments, compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or pharmaceutically acceptable salts thereof, wherein the subscript n is 1, 2, or 3. In some embodiments, compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or pharmaceutically acceptable salts thereof, are provided herein, wherein the subscript n is 0, 1, or 2. In some embodiments, compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or pharmaceutically acceptable salts thereof, are provided herein, wherein the subscript n is 0. In some embodiments, compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or pharmaceutically acceptable salts thereof, are provided herein, wherein the subscript n is 1. In some embodiments, compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or pharmaceutically acceptable salts thereof, are provided herein, wherein the subscript n is 2. In some embodiments, this document provides compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II) or (III), or pharmaceutically acceptable salts thereof, wherein the subscript n is 1 or 2.

[0076] In some embodiments, this document provides compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II) or (III), or pharmaceutically acceptable salts thereof, wherein each R 1b Independently for C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, halogen, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -NO2, or -CN. In some embodiments, this document provides compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or pharmaceutically acceptable salts thereof, wherein each R 1b Independently for C 1-6 Alkyl, C 1-6 Alkoxy, halogen, C 1-6 Haloalkoxy or -CN. In some embodiments, this document provides compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II) or (III), or pharmaceutically acceptable salts thereof, wherein each R 1b Independently for C 1-6 Alkyl, C 1-6 Alkyl or halogen. In some embodiments, compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II) or (III), or pharmaceutically acceptable salts thereof, wherein each R 1b Independently for C 1-3 Alkyl, C 1-3 Alkyl or halogen. In some embodiments, compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II) or (III), or pharmaceutically acceptable salts thereof, wherein each R1b Independently, it is Me, MeO, fluorine, or chlorine. In some embodiments, this document provides compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or pharmaceutically acceptable salts thereof, wherein each R 1b Independently for C 1-6 Alkyl groups. In some embodiments, compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II) or (III), or pharmaceutically acceptable salts thereof, wherein each R 1b Independently for C 1-6 Alkyl or halogen. In some embodiments, compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II) or (III), or pharmaceutically acceptable salts thereof, wherein each R 1b Independently methoxy, fluorine, or chlorine. In some embodiments, compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or pharmaceutically acceptable salts thereof, wherein each R 1b It can be either fluorine or chlorine.

[0077] In some embodiments, compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or pharmaceutically acceptable salts thereof, are provided herein, wherein the subscript m is 0, 1, or 2. In some embodiments, compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or pharmaceutically acceptable salts thereof, are provided herein, wherein the subscript m is 1 or 2. In some embodiments, compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or pharmaceutically acceptable salts thereof, are provided herein, wherein the subscript m is 0 or 1. In some embodiments, compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or pharmaceutically acceptable salts thereof, are provided herein, wherein the subscript m is 0. In some embodiments, compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or pharmaceutically acceptable salts thereof, are provided herein, wherein the subscript m is 1. In some embodiments, compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or pharmaceutically acceptable salts thereof, are provided herein, wherein the subscript m is 2. In some embodiments, this document provides compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II) or (III), or pharmaceutically acceptable salts thereof, wherein the subscript m is 1 or 2.

[0078] In some embodiments, this document provides compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II) or (III), or pharmaceutically acceptable salts thereof, wherein R 1c C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, halogen, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -NO2, or -CN. In some embodiments, compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or pharmaceutically acceptable salts thereof, wherein R 1c C 1-6 Alkyl, C 1-6 Alkyl or halogen. In some embodiments, compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II) or (III), or pharmaceutically acceptable salts thereof, wherein R 1c C 1-6 Alkyl or halogen. In some embodiments, compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II) or (III), or pharmaceutically acceptable salts thereof, wherein R 1c C 1-6 Alkyl groups. In some embodiments, compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II) or (III), or pharmaceutically acceptable salts thereof, wherein R 1c C 1-6Alkyl. In some embodiments, compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II) or (III), or pharmaceutically acceptable salts thereof, wherein R 1c It is a halogen. In some embodiments, this document provides compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II) or (III), or pharmaceutically acceptable salts thereof, wherein R 1b It is methoxy, fluorine, or chlorine. In some embodiments, R 1c It is either fluorine or chlorine.

[0079] In some embodiments, compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or pharmaceutically acceptable salts thereof, are provided herein, wherein the subscript p is 0, 1, or 2. In some embodiments, compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or pharmaceutically acceptable salts thereof, are provided herein, wherein the subscript p is 1 or 2. In some embodiments, compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or pharmaceutically acceptable salts thereof, are provided herein, wherein the subscript p is 0 or 1. In some embodiments, compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or pharmaceutically acceptable salts thereof, are provided herein, wherein the subscript p is 0. In some embodiments, this document provides compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II) or (III), or pharmaceutically acceptable salts thereof, wherein the subscript p is 1.

[0080] In some embodiments, this document provides compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II) or (III), or pharmaceutically acceptable salts thereof, wherein R 1d C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, halogen, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -NO2, or -CN. In some embodiments, compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or pharmaceutically acceptable salts thereof, wherein R 1d C 1-6 Alkyl, C 1-6 Alkyl or halogen. In some embodiments, compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II) or (III), or pharmaceutically acceptable salts thereof, wherein R 1d C 1-6 Alkyl or halogen. In some embodiments, compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II) or (III), or pharmaceutically acceptable salts thereof, wherein R 1d C 1-6 Alkyl groups. In some embodiments, compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II) or (III), or pharmaceutically acceptable salts thereof, wherein R 1d C 1-6Alkyl. In some embodiments, compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II) or (III), or pharmaceutically acceptable salts thereof, wherein R 1d It is a halogen. In some embodiments, this document provides compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II) or (III), or pharmaceutically acceptable salts thereof, wherein R 1d It is methoxy, fluorine, or chlorine. In some embodiments, R 1d It is either fluorine or chlorine.

[0081] In some embodiments, compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or pharmaceutically acceptable salts thereof, wherein the subscript r is 0, 1, 2, or 3. In some embodiments, compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or pharmaceutically acceptable salts thereof, wherein the subscript r is 1, 2, or 3. In some embodiments, compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or pharmaceutically acceptable salts thereof, are provided herein, wherein the subscript r is 0 or 1. In some embodiments, compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or pharmaceutically acceptable salts thereof, are provided herein, wherein the subscript r is 0. In some embodiments, this document provides compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II) or (III), or pharmaceutically acceptable salts thereof, wherein the subscript r is 1.

[0082] In some embodiments, this document provides compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II) or (III), or pharmaceutically acceptable salts thereof, wherein R 3 For H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, C 1-6 Halogenated alkyl or C 1-6 Haloalkoxy. In some embodiments, compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II) or (III), or pharmaceutically acceptable salts thereof, wherein R 3 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, C 1-6 Halogenated alkyl or C 1-6 Haloalkoxy. In some embodiments, compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II) or (III), or pharmaceutically acceptable salts thereof, wherein R 3 For H or C 1-6 Alkyl. In some embodiments, compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II) or (III), or pharmaceutically acceptable salts thereof, wherein R 3 C 1-6 Alkyl. In some embodiments, compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II) or (III), or pharmaceutically acceptable salts thereof, wherein R 3It is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or pharmaceutically acceptable salts thereof, wherein R 3 It is a methyl group.

[0083] In some embodiments, this document provides compounds of formula (J), or pharmaceutically acceptable salts thereof, wherein R 3a It may not exist, or it may be C. 1-6 Alkyl group. In some embodiments, compounds of formula (J) or pharmaceutically acceptable salts thereof are provided herein, wherein R 3a C 1-6 Alkyl group. In some embodiments, compounds of formula (J) or pharmaceutically acceptable salts thereof are provided herein, wherein R 3a It is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, this document provides a compound of formula (J), or a pharmaceutically acceptable salt thereof, wherein R... 3a The methyl group is used. In some embodiments, compounds of formula (J) or pharmaceutically acceptable salts thereof are provided herein, wherein R is a methyl group. 3a It does not exist.

[0084] In some embodiments, this document provides a compound of formula (J), or a pharmaceutically acceptable salt thereof, wherein dashed bonds a and b are bonds, and dashed bond c is absent. In some embodiments, this document provides a compound of formula (J), or a pharmaceutically acceptable salt thereof, wherein dashed bonds a and c are each bonds, and dashed bond b is absent. In some embodiments, this document provides a compound of formula (J), or a pharmaceutically acceptable salt thereof, wherein dashed bonds b and c are each bonds, and dashed bond a is absent.

[0085] In some embodiments, this document provides a compound of formula (J), or a pharmaceutically acceptable salt thereof, wherein the dashed bond a is a bond, and dashed bonds b and c are each independently absent or are bonds.

[0086] In some embodiments, this document provides a compound of formula (J), or a pharmaceutically acceptable salt thereof, wherein the dashed bond b is a bond, and dashed bonds a and c are either independently absent or are bonds.

[0087] In some embodiments, compounds of formula (J) or pharmaceutically acceptable salts thereof are provided herein, wherein dashed bond a is absent, and dashed bonds b and c are each independently absent or are bonds. In some embodiments, compounds of formula (J) or pharmaceutically acceptable salts thereof are provided herein, wherein dashed bonds a, b, and c are each absent.

[0088] In some embodiments, this document provides compounds of formula (J), or pharmaceutically acceptable salts thereof, having the structure of formula (II): (II).

[0089] In some embodiments, this document provides a compound of formula (J), or a pharmaceutically acceptable salt thereof, wherein the dashed bonds a, b and c are each bonds.

[0090] In some embodiments, this document provides compounds of formula (J), or pharmaceutically acceptable salts thereof, having the structure of formula (III): (III).

[0091] In some embodiments, this document provides compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II) or (III), or pharmaceutically acceptable salts thereof, having the following structures: , , , , , , , , , , , , , , , , , , , , , , , , or Or, or a pharmaceutically acceptable salt thereof.

[0092] In some embodiments, this document provides compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II) or (III), or pharmaceutically acceptable salts thereof, having the following structures: , , , , , , , , , , , , , , , , , , , , , , , , , , , or Or, or a pharmaceutically acceptable salt thereof.

[0093] In some embodiments, this document provides compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II) or (III), or pharmaceutically acceptable salts thereof, having the following structures: and ; and ,or and ; and ,or and ; and ,or and ; and ; and ; and and ; and ,or and ; and ,or and ; and ,or and ; and ,or and ; and ,or and ; and ,or and ; and ,or and ; and ,or and ; and ,or and ; and ,or and ; and ,or and ; and ,or and ; and ,or and ; and ,or and ; and ,or and ; and ,or and ; and ,or and ;or and ,or and Or, or a pharmaceutically acceptable salt thereof.

[0094] In some embodiments, this document provides compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II) or (III), or pharmaceutically acceptable salts thereof, having the following structures: , , , , , , , , , or Or, or a pharmaceutically acceptable salt thereof.

[0095] In some embodiments, this document provides compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II) or (III), or pharmaceutically acceptable salts thereof, having the following structures: , , or Or, or a pharmaceutically acceptable salt thereof.

[0096] In some embodiments, this document provides compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II) or (III), or pharmaceutically acceptable salts thereof, having the following structures: , , , , , or Or, or a pharmaceutically acceptable salt thereof.

[0097] In some embodiments, this document provides compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II) or (III), or pharmaceutically acceptable salts thereof, having the following structures: , , , , or Or, or a pharmaceutically acceptable salt thereof.

[0098] The compounds of the present invention may also be in the form of salts, such as acidic or basic salts of the compounds of the present invention. Typical examples of pharmaceutically acceptable salts include mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, etc.) salts, organic acid (fumaric acid, acetic acid, propionic acid, glutamic acid, citric acid, etc.) salts, and quaternary ammonium salts (iodomethane, iodoethane, etc.) salts. It is understood that pharmaceutically acceptable salts are non-toxic. More information on suitable pharmaceutically acceptable salts can be found in Remington Pharmaceutical Sciences, 17th edition, Mack Publishing, Easton, PA, 1985, which is incorporated herein by reference.

[0099] This invention also includes isotopically labeled compounds of this invention, wherein one or more atoms are substituted by one or more atoms having a specific atomic mass or mass number. In some embodiments, the compounds provided herein, such as compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1c), (Ja-1d), (Ja-1d), (Jb-2), (Jb-3), (Jb-4), (II), or (III), are isotopically labeled. In some embodiments, the compounds provided herein, such as compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), are isotopically enriched. Examples of isotopes that may be incorporated into the compounds of this invention include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, sulfur, and chlorine (such as... 2 H, 3 H, 13 C 14 C 15 N、 18 O、 17 O、 18 F, 35 S and 36 Cl). The isotope-labeled compounds of the present invention can be used to detect the tissue distribution of compounds, their prodrugs, and metabolites; preferred isotopes for such detection include 3 H and 14 C. In addition, in some cases, heavier isotopes (such as deuterium) are used. 2 Substituting H)) can provide increased metabolic stability, which brings therapeutic advantages such as prolonged in vivo half-life or reduced dosage requirements. The isotopically labeled compounds of the present invention can generally be prepared by methods known to those skilled in the art, i.e., by replacing non-isotopically labeled reagents with isotopically labeled reagents. The compounds of the present invention can be isotopically labeled at positions adjacent to basic amines, on aromatic rings, and on methyl groups of methoxy substituents.

[0100] This invention encompasses all tautomers and stereoisomers of the compounds of this invention, whether in mixture form or in pure or substantially pure form. The compounds of this invention may have an asymmetric center on a carbon atom, and therefore may exist as diastereomers or enantiomers, or mixtures thereof. All conformational isomers (e.g., cis and trans isomers) and all optical isomers (e.g., enantiomers and diastereomers), racemic mixtures, diastereomers, and other mixtures of such isomers, as well as solvates, hydrates, isomers, polymorphs, and tautomers are within the scope of this invention. Compounds according to the invention can be prepared using diastereomers, enantiomers, or racemic mixtures as starting materials. Furthermore, diastereomers and enantiomeric products can be separated by chromatography, fractional crystallization, or other methods known to those skilled in the art.

[0101] Compound Synthesis In some embodiments, this document provides methods for preparing compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), or (Jb-4), or pharmaceutically acceptable salts thereof. For example, compounds of formula (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), or (Jb-4), or pharmaceutically acceptable salts thereof, can be synthesized by the following method.

[0102] In some embodiments, compound 1 undergoes a reduction reaction to generate compound 2. In some embodiments, compound 3 undergoes an alkylation reaction to generate compound 3. In some embodiments, compound 3 undergoes a reduction reaction to generate compound 4. In some embodiments, compound 4 undergoes a cross-coupling reaction with compound 1a to generate compound 5. In some embodiments, compound 5 undergoes a substitution reaction to generate compound 6. In some embodiments, racemic compound 6 is separated into enantiomers compound 7 and compound 8. In some embodiments, R... 2 For methyl, R 3 It is methyl. In some embodiments, R 1a It can be Me, MeO, fluorine, or chlorine. In some embodiments, R 1b It can be Me, MeO, fluorine, chlorine, or CN. In some embodiments, n is 0, 1, or 2. In some embodiments, m is 0 or 1.

[0103] 5-HT 5-HT2 agonists are associated with promoting neuroplasticity (Ly et al., 2018). 5-HT2 antagonists can eliminate the neurogenesis and dendritic spine formation effects of hallucinogenic compounds with 5-HT2 agonist activity (e.g., DMT, LSD, and DOI). Furthermore, DMT and other psychedelic compounds promote dendritic branching complexity, dendritic spine density, and synapse formation through a 5-HT2-dependent process. Importantly, the neuroplasticity effects of the compounds presented in this paper are also blocked under these conditions, suggesting that 5-HT2 receptors play a role in their mechanism of action. Moreover, the regulation of 5-HT2 receptors appears to be important for neuroplasticity as well as for various psychological conditions such as anxiety disorders, depression, post-traumatic stress disorder (PTSD), and schizophrenia.

[0104] In addition, when 5HT 2A When the sensor is detected in antagonist mode, non-hallucinogenic compounds (e.g., lisuride and 6-MeO-DMT) compete with 5-HT. Furthermore, compounds such as 6-F-DET and ketanserin, which are not hallucinogenic in animals (e.g., humans), compete with 5-HT for binding in antagonist mode sensor detection. 2A In some embodiments, the compounds provided herein can prevent 5-HT from reacting with 5-HT. 2A Combined. In some implementations, 5HT 2A The sensor detects activity in antagonist mode. In some embodiments, the compounds provided herein can block 5-HT from reacting with 5-HT. 2A It binds and has non-hallucinogenic potential. In some embodiments, the compounds provided herein can block 5-HT from binding with 5-HT. 2A They bind and possess non-hallucinogenic potential. In some embodiments, the compounds provided herein block 5-HT and 5HT in an antagonistic mode. 2A They bind and have non-hallucinogenic potential. In some embodiments, the compounds provided herein block the binding of 5-HT in an antagonist mode and are non-hallucinogenic compounds. In some embodiments, the compounds provided herein inhibit the response of sensor detection in an antagonist mode and have non-hallucinogenic potential. In some embodiments, the compounds provided herein inhibit the response of sensor detection in an antagonist mode and are non-hallucinogenic compounds.

[0105] In some embodiments, the effect of compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III) on agonist mode sensor detection indicates that the compound is 5-HT. 2Areceptors and / or 5-HT 2C Non-hallucinogenic ligands for receptors. In some embodiments, the effect of the compounds described herein on antagonist mode sensor detection indicates that the compounds are 5-HT. 2A receptors and / or 5-HT 2C Non-hallucinogenic ligands for receptors. In some embodiments, the effect of the compounds described herein on agonist and antagonist mode sensor detection collectively indicates that the compound is a 5-HT receptor. 2A receptors and / or 5-HT 2C Non-hallucinogenic ligands of receptors.

[0106] This document describes, in some embodiments, non-hallucinogenic compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III) that exhibit therapeutic potential similar to hallucinogenic 5-HT2 agonists. In some embodiments, the non-hallucinogenic compounds described herein have better therapeutic potential for neurological disorders than hallucinogenic 5-HT2 agonists. In some embodiments, the compounds of the present invention are 5-HT 2A receptors and / or 5-HT 2C It acts as a regulator of receptors and promotes neural plasticity (e.g., cortical structural plasticity).

[0107] In some embodiments, compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III) are effective against 5-HT. 2A receptors and / or 5-HT 2C The receptor is active. In some embodiments, the compounds provided herein activate 5-HT 2A receptors and / or 5-HT 2C Receptors (e.g., allosteric regulation or regulation of 5-HT activation) 2A receptors and / or 5-HT 2C (Biotarget of the receptor) to trigger a biological response. In some embodiments, the compounds provided herein are selective 5-HT 2A Modulators and promoters of neural plasticity (e.g., cortical structural plasticity). In some embodiments, the compounds provided herein are selective 5-HT. 2CModulators, and promote neural plasticity (e.g., cortical structural plasticity). In some embodiments, promoting neural plasticity includes, for example, increasing dendritic spine growth, increasing synaptic protein synthesis, increasing synaptic responses, increasing dendritic branching complexity, increasing dendritic branching content, increasing dendritic spine formation, increasing neurite formation, or any combination thereof. In some embodiments, "increasing neural plasticity" includes, for example, increasing structural plasticity of the anterior cortex of the brain.

[0108] 5-HT 2C Agonists have been suggested for the treatment of multiple symptom domains of schizophrenia, including positive symptoms, negative symptoms, cognitive symptoms, and depressive symptoms, without the tolerance problems or adverse events associated with existing medications. 5-HT 2C 5-HT receptors are highly complex and regulated, widely distributed throughout the brain. 2C Receptors couple to multiple signal transduction pathways, thereby activating various intracellular signal transduction molecules. Furthermore, 5-HT... 2C The receptor has multiple allelic variants, and its coding region is susceptible to RNA editing. This complexity is also reflected in the application of agonists or antagonists in the treatment of schizophrenia. From neurochemical, electrophysiological, and behavioral perspectives, 5-HT... 2C Preclinical characteristics of the agonist suggest antipsychotic drug-like efficacy. In some embodiments, the compounds disclosed herein possess dual 5-HT... 2a Antagonists and 5-HT 2C Agonist activity.

[0109] In some embodiments, compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III) (e.g., 5-HT) 2A Regulators and / or 5-HT 2C The modulator is non-hallucinogenic. In some embodiments, compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III) (e.g., 5-HT) 2A Regulators and / or 5-HT 2CModulators are used to treat neurological disorders and do not cause dissociative side effects. In some embodiments, the hallucinogenic potential of the compounds described herein is evaluated in vitro. In some embodiments, the in vitro evaluated hallucinogenic potential of the compounds described herein is compared with the in vitro evaluated hallucinogenic potential of their hallucinogenic homologues. In some embodiments, compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III) exhibit lower in vitro hallucinogenic potential than their hallucinogenic homologues.

[0110] In some embodiments, compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III) (e.g., 5-HT) 2A Regulators and / or 5-HT 2C Modulators are used to treat neurological disorders. In some implementations, neurological disorders include decreased neural plasticity, decreased cortical structural plasticity, and 5-HT. 2A Decreased receptor levels, 5-HT 2C Increased receptor content, decreased dendritic branching complexity, loss of dendritic spines, decreased dendritic branching content, reduced dendritic spine formation, reduced neurite formation, neurite retraction, or any combination thereof.

[0111] In some embodiments, compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III) (e.g., 5-HT) 2A Regulators and / or 5-HT 2C Modulators are used to increase neuronal plasticity. In some embodiments, compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III) (e.g., 5-HT) 2A Regulators and / or 5-HT 2CModulators are used to treat brain disorders. In some embodiments, compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III) (e.g., 5-HT) 2A Regulators and / or 5-HT 2C (Regulators) are used to increase at least one of the translation, transcription or secretion of neurotrophic factors.

[0112] In some embodiments, compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), including their pharmaceutically acceptable salts and solvates, are non-psychotropic plasticizers. In some embodiments, non-psychotropic plasticizers can promote neuronal growth, improve neuronal structure, or combinations thereof.

[0113] IV. Pharmaceutical Compositions and Formulations In some embodiments, this article describes a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II) or (III), or a pharmaceutically acceptable salt thereof.

[0114] The compositions of the present invention can be formulated into various oral, injectable, and topical dosage forms. Oral formulations include tablets, pills, powders, sugar-coated tablets, capsules, liquids, lozenges, capsules, gels, syrups, slurries, suspensions, etc., suitable for oral administration. The compositions of the present invention can also be administered by injection, i.e., intravenous injection, intramuscular injection, intradermal injection, subcutaneous injection, duodenal injection, or intraperitoneal injection. Furthermore, the compositions described herein can also be administered by inhalation, for example, intranasal administration. Additionally, the compositions of the present invention can also be administered transdermally. The compositions of the present invention can also be administered via intraocular, intravaginal, and rectal routes, including suppositories, insufflation, powders, and aerosol formulations (e.g., steroid inhalers, 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 a compound of the present invention.

[0115] For the preparation of pharmaceutical compositions from the compounds of the present invention, a pharmaceutically acceptable carrier may be a solid or a liquid. Solid formulations include powders, tablets, pills, capsules, pouches, suppositories, and dispersible granules. The solid carrier may be one or more substances, which may also serve as diluents, flavoring agents, binders, preservatives, tablet disintegrants, or encapsulating materials. Details of formulation and administration techniques are described in detail in scientific and patent literature, for example, see the latest edition of Remington Pharmaceutical Sciences, Maack Publishing Co, Easton PA (“Remington’s”).

[0116] In powders, the carrier is a finely dispersed solid mixed with a finely dispersed active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary binding properties in an appropriate proportion and compressed into the desired shape and size. Powders and tablets preferably contain 5% or 10% to 70% of the compounds of the present invention.

[0117] Suitable solid excipients include, but are not limited to: magnesium carbonate; magnesium stearate; talc; pectin; dextrin; starch; astragalus gum; low-melting-point wax; cocoa butter; carbohydrates; sugars, including but not limited to lactose, sucrose, mannitol, or sorbitol, derived from corn, wheat, rice, potato, or other plant starches; cellulose, such as methylcellulose, hydroxypropyl methylcellulose, or sodium carboxymethylcellulose; and gums, including gum arabic and gum tragali; and proteins, including but not limited to gelatin and collagen. Disintegrants or solubilizers, such as croscarmellose, agar, alginate, or salts thereof, such as sodium alginate, may be added if necessary.

[0118] The sugar-coated tablet core is coated with a suitable coating, such as a concentrated sugar solution, which may also contain gum arabic, talc, polyvinylpyrrolidone, carbomer gel, polyethylene glycol and / or titanium dioxide, a lacquer solution, and a suitable organic solvent or solvent mixture. To identify the product or characterize the content (i.e., dosage) of the active compound, dyes or pigments may be added to the tablet or sugar-coated tablet coating. The pharmaceutical formulations of the present invention can also be taken orally, for example, as push-in capsules made using gelatin, and soft-sealable capsules made using a coating of gelatin and glycerin or sorbitol. Push-in capsules may contain the compounds of the present invention, a mixture of fillers or binders (such as lactose or starch), lubricants such as talc or magnesium stearate, and optionally, stabilizers. In soft capsules, the compounds of the present invention may be dissolved or suspended in a suitable liquid, such as fatty oils, liquid paraffin, or liquid polyethylene glycol, with or without stabilizers.

[0119] To prepare the suppositories, a low-melting-point wax (such as a mixture of fatty acid glycerides or cocoa butter) is first melted, and then the compound of the present invention is uniformly dispersed therein, for example by stirring. The molten, homogeneous mixture is then poured into a suitably sized mold, allowed to cool, and thus solidify.

[0120] Liquid formulations include solutions, suspensions, and emulsions, such as water or water / propylene glycol solutions. For parenteral injections, liquid formulations can be formulated as solutions in aqueous polyethylene glycol solutions.

[0121] Aqueous solutions suitable for oral administration can be prepared by dissolving the compounds of the present invention in water and adding suitable colorants, flavoring agents, stabilizers, and thickeners as needed. Aqueous suspensions suitable for oral administration can be prepared by dispersing finely dispersed active ingredients in water containing a viscous substance such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and gum arabic, as well as dispersants or wetting agents such as naturally occurring phospholipids (e.g., lecithin), condensation products of alkoxides and fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide and long-chain fatty alcohols (e.g., heptadecaethylene oxycetanol), condensation products of ethylene oxide and partial esters of fatty acids and hexitols (e.g., polyoxyethylene sorbitan monooleate), or condensation products of ethylene oxide and partial esters of fatty acids and hexitols (e.g., polyoxyethylene sorbitan monooleate). Aqueous suspensions may also contain one or more preservatives, such as ethylparaben or n-propylparaben; one or more colorants; one or more flavoring agents; and one or more sweeteners, such as sucrose, aspartame, or saccharin. The formulation can be adjusted for osmotic pressure.

[0122] This also includes solid dosage forms, which need to be converted into liquid formulations for oral administration shortly before use. These liquid forms include solutions, suspensions, and emulsions. In addition to the active ingredient, these formulations may also contain colorants, flavoring agents, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, etc.

[0123] Oily suspensions of the compounds of the present invention can be prepared by suspending them in vegetable oils (such as peanut oil, olive oil, sesame oil, or coconut oil) or mineral oils (such as liquid paraffin), or mixtures thereof. The oily suspensions may contain thickeners such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners (such as glycerin, sorbitol, or sucrose) may be added to provide palatable oral formulations. These formulations may be preserved by adding antioxidants (such as ascorbic acid). Examples of injectable oil carriers can be found in Minto. J. Pharmacol. Exp. Ther.281:93-102, 1997. The pharmaceutical formulations of this invention can also be in the form of oil-in-water emulsions. The oil phase can be the vegetable oils or mineral oils described above, or mixtures thereof. Suitable emulsifiers include naturally occurring gums, such as gum arabic and gum tragali; naturally occurring phospholipids, such as soybean lecithin; esters or partial esters derived from fatty acids and hexitan anhydrides, such as sorbitan monooleate; and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners and flavoring agents, as in formulations of syrups and elixirs. Such formulations may also contain demulcents, preservatives, or colorants.

[0124] The compositions of the present invention can also be delivered in the form of microspheres for slow release in vivo. For example, microspheres can be formulated for administration of drug-containing microspheres via intradermal injection, which release slowly subcutaneously (see Rao, J. Biomater Sci. Polym. Ed . 7:623-645, 1995); as a biodegradable and injectable gel formulation (see, e.g., 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 percutaneous and intradermal routes can achieve continuous delivery for weeks or months.

[0125] In some embodiments, the compositions of the present invention can be formulated for parenteral administration, such as intravenous (IV) administration, or administration into body cavities or organ cavities. The administration formulation typically comprises a solution in which the composition of the present invention is dissolved in a pharmaceutically acceptable carrier. Water and Ringer's solution (an isotonic sodium chloride solution) are acceptable carriers and solvents. Additionally, sterile fixative oils are commonly used as solvents or suspension media. For this purpose, any mild-tasting fixative oil can be used, including synthetic monoglycerides or diglycerides. Furthermore, fatty acids, such as oleic acid, can also be used in the preparation of the injection. These solutions are sterile and generally free of any harmful substances. These formulations can be sterilized using conventional, well-known sterilization techniques. Pharmaceutically acceptable adjuvants (such as pH adjusters and buffers, toxicity modifiers, such as sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate, etc.) may be added as needed to mimic physiological conditions. The concentration of the compositions of the present invention in these formulations can vary considerably, primarily based on liquid volume, viscosity, body weight, etc., depending on the specific route of administration and the patient's needs. For intravenous administration, the formulation can be a sterile injectable formulation, such as a sterile injectable aqueous or oily suspension. This suspension can be formulated using suitable dispersants or wetting agents and suspending agents according to existing technology. The sterile injectable formulation can also be a sterile injectable solution or suspension in a non-toxic, parenteral-acceptable diluent or solvent (such as a 1,3-butanediol solution).

[0126] In some embodiments, formulations of the compositions of the present invention can be delivered using liposomes, which fuse with or are endocytosed from cell membranes, i.e., by using ligands linked to or directly linked to oligonucleotides that bind to cell surface membrane protein receptors, thereby endocytosis. The compositions of the present invention can be “delivered” in vivo to target cells by using liposomes, particularly when the liposomes carry target cell-specific ligands on their surface or are preferentially directed to specific organs. (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).

[0127] The compositions of the present invention can be delivered by any suitable means, including oral, parenteral, and topical methods. Through the topical route, transdermal application can be formulated into plasters, solutions, suspensions, emulsions, gels, creams, ointments, pastes, gels, lotions, powders, and aerosols.

[0128] The pharmaceutical formulation is preferably in unit dose form. Thus, the formulation is subdivided into unit doses containing appropriate amounts of the compound of the present invention. The unit dose form can be a packaged formulation containing discrete quantities of the formulation, such as tablets in sachets, capsules, and powders in vials or ampoules. Alternatively, the unit dose form can be the capsule, tablet, sachets, or lozenges themselves, or a corresponding quantity of any of the above in a packaged form.

[0129] The compounds 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 weight and age, disease condition, etc. Suitable dosage ranges for the compounds 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 of the compounds of the present invention include about 1 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, or 1,000 mg.

[0130] The compounds of the present invention can be administered at any suitable frequency, interval, and duration. For example, the compounds of the present invention can be administered once per hour, or twice, three or more times per hour, once daily, or twice, three or more times daily, or once every 2, 3, 4, 5, 6, or 7 days to achieve the desired dose level. When the compounds of the present invention are administered more than once daily, representative 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 can be administered once, twice, three or more times, with each administration lasting for one hour, 1 to 6 hours, 1 to 12 hours, 1 to 24 hours, 6 to 12 hours, 12 to 24 hours, one day, 1 to 7 days, one week, 1 to 4 weeks, one month, 1 to 12 months, one year, or even indefinitely.

[0131] The composition may also contain other compatible therapeutic agents. The compounds described herein may be used in combination with each other, or in combination with other known active agents that can modulate glucocorticoid receptors, or in combination with adjuvant drugs that may be ineffective when used alone but may enhance the efficacy of the active agents.

[0132] The compounds of the present invention can be co-administered with another active agent. Co-administration includes administering the compounds and active agents 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 and active agents simultaneously, substantially simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or in any order. Furthermore, both the compounds and the active agents can be administered once daily, or twice, three times, or more daily to achieve the preferred daily dose level.

[0133] In some embodiments, co-administration can be achieved through co-formulation, i.e., preparing a single pharmaceutical composition comprising the compound and the active agent of the present invention. In some embodiments, the compound and the active agent of the present invention can be formulated separately.

[0134] The compounds and active agents of the present invention may be present in the compositions of the present invention in any suitable weight ratio, such as about 1:100 to about 100:1 (w / w), or about 1:50 to about 50:1, or about 1:25 to about 25:1, or about 1:10 to about 10:1, or about 1:5 to about 5:1 (w / w). The compounds of the present invention may be present with other active agents in any suitable 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 dosage ratios of the compounds and active agents of the present invention are also applicable to the compositions and methods of the present invention.

[0135] V. Treatment Methods In some embodiments, this document provides a method for treating a disease or disorder (e.g., but not limited to neurological diseases or disorders), the method comprising administering a therapeutically effective amount of the compound of the invention or a pharmaceutically acceptable salt thereof to a subject in need, thereby treating the disease or disorder.

[0136] In some embodiments, this document provides a method of treating a disease, comprising administering a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof to a subject in need, thereby treating the disease.

[0137] Nervous system diseases Neuronal plasticity and its changes have been attributed to numerous neurological diseases and disorders. For example, during development and adulthood, changes in the number and morphology of dendritic spines (e.g., length, crossing, density) accompany the formation, maintenance, and elimination of synapses; these changes are thought to establish and reshape connections within neural circuits. Furthermore, dendritic spine structural plasticity is coordinated with synaptic function and plasticity. For instance, dendritic spine enlargement is coordinated with long-term enhancement in neural circuits, while long-term inhibition is associated with dendritic spine shrinkage.

[0138] 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 connection patterns in neural circuits. For example, disease-specific disruptions in the shape, size, and / or number of dendritic spines are associated with neurological diseases and disorders, such as neurodegenerative diseases (e.g., Alzheimer's or Parkinson's) and neuropsychiatric diseases and disorders (e.g., depression or schizophrenia), suggesting that dendritic spines may serve as a common matrix in diseases associated with information processing deficits.

[0139] Unless otherwise stated, a neurological disease or disorder generally refers to a disease or disorder of an individual’s central nervous system (CNS) (e.g., the brain, spinal cord, and / or nerves).

[0140] In some embodiments, this document provides a method for treating neurological disorders or disturbances using compounds provided herein (e.g., compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II) or (III), or pharmaceutically acceptable salts or solvates thereof).

[0141] In some embodiments, this article provides compounds that can be used to treat a variety of brain disorders and other conditions. In some embodiments, the compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III) are 5-HT. 2A Modulators and can promote neural plasticity (e.g., cortical structural plasticity). In some embodiments, 5-HT... 2A Modifiers (e.g., 5-HT) 2AAgonists are used to treat brain disorders. In some embodiments, the compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III) are 5-HT. 2C Modulators, and can promote neural plasticity (e.g., cortical structural plasticity). In some embodiments, 5-HT 2C Modulators are used to treat brain disorders. In some implementations, brain disorders include decreased neuroplasticity, decreased cortical structural plasticity, and 5-HT. 2A Decreased receptor levels, 5-HT 2C Increased receptor content, decreased dendritic branching complexity, loss of dendritic spines, decreased dendritic branching content, reduced dendritic spine formation, reduced neurite formation, neurite retraction, or any combination thereof.

[0142] In some embodiments, the compounds provided herein (e.g., compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II) or (III), or pharmaceutically acceptable salts or solvates thereof) can improve the number and morphology of lost dendritic spines in neurological diseases or disorders.

[0143] In some embodiments, the compounds of the present invention are used to treat neurological disorders. In some embodiments, these compounds have, for example, anti-addictive, antidepressant, anti-anxiety properties, or combinations 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 migraine, headache (e.g., cluster headache), post-traumatic stress disorder (PTSD), anxiety disorder, depression, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, mental disorders, treatment-resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, and addiction (e.g., substance use disorder).

[0144] In some embodiments, the disorder is a headache disorder. In some embodiments, the 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 an addiction. In some embodiments, the disorder is a substance use disorder. In some embodiments, the disorder is an alcohol use disorder.

[0145] In some implementations, the neurological disorder is a neurodegenerative disease, Alzheimer's disease, or Parkinson's disease. In some implementations, the neurological disorder is a mental 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 disorder. In some implementations, the neuropsychiatric disorder or neurological disorder is a mental 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 disorder. In some implementations, the neuropsychiatric disorder or neurological disorder is an addiction (e.g., substance use disorder). In some implementations, the neuropsychiatric disorder or neurological disorder is depression. In some implementations, the neuropsychiatric disorder or neurological disorder is anxiety disorder. In some implementations, the neuropsychiatric disorder or neurological condition is post-traumatic stress disorder (PTSD). In some implementations, the neurological condition is stroke or traumatic brain injury. In some implementations, the neuropsychiatric disorder or neurological condition is schizophrenia.

[0146] In some embodiments, the compounds of the present invention are used to treat neuropsychiatric disorders. In some embodiments, the neuropsychiatric disorders are major depressive disorder, treatment-resistant depression, generalized anxiety disorder, post-traumatic stress disorder, obsessive-compulsive disorder, substance use disorder, or psychosis. In some embodiments, the psychosis is schizophrenia, bipolar disorder, or psychosis (AD-P) in Alzheimer's disease.

[0147] In some embodiments, the compounds of the present invention are used to treat pain. In some embodiments, the compounds of the present invention are used to treat migraines.

[0148] In some embodiments, the compounds of the present invention are used to treat neurodegenerative diseases. In some embodiments, the neurodegenerative disease is dementia, traumatic brain injury, or Parkinson's disease. In some embodiments, dementia is Alzheimer's disease, vascular dementia, Lewy body dementia, frontotemporal dementia, Huntington's disease, or mixed dementia. In some embodiments, the compounds of the present invention are used to treat behavioral and / or psychological symptoms of dementia. In some embodiments, the compounds of the present invention are used to treat motor symptoms, behavioral symptoms, and / or psychological symptoms of Parkinson's disease.

[0149] In some implementations, the disease is a neuropsychiatric disorder. In some implementations, the disease is a neurodegenerative disorder.

[0150] In some embodiments, the compounds of the present invention are used to treat neurodegenerative diseases, neuropsychiatric diseases, or substance use disorders. In some embodiments, the neurological disease or disorder is an injury. In some embodiments, the disease or disorder is anxiety disorder, mood disorder, psychotic disorder, personality disorder, eating disorder, sleep disorder, sexual disorder, impulse control disorder, substance use disorder, dissociative disorder, cognitive disorder, developmental disorder, or affective disorder. In some embodiments, the disease or disorder is a psychotic disorder. In some embodiments, the psychotic disorder is selected from schizophrenia, schizoaffective disorder, schizophrenia-like disorder, transient psychotic disorder, paranoia, common psychotic disorder, substance-induced psychotic disorder, paranoid dementia, psychotic depression, bipolar disorder, schizotypal personality disorder, paranoid personality disorder, schizotypal personality disorder, borderline personality disorder, post-traumatic stress disorder, obsessive-compulsive disorder, and dissociative disorder, or psychosis associated with a neurodegenerative disease. In some embodiments, the neurodegenerative disease is selected from Huntington's disease, Alzheimer's disease, Lewy body dementia, and Parkinson's disease. In some implementations, the psychotic disorder is schizophrenia or bipolar disorder. In some implementations, the method also includes administering a therapeutically effective amount of an additional therapeutic agent to the subject.

[0151] In some embodiments, the compounds of the present invention are used to treat brain disorders. In some embodiments, these compounds have, for example, anti-addiction, antidepressant, anti-anxiety properties, or combinations thereof. In some embodiments, the brain disorder is a neuropsychiatric illness. In some embodiments, the neuropsychiatric illness is a mood disorder or anxiety disorder. In some embodiments, the brain disorder includes, for example, migraine, cluster headache, post-traumatic stress disorder (PTSD), anxiety disorder, depression, schizophrenia, and addiction (e.g., substance use disorder). In some embodiments, the brain disorder includes, for example, migraine, addiction (e.g., substance use disorder), depression, and anxiety disorder.

[0152] In some embodiments, this document provides a method for increasing neural plasticity, the method comprising contacting a neuronal cell with an amount sufficient to increase the neural plasticity of the neuronal cell by a compound of the present invention or a pharmaceutically acceptable salt thereof, wherein, by Shore analysis, the compound produces an increase of more than 1.0-fold in the maximum number of dendritic crossings.

[0153] Neuroplasticity refers to the brain's ability to alter its structure and / or function throughout a subject's life. During a subject's life, new neurons can be generated and integrated into the central nervous system. Increasing neuroplasticity includes, but is not limited to: promoting neuronal growth, promoting neurite formation, promoting synapse formation, promoting dendrite formation, increasing dendritic branching complexity, increasing dendritic spine density, and increasing excitatory synapse formation in the brain. In some implementations, increasing neuroplasticity includes promoting neuronal growth, promoting neurite formation, promoting synapse formation, promoting dendritic formation, increasing dendritic branching complexity, and increasing dendritic spine density.

[0154] In some implementations, increasing neuroplasticity can treat neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, mental disorders, depression, addiction, anxiety disorders, 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 implementations, the neuropsychiatric disorder is bipolar disorder. In some implementations, the disorder is depression. In some implementations, the disorder is post-traumatic stress disorder (PTSD). In some implementations, the disorder is anxiety disorder. In some implementations, the disorder is a neurodegenerative disease. In some implementations, the disorder is Alzheimer's disease or Parkinson's disease. In some implementations, the disorder is Alzheimer's disease. In some implementations, the disorder is Parkinson's disease.

[0155] In some embodiments, the compounds of the present invention are used to increase neural plasticity. In some embodiments, the compounds for increasing neural plasticity have, for example, anti-addiction, antidepressant, anti-anxiety properties, or combinations thereof. In some embodiments, decreased neural plasticity is associated with neuropsychiatric disorders. In some embodiments, neuropsychiatric disorders are mood disorders or anxiety disorders. In some embodiments, neuropsychiatric disorders include, for example, migraines, cluster headaches, post-traumatic stress disorder (PTSD), schizophrenia, anxiety disorders, depression, and addictions (e.g., substance use disorders). In some embodiments, brain disorders include, for example, migraines, addictions (e.g., substance use disorders), depression, and anxiety disorders. In some embodiments, the disorder is a neuropsychiatric disorder.

[0156] In some embodiments, the experiments or tests used to determine the increase in neural plasticity of any compound of the present invention are phenotypic tests, dendrite formation tests, dendritic spur formation tests, synapse formation tests, Sholl analysis, concentration-response experiments, and 5-HT assays. 2A agonist testing, 5-HT 2A Antagonist detection, 5-HT 2A Combined detection or 5-HT 2ABlocking experiments (e.g., ketoselin blocking experiments). In some embodiments, the experiment or test used to determine the hallucinogenic potential of any compound of the present invention is the mouse head twitching response (HTR) test.

[0157] The compounds of the present invention can have the following properties: 5-HT 2A The activity of the modulator. In some embodiments, the compounds of the present invention have the function of 5-HT 2A The activity of the modulator. In some embodiments, the compounds of the present invention activate 5-HT. 2A Receptors (e.g., allosteric regulation or activation of 5-HT) 2A Regulation of the receptor's biological targets triggers a biological response. 5-HT 2A The agonistic effect is associated with promoting neural plasticity. In some implementations, 5HT... 2A Sensor detection is performed in either agonist or antagonist mode. In some implementations, 5HT 2A Sensor detection is performed in agonist mode.

[0158] In some embodiments, the compound described herein is selective 5-HT. 2A Modifier. In some embodiments, the compound described herein is 5-HT. 2A Modulators and promoters of neural plasticity (e.g., cortical structural plasticity). In some embodiments, the compounds described herein are selective 5-HT. 2A Modulators and promoters of neural plasticity (e.g., cortical structural plasticity). In some embodiments, promoting neural plasticity includes, for example, increased dendritic spine growth, increased synaptic protein synthesis, increased synaptic responses, increased dendritic branching complexity, increased dendritic branching content, increased dendritic spine formation, increased neurite formation, or any combination thereof. In some embodiments, increased neural plasticity includes, for example, increased cortical structural plasticity in the anterior part of the brain.

[0159] In some implementations, non-hallucinogenic 5-HT 2A Modifiers (e.g., 5-HT) 2A Agonists are used to treat diseases. In some implementations, non-hallucinogenic 5-HT... 2A Modifiers (e.g., 5-HT) 2A Agonists are used to increase neuroplasticity. In some implementations, non-hallucinogenic 5-HT... 2A Modifiers (e.g., 5-HT) 2A Agonists) to increase neural plasticity and dendritic spine density.

[0160] In some embodiments, experiments or tests used to determine whether any compound of the present invention increases neural plasticity include phenotypic detection, dendrite formation detection, dendritic spine formation detection, synapse formation detection, Sholl analysis, concentration-response experiments, and 5-HT. 2C agonist testing, 5-HT 2C Antagonist detection, 5-HT 2C Combined detection or 5-HT 2C Blocking experiments (e.g., ketoselin blocking experiments). In some embodiments, the experiment or test used to determine the hallucinogenic potential of any compound of the present invention is the mouse head twitching response (HTR) test.

[0161] The compounds of the present invention can have the following properties: 5-HT 2C The activity of the regulator. In some embodiments, the compounds of the present invention have the function of 5-HT 2C The activity of the modulator. In some embodiments, the compounds of the present invention activate 5-HT. 2C Receptors (e.g., allosteric regulation or activation of 5-HT) 2C Regulation of the receptor's biological targets triggers a biological response. 5-HT 2C The agonistic effect is associated with promoting neuroplasticity. In some implementations, 5HT... 2C Sensor detection is performed in either agonist or antagonist mode. In some implementations, 5HT... 2C Sensor detection is performed in agonist mode.

[0162] In some embodiments, the compound described herein is a selective 5-HT 2C Modifier. In some embodiments, the compound described herein is 5-HT. 2C Modulators and promoters of neural plasticity (e.g., cortical structural plasticity). In some embodiments, the compounds described herein are selective 5-HT. 2C Modulators and promoters of neural plasticity (e.g., cortical structural plasticity). In some embodiments, promoting neural plasticity includes, for example, increased dendritic spine growth, increased synaptic protein synthesis, increased synaptic responses, increased dendritic branching complexity, increased dendritic branching content, increased dendritic spine formation, increased neurite formation, or any combination thereof. In some embodiments, increased neural plasticity includes, for example, increased cortical structural plasticity in the anterior part of the brain.

[0163] In some implementations, non-hallucinogenic 5-HT 2C Modifiers (e.g., 5-HT) 2C Agonists are used to treat diseases. In some implementations, non-hallucinogenic 5-HT... 2C Modifiers (e.g., 5-HT) 2CAgonists are used to increase neuroplasticity. In some implementations, non-hallucinogenic 5-HT... 2C Modifiers (e.g., 5-HT) 2C Agonists are used to increase neural plasticity and dendritic spine density.

[0164] In some embodiments, this document provides a method for increasing neural plasticity and dendritic spine density, the method comprising contacting a neuronal cell with an amount sufficient to increase the neural plasticity of the neuronal cell and increase the dendritic spine density of the compound of the present invention or a pharmaceutically acceptable salt thereof.

[0165] Dendritic spines are dynamic, and their density, shape, and volume can change significantly over time. The growth or loss of dendritic spines, which contribute to dendritic spine density, may be important for strengthening neural pathways involved in learning, memory, and general cognitive function. Increasing dendritic spine density can be used to treat neurological disorders, such as, but not limited to, neurodegenerative and neuropsychiatric diseases.

[0166] Increased dendritic spine density can be measured using staining and immunocytochemical methods known to those skilled in the art. Staining methods include, but are not limited to, electron microscopy, Golgi staining, crystal violet staining, DAPI staining, and eosin staining. For example, Golgi staining can be used to measure dendritic spine density.

[0167] In some embodiments, compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II) or (III), or pharmaceutically acceptable salts thereof, may be used to promote neuronal growth and / or improve neuronal structure.

[0168] In some embodiments, the compound of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II) or (III), or a pharmaceutically acceptable salt thereof, is a non-psychotropic psychoplasticogen for the treatment of one or more diseases or disorders associated with loss of synaptic connectivity and / or plasticity.

[0169] In some embodiments, individuals who are given compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III) do not experience hallucinogenic events (e.g., at any point in time after the compound is administered to the individual).

[0170] In some implementations, this document provides a method for treating a disease or disorder in an individual in need, wherein the disease or disorder is a neurological disease or disorder.

[0171] In some embodiments, the present invention provides a compound (e.g., a pharmaceutically acceptable salt or solvation thereof) for modulating serotonin (5-HT) receptors. In some embodiments, the 5-HT receptor regulated by a compound of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III) is serotonin receptor 2A (5-HT receptor 2A). 2A In some embodiments, the 5-HT receptor regulated by compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III) is the serotonin receptor 2C (5-HT). 2C ).

[0172] In some embodiments, this document provides a 5-hydroxytryptamine receptor 2A (5-HT) 2A ) Regulators, used to treat one or more substances related to 5-HT 2A Diseases or disorders related to activity. In some embodiments, this document provides a 5-hydroxytryptamine receptor 2C (5-HT) 2C ) Regulators, used to treat one or more substances related to 5-HT 2C Diseases or disorders related to activity.

[0173] In some embodiments, compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or pharmaceutically acceptable salts thereof, are used to prepare medicaments for treating diseases or conditions in mammals, which benefit from inhibiting or reducing 5-HT. 2A Activity and / or 5-HT 2C active.

[0174] In some embodiments, compounds of formula (J), (Ja), (Ja-1), (Ja-1a), (Ja-1b), (Ja-1c), (Ja-1d), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II) or (III), or pharmaceutically acceptable salts thereof, are used to prepare medicaments for treating diseases or conditions in mammals that benefit from promoting neuronal growth and / or improving neuronal structure.

[0175] A method for treating any disease or condition described herein in a mammal requiring such treatment involves administering, in a therapeutically effective amount, a pharmaceutical composition containing at least one compound described herein or a pharmaceutically acceptable salt, active metabolite, prodrug, or pharmaceutically acceptable solvate thereof to the mammal.

[0176] In some embodiments, compositions containing the compounds described herein are administered for preventative and / or therapeutic treatment. In some therapeutic applications, these compositions are administered to mammals already suffering from the disease or condition in an amount sufficient to cure or at least partially suppress at least one symptom of the disease or condition. The effective dose for this purpose depends on the severity and course of the disease or condition, prior treatment, the mammal's health status, weight, and response to the drug, as well as the judgment of a healthcare practitioner. Therapeuticly effective doses may be determined through methods including, but not limited to, dose escalation and / or dose range clinical trials.

[0177] In preventative applications, compositions containing the compounds described herein are administered to mammals susceptible to or at risk of developing a specific disease, disability, or condition. Such amounts are defined as “preventatively effective amounts or doses.” In this use, the specific dosage also depends on the mammal’s health status, weight, etc. When used on mammals, the effective amount for this purpose will depend on the severity and course of the disease, disability, or condition, prior treatment, the mammal’s health status and response to the drug, and the judgment of a healthcare professional. In some embodiments, preventative treatment comprises administering a pharmaceutical composition containing the compounds described herein or pharmaceutically acceptable salts thereof to a mammal that has previously experienced symptoms of at least one treated disease and is currently in remission to prevent recurrence of symptoms of the disease or condition.

[0178] In some implementations, where the mammal’s condition does not improve, the compound is administered at the discretion of a healthcare professional for a prolonged period (i.e., over an extended time period, including throughout the mammal’s lifespan) to alleviate or otherwise control or limit the symptoms of the mammal’s disease or condition.

[0179] In some implementations, when the mammal's condition improves, the dosage of the administered drug is temporarily reduced or temporarily stopped for a period of time (i.e., a "drug holiday"). In some implementations, the length of the drug holiday ranges from 2 days to 1 year, including, by way of example only, 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 dosage reduction during the drug holiday, by way of example only, is 10%-100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.

[0180] Once the patient's condition improves, a maintenance dose will be administered if necessary. Subsequently, in specific implementation schemes, the dose or frequency of administration, or both, will be reduced depending on the symptom status until the level of improvement in the disease, disorder, or condition is maintained. However, in some implementation schemes, intermittent treatment on a long-term basis is required for mammals if any symptoms recur.

[0181] The amount of a specific drug corresponding to this quantity may vary depending on a variety of factors, such as the specific compound, the disease condition and its severity, and the characteristics of the subject or host requiring treatment (e.g., weight, sex), but is still determined based on the relevant circumstances of the case, including, for example, the specific drug administered, the route of administration, the condition being treated, and the subject or host being treated.

[0182] However, generally, the dosage for adult treatment typically ranges from 0.01 mg to 5000 mg daily. In some embodiments, the dosage for adult treatment is from about 1 mg to about 1000 mg daily. In some embodiments, the desired dosage may be conveniently presented as a single dose or in fractions administered simultaneously or at appropriate intervals, such as two, three, four or more sub-doses daily.

[0183] In some embodiments, the daily dose applicable to the compound described herein or a pharmaceutically acceptable salt thereof is from about 0.01 mg to about 50 mg per kg of body weight. In some embodiments, the amount of active ingredient in the daily dose or dosage form may be lower or higher than the range indicated herein, based on multiple variables in an individual treatment regimen. In some embodiments, the daily dose and unit dose may vary based on multiple variables, including but not limited to the activity of the compound used, the disease or condition to be treated, the method of administration, the individual subject's needs, the severity of the disease or condition being treated, and the practitioner's judgment.

[0184] The toxicity and efficacy of such treatment regimens are determined through standard pharmaceutical procedures in cell culture or laboratory animals, including but not limited to the determination of LD50. 50 and ED 50 The dose ratio between toxic effects and therapeutic effects is called the therapeutic index, which is expressed as LD50. 50 With ED 50 The ratio between. In some embodiments, data obtained from cell culture assays and animal studies are used to determine the therapeutically effective daily dose range and / or therapeutically effective unit dose for mammals (including humans). In some embodiments, the daily dose of the compounds described herein is within the range of ED (expiratory power cutoff) with minimal toxicity. 50 Within the cyclic concentration range. In some embodiments, the daily dose range and / or unit dose vary within this range depending on the dosage form and route of administration used.

[0185] In a further embodiment of any of the foregoing aspects, an effective amount of the compound described herein or a pharmaceutically acceptable salt thereof is: (a) administered systemically to a mammal; and / or (b) administered orally to a mammal; and / or (c) administered intravenously to a mammal; and / or (d) administered by injection to a mammal; and / or (e) administered locally to a mammal; and / or (f) administered neither systemically nor locally to a mammal.

[0186] In a further embodiment of any of the foregoing aspects, the compound includes a single application of an effective amount, and further embodiments include (i) the compound is applied once daily; or (ii) the compound is applied multiple times a day to mammals.

[0187] In further embodiments of any of the foregoing aspects, the method includes multiple administrations of an effective amount of the compound, and further embodiments in which (i) the compound is administered continuously or intermittently: such as in a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the compound is administered to mammals every 8 hours; (iv) the compound is administered to mammals every 12 hours; (v) the compound is administered to mammals every 24 hours. In further or alternative embodiments, the method includes a drug holiday, wherein administration of the compound is temporarily suspended or the dose of the administered compound is temporarily reduced; at the end of the drug holiday, administration of the compound is resumed. In one embodiment, the length of the drug holiday varies from 2 days to 1 year.

[0188] 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, the overall therapeutic benefit to the patient is enhanced). Alternatively, in some embodiments, the benefit experienced by the patient is increased by administering one of the compounds described herein together with another agent (including treatment regimens) that also has therapeutic benefit.

[0189] In some embodiments, when the compounds disclosed herein are administered in combination with one or more additional agents (such as additional therapeutically effective agents, adjuvants, etc.), different therapeutically effective doses of the compounds disclosed herein will be used in the formulation of the pharmaceutical composition and / or treatment regimen. The therapeutically effective doses of the drugs and other agents used in the combination treatment regimen may optionally be determined by a method similar to that described above for the active substance itself. Furthermore, the preventative / treatment methods described herein include rhythmic dosing, i.e., providing more frequent, lower doses to minimize toxic side effects. In some embodiments, the combination treatment regimen includes the following treatment: initiating administration of the compounds described herein or pharmaceutically acceptable salts thereof before, during, or after the use of the second agent described herein, and continuing until any time during treatment with the second agent or at any time after the discontinuation of treatment with the second agent. It also includes the following treatment: administering the compounds described herein or pharmaceutically acceptable salts thereof with the second agent used in combination simultaneously or at different times, and / or at decreasing or increasing intervals during treatment. The combination treatment also includes periodic treatments that begin and end at different times to assist in the clinical management of patients.

[0190] It should be understood that dosage regimens used to treat, prevent, or improve a disease for which remission is sought are adjusted based on various factors, such as the subject's disease or disorder; the subject's age, weight, sex, diet, and health status. Therefore, in some cases, the actual dosage regimen used may differ, and in some implementations, it may deviate from the dosage regimen specified herein.

[0191] VI. Examples Materials and Methods All reagents and solvents were purchased commercially and used as received. Unless otherwise specified, reactions were carried out under an inert N2 atmosphere using oven-dried glassware (120 °C). Liquids and solutions sensitive to air and moisture were transferred using syringes or stainless steel tubing. Organic solutions were concentrated by rotary evaporation under reduced pressure (~5 Torr).

[0192] Nuclear magnetic resonance (NMR) spectra were acquired on a Bruker 400 and measured at 400 MHz and 100 MHz, respectively. 1 H and 13C, and internal reference based on residual solvent signal. 1 The 1H NMR data are recorded as follows: chemical shift (δ, ppm), multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; quintet; m, multiply), coupling constant (Hz), and integral. 13 CNMR data are reported as chemical shifts (δ, ppm). Liquid chromatography-mass spectrometry (LC-MS) was performed using a Waters Alliance 2695 HPLC system equipped with a Waters Micromass ZQ detector.

[0193] For the final compounds prepared by chiral SFC, samples were separated at a preparative scale using a Berger Multigram II SFC system equipped with an SD-1 Varian dual pump, a Knauer K-2501 spectrophotometer set to 220 nm, a CO2 dewar flask with a cooler, and a G700 compression system (Mettler-Toledo, Newark, Delaware, USA). Analytical chiral SFC was performed on a Berger Analytical SFC system equipped with a dual pump (FCM-1200), an autosampler (ALS-3100), a column oven (TCM-200), and a diode array detector (DAD-1315A) (Mettler-Toledo, Newark, Delaware, USA).

[0194] A. General Program General Procedure 1: C7 Boration of Halogenated Indoles According to the revised document procedure ( J. Am. Chem. Soc. 2010, 132, 12, 4068-4069): In a vial, diethylsilane (1.16 mL, 9.0 mmol, 1.5 equiv) and [Ru(p-cymene)Cl2]2 (36.7 mg, 0.06 mmol, 0.01 equiv) were added to a mixture of appropriate haloindoles (6 mmol, 1.0 equiv) and toluene (3 mL). The mixture was bubbled with N2 gas (5 min), then sealed and stirred at ambient temperature for 16 h (for fluoroindoles) or at 80 °C for 4 h (for chloroindoles), and then concentrated under reduced pressure.

[0195] In a vial, add THF (6 mL), dtbpy (8 mg, 0.03 mmol, 0.005 equiv), B2Pin2 (1.52 g, 6.0 mmol, 1.0 equiv), HBpin (0.043 mL, 0.3 mmol, 0.05 equiv), and [Ir(OMe)(cod)]2 (9.9 mg, 0.015 mmol, 0.0025 equiv). Bubble the mixture with N2 for 5 min, then seal the vial. Stir the mixture at 80 °C for 16 h, then concentrate under reduced pressure.

[0196] Dissolve the reaction mixture in THF (12 mL), and then carefully add 3 M NaOAc dropwise at 0 °C. (aq) (2 mL). The solution was heated to ambient temperature and stirred for 3 h, then H2O (15 mL) was added. The mixture was extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was then purified by silica gel column chromatography (95:5, hexane / EtOAc) to give C7 boroide haloindoles.

[0197] General Procedure 2: Suzuki Coupling of C7 Boronized Halogenated Indoles 2M Na₂CO₃ was added to a mixture of a specified alkenyl halide (1.0 equiv) and an appropriate amount of C7 boroide haloindole (1.2 equiv, prepared by general procedure 1) in dioxane (0.1 M). 3(aq) (1.0 M) and Pd(PPh3)4 (0.05 equiv). The mixture was heated to 100 °C with stirring and held for 5 h, then cooled to ambient temperature. The mixture was diluted with H2O (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residues were purified by silica gel column chromatography (conditions for each example are reported below) to give the corresponding Suzuki conjugates.

[0198] General Procedure 3: Intramolecular N-alkylation of Halogenated Indoles TsCl (1.25 equiv), tetrabutylammonium hydrogen sulfate (0.05 equiv), and freshly crushed NaOH (4.0 equiv) were added to a 0°C cooled mixture of Suzuki-coupled haloindoles (1.0 equiv, prepared according to general procedure 2) in DCM (0.05 M). The mixture was stirred at ambient temperature for 16 h. The mixture was then poured into a vigorously stirred 1M NH4Cl solution. (aq)The layers were separated and the aqueous layer was further extracted with DCM (3 x 40 mL) in 125 mL solution. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residues were purified by silica gel column chromatography (conditions for each example are reported below) to give the corresponding isotretinoin ergot alkaloids.

[0199] General Synthesis Scheme 1: Alternative to General Procedure 1: C7 Boration of Halogenated Indoles At room temperature, bis(pinacol)diborane (1.5 equiv) and KOAc (3.0 equiv) were added to a stirred solution of 1.0 equiv of haloindole (1.0 equiv) and dioxane (10 vol). The reaction mixture was degassed with nitrogen for 20 minutes, and then Pd(dppf)Cl2 was added. . DCM (0.05 eq). The resulting reaction mixture was stirred at 90 °C for 16 hours, then cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with aqueous NaCl solution, dried over anhydrous Na₂SO₄, and the solids were removed by filtration. The filtrate was concentrated under vacuum. The crude product was purified by silica gel column chromatography to obtain the desired C₇ borohydride haloindole.

[0200] Alternative General Procedure 2: Suzuki Coupling of C7 Boronized Halogenated Indoles At room temperature, C7 borohydride haloindole (0.8 eq) was added to a stirred solution of dioxane (10 vol) of a specified alkenyl halide (1.0 eq), followed by Na₂CO₃ (3.0 eq). The reaction mixture was bubbled under nitrogen for 20 min, then Pd(PPh₃)₄ (0.05 eq) was added, and the resulting reaction was stirred at 90 °C for 16 h. The reaction mixture was cooled to room temperature, diluted with water, and then extracted with ethyl acetate. The combined organic layers were washed with NaCl (10 mL), dried over anhydrous Na₂SO₄, filtered to remove solids, and the filtrate was concentrated under vacuum. The crude product was purified by silica gel column chromatography to obtain the corresponding Suzuki coupling target.

[0201] Alternative to general procedure 3; intramolecular indole N-alkylation At 0 °C, crushed NaOH (8.0 eq) was added to a stirred solution of 1.0 eq of Suzuki-coupled indole in CHCl3 (10 vol), and the reaction mixture was stirred for 10 min. After heating to room temperature, p-toluenesulfonyl chloride (1.2 eq) was added, and the reaction was stirred for 1 h. Then, DMSO (10 vol) was added, and the reaction was stirred for another 1.5 h. After the reaction was complete, the crude reaction mixture was diluted with cold water and extracted with DCM. The combined organic layers were washed with aqueous NaCl solution, dried over anhydrous Na2SO4, filtered to remove solids, and the filtrate was concentrated under vacuum. The crude product was purified by silica gel column chromatography to obtain the corresponding isotretinoin ergot alkaloid.

[0202] General Synthesis Scheme 2: General Synthesis Scheme 3: B. Intermediate compounds Preparation of (3-bromo-1-methyl-1,2,5,6-tetrahydropyridin-2-yl)methanol 3-Bromo-2-(hydroxymethyl)-1-methylpyridine-1-onium iodide MeI (4.09 mL, 65.738 mmol, 6.0 equiv) was added to a solution of (3-bromopyridin-2-yl)methanol (2.060 g, 10.956 mmol, 1.0 eq) in MeCN (13.7 mL). The vial was capped and the solution was heated with stirring at 70 °C for 24 h, then cooled to ambient temperature. The suspension was cooled to 0 °C, filtered, and washed with hexane (2 x 10 mL). The resulting pale yellow solid was dried under reduced pressure to give 3-bromo-2-(hydroxymethyl)-1-methylpyridin-1-onium iodide (3.400 g, 94%). 1 H NMR (400 MHz, DMSO-) d 6) δ = 9.10 (d, J = 5.8 Hz, 1H), 8.91 (d, J = 8.6 Hz, 1H), 8.01 (dd, J = 8.0 Hz, 6.08 Hz, 1H), 6.19 (t, J = 5.76 Hz, 1H), 5.01 (d, J =5.76 Hz, 2H), 4.48 (s, 3H) ppm.13 C NMR (100 MHz, DMSO- d 6) δ = 154.0, 149.6, 147.2, 127.4, 124.4, 59.1, 46.9 ppm. LRMS (ES + ) m / z [M + H] + C7H9BrNO + Calculated value: 201.99; Measured value: 202.09.

[0203] (3-Bromo-1-methyl-1,2,5,6-tetrahydropyridin-2-yl)methanol To a 0 °C cooled solution of the obtained 2-(hydroxymethyl)-1-methylpyridine-1-iodide (3.000 g, 9.092 mmol, 1.0 equiv) in MeOH (181.8 mL), AcOH (2.60 mL, 45.460 mmol, 5.0 equiv) was added, followed by fractional addition of NaCNBH3 (1.257 g, 20.003 mmol, 2.2 equiv). The solution was heated to ambient temperature and stirred for 4 h, then concentrated under reduced pressure. The residue was dissolved in EtOAc (100 mL) and then added to 1 M NaOH (200 mL). The layers were separated, and the aqueous layer was further extracted with EtOAc (3 x 100 mL). The organic extracts were combined, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM of 3% MeOH) to give a pale yellow oil of (3-bromo-1-methyl-1,2,5,6-tetrahydropyridin-2-yl)methanol (1.420 g, 76%). 1 H NMR (400 MHz, CDCl3) δ =6.24 (t, J = 3.88 Hz, 1H), 4.50 (br s, 1H), 3.89 (dd, J = 11.2, 4.08 Hz, 1H),3.59 (dd, J = 11.1, 8.0 Hz, 1H), 3.15 – 3.07 (m, 1H), 3.06 – 2.97 (m, 1H), 2.72– 2.63 (m, 1H), 2.53 (s, 3H), 2.45 – 2.32 (m, 1H), 2.08 – 1.99 (m, 1H) ppm. 13CNMR (100 MHz, CDCl3) δ = 129.2, 120.4, 67.8, 60.6, 44.2, 42.2, 23.9 ppm. LRMS(ES + ) m / z [M + H] + C7H 13 NO + Calculated value: 206.02; Measured value: 206.12.

[0204] Preparation of (3-bromo-1,5-dimethyl-1,2,5,6-tetrahydropyridin-2-yl)methanol (3-Bromo-5-methylpyridin-2-yl)methanol CDI (3.601 g, 22.208 mmol, 1.2 equiv) was added to a 0 °C cooled solution of 3-bromo-5-methylpyridinecarboxylic acid (3.998 g, 18.507 mmol, 1.0 equiv) in THF (92.5 mL). The mixture was heated to ambient temperature and stirred for 4 h, then cooled to 0 °C. A 0 °C cooled solution of NaBH4 (2.100 g, 55.521 mmol, 1.0 equiv) in H2O (92.5 mL) was slowly transferred through a sleeve while stirring vigorously. The solution was heated to ambient temperature for 20 min, and then saturated NH4Cl was added dropwise at 0 °C. (aq) (100 mL). Add the solution to H2O (500 mL) and extract with EtOAc (5 × 100 mL). Extract the combined organic extracts with saturated NaHCO3. 3(aq) Wash with 50 mL of saline solution and 100 mL of brine, dry with Na2SO4, and concentrate under reduced pressure. The residue was purified by silica gel column chromatography (75% EtOAc in hexane) to give a pale yellow oil of (3-bromo-5-methylpyridin-2-yl)methanol (3.654 g, 98%). 1 H NMR (400 MHz, CDCl3) δ =8.33 (s, 1H), 7.72 – 7.66 (m, 1H), 4.70 (s, 2H), 4.24 – 3.62 (br s , 1H), 2.35 (s, 3H) ppm. 13 C NMR (100 MHz, CDCl3) δ = 153.6, 146.9, 140.8, 133.9, 118.4, 63.0, 17.8 ppm. LRMS (ES + ) m / z [M + H] + C7H9BrNO + Calculated value: 201.99; Measured value: 202.16.

[0205] 3-Bromo-2-(hydroxymethyl)-1,5-dimethylpyridine-1-onium iodide A solution of (3-bromo-5-methylpyridin-2-yl)methanol (3.505 g, 17.347 mmol, 1.0 equiv) and MeI (6.48 mL, 104.083 mmol, 6.0 equiv) in MeCN (21.7 mL) was heated to 60 °C in a sealed tube for 18 h. The resulting suspension was cooled to ambient temperature, and then EtOAc (100 mL) and hexane (50 mL) were added. The mixture was cooled to 0 °C and stirred, then filtered, washed with EtOAc (2 x 20 mL), and dried under vacuum to give 3-bromo-2-(hydroxymethyl)-1,5-dimethylpyridin-1-onium iodide (5.063 g, 85%) as a pale yellow solid. 1 H NMR (400MHz, DMSO-) d 6) δ = 9.06 (s, 1H), 8.81 (s, 1H), 6.14 (br s, 1H), 4.97 (s, 2H), 4.43 (s, 3H), 2.45 (s, 3H) ppm. 13 C NMR (100 MHz, DMSO-) d 6) δ = 151.0, 149.6, 147.0, 138.1, 123.6, 58.6, 46.7, 17.2 ppm. LRMS (ES + ) m / z [M + H] + C8H 11 BrNO + Calculated value: 216.00; Measured value: 216.14.

[0206] (3-Bromo-1,5-dimethyl-1,2,5,6-tetrahydropyridin-2-yl)methanol A mixture of 3-bromo-2-(hydroxymethyl)-1,5-dimethylpyridin-1-onium iodide (1.219 g, 3.544 mmol, 1.0 equiv) and AcOH (0.61 mL, 10.631 mmol, 3.0 equiv) in MeOH (35.4 mL) cooled to -10 °C was slowly added via a sleeve to a solution of NaCNBH3 (0.668 g, 10.631 mmol, 3.0 equiv) in MeOH (7.1 mL) cooled to -10 °C. The mixture was slowly heated to ambient temperature and stirred for 18 h, then concentrated under reduced pressure. The residue was dissolved in EtOAc (200 mL) and saturated NaHCO3 was added. 3(aq) (500 mL) with vigorous stirring. The layers were separated, and the aqueous layer was further extracted with EtOAc (3 x 100 mL). The combined organic extracts were washed with brine (100 mL), dried over Na2SO4, and dried under reduced pressure. The residue was purified by silica gel column chromatography (gradient elution: 1% MeOH DCM to 3% MeOH DCM) to give (3-bromo-1,5-dimethyl-1,2,5,6-tetrahydropyridin-2-yl)methanol (0.204 g, 26%) as a pale yellow, colorless oil in the form of a diastereomer mixture (major / minor 3:1).

[0207] .

[0208] 13 C NMR(100 MHz, CDCl3) δ = 137.2, 134.7, 121.2, 120.6, 68.3, 67.5,60.9, 59.6, 58.6, 51.0, 43.5, 42.8, 32.8, 28.2, 18.4, 18.1 ppm. LRMS (ES + ) m / z [M + H] + C8H 15 BrNO + Calculated value: 220.03; Measured value: 220.11. † indicates that it comes only from the major diastereomer. 1 HNMR signal; Indicates that it comes only from minor diastereomers 1 H NMR signal; unlabeled signal from both. 13 C NMR signals were reported directly without labeling.

[0209] Preparation of ethyl 5-bromo-6-(hydroxymethyl)nicotinic acid 5-Bromo-6-(1-Cyano-2-ethoxy-2-oxoethyl)methyl nicotinate K₂CO₃ (74.251 g, 539.205 mmol, 5.0 equiv) was added to a solution of methyl 5-bromo-6-chloronicotinate (27.012 g, 107.841 mmol, 1.0 equiv) in DMF (135 mL), followed by ethyl cyanoacetate (28.77 mL, 269.603 mmol, 2.5 equiv). The mixture was heated to 130 °C and stirred for 1 hour, then cooled to ambient temperature, and then to 0 °C. Under vigorous stirring, 4M HCl was added dropwise over 2 hours. (aq) Add 300 mL of H2O and stir the mixture at 0 °C for 1 hour, then filter. Wash the filter cake with ice-cold H2O (3 x 100 mL) and dry under vacuum to give methyl 5-bromo-6-(1-cyano-2-ethoxy-2-oxoethyl)nicotinate (33.191 g, 94%), as a yellow solid composed of a 9:1 tautomer mixture (via...). 1 (H NMR analysis).

[0210] 13 C NMR (100 MHz, DMSO-) d 6) δ = 170.2, 163.0, 152.9, 144.5, 140.3, 117.8, 116.0, 111.4, 66.4, 61.1, 53.0, 14.8 ppm. LRMS (ES + ) m / z [M + H] + cC 12 H 12 BrN2O4 + Calculated value: 327.00; Measured value: 327.17. † indicates only from the major tautomer. 1 H NMR signal; Indicates only from minor tautomers 1 H NMR signal; unlabeled signal from both. 13 C NMR signals only report signals from the major tautomers.

[0211] 3-Bromopyridine-2,5-dicarboxylic acid Methyl 5-bromo-6-(1-cyano-2-ethoxy-2-oxoethyl)nicotinate (32.463 g, 99.236 mmol, 1.0 equiv) was added to a solution of NaOH (13.893 g, 347.325 mmol, 3.5 equiv) in H₂O (248 mL) and stirred vigorously. The resulting mixture was heated to 40 °C, and then H₂O was carefully added dropwise over 1 hour. 2(aq) (30%) (73.135 g, 645.033 mmol, 6.5 equiv), then heated to 90 °C and held for 2 hours. The solution was cooled to ambient temperature, and then H₂O (124 mL) was added, followed by the dropwise addition of 4 M HCl over 1 hour with vigorous stirring. (aq) (124 mL). The resulting suspension was cooled at 0 °C for 2 hours and then filtered. The filter cake was washed with ice water (3 x 50 mL) and the solid was dried and collected. The combined aqueous filtrates were extracted with EtOAc (5 x 150 mL), dried with Na2SO4, and concentrated under reduced pressure. H2O (48 mL) was added to the residue, and the resulting mixture was cooled to 0 °C with stirring. The precipitate was filtered and washed with ice-cold H2O (3 x 10 mL) to give a second batch of product. The combined solids were dried under vacuum to give 3-bromopyridine-2,5-dicarboxylic acid (21.015 g, 86%) as a grayish-white solid. 1 H NMR (400 MHz, DMSO-) d 6 ) δ = 9.01 (d, J = 1.68 Hz, 1H), 8.51 (d, J = 1.72 Hz, 1H) ppm. 13 C NMR (100 MHz, DMSO- d 6 ) δ = 166.6, 164.6, 154.8, 148.5, 141.7, 129.0, 116.1 ppm. LRMS (ES + ) m / z [M + H] + C7H5BrNO4 + Calculated value: 245.94; Measured value: 246.18.

[0212] 3-Bromopyridine-2,5-dicarboxylic acid diethyl ester Oxaloyl chloride (21.09 mL, 245.895 mmol, 5.0 equiv) was added dropwise to a 0 °C cooled solution of 3-bromopyridine-2,5-dicarboxylic acid (12.099 g, 49.179 mmol, 1.0 equiv) and DMF (0.25 mL) in DCM (245.9 mL). The suspension was heated to ambient temperature and stirred for 12 hours, then concentrated under reduced pressure. The residue was dissolved in DCM (245.9 mL), and EtOH (123 mL) was slowly added. The solution was stirred for 20 min, then concentrated under reduced pressure. The residue was dissolved in DCM (250 mL), and then carefully added to saturated NaHCO3. 3(aq) In 500 mL, stir vigorously. Separate the layers, and further extract the aqueous layer with DCM (3 x 100 mL). Wash the combined organic extracts with brine (200 mL), dry with Na2SO4, and concentrate under reduced pressure. Purify the residue by silica gel column chromatography (15% EtOAc in hexane) to give diethyl 3-bromopyridine-2,5-dicarboxylic acid (12.409 g, 84%) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ = 9.14 (d, J = 1.72 Hz, 1H), 8.56 (d, J = 1.76 Hz, 1H), 4.54 – 4.39 (m, 4H), 1.48 – 1.38 (m, 6H) ppm. 13 C NMR (100 MHz, CDCl3) δ = 164.75, 163.37, 153.07, 148.64, 142.56, 128.66, 118.28, 62.81, 62.36, 14.32, 14.23 ppm. LRMS(ES + ) m / z [M + H] + C 11 H 13 BrNO4 + Calculated value: 302.00; Measured value: 302.04.

[0213] 5-Bromo-6-(hydroxymethyl)nicotinic acid ethyl ester Freshly ground CaCl2 (11.738 g, 105.771 mmol, 3.0 equiv) was added to a 0 °C cooled solution of 3-bromopyridine-2,5-dicarboxylic acid diethyl ester (12.309 g, 35.257 mmol, 1.0 equiv) in THF (58.8 g) and EtOH (117.5 g), followed by vigorous stirring. The mixture was heated to ambient temperature and stirred for 2 h, then cooled to 0 °C. 587.6 mL of 40% saturated NH4Cl solution was added dropwise, and the solution was heated to ambient temperature. THF and EtOH were then removed by rotary evaporation. The resulting suspension was stirred at 0 °C for 1 hour, then filtered, washed with ice-cold H2O (2 x 80 mL), and dried under vacuum to give ethyl 5-bromo-6-(hydroxymethyl)nicotinic acid (5.488 g, 60%), a pale yellow solid. 1 H NMR (400 MHz, CDCl3) δ = 9.11 (d, J = 1.48Hz, 1H), 8.45 (d, J = 1.68 Hz, 1H), 4.80 (s, 2H), 4.43 (q, J = 7.16 Hz, 2H), 3.87(br s, 1H), 1.42 (t, J = 7.12 Hz, 3H) ppm. 13 C NMR (100 MHz, CDCl3) δ = 164.0, 160.9, 147.7, 141.1, 126.9, 118.5, 63.7, 62.1, 14.4 ppm. LRMS (ES + ) m / z [M + H] + calcd for C9H 11 BrNO3 + Calculated value: 259.99; Measured value: 260.10.

[0214] Preparation of 4-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-indole Following general procedure 1, 4-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1-yl was prepared using 4-fluoroindole. H -Indole (0.700 g, 45%) is a brown solid. 1H NMR (400 MHz, CDCl3) δ 9.34 (s,1H), 7.62 (dd, J = 7.9, 5.6 Hz, 1H), 7.24 (dd, J = 3.3, 2.3 Hz, 1H), 6.82 (dd, J =10.5, 7.9 Hz, 1H), 6.65 (dd, J = 3.3, 2.3 Hz, 1H), 1.41 (s, 12H). 13 C NMR (100MHz, CDCl3) δ 160.40, 157.89, 144.18 (d, 1 J CF = 12.8 Hz), 130.68 (d, 2 J CF = 8.13Hz), 124.05, 115.88 ( 3 J CF = 21.6 Hz), 104.68 ( 4 J CF = 18.6 Hz), 98.13, 83.90, 25.01. LRMS (ES + ) m / z [M + H] + C 14 H 18 BFNO2 + = Calculated value 262.14; measured value 262.37.

[0215] Preparation of 5-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-indole Following general procedure 1, 5-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1-fluoroindole was prepared. H -Indole (1.15 g, 73%), is a lime-white solid. 1 H NMR (400 MHz, CDCl3) δ 9.21 (s,1H), 7.44 – 7.37 (m, 2H), 7.31 (t, J = 2.9 Hz, 1H), 6.52 (dd, J = 3.2, 2.1 Hz,1H), 1.41 (s, 12H).13 C NMR (100 MHz, CDCl3) δ 158.86, 156.53, 137.64, 127.53( 1 J CF = 9.54 Hz), 125.83, 116.44 ( 2 J CF = 24.5 Hz), 109.14 ( 3 J CF = 23.6 Hz), 102.03, 84.19, 25.01. LRMS (ES + ) m / z [M + H] + C 14 H 18 BFNO2 + = Calculated value 262.14; measured value 262.37.

[0216] Preparation of 6-fluoro-7-(4,4,5,5-tetraethyl-1,3,2-dioxaborane-2-yl)-1H-indole Following general procedure 1, 6-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1-yl was prepared using 6-fluoroindole. H -Indole (1.30 g, 83%), is a light purple solid. 1 H NMR (400 MHz, CDCl3) δ 9.37 (s,1H), 7.68 (ddd, J = 8.6, 5.4, 0.8 Hz, 1H), 7.25 (dd, J = 3.2, 2.3 Hz, 1H), 6.87(dd, J = 10.0, 8.6 Hz, 1H), 6.53 (dd, J = 3.3, 2.2 Hz, 1H), 1.43 (s, 12H). 13 C NMR (100 MHz, CDCl3) δ 166.25, 163.82, 140.83 ( 1 J CF = 13.2 Hz), 125.34 ( 2 J CF = 11.0Hz), 124.40 ( 3 JCF = 3.77 Hz), 123.43, 108.30 ( 4 J CF = 27.2 Hz), 102.10, 83.86. LRMS(ES + ) m / z [M + H] + C 14 H 18 BFNO2 + = Calculated value 262.14; Measured value 262.30.

[0217] Preparation of 4-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-indole Following general procedure 1, 4-chloroindole was applied to prepare 4-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1-yl-chloroindole. H -Indole (1.23 g, 74%), is a brown solid. 1 H NMR (400 MHz, CDCl3) δ 9.35 (s,1H), 7.58 (d, J = 7.5 Hz, 1H), 7.30 (dd, J = 3.3, 2.3 Hz, 1H), 7.16 (d, J = 7.5 Hz, 1H), 6.67 (dd, J = 3.2, 2.3 Hz, 1H), 1.41 (s, 12H). 13 C NMR (100 MHz, CDCl3) δ141.75, 129.99, 129.90, 125.81, 124.72, 119.32, 100.71, 84.05, 25.02. LRMS (ES + ) m / z [M + H] + C 14 H 18 BClNO2 + = Calculated value 278.11; Measured value 278.17.

[0218] Preparation of 5-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-indole Following general procedure 1, 5-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1-yl was prepared using 5-chloroindole. H-Indole (1.350 g, 81%), is a white solid. 1 H NMR (400 MHz, CDCl3) δ 9.24 (s,1H), 7.74 (d, J = 2.1 Hz, 1H), 7.64 (d, J = 2.2 Hz, 1H), 7.29 (dd, J = 3.2, 2.4 Hz, 1H), 6.51 (dd, J = 3.2, 2.2 Hz, 1H), 1.42 (s, 12H). 13 C NMR (100 MHz, CDCl3) δ139.36, 128.88, 128.21, 125.56, 125.29, 123.42, 101.72, 84.24, 25.02. LRMS (ES + ) m / z [M + H] + C 14 H 18 BClNO2 + = Calculated value 278.11; Measured value 278.11.

[0219] Preparation of 6-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-indole Following general procedure 1, 6-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1-yl was prepared using 6-chloroindole. H -Indole (1.25 g, 75%) is a green solid. 1 H NMR (400 MHz, CDCl3) δ 9.58 (s,1H), 7.66 (d, J = 9.1 Hz, 1H), 7.30 – 7.25 (m, 1H), 7.17 (d, J = 8.4 Hz, 1H), 6.55 (dd, J = 3.3, 2.2 Hz, 1H), 1.47 (s, 12H). 13 C NMR (100 MHz, CDCl3) δ 142.12, 135.20, 125.48, 124.69, 124.49, 121.80, 102.06, 83.93, 25.04. LRMS (ES + ) m / z [M+ H] + C14 H 18 BClNO2 + =Calculated value 278.11; Measured value 278.17.

[0220] Int-5a (((2S,5R)-1,5-dimethyl-3-(2-methyl-1H-indol-7-yl)-1,2,5,6-tetrahydropyridine- Preparation of 2-yl)methanol: Using the alternative universal procedure 2, Int-4 (1.0 g, 4.5 mmol, 1.0 eq) was converted to Int-5a and purified by column chromatography to give 320 mg (26%) of the title compound as a pale yellow semi-solid. ESI-MS m / z: 271.10 [M+H] + .

[0221] Preparation of Int-B (7-bromo-4-chloro-5-fluoro-1H-indole): At -78 °C, vinyl magnesium bromide (1M in THF) (79.4 mL, 79.4 mmol, 4.00 eq) was added over 20 minutes via a dropping funnel to a stirred solution of 1-bromo-4-chloro-5-fluoro-2-nitrobenzene (5.0 g, 20 mmol, 1.0 eq) in 100 mL of THF. The reaction mixture was then slowly heated to room temperature and stirred for 2 hours. The reaction mixture was quenched with saturated ammonium chloride solution (200 mL) and extracted with ethyl acetate (2 x 150 mL). The combined organic layers were washed with saturated brine solution (100 mL), dried over anhydrous Na₂SO₄, and concentrated. The crude material was purified by rapid column chromatography (25% EtOAc in hexane) to give 1 g (20%) Int-B as a yellow gelatinous solid. ESI-MS m / z: 249.6 [M+H]+.

[0222] Int-1b (4-chloro-5-fluoro-7-(4,4,5,5-tetraethyl-1,3-2-dioxaborane-2-yl)-IH-indole) preparation: Using the alternative universal procedure 1, Int-B (1.0 g, 4.0 mmol, 1.0 eq) was converted to Int-1b and purified by column chromatography to give 0.8 g (41%) of the title compound as a yellow solid. ESI-MS m / z: 296.1 [M+H] + .

[0223] Preparation of Int-5b (((2S,5R)-3-(4-chloro-5-fluoro-1H-indol-7-yl)-1,5-dimethyl-1,2,5,6-tetrahydropyridin-2-yl)methanol): Using the alternative general procedure 2, Int-4 (0.50 g, 2.3 mmol, 1.0 eq) was converted to Int-5b and purified by column chromatography to give 140 mg (20%) of the title compound as a pale yellow semi-solid. ESI-MS m / z: 309.0 [M+H] + .

[0224] Preparation of Int-D (7-bromo-5-chloro-4-fluoro-1H-indole): At -78 °C, vinyl magnesium bromide (1M in THF) (79.4 mL, 79.4 mmol, 4.00 eq) was added over 20 minutes via a dropping funnel to a stirred solution of Int-C (5.0 g, 20 mmol, 1.0 eq) in 100 mL of THF. The mixture was then slowly heated to room temperature and stirred for 2 hours. The reaction mixture was quenched with saturated ammonium chloride solution (200 mL) and extracted with ethyl acetate (2 x 150 mL). The combined organic layers were washed with saturated brine solution (100 mL), dried over anhydrous Na₂SO₄, and concentrated. The crude product was purified by rapid column chromatography (25% EtOAc in hexane) to give 0.9 g (18%) Int-D as a grayish-white semi-solid. ESI-MS m / z: 249.2 [M+H] + .

[0225] Int-lc (5-methoxy-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-indyl) Preparation of (dole): Using the alternative universal procedure 1, Int-D (0.90 g, 3.7 mmol, 1.0 eq) was converted to Int-1c and purified by column chromatography to give 1 g (93%) of the title compound as a yellow solid. ESI-MS m / z: 296.4 [M+H] + .

[0226] Int-5c ((2S,5R)-3-(5-chloro-4-fluoro-1H-indol-7-yl)-1,5-dimethyl-1,2,5,6-tetrahydropyridine Preparation of pyridin-2-yl)methanol: Using the alternative universal procedure 2, Int-4 (0.40 g, 1.8 mmol, 1.0 eq) was converted to Int-5c and purified by column chromatography to give 130 mg (23%) of the title compound as a brown solid. ESI-MS m / z: 309.1 [M+H] + .

[0227] Preparation of Int-F (7-bromo-4,5-difluoro-1H-indole) At -78 °C, vinyl magnesium bromide (1M in THF) (420 mL, 420 mmol, 4.00 equiv) was added dropwise over 20 minutes to a stirred solution of Int-E (25.0 g, 105 mmol, 1.00 eq) in 250 mL of THF. The resulting reaction mixture was stirred at room temperature for 3 hours, then diluted with water (100 mL) and extracted with ethyl acetate (2 × 500 mL). The combined organic layers were washed with an aqueous solution of NaCl (50 mL), dried over anhydrous Na₂SO₄, and the solid was removed by filtration. The filtrate was concentrated under vacuum. The crude product was purified by silica gel column chromatography (10% EtOAc in hexane) to give 8 g (33%) Int-F as a pale yellow solid. ESI-MS m / z: 233.0 [M+H] + .

[0228] Int-1d (4,5-difluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-indole) Preparation of (component): Using the alternative general procedure 1, Int-F (2.50 g, 10.8 mmol, 1.00 eq) was converted to Int-1d and purified by column chromatography to give 1.4 g (51%) of the title compound as a pale yellow solid. ESI-MS m / z: 280.2 [M+H] + .

[0229] Int-5d (((2S,5R)-3-(4,5-difluoro-1H-indol-7-yl)-1,5-dimethyl-1,2,5,6-tetrahydropyridine Preparation of pyridin-2-yl)methanol Using the alternative universal procedure 2, Int-4 (1.0 g, 4.5 mmol, 1.0 eq) was converted to Int-5d and purified by column chromatography to give 160 mg (12%) of the title compound as a pale yellow gelatinous solid. ESI-MS m / z: 393.2 [M+H] + .

[0230] Preparation of Int-H (7-bromo-4-methyl-1H-indole): At -78 °C, vinyl magnesium bromide (1M in THF) (93.5 mL, 93.5 mmol, 4.00 eq) was added dropwise over 20 minutes to a stirred solution of Int-G (5.0 g, 23 mmol, 1.0 eq) in 100 mL of THF. The reaction mixture was then slowly heated to room temperature and stirred for 2 hours. The reaction mixture was quenched with saturated ammonium chloride solution (200 mL) and extracted with ethyl acetate (2 × 150 mL). The combined organic layers were washed with saturated brine solution (100 mL), dried over anhydrous Na₂SO₄, and concentrated. The crude product was purified by rapid column chromatography (25% EtOAc in hexane) to give 2 g (40%) Int-H as a pale brown semi-solid. ESI-MS m / z: 211.2 [M+H] + .

[0231] Preparation of Int-le (4-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-indole) Note: Using the alternative universal procedure 1, Int-H (1.5 g, 7.1 mmol, 1.0 eq) was converted to Int-1e and purified by column chromatography to give 1 g (55%) of the title compound as a white solid. ESI-MS m / z: 258.1 [M+H] + .

[0232] Int-5e (((2S,5R)-1,5-dimethyl-3-(4-methyl-1H-indol-7-yl)-1,2,5,6-tetrahydropyridine- Preparation of 2-yl)methanol: Using the alternative universal procedure 2, Int-4 (1.0 g, 4.5 mmol, 1.0 eq) was converted to Int-5e and purified by column chromatography to give 320 mg (26%) of the title compound as a pale yellow semi-solid. ESI-MS m / z: 271.0 [M+H] + .

[0233] Preparation of Int-J (7-bromo-5-methyl-1H-indole): At -78 °C, vinyl magnesium bromide (1M in THF) (93.5 mL, 93.5 mmol, 4.00 eq) was added over 20 minutes via a dropping funnel to a stirred solution of Int-I (5.0 g, 23 mmol, 1.0 eq) in 100 mL of THF. The reaction mixture was then slowly heated to room temperature and stirred for 2 hours. The reaction mixture was quenched with saturated ammonium chloride solution (200 mL) and extracted with ethyl acetate (2 × 150 mL). The combined organic layers were washed with saturated brine solution (100 mL), dried over anhydrous Na₂SO₄, and concentrated. The crude product was purified by rapid column chromatography (25% EtOAc in hexane) to give 2 g (40%) Int-J as a white solid. ESI-MS m / z: = 211.4 [M+H]⁺.

[0234] Preparation of Int-1f (5-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-indole) Note: Using the alternative universal procedure 1, Int-J (1.0 g, 4.8 mmol, 1.0 eq) was converted to Int-lf and purified by column chromatography to give 0.8 g (66%) of the title compound. ESI-MS m / z: = 258.1 [M+H] + .

[0235] Int-5f (((2S,5R)-1,5-dimethyl-3-(5-methyl-1H-indol-7-yl)-1,2,5,6-tetrahydropyridine- Preparation of 2-yl)methanol: Using the alternative general procedure 2, Int-4 (340 mg, 1.54 mmol, 1.00 eq) was converted to Int-5f and purified by column chromatography to give 100 mg (24%) of the title compound as a brown gel-like solid. ESI-MS m / z: =271.0[M+H]+.

[0236] Preparation of Int-L (7-bromo-4-methoxy-1H-indole): At -78 °C, vinyl magnesium bromide (1M in THF) (86.2 mL, 86.2 mmol, 4.00 eq) was added over 20 minutes via a dropping funnel to a stirred solution of Int-K (5.0 g, 22 mmol, 1.0 eq) in 100 mL of THF. The reaction mixture was slowly heated to room temperature and stirred for 2 hours. The reaction mixture was quenched with 200 mL of saturated ammonium chloride solution and extracted with ethyl acetate (2 × 200 mL). The combined organic layers were washed with 100 mL of saturated brine solution, dried over anhydrous Na₂SO₄, and concentrated. The crude product was purified by rapid column chromatography (20% EtOAc in hexane) to give 1.9 g (93%) Int-L as a grayish-white semi-solid. ESI-MS m / z: 227.8 [M+H]⁺.

[0237] Preparation of Int-1g (4-methoxy-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-indole).

[0238] Using the alternative general procedure 1, Int-L (1.0 g, 6.69 mmol, 1.00 eq) was converted to Int-1 g and purified by column chromatography to give 1.2 g (66%) of the title compound as a pale yellow solid. ESI-MS m / z: 273.17 [M+H]+.

[0239] Int-5g (((2S,5R)-3-(4-methoxy-1H-indol-7-yl)-1,5-dimethyl-1,2,5,6-tetrahydropyridine Preparation of pyridin-2-yl)methanol: Using the alternative universal procedure 2, Int-4 (0.90 g, 4.1 mmol, 1.0 eq) was converted to Int-5 g, and purified by column chromatography to give 400 mg (34%) of the title compound as a pale yellow solid. ESI-MS m / z: 287.0 [M+H] + .

[0240] Preparation of Int-N (7-bromo-5-methoxy-1H-indole): At -78 °C, vinyl magnesium bromide (1M in THF) (172 mL, 172 mmol, 4.00 eq) was added over 20 minutes via a dropping funnel to a stirred solution of Int-M (10 g, 43 mmol, 1.0 eq) in 100 mL of THF. The reaction mixture was then slowly heated to room temperature and stirred for 3 hours. The reaction mixture was then quenched with saturated ammonium chloride solution (200 mL) and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with saturated brine solution (100 mL), dried over anhydrous Na₂SO₄, and concentrated. The crude product was purified by rapid column chromatography (2% EtOAc in hexane) to give 2.2 g (23%) Int-N as a grayish-white solid. ESI-MS m / z: 227.4 [M+H] + .

[0241] Int-1h (5-methoxy-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-indole) preparation: Using alternative general procedure 1, Int-N (1.0 g, 4.4 mmol, 1.0 eq) was converted to Int-1h and purified by column chromatography to give 900 mg (75%) of the title compound as a yellow solid. ESI-MS m / z: 273.18 [M+H] + .

[0242] Int-5h ((2S,5R)-3-(5-methoxy-1H-indol-7-yl)-1,5-dimethyl-1,2,5,6-tetrahydropyridine Preparation of 2-pyridyl)methanol: Using the alternative general procedure 2, Int-4 (0.40 g, 1.8 mmol, 1.0 eq) was converted to Int-5h and purified by column chromatography to give 220 mg (42%) of the title compound as a pale yellow semi-solid. ESI-MS m / z: 287.6.0 [M+H]+.

[0243] Preparation of Int-P (7-bromo-1H-indole-3-carboxylic acid): At -78 °C, lithium tert-butoxide (1M in THF) (255 mL, 255 mmol, 5.00 equiv) was added to a stirred solution of Int-O (10 g, 51 mmol, 1.0 equiv) in DMF (10 vol). Subsequently, CO2 gas was introduced using dry ice over 1 hour, and the reaction mixture was heated to ambient temperature. The resulting reaction mixture was heated to 90 °C and stirred for 24 h. After the reaction was complete, the reaction mixture was quenched with saturated ammonium chloride solution and extracted with EtOAc (2 x 40 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, concentrated to give a crude product, and purified by combi-flash (30% EtOAc in hexane) to give 8 g (65%) Int-P. ESI-MS m / z: 239.2 [MH] + .

[0244] Preparation of Int-Q (7-bromo-3-fluoro-1H-indole) H₂O (50 mL) was added to a stirred solution of Int-P (10 g, 42 mmol, 1.0 equiv) in DCM (100 mL) at 0 °C, followed by the addition of lithium carbonate (12.3 g, 167 mmol, 4.00 eq) and Selectfluor (29.5 g, 83.3 mmol, 2.00 equiv). The resulting reaction mixture was heated to ambient temperature and stirred for 4 hours. The reaction mixture was diluted with ice water (50 mL) and extracted with DCM (2 x 50 mL). The combined organic layers were washed with a saline solution (40 mL), dried over sodium sulfate, and concentrated. The crude product was purified by combined rapid chromatography to give 5 g (56%) Int-Q as a yellow solid. ESI-MS m / z: 216.0 [M+H] + .

[0245] Preparation of Int-1i (3-fluoro-7-(4,4,5,5-tetramethyl-13,2-dioxaborane-2-yl)-1H-indole): Using the alternative universal procedure 1, Int-Q (5.0 g, 19 mmol, 1.0 eq) was converted to Int-1i and purified by column chromatography to give 2 g (48%) of the title compound as a brown solid. ESI-MS m / z: 263.1 [M+H] + .

[0246] Int-5i (((2S,5R)-3-(3-fluoro-1H-indol-7-yl)-1,5-dimethyl-1,2,5,6-tetrahydropyridine-2- Preparation of methanol (based on methanol): Using the alternative universal procedure 2, Int-4 (0.80 g, 3.6 mmol, 1.0 eq) was converted to Int-5i and purified by column chromatography to give 600 mg (60%) of the title compound as a brown solid. ESI-MS m / z: 275.26 [M+H]+.

[0247] Int-5j (((2S,5R)-3-(3-chloro-1H-indol-7-yl)-1,5-dimethyl-1,2,5,6-tetrahydropyridine-2- Preparation of methanol (based on methanol): Using the alternative general procedure 2, Int-4 (0.50 g, 2.3 mmol, 1.0 eq) was converted to Int-5j and purified by column chromatography to give 250 mg (38%) of the title compound as a brown solid. ESI-MS m / z: 292.2 [M+H]+.

[0248] Int-5k (((2S,5R)-1,5-dimethyl-3-(3-methyl-1H-indol-7-yl)-1,2,5,6-tetrahydropyridine- Preparation of 2-yl)methanol: Using the alternative universal procedure 2, Int-4 (0.40 g, 1.8 mmol, 1.0 eq) was converted to Int-5k and purified by column chromatography to give 200 mg (40%) of the title compound as an off-white solid. ESI-MS m / z: 270.9 [M+H] + .

[0249] Int-51 (((2S,5R)-3-(2-chloro-1H-indol-7-yl)-1,5-dimethyl-1,2,5,6-tetrahydropyridine-2- Preparation of methanol (based on methanol): Using the alternative universal procedure 2, Int-4 (0.60 g, 2.7 mmol, 1.0 eq) was converted to Int-5L, and purified by column chromatography to give 150 mg (19%) of the title compound as a pale yellow semi-solid. ESI-MS m / z: 290.9 [M+H] + .

[0250] Preparation of Int-S (7-bromo-1H-indole-4-nitrile): At -78 °C, vinyl magnesium bromide (1M in THF) (178 mL, 178 mmol, 4.00 eq) was added over 20 minutes via a dropping funnel to a stirred solution of Int-R (10 g, 44 mmol, 1.0 eq) in 200 mL of THF. The reaction mixture was then slowly heated to room temperature and stirred for 2 hours. The reaction mixture was quenched with saturated ammonium chloride solution (200 mL) and extracted with ethyl acetate (2 × 150 mL). The combined organic layers were washed with saturated brine solution (100 mL), dried over anhydrous Na₂SO₄, and concentrated. The crude product was purified by rapid column chromatography (25% EtOAc in hexane) to give 3 g (30%) Int-S as a brown solid. ESI-MS m / z: 222.4 [M+H] + .

[0251] Preparation of Int-1m (7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-indole-4-nitrile): Using the alternative universal procedure 1, Int-S (2.0 g, 9.0 mmol, 1.0 eq) was converted to Int-1m and purified by column chromatography to give 1 g (41%) of the title compound as a yellow solid. ESI-MS m / z: 269.2 [M+H] + .

[0252] Int-5m (7-((2S,5R)-2-(hydroxymethyl)-1,5-dimethyl-1,2,5,6-tetrahydropyridin-3-yl)-1H-indyl Preparation of (dole-4-nitrile): Using the alternative general procedure 2, Int-4 (0.50 g, 2.3 mmol, 1.0 eq) was converted to Int-5m and purified by column chromatography to give 220 mg (34%) of the title compound as a pale yellow semi-solid. ESI-MS m / z: 281.9 [M+H] + .

[0253] Int-5n (((2S,5R)-3-(4-chloro-1H-indol-7-yl)-1,5-dimethyl-1,2,5,6-tetrahydropyridine-2- Preparation of methanol (based on methanol): Using the alternative universal procedure 2, Int-4 (0.50 g, 2.3 mmol, 1.0 eq) was converted to Int-5n and purified by column chromatography to give 230 mg (35%) of the title compound as a pale yellow semi-solid. ESI-MS m / z: 290.8 [M+H] + .

[0254] Int-5o (3-(4-fluoro-1H-indol-7-yl)-1,5-dimethyl-1,2,5,6-tetrahydropyridin-2-yl)methanol preparation: Using the alternative general procedure 2, Int-4 (3.0 g, 14 mmol, 1.0 eq) was converted to Int-5o and purified by column chromatography to give 950 mg (25%) of the title compound as a brown colloidal solid. ESI-MS m / z: 275.20 [M+H]+.

[0255] Preparation of Int-5p ((3-(5-fluoro-1H-indol-7-yl)-1,5-dimethyl-1,2,5,6-tetrahydropyridin-2-yl) (Synthesis of methanol): Using the alternative general procedure 2, Int-4 (0.80 g, 3.6 mmol, 1.0 eq) was converted to Int-5p and purified by column chromatography to give 380 mg (32%) of the title compound as a pale yellow semi-solid. ESI-MS m / z: 281.9 [M+H] + .

[0256] Preparation of Int-9p and Int-10p: 380 mg of the racemic int-5p was purified using Chiralpak IG (30 x 250 mm, 5 µm) with MP(A)CO2: 81 g / min and MP(B)Co-Solvent: 9 mL / min (7N methanol-ammonia in MeOH), for a total flow rate of 90 g-10%-100 Ba. The faster eluting peak was identified as Int-9p (80 mg), and the slower eluting peak was identified as Int-10p (100 mg).

[0257] Preparation of Int-5q ((3-(5-chloro-1H-indol-7-yl)-1,5-dimethyl-1,2,5,6-tetrahydropyridin-2-yl) (Synthesis of methanol) Using the alternative general procedure 2, Int-4 (0.50 g, 2.3 mmol, 1.0 eq) was converted to Int-5q and purified by column chromatography to give 240 mg (37%) of the title compound as a pale yellow semi-solid. ESI-MS m / z: 281.9 [M+H] + .

[0258] Preparation of Int-9q and Int-10q: 240 mg of racemic Int-5q was used in an IH column (30×250). Purification was performed using a flow rate of 5 μL / min. Mobile phase A consisted of 0.1% DEA in n-hexane, mobile phase B consisted of DCM and MEOH (1:1), eluent A:B:-90:10, and total flow rate (mL / min) was 42 mL / min. The fastest eluting peak was identified as Int-9q (40 mg), and the slowest eluting peak was identified as Int-10q (40 mg).

[0259] C. Compound Examples Example 1: 8-Methyl-7a,8,9,10-tetrahydronaphtho-7H-indolo[7,l-fg][1,7]naphthidine for and .

[0260] (3-(1H-indol-7-yl)-1-methyl-1,2,5,6-tetrahydropyridin-2-yl)methanol (3-bromo-1-methyl-1,2,5,6-tetrahydropyridin-2-yl)methanol (1.386 g, 6.726 mmol, 1.0 equiv) and indole-7-boronic acid pinacol ester (2.452 g, 10.088 mmol, 1.5 equiv) were dissolved in 2M Na2CO3. 3(aq) The solution of the mixture of (6.73 mL) and dioxane (67.3 mL) was bubbled with N2 for 10 h. Pd(PPh3)4 (0.389 g, 0.336 mmol, 0.05 equiv) was added, and the mixture was heated to 100 °C for 10 h with vigorous stirring, and then cooled to ambient temperature. The mixture was added to H2O (600 mL) and extracted with EtOAc (5 x 100 mL). The combined organic extracts were washed with brine (100 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (gradient elution: 100% DCM to 30% MeOH DCM) to give (3-(1 H (-indol-7-yl)-1-methyl-1,2,5,6-tetrahydropyridin-2-yl)methanol (0.901 g, 55%) is an off-white semi-solid. 1 H NMR (400 MHz, CDCl3) δ = 9.01 (br s,1H), 7.56 (d, J = 7.88 Hz, 1H), 7.19 (t, J = 2.8 Hz, 1H), 7.08 (t, J = 7.28 Hz, 1H), 6.94 (dd, J= 7.28 Hz, 0.8 Hz, 1H), 6.55 (dd, J = 3.22 Hz, 2.12 Hz, 1H), 6.10 – 6.05 (m, 1H), 3.84 – 3.48 (m, 2H), 3.36 – 3.24 (m, 2H), 3.12 – 3.00(m, 1H), 2.78 – 2.68 (m, 1H), 2.41 – 2.20 (m, 2H) ppm. 13 C NMR (100 MHz, CDCl3) δ = 135.3, 134.1, 128.1, 127.6, 124.7, 124.6, 120.8, 119.7, 119.5, 102.5, 66.1, 59.8, 48.8, 42.9, 24.8 ppm. LRMS (ES + ) m / z [M + H] + C 15 H 19 N2O + Calculated value: 243.15; Measured value: 243.09.

[0261] 8-Methyl-7a,8,9,10-tetrahydro-7H-indolo[7,1-fg][1,7]naphthidine TsCl (0.745 g, 3.907 mmol, 1.2 equiv) and tetrabutylammonium bisulfate (0.055 g, 0.163 mmol, 0.05 equiv) were added to a 0 °C cooled solution of (3-(1H-indol-7-yl)-1-methyl-1,2,5,6-tetrahydropyridin-2-yl)methanol (0.789 g, 3.256 mmol, 1.0 equiv) in DCM (65.1 mL), followed by freshly ground sodium hydroxide (0.521 g, 13.024 mmol, 4.0 equiv). The mixture was heated to ambient temperature and stirred for 2 hours, then 50% saturated NH4Cl was added. (aq) The solution was extracted with DCM (4 x 100 mL), washed with brine (100 mL), dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM in 1% MeOH), and then purified again by silica gel column chromatography (EtOAc in 1% MeOH) to give 8-methyl-7a,8,9,10-tetrahydro-7 H -Indodo[7,1- fg[1,7] Naphthylidine (0.381 g, 52%) is a brown oily substance. 1 H NMR (400 MHz, CDCl3) δ = 7.50 (d, J = 7.04Hz, 1H), 7.28 – 7.22 (m, 1H), 7.12 – 7.08 (m, 2H), 6.51 – 6.44 (m, 2H), 4.65(dd, J = 11.2, 5.32 Hz, 1H), 3.82 (t, J = 11.08 Hz, 1H), 3.44 – 3.33 (m, 1H), 3.05 – 2.95 (m, 1H), 2.72 – 2.54 (m, 5H), 2.31 – 2.20 (m, 1H) ppm. 13 C NMR (100MHz, CDCl3) δ = 133.2, 130.9, 126.5, 126.3, 120.4, 120.2, 119.9, 119.6,114.3, 101.3, 60.7, 52.9, 48.4, 44.4, 26.1 ppm. LRMS (ES + ) m / z [M + H] + C 15 C 17 N2 + Calculated value: 225.14; Measured value: 225.21.

[0262] Chiral separation of 8-methyl-7a,8,9,10-tetrahydro-7H-indolo[7,1-fg][1,7]naphthidine Racemic 8-methyl-7a,8,9,10-tetrahydro-7 H -Indodo[7,1- fg [1,7] Naphthylidine was isolated into its enantiomers by preparative chiral SFC (Chiralpak-IG 15 cm x 2 cm; isocratic method: 25% MeOH (0.1% diethylamine) / CO2; 100 bar, 60 mL / min; injection volume 0.5 mL, 3 mg / mL in MeOH).

[0263] 8-Methyl-7a,8,9,10-tetrahydro-7H-indolo[7,1-fg][1,7]naphthidine (Example 1A, first elution peak): analytical chiral SFC > 99.9% ee. t=4.42 min (Chiralpak-IG 25 cm x 0.46 cm; isocratic method: 25% MeOH (0.1% diethylamine) / CO2; 100 bar, 3 mL / min, wavelength 220 nm). Yellow waxy; LC-MS: m / z = 225.1 [M+H] + .

[0264] 8-Methyl-7a,8,9,10-tetrahydro-7H-indolo[7,1-fg][1,7]naphthidine (Example 1B, second elution peak): analytical chiral SFC > 99.9% ee. t =6.90 min (Chiralpak-IG 25 cm x 0.46 cm; isocratic method: 25% MeOH (0.1% diethylamine) / CO2; 100 bar. 3 mL / min. Wavelength 220 nm). Yellow waxy; LC-MS: m / z =225.2 [M+H] + .

[0265] Example 2: 8,10-Dimethyl-7a,8,9,10-tetrahydro-7H-indolo[7,1-fg][1,7]naphthidine (major) yes and ,or yes and .

[0266] (3-(1H-indol-7-yl)-1,5-dimethyl-1,2,5,6-tetrahydropyridin-2-yl)methanol The mixture of (3-bromo-1,5-dimethyl-1,2,5,6-tetrahydropyridin-2-yl)methanol (0.170 g, 0.772 mmol, 1.0 equiv) and indole-7-boronic acid pinacol ester (0.282 g, 1.159 mmol, 1.5 equiv) in dioxane (7.72 mL) and 2M Na₂CO₃ was prepared. 3(aq)The solution in the mixture (1.54 mL) was bubbled with N2 for 5 min. Pd(PPh3)4 (0.022 g, 0.0190 mmol, 0.025 equiv) was added, the mixture was heated to 100 °C and stirred for 5 h, and then cooled to ambient temperature. The mixture was added to H2O (150 mL) and extracted with EtOAc (4 x 75 mL). The combined organic extracts were washed with brine (50 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (gradient elution: EtOAc in 10% MeOH to EtOAc in 20% MeOH) to give (3-(1 H (-indol-7-yl)-1,5-dimethyl-1,2,5,6-tetrahydropyridin-2-yl)methanol (0.146 g, 74%) is a brown semi-solid, existing as a mixture of diastereomers (4:1 major / minor).

[0267] 13 C NMR(100 MHz, CDCl3) δ = 135.3, 134.9, 134.7, 134.5, 133.2, 133.0,128.3, 128.2, 124.8, 124.8, 124.4, 123.8, 121.1, 120.8, 120.1, 119.7, 119.6,119.3, 102.6, 102.3, 66.7, 64.9, 59.8, 59.6, 58.8, 53.8, 43.0, 42.4, 30.3, 26.8, 19.1, 18.6 ppm. LRMS (ES + ) m / z [M + H] + C 16 H 21 N2O + Calculated value: 257.17; Measured value: 257.26. † express 1 The H NMR signal comes only from the major diastereomers; express 1 H NMR signals are derived only from minor diastereomers; unspecified signals are derived from both. 13 C NMR signals were reported directly without labeling.

[0268] 8,10-Dimethyl-7a,8,9,10-Tetrahydro-7 H -Indolo[7,1-fg][1,7]naphthidine (major) To (3-(1)H TsCl (0.125 g, 0.655 mmol, 1.2 equiv) and tetrabutylammonium bisulfate (0.009 g, 0.027 mmol, 0.05 equiv) were added to a 0 °C cooled solution of (3:1 dr) (0.140 g, 0.546 mmol, 1.0 equiv) in DCM (10.9 mL). Freshly ground NaOH (0.087 g, 4.0 equiv, 2.184 mmol) was then added. The mixture was heated to ambient temperature and stirred vigorously for 3 h, then poured into H2O (200 mL) and extracted with DCM (4 x 50 mL). The combined organic extracts were washed with brine (50 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography in EtOAc (0.5% MeOH) to give 8,10-dimethyl-7a,8,9,10-tetrahydro-7a. H -Indodo[7,l-fg][1,7]naphthidine (major diastereomer) (0.089 g, 68%), is a light brown semi-solid. Minor diastereomers were not isolated. 1 HNMR(400 MHz, CDCl3) δ = 7.50 (d, J = 7.84 Hz, 1H), 7.28 (d, J = 7.32 Hz, 1H),7.12 – 7.06 (m, 2H), 6.48 (d, J = 3.0 Hz, 1H), 6.31 – 6.28 (m, 1H), 4.65 (dd, J =5.36, 11.2 Hz, 1H), 3.80 (t, J = 11.04 Hz, 1H), 3.35 – 3.26 (m, 1H), 3.0 (dd, J =5.0, 11.2 Hz, 1H), 2.83 – 2.70 (m, 1H), 2.56 (s, 3H), 2.20 (t, J = 10.68 Hz, 1H), 1.09 (d, J = 7.08 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ = 133.4, 130.0, 126.44, 126.35, 120.4, 119.6, 114.4, 101.3, 61.5, 60.7, 48.4, 44.2, 30.8, 18.8 ppm. LRMS (ES + ) m / z [M + H] + C 16 H 19 N2 + Calculated value: 239.15; Measured value: 239.25.

[0269] Chiral separation of 8,10-dimethyl-7a,8,9,10-tetrahydro-7H-indolo[7,1-fg][1,7]naphthidine (major) Racemic 8,10-dimethyl-7a,8,9,10-tetrahydro-7H-indolo[7,1- fg [1,7] Naphthylidine (mainly) was isolated into its enantiomers by preparation of a chiral SFC (Chiralpak-IG 25 cm x 2 cm; isocratic method: 25% MeOH (0.1% diethylamine) / CO2; 100 bar, 60 mL / min; injection volume 0.5 mL, 10 mg / mL in MeOH).

[0270] 8,10-Dimethyl-7a,8,9,10-tetrahydro-7H-indolo[7,1-fg][1,7]naphthidine (Example 2A, first elution peak): Analytical chiral SFC > 99.5% ee. t =4.41 min (Chiralpak-IG 25 cm x 0.46 cm; isocratic method: 25% MeOH (0.1% diethylamine) / CO2; 100 bar, 3 mL / min, wavelength 220 nm). Yellow solid; LC-MS: m / z = 239.1 [M+H] + .

[0271] 8,10-Dimethyl-7a,8,9,10-tetrahydro-7H-indolo[7,1-fg][1,7]naphthidine (Example 2B, second elution peak): Analytical chiral SFC > 99.9% ee. t =5.40 min (Chiralpak-IG 25 cm x 0.46 cm; isocratic method: 25% MeOH (0.1% diethylamine) / CO2; 100 bar, 3 mL / min, wavelength 220 nm). Yellow solid; LC-MS: m / z = 239.1 [M+H]+ .

[0272] Example 3: (8-Methyl-7a,8,9,10-tetrahydro-7H-indolo[7,1-fg][1,7]naphthid-10-yl)methanol (Main) (8-Methyl-7a,8,9,10-tetrahydro-7H-indolo[7,1-fg][1,7]naphthid-10-yl)methanol (Minor) for and ,or for and .

[0273] Ethyl 6-(hydroxymethyl)-5-(1H-indol-7-yl)nicotinic acid Ethyl 5-bromo-6-(hydroxymethyl)nicotinic acid (1.108 g, 4.260 mmol, 1.0 equiv) and pinacol indole-7-boronic acid (1.243 g, 5.112 mmol, 1.2 equiv) were reacted with dioxane (42.6 mL) and Na₂CO₃. 3(aq) The solution in (4.26 mL) was bubbled with N2 for 5 min. Pd(PPh3)4 (0.246 g, 0.213 mmol, 0.05 equiv) was added, and the mixture was heated to 90 °C and stirred for 8 hours, followed by cooling to ambient temperature. The mixture was poured into H2O (500 mL) and extracted with EtOAc (5 x 100 mL). The combined organic extracts were washed with brine (100 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (gradient elution: 30% hexane to 50% hexane of EtOAc) to give 6-(hydroxymethyl)-5-(1 H ethyl indo-7-yl nicotinic acid (0.956 g, 76%) is an off-white solid. 1 H NMR (400MHz, CDCl3) δ = 9.21 (d, J = 1.96 Hz, 1H), 8.43 (br s, 1H), 8.34 (d, J = 2.0 Hz, 1H), 7.74 (d, J = 7.96 Hz, 1H), 7.24 – 7.18 (m, 2H), 7.06 – 7.02 (m, 1H), 6.65(dd, J = 2.04, 3.29 Hz, 1H), 4.60 (s, 2H), 4.42 (q, J = 7.16 Hz, 2H), 3.31 (br s,1H), 1.41 (t,J = 7.16 Hz, 3H) ppm. 13 C NMR(100 MHz, CDCl3) δ = 165.1, 161.2,148.8, 139.2, 133.9, 132.1, 128.7, 125.5, 125.3, 122.7, 121.6, 120.1, 119.6,103.3, 62.4, 61.8, 14.4 ppm. LRMS (ES + ) m / z [M + H] + C 17 H 17 N2O3 + Calculated value: 297.33; Measured value: 297.38.

[0274] 10-(ethoxycarbonyl)-8-methyl-7H-indolo[7,1-fg][1,7]naphthidine-8-onium iodide To 6-(hydroxymethyl)-5-(1 H TsCl (0.202 g, 1.057 mmol, 1.2 equiv) and tetrabutylammonium bisulfate (0.015 g, 0.044 mmol, 0.05 equiv) were added to a 0 °C cooled solution of ethyl indole-7-yl nicotinate (0.261 g, 0.881 mmol, 1.0 equiv) in DCM (17.6 mL). Freshly ground NaOH (0.141 g, 3.523 mmol, 4.0 equiv) was then added. The mixture was heated to ambient temperature and stirred for 2 h, then poured into vigorously stirred DCM (150 mL) and 1 M NH4Cl. (aq) The mixture was prepared in 250 mL. The layers were separated, and the aqueous layer was further extracted with DCM (3 x 80 mL). The combined organic extracts were washed with brine (100 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The substance was purified by silica gel column chromatography (40% EtOAc in hexane) to give 7... H -Indodo[7,l-] fg [1,7] Naphthyl-10-carboxylic acid ethyl ester is a white solid. 1 H NMR (400 MHz, CDCl3) δ = 8.98 (d, J = 1.96 Hz, 1H), 8.64 (d, J= 2.0 Hz, 1H), 7.55 – 7.46 (m, 2H), 7.15 (d, J = 3.08 Hz, 1H), 7.09(t, J = 7.68 Hz, 1H), 3.55 (d, J = 3.04 Hz, 1H), 5.64 (s, 2H), 4.46 (q, J = 7.12Hz, 2H), 1.46 (t, J = 7.16 Hz, 3H) ppm. 13 C NMR (100 MHz, CDCl3) δ = 165.18,154.5, 148.9, 133.0, 130.7, 126.7, 126.4, 126.3, 125.9, 122.3, 120.7, 115.5,114.8, 103.0, 61.7, 50.7, 14.5 ppm. LRMS (ES + ) m / z [M + H] + C 17 H 15 N2O2 + Calculated value: 279.11; Measured value: 279.31.

[0275] 7 H -Indodo[7,l-] fg [1,7]Naphthyl-10-carboxylic acid ethyl ester was immediately dissolved in MeCN (2.2 mL) and MeI (1.1 mL) and heated in a sealed tube at 50 °C for 22 h. The suspension was cooled to ambient temperature and concentrated under reduced pressure. The resulting solid was stirred in 1:1 hexane / EtOAc (20 mL) at 0 °C for 1 h, then filtered, washed with an additional 1:1 hexane / EtOAc (10 mL), and dried under vacuum to give 10-(ethoxycarbonyl)-8-methyl-7 H -Indodo[7,1-fg][1,7]naphthidine-8-onium iodide (0.294 g, 79%) is a yellow solid. 1 H NMR (400 MHz, DMSO-) d 6 ) δ = 9.45 (d, J = 1.08 Hz, 1H), 9.27 (d, J = 1.12 Hz, 1H), 7.95 (d, J = 7.4 Hz, 1H), 7.65 (d,J = 7.92 Hz, 1H), 7.53 (d, J = 3.08 Hz, 1H), 7.13 (t, J = 7.68 Hz, 1H), 6.63 (d, J = 3.08 Hz, 1H), 6.18 (s, 2H), 4.49 (q, J = 7.12 Hz, 2H), 4.37 (s, 3H), 1.43 (t, J = 7.16 Hz, 3H) ppm. 13 C NMR (100 MHz, DMSO-) d 6 ) δ = 161.7, 152.4, 145.3,136.1, 132.1, 131.7, 128.5, 127.5, 125.8, 124.2, 121.0, 116.8, 112.3, 103.1,62.7, 47.1, 45.7, 14.0 ppm. LRMS (ES + ) m / z [M + H] + C 18 H 17 N2O2 + Calculated value: 293.13; Measured value: 293.23.

[0276] (8-Methyl-7a,8,9,10-tetrahydro-7H-indolo[7,1-fg][1,7]naphthid-10-yl)methanol (major) (8-Methyl-7a,8,9,10-tetrahydro-7H-indolo[7,1-fg][1,7]naphthid-10-yl)methanol (minor) To 10-(ethoxycarbonyl)-8-methyl-7 H LiBH4 (0.53 mL, 2.130 mmol, 5.0 equiv) was added dropwise to a mixture of indo[7,1-fg][1,7]naphthyl-8-onium iodide (0.179 g, 0.426 mmol, 1.0 equiv) cooled to 0 °C. The mixture was heated to ambient temperature and stirred for 2 hours. Three equal portions of LiBH4 were then added every 2 hours thereafter, and the solution was stirred for another 18 hours. The solution was then poured into a saturated NaHCO3 solution. 3(aq)In a mixture of 400 mL of EtOAc and 200 mL of EtOAc, the layers were stirred vigorously to separate the layers. The aqueous layer was further extracted with EtOAc (3 x 100 mL), and the combined organic extracts were washed with brine (100 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (gradient elution: 4% MeOH to 8% MeOH for EtOAc) to give (8-methyl-7a,8,9,10-tetrahydro-7a) H -Indolo[7,1-fg][1,7]naphthid-10-yl)methanol (primarily) (0.041 g, 38%) and (8-methyl-7a,8,9,10-tetrahydro-7 H -Indolo[7,1-fg][1,7]naphthid-10-yl)methanol (minor) (0.031 g, 29%), both are pale yellow solids.

[0277] 7a,8,9,10-tetrahydro-7 H -Indodo[7,1- fg [1,7]Naphthid-10-yl)methanol (primary). 1 H NMR (400MHz, DMSO-) d 6) δ = 7.41 (d, J = 7.8 Hz, 1H), 7.33 (d, J = 3.0 Hz, 1H), 7.21 (d, J =7.2 Hz, 1H), 7.00 (t, J = 7.64 Hz, 1H), 6.40 (d, J = 3.0 Hz, 1H), 6.39 – 6.36 (m,1H), 4.83 (dd, J = 5.36, 11.48 Hz, 1H), 4.78 – 4.70 (m, 1H), 3.59 (t, J = 11.24Hz, 1H), 3.51 – 3.44 (m, 1H), 3.41 – 3.34 (m, 1H), 3.22 – 3.13 (m, 1H), 3.02(dd, J = 5.2, 11.21 Hz, 1H), 2.75 – 2.64 (m, 1H), 2.46 (s, 3H), 2.15 (t, J =10.76 Hz, 1H) ppm. 13 C NMR (100 MHz, DMSO-) d6) δ = 131.6, 130.9, 127.3, 125.9,122.0, 119.9, 119.2, 119.1, 113.8, 100.5, 63.5, 60.4, 56.64, 47.4, 43.7, 38.9ppm. LRMS (ES + ) m / z [M + H] + C 16 H 19 N2O + Calculated value: 255.15; Measured value: 255.25.

[0278] (8-Methyl-7a,8,9,10-tetrahydro-7a) H -Indodo[7,1- fg [1,7]Naphthid-10-yl)methanol (minor). 1 HNMR(400 MHz, MeOD) δ = 7.39 (d, J = 7.88 Hz, 1H), 7.21 (d, J = 7.24 Hz 1H), 7.13(d, J = 3.04 Hz, 1H), 6.98 (t, J = 7.64 Hz, 1H), 6.42 – 6.36 (m, 2H), 4.72 (dd, J =5.4, 11.52 Hz, 1H), 3.76 – 3.59 (m, 3H), 3.28 – 3.20 (m, 1H), 3.07 – 3.01 (m,1H), 2.68 – 2.61 (m, 1H), 2.50 (s, 3H), 2.48 – 2.40 (m, 1H) ppm. 13 C NMR(100MHz, MeOD) δ = 134.5, 134.1, 127.8, 127.7, 121.2, 121.1, 120.6, 120.4, 115.2,101.9, 65.4, 62.1, 55.7, 49.0, 44.2, 39.6ppm. LRMS (ES + ) m / z [M + H] + C 16 H 19 N2O + Calculated value: 255.15; Measured value: 255.25.

[0279] Chiral separation of (8-methyl-7a,8,9,10-tetrahydro-7H-indolo[7,l-fg][1,7]naphthid-10-yl)methanol (primarily) Racemic (8-methyl-7a,8,9,10-tetrahydro-7a) H -Indodo[7,1- fg [1,7]Naphthid-10-yl)methanol (mainly) was isolated to its enantiomers via preparative chiral SFC using (Chiralpak-AD-H 25 cm x 3 cm; isocratic method: 40% EtOH (0.1% diethylamine) / CO2; 100 bar, 85 mL / min; injection volume 1 mL, 4 mg / mL in EtOH).

[0280] (8-Methyl-7a,8,9,10-tetrahydro-7a) H -Indodo[7,1- fg [1,7]Naphthid-10-yl)methanol (Example 3A, first elution peak): Analytical chiral SFC > 99.9% ee. R t =2.76 min (Chiralpak-AD-H 25 cm x 0.46 cm; isocratic method: 40% MeOH (0.1% diethylamine) / CO2; 100 bar, 3 mL / min). Brown solid; LC-MS: m / z = 255.2 [M+H] + (8-Methyl-7a,8,9,10-tetrahydro-7a) H -Indodo[7,1- fg [1,7]Naphthid-10-yl)methanol (Example 3B, second elution peak): Analytical chiral SFC > 99.9% ee. R t =3.32 min (Chiralpak-AD-H 25 cm x 0.46 cm; isocratic method: 40% MeOH (0.1% diethylamine) / CO2; 100 bar, 3 mL / min). Brown solid; LC-MS: m / z = 255.2 [M+H] + (8-Methyl-7a,8,9,10-tetrahydro-7a) H -Indodo[7,l-] fg Chiral separation of [1,7]naphthid-10-yl)methanol (minor) Racemic mixture (8-methyl-7a,8,9,10-tetrahydro-7a) H -Indodo[7,1- fg[1,7]Naphthid-10-yl)methanol (minor) was isolated into its enantiomers by preparative chiral SFC (Chiralpak-AD-H 25 cm x 3 cm; isocratic method: 40% EtOH (0.1% diethylamine) / CO2; 100 bar, 85 mL / min; injection volume 1 mL, 1 mg / mL in MeOH).

[0281] (8-Methyl-7a,8,9,10-tetrahydro-7a) H -Indodo[7,1- fg [1,7]Naphthid-10-yl)methanol (Example 3C, first elution peak): Analytical chiral SFC > 99.9% ee. R t =2.50 min (Chiralpak-AD-H 25 cm x 0.46 cm; isocratic method: 40% MeOH (0.1% diethylamine / CO2: 100 bar, 3 mL / min). Brown solid; LC-MS: m / z = 255.2 [M+H] + .

[0282] (8-Methyl-7a,8,9,10-tetrahydro-7a) H -Indodo[7,1- fg [1,7]Naphthid-10-yl)methanol (Example 3D, second elution peak): Analytical chiral SFC 98.2% ee. R t =3.05 min (Chiralpak-AD-H 25 cm x 0.46 cm; isocratic method: 40% MeOH (0.1% diethylamine) / CO2; 100 bar, 3 mL / min). Brown solid; LC-MS: m / z = 255.2 [M+H] + .

[0283] Example 13: 3-Fluoro-8-methyl-7a,8,9,10-tetrahydro-7 H -Indodo[7,l-] fg [1,7]Naphthyl for and .

[0284] (3-(4-Fluoro-1) H -Indol-7-yl)-1-ethyl-1,2,5,6-tetrahydropyridin-2-yl)methanol Following general procedure 2, (3-bromo-1-methyl-1,2,5,6-tetrahydropyridin-2-yl)methanol (2.43 mmol) was used to prepare (3-(4-fluoro-1-yl)-methyl-1,2,5,6-tetrahydropyridin-2-yl)-methyl ... H(-indol-7-yl)-1-methyl-1,2,5,6-tetrahydropyridin-2-yl)methanol (378 mg, 60%) was purified by silica gel column chromatography to give brown foam (gradient: 90:10:1 to 85:15:1, DCM / MeOH / NH4OH). 1 H NMR (400MHz, CDCl3) δ = 9.21 (s, 1H), 7.14 (t, J = 2.8 Hz, 1H), 6.83 (dd, J = 8.0, 4.9Hz, 1H), 6.73 (dd, J = 10.2, 8.0 Hz, 1H), 6.61 (dd, J = 3.2, 2.1 Hz, 1H), 6.01(s, 1H), 3.60 (dd, J = 10.7, 3.0 Hz, 1H), 3.45 (s, 1H), 3.31 – 3.16 (m, 2H), 3.02 (dt, J = 11.9, 5.1 Hz, 1H), 2.69 (ddd, J = 12.1, 8.1, 4.4 Hz, 1H), 2.52 (s, 3H), 2.41 – 2.28 (m, 1H), 2.29 – 2.18 (m, 1H). 13 C NMR (100 MHz, CDCl3) δ =155.65 ( 1 J CF = 246.4 Hz), 137.55 ( 2 J CF = 11.64 Hz), 134.75, 128.17, 124.47,121.21 ( 3 J CF = 7.53 Hz), 121.06 ( 4 J CF = 4.11 Hz), 104.05 ( 5 J CF = 19.48 Hz), 98.52, 66.30, 59.53, 49.02, 42.82, 23.99. LRMS (ES + ) m / z [M + H] +C 15 H 18 FN2O + = Calculated value 261.14; Measured value 261.23.

[0285] 3-Fluoro-8-methyl-7a,8,9,10-tetrahydro-7 H -Indodo[7,1- fg [1,7]Naphthyl Following general procedure 3, (3-(4-fluoro-1) H Preparation of 3-fluoro-8-methyl-7a,8,9,10-tetrahydro-7a)-indol-7-yl)-1-methyl-1,2,5,6-tetrahydropyridin-2-yl)methanol (0.769 mmol) H -Indodo[7,l-] fg [1,7] Naphthylidine (94.7 mg, 51%) was purified by silica gel column chromatography as a reddish-brown oil (gradient: 100:0 to 95:5, EtOAc / MeOH). 1 HNMR (400 MHz, CDCl3) δ = 7.14 (dd, J = 8.0, 4.3 Hz, 1H), 7.06 (d, J = 3.2 Hz, 1H), 6.73 (dd, J = 10.8, 8.0 Hz, 1H), 6.52 (d, J = 3.2 Hz, 1H), 6.40 (d, J = 6.2Hz, 1H), 4.63 (dd, J = 11.3, 5.4 Hz, 1H), 3.80 (t, J = 11.1 Hz, 1H), 3.34 (d, J =10.8 Hz, 1H), 3.05 – 2.93 (m, 1H), 2.70 – 2.59 (m, 2H), 2.56 (s, 3H), 2.32 –2.15 (m, 1H). 13 C NMR (100 MHz, CDCl3) δ = 155.63 ( 1 J CF = 248.8 Hz), 135.40 ( 2 J CF =12.54 Hz), 130.03, 126.35, 119.66 ( 3 JCF = 1.91 Hz), 116.32 ( 4 J CF = 3.73 Hz), 114.99 ( 5 J CF = 7.46 Hz), 114.88 ( 6 J CF = 23.52 Hz), 105.17 ( 7 J CF = 19.44 Hz), 97.64 ( 8 J CF = 1.46 Hz), 60.52, 52.77, 48.25, 44.26, 25.84. LRMS (ES + ) m / z [M + H] + C 15 H 16 FN2 + = Calculated value 243.13; Measured value 243.34.

[0286] 3-Fluoro-8-methyl-7a,8,9,10-tetrahydro-7 H -Indodo[7,l-] fg [1,7] Chiral separation of naphthidine.

[0287] Racemic 3-fluoro-8-methyl-7a,8,9,10-tetrahydro-7 H -Indodo[7,l-fg][1,7]naphthidine was isolated into its enantiomers by preparative chiral SFC (Chiralpak-IG 25 cm x 2 cm; isocratic method: 25% MeOH (0.1% diethylamine) / CO2; 100 bar, 60 mL / min; injection volume 0.75 mL, 5 mg / mL in MeOH).

[0288] 3-Fluoro-8-methyl-7a,8,9,10-tetrahydro-7 H -Indodo[7,1- fg [1,7] Naphthylidine (Example 13A, first elution peak): Analytical chiral SFC 99.8% ee. R t=3.16 min (Chiralpak-IG 25 cm x 0.46 cm; isocratic method: 30% MeOH (0.1% diethylamine) / CO2; 100 bar, 3 mL / min). Yellow solid; LC-MS: m / z = 243.1 [M+H] + .

[0289] 3-Fluoro-8-methyl-7a,8,9,10-tetrahydro-7 H -Indodo[7,1- fg [1,7] Naphthylidine (Example 13B, second elution peak): Analytical chiral SFC 99.9% ee. R t =4.7 min (Chiralpak-IG 25 cm x 0.46 cm; isocratic method: 30% MeOH (0.1% diethylamine) / CO2; 100 bar, 3 mL / min). Yellow solid; LC-MS: m / z = 243.1 [M+H] + .

[0290] Example 14: 2-Fluoro-8-methyl-7a,8,9,10-tetrahydro-7 H -Indodo[7,1- fg [1,7]Naphthyl for and .

[0291] (3-(5-Fluoro-1) H -indol-7-yl)-1-methyl-1,2,5,6-tetrahydropyridin-2-yl)methanol Following general procedure 2, (3-bromo-1-methyl-1,2,5,6-tetrahydropyridin-2-yl)methanol (2.43 mmol) was used to prepare (3-(5-fluoro-1) H (-indol-7-yl)-1-methyl-1,2,5,6-tetrahydropyridin-2-yl)methanol (320 mg, 51%), after purification by silica gel column chromatography, was a brown foam (gradient: 90:10:1 to 85:15:1, DCM / MeOH / NH4OH). 1 H NMR (400MHz, CDCl3) δ = 9.02 (s, 1H), 7.24 – 7.15 (m, 2H), 6.72 (dd, J = 10.0, 2.4 Hz, 1H), 6.49 (dd, J= 3.2, 2.1 Hz, 1H), 6.13 – 6.02 (m, 1H), 3.67 – 3.38 (m, 2H), 3.31 – 3.19 (m, 2H), 3.04 (dt, J = 12.1, 5.2 Hz, 1H), 2.70 (ddd, J = 12.1, 7.8,4.6 Hz, 1H), 2.53 (s, 3H), 2.42 – 2.18 (m, 2H). 13 C NMR (100 MHz, CDCl3) δ =157.67 ( 1 J CF = 234.9 Hz), 134.48 ( 2 J CF = 1.79 Hz), 131.50, 128.36, 128.20 ( 3 J CF =10.73 Hz), 126.20, 125.50 ( 4 J CF = 9.11 Hz), 109.11 ( 5 J CF = 26.57 Hz), 104.19 ( 6 J CF = 23.03 Hz), 102.59 ( 7 J CF = 5.76 Hz), 65.88, 59.62, 48.77, 42.79, 23.79. LRMS(ES + ) m / z [M + H] + C 15 H 18 FN2O + = Calculated value 261.14; Measured value 261.29.

[0292] 2-Fluoro-8-methyl-7a,8,9,10-tetrahydro-7 H -Indodo[7,1- fg [1,7]Naphthyl Following general procedure 3, (3-(5-fluoro-1) H2-Fluoro-8-methyl-7a,8,9,10-tetrahydro-7a)-indol-7-yl)-1-methyl-1,2,5,6-tetrahydropyridin-2-yl)methanol (0.769 mmol) to prepare 2-fluoro-8-methyl-7a,8,9,10-tetrahydro-7a) H -Indodo[7,1- fg [1,7] Naphthylidine (77.8 mg, 42%) was purified by silica gel column chromatography as a reddish-brown oil (gradient: 100:0 to 95:5, EtOAc / MeOH). 1 H NMR (400 MHz, CDCl3) δ = 7.16 – 7.07 (m, 2H), 6.98 (dd, J = 10.3, 2.2 Hz, 1H), 6.46 (d, J = 6.3 Hz, 1H), 6.42 (d, J = 3.0 Hz, 1H), 4.63 (dd, J = 11.2, 5.4Hz, 1H), 3.79 (t, J = 11.1 Hz, 1H), 3.40 – 3.29 (m, 1H), 3.05 – 2.95 (m, 1H), 2.69 – 2.59 (m, 2H), 2.56 (s, 3H), 2.32 – 2.18 (m, 1H). 13 C NMR (100 MHz, CDCl3) δ = 158.97 ( 1 J CF = 233.4 Hz), 130.23 ( 2 J CF = 2.49 Hz), 129.72, 127.70,126.08 ( 3 J CF = 10.58 Hz), 121.68, 120.43 ( 4 J CF = 9.81 Hz), 104.33 ( 5 J CF = 25.03Hz), 102.80 ( 6 J CF = 27.71 Hz), 101.25 ( 7 J CF= 5.26 Hz), 60.54, 52.67, 48.21, 44.21, 25.90. LRMS (ES + ) m / z [M + H] + C 15 H 16 FN2 + = Calculated value 243.13; Measured value 243.21.

[0293] 2-Fluoro-8-methyl-7a,8,9,10-tetrahydro-7 H -Indodo[7,l-] fg [1,7] Chiral separation of naphthidine Racemic 2-fluoro-8-methyl-7a,8,9,10-tetrahydro-7 H -Indodo[7,l-] fg [1,7] Naphthylidine was isolated into its enantiomers by preparative chiral SFC (Chiralpak-IG 25 cm x 2 cm; isocratic method: 25% MeOH (0.1% diethylamine) / CO2: 100 bar, 60 mL / min; injection volume 0.75 mL, 5 mg / mL in methanol).

[0294] 2-Fluoro-8-methyl-7a,8,9,10-tetrahydro-7 H -Indodo[7,1- fg [1,7] Naphthylidine (Example 14A, first elution peak): Analytical chiral SFC 99.9% ee. R t =3.31 min (Chiralpak-IG 25 cm x 0.46 cm; isocratic method: 30% MeOH (0.1% diethylamine) / CO2; 100 bar, 3 m / min). Yellow solid; LC-MS: m / z = 243.2 [M+H] + 2-Fluoro-8-methyl-7a,8,9,10-tetrahydro-7 H -Indodo[7,1- fg [1,7] Naphthylidine (Example 14B, second elution peak): Analytical chiral SFC 99.9% ee. R t =4.98 min (Chiralpak-IG 25 cm x 0.46 cm; isocratic method: 30% MeOH (0.1% diethylamine) / CO2; 100 bar, 3 mL / min). Yellow solid; LC-MS: m / z = 243.2 [M+H] + Example 15: l-Fluoro-8-methyl-7a,8,9,10-tetrahydro-7 H -Indolo[7,l-fg][1,7]naphthidine for and (3-(6-Fluoro-1) H -indol-7-yl)-1-methyl-1,2,5,6-tetrahydropyridin-2-yl)methanol Following general procedure 2, (3-(6-fluoro-1-methyl-1,2,5,6-tetrahydropyridin-2-yl)methanol (2.43 mmol) was used to prepare (3-(6-fluoro-1-methyl-1,2,5,6-tetrahydropyridin-2-yl)methanol. H (-indol-7-yl)-1-methyl-1,2,5,6-tetrahydropyridin-2-yl)methanol (0.400 mg, 63%), purified by silica gel column chromatography as a light purple foam (gradient: 90:10:1 to 85:15:1, DCM / MeOH / NH4OH). 1 H NMR (400MHz, CDCl3) δ = 9.01 (s, 1H), 7.45 (dd, J = 8.6, 5.1 Hz, 1H), 7.17 (dd, J = 3.3, 2.3 Hz, 1H), 6.84 (dd, J = 10.3, 8.6 Hz, 1H), 6.49 (dd, J = 3.3, 2.1 Hz, 1H), 6.06 (dt, J = 5.6, 2.1 Hz, 1H), 3.65 (dd, J = 10.8, 2.9 Hz, 1H), 3.37 – 2.83 (m,4H), 2.82 – 2.68 (m, 1H), 2.52 (s, 3H), 2.47 – 2.33 (m, 1H), 2.32 – 2.18 (m,1H). 13 C NMR (100 MHz, CDCl3) δ = 155.99 ( 1 J CF = 236.2 Hz), 135.95 ( 2 J CF = 8.77Hz), 130.29, 130.14, 125.06 ( 3 J CF = 4.16 Hz), 124.21, 120.14 ( 4J CF = 10.34 Hz), 111.13 ( 5 J CF = 21.93 Hz), 108.30 ( 6 J CF = 25.23 Hz), 102.33, 65.53, 59.64, 49.67, 42.92, 24.80. LRMS (ES + ) m / z [M + H] + C 15 H 18 FN2O + = Calculated value 261.14; Measured value 261.23.

[0295] 1-Fluoro-8-methyl-7a,8,9,10-tetrahydro-7 H -Indodo[7,1- fg [1,7]Naphthyl According to general procedure 3, (3-(6-fluoro-1) H Preparation of 1-fluoro-8-methyl-7a,8,9,10-tetrahydro-7a)-indol-7-yl)-1-methyl-1,2,5,6-tetrahydropyridin-2-yl)methanol (0.769 mmol) H -Indodo[7,1- fg [1,7] Naphthylidine (400 mg, 84%) was purified by silica gel column chromatography to give a yellow oil (gradient: 100:0 to 95:5, EtOAc / MeOH). 1 HNMR (400 MHz, CDCl3) δ = 7.35 (dd, J = 8.6, 4.3 Hz, 1H), 7.05 (d, J = 3.0 Hz, 1H), 6.86 (dd, J = 12.1, 8.6 Hz, 1H), 6.76 (d, J = 5.8 Hz, 1H), 6.43 (d, J = 3.0Hz, 1H), 4.59 (dd, J = 11.3, 5.2 Hz, 1H), 3.80 (t, J = 11.2 Hz, 1H), 3.35 – 3.24 (m, 1H), 3.03 – 2.93 (m, 1H), 2.40 – 2.26 (m, 1H).13 C NMR (100 MHz, CDCl3) δ =155.58 ( 1 J CF = 243.2 Hz), 133.36 ( 2 J CF = 9.56 Hz), 126.65 ( 3 J CF = 3.85 Hz), 126.30 ( 4 J CF = 11.31 Hz), 126.26 ( 5 J CF = 11.64 Hz), 122.51, 199.50 ( 6 J CF = 10.02 Hz), 109.62 ( 7 J CF = 25.95 Hz), 106.42 ( 8 J CF = 16.12 Hz), 101.16, 60.25, 52.46, 48.11, 44.35, 26.14. LRMS (ES + ) m / z [M + H] + C 15 H 16 FN2 + = Calculated value 243.13; Measured value 243.28.

[0296] 1-Fluoro-8-methyl-7a,8,9,10-tetrahydro-7 H -Indodo[7,1- fg [1,7] Chiral separation of naphthidine Racemic form l-fluoro-8-methyl-7a,8,9,10-tetrahydro-7 H -Indodo[7,1- fg [1,7] Naphthidine was isolated into its enantiomers by preparation of a chiral SFC (Chiralpak-IG 25 cm x 2 cm; isocratic method: 25% MeOH (0.1% diethylamine) / CO2; 100 bar, 60 mL / min; injection volume 0.75 mL, 5 mg / mL in MeOH).

[0297] l-Fluoro-8-methyl-7a,8,9,10-tetrahydro-7 H -Indodo[7,1- fg [1,7] Naphthylidine (Example 15A, first elution peak): Analytical chiral SFC 99.9% ee. R t =3.05 min (Chiralpak-IG 25 cm x 0.46 cm; isocratic method: 30% MeOH (0.1% diethylamine) / CO2; 100 bar, 3 mL / min). Yellow solid; LC-MS: m / z = 243.2 [M+H] + .

[0298] l-Fluoro-8-methyl-7a,8,9,10-tetrahydro-7 H -Indodo[7,1- fg [l,7] Naphthylidine (Example 15B, second elution peak): Analytical chiral SFC 99.8% ee. R t =4.13 min (Chiralpak-IG 25 cm x 0.46 cm; isocratic method: 30% MeOH (0.1% diethylamine) / CO2; 100 bar, 3 mL / min). Yellow solid; LC-MS: m / z = 243.2 [M+H] + .

[0299] Example 16: 3-Chloro-8-methyl-7a,8,9,10-tetrahydro-7 H -Indodo[7,l-] fg [1,7]Naphthyl for and (3-(4-chloro-1) H -indol-7-yl)-1-methyl-1,2,5,6-tetrahydropyridin-2-yl)methanol Following general procedure 2, (3-(4-chloro-1H-indol-7-yl)-1-methyl-1,2,5,6-tetrahydropyridin-2-yl)methanol (0.613 mmol) was used to prepare (3-bromo-1-methyl-1,2,5,6-tetrahydropyridin-2-yl)methanol (90 mg, 53%), which was purified by silica gel column chromatography to a brown foam (gradient: 90:10:1 to 85:15:1, DCM / MeOH / NH4OH). 1 H NMR (400MHz, CDCl3) δ = 9.34 (s, 1H), 7.22 (t, J = 2.9 Hz, 1H), 7.06 (d, J= 7.8 Hz, 1H), 6.83 (d, J = 7.8 Hz, 1H), 6.68 – 6.55 (m, 1H), 6.03 (t, J = 4.6 Hz, 1H), 4.05 (s,1H), 3.61 (d, J = 8.0 Hz, 1H), 3.33 – 3.19 (m, 2H), 3.14 – 2.99 (m, 1H), 2.74(ddd, J = 12.1, 7.8, 4.6 Hz, 1H), 2.55 (s, 3H), 2.43 – 2.19 (m, 2H). 13 C NMR (100MHz, CDCl3) δ = 135.62, 134.25, 128.33, 126.75, 125.28, 124.93, 123.38,121.46, 119.11, 101.12, 66.01, 59.38, 48.96, 42.70, 23.86. LRMS (ES + ) m / z [M +H] + C 15 H 18 ClN2O + = Calculated value 277.11; Measured value 277.10.

[0300] 3-Chloro-8-methyl-7a,8,9,10-tetrahydro-7H-indolo[7,1- fg [1,7]Naphthyl Following general procedure 3, (3-(4-chloro-1) H Preparation of 3-chloro-8-methyl-7a,8,9,10-tetrahydro-7a)-indol-7-yl)-1-methyl-1,2,5,6-tetrahydropyridin-2-yl)methanol (0.73 mmol) H -Indodo[7,1- fg [1,7] Naphthylidine (0.106 g, 56%) was purified by silica gel column chromatography (EtOAc) to a brown semi-solid. 1 H NMR (400 MHz, CDCl3) δ= 7.13 (d, J = 7.8 Hz, 1H), 7.09 (d, J = 3.08 Hz, 1H), 7.06 (d, J = 7.84 Hz, 1H), 6.54 (d, J= 3.04 Hz, 1H), 6.46 – 6.41 (m, 1H), 4.61 (dd, J = 11.6, 5.36 Hz, 1H), 3.78 (t, J = 11.12 Hz, 1H), 3.33 – 3.25 (m, 1H), 3.00 – 2.92 (m, 1H), 2.68 –2.50 (m, 5H), 2.28 – 2.18 (m, 1H) ppm. 13 C NMR (100 MHz, CDCl3) δ = 133.6,130.0, 127.0, 125.0, 124.4, 120.8, 120.1, 118.8, 115.2, 100.0, 60.4, 52.7,48.4, 44.3, 26.0 ppm. LRMS (ES + ) m / z [M + H] + C 15 H 16 ClN2 + = Calculated value 259.10; Measured value 259.15.

[0301] 3-Chloro-8-methyl-7a,8,9,10-tetrahydro-7 H -Indodo[7,l-] fg [1,7] Chiral separation of naphthidine Racemic 3-chloro-8-methyl-7a,8,9,10-tetrahydro-7 H -Indodo[7,1- fg [1,7] Naphthylidine was isolated into its enantiomers by preparative chiral SFC (Chiralpak-IG 25 cm x 2 cm; isocratic method: 30% MeOH (0.1% diethylamine) / CO2; 100 bar, 60 mL / min; injection volume 0.75 mL, 6 mg / mL in MeOH).

[0302] 3-Chloro-8-methyl-7a,8,9,10-tetrahydro-7 H -Indole[7,1- fg [1,7] Naphthylidine (Example 16A, first elution peak): Analytical chiral SFC 99.9% ee. R t=5.0 min (Chiralpak-IG 25 cm x 0.46 cm; isocratic method: 30% MeOH (0.1% diethylamine) / CO2; 100 bar, 3 mL / min). Yellow solid; LC-MS: m / z = 259.1 [M+H] + .

[0303] 3-Chloro-8-methyl-7a,8,9,10-tetrahydro-7 H -Indodo[7,1- fg [1,7] Naphthylidine (Example 16B, second elution peak): Analytical chiral SFC 99.9% ee. R t =7.6 min (Chiralpak-IG 25 cm x 0.46 cm; isocratic method: 30% MeOH (0.1% diethylamine) / CO2; 100 bar, 3 mL / min). Yellow solid; LC-MS: m / z = 259.1 [M+H] + .

[0304] Example 17: 2-Chloro-8-methyl-7a,8,9,10-tetrahydro-7 H -Indodo[7,l-] fg [l,7]Naphthyl for and (3-(5-chloro-1) H -indol-7-yl)-1-methyl-1,2,5,6-tetrahydropyridin-2-yl)methanol Following general procedure 2, (3-bromo-1-methyl-1,2,5,6-tetrahydropyridin-2-yl)methanol (1.02 mmol) was used to prepare (3-(5-chloro-1) H (-indol-7-yl)-1-methyl-1,2,5,6-tetrahydropyridin-2-yl)methanol (165 mg, 58%) was purified by silica gel column chromatography to give brown foam (gradient: 90:10:1 to 85:15:1, DCM / MeOH / NH4OH). 1 H NMR (400MHz, CDCl3) δ = 9.13 (s, 1H), 7.51 (d, J = 1.9 Hz, 1H), 7.18 (s, 1H), 6.91 (d, J= 1.9 Hz, 1H), 6.47 (s, 1H), 6.05 (s, 1H), 3.67 – 3.57 (m, 1H), 3.46 (s, 1H), 3.28 – 3.16 (m, 2H), 3.08 – 2.97 (m, 1H), 2.69 (ddd, J = 12.1, 8.2, 4.4 Hz,1H), 2.52 (s, 3H), 2.40 – 2.30 (m, 1H), 2.29 – 2.15 (m, 1H). 13 C NMR (100 MHz, CDCl3) δ = 134.41, 133.50, 129.01, 128.64, 125.93, 124.98, 121.00, 118.89,102.16, 66.05, 59.51, 49.07, 42.84, 24.01. LRMS (ES + ) m / z [M + H] + C 15 H 18 ClN2O + =Calculated value 277.11; Measured value 277.35.

[0305] 2-Chloro-8-methyl-7a,8,9,10-tetrahydro-7 H -Indodo[7,1- fg [1,7]Naphthyl Following general procedure 3, (3-(5-chloro-1) H 2-Chloro-8-methyl-7a,8,9,10-tetrahydro-7a)-indol-7-yl)-1-methyl-1,2,5,6-tetrahydropyridin-2-yl)methanol (0.397 mmol) H -Indodo[7,1- fg [1,7] Naphthylidine (0.068 g, 66%) was purified by silica gel column chromatography (EtOAc) as a brown oil. 1 H NMR (400 MHz, CDCl3)δ = 7.44 (d, J = 1.4 Hz, 1H), 7.20 (d, J = 1.28 Hz, 1H), 7.09 (d, J = 3.0 Hz, 1H),6.49 – 6.44 (m, 1H), 6.40 (d, J = 3.0 Hz, 1H), 4.61 (dd, J= 11.6, 5.36 Hz, 1H), 3.78 (d, J = 11.12 Hz, 1H), 3.36 – 3.28 (m, 1H), 3.02 – 2.94 (m, 1H), 2.69 –2.53 (m, 5H), 2.29 – 2.20 (m, 1H) ppm. 13 C NMR (100 MHz, CDCl3) δ = 131.5,130.0, 127.6, 127.1, 126.2, 121.8, 120.9, 118.8, 114.8, 101.0, 60.5, 52.7,48.3, 44.3, 26.0 ppm. LRMS (ES + ) m / z [M + H] + C 15 H 16 ClN2 + = Calculated value 259.10; Measured value 259.22.

[0306] 2-Chloro-8-methyl-7a,8,9,10-tetrahydro-7 H -Indodo[7,1- fg [1,7] Chiral separation of naphthidine Racemic 2-chloro-8-methyl-7a,8,9,10-tetrahydro-7 H -Indodo[7,1- fg [1,7] Naphthylidine was isolated into its enantiomers by preparation of chiral SFC (Chiralpak-IG 25 cm x 2 cm; isocratic method: 32% MeOH (0.1% diethylamine) / CO2: 100 bar, 60 mL / min; injection volume 0.75 mL, in methanol) 6 mg / mL.

[0307] 2-Chloro-8-methyl-7a,8,9,10-tetrahydro-7 H -Indodo[7,1- fg [1,7] Naphthylidine (Example 17A, first elution peak): Analytical chiral SFC 99.9% ee. R t =5.6 min (Chiralpak-IG 25 cm x 0.46 cm; isocratic method: 30% MeOH (0.1% diethylamine) / CO2; 100 bar, 3 mL / min). Yellow solid; LC-MS: m / z = 259.1 [M+H] + .

[0308] 2-Chloro-8-methyl-7a,8,9,10-tetrahydro-7 H -Indodo[7,1- fg [1,7] Naphthylidine (Example 17B, second elution peak): Analytical chiral SFC 99.8% ee. R t =7.8 min (Chiralpak-IG 25 cm x 0.46 cm; isocratic method: 30% MeOH (0.1% diethylamine) / CO2; 100 bar, 3 mL / min). Yellow solid; LC-MS: m / z = 259.1 [M+H] + .

[0309] Example 18: l-chloro-8-methyl-7a,8,9,10-tetrahydro-7 H -Indodo[7,l-] fg [1,7]Naphthyl for and (3-(6-chloro-1) H -indol-7-yl)-1-methyl-1,2,5,6-tetrahydropyridin-2-yl)methanol Following general procedure 2, (3-bromo-1-methyl-1,2,5,6-tetrahydropyridin-2-yl)methanol (1.46 mmol) was used to prepare (3-(6-chloro-1) H (-indol-7-yl)-1-methyl-1,2,5,6-tetrahydropyridin-2-yl)methanol (270 mg, 67%) was purified by silica gel column chromatography to give brown foam (gradient: 90:10:1 to 85:15:1, DCM / MeOH / NH4OH). 1 H NMR (400MHz, CDCl3) δ = 9.33 (s, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.18 (t, J = 2.8 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 6.55 – 6.46 (m, 1H), 5.98 (d, J = 6.2 Hz, 1H), 3.66(dd, J = 11.2, 3.2 Hz, 2H), 3.32 (s, 1H), 3.16 (d, J = 11.2 Hz, 1H), 3.01 (d, J =3.0 Hz, 1H), 2.79 (dt, J= 10.8, 5.4 Hz, 1H), 2.62 – 2.34 (m, 4H), 2.24 (d, J =17.3 Hz, 1H). 13 C NMR (100 MHz, CDCl3) δ = 136.85, 133.45, 130.29, 126.42,125.99, 125.49, 122.65, 120.74, 120.43, 102.30, 65.18, 59.33, 50.36, 42.99,25.33. LRMS (ES + ) m / z [M + H] + C 15 H 18 ClN2O + = Calculated value 277.11; Measured value 277.35.

[0310] 1-Chloro-8-methyl-7a,8,9,10-tetrahydro-7 H -Indodo[7,1- fg [1,7]Naphthyl Following general procedure 3, (3-(6-chloro-1) H Preparation of 1-chloro-8-methyl-7a,8,9,10-tetrahydropyridin-7a)-1-methyl-1,2,5,6-tetrahydropyridin-2-yl)methanol (0.485 mmol) H -Indodo[7,l-fg][l,7]naphthidine (0.091 g, 73%) was purified by silica gel column chromatography (EtOAc) to obtain a brown oil. 1 H NMR (400 MHz, CDCl3) δ = 7.34 (d, J = 8.4 Hz, 1H), 7.12 – 7.08 (m, 1H), 7.07 (d, J = 8.4 Hz, 1H), 7.05 (d, J = 3.04 Hz, 1H), 6.43 (d, J = 3.04 Hz, 1H), 4.57 (dd, J = 11.4, 5.2Hz, 1H), 3.87 (t, J = 11.12 Hz, 1H), 3.37 – 3.28 (m, 1H), 2.98 – 2.91 (m, 1H), 2.66 (td, J= 10.4, 3.84 Hz, 1H), 2.61 – 2.49 (m, 4H), 2.46 – 2.36 (m, 1H) ppm. 13 C NMR (100 MHz, CDCl3) δ = 133.9, 128.3, 127.6, 126.7, 124.9, 123.2, 122.9,119.9, 117.3, 101.2, 59.9, 51.2, 48.9, 44.5, 26.1 ppm. LRMS (ES + ) m / z [M + H] + C 15 H 16 ClN2 + = Calculated value 259.10; Measured value 259.28.

[0311] 1-Chloro-8-methyl-7a,8,9,10-tetrahydro-7 H -Indodo[7,1- fg [1,7] Chiral separation of naphthidine Racemic 1-chloro-8-methyl-7a,8,9,10-tetrahydro-7 H -Indodo[7,1- fg [1,7] Naphthidine was isolated into its enantiomers by preparation of a chiral SFC (Chiralpak-IG 25 cm x 2 cm; isocratic method: 30% MeOH (0.1% diethylamine) / CO2; 100 bar, 60 mL / min; injection volume 0.75 mL, 5 mg / mL in MeOH).

[0312] 1-Chloro-8-methyl-1-7a,8,9,10-tetrahydro-7 H -Indodo[7,1- fg [1,7] Naphthylidine (Example 18A, first elution peak): Analytical chiral SFC > 99.9% ee. R t =3.9 min (Chiralpak-IG 25 cm x 0.46 cm; isocratic method: 30% MeOH (0.1% diethylamine) / CO2; 100 bar, 3 mL / min). Yellow solid; LC-MS: m / z = 259.1 [M+H] + .

[0313] 1-Chloro-8-methyl-1-7a,8,9,10-tetrahydro-7 H -Indodo[7,1- fg[1,7] Naphthylidine (Example 18B, second elution peak): Analytical chiral SFC > 99.9% ee. R t =5.7 min (Chiralpak-IG 25 cm x 0.46 cm; isocratic method: 30% MeOH (0.1% diethylamine) / CO2; 100 bar, 3 mL / min). Yellow solid; LC-MS: m / z = 259.1 [M+H] + .

[0314] Example 19: 6a((7aS,10R)-5,8,10-trimethyl-7a,8,9,10-tetrahydro-7H-indolo[7,1-fg] Synthesis of [1,7]naphthidine: Using an alternative universal procedure 3, Int-5a (250 mg, 0.924 mmol, 1.00 equiv) was converted to 6a, followed by purification by column chromatography to give 80 mg (34%) of the title compound as a pale yellow semi-solid. ESI-MS m / z: 253.2 [M+H] + .

[0315] Example 20: Synthesis of 7a & 8a: 80 mg of racemic 6a was purified using Chiral Pak AD-H (20 mm × 250 mm, 5 µ). Mobile phase A: 0.1% isopropylamine in n-hexane, mobile phase B: ETOH, mobile phase A:B-90:10, flow rate: 20 mL / min. The faster eluting peak was designated as 7a, and the slower eluting peak was designated as 8a.

[0316] 7a: 15 mg, ESI-MS m / z: =253.2 [M+H] + ; 1 H NMR (400 MHz, methanol-) d 4) δ = 7.31 -7.26 (m, 1H), 7.15 (d, J = 7.3 Hz, 1H), 6.96 - 6.92 (m, 1H), 6.29 (s, 1H), 6.13(d, J = 0.9 Hz, 1H), 4.72 (dd, J = 5.5, 11.1 Hz, 1H), 3.50 (t, J = 11.1 Hz, 1H),3.29 - 3.24 (m, 1H), 3.08 - 3.02 (m, 1H), 2.75 (m,J = 3.5, 5.4, 7.0, 8.8 Hz,1H), 2.59 (s, 3H), 2.43 (d, J = 0.9 Hz, 3H), 2.21 (t, J = 10.9 Hz, 1H), 1.09 (d, J = 7.0 Hz, 3H) ppm.

[0317] 8a: 16 mg, ESI-MS m / z: 253.2 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ = 7.27 (d, J = 7.6 Hz, 1H), 7.12 (d, J = 7.1 Hz, 1H), 6.94 - 6.90 (m, 1H), 6.25 (s, 1H), 6.14 (d, J = 0.8 Hz, 1H), 4.72 - 4.68 (m, 1H), 3.45 - 3.40 (m, 1H), 3.17 - 3.11(m, 1H), 2.97 - 2.93 (m, 1H), 2.68 - 2.62 (m, 1H), 2.52 - 2.51 (m, 3H), 2.43- 2.40 (m, 3H), 2.09 - 2.04 (m, 1H), 1.01 (d, J = 7.0 Hz, 3H) ppm.

[0318] Example 21: 6b ((7aS,10R)-3-chloro-2-fluoro-8,10-dimethyl-7a,8,9,10-tetrahydro-7H-indole Synthesis of [7,1-fg][1,7]naphthidine Int-5b (120 mg, 0.389 mmol, 1.00 equiv) was converted to 6b using the alternative general procedure 3, and purified by column chromatography to give 28 mg (25%) of the title compound as a pale yellow gelatinous solid. ESI-MS m / z: 291.0 [M+H] + .

[0319] Example 22: Synthesis of 7b & 8b: 25 mg of racemic 6b was passed through an AD-H column (20 x 250 g / L). Purification was performed using hexane (5 µm) as mobile phase A and ethanol as mobile phase B. The eluent ratio was A:B:90:10, and the total flow rate was 20 mL / min. The faster eluting peak was designated as 7b, and the slower eluting peak was designated as 8b.

[0320] 7b: 4 mg, ESI-MS m / z: 291.3 [M+H] + ;H NMR (400 MHz, DMSO- d 6) δ = 7.52 (d, J =3.0 Hz, 1H), 7.31 (d, J = 10.8 Hz, 1H), 6.47 (d, J = 3.0 Hz, 1H), 6.44 (s, 1H), 4.87 (dd, J = 5.4, 11.8 Hz, 1H), 3.59 (t, J = 11.3 Hz, 1H), 3.19 - 3.15 (m, 1H), 2.96 (dd, J = 5.4, 11.2 Hz, 1H), 2.46 - 2.44 (m, 3H), 2.39 - 2.39 (m, 1H), 2.07(t, J = 10.6 Hz, 1H), 1.01 (d, J = 7.1 Hz, 3H) 8b: 4 mg, ESI-MS m / z: 291.3 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ = 7.52 (d, J = 3.1 Hz, 1H), 7.31 (d, J = 10.8 Hz, 1H), 6.48 - 6.44 (m, 2H), 4.87 (dd, J = 5.4, 11.8 Hz, 1H), 3.59 (t, J = 11.3 Hz, 1H), 3.20 - 3.13 (m, 2H), 2.96 (br dd, J =5.3, 10.4 Hz, 1H), 2.46 - 2.45 (m, 3H), 2.11 - 2.04 (m, 1H), 1.02 (d,J = 7.1Hz, 3H) ppm.

[0321] Example 23: 6c ((7aS,10R)-2-chloro-3-fluoro-8,10-dimethyl-7a,8,9,10-tetrahydro-7 H -Indole Synthesis of [7,1-fg][1,7]naphthidine: Int-5c (130 mg, 0.422 mmol, 1.00 equiv) was converted to 6c using the alternative general procedure 3, and purified by column chromatography to give 30 mg (25%) of the title compound as a pale yellow gelatinous solid. ESI-MS m / z: 291.0 [M+H] + .

[0322] Example 24: Synthesis of 7c & 8c: 30 mg of racemic 6c was purified by IG column (10 × 250 mm, 5 µm). Mobile phase A was 0.1% IP Amin in n-hexane, and mobile phase B was ETOH. The eluent ratio was A:B:99:01. The total flow rate was 8 mL / min. The faster eluting peak was designated as 7c, and the slower eluting peak was designated as 8c.

[0323] 7c: 7 mg, ESI-MS m / z: 291.3 [M+H] + ;H NMR (400 MHz, DMSO- d 6) δ = 7.47 -7.46 (m, 1H), 7.33 (s, 1H), 6.51 (d, J = 3.0 Hz, 1H), 6.39 (s, 1H), 4.87 (br d, J = 6.5 Hz, 1H), 3.59 (s, 1H), 3.15 - 3.12 (m, 1H), 2.95 (br d, J = 5.8 Hz, 1H), 2.63 (br d, J = 3.6 Hz, 1H), 2.44 (s, 3H), 2.06 (s, 1H), 1.02 (s, 3H) ppm.

[0324] 8c: 7 mg, ESI-MS m / z: 291.3 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ = 7.46 (d,J = 3.0 Hz, 1H), 7.34 (br d, J = 6.1 Hz, 1H), 6.52 (d, J = 3.0 Hz, 1H), 6.39 (br s,1H), 4.87 (br dd, J = 5.3, 11.6 Hz, 1H), 3.59 (br t, J = 11.4 Hz, 1H), 3.20 -3.11 (m, 1H), 2.95 (br dd, J = 5.3, 10.6 Hz, 1H), 2.65 - 2.57 (m, 1H), 2.46 -2.42 (m, 3H), 2.06 (br t, J = 10.5 Hz, 1H), 1.01 (d, J = 7.0 Hz, 3H) ppm.

[0325] Example 25: 6d((7aSJ0R)-2,3-difluoro-8,10-dimethyl-7a,8,9,10-tetrahydro-7H-indole Synthesis of [7,l-fg][1,7]naphthidine: Int-5d (130 mg, 0.445 mmol, 1.00 equiv) was converted to 6d using the alternative general procedure 3 and purified by column chromatography to give 20 mg (14%) of the title compound as a pale yellow gelatinous solid. ESI-MS m / z: 275.36 [M+H] + .

[0326] Example 26: Synthesis of 7d & 8d: 20 mg of the racemic mixture was purified by IG column (10 × 250 mm, 5 µm) on day 6. Mobile phase A: n-hexane; Mobile phase B: MEOH : ETOH (1:1); Elution buffer A: B: 90-10; Total flow rate (mL / min): 5 mL / min. The faster elution peak was designated as day 7, and the slower elution peak was designated as day 8.

[0327] 7d: 8 mg, ESI-MS m / z: 274.9 [M+H] + ; 1 H NMR (400 MHz, chloroform-) d 6) δ = 7.11 -7.04 (m, 2H), 6.53 (d, J= 3.0 Hz, 1H), 6.18 (s, 1H), 4.62 (dd, J = 5.3, 11.3 Hz, 1H), 3.75 (t, J = 11.1 Hz, 1H), 3.28 - 3.22 (m, 1H), 2.98 (dd, J = 5.2, 11.1 Hz,1H), 2.79 - 2.70 (m, 1H), 2.54 (s, 3H), 2.17 (t, J = 10.7 Hz, 1H), 1.07 (d, J =7.1 Hz, 3H) ppm.

[0328] 8d: 8 mg, ESI-MS m / z: 274.9 [M+H] + ; 1 ¹H NMR (400 MHz, chloroform-d) δ = 7.13 -7.05 (m, 2H), 6.56 - 6.51 (m, 1H), 6.18 (s, 1H), 4.62 (dd, J = 5.3, 11.3 Hz, 1H), 3.75 (t, J = 11.2 Hz, 1H), 3.28 - 3.22 (m, 1H), 2.99 (dd, J = 5.2, 11.1 Hz,1H), 2.74 (br d, J = 3.1 Hz, 1H), 2.54 (s, 3H), 2.18 (t, J = 10.7 Hz, 1H), 1.07(d, J = 7.1 Hz, 3H) ppm.

[0329] Example 27: Synthesis of 6e ((7aS, 10R)-3,8,10-trimethyl-7a,8,9,10-tetrahydro-7H-indolo[7, Synthesis of 1-fg][1,7]naphthidine: Using an alternative general procedure 3, Int-5e (250 mg, 0.925 mmol, 1.00 eq) was converted to 6e, and purified by column chromatography to give 70 mg (30%) of the title compound as a pale yellow semi-solid. ESI-MS m / z: 252.4 [M+H] + .

[0330] Example 28: Synthesis of 7e & 8e: 70 mg of the racemic int-6e was passed through a cellulose-3 column (20 x 250 mm). Purification was performed using a 5 µm (mm, 5 µm) mobile phase. Mobile phase A was hexane, and mobile phase B was ETOH-MEOH (1-1). Eluent A:B: 50-50. Total flow rate (mL / min): 20 mL / min. Peaks with faster elution rates were designated as 7e, and peaks with slower elution rates were designated as 8e.

[0331] 7e: 17.3 mg, ESI-MS m / z: 253.2 [M+H] + ; 1 H NMR (400 MHz, methanol-) d 4) δ = 7.18 -7.13 (m, 2H), 6.83 - 6.78 (m, 1H), 6.43 (d, J = 3.1 Hz, 1H), 6.26 (s, 1H), 4.81- 4.77 (m, 1H), 3.67 (t, J = 11.3 Hz, 1H), 3.29 - 3.24 (m, 1H), 3.09 - 3.01 (m,1H), 2.79 - 2.70 (m, 1H), 2.57 (s, 3H), 2.48 (s, 3H), 2.19 (t, J = 10.9 Hz, 1H), 1.08 (d, J = 7.0 Hz, 3H) ppm.

[0332] 8e: 17.1 mg, ESI-MS m / z: 253.3 [M+H] + ; 1 H NMR (400 MHz, methanol-) d 4) δ = 7.19 -7.13 (m, 2H), 6.83 - 6.76 (m, 1H), 6.43 (d, J = 3.1 Hz, 1H), 6.26 (s, 1H), 4.83- 4.78 (m, 1H), 3.67 (t, J = 11.3 Hz, 1H), 3.29 - 3.22 (m, 1H), 3.04 (dd, J=5.1, 11.0 Hz, 1H), 2.79 - 2.71 (m, 1H), 2.57 (s, 3H), 2.48 (s, 3H), 2.19 (t, J = 10.9 Hz, 1H), 1.08 (d, J = 7.1 Hz, 3H) ppm.

[0333] Example 29: 6f((7aS,10R)-2,8,10-trimethyl-7a,8,9,10-tetrahydro-7H-indolo[7,1-fg] Synthesis of [1,7]naphthidine: Using an alternative general procedure 3, Int-5f (100 mg, 0.370 mmol, 1.00 equiv) was converted to 6f and purified by column chromatography to give 30 mg (32%) of the title compound as a pale yellow semi-solid. ESI-MS m / z: 252.4 [M+H]+. Example 30: Synthesis of 7f & 8f 30 mg of the racemic 6f was purified by passing it through a Chiral Pak-IG column (30 mm x 250 mm, 5 µ). Mobile phase A: n-hexane. Mobile phase B: ETOH: MeOH (1:1), mobile phase A: B-80:20, flow rate: 42 mL / min. The faster elution peak was designated as 7f, and the slower elution peak was designated as 8f.

[0334] 7f: 8.5 mg, ESI-MS m / z 253.0 [M+H]+; 1 H NMR (400 MHz, DMSO-d6) δ = 7.27 -7.25 (m, 1H), 7.19 (s, 1H), 7.05 (s, 1H), 6.29 (d, J = 3.0 Hz, 1H), 6.27 (s,1H), 4.79 (dd, J = 5.4, 11.5 Hz, 1H), 3.55 (t, J = 11.3 Hz, 1H), 3.19 - 3.11 (m,1H), 2.95 (dd, J = 5.1, 11.0 Hz, 1H), 2.65 - 2.60 (m, 1H), 2.44 (s, 3H), 2.38(s, 3H), 2.05 (t, J = 10.6 Hz, 1H), 1.01 (d, J= 7.1 Hz, 3H) ppm.

[0335] 8f: 4 mg, ESI-MS m / z =253.0 [M+H]+; 1 H NMR (400 MHz, DMSO- d 6) δ = 7.26 (d, J = 3.0 Hz, 1H), 7.19 (s, 1H), 7.05 (s, 1H), 6.29 (d, J = 2.9 Hz, 1H), 6.28 -6.25 (m, 1H), 4.79 (dd, J = 5.4, 11.5 Hz, 1H), 3.55 (t, J = 11.3 Hz, 1H), 3.20 -3.10 (m, 1H), 2.95 (br dd, J = 5.1, 11.0 Hz, 1H), 2.65 - 2.58 (m, 1H), 2.44 (s,3H), 2.38 (s, 3H), 2.05 (br t, J = 10.6 Hz, 1H), 1.01 (d, J = 7.1 Hz, 3H) ppm.

[0336] Example 31: 6g of ((7aS,10R)-3-methoxy-8,10-dimethyl-7a,8,9,10-tetrahydro-7H-indole Synthesis of [7,1-fg][1,7]naphthidine: Using the alternative general procedure 3, Int-5g (200 mg, 0.699 mmol, 1.00 eq) was converted to 6g and purified by column chromatography to give 50 mg (26%) of the title compound as a pale yellow semi-solid. ESI-MS m / z: 269.58 [M+H]+.

[0337] Example 32: Synthesis of 7g & 8g: Pass 50 mg of racemic mixture (6 g) through an IG column (30 x 250 μm). Purification was performed using a flow rate of 5 µm (mm, 5 µm). Mobile phase A was hexane, mobile phase B was ETOH-MEOH, eluent A:B:60:40, and total flow rate (mL / min) was 42 mL / min. Peaks with faster elution rates were designated as 7 g, and peaks with slower elution rates were designated as 8 g.

[0338] 7g:15 mg,ESI-MS m / z: 269.3 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ = 7.21 (d, J = 3.0 Hz, 1H), 7.14 (d, J = 8.0 Hz, 1H), 6.50 (d, J = 8.0 Hz, 1H), 6.39 (d, J =3.0 Hz, 1H), 6.14 (s, 1H), 4.79 (dd, J = 5.3, 11.6 Hz, 1H), 3.86 (s, 3H), 3.55(t, J = 11.3 Hz, 1H), 3.14 - 3.08 (m, 1H), 2.93 (dd, J = 4.9, 11.1 Hz, 1H), 2.65- 2.58 (m, 1H), 2.44 (s, 3H), 2.04 (t, J = 10.6 Hz, 1H), 1.00 (d, J = 7.1 Hz, 3H)ppm。

[0339] 8g:18 mg,ESI-MS m / z: 269.3 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ = 7.21 (d, J = 3.0 Hz, 1H), 7.14 (d, J = 8.0 Hz, 1H), 6.50 (d, J = 8.0 Hz, 1H), 6.39 (d, J =3.0 Hz, 1H), 6.14 (s, 1H), 4.79 (dd, J = 5.4, 11.7 Hz, 1H), 3.86 (s, 3H), 3.55(t, J = 11.3 Hz, 1H), 3.14 - 3.09 (m, 1H), 2.93 (dd, J= 4.8, 10.8 Hz, 1H), 2.54- 2.53 (m, 1H), 2.45 - 2.44 (m, 3H), 2.04 (t, J = 10.6 Hz, 1H), 1.00 (d, J = 7.1Hz, 3H) ppm.

[0340] Example 33: 6h ((7aS,10R)-2-methoxy-8,10-dimethyl-7a,8,9,10-tetrahydro-7H-indole Synthesis of [7,1-fg][1,7]naphthidine: Using the alternative general procedure 3, 5h (180 mg, 0.629 mmol, 1.00 eq) was converted to Int-6h and purified by column chromatography to give 55 mg (33%) of the title compound as a pale yellow semi-solid. ESI-MS m / z: 269.58 [M+H]+.

[0341] Example 34: Synthesis of 7h & 8h: 55 mg of racemate was passed through an IG column (30X250) over 6 hours. Purification was performed using a 5 µm (mm) mobile phase. Mobile phase A consisted of 0.1% IPamine in n-hexane, and mobile phase B consisted of ETOH-MEOH (1-1). The eluent ratio was A:B:80:20. The total flow rate was 42 mL / min. Peaks with faster elution rates were designated at 7 h, and peaks with slower elution rates were designated at 8 h.

[0342] 7h: 8 mg, ESI-MS m / z: 269.6 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ = 7.30 -7.25 (m, 1H), 6.94 (d, J = 2.0 Hz, 1H), 6.87 (d, J = 2.0 Hz, 1H), 6.30 (d, J = 3.0Hz, 2H), 4.78 (dd, J = 5.3, 11.6 Hz, 1H), 3.77 - 3.74 (m, 3H), 3.54 (t, J = 11.3Hz, 1H), 3.17 - 3.11 (m, 1H), 2.95 (dd, J= 5.3, 11.0 Hz, 1H), 2.65 - 2.58 (m,1H), 2.44 (s, 3H), 2.05 (t, J = 10.6 Hz, 1H), 1.01 (d, J = 7.1 Hz, 3H) ppm.

[0343] 8h: 8 mg, ESI-MS m / z: 269.2 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ = 7.27 (d, J = 3.0 Hz, 1H), 6.94 (d, J = 2.0 Hz, 1H), 6.87 (d, J = 2.0 Hz, 1H), 6.30 (br d, J =2.9 Hz, 2H), 4.78 (dd, J = 5.3, 11.4 Hz, 1H), 3.76 (s, 3H), 3.54 (t, J = 11.3 Hz,1H), 3.17 - 3.12 (m, 1H), 2.95 (dd, J = 5.3, 10.6 Hz, 1H), 2.65 - 2.60 (m, 1H), 2.45 - 2.44 (m, 3H), 2.05 (t, J = 10.6 Hz, 1H), 1.01 (d, J = 7.1 Hz, 3H) ppm.

[0344] Example 35: 6i(7aS,10R)-4-fluoro-8,10-dimethyl-7a,8,9,10-tetrahydro-7H-indolo[7,1- Synthesis of fg][1,7]naphthidine: Using the alternative general procedure 3, Int-5i (250 mg, 0.912 mmol, 1.00 eq) was converted to 6i and purified by column chromatography to give 70 mg (30%) of the title compound as a pale yellow semi-solid. ESI-MS m / z: 257.32 [M+H]+.

[0345] Example 36: Synthesis of 7i & 8i: 70 mg of racemic 6i was passed through an AD-H column (20 x 250 mm, 5 µm) with MP(A) CO2 at 86.0 g / min and MP(B) cosolvent at 14.0 mL / min (ACN with AMM:IPA) (1:1). The total flow rate (mL / min) was 70 g - 20% - 100 bar. The faster elution peak was designated as 7i, and the slower elution peak was designated as 8i.

[0346] 7i: 12.3 mg, ESI-MS m / z: 257.3 [M+H]+; 1 H NMR (400 MHz, DMSO- d 6) δ = 7.39(d, J = 8.0 Hz, 1H), 7.34 (d, J = 2.9 Hz, 1H), 7.28 (d, J = 7.3 Hz, 1H), 7.04 (t, J =7.6 Hz, 1H), 6.33 (s, 1H), 4.69 (dd, J = 5.4, 11.5 Hz, 1H), 3.53 (t, J = 11.1 Hz,1H), 3.21 - 3.15 (m, 1H), 2.95 (dd, J = 5.3, 11.1 Hz, 1H), 2.65 - 2.60 (m, 1H), 2.45 - 2.42 (m, 3H), 2.07 (t, J = 10.6 Hz, 1H), 1.01 (d, J = 7.1 Hz, 3H) ppm.

[0347] 8i: 9.9 mg, ESI-MS m / z: 257.3 [M+H]+; 1 H NMR (400 MHz, DMSO- d 6) δ = 7.41 -7.38 (m, 1H), 7.35 (d, J = 2.9 Hz, 1H), 7.28 (d, J = 7.3 Hz, 1H), 7.04 (t, J = 7.6Hz, 1H), 6.34 (s, 1H), 4.69 (dd, J= 5.4, 11.6 Hz, 1H), 3.53 (t, J = 11.3 Hz,1H), 3.21 - 3.15 (m, 1H), 2.95 (dd, J = 4.8, 11.1 Hz, 1H), 2.65 - 2.60 (m, 1H), 2.45 - 2.43 (m, 3H), 2.06 (t, J = 10.5 Hz, 1H), 1.01 (d, J = 7.2 Hz, 3H) ppm.

[0348] Example 37: 6j ((7aS,10R)-4-chloro-8,10-dimethyl-7a,8,9,10-tetrahydro-7H-indolo[7,1- Synthesis of fg][1,7]naphthidine: Using the alternative general procedure 3, Int-5j (150 mg, 0.517 mmol, 1.00 eq) was converted to 6j and purified by column chromatography to give 40 mg (28%) of the title compound as a pale yellow semi-solid. ESI-MS m / z: 273.32 [M+H]+.

[0349] Example 38: Synthesis of 7j & 8j: 40 mg of racemic 6j was purified by passing it through an AD-H column (20 x 250 mm, 5 µm). The flow rates were: MP(A)CO2 86.0 g / min, MP(B) cosolvent 14.0 mL / min (ACN with AMM:IPA) (1:1), and total flow rate (mL / min) 70 g - 20% - 100 bar. The faster elution peak was designated as 7j, and the slower elution peak as 8j.

[0350] 7k: 9.8 mg, ESI-MS m / z: 273.2 [M+H]+; 1 H NMR (400 MHz, DMSO- d 6) δ = 7.51(s, 1H), 7.35 (d, J = 7.9 Hz, 1H), 7.32 (d, J = 7.3 Hz, 1H), 7.14 - 7.09 (m, 1H), 6.35 (s, 1H), 4.79 (dd, J = 5.4, 11.6 Hz, 1H), 3.58 (t, J= 11.3 Hz, 1H), 3.20 -3.13 (m, 1H), 2.95 (dd, J = 5.4, 11.0 Hz, 1H), 2.65 - 2.58 (m, 1H), 2.44 (s,3H), 2.07 (t, J = 10.6 Hz, 1H), 1.02 (d, J = 7.0 Hz, 3H) ppm.

[0351] 8j: 7.1 mg, 7.1 mg, ESI-MS m / z: 273.2 [M+H]+; 1 H NMR (400 MHz, DMSO- d 6) δ =7.53 - 7.50 (m, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 7.3 Hz, 1H), 7.14 -7.09 (m, 1H), 6.35 (s, 1H), 4.81 - 4.77 (m, 1H), 3.58 (t, J = 11.3 Hz, 1H), 3.17 (tdd, J = 3.5, 5.4, 7.3 Hz, 1H), 2.95 (dd, J = 5.1, 11.0 Hz, 1H), 2.66 -2.59 (m, 1H), 2.44 (s, 3H), 2.07 (t, J = 10.6 Hz, 1H), 1.02 (d, J = 7.1 Hz, 3H)ppm.

[0352] Example 39: Synthesis of 6k ((7aS,10R)-4,8,10-trimethyl-7a,8,9,10-tetrahydro-7H-indolo[7, Synthesis of 1-fg][1,7]naphthidine: Using the alternative general procedure 3, Int-5k (200 mg, 0.740 mmol, 1.00 equiv) was converted to 6k and purified by column chromatography to give 80 mg (30%) of the title compound as a pale yellow semi-solid. ESI-MS m / z: 253.3 [M+H]+.

[0353] Example 40: Synthesis of 7k and 8k: 80 mg of the racemic 6k was purified by passing it through a Chiarapulk-IC column (30 x 250 mm, 5 µm) with MP(A) CO2 at 63 g / min; MP(B) cosolvent at 37 mL / min (0.1% MeONH2 in EtOH); total flow rate (mL / min) 90 g - 30% -; 100 bar; diluent was EtOH + MeOH + 3 drops of THF. The faster eluting peak was identified as 7k, and the slower eluting peak was identified as 8k.

[0354] 7k: 12mg, ESI-MS m / z: 253.3 [M+H]+; 1 H NMR (400 MHz, DMSO- d 6) δ = 7.35 (d, J = 7.8 Hz, 1H), 7.20 (d, J = 7.3 Hz, 1H), 7.08 (d, J = 0.9 Hz, 1H), 6.97 (t, J = 7.6Hz, 1H), 6.27 (s, 1H), 4.73 (dd, J = 5.3, 11.4 Hz, 1H), 3.51 (t, J = 11.1 Hz,1H), 3.16 - 3.10 (m, 1H), 2.95 (dd, J = 5.2, 10.9 Hz, 1H), 2.65 - 2.60 (m, 1H), 2.46 - 2.44 (m, 3H), 2.26 - 2.23 (m, 3H), 2.06 (t, J = 10.6 Hz, 1H), 1.01 (d, J =7.1 Hz, 3H) ppm.

[0355] 8k: 13 mg, ESI-MS m / z: 253.3 [M+H]+; 1 H NMR (400 MHz, DMSO-d6) δ = 7.37 -7.32 (m, 1H), 7.20 (d, J = 7.3 Hz, 1H), 7.08 (d, J = 1.0 Hz, 1H), 6.97 (t, J= 7.6Hz, 1H), 6.27 (s, 1H), 4.76 - 4.71 (m, 1H), 3.51 (t, J = 11.2 Hz, 1H), 3.16 -3.11 (m, 1H), 2.95 (dd, J = 5.1, 11.2 Hz, 1H), 2.65 - 2.58 (m, 1H), 2.46 - 2.44(m, 3H), 2.25 (d, J = 0.9 Hz, 3H), 2.06 (t, J = 10.6 Hz, 1H), 1.01 (d, J = 7.1 Hz, 3H) ppm.

[0356] Example 41: Synthesis of 6l ((7aS,10R)-5-chloro-8,10-dimethyl-7a,8,9,10-tetrahydro-7H-indole) Synthesis of [7,1-fg][1,7]naphthidine: Using alternative general procedure 3, Int-5L (150 mg, 0.517 mmol, 1.00 eq) was converted to 6L and purified by column chromatography to give 50 mg (35%) of the title compound as a pale yellow semi-solid. ESI-MS m / z: 273.1 [M+H]+.

[0357] Example 42: Synthesis of 7l & 8l: 45 mg of the racemic mixture was purified by chiral CHIRALPAK AD-H (250 x 4.6 mm, 5 µm). Mobile phase A: IPAMINE in n-hexane; Mobile phase B: ETOH; A:B: 80:20; Flow rate: 1.0 mL / min; PDA: AD-H_013. The faster elution peak was designated as 7L, and the slower elution peak was designated as 8L.

[0358] 7l: 7 mg, ESI-MS m / z: 273.0 [M+H]+; 1 H NMR (400 MHz, METHA NOL- d 4) δ = 7.34(d, J = 7.9 Hz, 1H), 7.27 (d, J= 7.3 Hz, 1H), 7.07 - 7.03 (m, 1H), 6.40 (s, 1H), 6.36 (s, 1H), 4.81 - 4.79 (m, 1H), 3.52 - 3.46 (m, 1H), 3.37 - 3.34 (m, 1H),3.07 (dd, J = 5.0, 11.1 Hz, 1H), 2.79 - 2.72 (m, 1H), 2.63 - 2.58 (m, 3H), 2.23(t, J = 10.8 Hz, 1H), 1.10 (d, J = 7.1 Hz, 3H) 8l: 10 mg, ESI-MS m / z: 273.0 [M+H]+; 1 H NMR (400 MHz, METHANOL- d 4) δ = 7.38- 7.32 (m, 1H), 7.27 (d, J = 7.5 Hz, 1H), 7.08 - 7.02 (m, 1H), 6.42 - 6.34 (m,2H), 4.81 - 4.79 (m, 1H), 3.55 - 3.46 (m, 1H), 3.35 - 3.33 (m, 1H), 3.06 (dd, J = 5.2, 11.2 Hz, 1H), 2.80 - 2.71 (m, 1H), 2.60 (s, 3H), 2.22 (t, J = 10.9 Hz, 1H), 1.10 (d, J = 7.0 Hz, 3H) ppm.

[0359] Example 43: 6m ((7aS,10R)-8,10-dimethyl-7a,8,9,10-tetrahydro-7H-indolo[7,1-fg] Synthesis of [1,7]naphthyl-3-nitrile: Using the alternative general procedure 3, Int-5m (200 mg, 0.711 mmol, 1.00 eq) was converted to 6m and purified by column chromatography to give 45 mg (24%) of the title compound as a pale yellow semi-solid. ESI-MS m / z: 264.31 [M+H]+.

[0360] Example 44: Synthesis of 7m & 8m: 45 mg of racemic mixture 6 mg was passed through an IC3 column (20 x 250 nm). Purification was performed using a flow rate of 5 µm (mm). Mobile phase A: n-hexane, mobile phase B: ETOH-MEOH (1-1), eluent A:B:80:20, total flow rate (mL / min): 20 mL / min. Peaks with faster elution rates were designated as 7 µm, and peaks with slower elution rates were designated as 8 µm.

[0361] 7m: 8 mg, ESI-MS m / z: 264.2 [M+H]+; 1 H NMR (400 MHz, METHANOL- d 4) δ = 7.47- 7.40 (m, 2H), 7.39 - 7.35 (m, 1H), 6.59 - 6.54 (m, 2H), 4.94 - 4.90 (m,1H), 3.72 (t, J = 11.3 Hz, 1H), 3.38 - 3.34 (m, 1H), 3.09 - 3.05 (m, 1H), 2.83- 2.74 (m, 1H), 2.59 (s, 3H), 2.23 (t, J = 10.8 Hz, 1H), 1.11 (d, J = 7.1 Hz, 3H)ppm.

[0362] 8m: 8 mg, ESI-MS m / z: 264.2 [M+H]+; 1 H NMR (400 MHz, METHANOL- d 4) δ = 7.48- 7.42 (m, 2H), 7.39 - 7.35 (m, 1H), 6.59 - 6.54 (m, 2H), 4.94 - 4.90 (m,1H), 3.72 (t, J = 11.3 Hz, 1H), 3.37 - 3.34 (m, 1H), 3.07 (dd, J = 5.0, 11.3 Hz,1H), 2.83 - 2.74 (m, 1H), 2.60 - 2.56 (m, 3H), 2.23 (t, J = 10.8 Hz, 1H), 1.11(d, J = 7.1 Hz, 3H) ppm.

[0363] Example 45: Synthesis of 6n ((7aS,10R)-3-chloro-8,10-dimethyl-7a,8,9,10-tetrahydro-7H-indole) Synthesis of [7,1-fg][1,7]naphthidine: Using the alternative general procedure 3, Int-5n (200 mg, 0.689 mmol, 1.00 eq) was converted to 6n and purified by column chromatography to give 45 mg (24%) of the title compound as a pale yellow semi-solid. ESI-MS m / z: 273.20 [M+H]+.

[0364] Example 46: Synthesis of 7n & 8n: 45 mg of racemic 6n was passed through an IG column (30 x 250 μm). Purification was performed using a 5 μL solution (mm, 5 μL). Mobile phase A was IPAMINE in n-hexane; mobile phase B was DCM-IPA; eluent A:B: 95-05; total flow rate (mL / min) was 42 mL / min. The faster eluting peak was designated as 7n, and the slower eluting peak as 8n.

[0365] 7n: 6 mg, ESI-MS m / z: 273.2 [M+H]+; 1 H NMR (400 MHz, chloroform-) d ) δ = 7.17 (d, J =7.9 Hz, 1H), 7.11 (d, J = 3.0 Hz, 1H), 7.05 (d, J = 7.9 Hz, 1H), 6.53 (d, J = 3.0Hz, 1H), 6.27 (br s, 1H), 4.64 (br dd, J = 5.3, 11.1 Hz, 1H), 3.81 (br t, J =10.8 Hz, 1H), 3.33 - 3.24 (m, 1H), 3.06 - 2.97 (m, 1H), 2.82 - 2.71 (m, 1H), 2.57 (s, 3H), 2.20 (br t, J = 10.6 Hz, 1H), 1.08 (d, J = 7.0 Hz, 3H) ppm.

[0366] 8n: 8 mg, ESI-MS m / z: 273.2 [M+H]+; 1 1H NMR (400 MHz, chloroform M-)d ) δ = 7.17 (d, J = 7.9 Hz, 1H), 7.11 (d, J = 3.1 Hz, 1H), 7.05 (d, J = 7.9 Hz, 1H), 6.53 (d, J = 3.1Hz, 1H), 6.27 (s, 1H), 4.64 (dd, J = 5.4, 11.3 Hz, 1H), 3.80 (t, J = 11.1 Hz, 1H), 3.29 (br dd, J = 3.3, 5.6 Hz, 1H), 3.01 (br dd, J = 4.8, 10.9 Hz, 1H), 2.83- 2.71 (m, 1H), 2.56 (s, 3H), 2.20 (br t, J = 11.0 Hz, 1H), 1.08 (d, J = 7.1 Hz, 3H) ppm.

[0367] Example 47: Synthesis of 6o ((7aS,10R)-3-fluoro-8,10-dimethyl-7a,8,9,10-tetrahydro-7H-indole) Synthesis of [7,1-fg][1,7]naphthidine: Using the alternative general procedure 3, Int-5O (950 mg, 3.47 mmol, 1.00 eq) was converted to 6O and purified by column chromatography to give 390 mg (44%) of the title compound as a pale yellow semi-solid. ESI-MS m / z: 273.1 [M+H]+.

[0368] Example 48: Synthesis of 7o & 8o: 390 mg of racemic 6o was purified by chiral CHIRALPAK AD-H (250 x 4.6 mm, 5 µm). Mobile phase A: 0.1% IPAMINE in n-hexane; Mobile phase B: ETOH; A:B: 80:20; Flow rate: 1.0 mL / min; PDA: AD-H_013. The faster elution peak was designated as 7o, and the slower elution peak was designated as 8o.

[0369] 7o: 160 mg, ESI-MS m / z: 257.2 [M+H]+; 1 H NMR (400 MHz, CHLOR OFORM-d ) δ =7.18 - 7.14 (m, 1H), 7.05 (d, J = 3.1 Hz, 1H), 6.73 (dd, J = 8.1, 10.8 Hz, 1H),6.52 (d, J = 3.1 Hz, 1H), 6.21 (s, 1H), 4.64 (dd, J = 5.3, 11.3 Hz, 1H), 3.87 -3.75 (m, 1H), 3.34 - 3.26 (m, 1H), 3.04 - 2.97 (m, 1H), 2.83 - 2.70 (m, 1H),2.60 - 2.54 (m, 3H), 2.24 - 2.17 (m, 1H), 1.07 (d, J = 7.1 Hz, 3H) ppm。

[0370] 8o:120 mg,ESI-MS m / z: 257.2 [M+H]+; 1 H NMR (400 MHz, CHLORO FORM- d ) δ =7.18 - 7.13 (m, 1H), 7.06 (d, J = 3.1 Hz, 1H), 6.73 (dd, J = 8.0, 10.7 Hz, 1H),6.52 (d, J = 3.2 Hz, 1H), 6.22 (s, 1H), 4.64 (dd, J = 5.2, 11.2 Hz, 1H), 3.93 -3.67 (m, 1H), 3.39 - 3.19 (m, 1H), 3.08 - 2.89 (m, 1H), 2.87 - 2.70 (m, 1H),2.58 (br s, 3H), 2.28 - 2.12 (m, 1H), 1.08 (d, J = 7.1 Hz, 3H) ppm。

[0371] Example 49: Synthesis of 11p: Using an alternative universal procedure 3, Int-9p (50 mg, 0.18 mmol, 1.0 eq) was converted to 11p and purified by column chromatography to give 13 mg (27%) of the title compound. ESI-MS m / z: 257.2 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ = 7.40 (d, J = 2.9 Hz, 1H), 7.17 (dd, J = 2.2, 10.1 Hz, 1H), 7.09 (dd, J =2.2, 10.5 Hz, 1H), 6.39 (d, J = 3.1 Hz, 2H), 4.83 (dd, J = 5.4, 11.7 Hz, 1H), 3.57 (t, J = 11.3 Hz, 1H), 3.16 (dddd, J = 2.1, 3.5, 5.4, 10.9 Hz, 1H), 2.96 (dd, J = 5.2, 11.2 Hz, 1H), 2.53 - 2.52 (m, 1H), 2.45 (s, 3H), 2.06 (t, J = 10.6 Hz, 1H), 1.02 (d, J = 7.1 Hz, 3H) ppm.

[0372] Example 50: Synthesis of 12p: Using an alternative universal procedure 3, Int-10p (50 mg, 0.18 mmol, 1.0 eq) was converted to 12p and purified by column chromatography to give 15 mg (32%) of the title compound. ESI-MS m / z: 257.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ = 7.41 - 7.39 (m, 1H), 7.17 (dd, J = 2.2, 10.1 Hz, 1H), 7.09 (dd, J =2.1, 10.6 Hz, 1H), 6.39 (d, J= 2.9 Hz, 2H), 4.83 (dd, J = 5.4, 11.7 Hz, 1H), 3.59 - 3.54 (m, 1H), 3.16 (dddd, J = 2.1, 3.5, 5.3, 11.0 Hz, 1H), 2.96 (dd, J =5.4, 11.0 Hz, 1H), 2.69 - 2.62 (m, 1H), 2.45 (s, 3H), 2.06 (t, J = 10.6 Hz, 1H), 1.02 (d, J = 7.2 Hz, 3H) ppm.

[0373] Example 51: Synthesis of 11q: Using the alternative universal procedure 3, Int-9q (40 mg, 0.14 mmol, 1.0 eq) was converted to 11q and purified by column chromatography to give 7 mg (19%) of the title compound. ESI-MS m / z: 273.2 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ = 7.47 - 7.44 (m, 1H), 7.41 (d, J = 3.1 Hz, 1H), 7.24 (d, J = 1.6 Hz,1H), 6.42 - 6.39 (m, 2H), 4.84 (dd, J = 5.3, 11.7 Hz, 1H), 3.58 (t, J = 11.3 Hz,1H), 3.18 - 3.12 (m, 1H), 2.98 - 2.93 (m, 1H), 2.68 - 2.63 (m, 1H), 2.44 (s,3H), 2.06 (t, J = 10.6 Hz, 1H), 1.02 (d, J = 7.1 Hz, 3H) ppm.

[0374] Example 52: Synthesis of 12q: Using the alternative universal procedure 3, Int-l0q (40 mg, 0.18 mmol, 1.0 eq) was converted to 12q and purified by column chromatography to give 8 mg (21%) of the title compound. ESI-MS m / z: 273.2 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ = 7.46 - 7.43 (m, 1H), 7.41 (d, J = 2.9 Hz, 1H), 7.24 (d, J = 1.6 Hz,1H), 6.42 - 6.39 (m, 2H), 4.84 (dd, J = 5.4, 11.6 Hz, 1H), 3.61 - 3.55 (m, 1H), 3.17 - 3.12 (m, 1H), 2.96 (dd, J = 5.3, 11.3 Hz, 1H), 2.68 - 2.62 (m, 1H), 2.44(s, 3H), 2.06 (t, J = 10.6 Hz, 1H), 1.02 (d, J = 7.2 Hz, 3H) ppm.

[0375] Example 53: 7r ((7aS,10R)-10-methyl-7,7a,9,10-tetrahydro-8H-indolo[7,1-fg][1,7]- Synthesis of naphthidine-8-nitrile: At 0 °C, cyanogen bromide (2.89 g, 27.3 mmol, 10.0 equiv) was added in portions over 20 min to a stirred solution of 6r (Example 2; 0.65 g, 2.7 mmol, 1.0 eq) in CH2Cl2 (20 vol), and the reaction mixture was stirred at ambient temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with cold water (10 mL) and extracted with DCM (2 x 10 mL). The combined organic layers were washed with an aqueous solution of NaCl (10 mL), dried over Na2SO4, filtered to remove the solid, and the filtrate was concentrated under vacuum to give the crude product. The crude product was purified by rapid column chromatography (25% EtOAc / hexane) to give 350 mg (51%) of 7r as an off-white solid. ESI-MS m / z: 249.9 [M+H] + .

[0376] Example 54: 8r ((7aS,10R)-N,N-diethyl-7a,8,9,10-tetrahydro-7H-indolo[7,1-fg][1, Synthesis of naphthidine-10-formamide: To a stirred solution of 7r (0.35 g, 1.4 mmol, 1.0 equiv), glacial acetic acid (16 mL), zinc powder (1.18 g, 8.2 mmol, 13.0 equiv), and water (1.2 mL) were added. The resulting mixture was bubbled with nitrogen and heated at 100 °C for 3 hours. The reaction mixture was diluted with EtOAc (10 mL) and quenched with saturated sodium bicarbonate solution (2 x 10 mL). The organic layer was separated, dried over anhydrous sodium sulfate, and then concentrated. The crude product was purified by rapid column chromatography (4% MeOH in DCM) to give 180 mg (57%) 8r as a colorless gel-like solid. ESI-MS m / z: 225.2 [M+H] + .

[0377] Example 55: Synthesis of 9r-a & 9r-b: 30 mg of racemic 8r was purified by chiral CHIRALPAK AD-H (250 x 4.6 mm, 5 µm). Mobile phase A: 0.1% IPAMINE in n-hexane; mobile phase B: ETOH; A:B: 80:20; flow rate: 1.0 mL / min; PDA: AD_H013. The faster elution peak was designated as 9r-a, and the slower elution peak was designated as 9r-b.

[0378] 9r-a: 10 mg, ESI-MS m / z: 225.2 [M+H]+; 1 ¹H NMR (400 MHz, methanol-d⁴) δ = 7.43–7.38 (m, ¹H), 7.26 (d, ¹H) J = 7.4 Hz, 1H), 7.17 (d, J = 3.1 Hz, 1H), 7.01 (t, J =7.6 Hz, 1H), 6.40 (d, J = 3.0 Hz, 1H), 6.36 - 6.33 (m, 1H), 4.48 - 4.43 (m,1H), 3.96 (dddd, J = 2.3, 3.4, 5.7, 11.3 Hz, 1H), 3.76 - 3.69 (m, 1H), 3.29 -3.24 (m, 1H), 2.71 - 2.61 (m, 1H), 2.61 - 2.53 (m, 1H), 1.09 (d, J= 6.9 Hz, 3H) ppm.

[0379] 9r-b: 10 mg, ESI-MS m / z: 225.2 [M+H]+; 1 H NMR (400 MHz, methanol-d4) δ = 7.41 (d, J = 7.8 Hz, 1H), 7.26 (d, J = 7.3 Hz, 1H), 7.17 (d, J = 3.1 Hz, 1H), 7.01 (t, J =7.6 Hz, 1H), 6.41 (d, J = 3.1 Hz, 1H), 6.35 (s, 1H), 4.46 (dd, J = 5.7, 11.2 Hz,1H), 3.97 (dddd, J = 2.3, 3.4, 5.7, 11.2 Hz, 1H), 3.77 - 3.70 (m, 1H), 3.27 (brd, J = 5.4 Hz, 1H), 2.72 - 2.62 (m, 1H), 2.60 - 2.54 (m, 1H), 1.10 (d, J = 7.0Hz, 3H) ppm.

[0380] D. Biological Examples Biological Example 1: Detection Radioligand binding assays (5-HT2AR and 5-HT2CR). Competitive radioligand binding assays for 5-HT2AR and 5-HT2CR were performed using standard methods by Epis Therapeutics SA (Belgium, FAST-0505B, FAST-0507B). Except for 5.35, which was used as a hydrochloride salt, all compounds were tested in free base form. In short, the assay was conducted using a combination of binding buffer, membrane extract, and radioactive tracer. 3Competitive binding was performed in duplicate in the wells of a 96-well plate (MasterBlock, Greiner, 786201) containing the DOI and the test compound. Non-specific binding was determined by co-incubation with a 200-fold excess of the non-radioactive (cold) DOI competitor. Samples were incubated in a final volume of 0.1 mL at temperatures and times optimized for either 5-HT2AR or 5-HT2CR, followed by filtration through a filter plate. The filter membrane was washed six times with 0.5 mL of ice-cold wash buffer (optimized for 5-HT2AR), and 50 μL of Microscint 20 (Packard) was added to each well. The plate was incubated on a track shaker for 15 min, followed by TopCount™ counting at 1 min / well.

[0381] Radioligand binding assay (5-HT2BR). The competitive radioligand binding assay for 5-HT2BR was performed by Eurofins Cerep SA (Celle l'Evescault, France) using standard methods (catalog number 1333). All compounds were tested in free base form, except for 5.35, which was used as hydrochloride. Cell membrane homogenates (10 μg protein) were incubated at room temperature with 0.2 nM [125I](±)DOI in a buffer containing 50 mM Tris-HCl (pH 7.4), 5 mM MgCl2, 10 μM pagyline, and 0.1% ascorbic acid for 60 min, with or without the test compound. Nonspecific binding was determined in the presence of 1 μM (±)DOI. After incubation, samples were rapidly filtered under vacuum through a 96-well cell collector (Unifilter, Packard) through a glass fiber filter (GF / B, Packard) pre-impregnated with 0.3% PEI, and washed several times with ice-cold 50 mM Tris-HCl. After drying the filter, radioactivity was counted using a scintillation counter (Topcount, Packard) with a scintillation solution (cocktail) (Microscint 0, Packard). Results are expressed as the percentage of inhibition of specific binding of the control radioligand. The standard reference compound was (±) DOI, which was tested at several concentrations in each experiment to obtain competition curves, from which its IC50 was calculated.

[0382] IP1 assays (5-HT2AR and 5-HT2CR). IPOne HTRF assays for 5-HT2AR and 5-HT2CR were performed by EpisTherapeutics SA (Belgium, FAST-05051, FAST-05071) using standard methods. All compounds were tested in their free base form, except for 5.35, which was used in its hydrochloride form. Briefly, CHO-K1 cells expressing recombinant human 5-HT2AR or 5-HT2CR were cultured in antibiotic-free medium to mid-log phase, separated with PBS-EDTA, centrifuged, and then resuspended in stimulation buffer.

[0383] For the agonist assay, 5 μl of the test compound or reference agonist (α-Me-5-HT) diluted in stimulation buffer was dispensed into the wells of a 384-well plate. Then, 5 μL of cell suspension (20,000 cells) was added, and the plate was incubated at 37 °C with 5% CO2 for 60 min. After adding lysis buffer containing 5 μl each of the IP1-d2 and anti-IP1 cryptate assay reagents, the plate was incubated at room temperature for 1 h, and the fluorescence ratio was measured using the HTRF kit according to the manufacturer's instructions.

[0384] For the antagonist test, 5 μL of solution containing a reference agonist (α-Me-5-HT, with a final concentration equal to its EC50) was applied. 80 The test compound or reference antagonist (ketoserin for 5-HT2AR, methysergide for 5-HT2CR) diluted in the corresponding stimulation buffer was dispensed into the wells of a 384-well plate. Then, 5 μL of cell suspension (20,000 cells) was added, and the plate was incubated at 37 °C with 5% CO2 for 60 min. After adding lysis buffer containing 5 μL each of the IP1-d2 and anti-IP1 crypt compound detection reagents, the plate was incubated at room temperature for 1 h, and then the fluorescence ratio was measured using the HTRF kit according to the manufacturer's instructions.

[0385] IP1 assay (5-HT2BR). The 5-HT2BR IP1 assay was performed by Eurofins Cerep SA (Celle l'Evescault, France) using standard methods (catalog number 3344). Except for 5.35, which used hydrochloride, all experiments were performed using free base. Cells were suspended in buffer containing 10 mM Hepes / NaOH (pH 7.4), 4.2 mM KCl, 146 mM NaCl, 1 mM CaCl2, 0.5 mM MgCl2, 5.5 mM glucose, and 50 mM LiCl, and then distributed into microplates at a density of approximately 20,000 cells / well.

[0386] For agonist assays, culture plates were incubated at 37 °C for 30 min in the presence of buffer (basal control), the test compound, or a reference agonist. For stimulation control measurements, individual wells contained 1 μM 5-HT. After incubation, cells were lysed, and the fluorescent receptor (D2-labeled IP1) and fluorescent donor (anti-IP1 antibody labeled with a europium cavitation compound) were added. After incubation at room temperature for 60 min, fluorescence transfer was measured at λex = 337 nm and λem = 620 and 665 nm using a microplate reader (Envision, PerkinElmer). The IP1 concentration was determined by dividing the signal measured at 665 nm by the signal measured at 620 nm (ratio). The results were expressed as the percentage inhibition of the response to the 1 μM 5-HT control. The standard reference agonist, 5-HT, was tested at multiple concentrations in each experiment to generate concentration-response curves, from which its EC50 value was calculated.

[0387] For the antagonist assay, the culture plate was pre-incubated at room temperature for 5 min in the presence of buffer (basal control), the test compound, or the reference antagonist. Subsequently, a final concentration of the reference agonist 5-HT was added. For the basal control measurement, the individual test wells did not contain 5-HT. After incubation at 37 °C for 30 min, cells were lysed, and the fluorescent receptor (D2-labeled IP1) and the fluorescent donor (anti-IP1 antibody labeled with a europium cavitation compound) were added. After incubation at room temperature for 60 min, fluorescence transfer was measured using a microplate reader (Envision, Perkin Elmer) at λex = 337 nm and λem = 620 and 665 nm. The IP1 concentration was determined by dividing the signal measured at 665 nm by the signal measured at 620 nm (ratio). The results are expressed as the percentage inhibition of the 30 nM 5-HT control response. The standard reference antagonist was SB 206553, which was tested at multiple concentrations in each experiment to generate concentration-response curves and calculate its IC50 value.

[0388] Table 1. Detection of radioligand binding affinity, IP1 accumulation (agonist effect), and IP1 agonist inhibition (antagonist effect) of 5-HT2A

[0389] Table 2. Detection of radioligand binding affinity, IP1 accumulation (agonist effect), and IP1 agonist inhibition (antagonist effect) of 5-HT2B

[0390] Table 3. Detection of radioligand binding affinity, IP1 accumulation (agonist effect), and IP1 agonist inhibition (antagonist effect) of 5-HT2C.

[0391] Although the foregoing invention has been described in considerable detail through embodiments and descriptions for ease of understanding, those skilled in the art will understand that certain changes and modifications can be made within the scope of the appended claims. Furthermore, each reference provided herein is incorporated herein by full citation as if it were cited individually. In the event of any conflict between this application and the references provided herein, this application shall prevail.

Claims

1. A compound or a pharmaceutically acceptable salt thereof having the structure of formula (J): (J) in: R 1a R 1b R 1c and R 1d Each independently is C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, halogen, C 1-6 Haloalkyl, C 1-6 Haloalkoxy groups, -NO2, or -CN; Or, two R atoms on adjacent ring atoms 1a Groups combine to form C 4-8 Cycloalkyl or 4- to 8-membered heterocycloalkyl having one or two heteroatoms that are each independently N, O or S; R 2 For H, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl or C 1-6 Halogenated alkoxy groups; R 3 It does not exist, or it is H or C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, C 1-6 Halogenated alkyl or C 1-6 Halogenated alkoxy groups; R 3a It does not exist, or it is C. 1-6 alkyl; Or, R 3 and R 3a Combining to form 3- to 8-membered heterocyclic alkyl groups having 1 to 2 heteroatoms that are each independently N, O, or S; The dashed keys a, b, and c are either nonexistent or independent keys; When the dashed key b is a key, R 3a It does not exist; The subscripts m and p are each independently 0, 1, or 2; and The subscripts n and r are each 0, 1, 2 or 3 independently.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, having the structure of formula (Ja): (Yes).

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, having the structure of formula (Ja-1): (And-1).

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, having the structure of formula (Jb): (Jb)。 5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R 2 For H, C 1-6 Alkyl, C 1-6 Alkoxyalkyl or C 1-6 Hydroxyalkyl.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R 2 It can be H, Me, or CH2OH.

7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 2 It can be Me or CH2OH.

8. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein each R 1a Independently for C 1-6 Alkyl, C 1-6 Alkoxy, halogen, C 1-6 Halogenated alkoxy or -CN.

9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein each R 1a Independently for C 1-6 Alkyl, C 1-6 Alkoxy or halogen.

10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein each R 1a Independently for C 1-3 Alkyl, C 1-3 Alkoxy or halogen.

11. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein each R 1a It can be Me, MeO, fluorine, or chlorine independently.

12. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein each R 1a It is a halogen.

13. The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein each R 1a It can be either fluorine or chlorine.

14. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, wherein n is 0, 1 or 2.

15. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, wherein n is 0.

16. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, wherein n is 1 or 2.

17. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, wherein n is 1.

18. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, wherein n is 2.

19. The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein each R 1b Independently for C 1-6 Alkyl, C 1-6 Alkoxy, halogen, C 1-6 Halogenated alkoxy or -CN.

20. The compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein each R 1b Independently for C 1-6 Alkyl, C 1-6 Alkoxy or halogen.

21. The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein each R 1b Independently for C 1-3 Alkyl, C 1-3 Alkoxy or halogen.

22. The compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein each R 1b It can be Me, MeO, fluorine, or chlorine independently.

23. The compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein each R b It is a halogen.

24. The compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein each R b It can be either fluorine or chlorine.

25. The compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein each R b C 1-3 alkyl.

26. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 25, wherein n is 0, 1 or 2.

27. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 26, wherein n is 0.

28. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 26, wherein n is 1 or 2.

29. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 26, wherein n is 1.

30. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 26, wherein n is 2.

31. The compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, wherein R 3 For H or C 1-6 alkyl.

32. The compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein R 3 C 1-6 alkyl.

33. The compound according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, wherein R 3 It is a methyl group.

34. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, having the structure of formula (II): (II)。 35. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, having the structure of formula (III): (III)。 36. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , or Or, or a pharmaceutically acceptable salt thereof.

37. A pharmaceutical composition comprising a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 36.

38. A method of treating a disease, comprising administering to a subject in need a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 36, thereby treating the disease.

39. The method of claim 38, wherein the disease is a neuropsychiatric disease.

40. The method of claim 39, wherein the neuropsychiatric disorder is schizophrenia.

41. The method of claim 39, wherein the neuropsychiatric disorder is bipolar disorder.

42. The method of claim 38, wherein the disease is depression.

43. The method of claim 38, wherein the disease is post-traumatic stress disorder (PTSD).

44. The method of claim 38, wherein the disease is anxiety disorder.

45. The method of claim 38, wherein the disease is a neurodegenerative disease.

46. ​​The method of claim 38, wherein the disease is Alzheimer's disease or Parkinson's disease.

47. The method of claim 38, wherein the disease is Alzheimer's disease.

48. The method of claim 38, wherein the disease is Parkinson's disease.

49. The method of claim 38, wherein the disease is a headache disorder.

50. The method of claim 38, wherein the disease is migraine.

51. The method of claim 38, wherein the disease is cluster headache.

52. The method of claim 38, wherein the disease is addiction.

53. The method of claim 38, wherein the disorder is a substance use disorder.

54. The method of claim 38, wherein the disorder is alcohol use disorder.

55. The method of claim 38, wherein the disease is an anxiety disorder, mood disorder, psychotic disorder, personality disorder, eating disorder, sleep disorder, sexual disorder, impulse control disorder, substance use disorder, dissociative disorder, cognitive disorder, developmental disorder, or affectation disorder.

56. The method of claim 38, wherein the disease is a psychotic disorder.

57. The method of claim 56, wherein the psychotic disorder is selected from schizophrenia, schizoaffective disorder, schizophrenia-like disorder, transient psychotic disorder, delusional disorder, shared psychotic disorder, substance-induced psychotic disorder, delusional dementia, psychotic depression, bipolar disorder, schizotypal personality disorder, paranoid personality disorder, schizotypal personality disorder, borderline personality disorder, post-traumatic stress disorder, obsessive-compulsive disorder and dissociative disorder, or psychosis associated with neurodegenerative diseases.

58. The method of claim 45, wherein the neurodegenerative disease is selected from Huntington's disease, Alzheimer's disease, Lewy body dementia, and Parkinson's disease.

59. The method of claim 56, wherein the psychotic disorder is schizophrenia or bipolar disorder.

60. A method for increasing neural plasticity, the method comprising contacting a neuronal cell with an amount sufficient to increase the neural plasticity of the neuronal cell with a compound of any one of claims 1 to 36 or a pharmaceutically acceptable salt thereof, wherein the compound produces a greater than 1.0-fold increase in the maximum number of dendritic crossings as determined by Shore analysis.

61. A method for increasing neural plasticity and dendritic spine density, the method comprising contacting a neuronal cell with an amount sufficient to increase the neural plasticity of the neuronal cell and increase the dendritic spine density of the neuronal cell, of any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof.

Images