Phenoxy and benzyloxy substituted psychoplastogens and uses thereof

Abstract

Disclosed herein are compounds, compositions, and methods for promoting neuronal growth and / or improving neuronal structure using the compounds and compositions disclosed herein.Also described are methods for treating diseases or disorders mediated by loss of synaptic connectivity and / or plasticity, such as neurological diseases and disorders, using phenoxy or benzyloxy substituted psychogenic factors.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Application No. 63 / 387,222, filed December 13, 2022, and U.S. Provisional Application No. 63 / 290,036, filed December 15, 2021, each of which is incorporated by reference in its entirety herein.

[0002] Described herein are compounds, methods of making the compounds, pharmaceutical compositions and formulations containing the compounds, and methods of using the compounds in the treatment of diseases, disorders, or conditions that would benefit from promoting neuronal growth and / or improving neuronal structure. [Background technology]

[0003] Alterations in synaptic connectivity and plasticity have been observed in the brains of individuals with neurological diseases and disorders. Psychoplastogens promote neuronal growth and improve neuronal structure through mechanisms involving activation of AMPA receptors, tropomyosin receptor kinase B (TrkB), and mammalian target of rapamycin (mTOR). Modulators of these biological targets, such as ketamine, scopolamine, N,N-dimethyltryptamine (DMT), and rapastinel, have demonstrated psychoplastogenic properties. For example, ketamine can correct deleterious changes in neuronal structure associated with neurological diseases and disorders. Such structural changes include, for example, loss of dendritic spines and synapses in the prefrontal cortex (PFC), as well as reduced complexity of dendritic arbor. Additionally, pyramidal neurons in the PFC exert top-down control over brain regions that control motivation, fear, and reward. Psychedelic psychoplastogens have demonstrated antidepressant, anti-anxiety, and anti-addiction effects in clinical practice. Summary of the Invention

[0004] In some embodiments, provided herein is a compound of formula (I), or a pharma- ceutically acceptable salt or solvate thereof:

[0005] [ka] During the ceremony, - R 1 , R 2 , R 3 and R 4 each independently represents hydrogen, halogen, -OR a , alkyl, heteroalkyl, aryl, arylalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, or heterocycloalkyl, wherein each of the alkyl, heteroalkyl, aryl, arylalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted; Or, R 1 and R 2 , R 2 and R 3 , or R 3 and R 4 taken together with the carbon atom to which they are attached form an optionally substituted 5- or 6-membered ring; - R 5 is hydrogen, alkyl, haloalkyl, cycloalkyl, or heterocycloalkyl, where each alkyl, haloalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted; - R 6 is hydrogen, alkyl, haloalkyl, cycloalkyl, or heterocycloalkyl, each of which is optionally substituted; and - R ais hydrogen, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, cycloalkyl, or heterocycloalkyl, where each alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted; Here, R 1 , R 2 , R 3 and R 4 At least one of OR a where R a is aryl or arylalkyl, each of which is optionally substituted; (i)R 1 , R 3 , R 4 , R 5 and R 6 are each hydrogen, R 2 is not phenoxy, (ii)R 2 , R 3 , R 4 , R 5 and R 6 are each hydrogen, R 1 is not phenoxy, and (iii)R 1 , R 3 , R 4 and R 6 are hydrogen, and R 5 is methyl, R 2 is not benzyloxy.

[0006] In some embodiments, provided herein is a compound of formula (II), or a pharma- ceutically acceptable salt or solvate thereof:

[0007] [ka] During the ceremony, - R 1is hydrogen, halogen, alkyl, heteroalkyl, aryl, arylalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, or heterocycloalkyl, where each of alkyl, heteroalkyl, aryl, arylalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted or R 1 OR a ` and R a ` is a substituted aryl or an optionally substituted arylalkyl; - R 2 is hydrogen, - R 3 and R 4 Each of the groups is independently hydrogen, halogen, -OR a , alkyl, heteroalkyl, aryl, arylalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, or heterocycloalkyl, each of which is optionally substituted or Or, R 1 and R 2 , R 2 and R 3 , or R 3 and R 4 taken together with the carbon atom to which they are attached form an optionally substituted 5- or 6-membered ring; - R 5 is hydrogen, alkyl, haloalkyl, cycloalkyl, or heterocycloalkyl, where each alkyl, haloalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted; - R 6 is hydrogen, alkyl, haloalkyl, cycloalkyl, or heterocycloalkyl, each of which is optionally substituted; and - Ra is hydrogen, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, cycloalkyl, or heterocycloalkyl, where each alkyl, haloalkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted; Here, (i) R 2 , R 3 and R 4 At least one of is aryloxy or arylalkyloxy, each of which is optionally substituted or or (ii) R 1 is a substituted aryloxy or an optionally substituted arylalkyloxy.

[0008] In one embodiment, provided herein is a pharmaceutical composition comprising a compound disclosed herein, or a pharma- ceutically acceptable salt or solvate thereof, and at least one pharma- ceutically acceptable excipient.

[0009] In some embodiments, the compounds disclosed herein, or a pharma- ceutically acceptable salt or solvate thereof, are formulated for administration to a mammal by intravenous, subcutaneous, oral, inhalation, intranasal, transdermal, or ophthalmic administration. In some embodiments, the compounds disclosed herein, or a pharma- ceutically acceptable salt or solvate thereof, are in the form of a tablet, pill, capsule, liquid, suspension, gel, dispersion, solution, emulsion, ointment, or lotion.

[0010] In one embodiment, a method of promoting neural cell growth in a mammal is described herein, comprising administering to the mammal a compound described herein, or any pharma- ceutically acceptable salt or solvate thereof.

[0011] In another aspect, described herein is a method of improving neuronal structure, the method comprising administering to a mammal a compound provided herein, or a pharma- ceutically acceptable salt or solvate thereof.

[0012] In another embodiment, the 5-hydroxytryptamine receptor 2A (5-HT 2A Described herein is a method of modulating the activity of a .ALPHA.-associated agonist (Ala) receptor, the method comprising administering to a mammal a compound provided herein, or any pharma- ceutically acceptable salt or solvate thereof.

[0013] In another embodiment, the 5-hydroxytryptamine receptor 2A (5-HT 2A Described herein is a method of treating a disease or disorder in a mammal mediated by the action of 5-hydroxytryptamine (5-HT) at the endothelial cell surface (ESC) in a mammal comprising administering to the mammal a compound provided herein, or any pharma- ceutical acceptable salt or solvate thereof.

[0014] In another aspect, described herein is a method of treating a disease or disorder in a mammal mediated by loss of synaptic connectivity, plasticity, or a combination thereof, comprising administering to the mammal a compound provided herein, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the disease or disorder is a neurological disease or disorder.

[0015] In another embodiment, described herein is a method for treating a neurological disease or disorder in a mammal, comprising administering to the mammal a compound represented by the structure of (I), or a pharma- ceutically acceptable salt or solvate thereof;

[0016] [ka] During the ceremony, - R 1 , R 2 , R 3 and R 4 each independently represents hydrogen, halogen, -OR a, alkyl, heteroalkyl, aryl, arylalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, or heterocycloalkyl, wherein each of the alkyl, heteroalkyl, aryl, arylalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted; Or, R 1 and R 2 , R 2 and R 3 , or R 3 and R 4 taken together with the carbon atom to which they are attached form an optionally substituted 5- or 6-membered ring; - R 5 is hydrogen, alkyl, haloalkyl, cycloalkyl, or heterocycloalkyl, where each alkyl, haloalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted; - R 6 is hydrogen, alkyl, haloalkyl, cycloalkyl, or heterocycloalkyl, each of which is optionally substituted; and - R a is hydrogen, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, cycloalkyl, or heterocycloalkyl, where each of the alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted; Here, R 1 , R 2 , R 3 and R 4 At least one of OR a where R a is aryl or arylalkyl, each of which is optionally substituted; (i)R 1 , R 3 , R 4 , R 5and R 6 are each hydrogen, R 2 is not phenoxy, (ii)R 2 , R 3 , R 4 , R 5 and R 6 are each hydrogen, R 1 is not phenoxy, and (iii)R 1 , R 3 , R 4 and R 6 are hydrogen, and R 5 is methyl, R 2 is not benzyloxy This is subject to the conditions.

[0017] In some embodiments, the neurological disease or disorder is a neurodegenerative disease, a neuropsychiatric disease, or a substance use disease or disorder.

[0018] In some embodiments, the neurological disease or disorder is trauma.

[0019] In some embodiments, the neurological disease or disorder is selected from the group consisting of an anxiety disorder, a mood disorder, a psychiatric disorder, a personality disorder, an eating disorder, a sleep disorder, a sexual desire disorder, an impulse control disorder, a substance use disorder, a dissociative disorder, a cognitive disorder, a developmental disorder, and factitious disorder.

[0020] In some embodiments, the mammal is a human.

[0021] In any of the foregoing aspects, in further embodiments, an effective amount of a compound described herein, or a pharma- ceutically acceptable salt thereof, is (a) administered systemically to the mammal, and / or (b) administered orally to the mammal, and / or (c) administered intravenously to the mammal, and / or (d) administered by injection to the mammal.

[0022] In any of the above aspects, further embodiments comprising a single administration of an effective amount of the compound include further embodiments in which the compound is administered to the mammal once a day, or in which the compound is administered to the mammal multiple times during the day. In some embodiments, the compound is administered on a continuous dosing schedule. In some embodiments, the compound is administered on a continuous daily dosing schedule.

[0023] An article of manufacture is provided that includes packaging material, a formulation within the packaging material (e.g., a formulation suitable for topical administration), and a label indicating that the compound or composition, or a pharma- ceutically acceptable salt or solvate thereof, is used to promote neuronal growth and / or improve neuronal structure, or for the treatment, prevention, or amelioration of one or more symptoms of a disease or disorder associated with promoting neuronal growth and / or improving neuronal structure.

[0024] Other objectives, features, and advantages of the compounds, methods, and compositions described herein will become apparent from the following detailed description. However, it will be understood that the detailed description and specific examples, while illustrating specific embodiments, are given by way of example only, since various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from the detailed description.

[0025] The present disclosure provides non-hallucinogenic compounds that are useful for increasing neuronal plasticity as well as for treating a variety of neurological diseases and disorders.

[0026] Psychedelic compounds promote structural and functional neuroplasticity in key circuits, elicit therapeutic responses in multiple neuropsychiatric disorders, and provide beneficial neurological effects that can persist for months after a single dose. Compounds that can modify neural circuits controlling motivation, anxiety, and drug-seeking behavior have the potential to treat neurological diseases and disorders that mediate loss of synaptic connectivity and / or plasticity. Furthermore, such compounds may provide sustained therapeutic effects, e.g., because they may treat underlying pathological changes in the circuits.

[0027] In some embodiments, 5-HT 2A The antagonist is 5-HT 2A It abolishes the neuritogenic and spine-forming effects of hallucinogenic compounds with agonistic activity, such as DMT, LSD, and DOI, and inhibits 5-HT 2A They have shown a correlation between agonism and the promotion of neuroplasticity (Ly et al., 2018; Dunlap et al., 2020). However, the hallucinogenic and dissociative potential of such compounds limits their use in the clinic for neurological disorders, e.g., neuropsychiatric disorders (Ly et al., 2018).

[0028] In addition, non-hallucinogenic analogs of psychedelic compounds, such as lisuride and sumatriptan, have been investigated as treatments for various neurological diseases and disorders, including, but not limited to, neurodegenerative diseases (e.g., Alzheimer's disease and Parkinson's disease) and headaches (e.g., migraines).

[0029] Specific Terms Unless otherwise specified, definitions of the following terms used in this application are provided below. It should be noted that, as used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. In this application, the use of "or" means "and / or" unless otherwise specified. The use of the term "including," as well as other forms such as "include," "includes," and "included," is not limiting. The paragraph headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described.

[0030] As used herein, C1-C x is C1-C2, C1-C3, ... C1-C x By way of example only, a group designated as "C1-C4" indicates that the moiety has from 1 to 4 carbon atoms (i.e., the group contains 1 carbon atom, 2 carbon atoms, 3 carbon atoms, or 4 carbon atoms). Thus, by way of example only, "C1-C4 alkyl" indicates that the alkyl group has from 1 to 4 carbon atoms, i.e., the alkyl group is selected from methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.

[0031] "Alkyl" generally refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, e.g., having from 1 to 15 carbon atoms (e.g., C1-C 15Alkyl). Unless otherwise specified, alkyl is saturated or unsaturated (e.g., alkenyl containing at least one carbon-carbon double bond). The disclosure provided herein of "alkyl" is intended to include the independent elaboration of saturated "alkyl" unless otherwise specified. The alkyl groups described herein are typically monovalent, but may be divalent (sometimes also referred to herein as "alkylene" or "alkylenyl" groups). In certain embodiments, alkyl contains 1 to 13 carbon atoms (e.g., C1-C 13 In certain embodiments, the alkyl comprises 1-8 carbon atoms (e.g., C1-C8 alkyl). In other embodiments, the alkyl comprises 1-5 carbon atoms (e.g., C1-C5 alkyl). In other embodiments, the alkyl comprises 1-4 carbon atoms (e.g., C1-C4 alkyl). In other embodiments, the alkyl comprises 1-3 carbon atoms (e.g., C1-C3 alkyl). In other embodiments, the alkyl comprises 1-2 carbon atoms (e.g., C1-C2 alkyl). In other embodiments, the alkyl comprises 1 carbon atom (e.g., C1 alkyl). In other embodiments, the alkyl comprises 5-15 carbon atoms (e.g., C5-C6 alkyl). 15In other embodiments, the alkyl group comprises 5-8 carbon atoms (e.g., C5-C8 alkyl). In other embodiments, the alkyl group comprises 2-5 carbon atoms (e.g., C2-C5 alkyl). In other embodiments, the alkyl group comprises 3-5 carbon atoms (e.g., C3-C5 alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), and 1-pentyl (n-pentyl). The alkyl is attached to the remainder of the molecule by a single bond. Generally, each alkyl group is independently substituted or unsubstituted. Each description of "alkyl" provided herein includes a specific and explicit description of an unsaturated "alkyl" group unless otherwise specified. Similarly, unless otherwise specified in the specification, alkyl groups may be selected from the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR x , -SR x , -OC(O)-R x , -N(R x )2, -C(O)R x , -C(O)OR x , -C(O)N(R x )2, -N(R x )C(O)OR x , -OC(O)-N(R x )2, -N(R x )C(O)R x , -N(R x )S(O) t R x (t is 1 or 2), -S(O) t OR x (t is 1 or 2), -S(O) t R x (t is 1 or 2), and -S(O) t N(R x )2 (t is 1 or 2), where R xEach of is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl). In some embodiments, the alkyl group is substituted with one or more fluorines.

[0032] An "alkylene" group refers to a divalent alkyl radical. Any of the above monovalent alkyl groups may be alkylene by removal of a second hydrogen atom from the alkyl. In some embodiments, the alkylene is a C1-C6 alkylene. In other embodiments, the alkylene is a C1-C4 alkylene. Typical alkylene groups include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and the like. Unless otherwise specified herein, alkylene groups are optionally substituted as described above for alkyl groups herein.

[0033] The term "alkenyl" refers to a type of alkyl group in which at least one carbon-carbon double bond is present. In one embodiment, an alkenyl group has the formula -C(R)=CR2, where R refers to the remainder of the alkenyl group, which may be the same or different. In some embodiments, R is H or alkyl. Non-limiting examples of alkenyl groups include -CH=CH2, -C(CH3)=CH2, -CH=CHCH3, -C(CH3)=CHCH3, and -CH2CH=CH2.

[0034] The term "alkynyl" refers to a type of alkyl group in which at least one carbon-carbon triple bond is present. In one embodiment, an alkenyl group has the formula -C≡CR, where R refers to the remainder of the alkynyl group. In some embodiments, R is H or alkyl. Non-limiting examples of alkynyl groups include -C≡CH, -C≡CCH3, -C≡CCH2CH3, -CH2C≡CH.

[0035] An "alkoxy" group refers to a (alkyl)O- group, where alkyl is as defined herein.

[0036] The term "alkylamine" refers to -NH(alkyl) or -N(alkyl).

[0037] The term "aromatic" refers to a planar ring having a delocalized π-electron system containing 4n+2 π electrons, where n is an integer. The term "aromatic" includes both carbocyclic aryl ("aryl", e.g., phenyl) and heterocyclic aryl (or "heteroaryl" or "heteroaromatic") groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups.

[0038] The term "carbocyclic" or "carbocycle" refers to a ring or ring system in which the atoms forming the backbone of the ring are all carbon atoms. The term thus distinguishes carbocycles from "heterocyclic" rings or "heterocycles" in which the ring backbone contains at least one atom different from carbon. In some embodiments, at least one of the two rings of a bicyclic carbocycle is aromatic. In some embodiments, both rings of a bicyclic carbocycle are aromatic. In certain embodiments, a carbocyclyl contains 3 to 10 carbon atoms. In other embodiments, a carbocyclyl contains 5 to 7 carbon atoms. A carbocyclyl is attached to the remainder of the molecule by a single bond. A carbocyclyl or cycloalkyl is saturated (i.e., contains only a single C-C bond) or unsaturated (i.e., contains one or more double or triple bonds). Examples of saturated cycloalkyl include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Unsaturated carbocyclyls are also referred to as "cycloalkenyls." Examples of monocyclic cycloalkenyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. As used herein, unless otherwise stated, the term “carbocyclyl” includes any of the following: alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —Ry -OR x , -R y -OC(O)-R x , -R y -OC(O)-OR x , -R y -OC(O)-N(R x )2, -R y -N(R x )2, -R y -C(O)R x , -R y -C(O)OR x , -R y -C(O)N(R x )2, -R y -OR z -C(O)(R x )2, -R y -N(R x )C(O)OR x , -R y -N(R x )C(O)R x , -R y N(R x )S(O) t R x (t is 1 or 2), -R y -S(O) t R x (t is 1 or 2), -R y -S(O) t OR x (t is 1 or 2) and -R y S(O) t N(R x t is 1 or 2, where R xare each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl); R y each independently a direct bond or a straight or branched alkylene or alkenylene chain, where R z is a straight or branched alkylene or alkenylene chain, wherein each of the above substituents is unsubstituted unless otherwise specified.

[0039] As used herein, the term "aryl" refers to an aromatic ring in which each of the atoms forming the ring is a carbon atom. An aromatic monocyclic or polycyclic hydrocarbon ring system contains only hydrogen and carbon from 5 to 18 carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., contains a cyclic delocalized (4n+2) π-electron system according to Huckel's theory. Ring systems from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin, and naphthalene. Unless otherwise stated in this specification, the term "aryl" or the prefix "ar-" (as in "aralkyl") can be any of the following: alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R y -OR x , -R y -OC(O)-R x , -R y -OC(O)-OR x , -R y -OC(O)-N(R x )2, -R y -N(R x )2, -R y -C(O)R x , -R y -C(O)OR x , -R y -C(O)(R x )2, -R y -OR z -C(O)N(R x )2, -R y -N(R x )C(O)OR x , -R y -N(R x )C(O)R x , -Ry -N(R x )S(O) t R x (t is 1 or 2), -R y -S(O) t R x (t is 1 or 2), -R y -S(O) t OR x (t is 1 or 2), and -R y -S(O) t N(R x )2 (where t is 1 or 2), where R x are each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl); each R is independently a direct bond or a straight or branched alkylene or alkenylene chain; and R z is a straight or branched alkylene or alkenylene chain, where each of the above substituents is unsubstituted unless otherwise specified.

[0040] An "aralkyl", "aryl-alkyl" or "arylalkyl" is a radical of the formula -Rz -aryl radical, R z is an alkylene chain as defined above, e.g., methylene, ethylene, etc. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

[0041] The term "cycloalkyl" refers to a monocyclic or polycyclic aliphatic non-aromatic radical in which each of the atoms forming the ring (i.e., skeletal atoms) is a carbon atom. In some embodiments, the cycloalkyl is a spirocyclic or bridged compound. In some embodiments, the cycloalkyl is optionally fused with an aromatic ring, and the point of attachment is at a carbon that is not an aromatic ring carbon atom. Cycloalkyl groups include groups having 3 to 10 ring atoms. In some embodiments, the cycloalkyl group is selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbornyl, and bicyclic[1.1.1]pentyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cisdecalin, transdecalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, adamantyl, norbornyl, and decalinyl. In some embodiments, the cycloalkyl is a C3-C6 cycloalkyl.

[0042] The term "halo", or alternatively "halogen" or "halide", means fluoro, chloro, bromo, or iodo. In some embodiments, halo is fluoro, chloro, or bromo. In some embodiments, halo is fluoro or chloro.

[0043] For example, the term "fluoroalkyl" refers to an alkyl in which one or more hydrogen atoms are replaced with a fluorine atom, such as trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. In some embodiments, the alkyl portion of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group. In one embodiment, the fluoroalkyl is a C1-C6 fluoroalkyl.

[0044] The term "heteroalkyl" refers to an alkyl group, as defined above, in which one or more skeletal carbon atoms of the alkyl are replaced with a heteroatom (with an appropriate number of substituents or valences - e.g., -CH2- may be replaced with -NH-, -S-, or -O-). For example, each substituted carbon atom is independently replaced with a heteroatom, e.g., carbon is replaced with nitrogen, oxygen, selenium, or other suitable heteroatom. In some embodiments, each substituted carbon atom is independently replaced with oxygen, nitrogen (e.g., with -NH-, -NS(alkyl)-, or -N(aryl)-, or another substituent as contemplated herein), or sulfur (e.g., with -S-, -S(=O)-, or -S(=O)2-). In some embodiments, the heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In some embodiments, the heteroalkyl is attached to the remainder of the molecule at a heteroatom of the heteroalkyl. In some embodiments, the heteroalkyl is a C1-C2 18 In some embodiments, heteroalkyl is C-C 12Heteroalkyl. In some embodiments, heteroalkyl is C1-C6 heteroalkyl. In some embodiments, heteroalkyl is C1-C4 heteroalkyl. In some embodiments, heteroalkyl is or includes one or more cyclic groups. In some embodiments, heteroalkyl includes alkylamino, alkylaminoalkyl, aminoalkyl, heterocycloalkyl, heterocycloalkyl, and heterocycloalkylalkyl, as defined herein. Unless otherwise specified herein, heteroalkyl groups are optionally substituted as defined above for alkyl groups. In one embodiment, heteroalkyl is C1-C6 heteroalkyl.

[0045] "Heteroalkylene" refers to a divalent heteroalkyl group, as defined above, that links one portion of the molecule to another portion of the molecule. Unless otherwise specified, the heteroalkylene is optionally substituted as defined above for an alkyl group.

[0046] The term "heterocyclyl", "heterocycle", or "heterocyclic" refers to aromatic heterocycles (also known as heteroaryls) and heterocycloalkyl rings (also known as heteroalicyclic groups) containing 1 to 4 heteroatoms in the ring, where each heteroatom in the ring is independently selected from O, S, and N, and each heterocyclic group in the ring has 3 to 10 atoms in its ring system, provided that no ring contains two adjacent O or S atoms. Unless otherwise specified herein, a heterocyclyl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which optionally includes fused or bridged ring systems. The heteroatoms in a heterocyclyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocyclyl radical is partially or fully saturated. Heterocyclyl radicals are saturated (i.e., contain only a single C-C bond) or unsaturated (e.g., contain one or more double or triple bonds in the ring system). In some embodiments, heterocyclyl radicals are saturated. In some embodiments, heterocyclyl radicals are both saturated and substituted. In some embodiments, heterocyclyl radicals are unsaturated. A heterocyclyl is attached to the remainder of the molecule by any atom of the ring. Non-aromatic heterocyclic groups (also known as heterocycloalkyls) include rings having 3-10 atoms in their ring system, and aromatic heterocyclic groups include rings having 5-10 atoms in their ring system. Heterocyclic groups include benzo-fused ring systems.Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithio ranyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl, indolin-2-onyl, isoindolin-1-onyl, isoindolin-1,3-dionyl, 3,4-dihydroisoquinolin-1(2H)-onyl, 3,4-dihydroquinolin-2(1H)-onyl, isoindolin-1,3-dithionyl, benzo[d]oxazol-2(3H)-onyl, 1H-benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl, and quinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The foregoing groups are C-bonded (or C-linked) or N-bonded where possible.For embodiments, the group derived from pyrrole includes pyrrol-1-yl (N-linked) or pyrrol-3-yl (C-linked). Additionally, the group derived from imidazole includes imidazol-1-yl or imidazol-3-yl (both N-linked), or imidazol-2-yl, imidazol-4-yl, or imidazol-5-yl (all C-linked). Heterocyclic groups include benzo-fused ring systems. Non-aromatic heterocycles are optionally substituted with one or two oxo (=O) moieties, such as pyrrolidin-2-one. In some embodiments, at least one of the two rings of the bicyclic heterocycle is aromatic. In some embodiments, both rings of the bicyclic heterocycle are aromatic. Unless otherwise defined in this specification, the term "heterocyclyl" includes the following: alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl. optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R y -OR x , -R y -OC(O)-R x , -R y -OC(O)-OR x , -R y -OC(O)-N(R x )2, -R y -N(R x )2, -R y -C(O)R x , -R y -CO)OR x , -R y -C(O)N(R x )2, -R y -OR z -CO(R x )2, -Ry -N(R x )C(O)OR x , -R y -N(R x )C(O)R x , -R y N(R x )S(O) t R x (t is 1 or 2), -R y -S(O) t R x (t is 1 or 2), -R y -S(O) t OR x (t is 1 or 2), and -R y -S(O) t N(R x )2 (where t is 1 or 2), where R x are each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl); each R is independently a direct bond or a straight or branched alkylene or alkenylene chain; zis a straight or branched alkylene or alkenylene chain, where each of the above substituents is unsubstituted unless otherwise specified.

[0047] "Heterocyclylalkyl" refers to a group of the formula -R z -heterocyclyl radical, R z is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkyl radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkyl radical is optionally substituted as defined above for a heterocyclyl group.

[0048] "Heterocyclylalkoxy" refers to a heterocyclic group of the formula -OR z - refers to a radical attached by an oxygen atom of a heterocyclyl, R z is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkoxy radical is optionally substituted as defined above for a heterocyclyl group.

[0049] The term "heteroaryl" or alternatively "heteroaromatic" refers to an aryl group containing one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. Illustrative examples of heteroaryl groups include monocyclic heteroaryls and bicyclic heteroaryls. Monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Bicyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments, the heteroaryl contains 0-4 N atoms in the ring. In some embodiments, the heteroaryl contains 1-4 N atoms in the ring. In some embodiments, the heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, the heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, the heteroaryl is a C1-C9 heteroaryl. In some embodiments, the monocyclic heteroaryl is a C1-C5 heteroaryl. In some embodiments, the monocyclic heteroaryl is a 5- or 6-membered heteroaryl. In some embodiments, the bicyclic heteroaryl is a C6-C9 heteroaryl.In this specification, unless otherwise stated, the term "heteroaryl" includes any of the following: alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R. y -OR x , -R y -OC(O)-R x , -R y -OC(O)-OR x , -R y OC(O)-N(R x )2, -R y -N(R x )2, -R y -C(O)R x , -R y -C(O)OR x , -R y -C(O)N(R x )2, -R y -OR z -C(O)N(R x )2, -R y -N(R x )C(O)OR x , -R y -N(R x )C(O)R x , -R y -N(R x )S(O) t R x (t is 1 or 2), -R y -S(O) t R x (t is 1 or 2), -R y -S(O) t OR x (t is 1 or 2), -R y S(O) t N(R xt is meant to include heteroaryl radicals as defined above optionally substituted by one or more substituents selected from x are each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each R is independently a direct bond or a straight or branched alkylene or alkenylene chain; and R z is a straight or branched alkylene or alkenylene chain, where each of the above substituents is unsubstituted unless otherwise specified.

[0050] "Heteroarylalkyl" means a heteroaryl group of the formula -R z - refers to the heteroaryl radical, R zis an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.

[0051] "Heteroarylalkoxy" means a heteroaryl group represented by the formula -OR z - refers to a radical attached by an oxygen atom of a heteroaryl, R z is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkoxy radical is optionally substituted as defined above for a heteroaryl group.

[0052] A "heterocycloalkyl" or "heteroalicyclic" group refers to a cycloalkyl group containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl is fused with an aryl or heteroaryl. In some embodiments, the heterocycloalkyl is oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidin-2-onyl, pyrrolidine-2,5-dithionyl, pyrrolidine-2,5-dionyl, pyrrolidinonyl, imidazolidinyl, imidazolidin-2-onyl, or thiazolidin-2-onyl. The term heteroalicyclic also includes all cyclic forms of carbohydrates, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. In one embodiment, the heterocycloalkyl is a C2-C 10 In another embodiment, the heterocycloalkyl is a C4-C 10 Heterocycloalkyl. In some embodiments, a heterocycloalkyl contains 0-2 N atoms in the ring. In some embodiments, a heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms, and 0-1 S atoms in the ring.

[0053] The term "bond" or "single bond" refers to a chemical bond between two atoms or two moieties when the atoms connected by the bond are considered to be part of a larger substructure. In one embodiment, when a group described herein is a single bond, the referenced group is not present, thereby allowing for the formation of a bond between the remaining specified groups.

[0054] The term "moiety" refers to a specific segment or functional group of a molecule. A chemical moiety is often considered to be a chemical entity embedded in or attached to a molecule.

[0055] In general, each optionally substituted group is independently substituted or unsubstituted. Each description of an optionally substituted group provided herein includes an independent and explicit description of both the unsubstituted and substituted groups (e.g., substituted in certain embodiments and unsubstituted in other certain embodiments) unless otherwise specified. Unless otherwise specified, substituted groups provided herein (e.g., substituted alkyl) are substituted with one or more substituents, each of which may be any of the following: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR, -O- ... x , -SR x , -OC(O)-R x , -N(R x )2, -C(O)R x , -C(O)OR x , -C(O)N(R x )2, -N(R x )C(O)OR x , -OC(O)-N(R x )2, -N(R x )C(O)R x , -N(R x )S(O) t R x (t is 1 or 2), -S(O) t OR x (t is 1 or 2), -S(O) t N(R x t is 1 or 2, xare each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl). In some other embodiments, the optional substituents are independently selected from halogen, -CN, -NH, -NH(CH), -N(CH), -OH, -COH, -CO(C-C alkyl), -C(=O)NH, -C(=O)NH(C-C alkyl), -C(=O)N(C-C alkyl), -S(=O)NH, -S(=O)NH(C-C alkyl), -S(=O)N(C-C alkyl), C-C alkyl, C-C cycloalkyl, C-C fluoroalkyl, C-C heteroalkyl, C-C alkoxy, C-C fluoroalkoxy, -SC-C alkyl, -S(=O)C-C alkyl, and -S(=O)C-C alkyl. In some embodiments, optional substituents are independently selected from halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CF3, -OCH3, and -OCF3. In some embodiments, substituted groups are substituted with one or two of the foregoing groups. In some embodiments, optional substituents on aliphatic carbon atoms (acyclic or cyclic) include oxo (=O).

[0056] As used herein, the term "acceptable" with respect to a formulation, composition, or ingredient means having no lasting deleterious effects on the health status of the subject being treated.

[0057] The term "modulate" as used herein means to directly or indirectly interact with a target to alter the activity of the target, including, by way of example only, enhancing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or expanding the activity of the target. In some embodiments, "modulate" means to directly or indirectly interact with a target to reduce or inhibit receptor activity. In some embodiments, modulation is an increase or decrease in the amount, quality, or effect of a particular activity, function, or molecule. By way of example and not limitation, modulation of G protein-coupled receptors (e.g., 5HT 2A ) agonists, partial agonists, antagonists, and allosteric modulators (eg, positive allosteric modulators) are modulators of the receptor.

[0058] The term "modulator" as used herein refers to a molecule that interacts directly or indirectly with a target. The interaction includes, but is not limited to, agonist, partial agonist, inverse agonist, antagonist, or combinations thereof. In some embodiments, the modulator is an antagonist. A receptor antagonist is an inhibitor of receptor activity. An antagonist mimics a ligand that binds to a receptor and prevents receptor activation by the natural ligand. Preventing activation can have many effects. Whereas a natural agonist that binds to a receptor leads to increased cell function, an antagonist that binds to and blocks this receptor reduces receptor function.

[0059] The term "agonism," as used herein, refers to the activation of a receptor or enzyme by a modulator, i.e., an agonist, to produce a biological response.

[0060] The term "agonist," as used herein, generally refers to a modulator that binds to and activates a receptor or enzyme to produce a biological response. By way of example only, "5HT 2A "Agonists" are those that exert an effect on 5HT levels of approximately 100 μM or less. 2A EC for activity 50 In some embodiments, the term "agonist" includes full agonists or partial agonists. A "full agonist" refers to a modulator that binds to and activates a receptor with the maximal response that an agonist can elicit at the receptor. A "partial agonist" refers to a modulator that binds to and activates a given receptor but has partial efficacy at the receptor, i.e., less than the maximal response, compared to a full agonist.

[0061] The term "positive allosteric modulator," as used herein, generally refers to a modulator that binds to a site other than the orthosteric binding site and enhances or potentiates the effect of an agonist.

[0062] The term "antagonism," as used herein, generally refers to the inactivation of a receptor or enzyme by a modulator, i.e., an antagonist. Receptor antagonism, for example, is when a molecule binds to a receptor and blocks the function of the receptor.

[0063] The term "antagonist" or "neutral antagonist" as used herein generally refers to a modulator that binds to a receptor or enzyme and blocks a biological response. An antagonist may have no activity in the absence of an agonist or inverse agonist, but may block either activity such that the biological response is unchanged.

[0064] As used herein, the terms "administer", "administering", "administration" and the like refer to methods that can be used to enable delivery of a compound or composition to a desired site of biological action. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, or infusion), topical administration, and rectal administration. Those skilled in the art are familiar with administration techniques that can be used with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

[0065] The term "effective amount" or "therapeutically effective amount", as used herein, refers to a sufficient amount of an agent or compound being administered that relieves to some extent one or more of the symptoms of the disease or disorder being treated. The result includes reduction and / or alleviation of the signs, symptoms, or causes of the disease, or other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition containing a compound as disclosed herein that is required to clinically significantly reduce a disease symptom. An appropriate "effective" amount in an individual case is optionally determined using techniques such as dose escalation studies.

[0066] The terms "enhance" or "enhancing," as used herein, mean to increase or prolong, either in potency or duration, a desired effect. Thus, in regard to enhancing the effect of therapeutic agents, the term "enhancing" refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system. An "enhancing-effective amount," as used herein, refers to an amount sufficient to enhance the effect of another therapeutic agent in a desired system.

[0067] The terms "kit" and "article of manufacture" are used synonymously.

[0068] The term "subject" or "patient" includes mammals. Examples of mammals include, but are not limited to, members of the following classes of mammals: humans, non-human primates such as chimpanzees, and other ape and monkey species; farm animals such as cows, horses, sheep, goats, pigs, and the like; domestic animals such as rabbits, dogs, and cats; and laboratory animals, including rodents such as rats, mice, and guinea pigs. In one embodiment, the mammal is a human.

[0069] The terms "treat," "treating," or "treatment," as used herein, include alleviating, relieving, or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting a disease or condition, e.g., arresting the progression of a disease or condition, relieving a disease or condition, causing regression of a disease or condition, alleviating a condition caused by a disease or condition, or prophylactically and / or therapeutically arresting a symptom of a disease or condition.

[0070] The term "pharmaceutical acceptable," as used herein, generally refers to a substance, such as a carrier or diluent, that does not abrogate the biological activity or properties of a compound and is relatively non-toxic, i.e., the substance may be administered to an individual without causing undesired biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0071] The term "pharmaceutical acceptable salt", as used herein, generally refers to a form of a therapeutically active agent that consists of the cationic form of the therapeutically active agent in combination with a suitable anion, or, in an alternative embodiment, the anionic form of the therapeutically active agent in combination with a suitable cation. Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. S.M. Berge, L.D. Bighley, D.C. Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. P.H. Stahl and C.G. Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zurich: Wiley-VCH / VHCA, 2002. Pharmaceutical salts are typically more soluble than non-ionic species and are rapidly soluble in gastric and intestinal fluids, making them useful in solid dosage forms. Moreover, their solubility is often pH-dependent, allowing for selective dissolution in one or another part of the digestive tract, and this ability can be manipulated as an aspect of delayed and sustained release behavior.Furthermore, salt-forming molecules can be in equilibrium with neutral forms, allowing for regulation of passage through biological membranes.Provided herein are non-hallucinogenic compounds that promote neuronal growth and / or improve neuronal structure.

[0072] 5-HT 2A As used herein, the terms "significant" or "significantly" with respect to agonism means an EC 50 In 5-HT 2A Refers to a compound capable of providing receptor agonism.

[0073] In some embodiments, the compounds provided herein have potent potency at serotonin receptors (e.g., 5HT 2A In some embodiments, the compounds provided herein have improved physicochemical properties as a result of the loss of hydrogen bond donors, reduced total polar surface area, and improved central nervous system multiparameter optimization (MPO) scores. In some embodiments, the compounds provided herein have improved physicochemical properties as a result of the loss of hydrogen bond donors, reduced total polar surface area, and improved central nervous system multiparameter optimization (MPO) scores. 2A Described herein are non-hallucinogenic compounds that exhibit similar therapeutic potential as agonists. In some embodiments, the non-hallucinogenic compounds described herein inhibit the hallucinogenic 5-HT agonist for neurological disorders. 2A Offers greater therapeutic potential than agonists.

[0074] Neurologic abnormalities Neuronal plasticity and its changes are responsible for many neurological diseases and disorders. For example, during development and adulthood, changes in the number and morphology (e.g., length, intersections, density) of dendritic spines accompany the formation, maintenance, and elimination of synapses, and these changes are thought to establish and reconstruct connectivity within neural circuits. Furthermore, the structural plasticity of dendritic spines is coordinated with the function and plasticity of synapses. For example, the expansion of spines is coordinated with long-term potentiation in neural circuits, while long-term depression is associated with the shrinkage of spines.

[0075] Moreover, dendritic spines undergo experience-dependent morphological changes in living animals, and even subtle changes in dendritic spines can affect patterns of synaptic function, synaptic plasticity, and connectivity in neural circuits. For example, neurological diseases and disorders, such as neurodegenerative diseases and disorders (e.g., Alzheimer's disease and Parkinson's disease) and neuropsychiatric diseases and disorders (e.g., depression and schizophrenia), are accompanied by disease-specific disturbances in the shape, size, and / or number of dendritic spines, suggesting that dendritic spines serve as a common substrate in diseases involving impaired information processing.

[0076] In some embodiments, disclosed herein are methods of treating neurological diseases and disorders with a compound of formula (I), (IA), (IB) or (II), or any compound covered by such formulas, e.g., any compound set forth in Table 1, or a pharma- ceutically acceptable salt or solvate thereof.

[0077] In some embodiments, the neurological disease or disorder is a disease or disorder of the individual's central nervous system (CNS) (eg, the brain, spine, and / or nerves).

[0078] Types of neurological diseases and disorders include, but are not limited to, neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease, and dementia), headaches (e.g., migraines), brain injuries (e.g., stroke or traumatic brain injury), brain cancer, anxiety disorders (e.g., post-traumatic stress disorder (PTSD) or obsessive-compulsive disorder (OCD)), mood disorders (e.g., suicidal ideation, depression, or bipolar disorder), psychiatric disorders (e.g., schizophrenia or substance-induced psychosis), personality disorders, eating disorders (e.g., binge eating, disorders), sleep disorders, sexual desire disorders, impulse control disorders (e.g., gambling, compulsive sexuality, or kleptomania), substance use disorders (e.g., alcoholism, opioid addiction, or cocaine addiction), dissociative disorders (e.g., epilepsy, memory loss, or dissociative identity disorder), cognitive disorders (e.g., substance-induced cognitive dysfunction), developmental disorders (e.g., attention deficit hyperactivity disorder (ADHD)), autoimmune diseases (e.g., multiple sclerosis (MS)), pain (e.g., chronic pain), and factitious disorder. In some embodiments, the mammal treated with the compounds described herein has a disease or disorder that is or is related to a disease or disorder of the CNS.

[0079] Neurodegenerative diseases or disorders include, but are not limited to, Alzheimer's disease (AD), Parkinson's disease (PD), prion diseases, frontotemporal dementia, motor neuron disease (MND), Huntington's disease (HD), and Lewy body dementia (LBD).

[0080] Substance use disorders include, but are not limited to, substance abuse, addiction, and dependence, such as addiction to and dependence on alcohol, opioids (e.g., heroin, oxycodone, and hydrocodone), cocaine, amphetamines (e.g., methamphetamine), nicotine, cannabinoids (e.g., tetrahydrocannabinol (THC)), caffeine, phencyclidine, paint thinners, glues, steroids (e.g., anabolic steroids), barbiturates (e.g., phenobarbital), methadone, benzodiazepines (e.g., diazepam), and the like.

[0081] Impulse control disorders include, but are not limited to, gambling, kleptomania, trichotillomania, intermittent explosive disorder, pyromania, skin picking, compulsive buying, Tourette's syndrome, and compulsive sexual behavior.

[0082] Neuropsychiatric disorders include, but are not limited to, seizures (e.g., epilepsy) and attention deficit disorders (e.g., ADHD and autism), eating disorders (e.g., bulimia, anorexia, binge eating disorder, and pica), depression (e.g., clinical depression, persistent depressive disorder, bipolar disorder, postpartum depression, suicidal ideation, major depressive disorder, seasonal affective disorder, etc.), anxiety (e.g., panic attacks, social anxiety disorder, panic disorder, etc.), schizophrenia, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), substance-induced psychosis, and substance-induced cognitive dysfunction.

[0083] Brain injuries include, but are not limited to, stroke, traumatic brain injury, dementia pugilistica, and chronic traumatic brain injury (CTE).

[0084] In some embodiments, the compounds provided herein (e.g., compounds represented by the structure of Formula (I), (IA), (IB), or (II), or any compound covered by such formulas, e.g., any compound set forth in Table 1, or a pharma- ceutically acceptable salt or solvate thereof) improve the number of dendritic spines and dendritic spine morphology lost in neurological diseases and disorders.

[0085] 5-HT 2A 5-HT 2A 5-HT agonism correlates with promoting neuroplasticity (Ly et al., 2018). 2A The antagonist is 5-HT 2A It neutralizes the neuritogenic and spine-forming effects of hallucinogenic compounds with agonist activity, such as DMT, LSD, and DOI. In addition, DMT and other psychedelic compounds inhibit the 5-HT 2AIn some embodiments, cortical cultures are treated with 5-HT10, which promotes increased dendritic arbor complexity, dendritic spine density, and synaptogenesis through 5-HT10-dependent processes. 2A Pretreatment with the antagonist blocked the ability of 5-MeO-DMT to increase dendritic growth. Importantly, the psychoplastogenic effects of the compounds provided herein were also blocked under these conditions, implicating 5-HT in their mechanism of action. 2A This indicates that a receptor is involved.

[0086] Additionally, in some embodiments, non-hallucinogenic compounds (e.g., lisuride and 6-MeO-DMT) inhibit the 5HT 2A When the sensor assay is performed in antagonist mode, it competes off 5-HT. In addition, compounds that are non-hallucinogenic in animals (e.g., humans), such as 6-F-DET, ketanserin, and BOL148, compete off 5-HT in antagonist mode sensor assays. 2A In some embodiments, the compounds provided herein can compete with the binding of 5HT to 5-HT. 2A In some embodiments, the 5HT 2A The sensor assay is in antagonist mode. In some embodiments, the compounds provided herein inhibit the 5HT 2A In some embodiments, the compounds provided herein inhibit the binding of 5-HT to 5HT, and thus have the potential to be non-hallucinogenic. 2A In some embodiments, the compounds provided herein inhibit the binding of 5-HT to 5HT in an antagonistic manner and are non-hallucinogenic. 2AIn some embodiments, the compounds provided herein are non-hallucinogenic compounds that prevent the binding of 5-HT in antagonistic mode. In some embodiments, the compounds provided herein are non-hallucinogenic compounds that inhibit the response of a sensor assay in antagonistic mode. In some embodiments, the compounds provided herein are non-hallucinogenic compounds that inhibit the response of a sensor assay in antagonistic mode.

[0087] In some embodiments, the effect of the compounds provided herein on the agonist mode of the sensor assay is determined by whether the compound inhibits 5-HT 2A In some embodiments, the effect of the compounds provided herein on the antagonist mode of the sensor assay indicates that the compounds are non-psychedelic ligands of the 5-HT 2A In some embodiments, the effects of the compounds provided herein on both the agonist and antagonist modes of the sensor assays indicate that the compounds are non-psychedelic ligands of the 5-HT 2A This suggests that it is a non-hallucinogenic ligand for the receptor.

[0088] In some embodiments, the hallucinogenic 5-HT 2A Described herein are non-hallucinogenic compounds that exhibit similar therapeutic potential as agonists. In some embodiments, the non-hallucinogenic compounds described herein inhibit the hallucinogenic 5-HT agonist for neurological disorders. 2A In some embodiments, the compounds of the present disclosure provide therapeutic benefits over 5-HT agonists. 2A It is a modulator and promotes neuroplasticity (e.g., structural plasticity of the cortex).

[0089] Provided herein are compounds useful for treating the brain disorders and other diseases described herein (e.g., compounds represented by formula (I), formula (IA), formula (IB), or (II), or any compound covered by such formulas, e.g., compounds represented by the structures in Table 1). In some embodiments, the compounds provided herein are 5-HT 2A In some embodiments, 5-HT is a modulator that promotes neuroplasticity (e.g., cortical structural plasticity). 2A Modulators (e.g., 5-HT 2A In some embodiments, the brain disorders or other diseases described herein are characterized by reduced neuroplasticity, reduced plasticity of cortical structures, 5-HT 2A These include reduced receptor content, reduced dendritic arbor complexity, loss of dendritic spines, reduced dendritic branch content, reduced spine formation, reduced neuritogenesis, neurite retraction, or any combination thereof.

[0090] In some embodiments, the compounds provided herein are neuroplastic (eg, promote neuroplasticity (eg, cortical structural plasticity), such as increasing neurite outgrowth).

[0091] In some embodiments, the compounds provided herein are 5-HT 2A In some embodiments, the compounds provided herein have activity as 5-HT 2A Elicit a biological response by activating receptors (e.g., allosteric modulation or 5-HT 2A In some embodiments, the compounds provided herein selectively activate 5-HT 2AIt is a modulator and promotes neuroplasticity (e.g., cortical structural plasticity). In some embodiments, promoting neuroplasticity includes, for example, increasing dendritic spine growth, increasing the synthesis of synaptic proteins, strengthening synaptic response, increasing dendritic branching complexity, increasing dendritic branching content, increasing spine formation, increasing neuritogenesis, or any combination thereof. In some embodiments, increasing neuroplasticity includes, for example, increasing cortical structural plasticity in the anterior part of the brain.

[0092] In some embodiments, the compounds provided herein are 5-HT modulators (e.g., 5-HT 2A Agonists or 5-HT 2A In some embodiments, the compounds provided herein are 5-HT 2A Modulators (e.g. 5-HT 2A Agonist or 5-HT 2A In some embodiments, the compounds provided herein are 5-HT modulators and promote neuroplasticity, such as increased neurite outgrowth (e.g., cortical structural plasticity). In some embodiments, the compounds provided herein are 5-HT modulators and promote neuroplasticity (e.g., cortical structural plasticity) and are non-hallucinogenic.

[0093] In some embodiments, the compounds provided herein are 5-HT 2A In some embodiments, the compounds provided herein are 5-HT 2A In some embodiments, the compounds provided herein are 5-HT antagonists and promote neuroplasticity, such as increased neurite outgrowth (e.g., cortical structural plasticity). 2A In some embodiments, the compounds provided herein are capable of inhibiting 5-HT agonism and promote neuroplasticity, such as increased neurite outgrowth (e.g., cortical structural plasticity). 2AIt is unable to provide (significantly) agonism, promotes neuroplasticity (e.g., structural plasticity of the cortex), and has low potential for hallucinogenic activity (e.g., is non-hallucinogenic).

[0094] In some embodiments, the compounds provided herein are 5-HT 2A In some embodiments, the compounds provided herein are 5-HT 2A 5-HT agonists and promote neuroplasticity, such as increased neurite outgrowth (e.g., cortical structural plasticity). In some embodiments, the compounds described herein are 5-HT 2A In some embodiments, the compounds provided herein provide 5-HT agonism (significantly) and promote neuroplasticity, such as increased neurite outgrowth (e.g., cortical structural plasticity). 2A It provides agonism (significantly), promotes neuroplasticity (e.g., cortical structural plasticity), and has low potential for hallucinogenic effects (e.g., is non-hallucinogenic).

[0095] In some embodiments, 5-HT 2A Modulators (e.g., 5-HT 2A In some embodiments, the non-hallucinogenic 5-HT agonist is 2A Modulators (e.g., 5-HT 2A agonists) are used to treat neurological disorders, and the modulators do not induce dissociative side effects. In some embodiments, the hallucinogenic potential of the compounds described herein is evaluated in vitro. In some embodiments, the hallucinogenic potential of the compounds described herein evaluated in vitro is compared to the hallucinogenic potential of a hallucinogenic homolog evaluated in vitro. In some embodiments, the compounds provided herein do not elicit as much hallucinogenic potential in vitro as the hallucinogenic homolog.

[0096] In some embodiments, non-hallucinogenic 5-HT 2A Modulators (e.g., 5-HT2A agonists) are used to treat neurological disorders. In some embodiments, the neurological disorders are characterized by decreased neuroplasticity, decreased plasticity of cortical structures, 5-HT 2A These include reduced receptor content, reduced dendritic arbor complexity, loss of dendritic spines, reduced dendritic branch content, reduced spine formation, reduced neuritogenesis, neurite retraction, or any combination thereof.

[0097] In some embodiments, non-hallucinogenic 5-HT 2A Modulators (e.g., 5-HT 2A In some embodiments, non-hallucinogenic 5-HT agonists are used to increase neuronal plasticity. 2A Modulators (e.g., 5-HT 2A In some embodiments, non-hallucinogenic 5-HT agonists are used to treat brain disorders. 2A Modulators (e.g., 5-HT 2A Agonists are used to increase at least one of the translation, transcription, or secretion of a neurotrophic factor.

[0098] In some embodiments, the experiment or assay to determine the increase in neuronal plasticity of any compound of the present disclosure may include a phenotypic assay, a dendrite formation assay, a spine formation assay, a synaptogenesis assay, a Sholl analysis, a concentration-response experiment, a 5-HT 2A Agonist assay, 5-HT 2A Antagonist assay, 5-HT 2A Binding assay, or 5-HT 2A Blocking experiments (e.g., ketanserin blocking experiments). In some embodiments, the experiment or assay for determining the hallucinogenic potential of the compounds provided herein is a mouse head twitch response (HTR) assay.

[0099] compound In some embodiments, the compounds described herein, including their pharmaceutically acceptable salts, prodrugs, active metabolites, and solvates, are benzyloxy-substituted psychoplastogens. In some embodiments, the compounds described herein, including their pharmaceutically acceptable salts, prodrugs, active metabolites, and solvates, are phenoxy-substituted psychoplastogens. In some embodiments, the compounds described herein, including their pharmaceutically acceptable salts, prodrugs, active metabolites, and solvates, are psychoplastogens that include an indole moiety. In some embodiments, the compounds described herein, including their pharmaceutically acceptable salts, prodrugs, active metabolites, and solvates, are psychoplastogens that include an indole moiety fused to an azepine moiety. In some embodiments, the compounds described herein, including their pharmaceutically acceptable salts, prodrugs, active metabolites, and solvates, are psychoplastogens that contain a 1,2,3,4,5,6-hexahydroazepino[4,5-b]indole moiety substituted by a benzyloxy group. In some embodiments, the compounds described herein, including their pharmaceutically acceptable salts, prodrugs, active metabolites, and solvates, are psychoplastogens that contain a 1,2,3,4,5,6-hexahydroazepino[4,5-b]indole moiety substituted by a phenoxy group.

[0100] In some embodiments, the phenoxy- or benzyloxy-substituted psychoplastogen is a non-hallucinogenic phenoxy- or benzyloxy-substituted psychoplastogen. In some embodiments, the phenoxy- or benzyloxy-substituted psychoplastogen (e.g., as described herein) promotes neuronal growth, improves neuronal structure, or a combination thereof.

[0101] In some embodiments, provided herein is a compound of formula (I), or a pharma- ceutically acceptable salt or solvate thereof:

[0102] [ka] During the ceremony, - R 1 , R 2 , R 3 and R 4 Each of the groups is independently hydrogen, halogen, -OR a , alkyl, heteroalkyl, aryl, arylalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, or heterocycloalkyl, wherein each of the alkyl, heteroalkyl, aryl, arylalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted; Or, R 1 and R 2 , R 2 and R 3 , or R 3 and R 4 taken together with the carbon atom to which they are attached form an optionally substituted 5- or 6-membered ring; - R 5 is hydrogen, alkyl, haloalkyl, cycloalkyl, or heterocycloalkyl, where each alkyl, haloalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted; - R 6 is hydrogen, alkyl, haloalkyl, cycloalkyl, or heterocycloalkyl, each of which is optionally substituted; and - R ais hydrogen, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, cycloalkyl, or heterocycloalkyl, where each of alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted; Here, R 1 , R 2 , R 3 and R 4 At least one of OR a where R a is aryl or arylalkyl, each of which is optionally substituted.

[0103] In some embodiments of Formula (I), R 1 , R 3 , R 4 , R 5 and R 6 are each hydrogen, R 2 is not phenoxy. In some embodiments, R 2 , R 3 , R 4 , R 5 and R 6 are each hydrogen, R 1 is not phenoxy. In some embodiments, R 1 , R 3 , R 4 and R 6 are hydrogen, and R 5 is methyl, R 2 is not benzyloxy.

[0104] For any or all of the embodiments, the substituents are selected from among a subset of the listed alternatives.

[0105] In some embodiments of Formula (I), R 6 is unsubstituted or substituted alkyl, or hydrogen. In some embodiments, R 6 is hydrogen. In some embodiments, R 6is unsubstituted or substituted alkyl, for example methyl.

[0106] In some embodiments of Formula (I), R 5 is unsubstituted or substituted alkyl, or hydrogen. In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is unsubstituted or substituted alkyl, for example methyl.

[0107] In some embodiments of Formula (I), R 1 , R 2 , R 3 and R 4 At least one of OR a where R a is aryl or arylalkyl, each of which is optionally substituted. In some embodiments, R 1 , R 2 , R 3 and R 4 One of them is OR a where R a is aryl or arylalkyl, each of which is optionally substituted. In some embodiments, R 1 , R 2 , R 3 and R 4 At least one of OR a where R a is aryl or arylalkyl, each of which is optionally substituted; R 1 , R 2 , R 3 and R 4 The remainder of R are each hydrogen. 1 , R 2 , R 3 and R 4 One of them is OR a where R a is aryl or arylalkyl, each of which is optionally substituted; R 1 , R 2 , R3 and R 4 The remainder are each hydrogen.

[0108] In some embodiments of Formula (I), R 1 , R 2 , R 3 and R 4 At least one of OR a where R a is optionally substituted aryl. In some embodiments, R 1 , R 2 , R 3 and R 4 One of them is OR a where R a is optionally substituted aryl. In some embodiments, R 1 , R 2 , R 3 and R 4 At least one of OR a where R a is optionally substituted aryl, and R 1 , R 2 , R 3 and R 4 The remainder of R are each hydrogen. 1 , R 2 , R 3 and R 4 One of them is OR a where R a is optionally substituted aryl, and R 1 , R 2 , R 3 and R 4 The remainder are each hydrogen.

[0109] In some embodiments of Formula (I), R 1 , R 2 , R 3 and R 4 At least one of OR a There, R a is optionally substituted arylalkyl. In some embodiments, R1 , R 2 , R 3 and R 4 One of them is OR a where R a is optionally substituted arylalkyl. In some embodiments, R 1 , R 2 , R 3 and R 4 At least one of OR a where R a is optionally substituted arylalkyl; R 1 , R 2 , R 3 and R 4 The remainder of R are each hydrogen. 1 , R 2 , R 3 and R 4 One of them is OR a where R a is optionally substituted arylalkyl; R 1 , R 2 , R 3 and R 4 The remainder are each hydrogen.

[0110] In some embodiments of Formula (I), R 1 , R 2 , R 3 and R 4 In some embodiments, one of R is unsubstituted or substituted phenoxy. 1 is unsubstituted phenoxy. In some embodiments, R 1 is a substituted phenoxy. In some embodiments, R 2 is unsubstituted phenoxy. In some embodiments, R 2 is a substituted phenoxy. In some embodiments, R 3 is unsubstituted phenoxy. In some embodiments, R 3 is a substituted phenoxy. In some embodiments, R 4is unsubstituted phenoxy. In some embodiments, R 4 is a substituted phenoxy.

[0111] In some embodiments of Formula (I), R 1 , R 2 , R 3 and R 4 In some embodiments, one of R is unsubstituted or substituted benzyloxy. 1 is unsubstituted benzyloxy. In some embodiments, R 1 is a substituted benzyloxy. In some embodiments, R 2 is unsubstituted benzyloxy. In some embodiments, R 2 is a substituted benzyloxy. In some embodiments, R 3 is unsubstituted benzyloxy. In some embodiments, R 3 is a substituted benzyloxy. In some embodiments, R 4 is unsubstituted benzyloxy. In some embodiments, R 4 is a substituted benzyloxy.

[0112] In some embodiments of Formula (I), R 1 , R 2 , R 3 and R 4 At least one of R is selected from the group consisting of unsubstituted benzyloxy, benzyloxy substituted with at least one halogen (e.g., F, Cl, Br, I), unsubstituted phenoxy, and phenoxy substituted with at least one halogen (e.g., F, Cl, Br, I). 1 is unsubstituted benzyloxy. In some embodiments, R 1 is benzyloxy substituted with at least one halogen (e.g., F, Cl, Br, I). In some embodiments, R 1 is unsubstituted phenoxy. In some embodiments, R 1is phenoxy substituted with at least one halogen (e.g., F, Cl, Br, I). In some embodiments, R 2 is unsubstituted benzyloxy. In some embodiments, R 2 is benzyloxy substituted with at least one halogen (e.g., F, Cl, Br, I). In some embodiments, R 2 is unsubstituted phenoxy. In some embodiments, R 2 is phenoxy substituted with at least one halogen (e.g., F, Cl, Br, I). In some embodiments, R 3 is unsubstituted benzyloxy. In some embodiments, R 3 is benzyloxy substituted with at least one halogen (e.g., F, Cl, Br, I). In some embodiments, R 3 is unsubstituted phenoxy. In some embodiments, R 3 is phenoxy substituted with at least one halogen (e.g., F, Cl, Br, I). In some embodiments, R 4 is unsubstituted benzyloxy. In some embodiments, R 4 is benzyloxy substituted with at least one halogen (e.g., F, Cl, Br, I). In some embodiments, R 4 is unsubstituted phenoxy. In some embodiments, R 4 is phenoxy substituted with at least one halogen (e.g., F, Cl, Br, I).

[0113] In some embodiments of Formula (I), R 1 , R 2 , R 3 and R 4 At least one of R is selected from the group consisting of benzyloxy, 4-fluorobenzyloxy, phenoxy, and 4-fluorophenoxy. 1 is selected from the group consisting of benzyloxy, 4-fluorobenzyloxy, and 4-fluorophenoxy. 2is selected from the group consisting of benzyloxy, 4-fluorobenzyloxy, and 4-fluorophenoxy. 3 is selected from the group consisting of benzyloxy, 4-fluorobenzyloxy, and 4-fluorophenoxy. 4 is selected from the group consisting of benzyloxy, 4-fluorobenzyloxy, and 4-fluorophenoxy. 1 is benzyloxy. In some embodiments, R 1 is 4-fluorobenzyloxy. In some embodiments, R 1 is phenoxy. In some embodiments, R 1 In some embodiments, R 2 is benzyloxy. In some embodiments, R 2 is 4-fluorobenzyloxy. In some embodiments, R 2 is phenoxy. In some embodiments, R 2 In some embodiments, R 3 is benzyloxy. In some embodiments, R 3 is 4-fluorobenzyloxy. In some embodiments, R 3 is phenoxy. In some embodiments, R 3 In some embodiments, R 4 is benzyloxy. In some embodiments, R 4 is 4-fluorobenzyloxy. In some embodiments, R 4 is phenoxy. In some embodiments, R 4 is -fluorophenoxy.

[0114] In some embodiments, provided herein is a compound of formula (IA), or a pharma- ceutically acceptable salt or solvate thereof:

[0115] [ka] During the ceremony, - R 1 , R 3 and R 4 Each of the groups is independently hydrogen, halogen, -OR a , alkyl, heteroalkyl, aryl, arylalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, or heterocycloalkyl, wherein each of the alkyl, heteroalkyl, aryl, arylalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted; - R 2 is hydrogen, Or, R 1 and R 2 , R 2 and R 3 , or R 3 and R 4 taken together with the carbon atom to which they are attached form an optionally substituted 5- or 6-membered ring; - R 5 is hydrogen, alkyl, haloalkyl, cycloalkyl, or heterocycloalkyl, where each alkyl, haloalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted; - R 6 is hydrogen, alkyl, haloalkyl, cycloalkyl, or heterocycloalkyl, where each alkyl, haloalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted; And, - R a is hydrogen, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, cycloalkyl, or heterocycloalkyl, where each of alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted; Here, R 1 , R 3 and R4 At least one of OR a where R a is aryl or arylalkyl, each of which is optionally substituted.

[0116] In some embodiments of formula (IA), R 3 , R 4 , R 5 and R 6 are each hydrogen, R 1 is not phenoxy.

[0117] In some embodiments of formula (IA), R 1 , R 3 and R 4 One of them is OR a where R a is aryl or arylalkyl, each of which is optionally substituted.

[0118] In some embodiments of formula (IA), R 1 , R 3 and R 4 One of them is OR a where R a is aryl or arylalkyl, each of which is optionally substituted; R 1 , R 3 and R 4 The remainder are each hydrogen.

[0119] In some embodiments of formula (IA), R 1 , R 3 and R 4 In some embodiments of formula (IA), one of R 1 is unsubstituted or substituted phenoxy. In some embodiments of formula (IA), R 3 is unsubstituted or substituted phenoxy. In some embodiments of formula (IA), R 4 is unsubstituted or substituted phenoxy.

[0120] In some embodiments of formula (IA), R 1 , R 3 and R 4 In some embodiments of formula (IA), one of R 1 is unsubstituted or substituted benzyloxy. In some embodiments of formula (IA), R 3 is unsubstituted or substituted benzyloxy. In some embodiments of formula (IA), R 4 is unsubstituted or substituted benzyloxy.

[0121] In some embodiments of formula (IA), R 1 , R 3 and R 4 At least one of is selected from the group consisting of unsubstituted benzyloxy, benzyloxy substituted with at least one halogen, unsubstituted phenoxy, and phenoxy substituted with at least one halogen.

[0122] In some embodiments of formula (IA), R 1 , R 3 and R 4 At least one of is selected from the group consisting of benzyloxy, 4-fluorobenzyloxy, phenoxy, and 4-fluorophenoxy.

[0123] In some embodiments, provided herein is a compound of formula (IB), or a pharma- ceutically acceptable salt or solvate thereof:

[0124] [ka] During the ceremony, - R 1is hydrogen, halogen, alkyl, heteroalkyl, aryl, arylalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, or heterocycloalkyl, where each of alkyl, heteroalkyl, aryl, arylalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted or R 1 OR a ` and R a ` is a substituted aryl or an optionally substituted arylalkyl; - R 2 , R 3 and R 4 Each of the groups is independently hydrogen, halogen, -OR a , alkyl, heteroalkyl, aryl, arylalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, or heterocycloalkyl, wherein each of the alkyl, heteroalkyl, aryl, arylalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted; Or, R 1 and R 2 , R 2 and R 3 , or R 3 and R 4 taken together with the carbon atom to which they are attached form an optionally substituted 5- or 6-membered ring; - R 5 is hydrogen, alkyl, haloalkyl, cycloalkyl, or heterocycloalkyl, where each alkyl, haloalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted; - R 6 is hydrogen, alkyl, haloalkyl, cycloalkyl, or heterocycloalkyl, each of which is optionally substituted; and - R ais hydrogen, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, cycloalkyl, or heterocycloalkyl, where each of alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted; Here, (i) R 2 , R 3 and R 4 At least one of OR a where R a is aryl or arylalkyl, each of which is optionally substituted; or (ii) R 1 OR a `, where R a is a substituted aryl or an optionally substituted arylalkyl.

[0125] In some embodiments of formula (IB), R 1 , R 3 , R 4 , R 5 and R 6 are each hydrogen, R 2 is not phenoxy.

[0126] In some embodiments of formula (IB), R 1 , R 3 , R 4 , and R 6 are hydrogen, and R 5 is methyl, R 2 is not benzyloxy.

[0127] In some embodiments of formula (IB), R 2 , R 3 and R 4 One of them is OR a where R a is aryl or arylalkyl, each of which is optionally substituted.

[0128] In some embodiments of formula (IB), R2 , R 3 and R 4 One of them is OR a where R a is aryl or arylalkyl, each of which is optionally substituted; R 2 , R 3 and R 4 The remainder of each is hydrogen, and R 1 is hydrogen.

[0129] In some embodiments of formula (IB), R 1 OR a ` and R a In some embodiments of formula (IB), R is a substituted aryl or an optionally substituted arylalkyl. 1 OR a `, where R a ` is a substituted aryl or an optionally substituted arylalkyl; R 2 , R 3 and R 4 are each hydrogen.

[0130] In some embodiments of formula (IB), R 2 , R 3 and R 4 In some embodiments of formula (IB), one of R 1 is a substituted phenoxy. In some embodiments of formula (IB), R 1 , R 2 , R 3 and R 4 In some embodiments of formula (IB), one of R 2 , R 3 and R 4 At least one of R is selected from the group consisting of unsubstituted benzyloxy, benzyloxy substituted with at least one halogen, unsubstituted phenoxy, and phenoxy substituted with at least one halogen. 2 , R3 and R 4 At least one of is selected from the group consisting of benzyloxy, 4-fluorobenzyloxy, phenoxy, and 4-fluorophenoxy.

[0131] In some embodiments of formula (IB), R 1 is selected from the group consisting of unsubstituted benzyloxy, benzyloxy substituted with at least one halogen, and phenoxy substituted with at least one halogen. In some embodiments of formula (IB), R 1 is selected from the group consisting of benzyloxy, 4-fluorobenzyloxy, and 4-fluorophenoxy.

[0132] In some embodiments, provided herein is a compound of formula (II), or a pharma- ceutically acceptable salt or solvate thereof:

[0133] [ka] During the ceremony, - R 1 is hydrogen, halogen, alkyl, heteroalkyl, aryl, arylalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, or heterocycloalkyl, where each of alkyl, heteroalkyl, aryl, arylalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted or R 1 OR a ` and R a ` is a substituted aryl or an optionally substituted arylalkyl; - R 2 is hydrogen, - R 3 and R 4 Each of the groups is independently hydrogen, halogen, -OR a, alkyl, heteroalkyl, aryl, arylalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, or heterocycloalkyl, each of which is optionally substituted; Or, R 1 and R 2 , R 2 and R 3 , or R 3 and R 4 taken together with the carbon atom to which they are attached form an optionally substituted 5- or 6-membered ring; - R 5 is hydrogen, alkyl, haloalkyl, cycloalkyl, or heterocycloalkyl, where each alkyl, haloalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted; - R 6 is hydrogen, alkyl, haloalkyl, cycloalkyl, or heterocycloalkyl, each of which is optionally substituted; and - R a is hydrogen, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, cycloalkyl, or heterocycloalkyl, where each alkyl, haloalkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted; Here, (i) R 2 , R 3 and R 4 at least one of R is aryloxy or arylalkyloxy, each of which is optionally substituted; or (ii) R 1 is a substituted aryloxy or an optionally substituted arylalkyloxy.

[0134] In some embodiments of Formula (II), R 3and R 4 At least one of OR a where R a is aryl or arylalkyl, each of which is optionally substituted. In some embodiments of Formula (II), R 3 and R 4 One of them is OR a where R a is aryl or arylalkyl, each of which is optionally substituted. In some embodiments of Formula (II), R 3 and R 4 At least one of OR a where R a is aryl or arylalkyl, each of which is optionally substituted; R 3 and R 4 The other of R is hydrogen. 1 is hydrogen. In some embodiments of formula (II), R 3 and R 4 One of them is OR a where R a is aryl or arylalkyl, each of which is optionally substituted; R 3 and R 4 The other of R is hydrogen. 1 is hydrogen.

[0135] In some embodiments of Formula (II), R 1 OR a ` and R a In some embodiments of formula (II), R 1 OR a `, where R a In some embodiments of formula (II), R 1 OR a `, where R a ` is a substituted aryl, R 3 and R 4Each is hydrogen. In some embodiments of Formula (II), R 1 OR a ', where Ra' is a substituted arylalkyl, and R 3 and R 4 are each hydrogen.

[0136] In some embodiments of Formula (II), R 3 and R 4 One of the groups is unsubstituted or substituted phenoxy.

[0137] In some embodiments of Formula (II), R 1 is a substituted phenoxy.

[0138] In some embodiments of Formula (II), R 1 , R 3 and R 4 is unsubstituted or substituted benzyloxy.

[0139] In some embodiments of Formula (II), R 3 and R 4 At least one of is selected from the group consisting of unsubstituted benzyloxy, benzyloxy substituted with at least one halogen, unsubstituted phenoxy, and phenoxy substituted with at least one halogen.

[0140] In some embodiments of Formula (II), R 3 and R 4 At least one of is selected from the group consisting of benzyloxy, 4-fluorobenzyloxy, phenoxy, and 4-fluorophenoxy.

[0141] In some embodiments of Formula (II), R 1 is selected from the group consisting of unsubstituted benzyloxy, benzyloxy substituted with at least one halogen, and phenoxy substituted with at least one halogen.

[0142] In some embodiments of Formula (II), R 1 is selected from the group consisting of benzyloxy, 4-fluorobenzyloxy, and 4-fluorophenoxy.

[0143] In some embodiments of Formula (II), R 3 is selected from the group consisting of benzyloxy, 4-fluorobenzyloxy, and 4-fluorophenoxy.

[0144] In some embodiments of Formula (II), R 6 is unsubstituted or substituted alkyl, or hydrogen. In some embodiments of formula (II), R 6 is hydrogen. In some embodiments of formula (II), R 6 is alkyl, for example methyl.

[0145] In some embodiments of Formula (II), R 5 is unsubstituted or substituted alkyl, or hydrogen. In some embodiments of formula (II), R 5 is hydrogen. In some embodiments of formula (II), R 5 is alkyl, for example methyl.

[0146] Representative compounds of formula (I), (IA), (IB), or (II) include, but are not limited to, the following:

[0147] [ka]

[0148] [ka] Or a pharma- ceutically acceptable salt or solvate thereof.

[0149] In some embodiments, provided herein are compounds having the structures provided in Table 1, stereoisomers thereof, or pharma- ceutically acceptable salts of said compounds or stereoisomers.

[0150] [Table 1-1]

[0151] [Table 1-2]

[0152] [Table 1-3]

[0153] [Table 1-4]

[0154] [Table 1-5]

[0155] [Table 1-6]

[0156] Any combination of the above groups for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof will be chosen by one of ordinary skill in the art to provide stable moieties and compounds.

[0157] Further forms of the compound In one embodiment, the compounds provided herein are in the form of pharmaceutically acceptable salts.In some embodiments, any compound provided herein is a pharmaceutically acceptable salt, such as any salt provided herein (e.g., the fumarate salt of the compound provided herein or the maleate salt of the compound provided herein).In some embodiments, any compound provided herein is a fumarate salt of the compound provided herein.In some embodiments, any compound provided herein is a maleate salt of the compound provided herein.

[0158] Similarly, active metabolites of such compounds having the same type of activity are included within the scope of the present disclosure.In addition, the compounds described herein can exist in unsolvated forms as well as solvated forms that contain pharma- ceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are considered to be disclosed herein as well.

[0159] In some embodiments, a pharma- ceutically acceptable salt is obtained by reacting a compound of Formula (I), (IA), (IB), or (II), or a compound of Table 1, with an acid. In some embodiments, a compound of Formula (I), (IA), (IB), or (II), or a compound of Table 1 (i.e., the free base form) is basic and is reacted with an organic or inorganic acid. Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and metaphosphoric acid. Organic acids include, but are not limited to, 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid (L), aspartic acid (L), benzenesulfonic acid, benzoic acid, camphoric acid (+), camphor-10-sulfonic acid (+), capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucohetic acid, glyceric acid, glycerol ... The acidic acids include protonic acid (D), gluconic acid (D), glucuronic acid (D), glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid (DL), lactobionic acid, lauric acid, maleic acid, malic acid (-L), malonic acid, mandelic acid (DL), methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, pyroglutamic acid (-L), salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid (+L), thiocyanic acid, toluenesulfonic acid (p), and undecylenic acid.

[0160] In some embodiments, a compound of Formula (I), (IA), (IB), or (II), or a compound of Table 1 (i.e., the free base form) is basic and is reacted with maleic acid.

[0161] In some embodiments, a compound represented by the structure of Formula (I), (IA), (IB), or (II), or a compound in Table 1 (i.e., the free base form) is basic and is reacted with fumaric acid.

[0162] In some embodiments, a pharma- ceutically acceptable salt is obtained by reacting a compound represented by the structure of Formula (I), (IA), (IB), or (II), or a compound of Table 1, with a base. In some embodiments, a compound represented by the structure of Formula (I), (IA), (IB), or (II), or a compound of Table 1, in its free base form, is acidic and is reacted with a base. In such a situation, the acidic proton of a compound represented by the structure of Formula (I), (IA), (IB), or (II), or a compound of Table 1, is replaced with a metal ion, such as a lithium, sodium, potassium, magnesium, calcium, or aluminum ion. In some cases, the compounds described herein may be used with, but are not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine, dicyclohexylamine, tetrahydrofuran ... In some embodiments, the compounds provided herein are prepared as sodium, calcium, potassium, magnesium, meglumine, N-methylglucamine, or ammonium salts. In other cases, the compounds described herein form salts with amino acids such as arginine and lysine. Acceptable inorganic bases used to form salts with compounds containing acidic protons include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydroxide, lithium hydroxide, and the like. In some embodiments, the compounds provided herein are prepared as sodium, calcium, potassium, magnesium, meglumine, N-methylglucamine, or ammonium salts.

[0163] Reference to pharmaceutically acceptable salts should be understood to include solvent addition forms. In some embodiments, solvates include either stoichiometric or non-stoichiometric solvents and are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein are conveniently prepared or formed during the process described herein. In addition, the compounds provided herein optionally exist in unsolvated as well as solvated forms.

[0164] The methods and formulations described herein also include the use of N-oxides (where appropriate) or pharma- ceutically acceptable salts of compounds having the structure of Formula (I), (IA), (IB), or (II), as well as active metabolites of these compounds that have the same type of activity.

[0165] In some embodiments, the organic radical (e.g., alkyl group, aromatic ring) moiety of the compound of formula (I), (IA), (IB), or (II) is susceptible to various metabolic reactions. By incorporating an appropriate substituent into the organic radical, this metabolic pathway is reduced, minimized, or eliminated. In certain embodiments, suitable substituents for reducing or eliminating the susceptibility of the aromatic ring to metabolic reactions are, by way of example only, halogen, deuterium, alkyl group, haloalkyl group, or deuterated alkyl group.

[0166] In another embodiment, the compounds described herein are labeled isotopically (e.g., with a radioisotope) or by other means, including but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0167] The compounds described herein include isotopically labeled compounds, which are identical to those detailed in the various formulas and structures presented herein except for the fact that one or more atoms are replaced with an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that can be incorporated into the present compounds include, for example, 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 35 S, 18 F, 36 Cl, 123 I, 124 I, 125 I, 131 I, 32 P, and 33 Isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, iodine, phosphorus, etc., such as P. In one embodiment, the isotopically labeled compounds described herein, e.g. 3 H and 14 Compounds incorporating a radioisotope such as C are useful for drug and / or substrate tissue distribution assays. In one embodiment, substitution with an isotope such as deuterium provides certain therapeutic advantages due to greater metabolic stability, for example, increased half-life in vivo or reduced dosage requirements. In some embodiments, one or more hydrogens in a compound of formula (I), (IA), (IB), or (II) are replaced with deuterium.

[0168] In some embodiments, the compounds represented by the structure of formula (I), (IA), (IB), or (II), or the compounds of Table 1, have stereocenters, each of which exists independently in either the R or S configuration. In some embodiments, the compounds represented by the structure of formula (I), (IA), (IB), or (II), or the compounds of Table 1, exist in the R configuration. In some embodiments, the compounds represented by the structure of formula (I), (IA), (IB), or (II), or the compounds of Table 1, exist in the S configuration. The compounds provided herein include all diastereomeric, individual enantiomeric, atropisomeric, and epimeric forms, and the appropriate mixtures thereof. The compounds and methods provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, and the appropriate mixtures thereof.

[0169] In some embodiments, the compositions provided herein comprise a racemic mixture of a compound represented by the structure of Formula (I), (IA), (IB), or (II), or a compound in Table 1. In some embodiments, the compounds provided herein are racemic mixtures of a compound represented by the structure of Formula (I), (IA), (IB), or (II), or a compound in Table 1.

[0170] Individual stereoisomers are obtained as desired by methods such as stereoselective synthesis and / or separation of stereoisomers by chiral chromatographic columns, or separation of diastereomers by non-chiral or chiral chromatographic columns, or crystallization and recrystallization in an appropriate solvent or mixture of solvents. In certain embodiments, a compound represented by the structure of formula (I), (IA), (IB), or (II), or a compound of Table 1, is prepared as its individual stereoisomer by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds / salts, separating the diastereomers, and recovering the optically pure individual enantiomers. In some embodiments, resolution of the individual enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein. In another embodiment, the diastereomers are separated by a separation / resolution technique based on differences in solubility. In other embodiments, separation of stereoisomers is carried out by chromatography, or by formation of diastereomeric salts and separation by recrystallization, or by chromatography, or by any combination thereof. Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley and Sons, Inc., 1981. In some embodiments, stereoisomers are obtained by stereoselective synthesis.

[0171] In some embodiments, the compounds described herein are prepared as prodrugs. In some embodiments, a prodrug is an agent that is converted to the parent drug in vivo. Prodrugs are often useful because, in some circumstances, they are easier to administer than the parent drug. Prodrugs are, for example, bioavailable by oral administration, whereas the parent drug is not. Additionally or alternatively, the prodrug has improved solubility in pharmaceutical compositions over the parent drug. In some embodiments, the design of the prodrug increases the effective water solubility. An example of a prodrug, without limitation, is a compound described herein that is administered as an ester ("prodrug"), but is then metabolically hydrolyzed to yield the active entity. A further example of a prodrug is a short peptide (polyamino acid) that is bonded to an acid group, and the peptide is metabolized to expose the active moiety. In certain embodiments, after in vivo administration, the prodrug is chemically converted to the biologically, pharma- ceutical, or therapeutically active form of the compound. In certain embodiments, the prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharma- ceutical, or therapeutically active form of the compound.

[0172] Prodrugs of the compounds described herein include, but are not limited to, esters, ethers, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, N-alkyloxyacyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, and sulfonate esters. See, for example, Design of Prodrugs, Bundgaard, A. Ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al., Ed.; Academic, 1985, vol. 42, p. 309-396; Bundgaard, H. "Design and Application of Prodrugs" in A Textbook of Drug Design and Development, Krosgaard-Larsen and H. Bundgaard, Ed., 1991, Chapter 5, p. 113-191; and Bundgaard, H., Advanced Drug Delivery Review, 1992, 8, 1-38. Each of these references is incorporated herein by reference. In some embodiments, the hydroxyl group of the compounds disclosed herein is used to form a prodrug, and the hydroxyl group is incorporated into an acyloxyalkyl ester, an alkoxycarbonyloxyalkyl ester, an alkyl ester, an aryl ester, a phosphate ester, a sugar ester, an ether, and the like. In some embodiments, the hydroxyl group in the compounds disclosed herein is a prodrug, where the hydroxyl is metabolized in vivo to provide a carboxylic acid group. In some embodiments, the carboxyl group is used to provide an ester or amide (i.e., a prodrug), which is then metabolized in vivo to provide a carboxylic acid group. In some embodiments, the compounds described herein are prepared as alkyl ester prodrugs.

[0173] Prodrug forms of the compounds described herein (prodrugs that are metabolized in vivo to produce compounds of Formula (I), (IA), (IB), or (II) as described herein) are included within the scope of the claims.

[0174] In some embodiments, any one of the hydroxyl, amino, and / or carboxylic acid groups is functionalized in a suitable manner to provide a prodrug moiety. In some embodiments, the prodrug moiety is as described above.

[0175] In additional or further embodiments, the compounds described herein are metabolized upon administration to an organism to produce metabolites that are used to produce a desired effect, including a desired therapeutic effect.

[0176] In some embodiments, a metabolite of a compound disclosed herein is a derivative of the compound that is formed when the compound is metabolized. In some embodiments, an "active metabolite" of a compound disclosed herein is a biologically active derivative of a compound provided herein that is formed when the compound is metabolized. In some embodiments, metabolism is the sum of processes by which a particular substance is altered by an organism, including but not limited to hydrolysis reactions and reactions catalyzed by enzymes. In some embodiments, an enzyme may result in a specific structural modification to a compound. For example, cytochrome P450 catalyzes a variety of oxidation and reduction reactions, while uridine diphosphate glucuronyltransferase catalyzes the transfer of activated glucuronic acid molecules to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines, and free sulfhydryl groups. In some embodiments, the metabolites of a compound disclosed herein are optionally identified by either administering the compound to a host and analyzing tissue samples from the host, or by incubating the compound with liver cells in vitro and analyzing the resulting compound.

[0177] Compound synthesis The compounds of formula (I), (IA), (IB), or (II) described herein are synthesized using standard synthetic techniques in combination with the methods described herein, or using methods known in the art.

[0178] Unless otherwise indicated, conventional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are employed.

[0179] The compounds are prepared using standard organic chemistry techniques, for example, as described in March's Advanced Organic Chemistry, 6th Edition, John Wiley and Sons, Inc. Alternative reaction conditions for the synthetic transformations described herein may be utilized, such as variations in solvents, reaction temperatures, reaction times, and different chemical reagents or other reaction conditions.

[0180] In some embodiments, the compounds described herein are synthesized as outlined in the Examples.

[0181] Pharmaceutical Compositions In some embodiments, provided herein are pharmaceutical compositions comprising a compound provided herein (e.g., a compound having a structure represented by Formula (I), (IA), (IB), or (II), or Table 1), and pharma- ceutically acceptable salts or solvates thereof. In some embodiments, the pharmaceutical composition further comprises at least one pharma- ceutically acceptable excipient.

[0182] In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharma- ceutical acceptable inactive ingredients that facilitate the processing of active compounds into pharmaceutical preparations. Appropriate formulations depend on the route of administration selected. Overviews of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference for disclosure.

[0183] In some embodiments, the compounds described herein are administered alone or in a pharmaceutical composition in combination with a pharma- ceutically acceptable carrier, excipient, or diluent. Administration of the compounds and compositions described herein can be accomplished by any method that allows delivery of the compound to the site of action. These methods include, but are not limited to, delivery via enteral routes (including oral, gastric, or duodenal feeding tubes, rectal suppositories, and rectal enemas), parenteral routes (injection or infusion, including intraarterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural, and subcutaneous), inhalation, transdermal, transmucosal, sublingual, buccal, and topical (including epithelial, dermal, enema, eye drops, ear drops, intranasal, vaginal) administration, although the most suitable route may depend, for example, on the disease or disorder of the recipient. By way of example only, the compounds described herein may be administered locally to the area in need of treatment, for example, by local infusion during surgery, topical application such as a cream or ointment, injection, catheter, or implantation. Administration may also be by direct injection at the site of the diseased tissue or organ.

[0184] In some embodiments, pharmaceutical compositions suitable for oral administration are presented as discrete units such as capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules, as a solution or suspension in an aqueous liquid or a non-aqueous liquid, or as an oil-in-water emulsion or a water-in-oil emulsion in an oil liquid. In some embodiments, the active ingredient is presented as a bolus, electuary, or paste.

[0185] Pharmaceutical compositions that can be used orally include tablets, push-fit capsules made of gelatin, as well as sealed soft capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, inert diluent or lubricant, surface active agent, or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. In some embodiments, the tablets are coated or scored and formulated to provide a delayed or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration. Push-fit capsules can contain the active ingredient in combination with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, active compound may be dissolved or suspended in suitable liquid, such as fatty oil, liquid paraffin, or liquid polyethylene glycol. In some embodiments, stabilizers are added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to tablets or dragee coatings for identification or to characterize different combinations of doses of active compound.

[0186] In some embodiments, the pharmaceutical composition is formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion. The formulation for injection may be presented in unit dosage form, for example, in ampoules or multi-dose containers, together with additional preservatives. The composition may take the form of a suspension, solution, or emulsion in an oily or aqueous vehicle, and may contain formulatory agents such as suspending, stabilizing, and / or dispersing agents. The composition may be presented in unit or multi-dose containers, for example, sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets of the kind described above.

[0187] Pharmaceutical compositions for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of active compounds, which may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the desired recipient; aqueous and non-aqueous sterile suspensions, which may contain suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compound to allow the preparation of highly concentrated solutions.

[0188] For example, it will be understood that, in addition to the ingredients mentioned above, among others, the compounds and compositions described herein may include other agents conventional in the art having regard to the type of formulation in question; for example, those suitable for oral administration may include flavoring agents.

[0189] Methods of Treatment, Dosages, and Treatment Regimens The compounds disclosed herein, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, are useful for promoting neuronal cell growth and / or improving neuronal cell structure.

[0190] Provided herein are non-hallucinogenic psychoplastogens useful for the treatment of one or more diseases or disorders associated with loss of synaptic connectivity and / or plasticity.

[0191] In some embodiments, provided herein is a method of promoting neuroplasticity (e.g., cortical structural plasticity) in an individual by administering to the individual a compound described herein (e.g., a compound represented by the structure of Formula (I), (IA), (IB), or (II), or a compound in Table 1). In some embodiments, providing herein is a method of promoting neuroplasticity (e.g., cortical structural plasticity) in an individual by administering to the individual a compound described herein (e.g., a compound represented by the structure of Formula (I), (IA), (IB), or (II), or a compound in Table 1). 2A Provided herein are methods for modulating 5-HT in an individual by administering to the individual a compound described herein (e.g., a compound represented by the structure of Formula (I), (IA), (IB), or (II), or a compound in Table 1). 2A Provided herein are methods of agonizing a brain disorder or other disease, in some embodiments, the individual has or is diagnosed with a brain disorder or other disease described herein.

[0192] In some embodiments, provided herein is a method of promoting neural cell growth in an individual, the method comprising administering a therapeutically effective amount of a compound or pharmaceutical composition provided herein (e.g., a compound having a structure represented by Formula (I), (IA), (IB), or (II), or a compound in Table 1) to an individual in need thereof.

[0193] In some embodiments, provided herein is a method of improving neuronal structure in an individual, the method comprising administering a therapeutically effective amount of a compound or pharmaceutical composition provided herein (e.g., a compound having a structure represented by Formula (I), (IA), (IB), or (II)), or a compound in Table 1) to an individual in need thereof.

[0194] In some embodiments, the 5-hydroxytryptamine receptor 2A5-HT 2A Provided herein are methods for modulating the activity of a vasopressin receptor agonist (vasopressin receptor agonist), comprising administering a therapeutically effective amount of a compound or pharmaceutical composition provided herein (e.g., a compound having a structure represented by Formula (I), (IA), (IB), or (II), or a compound in Table 1) to an individual in need thereof.

[0195] In some embodiments, the 5-hydroxytryptamine receptor 2A (5-HT 2A Provided herein are methods for treating a disease or disorder in an individual mediated by the action of 5-hydroxytryptamine (5-HT) at the endothelial cell surface (ESC) in a patient receiving treatment with 5-hydroxytryptamine (5-HT), the method comprising administering a therapeutically effective amount of a compound or pharmaceutical composition provided herein (e.g., a compound having a structure represented by Formula (I), (IA), (IB), or (II), or a compound in Table 1) to an individual in need thereof.

[0196] In some embodiments, provided herein is a method of treating a disease or disorder in an individual mediated by loss of synaptic connectivity, plasticity, or a combination thereof, comprising administering a therapeutically effective amount of a compound or pharmaceutical composition provided herein (e.g., a compound having a structure represented by Formula (I), (IA), (IB), or (II), or a compound in Table 1) to an individual in need thereof.

[0197] In some embodiments, provided herein is a method of treating a neurological disease or disorder in an individual, the method comprising administering a therapeutically effective amount of a compound or pharmaceutical composition provided herein (e.g., a compound having a structure represented by Formula (I), (IA), (IB), or (II), or a compound in Table 1) to an individual in need thereof.

[0198] In some embodiments, an individual administered a compound provided herein experiences a hallucinatory event. In some embodiments, an individual administered a compound provided herein does not experience a hallucinatory event. In some embodiments, an individual administered a compound provided herein experiences a hallucinatory event when the compound provided herein induces a particular maximum concentration (C max ) after which the individual experiences a hallucinatory event. In some embodiments, max ) is the hallucination threshold of the compounds provided herein. In some embodiments, the compounds provided herein are administered to an individual in need thereof below the hallucination threshold of the compounds provided herein.

[0199] In some embodiments, methods for treating a disease or disorder are described herein, wherein the disease or disorder is a neurological disease or disorder.

[0200] In some embodiments, the compounds of the present disclosure are used to treat neurological diseases. In some embodiments, the compounds provided herein have, for example, anti-addictive properties, anti-depressant properties, anti-anxiety properties, or a combination thereof.

[0201] In some embodiments, the neurological disease is a neuropsychiatric disease. In some embodiments, the neuropsychiatric disease is a mood disorder or an anxiety disorder. In some embodiments, the neurological disease is a migraine, a headache (e.g., cluster headache), post-traumatic stress disorder (PTSD), anxiety, depression, a neurodegenerative disorder, Alzheimer's disease, Parkinson's disease, a psychiatric disorder, treatment-resistant depression, suicidal ideation, a major depressive disorder, a bipolar disorder, schizophrenia, stroke, traumatic brain injury, and addiction (e.g., substance use disorder). In some embodiments, the neurological disease is a migraine or a cluster headache. In some embodiments, the neurological disease is a neurodegenerative disorder, Alzheimer's disease, or Parkinson's disease. In some embodiments, the neurological disease is a psychiatric disorder, treatment-resistant depression, suicidal ideation, a major depressive disorder, a bipolar disorder, schizophrenia, post-traumatic stress disorder (PTSD), addiction (e.g., substance use disorder), depression, or anxiety. In some embodiments, the neuropsychiatric disease is a psychotic disorder, treatment-resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, post-traumatic stress disorder (PTSD), addiction (e.g., substance use disorder), depression, or anxiety. In some embodiments, the neuropsychiatric disease or neurological disease is a post-traumatic stress disorder (PTSD), addiction (e.g., substance use disorder), schizophrenia, depression, or anxiety. In some embodiments, the neuropsychiatric disease or neurological disease is an addiction (e.g., substance use disorder). In some embodiments, the neuropsychiatric disease or neurological disease is depression. In some embodiments, the neuropsychiatric disease or neurological disease is anxiety. In some embodiments, the neuropsychiatric disease or neurological disease is post-traumatic stress disorder (PTSD). In some embodiments, the neurological disease is stroke or traumatic brain injury. In some embodiments, the neuropsychiatric disease or neurological disease is schizophrenia.

[0202] In some embodiments, the compounds disclosed herein, or pharma- ceutically acceptable salts, solvates, or stereoisomers thereof, are useful for modulating the 5-hydroxytryptamine (5-HT) receptor. In some embodiments, the 5-HT receptor modulated by the compounds and methods is the 5-hydroxytryptamine receptor 2A (5-HT 2A ).

[0203] In some embodiments, 5-HT 2A and (b) a 5-hydroxytryptamine receptor 2A (5-HT 2A) receptor antagonist useful for treating one or more diseases or disorders associated with 5-hydroxytryptamine receptor 2A (5-HT 2A) activity. 2A ) are provided herein.

[0204] In some embodiments, the compounds described herein, or pharma- ceutically acceptable salts thereof, inhibit 5-HT 2A for use in the preparation of a medicament for the treatment of a disease or disorder in a mammal that would benefit from the inhibition or reduction of activity.

[0205] In some embodiments, the compounds described herein, or pharma- ceutically acceptable salts thereof, are used in the preparation of a medicament for the treatment of a disease or disorder in a mammal that would benefit from promoting neuronal growth and / or improving neuronal structure.

[0206] Methods for treating any of the diseases or conditions described herein in a mammal in need of such treatment include administering to the mammal a therapeutically effective amount of at least one compound described herein, or a pharma- ceutically acceptable salt, active metabolite, prodrug, or pharma- ceutically acceptable solvate thereof.

[0207] In certain embodiments, compositions containing the compounds described herein are administered for preventive and / or therapeutic treatment. In certain therapeutic applications, the compositions are administered to a mammal already suffering from a disease or condition in an amount sufficient to cure or at least partially prevent at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous treatments, the mammal's health status, weight, and response to drugs, and the judgment of a medical professional. Therapeutically effective amounts are optionally determined by methods including, but not limited to, dose escalation and / or dose-finding clinical trials.

[0208] In prophylactic applications, compositions containing the compounds described herein are administered to a mammal susceptible to or at risk of a particular disease, disorder, or condition. Such an amount is defined as a "prophylactically effective amount or dose." In this application, the exact amount also depends on the mammal's health status, weight, and the like. When used in a mammal, the effective amount for this application will depend on the severity and course of the disease, disorder, or condition, previous treatments, the mammal's health status and response to the drugs, and the judgment of the medical practitioner. In one embodiment, prophylactic treatment involves administering a pharmaceutical composition containing a compound described herein or a pharma- ceutically acceptable salt thereof to a mammal that has previously experienced at least one symptom of the disease being treated and is now in remission, to prevent the recurrence of the disease or condition.

[0209] In certain embodiments where the mammal's condition does not improve, at the discretion of the medical practitioner, administration of the compound is administered chronically, i.e., for an extended period of time, including the lifetime of the mammal, to ameliorate or otherwise inhibit or limit the symptoms of the disease or disorder in the mammal.

[0210] In certain embodiments where the condition of the mammal is improved, the dose of the drug being administered is temporarily reduced or temporarily stopped for a period of time (i.e., a "drug holiday"). In certain embodiments, the length of the drug holiday is between 2 days and 1 year, such as, 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 reduction in dose during the drug holiday is between 10% and 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%.

[0211] Once improvement of the patient's condition has occurred, a maintenance dose is administered as necessary. Thereafter, in certain embodiments, the dosage or frequency of administration, or both, depending on the symptoms, is reduced to a level at which improvement of the disease, disorder, or condition is maintained. In certain embodiments, however, the mammal requires intermittent treatment on a long-term basis upon recurrence of symptoms.

[0212] The amount of a given drug that corresponds to such an amount will vary depending on factors such as the particular compound, the disease state and its severity, the identity of the subject or host requiring treatment (e.g., weight, sex), etc., but will nevertheless be determined according to the particular circumstances surrounding the case, including, for example, the particular drug being administered, the route of administration, the disease being treated, and the subject or host being treated.

[0213] In general, however, the doses used for adult human treatment typically range from 0.01 mg to 5000 mg per day. In one embodiment, the doses utilized for adult human treatment are from about 1 mg to about 1000 mg per day. In one embodiment, the desired dose is suitably presented as a single dose or as divided doses administered simultaneously or at appropriate intervals, for example, as two, three, four or more subdoses per day.

[0214] In one embodiment, a suitable daily dosage of the compound described herein or a pharma- ceutically acceptable salt thereof is about 0.01 to about 50 mg per kg of body weight. In some embodiments, the amount of active ingredient in the daily dosage or dosage form will be less than or greater than the ranges set forth herein, based on many variables related to the individual treatment regimen. In various embodiments, the daily dosage and unit dosage will vary depending on many variables, including, but not limited to, the activity of the compound used, the disease or condition being treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the medical practitioner.

[0215] The toxicity and therapeutic efficacy of such treatment regimens are discussed below, including but not limited to, LD 50 and ED 50 The dose ratio between toxic and therapeutic effects is the therapeutic index, which is defined as the LD 50 and ED 50 In certain embodiments, data obtained from cell culture assays and animal studies are used in formulating therapeutically effective daily dose ranges and / or therapeutically effective unit doses for use in mammals, including humans. In some embodiments, the daily dose of the compounds described herein falls within a range of circulating concentrations that include the ED50 with minimal toxicity. In certain embodiments, the daily dose range and / or unit dose varies within this range depending on the dosage form used and the route of administration utilized.

[0216] In any of the foregoing aspects, in further embodiments, an effective amount of a compound described herein, or a pharma- ceutically 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 non-systemically or locally to a mammal.

[0217] In any of the preceding embodiments, (i) the compound is administered once daily; or (ii) There are further embodiments which comprise a single administration of an effective amount of the compound, including further embodiments in which the compound is administered to the mammal multiple times over the course of a day.

[0218] In any of the foregoing aspects, there are further embodiments that include multiple administrations of an effective amount of the compound, including further embodiments in which (i) the compound is administered continuously or intermittently, such as in a single dose, (ii) the interval between multiple doses is every 6 hours, (iii) the compound is administered to the mammal every 8 hours, (iv) the compound is administered to the mammal every 12 hours, and (v) the compound is administered to the mammal every 24 hours. In further or alternative embodiments, the method includes a drug holiday, where administration of the compound is temporarily suspended or the dose of the compound being administered is temporarily reduced, and 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.

[0219] In one embodiment, the therapeutic effectiveness of one of the compounds described herein is enhanced by administration of an adjuvant (i.e., the adjuvant has minimal therapeutic benefit by itself, but when combined with another therapeutic agent, enhances the overall therapeutic benefit to the patient). Alternatively, in some embodiments, the benefit experienced by the patient is increased by administering one of the compounds described herein with another agent (which also includes a treatment regimen) that also has a therapeutic effect.

[0220] In certain embodiments, various therapeutically effective amounts of the compounds disclosed herein are utilized in formulating pharmaceutical compositions and / or in treatment regimens in which the compounds disclosed herein are administered in combination with one or more additional agents, such as additional therapeutically effective drugs, adjuvants, etc. The therapeutically effective amounts of drugs and other agents used in combination therapy regimens are optionally determined by means similar to those specified above for the active ingredients themselves. Additionally, the prevention / treatment methods described herein include the use of metronomic dosing, i.e., providing more frequent, lower doses to minimize toxic side effects. In some embodiments, combination therapy regimens include treatment regimens in which administration of the compounds described herein, or pharma- ceutically acceptable salts thereof, is initiated before, during, or after treatment with a second agent described herein, and continues at any time during or after the end of treatment with the second agent. Combination therapy regimens include treatments in which the compound described herein, or a pharma- ceutically acceptable salt thereof, and the second agent used in combination are administered at the same time or at different times and / or at intervals that increase or decrease the duration of treatment.Combination therapy also includes periodic treatments that are started and stopped at different times to aid in the clinical management of the patient.

[0221] It will be understood that the dosage regimen for treating, preventing, or ameliorating the disease for which relief is sought will be modified to accommodate a variety of factors (e.g., the disease or disorder from which the subject suffers; the age, weight, sex, diet, and medical condition of the subject). Thus, in some embodiments, the dosage regimen actually utilized will vary, and in some embodiments, will deviate from the dosage regimens set forth herein. EXAMPLES

[0222] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the claims provided herein.

[0223] overview All reagents are obtained from commercial sources and used without purification unless otherwise stated. DMSO is purified by passing through an activated alumina column under 12 psi of N2. Reactions are carried out using flame-dried glassware under reduced pressure (~1 torr). Compounds purified by chromatography are adsorbed onto silica gel prior to loading. Thin layer chromatography was performed using Millipore Silica Gel 60 F 254 The chromatograms are visualized by fluorescence quenching or by staining with aqueous ninhydrin or ceric ammonium molybdate (CAM).

[0224] Nuclear magnetic resonance (NMR) spectrum 1 H and 13 For C, the spectra were acquired on either a Bruker 400 operating at 400 and 100 MHz, a Varian 400 operating at 400 and 100 MHz, or a Varian 500 operating at 500 and 125 MHz, respectively, and were internally referenced according to the residual solvent signal. 1 H NMR data are reported as follows: chemical shift (δ, ppm), multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet), coupling constant (Hz), and integration. 13 C NMR data are reported as chemical shifts (δ, ppm). Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent LC-MS equipped with an Ion Trap or ELSD detector or a Waters LC-MS equipped with a UPLC detector.

[0225] General HPCL Conditions HPLC separation method A: Column: X-SELECT CSH(250 * 30mm) 5μ Mobile phase A: 10 mM ammonium bicarbonate in water Mobile phase B: Acetonitrile Flow rate: 25mL / min HPLC separation method B: Column: X-SELECT CSH(250 * 30mm) 5μ Mobile phase A: 0.1% TFA in water Mobile phase B: Acetonitrile Flow rate: 25mL / min HPLC separation method C: Chiral HPLC column: Chiralpak IC(250 * 30mm, 5μm) Mobile phase A: 0.1% DEA in n-hexane Mobile phase B: DCM:MeOH (50:50) Flow rate: 35.0mL / min

[0226] chemistry General synthesis scheme: Exemplary synthesis schemes: In some embodiments, the compounds provided herein are prepared as outlined in Scheme 1.

[0227] [ka]

[0228] In Scheme 1, in some embodiments, Ar is a substituted or unsubstituted aryl, or a substituted or unsubstituted aralkyl, as described elsewhere herein.

[0229] Representative Procedure 1: Preparation of intermediate I-3: To a stirred solution of intermediate I-1 (1.0 equiv.) in DMSO (10 vol.) is added intermediate I-2 (1.2 equiv.), followed by CuI (0.05 equiv.), K3PO4 (2.0 equiv.) and picolinic acid (0.1 equiv.) and the reaction mixture is stirred at 80° C. for 16 h. The crude reaction mixture is cooled to room temperature, diluted with ice-cold water and extracted with EtOAc. The combined organic layers are washed with ice-cold water followed by a brine solution. The combined organic layers are dried over Na2SO4, the solids are removed by filtration and the filtrate is concentrated under vacuum to give the crude reaction product which is purified by silica gel chromatography to give intermediate I-3.

[0230] Representative Procedure 2: Preparation of intermediate I-4: To a stirred solution of intermediate I-3 (1.0 equiv.) in HCl (6 M aq., 20 vol.) is added NaNO2 (2.0 equiv., aq., 14 vol.) at 0° C. and the reaction mixture is stirred for 2 h. To the reaction is added SnCl2 (3.0 equiv., 6 M aq. HCl, 6.5 vol.) dropwise and the reaction is allowed to warm slowly to room temperature and stirred for 3 h. The resulting solid is collected by filtration, washed with heptane, and dried under vacuum to give intermediate I-4.

[0231] Representative Procedure 3: Preparation of Compounds A and A': To a stirred solution of intermediate I-4 (1.0 equiv.) and commercially available intermediate I-5 (1.0 equiv.) in EtOH (0.1 M), HCl (6.0 equiv., 37% aqueous solution) is added at 0° C. The reaction mixture is slowly warmed to room temperature and stirred at 90° C. for 24 h. Upon completion, the volatiles are removed under vacuum and the crude oily residue is diluted with water, basified with NaOH (2.0 M aqueous solution), and extracted with EtOAc. The combined organic layers are washed with brine solution and the combined organic layers are dried over anhydrous Na2SO4. The solids are removed by filtration and the filtrate is concentrated under vacuum to give a regioisomeric mixture, which is separated by silica gel chromatography to give compounds A and A'. The chemical structures of compounds A and A' are assigned by using 1H-NMR spectroscopy techniques.

[0232] Representative Procedure 4: Preparation of compounds B and B': To a stirred solution of compound B (1.0 eq.) in a mixture of MeOH (5 vol.) and THF (5 vol.), a solution of formaldehyde (37% in water, 2.0 eq.) is added at room temperature and the reaction mixture is stirred for 1 h. The reaction mixture is cooled to 0° C., NaCNBH3 (2.0 eq.) is added in portions, and the reaction mixture is slowly warmed to room temperature and stirred for an additional 16 h. The volatiles are removed under vacuum and the crude reaction residue is washed with water and extracted with EtOAc. The combined organic layers are washed with aqueous NaCl, the organic layers are dried over anhydrous Na2SO4 and concentrated in vacuo. The crude reaction residue is purified by silica gel chromatography to give compound B. Compound B' is prepared using the same synthetic procedure except that compound A' is used as the starting material.

[0233] Representative Procedure 5: Preparation of intermediate I-6: To a stirred solution of compound A (1.0 equiv.) in CHCl (10 vol.) is added EtN (3.0 equiv.) followed by BocO (0.8 equiv.) at 0° C. The resulting reaction mixture is slowly warmed to room temperature and stirred for 4 h. The reaction mixture is diluted with ice-cold water and extracted with CHCl. ​​The combined organic layers are washed with aqueous NaCl, the organic layer is dried over anhydrous NaSO, the solids are removed by filtration, and the filtrate is concentrated under vacuum. The crude reaction residue is purified by silica gel chromatography to give compound I-6.

[0234] Representative Procedure 6: Preparation of intermediate I-7: To a stirred solution of intermediate I-6 (1.0 equiv.) in DMF (10 vol.) is added NaH (60% in mineral oil, 1.5 equiv.) at 0° C. The reaction mixture is stirred for 20 min and methyl iodide (1.5 equiv.) is added. The reaction mixture is slowly warmed to room temperature, stirred for 3 h, diluted with ice-cold water and extracted with EtOAc. The combined organic layers are washed with ice-cold water, aqueous NaCl, dried over anhydrous Na2SO4, the solids are removed by filtration and the filtrate is concentrated under vacuum. The crude reaction residue is purified by silica gel chromatography to give intermediate I-7.

[0235] Representative Procedure 7: Preparation of Compound C: To a stirred solution of intermediate I-7 (1.0 equiv.) in CHCl (10 vol.) is added HCl (5.0 equiv., 2 M solution in EtO) at 0° C. and the reaction mixture is allowed to warm slowly to room temperature and stirred for 6 h. The volatiles are removed in vacuo and the crude residue is triturated with diethyl ether to give compound C as the HCl salt.

[0236] Representative Procedure 8: Preparation of compound D: To a stirred solution of compound C (1.0 equiv.) in a mixture of MeOH (5 vol.) and THF (5 vol.), a solution of formaldehyde (2.0 equiv., 37% aqueous solution) is added at room temperature, the reaction mixture is stirred for 1 h, cooled to 0° C., and NaCNBH3 (2.0 equiv.) is added portionwise. The reaction mixture is allowed to warm to room temperature and stirred for an additional 16 h. The volatiles are removed under vacuum, the crude reaction residue is washed with water and extracted with EtOAc. The combined organic layers are washed with aqueous NaCl, the combined organic layers are dried over anhydrous Na2SO4, the solids are removed by filtration, and the filtrate is concentrated under vacuum. The crude reaction residue is purified by silica gel chromatography to give compound D.

[0237] Representative Procedure 9: Preparation of Fumarate Salt:

[0238] Fumaric acid is added to a sealed tube containing acetone. The suspension is heated to 40° C. until all fumaric acid is dissolved. A solution of the compound described herein as a free base in acetone is added dropwise at the same temperature, and the mixture is stirred for 1 hour. After the solution is cooled to room temperature, the solid is filtered, washed with acetone, and dried under reduced pressure to obtain the compound described herein as a fumarate salt.

[0239] Example 1: Preparation of 3-phenoxyaniline (I-3a): The title compound was obtained according to representative procedure 1 using iodobenzene (I-1a) and 3-aminophenol (I-2) and purified to give intermediate I-3a. ESI-Ms m / z: 185.85 [M+H]+.

[0240] Example 2: Preparation of 3-(4-fluorophenoxy)aniline (I-3b): The title compound was obtained according to representative procedure 1 using 1-fluoro 4-iodobenzene (I-1b) and 3-aminophenol (I-2) and purified to give intermediate I-3b. ESI-MS m / z=204.15 [M+H]+.

[0241] Example 3: Preparation of (3-phenoxyphenyl)hydrazine.HCl (I-4a): The title compound was obtained following representative procedure 2 using 3-phenoxyaniline (I-3a) and purified to give intermediate I-4a. ESI-MS m / z=200.90 [M+H]+.

[0242] Example 4: Preparation of (3-(4-fluorophenoxy)phenyl)hydrazine.HCl (I-4b): The title compound was obtained following representative procedure 2 using 3-(4-fluorophenoxy)aniline (I-3b) and purified to give intermediate I-4b. LCMS ESI-MS m / z=219.03 [M+H]+.

[0243] Example 5: Preparation of (3-(benzyloxy)phenyl)hydrazine.HCl (I-4c): According to representative procedure 2, 3-(benzyloxy)aniline (I-3c) was used to obtain the title compound, which was purified to give intermediate I-4c. ESI-Ms m / z: 215.12 [M+H]+.

[0244] Example 6: Preparation of (2-(benzyloxy)phenyl)hydrazine (I-4f): The title compound was obtained using 2-(benzyloxy)aniline (I-3c) following representative procedure 2 and purified to give intermediate I-4f. ESI-Ms m / z: 215.1 [M+H]+.

[0245] Example 7: Preparation of compounds 3 and 4: Following representative procedure 3, the title compound was obtained using I-4c and azepan-4-one hydrochloride (I-5), which was purified by HPLC separation method C to isolate compound 3 and compound 4. Compound 3: ESI-MS m / z=293.2 [M+H]+, 1 H NMR (DMSO-d6, 400MHz): δ 10.42(s,1H),7.48-7.28(m,5H),7.28-7.17(m,1H),6.79(d,J=2.0 Hz,1H),6.65(dd,J=8.5,2.1 Hz,1H),5.08(s,2H),2.93-2.83(m,4H),2.83-2.74(m,2H),2.71-2.66(m,2H). Following representative procedure 9, compound 3 was prepared to afford the corresponding fumarate salt. Compound 4: ESI-MS m / z=293.2[M+H]+. 1 H NMR(DMSO-d6,400 MHz):δ 10.67(s,1H),7.50-7.30(m,5H),6.87-6.79(m,2H),6.52-6.46(m,1H) ,5.15(s,2H),4.51-3.92(m,1H),3.18-3.13(m,2H),2.95-2.81(m,6H). Following representative procedure 9, compound 4 was prepared to afford the corresponding fumarate salt.

[0246] Example 8: Preparation of compounds 11 and 20: Following representative procedure 3, I-4a and azepan-4-one hydrochloride (I-5) were used to obtain the title compound, which was purified by HPLC separation method C to isolate compound 11 and compound 20. Following representative procedure 9, compound 11 provided the corresponding fumarate salt. Following representative procedure 9, compound 20 afforded the corresponding fumarate salt.

[0247] Example 9: Preparation of compounds 15 and 21: Following representative procedure 3, I-4b and azepan-4-one hydrochloride (I-5) were used to obtain the title compound, which was purified by HPLC separation method C to isolate compound 15 and compound 21. Following representative procedure 9, compound 15 afforded the corresponding fumarate salt. Following representative procedure 9, compound 21 afforded the corresponding fumarate salt.

[0248] Example 10: Preparation of compound 25: The title compound was obtained according to representative procedure 3 using 4-(benzyloxy)phenylhydrazine hydrochloride (I-4e) and azepan-4-one hydrochloride (I-5) and purified to give compound 25. Following representative procedure 9, compound 25 afforded the corresponding fumarate salt.

[0249] Example 11: Preparation of compound 27: The title compound was obtained according to representative procedure 3 using I-4f and azepan-4-one hydrochloride (I-5) and purified to give compound 27. ESI-Ms m / z: 293.2 [M+H]+. Following representative procedure 9, compound 27 afforded the corresponding fumarate salt.

[0250] Example 12: Preparation of compound 26: The title compound was obtained according to representative procedure 3 using I-4e and 1-methylazepan-4-one hydrochloride (I-5b) and purified to give compound 26. ESI-Ms m / z: 307.05 [M+H]+. Following representative procedure 9, compound 26 afforded the corresponding fumarate salt.

[0251] Example 13: Preparation of compound 28: The title compound was obtained according to representative procedure 3 using I-4f and 1-methylazepan-4-one hydrochloride (I-5b) and purified to give compound 28. 1H NMR(400 MHz,DMSO-d6)δ 10.78(br s,1H),7.54(d,J=7.4 Hz,2H),7.43-7.37(m,2H),7.37-7.30(m,1H),6.98(d,J=7.8 Hz,1H),6.83(t,J=7.8 Hz,1H),6.65(d,J=7.5 Hz,1H),5.23(s,2H),3.02-2.82(m,8H),2.59(s,3H) Following representative procedure 9, compound 28 afforded the corresponding fumarate salt.

[0252] Example 14: Preparation of compound 12: Following representative procedure 4, compound 11, formaldehyde and NaCNBH 3 were used to obtain the title compound, which was purified by HPLC separation method A to obtain compound 12. Following representative procedure 9, compound 12 was prepared to afford the corresponding fumarate salt.

[0253] Example 15: Preparation of compound 16: Following representative procedure 4, compound 15, formaldehyde and NaCNBH 3 were used to give the title compound, which was purified by A to give compound 16. Following representative procedure 9, compound 16 afforded the corresponding fumarate salt.

[0254] Example 16: Preparation of Compound 1: Following representative procedure 4, compound 3, formaldehyde and NaCNBH 3 were used to obtain the title compound, which was purified by A to obtain compound 1. Following representative procedure 9, compound 1 was prepared to afford the corresponding fumarate salt.

[0255] Example 17: Preparation of Compound 8: Following representative procedure 4, the title compound was obtained using compound 7 (example 43), formaldehyde and NaCNBH3, which was purified by A to give compound 8. ESI-Ms m / z: 325.2 [M+H]+. Following representative procedure 9, compound 8 afforded the corresponding fumarate salt.

[0256] Example 18: Preparation of compound 22: Following representative procedure 4, compound 21, formaldehyde and NaCNBH3 were used to obtain the title compound, which was purified by HPLC separation method A to obtain compound 22. ESI-Ms m / z: 311.2 [M+H]+. Following representative procedure 9, compound 22 afforded the corresponding fumarate salt.

[0257] Example 19: Preparation of tert-butyl 8-phenoxy-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (I-6a): Following representative procedure 5, the title compound was obtained using compound 11, Et3N, and Boc2O, which was purified to give intermediate I-6a. ESI-Ms m / z: 323.2 [M-56]+.

[0258] Example 20: Preparation of tert-butyl 8-(4-fluorophenoxy)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (I-6b): Following representative procedure 5, the title compound was obtained using compound 15, Et3N, and Boc2O, which was purified to give intermediate I-6b. ESI-Ms m / z: 397.2 [M+H]+.

[0259] Example 21: Preparation of tert-butyl 8-(benzyloxy)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (I-6c): The title compound was obtained according to representative procedure 5 using compound 3, Et3N, and Boc2O and purified to give I-6c. ESI-MS m / z=335.2 [M-56]+.

[0260] Example 22: Preparation of tert-butyl 10-(4-fluorophenoxy)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (I-6e): According to representative procedure 5, the title compound was obtained using compound 21, Et3N and Boc2O and purified to give I-6e. ESI-Ms m / z: 395.3 [M+H]+.

[0261] Example 23: Preparation of tert-butyl 10-(benzyloxy)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (I-6f): Following representative procedure 5, the title compound was obtained using compound 4, Et3N, and Boc2O, which was purified to give I-6f. ESI-Ms m / z: 393.2 [M+H]+.

[0262] Example 24: Preparation of tert-butyl 6-methyl-8-phenoxy-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (I-7a): Following representative procedure 6, the title compound was obtained using I-6a, NaH, and MeI, which was purified to give I-7a. ESI-MS m / z=393.2 [M+H]+.

[0263] Example 25: Preparation of tert-butyl 8-(4-fluorophenoxy)-6-methyl-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (I-7b): Following representative procedure 6, I-6b, NaH, and MeI were used to obtain the title compound which was purified to give I-7b.

[0264] Example 26: Preparation of tert-butyl 8-(benzyloxy)-6-methyl-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (I-7c): Following representative procedure 6, I-6c, NaH, and MeI were used to obtain the title compound which was purified to give intermediate I-7c.

[0265] Example 27: Preparation of tert-butyl 8-((4-fluorobenzyl)oxy)-6-methyl-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (I-7d): The title compound was obtained following representative procedure 6 using I-6d (example 42), NaH, and MeI, and purified to give I-7d. ESI-Ms m / z: 425.05 [M+H]+.

[0266] Example 28: Preparation of tert-butyl 10-(4-fluorophenoxy)-6-methyl-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (I-7e): The title compound was obtained following representative procedure 6 using I-6e, NaH, and MeI and purified to give I-7e; ESI-Ms m / z: 411.3 [M+H]+.

[0267] Example 29: Preparation of tert-butyl 10-(benzyloxy)-6-methyl-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (I-7f): The title compound was obtained following representative procedure 6 using I-6f, NaH, and MeI and purified to give I-7f. ESI-Ms m / z: 407.2 [M+H]+.

[0268] Example 30: Preparation of compound 13: Following representative procedure 7, the title compound was isolated as the HCl salt using I-7a and 2M HCl in EtO after trituration with diethyl ether. The HCl salt was basified with saturated aqueous NaHCO, extracted with EtOAc (2×20 ml), and evaporated to dryness to give compound 13. Following representative procedure 9, compound 13 afforded the corresponding fumarate salt.

[0269] Example 31: Preparation of compound 17: Following representative procedure 7, using I-7b and 2M HCl in Et2O, the title compound was isolated as the HCl salt after trituration with diethyl ether. The HCl salt is basified with saturated aqueous NaHCO3, extracted with EtOAc (2 x 20 ml) and dried to give compound 17. Following representative procedure 9, compound 17 was converted to the corresponding fumarate salt.

[0270] Example 32: Preparation of Compound 5: Following representative procedure 7, using I-7c and 2M HCl in Et2O, the title compound was isolated as the HCl salt after trituration with diethyl ether. The HCl salt is basified with saturated aqueous NaHCO3, extracted with EtOAc (2 x 20 ml) and dried to give compound 5. Following representative procedure 9, compound 5 afforded the corresponding fumarate salt.

[0271] Example 33: Preparation of Compound 9: Following representative procedure 7, the title compound was isolated as the HCl salt using I-7d and 2M HCl in Et2O after trituration with diethyl ether. The HCl salt was basified with saturated aqueous NaHCO3, extracted with EtOAc (2 x 20 ml) and dried to give compound 5. ESI-Ms m / z: 325.2 [M+H]+. Following representative procedure 9, compound 9 afforded the corresponding fumarate salt.

[0272] Example 34: Preparation of compound 23: Following representative procedure 7, the title compound was isolated as the HCl salt using I-7e and 2M HCl in Et2O after trituration with diethyl ether. The HCl salt was basified with saturated aqueous NaHCO3, extracted with EtOAc (2 x 20 ml) and dried to give compound 23. ESI-Ms m / z: 311.1 [M+H]+. Following representative procedure 9, compound 23 afforded the corresponding fumarate salt.

[0273] Example 35: Preparation of compound 19: Following representative procedure 7, the title compound was obtained using I-7f and 2M HCl in Et2O, which was triturated to give compound 19 as the HCl salt. The HCl salt was basified with saturated aqueous NaHCO3, extracted with EtOAc (2 x 20 ml), and dried to give compound 19. ESI-Ms m / z: 307.2 [M+H]+. Following representative procedure 9, compound 19 afforded the corresponding fumarate salt.

[0274] Example 36: Preparation of compound 18: Following representative procedure 8, compound 17, formaldehyde and NaCNBH3 were used to obtain the title compound, which was purified to obtain compound 18. Following representative procedure 9, compound 18 provided the corresponding fumarate salt.

[0275] Example 37: Preparation of Compound 6: Following representative procedure 8, the title compound was obtained using compound 5, formaldehyde and NaCNBH 3 , which was purified to give compound 6. Following representative procedure 9, compound 6 afforded the corresponding fumarate salt.

[0276] Example 38: Preparation of Compound 10: Following representative procedure 8, the title compound was obtained using compound 9, formaldehyde and NaCNBH3, which was purified to give compound 10. ESI-Ms m / z: 339.00 [M+H]+. Following representative procedure 9, compound 10 afforded the corresponding fumarate salt.

[0277] Example 39: Preparation of compound 24: Following representative procedure 8, the title compound was obtained using compound 23, formaldehyde and NaCNBH3, which was purified to give compound 24. ESI-Ms m / z: 325.20 [M+H]+. Following representative procedure 9, compound 24 afforded the corresponding fumarate salt.

[0278] Example 40: Preparation of compound 14: To a stirred solution of I-7a (110 mg, 1.0 equiv) in THF (1.1 ml) was added a solution of 2M LAH in THF (0.420 ml, 0.841 mmol, 3.0 equiv) at 0° C. The reaction mixture was refluxed for 3 h, quenched with ice-cold water, filtered through Celite, and washed with EtOAc (2×10 ml). The combined organic layers were washed with aqueous NaCl, dried over anhydrous Na2SO4, and concentrated under vacuum. The crude residue was purified using a CombiFlash® chromatography system to give compound 14. Following representative procedure 9, compound 14 was prepared to afford the corresponding fumarate salt.

[0279] As described for Scheme 1, the compounds in Table 2 are prepared using appropriately substituted anilines.

[0280] [Table 2-1]

[0281] [Table 2-2]

[0282] [Table 2-3]

[0283] [Table 2-4]

[0284] [Table 2-5]

[0285] [Table 2-6]

[0286] In some embodiments, the compounds provided herein are prepared as outlined in Scheme 2.

[0287] [ka]

[0288] Example 41: Preparation of tert-butyl 8-hydroxy-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (I-6g): To a stirred solution of I-6c (1.2 g, 3.05 mmol, 1 equiv) in MeOH (12 ml) under N2 atmosphere was added 10% Pd / C (1.29 g, w / w). The suspension was stirred at room temperature under H2 (60 psi) for 4 h. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to give the crude compound, which was purified using a CombiFlash® chromatography system (3% MeOH in CH2Cl2) purification to give I-6g (900 mg, 99%) as an off-white solid. ESI-Ms m / z: 301.1 [MH]+.

[0289] Example 42: Preparation of tert-butyl 8-((4-fluorobenzyl)oxy)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (I-6d): To a stirred solution of I-6g (650 mg, 2.14 mmol) in DMF (6.5 mL) was added cesium carbonate (1.39 g, 4.28 mmol) followed by 1-(bromomethyl)-4-fluorobenzene (404 mg, 2.14 mmol) and stirred at room temperature for 16 h. The reaction mixture was diluted with water and extracted with EtOAc (2×100 ml). The organic layer was washed with water, dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified using a CombiFlash® chromatography system (10% MeOH in DCM) to give I-6d (550 mg, 62%), ESI-MS m / z: 355.1 [M-56]+.

[0290] Example 43: Preparation of Compound 7: Following representative procedure 7, I-6d and 2M HCl in Et2O were used to give the title compound after neutralization of the reaction mixture with aqueous NaHCO3 and extraction with NaHCO3, resulting in compound 7. Following representative procedure 9, compound 7 afforded the corresponding fumarate salt.

[0291] The compounds in Table 3 are prepared as described in Scheme 2.

[0292] [Table 3]

[0293] In some embodiments, the compounds provided herein are prepared as outlined in Scheme 3.

[0294] [ka]

[0295] Example 44: Preparation of 5-(benzyloxy)-2-bromoaniline (I-3g): To a stirred solution of I-2c (20 g, 106 mmol, 1.0 equiv) in DMF (200 ml) was added potassium tert-butoxide (14.2 g, 127.2 mmol, 1.2 equiv) at 0° C. The reaction mixture was stirred for 30 min, benzyl bromide (15.9 g, 84.8 mmol, 0.8 equiv) was added at 0° C., the reaction mixture was slowly warmed to room temperature, and then stirred at room temperature for 16 h. The reaction mixture was quenched with ice-cold water (250 ml) and extracted with EtOAc (2×500 ml). The combined organic layers were washed with ice-cold water followed by aqueous NaCl. The organic layer was separated, dried over Na2SO4, and concentrated to give the crude material, which was purified using a CombiFlash® chromatography system (10-15% EtOAc / Hexanes) to give I-3g (16.5 g, 55%). ESI-Ms m / z: 280.0[M+H]+.

[0296] Example 45: Preparation of (5-(benzyloxy)-2-bromophenyl)hydrazine.HCl (I-4g): Following representative procedure 2, I-3g (10 g, 35.9 mmol), NaNO2 (4.98 g, 71.8 mmol), and SnCl2·2H2O (24.43 g, 107.7 mmol) were used to obtain the title compound after washing and drying, resulting in I-4g (10 g, 95%). ESI-Ms m / z: 292.90 [M+H].

[0297] Example 46: Preparation of compound 29: Following representative procedure 3, I-4g (5 g, 15.2 mmol), I-5b (2.3 g, 18.2 mmol), and concentrated HCl (2.65 mL) were used to obtain the title compound after purification by HPLC separation method A, resulting in compound 29 (500 mg). Following representative procedure 9, compound 29 afforded the corresponding fumarate salt.

[0298] Example 47: Preparation of Compound 2: Following representative procedure 9, compound 29 provided the corresponding fumarate salt. The reaction mixture was heated to reflux for 3 h. The reaction was quenched with saturated NH4Cl solution, extracted with 10% MeOH / DCM (2 x 50 ml), and the combined organic layers were washed with saturated NaHCO3 solution. The volatiles were removed under reduced pressure, and the residue was purified by HPLC separation method B to give compound 2. Following representative procedure 9, compound 2 was prepared to afford the corresponding fumarate salt.

[0299] The compounds in Table 4 are prepared as described in Scheme 3.

[0300] [Table 4]

[0301] Pharmaceutical Compositions Example A-1: ​​Parenteral pharmaceutical composition To prepare a parenteral pharmaceutical composition suitable for administration by injection (subcutaneous, intravenous), 1-1000 mg of a water-soluble salt of a compound described herein, or a pharma- ceutically acceptable salt or solvate thereof, is dissolved in sterile water and then mixed with 10 mL of 0.9% sterile saline. An appropriate buffer, along with an optional acid or base, is optionally added to adjust the pH. The mixture is incorporated into a dosage unit form suitable for administration by injection.

[0302] Example A-2: Oral Solution To prepare an orally delivered pharmaceutical composition, a sufficient amount of a compound described herein, or a pharma- ceutically acceptable salt thereof, is added to water (along with optional solubilizers, optional buffers, and taste-masking excipients) to obtain a 20 mg / mL solution.

[0303] Example A-3: Oral Tablet Tablets are prepared by mixing 20-50% by weight of a compound described herein, or a pharma- ceutically acceptable salt thereof, 20-50% by weight of microcrystalline cellulose, and 1-10% by weight of magnesium stearate, or other suitable excipients. Tablets are prepared by direct compression. The total weight of the compressed tablets is maintained at 100-500 mg.

[0304] Example A-4: Oral Capsules To prepare a pharmaceutical composition for oral delivery, 1-1000 mg of a compound described herein, or a pharma- ceutically acceptable salt thereof, is mixed with starch or other suitable powder mixture, and the mixture is incorporated into an oral dosage form, such as a hard gelatin capsule, suitable for oral administration.

[0305] In another embodiment, 1-1000 mg of a compound described herein, or a pharma- ceutically acceptable salt thereof, is placed into a size 4 capsule, or a size 1 capsule (hypromellose or hard gelatin) and the capsule is closed.

[0306] Biological Examples Hallucinogenic potential. The hallucinogenic compound 5-MeO-DMT produces a robust dose-dependent head twitch response (HTR) in mice. However, the isosteric compound 6-MeO-DMT is significantly less potent. As expected from the drug discrimination data, 6-MeO-DMT does not produce an HTR. Finally, potent plasticity-promoting compounds do not produce an HTR, demonstrating that hallucinogenic potential and psychoplastogenicity can be dissociated.

[0307] Hallucinogens (e.g., LSD and 5-MeO-DMT) act in an agonist mode to inhibit 5HT 2AIn addition, compounds that are hallucinogenic in animals (e.g., humans), such as 5-MeO-DMT, LSD, DMT, and DOI, can activate the 5HT sensor assay in an agonist mode, whereas their non-hallucinogenic congeners (lysulfide (LIS) and 6-MeO-DMT) cannot. 2A While activating the sensor assay, compounds that are non-hallucinogenic in animals (e.g., humans), such as 6-MeO-DMT, LIS, 6-F-DET, L-MDMA, R-MDMA, ketanserin, and BOL148, inhibit 5HT in an agonist mode. 2A In some embodiments, the hallucinogenic potential of the compounds provided herein is determined in vitro. In some embodiments, the hallucinogenic potential of the compounds provided herein is determined in vitro by activating the 5HT 2A In some embodiments, the 5HT 2A The sensor assay is in agonist or antagonist mode. In some embodiments, 5HT 2A The sensor assay is in agonist mode. In some embodiments, the compounds provided herein do not activate the sensor in agonist mode and have non-hallucinogenic potential. In some embodiments, the compounds provided herein do not activate the sensor in agonist mode and are non-hallucinogenic compounds.

[0308] In some embodiments, the hallucinogenic potential of the compounds provided herein is enhanced by the agonist mode of 5HT 2A The activity is evaluated in a sensor assay.

[0309] Additionally, in some instances, non-hallucinogenic compounds (e.g., lisuride and 6-MeO-DMT) may suppress the 5HT 2AWhen the sensor assay is performed in antagonist mode, it competes off 5-HT. In addition, compounds that are non-hallucinogenic in animals (e.g., humans), such as 6-F-DET, ketanserin, and BOL148, compete off 5-HT in the antagonist mode of the sensor assay. 2A In some embodiments, the compounds provided herein can compete with the binding of 5HT to 5-HT. 2A In some embodiments, the 5HT 2A The sensor assay is in antagonist mode. In some embodiments, the compounds provided herein inhibit the 5HT 2A In some embodiments, the compounds provided herein inhibit the binding of 5-HT to 5HT, and thus have the potential to be non-hallucinogenic. 2A In some embodiments, the compounds provided herein inhibit the binding of 5-HT to 5HT in an antagonistic manner and are non-hallucinogenic. 2A In some embodiments, the compounds provided herein are non-hallucinogenic compounds that prevent the binding of 5-HT in antagonistic mode. In some embodiments, the compounds provided herein are non-hallucinogenic compounds that prevent the binding of 5-HT in antagonistic mode. In some embodiments, the compounds provided herein are non-hallucinogenic compounds that inhibit the response of the sensor assay in antagonistic mode. In some embodiments, the compounds provided herein are non-hallucinogenic compounds that inhibit the response of the sensor assay in antagonistic mode.

[0310] In some embodiments, the results of the agonist mode sensor assay indicate that the compounds provided herein inhibit the 5-HT 2A In some embodiments, the results of the antagonist mode sensor assay suggest that the compounds provided herein are non-psychedelic ligands of the 5-HT 2A In some embodiments, the results of both the agonist and antagonist sensor assays indicate that the compounds provided herein are non-psychedelic ligands of the 5-HT 2AThis suggests that it is a non-hallucinogenic ligand for the receptor.

[0311] In some embodiments, the hallucinogenic potential of the compound is determined by its antagonistic mode of 5HT 2A Assessed in a sensor assay.

[0312] Forced swimming test. Increased cortical structural plasticity in the anterior brain mediates the sustained (>24 h) antidepressant-like effects of ketamine, and 5-HT 2A The therapeutic potential of the compounds provided herein is evaluated using their effects on forced swim test (FST) behavior, as this behavior plays a role in the therapeutic efficacy of agonists. First, a pre-test is performed to induce a depressive phenotype. Compounds are administered 24 hours after the pre-test, and the FST is performed 24 hours and 7 days after drug administration.

[0313] Neurite outgrowth assay. Alterations in the pattern of neurite outgrowth have been implicated in psychiatric and neurodegenerative disorders as well as trauma. Discovery of novel compounds that can positively affect neuritogenesis is important for developing new treatments for neurological diseases. In some examples, measurements of neurite outgrowth in rat cortical neurons using an automated image-based assay are used to determine the neuroplasticity effects of compounds provided herein. In some embodiments, compounds provided herein increase the pattern of neurite outgrowth. In some embodiments, compounds provided herein increase the average neurite length compared to a control. In some embodiments, compounds provided herein increase neurite branch points compared to a control. In some embodiments, compounds provided herein increase the average neurite length and neurite branch points compared to a control.

[0314] In some embodiments, the plastogenic potential of the compounds provided herein is assessed by measuring changes in neurite development.

[0315] Dendritic formation assay. Phenotypic screening has historically proven more successful than target-based approaches in identifying drugs with novel mechanisms of action. Using a phenotypic assay, compounds provided herein are tested for their ability to increase dendritic branching complexity in cultures of cortical neurons. After treatment, neurons are fixed and visualized using an antibody against MAP2, a cytoskeletal protein that localizes to the somatodendritic compartment of neurons. Sholl analysis is then performed to determine the maximum number of intersections (N max ) is used as a quantitative index of dendritic branching complexity. For statistical comparisons between specific compounds, the raw N max The values ​​are compared. Percent efficacy is the N of the vehicle (DMSO) and positive (ketamine) controls. max The values ​​are determined by setting them equal to 0% and 100%, respectively.

[0316] Animals. For dendrite formation experiments, timed-pregnant Sprague-Dawley rats are obtained from Charles River Laboratories (Wilmington, MA). In some instances, male and female C57BL / 6J mice are obtained from Jackson Laboratory (Sacramento, CA). In some instances, mice are housed in groups of 4-5 (same sex) in a temperature- and humidity-controlled room maintained on a 12-h light / dark cycle.

[0317] Dendritic formation - Sholl analysis. Neurons are plated in 96-well format (200 μL medium per well) at a density of approximately 15000 cells / well in Neurobasal (Life Technologies) containing 1% penicillin-streptomycin, 10% heat-inactivated fetal bovine serum, and 0.5 mM glutamine. After 24 hours, the medium is replaced with Neurobasal containing 1×B27 supplement (Life Technologies), 1% penicillin-streptomycin, 0.5 mM glutamine, and 12.5 μM glutamic acid. After 3 days in vitro (DIV3), cells are treated with compounds. Compounds tested in the dendritogenic assay are treated at 10 μM unless otherwise specified. Stock solutions of compounds in DMSO were first diluted 100-fold in Neurobasal and then further diluted 10-fold in each well (total dilution ratio = 1:1000; 0.1% DMSO concentration). Treatments are randomized. After 1 h, the medium is removed and replaced with fresh Neurobasal medium containing 1x B27 supplement, 1% penicillin-streptomycin, 0.5 mM glutamine, and 12.5 μM glutamic acid. Cells are grown for an additional 71 h. At that point, neurons are fixed by removing 80% of the medium and replacing it with a volume of 4% aqueous paraformaldehyde (Alfa Aesar) equal to 50% of the working volume of the well. Cells are then incubated at room temperature for 20 min, after which the fixative is aspirated and each well is washed twice with DPBS. Cells are permeabilized with 0.2% Triton X-100 (ThermoFisher) in DPBS for 20 min at room temperature without shaking. The plates are blocked with antibody dilution buffer (ADB) containing 2% bovine serum albumin (BSA) in DPBS for 1 h at room temperature. The plates are then incubated overnight at 4° C. with gentle shaking in ADB containing chicken anti-MAP2 antibody (1:10,000; EnCor, CPCA-MAP2). The next day, the plates are washed three times with DPBS and once with 2% ADB in DPBS.Plates were incubated in ADB containing anti-chicken IgG secondary antibody conjugated to Alexa Fluor 488 (Life Technologies, 1:500) for 1 h at room temperature and washed five times with DPBS. After the final wash, 100 μL of DPBS was added per well and imaged using a 20x objective on an ImageXpress Micro XL High-Content Screening System (Molecular Devices, Sunnyvale, CA).

[0318] Images are analyzed using ImageJ Fiji (version 1.51W). First, images corresponding to each treatment are sorted into individual folders and blinded for data analysis. Plate controls (both positive and negative) are used to ensure that the assay is working properly as well as to visually determine appropriate values ​​for brightness / contrast and threshold to be universally applied to the rest of the randomized images. Brightness / contrast settings are then applied and approximately 1-2 individual pyramidal-like neurons (i.e., no bipolar neurons) per image are selected with the rectangular selection tool and saved as separate files. Neurons that do not overlap extensively with other cells or extend significantly out of the field of view are selected. Threshold settings are then applied to individual images. Artefacts and dendrites originating from neighboring neurons are removed with the paintbrush tool (clean-up stage), then the center of the neuron is selected with the point tool, images are saved and processed using the following Sholl analysis batch macro: run(“Sholl Analysis...”,“starting=0 ending=NaN radius_step=2 #_samples=1 integration=Mean enclosing=1 #_primary=4 infer fit linear polynomial=[Best fitting degree] most semi-log normalizer=Area create background=228 save do”); Sholl analysis circle radius = 2 pixel increment = 0.67 μm. All images are taken and analyzed by an experimenter blinded to treatment conditions. An average Sholl plot for each treatment is created by averaging the number of crossings for each neuron at each separate radius. N max Values ​​are simply determined by identifying the maximum value of each plot. For each treatment, neurons are selected from at least 6 wells across 2 plates (9 sites / well x 3 wells / plate x 2 plates). Each plate is prepared with neurons obtained from an independent pregnant female parent).

[0319] Spine formation experiments are performed as previously described (Ly, C. et al., 2018), except that cells are treated at DIV19 and fixed 24 h after treatment at DIV20. Images are taken with a Nikon HCA Confocal microscope a equipped with a 100x / NA 1.45 oil objective. DMSO and ketamine (10 μM) are used as vehicle and positive controls, respectively.

[0320] Serotonin 5-HT2A in vitro radioligand binding competition assay. 5-HT2A radioligand binding competition assays were performed using conventional methods at Epics Therapeutics SA (Belgium, FAST-0505B). Briefly, competitive binding was performed in duplicate in wells of a 96-well plate (Master Block, Greiner, 786201) containing binding buffer (optimized for each receptor), membrane extract (amount of protein / well optimized for each receptor), radiotracer [3H]-DOI (final concentration optimized for each receptor), and test compound. Nonspecific binding was determined by coincubation with a 200-fold excess of cold competitor. Samples were incubated in a final volume of 0.1 ml at the optimal temperature and duration for each receptor and then filtered onto a filter plate. Filters were washed six times with 0.5 ml of ice-cold wash buffer (optimized for each receptor) and 50 μl of Microscint 20 (Packard) was added to each well. Plates were incubated for 15 min on an orbital shaker and then counted in a TopCount™ for 1 min / well.

[0321] Serotonin 5-HT 2A In vitro cellular IPOne agonism assay. 5-HT 2A The IPOne HTRF assay was performed at Epics Therapeutics SA (Belgium, FAST-0505I) using conventional methods. Briefly, human recombinant 5-HT47 grown to mid-log phase in antibiotic-free culture medium was used. 2A CHO-K1 cells expressing the receptor were detached with PBS-EDTA, centrifuged, and resuspended in medium without antibiotic buffer. 20,000 cells were dispensed into a 96-well plate and incubated overnight at 37°C, 5% CO2.

[0322] For agonist testing, the medium was removed and 20 μl of assay buffer and 20 μl of test compound or reference agonist were added into each well. Plates were incubated at 37° C., 5% CO2 for 60 min.

[0323] After adding lysis buffer containing IP1-d2 and anti-IP1 cryptate detection reagent, the plates were incubated at room temperature for 1 h, and the fluorescence ratio was measured using an HTRF kit according to the manufacturer's specifications.

[0324] Serotonin 5-HT2C in vitro radioligand binding competition assay. 5-HT2C edited (accession no. AAF35842.1) radioligand binding competition assays were performed using conventional methods at Epics Therapeutics SA (Belgium, FAST-0507B). Briefly, competitive binding was performed using binding buffer (optimized for each receptor), membrane extracts (amount of protein / well optimized for each receptor), radioactive tracer [ 3 H]-DOI (final concentration optimized for each receptor), and test compounds were performed in duplicate in wells of a 96-well plate (Master Block, Greiner, 786201). Nonspecific binding was determined by co-incubation with a 200-fold excess of cold competitor. Samples were incubated in a final volume of 0.1 ml at the optimal temperature and duration for each receptor and then filtered onto a filter plate. Filters were washed six times with 0.5 ml ice-cold wash buffer (optimized for each receptor) and 50 μl Microscint 20 (Packard) was added to each well. Plates were incubated for 15 min on an orbital shaker, followed by counting in a TopCount™ for 1 min / well.

[0325] Serotonin 5-HT2C in vitro cellular IPOne agonism assay. 5-HT2C IPOne HTRF assay was performed at Epics Therapeutics SA (Belgium, FAST-0507I) using conventional methods. Briefly, CHO-K1 cells expressing human recombinant 5-HT2C editing receptor (accession number AAF35842.1) grown to mid-log phase in antibiotic-free culture medium were detached with PBS-EDTA, centrifuged, and resuspended in antibiotic buffer-free medium. 20,000 cells were dispensed into 96-well plates and incubated overnight at 37°C, 5% CO2.

[0326] For agonist testing, the medium was removed and 20 μl of assay buffer and 20 μl of test compound or reference agonist were added into each well. Plates were incubated at 37° C., 5% CO2 for 60 min.

[0327] After adding lysis buffer containing IP1-d2 and anti-IP1 cryptate detection reagent, the plates were incubated at room temperature for 1 h and the fluorescence ratio was measured using an HTRF kit according to the manufacturer's specifications.

[0328] The compounds provided herein can be used to inhibit serotonin 5-HT 2A and 5-HT2C were tested in in vitro radioligand binding and cellular IPOne agonism assays. The binding and agonism functional potencies of the compounds (their IC 50 or EC 50 (denoted by) are shown in Table 5.

[0329] [Table 5-1]

[0330] [Table 5-2]

[0331] Serotonin 5-HT2A and 5-HT2C In Vitro Cellular IPOne Agonism Assays. 5-HT2A IPOne HTRF assays were performed using conventional methods at Epics Therapeutics SA (Belgium, FAST-0505I) in antagonist mode. Briefly, CHO-K1 cells expressing human recombinant 5-HT2A receptors grown to mid-log phase in antibiotic-free culture medium were detached with PBS-EDTA, centrifuged, and resuspended in antibiotic buffer-free medium. 20,000 cells were dispensed into 96-well plates and incubated overnight at 37°C, 5% CO2.

[0332] For antagonist testing, the reference agonist α-Me-5HT was added and the fluorescent signal was monitored for several minutes, followed by addition of 20 μl of assay buffer and 20 μl of test compound or the reference antagonist ketanserin to each well. Plates were incubated at 37° C., 5% CO2 for 60 minutes.

[0333] After adding lysis buffer containing IP1-d2 and anti-IP1 cryptate detection reagent, the plates were incubated for 1 h at room temperature and the fluorescence ratio was measured using an HTRF kit according to the manufacturer's specifications.

[0334] The compounds provided herein can be used to inhibit serotonin 5-HT 2A and 5-HT2C are tested in in vitro radioligand binding and cellular IPOne antagonism assays. The antagonistic functional potency of the compounds (their IC 50 or EC 50 (denoted by) are shown in Table 6.

[0335] [Table 6]

[0336] Neurite outgrowth assay. Altered patterns of neurite outgrowth are implicated in traumatic injury as well as psychiatric and neurodegenerative disorders. The discovery of novel compounds that can positively affect neuritogenesis is important for developing new treatments for neurological diseases. Measurement of neurite outgrowth of rat cortical neurons using an automated image-based assay is used to determine the neuroplasticity effects of the compounds described in this invention. The neurite outgrowth assay was performed at Neurofit SAS (France) as described below.

[0337] Pregnant Wistar rats (Janvier; France) were used for the studies. Wistar rats were delivered 6 days before use. Upon arrival at Neurofit's animal facility, Wistar rats were housed one per cage and maintained in a room with controlled temperature (21–22 °C) and a reversed light / dark cycle (12 h / 12 ​​h; lights on: 17:30–05:30; lights off: 05:30–17:30) with food and water available ad libitum.

[0338] Female Wistar rats on day 17 of gestation were killed by cervical dislocation and fetuses were removed from the uterus. The brains were placed in ice-cold Leibovitz medium (L15, Gibco, Fisher bioblock, France). The cerebral cortex was dissected and the meninges were carefully removed. Cortical neurons were dissociated by trypsinization (trypsin-EDTA, Gibco) in the presence of 0.1 mg / ml DNAse I (Roche, France) for 30 min at 37°C. The reaction was stopped by the addition of Dulbecco's modified Eagle's medium (DMEM; Gibco) containing 10% fetal bovine serum (FBS; Gibco). The suspension was triturated with a 10 ml pipette using a needle syringe 21 G and centrifuged at 350 × g for 10 min at room temperature. Dissociated cell pellets were resuspended in medium consisting of Neurobasal (Gibco) supplemented with 2% B27 supplement (Gibco), 0.5 mM L-glutamine (Gibco) and antibiotic-antimicrobial mixture. Viable cells were counted in a Neubauer cytometer using a trypan blue dye exclusion test (Sigma). Cells were seeded at a density of 10,000 cells per well in poly-L-lysine pre-coated 96-well plates (Costar). Different concentrations of test compounds were added to the cultures. Donepezil (positive control) was tested at 250 nM.

[0339] After plating for 72 h (3 days), cultures were fixed with paraformaldehyde (4%, Sigma) in PBS for 30 min at 4 °C. Next, cells were successively permeabilized with 0.1% Triton X100 for 30 min, saturated with PBS containing 3% BSA, and incubated with anti-βIII tubulin antibody (Sigma) at 1 / 10 000 in PBS containing 0.5% BSA for 1 h. Cells were washed three times with PBS containing 0.5% BSA and incubated with goat anti-mouse antibody conjugated with AF488 (Invitrogen A11001) diluted at 1 / 1000 in PBS containing 0.5% BSA for 1 h. Finally, nuclei were stained with DAPI 1 mg / ml at 1 / 1000 in PBS containing 0.5% BSA. After washing with PBS, plates were photographed and neurite networks were examined and analyzed using High-Content Screening (CellInsight, Thermo Scientific). The mean neurite number per neuron and the mean total neurite length per neuron were the main parameters analyzed. Data were analyzed using analysis of variance (ANOVA). Fisher's Protected Least Significant Difference test was used for multiple comparisons. A p value ≦0.05 was considered significant. The software used was StatView 5.0 from SAS Institute.

[0340] In some embodiments, the compounds of the present invention increase the pattern of neurite outgrowth. In some embodiments, the compounds of the present invention increase the average length of neurites compared to controls. In some embodiments, the compounds of the present invention increase the branch points of neurites compared to controls. In some embodiments, the compounds of the present invention significantly increase the number of new neurites and / or the average neurite length compared to controls.

[0341] The plastogenic potential of the compounds (as measured by neurite outgrowth procedure B) is shown in Table 7.

[0342] [Table 7]

[0343] 5HT 2A Sensor assay: HEK293T(ATCC)5HT 2A The sensor stable line (sLight1.3s) is generated via lentiviral transduction of HIV-EF1α-sLight1.3 and grown from a single colony. Lentivirus is generated using the second generation lentiviral plasmids pHIV-EF1α-sLight1.3, pHCMV-G, and pCMV-deltaR8.2.

[0344] For screening, sLight1.3s cells are plated in 96-well plates at a density of 40000 24 hours prior to imaging. On the day of imaging, compounds dissolved in DMSO are diluted from a 100 mM stock solution to working concentrations of 1 mM, 100 μM, and 1 μM with a DMSO concentration of 1%. Immediately prior to imaging, cells grown in DMEM (Gibco) are washed twice with HBSS (Gibco) and 180 μL of HBSS for agonist mode and 160 μL of HBSS for antagonist mode are added to each well after the final wash. In agonist mode, images are taken before and after the addition of 20 μL of compound working solution to wells containing 180 μL of HBSS. This results in final compound concentrations of 100 μM, 10 μM, and 100 nM with a DMSO concentration of 0.1%. In antagonist mode, images are taken before and after the addition of 20 μL of 900 nM 5-HT, and again after the addition of 20 μL of compound working solution to give a final concentration of 100 nM 5HT, and DMSO concentration of 0.1% and final compound concentrations of 100 μM, 10 μM, and 100 nM. Compounds are tested in triplicate (3 wells) for each concentration (100 μM, 10 μM, and 100 nM). In addition, controls of 100 nM 5HT and 0.1% DMSO can also be imaged within each plate.

[0345] Imaging is performed using a Leica DMi8 inverted microscope equipped with a 40x objective, using a FITC preset of excitation 460 nm and emission 512-542 nm. 2A The cell membrane where the sensor is targeted is autofocused using adaptive focus control, and five images are taken from different areas in the well, with each image processed from 2x2 binning.

[0346] For data processing, the membrane from each image is segmented and analyzed using a custom algorithm written in MATLAB to generate a single raw fluorescence intensity value. For each well, the five raw fluorescence intensity values ​​generated from the five images are averaged and the change in fluorescence intensity (dFF) is calculated as follows: dFF=(F sat -F apo ) / F apo

[0347] For both agonist and antagonist modes, the fluorescence intensity value before compound addition in HBSS alone was used as the Fapo value, and the fluorescence intensity value after compound addition was used as the Fsat value.

[0348] For agonist mode, data are as percent activation relative to 5HT, where 0 is the mean of DMSO wells and 100 is the mean of 100 uM 5HT wells. For antagonist mode, the inactivation score is calculated as follows: Inactivation score = (dFFF(compound + 5HT) - dFF(5HT)) / dFF(5HT)

[0349] Head twitch response (HTR) experiments. C57BL / 6J mice (9-10 weeks old) were housed according to an IACUC approved protocol. Mice were allowed to habituate for at least 30 min in the test cage, injected intraperitoneally with compound (5 ml / kg injection volume), returned to an empty test cage, and filmed for 20 min. Each video was scored for the number of head twitches by a trained observer blinded to treatment condition.

[0350] Forced swim test (FST). Male Sprague Dawley rats are obtained from Envigo (Indianapolis, IN) and housed three per cage according to an IACUC approved protocol. All experiments are conducted in clear acrylic forced swim chambers (40 cm high, 20.3 cm diameter) at ambient temperatures (20°C and 23°C) under artificial lighting during the light-dark cycle. Only one rat is placed in the swim chamber at a time for each swim test. The water is changed and the chamber is cleaned after each animal. All rats undergo two swim sessions. The water depth is 16 cm for the first swim session and 30 cm for the second swim session, and water temperature is maintained at 23±1°C for all swim sessions. During the FST, animals undergo a 15-min swim session (pre-swim), followed by 15 min drying with paper towels and returning to their home cage. After the habituation session, rats are injected with either saline, ketamine (positive control), or test compound, returned to their home cage, and tested in a second FST (second swim test) lasting 5 min up to 24 h later. The second swim test is videotaped for scoring. Body weight is measured on both days. The second swim test is scored using a time-sampling method in which trained technicians observe the animals during the videotaped test every 5 seconds and record the behaviors observed. Immobility, climbing, and swimming behaviors are scored.

[0351] Statistical Analysis. Treatments were randomized and data were analyzed by an experimenter blinded to treatment conditions. Statistical analysis was performed using GraphPad Prism (version 8.1.2). Comparisons were planned prior to each experiment.

[0352] The examples and embodiments described herein are for illustrative purposes only, and various modifications and changes suggested to those skilled in the art are intended to be included within the spirit and scope of this specification and the scope of the appended claims.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, 【Chemistry 1】 During the ceremony, -R １ , R ３ and R ４ each independently represents hydrogen, halogen, or —OR ａ , alkyl, heteroalkyl, aryl, arylalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, heteroalkyl, aryl, arylalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted; R 2 is hydrogen; Or, R １ and R ２ , R ２ and R ３ , or R ３ and R ４ taken together with the carbon atoms to which they are attached form an optionally substituted 5- or 6-membered ring; -R ５ is hydrogen or methyl, -R ６ is hydrogen, alkyl, haloalkyl, cycloalkyl, or heterocycloalkyl, where each alkyl, haloalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted; and -R ａ is hydrogen, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted; Here, R １ , R ３ and R ４ At least one of ａ where R ａ is aryl or arylalkyl, each of which is optionally substituted; However, R ３ , R ４ , R ５ and R ６ are each hydrogen, then R ２ is not phenoxy, or a pharmaceutically acceptable salt or solvate thereof.

2. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein one of R 1 , R 3 and R 4 is OR a , R a is aryl or arylalkyl, each of which is optionally substituted, and the remainder of R 1 , R 3 and R 4 are each hydrogen.

3. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein one of R 1 , R 3 and R 4 is unsubstituted or substituted phenoxy.

4. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein one of R 1 , R 3 and R 4 is unsubstituted or substituted benzyloxy.

5. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein at least one of R 1 , R 3 and R 4 is selected from the group consisting of unsubstituted benzyloxy, benzyloxy substituted with at least one halogen, unsubstituted phenoxy, and phenoxy substituted with at least one halogen.

6. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein at least one of R 1 , R 3 and R 4 is selected from the group consisting of benzyloxy, 4-fluorobenzyloxy, phenoxy and 4-fluorophenoxy.

7. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 is hydrogen or methyl. 【Request Item 8】 【Chemistry 2-1】 【Chemistry 2-2】 or a pharmaceutically acceptable salt or solvate thereof.

9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

10. Use of a compound of any one of claims 1 to 8, or any pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for treating a neurological disease or disorder in a mammal, wherein the neurological disease or disorder is a neurodegenerative, neuropsychiatric, or substance use disease or disorder, the neurological disease or disorder is trauma, or the neurological disease or disorder is selected from the group consisting of anxiety disorders, mood disorders, psychiatric disorders, personality disorders, eating disorders, sleep disorders, sexual desire disorders, impulse control disorders, substance use disorders, dissociative disorders, cognitive disorders, developmental disorders, and factitious disorder.

Images