CN118742551A - Phenoxy and benzyloxy substituted psychotropic agents and their uses - Google Patents

Abstract

Disclosed herein are compounds, compositions, and methods of using the compounds and compositions disclosed herein to promote neuronal growth and/or improve neuronal structure. Also described are methods of using phenoxy or benzyloxy substituted psychoremodeling agents to treat diseases or conditions mediated by loss of synaptic connectivity and/or plasticity, such as neurological diseases and conditions.

Description

Phenoxy and benzyloxy substituted psychotropic agents and their uses

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application Serial No. 63/387,222, filed on December 13, 2022, and U.S. Provisional Application Serial No. 63/290,036, filed on December 15, 2021, both of which are incorporated herein by reference in their entireties.

Technical Field

Described herein are compounds, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds for treating conditions, diseases or disorders that would benefit from promoting neuronal growth and/or improving neuronal structure.

Background Art

Altered synaptic connectivity and plasticity have been observed in the brain of individuals suffering from neurological diseases and disorders. Psychoplastogens promote neuronal growth and improve neuronal structure by mechanisms involving activation of AMPA receptors, tropomyosin receptor kinase B (TrkB) and mammalian target of rapamycin (mTOR). Regulators of these biological targets, such as ketamine, scopolamine, N, N-dimethyltryptamine (DMT) and rapastinel have been shown to have psychoremodeling properties. For example, ketamine can correct the harmful changes in neuronal structure associated with neurological diseases and disorders. Such structural changes include, for example, the loss of dendritic spines and synapses in the prefrontal cortex (PFC), and the reduction of dendritic arbor complexity. In addition, pyramidal neurons in the PFC show top-down control over the areas of control motivation, fear and reward in the brain. Psychedelic psychoremodeling agents have been clinically demonstrated to have antidepressant, antianxiety and anti-addiction effects.

Summary of the invention

In some embodiments, provided herein is a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof:

in:

- each of R ¹ , R ² , R ³ and R ⁴ is independently hydrogen, halogen, -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;

or any one of ^R1 and ^R2 , ^R2 and ^R3 , or ^R3 and ^R4 and the carbon atoms to which they are attached

The atoms are taken together to form an optionally substituted 5- or 6-membered ring;

-R ⁵ is hydrogen, alkyl, haloalkyl, cycloalkyl or heterocycloalkyl, wherein each alkyl, halo

The haloalkyl, cycloalkyl or heterocycloalkyl is optionally substituted;

- ^R6 is hydrogen, alkyl, haloalkyl, cycloalkyl or heterocycloalkyl, wherein each alkyl, haloalkyl, cycloalkyl or heterocycloalkyl is optionally substituted; and

^-Ra is hydrogen, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, cycloalkyl or heterocycloalkyl, wherein each alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, cycloalkyl or heterocycloalkyl is optionally substituted;

wherein at least one of R ¹ , R ² , R ³ and R ⁴ is OR ^a , wherein R ^a is aryl or arylalkyl, each of which is optionally substituted;

The conditions are:

(i) when R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ are each hydrogen, then R ² is not phenoxy;

(ii) when R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are each hydrogen, then R ¹ is not phenoxy;

and

(iii) When R ¹ , R ³ , R ⁴ and R ⁶ are each hydrogen and R ⁵ is methyl, then R ² is not benzyloxy.

In some embodiments, provided herein is a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof:

in:

-R ¹ is hydrogen, halogen, 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, or R ¹ is OR ^a `, wherein Ra <sup>a</sup> ` is substituted aryl or optionally substituted arylalkyl;

^-R2 is hydrogen;

-R ³ and R ⁴ are each independently hydrogen, halogen, -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;

or any one of ^R1 and ^R2 , ^R2 and ^R3 , or ^R3 and ^R4 and the carbon atoms to which they are attached

The atoms are taken together to form an optionally substituted 5- or 6-membered ring;

-R ⁵ is hydrogen, alkyl, haloalkyl, cycloalkyl or heterocycloalkyl, wherein each alkyl, halo

The haloalkyl, cycloalkyl or heterocycloalkyl is optionally substituted;

- ^R6 is hydrogen, alkyl, haloalkyl, cycloalkyl or heterocycloalkyl, wherein each alkyl, haloalkyl, cycloalkyl or heterocycloalkyl is optionally substituted; and

^-Ra is hydrogen, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, cycloalkyl or heterocycloalkyl, wherein each alkyl, haloalkyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted;

wherein (i) at least one of R ² , R ³ and R ⁴ is an aryloxy group or an arylalkoxy group, each of which is optionally substituted; or (ii) R ¹ is a substituted aryloxy group or an optionally substituted arylalkoxy group.

Provided herein is a pharmaceutical composition comprising a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are formulated for administration to mammals by intravenous administration, subcutaneous administration, oral administration, inhalation, intranasal administration, dermal administration or ocular administration. In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are in the form of tablets, pills, capsules, liquids, suspensions, gels, dispersions, solutions, emulsions, ointments or lotions.

In one embodiment, described herein is a method of promoting neuronal growth in a mammal comprising administering to the mammal a compound described herein, or any pharmaceutically acceptable salt or solvate thereof.

In another embodiment, described herein is a method of improving neuronal structure comprising administering to a mammal a compound provided herein, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, described herein is a method of modulating the activity of a serotonin receptor 2A (5-HT _2A ) receptor in a mammal comprising administering to the mammal a compound provided herein, or any pharmaceutically acceptable salt or solvate thereof.

In another embodiment, described herein is a method of treating a disease or condition mediated by the action of serotonin (5-HT) at serotonin receptor 2A (5- _HT2A ) in a mammal comprising administering to the mammal a compound provided herein or any pharmaceutically acceptable salt or solvate thereof.

In another embodiment, described herein is a method of treating a disease or condition mediated by loss of synaptic connectivity, plasticity, or a combination thereof in a mammal, comprising administering to the mammal a compound provided herein, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the disease or condition is a neurological disease or condition.

In another embodiment, described herein is a method for treating a neurological disease or disorder in a mammal, the method comprising administering to the mammal a compound represented by the structure of formula (I), or a pharmaceutically acceptable salt or solvate thereof:

in:

- each of R ¹ , R ² , R ³ and R ⁴ is independently hydrogen, halogen, -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;

or any one of ^R1 and ^R2 , ^R2 and ^R3 , or ^R3 and ^R4 and the carbon atoms to which they are attached

The atoms are taken together to form an optionally substituted 5- or 6-membered ring;

-R ⁵ is hydrogen, alkyl, haloalkyl, cycloalkyl or heterocycloalkyl, wherein each alkyl, halo

The haloalkyl, cycloalkyl or heterocycloalkyl is optionally substituted;

- ^R6 is hydrogen, alkyl, haloalkyl, cycloalkyl or heterocycloalkyl, wherein 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

The alkyl or heterocycloalkyl group is optionally substituted;

- wherein at least one of R ¹ , R ² , R ³ and R ⁴ is OR ^a , wherein ^Ra is aryl or arylalkyl, each of which is optionally substituted;

The conditions are:

(i) when R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ are each hydrogen, then R ² is not phenoxy;

(ii) when R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are each hydrogen, then R ¹ is not phenoxy;

and

(iii) When R ¹ , R ³ , R ⁴ and R ⁶ are each hydrogen and R ⁵ is methyl, then R ² is not benzyloxy.

In some embodiments, the nervous system disease or disorder is a neurodegenerative, neuropsychiatric, or substance use disease or disorder.

In some embodiments, the nervous system disease or disorder is an injury.

In some embodiments, the neurological disease or disorder is selected from anxiety disorders, mood disorders, psychotic disorders, personality disorders, eating disorders, sleep disorders, sexual behavior disorders, impulse control disorders, substance use disorders, dissociative disorders, cognitive disorders, developmental disorders, and factitious disorders.

In some embodiments, the mammal is a human.

In any of the foregoing aspects are further embodiments wherein an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, is: (a) administered systemically to a mammal; and/or (b) administered orally to a mammal; and/or (c) administered intravenously to a mammal; and/or (d) administered to a mammal by injection.

In any of the foregoing aspects are additional embodiments comprising a single administration of an effective amount of the compound, including further embodiments wherein the compound is administered to a mammal once daily or the compound is administered to a mammal multiple times over the span of a day. In some embodiments, the compound is administered in a continuous dosing regimen. In some embodiments, the compound is administered in a continuous daily dosing regimen.

Articles of manufacture are provided that include 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 pharmaceutically acceptable salt or solvate thereof, is used to promote neuronal growth and/or improve neuronal structure, or to treat, prevent, or improve one or more symptoms of a disease or disorder associated with promoting neuronal growth and/or improving neuronal structure.

Other objects, features and advantages of the compounds, methods and compositions described herein will become apparent from the following detailed description. However, it should be understood that the detailed description and specific examples, while indicating particular embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the present disclosure will become apparent to those skilled in the art from this detailed description.

DETAILED DESCRIPTION

The present disclosure provides non-psychedelic compounds that can be used to treat various neurological diseases and disorders and to increase neuronal plasticity.

Psychedelic compounds promote structural and functional neuroplasticity in key circuits, elicit therapeutic responses in a variety of neuropsychiatric conditions, and produce beneficial neurological effects that can persist for months after a single administration. Compounds that are able to modify neural circuits that control motivation, anxiety, and drug-seeking behavior have the potential to treat neurological diseases and conditions mediated by loss of synaptic connectivity and/or plasticity. In addition, such compounds may produce sustained therapeutic effects because, for example, it is possible to treat underlying pathological changes in the circuits.

In some embodiments, 5-HT _2A antagonists eliminate the neuritogenic and dendritic spine-forming effects of hallucinogenic compounds with 5-HT _2A agonist activity (e.g., DMT, LSD, and DOI), demonstrating the relevance of 5-HT _2A agonism to the promotion of neural plasticity (Ly et al., 2018; Dunlap et al., 2020). However, the hallucinogenic and dissociative potential of such compounds limits the clinical application of these compounds in neurological diseases, such as, for example, neuropsychiatric diseases. (Ly et al., 2018).

In addition, non-psychedelic analogs of psychedelic compounds, such as, for example, lisuride and sumatriptan, have been examined as therapeutic agents for various neurological diseases and disorders, such as, but not limited to, neurodegenerative diseases (e.g., Alzheimer's disease and Parkinson's disease) and headaches (e.g., migraine).

Certain terms

Unless otherwise stated, the following terms used in this application have the definitions given below. It must be noted that the singular forms "a", "an", and "the" as used in the specification and the appended claims include plural references unless the context clearly dictates otherwise. In this application, the use of "or" means "and/or" unless otherwise stated. The use of the term "comprising" and other forms such as "include", "includes", and "included" is not limiting. The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described.

As used herein, _C1 - _Cx includes _C1 - _C2 , _C1 - _C3, ... _C1 - _Cx . By way of example only, a group designated " _C1 - _C4 " indicates that there are one to four carbon atoms in the moiety, i.e., groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms, or 4 carbon atoms. Thus, by way of example only, " _C1 - _C4 alkyl" indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

"Alkyl" generally refers to a straight or branched hydrocarbon group consisting only of carbon and hydrogen atoms, such as having one to fifteen carbon atoms (e.g., C ₁ -C ₁₅ alkyl). Unless otherwise specified, an alkyl group is saturated or unsaturated (e.g., an alkenyl group, which includes at least one carbon-carbon double bond). Unless otherwise specified, the disclosure of "alkyl" provided herein is intended to include independent descriptions of saturated "alkyl". The alkyl groups described herein are generally monovalent, but may also be divalent (which may also be described herein as "alkylene" or "alkylenyl" groups). In certain embodiments, an alkyl group includes one to thirteen carbon atoms (e.g., C ₁ -C ₁₃ alkyl). In certain embodiments, an alkyl group includes one to eight carbon atoms (e.g., C ₁ -C ₈ alkyl). In other embodiments, an alkyl group includes one to five carbon atoms (e.g., C ₁ -C ₅ alkyl). In other embodiments, an alkyl group includes one to four carbon atoms (e.g., C ₁ -C ₄ alkyl). In other embodiments, the alkyl group includes one to three carbon atoms (e.g., C ₁ -C ₃ alkyl). In other embodiments, the alkyl group includes one to two carbon atoms (e.g., C ₁ -C ₂ alkyl). In other embodiments, the alkyl group includes one carbon atom (e.g., C ₁ alkyl). In other embodiments, the alkyl group includes five to fifteen carbon atoms (e.g., C ₅ -C ₁₅ alkyl). In other embodiments, the alkyl group includes five to eight carbon atoms (e.g., C ₅ -C ₈ alkyl). In other embodiments, the alkyl group includes two to five carbon atoms (e.g., C ₂ -C ₅ alkyl). In other embodiments, the alkyl group includes three to five carbon atoms (e.g., C ₃ -C ₅ alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (isopropyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl group is attached to the rest of the molecule by a single bond. Typically, each alkyl group is independently substituted or unsubstituted. Unless otherwise indicated, each recitation of "alkyl" provided herein includes a specific and explicit recitation of an unsaturated "alkyl" group. Similarly, unless stated otherwise specifically in the specification, an alkyl group is optionally substituted with one or more of the following substituents: halogen, cyano, nitro, oxo, thioxo, imino, oxime, trimethylsilanyl, ^-ORx , ^-SRx , -OC(O) ^-Rx , -N( ^Rx ) ₂ , -C(O) ^Rx , -C(O) ^ORx , -C(O)N( ^Rx ) ₂ , -N( ^Rx )C(O) ^ORx , -OC(O)-N( ^Rx ) ₂ , -N( ^Rx )C(O ^)Rx , -N( ^Rx )S( _O ) _tRx (wherein t is 1 or 2), -S(O ^{) tORx} (wherein t is 1 or 2), -S(O) _tRx (wherein t is 1 or 2), and -S(O) _tN ( ^Rx ) ₂ (wherein ^t is 1 or 2), wherein each R ^X is independently hydrogen, alkyl (optionally substituted with halogen, hydroxyl, methoxyl or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxyl, methoxyl or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxyl, methoxyl or trifluoromethyl), aryl (optionally substituted with halogen, hydroxyl, methoxyl or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxyl, methoxyl or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxyl, methoxyl or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxyl, methoxyl or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxyl, methoxyl or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxyl, methoxyl or trifluoromethyl). In some embodiments, alkyl is substituted with one or more fluorines.

An "alkylene" group refers to a divalent alkyl group. Any of the above monovalent alkyl groups can be alkylene by extracting the second hydrogen atom from the alkyl group. In some embodiments, the alkylene group is a C ₁ -C ₆ alkylene group. In other embodiments, the alkylene group is a C ₁ -C ₄ alkylene group. Typical alkylene groups include, but are not limited to, -CH ₂ -, -CH(CH ₃ )-, -C(CH ₃ ) ₂ -, -CH ₂ CH ₂ -, -CH ₂ CH(CH ₃ )-, -CH ₂ C(CH ₃ ) ₂ -, -CH ₂ CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ CH ₂ -, and the like. Unless otherwise specifically stated in the specification, an alkylene chain is optionally substituted as described herein for alkyl groups.

The term "alkenyl" refers to a type of hydrocarbon group in which at least one carbon-carbon double bond is present. In one embodiment, the alkenyl group has the formula -C(R)=CR ₂ , where R refers to the remainder of the alkenyl group, which may be the same or different. In some embodiments, R is H or an alkyl group. Non-limiting examples of alkenyl groups include -CH=CH ₂ , -C(CH ₃ )=CH ₂ , -CH=CHCH ₃ , -C(CH ₃ )=CHCH ₃ , and -CH ₂ CH=CH ₂ .

The term "alkynyl" refers to a type of hydrocarbon group in which at least one carbon-carbon triple bond is present. In one embodiment, the 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≡CCH ₃ , -C≡CCH ₂ CH ₃ , -CH ₂ C≡CH.

"Alkoxy" means an (alkyl)O- group where alkyl is as defined herein.

The term "alkylamine" refers to -NH(alkyl) or -N(alkyl) ₂ .

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

The term "carbocyclic" or "carbocycle" refers to a ring or ring system in which the atoms forming the ring skeleton are all carbon atoms. Therefore, the term distinguishes carbocycle from "hetero" ring or "heterocycle", in which the ring skeleton contains at least one atom different from carbon. In some embodiments, at least one of the two rings of the bicyclic carbocycle is aromatic. In some embodiments, both rings of the bicyclic carbocycle are aromatic. In certain embodiments, the carbocyclyl includes three to ten carbon atoms. In other embodiments, the carbocyclyl includes five to seven carbon atoms. The carbocyclyl is attached to the rest of the molecule by a single bond. Carbocyclyl or cycloalkyl is saturated (i.e., containing only a single C-C bond) or unsaturated (i.e., containing one or more double or triple bonds). Examples of saturated cycloalkyl include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Unsaturated carbocyclyl is also referred to as "cycloalkenyl". Examples of monocyclic cycloalkenyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclic groups include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, etc. Unless otherwise specifically stated in the specification, the term “carbocyclyl” is intended to include carbocyclyl groups optionally substituted by one or more substituents independently selected from 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 ^{- ORx} , -Ry ^- OC(O) ^-Rx , -Ry ^- OC(O) ^-ORx , -Ry ^- OC(O)-N( ^Rx ) ₂ , -Ry ^- N( ^Rx ) ₂ , -Ry ^- C(O) ^Rx , -Ry ^- C(O) ^ORx , ^-Ry- -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 (where t is 1 or 2), -R ^y -S(O) _t R ^x (where t is 1 or 2), -R ^y -S(O) _t OR ^x (where t is 1 or 2) and -R ^y -S(O) _t N(R ^x ) ₂ (where t is 1 or 2), where each R ^X is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aryl (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), heterocycloalkyl (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 ^y 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, and wherein each of the above substituents is unsubstituted unless otherwise specified.

The term "aryl" as used herein refers to an aromatic ring in which each atom forming the ring is a carbon atom. An aromatic monocyclic or polycyclic hydrocarbon ring system contains only hydrogen and carbon from five to eighteen carbon atoms, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) π electron system according to the Hückel 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 specifically stated in the specification, the term “aryl” or the prefix “ar-” (such as in “aralkyl”) is intended to include aryl groups optionally substituted by one or more substituents independently selected from 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, -Ry ^{- ORx} , -Ry ^- OC(O) ^-Rx , -Ry ^- OC(O) ^-ORx , -Ry ^- OC(O)-N( ^Rx ) ₂ , -Ry ^- N( ^Rx ) ₂ , -Ry ^{- C} (O) ^Rx , -Ry- -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 (} where t is 1 or 2), _-R ^y -S(O) _t OR ^x (where t is 1 or 2), and -R ^{y -S} (O) _t N(R ^x ) ₂ (where t is 1 or 2), where each R ^X is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aryl (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), heterocycloalkyl (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 ^y 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, and wherein each of the above substituents is unsubstituted unless otherwise specified.

"Aralkyl", "aryl-alkyl" or "arylalkyl" refers to a radical of the formula ^-Rz -aryl, where ^Rz is an alkylene chain as defined above, e.g., methylene, ethylene, etc. The alkylene chain portion of the aralkyl is optionally substituted as described above for alkylene chains. The aryl portion of the aralkyl is optionally substituted as described above for aryl groups.

The term "cycloalkyl" refers to a monocyclic or polycyclic aliphatic, non-aromatic group in which each atom (i.e., backbone atom) forming the ring is a carbon atom. In some embodiments, the cycloalkyl is a spirocyclic or bridged compound. In some embodiments, the cycloalkyl is optionally fused to an aromatic ring, and the point of attachment is on a carbon that is not an aromatic ring carbon atom. The cycloalkyl group includes groups having 3 to 10 ring atoms. In some embodiments, the cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbornyl and bicyclo[1.1.1]pentyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, 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 C ₃ -C ₆ cycloalkyl.

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, halogen is fluoro or chloro.

The term "fluoroalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by fluorine atoms, such as, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. In some embodiments, the alkyl portion of the fluoroalkyl group is optionally substituted as defined above for an alkyl group. In one embodiment, the fluoroalkyl group is a C ₁ -C ₆ fluoroalkyl group.

The term "heteroalkyl" refers to an alkyl group as defined above, wherein one or more of the backbone carbon atoms of the alkyl group is replaced by a heteroatom (with an appropriate number of substituents or valences, e.g., _-CH2- can be replaced by -NH-, -S-, or -O-). For example, each substituted carbon atom is independently substituted by a heteroatom, such as where the carbon is substituted by nitrogen, oxygen, selenium, or other suitable heteroatom. In some embodiments, each substituted carbon atom is independently substituted by oxygen, nitrogen (e.g., -NH-, -N(alkyl)-, or -N(aryl)-, or with another substituent as contemplated herein), or sulfur (e.g., -S-, -S(=O)-, or -S(=O) _2- ). In some embodiments, the heteroalkyl group is attached to the remainder of the molecule at a carbon atom of the heteroalkyl group. In some embodiments, the heteroalkyl group is attached to the remainder of the molecule at a heteroatom of the heteroalkyl group. In some embodiments, the heteroalkyl group is a _C1 - _C18 heteroalkyl group. In some embodiments, the heteroalkyl group is a _C1 - _C12 heteroalkyl group. In some embodiments, heteroalkyl is C ₁ -C ₆ heteroalkyl. In some embodiments, heteroalkyl is C ₁ -C ₄ heteroalkyl. In some embodiments, heteroalkyl is or includes one or more cyclic groups. In some embodiments, heteroalkyl includes alkylamino, alkylaminoalkyl, aminoalkyl, heterocyclyl, heterocycloalkyl, heterocycloalkyl and heterocycloalkylalkyl, as defined herein. Unless otherwise specifically stated in the specification, heteroalkyl is optionally substituted as defined above for alkyl. In one embodiment, heteroalkyl is C ₁ -C ₆ heteroalkyl.

"Heteroalkylene" refers to a divalent heteroalkyl group as defined above that links one part of the molecule to another part of the molecule. Unless otherwise specifically stated, a heteroalkylene group is optionally substituted as defined above for an alkyl group.

The term "heterocyclyl", "heterocycle" or "heterocyclic" generally refers to heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings (also known as heteroalicyclics) containing one to four heteroatoms in the ring, wherein each heteroatom in the ring is selected from O, S and N, wherein each heterocyclyl has 3 to 10 atoms in its ring system, and the condition is that any ring does not contain two adjacent O or S atoms. Unless otherwise specifically stated in the specification, the heterocyclyl is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which optionally contains a fused or bridged ring system. The heteroatoms in the heterocyclyl are optionally oxidized. One or more nitrogen atoms (if present) are optionally quaternized. The heterocyclyl is partially or fully saturated. The heterocyclyl is saturated (i.e., contains only a single C-C bond) or unsaturated (e.g., contains one or more double bonds or triple bonds in the ring system). In some embodiments, the heterocyclyl is saturated. In some embodiments, the heterocyclyl is saturated and substituted. In some embodiments, the heterocyclyl is unsaturated. The heterocyclic group is attached to the rest of the molecule by any atom on the ring. Non-aromatic heterocyclic groups (also referred to as heterocycloalkyl) are included in rings with 3 to 10 atoms in their ring system, and aromatic heterocyclic groups are included in rings with 5 to 10 atoms in their ring system. Heterocyclic groups include benzo-fused ring systems. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinone, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridine, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxetanyl, thietanyl, oxazepine Base, diazepine Thiazepine 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothiophenyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl 1H-benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl and quinolinyl. Examples of aromatic heterocyclic groups are pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, benzofuranyl, cinnozinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl and furopyridinyl. The above groups may be C-attached (or C-attached) or N-attached where possible. For embodiments, the group derived from pyrrole comprises pyrrole-1-yl (N-attached) or pyrrole-3-yl (C-attached). In addition, the group derived from imidazole comprises imidazole-1-yl or imidazole-3-yl (both N-attached) or imidazole-2-yl, imidazole-4-yl or imidazole-5-yl (both C-attached). The heterocyclic group comprises a benzo-fused ring system. The non-aromatic heterocycle is 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 specifically stated in the specification, the term "heterocyclyl" is intended to include heterocyclyl groups as defined above, which are optionally substituted by one or more substituents selected from 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 ^{- ORx} , -Ry ^- OC(O)-Rx, -Ry ^- OC(O) ^-ORx , -Ry ^- OC(O)-N(Rx ⁾ ₂ , -Ry ^- N( ^Rx ) ₂ , -Ry ^- C(O ^{)Rx ,} -Ry ^- C(O) ^ORx , -Ry- ^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 (where t is 1 or 2), -R ^y -S(O) _t R ^x (where t is 1 or 2), - R ^y -S(O) _t OR ^x (where t is 1 or 2) and -R ^y -S(O) _t N(R ^x ) ₂ (where t is 1 or 2), where each R ^x is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aryl (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 ^y 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, and wherein each of the above substituents is unsubstituted unless otherwise specified.

"Heterocyclylalkyl" refers to a radical of the formula ^-Rz -heterocyclyl, wherein ^Rz is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl at the nitrogen atom. The alkylene chain of the heterocyclylalkyl is optionally substituted as defined above for an alkylene chain. The heterocyclyl portion of the heterocyclylalkyl is optionally substituted as defined above for a heterocyclyl radical.

"Heterocyclylalkoxy" refers to a radical bonded through the oxygen atom of the formula ^-ORz -heterocyclyl, wherein ^Rz is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl at the nitrogen atom. The alkylene chain of the heterocyclylalkoxy is optionally substituted as defined above for an alkylene chain. The heterocyclyl portion of the heterocyclylalkoxy is optionally substituted as defined above for a heterocyclyl.

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 heteroaryl groups and bicyclic heteroaryl groups. Monocyclic heteroaryl groups include pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl and furazanyl. Bicyclic heteroaryl groups include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine and pteridine. In some embodiments, heteroaryl contains 0-4 N atoms in the ring. In some embodiments, the heteroaryl group contains 1-4 N atoms in the ring. In some embodiments, the heteroaryl group contains 0-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, the heteroaryl group contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, the heteroaryl group is C ₁ -C ₉ heteroaryl. In some embodiments, the monocyclic heteroaryl group is C ₁ -C ₅ heteroaryl. In some embodiments, the monocyclic heteroaryl group is a 5-membered or 6-membered heteroaryl. In some embodiments, the bicyclic heteroaryl group is a C ₆ -C ₉ heteroaryl. Unless otherwise specifically stated in the specification, the term "heteroaryl" is meant to encompass heteroaryl groups as defined above, which are optionally substituted by one or more substituents selected from 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, -Ry ^{- ORx} , -Ry ^- OC(O) ^-Rx , -Ry ^- OC(O) ^-ORx , -Ry ^- OC(O)-N( ^Rx ) ₂ , -Ry ^- N( ^Rx ) ₂ , -Ry ^{- C} (O) ^Rx , -Ry- -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 (} where t is 1 or 2), _-R ^y -S(O) _t OR ^x (where t is 1 or 2), and -R ^{y -S} (O) _t N(R ^x ) ₂ (where t is 1 or 2), where each R ^X is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aryl (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 ^y 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, and wherein unless otherwise specified, each of the above substituents is unsubstituted.

"Heteroarylalkyl" refers to a radical of the formula ^-Rz -heteroaryl, wherein ^Rz is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl at the nitrogen atom. The alkylene chain of the heteroarylalkyl is optionally substituted as defined above for an alkylene chain. The heteroaryl portion of the heteroarylalkyl is optionally substituted as defined above for a heteroaryl group.

"Heteroarylalkoxy" refers to a radical bonded through an oxygen atom of the formula ^-ORz -heteroaryl, wherein ^Rz is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl at the nitrogen atom. The alkylene chain of the heteroarylalkoxy is optionally substituted as defined above for an alkylene chain. The heteroaryl portion of the heteroarylalkoxy is optionally substituted as defined above for a heteroaryl group.

"Heterocycloalkyl" or "heteroalicyclic" groups refer to cycloalkyl groups containing at least one heteroatom selected from nitrogen, oxygen and sulfur. In some embodiments, heterocycloalkyl groups are fused to aryl or heteroaryl groups. In some embodiments, heterocycloalkyl groups are oxazolidinone groups, pyrrolidinone groups, tetrahydrofuranyl groups, tetrahydrothiophenyl groups, tetrahydropyranyl groups, tetrahydrothiopyranyl groups, piperidinyl groups, morpholinyl groups, thiomorpholinyl groups, piperazinyl groups, piperidin-2-one groups, pyrrolidine-2,5-disulfinyl groups, pyrrolidine-2,5-dione groups, pyrrolidinone groups, imidazolidinyl groups, imidazolin-2-one groups or thiazolidin-2-one groups. The term heteroalicyclic also includes all ring forms of carbohydrates, including but not limited to monosaccharides, disaccharides and oligosaccharides. In one embodiment, heterocycloalkyl groups are C ₂ -C ₁₀ heterocycloalkyl groups. In another embodiment, heterocycloalkyl groups are C ₄ -C ₁₀ heterocycloalkyl groups. In some embodiments, the heterocycloalkyl group contains 0-2 N atoms in the ring. In some embodiments, the heterocycloalkyl group contains 0-2 N atoms, 0-2 O atoms, and 0-1 S atoms in the ring.

The term "bond" or "single bond" refers to a chemical bond between two atoms or two moieties, where 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 bond, the group referred to is absent, thereby allowing a bond to form between the remaining identified groups.

The term "moiety" refers to a specific fragment or functional group of a molecule. A chemical moiety is generally considered to be a chemical entity embedded in or attached to a molecule.

Typically, the optionally substituted groups are each independently substituted or unsubstituted. Unless otherwise indicated, each description of the optionally substituted groups provided herein includes independent and explicit descriptions of both unsubstituted and substituted groups (e.g., substituted in certain embodiments, and unsubstituted in certain other embodiments). Unless otherwise indicated, a substituted group (e.g., substituted alkyl) provided herein is substituted with one or more substituents, each of which is independently selected from the group _consisting of halo, cyano, nitro, oxo, thio, imino, oxime, trimethylsilyl, ^-ORx , ^-SRx , -OC(O) ^-Rx , -N( ^Rx ), -C(O) ^Rx , -C(O) ^ORx , -C(O)N( ^Rx ), -N( ^Rx )C ₍ O) ^ORx , -OC(O)-N(Rx), -N( ^Rx )C(O) ^Rx , -N( ^{Rx )} S(O) _tRx (wherein t is 1 or ₂ ), -S(O) ^tORx (wherein t is 1 or 2), -S(O) _tRx (wherein t is ¹ or ₂ ) ^, and -S(O) _tN ( ^Rx ) _. (wherein t is 1 or 2), wherein each ^Rx 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), 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, _-NH2 , -NH( _CH3 ), -N( _CH3 ) ₂ , -OH, _-CO2H , _-CO2 ( _C1 - _C4alkyl ), -C(=O) _NH2 , -C(=O)NH( _C1 -C4alkyl), -C(=O)N(C1-C4alkyl) ₂ , -S(=O) _2NH2 , _-S (=O) _2NH ( _C1 - _{C4alkyl), -S(=O)2N(C1-C4alkyl)2 , C1 - C4alkyl , C3 - C6cycloalkyl , C1} - _{C4fluoroalkyl} , C1 _{- C4heteroalkyl} , _{C1 -} C4alkoxy, _{C1 - C4fluoroalkoxy} , -S1 _{- C4} In some embodiments, the optional substituents _are independently selected from halogen, -CN, -NH ₂ , -OH, -NH( _{CH 3} ), -N(CH ₃ ) ₂ , -CH ₃ , -CH ₂ CH ₃ , -CF _{3 ,} -OCH ₃ and -OCF _{3 .} In some embodiments, the substituted groups are substituted with one or _two of the aforementioned groups. In some embodiments, the optional substituents on aliphatic carbon atoms (acyclic or cyclic) include oxo (═O ₎ .

The term "acceptable" with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.

As used herein, the term "modulate" means interacting with a target, either directly or indirectly, so as 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 prolonging the activity of the target. In some embodiments, "modulate" means interacting with a target, either directly or indirectly, so as 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 illustration and not limitation, agonists, partial agonists, antagonists, and allosteric modulators (e.g., positive allosteric modulators) of a G protein-coupled receptor (e.g., _5HT2A ) are modulators of the receptor.

As used herein, the term "modulator" refers to a molecule that interacts directly or indirectly with a target. Interactions include, but are not limited to, interactions of agonists, partial agonists, inverse agonists, antagonists, or combinations thereof. In some embodiments, the modulator is an antagonist. Receptor antagonists are inhibitors of receptor activity. Antagonists simulate ligands that bind to receptors and prevent receptor activation through natural ligands. Preventing activation may have many effects. If a natural agonist that binds to a receptor results in an enhancement of cellular function, an antagonist that binds to and blocks the receptor reduces that function of the receptor.

As used herein, the term "agonism" generally refers to the activation of a receptor or enzyme by a modulator or agonist to produce a biological response.

As used herein, the term "agonist" generally refers to a modulator that binds to a receptor or enzyme and activates the receptor to produce a biological response. By way of example only, a "5HT _2A agonist" may be used to refer to a compound that exhibits an EC ₅₀ of no more than about 100 μM relative to 5HT _2A activity. In some embodiments, the term "agonist" encompasses a full agonist or a partial agonist. A "full agonist" refers to a modulator that binds to and activates a receptor with the maximum response that an agonist can elicit on the receptor. A "partial agonist" refers to a modulator that binds to and activates a given receptor, but has a partial efficacy, i.e., less than the maximum response, on the receptor relative to a full agonist.

As used herein, the term "positive allosteric modulator" generally refers to a modulator that binds to a site other than the orthosteric binding site and enhances or amplifies the effect of an agonist.

As used herein, the term "antagonism" generally refers to the inactivation of a receptor or enzyme by a modulator or antagonist. For example, antagonism of a receptor is when a molecule binds to a receptor and blocks the function of the receptor.

As used herein, the term "antagonist" or "neutral antagonist" generally refers to a modulator that binds to a receptor or enzyme and blocks a biological response. An antagonist may be inactive in the absence of an agonist or inverse agonist, but may block the activity of either of them without causing a change in the biological response.

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

As used herein, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of an agent or compound administered that will alleviate to some extent one or more of the symptoms of the disease or condition being treated. Results include reduction and/or alleviation of the signs, symptoms, or causes of the disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition including a compound as disclosed herein required to provide a clinically significant reduction in disease symptoms. In any individual case, an appropriate "effective" amount is optionally determined using techniques such as a dose escalation study.

As used herein, the terms "enhance" or "enhancing" mean to increase or prolong in potency or duration a desired effect. Thus, with respect to enhancing the effect of a therapeutic agent, the term "enhance" refers to the ability to increase or prolong in potency or duration the effect of other therapeutic agents in a system. As used herein, an "enhancing-effective amount" refers to an amount sufficient to enhance the effect of another therapeutic agent in a desired system.

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

The term "subject" or "patient" encompasses mammals. Examples of mammals include, but are not limited to, any member of the class of mammals: humans, non-human primates such as chimpanzees and other apes and monkey species; livestock such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs and cats; laboratory animals, including rodents such as rats, mice and guinea pigs, etc. In one embodiment, the mammal is a human.

As used herein, the terms "treat," "treating," or "treatment" encompass alleviating, reducing, or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting a disease or condition, e.g., arresting the development of a disease or condition, relieving a disease or condition, causing regression of a disease or condition, relieving a condition caused by a disease or condition, or preventing symptoms of a disease or condition prophylactically and/or therapeutically.

The term "pharmaceutically acceptable" as used herein generally refers to a material (such as a carrier or diluent) that does not abrogate the biological activity or properties of the compound and is relatively nontoxic, i.e., the material can be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

As used herein, the term "pharmaceutically acceptable salt" generally refers to a form of a therapeutically active agent that consists of a cationic form of the therapeutically active agent in combination with a suitable anion, or in an alternative embodiment, consists of an 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/Zürich: Wiley-VCH/VHCA, 2002. Pharmaceutically acceptable salts are generally more soluble and dissolve faster in gastric and intestinal fluids than non-ionic substances and can therefore be used in solid dosage forms. Furthermore, because their solubility is generally a function of pH, selective dissolution in one or another portion of the digestive tract is possible, and this ability can be manipulated as an aspect of delayed and sustained release behavior. Furthermore, because salt-forming molecules can be in equilibrium with the neutral form, passage through biological membranes can be modulated. Provided herein are non-hallucinogenic compounds that promote neuronal growth and/or improve neuronal structure.

As used herein, the term "significant" or "significantly" with respect to a 5-HT _2A agonist refers to a compound that is capable of providing an agonist of the 5-HT _2A receptor with an EC ₅₀ of less than 10 μM.

In some embodiments, the compounds provided herein have comparable affinity for serotonin receptors (e.g., 5HT _2A ) compared to their psychedelic counterparts. In some embodiments, the compounds provided herein have improved physicochemical properties due to the loss of hydrogen bond donors, reduced total polar surface area and improved central nervous system multi-parameter optimization (MPO) scores. Non-psychedelic compounds are described herein in some embodiments, which exhibit therapeutic potential similar to that of psychedelic 5-HT _2A agonists. In some embodiments, the non-psychedelic compounds described herein provide better therapeutic potential for neurological diseases than psychedelic 5-HT _2A agonists.

Neurological disorders

Neuronal plasticity and its changes have been attributed to many neurological diseases and disorders. For example, during development and adulthood, changes in the number and morphology of dendritic spines (e.g., length, crossing, density) are accompanied by the formation, maintenance, and elimination of synapses; these changes are considered to establish and reshape connectivity within neuronal circuits. In addition, the structural plasticity of dendritic spines is coordinated with synaptic function and plasticity. For example, spine enlargement is coordinated with long-term potentiation in neuronal circuits, while long-term depression is associated with spine retraction.

Furthermore, dendritic spines undergo experience-dependent morphological changes in living animals, and even subtle changes in dendritic spines can affect synaptic function, synaptic plasticity, and patterns of connectivity in neuronal circuits. For example, disease-specific disruptions in the shape, size, and/or number of dendritic spines accompany neurological diseases and disorders, such as, for example, neurodegenerative (e.g., Alzheimer's disease or Parkinson's disease) and neuropsychiatric (e.g., depression or schizophrenia) diseases and disorders, suggesting that dendritic spines may serve as a common substrate for diseases involving deficits in information processing.

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 these formulae, such as any compound described in Table 1, or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, the neurological disease or disorder is a disease or disorder of the central nervous system (CNS) (eg, brain, spine, and/or nerves) of a subject.

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., migraine), 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), psychotic disorders (e.g., schizophrenia or substance-induced psychotic disorders), personality disorders, eating disorders (e.g., binge eating disorder), sleep disorders, sexual behavior disorders, impulse control disorders (e.g., gambling, compulsive sexual behavior, or kleptomania), substance use disorders (e.g., alcohol dependence, opioid addiction, or cocaine addiction), dissociative disorders (e.g., epilepsy, amnesia, or dissociative identity disorder), cognitive disorders (e.g., substance-induced cognitive disorders), 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 associated with a disease or disorder of the CNS.

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), Lewy body dementia (LBD), etc.

Substance use disorders include, but are not limited to, substance abuse, addiction, and dependence, such as to alcohol, opioids (e.g., heroin, oxycodone, and hydrocodone), cocaine, amphetamines (e.g., methamphetamine), nicotine, cannabinoids (e.g., tetrahydrocannabinol (THC)), caffeine, phencyclidine, paint thinner, glue, steroids (e.g., anabolic steroids), barbiturates (e.g., phenobarbital), methadone, benzodiazepines Addiction or dependence to drugs such as diazepam.

Impulse control disorders include but are not limited to gambling, kleptomania, trichotillomania, intermittent explosive disorder, pyromania, skin picking, compulsive buying, Tourette syndrome, and obsessive-compulsive behavior.

Neuropsychiatric disorders include but are not limited to seizures (e.g., epilepsy), 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 depression, etc.), anxiety disorders (e.g., panic attacks, social anxiety disorder, panic disorder, etc.), schizophrenia, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), substance-induced psychosis, substance-induced cognitive impairment, etc.

Brain injuries include but are not limited to stroke, traumatic brain injury, pugilistic dementia, chronic traumatic encephalopathy (CTE), etc.

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 these formulas, such as any compound described in Table 1, or a pharmaceutically acceptable salt or solvate thereof) improve the number of dendritic spines and dendritic spine morphology lost in neurological diseases and disorders.

5-HT _2A

5-HT _2A agonism is associated with the promotion of neuroplasticity (Ly et al., 2018). In some embodiments, 5-HT _2A antagonists eliminate the neurite generation and dendritic spine generation effects of hallucinogenic compounds such as DMT, LSD and DOI with 5-HT _2A agonist activity. In addition, DMT and other psychedelic compounds promote the increase of dendritic tree complexity, dendritic spine density and synaptogenesis through 5-HT _2A- dependent processes. In some embodiments, pretreatment of cortical cultures with 5-HT _2A antagonists blocks the ability of 5-MeO-DMT to increase dendritic growth. Importantly, the neuroplastic effects of the compounds provided herein are also blocked under these conditions, suggesting that 5-HT _2A receptors are in their mechanism of action.

In addition, in some embodiments, when the 5HT _2A sensor is run in antagonist mode, non-hallucinogenic compounds (e.g., risulide and 6-MeO-DMT) compete for 5-HT. In addition, compounds that are non-hallucinogenic in animals (e.g., humans), such as 6-F-DET, Ketanserin, BOL148, can compete with 5HT in antagonist mode sensor assays for binding to 5HT _2A . In some embodiments, the compounds provided herein prevent 5-HT from binding to 5HT _2A . In some embodiments, the 5HT _2A sensor assay is in antagonist mode. In some embodiments, the compounds provided herein prevent 5-HT from binding to 5HT _2A and have non-hallucinogenic potential. In some embodiments, the compounds provided herein prevent 5-HT from binding to 5HT _2A and are non-hallucinogenic. In some embodiments, the compounds provided herein that prevent 5-HT from binding to 5HT _2A in antagonist mode have non-hallucinogenic potential. In some embodiments, the compounds provided herein that prevent the binding of 5-HT in antagonist mode are non-hallucinogenic compounds. In some embodiments, the compounds provided herein that inhibit the response of a sensor assay in antagonist mode have non-hallucinogenic potential. In some embodiments, the compounds provided herein that inhibit the response of a sensor assay in antagonist mode are non-hallucinogenic compounds.

In some embodiments, the effects of the compounds provided herein on agonist mode sensor assays indicate that the compounds are non-psychedelic ligands of the 5-HT _2A receptor. In some embodiments, the effects of the compounds provided herein on antagonist mode sensor assays indicate that the compounds are non-psychedelic ligands of the 5-HT _2A receptor. In some embodiments, the effects of the compounds provided herein on agonist mode and antagonist mode sensor assays together indicate that the compounds are non-psychedelic ligands of the 5-HT _2A receptor.

In some embodiments, non-hallucinogenic compounds are described that exhibit similar therapeutic potential to hallucinogenic 5-HT _2A agonists. In some embodiments, the non-hallucinogenic compounds described herein offer better therapeutic potential for neurological diseases than hallucinogenic 5-HT _2A agonists. In some embodiments, the compounds of the present disclosure are 5-HT _2A modulators and promote neural plasticity (e.g., cortical structural plasticity).

Provided herein are compounds useful for treating brain disorders and other conditions described herein (e.g., compounds represented by the structures of Formula (I), (IA), (IB), or (II), or any compounds covered by these formulas, such as any compounds described in Table 1). In some embodiments, the compounds provided herein are 5-HT _2A modulators and promote neuroplasticity (e.g., cortical structural plasticity). In some embodiments, 5-HT _2A modulators (e.g., 5-HT _2A agonists) are used to treat brain disorders. In some embodiments, brain disorders or other conditions described herein include reduced neuroplasticity, reduced cortical structural plasticity, reduced 5-HT _2A receptor content, reduced dendritic arbor complexity, loss of dendritic spines, reduced dendritic branching content, reduced spinogenesis, reduced neurite generation, neurite retraction, or any combination thereof.

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

In some embodiments, provided herein are compounds having activity as 5-HT _2A regulators. In some embodiments, provided herein are compounds that trigger biological responses by activating 5-HT _2A receptors (e.g., allosteric regulation or regulation of biological targets that activate 5-HT _2A receptors). In some embodiments, provided herein are compounds that are selective 5-HT _2A regulators, and promote neuroplasticity (e.g., cortical structural plasticity). In some embodiments, the promotion of neuroplasticity includes, for example, increased dendritic spine growth, increased synaptic protein synthesis, enhanced synaptic responses, increased dendritic tree complexity, increased dendritic branch content, increased dendritic spines, increased neurite generation, or any combination thereof. In some embodiments, increased neuroplasticity includes, for example, increasing cortical structural plasticity in the anterior portion of the brain.

In some embodiments, the compounds provided herein are 5-HT modulators (e.g., 5-HT _2A agonists or 5-HT _2A antagonists). In some embodiments, the compounds provided herein are 5-HT _2A modulators (e.g., 5-HT _2A agonists or 5-HT _2A antagonists). In some embodiments, the compounds provided herein are 5-HT modulators, and promote neural plasticity (e.g., cortical structural plasticity), such as increasing neurite outgrowth. In some embodiments, the compounds provided herein are 5-HT modulators, promote neural plasticity (e.g., cortical structural plasticity), and are non-hallucinogenic.

In some embodiments, provided herein are compounds that are 5-HT _2A antagonists. In some embodiments, provided herein are compounds that are 5-HT _2A antagonists, and promote neuroplasticity (e.g., cortical structural plasticity), such as increasing neurite outgrowth. In some embodiments, provided herein are compounds that are not (significantly) provide 5-HT _2A excitement and promote neuroplasticity (e.g., cortical structural plasticity), such as increasing neurite outgrowth. In some embodiments, provided herein are compounds that are not (significantly) provide 5-HT _2A excitement, promote neuroplasticity (e.g., cortical structural plasticity), and have low potential for hallucinogenic activity (e.g., non-hallucinogenic).

In some embodiments, provided herein are compounds that are 5-HT _2A agonists. In some embodiments, provided herein are compounds that are 5-HT _2A agonists, and promote neuroplasticity (e.g., cortical structural plasticity), such as increasing neurite outgrowth. In some embodiments, provided herein are compounds that provide (significant) 5-HT _2A agonism and promote neuroplasticity (e.g., cortical structural plasticity), such as increasing neurite outgrowth. In some embodiments, provided herein are compounds that provide (significant) 5-HT _2A agonism, promote neuroplasticity (e.g., cortical structural plasticity), and have low potential for hallucinogenic activity (e.g., non-hallucinogenic).

In some embodiments, 5-HT _2A modulators (e.g., 5-HT _2A agonists) are non-hallucinogenic. In some embodiments, non-hallucinogenic 5-HT _2A modulators (e.g., 5-HT _2A agonists) are used to treat neurological diseases, and these modulators do not induce dissociative side effects. In some embodiments, the hallucinogenic potential of the compounds described herein is assessed in vitro. In some embodiments, the hallucinogenic potential of the compounds described herein assessed in vitro is compared with the hallucinogenic potential of the hallucinogenic homologues assessed in vitro. In some embodiments, the compounds provided herein induce less hallucinogenic potential in vitro than the hallucinogenic homologues.

In some embodiments, non-hallucinogenic 5-HT _2A modulators (e.g., 5-HT _2A agonists) are used to treat neurological diseases. In some embodiments, neurological diseases include reduced neural plasticity, reduced cortical structural plasticity, reduced 5-HT _2A receptor content, reduced dendritic arbor complexity, loss of dendritic spines, reduced dendritic branching content, reduced dendritic spine generation, reduced neurite generation, neurite retraction, or any combination thereof.

In some embodiments, non-hallucinogenic 5-HT _2A modulators (e.g., 5-HT _2A agonists) are used to increase neuronal plasticity. In some embodiments, non-hallucinogenic 5-HT _2A modulators (e.g., 5-HT _2A agonists) are used to treat brain disorders. In some embodiments, non-hallucinogenic 5-HT _2A modulators (e.g., 5-HT _2A agonists) are used to increase at least one of the translation, transcription, or secretion of neurotrophic factors.

In some embodiments, the assay or test to determine the increased neuronal plasticity of any compound of the present disclosure is a phenotypic assay, a dendrite formation assay, a dendritic spine formation assay, a synaptogenesis assay, a Sholl analysis, a concentration response assay, a 5-HT _2A agonist assay, a 5-HT _2A antagonist assay, a 5-HT _2A binding assay, or a 5-HT _2A blocking assay (e.g., a ketanserin blocking assay). In some embodiments, the assay or test to determine the hallucinogenic potential of the compounds provided herein is a mouse head twitch response (HTR) assay.

Compound

In some embodiments, the compounds described herein, including their pharmaceutically acceptable salts, prodrugs, active metabolites, and solvates, are benzyloxy substituted psychotropic agents. In some embodiments, the compounds described herein, including their pharmaceutically acceptable salts, prodrugs, active metabolites, and solvates, are phenoxy substituted psychotropic agents. In some embodiments, the compounds described herein, including their pharmaceutically acceptable salts, prodrugs, active metabolites, and solvates, are psychotropic agents comprising an indole moiety. In some embodiments, the compounds described herein, including their pharmaceutically acceptable salts, prodrugs, active metabolites, and solvates, are psychotropic agents comprising an indole moiety. In some embodiments, the compounds described herein, including pharmaceutically acceptable salts, prodrugs, active metabolites and solvates thereof, are psychotropic agents comprising a 1,2,3,4,5,6-hexahydroazepine substituted with a benzyloxy group. In some embodiments, the compounds described herein, including pharmaceutically acceptable salts, prodrugs, active metabolites and solvates thereof, are psychotropic agents comprising a 1,2,3,4,5,6-hexahydroazepine substituted with a phenoxy group. and [4,5-b]indole moiety.

In some embodiments, the phenoxy or benzyloxy substituted psychotropic agent is a non-psychedelic phenoxy or benzyloxy substituted psychotropic agent. In some embodiments, the phenoxy or benzyloxy substituted psychotropic agent (e.g., described herein) promotes neuronal growth, improves neuronal structure, or a combination thereof.

In some embodiments, provided herein is a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof:

in:

- each of R ¹ , R ² , R ³ and R ⁴ is independently hydrogen, halogen, -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;

or any one of ^R1 and ^R2 , ^R2 and ^R3 , or ^R3 and ^R4 and the carbon atoms to which they are attached

The atoms are taken together to form an optionally substituted 5- or 6-membered ring;

-R ⁵ is hydrogen, alkyl, haloalkyl, cycloalkyl or heterocycloalkyl, wherein each alkyl, halo

The haloalkyl, cycloalkyl or heterocycloalkyl is optionally substituted;

- ^R6 is hydrogen, alkyl, haloalkyl, cycloalkyl or heterocycloalkyl, wherein each alkyl, haloalkyl, cycloalkyl or heterocycloalkyl is optionally substituted; and

^-Ra is hydrogen, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, cycloalkyl or heterocycloalkyl, wherein each alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, cycloalkyl or heterocycloalkyl is optionally substituted;

wherein at least one of R ¹ , R ² , R ³ and R ⁴ is OR ^a , wherein ^Ra is aryl or arylalkyl, each of which is optionally substituted.

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

For any and all embodiments, substituents are selected from a subset of the listed alternatives.

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 ⁶ is unsubstituted or substituted alkyl, such as methyl.

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, such as methyl.

In some embodiments of formula (I), at least one of R ¹ , R ² , R ³ and R ⁴ is OR ^a , wherein ^Ra is aryl or arylalkyl, each of which is optionally substituted. In some embodiments, one of R 1, R ² , R ³ and R ⁴ is OR ^a , wherein ^Ra is aryl or arylalkyl, each of which is optionally substituted. In some embodiments, at least one of R ¹ , ^{R 2 ,} R ³ and R ⁴ is OR ^a , wherein ^Ra is aryl or arylalkyl, each of which is optionally substituted, and the remaining items of R ¹ , R ² , R ³ and R ⁴ are each hydrogen. In some embodiments, one of R ¹ , R ² , R ³ and R ⁴ is OR ^a , wherein ^Ra is aryl or arylalkyl, each of which is optionally substituted, and the remaining items of R ¹ , R ² , R ³ and R ⁴ are each hydrogen.

In some embodiments of formula (I), at least one of R ¹ , R ² , R ³ and R ⁴ is OR ^a , wherein ^Ra is an optionally substituted aryl. In some embodiments, one of R ¹ , R ² , R ³ and R ⁴ is OR ^a , wherein ^Ra is an optionally substituted aryl. In some embodiments, at least one of R ¹ , R ² , R ³ and R ⁴ is OR ^a , wherein ^Ra is an optionally substituted aryl, and the remaining items of R ¹ , R ² , R ³ and R ⁴ are each hydrogen. In some embodiments, one of R ¹ , R ² , R ³ and R ⁴ is OR ^a , wherein ^Ra is an optionally substituted aryl, and the remaining items of R ¹ , R ² , R ³ and R ⁴ are each hydrogen.

In some embodiments of formula (I), at least one of R ¹ , R ² , R ³ and R ⁴ is OR ^a , wherein ^Ra is an optionally substituted arylalkyl. In some embodiments, one of R ¹ , R ² , R ³ and R ⁴ is OR ^a , wherein ^Ra is an optionally substituted arylalkyl. In some embodiments, at least one of R ¹ , R ² , R ³ and R ⁴ is OR ^a , wherein ^Ra is an optionally substituted arylalkyl, and the remaining items of R ¹ , R ² , R ³ and R ⁴ are each hydrogen. In some embodiments, one of R ¹ , R ² , R ³ and R ⁴ is OR ^a , wherein ^Ra is an optionally substituted arylalkyl, and the remaining items of R ¹ , R ² , R ³ and R ⁴ are each hydrogen.

In some embodiments of formula (I), one of R ¹ , R ² , R ³ and R ⁴ is unsubstituted or substituted phenoxy. In some embodiments, R ¹ is unsubstituted phenoxy. In some embodiments, R ¹ is substituted phenoxy. In some embodiments, R ² is unsubstituted phenoxy. In some embodiments, R ² is substituted phenoxy. In some embodiments, R ³ is unsubstituted phenoxy. In some embodiments, R ³ is substituted phenoxy. In some embodiments, R ⁴ is unsubstituted phenoxy. In some embodiments, R ⁴ is substituted phenoxy.

In some embodiments of formula (I), one of R ¹ , R ² , R ³ and R ⁴ is unsubstituted or substituted benzyloxy. In some embodiments, R ¹ is unsubstituted benzyloxy. In some embodiments, R ¹ is substituted benzyloxy. In some embodiments, R ² is unsubstituted benzyloxy. In some embodiments, R ² is substituted benzyloxy. In some embodiments, R ³ is unsubstituted benzyloxy. In some embodiments, R ³ is substituted benzyloxy. In some embodiments, R ⁴ is unsubstituted benzyloxy. In some embodiments, R ⁴ is substituted benzyloxy.

In some embodiments of formula (I), at least one of R ¹ , R ² , R ³ and R ⁴ is selected from unsubstituted benzyloxy, benzyloxy substituted by at least one halogen (e.g., F, Cl, Br, I), unsubstituted phenoxy, and phenoxy substituted by at least one halogen (e.g., F, Cl, Br, I). In some embodiments, R ¹ is unsubstituted benzyloxy. In some embodiments, R ¹ is benzyloxy substituted by at least one halogen (e.g., F, Cl, Br, I). In some embodiments, R ¹ is unsubstituted phenoxy. In some embodiments, R ¹ is phenoxy substituted by 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 by at least one halogen (e.g., F, Cl, Br, I). In some embodiments, R ² is unsubstituted phenoxy. In some embodiments, R ² is a phenoxy group substituted with at least one halogen (e.g., F, Cl, Br, I). In some embodiments, R ³ is an unsubstituted benzyloxy group. In some embodiments, R ³ is a benzyloxy group substituted with at least one halogen (e.g., F, Cl, Br, I). In some embodiments, R ³ is an unsubstituted phenoxy group. In some embodiments, R ³ is a phenoxy group substituted with at least one halogen (e.g., F, Cl, Br, I). In some embodiments, R ⁴ is an unsubstituted benzyloxy group. In some embodiments, R ⁴ is a benzyloxy group substituted with at least one halogen (e.g., F, Cl, Br, I). In some embodiments, R ^{4 is an unsubstituted phenoxy group. In some embodiments, R 4 is} a phenoxy group substituted with at least one halogen (e.g., F, Cl, Br, I).

In some embodiments of formula (I), at least one of R ¹ , R ² , R ³ and R ⁴ is selected from benzyloxy, 4-fluorobenzyloxy, phenoxy and 4-fluorophenoxy. In some embodiments, R ¹ is selected from benzyloxy, 4-fluorobenzyloxy and 4-fluorophenoxy. In some embodiments, R ² is selected from benzyloxy, 4-fluorobenzyloxy and 4-fluorophenoxy. In some embodiments, R ^{3 is selected from benzyloxy, 4-fluorobenzyloxy and 4-fluorophenoxy. In some embodiments, R 4 is} selected from benzyloxy, 4-fluorobenzyloxy and 4-fluorophenoxy. In some embodiments, R ¹ is benzyloxy. In some embodiments, R ¹ is 4-fluorobenzyloxy. In some embodiments, R ¹ is phenoxy. In some embodiments, R ¹ is fluorophenoxy. 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 is fluorophenoxy. 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 is fluorophenoxy. 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.

In some embodiments, provided herein is a compound of formula (IA) or a pharmaceutically acceptable salt or solvate thereof:

in:

- Each of R ¹ , R ³ and R ⁴ is independently hydrogen, halogen, -OR ^a , alkyl, heteroalkyl, aryl, arylalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl or heterocycloalkyl, wherein each alkyl, heteroalkyl, aryl, arylalkyl, haloalkyl, hydroxyalkyl

The alkyl, aminoalkyl, cycloalkyl or heterocycloalkyl group is optionally substituted;

^-R2 is hydrogen;

or any one of ^R1 and ^R2 , ^R2 and ^R3 , or ^R3 and ^R4 and the carbon atoms to which they are attached

The atoms are taken together to form an optionally substituted 5- or 6-membered ring;

-R ⁵ is hydrogen, alkyl, haloalkyl, cycloalkyl or heterocycloalkyl, wherein each alkyl, halo

The haloalkyl, cycloalkyl or heterocycloalkyl is optionally substituted;

- ^R6 is hydrogen, alkyl, haloalkyl, cycloalkyl or heterocycloalkyl, wherein each alkyl, haloalkyl, cycloalkyl or heterocycloalkyl is optionally substituted; and

^-Ra is hydrogen, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, cycloalkyl or heterocycloalkyl, wherein each alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, cycloalkyl or heterocycloalkyl is optionally substituted;

wherein at least one of R ¹ , R ³ and R ⁴ is OR ^a , wherein R ^a is aryl or arylalkyl, each of which is optionally substituted.

In some embodiments of Formula (IA), when R ³ , R ⁴ , R ⁵ , and R ⁶ are each hydrogen, then R ¹ is not phenoxy.

In some embodiments of Formula (IA), one of R ¹ , R ^{3 ,} and R ⁴ is OR ^a , wherein ^Ra is aryl or arylalkyl, each of which is optionally substituted.

In some embodiments of Formula (IA), one of R ¹ , R ³ and R ⁴ is OR ^a , wherein ^Ra is aryl or arylalkyl, each of which is optionally substituted, and the remaining instances of R ¹ , R ³ and R ⁴ are each hydrogen.

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

In some embodiments of Formula (IA), one of R ¹ , R ^3, and R ⁴ is unsubstituted or substituted benzyloxy. In some embodiments of Formula (IA), 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.

In some embodiments of Formula (IA), at least one of R ¹ , R ^{3 ,} and R ⁴ is selected from unsubstituted benzyloxy, benzyloxy substituted with at least one halogen, unsubstituted phenoxy, and phenoxy substituted with at least one halogen.

In some embodiments of Formula (IA), at least one of R ¹ , R ³ , and R ⁴ is selected from benzyloxy, 4-fluorobenzyloxy, phenoxy, and 4-fluorophenoxy.

In some embodiments, provided herein is a compound of Formula (IB) or a pharmaceutically acceptable salt or solvate thereof:

in

-R is hydrogen, halogen, 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, or R ^{is OR ,} wherein ^Ra is substituted aryl or optionally substituted arylalkyl,

- each of R ² , R ³ and R ⁴ is independently hydrogen, halogen, -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;

or any one of R ¹ and R ² , R ² and R ³ , or R ³ and R ⁴ together with the carbon atoms to which they are attached form an optionally substituted 5- or 6-membered ring;

- R ⁵ is hydrogen, alkyl, haloalkyl, cycloalkyl or heterocycloalkyl, wherein each alkyl, haloalkyl, cycloalkyl or heterocycloalkyl is optionally substituted;

- ^R6 is hydrogen, alkyl, haloalkyl, cycloalkyl or heterocycloalkyl, wherein each alkyl, haloalkyl, cycloalkyl or heterocycloalkyl is optionally substituted; and

^-Ra is hydrogen, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, cycloalkyl or heterocycloalkyl, wherein each alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, cycloalkyl or heterocycloalkyl is optionally substituted;

wherein (i) at least one of R ² , R ³ and R ⁴ is OR ^a , wherein ^Ra is aryl or arylalkyl, each of which is optionally substituted; or (ii) R ¹ is OR ^a ' , wherein ^Ra is substituted aryl or optionally substituted arylalkyl.

In some embodiments of Formula (IB), when R ¹ , R ³ , R ⁴ , R ⁵ , and R ⁶ are each hydrogen, then R ² is not phenoxy.

In some embodiments of Formula (IB), when R ¹ , R ³ , R ^{4 ,} and R ⁶ are each hydrogen and R ⁵ is methyl, then R ² is not benzyloxy.

In some embodiments of Formula (IB), one of R ² , R ^{3 ,} and R ⁴ is OR ^a , wherein ^Ra is aryl or arylalkyl, each of which is optionally substituted.

In some embodiments of Formula (IB), one of R ² , R ³ and R ⁴ is OR ^a , wherein ^Ra is aryl or arylalkyl, each of which is optionally substituted, and the remainder of R ² , R ³ and R ⁴ are each hydrogen, and R ¹ is hydrogen.

In some embodiments of Formula (IB), R ¹ is OR ^a `, Ra <sup>a</sup> ` is substituted aryl or optionally substituted arylalkyl. In some embodiments of Formula (IB), R ¹ is OR ^a `, wherein Ra <sup>a</sup> ` is substituted aryl or optionally substituted arylalkyl, and R ² , R ³ and R ⁴ are each hydrogen.

In some embodiments of Formula (IB), one of R ² , R ³ and R ⁴ is unsubstituted or substituted phenoxy. In some embodiments of Formula (IB), R ¹ is substituted phenoxy. In some embodiments of Formula (IB), one of R ¹ , R ² , R ³ and R ⁴ is unsubstituted or substituted benzyloxy. In some embodiments of Formula (IB), at least one of R ² , R ³ and R ⁴ is selected from unsubstituted benzyloxy, benzyloxy substituted by at least one halogen, unsubstituted phenoxy and phenoxy substituted by at least one halogen. In some embodiments of Formula (IB), at least one of R ² , R ³ and R ⁴ is selected from benzyloxy, 4-fluorobenzyloxy, phenoxy and 4-fluorophenoxy.

In some embodiments of Formula (IB), R ¹ is selected from 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 benzyloxy, 4-fluorobenzyloxy, and 4-fluorophenoxy.

In some embodiments, provided herein is a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof:

in:

-R ¹ is hydrogen, halogen, 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, or R ¹ is OR ^a `, wherein Ra <sup>a</sup> ` is substituted aryl or optionally substituted arylalkyl;

^-R2 is hydrogen;

-R ³ and R ⁴ are each independently hydrogen, halogen, -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;

or any one of ^R1 and ^R2 , ^R2 and ^R3 , or ^R3 and ^R4 and the carbon atoms to which they are attached

The atoms are taken together to form an optionally substituted 5- or 6-membered ring;

-R ⁵ is hydrogen, alkyl, haloalkyl, cycloalkyl or heterocycloalkyl, wherein each alkyl, halo

The haloalkyl, cycloalkyl or heterocycloalkyl is optionally substituted;

- ^R6 is hydrogen, alkyl, haloalkyl, cycloalkyl or heterocycloalkyl, wherein each alkyl, haloalkyl, cycloalkyl or heterocycloalkyl is optionally substituted; and

^-Ra is hydrogen, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, cycloalkyl or heterocycloalkyl, wherein each alkyl, haloalkyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted;

wherein (i) at least one of R ² , R ³ and R ⁴ is an aryloxy group or an arylalkoxy group, each of which is optionally substituted; or (ii) R ¹ is a substituted aryloxy group or an optionally substituted arylalkoxy group.

In some embodiments of formula (II), at least one of R ³ and R ⁴ is OR ^a , wherein R ^a is aryl or arylalkyl, each of which is optionally substituted. In some embodiments of formula (II), one of R ³ and R ⁴ is OR ^a , wherein R ^a is aryl or arylalkyl, each of which is optionally substituted. In some embodiments of formula (II), at least one of R ³ and R ⁴ is OR ^a , wherein R ^a is aryl or arylalkyl, each of which is optionally substituted, another of R ³ and R ⁴ is hydrogen, and R ¹ is hydrogen. In some embodiments of formula (II), one of R ³ and R ⁴ is OR ^a , wherein R ^a is aryl or arylalkyl, each of which is optionally substituted, another of R ³ and R ⁴ is hydrogen, and R ¹ is hydrogen.

In some embodiments of formula (II), R ¹ is OR ^a ', wherein ^Ra ' is substituted aryl. In some embodiments of formula (II), R ¹ is OR ^a ', wherein ^Ra ' is optionally substituted arylalkyl. In some embodiments of formula (II), R ¹ is OR ^a ', wherein ^Ra ' is substituted aryl, and R ³ and R ⁴ are each hydrogen. In some embodiments of formula (II), R ¹ is OR ^a ', wherein ^Ra ' is substituted arylalkyl, and R ³ and R ⁴ are each hydrogen.

In some embodiments of Formula (II), one of R ³ and R ⁴ is unsubstituted or substituted phenoxy.

In some embodiments of Formula (II), R ¹ is substituted phenoxy.

In some embodiments of Formula (II), one of R ¹ , R ^{3 ,} and R ⁴ is unsubstituted or substituted benzyloxy.

In some embodiments of formula (II), at least one of R ³ and R ⁴ is selected from unsubstituted benzyloxy, benzyloxy substituted with at least one halogen, unsubstituted phenoxy, and phenoxy substituted with at least one halogen.

In some embodiments of Formula (II), at least one of R ³ and R ⁴ is selected from benzyloxy, 4-fluorobenzyloxy, phenoxy, and 4-fluorophenoxy.

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

In some embodiments of Formula (II), R ¹ is selected from benzyloxy, 4-fluorobenzyloxy, and 4-fluorophenoxy.

In some embodiments of Formula (II), R ³ is selected from benzyloxy, 4-fluorobenzyloxy, and 4-fluorophenoxy.

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, such as methyl.

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, such as methyl.

Representative compounds of formula (I), (IA), (IB) or (II) include, but are not limited to:

or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, provided herein are compounds having structures provided in Table 1, stereoisomers thereof, or pharmaceutically acceptable salts of the compounds or stereoisomers.

Table 1

Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are selected by one skilled in the art to provide stable moieties and compounds.

Other forms of compounds

In one embodiment, the compounds described herein are in the form of pharmaceutically acceptable salts. In some embodiments, any compound provided herein is a pharmaceutically acceptable salt, such as, for example, any salt described herein (such as, for example, a fumarate of a compound provided herein or a maleate of a compound provided herein). In some embodiments, any compound provided herein is a fumarate of a compound provided herein. In some embodiments, any compound provided herein is a maleate of a compound provided herein.

Likewise, active metabolites of these compounds having the same type of activity are included within the scope of the present disclosure. In addition, the compounds described herein may exist in unsolvated forms as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc. The solvated forms of the compounds given herein are also considered to be disclosed herein.

In some embodiments, a pharmaceutically 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., 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); acid); carbonic acid; cinnamic acid; citric acid; cyclohexylaminosulfonic acid; dodecylsulfuric acid; ethane-1,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactonic acid; gentisic acid; glucoheptonic 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.

In some embodiments, the compound represented by the structure of the compound of Formula (I), (IA), (IB), or (II) or the compound of Table 1 (ie, the free base form) is basic and reacted with maleic acid.

In some embodiments, the compound represented by the structure of the compound of Formula (I), (IA), (IB), or (II) or the compound of Table 1 (ie, the free base form) is basic and reacted with fumaric acid.

In some embodiments, a pharmaceutically 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, the compound represented by the structure of Formula (I), (IA), (IB) or (II) or a compound of Table 1 is acidic and reacts with a base. In such cases, the acidic protons of the compound represented by the structure of Formula (I), (IA), (IB) or (II) or a compound of Table 1 are replaced by metal ions (e.g., lithium, sodium, potassium, magnesium, calcium or aluminum ions). In some cases, the compounds described herein are coordinated with an organic base such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine. In other cases, the compounds described herein form salts with amino acids such as, but not limited to, arginine, lysine, and the like. Acceptable inorganic bases for forming 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, etc. In some embodiments, the compounds provided herein are prepared as sodium salts, calcium salts, potassium salts, magnesium salts, meglumine salts, N-methylglucamine salts, or ammonium salts.

It should be understood that reference to pharmaceutically acceptable salts includes solvent addition forms. In some embodiments, solvates contain stoichiometric or non-stoichiometric amounts of 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 in the processes described herein. In addition, the compounds provided herein are optionally present in unsolvated forms as well as solvated forms.

The methods and formulations described herein encompass the use of N-oxides (where appropriate) or pharmaceutically acceptable salts of compounds having the structure of Formula (I), (IA), (IB) or (II), as well as active metabolites of these compounds having the same type of activity.

In some embodiments, sites on the organic group (e.g., alkyl, aromatic ring) of a compound of Formula (I), (IA), (IB) or (II) are susceptible to various metabolic reactions. Incorporation of suitable substituents on the organic group will reduce, minimize or eliminate such metabolic pathways. In certain embodiments, suitable substituents that reduce or eliminate the sensitivity of the aromatic ring to metabolic reactions are (by way of example only) halogen, deuterium, alkyl, haloalkyl or deuterated alkyl.

In another embodiment, the compounds described herein are labeled isotopically (e.g., with a radioisotope) or by another other means, including but not limited to the use of a chromophore or fluorescent moiety, a bioluminescent label, or a chemiluminescent label.

The compounds described herein include isotopically labeled compounds, which are identical to those described in the various formulas and structures given herein, but for the fact that one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, iodine, phosphorus, such as, 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 P. In one embodiment, the isotopically labeled compounds described herein, for example those into which radioactive isotopes such as ³ H and ¹⁴ C are incorporated, are useful in drug and/or substrate tissue distribution assays. In one embodiment, substitution with an isotope such as deuterium provides certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements. In some embodiments, one or more hydrogens of a compound of Formula (I), (IA), (IB) or (II) are replaced with deuterium.

In some embodiments, the compounds represented by the structures of Formula (I), (IA), (IB) or (II) or the compounds of Table 1 have one or more stereocenters, and each stereocenter independently exists in the R configuration or the S configuration. In some embodiments, the compounds represented by the structures 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 structures of Formula (I), (IA), (IB) or (II) or the compounds of Table 1 exist in the S configuration. The compounds described herein include all diastereoisomers, single enantiomers, atropisomers and epimeric forms, and suitable mixtures thereof. The compounds and methods provided herein include all cis, trans, syn, trans, entgegen (E) and zusammen (Z) isomers, and suitable mixtures thereof.

In some embodiments, the compositions provided herein include a racemic mixture of a compound represented by the structure of Formula (I), (IA), (IB) or (II) or a compound of Table 1. In some embodiments, the compounds provided herein are racemates of a compound represented by the structure of Formula (I), (IA), (IB) or (II) or a compound of Table 1.

If desired, individual stereoisomers are obtained by methods such as stereoselective synthesis and/or separation of stereoisomers by chiral chromatographic columns or separation of diastereomers by achiral or chiral chromatographic columns or crystallization and recrystallization in a suitable 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 diastereomeric compounds/salts, separating the diastereomers and recovering optically pure individual enantiomers. In some embodiments, the resolution of individual enantiomers is performed using covalent diastereomeric derivatives of the compounds described herein. In another embodiment, diastereomers are separated by separation/resolution techniques based on solubility differences. In other embodiments, the separation of stereoisomers is performed by chromatography or by forming diastereomeric salts and by separation by recrystallization or chromatography or 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.

In some embodiments, the compounds described herein are prepared as prodrugs. In some embodiments, prodrugs are medicaments that are converted into parent drugs in vivo. Prodrugs are generally useful because, in some embodiments, they are easier to administer than parent drugs. For example, they are bioavailable by oral administration, while the parent is not. In addition or alternatively, compared with the parent drug, prodrugs also have improved solubility in pharmaceutical compositions. In some embodiments, the design of prodrugs increases effective water solubility. Non-limiting examples of prodrugs are compounds described herein, which are administered as esters ("prodrugs"), but are then metabolically hydrolyzed to provide active entities. Another example of prodrugs is a short peptide (polyamino acid) that is attached to an acid group, and peptides are metabolized to display active moieties on the acid group. In certain embodiments, when administered in vivo, prodrugs are chemically converted into biological, pharmaceutical or therapeutically active forms of the compound. In certain embodiments, prodrugs are enzymatically metabolized into biological, pharmaceutical or therapeutically active forms of the compound by one or more steps or processes.

Prodrugs of the compounds described herein include, but are not limited to, esters, ethers, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, N-alkoxyacyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphates and sulfonates. 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 which is incorporated herein by reference. In some embodiments, the hydroxyl group in the compounds disclosed herein is used to form a prodrug, wherein 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, wherein the hydroxyl group is then 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.

Prodrug forms of the compounds described herein are included within the scope of the claims, wherein the prodrug is metabolized in vivo to produce a compound of Formula (I), (IA), (IB) or (II) as described herein.

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

In additional or further embodiments, the compounds described herein are metabolized upon administration to an organism in need thereof to produce a metabolite, which metabolite is subsequently used to produce a desired effect, including a desired therapeutic effect.

In some embodiments, the metabolites of compounds disclosed herein are derivatives of the compounds formed when the compounds are metabolized. In some embodiments. The "active metabolites" of compounds provided herein are biologically active derivatives of compounds provided herein formed when the compounds are metabolized. In some embodiments, metabolism is the sum of the process (including but not limited to hydrolysis reaction and the reaction catalyzed by enzyme) of changing a specific substance by an organism. In some embodiments, enzymes can produce specific structural changes to compounds. For example, cytochrome P450 catalyzes various oxidation and reduction reactions, and UDP-glucuronyl transferase catalyzes the transfer of activated glucuronic acid molecules to aromatic alcohols, fatty alcohols, carboxylic acids, amines and free sulfhydryl groups. In some embodiments, metabolites of compounds disclosed herein are optionally identified by administering compounds to a host and analyzing tissue samples from the host, or by incubating compounds with hepatocytes in vitro and analyzing the resulting compounds.

Synthesis of compounds

The compounds of Formula (I), (IA), (IB) or (II) described herein are synthesized using standard synthetic techniques or using methods known in the art in combination with methods described herein.

Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are used.

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

In some embodiments, the compounds described herein are synthesized as described in the Examples.

Pharmaceutical composition

In some embodiments, provided herein is a pharmaceutical composition comprising a compound provided herein (e.g., a compound having a structure represented by Formula (I), (IA), (IB) or (II) or a compound of Table 1) and a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition further comprises at least one pharmaceutically acceptable excipient.

In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that aid in processing the active compounds into pharmaceutically useful preparations. Suitable formulations depend on the route of administration selected. An overview of the pharmaceutical compositions described herein is found in, for example, 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, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seven Ed. (Lippincott Williams & Wilkins 1999), which disclosures are incorporated herein by reference.

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

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 liquid emulsion or a water-in-oil liquid emulsion. In some embodiments, the active ingredient is presented as a bolus, a granule, or a paste.

Orally usable pharmaceutical compositions include tablets, push-in capsules made of gelatin, and soft sealed capsules made of gelatin and plasticizers such as glycerol or sorbitol. Tablets can be made by compression or molding, optionally containing one or more auxiliary ingredients. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form (such as powder or granules) in a suitable machine, optionally mixed with a binder, an inert diluent or a lubricating surfactant or dispersant. Molded tablets can be prepared by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine. In some embodiments, the tablets are coated or scored and formulated to provide a slow or controlled release of the active ingredient therein. The dosage of all preparations for oral administration should be suitable for such administration. Push-in capsules can contain a mixture of active ingredients with fillers such as lactose, binders such as starch and/or lubricants such as talc or magnesium stearate and optionally stabilizers. In soft capsules, the active compound can be dissolved or suspended in a suitable liquid such as a fatty oil, liquid paraffin or liquid polyethylene glycol. In some embodiments, stabilizers are added. The dragee core is provided with a suitable coating. For this purpose, concentrated sugar solutions can be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to the tablet or dragee coating to identify or characterize the different combinations of active compound dosages.

In some embodiments, the pharmaceutical composition is formulated for parenteral administration by injection (e.g., by pill injection or continuous infusion). Injectable preparations can be present in unit dosage form, such as in ampoules or in multi-dose containers, and preservatives are added. The composition can take the form of a suspension, solution, or emulsion in an oily or aqueous vehicle, and can contain a formulation agent, such as a suspending agent, a stabilizer, and/or a dispersant. The composition can be present in a unit dose or multi-dose container (e.g., sealed ampoules and vials), and can be stored in powder form or under freeze drying (lyophilization), only requiring the addition of a sterile liquid carrier, such as saline or sterile pyrogen-free water, immediately before use. Temporary injections and suspensions can be prepared by sterile powders, granules, and tablets of the aforementioned types.

Pharmaceutical compositions for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compound, which may contain antioxidants, buffers, bacteriostats, and solutes that make the preparation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or 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 a suitable stabilizer or an agent that increases the solubility of the compound to allow the preparation of a highly concentrated solution.

It should be understood that in addition to the ingredients particularly mentioned above, 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.

Treatment methods, administration and treatment regimens

The compounds disclosed herein or pharmaceutically acceptable salts, solvates or stereoisomers thereof can be used to promote neuron growth and/or improve neuron structure.

Provided herein are non-hallucinogenic psychotropic agents useful for treating one or more diseases or conditions associated with loss of synaptic connectivity and/or plasticity.

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 of Table 1). In some embodiments, provided herein is a method of modulating 5-HT _{2A 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 of Table 1). In some embodiments, provided herein is a method of agonizing 5-HT 2A} 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 of Table 1). In some embodiments, the individual suffers from or is diagnosed with _a brain disorder or other condition described herein.

In some embodiments, provided herein is a method of promoting neuronal growth in an individual in need thereof, comprising administering to an individual in need thereof 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 of Table 1).

In some embodiments, provided herein is a method of improving neuronal structure in an individual in need thereof, comprising administering to an individual in need thereof 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 of Table 1).

In some embodiments, provided herein is a method of modulating the activity of a serotonin receptor 2A (5-HT _2A ) receptor in an individual in need thereof, comprising administering to the individual in need thereof a therapeutically effective amount of a compound or pharmaceutical composition provided herein (eg, a compound having a structure represented by Formula (I), (IA), (IB) or (II) or a compound of Table 1).

In some embodiments, provided herein are methods of treating a disease or condition mediated by the action of serotonin (5-HT) at serotonin receptor 2A (5-HT _2A ) in an individual in need thereof, comprising administering to the individual in need thereof 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 of Table 1).

In some embodiments, provided herein is a method of treating a disease or condition mediated by loss of synaptic connectivity, plasticity, or a combination thereof in an individual in need thereof, comprising administering to the individual in need thereof 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 of Table 1).

In some embodiments, provided herein is a method of treating a neurological disease or disorder in an individual in need thereof, comprising administering to the individual in need thereof 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 of Table 1).

In some embodiments, individuals administered with the compounds provided herein have hallucinogenic events. In some embodiments, individuals administered with the compounds provided herein do not have hallucinogenic events. In some embodiments, individuals administered with the compounds provided herein have hallucinogenic events after the compounds provided herein reach a specific maximum concentration ( _Cmax ) in the individual. In some embodiments, the specific maximum concentration ( _Cmax ) in the individual is the hallucinogenic threshold of the compounds provided herein. In some embodiments, the compounds provided herein are administered to individuals in need at a threshold lower than the hallucinogenic threshold of the compounds provided herein.

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

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-addiction properties, anti-depressant properties, antianxiety properties, or a combination thereof.

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

In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, can be used to modulate 5-hydroxytryptamine (5-HT) receptors. In some embodiments, the 5-HT receptor modulated by the compounds and methods is 5-hydroxytryptamine receptor 2A (5- _HT2A ).

In some embodiments herein are provided modulators of serotonin receptor 2A (5-HT _2A ) that are useful for treating one or more diseases or conditions associated with 5-HT _2A activity.

In some embodiments, the compounds described herein, or pharmaceutically acceptable salts thereof, are used in the preparation of a medicament for treating a disease or condition in a mammal that would benefit from inhibition or reduction of 5- _HT2A activity.

In some embodiments, the compounds described herein, or pharmaceutically acceptable salts thereof, are used in the preparation of a medicament for treating a disease or condition in a mammal that would benefit from promoting neuronal growth and/or improving neuronal structure.

The method for treating any of the diseases or conditions described herein in a mammal in need of such treatment involves administering to the mammal a pharmaceutical composition comprising at least one compound described herein, or a pharmaceutically acceptable salt, active metabolite, prodrug, or pharmaceutically acceptable solvate thereof, in a therapeutically effective amount.

In certain embodiments, compositions containing compounds described herein are administered for preventive and/or therapeutic treatment. In certain therapeutic applications, the composition is administered to a mammal already suffering from a disease or condition in an amount sufficient to cure or at least partially inhibit at least one of the symptoms of the disease or condition. The effective amount for such use depends on the severity and course of the disease or condition, previous therapy, the health status of the mammal, body weight and response to the drug, and the judgment of a health care practitioner. The therapeutically effective amount is optionally determined by methods including, but not limited to, dose escalation and/or dose range clinical trials.

In preventive applications, a composition containing a compound as described herein is 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 use, the exact amount also depends on the health status, weight, etc. of the mammal. When used in mammals, the effective amount for this use will depend on the severity and course of the disease, disorder, or condition, previous therapy, the health status of the mammal and the response to the drug, and the judgment of a health care professional. In one embodiment, preventive treatment comprises administering a pharmaceutical composition comprising a compound as described herein or a pharmaceutically acceptable salt thereof to a mammal, so as to prevent the recurrence of symptoms of a disease or condition, the mammal having previously experienced at least one symptom of the disease being treated and is currently in remission.

In certain embodiments where the mammal's condition does not improve, the compound is administered chronically, i.e., for an extended period of time, including throughout the life span of the mammal, in order to ameliorate or otherwise control or limit the symptoms of the mammal's disease or condition, at the discretion of the health care professional.

In certain embodiments where the mammalian condition does improve, the dose of the administered drug is temporarily reduced or temporarily suspended for a period of time (i.e., a "drug holiday"). In specific embodiments, the length of the drug holiday is between 2 days and 1 year, including, by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or more than 28 days. By way of example only, the dose reduction during the drug holiday is 10%-100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.

Once improvement of the patient's condition occurs, a maintenance dose is administered as necessary. Subsequently, in specific embodiments, depending on the symptoms, the dose or the frequency of administration, or both, is reduced to a level that maintains the improved disease, disorder or condition. However, in certain embodiments, upon any recurrence of symptoms, the mammal requires intermittent treatment on a long-term basis.

The amount of a given agent corresponding to such amounts varies depending on factors such as the specific compound, the disease condition and its severity, the characteristics of the subject or host in need of treatment (e.g., weight, sex), etc., but will still be determined by the specific circumstances surrounding the case, including, for example, the specific agent administered, the route of administration, the condition being treated, and the subject or host being treated.

However, in general, dosages for adult treatment are generally in the range of 0.01 mg to 5000 mg per day. In one embodiment, dosages for adult treatment are from about 1 mg to about 1000 mg per day. In one embodiment, the desired dosage is conveniently administered in a single dose or in divided doses simultaneously or at appropriate intervals, for example, as two, three, four or more divided doses per day.

In one embodiment, the daily dose suitable for the compound described herein or its pharmaceutically acceptable salt is about 0.01 mg/kg/body weight to about 50 mg/kg/body weight. In some embodiments, based on many variables about individual treatment regimens, the amount of active substance in the daily dose or dosage form is lower or higher than the range described herein. In various embodiments, the daily dose and unit dose are changed according to many variables, including but not limited to the activity of the compound used, the disease or condition to be treated, the mode of administration, the needs of the individual subject, the severity of the disease or condition to be treated, and the judgment of the physician.

The toxicity and efficacy of such treatment regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including but not limited to the determination of _LD50 and _ED50 . The dose ratio between toxic and therapeutic effects is the therapeutic index, and it is expressed as the ratio between _LD50 and _ED50 . In certain embodiments, the data obtained from cell culture assays and animal studies are used to formulate therapeutically effective daily dose ranges and/or therapeutically effective unit doses for mammals (including humans). In some embodiments, the daily dose of the compound described herein is within the 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 used.

In any of the aforementioned aspects are further embodiments wherein an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof, is: (a) administered systemically to a mammal; and/or (b) administered orally to a mammal; and/or (c) administered intravenously to a mammal; and/or (d) administered by injection to a mammal; and/or (e) administered topically to a mammal; and/or (f) administered non-systemically or topically to a mammal.

In any of the foregoing aspects are additional embodiments comprising a single administration of an effective amount of the compound, including additional embodiments wherein (i) the compound is administered once daily; or (ii) the compound is administered to the mammal multiple times over the span of a day.

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

In one embodiment, the therapeutic effect of one of the compounds described herein is enhanced by administration of an adjuvant (i.e., the adjuvant itself has minimal therapeutic benefit, but in combination 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 that also has therapeutic benefit (which also comprises a therapeutic regimen).

In certain embodiments, when the compounds disclosed herein are administered in combination with one or more additional agents (such as additional therapeutically effective drugs, adjuvants, etc.), different therapeutically effective doses of the compounds disclosed herein will be used to prepare pharmaceutical compositions and/or for use in treatment regimens. The therapeutically effective doses of the drugs and other agents used in the combined treatment regimen are optionally determined by means similar to those described above for the active substance itself. In addition, the prevention/treatment methods described herein encompass the use of metronomic administration, i.e., providing more frequent, lower doses in order to minimize toxic side effects. In some embodiments, the combined treatment regimen encompasses such a treatment regimen, wherein the compound described herein or a pharmaceutically acceptable salt thereof is administered before, during, or after treatment with the second agent described herein, and continues until any time during treatment with the second agent or after treatment with the second agent is terminated. It also includes treatment in which the compound described herein or a pharmaceutically acceptable salt thereof and the second agent used in combination are administered simultaneously or at different times and/or at reduced or increased intervals during the treatment period. The combined treatment further includes regular treatments that start and stop at different times to assist in the clinical management of patients.

It should be understood that the dosage regimen for treating, preventing or improving the disease for which relief is sought varies according to a variety of factors (e.g., the disease or condition suffered by the subject; the age, weight, sex, diet and medical condition of the subject). Therefore, in some embodiments, the dosage regimen actually employed varies, and in some embodiments, deviates from the dosage regimen described herein.

Example

The following examples are provided for illustrative purposes only and do not limit the scope of the claims provided herein.

generally

Unless otherwise noted, all reagents are commercially available and used without purification. DMSO is purified by passing through an activated alumina column under 12psi _N2 . Flame-dried glassware is used to react under reduced pressure (about 1 Torr). The compounds purified by chromatography are adsorbed onto silica gel before loading. Thin layer chromatography is carried out on Millipore silica gel 60F ₂₅₄ silica gel plates. The visualization of chromatographic chromatography is achieved by fluorescence quenching or by staining with ninhydrin or aqueous ceric ammonium molybdate (CAM).

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

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

Chemical

General synthesis scheme:

Exemplary synthetic scheme:

In some embodiments, the compounds provided herein are prepared as outlined in Scheme 1.

Solution 1

In Scheme 1, in some embodiments, Ar is substituted or unsubstituted aryl or substituted or unsubstituted arylalkyl, as described elsewhere herein.

Representative Procedure 1: Preparation of Intermediate I-3:

To a stirred solution of intermediate I-1 (1.0 eq.) in DMSO (10 vol.) was added intermediate I-2 (1.2 eq.), followed by CuI (0.05 eq.), K ₃ PO ₄ (2.0 eq.) and picolinic acid (0.1 eq.), and the reaction mixture was stirred at 80° C. for 16 h. The crude reaction mixture was cooled to room temperature, diluted with ice-cold water and extracted with EtOAc. The combined organic layers were washed with ice-cold water and then with brine solution. The combined organic layers were dried over Na ₂ SO ₄ , the solids were removed by filtration, and the filtrate was concentrated in vacuo to provide a crude reaction product, which was purified by silica gel chromatography to give intermediate I-3.

Representative Procedure 2: Preparation of Intermediate I-4:

To a stirred solution of intermediate I-3 (1.0 eq) in HCl (6M aqueous solution, 20 vols) was added NaNO ₂ (2.0 eq, aqueous solution, 14 vols) at 0°C, and the reaction mixture was stirred for 2 hours. SnCl ₂ (3.0 eq, 6M aqueous HCl solution, 6.5 vols) was added dropwise to the reaction mixture, and the reaction was slowly warmed to room temperature and stirred for 3 hours. The resulting solid was collected by filtration, washed with heptane and dried under vacuum to provide intermediate I-4.

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) at 0°C was added HCl (6.0 equiv., 37% aqueous solution). The reaction mixture was allowed to slowly warm to room temperature and stirred at 90°C for 24 hours. Upon completion, the volatiles were removed in vacuo, and the crude oily residue was diluted with water, basified with NaOH (2.0 M aqueous solution), and extracted with _EtOAc . The combined organic layers were washed with brine solution and dried over anhydrous _Na2SO4 . The solids were removed by filtration and the filtrate was concentrated in vacuo to provide a regioisomeric mixture, which was separated by silica gel chromatography to give compounds A and A'. The chemical structures of compounds A and A' were determined by using 1H-NMR spectroscopy techniques. Representative Procedure 4: Preparation of Compounds B and B':

At room temperature, formaldehyde solution (37% aqueous solution, 2.0 equivalents) was added to a stirred solution of compound B (1.0 equivalents) in a mixture of MeOH (5 volumes) and THF (5 volumes), and the reaction mixture was stirred for 1 hour. The reaction mixture was cooled to 0°C, NaCNBH ₃ (2.0 equivalents) was added portionwise, and the reaction mixture was slowly warmed to room temperature and stirred for another 16 hours. Volatiles were removed in vacuo, the crude reaction residue was washed with water and extracted with EtOAc. The combined organic layers were washed with NaCl aqueous solution, the organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. The crude reaction residue was purified by silica gel chromatography to provide compound B. Compound B' was prepared using the same synthesis procedure but using compound A' as starting material.

Representative Procedure 5: Preparation of Intermediate I-6:

To a stirred solution of compound A (1.0 eq.) in CH ₂ Cl ₂ (10 vols) was added Et ₃ N (3.0 eq.) followed by Boc ₂ O (0.8 eq.) at 0° C. The resulting reaction mixture was slowly warmed to room temperature and stirred for 4 hours. The reaction mixture was diluted with ice-cold water and extracted with CH ₂ Cl _2. The combined organic layers were washed with aqueous NaCl solution, the organic layer was dried over anhydrous Na ₂ SO ₄ , the solids were removed by filtration, and the filtrate was concentrated in vacuo. The crude reaction residue was purified by silica gel chromatography to provide intermediate I-6.

Representative Procedure 6: Preparation of Intermediate I-7:

To a stirred solution of intermediate I-6 (1.0 eq.) in DMF (10 vol.) at 0°C was added NaH (60% in mineral oil, 1.5 eq.). The reaction mixture was stirred for 20 min, and methyl iodide (1.5 eq.) was added. The reaction mixture was slowly warmed to room temperature and stirred for 3 h, diluted with ice-cold water and extracted with EtOAc. The combined organic layers were washed with ice-cold water, _aqueous NaCl solution, dried over anhydrous _Na2SO4 , the solids were removed by filtration, and the filtrate was concentrated in vacuo. The crude reaction residue was purified by silica gel chromatography to afford intermediate I-7. Representative Procedure 7: Preparation of Compound C:

To a stirred solution of intermediate I-7 (1.0 eq) in _CH2Cl2 (10 vol) was added HCl (5.0 eq, _2M in _Et2O ) at 0°C and the reaction mixture was slowly warmed to room temperature and stirred for 6 hours. The volatiles were removed in vacuo and the crude residue was triturated with ether to afford Compound C as the HCl salt.

Representative Procedure 8: Preparation of Compound D:

To a stirred solution of compound C (1.0 eq.) in a mixture of MeOH (5 vol.) and THF (5 vol.) was added formaldehyde solution (2.0 eq., 37% in water) at room temperature, the reaction mixture was stirred for 1 hour, cooled to 0°C, and NaCNBH ₃ (2.0 eq.) was added portionwise. The reaction mixture was slowly warmed to room temperature and stirred for an additional 16 hours. The volatiles were removed in vacuo, the crude reaction residue was washed with water and extracted with EtOAc. The combined organic layers were washed with an aqueous NaCl solution, dried over anhydrous Na ₂ SO ₄ , the solids were removed by filtration, and the filtrate was concentrated in vacuo. The crude reaction residue was purified by silica gel chromatography to provide compound D.

Representative Procedure 9: Preparation of Fumarate Salt:

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

Example 1: Preparation of 3-phenoxyaniline (I-3a):

The title compound was obtained and purified according to Representative Procedure 1 using iodobenzene (I-1a) and 3-aminophenol (I-2) to afford intermediate I-3a; ESI-MS m/z: 185.85 [M+H] + .

Example 2: Preparation of 3-(4-fluorophenoxy)aniline (I-3b):

The title compound was obtained and purified according to Representative Procedure 1 using 1-fluoro-4-iodobenzene (I-1b) and 3-aminophenol (I-2) to afford Intermediate I-3b; ESI-MS m/z = 204.15 [M+H] + .

Example 3: Preparation of (3-phenoxyphenyl)hydrazine hydrochloride (I-4a):

According to Representative Procedure 2, using 3-phenoxyaniline (I-3a), the title compound was obtained and purified to provide intermediate I-4a; ESI-MS m/z = 200.90 [M+H] + .

Example 4: Preparation of (3-(4-fluorophenoxy)phenyl)hydrazine hydrochloride (I-4b): According to Representative Procedure 2, using 3-(4-fluorophenoxy)aniline (I-3b), the title compound was obtained and purified to provide intermediate I-4b; ESI-MS m/z = 219.03 [M+H] +.

Example 5: Preparation of (3-(benzyloxy)phenyl)hydrazine hydrochloride (I-4c):

According to Representative Procedure 2, using 3-(benzyloxy)aniline (I-3c), the title compound was obtained and purified to provide intermediate I-4c; ESI-MS m/z: 215.12 [M+H] + .

Example 6: Preparation of (2-(benzyloxy)phenyl)hydrazine (I-4f):

According to Representative Procedure 2, using 2-(benzyloxy)aniline (I-3f), the title compound was obtained and purified to provide intermediate I-4f; ESI-MS m/z: 215.1 [M+H] + .

Example 7: Preparation of compounds 3 and 4:

According to Representative Procedure 3, I-4c and aza -4-one hydrochloride (I-5) to obtain the title compound, and purified by HPLC separation method C to separate compound 3 and compound 4. Compound 3: ESI-MS m/z=293.2 [M+H]+; ¹ HNMR (DMSO-d6, 400 MHz): δ10.42 (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 afforded the corresponding fumarate salt.

Compound 4: ESI-MS m/z=293.2 [M+H]+; ¹ H NMR (DMSO-d6, 400 MHz): δ10.67 (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 provided the corresponding fumarate.

Example 8: Preparation of Compounds 11 and 20:

According to Representative Procedure 3, I-4a and aza -4-keto hydrochloride (I-5) to obtain the title compound, and purified by HPLC separation method C to separate compound 11 and compound 20.

Following Representative Procedure 9, compound 11 afforded the corresponding fumarate salt.

Following Representative Procedure 9, compound 20 afforded the corresponding fumarate salt.

Example 9: Preparation of Compounds 15 and 21:

According to Representative Procedure 3, I-4b and aza -4-keto hydrochloride (I-5) to obtain the title compound, and purified by HPLC separation method C to separate 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.

Example 10: Preparation of Compound 25:

According to Representative Procedure 3, 4-(benzyloxy)phenylhydrazine hydrochloride (I-4e) and azathionylamine were used. -4-one hydrochloride (I-5) to obtain the title compound and purify to give compound 25.

Following Representative Procedure 9, compound 25 afforded the corresponding fumarate salt.

Example 11: Preparation of Compound 27:

According to representative procedure 3, I-4f and aza -4-keto hydrochloride (I-5) to obtain the title compound and purify to give compound 27. ESI-MS m/z: 293.2 [M+H] +.

Following Representative Procedure 9, compound 27 afforded the corresponding fumarate salt.

Example 12: Preparation of Compound 26:

According to Representative Procedure 3, I-4e and 1-methylazepine were used. -4-ketohydrochloride (I-5b) to obtain the title compound and purify to give compound 26; ESI-MS m/z: 307.05 [M+H]+. Following Representative Procedure 9, compound 26 afforded the corresponding fumarate salt.

Example 13: Preparation of Compound 28:

According to Representative Procedure 3, I-4f and 1-methylazepine were used. -4-keto hydrochloride (I-5b), the title compound was obtained and purified to give compound 28; ¹ H NMR (400 MHz, DMSO-d ₆ ) 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.

Example 14: Preparation of Compound 12:

The title compound was obtained according to Representative Procedure 4 using compound 11, formaldehyde and NaCNBH ₃ and purified by HPLC separation method A to give compound 12 .

Following Representative Procedure 9, compound 12 afforded the corresponding fumarate salt

Example 15: Preparation of Compound 16:

The title compound was obtained and purified to give compound 16 according to Representative Procedure 4 using compound 15, formaldehyde and NaCNBH ₃ .

Following Representative Procedure 9, compound 16 afforded the corresponding fumarate salt.

Example 16: Preparation of Compound 1:

The title compound was obtained and purified to give Compound 1 according to Representative Procedure 4 using Compound 3, formaldehyde and _NaCNBH3 .

Following Representative Procedure 9, compound 1 provides the corresponding fumarate salt.

Example 17: Preparation of Compound 8:

The title compound was obtained and purified according to Representative Procedure 4 using compound 7 (Example 43), formaldehyde and NaCNBH ₃ to afford compound 8; ESI-MS m/z: 325.2 [M+H] + .

Following Representative Procedure 9, compound 8 afforded the corresponding fumarate salt.

Example 18: Preparation of Compound 22:

The title compound was obtained according to Representative Procedure 4 using compound 21, formaldehyde and NaCNBH ₃ and purified by HPLC separation method A to give compound 22; ESI-MS m/z: 311.2 [M+H] + .

Following Representative Procedure 9, compound 22 afforded the corresponding fumarate salt.

Example 19: 8-phenoxy-1,4,5,6-tetrahydroazepine Preparation of tert-butyl indole-3(2H)-carboxylate (I-6a):

The title compound was obtained and purified according to Representative Procedure 5 using compound 11, _Et3N and _Boc2O to provide intermediate I-6a; ESI-MS m/z: 323.2 [m-56]+.

Example 20: 8-(4-Fluorophenoxy)-1,4,5,6-tetrahydroazepine Preparation of tert-butyl indole-3(2H)-carboxylate (I-6b):

The title compound was obtained and purified according to Representative Procedure 5 using compound 15, Et ₃ N and Boc ₂ O to provide intermediate I-6b; ESI-MS m/z: 397.2 [M+H] + .

Example 21: 8-(Benzyloxy)-1,4,5,6-tetrahydroazepine Preparation of tert-butyl indole-3(2H)-carboxylate (I-6c):

The title compound was obtained and purified according to Representative Procedure 5 using compound 3, _Et3N and _Boc2O to provide I-6c; ESI-MS m/z = 335.2 [m-56]+.

Example 22: 10-(4-Fluorophenoxy)-1,4,5,6-tetrahydroazepine Preparation of tert-butyl indole-3(2H)-carboxylate (I-6e):

The title compound was obtained and purified according to Representative Procedure 5 using compound 21, _Et3N and _Boc2O to provide I-6e; ESI-MS m/z: 395.3 [MH]+.

Example 23: 10-(Benzyloxy)-1,4,5,6-tetrahydroazepine Preparation of tert-butyl indole-3(2H)-carboxylate (I-6f):

The title compound was obtained and purified according to Representative Procedure 5 using compound 4, _Et3N and _Boc2O to provide I-6f; ESI-MS m/z: 393.2 [M+H]+.

Example 24: 6-Methyl-8-phenoxy-1,4,5,6-tetrahydroazepine Preparation of tert-butyl indole-3(2H)-carboxylate (I-7a):

The title compound was obtained and purified according to Representative Procedure 6 using I-6a, NaH and MeI to afford I-7a; ESI-MS m/z = 393.2 [M+H]+.

Example 25: 8-(4-Fluorophenoxy)-6-methyl-1,4,5,6-tetrahydroazepine Preparation of tert-butyl indole-3(2H)-carboxylate (I-7b):

The title compound was obtained and purified according to Representative Procedure 6 using I-6b, NaH and MeI to afford I-7b.

Example 26: 8-(Benzyloxy)-6-methyl-1,4,5,6-tetrahydroazepine Preparation of tert-butyl indole-3(2H)-carboxylate (I-7c):

The title compound was obtained and purified according to Representative Procedure 6 using I-6c, NaH and MeI to afford intermediate I-7c.

Example 27: 8-((4-fluorobenzyl)oxy)-6-methyl-1,4,5,6-tetrahydroazepine Preparation of tert-butyl indole-3(2H)-carboxylate (I-7d):

The title compound was obtained and purified according to Representative Procedure 6 using I-6d (Example 42), NaH and MeI to afford I-7d; ESI-MS m/z: 425.05 [M+H]+.

Example 28: 10-(4-Fluorophenoxy)-6-methyl-1,4,5,6-tetrahydroazepine Preparation of tert-butyl indole-3(2H)-carboxylate (I-7e):

The title compound was obtained and purified according to Representative Procedure 6 using I-6e, NaH and MeI to give I-7e; ESI-MS m/z: 411.3 [M+H] + .

Example 29: 10-(Benzyloxy)-6-methyl-1,4,5,6-tetrahydroazepine Preparation of tert-butyl indole-3(2H)-carboxylate (I-7f):

The title compound was obtained and purified according to Representative Procedure 6 using I-6f, NaH and MeI to provide I-7f; ESI-MS m/z: 407.2 [M+H]+.

Example 30: Preparation of Compound 13:

The title compound was isolated as the HCl salt after trituration with ether according to Representative Procedure 7 using I-7a and 2M HCl in Et ₂ O. The HCl salt was basified with saturated aqueous NaHCO ₃ solution, extracted with EtOAc (2 x 20 ml), evaporated and dried to give Compound 13.

Following Representative Procedure 9, compound 13 afforded the corresponding fumarate salt.

Example 31: Preparation of Compound 17:

The title compound was isolated as the HCl salt after trituration with ether using I-7b and 2M HCl in Et ₂ O according to Representative Procedure 7. The HCl salt was basified with saturated aqueous NaHCO ₃ solution, extracted with EtOAc (2 x 20 ml) and dried to give Compound 17.

Following Representative Procedure 9, compound 17 afforded the corresponding fumarate salt.

Example 32: Preparation of Compound 5:

The title compound was isolated as the HCl salt after trituration with ether according to Representative Procedure 7 using I-7c and 2M HCl in Et ₂ O. The HCl salt was basified with saturated aqueous NaHCO ₃ solution, extracted with EtOAc (2 x 20 ml) and dried to give Compound 5.

Following Representative Procedure 9, compound 5 afforded the corresponding fumarate salt.

Example 33: Preparation of Compound 9:

The title compound was isolated as the HCl salt after trituration with ether using I-7d and 2M HCl in _Et2O according to Representative Procedure 7. The HCl salt was basified with saturated aqueous _NaHCO3 , extracted with EtOAc (2 x 20 ml) and dried to give compound 9. ESI-MS m/z: 352.2 [M+H]+.

Following Representative Procedure 9, compound 9 afforded the corresponding fumarate salt.

Example 34: Preparation of Compound 23:

Following Representative Procedure 7, using I-7e and 2M HCl in _Et2O , the title compound was isolated as the HCl salt after trituration with ether. The HCl salt was basified with saturated aqueous _NaHCO3 , extracted with EtOAc (2 x 20 ml) and dried to afford 23; ESI-MS m/z: 311.1 [M+H]+. Following Representative Procedure 9, compound 23 afforded the corresponding fumarate salt.

Example 35: Preparation of Compound 19:

The title compound was obtained and triturated according to Representative Procedure 7 using I-7f and 2M HCl in _Et2O 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.

Example 36: Preparation of Compound 18:

The title compound was obtained and purified to provide Compound 18 according to Representative Procedure 8 using Compound 17, formaldehyde and NaCNBH ₃ .

Following Representative Procedure 9, compound 18 afforded the corresponding fumarate salt.

Example 37: Preparation of Compound 6:

The title compound was obtained and purified to provide compound 6 according to Representative Procedure 8 using compound 5, formaldehyde and NaCNBH ₃ .

Following Representative Procedure 9, compound 6 afforded the corresponding fumarate salt.

Example 38: Preparation of Compound 10:

The title compound was obtained and purified according to Representative Procedure 8 using compound 9, formaldehyde and NaCNBH ₃ to provide compound 10; ESI-MS m/z: 339.00 [M+H] + .

Following Representative Procedure 9, compound 10 afforded the corresponding fumarate salt.

Example 39: Preparation of Compound 24:

The title compound was obtained and purified according to Representative Procedure 8 using compound 23, formaldehyde and NaCNBH ₃ to provide compound 24; ESI-MS m/z: 352.20 [M+H] + .

Following Representative Procedure 9, compound 24 afforded the corresponding fumarate salt.

Example 40: Preparation of Compound 14:

To a stirred solution of I-7a (110 mg, 1.0 eq.) in THF (1.1 ml) at 0°C was added 2M LAH in THF (0.420 ml, 0.841 mmol, 3.0 eq.). The reaction mixture was refluxed for 3 h, quenched with ice-cold water, filtered through celite, and washed with EtOAc (2 x 10 ml). The combined organic layers were washed with aqueous NaCl solution, dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo. The crude residue was purified by a chromatography system to afford compound 14. Following Representative Procedure 9, compound 14 afforded the corresponding fumarate salt.

As described in Scheme 1, the compounds in Table 2 were prepared as described for Scheme 1 using appropriately substituted anilines.

Table 2

**Spectral data of the corresponding fumarate salt

In some embodiments, compounds are prepared as outlined in Scheme 2.

Solution 2

a Reagents and conditions: i) Pd/C (w/w), H ₂ , MeOH (10 vol), RT, 4 h; ii) Cs ₂ CO ₃ (2 eq), 4-fluorobenzyl bromide (1 eq), DMF (10 vol), 0° C. to RT, 16 h; iii) 2M HCl in ether (6 vol), CH ₂ Cl ₂ (10 vol), 0° C. to RT, 2 h

Example 41: 8-Hydroxy-1,4,5,6-tetrahydroazepine Preparation of tert-butyl indole-3(2H)-carboxylate (I-6g):

To a stirred solution of I-6c (1.2 g, 3.05 mmol, 1 eq.) in MeOH (12 ml) was added 10% Pd/C (1.29 g, w/w) under _N2 atmosphere. The above suspension was stirred under _H2 (60 psi) at RT for 4 h. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure to afford the crude compound which was used Purification by chromatography system (3% MeOH in CH ₂ Cl ₂ ) afforded I-6g (900 mg, 99%) as an off-white solid; ESI-MS m/z: 301.1 [MH] + .

Example 42: 8-((4-Fluorobenzyl)oxy)-1,4,5,6-tetrahydroazepine Preparation of tert-butyl 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 RT for 16 hours. The reaction mixture was diluted with water and extracted with EtOAc (2 x 100 mL). The organic layer was washed with water, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The crude residue was purified by chromatography system (10% MeOH in DCM) to afford I-6d (550 mg, 62%), ESI-MS m/z: 355.1 [M-56]+.

Example 43: Preparation of Compound 7:

According to Representative Procedure 7, using I-6d and 2M HCl in _Et2O , the title compound was obtained after neutralization of the reaction mixture with aqueous _NaHCO3 and extraction _{with CH2Cl2} to give Compound 7. Following Representative Procedure 9, Compound 7 afforded the corresponding fumarate salt.

The compounds in Table 3 were prepared as described for Scheme 2.

Table 3

* Spectral data of the corresponding fumarate salt

In some embodiments, compounds are prepared as outlined in Scheme 3.

Solution 3

a Reagents and conditions: 1) KOtBu (1.2 eq), DMF (10 vol), 0°C, BnBr (1 eq), RT, 16 h; ii) NaNO ₂ (2 eq), 6M HCl (20 vol), 0°C to RT, 2 h. SnCl ₂ .2H ₂ O (3 eq) in 6M HCl (8.5 vol), 0°C to RT, 3 h; iii) 1-methylazepine -4-Ketohydrochloride, 0.1 M EtOH, concentrated HCl (6 eq.), reflux, 24 h; iv) 2 M LAH in THF (2 eq.), reflux.

Example 44: Preparation of 5-(benzyloxy)-2-bromoaniline (I-3g):

To a stirred solution of I-2c (20 g, 106 mmol, 1.0 eq.) in DMF (200 ml) at 0 °C was added potassium tert-butoxide (14.2 g, 127.2 mmol, 1.2 eq.). The reaction mixture was stirred for 30 min, benzyl bromide (15.9 g, 84.8 mmol, 0.8 eq.) was added at 0 °C, and the reaction mixture was slowly warmed to room temperature and then stirred at RT for 16 h. The reaction mixture was quenched with ice-cold water (250 ml) and extracted with EtOAc (2 x 500 ml). The combined organic layers were washed with ice-cold water and then with aqueous NaCl solution. The organic layer was separated, dried over Na ₂ SO ₄ and concentrated to give the crude material, which was used Purification by chromatography system (10-15% EtOAc/hexanes) gave I-3g (16.5 g, 55%); ESI-MS m/z: 280.0 [M+H]+.

Example 45: Preparation of (5-(benzyloxy)-2-bromophenyl)hydrazine hydrochloride (I-4g): According to Representative Procedure 2, using I-3g (10 g, 35.9 mmol), _NaNO2 (4.98 g, 71.8 mmol) and _SnCl2.2H2O ( _24.43 g, 107.7 mmol), the title compound was obtained after washing and drying to provide I-4g (10 g, 95%); ESI-MS m/z: 292.90 [M+H].

Example 46: Preparation of Compound 29:

The title compound was obtained after purification by HPLC separation method A according to Representative Procedure 3 using I-4g (5 g, 15.2 mmol), I-5b (2.3 g, 18.2 mmol) and concentrated HCl (2.65 mL) to afford Compound 29 (500 mg).

Following Representative Procedure 9, compound 29 afforded the corresponding fumarate salt.

Example 47: Preparation of Compound 2:

To a stirred solution of compound 29 (1.5 g, 3.89 mmol, 1.0 eq.) in THF (15 ml) was added 2M LAH in THF (5.83 ml, 11.6 mmol, 3.0 eq.) at 0°C. The reaction mixture was heated at 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 obtain compound 2.

Following Representative Procedure 9, compound 2 afforded the corresponding fumarate salt.

The compounds in Table 4 were prepared as described in Scheme 3.

Table 4

* Spectral data of the corresponding fumarate salt

Pharmaceutical composition

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 pharmaceutically acceptable salt or solvate thereof is dissolved in sterile water and then mixed with 10 mL of 0.9% sterile saline. A suitable buffer and optional acid or base are optionally added to adjust the pH. The mixture is incorporated into a dosage unit form suitable for administration by injection.

Example A-2: Oral Solution

To prepare a pharmaceutical composition for oral delivery, a sufficient amount of a compound described herein, or a pharmaceutically acceptable salt thereof, is added to water (along with optional solubilizers, optional buffers, and taste-masking excipients) to provide a 20 mg/mL solution.

Example A-3: Oral Tablet

Tablets are prepared by mixing 20-50% by weight of a compound described herein or a pharmaceutically 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 tablet is maintained at 100-500 mg.

Example A-4: Oral capsule

To prepare a pharmaceutical composition for oral delivery, 1-1000 mg of a compound described herein or a pharmaceutically acceptable salt thereof is mixed with starch or other suitable powder mixtures. The mixture is incorporated into oral dosage units suitable for oral administration, such as hard gelatin capsules.

In another embodiment, 1-1000 mg of a compound described herein or a pharmaceutically acceptable salt thereof is placed in a size 4 capsule or a size 1 capsule (hydroxypropyl methylcellulose or hard gelatin), and the capsule is sealed.

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 based on drug identification data, 6-MeO-DMT does not produce HTR. Finally, potent plasticity-promoting compounds do not produce HTR, suggesting that hallucinogenic potential and psychoplasticity can be decoupled.

Hallucinogens (e.g., LSD and 5-MeO-DMT) can activate the 5HT _2A sensor assay in agonist mode, but their non-hallucinogenic homologues (lisulide (LIS) and 6-MeO-DMT) cannot activate the sensor assay. In addition, compounds that are hallucinogenic in animals (e.g., humans), such as, for example, 5-MeO-DMT, LSD, DMT, DOI, activate the 5HT _2A sensor assay in agonist mode, while compounds that are non-hallucinogenic in animals (e.g., humans), such as, for example, 6-MeO-DMT, LIS, 6-F-DET, L-MDMA, R-MDMA, ketanserin, BOL148, do not activate the 5HT _2A sensor assay in agonist mode. 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 using a 5HT _2A sensor assay. In some embodiments, the 5HT _2A sensor assay is in agonist mode or antagonist mode. In some embodiments, the 5HT _2A 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.

In some embodiments, the hallucinogenic potential of the compounds provided herein is assessed in a _5HT2A sensor assay in agonist mode.

In addition, in some cases, when the 5HT _2A sensor is run in antagonist mode, non-hallucinogenic compounds (e.g., risulide and 6-MeO-DMT) compete for 5-HT. In addition, compounds that are non-hallucinogenic in animals (e.g., humans), such as, for example, 6-F-DET, ketanserin, BOL148, can compete with 5HT in antagonist mode sensor assays for binding to 5HT _2A . In some embodiments, the compounds provided herein prevent 5-HT from binding to 5HT _2A . In some embodiments, the 5HT _2A sensor assay is in antagonist mode. In some embodiments, the compounds provided herein prevent 5-HT from binding to 5HT _2A and have non-hallucinogenic potential. In some embodiments, the compounds provided herein prevent 5-HT from binding to 5HT _2A and are non-hallucinogenic. In some embodiments, the compounds provided herein that prevent 5-HT from binding to 5HT _2A in antagonist mode have non-hallucinogenic potential. In some embodiments, the compounds provided herein that prevent 5-HT from binding in antagonist mode are non-hallucinogenic compounds. In some embodiments, the compounds provided herein that inhibit a response of a sensor assay in antagonist mode have non-hallucinogenic potential. In some embodiments, the compounds provided herein that inhibit a response of a sensor assay in antagonist mode are non-hallucinogenic compounds.

In some embodiments, the results of the agonist mode sensor assay indicate that the compounds provided herein are non-hallucinogenic ligands of the 5-HT _2A receptor. In some embodiments, the results of the antagonist mode sensor assay indicate that the compounds provided herein are non-hallucinogenic ligands of the 5-HT _2A receptor. In some embodiments, the results of the agonist mode and antagonist mode sensor assays together indicate that the compounds provided herein are non-hallucinogenic ligands of the 5-HT _2A receptor.

In some embodiments, the hallucinogenic potential of compounds is assessed in a _5HT2A sensor assay in antagonist mode.

Forced swimming test. Since the increased cortical structural plasticity in the anterior part of the brain mediates the sustained (>24h) antidepressant-like effect of ketamine and plays a role in the therapeutic effect of 5-HT2A agonists, the effects of the compounds on the forced swimming test (FST) behavior are used to evaluate the therapeutic potential of the compounds provided herein. First, the pretest is used to induce a depressive phenotype. The compound is administered 24h after the pretest, and the FST is performed 24h and 7d after drug administration.

Neurite outgrowth assay. Changes in neurite outgrowth patterns are associated with neurodegenerative disorders and traumatic injuries. The discovery of compounds that can positively affect neurite generation is important for developing new therapeutic drugs for nervous system diseases. In some cases, automated image-based assays are used to measure neurite outgrowth in rat cortical neurons to determine the neuroplasticity effects of compounds provided herein. In some embodiments, provided herein are compounds that increase the pattern of neurite outgrowth. In some embodiments, compared to a control, provided herein are compounds that increase the average length of neurites. In some embodiments, compared to a control, provided herein are compounds that increase neurite branching points. In some embodiments, compared to a control, provided herein are compounds that increase neurite average length and neurite branching points.

In some embodiments, the plasticity potential of the compounds provided herein is assessed by measuring changes in neurite development.

Dendritic growth assay. Phenotypic screening has historically proven to be more successful in identifying drugs with new mechanisms of action than target-based approaches. Using phenotypic assays, the compounds provided herein were tested for their ability to increase dendritic arbor complexity in cultures of cortical neurons. After treatment, neurons were fixed and observed using antibodies against MAP2, a cytoskeletal protein localized to the somatodendritic compartment of neurons. Sholl analysis was then performed, and the maximum number of intersections (N _max ) was used as a quantitative measure of dendrite complexity. For statistical comparisons between specific compounds, the original N _max values were compared. The percent efficacy was determined by setting the N _max values of the vehicle (DMSO) and positive (ketamine) controls to 0% and 100%, respectively.

Animals. For dendrite formation experiments, timed pregnant Sprague Dawley rats were obtained from Charles River Laboratories (Wilmington, MA). In some cases, male and female C57BL/6J mice were obtained from Jackson Laboratory (Sacramento, CA). In some cases, mice were housed in a temperature and humidity controlled room, 4-5 per group (same sex), maintaining a 12 h light/dark cycle.

Dendrite generation-Sholl analysis. Neurons were plated in 96-well format (200 μL of culture medium per well) at a density of approximately 15,000 cells/well in Neurobasal (Life Technologies) containing 1% penicillin-streptomycin, 10% heat-inactivated fetal bovine serum and 0.5 mM glutamine. After 24 h, the culture medium was replaced with Neurobasal containing 1x B27 supplement (Life Technologies), 1% penicillin-streptomycin, 0.5 mM glutamine and 12.5 μM glutamate. After 3 days of in vitro culture (DIV3), cells were treated with compounds. Unless otherwise stated, the compounds tested in the dendrite generation assay were treated at 10 μM. The stock solution of the compound in DMSO was first diluted 100 times in Neurobasal, and then diluted 10 times in each well (total dilution = 1:1000; 0.1% DMSO concentration). Treatment was randomized. After 1 h, the culture medium was removed and replaced with new Neurobasal medium containing 1x B27 supplement, 1% penicillin-streptomycin, 0.5 mM glutamine and 12.5 μM glutamate. The cells were grown for an additional 71 h. At this point, neurons were fixed by removing 80% of the culture medium and replacing the culture medium with a 4% aqueous paraformaldehyde solution (Alfa Aesar) equal to 50% of the working volume of the well. The cells were then incubated at room temperature for 20 min, the fixative was then aspirated, and each well was washed twice with DPBS. At room temperature, the cells were permeabilized for 20 min using 0.2% Triton X-100 (ThermoFisher) in DPBS without shaking. At room temperature, the plate was blocked for 1 h with antibody dilution buffer (ADB) containing 2% bovine serum albumin (BSA) in DPBS. The plate was then incubated overnight at 4 ° C in ADB containing chicken anti-MAP2 antibody (1:10,000; EnCor, CPCA-MAP2) with gentle shaking. The next day, the plates were washed three times with DPBS and once with 2% ADB in DPBS. The plates were incubated at room temperature for 1 h in ADB containing an anti-chicken IgG secondary antibody conjugated to Alexa Fluor 488 (Life Technologies, 1:500) and washed five times with DPBS. After the last wash, 100 μL of DPBS was added to each well and imaged on an ImageXpress Micro XL high-content screening system (Molecular Devices, Sunnyvale, CA) with a 20x objective.

Images were analyzed using ImageJ Fiji (version 1.51W). First, images corresponding to each treatment were sorted into separate folders, which were then subjected to blind data analysis. Plate controls (positive and negative) were used to ensure that the assay was working properly, as well as to visually determine appropriate values for brightness/contrast and thresholds to be applied universally to the remaining random images. Next, brightness/contrast settings were applied and approximately 1-2 individual pyramidal neurons (i.e., no bipolar neurons) were selected in each image using the rectangular selection tool and saved as separate files. Neurons that did not overlap extensively with other cells or extend beyond the field of view were selected. Threshold settings were then applied to separate images. The brush tool was used to eliminate artifacts and branch processes originating from neighboring neurons (clearing stage). Next, the point tool was used to select the center of the neuron, and the image was saved and processed using the following Sholl analysis batch processing macro:

run("Sholl analysis...", "start=0 end=NaN radius_step=2 #_sample=1 integration=average closed=1 #_primary=4 extrapolate fit linear polynomial=[best fit] max semilog normalizer=area create background=228 save do");

Sholl analysis circle radius = 2 pixel increment = 0.67 μm. All images were taken and analyzed by an experimenter who was blind to the treatment conditions. The number of intersections per neuron at each different radius was averaged to produce the average Sholl graph for each treatment. The N _max value was simply determined by determining the maximum value of each graph. For each treatment, neurons were selected from at least 6 holes distributed on 2 plates (9 sites/well x 3 holes/plate x 2 plates). Each plate was prepared using neurons obtained from independent pregnant mothers).

Dendritic spine formation assay. Dendritic spine formation assay was performed as previously described, except that cells were treated at DIV19 and fixed after 24 h of treatment at DIV20. (Ly, C. et al., 2018) These images were taken on a Nikon HCA confocal microscope with a 100x/NA 1.45 oil objective. DMSO and ketamine (10 μM) were used as vehicle and positive control, respectively.

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

Serotonin 5-HT2A In vitro Cell IPOne agonism assay. The 5-HT2A IPOne HTRF assay was performed using conventional methods at Epics Therapeutics SA (Belgium, FAST-0505I). Briefly, CHO-K1 cells expressing human recombinant 5-HT2A receptors grown to mid-logarithmic phase in antibiotic-free medium were detached with PBS-EDTA, centrifuged, and resuspended in medium without antibiotic buffer. 20,000 cells were distributed in 96-well plates and incubated overnight at 37°C in 5% _CO2 .

For agonist testing, remove the medium and add 20 μl of assay buffer plus 20 μl of test compound or reference agonist to each well. Incubate the plate at 37°C with 5% _CO2 for 60 min.

After adding lysis buffer containing IP1-d2 and anti-IP1 cryptate detection reagent, the plate was incubated for 1 hour at room temperature and the fluorescence ratio was measured using the HTRF kit according to the manufacturer's instructions.

Serotonin 5-HT2C in vitro radioligand binding competition assay. 5-HT2Cedited (Accession No. AAF35842.1) radioligand binding competition assay was performed at Epics Therapeutics SA (Belgium, FAST-0507B) using conventional methods. Briefly, competition 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 optimized for each receptor/well), radioactive tracer [ ³ H]-DOI (final concentration optimized for each receptor) and test compound. Nonspecific binding was determined by co-incubation with a 200-fold excess of cold competitor. The sample was incubated in a final volume of 0.1 ml at a temperature and duration optimized for each receptor and then filtered on a filter plate. The filter was 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. The plates were incubated on an orbital shaker for 15 min and then counted for 1 min/well using a TopCount™.

Serotonin 5-HT2C in vitro cell IPOne agonist assay. The 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 edited receptors (Accession No. AAF35842.1) grown to mid-logarithmic phase in medium without antibiotics were separated with PBS-EDTA, centrifuged, and resuspended in medium without antibiotic buffer. 20,000 cells were distributed in 96-well plates and incubated overnight at 37°C in 5% _CO2 .

For agonist testing, remove the medium and add 20 μl of assay buffer plus 20 μl of test compound or reference agonist to each well. Incubate the plate at 37°C with 5% _CO2 for 60 min.

After adding lysis buffer containing IP1-d2 and anti-IP1 cryptate detection reagent, the plate was incubated for 1 hour at room temperature and the fluorescence ratio was measured using the HTRF kit according to the manufacturer's instructions.

The compounds provided herein were tested in serotonin 5-HT2A and 5-HT2C in vitro radioligand binding and cell IPOne agonism assays. The binding and agonistic functional potency of the compounds (as indicated by their IC ₅₀ or EC ₅₀ ) are shown in Table 5.

Table 5

A: IC50 or EC50 is <0.010μM; B: IC50 or EC50 is 0.010μM-0.100μM; C: IC50 or EC50 is 0.101μM-1μM; D: IC50 or EC50 is 1.001μM-10μM; E: IC50 or EC50 is >10μM

Serotonin 5-HT2A and 5-HT2C in vitro cell IPOne antagonism assay. The 5-HT2A IPOne HTRF assay was performed in antagonism mode using conventional methods at Epics Therapeutics SA (Belgium, FAST-0505I). Briefly, CHO-K1 cells expressing human recombinant 5-HT2A receptors grown to mid-logarithmic phase in antibiotic-free medium were detached with PBS-EDTA, centrifuged, and resuspended in medium without antibiotic buffer. 20,000 cells were distributed in 96-well plates and incubated overnight at 37°C in 5% _CO2 .

For antagonist testing, add the reference agonist a-Me-5HT to each well and monitor the fluorescence signal for several minutes before adding 20 μl of assay buffer plus 20 μl of test compound or reference antagonist ketanserin. Incubate the plate at 37°C with 5% _CO2 for 60 min.

After adding lysis buffer containing IP1-d2 and anti-IP1 cryptate detection reagent, the plate was incubated for 1 hour at room temperature and the fluorescence ratio was measured using the HTRF kit according to the manufacturer's instructions.

The compounds provided herein were tested in serotonin 5-HT2A and 5-HT2C in vitro radioligand binding and cellular IPOne antagonism assays. The antagonistic functional potency of the compounds (as shown by their IC ₅₀ or EC ₅₀ ) is shown in Table 6.

Table 6

A: IC50 or EC50 is <0.010μM; B: IC50 or EC50 is 0.010μM-0.100μM; C: IC50 or EC50 is 0.101μM-1μM; D: IC50 or EC50 is 1.001μM-10μM; E: IC50 or EC50 is >10μM; n.d. means not determined.

Neurite outgrowth assay. Changes in neurite outgrowth patterns are associated with psychiatric and neurodegenerative diseases and traumatic injuries. The discovery of new compounds that can positively affect neurite generation is important for developing new therapeutic drugs for neurological diseases. The use of automated image-based assays to measure neurite outgrowth in rat cortical neurons is used to determine the neuroplasticity effects of the compounds of the invention. Neurite outgrowth assays were performed at Neurofit SAS (France) as described below.

Pregnant Wistar rats (Janvier; France) were used for the study. They were delivered 6 days before use. Upon arrival at the Neurofit animal facility, they were housed one per cage and kept in a room with controlled temperature (21-22°C) and opposite light-dark cycle (12h/12h; lights on: 17:30-05:30; lights off: 05:30-17:30), with food and water available ad libitum.

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

After 72h (3 days) of plating, the culture was fixed with paraformaldehyde in PBS (4%, Sigma) for 30min at 4°C. Then, the cells were permeabilized continuously for 30min with 0.1% Triton X100, saturated with PBS containing 3% BSA, and incubated with anti-βIII tubulin antibody (Sigma) at 1/10000 in PBS containing 0.5% BSA for 1h. The cells were washed three times with PBS containing 0.5% BSA, and they were incubated with goat anti-mouse antibody coupled to AF488 (Invitrogen A11001) diluted at 1/1000 in PBS containing 0.5% BSA for 1h. Finally, the nuclei were stained with 1mg/mL DAPI at 1/1000 in PBS containing 0.5% BSA. After rinsing with PBS, the plates were photographed and high content screening (CellInsight, Thermo Scientific) was used to examine and analyze the neurite network. The average number of neurites per neuron and the average total length of neurites per neuron were the main parameters analyzed. Data were analyzed using analysis of variance (ANOVA). Fisher's least significant difference test was used for multiple comparisons. p value ≤ 0.05 was considered significant. The software used was StatView 5.0 from SAS Institut.

In some embodiments, the compounds of the present invention increase the pattern of neurite outgrowth. In some embodiments, compared with a control, the compounds of the present invention increase the average length of neurites. In some embodiments, compared with a control, the compounds of the present invention increase neurite branching points. In some embodiments, compared with a control, the compounds of the present invention significantly increase the number of new neurites and/or average neurite length.

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

Table 7

A: Statistically significant mean increases as percentage of DMSO control at 10 μM or lower.

B: No statistically significant mean increase as a percentage of DMSO control at 10 μM or below.

n.d. means not determined.

5HT _2A sensor assay. A HEK293T (ATCC) 5HT2A sensor stable line (sLight1.3s) was generated via lentiviral transduction of HIV-EF1α-sLight1.3 and propagated from single colonies. Lentivirus was produced using the second generation lentiviral plasmids pHIV-EF1α-sLight1.3, pHCMV-G and pCMV-δR8.2.

For screening, sLight1.3s cells were plated at a density of 40,000 in 96-well plates 24 hours before imaging. On the day of imaging, compounds dissolved in DMSO were diluted from 100mM stock solutions to working concentrations of 1mM, 100μM, and 1μM, with a DMSO concentration of 1%. Just before imaging, cells grown in DMEM (Gibco) were washed 2 times with HBSS (Gibco), and after the last wash, 180μL of HBSS was added to each well in agonist mode, or 160μL of HBSS was added in antagonist mode. For agonist mode, images were taken before and after adding 20μL of compound working solution to a well containing 180μL of HBSS. This produces final compound concentrations of 100μM, 10μM, and 100nM, with a DMSO concentration of 0.1%. For antagonist mode, images were taken before and after adding 20 μL of 900 nM 5-HT, and again after adding 20 μL of compound working solution (to produce a final concentration of 100 nM for 5HT and a final concentration of 100 μM, 10 μM, and 100 nM for compounds, with a DMSO concentration of 0.1%). Each concentration (100 μM, 10 μM, and 100 nM) of the compound was tested in triplicate (3 wells). In addition, within each plate, 100 nM 5HT and 0.1% DMSO controls can also be imaged.

Imaging was performed using a Leica DMi8 inverted microscope with a 40x objective using the FITC presets of 460 nm excitation and 512-542 nm emission. For each well, the cell membrane targeted by the 5HT2A sensor was automatically focused using adaptive focus control, and 5 images were taken from different areas within the well, each image being processed by 2x2 pixel binning.

For data processing, the membrane from each image was segmented and analyzed using a custom algorithm written in MATLAB, generating a single raw fluorescence intensity value. For each well, the 5 raw fluorescence intensity values generated from 5 images were averaged, and the change in fluorescence intensity (dFF) was calculated as:

dFF＝(F _sat -F _apo )/F _apo

For both the agonist mode and the antagonist mode, only the fluorescence intensity values before compound addition in HBSS were used as F _apo values, whereas the fluorescence intensity values after compound addition were used as F _sat values.

For agonist mode, data are presented 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 was calculated as:

Inactivation score = (dFFF(compound + 5HT) - dFF(5HT)) / dFF(5HT)

Head Twitch Response (HTR) Experiment. C57BL/6J mice (9-10 weeks old) were housed according to IACUC-approved protocols. Mice were acclimated to the test cage for at least 30 min, injected intraperitoneally with compound (injection volume 5 ml/kg), returned to an empty test cage, and filmed for 20 min. The number of head twitches in each video was scored by a trained observer who was blinded to the treatment conditions.

Forced swimming test (FST). Male Sprague Dawley rats were obtained from Envigo (Indianapolis, IN) and housed in 3 rats per cage according to the IACUC approved protocol. All experiments were conducted in a forced swimming chamber consisting of transparent acrylic (height = 40 cm; diameter = 20.3 cm) at ambient temperature (20 ° C and 23 ° C) under artificial lighting during the light-on portion of the light/dark cycle. For each swimming test, only one rat was placed in the swimming chamber at a time. The water was changed and the chamber was cleaned between each animal. All rats were exposed to two swimming trainings. The water depth was 16 cm in the first swimming training, and the water depth was 30 cm in the second swimming training, and the water temperature was maintained at 23 ± 1 ° C for all swimming trainings. During the FST, the animals underwent 15 min of swimming training (before swimming), lasted for 15 minutes, wiped dry with a paper towel, and then returned to the cage where they lived. After the adaptation training, rats were injected with saline, ketamine (positive control) or test compounds, returned to the home cage, and then tested in the second FST (secondary swimming test) lasting from 5 minutes to 24 hours. The second swimming test was video recorded for scoring. Body weight was measured on both days. The scoring of the second swimming test was performed by a trained technician using a time sampling technique, in which the animals in the video-recorded test were observed every 5 seconds and the observed behavior was recorded. The measurements recorded were immobility, climbing and swimming behavior.

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 before performing each experiment.

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

Claims (63)

1. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof:

Wherein:

-each of R ¹、R²、R³ and R ⁴ is independently hydrogen, halogen, -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;

Or any of R ¹ and R ²、R² and R ³, or R ³ and R ⁴, 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, wherein each alkyl, haloalkyl, cycloalkyl or heterocycloalkyl is optionally substituted;

-R ⁶ is hydrogen, alkyl, haloalkyl, cycloalkyl or heterocycloalkyl, wherein 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;

Wherein at least one of R ¹、R²、R³ and R ⁴ is OR ^a, wherein R ^a is aryl OR arylalkyl, each of which is optionally substituted;

The conditions are as follows:

(i) When R ¹、R³、R⁴、R⁵ and R ⁶ are each hydrogen, then R ² is not phenoxy;

(ii) When R ²、R³、R⁴、R⁵ and R ⁶ are each hydrogen, then R ¹ is not phenoxy; and

(Iii) When R ¹、R³、R⁴ and R ⁶ are each hydrogen and R ⁵ is methyl, then R ² is not benzyloxy.

2. The compound of claim 1, wherein R ⁶ is unsubstituted or substituted alkyl, or hydrogen.

3. The compound of claim 1 or2, wherein R ⁶ is hydrogen.

4. The compound of claim 1 or 2, wherein R ⁶ is methyl.

5. The compound of any one of claims 1-4, wherein R ⁵ is unsubstituted or substituted alkyl, or hydrogen.

6. The compound of any one of claims 1-5, wherein R ⁵ is hydrogen.

7. The compound of any one of claims 1-5, wherein R ⁵ is methyl.

8. The compound of any one of claims 1-7, wherein one of R ¹、R²、R³ and R ⁴ is OR ^a, wherein R ^a is aryl OR arylalkyl, each of which is optionally substituted.

9. The compound of any one of claims 1-8, wherein one of R ¹、R²、R³ and R ⁴ is OR ^a, wherein R ^a is aryl OR arylalkyl, each of which is optionally substituted, and the remaining items in R ¹、R²、R³ and R ⁴ are each hydrogen.

10. The compound of any one of claims 1-9, wherein one of R ¹、R²、R³ and R ⁴ is unsubstituted or substituted phenoxy.

11. The compound of any one of claims 1-9, wherein one of R ¹、R²、R³ and R ⁴ is unsubstituted or substituted benzyloxy.

12. The compound of any one of claims 1-11, wherein at least one of R ¹、R²、R³ and R ⁴ is selected from unsubstituted benzyloxy, benzyloxy substituted by at least one halogen, unsubstituted phenoxy, and phenoxy substituted by at least one halogen.

13. The compound of any one of claims 1-12, wherein at least one of R ¹、R²、R³ and R ⁴ is selected from benzyloxy, 4-fluorobenzyloxy, phenoxy and 4-fluorophenoxy.

14. The compound of any one of claims 1-13, wherein R ¹ is selected from benzyloxy, 4-fluorobenzyloxy and 4-fluorophenoxy.

15. The compound of any one of claims 1-14, wherein R ³ is selected from benzyloxy, 4-fluorobenzyloxy and 4-fluorophenoxy.

16. The compound of claim 1, wherein

-Each of R ¹、R³ and R ⁴ is independently hydrogen, halogen, -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 any of R ¹ and R ²、R² and R ³, or R ³ and R ⁴, 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, wherein each alkyl, haloalkyl, cycloalkyl or heterocycloalkyl is optionally substituted;

-R ⁶ is hydrogen, alkyl, haloalkyl, cycloalkyl or heterocycloalkyl, wherein 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;

Wherein at least one of R ¹、R³ and R ⁴ is OR ^a, wherein R ^a is aryl OR arylalkyl, each of which is optionally substituted;

With the proviso that when R ³、R⁴、R⁵ and R ⁶ are each hydrogen then R ¹ is not phenoxy.

17. The compound of claim 16, wherein one of R ¹、R³ and R ⁴ is OR ^a, wherein R ^a is aryl OR arylalkyl, each of which is optionally substituted.

18. The compound of claim 16 OR 17, wherein one of R ¹、R³ and R ⁴ is OR ^a, wherein R ^a is aryl OR arylalkyl, each of which is optionally substituted, and the remaining items in R ¹、R³ and R ⁴ are each hydrogen.

19. The compound of any one of claims 16-18, wherein one of R ¹、R³ and R ⁴ is unsubstituted or substituted phenoxy.

20. The compound of any one of claims 16-18, wherein one of R ¹、R³ and R ⁴ is unsubstituted or substituted benzyloxy.

21. The compound of any one of claims 16-20, wherein at least one of R ¹、R³ and R ⁴ is selected from unsubstituted benzyloxy, benzyloxy substituted by at least one halogen, unsubstituted phenoxy and phenoxy substituted by at least one halogen.

22. The compound of any one of claims 16-21, wherein at least one of R ¹、R³ and R ⁴ is selected from benzyloxy, 4-fluorobenzyloxy, phenoxy and 4-fluorophenoxy.

23. The compound of claim 1, wherein

-R ¹ is hydrogen, halogen, 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, OR R ¹ is OR ^a ', wherein R ^a' is substituted aryl OR optionally substituted arylalkyl,

-Each of R ²、R³ and R ⁴ is independently hydrogen, halogen, -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;

Or any of R ¹ and R ²、R² and R ³, or R ³ and R ⁴, 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, wherein each alkyl, haloalkyl, cycloalkyl or heterocycloalkyl is optionally substituted;

-R ⁶ is hydrogen, alkyl, haloalkyl, cycloalkyl or heterocycloalkyl, wherein 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;

Wherein (i) at least one of R ²、R³ and R ⁴ is OR ^a, wherein R ^a is aryl OR arylalkyl, each of which is optionally substituted; OR (ii) R ¹ is OR ^a 'wherein R ^a' is substituted aryl OR optionally substituted arylalkyl;

The conditions are as follows:

(i) When R ¹、R³、R⁴、R⁵ and R ⁶ are each hydrogen, then R ² is not phenoxy; and

(Ii) When R ¹、R³、R⁴ and R ⁶ are each hydrogen and R ⁵ is methyl, then R ² is not benzyloxy.

24. The compound of claim 23, OR a pharmaceutically acceptable salt OR solvate thereof, wherein one of R ²、R³ and R ⁴ is OR ^a, wherein R ^a is aryl OR arylalkyl, each of which is optionally substituted.

25. The compound of claim 23 OR 24, OR a pharmaceutically acceptable salt OR solvate thereof, wherein one of R ²、R³ and R ⁴ is OR ^a, wherein R ^a is aryl OR arylalkyl, each of which is optionally substituted, the remaining items of R ²、R³ and R ⁴ are each hydrogen, and R ¹ is hydrogen.

26. The compound of claim 23, wherein R ¹ is OR ^a ', wherein R ^a' is substituted aryl OR optionally substituted arylalkyl.

27. The compound of claim 23 OR 26, wherein R ¹ is OR ^a ', wherein R ^a' is substituted aryl OR optionally substituted arylalkyl, and R ²、R³ and R ⁴ are each hydrogen.

28. The compound of any one of claims 23-27, wherein one of R ²、R³ and R ⁴ is unsubstituted or substituted phenoxy, or wherein R ¹ is substituted phenoxy.

29. The compound of any one of claims 23-27, wherein one of R ¹、R²、R³ and R ⁴ is unsubstituted or substituted benzyloxy.

30. The compound of any one of claims 23-29, wherein at least one of R ²、R³ and R ⁴ is selected from unsubstituted benzyloxy, benzyloxy substituted by at least one halogen, unsubstituted phenoxy and phenoxy substituted by at least one halogen.

31. The compound of any one of claims 23-29, wherein at least one of R ²、R³ and R ⁴ is selected from benzyloxy, 4-fluorobenzyloxy, phenoxy and 4-fluorophenoxy.

32. The compound of any one of claims 23-29, wherein R ¹ is selected from unsubstituted benzyloxy, benzyloxy substituted by at least one halogen, and phenoxy substituted by at least one halogen.

33. The compound of any one of claims 23-29, wherein R ¹ is selected from benzyloxy, 4-fluorobenzyloxy and 4-fluorophenoxy.

34. The compound of claim 1, wherein

-R ¹ is hydrogen, halogen, 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, OR R ¹ is OR ^a ', wherein R ^a' is substituted aryl OR optionally substituted arylalkyl;

-R ² is hydrogen;

R ³ and R ⁴ are each independently hydrogen, halogen, -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;

Or any of R ¹ and R ²、R² and R ³, or R ³ and R ⁴, 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, wherein each alkyl, haloalkyl, cycloalkyl or heterocycloalkyl is optionally substituted;

-R ⁶ is hydrogen, alkyl, haloalkyl, cycloalkyl or heterocycloalkyl, wherein 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, cycloalkyl or heterocycloalkyl is optionally substituted;

Wherein (i) at least one of R ²、R³ and R ⁴ is aryloxy or arylalkoxy, each of which is optionally substituted; or (ii) R ¹ is substituted aryloxy or optionally substituted arylalkoxy.

35. The compound of claim 34, wherein one of R ³ and R ⁴ is OR ^a, wherein R ^a is aryl OR arylalkyl, each of which is optionally substituted.

36. The compound of claim 34 OR 35, wherein one of R ³ and R ⁴ is OR ^a, wherein R ^a is aryl OR arylalkyl, each optionally substituted, the other of R ³ and R ⁴ is hydrogen, and R ¹ is hydrogen.

37. The compound of claim 34, wherein R ¹ is OR ^a ', wherein R ^a' is substituted aryl OR optionally substituted arylalkyl.

38. The compound of claim 34 OR 37, wherein R ¹ is OR ^a ', wherein R ^a' is substituted aryl OR optionally substituted arylalkyl, and R ³ and R ⁴ are each hydrogen.

39. The compound of any one of claims 34-38, wherein one of R ³ and R ⁴ is unsubstituted or substituted phenoxy, or wherein R ¹ is substituted phenoxy.

40. The compound of any one of claims 34-38, wherein one of R ¹、R³ and R ⁴ is unsubstituted or substituted benzyloxy.

41. The compound of any of claims 34-40, wherein at least one of R ³ and R ⁴ is selected from unsubstituted benzyloxy, benzyloxy substituted by at least one halogen, unsubstituted phenoxy and phenoxy substituted by at least one halogen.

42. The compound of any of claims 34-40, wherein at least one of R ³ and R ⁴ is selected from benzyloxy, 4-fluorobenzyloxy, phenoxy and 4-fluorophenoxy.

43. The compound of any of claims 34-40, wherein R ¹ is selected from unsubstituted benzyloxy, benzyloxy that is substituted by at least one halogen, and phenoxy that is substituted by at least one halogen.

44. The compound of any of claims 34-40, wherein R ¹ is selected from benzyloxy, 4-fluorobenzyloxy and 4-fluorophenoxy.

45. The compound of any of claims 34-40, wherein R ³ is selected from benzyloxy, 4-fluorobenzyloxy and 4-fluorophenoxy.

46. The compound of any one of claims 16-45, wherein R ⁶ is unsubstituted or substituted alkyl, or hydrogen.

47. The compound of any one of claims 16-46, wherein R ⁶ is hydrogen.

48. The compound of any one of claims 16-46, wherein R ⁶ is methyl.

49. The compound of any one of claims 16-48, wherein R ⁵ is unsubstituted or substituted alkyl, or hydrogen.

50. The compound of any one of claims 16-49, wherein R ⁵ is hydrogen.

51. The compound of any one of claims 16-49, wherein R ⁵ is methyl.

52. A compound which is:

Or a pharmaceutically acceptable salt or solvate thereof.

53. A pharmaceutical composition comprising a compound of any one of claims 1-52, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

54. A method of promoting neuronal growth in a mammal comprising administering to the mammal a compound of any one of claims 1 to 52, or any pharmaceutically acceptable salt or solvate thereof.

55. A method of improving neuronal structure in a mammal comprising administering to the mammal a compound of any one of claims 1 to 52, or any pharmaceutically acceptable salt or solvate thereof.

56. A method of modulating the activity of a 5-hydroxytryptamine receptor 2A (5-HT _2A) receptor in a mammal comprising administering to the mammal a compound of any one of claims 1 to 52, or any pharmaceutically acceptable salt or solvate thereof.

57. A method of treating a disease or disorder mediated by the action of 5-hydroxytryptamine (5-HT) on 5-hydroxytryptamine receptor 2A (5-HT _2A) in a mammal, comprising administering to the mammal a compound of any one of claims 1 to 52, or any pharmaceutically acceptable salt or solvate thereof.

58. A method of treating a disease or disorder mediated by loss of synaptic connectivity, plasticity, or a combination thereof in a mammal, comprising administering to the mammal a compound as described in any one of claims 1 to 52, or any pharmaceutically acceptable salt or solvate thereof.

59. A method for treating a neurological disease or disorder in a mammal, the method comprising administering to the mammal a compound of any one of claims 1 to 52, or any pharmaceutically acceptable salt or solvate thereof.

60. The method of claim 59, wherein the neurological disease or disorder is a neurodegenerative, neuropsychiatric, or substance-using disease or disorder.

61. The method of claim 59, wherein the neurological disease or disorder is injury.

62. The method of claim 59, wherein the neurological disease or disorder is selected from anxiety disorders, mood disorders, psychotic disorders, personality disorders, eating disorders, sleep disorders, sexual behavior disorders, impulse control disorders, substance use disorders, dissociative disorders, cognitive disorders, developmental disorders, and sexual disorders.

63. The method of any one of claims 54-62, wherein the mammal is a human.