Substituted benzylpyrrolidines and uses thereof

Abstract

This disclosure relates in some aspects to novel compounds comprising a substituted benzylpyrrolidine pharmacophore, and analogs thereof. In some aspects, the disclosure further relates to compositions containing the compounds, methods of synthesizing the compounds, and methods of using the compounds. In some aspects, the compounds are useful as therapeutic agents for treating medical conditions, for example by modulating neurotransmission.

Description

[0001] SUBSTITUTED BENZYLPYRROLIDINES AND USES THEREOF

[0002] Gregory E. Dwulet

[0003] CROSS-REFERENCE

[0004]

[0001] Priority is claimed under PCT Art. 8(1) and Rule 4.10 to U.S. Prov. App. No. 63 / 632,552, filed April 11 , 2024, which is fully incorporated by reference for all purposes.

[0005] FIELD OF THE INVENTION

[0006]

[0002] This disclosure relates in some aspects to novel compounds comprising a substituted benzylpyrrolidine pharmacophore, and analogs thereof. In some aspects, the disclosure further relates to compositions containing the compounds, methods of synthesizing the compounds, and methods of using the compounds. In some aspects, the compounds are useful as therapeutic agents for treating medical conditions, for example by modulating neurotransmission.

[0007] BACKGROUND OF THE INVENTION

[0008]

[0003] In recent years, there has been renewed scientific and commercial interest in serotonergic compounds, including those historically classified as psychedelics, such as psilocybin, ayahuasca, and lysergic acid diethylamide. This resurgence has helped illuminate the potential of serotonin-2A (5-HT2A) receptor agonists for addressing unmet medical needs, particularly in the treatment of neuropsychiatric and neurological disorders. Much of the existing research has centered on naturally occurring or synthetic / semi-synthetic "classical" psychedelics, which often produce hallucinogenic effects that can limit their clinical utility. These compounds may also be associated with acute psychological or physiological side effects and face significant regulatory barriers, particularly in jurisdictions like the United States where many are classified as Schedule I substances under the Controlled Substances Act and the Federal Analogue Act. Accordingly, there remains a need for the development of novel 5-HT2A receptor agonists, particularly those that retain therapeutic efficacy while minimizing or eliminating side effects.

[0009] INCORPORATION BY REFERENCE

[0010]

[0004] All patents, publications, and non-patent literature cited herein are incorporated by reference in their entirety, as though each were individually and fully set forth in this disclosure. However, the inclusion of such references should not be interpreted as an acknowledgment that any cited material is from an analogous field or directly relevant to the present invention. Furthermore, no citation should be considered an admission that the referenced document or its contents constitute prior art or part of the common general knowledge in any jurisdiction.

[0011] BRIEF SUMMARY OF THE INVENTION

[0012]

[0005] The following provides a brief summary of certain embodiments of the invention to facilitate a general understanding thereof. This summary is not a comprehensive overview and is not intended to highlight essential or critical aspects of the invention or define its scope. Rather, it serves solely as an introduction to the more detailed description that follows.

[0013]

[0006] In one aspect, provided is a compound having the structure of Formula (I): wherein: n is 1 , 2, or 0;

[0014] R2is CrC6alkoxy or H, or R2is taken together with R3and the intervening atoms to form a 5- or 6-membered heterocyclyl;

[0015] R3is H, or R3or taken together with R2and the intervening atoms to form a 5- or 6-membered heterocyclyl;

[0016] R4is Br, F, Cl, I, CrC6alkyl, C2-C8alkenyl, C2-C8alkynyl, CrC6alkoxy, CrC6alkylthio, C3-C6cycloalkylthio, C2-C8alkenylthio, CrC6haloalkylthio, CrC6haloalkyl, CrC6haloalkoxy, C3-C8cycloalkyl, CrC6alkylene-C3-C8cycloalkyl, 4- to 8-membered heterocycloalkyl, CN, NO2, NH2, or H;

[0017] R5is CrC6alkoxy or H, or R5is taken together with R6and the intervening atoms to form a 5- or 6-membered heterocyclyl; and

[0018] R6is H, or R6is taken together with R5and the intervening atoms to form a 5- or 6-membered heterocyclyl; or a pharmaceutically acceptable salt, stereoisomer, solvate, or isotopic derivative thereof.

[0019]

[0007] In some embodiments (or “in embodiments,” as shorthand), the compound has the structure of Formula (II):

[0020]

[0008] In embodiments, the compound has the structure of Formula (III):

[0021]

[0009] In embodiments, n is 1 . In embodiments, n is 2. In embodiments, n is 0.

[0022]

[0010] In embodiments, R2is C^Cg alkoxy or H. In embodiments, R2is CrC6alkoxy. In embodiments, R2is methoxy. In embodiments, R2is ethoxy. In embodiments, R2is taken together with R3and the intervening atoms to form a 5- or 6-membered heterocyclyl. In embodiments, R2is taken together with R3and the intervening atoms to form a 5-membered heterocyclyl. In embodiments, R2is taken together with R3and the intervening atoms to form a furanyl or dihydrofuranyl.

[0023]

[0011] In embodiments, R3is H. In embodiments, R3is taken together with R2and the intervening atoms to form a 5- or 6-membered heterocyclyl.

[0024]

[0012] In embodiments, R4is Br, F, Cl, I. In embodiments, R4is Br. In embodiments, R4is CrCg alkyl. In embodiments, R4is methyl. In embodiments, R4is ethyl. In embodiments, R4is n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl. In embodiments, R4is C^Cg alkylthio. In embodiments, R4is methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, sec-butylthio, isobutylthio, or tert-butylthio. In embodiments, R4is C^Cg haloalkylthio. In embodiments, R4is trifluoromethylthio, 2-fluoroethylthio, 2,2-difluoroethylthio, 2,2,2-trifluoroethylthio, 3-fluoropropylthio, or 4-fluorobutylthio. In embodiments, R4is C2-C8alkenylthio. In embodiments, R4is allylthio or methallylthio. In embodiments, R4is CN. In embodiments, R5is C^Cg alkoxy or H.

[0025]

[0013] In embodiments, R5is C^Cg alkoxy. In embodiments, R5is methoxy. In embodiments, R5is ethoxy. In embodiments, R5is taken together with R6and the intervening atoms to form a 5- or 6-membered heterocyclyl. In embodiments, R5is taken together with R6and the intervening atoms to form a 5-membered heterocyclyl. In embodiments, R5is taken together with R6and the intervening atoms to form a furanyl or dihydrofuranyl.

[0026]

[0014] In embodiments, R6is H. In embodiments, R6is taken together with R5and the intervening atoms to form a 5- or 6-membered heterocyclyl.

[0027]

[0015] Also provided is a compound selected from Table 1 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or isotopic derivative thereof.

[0028]

[0016] In embodiments, the compound has the structure of:

[0029]

[0017] In embodiments, the compound has the structure of:

[0030]

[0031]

[0019] In embodiments, the compound has S-stereochemistry. In embodiments, the compound has R-stereochemistry.

[0032]

[0020] Also provided is a pharmaceutical composition comprising the compound of any of the disclosed embodiments, or a pharmaceutically acceptable salt, stereoisomer, isotopolog, or solvate thereof, and one or more pharmaceutically acceptable excipients. In embodiments, the pharmaceutical composition is formulated for oral, mucosal, rectal, transdermal, subcutaneous, intravenous, intramuscular, inhaled, or intranasal administration. In embodiments, the pharmaceutical composition is in unit dosage form.

[0033]

[0021] Also provided is a method of treating a medical condition in a subject, comprising administering to the subject the compound or pharmaceutical composition of any of the disclosed embodiments.

[0034]

[0022] In embodiments, the medical condition is a neurodegenerative disease. In embodiments, the neurodegenerative disease is a neurodegenerative movement disorder. In embodiments, the neurodegenerative movement disorder is Parkinson’s disease, amyotrophic lateral sclerosis, multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, and Huntington’s disease. In embodiments, the neurodegenerative disease is Alzheimer’s disease, Lewy body dementia, frontotemporal dementia.

[0035]

[0023] In embodiments, the medical condition is a hormone-related neurological or cognitive disorder. In embodiments, the hormone-related neurological or cognitive disorder is menopause-associated cognitive disturbance, menopausal depression, climacteric-related mood disorder, or postpartum depression.

[0036]

[0024] In embodiments, the medical condition is a pain disorder. In embodiments, the pain disorder is chronic migraine, cluster headache, trigeminal neuralgia, fibromyalgia, or a neuropathic pain disorder.

[0037]

[0025] In embodiments, the medical condition is caused by a neurological injury. In embodiments, the neurological injury is ischemic stroke, traumatic brain injury, and spinal cord injury.

[0038]

[0026] Also provided is the compound or pharmaceutical composition of any of the disclosed embodiments for use in treating a medical condition. Also provided is the compound or pharmaceutical composition of any of the disclosed embodiments for the manufacture of a medicament for treating a medical condition. Also provided is the use of the compound or pharmaceutical composition of any of the disclosed embodiments for treating a medical condition. Also provided is a method of manufacturing a compound having the structure of Formula (I), (II), or (III), or any subformula thereof.

[0039] DETAILED DESCRIPTION OF THE INVENTION

[0040]

[0027] The phenylalkylamine pharmacophore is commonly found in biologically active molecules, including neurotransmitters (e.g., dopamine) and psychoactive drugs (e.g., amphetamines, cathinones). The phenylalkylamine core is also a feature of psychedelic phenethylamines, such as mescaline and "2C" or "2C-X" compounds. 2C compounds are 2,5-dimethoxyphenethylamines, often having an additional substituent at the 4-position.

[0041]

[0028] Although some 2C compounds are recognized to have therapeutic potential, many of these compounds are potent hallucinogens and can cause adverse effects (e.g., physical and psychological side effects). Additionally, these compounds frequently exhibit activity at multiple serotonin receptor subtypes within the 5-HT2 family. The 5-HT2A, 5-HT2B, and 5-HT2C receptors share high sequence homology and as a result, many phenylalkylamine drugs lack receptor selectivity. This promiscuity can lead to undesirable pharmacological effects: for example, activation of the 5-HT2B receptor has been associated with cardiac valvulopathy, while 5-HT2C activation may functionally oppose certain effects of 5-HT2A activation in vivo.

[0042]

[0029] Accordingly, there is an ongoing need for new chemical entities that retain advantages of certain known phenylalkylamines, introduce new advantageous properties and biochemical functionalities, and / or mitigate downsides of known compounds. Provided herein are compounds that address these and other needs.

[0043] A. General Definitions and Terms

[0044]

[0030] Unless defined otherwise, all terms herein have the meaning as commonly understood by one having ordinary skill in the art to which this invention belongs, e.g., biology, neuroscience, pharmacology, organic chemistry, synthetic chemistry, and medicinal chemistry. Specific definitions to assist in understanding the embodiments are below and throughout; however, such definitions are for the purpose of describing particular embodiments, and are not intended to limit the scope of the invention.

[0045]

[0031] As used herein, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Although “one or more” may be used to underscore the possibility of multiple elements in particular embodiments, its absence does not signify the singular only.

[0046]

[0032] The terms “comprising,” “including,” “such as,” and “having” are intended to be inclusive and not exclusive, allowing for the presence of additional elements beyond those explicitly recited. The term “or” should be interpreted as “and / or” unless the context dictates otherwise. Expressions such as “at least,” “greater than,” and “less than” include the specified values. Numerical ranges, such as “between 1 and 10,” include both endpoints.

[0047]

[0033] Numerical values and parameters used to describe and claim certain embodiments of the invention should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Unless otherwise specified, all such values and parameters are to be understood as being modified by the term “about.” In embodiments, “about” refers to plus or minus ten percent (± 10%) of the value or parameter. In embodiments, “about” refers to plus or minus five percent (± 5%) of the value or parameter. Reference to “about” a value or parameter also includes embodiments that are directed to that value or parameter per se. For example, “about X” includes a description of “X.”

[0048]

[0034] The term “substantially,” where it is applied to modify a feature or limitation herein, will be read in the context of the invention and in light of the knowledge in the art to provide the appropriate certainty, e.g., by using a standard that is recognized in the art for measuring the meaning of “substantially” as a term of degree, or by ascertaining the scope as would one of skill in the art.

[0049]

[0035] “Alkyl” includes straight or branched hydrocarbon radicals having the number of carbon atoms specified and having any degree or level of saturation, i.e., groups having exclusively single carbon-carbon bonds, groups having one or more double carbon-carbon bonds, groups having one or more triple carbon-carbon bonds and groups having mixtures of single, double and triple carbon-carbon bonds. Where a specific level of saturation is intended, the terms "alkanyl," "alkenyl," and "alkynyl" may be used. In embodiments, an alkyl group comprises between 1 and 10 carbon atoms (i.e., a “C1-C20alkyl”), between 1 and 10 carbon atoms (i.e., a “CrC alkyl”), 1 and 8 carbon atoms (i.e., a “CrC8alkyl”), 3 and 10 carbon atoms (i.e., a “C3-C10alkyl”), 3 and 8 carbon atoms (i.e., a “C3-C8alkyl”), 1 and 6 carbon atoms (i.e., a “CrC6alkyl”), 1 and 5 carbon atoms (i.e., a “CrCs alkyl”), or 1 and 4 carbon atoms (i.e., a “C1-C4alkyl”). In embodiments, an alkyl group comprises greater than 20 carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and the like, including isomers thereof (e.g., n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, etc.). Disclosure of an specific alkyl group (e.g., propyl) also therefore includes disclosure of its isomers. An alkyl group can be substituted or unsubstituted.

[0050]

[0036] “Alkenyl” refers to an unsaturated univalent hydrocarbon chain, having at least one degree of olefinic unsaturation (i.e., at least one carbon-carbon double bond moiety of the formula C=C), and having the number of carbon atoms specified (e.g., C2-C10alkenyl means a univalent hydrocarbon chain having between two and ten carbon atoms, inclusive, and having at least one carbon-carbon double bond). An alkenyl group can be linear (i.e., unbranched) or branched. Each carbon-carbon double bond of an alkenyl group may independently be in either the cis or trans configuration (or alternatively, in the “E” or “Z” configuration) about the double bond. In embodiments, an alkenyl group comprises between 2 and 20 carbon atoms (i.e., a “C2-C20alkenyl”), 2 and 10 carbon atoms (i.e., a “C2-C10alkenyl”), 2 and 8 carbon atoms (i.e., a “C2-C8alkenyl”), 3 and 10 carbon atoms (i.e., a “C3-C10alkenyl”), 3 and 8 carbon atoms (i.e., a “C3-C8alkenyl”), 2 and 6 carbon atoms (i.e., a “C2-C6alkenyl”), 2 and 5 carbon atoms (i.e., a “C2-C5alkenyl”), or 2 and 4 carbon atoms (i.e., a “C2-C4alkenyl”). In embodiments, an alkenyl group comprises greater than 20 carbon atoms. Examples of alkenyl groups include ethenyl (i.e., vinyl), propenyl, butenyl, butadienyl, and the like, including positional and geometric isomers thereof (e.g., prop-1 -enyl, prop-2-enyl (i.e., allyl), 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1 , 3-dienyl, etc.). An alkenyl group can be substituted or unsubstituted.

[0051]

[0037] “Alkynyl” refers to an unsaturated univalent hydrocarbon chain, having at least one degree of acetylenic unsaturation (i.e., at least one carbon-carbon triple bond moiety of the formula C=C), and having the number of carbon atoms specified (e.g., C2-C10alkynyl means a univalent hydrocarbon chain having between two and ten carbon atoms, inclusive, and having at least one carbon-carbon triple bond). An alkynyl group can be linear (i.e., unbranched) or branched. In embodiments, an alkynyl group comprises between 2 and 20 carbon atoms (i.e., a “C2-C20alkynyl”), 2 and 10 carbon atoms (i.e., a “C2-C10alkynyl”), 2 and 8 carbon atoms (i.e., a “C2-C8alkynyl”), 3 and 10 carbon atoms (i.e., a “C3-C10alkynyl”), 3 and 8 carbon atoms (i.e., a “C3-C8alkynyl”), 2 and 6 carbon atoms (i.e., a “C2-C6alkynyl”), 2 and 5 carbon atoms (i.e., a “C2-C5alkynyl”), or 2 and 4 carbon atoms (i.e., a “C2-C4alkynyl”). In embodiments, an alkynyl group comprises greater than 20 carbon atoms. Examples of alkynyl groups include ethynyl (i.e., acetylenyl), propynyl, butynyl, and the like, including positional isomers thereof (e.g., prop-1 -ynyl, prop-2-ynyl (i.e., propargyl), but-1-ynyl, but-2-ynyl, but-3-ynyl, etc.). An alkynyl group can be substituted or unsubstituted.

[0052]

[0038] “Alkylene” refers to a saturated or unsaturated bivalent hydrocarbon chain having the number of carbon atoms specified (e.g., CrC10alkylene means a saturated or unsaturated bivalent hydrocarbon chain having between one and ten carbon atoms, inclusive). An alkylene can be linear (i.e., unbranched) or branched. In embodiments, an alkylene comprises between 1 and 20 carbon atoms (i.e., a “CrC20alkylene”), 1 and 10 carbon atoms (i.e., a “C1-C10alkylene”), 1 and 8 carbon atoms (i.e., a “C^-Cs alkylene”), 3 and 10 carbon atoms (i.e., a “C3-C10alkylene”), 3 and 8 carbon atoms (i.e., a “C3-C8alkylene”), 1 and 6 carbon atoms (i.e., a “CrCe alkylene”), 1 and 5 carbon atoms (i.e., a “C^Cg alkylene”), or 1 and 4 carbon atoms (i.e., a “C^ alkylene”). In embodiments, an alkylene comprises greater than 20 carbon atoms. Examples of alkylene include methylene (i.e., -CH2-), ethylene (i.e., -CH2CH2-), ethenylene (i.e., vinylene; -CH=CH-), ethynylene (i.e., -C=C-), propylene (i.e., -CH2CH2CH2- -CH(CH3)CH2-, -CH2CH(CH3)-), propenylene, propynylene, butylene, butenylene, butynylene, and the like, including all positional and geometric isomers thereof. An alkylene can be substituted or unsubstituted.

[0053]

[0039] “Aryl” refers to an aromatic hydrocarbon ring system having the specified number of ring carbon atoms (e.g., C6-C10aryl refers to an aromatic hydrocarbon ring system having between 6 and 10 ring carbon atoms, inclusive). “Aryl” includes monocyclic aromatic hydrocarbons (e.g., phenyl) as well as bicyclic and polycyclic aromatic hydrocarbons. Examples of bicyclic aryl include biphenyl (e.g., 1 ,1’-biphenyl) and fused bicycles, such as naphthyl. Exemplary aryls include those derived from benzene, naphthalene, anthracene, phenanthrene, fluorene, pyrene, perylene, chrysene, and triphenylene. An aryl can be substituted or unsubstituted.

[0054]

[0040] “Acyl” refers to a group of the formula — C(=O)R, where R is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or heterocyclyl as defined herein, each of which may optionally be substituted. Examples include formyl, acetyl, propionyl, benzoyl, and cinnamoyl. An acyl group can be substituted or unsubstituted.

[0055]

[0041] “Oxo” refers to =0.

[0056]

[0042] “Cycloalkyl” refers to a saturated univalent hydrocarbon ring having the number of carbon atoms specified (e.g., C6-C10cycloalkyl refers to an aromatic hydrocarbon ring system having between 6 and 10 ring carbon atoms, inclusive). A cycloalkyl may comprise a single ring (as in, e.g., cyclohexyl) or multiple rings (as in, e.g., adamantyl). A cycloalkyl comprising more than one ring may be fused, spiro, or bridged, or combinations thereof. In embodiments, a cycloalkyl comprises between 3 and 12 carbon atoms (i.e., a “C3-C12cycloalkyl”), 3 and 10 carbon atoms (i.e., a “C3-C10cycloalkyl”), 3 and 8 carbon atoms (i.e., a “C3-C8cycloalkyl”), or 3 and 6 carbon atoms (i.e., a “C3-C6cycloalkyl”). In embodiments, a cycloalkyl comprises greater than 12 carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, and the like. A cycloalkyl can be substituted or unsubstituted.

[0057]

[0043] “Cycloalkenyl” refers to a saturated or partially unsaturated hydrocarbon ring system having the number of carbon atoms specified (e.g., C6-C10cycloalkenyl refers to an aromatic hydrocarbon ring system having between 6 and 10 ring carbon atoms, inclusive). A cycloalkyl may have one or more alkenyl (each of which may be in any geometric configuration) and / or alkynyl groups. Exemplary cycloalkenyl groups include cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. A cycloalkenyl can be substituted or unsubstituted.

[0058]

[0044] “Heteroaryl” refers to an aromatic ring system comprising one or more heteroatoms (e.g., N, O, S, Se) and having the specified number of ring atoms (e.g., 6- to 10-membered heteroaryl refers to an aromatic ring system comprising one or more heteroatoms and having between 6 and 10 ring atoms, inclusive). “Heteroaryl” includes monocyclic aromatic rings (e.g., pyridinyl, furyl, thienyl) as well as bicyclic and polycyclic aromatic rings (e.g., e.g., benzofuranyl, quinolinyl, isoquinolinyl, indolyl), which may or may not be fused. Exemplary heteroaryls include pyrrole, pyridine, bipyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (1 ,2,3-, 1 ,2,4- and 1 ,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, isoxazole, benzopyrroles (e.g., indole, isoindole), benzopyridines (e.g., quinoline, isoquinoline), benzopyrazine, benzopyrimidine, benzopyridazines (e.g., phthalazine, cinnoline), benzothiophene, and benzofuran. A heteroaryl can be substituted or unsubstituted.

[0059]

[0045] “Heterocyclyl” or “heterocycloalkyl” refers to a saturated or partially unsaturated ring system comprising one or more heteroatoms (e.g., N, 0, S, Se) and having the specified number of ring atoms (e.g., 6- to 10-membered heterocyclyl refers to an aromatic ring system comprising one or more heteroatoms and having between 6 and 10 ring atoms, inclusive). Examples include pyrrolidine, piperidine, morpholine, thiomorpholine, tetrahydrofuran, oxane, oxazolidine, thiazolidine, dioxane, dithiolane, and quinuclidine. Heterocyclyl groups may be substituted or unsubstituted.

[0060]

[0046] “Hydroxyalkyl” refers to a univalent alkyl group in which one or more of the hydrogen atoms are replaced by a hydroxy group. Exemplary hydroxyalkyl groups include 2-hydroxyethyl, 3-hydroxy- propyl, 2-hydroxypropyl and 2, 2-dihydroxyethyl. A hydroxyalkyl may be substituted or unsubstituted.

[0061]

[0047] “Alkylthio” or “thioalkyl” refers to the formula —SR, wherein R is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, or heterocyclyl, as defined herein, each of which may optionally be substituted. A non-limiting list of alkylthio are methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, iso-butylthio, sec-butylthio, phenylthio, and benzylthio. An alkylthio may be substituted or unsubstituted.

[0062]

[0048] “Aminoalkyl” refers to a univalent alkyl group in which one or more of the hydrogen atoms are replaced by an amino group. Each amino group can be a primary, secondary, or tertiary amine, or a quaternary ammonium. Examples of aminoalkyl groups include aminomethyl, aminoethyl, 2-aminoethyl, 3-ami nopropyl, N-methylaminoethyl, and N,N-dimethylaminopropyl. An aminoalkyl group can be substituted or unsubstituted.

[0063]

[0049] “Haloalkyl” refers to a univalent alkyl group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., F, Cl, Br, I). Where an alkyl is substituted by more than one halogen, it may be referred to using a prefix corresponding to the number of halogen substitutions. For example, dihaloalkyl refers to an alkyl substituted by two halo groups, which may be, but are not necessarily, the same halogen. Examples of haloalkyl groups include difluoromethyl, bromofluoromethyl, trifluoromethyl, and 2-fluoroethyl..

[0064]

[0050] “Carbamoyl” refers to a univalent group of the formula — C(O)NR2, where each R is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or heterocyclyl, as defined herein, each of which may optionally be substituted. Examples of carbamoyl groups include — C(O)NH2(primary carbamoyl), — C(O)NHR (secondary carbamoyl), and — C(O)NR2(tertiary carbamoyl). A carbamoyl group can be substituted or unsubstituted.

[0065]

[0051] “Amido” refers to a univalent group of the formula — C(O)NR2, where each R is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or heterocyclyl, as defined herein. Examples of amido groups include — C(O)NH2, — C(O)NHR, and — C(O)NR2. An amido group can be substituted or unsubstituted.

[0066]

[0052] “Substituted” unless otherwise specified means that a group may be unsubstituted, or substituted by one or more of the substituents listed for that group. When a group is described as being “unsubstituted or substituted” or “optionally substituted” if substituted, the substituent(s) may be selected from one or more of the indicated substituents. When there are more than one substituents, the substituents may be the same or different. If no substituents are indicated for an “optionally substituted” or “substituted” group, it is meant that the indicated “optionally substituted” or “substituted” group may be substituted with one or more group(s) individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), (heterocyclyl)alkyl, hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, azido, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, an amino, a mono-substituted amino group, a di-substituted amino group, and a tri-substituted amino group.

[0067]

[0053] Additional definitions and abbreviations are provided elsewhere herein.

[0068] B. Compounds

[0069]

[0054] In one aspect, provided is a compound having the structure of Formula (I): wherein: n is 0, 1 , or 2;

[0070] R2is H or CrC6alkoxy, or R2is taken together with R3and the intervening atoms to form a 5- or 6-membered heterocyclyl;

[0071] R3is H, or R3or taken together with R2and the intervening atoms to form a 5- or 6-membered heterocyclyl;

[0072] R4is H, F, Cl, Br, I, CrC6alkyl, C2-C8alkenyl, C2-C8alkynyl, CrC6alkoxy, CrC6alkylthio, C3-C6cycloalkylthio, C2-C8alkenylthio, CrC6haloalkylthio, CrC6haloalkyl, CrC6haloalkoxy, C3-C8cycloalkyl, CrC6alkylene-C3-C8cycloalkyl, 4- to 8-membered heterocycloalkyl, — CN, -NO2, or — NH2;

[0073] R5is H or CrC6alkoxy, or R5is taken together with R6and the intervening atoms to form a 5- or 6-membered heterocyclyl; and

[0074] R6is H, or R6is taken together with R5and the intervening atoms to form a 5- or 6-membered heterocyclyl; or a pharmaceutically acceptable salt, stereoisomer, solvate, or isotopic derivative thereof.

[0075]

[0055] In some embodiments of Formula (I), n is 0, 1 , 2 or 3. In embodiments, n is 0. In embodiments, n is 1. In embodiments, n is 2.

[0076]

[0056] In some embodiments of Formula (I), R2is H or CrC6alkoxy, or R2is taken together with R3and the intervening atoms to form a 5- or 6-membered heterocyclyl. In embodiments, R2is H. In embodiments, R2is CrC6alkoxy. In embodiments, R2is methoxy (— OCH3). In embodiments, R2is ethoxy (— OCH2CH3). In embodiments, R2is n-propoxy (— OCH2CH2CH3). In embodiments, R2is isopropoxy (— OCH(CH3)2). In embodiments, R2is taken together with R3and the intervening atoms to form a 5- or 6-membered heterocyclyl. In embodiments, R2is taken together with R3and the intervening atoms to form a 5-membered heterocyclyl (e.g., furanyl, dihydrofuranyl). In embodiments, R2is taken together with R3and the intervening atoms to form a 6-membered heterocyclyl (e.g., pyranyl, dihydropyranyl).

[0077]

[0057] In some embodiments of Formula (I), R3is H, or R3is taken together with R2and the intervening atoms to form a 5- or 6-membered heterocyclyl. In embodiments, R3is H. In embodiments, R3is taken together with R2and the intervening atoms to form a 5- or 6-membered heterocyclyl.

[0078]

[0058] In some embodiments of Formula (I), R4is H, F, Cl, Br, I, CrC6alkyl, C2-C8alkenyl,

[0079] C2-C8alkynyl, CrC6alkoxy, CrC6alkylthio, C3-C6cycloalkylthio, C2-C8alkenylthio, CrC6haloalkylthio, CrC6haloalkyl, CrC6haloalkoxy, C3-C8cycloalkyl, CrC6alkylene-C3-C8cycloalkyl, 4- to 8-membered heterocycloalkyl, — CN, — NO2, or — NH2. In embodiments, R4is H. In embodiments, R4is F. In embodiments, R4is Cl. In embodiments, R4is Br. In embodiments, R4is I. In embodiments, R4is CrC6alkyl. In embodiments, R4is methyl. In embodiments, R4is ethyl. In embodiments, R4is n-propyl. In embodiments, R4is isopropyl. In embodiments, R4is n-butyl. In embodiments, R4is sec-butyl. In embodiments, R4is isobutyl. In embodiments, R4is tert-butyl. In embodiments, R4is C2-C8alkenyl. In embodiments, R4is ethenyl. In embodiments, R4is allyl. In embodiments, R4is C2-C8alkynyl. In embodiments, R4is ethynyl. In embodiments, R4is CrC6alkoxy. In embodiments, R4is methoxy. In embodiments, R4is ethoxy. In embodiments, R4is n-propoxy. In embodiments, R4is isopropoxy. In embodiments, R4is CrC6alkylthio. In embodiments, R4is methylthio. In embodiments, R4is ethylthio. In embodiments, R4is propylthio (i.e., n-propylthio, isopropylthio). In embodiments, R4is butylthio (e.g., tert-butylthio, isobutylthio). In embodiments, R4is C3-C6cycloalkylthio (e.g., cyclopropylthio). In embodiments, R4is C2-C8alkenylthio (e.g., allylthio, methallylthio). In embodiments, R4is CrC6haloalkylthio (e.g., 2-fluoroethylthio, trifluoromethylthio, 2,2,2-trifluoroethylthio). In embodiments, R4is C^Ce haloalkyl (e.g., trifluoromethyl). In embodiments, R4is CrC6haloalkoxy (e.g., fluoromethoxy, difluoromethoxy, trifluoromethoxy). In embodiments, R4is C3-C8cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl). In embodiments, R4is CrC6alkylene-C3-C8cycloalkyl (e.g., cyclopropylmethyl, cyclopropylethyl). In embodiments, R4is 4- to 8-membered heterocycloalkyl. In embodiments, R4is — CN. In embodiments, R4is — NO2. In embodiments, R4is — NH2.

[0080]

[0059] In some embodiments of Formula (I), R5is H or CrC6alkoxy, or R5is taken together with R6and the intervening atoms to form a 5- or 6-membered heterocyclyl. In embodiments, R5is H. In embodiments, R5is CrC6alkoxy. In embodiments, R5is methoxy (— OCH3). In embodiments, R5is ethoxy (— OCH2CH3). In embodiments, R5is n-propoxy (— OCH2CH2CH3). In embodiments, R5is isopropoxy (— OCH(CH3)2). In embodiments, R5is taken together with R6and the intervening atoms to form a 5- or 6-membered heterocyclyl. In embodiments, R5is taken together with R6and the intervening atoms to form a 5-membered heterocyclyl (e.g., furanyl, dihydrofuranyl). In embodiments, R5is taken together with R6and the intervening atoms to form a 6-membered heterocyclyl (e.g., pyranyl, dihydropyranyl).

[0081]

[0060] In some embodiments of Formula (I), R6is H, or R6is taken together with R5and the intervening atoms to form a 5- or 6-membered heterocyclyl. In embodiments, R6is H. In embodiments, R6is taken together with R5and the intervening atoms to form a 5- or 6-membered heterocyclyl.

[0082]

[0061] In embodiments, the compound has the structure of Formula (II): wherein: n is 0, 1 , or 2;

[0083] R2is H or CrC6alkoxy;

[0084] R4is H, F, Cl, Br, I, CrC6alkyl, C2-C8alkenyl, C2-C8alkynyl, CrC6alkoxy, CrC6alkylthio, C3-C6cycloalkylthio, C2-C8alkenylthio, CrC6haloalkylthio, CrC6haloalkyl, CrC6haloalkoxy, C3-C8cycloalkyl, CrC6alkylene-C3-C8cycloalkyl, 4- to 8-membered heterocycloalkyl, — CN, — NO2, or — NH2; and

[0085] R5is H or CrC6alkoxy; or a pharmaceutically acceptable salt, stereoisomer, solvate, or isotopic derivative thereof.

[0086]

[0062] In some embodiments of Formula (II), n is 0, 1 , 2 or 3. In embodiments, n is 0. In embodiments, n is 1. In embodiments, n is 2.

[0087]

[0063] In some embodiments of Formula (II), R2is H or CrC6alkoxy. In embodiments, R2is H. In embodiments, R2is CrC6alkoxy. In embodiments, R2is methoxy (— OCH3). In embodiments, R2is ethoxy (— OCH2CH3). In embodiments, R2is n-propoxy (— OCH2CH2CH3). In embodiments, R2is isopropoxy (— OCH(CH3)2).

[0088]

[0064] In some embodiments of Formula (II), R4is H, F, Cl, Br, I, C^Cg alkyl, C2-C8alkenyl,

[0089] C2-C8alkynyl, CrC6alkoxy, CrCg alkylthio, C3-C6cycloalkylthio, C2-C8alkenylthio, CrCg haloalkylthio, CrC6haloalkyl, CrCg haloalkoxy, C3-C8cycloalkyl, CrCg alkylene-C3-C8cycloalkyl, 4- to 8-membered heterocycloalkyl, — CN, — NO2, or — NH2. In embodiments, R4is H. In embodiments, R4is F. In embodiments, R4is Cl. In embodiments, R4is Br. In embodiments, R4is I. In embodiments, R4is CrCg alkyl. In embodiments, R4is methyl. In embodiments, R4is ethyl. In embodiments, R4is n-propyl. In embodiments, R4is isopropyl. In embodiments, R4is n-butyl. In embodiments, R4is sec-butyl. In embodiments, R4is isobutyl. In embodiments, R4is tert-butyl. In embodiments, R4is C2-C8alkenyl. In embodiments, R4is ethenyl. In embodiments, R4is allyl. In embodiments, R4is C2-C8alkynyl. In embodiments, R4is ethynyl. In embodiments, R4is CrC6alkoxy. In embodiments, R4is methoxy. In embodiments, R4is ethoxy. In embodiments, R4is n-propoxy. In embodiments, R4is isopropoxy. In embodiments, R4is C^Cg alkylthio. In embodiments, R4is methylthio. In embodiments, R4is ethylthio. In embodiments, R4is propylthio (i.e., n-propylthio, isopropylthio). In embodiments, R4is butylthio (e.g., tert-butylthio, isobutylthio). In embodiments, R4is C3-C6cycloalkylthio (e.g., cyclopropylthio). In embodiments, R4is C2-C8alkenylthio (e.g., allylthio, methallylthio). In embodiments, R4is CrCg haloalkylthio (e.g., 2-fluoroethylthio, trifluoromethylthio, 2,2,2-trifluoroethylthio). In embodiments, R4is C^Cg haloalkyl (e.g., trifluoromethyl). In embodiments, R4is C^Cg haloalkoxy (e.g., fluoromethoxy, difluoromethoxy, trifluoromethoxy). In embodiments, R4is C3-C8cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl). In embodiments, R4is CrCg alkylene-C3-C8cycloalkyl (e.g., cyclopropylmethyl, cyclopropylethyl). In embodiments, R4is 4- to 8-membered heterocycloalkyl. In embodiments, R4is — CN. In embodiments, R4is — NO2. In embodiments, R4is — NH2.

[0090]

[0065] In some embodiments of Formula (II), R5is H or CrCg alkoxy. In embodiments, R5is H. In embodiments, R5is CrCg alkoxy. In embodiments, R5is methoxy (— OCH3). In embodiments, R5is ethoxy (— OCH2CH3). In embodiments, R5is n-propoxy (— OCH2CH2CH3). In embodiments, R5is isopropoxy (-OCH(CH3)2).

[0091]

[0066] In embodiments, the compound has the structure of Formula (III): wherein: n is 0, 1 , or 2; R2is H or CrC6alkoxy;

[0092] R4is H, F, Cl, Br, I, CrC6alkyl, C2-C8alkenyl, C2-C8alkynyl, CrC6alkoxy, CrC6alkylthio, C3-C6cycloalkylthio, C2-C8alkenylthio, CrC6haloalkylthio, CrC6haloalkyl, CrC6haloalkoxy, C3-C8cycloalkyl, CrC6alkylene-C3-C8cycloalkyl, 4- to 8-membered heterocycloalkyl, — CN, — NO2, or — NH2; and

[0093] R5is H or CrC6alkoxy; or a pharmaceutically acceptable salt, stereoisomer, solvate, or isotopic derivative thereof.

[0094]

[0067] In some embodiments of Formula (III), n is 0, 1 , 2 or 3. In embodiments, n is 0. In embodiments, n is 1. In embodiments, n is 2.

[0095]

[0068] In some embodiments of Formula (III), R4is H, F, Cl, Br, I, CrC6alkyl, C2-C8alkenyl,

[0096] C2-C8alkynyl, CrC6alkoxy, CrC6alkylthio, C3-C6cycloalkylthio, C2-C8alkenylthio, CrC6haloalkylthio, CrC6haloalkyl, CrC6haloalkoxy, C3-C8cycloalkyl, CrC6alkylene-C3-C8cycloalkyl, 4- to 8-membered heterocycloalkyl, — CN, — NO2, or — NH2. In embodiments, R4is H. In embodiments, R4is F. In embodiments, R4is Cl. In embodiments, R4is Br. In embodiments, R4is I. In embodiments, R4is CrC6alkyl. In embodiments, R4is methyl. In embodiments, R4is ethyl. In embodiments, R4is n-propyl. In embodiments, R4is isopropyl. In embodiments, R4is n-butyl. In embodiments, R4is sec-butyl. In embodiments, R4is isobutyl. In embodiments, R4is tert-butyl. In embodiments, R4is C2-C8alkenyl. In embodiments, R4is ethenyl. In embodiments, R4is allyl. In embodiments, R4is C2-C8alkynyl. In embodiments, R4is ethynyl. In embodiments, R4is CrC6alkoxy. In embodiments, R4is methoxy. In embodiments, R4is ethoxy. In embodiments, R4is n-propoxy. In embodiments, R4is isopropoxy. In embodiments, R4is CrC6alkylthio. In embodiments, R4is methylthio. In embodiments, R4is ethylthio. In embodiments, R4is propylthio (i.e., n-propylthio, isopropylthio). In embodiments, R4is butylthio (e.g., tert-butylthio, isobutylthio). In embodiments, R4is C3-C6cycloalkylthio (e.g., cyclopropylthio). In embodiments, R4is C2-C8alkenylthio (e.g., allylthio, methallylthio). In embodiments, R4is CrC6haloalkylthio (e.g., 2-fluoroethylthio, trifluoromethylthio, 2,2,2-trifluoroethylthio). In embodiments, R4is CrC6haloalkyl (e.g., trifluoromethyl). In embodiments, R4is CrC6haloalkoxy (e.g., fluoromethoxy, difluoromethoxy, trifluoromethoxy). In embodiments, R4is C3-C8cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl). In embodiments, R4is CrC6alkylene-C3-C8cycloalkyl (e.g., cyclopropylmethyl, cyclopropylethyl). In embodiments, R4is 4- to 8-membered heterocycloalkyl. In embodiments, R4is — CN. In embodiments, R4is — NO2. In embodiments, R4is — NH2.

[0097]

[0069] In embodiments, the compound has the structure of any of Formulas (IV-XII):

[0098]

[0099]

[0070] In embodiments, the compound is selected from Table 1 .

[0100]

[0101]

[0071] The disclosure also includes pharmaceutically acceptable salts of disclosed compounds. The term "pharmaceutically acceptable salt" refers to a salt form of a compound that is suitable for use in pharmaceutical formulations. Such salts are generally produced by reacting the compound with a pharmaceutically acceptable acid or base in a solvent. Pharmaceutically acceptable acids include both inorganic (e.g., hydrochloric, hydrobromic) and organic (e.g., acetic, p-toluenesulfonic) acids. Likewise, pharmaceutically acceptable bases may be inorganic (e.g., sodium bicarbonate, calcium hydroxide) or organic (e.g., amine-containing). In embodiments, the salt is an acid addition salt, wherein one or more basic (i.e., protonatable) functional groups (e.g., an amine) of the compound is protonated by addition of a pharmaceutically acceptable acid. One of skill in the art can select suitable acids and bases to produce a salt of a compound with a desired, pharmaceutically acceptable counterion (see, e.g., Stahl, P. H., & Wermuth, C. G. (Eds.). (2002). Handbook of Pharmaceutical Salts: Properties, Selection, and Use. Wiley-VCH). Pharmaceutically acceptable acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, oxalic acid, propionic acid, maleic acid, tartaric acid, trifluoroacetic acid, citric acid, lactic acid, salicylic acid, oleic acid, tannic acid, pantothenic acid, succinic acid, gentisic acid, fumaric acid, glucuronic acid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid. Pharmaceutically acceptable bases include, for example, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, ammonium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, lithium hydroxide, triethanolamine, diethanolamine, ethanolamine, N-methylglucamine, morpholine, piperazine, dibenzylamine, arginine, procaine, and other alkali metal hydroxides, alkaline earth metal hydroxides, and organic amines. The disclosure includes all possible ionized forms of disclosed compounds, including those formed by protonation, deprotonation, or otherwise ionization (e.g., quaternization) of any ionizable functional groups, including zwitterionic forms.

[0102]

[0072] Where tautomeric forms may be present for any of the compounds described herein, each and every tautomeric form is intended even though only one or some of the tautomeric forms may be explicitly depicted. The tautomeric forms specifically depicted may or may not be the predominant forms in solution or when used according to the methods described herein.

[0103]

[0073] The disclosure also includes all possible stereochemical (e.g., enantiomeric, diastereomeric) forms of disclosed compounds, including mixtures thereof (both racemic and non-racemic), regardless of which form is explicitly depicted. Stereoisomers of the compounds can be synthesized using chiral synthons or reagents, or separated using standard resolution techniques. Such techniques are known to those of skill in the art, and include selective crystallization, enzymatic resolution, kinetic resolution, and chiral chromatography. Compounds with geometric asymmetry, such as those containing olefinic double bonds, may exist as E or Z (or cis and trans) isomers; all possible geometric configurations of the compounds are also disclosed.

[0104]

[0074] In embodiments, the compound is an R-stereoisomer having the structure of Formula (R-l), (R-ll), or (R-lll):

[0105]

[0106]

[0075] In embodiments, the compound is an S-stereoisomer having the structure of Formula (S-l), (S-ll), or (S-lll):

[0107]

[0076] The disclosure also encompasses isotopically-labeled and / or isotopically-enriched forms of the compounds. Such compounds contain non-natural proportions of atomic isotopes at one or more positions within their structure. In embodiments, the compounds are isotopically-labeled, meaning that one or more atoms are replaced by an isotope of the same element. Exemplary isotopes that can be incorporated into these compounds include hydrogen (2H,3H), carbon (11C,13C,14C), nitrogen (13N), oxygen (15O,17O), phosphorus (32P), sulfur (35S), chlorine (36CI), and fluorine (18F). The use of heavier isotopes, such as deuterium (2H), may enhance the metabolic stability of a compound, potentially increasing in vivo half-life and / or reducing dosage requirements. Isotopically-labeled compounds can typically be synthesized using standard methods known to those skilled in the art, or by adapting the procedures described herein, substituting isotopically-labeled reagents for their non-labeled counterparts.

[0108]

[0077] The disclosure also includes all metabolites of the compounds. Metabolites include any chemical species generated by a biotransformation of any of the compounds, such as intermediates and products of metabolism of a compound, such as would be produced in vivo following administration to a human.

[0109]

[0078] The disclosure also includes prodrugs of disclosed compounds. A "prodrug" is a precursor of a biologically active pharmaceutical agent, which may undergo a chemical or a metabolic conversion to become the biologically active agent. Typical examples of prodrugs include compounds with biologically labile or cleavable groups on a functional moiety of the active compound (e.g., an amine). Commonly used functional groups include esters, carbonates, carbamates, amides, phosphates, and sulfonamides. These functional groups can be attached to the drug molecule via a linker that is designed to be cleaved under specific physiological conditions, such as enzymatic hydrolysis or pH-dependent cleavage.

[0110]

[0079] The disclosure also includes polymorphs of disclosed compounds. Certain disclosed compounds that exist in crystalline form (as the freebase and / or as a salt or solvate) may exhibit polymorphism. Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs may exhibit different melting points, infrared spectra, and X-ray powder diffraction patterns, which may be used for identification. Different polymorphs may be produced by various means known to those of skill in the art, for example, by subjecting a compound to changes in temperature, pressure, or solvent. Polymorphs may also be obtained by recrystallization; various factors such as the recrystallization solvent, rate of crystallization, and temperature may cause one or more polymorphs to dominate. Polymorphs may also spontaneously interconvert under certain conditions.

[0111]

[0080] Disclosed compounds are generally administered as part of a pharmaceutical composition or formulation and are prepared for inclusion therein as isolated or purified compounds. As used herein, “isolated,” “purified,” or “substantially pure” refers to material that is largely free from components typically present during synthesis, manufacture, or production. A compound is considered “isolated,” “purified,” or “substantially pure” if it has a chromatographic purity exceeding 90%, preferably above 95%, 96%, 97%, 98%, 99%, 99.5%, or most preferably 99.9%, as determined by HPLC area normalization or a similar detection method. Preferably, the substantially pure compound is free of other active compounds not intended for administration. In this context, “substantially free” means no unintended active compounds are detectable by HPLC or similar methods or are below a specified detection threshold as outlined above.

[0112] C. Methods of Synthesis

[0113]

[0081] In another aspect, provided are methods of preparing disclosed compounds, such as by chemical synthesis. Specific examples for the chemical synthesis and characterization of disclosed compounds are provided in the Examples, and other like compounds can be synthesized by similar methods, or according to general methods disclosed herein or otherwise known to those of ordinary skill in the art. Specific reaction conditions (e.g., temperatures, times, solvent choice and amount, reagent amounts) and purification conditions will be readily appreciated by a person of ordinary skill in the art. Any required starting materials are either disclosed in the literature or would be readily accessible to a person of ordinary skill in the art based on well-established synthetic methodologies.

[0114]

[0082] In embodiments, a disclosed compound can be prepared according to the following general reaction sequence, wherein X1and X2are each independently halogen (e.g., Cl, Br, I) or another suitable leaving group (e.g., tosylate, mesylate) and PG is a protecting group (e.g., Boc, Cbz, etc.):

[0115]

[0083] In brief, a suitable aryl halide precursor (A) can be formed into an organometallic reagent (e.g., using a suitable metal, such as Mg or Li) and then reacted with an acyl halide (B) to yield intermediate C. The acyl halide (B) can be generated by reaction of the corresponding carboxylic acid with a reagent such as thionyl chloride or oxalyl chloride. Subsequently, intermediate C can be converted to the final product (i.e., a compound of Formula (I)) by reduction of the ketone according to standard techniques (e.g., in one step, using a strong reducing agent such as lithium borohydride; or in two steps, first reducing to the alcohol using a milder reducing agent such as sodium borohydride, then reducing the alcohol to the alkane using a reagent such as triethylsilane in trifluoroacetic acid). Deprotection can also be accomplished by standard techniques, depending on the protecting group (e.g., trifluoroacetic acid in dichloromethane to remove Boc, hydrogen gas and Pd / C to remove Cbz).

[0116]

[0084] In embodiments, a disclosed compound can be prepared according to the following general reaction sequence, wherein wherein X1is halogen (e.g., Cl, Br, I) or another suitable leaving group

[0117] (e.g., tosylate, mesylate) and PG is a protecting group (e.g., Boc, Cbz, etc.):

[0118]

[0085] In brief, a compound is synthesized by photoinduced cross-coupling of a suitable aryl halide precursor (A) with a protected, hydroxylated azetidine, pyrrolidine, or piperidine reagent (D) under dual photoredox / nickel catalysis, to yield a compound of Formula (I) comprising a protecting group on the azetidine, pyrrolidine, or piperidine amine. The reaction is initiated by combining the aryl halide (A) with a photocatalyst (e.g., I r(ppy)2(dtbbpy)PF6, lr[dF(CF3)ppy]2(dtbbpy)PF6, or [Ru(bpy)3]CI2), a nickel source (e.g., NiBr2(dtbbpy), NiCI2(dme), or Ni(acac)2with a separate ligand such as dtbbpy or bpy), and an organic base such as quinuclidine (alternatively, triethylamine or DIPEA) in a mixed solvent system (e.g., fert-butyl methyl ether / DMA, acetonitrile / DMA, or DME / EtOAc) under nitrogen. In parallel, the amine substrate (D) is preactivated with an N-heterocyclic carbene (NHC) and a base such as pyridine (alternatively, 2,6-lutidine or imidazole) in a suitable ether solvent such as fert-butyl methyl ether or THF. After preactivation, the amine solution is added to the aryl halide mixture, and the combined reaction is irradiated with visible light (e.g., 450-475 nm) at elevated temperature (e.g., 60-80 °C) to yield the coupled intermediate. This intermediate can be further transformed into a compound of Formula (I) by reduction (e.g., catalytic hydrogenation, hydride-based reduction, or radical-mediated deoxygenation) and deprotection of the amine protecting group (e.g., removal of Boc using trifluoroacetic acid, Cbz using hydrogenation over Pd / C, or Fmoc using piperidine in DMF).

[0119]

[0086] Common protecting groups that may be used in the synthesis of disclosed compounds include tert-butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), allyloxycarbonyl (Alloc), 2,2,2-trichloroethoxycarbonyl (Tree), methoxycarbonyl (Moc), 2-tri methylsi ly lethoxycarbonyl (Teoc), 1 -(4, 4-di methyl-2, 6-d ioxocyclohex- 1 -yl ide ne)ethyl (Dde),

[0120] 1-(4-isovaleryl-2,6-dioxocyclohex-1-ylidene)ethyl (IvDde), trityl (Trt),

[0121] 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl (Pbf), 4-methyltrityl (Mtt), tert-butyl (tBu), methyl ester (OMe), benzyl ester (OBn), and fluorenylmethyl ester (OFm). Descriptions of protecting groups and their use can be found in the literature (see, e.g., General descriptions of protecting groups can be found in the literature: Greene, T.W. Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991 ; Kocienski, P.J. Protecting Groups, Thieme, Stuttgart, 2005.) The selection of suitable protecting groups and suitable reaction conditions for protection and deprotection is readily conducted by one of skill in the art in view of the disclosure herein.

[0122]

[0087] In embodiments, aryl halide precursors having a desired substitution pattern on the phenyl ring (i.e., R2, R3, R4, R5, and R6) may not be commercially available. In these cases, modifications of the above exemplary synthesis routes may be necessary; such modifications are readily apparent to one of skill, and may be performed according to well-established procedures in organic chemistry. Alternatively, or additionally, certain substituents may be added following the synthesis of the core ring structure. For example, compounds having a 4-halo substituent (i.e., wherein R4= F, Cl, Br, I) may be obtained by electrophilic halogenation, for example:

[0123]

[0088] Subsequently, a 4-halo group may be chemically converted to a variety of other functional groups by known techniques. For example, compounds wherein R4= alkylthio, alkenylthio, cycloalkylthio, or substituted analogs thereof, can be synthesized from the corresponding aryl bromide according to methods described in Itoh T & Mase T. Org Lett. 2004; 6(24):4587— 4590.

[0089] Likewise, compounds wherein R4= haloalkyl can be synthesized from the corresponding aryl iodide according to methods disclosed in Nichols et al. J Med Chem. 1994;37:4346-4351.

[0124]

[0090] In general, methods for synthesizing known phenethylamines (e.g., 2C-X and DOx-type compounds) can be used to obtain a desired substitution pattern on the phenyl moiety (see, e.g., Shulgin and Shulgin, PiHKAL: A Chemical Love Story, Transform Press (1991); Shulgin, A. T., Manning, T., & Daley, P. F. The Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds. Transform Press (2011); and Nichols, D.E. Chemistry and Structure-Activity Relationships of Psychedelics. In: Halberstadt, A.L., Vollenweider, F.X., Nichols, D.E. (eds) Behavioral Neurobiology of Psychedelic Drugs. Current Topics in Behavioral Neurosciences, vol 36. Springer (2017), and references therein) with adaptations to these methods as needed for compatibility with the above exemplary synthesis routes being apparent and within the capabilities of one of skill.

[0125]

[0091] In another aspect, provided is a a method of manufacturing a compound having the structure of Formula (I), comprising:

[0126] 1 . contacting a compound of Formula (A), metal reagent (e.g., Mg, Li) to form an organometallic precursor, then

[0127] 2. contacting the organometallic precursor with a compound of Formula (B), produce an intermediate having the structure of Formula (C): then

[0128] 3. reducing the intermediate having the structure of Formula (C) to produce an intermediate having the structure of Formula (E), then

[0129] 4. deprotecting intermediate having the structure of Formula (E) to yield the compound of Formula (I), wherein: n, R2, R3, R4, R5, and R6are as defined for Formula (I),

[0130] X1and X2are each independently halogen (e.g., Cl, Br, I) or another suitable leaving group (e.g., tosylate, mesylate), and

[0131] PG is a protecting group (e.g., Boc, Cbz, etc.).

[0132]

[0092] In another aspect, provided is a a method of manufacturing a compound having the structure of Formula (I), comprising:

[0133] 1 . contacting a compound of Formula (A), under photoinduced cross-coupling conditions to produce an intermediate having the structure of Formula (E), then

[0134] 2. deprotecting intermediate having the structure of Formula (E) to yield the compound of Formula (I), wherein: n, R2, R3, R4, R5, and R6are as defined for Formula (I),

[0135] X1is halogen (e.g., Cl, Br, I) or another suitable leaving group (e.g., tosylate, mesylate), and PG is a protecting group (e.g., Boc, Cbz, etc.).

[0136] D. Pharmaceutical Compositions

[0137]

[0093] In another aspect, provided are pharmaceutical compositions comprising a disclosed compound, and methods of preparing such compositions. A “pharmaceutical composition” is a composition comprising a compound and one or more pharmaceutically acceptable excipients, such as carriers, diluents, binders, stabilizers, preservatives, and other formulation aids and inactive ingredients known to those of skill in the art. Such compositions can be prepared by standard techniques such as disclosed in e.g., in Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, Pa., 20th ed. (2000).

[0138]

[0094] The term “pharmaceutically acceptable” denotes ingredients that are generally safe and, within sound medical judgment, suitable for human or animal use without undue toxicity, irritation, allergic response, or complications, considering a reasonable risk-benefit ratio.

[0139]

[0095] In embodiments, the pharmaceutical composition comprises a binder. Binders include, for example, povidone, microcrystalline cellulose, hydroxypropyl methylcellulose, starch, gelatin, polyethylene glycol, pregelatinized starch, and carbomers. In embodiments, the pharmaceutical composition comprises a binder at a concentration of about 1 % to 10% w / w.

[0140]

[0096] In embodiments, the pharmaceutical composition comprises a diluent. Diluents include, for example, lactose, mannitol, microcrystalline cellulose, starch, calcium phosphate, sorbitol, sucrose, and dextrose. In embodiments, the pharmaceutical composition comprises one or more diluents at a total concentration of about 5% to 80% w / w with respect to the total weight of the composition.

[0141]

[0097] In embodiments, the pharmaceutical composition comprises a disintegrant. Disintegrants include, for example, croscarmellose sodium, sodium starch glycolate, crospovidone, alginic acid, carboxymethylcellulose, and ion-exchange resins. In embodiments, the pharmaceutical composition comprises one or more disintegrants at a total concentration of about 2% to 10% w / w with respect to the total weight of the composition.

[0142]

[0098] In embodiments, the pharmaceutical composition comprises a carrier. Carriers include, for example, lactose, cellulose, starch, mannitol, sorbitol, microcrystalline cellulose, magnesium stearate, and polyvinylpyrrolidone (PVP). In embodiments, the pharmaceutical composition comprises one or more carriers at a total concentration of between about 1 % and 95% w / w with respect to the total weight of the composition.

[0143]

[0099] In embodiments, the pharmaceutical composition comprises a pH adjuster. pH adjusters include, for example, sodium hydroxide, potassium hydroxide, hydrochloric acid, citric acid, acetic acid, phosphoric acid, sodium bicarbonate, sodium carbonate, and ammonium hydroxide. In embodiments, the pharmaceutical composition comprises one or more pH adjusters at a total concentration of between about 0.01 % and 10% w / w with respect to the total weight of the composition.

[0144]

[0100] In embodiments, the pharmaceutical composition comprises a thickener. Thickeners include, for example, hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose (CMC), xanthan gum, guar gum, alginates, polyvinyl alcohol (PVA), and methylcellulose. In embodiments, the pharmaceutical composition comprises one or more thickeners at a total concentration of between about 0.1 % and 10% w / w with respect to the total weight of the composition.

[0145]

[0101] In embodiments, the pharmaceutical composition comprises an emulsifier. Emulsifiers include, for example, polysorbate 80, lecithin, cetyl alcohol, stearyl alcohol, sorbitan esters, polyoxyethylene stearates, and glycerin monostearate. In embodiments, the pharmaceutical composition comprises one or more emulsifiers at a total concentration of between about 0.1 % and 5% w / w with respect to the total weight of the composition.

[0146]

[0102] In embodiments, the pharmaceutical composition comprises a lubricant. Lubricants include, for example, magnesium stearate, stearic acid, talc, calcium stearate, zinc stearate, polyethylene glycol, and sodium stearyl fumarate. In embodiments, the pharmaceutical composition comprises one or more lubricants at a total concentration of about 0.25% to 5% w / w with respect to the total weight of the composition.

[0147]

[0103] In embodiments, the pharmaceutical composition comprises a glidant. Glidants include, for example, colloidal silicon dioxide, talc, magnesium trisilicate, and calcium phosphate. In embodiments, the pharmaceutical composition comprises one or more glidants at a total concentration of about 0.1 % to 2% w / w with respect to the total weight of the composition.

[0148]

[0104] In embodiments, the pharmaceutical composition comprises a surfactant. Surfactants include, for example, sodium lauryl sulfate, polysorbate 80, poloxamers, lecithin, sorbitan esters, and bile salts. In embodiments, the pharmaceutical composition comprises one or more surfactants at a total concentration of about 0.1 % to 5% w / w with respect to the total weight of the composition.

[0149]

[0105] In embodiments, the pharmaceutical composition comprises a preservative. Preservatives include, for example, benzyl alcohol, parabens (methylparaben, propylparaben), benzoic acid, sorbic acid, chlorobutanol, and phenol. In embodiments, the pharmaceutical composition comprises one or more preservatives at a total concentration of about 0.01 % to 1 % w / w with respect to the total weight of the composition.

[0150]

[0106] In embodiments, the pharmaceutical composition comprises a stabilizer. Stabilizers include, for example, ascorbic acid, citric acid, sodium metabisulfite, tocopherols, tartaric acid, sodium bicarbonate, and phosphates. In embodiments, the pharmaceutical composition comprises one or more stabilizers at a total concentration of about 0.01 % to 5% w / w with respect to the total weight of the composition.

[0151]

[0107] In embodiments, the pharmaceutical composition comprises a sweetener or flavoring agent. Sweeteners and flavoring agents include, for example, sucralose, aspartame, saccharin, acesulfame potassium, menthol, vanillin, peppermint oil, and fruit extracts. In embodiments, the pharmaceutical composition comprises one or more sweeteners or flavoring agents at a total concentration of about 0.1 % to 5% w / w with respect to the total weight of the composition.

[0152]

[0108] In embodiments, the pharmaceutical composition comprises a solvent. Preferred solvents are those generally regarded as safe for human use and are commonly used in oral, injectable, and topical formulations. Solvents include, for example, water, ethanol, propylene glycol, polyethylene glycol, glycerin, isopropyl alcohol, butylene glycol, methylparaben, propylparaben, sorbitol, and sodium chloride. In embodiments, the pharmaceutical composition comprises one or more solvents (collectively referred to as a “solvent system”) at a total concentration of between about 0.1 % and 90% with respect to the total weight of the composition, depending on the formulation, properties of the compound, and route of administration.

[0153]

[0109] It should be understood that the classification of excipients into specific categories is for convenience and ease of reference only, and no particular limitation should be inferred based on such classification. A single excipient may serve multiple functions within a pharmaceutical composition, depending on its concentration, formulation, and intended use. For example, microcrystalline cellulose may function as both a binder and a diluent, while sodium lauryl sulfate may act as both a surfactant and a wetting agent. The descriptions provided herein are not intended to be exhaustive, and the selection and use of excipients should be guided by the specific formulation requirements and the knowledge of those skilled in the art.

[0154]

[0110] Pharmaceutical compositions may be administered via various routes, including oral, mucosal (buccal, sublingual), rectal, transdermal, subcutaneous, intravenous (IV), intramuscular, inhaled, and intranasal; and may be formulated specifically for that route of administration. For example, a pharmaceutical composition for oral administration may be formulated as an oral solid or liquid dosage form. As another example, a pharmaceutical composition for intravenous, intramuscular, or subcutaneous administration may be formulated as an IV solution, or a lyophilized powder for reconstitution. As yet another example, a pharmaceutical composition for transdermal or topical administration may be formulated as a salve or paste. All such formulations, as well as unit dosage forms thereof, are included in the disclosure, including: tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, cataplasms (poultices), pastes, powders, dressings, creams, solutions, patches, aerosols (e.g., nasal spray or inhalers), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions or water-in-oil liquid emulsions), solutions and elixirs.

[0155]

[0111] In embodiments, such as wherein the pharmaceutical composition is a solid dosage form, the composition comprises a compound at a concentration of between about 0.1 % and 90% w / w, including between about 1% and 5% w / w, 5% and 10% w / w, 10% and 20% w / w, 15% and 30% w / w, 20% and 30% w / w, 20% and 40% w / w, 30% and 40% w / w, 30% and 50% w / w, 40% and 60% w / w, 50% and 70% w / w, 60% and 80% w / w, 70% and 80% w / w, 70% and 90% w / w, 80% and 90% w / w, 0.1% and 10% w / w, 10% and 40% w / w, 40% and 80% w / w, and 80% and 90% w / w.

[0156]

[0112] In embodiments, such as wherein the pharmaceutical composition is a liquid dosage form, the composition comprises a compound at a concentration of between about 0.01 mg / mL and 200 mg / mL, including between about 0.01 mg / mL and 0.1 mg / mL, 0.1 mg / mL and 1 mg / mL, 1 mg / mL and 5 mg / mL, 5 mg / mL and 10 mg / mL, 10 mg / mL and 20 mg / mL, 15 mg / mL and 25 mg / mL, 20 mg / mL and 30 mg / mL, 25 mg / mL and 35 mg / mL, 30 mg / mL and 40 mg / mL, 35 mg / mL and 50 mg / mL, 40 mg / mL and 60 mg / mL, 50 mg / mL and 70 mg / mL, 60 mg / mL and 80 mg / mL, 70 mg / mL and 100 mg / mL, 80 mg / mL and 120 mg / mL,

[0157] 100 mg / mL and 150 mg / mL, 120 mg / mL and 180 mg / mL, 150 mg / mL and 200 mg / mL, and 200 mg / mL and

[0158] 300 mg / mL.

[0159]

[0113] As will be appreciated by one of skill in the art, the concentration of the compound in the pharmaceutical composition may vary according to the route of administration, desired dose, and pharmacokinetic and pharmacodynamic properties of the compound.

[0160] E. Kits

[0161]

[0114] The present disclosure further provides kits for carrying out the methods of the invention, comprising one or more of the disclosed compounds or a composition comprising one or more of the disclosed compounds. The kits may be used for any of the uses described herein, and according to any of the methods disclosed herein, and, accordingly may contain instructions for the treatment of a medical condition.

[0162]

[0115] Kits generally comprise suitable packaging. Kits may comprise one or more containers comprising any compound described herein. Each component (if there is more than one component) can be packaged in separate containers or some components can be combined in one container where cross-reactivity and shelf life permit. Kits may be in unit dosage forms, bulk packages (e.g., multi-dose packages) or sub-unit doses. For example, kits may be provided that contain sufficient doses of a compound as disclosed herein and / or additional active compounds useful for treating a disease according to a disclosed method to provide effective treatment of an individual for an extended period, such as a week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more. Kits may also include multiple unit doses of the compounds and instructions for use and be packaged in quantities sufficient for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies). Kits may optionally include a set of instructions, generally written instructions, although electronic storage media containing instructions are also acceptable, relating to the use of component(s) according to disclosed methods. Instructions included with a kit generally include information as to the components and their administration to an individual.

[0163] F. Methods of Use

[0164]

[0116] In some aspects are provided methods of using the disclosed compounds and pharmaceutical compositions comprising the compounds, such as by administering a therapeutically effective amount of a compound or pharmaceutical composition thereof to a subject having a medical condition (e.g., a disease or disorder), thereby treating the medical condition.

[0165]

[0117] It should be understood that any embodiment referring to the administration or use of a disclosed compound should also be interpreted to encompass the administration or use of a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt, stereoisomer, isotopolog, or solvate thereof, unless explicitly stated otherwise.

[0166]

[0118] In embodiments, a disclosed compound is administered to a subject by one or more routes of administration, including, e.g., oral, mucosal, rectal, subcutaneous, intravenous, intramuscular, intranasal, inhaled, ocular, intraocular, topical, and transdermal routes.

[0167]

[0119] In embodiments, “treating” or “treatment” refers to treating a disease or disorder in a subject, and preferably in a human, and includes causing a desired biological or pharmacological effect, such as: (a) inhibiting a disorder, i.e., arresting its development; (b) relieving a disorder, i.e., causing regression thereof; (c) protecting from or relieving a symptom or pathology caused by or related to a disorder; (d) reducing, decreasing, inhibiting, or ameliorating one or more symptoms or pathologies associated with a disorder; and (e) inhibiting or preventing the worsening or progression of symptoms or pathologies associated with a disorder or comorbid with a disorder. Other such measurements, benefits, and surrogate or clinical endpoints, alone or in combination, will be understood to one of skill in view of the teachings herein and the knowledge in the art.

[0168]

[0120] The terms “subject,” “user,” “patient,” and “individual” may be used interchangeably herein, and refer to any mammal, although preferably humans. Such terms will be understood to include one who has an indication for which a disclosed compound, composition, or method may be efficacious, or who otherwise may benefit from the invention. In general, all of the disclosed compounds, compositions, and methods will be appreciated to work for all individuals, although individual variation is to be expected, and will be understood.

[0169]

[0121] In embodiments, the medical condition is a mental, behavioral, or neurodevelopmental disorder. The ICD-11 , which is incorporated by reference herein in its entirety, defines “mental, behavioral, or neurodevelopmental disorders” as syndromes characterized by clinically significant disturbance in an individual's cognition, emotional regulation, or behavior that reflects a dysfunction in the psychological, biological, or developmental processes that underlie mental and behavioral functioning. Such disorders include, but are not limited to, neurodevelopmental disorders, schizophrenia or other primary psychotic disorders, catatonia, mood disorders, anxiety or fear-related disorders, obsessive-compulsive or related disorders, disorders specifically associated with stress, dissociative disorders, feeding (or eating) disorders, elimination disorders, disorders of bodily distress or bodily experience, disorders due to substance use or addictive behaviors, impulse control disorders, disruptive behavior or dissocial disorders, personality disorders (and related traits), paraphilic disorders, factitious disorders, neurocognitive disorders, mental or behavioral disorders associated with pregnancy, childbirth or the puerperium, sleep-wake disorders, sexual dysfunctions, and gender incongruence.

[0170]

[0122] A mental, behavioral, or neurodevelopmental disorder where otherwise undefined, will be understood to refer to the disorder as defined in the ICD-11. Terms that define specific diseases and disorders generally shall refer to the criteria in the ICD-11, however, it will be appreciated that disclosed methods are equally applicable to patients having an equivalent underlying disorder, whether that disorder is diagnosed based on the criteria in ICD-11 , ICD-10, DSM-5, or DSM-IV (each of which is incorporated by reference herein in its entirety) whether the diagnosis is based on other clinically acceptable criteria, or whether the patient has not yet had a formal clinical diagnosis.

[0171]

[0123] In embodiments, a disclosed compound is used to treat a neurodegenerative disease. In embodiments, a subject has a neurodegenerative disease. In embodiments, a subject is at risk of a neurodegenerative disease. The diagnosis of a neurodegenerative disease and determining that a subject is at risk of a neurodegenerative disease will be known to those in the art. Examples of neurodegenerative diseases treatable using a disclosed compound include Parkinson’s disease, Alzheimer’s disease, Lewy body dementia, multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, frontotemporal dementia, and amyotrophic lateral sclerosis.

[0172]

[0124] In embodiments, a disclosed compound is used to treat a neurodegenerative movement disorder. In embodiments, a subject has a neurodegenerative movement disorder. In embodiments, a subject is at risk of a neurodegenerative movement disorder. The diagnosis of a neurodegenerative movement disorder and determining that a subject is at risk of a neurodegenerative movement disorder will be known to those in the art. Examples of neurodegenerative movement disorders treatable using a disclosed compound include Parkinson’s disease, multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, and Huntington’s disease.

[0173]

[0125] In embodiments, a disclosed compound is used to treat a hormone-related neurological or cognitive disorder. In embodiments, a subject has a hormone-related neurological or cognitive disorder. In embodiments, a subject is at risk of a hormone-related neurological or cognitive disorder. The diagnosis of a hormone-related neurological or cognitive disorder and determining that a subject is at risk of such a disorder will be known to those in the art. Examples include menopause-associated cognitive disturbance, menopausal depression, climacteric-related mood disorder, postpartum depression, and other central nervous system effects of estrogen deficiency or hormone dysregulation.

[0174]

[0126] In embodiments, a disclosed compound is used to treat a pain disorder. In embodiments, a subject has a pain disorder. In embodiments, a subject is at risk of a pain disorder. The diagnosis of a pain disorder and determining that a subject is at risk of a pain disorder will be known to those in the art. Examples of pain disorders treatable using a disclosed compound include chronic migraine, cluster headache, trigeminal neuralgia, fibromyalgia, and neuropathic pain including diabetic neuropathy and postherpetic neuralgia.

[0175]

[0127] In embodiments, a disclosed compound is used to treat an inflammatory disorder. In embodiments, a subject has an inflammatory disorder. In embodiments, a subject is at risk of an inflammatory disorder. The diagnosis of an inflammatory disorder and determining that a subject is at risk of an inflammatory disorder will be known to those in the art. Examples of inflammatory disorders treatable using a disclosed compound include asthma, inflammatory bowel disease including Crohn’s disease and ulcerative colitis, rheumatoid arthritis, multiple sclerosis, and other immune-mediated or cytokine-driven inflammatory conditions.

[0176]

[0128] In embodiments, a disclosed compound is used to treat a neurological injury or to promote recovery following a neurological injury. In embodiments, a subject has experienced a neurological injury. In embodiments, a subject is at risk of long-term functional impairment following a neurological injury. The diagnosis of a neurological injury and determining that a subject is at risk of long-term sequelae will be known to those in the art. Examples include ischemic stroke, traumatic brain injury, and spinal cord injury.

[0177]

[0129] In embodiments, a disclosed compound is used to treat a postviral or postinfectious neurological disorder. In embodiments, a subject has such a disorder. In embodiments, a subject is at risk of such a disorder. Examples include cognitive impairment, fatigue, or neuroinflammatory sequelae following infection, including post-acute sequelae of SARS-CoV-2 infection (PASC or “long COVID”).

[0178]

[0130] In embodiments, a disclosed compound is used to treat a disorder caused by or associated with a decrease in neuroplasticity. In embodiments, a subject has decreased neuroplasticity. In embodiments, a subject is at risk of decreased neuroplasticity.

[0179]

[0131] In embodiments, a disclosed compound is used to treat a disorder caused by or associated with dysregulated synaptic transmission, receptor signaling, or intracellular signal transduction. In embodiments, a subject has such a disorder. In embodiments, a subject is at risk of such a disorder. Examples include disorders involving dysregulated serotonergic, dopaminergic, glutamatergic, or GABAergic signaling, including those not otherwise classified.

[0180]

[0132] In embodiments, a method comprises administering a compound to a subject at a dose of between about 0.01 mg and about 1000 mg per unit dose, including, for example, between about 0.1 mg and about 100 mg per unit dose, between about 1 mg and 1000 mg per unit dose, between about 0.1 mg and about 500 mg per unit dose, between about 1 mg and about 400 mg per unit dose, between about 10 mg and about 300 mg per unit dose, between about 20 mg and about 200 mg per unit dose, between about 50 mg and about 150 mg per unit dose, between about 100 mg and about 500 mg per unit dose, between about 150 mg and about 1000 mg per unit dose, and between about 200 mg and about 800 mg per unit dose. In embodiments, a unit dose of a compound is greater than about 1000 mg. In embodiments, a unit dose of a compound is less than about 0.01 mg.

[0181]

[0133] In embodiments, a unit dose of a compound is between about 0.01 mg / kg and about 20 mg / kg (calculated based on the kilogram weight of the patient), including, for example, between about 0.05 mg / kg and about 10 mg / kg, between about 0.1 mg / kg and about 5 mg / kg, between about 0.2 mg / kg and about 3 mg / kg, between about 0.5 mg / kg and about 2 mg / kg, and between about 1 mg / kg and about 1.5 mg / kg. In embodiments, a unit dose of a compound is greater than about 20 mg / kg. In embodiments, a unit dose of a compound is less than about 0.01 mg / kg.

[0182]

[0134] In embodiments, a method comprises administering between about 1 and 10 unit doses of a compound per day during a treatment course. In embodiments, a method comprises administering a compound once per day. In embodiments, a method comprises administering a compound twice per day. In embodiments, a method comprises administering a compound three times per day. In embodiments, a method comprises administering a compound five times per day. In embodiments, a treatment course is at least one week, two weeks, three weeks, 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, or 24 months. In embodiments, a treatment course is greater than 24 months, depending on the subject's condition, response to treatment, and clinical judgment. The duration of the treatment course can be adjusted based on the subject’s progress and clinical need.

[0183]

[0135] The compound may be administered continuously, for example, on a daily basis, or intermittently, such as once weekly or with periodic breaks. For example, a treatment course may comprise a pattern in which a compound is administered daily (e.g., between 1 and 10 unit doses per day) for seven days followed by a break for seven days (i.e., during which no compound is administered); and this cycle may be repeated for any time period, such as two months, four months, six months, or longer.

[0184]

[0136] It will be appreciated that dosages may vary depending on factors such as whether the treatment is therapeutic or prophylactic, the onset, progression, severity, frequency, duration, or susceptibility of the symptom being treated, the desired clinical endpoint, prior or concurrent treatments, general health, age, gender, and race of the subject, bioavailability, potential adverse side effects (systemic, regional, or local), the presence of other disorders or diseases in the subject, and other factors known to those skilled in the art (e.g., medical or familial history). One skilled in the art, guided by the teachings herein, will understand the factors that influence the dosage, frequency, and timing required to achieve a therapeutic effect or benefit, while also minimizing adverse effects.

[0185]

[0137] In embodiments, the actual dose administered will be determined by a physician in consideration of the relevant circumstances, including the disorder being treated, the chosen route of administration, the specific composition or formulation used, the age, weight, and response of the individual patient, and the severity of the patient’s symptoms. As such, any disclosed dosage ranges are not intended to limit the scope of the disclosure. In certain cases, a dosage below the lower limit of a disclosed range may still be effective, while higher doses may be employed without causing harmful side effects, provided that such larger doses may be divided into smaller doses for administration, either together or separately.

[0186]

[0138] In another aspect, provided are methods of using the disclosed compounds and pharmaceutical compositions comprising the compounds for increasing neuroplasticity in a subject. In embodiments, increasing neuroplasticity in a subject by administering a disclosed compound or pharmaceutical composition comprising a compound contributes to a therapeutic effect of the compound and / or treats a disease or disorder in a subject. In embodiments, administration of a disclosed compound increases neuritogenesis in a subject. In embodiments, administration of a disclosed compound increases spinogenesis in a subject. In embodiments, administration of a disclosed compound increases synaptogenesis in a subject. In embodiments, administration of a disclosed compound to a subject increases the number of dendritic branches, the number of dendritic crossings, the density of dendritic spines, the density of synapses (i.e., number of synapses per neuron), or total dendritic length. These factors can be measured using a Sholl analysis and other techniques known to those of skill in the art (Ly et al. ACS Pharmacol Transl Sci. 2020;4(2):452-460).

[0187] G. Combination Therapy

[0188]

[0139] It should be readily appreciated that, while the disclosed compounds may, in some embodiments, be used alone and are effective as such (i.e., as monotherapy), the methods of the invention also encompass the administration of an additional active agent. The additional active agent may be co-formulated with the compound in the same pharmaceutical composition or administered separately in a distinct composition, in accordance with best medical judgment and standard medical practices.

[0189]

[0140] An additional active agent may be used (and in some embodiments included alongside a disclosed compound in a pharmaceutical composition) to enhance or complement the therapeutic efficacy of the compound, reduce adverse effects, improve pharmacokinetic or pharmacodynamic profiles, enhance bioavailability or stability, or provide an additive or synergistic therapeutic effect.

[0190]

[0141] In embodiments, the additional active agent is an amino acid, anxiolytic, antidepressant, antipsychotic, anti-PTSD agent, dissociative agent, empathogen, psychedelic, plasticity-enhancing agent, psychoplastogen, neuroprotective agent, anti-addiction agent, metabolic modulator, appetite suppressant, orexigenic agent, antiulcer agent, antihistamine, antihypertensive agent, anticonvulsant, antiepileptic agent, bronchodilator, stimulant, sedative, nootropic, cognitive enhancer, serotonin precursor, serotonin releaser, serotonin reuptake inhibitor, phenethylamine, terpene, vitamin, or micronutrient.

[0191]

[0142] In embodiments, the additional active agent is a dopamine agonist (e.g., pramipexole, ropinirole, apomorphine), L-DOPA or DOPA decarboxylase inhibitor (e.g., carbidopa), monoamine oxidase inhibitor (e.g., selegiline, rasagiline), NMDA receptor antagonist (e.g., memantine, dextromethorphan), AMPA modulator, cholinesterase inhibitor (e.g., donepezil, galantamine), GABAergic modulator (e.g., alprazolam, gabapentin, valproic acid), kappa opioid receptor antagonist (e.g., nor-BNI, aticaprant), sigma-1 receptor agonist (e.g., fluvoxamine, PRE-084), or anti-inflammatory agent (e.g., minocycline, ibudilast, or corticosteroids). In embodiments, the additional agent is a hormone or hormone modulator, such as estradiol, selective estrogen receptor modulators (e.g., raloxifene, bazedoxifene), or aromatase inhibitors (e.g., letrozole). In embodiments, the additional agent is a neurotrophic modulator, such as a TrkB agonist, a PDE4 inhibitor (e.g., rolipram), or a BDNF mimetic. In embodiments, the additional agent is a non-opioid analgesic, such as acetaminophen, NSAIDs, sodium channel blockers (e.g., lamotrigine, carbamazepine), or cannabinoid receptor agonists.

[0192]

[0143] The specific selection, dosing, and administration of any additional active agent in combination with a disclosed compound can be determined in accordance with best medical practices, the judgment of a treating physician, and established guidelines in the art. The appropriate dosage, schedule, and route of administration for such agents may depend on factors such as the specific agent(s) selected, the patient's overall health status, the type and stage of the disease or disorder being treated, and any concomitant therapies. In embodiments, dosing regimens for additional active agents are based on standard clinical guidelines and known therapeutic ranges as established in the literature or regulatory approvals. Nothing herein should be construed as limiting the scope of potential combinations or precluding the use of alternative agents, formulations, or dosing regimens that would be apparent to those skilled in the art.

[0193] H. Examples

[0194]

[0144] The invention can be further understood by reference to the following examples, which are provided by way of illustration and are not meant to be limiting.

[0195]

[0145] (R)-2-(4-bromo-2,5-dimethoxybenzyl)pyrrolidine and (S)-2-(4-bromo-2,5-dimethoxybenzyl) pyrrolidine were separately prepared according to the following reaction sequence, as described in Examples 1 and 2.

[0196]

[0197]

[0146] (R)-2-(2,5-dimethoxybenzyl)pyrrolidine and (S)-2-(2,5-dimethoxybenzyl)pyrrolidine were separately prepared according to the following reaction sequence, as described in Examples 3 and 4.

[0198] Example 1. Synthesis of ( / ?)-2-(4-bromo-2,5-dimethoxybenzyl)pyrrolidine

[0199]

[0147] Step 1. 1. tert-butyl (R)-2-(4-bromo-2,5-dimethoxybenzyl)pyrrolidine-1 -carboxylate

[0200]

[0148] Solution A: A solution of 1 ,4-dibromo-2,5-dimethoxybenzene (1 g, 3.379 mmol, 1 equiv) and lr(ppy)2(dtbbpy)PF6(0.09 g, 0.101 mmol, 0.03 equiv) and NiBr2(dtbbpy) (0.16 g, 0.338 mmol, 0.1 equiv) and quinuclidine (0.66 g, 5.913 mmol, 1 .75 equiv) in DMA (33 mL) was stirred at room temperature for 10 minutes under nitrogen atmosphere.

[0201]

[0149] A solution of tert-butyl (R)-2-(hydroxymethyl)pyrrolidine-1 -carboxylate (1.19 g, 5.913 mmol, 1.75 equiv) and NHC (2.14 g, 5.406 mmol, 1.6 equiv) in t-BuOMe (26 mL) was stirred at room temperature for 10 minutes under nitrogen atmosphere. To the above mixture was added pyridine (0.43 g, 5.406 mmol, 1.6 equiv) in t-BuOMe (7 mL) dropwise over 2 minutes at room temperature. The resulting mixture was stirred at room temperature for an additional 20 minutes. The resulting mixture was filtered. After filtration, the filtrate was added into the solution A dropwise. The reaction was stirred at 70 °C in a CORNING Advance Flow reactor with a 475 nM lamp for 1 hour.

[0202]

[0150] The resulting mixture was diluted with H2O (30 mL). The resulting mixture was extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford the title compound (1 g, crude) as a brown oil. LC-MS: (ES, m / z): 400.10 [M+H]+.

[0203]

[0151] Step 2. (R)-2-(4-bromo-2, 5-dimethoxybenzyl)pyrrolidine

[0204]

[0152] A solution of tert-butyl (R)-2-(4-bromo-2,5-dimethoxybenzyl)pyrrolidine-1-carboxylate (1 g, crude) in HCI in 1 ,4-dioxane(4.0 M) (10 mL) was stirred at room temperature for 30 minutes. The residue was dissolved in H2O (20 mL). The organic layer was extracted with MTBE (3 x 20 mL). The combined aqueous layers were basified to pH 11 with NH3*H2O. The resulting mixture was filtered and washed with DCM / MEOH=10 / 1 (3 x 20 mL). After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase flash with the following conditions (ACN / H2O(10mmol / L NH4HC03)=70 / 30) to afford the title compound (125.2 mg, 16.70% yield, 98.1% purity) as a yellow oil. LC-MS: (ES, m / z): 300.05, 302.05 [M+H]+.1H NMR (300 MHz, DMSO-d6) 5 7.15 (s, 1 H), 6.99 (s, 1 H), 3.78 (s, 3H), 3.75 (s, 3H), 3.50-3.60 (m, 1 H), 3.31-3.15 (m, 1 H), 3.01-2.87 (m, 1 H), 2.83-2.70(m, 1 H), 2.66 (d, J = 6.9 Hz, 2H), 1.80-1.50 (m, 3H), 1.34-1.30 (m, 1 H).

[0205] Example 2. Synthesis of (S)-2-(4-bromo-2,5-dimethoxybenzyl)pyrrolidine

[0206]

[0153] Step 1. 1. tert-butyl (S)-2-(4-bromo-2,5-dimethoxybenzyl)pyrrolidine-1 -carboxylate

[0207]

[0154] Solution A: A solution of 1 ,4-dibromo-2,5-dimethoxybenzene (1 g, 3.379 mmol, 1 equiv) and lr(ppy)2(dtbbpy)PF6(0.09 g, 0.101 mmol, 0.03 equiv) and NiBr2(dtbbpy) (0.16 g, 0.338 mmol, 0.1 equiv) and quinuclidine (0.66 g, 5.913 mmol, 1 .75 equiv) in DMA (33 mL) was stirred at room temperature for 10 minutes under nitrogen atmosphere.

[0208]

[0155] A solution of tert-butyl (2S)-2-(hydroxymethyl)pyrrolidine-1 -carboxylate (1.19 g, 5.913 mmol, 1.75 equiv) and NHC (2.14 g, 5.406 mmol, 1.6 equiv) in t-BuOMe (26 mL) was stirred at room temperature for 10 minutes under nitrogen atmosphere. To the above mixture was added pyridine (0.43 g, 5.406 mmol, 1.6 equiv) in t-BuOMe (7 mL) dropwise over 2 minutes at room temperature. The resulting mixture was stirred at room temperature for an additional 20 minutes. The mixture was filtered. After filtration, the filtrate was added into solution A dropwise. The reaction was stirred at 70 °C in a CORNING Advance Flow reactor with a 475 nM lamp for 1 hour.

[0209]

[0156] The mixture was diluted with H2O (30 mL). The resulting mixture was extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (3 x 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford the title compound (1 g, crude) as a brown oil. LC-MS: (ES, m / z): 400.10 [M+H]+.

[0210]

[0157] Step 2. (S)-2-(4-bromo-2, 5-dimethoxybenzyl)pyrrolidine

[0211]

[0158] A solution of tert-butyl (S)-2-(4-bromo-2,5-dimethoxybenzyl)pyrrolidine-1 -carboxylate (1 g, crude) in HCI in 1 ,4-dioxane (4.0 M) (10 mL) was stirred at room temperature for 30 minutes. The residue was dissolved in H2O (20 mL). The organic layer was extracted with MTBE (3 x 20 mL). The combined aqueous layers were basified to pH 11 with NH3*H2O. The resulting mixture was filtered and washed with DCM / MeOH = 10 / 1 (3 x 20 mL). After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase flash with the following conditions (ACN / H2O (10 mmol / L NH4HCO3) = 70 / 30) to afford the title compound (137.0 mg, 18.27% yield, 99.5% purity) as a yellow oil. LC-MS: (ES, m / z): 300.00, 302.00 [M+H]+.1H NMR (300 MHz, DMSO-d6) 5 7.13 (s, 1 H), 6.97 (s, 1 H), 3.77 (s, 3H), 3.75 (s, 3H), 3.20-3.05 (m, 2H), 2.93-2.80 (m, 1 H), 2.73-2.61 (m, 1 H), 2.60 (d, J = 6.9 Hz, 2H), 1.75-1.48 (m, 3H), 1.36-1.20 (m, 1 H).

[0212] Example 3. Synthesis of ( / ?)-2-(2,5-dimethoxybenzyl)pyrrolidine

[0213]

[0159] Step 1. tert-butyl (R)-2-(2,5-dimethoxybenzyl)pyrrolidine-1-carboxylate

[0214]

[0160] Solution A: A solution of 2-bromo-1 ,4-dimethoxybenzene (1 g, 4.607 mmol, 1 equiv) and lr(ppy)2(dtbbpy)PF6(0.13 g, 0.138 mmol, 0.03 equiv) and NiBr2(dtbbpy) (0.22 g, 0.461 mmol, 0.1 equiv) and quinuclidine (0.90 g, 8.062 mmol, 1.75 equiv) in DMA (46 mL) was stirred at room temperature for 10 minutes under nitrogen atmosphere.

[0161] A solution of tert-butyl (R)-2-(hydroxymethyl)pyrrolidine-1 -carboxylate (1.62 g, 8.062 mmol, 1.75 equiv) and NHC (2.91 g, 7.371 mmol, 1.6 equiv) in t-BuOMe (37 mL) was stirred at room temperature for 10 minutes under nitrogen atmosphere. To the above mixture was added pyridine (0.58 g, 7.371 mmol, 1 .6 equiv) in MTBE (9 mL) dropwise over 2 minutes at room temperature. The resulting mixture was stirred at room temperature for an additional 20 minutes. The resulting mixture was filtered. After filtration, the filtrate was added into the Solution A dropwise. The reaction was stirred at 70 °C in a CORNING Advance Flow reactor with a 475 nM lamp for 2 hours.

[0215]

[0162] The resulting mixture was diluted with H2O (50 mL). The resulting mixture was extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford the title compound (1 g, crude) as a brown oil. LC-MS: (ES, m / z): 322.19 [M+H]+.

[0216]

[0163] Step 2. (R)-2-(2, 5-dimethoxybenzyl)pyrrolidine

[0217]

[0164] A solution of tert-butyl (R)-2-(2,5-dimethoxybenzyl)pyrrolidine-1 -carboxylate (1 g, crude) in HCI in 1 ,4-dioxane (4.0 M) (10 mL) was stirred at room temperature for 30 minutes. The residue was dissolved in H2O (20 mL). The organic layer was extracted with MTBE (3 x 20 mL). The combined aqueous layers were basified to pH 11 with NH3*H2O. The resulting mixture was filtered and washed with DCM / MEOH=10 / 1 (3 x 20 mL). After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase flash with the following conditions (ACN / H2O(10mmol / L NH4HC03)=60 / 40) to afford the title compound (129.0 mg, 18.74% yield, 99.7% purity) as a yellow oil. LC-MS: (ES, m / z): 222.10 [M+H]+.1H NMR (300 MHz, DMSO-d6) 5 6.85 (d, J = 8.7 Hz, 1 H), 6.79-6.67 (m, 2H), 3.70 (s, 3H), 3.67(s, 3H), 3.17-3.08 (m, 2H), 2.96-2.78 (m, 1 H), 2.74-2.62 (m, 1 H), 2.61-2.54 (m, 2H), 1.74-1.49 (m, 3H), 1.35-1.18 (m, 1 H).

[0218] Example 4. Synthesis of (S)-2-(2,5-dimethoxybenzyl)pyrrolidine

[0219]

[0165] Step 1. tert-butyl (S)-2-(2, 5-dimethoxybenzyl)pyrrolidine-1-carboxylate

[0220]

[0166] Solution A: A solution of 2-bromo-1 ,4-dimethoxybenzene (1 g, 4.607 mmol, 1 equiv) and lr(ppy)2(dtbbpy)PF6(0.13 g, 0.138 mmol, 0.03 equiv) and NiBr2(dtbbpy) (0.22 g, 0.461 mmol, 0.1 equiv) and quinuclidine (0.90 g, 8.062 mmol, 1.75 equiv) in DMA (46 mL) was stirred at room temperature for 10 minutes under nitrogen atmosphere.

[0221]

[0167] A solution of tert-butyl (2S)-2-(hydroxymethyl)pyrrolidine-1 -carboxylate (1.62 g, 8.062 mmol, 1.75 equiv) and NHC (2.91 g, 7.371 mmol, 1.6 equiv) in t-BuOMe (37 mL) was stirred at room temperature for 10 minutes under nitrogen atmosphere. To the above mixture was added pyridine (0.58 g, 7.371 mmol, 1.6 equiv) in MTBE (9 mL) dropwise over 2 minutes at room temperature. The resulting mixture was stirred at room temperature for an additional 20 minutes. The resulting mixture was filtered. After filtration, the filtrate was added into solution A dropwise. The reaction was stirred at 70 °C in a CORNING Advance Flow reactor with a 475 nM lamp for 2 hours.

[0222]

[0168] The mixture was diluted with H2O (50 mL). The resulting mixture was extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (3 x 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford the title compound (1 g, crude) as a brown oil. LC-MS: (ES, m / z): 322.19 [M+H]+.

[0223]

[0169] Step 2. (S)-2-(2, 5-dimethoxybenzyl)pyrrolidine

[0224]

[0170] A solution of tert-butyl (S)-2-(2,5-dimethoxybenzyl)pyrrolidine-1 -carboxylate (1 g, crude) in HCI in 1 ,4-dioxane(4.0 M) (10 mL) was stirred at room temperature for 30 minutes. The residue was dissolved in H2O (20 mL). The organic layer was extracted with MTBE (3 x 20 mL). The combined aqueous layers were basified to pH 11 with NH3*H2O. The resulting mixture was filtered and washed with DCM / MeOH = 10 / 1 (3 x 20 mL). After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase flash with the following conditions (ACN / H2O (10mmol / L NH4HCO3) = 60 / 40) to afford title compound (123.0 mg, 17.86% yield, 98.9% purity) as a yellow oil. LC-MS: (ES, m / z): 222.10 [M+H]+.1H NMR (300 MHz, DMSO-d6) 5 6.85 (d, J= 8.7 Hz, 1 H), 6.79-6.67 (m, 2H), 3.70 (s, 3H), 3.67 (s, 3H), 3.17-3.08 (m, 2H), 2.96-2.81 (m, 1 H), 2.74-2.62 (m, 1 H), 2.61-2.51 (m, 2H), 1.74-1.49 (m, 3H), 1.35-1.18 (m, 1 H).

[0225] Example 5. In Vitro Serotonin Receptor Functional Activity

[0226]

[0171] The agonist effects of disclosed compounds at human 5-HT2A, 5-HT2B, and 5-HT2C receptors expressed in HEK293 cells were characterized in a calcium flux assay using the FLIPR® Calcium 6 Assay Kit (Molecular Devices, San Jose) according to the manufacturer’s instructions.

[0227]

[0172] General Assay Preparation: Cells were cultured in DMEM / F12 medium supplemented with 10% dialyzed fetal bovine serum (FBS), 1 x penicillin-streptomycin, and 600 pg / mL hygromycin B at 37 °C and 5% CO2. One day prior to the assay, cells were detached using TrypLE™ Express, counted, and assessed for viability. Only cell suspensions with >85% viability were used.

[0228]

[0173] Cells were seeded into 384-well cell plates at densities of 20,000 cells / well for 5-HT2A assays and 12,000 cells / well for 5-HT2B and 5-HT2C assays, in 30 pL / well culture medium. Plates were incubated overnight at 37 °C in a humidified atmosphere containing 5% CO2.

[0229]

[0174] On the day of the assay, dye solutions (2x final concentration) were prepared according to the FLIPR® Calcium 6 Assay Kit protocol by diluting the dye in assay buffer (20 mM HEPES in 1 x HBSS, pH 7.4), adding probenecid to a final concentration of 5 mM, and vortexing the mixture for 1-2 minutes.

[0175] Culture medium was removed from the cell plates by flicking them onto absorbent paper towels. Then, 10 pL of assay buffer and 10 pL of dye solution were added to each well. Plates were agitated on a plate shaker at 600 rpm for 2 minutes and incubated at 37 °C for 2 hours, followed by an additional 15-minute incubation at room temperature (25 °C).

[0230]

[0176] Compound Preparation: Triplicate test compound solutions in assay buffer (3x final concentration) were prepared as follows: (1) Reference compounds (serotonin HCI for the 5-HT2A and 5-HT2C assays, and RU24969 for the 5-HT2B assays) were diluted to the desired concentration in DMSO and added to a 384-well compound plate; (2) Serial dilutions were performed by adding 1 mM and 33.3 mM test compounds (for 5-HT2A assays) or 1 mM test compounds (for 5-HT2B and 5-HT2C assays), followed by 3-fold serial dilutions, then compounds were transferred (90 nL / well) to a fresh 384-well compound plate using an Echo acoustic liquid handler, and 30 pL / well of assay buffer was added; (3) The plate was mixed on a plate shaker for 2 minutes.

[0231]

[0177] Assay Execution: The cell plates, compound plates, and tips were loaded into the FLIPR system. Then, 10 pL of the compound solutions were automatically transferred to each well of the cell plates. The fluorescence signal was recorded every second for 160 seconds to capture the calcium response under agonist mode.

[0232]

[0178] Data Analysis: Fluorescence data were collected using the FLIPR system, and calcium mobilization was quantified as relative fluorescence units (RFU). Data analysis proceeded as follows:

[0233]

[0179] Normalization of RFU Signals: The calcium response was normalized by calculating the change in fluorescence (RFU) over a defined time window, where Fmax and Fmin represent the maximum and minimum fluorescence values, respectively: RFU = Fmax - Fmin.

[0234]

[0180] Calculation of Percentage Activation: Percent activation for each compound concentration was calculated relative to the maximum response of the reference agonist using the following equation:

[0235] % Activation = 100 * (RFUtest- RFU / (RFUra- RFU,C);

[0236]

[0181] wherein RFUtest= is the RFU for the test compound at test concentration, RFU|Cis the RFU of the low control, and RFUrais the RFU for the top concentration of the reference agonist.

[0237]

[0182] Curve Fitting and EC50 Determination: Dose-response curves were generated by plotting % activation versus the logarithm of compound concentration. EC50 values were obtained by fitting the data to a four-parameter logistic model (Hill equation) using XLfit (I DBS).

[0238]

[0183] Results: Results (EC50, Emax, and selectivities) are shown below in Table 2. Table 2. In Vitro Serotonin Receptor Functional Activity for Disclosed Compounds at Human 5-HT2A, 5-HT2B, and 5-HT2C Receptors

[0239] Example 6. In Vivo Hallucinogenic Activity in Rodent Head-Twitch Response Assay

[0240]

[0184] The head twitch response (HTR) in mice is a well-established behavioral assay used to predict hallucinogenic activity in humans (see, e.g., Halberstadt et al., J. Psychopharmacol., 2011 ; Glatfelter et al., ACS Pharmacol. Transl. Sci. , 2022), and is used to distinguish between hallucinogenic and non-hallucinogenic 5-HT2A agonists.

[0241]

[0185] Animals and Housing: Adult male C57BL / 6J mice (aged 2-4 months, 20-30 g) are used for all experiments. Animals are housed individually under standard conditions (12:12 h light / dark cycle; lights on at 07:00), with ad libitum access to food and water.

[0242]

[0186] Compound Administration: Test compounds are prepared in a vehicle solution (e.g., water containing 5% Tween 80) and administered intraperitoneally or subcutaneously at a dose volume of 0.01 mL / g body weight. A range of doses is tested to generate dose-response data.

[0243]

[0187] Experimental Procedures: On the test day, mice are transferred in their home cages to the experimental room and allowed to acclimate for 1 hour. Following injection with either test compound or vehicle, mice are placed in transparent cylindrical acrylic arenas (~7.5 inches in diameter) positioned within locomotor activity monitoring enclosures. A white paper substrate beneath each arena provides contrast for video tracking. Overhead video is recorded at 120 frames per second (960p resolution) for 30 minutes using cameras mounted approximately 10 inches above the arenas. All testing occurs during the light phase, between 09:00 and 17:00. Animals are randomly assigned to treatment conditions. To avoid tolerance effects, each mouse is tested no more than once every 1-2 weeks. Video recordings are saved for subsequent analysis.

[0244]

[0188] HTR Quantification: Behavioral data are analyzed using commercially available software (e.g., TopScan, Clever Sys Inc.) adapted to detect HTRs by tracking ear movement. For each video, the software is configured with a background model, an arena map, and a dynamic color model optimized to track ear motion under specific lighting conditions. Mouse ID, treatment group, and experiment metadata are input into the software for each session. The software conducts automated scoring of HTR events, which are then reviewed manually via playback of short video clips corresponding to each detected event. False positives can be removed, and confirmed events retained. Data are exported for downstream analysis. In addition to automated scoring, two trained, blinded observers independently score HTR events in 5-minute intervals across the 30-minute recording period. Observer scores are averaged for each session and compared to software-generated counts.

[0245]

[0189] Data Analysis: Visual and automated scores are analyzed using two-way ANOVA (factors: scoring method x treatment), followed by Tukey’s post hoc tests for pairwise comparisons. Correlation between manual and automated scoring is assessed via Pearson’s r. Dose-response curves are analyzed using nonlinear regression to determine ED50 values. All statistical analyses are performed using GraphPad Prism or equivalent software.

[0246]

[0190] Results: The total number of HTRs observed in each treatment group and the calculated ED50 values provide a quantitative measure of the hallucinogenic potential of test compounds. Results are expected to show that certain disclosed compounds are unlikely to produce hallucinogenic effects in humans, despite potently agonizing the 5-HT2A receptor.

[0247] Example 7. In Vivo Pharmacokinetics and Brain Penetration

[0248]

[0191] The pharmacokinetic properties and brain penetration of disclosed compounds are evaluated in adult male CD-1 mice. Compounds are formulated in 5% Tween 80 in water and administered via oral gavage at 10 mg / kg (n=3 per timepoint). An additional cohort receives an intravenous dose of 1 mg / kg for bioavailability assessment.

[0249]

[0192] Blood and brain samples are collected at 0.25, 0.5, 1 , 2, 4, and 6 hours post-dosing. Plasma is isolated via centrifugation, and brain tissue is homogenized in phosphate-buffered saline. Compound concentrations in plasma and brain homogenates are quantified using LC-MS / MS with a validated matrix-matched standard curve.

[0250]

[0193] Pharmacokinetic parameters including Cmax, Tmax, AUG, half-life, clearance, and volume of distribution are determined using non-compartmental analysis. Oral bioavailability is calculated by comparing dose-normalized AUG values between oral and intravenous routes. Brain penetration is assessed by calculating brain-to-plasma concentration ratios at each timepoint.

[0251] Example 8. In Vivo Evaluation of Motor Effects in a Rat Model of Parkinson’s Disease

[0252]

[0194] The ability of disclosed compounds to improve motor deficits is evaluated in a unilateral 6-hydroxydopamine (6-OHDA) rat model of Parkinson’s disease (as described in, e.g., Angela Cenci M & Crossman AR. Mov Disord. 2018;33(6):889-899). Adult male Sprague-Dawley rats are anesthetized with sodium pentobarbital (40 mg / kg, i.p.) and placed in a stereotaxic apparatus. A total of 32 pg of 6-OHDA in 8 pL of saline containing 0.02% ascorbic acid is infused into the right medial forebrain bundle (MFB). Three weeks post-lesion, rats are screened for lesion success using apomorphine-induced rotation testing (0.5 mg / kg, i.p.). Animals exhibiting >7 contralateral rotations per minute are considered adequately lesioned.

[0253]

[0195] On test days, rats receive subcutaneous injections of vehicle or test compound (0.3, 1 , or 3 mg / kg), and motor function is assessed using apomorphine-induced rotations (number of turns over 60 minutes), the open field test (total locomotion, rearing), and the cylinder test (forelimb use asymmetry). Improvement in motor behavior relative to vehicle-treated controls is interpreted as evidence of therapeutic efficacy in alleviating Parkinsonian motor deficits.

[0254]

[0196] To assess the antidyskinetic potential of disclosed compounds, L-DOPA-induced dyskinesia is modeled in rats with unilateral 6-OHDA lesions of the medial forebrain bundle, as described above. Following confirmation of successful lesioning via apomorphine-induced rotations, rats receive daily intraperitoneal injections of L-DOPA (25 mg / kg) plus benserazide (6.25 mg / kg) for 21 consecutive days to induce stable dyskinesia. On test days, rats are randomly assigned to receive vehicle or the disclosed compound (0.3, 1 , or 3 mg / kg, s.c.) 30 minutes prior to L-DOPA administration. Abnormal involuntary movements (AIMs) are scored every 20 minutes for 2 hours by blinded observers using a standardized scale encompassing axial, limb, and orofacial components. Total AIM scores are compared between treatment groups using repeated-measures ANOVA. A significant reduction in AIMs without suppression of general locomotion indicates antidyskinetic activity consistent with modulation of serotonergic pathways.

[0255] Example 9. In Vivo Evaluation of Antidepressant and Cognitive Effects in an Ovariectomized Rat Model of Menopause

[0256]

[0197] Disclosed compounds are evaluated in a preclinical model of estrogen-deficiency-related mood and cognitive dysfunction using ovariectomized (OVX) female rats. Bilateral ovariectomy is performed under isoflurane anesthesia in adult female Sprague-Dawley rats (10-12 weeks old). Sham-operated animals undergo identical procedures without ovary removal. Following surgery, animals recover for 14 days to allow for establishment of an estrogen-deficient state.

[0257]

[0198] Rats are then randomized to receive once-daily subcutaneous injections of vehicle or test compound (0.3, 1, or 3 mg / kg) for 14 consecutive days. During the final 5 days of dosing, animals undergo behavioral testing to assess mood-related and cognitive outcomes:

[0258]

[0199] Forced Swim Test (FST): To assess behavioral despair, rats are placed in a water-filled cylinder for 6 minutes. Time spent immobile is recorded during the last 4 minutes. Reduced immobility in compound-treated OVX rats relative to vehicle is interpreted as an antidepressant-like effect.

[0259]

[0200] Novel Object Recognition (NOR): To assess recognition memory, rats are habituated to an arena, then exposed to two identical objects. After a 24-hour delay, one object is replaced with a novel item. Exploration time for each object is recorded. Increased discrimination index in treated animals indicates enhanced memory performance.

[0260]

[0201] At study completion, serum estradiol levels are confirmed to be low in OVX animals. Brains are collected for hippocampal analysis of, BDNF expression (Western blot and qPCR), 5-HT2A receptor density (radioligand binding or immunohistochemistry), and synaptic plasticity markers (e.g., PSD-95, synaptophysin). Improvement in behavioral endpoints in OVX rats, together with restoration of BDNF-5-HT2A signaling in the hippocampus, is interpreted as a disease-modifying effect consistent with estrogen-compensatory serotonergic modulation.

[0261]

[0202] The foregoing description has been provided to illustrate certain aspects of the present invention and to facilitate an understanding of the embodiments set forth herein. However, it should be understood that the described embodiments are merely exemplary and are not intended to limit the scope of the invention in any manner. All disclosed specific compositions and methods are only exemplary, and may be readily utilized by one of skill in the art for modifying or designing other compositions and methods for carrying out the same purposes as disclosed herein. Such equivalent compositions and methods are also within the scope of the invention as set forth in the claims.

Claims

CLAIMSThe invention claimed is:1 . A compound having the structure of Formula (I):wherein: n is 1 , 2, or 0;R2is CrC6alkoxy or H, or R2is taken together with R3and the intervening atoms to form a 5- or 6-membered heterocyclyl;R3is H, or R3or taken together with R2and the intervening atoms to form a 5- or 6-membered heterocyclyl;R4is Br, F, Cl, I, CrC6alkyl, C2-C8alkenyl, C2-C8alkynyl, CrC6alkoxy, CrC6alkylthio, C3-C6cycloalkylthio, C2-C8alkenylthio, CrC6haloalkylthio, CrC6haloalkyl, CrC6haloalkoxy, C3-C8cycloalkyl, CrC6alkylene-C3-C8cycloalkyl, 4- to 8-membered heterocycloalkyl, CN, NO2, NH2, or H;R5is CrC6alkoxy or H, or R5is taken together with R6and the intervening atoms to form a 5- or 6-membered heterocyclyl; andR6is H, or R6is taken together with R5and the intervening atoms to form a 5- or 6-membered heterocyclyl; or a pharmaceutically acceptable salt, stereoisomer, solvate, or isotopic derivative thereof.

2. The compound of claim 1 , wherein n is 1 .

3. The compound of claim 1 , wherein n is 2.

4. The compound of claim 1 , wherein n is 0.

5. The compound of claim 1 , wherein R2is CrC6alkoxy or H.

6. The compound of claim 5, wherein R2is CrC6alkoxy.

7. The compound of claim 6, wherein R2is methoxy.

8. The compound of claim 6, wherein R2is ethoxy.

9. The compound of claim 1, wherein R2is taken together with R3and the intervening atoms to form a5- or 6-membered heterocyclyl.

10. The compound of claim 9, wherein R2is taken together with R3and the intervening atoms to form a 5-membered heterocyclyl.11 . The compound of claim 10, wherein R2is taken together with R3and the intervening atoms to form a furanyl or dihydrofuranyl.

12. The compound of claim 1 , wherein R3is H.

13. The compound of claim 1, wherein R3is taken together with R2and the intervening atoms to form a 5- or 6-membered heterocyclyl.

14. The compound of claim 1, wherein R4is Br, F, Cl, I.

15. The compound of claim 14, wherein R4is Br.

16. The compound of claim 1 , wherein R4is CrCg alkyl.

17. The compound of claim 16, wherein R4is methyl.

18. The compound of claim 16, wherein R4is ethyl.

19. The compound of claim 16, wherein R4is n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl.

20. The compound of claim 1 , wherein R4is C^Cg alkylthio.21 . The compound of claim 20, wherein R4is methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, sec-butylthio, isobutylthio, or tert-butylthio.

22. The compound of claim 1 , wherein R4is C^Cg haloal kylth io.

23. The compound of claim 22, wherein R4is trifluoromethylthio, 2-fluoroethylthio, 2, 2-difluoroethylthio, 2,2,2-trifluoroethylthio, 3-fluoropropylthio, or 4-fluorobutylthio.

24. The compound of claim 1 , wherein R4is C2-C8alkenylthio.

25. The compound of claim 24, wherein R4is allylthio or methallylthio.

26. The compound of claim 1 , wherein R4is CN.

27. The compound of claim 1 , wherein R5is CrCg alkoxy or H.

28. The compound of claim 27, wherein R5is CrCg alkoxy.

29. The compound of claim 28, wherein R5is methoxy.

30. The compound of claim 28, wherein R5is ethoxy.31 . The compound of claim 1, wherein R5is taken together with R6and the intervening atoms to form a5- or 6-membered heterocyclyl.

32. The compound of claim 31 , wherein R5is taken together with R6and the intervening atoms to form a 5-membered heterocyclyl.

33. The compound of claim 32, wherein R5is taken together with R6and the intervening atoms to form a furanyl or dihydrofuranyl.

34. The compound of claim 1 , wherein R6is H.

35. The compound of claim 1 , R6is taken together with R5and the intervening atoms to form a 5- or6-membered heterocyclyl.

36. The compound of claim 1, having the structure of Formula (II):

37. The compound of claim 36, wherein n is 1 .

38. The compound of claim 36, wherein n is 2.

39. The compound of claim 36, wherein n is 0.

40. The compound of claim 36, wherein R2is C^Cg alkoxy.41 . The compound of claim 40, wherein R2is methoxy.

42. The compound of claim 40, wherein R2is ethoxy.

43. The compound of claim 36, wherein R4is Br, F, Cl, I.

44. The compound of claim 43, wherein R4is Br.

45. The compound of claim 36, wherein R4is C^Cg alkyl.

46. The compound of claim 45, wherein R4is methyl.

47. The compound of claim 45, wherein R4is ethyl.

48. The compound of claim 45, wherein R4is n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl.

49. The compound of claim 36, wherein R4is CrCg alkylthio.

50. The compound of claim 49, wherein R4is methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, sec-butylthio, isobutylthio, or tert-butylthio.51 . The compound of claim 36, wherein R4is CrCg haloalkylthio.

52. The compound of claim 51 , wherein R4is trifluoromethylthio, 2-fl uoroethylthio, 2, 2-difl uoroethylthio,2, 2, 2-trifl uoroethylthio, 3-fluoropropylthio, or 4-fluorobutylthio.

53. The compound of claim 36, wherein R4is C2-C8alkenylthio.

54. The compound of claim 53, wherein R4is allylthio or methallylthio.

55. The compound of claim 36, wherein R4is CN.

56. The compound of claim 36, wherein R5is C^Cg alkoxy.

57. The compound of claim 56, wherein R5is methoxy.

58. The compound of claim 56, wherein R5is ethoxy.

59. The compound of claim 1, having the structure of Formula (III):

60. The compound of claim 59, wherein n is 1 .61 . The compound of claim 59, wherein n is 2.

62. The compound of claim 59, wherein n is 0.

63. The compound of claim 59, wherein R4is Br, F, Cl, I.

64. The compound of claim 63, wherein R4is Br.

65. The compound of claim 59, wherein R4is CrC6alkyl.

66. The compound of claim 65, wherein R4is methyl.

67. The compound of claim 65, wherein R4is ethyl.

68. The compound of claim 65, wherein R4is n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl.

69. The compound of claim 59, wherein R4is C^Cg alkylthio.

70. The compound of claim 69, wherein R4is methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, sec-butylthio, isobutylthio, or tert-butylthio.71 . The compound of claim 59, wherein R4is C^Cg haloalkylthio.

72. The compound of claim 71 , wherein R4is trifluoromethylthio, 2-fl uoroethylthio, 2, 2-difl uoroethylthio,2, 2, 2-trifl uoroethylthio, 3-fluoropropylthio, or 4-fluorobutylthio.

73. The compound of claim 59, wherein R4is C2-C8alkenylthio.

74. The compound of claim 73, wherein R4is allylthio or methallylthio.

75. The compound of claim 59, wherein R4is CN.

76. The compound of claim 1, having S-stereochemistry.

77. The compound of claim 1, having R-stereochemistry.

78. A selected from Table 1 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or isotopic derivative thereof.

79. The compound of claim 78, having the structure of:

80. The compound of claim 78, having the structure of:

82. The compound of claim 78, having S-stereochemistry.

83. The compound of claim 78, having R-stereochemistry.

84. A pharmaceutical composition comprising the compound of any of claims 1-83, or a pharmaceutically acceptable salt, stereoisomer, isotopolog, or solvate thereof, and one or more pharmaceutically acceptable excipients.

85. The pharmaceutical composition of claim 84, formulated for oral, mucosal, rectal, transdermal, subcutaneous, intravenous, intramuscular, inhaled, or intranasal administration.

86. The pharmaceutical composition of claim 84, in unit dosage form.

87. A method of treating a medical condition in a subject, comprising administering to the subject the compound of any of claims 1 -83.

88. The method of claim 87, wherein the medical condition is a neurodegenerative disease.

89. The method of claim 88, wherein the neurodegenerative disease is a neurodegenerative movement disorder.

90. The method of claim 89, wherein the neurodegenerative movement disorder is Parkinson’s disease, amyotrophic lateral sclerosis, multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, and Huntington’s disease.91 . The method of claim 88, wherein the neurodegenerative disease is Alzheimer’s disease, Lewy body dementia, frontotemporal dementia.

92. The method of claim 87, wherein the medical condition is a hormone-related neurological or cognitive disorder.

93. The method of claim 92, wherein the hormone-related neurological or cognitive disorder is menopause-associated cognitive disturbance, menopausal depression, climacteric-related mood disorder, or postpartum depression.

94. The method of claim 87, wherein the medical condition is a pain disorder.

95. The method of claim 94, wherein the pain disorder is chronic migraine, cluster headache, trigeminal neuralgia, fibromyalgia, or a neuropathic pain disorder.

96. The method of claim 87, wherein the medical condition is caused by a neurological injury.

97. The method of claim 96, wherein the neurological injury is ischemic stroke, traumatic brain injury, and spinal cord injury.

98. The compound of any of claims 1 -83, or a pharmaceutically acceptable salt, stereoisomer, solvate, or isotopic derivative thereof, for use in treating a medical condition.

99. The compound of any of claims 1 -83, or a pharmaceutically acceptable salt, stereoisomer, solvate, or isotopic derivative thereof, for the manufacture of a medicament for treating a medical condition.

100. Use of the compound of any of claims 1-83, or a pharmaceutically acceptable salt, stereoisomer, solvate, or isotopic derivative thereof, for treating a medical condition.

101. The pharmaceutical composition of any of claims 84-86 for use in treating a medical condition.

102. The pharmaceutical composition of any of claims 84-86 for the manufacture of a medicament for treating a medical condition.

103. Use of the pharmaceutical composition of any of claims 84-86 for treating a medical condition.

104. A method of manufacturing a compound having the structure of Formula (I),wherein: n is 1 , 2, or 0;R2is CrC6alkoxy or H, or R2is taken together with R3and the intervening atoms to form a 5- or 6-membered heterocyclyl;R3is H, or R3or taken together with R2and the intervening atoms to form a 5- or 6-membered heterocyclyl;R4is Br, F, Cl, I, CrC6alkyl, C2-C8alkenyl, C2-C8alkynyl, CrC6alkoxy, CrC6alkylthio, C3-C6cycloalkylthio, C2-C8alkenylthio, CrC6haloalkylthio, CrC6haloalkyl, CrC6haloalkoxy, C3-C8cycloalkyl, CrC6alkylene-C3-C8cycloalkyl, 4- to 8-membered heterocycloalkyl, CN, NO2, NH2, or H;R5is CrC6alkoxy or H, or R5is taken together with R6and the intervening atoms to form a 5- or 6-membered heterocyclyl; andR6is H, or R6is taken together with R5and the intervening atoms to form a 5- or 6-membered heterocyclyl; or a pharmaceutically acceptable salt, stereoisomer, solvate, or isotopic derivative thereof.

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