WO2024259242A1

WO2024259242A1 - 5-ht2a receptor modulators and methods of use thereof

Info

Publication number: WO2024259242A1
Application number: PCT/US2024/034021
Authority: WO
Inventors: Paul Galatsis; Urjita H. SHAH
Original assignee: Transneural Therapeutics Inc
Current assignee: Transneural Therapeutics Inc
Priority date: 2023-06-16
Filing date: 2024-06-14
Publication date: 2024-12-19
Anticipated expiration: 2025-12-16

Abstract

The disclosure provides compounds, e.g., compounds of Formula I, and their use in treating medical diseases or disorders, such as psychiatric and neurological disorders. Pharmaceutical compositions and methods of making various tetrahydropyridine and piperidine compounds are provided. The compounds are contemplated to be modulators of the 5 -hydroxy tryptamine 2A (5- HT2A) receptor.

Description

5-HT2A RECEPTOR MODULATORS AND METHODS OF USE THEREOF

Cross-Reference to Related Applications

[0001] This application claims priority to U.S. Provisional Application No. 63/508,573, filed on June 16, 2023; the disclosure of which is incorporated herein by reference.

Background

[0002] Modulators of the 5-hydroxytryptamine 2A receptor (5-HT2AR) are sought after as potential pharmaceuticals for a variety of psychiatric and neurological diseases and disorders including, but not limited to, depression, anxiety, post-traumatic stress disorder, obsessive compulsive disorder, substance abuse, eating disorders, migraine headaches, and/or cluster headaches, Alzheimer’s Disease, Parkinson’s Disease, and various somatic illnesses including, but not limited to, various inflammatory, cardiovascular, and/or pain disorders. Although many 5- HT2AR modulators have been developed, few are selective for this receptor over related subtypes, for example, the 5-HT2B receptor, a toxicology anti-target strongly implicated in serious side effects including drug-induced valvular heart disease.

[0003] Thus, there is a need for the development of safe and effective compounds that are 5- HT2A receptor modulators, for example, modulators that demonstrate selective functionality for, and/or binding to, the 5-HT2A receptor over the 5-HT2B receptor.

Summary

[0004] The disclosure is directed, in part, to modulators of the 5-hydroxytryptamine 2A (5- HT2A) receptor. Also disclosed herein are pharmaceutical compositions comprising at least one disclosed compound and a pharmaceutically acceptable carrier.

[0005] For example, disclosed herein is a compound represented by Formula I:

or a pharmaceutically acceptable salt and/or a stereoisomer thereof, wherein single bond, X is CR^X, and Y is C(R^Y)2; or double bond, X is C, and Y is C(R^Y); A is selected from the group consisting of 8-10 membered fused bicyclic heteroaryl, 12-14 membered fused tricyclic heteroaryl, and 8-10 membered fused bicyclic heterocyclyl; wherein ring A may be substituted on one or more substituents selected from R^A;

R^A is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, -NR^aR^b, -C(O)-NR^aR^h, -Ci-Cs alkyl, -C3 Ce cycloalkyl, Ci-Ce alkoxy, 4-7 membered heterocyclyl, and 5-6 membered heteroaryl; wherein Ci-Ce alkyl, -C3-C6 cycloalkyl, Ci-Ce alkoxy, heterocyclyl, and heteroaryl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, -NR^aR^b, -C(O)-NR^aR^b, and C1-C3 alkoxy;

R^x and R^Yare each independently selected from the group consisting of hydrogen and -Ci- C3 alkyl; or R^x and R' are joined together to form -CH2-;

R¹ is selected from the group consisting of hydrogen, Ci-Ce alkyl, and -CH2-phenyl; wherein Ci-Ce alkyl and phenyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and C1.C3 alkoxy;

R² and R³ are each independently selected from the group consisting of hydrogen and Ci- Ce alkyl;

R⁴ and R⁵ are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, Ci-Ce alkyl, and Ci-Ce alkoxy; wherein Ci-Ce alkyl and Ci-Ce alkoxy may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and C1-C3 alkoxy;

R⁶ and R⁷ are each independently selected from the group consisting of hydrogen and Ci- Ce alkyl; and

R^a and R^b are each independently selected from the group consisting of hydrogen and Ci- Ce alkyl.

[0006] Also disclosed herein is a compound represented by Formula IIA or Formula IIB:

or a pharmaceutically acceptable salt and/or a stereoisomer thereof, wherein A is selected from the group consisting of:

X, Y, and Z are selected from the group consisting of NR^C, O, and S;

R^a, R^b, R^c, and R^d are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, 5-9 membered heterocyclyl, and -C1-C3 alkyl; wherein -C1.C3 alkyl may optionally be substituted by hydroxyl, halogen, -NH2, and -C(0)NH2;

R¹ is selected from the group consisting of hydrogen, -C1-C3 alkyl, and -CH2-phenyl, wherein phenyl may optionally be substituted by hydroxyl;

R² and R³ are each independently selected from the group consisting of hydrogen and - CH3; and

R⁴ and R⁵ are each independently selected from the group consisting of hydrogen and - CH₃.

[0007] Further disclosed herein are pharmaceutical compositions comprising at least one compound of the disclosure and at least one pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical compositions comprise at least one additional therapeutic agent that treats, ameliorates, and/or prevents a neurological disease and/or disorder.

[0008] In another embodiment, provided herein are methods of ameliorating, and/or preventing a neurological disease or disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of any of the compounds described herein, or a pharmaceutical composition thereof. In certain embodiments, the neurological disease or disorder is selected from the group consisting of, for example, depression, anxiety, substance abuse, and headache.

[0009] Also disclosed herein are methods of selectively modulating the 5-hydroxytryptamine 2A (5-HT2A) receptor in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.

Detailed Description [0010] The features and other details of the disclosure will now be more particularly described. Before further description of the present disclosure, certain terms employed in the specification, examples and appended claims are collected here. These definitions should be read in light of the remainder of the disclosure and as understood by a person of skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art.

[0011] Definitions

[0012] The term “treating” includes any effect, e.g., lessening, reducing, modulating, or eliminating, that results in the improvement of the condition, disease, disorder and the like.

[0013] The term “alkyl” as used herein refers to a saturated straight or branched hydrocarbon. Exemplary alkyl groups include, but are not limited to, straight or branched hydrocarbons of 1-6, 1-4, or 1-3 carbon atoms, referred to herein as Ci-6 alkyl, Ci-4 alkyl, and C1-3 alkyl, respectively. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl- 1-butyl, 3-methyl-2-butyl, 2-methyl-l -pentyl, 3 -methyl- 1 -pentyl, 4-methyl-l -pentyl, 2-methyl-2- pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l -butyl, 3,3-dimethyl-l-butyl, 2- ethyl-l-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.

[0014] The term “alkenyl” as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond. Exemplary alkenyl groups include, but are not limited to, a straight or branched group of 2-6 or 3-4 carbon atoms, referred to herein as C1-C5 alkenyl, C2-C6 alkenyl, and C3-C4 alkenyl, respectively. Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, etc.

[0015] The term “alkynyl” as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond. Exemplary alkynyl groups include, but are not limited to, straight or branched groups of 2-6, or 3-6 carbon atoms, referred to herein as C2-6 alkynyl, and C3-6 alkynyl, respectively. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, etc.

[0016] The term “alkoxy” as used herein refers to a straight or branched alkyl group attached to oxygen (alkyl-O-). Exemplary alkoxy groups include, but are not limited to, alkoxy groups of 1-6 or 2-6 carbon atoms, referred to herein as C1-C5 alkoxy, Ci-Ce alkoxy, and C2-C6 alkoxy, respectively. Exemplary alkoxy groups include, but are not limited to methoxy, ethoxy, isopropoxy, etc. [0017] The term “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 p electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“Ce-i4 aryl”). In some embodiments, an aryl group has six ring carbon atoms (“Ce aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“Cio aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“Cu aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Particularly, aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Examples of representative substituted aryls include the following

wherein one of R⁵⁶ and R⁵⁷ may be hydrogen and at least one of R⁵⁶ and R⁵⁷ is each independently selected from Ci-Cs alkyl, Ci-Cs haloalkyl, 4-10 membered heterocyclyl, alkanoyl, Ci-Cs alkoxy, heteroaryl oxy, alkylamino, arylamino, heteroarylamino, NR⁵⁸COR⁵⁹, NR⁵⁸SOR⁵⁹ NR^SCER³⁹, COOalkyl, COOaryl, CONR⁵⁸R⁵⁹, CONR⁵⁸OR⁵⁹, NR⁵⁸R⁵⁹, SO₂NR⁵⁸R⁵⁹, S-alkyl, SOalkyl, SCEalkyl, Saryl, SOaryl, SCharyl; or R⁵⁶ and R³⁷may be joined to form a cyclic ring (saturated or unsaturated) from 5 to 8 atoms, optionally containing one or more heteroatoms selected from the group N, O, or S. R⁶⁰ and R⁶¹ are each independently hydrogen, Ci-Cs alkyl, C1-C4 haloalkyl, C3- C10 cycloalkyl, 4-10 membered heterocyclyl, Ce-Cio aryl, substituted Ce-Cio aryl, 5-10 membered heteroaryl, or substituted 5-10 membered heteroaryl.

[0018] The term “carbonyl” as used herein refers to the radical -C(O)-.

[0019] The term “cyano” as used herein refers to the radical -CN. [0020] The terms “cycloalkyl” or a “carbocyclic group” as used herein refers to a saturated or partially unsaturated hydrocarbon group of, for example, 3-6, or 4-6 carbons, referred to herein as C3-C10 cycloalkyl, C3-6 cycloalkyl or C4-6 cycloalkyl, respectively. Exemplary cycloalkyl groups include, but are not limited to, cyclohexyl, cyclopentyl, cyclopentenyl, cyclobutyl, or cyclopropyl.

[0021] The terms “halo” or “halogen” as used herein refer to F, Cl, Br, or I.

[0022] The terms “haloalkyl” as used herein refers to an alkyl radical in which the alkyl group is substituted with one or more halogens. Typical haloalkyl groups include, but are not limited to, trifluoromethyl (i.e., CF3), difluoromethyl, fluoromethyl, chloromethyl, dichloromethyl, dibromoethyl, tribromomethyl, tetrafluoroethyl, and the like. Exemplary haloalkyl groups include, but are not limited to, straight or branched hydrocarbons of 1-6, 1-4, or 1-3 carbon atoms substituted with a halogen (i.e., Cl, F, Br, and I), referred to herein as C1-6 haloalkyl, C1.4 haloalkyl, and C1-3 haloalkyl, respectively.

[0023] The term “hetero” when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g., heteroalkyl, cycloalkyl, e.g., heterocyclyl, aryl, e.g., heteroaryl, cycloalkenyl, e.g., cycloheteroalkenyl, and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms.

[0024] The terms “heteroaryl” or “heteroaromatic group” as used herein refers to an aromatic 5-10 membered ring system containing one or more heteroatoms, for example one to three heteroatoms, such as nitrogen, oxygen, and sulfur. The term may also be used to refer to a 5-7 membered monocyclic heteroaryl or an 8-10 membered bicyclic heteroaryl. Where possible, said heteroaryl ring may be linked to the adjacent radical though carbon or nitrogen. Examples of heteroaryl rings include but are not limited to furan, thiophene, pyrrole, pyrrolopyridine, indole, thiazole, oxazole, isothiazole, isoxazole, imidazole, benzoimidazole, imidazopyridine, pyrazole, triazole, pyridine or pyrimidine, etc.

[0025] The terms “heterocyclyl,” “heterocycle,” or “heterocyclic group” are art-recognized and refer to saturated or partially unsaturated 4-10 membered ring structures, whose ring structures include one to three heteroatoms, such as nitrogen, oxygen, and sulfur. Where possible, heterocyclyl rings may be linked to the adjacent radical through carbon or nitrogen. The term may also be used to refer to 4-10 membered saturated or partially unsaturated ring structures that are bridged, fused or spirocyclic ring structures, whose ring structures include one to three heteroatoms, such as nitrogen, oxygen, and sulfur. Examples of heterocyclyl groups include, but are not limited to, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, oxetane, azetidine, tetrahydrofuran, dihydrofuran, dihydropyran, tetrahydropyran, etc. In some embodiments, the heterocycle is a spiro heterocycle (e.g., 2,8-diazaspiro[4.5]decane). In some embodiments, the heterocycle is a bridged heterocycle (e.g., octahydro-lH-4,7-methanoisoindole). "Spiro heterocyclyl," or “spiro heterocycle” refers to a polycyclic heterocyclyl with rings connected through one common atom (called a spiro atom), wherein the rings have one or more heteroatoms selected from the group consisting of N, O, and S(O)_m (wherein m is an integer of 0 to 2) as ring atoms.

[0026] The terms “hydroxy” and “hydroxyl” as used herein refer to the radical -OH.

[0027] The term “oxo” as used herein refers to the radical =0.

[0028] “Pharmaceutically or pharmacologically acceptable” include molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate. For human administration, preparations should meet sterility, pyrogenicity, and general safety and purity standards as required by FDA Office of Biologies standards.

[0029] The term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” as used herein refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.

[0030] The term “pharmaceutical composition” as used herein refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.

[0031] ‘Individual,” “patient,” or “subject” are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans. The compounds of the disclosure can be administered to a mammal, such as a human, but can also be administered to other mammals such as an animal in need of veterinary treatment, e.g., domestic animals (e.g., dogs, cats, and the like), farm animals (e g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like). “Modulation” includes antagonism (e.g., inhibition), inverse agonism, agonism, biased agonism, biased signal transduction, functionally selective agonism, partial antagonism and/or partial agonism.

[0032] In the present specification, the term “therapeutically effective amount” means the amount of the subject compound that will elicit the biological or medical response of a tissue, system or animal, (e.g., mammal or human) that is being sought by the researcher, veterinarian, medical doctor or other clinician. The compounds of the disclosure are administered in therapeutically effective amounts to treat a disease. Alternatively, a therapeutically effective amount of a compound is the quantity required to achieve a desired therapeutic and/or prophylactic effect.

[0033] The term "pharmaceutically acceptable salt(s)" as used herein refers to salts of acidic or basic groups that may be present in compounds used in the compositions. Compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including, but not limited to, malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, /?-toluenesulfonate and pamoate (i.e., l,l'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Compounds included in the present compositions that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, particularly calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts. Compounds included in the present compositions that include a basic or acidic moiety may also form pharmaceutically acceptable salts with various amino acids. The compounds of the disclosure may contain both acidic and basic groups; for example, one amino and one carboxylic acid group. In such a case, the compound can exist as an acid addition salt, a zwitterion, or a base salt. [0034] The compounds of the disclosure may contain one or more chiral centers and, therefore, exist as stereoisomers. The term “stereoisomers” when used herein consist of all enantiomers or diastereomers. These compounds may be designated by the symbols “(+),”

“R” or “S,” depending on the configuration of substituents around the stereogenic carbon atom, but the skilled artisan will recognize that a structure may denote a chiral center implicitly. The present disclosure encompasses various stereoisomers of these compounds and mixtures thereof. Mixtures of enantiomers or diastereomers may be designated “(±)” in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly.

[0035] The compounds of the disclosure may contain one or more double bonds and, therefore, exist as geometric isomers resulting from the arrangement of substituents around a carbon-carbon double bond. The symbol — denotes a bond that may be a single, double or triple bond as described herein. Substituents around a carbon-carbon double bond are designated as being in the “Z” or “E” configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the “E” and “Z” isomers. Substituents around a carbon-carbon double bond alternatively can be referred to as “cis” or “trans,” where “cis” represents substituents on the same side of the double bond and “trans” represents substituents on opposite sides of the double bond.

[0036] Compounds of the disclosure may contain a carbocyclic or heterocyclic ring and therefore, exist as geometric isomers resulting from the arrangement of substituents around the ring. The arrangement of substituents around a carbocyclic or heterocyclic ring are designated as being in the “Z” or “E” configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting carbocyclic or heterocyclic rings encompass both “Z” and “E” isomers. Substituents around a carbocyclic or heterocyclic rings may also be referred to as “cis” or “trans”, where the term “cis” represents substituents on the same side of the plane of the ring and the term “trans” represents substituents on opposite sides of the plane of the ring. Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are designated “cis/trans

[0037] Individual enantiomers and diastereomers of compounds of the present disclosure can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) salt formation employing an optically active resolving agent, (3) direct separation of the mixture of optical enantiomers on chiral liquid chromatographic columns or (4) kinetic resolution using stereoselective chemical or enzymatic reagents. Racemic mixtures can also be resolved into their component enantiomers by well-known methods, such as chiral-phase liquid chromatography or crystallizing the compound in a chiral solvent. Stereoselective syntheses, a chemical or enzymatic reaction in which a single reactant forms an unequal mixture of stereoisomers during the creation of a new stereocenter or during the transformation of a preexisting one, are well known in the art. Stereoselective syntheses encompass both enantio- and diastereoselective transformations and may involve the use of chiral auxiliaries. For examples, see Carreira and Kvaemo, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.

[0038] The compounds disclosed herein can exist in solvated as well as unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the disclosure embrace both solvated and unsolvated forms. In one embodiment, the compound is amorphous. In one embodiment, the compound is a single polymorph. In another embodiment, the compound is a mixture of polymorphs. In another embodiment, the compound is in a crystalline form.

[0039] The disclosure also embraces isotopically labeled compounds of the disclosure which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷0, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶C1, respectively. For example, a compound of the disclosure may have one or more H atom replaced with deuterium.

[0040] Certain isotopically labeled disclosed compounds (e.g., those labeled with ³H and ¹⁴C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., ³H) and carbon- 14 (i.e., ¹⁴C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., ²H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Isotopically labeled compounds of the disclosure can generally be prepared by following procedures analogous to those disclosed in the examples herein by substituting an isotopically labeled reagent for a non- isotopically labeled reagent.

[0041] The term “prodrug” refers to compounds that are transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable salt, hydrate, or solvate of the compound. The transformation may occur by various mechanisms (such as by esterase, amidase, phosphatase, oxidative and or reductive metabolism) in various locations (such as in the intestinal lumen or upon transit of the intestine, blood or liver). Prodrugs are well known in the art (for example, see Rautio, Kumpulainen, et al., Nature Reviews Drug Discovery 2008, 7, 255). For example, if a compound of the disclosure or a pharmaceutically acceptable salt, hydrate or solvate of the compound contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as (Ci-s)alkyl, (C2- i2)alkyl carbonyl oxymethyl, l-(alkylcarbonyloxy)ethyl having from 4 to 9 carbon atoms, 1 -methyl - l-(alkylcarbonyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxy carbonyloxymethyl having from 3 to 6 carbon atoms, 1 -(alkoxy carbonyloxy )ethyl having from 4 to 7 carbon atoms, 1-methyl- 1 -(alkoxycarbonyl oxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, l-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(Ci-2)alkylamino(C2- а)alkyl (such as P-dimethylaminoethyl), carbarn oyl-(Ci-2)alkyl, N,N-di(Ci-2)alkylcarbamoyl-(Ci- 2)alkyl and piperidino-, pyrrolidine-, or morpholino(C2-3)alkyl.

[0042] Similarly, if a compound of the disclosure contains an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as (Ci-6)alkylcarbonyloxymethyl, l-((Ci-6)alkylcarbonyloxy)ethyl, l-methyl-l-((Ci- б)alkylcarbonyloxy)ethyl (Ci-e)alkoxycarbonyl oxymethyl, N-(Ci-6)alkoxycarbonylaminomethyl, succinoyl, (Ci-6)alkylcarbonyl, a-amino(Ci-4)alkylcarbonyl, arylalkylcarbonyl and a- aminoalkylcarbonyl, or a-aminoalkylcarbonyl-a-aminoalkylcarbonyl, where each a- aminoalkylcarbonyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH)2, -P(O)(O(Ci-6)alkyl)2 or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate).

[0043] If a compound of the disclosure incorporates an amine functional group, a prodrug can be formed, for example, by creation of an amide or carbamate, an N-alkylcarbonyloxyalkyl derivative, an (oxodioxolenyl)methyl derivative, an N-Mannich base, imine or enamine. In addition, a secondary amine can be metabolically cleaved to generate a bioactive primary amine, or a tertiary amine can metabolically cleaved to generate a bioactive primary or secondary amine. For examples, see Simplicio, et al., Molecules 2008, 13, 519 and references therein.

[0044] Compounds

[0045] The disclosure is directed to, in part, to compounds that are modulators of the 5- hydroxytryptamine 2A (5-HT2A) receptor. In some embodiments, the modulators of the disclosure exhibit selective functionality for, and/or binding to, the 5-HT2A receptor over the 5- HT2B and/or 5-HT2C receptor. In certain embodiments, compounds of the disclosure can be used to treat a variety of neurological diseases and disorders including, but not limited to, depression, anxiety, substance abuse, migraine headaches, and/or cluster headaches.

[0046] For example, disclosed herein is a compound represented by Formula I:

or a pharmaceutically acceptable salt and/or a stereoisomer thereof, wherein single bond, X is CR^X, and Y is C(R )2; or ' is a double bond, X is C, and Y is C(R^Y);

A is selected from the group consisting of 8-10 membered fused bicyclic heteroaryl, 12-14 membered fused tricyclic heteroaryl; and 8-10 membered fused bicyclic heterocyclyl; wherein ring A may be substituted on one or more substituents selected from R^A;

R^A is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, -NR^aR^b, -C(O)-NR^aR^b, -Ci-Cs alkyl, -C3-C6 cycloalkyl, Ci-Ce alkoxy, 4-7 membered heterocyclyl, and 5-6 membered heteroaryl; wherein Ci-Ce alkyl, -C3-C6 cycloalkyl, Ci-Ce alkoxy, heterocyclyl, and heteroaryl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, -NR^aR^b, -C(O)-NR^aR^b, and C1-C3 alkoxy;

R^x and R^Yare each independently selected from the group consisting of hydrogen and -Ci- C3 alkyl; or R^x and R^Y are joined together to form -CH2-; R¹ is selected from the group consisting of hydrogen, Ci-Cg alkyl, and -CH2-phenyl; wherein Ci-Ce alkyl and phenyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and C1-C3 alkoxy;

R⁶ and R⁷ are each independently selected from the group consisting of hydrogen and Cn Ce alkyl; and

[0047] In some embodiments, each R^x and R^Y are hydrogen. For example, in certain embodiments a compound disclosed herein is represented by:

[0048] In other embodiments, R⁶ and R⁷are hydrogen. For example, in certain embodiments a compound disclosed herein is represented by:

[0049] In some embodiments, for example, A is selected from the group consisting of

R^c is selected from the group consisting of hydrogen and C1-C3 alkyl;

R^d is selected from the group consisting of halogen, hydroxyl, cyano, -C1.C3 alkyl, -C1-C3 alkoxy, -C3-C4 cycloalkyl, 4-6 membered heterocyclyl, and 5-6 membered heteroaryl; wherein - C1-C3 alkyl may optionally be substituted by one, two, or three substituents each independently selected from the group consisting of halogen, hydroxyl, -NH2, -C(0)-NH2, and -OCH3;

R^e is selected from the group consisting of hydrogen, halogen, cyano, and -C1.C3 alkyl; and m is 0, 1, 2, or 3.

[0050] In other embodiments, for example, R^c is selected from the group consisting of hydrogen and C1-C3 alkyl; R^d is selected from the group consisting of halogen, hydroxyl, cyano, - CH2OH, -CH2NH2, -CH₂C(O)NH₂, -CH2CH2OH, -CH2CH2NH2, furanyl, and pyrrolidinyl; and R^e is selected from the group consisting of hydrogen, halogen, cyano, and -C1-C3 alkyl.

[0051] In further embodiments, A is selected from the group consisting of, for example,

[0052] In some embodiments, R² and R³ are each independently selected from the group consisting of hydrogen and -CH3. In other embodiments, R² and R³ are each hydrogen. In still other embodiments, R² and R³ are each -CH3. In further embodiments, R² is hydrogen and R³ is - CH3. In some embodiments, R⁴ and R⁵ are each independently selected from the group consisting of hydrogen and -CH3. In other embodiments, R⁴ and R⁵ are each hydrogen. In still other embodiments, R⁴ and R⁵ are each -CH3 In further embodiments, R⁴ is hydrogen and R^? is -CH3. In some embodiments, R¹ is hydrogen. In certain embodiments, R¹ is selected from the group consistin g of hydrogen,

[0053] Also disclosed herein is a compound represented by Formula IIA or Formula IIB:

or a pharmaceutically acceptable salt and/or a stereoisomer thereof, wherein

A is selected from the group consisting of

X, Y, and Z are selected from the group consisting of NR^C, O, and S;

R^a, R^b, R^c, and R^d are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, 5-9 membered heterocyclyl, and -C1-C3 alkyl; wherein -C1.C3 alkyl may optionally be substituted by hydroxyl, halogen, -NH2, and -C(O)NH2;

R¹ is selected from the group consisting of hydrogen, -C1-C3 alkyl, and -CFB-phenyl, wherein phenyl may optionally be substituted by hydroxyl;

[0054] In some embodiments, the compound is a compound identified in Table 1 below or a pharmaceutically acceptable salt thereof. Table 1. Exemplary compounds.

[0055] Procedures for making compounds described herein are provided in the examples below. In the reactions described below, it may be necessary to protect reactive functional groups (such as hydroxyl, amino, thio, or carboxyl groups) to avoid their unwanted participation in the reactions. The incorporation of such groups, and the methods required to introduce and remove them are known to those skilled in the art (for example, see Greene, Wuts, Protective Groups in Organic Synthesis. 2nd Ed. (1999)). The deprotection step may be the final step in the synthesis such that the removal of protecting groups affords compounds as disclosed herein. Starting materials used in the following scheme can be purchased or prepared by methods described in the chemical literature, or by adaptations thereof, using methods known by those skilled in the art. The order in which the steps are performed can vary depending on the groups introduced and the reagents used, but would be apparent to those skilled in the art.

[0056] Compounds disclosed herein, or any of the intermediates described in the schemes above, can be further derivatized by using one or more standard synthetic methods known to those skilled in the art. Such methods can involve substitution, oxidation or reduction reactions. These methods can also be used to obtain or modify disclosed compounds or any preceding intermediates by modifying, introducing or removing appropriate functional groups. [0057] Where it is desired to obtain a particular enantiomer of a disclosed compound, this may be produced from a corresponding mixture of enantiomers by employing any suitable conventional procedure for resolving enantiomers known to those skilled in the art. For example, diastereomeric derivatives (such as salts) can be produced by reaction of a mixture of enantiomers of a disclosed compound (such a racemate) and an appropriate chiral compound (such as a chiral base). The diastereomers can then be separated by any conventional means such as crystallization or chromatography, and the desired enantiomer recovered (such as by treatment with an acid in the instance where the diastereomer is a salt). Alternatively, a racemic mixture of esters can be resolved by kinetic hydrolysis using a variety of biocatalysts (for example, see Patel Stereoselective Biocatalysts, Marcel Decker; New York 2000).

[0058] In another resolution process a racemate of disclosed compounds can be separated using chiral High Performance Liquid Chromatography. Alternatively, a particular enantiomer can be obtained by using an appropriate chiral intermediate in one of the processes described above. Chromatography, recrystallisation and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular geometric isomer of the disclosure.

[0059] In an alternative embodiment, disclosed compounds may also comprise one or more isotopic substitutions. For example, hydrogen may be ²H (D or deuterium) or ³H (T or tritium); carbon may be, for example, ¹³C or ¹⁴C; oxygen may be, for example, ¹⁸O; nitrogen may be, for example, ¹⁵N, and the like. In other embodiments, a particular isotope (e.g., ³H, ¹³C, ¹⁴C, ¹⁸O, or ¹⁵N) can represent at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9% of the total isotopic abundance of an element that occupies a specific site of the compound.

[0060] Methods

[0061] Another aspect of the disclosure provides methods of treating patients suffering from a neurological disease or disorder. In particular, in certain embodiments, the disclosure provides a method of treating the below medical indications comprising administering to a patient in need thereof a therapeutically effective amount of a compound described herein. [0062] For example, provided herein is a method of treating a neurological disease or disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, e.g., a compound of Formula I or Formula II. Also provided herein is a method of treating a neurological disease or disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising a compound disclosed herein, e g., a compound of Formula I or Formula II, and a pharmaceutically acceptable excipient.

[0063] Non-limiting examples of a neurological disease or disorder include depression, anxiety, substance abuse, and headaches. Headaches that can be treated with the methods herein include, but are not limited to, migraine headaches and cluster headaches.

[0064] For example, in some embodiments the methods described herein may include treating a depressive disorder in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, or a pharmaceutical composition thereof. In some embodiments, the depressive disorder may be major depressive disorder. In other embodiments, the depressive disorder may include treatment resistant depressions.

[0065] In certain embodiments, the methods described herein may include treating an anxiety disorder in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, or a pharmaceutical composition thereof. In some embodiments, the anxiety disorder may be generalized anxiety disorder. In other embodiments, the anxiety disorder may be social anxiety disorder.

[0066] In further embodiments, the methods described herein may include treating a trauma and/or stress disorder in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, or a pharmaceutical composition thereof. In some embodiments, such a disorder may be post-traumatic stress disorder. In other embodiments, such a disorder may be an adjustment disorder.

[0067] In certain embodiments, the methods described herein may include treating obsessive compulsive disorder, for example, body dysmorphic disorder, in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.

[0068] In other embodiments, the methods described herein may include treating an eating disorder in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, or a pharmaceutical composition thereof. In some embodiments, the eating disorder may be anorexia. In other embodiments, the eating disorder may be bulimia.

[0069] In still further embodiments, the methods described herein may include treating a sleep-wake disorder, for example, insomnia, in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.

[0070] In some embodiments, the methods described herein may include treating a psychotic disorder, for example, insomnia, in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, or a pharmaceutical composition thereof. In some embodiments, the psychotic disorder may be schizophrenia. In other embodiments, the psychotic disorder may be schizoaffective disorder. In still other embodiments, the psychotic disorder may be schizotypal personality disorder.

[0071] In certain embodiments, the methods described herein may include treating substance-related disorders and/or addictive disorders in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, or a pharmaceutical composition thereof. In some embodiments, such a disorder may be alcohol use disorder. In other embodiments, such a disorder may be opioid use disorder. In still other embodiments, such a disorder may be tobacco use disorder. For example, in some embodiments a compound disclosed herein may be useful in facilitating smoking cessation.

[0072] In certain other embodiments, the methods described herein may include treating a neurocognitive disorder in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, or a pharmaceutical composition thereof. In some embodiments, the neurocognitive disorder may include those due to a primary neurodegenerative disease, for example, Alzheimer’s disease or Parkinson’s disease.

[0073] In some embodiments, the methods described herein may include treating a personality disorder in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, or a pharmaceutical composition thereof. In other embodiments, the methods described herein may include treating an autism spectrum disorder in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, or a pharmaceutical composition thereof. [0074] In further embodiments, the methods described herein may include treating a bipolar disorder in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, or a pharmaceutical composition thereof. In some embodiments, the bipolar disorder may be bipolar I disorder. In other embodiments, the bipolar disorder may be bipolar II disorder.

[0075] In other embodiments, the methods described herein may include treating a pain disorder in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, or a pharmaceutical composition thereof. In some embodiments, the pain disorder may be neuropathic pain. In other embodiments, the pain disorder may be migraine. In still other embodiments, the pain disorder may be cluster headache. In further embodiments, the pain disorder may be trigeminal neuralgia. In still further embodiments, the pain disorder may be cancer pain. In certain embodiments, the pain disorder may be regional pain disorder. In yet other embodiments, the pain disorder may be phantom limb pain. In some embodiments, a contemplated pain disorder may be a chronic pain.

[0076] In certain embodiments, a compound disclosed herein, e.g., a compound of Formula I or Formula II, may exhibit anxiolytic, anti -depressive, and anti-drug abuse actions, without exhibiting substantial psychedelic actions, for example, hallucinogenic actions. For example, a contemplated (5-HT2A) receptor modulator of the present disclosure may confer anti-depressant like activities without incurring psychedelic drug-like actions. For example, in some embodiments, a compound disclosed herein may be safe an effective for use in a method described herein, yet lack the hallucinogenic effects of known psychedelics such as, for example, DMT and psilocybin.

[0077] This disclosure also provides a method of selectively modulating the 5- hydroxytryptamine 2A (5-HT2A) receptor. The method includes administering to a patient a compound disclosed herein, e.g., a compound of Formula I or Formula II, a pharmaceutically acceptable salt and/or stereoisomer thereof, wherein the compound selectively modulates the 5- HT2A over the 5-HT2B and/or 5-HT2C receptor. The method of selectively modulating the 5- HT2A receptor can be used to treat, ameliorate, and/or prevent diseases or disorders that are affected by, associated with, or would benefit from selective modulation at the 5-HT2A receptor. In selectively modulating the 5-HT2A receptor over the 5-HT2B and/or 5-HT2C receptor, the method provides, for example, reduced side effects such as, but not limited to, drug-induced valvular heart disease associated with modulating the 5-HT2B receptor.

[0078] In certain embodiments, a method described herein further comprises administering to the patient an additional therapeutic agent that treats a neurological disease or disorder, or that treats a disease or disorder that is affected by, associated with, or would benefit from selective modulation at the 5-HT2A receptor.

[0079] Contemplated patients include not only humans, but other animals such as companion animals (e.g., dogs, cats), domestic animals (e.g., cow, swine), and wild animals (e.g., monkeys, bats, snakes).

[0080] Compounds described herein can be administered in combination with one or more additional therapeutic agents to treat a disorder described herein. For clarity, contemplated herein are both a fixed composition comprising a disclosed compound and another therapeutic agent such as disclosed herein, and methods of administering, separately a disclosed compound and a disclosed therapeutic. For example, provided in the present disclosure is a pharmaceutical composition comprising a compound described herein, one or more additional therapeutic agents, and a pharmaceutically acceptable excipient. In some embodiments, a disclosed compound and one additional therapeutic agent is administered. In some embodiments, a disclosed compound as defined herein and two additional therapeutic agents are administered. In some embodiments, a disclosed compound as defined herein and three additional therapeutic agents are administered. Combination therapy can be achieved by administering two or more therapeutic agents, each of which is formulated and administered separately. For example, a disclosed compound and an additional therapeutic agent can be formulated and administered separately. Combination therapy can also be achieved by administering two or more therapeutic agents in a single formulation, for example a pharmaceutical composition comprising a disclosed compound as one therapeutic agent and one or more additional therapeutic agents. For example, a disclosed compound and an additional therapeutic agent can be administered in a single formulation. Other combinations are also encompassed by combination therapy. While the two or more agents in the combination therapy can be administered simultaneously, they need not be. For example, administration of a first agent (or combination of agents) can precede administration of a second agent (or combination of agents) by minutes, hours, days, or weeks. Thus, the two or more agents can be administered within minutes of each other or within 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours of each other or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14 days of each other or within 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks of each other. In some cases, even longer intervals are possible. While in many cases it is desirable that the two or more agents used in a combination therapy be present within the patient's body at the same time, this need not be so.

[0081] Combination therapy can also include two or more administrations of one or more of the agents used in the combination using different sequencing of the component agents. For example, if agent X and agent Y are used in a combination, one could administer them sequentially in any combination one or more times, e.g., in the order X-Y-X, X-X-Y, Y-X-Y, Y-Y-X, X-X-Y- Y, etc.

[0082] For example, the methods described herein include administering to the patient a therapeutically effective amount of at least one compound of Formula I or Formula II, as described herein, which is optionally formulated in a pharmaceutical composition. In various embodiments, a therapeutically effective amount of at least one compound described herein, e.g., a compound of Formula I or Formula II, present in a pharmaceutical composition is the only therapeutically active compound in a pharmaceutical composition. In certain embodiments, the method further comprises administering to the patient an additional therapeutic agent that treats a neurological disease or disorder or that treats a disease or disorder that is affected by, associated with, or would benefit from selective modulation at the 5-HT2A receptor.

[0083] For example, in some embodiments the methods described herein can include administering to the patient one or more additional therapeutic agents in combination with a compound disclosed herein. In certain embodiments, the one or more additional therapeutics agents that may be administered in combination with a compound disclosed herein may be a selective serotonin reuptake inhibitor (SSRI). In some embodiments, the selective serotonin reuptake inhibitor may be selected from the group consisting of, for example, fluoxetine, paroxetine, sertraline, citalopram and escitalopram. In other embodiments, the one or more additional therapeutics agents may be a serotonin and norepinephrine reuptake inhibitor (SNRI). For example, the serotonin and norepinephrine reuptake inhibitor may be selected from the group consisting of, e.g., duloxetine, venlafaxine, desvenlafaxine, and levomilnacipran. In still other embodiments, the one or more additional therapeutics agents may be selected from the group consisting of, for example, trazodone, mirtazapine, vortioxetine, vilazodone and bupropion. In certain embodiments, the one or more additional therapeutics agents may be a tricyclic antidepressant. For example, in some embodiments the tricyclic antidepressant may be selected from the group consisting of, e.g., imipramine, nortriptyline, amitriptyline, doxepin and desipramine. In further embodiments, the one or more additional therapeutics agents may be a monoamine oxidase inhibitor (MAOI). For example, in some embodiments the monoamine oxidase inhibitor may be selected from the group consisting of, e.g., tranylcypromine, phenelzine and isocarboxazid. In other embodiments, the one or more additional therapeutics agents may be, for example, a lithium compound, e.g., a lithium salt, e.g., lithium carbonate, lithium acetate, lithium sulfate, lithium citrate, lithium orotate, or lithium gluconate. In some embodiments, the one or more additional therapeutics agents may be, for example, ketamine or esketamine. In certain embodiments, the one or more additional therapeutics agents may be, for example, dextromethorphan. In other embodiments, the one or more additional therapeutics agents may be, for example, D-methadone.

[0084] In some embodiments, administering the compound(s) described herein to the patient allows for administering a lower dose of the additional therapeutic agent as compared to the dose of the additional therapeutic agent alone that is required to achieve similar results in treating, ameliorating, and/or preventing a neurological disease or disorder or in treating, ameliorating, and/or preventing a disease or disorder that is affected by, associated with, or would benefit from selective modulation at the 5-HT2A receptor in the patient. For example, in certain embodiments, the compound(s) described herein enhance(s) the activity of the additional therapeutic compound, thereby allowing for a lower dose of the additional therapeutic compound to provide the same effect.

[0085] In particular, in certain embodiments, the disclosure provides a method of treating the above medical indications comprising administering a subject in need thereof a therapeutically effective amount of a compound described herein, e.g., a compound of Formula I or Formula II. [0086] Pharmaceutical Compositions and Kits

[0087] Another aspect of the disclosure provides pharmaceutical compositions comprising compounds as disclosed herein formulated together with a pharmaceutically acceptable carrier. In particular, the present disclosure provides pharmaceutical compositions comprising compounds as disclosed herein formulated together with one or more pharmaceutically acceptable carriers. These formulations include those suitable for oral, rectal, topical, intranasal, buccal, parenteral (e g., subcutaneous, intramuscular, intradermal, or intravenous) rectal, vaginal, or aerosol administration, although the most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used. For example, disclosed compositions may be formulated as a unit dose, and/or may be formulated for oral or subcutaneous administration.

[0088] Exemplary pharmaceutical compositions of this disclosure may be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains one or more of the compound of the disclosure, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral applications. The active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the disease.

[0089] For preparing solid compositions such as tablets, the principal active ingredient may be mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as com starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the disclosure, or a non-toxic pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

[0090] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the subject composition is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fdlers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0091] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent. Tablets, and other solid dosage forms, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceuticalformulating art.

[0092] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the subject composition, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof.

[0093] Suspensions, in addition to the subject composition, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0094] Formulations for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing a subject composition with one or more suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the body cavity and release the active agent.

[0095] Dosage forms for transdermal administration of a subject composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active component may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.

[0096] The ointments, pastes, creams and gels may contain, in addition to a subject composition, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0097] Powders and sprays may contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays may additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane. [0098] Compositions and compounds of the present disclosure may alternatively be administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound. A non-aqueous (e.g., fluorocarbon propellant) suspension could be used. Sonic nebulizers may be used because they minimize exposing the agent to shear, which may result in degradation of the compounds contained in the subject compositions. Ordinarily, an aqueous aerosol is made by formulating an aqueous solution or suspension of a subject composition together with conventional pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers vary with the requirements of the particular subject composition, but typically include non-ionic surfactants (Tweens®, Pluronics®, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols. Aerosols generally are prepared from isotonic solutions.

[0099] Pharmaceutical compositions of this disclosure suitable for parenteral administration comprise a subject composition in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[00100] Examples of suitable aqueous and non-aqueous carriers which may be employed in the pharmaceutical compositions of the disclosure include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate and cyclodextrins. Proper fluidity may be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[00101] In another aspect, the disclosure provides enteral pharmaceutical formulations including a disclosed compound and an enteric material, and a pharmaceutically acceptable carrier or excipient thereof. Enteric materials refer to polymers that are substantially insoluble in the acidic environment of the stomach, and that are predominantly soluble in intestinal fluids at specific pHs. The small intestine is the part of the gastrointestinal tract (gut) between the stomach and the large intestine, and includes the duodenumjejunum, and ileum. The pH of the duodenum is about 5.5, the pH of the jejunum is about 6.5 and the pH of the distal ileum is about 7.5. Accordingly, enteric materials are not soluble, for example, until a pH of about 5.0, of about 5.2, of about 5.4, of about 5.6, of about 5.8, of about 6.0, of about 6.2, of about 6.4, of about 6.6, of about 6.8, of about 7.0, of about 7.2, of about 7.4, of about 7.6, of about 7.8, of about 8.0, of about 8.2, of about 8.4, of about 8.6, of about 8.8, of about 9.0, of about 9.2, of about 9.4, of about 9.6, of about 9.8, or of about 10.0. Exemplary enteric materials include cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate, cellulose acetate maleate, cellulose acetate butyrate, cellulose acetate propionate, copolymer of methylmethacrylic acid and methyl methacrylate, copolymer of methyl acrylate, methylmethacrylate and methacrylic acid, copolymer of methylvinyl ether and maleic anhydride (Gantrez ES series), ethyl methyacrylate- methylmethacrylate-chlorotrimethylammonium ethyl acrylate copolymer, natural resins such as zein, shellac and copal collophorium, and several commercially available enteric dispersion systems (e. g. , Eudragit L30D55, Eudragit FS30D, Eudragit L100, Eudragit S100, Kollicoat EMM30D, Estacryl 30D, Coateric, and Aquateric). The solubility of each of the above materials is either known or is readily determinable in vitro. The foregoing is a list of possible materials, but one of skill in the art with the benefit of the disclosure would recognize that it is not comprehensive and that there are other enteric materials that would meet the objectives of the present disclosure.

[00102] The disclosure also provides kits for use by, e.g., a consumer in need of treatment of a disease or disorder described herein. Such kits include a suitable dosage form such as those described above and instructions describing the method of using such dosage form to mediate, reduce or prevent inflammation. The instructions would direct the consumer or medical personnel to administer the dosage form according to administration modes known to those skilled in the art. Such kits could advantageously be packaged and sold in single or multiple kit units. An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. Preferably the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.

[00103] It may be desirable to provide a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested. Another example of such a memory aid is a calendar printed on the card, e.g., as follows “First Week, Monday, Tuesday, . . . etc. . . . Second Week, Monday, Tuesday, . . etc. Other variations of memory aids will be readily apparent. A “daily dose” can be a single tablet or capsule or several pills or capsules to be taken on a given day. Also, a daily dose of a first compound can consist of one tablet or capsule while a daily dose of the second compound can consist of several tablets or capsules and vice versa. The memory aid should reflect this.

[00104] Exemplary Embodiments of the Invention

[00105] El. A compound represented by Formula I:

or a pharmaceutically acceptable salt and/or a stereoisomer thereof, wherein

X i_s a single bond, X is CR^X, and Y is C(R^A)2; or

X is a double bond, X is C, and Y is C(R^Y);

A is selected from the group consisting of 8-10 membered fused bicyclic heteroaryl, 12-14 membered fused tricyclic heteroaryl, and 8-10 membered fused bicyclic heterocyclyl; wherein ring A may be substituted on one or more substituents selected from R^A;

R^A is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, -NR^aR^b, -C(O)-NR^aR^b, -Ci-Ce alkyl, -C3-C6 cycloalkyl, Ci-Ce aCe alkoxy, 4-7 membered heterocyclyl, and 5-6 membered heteroaryl; wherein Ci-Ce aCe alkyl, -C3-C6 cycloalkyl, Ci-Ce aCe alkoxy, heterocyclyl, and heteroaryl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, -NR^aR^b, -C(O)-NR^aR^b, and C1-C3 alkoxy;

R^x and R^Y are each independently selected from the group consisting of hydrogen and -Ci- C3 alkyl; or R^x and R^Y are joined together to form -CH2-;

R¹ is selected from the group consisting of hydrogen, Ci-Ce aCe alkyl, and -CH2-phenyl; wherein Ci-Ce alkyl and phenyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and C1.C3 alkoxy;

R⁴ and R⁵ are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, Ci-Ce alkyl, and Ci-Ce alkoxy; wherein Ci-Ce alkyl and Ci-Ce alkoxy may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and C1-C3 alkoxy; R⁶ and R⁷ are each independently selected from the group consisting of hydrogen and Ci- C , alkyl; and

[00106] E2. The compound of El, wherein each R^x and R are hydrogen.

[00107] E3. The compound of El or E2, wherein the compound is represented by:

[00108] E4. The compound of any one of E1-E3, wherein R⁶ and R⁷ are hydrogen.

[00109] E5. The compound of any one of E1-E4, wherein the compound is represented by:

[00110] E6. The compound of any one of E1-E5, wherein A is selected from the group consisting of

R^c is selected from the group consisting of hydrogen and C1-C3 alkyl;

R^d is selected from the group consisting of halogen, hydroxyl, cyano, -C1-C3 alkyl, C1-C3 alkoxy, -C3-C4 cycloalkyl, 4-6 membered heterocyclyl, and 5-6 membered heteroaryl; wherein - C1-C3 alkyl may optionally be substituted by one, two, or three substituents each independently selected from the group consisting of halogen, hydroxyl, -NH2, -C(0)-NH2, and -OCH3;

[00111] E7. The compound of E6, wherein:

R^c is selected from the group consisting of hydrogen and C1.C3 alkyl;

R^d is selected from the group consisting of halogen, hydroxyl, cyano, -CH2OH, -CH2NH2, -CH2C(O)NH2, -CH2CH2OH, -CH2CH2NH2, furanyl, and pyrrolidinyl; and

R^e is selected from the group consisting of hydrogen, halogen, cyano, and -C1-C3 alkyl. [00112] E8. The compound of any one of E1-E7, wherein A is selected from the group consisting of

[00113] E9. The compound of any one of E1-E8, wherein R² and R³ are each independently selected from the group consisting of hydrogen and -CH3.

[00114] E10. The compound of any one of E1-E9, wherein R² and R³ are each hydrogen.

[00115] El l. The compound of any one of E1-E9, wherein R² and R³ are each -CH3

[00116] E12. The compound of any one of E1-E9, wherein R² is hydrogen and R³ is -CH3. [00117] E13. The compound of any one of El -El 2, wherein R⁴ and R³ are each independently selected from the group consisting of hydrogen and -CH3.

[00118] E14. The compound of any one of E1-E13, wherein R⁴ and R⁵ are each hydrogen.

[00119] El 5. The compound of any one of El -El 3 wherein R⁴ and R³ are each -CH3.

[00120] E16. The compound of any one of E1-E13, wherein R⁴ is hydrogen and R³ is -CH3.

[00121] E17. The compound of any one of E1-E16, wherein R¹ is selected from the group consisting of hydrogen,

[00122] E18. The compound of any one of E1-E16, wherein R¹ is hydrogen.

[00123] E19. A compound represented by Formula IIA or Formula IIB:

or a pharmaceutically acceptable salt and/or a stereoisomer thereof, wherein

A is selected from the group consisting of:

X, Y, and Z are selected from the group consisting of NR^C, O, and S;

R^a, R^b, R^c, and R^d are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, 5-9 membered heterocyclyl, and -C1.C3 alkyl; wherein -C1.C3 alkyl may optionally be substituted by hydroxyl, halogen, -NH2, and -C(O)NH2;

R¹ is selected from the group consisting of hydrogen, -C1-C3 alkyl, and -CFE-phenyl, wherein phenyl may optionally be substituted by hydroxyl;

R⁴ and R³ are each independently selected from the group consisting of hydrogen and -CH3. [00124] E20. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt and/or stereoisomer thereof.

[00125] E21. A pharmaceutical composition comprising a compound of any one of E1-E20 and a pharmaceutically acceptable excipient.

[00126] E22. A method of treating a psychiatric or neurological disease or disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of any one of E1-E20.

[00127] E23. A method of treating a psychiatric or neurological disease or disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising a compound of any one of E1-E20 and a pharmaceutically acceptable excipient.

[00128] E24. The method of E22 or E23, wherein the psychiatric or neurological disease or disorder is selected from the group consisting of depression, anxiety, substance abuse, and headache.

Examples

[00129] The compounds described herein can be prepared in a number of ways based on the teachings contained herein and synthetic procedures known in the art. In the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be chosen to be the conditions standard for that reaction, unless otherwise indicated. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule should be compatible with the reagents and reactions proposed. Substituents not compatible with the reaction conditions will be apparent to one skilled in the art, and alternate methods are therefore indicated. The starting materials for the examples are either commercially available or are readily prepared by standard methods from known materials.

[00130] General Information

[00131] Reagents and solvents were received from commercial sources without further purification unless specified or prepared by literature methods. ’H NMR and ¹³C NMR spectra were recorded on a 300 or 400 MHz Bruker spectrometer, using DMSO-t/g, CDCI3 or CD3OD as the solvent with tetramethylsilane (TMS) as the internal standard at room temperature. Chemical shifts were given in § relative to TMS, the coupling constants J were given in Hz. LCMS analytical method and instruments were generated using one of the following methods. Detection was performed by UV (254 nm) and ELSD for all methods.

[00132] Method A (LCMS 17,41,42,50,52)

[00133] Experiments were performed on a SHIMADZU® 20A HPLC with a C18-reverse- phase column (30 x 3.0 mm Express C18, 2.7pm particle size), elution with solvent A: Water / 0.1%FA; solvent B: Acetonitrile/0.07%FA:

Gradient - Time flow ml/min %A %B

0.01 1.5 95 5

1.20 1.5 0 100

1.80 1.5 0 100

1.82 1.5 95 5

2.00 1.5 95 5

[00134] Method B (LCMS 17,41,42,47, 50,52)

[00135] Experiments were performed on a SHIMADZU® 20A HPLC with a C18-reverse- phase column (30 x 3.0 mm Express C18, 2.7pm particle size), elution with solvent A: Water / 0.1%FA; solvent B: Acetonitrile/0.07%FA: Gradient - Time flow ml/min %A %B

0.01 1.5 95 5

0.70 1.5 0 100

1.10 1.5 0 100

1.12 1.5 95 5

1.20 1.5 95 5

[00136] Method C (LCMS25)

[00137] Experiments were performed on a SHIMADZU® 20A HPLC with a C18-reverse- phase column (50 x 3.0 mm Kinetex® EVO Cl 8, 2.6pm particle size), elution with solvent A:

Water / (5mmol/L) NH4HCO3; solvent B: Acetonitrile:

Gradient - Time flow ml/min %A %B

0.01 1.2 90 10

1.20 1.2 5 95

1.80 1.2 5 95

1.82 1.2 90 10

2.00 1.2 90 10

[00138] Method D (LCMS25)

[00139] Experiments were performed on a SHIMADZU® 20A HPLC with a C18-reverse- phase column (50 x 3.0 mm Kinetex® EVO Cl 8, 2.6pm particle size), elution with solvent A: Water / (5mmol/L) NH4HCO3; solvent B: Acetonitrile:

Gradient - Time flow ml/min %A %B

0.01 1.2 90 10

2.00 1.2 5 95

2.70 1.2 5 95

2.75 1.2 90 10

3.00 1.2 90 10

[00140] Method E (LCMS40)

[00141] Experiments were performed on a SHIMADZU® 20A HPLC with a C18-reverse- phase column (30 x 3.0 mm Express C18, 2.7pm particle size), elution with solvent A: Water /

0.05%TFA; solvent B: Acetonitrile/0.05%TFA:

Gradient - Time flow ml/min %A %B

0.01 1.5 95 5 1.20 1.5 0 100

1.80 1.5 0 100

1.82 1.5 95 5

2.00 1.5 95 5

[00142] Method F (LCMS45 )

[00143] Experiments were performed on a SHIMADZU® 20A HPLC with a C18-reverse- phase column (50 x 3.0 mm Poroshell HPH-C18,2.7pm particle size), elution with solvent A: Water / 0.04%NH4H20; solvent B: Acetonitrile:

Gradient - Time flow ml/min %A %B

0.01 1.2 90 10

1.20 1.2 5 95

1.80 1.2 5 95

1.82 1.2 90 10

2.00 1.2 90 10

[00144] Method G (LCMS45)

[00145] Experiments were performed on a SHIMADZU® 20A HPLC with a C18-reverse- phase column (50 x 3.0 mm Poroshell HPH-C18,2.7pm particle size), elution with solvent A:

Water / 0.04%NH4H20; solvent B: Acetonitrile:

Gradient - Time flow ml/min %A %B

0.01 1.2 90 10

2.00 1.2 5 95

2.70 1.2 5 95

2.75 1.2 90 10

3.00 1.2 90 10

[00146] Method H (LCMS46,48)

[00147] Experiments were performed on a SHIMADZU® 20A HPLC with a C18-reverse- phase column (50 x 3.0 mm Poroshell HPH-C18,4.0pm particle size), elution with solvent A: Water / (5mmol/L) NH4HCO3; solvent B: Acetonitrile:

Gradient - Time flow ml/min %A %B

0.01 1.5 90 10

2.00 1.5 5 95

2.70 1.5 5 95 2.75 1.5 90 10

3.00 1.5 90 10

[00148] Method I (LCMS46,48)

[00149] Experiments were performed on a SHIMADZU® 20 A HPLC with a C18-reverse- phase column (50 x 3.0 mm Poroshell HPH-C18,4.0pm particle size), elution with solvent A: Water / (5mmol/L) NH4HCO3; solvent B: Acetonitrile:

Gradient - Time flow ml/min %A %B

0.01 1.5 90 10

1.20 1.5 5 95

1.80 1.5 5 95

1.82 1.5 90 10

2.00 1.5 90 10

[00150] Method J (LCMS49)

[00151] Experiments were performed on a SHIMADZU® 20A HPLC with a C18-reverse- phase column (30 x 2.0 mm Poroshell 120 EC-C18, 1.9pm particle size), elution with solvent A:

Water / 0.1% FA; solvent B: Acetonitrile/0.07% FA:

Gradient - Time flow ml/min %A %B

0.01 1.5 95 5

1.20 1.5 0 100

1.80 1.5 0 100

1.82 1.5 95 5

2.00 1.5 95 5

[00152] Method K (LCMS49)

[00153] Experiments were performed on a SHIMADZU® 20A HPLC with a C18-reverse- phase column (30 x 2.0 mm Poroshell 120 EC-C18, 1.9pm particle size), elution with solvent A:

Water / 0.1% FA; solvent B: Acetonitrile/0.07% FA:

Gradient - Time flow ml/min %A %B

0.01 1.5 95 5

0.70 1.5 0 100

1.10 1.5 0 100

1.12 1.5 95 5

1.20 1.5 95 5 [00154] Method L (LCMS51,53)

[00155] Experiments were performed on a SHIMADZU® 20A HPLC with a C18-reverse- phase column (50 x 3.0 mm Kinetex® EVO-C18, 2.6pm particle size), elution with solvent A: Water / (5mmol/L) NH4HCO3; solvent B: Acetonitrile/ Acetonitrile:

Gradient - Time flow ml/min %A %B

0.01 1.2 90 10

2.00 1.2 5 95

2.70 1.2 5 95

2.75 1.2 90 10

3.00 1.2 90 10

[00156] Method M (LCMS51,53)

[00157] Experiments were performed on a SHIMADZU® 20A HPLC with a C18-reverse- phase column (50 x 3.0 mm Kinetex® EVO-C18, 2.6pm particle size), elution with solvent A: Water 5mM Nl l-fl lCO?; solvent B: Acetonitrile/ Acetonitrile:

Gradient - Time flow ml/min %A %B

0.01 1.2 90 10

1.20 1.2 5 95

1.80 1.2 5 95

1.82 1.2 90 10

2.00 1.2 90 10

[00158] Method N (LCMS60)

[00159] Experiments were performed on a SHIMADZU® 20A HPLC with a C18-reverse- phase column (30 x 3.0 mm Agilent EC-C 18, 1.9pm particle size), elution with solvent A: Water / 0.1%FA; solvent B: Acetonitrile/0.07%FA:

Gradient - Time flow ml/min %A %B

0.01 1.5 95 5

1.20 1.5 0 100

1.80 1.5 0 100

1.82 1.5 95 5

2.00 1.5 95 5

[00160] Method O (LCMS61) [00161] Experiments were performed on a SHIMADZU® 20A HPLC with a C18-reverse- phase column (30 x 2.0 mm Gemini NX-C18, 3.0pm particle size), elution with solvent A: (5mmol/L) NH4HCO3; solvent B: Acetonitrile:

Gradient - Time flow ml/min %A %B

0.01 1.2 90 10

1.20 1.2 5 95

1.80 1.2 5 95

1.82 1.2 90 10

2.00 1.2 90 10

[00162] Method P (LCMS63)

[00163] Experiments were performed on a SHIMADZU® 20A HPLC with a C18-reverse- phase column (30 x 3.0 mm Halo C18, 100 A, 2.0 pm particle size), elution with solvent A: Water

/ 0.05%TFA; solvent B: Acetonitrile/0.05%TFA:

Gradient - Time flow ml/min %A %B

0.01 1.5 95 5

1.20 1.5 0 100

1.80 1.5 0 100

1.82 1.5 95 5

2.00 1.5 95 5

[00164] Method 0 (LCMS63)

[00165] Experiments were performed on a SHIMADZU® 20A HPLC with a C18-reverse- phase column (30 x 3.0 mm Halo C18, 100 A, 2.0 pm particle size), elution with solvent A: Water

/ 0.05%TFA; solvent B: Acetonitrile/0.05%TFA:

Gradient - Time flow ml/min %A %B

0.01 1.5 95 5

0.70 1.5 0 100

1.10 1.5 0 100

1.12 1.5 95 5

1.20 1.5 95 5

[00166] Example 1: Synthesis of 4-(benzofuran-3-yl)piperidine (Compound 117)

[00167] tert-butyl 4-(benzofuran-3-yl)-3, 6-dihydropyridine-l (2H)-carboxylate. A mixture of 3 -bromo- 1 -benzofuran (1.00 g, 5.07 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)-3,6-dihydro-27/-pyridine-l-carboxylate (3.14 g, 10.2 mmol), Pd(dppf)Ch (742 mg, 1.01 mmol) and K2CO3 (2.10 g, 15.2 mmol) in 1,4-dioxane (10 mL) and H2O (2 mL) was stirred for 2 h at 80°C under an N2 atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by chromatography (SiCh) eluting with PE/EA (10:1) to afford the desired product as an off-white solid (750 mg; 49 % yield). LCMS 45 (Method G) (ESI) ) C18H21NO3 calcd 299. 15; found [M + H] ⁺: 300.

[00168] tert-butyl 4-(benzofuran-3-yl)piperidine-l-carboxylate. A solution of Zc/7-butyl 4-(l- benzofuran-3-yl)-3,6-dihydro-2//-pyri dine- 1 -carboxylate (700 mg, 2.33 mmol) and Pd/C (100 mg) in MeOH (10 mL) was stirred overnight at rt under a H2 atmosphere. The reaction mixture was filtered, the filter cake washed with MeOH (3 x 10 mL) and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE/EA (6: 1) to afford the desired product as an off-white solid (520 mg, 74 % yield). LCMS 45 (Method G) (ESI) C18H23NO3 calcd 301.17; found [M + H] ⁺: 302.

[00169] 4-(benzofuran-3-yl)piperidine. To a stirred solution of tert-butyl 4-(l-benzofuran-3- yl)piperidine-l-carboxylate (530 mg, 1.75 mmol) in DCM (10 mL) was added TFA (5 mL) at rt. The reaction mixture was stirring for 15 min before being concentrated under reduced pressure. The residue was purified by chromatography (conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 20 min; detector, UV 254 nm) to afford the desired product as a white solid (271 mg, 74.8 % yield). LCMS 45 (Method G) (ESI) ) C13H15NO calcd 201.12; found [M + H] ⁺: 202. ‘H NMR (400 MHz, DMSO- ) 5 8.40 (s, 1H), 7.81 (s, 1H), 7.76 (d, J= 7.6 Hz, 1H), 7.56 (d, J= 8. 1 Hz, 1H), 7.41 - 7.23 (m, 2H), 3.28 (d, J= 12.0 Hz, 2H), 3.17 - 2.83 (m, 3H), 2.06 (d, J= 13.6 Hz, 2H), 1.96 - 1.68 (m, 2H).

[00170] Example 2: Synthesis of 3-(piperidin-4-yl)-l-benzofuran-5-ol (Compound 118)

[00171] 3-bromo-5-methoxybenzofuran. To a solution of 5-methoxy-benzofuran (5.0 g, 33.8 mmol) inDCM (50 mL) at 0°C under N2 atmosphere was added Br2 (5.39 g, 33.8 mmol) dropwise. The reaction mixture was stirred for 1 h before quenching with 50 mL of sat sodium hyposulfite at 0°C. Then it was extracted with DCM (3 x 50 mL) and the combined organic phase was concentrated under reduced pressure. The residue was purified by chromatography (SiCL) eluting with PE/EA (60: 1) to afford the desired product as a white solid (5.6 g, 73 % yield). GCMS (ESI) C₉H₇BrO₂ cal cd 225.96; found [M+H]⁺: 227.

[00172] Tert-butyl 4-(5-methoxy-l-benzofuran-3-yl)-3,6-dihydro-2H-pyridine-l- carboxylate. A solution of 3 -bromo-5 -methoxy- 1 -benzofuran (4.9 g, 21.6 mmol), Zc/7-butyl 4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2 7-pyridine-l-carboxylate (10.0 g, 32.4 mmol), K2CO3 (8.95 g, 64.7 mmol), and Pd(dppf)C12 (3.16 g, 4.32 mmol) in 1,4-dioxane (18 mL) and H2O (2 mL) was stirred for 2 h at 80 °C under N2 atmosphere. The reaction mixture was then extracted with EtOAc (3 x 100 mL), the combined organic extracts were dried over anhydrous Na2SO4 and the filtrate concentrated under reduced pressure. The residue was purified by chromatography (SiCh) eluting with PE/EA (10: 1) to afford the desired product as a white solid (5.6 g, 79% yield). LCMS 47 (ESI) C19H23NO4 calcd 329.16; found [M+H]⁺: 330.

[00173] tert-butyl 4-(5-methoxy-l-benzofuran-3-yl) piperidine-l-carboxylate. To a stirred solution of /c77-butyl 4-(5-methoxy-l-benzofuran-3-yl)-3,6-dihydro-2//-pyridine-l-carboxylate (5.6 g, 17.0 mmol) in 50 mL ofMeOH was added Pd/C (0.54 g, 5.10 mmol) in portions at rt under an H2 atmosphere. The reaction mixture was stirred for 4 h at rt before being filtered through Celite. The filter cake was washed with MeOH (3 x 100 mL) and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiCh) eluting with PE/EA (12: 1) to afford the desired product as an off-white solid (2.2 g, 39 %yield). LCMS 49 (Method K) (ESI) C19H25NO4 calcd 331.18; found [M+H]⁺: 332.

[00174] 3-(piperidin-4-yl)-l-benzofuran-5-ol. A solution of tert-butyl 4-(5-methoxy-l- benzofuran-3-yl) piperidine-1 -carboxylate (500 mg, 1.51 mmol) in 10 mL of DCM was added BB (1.43 mL, 15.1 mmol) for 2 h at 0 °C under an N2 atmosphere before the reaction mixture was quenched by the addition of water/ice (10.0 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 100 mL), the combined organic extracts dried over anhydrous Na2SC>4, filtered and filtrate was concentrated under reduced pressure. The residue was purified by chromatography (column, C18; mobile phase, MeCN in water (0.1% TFA), 10% to 20% gradient in 20 min; detector, UV 254 nm) to afford the desired product as an off-white solid (139 mg, 40 % yield). LCMS 40 (ESI) C13H15NO2 calcd 217.11; found [M+H]⁺: 218.15. ¹H NMR (400 MHz, DMSO-c >) 8 9.23 (s, 1H), 8.64 (s, 1H), 8.49 (s, 1H), 7.90 (d, J = 2.2 Hz, 1H), 7.25 (dd, J= 8.8, 1.0 Hz, 1H), 7.12 (dd, J= 2.2, 1.0 Hz, 1H), 6.83 (d, J= 8.8 Hz, 1H), 3.52 - 3.35 (m, 3H), 3.04 (q, J = 12.2 Hz, 2H), 2.40 - 2.29 (m, 2H), 1.72 (d, J= 13.8 Hz, 2H).

[00175] Example 3: Synthesis of 3-(piperidin-4-yl)-2,3-dihydrobenzofuran-5-ol

(Compound 121)

[00176] 2-chloro-l-(2-hydroxy-5-methoxyphenyl)ethan-l-one. To a stirred solution of l-(2- hydroxy-5-methoxyphenyl)ethanone (5.00 g, 30.1 mmol) in 20 mL of dichloroethane/methanol (1 : 1) was added benzyl trimethylazanium dichloroiodanuide (16.8 g, 48.1 mmol). The reaction mixture was stirred for 12 h at 70°C before being extracted with dichloromethane (3 x 250 mb). The combined organic extracts were washed with water (1 x 100 mL), dried over anhydrous MgSO4, filtered, and the filtrate concentrated under reduced pressure. The residue was purified chromatography (Si O2) eluting with 20% of ethyl acetate in petroleum ether to afford the desired product as a yellow solid (2.50 g, 41 % yield). LCMS 49 (Method K) (ESI) [M+H]⁺: 201.

[00177] 5-methoxybenzofuran-3(2H)-one. A solution of 2-chloro-l-(2-hydroxy-5- methoxyphenyl)-ethanone (2.50 g, 12.4 mmol) in 20 mL of methanol was added AcONa (1.02 g, 12.4 mmol) was stirred for 3 h at 65 °C. The reaction mixture was extracted with di chloromethane (3 x 250 mL), the combined organic extracts were washed with water (1 x 100 mL), dried over anhydrous MgSCL, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography (SiCh) eluting with 25% of ethyl acetate in petroleum ether to afford the desired product as an off-white solid (0.82 g, 40 % yield). This material was used directly in the next step.

[00178] 5-methoxybenzofuran-3-yl trifluoromethanesulfonate. To a stirred solution of 5- methoxy-2Z7-l-benzofuran-3-one (0.82 g, 4.91 mmol) in 40 mL of dichloromethane was added A-ethyl-A-isopropylpropan-2-amine (1.29 g, 9.91 mmol). The reaction mixture was stirred at rt under N2 for 20 min before slowly adding trifluoromethanesulfonic anhydride (2.11 g, 7.52 mmol). Upon completion of the reaction, it was diluted with 300 mL of water and extracted with dichloromethane (3 x 250 mL), the combined organic extracts were dried over anhydrous MgSCU After filtration, the filtrate was concentrated under reduced pressure and the crude product was purified by chromatography (Si O2) eluting with 30% of ethyl acetate in petroleum ether to afford the desired product as an off-white solid (0.70 g, 47% yield). LCMS 49 (Method K) (ESI) C10H7F3O5S calcd 296.00; found [M+H]⁺: 297.

[00179] tert-butyl 4-(5-methoxybenzofuran-3-yl)-3,6-dihydropyridine-l(2H)-carboxylate. A mixture of 5-methoxy-l-benzofuran-3-yl trifluoromethanesulfonate (0.70 g, 2.41 mmol), tertbutyl 4-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)-3,6-dihydro-2 -pyridine-l -carboxylate (1.10 g, 3.51 mmol), [1,T-Bis(diphenylphosphino)ferrocene]dichloropalladium (0.35 g, 0.52 mmol) and K2CO3 (0.65 g, 4.71 mmol) in 5 mL of dioxane/IUO (4: 1) was stirred for 2 h at 80 °C. Then the mixture diluted with 100 mL of water and extracted with di chloromethane (3 x 100 mL). The combined organic extracts dried over anhydrous MgSCL, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography ( Si O2) eluting with 15% of ethyl acetate in petroleum ether to afford the desired product as a yellow oil (0.42g, 54% yield). LCMS 49 (Method J) (ESI) C19H23NO4 calcd 329.16; found [M+H]⁺: 330.

[00180] tert-butyl 4-(5-methoxy-2,3-dihydrobenzofuran-3-yl)piperidine-l-carboxylate. To a stirred solution of tert-butyl 4-(5-methoxy-l-benzofuran-3-yl)-3,6-dihydro-27/-pyridine-l- carboxylate (0.42 g, 1.31 mmol) in 10 m of MeOH under an N2 atmosphere was added Pd/C (10.0 %, 0.06 g). The mixture was stirred at room temperature for 4 h under balloon of H2 before being filtered and concentrated under reduced pressure. The crude product was purified by HPLC chromatography (column, Cl 8 column; mobile phase, acetonitrile in Water (0.1% NH4HCO3), 40% to 80% gradient in 20 min) to afford the desired product as a colorless oil (0.27 g, 64 % yield). LCMS 47 (ESI) C19H27NO4 calcd 333.19; found [M+H]⁺: 334.

[00181] 3-(piperidin-4-yl)-2,3-dihydrobenzofuran-5-ol. To a stirred solution of /crz-butyl 4- (5-methoxy-2,3-dihydro-l-benzofuran-3-yl)piperidine-l-carboxylate (270.0 mg, 0.81 mmol) in 20 mL of dichloromethane at 0 °C under N2 atmosphere was added BBrs (284.0 mg, 1.10 mmol). The reaction mixture was stirred for 30 min before being quenched by the addition of water/ice (100 mL) at 0 °C. After filtration, the filtrate was concentrated under reduced pressure and the crude product was purified by HPLC chromatography (column, C18 column; mobile phase, acetonitrile in Water (0.1% NH4HCO3), 5% to 30% gradient in 20 min; detector, UV 200 nm) to afford the desired product as a white solid (55.8 mg, 31 %yield). LCMS 63 (Method P) (ESI) C13H17NO2 calcd 219.13; found [M+H]⁺: 220.05. 'H NMR (400 MHz, DMSO-tZ₆) 8 8.63 (d, J = 98.0 Hz, 1H), 6.62 (d, J= 2.5 Hz, 1H), 6.54 - 6.45 (m, 2H), 4.39 - 4.36 (m, 1H), 4.30 - 4.28 (m, 1H), 3.99 (s, 1H), 3.21 (s, 1H), 2.92 (s, 1H), 2.70 - 2.52 (m, 1H), 2.41 (s, 1H), 1.69 - 1.49 (m, 2H), 1.32 (s, 1H), 1.24 - 0.94 (m, 2H).

[00182] Example 4: Synthesis of 4-(2,3-Dihydrobenzofuran-4-yl)piperidine (Compound 123)

[00183] tert-Butyl 4-(2,3-dihydro-l-benzqfuran-4-yl)-3,6-dihydro-2H-pyridine-l- carboxylate. To a solution of 4-bromo-2,3-dihydro-l-benzofuran (300.0 mg, 1.50 mmol), l-(tert- butoxycarbonyl)-3,6-dihydro-2/7-pyridin-4-ylboronic acid (414.5 mg, 1.82 mmol), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (249.0 mg, 0.34 mmol) and K2CO3 (624.1 mg, 4.52 mmol) in 1,4-dioxane (2 ml) and H2O (1 mL) was stirred at 90 °C under an N2 atmosphere for 1 h. The mixture was allowed to cool to room temperature and filtered. The residue was washed with dioxane (5 mL) and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (50% of ethyl acetate in petroleum ether) to afford the desired product as an off-white liquid (250.0 mg, 55.2% yield). LCMS 49 (Method K) (ESI) C18H23NO3 calcd 301.17; Found [M+H]⁺:302. 'H NMR (400 MHz, DMSO-^J 8 7.07 (t, J= 7.8 Hz, 1H), 6.76 (d, J= 7.7 Hz, 1H), 6.67 (d, J= 7.9 Hz, 1H), 5.88 (s, 1H), 4.47 (t, J= 8.6 Hz, 2H), 3.51 (t, J= 5.5 Hz, 2H), 3.34 (s, 2H), 3.21 (t, J= 8.6 Hz, 2H), 2.40 (s, 2H), 1.43 (s, 9H).

[00184] tert-Butyl 4-(2,3-dihydro-l-benzofuran-4-yl)piperidine-l-carboxylate. A solution of te/7-butyl 4-(2, 3 -dihydro- l-benzofuran-4-yl)-3,6-dihydro-27/-pyri dine- 1 -carboxylate (250.0 mg, 0.83 mmol) and Pd/C (50 mg, m/m=20%) in methanol (5 mL) was hydrogenated for 1 h at room temperature. The resulting mixture was filtered and the residue was washed with methanol (5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, Cis silica gel; mobile phase, methanoic acid solution in acetonitrile, 5% to 95% gradient in 20 min; detector, UV 254 nm to afford the desired product as an off-white liquid (225.0 mg, 89.6% yield). LCMS 47 (ESI) C18H25NO3 calcd 303.18; Found [M+H]’:304.

[00185] 4-(2,3-Dihydrobenzofuran-4-yl)piperidine. A solution of tert-butyl 4-(2,3-dihydro-l- benzofuran-4-yl)piperidine-l -carboxylate (225.0 mg, 0.74 mmol) in dichloromethane (2 mL) was treated with HC1 (gas) in 1,4-dioxane (5.0 mb, 4 M)) for 30 min at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, Cis silica gel; mobile phase, ammonia bicarbonate solution in acetonitrile, 5% to 95% gradient in 20 min; detector, UV 254 nm to afford the desired product as a white solid (109.1 mg, 72.3% yield). LCMS 45 (Method G) (ESI) C13H17NO cal cd 203. 13; Found [M+H]⁺: 204.10 'l l NMR (400 MHz, DMSO-t/₆) 87.05 (t, J= 7.8 Hz, 1H), 6.67 (d, J= 7.7 Hz, 1H), 6.60 (d, J= 7.9 Hz, 1H), 4.50 (t, J = 8.7 Hz, 2H), 3.16 (t, J = 8.7 Hz, 4H), 2.77 - 2.63 (m, 3H), 1.80 - 1.52 (m, 4H).

[00186] Example 5: IP1 Accumulation Assay

[00187] The functional activity of disclosed compounds is measured using an IP1 (inositol monophosphate) accumulation assay. The effects of disclosed compounds on IP1 production (a proxy for G_q activation) was measured in HEK 293 cells expressing human serotonin 2A receptors (5-HT2AR) using a Homogeneous Time Resolved Fluorescence (HTRF) assay. Standard protocols are followed. Briefly, a cell suspension and test compound/s is incubated in a standard buffer. Following incubation, the cells are lysed, and the fluorescence acceptor and donor are added. After incubation the fluorescence transfer is measured, and data is analyzed using GraphPad Prism to generate concentration response curves. The results are shown in Table 2, where A = <100; B = 100 to 1000; C = >1000 to 10000; D = >10000; E = inactive; and +++ = >90; ++ = 75 to 90; + = 50 to <75%; - = <50 %; and NC = not calculated.

Table 2.

Incorporation By Reference

[00188] All publications and patents mentioned herein, including those items listed below, are hereby incorporated by reference in their entirety for all purposes as if each individual publication or patent was specifically and individually incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

Equivalents and Scope

[00189] In the claims articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.

[00190] Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular elements and/or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms “comprising” and “containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise. [00191] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the invention can be excluded from any claim, for any reason, whether or not related to the existence of prior art.

[00192] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims.

Claims

The claimed invention is:

1. A compound represented by Formula I:

or a pharmaceutically acceptable salt and/or a stereoisomer thereof, wherein single bond, X is CR^X, and Y is C(R^Y)2; or double bond, X is C, and Y is C(R^Y);

A is selected from the group consisting of 8-10 membered fused bicyclic heteroaryl, 12- 14 membered fused tricyclic heteroaryl, and 8-10 membered fused bicyclic heterocyclyl; wherein ring A may be substituted on one or more substituents selected from R^A;

R^A is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, -NR^aR^b, -C(O)-NR^aR^b, -Ci-Ce alkyl, -C3-C6 cycloalkyl, Ci-Ce alkoxy, 4-7 membered heterocyclyl, and 5-6 membered heteroaryl; wherein Ci-Ce alkyl, -C3-C6 cycloalkyl, Ci-Ce alkoxy, heterocyclyl, and heteroaryl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, -NR^aR^b, -C(O)-NR^aR^b, and C1.C3 alkoxy;

R^x and R^Y are each independently selected from the group consisting of hydrogen and - C1-C3 alkyl; or R^x and R^Y are joined together to form -CH2-;

R¹ is selected from the group consisting of hydrogen, Ci-Ce alkyl, and -CFF-phenyl; wherein Ci-Ce alkyl and phenyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and C1.C3 alkoxy;

R⁴ and R are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, Ci-Ce alkyl, and Ci-Ce alkoxy; wherein Ci-Ce alkyl and Ci-Ce alkoxy may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and C1-C3 alkoxy;

R⁶ and R⁷ are each independently selected from the group consisting of hydrogen and Ci- Ce alkyl; and R^a and R^b are each independently selected from the group consisting of hydrogen and Ci- C , alkyl.

2. The compound of claim 1, wherein each R^x and R^Y are hydrogen.

3. The compound of claim 1 or 2, wherein the compound is represented by:

4. The compound of claim 1 or 2, wherein R⁶ and R⁷are hydrogen.

5. The compound of claim 1 or 2, wherein the compound is represented by:

6. The compound of claim 1 or 2, wherein A is selected from the group consisting of

R^c is selected from the group consisting of hydrogen and C1-C3 alkyl;

R^d is selected from the group consisting of halogen, hydroxyl, cyano, -C1-C3 alkyl, C1.C3 alkoxy, -C3-C4 cycloalkyl, 4-6 membered heterocyclyl, and 5-6 membered heteroaryl; wherein - C1-C3 alkyl may optionally be substituted by one, two, or three substituents each independently selected from the group consisting of halogen, hydroxyl, -NH₂, -C(O)-NH₂, and -OCH3;

R^e is selected from the group consisting of hydrogen, halogen, cyano, and -C1-C3 alkyl; and m is 0, 1, 2, or 3.

7. The compound of claim 6, wherein:

R^c is selected from the group consisting of hydrogen and C1-C3 alkyl;

R^d is selected from the group consisting of halogen, hydroxyl, cyano, -CH2OH, - CH2NH2, -CH₂C(O)NH₂, -CH₂CH₂OH, -CH2CH2NH2, furanyl, and pyrrolidinyl; and

R^e is selected from the group consisting of hydrogen, halogen, cyano, and -C1-C3 alkyl.

8. The compound of claim 1 or 2, wherein A is selected from the group consisting of

9. The compound of claim 1 or 2, wherein R² and R³ are each independently selected from the group consisting of hydrogen and -CH3.

10. The compound of claim 1 or 2, wherein R² and R³ are each hydrogen.

11. The compound of claim 1 or 2, wherein R² and R³ are each -CH3.

12. The compound of claim 1 or 2, wherein R² is hydrogen and R³ is -CH3.

13. The compound of claim 1 or 2, wherein R⁴ and R⁵ are each independently selected from the group consisting of hydrogen and -CH3.

14. The compound of claim 1 or 2, wherein R⁴ and R⁵ are each hydrogen.

15. The compound of claim 1 or 2wherein R⁴ and R⁵ are each -CH3.

16. The compound of claim 1 or 2, wherein R⁴ is hydrogen and R⁵ is -CH3.

17. The compound of claim 1 or 2, wherein R¹ is selected from the group consisting of hydrogen,

18. The compound of claim 1 or 2, wherein R¹ is hydrogen.

19. A compound represented by Formula IIA or Formula IIB :

or a pharmaceutically acceptable salt and/or a stereoisomer thereof, wherein

A is selected from the group consisting of:

X, Y, and Z are selected from the group consisting of NR^C, O, and S;

R^a, R^b, R^c, and R^d are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, 5-9 membered heterocyclyl, and -C1-C3 alkyl; wherein -C1-C3 alkyl may optionally be substituted by hydroxyl, halogen, -NH2, and -C(0)NH2;

R⁴ and R^? are each independently selected from the group consisting of hydrogen and - CH₃.

20. A compound selected from the group consisting of

or a pharmaceutically acceptable salt and/or stereoisomer thereof.

21. A pharmaceutical composition comprising a compound of any one of claims 1, 19, and 20 and a pharmaceutically acceptable excipient.

22. A method of treating a psychiatric or neurological disease or disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1, 19, and 20.

23. A method of treating a psychiatric or neurological disease or disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising a compound of any one of claims 1, 19, and 20 and a pharmaceutically acceptable excipient.

24. The method of claim 22, wherein the psychiatric or neurological disease or disorder is selected from the group consisting of depression, anxiety, substance abuse, and headache.

25. The method of claim 23, wherein the psychiatric or neurological disease or disorder is selected from the group consisting of depression, anxiety, substance abuse, and headache.