WO2024259250A2 - 5-ht2a receptor modulators and methods of use thereof - Google Patents

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 benzisoxazole and benzoisothiazole compounds are provided. The compounds are contemplated to be modulators of the 5-hydroxytryptamine 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. 63/508,569, 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 -hydroxy tryptamine 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^)2; or double bond, X is C, and Y is C(R^Y); W is selected from the group consisting of O, and S;

R^x and R' 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-;

R^A is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, -NR^aR^b, -C(O)-NR^aR^h, -Ci-Cs alkyl, -Cs-C cycloalkyl, Ci-Cg alkoxy, phenyl. 4-7 membered heterocyclyl, and 5-6 membered heteroaryl, wherein Ci-Cg alkyl, -C3-C6 cycloalkyl, Ci-Cg alkoxy, phenyl, 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;

R¹ is selected from the group consisting of hydrogen, Ci-Cg alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C3-C6 cycloalkyl, -CH2-phenyl, -CH2-CH2-phenyl, -CH2-(5-10 membered heteroaryl), and -CH2-(5-10 membered heterocyclyl); wherein Ci-Cg alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C3- Cg cycloalkyl, phenyl, heteroaryl, and heterocyclyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, deuterium, and C1-C3 alkoxy;

R² and R³ are each independently selected from the group consisting of hydrogen and Ci- Cg alkyl; wherein Ci-Cg alkyl, 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, -NR^aR^b; -NR^a-C(O)-NR^aR^b, -CO2H, Ci-Cg alkyl, Ci-Cg alkoxy, and phenyl; wherein Ci- Cg alkyl, Ci.Cg alkoxy and phenyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, -NR^aR^b, and C1-C3 alkoxy;

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

R^a and R^b are each independently selected from the group consisting of hydrogen and Ci- Cg alkyl; and m is 0, 1, 2, or 3.

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

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

X is O or S;

R^A is independently selected for each occurrence from the group consisting of fluoro, chloro, bromo, iodo, hydroxyl, cyano, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -OCH3, - OCH2CH3, -OCH2CH2CH3, -OCH(CH₃)2, -CF₃, -CHF₂, -OCF3, -OCHF2, -CH2OH, -CH2NH2, - CH2C(O)NH2, -CH2CH2OH, -CH2CH2NH2, cyclopropyl, cyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, oxiranyl, azetidinyl, phenyl, triazolyl, and oxadiazolyl; wherein tetrahydropyrrolyl, piperidinyl, piperazinyl, and azetidinyl may optionally be substituted with -CH ;

R² and R³ are each independently selected from the group consisting of hydrogen, hydroxyl, -CH3, -CH₂OH, and -NH-C(O)-N(CH₂CH₃)2;

R¹ is selected from the group consisting of hydrogen, -CH3,

, and m is 0, 1, 2, or 3.

[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-ealkyl, Ci.4alkyl, and Ci-salkyl, 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-1 -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-14 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 (“C10 aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“Ci 4 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, NR^?8SOR⁵⁹ NR^SCER⁵⁹, COO-alkyl, COO-aryl, CONR⁵⁸R⁵⁹, CONR⁵⁸OR⁵⁹, NR⁵⁸R⁵⁹, SO₂NR⁵⁸R⁵⁹, S-alkyl, SO-alkyl, SCE-alkyl, S-aryl, SO-aryl, SCh-aryl; or R³⁶ and R⁵⁷may 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, Cg-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, di chloromethyl, 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, p-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 “£” 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)alkylcarbonyloxymethyl, l-(alkylcarbonyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl- 1 -(alkylcarbonyl oxy)-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 -(alkoxy carbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminom ethyl 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- s)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, 1 -methyl- l-((Ci- 6)alkylcarbonyloxy)ethyl (Ci-6)alkoxycarbonyloxymethyl, N-(Ci.e)alkoxy carbonylaminomethyl, 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(0)(0H)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 double bond, X is C, and Y is C(R^Y);

W is selected from the group consisting of O, and S;

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-;

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, phenyl. 4-7 membered heterocyclyl, and 5-6 membered heteroaryl, wherein Ci-Ce alkyl, -C3-C6 cycloalkyl, Ci-Ce alkoxy, phenyl, 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;

R¹ is selected from the group consisting of hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C3-C6 cycloalkyl, -CH2-phenyl, -CH2-CH2-phenyl, -CH2-(5-10 membered heteroaryl), and -CH2-(5-10 membered heterocyclyl); wherein Ci-Cg alkyl, C2-C6 alkenyl, C2 G5 alkynyl, -C3- Cg cycloalkyl, phenyl, heteroaryl, and heterocyclyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, deuterium, and C1-C3 alkoxy;

R² and R³ are each independently selected from the group consisting of hydrogen and Ci- Cg alkyl; wherein Ci-Cg alkyl, 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, -NR^aR^b; -NR^a-C(O)-NR^aR^b, -CO2H, Ci-Cg alkyl, Ci-Cg alkoxy, and phenyl; wherein Ci. Cg alkyl, Ci-Ce alkoxy and phenyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, -NR^aR^b, and C1-C3 alkoxy;

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

R^a and R^b are each independently selected from the group consisting of hydrogen and Ci- Cg alkyl; and m is 0, 1, 2, or 3.

[0047] In some embodiments, a compound disclosed herein is represented by, for example,

[0048] In some embodiments, R^A is independently selected from each occurrence from the group consisting of fluoro, chloro, bromo, iodo, hydroxyl, cyano, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH₃)₂, -OCH₃, -OCH2CH3, -OCH₂CH₂CH₃, -OCH(CH₃)₂, -CF₃, -CHF₂, -0CF3, -OCHF₂, - CH₂OH, -CH₂NH₂, -CH₂C(O)NH₂, -CH₂CH₂OH, -CH₂CH₂NH₂, cyclopropyl, cyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, oxiranyl, azetidinyl, phenyl, triazolyl, and oxadiazolyl; wherein tetrahydropyrrolyl, piperidinyl, piperazinyl, and azetidinyl may optionally be substituted with -CH3. For example, in certain embodiments R^A is independently selected for each occurrence from the group consisting of fluoro, chloro, iodo, cyano, and -CH3.

[0049] In some embodiments, m is 3.

[0050] For example, in certain embodiments A is selected from the group consisting of

wherein X is O or S.

[0051] In other embodiments, m is 2. For example, in some embodiments A is selected from the group consisting of

wherein X is O or S.

[0052] In further embodiments, m is 1. For example, in some embodiments A is selected from the group consisting of

wherein X is O or S.

[0053] In some embodiments, R² and R³ are hydrogen. In other embodiments, R⁶ and R⁷ are hydrogen. In still other embodiments, R⁴ and R⁵ are each independently selected from the group consisting of hydrogen, hydroxyl, -CH3, -CH₂OH, and -NH-C(O)-N(CH₂CH3)₂. In further embodiments, R⁴ is hydrogen. In some embodiments, for example, R^? is selected from the group consisting of hydrogen, hydroxyl, -CH3, -CH2OH, and -NH-C(O)-N(CH2CH3)2. For example, in certain embodiments R⁵ is hydrogen or -CH3.

[0054] In other embodiments, R¹ is hydrogen. In other embodiments, R¹ is selected from the group consisting of, for example, hydrogen, -CH3,

[0055] Also disclosed herein is a compound represented by Formula IIA, Formula IIB, or Formula IIC: compound represented by Formula IIA, Formula IIB, or Formula IIC:

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

X is O or S;

R^A is independently selected for each occurrence from the group consisting of fluoro, chloro, bromo, iodo, hydroxyl, cyano, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)₂, -OCH3, - OCH2CH3, -OCH2CH2CH3, -OCH(CH₃)₂, -CF₃, -CHF₂, -0CF3, -OCHF₂, -CH₂OH, -CH₂NH₂, - CH2C(O)NH2, -CH2CH2OH, -CH2CH2NH2, cyclopropyl, cyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, oxiranyl, azetidinyl, phenyl, triazolyl, and oxadiazolyl; wherein tetrahydropyrrolyl, piperidinyl, piperazinyl, and azetidinyl may optionally be substituted with -CH3;

R² and R³ are each independently selected from the group consisting of hydrogen, hydroxyl, -CH3, -CH2OH, and -NH-C(O)-N(CH₂CH₃)2;

R¹ is selected from the group consisting of hydrogen, -CH3,

, and m is 0, 1, 2, or 3.

[0056] In some embodiments, R^A is independently selected for each occurrence from the group consisting of, for example, fluoro, chloro, iodo, cyano, and -CH3. In other embodiments, m is 3. In still other embodiments, m is 2. In further embodiments, m is 1. In some embodiments, R⁴ is hydrogen. In certain embodiments, R^? is selected from the group consisting of hydrogen, hydroxyl, -CH3, -CH2OH, and -NH-C(O)-N(CH2CH.3)2. In further embodiments, R⁵ is hydrogen or -CH3. In other embodiments, R¹ is hydrogen.

[0057] In some embodiments, the compound is a compound identified in Table 1 below or a pharmaceutically acceptable salt thereof.

Table 1. Exemplary compounds.

[0058] 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.

[0059] 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.

[0060] 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).

[0061] 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.

[0062] 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.

[0063] Methods

[0064] 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.

[0065] 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.

[0066] 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.

[0067] 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.

[0068] 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.

[0069] 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.

[0070] 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. [0071] 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.

[0072] 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.

[0073] 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.

[0074] 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.

[0075] 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.

[0076] 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.

[0077] 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.

[0078] 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.

[0079] 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.

[0080] 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.

[0081] 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.

[0082] 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).

[0083] 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.

[0084] 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.

[0085] 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.

[0086] 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.

[0087] 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.

[0088] 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. [0089] Pharmaceutical Compositions and Kits

[0090] 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 ., 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.

[0091] 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.

[0092] 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.

[0093] 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) fdlers 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 fillers 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.

[0094] 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.

[0095] 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.

[0096] 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. [0097] 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.

[0098] 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.

[0099] 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.

[00100] 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.

[00101] 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.

[00102] 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.

[00103] 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.

[00104] 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 LI 00, Eudragit SI 00, 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.

[00105] 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.

[00106] 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.

[00107] Exemplary Embodiments of the Invention

[00108] El. A compound represented by Formula I:

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

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

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

W is selected from the group consisting of O, and S;

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-;

R^A is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, -NR^aR^b, -C(O)-NR^aR^b, -Ci-Cg alkyl, -C3-C6 cycloalkyl, Ci-Ce alkoxy, phenyl. 4-7 membered heterocyclyl, and 5-6 membered heteroaryl, wherein Ci-Ce alkyl, -C3-C6 cycloalkyl, Ci-Ce alkoxy, phenyl, 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;

R¹ is selected from the group consisting of hydrogen, Ci-Cg alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C3-C6 cycloalkyl, -CH2-phenyl, -CFE-CEb-phenyl, -CH2-(5-10 membered heteroaryl), and -CH2-(5-10 membered heterocyclyl); wherein Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C3- Cg cycloalkyl, phenyl, heteroaryl, and heterocyclyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, deuterium, and C1-C3 alkoxy;

R² and R³ are each independently selected from the group consisting of hydrogen and Ci- Cg alkyl; wherein Ci-Cg alkyl, 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, -NR^aR^b; -NR^a-C(O)-NR^aR^b, -CO2H, Ci-Ce alkyl, Ci-Ce alkoxy, and phenyl; wherein Ci. C& alkyl, Ci-Ce alkoxy and phenyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, -NR^aR^b, and C1-C3 alkoxy;

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

R^a and R^b are each independently selected from the group consisting of hydrogen and Ci- G> alkyl; and m is 0, 1, 2, or 3.

[00109] E2. The compound of El, wherein the compound may be represented by

[00110] E3. The compound of El or E2, wherein R^A is independently selected from each occurrence from the group consisting of fluoro, chloro, bromo, iodo, hydroxyl, cyano, -CH3, - CH2CH3, -CH2CH2CH3, -CH(CH₃)₂, -OCH₃, -OCH2CH3, -OCH2CH2CH3, -OCH(CH₃)₂, -CF₃, - CHF₂, -OCF3, -0CHF2, -CH2OH, -CH2NH2, -CH₂C(O)NH₂, -CH₂CH₂OH, -CH₂CH₂NH₂, cyclopropyl, cyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, oxiranyl, azetidinyl, phenyl, triazolyl, and oxadiazolyl; wherein tetrahydropyrrolyl, piperidinyl, piperazinyl, and azetidinyl may optionally be substituted with - CH₃

[00111] E4. The compound of any one of E1-E3, wherein R^A is independently selected for each occurrence from the group consisting of fluoro, chloro, iodo, cyano, and -CH3

[00112] E5. The compound of any one of E1-E4, wherein m is 3.

[00113] E6. The compound of any one of E1-E5, wherein A is selected from the group consisting of

wherein X is O or S.

[00114] E7. The compound of any one of E1-E4, wherein m is 2.

[00115] E8. The compound of any one of E1-E4 and E7, wherein A is selected from the group consisting of

wherein X is O or S.

[00116] E9. The compound of any one of E1-E4, wherein m is 1.

[00117] E10. The compound of any one of E1-E4 and E9, wherein A is selected from the group consisting of

wherein X is O or S.

[00118] El l. The compound of any one of El -El 0, wherein R² and R³ are hydrogen.

[00119] E12. The compound of any one ofEl-El 1 , wherein R⁶ and R⁷ are hydrogen.

[00120] E13. The compound of any one of El -El 2, wherein R⁴ and R⁵ are each independently selected from the group consisting of hydrogen, hydroxyl, -CH3, -CH2OH, and -NH-C(O)- N(CH₂CH₃)₂

[00121] E14. The compound of any one of E1-E13, wherein R⁴ is hydrogen.

[00122] E15. The compound of any one of E1-E14, wherein R⁵ is selected from the group consisting of hydrogen, hydroxyl, -CH3, -CH₂OH, and -NH-C(O)-N(CH₂CH3)₂.

[00123] E16. The compound of any one of E1-E15, wherein R⁵ is hydrogen or -CH₃ [00124] E17. The compound of any one of E1-E16, wherein R¹ is selected from the group consisting of hydrogen,

[001251 El 8. The compound of any one of El -El 7, wherein R¹ is hydrogen.

[00126] E19. A compound represented by Formula IIA, Formula IIB, or Formula IIC:

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

X is O or S;

R^A is independently selected for each occurrence from the group consisting of fluoro, chloro, bromo, iodo, hydroxyl, cyano, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -OCH3, - OCH2CH3, -OCH2CH2CH3, -OCH(CH₃)₂, -CF₃, -CHF₂, -OCF3, -OCHF2, -CH2OH, -CH2NH2, - CH2C(O)NH2, -CH2CH2OH, -CH2CH2NH2, cyclopropyl, cyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, oxiranyl, azetidinyl, phenyl, triazolyl, and oxadiazolyl; wherein tetrahydropyrrolyl, piperidinyl, piperazinyl, and azetidinyl may optionally be substituted with -CH3;

R² and R³ are each independently selected from the group consisting of hydrogen, hydroxyl, -CH₃, -CH₂OH, and -NH-C(O)-N(CH₂CH3)₂;

R¹ is selected from the group consisting of hydrogen, -CH3,

, and m is 0, 1, 2, or 3.

[00127] E20. The compound of E19, wherein R^A is independently selected for each occurrence from the group consisting of fluoro, chloro, iodo, cyano, and -CH3.

[00128] E21 . The compound of El 9 or E20, wherein m is 3.

[00129] E22. The compound of E19 or E20, wherein m is 2.

[00130] E23. The compound of E19 or E20, wherein m is 1.

[00131] E24. The compound of any one of E1-E23, wherein R⁴ is hydrogen. [00132] E25. The compound of any one of E1-E24, wherein R⁵ is selected from the group consisting of hydrogen, hydroxyl, -CH3, -CH2OH, and -NH-C(O)-N(CH2CH3)2.

[00133] E26. The compound of any one of E1-E25, wherein R⁵ is hydrogen or -CH3

[00134] E27. The compound of any one of E1-E26, wherein R¹ is hydrogen.

[00135] E28. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt and/or stereoisomer thereof.

[00136] E29. A pharmaceutical composition comprising a compound of any one of E1-E28 and a pharmaceutically acceptable excipient.

[00137] E30. 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-E28.

[00138] E31. 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-E28 and a pharmaceutically acceptable excipient. [00139] E32. The method of E30 or E31, wherein the psychiatric or neurological disease or disorder is selected from the group consisting of depression, anxiety, substance abuse, and headache.

Examples

[00140] 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.

[00141] General Information

[00142] 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-c/e, CDCh or CD3OD as the solvent with tetramethylsilane (TMS) as the internal standard at room temperature. Chemical shifts were given in <5 relative to TMS, the coupling constants ./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.

[00143] Method A (LCMS17,41,42,50,52)

[00144] Experiments were performed on a SHIMADZU® 20A HPLC with a C18-reverse- phase column (30 x 3.0 mm Express Cl 8, 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

[00145] Method B (LCMS 17,41,42,47, 50,52)

[00146] 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

[00147] Method C (LCMS25)

[00148] 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

[00149] Method D (LCMS25)

[00150] 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:

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 [00151] Method E (LCMS40)

[00152] 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

[00153] Method F (LCMS45)

[00154] 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

[00155] Method G (LCMS45)

[00156] 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

[00157] Method H (LCMS46,48) [00158] 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

[00159] Method I (LCMS46,48)

[00160] 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

1.20 1.5 5 95

1.80 1.5 5 95

1.82 1.5 90 10

2.00 1.5 90 10

[00161] Method J (LCMS49)

[00162] 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

[00163] Method K (LCMS49)

[00164] 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

[00165] Method L (LCMS51,53)

[00166] 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

[00167] Method M (LCMS51,53)

[00168] 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 NH4HCOs; 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

[00169] Method N (LCMS60)

[00170] Experiments were performed on a SHIMADZU® 20A HPLC with a C18-reverse- phase column (30 x 3.0 mm Agilent® 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

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

[00171] Method O (LCMS61)

[00172] 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

[00173] Method P (LCMS63)

[00174] 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

[00175] Method 0 (LCMS63)

[00176] 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 [00177] Example 1: Synthesis of 3-(l,2,5,6-tetrahydropyridin-3-yl)-l,2-benzothiazole-7- carbonitrile (Compound 104)

[00178] Methyl 2-bromo-3-iodobenzoate. To a stirred solution of 2 -bromo-3 -iodobenzoic acid (5.00 g, 15.29 mmol) in MeOH (50.0 mL) was added SOCh (2.00 g, 16.82 mmol) dropwise at 0 °C and stirred overnight at 60 °C under an N2 atmosphere. The resulting mixture was concentrated under reduced pressure. The aqueous layer was extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with water (20 mL), dried over anhydrous Na2SO4. After fdtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiCL) eluting with PE / EA (5: 1) to afford the desired product as a yellow solid (4.00 g, 76.7% yield). ’H NMR (400 MHz, CDCh) 5 8.15 - 8.10 (m, 1H), 7.83 - 7.79 (m, 1H), 7.56 - 7.50 (m, 1H), 3.51 (s, 3H).

[00179] Methyl 2-brotno-3-cy anobenzoate. A solution of methyl 2-bromo-3 -iodobenzoate (4.00 g, 11.73 mmol), Pd(PPh₃)₄ (1.36 g, 1.17 mmol) and Zn(CN)₂ (4.13 g, 35.20 mmol) in DMA (40.0 mL) was stirred for 2 h at 100 °C under an N2 atmosphere. The aqueous layer was extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with water (20 mL), dried over anhydrous Na2SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5:1) to afford the desired product as a yellow solid (2.00 g, 71.0% yield). 'H NMR (400 MHz, DMSO-c/₆) 8 8.14 - 8.10 (m, 1H), 8.06 - 8.02 (m, 1H), 7.74 - 7.68 (m, 1H), 3.90 (s, 3H).

[00180] 2-Bromo-3-cyanobenzoic acid. A solution of methyl 2-bromo-3 -cyanobenzoate (2.00 g, 8.33 mmol) and LiOH (0.70 g, 16.66 mmol) in THF (20.0 mb) and H2O (10.0 mb) was stirred for 2 h at room temperature under an N2 atmosphere. 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, MeCN in Water (0.1 % FA), 00 % to 50 % gradient in 30 min; detector, UV 254 nm to afford the desired product as a yellow solid (1.50 g, 79.7% yield). LCMS 52 (Method A) (ESI) C₈H₄BrNO2 calcd 224.94; Found [M - H]’:224. 'H NMR (400 MHz, CDCh) 8 8.17 - 8.12 (m, 1H), 7.85 - 7.81 (m, 1H), 7.55 - 7.53(m, 1H).

[00181] 2-Bromo-3-cyanobenzamide. To a stirred solution of 2-bromo-3 -cyanobenzoic acid (1.50 g, 6.64 mmol) in DMF (20.0 mb) was added NH₄C1 (3.55 g, 66.36 mmol), DIEA (2.57 g, 19.91 mmol), and HATU (3.79 g, 9.95 mmol) in portions at room temperature. The resulting mixture was stirred for 1 h at room temperature under an N2 atmosphere. The residue was purified by reversed-phase flash chromatography with the following conditions: column, Cis silica gel; mobile phase, MeCN in Water (0.1 % FA), 0 % to 50 % gradient in 30 min; detector, UV 254 nm to afford the desired product as a yellow solid (1.00 g, 67.0% yield). LCMS 46 (Method H) (ESI) CsH₅BrN₂O calcd 223.96; Found [M - H]’:223. 'H NMR (400 MHz, CDCh) 87.81 - 7.77 (m, 1H), 7.76 - 7.21 (m, 1H), 7.55 - 7.49 (m, 1H).

[00182] 3-oxo-2H-l,2-benzothiazole-7-carbonitrile. A solution of 1,10-phenanthroline (0.24 g, 1.33 mmol) and Cui (0.25 g, 1.33 mmol) in DMF (10.0 mb) was stirred for 15 min at room temperature under an N2 atmosphere followed by the addition of 2-bromo-3 -cyanobenzamide (1.00 g, 4.44 mmol), octathiocane (1.48 g, 5.78 mmol) and K2CO3 (0.80 g, 5.78 mmol) in portions at room temperature. The resulting mixture was stirred for 15 min at room temperature under an N2 atmosphere and then it was stirred for 2 h at 110 °C under nitrogen atmosphere. The residue was purified by reversed-phase flash chromatography with the following conditions: column, Cis silica gel; mobile phase, MeCN in Water (0.1 % FA), 0 % to 50 % gradient in 30 min; detector, UV 254 nm to afford the desired product as a yellow solid (600.0 mg, 76.6% yield). LCMS 49 (Method K) (ESI) CsH₄N₂OS calcd 176; Found [M - H] ’: 175. 'H NMR (400 MHz, DMSO-th) 8 8.10 - 8.04 (m, 1H), 7.98 - 7.93 (m, 1H), 7.46 - 7.40 (m, 1H). [00183] 3-chloro-l, 2-benzothiazole-7-carbonitrile. To a stirred solution of 3-oxo-2/7- l ,2- benzothiazole-7-carbonitrile (600.0 mg, 3.41 mmol) in POCL (6.0 mL) was added pyridine (404.1 mg, 5.11 mmol) dropwise at room temperature under an N2 atmosphere. The final reaction mixture was irradiated with microwave radiation for 2 h at 120 °C. The reaction was quenched with water at 0 °C. The aqueous layer was extracted with CH2CI2 (3 x 20 mL). The combined organic extracts were washed with water (20 mL), dried over anhydrous NazSCL. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiCL) eluting with PE / EA (3 : 1) to afford the desired product as a yellow solid (300.0 mg, 45.3% yield). LCMS 49 (Method K) (ESI) C8H3CIN2S calcd 193.97; Found [M - H]’: 193. ’H NMR (400 MHz, DMSO- 6) 8 8.48 - 8.43 (m, 1H), 8.42 - 8.38 (m, 1H), 7.89 - 7.83 (m, 1H).

[00184] tert-butyl 3-(7-cyano-l,2-benzothiazol-3-yl)-5,6-dihydro-2H-pyridine-l- carboxylate. A solution of 3-chloro-l, 2-benzothiazole-7-carbonitrile (300.0 mg, 1.54 mmol), Pd(dppf)C12.CH2C12 (62.8 mg, 0.08 mmol), K2CO3 (639.1 mg, 4.62 mmol), and tert-butyl 3- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydro-27/-pyridine-l-carboxylate (714.9 mg, 2.31 mmol) in dioxane (2.0 mL) and H2O (1.0 mL) was stirred for 2 h at 80 °C under an N2 atmosphere. The aqueous layer was extracted with EtOAc (3 x 5 mL). The combined organic extracts were washed with water (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiCL) eluting with PE / EA (5: 1) to afford the desired product as a yellow solid (150.0 mg, 28.5% yield). ’HNMR (400 MHz, DMSO-tL) 8 8.66 (d, J= 8.3 Hz, 1H), 8.27 (d, J= 7.3 Hz, 1H), 7.78 - 7.70 (m, 1H), 6.83 - 6.77 (m, 1H), 4.41 (d, J= 3.0 Hz, 2H), 3.60 - 3.53 (m, 2H), 2.46 - 2.37 (m, 2H), 1.44 (s, 9H).

[00185] 3-(l,2,5,6-tetrahydropyridin-3-yl)-l,2-benzothiazole-7-carbonitrile. A solution of te/7-butyl 3-(7-cyano-l,2-benzothiazol-3-yl)-5,6-dihydro-2/f-pyridine-l-carboxylate (100.0 mg, 0.29 mmol,) in dioxane (0.5 mL) and HC1 (gas) in dioxane (0.5 mL) was stirred for 1 h at room temperature under an N2 atmosphere. The resulting mixture was concentrated under reduced pressure. The mixture was basified to pH 9 with saturated ISfeCCL (aq.). The crude product (100.0 mg) was purified by Prep-HPLC with the following conditions (Column: XB ridge Prep OBD Cl 8 Column, 30*150 mm, 5pm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 18% B to 38% B in 30 min; Wave Length: 254/220 nm; RTl(min): 10.02) to afford the desired product as a yellow solid (5.9 mg, 8.4% yield). LCMS 48 (Method I) (ESI) C13H11N3S calcd 241.07; Found [M+H]⁺:242.15. H NMR (400 MHz,

CD₃OD) 5 8.59 - 8.52 (m, 1H), 8.07 - 8.01 (m, 1H), 7.71 - 7.63 (m, 1H), 6.73 - 6.66 (tn, 1H), 3.94 - 3.83 (m, 2H), 3.10 - 3.01 (m, 2H), 2.50 - 2.39 (m, 2H).

[00186] Example 2: Synthesis of 7-Fluoro-3-(l,2,5,6-tetrahydropyridin-3- yl)benzo[d]isothiazole (Compound 106)

[00187] 2-Bromo-3-fluorobenzamide. To a stirred mixture of 2-bromo-3-fluorobenzoic acid

(6.00 g 27.40 mmol) in DMF (50 mL) were added NH₄C1 (14.60 g, 273.96 mmol), HATU (15.60 g, 41.09 mmol, 1.5 equiv) and DIEA (10.60 g, 82.19 mmol) in portions at room temperature. The resulting mixture was stirred for 1 h at room temperature under an N2 atmosphere. The residue was purified by reversed-phase flash chromatography with the following conditions: column, Ci8 silica gel; mobile phase, MeCN in water (0.1 % FA), 0 % to 50 % gradient in 55 min; detector, UV 254 nm. The resulting mixture was concentrated under vacuum to afford the desired product as a white solid, 1.4 g, 23.4% yield. ¹H NMR (400 MHz, DMSO-t/₍₎) 8 7.94 (s, 1H), 7.67 (s, 1H), 7.53 - 7.33 (m, 2H), 7.24 (d, J= 1.7 Hz, 1H).

[00188] 7-Fluoro-2H-l,2-benzothiazol-3-one. To a stirred solution of 1,10-phenanthroline (5.4 mg, 0.03 mmol) in DMF (5 mL) was added Cui (5.7 mg, 0.03 mmol) and the resulting mixture was stirred for 15 min at room temperature under an N2 atmosphere followed by the addition of 2- bromo-3 -fluorobenzamide (20.0 mg, 0.09 mmol), K2CO3 (469.7 mg, 3.39 mmol) and Ss (108.7 mg, 3.39 mmol) in portions at room temperature. The resulting mixture was stirred for 2 h at 110 °C under an N2 atmosphere. The residue was purified by reversed-phase flash chromatography with the following conditions: column, Cis silica gel; mobile phase, MeCN in water (0.1 % FA), 0 % to 50 % gradient in 55 min; detector, UV 254 nm. The resulting mixture was concentrated under vacuum to afford the desired product as a white solid (400 mg, 90.4% yield). LCMS 60 (ESI) C7H4FNOS calcd 169; Found [M+H]⁺: 170. 'H NMR (400 MHz, DMSO-c/₆) 6 12.42 (s, 1H), 7.82 - 7.74 (m, 1H), 7.52 (d, J= 62 Hz, 2H).

[00189] 3-Chloro-7-fluoro-l,2-benzothiazole. To a stirred solution of 7-fluoro-2//-l ,2- benzothiazol-3-one (540.0 mg, 3.19 mmol) in POCI3 (4 mL) was added pyridine (504.9 mg, 6.38 mmol). The resulting mixture was stirred for 1 h at 140 °C under an N2 atmosphere. The reaction was quenched with water (10 mL) at room temperature. The resulting mixture was extracted with CH2CI2 (3 x 40 mL), and dried over anhydrous Na2SC>4. The resulting mixture was concentrated under vacuum. The residue was purified by chromatography (S1O2) eluting with PE / EA (7: 1) to afford the desired product as a white solid (240.0 mg, 40.0% yield). LCMS 52 (Method A) (ESI) C7H3CIFNS calcd 186.97; Found [M+H]⁺: 188. ^XH NMR (400 MHz, CDCI3) 57.87 - 7.80 (m, 1H), 7.51 (d, J = 7.9, 4.5 Hz, 1H), 7.29 (d, J= 9.3 Hz, 1H).

[00190] tert-Butyl 3-(7-fluoro-l,2-benzothiazol-3-yl)-5,6-dibydro-2H-pyridine-l- carboxylate. To a stirred solution of 3-chloro-7-fluoro-l,2-benzothiazole (290.9 mg, 1.54 mmol) in dioxane (3.0 mL) and H2O (1.0 mL) were added /c77-butyl 3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-5,6-dihydro-2 7-pyridine-l -carboxylate (716.9 mg, 2.31 mmol), Pd(dppf)C12 (113.1 mg, 0.15 mmol) and K2CO3 (640.8 mg, 4.63 mmol). The resulting mixture was stirred for 1 h at 80 °C under an N2 atmosphere. The aqueous layer was extracted with EtOAc (3 x 40 mL), dried over anhydrous Na2SC>4 and concentrated under vacuum. The residue was purified by chromatography (SiCh) eluting with PE / EA (6:1) to afford the desired product as a white oil (400.0 mg, 77.3% yield). LCMS 52 (Method A) (ESI) C17H19FN2O2S calcd 334.12; Found [M+H]⁺:335. 'H NMR (400 MHz, CDCI3) 8 7.95 (d, J = 8.2 Hz, 1H), 7.42 (d, ,7 = 8.0 Hz, 1H), 7.24 - 7.12 (m, 1H), 6.61 (s, 1H), 4.50 (d, J= 2.5 Hz, 2H), 3.65 (d, J= 5.8 Hz, 2H), 2.45 (d, J = 6.9 Hz, 2H), 1.51 (s, 9H).

[00191] 7-fluoro-3-(l,2,5,6-tetrahydropyridin-3-yl)benzo[d]isothiazole. A solution of bis (Zc’/V-butyl 3-(7-fluoro-l,2-benzothiazol-3-yl)-5,6-dihydro-2 /-pyridine-l -carboxylate) (200.0 mg, 0.29 mmol) in dioxane (2.0 mL) and HC1 (gas) in 1,4-dioxane (2.0 mL) was stirred for 1 h at room temperature under an N2 atmosphere. The mixture was basified to pH 9 with saturated Na2COi (aq.). The crude product was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Prep C18 OBD Column, 30 x 150 mm, 5m; Mobile Phase A: Water (0.1 % FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 25 % B in 10 min; Wave Length: 254 nm/220 nm; RTl(min): 9.32) to afford the desired product as a white solid (36.9 mg, 27.9% yield). LCMS 52 (Method A) (ESI) C12H11FN2S calcd 234.06; Found [M+H]⁺:234.95. 'H NMR (400 MHz, DMSO- e) 5 8.14 (d, J= 8.0 Hz, 1H), 7.64 - 7.48 (m, 2H), 6.68 (d, J= 2.2 Hz, 1H), 3.72 (d, J= 2.5 Hz, 2H), 2.89 (d, J= 5.6 Hz, 2H), 2.28 (d, 2.8 Hz, 2H).

[00192] Example 3: Synthesis of 7-Methyl-3-(l,2,5,6-tetrahydropyridin-3-yl)-l,2- benzothiazole (Compound 108)

[00193] 2-(Benzylsulfanyl)-3-methylbenzonitrile. To a stirred solution of 2-fluoro-3- methylbenzonitrile (1.00 g, 7.40 mmol) and benzyl mercaptan (1.08 g, 14.80 mmol) in 1,4-dioxane (10 mL) was added NaH (0.2 g, 11.10 mmol) in portions at 0 °C under an N2 atmosphere. The resulting mixture was stirred for an additional 30 min at 80 °C. The reaction was quenched with water at 0 °C. The aqueous layer was extracted with EtOAc (3 x 50 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiCh) eluting with petroleum ether: ethyl acetate (5:1) to afford the desired product as a white solid (1.20 g, 67.7% yield). LCMS 50 (Method A) (ESI) C15H13NS calcd 239.08; Found [M+H] ¹ : 240.

[00194] 3-Methyl-2-sulfanylbenzonitrile. To a stirred solution of 2-(benzylsulfanyl)-3- methylbenzonitrile (300.0 mg, 1.25mmol) in toluene (3 mL) was added AICI3 (501.3 mg, 3.75 mmol) in portions at 0 °C. The resulting mixture was stirred for an additional 1 h at room temperature. The reaction was quenched with water at 0 °C and the resulting mixture was extracted with EtOAc (2 x 100 mL). After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO ) eluting with petroleum ether: ethyl acetate (5: 1) to afford the desired product as a yellow liquid (120.0 mg, 64.1% yield). LCMS 50 (Method A) (ESI) C₈H₇NS calcd 149.03; Found [M+H]⁺: 150.

[00195] 3-Bromo-7-methyl-l,2-benzothiazole. To a stirred solution of 3-methyl-2- sulfanylbenzonitrile (110.0 mg, 0.73 mmol) in ethyl acetate was added Br2 (200.2 mg, 1.25 mmol) dropwise at 0 °C. The resulting mixture was stirred for an additional 30 min at room temperature. The reaction was quenched with thiosulphate solution at 0 °C. The aqueous layer was extracted with EtOAc (2 x 100 mL). The residue was purified by chromatography (SiCh) eluting with petroleum ether: ethyl acetate (10: 1) to afford the desired product as a yellow liquid (124.0 mg, 73.7% yield). LCMS 47 (ESI) C₈H₆BrNS calcd 226.94; Found [M+H]⁺:228.

[00196] tert-Butyl 3-(7-methyl-l,2-benzothiazol-3-yl)-5,6-dihydro-2H-pyridine-l- carboxylate. A mixture of 3-bromo-7-methyl-l,2-benzothiazole (100.0 mg, 0.43 mmol), Z^/7-butyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydro-2//-pyridine-l-carboxylate (126.6 mg, 0.05 mmol), K2CO3 (181.7 mg, 1.31 mmol) and Pd(dppf)Ch (71.4 mg, 0.08 mmol) in dioxane (2 mL) and H2O (0.5 mL) was stirred for 2 h at 80 °C under an N2 atmosphere. The aqueous layer was extracted with EtOAc (2 x 100 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with petroleum ether: ethyl acetate (5:1) to afford the desired product as a yellow oil (140.0 mg, 96.6% yield). LCMS 49 (Method J) (ESI) CI₈H22N₂O₂S calcd 330.14; Found [M+H]⁺:331.

[00197] 7-Methyl-3-(l,2,5,6-tetrahydropyridin-3-yl)-l,2-benzothiazole. A mixture of tert- butyl 3-(7-methyl-l,2-benzothiazol-3-yl)-5,6-dihydro-2//-pyridine-l-carboxylate (100.0 mg, 0.30 mmol) in HC1 (gas) in 1,4-di oxane (5 mL, 4 M) was stirred for 30 min at room temperature under air atmosphere. The mixture was basified to pH 8 with saturated ISfeCCh (aq.). The resulting mixture was concentrated under reduced pressure. The crude product (55.8 mg) was purified by Prep-HPLC with the following conditions, Column: XBridge Prep Phenyl OBD Column 19*250 mm, 5m; Mobile Phase A: lOmmol/L NH4HC03+0.05%NH3H20, Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 5% B to 5% B in 1 min, 5% B to 30% B in 2 min, 30% to 45% B in 10 min; Wave Length: 254nm/220nm nm; RTl(min): 7.4. to afford the desired product as a white solid (29.1 mg, 41.7% yield). LCMS 63 (Method P) (ESI) CI3H14N2S calcd 230.09; Found [M+H]⁺:231.10.¹H NMR (400 MHz, DMSO-t/₆) 5 8.10 (d, J = 7.8 Hz, 1H), 7.47 (t, J = 7.4 Hz, 1H), 7.43 (d, J= 6.9 Hz, 1H), 6.62 (dd, J= 5.2, 2.8 Hz, 1H), 3.75 - 3.69 (m, J= 2.5 Hz, 2H), 2.90 (t, J= 5.7 Hz, 2H), 2.55 (s, 3H), 2.33 - 2.23 (m, J= 5.9, 3.0 Hz, 2H). [00198] Example 4: Synthesis of 6,7-difluoro-3-(l,2,5,6-tetrahydropyridin-3-yl)-l,2- benzothiazole (Compound 109)

c acid

(2.00 g, 8.43 mmol), HATU (4.80 g, 12.65 mmol), NH₄C1 (4.51 g, 84.39 mmol) and DIEA (3.27 g, 25.31 mmol) in DMF (10 mL) was stirred for 2 h at room temperature under an N2 atmosphere.

The residue was purified by reversed-phase flash chromatography with the following conditions: column, Cis silica gel; mobile phase, acetonitrile water (0.1% formic acid), 10% to 50% gradient in 30 min; detector, UV 254 nm to afford the desired product as a white solid (1.50 g, 75.3% yield). LCMS 60 (ESI) C7H₄BrF₂NO calcd 234.94; Found [M-H] :234. ’H NMR (400 MHz, DMSO-t/e) 5 7.95 (s, 1H), 7.70 (s, 1H), 7.54 - 7.44 (m, 1H), 7.32 - 7.26 (m, 1H).

[00200] 6, 7-Difluoro-2H-l,2-benzothiazol-3-one. To a solution of 1 , 10-phenanthroline (343.5 mg, 1.90 mmol) in DMF (5 ml) was added Cui (363.1 mg, 1.90 mmol) at 25 °C and stirred for 15 min. Then 2-bromo-3,4-difluorobenzamide (1.50 g, 6.35 mmol), K2CO3 (1.14 g, 8.26 mmol) and sulfur (264.39 mg, 8.26 mmol) were added and stirred for 15 min, followed by stirring for 2 h at 110 °C. The residue was purified by reversed-phase flash chromatography with the following conditions: column, Ci8 silica gel; mobile phase, acetonitrile in water (0.1% formic acid), 10% to 50% gradient in 30 min; detector, UV 254 nm to afford the desired product as a white solid (1.00 g, 84.0% yield). LCMS 49 (Method K) (ESI) C7H3F2NOS calcd 186.99; Found [M+H]⁺: 188. 'H NMR (400 MHz, DMSO ₆) 8 12.57 (s, 1H), 7.77 - 7.68 (m, 1H), 7.57 - 7.48 (m, 1H).

[00201] 3-Chloro-6, 7-difluoro-l,2-benzothiazole. A solution of 6,7-difluoro-2//-L2- benzothiazol-3-one (1.00 g, 5.34 mmol) and pyridine (633.9 mg, 8.01 mmol) in POCI3 (8 mL) was stirred for 2 h at 140 °C under an N₂ atmosphere. The reaction was quenched with water at 0 °C and concentrated under vacuum. The residue was purified by chromatography (SiCh) eluting with petroleum ether / ethyl acetate (6: 1 ) to afford the desired product as a white solid (600.0 mg, 54.6% yield). LCMS 49 (Method K) (ESI) C7H2CIF2NS calcd 204.96; Found [M+H]⁺:206. 'HNMR (400 MHz, DMSO-tL) 6 8.06 - 7.98 (m, 1H), 7.87 - 7.78 (m, 1H).

[00202] tert-Butyl 3-(6, 7-difluoro-l ,2-benzothiazol-3-yl)-5,6-dihydro-2H-pyridine-l- carboxylate. A solution of 3-chloro-6, 7-difluoro-l, 2-benzothiazole (600.0 mg, 2.91 mmol), tert- butyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5, 6-dihydro-2/7-pyridine-l -carboxylate (1.35 g, 4.37 mmol), Pd(dppf)Ch (213.52 mg, 0.29 mmol), K2CO3 (1.20 g, 8.75 mmol) and H2O (4 mL) in dioxane (8 mL) was stirred for 2 h at 80 °C under an N2 atmosphere. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 30 mL) and the combined organic extracts were concentrated under reduced pressure. The residue was purified by chromatography (SiCh) eluting with petroleum ether / ethyl acetate (7: 1) to afford the desired product as a white solid (200.0 mg, 19.4% yield). LCMS 72 (ESI) C17H18F2N2O2S calcd 352.11; Found [M+H]⁺:353. ‘HNMR (400 MHz, DMSO-t/₆) 8 8.18 (dt, J= 9.0, 1.3 Hz, 1H), 7.69 (q, J = 8.8 Hz, 1H), 6.83 - 6.73 (m, 1H), 4.38 (q, J= 2.4 Hz, 2H), 3.55 (t, J= 5.8 Hz, 2H), 2.39 - 2.43 (m, 2H), 1.44 (s, 9H).

[00203] 6, 7-Difluoro-3-(l, 2, 5, 6-tetrahydropyridin-3-yl)-l, 2-benzothiazole. To a solution of ter -butyl 3-(6,7-difluoro-l,2-benzothiazol-3-yl)-5,6-dihydro-2H-pyridine-l -carboxylate (100.0 mg, 0.28 mmol) in dioxane (2 mL) was added HC1 (2 mL, 4 M in 1,4-di oxane) dropwise and the resulting mixture was stirred for 2 h at room temperature under an N2 atmosphere. The mixture was concentrated under reduced pressure, and the residue was dissolved in MeOH (2 mL) and basified to pH 8 with saturated ISfeCCL (aq.). The mixture was concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18 ExRS 30*150 mm, 5m; Mobile Phase A: Water (lOmmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 32% B to 58% B in 7 min; Wavelength: 254nm/220nm nm; RTl(min): 6.15) to afford the desired product as a white solid (25.3 mg, 34.8%) yield. LCMS 46 (Method I) (ESI) C12H10F2N2S calcd 252.05; Found M + H]⁺:253. ‘HNMR (400 MHz, DMSO- de) 8 8.13 - 8.06 (m, 1H), 7.74 - 7.62 (m, 1H), 6.66 (d, J= 4.2 Hz, 1H), 3.70 (s, 2H), 2.89 - 2.72 (m, 2H), 2.28 (d, J = 5.1 Hz, 2H).

[00204] Example 5: Synthesis of 5,7-difluoro-3-(l,2,5,6-tetrahydropyridin-3-yl)-l,2- benzothiazole (Compound 110)

[00205]

difluorobenzoic acid (1.00 g, 4.21 mmol) in DMF (10 mL) was added NH4CI (2.26 g, 42.19 mmol), DIEA (1 .64 g, 12.65 mmol) and HATU (2.41 g, 6.32 mmol). The resulting mixture was stirred for 1 h at room temperature under an N2 atmosphere. The residue was purified by reversed-phase flash chromatography with the following conditions: column, Cis silica gel; mobile phase, MeCN in water (0.1% FA), 0% to 30% gradient in 20 min; UV 254 nm to afford the desired product as a yellow oil (750.0 mg, 75.3% yield). LCMS 42 (Method A) (ESI) C7H₄BrF₂NO calcd 234.94; Found [M+H]⁺:236. ^XH NMR (400 MHz, CDCI3) 87.25 - 7.19 (m, 1H), 7.04 - 6.97 (m, 1H), 6.09 (s, 2H).

[00206] 5, 7-Difluoro-2H-l,2-benzothiazol-3-one. To a mixture of 1,10-phenanthroline (171.7 mg, 0.95 mmol) and Cui (181.5 mg, 0.95 mmol) in DMF (10 mL) was added 2-bromo-3,5- difluorobenzamide (750.0 mg, 3.17 mmol), sulfur (132.1 mg, 4.13 mmol) and K2CO3 (570.9 mg, 4.13 mmol). The resulting mixture was stirred for 15 min at room temperature and for 2 h at 110 °C under an N₂ atmosphere. The mixture was purified by reversed-phase flash chromatography with the following conditions: column, Cis silica gel; mobile phase, MeCN in water (0.1% FA), 0% to 50% gradient in 30 min; UV 254 nm to afford the desired product as a white solid (380.0 mg, 63.8% yield). LCMS 17 (Method A) (ESI) C7H3F2NOS calcd 186.99; Found [M+H]⁺: 188. 'H NMR (300 MHz, DMSO-r/₆) 8 12.70 (s, 1H), 7.77 - 7.66 (m, 1H), 7.65 - 7.56 (m, 1H).

[00207J 3-Chloro-5,7-difluoro-l,2-benzothiazole. To a stirred mixture of 5,7-difluoro-27/- l,2-benzothiazol-3-one (380.0 mg, 2.03 mmol) in POCI3 (5 mL) was added pyridine (240.9 mg, 3.04 mmol). The resulting mixture was stirred for 2 h at 140 °C under an N2 atmosphere. The reaction was quenched with ice water at 0 °C. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with water (3 x 10 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiCE) eluting with PE / EA (9:1) to afford the desired product as a white solid (200.0 mg, 47.9% yield). 'H NMR (400 MHz, CDCI3) 8 7.56 - 7.50 (m, 1H), 7.18 - 7.09 (m, 1H).

[00208] tert-Butyl 3-(5, 7-difluoro-l ,2-benzothiazol-3-yl)-5,6-dihydro-2H-pyridine-l- carboxylate. To a stirred mixture of 3-chl oro-5, 7-difluoro-l, 2-benzothiazole (200.0 mg, 0.97 mmol) in dioxane (4 m ) and H2O (2 m ) was added zc/7-butyl 3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-5,6-dihydro-2 7-pyridine-l -carboxylate (451.1 mg, 1.45 mmol), K2CO3 (403.3 mg, 2.91 mmol) and Pd(dppf)Ch (71.1 mg, 0.09 mmol). The resulting mixture was stirred for 1 h at 80 °C under an N2 atmosphere. The resulting mixture was extracted with EtOAc (3 x 10 mb). The combined organic extracts were washed with water (3 x 10 mL), and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (9:1) to afford the desired product as a white solid, (270.0 mg, 78.7% yield). LCMS 52 (Method A) (ESI) C17H18F2N2O2S calcd 352.11; Found [M+H]⁺:353. ^rH NMR (300 MHz, DMSO-t/₆) 3 8.10 - 8.01 (m, 1H), 7.80 - 7.70 (m, 1H), 6.79 (s, 1H), 4.39 (d, J = 2.8 Hz, 2H), 3.60 - 3.51 (m, 2H), 2.40 (d, J = 5.5 Hz, 2H), 1.44 (s, 9H).

[00209J 5, 7-Difluoro-3-(l, 2, 5, 6-tetrahydropyridin-3-yl)-l, 2-benzothiazole. To a stirred mixture of tert-butyl 3-(5, 7-difluoro-l, 2-benzothiazol-3-yl)-5,6-dihydro-2/7-pyridine-l- carboxylate (150.0 mg, 0.42 mmol) in dioxane (1 mL) was added HC1 (gas) in 1,4-dioxane (1 mL). The resulting mixture was stirred for 1 h at room temperature under an N2 atmosphere. The resulting mixture was concentrated under vacuum. The mixture was neutralized to pH 7 with saturated Na2CO3 (aq.). The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column 30*150 mm, 5m; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 5% B in 1.5 min, 5% B to 25% B in 2 min, 25% B to 43% B in 9 min; Wave Length: 254 nm/220 nm nm; RTl(min): 9.2) to afford the desired product as a white solid (13.6 mg, 12.6% yield). LCMS 40 (ESI) C12H10F2N2S calcd 252.05; Found [M+H]⁺:253.05. ’H NMR (400 MHz, DMSO- t/₆) 8 8.08 - 7.90 (m, 1H), 7.85 - 7.63 (m, 1H), 6.67 (d, J = 4.2 Hz, 1H), 3.71 - 3.68 (m, 2H), 2.96 - 2.83 (m, 2H), 2.28 (d, J= 2.8 Hz, 2H). [00210] Example 6: Synthesis of 4,7-Difluoro-3-(l,2,5,6-tetrahydropyridin-3-yl)-l,2- benzothiazole (Compound 111)

[00211] 2-Bronw-3,6-difluorobenzamide. A solution of 2-bromo-3,6-difluorobenzoic acid (3.00 g, 12.65 mmol), NH₄C1 (6.77 g, 126.58 mmol), DIEA (4.91 g, 37.97 mmol) and HATU (7.22 g, 18.98 mmol) in DMF (10 mb) was stirred for 2 h at room temperature under an N2 atmosphere. The mixture was purified by reversed-phase flash chromatography with the following conditions: column, Cis silica gel; mobile phase, MeCN in water (0.1% FA), 10% to 50% gradient in 30 min; UV 254 nm. The resulting mixture was concentrated under vacuum to afford the desired product as a white solid (1.00 g, 33.4% yield). LCMS 54 (ESI) CTEUB^NO calcd 234.94; Found [M+H]⁺:236. ‘H NMR (400 MHz, DMSC ,) 8 8.16 (s, 1H), 7.92 (s, 1H), 7.43 - 7.24 (m, 2H).

[00212] 4,7-Difluoro-2H-l,2-benzothiazol-3-one. A solution of 1, 10-phenanthroline (230.0 mg, 1.27 mmol) in DMF (1 m ) was treated with Cui (242.0 mg, 1.27 mmol) for 15 min at room temperature under an N2 atmosphere followed by the addition of K2CO3 (761.2 mg, 5.50 mmol), Ss (176.2 mg, 5.50 mmol) and 2-bromo-3,6-difluorobenzamide (1.00 g, 4.23 mmol) dropwise at room temperature. The resulting mixture was stirred for 1 h at 110 °C under an N2 atmosphere. The residue was purified by reversed-phase flash chromatography with the following conditions: column, Cis silica gel; mobile phase, MeCN in water (0.1% FA), 10% to 50% gradient in 30 min; UV 254 nm to afford the desired product as a white solid (400.0 mg, 50.4% yield). LCMS 50 (Method B) (ESI) C7H3F2NOS calcd 186.99; Found [M+H]⁺: 188. ¹ H NMR (400 MHz, DMSO-t/₆) 8 7.15 - 7.06 (m, 1H), 6.89 - 6.81 (m, 1H). [00213] 3-Chloro-4, 7-difluoro-l,2-benzothiazole. A solution of 4,7-difluoro-2rt-L2- benzothiazol-3 -one (400.0 mg, 2.13 mmol) and pyridine (253.5 mg, 3.20 mmol) in POCI3 (3 mL) was stirred for 2 h at 140 °C under an N2 atmosphere. The reaction was quenched with water at 0 °C. The mixture was extracted with CH2CI2 (2 x 100 mL) and the combined organic phase was concentrated under vacuum. The residue was purified by chromatography (SiCL) eluting with PE / EA (6: 1) to afford the desired product as a white solid (150.0 mg, 34.1% yield). LCMS 47 (ESI) C7H2CIF2NS calcd 204.96; Found [M+H]⁺:206. 'HNMR (400 MHz, DMSO-t/₆) 67.67 - 7.58 (m, 1H), 7.49 - 7.41 (m, 1H).

[00214] tert-Butyl 3-(4, 7-difluoro-l,2-benzothiazol-3-yl)-5,6-dihydro-2H-pyridine-l- carboxylate. A solution of 3-chloro-4,7-difluoro-l,2-benzothiazole (150.0 mg, 0.73 mmol), tertbutyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydro-2//-pyridine-l -carboxylate (338.3 mg, 1.09 mmol), Pd(dppf)C12 (53.3 mg, 0.07 mmol) and K2CO3 (302.4 mg, 2.19 mmol) in H2O (1 mL) and dioxane (2 mL) was stirred for 2 h at 80 °C under an N2 atmosphere. The aqueous layer was extracted with EtOAc (4 x 100 mL). The combined organic extracts were concentrated under vacuum. The residue was purified by chromatography (SiCh) eluting with PE / EA (7: 1) to afford the desired product as a white solid (100.0 mg, 38.9% yield). LCMS 47 (ESI) C17H18F2N2O2S calcd 352.11 [M+H]⁺:353. 'HNMR (400 MHz, DMSO-t/₆) 6 7.58 (d, J= 3.0 Hz, 1H), 7.40 (ddd, J= 10.7, 8.6, 3.5 Hz, 1H), 6.44 (dp, J= 6.0, 2.2 Hz, 1H), 4.44 - 4.27 (m, 2H), 3.53 (t, J= 5.7 Hz, 2H), 2.34 - 2.22 (m, 2H), 1.44 (s, 9H).

[00215] 4, 7-Difluoro-3-(l,2,5,6-tetrahydropyridin-3-yl)-l,2-benzothiazole. To a stirred solution of rt-butyl 3-(4,7-difluoro-l,2-benzothiazol-3-yl)-5,6-dihydro-2rt-pyridine-l- carboxylate (100.0 mg, 0.28 mmol, 1.0 equiv) in dioxane (2 mL) was added HC1 (2 mL, 4 M in 1,4-di oxane) dropwise and the resulting mixture was stirred for 2 h at room temperature under an N2 atmosphere. The mixture was concentrated under reduced pressure, the residue was dissolved with MeOH (2 mL) and basified to pH 8 with saturated ISfeCCL (aq.). The resulting mixture was concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18 ExRS 30*150 mm, 5m; Mobile Phase A: Water (lOmmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 35% B to 65% B in 7 min; Wavelength: 254nm/220nm nm; RTl(min): 4.62) to afford the desired product as a white solid (55.2 mg, 76.5% yield). LCMS 48 (Method I) (ESI) C12H10F2N2S calcd 252.05; Found [M+H]⁺:253.15. H NMR (400 MHz, DMSO-rL) 8 7.56 (td, J= 8.6, 3.0 Hz, 1H), 7.37 (ddd, J = 10.9, 8.6, 3.5 Hz, 1H), 6.43 - 6.22 (m, 1H), 3.65 (s, 2H), 2.88 (t, J= 5.7 Hz, 2H), 2.21 (dt, J= 6.7,

3.0 Hz, 2H).

[00216] Example 7: Synthesis of 6-Fluoro-3-(l,2,5,6-tetrahydropyridin-3-yl)-l,2- benzoxazole (Compound 121)

[00217] tert-Butyl 3-(2,4-difluorobenzoyl)-4-oxopiperidine-l-carboxylate. To a stirred solution of LiHMDS (210.7 mL, 1 M in THF) in THF (400 mL) was added tert-butyl 4- oxopiperidine-1 -carboxylate (40.00 g, 200.75 mmol) dropwise at 0 °C and stirred for 20 min at 0 °C under an N2 atmosphere. To the above mixture was added 2,4-difluorobenzoyl chloride (37.21 g, 210.78 mmol) dropwise at 0 °C and stirred for 30 min at 0 °C. The reaction was quenched with 500 mL of sat. NH4CI (aq.) at 0 °C and extracted with CH2CI2 (3 x 1000 mL). The combined organic extracts was dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure to afford the desired product as a yellow crude oil (36.00 g, 53 % yield). LCMS 54 (ESI) C17H19F2NO4 calcd 339.13; Found [M+H]⁺: 340.

[00218] tert-Butyl 3-[(2,4-difluorophenyl) (hydroxy)methyl]-4-hydroxypiperidine-l- carboxylate. To a stirred solution of terLbutyl 3-(2,4-difluorobenzoyl)-4-oxopiperidine-l- carboxylate (36.00 g, 106.09 mmol) inMeOH (400 mL) was added NaBH4 (16.05 g, 424.35 mmol) in portions at 0 °C and stirred for 1 h at room temperature under an N2 atmosphere. The reaction was quenched with 100 mL of water at room temperature and extracted with CH2CI2 (3 x 100 mL). The combined organic extracts was dried over anhydrous Na₂SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO₂) eluting with PE /EA (5: 1) to afford the desired product as a yellow crude oil (19.00 g, 52 % yield). LCMS 54 (ESI) CI₇H23F2NO₄ calcd 343. 16; Found [M+H]⁺: 344.

[00219] tert-Butyl 3-(2,4-difluorobenzoyl)-4-hydroxypiperidine-l-carboxylate. To a stirred solution of Zc/7-butyl 3-[(2,4-difluorophenyl)(hydroxy)methyl]-4-hydroxypiperidine-l- carboxylate (19.00 g, 55.33 mmol) in DCM (200 m ) was added MnO₂ (72.16 g, 830.01 mmol) and stirred overnight at room temperature under an N2 atmosphere. The resulting mixture was filtered, the residue was washed with CH2Q2 (3 x 100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO₂) eluting with PE/EA (5: 1) to afford the desired product as a yellow oil (8.40 g, 44 % yield). LCMS 54 (ESI) C17H21F2NO4 calcd 341.14; Found [M+H]⁺: 342. ^JH NMR (400 MHz, D SC ,) 8 7.92 - 7.80 (m, 1H), 7.45 - 7.35 (m, 1H), 7.26 - 7.19 (m, 1H), 4.84 (d, J = 42 Hz, 1H), 4.17 (d, J= 4.1 Hz, 1H), 3.94 - 3.83 (m, 1H), 3.72 - 3.64 (m, 1H), 3.28 (s, 1H), 2.50 (s, 1H), 1.68 - 1.61 (m, 2H), 1.40 (d, J= 4.0 Hz, 9H).

[00220] tert-Butyl 3-[(lE)-(2,4-difluorophenyl)(hydroxyimino)methyl]-4- hydroxypiperidine-l-carboxylate. To a stirred solution of /crZ-butyl 3-(2,4-difluorobenzoyl)-4- hydroxypiperidine-1 -carboxylate (8.40 g, 24.61 mmol) in MeOH (6 mL) was added hydroxylamine hydrochloride (2.05 g, 29.53 mmol) and AcONa (2.42 g, 29.53 mmol) and stirred overnight at 40 °C under an N₂ atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by chromatography (SiO₂) eluting with PE / EA (5: 1) to afford the desired product as a white solid (5.90 g, 67 % yield). LCMS 54 (ESI) C17H22F2N2O4 calcd 356.15; Found [M+H]⁺: 357. ¹HNMR (400 MHz, DMSO-cZ₆) 8 10.99 (s, 1H), 7.43 - 7.34 (m, 1H), 7.29 - 7.21 (m, 1H), 7.15 - 7.08 (m, 1H), 4.64 (d, J= 3.9 Hz, 1H), 3.82 - 3.66 (m, 2H), 3.09 (d, J = 72.2 Hz, 2H), 2.57 (d, J = 11.2 Hz, 1H), 1.63 - 1.44 (m, 2H), 1.39 (s, 9H).

[00221] tert-Butyl 3-(6-fluoro-l,2-benzoxazol-3-yl)-4-hydroxypiperidine-l-carboxylate. To a stirred solution of te/7-butyl 3-[(lE)-(2,4-difluorophenyl)(hydroxyimino)methyl]-4- hydroxypiperidine-1 -carboxylate (5.90 g, 16.55 mmol) in THF (4 mL) was added Z-BuOK (2.42 g, 21.52 mmol) and stirred for 1 h at room temperature under an N₂ atmosphere. The reaction was quenched with 100 mL of sat. NH4CI (aq.) at room temperature and extracted with CH₂C1₂ (3 x 100 mL). The combined organic extracts was dried over anhydrous Na₂SO₄. After filtration, 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, MeCN in Water (0.1% FA), 0% to 50% gradient in 30 min; UV 254 nm to afford the desired product as a yellow oil (3.30 g, 59 % yield). LCMS 54 (ESI) C17H21FN2O4 calcd 336.15; Found [M+H]⁺: 337. ^ NMR (400 MHz, DMSO-rL) 6 8.07 - 7.98 (m, 1H), 7.72 - 7.64 (m, 1H), 7.32 - 7.23 (m, 1H), 4.93 (s, 1H), 3.85 (s, 2H), 3.64 (s, 2H), 3.47 (s, 1H), 1.79 (s, 2H), 1.46 - 1.34 (m, 9H).

[00222] tert-Butyl 3-(6-fluoro-l,2-benzoxazol-3-yl)-5, 6-dihydro-2H-pyridine-l -carboxylate. To a stirred solution of ze/7-butyl 3-(6-fluoro-l,2-benzoxazol-3-yl)-4-hydroxypiperidine-l- carboxylate (3.30 g, 9.81 mmol) in DCE (2 mb) was added Burgess reagent (3.51 g, 14.72 mmol) and stirred for 1 h at 100 °C under an N2 atmosphere. The mixture was concentrated under reduced pressure and the residue was purified by reversed-phase flash chromatography with the following conditions: column, Cis silica gel; mobile phase, MeCN in Water (0.1% FA), 0% to 70% gradient in 30 min; UV 254 nm to afford the desired product as a yellow oil (1.10 g, 35.2% yield). LCMS 54 (ESI) C17H19FN2O3 calcd 318.14; Found [M+H]⁺:319. 'H NMR (400 MHz, CDCI3) 8 7.84 - 7.76 (m, 1H), 7.30 - 7.27 (m, 1H), 7.15 - 7.05 (m, 1H), 6.82 (s, 1H), 4.47 (s, 2H), 3.65 (s, 2H), 2.46 (d, J= 6.1, 2.8 Hz, 2H), 1.50 (s, 9H).

[00223] 6-Fluoro-3-(l,2,5,6-tetrahydropyridin-3-yl)-l,2-benzoxazole. A solution of tert- butyl 3-(6-fluoro-l,2-benzoxazol-3-yl)-5,6-dihydro-2/Z-pyridine-l-carboxylate (1.10 g, 3.45 mmol) in HC1 (gas) in 1,4-dioxane (11 mL, 4 M) was stirred for 1 h at room temperature under an N2 atmosphere and concentrated under vacuum. The residue was dissolved with 0.5 mL of MeOH and it was basified to pH 9 with saturated Na2CC>3 (aq.). The resulting mixture was purified by reversed-phase flash chromatography with the following conditions: column, Cis silica gel; mobile phase, MeOH in Water (10 mmol/L NH4HCO3), 0% to 40% gradient in 30 min; UV 254 nm to afford the desired product as a white solid (439 mg, 57 % yield). LCMS 40 (ESI) C12H11FN2O calcd 218.09; Found [M+H]⁺: 219.00. ’H NMR (400 MHz, DMSO-t7₆) 8 8.18 - 8.08 (m, 1H), 7.77 - 7.67 (m, 1H), 7.36 - 7.25 (m, 1H), 6.97 (d, J= 4.3 Hz, 1H), 3.71 - 3.61 (m, 2H), 2.89 (s, 2H), 2.35 - 2.23 (m, 2H).

[00224] Example 8: Synthesis of 3-(l,2,5,6-tetrahydropyridin-3-yl)-l,2-benzoxazole (Compound 122)

[00225J tert-Butyl 3-(2-fluorobenzoyl)-4-oxopiperidine-l-carboxylate. To a stirred solution of tert-butyl 4-oxopiperidine-l -carboxylate (5.00 g, 25.09 mmol) in THF (50 mL) was added LiHMDS (26 mL, 1 M in THF) dropwise at 0 °C and stirred for 20 min at 0 °C under a N2 atmosphere. To the above mixture was added 2-fluorobenzoyl chloride (3.96 g, 25.09 mmol) dropwise at 0 °C and the resulting mixture was stirred for additional 30 min at 0 °C. The reaction was quenched with 50 mL of sat. NH4CI (aq.) at 0 °C and the resulting mixture was extracted with CH2Ch (3 x 100 mL). The combined organic extracts were dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure to afford the desired product as a yellow crude oil (4.00 g, 49.7% yield). LCMS 50 (ESI) C17H20FNO4 calcd 321.14; Found [M+H]⁺:322.

[00226] tert-Butyl 3-[(2-fluorophenyl)(hydroxy)methyl]-4-hydroxypiperidine-l-carboxylate. To a stirred mixture of ter/-butyl 3 -(2-fluorobenzoyl)-4-oxopiperidine-l -carboxylate (4.00 g, 12.45 mmol) in MeOH (200 mL) was added NaBH4 (1.88 g, 49.82 mmol) in portions at 0 °C and stirred for 1 h at room temperature. The reaction was quenched with 40 mL of water at 0 °C and the resulting mixture was concentrated under vacuum and extracted with EtOAc (3 x 40 mL). The combined organic extracts was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiCL) eluting with PE/EA (3:1) to afford the desired product as a white crude solid (1.90 g, 46.9% yield). LCMS 47 (ESI) C17H24FNO4 calcd 325. 17; Found [M+H]⁺:326.

[00227] tert-Butyl 3-(2-fluorobenzoyl)-4-hydroxypiperidine-l-carboxylate. To a stirred mixture of ze/7-butyl 3-[(2-fluorophenyl)(hydroxy)methyl]-4-hydroxypiperidine-l-carboxylate (1.90 g, 5.84 mmol) in DCM (200 mb) was added MnCE (7.62 g, 87.64 mmol) and stirred overnight at room temperature under an N2 atmosphere. The resulting mixture was fdtered, the residue was washed with CH2CI2 (3 x 10 m ). The fdtrate was concentrated under reduced pressure. The residue was purified by chromatography (S1O2) eluting with PE/EA (1 :1) to afford the desired product as white solid (1.40 g, 74.5% yield). LCMS 49 (ESI) C17H22FNO4 calcd 323.15; Found [M+H]⁺:324. 'H NMR (300 MHz, DMSC ,) 6 7.52 (d, J = 7.4 Hz, 1H), 7.36 - 7.33 (m, 1H), 7.28 - 7.25 (m, 2H), 4.85 (d, J = 4.1 Hz, 1H), 4.19 (s, 1H), 3.93 (s, 1H), 3.70 (d, J = 13.4 Hz, 1H), 3.28 (s, 1H), 3.13 - 2.94 (m, 1H), 1.65 (s, 2H), 1.40 (s, 9H).

[00228] tert-Butyl 3-[(lE)-(2-fluorophenyl)(hydroxyimino)methyl]-4-hydroxypiperidine-l- carboxylate. To a stirred solution of /e/7-butyl 3-(2-fluorobenzoyl)-4-hydroxypiperidine-l- carboxylate (1.40 g, 4.33 mmol) and hydroxylamine hydrochloride (361.3 mg, 5.19 mmol) in EtOH (100 mb) was added AcONa (426.4 mg, 5.19 mmol) and the resulting mixture was stirred overnight at room temperature under an N2 atmosphere. The resulting mixture was concentrated under reduced pressure and the residue was diluted with H2O (20 mb), the aqueous layer was extracted with EtOAc (3 x 10 mb). The combined organic extracts were dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiCL) eluting with PE/EA (1 : 1) to afford the desired product as white solid (730.0 mg, 49.9% yield). LCMS 49 (ESI) C17H23FN2O4 calcd 338.16; Found [M+H]⁺:339. 'H NMR (400 MHz, DMSO-rL) 8 10.91 (s, 1H), 7.44 - 7.36 (m, 1H), 7.35 - 7.29 (m, 1H), 7.24 - 7.17 (m, 2H), 4.62 (d, J = 3.8 Hz, 1H), 3.74 (d, J= 30.7 Hz, 2H), 3.17 (s, 2H), 2.56 (d, J = 11.1 Hz, 1H), 1.57 (d, J= 12.8 Hz, 2H), 1.39 (s, 9H).

[00229] tert-Butyl 3-(l,2-benzoxazol-3-yl)-4-hydroxypiperidine-l-carboxylate. To a stirred solution of /c/7-butyl 3-[(l£')-(2-fluorophenyl)(hydroxyimino)methyl]-4-hydroxypiperidine-l- carboxylate (730.0 mg, 2.16 mmol) in THF (10 mL) was added Z-BuOK (629.8 mg, 5.61 mmol) at 0 °C and stirred for 1 h at room temperature under an N2 atmosphere. The reaction was quenched with 50 mL of sat. NH4CI (aq.) at room temperature. The resulting mixture was extracted with CH2CI2 (3 x 50 mL). The combined organic extracts was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, Ci8 silica gel; mobile phase, MeCN in Water (0.1 % FA), 0% to 40% gradient in 30 min; UV 254 nm to afford the desired product as yellow solid (300.0 mg, 43.65% yield). LCMS 50 (ESI) C17H22N2O4 calcd 318.16; Found [M+H]⁺:319. 'H NMR (300 MHz, DMSO-t/₆) 8 7.99 (d, J= 7.9 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.63 (d, J= 7.6 Hz, 1H), 7.37 (d, J= 1 A Hz, 1H), 5.01 - 4.83 (m, 1H), 4.32 (s, 1H), 3.89 (s, 1H), 3.67 (s, 2H), 3.45 (d, J= 6.7 Hz, 1H), 1.82 (d, J= 8.7 Hz, 2H), 1.49 - 1.20 (m, 9H). [00230] Tert-butyl 3-(l₎2-benzoxazol-3-yl)-5,6-dihydro-2H-pyridine-l-carboxylate. To a stirred solution of Zc/7-butyl 3 -(l,2-benzoxazol-3-yl)-4-hydroxypiperi dine- 1 -carboxylate (300.0 mg, 0.94 mmol) in DCE (1 m ) was added the Burgess reagent (337.0 mg, 1.41 mmol) and stirred for 30 min at 100 °C under an N2 atmosphere. The residue was purified by reversed-phase flash chromatography with the following conditions: column, Cis silica gel; mobile phase, MeCN in Water (10 mmol/L NH4HCO3), 0% to 40% gradient in 30 min; UV 254 nm to afford the desired product as a yellow oil (90.0 mg, 31.8% yield). LCMS 60 (ESI) C17H20N2O3 calcd 300.15; Found [M+H]⁺:301. 'H NMR (400 MHz, CDCI3) 8 7.86 (d, J= 8.0 Hz, 1H), 7.57 (d, J = 15.2 Hz, 2H), 7.34 (d, J= 1A Hz, 1H), 6.87 (s, 1H), 4.50 (s, 2H), 3.65 (d, J= 5.7 Hz, 2H), 2.55 - 2.35 (m, 2H), 1.51 (s, 9H).

[00231J 3-(l,2,5,6-Tetrahydropyridin-3-yl)-l,2-benzoxazole. HC1 (gas) in 1,4-dioxane (1 mL, 4 M) was added to tert-butyl 3-(l,2-benzoxazol-3-yl)-5,6-dihydro-27/-pyridine-l-carboxylate (90.0 mg, 0.29 mmol) and stirred for 30 min at room temperature under an N2 atmosphere. The resulting mixture was concentrated under vacuum and basified to pH 8 with saturated Na2CC>3 (aq.). The resulting mixture was purified by reversed-phase flash chromatography with the following conditions: column, Cis silica gel; mobile phase, MeCN in Water (10 mmol/L NH4HCO3), 0% to 50% gradient in 30 min; UV 254 nm to afford the desired product as a white solid (10.9 mg, 18.3% yield). LCMS 51 (ESI) C12H12N2O calcd 200.09; Found [M+H]⁺:201.05. ^JH NMR (400 MHz, CD3OD) 8 8.02 (d, J= 8.0 Hz, 1H), 7.68 - 7.58 (m, 2H), 7.47 - 7.37 (m, 1H), 7.02 (s, 1H), 3.97 - 3.85 (m, 2H), 3.14 (s, 2H), 2.51 (s, 2H).

[00232] Example 9: IP1 Accumulation Assay

[00233] 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

[00234] 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

[00235] 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.

[00236] 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.

[00237] 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.

[00238] 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 )2; or double bond; X is C; and Y is C(R^Y);

W is selected from the group consisting of O, and S;

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-;

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, phenyl. 4-7 membered heterocyclyl, and 5-6 membered heteroaryl; wherein Ci-Ce alkyl, -C3-C6 cycloalkyl, Ci-Ce alkoxy, phenyl, 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;

R¹ is selected from the group consisting of hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C3-C6 cycloalkyl, -CFh-phenyl, -CH2-CH2-phenyl, -CH2-(5-10 membered heteroaryl), and -CH2-(5-10 membered heterocyclyl); wherein Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C3- Ce cycloalkyl, phenyl, heteroaryl, and heterocyclyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, deuterium, and C1-C3 alkoxy;

R² and R³ are each independently selected from the group consisting of hydrogen and Ci- Ce alkyl; wherein Ci-Ce alkyl, 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, -NR^aR^b; -NR^a-C(O)-NR^aR^b, -CO₂H, Ci-Ce alkyl, Ci-Ce alkoxy, and phenyl; wherein Ci-Ce alkyl, Ci-Ce alkoxy and phenyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, - NR^aR^b, and C1-C3 alkoxy;

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

R^a and R^b are each independently selected from the group consisting of hydrogen and Ci- Ce alkyl; and m is 0, 1, 2, or 3.

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

3. The compound of claim 1 or 2, wherein R^A is independently selected from each occurrence from the group consisting of fluoro, chloro, bromo, iodo, hydroxyl, cyano, -CH3, -CH2CH3, - CH₂CH₂CH₃, -CH(CH₃)₂, -0CH3, -OCH₂CH₃, -OCH₂CH₂CH₃, -OCH(CH₃)₂, -CF₃, -CHF₂, - 0CF3, -OCHF₂, -CH₂OH, -CH₂NH₂, -CH₂C(O)NH₂, -CH₂CH₂OH, -CH₂CH₂NH₂, cyclopropyl, cyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, oxiranyl, azetidinyl, phenyl, triazolyl, and oxadiazolyl; wherein tetrahydropyrrolyl, piperidinyl, piperazinyl, and azetidinyl may optionally be substituted with -CH3.

4. The compound of claim 1 or 2, wherein R^A is independently selected for each occurrence from the group consisting of fluoro, chloro, iodo, cyano, and -CH3.

5. The compound of claim 1 or 2, wherein m is 3.

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

wherein X is O or S.

7. The compound of claim 1 or 2, wherein m is 2.

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

wherein X is O or S.

9. The compound of claim 1 or 2, wherein m is 1.

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

wherein X is O or S.

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

12. The compound of claim 1 or 2, wherein R⁶ and R⁷ are hydrogen.

13. The compound of claim 1 or 2, wherein R⁴ and R⁵ are each independently selected from the group consisting of hydrogen, hydroxyl, -CH3, -CH2OH, and -NH-C(O)-N(CH2CH3)2.

14. The compound of claim 1 or 2, wherein R⁴ is hydrogen.

15. The compound of claim 1 or 2, wherein R⁵ is selected from the group consisting of hydrogen, hydroxyl, -CH3, -CH₂OH, and -NH-C(O)-N(CH₂CH3)₂.

16. The compound of claim 1 or 2, wherein R⁵ is hydrogen or -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, Formula IIB, or Formula IIC:

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

X is O or S;

R^A is independently selected for each occurrence from the group consisting of fluoro, chloro, bromo, iodo, hydroxyl, cyano, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -OCH3, - OCH₂CH₃, -OCH₂CH₂CH₃, -OCH(CH₃)₂, -CF₃, -CHF₂, -OCF₃, -OCHF₂, -CH₂OH, -CH₂NH₂, - CH₂C(O)NH₂, -CH₂CH₂OH, -CH₂CH₂NH₂, cyclopropyl, cyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, oxiranyl, azetidinyl, phenyl, triazolyl, and oxadiazolyl; wherein tetrahydropyrrolyl, piperidinyl, piperazinyl, and azetidinyl may optionally be substituted with -CH₃;

R² and R³ are each independently selected from the group consisting of hydrogen, hydroxyl, -CH₃, -CH₂OH, and -NH-C(O)-N(CH₂CH₃)₂;

R¹ is selected from the group consisting of hydrogen, -CH₃,

, and m is 0, 1, 2, or 3.

20. The compound of claim 19, wherein R^A is independently selected for each occurrence from the group consisting of fluoro, chloro, iodo, cyano, and -CH₃.

21. The compound of claim 19 or 20, wherein m is 3.

22. The compound of claim 19 or 20, wherein m is 2.

23. The compound of claim 19 or 20, wherein m is 1.

24. The compound of claim 1 or 19, wherein R⁴ is hydrogen.

25. The compound of claim 1 or 19, wherein R³ is selected from the group consisting of hydrogen, hydroxyl, -CH₃, -CH₂OH, and -NH-C(O)-N(CH₂CH₃)₂.

26. The compound of claim 1 or 19, wherein R³ is hydrogen or -CH₃.

27. The compound of claim 1 or 19, wherein R¹ is hydrogen.

28. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt and/or stereoisomer thereof.

29. A pharmaceutical composition comprising a compound of any one of claims 1, 19, and 28 and a pharmaceutically acceptable excipient.

30. 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 28.

31. 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 28 and a pharmaceutically acceptable excipient.

32. The method of claim 30, wherein the psychiatric or neurological disease or disorder is selected from the group consisting of depression, anxiety, substance abuse, and headache.

33. The method of claim 31, wherein the psychiatric or neurological disease or disorder is selected from the group consisting of depression, anxiety, substance abuse, and headache.