TW202440563A - 2-phenylmorpholine and 2-phenyl(thio)morpholine compounds and uses thereof - Google Patents

Abstract

Provided herein is a compound of Structural Formula I: or a pharmaceutically acceptable salt thereof, wherein values for the variables (e.g., X, Y, R1, R2, R3, R4, m, n, o) are as disclosed herein. Also provided herein are pharmaceutical compositions comprising a compound of Structural Formula I, or a pharmaceutically acceptable salt thereof, and methods of using the compounds, pharmaceutically acceptable salts thereof and pharmaceutical compositions of the foregoing, e.g., to treat a neurological or psychiatric disease or disorder, or a metabolic disease, disorder or condition.

Description

2-Phenylmorpholine and 2-phenyl(thio)morpholine compounds and uses thereof

The present invention relates to 2-phenylmorpholine and 2-phenyl(thio)morpholine compounds and pharmaceutical compositions thereof, which are agonists of the protein TAAR1 and are useful for treating neurological and psychiatric diseases and disorders and metabolic diseases, disorders and conditions.

Treatments for neurological or psychiatric diseases and disorders often target certain neurotransmitter sites. For example, _D2 dopamine receptors have become the primary target of typical and atypical antipsychotics used to treat a variety of neurological or psychiatric diseases or disorders. Wang et al., NATURE 555 , 269-273 (2018). However, many drugs that target _D2 dopamine receptors can cause serious or potentially life-threatening side effects. Wang et al., NATURE 555 , 269-273 (2018). Despite decades of research into the mechanisms of action of non- _D2 dopamine receptors, the development of safe and effective non-D2 _dopamine receptor therapies remains challenging. Girgis et al., J. PSYCHIATRIC RES. (2018), https://doi.org/10.1016/j.jpsychires.2018.07.006. In a comprehensive review of the literature on experimental treatments for schizophrenia (one of many neurological or psychiatric diseases and disorders), including 250 studies conducted between 1970 and 2017, including glutamine-agonistic, serotonin-agonistic, choline-agonistic, neuropeptide-agonistic, hormonal-based, dopamine-agonistic, metabolic, vitamin/natural therapy, histamine-agonistic, infection/inflammatory-based, and other mechanisms of treatment for schizophrenia, Girgis stated: “Despite the existence of several promising [non-D Despite there being several promising [non-D ₂ dopamine receptor] targets, such as allosteric modulation of the NMDA _and α7 nicotinic receptors, we cannot confidently state that any of the mechanistically novel experimental treatments covered in this review are definitely effective for the treatment of schizophrenia and ready for clinical use."

Therefore, there is a need for therapeutic agents for treating neurological and psychiatric diseases and disorders.

Provided herein is a compound having the following structural formula I: , or a pharmaceutically acceptable salt thereof, wherein the values of the variables (e.g., X, Y, R ¹ , R ² , R ³ , R ⁴ , m, n, o) are as disclosed herein.

Also provided herein is a pharmaceutical composition comprising a compound of the present invention and one or more pharmaceutically acceptable carriers.

Also provided herein is a pharmaceutical combination comprising a compound of the invention and one or more additional therapeutic agents.

Also provided herein is a method of treating a neurological or psychiatric disease or disorder (e.g., a neurological or psychiatric disease or disorder disclosed herein) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the invention or a pharmaceutical composition or combination disclosed herein.

Also provided herein is a method of treating a metabolic disease, disorder or condition (e.g., a metabolic disease, disorder or condition disclosed herein) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the invention or a pharmaceutical composition or combination disclosed herein.

Also provided herein is a method of agonizing TAAR1 in a subject in need thereof, comprising administering to the subject a compound of the present invention or a pharmaceutical composition or combination disclosed herein in an amount sufficient to agonize TAAR1 in the subject.

The present invention also provides a compound of the present invention or a pharmaceutical composition or combination disclosed herein for use in treating a disease, disorder or condition disclosed herein (e.g., a neurological or psychiatric disease or disorder; a metabolic disease, disorder or condition) in a subject. The present invention also provides the use of a compound of the present invention or a pharmaceutical composition or combination disclosed herein for the preparation of a medicament for treating a disease, disorder or condition disclosed herein (e.g., a neurological or psychiatric disease or disorder; a metabolic disease, disorder or condition).

Cross-reference to related applications

This application claims priority to U.S. Provisional Application No. 63/385,164 filed on November 28, 2022, the entire contents of which are hereby incorporated by reference.

The following are descriptions of the embodiments.

This article provides definitions that help explain the present invention. Where appropriate, terms used in the singular will also include the plural. Unless the context clearly indicates otherwise, the terms used herein have the following meanings.

All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples or exemplary language (e.g., "such as") is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. Definitions

Unless otherwise indicated herein or clearly contradicted by context, the terms "a", "an", "the" and similar terms used in the context of the present invention (especially in the context of the claims) should be construed to cover both the singular and the plural.

As used herein, the term "alkyl" refers to a branched or straight chain monovalent hydrocarbon group having a specified number of carbon atoms and the general formula _{CnH2n + 1} . Thus, the term "( _{C1 - C6} )alkyl" refers to a branched or straight chain monovalent hydrocarbon group of the general formula _{CnH2n + 1} , where n is 1, ₂ , 3, 4, 5, or 6. In some embodiments, the alkyl group is a ( _C1 - _C6 )alkyl group. In some embodiments, the alkyl group is a ( _C1 - _C3 )alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, di-butyl, tertiary butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, 3,3-dimethylpropyl, hexyl, 2-methylpentyl, and the like.

As used herein, the term "alkoxy" refers to an alkyl group attached through an oxygen bonding atom, wherein the alkyl group is as described herein. "(C ₁ -C ₆ )alkyl" refers to an alkoxy group wherein the (C ₁ -C ₆ )alkyl group is attached through an oxygen bonding atom. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and butoxy (e.g., tert-butoxy).

As used herein, "alkoxyalkyl" refers to an alkoxy group attached through an alkyl group, wherein the alkoxy group and the alkyl group are as described herein. "(C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl" refers to an alkoxy group wherein the (C ₁ -C ₆ )alkyl group is attached to the (C ₁ -C ₆ )alkyl group through an oxygen bonding atom. Examples of alkoxyalkyl groups include methoxymethyl, ethoxymethyl, methoxyethyl, and ethoxyethyl.

As used herein, "amino" means -NH ₂ .

As used herein, "cyano" or "-CN" means -C≡N.

As used herein, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic (e.g., bicyclic, tricyclic) aliphatic hydrocarbon ring system having a specified number of carbon atoms. Thus, "(C ₅ -C ₈ )cycloalkyl" means a cycloalkyl ring system having 5 to 8 ring carbons. In some embodiments, the cycloalkyl is (C ₃ -C ₈ )cycloalkyl. In some embodiments, the cycloalkyl is (C ₃ -C ₆ )cycloalkyl. In some embodiments, the cycloalkyl is (C ₃ -C ₅ )cycloalkyl. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, and norbenzyl.

As used herein, "halogen" and "halogen" refer to fluorine, chlorine, bromine or iodine. In some embodiments, the halogen is fluorine, chlorine or bromine. In some embodiments, the halogen is fluorine or chlorine. In some embodiments, the halogen is fluorine.

As used herein, "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are independently replaced by a halogen, wherein the alkyl group and the halogen are as described herein. "Halogenalkyl" includes monohalogenalkyl, polyhalogenalkyl and perhalogenalkyl. "(C ₁ -C ₆ )halogenalkyl" refers to a (C ₁ -C ₆ )alkyl group in which one or more hydrogen atoms are independently replaced by a halogen. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl and heptachloropropyl.

As used herein, "haloalkoxy" refers to a haloalkyl group attached through an oxygen bonding atom, wherein the haloalkyl group is as described herein. "(C ₁ -C ₆ )haloalkoxy" refers to a haloalkoxy group wherein the (C ₁ -C ₆ )haloalkyl group is attached through an oxygen bonding atom. Examples of haloalkoxy include, but are not limited to, trifluoromethoxy, difluoromethoxy, 2,2,2 trifluoroethoxy, and pentafluoroethoxy.

As used herein, the term "heteroatom" refers to nitrogen (N), oxygen (O), or sulfur (S) atoms. When a heteroatom is S, it may be singly or doubly oxidized (i.e., -S(O)- or -S(O) ₂ ) as appropriate. Unless otherwise indicated, any heteroatom with unsaturated valences is assumed to have hydrogen atoms sufficient to satisfy the valences.

As used herein, the term "heteroaryl" refers to a monocyclic or polycyclic aromatic hydrocarbon ring system having a specified number of ring atoms, wherein at least one carbon atom in the ring has been replaced by a heteroatom. Thus, "(C ₅ -C ₆ )heteroaryl" refers to a heteroaryl ring system having five or six ring atoms. Typically, heteroaryl groups have 5 to 15, 5 to 10, 5 to 9, 5 to 6, 5 or 6 ring atoms. Heteroaryl ring systems may consist of single or fused ring systems. Typical monocyclic heteroaryl groups are 5-6 membered rings containing one to three (e.g., one, two, or three) heteroatoms independently selected from oxygen, sulfur, and nitrogen (e.g., one, two, or three ring heteroatoms, each of which is nitrogen; one or two ring heteroatoms, one or both of which are nitrogen and one of which is oxygen or sulfur). Typical fused heteroaryl ring systems are 9-10 membered ring systems containing one to four heteroatoms independently selected from oxygen, sulfur, and nitrogen. Fused heteroaryl ring systems can consist of two heteroaryl rings fused together or a heteroaryl ring fused to an aryl ring (e.g., phenyl). Examples of heteroaryl groups include, but are not limited to, pyrrolyl, pyridinyl (e.g., pyridin-2-yl, pyridin-3-yl, pyridin-4-yl), pyrazolyl (e.g., pyrazol-2-yl, pyrazol-3-yl, pyrazol-4-yl), pyrimidinyl (e.g., pyrimidin-3-yl, pyrimidin-4-yl), indolyl, indolinyl, isoindolyl, indazolyl, thienyl, furanyl, benzofuranyl, dihydrobenzofuranyl, dihydroisobenzofuranyl, oxazolyl (e.g., oxazol-2-yl), isoxazolyl (e.g., isoxazol-4-yl), imidazolyl (e.g., imidazolyl), thiadiazolyl (e.g., 1,2, 4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl), thiazolyl (e.g., thiazol-2-yl, thiazol-4-yl, thiazol-5-yl), isothiazolyl (e.g., isothiazol-5-yl), triazolyl, tetrazolyl, trioxazolyl, pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl), pyrimidinyl (e.g., pyrimidin-2-yl), purinyl, benzimidazolyl, quinolyl, isoquinolyl, quinolinyl, tetrahydroquinolyl, benzofuranyl, benzopyranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, 1 H - benzo[ d ][1,2,3]triazolyl, pyrazolopyridinyl (e.g., pyrazolo[1,5- a ]pyridinyl), thiazolyl (e.g., thiazolyl[4,5- b ]pyridinyl), benzothiazolyl (e.g., benzo[ d ]thiazol-2-yl), and the like.

As used herein, the term "heterocyclic group" refers to a saturated or partially saturated and non-aromatic monocyclic or polycyclic (e.g., bicyclic, tricyclic) ring system having the specified number of ring atoms, wherein at least one carbon atom in the ring system has been replaced by a heteroatom independently selected from oxygen, sulfur and nitrogen. Thus, "(C ₃ -C ₇ )heterocyclic group" means a heterocyclic group having 3 to 7 ring atoms. "Heterocyclic group" includes monocyclic, fused, bridged and spirocyclic rings. In some embodiments, the heterocyclyl is (C ₃ -C ₇ )heterocyclyl, (C ₅ -C ₆ )heterocyclyl, (C ₅ )heterocyclyl, or (C ₆ )heterocyclyl. In some embodiments, the heterocyclyl (e.g., (C ₃ -C ₇ )heterocyclyl) is a saturated heterocyclyl.

The heterocyclic group may contain 1 to 7, 1 to 5, 1 to 3, 1 to 2, 1 or 2 heteroatoms. If the valence permits, the heterocyclic group may be attached at a heteroatom or a carbon atom. Examples of heterocyclic groups include, but are not limited to, azocyclobutanyl, oxacyclobutanyl, piperidinyl, piperonyl, pyrrolyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, oxolinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropyranyl, 1,4-dioxacyclohexanyl, 1, 4-oxathiocyclohexanyl, hexahydropyrimidinyl, 3-azabicyclo[3.1.0]hexyl, azacycloheptanyl, 3-azabicyclo[3.2.2]nonyl, decahydroisoquinolinyl, 2-azaspiro[3.3]heptyl, 2-oxathio-6-azaspiro[3.3]heptyl, 2,6-dihydroquinolinyl, azaspiro[3.3]heptyl, 8-aza-bicyclo[3.2.1]octyl, 3,8-diazabicyclo[3.2.1]octyl, 3-oxa-8-aza-bicyclo[3.2.1]octyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 2-oxa-5- aza-bicyclo[2.2.1]heptyl, 2,5-diaza-bicyclo[2.2.1]heptyl, 1,4-dioxa-8-aza-spiro[4.5]decyl, 3-oxa-1,8-diazaspiro[4.5]decyl, octahydropyrrolo[3,2-b]pyrrolyl and the like.

As used herein, "hydroxy" means -OH.

As used herein, the term "substituted" means that at least one (e.g., one, two, three, four, five, six, etc., one to five, one to four, one to three, one to two) hydrogen atom is replaced with a non-hydrogen substituent, provided that the normal valence is maintained and the substitution results in a stable compound. Unless otherwise indicated, an "optionally substituted" group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from the specified group, the substituent at each position may be the same or different. Alternatively, an "optionally substituted group" may be unsubstituted.

When the substituent is a pendoxy group, two hydrogens on a single atom are replaced by the substituent. Pendoxy substituents are not present on aromatic moieties.

When one or more nitrogen atoms are present in the compounds of the present invention, the one or more nitrogen atoms can be independently converted to N -oxides to provide other compounds of the present invention by treatment with an oxidizing agent (e.g., m -CPBA and/or hydrogen peroxide). Therefore, the nitrogen atoms shown and claimed are considered to cover both the shown nitrogen and its N -oxide (N→O) derivative.

When any variable occurs more than one time in any component or formula of a compound, its definition at each occurrence is independent of its definition at each additional occurrence. Thus, for example, if a group is shown as substituted with 0 to 3 substituents, the group may be unsubstituted or substituted with up to three substituents, and each substituent is selected independently of the other substituent or substituents. Thus, for example, the value of each ^R2 in a compound of formula I is independent of its value at each additional occurrence, such that one occurrence of ^R2 may be F, and another occurrence of ^R2 may be hydroxy.

When one or more bonds to a substituent are shown crossing a bond connecting two atoms in a ring (e.g., the bonds to ^R and/or ^R in Formula I) or crossing a circle representing a ring, such substituent may be bonded to any substitutable carbon atom in the ring. In addition, when the ring through which the bond to the substituent crosses is polycyclic, the substituent may be bonded to any substitutable carbon atom of the ring or ring system through which the bond to the substituent crosses. When a substituent is listed without indicating that the substituent is bonded to an atom in the remainder of the compound of a given formula, such substituent may be bonded through any atom in such substituent.

Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

One of ordinary skill will appreciate that, for example, a keto (-C(H)C(O)-) group in a molecule can interconvert to its enol form (-C=C(OH)-). The present invention is intended to encompass all possible interconverters, even when a structure depicts only one of them.

The phrase "pharmaceutically acceptable" means that the substance or composition modified by the phrase must be suitable for use in contact with the tissues of humans and lower animals within the scope of sound medical judgment without unusual toxicity, irritation, allergic reaction and the like, and commensurate with a reasonable benefit/risk ratio. If the substance is part of a composition or formulation, it must also be chemically and/or toxicologically compatible with the other ingredients in the composition or formulation.

Unless otherwise specified, the term "compound of the present invention" refers to compounds of any formula described herein (e.g., compounds of formula I, compounds of subformulas of formula I, such as compounds of formula Ia and/or Ib) and isomers, such as stereoisomers (including non-mirror isomers, mirror isomers and racemates), geometric isomers, configurational isomers (including rotational isomers and hysteresis isomers), tautomers, isotopically labeled compounds (including deuterium substitution) and inherently formed partial bodies (e.g., polymorphs and/or solvates, such as hydrates). When there are partial bodies capable of forming salts, salts are also included, especially pharmaceutically acceptable salts.

The compounds of the present invention may have asymmetric centers, chiral axes and chiral planes (for example, as described in E. L. Eliel and S. H. Wilen, Stereo-chemistry of Carbon Compounds, John Wiley & Sons, New York, 1994, pp. 1119-1190), and exist in the form of racemic mixtures, individual isomers (for example, non-mirror isomers, mirror isomers, geometric isomers, configurational isomers (including rotational isomers and hysteresis isomers), tautomers) and intermediate mixtures. All possible isomers and mixtures thereof are included in the present invention.

As used herein, the term "isomers" refers to different compounds that have the same molecular formula but differ in arrangement and configuration of the atoms.

"Mirror isomers" are a pair of stereoisomers that are nonsuperimposable mirror images of each other. A 1:1 mixture of a pair of mirror isomers is a "racemic" mixture. Where appropriate, the terms "racemate" or "racemic" are used to designate a racemic mixture. When specifying the stereochemistry of the compounds of the invention, the conventional RS system is used to specify single stereoisomers with two chiral centers of known relative and absolute configuration (e.g., (1S,2S)); single stereoisomers with known relative configuration but unknown absolute configuration are specified with an asterisk (e.g., (R*), (S*), (1R*,2R*)); and racemates are specified with two letters (e.g., (1RS,2RS) as a racemic mixture of (1R,2R) and (1S,2S); (1RS,2SR) as a racemic mixture of (1R,2S) and (1S,2R)). "Non-mirror isomers" are stereoisomers that have at least two asymmetric atoms and are not mirror images of each other. Absolute stereochemistry can be assigned according to the Cahn-Ingold-Prelog R-S system.

When the compound is pure mirror image isomers, the stereochemistry at each chiral carbon can be assigned by R or S. The resolved compound can be assigned as (+) or (-) depending on the direction (right-handed or left-handed) of rotation of plane polarization at the wavelength of the sodium D line. Alternatively or additionally, the resolved compound can be defined by the respective retention times of the corresponding mirror image isomers/non-mirror image isomers by chiral HPLC.

Graphical representations of racemic or mirror-isomerically pure compounds used herein are adapted from a modified version of Maehr J. Chem. Ed. 62, 114-120 (1985): Simple lines provide no information about stereochemistry but convey only connectivity; solid and dashed wedges are used to represent absolute configuration of chiral elements; bold solid and bold dashed lines indicate relative stereochemistry for which absolute configuration is uncertain. For example, the graphic representation: Indicates a mirror image isomer, which is either: or . Similarly, for Another mirror image isomer of , and is either of the following two representations: or . express: Indicates a single mirror image isomer with the depicted absolute configuration.

The mirror image excess (ee) percentage is defined as the absolute difference between the molar fractions of each mirror image isomer multiplied by 100% and can be expressed by the following equation: ee , where R and S represent the respective fractions of each mirror image isomer in the mixture such that R + S = 1. When a single mirror image isomer is named or depicted by structure, the depicted or named mirror image isomer is present with an ee of at least or about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.9%.

The non-image isomer excess (de) is defined as the absolute difference between the molar fractions of each non-image isomer multiplied by 100% and can be expressed by the following equation: , wherein D1 and (D2 + D3 + D4 ...) represent the respective fractions of each non-mirror image isomer in the mixture such that D1 + (D2 + D3 + D4 ...) = 1. When a single non-mirror image isomer is named or depicted by structure, the depicted or named non-mirror image isomer is present in at least or about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 99.9%.

In some embodiments, an isomer (e.g., non-mirror isomer, mirror isomer) can be provided that is substantially free of one or more corresponding isomers (e.g., one or more non-mirror isomers/mirror isomers). When the isomer is "substantially free" of one or more corresponding isomers, the ee or de of the depicted or named compound is at least about 50%, such as at least or about: 50%, 60%, 70%, 75%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.9%.

Geometric isomers can exist when a compound contains a double bond or some other property that imparts a certain structural rigidity to the molecule. If the compound contains a double bond, the double bond can be in the E- or Z - configuration. If the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituent can have a cis- or trans-configuration.

Configurational isomers (or conformational isomers) are isomers that differ by rotation about one or more bonds. Rotational isomers are conformational isomers that differ by rotation about only a single bond.

As used herein, the term "hypothalamic isomers" refers to structural isomers based on axial or planar chirality resulting from restricted rotation in a molecule.

Optically active (R)-isomers and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using known techniques (e.g., separation on chiral SFC or HPLC columns such as CHIRALPAK® and CHIRALCEL® columns available from DAICEL Corp. or other equivalent columns using appropriate solvents or solvent mixtures to achieve a suitable separation).

The compounds of the present invention can be isolated in optically active or racemic forms. Optically active forms can be prepared by resolution of racemic forms or by synthesis from optically active starting materials. All methods for preparing the compounds of the present invention and the intermediates prepared therein are considered to be part of the present invention. When mirror image isomers or non-mirror image isomers are prepared, they can be separated by known methods, for example by chromatography or fractional crystallization.

Depending on the process conditions, the final products of the present invention are obtained in free (neutral) form or in salt form. Both free forms and salts of these final products are within the scope of the present invention. If so desired, one form of the compound can be converted into another form. A free base or acid can be converted into a salt; a salt can be converted into a free compound or another salt; a mixture of isomeric compounds of the present invention can be separated into individual isomers.

Pharmaceutically acceptable salts are preferred. However, other salts may be suitable, for example, for use in isolation or purification steps that may be employed during preparation and are therefore encompassed within the scope of the present invention.

The phrase "pharmaceutically acceptable" means that the substance or composition modified by the phrase must be suitable for use in contact with the tissues of humans and lower animals within the scope of sound medical judgment without unusual toxicity, irritation, allergic reaction and the like, and commensurate with a reasonable benefit/risk ratio. If the substance is part of a composition or formulation, it must also be chemically and/or toxicologically compatible with the other ingredients in the composition or formulation.

As used herein, "pharmaceutically acceptable salts" refer to salts derived from suitable inorganic and organic acids and bases which are suitable, within the scope of sound medical judgment, for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reaction, and the like and commensurate with a reasonable benefit/risk ratio.

Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like. Pharmaceutically acceptable acid addition salts include but are not limited to: acetate, ascorbate, adipate, aspartate, benzoate, benzenesulfonate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, decanoate, chloride / Hydrochloride, Chlorophylline, Citrate, Ethane Disulfonate, Fumarate, Gluceptate, Gluconate, Glucuronate, Glutamate, Glutarate, Hydroxyacetate, Hippurate, Hydroiodate/Iodide, Hydroxyethanesulfonate, Lactate, Lactobionate, Lauryl sulfate, apple acid salt, cis-butenedioate, malonate/hydroxymalonate, mandelate, methanesulfonate, methylsulfate, galactoate, naphthoate, naphthylsulfonate, niacinate, nitrate, octadecanoate, oleate, oxalate, palmitate , bis(hydroxynaphthoate), phenylacetate, phosphate/hydrogenphosphate/dihydrogenphosphate, polygalacturonate, propionate, salicylate, stearate, succinate, sulfamate, sulfosalicylate, tartrate, toluenesulfonate, trifluoroacetate, and hydroxynaphthoate.

Pharmaceutically acceptable base addition salts may be formed from inorganic and organic bases. Inorganic bases from which salts may be derived include, for example, ammonium salts and metals from rows I to XII of the periodic table. In certain embodiments, the salt is derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, or copper; particularly suitable salts include ammonium, potassium, sodium, calcium, and magnesium salts. Organic bases from which salts may be derived include, for example, primary, secondary, and tertiary amines; substituted amines including naturally occurring substituted amines; cyclic amines; base ion exchange resins and the like. Examples of organic amines include, but are not limited to, isopropylamine, benzathine, cholate, diethanolamine, diethylamine, lysine, meglumine, piperidine, and sulfamethoxazole.

Salts, such as pharmaceutically acceptable salts of the compounds of the present invention, can be synthesized from parent compounds containing a basic or acidic moiety by conventional chemical methods. Generally, these salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of an appropriate base or acid in water or in an organic solvent or in a mixture of the two; generally, non-aqueous media (such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile) are preferred.

It should be understood that when the compounds of the present invention contain more than one alkaline moiety or more than one acidic moiety, each such moiety can independently participate in the formation of acid addition salt forms or base addition salt forms, and all possible salt forms are included in the present invention. In addition, when two or more moieties of the compounds of the present invention are in salt form, the anions or cations forming the two or more salt forms may be the same or different. Typically, the anions or cations forming the two or more salt forms are the same. The anions or cations in the salts of the compounds of the present invention are 3:1, 2:1, 1:1, 2:1, 3:1, 4:1 and 5:1. In some embodiments, the molar ratio of anions or cations (e.g., anions) in the salt of the compound of the invention to the compound of the invention is 1:1 (e.g., in the monohydrochlorides of compounds 26 and 27). In some embodiments, the molar ratio of anions or cations (e.g., anions) in the salt of the compound of the invention to the compound of the invention is 2:1 (e.g., in the dihydrochloride of compound 6).

Lists of suitable salts are found in Allen, L.V., Jr., ed., Remington: The Science and Practice of Pharmacy, 22nd ed., Pharmaceutical Press, London, UK (2012), the relevant disclosure of which is hereby incorporated by reference in its entirety.

Compounds of the present invention containing groups capable of acting as donors and/or acceptors of hydrogen bonds may be capable of forming co-crystals with suitable co-crystal formers. Such co-crystals can be prepared from compounds of the present invention by known co-crystal formation procedures. Such procedures include grinding, heating, co-subliming, co-melting or contacting the compounds of the present invention with the co-crystal formers in solution under crystallization conditions, and isolating the co-crystals thereby formed. Suitable co-crystal formers include those described in WO 2004/078163. Therefore, the present invention further provides co-crystals comprising compounds of the present invention and co-crystal formers.

Any formula given herein is also intended to represent unlabeled forms of the compounds as well as isotopically labeled forms. Isotopically labeled compounds have structures depicted by the formulas given herein, except that one or more atoms are replaced with atoms having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as ² H, ³ H, ¹¹ C, 13 C, ¹⁴ C, ¹⁵ N, ¹⁸ F, ³¹ P, ³² P, ³⁵ S, ³⁶ Cl, ¹²³ I, ¹²⁴ I, and ¹²⁵ I, ^respectively . The invention includes various isotopically labeled compounds as defined herein, for example, those compounds in which radioactive isotopes such as ³ H and ¹⁴ C are present, or those compounds in which non-radioactive isotopes such as ² H and ¹³ C are present. Such isotopically labeled compounds are useful in metabolic studies (using ¹⁴ C); reaction kinetic studies (using, for example, ² H or ³ H); detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution analysis; or for radiotherapy of patients. In particular, ¹⁸ F or labeled compounds may be particularly desirable for PET or SPECT studies.

In addition, substitution with heavier isotopes, especially deuterium (i.e., ^2H or D), can provide certain therapeutic advantages resulting from greater metabolic stability, such as increased half-life in vivo or reduced dosage requirements or improved therapeutic index. It should be understood that in this context, deuterium is considered a substituent of the compounds of the present invention. The concentration of such heavier isotopes (especially deuterium) can be defined by an isotopic enrichment factor. As used herein, the term "isotopic enrichment factor" means the ratio between the isotopic abundance of a specified isotope and the natural abundance. Where a substituent in a compound of the invention is represented by deuterium, such compounds have an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation) or at least 6633.3 (99.5% deuterium incorporation).

Isotopically labeled compounds of the present invention can generally be prepared by known techniques known to those skilled in the art, or by methods disclosed in the schemes or in the examples and preparations described below (or methods analogous to those described below), by replacing the non-isotopically labeled reagents originally employed with appropriate or readily available isotopically labeled reagents. Such compounds have a variety of potential uses, such as standards and reagents for determining the ability of potential pharmaceutical compounds to bind to target proteins or receptors, or for in vivo or in vitro imaging of compounds of the present invention bound to biological receptors.

The term "solvent" means a physical association of a compound of the invention with one or more solvent molecules (whether organic or inorganic). This physical association includes hydrogen bonding. In certain circumstances, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvent will be able to separate. The solvent molecules in the solvent can exist in an ordered and/or disordered arrangement. The solvent can contain stoichiometric or non-stoichiometric amounts of solvent molecules. "Solvate" covers both solution phase and solid phase solvents. Examples of solvents include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solubilization methods are generally known in the art.

"Pharmaceutically acceptable carriers" refer to media generally recognized in the art for delivering biologically active agents to animals (especially mammals), including generally recognized as safe (GRAS) solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delay agents, Buffers, salts, preservatives, drug stabilizers, binders, buffers (e.g., maleic acid, tartaric acid, lactic acid, citric acid, acetic acid, sodium bicarbonate, sodium phosphate and the like), disintegrants, lubricants, sweeteners, flavorings, dyes and the like, and combinations thereof, will be familiar to those skilled in the art (see, e.g., Allen, LV, Jr et al., Remington : The Science and Practice of Pharmacy (Vol. 2), 22nd Edition, Pharmaceutical Press (2012).

The "subject" contemplated for administration is a human (i.e., a male or female of any age group, such as a pediatric subject (e.g., an infant, child, or adolescent) or an adult subject (e.g., a young, middle-aged, or elderly person)) or a non-human animal. In certain embodiments, the non-human animal is a mammal (e.g., a primate (e.g., a crab-eating macaque or a Gangetic monkey), a commercially relevant mammal (e.g., a cow, a pig, a horse, a sheep, a goat, a cat, or a dog), or a bird (e.g., a commercially relevant bird, such as a chicken, a duck, a goose, or a turkey). In certain embodiments, the non-human animal is a fish, a reptile, or an amphibian. The non-human animal can be any The term "patient" refers to a human individual in need of treatment for a disease or condition. An individual (e.g., a human) is "in need of" treatment if the individual (e.g., a human) would benefit biologically, medically, or in terms of quality of life from such treatment, e.g., if the individual suffers from a disease or condition, such as the diseases or conditions disclosed herein.

As used herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease or disorder described herein, or one or more symptoms thereof. In some embodiments, treatment may be achieved by administering a drug or medical care to a subject suffering from a disease or disorder, such as those disclosed herein. In some embodiments, treatment may be achieved by administering a drug or medical care to a subject after one or more symptoms have developed. In other embodiments, treatment may be achieved by administering a drug or medical care to a subject in the absence of symptoms. For example, a drug or medical care may be administered to a susceptible individual before the onset of symptoms (e.g., based on a history of symptoms and/or based on genetic or other susceptibility factors). Administration of the drug or medical care may also continue after symptoms have resolved, e.g., to prevent or delay their recurrence.

As used herein, the term "therapeutically effective amount" refers to an amount of a therapeutic agent (such as a compound of the present invention) sufficient to achieve treatment when administered to an individual (such as a human). The amount of the therapeutic agent that constitutes a "therapeutically effective amount" will vary depending on, for example, the therapeutic agent, the condition being treated and its severity, the mode of administration, the duration of treatment, or the individual to be treated (such as the age, weight, health condition of the individual), but can be routinely determined by a person of ordinary skill in the art based on his or her own knowledge and the present invention. In embodiments, a "therapeutically effective amount" achieves treatment as measured by a statistically significant change in one or more indications, symptoms, signs, diagnostic tests, vital signs, and the like. In other embodiments, a "therapeutically effective amount" treats or prevents a condition as measured by the lack of a statistically significant change in one or more indications, symptoms, signs, diagnostic tests, vital signs, and the like.

The dosing regimen may affect what constitutes a therapeutically effective amount. For example, several divided doses and staggered doses may be administered daily or sequentially, or the dose may be given as a continuous infusion, or may be a bolus injection. Furthermore, the dose may be proportionally increased or decreased as indicated by the exigencies of the therapeutic or preventive situation. Compounds

The first embodiment is a compound having the following structural formula: (I), or a pharmaceutically acceptable salt thereof, wherein: X is O, S, S(O) or S(O) ₂ ; Y is O, S, S(O) or S(O) ₂ ; R ¹ is (C ₅ -C ₁₀ ) heteroaryl optionally substituted by (R ¹⁰ ) _p , such that when p is 0, R ¹ is unsubstituted; each R ¹⁰ is independently halogen, hydroxyl, cyano, (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) halogenalkyl, (C ₁ -C ₃ ) alkoxy(C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkoxy, (C ₃ -C ₆ ) cycloalkyl, (C ₃ -C ₆ ) heterocyclo, phenyl, pyridyl, amino or -C(O)NR ¹¹ R ¹² , or two R ¹⁰ on adjacent atoms of R ¹ together form -CH ₂ -O-CH ₂ -, -CH ₂ CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ CH ₂ -, -O-CH ₂ -O-, or -O-CH ₂ CH ₂ -O-; R ¹¹ and R ¹² are each independently hydrogen or (C ₁ -C ₃ ) alkyl; p is 0, 1, 2, 3 or 4; each R ² is independently halogen, hydroxy, cyano, (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) halogenalkyl, (C ₁ -C ₃ ) alkoxy( _C 1 -C ₃ ) alkyl, (C ₁ -C ₃ ) alkoxy or (C ₃ -C ₆ ) cycloalkyl; each R ³ is independently (C ₁ -C ^R3 is hydrogen _or ( _C1 -C3) alkyl _{; m is 0 , 1 , 2 , 3 or 4} ; n is _{0 , 1 , 2} , _{3 or 4} ; _{and o} ^is _{0 or 1 .}

The second embodiment is a compound having the following structural formula: (I), or a pharmaceutically acceptable salt thereof, wherein: X is O, S, S(O) or S(O) ₂ ; Y is O, S, S(O) or S(O) ₂ ; R ¹ is (C ₅ -C ₁₀ ) heteroaryl substituted by (R ¹⁰ ) _p ; each R ¹⁰ is independently halogen, hydroxy, cyano, (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) halogenalkyl, (C ₁ -C ₃ ) alkoxy(C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkoxy, (C ₃ -C ₆ ) cycloalkyl, (C ₃ -C ₆ ) heterocyclic, phenyl, pyridyl, amino or -C(O)NR ¹¹ R ¹² , or R two R ¹⁰ on adjacent atoms of ^{R 1} together form -CH ₂ -O-CH ₂ -, -CH ₂ CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ CH ₂ -, -O-CH ₂ -O-, or -O-CH ₂ CH ₂ -O-; R ¹¹ and R ¹² are each independently hydrogen or (C ₁ -C ₃ ) alkyl; p is 0, 1, 2, 3 or 4; each R ² is independently halogen, hydroxy, cyano, (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) halogenalkyl, (C ₁ -C ₃ ) alkoxy(C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkoxy or (C ₃ -C ₆ ) cycloalkyl; each R ³ is independently (C ₁ -C ₃ ) alkyl; R ⁴ is hydrogen or (C ₁ -C ₃ )alkyl; m is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3 or 4; and o is 0 or 1.

In the first aspect of the first or second embodiment, X is O or S. The values of the remaining variables are as described in the first or second embodiment.

In the second aspect of the first or second embodiment, X is 0. The values of the remaining variables are as described in the first or second embodiment or the first aspect thereof.

In the third aspect of the first or second embodiment, Y is 0. The values of the remaining variables are as described in the first or second embodiment or its first or second aspect.

In the fourth aspect of the first or second embodiment, Y is S. The values of the remaining variables are as described in the first or second embodiment or the first to third aspects thereof.

In a fifth aspect of the first or second embodiment, R ¹ is (C ₅ -C ₁₀ ) heteroaryl substituted with (R ¹⁰ ) _p . The values of the remaining variables are as described in the first or second embodiment or the first to fourth aspects thereof.

In the sixth aspect of the first or second embodiment, R ¹ is (C ₅ -C ₆ )heteroaryl substituted with (R ¹⁰ ) _p . The values of the remaining variables are as described in the first or second embodiment or the first to fifth aspects thereof.

In the seventh aspect of the first or second embodiment, the heteroaryl group of R ¹ contains one, two or three ring nitrogen atoms. The values of the variables are as described in the first or second embodiment or the first to sixth aspects thereof.

In the eighth aspect of the first or second embodiment, the heteroaryl group of R ¹ contains one or two ring heteroatoms, each of which is nitrogen. The values of the variables are as described in the first or second embodiment or the first to seventh aspects thereof.

In the ninth aspect of the first or second embodiment, the heteroaryl group of R ¹ contains two or three ring heteroatoms, one or two of the two or three ring heteroatoms are nitrogen and one of the two or three ring heteroatoms is oxygen or sulfur. The values of the variables are as described in the first or second embodiment or the first to eighth aspects thereof.

In the tenth aspect of the first or second embodiment, the heteroaryl group of R ¹ is pyrimidinyl, pyrimidinyl, pyrimidinyl, pyridinyl, pyrazolyl, imidazolyl, thiadiazolyl, thiazolyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazolopyridinyl, pyrimidinyl, thiazolopyridinyl or benzothiazolyl. The values of the variables are as described in the first or second embodiment or the first to ninth aspects thereof.

In the eleventh aspect of the first or second embodiment, the heteroaryl group of R ¹ is thiazol-3-yl, thiazol-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrazol-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazol-2-yl, pyrazol-3-yl, pyrazol-4-yl, imidazol-4-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-5-yl, isoxazol-4-yl, oxazol-2-yl, pyrazolo[1,5- a] ]pyridinyl, thiazol-1-yl, thiazolo[4,5- b ]pyridinyl or benzo[ d ]thiazol-2-yl. The values of the variables are as described in the first or second embodiment or the first to tenth aspects thereof.

In the twelfth aspect of the first or second embodiment, each R ¹⁰ is independently halogen, hydroxyl, cyano, (C ₁ -C ₃ )alkyl, (C ₁ -C ₃ )haloalkyl, (C ₁ -C ₃ )alkoxy (C ₁ -C ₃ )alkyl, (C ₁ -C ₃ )alkoxy, (C ₃ -C ₆ )cycloalkyl, (C ₃ -C ₆ )heterocyclic, phenyl, pyridyl, amino or -C(O)NH _2. The values of the remaining variables are as described in the first or second embodiment or the first to eleventh aspects thereof.

In the thirteenth aspect of the first or second embodiment, each R ¹⁰ is independently fluoro, methyl, methoxymethyl, methoxy, amino, trifluoromethyl, cyclopropyl, hydroxyl, cyano, pyridyl or -C(O)NH _2. The values of the remaining variables are as described in the first or second embodiment or the first to twelfth aspects thereof.

In the fourteenth aspect of the first or second embodiment, p is 0, 1 or 2. When p is 0, R ¹ is unsubstituted. The values of the remaining variables are as described in the first or second embodiment or the first to thirteenth aspects thereof.

In the fifteenth aspect of the first or second embodiment, p is 0 or 1. When p is 0, R ¹ is unsubstituted. The values of the remaining variables are as described in the first or second embodiment or the first to fourteenth aspects thereof.

In the sixteenth aspect of the first or second embodiment, p is 0. When p is 0, R ¹ is unsubstituted. The values of the remaining variables are as described in the first or second embodiment or the first to fifteenth aspects thereof.

In the seventeenth aspect of the first or second embodiment, ^R1 is The values of the remaining variables are as described in the first or second embodiment or the first to sixteenth aspects thereof.

In the eighteenth aspect of the first or second embodiment, R ² is a halogen group. The values of the remaining variables are as described in the first or second embodiment or the first to seventeenth aspects thereof.

In the nineteenth aspect of the first or second embodiment, R ² is fluorine. The values of the remaining variables are as described in the first or second embodiment or the first to eighteenth aspects thereof.

In the twentieth aspect of the first or second embodiment, each R ³ is independently methyl or ethyl (and in other aspects, each R ³ is methyl). The values of the remaining variables are as described in the first or second embodiment or the first to nineteenth aspects thereof.

In the twenty-first aspect of the first or second embodiment, m is 0 or 1. The values of the remaining variables are as described in the first or second embodiment or the first to twentieth aspects thereof.

In the twenty-second aspect of the first or second embodiment, m is 0. The values of the remaining variables are as described in the first or second embodiment or the first to twenty-first aspects thereof.

In the twenty-third aspect of the first or second embodiment, m is 1. The values of the remaining variables are as described in the first or second embodiment or the first to twenty-second aspects thereof.

In the twenty-fourth aspect of the first or second embodiment, n is 0, 1 or 2. The values of the remaining variables are as described in the first or second embodiment or the first to twenty-third aspects thereof.

In the twenty-fifth aspect of the first or second embodiment, n is 0. The values of the remaining variables are as described in the first or second embodiment or the first to twenty-fourth aspects thereof.

In the twenty-sixth aspect of the first or second embodiment, o is 0. The values of the remaining variables are as described in the first or second embodiment or the first to twenty-fifth aspects thereof.

In the twenty-seventh aspect of the first or second embodiment, o is 1. The values of the remaining variables are as described in the first or second embodiment or the first to twenty-sixth aspects thereof.

In the twenty-eighth aspect of the first or second embodiment, X is O or S and Y is O. The values of the remaining variables are as described in the first or second embodiment or the first to twenty-seventh aspects thereof.

In the twenty-ninth aspect of the first or second embodiment, X is O or S; Y is O; R ¹ is (C ₅ -C ₁₀ ) heteroaryl substituted by (R ¹⁰ ) _p ; and each R ¹⁰ is independently halogen, hydroxy, cyano, (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) halogenalkyl, (C ₁ -C ₃ ) alkoxy (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkoxy, (C ₃ -C ₆ ) cycloalkyl, (C ₃ -C ₆ ) heterocyclo, phenyl, pyridyl, amino, or -C(O)NH _2. The values of the remaining variables are as described in the first or second embodiment or the first to twenty-eighth aspects thereof.

In the thirtieth aspect of the first or second embodiment, Y is O or S. The values of the remaining variables are as described in the first or second embodiment or the first to twenty-ninth aspects thereof.

In the thirty-first aspect of the first or second embodiment, R ⁴ is hydrogen, methyl or ethyl (and in other aspects, R ⁴ is hydrogen or methyl). The values of the remaining variables are as described in the first or second embodiment or the first to thirtieth aspects thereof.

In the thirty-second aspect of the first or second embodiment, R ⁴ is hydrogen. The values of the remaining variables are as described in the first or second embodiment or the first to thirty-first aspects thereof.

The third embodiment is a compound having the following structural formula: (Ia), or a pharmaceutically acceptable salt thereof, wherein the values of variables (e.g., X, Y, R ¹ , R ² , R ³ , R ⁴ , m, n, o) are as described in the first or second embodiment or any aspect thereof.

The fourth embodiment is a compound having the following structural formula: (Ib), or a pharmaceutically acceptable salt thereof, wherein the values of variables (e.g., X, Y, R ¹ , R ² , R ³ , R ⁴ , m, n, o) are as described in the first or second embodiment or any aspect thereof.

The fifth embodiment is a compound having the structural formula in Table 1, or a pharmaceutically acceptable salt thereof. Table 1.

In one aspect of any of the foregoing embodiments, the compound has the following structural formula: , or a pharmaceutically acceptable salt thereof. In one aspect, in one aspect of any one of the foregoing embodiments, the compound has the following structural formula: , or a pharmaceutically acceptable salt thereof. In one aspect, in one aspect of any one of the foregoing embodiments, the compound has the following structural formula: , or a pharmaceutically acceptable salt thereof. In one aspect, in one aspect of any one of the foregoing embodiments, the compound has the following structural formula: , or a pharmaceutically acceptable salt thereof. In one aspect, in one aspect of any one of the foregoing embodiments, the compound has the following structural formula: , or a pharmaceutically acceptable salt thereof. In one aspect, in one aspect of any one of the foregoing embodiments, the compound has the following structural formula: , or a pharmaceutically acceptable salt thereof. In one aspect, in one aspect of any one of the foregoing embodiments, the compound has the following structural formula: , or a pharmaceutically acceptable salt thereof.

Methods for making the compounds of the invention are described in the examples herein and are known to those skilled in the art. Pharmaceutical Compositions, Combinations and Kits

The compounds of the invention are typically used, for example, in pharmaceutical compositions (eg, pharmaceutical compositions comprising a compound of the invention and one or more pharmaceutically acceptable carriers), for example, according to the methods described herein.

In certain embodiments, provided herein is a composition (e.g., a pharmaceutical composition) comprising a compound of the invention (e.g., a therapeutically effective amount of a compound of the invention) and one or more pharmaceutically acceptable carriers. Examples of carriers and excipients are well known to those skilled in the art and are described in detail in, for example, Ansel, Howard C. et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R. et al., Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, light shielding agents, lubricants, processing aids, coloring agents, sweeteners, aromas, flavorings, diluents and other known additives that make the drug (e.g., the compound of the present invention or its pharmaceutical composition) exquisitely presented or help manufacture pharmaceutical products (e.g., drugs).

Preferably, the pharmaceutically acceptable carrier is sterile. The pharmaceutical composition can be formulated for specific administration routes such as oral administration, parenteral administration (e.g., intravenous administration), and rectal administration. In addition, the pharmaceutical composition of the present invention can be prepared in solid form (including but not limited to capsules, tablets, pills, granules, powders or suppositories) or in liquid form (including but not limited to solutions, suspensions or emulsions). The pharmaceutical composition may be subjected to conventional pharmaceutical operations, such as sterilization, and/or may contain conventional inert diluents, lubricants or buffers, and adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers and buffers. Typically, the pharmaceutical composition is a tablet or gelatin capsule containing the active ingredient and one or more of the following: a)   diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b)   lubricants, such as silicon dioxide, talc, stearic acid, magnesium or calcium stearic acid and/or polyethylene glycol; c)   binders, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; d)   disintegrants, such as starch, agar, alginic acid or its sodium salt or foaming mixture; and e)  Adsorbents, colorants, flavorings and sweeteners. Tablets may be film-coated or enteric-coated according to methods known in the art.

The compositions of the present invention may be administered orally, parenterally, by inhalation, topically, rectally, nasally, buccally, sublingually, vaginally, or via an implantable device. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously. The sterile injectable form of the compositions of the present invention may be an aqueous or oily suspension. Such suspensions may be formulated using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, in the form of a solution in 1,3-butanediol. Among the acceptable vehicles and solvents, water, Ringer's solution and isotonic sodium chloride solution may be used. In addition, sterile non-volatile oils are conventionally used as solvents or suspension media. The pharmaceutically acceptable compositions of the present invention may be orally administered in any orally acceptable dosage form, including capsules, tablets, aqueous suspensions or solutions.

Compositions suitable for oral administration include compounds of the invention (e.g., compounds of Formula I or its subformulae, or pharmaceutically acceptable salts thereof) in the form of tablets, buccal tablets, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use are prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives to provide pharmaceutically refined and palatable preparations. Tablets may contain the active ingredient in admixture with pharmaceutically acceptable nontoxic excipients suitable for the manufacture of tablets. Such excipients are, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrants such as corn starch or alginic acid; binders such as starch, gelatin or gum arabic; and lubricants such as magnesium stearate, stearic acid or talc. Tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period of time. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. Formulations for oral use may be presented in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin; or in the form of soft gelatin capsules in which the active ingredient is mixed with water or an oil medium such as peanut oil, liquid paraffin or olive oil.

Certain injectable compositions contain a compound of the invention (e.g., a compound of formula I or its subformulae, or a pharmaceutically acceptable salt thereof) in the form of an aqueous isotonic solution or suspension, and certain suppositories containing a compound of the invention (e.g., a compound of formula I or its subformulae, or a pharmaceutically acceptable salt thereof) are advantageously prepared from a fat emulsion or suspension. Such compositions may be sterilized and/or contain adjuvants, such as preservatives, stabilizers, wetting agents or emulsifiers, solubility promoters, salts for regulating osmotic pressure, and/or buffers. In addition, they may also contain other therapeutically valuable substances. The compositions are prepared according to known mixing, granulating or coating methods, and contain about 0.1-75% of the active ingredient, or about 1-50% of the active ingredient.

Compositions suitable for transdermal administration include a compound of the invention (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt thereof) and a suitable carrier. Carriers suitable for transdermal delivery include absorbable pharmacologically acceptable solvents to assist in passage through the host's skin. For example, the transdermal device is in the form of a bandage comprising a backing member, a reservoir containing the compound and, if appropriate, a carrier, an optional rate-controlling barrier that delivers the compound to the host's skin at a controlled and predetermined rate over a prolonged period of time, and means for securing the device to the skin.

Compositions comprising a compound of the invention (e.g., a compound of Formula I or a subformulae thereof, or a pharmaceutically acceptable salt thereof) suitable for topical application (e.g., to the skin and eyes) include aqueous solutions, suspensions, ointments, creams, gels or spray formulations, e.g., for delivery by aerosol or the like. Such topical delivery systems will be particularly suitable for dermal administration, e.g., for the treatment of skin cancer, e.g., for preventive use in the form of sunscreens, lotions, sprays and the like. Thus, they are particularly suitable for topical (including cosmetic) formulations well known in the art. Such formulations may contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.

As used herein, topical administration may also involve inhalation or intranasal administration. Compositions suitable for inhalation or intranasal administration may be conveniently delivered in dry powder form (alone; as a mixture, for example, a dry blend with lactose; or mixed component particles, for example, mixed with phospholipids) from a dry powder inhaler, or in aerosol spray form from a pressurized container, pump, atomizer, nebulizer or aerosol dispenser, with or without a suitable propellant.

The present invention further provides anhydrous pharmaceutical compositions and dosage forms comprising compounds provided herein (e.g., compounds of Formula I or its subformulae) or pharmaceutically acceptable salts thereof, because water can promote the degradation of certain compounds. The anhydrous pharmaceutical compositions and dosage forms of the present invention can be prepared using anhydrous or low-water-containing ingredients and low-water or low-humidity conditions. Anhydrous pharmaceutical compositions can be prepared and stored in a manner that maintains their anhydrous nature. Therefore, anhydrous compositions are packaged using materials known to prevent exposure to water so that they can be included in a suitable prescription set. Examples of suitable packaging include, but are not limited to, airtight sealed foils, plastics, unit dose containers (e.g., vials), blister packaging, and strip packaging.

The present invention further provides pharmaceutical compositions and dosage forms comprising one or more agents that reduce the decomposition rate of the active ingredient of the compound of the present invention (e.g., a compound of Formula I or its subformula, or a pharmaceutically acceptable salt thereof). Such agents referred to herein as "stabilizers" include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.

The compounds of the present invention (e.g., compounds of Formula I or its subformulae, or pharmaceutically acceptable salts of the foregoing) are generally formulated into pharmaceutical dosage forms to provide easily controllable drug dosages and to provide patients with an elegant and easy-to-handle product. Of course, the dosing regimen of the compounds of the present invention will vary depending on known factors such as the pharmacodynamic characteristics of a particular agent and its mode and route of administration; the species, age, sex, health condition, medical condition, and weight of the recipient; the nature and extent of symptoms; the type of concurrent treatment; the frequency of treatment; the route of administration, the patient's renal and liver function, and the desired effect. The compounds of the present invention may be administered in a single daily dose, or the total daily dose may be administered in divided doses, such as twice, three, or four times a day.

In some cases, it may be advantageous to administer a compound of the invention (eg, a compound of Formula I or a subformulae thereof, or a pharmaceutically acceptable salt of the foregoing) in combination with one or more additional therapeutic agents.

The term "combination therapy" refers to the administration of two or more therapeutic agents to treat the diseases or conditions described herein. Such administration encompasses the co-administration of the therapeutic agents in a substantially simultaneous manner, such as in a single capsule form with a fixed ratio of active ingredients. Alternatively, such administration encompasses the co-administration of each active ingredient in multiple or separate containers (e.g., capsules, powders, and liquids). Such administration also encompasses the use of various types of therapeutic agents at approximately the same time or at different times in a sequential manner. The compounds of the present invention (e.g., compounds of Formula I or its subformulae, or pharmaceutically acceptable salts of the foregoing) and one or more additional therapeutic agents may be administered via the same route of administration or via different routes of administration. Prior to administration, the powder and/or liquid may be reconstituted or diluted to the desired dosage. In general, the treatment regimen will provide the beneficial effects of the drug combination in treating the diseases or conditions described herein.

Compositions for combination therapy will be formulated together as a pharmaceutical combination, or provided for separate administration (e.g., in a kit). Therefore, another embodiment is a pharmaceutical combination comprising a compound of the invention (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt of the foregoing) (e.g., a therapeutically effective amount of a compound of the invention) and one or more additional therapeutic agents (e.g., a therapeutically effective amount of one or more other therapeutic agents). The pharmaceutical combination may further comprise one or more pharmaceutically acceptable carriers, such as one or more pharmaceutically acceptable carriers described herein.

Another embodiment is a kit comprising a compound of the invention (e.g., a pharmaceutical composition comprising a compound of the invention) and one or more additional therapeutic agents (e.g., one or more pharmaceutical compositions comprising one or more additional therapeutic agents). The kits of the invention typically include instructions for administering the therapeutic agents contained therein, for example, to treat a disease or condition described herein.

In the combination therapy of the present invention, the compound of the present invention and the other therapeutic agent may be manufactured and/or formulated by the same or different manufacturers. In addition, the compound of the present invention and the other therapeutic agent may be integrated into the combination therapy in the following situations: (i) before the combination product is handed over to the physician (for example, in the case of a kit containing the compound of the present invention and the other therapeutic agent); (ii) by the physician himself (or under the guidance of the physician) shortly before administration; (iii) by the patient himself, for example, during the sequential administration of the compound of the present invention and the other therapeutic agent.

Suitable pharmaceutical agents that can be used in combination with the compounds of the present invention include anti-Parkinson's drugs, anti-Alzheimer's drugs, antidepressants, antipsychotics, anti-ischemic drugs, CNS sedatives, anticholine agonists, nootropics, epilepsy drugs, attention (e.g., attention deficit disorder (ADD)/attention deficit hyperactivity disorder (ADHD)) drugs, sleep-promoting drugs, wakefulness-promoting drugs, analgesics, anti-obesity drugs (e.g., appetite suppressants), anti-diabetic agents, anti-hyperglycemic agents, lipid-lowering agents, and anti-hypertensive agents.

Suitable anti-Parkinson's disease drugs include dopamine replacement therapy (e.g., L-DOPA, carbidopa, catechol O-methyltransferase (COMT) inhibitors such as entacapone or tolcapone), dopamine agonists (e.g., D1 agonists, D2 agonists, mixed D1/D2 agonists, bromocriptine, pergolide, cabergoline, ropinirole, ), pramipexole, piribedil, or a combination of apomorphine and domperidone), histamine H2 antagonists, monoamine oxidase inhibitors (such as selegiline, rasagiline, safinamide, and tranylcypromine), certain atypical antipsychotics, such as pimavanserin (a non-dopaminergic atypical antipsychotic and inverse agonist of the serotonin 5-HT _2A receptor), and ramantadine.

The compounds of the invention may be used in combination with: levodopa (with or without a selective extracerebral decarboxylase inhibitor such as carbidopa or benserazide); anticholine agonists such as biperiden (in the form of its hydrochloride or lactate, as appropriate) and trihexyphenidyl (benzhexol) hydrochloride; COMT inhibitors such as entacapone or tolcapone; monoamine oxidase (MAO) inhibitors. A/B inhibitors; antioxidants; A2a adenosine receptor antagonists; choline agonists; N-methyl D-aspartate (NMDA) receptor antagonists; serotonin receptor antagonists; and dopamine receptor agonists such as alentemol, bromocriptine, fenoldopam, lisuride, naxagolide, pergolide, or pramipexole. It will be appreciated that dopamine agonists may be in the form of pharmaceutically acceptable salts, such as alendronate hydrobromide, bromocriptine mesylate, fenoldopam mesylate, nagolide hydrochloride and pergolide mesylate. Ergolide and pramipexole are usually used in non-salt form.

Suitable anti-Alzheimer's disease drugs include β-secretase inhibitors; γ-secretase inhibitors; cholinesterase inhibitors, such as donepezil, galantamine or rivastigmine); HMG-CoA reductase inhibitors; nonsteroidal anti-inflammatory drugs (NSAIDs), including ibuprofen; vitamin E; and anti-amyloid antibodies. In some embodiments, the anti-Alzheimer's disease drug is memantine.

Suitable antidepressants and antianxiety agents include norepinephrine reuptake inhibitors (including tertiary amine tricyclic compounds and diamine tricyclic compounds), selective serotonin reuptake inhibitors (SSRI), monoamine oxidase inhibitors (MAOI), reversible inhibitors of monoamine oxidase (RIMA), serotonin and norepinephrine reuptake inhibitors (SNRI), corticotropin releasing factor (CRF) antagonists, α-adrenaline receptor antagonists, neurokinin-1 receptor antagonists, atypical antidepressants, benzodiazepines, 5-HT1A agonists or antagonists, especially 5-HT1A partial agonists and corticotropin releasing factor (CRF) antagonists.

Specific, suitable antidepressants and antianxiety agents include amitriptyline, clomipramine, doxepin, imipramine, and trimipramine; amoxapine, desipramine, citalopram, escitalopram, maprotiline, nortriptyline, and tadalafil. protriptyline; fluoxetine, fluvoxamine, paroxetine, and sertraline; isocarboxazid, phenelzine, tranylcypromine, and selegiline; moclobemide: venlafaxine; desvenlafaxine xine, duloxetine; aprepitant; bupropion, vilazodone, mirtazapine, lithium, nefazodone, trazodone, and viloxazine; alprazolam, chlordiazepoxide, clonazepam, chlorazep ate), diazepam, halazepam, lorazepam, oxazepam and prazepam; buspirone, flesinoxan, gepirone and ipsapirone, reboxetine, vortioxetine, clorazepate and ketamine, and pharmaceutically acceptable salts thereof. In some embodiments, the suitable antidepressant and antianxiety agent is tianeptine, or a pharmaceutically acceptable salt thereof.

Antipsychotics are usually classified as "typical" and "atypical" antipsychotics. In general, typical antipsychotics act on the dopamine-stimulated system, blocking dopamine type 2 (D2) receptors. Atypical antipsychotics have lower affinity and occupancy for dopamine-stimulated receptors and higher occupancy for serotonin-stimulated 5-HT2A receptors. Commonly used typical antipsychotics include: haloperidol, loxapine, thioridazine, molindone, thiothixene, fluphenazine, mesoridazine, trifluoperazine, perphenazine, and chlorpromazine. Commonly used atypical antipsychotics include aripiprazole, clozapine, ziprasidone, risperidone, quetiapine, and olanzapine.

Suitable antipsychotics and mood stabilizers include D2 antagonists, 5HT2A antagonists, atypical antipsychotics, lithium and anticonvulsants. Specific, suitable antipsychotics and mood stabilizers include chlorpromazine, fluphenazine, haloperidol, amisulpride, phenazone, thioridazine, trifluoperazine, aripiprazole, asenapine, clozapine, olanzapine, paliperidone, brepizole, paliperidone, calipiramide, pimavanserin, iloperidone, lumateperone, MIN-101, quetiapine, risperidone, zirasidone, lurasidone, flupentixol, levomiprofen, tadalafil, tadalafil, sirolimus ... levomepromazine, pericyazine, phenazone, pimozide, prochlorperazine, zuclopenthixol, olanzapine and fluoxetine, lithium, carbamazepine, lamotrigine, valproic acid, iloperidone, thiothixene, gabapentin, tiagabine, and their pharmaceutically acceptable salts.

Suitable epilepsy drugs include levetiracetam, oxcarbazepine, clobazam, retigabine, zonisamide, felbamate, esclicarbazepine acetate, lacosamide, carbamazepine, tiagabine, methsuximide, progabide, valproic acid, lamotrigine, brivaracetam, rufinamide, topiramate and perampanel.

Suitable attention medications include methyl phenidate, atomoxetine, guanfacine, D-amphetamine, lisdexamphetamine, methylamphetamine, and clonidine.

Suitable sleep-promoting drugs include ramelteon, triazolam, zopiclone, eszopiclone, zolpidem, temazepam and trazodone.

Suitable wakefulness-enhancing drugs include modafinil, D-amphetamine, caffeine, and armodafinil.

Suitable analgesics include dextromethorphan, tapentadol, buprenorphine, codeine, fentanyl, hydrocodone, hydromorphone, morphine, naloxegol, oxycodone, tramadol, gabapentil, difluprednate, pregabalin, acetyl salicylic acid, bromfenac, diclofenac, diflunisal, indomethacin, ketorolac, meoxican and naproxen.

Suitable lipid-lowering agents that can be used in combination with the compounds of the present invention include, but are not limited to, bile acid chelators, HMG-CoA reductase inhibitors, HMG-CoA synthase inhibitors, cholesterol absorption inhibitors, acyl coenzyme A-cholesterol acyltransferase (ACAT) inhibitors, cholesterol ester transfer protein (CETP inhibitors), squalene synthase inhibitors, peroxisome proliferator-activated receptor (PPAR)-α agonists, farnesoid X receptor (FXR) modulators, liver X receptor (LX R) regulators, lipoprotein synthesis inhibitors, renin-angiotensin system inhibitors, PPAR-δ partial agonists, bile acid reabsorption inhibitors, PPAR-γ agonists, triglyceride synthesis inhibitors, microsomal triglyceride transport inhibitors, transcriptional regulators, squalene epoxidase inhibitors, low-density lipoprotein receptor inducers, platelet aggregation inhibitors, 5-lipoxygenase (5-LO) or 5-lipoxygenase activating protein (FLAP) inhibitors, niacin and niacin-bound chromium.

Suitable antihypertensive agents that can be used in combination with the compounds of the present invention include, but are not limited to, diuretics, β-adrenaline blockers, calcium channel blockers, angiotensin converting enzyme (ACE) inhibitors, neutral endopeptidase inhibitors, endothelin antagonists, vasodilators, angiotensin II receptor antagonists, α/β adrenaline blockers, α1 blockers, α2 agonists, aldosterone inhibitors, halocorticoid receptor inhibitors, renin inhibitors and angiopoietin 2 binding agents.

Suitable antidiabetic agents that can be used in combination with the compounds of the present invention include, but are not limited to, other acetyl-CoA carboxylase (ACC) inhibitors, diacylglycerol O-transferase 1 (DGAT-1) inhibitors, AZD7687, LCQ908, DGAT-2 inhibitors, monoacylglycerol O-acyltransferase inhibitors, phosphodiesterase 10 inhibitors, (PDE-10) inhibitors, 5-AMP-activated protein kinase (AMPK) activators, sulfonylureas (e.g., acetohexamide, chlorpropamide, diabinese, glibenclamide, glipizide, glyburide, blimipiride, gliclazide, glipentide, gliquidone, glisolamide, tolbutamide, tolazamide, tolbutamide), meglitinides, α-amylase inhibitors (e.g., tendamistat, treastatin, AL-3688), α-glucosidase inhibitors (e.g., acarbose), α-glucosidase inhibitors (e.g., adiposine, camiglibose, emiglitate, miglitol, voglibose, pradimacin-Q pradimicin-Q, sarbostatin), PPAR-γ agonists (e.g., balaglitazone, ciglitazone, darglitazone, englitazone, isaglitazone, pioglitazone, rosiglitazone, troglitazone), PPAR-α/γ agonists (e.g., C LX-0940, GW-1536, GW-1929, GW-2433, KRP-297, L-796449, LR-90, MK-0767, SB-219994), biguanides (e.g. metformin, buformin), glucagon-like peptide-1 receptor (GLP-1) modulators (e.g. exendin-3, exendin-4), liraglutide, albiglutide, exenatide (Byetta), taspoglutide, lixisenatide, dulaglutide, semaglutide, N,N-9924, TTP-054, protein tyrosine phosphatase 1B (PTP-1B) inhibitors (trodusquemine, hyrtiosal extract), sempervivin-1 (SIRT-1) inhibitors (e.g. resveratrol, GSK2245840, GSK184072), DPP-IV inhibitors (e.g. sitagliptin, vildagliptin, alogliptin, dutogliptin, linagliptin, saxagliptin), insulin secretagogues, fatty acid oxidation inhibitors, A2 antagonists, c-Jun N -terminal kinase (JNK) inhibitors, glucokinase activators (such as TTP-399, TTP-355, TTP-547, AZD1656, ARRY403, MK-0599, TAK-329, AZD5658, GKM-001), insulin, insulin mimetics, glycogen phosphorylase inhibitors (such as GSK1362885), pulsatile polypeptide receptor 2 (VPAC2) receptor agonists, sodium/glucose cotransporter 2 (SGLT2) inhibitors (dapagliflozin, canagliflozin, BI-10733, tofogliflozin, ASP-1941, THR1474, TS-071, ISIS388626, LX4211), glucagon receptor modulators, G protein-coupled receptor 119 (GPR119) modulators (e.g. MBX-2982, GSK1292263, APD597, PSN821), FGF21 derivatives, TGR5 (GPBAR1) receptor agonists (e.g. INT777), GPR40 agonists (e.g. TAK-875), GPR120 agonists, niacin receptor (HM74A) agonists, SGLT1 inhibitors (e.g. GSK1614235), carnitine ester transferase inhibitors, fructose 1,6-bisphosphatase inhibitors, aldose reductase inhibitors, salvocorticoid receptor inhibitors, rapamycin target complex 2 (TORC2) inhibitors, CC chemokine receptor 2 (CCR2) inhibitors, CCR5 inhibitors, protein kinase C (PKC; e.g., PKC-α, PKC-β, PKC-γ) inhibitors, fatty acid synthase inhibitors, serine phosphotransferase inhibitors, GPR81 modulators, GPR39 modulators, GPR43 modulators, GPR41 modulators, GPR105 modulators, Kv1.3 inhibitors, retinol binding protein 4 inhibitors, glucocorticoid receptor modulators, somatostatin receptor (e.g., SSTR1, SSTR2, SSTR3, SSTR5) inhibitors, pyruvate dehydrogenase kinase isoform 2 (PDHK2) inhibitors, PDHK4 inhibitors, mitogen-activated protein kinase 4 (MAP4K4) inhibitors, IL1-β modulators, and RXR-α modulators.

Suitable anti-obesity agents include, but are not limited to, 11-β-hydroxysteroid dehydrogenase 1 inhibitors, stearoyl-CoA desaturase (SCD-1) inhibitors, melanocortin 4 receptor (MCR-4) agonists, cholecystokinin A receptor (CCK-A) agonists, monoamine reuptake inhibitors (e.g., sibutramine), sympathomimetic agents, β-3-adrenaline agonist receptor agonists, dopamine receptor agonists (e.g., bromocriptine), melanocyte stimulating hormone and its analogs, 5-HT _2C agonists (e.g., lorcaserin/Belviq), melanin concentrating hormone antagonists, leptin, leptin analogs, leptin agonists, galanin antagonists, lipase inhibitors (e.g., tetrahydrolipstatin/Orlistat), anorexia (e.g., bombesin agonists), neuropeptide Y (NPY) antagonists (e.g., velneperit), PYY _{3 - 36} (and its analogs), BRS3 modulators, mixed opioid receptor antagonists, pseudothyroid agents, dehydroepiandrosterone, glucocorticoid agonists or antagonists, orexin antagonists, GLP-1 agonists, ciliary neurotrophic factors (e.g., Axokine), human AGRP inhibitors, H3 antagonists or inverse agonists, nerve MetAp2 inhibitors (such as ZGN-433), glucagon, gastric inhibitory polypeptide (GIP) and glucagon-like peptide 1 Agents with mixed modulatory activity at two or more of the GLP1 receptors (e.g., MAR-701, ZP2929), norepinephrine reuptake inhibitors, opioid antagonists (e.g., naltrexone), cannabinoid receptor 1 (CB1) antagonists or inverse agonists, gastrin agonists or antagonists, oxytocin and its analogs, monoamine uptake inhibitors (e.g., tesofensine) and combinations (e.g., buproprion plus zonisamide (Empatic), pramlintide plus metreleptin, buproprion plus naltrexone (Contrave), phentermine plus topiramate) (Qsymia).

In some embodiments, the anti-obesity agent used in combination with the compounds of the present invention is selected from the group consisting of digestive tract selective MTP inhibitors (e.g., dilopride, mitratapide, implitapide, R56918), CCK-A agonists, 5-HT _2C agonists (e.g., lorcaserin/bevic), MCR4 agonists, lipase inhibitors (e.g., Cetilistat), PYY _3-36 (including analogs and pegylated analogs thereof), opioid antagonists (e.g., naltrexone), oleylestrone, obinepitide, pramlintide, tasofolcin _{, leptin} , bromocriptine, orlistat, AOD-9604, and sibutramine.

In some embodiments, the compounds of the invention and compositions disclosed herein can be used in combination with other therapies. Suitable therapies include psychotherapy, cognitive behavioral therapy, electroconvulsive therapy, transcranial magnetic stimulation, vagus nerve stimulation, and deep brain stimulation. Other suitable therapies include adjusting the individual's diet and/or exercise program.

For ease of administration and uniformity of dosage, the compounds and compositions of the present invention are preferably formulated in unit dosage form. As used herein, the expression "unit dosage form" refers to a physically discrete unit of a drug suitable for an individual to be treated. However, it should be understood that the total daily dosage of the compounds and compositions of the present invention will be determined by the attending physician within the scope of reasonable medical judgment.

The amount of the compound of the invention that can be combined with a carrier material to produce a composition in a single dosage form will vary depending on a variety of factors, including, for example, the host being treated and the specific mode of administration. For example, a unit dosage form may contain about 1 to about 1000 mg of active ingredient for an individual of about 50 to about 70 kg, or about 1 to about 500 mg, about 1 to about 250 mg, about 1 to about 150 mg, about 0.5 to about 100 mg, or about 1 to about 50 mg of active ingredient for an individual of about 50 to about 70 kg. In some embodiments, a unit dosage form contains about 1 mg to about 50 mg of the compound of the invention, such as about 5 mg to about 45 mg, about 10 mg to about 40 mg, about 10 mg to about 30 mg, or about 20 mg. It should also be understood that the specific dosage and treatment regimen for any particular individual will depend on a variety of factors, including the activity of the specific compound used, age, weight, general health, sex, diet, time of administration, excretion rate, drug combination, and the judgment of the treating physician and the severity of the specific disease being treated. The amount of the compound of the present invention in the composition will also depend on the specific compound in the composition.

Pharmaceutical compositions (or formulations) for administration may be packaged in a variety of ways, depending on the method used to administer the drug. Generally, an article for distribution includes a container in which the pharmaceutical formulation is stored in an appropriate form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like. The container may also include a tamper-evident fitting to prevent easy access to the contents of the package. Additionally, the container is affixed with a label describing the contents of the container. The label may also include appropriate warnings.

In some embodiments, the concentration of one or more therapeutic agents provided in the pharmaceutical composition is less than 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0. 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001% w/w, w/v or v/v.

In some embodiments, the concentration of one or more therapeutic agents provided in the pharmaceutical composition is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%, 19%, 18.75%, 18.50%, 18.25%, 18%, 17.75%, 17.50%, 17.25%, 17%, 16.75%, 16.50%, 16.25%, 16%, 15.75%, 15.50%, 15 .25%, 15%, 14.75%, 14.50%, 14.25%, 14%, 13.75%, 13.50%, 13.25%, 13%, 12.75%, 12.50%, 12.25%, 12%, 11.75 %, 11.50%, 11.25%, 11%, 10.75%, 10.50%, 10.25%, 10%, 9.75%, 9.50%, 9.25%, 9%, 8.75%, 8.50%, 8.25%, 8%, 7. 75%, 7.50%, 7.25%, 7%, 6.75%, 6.50%, 6.25%, 6%, 5.75%, 5.50%, 5.25%, 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3 .50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 125%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.0 0.002%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w/w, w/v, or v/v.

In some embodiments, the concentration of one or more therapeutic agents provided in the pharmaceutical composition is in the range of about 0.0001% to about 50%, about 0.001% to about 40%, about 0.01% to about 30%, about 0.02% to about 29%, about 0.03% to about 28%, about 0.04% to about 27%, about 0.05% to about 26%, about 0.06% to about 25%, about 0.0 From about 7% to about 24%, from about 0.08% to about 23%, from about 0.09% to about 22%, from about 0.1% to about 21%, from about 0.2% to about 20%, from about 0.3% to about 19%, from about 0.4% to about 18%, from about 0.5% to about 17%, from about 0.6% to about 16%, from about 0.7% to about 15%, from about 0.8% to about 14%, from about 0.9% to about 12%, from about 1% to about 10% w/w, w/v or v/v.

In some embodiments, the concentration of one or more therapeutic agents provided in the pharmaceutical composition is in the range of about 0.001% to about 10%, about 0.01% to about 5%, about 0.02% to about 4.5%, about 0.03% to about 4%, about 0.04% to about 3.5%, about 0.05% to about 3%, about 0.06% to about 2.5%, about 0.07% to about 2%, about 0.08% to about 1.5%, about 0.09% to about 1%, about 0.1% to about 0.9% w/w, w/v or v/v. Methods of Use

It has now been discovered that compounds of the invention modulate (e.g., agonize) trace amine associated receptor 1 (TAAR1). Thus, provided herein are methods of modulating (e.g., agonizing) TAAR1 in a cell (e.g., a cell expressing TAAR1), comprising contacting the cell with a compound of the invention (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt thereof, such as a therapeutically effective amount of a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt thereof).

When the methods described herein comprise contacting a cell with a compound of the invention, it is understood that the method can be performed in vitro, ex vivo, or in vivo. Thus, some embodiments comprise contacting the cell ex vivo. Some embodiments comprise contacting the cell ex vivo. Some embodiments comprise contacting the cell in vivo, for example when the cell is in a subject such as a human (e.g., a subject in need thereof).

Thus, also provided herein is a method of modulating (e.g., agonizing) TAAR1 in a subject in need thereof (e.g., a subject suffering from a disease, disorder, or condition described herein, such as a neurological or psychiatric disease or disorder, or a metabolic disease, disorder, or condition described herein), comprising administering to the subject a compound of the invention (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt thereof). Some embodiments comprise administering to the subject a therapeutically effective amount of a compound of the invention. Some embodiments comprise administering a compound of the invention in an amount sufficient to modulate (e.g., agonize) TAAR1 in the subject.

The compounds of the invention may selectively modulate (eg, agonize) TAAR1, or they may exhibit activities instead of or in addition to TAAR1 modulating activity. For example, certain compounds of the invention have been found to modulate (eg, agonize) the serotonin 1A receptor (5-HT1A).

Thus, in certain embodiments, the compounds of the invention are selective for TAAR1, e.g., selectively stimulating TAAR1 in a cell or an individual. When a compound is described herein as being "selective" for a particular target, such as TAAR1, the compound binds to the designated target more than, for example, another target or other potential target encountered in the cell. Selectivity can be measured by dividing the EC ₅₀ or IC ₅₀ value of the compound modulating (e.g., stimulating, inhibiting) the activity of a particular target by the EC ₅₀ or IC ₅₀ value of the compound modulating (e.g., stimulating, inhibiting) the activity of another target. Selectivity can also be measured by dividing the K _d value of the adduct of the compound with the particular target by the K _d value of the adduct of the compound with the other target. Under similar testing conditions, the selectivity can be at least 2-fold, at least 3-fold, at least 5-fold, at least 10-fold, at least 30-fold, at least 50-fold, at least 100-fold, or greater than 100-fold.

In other embodiments, the compounds of the invention modulate (e.g., agonize) 5-HT1A. In other embodiments, the compounds of the invention modulate (e.g., bind to) 5-HT1A. For example, in certain embodiments, the compounds of the invention modulate (e.g., agonize) 5-HT1A and modulate (e.g., agonize) TAAR1. In certain embodiments, the compounds of the invention modulate (e.g., bind to) 5-HT1A and modulate (e.g., agonize) TAAR1.

Provided herein are methods for modulating (e.g., stimulating) 5-HT1A in a cell (e.g., a cell expressing 5-HT1A), comprising contacting the cell with a compound of the invention (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt thereof, such as a therapeutically effective amount of a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt thereof).

Also provided herein is a method of modulating (e.g., agonizing) 5-HT1A in a subject in need thereof (e.g., a subject suffering from a disease, disorder, or condition described herein, such as a neurological or psychiatric disease or disorder, or a metabolic disease, disorder, or condition described herein), comprising administering to the subject a compound of the invention (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt thereof). Some embodiments comprise administering to the subject a therapeutically effective amount of a compound of the invention. Some embodiments comprise administering a compound of the invention in an amount sufficient to modulate (e.g., agonize) 5-HT1A in the subject.

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition ("DSM-5"), published by the American Psychiatric Association in 2013, and revisions or supplements, provides a standard diagnostic system upon which the skilled person relies for the diagnosis of a wide variety of diseases and conditions and is hereby incorporated by reference in its entirety. DSM-5 attempts to include most patients with subsyndromal mixed symptoms (including mixed specifiers). In addition, the International Classification of Diseases (ICD 11) coding system is a recognized system for conveying specific diagnoses (e.g., for billing purposes in the United States) and is hereby incorporated by reference in its entirety. Chapter 5 of ICD 11 deals with endocrine, nutritional or metabolic disorders, and Chapter 6 of ICD 11 deals with mental, behavioural or neurodevelopmental disorders.

The present invention relates to the use of the compounds of the present invention and the compositions disclosed herein for treating a neurological or psychiatric disease or disorder. Thus, provided herein is a method for treating a neurological or psychiatric disease or disorder in an individual in need thereof, comprising administering a compound of the present invention (e.g., a therapeutically effective amount of a compound of the present invention) to the individual. In some embodiments, the neurological or psychiatric disease or disorder is described in Chapter 6 of the revised or supplemented DSM-5 or International Statistical Classification of Diseases (ICD 11) coding system.

Non-limiting examples of categories of neurological or psychiatric diseases or disorders include movement disorders; cognitive disorders; pain; neurodevelopmental disorders; schizophrenia spectrum and other psychiatric disorders; bipolar disorder and related disorders; depression; anxiety disorders; obsessive-compulsive disorder and related disorders; trauma and stress-related disorders; dissociative disorders; somatic symptoms and related disorders; eating and eating disorders; elimination disorders; sleep-wake disorders; sexual dysfunction; gender dysphoria; disruptive, impulse control and conduct disorders; substance-related and addiction disorders; neurocognitive disorders; personality disorders; paraphilia; other psychiatric disorders; and drug-induced movement disorders and other side effects of drugs. Non-limiting examples of neurological or psychiatric diseases or disorders include: movement disorders

Tremor; dyskinesia; hypotonia; tics; dysphonia; ataxia (e.g., spinocerebellar ataxia); myoclonus; spontaneous tremor; epilepsy; tardive dyskinesia; restless legs syndrome; Tourette syndrome; multiple system atrophy (MSA); multiple sclerosis; Huntington's Disease; Parkinson's disease Disease); Parkinsonism; atypical Parkinson's disease (including, for example, Parkinson's disease tremor); Wilson's Disease; stroke. Examples of akinesia and akinesia-catalepsy syndrome include Parkinson's disease, drug-induced Parkinson's disease, postencephalitis Parkinson's disease, secondary Parkinson's disease, Parkinson's plus syndrome, atypical Parkinson's disease Parkinson's disease, idiopathic Parkinson's disease, progressive supranuclear palsy, multiple systems atrophy, corticobasal degeneration, Parkinson's disease-ALS dementia syndrome and basal ganglia calcification, Drug-induced Parkinson's disease (such as neuroleptic-induced Parkinson's disease, neuroleptic malignant syndrome, neuroleptic-induced acute hypotonia, neuroleptic-induced acute akathisia, neuroleptic-induced delayed dyskinesia and drug-induced postural tremor), Tourette syndrome, epilepsy, muscle spasms and conditions related to muscle spasms or weakness, including tremor. Examples of dyskinesia include drug-induced dyskinesia (e.g., L-DOPA), tremors (e.g., static tremor, postural tremor, intention tremor), chorea (e.g., Sydenham's chorea, Huntington's Leydens disease, benign hereditary chorea, neuroacanthocytosis, symptomatic chorea, drug-induced chorea and hemiprojection), muscle claudication (including generalized and focal muscle claudication) , tics (including simple tics, complex tics and symptomatic tics). Examples of hypotonia include generalized hypotonia, idiopathic hypotonia, drug-induced hypotonia, symptomatic hypotonia, episodic hypotonia, focal hypotonia, blepharospasm, oral hypotonia Mandibular hypotonia, spasmodic dysphonia, spasmodic torticollis, axial hypotonia, hypotonic writer's cramp, and hemiplegic hypotonia. Other examples of movement diseases or disorders include stereotypic movement disorders, persistent (chronic) movement disorders, drug-induced movement disorders, psychogenic movement disorders, substance/drug-induced movement disorders, extrapyramidal movement disorders, and hyperkinetic movement disorders. , akinetic dyskinesia, alternating hemiplegia, Angelman syndrome, Hallervorden-Spatz Disease, ataxia, odontocerebellar ataxia, Telangiectatic ataxia (Louis-Bar syndrome), Friedreich's Ataxia, hereditary spinal ataxia, hereditary myelosclerosis, Machado-Joseph disease Disease), spinocerebellar ataxia, progressive myoclonic ataxia, athetosis, twitching, blepharospasm (eye twitching), cerebral palsy, tardive hypotonia, tardive dyskinesia Difficult, idiopathic torsional hypotonia, torsional hypotonia, focal Muscle hypotonia, idiopathic familial hypotonia, idiopathic non-familial hypotonia, cervical hypotonia (spastic torticollis), primary hypotonia, orofacial hypotonia, developmental coordination disorder, bulbar muscle atrophy (Kennedy's disease) Disease), Shy-Drager syndrome (Shy-Drager syndrome) Syndrome) and Stiff-Person Syndrome/Stiff-Man Syndrome. In some embodiments, the present invention provides a method for treating one or more symptoms of epilepsy and/or epileptic seizures, including abdominal epilepsy, absence epileptic seizures, acquired epilepsy, Acquired epileptic aphasia, Aicardi syndrome, Alpers' disease, Alpers-Huttenlocher syndrome, Angelman syndrome, benign Focal epilepsy, benign focal epilepsy of childhood, benign intracranial hypertension, benign rolandic epilepsy epilepsy, BRE), CDKL5 disorder, childhood absence epilepsy, odontocerebellar ataxia, Doose syndrome, Dravet syndrome, cognitive impairment focal epileptic seizures, epilepsy with grand mal, epilepsy with myoclonic-absence, epileptic hemiplegia, febrile epileptic seizure, focal epileptic seizure, frontal lobe epilepsy, generalized tonic-clonic epileptic seizure, hereditary epilepsy, Glu t1 deficiency syndrome, hypothalamic hamartoma, idiopathic epilepsy, idiopathic generalized epilepsy, idiopathic location-related epilepsy, idiopathic focal epilepsy, idiopathic epileptic seizure, juvenile absence Epilepsy, juvenile myoclonic epilepsy, Lafora disease disease), Lafora progressive myoclonic epilepsy, Landau-Kleffner syndrome, Lassueur-Graham-Little syndrome, Lennox syndrome Lennox syndrome, Lennox-Gastaut syndrome, drug-refractory epilepsy, medial temporal sclerosis, myoclonic epileptic seizures, neonatal epilepsy, occipital epilepsy, Ohtawara Ohtahara syndrome, Panayiotopoulos syndrome syndrome), parietal epilepsy, PCDH19 epilepsy, photosensitive epilepsy, progressive myoclonic epilepsy, Rasmussen's encephalitis, Rasmussen's syndrome, refractory epilepsy , epilepsy, epilepsy continua, Sturge-Weber syndrome, symptomatic generalized epilepsy, symptomatic focal epilepsy, TBCK-related ID syndrome, temporal epilepsy, temporal epilepsy , tonic-clonic seizures, West syndrome syndrome), tremor, cerebellar tremor, cerebellar outflow tract tremor, intention tremor, spontaneous tremor, benign spontaneous tremor, Parkinson's tremor, and drug-induced postural tremor. Cognitive impairment

Alzheimer's disease; cognitive impairment; dementia (including, for example, semantic dementia; frontotemporal dementia; dementia with depressive traits; subcortical dementia; dementia with Lewy bodies; Parkinson's disease-ALS dementia complex; dementia associated with another disease or condition including Alzheimer's disease; ischemia; multi-infarct dementia; trauma; vascular problems; stroke; HIV disease; Parkinson's disease; Huntington's disease; Down syndrome; Pick's disease; Creutzfeldt-Jacob disease Disease); perinatal hypoxia or substance abuse); delirium; amnesia; or age-related cognitive decline. Cognitive impairment includes impairments in cognitive functions or domains, such as working memory, attention and alertness, verbal learning and memory, visual learning and memory, reasoning and problem-solving abilities (e.g., executive function, processing speed, and/or social cognition). Specifically, cognitive impairment may indicate poor attention, disorganized thinking, slowed thinking, difficulty comprehension, poor concentration, impaired problem-solving, poor memory, difficulty expressing thoughts and/or integrating thoughts, feelings, and behaviors, or difficulty eliminating unrelated thoughts. Cognitive impairment can manifest as cognitive deficits (defined by DSM-5 as complex attention, executive function, learning and memory, language, perceptual motor, social cognition); and sometimes associated with dopamine signaling deficits; and sometimes associated with basal ganglia dysfunction; and sometimes associated with motor activity disorders; and sometimes associated with impaired function of the prefrontal cortex. Pain

Myofibril pain; neuropathic pain (including, for example, post-herpetic (or post-herpetic) neuropathic pain, reflex sympathetic dystrophy/causalgia or neurotrauma, phantom limb pain, carpal tunnel syndrome, and peripheral neuropathy (such as diabetic neuropathy or neuropathy caused by chronic alcohol use)); sensitization with neuropathic pain; inflammatory pain; acute pain; nociceptive pain; arthritis pain; rheumatoid arthritis; osteoarthritis Arthritis; arthralgia; musculoskeletal pain; back pain; back pain; herniated disc; hip pain; visceral pain; headache; tension headache; acute tension headache; chronic tension headache; chronic cluster headache; common migraine; classic migraine; cluster headache; mixed headache; post-traumatic headache; eye fatigue headache; transient unilateral neuropathic (SUNCT) headache; SUNCT syndrome; Herpes zoster (Herpes Zoster; Acute herpes zoster; Shingles; Postherpetic neuralgia (herpes zoster); Cauterizing neuropathy; Central pain; Central pain syndrome; Chronic back pain; Neuralgia; Neuralgia syndrome; Neuropathy; Diabetic neuropathy; Diabetes-related neuropathy; Diabetes-related neuropathy; Fibritis; Chemotherapy-induced peripheral neuropathy; Peripheral nerve disease; Peripheral neuropathy; Neuropathy; Neurotrauma; Sensitization with neuropathic pain; Complex regional pain syndrome; Compression neuropathy; Craniofacial pain; Chronic joint pain; Chronic knee pain; Chronic pain syndrome; Cancer pain; Trigeminal neuralgia; Trigeminal neuralgia Doloreaux; Reflex sympathetic causalgia; Painful peripheral neuropathy; Spinal nerve injury; Arachnoiditis; Spinal pain; Bernhardt-Roth Syndrome (Meralgia Parasthetica); Carpal tunnel syndrome; Cerebrospinal fluid syndrome; Charcot-Marie-Tooth Disease; Hereditary motor and sensory neuropathy; Charcot-Marie-Tooth disease; Cluster-Tic syndrome Syndrome; coccygeal pain syndrome; compartment syndrome; degenerative disc disease; failed back surgery syndrome; pelvic genital pain/insertion disorder; gout; inflammatory pain; lumbar radiculopathy; neuroma (painful scar); pain associated with multiple sclerosis; pelvic floor disorders; phantom limb pain; piriformis syndrome; psychogenic pain; radicular pain syndrome; Raeder's Syndrome; referred pain; reflex sympathetic dystrophia syndrome; sciatica; sciatica: scoliosis; herniated disc; body pain; spinal stenosis; stiff person syndrome; repetitive pain; sympathetically maintained pain; Tolosa-Hunt syndrome Syndrome; whiplash; pain associated with Lyme Disease. Neurodevelopmental disorders

Intellectual disability (mental developmental disorder); global developmental delay; intellectual disability, not specified (mental developmental disorder); language disorder; speech and voice disorder; childhood speech impediment (stuttering); social (pragmatic) communication disorder; non-specific communication disorder; autism spectrum disorder (including, for example, Asperger's syndrome); pervasive developmental disorder; Rett syndrome Syndrome); and Fragile X Syndrome); attention-deficit/hyperactivity disorder; other specified attention-deficit/hyperactivity disorder; non-specified attention-deficit/hyperactivity disorder; specific learning disorder; childhood learning disorder; developmental coordination disorder; stereotypic movement disorder; tics; other specified tics; non-specified tics; other specified neurodevelopmental disorders; non-specified neurodevelopmental disorders. Schizophrenia spectrum and other psychiatric disorders

Schizophrenia (personality) disorder; delusional disorder; transient psychotic disorder; shared psychotic disorder; schizophreniform disorder; schizophrenia (delusional, deconstructive, catatonic, or undifferentiated); schizoaffective disorder; substance/medication-induced psychotic disorder; psychotic disorder attributed to another medical condition; tension associated with another mental illness (catatonic features); tension disorder attributed to another medical condition; unspecified tension disorder; other specified schizophrenia spectrum and other psychotic disorders; unspecified schizophrenia spectrum and other psychotic disorders. Schizophrenia is a disorder of unknown etiology that usually first appears in early adulthood and is marked by features such as psychotic symptoms, staged progression and development, and/or regression of social behavior and professional abilities. Characteristic psychotic symptoms are disorganized thought content (e.g., multiple, fragmented, incoherent, implausible or simply delusional content, or persecutory thoughts) and psychological disturbances (e.g., loss of association, delusional thoughts, incoherent speech), as well as disturbances of perception (e.g., hallucinations), affect (e.g., superficial or inadequate affect), self-perception, intention, impulse and/or interpersonal relationships, and psychomotor disturbances (e.g., catatonia). Other symptoms are also associated with this disorder. Schizophrenia is divided into several subgroups: the paranoid type, which is characterized by delusions and hallucinations without thought disorder, deconstructive behavior, and affective flattening; the deconstructive type, also called "hebephrenic schizophrenia," in which thought disorder and affective flattening are present; the catatonic type, in which psychomotor disturbances are prominent and symptoms may include catatonic stupor and waxy flexibility; and the undifferentiated type, in which psychotic symptoms are present but do not meet the criteria for the paranoid, deconstructive, or catatonic types. Symptoms of schizophrenia generally fall into three categories: positive, negative, and cognitive. Positive symptoms are those that represent an "excess" of normal experience, such as hallucinations and delusions. Negative symptoms are those in which the individual lacks normal experiences, such as lack of pleasure and social interaction. Cognitive symptoms are related to cognitive impairment in schizophrenia patients, such as lack of sustained attention and poor decision-making ability. Bipolar disorder and related conditions

Bipolar I disorder; Bipolar II disorder; Cyclothymic disorder; Substance/medication-induced bipolar disorder and related disorders; Bipolar disorder and related disorders attributed to another medical condition; Other specified bipolar disorder and related disorders; Unspecified bipolar disorder and related disorders; Characteristics of bipolar disorder and related disorders. Bipolar disorder (including bipolar I disorder and bipolar II disorder) is a serious psychiatric disorder that affects about 2% of the population and affects both sexes. It is a relapsing, remitting disorder characterized by cycles between periods of elevated mood (i.e., mania) and depression, unlike other disorders such as major depression and schizophrenia. Bipolar I disorder is defined by the occurrence of full-blown manic episodes, although most individuals experience periods of marked depression. Symptoms of mania include elevated or irritable mood, hyperactivity, grandiose mood, decreased need for sleep, racing thoughts, and in some cases psychosis. Depressive episodes are characterized by anhedonia, emotional sadness, despair, poor self-esteem, decreased concentration, and hypersomnia. Bipolar II disorder is defined by the occurrence of severe depressive episodes and hypomanic (less severe manic) episodes, although individuals spend significantly longer in the depressed state. Other associated conditions include cyclothymia. Depression

Depression; intrusive mood disorder; major depressive disorder (MDD) (unipolar depression); auxiliary major depressive disorder (aMDD); persistent depressive disorder (minor depression); premenstrual dysphoric disorder; substance/medication-induced depression; refractory depression; depression attributed to another medical condition; other specified depressive disorder; unspecified depressive disorder. Anxiety disorder

Anxiety; dissociative anxiety disorder; selective mutism; specific phobia; social anxiety disorder (social phobia); panic disorder; panic attack characteristics; cataplexy; generalized (or generalized) anxiety disorder; substance/medication-induced anxiety disorder; anxiety disorder attributed to another medical condition; other specific anxiety disorders; non-specific anxiety disorders. Anxiety disorders are characterized by fear, worry, and uneasiness, usually an exaggerated reaction to a situation, with generalized and inattentive manifestations. Anxiety disorders vary in the types of situations or objects that induce fear, anxiety, or avoidance behavior, as well as in the associated cognitive concepts. Anxiety differs from fear in that anxiety is an emotional response to a perceived future threat, whereas fear is associated with a perceived or real immediate threat. They also differ in the content of the associated thoughts or beliefs. Examples of anxiety disorders include dissociative anxiety disorder, selective mutism, specific phobia, social anxiety disorder (social phobia), panic disorder, panic attack characterization, phobia, generalized anxiety disorder, substance/medication-induced anxiety disorder, anxiety disorder attributed to another medical condition, illness anxiety disorder, social (pragmatic) communication disorder, other specific anxiety disorders, and non-specific anxiety disorders; stress-related disorders, including reactive attachment disorder, disinhibited social engagement disorder, post-traumatic stress disorder (PTSD), acute stress disorder, and adjustment disorder. Obsessive-compulsive disorder and related disorders

Obsessive-compulsive disorder; body dysmorphic disorder; hoarding disorder; trichotillomania (hair pulling disorder); excoriation (skin picking) disorder; substance/drug-induced obsessive-compulsive disorder and related conditions; obsessive-compulsive disorder and related conditions attributed to another medical condition; other specified obsessive-compulsive disorder and related conditions; unspecified obsessive-compulsive disorder and related conditions. Trauma and stress-related disorders

Reactive attachment disorder; disinhibited social engagement disorder; post-traumatic stress disorder; acute stress disorder; adjustment disorder; other specified trauma- and stress-related disorders; unspecified trauma- and stress-related disorders. Dissociative disorder

Dissociative identity disorder; Dissociative amnesia; Depersonalization/derealization disorder; Other specified dissociative disorder; Unspecified dissociative disorder. Physical symptoms and related conditions

Somatic symptom disorder; Illness anxiety disorder; Conversion disorder (functional neurological disorder); Psychological factors affecting other medical conditions; Factitious disorder; Other specified somatic symptoms and related conditions; Non-specified somatic symptoms and related conditions. Eating and eating disorders

Pica; Regurgitation disorder; Avoidant/restrictive food intake disorder; Anorexia nervosa; Bulimia nervosa; Other specific eating or eating disorder; Unspecified eating or eating disorder. Elimination disorder

Urinary incontinence; fecal incontinence; other specific excretion disorders; non-specific excretion disorders. Sleep - wake disorder

Insomnia; Narcolepsy; Narcolepsy; Obstructive sleep apnea; Central sleep apnea; Sleep-related hypoventilation; Circadian rhythm sleep-wake disorder; Non-rapid eye movement sleep arousal disorder; Sleep nightmares; Rapid eye movement (REM) sleep behavior disorder; Restless legs syndrome; Substance/drug-induced sleep disorder; Other specified insomnia; Non-specified insomnia; Other specified hypersomnia; Non-specified hypersomnia; Other specified sleep-wake disorder; Non-specified sleep-wake disorder. Sexual dysfunction

Delayed ejaculation; erectile dysfunction; female orgasmic disorder; female sexual interest/arousal disorder; pelvic genital pain/insertion disorder; male sexual desire disorder; premature (early) ejaculation; substance/drug-induced sexual dysfunction; other specific sexual dysfunction; non-specific sexual dysfunction. Gender dysphoria

Gender dysphoria; other specific gender dysphoria; nonspecific gender dysphoria. Disruptiveness, impulse control, and conduct disorder

Social disorder; oppositional defiant disorder; rage disorder; conduct disorder; antisocial personality disorder; pyromania; thievery; other specified destructive, impulse-control, and conduct disorders; unspecified destructive, impulse-control, and conduct disorders. Substance-related and addiction disorders

Addiction; Alcohol use disorder; Alcohol intoxication; Alcohol withdrawal; Nonspecific alcohol-related condition; Fetal alcohol syndrome; Caffeine intoxication; Caffeine withdrawal; Nonspecific caffeine-related condition; Cannabis use disorder; Cannabis intoxication; Cannabis withdrawal; Nonspecific cannabis-related condition; Phencyclidine use disorder; Other hallucinogen use disorder; Phencyclidine intoxication; Other hallucinogen intoxication; Hallucinogen persistent perception disorder; Nonspecific phencyclidine-related condition; Nonspecific hallucinogen-related condition; Inhalant use disorder; Inhalant intoxication; Nonspecific inhalant-related condition; Opioid use disorder; Opioid intoxication; opioid withdrawal; non-specified opioid-related disorder; sedative, hypnotic, or antianxiety use disorder; sedative, hypnotic, or antianxiety intoxication; sedative, hypnotic, or antianxiety withdrawal; non-specified sedative, hypnotic, or antianxiety related disorder; stimulant use disorder; stimulant intoxication; Stimulant withdrawal; non-specified stimulant-related disorder; tobacco use disorder; tobacco withdrawal; non-specified tobacco-related disorder; other (or unknown) substance use disorder; other (or unknown) substance intoxication; other (or unknown) substance withdrawal; non-specified other (or unknown) substance-related disorder; gambling disorder. Neurocognitive disorders

Delirium; other specific delirium; nonspecific delirium; severe and mild neurocognitive impairment; severe or mild neurocognitive impairment attributed to Alzheimer's disease; severe or mild frontotemporal neurocognitive impairment; severe or mild neurocognitive impairment with Lewy bodies; severe or mild vascular neurocognitive impairment; severe or mild neurocognitive impairment attributed to traumatic brain injury; severe or mild neurocognitive impairment induced by substance/drug ; severe or mild neurocognitive impairment due to HIV infection; severe or mild neurocognitive impairment due to prion disease; severe or mild neurocognitive impairment due to Parkinson's disease; severe or mild neurocognitive impairment due to Huntington's disease; severe or mild neurocognitive impairment due to another medical condition; severe or mild neurocognitive impairment due to multiple etiologies; unspecified neurocognitive disorder. Personality disorder

Dimensional model of personality disorders; general personality disorder; delusional personality disorder; schizotypal personality disorder; schizotypal personality disorder; antisocial personality disorder; borderline personality disorder; histrionic personality disorder; narcissistic personality disorder; avoidant personality disorder; dependent personality disorder; obsessive-compulsive personality disorder; personality change attributed to another medical condition; other specified personality disorder; non-specific personality disorder .

Voyeurism; exhibitionism; traumatism; sexual abuse; sexual sadism; pedophilia; fetishism; transvestite; other specific sexual preference disorders; non-specific sexual preference disorders. Other mental illnesses

Other specified psychiatric disorders attributed to another medical condition; Unspecified psychiatric disorders attributed to another medical condition; Other specified psychiatric disorders; Unspecified psychiatric disorders. Drug-induced movement disorders and other side effects of drugs

Neuroleptic-induced Parkinson's disease, other drug-induced Parkinson's disease; neuroleptic malignant syndrome; drug-induced acute hypotonia; drug-induced acute akathisia; tardive dyskinesia; tardive dyskinesia Atonia, tardive akathisia; drug-induced postural tremor; other drug-induced movement disorders; antidepressant withdrawal syndrome; other side effects of drugs. Symptoms of neurological or psychiatric diseases and conditions

Neurological or mental illness or disorder can manifest itself in a variety of symptoms. Non-limiting examples of symptoms of a neurological or psychiatric disease or disorder include symptoms such as apathy, depression, anxiety, cognitive impairment, psychosis, aggression, irritability, impulse control disorders, sleep disorders, elevated mood or irritability, hyperactivity, grandiosity, decreased need for sleep, racing thoughts, and in some cases psychosis, anhedonia, emotional sadness, despair, poor self-esteem, decreased concentration and hypersomnia, amyotrophic lateral sclerosis, primary lateral sclerosis, progressive muscular atrophy, progressive bulbar (atrophic) palsy, pseudobulbar palsy, spinal muscular atrophy (e.g., SMA type I (also known as Werdnig-Hoffmann disease) disease), SMA type II, SMA type III (also known as Kugelberg-Welander disease), and Kennedy's disease (also known as progressive spinobulbar muscular atrophy), Hallervorden-Spatz disease, Seitelberger disease (axonal dystrophy), adrenoleukodystrophy, Alexander Disease, autosomal dominant cerebellar ataxia (ADCA), pure autonomic failure (Bradbury-Eggleston Syndrome), CADASIL syndrome, and neuronal lipofuscin disorders such as Batten Disease (Spielmeyer-Vogt-Sjögren's disease), Alzheimer's disease, early-onset Alzheimer's disease, Alzheimer's type dementia, Cognition, Memory loss, Amnesia/amnesia syndrome, Consciousness impairment, Coma, Attention deficit, Speech impairment, Cognitive impairment, Aphasia, Apraxia, Mild cognitive impairment (MCI), Benign amnesia, Mild neurocognitive impairment, Severe neurocognitive impairment, Neurocognitive impairment due to disease (e.g., Huntington's disease, Parkinson's disease, Prion disease, Traumatic brain injury, HIV or AIDS), Binswanger's disease (Subcortical Leukoencephalopathy) and Capgras Syndrome; or any other symptoms associated with the neurological or psychiatric diseases or disorders disclosed herein.

Mental illness is a pathological condition of the brain characterized by identifiable symptoms that result in abnormalities in cognition, affect or mood, or in the highest integrated form of behavior. These disorders can vary in severity, duration, and functional impairment. Mental illness afflicts millions of people worldwide, causing enormous human suffering and economic burdens due to lost productivity.

Mood disorders are a type of psychiatric illness, usually defined as a heterogeneous group of often relapsing illnesses, including unipolar (depressive) and bipolar (manic-depressive) disorders, characterized by generalized mood disturbances, psychomotor dysfunction, and/or vegetative symptoms. Suicide is the most serious complication of mood disorders, accounting for 15% to 25% of deaths in untreated mood disorder patients; unrecognized or inadequately treated depression accounts for 50% to 70% of all completed suicides. Non-limiting examples of mood disorders include depression, major depression, severe depression, mild depression, severe depression without psychosis, severe depression with psychosis, depressive illness (formerly endogenous depression), atypical depression, low affective disorder, manic depression, bipolar depression, manic depression type I, manic depression type II, manic depression type III, cyclothymic disorder, and chronic hypomania.

In some embodiments, the neurological or psychiatric disease or disorder is a mood disorder.

In some embodiments, the neurological disorder is: depression (e.g., major depression or hypoglycemia); bipolar disorder, seasonal affective disorder; cognitive deficits; muscle fiber pain; pain (e.g., neuralgia); sleep-related disorders (e.g., sleep apnea, insomnia, narcolepsy, cataplexy), including those caused by psychiatric symptoms; chronic fatigue syndrome; attention deficit disorder (ADD); attention deficit hyperactivity disorder (ADHD); restless legs syndrome; schizophrenia ; anxiety (e.g., generalized anxiety disorder, social anxiety disorder, panic disorder); obsessive-compulsive disorder; post-traumatic stress disorder; seasonal affective disorder (SAD); premenstrual dysphoric disorder; postmenopausal vasomotor symptoms (e.g., hot flashes, diaphoresis); neurodegenerative diseases (e.g., Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis); manic disorder; depressive disorder; cyclothymia; obesity; and substance abuse or dependence (e.g., cocaine addiction, nicotine addiction).

Neurological disorders may also include disorders of brain function, including but not limited to Alzheimer's disease, Alzheimer's disease, cognition, memory loss, amnesia/amnesia syndrome, epilepsy, consciousness disorder, coma, attention deficit, speech disorder, Lennox syndrome, autism and ADHD.

In some embodiments, the neurological or psychiatric disease or condition comprises one or more of the following: mood disorders, bipolar disorder (BPD), bipolar disorder, sleep disorders, REM behavior disorders, psychotic disorders, Alzheimer's disease with agitation and/or psychosis, Parkinson's disease psychosis, schizophrenia, hypopsychotic syndrome, prodromal schizophrenia, and schizoaffective disorder. In some embodiments, the neurological or psychiatric disease or condition is one or more of the following: mood disorders, bipolar disorder (BPD), bipolar disorder, sleep disorders, REM behavior disorders, psychotic disorders, Alzheimer's disease with agitation and/or psychosis, Parkinson's disease psychosis, schizophrenia, hypopsychotic syndrome, prodromal schizophrenia, and schizoaffective disorder.

In some embodiments, the neurological or psychiatric disease or disorder is a psychotic disorder, such as schizophrenia (delusional, deconstructive, catatonic or undifferentiated), schizophrenia-like disorder, schizoaffective disorder, delusional disorder, transient psychotic disorder, shared psychotic disorder, psycho-affective disorder, attack, delirium, Parkinson's disease psychosis, agitated psychosis, psychotic disorder attributable to a general medical condition, Substance-induced or drug-induced psychotic disorders (e.g., phencyclidine, ketamine or other dissociative anesthetics, amphetamines or other stimulants, cocaine), affective-related psychoses, transient psychosis, schizoaffective disorder, and "schizophrenia spectrum" disorders such as schizotypal or schizotypal personality disorder, or psychotic-related disorders (e.g., severe depression, bipolar disorder, Alzheimer's disease and/or post-traumatic stress disorder), which may include positive, negative and/or cognitive symptoms of schizophrenia and other psychotic disorders; anxiety disorders, such as acute stress disorder, phobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attacks, panic disorder, post-traumatic stress disorder, dissociative anxiety disorder, social phobia, specific phobia, substance-induced anxiety and anxiety disorders attributed to Anxiety disorders as general medical conditions; substance-related disorders or addictions, such as substance-induced delirium, persistent dementia, persistent amnesia, psychotic or anxiety disorders, tolerance, dependence or withdrawal to substances including alcohol, amphetamines, marijuana, cocaine, hallucinogens, inhalants, nicotine, opioids, phencyclidine, sedatives, hypnotics or antianxiety drugs; and Alzheimer's disease with agitation and/or psychosis.

In some embodiments, the neurological or psychiatric disease or disorder is depression, such as but not limited to unipolar depression, seasonal depression, postpartum depression, atypical depression, tension depression, geriatric depression, intrinsic depression, melancholic depression, peripartum depression, reactive depression, chronic depression, bipolar depression, major depressive disorder (MDD), major depression with Mixed features (MDD-MF), refractory depressive disorder (TRD), and depression associated with depressed mood (sadness), poor concentration, insomnia, fatigue, appetite disturbances, excessive guilt and suicidal thoughts, premenstrual syndrome (PMS) and/or premenstrual dysphoric disorder (PDD), mood disorders attributed to general medical conditions, and/or substance-induced mood disorders.

In some embodiments, the neurological or psychiatric disease or condition is an eating disorder, such as but not limited to obesity, bulimia nervosa, pica, and compulsive eating disorder.

In some embodiments, the neurological or psychiatric disease or condition is a sleep disorder, such as but not limited to insomnia, restless sleep, jet lag, hypersomnia, cataplexy, sleep apnea, obstructive sleep apnea, REM sleep behavior disorder, restless legs syndrome, periodic limb movement disorder, circadian rhythm sleep disorder, delayed sleep phase disorder, sleepwalking, night terrors, bedwetting, rapid eye movement sleep behavior disorder, shift work sleep disorder, excessive daytime sleepiness, non-24-hour sleep-wake disorder, sleep paralysis, and narcolepsy.

In some embodiments, the neurological or psychiatric disease or disorder is bipolar disorder, such as but not limited to bipolar depression, bipolar I disorder, bipolar II disorder, cyclothymia, substance/medication-induced bipolar disorder and related disorders, bipolar disorder and related disorders attributed to another medical condition, other specified bipolar disorder and related disorders, and unspecified bipolar disorder and related disorders. Bipolar disorder (including bipolar I disorder and bipolar II disorder) is a serious psychiatric disorder with a prevalence of approximately 2% in the population and affects both men and women. It is a relapsing, remitting condition characterized by cycles between elevated mood (mania) and depression, which distinguishes it from other disorders such as major depression and schizophrenia.

Bipolar I disorder is defined as the occurrence of full-blown manic episodes, although most individuals experience significant depression. Symptoms of mania include elevated or irritable mood, hyperactivity, grandiosity, decreased need for sleep, racing thoughts, and in some cases psychosis. Depressive episodes are characterized by anhedonia, emotional sadness, despair, poor self-esteem, decreased concentration, and hypersomnia. Bipolar II disorder is defined as the occurrence of severe depressive episodes and hypomanic (less severe manic) episodes, although patients spend significantly longer in the depressed state. Other associated conditions include cyclothymia.

In bipolar II disorder, depressive episodes replace hypomania (relatively mild nonpsychotic periods of typically < 1 week). During hypomania, mood is optimistic, sleep need is decreased, and psychomotor activity accelerates beyond the patient's usual level. Typically, the shift is induced by circadian factors (e.g., falling asleep depressed and awakening in the early morning in a hypomanic state). Hypersomnia and overeating are characteristic and may recur seasonally (e.g., in the fall or winter); insomnia and loss of appetite occur during depressive periods. For some people, hypomanic periods are adaptive because they are associated with high energy, self-confidence, and extraordinary social functioning. Many patients experience a pleasurable mood boost, usually at the end of depression, which these patients will not report unless specifically asked.

People with severe depressive episodes and a family history of bipolar disorder (unofficially called bipolar III disorder) often display subtle hypomanic tendencies; their temperament is described as hyperactive (highly motivated, ambitious, and achievement-oriented).

In cyclothymic disorder, less severe hypomanic and mildly depressive periods follow an irregular course, each lasting a few days. Cyclothymic disorder is often a precursor to bipolar II disorder. But it can also present in an extreme mood form without the complications of a severe mood disorder. In such cases, brief periods of delayed depression with low self-confidence and increased sleep time alternate with increased excitement or enthusiasm and decreased sleep time. In another form, mildly depressive traits predominate; manic-depressive tendencies manifest themselves primarily in excitement or irritability caused by antidepressants. In chronic hypomania (a clinically rare form), euphoria predominates and sleep is habitually reduced to < 6 hours. People with this form are always overly cheerful, overconfident, overenergetic, overscheduled, unpredictable, overinvolved, and nosy; they rush off and chat with others impulsively and restlessly.

In some embodiments, the neurological or psychiatric disease or disorder is one or more of: bipolar I disorder, bipolar II disorder, cyclothymic disorder, other specified bipolar and related disorders or unspecified bipolar and related disorders, bipolar I disorder or bipolar II disorder with: anxious distress profile, mixed profile, rapid cycling, depressive profile, atypical profile, mood-congruent psychotic profile, mood-inconsistent psychotic profile, catatonic disorder, peripartum episodes, and/or seasonal patterns. A recent article by Hu et al. ( Prim Care Companion CNS Disord . 2014 ; 16(2): PCC.13r01599) highlights that bipolar disorder, although common in primary care settings, is often misdiagnosed or underdiagnosed. DSM-5 attempts to include a large proportion of patients with subsyndromal mixed symptoms, including mixed feature descriptions.

In some embodiments, the neurological or psychiatric disease or disorder is depression. Depression includes, but is not limited to, unipolar depression, seasonal depression, postpartum depression, atypical depression, tension depression, geriatric depression, intrinsic depression, melancholic depression, peripartum depression, reactive depression, chronic depression, bipolar depression, major depressive disorder (MDD), major depressive disorder with mixed features (MDD -MF), refractory depressive disorder (TRD), and minor depression, and is associated with depressed mood (sadness), poor concentration, insomnia, fatigue, appetite disturbances, excessive guilt and suicidal thoughts, premenstrual syndrome (PMS), premenstrual dysphoric disorder (PDD), mood disorders attributed to general medical conditions, and substance-induced mood disorders.

Depression is a mood disorder whose pathogenesis cannot be explained by any single cause or theory. Unfortunately, treatment options are limited for depressed patients who have a suboptimal clinical response to antidepressant therapy. Approximately 30% of patients who begin antidepressant therapy show a suboptimal or delayed clinical response to the first-line antidepressants commonly used to treat depression.

Typically, if a patient demonstrates a suboptimal or delayed clinical response after several weeks of antidepressant therapy, the clinician's initial approach is to increase the dose of the antidepressant. If the patient's response is still unsatisfactory after increasing the dose, the most common approach many clinicians will take is to: a) switch to a different antidepressant; or b) add a second antidepressant; or c) try to augment therapy by administering medications such as lithium carbonate, thyroid hormone (triiodothyronine), psychostimulants, modafinil, atypical antipsychotics, buspirone, or pindolol.

In its full syndromic presentation, clinical depression manifests as major depression with an episodic course and varying degrees of residual manifestations between episodes. Mood is typically melancholic, irritable, and/or anxious. The patient may appear distressed, with furrowed brows, drooping corners of the mouth, downcast posture, poor eye contact, and monosyllabic speech (or no speech). Morbid mood may be accompanied by guilt, self-deprecating thoughts, decreased ability to concentrate, indecisiveness, decreased interest in daily activities, social withdrawal, helplessness, despair, and recurrent thoughts of death and suicide. Sleep disturbances are common. Some patients suffer from such profound emotional distress that their tears dry up; they complain of an inability to experience normal emotions, including sadness, joy, and happiness, and of a sense that the world has become colorless, lifeless, and dead.

Depressive illness (formerly called endogenous depression) is characterized by marked psychomotor slowing (of thoughts and movements) or agitation (e.g., restlessness, clenched hands, strained speech), weight loss, irrational guilt, and loss of the ability to experience pleasure. Mood and activity vary from day to day, with the lowest point in the morning. Most patients with the depressive type complain of difficulty falling asleep, multiple awakenings, and insomnia in the middle of the night or early morning. Sexual desire is usually reduced or absent. Amenorrhea may occur. Anorexia and weight loss may cause emaciation and secondary electrolyte imbalance.

In atypical depression, anti-vegetative traits dominate the clinical picture; they include anxious phobic symptoms, nocturnal exacerbations, incipient insomnia, excessive sleepiness that often extends into the day, and binge eating with weight gain. Unlike patients with depression, patients with atypical depression are optimistic in the face of potentially positive events, but often fall into paralyzing depression in the face of the slightest adversity. Atypical depression overlaps considerably with bipolar II disorder.

In low mood disorder, depressive symptoms usually begin inadvertently in childhood or adolescence and persist intermittently or at a low level for years or decades; they may be complicated by severe depressive episodes (double depression). In pure mild depression, depressive manifestations are present at subcritical levels and overlap considerably with manifestations of melancholic temperament: habitual gloom, pessimism, lack of humor or fun; passive and lethargic; withdrawn; suspicious, critical, or complaining; self-critical, self-blaming, and self-defeating; and preoccupied with inadequacies, failures, and negative events.

A thorough evaluation of many people with depression reveals bipolar features, and as many as one in five people with depression also develop overt hypomania or mania. Most transitions from unipolar to bipolar disorder occur within five years of the onset of depressive symptoms. Predictors of transition include early onset of depression (< 25 years of age), postpartum depression, frequent episodes of depression, rapid improvement of mood with physical therapy (e.g., antidepressants, phototherapy, sleep deprivation, electroconvulsive therapy), and a three-generation family history of mood disorders.

Between episodes, people with bipolar disorder experience periods of depressed mood and high-energy activity; developmental and social impairment is more common in bipolar depression than in unipolar disorder. In bipolar disorder, depressive episodes are shorter (3 to 6 months), occur at younger ages, are more sudden, and have a shorter cyclicity (the time from one episode to the next) than in unipolar disorder. Cyclicity is particularly prominent in the rapid-cycling form of bipolar disorder (usually defined as ≥ 4 episodes/year). Depressive episodes in bipolar disorder are a difficult-to-treat component of BPD. For example, psychiatrists note that approximately 25% of all bipolar disorder patients become refractory during a manic episode, and approximately 70% become refractory during a depressive episode.

Thus, in some embodiments, the neurological or psychiatric disease or disorder is one or more of bipolar depression, major depressive disorder (MDD), persistent depressive disorder (minor depression), premenstrual dysphoric disorder (PMDD), major depression with mixed features (MDD-MF), depression attributed to another medical condition, other specific depressive disorder, unspecified depressive disorder, or refractory depressive disorder (TRD), and MDD with the following features of anxious distress, mixed features, depressive features, atypical features, mood-congruent psychotic features, mood-inconsistent psychotic features, catatonic disorder, peripartum episodes, seasonal patterns, and/or seasonal affective disorders.

It is understood that TRD is a term used in clinical psychiatry to describe cases of major depressive disorder (MDD) that have not responded adequately to an adequate course of at least two antidepressants.

In some embodiments, depression is associated with acute suicidal tendencies or suicidal ideation. The U.S. Food and Drug Administration has adopted a "black box" label warning indicating that antidepressants may increase the risk of suicidal thoughts and behaviors in some children, adolescents, and young adults (up to 24 years old) with depressive disorders such as MDD. In some embodiments, the compounds of the invention, the pharmaceutical compositions and combinations described herein do not increase the risk of suicidal thoughts and/or behaviors in children, adolescents, and/or young adults with depressive disorders such as MDD. Also provided herein is a method for treating one or more symptoms of depression (e.g., MDD) in a child, adolescent and/or young adult without increasing the risk of suicidal thoughts and/or behavior, comprising administering a compound of the invention (e.g., a therapeutically effective amount of a compound of the invention) to the child, adolescent or young adult.

In some embodiments, the neurological or psychiatric disease or disorder is schizophrenia. Schizophrenia is a disorder of unknown etiology that usually first appears in early adulthood and is marked by features such as psychotic symptoms, staged progression and development and/or regression of social behavior and professional abilities. Characteristic psychotic symptoms are disorganized thought content (e.g., multiple, fragmented, incoherent, unbelievable or simply delusional content, or persecution ideas) and psychological disorders (e.g., loss of association, delusional thoughts, incoherent speech), as well as perceptual disorders (e.g., hallucinations), affective disorders (e.g., superficial or inadequate emotions), self-perception, intention, impulse and/or interpersonal relationship disorders and psychomotor disorders (e.g., catatonia). Other symptoms are also associated with this disorder.

Schizophrenia is divided into several subgroups: the paranoid type, which is characterized by delusions and hallucinations without thought disorder, deconstructed behavior, and flat affect; the deconstructed type, also called "juvenile schizophrenia," in which thought disorder and flat affect are present; the catatonic type, in which prominent psychomotor disturbances are prominent and symptoms may include catatonic stupor and waxy flexion; and the undifferentiated type, in which psychotic symptoms are present but the criteria for the paranoid, deconstructed, or catatonic types are not yet met. The symptoms of schizophrenia generally fall into three major categories: positive, negative, and cognitive. Positive symptoms are those that represent an "excess" of normal experiences, such as hallucinations and delusions. Negative symptoms are those that represent a lack of normal experiences, such as anhedonia and lack of social interaction. Cognitive symptoms are related to cognitive impairment in schizophrenia patients, such as lack of sustained attention and poor decision-making ability.

In some embodiments, the neurological or psychiatric disease or disorder is one or more of the following: schizotypal (personality) disorder, delusional disorder, transient psychotic disorder, schizophrenia-like disorder, schizophrenia, schizoaffective disorder, substance/medication-induced psychotic disorder, psychotic disorder attributable to another medical condition, other specified schizophrenia spectrum and other psychotic disorders, unspecified schizophrenia spectrum and other psychotic disorders.

It should be understood that schizoaffective disorder includes a condition that includes aspects of both schizophrenia and mood disorders, such as major depression, bipolar disorder, etc.

In some embodiments, the neurological or psychiatric disease or condition is anxiety disorder. Anxiety disorders are characterized by fear, worry, and uneasiness, usually as an exaggerated reaction to a situation, manifested as generalized and inattentive. Anxiety disorders differ in the types of situations or objects that induce fear, anxiety, or avoidance behavior, as well as the associated cognitive concepts. Anxiety differs from fear in that anxiety is an emotional response to a perceived future threat, while fear is associated with a perceived or real immediate threat. They also differ in the content of the associated thoughts or beliefs. Examples of anxiety disorders include dissociative anxiety disorder, selective mutism, specific phobias, social anxiety disorder (social phobia), panic disorder, panic attack characterization, anophobia, generalized anxiety disorder, substance/medication-induced anxiety disorder, anxiety disorder attributable to another medical condition, illness anxiety disorder, social (pragmatic) communication disorders, other specific anxiety disorders, non-specific anxiety disorders, and stress-related disorders including reactive attachment disorder, disinhibited social engagement disorder, post-traumatic stress disorder (PTSD), acute stress disorder, and adjustment disorders.

In some embodiments, the neurological or psychiatric disease or condition is a sleep disorder, including those sleep disorders caused by psychiatric conditions, including but not limited to insomnia, restless sleep, jet lag, hypersomnia, cataplexy, sleep-related disorders (e.g., sleep apnea, insomnia, narcolepsy, cataplexy), obstructive sleep apnea, REM sleep behavior disorder, restless legs syndrome, periodic limb movement disorder, circadian rhythm sleep disorder, delayed sleep phase disorder, sleepwalking, night terrors, bedwetting, rapid eye movement sleep behavior disorder, shift work sleep disorder, excessive daytime sleepiness, non-24-hour sleep-wake disorder, sleep paralysis, and narcolepsy.

In some embodiments, the neurological or psychiatric disease or disorder is a social dysfunction. In some embodiments, the social dysfunction is a neurodevelopmental disorder, obsessive-compulsive disorder or disruptive, impulse control and conduct disorder. In some embodiments, the social dysfunction is a language disorder, a speech sound disorder, childhood dysphonia (stuttering), a social communication disorder, a developmental coordination disorder, a stereotyped movement disorder, a tic, Tourette's syndrome, a persistent (chronic) motor or vocal tic, a transient tic, another specific tic, an unspecified tic, an obsessive-compulsive disorder or an impulse control disorder. In some embodiments, the social dysfunction is a speech disorder, voice, childhood dyslexia (stuttering), social communication disorder, developmental coordination disorder, stereotyped movement disorder, tics, Tourette syndrome, persistent (chronic) motor or vocal tics, transient tics, another specific tic, or an unspecified tic. In some embodiments, the social dysfunction is a speech disorder, voice, childhood dyslexia (stuttering), or social communication disorder. In some embodiments, the social dysfunction is a language disorder, childhood dysphonia (stuttering), social communication disorder, developmental coordination disorder, stereotyped movement disorder, persistent (chronic) motor or vocal tics, transient tics, other specific tics, or unspecified tics.

In some embodiments, the neurological or psychiatric disease or condition is schizophrenia spectrum disorder. In some embodiments, the neurological or psychiatric disease or condition is schizophrenia. In some embodiments, the neurological or psychiatric disease or condition is Parkinson's disease. In some embodiments, the neurological or psychiatric disease or condition is depression. In some embodiments, the neurological or psychiatric disease or condition is aMDD. In some embodiments, the neurological or psychiatric disease or condition is anxiety disorder. In some embodiments, the neurological or psychiatric disease or condition is GAD.

Certain diseases, disorders or conditions, such as neurological or psychiatric diseases and disorders, may occur together. Some embodiments provide a method of treating two or more comorbid diseases, disorders or conditions described herein (e.g., two or more neurological or psychiatric diseases or disorders; a neurological or psychiatric disease or disorder and a metabolic disease, disorder or condition). An example of two common comorbid neurological or psychiatric diseases or disorders is psychosis and depression.

The present methods relate to the use of the compounds of the present invention and the compositions disclosed herein for treating metabolic diseases, disorders or conditions. Therefore, also provided herein is a method for treating a metabolic disease, disorder or condition in an individual in need thereof, comprising administering a compound of the present invention (e.g., a therapeutically effective amount of a compound of the present invention) to the individual. In some embodiments, the metabolic disease, disorder or condition is described in Chapter 5 of the International Classification of Diseases (ICD 11) coding system. Non-limiting examples of metabolic diseases, disorders or conditions described in Chapter 5 of the International Classification of Diseases (ICD 11) coding system include: endocrine diseases

Disorders of the thyroid gland or thyroid hormone system; diabetes mellitus; other glucose regulation or pancreatic endocrine disorders; disorders of the parathyroid gland or parathyroid hormone system; disorders of the pituitary hormone system; disorders of the adrenal gland or adrenal hormone system; disorders of the gonadal hormone system; certain puberty disorders; polyglandular dysfunction; endocrine disorders not elsewhere classified; neoplasms of the endocrine system; endocrine tumors.

Nutritional deficiencies; overweight, obesity, or excess of specific nutrients; nutritional or toxic disorders of the nervous system; other specified nutritional disorders; unspecified nutritional disorders. Metabolic diseases / disorders

Congenital metabolic abnormalities; Metabolite absorption or transport disorders; Fluid, electrolyte or acid-base balance disorders; Lipoprotein metabolism disorders or certain specific dyslipidemias; Metabolic or transport liver disease; Other metabolic disorders; Cystic fibrosis; Metabolic disorders following miscarriage, ectopic pregnancy or hydatidiform mole; Unspecified metabolic disorder.

In some embodiments, the metabolic disease, disorder or condition is obesity or obesity comorbidities, including but not limited to metabolic syndrome, dyslipidemia, type III dyslipidemia, hypertension, insulin resistance, diabetes (e.g., type 1 diabetes, type 2 diabetes), coronary artery disease and heart failure; overweight or weight gain; increased body mass index; metabolic syndrome; diabetes or diabetes-related disorders, including type 1 diabetes (insulin-dependent diabetes mellitus, IDDM) and type 2 diabetes (non-insulin-dependent diabetes mellitus, NIDDM); complications of diabetes, including but not limited to atherosclerosis, coronary heart disease, stroke, peripheral vascular disease, nephropathy, hypertension, neuropathy and nephropathy; impaired glucose tolerance; elevated blood sugar; insulin resistance; insulin insensitivity; hyperglycemia; fatty liver disease (e.g., nonalcoholic fatty liver disease); hepatoinsulin resistance; glycosuria; increased blood triglycerides; increased appetite; or dyslipidemia. In some embodiments, the metabolic disease, disorder or condition is increased body fat percentage, decreased lean mass percentage, high blood pressure (hypertension), cardiovascular disease, hyperglycemia, hyperuricemia or polycystic ovary syndrome.

A variety of criteria and combinations of criteria can be used to assess whether an individual has a metabolic disorder. Criteria indicative of metabolic disorders include, for example: (a) waist circumference ≥ 40 inches (101.6 cm) for men or ≥ 35 inches (88.9 cm) for women; (b) triglyceride concentration ≥ 150 mg/dL (1.69 mmol/L) or treatment with triglyceride-lowering medications; (c) HDL cholesterol concentration < 40 mg/dL (1.03 mmol/L) for men or < 50 mg/dL (1.29 mmol/L) for women or treatment with cholesterol-lowering medications; (d) fasting glucose concentration ≥ 100 mg/dL (5.6 mmol/L); (e) standing or supine blood pressure ≥ 130/85 mmHg, or is being treated with antihypertensive drugs. In some embodiments, the individual (e.g., an individual with a metabolic disorder) has three, four, or five of the above criteria (a) to (e).

In some embodiments, the subject (e.g., a subject with a metabolic disorder) has glucose-derived insulin resistance as evidenced by 5.7% ≤ HbA1c ≤ 6.4%. In some embodiments, the subject has glucose-derived insulin resistance as evidenced by fasting HOMA-IR ([insulin uIU/ml × glucose mg/dl] / 405) ≥ 2.22.

Weight gain (increased weight) is the most recognized metabolic side effect of atypical antipsychotics, although the magnitude varies by drug. Excessive weight gain has been significantly observed after treatment with olanzapine and clozapine, and is associated with many other atypical and typical antipsychotics. In addition, weight gain increases the risk of hyperglycemia and diabetes, which in turn leads to an increased risk of cardiovascular disease and mortality.

Gastric emptying and GI motility have a significant impact on appetite and energy expenditure. Inhibiting and/or delaying gastric emptying can increase satiety and thereby reduce food intake (Cifuentes, L.; Camilleri, M.; Acosta, A. Gastric Sensory and Motor Functions and Energy Intake in Health and Obesity—Therapeutic Implications. Nutrients 2021 , 13 , 1158. https://doi.org/10.3390/nu13041158). Obesity is associated with multiple metabolic abnormalities, including rapid gastric emptying and large empty stomach capacity, which may lead to increased food intake and appetite. GLP-1 receptor agonists, such as semaglutide and liraglutide, used for the treatment of type 2 diabetes and chronic weight management have been shown to delay gastric emptying in preclinical species and humans (van Can J, Sloth B, Jensen CB, Flint A, Blaak EE, Saris WH. Effects of the once-daily GLP-1 analog liraglutide on gastric emptying, glycemic parameters, appetite and energy metabolism in obese, non-diabetic adults. Int J Obes (Lond). 2014 Jun;38(6):784-93. doi: 10.1038/ijo.2013.162. Epub 2013 Sep 3. PMID: 23999198; PMCID: PMC4052428).

Without wishing to be bound by any particular theory, it is believed that the compounds of the present invention can delay gastric emptying, thereby improving glucose tolerance. The compounds of the present invention can also modulate homeostatic and hedonic neural circuits that control energy balance and eating.

Thus, in some embodiments, an individual (e.g., an individual with a metabolic disease, disorder, or condition) needs to delay gastric emptying based on the individual's feeling of fullness, hunger, and/or satiety after a meal. In some embodiments, an individual (e.g., an individual with a metabolic disease, disorder, or condition) needs to delay gastric emptying based on an increase in BMI following a diagnosis of schizophrenia or initiation of antipsychotic therapy. In some embodiments, an individual (e.g., an individual with a metabolic disease, disorder, or condition) needs to delay gastric emptying based on the ¹³ C Spirulina Breath Test (GEBT).

In some embodiments, the metabolic disease, disorder or condition is a metabolic syndrome. A metabolic syndrome (also referred to as metabolic syndrome X or syndrome X) is a combination of medical conditions that increase the risk of cardiovascular disease. According to Mottillo et al., JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY 54 ( 14 ) , 1113-32 (2010) and Saof-Ali et al., DIABETOLOGY & METABOLIC SYNDROME 12 ( 67 ) , (2020), the diagnosis of metabolic syndrome requires at least three of the following criteria (US National Cholesterol Education Program (NCEP), 2001 and revised NCEP, 2004): (1) central obesity (waist circumference: male >102 cm (approximately 40 inches); female >88 cm (approximately 35 inches)); (2) elevated triglycerides (≥ 150 mg/dl); (3) Decreased high-density lipoprotein (HDL) cholesterol (<40 mg/dl in men; <50 mg/dl in women); (4) Systemic hypertension (increased blood pressure) (systolic blood pressure ≥130/diastolic blood pressure ≥85 mm Hg); (5) Increased fasting glucose (≥110 mg/dl) [rNCEP increased fasting glucose (≥100 mg/dl)].

However, other criteria may support the diagnosis of a metabolic syndrome or metabolic disorder, such as body mass index (e.g., BMI > 30 kg/m ² ). Metabolic syndrome may also be associated with elevated total cholesterol. Elevated LDL cholesterol is marked by levels above about 100, about 130, about 160, or about 200 mg/dL. Abnormal glucose tolerance is defined as a two-hour glucose level (blood sugar) of about 140 to about 199 mg/dL (7.8 to 11.0 mmol) on a 75 g oral glucose tolerance test (according to the WHO and ADA). A blood sugar of about 200 mg/dl or higher is considered diabetes. Hyperglycemia or high blood sugar may be defined as a blood sugar level above about 7, about 10, about 15, or about 20 mmol/L. Hypoglycemia or low blood sugar can be defined as a pre-meal blood sugar level of less than about 4 or about 6 mmol/L (72 to 108 mg/dl) or a 2-hour post-meal blood sugar level of less than about 5 or about 8 mmol/L (90 to 144 mg/dl). Insulin resistance is defined as a state in which normal amounts of insulin produce a subnormal biological response. Insulin resistance can be measured by the hyperinsulinemic euglycemic clamp technique, the homeostasis model assessment (HOMA), or the quantitative insulin sensitivity test index (QUICKI). Hyperuricemia is an abnormally high level of uric acid in the blood, e.g., greater than 360 μmol/L (6 mg/dL) in women and greater than 400 μmol/L (6.8 mg/dL) in men. Polycystic ovary syndrome (PCOS) is associated with oligoovulation, anovulation, excess androgens, and/or polycystic ovaries. Metabolic syndrome can also be associated with acanthosis nigricans. Metabolic syndrome can also be associated with a proinflammatory state (e.g., elevated C-reactive protein levels in the blood, e.g., greater than 10 mg/L) and microalbuminuria (urinary albumin excretion rate ≥ 20 mg/min or albumin:creatinine ratio ≥ 30 mg/g).

In some embodiments, the metabolic disease, disorder or condition is fatty liver disease or a related condition. Fatty liver disease can be assessed by diagnostic methods known in the art, including liver enzyme tests (ALT, AST), liver ultrasound, FibroTest®, SteatoTest®, coagulation studies including international normalized ratio (INR), and blood tests including M30-Apoptosense ELISA, erythrocyte sedimentation rate, glucose, albumin and renal function. Fatty liver disease can also be associated with pro-inflammatory states (e.g., elevated levels of C-reactive protein in the blood, e.g., greater than 10 mg/L) and hepatocellular carcinoma. Fatty liver disease can also be associated with abetalipoproteinemia, glycogen storage disease, Weber-Christian disease, Wolman disease, acute fatty liver of pregnancy, lipodystrophy, inflammatory bowel disease, HIV and hepatitis C (especially genotype 3), and alpha 1-antitrypsin deficiency. Examples of fatty liver disease include nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), simple fatty liver (steatosis), cirrhosis, hepatitis, liver fibrosis, or fatty necrosis.

The compounds of the present invention can also be used to reduce body fat percentage, increase lean mass percentage or treat obesity (and related conditions). Therefore, provided herein are methods for reducing body fat percentage, increasing lean mass percentage or treating obesity (or related conditions) in individuals in need thereof, comprising administering a compound of the present invention (e.g., a therapeutically effective amount of a compound of the present invention) to the individual.

In some embodiments, the metabolic disease, disorder or condition is class I obesity, class II obesity, class III obesity, increased weight, increased body mass index (BMI), increased body volume index (BVI), increased body fat percentage, increased fat to muscle ratio, increased waist circumference, or increased waist-to-hip ratio. Class I obesity is characterized by a BMI of about 30 to about 35, class II obesity (severe obesity) is characterized by a BMI of about 35 to about 40, and class III obesity (morbid obesity) is characterized by a BMI of 40 or greater. A BMI greater than about 45 or 50 is considered to be extremely obese. Increased weight can be assessed taking into account age, sex, height, build, and/or race. An increased waist-to-hip ratio is defined as greater than about 0.9 for men and greater than about 0.7 for women.

In some embodiments, the individual has an excess BMI as defined by BMI ≥ 25, 27.5, or 30. In other embodiments, the individual has an excess BMI as defined by BMI ≥ 25, 27.5, or 30 and has a history of BMI < 25 kg/m ² prior to the diagnosis of schizophrenia, depression, or anxiety. In other embodiments, the individual has an excess BMI as defined by BMI ≥ 30 and has a history of BMI < 25 kg/m ² prior to the diagnosis of schizophrenia, depression, or anxiety, and the individual is taking a typical or atypical antipsychotic. In other embodiments, the individual has a BMI ≥ 25, 27.5, or 30 induced by a typical or atypical antipsychotic.

Metabolic disorders are interrelated and may lead to disorders across a variety of systems. Addressing core metabolic disorders can reduce the severity of a patient's associated conditions, including, for example: cardiovascular disorders, including, for example, ischemic heart disease, angina and myocardial infarction, congestive heart failure, hypertension, abnormal cholesterol levels, deep venous embolism and pulmonary embolism; neurological disorders, including, for example, stroke, meralgia, migraine, idiopathic hypertension and intracranial hypertension, depression (especially in women), and social stigma (social stigmatism); rheumatic and orthopedic conditions, including, for example, gout, mobility impairment, osteoarthritis, and low back pain; skin conditions, including, for example, stretch marks, acanthosis nigricans, lymphedema, and cellulitis; gastrointestinal conditions, including, for example, gastroesophageal reflux disease (GERD) and cholelithiasis (gallstones); respiratory conditions, including, for example, obstructive sleep apnea, obesity hypoventilation syndrome, asthma, and increased complications during general anesthesia; urological and nephrological conditions, including, for example, erectile dysfunction, urinary incontinence, chronic renal failure, and hypogonadism.

In some embodiments, the metabolic disease, disorder or condition is associated with a neurological or psychiatric disease or disorder, including, for example, any neurological or psychiatric disease or disorder described herein. In some embodiments, the neurological or psychiatric disease or disorder is described in the revised or supplemented DSM-5 or International Statistical Classification of Diseases (ICD 11) coding system.

The therapeutically effective amount of a therapeutic agent (e.g., a compound of the invention) to be administered to an individual according to the methods described herein can be determined by a clinician of ordinary skill using the guidance provided herein and other methods known in the art. For example, depending on the route of administration, a suitable dose may be, in particular, in the range of about 0.1 mg/kg to about 500 mg/kg or about 1 mg/kg to about 100 mg/kg. In another example, depending on the route of administration, a suitable dose may be, in particular, in the range of about 0.005 mg/kg to about 100 mg/kg. In another example, a suitable daily dose may be in the range of about 0.1 mg to 1 g.

Depending on the compound and the specific disease to be treated, the therapeutic agents described herein, including the compounds of the present invention, can be administered via a variety of routes of administration, including, for example, oral, dietary, topical, transdermal, rectal, parenteral (e.g., intraarterial, intravenous, intramuscular, subcutaneous injection, intradermal injection), intravenous infusion, and inhalation (e.g., intrabronchial, intranasal or oral inhalation, intranasal instillation) routes of administration. Administration can be local or systemic, as indicated. The preferred mode of administration can vary depending on the specific compound selected. In some embodiments, the compounds of the present invention are administered orally. In some embodiments, the compounds of the present invention are administered intravenously.

In some embodiments, the methods further comprise administering one or more additional therapies (e.g., one or more therapeutic agents) to the individual. In some embodiments, the one or more additional therapies comprise psychotherapy, cognitive behavioral therapy, electroconvulsive therapy, transcranial magnetic stimulation, vagal nerve stimulation, and deep brain stimulation. In some embodiments, the one or more additional therapies comprise modifying the individual's dietary plan and/or exercise plan.

In some embodiments, the methods further comprise administering to the individual one or more additional therapeutic agents (e.g., a therapeutically effective amount of one or more additional therapeutic agents). Examples of suitable additional therapeutic agents (e.g., for treating a neurological or psychiatric disease or condition described herein) include anti-Parkinson's disease agents, anti-Alzheimer's disease agents, anti-depressants, antipsychotics, anti-ischemic agents, CNS sedatives, anti-cholesterol stimulants, nootropics, epilepsy drugs, attention (e.g., ADD/ADHD) drugs, sleep promoting drugs, wakefulness promoting drugs, and analgesics. Examples of suitable additional therapeutic agents (e.g., for treating a metabolic disease, disorder, or condition described herein) include anti-obesity agents (e.g., appetite suppressants), anti-diabetic agents, anti-hyperglycemic agents, lipid-lowering agents, anti-hypertensive agents, anti-Parkinson's disease agents, anti-Alzheimer's disease agents, anti-depressants, antipsychotics, anti-ischemic agents, CNS sedatives, anticholine stimulants, nootropics, epilepsy drugs, attention (e.g., ADD/ADHD) drugs, sleep-promoting drugs, wakefulness-promoting drugs, and analgesics.

Other suitable additional therapies and treatments for use with the methods disclosed herein include the therapies and treatments discussed herein in conjunction with combination therapies and pharmaceutical combinations.

When administered in combination with another therapy, the compounds of the invention may be administered before, after, or simultaneously with the other therapy (e.g., one or more additional therapeutic agents). When two or more therapeutic agents are administered simultaneously (e.g., concurrently), the compounds of the invention and the other one or more therapeutic agents may be in separate formulations or in the same formulation. Alternatively, the compounds of the invention and the other therapy may be administered sequentially (e.g., as separate compositions) within an appropriate time frame as determined by an experienced clinician (e.g., a time sufficient to allow the pharmacological effects of the compounds of the invention and the other therapy to overlap). Example

The compounds of the present invention can be prepared in a variety of ways known to those skilled in the art of organic synthesis according to the methods, reaction schemes and examples provided herein. The compounds of the present invention can be synthesized using the methods described below and synthetic methods known in organic synthetic chemistry techniques or variations thereof understood by those skilled in the art. Preferred methods include, but are not limited to, the methods described below. The reaction is carried out in a solvent or solvent mixture suitable for the reagents and materials used and suitable for achieving the transformation. Those skilled in organic synthesis techniques will understand that the functional groups present on the molecule should be consistent with the proposed transformation. Sometimes a judgment will need to be made to modify the order of the synthetic steps or to select a particular process flow rather than another to obtain the desired compound of the present invention. Unless otherwise specifically stated, the examples are depicted in relative stereochemistry.

Starting materials are generally available from commercial sources such as Sigma Aldrich or other commercial suppliers, or prepared as described herein, or readily prepared using methods well known to those skilled in the art (e.g., by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-19, Wiley, New York (eds. 1967-1999), Larock, RC . , Comprehensive Organic Transformations , 2nd ed., Wiley-VCH Weinheim, Germany (1999), or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed., Springer-Verlag, Berlin, including supplements (also available via the Beilstein online database)).

For illustrative purposes, the reaction schemes depicted below provide potential routes for synthesizing the compounds of the present invention and key intermediates. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the compounds of the present invention. Although specific starting materials and reagents are described in the schemes and discussed below, other starting materials and reagents may be easily substituted to provide a variety of derivatives and/or reaction conditions. In addition, a variety of compounds prepared by the methods described below may be further modified according to the present invention using conventional chemical methods well known to those skilled in the art.

In preparing the compounds of the present invention, it may be necessary to protect the remote functional groups of the intermediates. The need for such protection will vary depending on the nature of the remote functional group and the conditions of the preparation method. The need for such protection is readily determined by one skilled in the art. For a general description of protecting groups and their uses, see Greene, TW et al., Protecting Groups in Organic Synthesis , 4th edition, Wiley (2007). Protecting groups incorporated in the preparation of the compounds of the present invention, such as the trityl protecting group, may appear as one regioisomer, but may also exist as a mixture of regioisomers.

The following abbreviations used hereinafter have the corresponding meanings: Ac acetyl; ACN acetonitrile; Aq aqueous solution; BSA bovine serum albumin; Boc tertiary butoxycarbonyl; BPO benzoyl peroxide; br wide; C benzoyl peroxide; cAMP cyclic adenosine monophosphate; CH ₂ Cl ₂ dichloromethane; Cs ₂ CO ₃ cesium carbonate; d doublet; DBU 1,8-diazabicyclo[5.4.0]undec-7-ene; dd doublet; dba dibenzylideneacetone; DCM dichloromethane; DEA diethylamine; DEAD diethyl azodicarboxylate; DIBAL-H diisobutylaluminum hydroxide; DIPEA/DIEA N , N -diisopropylethylamine; DIAD diisopropyl azodicarboxylate; DMA dimethylacetamide; DMAP 4-dimethylaminopyridine; DMF N,N -dimethylformamide; DMSO dimethylsulfoxide; EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; EDTA ethylenediaminetetraacetic acid; ESI electrospray ionization; EtOAc ethyl acetate; EtOH ethanol; g gram; h hour; HEPES (4-(2-hydroxyethyl)-1-piperidinium ethanesulfonic acid); HPLC high pressure liquid chromatography; HTRF homogeneous time resolved fluorescence; IPA isopropyl alcohol; kg kilogram; KRH Krebs-Ringers Henseleit buffer; L liter; LC liquid chromatography; LCMS liquid chromatography-mass spectrometry; LiOH lithium hydroxide; MeOH methanol; MS mass spectrometry; M molar; m multiplet; m-CPBA 3-chloroperoxybenzoic acid; Me methyl; min minute; mL milliliter; µM micromolar; MW microwave; m/z mass-to-charge ratio; nm nanometer; nM nanomole; N equivalent; NBS N -bromosuccinimide; n -BuLi N -butyllithium; NMO N -methylmorpholine- N -oxide; NMP N-methylpyrrolidone; NMR nuclear magnetic resonance; PBS-EDTA phosphate buffered saline-ethylenediaminetetraacetic acid; Pd(OAc) _2palladium (II) acetate; PG protecting group; Ph phenyl; PS polymer supported; rac racemic; rt s single peak; sat. saturated; SFC supercritical fluid chromatography; t trimodal; TBAF tetrabutylammonium fluoride; TBSCl tert-butyldimethylsilyl chloride; t-Bu tert-butyl; tert -BuBrettPhos 2-(di-tert-butylphosphino)-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl; TEA triethylamine; tol toluene; Tf trifluoromethanesulfonate (trifluoromethanesulfonate); TFA trifluoroacetic acid; TFE trifluoroethanol; THF tetrahydrofuran; TLC thin layer chromatography X-Phos 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl; X-Phos-Pd-G3 (2-Dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]methanesulfonate Palladium(II).

General Synthesis Scheme. The following examples are prepared, isolated and characterized using the methods disclosed herein. The following examples illustrate part of the scope of the present invention and are not intended to limit the scope of the present invention.

Unless otherwise specified, starting materials are generally available from non-limiting commercial sources such as TCI Fine Chemicals (Japan), Shanghai Chemhere Co., Ltd. (Shanghai, China), Aurora Fine Chemicals LLC (San Diego, CA), FCH Group (Ukraine), Aldrich Chemicals Co. (Milwaukee, Wis.), Lancaster Synthesis, Inc. (Windham, N.H.), Acros Organics (Fairlawn, N.J.), Maybridge Chemical Company, Ltd. (Cornwall, England), Tyger Scientific (Princeton, N.J.), AstraZeneca Pharmaceuticals (London, England), Chembridge Corporation (USA), Matrix Scientific (USA), Conier Chem & Pharm Co., Ltd (China), Enamine Ltd (Ukraine), Combi-Blocks, Inc. (San Diego, USA), Oakwood Products, Inc. (USA), Apollo Scientific Ltd. (UK), Allichem LLC. (USA) and Ukrorgsyntez Ltd (Latvia).

Unless otherwise indicated, the values for the variables (eg, ^R1 , ^R2 , ^R3 , ^R4 , m) described in the illustrations for the following schemes are as described herein for compounds of structural formula I.

General Scheme for the Synthesis of Arylmorpholine Precursors 1a. General Pathway for the Synthesis of Styrene C General Scheme 1b. General route for the synthesis of styrene E General Scheme 1c. General route for the synthesis of ether F General Scheme 1d. General route for the synthesis of bromohydrin H (R ⁷ , R ^8a , R ^8b are each independently hydrogen or R ³ ; and Y′ is OH or SH) General Scheme 1e. General route for the synthesis of azidoalcohols I (R ⁷ , R ^8a , R ^8b are each independently hydrogen or R ³ ; and Y′ is OH or SH) General Scheme 1f. General Pathway for Synthesis of Aldehyde J

Synthesis of aryl morpholine General Scheme 2a. General method for the synthesis of aryl morpholine D-2 (R ^5a , R ^5b , R ^6a , R ^6b , R ⁷ , R ^8a , R ^8b are each independently hydrogen or R ³ ; and Y′ is OH or SH) General Scheme 2b. General route for the synthesis of aryl morpholines I-2 , J-2 and K-2 (R ^5a , R ^5b , R ^6a , R ^6b , R ^8a , R ^8b are each independently hydrogen or R ³ ) General Scheme 2c. General route for the synthesis of arylmorpholine N-2 (R ^6a , R ^6b , R ⁷ , R ^8a , R ^8b are each independently hydrogen or R ³ ; and Y′ is OH or SH) General Scheme 2d. General route for the synthesis of arylmorpholine P-2 (R ^5a , R ^5b , R ^6a , R ^6b , R ^8a , R ^8b are each independently hydrogen or R ³ ; and Y′ is OH or SH) General Scheme 2e. General route for the synthesis of arylthiophenolines S-2 , T-2 and U-2 (R ^5a , R ^5b , R ^6a , R ^6b , R ⁷ are each independently hydrogen or R ³ ) General Scheme 2f. General route for the synthesis of aryl morpholine D-2 (R ^5a , R ^5b , R ^6a , R ^6b , R ⁷ , R ^8a , R ^8b are each independently hydrogen or R ³

Functional group interconversion General Scheme 3a. General procedure for removal of the TBS group to provide the alcohol ( B - 3 ) ( ^R5a , ^R5b , ^R6a , ^R6b , ^R7 , ^R8a , ^R8b are each independently hydrogen or ^R3 ) General Scheme 3b. General procedure for protecting amine C - 3 to provide Boc-protected D - 3 ( ^R5a , ^R5b , ^R6a , ^R6b , ^R7 , ^R8a , ^R8b are each independently hydrogen or ^R3 ; and Y' is OH or SH) General Scheme 3c. General procedure for removal of BOC protection to provide amine ( C - 3 ) ( ^R5a , ^R5b , ^{R6a, R6b , R7} , ^R8a , ^R8b are each independently hydrogen or ^R3 ; and Y' is OH or SH) General Scheme 3d. General procedure for the synthesis of aryl tinane ( F - 3 ) from aryl halide ( E - 3 ) ( ^R5a , ^R5b , ^R6a , ^R6b , ^R7 , ^R8a , ^R8b are each independently hydrogen or ^R3 ) General Scheme 3e. General procedure for the synthesis of aryl tinanes ( F -3) from aryl trifluoromethanesulfonates (H- 3 ) ( R5a ^{, R5b} , ^R6a , ^R6b , ^R7 , ^R8a , ^R8b are each independently hydrogen or ^R3 ) General Scheme 3f. General procedure for the synthesis of aryl trifluoromethanesulfonates ( G - 3) from aryl alcohols (B-3 ) ( R5a ^{, R5b} , ^R6a , ^R6b , ^R7 , ^R8a , ^R8b are each independently hydrogen or ^R3 ) General Scheme 3g. General procedure for the synthesis of aryl borate esters ( I - 3) from aryl halides (E-3 ) ( R5a ^{, R5b} , ^R6a , ^R6b , ^R7 , ^R8a , ^R8b are each independently hydrogen or ^R3 ) General Scheme 3h. General procedure for the synthesis of aryl bromides ( E - 3) from aryl trifluoromethanesulfonates (G-3 ) ( R5a ^{, R5b} , ^R6a , ^R6b , ^R7 , ^R8a , ^R8b are each independently hydrogen or ^R3 ) General Scheme 3i. General procedure for the synthesis of aryl alcohols ( K - 3 ) from the corresponding boronic acid ( J - 3 ). General Scheme 3j. General procedure for the synthesis of alkylated porphyrins ( L - 3 ) from the corresponding porphyrins ( C - 3 ) (when the reagent is HCHO, ^R4b is (C1)alkyl; when ^R4a is (C1)alkyl, ^R4b is (C2)alkyl, and when ^R4a is (C2)alkyl, ^R4b is (C3)alkyl.

Chiral separation general scheme 4a. Separation of racemic A - 4 to B - 4 and C - 4 ( ^R5a , ^R5b , ^R6a , ^R6b , ^R7 , ^R8a , ^R8b are each independently hydrogen or ^R3 ; W is ^R4 or a protecting group; and Y' is OH, SH, Br, Cl, I or ^YR1 )

General Scheme 5a of the compounds of the present invention . General procedure for synthesizing compound ( C-5 ) ( ^R5a , ^R5b , R6a, ^R6b , ^R7 , ^R8a , ^{R8b are} each independently hydrogen or ^R3 ) General Scheme 5b. General procedure for the synthesis of compound ( C-5 ) (R ^5a , R ^5b , R ^6a , R ^6b , R ⁷ , R ^8a , R ^8b are each independently hydrogen or R ³ ) General Scheme 5c. General procedure for synthesizing compound ( C-5 ) ( ^R5a , ^R5b , ^R6a , ^R6b , ^R7 , ^R8a , ^R8b are each independently hydrogen or ^R3 ) General Scheme 5d. General procedure for the synthesis of compound ( C-5 ) (R ^5a , R ^5b , R ^6a , R ^6b , R ⁷ , R ^8a , R ^8b are each independently hydrogen or R ³ ) General Scheme 5e. General procedure for the synthesis of compound ( C-5 ) ( ^R5a , ^R5b , ^R6a , ^R6b , ^R7 , ^R8a , ^R8b are each independently hydrogen or ^R3 ) General Scheme 5f. General procedure for the synthesis of compound ( G-5 ) (R ^5a , R ^5b , R ^6a , R ^6b , R ⁷ , R ^8a , R ^8b are each independently hydrogen or R ³ ) General Scheme 5g. General procedure for the synthesis of compound ( I-5 ) ( ^R5a , ^R5b , ^R6a , ^R6b , ^R7 , ^R8a , ^R8b are each independently hydrogen or ^R3 ) General Scheme 5g. General procedure for the synthesis of compound ( K-5 ) (R ^5a , R ^5b , R ^6a , R ^6b , R ⁷ , R ^8a , R ^8b are each independently hydrogen or R ³ )

Example 1. Synthesis of ( R ) -2-(2- fluoro -5-((6 -methylphenoxy ) phenyl ) pyroline ( Compound 1 ) a. Synthesis of (3- bromo - 4- fluorophenoxy ) ( tertiary butyl ) dimethylsilane

To a solution of 3-bromo-4-fluorophenol (250 g, 1.309 mol) in DCM (2.5 L) are added 1H -imidazole (107 g, 1.571 mol) and TBSCl (237 g, 1.571 mol). The reaction mixture is stirred at room temperature for 1 h. The reaction is monitored by TLC. The reaction mixture is filtered. After separation, the organic phase is washed with brine, dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo. The resulting residue is purified by silica gel column chromatography to provide (3-bromo- ₄ -fluorophenoxy)(tributyl)dimethylsilane ( I-1-2 ). b. Synthesis of 2-(5-(( tri-butyldimethylsilyl ) oxy )-2- fluorophenyl )-2- hydroxymorpholine -4- carboxylic acid tri- butyl ester

To a solution of (3-bromo-4-fluorophenoxy)(tributyl)dimethylsilane (318 g, 1.04 mol) in anhydrous THF (3 L) was added n -BuLi (2.5 M, 500 mL) at -78 °C under _N2 . The reaction was stirred at that temperature for 0.5 h. Then tributyl 2-oxoquinoline-4-carboxylate (230.5 g, 1.15 mol) was added to the reaction mixture in anhydrous THF (500 mL). The reaction was monitored by TLC. The reaction mixture was quenched with saturated aqueous _NH4Cl . The resulting biphasic mixture was transferred to a separatory funnel. The layers were separated and the aqueous phase was extracted with EtOAc (2 x 500 mL). The combined organics were washed with brine and dried over _{anhydrous Na2SO4} , filtered and concentrated in vacuo to provide crude 2-(5-((tri-butyldimethylsilyl)oxy)-2-fluorophenyl)-2-hydroxymorpholine-4-carboxylic acid tert-butyl ester ( Compound I-1-3 ). c. Synthesis of 2-(2- fluoro -5 -hydroxyphenyl ) morpholine -4- carboxylic acid tert-butyl ester

A solution of crude tributyl 2-(5-((tributyldimethylsilyl)oxy)-2-fluorophenyl)-2-hydroxymorpholine-4-carboxylate (396.8 g) in _Et3SiH (538 g, 4.625 mol) was stirred for 1 hour. TFA (527 g, 4.625 mol) was then added to the reaction. The reaction mixture was heated to 60-80°C and stirred overnight. The reaction was monitored by LCMS. The solvent was evaporated in vacuo. TBAF (928 mL, 1 M in THF, 0.928 mol) was added to the residue. The reaction was stirred at room temperature for 4 hours. The reaction was alkalized with saturated aqueous _NaHCO3 . Boc ₂ O (303 g, 1.392 mol) dissolved in EtOAc was then added to the reaction mixture. The reaction was stirred overnight. The resulting biphasic mixture was transferred to a separatory funnel. The layers were separated and the aqueous phase was extracted with EtOAc (2×500 mL). The combined organics were washed with brine and dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to provide a crude product (1040 g). The crude product was purified by silica gel column chromatography to provide tributyl 2-(2-fluoro-5-hydroxyphenyl)morpholine-4-carboxylate ( Compound I -1-4 ). d. Separation of tert-butyl 2-( 2- fluoro -5 -hydroxyphenyl ) morpholine -4- carboxylate using a chiral column

2-(2-Fluoro-5-hydroxyphenyl)morpholine-4-carboxylic acid tributyl ester was separated by chiral column separation using the following: Instrument: SFC-150 (Thar, Waters) Column: AD 25×250mm, 10µm (Daicel) Column temperature: 35℃ Mobile phase: CO ₂ /IPA (0.01% methylamine/methanol) = 91/9 Flow rate: 100 g/min Back pressure: 100 bar Detection wavelength: 220 nm Cycle time: 4.0 min Sample solution: 110 g dissolved in 1000 mL methanol Injection volume: 1.8 mL

Chiral analysis conditions: Instrument: Waters 2695; Column: Reflect C-Amylose A (4.6×250mm, 5µm); Column temperature: 30℃; Mobile phase: n-hexane/EtOH (0.1% DEA) = 80/20; Flow rate: 0.8 mL/min; Detection wavelength: 220 nm; Detector: W2996 PDA.

After removing the solvent from the chiral separation, the first eluting isomer, 2-(2-fluoro-5-hydroxyphenyl)morpholine-4-carboxylic acid tert-butyl ester ( Compound I-1-5- peak 1 , retention time from the analytical column = 5.25 min) and the second eluting isomer, ( S )-2-(2-fluoro-5-hydroxyphenyl)morpholine-4-carboxylic acid tert-butyl ester ( Compound I-1-5- peak 2 , retention time from the analytical column = 6.03 min) were obtained. e. Synthesis of (R)-2-{2- fluoro -5-[(6- methylpyridinium - 3- yl ) oxy ] phenyl } morpholine -4- carboxylic acid tert-butyl ester

To a solution of ( R )-2-(2-fluoro-5-hydroxyphenyl)morpholine-4-carboxylic acid tributyl ester ( Compound I-1-5- peak 1 , 120 mg, 403 µmol) in DMF (3 mL) was added CuBr (5.78 mg, 40.3 µmol), 2,2,6,6-tetramethylheptane-3,5-dione (59.3 mg, 322 µmol), 3-bromo-6-methylpyridine (104 mg, 604 µmol) and Cs ₂ CO ₃ (326 mg, 1.00 mmol). The reaction mixture was exchanged with N ₂ balloon three times. The reaction mixture was heated to 120 °C and stirred at that temperature for 16 h. Water (10 mL) and EtOAc (8 mL) were added to the reaction vessel and the resulting two-phase mixture was transferred to a separatory funnel. The layers were separated and the aqueous phase was extracted with EtOAc (2×8 mL). The combined organics were washed with brine (2×10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography with a gradient elution from EtOAc (20%) and petroleum ether (80%) to EtOAc (50%) and petroleum ether (50%) to provide ( R )-2-{2-fluoro-5-[(6-methylpyridinium-3-yl)oxy]phenyl}pyroline-4-carboxylic acid tributyl ester ( Compound I-1-6 ). f. Synthesis of (R)-2-(2- fluoro -5-((6 -methylpyridinium - 3- yl ) oxy ) phenyl ) pyroline

To a solution of ( R )-2-{2-fluoro-5-[(6-methylpyridinium-3-yl)oxy]phenyl}pyroline-4-carboxylic acid tributyl ester (120 mg, 308 µmol) in DCM (2 mL) was added HCl/ _Et2O (3M, 2 mL). The reaction was stirred at ambient temperature for 1 h. The reaction mixture was filtered and washed with _Et2O (5 mL), dried under vacuum to provide ( R )-2-{2-fluoro-5-[(6-methylpyridinium-3-yl)oxy]phenyl}pyroline ( Compound 1 ) as a 2HCl salt.

Compound 1. MS (ESI+) m/z : 290 (MH) ⁺ . ¹ H-NMR (300 MHz, CD ₃ OD) δ 8.31 (d, J = 9.0 Hz, 1 H), 8.11 (d, J = 9.0 Hz, 1 H), 7.52 (dd, J = 3.0, 5.4 Hz, 1 H), 7.36-7.27 (m, 2H), 5.14 (d, J = 10.5 Hz, 1 H), 4.25 (dd, J = 2.7, 13.2 Hz, 1 H), 4.08 (td, J = 12.6, 2.1 Hz, 1 H), 3.55 (d, J = 12.3 Hz, 1 H), 3.31-3.25 (m, 2H), 3.12 (t, J = 12.0 Hz, 1H), 2.82 (s, 3H).

Example 2. Synthesis of ( R )-2-(3-( pyrimidin -4 -yloxy ) phenyl ) pyrimidine ( Compound 2) a. Synthesis of (3- bromophenoxy )( tertiary butyl ) dimethylsilane

To a solution of 3-bromophenol ( Compound I-2-1 , 300 g, 1.73 mol) in DCM (3 L) was added 1H -imidazole (140 g, 2.07 mol) and tributyl(chloro)dimethylsilane (286 g, 1.90 mol) at 0 °C. The reaction was stirred at 0 °C for 2 h, then water (1 L) was added to the reaction vessel and the resulting biphasic mixture was transferred to a separatory funnel. The layers were separated, and the organic phase was extracted with DCM (2×300 mL) and washed with saturated aqueous NaCl (2×500 mL). The combined organics were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The obtained oil was purified by flash column chromatography using isocratic elution with petroleum ether (100%) to provide (3-bromophenoxy)(tertiary butyl)dimethylsilane ( Compound I-2-2 ). b. Synthesis of tertiary butyl (3- vinylphenoxy ) dimethylsilane

To _a solution of (3-bromophenoxy)(tertiary butyl)dimethylsilane ( Compound I-2-2 , 500 g, 1.56 mol) in toluene (4.5 L) were added tributyl(vinyl)tinane (542 g, 1.71 mol) and tetrakis(triphenylphosphine)palladium (18.0 g, 15.6 mmol) under N2. The reaction mixture was heated to 90°C and stirred at that temperature for 16 h. KF (500 g) and water (2 L) were added to the reaction vessel and the resulting two-phase mixture was stirred for 6 h. The resulting two-phase mixture was filtered and concentrated in vacuo to provide tertiary butyl(3-vinylphenoxy)dimethylsilane ( Compound I-2-3 ). c. Synthesis of 2- bromo -1-(3-(( tertiary butyldimethylsilyl ) oxy ) phenyl ) ethan -1- ol

To a solution of tributyl(3-vinylphenoxy)dimethylsilane ( Compound I-2-3 , 600 g, 1.27 mol) in dioxane (3 L) and H ₂ O (1.5 L) at 0°C was added acetic acid (76.2 g, 1.27 mol) and NBS (247 g, 1.39 mol). The reaction was stirred at ambient temperature for 3 h. Water (2 L) was added to the reaction vessel and the resulting biphasic mixture was transferred to a separatory funnel. The layers were separated and the organic phase was extracted with EtOAc (2×3 L) and washed with saturated aqueous NaCl (2×1 L). The combined organics were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography with a gradient elution from petroleum ether (100%) to petroleum ether (90%) and EtOAc (10%) to provide 2-bromo-1-{3-[(tributyldimethylsilyl)oxy]phenyl}ethan-1-ol ( Compound I-2-4 ). d. Synthesis of 1-(3-(( tributyldimethylsilyl ) oxy ) phenyl )-2-((2- hydroxyethyl ) amino ) ethan -1- ol

To a solution of 2-bromo-1-{3-[(tributyldimethylsilyl)oxy]phenyl}ethan-1-ol ( compound I-2-4 , 720 g, 1.08 mol) in MeOH (6 L) was added 2-aminoethan-1-ol (197 g, 3.24 mol). The reaction mixture was heated to 50 °C and stirred at that temperature for 16 h. The reaction solution was concentrated in vacuo. The resulting oil was purified by flash column chromatography with a gradient elution from DCM (100%) to DCM (90%) and MeOH (10%) to provide 1-{3-[(tributyldimethylsilyl)oxy]phenyl}-2-[(2-hydroxyethyl)amino]ethan-1-ol ( compound I-2-5 ). e. Synthesis of tributyl N-(2-{3-[( tributyldimethylsilyl ) oxy ] phenyl }-2- hydroxyethyl )-N-(2- hydroxyethyl ) carbamate

To a solution of 1-{3-[(tributyldimethylsilyl)oxy]phenyl}-2-[(2-hydroxyethyl)amino]ethan-1-ol ( Compound I-2-5 , 400 g, 898 mmol) in THF (1.5 L) and H ₂ O (1.5 L) was added sodium methaneperoxoate (112 g, 1.34 mol) and di-tributyl dicarbonate (215 g, 987 mmol). The reaction was stirred at ambient temperature for 3 h. Water (1 L) was added to the reaction vessel and the resulting biphasic mixture was transferred to a separatory funnel. The layers were separated and the aqueous phase was extracted with EtOAc (3×500 mL). The combined organics were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The obtained oil was purified by flash column chromatography using isocratic elution with EtOAc (5%) and petroleum ether (95%) to provide tributyl N- (2-{3-[(tributyldimethylsilyl)oxy] phenyl }-2-hydroxyethyl) -N- (2-hydroxyethyl)carbamate ( Compound I-2-6 ). f. Synthesis of tributyl 2-{3-[( tributyldimethylsilyl ) oxy ] phenyl } morpholine -4- carboxylate

To a solution of impure N- (2-{3-[(tributyldimethylsilyl)oxy]phenyl}-2-hydroxyethyl) -N- (2-hydroxyethyl)carbamic acid tributyl ester ( compound I-2-6 , 300 g, 728 mmol) in toluene ( ₁₀ L) at 0 °C under N2, _PPh3 (228 g, 873 mmol) and DIAD (176 g, 873 mmol) were added. The reaction mixture was heated to 50 °C and stirred at that temperature for 2 h. The reaction solution was directly concentrated in vacuo. The obtained oil was purified by flash column chromatography using a gradient elution of petroleum ether (100%) from petroleum ether (90%) and EtOAc (10%) to provide impure 2-{3-[(tri-butyldimethylsilyl)oxy]phenyl}morpholine-4-carboxylic acid tert-butyl ester ( Compound I-2-7 ). g. Synthesis of 2-(3- hydroxyphenyl ) morpholine- 4- carboxylic acid tert-butyl ester

To a solution of impure 2-{3-[(tri-butyldimethylsilyl)oxy]phenyl}morpholine-4-carboxylic acid tri-butyl ester ( Compound 1-2-7 , 175 g, about 60% purity) in THF (1 L) was added TBAF (444 mL, 444 mmol). The reaction was stirred at ambient temperature for 1 h. Water (500 mL) and EtOAc (200 mL) were added to the reaction vessel and the resulting biphasic mixture was transferred to a separatory funnel. The layers were separated and the aqueous phase was extracted with EtOAc (2×200 mL). The combined organics were washed with brine (200 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The obtained oil was purified by flash column chromatography with a gradient elution from petroleum ether (98%) and EtOAc (2%) to petroleum ether (90%) and EtOAc (10%) to provide tert-butyl 2-(3-hydroxyphenyl)-4-carboxylate ( Compound I-2-8 ). h. Chiral column separation of tert-butyl 2- (3- hydroxyphenyl ) -4- carboxylate

2-(3-Hydroxyphenyl)morpholine-4-carboxylic acid tributyl ester was separated by chiral column separation using the following: Instrument: SFC-150 (Thar, Waters) Column: AD 25×250mm, 10µm (Daicel) Column temperature: 35℃ Mobile phase: CO ₂ /IPA (0.01% methylamine/methanol) = 87/13 Flow rate: 100 g/min Back pressure: 100 bar Detection wavelength: 220 nm Cycle time: 2.0 min Sample solution: 48.5 g dissolved in 480 mL methanol Injection volume: 1.0 mL

Chiral analysis conditions: instrument: Waters 2695; column: Regis REFLECT C-Amylose A 4.6×250mm, 5µm; column temperature: 30℃; mobile phase: n-hexane/EtOH (0.1% DEA) = 90/10; flow rate: 0.8 mL/min; detection wavelength: 220 nm; detector: W2996 PDA.

After the solvent was removed, the first eluting isomer ( R )-2-(3-hydroxyphenyl)morpholine-4-carboxylic acid tert-butyl ester ( Compound I-2-9- peak 1 , retention time from the analytical column = 10.44 min) and the second eluting isomer ( S )-2-(3-hydroxyphenyl)morpholine-4-carboxylic acid tert-butyl ester ( Compound I-2-9- peak 2 , retention time from the analytical column = 11.66 min) were obtained. i. Synthesis of (R)-2-[3-( pyrimidin -4 -yloxy ) phenyl ] morpholine -4- carboxylic acid tert-butyl ester

To a solution of ( R )-2-(3-hydroxyphenyl)morpholine-4-carboxylic acid tributyl ester ( Compound I-2-9- peak 1 , 100 mg, 357 µmol) in DMF (2 mL) under _N2 was added 4-bromopyrimidine HBr (171 mg, 714 µmol) and DBU (270 mg, 1.78 mmol). The reaction mixture was heated to 60 °C and stirred at that temperature for 16 h. LCMS showed about 35% starting material remaining. Water (5 mL) and EtOAc (5 mL) were added to the reaction vessel and the resulting two-phase mixture was transferred to a separatory funnel. The layers were separated and the aqueous phase was extracted with EtOAc (3×5 mL). The combined organics were washed with brine and dried _over anhydrous _Na2SO4 . After filtration and vacuum concentration, the resulting oil was purified by flash column chromatography with a gradient elution from petroleum ether (90%) and EtOAc (10%) to petroleum ether (60%) and EtOAc (40%) to provide ( R )-2-[3-(pyrimidin-4-yloxy)phenyl]-pyrroline-4-carboxylic acid tributyl ester ( Compound I -2-10 ). j. Synthesis of (R)-2-[3-( pyrimidin -4 -yloxy ) phenyl ] -pyrroline

To a solution of ( R )-2-[3-(pyrimidin-4-yloxy)phenyl]porphyrin-4-carboxylic acid tributyl ester (16 mg, 44.7 µmol) in _Et2O (1 mL) was added HCl/ _Et2O (3M, 1 mL). The reaction was stirred at ambient temperature for 3 h. The reaction was concentrated in vacuo and the residue was washed with _Et2O (3 x 5 mL) to provide ( R )-2-[3-(pyrimidin-4-yloxy)phenyl]porphyrin ( Compound 2 ) as a 2HCl salt.

Compound 2. MS (ESI+) m/z : 258 (MH) ⁺ . ¹ H-NMR (300 MHz, CD ₃ OD) δ 8.95 (s, 1H), 8.81 (d, J = 5.7 Hz, 1 H), 7.54 (t, J = 8.1 Hz, 1 H), 7.41-7.35 (m, 3 H), 7.26 (d, J = 7.2 Hz, 1 H), 4.83 (d, J = 10.5 Hz, 1 H), 4.27 (dd, J = 3.6, 11.7 Hz, 1 H), 3.99 (td, J = 12.9, 3.0 Hz, 1 H), 3.53 (d, J = 13.5 Hz, 1 H), 3.31-3.25 (m, 2H), 3.11 (t, J = 12.0 Hz, 1H).

Example 3. Synthesis of ( R ) -2- ( 2 - fluoro - 5- ( pyrimidin - 4 - yloxy ) phenyl ) -2- ( 2 - fluoro - 5- ( pyrimidin - 4 - yloxy ) phenyl ) -4 - methyl ... ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​

Compound 3 was synthesized from compound 1-1-5- peak 1 and 4-bromopyrimidine hydrobromide as a 2HCl salt using a coupling and subsequent deprotection procedure similar to that in Example 2 .

Compound 3. MS (ESI+) m/z : 276 (MH) ⁺ . ¹ H-NMR (300 MHz, CD ₃ OD) δ 8.95 (s, 1H), 8.81 (d, J = 5.4 Hz, 1 H), 7.47-7.37 (m, 2 H), 7.30 (d, J = 6.9 Hz, 2 H), 5.12 (d, J = 10.8 Hz, 1 H), 4.25 (d, J = 12.3 Hz, 1 H), 4.03 (t, J = 11.1 Hz, 1 H), 3.55 (d, J = 12.6 Hz, 1 H), 3.34-3.25 (m, 2H) , 3.12 (t, J = 12.0 Hz, 1H). b. Synthesis of (S)-2-(2- fluoro -5-( pyrimidin -4 -yloxy ) phenyl ) morpholine -4- carboxylic acid tributyl ester

To a solution of ( S )-2-(2-fluoro-5-hydroxyphenyl)morpholine-4-carboxylic acid tributyl ester ( Compound I-1-5- peak 2 , 50 mg, 168 µmol) in DMF (2 mL) was added 4-chloropyrimidine HCl (50.7 mg, 336 µmol) and DBU (25.5 mg, 168 µmol). The reaction mixture was heated to 60 °C and stirred at that temperature for 5 h. Water (5 mL) was added to the reaction vessel and the resulting biphasic mixture was transferred to a separatory funnel. The layers were separated and the aqueous phase was extracted with EtOAc (3×5 mL). The combined organics were washed with brine and dried over anhydrous Na ₂ SO ₄ . After filtration and vacuum concentration, the resulting oil was purified by preparative thin layer chromatography using isocratic elution with EtOAc (25%) and petroleum ether (75%) to provide ( S )-2-[2-fluoro-5-(pyrimidin-4-yloxy)phenyl]-4-carboxylic acid tributyl ester ( Compound I -3-1 ). c. Synthesis of ( S )-2-(2-fluoro-5-(pyrimidin-4-yloxy)phenyl)-4-carboxylic acid

To a solution of ( S )-2-[2-fluoro-5-(pyrimidin-4-yloxy)phenyl]pyrimidine-4-carboxylic acid tributyl ester ( compound I-3-1 , 55 mg, 146 µmol) in _Et2O (1 mL) was added HCl/ _Et2O (3M, 1 mL). The reaction was stirred at ambient temperature for 3 h. The mixture was filtered and concentrated in vacuo. The resulting oil was purified by reverse phase HPLC with acetonitrile and water to provide ( S )-2-[2-fluoro-5-(pyrimidin-4-yloxy)phenyl]pyrimidine ( compound 4 ) as a free base.

Compound 4. MS (ESI+) m/z : 276 (MH) ⁺ . ¹ H-NMR (300 MHz, CD ₃ OD) δ 8.70 (s, 1H), 8.60 (d, J = 6.0 Hz, 1H), 7.29 (d, J = 3.0 Hz, 1H), 7.23-7.05 (m, 3H), 4.80-4.77 (m, 1H), 3.98 (d, J = 10.8 Hz, 1H), 3.76 (td, J = 11.4, 3.3 Hz, 1H), 3.08 (d, J = 12.3 Hz, 1H), 2.92-2.80 (m, 2H), 2.63 (t, J = 11.4 Hz, 1H).

To a solution of ( R )-2-(2-fluoro-5-(pyrimidin-4-yloxy)phenyl)morpholine 2HCl salt ( Compound 3 , 65 mg, 186 µmol) in MeOH (2 mL) was added acetic acid (22.3 mg, 372 µmol) and formaldehyde (58.6 mg, 744 µmol). The reaction was stirred at ambient temperature for 15 min. _NaBH3CN (50.5 mg, 744 µmol) was then added. The reaction was stirred at ambient temperature for 16 h. A saturated aqueous solution _{of Na2CO3} (5 mL) and EtOAc (5 mL) were added to the reaction vessel and the resulting biphasic mixture was transferred to a separatory funnel. The layers were separated and the aqueous phase was extracted with EtOAc (2 x 5 mL). _The combined organics were dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography to provide ( R )-2-[2-fluoro-5-(pyrimidin-4-yloxy)phenyl]-4-methylmorpholine ( Compound 5 ) as a free base.

Compound 5. MS (ESI+): m/z 290 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD): δ 8.69 (s, 1H), 8.61 (d, J = 6.7 Hz,1H), 7.31 -7.28 (m, 1H), 7.22-7.14 (m, 2H), 7.07 (d, J = 6.0 Hz, 1H), 4.78-4.64 (m, 1H), 3.99 (d, J = 10.8 Hz, 1H), 3.77 (t, J = 11.1 Hz, 1H), 3.01 (d, J = 11.4 Hz, 1H), 2.78 (d, J = 12.0 Hz, 1H), 2.33 (s, 3H), 2.30-2.23 (m, 1H), 2.03 (t, J = 10.8 Hz, 1H).

Example 4. Synthesis of ( R )-2-(2- fluoro -5-((5 - methylpyridinium - 3-yl ) oxy ) phenyl ) pyroline ( Compound 6 ) a . Synthesis of ( R)-2-(2- fluoro -5-((5- methylpyridinium - 3- yl ) oxy ) phenyl ) pyroline -4- carboxylic acid tributyl ester

To a solution of ( R )-2-(2-fluoro-5-hydroxyphenyl)morpholine-4-carboxylic acid tributyl ester ( Compound I-1-5- peak 1 , 120 mg, 403 µmol) in DMF (2 mL) was added 3-chloro-5-methylpyridinium (77.6 mg, 604 µmol) and Cs ₂ CO ₃ (326 mg, 1.00 mmol). The reaction was stirred at 120 °C for 16 h. Water (5 mL) was added to the reaction vessel and the resulting biphasic mixture was transferred to a separatory funnel. The layers were separated and the aqueous phase was extracted with EtOAc (3×5 mL). The combined organics were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting mixture was purified by flash column chromatography using isocratic elution with ethane (50%) and EtOAc (50%) to provide ( R )-2-{2-fluoro-5-[(5-methylpyridinium-3-yl)oxy]phenyl}pyroline-4-carboxylic acid tributyl ester ( Compound I-4-1 ). b. Synthesis of ( R )-2-(2-fluoro-5-((5-methylpyridinium-3-yl)oxy)phenyl)pyroline

To a solution of ( R )-2-{2-fluoro-5-[(5-methylpyridinium-3-yl)oxy]phenyl}pyroline-4-carboxylic acid tributyl ester ( Compound I-4-1 , 96 mg, 246 µmol) in _Et2O (1 mL) was added HCl/ _Et2O (3M, 1 mL). The reaction was stirred at ambient temperature for 3 h. The reaction was concentrated in vacuo and the residue was washed with _Et2O (3×5 mL) to provide ( R )-2-{2-fluoro-5-[(5-methylpyridinium-3-yl)oxy]phenyl}pyroline ( Compound 6 ) as a 2HCl salt.

Compound 6. MS (ESI+): m/z 290 (MH+); ¹ H NMR (300 MHz, DMSO- d6 ) δ 10.02 (br s, 1H), 9.80 (br s, 1H), 9.00-8.98 (m, 1H), 7.48-7.45 (m, 1H), 7.40-7.35 (m, 2H), 7.33-7.29 (m, 1H), 5.14 (d, J = 8.4 Hz, 1H), 4.10 (d, J = 9.3 Hz, 1H), 4.01 (t, J = 9.3 Hz , 1H), 3.39 (d, J = 9.0 Hz, 1H), 3.24 (d, J = 9.6 Hz, 1H), 3.13-3.04 (m, 2H), 2.40 (s, 3H).

Example 5. Synthesis of ( R )-2-(2- fluoro -5-( pyrimidin -2 -yloxy ) phenyl ) pyrimidine ( Compound 7)

Compound 7 was synthesized from compound 1-1-5- peak 1 and 2-bromopyrimidine using a nucleophilic substitution and subsequent deprotection procedure similar to that in Example 1 .

Compound 7. MS (ESI+): m/z 276 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ 8.60 (d, J = 4.8 Hz, 2H), 7.38 (d, J = 6.0 Hz, 1H), 7.26-7.22 (m, 3H), 5.10 (d, J = 11.4 Hz, 1H), 4.26 (dd, J = 3.0, 13.8 Hz, 1H), 4.02 (td, J = 11.7, 3.3 Hz, 1H), 3.54 (d, J = 12.6 Hz, 1H), 3.33-3.30 ( m, 2H), 3.13 (t, J = 11.9 Hz, 1H).

Example 6. Synthesis of ( R )-2-(3-( indole - 3 -yloxy ) phenyl ) -pyroline ( Compound 8) , ( S )-2-(3-( indole - 3 -yloxy ) phenyl ) -pyroline ( Compound 9) , ( R )-4- methyl -2-(3-( indole - 3 -yloxy ) phenyl ) -pyroline ( Compound 10) a. Synthesis of (R)-2-(3-( indole - 3- yloxy ) phenyl ) -pyroline ( Compound 8 )

Compound 8 was synthesized from compound I-2-9- peak 1 and 3-bromoindole as a 2HCl salt using a coupling and subsequent deprotection procedure similar to that in Example 1 .

Compound 8. MS (ESI+): m/z 258 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ 9.31 (d, J = 4.8 Hz, 1H), 8.35 (dd, J = 4.8, 9.3 Hz, 1H), 8.11 (d, J = 9.3 Hz, 1H), 7.55 (t, J = 8.1 Hz, 1H), 7.42 (br s, 2H), 7.31 (d, J = 7.5 Hz, 1H), 4.92-4.87 (m, 1H), 4.24 (dd, J = 3.0, 13.2 Hz, 1H), 4.04 (td, J = 12.9, 3.0 Hz, 1H), 3.56 (dd, J = 3.0, 12.0 Hz, 1H), 3.40-3.24 (m , 2H), 3.11 (t, J = 12.0 Hz, 1H). b. Synthesis of (S)-2-(3-( dithio ... 3- (3-amino ) phenyl ) morpholine ( Compound 9 )

Compound 9 was synthesized from compound I-2-9- peak 2 and 3-bromoindole as a 2HCl salt using a coupling and subsequent deprotection procedure similar to that in Example 1 .

Compound 9. MS (ESI+): m/z 258 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ 9.31-9.28 (m, 1H), 8.38-8.32 (m, 1H), 8.12 (d , J = 9.3 Hz, 1H), 7.54 (t, J = 8.1 Hz, 1H), 7.42 (br s, 2H), 7.32 (d, J = 8.1 Hz, 1H), 4.92-4.87 (m, 1H), 4.27 (dd, J = 3.3, 13.8 Hz, 1H), 4.04 ( td, J = 12.0, 3.0 Hz, 1H), 3.56 (d, J = 12.3 Hz, 1H), 3.40-3.32 (m, 2H), 3.13 (t, J = 12.0 Hz, 1H). c. Synthesis of (R)-4- methyl -2-(3-( indole - 3- yloxy) ) phenyl ) morpholine ( Compound 10 )

Compound 10 was synthesized from compound 8 as a 2HCl salt using a similar methylation as in Example 3 and a similar salt formation procedure as in Example 1 .

Compound 10. MS (ESI+): m/z 272 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ 9.32 (d, J = 4.5 Hz, 1H), 8.37-8.32 (m, 1H), 8.12 (d, J = 8.7 Hz, 1H), 7.56 (t, J = 8.1 Hz, 1H), 7.44-7.40 (m, 2H), 7.32 (d, J = 7.2 Hz, 1H), 4.88-4.85 (m, 1H), 4.28 (d, J = 12.6 Hz, 1H), 4.04 ( t, J = 12.8 Hz, 1H), 3.75 (d, J = 13.2 Hz, 1H), 3.54 (d, J = 12.0 Hz, 1H), 3.30-3.20 (m, 1H), 3.12 (t, J = 11.6 Hz, 1H), 2.96 (s, 3H).

Example 7. Synthesis of ( R )-2-(2- fluoro -5-( indole - 3 -yloxy ) phenyl ) -pyroline ( Compound 11) , ( S )-2-(2- fluoro -5-( indole - 3 -yloxy ) phenyl ) -pyroline ( Compound 12) , ( R )-2-(2- fluoro -5- ( indole - 3 -yloxy ) phenyl )-4- methylpyroline ( Compound 13) a. Synthesis of (R)-2-(2- fluoro -5-( indole - 3 -yloxy ) phenyl ) -pyroline ( Compound 11 )

Compound 11 was synthesized from compound 1-1-5- pyridine and 3-bromoindole as a 2HCl salt using a coupling and subsequent deprotection procedure similar to that in Example 1 .

Compound 11. MS (ESI+): m/z 276 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ 9.30 (d, J = 4.8 Hz, 1H), 8.32 (dd, J = 5.0, 9.2 Hz, 1H), 8.09 (d, J = 9.0 Hz, 1H), 7.54-7.51 (m, 1H), 7.36-7.31 (m, 2H), 5.12 (d, J = 11.1 Hz, 1H), 4.26 (dd, J = 3.6, 13.2 Hz, 1H), 4.06 (td, J = 12.0, 3.0 Hz, 1H), 3.56 (d, J = 12.9 Hz, 1H), 3.42-3.32 (m, 2H), 3.13 (t, J = 11.4 Hz, 1H). b. Synthesis of (S)-2-(2- fluoro -5-( indole - 3 -yloxy ) phenyl ) Phenyline ( Compound 12 )

Compound 12 was synthesized from compound 1-1-5- pyridine and 3-bromoindole as a 2HCl salt using a coupling and subsequent deprotection procedure similar to that in Example 1 .

Compound 12. MS (ESI+): m/z 276 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ 9.22 (d, J = 4.8 Hz, 1H), 8.19 (m, 1H), 7.94 ( d, J = 8.7 Hz, 1H), 7.56-7.50 (m, 1H), 7.33-7.36 (m, 2H), 5.12 (d, J = 10.5 Hz, 1H), 4.26 (br d, J = 13.8 Hz, 1H), 4.03 (br t, J = 11.1 Hz, 1H), 3.55 (d, J = 11.7 Hz, 1H), 3.42-3.32 (m, 2H), 3.13 (t, J = 12.3 Hz, 1H). c. Synthesis of (R)-2-(2- fluoro -5-( indole - 3 -yloxy ) phenyl )-4- methylmorpholine ( Compound 13 )

Compound 13 was synthesized from compound 11 as a 2HCl salt using a similar methylation as in Example 3 and a similar salt formation procedure as in Example 1 .

Compound 13. MS (ESI+): m/z 290 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ 9.22 (d, J = 3.9 Hz, 1H), 8.22-8.17 (m, 1H), 7.94 (d, J = 9.0 Hz, 1H), 7.51-7.49 (m, 1H), 7.34-7.28 (m, 2H), 5.12 (d, J = 12.0 Hz, 1H), 4.30 (d, J = 13.2 Hz, 1H), 4.03 (t, J = 11.9 Hz, 1H) , 3.72 (d, J = 12.0 Hz, 1H), 3.55 (d, J = 12.3 Hz, 1H), 3.27-3.22 (m, 1H), 3.15 (t, J = 12.0 Hz, 1H), 2.97(s, 3H).

Example 8. Synthesis of ( R* )-2-(2- fluoro -3-( indole - 3- yloxy ) phenyl ) -2-(2- fluoro -3-( indole - 3-yloxy ) phenyl )-2-( 2-fluoro-3- ( indole - 3-yloxy ) phenyl ) -2-(2-fluoro-3-( indole - 3- yloxy ) phenyl ) -2- (2 - fluoro-3-( indole - 3 - yloxy ) phenyl) -2- (2 -fluoro - 3 - hydroxy ...

Compound I-8-2 was synthesized from 3-bromo-2-fluorophenol and tert-butyl 2-(2-fluoro-3-hydroxyphenyl)-4-carboxylate using a procedure similar to that in Example 1. b. Chiral separation of tert -butyl 2-(2- fluoro -3 -hydroxyphenyl ) -4- carboxylate

2-(2-Fluoro-3-hydroxyphenyl)morpholine-4-carboxylic acid tributyl ester was separated by chiral column separation using the following: Instrument: SFC-150 (Thar, Waters) Column: AD 25×250mm, 10µm (Daicel) Column temperature: 35℃ Mobile phase: CO ₂ /IPA (0.01% methylamine/methanol) = 90/10 Flow rate: 100 g/min Back pressure: 100 bar Detection wavelength: 220 nm Cycle time: 2.0 min Sample solution: 170 mg dissolved in 8 mL Injection volume: 0.6 mL

Chiral analysis conditions: instrument: Waters 2695; column: Reflect I-Cellulose C 4.6×250mm, 5µm; column temperature: 30℃; mobile phase: n-hexane/ i -PrOH (0.1% DEA) = 90/10; flow rate: 0.8 mL/min; detection wavelength: 254 nm; detector: W2996 PDA.

After removing the solvent, the first eluting isomer ( R* )-2-(2-fluoro-3-hydroxyphenyl)-4-carboxylic acid tert-butyl ester ( Compound I-8-3- peak 1 , retention time from the analytical column = 7.29 min) and the second eluting isomer ( S* )-2-(2-fluoro-3-hydroxyphenyl)-4-carboxylic acid tert-butyl ester ( Compound I-8-3- peak 2 , retention time from the analytical column = 8.43 min) were obtained. c. Synthesis of (R*)-2-(2- fluoro -3-( indole - 3- yloxy ) phenyl ) -4-carboxylic acid ( Compound 14 )

Compound 14 was synthesized from compound I-8-3-pyrrole 1 and 3-bromoindole as 2 HCl salt using a similar synthetic procedure as in Example 1 .

Compound 14. MS (ESI+): m/z 276 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ 9.22 (d, J = 4.8 Hz, 1H), 8.20-8.16 (m, 1H), 7.99 (d, J = 9.0 Hz, 1H), 7.55 (t, J = 5.9 Hz, 1H), 7.46-7.37 (m, 2H), 5.12 (d, J = 10.8 Hz, 1H), 4.29 (dd, J = 3.3, 12.0 Hz, 1H), 4.04 (td, J = 11.4, 3.6 Hz, 1H), 3.50 (d, J = 13.2 Hz, 1H), 3.40-3.30 (m, 2H), 3.19 (t, J = 11.7 Hz, 1H). d. Synthesis of (S*)-2-(2- fluoro -3-( indole - 3- yloxy ) phenyl ) morpholine ( Compound 15 )

Compound 15 was synthesized from compound I-8-3- pyrrole 2 and 3-bromoindole as a 2HCl salt using a similar synthetic procedure as in Example 1 .

Compound 15. MS (ESI+): m/z 276 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ 9.17 (d, J = 4.2 Hz, 1H), 8.13-8.09 (m, 1H), 7.90 (d, J = 9.3 Hz, 1H), 7.54 (t, J = 5.7 Hz, 1H), 7.45-7.33 (m, 2H), 5.11 (d, J = 9.3 Hz, 1H), 4.28 (br d, J = 12.0 Hz, 1H), 4.03 (td, J = 13.8, 3.3 Hz , 1H), 3.50 (d, J = 12.9 Hz, 1H), 3.45-3.31 (m, 2H), 3.19 (t, J = 11.7 Hz, 1H).

Example 9. Synthesis of ( RS )-2- methyl -6-(3- ( indole - 3 -yloxy ) phenyl ) -morpholine , ( SR )-2- methyl -6-(3- ( indole -3 -yloxy ) phenyl ) -morpholine , ( RR )-2- methyl - 6-(3-( indole - 3 -yloxy ) phenyl ) -morpholine , ( SS )-2- methyl -6-(3-( indole - 3- yloxy ) phenyl ) -morpholine a. Synthesis of isomers of 3-(6- methylmorpholin -2- yl ) phenol

Compound I-9-2- lower spot and compound I-9-2- upper spot were synthesized from 2-bromo-1-(3-((tributyldimethylsilyl)oxy)phenyl)ethan-1-ol and 1-aminopropan-2-ol using a similar synthetic procedure as in Example 2. b. Synthesis of a single mirror image isomer of 3-(6- methylmorpholin -2- yl ) phenol The racemic lower spot was separated into two single mirror image isomers by chiral column separation using the following: Instrument: SFC-150 (Thar, Waters) Column: AD 25×250mm, 10µm (Daicel) Column temperature: 35℃ Mobile phase: CO ₂ /EtOH (0.01% methylamine/methanol) = 93/7 Flow rate: 100 g/min Back pressure: 100 bar Detection wavelength: 220 nm Cycle time: 2.5 min Sample solution: 375 mg dissolved in 10 mL Injection volume: 1.9 mL

Chiral analysis conditions: instrument: Waters 2695; column: AY-H 4.6×250mm, 5µm; column temperature: 30℃; mobile phase: n-hexane/ i -PrOH (0.1% DEA) = 90/10; flow rate: 1.0 mL/min; detection wavelength: 220 nm; detector: W2996 PDA.

After removing the solvent, the first elution mirror image isomer of 3-(6-methylmorpholin-2-yl)phenol ( compound I-9-2- lower spot - peak 1 , retention time from the analytical column = 5.61 min) and the second elution mirror image isomer of 3-(6-methylmorpholin-2-yl)phenol ( compound I-9-2- lower spot - peak 2 , retention time from the analytical column = 6.61 min) were obtained . c. Synthesis of a single mirror image isomer of 3-(6- methylmorpholin- 2- yl ) phenol

The racemic upper spot was separated by chiral column separation using the following: Instrument: SFC-150 (Thar, Waters) Column: AD 25×250mm, 10µm (Daicel) Column temperature: 35°C Mobile phase: CO ₂ /EtOH (0.01% methylamine/methanol) = 93/7 Flow rate: 100 g/min Back pressure: 100 bar Detection wavelength: 220 nm Cycle time: 2.5 min Sample solution: 400 mg dissolved in 10 mL Injection volume: 1.9 mL

Chiral analysis conditions: instrument: Waters 2695; column: AY-H 4.6×250mm, 5µm; column temperature: 30℃; mobile phase: n-hexane/EtOH (0.1% DEA) = 90/10; flow rate: 1.0 mL/min; detection wavelength: 220 nm; detector: W2996 PDA.

After removing the solvent, the first elution mirror image isomer of 3-(6-methylmorpholin-2-yl)phenol ( compound I-9-2- upper spot - peak 1 , retention time from the analytical column = 4.51 min) and the second elution mirror image isomer of 3-(6-methylmorpholin-2-yl)phenol ( compound I-9-2- upper spot - peak 2 , retention time from the analytical column = 5.61 min) were obtained. d. Synthesis of Compound 16

Compound 16 was synthesized from compound I-9-2- lower spot - peak 1 and 3-bromoindole as a 2HCl salt using a similar synthetic procedure as in Example 1 . Compound 16. MS (ESI+): m/z 272 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ 9.25 (d, J = 4.5 Hz, 1H), 8.27-8.22 (m, 1H), 8.00 (d, J = 9.0 Hz, 1H), 7.57 (t, J = 8.1 Hz, 1H), 7.45-7.43 (m, 2H), 7.29 (d, J = 8.4 Hz, 1H), 5.23-5.19 (m, 1H), 4.31-4.30 (m, 1H), 3.53-3.42 (m, 2H), 3.25-3.20 (m, 1H), 3.17-3.11 (m, 1H), 1.43 (d, J = 6.6 Hz, 3H). e. Synthesis of compound 17

Compound 17 was synthesized from compound I-9-2- lower spot - peak 2 and 3-bromoindole as 2 HCl salt using a similar synthetic procedure as in Example 1 .

Compound 17. MS (ESI+): m/z 272 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ 9.16 (d, J = 4.8 Hz, 1H), 8.13-8.09 (m, 1H), 7.85 (d, J = 9.0 Hz, 1H), 7.56 (t, J = 7.8 Hz, 1H), 7.43-7.41 (m, 2H), 7.27 (d, J = 7.5 Hz, 1H), 5.20 (t, J = 5.1 Hz, 1H), 4.30-4.27 (m, 1H), 3.49 ( d, J = 5.1 Hz, 2H), 3.30-3.20 (m, 1H), 3.17-3.07 (m, 1H), 1.42 (d, J = 6.9 Hz, 3H). f. Synthesis of compound 18

Compound 18 was synthesized from compound I-9-2- upper spot - peak 2 and 3-bromoindole as 2 HCl salt using a similar synthetic procedure as in Example 1 .

Compound 18. MS (ESI+): m/z 272 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ 9.26 (d, J = 4.5 Hz, 1H), 8.28-8.24 (m, 1H), 8.01 (d, J = 9.0 Hz, 1H), 7.54 (t, J = 8.1 Hz, 1H), 7.41-7.39 (m, 2H), 7.29 (d, J = 8.1 Hz, 1H), 4.93-4.85 (m, 1H), 4.12-4.07 (m, 1H), 3.51 (d, J = 12.9 Hz, 1H), 3.39-3.31 (m, 1H), 3.02 (t, J = 12.0 Hz, 1H), 2.90 (t, J = 12.0 Hz, 1H), 1.32 (d, J = 6.3 Hz, 3H). g. Synthesis of compound 19

Compound 19 was synthesized from compound I-9-2- upper spot - peak 1 and 3-bromoindole as 2HCl salt using a similar synthetic procedure as in Example 1 .

Compound 19. MS (ESI+): m/z 272 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ 9.29 (d, J = 4.5 Hz, 1H), 8.34-8.29 (m, 1H), 8.07 (d, J = 9.0 Hz, 1H), 7.55 (t, J = 8.1 Hz, 1H), 7.42-7.41 (m, 2H), 7.30 (d, J = 7.8 Hz, 1H), 4.94-4.89 (m, 1H), 4.12-4.07 (m, 1H), 3.51 (d, J = 12.0 Hz, 1H), 3.39-3.31 (m, 1H), 3.02 (t, J = 12.0 Hz, 1H), 2.90 (t, J = 12.0 Hz, 1H), 1.32 (d, J = 6.3 Hz, 3H).

In Example 9 and Table 1, asterisks indicate single stereoisomers with unknown absolute configuration and unknown relative configuration.

Example 10. Synthesis of ( R* )-2-(3- fluoro -5-( indole -3 -yloxy ) phenyl )-2-(3-fluoro-5-(indole-3-yloxy)phenyl)-2-(3-fluoro-5-(indole-3-yloxy)phenyl)-2-(3-fluoro-2-(3-hydroxyphenyl) ...hydroxyphenyl ) -2- ( 3 - hydroxyphenyl ) -2- ( 3 - hydroxyphenyl ) -2- ( 3- hydroxyphenyl ) -2- ( 3 - hydroxyphenyl )-2-(3-hydroxyphenyl)-2-(3-hydroxyphenyl ) -2- ( 3 - hydroxyphenyl ) -2- (

Compound I-10-2 was synthesized from 3-bromo-5-fluorophenol using a procedure similar to that in Example 2. b. Chiral separation of tert-butyl 2-(3- fluoro -5 - hydroxyphenyl ) morpholine -4- carboxylate

2-(3-Fluoro-5-hydroxyphenyl)morpholine-4-carboxylic acid tributyl ester was separated by chiral column separation using the following: Instrument: SFC-150 (Thar, Waters) Column: AD 25×250mm, 10µm (Daicel) Column temperature: 35℃ Mobile phase: CO ₂ /IPA (0.01% methylamine/methanol) = 90/10 Flow rate: 100 g/min Back pressure: 100 bar Detection wavelength: 220 nm Cycle time: 2.0 min Sample solution: 120 mg dissolved in 5 mL Injection volume: 0.5 mL

Chiral analysis conditions: instrument: Waters 2695; column: Reflect I-Cellulose C 4.6×250mm, 5µm; column temperature: 30℃; mobile phase: n-hexane/ i -PrOH (0.1% DEA) = 90/10; flow rate: 0.8 mL/min; detection wavelength: 254 nm; detector: W2996 PDA.

After removing the solvent, the first eluting isomer ( R* )-2-(3-fluoro-5-hydroxyphenyl)-4-carboxylic acid tert-butyl ester ( Compound I-10-3- peak 1 , retention time from the analytical column = 7.26 min) and the second eluting isomer ( S* )-2-(3-fluoro-5-hydroxyphenyl)-4-carboxylic acid tert-butyl ester ( Compound I-10-3- peak 2 , retention time from the analytical column = 8.66 min) were obtained. c. Synthesis of (R*)-2-(3- fluoro -5-( indole - 3- yloxy ) phenyl ) -4 -carboxylic acid ( Compound 20 )

Compound 20 was synthesized from compound I-10-3- pyrrole 1 and 3-bromoindole as a 2HCl salt using a similar synthetic procedure as in Example 1 .

Compound 20. MS (ESI+): m/z 276 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ 9.24 (d, J = 4.8 Hz, 1H), 8.19 (dd, J = 4.8, 9.0 Hz, 1H), 7.96 (d, J = 9.0 Hz, 1H), 7.32-7.13 (m, 3H), 4.92-4.87 (m, 1H), 4.25 (br d, J = 12.9 Hz, 1H), 4.03 (br t, J = 12.2 Hz, 1H), 3.55 (d, J = 12.6 Hz, 1H), 3.38-3.31 (m, 1H), 3.30-3.25 (m, 1H), 3.09 (t, J = 12.0 Hz, 1H). d. Synthesis of (S*)-2-(3- fluoro -5-( indole - 3 -yloxy ) phenyl ) pyroline ( Compound 21 )

Compound 21 was synthesized from compound I-10-3- pyrrole 2 and 3-bromoindole as a 2HCl salt using a similar synthetic procedure as in Example 1 .

Compound 21. MS (ESI+): m/z 276 (MH+); ¹ H NMR (300 MHz, CD ₃ OD) δ 9.17 (d, J = 4.8 Hz, 1H), 8.09 (dd, J = 4.8, 9.0 Hz , 1H), 7.83 (d, J = 9.3 Hz, 1H), 7.21-7.10 (m, 3H), 4.92-4.87 (m, 1H), 4.25 (d,d J = 3.9, 12.6 Hz, 1H), 4.02 (td, J = 11.4, 3.0 Hz, 1H), 3.54 (d , J = 12.9 Hz, 1H), 3.37-3.32 (m, 1H), 3.30-3.26 (m, 1H), 3.30-3.26 (t, J = 12.5 Hz, 1H).

Example 11. Synthesis of ( R* )-2-(4 -fluoro -3-( indole -3- yloxy ) phenyl ) -2- (4- fluoro -3-( indole -3 -yloxy ) phenyl )-2-(4-fluoro-3- ( indole - 3-yloxy)phenyl)-2-( 4 - fluoro -3- ( indole - 3- yloxy ) phenyl ) -2-(4-fluoro-3-( indole - 3 -yloxy ) phenyl ) -2-(4 -fluoro - 3 - hydroxy ...

Compound I-11-2 was synthesized from 3-bromo-6-fluorophenol and tert-butyl 2-(4-fluoro-3-hydroxyphenyl)-4-carboxylate using a procedure similar to that in Example 1. b. Chiral separation of tert -butyl 2-(4- fluoro -3 -hydroxyphenyl ) -4- carboxylate

2-(4-Fluoro-3-hydroxyphenyl)morpholine-4-carboxylic acid tributyl ester was separated by chiral column separation using the following: Instrument: SFC-150 (Thar, Waters) Column: AD 25×250mm, 10µm (Daicel) Column temperature: 35℃ Mobile phase: CO ₂ /IPA (0.01% methylamine/methanol) = 90/10 Flow rate: 100 g/min Back pressure: 100 bar Detection wavelength: 220 nm Cycle time: 2.0 min Sample solution: 220 mg dissolved in 7 mL Injection volume: 0.6 mL

Chiral analysis conditions: instrument: Waters 2695; column: Reflect C-Amylose A (4.6×250mm, 5µm); column temperature: 30℃; mobile phase: n-hexane/EtOH (0.1% DEA) = 90/10; flow rate: 0.8 mL/min; detection wavelength: 254 nm; detector: W2996 PDA.

After removing the solvent, the first eluting isomer ( R* )-2-(4-fluoro-3-hydroxyphenyl)-4-carboxylic acid tert-butyl ester ( Compound I-11-3- peak 1 , retention time from the analytical column = 10.60 min) and the second eluting isomer ( S* )-2-(4-fluoro-3-hydroxyphenyl)-4-carboxylic acid tert-butyl ester ( Compound I-11-3- peak 2 , retention time from the analytical column = 11.55 min) were obtained. c. Synthesis of (R*)-2-(4- fluoro -3-( indole - 3- yloxy ) phenyl ) -4 -carboxylic acid ( Compound 22 )

Compound 22 was synthesized from compound I-11-3- pyridinium and 3-bromoindole as a 2HCl salt using a similar synthetic procedure as in Example 1 .

Compound 22. MS (ESI+): m/z 276 (MH+); ¹ H NMR (300 MHz, CD ₃ OD) δ 9.22 (d, J = 4.5 Hz, 1H), 8.20-8.16 (m, 1H), 7.98 (d, J = 9.0 Hz, 1H), 7.53 (d, J = 6.0 Hz, 1H), 7.43-7.33 (m, 2H), 4.85-4.82 (m, 1H), 4.25 (d, J = 11.1 Hz, 1H), 4.01 (t, J = 12.6 Hz, 1H), 3.52 ( d, J = 12.6 Hz, 1H), 3.30-3.22 (m, 2H), 3.11 (t, J = 12.0 Hz, 1H). d. Synthesis of (S*)-2-(4- fluoro -3-( indole - 3 -yloxy ) phenyl ) pyroline ( Compound 23 )

Compound 23 was synthesized from compound I-11-3- pyrrole 2 and 3-bromoindole as a 2HCl salt using a similar synthetic procedure as in Example 1 .

Compound 23. MS (ESI+): m/z 276 (MH+); ¹ H NMR (300 MHz, CD ₃ OD) δ 9.22 (d, J = 4.5 Hz, 1H), 8.20-8.16 (m, 1H), 7.98 (d, J = 9.0 Hz, 1H), 7.53 (d, J = 6.0 Hz, 1H), 7.43-7.33 (m, 2H), 4.85-4.82 (m, 1H), 4.25 (d, J = 11.1 Hz, 1H), 4.01 (t, J = 12.6 Hz, 1H), 3.52 ( d, J = 12.6 Hz, 1H), 3.30-3.22 (m, 2H), 3.11 (t, J = 12.0 Hz, 1H).

Example 12. Synthesis of ( R )-2-(2- fluoro -5-( pyrimidin -5 -yloxy ) phenyl ) pyrimidine ( Compound 24)

Compound 24 was synthesized from compound 1-1-5- peak -1 and 5-bromopyrimidine using a nucleophilic substitution and subsequent deprotection procedure similar to that in Example 4 .

Compound 24. MS (ESI+): m/z 276 (MH+); ¹ H NMR (300 MHz, CD ₃ OD) δ 8.95 (s, 1H), 8.55 (s, 2H), 7.41-7.34 (m, 1H), 7.31-7.22 (m, 2H), 5.09 (d, J = 9.6 Hz, 1H), 4.26 (d, J = 12.3 Hz, 1H), 4.01 (t, J = 11.7 Hz, 1H), 3.53 (d, J = 12.3 Hz, 1H), 3.44-3.31 (m, 2H), 3.13 (t, J = 12.3 Hz, 1H).

Example 13. Synthesis of ( R )-2-(3-((6,7- dihydro - 5H - cyclopenta [ c ] indole - 3- yl ) oxy ) phenyl ) pyroline ( Compound 25)

Compound 25 was synthesized from compound I-2-9- peak 1 and 3-chloro-6,7-dihydro- 5H -cyclopenta[ c ]thiazolidine using a microwave nucleophilic substitution and subsequent deprotection procedure similar to that in Example 4 .

Compound 25. MS (ESI+): m/z 298 (MH+); ¹ H NMR (300 MHz, CD ₃ OD) δ 7.97 (s, 1H), 7.54 (t, J = 8.1 Hz, 1H), 7.42-7.40 (m, 2H), 7.29 (d, J = 7.8 Hz,1H), 4.85-4.82 (m, 1H), 4.24 (d, J = 12.9 Hz, 1H), 4.02 (t, J = 12.0 Hz, 1H), 3.54 (d, J = 12.6 Hz, 1H), 3.48-3.23 (m, 6H), 3.10 (t, J = 11.7 Hz, 1H), 2.46-2.36 (m, 2H).

Example 14. Synthesis of ( R )-6-(3-( indole - 3- yloxy ) phenyl ) oxazolin -3- one ( Compound 26) and ( S )-6-(3-( indole - 3 -yloxy ) phenyl ) oxazolin -3- one ( Compound 27) a. Synthesis of 3- (3- bromophenoxy ) oxazolin

To a solution of 3-bromophenol ( Compound I-14-1 , 3 g, 17.3 mmol) in DMF (50 mL) was added Cs ₂ CO ₃ (5.63 g, 17.3 mmol), 2,2,6,6-tetramethylheptane-3,5-dione (2.54 g, 13.8 mmol), copper bromide (248 mg, 1.73 mmol) and 3-bromotitanium (4.11 g, 25.9 mmol). The reaction mixture was heated to 120 °C and stirred at that temperature for 3 h. EtOAc (40 mL) and water (125 mL) were added to the reaction vessel and the resulting two-phase mixture was transferred to a separatory funnel. The layers were separated and the aqueous phase was extracted with EtOAc (2×40 mL). The combined organics were washed with brine (2×60 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography with isocratic elution from EtOAc (10%) and petroleum ether (90%) to EtOAc (25%) and petroleum ether (75%) to provide 3-(3-bromophenoxy)pyrimidine ( Compound I-14-2 ). b. Synthesis of 3- (3 -vinylphenoxy ) pyrimidine

To a solution of 3-(3-bromophenoxy)tetrakis(triphenylphosphine)palladium (558 mg, 483 μmol) and tributyl( vinyl )tin (6.12 g, 19.3 mmol) in toluene (45 mL) under _N2 was added. The reaction mixture was heated to 95 °C and stirred at that temperature for 16 h. The reaction vessel was concentrated in vacuo. The resulting oil was purified by flash column chromatography with isocratic elution from EtOAc (10%) and petroleum ether (90%) to EtOAc (25%) and petroleum ether (75%) to provide 3-(3-vinylphenoxy)tetrakis( compound I-14-3 ). c. Synthesis of 2- bromo -1-(3-( oxazolidin -3- yloxy ) phenyl ) ethan - 1- ol

To a solution of 3-(3-vinylphenoxy)pyrimidine ( Compound I-14-3 , 3 g, 15.1 mmol) in dioxane (30 mL) and H ₂ O (15 mL) at 0 °C was added NBS (2.95 g, 16.6 mmol) and acetic acid (906 mg, 15.1 mmol). The reaction was stirred at ambient temperature for 2 h. A saturated aqueous solution of Na ₂ CO ₃ (30 mL) was added to the reaction vessel and the resulting biphasic mixture was transferred to a separatory funnel. The layers were separated and the aqueous phase was extracted with EtOAc (2×30 mL). The combined organics were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The obtained oil was purified by flash column chromatography using an isocratic mixture of EtOAc (50%) and petroleum ether (50%) to provide 2-bromo-1-[3-(indole-3-yloxy)phenyl]ethan-1-ol ( Compound I-14-4 ). d. Synthesis of 2- azido -1-[3-( indole - 3 -yloxy ) phenyl ] ethan -1- ol

To a solution of 2-bromo-1-[3-(indole-3-yloxy)phenyl]ethan-1-ol ( Compound I-14-4 , 1.8 g, 6.09 mmol) in DMF (20 mL) was added NaN ₃ (1.18 g, 18.2 mmol). The reaction mixture was heated to 60 °C and stirred at that temperature for 16 h. Water (60 mL) and EtOAc (20 mL) were added to the reaction vessel and the resulting biphasic mixture was transferred to a separatory funnel. The layers were separated and the aqueous phase was extracted with EtOAc (2×20 mL). The combined organics were washed with brine (2×20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The obtained oil was purified by flash column chromatography using an isocratic mixture of EtOAc (50%) and petroleum ether (50%) to provide 2-azido-1-[3-(indole-3-yloxy)phenyl]ethan-1-ol ( Compound I-14-5 ). e. Synthesis of ethyl 2-(2 -azido -1-(3-( indole - 3 -yloxy ) phenyl ) ethoxy ) acetate

To a solution of _2- azido-1-[3-(indole-3-yloxy)phenyl]ethan-1-ol ( compound I-14-5 , 1.15 g, 4.47 mmol) in DMF (12 mL) was added sodium hydride (356 mg, 8.94 mmol) at 0 °C under N2. The reaction was stirred at ambient temperature for 15 min. Ethyl 2-bromoacetate (1.11 g, 6.70 mmol) was then added. The reaction was stirred at ambient temperature for 1 h. Water (30 mL) and EtOAc (10 mL) were added to the reaction vessel and the resulting biphasic mixture was transferred to a separatory funnel. The layers were separated and the aqueous phase was extracted with EtOAc (2 x 10 mL). The combined organics were washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography with isocratic elution from EtOAc (25%) and petroleum ether (75%) to EtOAc (50%) and petroleum ether (50%) to provide ethyl 2-{2-azido-1-[3-(indole-3-yloxy)phenyl]ethoxy}acetate ( Compound I-14-6 ). f. Synthesis of 6-(3-( indole - 3 -yloxy ) phenyl ) morpholin -3- one

To a solution of ethyl 2-{2-azido-1-[3-(indole-3-yloxy)phenyl]ethoxy}acetate ( Compound I-14-6 , 1.05 g, 3.05 mmol) in THF (20 mL) was added triphenylphosphine (2.39 g, 9.14 mmol). The reaction was stirred at ambient temperature for 15 min. H ₂ O (10 mL) was then added. The reaction mixture was heated to 60 °C and stirred at that temperature for 16 h. EtOAc (10 mL) was added to the reaction vessel and the resulting biphasic mixture was transferred to a separatory funnel. The layers were separated and the aqueous phase was extracted with EtOAc (2×10 mL). The combined organics were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography with a gradient elution from EtOAc (50%) and petroleum ether (50%) to EtOAc (50%) and THF (50%) to provide 6-[3-(pyridinium-3-yloxy)phenyl]pyridin-3-one ( Compound I-14-7 ). g. Chiral column separation of 6-(3-( pyridinium - 3 -yloxy ) phenyl ) pyridin -3- one

6-(3-(3-pyridin-3-yloxy)phenyl)morpholin-3-one was separated by chiral column separation using the following: Instrument: SFC-150 (Thar, Waters), Column: AD 25×250 mm, 10µm (Daicel), Column temperature: 35°C, Mobile phase: CO ₂ /EtOH (0.01% methylamine/methanol) = 55/45, Flow rate: 100 g/min, Back pressure: 100 bar, Detection wavelength: 220 nm, Cycle time: 2.0 min, Sample solution: 300 mg dissolved in 10 mL methanol Injection volume: 1.0 mL

Chiral analysis conditions: Instrument: Waters 2695; Column: Reflect C-Amylose A (4.6×250mm, 5µm); Column temperature: 30℃; Mobile phase: n-hexane/EtOH (0.1% DEA) = 40/60; Flow rate: 0.8 mL/min; Detection wavelength: 254 nm; Detector: W2996 PDA.

After the solvent was removed, the first eluting isomer ( S )-6-(3-(pyrimidine-3-yloxy)phenyl)-3-oxo-1-one ( Compound I-14-8- peak 1 , retention time from the analytical column = 9.08 min) and the second eluting isomer ( R )-6-(3-(pyrimidine-3-yloxy)phenyl)-3-oxo-1-one ( Compound I-14-8- peak 2 , retention time from the analytical column = 14.78 min) were obtained. h. Synthesis of (R)-6-[3-( pyrimidine -3- yloxy ) phenyl ] -3 - oxo - 1-one

To a solution of ( R )-6-[3-(indole-3-yloxy)phenyl]-pyrrolidone ( compound I-14-8- peak 2 , 30 mg, 110 µmol) in _Et2O (1 mL) was added HCl/ _Et2O (3M, 0.1 mL). The reaction was stirred at ambient temperature for 10 seconds. The reaction vessel was concentrated in vacuo and the resulting solid was washed with _Et2O (2 x 0.5 mL) to provide ( R )-6-[3-(indole-3-yloxy)phenyl]-pyrrolidone ( compound 26 ) as the HCl salt.

Compound 26. MS (ESI+): m/z 272 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ 9.11 (d, J = 4.5 Hz, 1H), 8.05-8.00 (m, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.49 (t, J = 7.8 Hz, 1H), 7.38-7.35 (m, 2H), 7.21 (d, J = 8.1 Hz, 1H), 4.92-4.85 (m, 1H), 4.33 (s, 2H), 3.55 (dd, J = 2.7 , 12.3 Hz, 1H), 3.46 (d, J = 11.1 Hz, 1H). i. Synthesis of (S)-6-[3-( pyridin -3- yloxy ) phenyl ] pyrin - 3- one

To a solution of ( S )-6-[3-(indole-3-yloxy)phenyl]pyrolin-3-one ( Compound I- 14-8- peak 1 , 30 mg, 110 µmol) in _Et2O (1 mL) was added HCl/ _Et2O (3M, 0.1 mL). The reaction was stirred at ambient temperature for 10 s. The reaction vessel was concentrated in vacuo and the resulting solid was washed with _Et2O (2 x 0.5 mL) to provide ( S )-6-[3-(indole-3-yloxy)phenyl]pyrolin-3-one ( Compound 27 ) as the HCl salt.

Compound 27. MS (ESI+): m/z 272 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ 9.26 (d, J = 5.1 Hz, 1H), 8.29-8.24 (m, 1H), 8.02 (d, J = 9.0 Hz, 1H), 7.51 (t, J = 8.1 Hz, 1H), 7.54-7.49 (m, 2H), 7.25 (d, J = 9.0 Hz, 1H), 4.91-4.90 (m, 1H), 4.33 (s, 2H), 3.55 (dd, J = 2.7 , 12.3 Hz, 1H), 3.44 (d, J = 10.5 Hz, 1H).

Example 15. Synthesis of 2-(3-( oxazolidin -3 -yloxy ) phenyl ) oxazolin - 3- one ( Compound 28) a. Synthesis of methyl 2- bromo -2-(3- methoxyphenyl ) acetate

To a solution of methyl 2-(3-methoxyphenyl)acetate ( Compound I-15-1 , 5 g, 27.7 mmol) in _CCl4 (100 mL) was added NBS (5.16 g, 29.0 mmol) and BPO (333 mg, 1.38 mmol). The reaction was stirred at 80 °C for 4 h under _N2 . A saturated aqueous solution of _NaHSO3 (40 mL) was added to the reaction vessel and the resulting biphasic mixture was transferred to a separatory funnel. The layers were separated and the organic phase was extracted with DCM (4×40 mL). The combined organics were washed with brine, dried over _{anhydrous Na2SO4} , filtered and concentrated in vacuo. The resulting mixture was purified by flash column chromatography using isocratic elution with ethane (95%) and EtOAc (5%) to provide methyl 2-bromo-2-(3-methoxyphenyl)acetate ( Compound I-15-2 ). b. Synthesis of methyl 2-(2-(( tert-butyloxycarbonyl ) amino ) ethoxy )-2-(3- methoxyphenyl ) acetate

To a solution of methyl 2-bromo-2-(3-methoxyphenyl)acetate ( compound I-15-2 , 500 mg, 1.92 mmol) in tributyl (2-hydroxyethyl)carbamate (927 mg, 5.76 mmol) was added AgOTf (590 mg, 2.30 mmol). The reaction was stirred at ambient temperature for 1 h. The reaction was filtered and concentrated in vacuo. The resulting mixture was purified by flash column chromatography using isocratic elution with ethane (80%) and EtOAc (20%) to provide methyl 2-(2-{[(tributyloxy)carbonyl]amino}ethoxy)-2-(3-methoxyphenyl)acetate ( compound I-15-3 ). c. Synthesis of 2-(3- methoxyphenyl ) morpholin -3- one

To a solution of methyl 2-(2-{[(tributyloxy)carbonyl]amino}ethoxy)-2-(3-methoxyphenyl)acetate ( Compound I-15-3 , 280 mg, 825 µmol) in DCM (3 mL) was added TFA (2 mL). The reaction was stirred at ambient temperature for 1 h. The reaction was concentrated in vacuo. A saturated aqueous solution of NaHCO ₃ (2 mL) was added to the reaction vessel and the resulting biphasic mixture was transferred to a separatory funnel. The layers were separated and the aqueous phase was extracted with DCM (3×5 mL). The combined organics were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was dissolved in DCM (5 mL) and Et ₃ N (151 mg, 1.50 mmol) was added. The reaction was stirred at ambient temperature for 2 h. The reaction was concentrated in vacuo. The resulting mixture was purified by flash column chromatography using isocratic elution of ethane (50%) and EtOAc (50%) to provide 2-(3-methoxyphenyl)morpholin-3-one ( Compound I-15-4 ). d. Synthesis of 2-(3- hydroxyphenyl ) morpholin -3- one

A solution of 2-(3-methoxyphenyl)morpholin-3-one ( Compound I-15-4 , 600 mg, 2.89 mmol) in DCM (500 mL) was cooled to 0 °C, followed by the addition of BBr ₃ (1.44 g, 5.78 mmol 1M, dissolved in DCM). The reaction was stirred at 0 °C for 2 h. A saturated aqueous solution of NaHCO ₃ was added to the reaction vessel until the pH reached 10. The resulting biphasic mixture was transferred to a separatory funnel. The layers were separated and the aqueous phase was extracted with DCM/MeOH (10:1, 3×20 mL). The combined organics were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting mixture was purified by flash column chromatography using isocratic elution with DCM (90%) and MeOH (10%) to provide 2-(3-hydroxyphenyl)morpholin-3-one ( Compound I-15-5 ). e. Synthesis of 2-(3-( pyridin - 3 -yloxy ) phenyl ) morpholin -3- one

To a solution of 2-(3-hydroxyphenyl)morpholin-3-one ( Compound I-15-5 , 140 mg, 724 µmol) in NMP (2 mL) was added _K2CO3 ( ₁₉₈ mg, 1.44 mmol) and 3-bromopyrimidine (171 mg, 1.08 mmol). The reaction was stirred at 140 °C for 2 h. The reaction was filtered and concentrated in vacuo. The resulting mixture was purified by flash column chromatography with isocratic elution of DCM (90%) and EtOAc (10%) to provide 2-[3-(pyrimidine-3-yloxy)phenyl]morpholin-3-one ( Compound 28 ).

To a solution of 2-[3-(indole-3-yloxy)phenyl]morpholin-3-one ( Compound 28 , 45 mg, 165 µmol) in _Et2O (1 mL) was added HCl/ _Et2O (3M, 1 mL). The reaction was stirred at ambient temperature for 15 min. The reaction was concentrated in vacuo and the residue was washed with _Et2O (3 x 5 mL) to provide 2-[3-(indole-3-yloxy)phenyl]morpholin-3-one ( Compound 28 ) as the HCl salt.

Compound 28. MS (ESI+): m/z 272 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ 9.36 (d, J = 4.5 Hz, 1H), 8.43 (dd, J = 5.1, 9.0 Hz, 1H), 8.21 (d, J = 9.0 Hz, 1H), 7.55-7.46 (m, 2H), 7.41 (s, 1H), 7.29 (d, J = 7.5 Hz, 1H), 5.19 (s, 1H), 4.05-4.00 (m, 1H), 3.95-3.91 (m, 1H), 3.62-3.54 (m, 1H), 3.42-3.31 (m, 1H).

Example 16. Synthesis of ( R )-2-(3-( pyrazolo [1,5- a ] pyridin -6 -yloxy ) phenyl ) pyroline ( Compound 29)

Compound 29 was synthesized from compound I-2-9- peak 1 and 6-bromopyrazolo[1,5- a ]pyridine as the HCl salt using a coupling and subsequent deprotection procedure similar to that in Example 1 .

Compound 29. MS (ESI+): m/z 296 (MH ⁺ ); ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 9.41 (brs, 2H), 8.65 (s, 1H), 8.00 (s, 1H) , 7.78 (d, J = 9.6 Hz, 1H), 7.42 (t, J = 8.4 Hz, 1H), 7.16-7.13 (m, 2H), 7.10-7.07 (m, 2H), 6.68 (s, 1H), 4.77 (d, J =10.5 Hz, 1H), 4.09 (d, J = 10.2 Hz, 1H), 3.89 (t, J =11.7 Hz, 1H), 3.43 (d, J =12.6 Hz, 1H), 3.22 (d, J =11.7 Hz, 1H), 3.10-3.03 (m, 1H), 2.99-2.92 (m, 1H).

Example 17. Synthesis of (R)-2-( 3 - ((6-( methoxymethyl ) oxathia -3- yl ) oxy ) phenyl ) pyroline ( Compound 30)

Compound 30 was synthesized from compound I-2-9- pyridine and 3-chloro-6-(methoxymethyl)pyridine as 2 HCl salt using similar nucleophilic substitution and subsequent deprotection procedures as in Example 4 .

Compound 30. MS (ESI+): m/z 302 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ 8.34 (d, J = 9.3 Hz, 1H), 8.14 (d, J = 9.3 Hz, 1H), 7.55 (t, J = 7.8 Hz, 1H), 7.43-7.40 (m, 2H), 7.32 (d, J = 7.8 Hz, 1H), 4.94 (s, 2H), 4.82-4.75 (m, 1H), 4.24 (d, J = 12.3 Hz, 1H), 4.03 (d, J =12.0 Hz, 1H), 3.58-3.51 (m, 4H), 3.39-3.31 (m, 1H), 3.30-3.21 (m, 1H), 3.10 (t, J =12.0 Hz, 1H).

Example 18. Synthesis of ( R )-6-(3-( oxo- 2- yl ) phenoxy ) oxo - 3- carboxamide ( Compound 31) a. Synthesis of (R)-2-(3-((6- cyanooxo - 3- yl ) oxy ) phenyl ) oxo -4- carboxylic acid tributyl ester

Compound I-18-1 was synthesized from compound I-2-9-1 and 6 -chloro-3-carboxylic acid nitrile using a nucleophilic substitution similar to that in Example 4. b. Synthesis of (R)-6-(3-( oxolin - 2- yl ) phenoxy ) carboxylic acid nitrile

To a solution of ( R )-2-{3-[(6-cyanotathion-3-yl)oxy]phenyl}pyroline-4-carboxylic acid tributyl ester ( Compound I -18-1 , 20 mg, 52.2 µmol) in DCM (2 mL) was added HCl/ _Et2O (1 mL). The reaction was stirred at ambient temperature for 2 h. The solvent was concentrated in vacuo. The solid was washed with _Et2O (3 x 2 mL) to provide ( R )-6-(3-(pyrolin-2-yl)phenoxy)pyrolin-3-carboxamide ( Compound 31 ) as 2 HCl salt.

Compound 31. MS (ESI+): m/z 301 (MH ⁺ ); ^1H NMR (300 MHz, _CD3OD ) δ 8.31 (d, J = 9.3 Hz, 1H), 7.56-7.51 (m, 2H), 7.38-7.35 (m, 2H), 7.26 (d, J = 9.0 Hz, 1H), 4.83-4.81 (m, 1H), 4.25 (d, J = 12.6 Hz, 1H), 3.99 (t, J = 12.0 Hz, 1H), 3.52 (d, J = 11.4 Hz, 1H), 3.45-3.31 (m, 2H), 3.12 (t, J =12.0 Hz, 1H).

Example 19. Synthesis of ( R* )-2-(2- fluoro -5-( pyridin -4 -yloxy ) phenyl ) -2-(2- fluoro -5- ( pyridin -4 -yloxy ) phenyl ) -2-(2-fluoro-5-(pyridin - 4 - yloxy ) phenyl )-2-(2-fluoro - 5-( pyridin -4-yloxy ) phenyl ) -2-(2-fluoro -5-( pyridin-4- yloxy ) phenyl )-2-(2-fluoro-5-(pyridin-4- yloxy )phenyl) -2-(2- fluoro -5-(pyridin -4 -yloxy ) phenyl ) -2-( 2- fluoro - 4 ...

To a solution of tributyl 2-(2-fluoro-5-hydroxyphenyl)morpholine-4-carboxylate ( Compound I -19-1 , 500 mg, 1.68 mmol) in DMF (10 mL) were added Cs ₂ CO ₃ (1.37 g, 4.20 mmol), CuBr (24.0 mg, 168 µmol), 2,2,6,6-tetramethylheptane-3,5-dione (246 mg, 1.34 mmol) and 4-iodopyridine (516 mg, 2.52 mmol). The reaction mixture was heated to 120 °C and stirred at that temperature for 16 h. Water (20 mL) was added to the reaction vessel and extracted with EtOAc (2×10 mL). The layers were separated and the organic phase was washed with saturated aqueous NaCl solution (2×10 mL). The combined organics were dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography using isocratic elution with EtOAc (25%) and petroleum ether (75%) to provide tributyl 2-[2-fluoro- _5- (pyridin-4-yloxy)phenyl]morpholine-4-carboxylate ( Compound I -19-2 ). b. Synthesis of 2-(2- fluoro -5-( pyridin -4 -yloxy ) phenyl ) morpholine

To a solution of tributyl 2-[2-fluoro-5-(pyridin-4-yloxy)phenyl]morpholine-4-carboxylate ( Compound I -19-2 , 600 mg, 1.60 mmol) in DCM (5 mL) was added HCl/ _Et2O (5 mL). The reaction was stirred at ambient temperature for 2 h. The reaction mixture was concentrated in vacuo. A saturated aqueous solution _{of Na2CO3} (5 mL) was added to the reaction vessel. The mixture was extracted with DCM/MeOH (10/1, 3×5 mL). The layers were separated and the organic phase was washed with a saturated aqueous solution of NaCl (2×10 mL). The combined organics were dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo to provide 2-[2-fluoro- _5- (pyridin-4-yloxy)phenyl]morpholine ( Compound I -19-3 ). c. Chiral column separation of 2-(2- fluoro -5-( pyridin -4 -yloxy ) phenyl ) morpholine

2-(2-Fluoro-5-(pyridin-4-yloxy)phenyl)morpholine was separated by chiral column separation using the following: Instrument: SFC-150 (Thar, Waters) Column: AD 25×250mm, 10µm (Daicel) Column temperature: 35℃ Mobile phase: CO ₂ /MeOH (0.01% methylamine/methanol) = 80/20 Flow rate: 100 g/min Back pressure: 100 bar Detection wavelength: 220 nm Cycle time: 4.0 min Sample solution: 300 mg dissolved in 10 mL methanol Injection volume: 1.6 mL

Chiral analysis conditions: Instrument: Waters 2695; Column: Reflect C-Amylose A (4.6×250mm, 5µm); Column temperature: 30℃; Mobile phase: n-hexane/EtOH (0.1% DEA) = 60/40; Flow rate: 0.8 mL/min; Detection wavelength: 220 nm; Detector: W2996 PDA.

After removing the solvent, the first eluting isomer ( R* )-2-(2-fluoro-5-(pyridin-4-yloxy)phenyl)-morpholine ( Compound I-19-4- peak 1 , retention time from the analytical column = 9.26 min) and the second eluting isomer ( S* )-2-(2-fluoro-5-(pyridin-4-yloxy)phenyl)-morpholine ( Compound I-19-4- peak 2 , retention time from the analytical column = 11.51 min) were obtained. d. Synthesis of (R*)-2-(2- fluoro -5-( pyridin -4 -yloxy ) phenyl ) -morpholine

To a solution of ( R* )-2-[2-fluoro-5-(pyridin-4-yloxy)phenyl]morpholine ( Compound I-19-4- peak 1 , 118 mg, 430 µmol) in MeOH (0.5 mL) was added HCl/ _Et2O (0.5 mL). The reaction was stirred at ambient temperature for 10 min. The solvent was evaporated to give a viscous oil. The resulting oil was dissolved in MeOH (0.5 mL). And then _Et2O (2 mL) was added. Most of the solvent was removed. The remaining solvent was evaporated to dryness in vacuo to provide ( R* )-2-[2-fluoro-5-(pyridin-4-yloxy)phenyl]morpholine ( Compound 32 ) as a 2HCl salt.

Compound 32. MS (ESI+): m/z 275 (MH ⁺ ); ^1H NMR (300 MHz, _CD3OD ) δ 8.73 (d, J = 7.2 Hz, 2H), 7.54-7.49 (m, 3H), 7.43-7.37 (m, 2H), 5.16 (d, J = 10.8 Hz, 1H), 4.25 (dd, J = 2.7, 13.2 Hz, 1H), 4.04 (td, J = 11.7, 2.7 Hz, 1H), 3.57 (d, J = 12.3 Hz, 1H), 3.40-3.30 (m, 2H), 3.17 (t, J = 12.0 Hz, 1H). e. Synthesis of (S*)-2-(2- fluoro -5-( pyridin -4 -yloxy ) phenyl ) morpholine

To a solution of ( S* )-2-[2-fluoro-5-(pyridin-4-yloxy)phenyl]morpholine ( Compound I-19-4- peak 2 , 119 mg, 439 µmol) in MeOH (0.5 mL) was added HCl/ _Et2O (0.5 mL). The reaction was stirred at ambient temperature for 10 min. The solvent was evaporated to give a viscous oil. The resulting oil was dissolved in MeOH (0.5 mL). And then _Et2O (2 mL) was added. Most of the solvent was removed. The remaining solvent was evaporated to dryness in vacuo to provide ( S* )-2-[2-fluoro-5-(pyridin-4-yloxy)phenyl]morpholine hydrochloride ( Compound 33 ).

Compound 33. MS (ESI+): m/z 275 (MH ⁺ ); ^1H NMR (300 MHz, _CD3OD ) δ 8.73 (d, J = 6.9 Hz, 2H), 7.54-7.49 (m, 3H), 7.43-7.37 (m, 2H), 5.16 (d, J = 10.5 Hz, 1H), 4.25 (dd, J = 3.0, 12.9 Hz, 1H), 4.05 (td, J = 11.1, 2.7 Hz, 1H), 3.57 (d, J = 12.6 Hz, 1H), 3.40-3.30 (m, 2H), 3.17 (t, J = 12.0 Hz, 1H).

Example 20. Synthesis of ( R* )-2-(3-( indole - 3 -yloxy ) phenyl ) thiophenoline ( Compound 34) and ( S* )-2-(3-( indole - 3 -yloxy ) phenyl ) thiophenoline ( Compound 35) a. Synthesis of 2-(3- methoxyphenyl ) thiophenoline -3- one

To a solution of methyl 2-bromo-2-(3-methoxyphenyl)acetate ( Compound I-15-2 , 2.5 g, 9.64 mmol, see Example 15) in EtOH (50 mL) was added 2-aminoethane-1-thiol hydrochloride (1.09 g, 9.64 mmol) and K ₂ CO ₃ (3.98 g, 28.9 mmol). The reaction mixture was heated to 80° C. and stirred at that temperature for 16 h. Water (0.5 mL) was added to the reaction vessel, followed by filtration and concentration in vacuo. The resulting oil was purified by flash column chromatography using isocratic elution from EtOAc (10%) and petroleum ether (90%) to EtOAc (100%) to provide 2-(3-methoxyphenyl)thiophenoline-3-one ( Compound I -20-1 ). b. Synthesis of 2-(3- methoxyphenyl ) thiophenoline -4- carboxylic acid tributyl ester

To a solution of 2-(3-methoxyphenyl)thiomorpholin-3-one ( Compound I -20-1 , 1.18 g, 5.28 mmol) in THF (20 mL) was added DIBAL-H (3.00 g, 21.1 mmol) under _N2 . The reaction mixture was heated to 80 °C and stirred at that temperature for 2 h. The reaction mixture was quenched by adding 0.84 mL _{of H2O} , followed by 0.84 mL of 20% aqueous NaOH, and 2.1 mL _{of H2O} . After stirring at room temperature for 15 min, _Mg2SO4 was added. After filtering through a diatomaceous earth pad, the filtrate was concentrated. The crude residue was directly Boc protected with Boc ₂ O (1.26 g, 5.80 mmol) and saturated aqueous Na ₂ CO ₃ solution. The reaction was stirred at ambient temperature for 1 h. Water (25 mL) and EtOAc (25 mL) were added to the reaction vessel and the resulting biphasic mixture was transferred to a separatory funnel. The layers were separated and the aqueous phase was extracted with EtOAc (3×25 mL). The combined organics were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The obtained oil was purified by flash column chromatography using isocratic elution of EtOAc (50%) and petroleum ether (50%) to provide tert-butyl 2-(3-methoxyphenyl)thiophenoline-4-carboxylate ( Compound I -20-2 ). c. Synthesis of tert- butyl 2-(3- hydroxyphenyl ) thiophenoline -4- carboxylate

To a solution of tributyl 2-(3-methoxyphenyl)thiomorpholine-4-carboxylate ( Compound I -20-2 , 650 mg, 2.10 mmol) in DCM (13 mL) was added _BBr3 (1.57 g, 6.30 mmol) at -10 °C under _N2 . The reaction was stirred at ambient temperature for 4 h. After alkalization with _{aqueous Na2CO3} , the crude mixture was directly Boc-protected with _Boc2O (503 mg, 2.31 mmol). The reaction was stirred at ambient temperature for 1 h. Water (15 mL) was added to the reaction vessel and the resulting biphasic mixture was transferred to a separatory funnel. The layers were separated and the aqueous phase was extracted with EtOAc (3×15 mL). _The combined organics were dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography using isocratic elution with EtOAc (50%) and petroleum ether (50%) to provide tert-butyl 2-(3-hydroxyphenyl)thiophenoline-4-carboxylate ( Compound I -20-3 ). d. Synthesis of tert -butyl 2-[3-( pyridin -3 -yloxy ) phenyl ] thiophenoline -4 - carboxylate

To a solution of tributyl 2-(3-hydroxyphenyl)thiomorpholine-4-carboxylate ( Compound I -20-3 , 326 mg, 1.10 mmol) in NMP (6 _mL ) were added 3-bromotitanium (262 mg, 1.65 mmol) and _K2CO3 (303 mg, 2.20 mmol). The reaction mixture was heated to 150 °C and stirred at that temperature for 4 h. Water (12 mL) was added to the reaction vessel and the mixture was extracted with EtOAc (3 x 15 mL). The combined organics _were dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography using isocratic elution from EtOAc (15%) and petroleum ether (85%) to EtOAc (35%) and petroleum ether (75%) to provide tert-butyl 2-[3-(pyridinium-3-yloxy)phenyl]thiophenoline-4-carboxylate ( Compound I -20-4 ). e. Chiral column separation of tert -butyl 2-[3-( pyridinium -3 -yloxy ) phenyl ] thiophenoline -4 -carboxylate

Tributyl 2-(3-(triazine-3-yloxy)phenyl)thiomorpholine-4-carboxylate was separated by chiral column separation using the following: Instrument: SFC-150 (Thar, Waters) Column: AD 25×250 mm, 10µm (Daicel), Column temperature: 35°C, Mobile phase: CO ₂ /IPA (0.01% methylamine/methanol) = 60/40, Flow rate: 100 g/min, Back pressure: 100 bar, Detection wavelength: 220 nm, Cycle time: 4.0 min, Sample solution: 295 mg dissolved in 7 mL methanol Injection volume: 0.5 ml

Chiral analysis conditions: instrument: Waters 2695; column: AY-H (4.6×250mm, 5µm); column temperature: 30℃; mobile phase: n-hexane/ i Pr-OH (0.1% DEA) = 60/40; flow rate: 0.8 mL/min; detection wavelength: 220 nm; detector: W2996 PDA.

After the solvent was removed, the first eluting isomer ( R* )-2-[3-(indole-3-yloxy)phenyl]thiophenoline-4-carboxylic acid tert-butyl ester ( Compound I -20-5- peak 1 , retention time from the analytical column = 13.53 min) and the second eluting isomer ( S* )-2-[3-(indole-3-yloxy)phenyl]thiophenoline-4-carboxylic acid tert-butyl ester ( Compound I -20-5- peak 2 , retention time from the analytical column = 20.45 min) were obtained. f. Synthesis of (R*)-2-[3-( indole - 3 -yloxy ) phenyl ] thiophenoline

To a solution of ( R* )-2-[3-(indole-3-yloxy)phenyl]thioporphyrin-4-carboxylic acid tributyl ester ( Compound I -20-5- peak 1 , 110 mg, 294 µmol) in _Et2O (1 mL) was added HCl/ _Et2O (3M, 1.5 mL). The reaction was stirred at ambient temperature for 4 h. After concentration, the solid was washed with _Et2O (3×2 mL) and dried in vacuo to provide ( R* )-2-[3-(indole-3-yloxy)phenyl]thioporphyrin ( Compound 34 ) as a 2-HCl salt.

Compound 34. MS (ESI+): m/z 274 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ 9.37 (d, J = 4.8 Hz, 1H), 8.27-8.22 (m, 1H), 8.00 (d, J = 9.0 Hz, 1H), 7.54 (t, J = 8.1 Hz, 1H), 7.41 (d, J = 7.5 Hz, 2H), 7.29 (d, J = 9.0 Hz, 1H), 4.41 (d, J = 12.0 Hz, 1H), 3.76-3.66 (m, 2H) , 3.45 (t, J = 12.0 Hz, 1H), 3.42-3.36 (m, 1H), 3.31-3.22 (m, 1H), 2.94 (d, J = 13.2 Hz, 1H). g. Synthesis of (S*)-2-[3-( indole - 3 -yloxy ) phenyl ] thiophene Phytophenone

To a solution of ( S* )-2-[3-(indole-3-yloxy)phenyl]thioporphyrin-4-carboxylic acid tributyl ester ( Compound I -20-5- peak 2 , 110 mg, 294 µmol) in _Et2O (1 mL) was added HCl/ _Et2O (3M, 1.5 mL). The reaction was stirred at ambient temperature for 4 h. After concentration, the solid was washed with _Et2O (3×2 mL) and dried in vacuo to provide ( S* )-2-[3-(indole-3-yloxy)phenyl]thioporphyrin ( Compound 35 ) as a 2HCl salt.

Compound 35. MS (ESI+): m/z 274 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ 9.22 (d, J = 4.8 Hz, 1H), 8.22-8.17 (m, 1H), 7.94 (d, J = 9.0 Hz, 1H), 7.54 (t, J = 8.1 Hz, 1H), 7.40 (d, J = 7.5 Hz, 2H), 7.28 (d, J = 9.0 Hz, 1H), 4.41 (d, J = 12.0 Hz, 1H), 3.76-3.66 (m, 2H) , 3.49 (t, J = 12.3 Hz, 1H), 3.42-3.36 (m, 1H), 3.31-3.22 (m, 1H), 2.94 (d, J = 13.2 Hz, 1H).

Example 21. Synthesis of ( R )-2-(3-((2- methylpyrimidin - 4- yl ) oxy ) phenyl ) pyrimidine ( Compound 36)

Compound 36 was synthesized from compound 1-2-9 - peak 1 and 4-chloro-2-methylpyrimidine as a 2HCl salt using a nucleophilic substitution and subsequent deprotection procedure similar to that in Example 4 .

Compound 36. MS (ESI+): m/z 272 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ 8.81 (d, J = 6.9 Hz, 1H), 7.56 (t, J = 7.8 Hz, 1H), 7.46-7.39 (m, 3H), 7.29 (d, J = 7.8 Hz, 1H), 4.95-4.90 (m, 1H), 4.25 (dd, J = 3.0, 13.2 Hz, 1H), 4.03 (td, J = 11.4, 2.7 Hz, 1H), 3.55 (d, J = 12.6 Hz, 1H), 3.39-3.33 (m, 2H), 3.11 (t, J = 12.0 Hz, 1H), 2.69 (s, 3H).

Example 22. Synthesis of ( R )-4-(3-( pyrrolidine -2- yl ) phenoxy ) pyrimidin -2- amine ( Compound 37)

Compound 37 was synthesized in the form of a free base from compound 1-2-9 - peak 1 and 4-chloropyrimidin-2-amine using a nucleophilic substitution and subsequent deprotection procedure similar to that in Example 4 .

Compound 37. MS (ESI+): m/z 273 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ 8.06 (d, J = 6.0 Hz, 1H), 7.40 (t, J = 7.8 Hz, 1H), 7.24 (d, J = 7.8 Hz, 1H), 7.13 (s, 1H), 7.05 (d, J = 8.1 Hz, 1H), 6.15 (d, J = 6.0 Hz, 1H), 4.50 (d, J = 10.5 Hz, 1H), 3.99 (d, J = 10.5 Hz , 2H), 3.75 (td, J = 11.4, 3.9 Hz, 1H), 3.02 (d, J = 12.9 Hz, 1H), 2.95-2.82 (m, 2H), 2.66 (t, J = 10.8 Hz, 1H).

Example 23. Synthesis of ( R )-2-(3-( pyridin -2 -yloxy ) phenyl ) -pyroline ( Compound 38) and ( S )-2-(3-( pyridin -2 -yloxy ) phenyl ) -pyroline ( Compound 39)

Compound 38 was synthesized from compound I-2-9- peak 1 and 2-iodopyridine as 2 HCl salt using a coupling and subsequent deprotection procedure similar to that in Example 1 .

Compound 38. MS (ESI+): m/z 257 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ 8.35 (d, J = 5.4 Hz, 1H), 8.17 (t, J = 8.0 Hz, 1H), 7.55 (t, J = 7.8 Hz, 1H), 7.43-7.36 (m, 3H), 7.26 (d, J = 8.1 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 4.84-4.80 (m, 1H), 4.25 (dd, J = 3.3, 13.5 Hz, 1H), 4.00 (td, J =11.7, 3.0 Hz, 1H), 3.53 (d, J = 12.0 Hz, 1H), 3.38-3.29 (m, 2H), 3.11 (t, J = 12.2 Hz, 1H).

Compound 39 was synthesized from compound I-2-9- peak 2 and 2-iodopyridine as 2 HCl salt using a coupling and subsequent deprotection procedure similar to that in Example 1 .

Compound 39. MS (ESI+): m/z 257 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ 8.37 (d, J = 5.4 Hz, 1H), 8.23-8.17 (m,1H), 7.56 (t, J = 7.8 Hz, 1H), 7.46-7.38 (m, 3H), 7.27 (d, J = 8.4 Hz, 1H), 7.12 (d, J = 8.7 Hz, 1H), 4.93-4.91 (m, 1H), 4.25 (dd, J = 3.3, 13.2 Hz, 1H), 4.02 (td, J =11.7, 3.0 Hz, 1H), 3.54 (d, J = 13.2 Hz, 1H), 3.38-3.31 (m, 2H), 3.12 (t, J = 12.0 Hz, 1H).

Example 24. Synthesis of ( R )-2-(3-((6- fluoro - 3- yl ) oxy ) phenyl ) pyroline ( Compound 40)

Compound 40 was synthesized from compound 1-2-9 - pyridine and 3,6-difluorothiazide as 2 HCl salt using similar nucleophilic substitution and subsequent deprotection procedures as in Example 4 .

Compound 40. MS (ESI+): m/z 276 (MH+); ¹ H NMR (300 MHz, CD ₃ OD) δ 7.65-7.59 (m, 2H), 7.49 (t, J = 8.1 Hz, 1H), 7.33-7.31 (m, 2H), 7.21 (d, J = 8.4 Hz, 1H), 4.87-4.81 (m, 1H), 4.24 (d, J = 12.9 Hz, 1H), 3.99 (t, J = 11.4 Hz, 1H), 3.51 (d, J = 12.9 Hz, 1H), 3.39-3.33 (m, 1H), 3.28-3.21 (m, 1H), 3.10 (t, J = 1 = 12.0 Hz, 1H).

Example 25. Synthesis of ( R )-2-(3-((2- methylpyrimidin - 5- yl ) oxy ) phenyl ) pyrimidine ( Compound 41)

Compound 41 was synthesized from compound 1-2-9 - peak 1 and 5-bromo-2-methylpyrimidine as a 2HCl salt using a coupling and subsequent deprotection procedure similar to that in Example 1 .

Compound 41. MS (ESI+): m/z 272 (MH ⁺ ); ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 9.92-9.82 (m, 2H), 8.56 (s, 2H), 7.45 (t, J = 5.7 Hz, 1H), 7.21 (d, J = 5.7 Hz, 1H), 7.12-7.10 (m, 2H), 4.84 (d, J = 7.2 Hz, 1H), 4.09 (d, J = 9.3 Hz, 1H), 3.95 (t, J = 9.0 Hz, 1H), 3.42 ( d, J = 9.3 Hz, 1H), 3.21 (d, J = 9.0 Hz, 1H), 3.11-3.04 (m, 1H), 3.03-2.93 (m, 1H), 2.64 (s, 3H).

Example 26. Synthesis of ( R )-2-(3-( pyrimidin -5 -yloxy ) phenyl)-pyrroline ( Compound 42 ) and ( S )-2-(3-( pyrimidin -5 -yloxy ) phenyl ) -pyrroline ( Compound 43)

Compound 42 was synthesized from compound 1-2-9 - peak 1 and 5-bromopyrimidine as a 2HCl salt using a nucleophilic substitution and subsequent deprotection procedure similar to that in Example 4 .

Compound 42. MS (ESI+): m/z 258 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ 8.96 (s, 1H), 8.57 (s, 2H), 7.50 (t, J = 6.0 Hz, 1H), 7.31 (br d, J = 5.7 Hz, 1H), 7.24 (s, 1H), 7.17 (dd, J = 1.5, 6.0 Hz, 1H), 4.83-4.78 (m, 1H), 4.24 (dd, J = 2.8, 10.2 Hz, 1H), 4.02-3.96 (m, 1H), 3.50 (d, J = 9.9 Hz, 1H), 3.35-3.27 (m, 2H), 3.09 (t, J = 9.0 Hz, 1H).

Compound 43 was synthesized from compound 1-2-9- peak 2 and 5-bromopyrimidine using a nucleophilic substitution and subsequent deprotection procedure similar to that in Example 4 .

Compound 43. MS (ESI+): m/z 258 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ 8.95 (s, 1H), 8.55 (s, 2H), 7.50 (t, J = 8.0 Hz, 1H), 7.31 (br d, J = 8.1 Hz, 1H), 7.23 (s, 1H), 7.16 (br d, J =7.8 Hz, 1H), 4.80-4.75 (m, 1H), 4.26 (br d, J = 10.2 Hz, 1H), 4.03-3.94 (m, 1H) , 3.50 (d, J = 12.6 Hz, 1H), 3.29-3.22 (m, 2H), 3.10 (t, J = 11.7 Hz, 1H).

Example 27. Synthesis of ( R )-2-(3-((4- methylpyridin - 3- yl ) oxy ) phenyl ) pyroline ( Compound 44)

Compound 44 was synthesized from compound 1-2-9 - pyridine and 3-chloro-4-methylthiazolidine as a 2HCl salt using a nucleophilic substitution and subsequent deprotection procedure similar to that in Example 4 .

Compound 44. MS (ESI+): m/z 272 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ 9.19 (d, J = 5.4 Hz, 1H), 8.28 (d, J = 4.5 Hz, 1H), 7.55 (t, J = 8.4 Hz, 1H), 7.50-7.40 (m, 2H), 7.31 (d, J = 7.5 Hz, 1H), 4.94-4.86 (m, 1H), 4.25 (d, J = 13.5 Hz, 1H), 4.02 (t, J = 12.9 Hz , 1H), 3.53 (d, J = 12.3 Hz, 1H), 3.47-3.31 (m, 2H), 3.10 (t, J = 12.0 Hz, 1H), 2.69 (s, 3H).

Example 28. Synthesis of ( R )-2-(2- fluoro -5-( pyridin - 2- yloxy ) phenyl ) pyroline ( Compound 45)

Compound 45 was synthesized from compound 1-1-5 - peak 1 and 2-iodopyrrolidone as a 2HCl salt using a coupling and subsequent deprotection procedure similar to that in Example 1 .

Compound 45. MS (ESI+): m/z 276 (MH+); ¹ H NMR (300 MHz, CD ₃ OD) δ 8.47 (s, 1H), 8.31 (d, J = 2.7 Hz, 1H), 8.14 (s , 1H), 7.38 (d, J = 6.0 Hz, 1H), 7.24 (d, J = 8.7 Hz, 1H), 5.10 (d, J = 11.1 Hz, 1H), 4.25 (dd, J = 3.3, 13.2 Hz, 1H), 4.02 (td, J = 11.7, 3.3 Hz, 1H ), 3.54 (d, J = 12.6 Hz, 1H), 3.40-3.31(m, 2H), 3.09 (t, J = 12.0 Hz, 1H).

Example 29. Synthesis of ( R )-2-(2- fluoro -5-((4- methylpyridin - 3- yl ) oxy ) phenyl ) pyroline ( Compound 46)

Compound 46 was synthesized from compound 1-1-5 - pyridine and 3-chloro-4-methylthiazolidine as 2HCl salt using similar nucleophilic substitution and subsequent deprotection procedures as in Example 4 .

Compound 46. MS (ESI+): m/z 290 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ 9.06 (d, J = 3.9 Hz, 1H), 8.08 (d, J = 3.6 Hz, 1H), 7.51-7.49 (m, 1H), 7.33-7.27 (m, 2H), 5.11 (d, J = 7.2 Hz, 1H), 4.25 (dd, J = 2.7, 9.6 Hz, 1H), 4.04 (td, J = 9.3, 1.8 Hz, 1H), 3.55 (d, J = 9.6 Hz, 1H), 3.38-3.31 (m, 1H), 3.30-3.27(m, 1H), 3.12 (t, J = 12.0 Hz, 1H), 2.61 (s, 3H).

Example 30. Synthesis of ( R )-2-(3-((5- methoxypyridin - 3- yl ) oxy ) phenyl ) pyroline ( Compound 47)

Compound 47 was synthesized from compound 1-2-9 - pyridine and 3-chloro-5-methoxypyridine as a 2HCl salt using a nucleophilic substitution and subsequent deprotection procedure similar to that in Example 4 .

Compound 47. MS (ESI+): m/z 288 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ 8.88 (s, 1H), 7.56 (t, J = 8.1 Hz, 1H), 7.43-7.41 (m, 2H), 7.31 (d, J = 8.4 Hz, 1H), 7.17 (d, J = 1.8 Hz, 1H), 4.84-4.78 (m, 1H), 4.26 (d, J = 11.4 Hz, 1H), 4.08 (s, 3H), 4.01 (t, J = 10.8 Hz, 1H), 3.54 (d, J = 12.9 Hz, 1H), 3.41-3.33 (m, 2H). 2H), 3.12 (t, J = 11.4 Hz, 1H).

Example 31. Synthesis of 2-(2- fluoro -5-( pyridin -3 -yloxy ) phenyl ) pyroline ( Compound 48)

Compound 48 was synthesized from racemic compound I -1-4 and 2-iodopyridine in 2HCl using a coupling and subsequent deprotection procedure similar to that in Example 1 .

Compound 48. MS (ESI+): m/z 275 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ 8.68 (d, J = 2.4 Hz, 1H), 8.60 (d, J = 5.4 Hz, 1H), 8.19-8.16 (m, 1H), 8.06-8.01 (m, 1H), 7.49-7.47 (m, 1H), 7.37-7.31 (m, 2H), 5.13 (d, J = 9.9 Hz, 1H), 4.26 (d, J = 13.2 Hz, 1H), 4.04 ( t, J = 13.2 Hz, 1H), 3.55 (d, J = 12.9 Hz, 1H), 3.39-3.33 (m, 2H), 3.16 (t, J = 12.0 Hz, 1H).

Example 32. Synthesis of ( R )-2-(3-((6- methylpyridin - 3- yl ) oxy ) phenyl ) pyroline ( Compound 49)

Compound 49 was synthesized from compound 1-2-9 - pyridine and 3-bromo-6-methylindole as a 2HCl salt using a coupling and subsequent deprotection procedure similar to that in Example 1 .

Compound 49. MS (ESI+): m/z 272 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ 8.24 (d, J = 6.9 Hz, 1H), 8.03 (d, J = 6.9 Hz, 1H), 7.53 (t, J = 6.0 Hz, 1H), 7.40-7.39 (m, 2H), 7.30-7.27 (m, 1H), 4.87-4.85 (m, 1H), 4.24 (d, J = 12.6 Hz, 1H), 4.02 (t, J = 9.3 Hz, 1H) , 3.53 (d, J = 9.6 Hz, 1H), 3.38-3.34 (m, 1H), 3.29-3.23 (m, 1H), 3.10 (t, J = 9.0 Hz, 1H), 2.80 (s, 3H).

Example 33. Synthesis of ( R )-2-(3-( pyridin -4 -yloxy ) phenyl ) pyroline ( Compound 50)

Compound 50 was synthesized from compound 1-2-9 - peak 1 and 4-iodopyridine as a 2HCl salt using a coupling and subsequent deprotection procedure similar to that in Example 1 .

Compound 50. MS (ESI+): m/z 257 (MH ⁺ ); ^1H NMR (300 MHz, _CD3OD ) δ 8.72 (d, J = 7.5 Hz, 2H), 7.63 (t, J = 8.1 Hz, 1H), 7.52-7.42 (m, 4H), 7.33-7.29 (m, 1H), 4.93-4.90 (m, 1H), 4.26 (d, J = 13.5 Hz, 1H), 4.02 (t, J = 11.7 Hz, 1H), 3.56 (d, J = 13.2 Hz, 1H), 3.42-3.32 (m, 2H), 3.13 (t, J = 11.4 Hz, 1H).

Example 34. Synthesis of ( R )-2-(3-((6-( trifluoromethyl ) oxathian - 3- yl ) oxy ) phenyl ) pyroline ( Compound 51)

Compound 51 was synthesized from compound 1-2-9 - pyridine and 3-bromo-6-(trifluoromethyl)pyridine as a 2HCl salt using a coupling and subsequent deprotection procedure similar to that in Example 1 .

Compound 51. MS (ESI+): m/z 326 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ 8.13 (d, J = 6.9 Hz, 1H), 7.62 (d, J = 6.9 Hz, 1H), 7.53 (t, J = 6.0 Hz, 1H), 7.38-7.36 (m, 2H), 7.28-7.25 (m, 1H), 4.84 (d, J = 8.4 Hz, 1H), 4.25 (d, J = 9.9 Hz, 1H), 4.00 (t, J = 9.0 Hz , 1H), 3.52 (d, J = 9.6 Hz, 1H), 3.36-3.33 (m, 1H), 3.30-3.24 (m, 1H), 3.13 (t, J = 9.0 Hz, 1H).

Example 35. Synthesis of ( R )-2-(3-( indole - 4- yloxy ) phenyl ) pyroline ( Compound 52)

Compound 52 was synthesized from compound 1-2-9 - peak 1 and 4-bromoindole hydrobromide as a 2HCl salt using a coupling and subsequent deprotection procedure similar to that in Example 1 .

Compound 52. MS (ESI+): m/z 258 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ 9.42 (d, J = 6.6 Hz, 1H), 9.31 (d, J = 3.0 Hz, 1H), 7.69-7.63 (m, 2H), 7.56-7.50 (m, 2H), 7.39-7.35 (m, 1H), 4.98-4.93 (m, 1H), 4.25 (d, J = 12.9 Hz, 1H), 4.04 (t, J = 11.7 Hz, 1H), 3.58 (d, J = 12.3 Hz, 1H), 3.44-3.32 (m, 2H), 3.14 (t, J = 12.0 Hz, 1H).

Example 36. Synthesis of ( R )-2-(2- fluoro -5-( indole - 4- yloxy ) phenyl ) pyroline ( Compound 53)

Compound 53 was synthesized from compound 1-1-5 - pyridinium hydrobromide as a 2HCl salt using a coupling and subsequent deprotection procedure similar to that in Example 1 .

Compound 53. MS (ESI+): m/z 276 (MH+); ¹ H NMR (300 MHz, CD ₃ OD) δ 9.37 (d, J = 6.9 Hz, 1H), 9.28 (d, J = 3.0 Hz, 1H ), 7.64-7.58 (m, 2H), 7.41 (d, J = 6.6 Hz, 2H), 5.15 (d, J = 10.8 Hz, 1H), 4.27 (d, J = 13.2 Hz, 1H), 4.04 (t, J = 12.0 Hz, 1H), 3.58 (d, J = 12.9 Hz , 1H), 3.45-3.33 (m, 2H), 3.16 (t, J = 12.0 Hz, 1H).

Example 37. Synthesis of ( R )-2-(3-((6 -cyclopropylthiazol - 3- yl ) oxy ) phenyl ) pyroline ( Compound 54)

Compound 54 was synthesized from compound 1-2-9 - pyridine and 3-bromo-6-cyclopropylpyridine as a 2HCl salt using a coupling and subsequent deprotection procedure similar to that in Example 1 .

Compound 54. MS (ESI+): m/z 298 (MH+); ¹ H NMR (300 MHz, CD ₃ OD) δ 8.24 (q, J = 6.3 Hz, 2H), 7.53 (t, J = 6.0 Hz, 1H ), 7.41-7.39 (m, 2H), 7.30 (d, J = 6.0 Hz, 1H), 4.88-4.84 (m, 1H), 4.24 (d, J = 12.3 Hz, 1H), 4.02 (t, J = 12.0 Hz, 1H), 3.52 (d, J = 9.3 Hz, 1H) , 3.38-3.34 (m, 1H), 3.29-3.23 (m, 1H), 3.10 (t, J = 9.0 Hz, 1H), 2.45-2.39 (m, 1H), 1.57-1.51 (m, 2H), 1.34-1.30 (m, 2H).

Example 38. Synthesis of ( R )-2-(3-((5- methylpyridin - 3- yl ) oxy ) phenyl ) pyroline ( Compound 55)

Compound 55 was synthesized from compound 1-2-9 - pyridine and 3-chloro-5-methylpyridine as a 2HCl salt using a nucleophilic substitution and subsequent deprotection procedure similar to that in Example 4 .

Compound 55. MS (ESI+): m/z 272 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ 9.33 (s, 1H), 8.08 (s, 1H), 7.55 (t, J = 8.1 Hz, 1H), 7.44-7.42 (m, 2H), 7.30 (d, J = 5.4 Hz, 1H), 4.93-4.90 (m, 1H), 4.24 (d, J = 13.8 Hz, 1H), 4.04 (t, J = 10.5 Hz, 1H), 3.54 (d, J = 12.3 Hz, 1H), 3.39-3.34 (m, 1H), 3.28-3.23 (m, 1H), 3.10 (t, J = 12.0 Hz, 1H), 2.65 (s, 3H).

Example 39. Synthesis of ( R* )-2-(2- fluoro -5-( pyridin -2 -yloxy ) phenyl ) -pyroline ( Compound 56) and ( S* )-2-(2- fluoro -5-( pyridin -2 -yloxy ) phenyl ) -pyroline ( Compound 57)

Compound 56 and Compound 57 were synthesized from Compound 1-1-4 and 2-iodopyridine as 2HCl salts using a coupling and subsequent deprotection procedure similar to that in Example 19 .

2-(2-Fluoro-5-(pyridin-2-yloxy)phenyl)morpholine was separated by chiral column separation using the following: Instrument: SFC-150 (Thar, Waters) Column: AD 25×250mm, 10µm (Daicel) Column temperature: 35℃ Mobile phase: CO ₂ /MeOH (0.01% methylamine/methanol) = 75/25 Flow rate: 100 g/min Back pressure: 100 bar Detection wavelength: 220 nm Cycle time: 3.5 min Sample solution: 560 mg dissolved in 10 mL methanol Injection volume: 1.0 mL

Chiral analysis conditions: instrument: Waters 2695; column: Reflect C-Amylose A (4.6×250mm, 5µm); column temperature: 30℃; mobile phase: n-hexane/EtOH (0.1% DEA) = 60/40; flow rate: 0.8 mL/min; detection wavelength: 254 nm; detector: W2996 PDA.

After removal of the solvent, the first eluting isomer ( R* ) - 2- (2-fluoro - 5- ( pyridin - 2 -yloxy) phenyl ...

Compound 56. MS (ESI+): m/z 275 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ 8.44 (d, J = 5.7 Hz, 1H), 8.33 (t, J = 7.3 Hz, 1H), 7.56-7.52 (m, 2H), 7.38-7.32 (m, 2H), 7.20 (d, J = 8.7 Hz, 1H), 5.15 (d, J = 11.1 Hz, 1H), 4.26 (d, J = 13.2 Hz, 1H), 4.06 (t, J = 12.0 Hz , 1H), 3.56 (d, J = 12.6 Hz, 1H), 3.40-3.34 (m, 2H), 3.17 (t, J = 12.0 Hz, 1H). Compound 57. MS (ESI+): m/z 275 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ 8.41 (d, J = 5.1 Hz, 1H), 8.28 (t, J = 7.9 Hz, 1H), 7.54-7.48 (m, 2H), 7.40-7.31 (m, 2H), 7.18 (d, J = 8.7 Hz, 1H), 5.15 (d, J = 10.2 Hz, 1H), 4.26 (d, J = 13.2 Hz, 1H), 4.05 (t, J = 12.0 Hz , 1H), 3.56 (d, J = 12.3 Hz, 1H), 3.39-3.34 (m, 2H), 3.16 (t, J = 12.0 Hz, 1H).

Example 40. Synthesis of ( R )-2-(3- ( benzyloxy ) phenyl ) morpholine ( Compound 58 )

Compound 58 was synthesized from compound 1-2-9 - peak 1 and 1-chlorobenzylamine as a 2HCl salt using a nucleophilic substitution and subsequent deprotection procedure similar to that in Example 4 .

Compound 58. MS (ESI+): m/z 308 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ 9.99 (s, 1H), 8.75 (d, J = 5.7 Hz, 1H), 7.58 ( d, J = 6.0 Hz, 1H), 8.50-8.46 (m, 1H), 8.40-8.36 (m, 1H), 7.58 (t, J = 6.0 Hz, 1H), 7.52 (s, 1H), 7.46-7.41 (m, 2H), 4.88-4.87 (m, 1H), 4.25 (d, J = 10.2 Hz, 1H), 4.03 (t, J = 9.3 Hz, 1H), 3.56 (d, J = 9.6 Hz, 1H), 3.38-3.35 (m, 1H), 3.29-3.24 (m, 1H), 3.13 (t, J = 9.0 Hz, 1H).

Example 41. Synthesis of ( R )-5-(3-( pyrrolidine -2 -yl ) phenoxy ) pyrimidin -2- amine ( Compound 59) a. Synthesis of (R)-2-(3-((( trifluoromethyl ) sulfonyl ) oxy ) phenyl ) pyrrolidine -4- carboxylic acid tributyl ester

To a solution of ( R )-2-(3-hydroxyphenyl)morpholine-4-carboxylic acid tributyl ester ( Compound I -2-9- peak 1 , 300 mg, 1.07 mmol) in DCM (5 mL) was added pyridine (253 mg, 3.21 mmol) and _Tf2O (451 mg, 1.60 mmol) at 0°C. The reaction mixture was stirred at that temperature for 1 h. 0.5 M aqueous HCl (3 mL) was added to the reaction vessel and the resulting biphasic mixture was transferred to a separatory funnel. The layers were separated and the aqueous _phase was extracted with DCM (3 x 5 mL). The combined organics were dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo. The resulting mixture was purified by flash column chromatography using isocratic elution with EtOAc (25%) and petroleum ether (75%) to provide ( R )-2-[3-(trifluoromethanesulfonyloxy)phenyl]-4-carboxylic acid tert-butyl ester ( Compound I -41-1 ). b. Synthesis of (R)-2-(3- bromophenyl ) -4- carboxylic acid tert- butyl ester

To a solution of ( R )-2-[3-(trifluoromethanesulfonyloxy)phenyl]morpholine-4-carboxylic acid tributyl ester ( Compound I -41-1 , 447.2 mg, 1.08 mmol) in 1,4-dioxane (7 mL) was added tert -BuBrettPhos (47.0 mg, 97.1 µmol), _Pd2 (dba)3 (29.6 mg, 32.4 µmol), KF (62.7 mg, 1.08 mmol) and KBr (514 mg, 4.32 mmol). The reaction mixture was heated to 100 °C and stirred at that temperature for 2 days. Water (7 ml) was added to the reaction vessel and the resulting two-phase mixture was transferred to a separatory funnel. The layers were separated and the aqueous phase was extracted with EtOAc (3×10 ml). _The combined organics were dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo. The resulting mixture was purified by flash column chromatography using isocratic elution with EtOAc (10%) and petroleum ether (90%) to provide ( R )-2-(3-bromophenyl)morpholine-4-carboxylic acid tert-butyl ester ( Compound I -41-2 ). c. Synthesis of (5- hydroxypyrimidin -2- yl ) carbamic acid tert-butyl ester

To a solution of (2-{[(tributyloxy)carbonyl]amino}pyrimidin-5-yl)boronic acid ( compound I -41-3 , 250 mg, 1.04 mmol) in THF (5 mL) were added NaOH (1.56 mL, 3.12 mmol) and _H2O2 ( _{235 mg, 2.08 mmol). The reaction was stirred at ambient temperature for 1 h. The reaction mixture was neutralized with 1 M HCl. A saturated aqueous solution of Na2S2O3 ( 5 mL} ) was then added. The resulting mixture was concentrated in vacuo and purified by flash column chromatography with isocratic elution of DCM (95%) and MeOH (5%) to provide tributyl N- (5-hydroxypyrimidin-2-yl)carbamate ( compound I -41-4 ). d. Synthesis of (R)-2-(3-((2-(( tert-butyloxycarbonyl ) amino ) pyrimidin -5- yl ) oxy ) phenyl ) morpholine -4- carboxylic acid tributyl ester

To a solution of ( R )-2-(3-bromophenyl)morpholine-4-carboxylic acid tributyl ester ( Compound I -41-2 , 130 mg, 379 µmol) in DMF (5 mL) were added 2,2,6,6-tetramethylheptane-3,5-dione (55.8 mg, 303 µmol), cesium carbonate (308 mg, 947 µmol), cuprous bromide (5.43 mg, 37.9 µmol) and N- (5-hydroxypyrimidin-2-yl)carbamic acid tributyl ester ( Compound I -41-4 , 119 mg, 568 µmol). The reaction mixture was heated to 120 °C and stirred at that temperature for 5 h. Water (15 mL) was added to the reaction vessel and the resulting two-phase mixture was transferred to a separatory funnel. The mixture was extracted with EtOAc (3×10 mL). The combined organics were washed with brine, dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo. The resulting mixture was purified by flash column chromatography using isocratic elution with EtOAc (50%) and petroleum _ether (50%) to provide ( R )-2-{3-[(2-aminopyrimidin-5-yl)oxy]phenyl}pyrimidine-4-carboxylic acid tributyl ester ( Compound I -41-5 ). e. Synthesis of (R)-5-(3-( pyrimidin -2- yl ) phenoxy ) pyrimidin -2- amine

To a solution of ( R )-2-{3-[(2-aminopyrimidin-5-yl)oxy]phenyl}pyrimidin-4-carboxylic acid tributyl ester ( Compound I -41-5 , 35.6 mg, 95.5 µmol) was added HCl/ _Et2O (3M, 0.5 mL). The reaction was stirred at ambient temperature for 1 h. The resulting solid was washed with _Et2O (3×2 mL) to provide 5-{3-[( R )-pyrimidin-2-yl]phenoxy}pyrimidin-2-amine ( Compound 59 ) as a 2HCl salt.

Compound 59. MS (ESI+): m/z 273 (MH ⁺ ). ¹ H NMR (300 MHz, CD ₃ OD) δ 8.50 (s, 2H), 7.45 (t, J = 8.1 Hz, 1H), 7.27-7.22 (m, 2H), 7.12 (d, J = 8.1 Hz, 1H ), 4.87-4.81 (m, 1H), 4.24 (d, J = 12.3 Hz, 1H), 4.01 (td, J = 12.0, 3.0 Hz, 1H), 3.47 (d, J = 13.5 Hz, 1H), 3.37-3.25 (m, 2H), 3.09 (t , J = 12.0 Hz, 1H).

Example 42. Synthesis of ( R )-2-(2- fluoro -5-((6- fluoro - 3- yl ) oxy ) phenyl ) -pyroline ( Compound 60) and ( R )-2-(3-((6 -fluoro - 3- yl ) oxy ) phenyl ) -pyroline ( Compound 61)

Compound 60 was synthesized from compound 1-1-5 - pyridine and 3,6 - pyridine as 2HCl salt using similar nucleophilic substitution and subsequent deprotection procedures as in Example 4 .

Compound 60. MS (ESI+): m/z 294 (MH ⁺ ); ^1H NMR (300 MHz, _CD3OD ) δ 7.71-7.59 (m, 2H), 7.42 (d, J = 4.2 Hz, 1H), 7.27-7.24 (m, 2H), 5.09 (d, J = 11.1 Hz, 1H), 4.25 (d, J = 11.1 Hz, 1H), 4.02 (t, J = 12.0 Hz, 1H), 3.53 (d, J = 12.0 Hz, 1H), 3.40-3.22 (m, 2H), 3.12 (t, J = 11.7 Hz, 1H).

To a solution of ( R )-2-{3-[(6-fluoropyridin-3-yl)oxy]phenyl}pyridin-4-carboxylic acid tributyl ester ( Compound I -42-1 , 50 mg, 133 µmol , intermediate in Example 24 ) was added HCl/ _Et2O (4M, 1 mL). The reaction was stirred at ambient temperature for 4 h. The resulting solid was purified by preparative HPLC to provide 6-{3-[( R )-pyridin-2-yl]phenoxy}pyridin-3-ol ( Compound 61 ) as a free base.

Compound 61. MS (ESI+): m/z 274 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ 7.39-7.33 (m, 2H), 7.20-7.16 (m, 2H), 7.06-7.02 (m, 2H), 4.48 (d, J = 9.3 Hz, 1H), 3.98 (d, J = 11.8 Hz, 1H), 3.74 (t, J = 11.1 Hz, 1H), 2.99 (d, J = 12.3 Hz, 1H), 2.92-2.81 (m, 2H), 2.64 (t, J = 12.0 Hz, 1H).

Example 43. Synthesis of ( RS )-3- methyl -2-(3-( indole -3 -yloxy ) phenyl ) -pyroline ( Compound 62 ) , ( SR )-3- methyl -2-(3-( indole - 3 -yloxy ) phenyl ) -pyroline ( Compound 63) , ( RR )-3- methyl -2-(3-( indole - 3 -yloxy ) phenyl ) -pyroline ( Compound 64) , ( SS )-3- methyl -2-(3-( indole - 3 -yloxy ) phenyl ) -pyroline ( Compound 65) a. Synthesis of 2- bromo -1-(3- hydroxyphenyl ) propan -1- one

To a solution of 1-(3-hydroxyphenyl)propan-1-one ( Compound I -43-1 , 5 g, 33.2 mmol) in DCM (50 mL) was added _Br2 (5.30 g, 33.2 mmol). The reaction was stirred at ambient temperature for 16 h. The reaction mixture was quenched with saturated aqueous _NaHCO3 (100 mL) and the resulting biphasic mixture was transferred to a separatory funnel. The layers were separated and the aqueous phase was extracted with DCM (2×50 mL). The combined organic phases were washed with saturated aqueous NaCl (2×50 mL), dried over _{anhydrous Na2SO4} , filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography using a gradient elution from petroleum ether (90%) and EtOAc (10%) to petroleum ether (85%) and EtOAc (15%) to provide 2-bromo-1-(3-hydroxyphenyl) propan -1-one ( Compound I -43-2 ). b. Synthesis of isomers of 2-(3- hydroxyphenyl )-3- methylmorpholine -4- carboxylic acid tributyl ester

A solution of 2-bromo-1-(3-hydroxyphenyl)propan-1-one ( Compound I -43-2 , 5 g, 21.8 mmol), formic acid (3.00 g, 65.3 mmol) and 2-aminoethan-1-ol (3.98 g, 65.3 mmol) in a sealed tube was heated at 140 °C for 16 h. LCMS showed the desired product and the starting material was consumed. THF (50 mL), _H2O (50 mL), di-tributyl dicarbonate (4.75 g, 21.8 mmol) and sodium bicarbonate (1.83 g, 21.8 mmol) were added to the reaction mixture. The mixture was stirred at room temperature for 1 h. The reaction was monitored by TLC and LCMS. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with saturated aqueous NaCl solution (2 x 40 mL), dried _over anhydrous _Na2SO4 , filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography with a gradient elution from petroleum ether (90%) and EtOAc (10%) to petroleum ether (80%) and EtOAc (20%) to provide tributyl 2-(3-hydroxyphenyl)-3-methylmorpholine-4-carboxylate as a yellow oil. The resulting oil was further purified by preparative TLC using isocratic elution with petroleum ether (85%) and EtOAc (15%) to provide tert-butyl 2-(3-hydroxyphenyl)-3-methylmorpholine-4-carboxylate ( Compound I -43-4- upper spot ) and tert-butyl 2-(3-hydroxyphenyl)-3-methylmorpholine-4-carboxylate ( Compound I -43-4- lower spot ). c. Synthesis of mirror image isomers of tert-butyl 2-(3- hydroxyphenyl )-3- methylmorpholine -4- carboxylate

2-(3-Hydroxyphenyl)-3-methylmorpholine-4-carboxylic acid tributyl ester ( Compound I -43-4 - upper spot ) was separated by chiral column separation using the following: Instrument: SFC-150 (Thar, Waters) Column: AD 25×250mm, 10µm (Daicel) Column temperature: 35℃ Mobile phase: CO ₂ /EtOH (0.01% methylamine/methanol) = 92/8 Flow rate: 100 g/min Back pressure: 100 bar Detection wavelength: 220 nm Cycle time: 2.0 min Sample solution: 100 mg dissolved in 3 mL methanol Injection volume: 0.5 mL

Chiral analysis conditions: Instrument: Waters 2695; Column: Reflect C-Amylose A (4.6×250mm, 5µm); Column temperature: 30℃; Mobile phase: n-hexane/EtOH (0.1% DEA) = 90/10; Flow rate: 0.8 mL/min; Detection wavelength: 220 nm; Detector: W2996 PDA.

After the solvent was removed, the first elution mirror image isomer of 2-(3-hydroxyphenyl)-3-methylmorpholine-4-carboxylic acid tert-butyl ester ( Compound I-43-5- peak 1 , retention time from the analytical column = 8.87 min) and the second elution mirror image isomer of 2-(3-hydroxyphenyl)-3-methylmorpholine-4-carboxylic acid tert-butyl ester ( Compound I-43-5- peak 2 , retention time from the analytical column = 7.71 min) were obtained . d. Synthesis of mirror image isomers of 2-(3- hydroxyphenyl )-3- methylmorpholine -4- carboxylic acid tert-butyl ester

2-(3-Hydroxyphenyl)-3-methylmorpholine-4-carboxylic acid tributyl ester ( Compound I -43-4 - lower spot , 100 mg, 340 µmol) was separated by chiral column separation using the following: Instrument: SFC-150 (Thar, Waters) Column: AD 25×250 mm, 10 µm (Daicel) Column temperature: 35°C Mobile phase: CO ₂ /EtOH (0.01% methylamine/methanol) = 92/8 Flow rate: 100 g/min Back pressure: 100 bar Detection wavelength: 220 nm Cycle time: 2.0 min Sample solution: 90 mg dissolved in 2 mL methanol Injection volume: 0.5 mL

Chiral analysis conditions: Instrument: Waters 2695; Column: Reflect C-Amylose A (4.6×250mm, 5µm); Column temperature: 30℃; Mobile phase: n-hexane/EtOH (0.1% DEA) = 95/5; Flow rate: 0.8 mL/min; Detection wavelength: 220 nm; Detector: W2996 PDA.

After removing the solvent, the first elution mirror image isomer of 2-(3-hydroxyphenyl)-3-methylmorpholine-4-carboxylic acid tert-butyl ester ( compound I-43-6- peak 1 , retention time from the analytical column = 16.76 min) and the second elution mirror image isomer of 2-(3-hydroxyphenyl)-3-methylmorpholine-4-carboxylic acid tert-butyl ester ( compound I-43-6- peak 2 , retention time from the analytical column = 20.20 min) were obtained. e. Synthesis of Compound 62

Compound 62 was synthesized from compound I-43-6- peak 1 and 3-bromoindole as a 2HCl salt using a coupling and subsequent deprotection procedure similar to that in Example 1 .

Compound 62. MS (ESI+) m/z : 272 (MH) ⁺ . ¹ H-NMR (300 MHz, CD ₃ OD) δ 9.25-9.18 (m, 1H), 8.16-8.11 (m, 1H), 7.90 (d, J = 9.0 Hz, 1H), 7.64 (t, J = 7.8 Hz, 1H), 7.50-7.46 (m, 2H), 7.41 (d, 8.1 Hz, 1H), 4.17-3.96 (m, 4H), 3.40-3.38 (m, 2H), 1.07 (d, J = 5.7 Hz, 3H). f. Synthesis of compound 63

Compound 63 was synthesized from compound I-43-6- pyridinium and 3-bromoindole as a 2HCl salt using a coupling and subsequent deprotection procedure similar to that in Example 1 .

Compound 63. MS (ESI+) m/z : 272 (MH) ⁺ . ¹ H-NMR (300 MHz, CD ₃ OD) δ 9.26-9.20 (m, 1H), 8.25-8.20 (m, 1H), 7.99 (d, J = 9.0 Hz, 1H), 7.67 (t, J = 7.8 Hz, 1H), 7.55-7.50 (m, 2H), 7.44 (d, J = 8.1 Hz, 1H), 4.20-4.02 (m, 4H), 3.43-3.40 (m, 2H), 1.09 (d, J = 5.7 Hz, 3H). g. Synthesis of compound 64

Compound 64 was synthesized from compound I-43-5- pyridinium and 3-bromoindole as a 2HCl salt using a coupling and subsequent deprotection procedure similar to that in Example 1 .

Compound 64. MS (ESI+) m/z : 272 (MH) ⁺ . ¹ H-NMR (300 MHz, CD ₃ OD) δ 9.25 (d, J = 4.2 Hz, 1H), 8.25 (dd, J = 4.8, 9.0 Hz, 1H), 8.01 (d, J = 8.7 Hz, 1H), 7.55 (t, J = 8.1 Hz, 1H), 7.42-7.39 (m, 2H), 7.33 (d, J = 8.4 Hz, 1H), 4.49 (d, J = 9.9 Hz, 1H), 4.20 (d, J = 13.6 Hz, 1H), 4.02-3.93 (m, 1H), 3.46-3.40 (m, 3H), 1.13 (d, J = 6.6 Hz, 3H). h. Synthesis of Compound 65

Compound 65 was synthesized from compound I-43-5- peak 2 and 3-bromoindole using a coupling and subsequent deprotection procedure similar to that in Example 1 .

Compound 65. MS (ESI+) m/z : 272 (MH) ⁺ . ¹ H-NMR (300 MHz, CD ₃ OD) δ 9.30 (d, J = 4.2 Hz, 1H), 8.32 (dd, J = 4.8, 9.0 Hz, 1H), 8.08 (d, J = 9.0 Hz, 1H), 7.56 (t, J = 8.1 Hz, 1H), 7.42-7.40 (m, 2H), 7.34 (d, J = 8.1 Hz, 1H), 4.50 (d, J = 9.6 Hz, 1H), 4.20 (d, J = 12.3 Hz, 1H), 4.03-3.93 (m, 1H), 3.53-3.40 (m, 3H), 1.13 (d, J = 6.6 Hz, 3H).

In Example 43 and Table 1, asterisks indicate single stereoisomers with unknown absolute configuration and unknown relative configuration.

Example 44. Synthesis of ( R* )-2-(4- fluoro -3-( pyrimidin -5 -yloxy ) phenyl ) -pyrimidine ( Compound 66) and ( S* )-2-(4 -fluoro -3-( pyrimidin - 5- yloxy ) phenyl ) -pyrimidine ( Compound 67) a. Synthesis of (R*)-2-(4 -fluoro -3-( pyrimidin - 5 -yloxy ) phenyl ) -pyrimidine ( Compound 66 )

Compound 66 was synthesized from compound I-11-3- peak -1 and 5-bromopyrimidine in the form of 2HCl salt using a similar synthetic procedure as in Example 4 .

Compound 66. MS (ESI+): m/z 276 (MH+); ¹ H NMR (300 MHz, CD ₃ OD) δ 8.96 (s, 1H), 8.56 (s, 2H), 7.51-7.37 (m, 3H), 4.83-4.73 (m, 1H), 4.24 (d, J = 10.5 Hz, 1H), 3.96 (t, J = 10.5 Hz, 1H), 3.47 (d, J = 12.6 Hz, 1H), 3.31-3.22 (m, 2H), 3.10 (t, J = 11.7 Hz, 1H). b. Synthesis of (S*)-2-(4- fluoro -3-( pyrimidin -5 -yloxy ) phenyl ) pyrimidine ( Compound 67 )

Compound 67 was synthesized from compound I-11-3- peak 2 and 5-bromopyrimidine using a similar synthetic procedure as in Example 4 as a 2HCl salt.

Compound 67. MS (ESI+): m/z 276 (MH+); ¹ H NMR (300 MHz, CD ₃ OD) δ 8.95 (s, 1H), 8.54 (s, 2H), 7.46-7.36 (m, 3H), 4.83-4.77 (m, 1H), 4.23 (d, J = 9.9 Hz, 1H), 3.98 (t, J = 10.8 Hz, 1H), 3.49 (d, J = 13.2 Hz, 1H), 3.31-3.20 (m, 2H), 3.10 (t, J = 11.7 Hz, 1H).

Example 45. Synthesis of ( R )-2-(3-((3-( trifluoromethyl )-1,2,4 -thiadiazol -5- yl ) oxy ) phenyl ) pyroline ( Compound 68)

Compound 68 was synthesized from compound 1-2-9 - peak 1 and 5-chloro-3-(trifluoromethyl)-1,2,4-thiadiazole as the HCl salt using a nucleophilic substitution and subsequent deprotection procedure similar to that in Example 4 .

Compound 68. MS (ESI+): m/z 332 (MH ⁺ ); ^1H NMR (300 MHz, _CD3OD ) δ 7.63-7.55 (m, 2H), 7.51-7.47 (m, 2H), 4.86-4.83 (m, 1H), 4.27 (d, J = 10.8 Hz, 1H), 4.01 (t, J = 11.4 Hz, 1H), 3.54 (d, J = 12.3 Hz, 1H), 3.39-3.33 (m, 2H), 3.11 (t, J = 11.7 Hz, 1H).

Example 46. Synthesis of ( R )-2-(3-( thiazolo [4,5- b ] pyridin -2 -yloxy ) phenyl ) pyroline ( Compound 69)

To a solution of ( R )-2-(3-hydroxyphenyl)morpholine-4-carboxylic acid tributyl ester ( Compound I-2-9- peak 1 , 50 mg, 178 µmol) in _CH3CN (1.5 mL) was added 2-chlorothiazolo[4,5- b ]pyridine (30.3 mg, 178 µmol) and _K2CO3 (49.1 mg, 356 µmol). The reaction was stirred at 80°C for 16 h. The reaction was filtered and concentrated _in vacuo. The resulting mixture was purified by flash column chromatography with isocratic elution of ethane (70%) and EtOAc (30%) to provide ( R )-tert-butyl 2-(3-(thiazolo[4,5-b]pyridin-2-yloxy)phenyl)morpholine-4-carboxylate, which was converted to the corresponding HCl salt using the deprotection procedure in Example 4 .

Compound 69. MS (ESI+): m/z 314 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ 9.00-8.95 (m, 1H), 8.70 (d, J = 5.4 Hz, 1H), 7.82-7.77 (m, 1H), 7.65-7.59 (m, 2H), 7.53-7.51 (m, 2H), 4.97-4.92 (m, 1H), 4.26 (d, J = 13.2 Hz, 1H), 4.04 (t, J = 11.1 Hz, 1H), 3.56 (d, J = 12.6 Hz, 1H), 3.40-3.33 (m, 2H), 3.12 (t, J = 12.0 Hz, 1H).

Example 47. Synthesis of ( R )-2-(3-((1,3,4- thiadiazol -2- yl ) oxy ) phenyl ) pyroline ( Compound 70)

Compound 70 was synthesized from compound 1-2-9 - peak 1 and 2-bromo-1,3,4-thiadiazole as the HCl salt using a nucleophilic substitution and subsequent deprotection procedure similar to that in Example 4 .

Compound 70. MS (ESI+): m/z 264 (MH ⁺ ); ^1H NMR (300 MHz, _CD3OD ) δ 9.03 (s, 1H), 7.56-7.47 (m, 2H), 7.40-7.36 (m, 2H), 4.82 (d, J = 13.8 Hz, 1H), 4.26 (d, J = 11.1 Hz, 1H), 3.99 (t, J = 13.2 Hz, 1H), 3.52 (d, J = 12.9 Hz, 1H), 3.39-3.34 (m, 1H), 3.28-3.24 (m, 1H), 3.10 (t, J = 12.0 Hz, 1H).

Example 48. Synthesis of ( R )-2-(3-((3-( methoxymethyl )-1,2,4- thiadiazol -5- yl ) oxy ) phenyl ) pyroline ( Compound 71) a. Synthesis of (R)-2-(3-((3 -bromo -1,2,4- thiadiazol -5- yl ) oxy ) phenyl ) pyroline -4- carboxylic acid tributyl ester

To a solution of ( R )-tributyl 2-(3-hydroxyphenyl)morpholine-4-carboxylate (300 mg, 1.07 mmol) in DMF (4 mL) was added 3-bromo-5-chloro-1,2,4-thiadiazole (255 mg, 1.28 mmol) and cesium carbonate (869 mg, 2.67 mmol). The reaction was stirred at ambient temperature for 2 h. Water (10 mL) and EtOAc (5 mL) were added to the reaction vessel and the resulting biphasic mixture was transferred to a separatory funnel. The layers were separated and the aqueous phase was extracted with EtOAc (3×5 mL). The combined organics were washed with brine (2×10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography with a gradient elution from petroleum ether (95%) and EtOAc (5%) to petroleum ether (75%) and EtOAc (25%) to provide ( R )-2-{3-[(3-bromo-1,2,4-thiadiazol-5-yl)oxy]phenyl}morpholine-4-carboxylic acid tert-butyl ester. b. Synthesis of (R)-2-(3-((3 -vinyl -1,2,4- thiadiazol -5- yl ) oxy ) phenyl ) morpholine- 4- carboxylic acid tert-butyl ester

To a solution of ( _R )-2-{3-[(3-bromo-1,2,4-thiadiazol-5-yl)oxy]phenyl}morpholine-4-carboxylic acid tributyl ester (480 mg, 1.08 mmol ) in toluene (8 mL) under N2 was added tetrakis(triphenylphosphine)palladium (62.4 mg, 54.0 µmol) and tributyl(vinyl)tinane (409 mg, 1.29 mmol). The reaction mixture was heated to 100 °C and stirred at that temperature for 20 h. Water (15 mL) and EtOAc (15 mL) were added to the reaction vessel and the resulting biphasic mixture was transferred to a separatory funnel. The layers were separated and the aqueous phase was extracted with EtOAc (3 x 15 mL). _The combined organics were dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography with a gradient elution from petroleum ether (95%) and EtOAc (5%) to petroleum ether (75%) and EtOAc (25%) to provide ( R )-2-{3-[(3-vinyl-1,2,4-thiadiazol-5-yl)oxy]phenyl}morpholine-4-carboxylic acid tert-butyl ester. c. Synthesis of (R)-2-(3-((3 -methylyl -1,2,4- thiadiazol-5 - yl ) oxy ) phenyl ) morpholine -4- carboxylic acid tert-butyl ester

To a solution of ( R )-2-{3-[(3-vinyl-1,2,4-thiadiazol-5-yl)oxy]phenyl}morpholine-4-carboxylic acid tributyl ester (277 mg, 711 µmol) in acetone (3 mL) and _H2O (1 mL) were added NMO (124 mg, 1.06 mmol) and _OsO4 (180 µg, 0.711 µmol). The reaction mixture was heated to 40 °C and stirred at that temperature for 1 h. EtOAc (10 mL) and water (10 mL) were added to the reaction vessel and the resulting biphasic mixture was transferred to a separatory funnel. The layers were separated and the aqueous phase was extracted with EtOAc (3 x 10 mL). The combined organics were washed with 0.1 M aqueous HCl (15 mL), brine (15 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was then dissolved in MeOH (2 mL) and H ₂ O (1 mL). Sodium periodate (455 mg, 2.13 mmol) was added to the above solution. The reaction was stirred at ambient temperature for 15 min. EtOAc (5 mL) and water (5 mL) were added to the reaction vessel and the resulting biphasic mixture was transferred to a separatory funnel. The layers were separated and the aqueous phase was extracted with DCM:MeOH = 10:1 (3×5 mL). The combined organics were washed with brine (2×10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography with a gradient elution from petroleum ether (95%) and EtOAc (5%) to petroleum ether (55%) and EtOAc (45%) to provide ( R )-2-{3-[(3-methylyl-1,2,4-thiadiazol-5-yl)oxy]phenyl}morpholine-4-carboxylic acid tert-butyl ester. d. Synthesis of (R)-2-(3-((3-( hydroxymethyl )-1,2,4- thiadiazol -5- yl ) oxy ) phenyl ) morpholine- 4- carboxylic acid tert-butyl ester

To a solution of ( R )-2-{3-[(3-methylyl-1,2,4-thiadiazol-5-yl)oxy]phenyl}morpholine-4-carboxylic acid tributyl ester (160 mg, 408 µmol) in THF (2 mL) was added _NaBH4 (46.1 mg, 1.22 mmol). The reaction mixture was cooled to 0 °C and stirred at that temperature for 15 min. Water (5 mL) and EtOAc (5 mL) were added to the reaction vessel and the resulting biphasic mixture was transferred to a separatory funnel. The layers were separated and the aqueous _phase was extracted with EtOAc (3 x 5 mL). The combined organics were dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography with a gradient elution from petroleum ether (90%) and EtOAc (10%) to petroleum ether (60%) and EtOAc (40%) to provide ( R )-2-(3-{[3-(hydroxymethyl)-1,2,4-thiadiazol-5-yl]oxy}phenyl)-4-carboxylic acid tert-butyl ester. e. Synthesis of (R)-2-(3-((3-( methoxymethyl )-1,2,4 -thiadiazol -5- yl ) oxy ) phenyl ) -4- carboxylic acid tert-butyl ester

To a solution of ( R )-tributyl 2-(3-{[3-(hydroxymethyl)-1,2,4-thiadiazol-5-yl]oxy}phenyl)morpholine-4-carboxylate (50 mg, 127 µmol) in DMF (2 mL) was added sodium hydride (9.14 mg, 381 µmol) and iodomethane (18.0 mg, 127 µmol). The reaction mixture was cooled to 0 °C and stirred at that temperature for 30 min. Water (5 mL) and EtOAc (5 mL) were added to the reaction vessel and the resulting biphasic mixture was transferred to a separatory funnel. The layers were separated and the aqueous phase was extracted with EtOAc (3 x 5 mL). The combined organics were washed with brine (2×10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography with a gradient elution from petroleum ether (95%) and EtOAc (5%) to petroleum ether (75%) and EtOAc (25%) to provide ( R )-2-(3-{[3-(methoxymethyl)-1,2,4-thiadiazol-5-yl]oxy}phenyl)-4-carboxylic acid tributyl ester. f. Synthesis of (R)-2-(3-((3-( methoxymethyl )-1,2,4- thiadiazol -5- yl ) oxy ) phenyl ) -4-carboxylic acid

To a solution of ( R )-2-(3-{[3-(methoxymethyl)-1,2,4-thiadiazol-5-yl]oxy}phenyl)porphyrin-4-carboxylic acid tributyl ester (29 mg, 71.1 µmol) in DCM (1 mL) was added HCl/ _Et2O (2 mL). The reaction was stirred at ambient temperature for 30 min. The reaction vessel was concentrated in vacuo and washed with _Et2O (3 x 2 mL) to provide ( R )-2-(3-{[3-(methoxymethyl)-1,2,4-thiadiazol-5-yl]oxy}phenyl)porphyrin ( Compound 71 ) as the HCl salt.

Compound 71. MS (ESI+): m/z 308 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ 7.57 (t, J = 7.8 Hz, 1H). 7.51-7.42 (m, 3H), 4.86-4.83 (m, 1H), 4.48 (s, 2H), 4.27 (d, J = 12.6 Hz, 1H), 4.00 (t, J = 13.2 Hz, 1H), 3.53 (d, J = 12.6 Hz, 1H), 3.43 (s, 3H), 3.40-3.33 (m, 2H), 3.11 (t, J = 11.7 Hz, 1H).

Example 49. Synthesis of ( R )-2-(3-( Phenoxy ) thiazole - 5- carbonitrile ( Compound 72 ) a. Synthesis of (R)-2-(3-((5- aminoformylthiazol -2- yl ) oxy ) phenyl ) -2- (4- carboxylic acid tributyl ester

To a solution of ( R )-2-(3-hydroxyphenyl)morpholine-4-carboxylic acid tributyl ester ( Compound I -2-9- peak 1 , 100 _mg , 357 µmol) in DMF (2 mL) was added 5-bromothiazole-2-carbonitrile (134 mg, 714 µmol), CuBr (10.2 mg, 71.4 µmol), _Cs2CO3 (290 mg, 892 _µmol ) and 2,2,6,6-tetramethylheptane-3,5-dione (52.4 mg, 285 µmol) under N2. The reaction was stirred at 120 °C for 16 h. Water (6 mL) was added to the reaction vessel and the resulting mixture was extracted with EtOAc (3×10 mL). The combined organics were washed with brine, dried over _{anhydrous Na2SO4} , filtered and concentrated in vacuo. The resulting mixture was purified by flash column chromatography using isocratic elution with ethane (70%) and EtOAc (30%) to provide ( R )-2-{3-[(5-aminoformyl-1,3-thiazol-2-yl)oxy]phenyl}pyroline-4-carboxylic acid tert-butyl ester ( Compound I -49-1 ). b. Synthesis of (R)-2-(3-((5- cyanothiazol -2- yl ) oxy ) phenyl ) pyroline- 4- carboxylic acid tert-butyl ester

To a solution of ( R )-2-{3-[(5-aminoformyl-1,3-thiazol-2-yl)oxy]phenyl}morpholine-4-carboxylic acid tributyl ester ( Compound I -49-1 , 40 mg, 98.6 µmol) in dioxane (1 mL) was added pyridine (38.8 mg, 492 µmol) and TFAA (51.6 mg, 246 µmol). The reaction was stirred at 30 °C for 16 h. The reaction was concentrated in vacuo. The resulting mixture was purified by flash column chromatography using isocratic elution with ethane (85%) and EtOAc (15%) to provide ( R )-2-{3-[(5-cyano-1,3-thiazol-2-yl)oxy]phenyl}morpholine-4-carboxylic acid tributyl ester ( Compound I -49-2 ). c. Synthesis of ( R )-2-(3-(morpholine-2-yl)phenoxy)thiazole-5-carbonitrile

To a solution of ( R )-2-{3-[(5-cyano-1,3-thiazol-2-yl)oxy]phenyl}pyroline-4-carboxylic acid tributyl ester ( Compound I -49-2 , 20 mg, 51.6 µmol) in DCM (1 mL) was added TFA (0.2 mL). The reaction was stirred at ambient temperature for 30 min. The reaction was concentrated in vacuo to provide 2-{3-[( R )-pyroline-2-yl]phenoxy}-1,3-thiazole-5-carbonitrile (13.8 mg, 48.1 µmol) as a colorless oil. To a solution of 2-{3-[( R )-Phenoxy-2-yl]-phenoxy}-1,3-thiazole-5-carbonitrile (14 mg, 48.7 µmol) in _Et2O (1 mL) was added HCl/ _Et2O (3M, 1 mL). The reaction was stirred at ambient temperature for 5 min. The reaction was concentrated in vacuo. The residue was washed with _Et2O (3 x 2 mL) to provide 2-{3-[( R )-Phenoxy-2-yl]-phenoxy}-1,3-thiazole-5-carbonitrile ( Compound 72 ) as the HCl salt.

Compound 72. MS (ESI+): m/z 288 (MH ⁺ ); ^1H NMR (300 MHz, _CD3OD ) δ 7.95 (s, 1H), 7.55 (t, J = 7.8 Hz, 1H), 7.47 -7.37 (m, 3H), 4.84 (d, J = 11.1 Hz, 1H), 4.26 (d, J = 12.6 Hz, 1H), 4.00 (t, J = 13.2 Hz, 1H), 3.52 (d, J = 12.3 Hz, 1H), 3.38-3.33 (m, 2H), 3.10 (t, J = 12.0 Hz, 1H).

Example 50. Synthesis of ( R )-2-(3-((3- methylisothiazol -5- yl ) oxy ) phenyl ) pyroline ( Compound 73)

Compound 73 was synthesized from compound 1-2-9 - peak 1 and 5-bromo-3-methylisothiazole using a nucleophilic substitution and subsequent deprotection procedure similar to that in Example 4 .

Compound 73. MS (ESI+): m/z 277 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ 7.51 (t, J = 8.1 Hz, 1H), 7.37-7.34 (m, 2H), 7.30-7.27 (m, 1H), 6.59 (s, 1H), 4.82 (d, J = 11.4 Hz, 1H), 4.26 (d, J = 13.2 Hz, 1H), 4.00 (t, J = 13.2 Hz, 1H), 3.51 (d, J = 13.2 Hz, 1H), 3.39- 3.33 (m, 2H), 3.09 (t, J = 12.0 Hz, 1H), 2.36 (s, 3H).

Example 51. Synthesis of ( R )-2-(3-((3 -methyl -1,2,4- thiadiazol -5- yl ) oxy ) phenyl ) pyroline ( Compound 74)

Compound 74 was synthesized from compound 1-2-9 - peak 1 and 5-bromo-3-methyl-1,2,4-thiadiazole as the HCl salt using a nucleophilic substitution and subsequent deprotection procedure similar to that in Example 4 .

Compound 74. MS (ESI+): m/z 278 (MH ⁺ ); ^1H NMR (300 MHz, _CD3OD ) δ 7.56 (t, J = 8.1 Hz, 1H), 7.48-7.40 (m, 3H), 4.83-4.78 (m, 1H), 4.27 (d, J = 12.6 Hz, 1H), 4.00 (t, J = 11.4 Hz, 1H), 3.53 (d, J = 12.0 Hz, 1H), 3.40-3.34 (m, 2H), 3.11 (t, J = 11.7 Hz, 1H), 2.43 (s, 3H).

Example 52. Synthesis of ( R )-2-(3-((4 -methylthiazol -2- yl ) oxy ) phenyl ) pyroline ( Compound 75)

Compound 75 was synthesized from compound 1-2-9 - peak 1 and 2-bromo-4-methylthiazole as the HCl salt using a coupling and subsequent deprotection procedure similar to that in Example 1 .

Compound 75. MS (ESI+): m/z 277 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ 7.54 (t, J = 7.8 Hz, 1H), 7.42-7.39 (m, 2H), 7.35-7.33 (m, 1H), 6.72 (s, 1H), 4.85 (d, J = 11.7 Hz, 1H), 4.26 (d, J = 10.2 Hz, 1H), 4.01 (t, J = 12.3 Hz, 1H), 3.51 (d, J = 12.6 Hz, 1H), 3.38- 3.32 (m, 2H), 3.09 (t, J = 11.7 Hz, 1H), 2.29 (s, 3H).

Example 53. Synthesis of ( R )-2-(5-((1,3,4- thiadiazol -2- yl ) oxy )-2- fluorophenyl ) pyroline ( Compound 76)

Compound 76 was synthesized from compound 1-1-5- peak 1 and 2-bromo-1,3,4-thiadiazole as the HCl salt using a nucleophilic substitution and subsequent deprotection procedure similar to that in Example 4 .

Compound 76. MS (ESI+): m/z 282 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ 9.04 (s, 1H), 7.61-7.58 (m, 1H), 7.46 -7.40 (m , 1H), 7.30 (t, J = 9.0 Hz, 1H), 5.11 (d, J = 11.1 Hz, 1H), 4.27 (d, J = 13.5 Hz, 1H), 4.03 (t, J = 11.7 Hz, 1H), 3.54 (d, J = 12.3 Hz, 1H), 3.38- 3.33 (m, 2H), 3.13 (t, J = 11.4 Hz, 1H).

Example 54. Synthesis of 3-(3-( pyrrolidine -2- yl ) phenoxy )-1,2,4 -thiadiazol -5- amine ( Compound 77) a. Synthesis of 3- bromo -1,2,4 - thiadiazol-5 - amine

To a solution of 3-bromo-5-chloro-1,2,4-thiadiazole ( compound I -54-1 , 4 g, 20.0 mmol) in EtOH (12 mL) was added ammonium hydroxide (2.8 mL, 20.0 mmol). The reaction mixture was heated to 70 °C and stirred at that temperature for 3 h. Water (10 mL) was added to the reaction vessel and the resulting mixture was extracted with DCM (5×20 mL). The combined organics were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to provide 3-bromo-1,2,4-thiadiazol-5-amine ( compound I -54-2 ). b. Synthesis of tributyl (3- bromo -1,2,4- thiadiazol -5- yl ) carbamate

To a solution of 3-bromo-1,2,4-thiadiazol-5-amine ( compound I -54-2 , 2.5 g, 13.8 mmol) in THF (30 mL) was added di-tert-butyl dicarbonate (3.60 g, 16.5 mmol) and DMAP (84.1 mg, 690 µmol). The reaction mixture was heated to 50 °C and stirred at that temperature for 2 h. The resulting mixture was purified by flash column chromatography with isocratic elution of EtOAc (10%) and petroleum ether (90%) to provide tri-butyl N- (3-bromo-1,2,4-thiadiazol-5-yl)carbamate ( compound I -54-3 ). c. Synthesis of (R)-2-(3-((5-(( tert-butyloxycarbonyl ) amino )-1,2,4 -thiadiazol -3- yl ) oxy ) phenyl ) morpholine- 4- carboxylic acid tert-butyl ester

To a solution of ( R )-2-(3-hydroxyphenyl)morpholine-4-carboxylic acid tert-butyl ester ( Compound I -2-9- peak 1 , 760 mg, 2.72 mmol) in toluene (10 mL) was added tert-butyl N- (3-bromo-1,2,4-thiadiazol-5-yl)carbamate ( Compound I -54-3 , 1.14 g, 4.08 mmol _{), Cs2CO3 (} 886 mg, 2.72 mmol) and XPhos-Pd-G3 (230 mg, 272 µmol). The reaction was stirred at 105 °C under _N2 for 24 h. Water (40 mL) was added to the reaction vessel and the resulting two-phase mixture was transferred to a separatory funnel. The layers were separated and the aqueous phase was extracted with EtOAc (3×40 mL). The combined organics were washed with brine, dried over _{anhydrous Na2SO4} , filtered and concentrated in vacuo. The resulting mixture was purified by flash column chromatography using isocratic elution with hexane (50%) and EtOAc (50%) to provide ( R )-2-{3-[(5-{[(tri-butyloxy)carbonyl]amino}-1,2,4-thiadiazol-3-yl)oxy]phenyl}-morpholine-4-carboxylic acid tert-butyl ester ( Compound I -54-4 ). d. Synthesis of (R)-2-(3-((5- amino -1,2,4- thiadiazol -3 - yl ) oxy ) phenyl ) morpholine -4- carboxylic acid tert- butyl ester

To a solution of ( R )-2-{3-[(5-{[(tri-butyloxy)carbonyl]amino}-1,2,4-thiadiazol-3-yl)oxy]phenyl}morpholine-4-carboxylic acid tri-butyl ester ( Compound I -54-4 , 670 mg, impure) in DCM (10 mL) was added TFA (3 mL). The reaction was stirred at ambient temperature for 4 h. A saturated aqueous solution of _NaHCO3 was added to the reaction vessel until the pH reached 10. EtOAc (10 mL) and di-tri-butyl dicarbonate (700 mg, 3.20 mmol) were added. The reaction was stirred at ambient temperature for 2 h. The resulting biphasic mixture was transferred to a separatory funnel. The layers were separated and the aqueous phase was extracted with EtOAc (3×10 mL). _The combined organics were dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo. The resulting mixture was purified by flash column chromatography using isocratic elution with hexanes (75%) and EtOAc (25%) to provide ( R )-2-{3-[(5-amino-1,2,4-thiadiazol-3-yl)oxy]phenyl}morpholine-4-carboxylic acid tributyl ester ( Compound I -54-5 ). e. Synthesis of (R)-3-(3-( morpholin -2- yl ) phenoxy )-1,2,4- thiadiazol -5- amine

To a solution of ( R )-2-{3-[(5-amino-1,2,4-thiadiazol-3-yl)oxy]phenyl}pyroline-4-carboxylic acid tributyl ester ( Compound I -54-5 , 25 mg, 66.0 µmol) in (3M) HCl/diethyl ether (1 mL). The reaction was stirred at ambient temperature for 2 h. The reaction was concentrated in vacuo and the residue was washed with _Et2O (3 x 4 mL) to provide 3-{3-[( R )-pyrolin-2-yl]phenoxy}-1,2,4-thiadiazol-5-amine ( Compound 77 ) as a 2HCl salt.

Compound 77. MS (ESI+): m/z 279 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD): δ 7.45 (t, J = 7.8 Hz, 1H), 7.34-7.24 (m, 3H) , 4.86 (d, J = 11.7 Hz, 1H), 4.25 (d, J = 10.5 Hz, 1H), 3.99 (t, J = 9.9 Hz, 1H), 3.50 (d, J = 11.4 Hz, 1H), 3.41 - 3.34 (m, 1H), 3.28 - 3.21 (m, 1H), 3.09 (t, J = 12.0 Hz, 1H).

Example 55. Synthesis of ( R )-2-(3-((5 -methyl -1,3,4- thiadiazol - 2- yl ) oxy ) phenyl ) pyroline ( Compound 78)

Compound 78 was synthesized from compound 1-2-9 - peak 1 and 2-bromo-5-methyl-1,3,4-thiadiazole as the HCl salt using a nucleophilic substitution and subsequent deprotection procedure similar to that in Example 4 .

Compound 78. MS (ESI+): m/z 278 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ 7.52 (t, J = 7.8 Hz, 1H), 7.44 (s, 1H), 7.39- 7.32 (m, 2H), 4.86 (d, J = 9.3 Hz, 1H), 4.25 (d, J = 13.5 Hz, 1H), 4.00 (t, J = 12.9 Hz, 1H), 3.51 (d, J = 12.9 Hz, 1H), 3.39-3.34 (m, 1H), 3.28- 3.23 (m, 1H), 3.09 (t, J = 12.0 Hz, 1H), 2.65 (s, 3H).

Example 56. Synthesis of ( R )-5-(3-( oxoline -2- yl ) phenoxy ) bromothiazol -2- amine ( Compound 79) a. Synthesis of (R)-2-(3-((2- aminothiazol -5- yl ) oxy ) phenyl ) oxoline -4- carboxylic acid tributyl ester

To a solution of ( _R )-2-(3-hydroxyphenyl)morpholine-4-carboxylic acid tributyl ester ( Compound I -2-9- peak 1 , 300 mg, 1.07 mmol) in THF (5 mL) was added NaH (213 mg, 5.35 mmol) under N2. The reaction was stirred at ambient temperature for 30 min. 5-Bromo- 1,3 -thiazol-2-amine (383 mg, 2.14 mmol) was then added to the reaction. The reaction was stirred at ambient temperature for 16 h. A saturated aqueous solution of _NH4Cl (5 mL) was added to the reaction vessel and the resulting biphasic mixture was transferred to a separatory funnel. The layers were separated and the aqueous phase was extracted with EtOAc (3 x 5 mL). _The combined organics were dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography with isocratic elution from EtOAc (5%) and petroleum ether (95%) to EtOAc (40%) and petroleum ether (60%) to provide ( R )-2-{3-[(2-amino-1,3-thiazol-5-yl)oxy]phenyl}morpholine-4-carboxylic acid tributyl ester ( Compound I -56-1 ). b. Synthesis of (R)-5-(3-( morpholin -2- yl ) phenoxy ) thiazol -2- amine

To a solution of ( R )-2-(3-((2-aminothiazol-5-yl)oxy)phenyl)pyroline-4-carboxylic acid tributyl ester ( compound I -56-1 , 20 mg, 52.9 µmol) in _Et2O (1 mL) was added HCl/ _Et2O (3M, 1 mL). The reaction was stirred at ambient temperature for 4 h. The mixture was filtered and concentrated in vacuo to provide 5-{3-[( R )-pyrolin-2-yl]phenoxy}-1,3-thiazol-2-amine ( compound 79 ) as a 2HCl salt.

Compound 79. MS (ESI+): m/z 278 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ 7.47 (t, J = 12.3 Hz, 1H), 7.30-7.26 (m, 2H), 7.21 (d, J = 8.4 Hz, 1H), 7.12 (s, 1H), 4.85-4.80 (m, 1H), 4.25 (d, J = 9.9 Hz, 1H), 4.01 (t, J = 11.4 Hz, 1H), 3.50 (d, J = 12.9 Hz, 1H), 3.41- 3.35 (m, 1H), 3.28-3.22 (m, 1H), 3.08 (t, J = 12.0 Hz, 1H).

Example 57. Synthesis of ( R )-5- methyl -4-(3-( oxolin -2- yl ) phenoxy ) isoxazol -3- amine ( Compound 80)

Compound 80 was synthesized from compound 1-2-9 - pyridine -1 and 4-bromo-5-methylisoxazol-3-amine as a 2HCl salt using a nucleophilic substitution and subsequent deprotection procedure similar to that in Example 4 .

Compound 80 . MS (ESI+): m/z 276 (MH+); ¹ H NMR (300 MHz, CD ₃ OD) δ 7.37 (t, J = 7.8 Hz, 1H), 7.10 (d, J = 8.1 Hz, 1H ), 7.03-6.98 (m, 2H), 4.74 (d, J = 10.5 Hz, 1H), 4.24 (d, J = 11.7 Hz, 1H), 3.97 (t, J = 11.7 Hz, 1H), 3.45 (d, J = 12.9 Hz, 1H), 3.39-3.33 (m, 1H) , 3.28-3.20 (m, 1H), 3.05 (t, J = 11.4 Hz, 1H), 2.15 (s, 3H).

Example 58. Synthesis of ( R )-2-(3-((2- methylthiazol -5- yl ) oxy ) phenyl ) pyroline ( Compound 81)

Compound 81 was synthesized from compound 1-2-9 - peak 1 and 5-bromo-2-methylthiazole as the HCl salt using a coupling and subsequent deprotection procedure similar to that in Example 1 .

Compound 81. MS (ESI+): m/z 277 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ 7.58 (s, 1H), 7.47 (t, J = 8.1 Hz, 1H), 7.30- 7.27 (m, 2H), 7.20 (d, J = 7.5 Hz, 1H), 4.81 (d, J = 11.4 Hz, 1H), 4.24 (d, J = 11.1 Hz, 1H), 3.99 (t, J = 13.5 Hz, 1H), 3.49 (m, J = 12.3 Hz, 1H) , 3.38-3.33 (m, 2H), 3.07 (t, J = 12.0 Hz, 1H), 2.78 (s, 3H).

Example 59. Synthesis of ( R )-3- methyl -4-(3-( oxazol -2- yl ) phenoxy ) isoxazol -5- amine ( Compound 82) a. Synthesis of (R)-2-(3-((5 -amino -3- methylisoxazol -4- yl ) oxy ) phenyl ) oxazol -4- carboxylic acid tributyl ester

To a solution of ( R )-2-(3-hydroxyphenyl)morpholine-4-carboxylic acid tributyl ester ( Compound I -2-9- peak 1 , 100 mg, 357 µmol) in DMF (2 mL) was added sodium hydride (21.3 mg, 535 µmol) at 0°C. The reaction was stirred at 0°C for 30 min. Pd(PPh ₃ ) ₂ Cl ₂ (25.0 mg, 35.7 µmol) and 4-bromo-3-methyl-1,2-oxazol-5-amine (69.3 mg, 392 µmol) were then added. The reaction mixture was heated to 50°C and stirred at that temperature for 16 h. Water (6 mL) was added to the reaction vessel. The mixture was extracted with EtOAc (2×2 mL). The layers were separated and the organic phase was washed with brine (2×2 mL). The combined organics were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography with a gradient elution from EtOAc (10%) and petroleum ether (90%) to EtOAc (20%) and petroleum ether (80%) to provide ( R )-2-{3-[(5-amino-3-methyl-1,2-oxazol-4-yl)oxy]phenyl}oxazol-4-carboxylic acid tributyl ester ( Compound I -59-1 ). b. Synthesis of (R)-3- methyl -4-(3-( oxazol -2- yl ) phenoxy ) isoxazol -5- amine

To a solution of ( R )-2-{3-[(5-amino-3-methyl-1,2-oxazol-4-yl)oxy]phenyl}oxoline-4-carboxylic acid tributyl ester ( Compound I -59-1 , 18 mg, 47.9 µmol) in DCM (0.2 mL) was added HCl/ _Et2O (0.2 mL). The reaction was stirred at ambient temperature for 1 h. The solvent was evaporated. The solid was washed with _Et2O (0.5 mL) to provide 3-methyl-4-{3-[( R )-oxoline-2-yl]phenoxy}-1,2-oxazol-5-amine ( Compound 82 ) as a 2HCl salt.

Compound 82. MS (ESI+): m/z 276 (MH+); ¹ H NMR (300 MHz, CD ₃ OD) δ 7.35 (t, J = 7.8 Hz, 1H), 7.07 (d, J = 7.8 Hz, 1H ), 7.00-6.95 (m, 2H), 4.74 (d, J = 10.2 Hz, 1H), 4.24 (d, J = 13.8 Hz, 1H), 3.97 (t, J = 13.2 Hz, 1H), 3.44 (d, J = 12.6 Hz, 1H), 3.37-3.33 (m, 1H) , 3.28-3.20 (m, 1H), 3.05 (t, J = 12.6 Hz, 1H), 1.98 (s, 3H).

Example 60. Synthesis of ( R )-2-(3-((4-( pyridin -2- yl ) thiazol -2- yl ) oxy ) phenyl ) pyroline ( Compound 83)

Compound 83 was synthesized from compound 1-2-9 - peak 1 and 2-bromo-4-(pyridin-2-yl)thiazole as a 2HCl salt using a coupling and subsequent deprotection procedure similar to that in Example 1 .

Compound 83. MS (ESI+): m/z 340 (MH ⁺ ); ^1H NMR (300 MHz, _CD3OD ): δ 8.74-8.54 (m, 3H), 8.38 (s, 1H), 7.97 (t, J = 5.7 Hz, 1H), 7.58-7.44 (m, 4H), 4.89-4.82 (m, 1H), 4.25 (d, J = 13.2 Hz, 1H), 4.04 (t, J = 11.4 Hz, 1H), 3.54 (d, J = 12.3 Hz, 1H), 3.38-3.31 (m, 2H), 3.12 (t, J = 12.6 Hz, 1H).

Example 61. Synthesis of ( R )-2-(3-((5 -methylthiazol -2- yl ) oxy ) phenyl ) pyroline ( Compound 84)

Compound 84 was synthesized from compound 1-2-9 - peak 1 and 2-bromo-5-methylthiazole as the HCl salt using a coupling and subsequent deprotection procedure similar to that in Example 1 .

Compound 84. MS (ESI+): m/z 277 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD): δ 7.50 (t, J = 7.5 Hz, 1H), 7.38-7.34 (m, 2H) , 7.28 (d, J = 8.1 Hz, 1H), 6.98 (s, 1H), 4.82 (d, J = 10.8 Hz, 1H), 4.25 (d, J = 10.8 Hz, 1H), 3.99 (t, J = 10.2 Hz, 1H), 3.50 (d, J = 12.3 Hz, 1H) , 3.38-3.25 (m, 2H), 3.08 (t, J = 11.7 Hz, 1H), 2.37 (s, 3H).

Example 62. Synthesis of ( R )-2-(3-((2-( methoxymethyl ) thiazol -4- yl ) oxy ) phenyl ) pyroline ( Compound 85)

Compound 85 was synthesized from compound 1-2-9 - peak 1 and 4-bromo-2-(methoxymethyl)thiazole as the HCl salt using a coupling and subsequent deprotection procedure similar to that in Example 1 .

Compound 85. MS (ESI+): m/z 307 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD): δ 7.40 (t, J = 8.1 Hz, 1H), 7.19 (d, J = 7.8 Hz , 1H), 7.14 (s, 1H), 7.04 (d, J = 8.4 Hz, 1H), 6.70 (s, 1H), 4.77 (d, J = 9.6 Hz, 1H), 4.65 (s, 2H), 4.25 (d, J = 13.2 Hz, 1H), 3.97 (t, J = 14.4 Hz, 1H), 3.48 (s, 3H), 3.46 (d, J = 11.4 Hz, 1H), 3.35-3.05 (m, 2H), 3.07 (t, J = 11.4 Hz, 1H).

Example 63. Synthesis of ( R )-2-(2- fluoro -5-((2-( methoxymethyl ) thiazol -4- yl ) oxy ) phenyl ) pyroline ( Compound 86)

Compound 86 was synthesized from compound 1-1-5 - peak 1 and 4-bromo-2-(methoxymethyl)thiazole as the HCl salt using a coupling and subsequent deprotection procedure similar to that in Example 1 .

Compound 86. MS (ESI+): m/z 325 (MH ⁺ ); ^1H NMR (300 MHz, _CD3OD ): δ 7.26-7.24 (m, 1H), 7.21-7.08 (m, 2H), 6.67 (s, 1H), 5.07 (d, J = 10.5 Hz, 1H), 4.64 (s, 2H), 4.25 (d, J = 13.2 Hz, 1H), 4.01 (t, J = 11.7 Hz, 1H), 3.56-3.52 (m, 1H), 3.48 (s, 3H), 3.37-3.24 (m, 2H), 3.09 (t, J = 12.3 Hz, 1H).

Example 64. Synthesis of ( R )-2-(3-((4 -methylthiazol -5- yl ) oxy ) phenyl ) pyroline ( Compound 87)

Compound 87 was synthesized from compound 1-2-9 - peak 1 and 5-bromo-4-methylthiazole as the HCl salt using a coupling and subsequent deprotection procedure similar to that in Example 1 .

Compound 87 . MS (ESI+): m/z 277 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD): δ 9.15 (s, 1H), 7.45 (t, J = 8.1 Hz, 1H), 7.27 -7.22 (m, 2H), 7.10 (d, J = 7.8 Hz, 1H), 4.81 (d, J = 11.1 Hz, 1H), 4.23 (d, J = 11.4 Hz, 1H), 3.99 (t, J = 11.1 Hz, 1H), 3.49 (d, J = 12.6 Hz, 1H) , 3.43-3.42 (m, 1H), 3.30-3.23 (m, 1H), 3.07 (t, J = 11.7 Hz, 1H), 2.34 (s, 3H).

Example 65. Synthesis of ( R )-3- methyl -4-(3-( oxazol -2- yl ) phenoxy ) isoxazol -5- amine ( Compound 88) a. Synthesis of (R)-2-(3-((3 -methylisoxazol -4- yl ) oxy ) phenyl ) oxazol -4- carboxylic acid tributyl ester

To a solution of ( R )-2-{3-[(5-amino-3-methyl-1,2-oxazol-4-yl)oxy]phenyl}morpholine-4-carboxylic acid tributyl ester ( compound 1-59-1 , 100 mg, 266 µmol, see Example 59) in AcOH/ _H2O /THF (1 mL/1 mL/1 mL) was slowly added sodium nitrite (183 mg, 2.66 mmol). The reaction was stirred at ambient temperature for 2 h. A saturated aqueous solution _{of Na2CO3} (5 mL) was added to the reaction vessel and extracted with EtOAc (2×5 mL). The layers were separated and the organic phase was washed with a saturated aqueous solution of NaCl (2×5 mL). The combined organics were dried over _{anhydrous Na2SO4} , filtered and concentrated in vacuo. The resulting oil was purified by preparative thin layer chromatography using isocratic elution with EtOAc (25%) and petroleum ether (75%) to provide ( R )-2-{3-[(3-methyl-1,2-oxazol-4-yl)oxy]phenyl}oxoline-4-carboxylic acid tributyl ester ( Compound I -65-1 ). b. Synthesis of (R)-2-(3-((3- methylisoxazol -4 -yl ) oxy ) phenyl ) oxoline

To a solution of ( R )-2-{3-[(3-methyl-1,2-oxazol-4-yl)oxy]phenyl}pyroline-4-carboxylic acid tributyl ester ( Compound I -65-1 , 26.9 mg, 74.6 µmol) in DCM (0.5 mL) was added HCl/ _Et2O (0.5 mL). The reaction was stirred at ambient temperature for 1 h. The solvent was evaporated to give a viscous oil. The resulting oil was washed with _Et2O (2×1 mL) and evaporated to dryness in vacuo to provide ( R )-2-{3-[(3-methyl-1,2-oxazol-4-yl)oxy]phenyl}pyroline ( Compound 88 ) as the HCl salt.

Compound 88. MS (ESI+): m/z 261 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD): δ 8.62 (s, 1H), 7.40 (t, J = 7.8 Hz, 1H), 7.16 (d, J = 7.8 Hz, 1H), 7.11 (s, 1H), 7.04 (d, J = 8.4 Hz, 1H), 4.76 (d, J = 11.1 Hz, 1H), 4.23 (d, J = 12.3 Hz, 1H), 3.98 (t, J = 11.7 Hz, 1H), 3.46 ( d, J = 12.3 Hz, 1H), 3.35-3.20 (m, 2H), 3.06 (t, J = 11.7 Hz, 1H), 2.15 (s, 3H).

Example 66. Synthesis of ( R )-2-(3-((5-( trifluoromethyl )-1,3,4- thiadiazol -2- yl ) oxy ) phenyl ) pyroline ( Compound 89)

Compound 89 was synthesized from compound 1-2-9 - peak 1 and 2-chloro-5-(trifluoromethyl)-1,3,4-thiadiazole as the HCl salt using a nucleophilic substitution and subsequent deprotection procedure similar to that in Example 4 .

Compound 89. MS (ESI+): m/z 332 (MH ⁺ ); ^1H NMR (300 MHz, _CD3OD ): δ 7.57-7.55 (m, 2H), 7.46-7.43 (m, 2H), 4.86 (d, J = 12.3 Hz, 1H), 4.26 (d, J = 12.3 Hz, 1H), 4.00 (t, J = 11.7 Hz, 1H), 3.53 (d, J = 12.3 Hz, 1H), 3.38-3.30 (m, 2H), 3.11 (t, J = 11.4 Hz, 1H).

Example 67. Synthesis of ( R )-2-(3-((6- fluorobenzo [ d ] thiazol -2- yl ) oxy ) phenyl ) pyroline ( Compound 90)

Compound 90 was synthesized from compound I -2-9- peak 1 and 2-bromo-6-fluorobenzo[ d ]thiazole as the HCl salt using a coupling and subsequent deprotection procedure similar to that in Example 1 .

Compound 90. MS (ESI+): m/z 331 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD): δ 7.62-7.59 (m, 2H), 7.53 (d, J = 7.8 Hz, 1H), 7.47 (s, 1H), 7.42-7.39 (m, 2H), 7.19 (t, J = 6.3 Hz, 1H), 4.85 (d, J = 11.7 Hz, 1H), 4.26 (d, J = 11.4 Hz, 1H), 4.00 (t, J = 11.1 Hz, 1H), 3.53 (d, J = 12.9 Hz, 1H), 3.37-3.31 (m, 2H), 3.12 (t, J = 12.3 Hz, 1H).

Example 68. Synthesis of ( R )-2-(3-( pyrrolidine -2- yl ) phenoxy ) thiazole -4- carbonitrile ( Compound 91) a. Synthesis of (R)-2-(3-((4- cyanothiazol -2- yl ) oxy ) phenyl ) pyrrolidine -4- carboxylic acid tributyl ester

To a solution of ( R )-2-(3-hydroxyphenyl)morpholine-4-carboxylic acid tributyl ester ( Compound I -2-9- peak 1 , 120 mg, 429 µmol) in DMF (4 mL) was added 2,2,6,6-tetramethylheptane-3,5-dione (63.2 mg, 343 µmol), 2-bromo-1,3-thiazole-4-carbonitrile (162 mg, 858 µmol), cesium carbonate (348 mg, 1.07 mmol) and cuprous bromide (6.13 mg, 42.9 µmol). The reaction mixture was heated to 120 °C and stirred at that temperature for 16 h. Water (12 mL) was added to the reaction vessel and the resulting mixture was extracted with EtOAc (3×10 mL). The combined organics were dried over anhydrous _{Na2SO4 ,} filtered and concentrated in vacuo. The resulting mixture was purified by flash column chromatography using isocratic elution with EtOAc (25%) and petroleum ether (75%) to provide ( R )-2-{3-[(4-cyano-1,3-thiazol-2-yl)oxy]phenyl}morpholine-4-carboxylic acid tributyl ester ( Compound I -68-1 ). b. Synthesis of (R)-2-(3-( morpholin -2- yl ) phenoxy ) thiazole -4- carbonitrile

To a solution of ( R )-2-{3-[(4-cyano-1,3-thiazol-2-yl)oxy]phenyl}morpholine-4-carboxylic acid tributyl ester ( Compound I -68-1 , 100 mg, 258 µmol) in DCM (3 mL) was added TFA (0.6 mL, 258 µmol). _A saturated aqueous solution of NaHCO3 (5 mL ₎ was added to the reaction vessel and the resulting biphasic mixture was transferred to a separatory funnel. The layers were separated and the aqueous phase was extracted with EtOAc (3×5 mL). The combined organics were dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography eluting with isocratic mixtures of MeOH (10%) and DCM (90%) to provide 2-{3-[( R )-morpholin-2-yl]phenoxy}-1,3-thiazole-4-carbonitrile free base.

To a solution of 2-{3-[( R )-Zorin-2-yl]phenoxy}-1,3-thiazole-4-carbonitrile (60 mg, 208 µmol) in _Et2O (2 mL) was added HCl/ _Et2O (3 M, 0.1 mL). The reaction was stirred at ambient temperature for 5 min. The resulting solid was washed with _Et2O (3 x 2 mL) to provide 2-{3-[( R )-Zorin-2-yl]phenoxy}-1,3-thiazole-4-carbonitrile ( Compound 91 ) as the HCl salt.

Compound 91. MS (ESI+): m/z 288 (MH ⁺ ); ^1H NMR (300 MHz, _CD3OD ): δ 8.01 (s, 1H), 7.54 (t, J = 7.8 Hz, 1H), 7.44-7.34 (m, 3H), 4.83 (d, J = 11.7 Hz, 1H), 4.26 (d, J = 11.7 Hz, 1H), 3.98 (t, J = 10.2 Hz, 1H), 3.52 (d, J = 12.9 Hz, 1H), 3.37-3.30 (m, 2H), 3.11 (t, J = 11.4 Hz, 1H).

Example 69. Synthesis of ( R )-2-(3-( thiazolo [5,4- b ] pyridin -2 -yloxy ) phenyl ) pyroline ( Compound 92)

Compound 92 was synthesized from compound I -2-9- peak 1 and 2-bromothiazolo[5,4- b ]pyridine as the HCl salt using a coupling and subsequent deprotection procedure similar to that in Example 1 .

Compound 92. MS (ESI+): m/z 314 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD): δ 8.42 (d, J = 3.6 Hz, 1H), 7.99 (d, J = 8.1 Hz, 1H), 7.60-7.54 (m, 1H), 7.50-7.47 (m, 2H), 7.45-7.42 (m, 2H), 4.85 (d, J = 11.7 Hz, 1H), 4.26 (d, J = 12.0 Hz, 1H), 4.00 (t, J = 11.1 Hz, 1H), 3.53 (d, J = 12.3 Hz, 1H), 3.37-3.30 (m, 2H), 3.13 (t, J = 12.6 Hz, 1H).

Example 70. Synthesis of ( R )-2-(3-((2- methylthiazol -4- yl ) oxy ) phenyl ) pyroline ( Compound 93)

Compound 93 was synthesized from compound 1-2-9 - peak 1 and 4-bromo-2-methylthiazole as the HCl salt using a coupling and subsequent deprotection procedure similar to that in Example 1 .

Compound 93. MS (ESI+): m/z 277 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD): δ 7.41-7.39 (m, 1H), 7.22-7.16 (m, 2H), 7.06 (d, J = 8.1 Hz, 1H), 6.55 (s, 1H), 4.78 (d, J = 11.7 Hz, 1H), 4.23 (d, J = 12.3 Hz, 1H), 3.98 (t, J = 11.7 Hz, 1H), 3.47 (d, J = 12.6 Hz, 1H), 3.36-3.24 (m, 2H), 3.07 (t, J = 12.3 Hz, 1H), 2.67 (s, 3H).

Example 71. Synthesis of ( R )-2-(2- fluoro -5-((2- methylthiazol -4- yl ) oxy ) phenyl ) pyroline ( Compound 94)

Compound 94 was synthesized from compound 1-1-5 - peak 1 and 4-bromo-2-methylthiazole using a coupling and subsequent deprotection procedure similar to that in Example 1 .

Compound 94. MS (ESI+): m/z 295 (MH ⁺ ); ^1H NMR (300 MHz, _CD3OD ): δ 7.26-7.07 (m, 3H), 6.49 (s, 1H), 5.06 (d, J = 11.4 Hz, 1H), 4.25 (d, J = 12.6 Hz, 1H), 4.01 (t, J = 8.1 Hz, 1H), 3.50 (d, J = 12.3 Hz, 1H), 3.37-3.30 (m, 2H), 3.10 (t, J = 12.0 Hz, 1H), 2.64 (s, 3H).

Example 72. Synthesis of ( R )-2-(3-((5- fluorothiazol -2- yl ) oxy ) phenyl ) pyroline ( Compound 95)

Compound 95 was synthesized from compound 1-2-9 - peak 1 and 2-bromo-5-fluorothiazole as the HCl salt using a coupling and subsequent deprotection procedure similar to that in Example 1 .

Compound 95. MS (ESI+): m/z 281 (MH ⁺ ); ^1H NMR (300 MHz, _CD3OD ): δ 7.51 (t, J = 7.8 Hz, 1H), 7.37-7.27 (m, 3H), 6.93 (s, 1H), 4.79 (d, J = 11.4 Hz, 1H), 4.25 (d, J = 11.4 Hz, 1H), 3.97 (t, J = 11.4 Hz, 1H), 3.49 (d, J = 13.2 Hz, 1H), 3.40-3.30 (m, 2H), 3.08 (t, J = 12 Hz, 1H).

Example 73. Synthesis of ( R )-2-(3-((5- methylthiazol -4- yl ) oxy ) phenyl ) pyroline ( Compound 96)

Compound 96 was synthesized from compound 1-2-9 - peak 1 and 4-bromo-5-methylthiazole as the HCl salt using a coupling and subsequent deprotection procedure similar to that in Example 1 .

Compound 96. MS (ESI+): m/z 277 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD): δ 8.72 (s, 1H), 7.35 (t, J = 7.8 Hz, 1H), 7.11 (d, J = 7.5 Hz, 1H), 7.01 (s, 1H), 6.88 (d, J = 8.1 Hz, 1H), 4.75 (d, J = 11.1 Hz, 1H), 4.22 (d, J = 11.1 Hz, 1H), 3.97 (t, J = 11.1 Hz, 1H), 3.45 ( d, J = 12.9 Hz, 1H), 3.30-3.23 (m, 2H), 3.05 (t, J = 11.7 Hz, 1H), 2.31 (s, 3H).

Example 74. Synthesis of ( R )-2-(2- fluoro -5-((5- methylthiazol -4- yl ) oxy ) phenyl ) pyroline ( Compound 97)

Compound 97 was synthesized from compound 1-1-5 - peak 1 and 4-bromo-5-methylthiazole using a coupling and subsequent deprotection procedure similar to that in Example 1 .

Compound 97. MS (ESI+): m/z 295 (MH ⁺ ); ^1H NMR (300 MHz, _CD3OD ): δ 8.70 (s, 1H), 7.13-7.09 (m, 2H), 6.97-6.92 (m, 1H), 5.05 (d, J = 11.4 Hz, 1H), 4.24 (d, J = 12.6 Hz, 1H), 4.00 (t, J = 11.4 Hz, 1H), 3.49 (d, J = 11.7 Hz, 1H), 3.36-3.30 (m, 2H), 3.07 (t, J = 11.4 Hz, 1H), 2.32 (s, 3H).

Example 75. Synthesis of ( R )-2-(3-((1,2,4- thiadiazol -3- yl ) oxy ) phenyl ) pyroline ( Compound 98) a. Synthesis of (R)-2-(3-((5-(( tert-butyloxycarbonyl ) amino )-1,2,4- thiadiazol -3- yl ) oxy ) phenyl ) pyroline -4- carboxylic acid tributyl ester

To a solution of ( R )-2-(3-hydroxyphenyl)morpholine-4-carboxylic acid tert-butyl ester ( Compound I -2-9- peak 1 , 760 mg, 2.72 mmol) in toluene (10 mL) was added tert-butyl N- (3-bromo-1,2,4-thiadiazol-5-yl)carbamate (1.14 g, 4.08 mmol), _Cs2CO3 ( ₈₈₆ mg, 2.72 mmol) and XPhos-Pd-G3 (230 mg, 272 µmol). The reaction was stirred at 105 °C under _N2 for 24 h. Water (40 mL) was added to the reaction vessel and the resulting two-phase mixture was transferred to a separatory funnel. The layers were separated and the aqueous phase was extracted with EtOAc (3×40 mL). The combined organics were washed with brine, dried over _{anhydrous Na2SO4} , filtered and concentrated in vacuo. The resulting mixture was purified by flash column chromatography using isocratic elution with ethane (50%) and EtOAc (50%) to provide ( R )-2-{3-[(5-{[(tri-butyloxy)carbonyl]amino}-1,2,4-thiadiazol-3-yl)oxy]phenyl}-pyroline-4-carboxylic acid tert-butyl ester ( Compound I -75-1 ). b. Synthesis of (R)-2-(3-((5 -amino -1,2,4- thiadiazol-3 - yl ) oxy ) phenyl ) -pyroline -4- carboxylic acid tert-butyl ester

To a solution of ( R )-2-{3-[(5-{[(tri-butyloxy)carbonyl]amino}-1,2,4-thiadiazol-3-yl)oxy]phenyl}morpholine-4-carboxylic acid tri-butyl ester ( Compound I -75-1 , 670 mg, 741 µmol) in DCM (10 mL) was added TFA (3 mL). The reaction was stirred at ambient temperature for 4 h. A saturated aqueous solution _{of Na2CO3} was added to the reaction vessel until the pH was adjusted to 10. EtOAc (10 mL) and di-tri-butyl dicarbonate (700 mg, 3.20 mmol) were added to the mixture. The reaction was stirred at ambient temperature for 2 h. The resulting biphasic mixture was transferred to a separatory funnel. The layers were separated and the aqueous phase was extracted with EtOAc (3×10 mL). _The combined organics were dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo. The resulting mixture was purified by flash column chromatography using isocratic elution with ethane (75%) and EtOAc (25%) to provide ( R )-2-{3-[(5-amino-1,2,4-thiadiazol-3-yl)oxy]phenyl}morpholine-4-carboxylic acid tert-butyl ester ( Compound I -75-2 ). c. Synthesis of (R)-2-[3-(1,2,4- thiadiazol -3 -yloxy ) phenyl ] morpholine- 4- carboxylic acid tert-butyl ester

To a solution of ( R )-2-{3-[(5-amino-1,2,4-thiadiazol-3-yl)oxy]phenyl}morpholine-4-carboxylic acid tributyl ester ( Compound I -75-2 , 90 mg, 237 µmol) in dioxane (3 mL) was added tributyl nitrite (26.8 mg, 260 µmol). The reaction was stirred at 50 °C for 1 h. A saturated aqueous solution of NaHSO ₃ was added to the reaction vessel and the resulting biphasic mixture was transferred to a separatory funnel. The layers were separated and the aqueous phase was extracted with EtOAc (3×5 mL). The combined organics were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting mixture was purified by flash column chromatography using isocratic elution with ethane (80%) and EtOAc (20%) to provide ( R )-2-[3-(1,2,4-thiadiazol-3-yloxy)phenyl]morpholine-4-carboxylic acid tributyl ester ( Compound I -75-3 ). d. Synthesis of (R)-2-(3-((1,2,4- thiadiazol -3- yl ) oxy ) phenyl ) morpholine

To a solution of ( R )-2-[3-(1,2,4-thiadiazol-3-yloxy)phenyl]pyroline-4-carboxylic acid tributyl ester ( Compound I -75-3 , 53 mg, 145 µmol) in _Et2O (0.5 mL) was added HCl/ _Et2O (3M, 0.5 mL). The reaction was stirred at ambient temperature for 2 h. The reaction was concentrated in vacuo and the residue was washed with _Et2O (3×4 mL) to provide ( R )-2-[3-(1,2,4-thiadiazol-3-yloxy)phenyl]pyroline ( Compound 98 ) as the HCl salt.

Compound 98. MS (ESI+): m/z 264 (MH ⁺ ); ^1H NMR (300 MHz, _CD3OD ): δ 10.05 (s, 1H), 7.51 (t, J = 7.8 Hz, 1H), 7.40-7.30 (m, 3H), 4.83 (d, J = 11.1 Hz, 1H), 4.27 (d, J = 12.0 Hz, 1H), 4.02 (t, J = 11.7 Hz, 1H), 3.52 (d, J = 12.9 Hz, 1H), 3.39-3.27 (m, 2H), 3.12 (t, J = 12.0 Hz, 1H).

Example 76. Synthesis of ( R )-2-(5-((1,2,4- thiadiazol -3- yl ) oxy )-2- fluorophenyl ) pyroline ( Compound 99)

Compound 99 was synthesized from compound 1-1-5 - peak 1 and (3-bromo-1,2,4-thiadiazol-5-yl)carbamic acid tert-butyl ester as the HCl salt using a coupling and subsequent deprotection procedure similar to that in Example 75 .

Compound 99. MS (ESI+): m/z 282 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD): δ 10.02 (s, 1H), 7.50-7.49 (m, 1H), 7.35-7.33 ( m, 1H), 7.27-7.21 (m, 1H), 5.09 (d, J = 11.1 Hz, 1H), 4.27 (d, J = 10.8 Hz, 1H), 4.01 (t, J = 11.4 Hz, 1H), 3.53 (d, J = 12.6 Hz, 1H), 3.31- 3.28 (m, 2H), 3.12 (t, J = 12.0 Hz, 1H).

Example 77. Synthesis of ( R )-2-(3-((1,2,4- thiadiazol -5- yl ) oxy ) phenyl ) pyroline ( Compound 100)

Compound 100 was synthesized from compound 1-2-9 - peak 1 and 5-bromo-1,2,4-thiadiazole as the HCl salt using a nucleophilic substitution and subsequent deprotection procedure similar to that in Example 4 .

Compound 100. MS (ESI+): m/z 264 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD): δ 8.21 (s, 1H), 7.57 (t, J = 7.8 Hz, 1H), 7.51 (s, 1H), 7.46-7.41 (m, 2H), 4.83 (d, J = 10.8 Hz, 1H), 4.27 (d, J = 10.5 Hz, 1H), 4.00 (t, J = 12.0 Hz, 1H), 3.52 (d, J = 13.2 Hz, 1H), 3.37-3.30 (m, 2H), 3.11 (t, J = 11.4 Hz, 1H).

Example 78. Synthesis of ( R )-2-(5-((1,2,4- thiadiazol -5- yl ) oxy )-2- fluorophenyl ) pyroline ( Compound 101)

Compound 101 was synthesized from compound 1-1-5 - pyridine and 5-bromo-1,2,4-thiadiazole as the HCl salt using a nucleophilic substitution and subsequent deprotection procedure similar to that in Example 4 .

Compound 101. MS (ESI+): m/z 282 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD): δ 8.21 (s, 1H), 7.64-7.61 (m, 1H), 7.51-7.47 ( m, 1H), 7.33 (t, J = 9.3 Hz, 1H), 5.11 (d, J = 11.1 Hz, 1H), 4.27 (d, J = 10.2 Hz, 1H), 4.03 (t, J = 11.7 Hz, 1H), 3.55 (d, J = 12.3 Hz, 1H) , 3.39-3.30 (m, 2H), 3.13 (t, J = 11.4 Hz, 1H).

Example 79. Synthesis of ( R )-2-(3-( thiazol -4- yloxy ) phenyl ) morpholine ( Compound 102)

Compound 102 was synthesized from compound 1-2-9 - peak 1 and 4-bromothiazole as the HCl salt using a coupling and subsequent deprotection procedure similar to that in Example 1 .

Compound 102. MS (ESI+): m/z 263 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD): δ 8.88 (s, 1H), 7.41 (t, J = 7.8 Hz, 1H), 7.20 (d, J = 7.8 Hz, 1H), 7.15 (s, 1H), 7.05 (d, J = 8.1 Hz, 1H), 6.79 (d, J = 2.1 Hz, 1H), 4.78 (d, J = 11.1 Hz, 1H), 4.22 (d, J = 10.2 Hz, 1H), 3.99 ( t, J = 11.7 Hz, 1H), 3.47 (d, J = 12.9 Hz, 1H), 3.34-3.28 (m, 2H), 3.07 (t, J = 11.7 Hz, 1H).

Example 80. Synthesis of ( R )-2-(2- fluoro -5-( thiazol -4- yloxy ) phenyl ) pyroline ( Compound 103)

Compound 103 was synthesized from compound 1-1-5 - peak 1 and 4-bromothiazole as the HCl salt using a coupling and subsequent deprotection procedure similar to that in Example 1 .

Compound 103. MS (ESI+): m/z 281 (MH ⁺ ); ^1H NMR (300 MHz, _CD3OD ): δ 8.85 (s, 1H), 7.27-7.25 (m, 1H), 7.21-7.11 (m, 2H), 6.76 (d, J = 2.4 Hz, 1H), 5.06 (d, J = 11.1 Hz, 1H), 4.26 (d, J = 10.5 Hz, 1H), 4.00 (t, J = 11.4 Hz, 1H), 3.50 (d, J = 13.2 Hz, 1H), 3.32-3.29 (m, 2H), 3.09 (t, J = 11.4 Hz, 1H).

Example 81. Synthesis of ( R )-2-(3-( thiazol -2- yloxy ) phenyl ) pyroline ( Compound 104)

Compound 104 was synthesized from compound 1-2-9 - peak 1 and 2-bromothiazole as the HCl salt using a coupling and subsequent deprotection procedure similar to that in Example 1 .

Compound 104. MS (ESI+): m/z 263 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD): δ 7.51 (t, J = 7.8 Hz, 1H), 7.39-7.31 (m, 2H) , 7.29-7.26 (m, 2H), 7.11 (d, J = 3.6 Hz, 1H), 4.82 (d, J = 11.1 Hz, 1H), 4.25 (d, J = 10.5 Hz, 1H), 3.99 (t, J = 11.1 Hz, 1H), 3.51 (d, J = 12.9 Hz , 1H), 3.37-3.30 (m, 2H), 3.09 (t, J = 12.0 Hz, 1H).

Example 82. Synthesis of ( R )-2-(3-((1- methyl - 1H - pyrazol -3- yl ) oxy ) phenyl ) pyroline ( Compound 105)

Compound 105 was synthesized from compound 1-2-9 - peak 1 and 3-bromo-1-methyl- 1H -pyrazole as the HCl salt using a coupling and subsequent deprotection procedure similar to that in Example 1 .

Compound 105. MS (ESI+): m/z 260 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD): δ 7.51 (s, 1H), 7.36 (t, J = 8.1 Hz, 1H), 7.15 (s, 2H), 7.06 (d, J = 8.4 Hz, 1H), 5.79 (s, 1H), 4.75 (d, J = 11.4 Hz, 1H), 4.23 (d, J = 12.6 Hz, 1H), 3.97 (t, J = 10.8 Hz, 1H), 3.79 (s, 3H), 3.45 (d, J = 11.4 Hz, 1H), 3.32-3.26 (m, 2H), 3.08 (t, J = 12 Hz, 1H).

Example 83. Synthesis of ( R )-2-(3-((1- methyl - 1H - imidazol -4- yl ) oxy ) phenyl ) pyroline ( Compound 106)

Compound 106 was synthesized from compound 1-2-9 - peak 1 and 4-bromo-1-methyl- 1H -imidazole as the HCl salt using a coupling and subsequent deprotection procedure similar to that in Example 1 .

Compound 106. MS (ESI+): m/z 260 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD): δ 8.60 (s, 1H), 7.51 (t, J = 8.1 Hz, 1H), 7.35-7.32 (m, 2H), 7.23 (d, J = 7.2 Hz, 1H), 7.16 (s, 1H), 4.75-4.73 (m, 1H), 4.23 (d, J = 13.5 Hz, 1H), 4.04 (t, J = 12.6 Hz, 1H), 3.91 (s, 3H), 3.53 (d, J = 12.0 Hz, 1H), 3.46-3.23 (m, 2H), 3.12 (t, J = 11.7 Hz, 1H).

Example 84. Synthesis of ( R )-2-(2- fluoro -5-( thiazol -2- yloxy ) phenyl ) pyroline ( Compound 107)

Compound 107 was synthesized from compound 1-1-5 - peak 1 and 2-bromothiazole as the HCl salt using a coupling and subsequent deprotection procedure similar to that in Example 1 .

Compound 107. MS (ESI+): m/z 281 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD): δ 7.53-7.51 (m, 1H), 7.40-7.34 (m, 1H), 7.31- 7.24 (m, 2H), 7.12 (d, J = 3.9 Hz, 1H), 5.11 (d, J = 10.8 Hz, 1H), 4.26 (d, J = 12.3 Hz, 1H), 4.03 (t, J = 11.7 Hz, 1H), 3.53 (d, J = 12.3 Hz, 1H) , 3.38-3.30 (m, 2H), 3.12 (t, J = 12.0 Hz, 1H).

Example 85. Synthesis of ( R )-2- ( 2- fluoro -5- ( oxazol - 2 - yloxy ) phenyl ) pyroline ( Compound 108) a. Synthesis of (R)-2-(2- fluoro -5-( oxazol -2 -yloxy ) phenyl ) pyroline -4- carboxylic acid tributyl ester

Compound I-85-1 was synthesized from compound I - 1-5-1 and 2-bromooxazole using a coupling procedure similar to that in Example 1. b. Synthesis of ( R )-2-(2- fluoro -5-( oxazol -2- yloxy ) phenyl ) oxoline

Compound ( R )-2-[2-fluoro-5-(1,3-oxazol-2-yloxy)phenyl]morpholine-4-carboxylic acid tributyl ester ( Compound I -85-1 , 48 mg, 131 µmol) was added to a mixture of PhOH in DCM (4M, 0.6 mL) and TMSCI in DCM (4M, 0.2 mL). The reaction was stirred at ambient temperature for 1 h. Aqueous NaOH (1 M, 1 mL) was added to the reaction vessel and the resulting biphasic mixture was transferred to a separatory funnel. The layers were separated and the aqueous phase was extracted with DCM (3×2 mL). The combined organics were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography with isocratic elution in DCM (95%) and MeOH (5%) to provide ( R )-2-[2-fluoro-5-(1,3-oxazol-2-yloxy)phenyl]morpholine. To a solution of ( R )-2-[2-fluoro-5-(1,3-oxazol-2-yloxy)phenyl]morpholine (29 mg, 109 µmol) in _Et2O (1 mL) was added HCl/ _Et2O (3M, 0.1 mL). The reaction was stirred at ambient temperature for 5 min. The mixture was filtered and evaporated to dryness in vacuo to provide ( R )-2-[2-fluoro-5-(1,3-oxazol-2-yloxy)phenyl]morpholine ( Compound 108 ) as an HCl salt.

Compound 108. MS (ESI+): m/z 265 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD): δ 7.60 (s, 1H), 7.54-7.53 (m, 1H), 7.41-7.35 ( m, 1H), 7.26 (t, J = 9.6 Hz, 1H), 6.94 (s, 1H), 5.08 (d, J = 11.1 Hz, 1H), 4.27 (d, J = 11.1 Hz, 1H), 4.00 (t, J = 11.1 Hz, 1H), 3.52 (d, J = 11.4 Hz, 1H), 3.37-3.30 (m, 2H), 3.12 (t, J = 11.7 Hz, 1H).

Example 86. Synthesis of ( R )-2-(3-( thiazol -5- yloxy ) phenyl ) morpholine ( Compound 109)

Compound 109 was synthesized from compound 1-2-9 - peak 1 and 5-bromothiazole using a coupling and subsequent deprotection procedure similar to that in Example 1 .

Compound 109. MS (ESI+): m/z 263 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD): δ 8.82 (s, 1H), 7.60 (s, 1H), 7.45 (t, J = 8.1 Hz, 1H), 7.26-7.24 (m, 2H), 7.18-7.15 (m, 1H), 4.78 (d, J = 11.1 Hz, 1H), 4.23 (d, J = 12.6 Hz, 1H), 3.97 (t, J = 11.4 Hz, 1H), 3.48 (d, J = 12.6 Hz, 1H), 3.36-3.30 (m, 2H ) , 3.0 Hz, 1H).

Example 87. Synthesis of ( R )-2-(2- fluoro -5-( thiazol -5- yloxy ) phenyl ) pyroline ( Compound 110)

Compound 110 was synthesized from compound 1-1-5 - peak 1 and 5-bromothiazole as the HCl salt using a coupling and subsequent deprotection procedure similar to that in Example 1 .

Compound 110. MS (ESI+): m/z 281 (MH ⁺ ); ^1H NMR (300 MHz, _CD3OD ): δ 8.76 (s, 1H), 7.56 (s, 1H), 7.35-7.34 (m, 1H), 7.23-7.21 (m, 2H), 5.06 (d, J = 11.1 Hz, 1H), 4.26 (d, J = 12.3 Hz, 1H), 4.00 (t, J = 11.1 Hz, 1H), 3.50 (d, J = 10.5 Hz, 1H), 3.45-3.34 (m, 2H), 3.08 (t, J = 12.0 Hz, 1H).

Example 88. Synthesis of ( R )-2-(3-((1- methyl - 1H - pyrazol -4- yl ) oxy ) phenyl ) pyroline ( Compound 111)

Compound 111 was synthesized from compound 1-2-9 - peak -1 and 4-bromo-1-methyl- 1H -pyrazole as the HCl salt using a coupling and subsequent deprotection procedure similar to that in Example 1 .

Compound 111. MS (ESI+): m/z 260 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD): δ 7.54 (s, 1H), 7.36-7.31 (m, 2H), 7.08-7.06 (m, 2H), 7.00 (d, J = 8.1 Hz, 1H), 4.73 (d, J = 9.6 Hz, 1H), 4.23 (d, J = 12.3 Hz, 1H), 3.96 (t, J = 13.2 Hz, 1H), 3.87 (s, 3H), 3.44 (d, J = 12.0 Hz, 1H), 3.31-3.23 (m, 2H), 3.05 (t, J = 11.7 Hz , 1H ) . Example 89. Synthesis of ( R * ) - 2- ( 3 - methyl - 5- ( indole - 3 - yloxy ) phenyl ... ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Compound I-89-2 was synthesized from 3-bromo-5-methylphenol and tert-butyl 2-(3-methyl-5-hydroxyphenyl)-4-carboxylate using a procedure similar to that in Example 1. b. Chiral separation of tert -butyl 2-(3- methyl -5- hydroxyphenyl ) -4- carboxylate 2-(3-Methyl-5-hydroxyphenyl)morpholine-4-carboxylic acid tributyl ester was separated by chiral column separation using the following: Instrument: SFC-150 (Thar, Waters) Column: AD 25×250mm, 10µm (Daicel) Column temperature: 35℃ Mobile phase: CO ₂ /IPA (0.01% methylamine/methanol) = 85/15 Flow rate: 100 g/min Back pressure: 100 bar Detection wavelength: 220 nm Cycle time: 2.0 min Sample solution: 2.7 g dissolved in 20 mL methanol Injection volume: 0.5 mL Chiral analysis conditions: Instrument: Waters 2695; Column: Reflect C-Amylose A 4.6×250mm, 5µm; column temperature: 30℃; mobile phase: n-hexane/ i -PrOH (0.1% DEA) = 90/10; flow rate: 1.0 mL/min; detection wavelength: 220 nm; detector: W2996 PDA. After the solvent was removed, the first eluting isomer ( R* )-2-(3-methyl-5-hydroxyphenyl)-4-carboxylic acid tert-butyl ester ( Compound I-89-3- peak 1 , retention time from the analytical column = 8.79 min) and the second eluting isomer ( S* )-2-(3-methyl-5-hydroxyphenyl)-4-carboxylic acid tert-butyl ester ( Compound I-89-3- peak 2 , retention time from the analytical column = 13.23 min) were obtained. c. Synthesis of (R*)-2-(3- methyl -5-( indole - 3 -yloxy ) phenyl ) -4- carboxylic acid ( Compound 112 ) Compound 112 was synthesized from compound I-89-3- pyridinium and 3-bromoindole as a 2HCl salt using a similar synthetic procedure as in Example 1 . Compound 112. MS (ESI+): m/z 272 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ 9.29 (d, J = 4.2 Hz, 1H), 8.33-8.29 (m, 1H), 8.06 (d, J = 9.0 Hz, 1H), 7.24 (s, 1H), 7.19 (s , 1H), 7.13 (s , 1H), 4.82 (d, J = 11.1 Hz, 1H), 4.23 (dd, J = 12.6, 2.7 Hz, 1H), 4.01 (td, J = 12.6, 2.7 Hz, 1H), 3.51 (d, J = 12.9 Hz, 1H), 3.37-3.30 (m, 1H), 3.29-3.23 (m, 1H), 3.09 (t, J = 12.0 Hz, 1H), 2.41 (s , 3H). d. Synthesis of (S*)-2-(3- methyl -5-( indole - 3 -yloxy ) phenyl ) pyroline ( Compound 113 ) Compound 113 was synthesized from compound I-89-3- pyrrole 2 and 3-bromoindole as a 2HCl salt using a similar synthetic procedure as in Example 1 . Compound 113. MS (ESI+): m/z 272 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ 9.30 (d, J = 4.2 Hz, 1H), 8.34-8.30 (m, 1H), 8.07 (d, J = 9.0 Hz, 1H), 7.24 (s, 1H), 7.19 (s , 1H), 7.13 (s , 1H), 4.84 (d, J = 11.1 Hz, 1H), 4.23 (dd, J = 12.6, 2.7 Hz, 1H), 4.01 (td, J = 12.6, 2.7 Hz, 1H), 3.50 (d, J = 12.9 Hz, 1H), 3.37-3.30 ( m , 1H ) , 3.29-3.23 ( m , 1H), 3.09 ( t, J = 12.0 Hz , 1H ), 2.41 ( s , 3H ) . Example 90. Synthesis of ( R * ) - 2- ( 2,4 - difluoro - 5- ( indole - 3 - yloxy ) phenyl ... Compound I-90-2 was synthesized from 5-bromo-2,4-difluorophenol and tert- butyl 2-oxo-pyroline-4-carboxylate using a procedure similar to that in Example 1. b. Synthesis of tert-butyl 2-(2,4 -difluoro -5-( pyrox -3 -yloxy ) phenyl ) pyroline -4 - carboxylate Compound I-90-3 was synthesized from compound I-90-2 and 3-bromopyrimidine in the form of 2HCl salt using a synthetic procedure similar to that in Example 1. c. Chiral separation of tributyl 2-(2,4 -difluoro -5-( pyrimidine - 3 -yloxy ) phenyl ) morpholine -4- carboxylate Tributyl 2-(2,4-difluoro-5-(tazoline-3-yloxy)phenyl)morpholine-4-carboxylate was separated by chiral column separation using the following: Instrument: SFC-150 (Thar, Waters) Column: AD 25×250mm, 10µm (Daicel) Column temperature: 35℃ Mobile phase: CO ₂ /IPA (0.01% methylamine/methanol) = 90/10 Flow rate: 100 g/min Back pressure: 100 bar Detection wavelength: 220 nm Cycle time: 1.5 min Sample solution: 68 mg dissolved in 3 mL methanol Injection volume: 1.0 mL Chiral analysis conditions: Instrument: Waters 2695; Column: Reflect C-Amylose A 4.6×250mm, 5µm; column temperature: 30℃; mobile phase: n-hexane/ i -PrOH (0.1% DEA) = 85/15; flow rate: 1.0 mL/min; detection wavelength: 254 nm; detector: W2996 PDA. After the solvent was removed, the first eluting isomer ( R* )-2-(2,4-difluoro-5-(indole-3-yloxy)phenyl)-4-carboxylic acid tert-butyl ester ( Compound I-90-4- peak 1 , retention time from the analytical column = 11.59 min) and the second eluting isomer ( S* )-2-(2,4-difluoro-5-(indole-3-yloxy)phenyl)-4-carboxylic acid tert-butyl ester ( Compound I-90-4- peak 2 , retention time from the analytical column = 13.04 min) were obtained . d. Synthesis of (R*)-2-(2,4- difluoro -5-( indole - 3- yloxy ) phenyl ) -4-carboxylic acid tert- butyl ester ( Compound 114 ) Compound 114 was synthesized using a similar synthetic procedure as in Example 1 from compound I-90-4- peak 1 and HCl/ _Et2O as a 2HCl salt. Compound 114. MS (ESI+): m/z 294 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ 9.20 (d, J = 4.5 Hz, 1H), 8.16-8.11 (m, 1H), 7.94 (d, J = 9.0 Hz, 1H), 7.56-7.50 (m, 1H), 7.19 (t, J = 9.3 Hz, 1H), 5.22 (d, J = 8.7 Hz, 1H), 4.20 (dd, J = 12.9, 2.1 Hz, 1H), 4.00 (td, J = 13.2, 3.0 Hz, 1H), 3.64-3.52 (m, 2H), 3.39-3.34 (m, 1H), 3.25-3.22 (m, 1H). e. Synthesis of (S*)-2-(2,4 -difluoro -5-( indole - 3- yloxy ) phenyl ) pyroline ( Compound 115 ) Compound 115 was synthesized using a similar synthetic procedure as in Example 1 from compound I-90-4- peak 2 and HCl/ _Et2O as a 2HCl salt. Compound 115. MS (ESI+): m/z 294 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ 9.19 (d, J = 4.5 Hz, 1H), 8.15-8.10 (m, 1H), 7.93 (d, J = 9.0 Hz, 1H), 7.56-7.48 (m, 1H), 7.19 (t, J = 9.3 Hz, 1H), 5.21 (d, J = 9.0 Hz, 1H), 4.20 (dd, J = 13.2, 2.4 Hz, 1H), 4.00 (td, J = 13.2, 2.4 Hz, 1H), 3.64-3.52 (m, 2H), 3.43-3.40 (m, 1H), 3.28-3.23 (m, 1H). Example 91. Synthesis of ( R* )-2-(2,3 -difluoro -5- ( indole - 3 - yloxy ) phenyl ) -pyroline ( Compound 116) , ( S* )-2-(2,3 - difluoro -5-( indole -3 -yloxy ) phenyl ) -pyroline ( Compound 117) a. Synthesis of tertiary butyl (3,4 - difluorophenoxy ) dimethylsilane To a solution of 3,4-difluorophenol (8 g, 61.4 mmol) in DCM (160 mL) was added tributyl(chloro)dimethylsilane (13.8 g, 92.1 mmol) and imidazole (10.4 g, 153 mmol). The reaction mixture was cooled to 0 °C and stirred at that temperature for 30 min. Water (100 mL) was added to the reaction vessel and the resulting biphasic mixture was transferred to a separatory funnel. The layers were separated and the aqueous _phase was extracted with DCM (2 x 50 mL). The combined organics were dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo. The obtained oil was purified by flash column chromatography using isocratic elution with petroleum ether (100%) to provide tert-butyl(3,4-difluorophenoxy)dimethylsilane (14.6 g, 59.7 mmol) ( Compound I-91-2 ) as a colorless oil. b. Synthesis of 5-(( tert-butyldimethylsilyl ) oxy )-2,3 -difluorobenzaldehyde To a solution of tert-butyl(3,4-difluorophenoxy)dimethylsilane (14.6 g, 59.7 mmol) and bis[2-(dimethylamino)ethyl](methyl)amine (31.0 g, 179 mmol) in THF (300 mL) was added s -BuLi (59.6 mL, 77.6 mmol) dropwise at -78 °C. The reaction was stirred at -78 °C for 30 min. DMF (5.22 g, 71.6 mmol) was then added. The reaction was stirred at -78 °C to rt for 2 h. A saturated aqueous solution of NH ₄ Cl (100 mL) was added to the reaction vessel and the resulting biphasic mixture was transferred to a separatory funnel. The layers were separated and the aqueous phase was extracted with EtOAc (2×300 mL). _The combined organics were dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography with isocratic elution from petroleum ether (50%) to EtOAc (50%) to provide 5-[(tributyldimethylsilyl)oxy]-2,3-difluorobenzaldehyde (7.50 g, 27.5 mmol) ( Compound I-91-3 ) as a yellow oil. c. Synthesis of tert-butyl (3,4 -difluoro -5- vinylphenoxy ) dimethylsilane To a solution of methyltriphenylphosphonium bromide (17.6 g, 49.5 mmol) in THF (250 mL) was slowly added tert -BuOK (49.5 mL, 49.5 mmol, 1 M in THF) at 0 °C. The reaction was stirred at 0 °C for 30 min. 5-[(tributyldimethylsilyl)oxy]-2,3-difluorobenzaldehyde (7.5 g, 27.5 mmol, dissolved in THF) was added and the reaction was stirred at 0 °C to rt for 4 h. Water (30 mL) was added to the reaction vessel and the resulting biphasic mixture was transferred to a separatory funnel. The layers were separated and the aqueous phase was extracted with EtOAc (3 x 60 mL). The combined organics were dried _over anhydrous _Na2SO4 , filtered and concentrated in vacuo. The obtained oil was purified by flash column chromatography using isocratic elution with EtOAc (5%) and petroleum ether (95%) to provide tert-butyl (3-vinyl-4,5-difluorophenoxy) dimethylsilane (2.20 g, 8.13 mmol) ( Compound I-91-4 ) as a yellow oil. d. Synthesis of tert - butyl 2-(2,3 -difluoro -5-( pyridin - 3 -yloxy ) phenyl ) morpholine -4- carboxylate Compound I-91-5 was synthesized from I-91-4 using procedures similar to those in Example 2 (steps 1 to 5) and Example 1 (step 6). e. Chiral separation of tributyl 2-(2,3 -difluoro -5-( pyridinium - 3 -yloxy ) phenyl ) morpholine- 4- carboxylate Tributyl 2-(2,3-difluoro-5-(tazoline-3-yloxy)phenyl)morpholine-4-carboxylate was separated by chiral column separation using the following: Instrument: SFC-150 (Thar, Waters) Column: AD 25×250mm, 10µm (Daicel) Column temperature: 35℃ Mobile phase: CO ₂ /IPA (0.01% methylamine/methanol) = 90/10 Flow rate: 100 g/min Back pressure: 100 bar Detection wavelength: 220 nm Cycle time: 2.0 min Sample solution: 55 mg dissolved in 2 mL Injection volume: 1.0 mL Chiral analysis conditions: Instrument: Waters 2695; Column: Reflect C-Amylose A 4.6×250mm, 5µm; column temperature: 30℃; mobile phase: n-hexane/ i -PrOH (0.1% DEA) = 85/15; flow rate: 1.0 mL/min; detection wavelength: 254 nm; detector: W2996 PDA. After removing the solvent, the first eluting isomer ( R* )-2-(2,3-difluoro-5-(indole-3-yloxy)phenyl)-4-carboxylic acid tert-butyl ester ( Compound I-91-6- peak 1 , retention time from the analytical column = 9.71 min) and the second eluting isomer ( S* )-2-(2,3-difluoro-5-(indole-3-yloxy)phenyl)-4-carboxylic acid tert-butyl ester ( Compound I-91-6- peak 2 , retention time from the analytical column = 11.06 min) were obtained. f. Synthesis of (R*)-2-(2,3 -difluoro -5-( indole - 3 -yloxy ) phenyl ) -4-carboxylic acid tert-butyl ester ( Compound 116 ) Compound 116 was synthesized using a similar synthetic procedure as in Example 1 from compound I-91-6- peak 1 and HCl/ _Et2O as a 2HCl salt. Compound 116. MS (ESI+): m/z 294 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ 9.15 (d, J = 4.5 Hz, 1H), 8.07-8.02 (m, 1H), 7.87 (d, J = 8.7 Hz, 1H), 7.55-7.47 (m, 1H), 7.18 (t, J = 8.7 Hz, 1H), 5.21 (d, J =8.7 Hz, 1H), 4.21 (d, J =10.8 Hz, 1H), 4.04-3.94 (m, 1H), 3.63-3.51 (m, 2H), 3.48-3.34 (m, 2H). g. Synthesis of (S*)-2-(2,3 -difluoro -5-( pyridazine - 3- yloxy ) phenyl ) pyroline ( Compound 117 ) Compound 117 was synthesized using a similar synthetic procedure as in Example 1 from compound I-91-6- peak 2 and HCl/ _Et2O as a 2HCl salt. Compound 117. MS (ESI+): m/z 294 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ 9.15 (d, J = 4.5 Hz, 1H), 8.09-8.04 (m, 1H), 7.86 (d, J = 8.7 Hz, 1H), 7.55-7.47 (m, 1H), 7.18 (t, J = 8.9 Hz, 1H), 5.21 (d, J =8.7 Hz, 1H), 4.21 (d, J =12.3 Hz, 1H), 4.00 (td, J = 11.1, 3.0 Hz, 1H), 3.63-3.51 (m, 2H), 3.48-3.34 (m, 2H). Example 92. Synthesis of ( R * )-2-(3- fluoro -5-( pyrimidin - 5-yloxy ) phenyl ) -2-(3- fluoro -5-( pyrimidin -5 -yloxy ) phenyl )-2-(3-fluoro- 5- (pyrimidin-5-yloxy) phenyl )-2-(3-fluoro-5-(pyrimidin - 5-yloxy ) phenyl )-2-(3 - fluoro-5-(pyrimidin - 5- yloxy ) phenyl ) -2-(3-fluoro- 5- (pyrimidin-5- yloxy ) phenyl ) -2-(3- fluoro -5- (3- hydroxyphenyl ) -2-(3-fluoro -5 - hydroxyphenyl)-2 ... Compound I-92-2 was synthesized from 3-bromo-5-fluorophenol and tert-butyl 2-(3-fluoro-5-hydroxyphenyl)-4-carboxylate using a procedure similar to that in Example 1. b. Chiral separation of tert -butyl 2-(3- fluoro -5 -hydroxyphenyl ) -4- carboxylate 2-(3-Fluoro-5-hydroxyphenyl)morpholine-4-carboxylic acid tributyl ester was separated by chiral column separation using the following: Instrument: SFC-150 (Thar, Waters) Column: AD 25×250mm, 10µm (Daicel) Column temperature: 35℃ Mobile phase: CO ₂ /IPA (0.01% methylamine/methanol) = 90/10 Flow rate: 100 g/min Back pressure: 100 bar Detection wavelength: 220 nm Cycle time: 2.0 min Sample solution: 360 mg dissolved in 20 mL methanol Injection volume: 1 mL Chiral analysis conditions: Instrument: Waters 2695; Column: Regis REFLECT C-Amylose A (4.6×250mm, 5µm); column temperature: 30℃; mobile phase: n-hexane/EtOH (0.1% DEA) = 90/10; flow rate: 0.8 mL/min; detection wavelength: 220 nm; detector: W2996 PDA. After removing the solvent, the first eluting isomer ( R* )-2-(3-fluoro-5-hydroxyphenyl)-4-carboxylic acid tert-butyl ester ( Compound I-92-3- peak 1 , retention time from the analytical column = 9.86 min) and the second eluting isomer ( S* )-2-(3-fluoro-5-hydroxyphenyl)-4-carboxylic acid tert-butyl ester ( Compound I-92-3- peak 2 , retention time from the analytical column = 9.07 min) were obtained. c. Synthesis of ( R* )-2-(3-fluoro-5-(pyrimidin-5-yloxy)phenyl)-4-carboxylic acid ( Compound 118 ) Compound 118 was synthesized from compound I-92-3- pyridinium and 3-bromoindole as a 2HCl salt using a similar synthetic procedure as in Example 4 . Compound 118. MS (ESI+): m/z 276 (MH+); ¹ H NMR (300 MHz, CD ₃ OD) δ 8.99 (s , 1H), 8.61 (s , 2H), 7.09 (d, J = 9.3 Hz, 1H), 7.03 (s , 1H), 6.97 (d, J = 9.6 Hz, 1H), 4.86-4.83 (m , 1H), 4.28-4.22 (m, 1H), 4.01-3.92 (m, 1H), 3.51 (d, J = 12.9 Hz, 1H), 3.38-3.33 (m, 1H), 3.19-3.16 (m, 1H), 3.07 (t, J = 11.6 Hz, 1H). d. Synthesis of ( S* )-2-(3-fluoro-5-(pyrimidin-5-yloxy)phenyl)pyrimidine ( Compound 119 ) Compound 119 was synthesized from compound I-92-3- pyrrole and 3-bromoindole as a 2HCl salt using a similar synthetic procedure as in Example 4 . Compound 119. MS (ESI+): m/z 276 (MH+); ¹ H NMR (300 MHz, CD ₃ OD) δ 9.01 (s, 1H), 8.63 (s, 2H), 7.11 (d, J = 9.3 Hz, 1H), 7.04 (s, 1H), 6.98 (d, J = 9.6 Hz, 1H), 4.86-4.83 (m, 1H), 4.25 (dd, J = 13.2, 3.0 Hz, 1H), 4.02 (td, J = 13.2, 3.0 Hz, 1H), 3.51 (d, J = 12.3 Hz, 1H), 3.41-3.36 (m, 1H), 3.25-3.19 ( m , 1H ) , 3.07 ( t , J = 12.0 Hz , 1H ) . Example 93. Synthesis of ( R * ) - 2- ( 3- ( trifluoromethyl ) phenyl ... trifluoromethyl ) phenyl ) -2- ( 3 ​ ​ ​ ​ ​ ​ ​ ​ Compound I-93-2 was synthesized from 3-bromo-5-(trifluoromethyl)phenol and tert-butyl 2-(3- hydroxy-5-(trifluoromethyl)phenyl)-4-carboxylate using a procedure similar to that in Example 1. b. Chiral separation of tert- butyl 2-(3- hydroxy -5-( trifluoromethyl ) phenyl ) -4- carboxylate Tributyl 2-(3-hydroxy-5-(trifluoromethyl)phenyl)morpholine-4-carboxylate was separated by chiral column separation using the following conditions: Instrument: SFC-150 (Thar, Waters) Column: AD 25×250mm, 10µm (Daicel) Column temperature: 35℃ Mobile phase: CO ₂ /IPA (0.01% methylamine/methanol) = 85/15 Flow rate: 100 g/min Back pressure: 100 bar Detection wavelength: 220 nm Cycle time: 2.0 min Sample solution: 4.5 g dissolved in 50 mL methanol Injection volume: 0.5 mL Chiral analysis conditions: Instrument: Waters 2695; Column: AY-H (4.6×250mm, 5µm); column temperature: 30℃; mobile phase: n-hexane/ i PrOH (0.1% DEA) = 93/7; flow rate: 0.8 mL/min; detection wavelength: 254 nm; detector: W2996 PDA. After the solvent was removed, the first eluting isomer ( R* )-2-(3-hydroxy-5-(trifluoromethyl)phenyl)-4-carboxylic acid tert-butyl ester ( Compound I-93-3- peak 1 , retention time from the analytical column = 7.43 min) and the second eluting isomer ( S* )-2-(3-hydroxy-5-(trifluoromethyl)phenyl)-4-carboxylic acid tert-butyl ester ( Compound I-93-3- peak 2 , retention time from the analytical column = 13.08 min) were obtained. c. Synthesis of (R*)-2-(3-( trifluoromethyl )phenyl)-2-(3- hydroxy -3- yloxy )-5-( trifluoromethyl ) phenyl ) -4 -carboxylic acid tert-butyl ester ( Compound 120 ) Compound 120 was synthesized from compound I-93-3- pyridinium and 3-bromoindole as a 2HCl salt using a similar synthetic procedure as in Example 4 . Compound 120. MS (ESI+): m/z 326 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ 9.27 (d, J = 4.5 Hz, 1H), 8.33-8.22 (m, 1H), 8.03 (d, J = 9.0 Hz, 1H), 7.75 (s, 1H), 7.70 (s, 2H), 5.07-4.93 (m, 1H), 4.29 (dd, J = 12.6, 3.0 Hz, 1H), 4.05 (td, J = 12.6, 3.0 Hz, 1H), 3.60 (d, J = 13.5 Hz, 1H), 3.39-3.30 (m, 2H), 3.13 (t, J = 12.0 Hz, 1H) . d. Synthesis of ( S*)-2-( 3- ( trifluoromethyl ) phenyl ) pyroline ( Compound 121 ) Compound 121 was synthesized from compound I-93-3- pyridinium and 3-bromoindole as a 2HCl salt using a similar synthetic procedure as in Example 4 . Compound 121. MS (ESI+): m/z 326 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ 9.29 (d, J = 4.3 Hz, 1H), 8.30-8.26 (m, 1H), 8.07 (d, J = 9.0 Hz, 1H), 7.75 (s, 1H), 7.70 (s, 2H), 4.98-4.89 (m, 1H), 4.28 (dd, J = 12.6, 3.0 Hz, 1H), 4.05 (td, J = 12.6, 3.0 Hz, 1H), 3.60 (d, J = 13.5 Hz, 1H), 3.40-3.32 (m, 2H), 3.13 ( t , J = 12.0 Hz , 1H ) . Example 94. Synthesis of ( R * ) - 2- ( 4 - methyl - 3- ( indole - 3 - yloxy ) phenyl ... ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Compound I-94-2 was synthesized from 3-bromo-6-methylphenol and tert-butyl 2-(4-methyl-3-hydroxyphenyl)-4-carboxylate using a procedure similar to that in Example 1. b. Chiral separation of tert -butyl 2-(4- methyl -3- hydroxyphenyl ) -4- carboxylate 2-(4-Methyl-3-hydroxyphenyl)morpholine-4-carboxylic acid tributyl ester was separated by chiral column separation using the following: Instrument: SFC-150 (Thar, Waters) Column: AD 25×250mm, 10µm (Daicel) Column temperature: 35℃ Mobile phase: CO ₂ /IPA (0.01% methylamine/methanol) = 88/12 Flow rate: 100 g/min Back pressure: 100 bar Detection wavelength: 220 nm Cycle time: 2.0 min Sample solution: 2.8 g dissolved in 25 mL methanol Injection volume: 0.5 mL Chiral analysis conditions: Instrument: Waters 2695; Column: AY-H (4.6×250mm, 5µm); column temperature: 30℃; mobile phase: n-hexane/ i PrOH (0.1% DEA) = 85/15; flow rate: 0.8 mL/min; detection wavelength: 254 nm; detector: W2996 PDA. After removing the solvent, the first eluting isomer ( R* )-2-(4-methyl-3-hydroxyphenyl)-4-carboxylic acid tert-butyl ester ( Compound I-94-3- peak 1 , retention time from the analytical column = 6.01 min) and the second eluting isomer ( S* )-2-(4-methyl-3-hydroxyphenyl)-4-carboxylic acid tert-butyl ester ( Compound I-94-3- peak 2 , retention time from the analytical column = 7.54 min) were obtained. c. Synthesis of (R*)-2-(4 -methyl -3-( indole - 3- yloxy ) phenyl ) -4 -carboxylic acid ( Compound 122 ) Compound 122 was synthesized from compound I-94-3- pyridinium and 3-bromoindole as a 2HCl salt using a similar synthetic procedure as in Example 4 . Compound 122. MS (ESI+): m/z 272 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ 9.28 (d, J = 4.8 Hz, 1H), 8.31 (dd, J = 9.0, 4.8 Hz, 1H), 8.08 (d, J = 9.0 Hz, 1H), 7.41 (d, J = 8.1 Hz, 1H), 7.33-7.30 (m, 2H), 4.81 (dd, J = 9.6, 1.2 Hz, 1H), 4.25-4.19 (m, 1H), 4.04 (td, J = 13.8, 3.0 Hz, 1H), 3.49 (d, J = 12.9 Hz, 1H), 3.36-3.32 (m, 1H), 3.26-3.22 (m, 1H), 3.09 (t, J = 12.0 Hz, 1H), 2.19 (s, 3H). d. Synthesis of (S*)-2-(4 -methyl -3-( indole - 3 -yloxy ) phenyl ) pyroline ( Compound 123 ) Compound 123 was synthesized from compound I-94-3- pyrrole 2 and 3-bromoindole as a 2HCl salt using a similar synthetic procedure as in Example 4 . Compound 123. MS (ESI+): m/z 272 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ 9.32 (d, J = 4.5 Hz, 1H), 8.37 (dd, J = 9.0, 4.8 Hz, 1H), 8.15 (d, J = 9.0 Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.34-7.32 (m, 2H), 4.82 (d, J = 9.9 Hz, 1H), 4.25-4.19 (m, 1H), 4.00 (td, J = 13.8, 3.0 Hz, 1H), 3.49 (d, J = 12.9 Hz, 1H), 3.36-3.32 (m, 1H), 3.26-3.22 (m, 1H), 3.09 (t, J = 12.0 Hz, 1H), 2.20 (s, 3H). Example 95. Synthesis of ( S* )-5-(3-( indole - 3 - yloxy ) phenyl )-4- oxa -7- azaspiro [2.5] octane ( Compound 124) , ( R* )-5-(3-( indole -3 -yloxy ) phenyl ) -4- oxa -7- azaspiro [2.5] octane ( Compound 125) a. Synthesis of (2-(3-(( tributyldimethylsilyl ) oxy ) phenyl )-2- hydroxyethyl )((1- hydroxycyclopropyl ) methyl ) carbamic acid tributyl ester Compound I-95-1 was synthesized from 3-bromophenol and 1-(aminomethyl)cyclopropan-1-ol using a procedure similar to that in Example 2. b. Synthesis of 5-(3- hydroxyphenyl )-4- oxa -7- azaspiro [2.5] octane -7- carboxylic acid tributyl ester A solution of tert-butyl N- (2-{3-[(tert-butyldimethylsilyl)oxy]phenyl}-2-hydroxyethyl) -N -[(1-hydroxycyclopropyl)methyl]carbamate (3 g, 6.85 mmol) in aqueous HBr (48%, 20 mL) was heated to 90 °C and stirred at that temperature for 2 h. The reaction was neutralized with saturated aqueous NaHCO _3. NaHCO ₃ (5.75 g, 68.4 mmol) and di-tert-butyl dicarbonate (1.64 g, 7.53 mmol) were then added to the reaction vessel. THF (20 mL) was added to the reaction and stirred at ambient temperature for 30 min. EtOAc (20 mL) was added to the reaction vessel and the resulting biphasic mixture was transferred to a separatory funnel. The layers were separated and the aqueous _phase was extracted with EtOAc (3 x 30 mL) and washed with brine (60 mL). The combined organics were dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography with a gradient elution from petroleum ether (95%) and EtOAc (5%) to petroleum ether (80%) and EtOAc (20%) to provide tributyl 5-(3-hydroxyphenyl)-4-oxazolidin-7-azaspiro[2.5]octane-7-carboxylate (370 mg, 1.21 mmol) as a yellow oil. c. Chiral separation of tert-butyl 5-(3- hydroxyphenyl )-4- oxa -7- azaspiro [2.5] octane -7 -carboxylate 5-(3-Hydroxyphenyl)-4-oxa-7-azaspiro[2.5]octane-7-carboxylic acid tributyl ester was separated by chiral column separation using the following: Instrument: SFC-150 (Thar, Waters) Column: AD 25×250mm, 10µm (Daicel) Column temperature: 35℃ Mobile phase: CO ₂ /IPA (0.01% methylamine/methanol) = 93/7 Flow rate: 100 g/min Back pressure: 100 bar Detection wavelength: 220 nm Cycle time: 2.0 min Sample solution: 380 mg dissolved in 10 mL Injection volume: 1.0 mL Chiral analysis conditions: Instrument: Waters 2695; Column: AY-H 4.6×250mm, 5µm; column temperature: 30℃; mobile phase: n-hexane/EtOH (0.1% DEA) = 95/5; flow rate: 1.0 mL/min; detection wavelength: 220 nm; detector: W2996 PDA. After removing the solvent, the first eluting isomer ( R* )-5-(3-hydroxyphenyl)-4-oxa-7-azaspiro[2.5]octane-7-carboxylic acid tert-butyl ester ( Compound I-95-2- peak 1 , retention time from the analytical column = 9.65 min) and the second eluting isomer ( S* )-5-(3-hydroxyphenyl)-4-oxa-7-azaspiro[2.5]octane-7-carboxylic acid tert-butyl ester ( Compound I-95-2- peak 2 , retention time from the analytical column = 7.77 min) were obtained. d. Synthesis of (R*)-5-(3-( tazo - 3 -yloxy ) phenyl )-4- oxa -7- azaspiro [2.5] octane ( Compound 125 ) Compound 125 was synthesized from compound I-95-2- pyridinium and 3-bromopyridinium as a 2HCl salt using a similar synthetic procedure as in Example 4 . Compound 125. MS (ESI+): m/z 284 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ 9.24 (d, J = 4.2 Hz, 1H), 8.24 (dd, J = 9.0, 4.8 Hz, 1H), 7.99 (d, J = 9.0 Hz, 1H), 7.53 (t, J =8.1 Hz, 1H), 7.40-7.37 (m, 2H), 7.29 (d, J = 8.7 Hz, 1H), 4.98 (d, J = 11.1 Hz, 1H), 3.73 (d, J = 12.9 Hz, 1H), 3.58 (d, J = 13.2 Hz, 1H), 3.31-3.14 (m, 1H), 2.96 (d, J = 12.9 Hz, 1H), 1.07-0.97 (m, 2H), 0.94-0.87 (m, 2H). e. Synthesis of (S*)-5-(3-( indole - 3 -yloxy ) phenyl )-4- oxazolidin -7- azaspiro [2.5] octane ( Compound 124 ) Compound 124 was synthesized from compound I-95-2- pyridinium and 3-bromoindole as a 2HCl salt using a similar synthetic procedure as in Example 4 . Compound 124. MS (ESI+): m/z 284 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ 9.13 (d, J = 4.5 Hz, 1H), 8.05 (dd, J = 9.0, 4.8 Hz, 1H), 7.78 (d, J = 8.7 Hz, 1H), 7.52 (t, J =8.1 Hz, 1H), 7.37-7.33 (m, 2H), 7.26 (d, J = 8.4 Hz, 1H), 4.98-495 (m, 1H), 3.73 (d, J = 12.9 Hz, 1H), 3.58 (d, J = 12.9 Hz, 1H), 3.22-3.18 (m, 1H), 2.96 (d, J = 12.9 Hz, 1H), 1.07-0.97 (m, 2H), 0.94-0.84 (m, 2H). Example 96. Synthesis of ( S* )-2,2 -dimethyl -6-(3-( indole - 3 - yloxy ) phenyl ) -pyroline ( Compound 126) , ( R* )-2,2 -dimethyl -6-(3-( indole -3- yloxy ) phenyl ) -pyroline ( Compound 127) a. Synthesis of tributyl 6-( 3- hydroxyphenyl )-2,2- dimethyl-pyroline -4- carboxylate Compound I-96-1 was synthesized from 3-bromophenol using a procedure similar to that in Example 2 (steps 1 to 5) and Example 95 (step 6). b. Chiral separation of tert-butyl 6-(3 -hydroxyphenyl )-2,2- dimethylmorpholine -4- carboxylate 6-(3-Hydroxyphenyl)-2,2-dimethylmorpholine-4-carboxylic acid tributyl ester was separated by chiral column separation using the following: Instrument: SFC-150 (Thar, Waters) Column: AD 25×250mm, 10µm (Daicel) Column temperature: 35℃ Mobile phase: CO ₂ /IPA (0.01% methylamine/methanol) = 92/8 Flow rate: 100 g/min Back pressure: 100 bar Detection wavelength: 220 nm Cycle time: 2.0 min Sample solution: 400 mg dissolved in 10 mL Injection volume: 1.0 mL Chiral analysis conditions: Instrument: Waters 2695; Column: AY-H 4.6×250mm, 5µm; column temperature: 30℃; mobile phase: n-hexane/EtOH (0.1% DEA) = 95/5; flow rate: 1.0 mL/min; detection wavelength: 254 nm; detector: W2996 PDA. After removing the solvent, the first eluting isomer ( R* )-6-(3-hydroxyphenyl)-2,2-dimethylmorpholine-4-carboxylic acid tert-butyl ester ( Compound I-96-2- peak 1 , retention time from the analytical column = 8.06 min) and the second eluting isomer ( S* )-6-(3-hydroxyphenyl)-2,2-dimethylmorpholine-4-carboxylic acid tert-butyl ester ( Compound I-96-2- peak 2 , retention time from the analytical column = 5.76 min) were obtained. c. Synthesis of (R*)-2,2 -dimethyl -6-(3-( indole - 3 -yloxy ) phenyl ) morpholine ( Compound 127 ) Compound 127 was synthesized from compound I-96-2- pyridinium and 3-bromopyridinium as a 2HCl salt using a similar synthetic procedure as in Example 4 . Compound 127. MS (ESI+): m/z 286 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ 9.21 (d, J = 3.9 Hz, 1H), 8.18 (dd, J = 9.0, 4.8 Hz, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.59-7.50 (m, 1H), 7.41-7.38 (m, 2H), 7.27 (d, J = 8.4 Hz, 1H), 5.07 (d, J = 11.1 Hz, 1H), 3.45 (d, J = 11.4 Hz, 1H), 3.33-3.31 (m ,1H), 3.05-3.01 (m, 1H), 2.99 -2.90 (m, 1H), 1.51 (s ,3H), 1.39 (s ,3H). d. Synthesis of (S*)-2,2 -dimethyl -6-(3-( indole - 3 -yloxy ) phenyl ) pyroline ( Compound 126 ) Compound 126 was synthesized from compound I-96-2- pyridinium and 3-bromoindole as a 2HCl salt using a similar synthetic procedure as in Example 4 . Compound 126. MS (ESI+): m/z 286 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ 9.34 (d, J = 4.8 Hz, 1H), 8.37 (dd, J = 9.0, 4.8 Hz, 1H), 8.15 (d, J = 9.0 Hz, 1H), 7.54 (t, J = 8.1 Hz, 1H), 7.43-7.39 (m, 2H), 7.30 (d, J = 7.5 Hz, 1H), 5.09 (d, J = 10.5 Hz, 1H), 3.47 (d, J = 12.3 Hz, 1H), 3.33-3.31 (m,1H), 3.06-3.01 (m, 1H), 2.99 -2.90 (m, 1H), 1.52 (s ,3H), 1.39 (s ,3H). Example 97. Synthesis of ( R )-2-(3-( thiazol -3- ylthio ) phenyl ) pyroline ( Compound 128 ) a. Synthesis of (2- hydroxy -2-(3- iodophenyl ) ethyl )(2- hydroxyethyl ) carbamic acid tributyl ester To a solution of 3-iodobenzaldehyde (24 g, 103 mmol) in CH ₃ CN (500 mL) was added trimethyl iodide (22.0 g, 108 mmol) and KOH (9.48 g, 169 mmol). The reaction mixture was heated to 60° C. and stirred at that temperature for 16 h. 2-Aminoethan-1-ol (18.8 g, 309 mmol) was added to the reaction mixture. The reaction was heated to 50° C. and stirred at that temperature overnight. The reaction mixture was filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography with a gradient elution from DCM (95%) and MeOH (5%) to DCM (90%) and MeOH (10%) to provide impure 2-[(2-hydroxyethyl)amino]-1-(3-iodophenyl)ethan-1-ol (19.0 g, 61.8 mmol) as a yellow oil. To a solution of impure 2-[(2-hydroxyethyl)amino]-1-(3-iodophenyl)ethan-1-ol (19 g, 61.8 mmol) in THF/H ₂ O (150/150 mL) were added NaHCO ₃ (10.3 g, 123 mmol) and di-tributyl dicarbonate (16.1 g, 74.1 mmol). The reaction was stirred at ambient temperature for 1 h. Water (100 mL) was added to the reaction vessel and extracted with EtOAc (2×100 mL). The layers were separated and the organic phase was washed with saturated aqueous NaCl (2×100 mL). The combined organics were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography with a gradient elution from EtOAc (25%) and petroleum ether (75%) to EtOAc (50%) and petroleum ether (50%) to provide tributyl N- [2-hydroxy-2-(3-iodophenyl)ethyl] -N- (2-hydroxyethyl)carbamate (10.0 g, 24.5 mmol) ( Compound I-97-2 ) as a yellow oil. b. Synthesis of 2-(3- iodophenyl ) morpholine -4- carboxylic acid tert- butyl ester To a solution of tributyl N- [2-hydroxy-2-(3-iodophenyl)ethyl] -N- (2-hydroxyethyl)carbamate (10 g, 24.5 mmol) in toluene (400 mL) at 0 °C was added triphenylphosphine (7.71 g, 29.4 mmol). The reaction was stirred at ambient temperature for 30 min. DIAD (5.94 g, 29.4 mmol) was then added. The reaction mixture was heated to 50 °C and stirred at that temperature for 3 h. The reaction mixture was concentrated in vacuo. The obtained oil was purified by flash column chromatography using isocratic elution with EtOAc (10%) and petroleum ether (90%) to provide tert-butyl 2-(3-iodophenyl)-4-carboxylate (5.60 g, 14.3 mmol) ( Compound I-97-3 ) as a yellow oil. c. Chiral separation of tert-butyl 2-(3- iodophenyl ) -4- carboxylate 2-(3-iodophenyl)morpholine-4-carboxylic acid tributyl ester was separated by chiral column separation using the following: Instrument: SFC-150 (Thar, Waters) Column: AD 25×250mm, 10µm (Daicel) Column temperature: 35℃ Mobile phase: CO ₂ /IPA (0.01% methylamine/methanol) = 95/5 Flow rate: 100 g/min Back pressure: 100 bar Detection wavelength: 220 nm Cycle time: 1.5 min Sample solution: 5.6 g dissolved in 500 mL methanol Injection volume: 0.5 mL Chiral analysis conditions: Instrument: Waters 2695; Column: AY-H (4.6×250mm, 5µm); column temperature: 30℃; mobile phase: n-hexane/EtOH (0.1% DEA) = 95/5; flow rate: 1.0 mL/min; detection wavelength: 220 nm; detector: W2996 PDA. After removing the solvent, the first eluting isomer ( R )-2-(3-iodophenyl)-4-carboxylic acid tert-butyl ester ( Compound I-97-4- peak 1 , retention time from the analytical column = 4.60 min) and the second eluting isomer ( S )-2-(3-iodophenyl)-4-carboxylic acid tert-butyl ester ( Compound I-97-4- peak 2 , retention time from the analytical column = 5.21 min) were obtained. d. Synthesis of (R)-2-(3-( Benzoylthio ) phenyl ) morpholine -4- carboxylic acid tert- butyl ester To a solution of ( R )-2-(3-iodophenyl)morpholine-4-carboxylic acid tributyl ester (2.2 g, 5.65 mmol) in xylene (40 mL) were added phenylthiocarboxylic acid (1.56 g, 11.3 mmol) , N , N -diisopropylethylamine (1.09 g, 8.47 mmol) and CuI (215 mg, 1.13 mmol). The reaction solution was exchanged with _N2 balloon three times and stirred at 120 °C for one day. Water (10 mL) was added to the reaction vessel and the resulting two-phase mixture was transferred to a separatory funnel. The aqueous phase was extracted with EtOAc (3×10 mL). The layers were separated and the organic phase was washed with saturated aqueous NaCl solution (3×10 mL). _The combined organics were dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography with a gradient elution from EtOAc (10%) and petroleum ether (90%) to EtOAc (50%) and petroleum ether (50%) to provide ( R )-2-[3-(benzoylthio)phenyl]morpholine-4-carboxylic acid tert-butyl ester (1.20 g, 3.00 mmol) ( Compound I-97-5 ) as a yellow oil. e. Synthesis of (R)-2-[3-( thiazol - 3 -ylthio ) phenyl ] morpholine -4- carboxylic acid tert-butyl ester To a solution of ( R )-2-[3-(benzoylthio) _phenyl ]morpholine-4-carboxylic acid tributyl ester (500 mg, 1.25 mmol) in MeOH (10 mL) was added _K2CO3 (517 mg, 3.75 mmol). The reaction was stirred at ambient temperature for 2 h. The starting material was completely consumed. The reaction mixture was then concentrated in vacuo. The resulting solid was dissolved in DMF (10 mL) and 3-bromotitanium (238 mg, 1.50 mmol) was then added. The reaction mixture was heated to 120 °C and stirred at that temperature for 16 h. Water (30 mL) was added to the reaction vessel and extracted with EtOAc (3 x 10 mL). The layers were separated and the organic phase was washed with saturated aqueous NaCl solution (2×10 mL). The combined organics were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography with a gradient elution from EtOAc (20%) and petroleum ether (80%) to EtOAc (30%) and petroleum ether (70%) to provide ( R )-2-[3-(pyridin-3-ylthio)phenyl]morpholine-4-carboxylic acid tributyl ester (125 mg, 334 μmol) ( Compound I-97-6 ) as a yellow solid. f. Synthesis of ( R )-2-(3-(pyridin-3-ylthio)phenyl)morpholine Compound 128 was synthesized from compound I-97-6 and HCl as a 2HCl salt using a similar synthetic procedure as in Example 1 . Compound 128. MS (ESI+): m/z 274 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ 9.16 (d, J = 4.2 Hz, 1H), 7.96-7.91 (m, 1H), 7.80 (d, J = 9.0 Hz, 2H), 7.71-7.68 (m, 1H), 7.62-7.56 (m, 2H), 4.88-4.84 (m, 1H), 4.25 (dd, J = 13.2, 3.0 Hz, 1H), 4.00 (td, J = 13.2, 3.0 Hz, 1H), 3.53 (d, J = 12.3 Hz, 1H), 3.38-3.30 (m, 2H), 3.12 (t, J = 12.3 Hz, 1H). Example 98. Synthesis of ( R )-2-(3-(( R* )- indole - 3 -ylsulfinyl ) phenyl ) -morpholine ( Compound 129) , ( R )-2-(3-(( S* )- indole - 3- ylsulfinyl ) phenyl ) -morpholine ( Compound 130) a. Synthesis of (R)-2-[3-( indole -3 - ylsulfinyl ) phenyl ] -morpholine -4- carboxylic acid tributyl ester To a solution of ( R )-2-[3-(thiazol-3-ylthio)phenyl]morpholine-4-carboxylic acid tributyl ester (100 mg, 267 µmol) in DCM (2 mL) was added m -CPBA ( _{55.2 mg, 320 µmol). The reaction was stirred at -10 °C for 3 h. Saturated aqueous Na2S2O3 ( 5} mL) was added to the reaction vessel and extracted with DCM (2 x 5 mL). The layers were separated and the organic phase was washed with saturated aqueous NaCl (2 x 5 mL). The combined organics were dried over _{anhydrous Na2SO4} , filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography with a gradient elution from EtOAc (30%) and petroleum ether (70%) to EtOAc (50%) and petroleum ether (50%) to provide ( R )-tert-butyl 2-[3-(indole-3-sulfinyl)phenyl]morpholine-4-carboxylate (70.0 mg, 179 µmol) as a colorless oil. b. Chiral separation of (R)-2-[3-( ta- [ 3 -sulfinyl ) phenyl ] morpholine - 4- carboxylic acid tert-butyl ester to (R)-2-(3-((R*)- ta- [ 3- sulfinyl ) phenyl ] morpholine- 4- carboxylic acid tert-butyl ester ( Compound I-98-2- Peak 1 ) and (R)-2-(3-((S*)- ta- [ 3 -sulfinyl ) phenyl ] morpholine -4- carboxylic acid tert- butyl ester ( Compound I-98-2- Peak 2 ) ( R )-2-[3-(tantalum-3-sulfinyl)phenyl]morpholine-4-carboxylic acid tributyl ester was separated by chiral column separation using the following conditions: Instrument: SFC-150 (Thar, Waters) Column: AD 25×250mm, 10µm (Daicel) Column temperature: 35℃ Mobile phase: _CO2 /EtOH (0.01% methylamine/methanol) = 60/40 Flow rate: 100 g/min Back pressure: 100 bar Detection wavelength: 220 nm Cycle time: 1.5 min Sample solution: 70 mg dissolved in 3 mL methanol Injection volume: 1.0 mL Chiral analysis conditions: Instrument: Waters 2695; Column: Regis REFLECT C-Amylose A (4.6×250 mm, 5µm); column temperature: 30℃; mobile phase: n-hexane/EtOH (0.1% DEA) = 60/40; flow rate: 0.8 mL/min; detection wavelength: 220 nm; detector: W2996 PDA. After the solvent was removed, the first eluting isomer ( R )-2-(3-(( R * )-pyrimidine-3-ylsulfinyl)phenyl)-4-carboxylic acid tert-butyl ester ( Compound I-98-2- peak 1 , retention time from the analytical column = 8.39 min) and the second eluting isomer ( R )-2-(3-(( S * )-pyrimidine-3-ylsulfinyl)phenyl)-4-carboxylic acid tert-butyl ester ( Compound I-98-2- peak 2 , retention time from the analytical column = 11.17 min) were obtained. c. Synthesis of ( R )-2-(3-(( R* )-pyrimidine-3-ylsulfinyl)phenyl)-4-carboxylic acid tert-butyl ester To a solution of ( R )-2-{3-[( R *)-pyridinium-3-sulfinyl]phenyl}morpholine-4-carboxylic acid tributyl ester (38.3 mg, 98.3 µmol) in DCM (0.5 mL) at 0°C was added TFA (0.1 mL). The reaction was stirred at ambient temperature for 30 min. Saturated aqueous _Na2CO3 solution ( ₁ mL) was added to the reaction vessel and extracted with DCM/MeOH (10/1, 5×2 mL). The layers were separated and the organic phase was washed with saturated aqueous NaCl solution (2×2 mL ₎ . The combined organics were dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo. The resulting oil was purified by preparative thin layer chromatography eluting with isocratic DCM (90%) and MeOH (10%) to provide ( 2R )-2-{3-[( R *)-pyridazine-3-sulfinyl]phenyl}morpholine (9.21 mg, 31.8 µmol) ( Compound 129 ) as a light yellow solid. Compound 129. MS (ESI+): m/z 290 (MH ⁺ ); ¹ H NMR (300 MHz, CDCl ₃ ) δ 9.18 (d, J = 3.9 Hz, 1H), 8.18 (d, J = 8.1 Hz, 1H), 7.85 (br s, 1H), 7.77 (br s, 1H), 7.69-7.64 (m, 1H), 7.47 (br s, 2H), 4.52 (d, J = 9.9 Hz, 1H), 4.03 (d, J = 10.5 Hz, 1H), 3.75 (t, J = 10.2 Hz, 1H), 3.09-2.87 (m, 3H), 2.71 (t, J = 11.7 Hz, 1H). d. Synthesis of ( R )-2-(3-(( S* )-pyrimidine-3-ylsulfinyl)phenyl)morpholine Compound 130 was synthesized in free base form from compound I-98-2- peak 2 and TFA using a similar synthetic procedure as compound 129 above. Compound 130. MS (ESI+): m/z 290 (MH ⁺ ); ¹ H NMR (300 MHz, CDCl ₃ ) δ 9.18 (d, J = 3.9 Hz, 1H), 8.18 (d, J = 8.1 Hz, 1H), 7.89 (br s, 1H), 7.83 (br s, 1H), 7.79-7.67 (m, 1H), 7.44 (br s, 2H), 4.54 (d, J = 9.6 Hz, 1H), 4.03 (d, J = 10.8 Hz, 1H), 3.78 (t, J = 10.2 Hz, 1H), 3.09-2.87 (m, 3H), 2.75 (t, J = 10.8 Hz, 1H). Example 99. Synthesis of ( R )-2-(3-( indole -3- ylsulfonyl ) phenyl ) morpholine ( Compound 131 ) a. Synthesis of (R)-2-( 3-( indole - 3 -ylsulfonyl ) phenyl ) morpholine -4- carboxylic acid tributyl ester To a solution of ( R )-2-[3-(thiazol-3-ylthio)phenyl]morpholine-4-carboxylic acid tributyl ester (100 mg, 267 µmol) in DCM (2 mL) at 0°C was added m -CPBA (138 mg, 801 µmol). The reaction was stirred at 0°C for 3 h. _{Saturated aqueous Na2S2O3 (} 5 mL) was added to the reaction vessel and extracted with DCM (2×5 mL). The layers were separated and the organic phase was washed with saturated aqueous NaCl (2×5 mL). The combined organics were dried over _{anhydrous Na2SO4} , filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography using isocratic elution with EtOAc (35%) and petroleum ether (65%) to provide ( R )-2-[3-(indole-3-sulfonyl)phenyl]morpholine-4-carboxylic acid tributyl ester (31.0 mg, 76.4 µmol) ( Compound I-99-1 ) as an off- white solid. b. Synthesis of (R)-2-(3-( indole -3 -sulfonyl ) phenyl ) morpholine Compound 131 was synthesized using a similar synthetic procedure as in Example 1 from compound I-99-1 and HCl/Et ₂ O as a 2HCl salt. Compound 131. MS (ESI+): m/z 306 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ 9.37 (d, J = 3.9 Hz, 1H), 8.47 (d, J = 8.7 Hz, 1H), 8.21 (s, 1H), 8.08 (d, J = 7.8 Hz, 1H), 8.02-7.94 (m, 1H), 7.80 (d, J = 7.2 Hz, 1H), 7.71-7.62 (m, 1H), 4.95-4.90 (m , 1H), 4.28 (dd, J = 13.2, 3.0 Hz, 1H), 4.01 (td, J = 13.2, 3.0 Hz, 1H), 3.55 (d, J = 11.7 Hz, 1H), 3.44-3.34 (m, 2H), 3.09 (t, J = 11.7 Hz, 1H). Example 100. Synthesis of ( R )-2-(3-( pyrazolo [1,5- a ] pyridin -3 -yloxy ) phenyl ) pyroline ( Compound 132) Compound 132 was synthesized from compound 1-2-9 - peak -1 and 3-bromopyrazolo[1,5- a ]pyridine as the HCl salt using a coupling and subsequent deprotection procedure similar to that in Example 1 . Compound 132. MS (ESI+): m/z 296 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ 8.47 (d, J = 6.6 Hz, 1H), 7.89 (s, 1H), 7.38-7.32 (m, 2H), 7.19-7.06 (m, 3H), 7.00 (d, J = 8.1 Hz, 1H), 6.90 (t, J = 6.6 Hz, 1H), 4.72 (d, J = 9.9 Hz, 1H), 4.20 (d, J = 12.9 Hz, 1H), 3.95 (t, J = 14.7 Hz, 1H), 3.42 (d, J = 14.0 Hz, 1H), 3.25-3.15 (m, 2H), 3.03 (t, J = 11.4 Hz, 1H). Example 101. Synthesis of ( R )-2-(3-( imidazo [1,5- a ] pyridin -1 -yloxy ) phenyl ) pyroline ( Compound 133) Compound 133 was synthesized from compound 1-2-9 - peak 1 and 1-bromoimidazo[1,5- a ]pyridine as the HCl salt using a coupling and subsequent deprotection procedure similar to that in Example 1 . Compound 133. MS (ESI+): m/z 296 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ 8.13-8.09 (m, 2H), 7.30-7.21 (m, 2H), 7.03 (d, J = 7.5 Hz, 1H), 6.97 (s, 1H), 6.87 (d, J = 7.8 Hz, 1H), 6.71-6.60 (m, 2H), 4.43 (d, J = 9.6 Hz, 1H), 3.95 (d, J = 11.1 Hz, 1H), 3.74-3.70 (m, 1H), 2.96 (d, J = 13.6 Hz, 1H), 2.86-2.78 (m, 2H), 2.61 (t, J = 11.7 Hz, 1H). Example 102. Synthesis of ( R* )-2-(2- methyl -5-( indole - 3 -yloxy ) phenyl ) -pyroline ( Compound 134) , ( S* )-2-(2- methyl -5-( indole - 3 -yloxy ) phenyl ) -pyroline ( Compound 135) a. Synthesis of tributyl 2-(5 -hydroxy -2- methylphenyl ) -pyroline -4- carboxylate Compound I-102-2 was synthesized from 3-bromo-4-methylphenol and tert-butyl 2-(5 -hydroxy -2-methylphenyl)-4-carboxylate using a procedure similar to that in Example 1. b. Chiral separation of tert- butyl 2-(5- hydroxy -2- methylphenyl ) -4- carboxylate 2-(5-Hydroxy-2-methylphenyl)morpholine-4-carboxylic acid tributyl ester was separated by chiral column separation using the following: Instrument: SFC-150 (Thar, Waters) Column: AD 25×250mm, 10µm (Daicel) Column temperature: 35℃ Mobile phase: CO ₂ /IPA (0.01% methylamine/methanol) = 88/12 Flow rate: 100 g/min Back pressure: 100 bar Detection wavelength: 220 nm Cycle time: 2.0 min Sample solution: 0.99 g dissolved in 10 mL methanol Injection volume: 0.5 mL Chiral analysis conditions: Instrument: Waters 2695; Column: AY-H (4.6×250mm, 5µm); column temperature: 30℃; mobile phase: n-hexane/ i PrOH (0.1% DEA) = 85/15; flow rate: 0.8 mL/min; detection wavelength: 254 nm; detector: W2996 PDA. After removing the solvent, the first eluting isomer ( R *)-2-(5-hydroxy-2-methylphenyl)-4-carboxylic acid tert-butyl ester ( Compound I-102-3- peak 1 , retention time from the analytical column = 6.87 min) and the second eluting isomer ( S *)-2-(5-hydroxy-2-methylphenyl)-4-carboxylic acid tert-butyl ester ( Compound I-102-3- peak 2 , retention time from the analytical column = 9.04 min) were obtained. c. Synthesis of (R*)-2-(2- methyl -5-( pyridinium - 3 -yloxy ) phenyl ) -4 -carboxylic acid ( Compound 134 ) Compound 134 was synthesized from compound I-102-3- pyridinium and 3-bromoindole as a 2HCl salt using a similar synthetic procedure as in Example 4 . Compound 134. MS (ESI+): m/z 272 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ 9.27 (d, J = 4.8 Hz, 1H), 8.31-8.26 (m, 1H), 8.03 (d, J = 9.0 Hz, 1H), 7.42-7.34 (m, 2H), 7.18 (dd, J = 8.4, 2.4 Hz, 1H), 5.02 (d, J = 9.0 Hz, 1H), 4.24 (dd, J = 12.6, 3.0 Hz, 1H), 4.03 (td, J = 12.6, 3.0 Hz, 1H), 3.48 (d, J = 13.2 Hz, 1H), 3.40-3.32 (m, 2H), 3.05 (t, J = 12.0 Hz, 1H), 2.42 (s, 3H). d. Synthesis of (S*)-2-(2- methyl -5-( indole - 3 -yloxy ) phenyl ) pyroline ( Compound 135 ) Compound 135 was synthesized from compound I-102-3- pyrrole 2 and 3-bromoindole as a 2HCl salt using a similar synthetic procedure as in Example 4 . Compound 135. MS (ESI+): m/z 272 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ 9.20 (d, J = 4.8 Hz, 1H), 8.20-8.15 (m, 1H), 7.90 (d, J = 8.7 Hz, 1H), 7.40-7.32 (m, 2H), 7.17 (dd, J = 8.4, 2.4 Hz, 1H), 5.02 (d, J = 9.0 Hz, 1H), 4.24 (dd, J = 12.6, 3.0 Hz, 1H), 4.03 (td, J = 12.6, 3.0 Hz, 1H), 3.48 (d, J = 13.2 Hz, 1H), 3.40-3.32 (m, 2H), 3.05 (t, J = 12.0 Hz, 1H), 2.42 (s, 3H).

Cellular Assays. Certain compounds disclosed herein were tested for TAAR1 agonism and 5-HT _1A agonism and/or 5-HT _1A binding in functional cell assays.

TAAR1 agonism assay protocol : cAMP HTRF assay for the Gs- coupled receptor TAAR1 ( Euroscreen FAST - 0987C ) . CHO -K1 cells expressing the human TAAR1 receptor (accession number NP_612200.1) were grown in antibiotic-free medium (Advanced DMEM supplemented with 1% dialyzed fetal bovine serum) prior to the assay. The cells were separated by gentle washing with PBS-EDTA (5 mM EDTA), recovered by centrifugation, and resuspended in assay buffer (Clark-Ling-Henry buffer: 5 mM KCl, 1.25 mM MgSO ₄ , 124 mM NaCl, 25 mM HEPES, 13.3 mM glucose, 1.25 mM KH ₂ PO ₄ , 1.45 mM CaCl ₂ , 0.5 g/l BSA, supplemented with 1 mM isobutylmethylxanthine).

For TAAR1 agonist assays (performed in 384-well plates): 5 µl of cells (approximately 3,000 cells) were mixed with 5 µl of test compound diluted in assay buffer and then incubated for approximately 30 minutes at approximately room temperature. cAMP levels were measured using the Cisbio cAMP Gs Dynamic HTRF Kit (Cisbio, Bedford, MA). Dose-response curves were also plotted using the reference compound tyramine.

5 - HT1A agonism assay protocol : cAMP HTRF assay for the pharmacology of 5 - HT1A ( Euroscreen FAST - 500C ) for Gs- coupled receptors . CHO-K1 cells expressing human recombinant 5-HT _1A receptor grown in antibiotic-free medium prior to the assay were isolated by gentle washing with phosphate-buffered saline containing 5 mM EDTA, recovered by centrifugation, and resuspended in assay buffer (Clark-Heinz buffer: 5 mM KCl, 1.25 mM MgSO ₄ , 124 mM NaCl, 25 mM HEPES, 13.3 mM glucose, 1.25 mM KH ₂ PO ₄ , 1.45 mM CaCl ₂ , 0.5 g/l BSA, supplemented with 1 mM isobutylmethylxanthine).

The assay was performed in 384-well plates. 5 µl of cells (2,500 cells) were mixed with 5 µl of a mixture of test compound and 5 mM forskolin followed by incubation at room temperature for 30 min. cAMP levels were measured using the Cisbio cAMP Gs Dynamic HTRF Kit (Cisbio, Bedford, MA). Data are presented in comparison to p-tyramide.

5 - HT1A agonism assay protocol : GTPγS assay for the pharmacology of 5 - HT1A ( Euroscreen FAST - 500G ) . Membrane extracts prepared from CHO-K1 cells expressing recombinant human 5- _HT1A receptor were thawed on ice, diluted in assay buffer (20 mM HEPES pH 7.4; 100 mM NaCl, 10 µg/ml saponin, 3 mM MgCl ₂ , 0 to 0.1% BSA), and kept on ice. For agonist testing, 5 μg of membranes were mixed with 3 μM GDP (vol:vol). Simultaneously, 0.1 nM GTPγ[ ³⁵ S] was mixed with PVT-WGA SPA beads (50 mg/ml) (vol:vol). The following reagents were added sequentially to the wells of the Optiplate: 50 μL of test compound or reference ligand, 25 μL of membrane: GDP mixture, and 25 μL of GTPγ[35S]: beads mixture. The plate was incubated at room temperature for 30 minutes and then counted on a TopCountTM.

5 - HT1A Binding Assay Protocol : Radioligand competition assay for the pharmacology of 5-HT1A (Euroscreen FAST-500B). Radioligand competition binding was performed in duplicate in wells of a 96-well plate containing binding buffer ( 50 mM Tris ( pH 7.4), 0.1% ascorbic acid, 5 mM CaCl ₂ ), membrane extract (5 μg protein), radiolabel (0.39 nM [ ³ H]-8-OH-DPAT) and test compound. Nonspecific binding was determined by co-incubation with 1 μM 5-HT. Samples were incubated at room temperature for 60 minutes in a final volume of 0.1 ml and then filtered on filter plates (GF/C soaked in 5% polyethyleneimine). The filters were washed six times with 0.5 ml ice-cold wash buffer and 50 µl Microscint 20 (Packard) was added to each well. The plates were incubated on an orbital shaker for 15 min and then counted using a TopCountTM at 30 seconds/well.

The results of the cell assays are reported in Tables 2 to 4. In the indicated cell assays, "++++" compounds have EC ₅₀ or K _i of <100 nM; in the indicated cell assays, "+++" compounds have EC ₅₀ or K _i of 100 nM to <1 µM; in the indicated cell assays, "++" compounds have EC ₅₀ or K _i of 1 µM to less than 10 µM; and in the indicated cell assays, "+" compounds have EC ₅₀ or K _i of ≥10 µM. Unless otherwise indicated, 5-HT1A agonism in Table 1 was measured in the cAMP assay. Table 2. TAAR1 agonism EC ₅₀ Compound No. TAAR1 EC ₅₀ 1 ++ 2 ++++ 3 ++++ 4 +++ 5 ++ 6 ++ 7 ++ 8 ++++ 9 +++ 10 +++ 11 +++ 12 ++ 13 ++ 14 ++ 15 + 16 + 17 +++ 18 ++++ 19 ++++ 20 ++++ twenty one ++ twenty two ++++ twenty three ++ twenty four ++++ 25 +++ 26 ++ 27 + 28 ++ 29 +++ 30 + 31 ++++ 32 + 33 +++ 34 ++++ 35 +++ 36 ++++ 37 +++ 38 ++++ 39 ++ 40 ++++ 41 +++ 42 ++++ 43 +++ 44 ++ 45 +++ 46 + 47 +++ 48 +++ 49 +++ 50 ++++ 51 +++ 52 ++++ 53 +++ 54 +++ 55 +++ 56 ++ 57 +++ 58 ++++ 59 +++ 60 ++++ 61 +++ 62 + 63 + 64 + 65 + 66 +++ 67 +++ 68 +++ 69 ++++ 70 ++++ 71 +++ 72 +++ 73 ++++ 74 +++ 75 +++ 76 ++++ 77 +++ 78 ++++ 79 ++++ 80 +++ 81 ++++ 82 ++++ 83 +++ 84 ++++ 85 ++++ 86 +++ 87 ++ 88 ++++ 89 ++++ 90 ++++ 91 +++ 92 +++ 93 +++ 94 ++ 95 ++++ 96 ++ 97 ++ 98 ++++ 99 +++ 100 ++++ 101 ++++ 102 ++++ 103 ++++ 104 ++++ 105 +++ 106 +++ 107 ++++ 108 ++++ 109 ++++ 110 ++++ 111 +++ 112 ++++ 113 +++ 114 ++ 115 ++ 116 ++ 117 ++ 118 ++++ 119 +++ 120 ++ 121 ++ 122 ++ 123 ++ 124 ++++ 125 +++ 126 +++ 127 ++ 128 ++ 129 ++ 130 + 131 ++ 132 ++ 133 ++++ 134 + 135 + Table 3. 5-HT1A binding Ki Compound No. 5-HT1A Ki 2 ++++ 3 ++++ 8 ++++ 11 ++++ 18 ++ 20 +++ twenty two ++++ 26 + 28 + 30 +++ 32 +++ 33 ++++ 34 +++ 38 ++++ 39 +++ 40 ++++ 48 ++++ 50 ++++ 51 +++ 52 ++++ 53 ++++ 56 +++ 57 ++++ 60 ++++ 62 + 63 + 64 + 65 +++ 70 ++++ 76 ++++ 98 ++++ 100 ++++ 101 ++++ 102 ++++ 103 ++++ 104 ++++ 107 ++++ 108 ++++ 109 ++++ 110 ++++ 112 +++ Table 4. 5-HT1A agonist _EC50 Compound No. 5-HT1A EC ₅₀ (cAMP) 5-HT1A _EC50 (GTPγS) 1 ++++ 2 + 3 ++ 6 +++ 7 ++ 8 ++ ++ 9 + 10 + 11 ++++ 12 + 18 + 19 ++ 20 + ++ twenty two ++ ++ twenty four +++ 26 + 28 + 32 + 33 ++++ +++ 34 + + 38 +++ 39 + 40 ++ ++ 41 ++ 42 +++ 45 +++ 46 +++ 48 ++++ 49 ++ 50 +++ 51 + ++ 52 ++ 53 +++ 54 + 55 ++ 56 + 57 +++ +++ 58 + 60 ++++ ++ 68 + 70 +++ +++ 71 + ++ 72 + 73 ++++ 74 +++ 75 + 76 ++++ ++++ 77 ++ 78 +++ +++ 79 ++++ ++++ 80 + 81 +++ 82 + 83 ++++ 84 + 85 + 86 +++ 87 ++++ 88 ++ 89 + 90 +++ 91 ++++ 92 ++ 95 +++ 98 ++ +++ 100 ++ 101 +++ 102 +++ ++ 103 +++ +++ 104 +++ +++ 107 +++ +++ 108 +++ 109 ++++ 110 ++++ 112 ++ + 124 + ++

The teachings of all patents, published applications, and references cited herein are incorporated by reference in their entirety.

While exemplary embodiments have been particularly shown and described, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the embodiments covered by the appended claims.

Claims (53)

A compound having the following structural formula: (I), or a pharmaceutically acceptable salt thereof, wherein: X is O, S, S(O) or S(O) ₂ ; Y is O, S, S(O) or S(O) ₂ ; R ¹ is (C ₅ -C ₁₀ ) heteroaryl optionally substituted by (R ¹⁰ ) _p , such that when p is 0, R ¹ is unsubstituted; each R ¹⁰ is independently halogen, hydroxyl, cyano, (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) halogenalkyl, (C ₁ -C ₃ ) alkoxy(C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkoxy, (C ₃ -C ₆ ) cycloalkyl, (C ₃ -C ₆ ) heterocyclo, phenyl, pyridyl, amino or -C(O)NR ¹¹ R ¹² , or two R ¹⁰ on adjacent atoms of R ¹ together form -CH ₂ -O-CH ₂ -, -CH ₂ CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ CH ₂ -, -O-CH ₂ -O-, or -O-CH ₂ CH ₂ -O-; R ¹¹ and R ¹² are each independently hydrogen or (C ₁ -C ₃ ) alkyl; p is 0, 1, 2, 3 or 4; each R ² is independently halogen, hydroxy, cyano, (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) halogenalkyl, (C ₁ -C ₃ ) alkoxy( _C 1 -C ₃ ) alkyl, (C ₁ -C ₃ ) alkoxy or (C ₃ -C ₆ ) cycloalkyl; each R ³ is independently (C ₁ -C ^R3 is hydrogen _or ( _C1 -C3) alkyl _{; m is 0 , 1 , 2 , 3 or 4} ; n is _{0 , 1 , 2} , _{3 or 4} ; _{and o} ^is _{0 or 1 .} A compound having the following structural formula: (I), or a pharmaceutically acceptable salt thereof, wherein: X is O, S, S(O) or S(O) ₂ ; Y is O, S, S(O) or S(O) ₂ ; R ¹ is (C ₅ -C ₁₀ ) heteroaryl substituted by (R ¹⁰ ) _p ; each R ¹⁰ is independently halogen, hydroxy, cyano, (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) halogenalkyl, (C ₁ -C ₃ ) alkoxy(C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkoxy, (C ₃ -C ₆ ) cycloalkyl, (C ₃ -C ₆ ) heterocyclic, phenyl, pyridyl, amino or -C(O)NR ¹¹ R ¹² , or R two R ¹⁰ on adjacent atoms of ^{R 1} together form -CH ₂ -O-CH ₂ -, -CH ₂ CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ CH ₂ -, -O-CH ₂ -O-, or -O-CH ₂ CH ₂ -O-; R ¹¹ and R ¹² are each independently hydrogen or (C ₁ -C ₃ ) alkyl; p is 0, 1, 2, 3 or 4; each R ² is independently halogen, hydroxy, cyano, (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) halogenalkyl, (C ₁ -C ₃ ) alkoxy(C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkoxy or (C ₃ -C ₆ ) cycloalkyl; each R ³ is independently (C ₁ -C ₃ ) alkyl, R ⁴ is hydrogen or (C ₁ -C ₃ )alkyl; m is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3 or 4; and o is 0 or 1. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein X is O or S. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein X is O. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 4, wherein Y is O or S. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein Y is O. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein X is O or S, and Y is O. The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein X is O or S; Y is O; R ¹ is (C ₅ -C ₁₀ ) heteroaryl substituted by (R ¹⁰ ) _p ; and each R ¹⁰ is independently halogen, hydroxy, cyano, (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) haloalkyl, (C ₁ -C ₃ ) alkoxy (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkoxy, (C ₃ -C ₆ ) cycloalkyl, (C ₃ -C ₆ ) heterocyclo, phenyl, pyridyl, amino or -C(O)NH ₂ . The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein R ¹ is (C ₅ -C ₆ )heteroaryl substituted with (R ¹⁰ ) _p . The compound of any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, wherein the heteroaryl group of R ¹ contains one, two or three ring nitrogen atoms. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein the heteroaryl group of R ¹ contains one or two ring heteroatoms, and each of the one or two ring heteroatoms is nitrogen. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein the heteroaryl group of R ¹ contains two or three ring heteroatoms, one or two of which are nitrogen and one of which is oxygen or sulfur. The compound of any one of claims 1 to 8 and 10 to 12 or a pharmaceutically acceptable salt thereof, wherein the heteroaryl group of R ¹ is pyrimidinyl, pyrimidinyl, pyrimidinyl, pyridinyl, pyrazolyl, imidazolyl, thiadiazolyl, thiazolyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazolopyridinyl, pyrimidinyl, thiazolopyridinyl or benzothiazolyl. The compound of claim 13 or a pharmaceutically acceptable salt thereof, wherein the heteroaryl group of ^R1 is thiazol-3-yl, thiazol-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrazol-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazol-2-yl, pyrazol-3-yl, pyrazol-4-yl, imidazol-4-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-5-yl, isoxazol-4-yl, oxazol-2-yl, pyrazolo[1,5- a] ]pyridinyl, thiazol-1-yl, thiazolo[4,5- b ]pyridinyl or benzo[ d ]thiazol-2-yl. The compound of any one of claims 1 to 7 and 9 to 14 or a pharmaceutically acceptable salt thereof, wherein each R ¹⁰ is independently halogen, hydroxy, cyano, (C ₁ -C ₃ )alkyl, (C ₁ -C ₃ )haloalkyl, (C ₁ -C ₃ )alkoxy(C ₁ -C ₃ )alkyl, (C ₁ -C ₃ )alkoxy, (C ₃ -C ₆ )cycloalkyl, (C ₃ -C ₆ )heterocyclic, phenyl, pyridyl, amino or -C(O)NH ₂ . The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 15, wherein each R ¹⁰ is independently fluoro, methyl, methoxymethyl, methoxy, amino, trifluoromethyl, cyclopropyl, hydroxyl, cyano, pyridyl or -C(O)NH ₂ . The compound of any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, wherein p is 0, 1 or 2. The compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein p is 0 or 1. The compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein p is 0. The compound of any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, wherein R ¹ is . The compound of any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, wherein R ² is a halogen group. The compound of claim 21 or a pharmaceutically acceptable salt thereof, wherein R ² is fluorine. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 22, wherein each R ³ is independently methyl or ethyl. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 23, wherein R ⁴ is hydrogen, methyl or ethyl. The compound of claim 24 or a pharmaceutically acceptable salt thereof, wherein R ⁴ is hydrogen. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 25, wherein m is 0 or 1. The compound of claim 26 or a pharmaceutically acceptable salt thereof, wherein m is 0. The compound of claim 26 or a pharmaceutically acceptable salt thereof, wherein m is 1. The compound of any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof, wherein n is 0, 1 or 2. The compound of claim 29 or a pharmaceutically acceptable salt thereof, wherein n is 0. The compound of any one of claims 1 to 30 or a pharmaceutically acceptable salt thereof, wherein o is 0. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 30, wherein o is 1. The compound of any one of claims 1 to 32, which has the following structural formula: (Ia), or a pharmaceutically acceptable salt thereof. The compound of any one of claims 1 to 32, which has the following structural formula: (Ib), or a pharmaceutically acceptable salt thereof. A compound having the structural formula in Table 1 or a pharmaceutically acceptable salt thereof. A compound having the following structural formula: , or its pharmaceutically acceptable salts. A compound having the following structural formula: , or its pharmaceutically acceptable salts. A compound having the following structural formula: , or its pharmaceutically acceptable salts. A compound having the following structural formula: , or its pharmaceutically acceptable salts. A compound having the following structural formula: , or its pharmaceutically acceptable salts. A compound having the following structural formula: , or its pharmaceutically acceptable salts. A compound having the following structural formula: , or its pharmaceutically acceptable salts. A pharmaceutical composition comprising a compound according to any one of claims 1 to 42 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. A pharmaceutical composition comprising a compound of any one of claims 1 to 42 or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents. A method for treating a neurological or psychiatric disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 42 or a pharmaceutically acceptable salt thereof, a pharmaceutical composition of claim 43, or a pharmaceutical combination of claim 44. The method of claim 45, wherein the neurological or psychiatric disease or condition is schizophrenia spectrum disorder. The method of claim 45, wherein the neurological or psychiatric disease or disorder is Parkinson's disease. The method of claim 45, wherein the neurological or psychiatric disease or condition is depression. The method of claim 45, wherein the neurological or psychiatric disease or disorder is anxiety disorder. A method for treating a metabolic disease, disorder or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 42 or a pharmaceutically acceptable salt thereof, a pharmaceutical composition of claim 43, or a pharmaceutical combination of claim 44. The method of claim 50, wherein the metabolic disease, disorder or condition comprises one or more of the following: impaired glucose tolerance, elevated blood glucose, elevated fasting glucose, insulin resistance, insulin insensitivity, hyperglycemia, overweight or weight gain, increased body mass index, metabolic syndrome or diabetes. A method for agonizing TAAR1 in a subject in need thereof, comprising administering to the subject a compound of any one of claims 1 to 42 or a pharmaceutically acceptable salt thereof, a pharmaceutical composition of claim 43, or a pharmaceutical combination of claim 44 in an amount sufficient to agonize TAAR1 in the subject. The method of any of claims 45 to 52, further comprising administering to the individual one or more additional therapeutic agents.